NZ280218A - Phosphonic acid derivatives as intermediates - Google Patents

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New Zealand Paient Spedficaiion for Paient Number £80218 Priority Datefs): £&.\ID.:3.2 MtlNHMMMNM Specification Filed: ...Af..:./.Q. c.ex&: •;«).

Publication Datr.

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M.Z. PATr> ~ ) 2 OCT 1995 RECEIVED NEW ZEALAND PATENTS ACT, 1953 xt_ . Divided out of No. 248852 Filed 4 October 1993 Date: COMPLETE SPECIFICATION a-PHOSPHONOSTJLFONATE SQUALENE SYNTHETASE INHIBITORS AND METHOD We, E R SQUIBB & SONS INC, a corporation of Delaware having its offices at Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 -(followed by page 1A) 280? HX59a v" ^ - 1A - This is a divisional application of New Zealand Patent Specification No. 248852.

NZ 248852 relates to new a- phosphonosulfonate compounds which are useful in inhibiting cholesterol biosynthesis by inhibiting de novo squalene production, to hypocholesterolemic and antiatherosclerotic compositions containing such compounds and to a method of'using such 15 compounds for inhibiting cholesterol biosynthesis and atherosclerosis. The present invention relates to novel intermediates of the abovfementioned compounds.

Squalene synthetase is a microsomal enzyme which catalyzes the reductive dimerization of two 20 molecules of farnesyl pyrophosphate (FPP) in the presence of nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) to form squalene (Poulter, C.D.; Rilling, H.C., in "Biosynthesis of Isoprenoid Compounds", Vol. I, Chapter 8, pp. 413-25 441, J. Wiley and Sons, 1981, and references therein). This enzyme is the first committed step of the de novo cholesterol biosynthetic pathway. The selective inhibition of this step should allow HX59a the essential pathways to isopentenyl tRNA, ubiquinone, and dolichol to proceed unimpeded. Squalene synthetase along with HMG-CoA reductase have been shown to be down-regulated by receptor 5 mediated LDL uptake (Faust, J.R.; Goldstein, J.L.; Brown, M.S. Proc. Nat. Acad. Sci. U.S.A. 1979. 76, 5018-5022), lending credence to the proposal that inhibiting squalene synthetase will lead to an up-regulation of LDL receptor levels, as has been 10 demonstrated for HMG-CoA reductase, and thus ultimately should be useful for the treatment and prevention of hypercholesterolemia and atherosclerosis .

U.S. Patent No. 3,657,282 (Merck) (Division 15 U.S. Patent No. 3,822,296) discloses antibiotics of the structure R>^< fl^0H P OH wherein R = SO3H, SO2R*. H, hydrocarbyl other than alkyl (eg. alkenyl, alkynyl, phenyl and naphthyl), substituted hydrocarbyl, C02H, CO2R*, SO3NR2, heterocycle*, amino*, OH, OR, SH, SR, CHO, halogen, N02, CN, PO3H2, ASO3H2, acyl, -CHRiR3 where R1 = H, 25 Me; R3 = R as above, preferably at least one R not = H, R preferably contains 1-10 carbons. * = optionally substituted.

Starting materials employed to prepare the above antibiotics include 2802 HX59a r, >=Oz r r via epoxidation vm<; v-pc r r via ring closure wherein R can be SO3H, and X and Y are hydroxy or functional equivalent precursor to epoxide: eg. OH, halo, azide, RCO2-, RSO2O-, R2S+-, R3N+-, ArO-, R2PO2-, RSO2NR1-. One of X ar.d Y must be an oxygen radical.

EP 89/0-344-980 (Smith Kline) discloses a -antagonists of the structure wherein Y or Z may be -S02R, -P(R)0(0R), -PR20, -PO(OR)2» and amides.

WO 88/00061 (Amersham) discloses Technetium-99 complexes for bone scanning having the structure h2o3p- r1 r3 "(c)n —po3h2 r2 r4 wherein R1 and R3 = H, SO3H or alkyl substituted with SO3H and optionally one or more heteroatoms; R4 can also be SO3H or OH, NH2, NHMe, NMe2. lower alkyl substituted with a polar group; 280218 HX59a " R2 = same as R4 except not SO3H and n = 0, 1.

U.S. Patent No. 4,032,521 (Merck) discloses inter-mediates,in cephalosporin synthesis,of the 5 structures WO 90/07513 (Gas Research Institue) discloses electrolytes for fuel cells of the 10 structure y r (sofr1)* (r20)2p wherein R = organic radicals with 1 or more F 15 atoms; R1 = H, alkali metal, Zn, Cd; R2 = H, lower alkyl; r = 2, 3; and x, y = 1, 2, 3.

U.S. Patent No. 4,254,215 (Ciba Geigy AG) 20 discloses a process for photographic developers wherein one component of a developer solution is: HS-D-(W)n wherein n = 1 to 4.

D = optionally substituted, saturated or 25 unsaturated aliphatic radical (< 40 carbons), can 2 HX59a be interrupted by heteroatoms such as O, SO2, NH, NR.

W = PO3R2, SO3R, S02R, -NY-SO3R, -SO2NR2/ -SSO3R, CO2R, OH, NR3+, NR2, CONR2 • 5 DE 89/3739691-A (Hoechst) (Derwent # 89- 173507/24) discloses herbicides and plant growth regulators of the structure r5 O O RV II II ° " " r2 y i| nh l3I I r3 P wherein Y = CH, N; X = O, S; Z=CH, N; r1, r2 = C1-C6 alkyl or alkoxy; R3 = H, C1-C6 alkyl or alkoxy, C2-66 alkenyl, alkynyl, alkenyloxy, alkynyloxy; all optionally 15 substituted with one or more halogens; and R4 = H, C1-C4 alkyl or physiologically acceptable cation.

New intermediates are disclosed of the structures OO OO "\ll II R,\|l \\ R'-^N^NH, r2^ Vsch'||^nhj r3 ° r3 ° Burton, D.J., J. Am. Chem. Soc. 1989, 111, 1773-1776 discloses electrolytes and chelators of the structures HX59a (HO)2P(O)CF2S03Na (HO)2p(o)CF2S03H Su, D. ; Cen. W.; Kirchmeier, R.L.; Shreeve, J. M., Can. J. Chem. 1989, 67, 1795-1799, disclose 5 electrolytes and chelators of the structures (C2H50)2P(0)CFBrS03Na {C2H5O) 2P (O) CFHS03Na (HO) 2P(0)CFHS03Na (HO)2P (0)CFHS03H (C2H50)2P(0)CF(S03Na)(S02Na) (C2H50)2P(O)CF(S03Na)2 Farrjngton, G.K.; Kumar,A.; Wedler, F.C., 15 J. Med. Chem. 1985, 28, 1668-1673 discloses compound 10 as an inhibitor of aspartate transcarbamylase. Compound 24 is a synthetic intermediate. • HO2C O O O 1 II 11 II II Av 'S\ ^P(OH)2 PhO—S CH, p OPh NHII^ II L H02C NH || ^ II I OPh O O 24 Musicki, B.; Widlanski, T.S. Tetrahedron Lett.1991, 32, 1267-1270 discloses compound 4 as a synthetic intermediate.

Me O—.

AA/ CH2PO(OEt)2 2 18 HX59a • Carretero, J.C.; Demillequand, M.; Ghosez, L., Tetrahedron 1987, 43, 5125-5134 discloses O II (EtO)2P—CH2S03X la x = Et lb X = i-Pr 2a X = Li 2b X = n-Bu4N for use in the synthesis of vinyl phosphonates via a Horner-Emmons reaction.

Callahan, L.; Ng, K.; Geller, D.H.; Agarwal, K.; Schwartz, N.B., Analytical Biochemistry 1989, 177, 67-71 discloses an analog of ADP (adenosine diphosphate) of the structure NH, -o,s HO OH - 8 2 802 This invention is directed to an intermediate having the structure R9 wherein z I x = r1 c I s—c n—ch-j il I s chj o r z i H—C I s c — n — ch3 II I s ch3 O 7.

II I alkylo—S—C- II I o h O Z ll_l (c4H9)4N-o-^ "j1' O H z I or (c4h9)4N—o3s—c- r1 or having the structure z o x I IU°H r1—c — pc | oh s I ^ch3 S~C N CH3 or H o I H^Oalkyl c ) R1 C P' j Oalkyl s c n — ch, II I s ch, or 8a - 2802 18 n ° N H H a) Y—P (0-C-0-C-Ry) j I R* wherein Y is o o z o z o II H || | || I || Ry—C — O—C—O—S C ; HO—S C—P or I II I II I, R* O R1 O R1 O Z O II I II MO —S C P " li O R1 wherein R1 is a lipophilic group containing at least 7 carbons; Z is H, halogen, lower alkyl or lower alkenyl; and R9 is lower alkyl or arylalkyl; Rx is H, alkyl, aryl or arylalkyl; and Ry is alkyl, alkoxy, aryl or arylalkyl. 2 HX59a njp - 8b - Also described herein are a-phosphonosulfonate compounds which inhibit cholesterol biosynthesis, and thus 5 are useful as hypocholesterolemic and antiathero-scieroti.c agents and have the following structure I. o z o II I II I. r2 P—C S=0 r3o r1 or4 wherein R2 is OR5 or R5a, R3 and R5 are the same or different and are H, alkyl, arylalkyl, aryl, cycloalkyl, a metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester; RSa is H, alkyl, arylalkyl or aryl; R4 is H, alkyl, cycloalkyl, aryl, arylalkyl, metal ion or other pharmaceutically acceptable cations as defined below, or a prodrug ester; Z is H, halogen, lower alkyl or lower alkenyl; R1 a lipophilic group containing at least 7 carbons and is alkyl containing 7 to 25 carbons in the chain; alkenyl containing from 7 to 25 carbon atoms in the chain and from 1 to 6 double bonds; alkynyl containing 1 to 6 triple bonds; mixed alkenyl-alkynyl containing 1 to 5 double bonds and 1 to 5 triple bonds; and where in the above groups alkenyl and/or alkynyl may be substituted or unsubstituted; cycloalkyl; cycloheteroalkyl linked through a carbon on the ring or a heteroatom; aryl; heteroaryl; heteroarylalkyl; cycloalkylalkyl; cycloheteroalkylalkyl; or a group of the structure 9 - HX59a R\ r7—ap—-(ch2)p-r8 r8a wherein Ar is aryl (such as phenyl or naphthyl), heteroaryl (5 or 6 membered) and may include 5 one to three additional rings fused to Ar (such as aryl, cycloalkyl, heteroaryl or cyclo-heteroalkyl) and wherein (CH2>P contains from 1 to 15 carbons, preferably 2 to 12 carbons, in the chain and may include 0, 1, 2 or 3 double 10 bonds and/or 0, 1, 2 or 3 triple bonds in the normal chain, and may contain an ether or amino function in the chain, and/or may include 0, 1, 2 or 3 substituents as defined below for R6; and R6, R7' R8 and R8a are the same or different and are H, 15 alkyl containing 1 to 40 carbons, preferably from 3 to 25 carbons, alkoxy containing V to 40 carbons, preferably from 3 to 25 carbons, alkenyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkenyloxy containing 2 to 40 carbons, preferably 20 from 3 to 25 carbons, alkynyl containing 2 to 40 carbons, preferably from 3 to 25 carbons, alkynyl-oxy containing 2 to 40 carbons, preferably from 3 to 25 carbons, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, cycloalkyl, 25 cycloalkylalkyl, Ar-alkyl, (such as arylalkyl), ArO (such as aryloxy), Ar-amino (such as arylamino), hydroxy, halogen, nitro, Ar (such as aryl), amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, alkenyl, aryl or any 30 of the Ar groups mentioned above). thiol, alkylthio, Ar-thio (such as arylthio), alkyl-sulfinyl, Ar-sulfinyl (such as arylsulfinyl), 2^ y £.

HX59a * alkylsulfonyl, Ar-sulfonyl (such as arylsulfonyl), carboxy, cyano, alkoxycarbonyl, 'aminocarbonyl, alkylcarbonyloxy, Ar-carbonyloxy (such as arylcarbonyloxy), Ar-carbonylamino (such as 5 arylcarbonylamino) or alkylcarbonylamirxo, as well as any of the Ar groups as defined above, and preferably wherein the total number of carbons in the substituted Ar-(CH2)p- group exceeds 10 carbons; including pharmaceutically acceptable 10 salts thereof such as alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium, as well as zinc or aluminum and -.her FDA approved cations such as ammonium, choline, diethanolamine, ethylenediamine, 15 and salts of naturally occuring amino acids such as arginine, lysine, alanine and the like.

The (CH2) p group may contain 1, 2, 3 or more alkyl, alkoxy, alkenyl, alkynyl, hydroxy and/or halogen substituents as well as any of the 20 substituents defined for R6.

Thus, the compounds described herein include the following sub-genuses: IA o ? o II I II R50 P—C S=0 IB r3o ri or* o II r5»—p -—c s=0 r3o r1 or4 2802 HX59a' The term "prodrug esters" as employed herein includes prodrug esters which are known in the art for both phosphorus and carboxylic acids. Examples include the following groups: (1-5 alkanoyloxy)alkyl such as, | r» jj R3.

.C c c C R"° \ \ or wherein R18, R19 and R20 are H, alkyl, aryl or aryl-10 alkyl; however R180 cannot be HO. Examples of such prodrug esters include CH3CO2CH2-, ch3co2ch-, I ch t-C4H9CO2CH2-» or 15 (preferred) (ch3)2 O 11 c2h5ococh2-.

Other examples of suitable prodrug esters include o A o o O- R18 CHa- 2802 HX59a 18 <R21), R™ O-S- ,COjR: 0-5- R22 wherein R18 can be H, alkyl (such as methyl or t-butyl), arylalkyl (such as benzyl) or aryl (such as phenyl); R21 is H, alkyl, halogen or alkoxy, R22 is alkyl, aryl, arylalkyl or alkoxy1, and ni is 0, 1 or 2; or R3 and R5 can be linked together as in or 0 / O II ,0-C-R18 "Py (CH2)d °^O.C.R» II o (d is 0 to 3) Unless otherwise indicated, the term "lower alkyl" or "alkyl" as employed herein alone or as 15 part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, in the normal chain, more preferably 1 to 12 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, 20 isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as HX59a • well as such groups including 1 to 4 substituents such as F, Br, Cl or I or CF3, alkoxy, aryl» arylalkyl, alkenyl, cycloalkyl, amino, hydroxy, alkylamido, alkanoylamino, arylcarbonylamino, 5 nitro, cyano, thiol and/or alkylthio, as well as any of the other substituents as defined for R6.

Unless otherwise indicated, the term "cycloalkyl" as employed herein alone or as part of another group includes saturated or partially 10 unsaturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, any of which groups may 15 be substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, arylcarbonylamino, amino, nitro, cyano, thiol and/or alkylthio, as well as any of the other 20 substituents as defined for R6.

Unless otherwise indicated, the term "aryl" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, or 25 phenyl or naphthyl substituted with 1 to 4 substituents such as alkyl, halogen (Cl, Br or F), alkoxy, hydroxy, amino, alkanoylamino, arylcarbonylamino, aryl, arylalkyl, cycloalkyl, alkylamido, nitro, cyano, thiol and/or alkylthio, 30 as well as any of the other substituents as defined for R6.

The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein alone or as part of another group refers to alkyl groups as discussed 280218 HX59a ' 14 - above having an aryl substi'cuent, such as benzyl or phenethyl, or naphthylpropyl.

The term "lower alkoxy", "alkoxy", "aryloxy" or "aralkoxy" as employed herein alone or 5 as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.

The term "lower alkylthio", alkylthio", "arylthio" or "aralkyithio" as employed herein 10 alone or as part of another group includes any of the above alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.

The term "lower alkylamino", "alkylamino", "arylamino", or "arylalkylamino" as employed herein 15 alone or as part of another group includes any of the above alkyl. aryl or arylalkyl groups linked to a nitrogen atom.

The term "alkanoyl" as usegl*herein alone or as part of another group refers to alkyl linked to 20 a carbonyl group.

Unless otherwise indicated, the term "lower alkenyl" or "alkenyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, prefer-25 ably 3 to 30 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-'pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-30 octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4- dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl. alkynyl, aryl, arylalkyl, cycloalkyl. 280 HX59a amino, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano; thiol and/or alkylthio, as well as any of the other substituents as defined for R6.

Unless otherwise indicated, the term "lower alkynyl" or "alkynyl" as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 40 carbons, preferably 2 to 20 carbons in the normal chain, 10 which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl,3-undecynyl, 4-dodecynyl and the 15 like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, hydroxy, alkan9ylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, 20 and/or alkylthio, as well as any of the other substituents as defined for R6.

Examples of suitable (CH2)p groups include —CH=CH — CH2 , —CH2CH =CH , —C =C — CH2 —, CH3 —CH2C =CCH2 — , —c =CH — CH2—> (CH2)2 —, — (CH2)3 i —~(CH2)4 — j CH, I —(CHjJa —C —CH2CH2 , —CH2CH , —CH2CHCH2 I 1 I CH3 CH3 C2H5 —chch2 » —chch2ch2 » —chchch2 , I I II ch3 cshs | ch3 ch3 f"3 I —cho—c— ch2 , —(ch2)5 , —(ch2)2 -c —ch2 - , I I ch3 f cl <?h3 I I —ch2 —ch -ch2 —» —(ch2)2 -ch —, -ch2 —c -ch2 ■ ch3 ch 3 —ch2 —ch —ch — ch2 —, — ch2 —ch — ch2 — ch — , II I I ch3 ch3 ch3 ch3 oh och3 I I —ch —ch2ch2 # ch-ch2ch2 # „ — £ h2ochj— —och2ch2 » ch2nhch2— » —nhch2ch2— » ch, —n—choch2 — 1 «r I —ch2—n—ch2— ' or ch3 The term "halogen" or "halo" as used herein 15 refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.

The term "amino" as used herein refers to unsubstituted amino as well as monosubstituted 20 amino or disubstituted amino wherein the substituents may be alkyl and/or aryl.

The term "metal ion" refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and 25 calcium, as well as zinc and aluminum. 2 A £"b U 2 HX59a 17 - The term "cycloheteroalkyl" as used herein as an R1 s.ubstituent refers to a 5-, 6- or 7-membered saturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or 5 sulfur, linked to the carbon "C" of I P-C-S through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which 10 is defined above), such as O . dr. <5, o- and the like. The above groups may include 1 to 3 substituents such as any of the R6 groups as 20 defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

The term "heteroaryl" as an R1 substituent refers to a 5- or 6- membered aromatic ring which 25 includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur, which is linked.to the carbon "C" of 2 HX59a p-C-S, through a carbon atom or "a heteroatom, where I possible, optionally via the linker (CH2)p (which 5 is defined above), such as G- • G- • W fU>\) n^o f/y \=J . w and the like. The above groups include 1 to 3 substituents such as any of the R6 groups as 15 defined above. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.

The term cycloheteroalkylalkyl" as defined by R1 refers to cycloheteroalkyl groups as defined 20 above linked through a C atom or heteroatom to the "C" of I P-C-S group through a (CH2)P chain wherein p is I preferably 1 to 8.

The term "heteroarylalkyl" as defined by R1 refers to a heteroaryl group as defined above linked through a C atom or heteroatom to the 28 HX59a " "C" of P-C-S through a - (CH2)p-' chain I as defined above, where p is preferably 1 to 8. 5 Preferred are compounds of formula i and ia wherein r2 is or5 and r5 is a metal ion such as Na or K, or H or a pharmaceutically acceptable salt or more preferably a prodrug ester; R3 is H, a metal ion such as Na or K; 10 R4 is a metal ion such as Na or K; R1 is alkenyl such as h h xcv -chz c ch2 ch2 —(ch2)x — I I ch3 ch3 wherein (CH2>x is defined as (CH2)p above and x is preferably 2 to 8, h h h CHg ^ - 0. ,CH2 vCV ^-CH2 -C ^ ch2 ^ch2 ch2 — (ch2)m - I I I ch3 ch3 ch3 m is 1 to 5; (ch2)n — n = 1 to 15; R11, rlla, rllfa, and rllc are independently selected from H, alkyl such as propyl, alkoxy, such as methoxy or propyloxy, alkenyl such as 28 HX59a ' w I ch3 ,ch2 CH3V ^CH xCH2 -.CH *ch2 "c ^ \ ch3 ch3 p12a ch3 h (CH2)p- c=c / ch3 H2C=CH-CH2~; r12b wherein r12, r12a and r12b are independently selected from H, aryl (such as phenyl or naphthyl) alkylphenyl (such as p-propylphenyl, p-pentyl-phenyl), alkyl containing 1 to 20 carbons (such as p-heptyl), halo, alkoxy (such as methoxy or propyloxy), alkenyl (such as arylalkyloxy (such as phenethyloxy), alkenyloxy (such as aryloxy (such as phenoxy), phenylalkyl (such as benzyl, phenylpropyl), alkylphenoxy (such as ortho butylphenoxy), alkenylphenyl (such as ch. •3 n*. c =ch — ch3 CH3-C =CH(CH2)30 ) . ch3 0 9 HX59a" R14 (ch2)p.-C =CH — (CH2)p.— CH3 . or h r14—(cha ) p.—c—cha (chj) p. ch3 wherein R14 is aryl, heteroaryl, aryloxy, heteroaryloxy, cycloalkyl, heterocycloalkyl, and (CH2)p> and (CH2)p■ are as defined above for - (CH2)p-. Preferred p' and p" are independently 1 to 4; &rl-0-Ar2-(CH2)p- wherein Ar1 and Ar2 are independently selected from any of the Ar groups defined hereinbefore, and 15 (CH2)p is as defined hereinbefore.

/■* The compounds described herein may be prepared according to the following reaction sequences. 2802 HX59a ' Schemes; I. ia and II General Schemes for the Preparation of ot-Phosphonosul f onates Scheme I alkylation o o 0 O ^ II z || II z II „i „ , _TT. Rfo-Pv|,s=o R|°-P^I^S=° (III) 1 1XC I 1 C | XoI/ Br, C1 R^o |R?0 I X toaylate, rx° H Rx° cf3so2o- II IC <Ri» Ri» Ri are independently alkyl, aryl, 10 arylalkyl or cycloalkyl) deprotection _ H ? II RfO-P „ « ,s =0 I V| R*0 | OM 1 R1 ID or o o II Z II MO —P v I yS =0 J \y \ R*0 | OM or R1 0 0 II Z II MO—P v | yS =0 1 c I 4 or MO I OR* °r il 1 IE IF 0 O II z II MO — P » \/s =0 1 c I MO I OM R1 IG M=H, metal ion, or other pharmaceutically acceptable cation. 2 u HX59a' Scheme IA Preparation of Starting Phosphoriosulfonate II 0 ° ° Z-CH,—S=0 ► R1° T \'/s ° || 1) base !1 ? !! x2 S - —- - I > ' I J 2) CIP(O)(OR?)(OR?) RS0 r4q R5O 1 I 1 ^ H IIA IIB II Procedure employed is similar to that described by Carretero, J.C.; Demillequand, M.,-Ghosez, L., Tetrahedron, Vol. 43, 1987, pp 5125-10 5134.

Scheme II Alternatively, Z can be added after R1 (where Z = lower alkyl or halogen).

* O O base 0 0 c 11 H H 2) alkylation JJ Z jj ^ Rl° 0 ZX (XIIA) or Rl° ,1 C I ^ ,i C I Rio ,R*O ,R40 | balogenation | (IXXA1) IC' IC 8 HX59a Scheme III - Alkylation Reaction of Electrophiles III with Phosphonosulfonates II "to Yield Triesters IQ O Z O o ? o II I II II I II r5q —p—c—s =o + R1-x2 RS0 —P—c—s —o =3! nil (X2 is X or an -I L I . r3o r«o r*o r1 or4 acetate) 1 1 II IIIB IC NaH Part A. II + R1X IC DMP O Part b. ii + r6-ch=ch-ch2occh3 Pd°, base THF (allylic acetate-Type 1) 0 z o II I II R,0—P—C — S=0 1 I I R^O CH2 OR4x CH IC * CH R6 or o 11 ^OCCHj base Part C. II + R6—CH IC \:h=cha thf (allylic acetate - Type 2) 28 HX59a" o z o 5 II I II - r*0— p— c — s = 0 Hvdrocrenation ,1 I I A Part D. ic ^ R!° ch2 (where R1 is R6-CH=CH-CH2-) ' ic2 |»2 r6 * HX59a Scheme IV - Preparation of (Dialkoxyphosphinyl)-methanesulfonic Monoacid Salts ; o z o II I II A. R?0 —P—C—S=0 x ' H 3I R|0 r«o II R • I Base DMF 0 II Z I IIIA R« O —P— C—S =0 31 K 1 R^O R1 OM ID (R? ethyl or other l0alkyl) M = K, Na o II B . R?0 —P- r\O Z O I II •c —s =o I. 14 R1 OR« IC Part B(l) Rj = alkyl, cycloalkyl, arylalkyl (ICa) z I o II R^O I, I R1 OM Deprotection RfO p—c —S =0 ID 1) a) nh3/ch3oh, or b) MHCO3 or pyridine, or MOAc in CH3OH or cf3ch2oh, opt. H2O o r c) MI, DMF or d) MI, 18-crown-6, THF 2) MOH (optional), room temp.

ID Part B(2) Rj=aryl (ICb) MOH R.T. to 80°C Rfo p—c —S =0 31 K 1 R1 OM rD u HX59a ' Scheme V - Preparation of (Hydroxyalkoxyphos-phinvl)methanesulfonic Diacid Salts IE Monoacid salt Deprotection Diacid salt ID KOH or NaOH IE heat Scheme VI - Preparation of (Dihydroxyphosphinyl)-10 methanesulfonic Acid Monoesters IF Deprotection Monoester, acid or salt IC 1) Bromotrimethylsilane IP (TMSBr) optional proton scavenger # 2) MOH, room temp.

R!' Ri * allcir-L' cycloalkyl, arylalkyl 2&02 HX59a Scheme VII - Preparation of (Dihydroxyphosphinyl) methanesulfonic Acids IG ; o z o Deprotection II I II IC MO— P — C —S =0 I I I HO R1 OM IG 1) Trimethylsilyliodide(TMSI) or TMSI and a proton scavenger Part A. IC 2) MOH , , IG R * aryl 1) Conversion to ID as described in Part B(l) or B(2) Scheme IV 2) TMSBr or TMSBr and a proton scavenger 3) MOH Part B. IC - IG 1) TMSBr or TMS'Jr and a proton scavenger 2) KI, 18-crown-6, THF 3) MOH Part C. IC R* # aryl * ° HX59a' Schemes VIII, IX, IXA and X - General Schemes for the Preparation of a-(Alkyl-or Aryl-hydroxy-phosphinvl)sulfonates Scheme VIII 0 O 1 o o II Z || alKylacion || f || R P ~ I yS = 0 R P - I -S =0 1 C I K1-* 3I VI R|° hRJO Ri° I *1° V o o IK depcotactios .s> II ? II R p | s —o ,i Y'i Rl° , OM IL 00 M Z II R5'-'M/r° - RS'~i^r° hA | L MO | °M £> IM IN R*, R^ = alkyl, aryl, arylalkyl, cycloalkyl 2 HX59a Scheme IX o II 1) base c 0 SS.~~° 2> ClP(OR3)2 II Z, II / \ H P I S = ___Cg RjO phosphinylat ion | | Z—CH - - _ ,. . ■ I — *1° I R x° £i 3) HaO £i VI 10 alkylation H ? H deprotection »•- R P I s =0 IL, N / 1 IM or | C | hydroxy alky lat ion R*° I Rl° or or Rl 1N arylation jk Scheme IXA O II •s =o 2 -CH RjO I IID or VI 1) base 2) C1P(0R*)2 3) water 0 O II Z II — P \I/S =o 1 Y| R?0 I R*0 R1 Alkylat ion reaction ,Sa Rjo 0 0 II f II ? \V!=0 1 c i LRx° IK Alkylation Reaction Methodology product IK A .

C . or A .

C .

D . 1) >1 eq. of base R^avtAryl 2) R5a -Hal (Hal=I or Br) VIB Chlortrimethylsilane (TMSCl) Et3N •» R5a-Hal VIB 1) base 2) aldehyde 1) TMSCl, {C2H5)3M 2) aldehyde 1) base 2) aryl fcalide, Pd[P(C6H5)3]4 or Ni[P(CgHs)3]4 1) 2) R5a*Aryl R5a=R7CHOH R7=aryl, alkyl or H R5a=aryl J HX59a• Scheme X _ o o o l) strong base || Z || '■ ► RSa— P v 1 ,S =0 —r° 2~ s jvi R!." C1 r'° ir!° VII R5« — p Cl 3I R^O VIII 3) HjO O O NaH |, Z ,| RSa— P =° Rl-X I C I Rl° I Rl° III il IK Scheme XI - Preparation of (Hydroxyphosphinyl) methanesu3.Sonic Acids The diesters IL or IM are deprotected by treatment with aqueous alkali as shown below to yield the product IM. ° ? 1) NaOH or KOH II Z " IL or IM R5«— p | s heat | | MO | OM R1 IM HX59a * Scheme XIA - Preparation of (Hydroxyphosphinyl) methanesulfpTUg Acids, : Part A.

O Z O . II I II « R—P—C—S—OR* -1 L II 1 R|o R1 O IK MOH, H20 optional organic cosolvent e.g. C2H5OH 2 0 - 1 5 0 °C 0 Z II I —p—c- 1 !1 MO R1 IM ■S—OM II O Part B. 1) TMSBr, optional proton scavenger 2) MOH, H20 IK 0 Z O * I' 1 " 4 R—P — C — S — OR? 1 I II MO R1 O Dealkylat ion as per Scheme IV B(1) II IN (R*=alkyl, arylalkyl, cycloalkyl) • A Part c.

Dealkylation as per Scheme IV B(1) IK O Z O s II I II R * P — C S—OM 31 'x 11 R^O R1 O (R*=alkyl, arylalkyl, cycloalkyl) IL Method (1) 1) TMSBr, optional proton scavenger 2) MOH (opt.) or H2o IL IM or Method (2) MOH, H20 optional organic cosolvent -150°C Part D.

As in Scheme VII IK IM Part c (Rj=alkyl, aryl, arylalkyl Scheme XII - Preparation of a-Hydroxyphosphinyl methanesulfonic Acids (phosphonous acids) O Z O Dealkylation || | || pre£.=KI, acetone H-—P —C—S—OM A . IO 3I L II R'O R1 O IP IP 0 Z O Hydrolysis || | || MOH, H20 H — P—C—S — OM MO Jl1 O optional cosolvent IQ 7 HO O Z O R CHO I II I II organic base R7— C — P—C—S=0 IP | | | | , H R*0 R1 OM (R7 is H, alkyl, 1 aryl, arylalkyl) il« 2 HX59a" Scheme XIII - Alternative Route to IC or IK z o I II -c—s=o K 1 4 R1 OR* IIA 1) base (as in Scheme IA) 2) Cl-P(OR|) (R2) (RJ=ORi or RSa) 3) Oxidant (e.g. MCPBA, t-C4H9OOH, H202 or I2/H2O> IC (R2=ORI) (R or 2 _ IK »5a \ Scheme XIV - Preparation of Prodrugs Part A IF AgX ( Rj * aryl) (X1«N03, CIO4, CF3SO3) O Z O \ll I " Ago P C s=o ' 1 R1 OR* IR Ha Rx O , I JJ 1-C-O-C- Ry H XI (Hal=Cl,Br,I) (Ry-C-0-C-0 —)— II I 2 O Rx O Z O II I II -P — c — s=o K 1 4 R1 OR* I s IS Dealkylat ion (as per Scheme IV B(1) (except CH3OH, NH3) * aryl H (Ry-C-0-C-0 II I O Rx I T O Z O II I II 4t P—c—s = o K 1 R1 OM (RY= aryl, aralkyl, alkyl or alkoxy) (Rx= aryl, aralkyl, alkyl or H) HX59a Part B IG AgX1 * ~ ° 2 ° Ag°\ll I II p ~ o 2 to 4 equiv.

M=Ag, Na, K or H XI IT Scheme XV - Preparation of Individual Enantiomers of Formula I Compounds part h R9 R9 (R,R)-Diamine XXR (or (S,S)-Diamine XXS)(R9=alkyl or arylalkyl) R9 Cyclic Phosphonamide Formation , XXI 1) Anion Formation 2) Alkylation, RxX (III) XXII XXI e - ^ & y ^ HX59a" 1) Anion Formation 2) Sulfuration Reaction ■S-ECO z I R9 3) Separate Isomers XXIX XXIIIS (Major when Z=H) + XXIIIR (Minor when Z=H) When (S,S)-Diamine XXS is used as starting material, a-(R) is Major Isomer where (Z=H) and a-(S) is Minor Isomer (Z=H) R9 I ■'* ° O N/ Acid Z ||^OH Z ||/ Hydrolysis R Yw —- ■ s^ I f I s ' A.- j XXIIIS N a- (S) a-(S) isomer xxivs Z J OM R 1) Oxidation J[ °M XXIVS 2) Salt Formation O |J OM a- (S) IS 280218 HX59a ' X f S/N £ ] s I X> XXIIIR a-(R) Isomer O Acid Hydrolysis XXIVR 11 oj;ld"io° Nm 2) Salt Formation >.SV 0*^|| 0M o N A | XXIVR «"<*> (R) IR References on asymmetric reaction of chiral phosphonates: Hanessian, S., Delorme, D. , Beaudoin, S., LeBlanc (1984) chemica Scripta 25, 5-11.

Hanessian, S., Bennani, Y.L., Delorme, D. (1990) Tetrahedron Lett. 45, 6461-6464.

Hanessian, S., Bennani, Y.L. (1990) Tetrahedron Lett. 45, 6465-6468. 28 HX59a" Scheme XV Part A(l) - Alternate Routes to XXII (Used in Scheme XV. Part A) a ) R9 CH3 P—Cl I Cl (R,R)-Diamine XXR (or (S,S)-Diamine XXS) XXIA 1) Anion Formation 2) Alkylation (R1*) CH- _y/ -• l XXIA R1* R9 I O N 11/ CO J.

XX XB Diamine XXR (or XXS) o 'UC1 R1^ ^ Cl b) XXIA 1) Anion Formation 2) Alkylation or Halogenation R9 o N, \\/ I XXIC 80? HX59a "' 40 - 1) Anion Formation 2) RlX XX IC -4"CO z R9 XXII c ) 1) Anion Formation 2) Alkylation or Halogenation XXIB XXII / 8 n ° HX59a 18 41 - Scheme XV Part B R9 I Z-HaC P, V \ 'X) 1) Anion Formation 2) Sulfuration (S8) 3) Thlocarbamoylation XXV I XXI (from (R,R)-Diamine XXR) R9 HON. tw N* XXV I R9 O i I XXIIIS (Minor Isomer a- (S) when Z=H) XXV x T n/ YvU 1) anion formation 2) alkylation R1Hal ,-'R9 O N , ? «/ R\U-\ X> d I XXIIIR (Major Isomer a-(R) when Z=H) When (S,S)-Diamine XXS is the starting material, the a-(S) isomer XXIIIS is obtained as the major 10 product when ZbH.

HX59a ? 9 XXIIIS XXIIIR I I Continue as in Scheme XV Part A I IS IR 2802 18 HX59a ' Scheme XV Part C R9 R9 | Phosphorous | HNa Diamide ° n Formation X) H <o N ^ HN R9 XXR R9 (R,R)-Diamine XXVXI (or (S, S)-Diamine (XXS)) 1) Condensation Reaction R1CHO (XXVIII) Silylating Agent XXVII XXIXS + XXIXR 2) Separate Isomers R9 R9 ° N/# N. i ? "/ , ? "/ r^i ■+ vO " "Y'sJU Ma3SiO I Me3SiO I R9 R9 XXIXR XXIXS I Fluoride Source R1 OH I 5H I R9 R9 XXXR XXXS Alternatively, isomers can be separated at the alcohol stage, that is, XXXR and XXXS. 280? ii HX59a XXXR XXXS Mitsunobu Displacement * -{*60 -+TO I R' ? L S I J «' ? A.

I S N I XXIIIR' J a-(R) a-(s) I I Continue as in Scheme XV Part A I I- XR IS *P. Rollin, Tetrahedron Lett. 1986, 27, 4169-4170 Part C (1) 1) Condensation Reaction RiCHo (XXVIII) Various Bases including Fluoride XXVII XXXR + XXXS 2) Separate Isomers HX59a 2802 18 Scheme XVI - Alternate Preparation of Individual Enantiomers of Formula I Compounds Rs . 1 i HN, Acid Cl Formation _ I X) -=1- -CO I N V HN Rs XXR I (R,R)-Diamine (or s,S-Diamine XXS) r9 XXXI 2802 HX59a ' xxxi Coupling Reaction R9 I O Ny z LiCHSG3Re (xxxia) R^°-y I Anion Formation Z-CH2-S03-Ra (xxx.ib) tW H K r xxxii (Ra=alkyl or cycloalkyl) Dealkylation BU4N+X" R o I BuaN+-0" ? 2) * +\XJ _1 H I, r xxxiii 1) Dianion Formation Alkylat ion X BUi on & XXXIV R9 ion | /iECO -o3s I R9 Major Isomer is (S) at the a-center when Z is H (S,S-Diamine XXS will give the (R)-isomer IR as the major product when Z is E) *+ 1) Acid Hydrolysis 2) Ion Exchange O Z || .OM < OM 0^|| OM O IS 2802 1 HX59a • 47 - Scheme XVII - Preparation of Individual Enant-.irariPr HO^ ^ ,OH Rl ^CH3 CH3 CH] RlCHO ((S,S)-Diol)) XXVIII XT Acetal format i Acid Catalyst - XL Formation CH3 (Chiral Auetal) Acetal Opening h Reaction R1^! ..PO (OAlkyl) a TiCl4 P (OAlkyl) 3 Y XL Ref. 1 C«3 CH3 XLI Mcobol RlY.PO<OAl*yl), E11„initioll Oxidation T of. 3.But..n..

XL X fc- ■ O 2-one Ref. 1 T ^-XLIII XLI I CHs CH3 A1) R'^POIOAlkyl,, \m.,K ^sJ,Zn (OAlkyl), | DIAD-Ph3P : Me2N.

XL 111 Mit sunobu Displacement || XLIV Ref. 2 Dealkylat ion TMSBr or TMSI XLIV H R1vv|x.PO(OH)2 MbjN^ XLV Y HJ^l 1) Oxidation H fj 2) Salt Formation ni | ^OM XLV ; OM o || OM O (R)-enantiomer (IR) Use (R/R)-diol to obtain (S)-enantiomer (IS) References ; (1) Yonomatsu T.; Shibuya, S., Tetrahedron Asymmetry 1992, 3, 377-378 (2) P. Rollin, Tetrahedron Lett. 1986, 27, 4169-4170 HX59a Scheme XVIII - Purification of Desired Enantiomer Ion Exchange Resin Rl ? |UOM "•Forro - z n .OH ~T 0,1 R"-J/p^0„ | Ion Exchange Resin i M+ Form s °1 0M „r O II OH Basificction with (S)-enantiomer (IS) MOH or ((R)-enantiomer (IR)) O 1 2 II, -°- 2 equiv Amine R \ | V* O IQ IQ JZ Y OH o^n^o H+ Form O Ion Exchange Resin (Amine-H+) 2 IQ 1 Diamine Salts (IQ1) are useful for purification ?md improvement of enantiomeric excess, especially by recrystallization Ion Exchange Resin z |j OM M+Form R1^ I OM or z Y Basification with MOH IQ ' O || OM O (S)-enantiomer (IS) or ((R)-enantiomer (IR)) 2.1 HX59a Scheme XIX - Preparation of Prodrugs of Desired Enantiomer « 41 Z It -OM Silver Salt Formation AgNQ3 (s)-enantiomer (IS) Ago 11 ,°Ag -R a II o -OAg IAg vt- xi ° R* Hal IAg LI Silver Assisted Alkylation Solvolysis in Water + Optional Water Miscible Solvent I H 0 H 1 RX I O RX H Z II o +°Y R* O Ry LI Optionally Containing Anisole, Thioanisole, 2,6-Di-t-butylpyridine V t | H O H | 0\|/°vJJ/0^0 Ry R1 S Z II O LIIS [a-(s) ] R* II ^-OH 28 0? HX59a* LIXS Salt Formation (S)-enantiomer (can use (R) -enantiomer IR to form (R) -enantiomer of IS'and LIIS, i.e. IR'and LIIR) compounds described herein as IC may be prepared by alkylating the phosphonosulfonate II by reacting II with compound III in the presence of an appropriate 10 base and an inert organic solvent under an inert atmosphere to form IC, followed by deprotection to the various acid forms ID, IE, IF and IG. phosphonosulfonate II is employed in a molar ratio 15 to compound III of within the range of from about 5:1 to about 0.8:1, and preferably from about 3:1 to about 1.2:1. The reaction is carried out under an inert atmosphere, such as argon, initially preferably at a reduced temperature of within the 20 range of from about -78 to about 80°C, and more preferably from about 0 to about 50°C, although the reaction may be completed at room temperature. for use herein include, but are not limited to 25 dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA) or diethyl ether (Et20) , or mixtures thereof.

Referring to "General Reaction"" Scheme? I, In carrying out the above reaction, the Examples of inert organic solvents suitable 0 Q n A H&PW- I Examples of bases suitable for use in carrying out the above reaction-include, but are not limited to, alkali metal hydrides, such as sodium hydride (which is preferred), potassium 5 hydride, lithium-, sodium- or potassium bis(tri-methylsilyl)amide, lithium diisopropylamide or butyllithium.

Referring to Scheme IA, starting compounds of formula IIC wherein RJ^, Ri> and r} of II as defined in Scheme I may be prepared by reacting starting sulfonate IIA with a strong base such as any of those used in Scheme I, in the presence of or followed by chlorophosphate IIB, and an int^t organic solvent such as used in Scheme I, to form 15 IIC.

In carrying out the reaction of Scheme IA, chlorophosphate IIB will be employed in a molar ratio to sulfonate IIA of within the range of from about 3:1 to about 1:2, and preferably from about 20 2.0:1 to about 1:1. The reaction is carried out at a temperature of within the range of from about -100° to about 30°C, and preferably from about -90° to about 0°C.

Referring to Scheme II, compounds of the 25 invention IC may be prepared by alkylating the phosphonosulfonate IC" with an alkylhalide, ZX (IIIA) (Z is alkyl and X is as defined in Scheme I), or with a halogenating agent ZX1 (where Z is halogen except F and X1 is succinimido, Cl, Br or 30 I, or OH; when Z is F, ZX1 is XeF2), 280? HX59a " W alkyl (or H) A alkyl | ffi alkyl (or H) (or H)I F Q0S02CF3 °2s<v ^soa N I F The above reactions are carried out in the presence of appropriate inert organic solvent as described above, under an inert atmosphere, to form IC.

In carrying out the above Reaction, the 10 phosphonosulfonate IC' is employed in a molar ratio to compound IIIA or IIIA* of within the range of from about 2:1 to about 0.2:1, and preferably from about 1.5:1 to about 0.7:1. The reaction is carried out under an inert atmosphere, such as 15 argon, initially preferably at a reduced temperature of within the range of from about -78° to about 80°C, and more preferably from about 0°C to about 50°C, although the reaction may be completed at room temperture. Bases and solvents 20 appropriate for this reaction are as described for Scheme I.

Referring to Scheme III Part A, compounds described herein as IC may be prepared by alkylating the phosphonosulfonate II with compound III in the 25 presence of an appropriate base and an inert o o II II or csHs—s N—s C6Hs O F O 2802 HX59a ' organic solvent (as described hereinbefore with respect to Scheme I) preferably dimethylformamide (DMF), under an inert atmosphere to form IC.

In carrying out the above reaction, the 5 phosphonosulfonate II is employed in a molar ratio to compound III of within the range of from about 5:1 to about 0.8:1, and preferably from about 3:1 to about 1.5:1. The reaction is carried out under an inert atmosphere, such as argon, initially 10 preferably at a reduced temperature of within the range of from about -78° to about 80°C, and more preferably from about 0 to about 50°C, although the reaction may be completed at room temperature.

Referring to Schemes III PartB and III Part 15 C, compounds described herein as IC' may be prepared through the palladium catalyzed base promoted coupling of allylic acetates (Types 1 or 2) with the phosphonosulfonate II to provide the coupled product of the invention IC'. Either allylic 20 isomer serves as a substrate in the reaction.

In carrying out the above reactions, the phosphonosulfonate II is employed in a molar ratio to allylic acetate of within the range of from about 5:1 to about 0.8:1, and preferably from about 25 3:1 to about 1.5:1. The reaction is carried out under an inert atmosphere, such as argon, initially preferably at a reduced temperature of within the range of from about -78° to about 110°C, and more preferably from about 0 to about 80°C, although the 30 reaction may be completed at room temperature.

The above reactions are carried out in the presence of a suitable inert organic solvent as described hereinbefore with respect to Scheme I, preferably employing tetrahydrofuran (THF) or 1 HX59a' £.

A dimethylformamide (DMF). Suitable bases are sodium hydride and sodium bis(trimethylsilyl)amide, and preferably bis(trimethylsilyl)acetamide (BSA) in the presence of palladium (O) catalyst such as 5 Pd[P(CgHs)3 ] 4 .

The base or BSA is employed in a molar ratio to allylic acetate within the range of from about 4:1 to about 1:1, while the Pd(O) is employed in a molar ratio to allylic acetate of within the 10 range of from about 0.005:1 to about 0.5:1.

Referring to Scheme IV, Part A, the coupling reaction is carried out with (dialkoxyphosphinyl) methane sulfonate ethyl ester II to yield the sulfonate salt ID directly from the 15 reaction. The product emerges by means of a concomitant iodide promoted dealkylation of the sulfonate ester.

The Scheme IV Part A, reaction is carried out in a manner similar to Scheme I. 20 The sulfonate salt ID may also be formed as shown in Scheme IV, Part B(l) and (2). Part B(l) depicts the dealkylation of the sulfonate ester iCa to yield ID, using various reagents as shown in the reaction sequence set out hereinbefore, while B(2) 25 shows the cleavage of an aryl methanesulfonate ester ICb by aqueous alkali containing from about 5 to about 20% by weight base) and heating at a temperature within the range of from about 40° to about 100°C, to give ID.

Referring to Scheme v, the diacid salt ie is prepared by the further hydrolysis of monoacid id employing aqueous alkali (containing from about 5° to about 20% by weight base) optionally in the presence of a cosolvent, such as dimethoxyethane, 2 HX59a dioxane or THF, and heating at a temperature within the range of from about 40 to about 100°C.

Referring to Scheme VI, the (dihydroxyphosphinyl) methanesulfonic acid monoester IF is 5 prepared by the cleavage of the phosphorous ester IC (wherein rf and r| are each lower alkyl, arylalkyl, cycloalkyl and R^ is lower alkyl, arylalkyl, cycloalkyl or aryl) with bromotrimethyl-silane (TMSBr) , optionally in the presence of a 10 proton scavenger such as 2,4, 6-collidine, hexamethyl disilazane, alkyl, trimethylsilane, bis (trimethylsilyl)trifluoroacetamide, pyridine or triethylamini?, followed by aqueous alkali (as described above except that elevated temperatures 15 are not necessary) or water wherein the TMSBr is employed in a molar ratio to IC of within the range of from about 2:1 to about 15:1, preferably from about 2: to about 5:1. ,» Scheme VII Parts A, B and C sets out the 20 chemical processes employed for the deprotection of phosphonosulfonate triester IC to phosphonosulfonic acid IG.

In Scheme VII, Part A shows the direct deprotection of the ester IC through the agency of 25 trimethylsilyl iodide (TMSI) (employs a molar ratio of TMSI: IC of within the range of from about 3:1 to about 20:1, preferably from about 3.5:1 to about 5:1) optionally in the presence of a proton scavenger as defined above, and followed by aqueous 30 alkali (as described above) or water at a temperature of within the range of from about 0° to about 50°C.

In Scheme VII Part B, phosphonosulfonic triacid IG is formed via a two step process where 2802 HX59a' in the first step, the sulfonate ester is removed as described in Part B, Scheme IV and in the second step treatment with bromotrimethylsilane optionally in the presence of a proton scavenger as defined 5 above, yields the silyl esters which are then hydrolyzed via aqueous alkali (as described hereinbefore) or water.

In Scheme VII Part C, the phosphonate esters are removed (from IC) first with bromo-10 trimethylsilane (TMSBr) (employing a molar ratio of TMSBr:IC of within the range of from about 2:1 to about 20:1, preferably from about 2.5:1 to about 5:1) optionally in the presence of a proton scavenger as defined above, to provide the 15 intermediate bis(silyl)esters. Subsequent cleavage of the sulfonate ester with potassium iodide (18-crown-6, THF) and hydrolysis (MOH and H2O) yields the phosphonosulfonic triacid IG. ( Schemes VIII, IX, IXA and X relate to the 20 preparation of a-(alkyl- or aryl-hydroxyphosphinyl) sulfonates .

Schemes VIII and IX depict the general chemical process for the formation of diesters IK, and their deprotection to form IL and 10, 25 respectively.

Scheme IXA depicts the P-H route to diester IK. Starting sulfonate VI is treated with a strong base followed by dialkyl chlorophosphite (employing a molar ratio of dialkyl chlorophosphite:VI of 30 within the range of from 1:1 to about 10:1), followed by hydrolysis with water under acidic conditions, to form alkoxyphosphinyl sulfonate 10 which serves as an intermediate for the synthesis of substituted (alkyl- or aryl-alkoxyphosphinyl)- methylsulfonate diesters via alkylation of 10. The alkylation methods are shown in -Parts A, B, C and D.

In Scheme IXA Part A, diester IK where R53* 5 aryl is formed by selective alkylation of IO by treating 10 with base such as NaH, KH, LDA, butyllithium, Li-, Na- or K-bis(trimethylsilyl)-amide and a halide VIB of the structure VIB RsHal wherein Hal is I or Br, as described with respect to Scheme I.

In Scheme IXA Part B, diester IN where R5* aryl is formed by treatment of IO with chloro-trimethylsilane (TMSCl) and organic base such as 15 triethylamine (Et3N) in the presence of alkylating agent VIB. In carrying out this alkylation, the silane compound is employed in a molar ratio to IO of within the range of from about 1:1 to about 5:1, preferably from about 1:1 to about 3:1 while VIB is 20 employed in a molar ratio to IO of within the range of from about 0.8:1 to about 10:1.

In Scheme IXA Part C, IK where R5a is R7CHOH (and R7 is H, aryl or alkyl) is prepared by treating IO with base followed by aldehyde R7CHO, 25 carried out by employing a molar ratio of R7CHO to IO of from about 1:1 to about 10:1. Alternatively, IO can be treated with (CH3)3SiCl and an organic base (such as triethylamine) followed by an aldehyde, followed subsequently with a standard 30 desilylation reaction (such as tetrabutylaramonium fluoride in THF) to provide IK with R5=R7CHOH.

In Scheme IXA, Part D IO is reacted with an aryl halide in the presence of a base such as triethylamine and Pd[ P (C6H5) 3 ] 4 , Ni [P (C6H5) 3 ] 4 or HX59a ■ 2802 et other nickel and palladium catalysts, to yield IK when R5a is aryl.

Scheme X depicts the preparation of (hydroxyphospinyl)methanesulfonic acid diester IN by alkylation of diester V by treatment of V with base, such as NaH, and alkylating agent III as described hereinbefore in Scheme I. The intermediate V may be prepared via a coupling reaction of the alkylsulf onate VII with phosphohic 10 acid chloride VIII employing a molar ratio of VII:VIII of within the range of from about 0.5:1 to about 10:1, preferably from about 1.5:1 to about 3:1, similar to that described in Scheme IA, for the conversion of IIA to IIC.

Schemes XI and XIA depict various routes (A, B and C) for the deprotection of diesters IK to yield IM.

Scheme XII Part A depicts t;he preparation of salts IQ by dealkylating IO using techniques as 20 described hereinbefore, preferably with KI and acetone, to form monoester IP and then subjecting IP to hydrolysis to form salt IQ.

In Scheme XII Part B, the ester IP is treated with aldehyde (R7CHO) in the presence of 25 organic base such as triethylamine, diisopropyl-ethylamine or 1, 8-diazabicyclo[5.4.0]undec-7-ene, to form IK where R5a is R7CHOH. In this reaction, the aldehyde is employed in a molar ratio to IP of within the range of from about 1:1 to about 10:1, 30 preferably from about 1:1 to about 5:1.

Scheme XIII depicts an alternate route to IC where IIA is treated vritn base (as per Scheme IA) and chlorophosphite (as described hereinbefore) and an oxidant such as m-chloroperbenzoic acid 2802 HX59a " (MCPBA), t-C4H9COOH, hydrogen peroxide or I2/H2O to form IC.

Scheme XIV (Parts A and B) depict the preparation of prodrug esters. isomers or enantiomers of the formula I compounds described herein may be prepared diamine XXR (or (S,S)-diamine XXS) where Ra is 10 alkyl or aralkyl, with an alkyl phosphonic dihalide XXA, such as methylphosphonic dichloride, in the presence of a tertiary amine base and an aprotic solvent such as benzene, toluene, dichlororaethane or diethyl ether, to form the alkylphosphondiamide 15 XXI which is metalated with a base such as n-butyl-lithium, sec-butyllithium, t-butyllithium or lithium diisopropylamide, to form the lithium anion of XXI which is then alkylated by treatment the halide R*X (Ilia) such as the iodide 20 XXIB in the presence of an inert organic solvent such as tetrahydrofuran (THF), diethyl ether or dimethoxy-ethane or mixtures thereof, at a temperature within 25 the range of from about -90 to about 25°C, preferably from about -80 to about 0°C, to form XXII. Compound XXII is reacted with a base as above to form the lithium anion of XXII which is sulfurated with tetramethylthiuram disulfide or the 30 correspnding tetraethyl derivative at a temperature within the range of from about -100 to about 0°C, preferably from about -90 to about -60°C, to form a Referring to Scheme XV, the individual by treating the (R,R)- mixture of isomers XXIIIR and XXIIIS (which are novel compounds in accordance with the present invention).

Where the sulfuration is carried out at 5 below about 0°C, preferably at about -60°C to about -100°C, and the starting diamine is the (R,R) -diamine XXR and Z is H, a mixture of major XXIIIS (a—(S)) and minor XXIIIR (a-(R)) thiocarbamate isomers (about 3:1 mixture at -90°C) is obtained. 10 It should be noted that in the above and following discussions and schemes a-(R) and a-(S) refer to the enantiomeric configuration at the chiral carbon center adjacent to the phosphorus and sulfur moieties.

It will be appreciated that where the (S,S)-diamine XXS is employed in place of (R,R)~ diamine XXR and Z is H, the major isomer obtained will be the a-(R)-isomer XXIIIR. , The thiocarbamate isomers XXIIIS and XXIIIR 20 can be separated by chromatography on silica gel, crystallization or HPLC. The individual and separate diastereomers (XXIIIS and XXIIIR) are then separately subjected to acid hydrolysis (such as treatment with aqueous acid such as HC1), to form 25 compound XXIVR or XXIVS (which are novel compounds in accordance with the present invention) which are separately subjected to oxidation {such as reaction with H2O2 in the presence of formic acid, acetic acid or mixtures of formic and acetic acids) and 30 salt formation by base treatment or ion exchange chromatography, to form the individual enantiomers IS and IR of the invention.

In carrying out the reactions of Scheme XV, the starting (R,R)-diamine with R9=methyl is 28 ( HX5Va n, C) » L - 62 prepared by a two-step reductive methylation of the L-(+)-tartaric acid salt (available from racmeic 1,2-trans-cyclohexanediamine, Gasbol, F. et al (1972) Acta. Chem. Scand. 26, 3605 and Onuma, K. et 5 al, (1980) Bull. Chem. Soc. Jap. 53, 2012) as follows: lah xxr THF (r9=ch3) Other examples of XXR and XXS where R9 is alkyl or aralkyl are prepared as reported in the prior art as follows: Alexakis, A. et al, J. Org. Chem., 1992, 57, 1224-1237; Denmark, S. et al, J.

Org. Chem., 1991, 56, 5063-5079; flfcanessian, S. et /■ al. Tetrahedron, 1992, 33, 7659-7662; and Koeller, K.J. et al, Tetrahedron Lett., 1991, 32, 6297-6300.

The (R,R)-diamine XXR (or XXS) is employed in a molar ratio to the alkylphosphonic dichloride 20 XXA of within the range of from about 0.5:1 to about 3:1, preferably from about 0.9:1 to about 1.5:1. The amine base, such as triethylamine, pyridine, diisopropylethylamine will be employed in a molar ratio to the alkylphosphonic dichloride 25 XXIA of within the range of from about 1:1 to about 5:1, preferably from 1.5:1 to about 3:1.

The metalation (anion formation) of XXI is carried out at a temperature within the range of from about -90 to about 0°C, preferably from about 30 -80 to about -60°C, employing a molar ratio of base compound to alkylphosphondiamide XXI of within the a. NH2 CjHcOCOCl ^NHCOoCjHc NaOH /ynh2 toluone '^nhcojcjhj (4)-tartaric acid salt 280 k HX59a' range of from about 0.8:1 to about 2:1, preferably from about 0.9:1 to about 1.3:1." The alkylating agent R1X (III) where X is preferably iodide, but may be Cl or Br as well, will be employed in a 5 molar ratio to alkylphosphondiamide XXI of within the range of from about 1:1 to about 4:1, preferably from about 1:1 to about 2:1.

As seen in Scheme XVI Part A(l), compound XXII may be prepared by a variety of routes which 10 will be apparent to those skilled in the art.

The metalation of XXII is carried out at a temperature within the range of from about -100°C to about 0°C, preferably from about -60°C to about -80°C employing a molar ratio of base to XXII of 15 within the range of from about 2:1 to about 0.8:1, preferably from about 1.4:1 to about 0.9:1.

The lithium anion of XXII is then' sulfurated employing a molar ratio.* of tetramethyl-thiuram disulfide: lithium anion of XXII of within 20 the range of from about 3:1 to about 1:1, preferably from about 2:1 to about 1:1.

The acid hydrolysis of the individual isomer XXIIIS and XXIIIR to the corresponding thiocarbamate XXIVS and XXIVR, respectively, is 25 carried out by employing aqueous strong acid, such as aqueous HC1, formic acid or sulfuric acid, optionally in the presence of acetonitrile, dioxane or other inert organic solvent. The thiocarbamates XXIVS and XXIVR may be oxidized by conventional 30 techniques, for example, by reaction with hydrogen peroxide in the presence of acetic acid or formic acid, or mixtures thereof or peracids such as peracoiiic in acetic acid or metachloroperbenzoic acids in dichloromethane or diethyl ether, or using 28 HX59a Oxone in alcoholic solvents, to the sulfonic acid which is treated with alkali metal hydroxide, such as KOH, NaOH, or LiOH or an ion exchange resin to form the triacid salt, IS or IR.

Referring to Scheme XV Part B, in an alternate synthesis of the Part A method, alkylphosphondiamide XXI (or (S,S)-isomer) is metalated by reaction with a base as described 10 above, such as n-butyllithium, sec-butyllithium, t-butyllithium or lithium diisopropylamide in the presence of an inert organic solvent such as hexane, tetrahydrofuran or diethylether to form the lithium anion of XXI which is sulfurated by 15 treatment with sulfur and subjected to thiocarbamoylation with a dialkyl thiocarbamoyl halide to form XXV (a novel compound in accordance with the present invention). Compeund XXV is then metalated by treatment with a base as described 20 above, alkylated by treatment with R^-Hal and the resulting mixture of isomers XXIIIS and XXIIIR are separated as described hereinbefore. Isomers XXIIIS and XXIIIR may then be subjected to acid hydrolysis and oxidation and salt formation as 25 described with respect to XXIIIS and XXIIIR in Part A, to form IR and IS.

In carrying out the Scheme XV Part B method, the base, preferably n-butyllithium, is reacted with alkylphosphondiamine XXI under an 30 inert atmosphere such as argon or nitrogen at a temperature within the range of from about -100 to about 0°C, preferably from about -60 to about -80°C, employing a molar ratio of alkyllithium:XXI of within the range of from about 0.8:1 to about 2:1, preferably from about 1.2:1 to about 1:1.

The sulfuration reaction of lithiated XXI (with sulfur) is carried out at a temperature 5 within the range of from about -90 to about 0°C, preferably from about -80 to about -40°C, employing a molar ratio of sulfur:lithiated XXI of within the range of from about 4:1 to about 1:1, preferably from about 2:1 to about 1:1. 10 Thiocarbamoylaton of the sulfurated XXI with the dialkylthiocarbamoyl halide, preferably, dimethyl- or diethyl-thiocarbamoyl chloride is carried out at a temperature within the range of from about -60 to about 25°C, preferably from about 15 -30 to about 0°C, employing a molar ratio of dialkylthiocarbomoy1 halide:sulfurated XXI of within the range oi from about 4:1 to about 1:1, preferably from about 2:1 to about,»l:l. The thiocarbamoylation reaction is optionally carried 20 out in the presence of a weak organic base, such as triethylamine or pyridine.

The thiocarbamoylated compound XXV is metalated with a base, as described above, preferably n-butyllithium, at a temperature within 25 the range of from about -90 to about -60°C, preferably from about -80 to about -70°C, under an inert atmosphere such as argon or nitrogen, employing a molar ratio of alkyllithium: thiocarbamoylated compound XXV of within the range 30 of from about 2:1 to about 0.8:1, preferably from about 1.4:1 to about 0.9:1.

Alkylation of the lithiated XXV is carried out at a temperature within the range of from about -90 to about 0°C, preferably from about -80 to about -40°C, employing a molar ratio of R^al: lithiated XXV of within the range of from about 4:1 to about 0.8:1, preferably from about 1.5:1 to about 0.9:1. The alkylation is preferably 5 carried out in the presence of a weak base such as hexamethylphosphoramide (HMPA), or tetramethyl-ethylene diamine.

Still another alternative method for preparing the desired enantiomers of formula I 10 compounds is shown in Scheme XV Part C wherein starting (R,R)-diamine XXR (or the corresponding (S,S-)-diamine XXS) is made to undergo a phosphorous diamide formation by treating a 15 solution of XXR and weak organic base such as triethylamine or pyridine, in an inert organic solvent such as THF, dichloromethane or toluene, with phosphorus trichloride under pn inert atmosphere such as argon or nitrogen, and then 20 treating the resulting filtrate (chilled), under an inert atmosphere, such as argon, with water, and a tertiary amine base, to form the phosphorous diamide XXVII. The diamide XXVII may then be subjected to a condensation reaction with the 25 aldehyde XXVIII R1CH0 and a silylating agent such as, for example, bis(trimethylsilyl) acetamide, bis(trimethylsilyl) trifluoroacetamide or hexamethyl disilazane in the 30 presence of an inert organic solvent, such as methylene chloride, toluene or THF, under an inert atmosphere, such as argon or nitrogen, to form a mixture of protected isomers XXIXR (a-(R)isomer) and XXIXS (a-(S)isomer). 2& OP HX59a' - 67 The isomers XXIXR and XXIXS are separated by chromatography or other conventional means such as crystallization and each of the a-(R) isomer XXIXR and a-(S) isomer XXIXS in solution in an 5 inert organic solvent such as THF, diethyl ether, acetonitrile or dichloromethane, is separately treated with a fluoride source such as tetrabutylammonium fluoride, aqueous hydrofluoric acid or lithium tetrafluoroborate, to fotiti the 10 compounds XXXR and XXXS.

Each of the isomers XXXR and XXXS can then be separately made to undergo a Mitsunobu displacement (Rollin, P., Tetrahedron Lett. 1986, 27, 4169-4170) wherein each of XXXR and XXXS is 15 separately treated with dimethyl (or diethyl) dithiocarbamic acid, zinc salt, and triphenyl-phosphine, tributylphosphine, triethylphosphite and diethyl diazodicarboxylate (DEAD) ,or diisopropyl azodicarboxylate (DIAD), in the presence of an 20 inert organic solvent such as THF, toluene, or dichloromethane, under an inert atmosphere such as argon or nitrogen, to form the separate isomers XXIIIS' and XXIIIR" which may be converted to the IS and IR isomers, respectively, as described in 25 Scheme XV Part A. Alternatively, the isomer separation can be carried out at the stage of XXXR and XXXS.

If desired, the phosphorous diamide XXVII may be converted directly into the alcohols XXXR 30 and XXXS by subjecting XXVII to a condensation reaction with aldehyde XXVIII in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine. basic alumina or a fluoride source such as described above or potassium or ' 0 2 HX59a ' 68 - cesium fluoride, to form a mixture of XXXR and XXXS.

In carrying out the Scheme XV Part C method, the diamine XXR (or XXS) is reacted with 5 phosphorus trichloride at a temperature of within the range of from about 50°C to about -80°C, preferably from about 0°C to about -80°C, employing a molar ratio of trichloride:XXR of within the range of from about 3:1 to about 0.8:1, preferably 10 from about 1.5:1 to about 1:1.

The condensation reaction of the phosphorus diamide XXVII with the aldehyde XXVIII is carried out employing a molar ratio of diamide XXVII:aldehyde XXVIII of within the range of from 15 about 2:1 to about 0.8:1, preferably from about 1.5:1 to about 1:1, and a molar ratio of silyl protecting compound:XXVII of within the range of from about 3:1 to about 1:1, orefe^ably from about 1.5:1 to about 1:1.

Reaction of the individual isomers XXIXS and XXIXR with the fluoride source is carried out employing a molar rat.j of fluoride source to XXIXS or XXIXR of within the range of from about 4:1 to about 1:1, preferably from about 2:1 to about 25 1.1:1.

Where the phosphorus diamide XXVII is converted directlv to the isomers XXXR and XXXS (see Scheme XV Part C(l)), the condensation reaction of XXVII with the aldehyde XXVIII and base 30 or fluoride source as described above will be carried out essentially under similar conditions previously described for formation of XXIXS and XXIXR, and XXXS and XXXR. 2 f: q HX59a " 69 The Mitsunobu displacement of XXXR and XXXS is carried out employing a molar ratio of dimethyl-dithiocarbamic acid or diethyl derivative, zinc salt or equivalent: XXXS or XXXR of within the 5 range of from about 2:1 to about 0.5:1, preferably from about 1.5:1 to about 0.6:1, and a molar ratio of triphenylphosphine or equivalent:XXXR or XXXS of within the range of from about 4:1-to about 1:1, preferably from about 2:1 to about 1:1. 10 a preferred method for forming the desired enantiomers of formula I is shown in Scheme XVI wherein a solution of the (R,R)-diamine XXR (or the corresponding (S,S)-diamine XXS where the a-(R) product is desired) in an aprotic solvent such as 15 toluene, benzene, dichloromethane or THF, and weak organic base such as triethylamine, pyridine or diisopropylethylamine is treated with phosphorus oxychloride to form the acid chloride XXXI which in solution with an inert organic solvent such as THF, 20 diethylether or dimethoxyethane is subjected to a coupling reaction with LiCHS03Ra (XXXIA) i z (prepared by reaction of an alkylmethanesulfonate 25 XXXIB with alkyllithium) to form the sulfonate XXXII (which is a novel intermediate in accordance with the present invention). Sulfonate XXXII is dealkylated by treatment with a dealkylating agent such as tetrabutylammonium iodide, in the presence 30 of an inert organic solvent such as THF, diethylether or acetone, to form sulfonate XXXIII (which is a novel intermediate in accordance with the present invention) which is made to undergo dianion formation by reaction with a metalating agent such 2HQ2 ] HX59a • as n-butyllithium, sec-butyllithium, t-butyllithium or lithium diisopropylamide, under an inert atmosphere such as argon or nitrogen, in the presence of an inert organic solvent such as 5 hexane, THF or diethyl ether, and is then treated with alkylating agent R1Hal in an inert organic solvent such as THF, diethyl ether or hexane to form XXXIV (which is a novel intermediate in accordance with the present invention) optionally 10 in the presence of hexamethyl phosphoramide (HMPA) or tetramethyl ethylenediamine (TMEDA). XXXIV may be subjected to acid hydrolysis and ion exchange to form the individual enantiomer IS, when Z is H.

As indicated, where the starting diamine XX 15 is the (S,S)-enantiomer XXS, the final product will be the IR (R)-enantiomer, when Z is H.

In carrying out the Scheme XVI method, the phosphorus oxychloride will be employed in a molar ratio to the diamine XXR of within the range of 20 from about 1.5:1 to about 0.8:1, preferably from about 1.1:1 to about 0.9:1. The reaction will be carried out at a temperature within the range of from about -20 to about 40°C, preferably from about 0 to about 25°C. z j In forming lichso3r (xxxia) (where alkyl is preferably ethyl or cyclohexyl) the alkylmethane-sulfonate XXXIB is reacted v;ith the alkyllithium or other strong base at a temperature within the range of from about -90 to about 0°C, employing a molar 30 ratio of alkyllithium:sulfonate XXXIB of within the range of from about 1.2:1 to about 0.8:1, preferably from about 1.1:1 to about 0.9:1. 280 k HX59a• The LiCHS03Ra i z compound XXXIA will be reacted with the acid chloride XXXI at a temperature within the range of 5 from about -90 to about 0°C, preferably from about -80 to about -30°C, employing a molar ratio of Li compound XXXIA to XXXI of within the range of from about 4:1 to about 1:1, preferably from about 2.5:1 to about 1.5:1.

The dealkylation of sulfonate XXXII is carried out employing a molar ratio of iodide:XXXII of within the range of from about 1.5:1 to about 0.9:1, preferably about 1:1.

In the dianion formation, sulfonate XXXIII 15 is treated with the base at a temperature within the range of from about -100 to about 0°C, preferably from about -90 to about -60°C, employing a molar ratio of base:XXXlll of within the range of from about 2:1 to about 0.8:1, preferably from 20 about 1.5:1 to about 1:1.

The lithiated XXXIII compound is alkylated with R^-Hal at a temperature within the range of from about -100 to about 0°C, preferably from about -90 to about -60°C, employing a molar ratio of 25 R^al: lithiated halide of within the range of from about 2:1 to about 1:1, preferably from about 1.5:1 to about 1.1:1.

The alkylated sulfonate XXXIV is made to undergo acid hydrolysis by treating XXXIV with 30 strong aqueous acid, such as HCl, sulfuric or formic acids, and then with base such as KOH, NaOH or LiOH to form the major isomer IS where (S) is at the a-center when 2 is H. As indicated, where the starting (S,S)-diamine XXS is employed, the major 280218 HX59a ' isomer obtained is IR where (R) is at the a-center when Z is H.

An alternative preferred method for forming the desired enantiomers described herein is shown 5 in Scheme XVII. The starting aldehyde XXVIII (can be prepared by reaction of the alcohol R1CH20H with methylsulfoxide, and oxalyl chloride in the presence of weak organic base such as triethylamine, that is the Swern oxidation or other 10 standard alcohol oxidations), is treated with (2S,4S)-(+)-pentanediol (or the corresponding (2R,4R)-isomer) and p-toluenesulfonic acid in the presence of an inert solvent such as benzene, toluene or dichloroethane, to form the chiral 15 acetal XL. Chiral acetal XL is subjected to an acetal opening reaction wherein acetal XL is reacted with a trialkylphosphite, such as triethylphosphite, in the presencer'of titanium (IV) chloride, and an inert organic solvent such as 20 methylene chloride, toluene or benzene, under an inert atmosphere such as argon or nitrogen, to form the alcohol XLI which is oxidized via the Swern oxidation, pyridinium chlorochxomate (PCC) or Jones reagent under standard conditions, to form XLII. 25 The 3-butene-2-one portion of XLII is eliminated by treating XLII with p-toluenesulfonic acid or methanesulfonic acid in the presence of dioxane, or acetonitrile and water to form the diester XLIII which is subjected to a Mitsunobu displacement 30 under the same conditions as described for the conversion of XXXS/R to XXIIIS'/R'. See P. Rollin, supra, to form XLIV. Compound XLIV is dealkylated by reaction with a dealkylating agent such as bromotrimethylsilane or iodotrimethylsilane in the HX59a ' - 73 presence of an inert organic solvent such as methylene chloride, benzene or roluene, under an inert atmosphere such as argon or nitrogen, to form the diacid XLV which is oxidized by treatment with 5 hydrogen peroxide in formic acid, acetic acid or mixtures thereof or other oxidants as described for Scheme XV, and then treated with alkali metal hydroxide such as KOH, NaOH or LiOH, or ion exchange resin as described hereinbefore to form 10 the (R)-enantiomer IR.

It will be appreciated that in carrying out the above method, where the aldehyde XXVIII is reacted with the (R,R)-diol, the final product obtained will be the a-(S)-enantiomer IS.

In carrying out the method of Scheme XVII, the (2S,4S)-(+)-pentanediol will be reacted with the starting aldehyde XXVIII at a temperature within the range of from about 25^to about 100°C, preferably from about 60 to about 90°C, employing a 20 molar ratio of diol:XXVII of within the range of from about 4:1 to about 0.8:1, preferably from about 2:1 to about 1:1. The resulting chiral acetal XL is reacted with the trialkylphosphite and titanium(IV)chloride or equivalent at a temperature 25 within the range of from about -90 to about -20°C, preferably from about -80 to about -40°C, employing a molar ratio of phosphite:xl of within the range of from about 5:1 to about 1:1, preferably from about 3:1 to about 2:1, and a molar ratio of 30 phosphite:titanium tetrachloride of within the range of from about 3:1 to about 1:1, preferably from about 1.2:1 to about 1.6:1, to form alcohol XLI. 2 b I? HX59a ' The oxidation of alcohol XLI is carried out at a temperature within the range of from about -80 to about 0°C, and the elimination reaction involving XLII is carried out at a temperature 5 within the range of from about 30 to about 150°C, preferably from about 80 to about 120°C, employing a molar ratio of p-toluenesulfonic acid or equivalent:XLII of within the range of from about 0.5:1 to about 0.005:1, preferably from about 0.1:1 10 to about 0.05:1.

The Mitsunobu displacement reaction is as described previously for Scheme XV Part C.

Dealkylation of XLIV is carried out employing a molar ratio of dealkylating agent:XLIV 15 of within the range of from about 10:1 to about 2:1, preferably from about 6:1 to about 4:1.

Scheme XVIII sets out a purification procedure wherein the desired individual enantiomers (salt thereof) is subjected to ion 20 exchange (H+ form) such as by treatment with AG 50-X8 ion exchange resin, to form the free triacid IQ which is treated with an amine such as adamantanamine or (S) -(-)-a-methylbenzylamine (under an inert atmosphere such as argon where the 25 latter.amine is employed), in a molar ratio of amine:IQ within the range of from about 2.2:1 to about 1.9:1, preferably about 2:1, to form the corresponding bis-amine salt IQ' which is separated out by recrystallization. The so-formed diamine 30 salt IQ' may be treated with ion exchange resin (M+ form) such as Ag50-X8 (K+ form) or basified with MOH (where M is K, Li or Na) to form the purified enantiomer. Amine salts IQ' of chiral amines and racemic triacid I may be used to resolve the 280 2 HX59a' racemate into a-(R) and (a)-S isomers by recrystallization.

If desired, the diamine salt IQ" may be treated with ion exchange resin (H+ form) to form 5 the triacid IQ which may be treated with ion exchange resin (M+ form) or basified with MOH to form the purified enantiomers, IS or IR.

Scheme XIX set out a reaction sequence for preparing prodrugs of the desired enantiomer. As 10 seen, the starting enantiomer IS (or IR) is treated with a silver salt such as silver nitrate to form the silver salt IAg which is alkylated by treatment of IAg (optionally in the presence of 4A molecular sieves, anisole, thioanisole, 2,6-di-t-butyl-15 pyridine and mixtures thereof) with alkylating agent XI to form triester LI.

The triester LI is subjected to solvolysis in water, or optionally a water-mi-fecible solvent such as ethanol, methanol, 2,2,2-trifluoroethanol, 20 acetonitrile or mixtures of water and the organic solvent, at 0°C to 60°C, to form the diester LII which is made to undergo salt formation by treatment of LII with an alkali metal phosphate buffer, such as potassium phosphate buffer, or ion 25 exchange, to form the salt IS' .

The various acid and salt forms of the invention ID, IE, IF, IG, IL, IM, IN, IO, IP, IQ, IR, IS, IR', IS', LIIR, LIIS, IT and IU can be interconverted by standard means, including ion 30 exchange chromatography. It should be understood that all acids can be isolated either as salts (M=pharmaceutically acceptable cations such as Li+, Na+, K+, NH4+) , or free acids (M=H). 2802 HX59a ' Examples of starting alkylating agents that is RXX or R^-Hal suitable for use' herein include the following which are either known in the literature or are simple derivatives of known compounds 5 prepared by employing conventional procedures.

It will be appreciated that the R*X compounds listed in the following table represent all possible stereoisomers. / 28 0 2 HX59a 77 - R^-Hal where Hal is Cl, Br or I, or Otosyl or OSO2CF3 is as follows in A. through F.

A * R\ ^CHv /CHa -CH /Ha .CH V / CH2 c \CHj Nc (CHJ ) n R" CHj 3 CHj R17 CH CH2 _ y 17 V \„/ \ </\ / R \ / ' c (CHj), or i=CH »" | rle \ CH 3 (CHa)n- n is 1 to 8 ra-z m 1. c2h5 ch3 2. CH3 C2H5 3 . 11-C3H7 CH3 4. CH3 n-C^Hg 5. t —C4H9 CH3 -(ch2)s»- s' =4 to 6 7 . h h 8 . F F 20 9 . c1 c1 . ch2f ch3 11. -ch=ch2 h 12. CF3(CH2)t H t o 0 to 8 2n ^ fr"< 8 u ^ HX59a • >CHa ,CH -,CH2 .CH / B. alkyl-(CH2)t c CH2 C CHa or 2. or | j (aryl) iHj CH3 CHa / \y\ / alkyl-(CH2)t c ch3 or j (n is 1 to 8) '■ryl) CH, alkyl(CH2)t- 1. CH3(CH2)t where t is 0 to 8 ch3^ C-(CH2)t- where t is 0 to 8 ch^ | h (CHj) t ~ 3. ( - V- (CHi) i-— where t is 0 to 8 4. ( n >— (CH,),.— where t is 0 to 8 . i<°)~ (CHj)t — i y\ l 10 J (CHj ) t — Rv ,(CHs)t- " xs 79 W V - t HX59a " Ctii* > * 7 . 8 .

(CH2), O O f— (CH2)t- 9. CP3(CH2)t- .

CP3 \ cpf ,CH-(CH2)t- li. 12 .

O-(CHj)t- <°> <°>- N-(CH2)t- 13 .

./■ S-(CHj)t . -0-(CHj)t- (CH2)5v 15 " ( (CHa)t- *:eu2 HX59a" Examples 5 to 10, t = 0 to 8 Ri, R2 and R3 may be the same or different and can 5 be any of the radicals included in R6.

Examples 11 to 15 t = 1 to 8 x = 3 to 8 CH3 CH3 I I c. CH3-C0C-CH2 CH2-C = C-CH2 -4- t (CH2)a- t = 0,1,2,3 n=0 to 8 CH3 CH3 i i H-C-CH2-CH2 -*-CH2-CH-CH2-CH2 t(CH2)n- i ch3 n=0 to 8 t= 0,1,2,3 d . 1 . 2 . 3 . 4 . . 6 . 7 . 8 . 9 . 11 12 13 280 2 hx59a' ^ ch 3 v .j.ch chj .ch . ch2 .ch / , ch2 \ chj \ (cha) n JU I I r" r» noX to 8 or chsv ^.ch ch, .ch y n<= v*' \ * \ / / ch» c (chj) „ I ^22 n=l to 8 fi.21 g2 2 r2 2 c2h5 c2h5 ch3 ch3 ch3 c2h5 ch3 c2h5 c2h5 c2h5 c2h5 c2h5 ch3 c2hs ch3 ch3 h ch3 ch3 ch3 h h h h cf3 ch3 ch3 ch3 cf3 ch3 ch3 ch3 cf3 cf3 cf3 ch3 cf3 cf3 cf3 E . 1 . 2 . 3 . 4 . . 6 . 7 . 8 . 9 . 11 12 13 14 26 0 2 HX59a " ch, I ch} r24 r25 - I I ,ch2 „ch ch ,c . / "(ch2)n \ ^ch. .chj ch ch ,c C ^ \ / \ # \ / \ S \ ch1 c ch, c I cha or H r2* r25 I I ch, .C JCH ,C . / ch v* v../ \ / ch r2s <ch2), i26 Del tO 8 &24 h h h ch3s F CH3 h h h h h h h h b.25 i h ch3 ch3 CH3 ch3 ch3 ch3 cp3 c 1 ch3 ch3 cf3 ch3 &2 6 h i ch3 h H •'* h ch3 c 1 H H (CH3)3si F ch3 cf3 HX59a F. Other examples of R1 include the following 1. ch3. ^ch2 JLch2 ^ch2 >ch2 ^ch2 / ch ^chj^ "ch ^chjjn "?h ""(chjja ch3 ch3 (n is 0, 1) 2 . CH3^ ^CH, LCHa „CH, -v-CH, ^CH j^cmj -yum ch' nCH- ^ **ch "chtj n xch" v(ch2).

I I ^ I ch3 ch3 ch3 (n is 0, 1) 3 . cj*3 .ch jlch2 .ch2 -^ch2 -ch jLch2 - -ch ^«2 >^«2. ^s5-c« / ^ch> """ch ^ (ch2) n i ch, ch, ch3 *3 (n is 0, 1) / 4. chj ch ^ch2 ^ ^ch2-c =c-(ch2)m \ f ^-ch2 c chj i 1 chj ch> . chj ^ch, ^ch ch, ch / CBf "chj xch ch2 c (cha)n ch3 6 • cb\./^ch/ch Y^y: (ch2)m I. CH, n is 1, 2) *1 ch3 3 7. ch. .CH ^h, ^ch 6ch, chv }<ch,, \c^ ^^cha c chj v c cha' n >2' i (n is 0, 1) i ^3 ch, c1 ch, In Examples 1 to 5, m is 1 to 8. In Examples 6 and 7, m is 0 to 8.

HX59a ch3 8. CHa ^CH ^ CH^ CH^ -C^ ^CH; "C*^ (CHJ)„ I I CHj I chj 9 - ch3_ ^.chv ^cha ^ch ^-ch^ / \c<^ CHj^ "C^ CH2 (CHJ) n i i L CaHs CH3 CH3 CHj . ^ch>* ^cn\ ^c\ ^ch2^ ,^c» / CHj^ CHj CHJ C"^ (CHj ) n I I chj chj CHj « , 11 • i i i ch3 ch3 ch3 (m is 1, 2) .* CHj ^<ch ^chj ch ^-ch2 /^Cx / 12. CH-^ CHj ^CHj vCH ^(CH2)n I I cjhs chj CHj i 13. ch3 >. ^.ch ^ch2 ^ch ^ch ^ch \ ^ n ^ *»„„ s ^ s,^t, C CHj c ^ CHj C ^ (CHj), I I I CjH5 CH3 CHj In Examples 8 to 13, n is 1 to 8. 2 HX59a* 14 - CH, ^ ^.CH CH, c ch, i -c cha ^ ch2 ^ ch2 "ch n/rn.l 1 ch3 I <CH2), ch, (n is 1 to 8) f i . CH3 ^.ch ^ch2 .c CH2 ~~~cr ^ch2 ch / *ch2 nch2)n ch3 (n is 1 to 8) ch3 ch, 16. ch '•^~^C^cn£C\^a'-*cS?)T'"~ I ch3 I ch3 (n is 1, 2) (m is 0 to 8) 17 .

H i CHs%^c' CHj CH, F i 'ch2 >^c\ / I ch3 (n is 1 to 8) 18. CH3 ^.CH2 C' CH, "c CH, *c / (CH;)n j. to 8) ch3 ^■CH2 ^^^31 - C=C vch- ^ (chj),, 19 - ch3- c= c vch 2 ^C . CH3- c= C - (CH2) n- (n = 4-12) (n is 1 to 8) 2802 18 HX59a p x / v (CB2 .CH v v(CH2) m- ch3 x = h, f, ch3 n is 1 or 2 m is 0 to 8 22. CH3- C= C - (CH2)n-C =C-(CH2)m- (n = 0-10) (m is 0 to 8) 23 OH H /ch, .c. v-(chj)„- 1 \ I ^41 n is 1 to 3 m is 0 to 8 R40 = H, alkyl, cycloalkyl, or aryl such as methyl, ethyl, isopropyl, ppntyl, phenyl / and cyclopentyl R41 = alkyl such as methyl, ethyl or halo 15 such as Cl or F 24 och3 h /ch, .1 vlch,).- 1 \ I l41 (m is I to 8) (n is 1 to 3) h i V(CH2>»- ^cha -/-ch2 v" 2 5 - R*°o -CHa^ CH^yn (m is 1 to 8) (n is 1 to 3) 2tsO 2 hx59a' oh i 26. R10^ H ir h i v<ch2)a- R41 (m is 0 to 8) (n is l to 3) 27 {CHj H i x ^c v(chj)m- >c n I / (in is 0 to 8) R41 (n is 1 to 3) 2 8 . r«° -X-f ch, ^ch ^ch i ch3 v(ch2)n 7n (m is 0 to 8) (n is 1 to 3} {X is 0, S, NH) 29. R40 ch3 i —x >cha' X is O, S, NH, CHj) (m is 0 to 8) (n is 1 to 3) -ch CH % (CH3)n- 280 2 HX59a " Additional compounds described herein are set out below. o R42 R43 R44 R45 R46 t ) H H h h n-C3H7 3 31) H h h H H-C4H9 3 32) H H H h (ch3)2-c=ch- 4 33) H H h h (CH3)2-c=ch-ch2- 2 34) CH3 h ch3 H t>-ch2- 3 ) h h ch3 H (ch3)2-ch-ch2-0- 3 36) h CH3 ch3 h n-C3H7 3 37) CH3O H h H n^C4Hg 3 38) H H H H (ch3)2"c=ch- 3 39) H H H H (ch3)2-c=ch-ch2- 4 40) CH3 H H H |>-ch2- 41) f H ch3 h n-C3h7 3 42) ch3 H f H n-C4Hg 3 43) H ch3 H CH3 (ch3)2-c=ch- 3 44) H H h cf3 (ch3)2-c=ch-ch2- 3 45) H H h f [>-ch2- 3 46) H Cl cl h ch2=ch-ch2- 3 47) ch3 h h h C4H9 3 48) H H oh h c3h7 3 49) H H OCK3 h c3h7 4 50) H H ch3 H c3h7 3 51) H oh h h c3h7 3 52) H och3 h H c3h7 4 53) H CH3 h h C3H7 3 2is 02 HX59a" R2 = H, OMetal, alkyl, aryl R3 = H, metal ion or alkyl R4 = H, metal ion or alkyl 54) r 'so3r4 55 ) X1 = - (CH2 ) n-' -CH=CH-CH2-n = 1 to 6 6) r2por3 / W so3r4 Re 54) to 56) R is n-C3H7, n-C4H9, (CH3)2-C=CH-, CH3-CH=CH-CH2-, (CH3)2-CH=CH-CH2-, CH2=CH-CH20-, (CH3)2-CH-0-, (CH3) 2CHCH20-, ^-CH2-, CH2=CH-CH2- , CH2=CH-CH2CH2-, phenyl, pyridyl 57) ch, ^ch jtcha c I ch3 r2por3 / ,^c" >(CH1>P-C Z c"^ chj) „ x j ' so3r4 ch3 2 3 U £ HX59a 58) Z = Cl, F, alkyl such as methyl, ethyl, propyl or ally1 n = 0, 1. 2 p!= 0 - 8 m = 2 - 8 In compounds 49) to 52) R3 = H, metal ion or alkyl R4 = H, metal ion, alkyl or aryl R2 = H, Ometal, alkyl, aryl o f , l' k»* ■k rvk_- ./i ch or2 co2r4 X is O, S NH, SO, SO2, CR5R6, C=0 R1, R2, R3, R4, R5 and R6 are independently H, ♦ halogen, Ci-Csalkyl, Ci-Csalkenyl, 'Ci-Csalkoxy, aryl, arylalkyl, aryloxy; for R5 ar.--' p.6, halogen can be fluorine only. (ch2)p- 2 n o vj HX59a (ch2)p- -(ch2)p- (ch2)p- (CHj).

R is as defined for 54) to 56) <ch2)p- r2 ../if (ch2)p- 92 (ch2), (CHj ) p- rO (CHj)p- (CHj)p- -(CHj), <CH2) X = bond, 0, NH, S, CH2, CR5R6 p = 1 to 8 n = 0 to 4; R1, R2' R5 and R6 are independently halogen, alkyl, alkenyl, alkoxy, aryl, H, aryloxy; for R5 and R6 halogen can be fluorine only.

Preferred are enantiomers of compounds of formula I in the (S) configuration of the above preferred compounds, that is D U o HX59a - 93 i s o z ii .or5 pc OR3 o^h^or4 o wherein Z is H, R1 is preferably Ar^O-Ar2-(CH2) p-, R3, R5 and R4 are an alkali metal such as K or Na.

More preferred are prodrug (P.D.) esters of the (S)-enantiomer (IS), that is o Z || J> Prodrug ester r1^ | .pc' O Prodrug ester IS (P.D.) o^u^om o Most preferred are compounds of formula IS 10 where R1 is Ari-O-Ar2- (CH2) p-,» R4 is an alkali metal such as K or Na Z is H and Prodrug ester is bis(pivaloyloxymethyl) ester.

In addition, in accordance with the present invention new intermediates are provided which are prepared as described above, and have the following formulae: rs O N a ) \ R -co n v 9 ■2r n 9 «■ i/ HX59a z . i R1 C | (XXIIIS or XXIIIR, S \\ | °H3 XXIIIS' or XXIIIR') s ch3 i x= h — c s—c n—ch3 (xxv) ii i s ch3 alkylO—S- Z i -c- i h (XXXII) x = z i (c4H9)<N*-o3s c- (XXXIV) b ) C ) z o , i iu°h r1 c — pc | oh s i ^ch3 s = c— ch3 h o i h^oalkyl ■c—p^ Oalkyl (XXIV) A or B XLV (XLIV) S- •c—n—ch3 ii i s ch3 d) o ii y~p- o h » -(o-c-o-c-r")2 r10 o o z ii h ii | y_ rll c — o — c — o — S-^—C ( iii ) L 11 K r10 o r1 o z o " 1 'i ,ttt> HO — S C—P (LII) i' i, O R1 O Z O ii i ii Y= MO—S—C—P (IS' or IR*) ii i O R1 The compounds of Formula I described herein inhibit cholesterol biosynthesis by inhibition of de novo squalene production. These compounds 10 inhibit the squalene synthetase enzyme and, in addition, some of the compounds of Formula I inhibit other enzymes in the pathway from isopentenyl diphosphate to squalehe, that is, farnesyl diphosphate synthetase and isopentenyl 15 diphosphate-dimethylallyl diphosphate isomerase.

The compounds described herein are useful in treating hyperlipoproteinemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemr.a, combined hypercholesterolemia and hypertri-20 glyceridemia, and/or in preventing development of and/or treating atherosclerosis. Thus, the compounds described herein may be used to treat diseases such as chylomicronemia syndrome, Type I hyperlipoproteinemia, familial combined 25 hyperlipoproteinemia, familial hypertriglyceridemia, mixed hyperlipoproteinemia, familial hypercholesterolemia and Type III hyperlipoproteinemia and/or atherosclerosis. 2 HX59a In addition, the compounds described herein may increase plasma high density lipoprotein cholesterol levels.

The compounds described herein may also be 5 useful in inhibiting formation of gallstones, treating hepatitis D (by virtue of protein prenyltransferase inhibition, Glenn et al, Science, Vol. 256, pp. 1331-1333, May 29, 1992), treating tumors, lowering blood pressure, xowering blood 10 sugar, treating diabetes mellitus, treating inflammation, as a diuretic, as an inotropic agent, as an anti-arthritic (antirheumatic) agent, in treating other diseases of calcium and phosphate metabolism including treatment of bone resorption, 15 Paget's disease, osteoporosis, calcification of joints, implants and metastasis, as antitartar and anticalculus agents in toothpastes and mouthwashes, treating various stones and calculi, treating sickle cell anemia, treating hypoxia and ischemic 20 tissue, and as an anti-ameobal agent, as well as for use in complexes with technetium-99m and radioiodinated derivatives for use as diagnostics.

U.S. appication Serial No. 774,957, filed October 11, 1991, discloses that post-translational 25 modification of caax box containing proteins may be inhibited by administering a protein-prenyl transferase inhibitor which inhibits the transfer of the prenyl group [such as farnesyl (in the case of ras oncogene products), geranyl or 30 geranylgeranyl] to the cysteine of the caax box by the protein-prenyl transferase enzyme. The protein-prenyl transferase inhibitor will block the protein-prenyl transferase enzyme from catalyzing the transfer of the prenyl group (for example. 2 p v c HX59a farnesyl, geranyl or geranyl-geranyl) from the prenyl pyrophosphate to the cys"residue of the CAAX box, such as the ras p21 cys, or to the CAAX box cysteine of other CAAX box containing proteins. In 5 the case of ras p21 oncogene products, inasmuch as the cys is not farnesylated, in the presence of the protein prenyl transferase inhibitor, it cannot effect interaction of the ras protein with the membrane so that neoplastic transformation of the 10 cell will be prevented. In this manner protein-prenyl transferase inhibitors prevent neoplastic transformation of the cell, thereby acting as an anti-cancer agent for the treatment of and/or prevention of ras-related tumors. 15 Examples of CAAX box containing proteins which have been demonstrated or are believed to undergo prenylation include, but are not limited to, ras, nuclear lamins, a or y subunits of heterotrimeric G-proteins, "'-subunits of retinal 20 transducin, G25K and K-rev p21, and protein families including rho, rap, rac, ral, and rab.

Described herein is a method for blocking or preventing the prenylation of CAAX box concfining proteins such as ras oncogene products, 25 and thereby inhibit disease promoting effects of the CAAX box containing protein or more specifically prevent and/or treat ras-re.lated tumors, by administering to a patient in need of treatment a therapeutic amount of a compound of 30 Formula I described herein which serves as a protein-prenyl transferase inhibitor.

The Formula I protein-prenyl transferase inhibitors, unlike HMG CoA reductase inhibitors, will interfere wit prenylation of the ras oncogene 280218 HX59a products and inhibit their transforming activity, yet may or may not interfere with Che synthesis of FPP, a precursor in the synthesis of ubiquinones, dolichols and Haem A.

The compounds described herein may also be employed in combination with an antihyperlipopro-teinemic agent, hypocholesterolemic agent, and/or hypotriglyceridemic agent, and/or antiathero-sclerotic agent such as one or more HMG CoA 10 reductase inhibitors, for example, pravastatin, lovastatin, simvastatin, velostatin, fluvastatin, rivastatin, compactin, SDZ-63,370 (Sandoz), CI-981 (W-L), HR-780, L-645,164, CL-274,471, dalvastatin, a-, (I-, and 7-tocotrienol, (3R,5S,6E)-9,9-bis(4- fluorophenyl)-3,5-dihydroxy-8-(1-methyl-lH- tetrazol-5-yl)-6,8-nonadienoic acid, L-arginine salt, (S)-4-[[2-[4-(4-fluorophenyl)-5-methyl-2-(1-methylethyl),-6-phenyl-3-pyridinyll^thenyl] hydroxyphosphinyl] -3-hydroxybutanoic acid, disodium salt, 20 BB-476, (British Biotechnology), dihydrocompactin, [4R-[4a, 6fS(E)]3-6-[2-[5-(4-fluorophenyl)-3 -(1- methylethyl)-1-(2-pyridinyl)-lH-pyrazol-4-yl]ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-one, and/or lH-pyrrole-l-heptanoic acid, 2-(4-25 fluorophenyl)-p,8-dihydroxy-5-(1-methylethyl!-3- phenyl-4-[(phenylamino)carbonyl]calcium salt[R-(R*,R*)]; one or more fibric acid derivatives such as clofibrate, bezafibrate, Lopid(gemfibrozil) one or more other cholesterol biosynthesis inhibitors, 30 such as NB-598, N-(1-oxododecyl)-4a,10-dimethyl-8-aza-trans-decal-3P~ol, 2,4-undecadienoic acid, 11- [3-{hydroxymethyI)-4-oxo-2-oxetanyl]-3,5,7-trimethyl-, [2R-[2a(2E,4E,7R*),3P]]; one or more bile acid sequestrants, for example, 2 HX59a V. C 99 - cholestyramine, colestipol, polidexide (DEAE-Sephadex); one or more antioxidants, for example probucol and Vitamin E; and/or one or more other lipid lowering and/or antiatherosclerotic agents, 5 for example nicotinic acid or derivatives thereof, neomycin, p-aminosalicylic acid, probucol, hydroxy-propylmethylcellulose, LS-2904, ethanol, 2-[[1— methyl-2- [3 - (trif luoromethyl) phenyl] ethyl] amino] -benzoate (ester).

The above compounds to be employed in combination with the squalene synthetase inhibitor described herein will be used in amounts as indicated in the Physicians' Desk Reference (PDR).

The compounds described herein may also be. 15 employed with sodium lauryl sulfate of other pharmaceutically acceptable detergents to enhance oral bioavailability of such compounds.

Inhibition of squalene synthetase may be measured by the following procedure. 20 Rat liver microsomal squalene synthetase activity is measured using farnesyl diphosphate as substrate and quantitating squalene synthesis using gas chromatographic analysis. The assay was developed by modifying conditions originally 25 described by Agnew (Methods in Enzymology 110:357, 1985).

Also described herein is a pharmaceutical composition consisting of at least one of the compound described herein such 30 as Formula I, in association with a pharmaceutical vehicle or diluent. The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of 2 c- t- /1 HX5Sa • desired administration. The compounds can be administered to mammalian species including humans, monkeys, dogs, etc., by an oral route, for example, in c'ne form of tablets, capsules, granules or 5 powders, or they can be administered by a parenteral route in the form of injectable preparations- The dose for adults is preferably between 200 and 2,000 mg per day, which can be administered in a single dose or in the form of 10 individual doses from 1-4 times per day.

A typical capsule for oral administration contains active ingredient (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a 15 No. 1 gelatin capsule.

A typical injectible preparation is produced by asceptically placing 250 mg of sterile active ingredient into a vial, asceptically freeze-drying and sealing. For use, the contents of the 20 vial ar^ mixed with 2 mL of physiological saline, to produce an injectible preparation.

The following Examples represent preferred embodiments of the compounds describefl herein. 2 8 (i £ HX59a ' Introduction to Experimental All temperatures are reported in degress Centigrade. 1H and 13C chemical shifts are reported as 5 5-values with respect to Me4Si (8=0). 31P spectra were obtained using 85% H3PO4 as an external reference (8=0). Coupling constants J are reported in Hz. For mass spectra (mass spec or MS) the value utilized for the parent M is that of the salt 10 form which was prepared and tested.

All reactions were carried out under an atmosphere of dry argon or nitrogen. The following reagents and solvents were distilled prior to use from the indicated drying agents, where applicable: 15 CH2CI2/ 2, 4 , 6- collidine, and diisopropylamine (CaH2); THF and diethyl ether (K, benzophenone); N,N-diethyltrimethylsilylamine and oxalyl chloride. Benzene was passed through neutra " alumina (activity I) and stored over 4A-mo3ecular sieves. 20 Lithium bromide was dried at 100°C over P2C>5-{E,E)- Farnesol was purchased from Aldrich Chemical Company.

TLC was performed on E. Merck Silica Gel 60 F-254 plates (0.25 mm) or E. Merck Cellulose F 25 plates (0.1 mm). Flash chromatography was carried out using E. Merck Kxeselgel 60 (230-400 mesh).

Reverse-phase chromatographic purification of salts or mixed ester salts was carried on CHP20P gel or SP207SS gel, highly porous, polystyrene-30 divinyl benzene copolymers available from Mitsubishi chemical industries. The indicated general procedure was followed: An FMI Model RP-SY pump was utilized for solvent delivery. A column of CHP20P or SP207SS (2.5 cm diameter, 12-22 cm 280 HX59a " 102 height) ws slurry packed and washed with water (500-1000 mL), and a basic, aqueous solution of the crude salt was applied to the top of the column. Typically, the column was eluted with water, 5 followed by a gradient composed of increasing concentrations of acetonitrile or methanol in water. The gradient was created by placing the tip of a tightly stoppered separatory funnel containing 300-500 mL of the organic solvent, or an aqueous-10 organic mixture, just beneath the surface of a reservoir containing 300-500 mL of pure water. To start the gradient, the stopcock of the separatory funnel was opened, so that as the solvent was withdrawn by the pump from the reservoir, it was 15 replaced with the solvent from the separatory funnel. HPLC-grad.e solvents were employed. Fractions were collected (10-15 mL each) at a flow rate of 5-10 mL per minute. Those,, ^fractions that contained pure product as judged by TLC or HPLC 20 were pooled, the organic solvents were evaporatea and the aqueous residue was lyophilized to dryness.

Example 1 (E, E) -(6,10,14-Trimethyl-2-phosphono-5,9,13-penta-25 decatriene-1-sulfonic acid, trisodium salt farnesol (Aidrich, further purified by flash chromatography) in 10 mL of distilled ether at 0°C under argon in the dark was treated dropwise with a solution of 195 p.L (2.05 mn.ol, 0.45 eq. ) of PBr3 in A. Bishomofarnesol (1) (E,E)-3,7,11,-Trimethyl-2, 6,10-dodeca- trienvl bromide (farnesvl bromide) A solution of 1.00 g (4.5 mmol) of (E,E)- HX59a 2 mL of diethyl ether (ether). The resultant mixture was stirred at 0°C for one hour, then quenched with water and separated. The organic phase was washed with 5 mL of H2O, 5 mL of 5 saturated NaHCC>3, and 5 mL of brine, dried over Na2SC>4 and evaporated to give 1.26 g (98%) of crude bromide as a clear oil.

TLC Silica (2:8 ethyl acetate:hexane) Rf=0.69. (2) (E,E)-5,9, 13-Trimethyl-4,8,12-tetra- decatrienoic acid. i, i-dimethvlethyl ester To a solution of 9.60 mL (68.5 mmol, 1.5 eq.) of diisopropylamine in 100 mL of tetrahydro-15 furan (THF) at -78°C under argon was added 28.2 mL (45.0 mmol, 1.0 eq.) of 1.6 M n-butyllithium in hexanes over 20 minutes. After warming to 0°C for 15 minutes, the solution was recooied to -78°C and 6.05 mL (45 mmol, 1.0 eq.) of t-butyl acetate was 20 added over 20 minutes. After an additional 15 minutes, 16.0 mL (92 mmol, 2.05 eq.) of hexamethyl-phosphoramide (HMPA) was added, followed by a solution of 12.53 g (45.0 mmol) of Part A(l) farnesyl bromide in 100 mL of THF over 20 minutes. 25 The reaction was stirred at -78°C for 2.5 hours, quenched with saturated NH4CI and allowed to warm to room temperature. After diluting with 400 mL of ethyl acetate, the mixture was washed with four 100 mL portions of water, and 200 mL of brine, dried 30 over MgSC>4 and evaporated to provide 12.96 g of crude product as a yellow oil. Purification by flash chromatography on 1 kg of. silica gel, eluted with 1:9 ethyl acetate:petroleum ether afforded £h u ^ HX59a " 9.39 g (65%) of title compound as a pale yellow oil.

TLC Silica gel (2:98 ethyl acetate:hexane) rf=0.16.

IR(neat) 2977, 2925, 2857, 1733, 1452, 1368, 1258, 1149 cm"1.

Mass spec. (CI-CH4/N2O) (+ ions) m/e 165 (M+H-C4H8) , 247, 183, 137, 68, 67. (- ions) m/e 319 (M-H), 279, 251, 100. (3) Bishomofarnesol To a stirred solution of 5.00 g (15.6 mmol) 15 of Part (2) compound in 45 mL of dry diethyl ether at 0°C under argon was added 592 mg (15.6 mmol, 1 mol - eq.) of lithium aluminum hydride, and the resulting suspension was stirred at room temperature for 20 hours. After cooling to 0°C, the 20 reaction was quenched by treating with 5 mL of H2O, 5 mL of 15% NaOH, and 15 mL of H2O and stirring the suspension for 1/2 hour. After adding Na2S04, the slurry was filtered through Celite, washing well with diethyl ether and evaporated to obtain 3.62 g 25 of crude product. Purification by flash chromatography on 300 g of silica gel, eluted with 1:9 ethyl acetate:petroleum ether provided 3.516 g (90%) of bishomofarnesol as a colorless liquid.

TLC Silica gel (2:8 ethyl acetate (EtOAc):hexane) Rf=0.19.

IR(neat) 3330, 2964, 2926, 2873, 2958, 1448, 1384, 1107, 1059, 401 cm"1. 28 0 2 HX59a " Mass Spec (CI-CH4/N2O, + ions) m-/e 251 (M+H) , 249 (M+H-H2), 137, 123, 109, 69.

A1. Bishomofarnesol (alternative preparation) (1) (E,E) - (3,7,11-Tnmethy 1-2, 6,10-undecadienyl)propanedicarboxylie acid, diethyl ester To a suspension of 1.62 g (40.5 mmol. 3 eq.) of a 60% suspension of sodium hydride in mineral oil (washed three times with pentane) in 150 mL of tetrahydrofuran at room temperature under argon was slowly added 6.15 mL (40.5 mmol, 3 eq.) 15 of diethyl malonate. The resulting solution was stirred for 0.5 hours, then treated with a solution of 3.83 g (13.5 mmol) of farnesyl bromide in 10 mL of tetrahydrofuran. After stirring for 6 hours, the reaction was quenched with saturated NH4CI and 20 diluted with 300 mL of diethyl ether. The organic layer was washed with two 100 mL portions of water and 100 mL of brine, dried over MgSC>4 and evaporated and the bulk of the diethyl malonate removed by spinning under high vacuum to afford 25 4.29 g (87%) of crude title product.

TLC Silica gel (ethyl acetate:hexane 1:9) Rf=0.37.

(TLC shows slight amount of diethyl malonate and a 30 second by-product.) (2) (E,E)-5,9,13-Trimethyl-4,8,12-tetra- i3ecatrienoic acid, ethyl ester 280? HX59a A mixture of 4.103 g (11.2 mmol) of Part A1 (1) diester, 200 p.L (11.2 mmol, 1 eq. ) of water and 950 mg (22.4 mmol, 2 eq.) of lithium chloride in 20 mL of dimethyl sulfoxide was heated at reflux 5 (~190°C) for four hours. After cooling, the reaction mixture was diluted with 180 mL of a 1:1 mixture of diethyl ether: petroleum ethe^- and washed with five 50 mL portions of water and 50 mL of brine, dried over MgSC>4 and evaporated to yield 10 3.623 g of crude product as a yellow-orange oil.

Kugelrohr distillation at 180°C (meter setting) and 0.025 mm allowed the collection of 2.100 g of a pale yellow oil, which was, however, still contaminated (by TLC). The distillation, 15 therefore, is unnecessary and should not be performed. Flash chromatography on 180 g of silica gel, eluted with 3:97 ethyl acetate .-petroleum ether provided 1.844 g (56%) of desired title product as a pale yellow oil.

TLC Silica gel (ethyl acetate:hexane 5:95) Rf=0.27. (3) Bishomofarnesol A solution of 7.05 g (24 mmol) of Part A1 25 (2) monoester in 65 mL of dry diethyl ether at 0°C under argon was treated in portions with 915 mg (24 mmol) of lithium aluminum hydride and stirred at room temperature for three hours, After cooling to 0°C, the reaction was quenched with 7 mL of water, 30 7 mL of 15% NaOH, then stirred for 15 minutes. Additional 2i mL of water was added, and the reaction was stirred 0.5 hours, then dried with Na2SC>4. The mixture was filtered through Celite, washing well with diethyl ether, and evaporated to L-~r, HX59a ' give 5.665 g of a colorless oil. Purification by flash chromatography on silic ge'l eluted with 15:85 ethyl acetate:petroleum ether provided 5.23 g (87%) of title compound as a colorless oil.

TLC Silica gel (2:8 ethyl acetate:hexanes) Rf=0.21.

IR(neat) 3330, 2964, 2926, 2873, 2858. 1448, 1384, 1107, 1059, 401 cm"1.

Mass Spec VCI-CH4/N2O, + ions) m/e 251 (M+H) , 249 (M+H-H2), 137, 123, 109, 69.

B. (E,E)-5,9,13-Trimethyl-4,8,12-tetra-15 decatrien-l-ol. methanesulfonate ester To a stirred solution of 2.02 g (8.07 mmol) of bishomofarnesol (prepared as described in Example 1, Part A) in 20 mL of diqhloromethane at 0°C was added 2.2 mL (16.1 mmol) of triethylamine 20 followed by 0.69 mL (8.90 mmol) of methanesulfonyl chloride, dropwise over 15 • ntues. After stirring for 1.5 hours at 0°C, the ction was diluted with dichloromethane, washed with 20 mL each of 10% HCl, saturated N:\HCO3 and brine, dried (MgS04) and 25 evaporated to give 2.71 g (100%) of the crude title mesylate as a colorless oil.

TLC Silica gel (CH2CI2) Rf=0.46. 30 C. (E, E) -14-Iodo-2, 6,10-trimethyl-2 , 6, ?.0- tetraflecatriene The crude Example 1, Part B mesylate prepared from 441.1 mg (1.76 mmol) of the corresponding alcohol according to the procedure of Example 2802 HX59a 108 1, Part B, was dissolved in 5 mL of acetone and treated with 530 mg (3.52 mmol) of sodium iodide. The reaction was allowed to stir for 16 hours at room temperature followed by 5 hours at reflux.

The suspension was diluted with hexane and stirred with dilute aqueous sodium bisulfite to discharge to yellow color. The organic layer was washed with water and brine, dried (MgS04), and evaporated to provide 577 mg of crude product. Flash chromato-10 graphy on 35 g of silica gel eluted with hexane gave 550.9 mg (87%) of title iodide as a colorless liquid.

TLC Silica gel (hexane) Rf=0.31.

Mass Spec (CI-CH4/K2O, + ions) m/e 361, 359 (M+H) 137 .

D. (Diethoxyphosphinyl)methanesulfonic acid, ethvl ester A solution of ethyl methanesulfonate (4.27 mL, 40.3 mmol) in 100 mL of dry THF was treated at -78°C with 19.3 mL (44.4 mmol) of n-BuLi in hexane. After 15 min. diethyl chlorophosphate (3.30 ml, 25 22.2 mmol) was added. The solution was kept at -78°C for 0.5 h and allowed to stay at -50°C for 1 h. Saturated ammonium chloride (75 mL) wes added to the solution and the mixture warmed tc room temperature. The mixture was conce xrated (THF 30 removed), diluted with water and extracted with methylene chloride (3 X 70 mL). The combined organic fractions were dried (MgSC>4), concentrated and purified by distillation to yield 3.86 g (70%) of title compound.

HX59a - 109 b.p. 120-130°C, 1 mm Hg.

Ref. Carretero, J. C.; Demillequ, M.; Ghosez, L.

Tetrahedron Vol. 43, 1987, pp 5125.

E. (E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, sodium salt ; To a suspension of .19 2 mg (8.00 mmol) of NaH in 6 mL of dry DMF at 0°C under argon was added 2.16 g (8.33 mmol) of Part D sulfonate over 15 min. to give a yellow solution. The reaction was allowed to warm to room temperature and stir for 15 0.5 h when 1.00 g (2.77 mmol) of Part C iodide was added in one portion. The reaction mixture was stirred for 18 h when it was quenched with 10 mL of saturated NaCl solution and diluted with 50 mL of ethyl acetate. The layers were separated, the 20 organics dried (Na2S04> and evaporated to provide a crude glass. The glass was dissolved with 2.0 mL of 1 M NaOH solution and purified by MPLC on a column of CHP20P gel (2.5 cm diam. X 15 cm height) eluting with water (150 mL), followed by a gradient 25 created by the gradual addition of 400 mL of acetonitrile to a reservoir of 2 50 mL of water. Approximately 8 mL fractions were collected. The aqueous solution was concentrated and lyophilized to provide 0.78 g (57%) of title compound as a 30 glass.

TLC Silica gel (8:1:1 propanoi/conc. NH3/water) Rf=0.75. 2 n o HX59a IR (film) 3476 2921, 1664, 1444, 1383, 1241, 1029, 968, 815 cm"1.

Mass Spec (FAB, + ions) m/e 510 (M+Na).

F. (E, E)-6 ,10,14-Trimethyl-l-phosphono-5,9,13-pentadecatriene-l-sulfonic acid, trisodium salt To a stirred solution of 0.75 g (1.50 mmol) 10 of Part E salt in 8 mL of dichloromethane at room temperature was added 0.54 g (4.50 mmol) of 2,4,6-collidine followed by 0.82 g (5.35 mmol) of bromotrimethylsilane. The reaction was allowed to stir at room temperature for 14 h when the solvent was 15 evaporated and the semisolid residue pumped (= 1 mm press e) for 0.5 h. The res;idue was dissolved by adding 6.6 mL (6.60 mmol), of 1 M NaOH solution then diluting with 15 mL of water.The solution was freeze dried to provide an off white solid. 20 The solid was purified by MPLC on a column of CHP20P gel (2.5 cm diam. X 15 cm height) eluting with water (150 mL) followed by a gradient created by the gradual addition of 400 mL of acetonitrile to a reservoir of 250 mL of water. Approximately 25 10 mL fractions were collected. The acetonitrile was removed under reduced pressure and the aqueous solution was lyophilized to provide 0.3 4 g (46.5%) of the title compound as a white lyophilane.

TLC Silic§. gel (5:4:1 n-propanol/conc. ammonia/water) Rf=0.75 .

IR (KBr) 3438, 2966, 2926, 2859, 1636, 1449, 1206, 1137, 1110, 976 cm"1.

- Ill - 28 0 HX59a " Mass Spec (FAB, + ions) m/e 475" (M+H), 453 (M-Na+2H).

Anal. Calc'd for Ci8H3o06Na3PS + 1.70 H20: C, 42.80; H, 6.67; P, 6.13; S, 6.35 Found: C, 42.80; H, 7.01; P, 6.24; S, 6.56.

Example IA (E, E)-6,10,14-Trimethyl-l-phosphono-5, 9,13 - pentadecatriene-1-sulfonic acid, trisodium salt A. Methanesulfonic acid, cvclohexvl ester To a stirred solution of 25.0 g (0.25 mol) 15 of cyclohexanol (purchased from the Aldrich Chemical Company and used without purification) and 27.3 g (0.27 mol) of triethylamine in 500 mL of ether at -15°C was added 28.6 g (0,.»25 mol) of methanesulfonyl chloride in 50 mL of ether dropwise 20 over 35 min. The reaction was warmed to 0°C and stirred for 1 h when the mixture was diluted water and washed with aqueous solutions of IN HCl and brine. The organics were dried (MgS04) and concentrated under reduced pressure to provide 43.0 25 g , 96% yield of title mesylate as a colorless oil. The mesylate was used without further purification. 2 ^ X" HX59a ' - 112 B. (Diethoxyphosphiny1)methanesulfonic acid, cvclohexvl ester ; To a rapidly stirred, nitrogen-purged [Note 1] solution of 24.4 g (137 mmol) of Part A 5 mesylate in 600 mL of THF under nitrogen at -78°C was added 55 mL (137.5 mmol, 2.5 M in hexanes) of n-butyl-lithium over 35 min. The temperature was not allowed to rise above -7 0°C [NOTE 2]. After an additional 10 min, 11.8 g (68.5 mmol) of freshly 10 distilled diethyl chlorophosphate was added to the resulting slightly turbid solution at a rate to keep the temperature below -70°C. The reaction mixture was stirred for 45 min and then a solution of 8.30 g (138 mmol) of glacial acetic acid in 25 15 mL of THF was added over 5 minutes. The reaction mass was warmed to room temperature and evaporated at 30°C at reduced pressure. The residue was partitioned between 250 mL of dichloromethane and 75 mL of water and extracted twice with 20 dichloromethane. The extracts were combined, dried over MgS04 and evaporated. The crude product was purified by flash chromatography [NOTE 3] (8 x 50 cm column, 2 L of dichloromethane, then 4 L of 11:89 ether/dichloromethane, then 2 L of 1:4 25 ether/dichloromethane) to give title compound as a colorless oil, 11.4 g, 53%.

TLC Silica gel, (11:89 ether/dichloromethane) Rf = 0.20.

NOTE 1. The reaction is run under a rapid nitrogen stream in an attempt to rigorously exclude oxygen from the system. 28 0 i-J/ *. '> hx59a NOTE 2. Efficient and rapid mechanical stirring is essential to prevent formation of the impurities sometimes seen in this reaction.

NOTE 3. In an independent experiment, a 15.5 g sample of crude material was chromatographed on 850 g of silica gel eluted with 20:80 isopropanol/hexane, collecting 50 mL fractions. 10 Fractions 61-85 were combined to provide 13.8 g (73 %) yield of pure triester.

C. (E,E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, cvclohexvl ester To a suspension of 0.57 g (23.7 mmol, 1.9 eq. ) of NaH in 50 mL of dry DMF at -20°C under argon was added 9.00 g (28.7 mmol, ,.*2.3 eq.) of Part B sulfonate over 15 min. to give a yellow solution. 20 The reaction was allowed to warm to room temperature and stir for 0.5 h when 4.4 8 g (12.4 6 mmol, 1 eq.) of Example 1 Part C iodide was added in one portion. The reaction mixture was stirred for 12 h when it was quenched with 100 mL of saturated NaCl 25 solution and diluted with 250 mL of ether. The layers were separated, the organics dried (Na2S04) and evaporated to provide a crude oil. Flash chromatography was performed on 500 g of silica gel eluting with 3:7 ethyl acetate/hexane to provide 30 5.20 g (7 6%) of title compound in the form of a pale yellow oil.

TLC Silica gel (1:1 ethyl acetate/hexanes) rf=0.60.

HX59a IR (film) 2934, 2861, 1449, 1352, 1260, 1173, 1053, 1024, 930 cm-1.

Mass Spec. (CI, + ions) m/e 564 (M+NH4), 547 (M+H), 5 482 (M+NH4-C6Hio) . 465 (M+H-C6Hi0).

D. (E,E)-6,10,14-Trimethyl-l-phosphono-5,9,13-pentadecatriene-l-sulfonic acid, trisodinm salt To a solution of 1.00 g (1.82 mmol) of Part C compound and 20 mL of methanol in a sealable tube at 0°C was added NH3 (g) until the solution was saturated. The tube was sealed and placed in an oil bath at 75°C for 16 h, at which point the tube 15 was opened and the volatiles removed under reduced pressure. The remainder was dissolved in dry toluene and evaporated two times (2 X 7.0 mL) leaving an amber oil. The oil was dissolved in 10 ml of dry methylene chloride and treated with 2.40 20 ml (9.0 mmol) of bis(trimethylsilyl)trifluoroacetamide (BSTFA) for 0.5 h, followed by 0.79 mL (6.0 mmol) of bromotrimethylsilane. The reaction mixture was stirred for 18 h when the solvent was evaporated and the residue pumped (= 0.5 mm 25 pressure) for 0.5 h. The remainder was dissolved by adding 50 ml (10 mmol) of 0.2 M NaOH solution and stirring vigorously for ten min. The soapy solution was freeze dried to provide a white solid. The solid was purified by MPLC on a column of 30 CHP20P gel (0.30 l) eluting with water (0.5 L) followed by isocratic elution with 15% acetonitrile in water. Approximately 25 mL fractions were collected. Pure fractions were pooled and the aqueous solution lyophilized to provide 0.80 g HX59a' (91%) of title salt as a white lyophilate. The lyophilate was diluted with 0.6-mL of water and the mixture mashed to a gummy white solid. The solid was repeatedly washed and mashed with acetone (3 X 5 4 mL) until a granular solid resulted. The granular solid was dried under vacuum for 10 h and collected to yield 0.75 g (85%) of title salt as a fine white powder.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) Rf=0.35.

IR (KBr) 3434, 2924, 2857, 1667, 1449, 1209, 1136, 1109, 976 cm-1. 1 j Mass Spec (FAB, + ions) m/e 497 (M+Na), 475 (M+H).

Anal. Calc'd for Ci8H30O6Na3PS + 0,81 H20: C, 44.20; H, 6.52; P, 6.33; S, 6.55 20 Found: C, 43.83; H, 6.93; P, 6.02; S, 6.69. example (E,E)-6,10,14-Trimethyl-1-phosphono-5,9,13-pc-ntadecatriene-l-sul f onic acid, tripotassium salt To a solution of 11.11 g (20.3 mmol) of Example IA, Part C compound and 120 mL of methanol in a sealable tube at 0°C was added NH3 (g) until the solution was saturated. The tube was sealed 30 and placed in an oil hath at 65°C for 24 h, at which point ths tut s opened and the volatiles removed under redu*". pressure. The remainder was dissolved in a 1:1 mixture of dry toluer>e/hexamothvl disilazane (HMDS) and evaporated HX59a two times (2 x 60 mL), leaving an amber oil. The oil was dissolved in 70 mL of dry methylene chloride and treated with 21. <1 mL (101.6 mmol) of HMDS for 0.5 h at RT. The mixture was then treated 5 with 16.0 mL (121.9 mmol) of bromotrimethylsilane. The reaction was allowed t.o stir at RT for 45 h when the solvent was evaporated and the residue pumped (=0.5 mm pressure, 35°C) for 0.5 h. The remainder was dissolved by adding 120 mL (120 mmol) 10 of 1 M KOH solution and stirring vigorously for ten min. The soapy solution was freeze dried to provide a white solid. The solid was purified by MPLC on a column of CHP20P gel (1 L ) eluting with water (2 L) followed by a stepwise gradient created 15 by the addition of: 1:9 acetonitrile/water (1.5 L) , 1.5:8.5 acetonitrile/water (1.5 L), 2:8 acetonitrile/water (1 L) and finally 2.5:7.5 acetonitrile/water (1 L). Approximately 50 mL fractions were collected. Fractions 52 to 83 were 20 pooled, the acetonitrile was removed under reduced pressure and the aqueous solution lyophilized to provide 8.11 g (78%) of title compound as a white lyophilate which was 98.5% pure by HPLC. The lyophilate was dissolved with 16 mL of water, and 25 40 mg (0.5 mol %) of Trolox was added. The product was precipitated with 16 mL acetone, and the precipitate was repeatedly washed (2 x 8 mL) and mashed with acetone until a solid resulted. The solid was dried under vacuum for 24 h and collected 30 to yield 7.58 g (72%) of title compound as a fine white powder.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) Rf=0.35.

HX59a IR (KBr) 3435, 2924, 2857, 1632,- 1449, 1204, 1140, 1109, 974 cm"1.

Mass Spec (FAB, + ions) m/e 561 (M+K), 523 (M+H), 485 (M-K+2H).

Anal. Calc'd for C3.8H30O6K3PS + 0.59 H2O: C, 40.53; H, 5.89; P, 5.81; S, 6.13 10 Found: C, 40.50; H, 6.20; P, 5.67; S, 5.91.

Example 2 (E) -6,10-Dimethyl-l-phosphono-5 , 9-undecadiene-I-sulfonic acid, trisodium salt The title compound was prepared as described herein and has the following properties.

* TLC Silica gel (5:4:1 n-propanol/conc. 20 ammonia/water) Rf=0.45.

IR (KBr) 3425, 2964, 2926, 2858, 1641, 1450, 1203, 1099, 1053, 974 cm-1.

Mass Spec (FAB, + ions) m/e 429 (M+Na), 407 (M+H), 385 (M-Na+2H).

Anal. Calc'd for Ci3H22C>6Na3PS + 1.58 H2O: C, 35.92; H, 5.83; P, 7.13; S, 7.38 30 Found: C, 35.92; H, 5.99; P, 7.24; S, 7.28 Example 3 a-Phosphono-[1,1'-biphenyl] -4-butanesulfonic acid, trisodium salt The title compound was prepared as described herein and has the following properties.

TLC Silica gel (5:4:1 n-propanol/conc. ammonia/water) Rf=0.45.

IR (KBr) 3433, 3029, 2931, 1636, 1487, 1450, 1202, 1094, 1053, 973 cm"1.

Mass Spec (FAB. + ions) m/e 459 (M+Na), 437 (M+H), 415 (M-Na+2H).

Anal. Calc'd for Ci6Hi606Na3PS + 2.00 H20: 15 C, 40.69; H, 4.27; P, 6.56; S, 6.79 Found: C, 40.90; H, 4.39; P, 6.43; S, 6.89.

Example 4 (E) -4-- U-Heptylphenyl) -l-phosphono-3-butene-1-20 sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3414, 2924, 2853, 1653, 1198, 1154, 1092, 972 cm"1.

Anal. Calc'd for C17H24K3O6PS•2.25 H2O: C, 37.45; H, 5.27; P, 5.68; S. 5.88 30 Found: C, 37.09; H, 5.43; P, 6.08; S, 6.12.

MS (FAB, + ions) m/e 543 (M+K), 505 (M+H). 423 (M-2K-3H). 0 Example 5 4-Heptyl-a-phosphonobenzenebutanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3434, 2926, 2855, 1649, 1460, 1200, 1084, 1049, 966 cm"1.

Anal. Calc'd for Ci7H26K306PS•0.75 H20: C, 39.25; H, 5.33; P, 5.95; S, 6.16 Found: C, 39.45; H, 5.72; P, 5.71; S, 5.83.

MS (FAB, + ions) m/e 545 (m+k), 507 (m+h), 469 (M-K+2H). example 6 (E)-4-(4'-Propyl[l,1'-biphenyl]-4-yl)-1-phosphono-20 3-butene-1-sulfonic acid, tripotassium salt A. (E)—(4'-propyl[1,1*-biphenyl]-4-yl)-2-propen-l-ol. acetate ester A(1). (E)-(4'-Propyl[1,1'-biphenyl]-4-yl)- 2-propenoic acid, n-butvl ester A stirred solution of 4.13 g (15 mmol) of 4-bromo-4'-n-propylbiphenyl, 106 mg (0.35 mmol) of • tri-p-tolylphosphine, 2.7 mL (19 mmol) of n-butyl 30 acrylate, 7.4 mL (30.8 mmol) of tributylamine and 10 mg (0.1 mmol) of hydroquinone was purged with a stream of nitrogen gas for 20 min at room temperature. To this mixture was added 4 mg (0.018 mmol) of palladium acetate. The reaction was 2«o; HX59a ' - 120 - kJ Co heated to 150 °C for 18 h under argon and then cooled to room temperature. The resulting slurry was diluted with ether, extracted twice with 50 mL of 1 M hydrochloric acid, once with brine and once 5 with saturated sodium bicarbonate solution. The organic phase was dried (MgSO*) and evaporated. The crude product (4.5 g) was purified by flash chromatography on silica gel (5 x 25 cm column) eluted with 1 L of hexanes and then 1:1 10 dichloromethane/hexanes to give 4.08 g (81%) of title ester as a colorless oil.

A(2). (E)-(4'-Propyl[1,1'-biphenyl]-4-yl)- 2-propen-l-ol. acetate ester To a stirred solution of 3.22 g (10.0 mmol) of Part A(l) ester in 50 mL of dichloromethane at 0 °C under nitrogen was added a solution of 22 mL (22 mmol, 1 M in hexanes) of diisobuty^aluminum hydride / over 5 min. The resulting pale yellow solution was 20 stirred for 2 h and then quenched with 2 mL of methanol. The solution was then treated with 150 mL of 1 M potassium sodium tartrate. A gel formed which dissolved within 5 min. The reaction mixture was extracted twice with ether. The extracts were 25 combined, dried (Na2SO^) and evaporated. The resulting oil (2.6 g) was dissolved in 25 mL of THF, cooled to 0°C under nitrogen and 4.6 mL (25 mmol) of diisopropylethylamine and 2.4 mL (25 mmol) of acetic anhydride was added. After 1 h, the 30 reaction mixture was diluted with ether, washed twice with 1 M hydrochloric acid once wtih brine and once with saturated sodium bicarbonate. The organic phase was dried (MgSO») and evaporated onto 10 g of silica gel. Purification by flash HX59a chromatography on silica gel (5 x 20 cm column) eluted with 9:11 dichloromethane:hexane to give title compound as a colorless oil, 2.21 g, 88% from Part A{1) ester.

B. (E) -1- (Diethoxyphosphinyl)-4- (4 ' -propylfl,1'-biphenyl]-4-yl)-3-butene-l- sulfonic acid, cvclohexvl ester To a stirred solution of 1.91 g (6.50 mmol) 10 of Part A compound, 2.5 mL (10 mmol, 1.5 equiv.) of bis(tri-methylsilyl)acetamide, 3.00 g (9.5 mmol, 1.46 equiv.) of Example IA, Part B sulfonate and 180 mg (0.7 mmol) of triphenylphosphine in 10 mL of THF under argon was added 400 mg (0.35 mmol) of 15 tetrakis(tri-phenylphosphine)palladium. The resulting mixture was heated to reflux for 1 hour. The reaction was cooled, evaporated, diluted with ether and washed once with 10% citric acid and thrice with water. The organic phase was dried 20 (MgS04) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column) eluted with 3:97 ether/dichloromethane gave title compound as a colorless oil, 2.3 2 g, 65% yield.

C. (E)-4-(4'-propyl[1,1'-biphenyl]-4-yl)- l-phosphono-3-butene-l-sulfonic acid, tripotassium salt To a stirred solution of 578 mg (1.05 mmol) of Part B compound in 5 mL of dichloromethane under 30 argon at room temperature was added 560 mL (2.1 mmol) of bis (trimethylsilyl)trifluoroacetamide and then 560 mL (4.2 mmol) of bromotrimethylsilane. After 72 h, the resulting clear solution was evaporated at 25°C and the residue dissolved in 5 280 HX59a " mL of THF. To this stirred solution was added 180 mg (1.1 mmol) of dried, finely ground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. The resulting slurry was heated to reflux for 20 h, 5 evaporated and then stirred for 1 h with 8 mL (4 mmol) of 0.5 M potassium hydroxide solution. The solution was lyophilized and then purified by MPLC (2.5x20 cm column of Mitsubishi Kasei Sepadbeads SP-207SS resin): 11.5 mL fractions, 7 mL/min flow 10 rate, eluted with 200 mL of water and then a . gradient prepared from 400 mL of water and 4 50 mL of 2:1 acetonitrile/water). Fractions 20-34 were collected and lyophilized to give title salt as a white solid, 505 mg, 85% yield.

IR (KBr pellet) 3422, 2959, 2930, 2870, 1653, 1497, 1202, 1080, 968 cm"1.

* Anal. Calc'd for Ci9H20K3O6PS•2.2 H2O: 20 C, 40.45; H, 4.36; P, 5.49; S, 5.68 Found: C, 40.11; H, 4.70; P, 5.18; S, 5.95.

MS (FAB, + ions) m/e 563 (M+K) , 525 (M+H) , 487 (M-K+2H) .

Example 7 a-Phosphono-4 ' -Propyl [1,1' -biphenyl] -4-butane-sulfonic acid, tripotassium salt A. a-(Diethoxyphosphinyl)-4'-propyl[1,1'- biphenyl]-4-butanesulfonic acid, cyclohexyl ester To a ni'-rogen-purged solution of 1.30 mg (2.37 mmol) of Example 6 Part B compound in 50 mL 28 HX59a' of ethyl acetate in a 500 mL one-neck round bottom flask was attached a hydrogen-filled rubber bladder of approximately 1 L capacity. The reaction mixture was vigorously stirred for 16 h, purged 5 with nitrogen, filtered through Celite and the filtrate evaporated. The oily residue was redissolved in dichlormethane, filtered through a 0.75 H (micron) filter and re-evaporated to give title compound as a colorless oil, 1.28 g, 98% 10 yield. The product was used without further purification.

B. a-Phosphono-4'-propyl[1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt 15 To a stirred solution of 1.14 g (2.06 mmol) of Part A compound in 10 mL of dichloromethane under argon at room temperature was added 1.10 mL (8.3 mmol) of bromotrimethylsilane. After 24 h, the resulting clear solution was evaporated at 25 20 °C and the residue dissolved in 10 mL of THF. To this stirred solution was added 340 mg (2.1 mmol) of dried, finely ground potassium iodide and 5 mg (0.02 mmol) of 18-crown-6. The resulting slurry was heated to reflux for 24 h, evaporated and then 25 stirred for 1 h with 8 mL (8 mmol) of 1.0 M potassium hydroxide solution. The solution was lyophilized and then purified by MPLC (2.5x20 cm column of Mitsubishi Kasei Sepadbeads SP207SS resin): 11.5 mL fractions, 7 mL/min flow rate, 30 eluted with 200 mL of water and then a gradient prepared from 400 mL of water and 450 mL of 1:1 acetonitrile/water). Fractions 27-31 were collected and lyophilized to give title compound as a white solid, 450 mg, 39% yield. 2502 IR (KBr pellet) 3432, 2957, 2930, 2870, 1636, 1499, 1198, 1080, 1049, 966 cm"1.

Anal. Calc'd for C19H22K3O6PS•1.9 H2O: C, 40.68; H, 4.64; P, 5.52; S, 5.72 Found: C, 40.69; H, 5.00; P, 5.46; S, 6.00.

MS (ion spray, + ions) m/e 495 (M-3K+4H+2CH3CN) , 10 492 (M-2K+3H+CH3CN), 489 (M-K+2H), 454 (M-3K+4H+CH3CN), 451 (M-2K+3H), 413 (M-3K+4H). example 8 4- (2-Phenylethoxy)-a-phosphonobenzenebutanesulfonic 15 acid, diootassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3434, 3088, 2936, 2868, 1636, 1512, 1198, 1076, 966 cm"1.

Anal. Calc'd for C18H21K2O7PS•3.75 H2O: C, 38.73; H, 5.15; P, 5.55, S, 5.74 25 Found: C, 38.73; H, 5.10; P, 5.24; S, 5.51.

MS (FAB, + ions) rn/e 567 (M+2K-H), 529 (M+K). <280 2 Example 9 6- (Hexyloxy) -cc-phcaphono-2-naphthalenebutane-sulfonic acid, diootassium salt A. 2-Bromo-6-(hexvloxv)naphthalene To a stirred solution of 4.46 g (20.0 mmol) of 6-bromo-2-naphthalenol (obtained from Aldrich Chemical Company (*B7,340-6) and used without purification), in 20 mL of DMF at room temperature 10 under argon was added 480 mg (20 mmol) of 95% sodium hydride over the course of 15 min. The resulting light yellow solution was stirred 30 min and 3.5 mL (22 mmol) of 1-bromohexane was added. The reaction was heated to 50°C and stirred for 60 15 min. The reaction was quenched with ice water, the resultings solids filtered, washed with water and dried in vacuo at 60°C. Purification of the residue by chromatography on silica gel (5 x 20 cm column, hexanes as elutant) gave 5.00 a. 81% yield, 20 of title compound as a colorless oil.

B. a-Ethenyl-6-(hexyloxy)-2-naphthalene- methanol To a stirred solution of 2.23 g (7.25 mmol) 25 of Part A compound in 25 mL of THF under argon at -78°C was added a solution of 8.5 mL (14.5 mmol) of 1.7 M t-butyllithium in pentane over 10 min. After 15 min, a yellow slurry had formed. This was warmed to 0°C and the resulting organic solution 30 was stirred for 30 min. To this reaction mixture was added 550 mL (9.5 mmol, 1.3 equivalents) of freshly distilled acrolein at a rate to keep the temperature below 5°C. After an additional 30 min, the reaction was quenched with saturated ammonium 280 218.

HX59a 126 - chloride solution, extracted twice with ether, dried (MgS04) and evaporated. Recrystallization from hexanes gave title compound as a white solid, mp 47-48°C, 1.83 g, 89%.

C. a-Ethenyl-6-(hexyloxy)-2-naphthalene- methanol. acetate ester To a solution of 1.43 g (5.0 mmol) of Part B compound and 1.1 mL (8 mmol) of triethylamine in 10 15 mL of CH2CI2 at room temperature under argon was added 0.7 mL (6.6 mmol) of acetic anhydride and 20 mg (0.16 mmol) of 4-dimethylaminopyridine. After 10 min, the reaction mixture was evaporated, diluted with ether, washed once with 10% citric 15 acid, once with water, once with saturated sodium bicarbonate solution, dried (MgS04) and evaporated to give title compound as a colorless oil, 1.54 g, / 94%. The compound was used without further purification for the subsequent reaction.

D. (E)-1-(Diethoxyphosphinyl)-4- [6-(hexyloxy)-2-naphthalenyl ] -3-butenesulfonic acid, cvclohexvl ester To a stirred solution of 1.47 g (4.5 mmol) of Part C compound, 1.55 mL (6.6 mmol, 1.5 equiv.) of bis (trimethylsilyl)acetamide, 1.85 g (5.85 mmol, 1.3 equiv.) of Example IA, Part B sulfonate and 125 mg (0.5 mmol) of triphenylphosphine in 10 mL of THF under argon was added 270 mg (0.24 mmol) of 30 tetrakis(triphenylphosphine)palladium. The resulting mixture was heated lo reflux for 1 hour. The reaction was cooled, evaporated, diluted with ether and washed once with 10% citric acid and thrice with water. The organic phase was dried 28QZ HX59a 127 - (MgS04) and evaporated. Purifica-tion by flash chromatography on silica gel (5 x 20 cm column) eluted with 1:24 ether/dichloromethane gave title compound as a colorless oil,1.06 g, 41% yield.

E. a-(Diethoxyphosphinyl) -6- (hexyloxy) -2-naphthalenebutanesulfonic acid, cyclohexyl ester To an argon-purged solution of 9 65 mg (1.66 mmol) of Part D compound and 100 mg of 10% palladium-on-carbon in 15 mL of ethyl acetate in a 500 mL one-neck round bottom flask was attached a hydrogen-filled rubber bladder of approximately 1 L capacity. The reaction mixture was vigorously 15 stirred for 16 h, purged with nitrogen, filtered through Celite and the filtrate evaporated. The oily residue was redissolved in dichlormethane, filtered through a 0.75 |i (micron)' filter and re- evaporated to give title compound as a colorless 20 oil, 950 mg, 98% yield. The product was used without further purification.

F. 6-(Hexyloxy)-a-phosphono-2- naphthalenebutanesulfonic acid, 25 dipotassium salt To a stirred solution of 885 mg (1.52 mmol) of Part E compound in 10 mL of dichloromethane under argon at room temperature was added 800 |J.L (8.9 mmol) of bromotrimethylsilane. After 18 h, Q the resulting clear solution was evaporated at 25 C and the residue dissolved in 15 mL of THF. To this stirred solution was added 320 mg (1.9 mmol) of dried, finely ground potassium iodide and 3 mg (0.01 mmol) of 18-crown-6. The resulting slurry 19 128 was heated to reflux for 24h, evaporated and then stirred for 1 h with 9 mL (4.5 mmol) of 0.5 M potassium hydroxide solution. The solution was lyophilized and then purified by MPLC (2.5x20 cm 5 column of Mitsubishi Kasei Sepadbeads CHP-20P resin): 11.5 mL fractions, 7 mL/min flow rate, eluted with 200 mL of water and then a gradient prepared from 400 mL of water and 450 mL of 1:1 acetonitrile/water). Fractions 44-52 were collected 10 and lyophilized to give title compound as a white solid, 475 mg, 53% yield.

IR (KBr pellet) 3434, 3057, 2932, 2861, 1653, 1605, 1181, 1076, 966 cm"1.

Anal. Calc'd for C20H27K2O7PS•3 . 81 H2O: C, 40.76; H, 5.92; p, 5.26; S, 5.44 Found: C, 40.76; H, 5.81; p, 5.^5; S, 5.35.

MS (FAB, + ions) m/e 559 (M+K), 521 (M+H). 4-[(5-Methyl-4-hexenyl)oxy]-a-phosphonobenzene-butanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3432, 2963, 2928, 2866, 1636, 30 1512, 1242, 1202, 1080, 966 cm"1.

Anal. Calc'd for C17H24K3O7PS•1.33 H2O: C, 37.49; H, 4.93; p, 5.69; S, 5.89 Found: C, 37.48; H, 5.28; p, 5.62; S, 5.64.

Example 10 MS (FAB. + ions) m/e 559 (M+K) ,- 521 (M+H), 483 (M-K+2H).

Example 11 1-Phosphono-l-pentadecanesulfonic acid, tripotas-sium salt A. (Diethoxyphosphinyl) methanesulfonic acid. 1-methvlethvl ester To a rapidly stirred solution of 8.28 g (60 mmol) of isopropyl methanesulfonate in 150 mL of THF at -73°C (internal temp.) was added 25 mL (60 mmol) of 2.4 M n-butyllithium dropwise over 20 min. 15 The internal temperature was not allowed to rise above -69°C throughout the course of the addition. After an additional 15 min., 5.17 g (30 mmol) of freshly distilled diethyl chlorophosphate was added at a rate to keep the solution temperature below 20 -69°C. The reaction mixture was stirred for 0.3 h at -73°C and for 0.5 h at -40°C when it was quenched with 125 mL of saturated NH4CI solution. The reaction mass was warmed to room temperature and the THF removed under reduced pressure. The 25 remainder was partitioned between methylene chloride and water (3 X 75 mL). The extracts were dried (Na2S04), concentrated, and purified by flash chromatography (350 g silica gel) eluting with 1:1 methylene chloride/ether to provide 5.20 g (67%) of 30 title compound as a colorless oil.

TLC Silica gel (1:1 methylene chloride/ether) Rf=0 .37. 280218 HX59a 130 - B. 1-(Diethoxyphosphinyl)pentadecane-sulfonic acid, 1-methvlethvl ester To a suspension of 0.10 g (4.38 mmol) of NaH in 7 mL of dry DMF at 0°C under argon was added 5 1.20 g (4.38 mmol) of Part A compound over 5 min. to give a yellow solution. The reaction was allowed to warm to room temperature and stir for 0.5 h when 0.55 g (2.00 mmol) of tetradecanyl bromide was added in one portion. The reaction 10 mixture was stirred for 24 h when it was quenched with 20 mL of saturated NaCl solution and diluted with 50 mL of ether. The layers were separated, the organics dried (Na2S04) and evaporated to provide a crude oil. Flash chromatography was 15 performed on 100 g of silica gel eluting with 3:7 ethyl acetate/hexane to provide 0.30 g (31 %) of title compound in the form of a pale yellow oil.

/ TLC Silica gel (1:1 ethyl acetate/hexanes) Rf=0.50.

IR (film) 2924, 2853, 1466, 1358, 1260, 1177, 105J, 1024, 930 cm"1.

Mass Spec (CI, + ions) m/e 488 (M+NH4), 471 (M+H), 25 347 (M+H-SO3C3H8).

C. l-phosphono-l-pentadecanesulfonic acid, tripor.assium salt To a stirred solution of 0.25 g (0.53 mmol) of Part 30 B corp'vund in 5 mL of dichloromethane at 0°C and in the dark was added 4.24 g (2.12 mmol) of iodotrimethylsilane. The reaction was allowed to stir for 16 h when the solvent was evaporated and the semisolid residue pumped (= 1 mm pressure) for 9 0.5 h. The residue was dissolved by adding 3 mL of 1 M (3.0 mmol) KOH solution and -freeze dried to provide an off white solid. The solid was purified by MPLC on a column of CHP20P gel (2.5 cm diam. X 5 15 cm height) eluting with water (100 mL) followed by a gradient created by the gradual addition of 400 mL of acetonitrile to a reservoir of 250 mL of water. Approximately 7 mL fractions were collected. The acetoriitrile was removed under 10 reduced pressure and the aqueous solution was lyophilized to provide 0.15 g (62%) of title salt as a white lyophilate.

TLC Silica gel (6:3:1 n-propanol/conc. 15 ammonia/water) Rf=0.40.

IR (KBr) 3443, 2920, 2851, 1653, 1468, 1215, 1163, 1045, 966 cm"1.

Mass Spec (FAB, + ions) m/e 525 (M+K), 487 (M+H).

Anal. Calc'd for C15H30O6K3PS + 2.19 H2O: C, 34.24; H, 6.59; P, 5.89; S, 6.09 Found: C, 34.03; H, 6.88; P, 5.57; S, 6.02.

Example 12 (E)-10,14-Dimethyl-l-phosphono-9,13-pentadecadiene-1-sulfonic acid, dipotassiurn salt A. Dichloro [fl-(1-hexanolato (2 -)-C6-.O1] ]- dimaanesium To a stirred solution of 11.00 g (80.0 mmol) of 6-chloro-l-propanol (Aldrich) in 20 mL of THF at -20°C was added 27.0 mL (81.0 mmol) of 3.0 M HX5 132 - 68021& methylmagnesium chloride in THF dropwire over 25 minutes. After 0.5 hours at -20°C, the reaction was allowed to warm to room temperature and 2.88 g (118.0 mmol) of magnesium turnings were added and 5 the reaction was heated to reflux. The reaction was initiated by adding a few crystals of iodine at the start of reflux and after 1 hour of heating. After 2 hours at reflux the reaction was cooled to room temperature providing the Grignard solution. 10 The molarity of the reaction mixture was determined by titration: 5.20 mL (2.60 mmol) of a 0.5 M solution of 2-propanol in benzene was slowly added to a blood red solution of 2-2'-biquinoline (indicator) in benzene and 2.0 mL of the freshly 15 prepared Grignard solution. The endpoint color was light green and the molarity was determined to be 1.3 M.

* / B. (E)-9,13-Dimethyl-8,12-tetradecadiene- A solution of 21.5 mL (28.0 mmol) of 1.3 M Part A Grignard reagent in THF and 5.0 mL of HMPA at 0°C was treated dropwise with 1.21 g (7.0 mmol) of geranyl chloride in 7 mL of THF over 7 minutes. 25 After the addition the reaction was allowed to warm to room temperature and stir for 2 hours, at which point the reaction was diluted with ether and quenched with 50 mL (50.0 mmol) of 1 M HCl solution. The organic layer was washed two times 30 with NH4CI solution, dried over MgSC>4 and evaporated to provide a crude oil. Flash chromatography was performed on 125 g of silica gel packed, loaded and eluted with 1:4 ethyl acetate/hexanes to 480 HX59a ' provide 1.10 (66%) of title alcohol as an amber oil.

TLC Silica gel (1:9 ethyl acetate:hexane) Rf=0.20.

IR (CCI4 solution) 3636, 2928, 2854, 1450, 1377, 1055 cm-1.

MS (CI, NH3, + ions) 256 (M+NH4).

C. (E)-9,13-Dimethyl-3 , 12-tetradecadien-l- vl iodide To a stirred solution of 1.10 g (4.62 mmol) of Part B alcohol and 1.40 mL (10.00 mmol) of 15 triethylamine in 10 mL of methylene chloride at 0°C was added 0.37 mL (4.80 mmol) of methanesulfonyl chloride dropwise over 15 minutes. After 1 hour at 0°C the reaction was diluted with e£her and washed / with aqueous solutions of NH4CI, NaHCC>3, and brine. 20 The organic layer was dried (MgSC>4) and concentrated under reduced pressure to provide 1.42 g (- 4.5 mmol> of the crude mesylate. The residual oil was dissolved in 25 mL of acetone and treated with 3.00 g (20.0 mmol) of Nal. The resulting 25 suspension was heated to reflux for 4 hours and diluted with ether, washed with brine, dried over MgS04, and concentrated to provide a yellow oil. Flash chromatography was performed on 100 g of silica gel packed, loaded and eluted with hexanes 30 to provide 1.10 g (68% overall yield) of title iodide in the form of a colorless oil.

TLC Silica gel (hexanes) Rf=0.45.

IR (CC14 solution) 2962, 2928, 2854, 1450, 1375, cm-1.

MS (CI, NH3l + ions) 366 (M+NH4), 348 (M).

D. (E)-a-(Diethyoxyphosphinyl)-10,14- dimethyl-9,13-pentadecadiene-1-sulfonic acid, cvclohexvl ester To a stirred suspension of 191 mg (4.77 10 mmol, 2 eq.) of sodium hydride (as a 60% mineral oil dispersion) in 2 mL of dry dimethylformamide (DMF) at 0 °C was added a solution of 1.50 g (4.77 mmol, 2 eq.) of Example IA Part B sulfonate in 3 mL of DMF dropwise over 7 min. The solution was 15 warmed to RT and stirred for 50 min. To the resulting clear yellow solution was added a solution of 831 mg (2.39 mmol, 1 eq.) of Part C iodide in 3 mL of dry DMF dropwis^«over 5 min. The reaction was stirred at RT for 16 h diluted with 20 ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ether (2 x 20 mL) and the combined organic layers were washed with brine, dried (MgS04), and concentrated to afford 1.77 g of a yellow oil. Flash chromatography was 25 performed on 300 g of silica gel eluting with 30% ethyl acetate in hexanes. Fractions (40 mL each) containing clean product by TLC were pooled and concentrated to afford, after high vac (0.25 mmHg) removal of solvent remnants, 7 82 mg (61%) of title 30 compound as a clear yellow oil.

TLC Silica gel (10% ether in CH2CI2): Rf 0.50. 0 HX5 135 - 280 216 E. (E)-10,14-Dimethyl-l-phosphono-9,13-pentadecadiene-l-sulfonie acid, dipotasium salt To a solution of 515 mg (0.96 mol, 1 eq.) of 5 Part D compound in 10 mL of methanol at 0°C was bubbled ammonia until the solution was saturated. The reaction tube was then sealed and heated at 7 5 °C for 16 h. The reaction mixture was allowed to cool to RT and then concentrated. The oily residue 10 was dried by coevaporation with toluene (2x). High vac (0.25 mmHg) removal of solvent remnants afforded 480 mg of light yellow oil.

To a solution of the yellow oil in 4 mL of dry dichloromethane at RT was added 636 jiL (4.81 15 mmol, 5 eq.) of 2,4,6-collidine all at once. To the resulting clear light yellow solution was added 890 HL (6.74 mmol, 7 eq.) of bromotrimethylsilane (TMSBr) dropwise over 3 min. As tie TMSBr was added a white precipitate formed and upon 20 completion of TMSBr addition, 1 mL of dichloromethane was added to the thick reaction mixture to facilitate stirring. After 17 h at RT the reaction was concentrated and the resulting semisolid was placed on high vac (0.25 mm Hg) for 1 h. The 25 residue was dissolved by adding 4.8 mL (5 eq.) of 1 M potassium hydroxide followed by 10 mL of water and lyophilized to afford an off-white lyophilate. The lyophilate was purified by MPLC on a column cf CHP20P (2.5 cm x 25 cm) eluting initially with 150 30 mL of water followed by a gradient formed by the gradual addition of 400 mL of 30% acetonitrile in water to a reservoir containing 400 mL of 10% acetonitrile in water. Fractions containing clean product by HPLC (Method 8) were pooled and 280 2 HX59a • concentrated. The semisolid residue was taken up in water, filtered, concentrated and finally triturated with acetone to afford, after high vac (0.025 mm Hg) removal of acetone remnants, 207 mg 5 (43%) of title salt in the form of a white solid.

TLC silica gel (5:4:1 n-propanol:ammonium hydroxide:water): Rf 0.39 IR (KBr) 3450(br), 2920, 2851, 1462, 1215, 1080, 1040 cm-1.

MS (FAB, + ions) m/z 473 (M + H), 511 (M + K) , 549 (M - H + K) .

Anal. Calc'd for C17H31O6PSK2 • 1.4 H2O: C, 41.01; H, 6.84; S, 6.44; P, 6.22 Found: C, 41.19; H, 6.52; S, 6.30; P. 5.95 / Example 13 (E,E)-6,10,14-Trimethyl-l-phosphono-5,9,13-pentade-catriene-l-sulfonic acid, phenyl ester, dipotassium salt The title compound was prepared as described herein and has the following properties.

TLC Silica gel (7:2:1 n-propanol:ammonium hydroxide:water): Rf 0.38.

IR (KBr): 3410 (br), 2965, 2924, 1636, 1487, 1339, 1194, 1148, 1098 cm"1.

MS (fab, + ions): m/z 523 HX59a t$0111 (M - K + 2H)+, 561 (M + H)+, 599 (M + K)+.

Anal. Calc'd for C24H35O6PSK2 • 0.84 H2O: C, 50.05; H, 6.42; P, 5.38; S, 5.72 Found: C. 50.05; H, 6.74; P, 5.11; S, 5.45 Example 14 (E, E) -9,13,17-Trimethyl-l-phosphono-8,12,16-octade-catriene-1-sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC Silica gel (6:3:1 n-propanol/NH4OH/H2O): 15 Rf = 0.21 IR (KBr) 2924, 2855, 1624. 1449, 1383, 1213, 1148, 1092, 1044, 966, 714 cm"1.

MS (FAB, + ions) m/z 527 (M+2H-K), 565 (M+H), 603 (M+K) .

Anal. Calc'd for C21H36K3O6PS • 1.0 equiv H2O: C, 43.27; H, 6.57; P, 5.31; S, 5.50. 25 Found: C, 42.93; H, 6.93; P, 5.03; S, 5.87.

Example 15 (E, E) -1- (Ethoxyhydroxyphosphiny1)-6,10,14-trimeth-yl-5,9,13-pentadecatriene-l-sulfonic acid, dipotas-30 sium salt To a solution of 0.44 g (0.80 mmol) of Example lA Part C compound and 10 mL of methanol in a sealable tube at 0°C was added NH3 (g) until the fj$02.. solution was saturated. The tube was sealed and placed in an oil bath at 70°C for 24 h, at which point the tube was opened and the volatiles removed under reduced pressure. The remainder was 5 dissolved in dry ethanol and evaporated two times (2 X 10 mL) leaving an amber oil. The oil was dissolved in 4.0 mL of a 1:1 ethanol/water solution and treated with 0.45 g (8.00 mmol) of potassium hydroxide. The mixture was heated to 80°C for 72 h 10 when the solvent was evaporated and the residue pumped (= 0.5 mm pressure) for 0.5 h. The remainder was purified by MPLC on a column of CHP20P gel (2.5 cm diam. X 20 cm height) eluting with water (150 mL) followed by a gradient created 15 by the gradual addition of 400 mL of acetonitrile to a reservoir of 3 50 mL of water. Approximately 7 mL fractions were collected. Pure fractions were combined and the acetonitrile was removed under /• reduced pressure. The aqueous solution was 20 lyophilized to provide 0.30 g (74%) of title salt as a white lyophilate.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) Rf=0.55.

IR (KBr) 3459, 3052, 2969, 2926, 2859, 1636, 1445, 1383, 1221, 1105, 1190, 1055. 1038, 945 cm"1.

Mass Spec (FAB, + ions) m/e 551 (M+K), 513 (M+H).

Anal. Calc'd for C20H35O6K2PS: C, 46.85; H, 6.88; P, 6.04; S, 6.25 Found: C, 46.76; H, 6.89; P, 5.67; S, 6.60. 139 2ffff example 16 (E) -8,12-Dirnethy 1 -1 -phosphono-7,11 -tridecadiene-1 -sulfonic acid, diootassium salt herein and has the following properties.

TLC silica gel (5:4:1 n-propanol:ammonium hydroxide:water) : Rf 0.39 IR (KBr): 3450(br), 2924, 2855, 1653, 1447, 1209, 1148, 1044 cm~l.

MS (FAB, + ions): m/z 445 (M+H), 483 (M + K), 15 521 (M - H + 2K) .

Anal. Calc'd for C15H27O6PSK2 • 3.2 H2O: C, 35.87; H, 6.70; S, 6..38; P, 6.17 Found: C, 35.91; H, 6.30; S, 6.11; P, 6.10 The title compound was prepared as described 2B0 2 Example 3,7 a-Phosphono[1,1'-biphenyl]-4-heptanesulfonic acid, tripotassium salt A. 4-(6-Iodohexvl) f1.11-biohenvl1 A (1) . 6-{[1,1'-Biphenyl]-4-yl)-6- hexvn-l-ol To suspension of 0.3 61 g (2.04 mmol, 0.02 10 eq) of palladium chloride and 1.07 g (4.08 mmol, 0.04 eq) of triphenylphosphine in 3 00 mL of diethylamine at room temperature was added 2 6.1 g (112 mmol, 1.1 eq) of 4-bromobiphenyl ( from Aldrich) followed by 0.7 66 g (4.08 mmol, 0.04 eq) 15 of copper (I) iodide (99.999% pure, from Aldrich). After 5 min, 10.0 g (102 mmol, 1.0 eq) of 5-hexyn-l-ol (from Aldrich) was added neat. After 43 h, the reaction was concentrated and the residue was partitioned between water (250 mL) and CH^Clo (2 50 20 mL). The aqueous solution was extracted with CH2CI2 and the combined organic solutions were concentrated. To remove the catalyst the residue was filtered through silica gel (40 g) eluting initially with CH2CI2 ,then with CH^Cl? containing 2% 25 EtOAc. Concentration afforded 31.9 g of a brownish orange solid which was chromatographed on silica gel (400 g) eluting with 2% EtOAc in CH^Clo (4 L)', then 4% EtOAc in CH2C1; (2 L) . The isolated solid was then recrystallized from chloroform/hexanes to 30 afford 16.2 g (64%) of the title compound as a white solid; m.p. 64.0-64.5°C.

TLC Silica gel (25% EtOAc in hexanes): Rf 0.14. hx59 £80218 A(2). f1.1'-Biphenvll-4-hexanol To a solution of 9.0 g (36 mmol, 1 eq) of Part A(1) alcohol in 100 mL of THF was added 300 mg (0.36 mmol, 0.01 eq) of 10% palladium on activated 5 carbon. The resulting heterogeneous mixture was placed under an H2 atmosphere at RT . After 67 h, the reaction was filtered through Celite and the filter cake was washed with Et20 and CH2C1;. Concentration afforded 9.07 g (99%) of the title 10 compound as a fluffy white solid; m.p. 77.0-77.5°C TLC Silica gel (25% EtOAc in hexanes): Rr 0.19.

A(3). 4- (6-1odohexv1) fl.1'-biohenvll To a solution of 7.00 g (28 mmol, 1.0 eq) of Part A(2) biphenylhexanol in 30 mL of dry THF were added 8.66 g (33 nunol, 1.2 eq) of triphenylphosphine and 4.50 g (66 mmol, 2.4,,*eq) of imidazole. To the resulting homogeneous solution 20 was added dropwise a solution of 8.38 g (33 mmol, 2.4 eq) of iodine in 40 mL of dry THF over 25 min. After 45 min, the reaction was diluted with Et20 and washed with 10% aqueous sodium bisulfite, brine and dried (MgS04) . The solution was filtered and 25 the volume was reduced approximately by 50%.

Silica gel (35 g) was added and the remainder of the solvent was removed. The product adsorbed onto silica gel was loaded onto a pre-equilibrated column (hexanes) of silica gel (20 g) and eluted 30 with hexanes. Fractions containing clean product were pooled and concentrated to afford 9.40 g (94%) of the title compound as a clear, colorless oil.

TLC Silica gel (25% EtOAc in hexanes): R, 0.69.

HX59280 218 B. Methanesulfonic acid,- phenyl ester To a solution of 40.0 g (0.42 mol, 1 eq.) of phenol in 250 mL of dichloromethane at 0°C was 5 added 250 mL (1.8 mol, 4.2 eq.) of triethylamine. After 5 min, 49.3 mL (0.64 mol, 1.5 eq.) of methanesulfonyl chloride was added dropwise over 20 min. The resulting cloudy yellow solution was warmed to RT and stirred for 14 h. The reaction 10 was partitioned between ether (2 50 mL) and water (100 mL) and the resulting organic layer was washed with cold 6 N hydrochloric acid (2 x 200 mL) . The combined aqueous layers were extracted with ether (2 x 50 mL) and the combined organic layers were 15 washed with water (100 mL) , saturated sodium bicarbonate (200 mL), brine (200 mL) , dried (MgS04) and concentrated. Recrystallization of the orange solid from isopropanol afforded 44»94 g (61%) of the title compound as light yellow crystals? mp 20 58.0-58.5°C.

TLC Silica gel (25% ethyl acetate in hexanes) : Rf 0.29.

C. (Diethoxyphosphinyl)methanesulfonic • acid, phenyl ester To a turbid solution of 174 mL (0.174 mol, 1 eq.) of potassium bis(trimethylsilyl)amide (20% by weight in tetrahydrofuran (THF) from Callory Chem.) 30 at -88°C (internal temperature) was added a solution of 30.0 g (0.174 mol, 1 eq.) of Part B compound in 75 mL of dry THF at a rate to keep the internal temperature below ~85°C (addition took 20 min) . The reaction was stirred for 5 min at -85 °C tmiw then 15.2 mL (104 mmol, 0.6 eq.) of freshly distilled diethylchlorophosphate- was added dropwise at a rate that kept the temperature below -72°C (addition took 13 min). After stirring at -65°C 5 for lh, the reaction was quenched at -65°C by the addition of a solution of 9.97 mL (0.174 mol, 1 eq. ) of acetic acid in 25 mL of THF over 5 min. The resulting solution was warmed to RT and the majority of the solvent was removed in vacuo. The 10 residue was partitioned between dichloromethane (300 mL) and water (1G0 mL). The aqueous layer was extracted with dichloromethane (2 x 20 mL) and the combined organic layers were dried (MgS04) and concentrated to afford 43.82 g of solid/liquid 15 mixture. The product was isolated by flash chromatography on silica gel (1000 g) eluting with 7 : 3 ethyl acetate : hexanes. Fractions (40 mL each) containing clean product by T1LC were pooled to afford 17.19 g (54%) of title compound as a 20 white solid; m.p. 50.5-51.5°C.

TLC Silica gel (10% ether in dichloromethane): Rf 0.38.

D. a-(Diethoxyphosphinyl)[1,1'-biphen- vl 1 — 4 — heptanesii 1 fonic acid, phenyl ester To a stirred suspension of 329 mg (8.23 mmol, 2 eq.) of sodium hydride (as a 60% mineral oil dispersion) in 3 mL of dry dimethylformamide 30 (DMF) at 0°C was added a solution of 2.54 g (8.23 mmol, 2 eq.) of Part C compound in 6 mL of DMF dropwise over 10 min. The solution was warmed to RT and stirred for 30 min. To the resulting clear yellow solution was added a solution of 1.50 g (4.12 mmol, 1 eq.) of Part A iodide in 6 mL of dry DMF dropwise over 5 min. The reaction was stirred at RT for 43 h, diluted with ether (200 mL) and washed with water (100 mL) . The aqueous layer was 5 extracted with ether (2 x 25 mL) and the combined organic layers were washed with brine, dried (MgS04), and concentrated to afford 3.36 g of a yellow oil. Flash chromatography was performed on 400 g of silica gel eluting with 40% ethyl acetate 10 in hexanes. Fractions (40 mL each) containing clean product by TLC were pooled and concentrated to afford, after high vac (0.25 mmHg) removal of solvent remnants, 1.06 g of a clear yellow oil, as well as 742 mg of the desired product contaminated 15 with dialkylated material. The contaminated material was rechromatographed on 200 g of silica gel and the clean product was combined with the previously isolated product to afford 1.375 g (61%) of title compound as a clear light yellow oil.

TLC Silica gel (10% ether in CH2CI2): Rf 0.57.

E. a-Phosphono[1,1'-biphenyl]-4-heptane- sulfonic acid, tripotassium salt To a solution of 600 mg (1.1 mmol, 1 eq. ) of Part D compound in 5 ml of dioxane at rt was added 1.1 mL (1.1 mmol, 1 eq.) of 1 M potassium hydroxide. The initially turbid solution became homogeneous within 2 h. After 19 h, starting 30 material was still evident by tlc as well as a lower Rf spot (presumably due to over hydrolysis) . An additional 1.1 mL (1.1 mmol, 1 eq. ) of KOH was added and reaction was stirred for 16 h (35 h total) at RT. The reaction mixture was HX59a„" ^ 880 concentrated ard the residual yellow oil was co-evaporated with toluene (4x) to "remove water and placed on high vac (0.25 mmHg) for 2 h to afford a yellow solid.

To a heterogeneous solution of the yellow solid in 5 mL of dry dichloromethane at RT was added 1.45 mL (11.0 mmol, 10 eq.) of bromotrimethylsilane (TMSBr) dropwise over 3 min. As the TMSBr was added the solution began to clear and 10 upon completion of TMSBr addition the reaction was nearly homogeneous. After 17 h, an additional 750 J1L (5.7 mmol, 5.1 eq.) of TMSBr was added to complete consumption of the intermediate monoester. After 22 h (39 h total) at RT, the reaction was 15 concentrated and the resulting oil was placed on high vac (0.25 mm Hg) for 13 h. The residue was dissolved by adding 4.4 mL (4.4 mmol, 4 eq.) of 1 M potassium hydroxide followed by 2Q*mL of water and sonicating at 40°C for 10 min. The crude product 20 was purified by MPLC on a column of CHP20P (2.5 cm x 25 cm) eluting initially with 150 mL of water followed by a gradient formed by the gradual addition of 400 mL of acetonitrile in water to a reservoir containing 400 mL of water. Fractions 25 containing clean product were pooled and concentrated. The semisolid residue was taken up in water, filtered and lyophilized to afford 243 mg (39%) of a white lyophilate.

TLC silica gel (5:4:1 n-propanol: ammonium hydroxide:water): Rf 0.38.

IR (KBr): 3403(br), 2928, 2857, 1651, 1202, 1163, 1072 cm"1.

HX59a '' 146 - MS (FAB): m/z 489 (M - K + 2HT) +, 527 (M + H) + .

Anal. Calcd for C19H22O6PSK3 • 2.31 H2O: 5 C, 40.15; H, 4.72; S, 5.64; P. 5.45 Found: C, 40.15; H, 4.89; S, 5.60; P, 5.47 Example 18 (E)-4-(4'-Pentyl[1,1'-biphenyl]-4-yl)-1-phosphono-10 3-butene-1-sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3430, 2928, 2855, 1636, 1497, 1202. 1078, 968 cm-1.

Anal. Calc'd for C21H24K3O6PS•2.2 ^20: C, 42.58; H, 4.83; P, 5.23; S, 5.41 20 Found: C, 42.18; H, 5.19; P, 5.63; S, 5.42.

MS (FAB, + ions) m/e 591 (M+K), 553 (M+H), 515 (M-K+2H).

Example 19 a-Phosphono-4'-Pentyl[l,1'-biphenyl]-4-butanesul-fonic acid, tripotassium salt The title compound was prepared as 30 described herein and has the following properties.

IR (KBr pellet) 3424, 3088, 2928, 2859, 1663, 1499, 1202, 1082, 1049, 966 cm"1.

HX59a" Anal. Calc'd for C21H26K3O6PS • 1. 42 H2O: ^^0 2^ C, 43.46; H, 5.01; P, 5.34; S, 5.52 Found: C, 43.46; H, 4.93; P, 5.37; S, 5.25.

MS (FAB, + ions) m/e 593 (M+K) , 555 (M+H) , 517(M-K+2H).

Example 20 4- (2-Naphthalenyl) -a-phosphonobenzenebutanesul-10 fonic acid, tripotassium salt A. 2-(4-Bromophenvl)naphthalene To a stirred solution of 4.14 g (20.0 mmol) of 2-bromonaphthalene in 50 mL of THF at -7 8°C 15 under nitrogen was added a solution of 23.5 mL (40.0 mmol, 1.7 Jg in pentane) of t-butyllithium over 10 minutes. The resulting slurry was stirred for 30 minutes and then warmed to.'0°C for 15 minutes. To this deep indigo solution was added a 20 solution of 3.50 g (25.6 mmol) of thrice-fused zinc chloride in 25 mL of THF. The resulting light yellow solution was warmed to room temperature and stirred for 1 hour. After cooling to -78°C, a solution of 5.66 g (20.0 mmol) l-bromo-4-25 iodobenzene and 300 mg (0.26 mmol) of tetrakis- (triphenylphosphine)palladium in 20 mL of THF was added over the course of 15 minutes. After an additional 20 min, the cooling bath was removed, the reaction stirred at room temperature for 16 30 hours and then quenched with 50 mL of 2 M hydrochloric acid. The mixture was extracted thrice with ether, the extracts combined, washed once with saturated sodium bicarbonate solution and once with 10% sodium thiosulfate. The organic HX59a £ftO extract was dried (MgS04) and evaporated. The crude product was purified by flash chromatography on silica gel (5 x 2 5 cm column, hexanes as elutent) to give 4.05 g (72%) of title compound as 5 a white solid, nip 121-123°C.

B. a-Ethenyl-4-(2-naphthalenyl)benzene- methanol. acetate ester To a stirred solution of 2.59 g (9.13 mmol) 10 of Part A compound in 20 mL of THF at -7 8 oC under nitrogen was added a solution of 10.8 mL (18.4 mmol, 1.7 M in pentane) of t-butyllithium over 20 minutes. The resulting magenta slurry was warmed to 0°C and stirred for 1 h. To the resulting 15 solution was added 0.8 mL (14 mmol) of freshly distiiled acrolein over 5 min. The resulting light yellow solution was stirred for 1 hour and then quenched with saturated ammonium cfrloride. The mixture was extracted twice with ether, dried 20 (MgSC>4) and evaporated to give a white solid.

The solid was dissolved in 50 mL of dichloromethane, stirred under nitrogen at room temperature and treated with 2.0 mL (14.4 mmol) of triethylamine, 1,23 mL (13 mmol) of acetic 25 anhydride and 50 mg (0.4 mmol) of DMAP. After 16 h, the reaction mixture was evaporated, redissolved in ether and washed once with 10% citric acid solution, once with brine and once with saturated sodium bicarbonate solution. The organic phase was 30 dried (MgS04) and evaporated. The crude product was purified by flasli chromatography on silica gel (5 x 20 cm column, 1:1 dichloromethane/hexanes as elutent) to give 1.83 g (66% from Part A compound) o of title compound as a white solid, mp 61-63 C.

HX59a C. (E)-1-(Diethoxyphosphinyl)-4- [4-(2-naphthaleny1) phenyl ] - 3 -butene -1 - sul fonic acrid. 1 -methvlethvl ester To a stirred solution of 1.55 g (5.13 mmol) of Part B "ompound, 2.75 mL (12.9 mmol, 2.5 equivalents) of bis(trimethylsilyl)acetamide, 2.81 g (10.2 mmol, 2.0 equivalents) of Example 11, Part A sulfonate and 125 mg (0.48 mmol) of triphenyl-10 phosphine in 10 mL of THF under- nitrogen was added 270 mg (0.24 mmol) of tetrakis(triphenylphosphine) -palladium. The resulting mixture was heated to 45°C for 2 h. The reaction was cooled and evaporated and pumped at room temperature @ 0.2 15 Torr for 24 hours. The residue was diluted with dichloromethane and evaporated onto 5 g of silica gel. Purification by flash chromatography on silica gel (5 x 20 cm column) eluteti with 1:16 ether/dichloromethane gave title compound as a 20 yellow oil, 950 mg, 36% yield.

D. a-(Diethoxyphosphinyl) -4-(2-naphthalenyl) benzenebutanesulfonic acid, 1-methvlethvl ester To a nitrogen-purged solution of 950 mg (1.85 mmol) of Part C compound and 350 mg of 10% Pd/C in 25 mL of ethyl acetate in a 200 mL one-neck round bottom flask was attached a hydrogen-filled rubber bladder of approximately 1 L capacity. The 30 reaction mixture was vigorously stirred for 16 h, purged with nitrogen, filtered through Celite and the filtrate evaporated. The oily residue was redissolved in dichlormethane, filtered through a 0.75 m filter and re-evaporated to give title HX59a * compound as a colorless oil, 960 mg, 100% yield. The product was used without further purification.

E. 4-(2-Naphthalenyl)-a-phosphonobenzene- butanesulfonic acid, tripotassium salt To a stirred solution of 950 mg (1.81 mmol) of Part D compound in 10 mL of dichloromethane under nitrogen at room temperature was added 1.4 mL (10.5 mmol) of bromotrimethylsilane. After 24 h, 10 the resulting clear solution was evaporated at 2 5°C and the residue dissolved in 10 mL of THF. To this stirred solution was added 0.5 g (3 mmol) of dried, finely ground potassium iodide and 6 mg (0.02 mmol) of 18-crown-6. The resulting slurry was heated to 15 reflux for 20 h, evaporated and then stirred for 1 h with 12 mL (6 mmol) of 0.5 M potassium hydroxide solution. The solution was lyophilized and then purified by MPLC (2.5x20 cm column,.of CHP20P resin): 11.5 mL fractions, 7 mL/min flow rate, 20 eluted with 200 mL of water and then a gradient prepared from 400 mL of water and 450 mL of 2:1 acetonitrile/water). Fractions 66-72 were collected and lyophilized to give title salt as a white solid, 560 mg, 55% yield.

IR (KBr pellet) 3418, 3055, 2934, 2864, 1661, 1503, 1339, 1196, 1078, 966 cm"1.

MS (FAB, + ions) m/e 573 (M+K), 535 (M+H), 497 30 (M-K+2H) .

Anal. Calc'd for C20H18K3PSO6•1.3H20: C, 43.04; H, 3.72; P, 5.55; S, 5.74 Found: C, 43.04; H, 3.86; P, 5.79; S, 6.09.

Example 21 ' 4-Phenoxy-a-phosphonobenzenebutanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC (silica gel) (6:3:1 /3-propanol/NH40H/H20) : 10 Rf = 0.15 IR (KBr) 3042, 2936, 2864, 1663, 1589, 1507, 1489, 1240, 1198, 1076, 966 cm-1.

MS (FAB, + ions) m/z 463 (M+2H-K), 501 (M+H), 539 (M+K).

Anal. Calc'd for C16H16K3O7PS • 1..Q equiv H2O: C, 37.05; H, 3.50; P, 5.97; S, 6.18. 20 Found: C. 36.77; H, 3.86; P, 6.42; S, 6.48. l-Phosphono-7-(4-propylphenoxy)-1-heptanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC (silica gel) (6:3:1 n-propanol/NH40H/H20): 30 Rf = 0.21 IR (KBr) 2932, 2868, 1636, 1512, 1200, 1074, 966 cm_;I .

HX59a ms (FAB, + ions) m/z 509 (m+h), 547 (M+K) H v Anal. Calc'd for c16h24k3o7ps • 1.6 equiv h2o: C, 35.75; H, 5.10; P, 5.76; S, 5.97. 5 Found: C, 35.79; H, 5.49; P, 5.54; S, 5.95.

Example 23 a-Phosphono-4- (4-propylphenoxy) benzenebutanesul-fonic acid, tripotassium salt A. 4 -(4-Propvlphenoxv)benzaldehvde Anhydrous potassium carbonate (14.9 g, 0.12 mol) was added to a mixture of 4-propylphenol (13.6 g, 0.10 mol) and 4-fluorobenzaldehyde (12.4 g, 0.10 mol) in N,N-dimethylacetamide (100 mL) under argon.

The heterogeneous mixture was brought to reflux, maintained at that temperature for 5 h, then cooled to RT. Water (100 mL) and QH2CI2 (100 mL) /* were added, resulting in a tri-phase system. The 20 bottom layer was removed; the middle layer was dried over MgS04; and, the top layer was extracted with CH2CI2 (100 mL) and dried over MgS04. The dried layers were combined and concentrated in vacuo at 50 °C to give an orange oil. The crude 25 product was purified by distillation to give title compound (16.6 g, 69%) as a colorless oil. bp 133-150°C (0.2 mm Hg) B. a-Ethenyl-4-(4-propylphenoxy)benzene-30 methanol, acetate ester A solution of Part A compound (2.00 g, 8.33 mmol) in thf (15 mL) was added dropwise over 10 min to a solution of vinylmagnesium bromide (9.2 mL, 1.0M in thf, 9.2 mmol) in thf (15 mL) at -40°C 218 2a0 HX59a under argon. The reaction was warmed to -20°C over 30 min, whereupon the heterogeneous mixture went to clear yellow. Additional vinylmagnesium bromide (1.5 mL, 1.0M in THF, 1.5 mmol) was added dropwise.

The reaction was stirred at -20°C for 10 min, then quenched by addition of saturated NH4CI (10 mL). The solvent was removed in vacuo, and the mixture was diluted with diethyl ether (50 mL). The organic layer was washed with water (10 mL), IN HCl 10 (10 mL), and brine (20 mL), then dried over MgS04. Evaporation gave the alcohol (2.6 g) as a yellow oil.

Acetic anhydride (0.94 mL, 10.0 mmol), triethylamine (2.3 mL, 16.7 mmol), and 4-dimethyl-15 aminopyridine (10 mg, 0.08 mmol) were added to a solution of the crude alcohol in CH2CI2 (30 mL) under argon. The yellow reaction was stirred at RT for 2.5 h, diluted with CH2CI2 (50-*mL), and washed with water and brine (20 mL each), then dried over 20 MgS04. Evaporation gave a heterogeneous yellow oil, which was purified by flash chromatography on silica gel (150 g) eluted with 3:97 EtOAc/hexane to give title compound (1.85 g, 72%) as a pale yellow oil.

C. (E) -1-(Diethoxyphosphinyl)-4-[4-(4-propylphenoxy)phenyl]-3-butene-l-sulfonic acid. 1-methvlethvl ester Tetrakis(triphenylphosphine)palladium (196 30 mg, 0.17 mmol) was added to a mixture of Part B compound (1.74 g, 5.61 mmol). Example 11, Part A compound (3.07 g, 11.2 mmol), bis(trimethylsilyl)-acetamide (2.8 mL, 11 mmol), and triphenylphosphine (73 mg, 0.28 mmol) in THF (20 mL).. The reaction HX59a " - 154 - - w - t • 2fl021ff was heated at 45°C for 3 h, cooled to RT, and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography on silica gel (200 g) eluted with a step gradient 5 of 30:70 EtOAc/hexane to 40:60 EtOAc/hexane to afford title compound (706 mg, 24%) as a colorless oil.

D. 1-(Diethoxyphosphinyl)-4-(4-propyl-10 phenoxy)benzenebutanesulfonic acid, 1- methvlethvl ester A mixture of Part C compound (700 mg, 1.34 mmol) and 10% palladium on carbon (40 mg) in EtOAc (5 mL) was stirred at RT under an atmosphere of H2 15 (balloon) overnight, then was filtered through a pad of Celite with the aid of CH2C12- Evaporation gave title compound (669 mg, 95%) as a colorless oil. s' E. a-Phosphono-4-(4-propylphenoxy)benzene- butanesulfonic acid, tripotassium salt Ammonia gas was bubbled through a solution of Part D compound (610 mg, 1.16 mmol) in methanol (10 mL) for 10 min at RT. During the saturation, 25 the solution turned yellow and became slightly exothermic. The reaction mixture was heated at 75°C in a sealed tube overnight (20 h), then cooled to RT. The reaction was concentrated in vacuo, and the residue was azeotroped with toluene (2 x 10 mL) 30 to give a pale yellow oil.

The crude product prepared above was dissolved in CH2CI2 (6 mL) under argon and bromotrimethylsilane (1.1 mL, 8.1 mmol) was added dropwise. The cloudy yellow reaction was stirred HX59a 155 - 2fl0 21i ¥1 ___ r at RT overnight (19 h) , concentrated in vacuo, and pumped at high vacuum for 3 h.

The crude residue prepared above was dissolved in IN KOH (5.8 mL, 5.8 mmol) and stirred 5 at RT for 15 min, diluted with water (5 mL), then lyophilized to give a white solid. Purification was performed by chromatography on CHP20P gel (2.5 x 20 cm column) eluted with water followed by a gradient created by the gradual addition of 10 acetonitrile to a reservoir of water. The product fractions were concentrated to approximately a 5 mL volume, then lyophilized to provide title salt (445 mg, 71%) as a white solid.

TLC (silica gel) (6:3:1 n-propanol/NH4OH/H2O): Rf = 0.18 IR (KBr) 2959, 2870, 1503, 1240, 1200, 1078, 966 cm"-'-.

MS (FAB, + ions) m/z 543 (M+H), 581 (M+K).

Anal. Calc'd for C19H22K3O7PS • 2.0 equiv H2O: C, 39.43; H, 4.53; P, 5.35; S, 5.54. 25 Found: C, 39.63; H, 4.70; P, 5.18; S, 5.50.

Example 24 (E, E) -1-(Diethoxyphosphinyl)-6,10,14-trimethyl-5.9.13-pentadecatriene-l-sulfonic acid, sodium salt To a solution of 0.50 g (0.91 mmol) of Example lA Part C compound and 10 mL of methanol in a sealable tube at 0°C was added NH3 (g) until the solution was saturated. The tube was sealed and HX§9a ' <y f>' it 4 v ■•) placed in an oil bath at 70°C for 24 h, at which point the tube was opened and th£ volatiles removed under reduced pressure. The remainder was dissolved with 1.20 mL (1.20 mmol) of 1 N sodium 5 hydroxide solution. The compound was purified by MPLC by loading the basic solution on a column of CHP20P gel (2.5 cm diam. X 20 cm height) and eluting with water (150 mL) followed by a gradient created by the gradual addition of 400 mL of 10 acetonitrile to a reservoir of 3 50 mL of water.

Approximately 7 mL fractions were collected. Pure fractions (#30-34) were combined and the acetonitrile was removed under reduced pressure. The aqueous solution was lyophilized to provide 15 0.39 g (87%) of title sale as an amber oil.

TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) Rf=0.80. ,♦ IR (CHCI3) 3459, 2969, 2926, 2859, 1647, 1445, 1236, 1165, 1098, 1069, 1034, 970 cm"1.

Mass Spec (FAB, + ions) m/e 509 (M+Na).

Anal. Calc'd for C22H40O6NaPS-0.73 H2O: C, 53.91; H, 8.31; P, 6.32; S, 6.54 Found: C, 53.91; H, 8.23; P, 6.17; S, 6.33. example 25 (E)-6-Methyl-10-phenyl-l-phosphono-5-decene-l-sulfonic acid, tripotassium salt The ti-tle compound was prepared as described herein and has the following properties. 2R0218' HX59a XR (KBr) 3424, 2932, 2857, 1653, 1200, 1080, 966 cm--'-.

MS (Ion Spray, + ions) 429 (M-2K+3H), 467 (M-K+2H), 505 (M+H).

Anal. Calc'd. for C17H24K3PO6S-2.1 H2O: C, 37.64; H, 5.24; P, 5.71; S, 5.91 10 Found: C, 37.64; H, 5.19; P, 5.34; S, 6.09 Example 26 4-(3-Phenylpropyl)-a-phosphonobenzenebutanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the folloving properties.

IR (KBr pellet) 3428, 3084, 2934, 2859, 1659, 20 1514, 1196, 1107, 1084, 966 cm"1.

Anal. Calc'd for C20HI8K3O6PS• 1.1 H20-.

C, 41.77; H, 4.46; P, 5.67; S, 5.87 Found: C, 41.77; H, 4.68; P, 5.46; S,6.08.

MS (FAB, + ions) m/e 565 (M+K), 527 (M+H), 489 (M-K+2H).

Example 27 (E,E)-1-(Hydroxymethylphosphinyl)-6,10,14-trimeth-yl-5,9,13-pentadecatriene-l-sulfonic acid, dipotassitim salt ; The title compound was prepared as described herein and has the following properties.

TLC Silica gel (7:2:1 n-propanol:ammonium 10 hydroxide:water) : Rf 0.47.

IR (KBr) 2922, 2857, 1213, 1183, 1088, 1034 cm-1.

MS (FAB, + ions) m/z 483 (M+H), 445 (M+2H-K), 407 15 (M+3H-2K) .

Anal. Calcd. for C19H33O5PSK2 : C, 47.28; H, 6.89; P, 6.,42; S, 6.64 Found: C, 47.30; H, 6.92; P, 6.04; S, 6.94 Example 23 (E,E)-1-(Hydroxyphosphinyl)-6,10,14-trimethyl- ,9,13-pentadecatriene-l-sulfonic acid, dipotassium salt A. (E,E)-6,10,14-Trimethyl-5,9,13-penta- decatriene-1-sulfonic acid, ethvl ester n-Butyllithium (11.1 mL, 2.5 M in hexanes, 27.8 mmol) was added dropwise over 15 min to a 30 solution of ethyl methanesulfonate (5.17 g, 41.7 mmol) in THF (50 mL) at -78°C under argon. The clear colorless reaction mixture was stirred at -78°C for 20 min, whereupon a solution of Example 1 Part C iodide (5.00 g, 13.9 mmol) in THF (10 mL) HX59 £fi02lfl was added dropwise over 10 rain. The reaction was warmed, to -60°C (internal temperature) and stirred at that temperature for 1.5 h. The reaction was then warmed to -20°C over 2 h, then quenched by 5 addition of saturated NH4CI (20 mL). Diethyl ether (300 mL) was added, and the organic layer was washed with water (2 x 50 mL) and brine (10 mL), then dried over MgS04. Evaporation gave a yellow oil, which was purified by flash chromatography on 10 silica gel (200 g) eluting with a step gradient of 5:95 to 8:92 EtOAc/hexane to provide title compound (3.61 g, 73%) as a colorless oil.

B. (E,E)-1-(Ethoxyphosphinyl) -6 ,10.14-15 trimethyl-5,9,13-pentadecatriene-l- sulfonic acid, ethvl ester n-Butyllithium (2.7 mL, 2.5 M in hexanes, 6.7 mmol) was added dropwise to a solution of Part A compound (2.00 g, 5.62 mmol) in THF (15 mL) at 20 -78°C under argon. The yellow reaction was stirred at -78°C for 30 min, whereupon diethyl chlorophosphite (2.4 mL, 16.9 mmol) was added rapidly in one portion. The colorless reaction was stirred at -78°C for 1 h, then allowed to warm to RT over 2.5 25 h. The reaction was diluted with anhydrous diethyl ether (50 mL). Water (10 mL) was then added, and the resultant biphase mixture was stirred vigorously at RT for 1 h. The aqueous layer was removed, and the organic layer was washed with 30 water (10 mL) and brine (15 mL) , then dried over MgS04. Evaporation gave a colorless oil, which was purified by flash chromatography on CC7 buffered silica gel (250 g) eluting with a step gradient of 25:75 to 35:65 to 45:55 EtOAc/hexane to give title compound (2.07 g, 82%) as a colorless oil as a 1:1 mixture of diastereomers.

C. (E,E)-1-(Hydroxyphosphinyl)-6,10,14-5 trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, dipotassium salt Potassium iodide (317 mg, 1.91 mmol) was added to a solution of Part B compound (816 mg, 1.82 mmol) in acetone (10 mL) under argon. As the 10 mostly insoluble potassium iodide reacted, the product precipitated out of the reaction mixture. The white heterogeneous reaction was stirred at RT overnight, concentraced in vacuo, then pumped at high vacuum to give a white solid. 15 The crude sulfonate salt was dissolved in IN KOH (3.6 mL, 3.6 mmol), then chromatographed on CHP-20P gel (2.5 x 20 cm column) eluting with water followed by a gradient created by jahe gradual addition of acetonitrile to a reservoir of water. 20 The product fractions were concentrated in vacuo to give an opaque white gum. Acetone (2 mL) was added and the product was precipitated out as a solid. The solid was filtered, washed with acetone (2x5 mL) , then pumped at high vacuum to give title salt 25 (507 mg, 60%) as a white solid.

TLC (silica gel) (7:2:1 n-propanol/NH40H/H20): Rf = 0.43 IR (KBr) 2928, 2857, 2288, 1202, 1094 era-1.

MS (ES, + ions) m/z 393 (M+3H-2K), 410 [(M+2H- 2K)+NH4], 427 [(M+2H-2K)+NH3+NH4], 431 (M+2H-K) , 448 [(M+2H-K)+NH3], 469 (M+H).

Uftoz Anal. Calc'd for C18H31K2O5PS: C, 46.13; H, 6.67; P, 6.61; S, 6.84.

Found: C, 46.18; H, 6.68; P, 6.28; S, 7.17.

Example 29 4-(Phenylmethyl)-a-phosphonobenzenebutanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

IR (KBr pellet) 3426, 3063, 2934, 2864, 1636, 1198, 1074, 966 cm-1.

MS (FAB, + ions) m/e 536 (M+K), 499 (M+H), 461 (M-K+2H).

♦ Anal. Calc'd for C17H18K3PSO6•1•IH2O: 20 C, 39.33; H, 3.94; P, 5.97; S, 6.18 Found: C, 39.33; H, 4.06; P, 5.71; S, 5.89.

Example 30 (E, E)-1-[Hydroxy(methoxymethyl)phosphinyl)-6,10,14-25 trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, dipotassium salt A. (Methoxymethyl)phosphonic acid, diethyl ester To a sample of 17.90 mL (0.104 mol) of triethylphosphite at -78°C under argon was added dropwise 8.50 mL (0.104 mol) of bromomethyl methyl ether. The mixture slowly warmed to RT and stirred for 24 h, when it was fractionally distilled (bp HX59a 100°C, 5 mm) to provide 16.22 g (98%) of title compound as a pale yellow oil.

TLC Silica gel (Ethyl acetate) Rf=0.50.

B. Chloro(methoxymethyl)phosphinic acid, ethvl ester To a solution of 5.0 g (27.6 mmol, 1 eq) of Part A compound in 5 mL of dry benzene at 0°C was 10 added 5.75 g (27.6 mmol, 1 eq) of phosphorus pentachloride as a solid in one portion. The resulting heterogeneous solution was stirred at 0°C for 5 min, then warmed to room temperature and stirred for 5 min. The x'esulting homogeneous 15 solution was heated at reflux for 1 h, cooled to room temperature and concentrated. The residue was co-evaporated twice with benzene followed by exposure to high vacuum (0.25 mmHgi for 1 h to afford 4.52 g (95%) of title compound as a yellow 20 liquid which was used in the next step without purification.

C. [Ethoxy(methoxymethyl)phosphinyl]-methanesulfonic acid, cvclohexvl ester To a solution of 9.84 g (55.2 mmol, 2.1 eq) of Example IA Part A mesylate compound in 200 mL of dry tetrahydrofuran (THF) at -75°C (internal temperature) was added dropwise via syringe 22.1 mL (55.2 mmol, 2.1 eq) of a 2.5 M n-butyllithium 30 solution in hexanes at a rate that kept the temperature below -71°C (over 40 min). The resulting solution was stirred for 5 min at -7 5°C. A solution of 4.52 g (26.2 mmol, 1 eq) of freshly prepared Part B compound in 20 mL of THF was added HX59a " dropwise at a rate to keep the temperature below -71°C (over 30 min) and the resulting light brown solution was stirred at -75'-'C for 1 h. The reaction was quenched by addition of a solution of 5 3.16 mL (55.2 mmol, 2.1 eq) of glacial acetic acid in 15 mL of THF over 5 min, then allowed to warm to room temperature. The solution was concentrated and the viscous residue was taken up in dichloromethane (250 mL), washed with water (100 mL), brine 10 (100 mL) , dried (MgSO..) and concentrated to afford 12.4 g of a light brown oil. The desired product was isolated by flash chromatography on silica gel (250 g) eluting with ethyl acetate. The fractions containing product by TLC were combined and 15 concentrated to afford a solid which was contaminated by an unknown impurity as evidenced by extraneous peaks in the JH NMR spectrum. The solid was recrystallized from hexanes/chloroform to afford 5.04 g (61%) of the title compound as & 20 white solid, m.p. 78.5-79.5°C.

TLC Silica gel (ethyl acetate) R:- 0.40.

D. (E,E)-1-[Ethoxy(methoxymethyl)phosphin-25 yl]-6,10,14-trimethyl-5,9,13-pentadeca- triene-1-sulfonic acid, cvclohexvl ester— To a suspension of 222 mg (5.6 mmol, 2 eq) of sodium hydride (as a 60% dispersion in mineral oil) in 1 mL of dry dimethylformamide (DMF) at 0°C 30 was added a solution of 1.74 q (5.6 mmol, 2 eq) of Part C compound in 4 mL of DMF dropwise over 10 min. The bubbling heterogeneous mixture was allowed to warm to room temperature and stir for 30 min. To the resulting homogeneous solution was HX59a ' added a solution of 1.0 g (2.8 mmol, 1 eq) of Example 1 Part C iodide in 3 mL "of DMF. After 20 h, the reaction was diluted with brine (25 mL). The resulting cloudy solution was extracted with 5 ether (1 x 100 mL, 3 x 15 roL) , dried (MgSO/i) and concentrated to afford 1.64 g of a yellow oil. The desired product was isolated by flash chromatography on silica gel (250 g) eluting with 40% ethyl acetate in hexanes. Fractions containing clean 10 product by TLC were pooled and concentrated to afford 801 mg (52%) of title compound as a viscous yellow oil.

TLC Silica gel (1:1 ethyl acetate:hexanes): 15 Rf 0.23.

E. (E,E)-1-[Hydroxy(methoxymethyl)phos-phinyl) -6,10, 14-trimethyl9,13-penta-aecatriene-l-sulfonic acid, dipotassium 20 salt To a solution of 600 mg of Part D compound in 12 mL of dry methanol at 0"C was introduced ammonia until the solution was saturated. The tube was sealed with a threaded teflon cap fitted with 25 an O-ring and heated at 75°C for 16 h. The volatiles were removed in vacuo and the oily residue was co-evaporated twice with toluene before placing on high vac (0.25 mrnHg) for three hours. To the resulting clear yellow oil was added 7 mL of 30 dry CH2CI2 followed by 806 HL (6.1 mmol, 4.5 eq) of dry 2,4,6-collidine. To the resulting light yellow clear solution was added 1.25 mL (9.5 mmol, 7 eq) of bromotrimethylsilane (TMSBr) and the resulting white heterogeneous mixture was stirred at room HX59a ' temperature. After 21 h, the reaction mixture concentrated and placed on high vac (0.25 mmHg) for 30 min. The resulting yellow white solid was dissolved by adding 7.0 mL (7.0 mmol, 5.2 eq) of 1 5 M potassium hydroxide, and the resulting solution was frozen and lyophilized. The light brown lyophilate was dissolved in water and chromatographed on a column of CHP20P (2.5 cm x 25 cm) eluting initially with water (150 mL) followed 10 a gradient formed by the gradual addition of a 63% solution of acetonitrile in water (400 mL) to a reservoir containing water (400 mL). No fractions (10 mL each) containing clean product by HPLC were obtained. The fractions containing approximately 15 2% of an impurity (which eluted just before the desired product) were pooled, concentrated and rechromatographed using a step gradient. After eluting with water (150 mL) the column was eluted with 15% acetonitrile in water (300 mL) followed by 20 20% acetonitrile in water (500 mL). Fractions containing pure product by HPLC were concentrated and the residual waxy residue was triturated with acetone to afford 245 mg of title salt (35%) as a white solid.

TLC Silica gel (7:2:1 n-propanol:ammonium nydroxide:water): Rf 0.42.

IR (KBr): 3437, 2926, 1449, 1200, 1076, 1030 cm-1.

MS (fab, + ions) m/z 551 (M + K), 513 (m+h).

HX59a " Anal. Calc'd for C20H35O6PSK2 *0.55 H2 C, 45.96; H, 6.96; P,"5.93; S, 6.13 Found: C, 45.96; H, 6.80; P, 5.54; S, 6.50 Example 31 (E,E) -1-tHydroxy (hydroxymethyl)phosphinyl) -6,10,14-trimethyl-5% 9,13-pentadecatriene-l-sulfonic acid, tiipptassium salt. s b 02i(r Potassium iodide (370 mg, 2.23 mmol) was added to a solution of Example 2 8 Part B compound (950 mg, 2.12 mmol) in acetone (10 mL) under argon. As the mostly insoluble potassium iodide reacted, the product precipitated out of the reaction 15 mixture. The white heterogeneous reaction was stirred at RT overnight, concentrated in vacuo, then pumped at high vacuum to give a white solid.

A heterogeneous mixture of/-*the sulfonate salt paraformaldehyde (254 mg, 8.48 mmol), and 20 diisopropylethylamine (184 mL, 1.06 mmol) in absolute ethanol (7 mL) was heated at 60°C under argon. After 15 min, the reaction went from milky white to clear and colorless. After 7 h at 60°C, the reaction was allowed to cool to RT. The 25 reaction was concentrated in vacuo, then pumped at high vacuum to give a white semi-solid.

Aqueous KOH (6.4 mL, IN, 6.4 mmol) was added to the mono-ester prepared above. The initially white foamy dispersion was stirred at RT 30 under argon overnight, after which time the reaction was clear and colorless. The reaction mixture was chromatographed on CHP20P gel (2.5 x 20 cm column) eluting with water followed by a gradient created by the gradual addition of HX59a • acetonitrile to a reservoir of water. The product fractions were concentrated in vacuo to give an opaque white gum. Acetone (5 mL) was added and the product was precipitated out as a solid. The solid 5 was filtered, washed with acetone (3x5 mL), then pumped at high vacuum to give the title product (520 mg, 49%) as a white solid.

TLC (silica gel) (7:2:1 n-propanol/NH40H/H20): 10 Rf = 0.36 IR (KBr) 3430. 2926, 1636, 1449, 1204, 1078, 1024 cm"1.

Mass Spec (FAB, + ions) m/z 499 (M+H), 53"' (M+K) .

Anal. Calc'd for C19H33K2O6PS: C, 45.76; H, 6.67; P, 6.2d; S, 6.43.

Found: C, 45.41; H, 6.92; P, 6.47; S, 6.77.

Example 32 (E, E) -7,11,15-Trimethyl-2-phosphono-6,10,14-hexa- decatriene-2-sulfonic acid, tripotassium salt A. (E,E)-7,11,15-Trimethyl-2-(diethoxy phosphinyl) -6,10,1i-hexadecatriene-2- sulfonic acid, cvclohexvl ester To a suspension of 47 mg (1.2 mmol. 1.1 eq) of sodium hydride (as a 60% mineral oil dispersion) 30 in 1 mL of dry DMF at 0°C was added a solution of 580 mg (1.1 mmol, 1 eq) of Example lA Part C compound in 2 mL of DMF over 1 min. The bubbling solution was allowed to warm to RT and stirred for 30 min. To the resulting yellow homogeneous HX59a ' 168 - 280 i solution of anion at RT was added 2 64 |IL (4.2 mmol, 4 eq) of methyl iodide over 1 min. After 16 h, the turbid yellow reaction mixture was diluted with ether (100 mL) and washed with brine (50 mL) . The 5 aqueous layer was extracted with ether (2 x 15 mL) and the combined organic layers were dried (MgSC>4) and concentrated to afford 583 mg of a light yellow cloudy oil. 1H NMR of the crude oil indicated no unalkylated starting material was present. The 10 desired product was isolated via flash chromatography on silica gel (75 g) eluting with 35% ethyl acetate in hexanes. Fractions containing the desired product by TLC were pooled and concentrated to afford 418 mg (68%) of title compound as a clear 15 viscous oil.

TLC Silica gel (10% ether in CH2CI2): Rf 0.46.

* B. (E, E) -7,11,15-Trimethyl-2-phosphono-20 6,10,14-hexadecatriene-2-sulfonic acid, tripotassium salt To a solution of 408 mg of Part A compound in 8 mL of dry methanol at 0°C was introduced ammonia until the solution was saturated. The tube 25 was sealed with a threaded teflon cap fitted with an O-ring and heated at 75°C for 17 h. The volatiles were removed in vacuo and the oily residue was co-evaporated twice with toluene before placing on high vac (0.25 mmHg) for three hours. 30 To the resulting clear yellow oil was added 4 mL of dry CH2CI2 followed by 7 69 HL (5.b mmol, 8 eq) of dry 2,4,6-collidine. To the resulting light yellow clear solution was added 7 68 jiL (5.8 mmol, 8 eq) of bromotrimethylsilane (TMSBr) and the resulting HX59a white heterogeneous mixture was stirred at temperature. After 84 h, the reaction mixture was concentrated and placed on high vac (0.25 mmHg) overnight. The resulting yellow white solid was 5 dissolved by adding 5.0 mL (5.0 mmol, 6.8 eq) of 1 M potassium hydroxide (pH 12.45) and 5 mL of water ani the resulting solution (pH 12.35) was frozen and lyophilized. The light brown lyophilate was dissolved in water and chromatographed on a column 10 of CHP20P (2.5 cm x 25 cm) eluting initially with water (150 mL) followed a gradient formed by the gradual addition of acetonitrile (400 mL) to a reservoir containing water (400 mL). Fractions (10 mL each) were collected and analyzed by HPLC 15 (Method 8). One fraction contained material >98% pure. This fraction was concentrated, taken up in a minimum volume of water, filtered and preciptated using acetone. The resulting solid was dryed on high vac to afford 134 mg of an off-white solid 20 which did not pass elemental analysis. The >95% material from the column above was rechromato-graphed on CHP20P under isocrat;ric conditions with 20% acetonitrile in water. Fractions containing £98% material were combined with the >98% material 25 obtained from the first column, dissolved in water and concentrated. The resulting glassy solid was triturated with acetone to afford, after high vacuum removal of the acetone remnants, 94 mg title salt in the form of an off-white solid (24%) .

TLC Silica gel (5:4:1 n-propanol:ammonium hydroxide:water): Rf 0.24.

IR (KBr): 3434, 2928, 1452, 1202 cm"1.

HX59a ' 170 - MS (FAB, + ions) m/z 499 (M + '2H - K) , 521 (M - K + Na + H) , 537 (M + H).

Anal. Calc'd for Ci9H3206PSK?.«0. 5 H2O: C, 41.81; H, 6.09; P, 5.67 Found: C, 42.20; H, 6.41; P, 4.94.

Example 3 3 4'- (2-Methyl-l-propenyl)-a-phosphono[1,1'-biphen-vll—4—butanesulfonic acid, tripotassium salt A. l-Bromo-4- (2-methvl-l-propenvl)benzene To a stirred slurry of 17.29 g (40.0 mmol) 15 of isopropyltriphenylphosphonium iodide and 500 mg (2 mmol) of 18-crown-6 in 100 mL of THF under nitrogen at 5°C was added 4.50 g (40.0 mmol) of potassium t-butoxide over 5 min. ^Uhe resulting deep red-orange slurry was stirred 10 min and then 20 a solution of 6.50 g (35.0 mmol) 4-bromobenzalde-hyde in 40 mL of THF was added at a rate to keep the temperature below +10°C. The resulting bright yellow slurry was stirred for 20 min and then poured into 300 mL of hexanes. The solids were 25 filtered off and the filtrate evaporated. This residue was purified by flash chromatography (5x15 cm column) and eluted with hexanes to provide 5.66 g (77%) of title bromide as a colorless oil.

TLC Silica gel (hexanes) Rf=0.32. 280? Anal. Calc'd for CioHnBr: C, 56.90; H, 5.25 Found: C, 56.83; H, 5.22.

HX59a MS (CI-NH3/ - ions) m/e 209 (M-H).

B. 4'-(2-Methyl-1-propeny1)[1,1'-5 biphenyl]-4-carboxylie acid, methyl ester To a stirred solution of 52 mL (88.4 mmol, o 1.7 M in pentane) of t-butyllithium at -78 C under argon was added a solution of 7.92 g (37.5 mmol) of 10 Part A bromide in 15 mL of THF over 10 minutes. The resulting deep red slurry was stirred for 1 hour, warmed to -22°C and a solution of 6.16 g (45.2 mmol) of thrice-fused zinc chloride in 40 mL of THF was added over 20 minutes. The light 15 yellow, faintly turbid solution was stirred for 1 hour and then cannulated into a stirred solution of 7.04 g (26.9 mmol) of methyl 4-iodobenzoate and 600 mg (0.52 mmol) of tetrakis (tripheny»lphosphine) -palladium in 30 mL of THF at -22°C under argon. 20 After the addition was complete, the reaction was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with ether, washed successively with 1 M hydrochloric acid, saturated sodium bicarbonate and saturated 25 sodium sulfite solution. The organic extract was dried (MgS04) and evaporated to give a dark brown solid. Recrystallization from methanol gave title ester as a light yellow solid, mp 66-68°C, 6.13 g, 86% yield.

C . 4 ' - (2-Methyl-l-propenyl)[1,1'- biphenvll-4-methanol To a stirred solution of 3.00 g (11.3 mmol) of Part B ester in 10 mL of THF at room temperature £80? HX59a ' ■80 ?1 under nitrogen was added 6.0 mL of lithium aluminum hydride solution (1.0 M in THF,-6.0 mmol). After 1 hour, the reaction was quenched with 1 mL of brine and then sufficient 1 M hydrochloric acid to bring 5 the solution to pH 1. The resulting mixture was extracted twice with ether, the combined extracts washed with saturated sodium bicarbonate solution, dried (MgS04) and evaporated. Purification by flash chromatography on silica gel (5 x 10 cm 10 column, 3:97 ether/dichloromethane as elutent) gave title alcohol as a colorless oil, 2.42 g, 90% yield.

D. 4 -(Bromomethyl)-4'-(2-methyl-l-15 propenv1) f1.1'-biphenv1 1 To a stirred solution of 2.82 g of triphenylphosphine (8.4 mmol) and 2.33 g (9.79 mmol) of Part C alcohol in 3 0 mL of dichloromethane under argon at -40°C was added 1.92 g (11.7 mmol) 20 of N-bromosuccinimide over 20 minutes. After 1 hour, the reaction mixture was evaporated onto 10 g of silica gel. Purification by flash chromatography on silica gel (5 x20 cm column, 12% CH2CI2 in hexanes as the elutent) gave title bromide as a 25 colorless oil, 2.75 g, 93% yield.

E. 4'-(2-Methyl-l-propenyl)[1,1'— biphenyl]-4-propanoic acid, 1,1-dimethvlethvl ester To a stirred solution of 1.01 mL (7.2 mmol) of diisopropylamine in 15 mL of THF at -5°C under argon was added 2.8 mL (7.0 mmol, 2.5 M in hexane) of n-butyllithium at a rate to keep the temperature o below 0 C. After stirring the resulting pale 880218 HX59a yellow solution for 15 minutes, 3.0 mL (17 mmol) of hexamethylphosphoramide was adde'd. After an additional 15 minutes, the deep yellow solution was cooled to -78°C and 0.98 mL (7.2 mmol) of t-butyl 5 acetate was added over the course of 5 minutes.

The solution was stirred for 30 minutes and then a solution of 1.75 g (5.8 mmol) of Part D bromide in 10 mL of THF was added over 5 minutes. The reaction mixture was stirred for 8 hours at -78°C, 10 quenched with 10% citric acid solution and extracted twice with ether. The extracts were combined, washed twice with water, once with saturated sodium bicarbonate solution, dried (MgS04) and evaporated. Purification by flash 15 chromatography on silica gel (5 x 20 cm column, 1:1 hexanes/dichloromethane as elutent) gave title ester as a white foamy solid, 1.85 g, 95% yield.

* F. 4'- (2-Methyl-l-propenyl)[1,1'- biohenvll-4-propanol To a stirred solution of 1.08 g (3.20 mmol) of Part E ester in 5 mL of THF at room temperature under nitrogen was added 2.0 mL of lithium aluminum hydride solution (1.0 M in THF, 2.0 mmol). The 25 reaction was heated to reflux for 1 hour, quenched with 1 mL of brine and then sufficient 1 M hydrochloric acid to bring the solution to pH 1. The resulting mixture was extracted twice with ether, the combined extracts washed with saturated 30 sodium bicarbonate solution, dried (MgS04) and evaporated. The oily residue was passed through a 2 cm high pad of silica gel, eluting with dichloromethane to give title alcohol as a white solid, 0.824 g, 97% yield.

HX59a 2802 G. 4- (3-Iodopropyl) -4 ' -"(2-methyl-1- nrnpenvl) f 1. 1'-biphenvl 1 To a stirred solution of 813 rng (3.05 mmol) 5 of Part F alcohol, 882 mg (3.36 mmol) of triphenylphosphine and 440 mg (6.4 mmol) of imidazole in 20 mL of THF was added a solution of 813 mg (3.2 mmol) of iodine in 10 mL of THF over 20 min. After 10 min, the light yellow reaction mixture was diluted 10 with hexanes and washed once each with 10% sodium bisulfite solution, water and brine. The organic layer was dried (MgS04) and evaporated onto 5 g silica gel. Purification by flash chromatography on silica gel (5x5 cm column) eluted with 15 dichloromethane gave title iodide, 1.11 g (97%) as a white solid, mp 58-61°C.

H. 4'-(2-Methyl-1-propeny1}-a-phosphono-[1,1'-biphenyl]-4-butanesulfonic acid, cvclohexvl ester To a stirred slurry of 85 mg (2.1 mmol, 60% mineral oil dispersion) of sodium hydride in 3 mL of DMF under argon at -10°C was added a solution of 670 mg (2.4 mmol, 1.3 equiv.) of Example lA Part 25 B compound in 1 mL of DMF. After addition was complete, the reaction was warmed to room temperature and stirred for 30 min. To the resulting solution was added a solution of 700 mg (1.86 mmol) of Part G compound in 1 mL of DMF. The 30 reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid and thrice with water. The organic phase was dried (MgSC>4) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column) HX59a • - 175 - ^ '280 eluted with 1:24 ether/dichloromethane gave title salt as a colorless oil, 610 rng,-62% yield.

I. 4'-(2-Methyl-l-propenyl)-a-phosphono- [1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt A solution of 500 mg (0.89 mmol) of Part H ester in 15 mL of methanol under argon at room temperature was saturated with ammonia gas. The 10 flask containing the reaction mixture was sealed O and heated to 75 C. After 16 h, the reaction was cooled to room temperature and evaporated under dry conditions. The residue was dissolved in 10 mL of dichloromethane and 0.59 mL (4.5 mmol) of 2,4,6-15 collidine and then 940 mL (7.1 mmol) of bromotrimethylsilane was added. After 24 h, the resulting clear solution was evaporated at 25°C and then stirred for 1 h with 8 mL (4 mmol) ,of 0.5 £2 potassium hydroxide solution. The solution was 20 lyophilized and then purified by MPLC (2.5x20 cm column of Mitsubishi Kasei Sepadbeads HP-20 resin): 11.5 mL fractions, 7 mL/min flow rate, eluted with water and then a gradient prepared from 400 mL of water and 450 mL of 2:1 acetonitrile/water). 25 Fractions 3 9-48 were collected and lyophilized to give title salt as a white solid, 310 mg, 62% yield.

IR (KBr pellet) 3403, 29.67, 2932, 1653, 1497, 30 1184, 1051, 966 cm"1.

Anal. Calc'd for C20H22K306PS-1.5 H20: C, 42.46; H, 4.45; P, 5.47; S, 5.67 Found: C, 42.35; H, 4.80; P, 5.20; S, 6.06.

HX59a 2 8# 218 Mass Spec (FAB, + ions) m/e 57-7 (M+K) , 5 501 (M-K+2H).

Example 3 4 4'-Butyl-a-phosphono[1,1'-biphenyl]-4-butanesul-fonic acid, tripot_assium salt The title compound was prepared as 10 described herein and has the following properties.

IR (KBr pellet) 3424, 3027,2957, 2930, 2859, 1653, 1499, 1200, 1078, 966 cm"1.

Anal. Calc'd for C20H24K306PS-0.75 H20: C, 43.34; H, 4.64; P, 5.59; S, 5.78 Found: C, 43.01; H, 4.88; P, 5.16; S, 6.21.

Mass Spec (FAB, + ions) m/e 579 (M+K), 541 (M+H), 20 503 (M-K+2H), 465 (M-2K+3H).

Example 3 5 (E)-6-Methyl-l-phosphono-9-(4-propylphenyl)-5-nonene-1-sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC (5:4:1 n-propanol/ammonium hydroxide/water) 30 Rf = 0.22.

MS (FAB, +ions) 533 (M+H), 457 (M+H-K).

HX59a IR (KBr) 3235, 2934, 2872, 1653, 1458, 1144, 1098, 1052, 964 cm"1.

V v Anal. Calc'd for Ci9H2806psK3~H20: C, 41.43; H, 5.49; S, 5.82; P, 5.62; Found C, 41.43; H, 5.72; S, 6.23; P, 5.29.

ExampJLe 35A 2,2-Dimethylpropanoic acid, (E) -8-iodo-5-methyl-4-10 octen-l-vl ester The title compound was prepared as described herein and has the following properties.

TLC Silica gel (8:2 hexane/ethyl acetate) Rf=0.81.

Example 3 6 (E)-6-Methy1-8-pheny1-1-phosphono-5-oc t ene-1-sul-fonic acid, tripotassium salt A. 4-r(t-Butvldimethvlsilvl)oxv1-1-butanol To a solution of 300 mL of THF, 90 g (1 mol) of butanediol and 13.6 g (0.20 mol) of imidazole was added 30.1 g (0.20 mol) of t-butyldimethylsilyl 25 chloride in 50 mL of THF. After 2 h the reaction mixture was diluted with 700 mL of water and 500 mL of diethyl ether. The layers were equilibrated and separated. The organic fraction was washed with water, dried (MgS04) and concentrated to leave 38.7 30 g (95%) of title alcohol as a colorless oil.

TLC Silica gel (3:7 ehtyl acetate/hexane) Rf=0.35.

HX59a' IR (neat) 3450, 2940, 2880, 1465, 1385, 1250, 1100, 1055, 835, 770 cm"1.

Mass Spec (ci-nh31 + ions) m/e 205 (m+h).

B. 4-T(t-Butvldimethvlsilvl)oxvlbutanol To a solution of 1CT0 ml of methylene chloride and 3.21 g (41.17 mmol) of methyl sulfoxide at -78°C was added 6.67 g (37.74 mmol) of 10 oxalyl chloride dropwise over 15 min. After gas evolution ceased (= 15 min.), 7.0 g (34.31 mmol) of Part A alcohol was added to the reaction mixture. The mixture was stirred at -78°C for 0.5 h, when 13.8 g (137.2 mmol) of triethylamine was added 15 rapidly over 4 min. The mixture was warmed to -20°C over 0.5 h and quenched with 200 mL of ether and 200 mL of water. The layers were equilibrated and separated. The organic fraction was dried (Na2S04) and concentrated to leave 5.85 g (85%) of 20 title aldehyde as a colorless oil.

TLC Silica gel (1:9 ethyl acetate/hexane) Rf=0.45.

C. (E)-2-Methyl-6-[(t-butyldimethyl-25 silyl)oxy]-2-hexenoic acid, ethyl ester To a solution of 8.62 g (36.25 mmol) of triethyl 2-phosphonopropionate in 50 mL of THF at 0°C was added 0.84 g (35.0 mmol) of NaH in three 30 equal portions over 15 min. After gas evolution ceased, 5.85 g (29 mmol) of Part B aldehyde was added in one portion. The mixture was warmed to RT over 30 min. and diluted with 100 NH4CI solution and 100 mL of ether. The layers were equilibrated HX59a and separated. The organic fraction was dried (Na2S04> and concentrated. The remainder was purified by flash chromatography (300 g of silic gel) with 5:95 ethyl acetate/hexanes to yield 5.50 5 g (66%) of title ester as an amber oil. 280? 18 TLC Silica gel (1:9 ethyl acetate/hexanes) Rf=0.33.

D. (E)-2-Methyl-6-[(t-butyldimethyl- silvl)oxvl-2-hexen-l-ol To a solution of 25 mL of dichloromethane and 5.20 g (18.18 mmol) of Part C ester at -78°C was added 40 mL (40 mmol) of a IM solution of diisobutylaluminum hydride in cyclohexane over 20 15 min. After 1 h, the mixture was diluted with 100 mL (100 mmol) of an aqueous IM solution of sodium potassium tartrate and 100 mL of ether. The mixture was stirred at RT for 2.5 fy when the layers were separated, the organics dried (Na2S04) and 20 concentrated. The remainder was purified by flash chromatography (250 g silica gel) with 15:85 ethyl acetate/hexanes to yield 3.0 g (67%) of title alcohol as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexanes) Rf=0.45.

IR (film) 3347, 2953, 2859, 1472, 1406, 1256, 1098, 837 cm"1.

Mass Spec (CI-NH3, + ions) m/e 262 (M+NH4), 245 (M+h), 227 (m+h-h20).

HX52a ' 280219 E. (E)-l-Chloro-2-methvl-6-((t-butyl-dimethv 1 silv 1) oxv 1 -2-hexene To a solution of 30 mL of dichloromethane, 3.00 g (13.30 mmol) of Part D alcohol and 2.83 g 5 (28.00 mmol) of triethylamine at 0°C was added 1.60 g (14.00 mmol) of methanesulfonyl chloride in 5 mL of dichloromethane. After 2 h the reaction mixture was diluted with 70 mL of water and 125 mL of diethyl ether. The layers were equilibrated and 10 separated. The organic fraction was washed with water, dried (Na2S04) and concentrated to leave the crude mesylate. The residue was diluted with 10 mL of dimethylformamide and treated with 1.70 g (40.00 mmol) of LiCl. The reaction mixture was stirred at 15 RT for 6 h, at which point it was diluted with 100 mL of ether and 100 mL of water. The layers were equilibrated and the organic fraction dried (Na2SC>4) and concentrated. The residue was purified by flash chromatography (100 g of silica 20 gel) with 2:98 ethyl acetate/hexane to yield 1.20 g (35%) of title chloride as an amber oil.

TLC Silica gel (1:9 ethyl acetate/hexane) Rf=0.80.

IR (film) 2930, 2859, 1472, 1339, 1256, 1103, 837 cm"1.

Mass Spec (CI-NH3, + ions) m/e 263, 265 (M+H), 227 (M+H-HCl).

F. (E)-3-Methy1-1-phenyl-7-[(t-butyl-dimethvlsilvl)oxv1-3-heotene A solution of 3 mL (6 mmol) of 2 M benzyl-magnesium chloride in THF and 2 mL of HMPA at 0°C HX59a ' " 181 ~ 2^02 was treated dropwise with 1.0 g (3.80 mmol) of Part E chloride in 5 mL of THF over 5*min. The solution was allowed to warm to RT and srir for 2 h, at which point the reaction was diluted with ether and 5 3 mL (3 mmol) of IN HCl solution. The organic layer was washed two times with NH4CI solution, dried (MgS04) and concentrated to an oil. The oil was purified by flash chromatography performed on 125 g of silica gel packed, loaded and eluted with 10 3:95 ethyl acetate/hexane to provide 1.10 g (91%) of title compound as a colorless oil.

TLC Silica gel (5:95 ethyl acetate/hexane) Rf=0.80.

IR (film) 3086, 3063, 3028, 2930, 2859, 1603, 1497, 1472, 1256, 1101, 1032, 1007. 964, 837 cm"!.

Mass Spec (CI-NH3, + ions) m/e 336 ,.(M+NH4) , 319 (m+h) .

G. (E)-5-Methvl-7-phenyl-4-hepten-l-ol A solution of 2 mL of THF and 1.10 g (3.45 mmol) of Part F compound at 0°C was treated dropwise with 0.30 mL (5.00 rnmol) of acetic acid 25 and 4.0 mL (4.00 mmol) of a IM tetrabutylammonium fluoride solution in THF. The solution was allowed to warm to RT and stir for 48 h, at which point the reaction was diluted with 50 mL of ether and 25 mL of NaHC03 solution. The organic layer 30 was washed two times with NaHC'03 solution, dried (MgS04) and concentrated to an oil. Flash chromatography was performed on 80 g of silica gel packed, loaded and eluted with 3:7 ethyl HX59a 2 af) 2,18 acetate/hexane to provide 0.59 g (81^)^ of'^tixle alcohol as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexane) Rf=0.60.

IR (film) 3339, 3027, 2932, 2859, 1603, 1452, 1385, 1231, 1181, 1057, 698 cm"1.

Mass Spec (CI-NH31 + ions) m/e 222 (M+NH4), 205 10 (M+H).

H. (E)-l-Iodo-5-methvl-7-phenvl-4-heotene To a stirred solution of 0.59 g (2.89 mmol) of Part G alcohol and 0.66 mL (6.00 mmol) of 15 triethylamine in 10 mL of methylene chloride at 0°C was added 0.37 g (3.20 mmol) of methanesulfonyl chloride dropwise over 10 min. After 1 h at 0°C the reaction was diluted with ether and washed with aqueous solutions of NH4CI, NaHCC>3, and brine. The 20 organics were dried (Na2S04) and concentrated under reduced pressure to provide the crude mesylate. The residual oil was dissolved in 25 mL of acetone and treated with 1.00 g (6.66 mmol) of Nal. The resulting solution was stirred at RT for 36 h and 25 diluted with ether. The organics were washed with water, dried over MgS04, and concentrated to provide a yellow oil. Flash chromatography was performed on 100 g of silica gel packed, loaded and eluted with hexanes to provide 0.68 g (2.16 mmol, 30 100% overall yield) of title iodide as a colorless oil.

TLC Silica gel (hexane) Rf=0.27.

HX59a ". 2Mt' 1603, 1495, 1452, Mass Spec (CI-NH3, + ions) m/e 332 (M+NH4), 314 5 (M) .

I. (E) -1-(Diethoxyphosphinyl)-6-methyl-8-phenyl-5-octenesulfonic acid, cyclohexyl ester To a suspension of 83 mg (3.44 mmol) of NaH in 7 mL of dry DMF at 0°C under argon was added 1.25 g (4.00 mmol) of Example lA Part B sulfonate over 15 min. to give a yellow solution. The reaction was allowed to warm to room temperature 15 and stir for 0.5 h when 0.60 g (1.91 mmol.) of Part H iodide was added in one portion. The reaction mixture was stirred for 18 h when it was quenched with saturated aq NH4CI solution apd diluted with ether. The organic fraction was washed with water, 20 brine, dried (Na2S04) and evaporated to provide a crude yellow oil. Flash chromatography was performed on 75 g of silica gel eluted with 4:6 ethyl acetate/hexane to provide 0.76 g (79%) of title compound as a pale yellow oil.

TLC Silica gel (3:7 ethyl acetate/hexane) Rf=0.28.

IR (film) 3059, 3026, 2938, 2863, 1454, 1354, 1261, 1172, 1053, 1022, 927, 866 cm-1.

IR (film) 3061, 3027, 2932, 2857, 1204, 1165, 1030, 743, 698 cm"1." Mass Spec (CI-NH3, + ions) m/e 518 (M+NH4), 436 (m+NH4-c6h10)• HX59a J. (E)-6-Methyl-8-phenyl-l-phosphono-5-oct-.erie-l-sulfonic acid, tripotassium salt To a solution of 0.76 g (1.52 mmol) of Part I compound and 10 mL of methanol in a sealable tube 5 at 0°C was added NH3 (g) until the solution was saturated. The tube was sealed and placed in an oil bath at 60°C for 24 h, at which point the tube was opened and the volatiles removed under reduced pressure. The remainder was dissolved in a 1:3 10 hexamethyldisilazano/toluene solution and evaporated two tirr.es (2 X 10 mL) leaving a colorless viscous oil. The oil was dissolved in 7 mL of dry methylene chloride and treated with 1.48 mL (7.00 mmol) of hexamethyldisilazane and 1.00 mL 15 (7.50 mmol) of bromotrimethylsilane. The reaction was allowed to stir at RT for 18 h when the solvent was evaporated and the residue pumped (= 0.5 mm pressure) for 0.5 h. The remainder was dissolved by adding 5 mL (5 mmol) of 1 M KOH solution and 20 stirring vigorously for ten min. The soapy solution was freeze dried to provide a white solid. The solid was purified by MPLC on a column of CHP20P gel (250 mL ) eluting with water (150 mL) followed by a gradient created by the gradual 25 addition of 500 mL of acetonitrile to a reservoir of 300 mL of water. Approximately 7 mL fractions were collected. Fractions 26 to 30 were pooled, the acetonitrile was removed under reduced pressure and the aqueous solution lyophilized to provide 30 0.45 g (63%) of title compound as a white lyophilate which was 98.5% pure by HPLC.

TLC Silica gel (6:3:1 n-propanol/conc. NH3/water) Rf=0.17.

HX59a • 23021® IR (KBr) 3418, 3063, 3027, 2934, 2863, 1663, 1454, 1383, 1196, 1111, 1086, 1047, 964, 698 cm"1.

Mass Spec (FAB, + ions) m/e 515 (M+K), 477 (M+H), 439 (M-K+2H) .

Anal. Calc'd C, Found: C, for C15H20O6SPK3 + 35.95; H, 4.57; P, 36.26; H, 4.76; P, 1.36 H2O: 6.18; S, 6.40 5.84; S, 6.21.

Example 37 (E, E)-7,11,15-Trimethyl-l-phosphono-6,10,14-hexa-decatriene-1-sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC (Silica gel, 7:2:1 n-propanol/ammonia/water) 20 Rf = 0.10.

MS (Ion Spray, -ions) 421 (M-3K+2H).

IR (KBr) 3457, 2965, 2926, 2857, 16559, 1624, 1451, 25 1400, 1383, 1213, 1173, 1140, 1090, 1044, 966, 885, 837, 785, 694, 644, 556 cm"1.

Anal. Calc'd for C19H32O6SPK3-1.2IH2O: C, 40.85; H, 6.21; P, 5.54; S, 5.74. 30 Found: C, 40.85; H, 6.32; P, 5.75; S, 5.60.

HX59a ' Example 38 2.3 ^ (all-E)-7,11,15-Trimethyl-l-phosphono-4-(3,7,11-trimethyl-2,6,10-dodecatrienyl)-6,10,14-hexadecatriene-1 -sulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC (Silica gel, 7:2:1 n-propanol/ammonia/water) 10 Rf = 0.13.

MS (FAF, + ions) m/e 779 (M+K), 742 (M+H), 703 (M+2H-K).

IR (KBr) 3443, 2969, 2924, 2857, 1678, 1451, 1400, 1383, 1208, 1090, 1045, 968, 891, 835, 721 cr!.

Anal. Calc'd for C^H5^0(-,PSK,-2 . 28H-Q-KOH: C, 48.71; H, 7.40; S, 3.82; P, 3.69; 20 Found C, 48.71; H, 7.47; S, 4.05; P, 3.91.

Example 39 (E,E) -4-Hydroxy-6,10,14-trimethyl-l-phosphono-5,9,13-pentadecatriene-l-sulfonic acid, 25 tripotassium salt A. (E,E)-3,7,11-Trimethy1-2,6,10- dodecatrienal To a CH2Cl2 solution (15 mL) of oxalyl 30 chloride (7.81 mL, 87.7 mmol) was added dimethyl sulfoxide (12.5 mL, 175.4 mmol) dropwise over 30 min at -60°C. The resulting clear solution was stirred at this temperature for 20 min. A solution of trans, trans- farnesol (Aldrich Chemical Co.) HX59a ' - 187 - " m 2S021® (15 g, 67.5 mmol) in CH2CI2 (325 mL) was added dropwise over 15 min. The reaction mixture became cloudy white during addition. The heterogeneous reaction mixture was stirred at -60°C for 30 min, 5 whereupon triethylamine (56.4 mL, 405 mmol) was added dropwise over 10 min. The reaction mixture became thick. The reaction mixture was allowed to warm to RT over 1 h. Ethyl ether (800 mL) was added and the organic layer was washed with HiO 10 (500 mL) , brine (500 mL) and dried over MgSC>4.

Evaporation gave 15 g (100%) of title compound as a crude oil.

B. (E, E) -3-Hydroxy-5 , 9 , 13 - trimethyl - 4 ,8,12-15 tetradecatrienoic acid, 1,1-dimethylethyl ester n-Butyllithium solution (32.4 mL, 2.5 M in THF, 81.0 mmol) was added dropwise,»to a solution of diisopropylamine (11.35 mL, 81.0 mmol) in THF (20 20 mL) at 0°C. After stirring 15 min, the reaction solution was cooled to -78°C. tert-Butyl acetate (7.07 mL, 84.3 mmci) in THF (50 mL) was added dropwise and stirring was continued for 30 min. A solution of Part A compound (15 g, 67.5 mmol) was 25 added dropwise over 30 min and stirring was continued at -78°C for 1 h. Water (100 mL) was added and reaction mixture was warmed to RT. The reaction mixture was diluted with ethyl acetate (500 mL) and the organic layer was washed with h2o 30 (500 mL), brine (500 mL) and dried over MgS04.

Evaporation gave a crude oil. Flash chromatography was performed on 1 kg silica gel, loaded and eluted with 10:90 ethyl acetate/hexane. The pure HX59a fractions were combined and evaporated to give 16.0 g (71%) of title compound as a yellowish oil.

C. (E,E)-5,9,13-Trimethyl-3-[[ (1,1-5 dimethylethyl)dimethylsilyl]oxy]-4,8,12-tetradecatrienoic acid, 1,1-dimethylethyl ester tert-Butyldimethylsilyl chloride (2.96 g, 19.7 mmol) was added to a mixture of Part B 10 compound ( 6.0 g, 17.9 rrunol) and imidazole (1.58 g, 23.2 mmol) in DMF (50 mL) at RT. The reaction mixture was stirred at RT for 2 h, then partitioned between ethyl ether (800 mL) and H^O (500 mL). The aqueous layer was extracted with ethyl ether (200 15 mL). The combined organic layers were washed with H2O (2 x 500 mL), brine (2 x 500 mL) and dried over MgSOij. Evaporation gave 8.01 g (100%) of title compound as a crude oil.

D. (E,E)-5,9,13-Trimethyl-3-[[(1,1- dimethylethyl)dimethylsilyl]oxy]-4,8,12- tetradecatrien-1-ol Diisobutylaluminum hydride solution (39.3 mL, IM in toluene, 39.3 mmol) was added dropwise to 25 a solution of Part C compound (8.0 g, 17.9 mmol) in toluene (70 mL) at 0°C under argon. Stirring was continued for 1.5 h. Methanol (5 mL) was added until bubbling ceased. AIM potassium sodium tartrate solution (300 mL) was added and vigrous 30 stirring was begun. After a few minutes the reaction mixture gelatinized. Stirring was continued for 1 h. Ethyl acetate (500 mL) was added and the organic layer was washed with brine (500 mL), then dried over MgSO*. Evaporation gave HX59a a pale yellow oil. Purification was performed by flash chromatography on 750 g silica gel, loaded and eluted with 10% ethyl acetate in hexane. Pure fractions were combined and evaporated to give 4.5 5 g (65%) of title compound as a colorless oil.

E. (E, E)-5,9,13-Trimethyl-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4, 8 ,12-tetradecatrien-l-vl iodide To a mixture of Part D alcohol (4.50 g, 11.84 mmol), triphenylphosphine (3.40 g, 13.0 mmol) and imidazole (1.60 g, 23.7 mmol) in THF (30 mL) , a solution of iodine (2.83 g, 13.0 mmol) in THF (5 mL) was added dropwise at RT. After stirring for 15 20 min, hexane (300 mL) was added to dilute the reaction mixture. The organic layer was washed with 10% sodium bisulfite (100 mL), saturated sodium bicarbonate (300 mL), brine,* (300 mL) and dried over MgS04. The filtrate was evaporated to a 2fi volume of 100 mL, silica gel (10 g) was added and evaporation was continued to dryness. Flash chromatography was performed on 500 g silica gel, loaded and eluted with 1:99 ethyl acetate/hexane. Pure fractions were combined and evaporated to give 25 5.2 g (90%) of title compound as a colorless oil.

F. (E, E)-1-(Diethoxyphosphinyl)-6,10,14-trimethyl-4-[[ (1,1-dimethylethyl)dimethylsilyl] oxy] -5,9,13-pentadecatriene-l-sulfonic acid, cvclohexvl ester To a suspension of sodium hydride (0.51 g, 21.22 mmol) in DMF (12 mL) under argon, a solution of Example lA Part B sulfonate (8.3 g, 26.53 mmol) in DMF (12 mL) was added dropwise over 10 min at 2PO?I* HX59a• 0°C (ice bath) . The ice bath was removed and the reaction mixture was stirred at*RT until the reaction solution was clear. The reaction was recooled to 0°C, and a solution of Part E compound 5 (5.2 g, 10.61 mmol) in DMF (12 mL) was added dropwise over 15 min. Stirring was continued for 2 h. The reaction mixture was warmed to RT and stirring was continued overnight. Diethyl ether (300 mL) was added to dilute reaction solution. 10 The organic layer was washed with H20 (200 mL), brine (200 mL) and dried over MgSO*. Evaporation gave a crude oil. Flash chromatography was performed on 450 g silica gel, loaded and eluted with 10:90 isopropanol/hexane. Pure fractions were 15 combined and evaporated to give 4.8 g (70%) of title compound as a colorless oil.

G. (E, E) -1- (Diethoxyphosphinyl) -4-hydroxy- 6,10,14-trimethyl-5, 9 ,13-pentadecatriene-1-20 sulfonic acid, cvclohexvl ester A stock HF/pyridine(Py) /THF solution was prepared by combining commercial HFX • pv (2 mL) and dry pyridine (4 mL) in THF (14 mL).

Part F compound (4.8 g, 7.10 mmol) was dissolved in a stock solution of HF/Py/THF (200 mL) at RT. The reaction mixture was stirred at RT overnight. Ethyl acetate (500 mL) was added and 30 the organic layer was washed with H^O (100 mL), IN HCl (100 mL) , saturated sodium bicarbonate (100 mL), brine (100 mL) and dried over MgS04. Evaporation gave a crude oil. Flash chromatogrophy was performed on 300 g silica gel, loaded and HX59a 191 - eluted with 1:1 ethyl acetate/hexane. Pure fractions were combined and evaporated to give 1.85 g (68%) of title compound as a colorless oil.

H. (E,E)-4-Hydroxy-6, 10,14-trimethyl-l- phosphono-5,9,13-pentadecatriene-l-sulfonic acid, tripotassium salt To a solution of Part G compound (1.00 g, 1.79 mmol) in methanol (20 mL) was bubbled 10 anhydrous ammonia gas until the solution was saturated. Then the sealed tube containing the reaction mixture was heated in an oil bath (70°C) overnight. The reaction mixture was evaporated to dryness. Purification was performed by 15 chromatography on CHP20P gel (2.5 x 20 cm), loaded and eluted with water followed by gradual addition of CH3CN to a reservoir of water. The pure fractions were combined, evaporated, and azeotroped with toluene. To a stirred solution of the 20 resulting residue (780 mg, 1.57 mmol) and collidine (1.03 mL, 7.85 mmol) in dichloromethane (10 mL) at RT under argon was added bromotrimethylsilane (1.66 mL, 12.56 mmol). The mixture was stirred at RT for 20 h. The solvent was evaporated and the residue 25 was pumped at high vacuum for 2 h. The residue was dissolved in 1 M potassium hydroxide (10 ml, 10 mmol) and the reaction mixture was stirred for 2 h. The solution was lyophilized to give a white solid. The crude product was purified by chromatography on 30 CHP20P gel (2.5 x 20 cm), loaded and eluted with water followed by gradual addition of CH3CN to a reservoir of water. The combined pure fractions were evaporated to remove CH;CN and the remaining aqueous solution was precipitated with acetone to provide 220 mg (30%) of title compound as a white solid.

IR (KBr) 2924, 1661, 1198, 1082, 964 cm -1.

MS (FAB, +ions) m/z 521 [(M+H)-H20], 539 (M+H), 577 (M+K).

Anal. Calcd for C18H30KJO7PS 1.0 H20: 10 C, 38.83; H, 5.79; P, 5.56; S, 5.76 Found: C, 38.85; H, 5.84; P, 5.33; S, 5.57.

Example 40 3-Phenoxy-cx-phosphonobenzenebutanesulfonic acid, 15 tripotassium salt A. (E)-3- (3-Phenoxyphenyl)-2-propenoic acid, ethyl ester Triethyl phosphonoacetate (6.5 mL, 32.8 20 mmol) was added dropwise to a suspension of sodium hydride (0.73 g, 30.2 mmol) in THF (40 mL) at 0°C under argon. The ice bath was removed and the suspension was stirred at RT for 20 min, at which time a clear colorless solution resulted. The 25 reaction solution was recooled to -78°C and a solution of 3-phenoxybenzaldehyde (5.0 g, 25.2 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred at -78°C for 4 5 min. After warming to RT, the reaction was quenched with 30 saturated ammonium chloride solution. Diethyl ether (200 mL) was added, the organic layer was washed with H2O (50 mL) , brine (50 mL) and dried over MgS04. Evaporation gave 4.0 g of title ester (96%) as a colorless oil. 2802 HX59a 193 - B. 3-Phenoxybenzenepropanoic acid, ethvl ester A mixture of Part A ester (6.5 g, 24.3 mmol) 5 and palladium on carbon (10%, 300 mg) in ethyl acetate (50 mL) was stirred under a hydrogen atmosphere (balloon) overnight at RT. The reaction mixture was filtered through Celite. Evaporation of filtrate gave a crude oil. Purification was 10 performed by flash chromatography on 400 g silica gel, loaded and eluted with 10% ethyl acetate in hexane. Pure fractions were combined and evaporation gave 5.45 g of title ester (84%) as a colorless oil.

C. 3-Phenoxvbenzenepropanol Lithium aluminum hydride solution (20.5 mL, IM in THF, 20.5 mmol) was added dropwise to a solution of Part B ester (5.45 g, 20.5 mmol) in THF 20 (50 mL) at 0°C under argon. Stirring was continued for 10 min. Ethyl acetate (5 mL) was added until bubbling ceased. Ethyl ether (300 mL) was added and the organic layer was washed with IN HCl solution (2 xl50 mL), H20 (150 mL), saturated 25 sodium bicarbonate (150 mL), and brine (150 mL), then dried over MgS0<. Evaporation gave a pale yellow oil. Purification was performed by flash chromatography on 500 g silica gel, loaded and eluted with 15% ethyl acetate in hexane. Pure 30 fractions were combined and evaporated to give 4.2 g of title alcohol (90%) as a colorless oil. 280 7 HX59a * D. 1-(3-Iodopropvl)-3-ohenoxvbenzene Iodine (1.80 g, 7.24 mmol) in THF (5 mL) was added to a mixture of Part C alcohol (1.5 g, 6.58 mmol), triphenylphosphine (1.90 g, 7.24 mmol) and 5 imidazole (0.89 g, 13.2 mmol) in THF (15 mL). The reaction mixture was stirred at RT for 20 min, then diluted with hexane (200 ml). The organic layer was washed with 10% sodium bisulfite (50 mL) , saturated sodium bicarbonate (50 mL) , brine (50 mL) 10 and dried over MgSO<. The solvent was evaporated to 100 ml volume, 10 g silica gel was added and the mixture was evaporated to dryness. Flash chromatography was performed on 100 g silica gel, loaded and eluted with hexane. Pure fractions were 15 combined and evaporated to give 1.70 g of title iodide (76%) as a colorless oil.

E. 3-Phenoxy-a-(diethoxyphpsphinyl)-benzenebutanesulfonic acid, cvclohexvl ester To a stirred suspension of sodium hydride (241 mg, 10.1 mmol) in DMF (10 mL) at 0°C under argon. Example lA Part B sulfonate (3.95 g, 12.6 mmol) in DMF (4 mL) was added dropwise over 15 min. The ice bath was removed and the reaction mixture 25 was stirred at RT for 30 min. The reaction mixture was recooled to 0°C and a DMF solution (10 mL) of Part D iodide (1.7 g, 5.03 mmol) was added dropwise over 15 min. The mixture was stirred at 0°C for 2 h. The ice bath was removed and the reaction 30 mixture was stirred at RT overnight. The mixture was diluted with 300 rnl of Et.->0 and washed with H2O (150 ml), brine (150 mL) and dried over MgSO^. Evaporation gave a crude oil. Purification was performed by flash chromatography on 100 g silica 28021 HX59a * 195 - gel, loaded and elutod with 25% ethyl acetate in hexane. The pure fractions were combined and evaporated to provide 1.5 g of title compound (57%) as a colorless oil.

F. 3-Phenoxy-a-phosphonobenzenebutane- sulfonic acid, tripotassium salt Ammonia gas was bubbled through a solution of Part E compound (1.20 g, 2.2 3 mmol) in methanol 10 (20 mL) until the solution was saturated. The sealed tube was heated at 7 0°C overnight. The reaction mixture was cooled to RT, evaporated to dryness and azeotroped with toluene. To a stirred solution of the resulting residue in dichloro-15 methane (10 mL) at RT under argon was added bromotrimethylsilane (2.6 mL, 19.6 mmol). The mixture was stirred at RT for 20 h. The solvent was evaporated and the residue was ,pumped at high vacuum for 2 h. The residue was dissolved in 1 M 20 potassium hydroxide (10 mL, 10 mmol) and the reaction mixture was stirred for 2 h. The solution was lyophilized to give a white solid. The crude product was purified by chromatography on CHP20P gel (2.5 x 20 cm), loaded and eluted with water and 25 followed by a gradient created by the gradual addition of CH3CN to a reservior of water. The combined pure fractions were concentrated to about 5 mL volume then lyophilized to provide 780 mg (47%) of title compound as a white solid.

IR (KBr) 2957, 1613, 1595, 1489, 1250, 1202, 1074, 966 cm"1 28021 HX59a " Mass Spec (FAB, + ions) m/z 463 (M-K+2H), 501 (M+H), 539 (M+K).

Anal. Calc'd for Ci^H^KjCbPS • 1.8 equiv H2O: 5 C, 36.05; H, 3.71; p, 5.81; S, 6.01.

Found: C, 36.05; H, 3.97; p, 5.58; S, 6.06.

Example 41 (E, E)-1-[Bis[(2,2-Dimethyl-l-oxopropoxy)methoxy]-10 phosphinyl]-6,10,14-trimethyl-5,9,13- pentadecatriene-1-su1fonic acid, cvclohexvl ester A. 2,2-Dimethylpropanoic acid, iodomethyl ester Sodium iodide (dried) (15.0 g, 100 mmol) was added in one portion to a solution of 2,2-dimethyl-propanoic acid, chloromethyl ester (10.0 g, 66.7 mmol) in dry acetonitrile (80 mL) at RT under argon. The heterogeneous reaction was stirred at 20 RT for 6 h, then concentrated in vacuo. The residue was partitioned between toluene (150 mL) and 5% sodium bisulfite (40 mD. The organic layer was washed with 5% sodium bisulfite (40 mL) and water (20 iriL) , then dried over MgSOs. Evaporation 25 gave title iodide (12.1 g, 75%) as a pale yellow oil.

B. (E,E)-1-Phosphono-6,10,14-trimethyl-pentadecatriene-l-sulfonic acid, cyclohexyl ester, disilver salt Bromotrimethylsilane (1.45 mL, 11.0 mmol) was added dropwise to a solution of Example IA Part C sulfonate (1.50 g, 2.75 mmol) and allyltrimethyl-silane (4.36 mL, 27.5 mmol) in CH:C1:- (5 mL) at RT 28021 HX59a ' under argon. The clear yellow reaction was stirred at RT for 52 h, concentrated in vacuo, then pumped at high vacuum overnight to give an orange oil.

The crude silyl ester prepared above was 5 dissolved in IN KOH (6.05 mL, 6.05 mmol) over 15 min, then added dropwise over 5 min to a solution of silver nitrate (1.17 g, 6.88 mmol) in water (100 mL) under argon in the dark (Al foil). The resultant tan suspension was stirred at RT for 10 10 min, then the reaction mixture was lyophilized to give a tan solid. The lyophilate was partitioned between toluene (50 mL) and water (50 mL). The aqueous layer was extracted with toluene (3 x 50 mL). The combined organic extracts were washed 15 with water containing a few drops of brine (20 mL), then dried over Na7S04. Evaporation followed by pumping under high vacuum fox- 30 min gave title compound (1.91 g, 99%) as a brown^gum.

C. (E,E)-1-[Bis[(2,2-Dimethyl-1-oxo- propoxy)methoxy]phosphinyl-6,10,14-trimethyl-5,9,13-pentadecatriene-l- sulfonic acid, cvclohexvl ester A solution of Part B compound (1.91 g, 2.71 25 mmol) in toluene (20 mL) was cooled to 0°C under argon. A solution of Part A ester (1.66 g, 6.88 mmol) in toluene (5 mL) was added to the brown solution over 5 min. After 5 min at 0°C, a solid precipitated out of solution. The reaction was 30 stirred an additional 15 min, then filtered through a 0.45 (lm filter. The filtrate was concentrated in vacuo to give a pale yellow oil, which was purified by flash chromatography on silica gel (100 g) O (% *'•' U C HX59a' eluting with 15:85 EtOAc/hexane to provide title compound (1.34 g, 67%) as a colorless oil.

TLC (20:80 EtOAc/hexane): R; = 0.21 IR (neat) 2965, 2936, 1757, 1134, 959 cm"J.

MS (CI, NH3) m/z 736 (M+NH.,).

Anal. Calc'd for C^H^Ot:-PS: C, 60.15; H, 8.83; P, 4.31; S, 4.46. Found: C, 60.08; H, 9.03; P, 4.47; S, 4.18.

Example 42 (E,E) -1- [Bis[ (2,2-Dimethyl-l-oxopropoxy)methoxy] -phosphinyl]-6,10,14-trimethyl-5,9,13- pentadecatriene-1-sulfonic acid, monopotassium salt / Potassium acetate (403 mg, 4.11 mmol) was 20 added to a solution of Example 41 compound (982 mg, 1.37 mmol) in 2,2,2-trifluoroethanol/water (10:1, 10 mL) at RT under argon. After dissolution, the clear colorless reaction was heated at 40°C overnight (18 h), then concentrated in vacuo. The 25 slightly colored oil was dissolved in EtOAc (30 mL) and washed with saturated KHCO..- (2 x 5 mL) and half-saturated KC1 (10 mL). The organic layer was dried over anhydrous KCl. Evaporation followed by pumping under high vacuum overnight gave title salt 30 (893 mg, 97%) as a colorless oil.

TLC (10:90 MeOH/CH2CliO : R-- = 0.18 IR (neat) 2969, 2920, 1755, 1248, 1136, 1005 cnr1. 2R0?1 HX59a " MS (FAB, + ions) m/z 713 (M+K), 675 (M+H).

Anal. Calc'd for C30H52KO10PS C, 53.39; H, 7.77 Found: C, 53.30; H, 7.81 P, 4.59; S, 4.75 P, 4.84; S, 5.19 Example 43 a-Phosphono(1,1':4',1"-terphenvl]-4 "-butanesulfonic 10 acid, tripotassium salt A. 4-Aminobenzenepropanoic acid, ethyl ester A 500 mL P<?.rr hydroge-nation vessel was 15 charged with 12.36 g (55.9 mmol) of (E)-3-(4- nitrophenyl)-2-propenoic acid, ethyl ester, 100 mL of absolute ethanol, 15 mL of concentrated hydrochloric acid and 0.75 g of 10%, palladium-on- / activated charcoal. The slurry was purged with 20 nitrogen and then agitated under an initial pressure of 44.5 psi of hydrogen gas. After 16 h, 18.5 psi had been consumed. The flask was evacuated, purged again with nitrogen and the contents filtered through Celite and evaporated. 25 The residue was dissolved in water and adjusted to pH 9-with solid sodium carbonate. The resulting mixture was extracted thrice with dichloromethane and the combined organic extracts dried over Na2S04, filtered and evaporated to provide 9.31 g, 86% of 30 title compound as a yellow oil, sufficiently pure for use in subsequent reactions. 2R0218 HX59a B. 4-Iodobenzenepropanoic acid, ethvl ester To a stirred solution of*6.48 g (33.6 mmol) of Part A amine in 10 mL (120 mmol) of diiodomethane under nitrogen at room temperature 5 was added 9 mL (67 mmol) of isoamyl nitrite over 10 min. The orange solution was stirred for 30 min and then heated to 80°C for 2 h. The deep orange solution was diuted with ether and washed once with 2 M HCl, once with water, once with saturated 10 sodium bicarbonate solution and once, with saturated sodium bisulfite solution. The organic phase was dried (MgSOij) and evaporated. Purification by flash chromatography on silica gel (5 x 20 cm column) eluted with 3:2 hexanes/dichloromethane 15 gave title iodide as a colorless oil, 8.65 g, 85% yield.

C. [1,141"-Terphenyl]-A-propanoic acid, ethyl ester To a stirred solution of 1.17 g (5.0 mmol) of 4-bromobiphenyl in 10 mL of THF at -75°C under argon was added 5.9 mL (10.0 mmol, 1,7 M in pentane) of t-butyllithium dropwise over 15 min. After an additional 15 min, the blue-green so1.ution 25 was warmed to 0"C, stirred 30 min and a solution of 1.86 g (14 mmol) thrice-fused zinc chloride in 15 mL of THF was added. The resulting colorless, turbid solution was stirred for 1 h and then a solution of 1.00 g (3.3 mmol) of Part B iodide and 30 0.3 g (0.26 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO;) and evaporated. 2PO?1r HX59a ■ Purification by flash chromatography on silica gel (5 x 15 cm column) eluted with 1-1:9 hexanes/dichloromethane gave title ester as an off-white solid, 1.07 g , 98% yield, mp 172-174°C.

D. fl.1:4■.1"-Terphenvll-4-propanol To a stirred solution of 1.00 g (3.0 mmol) of Part C ester in 5 mL of THF under nitrogen at room temperature was added 3 mL (3 mmol) of 1 M 10 lithium aluminium hydride in THF. The reaction was stirred for 1 h, quenched with brine and brought to pH 1 with 2 M H2SO4. Extracted thrice with 100 mL portions of ethyl acetate. The organic extracts were combined, dried (MgSO^) and evaporated to give 15 title alcohol as gray flakes, mp 210-212°C, 740 mg. 86% yield. The compound was used without further purification. t s E. 4-(3-lodopropvl) f1.1':4'.1"-terphenvll 20 To a stirred solution of 720 mg (2.50 mmol) of Part D title alcohol, 660 mg (2.51 mmol) of triphenylphosphine, and 375 mg (5.5 mmol) of imidazole in 20 mL of THF under argon at room temperature was added a solut?vn of 640 mg (2.5 25 mmol) of iodine in 5 mL of THF, dropwise over 20 min. After addition was complete, the reaction was diluted with hexanes and washed once with saturated sodium bisulfite solution. The organic phase was dried (MgS04) and evaporated. Purification by 30 flash chromatography on silica gel (5 x 10 cm column) eluted with CH^Cl- gave title iodide as a white solid, 860 mg, 86% yield.

HX59a - F. a- (Diethoxyphosphinyl) [1,1': 4 ', 1" - terphenyl]-4-butanesulfonic acid, cyclohexyl ester To a stirred slurry of 145 mg (3.6 mmol, 60% 5 mineral oil dispersion) of sodium hydride in 3 mL of DMF under argon at -10°C was added a solution of 1.26 g (4.0 mmol) of Example IA Part B sulfonate in 2 mL of DMF. After addition was complete, the reaction was warmed to room temperature and stirred 10 for 30 min. To the resulting solution was added 800 mg (2.00 mmol) of Part E title iodide as a powdered solid. The reaction mixture was diluted with 1.5 mL of THF to form a turbid slurry. The reaction was stirred for 16 h, diluted with 100 mL 15 of ether and washed once with 10% citric acid and thrice with water. The organic phase was dried (MgS04) and evaporated. Purification by flash chromatography on silica gel (5 x ,15 cm column) eluted with 1:19 ether/dichloromethane gave title 20 compound as a colorless oil, 620 mg, 53% yield.

G. a-Phosphono[1,1*:4',1"-terphenyl5-4"-butanesulfonic acid, tripotassium salt To a stirred solution of 590 mg (1 mmol) of 25 Part F compound in 7 mL of dichloromethane under argon at room temperature was added 420 |iL (3 mmol) of bromotrimethylsilane. After 24 h, the resulting clear solution was evaporated at 25°C and the residue dissolved in 10 mL of THF. To this stirred 30 solution was added 550 mg (3.3 mmol) of dried, finely ground potassium iodide and 5 mg (0.015 rnmol) of 18-crown-6. The resulting slurry was heated to reflux for 24 h, evaporated and then suirred for 1 h w? th 6 mL (3 rnmol) of 0.5 H £o0 21B HX59a • potassium hydroxide solution. The solution was lyophilized and then purified by*MPLC (2.5x20 cm column of Mitsubishi Kasei Sepabeads CHP20P resin): 11.5 mli fractions, 7 mL/min flow rate, eluted with 5 140 mL water and then a gradient of 500 mL 3:2 acetonitrile/H20 into 450 mL H-O) . Fractions 41-49 were collected and lyophilized to give title compound as a white solid, 480 mg, 78% yield.

IR (KBr pellet) 3407, 3092, 2932, 2864, 1634, 1485, 1198, 1078, 1049, 966 cm"! .

Anal. Calc'd for C^^oKhO.-PS-3 .1 H:0: C, 42.83; H, 4.29; P, 5.02; S, 5.20 15 Found: C, 42.83; H, 4.19; P, 5.03; S, 5.18.

MS (FAB, + ions) m/e 561 (M+H), 523 (M-K+2H), 485 (M-2K+3H).

Example 44 4-(2-Methylphenoxy)-a-phosphonobenzenebutane-sulfonic acid, tripotassium salt The title compound was prepared as 25 described herein and has the following properties.

TLC (n-propanol/NH4OH/H2O5 : 4 :1) (silica gel) (Rf=0.26) IR (KBr) 2951, 2932, 1653, 1507, 1240, 1204, 1076, 966, 878 cm"1 MS (FAB, + ions) m/z 477 (M-K+2H), 515 (M+H). 553 (M+K).

HX59a " Anal. Calcd for C17H18K3O7PS • 2.3* equiv H?0: C, 36.72; H, 4.10; P, 5.57; S, 5.77.

Found: C, 36.72; H, 3.91; P, 5.51; S, 5.54.

Example 45 3- (3-Propylphenoxy) -a-phosphonobenzenebutane-sulfonic acid, tripotassium salt A. 3-Iodobenzenepropanoic acid. et-.hvl ester (1). (E)-3-(3-Nitrophenyl)-2-propenoic acid, ethvl ester A mixture of 3-nitrocinnamic acid (11.7 g, 15 60.6 mmol), concentrated sulfuric acid (0.16 mL, 3.03 mmol) and absolute ethanol (120 mL) was refluxed overnight. The reaction mixture was poured into ice water ( 400 mL) . yhe mixture was extracted with ethyl ether (500 mL x 2). The 20 organic layer was washed with saturated sodium bicarbonate solution (100 mL x 2), water (100 mL x 2), brine (100 mL x 2) and dried over magnesium sulfate. Evaporation gave L. cle compound (12.0 g, 99%) as a colorless oil. (2) 3-Aminobenzenepropanoic acid, ethvl ester A Parr hydrogenation vessel was charged with Part (1) compound (12.0 g, 54.3 mmol), concentrated 30 HCl (15 mL, 0.15 mmol), 10% palladium on carbon (750 mg) and absolute ethanol (75 mL). The slurry was purged with nitrogen and agitated under an initial pressure of 45 psi of hydrogen gas. After 16 h, the flask was evacuated and the contents ^80 2 HX59a * filtered through Celite and evaporated. The residue was dissolved in water and adjusted to pH 9 with solid sodium carbonate. The resulting mixture was extracted with dichloromethane (250 mL x 2).

The combined extracts were evaporated to give the title compound (8.7 g, 86%) as an oil. (3) 3-Iodobenzenepi-opanoic acid, ethvl ester To a solution of Part (2) compound (7.2 g, 32 mmol) in diiodomethane (10.3 mL, 128 mmol) under argon at RT was added isoamyl nitrite (6.5 mL, 64 mmol) over 10 min. The brownish solution was stirred at RT for 40 min and then heated to 80°C 15 for 2 h. Ethyl ether (300 mL) was added to the reaction and the organic layer was washed with IN hydrochloric acid (70 mL x 2), water (70 mL), saturated sodium bicarbonate (70 ml> x 2) , 10% sodium bisulfite solution (30 mL) and dried over 20 magnesium sulfate. Purification was performed by flash chromatography on 800 g silica gel, loaded and eluted with 7% ethyl acetate in hexane. Pure fractions were combined and evaporated to give the title compound (4.1 g, 42%) as a colorless oil. b. 3-PrppylphenQl (1) 3-(l-Propenvl)phenol To a suspension of (ethyl)triphenylphos-30 phonium bromide (35 g, 94.3 mmol) in THF (95 mL) was added potassium bis (trimethylsilyl)amide (180 ml, 0.5 M in toluene, 90.2 mmol) dropwise. The reaction was stirred at 0"C for 30 min, then a solution of 3-hydroxy-benzaldehyde (5 g, 41.0 mmol) 0 218 HX59a ' in THF (5 mL) was added dropwise. After addition the reaction was stirred at 0"C "for lh. Ethyl ether (200 mL) was added to dilute the reaction. The organic layer was washed with water (50 mL x 5 2) , brine (50 mL x 2) and dried over magnesium sulfate. Purification was performed by flash chromatography on 600 g silica gel, loaded and eluted with 10% ethyl acetate in hexane. Pure fractions were combined and evaporated to give the 10 title compound (5.1 g, 93%) as a colorless oil. (2) 3-Propylphenol To a mixture of Part B(l) compound (3 g, 22.4 mmol) and 10 % palladium on carbon (150 mg) in 15 THF (25 mL) was connected a hydrogen balloon.

Hydrogenation was maintained at RT overnight. The mixture of reaction was filtered through Celite. The resulting clear solution was evaporated to give the title compound (2.97 g, 100%) as a yellowish 20 oil.

C. 3 -(3-Propylphenoxy)benzenepropanoic acid, ethvl ester To a suspension of sodium hydride (155 mg, 25 6.44 mmol) in pyridine (25 mL) was added a solution of Part B compound (1.5 g, 11.0 mmol) in pyridine (2.5 mL) at 0°C under argon. Stirring was continued until the solution was clear (15 min). The reaction was warmed to RT, and a solution of 30 Part A compound (2.5 g, 8.27 mmol) in pyridine (2.5 mL) was added to the reaction followed by copper bromide-dimethyl sulfide complex (2.27 g, 11.0 mmol). The reaction was refluxed for 24 h. The reaction was cooled to RT. The mixture of reaction £b\) 21 HX59a ■ 207 - was filtered and evaporated to dryness. Ethyl ether (250 mL) was added to the resulting residue, and the organic layer was washed with IN HCl (2 x 50 mL), water (2 x 50 mL), saturated sodium 5 bicarbonate solution (50 mL), brine (50 mL) and dried over MgS04. Purification was performed by flash chromatography on 200 g silica gel, loaded and eluted with 10% ethyl acetate in hexane. Pure fractions were combined and evaporated to give the 10 title compound (1.68 g, 65%) as a colorless oil.

D. 3-(3-Propylohenoxv)benzenepropanol Lithium aluminum hydride solution (5.29 mL, IM in THF, 5.29 mmol) was added dropwise to a 15 solution of Part C compound (1.65 g, 5.29 mmol) in THF (10 mL) at 0°C under argon. Stirring was continued for 10 min. Ethyl acetate (5 mL) was added to destroy excess LAH. EthyO. ether (2 00 mL) was added and the organic layer was washed with IN 20 HCl solution (2 x 50 mL), HO (50 mL), saturated sodium bicarbonate solution (50 mL), and brine (50 mL), then dried over MgSO^. Evaporation gave the title compound (1.3 g, 91%) as a colorless oil.

E. 1-(3-Iodopropyl)-3-((3-propylphenoxy)- benzene A solution of iodine (1.35 g, 5.3 mmol) in THF (5 mL) was added to a mixture of Part D compound (1.3g, 1.43 mmol), triphenylphosphine 30 (1.39 g, 5.3 mmol) and imidazole (655 mg, 9.64 mmol) in THF (15 mL). The reaction mixture was stirred at RT for 10 min, then diluted with hexane (200 ml). The organic layer was washed with 10% sodium bisulfite (50 mL.) , saturated sodium HX59a " bicarbonate (50 mL), brine (50 mL) and dried over MgSC>4. The solvent was evaporated to 100 mL volume, 6 g silica gel was added, and the mixture was evaporated to dryness. Flash chromatography 5 was performed on 200 g silica gel, loaded and eluted with hexane. Pure fractions were combined and evaporated to give the title compound (1.6 g, 88%) as a colorless oil.

F. a-(Diethoxyphosphinyl)benzenebutane- sulfonic acid, cvclohexvl ester To a stirred suspension of sodium hydride (126 mg, 5.26 mmol) in DMF (5 mL) at 0°C under argon, Exaple lA Part B sulfonate (2.1 g, 6.58 15 mmol) in DMF (2 mL) was added dropwise over 15 min. The ice bath was removed and the reaction mixture was stirred at RT for 30 min. The reaction mixture was recooled to O'C and a solution, *of Part E compound (1.0 g, 2.63 mmol) in DMF (2 mL) was added 20 dropwise over 15 min. The mixture was stirred at 0°C for 2 h. The ice bath was removed and the reaction mixture was stirred at RT overnight. The mixture was diluted with ethyl ether (250 mL) and washed with H2O (50 ml), brine (50 mL) and dried 25 over MgS04. Evaporation gave a crude oil.

Purification was performed by flash chromatography on 150 g silica gel, loaded and eluted with 30% ethyl acetate in hexane. The pure fractions were combined and evaporated to provide the title 30 compound (1.1 g, 74%) as a colorless oil. 28021 HX59a " G. 3-(3-Propylphenoxy)-oc-phosphonobenzene- butanesulfonic acid. tripotassium salt Ammonia gas was bubbled through a solution of Part F compound (800 mg, 2.19 mmol) in methanol 5 (10 mL) until the solution was saturated. The sealed tube containing the reaction was heated at 70°C overnight. The reaction mixture was cooled to RT, evaporated to dryness and azeotroped with toluene (2 x 20 mL). To a stirred solution of the 10 resulting residue in dichloromethane (10 mL) at RT under argon was added bromotrimethylsilane (2.22 mL, 15.3 mmol). The mixture was stirred at RT for 20 h. The solvent was evaporated and the residue was pumped at high vacuum for 2 h. The residue was 15 dissolved in 1 M potassium hydroxide (8 mL, 8 mmol) and the reaction mixture was stirred for 2 h. The resulting clear solution was purified by chromatography on CHP20P gel (2.5 2? 20 cm), loaded and eluted with water followed by a gradient 20 created by the gradual addition of CH^CSJ to a reservior of water. The combined pure fractions were concentrated to about 5 mL volume then lyophilized to provide the title compound (500 mg, 42%) as a white solid.

IR (KBr) 2959, 2932, 1605, 1578, 1254, 1200, 1157. 1076, 966, 696 cnr! MS (FAB, + ions) m/z 505 (M-K+2H), 543 (M+H), 30 581 (M+K).

Anal. Calcd for Cif.H22K.iOPS • 1.7 equiv H^O: C. 39.80; H, 4.47; P, 5.40; S, 5.59.

Found: C, 39.85; H, 3.43; P, 5.25; S, 5.68. to £0U L HX59a Example 4 6 * 6-Methyl-a-phosphonobenzeneoctanesulfonic acid, tripotassium salt The title compound was prepared as described herein and has the following properties.

TLC Silica gel (6:3:1 n-propanol/conc. NHj/water) 10 Rf=0.17.

IR (KBr) 3427, 3065, 3027, 2926, 2859, 1636, 1497, 1377, 1209, 1148, 1084, 1044, 968, 698 cm"1.

Mass Spec (FAB, + ions) m/e 517 (M+K), 479 (M+H), 441 (M-K+2H).

Anal. Calc'd for C15H22O6SPK3 + 0.,54 H2O: C, 36.89; H, 4.76; P, 6.34; S, 6.56 20 Found: C, 36.59; H, 5.10; P, 6.01; S, 6.83.

Example 47 3-(2-Butylphenoxy)-a-phosphonobenzenepropane-sulfonic acid, tripotassium salt A. Tetrahv<jrp-2-Phgpo^v-?ii-pvra" Phenol (10 g, 106 mmol) was dissolved in 3,4-dihydro-2H-pyran (29 mL, 318 mmol) and one drop concentrated HCl was added at RT. The reaction was 30 stirred at RT overnight. Ethyl ether (500 mL) was added to dilute the reaction. The organic layer was washed with water (2 x 100 mL), saturated sodium bicarbonate (2 x 100 mL), brine (2 x 100 mL) and i^b 0 21 HX59a ' dried over MgSOjj. Evaporation gave title compound (17 g, 100%) as a colorless oil." B. 2-(2-Butvlphenoxv)tetrahvdro-2H-pvran 5 To a solution of Part A compound (5 g, 31.3 mmol) in THF (69 mL) and ethyl ether (37 mL) was added dropwise a solution of 2.5 M n-butyllithium in hexane (15.5 mL, 38.8 mmol) at 0°C over 10 min. After an additional 30 min at O'C, the reaction was 10 allowed to warm to RTfor 5 h. The reaction was recooled to 0°C and iodobutane (7.55 mL, 66.4 mmol) was added. After 10 min at 0°C/ the reaction was allowed to warm to RT and stirring was continued overnight. Ethyl ether (300 mL) was added to dilute 15 the reaction, and the organic layer was washed with IN HCl (2 x 50 mL), saturated sodium bicarbonate (2 x 50 mL), brine (2 x 50 mL) and dried over MgS04. Evaporation gave title compound (6y0 g, 89 %) as a crude oil. c. s-ButyiLphenQl To a solution of Part B compound (6.0 g, 27.8 mmol) in dioxane (250 mL) was added 10% HCl solution (100 mL) at RT. The reaction was stirred 25 at RT for 3.5 h. Ethyl ether (200 mL) was added to dilute the reaction. The organic layer was washed with saturated sodium bicarbonate solution (2 x 100 mL), brine (2 x 100 mL) and dried over MgS04. Purification was performed by flash chromatography 30 on silica gel (500 g), loaded and eluted with 10 % ethyl acetate in hexane. Pure fractions was combined and evaporated to give title compound (3.0 g, 70%) as a colorless oil. 280218 HX59a' D. 3-(2-Butylphenoxy)benzenepropanoic acid, ethyl ester : To a suspension of potassium hydride (572 mg, 14.3 mmol)[obtained by washing a 35 wt.% 5 suspension of KH in mineral oil with hexane several times followed by evaporation of excess hexane] in pyridine (20 mL) was added a solution of Part C compound (2.2 g, 14.3 mmol) in pyridine (2.5 mL) at 0 °C under argon. Stirring was continued until the 10 solution was clear (15 min). The reaction was warmed to RT, and a solution of Example 45 Part A iodide (2.9 g, 9.53 mmol) in pyridine (2.5 mL) was added to the reaction followed by copper bromide-dimethyl sulfide complex (2.94 g, 14.3 mmol). The 15 reaction was refluxed for 16 h. Ethyl ether (150 mL) was added to dilute the reaction. The resulting mixture was filtered through Celite, the filtrate was evaporated to dryness. Ethyl ejther (200 mL) was added and the organic layer was washed with IN HCl 20 (2 x 50 mL), water (2 x 50 mL), IN potassium hydroxide solution (2 x 50 mL), brine (50 mL) and dried over MgS04. Purification was performed by flash chromatography on 200 g silica gel, loaded and eluted with 7% ethyl acetate in hexane. Pure 25 fractions were combined and evaporated to give title compound (1.2 g, 38%) as a colorless^oil.

E. 3 -(2-Butvlphenoxv)benzenepropanol Lithium aluminum hydride (LAH) solution (2.52 mL, IM in THF, 2.52 mmol) was added dropwise to a solution of Part D compound (820 mg, 2.52 mmol) in THF (8 mL) at 0°C under argon. Stirring was continued for 10 min. Methanol (5 mL) was added to destroy excess LAH. Ethyl ether (150 mL) was *bu218.

*TT HX59a ' added and the organic layer was washed with IN HCl solution (2 x 50 mL) , (50 mL) , saturated sodium bicarbonate solution (50 mL), and brine (50 mL), then dried over MgS04. Evaporation gave title 5 compound (620 mg, 87%) as a colorless oil.

F. 1-(2-Butylphenoxy)-3-(3-iodopropyl)- benzene A solution of iodine (539 mg, 2.32 mmol) in 10 THF (2 mL) was added to a mixture of Part E alcohol (600 mg, 2.11 mmol), triphenylphosphine (607 mg, 2.32 mmol) and imidazole (287 mg, 4.22 mmol) in THF (10 mL). The reaction mixture was stirred at RT for 10 min, then diluted with hexane (150 ml). The 15 orgcinic layer was washed with 10% sodium bisulfite (50 mL), saturated sodium bicarbonate (50 mL), brine (50 mL) and dried over MgSO,;. The solvent was evaporated to 100 ml volume, 5 g sj»lica gel was added, and the mixture was evaporated to dryness. 20 Flash chromatography was performed on 100 g silica gel, loaded and eluted with hexane. Pure fractions were combined and evaporated to give title compound (720 mg, 87%) as a colorless oil.

G. 3-(2-Butylphenoxy)-a-(diethoxyphos phinyl) benzenebutanesulfonic acid, cvclohexvl ester To a stirred suspension of sodium hydride (45.2 mg, 1.89 mmol) in DMF (2 mL) at 0°C under 30 argon, Example IA Part B sulfonate (642 mg, 2.04 mmol) in DMF (2 mL) was added dropwise over 15 min. The ice bath was removed and the reaction mixture was stirred at RT for 30 min. The reaction mixture was recooled to 0°C and a solution of Part F ^ \j L ^ HX59a * compound (620 mg, 1.57 mmol) in DMF (2 mL) was added dropwise over 15 min. The"mixture was stirred at 0°C for 2 h. The ice bath was removed and the reaction mixture was stirred at RT overnight. The 5 mixture was diluted with ethyl ether (150 mL) and washed with HoO (50 mL) , brine (50 mL) and dried over MgS04. Evaporation gave a crude oil. Purification was performed by flash chromatography on 150 g silica gel, loaded and eluted with 25% 10 ethyl acetate in hexane. The pure fractions were combined and evaporated to provide title compound (650 mg, 71%) as a colorless oil.

H. 3-(2-Butylphenoxy)-a-phosphonobenzene-15 butanesulfonic acid, tripotassium salt Ammonia gas was bubbled through a solution of Part G compound (650 mg, 1.12 mmol) in methanol (10 mL) until the solution was saturated. The sealed tube was heated at 70-C overnight. The 20 reaction mixture was cooled to RT, evaporated to dryness and azeotroped with toluene (2 x 20 mL). To a stirred solution of the resulting residue in dichloromethane (10 mL) at RT under argon was added bromotrimethylsilane (1.10 rnL, 7.84 .Timol). The 25 mixture was stirred at RT for 20 h. The solvent was evaporated and the residue was pumped at high vacuum for 2 h. The residue was dissolved in 1 M potassium hydroxide (8 mL, 8 mmol) and the reaction mixture was stirred for 2 h. The solution was 30 lyophilized to give a white solid. The crude product was purified by chromatography on CHP20P gel (2.5 x 20 cm), loaded and eluted with water and followed by a gradient created by the gradual addition of CHjiCN to a reservior of water. The 280218 *"* HX59a • combined pure fractions were concentrated to about 5 mL volume then lyophilized to -provide title compound (350 mg, 56%) as a white solid.

IR (KBr) 2957, 2932, 1613, 1578, 1485, 1248, 1219, 1072, 964, 557 cm-.

MS (FAB, + ions) m/z 557 (M+H), 595 (M+K).

Anal. Calc'd for CtoHimK^OtPS + 1.8 equiv H20: C, 40.77; H, 4.72; P, 5.26; S. 5.44. Found: C, 40.84; H, 4.87; P, 5.10; S, 5.38.

Example 43 (E,E)-l-Fluoro-6,10,14-trimethyl-l-phosphono- ,9,13-pentadecatriene-l-sulfonic acid, tripotassium Sftlt t A. (E,E)-1-(Diethoxyphosphinyl)-1-fluoro-20 5,9,13-pentadecatriene-l-sulfonic acid, cvclohexvl ester To a suspension of 81 mg (2.0, mmol, 1.1 eq) of sodium hydride (as a 60% mineral oil dispersion) in 1 mL of THF at 0°C was added a solution of 1.0 g 25 (1.8 mmol, 1 eq) of Example IA Part C compound in 3 mL of THF. The bubbling solution was warmed to RT and stirred for 30 min, then cooled to -78°C. A solution of 721 mg (2.3 mmol, 1.25 eq) of N-fluurobenzenesulfonimide in 2 mL of THF was added 30 over ? min and the reaction was stirred at -78°C for 1 h, then warmed to RT and stirred for 2 h. The reaction was quenched by the addition of saturated ammonium chloride, then diluted with ether. The aqueous layer was extracted with ether 280218 HX59a * 216 - and the combined organic solutions were stirred with 10% sodium thiosulfate for'30 min. The organic layer was washed with 10% KOH, dried and concentrated. Flash chromatography of the crude product on silica gel (75 g) eluting with 25% ethyl acetate in hexane afforded 674 mg (65%) of title compound as a clear colorless oil.

TLC Silica gel (10% ether in CH2Cl2) Rt-=0.78.

B. (E,E)-l-Fluoro-6,10,14-trimethyl-1-phosphono-5,9,13-pentadecatriene-l- sulfonic acid, tripotassium salt To a solution of 660 mg (1.2 mmol, 1 eq) of 15 Part A compound in 10 mL- of methanol at 0°C in a thick-walled, sealable tube was bubbled ammonia until the solution was saturated. The reaction tube was then sealed and heated at* 75°C for 19 h. The reaction mixture was allowed to cool to RT and 20 concentrated. The oily residue was coevaporated once with toluene, then with 10% hexamethvldisi-lazane in toluene (2 x 10 mL) to afford a clear oil.

To a solution of the oil in 5 mL of dry 25 CH2Cl2 at RT was added 986 fiL (4.7 mmol, 4 eq) of hexamethyldisilazane followed by 771 ^L (5. Li mmol, 5 eq) of bromotrimethylsilane (TMSBr) dropwise over 1 min. After 22 h at RT, the reaction was concentrated and the resulting semisolid was placed 30 on high vacuum (0.25 mm Hg) for 1 h. The residue was dissolved by adding 4.7 mL (4 eq) of 1 M potassium hydroxide followed by 5 mL of water, frozen and lyophilized to afford an off-white lyophilate. Th- lyophilate was purified by MPLC on 280218 — HX59a a column of CHP20P (2.5 cm x 25 cm) eluting initially with 150 mL of water followed by a gradient formed by gradual addition of 400 mL of 50% acetonitrile in water to a reservoir containing 5 400 mL of water. Fractions containing pure product were pooled, concentrated, filtered, frozen and lyophilized. The lyophilate was dissolved in a minimum amount of water and concentrated. The resulting semisolid residue was triturated with 10 acetone to afford, after high vacuum (0.025 mm Hg) removal of acetone remnants, 236 mg (60%) of a white solid.

TLC silica gel (5:4:1 n-propanol:ammonium 15 hydroxide:water): Rf=0.43.

IR (KBr): 3426(br), 2969, 2926, 2857, 1663,1451, 1213, 1101, 982 cnr';.

Mass Spec (FAB, + ions): m/z 541 (M + H) , 503 (M + 2H - K).

Anal. Calcd for C-,H_ .0. FPSK, + 1.13 HO: C, 38.53; H, 5.62; S, 5.71; P, 5.52 25 Found: C, 38.53 ; H, 5.87; S, 5.40; P, ri.38.

Example 49 (E, E) -1-[Bis[l- (1-Oxopropoxy)ethoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-l-sulfonic 30 acid, monopotassium salt A. ££.QB-3noiC acid. 1-chloroethvl ester To freshly fused zinc chloride (50 mg) was added CH2CI2 (20 mL) followed by propionyl chloride 280 218 HX59a (10.0 g, 108 mmol). The mixture was cooled to 10°C and acetaldehyde (6.0 mL, 108 mmol) was added over 5 min. The brov:n reaction was allowed to warm to RT, then stirred at that temperature overnight.

The reaction was diluted with CH2CI2 (50 mL) and washed with 20% aqueous sodium acetate (20 mL). The organic layer was dried over MgSO^ and evaporated to give a brown oil, which was distilled under high vacuum (0.5 torr) to give title compound 10 (1.48 g, 10%) in the form of <a clear, colorless liquid bp 28-31°C B. (E,E)-1-[Bis[1-(1-Oxopropoxy)ethoxy]-phosphinyl]-6,10,14-trimethyl-5,9, 13-15 pentadecatriene-l-sulfonic acid, mnnnnotassium salt A solution of Example IB tripotassium salt (500 mg, 0.953 mmol) in water (3 mlr) was added dropwise slowly via syringe pump at a rate of 0.24 20 mL/min to a solution of silver nitrate (586 mg, 3.44 mmol) in water (2 mL) at RT under argon. A white precipitate began to form immediately upon addition. The reaction was stirred at RT for 10 min, then filtered. The solid obtained was washed 25 with water (2x2 mL) and diethyl ether (2 mL), then pumped under high vacuum for 7 h to give 567 mg of a silver salt in the form of a white solid.

To a suspension of the silver salt prepared above in CH^Cl^ (2 irL) under argon in the dark at RT 30 was added 2,4 , 6-collidine (110 |iL, 0.836 mmol) followed by a solution of Part A compound (568 mg, 4.18 mmol) in CH^Cl: (1 mL) . The reaction was stirred at RT for 6 h, filtered through Celice with the aid of Ch'^Cl^, then concentrated in vac jo t o Z8Q218 HX59a give an opaque oil. The crude material was dissolved in EtOAc (10 mL) and washed with IN HCl (5x2 mL) , saturated KHCO.< (2x2 mL) , and saturated KCl (2 mL), Chen dried over anhydrous 5 KCl. Evaporation gave a pale yellow oil, which was chromatographed (2.5 x 20 cm CHP20P gel, 10 mL fractions, water elution followed by a gradient of acetonitrile in water). The product-containing fractions were combined and evaporated to give ah 10 opaque gum, which was dissolved in CH;C1; and dried over anhydrous KCl. Evaporation gave title compound (369 mg, 68%) as a colorless oil as a mixture of four diastereomers.

TLC (silica gel) (15:85 MeOH/CH^Cl:) : Rr- = 0.42.

IR (neat) 2940, 2924, 1751, 1256, 1209, 1107, 1084, 1047, 978, 949 cnr; .

M ss Spec (FAB, + ions) m/z 685 (M+K).

Anal. Calcd for C2aH.^KO:. PS: C, 51.99; H, 7.48; P, 4.79; S, 4.96. Found: C, 51.69; H, 7.49; P, 4.44; S, 5.92. i>eU2'° ^ - 220 - The following additional examples may be prepared employing procedures set out hereinbefore including in the working Examples. 50. (E)-6-methyl-10-phenyl-l-phosphono-5- decene-l-sulfonic acid, tripotassium salt; Mas Spec (FAB, + ions) m/z 519 (M+H), 481 (M+2H-K).

Anal. Calcd for CisH2606SPK3 + 1 .3 H20: 10 C, 39.82; H, 5.33; P, 5.70; S, 5.90 Found: C, 39.82; H, 5.63; P, 5.49; S, 5.65. 51. (E)-9-cyclopentyl-6-methyl-l-phos-phono-5-nonene-1-sulfonic acid, tripotassium salt; 15 Mass Spoc (Ion Spray, + ions) m/z 445 (M-K+2H), 483 (M+H).

Anal. Calcd for C15H26O6SPK3+O.70 H20: C, 3 6,39; H, 5.57: p, 6,>26; S, 6.48 Found: C, 3 6.60; H, 5.98; P, 5.92; S, 6.23. 52 . a-phosphono-4'-methyl[1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt; Mass Spec (electrospray, CH2CN, NH3, + ions) m/_ 508 (M-3K+4H+3CH3CN), 467 (M-3K+4H+2CH2CN), 461 (M-K+2H) , 443 C4-3K+3H+NH4+CH?.CN) , 426 (M-3K+4H+CH3CN) , 423 (M+H-2K), 40^. (M-3K+3H+NH4) , 385 (M-3K+4H).

Anal. Calcd for C17H18K3O6PS + 1. 4 H2O: 30 C, 38.98; H, 4.00; P, 5.91; S, 6.12 Found: C, 39.32; H, 4.03; P, 6.12; S, 5.73. 53. a-phosphono-4-(3-propylphenoxy)-benzene-butanesulfonic acid, tripotassium salt; /SO 218 Vf HX59a Mass Spec (FAB, + ions) m/z 429 (M+4H-3K), 467 (M+3H-2K), 505 (M+2H-K), 543 (M+H).

Anal. Calcd for C19H22K3O7PS+O.5 H2O: C, 41.36; H, 4.20; P, 5.61; S, 5.81 5 Found: C, 41.17; H, 3.96; P, 5.40; S, 5.98. 54. 4'-ethyl-a-phosphono[1,1"-biphenyl]-4-butaneaulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 551 (M+K), 513 (M+H), 10 475 (M-K+2H).

Anal. Calcd for C18H20K3O6PS+I.2 H2O: C, 40.48; H, 4.22; P, 5.80; S, 6.00 Found: C, 40.17; H, 4.32; P, 5.97; S, 6.45. 55. 4'-chloro-a-phosphono[1,1'-biphenyl]- 4-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, ions) m/z 557/9 (M+K) , 519/21 (M+H), 481/3 (M-K+2H).

Anal. Calcd for C16H15CIK3O6PS+O.75 H2O: 20 C, 36.10; H, 3.12; Cl, 6.66; P, 5.82; S, 6.02 Found: C, 3 5.88; H, 3.02; Cl, 6.88; P, 5.62; S, 6.42. 56. 14-methyl-1-phosphono-13-pentadecene- 1-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 537 (M+K), 499 (M+H), 461 (M-K+2H).

Anal. Calcd for C3.6H30O6SPK3 + 2.3 H2O: 30 C, 35.63; H, 6.45; P, 5.74; S, 5.94 Found: C, 35.63; H, 6.27; P, 5.71; S, 6.14. ■1^2 IS w HX59a " 222 - 57. 4- (phenylthio) -ot-phosphonobenzene-butane-sulfonic acid, tripotassium salt; Mass Spec (FAB, +ions) m/z 441 (M+3H-2K), 479 (M+2H-K) , 517 (M+H).

Anal. Calcd for C16H16K3O6PS2+1. 6 H2O: C, 35.23; H, 3.55; P, 5.68; S, 11.76 Found: C, 34.89; H, 3.79; P, 5.46; S, 12.19. 58. a-phosphono-4-propylbenzeneoctane-10 sulfonic acid, tripotassium salt; Mass Spec (electrospray, + ions) m/z 427 [(M+3H-3K)+NH3+NH4] , 448 [(M+2H-2K)+NH4], 469 (M+2H-K). Anal. Calcd for C17H26K3O6PS+I.0 H2O: C, 38.91; H, 5.38; P, 5.90; S, 6.11 15 Found: C, 39.22; H, 5.27; P, 5.50; S, 6.14. 59. a-phosphono-3 -(4-propylphenoxy)-benzene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 505 (M-K+2H), 543 (M+H), 581 (M+K).

Anal. Calcd for C3.9H22X3O7PS + I.4 H2O: C, 40.18; H, 4.40; P, 5.45; S, 5.65 Found: C, 40.16; H, 4.72; P, 5.42; S, 6.06. 60. 4- [3-(2-methyl-1-propenyl)phenoxy]-a- phosphonobenzenebutanesulfonic acid, tripotassium salt ; Mass Spec (FAB, + ions) m/z 517 (M-K+2.H) , 555 (M+H), 593 (M+K).

Anal. Calcd for C20H22K3C7PS + 1.0 H2O: C, 41.94; H, 4.^2; P, 5.42; S, 5.60 Found: C, 42.01; H, 4.x0; P, 5.53; S, 5.57. 280218 HX59a - 223 - 61. (10S)-10,14-dimethyl-l-phosphono-13-pentadecene-1-sulfonic acid, dipotassium salt; Mass Spec (FAB, + ions) m/z 513 (M+H), 457 (M+2H-K), 437 (M+3H-2K).

Anal. Calcd for C17H33O6PSK2 + 2.0 H2O: C, 39.98; H, 7.30; P, 6.06; S, 6.28 Found: C, 39.92; H. 6.99; P, 5.89; S, 6.27. 62. (E,E)-1-phosphono-3-[(3,7,11-trimeth-10 yl-2,6,10-dodecatrienyl)oxy]-1-propanesulfonic acid, tripotassium salt; Mass Spec (FAB) , + ions) m/z 577 (M+K) , 539 (M+H) . Anal. Calcd for C18H30O7PSK3 + 1.25 H2Q: C, 38.51; H, 5.84; P, 5.52; S, 5-94 15 Found: C, 38.51; H. 5.95; P, 5.18; S, 5.52. 63. (E,E)-6,10,14-trimethyl-l-phosphono-5,9,13-pentadecatriene-l-sulfonic acid, 4-(methylthio)phenyl ester, dipotassium salt; 20 Mass Spec (FAB, + ions) m/z 645 (M+K), 607 (M+H) . Anal. Calcd for C25H370gPS2K2 + 4. 6 H2O: C, 43.53; H, 6.75; P, 4.49; S, 9.30 Found: C, 43.16; H, 6.25; P, 4.26; S, 9.53. 64. 4-(3-methylphenoxy)-a-phosphono- benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 515 (M+H), 553 (M+K). Anal. Calcd for C17H18K3O7PS + 2 .1 H20: C, 36.96; H, 4.05; P, 5.61; S, 5.80 30 Found: C, 36.94; H, 4.40; P, 5.49; S, 5.94. *80218 HX59a 65. (E.E)-1-[bis[[(cyclohexylacetyl)oxy]-methoxy]phosphinyl] -6,10,14-trim"ethyl-5, 9,13-pentadecatriene-l-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 793 (M+K).

Anal. Calcd for C36H60KO10PS: C, 57.27; H, 8.01; P, 4.10; S, 4.25 Found: C, 57.06; H, 8.03; P, 4.01; s, 4.56. 66. (E, E)-1-[bis[ (benzoyloxy) rriethoxy] phos- phinyl]-6,10,14-trimethyl-5, S,13-pentadecatriene-l-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 753 (M+K).

Anal. Calcd for C34H44PSO10K+0.53 H2O: 15 C, 56.37; H, 6.27; P, 4.28; S. 4.4 3 Found: C, 5 6.37; H, 6.32; P, 4.37; S, 4.32. 67 . 4- (benzoylpheny laminoj.-a-phosphono-benzene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 642 (M+K), 604 (M+H), 566 (M-K+2H).

Anal. Calcd for C23H2iNC>7SPK3 + 4.0 H2O: C, 40.88; H, 4.33; N, 2.07; P, 4.58; S, 4.74 Found: C, 40.71; H, 4.28; N, 2.12; P, 4.76; S, 4.87. 68 . 3- (benzoylphenylamino) -a-phosphono-benzene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 642 (M+K), 604 (M+H), 566 (M-K+2H). |§6'tfg HX59a " Anal. Calcd for C23H2:lN07SPK3 + 2 . 50 H20: C, 42.58; H, 4.04; N, 2.16; P, 4.77; S, 4.94 Found: C, 42.73; H, 4.24; N, 2.47; P, 4.56; 5 S, 4.88. 69. 4- (phenylamino)-a-phcsphonobenzene-butanesulfonic acid, tripotassium salt; Mass Spec (F^B, + ions) rn/z 538 (M+K), 500 (M+H), 10 462 (M-K+2H).

Anal. Calcd for Ci6Hi7N06SPK3 + 2 .0 H20: C, 35.87; H, 3.95; N, 2.61; P, 5.78 Found: C, 36.08; H, 3.96; N, 2.47; P, 5.61. 70. 3 -(phenylamino)-a-phosphonobenzene- butane-sulfonic acid, tripotassium salt; Mass spec (FAB, + ions) m/z 538 (M+K), 500 (M+H), 462 (M-K+2H).

Anal. Calcd for C16H17NO6SPK3 + 1.0 H20: 20 C, 37.12; H, 3.70; N, 2.71; P, 5.98; S, 6.19 Found: C, 36.97; H, 3.99; N, 2.47; p, 5.98; S, 6.14 71. 4-(phenylsulfinyl)-a-phosphonobenzene- butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 457 (M-2K+3H), 495 (M-K+2H), 533 (M+H).

Anal. Calcd for Ci6HigK307PS2 + l. 2 H20: 30 C, 34.67; H, 3.35; P, 5.59; S, 11.57 Found: C, 34.68; H, 3.23; P, 5.27; S, 11.41 72. 4- (2-methylphenoxy)-a-phosphono-benzenebutanesulfonic acid, tiipotassium salt; HX59a Mass Spec (FAB, + ions) m/z 477 (M-K+2H), 515 (M+H), 553 (M+K).

Anal. Calcd for C17H18K3O7PS+2.3 H2O: C, 36.72; H, 4.10; P, 5.57; S, 5.77 5 Found: C, 36.72; H, 3.91; P, 5.51; S, 5.54 73 . 4-phenoxy-a-phosphonobenzenepentane-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 476 (M-K+2H), 515 10 (M+H), 553 (M+K).

Anal. Calcd for C17H18K3O7PS + 1.3 H2O: C, 37.95; H, 3.86; P, 5.76; S, 5.96 Found: C, 38.15; H, 4.26; P, 5.63; S, 6.48 74. 4- (2-Fluorophenoxy)-a-phosphono- benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 431 (M-K+2H), 519 (M+H), 557 (M+K).

Anal. Calcd for C16H15FK3O7PS+2.6 H2O: 20 C, 33.99; H, 3.60; P, 5.48; S, 5.67 Found: C, 34.14; H 3.34; P, 5.53; S. 5.27 75. 4-(2-methoxyphenoxy)-a-phosphono-benzer.ebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 493 (M-K+2H), 531 (M+H), 569 (M+K).

Anal. Calcd for C17H18K3O3PS + 2.6 H2O: C, 35.36; H, 4.05; P, 5.36; S, 5.55 Found: C, 35.37; H, 3.81; P, 5.46; S, 5.47 76. (E,E)-l-[bis[((1-oxoheptyl)oxy]-methoxy]-phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, monopotassium salt; 218 HX59a Mass Spec (FAB, 4 ions) m/z 769 (M+K), 731 (M+H). Anal. Calcd for C34H60PSO10K+O . 06- H2O: C, 55.79; H, 8.28; P, 4.23; S, 4.38 Found: C, 55.79; H, 8.38; P, 4.31; S, 4.00 77. 4-[(4-bromophenyl)thio] -a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec HRMS (FAB, + ions) calcd for Ci6Hi779BrK206PS2: 556.8662 (M-K+2H) Found: 556.8691 Anal. Calcd for Ci6Hi5BrK306PS2 + l'. 8 H20: C, 30.60; H, 2.99; P, 4.93; S, 10.21 Found: C, 30.89; H, 3.06; P, 4.54; S, 10.16 78. 4-(phenylsulfonyl)-a-phosphonobenzene- butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) rn/z 473 (M-2K+3H) , 511 (M-K+2H) , 549 (M+H) . 587 (M+K).

Anal. Calcd for C16H16K3O8PS2 + 2. 6 H20: 20 C, 32.27; H, 3.59; P, 5.20; S, 10.77 Found: C, 32.63; H, 3.54; P, 4,80; S, 9.55 7 9. 4-phenoxy-a-phosphonobenzenepropane-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 449 (M--K+2H) , 487 (M+H) , 525 (M+K) .

Anal. Calcd for C15H14K3O7PS + 1.3 H2O: C, 35.34; H. 3.28; P, 6.08, S, 6.29 Found: C, 35.34; H, 3.49; P, 5.92; S, 6.48 80. 6-methyl-9-phenyl-a-phosphono-5 -nonene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H) Anal. Calcd for C16H22PSO6K3 + 3 . 6 H2O: C, 34,62; H, 5.29; P," 5.58; S, 5.78 Found: C, 34.29; H, 5.01; P, 5.60; S, 5.74 81. (E, E)-1-[bis [ (2-methy1-1-oxopropoxy)- methoxy]phosphinyl]-6,10,14-trimethyl-5,9,13-pentadecatriene-l-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 635 (M+K).

Anal. Calcd for C28H4SPSO10K+1.0 H20: 10 C, 50.54; H, 7.58; P, 4.51; S, 4.82 Found: C, 50.54; H, 7.47; P, 4.51; S, 4.85 82. 4-(2-butylphenoxy)-oc-phosphonobenzene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 519(M-K+2H), 557 (M+H), 595 (M+K).

Anal. Calcd for C20H24K2O7PS + 1.3 H2O: C, 41.36; H, 4.63; P, 5^33; S, 5.52 Found: C, 41.36; H, 4.98; P, 5.04; S, 5.54 83 . (E) -6-methyl-7- (4-rnethylphenoxy) -1-phos-phono-5-heptene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 531 (M+K), 493 (M+H), 455 (M-K+2H).

Anal. Calcd for C15H20O7PSK3+2.1 H2O: C, 33.96; H, 4.60; P, 5.84; S, 6.04 Found: C, 34.34; H, 5.00; P, 6.11; S, 5.81 84. (E)-6-methy1-8-(4-methylphenyl)-1-30 phosphono-5-ontenyl-l-sulfonic acid, tripotassium salt ; Mass Spec (FAB, + ions) m/z 529 (M+K) , 491 (M+H) , 453 (M-K+2H). &o U *<L i d - - - HX59a" Anal. Calcd for C16H22O6PSK3+I.74 H2O: C, 36.82; H, 4.92; P," 5.93; S, 6.14 Found: C, 36.82; H, 5.35; P, 5.98; S, 6.11 85. (E)-6-methyl-7 -(3-methylphenoxy) -1- phosphono-5-heptene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) 531 (M+K), 493 (M+H), 455 (M-K+2H).

Anal. Calcd for C15H20O7PSK3 + 0. 85 H2O: C, 35.47; H, 4.30; P, 6.10; S, 6.31 Found: C, 35.91; H, 4.73; P, 6.34; S, 6.42 86 . 4-(1-naphthaleny1)-a-phosphonobenzene-15 butanesulfonic acid, tripotassium salt; i.dss Spec (FAB, + ions) m/z 535 (M+H) , 497 (M-K+2H), 459 (M-2K+3H).

Anal. Calcd for C20H18K3O6PS + 2 .24 H^O: C, 41.77; H, 3.94; S, 5.58; P, 5.39 20 Found: C, 42.17; H, 4.38; S, 5.24; P, 5.50 87 . 4- (2, 6-dirnethylphenoxy) -a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 491 (M-K+2H), 529 (M+H), 567 (M+K).

Anal. Calcd for C18H20K3O7PS + 2 .9 H2O: C, 37.17; H, 4.48; P, 5.32; S, 5.51 Found: C, 37.17; H, 4.44; P, 5.12; S, 5.91 88. 3-(3-methylphenoxy)-a-phosphono- benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 553 (M+K), 515 (M+H). 280218 hx59a Anal. Calcd for C17H18K3O7PS+I.5 H2O: C, 37.69; H, 3.91; P,'5.72; S, 5.92 Found: C, 37.74; H, 3.92; P, 5.78; S, 6.24 89. (E)-6,10-dimethyl-l-phosphono-5,9- pentadecadiene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 549 (M+K), 511 (M+H), 473 (M+2H-K).

Anal. Calcd for C17H30O6PSK3+O.35 H20: 10 C, 39.49; H, 5.93; P, 5.99; S, 6.20 Found: C, 39.51; H, 6.16; P, 5.17; S, 5.98 90. 4-(2-benzofuranyl)-a-phosphonobenzene-butanesulfonic acid, tripotassium salt; Mass Spec m/z (FAB, + ions) 525 (M+H), 487 (M-K+2H), 449 (M-2K+3H).

Anal. Calcd for C1SH16K3PO7PS +4.5 H20: C, 35.56; H, 4.17; P, 5,.11; S, 5.29 Found: C, 35.66; H, 4.18; P, 4.83; S, 4.95 91. a-phosphono-4 ' - propyl [1,1' -biphenyl ] -4-pentanesulfonic acid, tripotassium salt, Mass Spec (FAB, + ions) m/z 541 (M+H), 503 (M+2H-K), 465 (M+3H-2K).

Anal. Calcd for C20H24O6PSK3 +1. 26 H2O: C, -12.64; K, 4.47; P, 5.50; S, 5.69 Found: C, 42.64; H, 5.11; P, 5.20; S, 5.90 92. 3-(2-methylphenoxy)-a-phosphono-30 benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 515 (M+H), 553 (M+K) Anal. Calcd for C17H18K3O7PS+1.7 h20: C, 37.45; H, 3.96; P, 5.63; S, 5.88 Found: C, 37.49; H, 4.07; P. 5.66; S, 6.00 280218 HX59a . 93 . a-[bis[(2, 2-dimethyl-1-oxopropoxy)-methoxy]phosphiny1]-3-phenoxyben z enebu tanesulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 653 (M+H), 691 (M+K). Anal. Calcd for C28H38KO10PS: C, 51.52; H, 5.87; P, 4.75; S, 4.91 Found: C, 51.33; H, 5.62; P, 4.54; S, 4.75 94. 11-phenyl-l-phosphono-l-undecane- sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 545 (M+K), 507 (M+H), 469 (M+2H-K).

Anal. Calcd for C17H26K3O6PS + 0.5 H20: 15 C, 39.59; H, 5.28; P, 6.01; S, 6.22 Found: C, 39.61; H, 5.44; P, 5.77; S, 6.46 95. a-phosphonobenzeneoctanesulfonic acid, * tripotassium salt; ' Mass Spec (FAB, + ions) m/z 503 (M+K), 465 (M+H). Anal. Calcd for C14H20K3O6PS+2 .2 H2O: C, 33.34; H, 4.88; P, 6.14; S, 6.36 Found: C, 33.34; H, 4.94; P, 5.99; S, 6.17 96. l-phosphono-7-(4-pentylphenoxy)-1- heptanesulfonic acid, tripotassium salt; Mass Spec (ion spray, + ions) m/z 464 (M+4H-3K+CH3CN), 461 (M+3H-2K), 423 (M+4H-3K).

Anal. Calcd for C18H28K3O7PS+1.34 H2O: 30 C, 38.55; H, 5.51; P, 5.52; S, 5.72 Found: C, 38.55; H, 5.66; P, 5.11; S, 6.01 97 . a-phosphono-3'-propyl[1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt: 28 0 21 HX59a" Mass Spec (FAB, + ions) m/z 565 (M+K), 527 (M+H), 489 (M-K+2H), 451 (M-2K+3H) Anal. Calcd for C19H22O6PSK3 + 1.0 H20: C, 41.84; H, 4.45; S, 5.88; p, 5.68 Found: C, 41.84; H, 4.74; S, 6.14; p, 5.30 98. 4- (4 -methylphenoxy ) -oc-phosphonobenzene butanesulfonic acid, tripotassium salt: Mass Spec (FAB, + ions) m/z 553 (m+k), 515 (M+H), 10 477 (M+2H-K) Anal. Calcd for c17h18k3o7ps + 1.7 h20: C, 37.45; H, 3.96; P, 5.68; S, 5.88 Found: C, 37.38; H, 3.79; P. 5.38; S, 6.24 99. (E,E)-4,8,12-trimethyl-1-phosphono- 3,7,11-tridecatriene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 533 (ty+K), 495 (M+H), 457 fM+2H-K) Anal. Calcd for Ci6H26PS06K?*l . 00 H20: C, 37.49; H, 5.50; P, 6.04; S, 6.25 Found: C, 37.40; H, 5.54; P, 6.08; S, 6.69 100. (E) -6-methyl-7-phenoxy-1-phosphono-5-25 heptenyl-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 517 (m+k), 479 (M+H), 441 (M-K+2H) Anal. Calcd for c14h18o7psk2 + 2. 0 h20: C, 32.67; H, 4.31; P. 6.02; S, 6.23 30 Found: C, 32.28; H, 4.25; P, 5.78; S, 6.11 101. (E)-6-methyl-7 -(4-propylphenoxy)-1-phosphono-5-heptene-l-sulfcnic acid, tripotassium salt; 280218 ~~ HX59a"" Mass Spec (FAB, + ions) m/z 521 (M+H), 483 (M-K+2H), 445 (M-2K+3H) Anal. Calcd for C17H25O7PSK2 + 1.85 H2O: C, 39.57; H, 5.61; P, 6.00; S, 6.21 5 Found: C, 39.18; H, 5.23; P, 6.14; S, 6.41 102.(E)-6-methyl-8-(3-methylphenyl) -1-phosphono-5-octenyl-1-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 529 (M+K), 491 (M+H), 453 (M-K+2H) Anal. Calcd for C16H2206PSK2 + 1.03 H20: C, 37.74; H, 4.75; P, 6.08; S, 6.30 Found: C, 37.99; H, 5.21; P, 5.90; S, 6.60 103. (E)-6-methyl-1-phosphono-7-(3-propyl-phenoxy)-5-heptene-l-sulfonic acid, tripotassium salt; , Mass Spec (FAB, + ions) m/z 521 (M+H), 483 (M-20 K+2H), 445 (M-2K+3H), 407 (M-3K+4H) Anal. Calcd for C17H24O7PSK3+0.64 ii2(->: C, 38.37; H, 4.79; P, 5.82; S, 6.02 Found: C, 38.37; H, 5.12; P, 5.83; S, 5.81 104. (E)-6-methyl-7-(2-methylphenoxy)-1- phosphono-5-heptene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 531 (M+K), 493 (M+H), 455 (M-K+2H) Anal. Calcd for Ci5H20O7PSK?. + l. 46 H2O: C, 34.72; H, 4.45; P. 5.97; S, 6.18 Found: C. 34.72; H, 4.90; P. 5.58; S, 5.92 'c.t8 """ HX59a ' 105. (E,E)-6,10,14-trimethyl-1-phosphono-5, 9-pentadecadiene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 563 (M+K), 525 (M+H), 5 487 (M+2H-K) Anal. Calcd for C18H32O6PSK3+2.0 H2O: C, 38.55; H, 6.47; P, 5.52; S, 5.72 Found: C, 38.93; H, 6.87; P, 5.62; S, 5.49 106. 4'-phenoxy-a-phosphono[1,1'-biphenyl]- butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 577 (M+:-i) , 539 (M-K+2H), 501 (M-2K+3H) Anal. Calcd for C22H30K3O7PS+I.6 H20: 15 C, 43.64; H, 3.86; P, 5.11; S, 5.29 Found: C, 43.73; H, 3.97; P, 4.71; S, 5.30 107. a-phosphono-4•-propyl 11.1•-biphenyl]-4-propanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 551 (M+K), 513 (M+H), 475 (M-K+2H) Anal. Calcd for CisH2oK306PJ+4.1 H20; C, 36.90; H, 4.84; p, 5.29; S, 5-47 Found: C, 3 6.90; H, 4.68; P, 5.05; S, 5.67 108. 3 -(4-methylphenoxy)-a-phosphono-benzenebutanesuifonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 477 (M-k+2H), 515 (M+H), 553 (M+K) Anal. Calcd for Q->HlsK307PS+2 .1 H20: C, 36 K. 4.05; P, 5.61; S, 5.80 Found: C, 3"7 h, 4.42; P, 5.43; S, 5.42 *80 2 io HX59a ' 109. (E)-8-phenyl-1-phosphono-5-octene-1-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 501 (M+K), 463 (M+H), 425 (M-K+2H) Anal. Calcd for C14H18O6PSK3 + 3.0 H2O: C, 32.50; H, 4.69; P, 5.99; S, 6.20 Found: C, 32.50; H, 4.73; P, 6.03; S, 6.40 110. 2'-methoxy-a-phosphono-4'-propyl[1,1'-10 biphenyl]-4-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 519 (M+2H-K), 481 (M+3H-2K) Anal. Calcd for C20H24K3O7PS + 2.3 H20: C, 40.16; H, 4 82; P, 5.18; S, 5.36 Found: C, 40.14; H, 4.83; P, 4.79; S, 5.44 111. (E,E)-6,10-dimethy1-12-phenyl-1-phosphono-5,9-dodecadiene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 533 (M+K), 545 (M+H), 507 (M+2H-K) Anal. Calcd for C20H28O6PSK3+O.3 H2O: C, 42.96; H, 5.34; P, 5.54; S, 5.73 Found: C, 42.96; H, 5.74; P, 5.65; S, 5.72 112 . (E)-6-methyl-7-(phenylthio)-1- phosphono-5-heptenyl-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 533 (M+K), 495 (M+H), 30 457 (M-K+2H), 419 (M-2K+3H) Anal. Calcd for C14H1SO6PS2K3 + 3 . 8 H20: C, 29.87; H, 4.58; P, 5.50; S, 11.39 Found: C, 29.87; H, 4.73; ?, 5.48; S, 11.52 L: j Ut5& -1 8 - 23 6 - 113. 3-phenoxy-a-phosphonobenzenepropane-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 499 (M+2H-K), 487 (M+H). 525 (M+K) Anal. Calcd for C15H14K3O7PS + 1.6 H2O: C, 34.95; H, 3.36; P, 6.01; S, 6.22 Found: C, 34.91; H, 3.31; P, 5.93; S, 6.23 114. 2'-(methoxymethoxy)-a-phosphono-4'-10 propyl[1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 625 (m+k), 586 (m+H), 549 (M+2H-K) Anal. Calcd for C21H26K3O8PS + 2.4 H20: C, 40.03; H, 4.93; P. 4.92; S, 5.09 Found: C, 40.03; H, 5.03; P. 4.80; S, 5.42 115. 2•-hydroxy-a-phosphon©-4'-propyl[1,1'-biphenyl]-4-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 581 (M+K), 543 (M+H), 467 (M+2H-K) Anal. Calcd for Ci9H22PS07K3 + 2.7 H2O.

C, 38.59; H, 4.67; P, 5.24; S, 5.42 Eound: C, 38.59; H, 4.58; P, 5.07; S, 5.56 116. a-phosphono-4'-(2-pyridiny1)[1,1'-biphenyl]-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 562 (M+H), 524 (M-K+2H), 486 (M-2K+3H) Anal. Calcd for C2iHi9NC>6PSK3 + 2 .'5 H2O: C, 41.57; H, 3.99; N, 2.31; P, 5.10; S, 5.28 Found: C, 41.48; H, 3.90; N, 2.40; P, 4.78; S, 5.27 d HX59a 117 . (E)-6-methyl-7-phenyl-1-phosphono-5-heptene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 501 (M+K), 463 (M+H), 4 25 (M-K+2H) Anal. Calcd for C14H18O6PSK3+2 . 9 H2O: C, 32.67; H, 4.66; P, 6.02; S, 6.23 Found: C, 32.67; H, 4.63; P, 6.13; S, 6.02 118. a-fluoro-3-phenoxy-a-phosphonobenzene-10 butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 519 (M+H), 481 (M+2H-K), 440 (M+3H-2K) Anal. Calcd for C16H15FO7PSK3+I.4 H2O: C, 35.33; H, 3.30; P, 5.69; S, 5.89 15 Found: C, 35.73; H, 3.71; P, 5.77; S, 6.09 119. (E)-6 methyl-2-.2-methylpheny1)-1-phosphono-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 523 (M+K), 491 (M+H), 453 (M-K+2H) Anal. Calcd for C16H22PSO6K3 + 2.2 h'20: C, 36.21; H, 5.02; P, 5.84; S, 6.04 Found: C, 36.29; H, 4.96; ?, 5.44; S, 6.40 120. 3-(2-naphthalenyioxv)-a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 513 (M-K+2H), 551 (M+H), 589 (M+K) Anal. Calcd for C20H18K3O7PS +3 . 8 H2O: C, 38.80; H, 4.17; ?, 5.00; S, 5.18 Found: C, 38.69; H, 4.04; F, 5.10; S, 4.96 X5=?a 121. (E)-6-methyl-l-phosphono-8-(4-propyl-phenyl)-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 557 (M+K), 519 (M+H), 5 481 (M-K+2H) Anal. Calcd for C18H26PSO6K3+3.36 mol H2O: C, 37.32; H, 5.69; P, 5.35; S, 5.53 Found: C, 37.32; H, 5.68; P, 5.46; S, 5.66 122. (E)-8-(3-methoxyphenyl)-6-methyl-l- phosphono-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 545 (M+K), 507 (M+H), 469 (M-K+2H) Anal. Calcd for C16H22PSO7K3+2.3 H2O: C, 35.04; H, 4.90; P, 5.65; S, 5.85 Found: C, 35.04; H, 5.19; P, 5.54; S, 5.41 t 123. a-phosphono-4'-(1-piperidinyl)[1,1'-20 biphenyl]-4-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 606 (M+K), 568 (M+H), 530 (M-K+2H), 492 (M-2K+3H) Anal. Calcd for C21H25K3NO5PS + 2 .7 H2O: C, 40.92; H, 4.97; N, 2.27; P, 5.02; S, 5.20 25 Found: C, 40.93; H, 4.96; N, 2.00; P, 4.S3; S, 5.53 124. ^-methyl-a-phosphono-4-propylbenzene-octanesulfonic acid, tripotassium salt; Mass Spec (Electrospray, - ions) m/z 405(M-3K+2H) 30 Anal. Calcd for C18H2SO5PSK3 + 1. 92 H2O: C, 38.93; H, 5.78; P, 5.58; S, 5.77 Found: C. 38.93; H, 6.05; P, 5.45; S, 5.90 im 218 sf HX59a * - 239 125. C' 2-dimethyl-a-phosphonobenzeneoctane sulfonic acid, tripotassium salt; Mass Spec (Electrospray, - ions) m/z 377 (M-3K+2H) Anal. Calcd for C16H24O6PSK3 + I.2 H2O: 5 C, 37.37; H, 5.17; P, 6.23; S, 6.02 Found: C, 37.87; H, 5.65; P, 6.10; S, 5.80 126 . 3- (1-naphthalenyloxy) -oc-phosphono-benzenebutancsulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 475 (M-2K+3H), 513 (M-K+2H), 551 (M+H), 589 (M+K) Anal. Calcd for C20H13K3O7PS+2 .5 H2O: C, 40.32; H, 3.89; P, 5.20; S, 5.38 Found: C, 40.42; H, 4.17; P, 5.41; S, 5.09 127 . 3-(cyclohexyloxy)-a-phosphonobenzene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 545 (M*+K) , 507 (M+H), 469 (M-K+2H).

Anal. Calcd for C16H22O7PSK3+4.2 H20: C, 32.98; H, 5.27; P, 5.32; S, 5.50 Found: C, 32.98; H, 5.25; P, 5.65; S, 5.18, 128. 3-(3-ethylphenoxy)-a-phosphonobenzene 25 butanesulfonic acid, tripotassium .alt; Mass Spec (FAB, + ions) m/z 491 (M-K+2H), 529 (M+H), 567 (M+K).

Anal . Calcd for C18H20K3O7PS +1. 6 H2O: C, 38.78; H, 4.19; P, 5.56; S, 5.75 30 Found: C, 38.94; H, 4.47; P, 5.32; S, 5.31. 129. a-phosphono-3-[3 -(trifluoromethyl)-phenoxy]benzenebutanesulfonic acid, tripotassium salt; 'L\ 8 HX59a ' Mass Spec (FAB, + ions) m/z 431 (M-K+2H), 569 (M+H), 607 (M+K) Anal. Calcd for C17H15F3K3O7PS + 1.6 H2O: C, 34.18; H, 3.07; p, 9.54; P, 5.18; S, 5.37 5 Found: C, 34.21; H, 3.15; F, 9.20; P, 5.02; S, 5.51 130. (E)-6-methyl-l-phosphono-8-[3-(trifluoromethyl)phenyl]-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (Ion Spray, - ions) m/z 429 (M-3K+2H) , 411 (M-3K+2H-H20).

Anal. Calcd for C16Hi9F?.K?.PSOr, + 2 .3 H2Or C, 32.78; H, 4.06; P, 5.28; S, 5.47 Found: C, 32.78; H, 4.41; ?, 5.55; S, 5.86. 131. 3-phenoxy-a-phosphonobenzenepentane-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 477 (M+2H-K), 515 (M+H), 553 (M+K) Anal. Calcd for C17H18K3O7PS + 1.3 h20: C, 37.95; H, 3.86; P, 5.76; S, 5.96 Found: C, 37.95; H, 4.24; P, 5.56; S, 5.97. 132. 3-[2- (3-methylbutyl)phenoxy]-a-phos-25 phonobenzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 533 (M-K+2H), 571 (M+H), 609 (M+K) Anal. Calcd for C2iH26K:<07PS + .1.5 H20: C, 42.19; H, 4.85; P, 5.13; S, 5.3 6 30 Found: C, 42.33; H, 5.15; P, 4.96; S, 5.02. a ,218 HX59a ' 241 - 133. 3-[2-(3-methyl-2-butenyl)phenoxy]-a-phosphonobenzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 569 (M+H), 607 (M+K) 5 Anal. Calcd for C21H24K3O7PS+2.2 H20: C, 41.46; H, 4.71; P, 5.09; S, 5.27 Found: C, 41.64; H, 4.73; P, 5.11; S, 4.77. 134 . a-[bis[1-(1-oxopropoxy)ethoxy]phos-10 phinyl]-3-phenoxybenzenebutanesulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) 663 (M+K) Anal. Calcd for C26H34KO11PS: C, 49.99; H, 5.49; P, 4.96; S, 5.13 15 Found: C, 49.93; H, 5.54; P, 5.08; S, 5.44. 135. (E)-8-([l,l'-biphenyl]-4-yl)-6-methy1-l-phosphono-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/e 591 (M+K), 553 (M+H), 515 (M-K+2H) Anal. Calcd for C21H24PSOSK3 + 1.3 4 mol H20: C, 43.72; H, 4.66; P, 5.37; S, 5.56 Found: C, 43.72; H, 4.97; P, 5.31; S, 5.59. 136. 3-(2-cyclohexen-l-yloxy )-a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/e 543 (M+K), 505 (M+H), 467 (M-K+2H) Anal. Calcd for C26H20O7PSK3 + 5.22 H20: C. 32.10; H, 5.12; P, 5.17; S, 5.3 6 Found: C, 32.10; H, 4.84; P, 4.90; S, 5.71. *80 2.1,8 137. (E)-6-methyl-8-(2-naphthalenyl)-1-phosphono-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/e 565 (M+K), 527 (M+H) 5 Anal. Calcd for C19H22PSO6K3 + 4.10 mol H2O: C, 38.00; H, 5.07; P, 5.16; S, 5.34 Found: C, 38.39; H, 4.87; P, 5.31; S, 4.94. 138. 3-(phenylmethoxy)-a-phosphonobenzene-10 butanesulfonic acid, tripotassium salt; Mass Spec 515 (M+H), 477 (M-K+2H), 439 (M-2K+3H) Anal. Calcd for C17H18O7PSK2 + 3.5 H2O: C, 35.34; H, 4.36; P, 5.36; S, 5.55 Found: C, 35.34; H, 4.40; P, 5.03; S, 5.26. 139. 6 - ([1,1'-biphenyl]-4-yl)-a-phosphono-3-pyridinebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) 600 (M+K) ,.,562 (M+H) , 524 (M-K+2H), 486 (M-2K+3H) Anal. Calcd for C21H19NO6PSK3 + 2.3 H20: C, 41.82; H, 3.94; N, 2.32; P, 5.14; S, 5.32 Found: C, 42.21; H, 4.34; N, 2.30; P, 5.02; S, 5.34. 140. 3-(4-chlorophenoxy)-a-phosphonoben-zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 573 (M+K), 535 (M+H), 497 (M-K+2H), 463 (M-K-C1+3H! « oil 8 Anal. Calcd for Ci6Hi5C107PS->3K + 0.89 H20: C, 34.87; H, 3.07; P,"5.62; S, 5.82; Cl, 6.43 Found: C. 35.28; H, 3.51; P. 5.48; S, 5.97; Cl, 6.25. 141. 3-(3-chlorophenoxy)-a-phosphonoben-zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 459 (M-2K+3H) , 497 10 (M-K+2H), 535 (M+H) Anal. Calcd for C16H15CIK3O7PS + 1.5 H20: C, 34.19; H, 3.23; P, 5.51; S, 5.70 Found: C, 34.23; H, 3.66; P, 5.25; S, 5.91. 142. (E)-6-methyl-1-phosphono-8-(2- pyridinyl)-5-octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 516 (ty+K), 478 (M+H), 440 (M-K+2H) Anal. Calcd for C14H19NPSO6K3 + 1.30 H20: C, 33.58; H, 4.34; N, 2.80; P, 6.19 S, 6.40 Found: C, 33.54; H, 4.41; N, 2.84; P, 6.05 S, 6.07 143. 2-methoxy-5-phenoxy-a-phosphonoben-zenebutanoic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 569 (M+K), 531 (M+H), 493 (M-K+2H), 455 (M-2K+3H) Anal. Calcd for C17H18K3O8PS + 1.2 H20: C, 36.94; H, 3.73; P, 5.60; S, 5.80 Found: C, 37.37; H, 4.17; P, 5.36; S, 5.38. *£0 218.

*= - HX59a 144. (E.E)-1-[bis[2-methyl-1-(1-oxopropoxy ) propoxy] phosphinyl] -6,10,14"-trimethyl-5, 9 ,13-pentadecatriene-l-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) 703 (M+H), 741 (M+K) Anal. Cald for C32H56KO10PS: C, 54.68; H. 8.03; P. 4.41; S, 4.56 Found: C, 54.66; H, 8.07; P, 4.37; S, 4.37. 145. £-methyl-a-phosphono[l,1'-biphenyl]-4- octanesulfor.dc acid, tripotassium salt; Mass Spec (FAB, + ions) m/e (M+K), 555 (M+H), 517 (M-K+2H) Anal. Calcd for C21H26PSO6K3 + 2.47 mol H2O: 15 C, 42.09; H, 5.20; P, 5.17; S, 5.35 Found: C, 42.09; H, 5.18; P. 4.77; S, 5.02. 146. 4-(2-phenyl-5-pvridinyl)-a-phosphono-benzenebutanesulfonic acid, tripotassium salt; 20 Mass Spec (FAB, +ions) m/z 600 (M+K), 562 (M+H), 524 (M-K+2H) Anal. Calcd for C21H19NO6PSK?. + 1.9 H2O: C, 42.32; H, 3.86; N, 2.35; S, 5.38 P, 5.20 Found: C, 42.32; H, 4.21; N, 2.37; S, 5.27 P, 5.22. 147 . a- [bis[l- (2, 2-dirnethyl-l~oxopropoxy) -ethoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic 30 acid, monopotassium salt; Mass Spec (FAB, + ions) rn/z 719 (M+K) Anal. Calcd for C30H42KO11PS + 0.5 H2O: C, 52.24; H, 6.28; P, 4.49; S, 4.65 Found: C, 52.42; H, 6.21; P, 4.65; S, 5.39.

■* — ^ ^ HX59a - 245 148. 5-phenoxy-a-phosphono-2-thiophene-butanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 507 (M+H), 469 5 (M-K+2H), 431 (M-2K+3H) Anal. Calcd for C14H14O7PS2K3 + 2.04 H2O: C, 30.95; H, 3.35; P, 5.70; S, 11.80 Found: C, 30.95; H, 3.37; P, 5.33; S, 11.99. 149. 3-[2-(2-methoxyethyl)phenoxy]-a-phos- phonobenzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 543 (M-K+Na+H), 521 (M-K+2H), 483 (M-2K+3H) Anal. Calcd for C19H22OSPS•3K + 1.15 H20: 15 C, 39.38; H, 4.23; P, 5.34; S, 5.53 Found: C, 39.38; H, 4.51; P, 4.93; S, 5.34. 150. (E,E)-1-[bis[1-(benzqyloxy)ethoxy]-phosphinyl]-6,10,14-trimethyl-5,9,13-penta- decatriene-l-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) 731 (M+K) Ana.'.. Calcd for C36H48KO10PS + 0.3 H2O: C, 57.80; H, 6.54; P, 4.14; S, 4.29 Found: C, 57.80; H, 6.43; P, 4.00; S, 3.23. 151. (E,E)-a-[bis[2-methyl-1-(1-oxopro-po:cy)propoxy]phosphinyl ] -3 -phenoxybenzenebutanesulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 719 (M+K) Anal. Calcd for C30H42KO1 iPS : C, 52.93; h, 6.22; p, 4.55; s, 4.71 Found: C, 52.86; h, 5.33; p, 4.23; s, 5.10. 4a 0 2.

HX59a 152. 3-[2-(2-propenyl)phenoxy]-a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 465 (M-2K+3H), 503 (M-K+2H), 541 (M+H), 579 (M+K) Anal. Calcd for C19H20K3O7PS + 2.7 h20: C, 38.72; H, 4.34; P, 5.26; S, 5.44 Found: C, 38.79; H, 4.45; P, 5.00; S, 5.08. 153 . 2- (metoxymethoxy) -5-phenoxy-a-phos-10 phonobenzenebutanoic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 599 (M+K), 561 (M+H), 523 (M-K+2H) Anal. Calcd for C18H20K3O9PS + 2.9 H20: C, 35.24; H, 4.25; P, 5.05; S, 5.23 15 Found: C, 35.24; H, 4.13; P, 4.34; S, 5.57. 154. a-phosphono-3-(2-pyridinyloxy)benzenebutanesulfonic acid, tripotassium «*alt; Mass Spec m/z 540 (M+K), 502 (M+H), 464 (M-K+2H) 20 Anal. Calcd for C15H15NO7PSK3 + 2.63 H2O: C, 32.82; H, 3.72; N, 2.55; P 5.64; S, 5.84 Found: C, 32.87; H, 4.12; N, 2.50; P, 5.38; S, 6.22. 155. 3 -[2-phenylmethvl)phenoxy]-a-phos-phonobenzenebutanesulfonic acid, tripotassium salt; Mass Spec 629 (M+K), 591 (M+H), 553 (M-K+2H), 515 (M-2K+3H) Anal. Calcd for C23H22K3O7PS: C, 45.32; H, 3.98; N. 0.00; S, 5.26; P, 5.08 Found: C, 4 5.32; H, 4.25; N. 0.24; S, 5.54; P, 4.34.

L ^ HX59a " 156. 5-methyl-3-phenoxy~a-phosphonobenzene butanesulfonic acid, tripotassium salt; Mass Spec. (FAB, + ions) m/z 515 (m+h), 553 (m+k) 5 Anal. Calcd for c17h18k3o7ps + 2.5 h20: C, 36.48; H, 4.14; P, 5.53; S, 5.73 Found: C, 36.50; H, 3.98; P. 5.37; S, 5.47. 157 . 3- (3 — fluorophenoxy)-a-phosphonoben-10 zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 481 (M-K+2H), 519 (M+H) 557 (M+K) Anal. Calcd for C16H15FK3O7PS«2 . 4 H20: C, 34.20; H, 3.55; P, 5.51; S, 5.71 15 Found: C, 34.21; H, 3.45; P, 5.36; S, 6.04. 158. 3- (4-fluorophenoxy)-a-phosphonoben-zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) 557 (M+K), 519 (M+H), 481 20 (M-K+2H), 443 (M+2K+3H) Anal. Calcd for C16H15FO7PSK?. + 2.0 H2O: C, 34.65; H, 3.4 5; S. 5.78; P, 5.58; F, 3.43 Found: C, 34.92; H, 3.88; S, 6.12; P, 5.59; 25 F, 3.48. 159. a-[bis(1-(2-methyl-1-oxopropoxy)-ethoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 691 (M+K) Anal. Calcd for C28H38KO11PS: C, 51.52; H, 5.87; P, 4.75; S, 4.91 Found: C, 51.65; H, 5.93; P, 4.63; S, 5.89. *80 218 HX59a 160. 4-(2-benzoxazclyl)-a-phosphinylben-zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) 526 (M+K), 483 (M+H), 450 (M-K+2H) Anal. Calcd for C3.7H1SNO7PSK3 • 2 . 22 H20: C, 36.10; H, 3.46; N, 2.48; S, 5.67; P, 5.48 Found: C, 35.98; H, 3.66; N, 2.60; S, 5.46; P, 5.53 . 161. a-[bis[2-methyl-1-(2-methyl-1-oxopropoxy )propoxy]phosphinyl]-3-phenoxybenzenebutane-sulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 709 (M+K) Anal. Calcd for C32H46KO11PS: C, 54.22; H,. 6.54; P, 4.37; S, 4.52 Found: C, 53.98; H, 6.57; P, 3.86; S, 5.31. * / 162. a-[bis[l-(1-oxopropoxy)propoxy]phos-20 phinyl]-3-phenoxybenzenebutanesulfonic acid, monopotassium salt; Mass Spec (FAB, + ions) m/z 691 (M+K) Anal. Calcd for C28H3SKO11PS: C. 51.52; H, 5.87; P, 4.75; S, 4.91 25 Found: C, 51.75; H, 5.35; P, 4.54; S, 5.84. 163. 3-(3,4-dichlorophenoxy)-a-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion, for :<5C1) m/z 531 (M-K+2H) , 569 (M+H), 607 (M+K), (Cl isotope pattern) Anal. Calcd for Ci6Hi4Ci^K307PS• 1. 6 H20: C, 32.12; H, 2.90; P, 5.18; S, 5.36 Found: C, 32.10; H, 3.15; P, 5.16; S, 5.71.

HX59a' 164. 3-(2,3-dichlorophenoxy)-ot-phosphono-benzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion, for 35Cl) m/z 533 (M-K+2H), 569 (M+H), 607 (M+K), (Cl isotope pattern) Anal. Calcd for Ci6Hi4Cl207PS«2.2 H2O: C, 31.55; H, 3.04; P, 5.09; S, 5.26 Found: C, 31.54; H, 3.17; P, 4.75; S, 5.51. 165. 3-(2-phenoxyphenoxy)-a-phosphonoben-10 zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 555 (M-K+2H), 593 (M+H) 631 (M+K) Anal. Calcd for c22H?oK30sPS + 1.8 H2O: C, 42.27; H, 3.81; P, 4.95; S, 5.13 15 Found: C, 42-25; H, 3.91; P. 5.25; S, 4.88. 16 6. 3 -(2-benzoylphenoxy)-a-phosphonoben-zenesulfonic acid, tripotassium sfi'lt; Mass Spec (FAB, + ion) m/z 567 (M-K+2H), 605 (M+H) 20 643 (M+K) Anal. Calcd for C23H2oK?.0;?.PS + 3.1 H2O: C, 41.82; H, 4.00; P, 4.69; S, 4.85 Found: c, 41.86; H, 3.33; P, 4.69; S, 4.86. 167. (Z)-6-methyl-8-phenyl-l-phosphono-5- octene-l-sulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 515, (M+K). 477 (M+H) Anal. Calcd for C15H20PSO6K?. + 1.8 H2O: C, 35.36; H, 4.68; P, 6.08; S, 6.29 30 Found: C, 3 5.36; H, 4.67; P, 5.89; S, 6.00. 168. (E)-8- (2-fluorophenyl)-6-methyl-l-phosphono-5-octene-l-suifonic acid, tripotassium salt; Lq\J L • * r«apt HX59a ' Mass Spec (FAB, + ions) m/z 533 (M+K), 495 (M+H), 457 (M-K+2H) Anal. Calcd for C15H19FPSO6K3 + 3.50 H2O: C, 32.35; H, 4.69; P, 5.56; S, 5.76 5 Found: C, 32.35; H, 4.69; P. 5.6^; S, 5.76. 169. 3- (4-methoxyphenoxy)-a-phosphonoben-zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 569 (M+K), 531 (M+H), 10 493 (M-K+2H), 455 (M-2K+3H) Anal. Calcd for C^HiqOsPS• 3K + 1.71 H20: C, 36.36; H, 3.85; P, 5.52; S. 5.71 Found: C, 36.78; H, 4.00; P, 5.13; S, 5.54. 170. 3-(3-methoxyphenoxy)-cx-phosphonoben- zenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ion) m/z 531 (M+H), 569 (M-K) Anal. Calcd for C17H18K3O8PS + 1.7 h20: C, 36.38; H, 3.84; P, 5.52; S, 5.71 20 Found: C. 36.43; H, 4.16; P, 5.43; S, 5.66. 171. 3-(2-propoxyphenoxy)-a-phosphonoben-zenebutanoic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 25 521 (M-K+2H) Anal. Calcd for C19H22K3O8PS + 1.1 H20: C, 39.50; H, 4.21; P, 5.36; S, 5.55 Found: C, 39.50; H, 4.49; P, 5.09; S, 5.31. 172. a-phosphono-3-(2-propylphenoxy)ben zenebutanesulfonic acid, triootassiurn salt; Mass Spec (FAB, + ion) m/z 505 (M-K+2H), 543 (M+H), 581 (M+K) Cm O V (L ' ^ u HX59a Anal. Calcd for C19H22K3O7PS + 2.0 H2O: C, 39.43; H, 4.53; P,*5.35; S, 5.54 Found: C, 39.44; H. 4.42; P, 5.21; S, 5.85. 173. 3-[2-(2-ethoxymethyl)phenoxy ] -cc-phos- phonobenzenebutanesulfonic acid, tripotassium salt; Mass Spec (FAB, + ions) m/z 597 (M+K), 559 (M+H), 543 (M-K+Na+H) , 521 (M-K+2H) , 1041 (2M+K), 1079 (2M+2K-H), 1117 (2M+3K-2H) Anal. Calcd for Ci9H220sPS-3K + 1.43 H2O: C, 39.05; H. 4.29; P, 5.30; S, 5.49 Found: C, 39.05; H, 4.31; P, 5.11; S, 5.10.

Example 174 <x-[Bis[ (2, 2-Dimethyl-1-oxopropoxy)methoxy]phosphinyl]-3-phenoxybenzenebutanesulfonic acid, mono- potassium gelt » A. a-[Bis[2,2-dimethyl-1-oxopropoxy)- methoxy]phosphinyl] -3-phenoxybenzenebutane- sulfonic acid, cvclohexvl ester Bromotrimethylsilane (3.61 g, 23.63 mmol, 4 eq.) was added dropwise to a solution of Example 40, Part E ester (3.10 g, 5.90 mmol) and allyltrimethylsilane (4.71 g, 41.3 mmol) in dichloromethane (20 mL) at RT under argon. The clear reaction mixture was stirred at RT for 48 h, concentrated and pumped at high vacuum for 4 h to give a colorless oil.

The crude silyl ester prepared above (3.55 g, =5.88 mmol) was dissolved in 1 N KOH (12.7 mL, 12.7 mmol) over 10 min, then added slowly with vigorous stirring to a solution of silver nitrate (2.17 g, 12.76 mmol) in water (40 mL) under argon C\j *J C » •T - — ~ ~ HX59a ' in the dark. The resulting white gum was diluted with 40 mL of water, extracted With toluene (4x75 mL) and dried over Na2SC>4. The organics were filtered and concentrated to a thick gum. The gum 5 was diluted with 30 mL of toluene, cooled to 0°C and treated with 2,2-dimethvlpropanoic acid, iodomethyl ester (3.87 g, 16.00 mmol) in 20 mL of toluene over 15 min. After 5 min. at 0°C, a solid precipitated out of the solution. The reaction was 10 stirred an additional 0.5 h and warmed to room temperature. The mixture was stirred with Celite (4 g) for 6 min., filtered through a pad of Celite and concentrated to provide a yellov; oil. The oil was purified by flash column chromatography on 15 silica gel (200 g) eluting with (1.5 L) 20:80 ethyl acetate/hexane followed by (0.5 L) 40:60 ethyl acetate/hexane to provide 2.60 g (65%) of title compound as a colorless oil.

TLC Silica gel (3:7 ethyl acetate/hexanes) Rf=0.50.

B. a- [Bis[(2,2-Dimethyl-1-oxopropoxy)-methoxy) phosphinyl) -3 -phenoxybenzenebutane- sulfonic acid, monopotassium salt To a mixture of 1.07 g (11.00 mmol) of KOAc in 40 mL of a 9:1 trifluoroethanol/water (v/v) solution was added 2.50 g (3.59 n.r.oi) of Part A compound. After a homogeneous solution was obtained (= 15 min.), the solution was heated to 40°C (bath temp.) for 20 h and the solvent removed under reduced pressure. The remainder was diluted with water (5 mL) and concentrated. The residue was diluted with ethyl acetate, washed with solutions of KHCO3 (2x3 mL) and KCl (1x10 mL), Z80 Z18 HX59a ' ' dried over anhydrous KCl and evaporated to provide a pale yellow oil. The oil was "diluted with 15 mL of water (a soapy slurry formed) and freeze dried to provide 2.02 g (86%) of title compound as a 5 white lyophilate.

TLC Silica gel (1:9 methanol/dichloromethane) Rf=0.60.

IR (KBr) 3488, 3063, 2974, 1753, 1584, 1485, 1460, 1447, 1397, 1370, 1250, 1215, 1163, 1140, 1069, 1045, 1022, 1003, 963 cm"1.

Mass Spec (FAB, + ions) m/z 691 (M+K), 615 (M-15 K+2H) , 445 (M-C12H22O5+K) .

Anal. Calcd for C28H38O11SPK: C, 51.52; H, 5.87; P, 4„75; S. 4.91 Found: C, 51.38; H, 5.93; P, 4.65; S, 4.90.

Example 175 (S) -(-) -3-Phenoxy-a-phosphonobenzenebutanesulfonic acid. tripotessiuTn A. (IR,2R)-N,N"-Dimethyl-1,2-cyclo- hexanediamine .

Preparation of the title compound was carried out as described by Hanessian, S. et. al.

J. Amer. Chem. Soc. 1934, 106, 5754-5756, and Alexakis, A. el. al. J. Org. Chem. 1992, 57, 1224-1237, Galsbol, F. et al., Acta Chem. Scand. 1972, 26, 3605 and Onuma, K. et. al., Bull. Chem. Soc. Jpn. 1980, 53, 2012. 280218 — HX59a *" [Otspeclp = -150° CHCI3, (C=1) ; Literature ICCspec]^0 = -147°.

B. [3aR-(3aa, 7a(3) ]-Octahydro-1, 2, 3- trimethyl-lH-1,3,2-benzodiazaphosphole, 2-oxide To a solution of 4.0 g (28.1 mmol, 1 eq.) of Part A diamine and 7.92 mL (56.8 mmol, 2.02 eq) of 10 triethylamine in 64 mL of benzene at RT was added a solution of 3.74 g (28.1 mmol, 1 eq.) of methylphosphonic dichloride in 40 mL of benzene over 40 minutes. The heterogeneous mixture was stirred for 90 minutes at RT and then filtered 15 through a pad of Celite, rinsing well with ethyl acetate. Concentration of the organic solution afforded 5.67 g of a yellow oil. Flash chromatography of the oil on silicA gel (100 g), eluting with 7% methanol in ethyl acetate, afforded 20 4.59 g (81%) of the title compound as a white solid, m.p. 61-63°C.

TLC Silica gel (10% methanol in ethyl acetate): Rf 0.12.

C. [3aR-(3aa, 7a|3) ]-Octahydro-1, 3-dimethyl- 2 —[4-(3-phenoxyphenyl)butyl]-1H-1,3,2- benzodiazaphosphole. 2-oxide To a solution of 2.0 g (9.9 mmol, 1 eq.) of Part B compound in 15 mL of THF at -78°C was added dropwise 4.4 mL (10.9 mmol, 1.1 eq.) of 2.5 M n-BuLi in hexane. Addition of the alkyl lithium resulted in a gelatinous mixture tc which 5 mL of THF was added. The resulting opaque white solution was stirred for 1 hour at -75°c. A solution of 3.8 2802^8 Of , - HX59a • g (11.9 mmol, 1.2 eq.) of 3-(3-phenoxyphenyl)-propyliodide in 10 mL of THF was then added dropwise over 20 minutes. The reaction was stirred at -78°C for 2 hours, 0°C for 1 hour and RT for 19 5 hours. The reaction was quenched with methanol, diluted with ethyl acetate, washed with water and • dried (Na2SC>4). Concentration of the organic solution afforded 4.81 g of the crude product as a yellow oil. Flash chromatography of the oil on 10 silica gel (200 g), eluting with 5% methanol in ethyl acetate, afforded 3.78 g (92%) of the title compound as a viscous yellow oil.

TLC Silica gel (10% methanol in ethyl acetate): Rf 0.29.

D. [3aR-[2(R*),3aa,7ap]]-[l-[[(Dimethyl-amino)thioxomethy1]thio]-4- (3-phenoxy-phenyl)butyl]octahydro-1,3-dimethyl-2-1H-1.3.2-benzodiazaphosphole. 2-oxide and E. [3aR- [2 (S* ) , 3aa, 7a(3] ] - [1- [ [ (Dimethyl-amino)thioxomethy1]thio]-4-(3-phenoxy-phenyl)butyl]octahydro-1,3-dimethyl-2-1H- 1.3.2-benzodiazaphosphole. 2-oxide To a solution of 3.7 g (8.97 mmol, 1 eq) of Part C compound in 60 mL of THF at -7 5°C (internal temperature) was added dropwise 3.95 mL (9.87 mmol, 1.1 eq) of 2.5 M n-BuLi in hexanes at a rate to keep temperature below -70°C (15 min). The 30 reaction was stirred at -7 5°C for 2 h. The reaction was cooled to -90°C (liquid nitrogen/methanol slush) and 2.59 g (10.8 mmol, 1.2 eq) of tetramethylthiuram disulfide was added as a solid in small portions over 20 minutes. The 'tSQSls reaction was stirred at -90°C for 1 hour and then warmed to -7 0°C (dry ice/rnethandl) and stirred for 2 hours. The reaction was quenched by the addition of methanol (5 mL), warmed to RT and diluted with 5 ether. Concentration of the organic solution afforded 6.65 g of a yellow solid-oil mixture which contained title D a-(R) isomer and title E a-(S) isomer in a 1 : 3 ratio. Flash chromatography on silica gel (200 g) , eluti.ng with 2% methanol in 10 ethyl acetate, afforded 0.807 g (17%) of title D a-(R) isomer and 2.66 g (56%) of title E a-(S) isomer, each with >99% d.e. as judged by 31P NMR. 31P NMR (CDCI3, 121 MHz, ref. to 10% H3PO4 , 0 ppm) : 15 title D a-(R) isomer 41.6 ppm; title E a-(S) isomer 39.3 ppm.

TLC Silica gel (10% methanol in et>yl acetate): For title D a-(R) isomer Rf 0.46; for title E a-(S) 20 isomer Rf 0.37. (10% methanol in t-Butvl methyl ether): For title D a-(R) isomer R:0.45; for title E a-(S) isomer Rf 0.33.

F. (S) -a- [ [ (Dimethylarnino) thioxomethy 1 ] - thiol -3-phenowbenzenebutanephosphonic acid To a solution of 1.95 g (3.67 mmol, 1 eq) of title E a-(S) isomer in 35 rnL of acetonitrile was added 37 mL (110 mmol, 30 eq) of 3 N hydrochloric acid. The homogeneous solution was stirred at RT for 13 hours. The reaction was concentrated and the residue was dissolved in 20 mL of water and evaporated. A column of Bioivid AG-50W-X3 ion exchange resin, H* form (22 rnL bed volume, 37 meq) 28 U 218 HX59a' was equilibrated initially with water (50 mL), followed by 50% aqueous isopropanol (50 mL) . The residual oil was dissolved in 25 mL of 30% aqueous isopropanol and eluted slowly through the resin 5 with 30% aqueous isopropanol followed by evaporation to afford 1.47 g (94%) of the title compound as a clear viscous oil. tOspeclp + °-8° < c- i-0' MeOH) 31P NMR (CDCI3, 121 MHz, ref. to 10% H3PO4 , 0 ppm): 30.5 ppm.

TLC Silica gel (6:3:1 n-propanol:ammonium 15 hydroxide:water): Rf 0.59.

G. (S)-(-)-3-Phenoxy-a-phosphonobenzene- butanesulfonic acid tripotassium salt To 1.44 g (3.39 mmol, 1 eq) of Part F a-(S) 20 isomer was added 12 mL of acetic acid and mixture was allowed to stir to effect complete dissolution. A white precipitate formed after 15 minutes. To the heterogeneous reaction was added 1.35 mL of formic acid followed after 5 minutes by 2.08 mL 25 (20.3 mmol, 6 eq) of 30% hydrogen peroxide in water (exothermic: internal temperature increased to 38°C). The reaction became cloudy after 30 sec and a yellow precipitate became visible within 1 min. The reaction was monitored by reverse phase HPLC. 30 After 7 h, excess peroxide was decomposed by the slow addition of 622 |1L (3.48 mmol. 2.5 eq) of dimethyl sulfide (exothermic: internal temperature increased to 40°C). The reaction was diluted with water, filtered and concentrated. The residue was 280218 HX59a " dissolved in water (25 mL), concentrated, then redissolved in water (10 mL) and- the pH of the resulting solution (pH - 1.95) was brought to pH 12 with 1 N potassium hydroxide (12 mL). The basic 5 solution was lyophilized. The lyophilate was dissolved in water and chromatographed on CHP-20P gel (2.5 cm x 25 cm) eluting initially with water (1 L) followed by 10% CH-.CN in water. Fractions containing product were analyzed by HPLC, then 10 pooled and concentrated to afford a clear waxy residue which was dissolved in water, filtered and lyophilized to afford 1.42 g (82%) of the title compound as a white lyophilate.

TLC Silica gel (6:3:1 n-propanol : ammonium hydroxide : water): R:- 0.21.

(CCspecI2,? - 9.9° (c. 0.97, H20) .* Chiral HPLC analysis of enantiomeric excess was performed on a ChromTech a-acid glycoprotein (ocr AGP) column, eluted with 85% 0.1 M KH2PO4, 15% CH3CN, pH 4.6, in isocratic mode.

For this sample : ret. time 10.3 min, 99.65% (S)-isomer ret. time 18.8 min, 0.35% (R)-isomer therefore 99.3% enantiomeric excess.

MS (FAB, + ions): m/z 539 (M + K), 501 (M+H), 30 463 (M -K + 2H).

Anal. Calcd. for C16H16O7PSK?. + 0.7 5 H.O: C, 37.33; H, 3.43; P, 6.02; S, Found: C, 37.37; H. 3.44; P, 5.86; S, 6.24. 6.08 280218 HX59a Example 176 " (R) -( + )-3-Phenoxy-a-phosphonobenzenebutanesulfonic acid, tripotassium salt A. (R)-a-[[(Dimethylamino)thioxomethyl]- thiol-3-phenoxvbenzenebutaneohosohonic acid To a solution of 0.32 g (0.60 mmol, 1 eq) of Example 175 Part D a-(R)-isomer in 12 mL of acetonitrile was added IS mL (13 mmol, 30 eq) of 1 N hydrochloric acid. The initially opaque, milky white solution became homogeneous after 2 min and was stirred at RT for 14 h. The reaction was concentrated and the residue was dissolved in 15 methanol and passed through a column of Biorad AG-50W-X8 ion exchange resin, H' form (60 mL bed volume, 102 meq) which has been equilibrated with water (50 mL) , 0.1 N HCl (100 rnL) , .,«water (100 mL , pH of eluant - 7) and 10% methanol in water prior 20 to use. The column was eluted with methanol to afford 0.18 g (72%) of title compound as a clear viscous oil.

[Ospec]" ~ 2.3° (c. 2.6, MeOH) 31P NMR (CD3OD, 121 MHz, ref. to 10% H3PO4 , 0 ppm): 24.2 ppm.

TLC Silica gel (6:3:1 n-propanol:ammonium 30 hydroxide:water): Rf 0.56 B. (R)-(+)-3-Phenoxy-a-phosphonobenzene- butanesulfonic acid, tripotassium salt To a solution of 0.18 g (0.59 mmol, 1 eq) of Part A compound in 40 mL of 98% formic acid was 5 added 2.16 mL (21.2 mmol, 50 eq) of 30% hydrogen peroxide in water. The reaction became cloudy after 0.5 min and a precipitate formed after ~1 min. After 45 min, the reaction was concentrated and the residue was dissolved in water. The 10 solution was cooled to 0°C and the excess peroxide was decomposed by the slow addition of 25 mL of 1 N potassium sulfite. The solution was again concentrated and the residue was coevaporated twice with water. The residue was dissolved in 10 mL of 15 water and the pH of the solution (pH ~ 3) was brought to pH 12 with 1 N potassium hydroxide. The solution was then chromatographed on CHP-20P gel » (2.5 cm x 25 cm) eluting with wat£r. Fractions containing pure product were pooled and 20 concentrated to afford a clear waxy residue which was dissolved in water, filtered and lyophilized to afford 132 mg (56%) of .title compound as a white lyophilate.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water): Rf 0.21. la.p.cl" + 9-5° (c. 0.S9 H20) Chiral HPLC analysis of enantiomeric excess was performed on a ChromTech a-acid glycoprotein (ai~ AGP) column, eluted with 85% 0.1 M KH2P04, 15% CH3CN, pH 4.6 in an isocratic mode. 280218 HX59a 261 - For this sample: ret. time 17.8 min, 97.77% (R) -enantiomer ret. time 10.9 min, 2.23% (S)-enantiomer therefore 95.5% enantiomeric excess.

IR (KBr): 3412 (br), 3071, 2936, 2866, 1661, 1489, 1204, 107 6, 966 cm"1.

MS (FAB, + ions): m/z 539 (M + K), 501 (M + H), 463 (M-K + 2H).

Anal. Calcd for C16H16O7PSK3 + 3. 33 H2O: C, 34.28; H, 4.07; P.-5.52; S, 5.72 15 Found: C, 34.28; H, 3.99; P, 5.14; S, 5.79.

Example 177 [3aR- [2 (R*) , 3aa, 7a(J] ] - [ 1- [ [ (Dimethylamino) thioxo-methyl]thio]-4-(3-phenoxyphenyl)butyl]octahydro-20 1,3-dimethyl-2-lH-l,3,2-benzodiazaphosphole, 2-pyide and [3aR- [2 (S*) , 3aa, 7a|3] 3 - [1- [ [ (Dimethylamino) thioxo-methyl]thio]-4-(3-phenoxyphenyl)butyl]-octahydro-l,3-dimethyl-2-lH-l,3,2-benzodiazaphosphole, 2-oxide A. [3aR-(3a<x, 7af3) ]-2-[[[ (Dimethylamino) - thioxomethyl]thio]]octahydro-1,3-dimethyl- 1H-1.3.2-benzodiazaphosohole. 2-oxide To a stirred solution of 502 mg (2.48 mmol) of Example 17 5 Part B compound in 10 mL of THF under argon at -78°C was added 1.09 rnL (2.73 rnmol) of a 2.5 N solution of n-butyllithium in hexanes dropwise over 10 minutes. After stirring at -78°C for one hour, 87 mg (2.73 mmol) of sulfur was added 5 via a solid addition tube, and temperature of the reaction was raised to -20°C over 1 hour. The reaction mixture was treated with 0.93 mL (6.69 mmol) of triethylamine and 27 6 mg (2.23 mmol) of dimethylthiocarbamoyl chloride at -20°C, stirred 10 for 5 minutes, then allowed to warm to room temperature. The mixture was diluted with ether and washed with water. The aqueous layer was back extracted with ether and the organics were combined, dried and concentrated to afford 558 mg 15 of an oil. The crude product was purified by flash chromatography on silica gel (50 g) eluted with 96:4 ethyl acetate/methanol. Pure fractions were combined and concentrated to yield,,337 mg (47%) of title compound as a clear oil.

TLC (Silica gel. 9:1 ethyl acetate/methanol) Rf=0.35.

MS (CI, + ions) 332 (M+H). 31P NMR (CDCI3, 121 MHz) 37.7 ppm.

B. 3aR- [2 (R*) , 3aa, 7a|3] ] - [ 1- [ [ (Dimethylamino) thioxomethy1]thiol-4 -(3-phenoxy-30 phenyl)butyl]octahydro-1,3-dimethyl-2-lH- 1.3.2-benzodiazaphosphole. 2-oxide To a stirred solution of 89 mg (0.28 mmol) of Part A compound in 1 rnL of THF under argon at -78°C was added 122 |iL (0.31 rnmol) of a 2.5 N 280 21 HX59a" 263 solution of n-butyllithium in hexanes dropwise over 10 mintues. After 90 minutes at -78°C, 0.096 mL (0.55 mmol) of hexamethylphosphoramide was added, followed by 98 mg (0.30 mmol) of 3 -(3-phenoxy-5 phenyl)propyliodide in 1 mL of THF. After 28 hours at -78°C, the reaction was quenched with methanol and allowed to reach room temperature. The mixture was concentrated, then dissolved in ether and washed with water and brine, dried over sodium 10 sulfate, and concentrated to afford 129 mg of a yellow oil. The cx'ude product was purified by flash chromatography on silica gel (15 g) eluted with 98:2 ethyl acetate/methanol. Fractions (#11-19) containing pure material were combined and 15 concentrated to yield 50 mg (34%) of title a- (R)isomer as a clear oil.

TLC (Silica gel, 9:1 ethyl acetateVmethanol) Rf=0.45. concentrated to provide 10 rng (7%) of title isomer as a clear oil.

TLC (Silica gel, 9:1 ethyl acetate/methanol) 30 Rf=0 .39 .

MS (CI, + ions) 532 (M+H).

C. [3aR-[2(S*) ,3aa,7ap]]-[!-[[(Dimethylamino) thioxomethy1 ] thio]-4-(3-phenoxyphenyl )butyl]octahydro-1,3-dimethyl-2-lH- 1.3.2-benzodiazanhosphole. 2-oxide Fractions #21-30 were combined and 31P NMR (CDCI3, 121MHz) 39.2 ppm.

^ R V } U 280 218 HX59a ' The Parts B and C compounds may then be separated and subjected to acid hydrolysis and then oxidation and salt formation as described in 5 Example 175 to form the title compound of Examples 175 and 176.

Example 173 [3aR-[2 (R*),3aa, 7ap]]-[1-[[(Dimethylamino)thioxo-10 methyl]thio]-4- (3-phenoxyphenyl)butyl]octahydro-1.3-dimethyl-2-lH-l,3,2-benzodiazaphosphole, 2-gxide A. [3aR- (3aa,7aP)]-Octahydro-1, 3-dimethyl- 1H-1.3.2-benzodiazaphosphole. 2-oxide To a stirred solution of 497 mg (3.49 mmol) of Example 175 Part A (R,R)-diamine and 1.07 mL (7,89 mmol) of triethylamine in 25.-*mL of tetrahydrofuran (THF) under argon at -7 8°C was 20 added dropwise over 5 minutes 335 }JL (3.84 mmol) of phosphorus trichloride. The cloudy solution was allowed to warm to room temperature and was filtered under argon through a pad of celite and magnesium sulfate. The filtrate was chilled to 25 -78°C under argon and treated with 53 6 |iL of triethylamine and 63 |JL (3.49 mmol) of water. The mixture was allowed to warm to room temperature and was filtered under argon through a pad of celite and magnesium sulfate and concentrated to provide 30 544 mg (82%) of title compound as a yellow oil. 31P NMR (CDCI3, 121 MHz) 5 27.3 ppm. 8 HX59a ' 265 B. [3aR- [2 (R*) , 3aa, 7a|3) ] -Octahydro-1, 3-dimethyl-2-[4-(3-phenoxyphenyl)-1-[(trimethylsilyl) oxy] butyl] -lH-1,3,2-benzodi-azaphosohole. 2-oxide C. [3aR-(2 (S*) , 3aa,7a|3) ] -Octahydro-1, 3-dimethyl-2- [4 - (3-phenoxyphenyl) - l-[ (trimethylsilyl) oxy]butyl]-1H-1,3, 2-benzodi-azaphosphole. 2-oxide A solution of 544 mg (2.89 mmol) of Part A compound and 53 4 mg (2.22 rnrnol) of 3-phenoxy-benzenebutanal (Example ISO Part B) in 5 mL of methylene chloride under argon was treated with 814 j1l (3.33 mmol) of bis [ trimethylsilyl) acetamide at room temperature and stirred for 17 hours. The reaction was quenched with water and extracted with methylene chloride (3 x 3 5 mL). The combined organics were washed with brine, dried (sodium sulfate) , and concentrated to px-ovide 875 mg of a 20 yellow oil. The crude product mixture was purified by flash chromatography on silica gel (80 g) eluted with 2 L of 9:1 hexane/acetone followed by 2 L of 85:15 hexane/acetone and 1.5 L of 8:2 hexane/acetone. Fractions containing the more 25 polar a-(R) isomer (title B) were combined and concentrated to yield 135 mg (14%) of title B compound as a clear oil.

TLC Silica gel (1:1 hexane/acetone) Rf=0.29. 31P NMR (CDCl3, 121 MHz) 8 41.1 ppm.

Fractions #85-96 were combined and concentrated to yield 112 mg (12%) of the pure Part C a-(S)isomer. 2ijU '218 HX59a TLC Silica gel (1:1 hexane/acetone) Rf=0.31. 31P NMR (CDC13, 121 MHz) 5 27.3 ppm.

D, [3aR-[2(R*),3aoc,7aP)]-Octahydro-2-[1-hydroxy-4-(3-phenoxyphenyl)butyl]-1,3-dimethyl-lH-1,3,2-benzodiazaphosphole, 2-oxide To a stirred solution of 125 m: (0.20 mmol) of Part B isomer in 1 mL of THF was added 0.29 mL (0.29 mmol) of a 1.0 N solution of tetrabutyl-ammonium fluoride, in THF. After stirring for three hours at room temperature, the mixture was diluted 15 with ether, washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), and concentrated to provide 104 rng of a white solid. The crude product was purified bylash chromatography on silica gel (15 g) eluted with 20 97.5:2.5 ethyl acetate/methanol. Clean fractions (#41-71) were combined and concentrated to yield 100 mg (93%) of title compound as a white solid, m.p. 122-125°C.

TLC Silica gel (1:1 hexane/acetone) Rf=0.44. 31P NMR (CDCI3, 121 MHz) 5 41.1 ppm.

E. [3aR-[2 (R*),3aa,7aP]]-[1-[[(Dimethyl-30 amino)thioxomethy1]thio]-4-(3"phenoxyphenyl )butyl]octahydro-1,3-dimethyl-2-lH- 1,3, 2-benzodiazat)hosphole . 2-oxide To a stirred suspension of 56 mg (0.13 mmol) of Part D compound, 30 mg (0.09 rnmol) of dimethyl- t A n ) 18 HX59a ' 267 dithiocarbamic acid, zinc salt, and 47 mg (0.18 mmol) of triphenylphosphine in 1 mL of THF at 0°C under argon was added a solution of 52 |J.L (0.27 mmol) of diisopropyl azodic'arboxylate in 0.5 mL of 5 THF over fifteen minutes. The reaction was stirred at room temperature for 45 hours, then diluted with ether and quenched with water. The organics were washed with brine, dried (sodium sulfate), and concentrated to provide 150 rng of an oil. The 10 crude product was purified by flash chromatography on silica gel (15 g) eluted with ethyl acetate.

Pure fractions were combined and concentrated to yield 15 mg (21%) of title compound as a film, the a-(R)-isomer.

TLC Silica gel (1:1 hexane/acetone) Rf=0.20.

Note: This is identical to Example 17 5 Part D compound and is the precursor to the Example 17 6 compound.

MS (CI, + ions) 532 (M+H). 31P NMR (CDCI3, 121 MHz) 8 41.2 ppm.

Example 17 9 (S)-(-)-3-Phenoxy-a-phosphonobenzenebutanesulfonic acid, tripotassium salt A. [3aR-(3aa,7ap)]-2-Chlorooctahydro-1,3-30 dimethyl-lH-1,3,2-benzodiazaphosphole, 2- oxide A solution of 4.72 g (3 3.20 mmol) of Example 175 Part A diamine and 12.63 g (125.0 mmol) of triethylamine in 50 mL of toluene at 0° C was 280218 HX59a treated with 5.00 g (33.20 mmol) of phosphorus oxychloride dropwise over 15 min-. The reaction mixture was stirred for 10 min. at 0°C and warmed to RT. After 3 h the solids were filtered off and 5 the filtrate concentrated to a slurry. The slurry was purified by flash chromatography (100 g of silica gel) eluting with 15:85 acetone/toluene to provide 6.50 g (88%) of title chloride as a low melting solid.

TLC Silica gel (1:4 acetone/toluene) Rf=0.30.

B. [3aR-(3aa,7ap)]-Octahydro-1, 3-dimethyl-1H-1,3,2-benzodiazaphosphole-2-methane- sulfonic acid, ethvl ester. 2-oxide To a rapidly stirred solution of 6.20 g (50.0 mmol) of ethyl methanesulfonate in 150 mL of THF at -73 °C (internal temperature,) was added 20 mL (50 mmol) of 2.5 M n-butyllithium dropwise over 20 20 min (The internal temperature was not allowed to rise above -69°C throughout the addition of n-BuLi). After an additional 30 min., 5.56 g (25.0 mmol) of freshly prepared Part: a chloride in 25 mL of THF was added at a rate to keep the solution 25 temperature below -69°C. The reaction mixture was stirred for 0.3 h at -73°C and for 3 h at -30°C. The reaction mixture was poured into 250 mL of a rapidly stirring mixture of 1:1 saturated aqueous NaHC03 solution/ethyl acetate. The mixture was 30 partitioned between ethyl acetate and water (3 X 75 mL) . The organic extracts were dried (Na;;SOj;) and concentrated to an oil. The oil was purified by flash chromatography (200 g silica gel) eluting with methylene chloride (600 mL) followed by 93:7 280 218 dichloromethane/isopropanol (1000 mL) to provide 6.60 g (85%) of title compound as a low melting solid.

TLC Silica gel (1:9 2-propanol/dichloromethane) Rf=0.58.

IR (KBr) 2947, 2878, 1478, 1451, 1348, 1258, 1236, 1215, 1165, 1123, 1026, 1005, S18 cm"1.

Mass Spec (CI-NH3, + ions) rn/e 638 (2M+NH4)< 621 (2M+H), 328 (M+NH4)/ 311 (M+H).

Anal. Calc'd for C11H23N2O4PS: 15 C, 42.57; H, 7.47; N, 9.03; P, 9.89; S, 10.33 Found: C, 42.95; H, 7.55; N, 9.10; P, 9.81; S. 10.59. [a]2^ = -7 9° CHCl 5, (c=l) C. [3aR- (3aa, 7a(3) ] -Octahydro-1, 3-dimethyl-1H-1,3,2-benzodiazaphosphole-2-methane-sulfonic acid, tetrabutylammonium salt, 2-oxide A suspension of 5.00 g (16.12 mmol) of Part B compound and 6.02 g (16.29 rnmol) of tetrabutylammonium iodide in 30 mL of anhydrous THF at RT was stirred for 10 min. at 0°C and warmed to RT. After 30 30 h the clear solution was concentrated to a thick oil. The oil was dried under vacuum (0.00S mm Hg) overnight. The honey-like oil was used without further purification. 2 o o 218 HX59a '' Mass Spec (FAB, + ions) m/e 242 (Eu.;N) .

Mass Spec (high res., FAB, - ions) Calcd for C9H18O4N2PS: 281.0725 Found: 281.0717 [cx]2^ = -33.8° CH3OH, (c = l) D. (S)-(-)-3-Phenoxy-a-phosphonobenzene-butanesulfonic acid, tripotassium salt To a slurry of 3.29 g (6.29 mmol) of Part C compound in 20 mL of dry THF at -90°C (internal 15 temperature) under argon was added 3.0 mL (7.50 mmol) of 2.5 M n-BuLi in hexanes to give a yellow solution. After 0.5 h at -90°C the solution was treated with 2.10 g (6.29 mmol) of.-*3 -(2-phenoxyphenyl )propyl iodide in 6 mL of THF at such at rate 20 to keep the internal temperature below -8 5°C. The reaction mixture was stirred at -90°C for 3 h when it was gradually warmed to -74°C overnight. The mixture was quenched with 3 60 uL of acetic acid in 3 mL of THF and allowed to warm to RT. The mixture 25 was concentrated and acidified with 12 mL of 2M HCl solution (24 mmol). The reaction mass was extracted with hexane, the aqueous layer was heated to 80°C for 3 hours and then diluted with 2-propanol until a clear solution resulted. After 30 heating an additional hour the solve-:; i: was evaporated and the residue pumped (= C.5 mm pressure'for 0.5 h. The remainder was dissolved in 30 mL (30 mmol) of 1 M KOH solution and freeze dried to provide a cream colored solid. The solid HX59a" was diluted with water and eluted through 24 g of AG50X8 (63 meq, K* form) ion exdhange resin. Final purification was accomplished by MPLC on a column of CHP20P gel (125 mL) eluting with water (200 mL) 5 followed by a gradient created by the gradual addition of 500 mL of acetonitrile to a reservoir of 500 mL of water. Approximately 10 mL fractions were collected. Pure fractions were pooled, the acetonitrile was removed under reduced pressure and 10 the aqueous solution lyophilized to provide 1.48 g (47%) of title compound as a white lyophilate.

TLC Silica gel (6:3:1 propanol/ammonium hydroxide/water) Rt-=0.2 Chiral HPLC analysis of enantiomeric excess was performed on a ChromTech a-acid glycoprotein (al-AGP) column: isocratic 85% 0.1 M ^H^PO*/15% CH3CN, (pH 4.6) in isocratic mode.

For this sample title compound (S)-isomer: retention time = 10.3 min. 94% Example 176 compound {R)-isomer: retention time =19.0 min. 6% Therefore, the enaniomeric excess is 88%.

Anal. Calc'd C, Found: C, for Ci6Hi607PSK?. 35.54 ; H, .3.81; 3 5.54; H, 3.98; +2.2 H20: P, 5.73; S, 5.93 P, 5.42; S, 6.30. 2«U2 18 HX59a Example 180 (R)-{+)-3-Phenoxy-a-phosphonobenzenebutanesulfonic acid, tripotassium salt A. 4-(3-Phenoxyphenyl)butvl alcohol A(1) 3 -Phenoxvbenzv1 alcohol Sodium borohydride (9 61 mg, 25.3 mmol) was added in one portion to a solution of 3-phenoxy-10 benzaldehyde (10.0 g, 50.5 mmol) in methanol (150 mL) at RT under argon. Once the bubbling ceased, the reaction was stirred at RT for 5 min, then adjusted to pH 6 with glacial acetic acid (about 1 mL). The reaction was concentrated in vacuo to 15 give a residue, which was partitioned between EtOAc (200 mL) and saturated NaHCO? (50 mL). The organic layer was washed with water and brine (50 mL each), then dried over MgS04 . Evaporation gave title compound (10.1 g, 100%) as a tan oil.

A(2) 3-Phenoxvbenzvlbromide Phosphorus tribromide solution (11.0 mL, IM in CH2CI2, 11.0 mmol) was added over 5 min to a solution of Part 1(A) alcohol (2.00 g, 10.0 mmol) 25 in CH2CI2 (30 mL) under argon at RT. The yellow reaction was stirred at RT for 10 min, diluted with CH2CI2 (100 mL), and washed with saturated NaHC03 (2 x 30 mL). The organic layer was dried over MgS04. Evaporation gave a pale yellow oil, which 30 was purified by flash chromatography on silica gel (75 g) eluting with 10:90 CH-Cl Vhexane to provide title bromide (1.57 g, 60%) as a yellow oil. 280218 HX59a A (3) 4-(3-Phenoxvphenvlbutvl alcohol A Grignard solution of ClMg (CH2)30MgCl (19.2 mL, 0.6M in THF, 11.5 mmol) was added to a mixture of Part A(2) bromide (1.51 g, 5.74 mmol) and 5 copper (I) iodide (11 mg, 0.057 rnmol) in THF (10 mL) at 0°C under argon over a period of 5 min. The dark green reaction was stir-red at 0°C for 3 0 min, then quenched by dropwise addition of 2-propanol (2 mL). The reaction was diluted with diethyl ether 10 (100 mL) and washed with IN KHSO4 (2 x 50 mL). The aqueous layers were back-extracted with diethyl ether (20 mL). The combined organic layers were dried over MgS04. Evaporation gave a pale yellow oil, which was purified by flash chromotography on 15 silica gel (100 g) eluting wich 30:70 EtOAc/hexane to provide title alcohol (1.10 g, 79%) as a colorless oil.

* / B. 3-Phenoxvbenzenebutanal 20 To a stirred solution of 3.4 mL (48.6 rranol) of methyl sulfoxide in 50 mL of CH2CI2 under argon at -78°C was added 3.9 mL (44.5 mmol) of oxalyl chloride dropwise over 5 min. The reaction was stirred at -78°C for 0.5 h at which time 9.8 g 25 (40.4 mmol) of Part A alcohol in 15 mL of CH2CI2 was added dropwise. The reaction was stirred at -78°C for 20 min, warmed to -30°C for 5 min, cooled back down to -78°C and treated with 22.6 mL (162 mmol) of triethylamine. The reaction gradually 30 warmed to -20°C and was quenched with 150 mL of water. The mixture was diluted with a 1:1 mixture of hexanes/ethyl acetate and the layers were separated. The organics were dried over Na2S04 and 280218 HX59a " evaporated to dryness to provide 8.8 g (91%) of title compound as a pale yellow oil.

TLC Silica gel (70:30 hexanes/ethyl acetate) 5 Rf = 0.40.

C. 4,6-Dimethyl-2-[3-(3-phenoxyphenyl)- propvll-1.3-dioxane To a solution of 5.6 g (23.33 mmol) of Part 10 B aldehyde in 25 mL of benzene was added 2.4 g (23.33 mmol) of (2S,4S)-(+)-pentanediol and a 50 mg (0.36 mol) of p-toluenesulfonic acid. The reaction was reflu.ved for 2 h using a Dean-Stark trap for the azeotropic removal of water. The reaction was 15 diluted with ethyl acetate, washed with sat. NaHC03 solution, water, dried over MgS04 and evaporated to provide a crude yellow oil. Flash chromatography was performed on 300 g of silica gel eluting with 90:10 hexanes/ethyl acetate. Pure product 20 fractions were combined and evaporated to provide 5.5 g (72%) of title compound as a colorless oil.

TLC Silica gel (90:10 hexanes/ethyl acetate) Rf = 0.21. [<X]2^ - 13.1° (c=l, CH2C12) MS (CI-NH3, + ions) m/e 344 (M+NH4), 326 (M) .

D. [R-[R*(R* (R*) ] ] ] -CX- (3-Hydroxy-1- methylbutoxy)-3-phenoxybenzenebu cane- phosphonic acid, diethyl ester (Yokomatsu, T., Shibuya, S.. Tetrahedron Asvmmetrv 1992, 3, 377-8). 280 218 HX59a" To a solution of 2.9 mL (16.87 mmol) of triethyl phosphite in 7 mL of CH2C12 at -78°C under argon was added dropwise 1.5 mL (13.50 mmol) of titanium (IV) chloride. The resulting orange 5 solution was stirred at -78°C for 0.5 h at which time 2.2 g (6.75 mmol) of Part C compound in 5 mL of CH2CI2 was added dropwise over 0.5 h (internal temperature of the reaction maintained at -68°C). The reaction was stirred for 48 h at -78°C at which 10 time the reaction was poured into 200 mL of a 1:1 mixture of NaHC03/ethyl acetate and extracted. The organics were washed with water, brine, dried (MgS04) and evaporated to provide 2.0 g of a crude oil. Flash chromatography was performed on 200 g 15 of silica gel eluting with 4:1 dichloromethane/ acetone. Pure product fractions were pooled and evaporated to provide 1.5 g (48%) of title compound as a colorless oil.

TLC Silica gel (4:1 dichloromethane/acetone) Rf = 0.24 . [a]2^ +15.8 (c = 1, CH2CI2) IR (Film, CH2CI2) 3410, 3040, 2969, 2870, 1584, 1487, 1447, 1385, 1250, 1215, 1163, 1047 cm"1. 31P NMR (CDCI3, 121 MHz, ref. to 10% H3PO4, 0 ppm): 24.20 ppm.

HRMS (EI, + ions) m/z Calculated for C25H37O6P: M+ 464.2328 Found: 464.2316 2 HX59a " 276 E. (R)-a-Hydroxy-3-phenoxybenzene-butanephosphonic acid, diethyl ester To a solution of 3 mL (6.00 mmol) of 2.0 M oxalyl chloride in CH2CI2 in 3.5 mL of CH2CI2, 5 under argon at -70°C, was added dropwise 535 fiL (7.54 mmol) of DMSO (exothermic). This mixture was stirred at -70°C for 15 min at which time 1.4 g (3.02 mmol) of Part D compound in 5 mL of CH2CI2 was added dropwise. The reaction was stirred at 10 -70°C for 1 h, treated with 1.7 mL of triethylamine and allowed to warm to RT. The reaction was quenched with water and diluted with a 1:1 mixture of hexanes/ethyl acetate. The organics were dried (MgS04) and evaporated to provide 1.4 g of a crude 15 oil. The crude oil was treated with 14 mL of dioxane, 70 mg (0.37 mmol, 5%) of p-toluenesulfonic acid, 1.4 mL of water and refluxed for 0.5 h then cooled to RT. The mixture was diluted with a 1:1 mixture of water/NaHC03 and extracted 3 times with 20 CH2CI2• The organics were dried (MgS04) and evaporated to provide 1.2 g of a pale yellow oil. Flash chromatography was performed on 100 g of silica gel eluting with 4:1 dichloromethane/ acetone. Pure product fractions were combined and 25 evaporated to provide 690 mg (60%) of title compound as a colorless oil. [a] D -5.9° (c = 1, ChC 13) TLC Silica gel (4:1 dichloromethane/acetone) Rf = 0.23 .

IR (Film, CH2CI2) 3306, 2932, 1584, 14S5, 1445, 1385, 1250, 1215, 1163, 1142, 1096, 1051, 1026, 28^ 2 11* HX59a " 966 cm~l. !h (300 MHz, CDCI3): 8 7.30-6.70 (m, 9H) 4.15 (m, 4H) 3.95 (m, 1H) 3.87 (m. 1H) 2.61 (m, 2H) 1.95 (m, 1H) 1.70 (m, 3H) 1.30 (t, 6H, J = 7.1 Hz) ppm. 31P NMR (121 MHz, CDCI3, ref. co 10% H3PO4, 0 ppm): 25.28 ppm.

KRMS (FAB, + ions) m/z Calculated for C20H28O5P: (M+H)+ = 379.1675 FOUND: 379.1692 Anal. Calcd. for C20H27PO5 + 0.50 mol hjO. Effective MW = 337.40.

C, 62.00; H, 7.28; P, 7.99 Found: C, 62.00; H, 7.05; P, S.13.

F. (R)-a-[[(Dimethylamino)thioxomethy1)- thiol-3-phenoxvbenzenebutanephosphonic acid To a stirred slurry of 415 mg (1.10 mmol) of Part E compound, 585 mg (2.23 mmol) of triphenylphosphine and 252 mg (0.82 mmol) of 30 dimethyldithiocarbamic acid, zinc salt, in 3 mL of THF at 0°C under argon was added 4 46 mg (2.21 mmol) of diisopropyl diazodicarboxylate in 2 mL of THF over the course of 20 minutes. The resulting light yellow solution was allowed co warm to room HX59a temperature and stirred for 16 hours. The reaction mixture was then evaporated and immediately purified by flash chromatography (5 x 15 cm column, eluting with 1:3 ether/dichloromethane). Fractions 5 containing both the product and an impurity were collected, concentrated and re-chromatographed (5 x 15 cm column, 85:15 ethyl acetate/hexane). The resulting yellow oil still contained ca. 8-10% of diisopropyl dicarbazide as an impurity. The yield 10 of title compound was 4 90 mg (82% of 91% pure material). [a]2^ = 24.5° (c = 0.99, CHCl?,) G. (R) -( + )-3-Phenoxy-a-phosphonobenzene- butanesulfonic acid, tripotassium salt To a stirred solution of 410 mg (0.851 mmol) of Part F compound in 3 mL of CH2C:l*2 at room temperature under argon was added 0.7 mL (5.3 mmol) 20 of bromotrimethylsilane. The nearly colorless solution was stirred for 16 hours and then evaporated at less than 25-C. The residue was dissolved in 10 mL of dry methanol and stirred for 1 hour. Re-evaporation gave 358 mg (59%) of the 25 diacid as a colorless glass.

To a solution of 0.326 g (0.77 mmol, 1 eq) of the diacid in 50 ml, of 93% formic acid was added 4.2 mL (38 mmol, 50 eq) of 3 0%. hydrogen peroxide in water. The reaction became cloudy after 0.5 min 30 and a precipitate formed aftex- -2 min. After 1 h, the reaction was cooled to O'C and the excess peroxide was decomposed by the slow addition of 40 mL of 1 N potassium sulfite. The solution was concentrated and the residue was coevaporated twice 28w 218 HX59a " with water. The residue was dissolved in 10 mL of water and the pH of the solution (pH - 3) was brought to pH 12 with 1 N potassium hydroxide. The solution was then chromatographed on CHP-20P gel 5 (2.5 cm x 25 cm) eluting with water. Fractions containing product were analyzed by HPLC, then pooled and concentrated to afford a clear waxy residue which was dissolved in water, filtered and lyophilized to afford 201 mg (48%) of title 10 compound.

TLC Silica gel (6:3:1 n-propanol:ammonium hydroxide:water) : Rf 0.21.

Chiral HPLC analysis of enantiomeric excess was performed on a ChromTech a-acid glycoprotein (ai-AGP) column, eluted with 35% 0.1 M KH2PO4, 15% CH3CN, pH 4.6 in isocratic mode. ^ For title compound: ret. time 13.5 min, 93.95% (R)-enantiomer ret. time 11.2 min, 1.05% (S)-enantiomer therefore 97.9% enantiomeric excess of the (R)-isomer.

Anal. Calc'd for CieHi607PSK?. +2.5 H2O: C, 35.19; H, 3.S3; P, 5.67; S, 5.87 Found: C, 35.19; H, 3.54; P, 5.32; S, 6.27.

EXcWPJ-g 1,81 (S)-(-) -3-Phenoxy-a-phosphonobenzenebutanesul£onic acid. 1-adamantanamine (1:2) salt A sample of the (R)-(-)-trisalt (94:6, (S) : (R) ) prepared in Example 179 (70 mg, 0.14 mmol) was stirred with 3 g o& Ag50-X8 ion exchange resin (7.5 meq, H* form) for 1 h in 5 mL of water and 3 mL of methanol. The mixture was slowly eluted 10 through an additional column of Ag50-X8 ion exchange resin (1 g, 2.5 meq, H' form) with 1:1 methanol/water. Approximately 3 mL fractions were collected. Fractions # 2 to 7 were pooled, the methanol was removed under reduced pressure and the 15 aqueous solution lyophilized to provide 54 mg (100%) of the free acid form of the title salt as a thin film.

The free acid (54 mg, 0.14 mmol) in 3 mL of a 1:1 methanol/water solution was treated with 39 20 mg (0.28 mmol, 2 eq) of adamantanamine and the mixture stirred for 0.5 h. The mixture was concentrated to a white solid. The solid was recrystallized from hot water and 2-propanol. The white granules were collected to yield 79 mg (85 %) 25 of title salt as a 97:3 mixture of (S):(R) enantiomers. The recrystallization procedure was repeated to provide 66 mg (85 %) of title salt, as a white solid, mp 248-252°C. The two recrystalizations from hot 2-propanol/water 30 improved the ratio of (S):(R) enantiomers from 94:6 to 98:2 determined by HPLC as described on the a- acid glycoprotein column. 280218 HX59a' - 281 - TLC Silica gel (6:3:1 n-propanol/conc. ammonia/water) Rf=0.30.

IR (KBr) 3426, 3086, 3065, 3036, 2915, 2855, 1609, 5 1582, 1485, 1233, 1215, 1175, 1022, 882 cm"1.

Mass Spec (FAB, + ions) m/e 689 (M+H); (FAB, - ions) m/e 385 (M-2(C9H17N)+H).

Anal. Calc'd for C^Hr^ChN-PS + 1.00 H-O: C, 61.17; H, 7.84; N, 3.96; P, 4.38; S, 4.54.

Found: C, 61.26; H, 7.90; N, 4.00; P, 4.27; S, 4.74.

Regeneration of Metal Salt-.

Title salt (60 mg, 0.08 mmpJ.) was stirred with 1.5 mL of Ag50-X8 ion exchange resin (2.5 meq, 20 K+ form) for 2 h in 3 mL of water and 1 mL of methanol (pH =7). The mixture was slowly eluted through an additional column of Ag50-X8 ion exchange resin (1.5 mL, 2.5 meq, K" form) with 1:1 methanol/water-. Product containing fractions were 25 pooled, the methanol was removed under reduced pressure and the aqueous solution lyophilized co provide 38 mg (95 %) of the tripotassium salt as a white lyophilate.

Chiral HPLC analyis of enantiomeric excess was performed on a ChromTech a-acid glycoprotein (al-AGP) column eluted with isocratic 85% 0.1 M KH:P04, 15% CH3CN, pH 4.6. 280218 For this sample.

Example 181 (S)-isomer: retention time = 9.5 min. 98% Example 180 (R)-isomer: retention time =19.0 min. 5 2%, therefore a 96% enantiomeric excess of the (S)-isomer.

Example 182 (S)-(-)-3-Phenoxy-a-phosphonobenzenebutanesulfonic 10 acid. (S)-a-methvlbenzvlamine (1:2) salt A sample of the (-)-isomer (Example 17 5) (70 mg, 0.14 mmol) was stirz-ed with 3 g of Ag50-X8 ion exchange resin (7.5 meq, H+ form) for 1 h in 5 mL 15 of water and 3 mL of methanol. The mixture was slowly eluted through an additional column of Ag50-X8 ion exchange resin (1 g, 2.5 meq, H+ form) with 1:1 methanol/water. Approximately.3 mL fractions were collected. Fractions # 2 to 7 were pooled, 20 the methanol was removed under reduced pressure and the aqueous solution lyophilized to provide 54 mg (100%) of the free acid form of the title salt as a thin film. The free acid was used without further characterization.

The free acid in 3 mL of a 1:1 methanol/water solution was treated with 36 uL (0.28 mmol, 2 eq) of (S)-(-)-a-methylbenzylamine under argon. The mixture was stirred for 0.5 h and 30 concentrated to an oil. Recrystallization from 3 mL of hot acetonitrile and 3 drops of water followed by slow evaporation to dryness provided 60 mg (73%) of title diamine salt as needles, mp 160-163°C. 280218 HX59a " [a]2^ = -8.0° (methanol, c=l) IR (KBr) 3447, 3050, 3038, 2938, 2762, 1613, 1582, 5 1566, 1489, 1242, 1213, 1182, 1163, 1072, 1044, 1022, 924, 702 cm"1.

Mass Spec (FAB, + ions) m/e 629 (M+H); (FAB, - ions) m/e 385 (M-2 (CgHnN) +H) .

The needles were subjected to X-ray crystallographic studies, which demonstrated that the (-)-isomer had the (S)-stereochemistry at the a-carbon.

Example 133 (S)-a- [Bis[(2,2-dimethyl-1-oxopropoxy)methoxy]phosphinyl] -3-phenoxybenzenebutanesulfpnic acid, mono-potassium salt A. (S)-3-Phenoxy-a-phosphonobenzenebutane- sulfonic acid, trisilver salt A solution of Example 175 product (1.66 g, 3.32 mmol) in water (17 mL) was added over 3 0 min 25 via syringe pump to a vigorously stirred solution of silver nitrate (2.02 g, 11.9 mmol) in water (17 mL) under argon at RT in the dark. A white precipitate resulted immediately upon addition. Following addition, additional water (5 mL) was 30 added to aid stirring, and the thick slurry was stirred vigorously at RT for 15 min then filtered through a porosity D (10-20 |.im) glass fritted funnel. The solid was washed with water (2 x 40 mL) and diethyl ether (2 x 40 mL) then air-dried 2*0?1 8 HX59a" - 284 - for 15 min. The product was further dried by pumping under high vacuum in the dark overnight to give title compound (2.28 g, 97%) as a beige solid.

B. (S)-a-[Bis[(2,2-dimethyl-1-oxopropoxy)- methoxy ] phosphinyl ] - 3 -phenoxybenzenebutane- sulfonic acid, monopotassium salt A suspension of Part A compound (2.12 g, 3.00 mmol) and activated 4A molecular sieves (2.1 10 g) in CH2CI2 (25 mL) was stirred at RT in the dark under argon for 45 min. Anhydrous anisole (1.6 mL, 15.0 mmol) was added and the reaction was placed in a 20 *C water bath. To the suspension was added a solution of 2, 2-dirnethylpropanoic acid, iodomethyl 15 ester (2.18 g, 9.00 mmol) in CH.Cl; (5 mL) dropwise slowly over 15 min via syringe pump ensuring that the reaction temperature remained below 30*C. The reaction turned bright yellow during addition. The heterogeneous reaction was stirred vigorously at RT 20 in the dark for 40 min, then filtered through Celite with the aid of CH2CI2 (200 mL).

Evaporation of the filtrate gave 3.3 g of the crude triester a- [bis[(2,2-dimethyl-1-oxopropoxy)- methoxy ] phosphinyl ] -3 -phenoxybenzenebutanesulf onic 25 acid, (2,2-dimethyl-1-oxopropoxy)methyl ester as a yellow liquid.

The crude triester was dissolved in CHaCN/water (4:1, 40 mL) to give an opaque solution 30 containing a small amount of yellow precipitate.

The reaction was stirred at RT and progress of the solvolysis was monitored by 1H NMR (disappearance of the t-BuC02CH2- sulfonate signal at 5.8 ppm [in dg-DMSO]). When no sulfonate ester remained (8 h) 280218 HX59a ' the reaction was partitioned between EtOAc (150 mL) and saturated KCl (20 mL). The -resultant biphasic mixture was filtered to remove the yellow precipitate. The organic layer was washed with IM 5 potassium phosphate (pH=6.0, 2 x 20 mL) and saturated KCl (5 mL), then dried over anhydrous KCl. Evaporation followed by pumping under high vacuum for 1.5 h gave 2.0 g of a colorless oil.

CHP20P gel was stirred with 0.5M potassium phosphate buffer (pH=5.0, 1000 mL) for 4 h, then packed (5 x 25 cm column) and flushed with water (500 mL). The column was equilibrated with 5:95 CH3CN/water (1.5 L).

The crude product was dissolved in CH3CN (5 mL), then water (10 mL) was added. The solution was adjusted to pH 5.0 with IM potassium phosphate /' buffer (pH=7.0). The product solution was 20 chromatographed on CHP20P gel prepared above (25 mL fractions), eluted with 5:95 CH7CN/H2O (250 mL) followed by a gradient created by the gradual addition of 80:20 CH2CN/H2O (1200 mL) to a reservoir of 5:95 CH;<CN/H:0 (1200 mL) ) . Fractions 25 55-62 were combined and concentrated to a volume of 100 mL consisting almost entirely of water. The aqueous solution (pH=3.2) wss adjusted slowly to pH=5.0 with IM potassium phcrphate (pH=7.0), then concentrated to dryness. The resultant residue was 30 dissolved in CH3CN/H2O (1:4, 10 mL) and lyophilized to give title compound (1.12 g, 57%) as a white lyophilate.

TLC (silica gel)(10:90 MeOH/CH2Cl2) Rf 0.25 280218 HX59a 286 - Chiral purity was determined by -HPLC on a Chrom Tech a-acid glycoprotein column, with isocratic elution of 10 mM KH2P04/iPr0H/Me0H buffer 5 (78:16:6). This sample was 99.2% (S)-isomer (retention time = 23.5 min) and 0.8% (R)-isomer (retention time = 17.0 min) and therefore had a 98.4% enantiomeric excess favoring the (S)-isomer.

IR (KBr) 2974, 1755, 1584, 1485, 1250, 1215, 1140, 1024, 1003, 963 cm"1.

MS (FAB, + ions) 653 (M+H), 691 (M+K) Anal. Calcd. for C28H38KO11PS + 0.60 KH2PO4: C, 45.69; H, 5.38; P, 6.75 Found: C, 45.64; H, 5.43; P, 7.12. p t The compounds of Examples 42, 93, 174, 175 20 and 183 are particularly preferred.

Claims (1)

WHAT WE CLAIM IS:

1. An intermediate having the structure R9 O i "TO wherein z x= r1 c- I s — c — N—CH3 II I s ch3 R9 o r \XJ z I ■c I s — C — N — CH, II I s ch3 o z alkyl-0— s—c— II I o h o z ll_l <C4H9)4N"0-Jj o h I or (c«h9)4n+-o3s—c- r1 or having the structure z o . I IU°H R—C — P^T | oh S I ^ch3 S = c — CH, or having the following structure h o I ll^Oalkyl •c—p; 'Oalkyl s—c—n — ch3 II I s ch3 or having the following structure N.Z PATENT OFFICE 1 6 DEC 1996 RECEIVED 28 0 2 J8 288 - n ° II H II y—p—(o-c-o-c-Ry) a I Rx wherein Y is o o z o z o v II H || | || | || RY c — O — C—O—S c ; ho — S c p or •x 11 K 11 K rx o r1 0 r1 o z o II I II mo —s c p II I, o r1 wherein R1 is a lipophilic group containing at least 7 carbons; Z is H, halogen, lower alkyl or lower alkenyl; and R9 is lower alkyl or arylalkyl; Rx is H, alkyl, aryl or arylalkyl; and Ry is alkyl, alkoxy, aryl or arylalkyl. wMrwfead Asa#; Aa vmt. & son.