CA1307534C - Intermediates useful in the preparation of hmg-coa reductase inhibitors - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

There is provided compounds having the follow-ing general formula:

Description

-". 1 3075~4 ~ 7~9~

This is a di~isional of Canadian Application S.N. 495,158.

BACK&RQUND QF THE T~NvENTI-o-~
Endo et al~0 J _ Antibioticæ, XXI~, 1346 - tl976) described a ~rmentation product, ML-236~, with potent antihypercholesterole~ic activity whi~
act6 by ~ nhibiti~g ~M~-CoA Eeductase. This ~aterial, named compactin by Bro~n et al.. J,_5a~L,~Q~.
Perkin I, 1165 (1976) was ~hown to hav~ a de~e~hyl ~evalonolactone ~artial s~ru~ture and the ste~eochemist~y was studied.
1~ Shortly ther~a~r a che~i~ally ~i~ila~, natural prsduct MK-~03 ~mevinolln). Qbtaine~ by f~rmentation, wa~ i~olated and ch~ac~e~ized, by Mona~h~ et al., U.S. Pa~. No. 4,231,93~ ha~
been shown to have t~e sa~e de~ethyl ~evalonolact4~e ~ 2 ~ 17194 partial structure and the absolute stereochemical configuration has been determined and described in EPO publication No. 0,022,478 of Merck & Co. t Inc.
Totally synthetic analogs of these natural inhibitors have been prepared and described in Sankyo's U.S. Pat. No. 4,198,425 and Sankyols UnS~
Pat. No. 4,255,444 with no attempt being made to separate the stereo- and optical isomers~
Subsequently, as described in Merck~s EPO publication No. 0,024,348 and by Meyer, Ann. Chem., (1979), pages 484-491, similar totally synthetic analogs were separated into their stereoisomers and optical enantiomers. Furthermore, it was shown in EPO
publication No. 0,024,348 that essentially all of the HMG-CoA reductase activity resides in the 4(R)-trans species as is the case with khe naturally occurring compounds compactin and mevinolin.
In most of the prior art process for preparing the totally synthetic compounds, the lactone moiety of each compound had to be elaborated by a lengthy series of synthetic operations followed by very tedious and expensive chromatographic separation o~ the cis, trans racemates, or enantiomers, following which, the inactive cis-isomer would be discarded.
A process for the preparation of the lactone ring system in the correct optically active form was recently reported by Majewski et alO, Tetrahedron .
Lett., 1984, 2101-2104 utili2ing a (3S,5S) iodoketal of the following formula:

1 ~0753~

_ 3 _ 171g4 -X~CH2~h DEq~AILED DESCRIPT:I:ON OF THE INVENTION
The pre~ent invention relates to a noYel compound having the following general formula ~

R O ,.~ O

1~ bRS

~ CII) ~' o 0 wherein R5 is Cl 5 alkyl or ~enz~l and R- is Cl_5 alkyl, ~enzyl, C2_5 alko~yalkyl, such as CH3OCH2, or C3_6 alko~alkoxy~

a~kyl, such as C~3OCM2CH2OCH2~

Th~s noYel compound i5 useful in pxeparing ant~hypercholesterolemic agents having the following general str~atural ~ormula ~

1 30753~
_ 4 _ 1719 ~0 0 ,. ~ ~
~
\/

R

wherein Rl i~ sele~ted ~rom the group consi~eing o~:
(a) O
10CEI3 ~9 CH2 R CH~ CH3 15 Q~

wherei~ Q i~ \or R ~ H :or O~:
~E~3 R i~ hydrogen or rnethyl, and a, b, c, and d r2present optional double bo~ds, e~pecially wherQin b and d repre~er~t dou~le b~nd~ or a, b, c, and d are all 258 ingle bond~: or 1 30753~

(b) çH2 ~3 wh~reln R2 and R3 are independently Cl 3 alkyl or halo tF. Cl or Br) and R i8 lU hydrogen. phenyl, ~enzyloxy, sub~e~tuted phe~yl or 6ub~tituted benzyloxy in which the phenyl group ~n each c se i~ 6ub~tituted with o~e or more ~ub~tituent~ ~electe~ ~rom C~ 3 alkyl ~d halo . .
lS The process for preparing the compounds of formula ~I~ comprises:
(A) reactin~ a eompound of ~he fo~mula (II3:

R O O
~
~ ~R5 o whereln R5 i~ Cl_5 alkyl or ben2yl and R7 is Cl 5 alkyl, benzyl, C2 5 alkoxyal~yl, ~uch a~ CH3OC~2, or C3 6 al~oxyalkoxyalkyl~ such a~ C~3OC~2CH29C~2, wiSh a compound of the fo mula (I~

1 30753~

_ ~ _ 17194 R ~ (III) wherein Rl i8 def ined above, ~ is a me'cal atom or metal complex 6el~cted from Li, MgCl, MgBr . ~CuM~Cl ) 1/2 or (CuMgE~r ) 1/2 or an alkali rlletal ~Li, Na, or ~) plu~
an aryl 6ulfonyl group selected feom E~S02 or CH3 (~S02, followed by the ~emoval of the aryl sulf onyl group [Tro~t et al. Tetrahedron LettO, 1976, 3477]
to af f ord a compound of the f ormula ( IV):

~R 5 ~ OH

R ( IV) (E~) lactonizing the compound of the formula ( IV) under ~tandard acidic condition~ to aî f ord the compound of f o~mula (V~:

~-~o 3 o R (V~

1 3(.1753Dr and (C) r~moving the R group by ~uitable method~
known in th~ a~t [T. Greene, Pro~ective GrouP~ In Orqanic S~thegis, John Wiley &
Sons, 19~1~ pp 10-86~ or with an organoboron halide to afEord the compound of ormula (I).

In a preferred embodiment, the compounds of formula (I~ are those wherein Rl is (a) and R is hydrogen and R i8 hyd~ogen or methyl and b and d represent double bond~ or a, b~ e and d are single bond6.

- In a second preferred embodiment, the compounds o formula (I~ are those wherein i~ (b), R2 ~nd R independently are ~hloro, fluoro or methyl and R4 i~ hydrogen, 4-fluoro-3-methylphenyl or 4-fluorobenzyloxy. The most preferred compounds are tho~e wherein (1) R2 and ~3 are methyl and R4 i8 4-fluoro-3-methylphenyl;
(2) R~ and R3 are methyl and ~4 i8 4-~luoro-benzyloxy; and (3) RZ and R3 are chloro and R4 i~ hydroge~.
The reaction of the compound of the fo~mula (II~ with the compound o~ the formula ~III) is conducted at a temperature between -78 and 0C, preferably at -78C with warming to -20C for a period of from 1 to 12 hour~, most preferably 1 hour at -78C and 1 hour at -230C, in an inert solvent.
Illu~trative of ~uch inert 601ve~ are: ether6 or thioeth~r6 or mixture6 th~reof, such a~ die~hyl ether, tet~ahydrofuran, dimethoxyethane, dimethyl~ulfide and the like.

1 3075 3~
- 8 - 17~94 The amounts o~ reactant6 that are employed -in this reaction may vary between 0.1 an~ 1.0 equivalent~ o the compound of the formula SII) to each equivalent of the compound o~ the formula (III). ~owever, 0.4 equivalents of the compound o~
the formula tII) is pr~f~rred. The compound of the ~ormula (III) wherein X i~ (CuMgBr)l/2 is a preferred rea~tant.
The lactonization of the compound of ~he ~ormula (IV) i6 conducted at a temperature between 0 and 25~C, preferably at ambient ~emperature, for a period o~ from 1 to 12 hours, preferably 3 hours i~
an inert ~olvent with a catalytic amount of an acLd.
Illu~trative of such inert solve~ts ar~:
hydrocarbon~. such as, hexane, ~oluene, benzene, cyclohexane and the like: and ether6, ~uch as, diethylether, tetrahydrofuran, dimethoxyethane and the like. Illustrati~e of 6uch acid~ are organic acids, such a~ toluenesul~onic, benzenesul~on~c and the like and inorganic acids, ~uch as, hydrochloric. The preferred acid utllized in the lactonization i8 ~-toluene~ulfonlc acid.
The removal o~ the R protecting group i6 conducted at a temperature baeween -78 and 0C, preferably at -78 ~or a per~od .from l to 12 hour~, preferably 1 hour in an inert ~olve~t ~n the presence o~ an organoboron halide. Illustra~i~e of such inert solvent6 are: chlorinated hydrocarbons, such aB~
methylene chloride, chloro~or~, dichloroethane or low melting mixture~ thereof and the like.
.

1 ~0753/1 ~ 9 ~ 1719 The organoboron halide reactant 1 -repre~ented by the follQwing ~ormula:
R R BY
wherein R and R independently are Cl ~ alkyl, phenyl or when taken together with the boron atom to which they are attached form a 5, 6 or 7 membered ring or a bicyclic rin~ and Y i6 chloro or bromo.
The prefe~red organoboron halide i~ dimethylboron bromide. The amount of the organoboron halide utilized may vary between 1 and 10 equivalents for each equivalent of the compound of the formula (V), with 4 equivalent6 being pre~erred.
The starting material6 are either known or readily pre~ared according to the 6ynthetic pathway~
described belo~.
For compound~ o~ the formula (III) wherein R i6 (a) and ~ i8 a metal atom or me~al complex, Tetrahedron Lett., pp. 1373-6 (lg83) describes a procedure for preparing compound~ which can be readily converted into the de~ired compounds of the formula (III) u~ing standard reaction condition~.
For compound6 of the ~ormula (III) whereln X is ~ S02 or CH ~ S02, Tetrahedron L~tt-, 2P-1655-B (lg84) describe~ a procedure for preparing compound6 which can be read~ly converted into the de6ired compounds Or the ~ormula (III) u~ing ~tandard condition6. The compsund~ o~ the formula ~III) wherein Rl i6 (~) are known in the art.
The compound o~ the formula (II~ wherein ~5 ana R7 are described above are readily prepared according tc ~he following ~ynthetic pathway ~rom (S~-malic acid:

~ 30753~

-~ 2 OH ~ O O H
~1) (2) r3~

~ /\~\CC~2R ~,, Pr ~0 H~
\ ~4) (5) O ~ - ~02R ~ H ~Co2R5 Pr~ PrO
(6) (7 ~ /

CO~R ~ Y = ~ Co2R5 ~ (II~
PrO OH PrO OR
(8) t9) ~ 5~-M~ acid (13 iR ~educed under etan~ar~
reductio~ conditions using BH3.THF and then ketalized with acetone to givQ ~ompound ~2~.
Compound (2) iB 6ub~ected to a Swer~,oxidation to yield compound (3~, which, wi~hout i601ation, i~
treated under Wittig condition6 wi~h Ph3PCHC02R
to give Compound ~). Co~pound ~4) is hydrt)lyzed un~e~ acid condltions and ~ele~tively p~o~ec~ed v give Compound (S) w~er~in Pr i~ a protecting group sel~cted from benzoyl, ace~yl, triphenyl~ilyl or tert-butyla~phenyl6ilyl, pre~erablr t-bu~yl-diphenyl~ilyl. Compound (5) ~ 6 cyclized to Compounds 1 3075-~

~ 17194 (6~ and (7) under ba~ic conditions with concomi~ant migration of the Pr group. Compound (73 may be i60merized ~o the de~ired Compound (6) under basic condition6. Compound (6) is converted to Compound (8) u~ing an oeganoboranhalide R R BY, preferably dimethylboron broMide. Compound ~8) i~ treated with R7-halide to get Compound ~9) which is trea~ed with tetcaalkylam~onium fluoride oranalkalimetal alkoxide to afford the compound of formula (II).
The following Examples illu~trate the pre6ent invention and as such are ~ot to be considered as limiting the inveRtion set forth in the claims appended heceto.

E~AMPLE 1 Step (a): Preparation of (S)-1,2-0-Isopropylidene-butane~ -triol_ _ _ To a cold (0C), well-~tirred 601ution of (S~-malic acid (13.4 g, 100 mmol) in 300 ml dry tetrahydrofuran, under argon, was added dropwi6e (via capillary~ a tetrahydrofuran ~olution of borane-THF
complex (300 ml, 30p mmol) o~er a period of 3 hour6~
The cooling bath was removed and ~he resul~ant ~lur~y wa6 ~tirred at room temperature for 15 hour~. The reaction mixture was then cooled to 0C and carefully treated with dry methanol (100 ml). Ater warming to room temperatuce, the solvent waE evaporated. The re6idue wa~ evaporated three times with dry methanDl ~100 ml each) to ensure ~omplete methano}y~i~ of the reductio~ inter~ediate. BLi~f drying (0.1 mm) gave 10.3 g of the crude triol.

1 30753~

- 12 - 1719~
-This material was dissolved in aceton~ (300 ml) and a catalytic amount of ~-TsOH.H2O (0.95 g, 5 mmol) added. After 12 hours at room temperature the reaction mixture was quenched with triethylamine (0.70 ml, 5 mmol) and concentrated. The resultant oil was dissolved in ether (400 ml) and washed with water (3x50 ml) and brine (50 ml) and dried over MgSO4. Concentration and bulb-to-bulb distillation of the residue (air-bath temperature 85-95C, 0.15 mm; lit.l 55-61C, 0.05 mm) gave 11.7 g (80~) of the desired product. 1~ NMR (CDC13) analysis showed that this material contained ~10~ of the isomeric acetonide (S)-2,4-O-isopropylidene butane-1,2,4-trioll'2 and was used without further purification. This material exhibited IR (film) 3450, 2950, 1380 and 1050 cm 1; lH NMR (250 MHz, CDC13) S 1.38 (s, 3H), 1.43 (s, 3H), 1.79-1.88 (m, 2H), 2.55 (broad s, lH), 3061 (d,d, J=7.7Hz, lH), 3.80 (t, J-5.9Hz, 2H), 4.10 (d,d, J=7.0, 7~7Hz, lH), 4.28 (m, lH).

A. I. Meyers and J. P. Lawsonp 5etrahed~n Let-,, 23, 4883 ~1982).
S. Hanessian, A. Ugolini and M. Therien, Chem., 48~ 4427 (1983).

Step (b): Preparation of Ethyl (E)-(S)-O-~sopropyli-dene-5,6-dihydroxy-2-hexenoate A cold (-78C) stirred solution of oxalyl chloride (1.92 ml, 22 mmol) in 50 ml oE dry laethylene chloride, under argon, was treated with a solution of DMSO (3.55 ml, 2S mmol) in the same solvent (10 ml).
After stirring at-78C for 10 minutes a solution of ~ :~0753~
- 13 - 171g4 (S)-1,2-O-i60propylidene butane-1,2,4-t!~ol (2.92 g, 20 mmol) in 15 ml o~ methylene ~hloride was added.
The re~ultant 61urry was 6ti~red at -78~C fo~ 40 ~inutes, then treated with dii~opropyle~hylamine (17.5 ml. 100 mmol). The cooli~g bath wa~ removed and the reaction mixture wa6 ~tir~ed at room tempe~ature for 1 hour to afford a yellow 601ution of ~S)-O-i~opropylidene 4-oxy-butane-l,Z-diol.
Thi~ 601ution was cooled to 0C and trea~ed with carbethoxymethylenetriphenylpho6phorane (17.4 g, 50 mmol3 at 0C for 1 hou~ and at r~om temperatu~e for 4 hour6. The resultant ~olution wa~ dlluted ~ith ~ther (300 ml), wa~hed wieh water (3x50 ml), 10%
aqueou6 NaH804 (50 ml) and br~n~ {2x50 ml) and dried over MgS04. Removal of solYent gave a vi6cous oil. Ether (150 ml) and hexane (150 ml) w~re added and the mixture kept at -10C for 15 hourE.
Filtration o th~ whit~ prec~pitate (Ph3P=O) and removal o~ solvent gave the crude produ~t. Flash 20 ~hromatography (hexane-ethyl ace~ate 85:15) gave 3.60 g (a4%3 of ethyl (E)-(S)-Q-isopropylidene-5j6-dihydroxy-2-hexenoate: ~]D -19.0 ~ 2.43, MeOH); IR (film) 2994, 1727, 1661, 1372, 1269, 1172 and 1064 cm 1; lH NMR ~CDC133 1.30 (t.
25 J=7.011z, 3H), 1.36 t8, 3H), 1.43 (6, 3~), 2.39-2.60 (m, 2H), 3.59 (m, lH), 4.07 ~m, lH), 4.16-4.30 (buriea m, lH), 4.20 (q, J~7.0Hz, 2H), 5.92 ~d,t, J~15.5, 1.5Hz, lH), 6.92 (d,t, Jx15.5, 7.2 HZ~; ~S
m/e (relati~e inten6ity) 199 ~43), 101 l1003.
30 Anal. calcd. for CllH1804: :
C, ~1.66: ~, 8.4~.
Fsund: C. 61.42; EI, 8.4~.

~ 17194 SteP ~cl: Preparation of Ethyl (E)-(s~-5~6-aihya Z-hexenoate . .
To a 601ution o~ ethyl-(E)-~5)-0-isopropyli-dene-5,6-dihydroxy-2-hexenoate (5.35 g, 25 mmol) in 100 ml te~rahydrofuran wa~ added 1~ ~Cl (6~ ml). The reaction mixture ~as stirred at room temperature for 18 hour NaCl (10 g~ and ethyl acetate ~400 ml) were added. The organ;c l~yer was 6eparated and washed with ~rine (2~S0 ml). The aqueou6 was~ln~6 were extracted with ethyl acetate (2xlO0.~ the extra~t~ wa~hed with brine (25 mlj and ~he organic layer~ combined. ~rying (Mg504) and removal of solvent gave 4.04 g (93~) of a vi6cous oil. This material exhibited: IR (film) 3400, 1720~ 1657 and lO~o cm l; lH NMR (CDC13) 1.28 (t, J-7.0Hz, ~H), 2.25 (broad 8, lH), 2.39 (m, 2H), 2.58 ~broad 8, lH), 3.43-3.55 ~m, lH), 3.63-3,73 (m, lH), 3.81-3,92 (m, lH~, 4.18 (q, J=7.0H~, 2H), 5.91 td, J~16Hz, lH), 6.96 (dt. J_16, 6.6Hz, lH).
Anal. calcd. for C8H140~:
C, 55.16; H, 8.10.
Found: C, 5$.52; H, 8.08.

5teP (d~: Preparation o~ Ethyl (~)-(S)-6-t-butyldi-phenYl6iloxy-5_h droxy-Z-hexenoate To a cold (0C), stirred 501ution 0~ the diol ~rom Step ~c) (4.04 gO 23.2 mmol) in 116 ml dry methylene chloride, under argon, wa~ ~equentially added dii~opropylethylamine (6.08 ml, 34.8 mmol) 4-dimethylamino pyridi~e ~0 mg, 2.3 m~ol) and t-butyldiphe~ylsilyl chlor~de (7.5~ ~1, 29 mmol).
The react~o~ ure ~a~ ~tirred at 0c ~or 1 ~ur and then at room temperature ~or ~ hour6. ~ater - 15 - '1719~

(100 ml~ and ethe~ (~00 ml) were added. The organic layer waE ~eparated, wash~d with water (100 ml), ~aturat~d aqueou~ NaHC03 (50 ml~, 10% aqueou6 NaH504 (50 ml), and brine (50 ml). Drying (MgS0~) and removal of ~olve~t ga~@ t~e crude product. Puri~ication by fla~h chromatography ~300 g, SiO2, hexane-ethyl a~e~ate ~5:15) ga~e 9.41 g (98~) of e~entially pure mono-~iloxy alcohol. Thi~
ma~erial exhibited: ~a~D -10.0 ~c 1.23, MeOHa;
IR (film) 34B0, 2940, 1723, 1658, 159~, 1431, 1114 and 704 cm 1; H NMR tCDC1~ 1.07 (~ 9H), 1.28 (t, J=7.2Hz, 3H)o 2~36 (broad t, J-6.5Hz~ 2Hl, 2.53 (d, J=4.4Hz, lH), 3.53 (d,d, J~10.2, ~.7Hz, lH), 3.67 (d,d, J=10.2, 3.7 Hz, lH), 3.85 ~m, lH), ~.18 (q, J=7.2Hz, 2H~, 5.87 (d, J=15.5Hz, lH), 6.94 ~d,d, J=15.5, 7.3Hz, lH), 7.3~-7.49 (m, ~H), 7.60-7.6~ tm, 4H); ~S m/e (relative intensity) 355 ~5), 199 (100).
Anal. calcd. for C2gH3404Si C, 69.87; H, 7.~2.
Found: C, 70.22: H, 7.60.

SteP ~e!: ~reparation of Ethyl 2~R~-(4(S)-tert butyl-diphenyl~iloxytetrahydrofuran)acetate and .its 21S).4~ omer To a cold (0C), ~tirred ~olutio~ o~ ethyl (E)-(S)-6-t~rt-butyldiphen~18iloxy-(53-hydroYy-2-hexenoate (9.41 g, 23.0 mmol) in 200 ml dry ethanol, under argon, was added a solution o~ ~odium ethoxide (Z.3 mmol) i~ ethanol (30 ~1). S~irring wa~
continu~d at room temperatu~e ~or 2 hour~ and at 65C
for 4 hour~. The reac~ion mixture wa~ then coole~ ~o room temperature and quenched ~ith acetic acid (2.3 mmol~. Concen~ra~ion provided ~h~ crude produc~ a~ a 1 3(~753~
~ 16 - 1719 yellow oil (9.5 g~. TLC (hexane-2thyl a~etate, 4:1 and lH NMR ( 250 MHz, CDC13) analyses o~ ~he crude p;oduct indicated the pre6en~e of the de6ired ~ (Rf 0055) and ~ (R~ 0.53) product i~omers i~ a ratio of ~:1 along wieh a ~mall amoun~ of ~tarting material. Thi~ material wa6 purified in two batches by careful flash chromatography (300 g SiO2, eluant. hexane-ethyl acetate, 95:5) to a~ord after concentration of the appropriate fraction6 ~.51 g o~
pure 2~R),4(S)~ omer.
Further elution o the column (hexane-ethyl acetat~, 4:1) and combination of the appropriate frac~ions gav~ 4.80 g of a mixture o~ ~he 2(R),4(S)-and 2(S),4t5~-isumer6 along with a 6mall amount of ~tar~ing material. This material was di~601ved in etha~ol ~160 ml) and resub3eceed to the equilibrat~on conditions (1.16 mmol NaOEt) at 65C for 5 hour6.
Work-u~ and pur~fi~ation as outlined abo~e (30~ g SiO2, eluant: hexane-ethyl acetated 95:5 ~hen 20 4:1) gave 2.27 g of pure 2(R~,4(S)~ omer (total yield 6.77 g, 72~). ta]~ 7.81 (c 2.08. MeOH), IR
(film) 30ao, 2940, 173~, 1593, 1115 and 703 cm H NMR (250 MHz, CDC13) 1.06 (8, 9H), 1.26 ~t, J=7.2Hz, lH), 1.55 (d,d,d, J=15.~, 9.6, 5.6Hæ, lH), 25 2.07 (d,d,d, J-15.4, 5.6, 1.8Hz, lH), 2.4~ (d,d~
J=15.4, 5.9Hz, lH), 2.57 (d,d, J~15.2, 7.2Hz, lH).
3.72 (d,d,d, J~9.4, 2.6, 0.0Hz, lH), 3.84 (d,d, J-9.4, 4.6Hz, lH), 4.15 (g, J~7.2Hz, 2H), ~.45 ~m, lH), 4.57 (m, 1~); 7033 7.50 (m, 6H)~ 7.60-7.76 ~, 30 4~); MS m/e (r~lative inten61~y) 355 (11~, 199 (100~.
Anal. calcd. for C24H3~o4Si:
~, 69.87; ~, 7.82.
Found: C, 70.1~; H, 7.7~.

1 3075^~1 Further elution of the column (hexane-ethyl acetate~ 4:1~ and coll~ction of the appropriate fraction~ gave 0.98 g (10%~ o~ the 2(S),~(S)~a-iEomer. IR (film) 3081, 2942, 1738, 1593, 1113 and 70S cm ; H NMR (250 MHz, CDC13~ 1.07 t8, 9H), 1.27 (t, J=7.2Hz, 3H), 1.75 (d,d,d,d, J=13.1, 5.7, 3.4, 0.9Hz, lH), 2.16 (d,d,d, J-13.1,7.5, 6.3Hz, lH), 2.66 (d,~, J=15.4, 6.4Hæ, lH), 2.84 ~d~do J=15.4, 7.3Hz, 1~), 3.62 (d,d, J=9.4, 4.9Hz, lH), lo 3.81 (d.d.d. J=9.4, 2.8, 0.9Hz, lH9, 4.16 (q, 3=7.2Hz, 2H), 4.31 (m, lH), 4.43 (m~ lH3, 7.33-7.50 (m, 6H), 7.62-7.77 ~m, 4H~; US m~e (relative inten~ity~ 367 (14), 355 (109), 199 (61).

* 1~01 g (llS) o~ a mixture of the ~- and a-i~omer~ wa~ al60 ~ecove~ed.

S~ep (~): Preparation o~ Ethyl 6-bromo-5~5)-tert-but~ldiphenvl6iloxY-3~L-hydrox~hexanoate To a cold {0C~, stirred mixture o~ Qthyl 2~R)-(4(S)-tert-butyldiphenyl6110xytetrahydrofuran)-acetate (1.21 g, 2.93 mmol~ and dii60propylethyla~ne (51 ~1, 0.29 mmol) in 16.~ ml dry methylene chloride, under argon, was added a ~olutio~ o~
dimethylbo~on bro~ide (3.46 ml. 5.9~ mmol) in methylene chloLlde. The rea~tion ~ixture ~a~ then ~irred at room temperatu~e ~or 2 hou~s, diluted wit~
ethe~ ~100 ml) and qu~nch2d wi~h 6atu~ated agu~ous NaHC03 (10 ml). The organ~ laye~ wa~ ~eparatedO
washed w1th 10 ml portions of ~atura~ed aqu~ou~
Na~C03, water and brine and dried over MgS04.
Removal of solvent gave a yellow oil whi~h wa~
subje~ted ~o flash chromatography o~ ~ilica ~el teluant: hexane-eth~l acetate, 4:1) to af~ord 1.19 g 1 ~0753~1 (82%) of the purified p~oduct a6 a colorle s oil.
Thi6 material exhibited [a~D ~2-81 tc 1-~7~
MeOH); IR (film) 3430, 2938, 1725, 15~0, 1430, lllZ
and 700 cm 1 H NMR (250 MHz, CDC13) 1.08 (s, 9H), 1.26 (t, J=7.2Hz, 3H), 1.82 (m, 2H3, 2.30 (m, 2H), 3.05 (broad ~, lH), 3.39 ~d, J=3.7Hz, 2H), 4.10 (m, lH), 4.15 (q, J=7.2Hz, 2H~, 7.34-7.4B tm, 6H), 7.64-7.70 (m, 4H); M5 ~/e (relative intensity) 447 (4), 435 ~Z), 199 (100).
Anal. calcd. for C~4H3304SiBr:
C, 58.41; H, 6.74.
Found: C, sa . lg; H, 6.73.

Step_(g): Preparation of Ethyl 6-bromo-5(S)-tert-butyldiphenyl~iloxy-(3)-(R)-(methoxy-methoxy)hexanoate _ _ To a cold (-10C), stirred solution of ethyl 6-bromo-5(S)-tert-butyldiphenylsiloxy-(3~-(R)-hydroxy-hexanoa~e (0.84 g, 1.70 mmol~ in 5015 ml o~ dry acetonitrile, under argon, were sequentially added dii~spropylethyla~ine (0.~9 ml, 5.10 mmol), 4-N,N-dimethylaminopyridine tZl mg/ 0.17 mmol) and chloromethyl methyl ether (1.03 ~1, 13.6 mmol). The argon inlet was removed and the reaction ~ixture was ~tored at 3C for 24 hour~. The reac~ion mixture was then quenched with ~aturated (aqueous) NaHC03 (3 ml) and diluted with ether (60 ml). The organic layer wa~ separatedt washed with 6aturated aqueou6 NaHC03 (2xlO ml), water (10 ml), 10% aqueou~
30 NaHS04 (10 ml) water (10 ml) a~d brine (10 ml).
~rying (MgS04) and concent~a~ion gave a pale y~llow oil. Purification by flash chromatography ~n silica gel (60 g, eluant: h~xane-ethyl acetate, 4:1) I ~ ~) 7 5 ~ A

peovided 0.85 g t94t) of pure product. This mate~ial exhibit~d: ~a]D = 0.77 (c 1~6Bo CHC13) YR
tfilm) 3075, 2935, 1738, 1589 3 142~, 1031 and 701 cm ; H ~MR (250 MHz, CDC13) 1.08 (60 9H) .
1.24 (t, J=7.1Hz, 3H), 1.94 (broad t, J=6.0Hz, 2H), 2.26 (d,d, J=15.3, 5.2Hz, lH), 2.39 (d,d, J-15.3, 7.3Hz, lH), 3.18 (8~ 3H)~ 3.37 (d, J=4.3Hz, 2H~, 3.92 (m, 1~), 4.04 (m, lH~, 4.12 (g, J=7.1Hz, 2H), 4.50 (d, J=7.1Hz, A part of AB, lH)o 4.58 (d, J=7.1Hz, B
part of AB, lH), 7.33-7.46 (m, 6H), 7.65-7.74 (TQ, 4H); MS m/e ~relative intensity) 479 (28), 213 (100).
Anal. calcd. for C26~3705SiBr:
Cf 58.09; H, 6.97; Br, 14.B6.
Found: C, 58.33; H, 7.02; Rr, 14.79.
SteP lh): Preparation of Ethyl 5(S~,6 epoxy-3(Ra ~methoxvmethoxy)hexanoate ~ cold (0C), ~tirLed solu~ion o~ ethyl 6-bromo-5(S)-tert-butyldiphenyl6iloxy-3(R)-(methoxy-methoxy)hexanoate (0.~0 g, 1.49 mmol) in 3.8 ml dry tetrahydrofuran (THF). under arqon~ was ~reated with a ~olution of tetra-n butylammonium ~luoride t4-47 ml, 4.47 mmol: l.OM ~olutio~ in THF). The cooli~g bath was removed and the rea~ticn mlxture wa6 s~i~red at room temperature for 3 hour~. E~her (50 ml) was ~hen add~d and the mixture wa~hed with wat2r (5 m~), 10% aqueou6 NaHS04 (5 ml), wate~ (5 ml) and ~rine (5 ml). Drying t~g~04) and remo~al of ~olvent gave a pale yellow oil which wa ~ub3e~ted to ~lash chromatography on ~lica gel (20 ~, hexane-ethyl ac@tate, 4:1) to proYide 0.241 g (74%~ of the de~ired epoxide, ~alD -31.5 (c 0.98, M20~). IR ~ilm) 2938, 1736 and 1035 cm 1 1~ ~M~ (2S0 ~H~, 1 30753~
- 20 - ~7194 CDC13) 1.23 ~t, J-7.2Hz, 3~). 1.70-1.82 ~, lH), 1.86-1.99 (m, lH), 2.49 ~m, lH~, 2.56 (d,d, J=15.6, 5.0Hz, lH), 2.71 (d,d, J515.6, 6.0Hz, lH), 2.77 (m, lH), 3.08 ~m, lH), 3.38 ~, 3H), 4.16 (q, J=7.2Hz, 2H), 4.29 (m, lH), 4.67 (d, A par~ of AB, J=708Hz, lH), ~.72 ~d, B part of AB, J=7.8Hz, lH).
Anal. calcd. f Ol CloH1805:
C, 55.03; H, 8.31.
Found: C, 54.~2; ~, 8.39.

steP ~L: P~eparation of 2,~-Di~hlorobenzylmagne~ium bromide _ _ To stirred magnesium metal (0.121 ~, 5 m~ol) in 1.0 ml of dry ether, under argon, was added 0.5 ml of an ether solution of 2,4-dichlorobenzyl bromide (1.20 g, 5 mmol in 4.0 ml dry ether). A ~mall crystal of iodine wa~ added and ini~ia~ion o~ the reàction ~ook pla~e (exothermi~ within 5 minu~es.
20 The remaining solu~ion of 2,4-dichlorobenzyl bromide wa~ then added dropwi~e at such a rata as to maintain a ~ild reflux. A~ter the addition was complete the reaction mixture wa~ refluxed fsr 1 hour to afgord a colorle~ ~olu~ion oX 2,~-dichlorobenzylmagne~iu~
bromide in ether (about l.OM).

~t~ kL: Pre~ara~ion of E~hyl 7-(~,4-di~hloro-phenyl-5(R)-hydro~y-3(R)-(methoxymethoxy)-hePtanoate _ , To a cold (-78C), ~tirred su6pens~0n of cuprou~ bromide-dime~hyl ~ulfide ~omplex ~88 mg, 0.43 m~ol) in a ~ixture o~ dimethyl ~ul~ide (1.3 ml3 and eth~r (0.4 ml)~ under ar~on, wa~ added dropwi6e a 1 30753~

~olution of 2.~-dichlorob~nzylmagn~6ium bLomide ~0.88 ml, 0.88 mmol: 1.OM in ether ~ . The re6ultant orange 601u~ion wa~ stirred at -78C ~or 15 minu~es.
~olution o~ ethyl 5(S~.6-epoxy-3(R)-(methoxymethoxy)-hexanoate (72 mg, 0.33 mmol) in 0.5 ml dry ethel wa6 then added dropwi6e o~er a perlod of 3 minut~. Th~
reaction m~x~ure wa~ stirred at -78C for 1 hour and at -23C for 1 hour. Satueated aqueou6 NH4C1 ~0.5 ml) adjusted to pH 8 with concentra~ed NH40H~ and e~her (20 ml) ~ere added. A~ter warming to room temperature the organic layer was separat~d, wa~hed with 5 ml portion6 of ~aturated aqueous NH4Cl ~pH
8), water and brine and dried over MgS94.
Concentration and purification by fla6h chromato-graphy on 6ilica gel (eluant: hexane-ethy1 acetat~, 7:3) gave pure product, 124 mg ~100~). Thi6 materlal exhibited: t~]D +5.37 tc 0.85, MeOH); IR (film) 3480, 2943, 1738, 1591, 1477 and 1136 cm 1 H
NMR (250 ~Hz, CDC13) 1.26 St~ J=7.2Hz, 3H~, 1.66-1.87 (~, 4H), 2.50 ~,d, J-1500, 5.4Hz, 1~, 2.71 ~d,d. J~15.0, 6.3Hz, lH), 2.74-2.96 (m, 2H), 3.11 (broad s~ lH), 3.3g (6, 3H), 3.BO (~, lH~, 4.14 (q, J=7.2Hz, 2H), 4.22 (m, lH), 4.6g (d, A part o~
AB, J=6.7Hz. lH), 4.75 ~d, B part of AB, J-6.7Hz), 7.18 (m, 2H), 7.3~ (m, lH): ~S m/e (r~la~lve inten6ity) lS9 (~00~.
Anal. calcd. ~or C17H2405C12:
C, 53.~4; H, 6.38.
Found: C, 53.91: H, 6.50.

1 30753~

~ 22 ~ 1719 Step tc): Preparation of 6(R)-[2-(2,~-dichloro-phenyl)ethyl]-4(R)-(methoxymethoxy~tetra-hYdro-2H-pyran-2-one A mixture of 7-(2~4-dichlorophenyl)-5~R)-hydroxy-3(R)-(methoxymethoxy~heptanoate (100 mg, 0.26 mmol) and P-T~OH.H20 (5 mg, 0.026 mmol) in 1.30 ml benzene, under ar~on, was ~tirred at room te~perature for 3 hours. The reaction mixture was ~hen diluted with ether (20 ml), washed wi~h 2 ml portions of 6a~urated aqueou~ NaHC03, water and brine and dried over MgS04. Concentration and purif i~ation of the residue by flash chromatography (eluant: hexane-ethyl acetate, 4:1~ afforded 78 mg (90%) of the desired lactone~ [a]D ~32.4 tc 0.71, MeOH)i IR
(film) 2940, 1740. 15900 1475 and 1040 c~ ; H
NMR (250 MHz, CDC13) 1.75 (m, lH), 1.94 ~m, 2H), 2.07 (m, lH~, 2.65-3.05 (m, 4H), 3.35 ~8, 3H), 4.20 (m, lH), 4.63 (~, lH), 4.67 (8, 2H), 7.19 (~ 2H), 7.37 (~, lH) US m/e (relati~e inte~6ity) 332 (13 lS9 (100).

steP ~d): Preparation of 6(~)-[2~(2,4-dichloro-phenyl)e~hyl]-4(R)-hydroxy-tetrahydro-2H-eyra______e _ ~ _ To a cold (-78C), ~tirr0d ~olution o~ the corre~ponding methoxymethyl ether derivative from Step (c) (65 mg, 0.20 mmol) i~ 1.50 ml dry methylene chloride, under argon, was added a ~olution of dimethylboron bromide ~1.56~) ~0.51 ml, 0.80 mmol) i~
me~hylene chloride. Stirring wa~ continued at -7B~C
for 1 hour. The reaction mixture was then add~d to a eoom temperature s~irred ~ixture of tetrah~dro~uran (2.0 ml) and ~aturated aqueou~ ~aHC03 (2 ml).

1 ~0153~

After 3 minutes ether (20 ml~ was added and the srganic layer washed with 2 ml portions of ~aturated aqueous NaHC03, water and brine. Drying (MgS0 and ~oncentration gave the crude pro~u~t.
~urification by fla~h chromatography ~6 g, SiO2, eluant: hexane-ethyl acetat~, 4:1) gave 46 m~ (79%) of the de~ired produc~, ta3D +59 7 (c 1.10, CHC13). IR (~ilm) 3440, 1728, 1476, 1260 and 1050 cm 1 ; lH NMR (250 MHz, C~C13) 1.78 (m, ~
1.88-2.10 ~m, 3H~, 2.20 (d, J~3.6Hz, lH~, 2.64 (d,d,d, 3-16, 3.49 0.9Hz, lH), 2.76 ~d,d, J516, 4Hz, 1~, 2.77-3.05 (m, 2H), 4.41 (broad m, 1~ .71 (broad m, lH). 7.18 (s, 2H), 7.36 (~, lH); ~S m/e (relative inten6~ty) 288 (15), 159 (1003.
~nal. cal~d. for C13HlqO3Cl~:
C, 5~.00; ~, 4.88.
Found: C, 54.02: H, 4.89.

~ , , 1 .~rJ7s~

U~ilizing the gener~1 procedure6 o~ Example 2 and ta~ting from the appropriately sub~tltuted compound~ o~ the formula (III) and ethyl 5(S),6-epoxy-3(R)-(methoxymethoxy)h~xanoate the following compound6 of the formula ~I) are prepared:

Compound Number _ R

CH3~Q CH2 ~ ~ CH3 CH3 ~

CH3 ~ H CH2 4 CH3 CH3 ~ CH3 CH
o CH ~ O CH
CH3 ~ ~H3 . . .

1 30753ll ~ 25 - 1719 Compound Number CH3 ~ H Ct~2 6 C11 3 CH3~ CH3 ~.

o 7 C~3~c~3 8 Ci~c~3 C

O

CH /\~S: C~12 9 3 ~f~13 W

1 3f)753~
~ 26 - 1719 Compound N mber E~l C~13~' ~1 CH2 C:E~3 c~3~yryC~H3 W, 11 C~ CH~

12 ~ r E~3

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for preparing a compound having the following formula (II):

(II) wherein R5 is C1-5 alkyl or benzyl; and R7 is C1-5 alkyl, benzyl, C2-5 alkoxyalkyl, or C3-6 alkoxyalkoxalkyl, which comprises reacting a compound having the following formula (9):

(9) wherein R5 and R7 are as previously defined Y is chloro or bromo and Pr is a protecting group selected from benzoyl, acetyl, tri-phenylsilyl or tert-butyldiphenylsilyl with tertraalkyl-ammonium fluoride or an alkali metal alkoxide and recovering the desired product.

2. Process for preparing ethyl 5(S),6-epoxy-3(R)-(methocymethoxy)hexanoate which comprises reating ethyl 6-bromo-5(S)-tert-butyldiphenylsiloxy-3(R)-(methoxymethoxy)hexanoate with tetra-n-butylammonium fluoride and recovering the desired product.

3. A compound of the formula (II):

(II) wherein R5 is C1-5 alkyl or benzyl; and R7 is C1-5 alkyl, benzyl, C2-5 alkoxyalkyl, or C3-6 alkoxyalkoxyalkyl.

4. Ethyl 5(S),6-epoxy- (R)-(methoxymethoxy)-hexanoate.