CA2064217A1 - Bicyclic chiral compounds - Google Patents

Abstract

A compound of general formula I(a) and/or I(b) and/or I(c), in which R1 represents a methyl group or a group of the general formula -CH2.SO2.R2 or -CH2.SO2.NR2R3, in which each of R2 and R3 independently represents an alkyl, cycloalkyl or optionally substituted phenyl or phenalkyl group; each of R4, R5 and R6 independently represents a hydrogen atom or a methyl group; X represents a group of formula C(CH3)2 or, when both of R5 and R6 represent methyl groups, also represents a group of formula CH2; Q represents an oxygen or sulphur atom; and Y
represents a hydrogen atom, an alkali metal atom or a group of the general formula -COA in which A represents a halogen atom or an alkyl or alkoxy group optionally substituted by a phenyl, cycloalkyl, alkoxy or alkylcarbonyl group. The compounds are bicyclic optically active compounds and are useful in the synthesis of optical isomers and separation of optical isomers from mixtures.

Description

W 0 91/18890 4217 PCT/~B91lOOB3 LICYCLIC CHIRAL COMPOUNDS

The prc3ent inv~ntlon relates to novol bleyelle ehlral compounds.
Much resQareh i3 eurrently devotcd to methods of produelng optically actlvo eompounds. Soma ecmpounds ean b~ synthesiset direetly in a form containing an exe¢ss of a dn3ired isomer, u~ing optically active starting matorials or an optically active eatalyst, Other materials ara more eonveniently prepared in isomeric form by s0paration of th~ desired isomcr ro~ a mixture. A number of chiral raagents useul in sueh separations are kno~n.
Wa have now found a family of novel bieyclie optically active compount~ u~eful in tho separation of particular isomors from mixtures.
Accortlngly, tho pre3ent lnvontlc1n provlde~ a compound Oe the general ormula l(a), I(b) nnd/or I(e~1 Rl R4 Y

I(a) Itb) W O 91/18$90 PCr/G~91iaO893 ~ ~ ~rl Q

YN Rl O

~ R4 ~c) ~_ R6 - 10 in which R1 represents a methyl group or a group Oe the ganeralformula -CH2.S02.R2 or -CH2.So2~NR2R3~ ln whlch each o~ R2 and R3 Lndependently repregcnt3 an alkyl, cycloalkyl or optionally substituted phenyl or phenalkyl group; each o~ R4, R5 and R6 independently represents a hydrogen atom or a methyl group; X
represents a group of formula C(CH3)2 or, when both of R5 and R6 represent methyl groups, may al~o represent a group of formula CH2; Q
represents an oxygen or 3ulphur atom; and Y represents a hydrogen atom, an alkall metal atom or a group of the general formula -COA in which A repre3ents a halogen atom or ar~ alkyl or al~oxg group optionally substituted by a phenyl, cyc:loalkyl, alkoxy or alkylcarbonyl group.
Throughout this specification, .he structurally isomeric compounds I~a), I(b) and l(c) will be r~err~d to Jointly as the compounds I.
The compound3 I exlst ln a numb~r o~ optlcal and gaom0trlc i~omeric fon~s, and the formulae I(a), I~b) and I(c) should be under~tood to embrac~ all such forms.
An optio~ally eubstltuted phenyl or phcnalkyl group R2 and/or R3 may carry ona or more o~ the inert substltuents commonly carrl~d by a phenyl group~ Such sub~titunnt~ may for exa~ple by 3alectad ~rom halogen atom~ and alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, alkylcarbonyl and alkoxycarbonyl groups. In 3uch a group, any alkyl moiety pre~erably has ~rom 1 to 4, eapecia11y l or 2, carbon atom3. A
sub~tituted phcnyl group pretorab1y ha~ up to 3, e3paclally 1 or 2, 3ubstituent~. The alkyl molaty ln a phanalkyl ~roup pre~erably has , .... .

W O 91/18890 ~ ~217 PCT/GB91/00893 from l to 4, espocially l or 2, carbon atom3.
An alkyl group R2 and/or R3 preferably has up to 20, more pr0ferably up to lO, especially 4 to 8, carbon atoms A cycloalkyl group R2 and/or R3 i~ preerably a cyclopentyl or, o~peclally, cyclohexyl, group.
The number of carbon atoms in an alkyl or alkoxy group A ls not crucial. Preferably such a group ha3 up to 30 carbon atoms. Where a hlgher alkyl or alkoxy group is preferred, such a group may for example have from 15 to 30 carbon atoms. Where a lowor alkyl or alkoxy group is preferred, such a group preferably has up to 6, espeaially up to 4, carbo~ atoms. A cycloalkyl ~ub~tItuent on an alkyl or alkoxy group A is prsferably a cgclopentyl or cgclohexyl group and an alkoxy or al~ylcarbonyl substituent preferably has up to 6, especially up to 4, carbon atoms in th~ alkyl moietg.
Preferably Q represents an oxygen atom.
Compound~ (I) may be prepared by ring closure of a suitable precursor. The position of ring closure determines the proportion of each isomer I(a), I(b) ant/or I(c).
Accortingly, the invention iurther provides a process for the preparation of a co~pound of the general fonmula I(a), I(b~ and/or I(c), which comprises inducing ring closure in a compound of the general formula II
Rl ~4 ~ O.CO.Z (II) ~ X ¦ R6 ~, in which Rl, R4, ~5, R6 ant X have the meanlngs glven for the general formulae I(a), I(b) and I(c), and Z repreaent~ an -N3 group or a group o~ tne general fonmula -NH.o.S02.R7, ln which R7 rspre~ents an optionally substltuted phenyl group; and if de~ired,- converting the rasulting compound in whlch Y represents a hgdrogen atom into the correspondlng cs~opound ln whlch Y repre3ents an alkall metal or a group oi' ~ormula CO.A; and l~ de~lred, convertlng 8 re9ultlnB
compound in which Q represents an oxygen atom Into the corresponding W 0 91/18890 PCr/GB91/00893 compound in which Q ropresents a sulphur atom. The compounds of the general formula II are novel, and form a furthor aapect of the present invention.
In general, cyclisation of a cornpound of the general formula II
leads to a mixture of two or three o~ the pos~lble structural isomors I(a), I(b) and/or I(e). These isomers may be separated by known methods, for example chromatography. For preparation of a compound of the general formula I(a), R6 in the ~tartlng matsrial II must rapresent a hydrogen atom. For preparation of a compound of the general fomula I(b), R1 in the starting material II must represont a methyl group.
The O.CO.Z group in a eompound of the genoral formul~ II may be exo or endo to the bieyeloheptane ring, ant cyclisatlon leads to the corresponding compound I in which the oxazolidinone rinB is exo or endo to the bicycloheptane ring. A compound I(c) ean only be prepared from a compount of for~ula II in which ths O.CO.Z group is endo to the bieyeloheptane ring.
A compound of the general formula II in whieh Z is an -N3 group may be cyclised by heating, for example to a temperature in the range of from 70 to 300-C. The heating may be carried out in the presence or absenee o f a solvent. The spray pyrolysis apparatus deseribed in Accts. Chem. Res., 1987, 20, 18 or the llash vacuu~ pyrolysis apparatus deseribed ln EP-A-259103 may preferably be used. If a solvent is used, this may for example be a hydroearbon or a chlorohydrocarbon, proferably tetrachloroethane. Ultra-vlolet photolysis or microwave~ may also be used, again preferably in the presenee of a hydroearbon or chlorohydrocarbon solvent.
Whers Z in a compound of the general formula II rspr~sents a group of the general formula -NH.o.S02.~7, R7 may represent any suitable optionally substituted phenyl group, for example one of those listed for R2 above. Espeeially suitable groups R7 are phenyl and ~-nitrophenyl groups. Sueh a eompound of the general formula II may b~ eyellsed by treatmont with a base In a homogeneou~ or two phase system. ~xamples o~ the homogeneous system are the uao of amlne bases ~uch as triethylamine, or sodlum blcarbonate ln a chlorlnated solvent WO 91/18890 PCr/GB91/00893 2 ~ 2 'l '7 such as dichloromethane or hydrocarbon/substltuted hydrocarbon ~olvent such as nitromethane. Reaction ln an organic-sgueous two-phase sy3tem 1~ performad uslng a similar selectlon of organic 301vents with,preerably, aqueous sodlum blcarbonate as the bacic solution. In addition a qu~ternary ammonium or phosphonium ~alt a3 phase-trans~er catalyst, preferably bsnzyltriethylammonlum chloride, may be employed. The temperature may be for examplP in the ran8e 20-lOO'C, pref2rably 20-30-C.
A compound I in which Y repre~ent3 a hydrogen atom may be converted into the corrospcnding compound in whlch Y represents an alkali metal atom by reaction wlth a suitable strone base, and into the corresponding compound in whlch Y reprenents a group COA by reaction with a compound of formula HalCOA, in which Hal represent~ a halogen atom. Such conversion~ ma~ be carried out by known method3.
A compound I in which Q repre~ents an oxygen ato~ may be converted lnto the corresponding compound in which Q r0presents a ~ulphur ato~ by method~ analogous to known method~, or example by reaction w~th phosphorus pentasulphide or wlth Law~son's reagent.
A compound of the general fonmula II may be propared by reaction of a compound of the g~neral formula III:

Rl \ R4 ~ / _ O.CO.Cl (III) ~ _ R6 in which Rl, R4, R5, R6 and X have the meanings given for the general formula II, with an alkali or alkaline earth metal azide, preferably sodium azide, to produce a compound of the general formula II in which Z repreaents an -N3 group, or with hydroxyammonium chlorlde followed bg a compound o~ the guneral tormula Cl.S02.R7, or wlth a compound of formula NH20.So~.R7, in which R7 has the meanlng given for the genesal , , .

W O 91/18890 PCT/ICB9l/00893 formula II, to produce a compound of the gener~l formula II ln which Z
repre~ents an -NH.o.So2.R7 group.
A compound o~ the general ~ormula III may be prepared by reaction of a compound of the gsneral formula IV:

Rl ¦ R4 (IV) ~ OH

~ ~6 ~5 .
in which R1, R4, R5, R6 a~d X ha~e the m~aning3 giYen or the general fonmula II, with phosgene. The reaction i~ suitably carrisd out in the pr2~ence of a suitable solva~t, or example an sther such as diethyl ether, tetrahydrofuran or 1,4-dioxan and in the presence or absence of a base such as pyridine or triethylamine, at a temperature in the range o~ ~rom -lO-C to 20-C, preferably -5'C to lO'C. The reaction is preferably carried out under an inert atmo~phere.
The compounds of the formula IV are either naturally occuring or can be obtained ~rom naturally occurlng rompounds by kno~n meehots.
They includo endo-(ls)-l~7)7-trlmethylblcyclo-[2.2.l]-heptsn-2-ol ((-)-borneol); ento-(lR)-1,7,7-trimothylbicyclo[2.2.1]hept~n-2-ol ((+)-born~ol), preparable by reduction o~ (~)-camphor; exo-(lS)-1,7,7-trimethylbicyclo[2.2 1]heptan-2-olj preparable by LS-~electride re1uction of (-)-camphor; exo-(lR)-1,7,7-trllaethylbicyclo[2.2.1]heptan-2-ol, preparable by LS-selectrLds rednction of (~)-camphor; the reduction products of (-)-fenchone and (+)-~enchone; and the products preparabla by msthylation of (-)-camphor or (~)-c~mphor at the 3-positions followed bg reduction to the alcohol. LS-Selectride is the compound LiB(CH.CH3.CH(CH(CH3)2)3H, Compounds ln which Rl ropresents a group o~ the general ~ormula -CH2.S02.R2 or -CH2 S2 ~JR2R3 may be prepared W O 9l/18~90 PCT/GB91/00893 ,, 7 2 0 ~ ll 2 I 7 from the corr2sponding compounds in which Rl rqpresents a -CH2,S02,Cl group by known mathods, for example as described ln Tet Lstters 1984, 25, 5~5 The compounds I may ba used as resolving agants for othor optically-active compounds For example, compounds in whlch Y
represents -COHal where Hal is a halogan atom may be used to separate enantiomers of a~ines, amino-acids, alcohols or thiols whilst compounds in which Y represents an alkali metal atom may be used to separate enantiomers of acid halides or amino-Acid halides In addition, compoundæ I in which Y reprssents a group - COA whers A is an optionally substituted alkyl group, msy be used to react with non-optically active compounds, for ex~ple aldehydes, ketones, ~eto-acids and epoxides, generating optical centres stereoselectively Accordingly, the present invention al~o provides a process for separating enantiomers of a compound capable o~ reacting with a compound I, which comprises contacting a mixture of said enantiomera ~ith a compound I, and sepsr~ting the resulting components of the mixture The invention furthsr provides a process for generatinB an optically active carbon ato~ from an optically inactive carbon atom, which comprises reacting a compound oÇ the general fornula I in which A is an optionally substituted alkyl group, with an alkylating agent such as an aldehyde, ketone, keto-acid, alkyl halide or epoxide Co~pounds I in which Y rsprosents -COA where A is an unsaturated group of formula RC~CH- ~R~II,Me,~h or any ~ubstituted or unsaturated alkyl group) may be u~ed for reaction wlth chiral dienes, original rs~gent3 and 1,3-dipoles enabling, in some casas, the si~ultaneous gen2ration of more than one optically active centre in a singls step operation. Compounds oi' formula I in which Q represents a sul?hur atom are chiral derlvatising agents Oe improvet W sensitivity for chromatographic monitoring.
Compound~ Oe formula I in which Y represents CON~OH could also be used as a basis i'or ligands for complexing to metals as optically ... .. . .
active catalyst~ or reagents.
The following E~amples illustsate the invention. Examples 1, 2 and 9 describe ~he preparation Oe compounds Oe tha formula (III).

I
,-~ , ' ' ''' '' ;~

W O 9~/18890 PC~/C~91/00~93 .

Examples 3 to 5 and lO describe the preparatlon Oe compounds of the formula II. Examples 6 to 8, 11, 29 to 31 and 33 descrlbe the preparation of compounds I. Examples 28 to 32 d03cribe the use of compounds I.
Exam~le 1 Preparation of endo-(lS~ 7,7-trimethylbicyclo~2.2.1~h0pt~n-2-chloroformate A solution of endo-(lS)~ bornsol (9g, 5.8x10-2M) and dry pyridine (4.61g, 5.8xlO~2m) in anhydrous diethyl ether (200 ml) was added dropwise to a rapidly stirred solution of phosg0ne (20Z in toluene, 86 ml, 1.74xlO~lm) under argon at O'C. Th0 reaction mixture was stirred at room temperatur0 for 4 hours and ~ilter0d. The precipitate was washed well with anhydrous diethyl ether. The eth0r fractions were combined and evaporated in vacuo to yleld endo-(lS)-1,7,7-trimethylbicyclo[2,2,1]heptan-2-chloroformate as a pale yellow oil (12.1g, 97~); b.p.o.7 85'C (KuBelrhor)i P~]21 5D
-36.7-; [~]2l.0D~ -36.8-, c - 5.1 (EtOH); M+ 216.0917 C11~17ClO2 requires 216.0917; lH nmr (200 MHz, CDC13)S 0.8-O.9 (3s, 9H, 3xCH3), l.O - 2.5 (m, 7H), 5.0 (ddd, lH, CHO),~ max (thin film) 1780 cm~l.
Example 2 Prevaration of exo-~lS ~ methYLbic~clo~2.2.11 heDtan=2-chlorofor~ate Th~ method of Exa~ple 1 wa~ r0p~at~d u~iing exo-(lS)-1,7,7-trimethylbicyclo~2.2.1]1leptan-2-ol to produce the desired product in 86Z yield.
b.p.o.7 70'C; [oq21.5D - -54.5-, c - 4,9 (EtOH); lH nmr (200 MHz~
CDCl3)5 0.84 (s, 3H, CH3), 0.92 (m, 3H), 0.99 (s, 3R, CH3), 1.08 (s, 3H, CH3), 1.7 (m, 3H), 3.93 (dd, lH, J - 4.66 H3, CH).
- : ~ max thin film 1765 cm~l.
3G ExamPle 3 - ., PreDaration S '' endo-tlS)-1,7,7-trim0thylbicvclo[2.2.1l-heDtan-2-azidoformate endo-(lS)-1,7,7-Trim0thylbicyclo[2.2.1]h0ptan-2-chloroformate (lOg, 4.6xlO~2m), th0 p~oduct of Exsmple 1, in CH2C12 (50 ml) was add0d in one to a rap1dly stirred solution Oe sodium azidfl (6.0g, 9.2x10~2m) ,, . , . .. , , , .,, " . , _, .. .. .. .

:

W O 91/1$890 PCT/CB91/00893 2BS~217 and tetrabutylammonium bromide (0.2g) in water (50 ml). The reaction mixtura wa~ stirred for 4 hours, ~eparated and the squeous i'raction W3 extracted with CH2C12 (x2). CH2C12 fractions were combin~d, washed with H2O (xl), drled (MgS04) and evaporated in YacUo to yield a slightly yellow oil endo-(lS)-1,7,7-trimethylbicyclo[2.2.1]-heptan-2-azldoformate (10.1g, 98Z); b.p. 0.15 85-C (Kugelrhor); ~X]22.5D ~ -42.3-, c ~ 4.9 (EtOH);
M~ 223-13207 CllH17N32 require8 223.1321; lH nmr (200 MH~, CDC13) ~
0.86 (s, 3H, CH3), 0.87 (s, 3H, CH3), 0.89 (s, 3H, CH3), 1.08 (dd, lH, J - 13.96 H~, 3.~2 Hz, CH), 1.28 (m, 2H, CH2), 1.78 (m, 3H), 2.39 (m, lH, CH), 4.89 (m, lH, CHO). 13C nmr (50.3 ~Iz, CDC13)5 157.42 (C~0), 84.58 (CHO), 48.83 (quart. C), 47.77 (quart. C), 44.53 (CH), 36.10 (CH2~, 27.65 (CH2), 26.56 (CH2), 19.39 (CH3), 18.53 (CH3) 13.14 (CH3);
13C assignment~ are based on ~ t2 and 1r3/4 DEPT measurements; ~ max 2150, 2115 t-N3), 1720 (C~0) cm~l.
Exa_~e_4 PreParation, of h~ptsn-2-azidoformate The method of Exampl2 3 wa3 repeated u~iing exo-(lS)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-chloroform te to produce the desired product in 97Z yie:Ld.
- b.p.o.5 105-C; [o~322.0D ~ -19.5', c ~ 4.9 (EtOH); M+ 223.1321 CllH17N302 requir~ 223.1321, ~H nmr (:200 MHz, CDC13) $ 0.82 (8, 3H, CH3), 0.87 (~, 3~, C~3), 0.93 (8, 3H, CH3), 1.08 (m, 2H, CH2) 1.56 (m, 2H, CH2) 1.77 (m, 3H), 4.65 (m, lH, CHO); 13C nmr (50.3 M~z CDC13) 5 156.53 (C~0), 85.48 (CH0), 48.79 (quart. C), 46.63 (quart. C), 44.67 (CH), 38.11 (CH2), 33.2 (CH2), 26-60 (CH2)~ 19-67 (CH3), 19-43 (CH3)~
10.90 (CH3). ~ max (thi~ fil~) 2170, 2140 (N3), 1730 (C-0) cm~l.
~xample 5 .. ..
reparation oF _endo-(ls~ 7~7~-trimethylbicyclol2.2.llhoptan-2 p-nitrobenzenesulphonoxy carbamate The product oi' Exa~ple 1 (7g, 0.032~m) ln dlethyl ether (10 ml) ~as added dropwl~e to a cooled (O-C), stlrred mlxture of flnely ground hydroxyammonium chloride (2.5g, 0.035 M) and potasslum carbonate 35 (4.4g, 0.032 m) ln dlethyl cther containlng water (0.5 ml). The W O 91/18890 PCl/GB91/00893 ~r~ 10 mixture wa~ stirred at room temperature ~or 12 h, the prccipitate wa3 filtered off and the solvent ramoved in vacuo to gLve endo-lS-(-)bornyl-N-hydroxy-carbamat¢.
p-Nitrobenzenesulphonyl chloride (4.65g, 0.021 m) was added gradually to an ice-cooled, stirred solutlon o~ the N-hydroxycarbamate (0.021 m) in dry diethyl ether (150 ml). Triethylamine (0 018 m) in dry diethyl ether (25 ml) was added dropwise, en~uring that the reaction mixture remained acidic at all times. The mixture was stirred at room temperature for 48 hours, the precipitat~ was filtered off and the filtrate evaporated to give the required product, endo-lS-(-)-bornyl p-nltrobenzene-sulphonoxycarbamate as a yellow solid (7.63 g, 90%). This was recry~talllsed i'rom chloroform/hexane to giva flns, cream needle3, m.p. 138-139-C (Found: C, 51.5; H, 5.63;
N, 7.04. C17H22O7N2S requires C, 51.3; H, 5.6; N, 7.0Z); ~ max (mull) 15 3240, 3200, 1750, 1705, 1535 and 1195 cm~l;
lH nmr (200 MHz; CDC13)S 9.6 (lH, br s~, 8.27 (4H, m), 4.75 (lH, m), 2.4-0.6 (16H, cm); 13C (50 MHz; CDC13)~155.85, lS7.17, 139.15, 130.71, 123.98, 83.75, 48.79, 47.74, 4~.47, 35.94, 27.65, 26.64, 19.37, 18.47 and 12.97; mJz 398 (M+), 383, 340, 292, 264, 217, 203, 196, 188, 154, 136, 121, 107, 97, 79.
ExamDle 6 The product of Example 3 (20g, 8.96xlO~2m), was passed through a spray pyrolysi~ apparatus at 300-C snd a ~acuum of 0.1-0.05mm Hg.
Product was collected in a Yessel cooled with dry ice in an amount of 16.08g (92Z). This was puriflet by column chrometography using Fluka Kie~lgel 60 using initially n-hexane (200ml), petroleum ether 40-60:
ethyl acetate, g:l (500ml), 4:1 (500~1), 3:1 (lSOOml), to yield ploducts (a), (b) and (c) as follows.
(a, Endo-(9~ 4R~-l-oxa-3-aza-a.10.10-trimethYltricYclo~3,2.1.04.91 -decJn-2-one Yield 57% Spray Pyroly~is; m.p. 163 - 163.5-C, 1~]21.5D ~ -73.4'. c - 5.1 (EtOH); Found C, 67.6; H, 9.0; N, 7.2. CIlHl7NO2 requires C, -67.7; H, 8.8; N, 7.2X, lH nmr (200 MHz, CDC13) ~ 0.90 (9, 3H, CH3), 0.94 (g, 6H, 2 x CH3), 1.30 (m, 2H, CH2), 1.65 (m, 2H, CH2), 1.87 (m, lH, CH), 4.16 (dd, lH, J ~ 9.82 Hz, 4.68 ~z, CH) 4.60 (dt, lH, J ~

W O 91/18890 PCT/GB91tO0893 _ 11 2~ 217, 9.94 Hz, 1.68 Hz, CH), 5.56 ~b~, lH, NH); 13C nmr (50.3 MH~, CDCl3) S 160.50 (C-O), 85.71 (CH), 54.66 (CH), 49.04 (quart. C), 48.44 (CH), 29.51 (quart. C) 26.34 (CH2), 19.97 (CH3), 19.71 (CH2), 17.82 (C~3), 14.00 (CH3); ~ max 3300 (b3, NH), 1755 (s, C~O), 1715 (~, NH) cm~l, S (b) Endo-~10~ oxa-3-aza-11,11-dimethyltr$cyclo[4.3 1.05,1l-yndecan-2-o=e Yield 17Z; m.p. 170 - 171-C; [o~]23.0D ~72.1-, c - 5.1 (EtOH);
Found: C, 67.5; H, 8.8; N, 7.1. CllH17N02 requires C, 67.7; ~, 8.8;
N, 7.2Z; lH nmr (200 MHz, CDCl3) S 0.94 (8, 3H, CH3), 0.95 (s, 3H, CH3), 1.37 (m, 3H), 1.8 (m, 2H, CH2), 2.95 (dd, lH, J ~ 10.7 Hz, J -3.9 Hz, CHbN), 3.3 (d, lH, J - 10.7 Hz, CHa~7), 4.51 (ddd, lH, J ~ 10.1 Hz, 4.4 Hz, 2.0 Hz, CHO), 6.25 (b8, lH, NH); 13C nmr (50.3 MHz, CDCl3) 5 155.92 (C~O), 80.24 (CH), 46.16 (quart. C), 45.86 (CH), 44.48 (quart. C), 43.50 (CH2), 32.75 (CH2), 27.36 (CH2), 24.50 (CH2), 19.72 (CH3), 18.42 (CH3~; ~ max (KBr) 334S (bs, NH), 1713 (s~ C-O), 1668 (s, NH) .
(c) Endo-(4R,BS~-l-oxa-3-aæa-9.10.10-trimsthYltricYclo[3.1.1.11-decan-2-one 7ield 25Z; m.p. 170'C; Found: C, 67.4; H, 9.0; N, 7.1. CllH17N02 requires C, 67.7; H, 8;8; N, 7.2Z, lH ,~mr (200 MHz, CDCl3) S 3.45 (m, lH, CHN), 4.5 (m, lH~ CHO), 7.1 (b~, NH); 13C ~mr (50.3 MHz, CDCl3) S 152.31 (C~O), 82.69 (CH), 54.24 (CH), 48.58 ~quart. C), 46.10 (quart. C), 41.28 (CH), 39.22 (CH2), 36.63 (CH2), 19.24 (CH3), 18.64 (CH3), 11.07 (CH3).
In addition to the procedure described above, the product of Example 3 was pyroly~ed used a flash vacuum pyroly~is apparatus.
Product (a) wQa obtained in 46Z yield, product (b) in 23Z yield, and pIeduct (c) in 23Z yield.
Exsmple 7 The protuct o~ Example 4 WB8 pyrolyset by the procedures described in Example 6 to yield products (a) and (b) a~ ~ollows.
(a) Exo-(9~.4S)-l-oxa-3-aza-8.10.10-trimethYltricYclol3.2.1.04,91-decan-2-one Yield 58X (S.P.), 55% (F.V.P.); m.p. 153.5 - 154.5-C; 1~122-OD ' 35 15.1', c ~ 5 (73tOH); Found: C, 67.5; N, d.9; N " .2. C11N17N02 ,, ~
~ '' , " , W O 91/18890 PCT/CB91iO0893 t " _ requireis C, 67.7; H, 8.8; N, 7.2Z; lH nrnr (200 %Hz, CDC13) ~ 0.86 (s, 3~1, CH3), 0.95 (m, lH, CH), 1.00 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.59 (m, 3H), 1.83 (d, lH, J ~ 4,47 Hz, CH), 3.73 (d, lH, J ~ ~3.1 Hz, CH), 4.34 (d, 1~, J - 8.1 Hz, CH), 6.63 (bs, lH, NH); 13C nmr (50.3 M~{~, CDC13) 5 160.59 (C~0), 88.25 (CH), 68.48 (CH), 48.47 (C}l), 48.03 (quart. C), 46.17 (quart. C), 31.58 (CH2), 24.60 (CH2), 23.12 (CH3), 19.25 (CH3), 10.66 (CH3); ~ max (KBr) 3300 (bs, NH), 1765 (s, C~0), 1716 (s, NH) cm~l, (thin ~ilm) 3200 (bs, NH), 1745 (s, C~0), 1690 (s, NH~ C~
(b) Exo-(lOS~- -oxa-3-aza~ -dlmethyltricyclo[4~2~l~o5llolundocan 2-one Yleld 43% (S.P.), 27Z (F.V.P) m.p. 177 - 178-C; [ ]23.0D -+8.1', 1~]22.0D ~ +7.1~, c - 5.1 (EtOH); ~ound: C, 67.3; H, 8.8; N, 7.2.
CllH17N02 requires C, 67.6; H, 8.8; N, 7.1X; lH (200 ~Hz, CDC13)~0.89 (s, 3H, CH3), 1.09 (s, 3H, CH3), 1.10 (~, 2R, CH2), 1.75 (m, 4H), 2.10 (m, lH, CH), 3.27 (m, 2H, NCH2), 4.26 (dd, lH, J - 14.29 Hz, (7.15 Hz, CHO), 6.27 (b~, lH, NH); 13C nrnr (50.3 MHz, CDC13) S 154.95 (C-0), 83.13 (CH), 46.34 (quart. C), 44.98 (CH), 43.71 (quart. C) 39.78 (CH2), 38.08 (CH2), 30.59 (CH2~, 26.63 (CH2), 19.92 (2 x CH3); ~max (thin film) 3240 (bs, NH), 1690 (s, C-O) cm~l.
Exam~le 8 Pre~aration of Oxjazolid_~s~r3~y~lJl3lL~ Lwowski Ty~e ReaRent Benzyltriethyl~nonium chloride (0.lg, 4.39 mm.) wai~ added to a stirred mixture of the product of Example 5 (lB) (3-5 8-, 8.75 mm) in aqueous sodium hydrogen carbonate solution (lM, 50 ml), and dichlorornethane (180 ml.). The reaction mixture was stirred vigorously overnight at room tempera~ure, following which dichloromethane (100 ml.) was added and the mixturs washed with water (3 x 50 ml). The organic phase was dried (MgSO4) the ~olvent removed and the reaction mixture sub~ected to column chromatography (SiO2, gradient elution l0/90 v/v - 100/0 v/v ethyl acetate/n-hexane). Three ~ractions were collected in the ~ollowing order~
(a~ endo-~18~ 1,7,7-trlmst~y ~ .2.11heptan-2-carbamate (0.234g, 14X); rn.p. 12~ - 126'C; [d]22D ~ ~34-4'. c ~ 4.96 (EtOH);
M~ 197.1425 CllHlgNO2 requires 197,1421; lH nmr (200 MHz, CDC13) 5 WO 91/1~0 P~/GB91/00893 13 ~0~ 1~217 0.83 (s, 3H, CH3), 0.84 ~s, 3H, CH3), 0.88 (s, 3H, CH3), 0.97 (dd, lH, J - 13.7 Hz, 3.4 Hz), 1.19 (m, 2H), 1.61 (m, 2H), 1.84 (m, lH), 2.24 (~, lH), 4.74 (ddd, lH, J n 9.9 Hz, 3.3 Hz, 2Hz, CH0), 5.11 (b~, 2H, NH2); 13C (50.3 MHz, CDC13) ~ 157.5 (C~0), ao.4 (CH0), 48.6 5 (quart. C), 47.7 (qu~rt. C), 44.7 (C}l), 36,5 (CH2),, 27.8 (CH2), 26.7 (CH2), 19.5 (CH3), 18.6 (CH3), 13.3 (CH3); ~ max (KBr) 3480, 3340 (m, w, NH2), 1700, 1605 (8, m, CONH2) cm 1.
(b) Endo-(9S.4R)-l-oxa-3-aza-8.10.10-trimethYltricYclo~3.2.1Ø4.9 decan-2-one (0.74~, 43Z).
. . 10 (c) End~L~S)~l-Oxa-3-aza-11,11-dimethyltricYclo[4.2.1Ø5.10]
.i -undecan-2-one (0.62g, 36X).
Example 9 Prep~ration of oxo-~lR)-l-N,N-dicyclohexyl_ulphonamidomot yl-7,7-dimeth~lblcYclor2.2.11he~tan~2-chloro~ormate This compound wa~ preparsd from exo-(lR)-l-N,N-dicyclohe~glsulphonamidomethyl-7,7-dim~hylbicyclo[2.2;1]heptan-2-ol (lg, 2.52 x 10~3m) using th~ method ~hown in Example 1 in 97Z yield (1.12g, 2.44 x 10~3m) as a white crYst~llline solid; m.p. 129 - 131-C;
- Found: C, 60.1; H 8.4; N, 3.14. C23H3~NO4SCl requires C, 60.1;H, 8.3;
20 N, 3.0X; [d]21D - -39.2', c - 4.5 (CH2C12); lH nmr (200 ffHz, CDC13) 5 0.9 (s, 3%, CH3), 1.0 (s, 3H, CH3), 1.1 - 1.4 (m, 8H), 1.5 - 1.8 (m, 16H), 1.9 (m, 3~), 2.6 (d, lH, J - 14.4 Hz, CHS02), 3.2 ~d, lH, J ~
14.4 Hz, CHSO2), 3.3 (tt, 2H, CHN), 5.15 ~dt, lH, J ~ 7.11 Hz, 4.2 Hz, CH0); ~ ma~ (KBr) 1780 (8, C-O) cm~l.
~2!!~
_rc~sration of exo-(lX2-1-N,N-dicYclohex~lsulphonamidomethYl-7,7-dimethYlbicYclo~2.2.11heptan-2-azidoformate The ~ethod of Example 3 was repeated using tho product Oe Exampls 9 to produce this compound in 78X yield (0.32 B), 6.8 x 10~4m) as a white - 30 crystalline material; m.p. 143 - 144-C; [d]23D - -14.1-, c - 1.2 (CH2C12); Found: Cj 59.2; H, 8.4; N, 12.1. C23H3gN404S requires C, 59.2; H, 8.2; N, 12.0Z; m/z 466; 1~ nmr (200 MHz, CDC13) ~ 0.9 (g, 3H, CH3), 0.94 (B, 3H, CH3), 1.0 - 1.4 (m, 8H), ,.5 - 2.1 (m, 18H), 2.6 - (t, lH, J - 13,4 Hz CHS02), 3.1 (d, lH, J ~ 13.4 Hz, CHS02), 3.2 (tt, 2H, CHN), 5.0 (dd, lH, J - 7.0 Hz, CH0).

,.
, .

' ~, : , . .

W O 9l/l8890 PCT/CB91/00893 ~ 14 ~,Q~
Examele 11 7,7-dimet~ylbicyclo~2.2.11heptan-2-a~idoformate A solution of the above compound (0.826 g, 1.77 x 10~3m) in 1,1,2,2-tetrachloroethane (TCE, 50 ml.) was refluxed (147'C) under argon for 2 hours. The solvent was remo~ed in vacuo and the crude reaction mixture subjected to column column chromatography (SiO2, 50 g, gradient elution 95:5 40-60 pet. ether: ether to 100X ether).
Two fractions were collected containing hiBher Rf and lower ~f a~
viscous oils in a ratio of 2.64: 1 in yields of 55.5Z and 21%
re3pectively. The higher Rf material was exo-(9R,4S)-l-oxa-3-aza-8-N,N-dicyclohexyl-sulphonamidomethyl-10,10-dimethyltricyclo[3.2.1.04,9]decan-2-one; M~ 438.2549 C23H3gN2O4S
requirss 438.2552; [~]24D - - 38.9-, c~0.9 (EtOH); 1H nmr (200 MHz, CDC13) ~ 0.9 (s, 3H, CH3), 1.04 (s, 3H, CH3), 0.8 - 2.0 (m, 27H) 2.71 (d, lH, J ~ 13.4 Hz, CHSO2); 3.20 (d, lH, J - 13.4 Hz), CHSO~), 3.25 (tt, 2H), 3.77 (d, lH, J - 8.1 Hz, CHN), 4.98 (d, lH, J
~ a.l Hz, CHO), 6.7 (s, lH, NH).
Example 12 This exampl~ describas the conversion of a compound of formula I~a) in which Y is a hydrogen atom into the corresponding compound in which Y is a C2HsCO- group, and rescl:ion of the resulting compound with racemic benzaldehyte. In tho r~lactlon wlth benzaldehyde, a new optically active centre is generated.
(a~ Pre~aration of trimethYltricYclo~3.2.1.04,9]decan-2-one A solution of the product of example 6(a) (2g, 1.02 x 10~2m) in nnhydrous toluens (sodium) (100 ml.) was added to a stirred suspension of oil free ~odium hytride (0.27 g, 1.12 x 10~2m) in toluene (30ml.) under argon. The reaction mixture was heated under reflux ior 60 minutes, cooled to room temperature, and treated dropwise with propionyl chloride (l.Og, 1.08 x 10~2m) ln toluene (3 ml). The mixture was stirred for a ~urther 60 minutes, poured into saturated NaHCO3 solution and the two ~ractions were separated. The organic fraFtion was washed with water, dried (MgSO4) and e~aporated , _ ~ 15 20~217 to yield a colourless oil (2.62 g). The oil wa~ puri~ied by high vacuum distillation b.p.o.2S 165-C (Kugelrohr); 2.43 g., 95X;
[c~26D - -150.6', c ~ 5 (EtOH); M~ 251.1524, C14H21NO3 requires 251.1521; lH ~mr (200 MWz, CDC13) 5 o.go (9, 3H, CH3), 0.91 (s, 3H, CH3), 0.93 (s, 3H, CH3), 1.09 (t, 3~, C~3, .J ~ 7.34 ~z), 1.1 - 1.7 (m, 4H), 2.24 (t, lH, C~, J ~ 4.0 Hz), 2.90, dq, 2H, CH2, J ~ 7.73 Hz, 7.29 Hz), 4.45 - 4.6 (m, 2H); 13C nmr (50.3 MHz, CDC13) S 174.0 (C-O), 154.~ (C-O), 82.4 (C~O), 57.5 (CR), 49.2 (quart. C), 4a.3 (qu~rt. C), 47.6 (CH), 28.8 (CH2), 26.1 (CH2) 19.7 (CH2), 17.8 10 (CH3), 13.6 (CH3), 8.1 (CH3); ~ max (thin filrn) 1780 (s, C~O), 1700 (5, C-O) cm~l.
(b) Procedure for G erstion of Lithium Enolates and Sub~equent Aldol Reaction A solution of lithium diisopropylamide (2.18 mm, 1.1 eq.) was 15 prepared by addition of butyllithium (1.6 ~ in hexane, 1 eq., 1.36 M~) dropwise to a solution of anhydrous dii~opropylamine (0.221 g., O.31 ml, 2.18 mm, 1.1 eq.) in dry THF (30 ml.) at O-C. The reaction mixture ~a~ left at thi~ ~emperaturo ~or 0.5 hours before cooling to -78-C. The N-propionyllmide of part (a) (1.98 mm, 0.49B g, 1 eq.) was then added ~ a solution in T~F (5 ml) and the reaction mixture left for a further 0.5 hours at -78-C. Neat redistilled benzaldehyde was added rapidly (1.98 mm, 0.206 ml, 0.21 g, 1 eq.) ant the reaction guenched after 30 seconds ~ith saturatsd ammonium chloride solution (5 Ml). Water (50 ml) was added and the reaction products extracted into ether. The organlc layer was dried (MgSO~) and taken to dryne3s to give a white cry~talline mixture of the aldol adducts (0.69 g, 97Z, 1.92 ~m). 360 MHz nmr ~pectroscopy ~howed there to be all four possible diastereomeric aldol adducts - present iA a ratio of approximately 5S.4 : 28.7 : 10.3 : 5.7.
(c, Procedure ~or Generation o~ Dlbutxlboron En late and Subsequent Aldol Reaction - - - ~ - ` -~ o a solution of imide (300 mg, 1.2 mm) ln CH2C12 (5 ml) at O-C
was added di-n-butylboron triflate (lM, iA C~2C12, 1.31 ml, 1.31 m~) ~ollowed by dlisopropglethylamine (0.25 mol, 1.43 mm). The mixture was stirred for 30 minutes thcn cooled to -78'C and a , . ~ . ., ~ ,.. . .
: . , -: .
i solution of the aldehyde (1.31 mm) in THF (1 ml) was added dropwise The solution was stirred at ~78-C ~or 30 m1nutes and then at RT for 1.5 h. The mixture was quenched with pH7 phesphate buffer (SO ml) and the organic phase separated. The aqueous layer was extrscted w1th CH2C12 and the combined extract~ were evaporated in vacuo. The resulting oil was then troated with 30X w/v H22 (2 ml) in methanol (2 ml) at O'C for 1 hr. The mixture was then thoroughly extracted with ether and the extracts were dried (Na2S04) and evaporated. The products were isolated ~ollowing puri~ication by flash chromatography.
(i) Reactlon with isobutyraldehyde gave a slngle dia~tereolsomer (86Z) as a colourless solid meltlne point 161-2-C (ethyl acetate-petrol (Found: C, 66.8; H, 9.32; N, 4.44, ClgH2gN04 requires C, 66.84; H, 9.04; N, 4.33); ~ max (Nu~ol) 1770, 1660 cm~1; m/z (ci) 324 (M~ ~ 1, 20Z), 306(100Z), 252(95%), 196(80%), lH nmr ~ 4.64-4 (2H, m), 4.02 (lH, gd, J6, 2.5Hz), 3.52 (lH, dd, J8, 2.5Hz), 2.87 (lH, br, OH), 2.30 (lH, t, J4Hz), 1.75-1.58 (3H, m), 1.40 (lH, m) 1.?3 (3H, d, J7Hz), 1.15 (lH, m), 1.02 (3H, J7Hz), 0.99 (3H, s), 0.98 (3H, s), 0.97 (3H, s), 0.90 (3H, d, J7Hz).
(ii) Reaction with benzald~hyde gave a single dia~tereoisomer (52Z) as a colourle~s crystals melting point 136-7-C (ethyl acetate-petrol (Found: C, 66.62; H, 9.01; N, 4.32. C21H2gN04 requires C, 66.84; H, 9.04; N, 4.33); ~ max 1770, 1658 cm~1; lH nmr S 7.42-7.21 (5H, m), 5.12 (lH, d, ~3.5Hz), 4.58-4.45 (2H, m), 4.14 (1~, gd, J7,3.5Hz), 3.00 (lH, br, OH), 2.30 (lH, t, J4Hz), 1.73-1.55 ~2H, m), 1.44-1.05 (2H, m), 1.17 (3H, d, J7Hz), 0.98 (6H, brs) 0.95 ~3H, s).
Exam~le 13 Use of the N-carbamoYl chloride of endo-(9S,4R~-l-oxa-3-aza-8.10,10-trimethyltricYclol3.2.1.04,91decan-2-ono for the chromatoQraphlc resolution o~ R- and S-l-Phenvlethvlamine.
This Example describes the reaction of an equivalent o~ a compound I(a) with an amine, to produce two diastoreomeric products which can be separated by chromatography. A 20Z solution of phosgene ln toluene (83.7 ml, 16.75 g, 1.69 x 10~1m, 15 eq.) under argon was stirred overnight wlth calciu~ hydrido (0.2 g) to W O 91/18890 PC~r/GB91/00893 17 2 ~ , 1 7 remove free hydrogen chlorlde. The product o~ nxampl~ 6(a) ~2.2 B, 1.12 x lO~lm) in dry THF (50 ml) under argon wa~ treated dropwise with 1.6 M ~olutlon of n-butyl llthlum (7.75 ml, 0.79 g, 1.24 x 10~2m, 1.1 eq.) and stirred ~or 30 minute~ at room temperature. The phosgene solution W88 cooled to O'C in an 1CB bath and treated dropwise via a metal canula (id 2.2 ~ gc tubing) u#ing slight po~itive argon pressure wlth the lithlum ~alt over 15 ~inuts~. The reaction mlxture was stirrsd at room te~perature for 2 hour~ then filt~red. The praclpitate was wa3hed with THF and the organic fraction containing product and excs~s phosgene evaporatsd in vacuo to yield a white solid (moi~ture sensitiv0) (2.65 g, 91X).
FAB-MS (M+l)+ 258.08968 C12H17ClN03 requircs 258.0B969; lH nmr (60 MHz, CDC13) S 0.39 (S, 3H, CH3), 0.91 (S, 6H, 2 x CH3), 1.2-1.8 (~, 4H), 2.4 (m, lH), 4.7 (m,2H, CHO, CHN); 13C nmr (50.3 MHz, CDC13) S 150.57 (C~O), 144.66 (C-0), 81.84 (CH0), 60.15 (CHN), 49.39 (quart.c), 48.22 (quart.c), 48.03 (CH), 26.02 (CH2) 19-55 (CH21 CH3), 17.85 (CH3), 13.51 (C~3); ~ ma~ (nu~ol mull), 1833 (S, C-0, CO.Cl), 1745 (S, C-O) cm~l; ~ max (KBr) 1830 (S, C-O, CO.Cl), 1740 (S, C~O) cm~l.
The carbamoyl chloride (63 mg, 0.244 mm) w~s dissolved in toluene (sodium-dried, 5 ml.) with triethylamins (1.5 eg, 0.367 mm~. (~)-l-phenylethylamine (1.01 eq, 0.247 ~m) was then added neat to the reaction mlxtura and the re~ction refluxed for 1 hour. After cooling, ether (30 ml) was added and the reaction mixture extracted with hydrochlorlc acid (lM, 10 ml).
The organic layer was separated, dried (MgS04) and the solvents removed to yield an oily mixture ~95%, 79 mg) o~ diastereoisomeric ureas.
A HHichrom" column (25 cm. x 0.46 cm., 5 micron Sphsrisorb 30 SiO2, flow rate ~ 2 ml./min., detector - 260 nm) was us~d for the - H.P.L.C detsrmlnation of o~-values. The diast~rnomër~ were eluted .: with 1: 4 v/v ether : n-hexane. An o~-valvs of 2.01 was obtained.
The r~action was repeated on a larger scale (1.24 mm) and diastereoisomeric ursas were separated by column chromstography 35 (80g, ~Flash" Si42, gradlent elutlon 1 ~ 9 v/v to 1 ~ 1 v/v ether :
., ;.

... ..

r C'~ ~ ~

40 - 60 pet. eth~r) yielding 98X (0.407 g).
Highe~ aqtereomer lH nmr (200 k}sz~ CDC13) 5 0.89 (3, 3H, CH3)~
0.95 (s, 3H, CH3), 0.96 (9, 3H, CH3), 1.50 (d, 3H, J ~ 7.0 Hz), 1.75 - 2.0 (m, 4H), 2.27 (M, lH), 4.51 (m, 2H), 4.97 (m, 1~), 7.21 - 7.32 - ;
(m, 5H), 8.27 (d, lH, J ~ 7.5 Hz, N~).
Lower Rf dla~ter~omsr lH nmr (200 M~s~ CDCl3) ~ 0.89 (5, 3H~ C~l3)~
0.95 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.48 (d, 3H, J ~ 6.9 Hz), 1.75 - 2.0 (m, 4H), 2.24 (m, 1~), 4.58 (m, 2H), 5.02 (m, lH), 7.3 (m, 5H), 8.27 (d, lH, J ~ 7.6 Hz).
Example 14 Uae of the N-Carbamoyl Chloride of endo-(9S,4R~ oxa-3-aza-8,10,10-trimethyltr ~ .1 0 ~ or the Kln~tlc Resolution of R- and S-l-PhenYlethYlamine.
This Example differs from Example 13 in that an exces~ of amine is used. The compound I(a) reacts ~electively with one of the two isomers of the amine.
The carbamoyl chloride (2.5 g, 9.70 x 10~3m) in d1chloromethane (30 nsl) wa~ added dropwise over 4 hours to a stirred ice-cold solution of (~)-l-phenylethyla~ine (2.35 g, 1.94 x 10~2m) and triethylamine (0.98 g, 9.70 x 10-3M) in dichloromsthans (10 ml) under argon. The reaction mixture w~ls wa~hed with 2M HCL (10 ml), dried (MgS04) and evaporated in vacuo to yield a whita crys~alline mass (3.28 g, 98Z). ~he 2 diastereo~lers were separated by column chromatography to yield hiBher Rf dlastereomer (0.75 g, 23Z) and lower Rf diastereomer (2.4 g, 73%).
Example 15 The U~e of N-carbamo~l chloride of endo-(9S.4R)-l-oxa-aza-8,10slO-trimethyltricyclol3.2.1.04l9]decan-2-one For he ChromatoQraPhic resolution of R= an~d~S-M-M_thYl-2-PhenvlethYlamins A stirred 301ution of this carbamoyl chlorids (0.252 g, 9.7 x 10-4M) in ethsr (40 ml) under argon was tr~atsd with tristhylamins (0.14 g, 1.46 x 10~3m) followed by (~)-N-methyl-2-phenylethyl~smine (0.132 g, 9.78 x 10~4m). Ths reaultant mixture was kept at 20- for 60 minute~ then pour~d into water (30 ml). The 2 ~ractions wers ~epara~ed a~d th= other ~ractloD V~8 drlod (~gS0~) and cvapora~ed ~o . I
, , 20~ .1217 yield a mixture of the dia~tereomers.
An H.~.L.C. d -value of 1.2 was m~a~ur~d for the pair of diast~reomers ~1 : 1 v/v ether : n-hexane as eluant).
lH nmr (200 MHz, CDC13) ~ 0.90 (9, 3H), 0.91 ~9, 3H), 0.93 (5, 3H), 1.57 (9, 3H), 1.75 - 2.0 (m, 4H), 2.09 (m, lH), 2.71 (d, 3H, J ~ 7.0 Hz), 4.53 (dd, lH, J ~ 13.6 Hz, 1.2 Hz), 4.75 (dd, 1%, J ~ 13.4 Hz, 9.6 Hz), 4.81 (dd, lH, J ~ 13.6 Hz, 9.8 Hz), 5.50 (q, lH, J ~ 6.9 Hz), 5.55 (q, lH, J - 7.1 Hz), 7.3 ~M, 5H).
E~mpl~ 16 The Use of Sodiu Salt of endo-(9s.4R)-l-oxl _~laL~:~LI~Ll~
trimethyltric7clo~3.2.1.04.91dscan-2-one For The_Chromato~raphic Separation of R-_and S-2-Bromopropion~1 Bromid~
The ox~zolidinone (0.86a g, 4.45 m~) wa~ dlssolved in toluene (sodium dried, 20 ml). Sodium hydride wa~ added (ether washed, 1.1 15 eq, 0.117 g~ 4.875 ~m) and tha reaction magnetically stirred under argo~ for 1 hour at 20-C. 2-~romopropionyl bromide ~0.5 ml, 1.03 g, 4.77 mm) wa~ add~d neat to tho susp2n~ion of the ~odlum salt by m~an~ of a ~yri~g~ and the reaetion mixture ~tirred for a further hour ~t ambient temperaturo. After this time water (30 ml) was added and the reaction mixture extracted lnto ether. The ether solution was dried (MgS04) and taken to dryness to yield a white crystalline mixture of the two disa~tereiomers.
These could oa3ily be separat~d by column chromatography (80g, SiO2 5 : 95 v/v to 50 : 50 v/v eth~r/n-hex~ne) to yleld the high~r 25S Rf diastsreom~r in 36Z yield (0.524 g) and the lower R~ dla~tereomer in 52X yi~ld (0.763 g). An H.P.L.C. a -valu~ of 2.1 was measured using an eluant mixture of 20 : 80 v/v ether:n-h~x~ne.
HiQher Rf diastereomar - Fount: C, 50.8; H, 6.12; N, 4.2.
C14H20NO3Br requiros C, 50.9; H, 6.1; N, 4.2Z; m.p. 82 - 84-C; m/z 30 3 ', 329, 287, 285, 272, 270, 250, 206; M~ 329.0618 C14H2oO3N79Br requir~s 329.0627; 1H nmr (200 MHz, CDC13) ~ 0.96 (s, 3H), 0.97 (s, 3H), 0.99 (8, 3H), 1.0 - 1,75 (m, 4H), 1.83 (d, 3H, J - 6.8 Hz), 2.33 (m, lH~, 4.58 (m, 2H, CH0, CHN), 5.78 (q, lH, J - 6.8 Hz).
Lowor Rf diaster~omer - m/z 331, 329, 287, 285, 272, 270, 250, 206;
35 Ml 329.0617 C14H2oO3N79Br rsquir~s 329.0627; lH nmr (200 Wz, CDC13) I

~ .. . ... . . . . .. .. ... . .

~ 0.92 (s, 3H), 0.94 (s, 3H), 0.95 (s, 3H), 1.0 - 1.75 (m, 4H), 1.76 (d, 3H, J ~ 6.6 Hz), 2.28 (m, lH), 4.55 (m, 2H, CH0, CHN), 5.73 (q, lH, J ~ 6.6 Hz).
Exam~le 17 S The U e o~ Sodium_Salt of cndo-(9S~R)~l-oxa-3-aza-8,10,10-trimethyltricYclo[3.2.1.04,91decan-2-one For tho Chromato~raphic resolution_of R- and S-2-Phenyl~ropionY1 Chlorido The oxazolidinone (0.653 g, 3.35 x 10~3m) was dissolved in tolu~ne (20 ml, sodium driod) and sodium hydrido addod (ethor washod), (1.1 eq, 0.088 g, 3.68 x 10~3m). The reaction was stirred und~r argon for 1 hour at ambient t~mperature and treated with neat ~ 2-phenylpropionyl chlorida (0.56 g, 3.35 ~ 10~3m) added via a 3yring~ and the reaction stlrrcd for a further hour. Water was added (30 ml) and the raaction ~ixture oxtracted wlth other The ether layer was dried (MgS04) and taken to dryness to give a crude yield of a mixture of diasteroi~omeric amides (1.10 g, 97~).
A small portion of thi~ mix~ure was analysad by H.P.L.C. and an ~ -value of 2.08 measured using a 20 : 80 v/v mixture of ether and n-hexane as eluant.
The remaining crude reaction was sub~ected to column chro~otography and diastereoisomers easily separated (70 g, SiO2, 5 : 9 to 1 : 1, cther: n-hexane).
Hi~her RP diastareomer lH nmr (200 MHz, CDC13) ~ 0.91 (8, 3H), 0.95 (~, 3H), 0.97 t3, 3H), 1.0 - 1.4B tm, 2H), 1.49 td, 3H, J ~ 7.0 Hz), 1.57 - 1.73 (m, 2H), 2.34 (t, lH, J - 4.02 Hz), 4.45 (m, 2H, CH0, CHN), 5.18 (q, lH, J ~ 7.0 Hz), 7.3 tm, 5H).
Low~r_Rf diastereomer lH n~r (200 NHz, CDC13) ~ 0.88 (s, 3H), 0.91 (s, 3H)j 0.92 (5, 3H), 1.0 - 1.5 (m, 4H), 1.47 (d, 3H, J - 7.0 Hz), 2.18 tt, lH, J - 3,90 Hz), 4.46 (td, lH, J ~ 13.6 Hz, 1.2 Hz), 4.59 (dt, lH, J - 13.6 Hz, 9.8 Hz), 5.16 tq, lH, J ~ 7.0 Hz), 7.35 (m, -SH~; 13C nmr (50.3 MHz, CDC13) ~ 174.6, 153.7, 140.2, 128.4, 128.1, 127.0, 82.3, 57.6, 49.3, 48.4, 47.6, 42.8, 42.6, 26.1, 19.9, 19.8, 19.7, 13.7; ~ maxtKBr) 1770, 1700 t5, C-) cm~l-Example 18 3S Kinetic Re~olution of 2-ChloroDro~1OnYl Chlorlde with sodl~m salt , W O 91/18890 PC~r/GB91/008g3 . . .
21 2~ 217 of endo-(9R,4R)-l-oxa-3-azn-8,10, --trlmeth~ltr1CYC ol3.2.1.04.9]
decan-2-one Thls oxazolidinone (0.73 g, 3.74 x 10~3m) in dlchloromethane (10 ml) was added dropwise to a ~tirred suspen~ion of oil free ~odlum hydride (0.059 g, 3.74 x 10~3m) in ether (3 ml) under argon at O~C. The reactlon mixture was stlrrnd at 20- for 3 hour~, cooled to 0- and treated dropwise wlth 2-chloropropionyl chlorlde (0.95 g, 7.48 x 10 ~3m) in dlchloromethane (20 ml) over 6 hours. Whsn ~ddition waQ complete the reaction was ~tirred at 20-C for 1 hour and evaporated to dryness, taken up in dichloromethane (20 ml) and w~shed with water (5 ml), saturntsd NaHCO3 solutlon (10 ml), driéd ~MgSO4) and ~vaporat~d in ~acuo to yleld a white crystalline solid (0.81 g, B4~) o~ the diastereolsomerlc amides.
A ~ample was subJectad to H.P.L.C. and yialded an ~ -valus of 2.1 The products were separated easily by column chromatography (SlO2, 9 : 1 to 1 : 1 v/v n-hexane : ether) to yield:higher Rf dia~tereomer (0.5 ~) and lo~er Rf dia~tereomer (0.27 g).
Example 19 The Use of the N-Carbamoyl chloride of exo-(9S.4R)-l-oxa-3-aza-8~10?10-trimethgltricyclo[3 2.1.04,91decan-2-one for the Klnetic Re301ution of R- and S-l-Phen~lethYl~lmine The carbamoyl chloride (1.81 g., 7.02 x 10-3 m, 1 eq) in a~hydrouR dichloromethane (50 ml) wa~ ~dded drop~isa to an ice-cold solution of (~)-l-phenylethylamine (l.70g, 1.40 x 10~2m, 2 eq) and triethylamine ~0.70 g, 7.02 x 10~3m, 1 eq) In tichloromethane (10 ml) under argon over 7 hours. The ronction mixture was poured into 2~ HCl (5 ml). The two fractions were separatet, dried (MgSO4) and evaporated to yield two white 901it (2.3 8, 96~). H.P.L.C. analysis of the crude reaction mixture sho~cd that there had been selective diastereoisomeric urea format$on ln the ratio of 4 : 1 and an O~-value of l.3.
ExamPle 20 The conver~ion o~ endo-(9S.4R)-l-oxa-3-aza-8.10.10-trimethYltricvclo 13-2.1.04,91decan-2~one lnto comPounds where Y~COA in which A is RCH-C~-., ~ ,,., . ~, .. ...

W O 91tl8890 pCT/~91100893 ~ 22 (a) PreParation of acrYlate (R~H2 To an ice-cooled solution o~ oxa~olidinone of example 6(a) (0.5 g, 2.56 x 10~3m) in fr0shly distllled THF (ca 40 ml) under argon, ~eMgBr (3.0 M in dlethylether, 0.9 ml, 2.7 x 10-3m, 1.05 equiv.) w~s added. The resulting solutlon was then ~tirred at 0-C
for ten minutes before the temperature was lowered to -78'C.
Freshly distilled 2-propenoyl chlorLde (0.3 g, 3.3 x 10-3m, 1.3 equiv.) wa~ then added and the resulting solution stirred at -78-C
for ten minutes and then at 0-C for 75 minutes. The rsaction was then quenchsd with agueou~ ammonium chloride and extracted into e~her (3 x ca 75 ml). The combined organic extracts were washed with saturated NaHCO3, brine and trled ovor MgS04. FlltratLon and evaporatio~ of solvent in v~cuo yielded a solld which was purified by colu~n chromatogrsphy (60 g SiO2 7:1 n-hexane/EtOAc) yielding a 15 white solid ~0.48 g, 75~); melting point 8 47-50-C; ~ ~ ]21-5 -156.9-~ c-2-5a (C~2C12); M+-249-13648; C14HlgNO3 requires 249.136475; lH nmr (200 MHz, C~C13~ ~ 7.55 (dd, J~17 and 10.48Hz, lH), 6.50 (dd, J~17 and 1.92Hz, lH), 5.85 (dd, J-10.45 and 1.86Hz, ` 1~), 4.66-4.49 (cm, 2H, CHO and CHN), 2.31 (t, J~4.2Hz, lH), 20 1.70-1.09 (m, 4H, CH2), 0.97-0.95 (m~ 9H); 13C n~r (50.3 MHz, CDC13) ~ 164.96, 154.04, 131.3~, 127.19, 82.63, 57.82, 49.33, 48.44, 47.68, 26.18, 19.76, 19.66, 17.92, 13.67; ~ max (Nujol) 2930, 1770, 1690, 1620, 1460, 1415, 1380 cm~l.
(b) re~aratio _o~ crotona e (R~Me) - 25 To a freshly prepared, coolet (0'C) solutlon of Me~gBr (0.73 g, 6.15 x 10~3m, 1.2 equiv.) Ln freshly distLlled dlethylether (ca 30 ml), a solution of oxazolidinone (1 g, 5.13 x 10~3m) in freshly listilled THF (ca 30 ml) was atded. The resulting solutLon was allowed to stir at 0-C for twenty minutss before being cooled to 30 -7e'C. Freshly distilled crotonoyl chloride (0.65 g, 6.22 x 10~3m, 1.2 eguiv.) was then added and the resulting solution stirred at -78'C for twenty minute~ and then at 0-C ~or ca one hour. The reactLon Mixture was then allowed to 3tlr at ambLent t~mperature ; overnight a~er whLch tlme thLn layer chromatography revealed the ~ 35 prcsence of a trsce o~ ~tsrtLng Msterlal. The reaction mixture was ,- . ' W O 91/18890 PCT/CB91lO0893 23 2~217 quenchad wlth ammonium chloride soltltion and extracted into ether (3 x ca 50 ml). The combin~d ether e~tract~ w~re washod wlth saturated sodium bicarbonate solution and brine and drLed over - MgS04. Removsl of the solvent in vacuo ylelded a pale yellow solid 5 which was purified by flash chromatography (50 B SiO2 7:1 n-hexane/EtOAc) to yleld a white solld (1.15 g, ~5Z); melting polnt 117-121-C, [ ~ ]21.5D~-173.9', c~4.94 (CH2C12); M~263.15213 ClsH21N03 requires 263.152125; lH nmr (200 MHz, CDC13) ~ 7.27 (dq, J~15.25 and 1.50Hz, lH, CH-CHCO), 7.05 (dq, lH, J-15,26 and 6.56Hz, MeCH-CH-), 4.56 (ddd, J-9.8, 4.3 and 1.22Hz, CHN), 4.45 (ddd, J~9.78, 2,2 and 0.6Hz, lH, CHO), 2.24 (t, lH, J~4.2Hz, CH), 1.88 (dd, J-6.69 and 1.44Hz, 3H, CH3), 1.61-1.08 (cm, 4~, 2xCH2), 0.91-0.90 (2xS, 9H, CH3); 13C nmr (90.56 X~lz, CDC13) ~ 164.95, 154.05, 146.17, 121.65, 82.34, 57.76, ~9.25, 48.30, 47.78, 26.17, 19.71, 19.59, 18.19, 17.85, 13.60, ~ max (Nujol) 2920, 1763, 1682, 1635, 1375, 1208, 1050 cm~l. :
(c) ~ on of cinna~ate (R~Ph~
To a freshly prepared solution of ~eMgBr (0.38 g, 3.20 x 10~3m, 1 equiv.~, in dry diethylether (ca 11) ml) at O-C under argon, was added a solution of oxazolidinone (0.624 g, 3.2 x 10~3m) in dry THF
(ca 40 ml). The resulting solution ~/a3 stirred at O-C for ten minutes before being cooled to -78-C. A solution of cinna~oyl chloride ~0.64 g, 3.84 x 10-3~, 1.2 oquiv.) Ln dry THF (ca 5 ml) was then addet and thc rasulting solution stirrcd at -78-C for twenty mi~utes before being warmed to ambient temperature and stirred overnight. The reaction was quenched with saturated NH4Cl solution and the mixture concsntrated in vacuo, diluted with H20 (ca 20 ml) and extractsd lnto CH2C12 (3 x ca 60 ml). The combined extracts - -were washed with saturated NaHC03 and brine and dried over MgS04.
F.ltratlon and evaporation o~ the solYcnt y~elded a aolid which was purifie~ by-i'lash chromatography (60 g SiO2, 7;1 n-hoxane/EtOAc) to yield a white solid (0.84 g, 81%); melting point 169.5-170.5'C (4:1 n-hexane/di-isopropylsther), [o~23.5D~-133.0, c~4.22 (CH2C12);
M~325.16778 C2oH23N03 requires 325.167775; lH nmr (200 MHz, CDC13) ~ 8.00 (d, lH, 15.73Hz, CH~CNCO), 7.81 (d, lH, J-15.74Hz, PhC_-CH-), ",, ,, , , ., , ,,,, ,,.,,, , . , , , . , , , , , , , - . ...
, : , :
, W O 91/18890 PCT/GB91~00893 7.63-7.58 (cm, 2H, Ph), 7.39-7.34 (cm, 3H, Ph), 4.64 (ddd, lH, J-ll.l, 4.50 and 1.33Hz, CHN), 4.53 (dd, J~ll.l and 1.42Hz, lH, CH0), 2.35 (t, lH, J~8.41Hz, CH), 1.67-1.09 (cm, 4H, 2 x CH2), 0.98-0.97 (2xS, 9H, CH3); 13C nmr (90.56 I~Hz, CDC13) 5 165.16, 154.15, 145.80, 134.46, 130.33, 128.63, 12B.37, 116.90, 82.43, 57.94, 49.29, 48.35, 47.82, 26.20, 19.73 19.66, 17.88, 13.62; ~ max (Nujol) 2920, 1760, (C-0), 1680 (C~0), 1615 (C~C), 1378, 1368, 1210, 1048 cm~l.
Example 21 Reaction of endo-(9S,4R)-N-acrvloyl-l-oxa-3-aza-8.10.10-trimeth~ltricyclo~3:2:1:04~9]d~can-2-one with cycloP~ntadlene at -78'C
(a) Usin~ TiCl~OPri~7 a9 cata~lyst To a solution of acrylate (0.162 g, 6.51 x 10~4m) in dry CH2C12 (ca 2 ml) at -78-C under Ar waq added TiC14 (0.52 g, 2.74 x 10~3m, 4 equiv.) followcd by Ti(OPri)4 (0.74 B, 2.60 x 10-3~, 4 equiv.).
Fre~hly crack~d cyclopentadiene (0.43 g, 7.17 x 10~3m, 11 eguiv.) was then addot and th~ resulting solution stirred at -78-C for 21.5 hours before thin layer chromatography revealed that no starting material remain~d. The reaction mixture was poursd onto crushed ice-ant extracted into CH2C12 (3 x ca 20 ml). The ~ombined organ$c layers w~re washed with NaHC03 solution and brine and dr$ed over MgS04. Filtration and evaporation o~ the 301vent in vacuo yielded an oily solld whlch was puri~l'ed by ~lash chromatoeraphy (50 g SiO2, 25~j~ gradient elution n-hexane -> 1:1 n-hexane/~ther) yielding a white solid ~0.17 g, 83Z) which contained a mlxture of two endo i~omer~ in a ratio 2:1, which were sQparat~d by careful column chromatography (70 g "TLC" silica, eluting with 40:1 n-hexane/ether. Mlnor (higher Rf) i~omer; melting point 143-145.5'C (n-hexane~tiiaopropylether), [~ ]23D~-25.1', c~1.95 (CH2C112); M~315.18343 C19H25N03 r8quires ; 315.183425; lH nmr (360 MHz,-CDC13) $ 6.20 (dd, lH, J~5.64 and - 3.08Hz, ~CH), 5.85 (dd, lH, J-5.64 and 2.85Hz, ~C_), 4.49-4 48 (cm, 2H, CH0 and CHN), 3.28 (GS, lH, C_), 2.91 (GS, lH, CH), 2.27-2.15 (cm, lH, C_), 1.97 (ddd, lH, J~12.77, 9.09 and 3.74Hz, CH2), 1.68-1.06 (cm, 7H), 0.96 (S, 3H, CH3), 0.94 (S, 3H), 0.92 (S, 3H, '~; : ' ' ' . ~ , , ' ~ ' . , :, W O 91/18890 PCT/GB91~00893 2~S/.~2.1 ~
CH3); 13C nmr t50.3 MHZ, CDC13) S 174.51, 153.93, 137.65, 131.50, 82.26, 58.07, 4~.93, 49.23, 48.18, 47.76, 46.12, 43.09, 42.68, 29.42, 26.16, 19.55, 19.30, 17.83, 13.65; ~ max (Nu~ol) 2924, 1770 (C~0), 1755 (C~0), 1695 (C~C), 1280, 1220, 1040 cm~l. Major (lowsr S Rf) isomer, melting point 155-157.5-C, [o~]22D~-287.5', c~3.08 (CH2Cl2); Found C, 72.3; H, 8.0; N, 4.4 Cl~H2sN03 require3 C,72.5;
H, 8.05; N, 4.72. ~-315.18343 ClgH2sN03 requires 315.183425; lH
nmr (200 ~Hz, CDC13) ~ 6.20 (dd, J~5 6 and 3.0Hz, lH~CH), 5.77 (dd, J-5.6 and 2.8Hz, lH~CH), 4.51 (dtd, J~9.9, 4.2 and 1.2Hz, 1~), 4.45 10 (dd, J~9.3 and 1.3Hz, 1~), 4.03 (ddd, J-9.0, 4.4 and 3.4Hz, lH), 3.36 (GS, lH), 2.90 (GS, lH), 2.19 ~t, J~4.0~z, lH), 1.86 (ddd, J~12.6, 9,0 and 4.7Hz, lH), 1.70-1.08 (m, 7H), 0.95 (S, 3H, CH3), 0.93 (S, 3H, CH3), 0.90 (S, 3H, CH3); 13C nmr (50.3 MHz, CHC13) ~ 174.31, 153.89, 137.88, 130.95, 82.17, 57.62, 50.00, 49.1B, 48.18, 15 47.53, 46.26, 42.79, 42.63, 28.80, 26.14, 19.60, 19.35, 17.73, 13.55; ~ max (Nujol) 2920, 1790, 1775, 1640, 1460, 1380 cm~l.
(b) ~
To a solution of acrylate (0.102 g, 410 x 10~4m) in dry CH2Cl2 (ca 2 ml) under Ar at -78-C was added freshly cracked 20 cyclopentadiene (0.27 g, 4.1 x 10~3m). To this rapidly stirred solution Et2AlCl (1.8 M in toluene, 0 3 ml, 5.40 x 10-4m.
1.4 equiv.) ~7as added. After ca three minutes, the reaction was quenched ~ith HCl (2 m, ca 5 ml) and ~t~rrsd for five minutas. The organic layer ~7a8 separated off and the aqueous layer extract~d 25 further with CH2C12 (3 x ca 10 ml)'.-J~T.he combined organic layers were washed succes~ively with saturated NaHC03, brlne and dried over MgSO4. Filtration ant evaporatlon of the solv0nt in vacuo and 3ubs~quent purification bg column chromatography yielded a white ~olid (0.124 g, 98Z) which contained the same t~o endo isomers but in a ratio o~ 4:1.
~2~ ' . , Re~ction~of endo-~9s~4R~-N-l~L~a~L L_____ -aza-8.10.10 trimethyltrlcvclo 13:2:1:04.91decan-2-one with isoprene at -78'C
(a~ ,cl~o~
Using the same protocol as ~or example 21(a), the reaction was .. . . . . .. . . . . . .

co~ducted for 45.5 hours bofore quenching. Work-up provided a colourles~ oil (0.08 g, BOZ) which crystalll3ed on standing. 1}1 NMR
(360MHz) using a europium chiral shlft reaBent revealed that two i~omers were present ln a ratio 2:1.
(b) ~ L~ L~
Adopting tha same procedure as for example 21(b), work-up yielded a white solld (0.240 g, 94~) which contained the sams two i30mers in a ratio 5:1.
xam~le 23 Reaction of endo-(9S,4R)-N-crotonovl-l-oxa-3-aza-8.10,10 trimethyltricyclo~3:2:1: o4! 9!decan-2-one with cvclopentadlene at =78'C
(a) UsinR TiC12(0P ~ as catalvst To a solutlon of TlC14 (0.29, 1.53 x 10~3m, 4 equiv.) and Tl(O~ri)4 (0.43 8 1.51 x 10~3m, 4 equlv.) in drg CH2C12 (ca 2 ml) at -78-C under Ar, was added a 301utlon of crotonate (0.1 g, 3.8 x 10-4~) ln try CH~C12 (ca 3 ml). Freshly cracked cyclopentadlene (0.25 g, 3.79 x 10~3m) wa~ stded and the resultlng solution stirred at -787C for 20 hours. The reaction waq quenched by pouring onto crushed ice and extracted into CH2C12 (3 x ca 20 ml). The combinet organic extracts were washed successively with saturated NaHC03 and brlne, dried over ~gS04, flltered and the ~olvent removed in vacuo to yield a cloudy oll which was purified by flash ehromatography (50 B S102, grndient elutlon n-hexane -> 1:1 n-hsxane/ether) ylelding a whltc 8011d (0.115 g, 92%) which wa3 submitted fo~ study by 360 MHz lH NMR. Thls reYealot the pre~ence of ~our iso~er3 in the ratlo 83:56:18:6. Ma~or lsomers were not characterised, due to the dlfficultly in separatlon o2 these compounds.
(~) UsinR Et~AlCl as catalvst To a solution of crotonate (0.1 g, 3.8 x 10~4m) ln dry C~2C12 (ca 2 ml) at -78-C under argon, was added Et2AlCl (1.8 M ln toluene, 0.3 ml, 5.39 x 10~4m, 1.4 equlv.). To tha re3ultlng brlght yellow ... ..
complex was added r~pidly via connector, pre-eooled, ~reshly cracked cyclopentadlene (1 g, O.OlS, 40 equlv.~. After ca flve mlnutes the ......... . . .
, .
, W O 91/18890 PCf/cB91/00893 20~12i ~

colour had fadcd and the reaction mixtura was diluted with CH2C12 (ca 50 ml) and qucnched with dilut~ HCl (2M ca 10 ml) The organic layer was collected and the aqu~ous layer ~xtracted eurther with ether (3 x ca 20 ml). Thc combinad extracts were washed succes~ively with sa~urated NaHCO3, brine and dried over MgSO4 Flltration and e~aporation o~ the solvent in vacuo yielded a white solid (0.12 B, 96X) which contained the sam8 fou~ isOmQrs in ths ratio 36:8:2:8.
Exampl~ 24 10 The rnaotion of endo(9S,4R)-N-cinnam~yl-l-oxa-3-aza-8 10.10 trim~thyltr~ lo[3:2:1:04,9!dec~n-2-one with cyclopentadiene at -20-C usln~ Et~AlCl catal~st To a 3tirred solution of cinnamate (O.lOl g, 3.11 x 10~4m) in dry CHzCl~ (ca 2 ml) at -78-C und~r argon, was added ~t2AlCl (1.8 M
15 in toluene, 1 ml, 5.68 x 10~4m, 1.8 equiv.). To the rs~ultin~ deep yellow/orange complex was addcd rapidly, via connector, pre-cooled, fre~hl~ crackad cyclop~ntatien~ (1 g, 0.015m, 48 equiv.). The r~ulti~g solution was w~nmed to -20-C: and w~thin on~ minute the colour faded to pale green/yello~. Th0 reaction was qu~nched and wor~ed-up as or ex~mple~ 22(b) and 23(b), purified by flash chrom~togr~phy (50 g SiO2, grationt elutlon n-hexane -> lO:l n-hexaneJether -> 100Z cth~r) which yielded a whlt~ crystallinc solid (0.11 g, 92X) which was 3ubmitted ~or 360 MHz lH NMR. Only one isomer could be detected whlch had ~h~ following physical propertls~; melting point 131-134-C (4:1 ~
n-hexane/di-isopropylcthar), [~ ]21D--263.6-, c-2.54 (CH2C12);
~391.21473 C2sH2gNO3 requires 391.214725; lH nmr(360 MHz, CDC13) ~ 7.29-7 14 (cm, 5H, Ph), 6.52 (dd,lH, J-5.63 and 3.19Hz, .CH), 5.87 - (id, lH, ~5.63 and 2.75Hz, -CH), 4.57 (ddd, lH, J-9.89, 4,47 and 1- 18~z, CHN)~ 4.48 tdd, lH, J~9.7B and 1.59Hz, CHO), 4.22 (dd, lH, J~5.27 and 3.35Hz,` CH), 3.56 (GS, lH, CH), 3.34 (dd, lH, J~5.26 and 1.68Hz, CH), 3,01-2.99 (cm, lH, CH)m 2.25 (t, lH, J-4.22Hz, CH), 1.98 (Gd, lH, J-8.72Hz, CH2), 1.73-1.58 (dd, lH, J~8.69 and 1.69Hz, CHz, supcrimposed on cm, 2H), 1.45-1.39 (cm, lH), 1.25-1.14 (cm, lH), 0.98 (S, 3H, CH3), 0.97 (S, 3H, CH3), 0.94 (S, 3H, CH3).

~' ' '' ''' ' ' ' ' .

~r~ 28 13C nmr S 173.54, 153.91, 143.63, 140.08, 131.86, 128 24, 127.34, 125.B5, 82.24, 57.66, 50.33, 49.24, 48.31, 48.09, 47.51, 41.31, 46.12, 26.18, 19.71, 19.43, 17.83, 13.64; ~ max (Nu~ol) 2930, 1778 (2 x C-0), 1700 (C~tC), 1338, 1225, 1212, 1060 cm~l.
Example 25 CleavaRe of the cYcloadduct formed in examPle 24 from the chiral auxiliary : chiral ester formation To a solution o benzyl alcohol (0.272 Bt 2.52 x 10~3m, 2 equiv.) in dry THF (ca 5 ml) at -78-C under argon, was added 10 n-butyllithium (1.6 M in hexanas, 1 ml, 1.6 x 10~3m, 1.2 equiv.).
The resulting solution was ~tirred at -78'C for ca 30 minute~ before a solution of cinnimate cycloadduct (0.5 g, 1.28 x 10~3m) in dry THF
(ca 5 ml) was added dropwise. The reaction mixture wa~ then allowsd to stir at O-C for 75 minutes and then at ambient temperature for 2 3/4 hours, by which time thinlayer chromatography indicated that all the starting material had been consummed. The r~action was quenched with NH4C1 solution and conc~ntrated in vacuo. The re~idue was diluted in H20 (ca 40 ml) and extractet into CH2C12 (4 x ca 60 ml). ~he combined organic extract~ were washed successively with saturated NaHC03, brine and dried over MgSO4. Filtration and evaporation of the ~olvent in vacuo yielded an o$1 which was puri~ied by colw~ chromstography (60 B SiO2, gradlcnt ~lution n-hexane -> 19~ 9:1 n-hexane~ethe~ ->7:3 n-hexane/ether) yiolded the chirally pure ester (0.333 g, 86X). Further elutlon (1:4 25 n-hexane/ether yielded the récovered oxazolidinone (0.142 g, 57~).
Physioal data ~or ester; ~o~]21D--121.1-, c~1.36 (CH2Clz), lH nmr (200 MHz, CDC13) ~ 7.47-7.25 (cm, lOH, 2 x Ph), 6.51 (dd, lH, J-5.65 and 3.21Hz, ttCH), 6.17 (dd, J-5.65 and 2.75Hz, lH t~tCH), 5.26 (d, lH, J-12.40Hz, CH2), 5.17 (d, lH, Jt~12.42Hz, C_2), 3.34 (GS, lH, CH), 30 3.15 (Gd, Jtt3.63Hz, CH), 3.14-3.12 (cm, 2H), 1.88 (Gd, lH, J-~8.33Hz, CH2), 1;67 (dm, J~t8.68Hz, lH, CH2),~13C~nmr (50.3 MHz, CDC13) 173.76, 143.93, 138.89, 135.98, 134.17, 128.23, 127.B3, 127.76, 127.20, 125.79, 65.95, 51.99, 48.02, 47.18, 46.95, 46.11; ~ max (thin ~ilm) 2980, 1735, 1502, 1458, 1335, 1260, 1170 cm~l.
Example 26 '~ .

29 20~21 /

Reaction of endo~S.4R)-N ~cryloyl-l-oxa-3-aza-8~10L10 trimethyltr~yclo[3:2:1:04,91decan-2-ons with b~nzonltrlle oxide at O C
To a coolad (O-C), rapldly ntlrred solutlon o~ acrylato (0.10 g, 4.26 x 10~3m) and benzohydroximmoyl chloride ~0,068 g, 4.37 x 10~4m, 1 equiv.) in CH2Cl~ (ca 35 ml), a solution o~
triethyla~ine (0.049, 4.84 x 10~3m, 1.1 equiv.) in diethylether (ca 15 ml) was added over a period of 23 hours by mean3 oi' a syringe pump. The solvnn~s were then removed in vacuo snd dissolv~d in CH2C12 (ca 50 ml), cooled succes~lvely wlth H20 (ca 20 ml) ant a little brins (ca 5 ml), NsHCo3 solution, brlne and dried over MgSO4. Filtration flnd evaporatlon o~ th~ solvent in V8CUO yialded the crude product which was analysad by 200 MHz lH NMR and revealad the presence of two cycloadducts in a ration 4:1.
~8ElLt-Z~
U~e of endo ~ S~R)-N-Dropionyl-l-oza-3-aza-8.1-.10- :
trimethyltricyclo~3.2 1:04 ~ ecan-2-one in an a~mmetric d -bromlnation reaction and sub~equent chiral o~-flzido ~ropionate formation .
(a) A ~metric ~-bromination To a solution of imide (2.002 g, 7.97 x 10~3m) ln dry CH2C12 (ca 12 ml) at O-C under argon, W88 addad a solution of ~resh dibutylboron tri~lata (1~ in CH2C12, 8.8 ml, 8.76 x 10~3m, 1.1 equiv.), followed by Pri2EtN (1.24 g, 9.56 x 10~3m, 1.2 aqulv.) ln dry CH2C12 (ca 7 ml). Tha rasultlng pale yallow solution wa~
allowed to stir at O-C ~or one hour before being cooled to -78-C.
Tha resultant boron enola~e complex waa addad via connector to a pre-coolod ~-78-C) ~lurry o~ N-bromosuccinimide (2.134 B, 0.012m, ~ l.S equ$v.) in dry CH2C12 (ca 10 ml). The resulting mixtura was ; 30 stirred at -78'C ior 2 3/4 hours a~torwhich thin-layer chromatography revesled thst no starting mstorial was present. The reaction was quenched with pH7 pho~phate butter (O.lM, ca 20 ml) and the organic layar collscted. Ths aqu~ous layar was i'urther ..... . .. ....
extracted with CH2C12 (3 x ca 50 ml) snd tha comblnad extract3 were wsshed with brine and concentrsted in vacuo. The resldue was ., W O 91/18890 PCT/CB91/008g3 ~ ~ ~ ` 30 fJ ~

diluted in methanol (ca 20 ml) and hydrogen peroxide (100 volumes, 12 ml) added w1th ice-cooling and stlrring. Thi~ mlxture was allowed to stir at -78'C for 90 minute~ boforo be1ng concentrated under high vacuum. The residue was dlluted into H20 (ca 30 ml) and 5 extracted into CH2C12 (3 x ca 89 ml). Thc combined extracts were washed successively with extracted NaHC03 solution, brine and dried over MgS04. Filtration wand evaporation of the solvent in vacuo yielded a solid which was purifled by flash chromatography (100 g SiO2, gradient elutlon 20:1 n-hexane/ether -> 10:1 n-hexane/ether ->
10 ether) yielded a white solid (1.4 B- 53X) which 1~ the lower Rf diastereomer of e~ample 16.
(b) Con~ersion to C~-azido propionate To a solution of (2'~)-~ -bromocarboximide (0.6 g, 1.82 x 10~3rn) in CH2C12 (ca 30 ml) was added NaN3 (0.240 g, 15 3.69 x 10~3m, 2 equiv.) and a small amount of tertiarybutyl~mmonium bromide (as phase transfer catalyst) in H20 (ca 50 ml). The resulting solution was 3tirred thoroughly at ambl~nt temperature for 42.5 hours before the organic layer was collected and agueous layer further extracted with CH2C12 (2 x 30 ml). The combined organic extracts were washed with brlne and dr:Led o~er MgS04. Filtration and evaporation of the solvent in vacuo ylelded a whita solid (0.524 g, 99Z). 1H nmr (200 MHz, CDCl~ 4.97 (q, lH, J-6.89H~, CH), 4.59-4.51 (cm, 2H, CHN and CHO), 2.30-2.12 (cm, lH, CH), 181-1.00 (d, 3H, J~6.gH~, C 3 superimposed on cm, 4H, 2 x CH2), 0.95 25 (S, 3H, CH3), 0.95 (S, 3H, CH3), 0.93 (S, 3H, CH3); 13C nmr (50.3 MHz, CDC13) ~ 171.59, 153.47, 83.23, 57.52, 55.77, 49.34, 48.46, - 47.30, 26.04, 19.65, 19.52, 17.80, 16.64, 13.57. This moleculs can be cleaved fro~ the suxiliary to generate ~ -azido-prop10nic acid, - ~hich can be reduced to the homochirsl ~-amino-carboxgllc acid.
~ is obviou~ly a gsneral synthesis ~or any COA.
Exampls 28 Use of_endo-~?S~hR?-N-proPionyl-l-ozA-3-aza-8~lo~lo-trimeth~ ~ kylat_on reactlon~
(a) With benzyl bromide Ln the presence of NaI

W O 91/18890 PCr/Cn91/00~3 31 2~ 17 To a froshly prepared solutlon o~ LDA (0.11 g, B.94 x 10~3m, 1.1 equiv.) in dry THF ~5 ml) at -78-C undor argon, was added a solution of carboximide (0.200 Bt 7.97 x 10~4m) ln dry THF (ca 8 ml) dropwise. The re~ulting ~olutlon was ~tirred at -78'C ~or ca one hour before freshly distilled benzyl bromide (0.513 g, 4.06 x 10~3m, 5 equiv.), followed by NaI (pre-dried in vacuum oven, 0.146 g, 9.74 x 10~4m, 1.2 equiv.). The resulting ~olution ~as warmod to -8-C (KCl, H20(s)) and ~tirr~d overnight at that temperaturo. The reaction wa~ quenched with NH4Cl solution and concentrated in vacuo. The residual oil wa~ dilutod with H20 (ca 30 ml) and extracted into CH2Cl2 (4 x ca 60 ml). The combined organic extracts were ~a3hed succe~sively with sa~urated NaHC03, brin~ and dried over MgS04. Filtration and evaporation of the solvent in vacuo yielded an oil which wa~ purified by dry fl~sh chromatography (60 g SiO2, gradient elution n-hexane -~ 4:1 n-hexane/ether -> 1:1 n-hexane/ether -~ ether) yialding a white solid (0.218 g, 80X);
melting point 100.5-101.5~C (MeOH); [C~]21D~-63.40-, c-2.12 (CH2Cl2); Found C, 74.0, H, 8.16; N, 412. C21H27N03 requires C, 73.87; H, 7.97; N, 4.10; lH nmr (200 M~z, CDC13) ~ 7.30-7.12 (cm, 5H, Pb), 4.55 (ddd, lH, J-9.85, 4.27 end l.OHz, CHN), 4.38 (dd, lH, J~9.64 and lH2), 4.14 (m, lH), 3.12 (dd, J~13.18 and 7.23Hz, lH, CH2), 2.57 (dd, lH, J~13.19 and 7.76Hz, CH2), 2.17 (t, J~4.18Hz, lH, CH~, 1.52-1.11 (d, J-6.76H~, 3H, CH3 superlmpo#od on cm, 4H, 2 x CH2), 0.93-0.91 (2 x S, 9H, CH3); 13C nmr (50.3 MHz, CDC13) ~ 176.38, 153.76, 139.10, 129.04, 12~.06, 126.04, 82.16, 57.75, 49.16, 48.23, 47.47, 39.53, 39.41, 26.05, 19.69, 19.01, 17.83, 16.47, 13.64 ~ max 1760, 1680 cm~l. Thls was tho only 1~omor ~etected.
~L) With all~l bromide 30 - This wa3 con3tructod in the same ~ay a3 or bon2yl bromide, but - wlthout the u3e o~ NaI, and the react$on wa3 quonchod a~tor or hour~. Column chromatography yl~ldcd colourlcss crysta1s (70Z), melting point 79-89-C (aqueou3 MeOH). Found C, 69.7; H, 8.71; N, 4.73, C17H2sN03 requires C, 70.07, H, ô.65; N, 4.81; lH nmr S 5-79 (lH, m), 5.12-4.96 (2H, m), 4.60-4.49 (2H, m), 3.88 (lH, m), 2.51 WO 91/18890 PC'r/CB~1/008~3 (lH, m), 2.27 (1~, m), 2.15 (lH, m), 1.70-1.55 (2H, m) 1.39 (1~1, m), 1.20 (lH, m), 1.20 (lH, m) 1.15 (3H, d, J~6Hz), 0,98 (3H, S), 0,97 (S, 3H), 0 96 (S, 3H), Again, thls w~9 th~ only isomor detscted Exam~le 29 Pre~aration of Endo--~9sl4R)-l-oxa-3-aza-8llo~lo1--trimethvltricyclo[3~2~l~o4 dPcan-2-thione A solution of the product of example (6a) (0,5g,2.56mm) and phosphorus penta~ulphide (0.23g,0.513mm) was re~luxod ln sodium dried toluene (20ml) under argon. After an inltlal 2 hours the reaction mixture was monltoret hourly by tlc; then le~t overnlght and was stopped after 19 hours. The reaction mixture was then filtered, washed (dry ether) and evaporated in vacuo to yield a light brown solid (0.66g). This was dissolved in CH2C12 (30ml), waahed with H2O (2x20ml), dried with magnesium sulphate and filtered. Evaporation of ~he mother liquor in vacuo yielded endo-(9S,4R)-l-oxa-3-aza-8,10,10-trimethyltricyclo[3 2,1.04,9~-decan -2-thione as a colourles~, crystallibe solid (0.2g,40Z); m.p.
190-192-C; M+ 211.10308; CllH17NOS requires 211.10321; ~ max 3180 (N-H), 2960 (C-H), 1520 (C-N), 1380 (C-C), 1270 (C-O), 1175 (C-S);
max (EtOH) (~ ) 246nm (20.9x104); lH nmr (200MHz) S 0.91,0.96,0.98 (3s,9H,3xC~3), 1.24-1.49 (m,2H,lxCH2), 1.55-1.74 (m,2~,1xCH2), 1.95-1.99 (t,lH,lxCH), 4.33-4.41 (dd,l~,CH), 4.85-4.90 (dd,lH,CH), 7.93 (s,lH,NH); 13C nmr (50MHz) ~ 189.82 (C~S,q), 93.23 (t), 59.95 (t), 49.66 (q), 48.47 (t), 26.76 (d)-, 20.37 (d),719.79 (g), 18.10 (s~, 13.87 (s).
Example 30 Pre~aration o~ Endo-(9S,4R)-3-0ctadecox~carbonYl-l-oxa-~-aza-8.10.
10-trimethyltricyclo[3.2.1.04,91decan-2-one Octadecyl chloro~ormate (2.29g, 6.91 x 10~3m) in anhydrou~ dlethyl ; ~ ether (20 ml) wa~ added dropwlse to a rapldly atlrred suapension of the sodlum ~alt o~ the compound or Example 6(a) (1.50g;6.91 x 10~3m) - in anhydrous dlethyl cther (20 ml) under argon at 20'C. The reactlon mlxture wa~ stlrred ~or a ~urther 60 mlnutes, washsd once wlth saturated sodLum bicarbonate solutlon and then wlth water, .;'""'' '''"' ' ' , ' .

' 33 2 0 ~ ~ 2 ~ 7 dried (MgS04), and evaporat~d in vacuo to yl~ld a colourle~3 3011d (3.19g, 94Z) which was furthor purl~led oithor by recry3talllzalon from methanol (2.07g, 61X) or by madium-pr~s~urè llquld chromatography (S102; petroleum ethort ~thyl ncotntè gradlent 10:1-> 2:1) (3.018; 89Z)~ m,p.44-hS'; ~ 24D ~ ~ 16.3', c ~ 3.22 (ethanol); lH nmr (200MHz, CDC13) ~ 0.83 (m, 3H, - CH2CH3), 0.94 (8, 3H, CH3), 0.96 (s, 3H, CH3), 1.23 (m, 32H~-C16H32-)~ 1-7 (m~4H)~
2.18 (m,lH), 4.23(m, 2H, -OCH2-), 4.47 (s,lH, CHN), 4.48 (s,lH,CHO);
3C(50.3 NHz,CDC13) ~ 152.5 (C~0), 151.0 (C-0), 81.8 (CHO), 67.0 10 (-0-CH2), 57.9 (CHN), 49.3 (quart.C), 48.3 (CH), 31.8 (CH2), 29.5 (CH2), 28.9 (CH2), 28.4 (CH2), 26.1 (CH2), 25.5 (CH2), 25.5 (CH2), 22-5 (CH2) 19-8 (CH3), 19.6 (CH2), 17.9 (CH3), 13.9 (CH3), 13.7 (CH3); ~ max (thin Çllm) 1825, 1~03 (sh), 1731 (C~0) cm~l.
Example 31 Pre~aration _ [(4R,9S~exol-(+)-l-Oxa-3-aza-8-~henql-sulphorlYlmeth~rl-10.
10-dimethqltric~clo~3.2.1.04-91-decan-2-one [(2R)-exo]-(+)-l-Phenyl~ulphonylmethyl~-7~7-dlmethylbicyclo[2.2.1]
heptan-2-ol wa3 preparet from (lS)-(+)-10-camphorsulphonic acid as 20 de~cribed in Tetrahedron Letter3 25 (1984) 5889. Thls wa~ converted into the correspo~ding 2-chloro~ormate and the~ the 2-azidoformate by the method described in Example~ 1 and 3. The azidoformat~ had the following analysl3~
m.p. 117.5- (decomp.); [~]21.5D ~ -20.1-, c~2.52 (~tOH)~ FAB-MS
25 (M+l)~ 364.13311 C17H22N3O4S requlre~ 364.13309; lH nmr (200 MHz, CDC13) ~ 0.81 (s, 3H, CH3), 0.ô9 (s, 3H, CH3), 1.15 (m, lH), 1i5-2.0 (m, 6H), 2.92 (d, lH, CHHSO2, J ~ 14.03 Hz), 3.45 td, lH, CHHSO2, J ~ 14.03 Hz), 4.90 (m, lH, CHO), 7.5-7.7 ~m, 3H, aromatics), 7.95 (m, 2H, ~romatlc~). .
30 -~ A 301utlon of [(2R)-exo]-(+)-l-phonylsulphonylmothyl-7,7-dimethylblcyclo[2.2.1]heptan-2-azldoformate (4.5g, 1.23xl0~2m) in 1,1,2,2-tetrachloroothane (TC~) ~50ml) wa9 adted dropwl~e over 30 mlnutes to vlgorously bolllng TC~ (450ml) under argon. When the additlon was complcte, tho ~olvont wa~ romovod n vacuo to yleld a brown oll, whlch upon trlturatlon wlth dlethyl ethor (500ml) yisldod , ~ , , . , ., ",, . , . , , ~ ., .
,, . ,."~.... .. . . . .

W O 91/18890 PCT/~B91/00~93 a light brown solld (3,4g). The product was furthor purleied by recrystalllsRtlon ~rom 0thyl acetate (3 27g, 79Z), to glve the desired product [(4R,9S)-exo]-(~ Oxa-3-aza-8-phenyl-sulphonylmethyl-10,10-dlmethyltrlcylco[3.2.1.04~9]decan-2-one, whlch had the following analysiss m.p. 211 212'C; [~]21.1D - -63.2', c-2.82 (EtOH); FA~-MS (M~
336.12694. C17H22N04S requlres 336.12694; lH nmr (360 MHz, CDC13) ~ 0.86 (~, 3H, CH3), 0.97 (~, 3H, CH3), 1.30 (m, lH), 1,54 (m, lH), 1.73 (m, lH), 1.83 (m, lH), 1.97 (m, lH), 2.9S (d, lH, CHHS02), J ~
13.8 Hz), 3.48 (d, CHHS02, J - 13.8 Hz), 3.77 (d, lH, C}~, J ~ 8.21 Hz), 4.93 (d, lH, CHO, J ~ 8.13 Hz), 6.62 (bs, lH, NH), 7.51-7.55 (m, 2H, 3 aromatics), 7.59-7.64 (m, lH, 4 ~romatics), 7,91-7.94 (m, ; 2H, 2 aromntics); 13C nmr (50.3 MHz, CDC13) ~ 159.81 (C~O), 140.68 (Cl-~6H5)- 133-61(C4-C6Hs), 129.17 (C6Hs), 127.57 (C6Hs), 84.12 (C80), 60.43 (CHN), 53.72 (CH2SO~), 48.98 (quart. C), 47.18 (CH), 27.37 (CH2) 24.63 (CH2), 23.27 (CH3), 19.16 (CH3); ~ max (KBr) 3342 (br, ~), 1760 (8, C~O), 1717 (9, N~), 1320, 1160, 1138 (5, S02)cm~l.
ExamDle 32 This example describes the alkylaltion of a compound of formula I(a) in which Y is a C2H5CO- group to form a compound with a new optically active centre adjacent to the carbonyl group.
A solutlon of imide o~ part (a), Example 12 (300 mg, 1.2 ml) ln THF (5 ml) wa~ added slowly to a solution o~ LDA (1.3 mm) ln THF
(2 ml) at -78-C. A~ter stirring i'or lh at -78-C thc mlxturo waa warmed to -lO-C and a solutlon of the alkylatlng agsnt ~3.5 ml) in ; THF (2 ml) was added. The mixture was kept at -lO'C ~or 4h a~ter ~hich time reaction was complete as monitored by tlc. The mixture wa8 quenched using saturated aqueous ammonium chorlde and, ~ollowing st.andard agueou3 workup purlfication o~ the residue by ila~h : ~chromatography gave the product(s). --- (i) rcaction wlth iodoethane gave a single diastereoisomer ~17 mg, 6%) as a colourl~cs solld. Found~ M~, 279.182. C16H2sN03 requires M, 279.183); lH nmr 5 4.63-4.45 (2H, m), 3.69 ~1H, sextot, J-7Hz), 2.30 (lH, t, J-4Hz), 1.85-1.20 (6H, m), 1.15 (3H, d, J-H7z) 0.97 .. . . . .. . ... . ..

35 2 ~ S fl 2 l 7 (3H, s), 0.96 (3H,s) 0.95 (3H,s), 0.93 ~3H, t, J-7Hz). This mat~rlal was not characterised urther (ae~ above).
(ii) reaction with allyl bromidc gave a mixture of two diastereoi~omsr3 ratlo >10:1 (210 me, 70%) as colqurle~ cry3tal3 melting point 79-80-C (aqueou3 methanol) Éound: C, 69.7; H, 8.71; N, 4.73. C17H2sN03 requires C, 70.07; H, 8.65; N, 4.81; ~ max (Nujol~
1770, 1680 cm~l; m/z (ei) 291 (M+, lOOZ), 196 (20Z), 135 (18Z);
H n~r 5 5.79 (lH, m), 5.12-4.96 (2H, m), 4.60-4.49 (2H, m), 3.88 (lH, m) 2.51 (lH, m), 2.27 (lH, m), 2.15 (lH, m), 1.70-1.55 (2H, m), 1.39 (1~, m), 1.20 (lH, m), 1.15 (3H, d, J~6Hz), o.ga (3H, 9) 0.97 (3~, s) 0.96 (3~, 3).
(iii) reaction with PhCH2Br gave a single diastereoisomer (172 mg, 42Z) as colourle~s crystals melting point 100-101.5-C (~ethanol) Found: C, 74.0; H, 8.16; N, 4.12. C21H27N03 reguires C, 73.87; H, 7.97; N, 4.10; ~max(Nujol) 1760, 1~80 cm~l; m/z (ei) 341 (M+), 196, 177, 135, 118, 91; lH nmr ~ 7.26-7.13 (5H, m), 4.55 (lH, dd~, J-10.6Hz); 4.47 (lH, dt, J~lOHz), 4.17 (lH, sextet, J-7Hz), 3.14 (lH, dt, J~13.7Hz), 2.59 (lH, dd, J-13.7Hz), 2.19 (lH, t, J, 4Hz), 1.63-1.22 (3H, m), 1.15 (3H, d, J-7Hz), 0.95 (3H, s), 0.93 (6H, br.s), 0.67 (lH, m).
Example 33 (a) PreParation and PhY3ical Data for [(9S. 4R~-endol-3-(N-bsnzyloxvcarbam~te?-l-oxa-3-~Lza-8.10.lO~trimathyl-tricYclo ~3.2.1.04,91decan-2-one.
N-Chloroformyl derlvative of example 6(a) (2.57 g, 9.98 x 10~3m) in anhydrous dichloromethane (20 ml) was added dropwi~e to a stirred suspension of freshly sublimed ~'-benzylhydroxylamine hydrochlorite (aublimet 80 C/O.l ~m Hg) (:.5g g, 9.98 x 10~3m) and pyrldine (1.57 g, 1.99 x 10~2m) ln di hloromethans (20 ml) at O C under argon. The reaction mixture was stirred at room temperaturs ovornight and evaporated to dryn~s. The product wa~ obtained a9 A whit~ crystalllne aolid aiter ~la~h chromatography (2.78 g, 81Z). This compound will crystallize from diethylsther : n-hexane.
~elting point 86-87 C; [d ]D~-117 , c~2.0 (CH2C12); FAB-MS (M+l)+

,, , , - , . -, . . . ... . ..

345.18144 C1gH~5N2O~ requires 345.18142; lH nmr (360 MHz, CDC13) S 0.91 (S, 3H, CH3), 0.93 (S, 3H, CH3), 0.94 ~S, 3H, CH3), 1.2 ~m, lH, CH), 1.35 (m, lH, CH), 1.6 (m, 2H, CH2), 2.29 (m, lH, CH), 4.45 ~m, 2H, CHO, CHN), 4.90 ~S, 2H, ~hCH2O), 7.3-7.4 (m, SH, aromatics), 10.17 (bs, lH, NH); 13C nmr (50.3 MHz, C~C13) ~ 155.43 (C~O), 115.52 (C-O), 134.92 (Cl-aromatic), 128.96 (CH), 128.50 (CH), 128.33 (CH), 84.13 (CHO), 78.69 (OCH2), 57.30 (CHN), 49.29 (quart.c), 48.26 (quart.c), 47.94 (CH), 26.16 (CH2), 19.70 (CH2, CH3), 17.84 (CH3), 13.61 (CH3); ~ max (thin film) 3320 (m, NH), 1760 (S), 1715 (S, C-O, NEI) cm~l.
(b) Pre~ration and PhYsical Data for ~(9S,4R~-endol-3-~N-hydrox~carbamate)-l-oxa-3-a~a-8,10,10-trimethyltrlcYclo L32.1.04.91decan-2-one.
The N-benzyloxy derivative (2.57 g, 6.59 x 10~3m) and 1 drop of glacial acetic acid in m~thanol (50 ml) was added to lOI palladium on charcoal (0.2 g) suspended in methanol (5 ml). Thé resultant mixture was stirred under l atmosphere of h~drogen for S hours at room temperature and then filtered through a celite pad and evaporated in vacue to yield a white solid which was purified by fla~h chromatography (l.59 g, 95X). l`his compound will crystallize a~ needles from dichloromethane : petroleum ether 40-60. Melting point 120-C-121'C; ~O~]D--135.9', c~1.8 (ethanol); FAB-MS (M+1)~
255.13449 C12HlgN204 requires 255.13447; lH nmr t200 MHz, CDCl3) ~ 0.92 (S, 3H, CH3), 0.95 (S, 6H, 2 x CH3), 1.20 (m, 2H, CH2), 1.57 (m, 2~, CH2), 2.25 (m, lH, CH), 4.53 (m, 2H, CHO, CHN), 8.36 (b~, lH, OH), 10.1 (bs, lH, NH); 13C nmr (50.3 MHz, CDCl3) ~ 155.42 (C~O), 153.56 (C-O), 84.28 (CHO), 57.40 (CHN), 49.34 (quart.c), 48.32 (quart.c), 47.81 (CH), 26.11 (CH2), 19.6a (CH2, CH3), 17.85 (CH3), 13.64 (CH3); ~ max (evaporated film) 3449 (b, NHOH), 1755 ~2 ~ C~O~ cm~l.

- ; , - . . .

Claims (18)

Claims

1. A compound of the general formula I(a) and/or I(b) and/or I(c):- I(a) I(b) I(c) in which R1 represents a methyl group or a group of the general formula -CH2.SO2.R2 or -CN2.SO2.NR2R3, in which each of R2 and R3 independently represents an alkyl, cycloalkyl or optionally substituted phenyl or phenalkyl group, each of R4, R5 and R6 independently represents a hydrogen atom or a methyl group; X
represents a group of formula C(CH3)2 or, when both of R5 and R6 represent methyl groups, also represents a group of formula CH2; Q
represents an oxygen or sulphur atom; and Y represents a hydrogen atom, an alkali metal atom or a group of the general formula -COA in which A reresents a halogen atom or an alkyl or alkoxy group optionally substituted by a phenyl, cycloalkyl, alkoxy or alkylcarbonyl group.

2. A compound according to claim 1 in which the optionally substituted phenyl or phenalkyl group R2 and/or R3 carries one or more inert substituents.

3. A compound according to claim 2 in which the substituents are selected from halogen atoms and alkyl, alkoxy, haloalkyl, haloalkoxy, nitro, alkylcarbonyl and alkoxycarbonyl groups.

4. A compound according to claim 3 in which the alkyl moiety has from 1 to 4 carbon atoms.

5. A compound according to any of claims 2 to 4 in which the substituted phenyl group has up to 3 substituents.

6. A compound according to claim 2 in which the alkyl moiety in the phenalkyl group has from 1 to 4 carbon atoms.

7. A compound according to any of claims 1 to 6 in which the alkyl group R2 and/or R3 has up to 20 carbon atoms.

8. A compound according to claim 7 in which the alkyl group R2 and/or R3 has 4 to 8 carbon atoms.

9. A compound according to any of the preceding claims in which the alkyl or alkoxy group A has up to 30 carbon atoms.

10. A compound according to claim 1 or claim 9 in which the cycloalkyl substituent on an alkyl or alkoxy group A is a cyclopentyl or cyclohexyl group.

11. A compound according to claim 1 in which the alkoxy or alkylcarbonyl substituent A has up to 6 carbon atoms in the alkyl moiety.

12. A compound according to claim 1 in which Q represents an oxygen atom.

13. A compound of general formula:- (II) in which R1 represents a methyl group or a group of the general formula -CH2.SO2.R2 or -CH2.SO2.NR2R3, in which each of R2 and R3 independently represents an alkyl, cycloalkyl or optionally substituted phenyl or phenalkyl group; each of R4, R5 and R6 independently represents a hydrogen atom or a methyl group; Z
represents an -N3 group or a group of the general formula -NH.O.SO2.R7, in which R7 represents an optionally substituted phenyl group.

14. A process for the preparation of a compound according to any of claims 1 to 12 which comprises inducing ring closure in a compound according to claim 13.

15. A process for separating enantiomers of a compound capable of reacting with a compound according to any of claims 1 to 12 comprising contacting a mixture of said enantiomers with said compound and separating the resulting components of the mixture.

16. A process for generating a compound having an optically active carbon atom from a compound having an optically inactive carbon atom comprising reacting a compound according to any of claims 1 to 12 in which A is an optionally substituted alkyl group with an alkylating agent.

17. A process according to claim 16 in which the alkylating agent is an aldehyde, ketone, keto-acid, alkyl halide or epoxide.

18. Compounds containing an optically active carbon atom whenever prepared according to claims 16 or 17.