Preparation of chiral pyrrolidinone derivatives

A process for preparing a compound of formula IIa or IIb: ##STR1## wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5 independently represent hydrogen or C.sub.1 -C.sub.4 alkyl; and A is an optionally substituted aromatic or heteroaromatic ring system; the process comprising the steps of: PA0 (a) reacting a racemic mixture of a compound of formula II: ##STR2## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined for formulae IIa and IIb; with a sterically hindered chiral esterifying agent to form enantiomers of formulae IIIa and IIIb: ##STR3## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined for formulae IIa and IIb and R.sup.15 is a chiral sterically hindered residue; PA0 b) separating the diastereoisomers of formulae IIIa and IIIb; and PA0 (c) converting the diastereoisomers of formulae IIIa and IIIb separately to compounds of formulae IIa and IIb respectively by acid or base hydrolysis. If required, the unwanted enantiomer of formula IIa or IIb may be inverted to give the preferred isomer.

The present invention relates to a process for the preparation of chiral 
compounds which are active as herbicides. In particular, the invention 
relates to the preparation of chiral pyrrolidinone derivatives. 
Pyrrolidinone compounds which are active as herbicides are known from, for 
example, WO 94/13652 and WO 95/33719 (published after the priority date of 
the present application). These documents disclose compounds of formula I: 
##STR4## 
wherein Z is O, S or NR.sup.6 ; R.sup.2, R.sup.3, R.sup.4, R.sup.5 and 
R.sup.6 independently represent hydrogen or C.sub.1 -C.sub.4 alkyl; 
n is 0 or 1; 
Y is O, S or NR.sup.7 ; 
R.sup.7 is H, OH, CHO or NR.sup.17 R.sup.18, or C.sub.1 -C.sub.10 
hydrocarbyl or O(C.sub.1 -C.sub.10 hydrocarbyl) either of which may be 
substituted with up to two substituents chosen from OR.sup.17, COR.sup.17, 
COOR.sup.17, OCOR.sup.17, CN, halogen, S(O).sub.p R.sup.17, NR.sup.17 
R.sup.18, NO.sub.2, NR.sup.17 COR.sup.18, NR.sup.17 CONR.sup.18 R.sup.19, 
CONR.sup.17 R.sup.18 and heterocyclyl; 
R.sup.17, R.sup.18 and R.sup.19 independently represent hydrogen, C.sub.1 
-C.sub.6 hydrocarbyl or C.sub.1 -C.sub.6 halohydrocarbyl; 
p is 0, 1 or 2; 
alternatively: 
when Y is NR.sup.7 and either Z is NR.sup.6 or n is 0, R.sup.7 and the 
substituents of Z or R.sup.1 may together form a bridge represented by the 
formula --Q.sup.1 --Q.sup.2 -- or --Q.sup.1 --Q.sup.2 --Q.sup.3 --, where 
Q.sup.1, Q.sup.2 and Q.sup.3 independently represent CR.sup.13 R.sup.14, 
.dbd.CR.sup.13, CO, NR.sup.16, .dbd.N, O or S; 
R.sup.13 and R.sup.14 independently represent hydrogen, C.sub.1 -C.sub.4 
alkyl, OH or halogen; 
R.sup.16 represents hydrogen or C.sub.1 -C.sub.4 alkyl; 
R.sup.1 is hydrogen, or C.sub.1 -C.sub.10 hydrocarbyl or heterocyclyl 
having 3 to 8 ring atoms either of which may optionally be substituted 
with halogen, hydroxy, SO.sub.2 NR.sup.a R.sup.b (where R.sup.a and 
R.sup.b independently represent hydrogen or C.sub.1 -C.sub.6 alkyl), 
SiR.sup.c.sub.3 (where each R.sup.c is independently C.sub.1 -C.sub.4 
alkyl or phenyl), cyano, nitro, amino, mono- and dialkylamino (in which 
the alkyl groups have from 1 to 6 or more carbon atoms), acylamino, 
C.sub.1 -C.sub.6 alkoxy, C.sub.1 -C.sub.6 haloalkoxy, C.sub.1 -C.sub.6 
alkylthio, C.sub.1 -C.sub.6 alkylsulphinyl, C.sub.1 -C.sub.6 
alkylsulphonyl, carboxy, carboxyamide (in which the groups attached to the 
N atom may be hydrogen or optionally substituted C.sub.1 -C.sub.10 
hydrocarbyl), alkoxycarbonyl (wherein the alkoxy group may have from 1 to 
6 or more carbon atoms) or aryl; 
A is an aromatic or heteroaromatic ring system optionally substituted with 
one or more substituents selected from halogen, C.sub.1 -C.sub.10 
hydrocarbyl, O(C.sub.1 -C.sub.10 hydrocarbyl), S(O).sub.p (C.sub.1 
-C.sub.10 hydrocarbyl), cyano, nitro, SCN, SiR.sup.c.sub.3 (where each 
R.sup.c is independently C.sub.1 -C.sub.4 alkyl or phenyl), COR.sup.8, 
CR.sup.8 NOR.sup.9, NHOH, ONR.sup.8 R.sup.9, SF.sub.5, COOR.sup.8, 
SO.sub.2 NR.sup.8 R.sup.9, OR.sup.10 and NR.sup.11 R.sup.12 ; and in which 
any ring nitrogen atom may be quaternised or oxidised; 
alternatively, any two substituents of the group A may combine to form a 
fused 5- or 6-membered saturated or partially saturated carbocyclic or 
heterocyclic ring in which any carbon or quaternised nitrogen atom may be 
substituted with any of the groups mentioned above for A or in which a 
ring carbon atom may be oxidised; 
R.sup.8 and R.sup.9 independently represent hydrogen or C.sub.1 -C.sub.10 
hydrocarbyl; 
R.sup.10 is hydrogen, C.sub.1 -C.sub.10 hydrocarbyl, SO.sub.2 (C.sub.1 
-C.sub.10 hydrocarbyl), CHO, CO(C.sub.1 -C.sub.10 hydrocarbyl), 
COO(C.sub.1 -C.sub.10 hydrocarbyl) or CONR.sup.8 R.sup.9 ; 
R.sup.11 and R.sup.12 independently represent hydrogen, C.sub.1 -C.sub.10 
hydrocarbyl, O(C.sub.1 -C.sub.10 hydrocarbyl), SO.sub.2 (C.sub.1 -C.sub.10 
hydrocarbyl), CHO, CO(C.sub.1 -C.sub.10 hydrocarbyl), COO(C.sub.1 
-C.sub.10 hydrocarbyl) or CONR.sup.8 R.sup.9 ; 
any of the hydrocarbyl groups within the group A may optionally be 
substituted with halogen, hydroxy, SO.sub.2 NR.sup.a R.sup.b (where 
R.sup.a and R.sup.b independently represent hydrogen or C.sub.1 -C.sub.6 
alkyl), cyano, nitro, amino,, mono- and dialkylamino (in which the alkyl 
groups have from 1 to 6 or more carbon atoms), acylamino, C.sub.1 -C.sub.6 
alkoxy, C.sub.1 -C.sub.6 haloalkoxy, C.sub.1 -C.sub.6 alkylthio, C.sub.1 
-C.sub.6 alkylsulphinyl, C.sub.1 -C.sub.6 alkylsulphonyl, carboxy, 
carboxyamide (in which the groups attached to the N atom may be hydrogen 
or C.sub.1 -C.sub.10 hydrocarbyl optionally substituted with halogen), 
alkoxycarbonyl (wherein the alkoxy group may have from 1 to 6 or more 
carbon atom) or aryl. 
The expression "C.sub.1 -C.sub.10 hydrocarbyl" in the foregoing 
definitions, whether the expression is used on its own or as part of a 
larger radical such as, for example, C.sub.1 -C.sub.10 hydrocarbyloxy, is 
intended to include hydrocarbyl radicals of up to ten carbon atoms. 
Subclasses of such hydrocarbyl radicals include radicals with up to four 
or up to six carbon atoms. The expression "hydrocarbyl" is intended to 
include within its scope aliphatic, alicyclic, and aromatic hydrocarbyl 
groups and combinations thereof. It thus includes, for example, alkyl, 
alkenyl and alkynyl radicals, cyclopropyl, cyclopropylmethyl, cyclobutyl, 
cyclopentyl and cyclohexyl radicals, the adamantyl radical and the phenyl 
radical. The expression "heterocyclyl" in the foregoing definitions is 
intended to include both aromatic and non-aromatic radicals. Examples of 
heteroaromatic radicals include pyridyl, pyrimidyl, triazinyl, thienyl, 
furyl, oxazolyl, isoxazolyl and thiazolyl and examples of non-aromatic 
radicals include partially and fully saturated variants of the above. 
The expression "C.sub.1 -C.sub.6 alkyl" refers to fully saturated straight 
or branched hydrocarbon chains having from one to six carbon atoms. 
Examples include methyl, ethyl, n-propyl, iso-propyl, t-butyl and n-hexyl. 
Expressions such as "alkoxy", "cycloalkyl", "alkylthio", "alkylsulphonyl", 
"alkylsulphinyl" and "haloalkyl" should be construed accordingly. 
The expression "C.sub.2 -C.sub.6 alkenyl" refers to a straight or branched 
hydrocarbon chain having from two to six carbon atoms and at least one 
carbon-carbon double bond. Examples include ethenyl, 2-propenyl and 
2-hexenyl. Expressions such as cycloalkenyl, alkenyloxy and haloalkenyl 
should be construed accordingly. 
The expression "C.sub.2 -C.sub.6 alkynyl" refers to a straight or branched 
hydrocarbon chain having from two to six carbon atoms and at least one 
carbon-carbon triple bond. Examples include ethynyl, 2-propynyl and 
2-hexynyl. Expressions such as cycloalkynyl, alkynyloxy and haloalkynyl 
should be construed accordingly. 
Subclasses of the above include alkyl, alkenyl and alkynyl groups with up 
to 4 or up to 2 carbon atoms. 
In the context of the present specification the terms "aryl" and "aromatic 
ring system" refer to ring systems which may be mono-, bi- or tricyclic. 
Examples of such rings include phenyl, naphthalenyl, anthracenyl and 
phenanthrenyl. 
In the context of the present specification, the term "heteroaryl" refers 
to an aromatic ring system containing at least one heteroatom and 
consisting either of a single ring or of two or more fused rings. 
Preferably, single rings will contain up to 4 and bicyclic systems up to 5 
heteroatoms which will preferably be chosen from nitrogen, oxygen and 
sulphur. Examples of such groups include furyl, thienyl, pyrrolyl, 
pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 
1,2,5-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 
1,2,3,4-thiatriazolyl, 1,2,3,5-thiatriazolyl, pyridyl, pyrimidinyl, 
pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 
1,2,4,5-tetrazinyl, benzofuryl, benzisofuryl, benzothienyl, 
benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, 
benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, 
quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, 
quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and 
inndolizinyl. Nitrogen atoms in the ring may be quaternised or oxidised. 
In the context of the present specification, the term "fused saturated or 
partially saturated carbocyclic or heterocyclic ring system" refers to a 
fused ring system in which a 5- or 6-membered carbocyclic or heterocyclic 
ring which is not of aromatic character is fused to an aromatic or 
heteroaromatic ring system. Examples of such systems include 
benzoxazolinyl and benzodioxolyl. 
Halogen atoms which R.sup.13 and R.sup.14 may represent and with which 
R.sup.1, R.sup.7 and A may be substituted include chlorine, bromine, 
fluorine and iodine. 
The compounds described in WO 94/13652 and WO 95/33719 are chiral and so 
may exist in two enantiomeric forms. As is often the case with 
biologically active chiral compounds, one of the enantiomers is more 
active than the other. It would therefore be advantageous to be able to 
prepare the enantiomers separately. 
Key intermediates in the synthesis of pyrrolidinone herbicides are hydroxy 
pyrrolidinones of formula II: 
##STR5## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined in formula 
I. 
The present inventors have found that if separate enantiomers of such 
compounds can be formed, it is possible to convert these enantiomers into 
enantiomeric forms of compounds of formula I. 
Therefore, in a first aspect of the present invention there is provided a 
process for preparing a compound of formula IIa or IIb: 
##STR6## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined in formula 
I; 
the process comprising the steps of: 
(a) reacting a racemic mixture of a compound of formula II with a 
sterically hindered chiral esterifying agent to form enantiomers of 
formulae IIIa and IIIb: 
##STR7## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined in formula 
I and R.sup.15 is a chiral sterically hindered residue; 
(b) separating the diastereoisomers of formulae IIIa and IIIb; and 
(c) converting the diastereoisomers of formulae IIIa and IIIb separately to 
compounds of formulae IIa and IIb respectively by acid or base hydrolysis. 
Typically, the chiral sterically hindered esterifying agent will be a 
compound such as a camphanic acid chloride which, when reacted with a 
compound of formula II, will give a separable 1:1 mixture of the two 
diastereomers IIIa and IIIb. When the esterifying agent is camphanic acid 
chloride, R.sup.15 is camphanate. 
Step (a) of the reaction may be conducted in an organic solvent, for 
example a halogenated solvent such as dichloromethane (DCM), at a 
temperature of from 0.degree. to 50.degree. C., typically at room 
temperature. 
The separation process of step (b) may be achieved by any conventional 
means, for example fractional crystallisation or chromatography. 
The hydrolysis of step (c) may also be achieved by conventional means but 
it has been found to be particularly convenient to use base mediated 
hydrolysis at a temperature of from 0.degree. to 50.degree. C., typically 
room temperature. Suitable bases for this reaction include alkali metal 
hydroxides such as sodium hydroxide. The reaction will usually be 
conducted in an organic solvent in order to ensure solubility of the ester 
of formula IIIa or IIIb. Typical solvents include ethers, especially 
cyclic ethers such as tetrahydrofuran (THF). 
If required, the unwanted enantiomer of formula IIa or IIb may be inverted 
to give the preferred isomer. This may be achieved by, for example, 
reacting the compound of formula IIa or IIb with an esterifying agent, 
typically a carboxylic acid such as acetic or propionic acid in 
combination with a combination of agents such as triphenyl phosphine and 
diethyl azodicarboxylate (DEAD). The inversion reaction may be conducted 
in an organic solvent, typically an ether such as THF, and at a 
temperature of from 10.degree. to 50.degree. C., preferably room 
temperature. The resulting ester is then hydrolysed as described above. 
Compounds of formula II as defined above may be prepared from compounds of 
formula IV: 
##STR8## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined in formula 
I and R.sup.25 is a leaving group; under basic conditions. 
The cyclisation must be carried out under basic conditions and these may be 
provided by a strong base such as an alkali metal hydride, alkoxide or 
hydroxide. Sodium hydride and sodium methoxide or ethoxide have been found 
to be particularly suitable for this purpose. The reaction may be carried 
out in any suitable solvent. The solvent chosen will, however, depend to a 
large extent upon the base which is used. Thus, when the base is an alkali 
metal hydride, the solvent may be an organic solvent such as THF, whilst 
for an alkoxide, the corresponding alcohol is more appropriate. 
Although the group R.sup.25 may be any leaving group, halogen atoms such as 
chloro, bromo and iodo are particularly suitable. 
Compounds of formula IV may be prepared from compounds of formula V: 
##STR9## 
wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in formula I 
by reaction with a compound of formula VI: 
##STR10## 
wherein A is as defined in formula I. This reaction is carried out in the 
presence of a reagent such as boron tribromide, aluminium trichloride, tin 
tetrachloride or titanium tetrachloride, the reaction may take place in an 
organic solvent such as dichloromethane or dichloroethane. Compounds of 
formulae V and VI are readily available or may be prepared by methods 
known in the art. 
An alternative method for the preparation of compounds of formula II is by 
the reaction of a compound of formula V as defined above, wherein R.sup.2 
and R.sup.3 are preferably hydrogen and R.sup.4 and R.sup.5 are hydrogen, 
with a compound of formula VI as defined above. The reaction may be 
conducted in the absence of a solvent and at a temperature of from about 
100.degree. to 300.degree. C., preferably about 150.degree. C. This 
reaction works particularly well for compounds in which A is phenyl or 
substituted phenyl. 
In a second aspect of the invention, there is provided a process for 
preparing a compound of formula IIa or IIb as defined above; the process 
comprising heating a compound of formula Va or Vb: 
##STR11## 
wherein R.sup.2 and R.sup.3 are as defined in formula I and R.sup.4 and 
R.sup.5 are hydrogen; with a compound of formula VI as defined above. The 
reaction may be conducted in the absence of a solvent and at a temperature 
of from about 100.degree. to 300.degree. C., preferably about 150.degree. 
C. This reaction works particularly well for compounds in which A is 
phenyl or substituted phenyl. This aspect of the invention is particularly 
suitable for the production of compounds of formulae IIa and IIb in which 
R.sup.2 and R.sup.3 are hydrogen. 
The compounds of formulae Va and Vb may be produced by the reduction and 
subsequent lactonistation of an appropriately protected L- or D-malic acid 
derivative, for example as described by Cammas et al, Tetrahedron, 1993, 
4(8), 1925 and Gong et al, J. Org. Chem., 1990, 55, 4763. 
There are other methods for preparing compounds of formula II and 
therefore, in a third aspect of the invention, there is provided a process 
for preparing a compound of formula II so as to obtain an enantiomeric 
excess of a compound of formula IIa or IIb as defined above, the process 
comprising reacting a compound of formula VII: 
##STR12## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined in formula 
I; with a base followed by a sterically hindered chiral oxidising agent. 
In the present invention, the term "enantiomeric excess" is defined as: 
##EQU1## 
Using the process of this aspect of the invention, an enantiomeric excess 
(ee) of at least 10%, more usually at least 20% can be obtained. 
The base is preferably a strong base such as lithium hexamethyldisilazide 
and the deprotonation reaction may take place in an organic solvent, for 
example an ether, particularly a cyclic ether such as THF. The reaction 
will often take place at a reduced temperature, for example from 
-100.degree. to 10.degree. C., usually at about -78.degree. C. 
Suitable sterically hindered chiral oxidising agents include compounds such 
as (+) camphoryl sulfonyl oxaziridine. This second step of the reaction 
may also be conducted at a reduced temperature, for example from 
-100.degree. to 10.degree. C., again usually at about -78.degree. C. The 
solvent may be an organic solvent, for example a cyclic ether such as THF. 
As briefly mentioned above, compounds of formula 11 are intermediates in 
the preparation of herbicides of formula I and, therefore, in a further 
aspect of the invention there is provided a process for the preparation of 
a compound of formula Ia or Ib: 
##STR13## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, Y, Z, n and A are as 
defined in formula I; 
the process comprising preparing a compound of IIa or IIb by a process 
according to the first, second or third aspect of the invention and 
converting the compound of formula IIa or IIb to a compound of formula Ia 
or Ib by any suitable method. 
Examples of methods for converting compounds of formula II to compounds of 
formula I are described in WO 94/13652 and UK Patent Application No 
9501158 but any method may be used. 
For example, a compound of formula II may be converted to a compound of 
formula I by reaction with a compound of formula IX, X, XI or XII: 
##STR14## 
wherein R.sup.1 and R.sup.6 are as defined for formula I; resulting in the 
production of compounds of formula I in which Y is O and in which n is 0, 
Z is O, Z is NH and Z is NR.sup.6 respectively. 
Similarly, a compound of formula II may be reacted with a compound of 
formula XIII: 
##STR15## 
wherein R.sup.1 is as defined for formula I. This gives compounds of 
formula I in which Y and Z are both O. These reactions may be conducted in 
an organic solvent such as dichloromethane. 
Compounds of formula II may be converted into compounds of formula XIV: 
##STR16## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5 and A are as defined for 
formula I and R.sup.20 is chloro, methane sulfonyloxy or toluene 
sulfonyloxy. The compounds in which R.sup.20 is methane sulfonyloxy or 
toluene sulfonyloxy may be obtained by reaction with methane sulfonyl 
chloride or toluene sulfonyl chloride as appropriate although, in some 
cases, the compound in which R.sup.20 is chloro may be obtained, 
particularly in the reaction with methane sulfonyl chloride. The reaction 
may be conducted at a temperature of from 0.degree. to 30.degree. C., 
usually at about 5.degree. C., in an organic solvent such as 
dichloromethane and in the presence of a base such as triethylamine. 
Compounds of formula XIV may be converted into compounds of formula XV: 
##STR17## 
wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7 and A are as defined 
for formula I; by reaction with an alkali metal azide such as sodium azide 
to give the equivalent azide compound followed by reduction of the azide 
by any known method, for example using a 1,3-propane dithiol in a basic 
solvent, to give the appropriate compound of formula XV. The first step 
may be carried out at a temperature of from 0.degree. to 30.degree. C., 
but preferably at room temperature, in a solvent such as dimethyl 
formamide (DMF). The conversion of the azide to a compound of formula XV 
is preferably carried out under an inert atmosphere such as nitrogen at 
0.degree. to 30.degree. C., most suitably at room temperature. The solvent 
may be an amine such as triethylamine. 
Alternatively, a compound of formula XIV may be reacted with ammonia or an 
amine of formula NH.sub.2 R.sup.7. The reaction may be carried out at a 
temperature of from 0.degree. to 80.degree. C., preferably from 0.degree. 
to 50.degree. C. It is often the case that the reaction is initiated at 
0.degree. C. and subsequently allowed to warm to room temperature after 
most of the reactant has been converted to product. Usually, the reaction 
will take place in an organic solvent, particularly an ether such as 
diethyl ether or THF. 
Compounds of formula XV may be converted to compounds of formula I in which 
Y is NR.sup.7 by reaction with a compound of formula IX, X, XI or XII 
using the reaction conditions described above for the conversion of 
compounds of formula II to compounds of formula I. 
Compounds of formula XIV in which R.sup.20 is halogen may be converted to 
compounds of formulae XVI: 
##STR18## 
by reaction firstly with a thioacid of formula XVII: 
##STR19## 
wherein R.sup.1 is as defined for formula I; to give a compound of formula 
I in which Y is S and n is 0; followed by reaction with ammonia in a 
protic solvent such as methanol. The second step may be carried out at a 
temperature of -10.degree. to 10.degree. C., usually about 0.degree. C. 
The compound of formula XVI may be converted to a compound of formula I by 
reaction with a compound of formula IX, X, X/or XII as described above for 
compounds of formula II and compounds of formula XV. 
Compounds of formula I may also be converted to other compounds of formula 
I, For example, bridged compounds of formula I in which Y is NR.sup.7, Z 
is NR.sup.6 and R.sup.6 and R.sup.7 form a bridge may be synthesised in a 
variety of ways. 
Compounds in which the bridge is represented by the formula --Q.sup.1 
--C(.dbd.O)-- may be synthesised from compounds of formula I in which Z is 
NH and Y is N--Q.sup.1 --C(.dbd.O)--L in which L is a leaving group such 
as methoxy, ethoxy or chloro, and Q.sup.1 is as defined above. The 
reaction is preferably carried out in the presence of a strong base such 
as sodium hydride, suitably in a solvent such as THF. Usually, the 
reaction temperature will be in the range of 0.degree. to 80.degree. C., 
preferably room temperature. They may alternatively be synthesised from 
compounds of formula XIV in which R.sup.20 is a leaving group such as I or 
Br by reaction with an imidazolinedione of formula XVIII: 
##STR20## 
wherein R.sup.13 and R.sup.14 independently represent hydrogen or C.sub.1 
-C.sub.4 alkyl. The reaction is carried out in an organic solvent such as 
DMF or THF, in the presence of a strong base such as sodium hydride. 
Compounds in which the bridge is represented by the formula 
--C(.dbd.O)--C(.dbd.O)-- or --C(.dbd.O)--Q.sup.2 --C(.dbd.O)-- may be 
synthesised from compounds of formula I in which both Y and Z are NH by 
reaction with a compound of formula LC(.dbd.O)--C(.dbd.O)L or 
LC(.dbd.O)--Q.sup.2 --C(.dbd.O)L in which Q.sup.2 and L are as defined 
above. The reaction may be carried out in an organic solvent such as 
toluene at a temperature of from 30.degree. to 120.degree. C. Often, the 
reaction will be conducted at a temperature of about 80.degree. C. 
Compounds in which the bridge is represented by the formula --HC.dbd.CH-- 
may be synthesised from compounds of formula I in which Z is NH and Y is 
NCH.sub.2 CHL.sub.2, wherein L is a leaving group as defined above. The 
reaction may be carried out in a solvent such as THF under acidic 
conditions which may be provided by the presence of an aqueous inorganic 
acid such as hydrochloric acid. The reaction temperature may be from 
5.degree. to 50.degree. C. but will, in most cases, be room temperature. 
Compounds of formula I in which the bridge is represented by the formula 
--CH.dbd.CH-- may be converted to compounds of formula I in which the 
bridge is represented by --CH.sub.2 --CH.sub.2 -- by reduction, for 
example hydrogenation over a palladium or platinum catalyst. Catalytic 
hydrogenations may be carried out in a solvent such as ethyl acetate. The 
reaction usually proceeds at an acceptable rate at room temperature and at 
a pressure of from 1 to 5 bar. 
Compounds in which the bridge is represented by the formula 
--C(.dbd.O)--CH.sub.2 -- may be synthesised from compounds of formula I in 
which Y and Z are both NH by reaction with CHO--CHO. The reaction may be 
conducted under acidic conditions which may be provided by the presence of 
a catalytic amount of, for example, p-toluene sulphonic acid. An example 
of a suitable reaction solvent is toluene and the reaction is preferably 
carried out under Dean and Stark conditions at a temperature of from about 
80.degree. to 120.degree. C., typically at 110.degree. C. Similar reaction 
conditions may also be used for the synthesis of compounds of formula I in 
which the bridge is represented by the formula --CH.sub.2 --O--CH.sub.2 
--. However, in this case, paraformaldehyde is used in place of CHO--CHO. 
This particular reaction may be adapted by those skilled in the art for 
the synthesis of other bridged compounds. 
All of the reactions described above for the conversion of compounds of 
formula II to compounds of formula I can, of course, be applied to 
enantiomers of formulae IIa and IIb so as to produce enantiomers of 
formulae Ia and Ib. 
The compounds of formulae Ia and Ib are useful as herbicides and show 
activity against a broad range of weed species including monocotyledonous 
and dicotyledonous species. They show some selectivity towards certain 
species, and may be used, for example, as selective herbicides in soya, 
maize and rice crops. The compounds of formulae Ia and Ib may be used on 
their own to kill or severely damage plants, but are preferably used in 
the form of a composition comprising a compound of formula Ia or Ib in 
admixture with a carrier comprising a solid or liquid diluent. 
The invention will now be described in greater detail with reference to the 
following examples.

EXAMPLE 1 
Asymmetric oxidation of N-(3-trifluoromethyl)phenyl-2-pyrrolidinone to 
3-hydroxy-N-(3-trifluoromethyl) phenyl-2-pyrrolidinone 
To a solution of N-(3-trifluoromethyl)phenyl-2-pyrrolidinone (0.50 g) in 
THF (20 ml) at -78.degree. C. was added lithium hexamethyldisilazide (5.0 
ml of a 1M solution in hexane). The colour changed from yellow to red. 
(+)-Camphoryl sulfonyl oxaziridine (1.14 g) in THF (5.0 ml) was added and 
the colour changed back to yellow. The mixture was stirred for 30 min at 
-78.degree. C. and then added to sat. NH.sub.4 Cl (aq). Ether was added, 
the organic layer separated, dried (MgSO.sub.4) and evaporated. Cold ether 
was added to the residual oil and the solid imine by-product separated. 
The residue was purified by column chromatography eluting with ethyl 
acetate/hexane to give 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone (0.274 g). 
.sup.19 F NMR of racemic 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone (10 mg) in 
CDCl.sub.3 (1 ml) containing (R)-(-)-(9-anthryl)-2,2,2-trifluoroethanol 
(0.10 g) as a chiral solvent gave two distinct singlets in a 1:1 ratio 
corresponding to the two enantiomeric alcohols. Analysis of the oxidation 
product in a similar manner showed two singlets (-72.31 and -72.33 with 
CFCl.sub.3 as internal reference), but in an intensity ratio of 5:3, 
indicating an enantiomeric excess (ee) of approximately 20%. At this stage 
it was not possible to determine which enantiomer had been formed 
preferentially, although it later became apparent that the downfield 
signal (-72.31) corresponds to the (R) enantiomer. 
An alternative route to both enantiomers is described in Example 2. 
EXAMPLE 2 
Preparation of (3R)3-.sup.t 
butylcarbonyloxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone and (3S) 
3-.sup.t butylcarbonyloxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
a) (3R) 3-Hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone camphanic 
ester and (3S) 3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
camphanic ester 
A mixture of racemic 3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
(0.15 g), triethylamine (0.083 ml) and (1S)-(-)-camphanic acid chloride 
(0.134 g) in dichloromethane (10 ml) was stirred at room temperature 
overnight. The mixture was then washed with 2N HCl (aq), sat. NaHCO.sub.3 
(aq) and dried (MgSO.sub.4) to give a yellow oil after evaporation of the 
solvent. The oil was purified by column chromatography, eluting with 
ether/hexane (1:1) followed by ether/hexane (2:1 ) to give, in order of 
elution, (3R) 3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
camphanic ester as a gum (79 mg), .sup.1 H NMR (CDCl.sub.3) 5.75 (1H, t, 
H-3) inter alia, followed by (3S) 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone camphanic ester as a 
colourless solid (43 mg), .sup.1 H NMR (CDCl.sub.3) 5.73 (1H, t, H-3) 
inter alia. 
On a larger scale (50.225 g) the pure (3S) isomer (21.12 g) could be 
isolated by fractional crystallisation of the mixture of camphanic acid 
esters from ether/DCM/hexane. The remaining mixture (which contained 
mainly (3R)) was taken through a similar inversion process, via the 
acetate, to that outlined in Example 3. This mixture of camphanic acid 
esters was saponified, the alcohols inverted by Mitsonobu reaction giving 
a mixture of predominantly the (3S) acetate, .sup.1 H NMR (CDCl.sub.3) 
2.08-2.22 (4H, m), 2.66-2.80 (1H, m), 3.82-3.96 (2H, m), 5.48 (1H,t), 7.43 
(1H,d), 7.54 (1H, t), 7.93 (1H, s), 7.94 (1H, d) inter alia. Subsequent 
hydrolysis, re-esterification with (1S)-(-)-camphanic chloride and 
crystallisation of the major isomer, gave further pure (3S) 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone camphanic ester. 
b) (3R) 3-Hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone and (3S) 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
To a solution of (3R) 3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
camphanic ester (63 mg) in THF (5 ml) was added NaOH (12 mg) in water (1.2 
ml). An immediate colour change was observed. Tlc analysis indicated that 
the reaction was complete. The mixture was acidified with 2N HCl (aq) and 
extracted with ethyl acetate. The organic phase was washed with sat. 
NaHCO.sub.3 (aq), dried (MgSO.sub.4) and evaporated to give (3R) 
3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone (40 mg). Analysis of 
the product by .sup.19 F NMR (as described in Example 1) gave only one 
peak indicating an enantiomerically pure product. 
In an analogous reaction, the (3S) isomer (43 mg) was saponified to the 
corresponding (3S) alcohol (26 mg). 
c) (3R) 3-.sup.t 
Butylcarbonyloxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone and (3S) 
3-.sup.t butylcarbonyloxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone 
A mixture of (3R) 3-hydroxy-N-(3-trifluoromethyl)phenyl-2-pyrrolidinone (30 
mg), triethylamine (0.017 ml) and .sup.t butyl isocyanate (0.027 ml) in 
dichloromethane (5 ml) was stirred at room temperature. After 4 hours 
further .sup.t butyl isocyanate (0.027 ml) was added and stirring 
continued for 72 hours. After evaporation of the solvent, chromatography 
on silica, eluting with ethyl acetate/hexane (1:3) gave the (3R) carbamate 
(17 mg) a!.sub.D =-18.degree. (c=0.327 g/100 ml, DCM. 
In an analogous reaction, the (3S) alcohol (26 mg) gave the (3S) carbamate 
(24 mg) a!.sub.D =-17.degree. (c=0.426 g/100 ml DCM). 
The (3S) carbamate prepared via the larger scale crystallisation route gave 
a!.sub.D =-18.degree. (c=0.460 g/100 ml, DCM). Analysis by chiral phase 
HPLC on a No. 565 L-phenylglycine column, eluting with hexane/THF/MeCN 
(90:10:1) indicated an ee of 90%. 
EXAMPLE 3 
Preparation of (3R) 3-.sup.t 
butylcarbonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone and (3S) 
3-.sup.t butylcarbonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
a) (3R) 3-Hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone camphanic 
ester and (3S) 3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
camphanic ester 
A mixture of racemic 3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(0.511 g), triethylamine (0.28 ml) and (1S)-(-)-camphanic acid chloride 
(0.424 g) in dichloromethane (25 ml) was stirred for 18 hours at room 
temperature. Further camphanic acid chloride (0.424 g) was added and the 
mixture stirred for a further 24 hours. The reaction was washed with 2N 
HCl (aq), sat. NaHCO.sub.3 (aq) and dried (MgSO.sub.4). Evaporation and 
chromatography on silica, eluting with ethyl acetate/hexane (1:4) gave, in 
order of elution, (3R) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone camphanic ester 
(0.125 g), .sup.1 H NMR (CDCl.sub.3) 5.75 (1H, t, H-3) inter alia, 
followed by (3S) 3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
camphanic ester as a colourless solid, .sup.1 H NMR (CDCl.sub.3) 5.73 (1H, 
t, H-3) inter alia. The latter compound was submitted to single crystal 
x-ray analysis which confirmed the structure unambiguously. This 
determination was used to infer the configuration of compounds made 
directly from this camphanic acid ester, its enantiomer and by analogy, 
the N-(3-trifluoromethyl)phenyl series. 
On a larger scale (50 g of the 3-hydroxy pyrrolidinone), the pure (3S) 
camphanic acid ester (25.9 g) could be isolated by fractional 
crystallisation of the mixture of camphanic acid esters from 
ether/DCM/hexane. The pure (3R) camphanic acid ester (7 g) could be 
isolated by further crystallisation of the residue using ether. 
b) (3R) 3-Hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone and (3S) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
Saponification of the camphanic acid esters was achieved in an analogous 
manner to that described in Example 2b). Thus the (3R) camphanic acid 
ester (0.125 g) was hydrolysed to the (3R) hydroxy derivative (66 mg). 
.sup.19 F NMR analysis of the product (as described in Example 1 ) showed 
two peaks in a ratio of 100:3 (-59.22 and -59.23 with CFCl.sub.3 as 
internal standard) indicating an ee of 94%. The (3S) camphanic acid ester 
(0.282 g) was similarly hydrolysed to the (3S) hydroxy derivative (0.136 
g) a!.sub.D =-46.degree. (c=0.220 g/100 ml, DCM). .sup.19 F NMR analysis 
of the product (as described in Example 1) showed two peaks in a ratio of 
5:100 (-59.22 and -59.24 with CFCl.sub.3 as internal standard) indicating 
an ee of 90%. 
The (38) hydroxy product from the larger scale crystallization route (see 
step a)) gave two peaks in the ratio of 4:96 by .sup.19 F NMR analysis, 
indicating an ee of 92%. The (3R) alcohol could be inverted to the (3S) 
isomer by the method outlined in step d) below. 
c) (3R) 3-.sup.t 
Butylcarbonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone and (3S) 
3-.sup.t butylcarbonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
The (3R) alcohol (66 mg), prepared as described in step b) was converted to 
the corresponding carbamate (24 mg) a!.sub.D =+7.degree. (c=0.400 g/100 
ml, DCM) by an analogous procedure to that described in Example 2c). 
Similarly, the (3S) alcohol (136 mg) gave the corresponding carbamate (68 
mg) a!.sub.D =-11.degree. (c=0.400 g/100 ml, DCM). 
The (3S) carbamate prepared from the product of the larger scale 
crystallisation route gave a!.sub.D =-18.degree. (c=0.400 g/100 ml, DCM). 
Analysis by chiral phase HPLC on a No. 565 L-phenylglycine column, eluting 
with hexane/THF/MeCN (90:10:1 ) indicated an ee of 94%. 
d) Conversion of (3R) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone to (3S) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
i. (3S) 3-Acetoxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone. 
To a solution of (3R) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.93 g) in THF (20 
ml) was added triphenylphosphine (1.00 g) and acetic acid (0.24 g). 
Diethyl azodicarboxylate (DEAD) (0.69 g) in THF (10 ml) was added dropwise 
over 30 min. After a further 72 hours at room temperature, the mixture was 
evaporated and purified by column chromatography, eluting with ethyl 
acetate/hexane (1:2) to give the partially purified (3S) acetate (0.80 g), 
.sup.1 H NMR (CDCl.sub.3) 2.10-2.22 (4H, m), 2.67-2.79 (1H, m), 3.78-3.92 
(2H, m), 5.49 (1H,t), 7.05 (1H, dd), 7.40 (1H, t), 7.57 (1H, dd), 7.68 
(1H, s). 
ii. (3S) 3-Hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone. 
The acetate (0.80 g) prepared as in step i. was dissolved in THF (10 ml) 
and NaOH (0.20 g) in water (10 ml) added. After 20 min the mixture was 
extracted with ethyl acetate. The organic phase was washed with water, 
dried (MgSO.sub.4) and evaporated. The residue was recrystallised from 
ethyl acetate/hexane to give the pure (3S) hydroxy derivative (0.503 g). 
.sup.19 F NMR analysis of the product (as described in Example 1) showed 
two peaks in a ratio of 4:96, indicating an ee of 92% (similar to that 
obtained in Example 3b)), confirming the (3S) assignment. 
EXAMPLE 4 
Preparation of (3S) 3-(.sup.t 
butylcarbamoyl-N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
and (3R) 3-(.sup.t 
butylcarbamoyl-N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
a) (3R) 3-Methanesulfonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(3R) 3-Hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.45 g) was 
dissolved in DCM (10 ml) and cooled to 0.degree. C. To this was added 
triethylamine (0.25 ml) followed by methanesulfonyl chloride (0.14 ml). 
The mixture was stirred at 0.degree. C. for 30 min and then allowed to 
warm to room temperature and stirred for a further 90 min. The mixture was 
diluted with DCM, washed with water (.times.2), brine and dried 
(MgSO.sub.4). Evaporation of the solvent gave the mesylate (0.59 g) as 
clear oil which crystallised. 
In an analogous reaction, (3S) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.594 g) gave the 
corresponding (3S) mesylate (0.770 g). 
b) (3S) 3-(N-Methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone and 
(3R) 3-(N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(3R) 3-Methanesulfonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(0.59 g), prepared as described in step a), was dissolved in THF (15 ml) 
and cooled to 0.degree. C. Methylamine gas was bubbled through the 
solution for 15 min. The mixture was allowed to warm to room temperature 
for 20 min. The solution was treated with methylamine for a further 20 min 
and left to stand for 18 hours. Further methylamine was bubbled, through 
for 20 min and the reaction left for 6 hours. The volatiles were removed 
under reduced pressure. The residue was taken up in ethyl acetate, washed 
with water (.times.3), brine, dried (MgSO.sub.4) and the solvent 
evaporated. The residue was purified by chromatography, eluting with ethyl 
acetate/hexane (2:3 rising to 1:1 ), to give the (3S) amine (0.321 g) as 
an off white solid. Analysis of the product by .sup.19 F NMR (as described 
in Example 1) showed an ee of 86%. 
In an analogous reaction, (3S) 
3-methanesulfonyloxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.77 g) 
gave the (3R) amine (0.52 g). Analysis of the product by .sup.19 F NMR (as 
described in Example 1) showed an ee of 74%. 
c) (3S) 3-(.sup.t 
Butylcarbamoyl-N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
and (3R) 3-(.sup.t 
butylcarbamoyl-N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(3S) 3-(N-Methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.36 
g) prepared as in step b) was dissolved in DCM (5 ml) and treated with 
triethylamine (0.18 ml) followed by .sup.t butyl isocyanate. The reaction 
was stirred at room temperature for 18 hours, diluted with DCM, washed 
with 2N HCl (aq), brine and dried (MgSO.sub.4). The solvent was evaporated 
and the residue purified by chromatography on silica, eluting with 
EtOAc/hexane (7:3) to give the (35) urea (0.35 g) as a colourless solid, 
mp 127.degree.-130.degree. C. Analysis of the product by .sup.19 F NMR (as 
described in Example 1) showed an ee of 76%. 
In an analogous reaction, (3R) 
3-(N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.293 g) 
gave the corresponding (3R) urea (0.30 g) as a colourless solid after 
recrystallisation from ethyl acetate, mp 135.degree.-137.degree. C. 
Analysis of the product by .sup.19 F NMR (as described in Example 1) 
showed an ee of 44%. The recrystallisation enriches the product in the 
minor enantiomer. 
EXAMPLE 5 
Preparation of (3S) 3-(.sup.t butylacetyl-N-methylamino)-N-( 
3-trifluoromethoxy)phenyl-2-pyrrolidinone and (3R) 3-(.sup.t butylacetyl 
N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(3S) 3-(N-Methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.31 
g) (prepared as in Example 4b)) was dissolved in DCM (10 ml). To this was 
added triethylamine (0.17 ml), followed by .sup.t butylacetyl chloride 
(0.17 ml). The reaction was stirred at room temperature for 20 min, 
diluted with DCM, washed with water (.times.3), brine and dried 
(MgSO.sub.4). Evaporation of the solvent and purification of the residue 
by chromatography on silica gave the (3S) amide (0.395 g) as a colourless 
solid, mp 88.degree.-90.degree. C. Analysis of the product by .sup.19 F 
NMR (as described in Example 1) showed an ee of 86%. 
In an analogous reaction, (3R) 
3-(N-methylamino)-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone (0.200 g) 
gave the corresponding (3R) amide (0.254 g) as a colourless solid, mp 
86.degree.-88.degree. C. Analysis of the product by .sup.19 F NMR (as 
described in Example 1) showed an ee of 74%. 
EXAMPLE 6 
Alternative Preparation of (3R) 
3-hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
a) (3R) 3-Hydroxytetrahydrofuran-2-one 
Crude (2R) Methyl 2,4-dihydroxybutanoate (3.57 g, *) was dissolved in HCl 
(2M, 18 ml) and heated at reflux for 3 hours, until GC indicated a single 
product. The crude product was purified by Kugelruhr distillation, to give 
the furanone as an oil (1.34 g) b.p. 150.degree. C. (2.4.times.10.sup.-2 
mbar). 
.sup.1 H NMR (CDCl.sub.3) 2.15 (1H, m), 2.62 (1H, m), 3.82 (2H, m), 4.15 
(1H, br), 4.55 (2H, dd), 7.45 (2H, m), 7.88 (2H, m). 
* Produced from L-malic acid according to the methods of Cammas et al, 
Tetrahedron, 1993, 4(8), 1925 and Gong et al, J. Org. Chem., 1990, 55, 
4763. 
b) (3R) 3-Hydroxy-N-(3-trifluoromethoxy)phenyl-2-pyrrolidinone 
(3R) 3-Hydroxytetrahydrofuran-2-one (500 mg) and 3-trifluoromethylaniline 
(950 mg) were mixed and stirred at 150.degree. C. for a total of 35 hours 
until GC and .sup.1 H NMR showed that the reaction had proceeded to 
completion. Purification of the crude product on silica, eluting with 
EtOAc/hexane (8:2) gave the (3R) hydroxy derivative (790 mg). Analysis of 
the product by HPLC showed an enantiomer ratio of 92:8, indicating an ee 
of 84%.