Processes for the diastereoselective synthesis of nucleoside analogues

The present invention relates to highly diastereoselective processes for production of cis-nucleosides and nucleoside analogues and derivatives in high optical purity, and intermediates useful in those processes.

FIELD OF THE INVENTION 
The present invention relates to diastereoselective processes for preparing 
optically active cis-nucleosides and nucleoside analogues and derivatives. 
The novel processes of this invention allow the stereo-controlled 
synthesis of a given enantiomer of a desired cis-nucleoside or nucleoside 
analogue or derivative in high optical purity. This invention also relates 
to novel intermediates useful in the processes of this invention. 
BACKGROUND OF THE INVENTION 
Nucleosides and their analogues and derivatives are an important class of 
therapeutic agents. For example, a number of nucleosides have shown 
antiviral activity against retroviruses such as human immunodeficiency 
virus (HIV), hepatitis B virus (HBV) and human T-lymphotropic virus (HTLV) 
(PCT publication WO 89/04662 and European Patent publication 0349242 A2). 
Among the nucleosides shown to have antiviral activity are 
3'-azido-3'-deoxythymidine (AZT), 2'3'-dideoxy-cytidine (DDC), 
2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolane and 
2-hydroxymethyl-4-(guanin-9'-yl)-1,3-dioxolane (European Patent 
publication 0382526 A2 and European Patent publication 0377713 A2). 
Most nucleosides and nucleoside analogues and derivatives contain at least 
two chiral centers (shown as * in formula (A)), and exist in the form of 
two pairs of optical isomers (i.e., two in the cis-configuration and two 
in the trans-configuration). However, generally only the cis-isomers 
exhibit useful biological activity. 
##STR1## 
Different enantiomeric forms of the same cis-nucleoside may, however, have 
very different antiviral activities. M. M. Mansuri et al., "Preparation Of 
The Geometric Isomers Of DDC, DDA, D4C and D4T As Potential Anti-HIV 
Agents", Bioorg.Med.Chem. Lett., 1 (1), pp. 65-68 (1991). Therefore, a 
general and economically attractive stereoselective synthesis of the 
enantiomers of the biologically active cis-nucleosides is an important 
goal. 
Many of the known processes for producing optically active nucleosides and 
their analogues and derivatives modify naturally occurring (i.e., 
optically active) nucleosides by altering the base or by altering the 
sugar via reductive procedures such as deoxygenation or radical initiated 
reductions. C. K. Chu et al., "General Synthesis Of 
2',3'-Dideoxynucleosides And 2',3'-Didehydro-2',3'-Dideoxynucleosides," 
J.Org.Chem., 54, pp. 2217-2225 (1989). These transformations involve 
multiple steps, including protection and deprotection and usually result 
in low yields. Moreover, they begin with and maintain the optical activity 
of the starting nucleoside. Thus, the nucleosides produced by these 
processes are limited to specific analogues of the enantiomeric form of 
the naturally occurring nucleoside. In addition, these procedures require 
the availability of the naturally occurring nucleoside, often an expensive 
starting material. 
Other known processes for producing optically active nucleosides rely on 
conventional glycosylation procedures to add the sugar to the base. These 
procedures invariably give anomeric mixtures of cis- and trans-isomers 
which require tedious separation and result in lower yields of the desired 
biologically active cis-nucleoside. Improved glycosylation methods 
designed to yield only the cis-nucleoside require addition of a 2'- or 
3'-substituent to the sugar. Because the 2'- or 3'-substituent is only 
useful in controlling cis-nucleoside synthesis in one configuration (when 
the 2' or 3' substituent is trans- to the 4' substituent), multiple steps 
are required to introduce this substituent in the proper configuration. 
The 2'- or 3'-substituent must then be removed after glycosylation, 
requiring additional steps. L. Wilson and D. Liotta, "A General Method For 
Controlling Stereochemistry In The Synthesis Of 2'-Deoxyribose 
Nucleosides", Tetrahedron Lett., 31, pp. 1815-1818 (1990). Furthermore, to 
obtain an optically pure nucleoside product, the starting sugar must be 
optically pure. This also requires a series of time-consuming syntheses 
and purification steps. 
SUMMARY OF THE INVENTION 
The present invention overcomes the difficulties and shortcomings of the 
prior art and provides processes for producing optically active 
cis-nucleosides (1,3-oxathiolanes, 2,4-dioxolanes, and 1,3-dithiolanes) or 
nucleoside analogues and derivatives of formula (I) 
##STR2## 
wherein W is S, S.dbd.O, SO.sub.2, or 0; 
X is S, S.dbd.O, SO.sub.2, or 0; 
R.sub.1 is hydrogen or acyl; and 
R.sub.2 is a purine or pyrimidine base or an analogue or derivative 
thereof. 
The processes of this invention comprise the step of glycosylating a 
desired purine or pyrimidine base or analogue or derivative thereof with 
an intermediate of formula (IIa) or (IIb) 
##STR3## 
wherein R.sub.3 is a substituted carbonyl or carbonyl derivative and L is 
a leaving group. Glycosylation is accomplished using a Lewis acid of the 
formula (III) 
##STR4## 
wherein R.sub.5, R.sub.6, R.sub.7, and R.sub.8 are defined below and the 
resulting intermediate is reduced to give a nucleoside or nucleoside 
analogue or derivative of formula (I). 
The processes of this invention have the advantages of allowing preparation 
of a nucleoside of formula (I) (or analogues or derivatives thereof) 
without using expensive starting materials, cumbersome protection and 
deprotection steps or addition and removal of 2'- or 3'-substituents. The 
processes of this invention produce nucleosides in high yields, with high 
purity and high optical specificity. The processes of this invention have 
the further advantage of generating nucleosides whose stereoisomeric 
configuration can be easily controlled simply by the selection of the 
appropriate starting materials.

DETAILED DESCRIPTION OF THE INVENTION 
In the processes for preparing optically active compounds of this invention 
in a configurational- and diastereo-selective manner, the following 
definitions are used: 
R.sub.2 is a purine or pyrimidine base or an analogue or derivative 
thereof. 
A purine or pyrimidine base is a purine or pyrimidine base found in 
naturally occurring nucleosides. An analogue thereof is a base which 
mimics such naturally occurring bases in that their structures (the kinds 
of atoms and their arrangement) are similar to the naturally occurring 
bases but may either possess additional or lack certain of the functional 
properties of the naturally occurring bases. Such analogues include those 
derived by replacement of a CH moiety by a nitrogen atom, e.g., 
5-azapyrimidines such as 5-azacytosine) or vice versa (e.g., 
7-deazapurines, such as 7-deazaadenine or 7-deazaguanine) or both (e.g., 
7-deaza, 8-azapurines). By derivatives of such bases or analogues are 
meant those bases wherein ring substituents are either incorporated, 
removed, or modified by conventional substituents known in the art, e.g., 
halogen, hydroxyl, amino, C.sub.1-6 alkyl. Such purine or pyrimidine 
bases, analogues and derivatives are well known to those skilled in the 
art. 
A "nucleoside analogue or derivative" is a 1,3-oxathiolane, 2,4-dioxolane 
or 1,3-dithiolane which has been modified in any of the following or 
combinations of the following ways: base modifications, such as addition 
of a substituent (e.g., 5-fluorocytosine) or replacement of one group by 
an isosteric group (e.g., 7-deazaadenine); sugar modifications, such as 
substitution of the C-2 and C-3 hydroxyl groups by any substituent, 
including hydrogen (e.g., 2',3'-dideoxynucleosides); alteration of the 
site of attachment of the sugar to the base (e.g., pyrimidine bases 
usually attached to the sugar at the N-1 site may be, for example, 
attached at the N-3 or C-6 site and purines usually attached at the N-9 
site may be, for example, attached at N-7); alteration of the site of 
attachment of the base to the sugar (e.g., the base may be attached to the 
sugar at C-2, such as iso-DDA); or alteration of configuration of the 
sugar-base linkage (e.g., cis or trans configurations). 
R.sub.3 is a carbonyl substituted with hydrogen, hydroxyl, trialkylsilyl, 
trialkylsiloxy, C.sub.1-30 alkyl, C.sub.7-30 aralkyl, C.sub.1-30 alkoxy, 
C.sub.1-30 amine (primary, secondary or tertiary), C.sub.1-30 thiol; 
C.sub.6-20 aryl; C.sub.1-20 alkenyl; C.sub.1-20 alkynyl; 1,2-dicarbonyl, 
such as 
##STR5## 
substituted with C.sub.1-6 alkyl or C.sub.6-20 aryl; anhydrides such as 
##STR6## 
substituted with C.sub.1-6 alkyl or C.sub.6-20 aryl; azomethine 
substituted at nitrogen with hydrogen, C.sub.1-20 alkyl or C.sub.1-10 
alkoxy or C.sub.1-10 dialkylamino or at carbon with hydrogen, C.sub.1-20 
alkyl, or C.sub.1-20 alkoxy; thiocarbonyl (C.dbd.S) substituted with 
hydroxyl, C.sub.1-20 alkoxy, or C.sub.1-20 thiol; a homologue of carbonyl, 
e.g., 
##STR7## 
a homologue of thiocarbonyl, e.g., 
##STR8## 
or a homologue of azomethine, such as 
##STR9## 
The preferred substituted carbonyl/carbonyl derivatives are 
alkoxycarbonyls, such as methyl, ethyl, isopropyl, t-butyl and menthyl; 
carboxyls, diethylcarboxamide; pyrrolidine amide; methyl ketone and phenyl 
ketone. The more preferred substituted carbonyl/carbonyl derivatives are 
esters and carboxyls and the most preferred are esters. 
R.sub.4 is a chiral auxiliary. The term "chiral auxiliary" describes 
asymmetric molecules that are used to effect the chemical resolution of a 
racemic mixture. Such chiral auxiliaries may possess one chiral center 
such as methylbenzylamine or several chiral centers such as menthol. The 
purpose of the chiral auxiliary, once built into the starting material, is 
to allow simple separation of the resulting diastereomeric mixture. See, 
for example, J. Jacques et al., Enantiomers, Racemates And Resolutions, 
pp. 251-369, John Wiley & Sons, New York (1981). 
R.sub.5, R.sub.6 and R.sub.7 are independently selected from the group 
consisting of hydrogen, C.sub.1-20 alkyl (e.g., methyl, ethyl, t-butyl), 
optionally substituted by halogens (F, Cl, Br, I), C.sub.6-20 alkoxy 
(e.g., methoxy) or C.sub.6-20 aryloxy (e.g., phenoxy); C.sub.7-20 aralkyl 
(e.g., benzyl), optionally substituted by halogen, C.sub.1-20 alkyl or 
C.sub.1-20 alkoxy (e.g., p-methoxybenzyl); C.sub.6-20 aryl (e.g., phenyl), 
optionally substituted by halogens, C.sub.1-20 alkyl or C.sub.1-20 alkoxy; 
trialkylsilyl; halogens (F, Cl, Br, I). 
R.sub.8 is selected from the group consisting of halogen (F, Cl, Br, I); 
C.sub.1-20 sulphonate esters, optionally substituted by halogens (e.g., 
trifluoromethane sulphonate); C.sub.1-20 alkyl esters, optionally 
substituted by halogen (e.g., trifluoroacetate); polyvalent halides (e.g., 
triiodide); trisubstituted silyl groups of the general formula 
(R.sub.5)(R.sub.6)(R.sub.7)Si (wherein R.sub.5, R.sub.6, and R.sub.7 are 
as defined above); saturated or unsaturated selenenyl C.sub.6-20 aryl; 
substituted or unsubstituted C.sub.6-20 arylsulfenyl; substituted or 
unsubstituted C.sub.1-20 alkoxyalkyl; and trialkylsiloxy. 
L is a "leaving group", i.e., an atom or a group which is displaceable upon 
reaction with an appropriate purine or pyrimidine base, with or without 
the presence of a Lewis acid. Suitable leaving groups include acyloxy 
groups, alkoxy groups, e.g., alkoxy carbonyl groups such as ethoxy 
carbonyl; halogens such as iodine, bromine, chlorine, or fluorine; amido; 
azido; isocyanato; substituted or unsubstituted, saturated or unsaturated 
thiolates, such as thiomethyl or thiophenyl; substituted or unsubstituted, 
saturated or unsaturated seleno, seleninyl, or selenonyl compounds, such 
as phenyl selenide or alkyl selenide. 
A suitable leaving group may also be --OR, where R is a substituted or 
unsubstituted, saturated or unsaturated alkyl group, e.g., C.sub.1-6 alkyl 
or alkenyl group; a substituted or unsubstituted aliphatic or aromatic 
acyl group, e.g., a C.sub.1-6 aliphatic acyl group such as acetyl and a 
substituted or unsubstituted aromatic acyl group such as benzoyl; a 
substituted or unsubstituted, saturated or unsaturated alkoxy or aryloxy 
carbonyl group, such as methyl carbonate and phenyl carbonate; substituted 
or unsubstituted sulphonyl imidazolide; substituted or unsubstituted 
aliphatic or aromatic amino carbonyl group, such as phenyl carbamate; 
substituted or unsubstituted alkyl imidiate group such as 
trichloroacetamidate; substituted or unsubstituted, saturated or 
unsaturated phosphonate, such as diethylphosphonate; substituted or 
unsubstituted aliphatic or aromatic sulphinyl or sulphonyl group, such as 
tosylate; or hydrogen. 
As used in this application, the term "alkyl" represents a substituted (by 
a halogen, hydroxyl or C.sub.6-20 aryl) or unsubstituted straight chain, 
branched chain, or cyclic hydrocarbon moiety having 1 to 30 carbon atoms 
and preferably, from 1 to 6 carbon atoms. 
The terms "alkenyl" and "alkynyl" represent substituted (by a halogen, 
hydroxyl or C.sub.6-20 aryl) or unsubstituted straight, branched or cyclic 
hydrocarbon chains having 1 to 20 carbon atoms and preferably from 1 to 5 
carbon atoms and containing at least one unsaturated group (e.g., allyl). 
The term "alkoxy" represents a substituted or unsubstituted alkyl group 
containing from 1 to 30 carbon atoms and preferably from 1 to 6 carbon 
atoms, wherein the alkyl group is covalently bonded to an adjacent element 
through an oxygen atom (e.g., methoxy and ethoxy). 
The term "amine" represents alkyl, aryl, alkenyl, alkynyl, or aralkyl 
groups containing from 1 to 30 carbon atoms and preferably i to 12 carbon 
atoms, covalently bonded to an adjacent element through a nitrogen atom 
(e.g., pyrrolidine). They include primary, secondary and tertiary amines 
and quaternary ammonium salts. 
The term "thiol" represents alkyl, aryl, aralkyl, alkenyl or alkynyl groups 
containing from 1 to 30 carbon atoms and preferably from 1 to 6 carbon 
atoms, covalently bonded to an adjacent element through a sulfur atom 
(e.g., thiomethyl). 
The term "aryl" represents a carbocyclic moiety which may be substituted by 
at least one heteroatom (e.g., N, O, or S) and containing at least one 
benzenoid-type ring and preferably containing from 6 to 15 carbon atoms 
(e.g., phenyl and naphthyl). 
The term "aralkyl" represents an aryl group attached to the adjacent atom 
by an alkyl (e.g., benzyl). 
The term "alkoxyalkyl" represents an alkoxy group attached to the adjacent 
group by an alkyl group (e.g., methoxymethyl). 
The term "aryloxy" represents a substituted (by a halogen, trifluoromethyl 
or C.sub.1-5 alkoxy) or unsubstituted aryl moiety covalently bonded 
through an oxygen atom (e.g., phenoxy). 
The term "acyl" refers to a radical derived from a carboxylic acid, 
substituted (by a halogen (F, Cl, Br, I), C.sub.6-20 aryl or C.sub.1-6 
alkyl) or unsubstituted, by replacement of the --OH group. Like the acid 
to which it is related, an acyl radical may be aliphatic or aromatic, 
substituted (by a halogen, C.sub.1-5 alkoxyalkyl, nitro or O.sub.2) or 
unsubstituted, and whatever the structure of the rest of the molecule may 
be, the properties of the functional group remain essentially the same 
(e.g., acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, 
trifluoroacetyl, chloroacetyl, and cyclohexanoyl). 
A key feature of the processes of this invention is the use of a 
substituted carbonyl or carbonyl derivative as R.sub.3 instead of a 
protected hydroxymethyl group as previously described in the art. 
Surprisingly, the substituted carbonyl or carbonyl derivative is not 
cleaved by exposure to a Lewis acid, as would have been expected by one of 
skill in the art when a Lewis acid of formula (III) is added to a mixture 
of silylated purine or pyrimidine base and the chiral auxiliary-sugar 
compound obtained in Step 3. Instead, the substituted carbonyl/carbonyl 
derivative in the intermediate of formula (VI) forces the purine or 
pyrimidine base (R.sub.2) to add in the cis-configuration relative to the 
substituted carbonyl/carbonyl derivative group. Without a substituted 
carbonyl or carbonyl derivative attached to C4' (for example, when a 
hydroxymethyl group is instead used), the coupling procedures described in 
Step 4 will result in a mixture of cis- and trans-isomers. 
Another key feature of the processes of this invention is the choice of 
Lewis acid. The Lewis acids used in the preparation of compounds of 
formula (I) have the general formula (III) 
##STR10## 
wherein R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are as defined previously. 
These Lewis acids may be generated in situ or prepared using any method 
known in the art (e.g., A. H. Schmidt, "Bromotrimethylsilane and 
Iodotrimethylsilane-Versatile Reagents for Organic Synthesis", 
Aldrichimica Acta, 14, pp. 31-38 (1981). The preferred Lewis acids of this 
invention are iodotrimethylsilane and trimethylsilyl triflate. The 
preferred R.sub.5, R.sub.6 and R.sub.7 groups are methyl or iodine. The 
most preferred R.sub.5, R.sub.6 and R.sub.7 group is methyl. The preferred 
R.sub.8 groups are iodine, chlorine, bromine or sulphonate esters. The 
most preferred R.sub.8 groups are iodine and trifluoromethane sulphonate. 
In the preferred process of this invention, illustrated in Schemes 1 and 2, 
cis- and trans-isomers of a sugar of formula (II) 
##STR11## 
are separated by fractional crystallization and the desired 
configurational isomer selected. The selected cis- or the trans-isomer may 
then be resolved chemically, e.g., using a chiral auxiliary, 
enzymatically, or by other methods known in the art. The pure diastereomer 
is then coupled to a silylated purine or pyrimidine base in the presence 
of a Lewis acid to afford an optically active nucleoside of 
cis-configuration which is subsequently reduced to give a nucleoside of 
formula (I). 
Schemes 1A and 1B depict this preferred process as applied to any 
1,3-oxathiolane, 2,4-dioxolane or 1,3-dithiolane. 
##STR12## 
The various steps as illustrated in Schemes 1A and 1B may be briefly 
described as follows: 
Step 1: The starting carbonyl-sugar of formula (IV) can be prepared by any 
method known in the art. E.g., J. M. Mcintosh et al., "2-Mercaptoaldehyde 
Dimers and 2,5-Dihydrothiophenes from 1,3-oxathiolan-5-ones", Can. J. 
Chem., 61, pp. 1872-1875 (1983). The carbonyl group of this starting 
compound is reduced chemoselectively with a suitable reducing agent, such 
as disiamylborane to give the cis- and trans-isomers of formula (V). 
Ordinarily, less cis-isomer is produced than trans. 
Step 2: The hydroxyl group in the intermediate of formula (V) is readily 
converted to a leaving group by any method known in the art (e.g., T. W. 
Greene Protective Groups In Organic Synthesis, pp. 50-72, John Wiley & 
Sons, New York (1981)) to give the novel intermediates of formula (II). 
This anomeric mixture is then separated by fractional crystallization into 
the two configurational isomers. The solvent may be adjusted to select for 
either the cis- or trans-isomer. D. J. Pasto and C. R. Johnson, Organic 
structure Determination, pp. 7-10, Prentice-Hall, Inc., New Jersey (1969). 
Step 3: Either the cis- (Scheme 1A) or trans-isomer (Scheme 1B) of formula 
(II) is chemically resolved using a chiral auxiliary (R.sub.4). A suitable 
chiral auxiliary is one of high optical purity and where the mirror image 
is readily available, such as d- and 1-menthol. The resulting 
diastereomers of formula (VI) are easily separated by fractional 
crystallization. Alternatively, either the cis- or the trans-isomer may be 
resolved enzymatically or by other methods known in the art. Jacques et 
al., Enantiomers, Racemates And Resolutions, pp. 251-369, John Wiley & 
Sons, New York (1981). 
The optical purity of the diastereomer (VI, VII or I) can be determined by 
chiral HPLC methods, specific rotation measurements and NMR techniques. As 
a general rule, if the opposite enantiomer is desired, it may be obtained 
by using the mirror image of the chiral auxiliary initially employed. For 
example, if the chiral auxiliary d-menthol produces a (+)-enantiomer 
nucleoside, its mirror image, 1-menthol, will produce the (-)-enantiomer. 
Step 4: A previously silylated (or silylated in situ) purine or pyrimidine 
base or analogue or derivative thereof is then glycosylated with the 
resulting pure diastereomer in the presence of a Lewis acid of formula 
(III), such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate 
(TMSOTf), to give a nucleoside of cis-configuration of formula (VII). This 
nucleoside is optically active and is substantially free of the 
corresponding trans-isomer (i.e., it contains less than 20%, preferably no 
more than 10% and more preferably no more than 5% of the trans-isomer). 
The preferred silylating agent for pyrimidine bases are 
t-butyldimethylsilyl triflate 1,1,1,3,3,3 hexamethyldisilazane and 
trimethylsilyl triflate. It is believed that the bulky t-butyl group 
increases yields by weakening the interaction between the Lewis acid and 
silylated pyrimidine base. 
The preferred method of mixing reagents in Step 4 is to first add the 
chiral auxiliary-sugar of formula (VI) to the silylated purine or 
pyrimidine base. The Lewis acid of formula (III) is then added to the 
mixture. 
Step 5: The cis-nucleoside obtained in Step 4 may then be reduced with an 
appropriate reducing agent to remove the chiral auxiliary and give a 
specific stereoisomer of formula (I). The absolute configuration of this 
stereoisomer corresponds to that of the nucleoside intermediate of formula 
(VII). As shown in Scheme 1, either the cis- (Scheme 1A) or the 
trans-isomers (Scheme 1B) obtained in Step 2 will yield a cis end product. 
Schemes 2A and 2B illustrate the application of the process of Schemes 1A 
and 1B to the synthesis of the enantiomers of 
cis-2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolanes. Although this 
process is illustrated using specific reagents and starting materials, it 
will be appreciated by one of skill in the art that suitable analogous 
reactants and starting materials may be used to prepare analogous 
compounds. 
##STR13## 
The various steps illustrated in Schemes 2A and 2B may be briefly described 
as follows: 
Step 1: A mercaptoacetaldehyde monomer, preferably produced from a dimer, 
such as 2,5-dihydroxy-1,4-dithiane, in an appropriate solvent (preferably 
t-butylmethyl ether) is reacted with glyoxylic acid to give exclusively 
the trans-hydroxy acid of formula (VIII). 
Step 2: The acid of formula (VIII) is reacted with an acid chloride, such 
as acetyl chloride in the presence of pyridine and an acylation catalyst, 
such as 4-dimethylaminopyridine, or preferably with an acid anhydride such 
as acetic anhydride in the presence of acetic acid and an acylation 
catalyst, such as sulfuric acid, to give a diastereomeric mixture of cis- 
and trans-acetoxy acids of formula (IX). 
The racemic diastereomeric acid mixture obtained in Step 2 is fractionally 
crystallized using any combination of solvents (preferably benzene and 
ether) to give exclusively either the cis- or the trans-acetoxy acid of 
formula (IX) each as a racemic mixture. 
Step 3: Either the cis- or the trans-acetoxy acid of formula (IX) is 
reacted with an appropriate chiral auxiliary preferably, 1-menthol or 
d-menthol, in a suitable organic solvent, such as dichloromethane, using 
an activating agent, such as dicyclohexylcarbodiimide, and an 
esterification catalyst, such as 4-dimethylaminopyridine, to give a 
diastereomeric mixture of the cis- or trans-esters respectively. 
Alternatively, the compound of formula (IX) may be converted to an acid 
chloride by any means known in the art, such as with oxalyl chloride in an 
appropriate solvent, e.g., dichloromethane or N.sub.1 N-dimehylformamide. 
The acid chloride is then reacted with a chiral auxiliary in a suitable 
organic solvent using an esterification catalyst. 
Step 4: The above diastereomeric mixture of either the cis- or the 
trans-esters is fractionally crystallized using any combination of 
solvents (preferably ether and petroleum ether (40.degree.-60.degree. C.)) 
preferably at low temperature to give exclusively the cis- or the 
trans-acetoxy menthyl ester of formula (X), respectively. 
Step 5: Either the cis- or the trans-acetoxy compound of formula (X) is 
reacted with cytosine or other purine or pyrimidine base or analogue 
thereof. The purine or pyrimidine base or analogue is preferably 
previously silylated with hexamethyldisilazane or more preferably 
silylated in situ with t-butyldimethylsilyl triflate in a compatible 
organic solvent, such as dichloromethane containing a hindered base 
preferably 2,4,6-collidine. A Lewis acid of formula (III), preferably 
iodotrimethylsilane or trimethylsilyl triflate, is then added to give the 
cis-compound of formula (XI) in a highly diastereoselective manner. 
Step 6: The optically active cis-nucleoside of formula (XI) is reduced 
stereospecifically with a reducing agent preferably lithium 
triethylborohydride or more preferably lithium aluminum hydride in an 
appropriate solvent such as tetrahydrofuran or diethyl ether to give the 
compound of formula (XII) and menthol. 
A second process for the diastereoselective synthesis of compounds of 
formula (I) is illustrated by Schemes 3A and 3B and 4A and 4B. In the 
process of Schemes 3A and 3B carbonyl-sugar with an R.sub.3 substituent at 
C4' is reacted with a chiral auxiliary (R.sub.4) to give a diastereomeric 
mixture of two optically active chiral auxiliary sugars. The actual 
diastereomer produced depends on whether the (+) or (-) chiral auxiliary 
is used. This optically active mixture may be chemoselectively reduced and 
the resulting hydroxyl group converted to a leaving group to afford a 
diastereomeric mixture of four chiral auxiliary-sugars, two in the cis- 
configuration and two in the trans-configuration (Scheme 3B). Subsequent 
fractional crystallization gives a single diastereomer. 
Alternatively, the optically active mixture of chiral auxiliary-sugars may 
first be separated by chromatography or fractional crystallization and 
then reduced and the resulting hydroxyl group converted to a leaving group 
(Scheme 3A). Subsequent fractional crystallization yields any desired 
diastereomer. The solvent may be adjusted to select for either the cis- or 
the trans-isomer. Each isolated optically active diastereomer may be 
carried on further to compounds of formula (I) in a manner analogous to 
that described in Schemes 1 and 2. 
Schemes 3A and 3B depict the second process of this invention as applied to 
any 1,3-oxathiolane, 2,4-dioxolane or 1,3-dithiolane. 
##STR14## 
The various steps involved in the synthesis of the nucleosides of formula 
(I) as depicted in Schemes 3A may be briefly described as follows: 
Step 1: The starting material of formula (IV), prepared by any method known 
in the art, is reacted with a chiral auxiliary (see, e.g., T. W. Greene, 
"Protective Groups in Organic Synthesis", John Wiley and Sons, New York 
(1981) to yield a mixture of two diastereomers of formula (XIII). The 
particular mixture produced will depend on which chiral auxiliary (+ or -) 
is used. 
Step 2: The mixture of two diastereomers of formula (XIII) is separated by 
fractional crystallization or chromatography to yield one diastereomer of 
formula (XIII). 
Step 3: The single isomer of formula (XIII) is chemoselectively reduced by 
a suitable reducing agent, such as disiamylborane to give a mixture of two 
diastereomers of formula (XIV). 
Step 4: The hydroxyl groups of the two diastereomers of formula (XIV) are 
converted to leaving groups by any method known in the art to give a 
mixture of two diastereomers of formula (VI). 
Step 5: Either the cis- or trans-isomer is separated out of the mixture of 
two diastereomers of formula (VI), as obtained in Step 4, by fractional 
crystallization or chromatography. The solvent may be adjusted to select 
for the cis- or trans-isomer. 
Step 6: The single diastereomer of formula (VI) is reacted with previously 
silylated (or silylated in situ) purine or pyrimidine base or analogue or 
derivative. Then, addition of a Lewis acid of formula (III), such as 
iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMSOTf) yields a 
nucleoside of cis-configuration of formula (VII). This nucleoside is 
substantially free of the corresponding trans-isomer. 
Step 7: The optically active cis-nucleoside of formula (VII) is reduced 
stereospecifically with a reducing agent preferably lithium 
triethylborohydride or more preferably lithium aluminum hydride in an 
appropriate solvent such as tetrahydrofuran or diethyl ether to give the 
compound of formula (I) and menthol. 
Alternatively, as shown in Scheme 3B, the mixture of diastereomers of 
formula (XIII) is chemoselectively reduced with a suitable reducing agent, 
such as disiamylborane to give a mixture of four diastereomers of formula 
(XIV). The hydroxyl groups in this mixture of four diastereomers of 
formula (XIV) are converted to leaving groups any method in the art to 
afford a mixture of four diastereomers of formula (VI). Either a cis- or a 
trans-isomer of formula (VI) is separated out of the mixture of four 
diastereomers of formula (VI) by fractional crystallization or 
chromatography. The solvent may be adjusted to select for a cis- or 
trans-isomer. The single diastereomer of formula (VI) is reacted with 
previously silylated (or silylated in situ) purine or pyrimidine base or 
analogue or derivative. Then, addition of a Lewis acid of formula (III), 
such as iodotrimethylsilane (TMSI) or trimethylsilyl triflate (TMSOTf) 
affords a nucleoside of cis- configuration of formula (VII) which is 
reduced with an appropriate reducing agent to give a specific stereoisomer 
of formula (I). 
Schemes 4A and 4B illustrate the application of the process of Scheme 3 to 
the synthesis of the enantiomers of 
cis-2-hydroxymethyl-5-(cytosin-1'-yl)-1,3-oxathiolanes. Although this 
process is illustrated using specific reagents and starting materials, it 
will be appreciated by one of skill in the art that suitable analogous 
reactants and starting materials may be used to prepare analogous 
compounds. 
##STR15## 
The various steps involved in the synthesis of the nucleosides of formula 
(I) as depicted in Scheme 4 may be briefly described as follows: 
Step 1: The known mercaptoacetic acid of formula (XV) is reacted with an 
appropriate aldehyde of formula R.sub.3 CHO, wherein R.sub.3 is preferably 
an alkoxy carbonyl, such as menthyl glyoxylate and more preferably a 
carboxyl group, such as glyoxylic acid (see e.g., J. M. Mcintosh et al., 
"2-Mercaptoaldehyde Dimers and 2,5-Dihydrothiophenes from 
1,3-oxathiolan-5-ones", Can. J. Chem., 61, pp. 1872-1875 (1983)) in a 
compatible organic solvent, such as toluene, to give the intermediate of 
formula (XVI). 
Step 2: The compound of formula (XVI) is reacted with an appropriate chiral 
auxiliary, preferably 1-menthol or d-menthol in a compatible organic 
solvent, such as dichloromethane, using an activating agent, such as 
dicyclohexylcarbodiimide, and an esterification catalyst, such as 
4-dimethylaminopyridine, to give the compounds of formula (XVII). 
Step 3: The diastereomeric compounds of formula (XVII) are preferably 
separated by fractional crystallization (Scheme 4A), but may be carried on 
further without separation (Scheme4B). 
Step 4: The compounds of formula (XVII) are reduced with an appropriate 
reducing agent such as disiamylborane in a compatible organic solvent, 
such as tetrahydrofuran (A. Pelter et al., "Borane Reagents", Academic 
Press, p. 426 (1988)), to give the compounds of formula (XVIII). 
Step 5: The compounds of formula (XVIII) are reacted with an acid chloride 
or acid anhydride, such as acetic anhydride, in the presence of pyridine 
and an acylation catalyst, such as 4-dimethylaminopyridine, to give the 
compounds of formula (X). 
Step 6: The diastereomeric compounds of formula (X), if not already 
separated (Scheme 4A), are now separated preferably by fractional 
crystallization (Scheme 4B) to give either the cis- or the trans-acetoxy 
compound of formula (X). 
Step 7: Either the cis- or the trans-acetoxy compound of formula (X) is 
reacted with cytosine or other purine or pyrimidine base or analogue 
thereof. The purine or pyrimidine base or analogue is preferably 
previously silylated with hexamethyldisilazane or more preferably 
silylated in situ with t-butyldimethylsilyl triflate in a compatible 
organic solvent, such as dichloromethane containing a hindered base 
preferably 2,4,6-collidine. A Lewis acid, preferably one derived from the 
compounds of formula (III), more preferably iodotrimethylsilane or 
trimethylsilyl triflate, is then added to give the cis compound of formula 
(XI) in a highly diastereoselective manner. 
Step 8: The optically active cis-nucleoside of formula (XI) is reduced 
stereospecifically with a reducing agent, preferably lithium 
triethylborohydride, or more preferably, lithium aluminum hydride, in an 
appropriate solvent, such as tetrahydrofuran or diethyl ether, to give the 
compound of formula (XII). 
In the diastereoselective processes of this invention, the following 
intermediates are of particular importance: 
##STR16## 
wherein R.sub.3, R.sub.4 and L are as defined above; 
trans-5-hydroxyoxathiolane-2-carboxylic acid; 
(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5S-hydroxy-1,3-oxathiolane-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-hydroxy-1,3-oxathiolane-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5S-hydroxy-1,3-oxathiolane-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-hydroxy-1,3-oxathiolane-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate; 
(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate; 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate; 
(1'S,2'R,5'S)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate; 
(1'R,2'S,5'R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carbox 
ylate; 
(1'S,2'R,5'S)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carbox 
ylate; 
(1'S,2'R,5'S)-menthyl-5S-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane-2R-carb 
oxylate; 
(1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-4R-hydroxy-1,3-oxathiolane-2R-carboxylate and 
(1'S,2'R,5'S)-menthyl-4S-hydroxy-1,3-oxathiolane-2R-carboxylate; 
(1'S,2'R,5'S)-menthyl-4R-chloro-1,3-oxathiolane-2R-carboxylate and 
(1'S,2'R,5'S)-menthyl-4S-chloro-1,3-oxathiolane-2R-carboxylate; 
cis-2(N-methyl-N-methoxyaminocarbonyl)-5-(uracil-1'-yl)-1,3-oxathiolane; 
cis- and trans-2-benzoyl-5-acetoxy-1,3-oxathiolane; 
cis-2-(1'-pyrrolidinocarbonyl)-5-acetoxy-1,3-oxathiolane; 
cis-2-carbomethoxy-5-(5'-bromouracil-1'-yl)-1,3-oxathiolane; 
cis-2-carboxyl-5-(uracil-1'-yl)-1,3-oxathiolane; 
cis-2-(1'-pyrrolidinocarbonyl)-5-(uracil-1'-yl)-1,3-oxathiolane; 
cis 2-benzoyl-5-(uracil-1'-yl)-1,3-oxathiolane; 
cis- and trans-isopropyl 5-acetoxy-1,3-oxathiolane-2-carboxylate; 
cis-isopropyl-5-(cytosin-1'-yl)-1,3-oxathiolane-2-carboxylate; 
cis- and trans-t-butyl 5-acetoxy-1,3-oxathiolane-2-carboxylate; 
cis-t-butyl-5-(cytosin-1'-yl)-1,3-oxathiolane-2-carboxylate; 
cis- and trans-2-N,N-diethylaminocarbonyl-5-acetoxy-1,3-oxathiolane; 
cis-2-N,N-diethylaminocarbonyl-5-(cytosin-1'-yl)-1,3-oxathiolane; 
cis- and trans-2-carboethoxy-4-acetoxy-1,3-dioxolane; 
cis- and trans-2-carboethoxy-4-(thymin-1'-yl)-1,3-dioxolane; and 
cis- and trans-2-carboethoxy-4-(N-4'-acetylcytosin-1'-yl)-1,3-dioxolane. 
The following examples illustrate the present invention in a manner of 
which it can be practiced but, as such, should not be construed as 
limitations upon the overall scope of the processes of this invention. 
Except where specifically noted, all .alpha.!.sub.D measurements were 
recorded at ambient temperature. 
EXAMPLE 1 
1,3-OXATHIOLAN-5-ONE-2-CARBOXYLIC ACID 
##STR17## 
Toluene (700 mL), mercaptoacetic acid (38 mL, 50.03 g, 0.543 mol), and 
p-toluenesulfonic acid (1.0 g) were added to a solution of glyoxylic acid 
monohydrate (50.0 g, 0.543 mol) in 200 mL of THF in a 2 L round bottom 
flask equipped with a Dean-Stark trap and condenser. The resultant 
reaction mixture was refluxed for 3 hours until 24.0 mL of H.sub.2 O was 
azeotropically removed. The reaction mixture was cooled, followed by 
removal of solvent under reduced pressure to yield an off-white solid. 
This material was purified by recrystallization (hexanes-EtOAc) to give 
60.0 g of the product as a crystalline white solid: m.p. 
140.degree.-143.degree. C.; .sup.1 H NMR (DMSO) .delta. 3.84 (q, 2H, 
JAB=16.7 Hz), 6.00 (s, 1H). 
EXAMPLE 2 
TRANS-5-HYDROXYOXATHIOLANE-2-CARBOXYLIC ACID 
##STR18## 
A suspension of dithian-1,4-diol (82.70 g, 0.54 mol) and glyoxylic acid 
monohydrate (100.0 g, 1.09 mol) in tert-butyl methyl ether (1.1 L) was 
stirred under a blanket of nitrogen and heated to reflux under Dean and 
Stark conditions. The reflux was continued for 8 hours during which time 
15.3 mL (0.85 mol) of water was collected. The slightly turbid mixture was 
filtered, and the solvent was distilled at atmospheric pressure until a 
volume of 600 mL remained. Cyclohexane (340 mL) was added and the solution 
was cooled to 5.degree. C., seeded, and allowed to stir and crystallize. 
The suspension was stirred at 0.degree.-5.degree. C. for 2 hours. The 
product was isolated by filtration, washed with 100 mL of tert-butyl 
methyl ether-cyclohexane (2:1), and was dried overnight in vacuo at room 
temperature (94.44 g): m.p. 94.5.degree. C.; .sup.1 H NMR (DMSO) .delta. 
2.85 (dd, 1H, J=2.4, 10.5 Hz), 3.13 (dd, 1H, J=4.3, 10.5 Hz), 5.47 (s, 
1H), 5.84 (brs, 1H), 6.95 (d, 1H, J=4.7 Hz). 
EXAMPLE 3 
TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC-ACID 
##STR19## 
One drop of concentrated H.sub.2 SO.sub.4 was added to a thoroughly stirred 
solution of trans-5-hydroxyoxathiolane-2-carboxylic acid (7.0 g, 46.7 
mmol) in glacial acetic acid (40 mL) and acetic anhydride (15 mL, 15.9 
mmol) at ambient temperature. The resultant clear solution was stirred for 
1 hour and then poured onto crushed ice and brine (20 mL). This mixture 
was extracted with CH.sub.2 Cl.sub.2 (100 mL) and the combined extract was 
dried over anhydrous magnesium sulfate. The solvent was removed under 
reduced pressure to give 8.5 g (95%) of a light yellow syrup which 
consisted of trans- and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid in 
a 2:1 ratio. The mixture was dissolved in benzene (20 mL) and was left 
standing overnight during which white crystals were formed. A small amount 
of ether was added and the solid was collected by filtration and washed 
with more ether to give 2 g (22%) of 
trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid: m.p. 111.3.degree. C.; 
.sup.1 H NMR (DMSO) .delta. 2.03 (s, 3H), 3.21 (d, 1H, J=12 Hz), 3.32 (dd, 
1H, J=3, 12 Hz), 5.65 (s, 1H), 6.65 (d, 1H, J=4 Hz); .sup.13 C NMR (DMSO) 
.delta. 20.91, 36.51, 78.86, 99.15, 169.36, 170.04. 
EXAMPLE 4 
CIS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID 
##STR20## 
The filtrate obtained from Example 3 was concentrated under reduced 
pressure and redissolved in ether. This solution was kept at room 
temperature and cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid slowly 
crystallized out as a white solid (2.1 g, 23%): m.p. 111.7.degree. C.; 
.sup.1 H NMR (DMSO) .delta. 1.96 (s, 3H), 3.25-3.33 (m, 2H), 5.74 (S, 1H), 
6.69 (d, 1H, J=3 Hz); .sup.13 C NMR (DMSO) .delta. 21.0, 37.16, 79.57, 
98.58, 169.36, 170.69. 
EXAMPLE 5 
(1'R,2'S,5'R)-MENTHYL-1,3-OXATHIOLAN-5-ONE-2S-CARBOXYLATE AND 
(1'R,2'S,5'R)-MENTHYL-1,3-OXATHIOLAN-5-ONE-2R-CARBOXYLATE 
##STR21## 
Oxalyl chloride (11 mL, 123.6 mmol) was added through a dropping funnel 
over a period of 30 minutes to a stirred solution of 
1,3-oxathiolan-5-one-2-carboxylic acid (12.2 g, 82.4 mmol) in anhydrous 
THF (20 ml) and CH.sub.2 Cl.sub.2 (40 mL) at room temperature under an 
argon atmosphere. The resultant solution was heated at 65.degree. C. for 
30 minutes and then was concentrated in vacuo to give an oily product 
(11.6 g, 90%). The crude acid chloride obtained was redissolved in dry 
CH.sub.2 Cl.sub.2 (40 mL) and cooled at 0.degree. C. (1R,2S,5R)-menthol 
(12.8 g, 82.4 mmol) dissolved in CH.sub.2 Cl.sub.2 (25 mL) was slowly 
added to this cooled solution. The resultant solution was stirred at room 
temperature overnight. The reaction mixture was diluted with CH.sub.2 
Cl.sub.2 (200 mL) and washed with water, saturated aqueous NaHCO.sub.3 
solution, brine, and then was dried over anhydrous Na.sub.2 SO.sub.4. The 
solvent was removed and the crude product thus obtained was filtered 
through a short silica column (100 g, Merck) eluted with EtOAc-hexanes. 
Concentration of the appropriate fractions gave a 1:1 mixture of 
(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-1,3-oxathiolan-5-one-2R-carboxylate (20 g, 84.7% 
overall) as a viscous oil: .sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (3H), 
0.91 (6H), 1.00-1.15 (2H), 1.40-2.10 (6H), 3.56 (1H), 3.82 (1H), 4.80 
(1H). 5.62 (1H); .sup.13 C NMR .delta. 16.7, 21.2, 21.3, 22.5, 23.80, 
23.84, 26.7, 26.8, 30.6, 31.91, 31.94, 34.57, 40.6, 41.07, 47.5, 47.6, 
74.1, 74.2, 77.7, 168.1, 172.8. 
The above mixture (20 g) was dissolved in a minimum amount of 
pentane-petroleum ether (40.degree.-60.degree. C.) (1:2, 30 mL). The 
resultant solution was cooled at -70.degree. C. for 10 minutes and the 
crystalline compound that was formed was quickly collected by filtration 
and washed with more cold petroleum ether (10 mL). This crystalline 
compound, isolated in 12.5% yield, was found to consist of one isomer as 
indicated by .sup.1 H NMR and .sup.13 C NMR spectroscopy: m.p. 
78.5.degree.; .alpha.!.sub.D +31.7.degree. (c, 0.984, CHCl.sub.3); .sup.1 
H NMR (CDCl.sub.3) .delta. 0.77 (3H), 0.91 (6H), 1.00-1.15 (2H), 1.40-2.10 
(6H), 3.56 (1H), 3.82 (1H), 4.79 (1H), 5.62 (1H); .sup.13 C NMR 
(CDCl.sub.3) .delta. 16.7, 21.2, 22.5, 23.8, 26.7, 30.0, 32.0, 34.6, 41.1, 
47.6, 77.7, 168.1, 172.9. 
EXAMPLE 6 
(1'R,2'S,5'R)-MENTHYL-5S-HYDROXY-1,3-OXATHIOLANE-2S-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5R-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5S-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5R-HYDROXY-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR22## 
A freshly prepared solution of disiamylborane (13.4 mmol, 0.5M in THF) was 
added via canula to a stirred solution of a 1:1 mixture of the menthyl 
ester carboxylate of formula (XVII) (1.28 g, 4.47 mmol) in THF (10 mL) at 
0.degree. C. under an argon atmosphere. The resulting clear solution was 
stirred for 15 minutes at 0.degree. C. and 18 hours at ambient 
temperature. The reaction was quenched with methanol (5 mL), concentrated, 
and diluted with methylene chloride (20 mL). The resultant solution was 
washed with brine (5.times.2 mL) and dried over anhydrous magnesium 
sulfate. Removal of the solvent gave a clear oil. Subjecting this material 
to silica gel column chromatography (EtOAc-hexanes, 1:2, V/V) gave 0.65 g 
(50%) of the expected lactols in four diastereomeric forms: .sup.1 H NMR 
(CDCl.sub.3) .delta. 0.71-2.09 (m, 18H), 3.01-3.09 (m, 1H), 3.24-3.33 (m, 
1H), 4.66-4.83 (m, 1H), 5.53-5.59 (m, 1H), 5.88-6.09 (m, 1H). 
EXAMPLE 7 
(1'R,2'S,5'R)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE, 
(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR23## 
The four title compounds were prepared as a mixture by the following two 
methods. 
Method A 
Lactols of formula (XVIII) (0.65 g, 2.25 mmol) were dissolved in anhydrous 
pyridine (1.5 mL) and methylene chloride (5 mL). Acetyl chloride (0.5 mL, 
7.0 mmol) was slowly added to this solution at 0.degree. C. The resulting 
white suspension was stirred at ambient temperature for 3 hours. The 
reaction was then quenched with saturated aqueous ammonium chloride 
solution (1 mL). The mixture was extracted with methylene chloride 
(5.times.2 mL) and the combined extract was concentrated to give a brown 
gummy material. This material was subjected to column chromatography 
(EtOAc-hexane, 1:3 V/V) to provide 0.3 g of the four acetates as a light 
yellow oil: .sup.1 H NMR (CDCl.sub.3) .delta. 0.75 (d, 6H, J=7 Hz), 0.78 
(d, 6H, J=7 Hz), 0.88-0.94 (m, 24H), 0.97-2.03 (m, 36H), 2.10 (s, 9H), 
2.13 (s, 3H), 3.15 (d, 2H, J=12 Hz), 3.23-3.30 (m, 4H), 3.42 (dd, 1H, J=4, 
12 Hz), 3.44 (dd, 1H, J=4, 12 Hz), 4.65-4.75 (m, 4H), 5.61 (s, 1H), 5.62 
(s, 1H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 4H). 
Method B 
A solution of dicyclohexyl-carbodiimide (21.86 g, 0.106 mol) in 
dichloromethane (100 mL) was added to a 500 mL round bottom flask 
containing a solution of trans- and cis- 
5-acetoxy-1,3-oxathiolane-2-carboxylic acid (X) (18.5 g, 0.096 mol), 
(1R,2S,5R)-(-)-menthol (16.5 g, 0.106 mol), and 4-dimethylaminopyridine 
(1.17 g, 9.63 mmol) in dichloromethane (200 mL) at 0.degree. C. The 
resulting thick white slurry was stirred at room temperature for 3 hours 
at which time methanol (4.0 mL) and glacial acetic acid (2.0 mL) were 
added. After stirring for 10 minutes, the reaction mixture was diluted 
with hexanes (200 mL) and filtered through Celite. Subsequent removal of 
the solvent provided 32.5 g of the crude product. This substance was 
redissolved in hexanes (100 mL), filtered through Celite and concentrated 
to yield 30.5 g of material which was further purified by column 
chromatography (eluent: 100% hexanes to 5% EtOAc-hexanes) to give 5.5 g of 
a mixture (ca. 1:1) of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate; 10.28 g 
of a material which contained mainly the above two diastereomers along 
with (1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate; 7.6 g of 
a random mixture of the above four diastereomers; and 2.2 g of a mixture 
(ca. 1:1) of 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate. 
EXAMPLE 8 
(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR24## 
(1'R,2'S,5'R)-Menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate was 
prepared by the following three methods. 
Method A 
A mixture of 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate (5.5 g) 
obtained from Example 7 was dissolved in petroleum ether 
(40.degree.-60.degree. C.) containing a minimum amount of diethyl ether 
and cooled in a dry ice-acetone bath. The white solid precipitate was 
immediately collected by suction filtration to give 1.6 g of (1'R 
2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate: m.p. 
105.2.degree. C.; .alpha.!.sub.D -60.degree. (c, 0.51, CHCl.sub.3); 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (d, 3H, J=7 Hz), 0.91 (d, 3H, J=7 
Hz), 0.92 (d, 3H, J=7 Hz), 0.86-2.06 (m, 9H), 2.10 (s, 3H), 3.16 (d, 1H, 
J=12 Hz), 3.44 (dd, 1H, J=4, 12 Hz), 4.74 (dt, 1H, J=5, 12 Hz), 5.63 (s, 
1H), 6.79 (d, 1H, J=4 Hz); .sup.13 C NMR (CDCl.sub.3) .delta. 16.16, 
20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24, 40.62, 47.07, 
76.11, 79.97, 99.78, 168.60, 169.68. 
Method B 
A mixture of the four diastereomers of formula (X) (300 mg) was dissolved 
in n-pentane containing a minimum amount of diethyl ether and was kept at 
-20.degree. C. for 24 hours. The white needles formed were filtered 
quickly while cold to give 25 mg of material. The substance thus isolated 
was found to be identical in all respects with those obtained by Method A 
or C. 
Method C 
A solution of dicyclohexylcarbodiimide (1.362 g, 6.6 mmol) in 
dichloromethane (5 mL) was added to a 50 mL round bottom flask containing 
a solution of trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (1.16 g, 
6.04 mmol), (1R,2S,5R)-(-)-menthol (1.038 g, 6.60 mmol), and 
4-dimethylaminopyridine (75 mg, 0.62 mmol) in dichloromethane (10 mL) at 
0.degree. C. The resulting white slurry was stirred at room temperature 
for 3 hours at which time methanol (0.2 mL) and glacial acetic acid (0.2 
mL) were added. After stirring for 10 minutes, the reaction mixture was 
diluted with hexanes (25 ml), filtered through Celite, and concentrated. 
The crude product thus obtained was dissolved in hexanes (25 mL), filtered 
through Celite and concentrated to provide 1.98 g (100%) of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate and 
(1'R,2'S,5'R) -menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate: .sup.1 H 
NMR (CDCl.sub.3) .delta. 0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 
0.85-0.92 (m, 12H), 0.95-2.19 (m, 18H), 2.10 (s, 6H), 3.15 (d, 2H, J=12 
Hz), 3.42 (dd, 1H, J=4, 12 Hz), 3.44 (dd, 1H, J=4, 12 Hz),4.74 (dt, 2H, 
J=5, 12 Hz), 5.61 (s, 1H), 5.62 (s, 1H), 6.65 (s, 2H) 
The above mixture of diastereoisomers was dissolved in petroleum ether 
(40.degree.-60.degree. C.) containing a minimum amount of diethyl ether 
and was cooled in a dry ice-acetone bath. The white solid precipitate was 
immediately collected (620 mg) by suction filtration. This material was 
recrystallized again under the same conditions to yield 450 mg of a white 
solid. This compound was found to be identical in all respects to those 
prepared using either method A or method B. 
EXAMPLE 9 
(1'S,2'R,5'S)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR25## 
A solution of dicyclohexylcarbodiimide (491 mg, 2.38 mmol) in 
dichloromethane (7 mL) was added to a 50 mL round bottom flask containing 
a solution of trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (IX) (416 
mg, 2.2 mmol), (1S,2R,5S)-(+)-menthol (372 mg, 2.38 mmol), and 
4-dimethylamino-pyridine (26 mg, 0.21 mmol) in dichloromethane (5 mL) at 
0.degree. C. The resulting thick slurry was stirred at room temperature 
for 3 hours at which time methanol (0.2 mL) and glacial acetic acid (0.2 
mL) were added. After stirring for 10 minutes, the mixture was diluted 
with hexanes (25 mL), filtered through Celite, and concentrated. The crude 
product obtained was dissolved in hexanes (25 mL), filtered through 
Celite, and concentrated to produce 0.715 mg (100%) of two diastereomers, 
namely (1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate: .sup.1 H 
NMR (CDCl.sub.3) .delta. 0.75 (d, 6H, J=7 Hz), 0.85-0.92 (m, 12H), 
0.95-2.19 (m, 18H), 2.10 (s, 6H), 3.15 (d, 2H, J=12 Hz), 3.42 (dd, 1H, 
J=4, 12 Hz), 3.44 (dd, 1H, J=4, 12 Hz), 4.72 (dt, 2H, J=5, 12 Hz) 5.61 (s, 
1H), 5.62 (s, 1H), 6.65 (S, 2H). 
The above diastereomeric acetoxy menthyl esters mixture was dissolved in 
petroleum ether (40.degree.-60.degree. C.) containing a minimum amount of 
diethyl ether and was cooled in a dry ice-acetone bath. The white solid 
precipitate was immediately collected (200 mg) by suction filtration. This 
material was recrystallized again under the same conditions to yield 130 
mg (34% based on one enantiomer) of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2S-carboxylate: m.p. 
104.2.degree. C.; .alpha.!.sub.D +59.2.degree. (c, 1.02, CHCl.sub.3); 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (d, 3H, J=7 Hz), 0.91 (d, 3H, J=7 
Hz), 0.92 (d, 3H, J=7 Hz), 0.86-2.06 (m, 9H), 2.10 (s, 3H), 3.16 (d, 1H, 
J=12 Hz), 3.44 (dd, 1H,J=4, 12 Hz), 4.74 (dt, 1H, J=5, 12 Hz), 5.63 (s, 
1H), 6.79 (d, 1H, J=4 Hz); .sup.13 C NMR (CDCl.sub.3) .delta. 16.16, 
20.74, 21.11, 21.97, 23.29, 26.08, 31.38, 34.13, 37.24, 40.62, 47.07, 
76.11, 79.96, 99.78, 168.60, 169.68. 
EXAMPLE 10 
(1'R,2'S,5'R)-MENTHYL-5R-ACETOXY-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR26## 
(1'R,2'S,5'R)-Methyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate was prepared 
by the following two methods. 
Method A 
A saturated solution of a mixture of the four diastereomers (12.28 g), 
obtained in Example 7, was prepared in petroleum ether containing a 
minimum amount of diethyl ether and was kept at -20.degree. C. for 72 
hours. The white crystalline solid produced was isolated by filtration to 
give 1.6 g of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate: m.p. 
110.2.degree. C.; .alpha.!.sub.D -177.degree. (c, 0.7, CHCl.sub.3); 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.75 (d, 3H, J=7 Hz), 0.88 (d, 3H, J=7 
Hz), 0.92 (d, 3H, J=7 Hz), 0.97-2.02 (m, 9H), 2.12 (s, 3H), 3.22 (d, 1H, 
J=11 Hz), 3.29 (dd, 1H J=4, 11 Hz), 4.74 (dr, 1H, J=4, 11 Hz), 5.63 (s, 
1H), 6.65 (d, 1H, J=3 Hz); .sup.13 C NMR (CDCl.sub.3) .delta. 16.9, 20.69, 
21.19, 21.95, 23.29, 26.10, 31.34, 34.0, 37.62, 40.32, 46.82, 75.69, 
80.20, 99.36, 168.55, 170.23. 
Method B 
A solution of dicyclohexylcarbodiimide (118 mg, 0.572 mmol) in 
dichloromethane (5 mL) was added to a 25 mL round bottom flask containing 
a solution of cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (100 mg, 
0.52 mmol), (1R,2S,5R)-(-)-menthol (85 mg, 0.54 mmol), and 
4-dimethyl-aminopyridine (DMAP) (8 mg, 0.053 mmol) in dichloromethane (10 
ml) at 0.degree. C. The resulting white slurry was stirred at room 
temperature for 3 hours at which time methanol (0.1 mL) and glacial acetic 
acid (0.1 mL) was added. After stirring for 10 minutes, the mixture was 
diluted with hexanes (15 mL), filtered through Celite, and concentrated. 
The crude product obtained was dissolved in hexanes (15 mL), filtered 
through Celite, and concentrated to yield 170 mg (100%) of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate and 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate: .sup.1 H 
NMR (CDCl.sub.3) .delta. 0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 
0.88-0.94 (m, 12H), 0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 
3.23-3.30 (m, 4H), 4.65-4.75 (m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 
2H). 
The above mixture of diastereomers was recrystallized from petroleum ether 
(40.degree.-60.degree. C.) and a minimum amount of diethyl ether at room 
temperature. The white crystalline material formed was collected (95 mg) 
by filtration. This material was recrystallized again from diethyl 
ether-petroleum ether to yield 74 mg (78% based on one enantiomer) of 
(1'R,2'S,5'R) menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate. 
EXAMPLE 11 
(1'S,2'R,5'S)-MENTHYL-5S-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR27## 
A solution of dicyclohexylcarbodiimide (1.588 g, 7.7 mmol) in 
dichloromethane (7 mL) was added to a 50 ml round bottom flask containing 
a solution cis-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (1.36 g, 7 
mmol), (1S,2R,5S)-(+)-menthol (1.216 g, 7.7 mmol), and 
4-dimethylamino-pyridine (85 mg, 0.7 mmol) in dichloromethane (16 mL) at 
0.degree. C. The resulting thick slurry was stirred at room temperature 
for 3 hours. The reaction was quenched with methanol (0.4 mL) and glacial 
acetic acid (0.4 mL) and the mixture was stirred for 10 min. The resultant 
mixture was diluted with hexanes (25 mL), filtered through a pad of 
Celite, and concentrated. The crude material thus obtained was redissolved 
in hexanes (25 mL) and filtered through Celite. Removal of the solvent 
under reduced pressure yielded 2.3 g of a white solid (100%) which 
consisted of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate and 
(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate: .sup.1 H 
NMR (CDCl.sub.3) .delta. 0.75 (d, 3H, J=7 Hz), 0.78 (d, 3H, J=7 Hz), 
0.88-0.94 (m, 12H), 0.97-2.03 (m, 18H), 2.10 (s, 3H), 2.13 (s, 3H), 
3.23-3.30 (m, 4H), 4.65-4.74 (m, 2H), 5.63 (s, 1H), 5.64 (s, 1H), 6.64 (m, 
2H). 
The above mixture of diastereomers was recrystallized from petroleum ether 
(40.degree.-60.degree. C.) and a small amount of diethyl ether at room 
temperature to give 1.3 g of a white solid. This material was 
recrystallized again from diethyl ether-petroleum ether 
(40.degree.-60.degree. C.) to give 900 mg (78% based on one enantiomer) of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate: m.p. 
110.2.degree. C.; .alpha.!.sub.D +177.degree. (c, 1.0, CHCl.sub.3); 
.sup.1 H NMR (CDCl.sub.3) .delta. 0.75 (d, 3H, J=7 Hz), 0.89 (d, 3H, 
J=7Hz), 0.92 (d, 3H, J=7 Hz), 0.98-2.02 (m, 9H), 2.12 (s, 3H), 3.22 (d, 
1H, J=11 Hz), 3.29 (dd, 1H, J=4, 11 Hz), 4.74 (dt, 1H, J=11, 4 Hz), 5.63 
(s, 1H), 6.65 (d, 1H, J=3 Hz); .sup.13 C NMR (CDCl.sub.3) .delta. 16.9, 
20.69, 21.19, 21.95, 23.29, 26.10, 31.34, 34.09, 37.62, 40.32, 46.82, 
75.79, 80.20, 99.36, 168.55, 170.23. 
EXAMPLE 12 
(1'R,2'S,5'R)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR28## 
t-Butyl-dimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.79 mmol) was 
added to a suspension of cytosine (0.27 g, 2.5 mmol) in CH.sub.2 Cl.sub.2 
(2 mL) containing 2,4,6-collidine (0.65 ml, 4.92 mmol) at room 
temperature. The resultant mixture was stirred for 15 minutes and a clear 
solution was produced. A solution of 
(1'R,2'S,5'R)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (0.66 g, 
1.99 mmol) in methylene chloride (1.5 mL) was added to the mixture and 
stirring was continued for 5 minutes. Iodotrimethylsilane (0.31 mL, 2.18 
mmol) was introduced dropwise and a white precipitate was produced when 
the addition was completed. The reaction mixture was allowed to stir for 
18 hours. The reaction was quenched by addition of a saturated aqueous 
solution of Na.sub.2 S.sub.2 O.sub.3 (10 mL) and CH.sub.2 Cl.sub.2 (30 
mL). The organic layer was separated and washed with brine (2.times.10 
mL). The solvent was removed in vacuo to give a viscous oil which was 
suspended in diethyl ether (30 mL). To this suspension was added a 
saturated aqueous solution of NaHCO.sub.3 (20 mL) with vigorous stirring. 
A white precipitate appeared and the resultant suspension was diluted with 
hexanes (10 mL). The precipitate was collected by filtration to give 0.57 
g (75%) of a white solid. The .sup.1 H NMR spectrum of this material 
indicated that it was a mixture of the cis- and trans- diastereomers of 
the expected nucleoside in a 23:1 ratio. 
This product was purified further by recrystallization from 
EtOAc-hexanes-MeOH: .alpha.!.sub.D -144.degree. (c, 1.02, CHCl.sub.3); 
m.p. 219.degree. C. (decomposed); .sup.1 H NMR (CDCl.sub.3) .delta. 0.76 
(d, 3H, J=7 Hz), 0.85-0.94 (m, 6H), 1.02-1.10 (m, 2H), 1.42-2.06 (m, 7H), 
3.14 (dd, 1H, J=6.6, 12.1 Hz), 3.54 (dd, 1H, J=4.7, 12.1 Hz), 4.72-4.78 
(m, 1H), 5.46 (s, 1H), 5.99 (d, 1H, J=7.5 Hz), 8.43 (d, 1H, J=7.6 Hz); 
.sup.13 C (CDCl.sub.3) .delta. 16.1, 20.7, 21.9, 23.2, 26.4, 31.4, 34.0, 
36.3, 40.7, 47.1, 76.7, 78.4, 90.3, 94.6, 141.8, 155.4, 165.6, 169.8. 
EXAMPLE 13 
(1'S,2'R,5'S)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR29## 
2,4,6-Collidine (0.317 mL, 2.4 mmol) and t-butyldimethylsilyl 
trifluoromethanesulfonate (0.551 mL, 2.4 mmol) were added successively to 
a suspension of cytosine (133.3 mg, 1.2 mmol) in CH.sub.2 Cl.sub.2 (1 mL) 
at room temperature under an argon atmosphere. The resultant mixture was 
stirred for 15 minutes to produce a clear solution. A solution of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (330 mg, 1 
mmol) in CH.sub.2 Cl.sub.2 (0.5 mL) was introduced, followed by 
iodotrimethylsilane (0.156 ml, 1.1 mmol). The resultant mixture was 
stirred for 3 hours. The mixture was diluted with CH.sub.2 Cl.sub.2 (20 
mL) and washed successively with saturated aqueous NaHSO.sub.3, water, and 
brine. The solvent was evaporated and the residue was taken up in 
ether-hexanes (1:1, 10 mL) and saturated aqueous NaHCO.sub.3 (2 mL). 
Stirring was continued for 15 minutes. The aqueous layer was removed and 
the organic phase was centrifuged to give a white solid which was washed 
with hexanes (3.times.5 mL) and dried under vacuum. This substance, namely 
(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2R-carboxylate 
(380 mg, 100%) was contaminated with about 3% of 
(1'S,2'R,5'S)-menthyl-5R-(cytosin-1"-1,3-oxathiolan-2R-carboxylate (as 
indicated by its .sup.1 H NMR spectrum), was recrystallized from MeOH to 
give 
(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate: 
.alpha.!.sub.D -58.degree. (c, 0.506, CHCl.sub.3); m.p.: 235.degree. C. 
(decomposed)); .sup.1 H NMR (CDCl.sub.3) .delta. 0.80 (3H), 0.92 (6H), 
1.06 (2H), 1.37-2.10 (7H), 3.11 (1H), 3.55 (1H), 4.77 (1H), 5.47 (1H), 
5.79 (1H), 6.49 (1H), 8.37 (1H); .sup.13 C NMR (CDCl.sub.3) .delta. 6.8, 
21.3. 22.5, 23.9, 26.8, 32.0, 34.6, 37.0, 40.7, 47.4, 77.3, 79.3, 90.9, 
95.3, 142.9, 155.1, 164.9, 170.1. 
EXAMPLE 14 
(1'R,2'S,5'R)-MENTHYL-5R-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR30## 
2,4,6-collidine (0.317 mL, 2.4 mmol) and t-butyldimethylsilyl 
trifluoromethanesulfonate (0.551 mL, 2.4 mmol) were added successively to 
a suspension of cytosine (133.3 mg, 1.2 mmol) in CH.sub.2 Cl.sub.2 (1 mL) 
at room temperature under an argon atmosphere. The resultant mixture was 
stirred for 15 minutes and a clear solution was obtained. A solution of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolan-2S-carboxylate (330 mg, 1 
mmol) in CH.sub.2 Cl.sub.2 (0.5 mL) was introduced, followed by 
iodotrimethylsilane (0.156 mL, 1.1 mmol). Stirring was continued for 3 
hours. The mixture was diluted with CH.sub.2 Cl.sub.2 (20 mL) and washed 
successively with saturated aqueous NaHSO.sub.3, water, brine and then was 
concentrated. The residue was taken up in ether-hexanes (1:1, 10 mL) and 
saturated aqueous NaHCO.sub.3 (2 mL) and was stirred at room temperature 
for 15 minutes. The aqueous layer was removed and the organic phase was 
centrifuged to yield a white solid which was washed with hexanes 
(3.times.5 mL) and then dried under vacuum. The product 
(1'R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate 
(336.3 mg, 88%) contained about 6% of 
(1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate 
(NMR). This material was recrystallized from MeOH to give the desired 
product: .alpha.!.sub.D +56.degree. (c, 1.08, CHCl.sub.3); m.p.: 
235.degree. C. (decomposed); .sup.1 H NMR (CDCl.sub.3) .delta. 0.80 (3H) 
0.91 (6H), 1.00 (2H), 1.37-2.10 (7H), 3.11 (1H), 3.55 (1H), 4.77 (1H), 
5.47 (1H), 5.79 (1H), 6.49 (1H), 8.37 (1H); .sup.13 C NMR (CDCl.sub.3) 
.delta. 16.8, 21.3. 22.5, 23.9, 26.8, 32.0, 34.6, 36.8, 40.7, 47.4, 77.1, 
78.8, 90.9, 95.6, 141.9, 156.3, 166.6, 170.2. 
EXAMPLE 15 
(1'S,2'R,5'S)-MENTHYL-5R-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR31## 
2,4,6-collidine (0.106 mL, 0.8 mmol) and t-butyldimethylsilyl 
trifluoromethanesulfonate were added successively to a suspension of 
cytosine (44 mg, 0.4 mmol) in CH.sub.2 Cl.sub.2 (0.5 mL) at room 
temperature under an argon atmosphere. Stirring was continued at room 
temperature for 15 minutes and a clear solution was produced. A solution 
of (1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolan-2S-carboxylate (110 mg, 
0.33 mmol) in CH.sub.2 Cl.sub.2 (0.3 mL) was added, followed by 
iodotrimethylsilane (0.052 mL, 0.36 mmol). The resultant mixture was 
stirred at room temperature overnight and then was diluted with CH.sub.2 
Cl.sub.2 (10 mL). The mixture was washed successively with saturated 
aqueous NaHSO.sub.3, water, brine and concentrated under reduced pressure. 
The residue was taken up in ether-hexanes (1:1, 5 mL) and saturated 
aqueous NaHCO.sub.3 (1 mL) and stirring was continued at room temperature 
for 20 minutes. The aqueous layer was removed and the white solid 
suspended in the organic phase was collected by centrifugation. This solid 
was washed with hexanes (3.times.5 mL) and dried under vacuum to provide 
65 mg (51.2%) of 
(1'S,2'R,5'S)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate 
contaminated with approximately 5% of 
(1'S,2'R,5'S)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolan-2S-carboxylate as 
indicated by .sup.1 H NMR spectroscopy. Recrystallization of the crude 
material from MeOH-Et.sub.2 O gave the desired product: m.p. 
210.degree.-211.degree. C.; .alpha.!.sub.D +179.degree. (c, 0.66, 
CHCl.sub.3); .sup.1 H NMR (CDCl.sub.3) .delta. 0.77 (3H) 0.92 (6H), 1.00 
(2H), 1.37-2.10 (6H), 3.14 (1H), 3.55 (1H), 4.76 (1H), 5.46 (1H), 5.88 
(1H), 6.46 (1H), 8.38 (1H); .sup.13 C NMR (CDCl.sub.3) .delta. 16.8, 21.3. 
21.8, 22.5, 23.9, 26.7, 31.9, 34.7, 38.7, 40.9, 47.4, 76.4, 80.8, 100.0, 
169.1, 170.8 
The washings and the supernatant were combined and washed with 1N HCl, 
water, brine, and then was dried over Na.sub.2 SO.sub.4. Evaporation of 
the solvent yielded 53 mg (48%) of unreacted 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolan-2S-carboxylate. 
EXAMPLE 16 
2R-HYDROXYMETHYL-5S-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE 
##STR32## 
A solution of 
(1'R,2'S,5'R)-menthyl-5S-(cytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate 
(67 mg, 0.18 mmol) in THF (1 mL) was slowly added to a stirred suspension 
of lithium aluminum hydride (19 mg, 0.5 mmol) in THF (2 mL) at ambient 
temperature under an argon atmosphere. Stirring was continued for 30 
minutes. The reaction was then quenched with methanol (3 mL), followed by 
the addition of silica gel (5 g). The resultant slurry was stirred for 30 
minutes and then was transferred to a short column packed with Celite and 
silica gel and was eluted with a 1:1:1 mixture of EtOAc-hexane-methanol 
(50 mL). The eluate was concentrated and subjected to silica gel column 
chromatography (EtOAc-hexane-methanol, 1:1:1) to give a gummy solid. This 
solid was dried azeotropically with toluene to give 38 mg (94%) of the 
desired product: .alpha.!.sub.D -122.degree. (c, 1.01, MeOH); m.p. 
128.degree.-130.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta. 3.05 (dd, 
1H, J=4.3, 11.9 Hz) 3.42 (dd, 1H, J=5.3, 11.9 Hz), 3.76-3.89 (m, 2H), 
5.19-5.21 (m, 1H), 5.81 (d, 1H, J=7.6 Hz), 6.20-6.23 (m, 1H), 7.01-7.16 
(brm, 2H, exchangeable), 7.98 (d, 1H, J=7.5 Hz); .sup.13 C (CD.sub.3 OD) 
.delta. 38.5, 64.1, 88.0, 88.9, 95.7, 142.8, 157.9, 167.7. 
EXAMPLE 17 
2S-HYDROXYMETHYL-5R-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE 
##STR33## 
A solution of 
(1'R,2'S,5'R)-menthyl-5R-(cytosin-1"-yl)-1,3-oxathiolane-2S-carboxylate 
(102 mg, 0.27 mmol) in THF (3 mL) was slowly added to a stirred suspension 
of lithium aluminum hydride (20 mg, 0.54 mmol) in THF (2 mL) at ambient 
temperature under an argon atmosphere. Stirring was continued for 30 
minutes and the reaction was quenched with methanol (5 mL), followed by 
the addition of silica gel (7 g). The resultant slurry was stirred for 30 
minutes, transferred to a short column packed with Celite and silica gel 
and was eluted with a 1:1:1 mixture of EtOAc-hexane-MeOH (50 mL). The 
eluate was concentrated and subjected to silica gel column chromatography 
(EtOAc-hexane-MeOH, 1:1:1) to provided a gummy solid which was dried 
azeotropically with toluene to give 50 mg (82%) of a white solid as the 
product: .alpha.!.sub.D +125.degree. (c, 1.01, MeOH); m.p. 
130.degree.-132.degree. C.; .sup.1 H NMR (CD.sub.3 OD) .delta. 3.05 (dd, 
1H, J=4.3, 11.9 Hz), 3.42 (dd, 1H, J=5.3, 11.9 Hz), 3.76-3.89 (m, 2H), 
5.19-5.21 (m, 1H), 5.81 (d, 1H, J=7.6 Hz), 6.20-6.23 (m, 1H), 7.01-7.16 
(brm, 2H, exchangeable), 7.98 (d, 1H, J=7.5 Hz); .sup.13 C (CD.sub.3 OD) 
.delta. 38.5, 64.1, 88.0, 88.9, 95.7, 142.8, 157.9, 167.7. 
EXAMPLE 18 
(1'R,2'S,5'R) 
-MENTHYL-5R-(5'-FLUOROCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2S-CARBOXYLATE 
##STR34## 
To a suspension of 5-fluorocytosine (155 mg, 1.2 mmol) in CH.sub.2 Cl.sub.2 
(1 mL) at room temperature under an argon atmosphere was added, 
successively, 2,4,6-collidine (0.317 mL, 2.4 mmol) and 
t-butyldimethylsilyl trifluoromethane-sulfonate (0.551 mL, 2.4 mmol). The 
resultant mixture was stirred for 15 minutes and a clear solution was 
obtained. A solution of 
(1'R,2'S,5'R)-menthyl-5R-acetoxy-1,3-oxathiolane-2S-carboxylate (330 mg, 1 
mmol) in CH.sub.2 Cl.sub.2 (0.5 mL) was introduced, followed by 
iodotrimethylsilane (0.156 mL, 1.1 mmol). Stirring was continued for 3 
hours. The mixture was diluted with CH.sub.2 Cl.sub.2 (20 mL) and washed 
successively with saturated aqueous NaHSO.sub.3, water, brine and then was 
concentrated. The residue was taken up in ether-hexanes (1:1, 10 mL) and 
saturated aqueous NaHCO.sub.3 (2 mL) and stirred at room temperature for 
15 minutes. The aqueous layer was removed and the organic phase was 
centrifuged to afford a white solid which was washed with hexanes 
(3.times.5 mL) and then dried under vacuum. The product 
(1'R,2'S,5'R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carbo 
xylate (350 mg, 88%) thus obtained contained about 6% of 
(1'R,2'S,5'R)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carbo 
xylate (NMR). This material was recrystallized from MeOH/CH.sub.2 Cl.sub.2 
/benzene to give a crystalline product: .alpha.!.sub.D.sup.26 +22.degree. 
(c 0.19 MeOH); m.p. 216.degree.-218.degree. C., .sup.1 H NMR (CDCl.sub.3) 
.delta. 0.78 (d, 3H, J=7 Hz), 0.91 (t, 6H, J=7.3 Hz), 1.00 (m, 2H), 
1.39-2.04 (m, 7H), 3.12 (dd, 1H, J=6.6 Hz, 6.1 Hz), 3.52 (dd, 1H, J=4.7 
Hz, 6.1 Hz), 4.79 (dr, 1H, J=4.4 Hz, 4.3 Hz), 5.46 (S, 1 H), 5.75 (bs, 1H, 
exchangeable), 6.42 (5t, 1H, J=5.0 Hz), 8.10 (bs, 1H, exchangeable), 8.48 
(d, 1H, J=6.6 Hz); .sup.13 C NMR (CDCl.sub.3 -DMSO-d.sub.6): .delta. 16.7, 
21.2, 22.4, 23.7, 26.6, 31.8, 34.4, 36.6, 40.5, 47.2, 77.1, 79.1, 90.8, 
126.3 (d, J=33 Hz), 137.1 (d, J=244 Hz), 154.2, 158.3 (d, J=15 Hz), 170.1. 
EXAMPLE 19 
(1'S,2'R,5'S)-MENTHYL-5S-(5"-FLUOROCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOX 
YLATE 
##STR35## 
To a suspension of 5-fluorocytosine (180.0 mg, 1.4 mmol) in CH.sub.2 
Cl.sub.2 (1 mL) at room temperature under an argon atmosphere was added, 
successively, 2,4,6-collidine (0.46 mL, 3.5 mmol) and t-butyldimethylsilyl 
trifluoromethane-sulfonate (0.67 mL, 2.9 mmol). The resultant mixture was 
stirred for 15 minutes and a clear solution was obtained. A solution of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (414 mg, 
1.25 mmol) in CH.sub.2 Cl.sub.2 (0.6 mL) was introduced, followed by 
iodotrimethylsilane (0.18 mL, 1.27 mmol). The resultant mixture was 
stirred for 1 hour. The mixture was diluted with CH.sub.2 Cl.sub.2 (20 mL) 
and washed successively with saturated aqueous NaHSO.sub.3, water, and 
brine. The solvent was evaporated and the residue was taken up in 
ether-hexanes (1:1, 10 mL) and saturated aqueous NaHCO.sub.3 (2 mL). 
Stirring was continued for 15 minutes. The aqueous layer was removed and 
the organic phase was centrifuged to give a white solid which was washed 
with hexanes (3.times.5 mL) and dried under vacuum. This substance, namely 
(1'S,2'R,5'S) 
-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate (454 
mg, 91%) contained about 7% of 
(1'S,2'R,5'S)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carbo 
xylate (as indicated by its .sup.1 H NMR sepctrum), was recrystallized from 
benzene CH.sub.2 Cl.sub.2 -MeOH to give the title compound: 
.alpha.!.sub.D.sup.26 -20.degree. (c, 0.072,MeOH); m.p. 
220.degree.-222.degree. C. (decomposed), .sup.1 H NMR (CDCl.sub.3) .delta. 
0.80 (d, 3H, J=7 Hz), 0.90 (t, 6H, J=7 Hz), 1.0 (m, 2H), 1.39-2.04 (m, 
7H), 3.12 (dd, 1H, J=6.6 and 6 Hz), 3.52 (dd, 1H, J=5 and 6 Hz), 4.8 (dt, 
1H, J=4.4 and 4.3 Hz), 5.46 (s, 1H), 5.78 (bs, 1H, exchangeable), 6.42 (t, 
1H, J=5 Hz), 8.1 (bs, 1H exchangeable), 8.5 d, 1H, J=6.6 Hz); .sup.13 C 
(CDCl.sub.3) .delta. 16.2, 20.7, 21.9, 23.3, 26.2, 31.4, 34.0, 36.3, 40.1, 
46.8, 76.7, 78.7, 90.5, 125.9 (d. J=33 Hz), 136.5 (d, J=242 Hz), 153.7, 
158.2 (d, J=14 Hz), 169.6. 
EXAMPLE 20 
2S-HYDROXYMETHYL-5R-(5'-FLUOROCYTOSIN-1'-YL)-1,3-OXATHIOLANE 
##STR36## 
To a suspension of lithium aluminum hydride (10 mg, 0.54 mmol) in THF (1 
mL) at ambient temperature under an argon atmosphere was slowly added a 
solution of 
(1'R,2'S,5'R)-menthyl-5R-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2S-carbo 
xylate (54 mg, 0.135 mmol) in THF (2 mL). The reaction mixture was allowed 
to stir for 30 minutes, then quenched with excess methanol (2 mL), 
followed by the addition of silica gel (3 g). The resultant slurry was 
subjected to silica gel column chromatography (EtOAc-Hexane-MeOH, 1:1:1) 
to provide a gummy solid which was dried azeotropically with toluene to 
give 20.7 mg (63%) of a white solid as the product: .alpha.!.sub.D.sup.26 
+114.degree. (c, 0.12 MeOH); .sup.1 H NMR (DMSO-d6) .delta. 3.14 (dd, 1H, 
J=4.3, 11.9 Hz), 3.42 (dd, 1H J=5.3, 11.9 Hz), 3.76 (m,2H), 5.18 (m, 1H), 
5.42 (t, 1H, J=4.8 Hz), 6.14 (m, 1H), 7.59 (br m, 1H, exchangeable), 7.83 
(br m, 1H exchangeable), 8.20 (d, 1H, J=7.66 Hz). 
EXAMPLE 21 
2R-HYDROXYMETHYL-5S-(5'-FLUOROCYTOSIN-1'-YL)-1,3-OXATHIOLANE 
##STR37## 
To a stirred THF (2 mL) suspension of lithium aluminum hydride (22 mg, 1.13 
mmol) at ambient temperature under an argon atmosphere was slowly added a 
solution of (1'R, 2'S, 
5'R)-menthyl-5S-(5"-fluorocytosin-1"-yl)-1,3-oxathiolane-2R-carboxylate 
(91 mg, 0.23 mmol) in THF (8 mL). The reaction mixture was allowed to stir 
for 2 hours., and was quenched by addition of methanol (3 mL), followed by 
silica gel (5 g). The resultant slurry was stirred for 30 minutes. The 
mixture was then passed through a short pad of Celite and silica gel 
eluted with a 1:1:1 mixture of EtOAc-hexane-Methanol (10.times.5 mL). The 
eluate was concentrated and subjected to silica gel column chromatography 
(EtOAc-hexane-methanol, 1:1:1) to give a gummy solid. This solid was dried 
azeotropically with toluene to give 45 mg (80%) of the desired product: 
.alpha.!.sub.D.sup.26 -26.degree.-119.degree. (c 1.01, MeOH) .sup.1 H NMR 
(DMSO-d6) .delta. 3.14, (dd, 1H, J=4.3, 11.9 Hz), 3.42 (dd, 1H, J=5.3, 
11.9 Hz), 3.76 (m, 2H), 5.18 (m, 1H), 5.42 (t, 1H, J=4.8 Hz), 6.14 (m, 
1H), 7.59 (br m, 1H, exchangeable), 7.83 (br m, 1H exchangeable), 8.20 (d, 
1H J=7.66 Hz). 
EXAMPLE 22 
CIS-2(N-METHYL-N-METHOXYAMINOCARBONYL)-5-(URACIL-1'-YL)-1,3-OXATHIOLANE 
##STR38## 
Trimethylsilyl trifluoromethanesulphonate (TMSOTf) (107 .mu.L, 0,552 mmol) 
was introduced to a stirred suspension of uracil (31 mg, 0.276 mmol) in 
dichloromethane (1.5 mL) containing collidine (73 .mu.L, 0.552 mmol) under 
argon atmosphere. The resultant mixture was stirred for 15 minutes to 
provide a homogeneous solution. A solution of 
trans-2-(N-methyl-N-methoxyaminocarbonyl)-5-acetoxy-1,3-oxathiolane (50 
mg, 0.23 mmol) in dichloromethane (1 mL) was introduced, followed by 
iodotrimethylsilane (TMSI) (33 .mu.L, 0.23 mmol). The reaction was allowed 
to proceed for 2.5 hours and then was quenched with a solution of 
saturated NaHCO.sub.3 and Na.sub.2 S.sub.2 O.sub.3 (1:1). The resulting 
mixture was stirred for 5 minutes and then was transferred to a separatory 
funnel with the aid of more dichloromethane. The aqueous phase was removed 
and the organic layer was washed with saturated Na.sub.2 S.sub.2 O.sub.3, 
water, brine and then was dried (Na.sub.2 SO.sub.4). Evaporation of the 
solvent under reduced pressure afforded the crude product which was 
triturated with EtOAc-Hexane (1:1) to give 54 mg (87%) of the title 
compound as a white solid; .sup.1 H NMR (CDCl.sub.3): .delta. 3.14 (d of 
d, 1H, J=8.0, 11.8 Hz), 3.23 (s, 3H), 3.38 (d of d, 1H, J=4.7, 11.8 Hz), 
3.74 (s, 3H), 5.80 (d, 1H, J=8.2 Hz), 5.82 (s, 1H), 6.44 (d of d, 1H, 
J=4.7, 8.0 Hz), 8.64 (d, 1H, J=8.2 Hz), 9.64 (br s, 1H). 
EXAMPLE 23 
CIS- AND TRANS-2-BENZOYL-5-ACETOXY-1,3-OXATHIOLANE 
##STR39## 
Phenyl glyoxal monohydrate (608 mg, 4.0 mmol) and 
2,5-dihydroxy-1,4-dithiane (304 mg, 2.0 mmol) were heated for ca. 5 
minutes at 65.degree. C. until the reagents melted. The reaction mixture 
was diluted with dichloromethane (40 mL). Pyridine (1.32 mL, 16.0 mmol), 
4-dimethylamino-pyridine (DMAP) (48 mg), and acetyl chloride (0.85 mL, 
12.0 mmol) were added to the stirred solution at 0.degree. C. The reaction 
mixture was stirred at room temperature for 4.5 hours and diluted with 
brine solution (15 mL). The organic layer was separated, washed with 
sodium bicarbonate and brine solutions, dried (sodium sulfate), and 
evaporated to a brown liquid (1.80 g). The residue was purified by silica 
gel chromatography eluting with hexanes:EtOAc (3:1) to yield the trans and 
cis isomers (2.4:1 ratio) (714 mg, 71%); .sup.1 H NMR (CDCl.sub.3) .delta. 
2.0 (s, 3H), 2.14 (s, 3H), 3.15-3.25 (m, 1H), 3.35-3.45 (m, 1H), 6.42 (s, 
1H), 6.51 (s, 1H), 6.7 (m, 1H), 6.9 (m, 1H), 7.4-7.5 (m, 2H), 7.55-7.65 
(m, 1H), 7.9-8.0 (m, 2H). 
EXAMPLE 24 
CIS-2-(1'-PYRROLIDINOCARBONYL)-5-ACETOXY-1,3-OXATHIOLANE 
##STR40## 
To a solution of 5-acetoxy-oxathiolane-2-carboxylic acid (576 mg, 3.0 
mmol), pyridine (0.533 mL, 6.60 mmol), and dichloromethane (20 mL) at 
0.degree. C., was added oxalyl chloride (0.314 mL, 3.6 mmol). The reaction 
was stirred at 0.degree. C. for 30 minutes and then cooled to -70.degree. 
C. at which time pyrrolidine (0.5 mL, 6.0 mmol) was added in one portion. 
The reaction was stirred at room temperature for 2 hours followed by 
addition of 1N HCl (5 mL). The organic layer was separated, washed with 
sodium bicarbonate and brine solutions, dried (sodium sulfate), and 
concentrated to yield 0.851 g of crude product. This residue was purified 
by silica gel chromatography eluting with EtOAc:hexanes (9:1) to give 616 
mg (84%) of the desired product; .sup.1 NMR (CDCl.sub.3) .delta. 1.80-2.00 
(m, 4H), 2.11 (s, 3H), 3.20-3.35 (m, 2H), 3.40-3.55 (m, 4H), 5.76 (s, 1H), 
6.60 (m, 1H). 
EXAMPLE 25 
CIS-2-CARBOMETHOXY-5-(5'-BROMOURACIL-1'-YL)-1,3-OXATHIOLANE 
##STR41## 
Bis-trimethylsilyl-acetamide (4 mL, 16.2 mmol) was added to a suspension of 
5-bromouracil (1.5 g, 7.9 mmol) in dichloromethane (10 mL). The reaction 
was stirred for 30 minutes, yielding a clear solution. Then a 
dichloromethane solution (5 mL) of 
2-carbomethoxy-5-acetoxy-1,3-oxathiolane (1.6 g, 7.8 mmol cis:trans 1:2) 
was added, followed by TMSI (1.1 mL, 7.7 mmol). 
The reaction was stirred at ambient temperature for 18 hours and then 
sequentially treated with saturated aqueous solutions of Na.sub.2 S.sub.2 
O.sub.3 and NaHCO.sub.3 to give a white suspension. The suspension was 
filtered to remove the solid (unreacted base). The filtrate was 
concentrated and triturated with EtOAc-Hex (1:1) to give white solid which 
was filtered, washed and dried to give 0.98 g (38%) of the product. .sup.1 
H NMR (CDCl.sub.3) .delta. 3.2 (dd, 1H, J=7 and 12 Hz), 3.47 (dd, 1H, J=5 
and 12 Hz), 3.87 (s, 1H), 5.50 (s, 1H), 6.42 (dd, 1H, J=5 and 7 Hz), 8.72 
(s, 1H), 9.19 (br s, 1H). 
EXAMPLE 26 
CIS-2-HYDROXYMETHYL-5-(6'-CHLOROURACIL-1'-YL)-1,3-OXATHIOLANE 
##STR42## 
TMSOTf (4.5 mL, 27.3 mmol) was added to a suspension of 
bis-O-silyl-6-chlorouracil (9.5 g, 32.6 mmol) and 
2-carbethoxy-5-acetoxyoxathiolane (6.3 g, 27.4 mmol) in 1,2-dichloroethane 
(40 mL). The resulting clear solution was heated slowly up to 60.degree. 
C. and kept at this temperature for 1 hour, during which time a thick 
precipitate appeared. The reaction was cooled down to ambient temperature 
and the white precipitate was collected after filtration, washed and dried 
to give 3.5 g (42%) of the only cis nucleoside ester product (.sup.1 H 
NMR). To a tetrahydrofuran (THF) (50 mL) suspension of nucleoside ester 
product (2.6 g, 8.5 mmol), under argon atmosphere, was slowly added 
LiBH.sub.4 (0.4 g, 18.6 mmol). The reaction was stirred for 5 hours, then 
quenched with methanol. The solvent was removed, followed by subjecting 
the resulting gummy material to column chromatography (2:2:1, 
EtOAc-Hex-MeOH, v/v) to yield 1.9 g (85%) of the title nucleoside. The 
overall yield of these two transformations was 64%; HPLC purity (96%); mp 
202.degree.-204.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta. 3.09-3.30 
(1H), 3.38-3.47 (1H), 3.60-3.72 (2H), 4.45 (1H), 5.05-5.09 (1H), 5.27 
(1H), 5.59-5.62 (1H), 6.71-6.76 (1H); .sup.13 C NMR (DMSO-d.sub.6) .delta. 
32.6, 63.2, 64.2, 84.7, 87.9, 94.4, 106.6, 128.6, 164.4. 
EXAMPLE 27 
(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARB 
OXYLATE 
##STR43## 
To a stirred suspension of N-4-acetylcytosine (68 mg, 0.4 mmol) in 
dichloromethane (0.5 mL) containing 2,4,6-collidine (105 .mu.L, 0.8 mmol) 
under an argon atmosphere was added trimethylsilyl 
trifluoromethane-sulphonate (155 .mu.L, 0.8 mmol). The resulting mixture 
was stirred for 15 minutes to give a homogeneous solution. The substrate, 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (110 mg, 
0.333 mmol) was introduced into the above solution in one batch. In a 
separate flask equiped with a condensor, a solution of 
hexamethyldisilazane (34 .mu.L, 0.167 mmol) and iodine (42 mg, 0.167 mmol) 
in dichloromethane (0.5 mL) was refluxed under argon atmosphere for 30 
minutes. After it had cooled to room temperature, the purple solution 
formed was transferred, via a syringe, into the mixture containing the 
substrate and silylated base. 
The reaction mixture was kept at room temperature for 7 hours and then was 
quenched with a solution of a 1:1 mixture of saturated NaHCO.sub.3 and 
Na.sub.2 S.sub.2 O.sub.3. The resulting mixture was stirred for 5 minutes 
and then was transferred to a separatory funnel with the aid of more 
dichloromethane. The aqueous phase was removed and the organic layer was 
washed with saturated Na.sub.2 S.sub.2 O.sub.3, water, brine and then was 
dried (Na.sub.2 SO.sub.4). The solvent was removed under reduced pressure 
to provide 153 mg of crude product. To determine the ratio of the 
cis-(1'S,2'R,5'S)-menthyl-5S-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane-2 
R-carboxylate! and 
trans-(1'S,2'R,5'S)-menthyl-5R-(N-4"-acetylcytosin-1"-yl)-1,3-oxathiolane 
-2R-carboxylate! product isomers, the crude product was subjected to .sup.1 
H NMR analysis in CDCl.sub.3. Judging from the signals of the C6 protons 
of the cytosine moiety, the ratio of cis .delta. 8.70 (d, J=7.6 Hz)! to 
trans .delta. 7.79 (d, J=7.6 Hz)! was determined to be 7:1. 
EXAMPLE 28 
CIS-2-CARBOXYL-5-(URACIL-1'-YL)-1,3-OXATHIOLANE 
##STR44## 
Iodotrimethylsilane (118 .mu.L, 0.832 mmol) was added to a stirred 
suspension of bis-trimethylsilyluracil (122 mg, 0.475 mmol) and 
trans-2-carboxyl-5-acetoxy-1,3-oxathiolane (76 mg, 0.396 mmol) in 
dichloromethane (2.5 mL) containing collidine (53 .mu.L, 0.396 mmol). The 
resultant mixture was stirred for 18 hours at room temperature under argon 
atmosphere and then was quenched by the addition of 5 mL of a 0.5M 
solution of sodium carbonate. The aqueous phase was acidified with 1M HCl 
solution to pH 4, followed by extraction with tetrahydrofuran (3.times.6 
mL). The combined extract was dried over MgSO.sub.4 and the solvent was 
removed under reduced pressure. The crude product obtained was triturated 
with dichloromethane to provide a white suspension. The white solid was 
isolated by centrifugation and was dried under vacuum to afford 27 mg of 
the desired product whose .sup.1 H NMR spectrum indicated the presence of 
a small amount of uracil (ca. 10%) and an isomeric purity of .gtoreq.95%. 
The title compound displayed the following spectral characteristics: 
.sup.1 H NMR (DMSO d.sub.6) .delta.: 2.26 (d of d, 1H, J=4.9, 12.3 Hz), 
3.49 (d of d, 1H, J=5.2, 12.4 Hz), 5.57 (s, 1H), 5.71 (d of d, 1H, J=2.2, 
8.0 Hz; this signal collapsed to a doublet on treatment with D.sub.2 O 
(J=8.2 Hz)), 6.29 (t, 1H, J=5.2 Hz), 8.07 (d, 1H, J=8.2 Hz), 11.41 (br s, 
1H, exchanged with D.sub.2 O). 
EXAMPLE 29 
CIS 2-(1'-PYRROLIDINOCARBONYL)-5-(URACIL-1'-YL)-1,3-OXATHIOLANE 
##STR45## 
Iodotrimethylsilane (37 .mu.L, 1 equivalent) was added to a stirred 
solution of cis 2-(1'-pyrrolidinocarbonyl)-5-acetoxy-1,3-oxathiolane (64 
mg, 0.26 mmol) and bis-trimethylsilyluracil (80 mg, 1.2 equivalents) in 
dichloromethane (1.5 mL) under argon atmosphere. The reaction mixture was 
kept for 1 hour and 20 minutes at room temperature. The reaction was 
quenched with a solution of a 1:1 mixture of saturated Na.sub.2 S.sub.2 
O.sub.3 and NaHCO.sub.3 (2 mL), followed by dilution with dichloromethane 
(4 mL). The resultant mixture was stirred for 5 minutes and then was 
transferred to a separatory funnel with the aid of more dichloromethane. 
The aqueous phase was removed and the organic phase was washed with water, 
brine, and dried over anhydrous Na.sub.2 SO.sub.4. Removal of the solvent 
under reduced pressure and subjection of the crude product thus obtained 
to column chromatography (7% MeOH-EtOAc) afforded the 74 mg (95%) of the 
title compound; .sup.1 H NMR (CDCl.sub.3): .delta. 1.85-2.00 (m, 2H), 
2.00-2.15 (m,2H), 3.25-3.70 (m, 6H), 5.61 (s, 1H), 5.80 (d of d, 1H, 
J=2.3, 8.2 Hz), 6.44 (d of d, 1H, J=4.8, 7.0 Hz), 8.29 (br s, 1H), 8.88 
(d, 1H, J=8.1 Hz). 
EXAMPLE 30 
CIS 2-BENZOYL-5-(URACIL-1'-YL)-1,3-OXATHIOLANE 
##STR46## 
Trimethylsilyl trifluoromethanesulphonate (92 .mu.L, 0.475 mmol) was 
introduced to a stirred suspension of uracil (50 mg, 0.238 mmol) in 
dichloromethane (1.5 mL) containing collidine (63 .mu.L, 0.475 mmol) under 
argon atmosphere. The resultant mixture was stirred for 15 minutes to 
provide a homogeneous solution. A mixture (2.4:1, trans:cis) of 
2-benzoyl-5-acetoxy-1,3-oxathiolane (50 mg, 0.198 mmol) was added as a 
solution in dichloromethane (1.5 mL), followed by iodotrimethylsilane (28 
.mu.L, 0.198 mmol). The reaction was allowed to proceed for 22 hours and 
then was quenched with a solution of a 1:1 mixture of saturated 
NaHCO.sub.3 and Na.sub.2 S.sub.2 O.sub.3. The resulting mixture was 
stirred for 5 minutes and then was transferred to a separatory funnel with 
the aid of more dichloromethane. The aqueous phase was removed and the 
organic layer was washed with saturated Na.sub.2 S.sub.2 O.sub.3, water, 
brine and then was dried (Na.sub.2 SO.sub.4). Thin layer chromatography 
analysis of the crude product indicated that small amount of the starting 
material remain unreacted. The crude product was triturated with EtOAc to 
provide 26 mg (43%) of the title compound as a white solid; .sup.1 H NMR 
(DMSO): .delta. 3.19 (d of d, 1H, d of d, J=6.8, 12.1 Hz), 3.60 (d of d, 
1H, J=5.1, 12.2 Hz), 5.77 (d, 1H, J=8.2 Hz), 6.38 (d of d, 1H, J=5.2, 6.9 
Hz), 6.81 (s, 1H), 7.52-7.64 (m, 2H), 7.66-7.76 (m, 1H), 7.94-8.04 (m, 
2H), 8.22 (d, 1H, J=8.1 Hz), 11.44 (br s, 1H). 
EXAMPLE 31 
(1'R,2'S,5'R)-MENTHYL-5S-(CYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR47## 
A 12:1 mixture of (1'R,2'S,5'R)-menthyl 
5S-(N-4"-acetylcytosin-1"-yl)-oxathiolane-2R-oxathiolane carboxylate (cis 
isomer) and (1'R,2'S,5'R)-menthyl 
5R-(N-4"-acetylcytosin-1"-yl)-oxathiolane-2R-oxathiolane carboxylate 
(trans isomer) (47 mg,0.11 mmol) was dissolved in dichloromethane (0.5 mL) 
and 2-propanol (1 mL). Trifluoroacetic acid (0.2 mL) was added to this 
solution and the resultant mixture was heated at 60.degree. C. for 2 hours 
and then was kept at room temperature for 14.5 hours. The reaction mixture 
was diluted with dichloromethane and washed with saturated NaHCO.sub.3 
solution, water, brine, and then was dried (anhydrous Na.sub.2 SO.sub.4). 
The solvent was removed under reduced pressure and the product obtained 
was dried under vacuum to afford 40 mg (95%) of the title compounds. The 
.sup.1 H NMR spectrum of the above material suggested a purity of 
.gtoreq.97%. Based on the signals derived from the C6 hydrogen of the 
cytosine moiety present in both of the isomers, the 12:1 ratio of the cis 
(6 8.38 (d, J=7.3 Hz)! and trans (6 7.48 (d, J=7.3 Hz)! nucleosides was 
maintained. The major compound was obtained by fractional crystallization 
with methanol and displayed physical properties identical to those 
reported in this example. 
EXAMPLE 32 
(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARB 
OXYLATE 
##STR48## 
(1'S,2'R,5'S)-menthyl 5R-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg, 
0.166 mmol) in dichloromethane (0.5 mL) and iodotrimethylsilane (0.026 mL, 
0.166 mmol) were added to monosilylated N-4-acetylcytosine (59 mg, 0.198 
mmol), generated by refluxing N-4-acetylcytosine in 
1,1,1,3,3,3-hexamethyldisilazane (HMDS) overnight in the presence of 
catalytic amount of ammonium sulfate and subsequently removing HMDS, in 
dichloromethane (0.5 mL) under argon atmosphere at room temperature. The 
stirring was continued for 19 hours and thin layer chromatography showed 
almost complete consumption of the starting oxathiolane. The reaction 
mixture was diluted with dichloromethane, washed with saturated aqueous 
sodium bicarbonate, aqueous sodium thiosulfate and brine, dried over 
sodium sulfate, concentrated and dried to afford 70 mg (100%) of crude 
products. .sup.1 H NMR suggested cis:trans ratio at 15:1 and the presence 
of ca. 4.6% of unreacted oxathiolane. .sup.1 H NMR (CDCl.sub.3): 0.78 
(d,3H), 0.80-2.10 (m, 15H), 2.27 (s, 3H), 3.12-3.30 (m, 1H) 3.52-3.78 (m, 
1H), 4.78 (m, 1H), 5.51 (s, 0896H), 5.60 (s, 0.046H), 5.82 (s, 0.058H), 
.delta. 6.42 (t, 0.896H), 6.63 (dd, 0.046 H), 6.68 (d, 0.058H), 7.47 (d, 
0.954H), 7.77 (d, 0.058H), 8.70 (d, 0.896H). The major compound was 
isolated by crystallization from methanol or trituration with 
ethylacetate-ether mixtures. 
EXAMPLE 33 
(1'S,2'R,5'S)-MENTHYL-5S-(N-4"-ACETYLCYTOSIN-1"-YL)-1,3-OXATHIOLANE-2R-CARB 
OXYLATE 
##STR49## 
2,6-lutidine (0.023 mL, 0.199 mmol) and trimethylsilyl 
trifluoromethanesulfonate (0.038 mmol, 0.199 mmol) were added to 
N-4-acetylcytosine (30.5 mg, 0.199 mmol) in dichloromethane (0.2 mL) at 
room temperature under argon atmosphere. The mixture was stirred for 20 
minutes and a solution of 
(1'S,2'R,5'S)-menthyl-5S-acetoxy-1,3-oxathiolane-2R-carboxylate (55 mg, 
0.166 mmol) in dichloromethane (0.3 mL) and iodotrimethyl-silane (0.026 
mL, 0.166 mmol) were introduced successively. The stirring was continued 
for 2.5 hour and thin layer chromatography showed complete consumption of 
the starting oxathiolane. The reaction mixture was diluted with 
dichloromethane, washed with saturated aqueous sodium bicarbonate, aqueous 
sodium thiosulfate and brine, dried over sodium sulfate, concentrate and 
dried to afford 70 mg (100%) of crude products. .sup.1 H NMR suggested 
cis: trans ratio at 10:1 and no other impurity detectable by the spectrum. 
.sup.1 H NMR (CDCl.sub.3): 0.78 (d, 3H), 0.80-2.10 (m, 15H), 2.27 (s, 3H), 
3.16 (dd, 0.91H), 3.25 (d, 0.09H), 3.63 (dd, 0.91H), 3.74 (dd, 0.09H), 
4.78 (m, 1H), 5.51 (s, 0.91H), 5.82 (s, 0.09H); .delta. 6.42 (t, 0.91H), 
6.68 (d, 0.09H), 7.47 (d, 1H), 7.77 (d, 0.09H), 8.70 (d, 0.91H). 
EXAMPLE 34 
CIS- AND TRANS-ISOPROPYL 5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLATE 
##STR50## 
A solution of cis- and trans 5-acetoxy-1,3-oxathiolane-2-carboxylic acid 
(260 mg, 1.3528 mmol) and isopropanol (0.11 mL, 1.3528 mmol) in 
dichloromethane (4 mL) at 0.degree. C. was treated with 
dicyclohexylcarboiimide (DCC) (279 mg, 1.3528 mmol) in dichloromethane (1 
mL) and 4 dimethylaminopyridine (DMAP) (14 mg, 0.135 mmol). The mixture 
was stirred at room temperature overnight, then diluted with ether and 
filtered through a Celite.RTM. pad. The filtrate was concentrated and the 
residue was chromatographed on silica gel with ethyl acetate-hexane to 
give the products as a colorless oil (263 mg, 83%). .sup.1 H NMR 
(CDCl.sub.3): .delta. 1.26 (6H, d); 2.10, 2.11 (3H, s); 3.13-3.46 (2H, m); 
5.05 (1H, m); 5.60, 5.61 (1H, s); 6.63 (0.54H, m); 6.78 (0.46H, d). 
EXAMPLE 35 
CIS-ISOPROPYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE-2-CARBOXYLATE 
##STR51## 
2,4,6-collidine (0.23 mL, 1.74 mmol) and t-butyl-dimethylsilyl 
trifluoromethanesulfonate (0.4 mL, 1.74 mmol) were added to a suspension 
of cytosine (96.7 mg, 0.87 mmol) in dichloromethane (0.8 mL) at room 
temperature under argon atmosphere. The mixture was stirred for 25 minutes 
and a solution of cis:trans (1.2:1) isopropyl 
5-acetoxy-1,3-oxathiolane-2-carboxylate (168 mg, 0.717 mmol) in 
dichloromethane (0.8 mL) and a solution of iodotrimethylsilane (0.114 mL, 
0.788 mmol) were introduced successively. Stirring was continued for one 
hour and the reaction mixture was diluted with dichloromethane, washed 
with saturated aqueous sodium thiosulfate, water and brine, dried over 
sodium sulfate and concentrated. The residue was triturated with 
ether-hexane (1:1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 
mL). The aqueous layer was removed and the remaining mixture was 
centrifuged. 
The solid was washed twice with hexanes and the washings were combined with 
centrifugate, washed with 1N HCl, water and brine, dried and concentrated 
to give the unreacted starting material in virtually pure form (64 mg, 
38%, cis:trans=1:9). The white solid was dried and gave the products as a 
cis:trans mixture in 12:1 ratio (122.6 mg, 60%). .sup.1 H NMR 
(CDCl.sub.3): .delta. 1.30 (t, 6H), 3.11 (dd, 1H), 3.52 (dd, 1H), 5.11 (m, 
1H), 5.45 (s, 1H), 5.82 (d, 1H), 6.47 (dd, 0.92H), 6.72 (m, 0.08H), 7.49 
(d, 0.08H), 8.32 (d, 0.92H). 
EXAMPLE 36 
CIS- AND TRANS-T-BUTYL 5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLATE 
##STR52## 
A solution of cis- and trans- 5-acetoxy-1,3-oxathiolane-2-carboxylic acid 
(176 mg, 0.915 mmol) and t-butanol (0.095 mL, 0.915 mmol) in 
dichloromethane (4 mi,) at 0.degree. C. was treated with DCC (207 mg, 1 
mmol) in dichloromethane (1 mL) and DMAP (11 mg, 0.09 mmol). The mixture 
was stirred at room temperature overnight, then diluted with ether and 
filtered through a Celite.RTM. pad. The filtrate was concentrated and the 
residue was chromatographed on silica gel with ethyl acetate-hexane to 
give the products as a colorless oil (175 mg, 77%). .sup.1 H NMR 
(CDCl.sub.3): .delta. 1.46 (9H, d); 2.07, 2.09 (3H, s); 3.10-3.44 (2H, m); 
5.50, 5.52 (1H, s); 6.60 (0.42H, m); 6.74 (0.58H, d). 
EXAMPLE 37 
CIS-T-BUTYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE-2-CARBOXYXATE 
##STR53## 
2,4,6-collidine (0.187 mL, 1.4 mmol) and t-butyl-dimethylsilyl 
trifluoromethanesulfonate (0.325 mL, 1.4 mmol) were added to a suspension 
of cytosine (78.6 mg, 0.7 mmol) in dichloro-methane (0.6 mL) at room 
temperature under argon atmosphere. The mixture was stirred for 25 minutes 
and a mixture of cis and trans (1:1.4) t-butyl 
5-acetoxy-1,3-oxathiolane-2-carboxylic (146.5 mg, 0.59 mmol) in 
dichloromethane (0.6 mL) and iodotrimethylsilane (0.092 mL, 0.65 mmol) 
were introduced successively. Stirring was continued for one hour and the 
reaction mixture was diluted with dichloromethane, washed with saturated 
aqueous sodium thiosulfate, water and brine, dried over sodium sulfate and 
concentrated. The residue was triturated with ether-hexanes (1:1, 7 mL) 
and saturated aqueous sodium bicarbonate (1.5 mL). The aqueous layer was 
removed and the remaining mixture was centrifuged. The solid was washed 
twice with hexanes and the washings were combined with the centrifugate, 
washed with 1N HCl, water and brine, dried and concentrated to give the 
unreacted starting material in virtually pure form (77 mg, 52.6%, 
cis:trans=1:11). The white solid was dried and gave the products as a 
cis:trans mixture in 16:1 ratio (82.6 mg, 46.4%). .sup.1 H NMR 
(CDCl.sub.3): .delta. 1.50, 1.52 (s, 9H), 3.12 (dd, 0.94H), 3.20 (dd, 
0.06H), 3.52 (dd, 0.94H), 3.72 (dd, 0.06H), 5.37 (s, 0.94H), 5.75 (s, 
0.06H), 5.82 (d, 1H), 6.44 (dd, 0.94H), 6.71 (d, 0.06H), 7.49 (d, 0.06H), 
8.38 (d, 0.98H). 
EXAMPLE 38 
CIS- AND TRANS-2-N,N-DIETHYLAMINOCARBONYL-5-ACETOXY-1,3-OXATHIOLANE 
##STR54## 
A solution of cis- and trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid 
(119 mg, 0.62 mmol) and diethylamine (0.07 mL, 0.68 mmol) in 
dichloromethane (2 ml.) at 0.degree. C. was treated with DCC (140 mg, 0.68 
mmol) in dichloromethane (1 mL) and DMAP (7.6 mg, 0.06 mmol). The mixture 
was stirred at room temperature overnight, then diluted with ether and 
filtered through a Celite.RTM. pad. The filtrate was concentrated and the 
residue was chromatographed on silica gel with ethyl acetate-hexane to 
give the products as a colorless oil (84.5 mg, 55%). .sup.1 H NMR 
(CDCl.sub.3): .delta. 1.10, 1.40 (6H, t); 2.07, 2.10 (3H, s); 3.15-3.56 
(6H, m); 5.80, 5.87 (1H, s); 6.58 (0.53H, m); 6.83 (0.47H, d). 
EXAMPLE 39 
CIS-2-N,N-DIETHYLAMINOCARBONYL-5-(CYTOSIN-1'-YL)-1,3-OXATHIOLANE 
##STR55## 
2,4,6-collidine (0.108 mL, 0.82 mmol) and t-butyl-dimethylsilyl 
trifluoromethanesulfonate (0.188 mL, 0.82 mmol) were added to a suspension 
of cytosine (45.5 mg, 0.41 mmol) in dichloromethane (0.4 mL) at room 
temperature under argon atmosphere. The mixture was stirred for 25 minutes 
and a mixture of cis and trans (1.12:1) 
2-N,N-diethylamindocarbonyl-5-acetoxy-1,3-oxathiolane (84 mg, 0.34 mmol) 
in dichloromethane (0.4 mL) and a solution of iodotrimethylsilane (0.053 
mL, 0.375 mmol) were introduced successively. Stirring was continued for 
one hour and the reaction mixture was diluted with dichloromethane, washed 
with saturated aqueous sodium thiosulfate, water and brine, dried over 
sodium sulfate and concentrated. The residue was triturated with 
ether-hexane (1:1, 7 mL) and saturated aqueous sodium bicarbonate (1.5 
mL). The aqueous layer was removed and the remaining mixture was 
centrifuged. The solid was washed twice with hexanes and the washings were 
combined with centrifugate, washed with 1N HCl, water and brine, dried and 
concentrated to give the unreacted starting material in virtually pure 
form (17 mg, 20%, trans only). The white solid was dried to give the 
products as a cis:trans mixture in 24:1 ratio (47.5 mg, 47.5%). .sup.1 H 
NMR (DMSO-d.sub.6): .delta. 1.04 (t, 3H, J=7 Hz), 1.12 (t, 3H, J=7 Hz), 
3.17 (dd, 1H, J=5 Hz, 9 Hz), 3.30 (m, 4H), 3.53 (dd, 1H, J=5 Hz, 9 Hz), 
5.74 (d, 1H, J=7 Hz), 5.96 (s, 1H), 6.28 (t, 0.96H, J=5 Hz), 6.62 (m, 
0.04H), 7.16 (b.s., NH), 7.22 (b.s., NH), 7.60 (d, 0.04H), 8.46 (d, 0.96H, 
J=7 Hz). 
EXAMPLE 40 
(1'S,2'R,5'S)-MENTHYL-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR56## 
To a mixture of 
(1'S,2'R,5'S)-menthyl-5R-acetoxy-1,3-oxathiolane-2R-carboxylate (2.01 g, 
6.08 mmol) and triethylsilane (9.67 mL, 60.05 mmol) at room temperature 
under argon atmosphere was added trimethylsilyl trifluoromethanesulfonate 
(1.17 mL, 6.04 mmol). The reaction mixture was stirred at room temperature 
for 12 hours, then diluted with dichloromethane, washed with saturated 
aqueous solution of sodium bicarbonate, dried over anhydrous sodium 
sulfate, and evaporated to dryness in vacuo to afford crude product. 
Subsequent chromatography on silica gel using hexane-ethyl acetate as 
eluate gave the product as colourless oil (1.33 g, 80.5%) .sup.1 H NMR 
(CDCl.sub.3):.delta. 0.75-2.10 (m, 15H), 2.97-3.20 (m, 2H), 4.20-4.40 (m, 
4.72 (dt, 1H), 5.45 (s, 1H) .alpha.!.sub.D +104.degree. (c 1.16, 
CHCl.sub.3). 
EXAMPLE 41 
(1'S,2'R,5'S)-MENTHYL-4R-HYDROXY-1,3-OXATHIOLANE-2R-CAROBXYLATE AND 
(1'S,2'R,5'S)-MENTHYL-4S-HYDROXY-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR57## 
A mixture of (1'S,2'R,5'S)-menthyl-1,3-oxathiolane-2R-carboxylate (0.500 g, 
1.84 mmol) and benzoylperoxide (0.489 g, 97%, 1.96 mmol) in 20 mL benzene 
was heated to reflux for 6 hours. The organic solvent was removed in vacuo 
and the residue was diluted with dichloromethane, washed with saturated 
aqueous solution of sodium bicarbonate, dried over anhydrous sodium 
sulfate, and evaporated to dryness in vacuo to afford crude benzoate 
product. Subsequent chromatography by using hexane-ethyl acetate as eluate 
gave the benzoate as a solid (0.21 g, 30.3%). The mixture of the benzoate 
(0.200 g, 0.531 mmol) and potassium carbonate (0.073 g, 0.532 mmol) in 
THF-MeOH-H.sub.2 O (4 mL/5 mL/2 mL) was stirred at 0.degree. C. for 7 
hours and organic solvent was removed in vacuo. The residue was diluted 
with H.sub.2 O (7 mL), extracted with ether (10 mL), acidified with 
aqueous HCl, and extracted with dichloromethane. The dichloromethane layer 
was dried over sodium sulfate and evaporated to dryness in vacuo to afford 
crude product. Subsequent chromatography using hexane ether as eluent gave 
the product as a solid (67 mg, 43.7%) .sup.1 H NMR (CDCl.sub.3):.delta. 
0.75-2.10 (m, 15H), 4.03-4.83 (m, 2H), 5.52-5.75 (m, 2H). 
EXAMPLE 42 
(1'S,2'R,5'S)-MENTHYL-4R-CHLORO-1,3-OXATHIOLANE-2R-CARBOXYLATE AND 
(1'S,2'R,5'S)-MENTHYL-4S-CHLORO-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR58## 
To a mixture of 
(1'S,2'R,5'S)-menthyl-4R-hydroxy-1,3-oxathiolane-2R-carboxylate and 
(1'S,2'R,5'S)-menthyl-4S-hydroxy-1,3-oxathiolane-2R-carboxylate (40 mg, 
0.138 mmol) and methytrifluoromethansulfonyl chloride (18.24 .mu.L, 0.239 
mmol) in dichloromethane (5 mL) at room temperature under argon atmosphere 
was added triethylamine (57.99 mL, 0.416 mmol). The reaction mixture was 
stirred at room temperature for 2 hours then diluted with dichloromethane, 
washed with saturated aqueous solution of sodium bicarbonate, dried over 
anhydrous sodium sulfate, and evaporated to dryness in vacuo to afford 
crude product. Subsequent chromatography by using hexane ether as eluent 
gave the product as two diastereomers (18 mg, 42.3%, 14.6 mg, 34.2%) 
epimeric at C4. .sup.1 H NMR CDCl.sub.3):.delta. 0.75-2.05 (m, 15H), 4.55 
(m, 1H), 4.69 (m, 1H), 5.75 (m, 1H), 5.80 (m, 1H); .delta. 0.75-2.10 (m, 
15H), 4.33 (m, 1H), 4.78 (m, 1H), 5.56 (s, 1H), 5.68 (m, 1H). 
EXAMPLE 43 
CIS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE 
##STR59## 
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 
mg, 2.16 mmol), 85% meta-chloroperbenzoic acid (mCPBA) (68 mg, 3.81 mmol) 
and sodium carbonate (389 mg, 3.67 mmol) in dry dichloromethane (10 mL) 
was stirred under argon for 16 hours at room temperature. The resultant 
suspension was diluted with dichloromethane and water and stirred for 10 
minutes. The aqueous phase was removed and the organic phase was washed 
successively with saturated sodium thiosulfate, water, brine and then was 
dried over anhydrous magnesium sulfate. The solvent was removed under 
reduced pressure and the crude product thus obtained was subjected to 
flash column chromatography (30% EtOAc-Hexanes) to give the title compound 
(11% yield) which displayed the following spectral characteristics; .sup.1 
H NMR (CDCl.sub.3):.delta. 1.31 (t, 3H, J=7.2 Hz), 2.07 (s, 1H), 4.15 (d 
of d, 1H, J=4.5, 9.1 Hz), 4.21-4.29 (m, 3H), 5.42 (s, 1H), 6.39 (d of d, 
1H, J=2.4, 4.5 Hz); .sup.13 C NMR (CDCl.sub.3):.delta. 14.05, 20.97, 
29.69, 71.34, 94.04, 99.80, 167.19, 170.11. 
EXAMPLE 44 
TRANS 2-CARBOETHOXY-4-ACETOXY-1,3-DIOXOLANE 
##STR60## 
A 2.5:1 mixture of cis and trans-2-carboethoxy-4-acetyl-1,3-dioxolane (406 
mg, 2.16 mmol), 85% mCPBA (68 mg, 3.81 mmol) and sodium carbonate (389 mg, 
3.67 mmol) in dry dichloromethane (10 mL) was stirred under argon for 16 
hours at room temperature. The resultant suspension was diluted with 
dichloromethane and water and stirred for 10 minutes. The aqueous phase 
was removed and the organic phase was washed successively with saturated 
sodium thiosulfate, water, brine and then was dried over anhydrous 
magnesium sulfate. The solvent was removed under reduced pressure and the 
crude product thus obtained was subjected to flash column chromatography 
(30% EtOAc-Hexanes) to give the title compound (49% yield) which displayed 
the following spectral characteristics; .sup.1 H NMR (CDCl.sub.3):.delta. 
1.29 (t, 3H, J=7.2 Hz), 2.09 (s, 1H), 4.12 (d of d, 1H, J=0.9, 9.1 Hz), 
4.19-4.31 (m, 3H), 5.53 (s, 1H), 6.48 (d of d, 1H, J=0.9, 3.9 Hz). 
EXAMPLE 45 
CIS AND TRANS 2-CARBOETHOXY-4-(THYMIN-1'-YL)-1,3-DIOXOLANE 
##STR61## 
To a stirred suspension of thymine (44.5 mg, 0.353 mmol) in dichloromethane 
(1 mL) containing 2,6-lutidine (82 .mu.L, 0.706 mmol) under an argon 
atmosphere was added trimethylsilyl trifluoromethanesulphonate (136 .mu.L, 
0.706 mmol). The resulting mixture was stirred for 15 minutes to give a 
homogeneous solution. A solution of the substrate, ethyl 
4-acetoxy-1,3-dioxolane-2-carboxylate (60 mg, 0.294 mmol) in 
dichloromethane (1 mL) and iodotrimethylsilane (42 .mu.L, 0.294 mmol) was 
sequentially introduced into the above solution. The reaction mixture was 
stirred at room temperature for 5 hours and then was quenched with a 
half-saturated solution of Na.sub.2 S.sub.2 O.sub.3 (2 mL), followed by 
dilution with dichloromethane (5 mL). The resulting mixture was stirred 
for 5 minutes and then was transferred to a separatory funnel with the aid 
of more dichloromethane. The aqueous phase was removed and the organic 
layer was washed with saturated Na.sub.2 S.sub.2 O.sub.3, water, 1M HCl, 
brine and then was dried (Na.sub.2 SO.sub.4). The solvent was removed 
under reduced pressure to provide the crude product. This material was 
suspended in dichloromethane (.about.1.5 mL) and then was triturated with 
a 1:1 mixture of EtOAc-Hexane (.about.6 mL) to give 25 mg of the cis 
nucleoside as a white solid; .sup.1 H NMR (DMSO d.sub.6):.delta. 1.23 (t, 
3H, J=7.1 Hz), 1.78 (d, 3H, J=1 Hz), 4.15-4.30 (m, 4H), 4.38 (d of d, 1H, 
J=2.3, 9.8 Hz), 5.33 (s, 1H), 6.33 (d of d, 1H, J=2.3, 5.8 Hz), 7.52 (d, 
1H, J=1.1, Hz), 11.42 (br s, 1H). The triturate was concentrated and 
subjected to column chromatography (70% EtOAc-Hexane) to afford 26 mg of 
the two nucleoside as a 1:1 mixture; .sup.1 H NMR (CDCl.sub.3):.delta. 
1.33 (t, 1.5H, J=7.2 Hz), 1.35 (t, 1.5H, J=7.2 Hz), 1.91-1.99 (two 
overlapping d, 3H), 4.16 (d of d, 0.5H, J=1.9, 9.7 Hz), 4.20-4.38 (m, 3H), 
4.53 (d of d, 0.5H, J=5.8, 9.7 Hz), 5.30 (s, 0.5H), 5.72 (s, 0.5H), 6.44 
(d of d, 0.5H, J=3.3, 5.4 Hz), 6.60 (d of d, 0.5H, J=2.0, 5.8 Hz), 7.10 
(d, 0.5H, J=1.3 Hz), 7.75 (d, 0.5H, J=1.3 Hz), 9.40 (br s, 0.5H), 9.43 (br 
s, 0.5H). 
EXAMPLE 46 
CIS AND TRANS 2-CARBOETHOXY-4-(N-4'-ACETYLCYTOSIN-1'-YL)-1,3-DIOXOLANE 
##STR62## 
To a stirred suspension of N-acetylcytosine (66 mg, 0.430 mmol) in dry 
CH.sub.2 Cl.sub.2 (1.5 mL) under an argon atmosphere was added, 
successively, 2,6-lutidine (100 .mu.L, 0.859 mmol) and trimethylsilyl 
trifluoromethanesulphonate (166 .mu.L, 0.859 mmol). The resultant mixture 
was stirred for 25 minutes to produce a homogeneous solution. A solution 
of a 4:1 mixture of cis and trans-2-carboethoxy-4-acetoxy-1,3-dioxolane 
(73 mg, 0.358 mmol) in CH.sub.2 Cl.sub.2 (1 mL) was then introduced, 
followed by iodotrimethylsilane (51 .mu.L, 0.358 mmol). The reaction was 
allowed to proceed for 16 hours and then was quenched with saturated 
sodium thiosulfate. The resulting mixture was diluted with CH.sub.2 
Cl.sub.2 and was washed successively with saturated sodium thiosulfate, 
water, brine, and then was dried over anhyydrous magnesium sulfate. 
Removal of the solvent under reduced pressure gave the crude product which 
was purified by flash column chromatography (2% MeOH-EtOAc) to afford 44% 
of the title compounds as a 3:1 mixture of the cis and trans isomers; 
.sup.1 H NMR (CDCl.sub.3):.delta. 1.34 (t, 3H, J=7.0 Hz), 2.28 (s, 0.75H), 
2.29 (s, 0.25H), 4.21-4.35 (m, 3H), 4.36 (d of d, 0.75 H, J=5.2, 9.9 Hz), 
4.59 (d of d, 0.25H, J=5.2, 9.9 Hz), 5.39 (s, 0.75H), 5.77 (s, 0.25H), 
6.24 (d of d, 0.75H, J=2.8, 5.1 Hz), 6.39 (d of d, 0.25H, J=1.7, 5.1 Hz), 
7.49 (2 overlapping doublets, 1H), 7.79 (d, 0.25H, J=7.6 Hz), 8.40 (d, 
0.75H, J=7.6 Hz), 9.95 (br s, 1H). 
EXAMPLE 47 
(.+-.)-CIS AND TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID 
##STR63## 
Trans-5-hydroxy-1,3-oxathiolane-2-carboxylic acid (250 g, 1.67 mol) was 
added, in portions, to a stirred solution of acetic anhydride (0.625 L, 
6.62 mol) and methanesulphonic acid (5 mL, 77 mmol) at room temperature. 
The resultant clear solution was stirred at room temperature for 60 
minutes, slowly added to stirred aqueous 0.03M sodium bicarbonate solution 
(2.5L) and then the mixture was stirred for a further 60 minutes. Sodium 
chloride (750 g, 12.83 mol) was added and the mixture was stirred for a 
further 30 minutes, clarified, and then extracted with isopropyl acetate 
(1.times.1.25 L, 3.times.0.625 L). The combined extracts were concentrated 
to 1.25 L under reduced pressure. Xylene (2.5 L) was added and the mixture 
reconcentrated to 1.25 L under reduced pressure. The xylene 
addition/reconcentration procedure was repeated and the resultant 
suspension was cooled to room temperature and stirred for 18 hours. The 
solid was collected by vacuum filtration, washed with xylene (2.times.0.25 
L) and dried, in vacuo, at 40.degree.-45.degree. to give the title 
compound (265 g, 83%) which was shown, by comparison of .sup.1 H NMR 
spectra, to be a 65:35 mixture of the compounds of Examples 3 and 4. 
EXAMPLE 48 
5R-ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLIC ACID, SALT WITH 
1S,2R-.alpha.-(1-AMINOETHYL)BENZENEMETHANOL (1:1) 
##STR64## 
a) A solution of 1S,2R-.alpha.-(1-aminoethyl)benzenemethanol (125.9 g, 0.83 
mol) in isopropyl acetate (0.5L) was added to a stirred solution of (.+-.) 
cis-/trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (Example 47; 400 g, 
2.08 mol), in isopropyl acetate (4.2 L), at room temperature under a 
nitrogen atmosphere. The resultant solution was stirred for 10 minutes, 
seeded with authentic product (0.4 g) and stirred for a further 4 hours at 
room temperature. The suspension was stirred at 15.degree.-18.degree. for 
17 hours and the solid was collected by vacuum filtration, washed with 
isopropyl acetate (1.times.0.4 L, 1.times.0.2 L) and dried, in vacuo, at 
45.degree. to give the title compound (205.9 g, 28%). .alpha.!.sub.D 
+34.degree. (MeOH), mp 151.degree.-2.degree. (decomp), 
.delta.(DMSO-D.sub.6) 0.91 (d, 3H, J=6.8 Hz), 2.05 (s, 3H), 3.04 (d, 1H, 
J=11 Hz), 3.32 (dd, 1H, J=4.2 Hz), 3.40 (dq, 1H, J=6.8, 2.4 Hz), 4.97 (d, 
1H, J=2.4 Hz), 5.34 (s, 1H), ca. 6.4 (br, 1H), 7.2-7.4 (m, 5H), ca. 8.3 
(br, 3H). 
b) A solution of 1S,2R-.alpha.-(1-aminoethyl)benzenemethanol (177 mg, 1.17 
mmol) in isopropyl acetate (1 mL) was added to a stirred solution of 
(.+-.)-trans-5-acetoxy-1,3-oxathiolane-2-carboxylic acid (500 mg, 2.60 
mmol) in isopropyl acetate (6 mL) at 25.degree.-30.degree., and further 
isopropyl acetate (0.5 mL) was added. Crystallisation commenced after 5 
minutes. The suspension was stirred at 25.degree.-30.degree. for 18 hours 
and then the solid was collected by vacuum filtration, washed with 
isopropyl acetate (1 mL) and dried, in vacuo, at 40.degree. to give the 
title compound (353 mg, 40%), as shown by comparison of its .sup.1 H NMR 
spectrum with that of part (a). 
EXAMPLE 49 
(-)-TRANS-5-ACETOXY-1,3-OXATHIOLANE-2-CARBOXYLIC ACID 
##STR65## 
5M-Aqueous hydrochloric acid (126 mL, 0.63 mol) was added to a stirred 
suspension of the compound of Example 48 (180 g, 0.52 mol) in saturated 
aqueous sodium chloride (414 mL) at room temperature. The mixture was 
stirred at room temperature for 30 minutes, cooled to 10.degree. and 
stirred at this temperature for a further 30 minutes. The solid was 
collected by vacuum filtration, washed with chilled water (2.times.90 mL) 
and dried, in vacuo, at 33.degree. to give the title compound (81.3 g, 
81%). 
EXAMPLE 50 
(1'R,2'S,5'R)-MENTHYL-5R ACETOXY-1,3-OXATHIOLANE-2R-CARBOXYLATE 
##STR66## 
a) A solution of oxalyl chloride (66.5 g, 0.52 mol) in dichloromethane (120 
mL) was added over 30 minutes to a stirred cold (-5.degree.) mixture of 
N,N-dimethylformamide (32 mL) and dichloromethane (240 mL), and the 
suspension formed was stirred at -5.degree. to 0.degree. for 30 minutes. 
The compound of Example 49 (80 g, 0.42 mol) was added in portions and the 
resultant yellow solution was stirred at 0.degree. for 45 minutes. This 
solution was added over 60 minutes to a stirred, cold (-5.degree.) 
solution of (1R,2S,5R)-(-)-menthol (65.2 g, 0.425 mol) in dichloromethane 
(200 mL) and pyridine (84 mL, 1.04 mol) and the resultant suspension was 
stirred at 0.degree.-5.degree. for a further 2 hours. 
The reaction mixture was washed with 2M-aqueous hydrochloric acid 
(1.times.240 mL, 1.times.160 mL) and the combined aqueous acidic washes 
were back extracted with dichloromethane (160 mL). The organic phases were 
combined, clarified, and concentrated in vacuo to c.a. 240 mL, 
2,2,4-trimethylpentane (400 mL) was added and the solution concentrated, 
in vacuo, to 240 mL. Crystallisation of the product occurred during the 
distillation. Further 2,2,4-trimethylpentane (400 mL) was added and the 
mixture concentrated to c.a. 700 mL. The stirred suspension was then 
cooled to 5.degree. and aged for 60 minutes. The solid was collected by 
vacuum filtration, washed with 2,2,4-trimethylpentane (2.times.80 mL) and 
dried, in vacuo, at 33.degree. to give the title compound (93.2 g, 68%) as 
shown by comparison of the .sup.1 H NMR spectrum with that of Example 8. 
b) Oxalyl chloride (102 g, 0.80 mol) was added over 20 minutes to a 
stirred, cold (-10.degree.) mixture of N,N-dimethylformamide (63 mL) and 
dichloromethane (840 mL) and the suspension formed was stirred at 
-10.degree. to -6.degree. for 15 minutes. The compound of Example B (140 
g, 0.728 mol) was added and the resultant pale yellow solution was stirred 
at -8.degree. for 20 minutes. (1R,25,SR)-(-)-Menthol (126 g, 0.80 mol) was 
added followed by pyridine (140 mL, 1.73 mol), added over 50 minutes. The 
suspension formed was stirred at -9.degree. for 18 hours and then 1M 
aqueous hydrochloric acid (280 mL) was added. The separated aqueous acid 
phase was extracted with dichloromethane (140 mL) and the combined organic 
phases were washed with 1M aqueous hydrochloric acid (280 mL). The aqueous 
phase was back extracted with dichloromethane (140 mL) and the combined 
organic phases were washed with a solution containing sodium hydrogen 
carbonate (5.6 g) and sodium chloride (28 g) in water (266 mL). The 
aqueous phase was back extracted with dichloromethane (140 mL) and the 
combined organic phases were clarified and concentrated to 560 mL by 
distillation at atmospheric pressure. 2,2,4-Trimethylpentane (700 mL) was 
added and the solution was concentrated, in vacuo, to 700 mL. The 
2,2,4-trimethylpentane addition/reconcentration procedure was repeated, 
and the resultant solution was cooled to 17.degree. (seeded with authentic 
product (0.7 g) at 34.degree. and 23.degree.). The suspension was stirred 
at 17.degree. for 2 hours and the solid was collected by vacuum 
filtration, washed with 2,2,4-trimethylpentane (2.times.70 mL) and dried, 
in vacuo, at 43.degree. to give the title compound (332 g, 14%) as shown 
by comparison of the .sup.1 H NMR spectrum with that of Example 8). 
While we have presented a number of embodiments of our invention, many 
alternatives, modifications and variations of these embodiments will be 
apparent to those of ordinary skill in the art. Therefore, it will be 
appreciated that the scope of this invention is to be defined by the 
following claims, rather than the specific examples presented above.