Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing compound containing saccharide radical
Patent
1995-02-13
1998-02-03
Lilling, Herbert J.
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing compound containing saccharide radical
435 88, 435131, 435132, 435135, 435155, 435196, 435197, 435280, 435876, 556437, 556449, 560201, 560205, 568763, 568838, C12P 1938, C12P 1940, C12P 900, C12P 702
Patent
active
057143510
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to cyclopentene derivatives and also to their preparation and use.
BACKGROUND OF THE INVENTION
Carbocyclic nucleosides such as Carbovir are of therapeutic value. Their stereospecific synthesis is important.
EP-A-0424064 describes the enantioselective hydrolysis of the activity available in deposits NCIMB 40213 and 40249. See also Taylor et al, J. Chem. Soc. Chem. Comm. (1990) 1120.
SUMMARY OF THE INVENTION
This application concerns the enantiomers of cyclopentene derivatives of structures Ia, Ib, IIa and IIb wherein X (at the 1-position) represents hydrogen or an acyl group, and Y (on the CH.sub.2 OY group which is at the 4 or 5-position) represents hydrogen or a group that can be readily replaced by hydrogen, i.e. a protecting group, such as an acyl, triarylmethyl or trialkylsilyl group. These novel compounds may each be provided substantially free of other enantiomers.
DESCRIPTION OF THE INVENTION
An aspect of the invention is the means to introduce a heterocyclic base such as adenine in a single step to form a protected or unprotected carbocyclic nucleoside of formula III. Thus, for example, treatment of cyclopentene Ia (X.dbd.Ac, Y.dbd.H) with adenine in the presence of, say, a catalyst such as tetrakis(triphenylphosphine)palladium(O) and sodium hydride gives an unprotected nucleoside (III); similarly, treatment of cyclopentene Ia (X.dbd.Ac, Y.dbd.CPh.sub.3) with 6-chloropurine gives a protected nucleoside (III). Alternatively, direct reaction of IIa (X.dbd.H, Y.dbd.CPh.sub.3) with chloropurine in the presence of triphenylphosphine and diethyl azodicarboxylate (Mitsunobu conditions) also gives III. Similarly, Ib and IIb give an enantiomer of III.
The key individual enantiomeric synthons of this invention, Ia, Ib, IIa and IIb may be prepared from racemic mixtures Ia+Ib and IIa+IIb, wherein X.dbd.Ac or H by either lipase-catalysed enantioselective deacylation (X.dbd.Ac.fwdarw.X.dbd.H) or lipase-catalysed enantioselective acylation with vinyl acetate (X.dbd.H.fwdarw.X.dbd.Ac). A suitable lipase for the purpose is Pseudomonas fluorescens lipase, in which case the enantiomers Ib and IIb are substrates for the enzyme and Ia and IIa are not. The absolute configurations of the products may be determined by correlation with the tetraol of formula IV for which the assignment is known (see Tadano et al, J. Org. Chem. 54 (1989) 276), after dihydroxylation with osmium tetroxide.
The racemic compounds used as substrates for the biocatalytic resolution may be made by known methods. For example, the compounds in which CH.sub.2 OY is at the 4-position may be prepared by the Prins reaction onto cyclopentadiene. Such methods are described by Bajorek et al, J. Chem. Soc. Perkin Trans. 1 (1947) 1243, and Pawson et al, Chem. Ber. 114 (1981) 346. The reaction affords a mixture of diastereoisomers Ia/Ib+IIa/IIb, wherein X.dbd.Y.dbd.H. The diastereoisomers are separated conveniently as the trityl derivative (X.dbd.H, Y.dbd.CPh.sub.3), for instance by chromatography on silica gel. The group Y may be left as trityl in the biotransformation or altered to a different suitable protecting group such as tert-butyldimethylsilyl.
Compounds of formula I in which the CH.sub.2 OY group is at the 5-position may be prepared from the cycloadduct of formula V that is obtained by reaction between cyclopentene and glyoxylic acid. The Chart (below) shows an illustrative synthetic sequence to a compound of formula III: Step 1 involves, e.g. reduction with LiAlH.sub.4, treatment with NaIO.sub.4 and then NaBH.sub.4, and selective protection, e.g. with Ph.sub.3 CCl or t-BuMe.sub.2 SiCl; Step 2 comprises biotransformation, e.g. using a lipase, and vinyl acetate; Steo 3 comprises treatment with Pd(PPh.sub.3).sub.4, adenine and NaH.
The key biotransformation step is carried out by treatment of the secondary alcohol with an acyl donor such as vinyl acetate or butyric anhydride in an organic solvent such as tetrahydrofuran. Alternatively, the racemic secondary alcohol is acylated chemically and the
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Evans Christopher Thomas
Mackeith Rosemary
Roberts Stanley Michael
Shoberu Karoline
Chiroscience Limited
Lilling Herbert J.
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