合成路线1

The optically pure diol intermediate (VIII) can be obtained by several procedures. Aldol condensation of 3-chlorobenzaldehyde (XII) with the lithium enolate of ethyl acetate gives the hydroxy ester (XIII), which is reduced to racemic 1-(3-chlorophenyl)-1,3-propanediol (XIV) by means of LiAlH4 in Et2O. Ketalization of diol (XIV) with (-)-menthone (XV) employing trimethylsilyl triflate and hexamethyldisilazane produces the spiro ketal (XVI) as a diastereomeric mixture, from which the target (S)-diol (VIII) is obtained by fractional crystallization, followed by acidic ketal hydrolysis (1-3). In a different strategy utilizing an enantioselective reduction, 3’-chloroacetophenone (XVII) is condensed with diethyl carbonate by means of t-BuOK in THF to yield the keto ester (XVIII), which is selectively reduced to the (S)-hydroxy ester (XIX) by catalytic hydrogenation over a chiral ruthenium catalyst. After saponification of ester (XIX), the chiral hydroxy acid obtained (XX) is reduced to (VIII) with borane in THF. Similarly, the (S)-hydroxy acid (XX) can be produced by condensation of 3-chlorobenzoyl chloride (XXI) with the lithium enolate of trimethylsilyl acetate, followed by acidic desilylation to yield the keto acid (XXII), which is then reduced to (XX) utilizing (–)-B-chlorodiisopinocamphenylborane (DIP-Cl) in cold CH2Cl2 (1-5). In a further method, 3-chlorocinnamic acid (XXIII) is esterified with H2SO4/EtOH, followed by reduction with DIBAL to provide the cinnamyl alcohol (XXIV), which undergoes Sharpless asymmetric epoxidation to (XXV) with t-butyl hydroperoxide in the presence of (+)-diethyl tartrate. Reductive cleavage of the chiral epoxide obtained (XXV) by means of Red-Al then furnishes the target 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) (1, 2). Scheme 2.