合成路线1

The pyrrolidine building blocks are in turn synthesized as shown in Scheme 5. 3(R)-Hydroxypyrrolidine (IV) is protected as the N-Boc derivative (LIV), followed by O-alkylation with benzyl bromide and acidic deprotection of the resulting benzyl ether (LV) to furnish 3(R)-benzyloxypyrrolidine (II). Condensation of pyrrolidine (II) with cyclohexene oxide (XXXI) gives the trans-pyrrolidinocyclohexanol (LVI) as a diastereomeric mixture, which is separated either by crystallization with di-p-toluoyl-L-tartaric acid (DTTA) or by diastereoselective N-oxidation of the undesired diastereoisomer to furnish the target isomer (IX). Alternatively, intermediate (IX) can be obtained by ring opening of epoxide (XXXI) with pyrrolidine (II) in the presence of chiral catalysts. In a different strategy, enantioselective ring opening of cyclohexene oxide (XXXI) with B-bromodiisopinocamphenylborane provides the optically enriched trans-bromohydrin (LVII), which is then condensed with benzyloxypyrrolidine (II) to yield the (1S,2R)-pyrrolidinocyclohexanol (LVIII). Inversion of the configuration of alcohol (LVIII) to produce (IX) is then accomplished by Mitsunobu coupling with formic acid, followed by acidic hydrolysis of the resulting (1R,2R)-formate ester (LIX). Further synthetic strategies leading to the pyrrolidinocyclohexanol (IX) involve cyclization of (R,R)-2-aminocyclohexanol (LX) with 2(R)-benzyloxy-1,4-butanediol ditosylate (LXI), and condensation of (LX) with cyclohexanone (XXVI), followed by asymmetric hydroboration and oxidative work-up of the resulting enamine (LXII) (2). Alternatively, (R,R)-2-aminocyclohexanol (LX) can be converted to the intermediate acetoxysuccinimide (XII) by condensation with 2(R)-acetoxysuccinic anhydride (VI) (prepared from L-malic acid [LXIII] and acetyl chloride) to produce a regioisomeric mixture of succinamic acids (LXIVa) and (LXIVb), which undergoes cyclization to imide (XII) upon heating with acetyl chloride (4). Similarly, racemic trans-2-benzyloxycyclohexylamine (LXV) is resolved by enantioselective N-acylation with isopropyl methoxyacetate in the presence of lipase, followed by hydrolysis of the resulting (R,R)-methoxyacetamide (LXVI) to provide (LXVII) (5). Acylation of (R,R)-2-benzyloxycyclohexylamine (LXVII) with O-acetylmalic anhydride (VI), followed by cyclization with acetyl chloride, yields the N-(2-benzyloxycyclohexyl)succinimide (LXVIII), which is then debenzylated to (XII) by catalytic hydrogenation over Pd/C (4). Scheme 5.