合成路线1

Stereospecific methods to prepare aminopyrrolidine (X) have been developed starting from both enantiomers of trans-N-benzyl-2,3-dihydroxysuccinimide (XXIXa) and (XXIXb), generated respectively from D- and L-tartaric acid. Monoprotection of the (S,S)-diol (XXIXa) with one equivalent of TBDMSCl in the presence of imidazole in cold DMF followed by imide reduction with borane-THF complex leads to the pyrrolidine (XXXa), which after debenzylation with H2 and Pd/C and reprotection with Boc2O provides the tert-butyl carbamate (XXXIa). Alcohol (XXXIa) is then converted to the corresponding mesylate, which undergoes nucleophilic displacement by NaN3 in DMF to give the cis-azide (XXXII). Azide (XXXII) is then reduced by catalytic hydrogenation over Pd/C to afford the corresponding amine, which is protected with Boc2O, followed by desilylation with tetrabutylammonium fluoride to give the cis-alcohol (XXXIII). Inversion of the configuration of alcohol (XXXIII) to the trans-isomer (XXVIII) is then accomplished by mesylation with MsCl and Et3N followed by displacement with potassium acetate in DMF and acetate hydrolysis with K2CO3 in MeOH. Finally, compound (XXVIII) is methylated with iodomethane and NaH and subsequently deprotected with p-TsOH in i-PrOH .
Alternatively, the (R,R)-imide (XXIXb) is converted to the trans-diol derivative (XXXb) as before, and the N-benzyl group is then exchanged for a Boc group, giving alcohol (XXXIb). Alkylation of compound (XXXIb) with iodomethane and NaH affords the corresponding methyl ether, which is desilylated to alcohol (XXXIV) by means of TBAF in THF. Mesylation of alcohol (XXXIV), followed by displacement with lithium acetate produces the methoxy acetate (XXXV), which is hydrolyzed to the cis-alcohol (XXXVI) using K2CO3 in MeOH. Mesylation of alcohol (XXXVI) followed by displacement with NaN3 provides the azide (XXXVII). After reduction with H2 and Pd/C, the resulting amine is protected as the Boc derivative (XXXVIII) with Boc2O in EtOH. Finally, amine (XXXVIII) is alkylated with iodomethane and NaH, followed by deprotection with p-TsOH (X) .