An expedient synthesis of 7( S)-ethyl-8( R or S)-indolizidinols based on a thiophene reductive desulfurization

A new and expedient approach for the synthesis of prototypic alkyl-substituted indolidinols, namely 7( S)-ethyl-8( S)-indolizidinol and its 8( R)-epimer is described from readily available chiral non-racemic thienoindolizine-4,7-dione and 4-hydroxythienoindolizin-7-one. Chiral hexahydrothieno[2,3- f]indolizine-4,7-dione ( S)- 12 and the ancillary alcohol 13 were generated from thiophene-2-carboxaldehyde and ( S)-glutamic acid in three and four steps, respectively, in good overall yields and both high enantio- and diastereomeric purities. Applying a thiophene reductive desulfurization, compound 12 was readily converted into 7( S)-ethyl-8( S)-indolizidinol 9. The 8( R)-epimer of 9 was advantageously obtained using the Mitsunobu alcohol inversion or, starting from 13, by chemical separation after O-benzylation and lactam reduction. During these studies, the reduction of regioisomers of 12 and 13, namely 17 and 18, was investigated and the results obtained are also discussed.