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

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.

Graphical abstractA 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.Figure optionsDownload full-size imageDownload as PowerPoint slide