Structure Reassignment and Synthesis of Jenamidines A1/A2 Synthesis of (+)-NP25302 and Formal Synthesis of SB-311009 Analogues

摘要

The proposed structures of jenamidines A, B, and C (>1−3) were revised to jenamidines A1/A2, B1/B2, and C (>8->10). Jenamidines A1/A2 (>8) were synthesized from activated proline derivative >43 by conversion to >26 in two steps and 50% overall yield. Acylation of >26 with acid chloride >38d gave >39d, which was deprotected with TFA and then mild base to give >8 in 45% yield from >26. (−)-trans-2,5-Dimethylproline ethyl ester (>49) was prepared by the enantioselective Michael reaction of ethyl 2-nitropropionate (>51) and methyl vinyl ketone (>50) using modified dihydroquinine >60 as the catalyst. Further elaboration converted >49 to natural (+)-NP25302 (>12). A Wittig reaction of proline NCA (>76) with ylide >79 gave >72 as a 9/1 E/Z mixture in 27% yield completing a one step formal synthesis of SB-311009 analogues.