Catalyst‐ and Base‐Free Asymmetric Synthesis of Functionalized Prolines via One‐Pot Cascade Reactions

Abstract

A one pot, three‐step cascade reaction to provide functionalized proline derivatives was developed. The Michael addition reaction of N‐allylated proline and activated alkyne forms a zwitterionic intermediate that further undergoes cyclization and [2,3]‐rearrangement to provide Cα‐alkylated proline bicyclic derivatives. This transformation was highly stereoselective and the chirality of the N‐allylated prolines was completely transferred to the product via a C−N−C chirality transfer process. The developed reaction is operationally simple and does not require any reagents other than the substrates.magnified image

Collective Asymmetric Total Synthesis of C‐11 Oxygenated Cephalotaxus Alkaloids

“…According to this retrosynthetic scheme, all of the stereochemistry in the target alkaloids would be derived exclusively from a single stereocenter of proline. Prior to this study, as an approach for the conservation of chirality during α‐substitution of proline, we have developed a couple of C‐N‐C chirality transfer methods [13c–e] . For the high diastereoselectivity during the N ‐quaternization with allylic electrophiles, one method employed a rigid nitrogen‐fused bicyclic derivative H in which the nitrogen lone‐pair electrons were forced to be located on the convex face [13c] .…”

Recent asymmetric synthesis of natural products bearing an α-tertiary amine moiety via temporary chirality induction strategies

“…The Scheme 12 Total synthesis of (−)-FR901483 (Gaunt, 2018). [68][69][70][71][72][73][74][75] with limited examples of a-alkylation (Fig. 6b).…”

“…The N-to-C chirality transfer, the second step in this strategy, determines the diastereomeric ratio of the end product. The reactions employed in this step primarily involve [1,2]- or [2,3]-Stevens rearrangements, 68–75 with limited examples of α-alkylation (Fig. 6b).…”