Five-Step Total Synthesis of (±)-Aspidospermidine by a Lactam Strategy via an Azomethine Ylide

Abstract

A five-step total synthesis of (±)-aspidospermidine (1) based on a lactam strategy is reported. Our synthesis features an iridium-catalyzed reductive Michael addition/[3+2] cycloaddition cascade to give a tricyclic ketone intermediate from a simple lactam via an azomethine ylide. The developed strategy enables easily available lactams to be used as stable surrogates of multisubstituted amines and would be applicable to a unified total synthesis of complex Aspidosperma alkaloids.

Total Synthesis of (±)-Aspidospermidine, (±)-Aspidofractinine, (±)-Limaspermidine, and (±)-Vincadifformine via a Cascade and Common Intermediate Strategy

“…Here, we report a common intermediate strategy for the synthesis of Aspidosperma natural products, where the common intermediate is accessed through cascade reactions, and demonstrate the utility of this cascade strategy in the synthesis of (±)-aspidospermidine, − (±)-aspidofractinine, (±)-limaspermidine, and (±)-vincadifformine (Scheme b). , …”

“…The Aspidosperma alkaloids are a class of monoterpenoid indole alkaloids, which have seen significant interest as synthetic targets (Scheme a). − Their intriguing, densely fused polycyclic structures have inspired numerous strategies and methodologies to enable access to the eponymous aspidospermidine ( 1 ), − as well as many other members of this family. Of the strategies employed in total synthesis, divergent approaches based on a common intermediate are arguably the most powerful. , These approaches allow the synthesis of multiple natural products by late-stage modification of a single common intermediate.…”

Concise Total Synthesis of (−)‐Quinocarcin Enabled by Catalytic Enantioselective Reductive 1,3‐Dipolar Cycloaddition of Secondary Amides

“…Nevertheless, catalytic enantioselective transformation of amides to yield chiral amines remains largely an unexplored field because of the high stability and inertness of amide carbonyl group. In this regard, important advances have been made in the direct reductive 1,3‐dipolar cycloaddition reaction of amides by the groups of Huang, [7a] Chida/Sato, [19a,b] Dixon (Scheme 3, A), [19c] however, the catalytic enantioselective transformation remains unconquered. Inspired from the abovementioned precedents, and in connection with our continuous interests in the enantioselective reductive transformations of amides, [7c–e,g] we envisioned that the catalytic enantioselective transformation of secondary amides to chiral functionalized pyrrolidines could be achieved via a one‐pot enantioselective reductive 1,3‐dipolar cycloaddition reaction by the combined use of Ir and Cu‐catalyzed processes.…”

Enantioselective Total Synthesis of (−)-Hunterine A Enabled by a Desymmetrization/Rearrangement Strategy

“…Although at the outset of the synthesis it was unclear how this would be accomplished in the forward direction, an azide-olefin cycloaddition ultimately proved successful . Given that 1 does not contain an indole, construction of the highlighted C7 all-carbon quaternary center could not be accomplished in the same manner as in the synthesis of related MIAs, which commonly utilize strategies such as Fischer indole synthesis and nucleophilic indole alkylation (Scheme B). , Instead, we imagined forming the C7 quaternary center via an aza-Cope/Mannich rearrangement, developed by Overman and co-workers for the synthesis of similar 3-acyl pyrrolidine motifs, , tracing back to bicyclic alcohol 3 . Alcohol 3 could be formed via a convergent, diastereoselective 1,2-addition of vinyl species 4 to ketone 5 .…”