Expeditious and Divergent Total Syntheses of Aspidosperma Alkaloids Exploiting Iridium(I)‐Catalyzed Generation of Reactive Enamine Intermediates

Abstract

A new approach for the divergent total syntheses of (±)‐vincaminorine, (±)‐N‐methylquebrachamine, (±)‐quebrachamine, (±)‐minovine and (±)‐vincadifformine, each in less than 10 linear steps starting from a single δ‐lactam building block, is reported. Key to our route design is the late‐stage generation of reactive enamine functionality from stable indole‐linked δ‐lactams via a highly chemoselective iridium(I)‐catalyzed reduction. The efficiently formed secodine intermediates subsequently undergo either a formal Diels–Alder cycloaddition or a competitive Michael addition/reduction to access aspidosperma‐type alkaloids in excellent diastereoselectivities. Product selectivity could be controlled by changing the indole N‐protecting group in the reductive cyclization precursors. An asymmetric variant of this synthetic strategy for the synthesis of (+)‐20‐epi‐ibophyllidine is also described.

Divergent Strategy in Natural Product Total Synthesis

“…In 2016, Dixon and co-workers reported the divergent total syntheses of five Aspidosperma alkaloids (10, 85−88) from a secodine intermediate Int A formed in situ from lactam precursors 79, 80 or 81 (Scheme 8). 46 The lactams were formed from compound 75 through seven-step conventional transformations. Exposure of 79 or 80 to IrCl(CO)(PPh 3 ) 2 / TMDS resulted in the secodine intermediate Int A via the highly chemoselective iridium(I) catalyzed reduction.…”

Iridium-catalyzed reductive Ugi-type reactions of tertiary amides

“…Our group 43 – 45 has been working on developing new methodologies for the synthesis of amine-containing products from reactive hemiaminal intermediates, generated by the highly chemoselective, catalytic reduction of tertiary amides under mild conditions 46 – 50 . Looking to expand the diversity of product types accessible we considered isocyanides 51 – 53 as potential nucleophiles.…”

“…Looking to expand the diversity of product types accessible we considered isocyanides 51 – 53 as potential nucleophiles. Based on the known interaction between hemiaminals 10 and isocyanides and our own prior experience with both partners 43 – 45 , 54 – 56 , we hypothesized that isocyanides might, in the presence of an acid promoter, intercept the in situ formed iminium species, thus generating versatile nitrilium intermediates applicable for various Ugi-type reactions (Fig. 1d ).…”