A General Iridium-Catalyzed Reductive Dienamine Synthesis Allows a Five-Step Synthesis of Catharanthine via the Elusive Dehydrosecodine

Abstract

A new reductive strategy for the stereo- and regioselective synthesis of functionalized isoquinuclidines has been developed. Pivoting on the chemoselective iridium(I)-catalyzed reductive activation of β,γ-unsaturated δ-lactams, the efficiently produced reactive dienamine intermediates readily undergo [4 + 2] cycloaddition reactions with a wide range of dienophiles, resulting in the formation of bridged bicyclic amine products. This new synthetic approach was extended to aliphatic starting materials, resulting in the efficient formation of cyclohexenamine products, and readily applied as the key step in the shortest (five-step) total synthesis of vinca alkaloid catharanthine to date, proceeding via its elusive biosynthetic precursor, dehydrosecodine.

Multicatalysis protocol enables direct and versatile enantioselective reductive transformations of secondary amides

“…Amides are readily available from natural sources and through a variety of established methods from carboxylic acids and amines, as well as recently developed strategies such as amide-directed C─H bond activation and asymmetric coupling (3)(4)(5). These salient features of amides make them highly attractive starting materials for organic synthesis (6)(7)(8)(9)(10)(11)(12). Nevertheless, the inertness of amides renders the direct and chemoselective transformation of amides (9,13,14) a long-standing challenge in organic synthesis and multistep protocols have to be used (6,7).…”

“…Nevertheless, the inertness of amides renders the direct and chemoselective transformation of amides (9,13,14) a long-standing challenge in organic synthesis and multistep protocols have to be used (6,7). This is the case of the reductive alkylation of amides, an indispensable transformation for the synthesis of many biologically active alkaloids (6)(7)(8)(9)(10)(11)(12). During the past decade, considerable advancements on the direct transformations of amides have been achieved (14)(15)(16)(17)(18) either via the electrophilic activation of amides (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) or via catalytic partial reduction of amides (32)(33)(34)(35)(36)(37)(38)(39)(40).…”

1,2-Redox Transpositions of Tertiary Amides

“…Our group, among others, has reported extensively on the reductive functionalization of tertiary amides to α-substituted amines, via generation of transient silylated hemiaminals with exquisite chemoselectivity (21)(22)(23)(24)(25)(26). The application of the same reductive framework to access analogous β-functionalized amines has remained limited to a few isolated reports on the generation of enamines (27)(28)(29)(30)(31)(32). In the seminal report from Nagashima, a series of stable enamines were generated, however, the utilization of the enamine products was limited to an ex-situ cyclopropanation reaction.…”

An Integrated Building Block for Cascade Diels–Alder and Hetero-Diels–Alder Reactions

“…5 For example, the bisketene acts as an equivalent of DA diene giving convergent access to highly substituted p-hydro-quinones, 6 and the lactam could act as precursor of dienamine for late-stage DA cycloaddition toward stereo-and regioselective synthesis of functionalized isoquinuclidines. 7 Usually, the oligoenes, including dendralenes, 1,1-divinylallenes, and tetravinylthylene (TVE), were disclosed as multiple DA dienes that lead to iterative DA reaction and rapid generation of remarkably molecularly complex pericycles (Figure 1A). 8 Despite these advances, the integration of DA and hetero-Diels-Alder (HDA) reaction in a molecule in an iterative sequence has rarely been reported.…”

“…The DA reaction has been widely used in numerous fields, especially in the synthesis of natural products, and the stereoselective DA reaction and the biology of the biosynthetic DA reaction have also attracted a great deal of interest. , During the course of development of the DA reaction, new types of dienes and dienophiles have been explored with the aim of forming new scaffolds and applying them in the construction of privileged molecules . For example, the bisketene acts as an equivalent of DA diene giving convergent access to highly substituted p -hydroquinones, and the lactam could act as precursor of dienamine for late-stage DA cycloaddition toward stereo- and regioselective synthesis of functionalized isoquinuclidines . Usually, the oligoenes, including dendralenes, 1,1-divinylallenes, and tetravinylthylene (TVE), were disclosed as multiple DA dienes that lead to iterative DA reaction and rapid generation of remarkably molecularly complex pericycles (Figure A) .…”