Inverse hydride shuttle catalysis enables the stereoselective one-step synthesis of complex frameworks

Abstract

The rapid assembly of complex scaffolds in a single step from simple precursors identifies as an ideal reaction in terms of efficiency and sustainability. Indeed, the direct single-step synthesis of complex alkaloid frameworks remains an unresolved problem at the heart of organic chemistry in spite of the tremendous progress of the discipline. Herein, we present a broad strategy in which dynamically assembled ternary complexes are converted into valuable azabicyclic scaffolds based on the concept of inverse hydride shuttle catalysis. The ternary complexes are readily constructed in situ from three simple precursors and enable a highly modular installation of various substitution patterns. Upon subjection to a unique dual-catalytic system, the transient intermediates undergo an unusual hydride shuttle process that is initiated by a hydride donation event. Furthermore, we show that, in combination with asymmetric organocatalysis, the product alkaloid frameworks are obtained in excellent optical purity.

Fig. 1. Harnessing dynamically formed ternary complexes through inverse hydride shuttle catalysis.

a, Dynamically assembled complexes with unexploited synthetic potential: reversible preorganisation into ternary complexes and interrogation of routes able to convert the ternary complex directly into a complex scaffold. b, Azabicycles in natural products and pharmaceuticals. HCV, hepatitis C virus; GABA, γ-aminobutyric acid receptor. c, Azabicycles are formed in a single step, enabled by inverse hydride shuttle catalysis starting from ubiquitous starting materials. Fleeting cyclobutene intermediates are converted into complex frameworks with up to 99% yield, forming up to four new stereocentres with excellent enantioselectivity (up to 99% e.e.). EWG, electron-withdrawing group.

Fig. 2. Extensions of the inverse hydride shuttle concept: enantioselective synthesis, additional substrate class and mechanistic proposal.

a, Telescoped and enantioselective approaches for the synthesis of indolizidine building blocks. Telescoped approach starting directly from amine, aldehyde and nitroolefin. Enantioselective access to the azabicyclic frameworks is based on an organocatalysed enantioselective Michael addition prior to cyclobutane formation. b, Alternative Michael acceptors: synthesis of indolizidine derivatives bearing a trifluoromethyl ketone. c, Proposed mechanism for the conversion of enamine–Michael acceptor complexes, formed through dynamic assembly, into indolizidines via inverse hydride shuttle catalysis featuring both a Lewis acid and its respective hydride. LA, Lewis acid. Supplementary Sections 4.5, 4.6 and 4.7 for details. Products were formed as single diastereomers, unless stated otherwise.

Fig. 3. Targeted functionalisation reactions of the azabicyclic framework towards natural-product-like scaffolds.

Diazonium extrusion followed by ring contraction to forge 5,5-bicyclic scaffold 9 resembling the trachelanthamidine family. α-Oxidation followed by highly stereoselective nucleophilic allylation affording 10. Formation of a truncated aspeverin derivative 11 by α-cyanation. Reduction of the nitro-group and acetylation lead to an epiquinamide derivative 12. Trifluoroketone reduction affords 13, featuring a decorated lupinine framework. Polonovski–Potier reaction and acetone addition furnish 14, resembling crepidamine. Supplementary Section 4.8 for details.