DBU‐Catalyzed Ring‐Opening and Retro‐Claisen Fragmentation of Dihydropyranones

Anton Axelsson,Emmelie Hammarvid,Henrik Sundén,Martin Rahm

doi:10.1002/ejoc.202000858

Anton Axelsson, Emmelie Hammarvid + Show 2 more

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https://doi.org/10.1002/ejoc.202000858

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Abstract

We present a general protocol for the formal Michael addition of acetone to α,β‐unsaturated esters and amides, a transformation difficult to perform using current methods. The protocol comprises of an amidine catalyzed relay ring‐opening and fragmentation of 3,4‐dihydropyranones. The reaction proceeds under mild conditions, has a broad substrate scope and the products can be isolated in good to excellent yields. The method can be applied to homochiral substrates with total preservation of chiral information, generating products in high optical purity. Kinetic experiments supported by quantum chemical modeling indicate a mechanism in which the catalyst takes a bifunctional role, acting both as a Brønsted base and as a hydrogen‐bond donor.

Highlights

The Michael reaction is one of the most well-known and important reactions in synthetic organic chemistry.[1]
In addition to problematic electrophiles, some nucleophiles have proven challenging in asymmetric Michael reactions
Dihydropyranone 1 is stable in methanol in the absence of base, and no ring-opening is observed after 1 h

Summary

Introduction

The Michael reaction is one of the most well-known and important reactions in synthetic organic chemistry.[1] During the last three decades, a variety of catalytic methods for asymmetric Michael additions have been developed.[2] Despite the progress, some issues remain unsolved. In reactions with unactivated Michael acceptors, such as α, -unsaturated esters or amides, poor reactivity is observed due to low electrophilicity.[3] In addition to problematic electrophiles, some nucleophiles have proven challenging in asymmetric Michael reactions. Direct Michael addition of acetone is possible only with highly activated electrophiles such as nitroolefins and a thiourea-based catalyst or by indirect methods using RAMP/SAMP auxiliaries.[4] Here, we describe the DBU catalyzed ring-opening/ retro-Claisen fragmentation of dihydropyranones for the formal addition of acetone to unactivated Michael acceptors. The protocol is highly modular and allows for the asymmetric synthesis of both oxohexanoates and oxohexanamides

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Results

Conclusion