Enantioselective one-carbon expansion of aromatic rings by simultaneous formation and chromoselective irradiation of a transient coloured enolate.

Rakesh K Saunthwal,Andrew J Orr-Ewing,Jonathan Clayden,James Mortimer

doi:10.1039/d1sc06684f

Abstract

Enantioenriched seven-membered carbocycles are motifs in many molecules of structural and biological interest. We report a simple, practical, transition metal-free and mechanistically unusual method for the enantioselective synthesis of substituted cycloheptatrienes. By forming a coloured enolate with an appropriate absorption band and selectively irradiating in situ, we to initiate a tandem, asymmetric anionic and photochemical ring expansion of readily accessible N-benzylbenzamides. The cascade of reactions leading to the products entails enantioselective benzylic deprotonation with a chiral lithium amide, dearomatizing cyclization of the resulting configurationally defined organolithium to give an extended amide enolate, and photochemically induced formal [1,7]-sigmatropic rearrangement and 6π-electrocyclic ring-opening – the latter all evidently being stereospecific – to deliver enantioenriched cycloheptatrienes with embedded benzylic stereocentres.

Highlights

Saturated and partially saturated seven-membered carbocyclic derivatives are widely prevalent in bioactive natural products and pharmaceutical molecules.1 For example, (À)-colchicine, frondosin B and frondosin C show anti-in ammatory activities (Scheme 1a).2 There are many approaches to the synthesis of these compounds, but connective, enantioselective methods for preparing the parent unsaturated members of the class, cycloheptatrienes,3 with a single stereogenic sp3-hybridised carbon atom, are limited.An appealingly simple approach to these compounds is the one-carbon ring expansion of aromatic systems
The cascade starts with the enantioselective deprotonation and dearomatizing cyclization of an N-benzylbenzamide,17 a reaction that provided a key partially saturated isoindolinone intermediate for the synthesis of the (À)-isodomoic acids and other kainoids.17a–d We proposed that photochemical rearrangement of enolate anions resulting from widening this cyclisation to other substrates could provide an enantioselective version of Scheme 1c, and a general enantioselective route to the less substituted cycloheptatrienes that are unavailable by other methods
The product cycloheptatriene 4a was obtained in 60% yield with 93 : 7 er, con rming that the ring expansion from 2a to 4a can proceed with stereoselectivity

Summary

Introduction

Saturated and partially saturated seven-membered carbocyclic derivatives are widely prevalent in bioactive natural products and pharmaceutical molecules.1 For example, (À)-colchicine, frondosin B and frondosin C show anti-in ammatory activities (Scheme 1a).2 There are many approaches to the synthesis of these compounds, but connective, enantioselective methods for preparing the parent unsaturated members of the class, cycloheptatrienes,3 with a single stereogenic sp3-hybridised carbon atom, are limited.An appealingly simple approach to these compounds is the one-carbon ring expansion of aromatic systems. We show that the whole cascade of reactions from the simple achiral benzamide precursor to the chiral cycloheptatriene may be rendered enantioselective by using a chiral lithium amide base to perform an asymmetric deprotonation while simultaneously irradiating, with a visible light 40 W LED, the mixture of anions that is formed by rearrangement.

Results

Conclusion