Synthesis of Chiral Tetrasubstituted Azetidines from Donor–Acceptor Azetines via Asymmetric Copper(I)‐Catalyzed Imido‐Ylide [3+1]‐Cycloaddition with Metallo‐Enolcarbenes

Abstract

The all‐cis stereoisomers of tetrasubstituted azetidine‐2‐carboxylic acids and derivatives that possess three chiral centers have been prepared in high yield and stereocontrol from silyl‐protected Z‐γ‐substituted enoldiazoacetates and imido‐sulfur ylides by asymmetric [3+1]‐cycloaddition using chiral sabox copper(I) catalysis followed by Pd/C catalytic hydrogenation. Hydrogenation of the chiral p‐methoxybenzyl azetine‐2‐carboxylates occurs with both hydrogen addition to the C=C bond and hydrogenolysis of the ester.

Mukaiyama‐Preis: M. D. Burke und S. Matsunaga / Ryoji‐Noyori‐Preis und Paracelsus‐Preis: S. E. Denmark / Henry J. Albert‐Preis: M. P. Doyle / ORCS‐Preise: P. Chirik und J. J. Spivey / FNP‐Preis: M. Drąg

“…Sie entwickeln chirale Liganden für Dirhodium(II)‐Carboxylat‐ und Kupfer(I)‐Katalysatoren. In jüngeren Arbeiten befassten sie sich meist mit katalytischen Cycloadditionen von Enoldiazoverbindungen, wie in einer Angewandte‐Chemie ‐Zuschrift über eine kupferkatalysierte Synthese chiraler tetrasubstituierter Azetidine, und mit selektiven radikalischen Additionen.…”

Mukaiyama Award: M. D. Burke und S. Matsunaga / Ryoji Noyori Prize and Paracelsus Prize: S. E. Denmark / Henry J. Albert Award: M. P. Doyle / ORCS Awards: P. Chirik und J. J. Spivey / FNP Award: M. Drąg

“…They develop chiral ligands for dirhodium(II) carboxylate and copper(I) catalysts. Most recent contributions have been to catalytic cycloaddition of enoldiazo compounds, as exemplified by a Communication in Angewandte Chemie on a copper‐catalyzed synthesis of chiral tetrasubstituted azetidines, and to selective free radical addition reactions.…”

Azetidine synthesis enabled by photo-induced copper catalysis via [3+1] radical cascade cyclization

“…In addition, [3 + 1] formal ring expansion reactions were developed to construct azetidine upon strain release of the azacyclopropanes ( Figure 1 B). 16 , 17 , 18 , 19 , 20 , 21 , 22 Despite these developments, the intrinsic ring strain and its sterically congested nature rendered atom-economical access to the highly substituted, densely functionalized azetidines a challenging task from simple starting materials. Thus, a new synthetic approach to access azetidine scaffolds with varied substitutions and stereochemistry is needed.…”