Synthesis 2022; 54(06): 1537-1550
DOI: 10.1055/a-1713-8481
short review

Modern Synthesis and Chemistry of Stabilized Ketene N,O-Acetals

a   Medicinal Chemistry Knowledge Center, Stanford ChEM-H, Stanford University, 290 Jane Stanford Way, Stanford, CA 94305, USA
,
b   Department of Chemistry and Biochemistry, South Dakota State University, 1055 Campanile Avenue, Brookings, SD 57007, USA
› Author Affiliations


This article is dedicated to the late Sandra ‘Sandy’ Newman of the Van D. and Barbara B. Fishback Honors College at South Dakota State University.

Abstract

Ketene N,O-acetals are robust and versatile synthons. Herein, we outline the synthesis of stable ketene N,O-acetals in the twenty-first century. In addition, we review recent developments in the chemistry of ketene N,O-acetals, as it applies to the vinylogous Mukaiyama aldol reaction, electrolysis, and pericyclic transformations. While dated reports rely on in situ use, modern methods of ketene N,O-acetal synthesis are heavily oriented towards producing products with high ‘bench’ stability; moreover, in the present century, chemists typically enhance the stability of ketene N,O-acetals by positioning an electron-withdrawing group at the β-terminus or at the N-position. As propitious substrates in the vinylogous Mukaiyama aldol reaction, ketene N,O-acetals readily provide polyketide adducts with high regioselectivity. When exposed to electrolysis conditions, the title functional group forms a reactive radical cation and cleanly couples with a variety of activated olefins. Given their electron-rich nature, ketene N,O-acetals act as facile substrates in several rearrangement reactions; further, ketene N,O-acetals reserve the ability to act as either dienophiles or dienes in Diels–Alder reactions. Lastly, ketene N,O-acetals are seemingly more stable than their O,O-counterparts and more reactive than analogous N,N- or S,S-acetals; these factors, in combination, make ketene N,O-acetals advantageous substitutes for other ketene acetal homologues.

1 Introduction

2 Select Methods of Stabilization-Oriented Ketene N,O-Acetal Synthesis

3 Ketene N,O-Acetals in the Vinylogous Mukaiyama Aldol Reaction

4 Ketene N,O-Acetals in Anodic Coupling and Electrochemical Oxidation Reactions

5 Rearrangement and Diels–Alder Reactions of Ketene N,O-Acetals

6 Conclusions, Perspectives, and Directions



Publication History

Received: 10 November 2021

Accepted after revision: 06 December 2021

Publication Date:
06 December 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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