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1.1.1 Enamine Catalysis of Intramolecular Aldol Reactions

DOI: 10.1055/sos-SD-204-00001

Wang, X. -W.; Wang, Y.; Jia, J.Science of Synthesis: Asymmetric Organocatalysis, (201211.

General Introduction

In the mid-1890s, Emil Knoevenagel[‌1‌‌4‌] found that primary and secondary amines or their salts effectively catalyze the aldol condensation of keto esters or malonates with aldehydes or ketones, thereby laying the historical foundation for the development of modern aminocatalysis.[‌5‌] Since then, the Knoevenagel reaction has evolved into an extremely important and reliable method for CC bond formation that is frequently used in industry. Importantly, Knoevenagelʼs chemistry has inspired others to show that primary and secondary amines, amino acids, and carboxylic acid salts of amines can all serve as active catalysts for aldol-type reactions of aldehydes.[‌6‌‌12‌]

Piperidinium acetate catalyzed intramolecular aldol reactions of diketones and dialdehydes continue to be used in the total syntheses of steroids.[‌13‌,‌14‌] This reaction was presumed to proceed via an enamine intermediate,[‌13‌,‌14‌] a mechanism that was later confirmed[‌15‌] and further established.[‌16‌‌18‌] It has also been the subject of density functional theory calculations[‌19‌‌21‌] and nonlinear effect studies.[‌22‌,‌23‌]

Intramolecular aldol reactions can generally be classified into three different types, depending on the enolization mode of the aldol donor: enolendo aldolization, enolexo aldolization, or transannular aldolization (Scheme 1).[‌24‌,‌25‌] Moreover, enamine catalysis of these reactions can be asymmetric or nonasymmetric, depending on whether a chiral or achiral amine is used as the catalyst.[‌24‌] In this chapter, only synthetically useful approaches relevant to asymmetric aldolization reactions will be discussed.

Scheme 1 The Three Modes of Intramolecular Aldolization[‌24‌,‌25‌]