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3 ASYMMETRIC BASE ORGANOCATALYSIS

      Azusa Kondoh and Masahiro Terada

       Graduate School of Science, Tohoku University, Sendai, Japan

3.1. INTRODUCTION

Brønsted base catalysis – the catalysis by a small molecule having Brønsted basicity, such as an amine – is one of the most fundamental types of catalysis in organic chemistry. The catalysis enables the direct transformation of starting compounds into desired products in a highly atom‐economical fashion under mild reaction conditions and, thus, has been widely utilized in organic synthesis over a long period of time. In particular, the catalysis has recently attracted considerable attention as a family of “environmentally benign” organocatalysis, and the development of enantioselective reactions has been intensively explored by using chiral uncharged organobases as a catalyst [1]. Generally, the catalysis is initiated by the generation of an anionic nucleophile through the direct deprotonation of a pronucleophile by a Brønsted base catalyst (Figure 3.1). Then, the transformation of the anionic nucleophile, such as addition to an unsaturated bond, rearrangement, and isomerization, proceeds to generate a different anionic intermediate. Finally, the protonation of the resulting anionic intermediate with the conjugate acid of the Brønsted base catalyst (or the other molecule of a pronucleophile in some cases) occurs to provide the desired products along with the regeneration of the catalyst (or the anionic nucleophile), completing the catalytic cycle. In the case of enantioselective reactions, the transformation of the anionic nucleophile (and/or the protonation of the anionic intermediate) proceeds in a stereoselective fashion under the influence of the conjugate acid of a chiral Brønsted base catalyst, and an enantio‐enriched product can be obtained.

In establishing a new Brønsted base‐catalyzed reaction, one must take into account the balance of the acidities of a pronucleophile and a product and the basicity of a catalyst. In other words, both the effective generation of an anionic nucleophile and the efficient regeneration of a catalyst are essential to promote a catalytic reaction efficiently. If the basicity of a catalyst is not high enough to deprotonate a substrate, the reaction does not proceed. Therefore, the range of the pronucleophiles applicable to the reaction is highly dependent on the basicity of the employed catalysts. On the other hand, if the basicity of the anionic intermediate, that is the conjugate base of a product, is not high enough to deprotonate the conjugate acid of a catalyst, the catalyst turnover does not occur, and the reaction does not proceed at least in a catalytic fashion. Furthermore, in the case of catalytic enantioselective reactions, the application of a proper chiral catalyst is also critical to achieve high stereoselectivity. Therefore, the development of chiral catalysts is crucial to accomplish various types of catalytic enantioselective reactions. Indeed, a variety of chiral uncharged organobase catalysts has been developed to date, which has broadened the utility of asymmetric Brønsted base catalysis in organic synthesis.

Figure 3.1. General catalytic cycle for Brønsted base catalysis.

Figure 3.2. Relationship between basicity of uncharged organobases and acidity of representative pronucleophiles (including approximations based on the reported pK_BH+ in other solvents).

      Source: Based on [2].

In the field of asymmetric Brønsted base catalysis, chiral tertiary amines have been most widely employed as chiral Brønsted base catalysts. Chiral guanidines have also been used as alternative chiral catalysts over the decades. More recently, chiral organic molecules having a different type of Brønsted base functionality, such as a cyclopropenimine, an iminophosphorane, and a phosphazene (triaminoiminophosphorane), have emerged as efficient chiral Brønsted base catalysts. As a common feature of guanidine catalyst and the new types of organobase catalysts, their basicity is much higher than that of tertiary amine catalysts (Figure 3.2) [2]. Each class of chiral organobase catalysts offers many advantages, and a tremendous amount of applications has been found based on the advantages.

      In this chapter, we categorize the chiral organobase catalysts on the basis of their Brønsted base functionalities and present a brief overview of each category with representative catalysts and their selected applications. It should be noted that there are several excellent reviews on chiral tertiary amine catalysts [3], chiral guanidine catalysts [4], and the other chiral organobase catalysts [5]. In particular, the third edition of this book includes the detail СКАЧАТЬ