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 pKBH+ 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 of the background of chiral tertiary amine catalysts and their fundamental applications [6]. Therefore, as to the category of chiral tertiary amine catalysts, we here mainly focus on the recent applications. Although the chiral ion‐pair type Brønsted base catalysts, such as chiral ammonium betaines [7], and chiral anionic Brønsted base catalysts, such as chiral ureates [8], may also be categorized as a family of chiral organobase catalysts, only chiral uncharged organobase catalysts are discussed in this chapter.
3.2. CHIRAL TERTIARY AMINE CATALYSTS: CHIRAL ACID–BASE BIFUNCTIONAL CATALYSIS
In the field of asymmetric Brønsted base catalysis, one of the most important pioneering works would be a series of studies on enantioselective Michael additions conducted by Wynberg and co‐workers, in which cinchona alkaloids were employed as readily available chiral tertiary amine organobase catalysts [9]. For instance, they reported that the addition of aryl thiols to cyclic enones proceeded with moderate enantioselectivities by using cinchonidine (1a) as a catalyst (Scheme 3.1) [10]. In the report, the importance of the C9 hydroxy group as a hydrogen bond donor site, namely the bifunctional catalysis, was also suggested [11].
Scheme 3.1. Enantioselective addition of aryl thiols to cyclic enones catalyzed by 1a.
Source: Based on [10].
Cinchona alkaloids are complex small molecules containing five stereogenic centers, a basic quinuclidine nitrogen, a chiral secondary alcohol moiety, and a quinoline unit (Figure 3.3). A highlighted advantage of the use of cinchona alkaloid‐based chiral organobase catalyst is the attainability of either enantiomer of desired products owing to the availability of pseudo‐enantiomeric pairs, such as cinchonidine (1a)/cinchonine (1b) and quinine (1c)/quinidine (1d). Thus, cinchona alkaloids are nowadays not only used directly as a chiral organobase catalyst but also utilized as a versatile chiral scaffold for the development of various chiral organobase catalysts [4].
On the other hand, the prevailing design of chiral tertiary amine catalysts is the “chiral acid–base bifunctional catalyst,” in which an additional acidic hydrogen bond donor unit is introduced into a catalyst molecule along with a basic tertiary amine moiety. This catalyst design is based on the idea of dual activation of a pronucleophile and an electrophile; a chiral tertiary amine activates a pronucleophile and a hydrogen bond donor simultaneously activates an electrophile (Figure 3.4a).
There are three common structural motifs utilized widely in the development of chiral acid–base bifunctional catalysts. The first motif is the catalyst consisting of a tertiary amine and a double hydrogen donor unit, such as a thiourea, connected by a chiral two‐carbon linker (Figure 3.4b). In 2003, Takemoto and co‐workers developed the seminal amine‐thiourea bifunctional catalyst 2a [12]. They reported that catalyst 2a efficiently promoted the Michael addition of malonates to nitroalkenes in a highly enantioselective manner (Scheme 3.2).
Figure 3.3. Cinchona alkaloids and derivatives.
Figure 3.4. Chiral acid–base bifunctional catalysts.
Scheme 3.2. Enantioselective addition of malonates to nitroalkenes catalyzed by 2a. Source: