Catalytic Asymmetric Synthesis. Группа авторов
(Eq. 1.3) [4]. In these reactions, small organic molecules catalyze reactions enantioselectively. Since these discoveries, chemistry based on organocatalysts involving an enamine and an iminium ion as an intermediate has developed dramatically [5]. There are several advantages to performing reactions with organocatalysts: (i) exclusion of water and air is not necessary, (ii) the product is free from metal contamination, (iii) most of the organocatalysts are nontoxic, (iv) most reactions do not need low temperature or high temperature, and (v) it is easy to carry out the reaction on a large scale. Given these merits, many catalysts and reactions have been developed. In the previous book of this series published in 2010 [6], progress in the field of organocatalysis is nicely summarized up to 2010. In this chapter, a brief introduction to enamine and iminium ion species will be presented, including work before 2010, and more recent developments in this field will be expanded. Reactions using a combination of organocatalyst and photocatalyst, which have been developed recently, will be described in Chapter 9 of this book.
1.2. REPRESENTATIVE ORGANOCATALYSTS
1.2.1. Introduction
Enamines are generated from aldehydes or ketones upon reaction with secondary or primary amines, and the enamine can react with an electrophile to give an α‐functionalized derivative of the carbonyl compounds (Eq. 1.4).
α,β‐Unsaturated aldehydes or ketones also react with secondary or primary amines to generate an iminium ion, which has lower LUMO (lowest unoccupied molecular orbital) level compared with the parent α,β‐unsaturated carbonyl compound. A nucleophile reacts with the iminium ion to afford a β‐functionalized derivative of the carbonyl compound (Eq. 1.5).
Enamine and iminium ions are reactive species and many reactions involving these intermediates have been developed. Representative organocatalysts that have been used to generate enamines and iminium ions are presented in Figure 1.1.
Proline is a secondary amine catalyst that was first used in the intramolecular aldol reaction in the 1970s (Eq. 1.1). It is a bifunctional catalyst, possessing an amine moiety and an acid moiety (carboxylic acid) vide infra [3]. Imidazolidinone catalyst, which was developed by MacMillan, is a secondary amine catalyst prepared from phenylalanine [4]. Diarylprolinol silyl ether [7], which was developed by Jørgensen [8] and Hayashi [9] independently at the same time, is synthesized from proline; it is also a secondary amine catalyst. These two catalysts are not bifunctional catalysts, and do not possess an acid moiety. Cinchona amine‐based catalysts [10] are prepared from cinchona alkaloids, which are primary amines. This catalyst has several functional groups, and acts as a bifunctional catalyst.
Figure 1.1. Representative organocatalysts.
Figure 1.2. The reaction of enamines generated from diphenylprolinol silyl ether and proline.
The design concepts underlying bifunctional and monofunctional organocatalysts are different. Diphenylprolinol silyl ether, a monofunctional catalyst, reacts with an aldehyde to generate an enamine, in which one of the enantiofaces of the enamine is completely shielded by the bulky diphenyltrimethylsiloxymethyl moiety, and an electrophile approaches from the opposite side of this bulky substituent (Figure 1.2). Thus, the steric shielding of one of the enantiofaces is a key for the high enantioselectivity. Irrespective of the electrophile, high enantioselectivity is expected because the enantioface selectivity of the nucleophile is controlled by the catalyst. This is a contrast to bifunctional catalysts such as proline, in which an acid moiety activates the electrophile. Thus, the most suitable catalyst for a given reaction depends on the electrophile.
1.2.2. Reactivity of Diphenylprolinol Silyl Ether Catalyst and MacMillan’s Catalyst
Diphenylprolinol silyl ether catalyst and MacMillan’s catalyst are widely used in reactions involving enamine or iminium ion intermediates. In this section, the reactivity of these catalysts will be discussed.
Mayr investigated the nucleophilicity (N) of enamines, and the electrophilicity (E) of iminium ions of several pyrrolidines and imidazolidinones (Figure 1.3) [11]. For enamines, the nucleophilicity is evaluated by the reaction with diarylcarbenium ions, and it correlates poorly with the Brønsted basicities. The enamine, which is derived from diphenylprolinol silyl ether catalyst 2, is almost two orders of magnitude less reactive than the corresponding enamine prepared from pyrrolidine. The reduction of the reactivity is primarily due to the electron‐withdrawing inductive effect of the trimethylsiloxybenzhydryl group in diphenylprolinol silyl ether catalyst. The reactivity of the enamine generated from MacMillan’s catalyst 1 is another two to three orders of magnitude less reactive relative to the enamine of diphenylprolinol silyl ether catalyst, because of the inductive electron‐withdrawing effect of the extra endocyclic amide group in the catalyst, the pyramidalization of the enamine nitrogen, and the steric shielding of both faces of the C=C bond by the two alkyl groups at the 2‐position of the imidazolidinone ring.
In the case of iminium ions, the iminium ion generated from diphenylprolinol silyl ether is 20 times more electrophilic than the iminium ion derived from the parent pyrrolidine because of the electron‐withdrawing substituents. The iminium ion of MacMillan’s catalyst, which is useful for the Diels‐Alder reaction, is more reactive than the iminium ion derived from diphenylprolinol silyl ether.
These investigations indicate that MacMillan’s catalyst is more electron deficient, and that its iminium ion is reactive because of the lower LUMO level. Diphenylprolinol silyl ether catalyst possesses suitable nucleophilicity and electrophilicity of its enamine and its iminium ion, respectively. Thus, this catalyst is effective for domino reactions (see Figure 1.3).