Chiral compounds secondary amine catalysts

FIGURE 11.1. Chiral secondary amine catalysts used for the enamine mediated electrophilic a-amination of carhonyl compounds with azodicarboxylate esters. 

Inspired by the success of intramolecular addition and tautomerization of aldehydes with a pendant alkyne through cooperative catalysis of a secondary amine and an An complex, in 2008, Yang et al. reported a cascade reaction with the combination of a copper complex and an achiral secondary amine catalyst for the synthesis of attractive carbocycles [48]. This chemistry merged a pyrrolidine-promoted Michael addition via iminium ion intermediates and a Cu-catalyzed cycloisomerization protocol (Scheme 9.54). Various ketones and alkyne-tethered active methylene compounds could be converted into densely functionalized cyclopentene derivatives. Although the asymmetric version was not given, the chemistry described here was amenable for the implementation of asymmetric synthesis of such functionalized molecules by a combination of chiral amines and suitable Au complexes. 

Two years later, enantioselective variants of this type of cascade reaction were achieved by replacing the enones with relatively more active enals. Zhao et al. reported a cascade Michael/annulation process combining amino and palladium catalysis [49] to furnish cyclic products with improved complexity and diversity (Scheme 9.55). First, a secondary amine catalyst promoted Michael addition of alkyne-tethered active methylene compounds to a, 3-unsaturated aldehydes to produce optically active chiral aldehydes... 

Chiral amines (both primary and secondary amines) and amino acids have been used as catalysts for aldol reactions, Mannich-type reactions, and other reactions that proceed through enamine intermediates. An enamine-based catalytic cycle is shown in Scheme 2.1. The catalytic cycle includes formation of an iminium intermediate between a donor carbonyl compound and the amine-containing catalyst, the formation of an enamine intermediate from the iminium, C-C bond forma-... 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

Two representative organocatalytic reaction systems can be considered for nucleophilic a-substitution of carbonyl compounds, the issue of this chapter. One involves the in situ formation of a chiral enamine through covalent bond between organo-catalyst (mainly a chiral secondary amine such as proline) and substrate (mainly an aldehyde), followed by asymmetric formation of new bond between the a-carbon of carbonyl compound and electrophile. Detachment of organocatalyst provides optically active a-substituted carbonyl compound, and the free organocatalyst then participates in another catalytic cycle (Figure 6.1a) [2]. 

The use of chiral primary or secondary amines as covalent catalysts allows for the activation of carbonyl componnds for different reactions. Either the initially formed imininm species are the reactive intermediate (LUMO lowering), which is mainly the case when using a,p-unsatnrated carbonyl compounds, or the derived enamine can be ntilized for enolate-type reactions (HOMO activation), or, after a single electron oxidation of the enamine, a singly occnpied molecular orbital (SOMO) activation is possible (Scheme 6.18) [14, 31, 32], In addition, by combining these complementary activation modes, it has been possible to carry out organocascade reactions with excellent control of... 

Chiral imidazolidin-4-ones-chiral secondary amines-had already been successfully used in asymmetric synthesis before they started their own career as organo-catalysts [1]. They were deployed as chiral auxiliaries for alkylation processes [2], Michael additions [3], and aldol reactions [4], For syntheses of this class of catalyst see Reference [5]. The ability to activate both carbonyl compounds by enamine formation as well a, 3-unsaturated carbonyl compounds by intermediate formation of iminium ions makes imidazolidin-4-ones a valuable class of organocatalysts in both series. Thus, they can roughly be divided by their mode of activation into enamine [6] or iminium [7] catalysis (Scheme 4.1). These catalysts were successfully deployed in a wide range of several important enantioselective C-C bond formation and functionalization processes. Figure 4.1 shows the chiral imidazo-lidinones covered in this chapter. 

Several mechanisms, depending on the type of catalyst used, have been proposed to achieve the effective activation of the a-carbon of the carbonyl compound (Scheme 27.1). The use of a chiral primary or secondary amine as organocatalysts led to the formation of a nucleophilic enamine, which then reacts with the electrophilic heteroatom to give the new C-heteroatom bond. Two different types of interactions, steric or electronic, generated by the nature of the substitution at the chiral amine determine the stereochemical outcome of the reaction. Thus, for proUne and their derivatives [3], the approach of the electrophile by the Si-face is forced by the steric shielding of the Re-face of the enamine by the substituent at... 

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