Direct asymmetric aldol reactions

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Quaternary Ammonium Salt-Mediated Asymmetric Direct Aldol Reaction of Glycinate Benzophenone Schiff Base with 3-Phenylpropanal Under Phase-Transfer Conditions [6] (p. 145)... 

Saito S, Yamamoto H. Design of acid-base catalysis for the asymmetric direct aldol reaction. Acc. Chem. Res. 2004 37 570-579. 

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

Design of Acid-Base Catalysis for the Asymmetric Direct Aldol Reaction ... 

Progress in the study on the reaction mechanisms of proline-catalyzed asymmetric direct aldol reactions 06CJO1463. 

Reproduced from Tanaka K, Asakura A Muraoka T. Kalicki P. Urtanczyk-Upkawaka Z Asymmetric direct aldol reactions catalyzed by chiral amine mscrocycle-metaKll) complexes under soh/ent-lfee conditions. N J Chem 2013 37 2851-5. With permission from the Royal Society of Chemistry. 

Fteproduced from GuiSena G, del Carmen Hita M. Nijera C, Vidzquez SF Solvent-free asymmetric direct aldol reactions organocatalysed by recoverable (SJ-binam-L-prolinamide. Tetrahedron Asymm 2007 18 2300-4. Copyright (2007). with permission from Elsevier. 

A highly efficient solvent-free asymmetric direct aldol reaction organocatalyzed by recoverable (S)-Binam-L-Prollnamldes. ESI-MS evidence of the enamine-iminium formation. J Org Chem 2008 73 5933-43. Copyright (2008), American Chemical Society. 

Scheme 9.8 Asymmetric direct aldol reaction of ketones with reactive aldehydes.

The development of catalytic strategies towards the enantioenriched generation of p-hydroxy ketones via an aldol reaction was intensively promoted in recent years. In particular, the application of proline and proline-based amides and peptides as organocatalysts for the asymmetric direct aldol reaction was successfully investigated, by contributions from several researchers. ... 

Based on the observations obtained for i-proline-based dipeptides Gong and coworkers were the first to report an efficient catalytic protocol for the asymmetric direct aldol reaction of aldehydes with hydroxyacetone yielding a series of 1,4-diols as major product (1,2-diols just as minor product) in aqueous media providing good yields and excellent enantioselectivities. " ... 

Torii H, Nakadai M, Ishihara K, Saito S, Yamamoto H (2004) Asymmetric Direct Aldol Reaction Assisted by Water and a Proline-Derived Tetrazole Catalyst. Angew Chem Int Ed 43 1983... 

Catalytic Asymmetric Direct Aldol Reactions and Aldol-Tishchenko Reactions... 

Torii, H., Nakadai, M., Ishihara, K., Saito, S. and Yamamoto, H., Asymmetric direct aldol reaction assisted by water and a proline-derived tetrazole catalyst, Angew. Chem. Int. Ed., 2004,43,1983 1986. 

Asymmetric direct aldol reaction is a practical process to synthesize p-hydroxy-carbonyl compounds [28]. The phebox-Rh acetate complex 5- Pr serves also as an excellent catalyst for asymmetric direct aldol reaction of cyclic ketones with benzaldehyde derivatives (Scheme 24) [29]. For example, Scheme 24 shows that the reaction of cyclohexanone with 4-nitrobenzaldehyde using 5 mol% of 5- Pr and AgOTf gave the corresponding anri-p-hydroxyketone 36 preferentially in 79% yield with 87 % ee for the anti-isomer. The coupling reaction of cyclopentanone and acetone afforded p-hydroxyketones 37 and 38, respectively, with up to 91% ee. 

Gong reported on the use of L-prohne-based oHgopeptides (from di- to hexapeptides were tested) that catalyzed the asymmetric direct aldol reaction of... 

Luo S, Xu H, Li J, Zhang L, Cheng JP. A simple primary-tertiary diamine-Brpnsted acid catalyst for asymmetric direct aldol reactions of linear aliphatic ketones. J. Am. Chem. Soc. 2007 129 3074 3075. 

Hayashi and co-workers applied the asymmetric direct aldol reaction for the synthesis of chiral building block 75 for (+)-cytotrienin A 76," which is a microbial antitumor secondary metabolite. The diol 75 was synthesized with high enantioselectivity by means of the organo-catalytic aldol reaction of furfural 55 and propanal 39 in the presence of a catalytic amount of 4-acyloxy proline 74 (Scheme 27.13). The original procedure, i.e., with proline as a catalyst, was not effective for large-scale synthesis of 75 because of low yield and low diastereoselec-tivity. Total synthesis of (+)-cytotrienin A 76 was achieved in another 32 steps from diol 75. 

Inoue H, Kikuchi M, Ito J, Nishiyama H. Chiral Phebox-rho-dium complexes as catalysts for asymmetric direct aldol reaction. Tetrahedron 2008 64 493 99. 

Since 2(X)7, other chiral primary amines such as 35-39 (Fig. 5.1) have been synthesized and explored in the catalysis of asymmetric direct aldol reactions [21-23]. Maruoka developed primary amine catalysts 36 and 37 using a common chiral skeleton. Interestingly, these two catalysts demonstrated opposite chiral... 

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