Catalytic Asymmetric Multicomponent Reactions

Multicomponent reactions (MCRs) are one-pot processes combining three or more substrates simultaneously [1], MCR processes are of great interest, not only because of their atom economy but also for their application in diversity-oriented synthesis and in preparing libraries for the screening of functional molecules. Catalytic asymmetric multicomponent processes are particularly valuable but demanding and only a few examples have been realized so far. Here we provide an overview of this exciting and rapidly growing area. 

A large number of catalytic asymmetric MCR are based on deoxo-bisubstitution reactions of carbonyl compounds such as the Mannich and Strecker reactions in which an oxo-group is displaced by two new cr-bonds, one to a nitrogen atom and one to a carbon atom. Other examples of deoxo-bisubstitutions include tandem processes that involve an initial Knoevenagel condensation followed by either a nucleophilic or a cycloaddition. These processes are characterized by the conversion of a C O-K-bond into two new C-C-cr-bonds and have been termed carba-acetalizations. 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car- 

Multicomponent Reactions. Edited by Jieping Zhu, Hugues Bienayme Copyright 2005 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 3-527-30806-7 

The proline-catalyzed three-component Mannich reaction is proposed to proceed through the reaction of enamine a, formed by the reaction of the ketone with pro- 

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Seayad J, List B (2005) Catalytic asymmetric multicomponent reactions. In Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 277-299... 

Catalytic asymmetric multicomponent reactions have only been available for a few years but have already demonstrated great potential for the efficient synthesis of diverse chiral non-racemic compounds. However, a number of important dial-... 

In 2013, Sun and co-workers demonstrated an elegant catalytic asymmetric multicomponent reaction of indoles, aldehydes 35, and amines catalyzed by 2.5 mol% of CPA (l )-32b. The reaction has been designed for the... 

The enantioselective synthesis of taxol side chain and (-)-epi-cytoxazone were then accomplished with this type of dual catalytic asymmetric multicomponent reaction [120]. Starting with the recrystalUzed P-amino-a-hydroxyl acid derivatives 318, a relatively concise synthesis of taxol side chain 319 was carried out in 18% overall yield with >99% ee, while (-)-epi-cytoxazone 320 was synthesized in four steps from corresponding intermediates with 32% overall yield (Scheme 2.87). 

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centers continue to be important in both academic and industrial laboratories (Nicolaou et al. 2003, 2006). In particular, catalytic asymmetric multicomponent domino reactions, used in the course total syntheses of natural products and synthetic building blocks, are highly desirable (Nicolaou et al. 2003, 2006 Tietze and Beifuss 1993 Tietze 1996 Tietze and Haunert 2000 Wasilke et al. 2005 Ramon and Yus 2005 Guo and Ma 2006 Pellissier 2006 Pellisier 2006 Tietze... 

Z. Chen, B. Wang, Z. Wang, G. Zhu, J. Sun, Angew. Chem. Int. Ed. 2013, 52, 2027-2031. Complex bioactive alkaloid-type polycycles through efficient catalytic asymmetric multicomponent aza-Diels-Alder reaction of indoles with oxetane as directing group. 

Using either of the two non-covalent catalytic modes of activation several multicomponent reactions could be performed with unprecedented selectivity and/or in a metal-free fashion for the first time. Figure 42.5 gives an overview of organo-catalysts with a non-covalent mode of action that have already been successfully applied in asymmetric multicomponent reactions and which will be discussed in the following section. 

In 2008, Hu et al. applied the dual catalytic strategy successfully to asymmetric multicomponent reactions (Scheme 2.85). In the presence of the achiral rhodium salt and a chiral phosphoric acid 5j, the reaction of aldimines 148, alcohols 311, and diazoacetates 312 smoothly afforded enantioenriched p-amino-a-hydroxyl acid derivatives 313 with up to >99% ee. These results indicated that Brpnsted acid efficiently activated... 

Catalytic asymmetric dihydroxylations (ADs) are easy reactions to perform. The reaction actually requires water and is insensitive to oxygen and so can be carried out without fear of exposure to the atmosphere. The reaction uses a multicomponent reagent system, which allows... 

The Petasis reaction is a mild multicomponent reaction that allows the conden sation of a boronic acid, an amine, and a carbonyl derivative to generate an allylic amine. Although several diastereoselective Petasis reactions have been reported [106], the first catalytic asymmetric reaction was described in 2008 (Scheme 1.29) [107]. It was shown that the condensation proceeds in high yields and enantiomeric excesses, affording the corresponding protected a vinylglycine derivatives. 

Discovered in the middle of the 19th century, the Strecker reaction is one of the earliest atom-economic multicomponent reactions. Amino nitriles were simply obtained from ammonia, hydrogen cyanide and an aldehyde. These products are important intermediates for the synthesis of natural and unnatural a-aminoacids. Due to the ever-increased demand for enantioenri-chied a-aminoacids, the asymmetric Strecker reaction has emerged as a viable synthetic method. Since the first report published in 1996, the catalytic enantioselective cyanation of preformed imines was intensively studied and several excellent reviews were devoted to this topic. ... 

Combinations of enamine-iminium ion activations together with other organo-catalytic activations in asymmetric organocatalytic domino and multicomponent reactions have been developed to achieve the enantioselective consecutive formation of two or more bonds in a stereoselective fashion. 

In 2008, Frechet et al. reported a one-pot multicomponent asymmetric cascade reaction catalysed by soluble star polymers with highly branched non-interpenetrating catalytic cores. Therefore, in the presence of four... 

The acid chloride precursor for the multicomponent reaction was accessed (Scheme 11) through the method that was developed in the theopederin D synthesis. The sequence largely followed the excellent route that was reported by Nakata." Our variation on this route was the incorporation of a catalytic asymmetric (3-lactone formation" " from acetaldehyde and propionyl chloride in the presence of 44 to yield, after opening with the lithium enolate of t-butyl... 

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