Peptides as Asymmetric Organocatalysts

ANJA FINGERHUT, DOMINIK GRAU AND SVETLANA B. TSOGOEVA  

Department of Chemistry and Pharmacy, Organic Chemistry Chair I and Interdisciplinary Center for Molecular Materials (ICMM), University of Erlangen-Niirnherg, Henkestrasse 42, 91054 Erlangen, Germany Email svetlana.tsogoeva fau.de 

Inspired by efficient and stereospecific metal-free enzymatic processes, synthetic chemists have devoted much effort in recent years to the development of a broad spectrum of short peptide-based asymmetric catalysts, which mimic various qualities of enzymes. The structural diversity available with short peptide sequences and the fact that peptides offer to the reactants a more strictly defined asymmetric scaffold, compared to single amino acids, makes this class of molecules particularly promising for the development of a broad spectrum of organic catalysts with fine-tunable structural and electronic properties. 

The first examples of asymmetric short peptide catalysis emerged in the 1980s. An important milestone for short peptide-catalysed asymmetric reactions in general, was reported by Inoue and coworkers in 1979 in the context of an asymmetric cyanation of benzaldehyde employing synthetic 

Sustainable Catalysis Without Metals or Other Endangered Elements, Part 1 

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The use of L-proline, amides derived from it, and related amino acids and small peptides as asymmetric organocatalysts for aldols - and indeed many other reactions mentioned elsewhere in this chapter - expanded hugely in 2006. A review deals with the direct aldol case.96... 

For a recent review on amino acids and peptides as asymmetric organocatalysts see E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481-2495. 

Jarvo ER, Miller SJ (2002) Amino acids and peptides as asymmetric organocatalysts. Tetrahedron 58 2481-2495... 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

Figure 6.7 Thiazole modified peptides as organocatalysts for the asymmetric intramolecular...

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. ... 

An interesting new development came with the realisation of Miller that a range of enan-tioselective reactions for which peptides based on the imiodazole sidechain of histidine were used as organocatalysts could possibly serve as a model for the asymmetric intramolecular Michael-Stetter reaction as well [32]. To this end. Miller synthesised thiazole based peptide-modified organocatalysts that can be described as having a thio-histidine as the crucial anuno acid (see Hgure 6.7). The respective amino acid was reported as thiazolylalanine (Taz). 

In contrast to the early recognition of the importance of proline and proline-based secondary amine peptide catalysts as enzyme mimics, the potential of primary amines in asymmetric catalysis was much underestimated at that time, probably because of their known lower basicity in comparison to secondary amines. This is particularly surprising taking into consideration the fact that primary amino acid catalysis is of enormous importance in enzyme catalysis. For example, primaiy amines occur in the catalytic sites of several enzymes, such as type I aldolases, dehydratases, and decarboxylases. Therefore, primary amines as organocatalysts possess particular appeal. 

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