Elsevier

Tetrahedron: Asymmetry

Volume 20, Issue 1, 30 January 2009, Pages 1-63
Tetrahedron: Asymmetry

Tetrahedron: Asymmetry report number 104
Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

https://doi.org/10.1016/j.tetasy.2009.01.002Get rights and content

Abstract

The most recent papers describing the stereoselective synthesis of cyclic quaternary α-amino acids are collected in this review. The diverse synthetic approaches are classified according to the size of the ring and taking into account the bond that is formed to complete the quaternary skeleton.

Introduction

Linear peptides are highly flexible molecules that can adopt many conformations in solution and, of these, only a few are responsible for their biological activity. The construction of novel peptide sequences with tailor-made enhanced properties is one of the most challenging areas in biomimetic research. The incorporation of rigid amino acid surrogates provides very useful information on the bioactive conformation and results in beneficial physiological effects. Between these rigid amino acids the use of quaternary compounds is one of the most interesting approaches, and for this reason during the last few years many procedures toward the stereoselective synthesis of these compounds have been described. In this context, we have previously reviewed (1998 and 2000) the stereoselective synthesis of these interesting compounds,1, 2 and, taking into account the great quantity of procedures reported, more recently we have published an update on the stereoselective synthesis of the acyclic α-amino acids3 that we complete now with a corresponding update of the cyclic systems.

Before beginning the summary of the new procedures concerning the stereoselective synthesis of these cyclic derivatives, it is worth mentioning that apart from our own contributions, during the last years some reviews that have focused on particular aspects have been published in relation to the synthesis of some cyclic amino acid and derivatives,4, 5 the synthesis of heterosubstituted carbocyclic α-amino acids,6 the synthesis of some fluorinated acyclic and cyclic amino acids,7 the synthesis of unnatural α-amino acids,8 and the modelling and synthesis of some conformationally constrained amino acids.9 Much more recently, the synthesis of the family of enantiomerically pure 1-amino-2-phenylcycloalkanecarboxylic acids,10 an excellent review of 1-aminocyclopropane-carboxylic acids,11, 12 the catalytic asymmetric synthesis of α-amino acids including some quaternary derivatives,13 the synthesis of cyclic α-amino acids and their use in the preparation of stable conformational short peptides,14 and also some recent approaches toward the asymmetric synthesis of quaternary amino acids15 have been reported.

Nevertheless, and in spite of all these reviews, some of which are from a general point of view and others focused on some particular aspects or families of compounds, we review all methodologies in a manner that should be useful to organic experimentalists.

Some data concerning the structural analysis of cyclic amino acids in small and medium size Acnc (1-aminocycloalkanecarboxylic acids) have been completed during these years and the synthesis and structural studies of model peptides containing these cyclic amino acids have been reported.16, 17, 18, 19, 20, 21, 22, 23, 24 Apart from these classical rings, the conformational tendencies of other cyclic amino acids such as Hms(Ipr) or O,O-isopropylidene-α-hydroxymethylserine,25 Afc or 9-amino-9-fluorenecarboxylic acid,26, 27 Daf or 9-amino-4,5-diazafluorene-9-carboxylic acid,28, 29 Adt 4-amino-1,2-dithiolane-4-carboxylic acid,30 the axially chiral α-amino acids Bip and Bin31, 32, 33, 34, 35, 36, 37 or the Bip system incorporating a crown ether receptor38 have been reported. More recently, the synthesis and properties of antAib, a novel tetrasubstituted α-amino acid of the Ac5c type possessing a fused anthracene fluorophore have also been reported.39, 40

Theoretical calculations focused on the study of the conformational tendencies of 1-aminocycloalkanecarboxylic acids (Acnc) have been reported.41, 42, 43 Of these compounds the cyclopropane derivatives have attracted the attention of many researchers, probably due to the particular characteristics that the cyclopropane ring confers to the amino acid. When additional substituents are incorporated into the ring, two stereogenic centers are formed and, as a consequence, new stereoisomers are possible. In the particular case of the incorporation of one phenyl ring as a substituent (named, c3Phe), the compound can be considered as a constrained phenylalanine and in this case several theoretical studies have been reported44 to explain the behavior previously described by our group.45, 46 The presence of an additional phenyl group in a different carbon atom (c3diPhe) confers peculiar characteristics to the molecule, which have been reported both from an experimental47 and theoretical points of view.48 The case of the cyclopropane derivative in which both phenyl substituents are on the same carbon atom (c3Dip) seems particularly interesting since it has been reported that it confers important tendencies to give a γ-turn in some model peptides.49, 50 The structural tendencies of other cyclopropane derivatives such as c3Val51, 52 or other 2-phenyl-1-aminocycloalkanecarboxylic acids such as c5Phe53 and c6Phe54, 55, 56 have also been reported. Additionally, the theoretical study of 8-aminopentacycloundecane-8-carboxylic acid has been reported.57 Very recently, the helical screw sense exclusively governed by stereogenic centers in the side chain of some cyclic amino acids has been reported.58, 59, 60

Finally, some systematic structure–activity relationships between biological properties of peptides incorporating quaternary cyclic amino acids have also been reported.61, 62, 63

Section snippets

Using cyclic compounds as starting materials

One of the most useful methodologies to prepare 1-aminocycloalkanecarboxylic acids in a stereoselective manner involves the use of cyclic compounds (typically aldehydes but ketones for the synthesis of quaternary α-amino acids) as starting materials, although in this case the introduction of both functional groups (amino and carboxylic group) is necessary. Of all reported methodologies, the Strecker reaction64, 65 and related synthesis have been repeatedly used. The diastereoselective Strecker

Using cyclic compounds as starting materials

One of the most useful procedures to the stereoselective synthesis of these compounds involves alkylation reactions using the non-quaternary cyclic amino acids as starting materials whenever stereochemical control can be achieved. For example, Wulff et al.227 reported the highly diastereoselective alkylation of enantiopure aziridine-2-carboxylic acid ethyl esters 572 and 573228 with complete retention of the stereochemistry. In this context, treatment of 572 with LDA at −78 °C in

Concluding remarks

In this review, we have covered recent progress in the development of new synthetic methodologies for the preparation of cyclic α,α-dialkylamino acids, and we have also discussed extensions to well-established synthetic routes. The use of cyclic compounds as starting materials is one of the most convenient procedures reported.

The construction of the cycle using cyclization or cycloaddition reactions both in a diastereoselective or in an enantioselective manner is one excellent alternative. All

Acknowledgements

This work was carried out with the financial support of CONACYT-MEXICO (Projects 62271 and 44126), Ministerio de Educación y Ciencia–FEDER (Project CTQ2007-62245) and Gobierno de Aragón (Group E40 and Project MI041/2007). This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract Number N01-CO-12400. The content of this publication does not necessarily reflect the view or the policies of the Department of

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