Novel heterocyclic •-amino acids with sulfur-containing side-chains
Raymond C. F. Jones,*a Lisa J. Crumpling,a and James N. Ileyb
aDepartment of Chemistry, Loughborough University, Loughborough, Leics. LE11 3TU, UK
bDepartment of Chemistry, Open University, Walton Hall, Milton Keynes MK7 6AA, UK
E-mail:
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Dedicated to Professor Siegfried Blechert on the occasion of his 65th birthday
Abstract
S-Alkylation of an N-protected cysteine ester with a range of •-iodoalkyl heterocycles affords 11 novel non-proteinogenic heterocyclic amino acids having a sulfur atom in the backbone- heterocycle linker.
Keywords: Amino acid, heterocycle, cysteine, nucleobase
Introduction
Amongst the proteinogenic amino acids, there are only two examples of side chains carrying a heterocycle, namely histidine 1 and tryptophan 2 (Figure 1). On the other hand heterocyclic chemistry provides an enormous range of potential heterocyclic systems that might be exploited to replace the imidazole or indole moieties. As part of a programme to explore this possibility, we have previously reported on •-amino acids 3 (n = 0, 2, 3) carrying heterocycles in their side chains, including pyridine and isoxazole derivatives but in particular the pyrimidine and purine nucleobases tethered to the backbone with varying length carbon chains.1,2 These are potential •- PNA monomers,3,4 amongst many other possible applications, and are analogues of natural products such as discadenine.5 They are obtained by stereoselective conjugate radical addition to an optically active methylene oxazolidinone derived from S-methylcysteine,1 or by stereoselective C-alkylation of an ephedrine-based glycinamide.2 In pursuit of further variation in the heterocycle-backbone tether and the backbone-to-heterocycle linkage protocol, and to demonstrate diversity in the heterocycle, we report now the preparation of 11 novel heterocyclic amino acids 4 (n = 1, 2, 3) with sulfur-containing tethers, obtained by elaboration of cysteine (Figure 1).6,7 The strategy adopted (Scheme 1) was to alkylate the side chain sulfur atom of a cysteine derivative with haloalkyl heterocycles; the heterocycles employed were nucleobases (uracil, thymine, adenine) and the simpler analogues indole, benzimidazole, benzotriazole and purine. This C–S bond formation is distinct from those employed by others, and extends the
