Diastereoselective Synthesis of Cyclopropane Amino Acids Using Diazo Compounds Generated in Situ Luke A. Adams, Varinder K. Aggarwal,* Roger V. Bonnert, † Bettina Bressel, Russell J. Cox,* Jon Shepherd, Javier de Vicente, Magnus Walter, ‡ William G. Whittingham, ‡ and Caroline L. Winn School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K. v.aggarwal@bristol.ac.uk; r.j.cox@bris.ac.uk Received July 23, 2003 A simple and high-yielding method for the preparation of cyclopropane amino acids is described. The novel method involves the one-pot cyclopropanation of readily available dehydroamino acids using aryl and unsaturated diazo compounds generated in situ from the corresponding tosylhy- drazone salts. It was found that thermal 1,3-dipolar cycloaddition followed by nitrogen extrusion gave the cyclopropane amino acid derivatives with good E selectivity, while reactions in the presence of meso-tetraphenylporphyrin iron chloride gave predominantly the corresponding Z isomers. The synthetic utility of this process was demonstrated in the synthesis of (()-(Z)-2,3-methanophenyl- alanine [(()-(Z)-1], the anti-Parkinson (()-(E)-2,3-methano-m-tyrosine [(()-(E)-2], and the natural product (()-coronamic acid [(()-3]. Introduction The biological study of new amino acids, as well as their effect on the structure of peptides and in proteins, is a central goal in drug discovery. 1,2 These compounds are also used as a source of chiral materials, 3 food additives, 4 and agrochemicals. Cyclopropane amino acids, especially R-2,3-methanoamino acids, have recently found wide application in peptidomimetics due to their rigid conformation. The presence of the strained cyclopropane ring in an amino acid based drug may also lead to new interactions with an enzyme active site (or to a receptor), resulting in biological activity. 5 Enhanced specific binding can also be gained by “preorganization” of the amino acid side chain by attachment to the cyclopropane moiety. This then leads to issues of diastereoselectivity that must be addressed during synthesis. The R-2,3-methanoamino acids are the most common analogues of the naturally occurring amino acids includ- ing 2,3-methanophenylalanine (1) and 2,3-methano-m- tyrosine (2) (Figure 1). The 1R,2S enantiomer of the latter amino acid is the most potent competitive inhibitor of L-aromatic amino acid decarboxylase (dopa decarboxy- lase, DDC), a pyridoxal 5′-phosphate (PLP) dependent enzyme which catalyzes the decarboxylation of L-dopa and 5-hydroxy-L-tryptophan, thus playing a critical role in the biosynthesis of the important neurotransmitters ephedrine, norephedrine, and serotonin. 6 DDC inhibitors are used in the treatment of Parkinson’s disease. 7 Cy- clopropane amino acids such as coronamic acid (3) can also be found in nature, isolated after hydrolysis of the bacterial toxin coronatine from Pseudomonas syringae. 8 The synthesis of cyclopropane amino acids has at- tracted much curiosity. 9-12 The synthetic challenge in the * To whom correspondence should be addressed. † AstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Rd., Loughborough, Leics LE11 5RH, U.K. ‡ Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6ET, U.K. (1) Williams, R. M. Synthesis of Optically Active Amino Acids; Pergamon Press: Oxford, 1989. (2) Spatola, A. F. In Chemistry and Biochemistry of Amino Acids, Peptides, and proteins; Weinstein, B., Ed.; Marcel Dekker: New York, 1983; Vol. 7, p 267. (3) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis: Construc- tion of Chiral Molecules Using Amino Acids; Wiley & Sons: New York, 1987. (4) Mapelli, C.; Stammer, C. H.; Lok, S.; Mierke, D. F.; Goodman, M. Int. J. Pept. Protein Res. 1988, 32, 484-95. (5) Williams, R. M.; Fegley, G. J. J. Am. Chem. Soc. 1991, 113, 8796-8806. (6) Pletscher, A.; Gey, K. F.; Burkard, W. P. Handb. Exp. Pharmakol. 1966, 19, 593-735. (7) Ahmad, S.; Phillips, R. S.; Stammer, C. H. J. Med. Chem. 1992, 35, 1410-1417. (8) Parry, R. J.; Mafoti, R. J. Am. Chem. Soc. 1986, 108, 4681-4682. (9) Stammer, C. H. Tetrahedron 1990, 46, 2231-2254. (10) Burgess, K.; Ho, K. K.; Moyesherman, D. Synlett 1994, 575- 583. (11) Cativiela, C.; Diaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2000, 11, 645-732. FIGURE 1. R-2,3-Methanoamino acids. 10.1021/jo035060c CCC: $25.00 © xxxx American Chemical Society J. Org. Chem. XXXX, XX, A PAGE EST: 7.9 Published on Web 00/00/0000