Catalytic Asymmetric Syntheses of Tyrosine Surrogates Xiaojun Han,* Rita L. Civiello, Haiquang Fang, Dedong Wu, Qi Gao, Prasad V. Chaturvedula, John E. Macor, and Gene M. Dubowchik Neuroscience DiscoVery Chemistry, Research & DeVelopment, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492 xiaojun.han@bms.com ReceiVed July 21, 2008 Amino acid esters 5-11 as tyrosine mimics have been synthesized in excellent enantioselectivity (up to 99.6% ee) and in good overall chemical yields. The key step in the sequence was the Burk’s [Rh(COD)(2R,5R)-Et-DuPhos]BF 4 -catalyzed asymmetric hydrogenation of enamides with a variety of reactive functional groups. Introduction Tyrosine is one of four natural amino acids (histidine, phenylananine, tryptophan, and tyrosine) that contain aromatic moieties. In biological systems, the uniqueness of tyrosine rests on its phenolic -OH acting as both hydrogen bond donor and acceptor and its electron-rich aromatic ring capable of engaging in π-π stacking interactions. Tyrosine surrogates have been used in pharmaceutical research to improve the potency, pharmacokinetic properties and binding selectivity of target molecules. 1 As a part of a medicinal chemistry project, we required tyrosine surrogates 1 shown in Figure 1, where various NH- containing heterocycles could be used to probe SAR as well as provide good pharmacokinetic properties. For example, the presence of the heterocyclic ring could fine-tune the electron density of the phenyl ring and potentially modulate π-π stacking interactions in the active site. 2 We envisioned that these amino acid esters could be synthesized by the asymmetric hydrogenation of enamides 2, which could be obtained by olefination of aldehydes 3 and ylide 4. The structures of the amino acid esters synthesized in this paper are shown in Figure 2. The asymmetric synthesis of indole amino acid 6b and its cation-π interaction properties were reported. 3 A seven step racemic synthesis of free oxoindole amino acid 7 (without CBz protection) was reported in 1979. 4 Racemic amino acids 8-10 have been synthesized by the reaction of substituted benzyl bromides with sodioethylaceta- midomalonate or its equivalent, and were used as DOPA and dopamine analogues to study their effects on dopamine -hy- droxylase and tyrosinase. 5 They have also been prepared in racemic form by nitration of 4-aminophenylalanine to study their potential as inhibitors of norepinephrine biosynthesis. 6 The (1) (a) Song, Y.-L.; Peach, M.; Roller, P. P.; Qiu, S.; Wang, S.; Long, Y.-Q. J. Med. Chem. 2006, 49, 1585–1596. (b) Dolle, R. E.; Machaut, M.; Martinez- Teipel, B.; Belanger, S.; Cassel, J. A.; Stabley, G. J.; Graczky, T. M.; DeHaven, R. N. Bioorg. Med. Med. Chem. 2004, 14, 3545–3548. (2) (a) South, C. R.; Burd, C.; Weck, M. Acc. Chem. Res. 2007, 40, 63–74. (b) Lewis, D. F. V.; Jacobs, M. N.; Dickins, M. Drug DiscoVery Today 2004, 9, 530–7. (c) Nose, T. Peptide Science 2003, 39, 9–12. (3) Carlier, P. R.; Lam, P. C.-H.; Wong, D. M. J. Org. Chem. 2002, 67, 6256–6259. (4) Atkinson, J. G.; Wasson, B. K.; Fuentes, J. J.; Girard, Y.; Rooney, C. S. Tetrahedron Lett. 1979, 2857–2860. (5) (a) Loriga, M.; Paglietti, G.; Sparatore, F.; Pinna, G.; Sisini, A. IL Farmaco 1992, 47, 439–448. (b) Schmidhammer, H.; Hohenlohe-Oehringen, K. Sci. Pharm. 1983, 51, 8–16. (c) Zenker, N.; Talaty, C. N.; Callery, P. S.; Wright, J.; Hubbard, L. S.; Johnson, E. M., Jr. J. Heterocyclic Chem. 1983, 20, 435–437. (6) Milkowski, J. D.; Miller, F. M., Jr.; Zenker, N. J. Med. Chem. 1970, 13, 741–742. FIGURE 1. Tyrosine mimetics and their retro synthetic analysis. 10.1021/jo801577t CCC: $40.75  2008 American Chemical Society 8502 J. Org. Chem. 2008, 73, 8502–8510 Published on Web 10/15/2008