Practical Syntheses of β-Amino Alcohols via Asymmetric Catalytic Hydrogenation

Enantiomerically pure â-amino alcohols have been extensively used as building blocks for the syntheses of pharmaceuticals1 and insecticidal agents,2 as chiral ligands in asymmetric catalysis,3 or as auxiliaries4 and resolving agents5 in asymmetric synthesis. Furthermore, they can be converted to chiral oxazoline ligands, which show tremendous utility in various asymmetric catalytic processes.6 The broad application of amino alcohol derivatives has generated considerable interest in developing efficient synthetic routes to these compounds.7 Such amino alcohols generally are obtained by reduction of the corresponding R-amino acids or esters.8 However, not all of the precursor R-amino acids are readily available, and sometimes low yields are observed in this reduction. To overcome these deficiencies, several alternative asymmetric synthetic methods have been developed.9 In principle, asymmetric catalytic hydrogenation of protected â-hydroxy enamides is a practical way to generate such amino alcohols. Although high enantioselectivities and reactivities have been reported for the asymmetric hydrogenation of dehydroamino acids,10 there have been no reports describing the synthesis of â-amino alcohols via asymmetric catalytic hydrogenation of enamides as illustrated in Scheme 1. Herein, we describe the first highly enantioselective, practical synthesis of â-amino alcohols using BICP-Rh and Me-DuPhos-Rh complexes as the catalysts [BICP, 2,2′-bis(diphenylphosphino)-1,1′-dicyclopentane; DuPhos, 1,2-bis(2,5-dialkylphospholane)benzene]. The key elements of this method involve: (a) facile synthesis of R-hydroxy ketones, (b) new enamide formation procedure from oximes using Fe/ Ac2O in DMF as reagents, and (c) high enantioselectivity in the hydrogenation step. The basic strategy for the synthesis of chiral â-amino alcohols involves asymmetric hydrogenation of R-arylenamides with a MOM-protected â-hydroxy group.11 Rhcatalyzed asymmetric hydrogenation must tolerate the E and Z isomers of these enamides since preparation and isolation of the isomerically pure E and Z isomers are difficult. Another practical issue in this approach is the formation of the â-hydroxy-substituted enamide substrates. We have prepared these MOM-protected â-hydroxy-substituted enamides in gram quantities from readily available 2-haloacetophenone derivatives 3 as outlined in Scheme 2.11 The first step involves synthesis of 2-hydroxyacetophenone derivatives 4 through nucleophilic attack on corresponding 2-haloacetophenone by sodium formate. An in situ hydrolysis reaction then follows. Nucleophiles other than formate such as acetate or hydroxide are not desirable for the synthesis of 2-hydroxyacetophenone derivatives. Protection of the hydroxy group with methoxymethyl chloride (MOMCl) went smoothly, giving MOM-protected keto alcohol 5 in good yield. The key step in the synthesis of enamide 1 is the conversion of the corresponding oxime 6 of the MOMprotected keto alcohol by Fe/Ac2O in DMF. The reported † The Pennsylvania State University. ‡ DuPont Agricultural Products. (1) (a) Roemer, D.; Buescher, H. H.; Hill, R. C.; Pless, J.; Bauer, W.; Cardinaux, F.; Closse, A.; Hauser, D.; Huguenin, R. Nature 1977, 268, 547. (b) TenBrink, R. E. J. Org. Chem. 1987, 52, 418. (c) Fincham, C. I.; Higginbottom, M.; Hill, D. R.; Horwell, D. C.; O’Toole, J. C.; Ratcliffe, G. S.; Rees, D. C.; Roberts, E. J. Med. Chem. 1992, 35, 1472. (d) Auvin-Guette, C.; Rebuffat, S.; Prigent, Y.; Bodo, B. J. Am. Chem. Soc. 1992, 114, 2170. (2) Wu, S.; Takeya, R.; Eto, M.; Tomizawa, C. J. J. Pestic. Sci. 1987, 12, 221. (3) (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. (b) Butsugan, Y.; Araki, S.; Watanabe, M. 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W.; Singaram, B. J. Org. Chem. 1994, 59, 7746 and references therein. (c) Tillyer, R. D.; Boudreau, C.; Tschaen, D.; Dolling, U.-H.; Reider, P. J. Tetrahedron Lett. 1995, 36, 4337. (d) Fisher, G. B.; Goralski, C. T.; Nicholson, L. W.; Hasha, D. L.; Zakett, D.; Singaram, B. J. Org. Chem. 1995, 60, 2026. (e) Chang, H. T.; Sharpless, K. B. Tetrahedron Lett. 1996, 37, 3219. (f) Reddy, K. L.; Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207 and references therein. (10) (a) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York, 1993. (b) Sheldon, R. A. Chirotechnology; Marcel Dekker: New York, 1993. (c) Noyori, R. Asymmetric Catalysis In Organic Synthesis; John Wiley & Sons: New York, 1994. (11) The initial demonstration of this strategy was carried out by A. Casalnuovo, K. M. Sun, R. Shapiro, T. Pahutski, M. Angiolelli, and J. Feaster using Me-DuPhos-Rh and Me-BPE-Rh catalyst systems. DuPont Agrichicultural Products, private communication. Scheme 1