Electronic Effects on the Regio- and Enantioselectivity of the Asymmetric Aminohydroxylation of O-Substituted 4-Hydroxy-2-butenoates CHIH-YUAN CHUANG, VICTOR C. VASSAR, ZUPING MA, RAPHAE È L GENEY, AND IWAO OJIMA* Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York ABSTRACT Regio- and enantioselectivity in the asymmetric aminohydroxylation AA) reaction of O- substituted 4-hydroxy-2-butenoates as well as the mechanism of the reaction were studied. When the electronic properties of the phenyl group in a substrate were altered by using different substituents, two conflicting trends were observed: The O-benzoyl substrates showed greater regio- and enantioselectivity when an electron-donating substituent was attached at the C-4 position of the phenyl group, while the O- benzyl substrates exhibited better regio- and enantioselectivity with an electron-withdrawing substituent at the C-4 position of the phenyl moiety. Thus, these results have disclosed hitherto unknown re- markable electronic effects in the AA reaction. Detailed analysis of possible electronic interactions in the chiral catalystsubstrate complex has revealed the importance of dipolar aromaticaromatic interac- tions between the aromatic substituent of the substrate and the nitrogen heteroaromatic moiety of the chiral ligand for effective regiocontrol as well as enantioface selection in the AA reaction. A plausible model of the key intermediate in the AA reaction of O-substituted 4-hydroxy-2-butenoates is proposed. Chirality 14:151162, 2002. Ó 2002 Wiley-Liss, Inc. KEY WORDS: regioselectivity; enantioselectivity; aminohydroxylation; catalysis; asymmetric synthesis; electronic effect; hydroxybutenoate derivatives Catalytic aminohydroxylation transforms olefins to the corresponding b-N-tosylamino alcohols using chloramine- T as the nitrenoid source and water as the hydroxyl source in the presence of a catalytic amount of osmium tetrox- ide. 1,2 When chiral ligands, i.e., dihydroquinidine DHQD) and dihydroquinine DHQ) derivatives, were introduced by Sharpless et al. to this process, 35 this reaction became the catalytic asymmetric aminohydroxylation AA) pro- cess that serves as a powerful method for the enantio- selective synthesis of a variety of biologically relevant compounds. 58 The catalytic AA process is mechanisti- cally closely related to the well-established catalytic asymmetric dihydroxylation AD) reaction. 9 Accordingly, it has been shown that chiral DHQD and DHQ ligands, which were originally designed for the AD reaction, 911 are also effective in the AA reaction. Unlike the AD reac- tion, there is a regioselectivity issue in the AA reaction of unsymmetrical alkenes. Substrates such as styrene, cin- namate, and other unsymmetrical alkenes have been suc- cessfully employed in the AA reaction, achieving high regio- and enantioselectivity. 35 However, variable regi- oselectivity as well as enantioselectivity has been observed when using other types of alkene substrates. 5 In the course of our study on the structureactivity relationships of the second-generation taxoids, 12 we started our inves- tigation into the application of the AA process for the asymmetric synthesis of a variety of 3-alkenyl and 3-alky- lisoserines from 4-hydroxy-2-butenoates. While our inves- tigation was in progress, Janda and co-workers 13 reported the successful application of the AA reaction to a variety of O-substituted 4-hydroxy-2-butenoates and related sub- strates. Accordingly, we turned our attention to more mechanistic aspects of the AA reaction in this class of substrates and found two conflicting substituent effects on the regio- and enantioselectivity of the reaction depending on the substrate types within O-substituted 4-hydroxy-2- butenoates. Although Janda and co-workers 13 proposed that steric and electronic effects including aromaticaro- matic interactions could play an important role in deter- mining the regioselectivity of the AA reaction, their proposed mechanism does not address the two conflicting electronic substituent effects that we observed. This mechanistic mystery led us to look closely into possible substrateligand interactions in the AA reaction, which has unveiled unique aromaticaromatic interactions that are crucial for achieving high regio- and enantioselectivity. We describe here the hitherto unknown substituent effects in the AA reaction of O-substituted 4-hydroxy-2-butenoates Scheme 1) and a plausible mechanism that can accom- modate the observed mysterious substituent effects. MATERIALS AND METHODS O-Substituted 4-hydroxy-2-butenoates 1 were prepared through the benzoylation or benzylation of Z-2-buten-l,4- diol. Followed by ozonolysis of the resulting symmetric Contract grant sponsor: National Institutes of Health; Contract grant number: GM39226 * Correspondence to: Iwao Ojima, Distinguished Professor, Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400. E-mail: iojima@notes.cc.sunysb.edu Received for publication 8 May 2001; Accepted 24 June 2001 Ó 2002 Wiley-Liss, Inc. DOI 10.1002/chir.10050 CHIRALITY 14:151162 2002)