An organocatalytic, enantioselective oxy-Michael addition to achiral γ-and δ-hydroxy-α,β-enones was developed. The key transformation is an unprecedented, asymmetric conjugate addition triggered by complexation between an in situ generated boronic acid hemiester and a chiral amine catalyst. Functionally, the intermediate amine-boronate complex acts as a chiral hydroxide surrogate or synthon. The resultant chiral β-hydroxy-ketones are obtained in good to excellent yields and high ee following mild oxidative removal of the cyclic boronate. Natural products (R,12Z,15Z)-2-hydroxy-4-oxohenicosa-12,15-dienyl acetate and (+)-(S)-Streptenol A were synthesized to demonstrate the utility of this reaction.Structural motif 1 is present in a wide range of natural products and synthetic intermediates. 1 While Michael additions of hydroxide or synthetic equivalents to α,β-unsaturated carbonyls represent an attractive approach to this moiety, 2 the strong basicity of the former and generally poor nucleophilicity or lability of the latter often render this option problematic. In its place, the intramolecular oxy-Michael addition of hemiacetal/hemiketal-derived alkoxides has emerged as a popular alternative strategy, 3 although the resultant cyclic acetals/ketals can be difficult to remove. In some instances, satisfactory diastereoselectivity has been attained via exploitation of adjacent secondary hydroxy or amino stereocenters. 4,5 In 2001, Watanabe et al 6 introduced an asymmetric version of the oxy-Michael addition utilizing chiral hemiketals derived from D-glucose and D-fructose in the more challenging case of achiral γ/δ-hydroxy-α,β-enones. Herein, we reported an unprecedented organocatalytic, enantioselective oxyMichael addition to achiral γ/δ-hydroxy-α,β-enones and its use in the preparation of 1 (eq 1). 7 The key transformation is the asymmetric conjugate addition triggered by complexation between boronic acid hemiester 3, generated in situ from γ/δ-hydroxy-α,β-enones, and a chiral amine catalyst. Functionally, the intermediate amine-boronate complex acts as a chiral hydroxide surrogate or synthon. Mild, oxidative removal of the boronate moiety from the dioxaborolane (n = 0) or dioxaborinane (n = 1) adduct 2 furnishes 1 in good to excellent overall yield and % ee.Recently, this 8 and other laboratories 9 have highlighted the nucleophilic properties of organoboronic acids and the unique stereospecific reactions of their borate complexes. Despite E-mail: j.falck@UTSouthwestern.edu. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2009 January 9. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript expectations, when model compound (E)-4-hydroxy-1-phenyl-2-buten-1-one (4) was mixed with equimolar phenylboronic acid and activated 4Å molecular sieves in CH 2 Cl 2 (Table 1, entry 1), no intramolecular Michael addition was observed, even though the hemiester (3: R= Ph, n = 0) could be detected by 1 H and 13 C NMR. Inclusion of some common bases, viz., bicarbonat...