Enantioselective, Organocatalytic Oxy-Michael Addition to γ/δ-Hydroxy-α,β-enones:  Boronate-Amine Complexes as Chiral Hydroxide Synthons

Abstract

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...

Origin of Diastereocontrol in the Oxy‐Michael Reactions of δ‐Lactol Anions: A Computational and Experimental Study

“…[7] Other organocatalytic approaches have also been successful, including the secondary amine-catalysed addition of benzaldoxime to a,b-unsaturated aldehydes developed by Jørgensen; [8] and the bifunctional Brønsted acid-base catalytic intramolecular oxy-Michael reactions for boronic hemiesters developed by Falck. [9] Organocatalysed intramolecular oxy-Michael reactions have also been reported by Scheidt [10] and separately by Hintermann [11] in the enantioselective syntheses of flavanones. Many of these reactions have been found to be of use in the synthesis of natural products.…”

Asymmetric Synthesis with Silicon‐Based Bulky Amino Organocatalysts

“…Apart from the catalysts, the nature of the acidic additive and the reagent concentration were the crucial factors for obtaining a highly efficient and general catalytic system, so their slight difference is the additive of the aromatic acid and temperature. Both gave excellent results with the corresponding phosphine derivatives (91) in high yields and enantioselectivities under optimized conditions (Scheme 29). To shed more light on the origin of the enantioselectivity, Córdova et al performed density functional theory (DFT) calculations on the P À C bond-forming step.…”

“…In fact, literature examples are exclusively limited to the use of functionalized phenols as nucleophiles [91] and also a couple of elegant procedures have been reported by Jørgensen and co-workers [92] for the b-hydroxylation of a,b-unsaturated aldehydes using oximes as O-nucleophiles.…”

Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion

“…64 The essential role of the aryl BA for high enantioselectivity was underlined by the formation of racemic product in its absence. However, it was observed that enantioselectivity was highly dependent on the structure of the aryl BA employed.…”