High-Pressure Mediated Asymmetric Diels-Alder Reaction of Chiral Sulfinylacrylate Derivatives and Its Application to Chiral Synthesis of (-)-COTC and (-)-Gabosine C

The asymmetric Diels-Alder reactions of chiral sulfinylacrylate derivatives (1 and 2) with dienes (3-12) were examined under high-pressure (1.2 GPa) conditions.The endo cycloadduct (13e) obtained from sulfinyl acrylate (1) and 2-methoxyfuran (5) was converted to (-)-COTC (25) and (-)-gabosine C (26).The asymmetric Diels-Alder (D-A) reaction is one of the most efficient tools for constructing optically active cyclic compounds bearing up to four stereogenic centers in a single operation. 1In a large number of highly asymmetric D-A reactions, there are numerous examples of cycloadditions of chiral dienophiles with active dienes such as cyclopentadiene. 2Although considerable effort has been devoted to designing powerful chiral dienophiles which react with less active dienes such as furans, there are few successful examples of such cycloadditions. 3Having negative volume of activation, D-A reaction is amenable to high-pressure conditions. 4Moreover, high-pressure techniques have been known to be an efficient method not only for the synthesis of molecules sensitive to Lewis acid catalysis but also for enhancement of asymmetric induction. 5Applying this technique, asymmetric D-A reactions would proceed without a Lewis acid between unactivated dienophiles and less active dienes, 6 and this strategy could have wide application.In a previous report, 7 we demonstrated high-pressure mediated asymmetric D-A reaction of chiral sulfinylacrylate derivatives (1 8 and 2) with furan (4) or 2-methoxyfuran (5).We wish to report here the scope and limitations of this method and the application of the cycloadduct (13e) to the chiral synthesis of a glyoxalase I inhibitor, (-)-COTC (25) 3c,9 and (-)-gabosine C (antibiotic KD16-U1) (26) 10 in detail.(+)-Z-3-(2-exo-Hydroxy-10-bornyl)propenamide (2) was prepared in two steps from 10-mercapto-2-exoborneol 8 by successive Michael addition to propiolamide 11 and selective mCPBA oxidation in 43% overall yield.In order to establish the scope and limitations of high-pressure mediated asymmetric D-A reaction of the dienophiles (1 and 2), we investigated this reaction with various non-activated dienes (4-7, 9-12) and with Danishefsky's diene (8) (Figure 1).In our preliminary experiments, the steric course of the cycloaddition of 1 and 2 with cyclopentadiene (3) under high-pressure conditions was compared with that under atmospheric pressure conditions (Figures 1 and2).Reactions of 1 with 3 in CH 2 Cl 2 proceeded readily at rt under both atmospheric and high-pressure (1.2 GPa) conditions to give the same endo cycloadduct (13a) as a single diastereomer in 92 and 88% yields, respectively.Similar reactions of 2 with 3 in CH 2 Cl 2 /MeOH (1:1) under atmospheric or highpressure conditions gave endo cycloadduct (13b) and exo cycloadduct (14b) in 87 and 5% yields or 81 and 9% yields, respectively.All of these reactions proceeded with high diastereoselectivity and regioselectivity.The structure of 13a was confirmed by comparison of its spectral data with those in the literature 8 and the absolute configuration of product (13b) was determined by X-Ray diffraction analysis.From these results, the same steric course was suggested for the reaction of 1 or 2 with 3 under both atmospheric and high-pressure conditions.3b-e The conformation for C=C-S=O of 1 and 2 should be oriented s-trans due to strong dipole-dipole repulsion between sulfinyl and carbonyl groups.An attack of 3 from the less hindered face (lone pair-side) is favored to give adducts (13a,b) (Figure 3).Most of the attempts to achieve the D-A reactions of dienophiles (1 and 2) with dienes (4-12) under thermal conditions (50-100 °C) were unsuccessful and the starting dienophiles were recovered.