This article describes a highly effective catalytic asymmetric epoxidation method for olefins using potassium peroxomonosulfate (Oxone, Dupont) as oxidant and a fructose-derived ketone (1) as catalyst. High enantioselectivies have been obtained for trans-disubstituted and trisubstituted olefins which can bear functional groups such as tributylsilyl ether, acetal, chloride, and ester. The enantiomeric excesses for cis-olefins and terminal olefins are not high yet. The current epoxidation shows that the catalyst efficiency is enhanced dramatically upon raising the pH. Mechanistic studies show that the epoxidation mainly proceeds via a spiro transition state, which provides a model for predicting the stereochemical outcome of the reaction. The planar transition state is likely to be the main competing pathway. The extent of the involvement of the planar mode is subject to the steric effect of the alkyl groups on the olefins.

Epoxides are very important chiral building blocks for the synthesis of enantiomerically pure complex molecules. 1 Asymmetric epoxidation of olefins presents a powerful strategy for the synthesis of enantiomerically enriched epoxides. Great success has been achieved in the epoxidation of allylic alcohols 2 and unfuctionalized cis-olefins. 3 However, the epoxidation of trans-olefins bearing no allylic alcohol group with high enantiomeric excess still remains a challenging problem. 4 It was desirable to explore alternative systems for a solution. Among many other powerful methods for the epoxidation of olefins, 5 dioxiranes are remarkably versatile oxidation reagents, and their use as epoxidation reagents has risen to particular prominence. 6,7 The reaction is rapid and requires a simple workup. An important feature associated with dioxiranes is that they can be generated in situ from Oxone (potassium peroxomonosulfate) and a ketone, 8 which provides opportunities for asymmetric epoxidation when a chiral ketone is used.However, progress in the area of dioxirane-mediated asymmetric epoxidation has been limited. 9 The enantiomeric excess (ee) has been low (9-20%). Since dioxiranes have two reacting sites, it is crucial to limit possible competing approaches. Recently, some progress has been made in this regard. Yang reported an intriguing C 2 symmetric cyclic chiral ketone for asymmetric epoxidation. 10 An 87% ee was obtained in one case, although the ee values for most cases were low (5-50%).Herein we wish to report our efforts in the area of asymmetric epoxidation. We are utilizing ketones containing the following general features: (1) the stereogenic centers are close to the reacting center, resulting in efficient stereochemical communication between substrates and the catalyst; (2) the presence of a fused ring and a quaternary center R to the carbonyl group minimizes the epimerization of the stereogenic centers; (3) one face of the catalyst is sterically blocked to limit the possible competing approaches. Ketone 3 has these desirable structural features, and is readily prepared from very inexpensive Dfructose ($15/kg) by ketalization (acetone, HClO 4 , 0°C, 53%) and oxidation (PCC, rt, 93%). 11Initial studies involving ketone 3 in the epoxidation of transstilbene revealed that while the yield of stilbene epoxide increased with the reaction time, the enantiomeric excess decreased. Upon examination, we determined that ketone 3(1) For a review, see: Besse, P.; Veschambre, H. Tetrahedron 1994, 50, 8885-8927. (2) For a review, see: Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993; Chapter 4.1.(3) For leading references, see: (a) Collman, J. P.; Zhang, X.; Lee, V. b) References 7b and c and references cited therein. (9) (a) Curci, R.; Fiorentino, M.; Serio, M. R. J. Chem. Soc., Chem. Commun. 1984, 155-156. (b) Curci, R.; D'Accolti, L.; Fiorentino, M.; Rosa, A.Table 1. Asymmetric Epoxidation of Representative Olefins Catalyzed by Ketone 3 a aAll reactions wer...

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The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).

Quaternary carbon stereocenters are found in a broad range of organic compounds, including important bioactive natural products and medicinal agents. Given their ubiquity and the significant synthetic challenges they present, quaternary carbon stereocenters have long attracted great interest from synthetic organic chemists. Numerous efforts have been devoted to their construction, leading to a spectrum of strategies for creating stereogenic quaternary carbon centers. In this context, the semipinacol rearrangement has proven successful. In this extension of the pinacol rearrangement, the 1,2-carbon-to-carbon migration in a 1,2-diol has been expanded to include leaving groups other than the hydroxyl group. Over the past decade, our laboratory has explored the semipinacol rearrangement strategy for the stereoselective construction of quaternary carbon stereocenters. We have investigated various substrates, including 2,3-epoxy alcohols (also termed α-hydroxy epoxides), 2,3-aziridino alcohols, and allylic alcohols. Several promoters that effect the semipinacol rearrangement have been identified, including Lewis acids based on Al, Sm, B, Zn, and Ti for the rearrangement of α-hydroxy epoxides and 2,3-aziridino alcohols; cationic halogen species for the rearrangement of allylic alcohols; and cinchona alkaloids and chiral phosphoric acid for the asymmetric semipinacol rearrangement. Our research efforts have led to a series of valuable synthetic methods, including (1) a tandem semipinacol rearrangement and Meerwein-Ponndorf-Verley reduction, (2) a tandem semipinacol rearrangement and Tishchenko reaction, (3) a tandem semipinacol rearrangement with either an allylation or a propargylation, (4) a tandem semipinacol rearrangement and Schmidt reaction, (5) a semipinacol rearrangement of 2,3-aziridino alcohols, (6) a semipinacol rearrangement of allylic alcohols induced by halogen cation, (7) a tandem aziridination and semipinacol rearrangement of allylic alcohols, and (8) asymmetric semipinacol rearrangements with chiral organic catalysts. One hallmark of these reactions is the creation of stereogenic quaternary carbon centers with high levels of stereocontrol. In this Account, we describe the development of these synthetically useful methodologies and their successful application to the total syntheses of natural products. Our results demonstrate that the semipinacol rearrangement of carefully designed substrates constitutes an efficient approach to the stereoselective construction of quaternary carbon centers. These reactions have produced a broad array of useful compounds that lend themselves to further elaboration. Furthermore, the total synthesis of a series of alkaloids, with significant bioactivity and intriguing molecular architecture, was achieved through these semipinacol rearrangement strategies, highlighting their synthetic value.