Sulfur‐Ylide‐Mediated Synthesis of Functionalized and Trisubstituted Epoxides with High Enantioselectivity; Application to the Synthesis of CDP‐840

Abstract

The carbonyl group occupies a position of central importance in organic synthesis as it allows ready functionalization, for example, in the a, b, and g positions. Direct transformations into other versatile functional groups, such as alkenes and epoxides, further increase the importance of carbonyl groups in synthesis. The ability to conduct such transformations enantioselectively would be extremely useful, and toward this goal we recently reported a practical, catalytic, and asymmetric conversion of aldehydes into epoxides by using the sulfide 1 (Scheme 1).[1] The sulfide 1, which is readily available in both enantiomeric forms, was obtained in four steps in 48 % overall yield from camphorsulfonyl chloride.However, attempts to apply our catalytic process to the synthesis of CDP-840, through an epoxidation reaction with 4-pyridinecarboxaldehyde, were unsuccessful. In mapping out the scope of the catalytic process we discovered that, as well as the reactions of heteroaromatic aldehydes that bear basic groups, those of n-alkyl aliphatic aldehydes, a,b-unsaturated aldehydes, acetylenic aldehydes, and ketones gave either low yields, low diastereomeric ratios, or low enantioselectivities. [2] A further limitation of the catalytic process emerged when we attempted to use a,b-unsaturated hydrazones with the chiral sulfide 1, as only low yields were observed. As unsaturated epoxides [3] and epoxides that contain a basic nitrogen functionality are difficult to prepare by oxidative methods, we were keen to find a solution to this problem. Indeed, a common limitation in catalytic asymmetric synthesis is substrate specificity and one solution to the problem is to devise a stoichiometric process with good recovery of the chirality-transfer agent. An outstanding example is the Evans auxiliary, which, even though it is used in stoichiometric amounts, is widely employed as a result of its broad applicability, reliability, and recyclability. Although enantioselective epoxidations with stoichiometric quantities of sulfide have been described, their scope is limited. SolladiØ-Cavallo et al. have only described the reaction of Eliel's oxathiane benzyl sulfonium salt with aromatic, [4] heteroaromatic, [5] and a,b-unsaturated aldehydes.[6] Metzner and coworkers have reported moderate to high enantioselectivities in reactions of trans-2,5-dimethylthiolane benzyl sulfonium salt with aromatic and heteroaromatic aldehydes [7] and moderate enantioselectivities in related allyl sulfonium salt reactions.[8] Furthermore, it is not possible to access both enantiomers of these sulfides easily, which further limits their practical applications.Herein we describe a process for the epoxidation of a very broad range of carbonyl compounds, including ketones, in high yields and with high selectivities. Although stoichiometric quantities of sulfide were required, the resulting high Scheme 1. Catalytic and asymmetric epoxidation of aldehydes; conditions: Rh 2 (OAc) 4 (1 mol %), BnEt 3 N + Cl À (10 mol %), CH 3 CN, 40 8C.[*] Prof.

Effect of sulfide structure on enantioselectivity in catalytic asymmetric epoxidation of aldehydes: Mechanistic insights and implications

“…Conditions (18). To a stirred solution of the sulfonium salt (31 mg, 0.07 mmol) in a 9:1 acetonitrile͞water mixture (0.4 ml) at room temperature was added the freshly distilled benzaldehyde (8 l, 0.07 mmol) followed by powdered KOH (7 mg, 0.125 mmol).…”

“…A broad range of aldehydes, including aromatic, aliphatic, and certain ␣,␤-unsaturated aldehydes, could be converted into the corresponding epoxides in generally high yield with high levels of enantioselectivity and diastereoselectivity (17). Sulfide 1 could also be used in a stoichiometric variant of this process, which allows access to epoxides that are difficult to form using the catalytic protocol (18).…”

Synthesis and elaboration of trans 2,3-diaryloxiranes

“…Once preformed the salt 29 from either the bromide or the alcohol, the ylide was prepared using different bases in presence of a range of carbonyl compounds. The method proved effective for the synthesis of aryl-aryl, aryl-heteroaryl, aryl-alkyl, and aryl-vinyl epoxides 32 (Scheme 8). Scheme 8…”

Studies towards a biomimetic synthesis of α-cyclopiazonic acid: synthesis of 5-substituted isoxazole-4-carboxylic esters

“…In many cases, sulfonium salts can be synthesized directly from the corresponding alcohols by treatment of a suitable mineral acid (e.g., HBF 4 or HPF 6 ). 37,38 A variety of conditions was tested but the isoxazole 21 was unreactive, probably because it is rather electron-deficient (this reaction works best with electron-rich aromatics). As such, alcohol 21 was first converted into bromide 14.…”