Regio- and Stereoselective Epoxidation

Compound 2 was found to be stable under a wide range of thermal conditions and pH. Transformation to the ester 4 could be achieved easily under acidic conditions by use of trimethylsilylchloride or hydrochloride in methanol. In general, addition reactions to the conjugated diene system are controlled by the steric demand of the ring substituents and, furthermore, by the electron deficiency at the C5-C6 double bond, because of the electron-withdrawing effect of the carboxylic group [7b, 16, 17]. Thus, addition to 4 of meta-chloroperoxybenzoic acid (m-CPBA), used as the epoxidizing agent, occurs exclusively at double bond C3-C4. The stereochemistry of peroxide attack, and hence the configuration of the resulting epoxide, is directed by the functionality at C2. If this is an allylic hydroxyl group, m-CPBA coordinates by hydrogen bonding and forces the C2-C3 cis configuration of 5, as is proven by X-ray structural analysis (Scheme 6.4.5, Figure 6.4.1) [18]. When the same conditions are applied to the protected diol 6, which is easily obtained from 4 by sily-lation with TBDMS-triflate, the bulky 2-siloxy group shields the a-face of the cyclohexadiene plane hence attack of the peracid occurs regioselectively from the b-face resulting, after deprotection, in the formation of diastereomer 8 [17].

The reduction of the ester functionality of 6 to the corresponding alcohol 9 can be achieved efficiently by use of diisobutylaluminum hydride (DIBAL-H). Subse-



Scheme 6.4.5. Regio- and stereoselective epoxidation of 2,3-trans-CHD.

quent epoxidation with equimolar amounts of m-CPBA at low temperature results exclusively in the monoepoxide 10 [19]. Under more rigorous conditions (raised temperature, prolonged reaction time, and excess of oxidizing agent) bisepoxide 11 is formed in high yield (Scheme 6.4.6) [17, 20].

Both epoxides 10 and 11 already have the core structure of ent-senepoxide and iso-crotepoxide. Benzoylation of the free hydroxyl group, cleavage of the siloxy groups, and subsequent acetylation of the diol unit gives the stereoisomers of the natural products (Scheme 6.4.7) [17]. This approach to stereoisomers of the naturally occurring senepoxide and crotepoxide is characterized by a small number of reaction steps and high overall yield. Investigation of the regio- and stereoselective

Fig. 6.4.1. Molecular structure of epoxide 5 showing the C2-C3 cis configuration.



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