Allyl carbonates epimerization

Microsomal hydroxylation at allylic carbon atoms is commonly observed in drug metabolism. An illustrative example of allylic oxidation is given by the psychoactive component of marijuana. J -tetrahydnx annabinol J -THC. This molecule contains three allylic carbon centers (C-7. C-6. and C-3). Allylic hydroxylation occurs cxten.sively at C-7 to yield 7-hydroxy- j -THC as the major pla.sma metabolite in humans. " Pharmacological studies show that this 7-hydroxy metabolite is as active as, or even more active than. J -THC per se and may contribute significantly to the overall central nervous system (CNS) p.sychotomimctic effects of the parent compound. Hydroxylation also occurs to a minor extent at the allylic C-6 position to give both the epimeric ba- and 6/3-hydroxy metabolites. " Metaboli.sm does not occur at C-3, presumably becau.se of steric hindrance. 

In all cases examined the ( )-isomers of the allylic alcohols reacted satisfactorily in the asymmetric epoxidation step, whereas the epoxidations of the (Z)-isomers were intolerably slow or nonstereoselective. The eryfhro-isomers obtained from the ( )-allylic alcohols may, however, be epimerized in 95% yield to the more stable tlireo-isomers by treatment of the acetonides with potassium carbonate (6a). The competitive -elimination is suppressed by the acetonide protecting group because it maintains orthogonality between the enolate 7i-system and the 8-alkoxy group (cf the Baldwin rules, p. 316). 

Most dienones that have been reduced have structures such that they cannot give epimeric products. However, reduction of 17 -hydroxy-7,17a-dimethyl-androsta-4,6-dien-3-one (63) affords 17 -hydroxy-7j9,17a-dimethylandrost-4-en-3-one (64), the thermodynamically most stable product, albeit in only 16% yield. The remainder of the reduction product was not identified. Presumably the same stereoelectronic factors that control protonation of the / -carbon of the allyl carbanion formed from an enone control the stereochemistry of the protonation of the (5-carbon of the dienyl carbanion formed from a linear dienone. The formation of the 7 -methyl compound from compound (63) would be expected on this basis. 

The epimerization of (4R,9aR)-4-phenylperhydropyrido[2,l-c][l,4]oxazin-1-one at C9a carbon could be achieved by treatment with KN(SiMe3)2 in THF at 78 °C for 30 min to yield effectively the (4R,9aS) epimer (05TA3858). NaN(SiMe3)2 and LiN Pr2 proved to be less appropriate than KN(SiMe3)2, as they gave only 10% and 50% conversion, respectively. 9a-Substituted derivatives were obtained by alkylation of (4R,9flR)-4-phenyl-perhydropyrido[2,l-c][l,4]oxazin-l-one with alkyl iodides, allyl and benzyl bromides in THF in the presence of KN(SiMe3)2/ and HMPA at —78 °C for 1.5 h in 61-83% yields. 

Sialyl glycosides with a carbon linkage have also been prepared. Reaction of peracetylated 2- -chloro-2-deoxy-Neu5AclMe (55) with allyl(tri-7J-butyl) stannane, utilising radical coupling conditions, gave an epimeric mixture of the... 

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