Asymmetric hydroxylation of enolates using enantiopure (camphorylsulfonyl)oxaziridine derivatives and their applications in the synthesis of natural products

Bang-Chi Chen

doi:10.17918/00000604

The asymmetric hydroxylation of prochiral enolates to enantiomerically enriched [alpha]-hydroxy carbonyl compounds using non-racemic (camphorylsulfonyl)oxaziridine derivatives was investigated. Attempts to improve the asymmetric induction by refining the reaction conditions (temperature, bases, additives, etc) was successful in some cases. However, functionalization near the reactive site of the parent (camphorylsulfonyl)oxaziridine proved more general and effective in optimizing the stereoselectivity. (+)- and (-)-((8,8-Dimethoxycamphoryl)sulfonyl) oxaziridines were prepared in multi-gram quantities, in three steps from (camphorylsulfonyl)imine in >80% overall yield. This procedure involved selenium dioxide oxidation of the (camphorylsulfonyl)imine, ketal formation and biphasic oxidation. The dilithium (camphorylsulfonyl)imine dianion, generated by treatment of (camphorylsulfonyl)imine with 2.5 equivalents of LDA, was used to introduce functional groups adjacent to sulfonyl group. Technical grade (50-60%) instead of >95% m-chloroperbenzoic acid (m-CPBA) was used for the biphasic oxidation of functionalized (camphorylsulfonyl)imines to the corresponding oxaziridines. Studies of the oxidation of prochiral ketone enolates with (camphorylsulfonyl)oxaziridine derivatives revealed that the stereoselectivity is dependent on the enolate substitution pattern, oxaziridine structure and the reaction conditions (temperature, bases, additives, etc). While oxidation of the enolates of acyclic secondary ketones afforded high levels of asymmetric induction (>95% ee), oxidation of acyclic tertiary substituted ketone enolates derived from 2-methyl deoxybenzoin gave much lower enantiomeric excess (9-21% ee). In the asymmetric hydroxylation of the enolates of cyclic ketones such as 8-methoxytetralones and 5-methoxychromanones (skeletons found in many biologically active natural products), ((8,8-dimethoxycamphoryl)sulfonyl) oxaziridine was the reagent of choice affording the [alpha]-hydroxy carbonyl compounds in >95% ee. The AB-ring segment of [gamma]-rhodomycinone (94% ee), both (+)- and (-)-o-5,7-dimethyleucomol (>95% ee) and (+)-trimethylbrazilin (92% ee) were synthesized via the asymmetric enolate hydroxylation protocol. Transition state models were developed to rationalize these results. The products for the oxidation of [beta]-dicarbonyl substrates with (camphorylsulfonyl)oxaziridine derivatives proved substrate-dependent. For [beta]-diketone and acyclic [beta]-ketoesters, the oxidation products were racemic [alpha]-acyloxy ketone or [alpha]-acyloxy esters formed via a new type of Baeyer-Villiger rearrangement. For cyclic [beta]-ketoesters, the oxidation products were [alpha]-hydroxy-[beta]-ketoesters with high enantiomeric excess (up to >95% ee). This methodology was employed in the asymmetric synthesis of (+)-(R)-kjellmanianone (69% ee) and the AB-synthon of 4-demethoxydaunomicinone (95% ee). Oxidation of phosphorus ylides with N-sulfonyloxaziridines was also explored. Monosubstituted ylides afforded trans-alkenes while bisylides gave macrocyclic alkenes. Oxidation of disubstituted ylides produced [alpha]-dicarbonyl compounds. A "one-pot" procedure for the synthesis of [alpha]-diketone was also devised. A possible reaction mechanism was proposed.

Asymmetric hydroxylation of enolates using enantiopure (camphorylsulfonyl)oxaziridine derivatives and their applications in the synthesis of natural products

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Asymmetric hydroxylation of enolates using enantiopure (camphorylsulfonyl)oxaziridine derivatives and their applications in the synthesis of natural products

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