Investigations into novel applications of the ketone-catalyzed asymmetric epoxidation and progress toward the asymmetric total synthesis of merrilactone A

Abstract

The generation of enantiomerically pure compounds has been a constant challenge for organic chemists. The ability to synthesize a single enantiomer of a desired compound is of extreme importance for biologically active compounds. Oftentimes only one of a pair of enantiomers is biologically active, while the other is either inactive or deleterious. Enantioselective processes, especially those that are catalytic, have come to the forefront in today's synthetic laboratories, and catalytic asymmetric epoxidation reactions are no exception to this. Recently, an efficient asymmetric epoxidation method for simple, unfunctionalized olefins was reported using a fructose-derived ketone as catalyst and Oxone as oxidant. The use of this method for the asymmetric epoxidation of 2,2-disubstituted vinylsilanes has been investigated. The enantioselectivity of the reaction was found to be high in most cases. Following epoxidation, the substrates were desilylated to provide the corresponding 1,1-disubstituted terminal epoxides without loss optical purity.

The epoxidation of tryptophan derivatives has also been studied. It was found that these substrates do not readily participate in the asymmetric epoxidation, however limited results were obtained in the racemic epoxidation when the indole nitrogen of N-α-Boc- DL-tryptophan methyl ester was properly masked.

A novel ketone for use in the asymmetric epoxidation was also investigated. While the final target remained elusive, an interesting chelation effect was uncovered during the addition of organocerium and organolithium reagents to an advanced intermediate.

Finally, the total synthesis of the natural product mcrrilactone A was intensely studied. Merrilactone A has been shown to exhibit significant neurotrophic activity, such as greatly promoting neurite outgrowth in the primary cultures of fetal rat cortical neurons at concentrations from 10 μmol/L to 0.1 μmol/L. It consists of a densely functionalized pentacyclic ring system featuring two fused y-lactones and an oxetane ring. Key steps accomplished in the synthesis include a reagent-controlled stereoselective aldol reaction followed by substrate-controlled addition of vinyl lithium to the resulting β-hydroxyketone upon MOM protection of the newly formed alcohol.