Research Interest

The principal emphasis of Professor Comins' research program is the development of new synthetic methodologies and strategies for the asymmetric synthesis of alkaloids, natural products and biologically active compounds. He is particularly interested in the design of new synthetic reactions, especially practical, high-yield methods for the synthesis of complex organic molecules with specific stereochemistry. Several strategies based on heterocyclic and organometallic chemistry are under investigation.

Professor Comins' group presently consists of fifteen postdoctorals and graduate students, and is funded by the National Institutes of Health (NIH) and pharmaceutical companies. The NIH has been supporting his efforts toward developing methodology useful for the synthesis of compounds having a broad range of biological properties, i.e. neuroleptic, antihypertensive, anti-inflammatory, antitumor, and anticonvulsant activities. Other studies supported by the NIH include basic research on the development of synthetic methods for the synthesis of optically active compounds using novel heterocycles as chiral building blocks. The Comins group has accomplished the synthesis of over 40 alkaloids. Recent synthetic achievements include asymmetric syntheses of (+)-elaeokanine A, (+)-elaeokanine C, (-)-septicine, (-)-tylophorine, (-)-laudanosine, (+)-carnegine, (+)-glaucine, (-)-xylopinine, (-)-pumiliotoxin C, (-)-lasubine I, (+)-subcosine I, (-)-sedamine, (+)-camptothecin, (+)-10-hydroxycamptothecin, (-)-porantheridine, (-)-indolizidine 235B, (-)-indolizidine 205A, (+)-indolizidine 209D, (-)-indolizidine 207A, trans-decahydroquinoline alkaloid (+)-219A, piperidine alkaloid (+)-241D, (+)-dienomycin C, (+)-benzomorphan, (+)-metazocine, (-)-N_α-acetyl-N_β-methylphlegmarine, (-)-perhydrohistrionicotoxin, (+)-luciduline, (+)-cannabisativine, (+)-streptazolin, (+)-desoxoprosopinine, (+)-deoxynojirimycin, (+)-allopumiliotoxin 267A, (-)-N_α-methyl-N_β-acetylphlegmarine, (-)-phlegmarine, (-)-N_α-methylphlegmarine, (-)-N_β-methyl-phlegmarine, (+)-lennoxamine, and (+)-hyperaspine.

Methodologies for the regio- and stereoselective preparation of various substituted N-acyldihydropyridines and N-acyldihydropyridones are being explored. These heterocycles have considerable potential for use as chiral synthetic intermediates. A simple procedure for the preparation of enantiopure 2-substituted 2,3-dihydro-4-pyridones from chiral N-acylpyridinium salts has been developed in his laboratories. The diastereoselectivity obtained from these additional reactions has been as high at 98%. This novel asymmetric synthesis has recently allowed the preparation of several enantiometrically pure alkaloids. The Comins group is presently exploring approaches to the enantioselective synthesis of several Lycopodium alkaloids, i.e. phlegmarine, lycolucine and spirolucidine, as well as other natural products shown below.

Other research supported by the NIH is directed as studying intramolecular photocycloadditons of dihydropyridones, and at utilizing the cycloadducts as synthetic intermediates. The 2+2 photocycloadditions hold significant promise for the development of biologically important compounds.

His research supported by industry deals mainly with the development of practical syntheses of pharmaceutically important compounds. Recent work under a grant from Glaxo, Inc. resulted in a novel asymmetric synthesis of the antitumor alkaloid, camptothecin. This new synthesis is the shortest to date requiring only nine steps from readily available material. A six-step synthesis of racemic camptothecin was also developed. Eighteen patents have been issued and two applications have been filed to protect these novel and practical syntheses. This new approach to camptothecin has been used by scientists at Glaxo Wellcome to prepare potential anti-cancer drugs. Other projects of industrial interest include catalytic asymmetric reactions, i.e. asymmetric epoxidation of olefins, 1,4-addition reactions, solid-support synthesis of heterocycles, and catalytic oxidation of hydrocarbons.