Research Interests of Daniel L. Comins

Dr. Dan CominsProfessor Daniel Comins received his B.A. degree in Chemistry in 1972 from the State University of New York at Potsdam and his Ph.D. in 1977 from the University of New Hampshire. During 1977-1979, he was a Postdoctoral Associate under the direction of Professor A.I. Meyers at Colorado State University working on the total synthesis of the antitumor alkaloids N-methylmaysenine and maysine. He joined the faculty of Utah State University in 1979, became an Associate Professor in 1984, and moved to North Carolina State University as a Full Professor in 1989.

In 1994, Professor Comins received the NCSU Alumni Association Outstanding Research Award, and was an NCSU Inventors Award Recipient in the years 1993-96, 2000, and 2002-11. He was a consultant with Johnson and Johnson for eight years, and was or is presently a consultant with Boehringer Ingelheim, SePRO, Scynexis, BioNumerik Pharmaceuticals, the Research Triangle Institute, Vertellus Specialties, and 10 other companies. In 1995 and again in 1999, he was elected to the Advisory Board of the International Society of Heterocyclic Chemists. In 1995, he was selected as a member of the SUNY Alumni Honor Roll, and in 1997 he received the Minerva Award from SUNY-Potsdam. He has been or is a member of the Editorial Advisory Boards of Progress in Heterocyclic Chemistry, Letters in Organic Chemistry, Current Topics in Medicinal Chemistry, and Advances in Heterocyclic Chemistry. Since 1996, Professor Comins has been an Associate Editor of the Journal of Organic Chemistry. In 1998, he became a Japan Society Promotion of Science (JSPS) Research Fellow.

He was a recipient of the 2005 North Carolina ACS Distinguished Lecturer Award and the 2006 NCSU Distinguished Service Award. In 2005 he gave the 7th Charles Rees Lecture at the 17th Lakeland Symposium, Grasmere, UK. He was named a Fellow of the American Chemical Society (2010) and a member of the Honorary Editorial Board of Reports in Organic Chemistry (2011). In 2011, he was elected President of the International Society of Heterocyclic Chemistry (2013-2015). Recently, he was selected as a Fellow of the Royal Society of Chemistry (FRSC, 2015) and a Permanent Member of the Global Advisory Board, World Academy of Chemistry (2015). In addition to 12 book chapters and review articles, Professor Comins and coworkers have published over 230 papers including 40 U.S. patents in various areas of organic synthesis and medicinal chemistry.

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.

The Comins group develops 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 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. 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, (-)-Nα-acetyl-Nβ-methylphlegmarine, (-)-perhydrohistrionicotoxin, (+)-luciduline, (+)-cannabisativine, (+)-streptazolin, (+)-desoxoprosopinine, (+)-deoxynojirimycin, (+)-allopumiliotoxin 267A, (-)-Nα-methyl-Nβ-acetylphlegmarine, (-)-phlegmarine, (-)-Nα-methylphlegmarine, (-)-Nβ-methyl-phlegmarine, (+)-lennoxamine, (+)-hyperaspine. (-)-brevicolline, (-)-macrostomine, alkaloid (-)-205B, and (-)-cermizine D.

This picture depicts how the dihydropyridone heterocycle can be substituted in a regioselective manner using various reactions.

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 our laboratories. The diastereoselectivity obtained from these additional reactions has been as high at 98%. This versatile asymmetric synthesis has recently allowed the preparation of numerous enantiometrically pure alkaloids. The Comins group is presently exploring approaches to the enantioselective synthesis of several Lycopodium alkaloids, i.e. lycolucine and spirolucidine, as well as other natural products shown below.

This picture shows the chemical structures of natural products that the Comins group has synthesized in their laboratories.

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

Our research supported by industry deals mainly with the development of practical syntheses of pharmaceutically important compounds. Work under a grant from Glaxo, Inc. resulted in a novel asymmetric synthesis of the antitumor alkaloid, camptothecin. This novel synthesis is the shortest to date requiring only six steps from readily available material. Eighteen patents have been issued and two applications have been filed to protect these novel and practical syntheses. Other projects of industrial interest include catalytic asymmetric reactions, 1,4-addition reactions, synthesis of heterocycles, and preparation of nicotine derivatives.

Recently, we started a program in the nicotine area. Nicotine derivatives may be useful in the treatment of multiple human disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, migraines, depression, pain and others. After finding that substitution reactions of natural (S)-nicotine were difficult and underdeveloped, we studied this problem to find solutions. In the last few years we have published ten papers and have been awarded twelve patents in this area. We have developed methods to substitute every position of the pyridine ring of natural (S)-nicotine. Numerous analogues have been prepared in our laboratories and tested at Targacept, Inc. for various CNS activities. Several of our compounds have exhibited exciting activity and potential as pharmaceutical leads. Ongoing studies in our laboratories are directed at converting commercially available (S)-nicotine to useful compounds, such as pharmaceuticals, insecticides, synthetic intermediates, and ligands for asymmetric synthesis. Our six-step synthesis of (S)-brevicolline and five-step synthesis of (S)-macrostomine from natural nicotine are examples of how we are making nicotine a useful member of the chiral pool.

A stereoselective synthesis of acyclic amino alcohols containing multiple chiral centers has been developed using N-acyldihydropyridones as building blocks. Diastereomerically pure amino alcohols containing three to five contiguous stereocenters were prepared using this method.

We have collaborated with Professor David Muddiman (NCSU) on improving limits of detection of biomolecules by mass spectrometry. Our group has designed and synthesized several new tags that have improved the ESI response ratio for the detection of peptides and carbohydrates. This mass spectrometry-based proteomics research has great potential for contributions to medicine, biochemistry, and biology.

Concise Total Syntheses of Natural Products.
       As part of our research program over the years, we have developed strategies for the short synthesis of alkaloids. In the schemes below are depicted several syntheses that are 10 steps or less.