Robert B. Grossman
A.B., Princeton University, 1987
Ph.D. Massachusetts Institute of Technology, 1992
Our group develops new synthetic methods and applies them to the synthesis of natural products and biologically relevant compounds. Students learn skills that prepare them for employment in the pharmaceutical and contract synthesis industries.
Research Project 1: Double Annulation
Our group has discovered a suite of reactions we call the double annulation route to fused bicyclic compounds. In the first step of the double annulation, two good carbon acids connected by a tether and an ethynyl ketone undergo a double Michael reaction to give a carbocyclic or heterocyclic compound in what is formally an [n + 1] annulation.
The functionality in the double Michael adducts can be used to create a second (and sometimes even a third) carbocyclic or azacyclic ring in a second step. Bicyclic ring systems that can be produced include trans-decalins, trans-hydrindanes, trans- and cis-perhydroisoquinolines, trans- and cis-perhydro-2-pyrindines, trans-perhydroindoles, trans-perhydropyrrolo[3,2-c]pyridines, cis-perhydro[1,7]naphthyridines, and tricyclic N,N'-diacylaminals. The latter self-assemble in the solid state into "supramolecular chair cyclohexanes".
The utility of the double annulation for natural product synthesis is established by a very short, stereoselective synthesis of the putative structure of sacacarin, a clerodane diterpenoid. Our synthesis proves that the group that discovered this compound incorrectly determined the location of the bridging lactone carbonyl group. We have proposed a revised structure for sacacarin and have proved its correctness by synthesizing this compound from the putative sacacarin.
Current efforts are aimed at further expanding the scope of the double annulation reaction and applying it to the total synthesis of natural and unnatural products. We are now developing total syntheses of the biologically active alkaloids yohimbine, an a2-adrenergic receptor antagonist, and codeine, a representative of the morphine family.
Research Project 2: Polycyclic, Polyprenylated Acylphloroglucinols
We have recently begun a new program aimed at the synthesis of the polycyclic, polyprenylated acylphloroglucinols (PPAPs), a large group of natural products with fascinating chemical structures and biological activities. For example, hyperforin is thought to be the bioactive constituent in St. John's wort, an herbal remedy for depression. Garsubellin A has properties that make it a potential lead in the search for drugs to treat Alzheimer's disease. Xanthochymol prevents microtubule depolymerization, a property it shares with the anticancer drug Taxol. We are exploring both biomimetic and nonbiomimetic routes to these and other PPAPs.
Research Project 3: Loline Biosynthesis
We are elucidating the biosynthetic route to loline, a naturally occurring insecticide that is produced by fungi that live between the cell walls of certain grasses. Our role is to synthesize isotopically labelled putative biosynthetic intermediates. These compounds are fed to the fungi, and the loline that they produce is isolated and checked for isotopic enrichment. This project is being carried out in collaboration with Profs. Chris Schardl and Lowell Bush in the College of Agriculture. We are also exploring new total synthetic routes to loline.
Education Project: Web-Based Interactive Organic Chemistry Homework
In collaboration with Prof. Raphael A. Finkel of the Department of Computer Science, we have developed a Web-based interactive organic chemistry homework program, ACE Organic. In the typical organic chemistry course, students are assigned questions out of a textbook for which a solutions manual is available. Students struggle with a question for a few minutes, look up the answer, and then feel as if they understand how to answer the question themselves. A computer program that can tell students that their responses are incorrect without giving away the correct answer is likely to be a more effective teaching tool.
Many Web-based chemistry homework programs already exist, but ACE Organic has features that, to our knowledge, are not present in combination in any other homework program:
- ACE Organic permits students to draw structural responses to posed questions with a graphical interface. ACE questions are typically draw-the-product, spectroscopy, and nomenclature problems. We are working on extending this capability to mechanism and conformation problems. Most other Web-based homework programs require text-based, numeric, or multiple-guess responses, none of which are well-suited to organic chemistry, where responses are usually structural drawings.
- ACE Organic offers response-specific feedback to students who submit incorrect responses. The feedback that ACE provides depends on the structural characteristics of the response. The feedback corrects errors in the students' reasoning and guides them gently to the correct answers.
- ACE Organic permits instructors to add to or modify the question database. An instructor may want to add material not covered by the questions in the database, or an instructor might want to correct an error in a question or modify it to offer better feedback for incorrect responses.
Pearson is now marketing ACE Organic world-wide. Students who buy a new Pearson textbook receive access to ACE for only an additional $5; others may purchase access to ACE at $25–30. Contact your Pearson representative to obtain access to ACE.
We are grateful to the following organizations for funding our research:
Synthetic Organic and Organometallic Chemistry