Educational Background:

PhD, Columbia University, 1972 BA, Harvard University, 1969

Awards:

• Weiss Presidential Fellow, 2008 • Presidential Green Chemistry Challenge Award   (Small Business), 2007 • American Chemical Society Award for Creative   Invention, 2007 • Chemical Manufacturers Association National   Catalyst Award, 1999 • American Chemical Society Arthur C. Cope Scholar   Award, 1996 • Class of 1960 Scholars Fellow, Williams College,   1995 • Clark Distinguished Teaching Award, 1986 • American Cyanamid Award for the Advancement   of the Art and Science of Chemical Synthesis, 1985 • John Simon Guggenheim Memorial Foundation   Fellow, 1981 • Camille and Henry Dreyfus Teacher-Scholar   Grant Award, 1978 • Alfred P. Sloan Research Foundation Fellow, 1978 • Eli Lilly Young Scientist Award, 1976

Research Description:

Our group is devising innovative strategies for the design and development of new multicomponent reactions. A multicomponent reaction (MCR) is a process in which three or more reactants combine in one pot to form a product that incorporates structural features of each reagent. MCRs generate structural complexity in a single step, are usually highly efficient, selective, convergent, and atom-economical.

MCRs also serve as the cornerstones of both combinatorial chemistry and diversity-oriented synthesis, and thus have played a central role in the development of modern synthetic methodology for pharmaceutical and drug discovery research. Together with target-oriented synthesis, combinatorial chemistry expands structural variations in a lead compound of interest. Diversity-oriented synthesis is helpful in exploring large areas of chemical structure space in search of new bioactive small molecules that might not be identified by conventional natural product screening assays. While the two approaches are complementary, both benefit from the complexity-generating characteristics of MCRs.

IMPROVING AND INVENTING MCRs

We have devised a general approach to improving known MCRs (Figure 1) that takes advantage of a detailed knowledge of reaction mechanism. A typical 4-component reaction of interest in combinatorial synthesis would employ inputs A, B, C, and D, each representing a family of compounds. The overall transformation might be visualized as a linear series of individual bimolecular reactions successively producing the symbolic intermediates A–D and A–D–C on the way to the final MCR product, A–D–C–B. [Note: The progression from line segment to triangle to pyramid is only meant to connote increasing molecular complexity, and is not meant to imply or designate specific connectivity between inputs.]

Applying retrosynthetic analysis to intermediates A–D–C and A–D can also identify independent routes to those intermediates from X+Y or from Q+R+S, respectively, as indicated. It follows that combining X+Y with B (and likewise combining Q+R+S with C and B) would constitute new 3- and 5-component routes, respectively, to the same product of the cognate reaction of A+B+C+D, but from a more diverse set of commercially available reactants, thus broadening the potential scope of chemical library synthesis. A further advantage of the 5-component route is that the overall dimensionality of the MCR is enhanced, exponentially increasing the potential size of the synthetic library.

Thus, logical ways to reengineer (and thus improve) a known MCR can be described. Although it’s less obvious that creative and/or serendipitous elements discovering new MCRs can be logically defined, Figure 2 depicts a general strategy whereby mechanistic insights into a known MCR might serve as an innovation platform for finding new MCRs using a process nicknamed the single reactant replacement (SRR) approach.

This approach begins with a systematic assessment of the mechanistic and/or functional role of each reactant in a known MCR. Based on the resulting chemical insights, one input (A, in this case) is then replaced with a different input W that mimics the key chemical reactivity or property necessary for condensation to occur with B and C. By embedding additional reactivity or functionality (either explicit or latent) into W, the resulting MCR might be directed to a different outcome -- for example, either a new structural framework or ring system. Thus, the chemist’s mechanistic insight into a known MCR can serve as an innovation platform from which to design or create imaginative SRR substitutions.

While the newly-developed MCR might resemble the cognate reaction, the SRR process is iterative, and can be applied again, this time replacing one of the other components in the same fashion. After one or two SRR cycles, the new MCRs that emerge are likely to be quite distinctive, and bear little resemblance to their progenitors.

This logic-based approach for the rational design (or improvement) of multiple component reactions has proven to be highly successful as indicated by the new structures illustrated below, which were produced by just some of the successful MCRs developed in the our laboratory. The long-term goal of our research is to expand the useful repertoire of such reactions, which are important as complexity-generating tools in both combinatorial and diversity-oriented synthesis.

Selected Publications:

B. Ganem, R. R. Franke, "Paclitaxel from Primary Taxanes: A B. Ganem, R. R. Franke, "Paclitaxel from Primary Taxanes: A Perspective on Creative Invention in Organozirconium Chemistry," J. Org. Chem. 72, 3981 (2007).

L. Fan, E. Lobkovsky, B. Ganem, "Bioactive 2-Oxazolines: A New Approach via One-Pot, Four Component Reaction," Org. Lett. 9, 2015 (2007).

I. F. Clémençon, B. Ganem, "Tandem Multicomponent/Click Reactions: Synthesis of Functionalized Oxazoles and Tetrazoles from Acyl Cyanides," Tetrahedron, 63, 8665 (2007).

C. A. Simoneau, B. Ganem, "A Three-Component Fischer Indole Reaction," Nature Protocols 8, 1249 (2008).

L. Fan, A. M. Adams, B. Ganem, "Multicomponent Reaction Design: A One-pot Route to Substituted Glyceric Acid Amides from ±-Diazoketones," Tetrahedron Lett. 49, 5983 (2008).