	Schreiber: Expanding DOS
	Kahne: DOS Carboydrates
	Jacobsen: DOS Catalysts

Projects

Expanding the Scope of Diversity Oriented Synthesis

Co-led by Drs. Schreiber and Shaw, this CMLD project seeks to develop new synthetic approaches to libraries of structurally diverse small molecules in an effort to probe new biological pathways. The focus on structural diversity results from the hypothesis that a high degree of three-dimensional variation among small molecules that are screened will allow the maximum number of new biological phenomena to be revealed. The development of reaction pathways that produce different carbon connectivity among members of the same library requires the initiation of new concepts of synthetic analysis. The subprojects within Project 1 explore unique and complimentary approaches to the overall challenge of skeletal diversity.

Dr. Schreiber’s co-workers are each exploring the application of differential chemical reactivity to achieve skeletal diversity. Annaliese Franz is investigating the tunable nature of allylic silane reagents and their ability to engage in a variety of addition and annulation reactions. Peter Andreana is exploiting a unique level of regioselectivity in the ring-closing metathesis reactions of dienes that is imposed by the configuration of a single stereocenter in the substrates. Alex Taylor exploits the high level of stability imparted to normally unstable intermediates by attachment to the solid phase, which allows the use of reactive heterocycles in split/pool synthesis. Nilesh Kumar is generating skeletal and stereochemical diversity using a multiple tethering strategy. Ryan Looper is utilizing the Rh(II) catalyzed decomposition of diazoimides to generate polycyclic or acyclic alkaloids, predicated by the oxidation state of the dipolaraphile in a cyclization-cycloaddition cascade sequence.

Dr. Shaw’s co-workers are exploring linear synthetic approaches that rely on the systematic placement of functional groups that ultimately react with each other to determine the three-dimensional structure of the resultant small molecules. Pui Yee Ng exploits diastereoselective imine-anhydride cycloaddition ractions to systematically place amides susstituents in proximity to aryl halides so that a copper-mediated cyclization reaction will form distinct polycyclic lactams. Judy Mitchell employs an enantioselective methoxylozaxole-aldehyde (Suga-Ibata) addition reaction to produce oxazolidine intermediates which participate in a variety of differentiating pathways. Dr. Shaw has recently initiated a project that will use the integrated capabilities of the CMLD facility to assess the systematic variation of catalyst components on the efficiency and selectivity of several new synthetic transformations.

Personnel:

Stuart L. Schreiber, Ph.D.

Principal Investigator

stuart_schreiber@harvard.edu

Stuart Schreiber is an Investigator at the Howard Hughes Medical Institute and Morris Loeb Professor and Chair of the Department of Chemistry and Chemical Biology at Harvard University. He is a Founder and Director of the Harvard ICCB and its affiliated and NCI-sponsored Initiative for Chemical Genetics, and a member of The Rockefeller University Board of Trustees.

Dr. Schreiber is known for having developed systematic ways to explore biology, especially disease biology, using small molecules (precursors to therapeutic drugs that are used as bioprobes) and for his role in the development of the field of chemical biology. Using his chemical approach, he has discovered principles that underlie information transfer and storage in cells. He is a member of the National Academy of Sciences and the American Academy of Arts & Sciences (1995).

During the past twenty years, Dr. Schreiber has developed an integrated set of techniques that are systematizing the application of small molecules to biology. A key contribution was to formalize the planning of diversity-oriented synthesis (DOS). Using numerous applications of DOS, a chemistry technology platform developed at ICCB, and several powerful techniques for small molecule screening, many new insights into disease biology have been gained. Over 100 labs nationwide have performed chemical genetic screens at ICCB, leading to many both small molecule probes and insights into biology. To facilitate sharing of information derived from small molecules, Dr. Schreiber and ICCB created a public database named ChemBank, which was launched on the Internet in 2003.

Dr. Schreiber has founded several successful biotechnology firms, including Vertex Pharmaceuticals (VRTX; 1989), ARIAD Pharmaceuticals (ARIA; 1991) and, most recently, Infinity Pharmaceuticals (2001).

Schreiber Lab Home Page

Jared Shaw, Ph.D.

Project Leader

shaw@broad.mit.edu

Jared Shaw is an Institute Fellow at Harvard Medical School’s Institute for Chemistry and Cell Biology. Dr. Shaw received a B.S. in chemistry from the University of California, Berkeley. After working for one year developing chemically modified oligonucleotides for antisense therapy at Gilead Sciences, Dr. Shaw moved to the University of California, Irvine, earning a Ph.D. with Prof. Keith Woerpel. Dr. Shaw’s graduate work explored the reactivity of strained silicon compounds which later formed the foundation for new stereochemical models to explain the diastereoselectivity of reactions involving cyclic oxocarbenium ions. Before Joining the ICCB, Dr. Shaw was an NIH-sponsored postdoctoral researcher under the direction of Prof. David Evans (Harvard University), where he developed several new metal-catalyzed aldol processes.

Dr. Shaw’s current research efforts center on the development of new synthetic methodology and new strategies for the synthesis of skeletally diverse libraries of small molecules. In conjunction with these studies, Dr. Shaw is engaged in the discovery of new catat Dr. Shaw is also engaged in two active collaborations exploring the interaction of small molecules with the skeletal proteins that control division in prokaryotes (w/ Prof. D. Raychaudhuri, Tufts University) and endosymbiotic organelles (Prof. J. Nunnari, University of California, Davis). In collaboration with the Initiative for Chemical Genetics (ICG), Dr. Shaw has constructed a publicly accessible reaction database for the dissemination of new DOS pathways developed at the ICCB.

Annaliese Franz, Ph.D.

Postdoctoral Researcher

franz@fas.harvard.edu

Ryan Looper, Ph.D.

Postdoctoral Fellow

looper@fas.harvard.edu

Alex Taylor

Graduate Student

ataylor@fas.harvard.edu

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