Education: B.S., 1969, Wilkes College; Ph.D., 1973, Yale University
Awards: N.I.H. Postdoctoral Fellow, 1974, Columbia University; A. P.
Sloan Fellow, 1979; Eli Lilly Grantee Award, 1979; Dreyfus Teacher
Scholar, 1980; Ernest Guenther Award, 1988; ICI Pharmaceutical
Group's Stuart Award for Excellence in Chemistry, 1988; Arthur C.
Cope Scholar Award, 1990; Alexander von Humboldt Stiftung Award,
1991; ASSU Teaching Award, 1991; Hoagland Prize for Undergraduate
Teaching, Stanford, 1991; Fellow, American Academy of Arts and
Sciences, 1992; Bing Teaching Award, Stanford, 1992; National
Institutes of Health MERIT Award, 2003; Pfizer Research Award for
Synthetic Organic Chemistry, 1995; American Chemical Society Award
for Creative work in Synthetic Organic Chemistry, 1998; Dean's Award
for Distinguished Teaching, 2000; Fellow, American Association for the
Advancement of Science, 2001; American Chemical Society H.C.
Brown Award for Creative Research in Synthetic Methods, 2003;
Member National Academy of Science, 2003; National Institutes of
Health MERIT Award, 2006; The Hamilton Award (U. Nebraska), 2008; Wilbur Lucius Cross Medal (Yale Graduate Alumni), 2010;
Tetrahedron Prize for Creativity in Organic Chemistry, 2012.
Research Area: Organic, Organometallic, Synthesis, Catalysis,
Chemical Biology, Imaging, Drug Delivery, Molecular Therapeutics
Principal Research Interests
Our research involves studies in chemistry, biology, medicine, and
materials science. We are affiliated with the Medical School, Imaging
Center, Chemical Biology Program and Molecular Therapeutics
Program. A special emphasis is placed on training and research in
synthesis, inventing new reactions, and the use of synthesis to address
problems of significance in biology and medicine including eradication
of HIV/AIDS, overcoming resistant cancer, and treating cognitive
disorders like Alzheimer’s disease. Our studies include: 1) the design
and development of new reactions, methods, reagents, and strategies
that introduce novel ways of synthesizing molecules of biological or
medicinal significance; 2) synthetic and mechanistic organometallic
chemistry with an emphasis on new catalytic reactions; 3) mode of
action studies on medicinally important leads; 4) drug delivery and
novel mechanisms of transport into cells including the design and
development of new transporters of drugs and probes; 6) molecular
imaging; 7) new therapeutic strategies to address unsolved medical
problems; and 8) computer modeling and molecular recognition.
The key to achieving the “ideal synthesis” and greener chemistry is
step economy which in turn relies critically on the discovery or
invention of new reactions. New reactions are to synthesis what words
are to language. Without expanding our lexicon we are limited in what
we can do. Wender group members have discovered or invented over
25 new reactions including metal catalyzed 3+2, 4+4, 4+2, 5+2, 6+2,
6+1, 5+2+1, 4+2+2, 2+2+1, 5+1+2+1, 2+2+2+2 cycloadditions.
New reactions are being used in the synthesis of new therapeutic
leads, ligands for catalysis and materials.
Another area of emphasis is the development of new strategies to
treat disease. Current AIDS therapies stop disease progression by
targeting the active virus. This is important but requires chronic
treatment with associated cost, compliance and resistance problems.
We seek to target the latent virus, a strategy which if successful could
eradicate disease. These studies involve design, synthesis, mechanistic
biology, and preclinical research.
We are also investigating other medicinal leads selected for unique
activity and special clinical promise like bryostatin, currently in clinical
trials for the treatment of cancer. We have designed agents that are
better than bryostatin in various assays and we can supply these
agents through practical syntheses. Remarkably some of these agents
facilitate learning in animal models of cognitive dysfunction. These are
promising preclinical candidates for cancer and for Alzheimer’s disease.
Related opportunities at the interface of synthesis, biology and
medicine include studies on daphnanes, gnidimacrin and apoptolidin,
formidable synthetic challenges with unique clinical promise.
A grand challenge in science is developing strategies for breaching
biological barriers. In our studies, we use designed molecular
transporters that enable passage of a wide range of molecules into
cells, including small molecules, peptides, proteins, nucleic acids, and
nanoparticles. This research opens new opportunities in chemotherapy
and stem cell research and establishes a new tool of exceptional
breadth for studying biochemical pathways and for real time imaging.
It is being used in preclinical studies on overcoming resistant cancer.
- "Mechanistic and Computational Studies of Exocyclic Stereocontrol in the Synthesis of Bryostatin-like Cis-2, 6-Disubstituted 4-Alkylidenetetrahydropyrans by Prins Cyclization"; J. Org. Chem., 2013, 78(1), pp. 104-115.
- “Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro”, Nature Chemistry, 2012, 4, 705-710.
- “"Picolog,” a Synthetically-Available Bryostatin Analog, Inhibits Growth of MYC-Induced Lymphoma in Vivo”; Oncotarget, 2012, 3(1), 58-66.
- "Rhodium Dinaphthocyclooctatetraene Complexes: Synthesis, Characterization and Catalytic Activity in [5+2] Cycloadditions", Angewandte Chemie, 2012, Published online: 1 Feb 2012.
- “Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells”, PNAS, 2012, 109 (33), 13171-13176.
- “A molecular method for the delivery of small molecules and proteins across the cell wall of algae using molecular transporters”, PNAS, 2012, 109 (33), 13225-13230.
- "Function-Oriented Synthesis: Design, Synthesis and Evaluation of Potent Bryostatin Analogs that Modulate PKC Translocation Selectivity." Proc. Natl. Acad. Sci. USA. 2011, 108, 6721-6726.
- "Translating Nature's Library: the Bryostatins and Function-Oriented Synthesis." Isr. J. Chem. 2011, 51, 453-472.
- "Function Oriented Synthesis: Preparation and Initial Biological Evaluation of New A-Ring-Modified Bryologs", Tetrahedron, 2011, 67, 9998-10005.
- "Total Synthesis of Bryostatin 9", Journal of the American Chemical Society, 2011, 133(24), 9228-9231.
- “Gateway Synthesis of Daphnane Congeners and Their PKC Affinities and Cell-Growth Activities”, Nature Chemistry, 2011, 3, 615-619.
- “Translating Nature’s Library: the Bryostatins and Function-Oriented Synthesis” Israel J. Chem., 2011, 51, 453-472.
- "The Preparation of Cyclohelpt-4-Enones by Rhodium Catalyzed Intermolecular [5+2] Cycloaddition" Organic Syntheses, 2011, 88, 109-120.
- "Highly Efficient, Facile, Room Temperature Intermolecular [5+2] Cyclcoadditions Catalyzed by Cationic Rhodium(I): One Step to Cycloheptenes and Their Libraries" Organic Lett., 2010, 1604-1607.
- "Electronic and Steric Control of Regioselectivities in Rh(I)-Catalyzed (5+2) Cycloadditions: Experiment and Theory" J. Am. Chem. Soc., 2010, 10127-10135.
- "A Metal-Catalyzed Intermolecular [5+2] Cycloaddition / Nazarov Cyclization Sequence and Cascade" J.Am.Chem.Soc., 2010, 2532-2533.
- “An Approach to the Site-Selective Diversification of Apoptolidin A with Peptide-Based Catalysts”, Journal of Natural Products, 2009, 72(10), 1864-1869.
- “Apoptolidins E and F, New Glycosyated Macrolactones Isolated from Nocardopsis sp.” Organic Letters, 2009, 5474-5477.
- "The Synthesis of Highly-Substituted Cyclooctatetraene Scaffolds by Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on Regioselectivity, Dynamic Properties and Metal Chelation", Angewandte Chemie Int. Ed 2009, 7823-7826.
- "The Diene Effect: The Design, Development, and Mechaqnistic Investigation of Metal-Catalyzed Diene-yne, Diene-ene, and Diene-allene [2+2+1] Cycloaddition Reactions", Eur. J. Org. Chem., 2009, Volume 2010, Issue 1, Date: January 2010, Pages 19-32.
- "Rhodium(I)-Catalyzed [2+2], [2+2+2], and [2+2+2+2] Cycloadditions of Dienes or Alkynes with a Bis-ene", Organometallic, 2009, 28(20), 5841-5844.
- “Synthesis at the Molecular Frontier” Nature 2009, 460, 197-201.
- “Function Oriented Synthesis, Step Economy, and Drug Design”
Accts. Chem. Res. 2008, 40-49.
- “Practical Synthesis of Prostratin, DPP, and Their Analogs, Adjuvant
Leads Against Latent HIV” Science 2008, 649-652.
- “Efficient Synthetic Access to a New Family of Highly Potent
Bryostatin Analogues via a Prins-Driven Macrocyclization Strategy” J.
Am. Chem. Soc. 2008, 6658-6659.
- “Oligocarbonate Molecular Transporters: Oligomerization Based
Syntheses & Cell Penetrating Studies” J. Am. Chem. Soc. 2009, 131(45), 16401-16403.
- “Prolonging Microtubule Dysruption Enhances the Immunogenicity
of Chronic Lymphocytic Leukemia Cells” Clinical & Experimental
Immunology 2009, 158, 186-198.
- “The Synthesis of Highly-Substituted Cyclooctatetraene Scaffolds by
Metal-Catalyzed [2+2+2+2] Cycloadditions: Studies on
Regioselectivity, Dynamic Properties and Metal Chelation” Angewandte
Chemie Int. Ed 2009, 7823-7826.
- “Cyclocarboamination of Alkynes with Aziridines: … a Catalyzed
Formal [3+2] Cycloaddition” J. Am. Chem. Soc. 2009, 7528-7529.
- “A Cellular Model of Alzheimer’s Disease Therapeutic Efficacy: PKC
Activation Reverses A-beta induced biomarker Abnormality on Cultured
Fibroblasts” Neurobiology of Disease 2009, 332-339.
- “A Pro-apoptotic Signaling Pathway involving RasGRP, Erk and Bim
in B Cells” Experimental Hematology 2009, 122-134.
- “Overcoming Multidrug Resistance of Small Molecule Therapeutics
through Conjugation with Releasable Octaarginine Transporters” Proc.
Natl. Acad. Sci. USA 2008, 12128-12133.
- “Origins of Differences in Reactivities of Alkenes, Alkynes, and
Allenes in [Rh(CO)2Cl]2-Catalyzed (5+2) Cycloaddition Reactions with
Vinylcyclopropanes” J. Am. Chem. Soc. 2008, 2378-2379.mputer modeling and molecular recognition.