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Edward C. Taylor

Research Focus


Taylor’s career has involved pioneering studies in organic synthesis methodology, organometallic chemistry, natural products and medicinal chemistry. Early work included new approaches to the synthesis, inter alia, of purines, quinine, tetrahydrocannabinol, the molybdenum cofactor, biopterin, xanthopterin, urothione and Asperopterin B. Continuing features of his syntheses were exploitations of molecular rearrangements devised to simplify synthetic transformations. Together with a former postdoctoral associate, Alexander McKillop, and using new thallium-based reagents, they discovered some 130 new organic synthetic transformations. He was one of the first to recognize and highlight the remarkable versatility of heterocyclic N-oxides for synthetic transformations.

Taylor’s fascination with heterocyclic chemistry included pteridine chemistry. The pteridine ring system was first identified in a study of the constituents of butterfly wing pigments, and pteridines thus were initially viewed as occupying an esoteric, insignificant corner of natural product chemistry. We now know, however, that two pteridine derivatives, the molybdenum cofactor and folic acid, are critical components of all living cells, and are required for all forms of life. Cofactors derived from folic acid play key roles in a host of diverse metabolic reactions essential for the formation of DNA, RNA, ATP, amino acids and proteins. Taylor’s involvement in heterocyclic and folate chemistry included a search for inhibitors of folate-dependent enzymes, and led in the late 1970s to his discovery that (6R)-5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) blocked de novo purine biosynthesis, and exhibited unprecedented activity against a variety of solid tumors. To further explore and develop this promising new area, Princeton and Eli Lilly & Co. set up a collaborative research effort to search for further inhibitors of folate-dependent processes. This effort, that involved synthesis and evaluation of many hundreds of new potential agents, culminated in Taylor’s synthesis of a remarkable new oncolytic agent (N-{4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic acid) that became known as Alimta™ (pemetrexed disodium), licensed to, developed and marketed by Eli Lilly & Company. Alimta™ exhibits a remarkable breadth of antitumor activity that results from inhibition of three of the major folate-dependent enzymes in cellular metabolism. Alimta™, in combination with cis-platin, was approved by the FDA in 2004 for the treatment of malignant pleural mesothelioma, later in 2004 as a single agent for second-line non-small cell lung cancer (NSCLC), and several years later for first-line and maintenance therapy for NSCLC. It is now in use in more than 100 countries, and is in multiple further clinical trials, both in combination with other oncolytics and as a single agent, for a wide range of other solid tumors. Royalties to Princeton University from Lilly are responsible for the construction of the new chemistry building that opened in 2010.

Selected Recent Publications

  • Active Constituents of Hashish. Synthesis of d,1-∆6-3,4-trans-Tetrahydrocannabinol (with K. Lenard and Y. Shvo), J. Am. Chem. Soc., 88, 367 (1966).
     
  • A New Method for C-5 Functionalization of Pyrimidines. New Routes to Azapteridines and Purines. Synthesis of Fervenulin (with F. Sowinski), J. Am. Chem. Soc., 90, 1374 (1968).
     
  • An Unequivocal Synthesis of 6-Substituted Pteridine 8-Oxides, Pteridines, and 7,8-Dihydropteridines (with K. Lenard), J. Am. Chem. Soc., 90, 2424 (1968).
     
  • A New, General Synthesis of 2-, 8-, and 9-Substituted Adenines (with G.P. Beardsley and Y. Maki), J. Org. Chem., 36, 3211 (1971).
     
  • A Facile Synthesis of Quinine and Related Cinchona Alkaloids (with S.F. Martin), J. Am. Chem. Soc., 94, 6218 (1972).
     
  • An Unequivocal Total Synthesis of L-erythro-Biopterin (with P.A. Jacobi), J. Am. Chem. Soc., 96, 6781 (1974).
     
  • Synthesis of the Pyrimido(5,4-e)-as-triazine Antibiotics Fervenulin and 2-Methylfervenulone (MSD-92) (with F. Sowinski), J. Org. Chem., 40, 232l (1975).
     
  • Synthesis and Properties of 3-Oxo-1,2-diazetidinium Ylides (with N.F. Haley and R.J. Clemens), J. Am. Chem. Soc., 103, 7743 (1981).
     
  • Synthesis of Fused 1,2-Diazetidinones via an Intramolecular Horner-Emmons Reaction (with H.M.L. Davies), J. Org. Chem., 51, 1537 (1986).
     
  • Thallium(III) Salts as Oxidants in Organic Synthesis (with A. McKillop), in "Organic Syntheses by Oxidation with Metal Compounds", (W. J. Mijs and C. R. H. I. de Jonge, eds), Plenum Press, 1986, pp. 695-736.
     
  • Novel Cycloaddition Routes to Fused Heterocycles, Bull. Soc. Chim. Belges, 97, 599 (1988).
     
  • Studies on the Molybdenum Cofactor. An Unequivocal Total Synthesis of (±)-Urothione (with L. A. Reiter), J. Am. Chem. Soc., 111, 285 (1989).
     
  • New Pathways from Pteridines. Design and Synthesis of a New Class of Potent Selective Antitumor Agents, Lectures in Heterocyclic Chemistry, J. Heterocyclic Chem., 27, 1 1990).
     
  • A Convergent Synthesis of 5,10-Dideaza-5,6,7,8-tetrahydrofolic Acid (DDATHF) and 5,10-Dideaza-5,6,7,8-tetrahydrohomofolic Acid (HDDATHF). An Effective Principle for Carbonyl Group Activation (with P. M. Harrington), J. Org. Chem., 55, 3222 (1990).
     
  • A Dideazatetrahydrofolate Analogue Lacking a Chiral Center at C-6, N-{4-[2-(2-Amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic Acid, is an Inhibitor of Thymidylate Synthase (with Dietmar Kuhnt, Chuan Shih, Sharon M. Rinzel, Gerald B.Grindey, Julio Barredo, Mehrdad Jannatipour, and Richard G. Moran), J. Med. Chem., 35, 4450 (1992).
     
  • Synthesis of Conformationally-Constrained Glutamate Analogues of the Antitumor Agents DDATHF, LY254155 and LY231514 (with Lee D. Jennings, Zhenmin Mao, Baihua Hu, Jong-Gab Jun and Ping Zhou), J. Org. Chem., 62, 5392 (1997).
     
  • Exploitation of a New Route to Fused Pyrroles: Synthesis of TNP-351, Homo-MTA and 5-Arylpyrrolo[2,3-d]pyrimidines (with Bin Liu), Tetrahedron Letters, 40, 4027 (1999).
     
  • A New and Efficient Synthesis of Pyrrolo[2,3-d]pyrimidine Anticancer Agents: Alimta (LY231514, MTA), Homo-Alimta, TNP-351, and Some Aryl 5-Substituted Pyrrolo[2,3-d]pyrimidines (with Bin Liu), J. Org. Chem., 68, 9938-9947 (2003).

Edward C. Taylor

etaylor@princeton.edu
Frick Laboratory, 127
Phone: 609-258-3914

Faculty Assistant:
Denise D'Auria
denised@princeton.edu
Frick Laboratory, 228
Phone: 609-258-5202