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β-Amido zinc reagents 4 and 5 readily undergo β-elimination when prepared in THF, but when a polar aprotic solvent such as DMF is employed, β-elimination is suppressed. Using DMF, reaction of 4 with aryl iodides provides β-homophenylalanine derivatives (12 examples, 20-89% yield), and analogous reactions of 5 give γ-bishomophenylalanine derivatives (7 examples, 34-80% yield). The related zinc/copper reagents 17 and 18 are also useful intermediates that undergo subsequent crosscoupling reactions with a wide range of electrophiles (9 examples, 28-87% yield).

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The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.

M«0'^S^V'NH 'o chemists can play a leading role here. From their experiences in probing reaction mechanisms in vitro they can postulate likely intermediate metabolites and design experiments to follow the reaction sequences of drugs".2The majority of antitumor antibiotics inhibit cell division by interfering with the synthesis or use of nucleic acids.3 There is a constant need to discover new agents that interact with DNA in a mechanistically definable manner.4 In 1987 the Lederle5 and Bristol-Myers6 groups reported the unprecedented structures of calicheamicin 7i (1), esperamicin A, (2), Alb (3), and A2 (4), and the metabolite esperamicin X (5) (Chart I). They were isolated from fermentations of Micromonospora echinospora sp. calichensis and cultures of Actinomadura verrucosospora BBM 1675 and ATCC 39334, respectively. At present, these compounds are the most potent antitumor antibiotics known, being approximately 103 more active than adriamycin against murine tumors, and represent a new class of natural products based upon the Z-enediyne functionality.While they contain a number of unusual structural features such as the allylic trisulfide, a hydroxylamino sugar, and a Q-Q bridgehead double bond, it is the Z-enediyne that embues these molecules with a unique mechanism for cleaving DNA. It was proposed5'6 that the trisulfide is cleaved by nucleophilic attack at the central sulfur atom to give the thiol (or thiolate) 7, which can conjugatively add to Q to give the dihydrothiophene derivative(2) Ferguson, L. N. Chem. Soc. Rev. 1975, 4, 289.