Inhibition of cyclin-dependent kinases (CDKs) has emerged as an attractive strategy for the development of novel oncology therapeutics. Herein is described the utilization of an in vivo screening approach with integrated efficacy and tolerability parameters to identify candidate CDK inhibitors with a suitable balance of activity and tolerability. This approach has resulted in the identification of SCH 727965, a potent and selective CDK inhibitor that is currently undergoing clinical evaluation.

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Through a systematic examination of ligand and counterion effects, new protocols for a nearly quantitative and highly selective codimerization of ethylene and various functionalized vinylarenes have been discovered. In a typical reaction, 4-bromostyrene and ethylene undergo codimerization in the presence of 0.0035 equiv each of [(allyl)NiBr]2, triphenylphosphine, and AgOTf in CH2Cl2 at -56 degrees C to give 3-(4-bromophenyl)-1-butene in >98% yield and selectivity. Corresponding reactions with [(allyl)PdX]2 are much less efficient and less selective and may require further optimization before a viable system can be identified. Another useful protocol that gives comparable yield and selectivity involves the use of a single-component catalyst prepared from allyl 2-diphenylphosphinobenzoate, Ni(COD)2, and (C6F5)3B. Recognition of a synergistic relationship between a chiral hemilabile ligand (for example, (R)-2-methoxy-2'-diphenylphosphino-1,1'-binaphthyl, MOP) and a highly dissociated counteranion (BARF or SbF6) in an enantioselective version of the Ni-catalyzed reaction raises the prospects of developing a practical route for the synthesis of 3-arylbutenes. Several pharmaceutically relevant compounds, including widely used 2-arylpropionic acids, can be synthesized from these key intermediates. This reaction appears to be quite general. Synthesis of several new 2-diphenylphosphino-1,1-binaphthyl derivatives, prepared to probe the effect of hemilabile coordination on the efficiency and selectivity of the reaction, are also described.

New protocols for highly selective and nearly quantitative heterodimerization of ethylene or propylene with various functionalized vinylarenes are described. Under these conditions, which are compatible with a wide variety of functional groups, cylization of 1,6-dienes and hydrovinylation of norbornenes can also be accomplished. Also presented are possible strategies for stereochemical control, including a crucial role for hemilabile ligands in enantioselective catalysis.

Only a limited number of ligands have been successfully employed for the Ni-catalyzed asymmetric hydrovinylation reaction. Diarylphosphonites prepared from readily available carbohydrates in conjunction with a highly dissociated counterion ([3,5-(CF3)2-C6H3)4B]- or SbF6-) effect the hydrovinylation of 4-bromostyrene or 4-isobutylstyrene under ambient pressure of ethylene with the best overall selectivities reported to date for these important substrates. In a prototypical synthesis of a 2-arylpropionic acid, 3-(4-bromophenyl)-1-butene (prepared in 98% isolated yield and 89% ee from 4-bromostyrene) has been transformed into (R)-ibuprofen by Ni-catalyzed cross-coupling with i-BuMgBr, ozonolysis, and subsequent oxidation of the resulting aldehyde.