The suprafacial hydroxylation of olefins by osmium tetraoxide, though a much used synthetic method,' would become even more important if three conditions could be met: (1) modification to achieve high and predictable enantioselectivity and acyclic diastereoselectivity, (2) clarification of reaction mechanism, and (3) facilitated recovery and recycling of osmium. This paper reports progress on all three fronts. Several other laboratories have been actively involved in the development of chiral ligands for enantioselective dioxyosmylation of olefins, most notably those of Sharpless,2 Tomioka,3 Narasaka,, S n~d e r ,~ Hirama,6 and Cinquini,' with a gratifying measure of success. On the mechanistic side, the picture has been very unclear,' not only in terms of stereochemical detail but also with regard to the matter of [3 + 21 cycloaddition (O=Os=O + C=C)* and [2 + 21 cycloaddition (Os=O + C=C)932a93b pathways.

Amplification and overexpression of erbB2 (Her-2/neu) protooncogene has been linked to human malignancies including tumors of the breast, ovary, and stomach. It has been implicated in tumor growth, sensitivity to standard chemotherapy, prognosis of patients, and disease-free survival. Although the clinical use of trastuzumab (Herceptin) has prolonged the survival of breast cancer patients with erbB2-overexpressing tumors, there is an urgent need for more potent and orally bioavailable small-molecule inhibitors. CP-724,714 is a potent inhibitor of erbB2 receptor autophosphorylation in intact cells and is currently undergoing phase I clinical trials. Here, we describe the effects of CP-724,714 in vitro and in vivo in human breast cancer models. CP-724,714 is selective for inhibiting growth of HER2-driven cell lines. In addition, we show that it induces G 1 cell cycle block in erbB2-overexpressing BT-474 human breast carcinoma cells and inhibits erbB2 autophosphorylation in xenografts when administered p.o. to athymic mice. It induces a marked reduction of extracellular signal-regulated kinase and Akt phosphorylation, tumor cell apoptosis, and release of caspase-3. P.o. administration (q.d. or b.i.d.) of CP-724,714 inhibits the growth of erbB2-overexpressing tumors in athymic mice without overt adverse effects. [Cancer Res 2007;67(20):9887-93]

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