The preparation and utilization of specific biaryl systems, particularly those which suffer hindered rotation, is a demanding goal not only in the synthesis of natural products and pharmaceuticals, but also for example in the discovery of new reagents for asymmetric synthesis. This article will attempt to provide a topical review of modern, efficient processes for the specific preparation of biaryls. This appears to be of particular urgency, since, under the pressure of continually increasing demand, a wealth of new or modified synthetic approaches to the ever more important biaryl systems has been realized in recent years. The high standard which has been reached in this field is impressively demonstrated by regio-and stereoselective syntheses of important biaryl natural products such as steganone, ancistrocladine, ancistrocladisine, and dioncophylline A. Besides the utilization of asymmetric induction in the actual coupling step, the thermodynamically or kinetically controlled torsion of biaryl axes belongs to the most important concepts discussed.
Inhibition of tumor angiogenesis through blockade of the vascular endothelial growth factor (VEGF) signaling pathway is a new treatment modality in oncology. Preclinical findings suggest that blockade of additional pro-angiogenic kinases, such as fibroblast and platelet-derived growth factor receptors (FGFR and PDGFR), may improve the efficacy of pharmacological cancer treatment. Indolinones substituted in position 6 were identified as selective inhibitors of VEGF-, PDGF-, and FGF-receptor kinases. In particular, 6-methoxycarbonyl-substituted indolinones showed a highly favorable selectivity profile. Optimization identified potent inhibitors of VEGF-related endothelial cell proliferation with additional efficacy on pericyctes and smooth muscle cells. In contrast, no direct inhibition of tumor cell proliferation was observed. Compounds 2 (BIBF 1000) and 3 (BIBF 1120) are orally available and display encouraging efficacy in in vivo tumor models while being well tolerated. The triple angiokinase inhibitor 3 is currently in phase III clinical trials for the treatment of nonsmall cell lung cancer.
The biomimetic first total synthesis of michellamines A, B, and C (la-c), naturally occurring quateraryl alkaloids with high anti-HIV activity, is described. Key precursors are the molecular "halves" of michellamines, the antimalarial naphthylisoquinoline alkaloids korupensamine A (2a) and B (2b), which are likewise natural products. These "monomeric" naphthylisoquinoline alkaloids were prepared by Stille-type intermolecular aryl coupling of the 0-isopropyl-protected and trialkylstannyl-activated naphthalene building block 4 b Lo]Me OH Me OH l a OH Me Ib OH Me Me OH OH M Me ' O w M e \ N. " IC OH Medispose of four stereogenic centers and three biaryl axes, of which the two outer ones are stereogenic, whereas the inner one, which links the constitutionally identical molecular "halves", is conformatively unstable. The constitution and
A convergent total synthesis of the anti-HIV michellamines (1) is described. The tetraaryl skeleton of the michellamines was constructed by formation first of the inner (nonstereogenic) biaryl axis and subsequently of the two other (stereogenic) axes in a highly convergent manner. The key transformation features a double Suzuki-type cross-coupling reaction between binaphthalene ditriflate 26 and isoquinolineboronic acid 35. Ditriflate 26 is synthesized in six steps starting from diene 6 and 2,6-dibromobenzoquinone (9) in 21% overall yield. For large scale production of 26, a substantially shortened version of an existing procedure for the preparation of bisnaphthoquinone 13 was also developed, which allows for the preparation of 13 from benzoquinone and diene 6 in five steps and 67% overall yield. Binaphthoquinone 13 was subsequently converted into ditriflate 26 in three steps and 67% overall yield. By the described synthetic strategy, michellamines A (1a) and B (1b) are produced (1a:1b = 1:2.5) in 24.6% overall yield from diene 6. Curiously, none of the nonnaturally occurring atropoisomer 1c is formed.
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