Metal-Mediated Routes to Biaryls

描述（由申请人提供）：双芳基化合物代表了天然和非天然产品化学的主要领域。鉴于自然界中广泛存在含有联芳基轴的生理活性化合物，其中许多由于旋转受阻而具有轴向手性元素，因此需要方法来应对这些特殊的合成挑战。具有代表性的目标，突出了现有的局限性，但为这一领域的重大进展提供了机会，包括临床必需的抗生素万古霉素，以及有效的抗艾滋病双芳基，米歇尔胺。通过在芳基卤化物偶联伙伴中合理地放置内部膦配体，我们的关键铃木-联芳基偶联方法与万古霉素联芳基和米歇尔胺亚基相关的方向性将得到控制。另外，一个概念上的新进入立体控制双芳，如应用于万古霉素，将采用取代的非外消旋内炔的伯格曼环化。

DESCRIPTION (provided by applicant): Biaryls represent a major area of natural and unnatural products chemistry. Given the widespread occurrence of physiologically active compounds in Nature that contain a biaryl axis, many of which due to hindered rotation possess an element of axial chirality, methodology is needed to respond to these special synthetic challenges. Representative targets which highlight existing limitations yet which provide opportunities for significant advances in this area include the clinically essential antibiotic vancomycin, and the potent anti-AIDS biaryls, the michellamines. Using a judiciously placed internal phosphine ligand in an aryl halide coupling partner, the directionality associated with our key Suzuki-biaryl coupling-based approach to the vancomycin biaryl and the subunits of the michellamines will be controlled. Alternatively, a conceptually new entry to stereocontrolled biaryls, as applied to vancomycin, will be pursued using a Bergman cyclization of a substituted nonracemic endiyne. The chemistry of biaryl constructions, which is usually effected in solution using Pd(0) catalysis, is to be pursued via an alternative metal system: nickel. Proposed herein are new methods for heterogeneous catalysis based on Ni/C, to be examined under microwave conditions, and the next generation species nickel-on-graphite ("Ni/Cg"), which appears to offer a different reactivity profile. Finally, a new series of nonracemic ligands based on the binaphthyl core, in particular of NOBIN, will be constructed. The approach presented will provide entry to unprecedented substitution patterns on this ligand system, as well as opportunities for their mounting on a solid support for use, and re-use, under heterogeneous conditions. A particular, albeit representative, application of a novel substituted cyclo-NOBIN will be studied for selected asymmetric aldol reactions.