Bi(III)-Initiated Chemistry: Mechanistic Investigations of Catalytic Activity

描述（由申请人提供）：铋化合物最近作为有机合成的非常有用的试剂而蓬勃发展，并且催化量引发广泛的反应。一些最近开发的Bi（III）引发的方法已被用于合成抗肿瘤和抗真菌剂。除了铋催化剂的这些最新用途之外，许多先前记载的反应是经由中间体氧碳正离子的简单羰基保护和脱保护方案。然而，大多数这些反应中的实际催化活性物质是不确定的，目前正在进行相当大的辩论。铋（III）化合物的使用越来越多，主要是因为它们价格便宜，毒性非常低（BiBr 3的LD 50与NaCl相当），固态相对稳定，并且在典型的实验室条件下相当容易处理（吸湿性）。事实上，铋化合物已被广泛用于药物制剂超过400年。也许最广为人知的，医学上重要的铋（III）化合物是次水杨酸铋，Pepto-Bismol（r）的活性成分。本项目的具体目标是通过以下几个方面的研究来探讨无毒铋（III）化合物的反应机理：（1）铋（III）化合物与反应性有机底物之间的化学计量相互作用，羟醛和烯丙基化反应的反应速率、产率、转化数和分子量;（2）评价Mukaiyama与烯酮甲硅烷基缩醛的羟醛缩合反应中的交叉程度，以努力证明真正的催化剂;和（3）Bi（III）在潜在的非对映体反应中的评价以及与使用其它刘易斯酸和布朗斯台德酸作为引发剂获得的非对映体选择性的直接比较。拟议的研究将试图证明铋盐中高催化活性的真正来源。这些调查是至关重要的，了解这种多功能的类金属，并将提供基础的潜在的不对称合成新的合成方法的发展。药物和材料的有机合成通常依赖于金属作为催化剂进行许多关键转化。随着婴儿潮一代年龄的增长，对药物和材料的需求不断增加，化学家们正在努力寻找更环保的催化剂，如基于铋等无毒金属的催化剂。由于Bi（III）化合物最近在合成方法中获得了快速增长，因此应评估它们作为催化剂的作用以确定它们是否实际上是独特的催化剂以及它们与其他催化剂体系相比是否有益。我们提出了一些机械的问题，并提出实验来回答这些问题。

DESCRIPTION (provided by applicant): Bismuth compounds have recently blossomed as very useful reagents for organic synthesis and catalytic quantities initiate a wide-range of reactions. Some more recently developed Bi(III)-initiated methodologies have been used in the synthesis of antitumor and antifungal agents. Outside of these latest uses of bismuth catalysts, many of the previously documented reactions were simple carbonyl protection and deprotection protocols via intermediate oxocarbenium ions. The actual catalytically-active species in most of these reactions, however, is uncertain and currently under considerable debate. The growing use of bismuth(III) compounds is largely due to the facts that they are inexpensive, have very low toxicity (the LD50 for BiBr3 is comparable to that of NaCl), are relatively stable in the solid-state, and are fairly easy to handle under typical laboratory conditions (hygroscopic). In fact, bismuth compounds have been widely utilized in pharmaceutical preparations for over 400 years. Perhaps the most widely-known, medicinally important bismuth(III) compound is bismuth subsalicylate, the active ingredient in Pepto-Bismol (r). The specific aims of this project are to investigate the mechanisms of reaction non-toxic bismuth(III) compounds by studies in the following areas: (1) stoichiometric interactions between Bi(III) compounds and reactive organic substrates; reaction rates, yields, turnover numbers and molecularity of aldol and allylation reactions; (2) evaluation of the degree of crossover in Mukaiyama aldol reactions with ketene silyl acetals in efforts to document the true catalyst; and (3) the evaluation of Bi(III) in potentially diastereomeric reactions and direct comparisons to diastereoselectivities obtained using other Lewis and BrOnsted acids as initiators. The proposed studies will attempt to document the true source of the high catalytic activity in bismuth salts. These investigations are crucial to understanding this versatile metalloid and will provide the foundation for the development of new synthetic methodologies in potentially asymmetric syntheses. The organic synthesis of pharmaceuticals and materials often relies upon metals as catalysts for a number of key transformations. With increasing needs for medications and materials as Baby Boomers age, chemists are working toward finding more environmentally- friendly catalysts such as those based on non-toxic metals like bismuth. As Bi(III) compounds recently have enjoyed rapid growth in synthetic methodology, their role(s) as catalysts should be assessed to determine if they are, in fact, unique catalysts and if they are beneficial compared to other catalyst systems. We pose a number of mechanistic questions and propose experiments to answer those questions.