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

描述(申请人提供)：铋化合物最近作为非常有用的有机合成试剂而蓬勃发展，催化量引发了广泛的反应。一些最近发展起来的铋(III)引发的方法已被用于抗肿瘤和抗真菌药物的合成。除了铋催化剂的这些最新用途外，以前报道的许多反应都是通过中间氧碳正离子进行的简单的羰基保护和去保护协议。然而，在大多数这些反应中，实际的催化活性物种是不确定的，目前正在进行相当大的争论。铋(III)化合物的广泛使用在很大程度上是因为它们价格低廉，毒性非常低(BiBr3的LD50与氯化钠的LD50相当)，在固态中相对稳定，并且在典型的实验室条件下(吸湿性)相当容易处理。事实上，铋化合物在药物制剂中的广泛应用已有400多年的历史。也许最广为人知的、具有重要药用价值的铋(III)化合物是次水杨酸铋，它是Pepto-Bisol(R)的有效成分。本项目的具体目的是通过下列领域的研究来研究无毒的铋(III)化合物的反应机理：(1)铋(III)化合物与活性有机底物之间的化学计量相互作用；羟醛和烯丙化反应的反应速率、产率、周转次数和分子量；(2)评估Mukaiyama Aldol与烯酮硅基缩醛反应的交叉程度，以努力证明真正的催化剂；以及(3)评价铋(III)在潜在的非对映异构体反应中的作用，并直接与使用其他Lewis和Bronsted酸作为引发剂获得的非对映选择性进行比较。拟议的研究将试图证明铋盐高催化活性的真正来源。这些研究对于理解这种多功能的类金属是至关重要的，并将为开发潜在的不对称合成的新的合成方法提供基础。药物和材料的有机合成往往依赖于金属作为一些关键转化的催化剂。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，例如基于铋等无毒金属的催化剂。由于铋(III)化合物近年来在合成方法上获得了快速发展，应对它们作为催化剂的作用(S)进行评估，以确定它们是否确实是独特的催化剂，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问题，并提出了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.