Metalloprotein Catalysts for Asymmetric Synthesis

不对称合成中的金属蛋白催化剂 项目摘要 酶的精确的化学选择性、区域选择性和立体选择性使它们成为有机合成的有吸引力的工具， 特别是用于产生手性配体和用于合成药物和其它化合物的中间体， 生物活性分子。反映了这一概念，在制药行业中已经产生了巨大的兴趣。 工业界致力于整合高效、选择性、成本效益和可持续酶催化药物转化 合成和制造。然而，这方面的进展严重受阻，原因是， 天然酶催化的化学转化与通过化学方法获得的化学转化相比。 我们先前NIH资助的研究的分支导致了肌红蛋白的发现，肌红蛋白是一种小的，强大的， 结构可调的含血红素的蛋白-，构成了一个非常有前途的和通用的支架， 用于碳烯转移反应的高效和立体选择性的生物催化剂。基于这些令人兴奋的结果，建议 研究的目的是研究和扩展这些血红素蛋白催化剂在宽范围的卡宾上的范围， 可用于构建碳-碳、碳-氮和碳-硫键的介导转化。一组 将研究和利用互补策略来增强和调节催化活性、化学和生物活性。 这些催化剂的立体选择性。此外，对这些反应的机制和对 催化剂结构和反应性/选择性之间的相关性将通过实验， 计算和光谱研究。这些努力将有助于确定指导原则， 设计和开发具有高活性的肌红蛋白基催化剂的一般合理驱动策略， 微调的化学选择性、区域选择性和立体选择性，用于进行各种不对称卡宾插入反应。这些 系统将为药物化学和药物发现提供直接价值的手性构建模块 努力这类新的金属蛋白催化剂的合成效用将通过其 用于制备具有合成挑战性的药物分子的应用。最终，这项研究预计将有一个 对提供新的有效的，选择性的和可持续的生物催化战略，促进重大影响 不对称卡宾转移反应，从而克服了该领域的突出挑战。

Metalloprotein catalysts for asymmetric synthesis Project Summary The exquisite chemo-, regio-, and stereoselectivity of enzymes make them attractive tools for organic synthesis, in particular for the generation of chiral synthons and intermediates for the synthesis of pharmaceuticals and other biologically active molecules. Reflecting this notion, there have been significant interest within the pharmaceutical industry toward integrating efficient, selective, cost-effective, and sustainable enzyme-catalyzed transformations for drug synthesis and manufacturing. Progress in this direction is critically hampered, however, by the inherently limited range of chemical transformations catalyzed by natural enzymes as compared to those accessible through chemical methods. Ramifications of our prior NIH-funded research have led to the discovery that myoglobin—a small, robust, and structurally tunable heme-containing protein—, constitutes a very promising and versatile scaffold for developing efficient and stereoselective biocatalysts for carbene transfer reactions. Building upon these exciting results, the proposed research aims at investigating and extending the scope of these hemoprotein catalysts across a broad range of carbene- mediated transformations useful for the construction of carbon−carbon, carbon−nitrogen, and carbon−sulfur bonds. A set of complementary strategies will be investigated and leveraged to enhance and modulate the catalytic activity, chemo- and stereoselectivity of these catalysts. Furthermore, valuable insights into the mechanism of these reactions and into correlations between catalyst structure and reactivity/selectivity will be gained through a combination of experimental, computational, and spectroscopic studies. These efforts will contribute to the definition of guiding principles and a general, rationally driven strategy for the design and development of myoglobin-based catalysts with high activity and fine-tuned chemo-, regio- and stereoselectivity for executing a variety of asymmetric carbene insertion reactions. These systems will provide access to chiral building blocks of immediate value for medicinal chemistry and drug discovery efforts. The synthetic utility of this new class of metalloprotein catalysts will be further demonstrated through their application for the preparation of synthetically challenging drug molecules. Ultimately, this research is expected to have a major impact toward making available new efficient, selective, and sustainable biocatalytic strategies for promoting asymmetric carbene transfer reactions, thereby overcoming outstanding challenges in this field.