Expanding the synthetic utility of enzymes

项目摘要 在复杂性构建转化中实现选择性对于能够获得目标分子至关重要 具有影响人类健康的潜力，例如具有用于研究生物学的潜在药物和化学探针， 系统.虽然在开发复杂结构的化学方法方面取得了重大进展， 反应，它往往仍然是具有挑战性的进行这些转化与高水平的化学-，现场-和 对复杂或官能团密集分子的立体选择性。与小分子催化剂和 试剂、酶通常已经发展到以高水平的选择性进行反应。的发现 特定的酶促反应和这些催化剂的效用的开发具有使得能够 合成策略，使我们能够获得具有强大生物活性的新分子。这项建议 描述了几种策略，用于开发强大的酶介导的反应，并利用这些工具， 具有制药潜力的分子的流线型合成。 该NIGMS提案的目标是为合成化学家提供高选择性，高效，良好的- 将具有特征的和可持续的生物催化方法规划为实现目标的综合方法 分子。使用来自天然产物生物合成途径和靶向蛋白质家族的酶作为 首先，我们将阐明特定酶的天然化学功能和机制。从这个 初始基准，我们使用生物信息学工具，结构分析，计算建模，进化 方法来组装面板的互补生物催化剂的实用合成社区。我们 随后寻求使用每个蛋白质类提供的平台来设计新的反应并应用这些反应。 方法，以简化合成与人类健康有关的分子。我的团队寻求生物催化 解决那些继续挑战现代合成化学家的反应，包括选择性C-H 羟基化、位点选择性和立体选择性氧化脱芳构化，以及化学选择性和立体选择性脱芳构化。 α-氨基酸的衍生化。展望未来，我们将继续在这些领域开展工作， 开发生物催化的C-C键形成反应，羟基化以外的C-H官能化反应，以及 构建和精细化功能团密集分子如核苷酸的策略。 总之，该提案描述了化学选择性、位点选择性和立体选择性转化的发展 由酶介导。这些方法将直接使复杂的生物活性的合成 与人类健康相关的分子。

PROJECT SUMMARY Achieving selectivity in complexity-building transformations is critical for being able to access target molecules with potential to impact human health such has potential drugs and chemical probes for studying biological systems. Although significant strides have been made in developing chemical methods for complexity-building reactions, it often remains challenging to carry out these transformations with high levels of chem-, site- and stereoselectivity on complex or functional group dense molecules. In contrast to small molecule catalysts and reagents, enzymes often have evolved to carry out reactions with high levels of selectivity. The discovery of specific enzymatic reactions and development of the utility of these catalysts has the potential to enable to synthetic strategies and grant us access to new molecules with potent biological activity. This proposal describes several strategies for developing robust enzyme-mediated reactions and leveraging these tools for the streamlined synthesis of molecules with pharmaceutical potential. The goal of this NIGMS proposal is to provide synthetic chemists with highly selective, efficient, well- characterized and sustainable biocatalytic methods to be planned into synthetic approaches toward target molecules. Using enzymes from natural product biosynthetic pathways and targeted protein families as a starting point, we will elucidate the natural chemical function and mechanism of a given enzyme. From this initial benchmark, we use bioinformatic tools, structural analysis, computational modeling, and evolutionary approaches to assemble panels of complementary biocatalysts of utility to the synthetic community. We subsequently seek to use the platform provided by each protein class to design new reactions and apply these methods to the streamlined synthesis of molecules relevant to human health. My group seeks biocatalytic solutions to reactions that continue to challenge modern synthetic chemists including selective C–H hydroxylation, site- and stereoselective oxidative dearomatization, and the chemo- and stereoselective derivatization of a-amino acids. Moving forward, we continue to work in these areas and are seeking to develop biocatalytic C–C bond forming reactions, C–H functionalization reactions beyond hydroxylation, and strategies for building and elaborating functional group dense molecules such as nucleotides. In summary, this proposal describes the development of chemo-, site- and stereoselective transformations mediated by enzymes. These methods will directly enable the synthesis of complex biologically active molecules relevant to human health.