New Catalytic and Enantioselective Reactions

新的催化和对映选择性反应

• 批准号: 6752510
• 负责人: AMIR H HOVEYDA
• 金额: $ 30万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6752510
• 关键词: alkyl group; aminoacid; carbonyl compound; catalyst; chemical addition; chemical synthesis; epoxides; imines; peptide chemical synthesis; stereochemistry

Reactions that are catalytic, proceed with outstanding selectivity, are efficient and use inexpensive materials can dramatically shorten the time between conception and large-sale preparation and marketing of a therapeutic agent. According, the objective of the proposed research is to develop new catalytic asymmetric carbon-carbon bond-forming processes that can be used in the preparations of molecules important to human health care. The proposed research will focus on catalytic asymmetric preparations of chiral amines and alcohols, particularly those not accessible through available catalytic methods. For example, our preliminary success with enantioselective additions of alkyl groups to aryl and alkyl imines to provide chiral amines will be extended to alpha-carbonyl-containing imines and ketimines. Catalytic asymmetric additions of alkyl, aryl, alkenyl, and alkynyl groups into these types of substrates will provide concise entries into biomedically important natural and unnatural amino acid and derivatives. Likewise, an intramolecular variation of this carbon-carbon bond forming process will be advanced. The addition of aromatic groups into tethered imines (Pictet-Spengler Reaction) will be developed into an asymmetric process catalyzed by Lewis acidic metals modified by chiral peptidyl ligands. In a related manner, the enantioselective addition of alkyl group into ketones to general chiral, non-racemic tertiary alcohols will be developed into a general catalytic asymmetric transformation. Given the lack of catalytic methods to synthesize chiral tertiary alcohols, success with this reaction will significantly enhance the availability and reduce the cost of preparation of numerous medicinally important compounds. In all segments of the proposed studies, the utility of new asymmetric catalytic transformations will be highlighted with efficient and selective synthesis of several medicinally important targets. Furthermore, once a catalytic asymmetric process has been demonstrated, the corresponding reaction mechanism will be probed to enhance further the overall selectivity and reactivity of the process. New reaction methods to be developed will involve catalysis by Lewis acidic metals modified by chiral peptidyl ligands that can serve as bifunctional catalysts. Amino acids are inexpensive, readily available in enantiomerically pure form, and peptide synthesis has been worked out in both solution and solid phase, simultaneous preparation of multiple ligand structures is straightforward. Accordingly, a unique and useful feature of the peptide-based chiral ligands is the facility with which they can be prepared and examined so that optimal levels of reactivity and selectivity can be achieved.

催化性反应，具有突出的选择性，效率高，使用廉价的材料可以大大缩短治疗剂从构思到大规模销售和销售之间的时间。因此，提出的研究目的是开发新的催化不对称碳-碳键形成工艺，可用于制备对人类保健重要的分子。提议的研究将集中于手性胺和醇的催化不对称制备，特别是那些无法通过现有的催化方法获得的。例如，我们在芳基亚胺和烷基亚胺上对映选择性添加烷基以获得手性胺的初步成功将扩展到含-羰基亚胺和酮胺。催化不对称添加烷基、芳基、烯基和炔基到这些类型的底物中，将为生物医学上重要的天然和非天然氨基酸及其衍生物提供简明的入口。同样，这种碳-碳键形成过程的分子内变化将被推进。手性肽基配体修饰的刘易斯酸性金属催化的芳香基团加成系联亚胺反应（Pictet-Spengler反应）将发展为不对称反应。与之相关的是，一般手性、非外消旋叔醇的烷基到酮的对映选择性加成将发展为一般催化不对称转化。鉴于缺乏催化合成手性叔醇的方法，该反应的成功将显著提高许多重要药用化合物的可用性并降低制备成本。在提出的研究的所有部分，新的不对称催化转化的效用将突出与几个重要的医学目标的高效和选择性合成。此外，一旦证明了催化不对称过程，将探索相应的反应机理，以进一步提高该过程的整体选择性和反应活性。新的反应方法将涉及手性肽基配体修饰的路易斯酸性金属催化，可以作为双功能催化剂。氨基酸价格低廉，对映体纯形式容易获得，并且在溶液和固相中都可以合成肽，同时制备多种配体结构是很简单的。因此，基于肽的手性配体的一个独特而有用的特征是它们可以被制备和检查的设施，以便达到最佳的反应性和选择性水平。