New Catalytic and Enantioselective Reactions

具有催化作用、具有出色的选择性、高效且使用廉价材料的反应可以极大地缩短从受孕到治疗剂的大规模销售准备和销售之间的时间。据介绍，这项拟议研究的目标是开发新的催化不对称碳-碳键形成过程，可用于制备对人类健康至关重要的分子。拟议的研究将集中在手性胺和醇的催化不对称制备，特别是那些通过现有催化方法无法获得的手性胺和醇的催化不对称制备。例如，我们在芳基和烷基亚胺对映体选择性加成以提供手性胺方面的初步成功将扩展到含α-甲酰亚胺和酮亚胺。这些类型的底物中的烷基、芳基、烯基和炔基的催化不对称加成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也将被推进。芳香族基团的加成反应(Pictet-Spengler反应)将发展为一个不对称的过程，该过程由手性多肽配体修饰的Lewis酸性金属催化。相应地，一般的手性、非外消旋叔醇的烷基与酮的不对称加成反应将发展为一般的催化不对称转化。由于目前尚无合成手性叔醇的催化方法，该反应的成功将极大地提高手性叔醇的可得性，并降低众多具有重要药用价值的化合物的制备成本。在拟议研究的所有部分中，将通过高效和选择性地合成几个医学上重要的目标来突出新的不对称催化转化的效用。此外，一旦证明了催化不对称过程，将进一步探讨相应的反应机理，以进一步提高该过程的整体选择性和反应性。有待开发的新反应方法将包括用手性多肽配体修饰的Lewis酸性金属作为双功能催化剂进行催化。氨基酸价格低廉，易于以对映体纯的形式获得，而且多肽的合成已经在溶液和固相中完成，同时制备多个配体结构是直接的。因此，基于多肽的手性配体的一个独特和有用的特征是可以用来制备和检测它们，从而达到最佳的反应性和选择性水平。

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.