New Catalytic and Enantioselective Reactions

具有催化性、以突出的选择性进行、有效且使用廉价材料的反应可以显著缩短治疗剂的构思和大规模销售制备与销售之间的时间。因此，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催化不对称制备手性胺和醇，特别是那些无法通过现有的催化方法。例如，我们在芳基和烷基亚胺上对映选择性加成烷基以提供手性胺的初步成功将扩展到含α-羰基的亚胺和酮亚胺。将烷基、芳基、烯基和炔基催化不对称加成到这些类型的底物中将提供对生物医学上重要的天然和非天然氨基酸及其衍生物的简明条目。同样，这种碳-碳键形成过程的分子内变化将被推进。芳香族基团与束缚亚胺的加成反应（Pictet-Spengler反应）将发展为手性肽基配体修饰的刘易斯酸性金属催化的不对称反应。在相关的方式，不对称加成的烷基基团到酮一般手性，非外消旋叔醇将发展成为一个通用的催化不对称转化。由于缺乏合成手性叔醇的催化方法，该反应的成功将显著提高许多具有医学重要性的化合物的可用性并降低其制备成本。在拟议的研究的所有部分，新的不对称催化转化的效用将突出与几个医学上重要的目标的有效和选择性的合成。此外，一旦催化不对称过程已经被证明，相应的反应机理将被探索，以进一步提高该过程的整体选择性和反应性。待开发的新反应方法将涉及通过手性肽基配体修饰的刘易斯酸性金属的催化作用，所述手性肽基配体可用作双功能催化剂。氨基酸是廉价的，容易以对映体纯的形式获得，并且肽合成已经在溶液和固相中进行，同时制备多个配体结构是简单的。因此，基于肽的手性配体的独特和有用的特征是它们可以被制备和检查的便利性，使得可以实现最佳水平的反应性和选择性。

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.