Development of New Catalytic and Enantioselective Reactions

新催化和对映选择性反应的发展

• 批准号: 8895345
• 负责人: AMIR H HOVEYDA
• 金额: $ 31.3万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895345
• 关键词: Alcohols; Aldehydes; Amines; Anti-Inflammatory Agents; Anti-inflammatory; Antimalarials; Antineoplastic Agents; Aspartic Endopeptidases; Biological Factors; Boron; Carbon; Chemistry; Copper; Data; Development; Elements; Family; Gel Chromatography; Halogens; Health; Healthcare; Hour; Housing; Human; Hydrogen Bonding; In Situ; Investigation; Ketones; Laboratories; Ligands; Methods; Pharmaceutical Chemistry; Preparation; Process; Protease Inhibitor; Protocols documentation; Protons; Reaction; Reagent; Research; Salts; Temperature; antitumor agent; base; bielschowskysin; catalyst; cost effective; design; diene; functional group; innovation; member; programs; research study; silochrome; toxic metal

DESCRIPTION (provided by applicant): Amines and alcohols are functional groups that are found in a great number of biologically active molecules; in many instances, these structural units contain N- or O- substituted tertiary or quaternary carbon stereogenic centers. Design and development of transformations that are promoted by a readily accessible and reliable set of catalysts and which afford amines and alcohols in high enantiomeric purity is thus a compelling objective of research in modern chemistry. Other important attributes of such reactions is that the chiral catalysts do not require precious and/or expensive elements, reagents are robust, readily accessible and do not contain toxic metals (such as Cr or Sn). It is equally important that reactions proceed at ambient temperature and are complete within a few hours (ideally, in less than eight hours). Research in this program is focused on the design, synthesis and development of a range of easily accessible chiral catalysts that allow for the efficient and enantioselective addition of a variety of readily available and robust unsaturated organoboron reagents to aldimines, aldehydes, ketones and ketoimines. One class of catalysts require the inexpensive and abundant salts of copper and chiral ligands that can be prepared in no more than five steps. Another catalyst class, more recently discovered in our laboratories, is boron-based, is generated in situ and the requisite chiral ligand can be prepared in four simple steps in high yield from cheap and commercially available materials; it can be purified without silica gel chromatography or distillation. We plan to utilize the above catalysts, which were designed in-house, in the development of highly efficient, diastereo- and enantioselective additions of allenyl, homoallenyl, dienyl, and halo- or alkoxy-substituted allyl(pinacolato)boron reagents to an assortment of readily accessible aldimines, ketones, aldehydes and ketoimines. The resulting products can be functionalized in a wide range of manners, thus allowing access to a great number of valuable amines and alcohols in high yield and enantiomeric purity. In nearly all cases, alternative catalytic methods for enantioselective synthesis of the resulting products are unavailable; in many cases, there are also no stoichiometric approaches known either. Selected conceptually innovative aspects of our investigations are: use of a single proton and H-bond to achieve high activity and selectivity; design of catalysts that allow high efficiency and stereoselectivity through a single point of contact, use of F atoms as H-bond acceptors to achieve high efficiency and enantioselectivity, and the use of unprotected ketoimines in various catalytic transformations. The utility of catalysts and methods developed will be demonstrated by application to the concise synthesis of a number of biologically active natural products, which include anti-tumor agent cyclooroidin, anti-inflammatory agent bisavenanthramide B-3, anti-malarial bielschowskysin, anti-inflammatory setileuton, and members of a recently discovered family of aspartyl protease inhibitors.

说明（由申请人提供）：胺和醇是在大量生物活性分子中发现的官能团;在许多情况下，这些结构单元含有N-或O-取代的叔碳或季碳立体中心。因此，设计和开发由容易获得和可靠的一组催化剂促进的转化，并提供高对映体纯度的胺和醇，是现代化学研究的一个引人注目的目标。此类反应的其他重要属性是手性催化剂不需要贵重和/或昂贵的元素，试剂是稳健的、容易获得的并且不含有毒金属（例如Cr或Sn）。同样重要的是 反应在环境温度下进行，并在几小时内完成（理想地，少于8小时）。该计划的研究重点是设计，合成和开发一系列易于获得的手性催化剂，这些催化剂可以将各种易得且稳定的不饱和有机硼试剂有效和对映选择性地添加到醛亚胺，醛，酮和酮亚胺中。一类催化剂需要廉价且丰富的铜盐和手性配体，其可以在不超过五个步骤中制备。我们实验室最近发现的另一类催化剂是硼基的，它是原位生成的，所需的手性配体可以通过四个简单的步骤制备， 从廉价和商业上可获得的材料得到高收率;它可以在没有硅胶色谱或蒸馏的情况下纯化。我们计划利用上述内部设计的催化剂，开发丙二烯基、高丙二烯基、二烯基和卤代或烷氧基取代的烯丙基（频哪醇合）硼试剂与一种氢化物的高效、非对映和对映选择性加成。 容易获得的醛亚胺、酮、醛和酮亚胺的分类。所得产物可以以多种方式官能化，从而允许以高产率和对映体纯度获得大量有价值的胺和醇。在几乎所有的情况下，对映选择性合成所得产物的替代催化方法是不可用的;在许多情况下，也没有已知的化学计量方法。我们的调查选择的概念上的创新方面是：使用一个单一的质子和H-键，以实现高活性和选择性;设计的催化剂，允许高效率和立体选择性，通过一个单一的接触点，使用F原子作为H-键受体，以实现高效率和对映体选择性，以及使用未保护的酮亚胺在各种催化转化。所开发的催化剂和方法的效用将通过应用于许多生物活性天然产物的简明合成来证明，所述天然产物包括抗肿瘤剂环孢菌素、抗炎剂bisavenanthramide B-3、抗疟疾的bielschowskysin、抗炎的setileuton和最近发现的乙酰基蛋白酶抑制剂家族的成员。