Phosphine-Catalyzed Annulations and Their Applications

磷化氢催化环化及其应用

基本信息

批准号：
7825261
负责人：
OHYUN KWON
金额：
$ 27.2万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2014-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Naturally occurring small organic molecules, such as alkaloids, are isolated in optically active forms. The overall pharmacological importance of alkaloids has attracted much scientific interest for these classes of natural products over the years. Alkaloids are the main agents of many ancient folk medicines. These naturally occurring agents are still widely used, but modern synthetic organic chemistry has made it possible to produce a supplementary group of semi-synthetic analogs that have served to extend the range of usefulness of the alkaloids. The focus in our research is to develop new reactions that will enhance the dexterity of organic synthesis as a whole. This proposal addresses our preliminary findings in the area of phosphine-catalyzed annulations and their applications in the chemical synthesis of natural products of medicinal significance. The reactions we have developed are new and hold tremendous potential in synthesizing chiral heterocycles, which can be used as starting materials for a variety of syntheses. In particular, we surmised that a [4+2] annulation of 2-alkyl-2,3-butadienoates with aldimines to form tetrahydropyridines could be geared to the chemical synthesis of indole alkaloids, such as hirsuteine, hirsutine, alstonerine, macroline, alstomicine, and reserpine. Despite the advent of numerous catalytic asymmetric reaction processes, syntheses of these alkaloids in enantiomerically pure forms currently rely on either chemical resolution or use of enantiomerically pure starting materials. Of course, catalytic asymmetric processes are ideal from an economic and environmental standpoint. Therefore, we propose design and synthesis of new chiral phosphines from naturally occurring carbohydrates. Our strategy is especially desirable since carbohydrates are one of nature's most abundant and cheap sources of chirality and thereby provide cost effective starting materials for catalyst synthesis. Using these chiral phosphines in our [4+2] annulation in catalytic asymmetric fashion, we can efficiently prepare the target alkaloid molecules in their natural forms, starting from cheaper racemic starting materials. The targets chosen are highly relevant to national public health, specifically the treatment of the common cold, hypertension, amoebic dysentery, malaria, arrhythmia, and cancer. For example, hirsutine, one of the target natural products, shows to be 11 to 20 times more effective against the influenza A virus (subtype H3N2) than the clinically used ribavirin.

描述（由申请人提供）：天然存在的小有机分子，例如生物碱，以光学活性形式分离。多年来，生物碱的整体药理学重要性引起了人们对此类天然产物的极大兴趣。生物碱是许多古老民间药物的主要成分。这些天然存在的试剂仍然被广泛使用，但现代合成有机化学已经使得生产一组补充的半合成类似物成为可能，这些半合成类似物有助于扩大生物碱的用途范围。我们研究的重点是开发新的反应，以提高整个有机合成的灵活性。该提案阐述了我们在膦催化环化领域的初步发现及其在具有药用意义的天然产物的化学合成中的应用。我们开发的反应是新的，在合成手性杂环方面具有巨大的潜力，可用作各种合成的起始材料。特别是，我们推测2-烷基-2,3-丁二烯酸酯与醛亚胺的[4+2]环化形成四氢吡啶可用于吲哚生物碱的化学合成，例如hirsuteine、hirsutine、alstonerine、macroline、alstomicine和利血平。尽管出现了许多催化不对称反应方法，但对映体纯形式的这些生物碱的合成目前依赖于化学拆分或使用对映体纯的起始材料。当然，从经济和环境的角度来看，催化不对称过程是理想的。因此，我们建议从天然存在的碳水化合物中设计和合成新的手性膦。我们的策略是特别理想的，因为碳水化合物是自然界最丰富和最便宜的手性来源之一，从而为催化剂合成提供了具有成本效益的起始材料。在我们的[4+2]环化中以催化不对称方式使用这些手性膦，我们可以从更便宜的外消旋起始材料开始，有效地制备天然形式的目标生物碱分子。所选目标与国家公共卫生高度相关，特别是普通感冒、高血压、阿米巴痢疾、疟疾、心律失常和癌症的治疗。例如，目标天然产物之一的多毛素（hirsutine）对甲型流感病毒（H3N2亚型）的功效比临床使用的利巴韦林高11至20倍。