Phosphine-Catalyzed Annulations and Their Applications

描述（由申请人提供）：天然存在的小有机分子，如生物碱，以光学活性形式分离。多年来，生物碱的整体药理重要性吸引了许多科学对这类天然产物的兴趣。生物碱是许多古代民间药物的主要成分。这些天然存在的物质仍然被广泛使用，但现代合成有机化学已经使生产一组补充的半合成类似物成为可能，这些类似物扩大了生物碱的用途范围。我们研究的重点是开发新的反应，以提高有机合成的整体灵活性。本提案阐述了我们在膦催化环及其在具有药用意义的天然产物化学合成中的应用领域的初步发现。我们所开发的反应是新的，在合成手性杂环化合物方面具有巨大的潜力，可以作为各种合成的起始原料。特别是，我们推测，2-烷基-2,3-丁二烯酸酯与醛胺形成四氢吡啶的[4+2]环可能与吲哚类生物碱的化学合成有关，如毛须碱、毛须碱、阿尔斯通碱、巨碱、阿尔斯通碱和利血平。尽管出现了许多催化不对称反应过程，但这些对映体纯形式的生物碱的合成目前依赖于化学分解或使用对映体纯起始材料。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，我们提出从天然存在的碳水化合物中设计和合成新的手性膦。我们的策略是特别可取的，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，因此为催化剂合成提供了成本有效的起始材料。在我们的[4+2]环中以催化不对称的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，有效地制备天然形态的目标生物碱分子。所选择的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毛素对甲型流感病毒（H3N2亚型）的有效性是临床使用的利巴韦林的11至20倍。

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.