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。生物碱的整体药理学重要性多年来吸引了对这些类别的天然产物的许多科学兴趣。生物碱是许多古老民间药物的主要成分。这些天然存在的药剂仍然被广泛使用，但是现代合成有机化学已经使得有可能产生补充组的半合成类似物，其用于扩展生物碱的有用范围。我们研究的重点是开发新的反应，以提高有机合成的灵活性。该提案涉及我们在膦催化成环及其在具有药用意义的天然产物的化学合成中的应用领域的初步研究结果。我们开发的反应是新的，在合成手性杂环化合物方面具有巨大的潜力，可以用作各种合成的起始原料。特别地，我们推测2-烷基-2，3-丁二烯烯酸酯与醛亚胺形成四氢吡啶的[4+2]环化反应可用于吲哚生物碱的化学合成，例如毛苏汀、毛苏汀、阿尔斯通、大环碱、阿尔斯通霉素和利血平。尽管出现了许多催化不对称反应过程，这些生物碱的对映体纯的形式的合成目前依赖于化学拆分或使用对映体纯的原料。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，我们提出了设计和合成新的手性膦从天然存在的碳水化合物。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成本有效的起始材料。使用这些手性膦在我们的[4+2]成环催化不对称的方式，我们可以有效地制备目标生物碱分子在其天然形式，从更便宜的外消旋起始材料。选定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，靶向天然产物之一的毛素显示出比临床上使用的利巴韦林更有效地对抗甲型流感病毒（亚型H3 N2）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.