Phosphine-Catalyzed Annulations and their Applications

项目摘要 本申请的首要目标是开发新的催化剂和反应，以增强催化剂的活性。 与医学相关的天然产物目标和药物的化学合成。我们特别 阐述了设计易于还原的应变和桥接双环氧化膦的基本原理 回到原位的膦。一种新的[2.2.1]双环氧化膦已经在两种情况下表现出反应性， 催化Wittig和Staudinger反应，上级于当时已知的最佳替代品， 发明的理论研究预测，我们确实已经实验证明， [2.1.1]双环膦氧化物甚至比任何其它已知的膦氧化物更具反应性。 考虑到由氧化膦的形成驱动的反应的普遍性，以及它们的环境影响， 因此，我们提出的研究应该对有机合成产生重大影响。我们的灵感来自于 [2.2.1]双环膦氧化物源自Hyp-derived手性膦（HypPhos）， 在上一个供资期间开发的。在[2.2.1]双环氧化膦的更大能力的基础上， 我们将应用HypPhos（氧化物）催化不对称Staudinger、Wittig、Mitsunobu和阿佩尔反应。 HypPhos（氧化物）已经在促进对映选择性Mitsunobu方面显示出巨大的潜力 和阿佩尔反应以及催化不对称Staudinger/aza-Wittig反应的第一个成功实例。 我们还从香芹酮产生了新的[2.2.1]和[2.1.1]双环手性膦（"CarvoPhos"）。的 CarvoPhos（氧化物）应该是多用途的催化剂，因为香芹酮的两种对映体都是天然丰富的。 我们还将探索我们的方法的模块化手性膦在合成（邻羟基苄基）- 用于氧化还原中性氧化膦催化的Mitsunobu和阿佩尔反应的HypPhos和-CarvoPhos氧化物。 为了建立对映选择性丙二烯亚胺[4 + 2]成环的令人兴奋的结果，我们还提出了一个独特的 阿奎米林生物碱的组装策略。利用膦的能力， 作为有机催化剂和作为均相过渡金属催化剂上的配体，我们设计了一种串联的 卤代醇和活化乙炔的Michael − Heck反应组装5-和6-元碳 和杂环。一种使用γ-卤代烯丙醇的特定Michael-Heck方法是一种强有力的策略， 组装具有几乎任何取代模式的呋喃，同时还提供了几种结构上的 不同的呋喃倍半萜。目前，我们有10种不同的HypPhos膦可商购 通过Sigma-Aldrich;我们将再次与他们合作，制造我们的手性膦和氧化膦 提供给科学界。许多研究小组已经将HypPhos用于各种 对映选择性化学催化。我们预计，拟议的研究将同样具有重大意义。 影响化学合成。总的来说，在这个项目中开发的催化剂和反应将允许 生物活性药物和天然产物靶标的对映选择性制备。

PROJECT SUMMARY The overarching goal of this application is the development of new catalysts and reactions to empower the chemical synthesis of medicinally relevant natural product targets and pharmaceuticals. Specifically, we formulate a rationale for designing strained and bridged bicyclic phosphine oxides that can readily be reduced back to phosphines in situ. A novel [2.2.1] bicyclic phosphine oxide has already exhibited reactivity, in both catalytic Wittig and Staudinger reactions, superior to that of the best alternatives known at the time of its invention. Theoretical investigations predicted, and we have indeed proved experimentally, that the proposed [2.1.1] bicyclic phosphine oxides would be even more reactive than any other known phosphine oxides. Considering the ubiquity of reactions driven by the formation of phosphine oxides, and their environmental consequences, our proposed research should have significant impact on organic synthesis. Our inspiration for the [2.2.1] bicyclic phosphine oxides originated from the Hyp-derived chiral phosphines (“HypPhos”) that we developed during the last funding periods. Building on the greater faculty of the [2.2.1] bicyclic phosphine oxides, we will apply the HypPhos (oxides) to catalytic asymmetric Staudinger, Wittig, Mitsunobu, and Appel reactions. The HypPhos (oxides) have already displayed tremendous potential in facilitating enantioselective Mitsunobu and Appel reactions and the first successful example of a catalytic asymmetric Staudinger/aza-Wittig reaction. We have also created new [2.2.1] and [2.1.1] bicyclic chiral phosphines (“CarvoPhos”) from carvone. The CarvoPhos (oxides) should be versatile catalysts because both enantiomers of carvone are naturally abundant. We will also explore the modularity of our approach to chiral phosphines in the syntheses of (o-hydroxybenzyl)- HypPhos and -CarvoPhos oxides for redox-neutral phosphine oxide-catalyzed Mitsunobu and Appel reactions. To build upon the exciting results of enantioselective allene–imine [4+2] annulation, we also put forth a unique strategy for the assembly of akuammilline alkaloids. Capitalizing on the capacity of phosphines to function both as organic catalysts and as ligands on homogeneous transition metal catalysts, we have devised a tandem Michael−Heck reaction of haloalcohols and activated acetylenes for the assembly of 5- and 6-membered carbo- and heterocycles. One particular Michael−Heck process, employing γ-haloallyl alcohols, is a powerful tactic for assembling furans with almost any substitution pattern, while also providing access to several structurally disparate furan sesquiterpenes. At present, 10 of our different HypPhos phosphines are commercially available through Sigma–Aldrich; we will collaborate with them again to make our chiral phosphines and phosphine oxides available to the scientific community. Many research groups have already used HypPhos in a variety of enantioselective chemical catalyses. We anticipate that the proposed research will, similarly, have a significant impact on chemical synthesis. Collectively, the catalysts and reactions developed in this project will allow the enantioselective preparation of biologically active pharmaceuticals and natural product targets.