Phosphine-Catalyzed Annulations and their Applications

项目摘要 该项目的总体目标是开发新的催化剂和反应，以增强化学合成 具有生物活性的天然产物靶点和药物。特别是，我们制定了一个理由， 设计应变和桥连的双环氧化膦，其可以容易地还原回膦， 氧化膦原位形成。一种新的桥连[2.2.1]双环氧化膦已经显示出 反应性，在催化Wittig和Staudinger反应中，上级当今已知的最佳替代品。 实验和理论研究已经预测，所提出的[2.1.1]双环氧化膦 会变得更加活跃考虑到由氧化膦的形成驱动的反应的普遍性， (e.g., Staudinger，Wittig，Mitsunobu和阿佩尔反应）及其环境后果，我们提出了 研究应该对有机合成产生重大影响。桥[2.2.1]双环的灵感 氧化膦来源于我们开发的反式-4-羟基-L-脯氨酸（Hyp）衍生的手性膦 在最后一个融资期。基于[2.2.1]双环氧化膦的更大能力，我们将应用 Hyp-derived 2-氮杂-5-磷杂双环[2.2.1]庚烷催化不对称Staudinger，Wittig，Mitsunobu， 和阿佩尔反应。这些手性膦已经在促进生物多样性方面表现出巨大的潜力。 对映选择性Mitsunobu和阿佩尔反应和第一个成功的例子，催化不对称 Staudinger/aza-Wittig反应我们还将从香芹酮中生成新的桥连[2.2.1]双环手性膦。 香芹酮衍生的P-手性膦应该是通用催化剂，因为香芹酮的两种对映体都是 天然丰富，因此价格低廉。利用膦的能力， 有机催化剂和配体上的均相过渡金属催化剂，我们建议开发一个串联 烯基卤化物与活化炔类的Michael-Heck反应用于5-和6-元环的组装 碳环和杂环。使用碘醇的一种特定的Michael-Heck方法是一种强有力的工具， 组装几乎任何取代模式的呋喃，并提供了几种结构不同的 呋喃倍半萜类天然产物。我们已经制备了10种不同的Hyp-derived手性膦 我们将再次与他们合作， 氧化物和手性膦。许多研究小组已经使用 Hyp-derived膦在多种催化反应中的应用。我们预计，拟议的研究将有一个 对化学合成也有类似的重大影响。总的来说，在此过程中开发的催化剂和反应 本申请将允许对映选择性地制备具有医学意义的药物和天然药物。 产品目标。

PROJECT SUMMARY The overarching goal of this project is to develop new catalysts and reactions to empower the chemical synthesis of biologically active natural product targets and pharmaceuticals. In particular, we formulate a rationale for designing strained and bridged bicyclic phosphine oxides that can be readily reduced back to phosphines after the phosphine oxides are formed in situ. A new bridged [2.2.1] bicyclic phosphine oxide has already displayed reactivity, in both catalytic Wittig and Staudinger reactions, superior to that of the best alternatives known today. Experimental and theoretical investigations have predicted that the proposed [2.1.1] bicyclic phosphine oxides would be even more reactive. Considering the ubiquity of reactions driven by the formation of phosphine oxides (e.g., Staudinger, Wittig, Mitsunobu, and Appel reactions), and their environmental consequences, our proposed research should have significant impact on organic synthesis. Our inspiration for the bridged [2.2.1] bicyclic phosphine oxide originated from the trans-4-hydroxy-L-proline (Hyp)–derived chiral phosphines we developed during the last funding period. Building on the greater faculty of the [2.2.1] bicyclic phosphine oxide, we will apply the Hyp-derived 2-aza-5-phosphabicyclo[2.2.1]heptanes to catalytic asymmetric Staudinger, Wittig, Mitsunobu, and Appel reactions. These chiral phosphines have already exhibited tremendous potential in facilitating enantioselective Mitsunobu and Appel reactions and the first successful example of a catalytic asymmetric Staudinger/aza-Wittig reaction. We will also create new bridged [2.2.1] bicyclic chiral phosphines from carvone. Carvone-derived P-chiral phosphines should be versatile catalysts because both enantiomers of carvone are naturally abundant and, therefore, inexpensive. Capitalizing on the capacity of phosphines to serve as both organic catalysts and ligands on homogeneous transition metal catalysts, we propose to develop a tandem Michael-Heck reaction of alkenyl halides and activated acetylenes for the assembly of 5- and 6-membered carbo- and heterocycles. One particular Michael-Heck process employing iodoalcohols is a powerful tool for assembling furans of almost any substitution pattern and provides access to several structurally disparate furanosesquiterpenoid natural products. We have already made 10 different Hyp-derived chiral phosphines commercially available through Sigma–Aldrich and will collaborate with them again to make our phosphine oxides and chiral phosphines available to the scientific community. Many research groups have already used Hyp-derived phosphines in a variety of catalysis reactions. We anticipate that the proposed research will have a similar significant impact on chemical synthesis. Collectively, the catalysts and reactions developed in this application will allow the enantioselective preparation of medicinally significant pharmaceuticals and natural product targets.