Phosphine-Catalyzed Annulations and their Applications

项目总结 该项目的首要目标是开发新的催化剂和反应以增强化学合成的能力。 生物活性天然产物靶标和药物。特别是，我们制定了一个基本的 设计应变和桥联的双环膦氧化物，可以很容易地还原为磷化氢 磷化氢氧化物是在原位形成的。一种新的桥联[2.2.1]双环氧膦已经展示 在催化Wittig反应和Staudinger反应中，反应性都优于目前已知的最好的替代品。 实验和理论研究都预测了所提出的[2.1.1]双环膦氧化物 会变得更加被动。考虑到由磷化氢氧化物的形成所驱动的反应的普遍性 (例如，Staudinger、Wittig、Mitsunobu和Appl反应)及其对环境的影响，我们的建议 研究应该对有机合成产生重大影响。我们对桥式[2.2.1]双环的启发 氧化膦来源于我们开发的反式-4-羟基-L-脯氨酸(Hyp)手性膦 在上一个资助期内。在[2.2.1]双环氧膦的更大能力的基础上，我们将应用 2-氮杂-5-磷杂双环[2.2.1]庚烷催化不对称Staudinger，Wittig，Mitsunobu， 和表象反应。这些手性膦化合物已经显示出巨大的潜力 对映体选择性Mitsunobu反应和Appl反应及第一个成功的催化不对称反应实例 Staudinger/Aza-Wittig反应。我们还将从香芹酮中合成新的桥联[2.2.1]双环手性膦。 香芹酮衍生的P-手性膦应该是通用的催化剂，因为香芹酮的两个对映体都是 天然资源丰富，因此价格低廉。充分利用磷化氢既可用作 有机催化剂和配体上的均相过渡金属催化剂，我们建议开发串联 卤代烯烃与活性乙炔的Michael-Heck反应合成5元和6元化合物 碳酸和杂环。使用碘醇的一种特殊的Michael-Heck过程是一种强大的工具 组装几乎任何替换模式的呋喃，并提供对几个结构不同的 呋喃半萜类天然产物。我们已经合成了10种不同的超衍生物手性膦 通过Sigma-Aldrich进行商业销售，并将再次与他们合作制造我们的磷化氢 科学界可获得的氧化物和手性膦。许多研究小组已经使用了 羟基膦在各种催化反应中的应用。我们预计拟议的研究将有一个 类似的对化学合成的重大影响。总的来说，在这个过程中开发的催化剂和反应 应用将允许对映体选择性地制备具有重要药用价值的药物和天然药物 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.