Phosphine-Catalyzed Annulations and Their Applications

描述（由申请人提供）：本申请的总体目标是设计和开发对旋选择性膦催化环，并将其应用于天然产物、其类似物和具有药用意义的非天然小有机分子的化学合成中。基于我们对磷化氢催化反应的成功研究及其在全合成药用天然产物[(+)-ibophyllidine（¿）-alstonerine,（¿）-macroline,（¿）-hirsutine， 3-脱氧异克拉辛酸，异克拉辛酸，异克拉辛醇]中的应用，我们提出了新的磷化氢催化反应和新型手性磷化氢的发展。具体来说，我们将从天然存在的氨基酸（反式4-羟基- l -脯氨酸）和萜类（香芹酮）制备三个新的[2.2.1]双环奇拉膦家族。这些新的膦在促进亚胺和烯基间的[3+2]和[4+2]环对映选择性方面已经显示出巨大的潜力。在这些令人兴奋的初步观察结果的基础上，我们提出通过对映选择性烯-亚胺[3+2]和[4+2]环分别合成(-)-放射茶酸和(+)- ajmaline，并通过催化不对称烯-亚胺[4+2]环合成另一种吲哚类生物碱(+)-hirsutin。此外，我们希望开发新的磷化氢催化和介导的反应。我们将研究和扩展新反应发展领域的两个假设：(i)串联加成/维提格烯烃和（ii）顺序膦/过渡金属催化。本研究将极大地扩展有机反应的原理，为合成有机化学家的工具箱提供新的方法和试剂。要成功地实现我们的三个具体目标，需要许多创新。我们在所有三个具体领域的初步结果都很强劲，支持进一步成功的可能性。本提案中描述的小分子具有重要的医学意义，具有与诸如血栓形成[(-)-放线素酸]，高血压和心律失常[(+)-ajmaline]，流感[(+)-hirsutin]，神经系统疾病（谷氨酸受体拮抗剂）以及心脏病和癌症（shihunidine）等疾病相关的活性。该研究的成功完成将通过引入一系列易于从廉价天然产物中获得的新的手性膦，对合成有机化学界产生重大影响；事实上，我们正在与Sigma-Aldrich合作，将这些手性膦提供给科学界。除了在提出的有机催化反应中使用这些手性膦外，它们还可以作为过渡金属催化过程的配体。因此，所提出的研究可以显著提高各种合成有机工艺的效率。

DESCRIPTION (provided by applicant): The overall objective of this application is to design and develop enantioselective phosphine-catalyzed annulations and to apply them in the chemical syntheses of natural products, their analogs, and unnatural small organic molecules of medicinal significance. Building on our successful studies of phosphine catalysis reactions and their applications in the total syntheses of medicinally useful natural products [(+)-ibophyllidine (¿)-alstonerine, (¿)-macroline, (¿)-hirsutine, 3-deoxyisoochracinic acid, isoochracinic acid, isoochracinol], here we propose the development of new phosphine catalysis reactions and novel chiral phosphines. Specifically, we will prepare three families of new [2.2.1] bicyclic chira phosphines from a naturally occurring amino acid (trans-4-hydroxy-L-proline) and a terpenoid (carvone). These new phosphines have already displayed tremendous potential in facilitating enantioselective [3+2] and [4+2] annulations between allenes and imines. To build on these exciting preliminary observations, we propose to synthesize (-)-actinophyllic acid and (+) - ajmaline through enantioselective allene-imine [3+2] and [4+2] annulations, respectively, and another indole alkaloid, (+)-hirsutine, through the catalytic asymmetric allene-imine [4+2] annulation. In addition, we wish to develop new phosphine-catalyzed and -mediated reactions. We will examine and expand upon two hypotheses in the area of new reaction development: (i) tandem umpolung addition/Wittig olefination and (ii) sequential phosphine/transition metal catalysis. The proposed research could significantly expand the principles of organic reactions and provide new methods and reagents for the synthetic organic chemist's toolbox. Many innovations will be necessary to successfully implement our three specific aims. Our preliminary results have been strong in all three specific areas, supporting the likelihood of further successes. The small molecules described in this proposal are medicinally important, possessing activities related to diseases such as thrombosis [(-)-actinophyllic acid], hypertension and arrhythmia [(+)-ajmaline], influenzas [(+)-hirsutine], neurological disorders (glutamate receptor antagonist), and cardiac diseases and cancer (shihunidine). Successful completion of this proposed study would significantly impact the synthetic organic chemistry community by introducing a series of new chiral phosphines readily accessible from inexpensive natural products; in fact, we are collaborating with Sigma-Aldrich to make these chiral phosphines available to the scientific community. In addition to using these chiral phosphines in the proposed organocatalysis reactions, they should also serve as ligands for transition metal-catalyzed processes. Therefore, the proposed research could significantly increase the efficiencies of various synthetic organic processes.