Phosphine-Catalyzed Annulations and Their Applications

描述(申请人提供)：本申请的总体目标是设计和开发对映体选择性的膦催化环状化合物，并将其应用于天然产物、其类似物和具有药用价值的非天然有机小分子的化学合成中。在我们对膦催化反应的成功研究及其在医药用途天然产物[(+)-ibophyllidine(�)-alstonerine，(�)-manline，(�)-hirsutin，3-脱氧异黄酸，异黄皮酸，异黄皮酚]全合成中的应用的基础上，我们提出了新的膦催化反应和新型手性膦的开发。具体地说，我们将从天然氨基酸(反式-4-羟基-L-脯氨酸)和萜类化合物(香芹酮)中制备三个系列的新的[2.2.1]双环手性膦。这些新的膦化合物在促进烯烃和亚胺之间的对映选择性[3+2]和[4+2]环化方面已经显示出巨大的潜力。为了建立在这些令人兴奋的初步观察的基础上，我们建议分别通过对映体选择性联烯亚胺[3+2]和[4+2]环合成(-)-放线叶酸和(+)-艾季马林，并通过催化不对称联烯-亚胺[4+2]环合成另一种吲哚生物碱(+)-多毛苷。此外，我们希望开发新的磷化氢催化和介导的反应。我们将考察和扩展新反应发展领域的两个假设：(I)串联Upolung加成/Wittig烯化和(Ii)顺序膦/过渡金属催化。这项研究将极大地扩展有机化学反应的原理，并为合成有机化学家的工具箱提供新的方法和试剂。要成功实现我们的三个具体目标，许多创新是必要的。我们在所有三个具体领域的初步结果都很强劲，支持了进一步成功的可能性。本建议中描述的小分子具有重要的医学价值，具有与血栓形成[(-)-放线叶酸]、高血压和心律失常[(+)-阿吉马林]、流感病毒[(+)-多毛]、神经疾病(谷氨酸受体拮抗剂)、心脏疾病和癌症(紫草碱)等疾病相关的活性。这项拟议的研究的成功完成将对合成有机化学界产生重大影响，因为它将引入一系列新的手性膦，这些膦很容易从廉价的天然产品中获得；事实上，我们正在与Sigma-Aldrich合作，使科学界能够获得这些手性膦。除了在所提出的有机催化反应中使用这些手性膦外，它们还应该作为过渡金属催化过程的配体。因此，拟议的研究可以显著提高各种合成有机过程的效率。

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.