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映选择性膦催化的环化，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。本文基于我们对膦催化反应及其在天然药物[（+）-异叶绿啶（β）-阿尔斯通碱、（β）-大环碱、（β）-毛藤碱、3-脱氧异赭曲霉酸、异赭曲霉酸、异赭曲霉醇]全合成中的应用的成功研究，提出了新的膦催化反应和新型手性膦化合物的开发。具体而言，我们将从天然存在的氨基酸（反式-4-羟基-L-脯氨酸）和萜类化合物（香芹酮）制备三个新的[2.2.1]双环手性膦家族。这些新的膦化合物在促进联烯和亚胺之间的[3+2]和[4+2]成环反应方面已经显示出巨大的潜力。基于这些令人兴奋的初步观察，我们建议分别通过对映选择性的丙二烯-亚胺[3+2]和[4+2]成环反应合成（-）-放线菌酸和（+）-阿曲林，以及通过催化不对称丙二烯-亚胺[4+2]成环反应合成另一种吲哚生物碱（+）-毛果亭。此外，我们希望开发新的膦催化和介导的反应。我们将研究和扩展在新的反应发展领域的两个假设：（i）串联umpolung加成/Wittig烯烃化和（ii）连续膦/过渡金属催化。这项研究将极大地拓展有机反应的原理，为有机合成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，就必须进行许多创新。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。在该建议中描述的小分子在医学上是重要的，具有与疾病相关的活性，所述疾病例如血栓形成[（-）-放线菌酸]、高血压和心律失常[（+）-阿曲亭]、流感[（+）-毛素]、神经障碍（谷氨酸受体拮抗剂）和心脏病和癌症（shihunidine）。这项拟议研究的成功完成将通过引入一系列新的手性膦来显著影响合成有机化学界，这些手性膦很容易从廉价的天然产物中获得;事实上，我们正在与Sigma-Aldrich合作，使这些手性膦可用于科学界。除了在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，拟议的研究可以显着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.