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.

Public Health Relevance

The natural products and pharmacologically relevant compounds stemming from this project have significant biomedical ramifications, specifically in thrombosis, hypertension, influenzas, cardiac diseases, cancer and several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson's disease, Alzheimer's disease and pain.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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University of California Los Angeles
Schools of Arts and Sciences
Los Angeles
United States
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Zhou, Qing-Fa; Zhang, Kui; Cai, Lingchao et al. (2016) Phosphine-Catalyzed Intramolecular Cyclizations of α-Nitroethylallenoates Forming (Z)-Furanone Oximes. Org Lett 18:2954-7
Cai, Lingchao; Zhang, Kui; Kwon, Ohyun (2016) Catalytic Asymmetric Total Synthesis of (-)-Actinophyllic Acid. J Am Chem Soc 138:3298-301
Lu, Jie; Yoshimura, Kohei; Goto, Koichi et al. (2015) Nanoformulation of Geranylgeranyltransferase-I Inhibitors for Cancer Therapy: Liposomal Encapsulation and pH-Dependent Delivery to Cancer Cells. PLoS One 10:e0137595
Xie, Letian X; Williams, Kevin J; He, Cuiwen H et al. (2015) Resveratrol and para-coumarate serve as ring precursors for coenzyme Q biosynthesis. J Lipid Res 56:909-19
Shimizu, Hirohito; Schredelseker, Johann; Huang, Jie et al. (2015) Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity. Elife 4:
Chang, Jae Won; Zuhl, Andrea M; Speers, Anna E et al. (2015) Selective inhibitor of platelet-activating factor acetylhydrolases 1b2 and 1b3 that impairs cancer cell survival. ACS Chem Biol 10:925-32
Zhou, Qing-Fa; Zhang, Kui; Kwon, Ohyun (2015) Stereoselective Syntheses of α,β-Unsaturated γ-Amino Esters Through Phosphine-Catalyzed γ-Umpolung Additions of Sulfonamides to γ-Substituted Allenoates. Tetrahedron Lett 56:3273-3276
Fan, Yi Chiao; Kwon, Ohyun (2015) Synthesis of Functionalized Alkylidene Indanes and Indanones through Tandem Phosphine-Palladium Catalysis. Org Lett 17:2058-61
Dupper, Nathan J; Kwon, Ohyun (2015) Functionalized α,α-dibromo esters through Claisen rearrangements of dibromoketene acetals. Org Lett 17:1054-7
Zhang, Kui; Cai, Lingchao; Jiang, Xing et al. (2015) Phosphine-Mediated Iterative Arene Homologation Using Allenes. J Am Chem Soc 137:11258-61

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