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)
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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Henry, Christopher E; Xu, Qihai; Fan, Yi Chiao et al. (2014) Hydroxyproline-derived pseudoenantiomeric [2.2.1] bicyclic phosphines: asymmetric synthesis of (+)- and (-)-pyrrolines. J Am Chem Soc 136:11890-3
Wang, Zhiming; Xu, Xingzhu; Kwon, Ohyun (2014) Phosphine catalysis of allenes with electrophiles. Chem Soc Rev 43:2927-40
Fan, Yi Chiao; Kwon, Ohyun (2013) Advances in nucleophilic phosphine catalysis of alkenes, allenes, alkynes, and MBHADs. Chem Commun (Camb) 49:11588-619
Florian, Amy E; Lepensky, Christopher K; Kwon, Ohyun et al. (2013) Flow cytometry enables a high-throughput homogeneous fluorescent antibody-binding assay for cytotoxic T cell lytic granule exocytosis. J Biomol Screen 18:420-9
Andrews, Ian P; Blank, Brian R; Kwon, Ohyun (2012) Phosphine-catalyzed intramolecular ýý-umpolung addition of *-aminoalkylallenic esters: facile synthesis of 3-carbethoxy-2-alkyl-3-pyrrolines. Chem Commun (Camb) 48:5373-5
Chan, Lai N; Fiji, Hannah D G; Watanabe, Masaru et al. (2011) Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I. PLoS One 6:e26135
Choi, Jayoung; Mouillesseaux, Kevin; Wang, Zhiming et al. (2011) Aplexone targets the HMG-CoA reductase pathway and differentially regulates arteriovenous angiogenesis. Development 138:1173-81
Cruz, Daniel; Wang, Zhiming; Kibbie, Jon et al. (2011) Diversity through phosphine catalysis identifies octahydro-1,6-naphthyridin-4-ones as activators of endothelium-driven immunity. Proc Natl Acad Sci U S A 108:6769-74
Na, Risong; Jing, Chengfeng; Xu, Qihai et al. (2011) Phosphine-catalyzed annulations of azomethine imines: allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways. J Am Chem Soc 133:13337-48
Fan, Yi Chiao; Kwon, Ohyun (2011) Diversity-oriented synthesis based on the DPPP-catalyzed mixed double-Michael reactions of electron-deficient acetylenes and *-amino alcohols. Molecules 16:3802-25

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