This proposal centers on the development of new tether methods to be championed in the context of complex synthetic challenges to aid in solving biologically relevant problems in order to advance current drug discovery efforts towards the ultimate goal of developing novel therapeutic agents and probes to treat human disease. While historical and traditional views toward the use of phosphates in organic synthesis were skeptical, the body of evidence provided in the last granting period has highlighted the versatilit of phosphates as synthetic tools. In tune with previous work, the development of additional tethered processes will establish these methods as practical and advantageous pathways to the total synthesis of natural products. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) IKD-8344, which has shown potent anthelmintic acvitivity, cytotoxicity and anti antifungal activity against different cell lines;(2) Reidispongiolide A, an actin-binding 26-membered macrolide that has potential in the treatment of multi- drug resistant tumors;(3) Dictyostatin, which has been shown to have antitumor/antimitotic activity against several cell lines;(4) Leustroducsin B (LSN-B), which has shown antitumor activity and has potential as a novel hematopoietic growth factor (HGF) with application to a number of hematopoietic diseases;and (5) Franklinolides A-C, which display cytotoxicity against several cancer cell lines. Taken collectively, the development of this approach represents an integrated platform for the emergence of new and powerful tether systems for use in small molecule synthesis that will aid in molecular design and chemical synthesis of analogs for biological investigations.
This project entitled Methods for Bioactive Compound Synthesis focuses on the development of new tether-mediated synthetic methods for the construction of complex bioactive natural products. These methods will aid in the design and chemical synthesis of analogs for use in chemical biology investigations with collaborators. Ultimately, this study aims to advance current drug discovery efforts towards the goal of developing novel therapeutic agents and probes to treat human disease.
|Markley, Jana L; Hanson, Paul R (2017) P-Stereogenic Bicyclo[4.3.1]phosphite Boranes: Synthesis and Utility of Tunable P-Tether Systems for the Desymmetrization of C2-Symmetric 1,3-anti-Diols. Org Lett 19:2552-2555|
|Markley, Jana L; Hanson, Paul R (2017) P-Tether-Mediated, Iterative SN2'-Cuprate Alkylation Strategy to Skipped Polyol Stereotetrads: Utility of an Oxidative ""Function Switch"" with Phosphite-Borane Tethers. Org Lett 19:2556-2559|
|Bodugam, Mahipal; Javed, Salim; Ganguly, Arghya et al. (2016) A Pot-Economical Approach to the Total Synthesis of Sch-725674. Org Lett 18:516-9|
|Markley, Jana L; Maitra, Soma; Hanson, Paul R (2016) Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of P-Stereogenic, Z-Configured Bicyclo[7.3.1]- and Bicyclo[8.3.1]phosphates. J Org Chem 81:899-911|
|Maitra, Soma; Bodugam, Mahipal; Javed, Salim et al. (2016) Synthesis of the C9-C25 Subunit of Spirastrellolide B. Org Lett 18:3094-7|
|Javed, Salim; Bodugam, Mahipal; Torres, Jessica et al. (2016) Modular Synthesis of Novel Macrocycles Bearing ?,?-Unsaturated Chemotypes through a Series of One-Pot, Sequential Protocols. Chemistry 22:6755-6758|
|Maitra, Soma; Markley, Jana L; Chegondi, Rambabu et al. (2015) Phosphate Tether-Mediated Ring-Closing Metathesis for the Generation of Medium to Large, P-Stereogenic Bicyclo[n.3.1]phosphates. Tetrahedron 71:5734-5740|
|Hanson, Paul R; Jayasinghe, Susanthi; Maitra, Soma et al. (2015) Phosphate tethers in natural product synthesis. Top Curr Chem 361:253-71|
|Chegondi, Rambabu; Hanson, Paul R (2015) Synthetic Studies to Lyngbouilloside: A Phosphate Tether-Mediated Synthesis of the Macrolactone Core. Tetrahedron Lett 56:3330-3333|
|Jayasinghe, Susanthi; Venukadasula, Phanindra K M; Hanson, Paul R (2014) An efficient, modular approach for the synthesis of (+)-strictifolione and a related natural product. Org Lett 16:122-5|
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