The purpose of this proposal is to implement phosphate triester tether methods for the synthesis of complex biologically relevant natural products. We have provided empirical evidence that counters historical and traditional views associated with the utilization of phosphates in synthesis. The logic of implementing phosphate-tethers is predicated in a number of salient features inherent to phosphorus, including: (i) facile multivalent coupling pathways (ii) chirality at phosphorus, (iii) multivalent activation to corresponding carbinol centers via innate leaving group ability within the phosphate tether, (iv) an orthogonal stability/reactivity profile that imparts protecting group features, and (v) inherent nucleophilic characteristics in pendant phosphate esters/acids that enable iodophosphonylation protocols. The proposed method will serve as the cornerstone in the asymmetric synthesis of (1) cytostatin, which is known to inhibit cell adhesion to the extra-cellular matrix by selectively inhibiting protein phosphatase 2A and has been shown to prevent metastasis, inhibit tumor cell growth, inhibit cell adhesion and cause apoptosis in certain cell lines;(2) 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;(3) fostriecin, a potent phosphatase inhibitor that displays in vitro activity against a broad range of cancerous cell lines including lung cancer, breast cancer, and ovarian cancer, as well as in vivo antitumor activity;(4) dolabelides A and B which are a family of recently isolated 22- and 24-membered macrolides that exhibit promising cytotoxicity properties against HeLaSa cells and (5) Iso-migrastatin, a natural product isolated from Streptomyces platens is and a member of the migrastatin family. Migrastatin is a shunt metabolite of iso-migrastatin and has been found to be a potent tumor cell migration inhibitor. The development of this innovative approach represents an integrated platform for the emergence of a new and powerful tether for small molecule synthesis. Overall, the phosphate tether will serve a multi- faceted role as a coupling agent, protecting group, latent leaving group and pendant nucleophile providing multivalent activation and ultimately dictating selective cleavage reactions within several bicyclic and monocyclic phosphate triesters.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM077309-04S1
Application #
8450560
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-05-01
Project End
2012-12-04
Budget Start
2010-05-01
Budget End
2012-12-04
Support Year
4
Fiscal Year
2012
Total Cost
$87,268
Indirect Cost
$27,868
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
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
Javed, Salim; Bodugam, Mahipal; Torres, Jessica et al. (2016) Modular Synthesis of Novel Macrocycles Bearing α,β-Unsaturated Chemotypes through a Series of One-Pot, Sequential Protocols. Chemistry 22:6755-8
Maitra, Soma; Bodugam, Mahipal; Javed, Salim et al. (2016) Synthesis of the C9-C25 Subunit of Spirastrellolide B. Org Lett 18:3094-7
Hanson, Paul R; Jayasinghe, Susanthi; Maitra, Soma et al. (2015) Phosphate tethers in natural product synthesis. Top Curr Chem 361:253-71
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
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
Hanson, Paul R; Jayasinghe, Susanthi; Maitra, Soma et al. (2014) A modular phosphate tether-mediated divergent strategy to complex polyols. Beilstein J Org Chem 10:2332-7
Chegondi, Rambabu; Maitra, Soma; Markley, Jana L et al. (2013) Phosphate-tether-mediated ring-closing metathesis for the preparation of complex 1,3-anti-diol-containing subunits. Chemistry 19:8088-93

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