The development of novel desymmetrization methods on a variety of phosphorus templates en route to structurally diverse alpha- aminophosphonic acids, phosphorus containing glycomimetics, and P-chiral synthons is the major goal of this study. These compounds have a wide array of applications and can serve as: i) potential inhibitors and probes of numerous enzymatic processes, ii) phosphorus analogs of sugars as potential glycosidase inhibitors, iii) conformationally restricted phosphorus analogs of amino acids, and iv) unique scaffolds for the construction of complex acyclic organic molecules. A novel desymmetrization strategy en route to highly functionalized phosphonates and phosphonamides possessing a stereogenic phosphorus atom (P-chiral) will serve as the cornerstone of the proposed method. This strategy involves: 1) the rapid assembly of pseudo C2-symmetrical phosphoryl templates; 2) the desymmetrization of these templates employing a variety of synthetic protocols; 3) the functionalization of the resulting building blocks en route to numerous acyclic alpha- aminophosphonic acids, phosphonoglycomimetics, and bicyclic P-chiral alpha-aminophosphonic acids as potential pharmacological agents; and 4) the stereocontrolled synthesis of an array of highly functionalized acyclic precursors to showcase the synthetic utility of these P-chiral building blocks. The proposed methods are unique in that a novel diastereotopic differentiation will be used to generate the P-chiral building blocks. The implementation of this method on phosphorus templates represents a new area in the utilization of molecular symmetry to generate chiral molecules. The primary focus of this study is the establishment of the """"""""phosphorus template method"""""""" as a new approach for the construction of complex organophosphorus containing molecules and as a new paradigm for acyclic stereocontrol.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM058103-05
Application #
6555839
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1998-08-01
Project End
2005-07-31
Budget Start
2002-08-01
Budget End
2005-07-31
Support Year
5
Fiscal Year
2002
Total Cost
$204,130
Indirect Cost
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Whitehead, Alan; McReynolds, Matthew D; Moore, Joel D et al. (2005) Multivalent activation in temporary phosphate tethers: a new tether for small molecule synthesis. Org Lett 7:3375-8
Stoianova, Diana S; Whitehead, Alan; Hanson, Paul R (2005) P-heterocyclic building blocks: application to the stereoselective synthesis of P-sugars. J Org Chem 70:5880-9
McReynolds, Matthew D; Dougherty, Joseph M; Hanson, Paul R (2004) Synthesis of phosphorus and sulfur heterocycles via ring-closing olefin metathesis. Chem Rev 104:2239-58
Moore, Joel D; Byrne, Robert J; Vedantham, Punitha et al. (2003) High-load, ROMP-generated oligomeric bis-acid chlorides: design of soluble and insoluble nucleophile scavengers. Org Lett 5:4241-4
Moore, Joel D; Herpel, Russell H; Lichtsinn, Joy R et al. (2003) ROMP-generated oligomeric sulfonyl chlorides as versatile soluble scavenging agents. Org Lett 5:105-7
Harned, Andrew M; Mukherjee, Shubhasish; Flynn, Daniel L et al. (2003) Ring-opening metathesis phase-trafficking (ROMpt) synthesis: multistep synthesis on soluble ROM supports. Org Lett 5:15-8
Moore, Joel D; Sprott, Kevin T; Wrobleski, Aaron D et al. (2002) Double diastereoselective intramolecular cyclopropanation to P-chiral [3.1.0]-bicyclic phosphonates. Org Lett 4:2357-60
Moore, Joel D; Sprott, Kevin T; Hanson, Paul R (2002) Conformationally constrained alpha-boc-aminophosphonates via transition metal-catalyzed/curtius rearrangement strategies. J Org Chem 67:8123-9
McReynolds, Matthew D; Sprott, Kevin T; Hanson, Paul R (2002) A concise route to structurally diverse DMP 323 analogues via highly functionalized 1,4-diamines. Org Lett 4:4673-6
Sprott, K T; McReynolds, M D; Hanson, P R (2001) A temporary phosphorus tether/ring-closing metathesis strategy to functionalized 1,4-diamines. Org Lett 3:3939-42

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