The specific aims and long-term objectives of this proposal are to use heterocumulenes (ketenes, ketenimines, and their synthetic equivalents) for new applications in asymmetric catalysis, namely the asymmetric synthesis of beta-lactams (especially the trans diastereomers), catalytic asymmetric halogenation (chlorination, bromination and iodination), and catalytic asymmetric alpha-nitration. We also propose the development of new bifunctionally (Lewis acid-chiral nucleophile) catalyzed asymmetric reactions, including [2+2] as well as [4+2] cycloadditions of ketene enolates. All the chiral, optically enriched products of our reactions are meant to be either pharmacologically active, or to represent key intermediates and branch points in the synthesis of medicinally or academically interesting target molecules. In order to benefit public health, we have established a collaboration with Dr. Samuel Deanmeade, M.D. (JHU Med.) to synthesize beta-lactams to develop a new, sensitive test for prostate specific antigen (PSA). PSA is a marker for prostate cancer, and its measurement may be useful to facilitate diagnosis of the disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM064559-05A1
Application #
7145673
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2002-01-01
Project End
2009-12-31
Budget Start
2006-07-05
Budget End
2006-12-31
Support Year
5
Fiscal Year
2006
Total Cost
$243,398
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Erb, Jeremy; Paull, Daniel H; Dudding, Travis et al. (2011) From bifunctional to trifunctional (tricomponent nucleophile-transition metal-lewis acid) catalysis: the catalytic, enantioselective ?-fluorination of acid chlorides. J Am Chem Soc 133:7536-46
Erb, Jeremy; Alden-Danforth, Ethan; Kopf, Nathan et al. (2010) Combining asymmetric catalysis with natural product functionalization through enantioselective alpha-fluorination. J Org Chem 75:969-71
Paull, Daniel H; Weatherwax, Anthony; Lectka, Thomas (2009) Catalytic, asymmetric reactions of ketenes and ketene enolates. Tetrahedron 65:3771-6803
Abraham, Ciby J; Paull, Daniel H; Dogo-Isonagie, Cajetan et al. (2009) Diastereoselective Synthesis of trans-beta-Lactams Using a Simple Multifunctional Catalyst. Synlett 10:1651-1654
Abraham, Ciby J; Paull, Daniel H; Bekele, Tefsit et al. (2008) A surprising mechanistic ""switch"" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives. J Am Chem Soc 130:17085-94
Paull, Daniel H; Scerba, Michael T; Alden-Danforth, Ethan et al. (2008) Catalytic, asymmetric alpha-fluorination of acid chlorides: dual metal-ketene enolate activation. J Am Chem Soc 130:17260-1
Paull, Daniel H; Abraham, Ciby J; Scerba, Michael T et al. (2008) Bifunctional asymmetric catalysis: cooperative Lewis acid/base systems. Acc Chem Res 41:655-63
Alden-Danforth, Ethan; Scerba, Michael T; Lectka, Thomas (2008) Asymmetric cycloadditions of o-quinone methides employing chiral ammonium fluoride precatalysts. Org Lett 10:4951-3
Paull, Daniel H; Alden-Danforth, Ethan; Wolfer, Jamison et al. (2007) An Asymmetric, bifunctional catalytic approach to non-natural alpha-amino acid derivatives. J Org Chem 72:5380-2
Bekele, Tefsit; Shah, Meha H; Wolfer, Jamison et al. (2006) Catalytic, enantioselective [4 + 2]-cycloadditions of ketene enolates and o-quinones: efficient entry to chiral, alpha-oxygenated carboxylic acid derivatives. J Am Chem Soc 128:1810-1

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