A Specific Aims. The main objectives of this proposal are 1) to develop an efficient, inexpensive method for the generation of contaminant free, reactive ketenes, and 2) to apply this new methodology to a number of diverse catalytic asymmetric transformations that represent important problems in synthetic organic chemistry, including the catalytic, asymmetric synthesis of Beta-lactams; catalytic, asymmetric halogenation reactions; polycomponent or tandem catalytic reactions; and asymmetric catalysis on columns. Most of our proposed methodology depends on the putative intermediacy of enolates derived from the reaction of ketenes and catalytic nucleophiles. All the optically enriched, chiral products of our reactions are meant to be either pharmacologically active, or potentially so, or to represent key intermediates and branch points in the synthesis of medicinally or academically interesting target molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064559-02
Application #
6620589
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-01-01
Project End
2005-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
2
Fiscal Year
2003
Total Cost
$222,179
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
Wolfer, Jamison; Bekele, Tefsit; Abraham, Ciby J et al. (2006) Catalytic, asymmetric synthesis of 1,4-benzoxazinones: a remarkably enantioselective route to alpha-amino acid derivatives from o-benzoquinone imides. Angew Chem Int Ed Engl 45:7398-400

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