The general hypothesis of this proposal is that cycloadducts from Diels-Alder reactions of dienes with transient acyl nitroso moieties, generated by oxidation of hydroxamic acids, can serve as versatile building blocks for syntheses of a number of important and often novel bioactive molecules.
The specific aims i nclude (1) methodology development and enhancement, and (2) applications to the syntheses and study of focused targets. Methodology enhancement will include hydroxamate, 1, and diene, 3, variation, alternative asymmetric methods, and determination of the scope and limitations of a new pi-allyl polarity reversal process that will significantly increase synthetic versatility. Applications will include both nucleophilic and electrophilic C-O bond cleavage of 4 with N-O bond retention, in both intermolecular and intramolecular processes; N-O bond cleavage to give substituted carbocycles 5; and C=C bond reactions to give 6 and other intermediates. Products from these reactions will be used to prepare focused sets of targets, including: novel 5-lipoxygenase inhibitors, neuraminidase inhibitors, benzodiazepines, diazepines, carbocyclic nucleosides and analogs (aristeromycin, carbavir, abacavir, stavudine, carbocyclic oxanosine, and their nor analogs, carbocyclic forms of polyoxins, sinefungin, nucleoside Q, puromycin and analogs), novel phosphodiesterase inhibitors, streptazolin, novel oxazolidinone antibiotics, diketopiperazines (tryprostatin analogs), novel amino acids and peptides related to bacterial diaminopimelic acids (DAP) as well as new amino acids and peptides that represent the first of a novel class of antibiotics. That this tremendous variety of targets can be accessed from the same set of precursors attests to the tremendous potential of readily available acylnitroso cycloaddition products for the design, synthesis and study of bioactive compounds, many of which will be novel.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068012-03
Application #
6890273
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2003-05-15
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$294,030
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
Carosso, Serena; Miller, Marvin J (2014) Nitroso Diels-Alder (NDA) reaction as an efficient tool for the functionalization of diene-containing natural products. Org Biomol Chem 12:7445-68
Ji, Cheng; Lin, Weimin; Moraski, Garrett C et al. (2012) Syntheses and biological studies of novel spiropiperazinyl oxazolidinone antibacterial agents using a spirocyclic diene derived acylnitroso Diels-Alder reaction. Bioorg Med Chem 20:3422-8
Bolger, Joshua K; Tian, Wen; Wolter, William R et al. (2011) Synthesis and evaluation of 5-lipoxygenase translocation inhibitors from acylnitroso hetero-Diels-Alder cycloadducts. Org Biomol Chem 9:2999-3010
Tardibono Jr, Lawrence P; Miller, Marvin J; Balzarini, Jan (2011) Enantioselective syntheses of carbocyclic nuleosides 5'-homocarbovir, epi-4'-homocarbovir and their cyclopropylamine analogs using facially selective Pd-mediated allylations. Tetrahedron 67:825-829
Bodnar, Brian S; Miller, Marvin J (2011) The nitrosocarbonyl hetero-Diels-Alder reaction as a useful tool for organic syntheses. Angew Chem Int Ed Engl 50:5630-47
Bolger, Joshua; Miller, Marvin (2011) Diaryl Ether Containing N-Hydroxycarbamates from Nitroso Cycloadducts. Tetrahedron Lett 52:2268-2271
Cesario, Cara; Miller, Marvin J (2010) Palladium(0)/indium iodide-mediated allylations of electrophiles generated from the hydrolysis of Eschenmoser's salt: One-pot preparation of diverse carbocyclic scaffolds. Tetrahedron Lett 51:3050-3052
Ji, Cheng; Miller, Marvin J (2010) Cyclopropanation of nitroso Diels-Alder cycloadducts and application to the synthesis of a 2',3'-methano carbocyclic nucleoside. Tetrahedron Lett 51:3789-3791
Cesario, Cara; Tardibono, Lawrence P; Miller, Marvin J (2010) Syntheses of carbocyclic aminonucleosides and (-)-epi-4'-carbocyclic puromycin: Application of palladium(0)/indium iodide-allylations and tethered aminohydroxylations. Tetrahedron Lett 51:3053-3056
Cesario, Cara; Tardibono Jr, Lawrence P; Miller, Marvin J (2009) Titanocene(III) chloride-mediated reductions of oxazines, hydroxamic acids, and N-hydroxy carbamates. J Org Chem 74:448-51

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