Synthetic chemistry is the technology underlying modern drug development. The successful mapping of the human genome was the first step towards identifying new receptors and pathways to treat chronic diseases. The path from bimolecular targets to realizing improvements in human health usually requires the synthesis of small molecule agonists, antagonists, or inhibitors. In this proposal we will develop a potentially powerful method to synthesize small nitrogen and oxygen spiro rings. New synthetic methods such as this one are an enabling technology for improving human health. The reductive cleavage of nitrile is a rarely used method for generating alkyllithium reagents. In many six-membered rings this reaction is completely stereoselective, and the resulting alkyllithium will couple with electrophiles with retention of configuration. We propose to use this reductive lithiation reaction, in combination with facile alkylations adjacent to nitrile groups, to develop a general and stereoselective synthesis of spiro rings. This method will be developed to prepare the spiro-tetrahydropyran rings. These reductive cyclization reactions will be used in a general synthesis of contrathermodynamic spiroacetals, structures commonly found in complex natural products. The third area of development is in the synthesis of spiropiperidines, where modification of the substrate will allow either configuration of the spiropiperidine to be prepared selectively. The synthetic targets for this proposal are segments of natural products and natural products themselves. Segments of altohyrtin (spongistatin) and azaspiracid will be prepared using the approach to contrathermodynamic spiroacetals. Histrionicotoxin and pinnaic acid will be prepared using the spiropiperidine method. These compounds are of interest to synthetic and medicinal chemists, and have the types of rigid, polycyclic and polar structures found to show high bioactivity in many assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065338-02
Application #
6623001
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Schwab, John M
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$232,653
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Perry, Matthew A; Morin, Matthew D; Slafer, Brian W et al. (2012) Total synthesis of lepadiformine alkaloids using N-Boc ?-amino nitriles as trianion synthons. J Org Chem 77:3390-400
Perry, Matthew A; Morin, Matthew D; Slafer, Brian W et al. (2010) Fully substituted carbon centers by diastereoselective spirocyclization: stereoselective synthesis of (+)-lepadiformine C. J Am Chem Soc 132:9591-3
Malathong, Viengkham; Rychnovsky, Scott D (2009) Polyol synthesis with beta-oxyanionic alkyllithium reagents: syntheses of aculeatins A, B, and D. Org Lett 11:4220-3
Bahde, Robert J; Rychnovsky, Scott D (2008) Cyclization via carbolithiation of alpha-amino alkyllithium reagents. Org Lett 10:4017-20
Huckins, John R; de Vicente, Javier; Rychnovsky, Scott D (2007) Synthesis of the C1-C52 fragment of amphidinol 3, featuring a beta-alkoxy alkyllithium addition reaction. Org Lett 9:4757-60
La Cruz, Thomas E; Rychnovsky, Scott D (2007) A reductive cyclization approach to attenol A. J Org Chem 72:2602-11
Vellucci, Danielle; Rychnovsky, Scott D (2007) Diastereoselective synthesis of the pectenotoxin 2 non-anomeric AB spiroacetal. Org Lett 9:711-4
La Cruz, Thomas E; Rychnovsky, Scott D (2006) Stereoselectivity of intramolecular SN' cyclizations of alkyllithium reagents on methoxy alkenes. J Org Chem 71:1068-73
La Cruz, Thomas E; Rychnovsky, Scott D (2005) Synthesis of the spirofungin B core by a reductive cyclization strategy. Org Lett 7:1873-5
Morin, Matthew D; Rychnovsky, Scott D (2005) Reductive spiroannulation of nitriles with secondary electrophiles. Org Lett 7:2051-3

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