Asymmetric nitro-De-n-bearing quaternary stereocenters are ubiquitous structural motifs found in an enormous number of bioactive molecules. Consequently the development of synthetic methods is of fundamental importance. The long-term objectives of this project therefore are a) to investigate the pi-face selective Ar1-n spirocyclization of N-alkoxy-N-acylnitrenium ions as a novel approach to the preparation of such stereocenters and b) to utilize the azaspirodienone products of this dearomatization reaction as building blocks in the synthesis of a diverse range of important natural products and other pharmacologically active target molecules.
The specific aims of the research to be undertaken are: i) to expand our investigation of the diastereoselective Ar1-5 nitrenium ion cyclization in order to optimize n-facial selectivity and develop a more detailed understanding of the key stereochemical features of this versatile reaction; ii) to develop an ortho-aryl auxiliary-based strategy to control the absolute pi-facial selectivity of nitrenium ion cyclization and subsequently utilize this in a concise synthesis of (-)-perhydrohistrionicotoxin; iii) to investigate the stereocontrolled Ar1-6 nitrenium ion cyclization as a novel and efficient method for the asymmetric preparation of 1-azaspiro[5.5]undecanes including fasicularin, a novel cytotoxic marine alkaloid; iv) to evaluate the Ar1-7 nitrenium ion spirocyclization as a method for the synthesis of [5.6]azaspiranes. The dienone-phenol rearrangement of this ring system will be studied since it will provide rapid access to the benzazocine core of the potent anticancer agent FR900482; v) to utilize the azaspirodienone products of nitrenium ion-induced dearomatization as masked 2-amino-l,3- dicarbonyl and 2-amino-l,6-dicarbonyl synthons. Specifically, this novel synthetic strategy will be employed in the preparation of a range of bioactive alpha,alpha-disubstituted pyrrolidine natural products, including the neuroexcitotoxin (-)-dysibetaine, the neurotrophic agent (+)-Iactacystin, and (-)-kaitocephalin, the only naturally occurring AMPA receptor antagonist; and vi) to investigate the endo-trig Ar1-n nitrenium ion cyclization of arylalkylhydroxamates and then utilize this process in an expeditious asymmetric synthesis of the structural core of (-)-tetrodotoxin. Since the synthetic potential of N-alkoxy-N-acylnitrenium ions remains untapped and the issue of stereccontrol during Ar1-n oxidative dearomatizations has hitherto been largely unexplored, it is anticipated that this project will represent a significant contribution to the field of organic synthesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Illinois at Chicago
Schools of Arts and Sciences
United States
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Wardrop, Duncan J; Komenda, John P (2012) Dehydrative fragmentation of 5-hydroxyalkyl-1H-tetrazoles: a mild route to alkylidenecarbenes. Org Lett 14:1548-51
de Jong, Sam; Nosal, Daniel G; Wardrop, Duncan J (2012) Methods for direct alkene diamination, new & old. Tetrahedron 68:4067-4105
Wardrop, Duncan J; Bowen, Edward G (2011) Nitrenium ion-mediated alkene bis-cyclofunctionalization: total synthesis of (-)-swainsonine. Org Lett 13:2376-9
Wardrop, Duncan J; Bowen, Edward G; Forslund, Raymond E et al. (2010) Intramolecular oxamidation of unsaturated O-alkyl hydroxamates: a remarkably versatile entry to hydroxy lactams. J Am Chem Soc 132:1188-9
Bowen, Edward G; Wardrop, Duncan J (2010) Diastereoselective nitrenium ion-mediated cyclofunctionalization: total synthesis of (+)-castanospermine. Org Lett 12:5330-3
Wardrop, Duncan J; Waidyarachchi, Samanthi L (2010) Synthesis and biological activity of naturally occurring ?-glucosidase inhibitors. Nat Prod Rep 27:1431-68
Bowen, Edward G; Wardrop, Duncan J (2009) Total synthesis of the alpha-glucosidase inhibitors schulzeine A, B, and C and a structural revision of schulzeine A. J Am Chem Soc 131:6062-3
Dickson, David P; Wardrop, Duncan J (2009) Total synthesis of (+/-)-agelastatin A, a potent inhibitor of osteopontin-mediated neoplastic transformations. Org Lett 11:1341-4
Wardrop, Duncan J; Burge, Matthew S (2005) Nitrenium ion azaspirocyclization-spirodienone cleavage: a new synthetic strategy for the stereocontrolled preparation of highly substituted lactams and N-hydroxy lactams. J Org Chem 70:10271-84
Wardrop, Duncan J; Burge, Matthew S (2004) Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy. Chem Commun (Camb) :1230-1