Abstract

Despite a wealth of research pertaining to metal catalyzed cycloadditions, to date, there are no reports of metal catalysts for intramolecular alkene (2+2)cycloaddition. We herewith describe the first metal catalyst for intramolecular cyclobutanation. This methodology allows for facile assembly of bicyclo(3.2.0)heptane ring systems. Related photochemical processes generally exhibit poor levels of stereoselectivity and are inefficient for acyclic substrates due to quenching of the excited state via alkene isomerization. In contrast, our metal catalyst for alkene (2+2)cycloaddition is viable for acyclic precursors and all cycloadducts are obtained as single stereoisomers. This methodology will be utilized in a general synthetic approach to members of the bourbonane and spatane families of natural products. Certain members of the spatane family strongly inhibit cell division in human melanoma and 224C astrocytoma neoplastic cell lines. Spatol's antimitotic activity is attributed to inhibition of microtubule assembly. Finally, strategies for development of enantioselective variants of this methodology are outlined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM065149-01
Application #
6455193
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-03-01
Project End
2006-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
1
Fiscal Year
2002
Total Cost
$187,500
Indirect Cost

  Institution

Name
University of Texas Austin
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712

  Publications

Yang, Jingkui; Felton, Greg A N; Bauld, Nathan L et al. (2004) Chemically induced anion radical cycloadditions: intramolecular cyclobutanation of bis(enones) via homogeneous electron transfer. J Am Chem Soc 126:1634-5
Koech, Phillip K; Krische, Michael J (2004) Catalytic addition of metallo-aldehyde enolates to ketones: a new C-C bond-forming hydrogenation. Org Lett 6:691-4
Cho, Chang-Woo; Kong, Jong-Rock; Krische, Michael J (2004) Phosphine-catalyzed regiospecific allylic amination and dynamic kinetic resolution of Morita-Baylis-Hillman acetates. Org Lett 6:1337-9
Yang, Jingkui; Cauble, David F; Berro, Adam J et al. (2004) Anion radical [2 + 2] cycloaddition as a mechanistic probe: stoichiometry- and concentration-dependent partitioning of electron-transfer and alkylation pathways in the reaction of the Gilman reagent Me2CuLi.LiI with bis(enones). J Org Chem 69:7979-84
Bocknack, Brian M; Wang, Long-Cheng; Krische, Michael J (2004) Desymmetrization of enone-diones via rhodium-catalyzed diastereo- and enantioselective tandem conjugate addition-aldol cyclization. Proc Natl Acad Sci U S A 101:5421-4
Koech, Phillip K; Krische, Michael J (2004) Phosphine catalyzed alpha-arylation of enones and enals using hypervalent bismuth reagents: regiospecific enolate arylation via nucleophilic catalysis. J Am Chem Soc 126:5350-1
Jang, Hye-Young; Huddleston, Ryan R; Krische, Michael J (2004) Hydrogen-mediated C-C bond formation: catalytic regio- and stereoselective reductive condensation of alpha-keto aldehydes and 1,3-enynes. J Am Chem Soc 126:4664-8
Wang, Jian-Cheng; Krische, Michael J (2003) Intramolecular organocatalytic [3+2] dipolar cycloaddition: stereospecific cycloaddition and the total synthesis of (+/-)-hirsutene. Angew Chem Int Ed Engl 42:5855-7
Huddleston, Ryan R; Jang, Hye-Young; Krische, Michael J (2003) First catalytic reductive coupling of 1,3-diynes to carbonyl partners: a new regio- and enantioselective C-C bond forming hydrogenation. J Am Chem Soc 125:11488-9
Jellerichs, Bradley G; Kong, Jong-Rock; Krische, Michael J (2003) Catalytic enone cycloallylation via concomitant activation of latent nucleophilic and electrophilic partners: merging organic and transition metal catalysis. J Am Chem Soc 125:7758-9

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