Asymmetric Total Synthesis of Cylindrocyclophanes A and F through Cyclodimerization and a Ramberg- Bäcklund Reaction R R Me Me OH HO Me H Me H HO OH cylindrocyclophane A: R = OH cylindrocyclophane F: R = H K. C. Nicolaou, Ya-Ping Sun, Henry Korman and David Sarlah Angew. Chem. Int. Ed. 2010, 49, 5875-5878. Current Literature Presentation: 8/28/10 David Arnold David Arnold @ Wipf Group Page 1 of 11 9/26/2010
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Asymmetric Total Synthesis of Cylindrocyclophanes Aand F through Cyclodimerization and a Ramberg-
Bäcklund Reaction
R
R
Me
MeOHHO
MeH
MeH
HO OH
cylindrocyclophane A: R = OHcylindrocyclophane F: R = H
K. C. Nicolaou, Ya-Ping Sun, Henry Korman and David SarlahAngew. Chem. Int. Ed. 2010, 49, 5875-5878.
Current Literature Presentation: 8/28/10David Arnold
David Arnold @ Wipf Group Page 1 of 11 9/26/2010
Cylindrocyclophanes A – F: Isolation, Biological Activities andPreliminary SAR Data
• Cylindrocyclophane A was first isolated in 1990 by Moore et al. from the blue-green algae Cylindrospermum licheniforme Kutzing.• Cylindrocyclophane B-F were later isolated in 1992 again by Moore et al.• This class of compounds has been found to be biologically active showing moderate cytotoxicity against
several tumor cell lines.• Plemininary SAR data has been obtained for (-) cylindrocyclophane A, (+) cylindrocyclophane A, 1 and2 as cell growth inhibitors against human colon cancer cell line HCT116.
Previous Total Syntheses of Cylindrocyclophanes A and/or F:Key Cyclodimerization Approaches
• Amos B. Smith, III: Utilization of a cross olefin metathesis / ring closing metathesis cyclodimerizationapproach to the synthesis of both (-)-cylindrocyclophanes A and F.
• Thomas R. Hoye: Utilization of a double Horner-Emmons cyclodimerization approach to the synthesisof (-)-cylindrocyclophane A.
Me
MeOMeMeO
Me
Me
MeO OMe
CM/RCM
CM/RCM
MeOMeMeO
Me
Smith et. al.
R
R
R
R = H or OH
Me
MeOMeMeO
CO2Me
CO2Me
MeO OMe
Horner-Emmons
OMeMeO
O
(MeO)2P
CO2Me
OMeHoye et. al.
David Arnold @ Wipf Group Page 3 of 11 9/26/2010
Smith’s First Generation Synthesis of (-)-Cylindrocyclophane F
• The Nicolaou group has demonstrated an elegant synthesis of (-) cylindrocyclophane F and formalsynthesis of (-) cylindrocyclophane A utilizing a key SN2 dimerization and Ramberg-Bäcklund reactionstrategy to generate the [7.7]paracyclophane framework.
• The Nicalou synthesis has the advantage of generating both cylindrocyclophanes from a commonintermediate 1; a strategy that may provide useful for the derivatization of this family of compoundsfor further SAR studies against tumor cell lines.