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Monday, August 20, 2007
Douglass F. Taber
University of Delaware

New Directions in C-C Ring Construction: The Overman Synthesis of Guanacastepene N

The opening of epoxides by ketone enolates is notoriously difficult. Marie E. Krafft of Florida State University has found (Chem. Commun. 2006, 2977. ) a simple solution to this problem. On exposure to the simple organocatalyst PMe3, the epoxy ketone 1, readily prepared in enantiomerically-pure form, was smoothly converted to the cyclopentane 2.

Transition metal catalysis allows many C-C bond-forming reactions that are not otherwise available. Chaozhong Li of the Shanghai Institute of Organic Chemistry has reported (J. Org. Chem. 2006, 71, 6427. ) the Cu-mediated cyclization of the o-bromophenyl ketone 3 to 4.

Many examples of Au catalysis for organic synthesis have been reported recently. One of the most elegant is the transformation of 5 to 6 developed (J. Am. Chem. Soc. 2006, 128, 12614. ) by Fabien Gagosz of the Ecole Polytechnique. Allylic acetates such as 5 are readily prepared in high ee, by enantioselective reduction of the ketone or by enantioselective addition of an alkynyl anion to the aldehyde. This makes 5-alkyl cyclohexenones such as 6 readily available in high ee.

There have also been advances in polycyclic ring construction. Chulbom Lee of Princeton University has been exploring (J. Am. Chem. Soc. 2006, 128, 14818. ) the reactivity of metal alkynyls and metal vinylidenes derived from terminal alkynes. Deprotonation of the alkynyl Rh-H derived from 7 led to a species that was nucleophilic at the β carbon. Intramolecular alkylation ensued, leading to an intermediate Rh vinylidene 8 that then inserted into the alkene to give 9. In related work (J. Am. Chem. Soc. 2006, 128, 15598. ) the intermediate Rh vinylidene inermediate was used to effect intramolecular conjugate addition.

Free radical cyclizations can be surprisingly selective. Johann Mulzer of the Universitšt Wien has observed (Eur. J. Org. Chem. 2006, 901. ) that reduction of 10 proceeded to give 11 with high diastereocontrol. The Z isomer of 10 worked equally well, but diastereocontrol was much lower with the corresponding methyl ester or with a bulkier silyl ether.

The cyclization of 13 reported (Org. Lett. 2006, 8, 5433. ) by Juan M. Cuerva and J. Enrique Oltra of the University of Granada, which probably also involves single electron transfer, also proceeded with high diastereocontrol. Note that in this case, the newly-formed bonds are each equatorial on the forming cyclohexane ring.

The key feature of the guanacastepenes, represented by guanacastepene N (21), is the central highly-substituted cycloheptane ring. In his synthesis of 21 (J. Am. Chem. Soc. 2006, 128, 13095. ), Larry E. Overman of the University of California, Irvine, prepared this central ring by the intramolecular Heck cyclization of the alkenyl triflate 19. This 7-endo cyclization, proceeding by initial addition to the distal end of the alkene, is unusual, in that the intramolecular Heck reaction usually proceeds to give the 6-exo product.

D. F. Taber, Org. Chem. Highlights 2007, August 27.
URL: https://www.organic-chemistry.org/Highlights/2007/27August.shtm