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Organic Chemistry Highlights

Total Synthesis

Monday, April 4, 2005
Douglass Taber
University of Delaware

Total Synthesis of ()-Sordaricin

Carbohydrate derivatives of sordaricin 3 are clinically-effective antifungal agents, but development efforts were halted when a suffficient supply of 3 could not be established. Koichi Narasaka of the University of Tokyo recently reported (Chem. Lett. 2004, 33, 942. DOI: 10.1246/cl.2004.942) a total synthesis of 3, based on the elegant Pd-mediated cyclization of 1 to 2.

The 5-7-5 skeleton of 1 was assembled from cyclohexenone 4 by conjugate addition followed by enolate trapping. Simmons-Smith cyclopropanation of 5 led to the cyclopropyl alcohol 6. Generation of the oxy radical from 6 led to fragmentation to give 7, which further cyclized to give 8. Note that the seven-membered ring is flexible enough that the radical cyclization delivers the required trans ring fusion. Annulation to 9 followed by kinetically-controlled conjugate addition then gave 10.

The β-keto ester was protected as the enol acetate, then the ketone 12 was homologated to the carbonate 1. Despite the strain in the [2.2.1] system being formed, the Pd-mediated cyclization of 1 to 2 proceeded smoothly.

To complete the synthesis, the ketone of 2 was homologated to the alkene 12. Selective oxidative cleavage of the two vinyl groups followed by reduction provided the diol, the less encumbered alcohol of which was protected to deliver the fully-differentiated ester 13. Oxidation followed by ester cleavage then gave 3.

D. F. Taber, Org. Chem. Highlights 2005, April 4.