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Organic Chemistry Highlights

Total Synthesis

Monday, September 4, 2017
Douglass F. Taber
University of Delaware

The Raghavan Synthesis of Brefeldin A

Brefeldin A (3), isolated from the fungus Penicillium brefeldianum, evokes abiding interest as a specific inhibitor of protein transport to the Golgi apparatus. To assemble 3, Sadagopan Raghavan of the Indian Institute of Chemical Technology took advantage (J. Org. Chem. 2016, 81, 10912. DOI: 10.1021/acs.joc.6b01964) of the stereocontrolled cyclization of 1 to 2.

The other half of 3 was constructed starting from the ketone 4. Enantioselective reduction led to 5, that was esterified with 6 to give the phosphonate 7. Hydrogenation followed by deprotection and oxidation gave 8, that was condensed with the Ohira reagent (9) to give 10. Semi-hydrogenation completed the preparation of 11.

The enyne 1 was prepared from epichlorohydrin 12. Opening of the epoxide with the Grignard reagent 13 followed by displacement of the chloride with thiophenol and protection led to 14. Addition of 15 to the derived α-chloro sulfide delivered 1 with high diasterocontrol.

The Ru catalyzed cyclization of 1 proceeded to give 2 as the dominant (13:1) diastereomer. The clean control of the geometry of the trisubstituted alkene was important, allowing the transfer of ring to side chain stereocontrol in the subsequent Mislow-Evans rearrangement, quenched with 16, to give 17.

Cyclization of 17 to the bromoether 18 served to protect the free alcohol, and also established a scaffold to direct the subsequent hydrogenation. Zinc reduction released the alcohol 19, that was protected, osmylated and cleaved to give the cis aldehyde. Epimerization completed the preparation of the trans aldehyde 20.

Remarkably, Ru-catalyzed cross metathesis of the derived alkene proceeded smoothly to give 21, unimpeded by the phosphonate. Oxidation and intramolecular Horner-Emmons cyclization led to 22, that was deprotected to give brefeldin A (3).

Karl J. Hale of The Queen's University Belfast recently reported (Org. Lett. 2016, 18, 4254. DOI: 10.1021/acs.orglett.6b02002) a complementary assembly of brefeldin A (3), starting from glucose.

D. F. Taber, Org. Chem. Highlights 2017, September 4.