Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, January 7, 2008
Douglass F. Taber
University of Delaware

The Sammakia Synthesis of the Macrolide RK-397

The polyene macrolide RK-397 (3), isolated from soil bacteria, has antifungal, antibacterial and anti-tumor activity. Tarek Sammakia of the University of Colorado has described (Angew. Chem. Int. Ed. 2007, 46, 1066. DOI: 10.1002/anie.200602601) the highly convergent coupling of 1 with 2, leading to 3.

The preparation of 1 depended on the powerful methods that have been developed for acyclic stereocontrol. Beginning with the allylic alcohol 4, Sharpless asymmetric epoxidation established the absolute configuration of 5. Following the Jung “non-aldol aldol” protocol, exposure of 5 to TMSOTf delivered the aldehyde 6 in high de. Condensation of 6 with the lithium enolate of acetone also proceeded with high de. The resulting alcohol was protected as the MOM ether, to direct the stereoselectivity of the subsequent aldol condensation with 8. Selective β-elimination followed by reduction and protecting group exchange then gave 1.

The preparation of 2 took advantage of the power of Brown asymmetric allylation. Allylation of the symmetrical 11 led to the diol 12. This was desymmetrized by selective acetonide formation, to give 13. Ozonolysis, reductive work-up, and protection of the newly-formed 1,3-diol gave 14, setting the stage for oxidation and asymmetric allylation to give 15. Reductive deprotection and oxidation then delivered the acetonide 2.

The tris acetonide 16 was assembled by addition of the enolate derived from 1 to the aldehyde 2, followed by reduction and protection. Kinetically-controlled metathesis with 17 established the triene 18. Phosphonate-mediated homologation to the pentaene 19 followed by hydrolysis and Yamaguchi macrolactonization then completed the synthesis of the macrolide RK-397 (3).

D. F. Taber, Org. Chem. Highlights 2008, January 7.