Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, June 3, 2019
Douglass F. Taber
University of Delaware

The Sarpong Synthesis of Phomactin A

Richmond Sarpong of the University of California, Berkeley envisioned a general synthetic route to the phomactins, exemplified by phomactin A (3), based on the cyclization of 1 to 2. The challenge in this approach was the preparation of the highly substituted cyclohexene core of 1 (Nature Chem. 2018, 10, 938. DOI: 10.1038/s41557-018-0084-x).

The acyclic half 6 of 1, already known from previous work by Eric J. Thomas of the University of Manchester, was readily prepared from the alkyne 4. The Negishi protocol converted 4 to 5, that was then silylated to give 6 (Tetrahedron 2015, 71, 7293. DOI: 10.1016/j.tet.2015.04.005).

The authors chose to prepare the cyclohexene of 1 from the inexpensive carvone 7. The key enabling transformation was the reductive cylization of the derived epoxide 8 to the diastereomeric mixture of the cyclobutanes 9 and 10, first reported by Franciso A. Bermejo and Alfonso Fernández Mateos of the Universidad de Salamanca (Tetrahedron 2006, 62, 8933. DOI: 10.1016/j.tet.2006.07.020).

The readily separable diol 10, with the correct relative and absolute configuration for conversion to 1, was carried on to the sulfide 11. The cyclobutane was cleaved selectively, to give 12. Oxidation led to the sulfone 13, that was converted by methyl lithium addition followed by dehydration to the diene 14. Allylic oxidation gave the aldehyde 15. Addition of the alkenyl lithium derived from 6 followed by protection, deprotection and conversion of the allylic alcohol to the corresponding bromide then completed the assembly of 1.

The cyclization of 1 to 2 proceeded smoothly, as did the subsequent desulfurization. Deprotection followed by oxidation and reduction then completed the synthesis of the allylic alcohol 16, a versatile intermediate for the preparation of many members of the phomactin family. To reach phomactin A (3), the allylic alcohol was doubly epoxidized to 17. Allylic displacement with acetate delivered 18, that was oxidized, deacetylated and cyclized to 3.

D. F. Taber, Org. Chem. Highlights 2019, June 3.