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Organic Chemistry Highlights

Total Synthesis

Monday, October 1, 2018
Douglass F. Taber
University of Delaware

The Nagorny Synthesis of Cannogenol and Cannogenol-3-O-α-L-rhamnoside

Cannogenol-3-O-α-L-rhamnoside (4) is a cardiac glycoside isolated from lily of the valley, Convallaria majalis. Pavel Nagorny of the University of Michigan devised a practical enantioselective synthesis of 4, based on the enantioselective Cu-catalyzed coupling of 1 and 2 that led to 3 (Org. Lett. 2018, 20, 154. DOI: 10.1021/acs.orglett.7b03513).

The starting materials for the synthesis were readily prepared. Ethoxycarbonylation of the vinylogous ester 5 followed by hydrolysis gave the diketone 5, that on exposure to PCl3 was converted to 1. Exposure of 7 to oxalyl bromide led to the bromoalkene, that was coupled with hexabutylditin to give stannylated butenolide 8.

Stirring 9 with 10 in water without other added reagents led to the aldehyde 11. Wittig reaction with 12 then completed the assembly of 2.

Stirring two equivalents of 1 with 2 and 0.1 equivalent of the Cu* catalyst under neat conditions for two days led to an intermediate, that was cyclized with acid to give the kinetic product 3. On exposure to NaHMDS, this was equilibrated to the thermodynamically more favorable 12, via a retroaldol-aldol process. Reduction followed by hydrolysis gave the dienone 13, that was hydrogenated under carefully defined conditions, then oxidized with DMP and selectively reduced to 14.

Iodination of the remaining ketone of 14 led to 15, that was protected, then coupled with 8, leading to 16. Before 16 could be selectively hydrogenation, the alcohol that otherwise would have directed the facial of the hydrogenation had to first be protected. Global deprotection then completed the synthesis of the aglycone cannogenenol 17.

The synthesis provided a sufficient supply of 17 that it was possible to develop conditions for the glycosidation. While neither the primary acetate nor the 4-bromobenzoate could be removed under the conditions of benzoate removal from the sugar, protection of the primary alcohol with 18 to give 20 allowed coupling with 19 and deprotection, completing the synthesis of Cannogenol-3-O-α-L-rhamnoside (4).

D. F. Taber, Org. Chem. Highlights 2018, October 1.