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Organic Chemistry Highlights

Total Synthesis

Monday, September 4, 2023
Douglass F. Taber
University of Delaware

The Renata Synthesis of Gedunin

Gedunin (3), isolated from the Indian neem tree Azadirachta indica, modulates the activity of Hsp90. En route to 3, Hans Renata of Rice University devised the diastereoselective H-atom transfer cyclization of 1 to 2 (J. Am. Chem. Soc. 2022, 144, 19238. DOI: 10.1021/jacs.2c09048).

The convergent assembly of the triene 1 began with furfuryl alcohol 4 and racemic isoprene monoepoxide 5. Following the Krische protocol, coupling of the two led to the diol 6 with high diastereo- and enantioselectivity. The derived monoacrylate 8 was cyclized, then carried on to the iodide 9.

The inertness of the A ring of sclareolide 10 allowed ready conversion, via methyl ketone formation, Baeyer-Villiger oxidation and dehydration, to the alkene 11. Ozonolysis followed by β-elimination delivered the enone 12, that was oxidized by a cytochrome P450 variant to install the equatorial secondary hydroxyl on the A ring. Reductive conjugate addition of 9 to 13 gave the ketone 14, that was carried on to 1.

The cyclization of 1 to 2 proceeded by reductive H-atom transfer, presumably via the intermediate free radical 15.

Conversion of the ketone 2 to the corresponding bis silyl enol ether necessitated concomitant silylation of the secondary alcohol. After Pd-mediated oxidation, desilylation followed by acetylation led to the diene 16. Diastereoselective epoxidation completed the synthesis of gedunin (3).

In the words of the authors regarding the selective cytochrome P450 variants used in this study, "although virtual docking was used to rationalize empirical observations after the fact and in related studies, its general agreement with experimental results points to the possibility of using virtual prescreening of substrate candidates in future chemoenzymatic route development."

D. F. Taber, Org. Chem. Highlights 2023, September 4.