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Organic Chemistry Highlights

Total Synthesis

Monday, October 4, 2021
Douglass F. Taber
University of Delaware

The Tsukano/Takemoto Synthesis of Lyconesidine B

Lyconesidine B (3), isolated from the club moss Lycopodium chinense, showed significant toxicity against murine lymphoma L1210 cells. Chihiro Tsukano and Yoshiji Takemoto of Kyoto University assembled the central cyclohexane ring of 3 by the intramolecular cyclopropanation of the diazo ketone 1, followed by fragmentation and reduction (Org. Lett. 2021, 23, 676. DOI: 10.1021/acs.orglett.0c03816).

The preparation of 1 began with the enol triflate 4, prepared in two steps from valerolactam. Pd-catalyzed coupling with 5 followed by selective reduction gave 6, that was formylated with the Vilsmeier reagent, leading, after reduction and silylation, to the ester 7. Condensation with the lithium salt of acetonitrile followed by diazo transfer with the reagent 8 completed the assembly of 1.

The Rh-catalyzed cyclization of 1 would initially have given the unstable cyclopropane 9, that spontaneously opened to 10. In situ reduction with 11 then delivered the α-cyano ketone 2.

The authors envisioned closing the five-membered ring and the seven-membered ring of 3 by ring closing alkene/alkyne/alkene metathesis. To this end, the nitrile 2 was converted to the alkyne 13 by O-allylation followed by deprotection, oxidation and exposure to the Ohiro-Bestmann reagent 12. Allylic rearangement followed by reductive removal of the cyano group, deprotection and alkylation with crotyl bromide led to the quaternary ammonium 14. With the nonbonding electrons of the nitrogen tied up, the double ring formation proceeded smoothly, leading, after dealkylation, to the diene 15.

Monoepoxidation under Payne conditions gave the N-oxide 16, that was reduced, protected and hydrogenated again, to give the ketone 17. Condensation of the derived silyl enol ether with paraformaldehyde followed by hydrolysis led to the diol 18. Selective silylation of the primary alcohol followed by reduction gave 19, that was carried on to lyconesidine B (3).

The diazo ketone 1 is prochiral. It is possible that a handed catalyst could deliver, after reduction, enantiomerically-enriched 2.

D. F. Taber, Org. Chem. Highlights 2021, October 4.