The Zhai Synthesis of (+)-Harringtonolide
(+)-Harringtonolide (3), isolated from the bark of the Chinese shrub Cephalotaxus harringtonia, showed nanomolar cytotoxicity against KB tumor cells. Hongbin Zhai of Lanzhou University envisioned (Angew. Chem. Int. Ed. 2016, 55, 11638. ) the assembly of 3 by the generation of the carbene from the diazo ketone of 1, and addition of that carbene onto the adjacent ketone to generate a 1,3-dipole. Intramolecular addition of that dipole to the distal alkyne would give 2.
The construction of the highly substituted cis decalone 1 began with m-anisic acid (4). Birch reduction followed by esterification converted 4 to 5. Enantioselective reduction set the absolute configuration of 6, and thus ultimately of 1 and of 3. Esterification of 6 with sorbic acid gave 7, internal Diels-Alder cycloaddition of which led to 8. A deprotonation/kinetic quench step had to be added, because substantial migration of the double bond into conjugation with the lactone carbonyl was observed under the extreme conditions (180°, 24 h) of the cyclization. Reduction of 8 followed by the addition of propargyl magnesium bromide and protection delivered 9 as a mixture of diastereomers, each of which was eventually carried on to the natural product 3. Hydrochlorination of the ketone derived from 9 proceeded with high regio- and stereocontrol, to give, after protection, the ester 10. Alkylation followed by saponification of the ester and exposure of the intermediate mixed anyhydride to diazomethane completed the construction of the diazo ketone 1.
The cyclization to 2 was carried out by the syringe pump addition of 1 to 10 mol % of Rh2(OAc)4 in toluene at reflux. If this transformation were to be scaled, much lower catalyst loadings could be expected with the more soluble Rh octanoate, or with Du Bois's more durable Rh2(esp)2.
Deprotection of 2 led to the diol 11. Remarkably, on deprotonation 11 could be cyclized to the desired cyclic ether 12, with only minor competing formation of the alternative epoxide. To form the lactone, the remaining alcohol was oxidized to the ketone 13, then reduced. Lactone formation followed by oxidation to restore the seven-membered ring ketone set the stage for enol ether formation, to give 14. On treatment with Me2AlCl, the diene 14 was converted to (+)-harringtonolide (3).