Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, February 4, 2019
Douglass F. Taber
University of Delaware

The He/Lee Synthesis of Basiliolide C

The basiliolides, exemplified by basilioside C (3), show inhibitory activity against SERCA, the Ca2+ ATPase of the endoplasmic reticulum. Following the work of Stoltz (Intramolecular Diels-Alder Cycloaddition: 7-Isocyanoamphilecta-11(20),15-diene (Miyaoka),
(-)-Scabronine G (Kanoh), Basiliolide B (Stoltz), Hirsutellone B (Uchiro), Echinopine A (Chen) 2012, August 27), Shuzhong He of Guizhou University and Chi-Sing Lee of Peking University Shenzhen Graduate School could be confident that 1 would cyclize smoothly to 2. The challenge was the assembly of 1 with its adjacent acyclic stereogenic centers (Eur. J. Org. Chem. 2018, 196. DOI: 10.1002/ejoc.201701211).

The beginning point for the synthesis was the diazo acetate 4, readily prepared in one pot from commercial geraniol. In an intriguing sequence, aldol reaction with furfural 5 and oxidation with IBX to 6 could be carried out in a single step. Cyclization led to 7, that was reduced with high diastereoselectivity to 8. The lactone was saponified and the acid protected as the corresponding allyl ester, then the liberated alcohol was converted to the iodide 9. On reduction, the cyclopropane was opened and the resulting enolate was quenched, following the Fráter-Seebach precedent, to set the last stereogenic center of 10 and thus of 1. Achmatowicz oxidation followed by protection of the hemiacetal with methyl iodide led to the enone 11. Selective allylic oxidation converted 11 into 12, that was condensed with 13 to give an intermediate ester. Hydrolysis and in situ oxidation followed by alkene equilibration then completed the assembly of 1.

The intramolecular Diels-Alder conversion of 1 to 2 was most efficiently carried out at relatively modest temperature for ten days. Deprotection of the allyl ester followed by activation and intramolecular acylation then completed the synthesis of basiliolide C (3). It is impressive that the final conversion was carried out on 250 mg of 2, leading to 122 mg of the natural product.

The cyclopropane 7 was racemic. The authors explored the several known enantiomerically-pure Rh(II) catalysts for this transformation, but the Hashimoto catalysts that gave the most encouraging ee gave discouragingly low yields. Our observation (Metal-mediated C-C Ring Construction: The Carreira Synthesis of (+)-Asperolide C 2014, August 18) has been that Rh carbenes derived from such α-aryl diazo esters are longer lived than most, and so are susceptible to interception by adventitious oxygen. Reasonable cyclization yields could be achieved if oxygen was rigorously excluded.

D. F. Taber, Org. Chem. Highlights 2019, February 4.