Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, September 6, 2021
Douglass F. Taber
University of Delaware

The Lou Synthesis of Euphoranginol C

The diterpenoid euphoranginol C (3) was isolated from Euphorbia wangii Oudejans, a flowering plant of Gansu Province, China. Hong-Xiang Lou of Shandong University envisoned assembly of the bicyclo [3.2.1] octane subunit of 3 by intramolecular photochemical [2+2] cyclization of the diene 1, followed by acid-mediated fragmentation to 2 (Angew. Chem. Int. Ed. 2020, 59, 19919. DOI: 10.1002/anie.202009128).

Following the procedure of Floreancig, coupling of geranyl chloride 4 with 1-trimethylsilylpropyne followed by treatment with TBAF gave the alkyne 5. Sharpless asymmetric dihydroxylation followed by selective monomesylation delivered the epoxide 6, that was cyclized, then protected, leading to the bromoalkene 7. Lithiation of 7 followed by the addition of DMF gave the aldehyde, that was reduced to the alcohol, and carried on the allylic bromide 8. Alkylation of the vinylogous ester 9 with 8 led to 1 as a separable mixture of diastereomers.

The photochemical [2+2] intramolecular cycloaddition of 1 gave preferentially the isolable cyclobutane 10. The preponderance of 10 over its regioisomer was supported by DFT calculations. Acid-mediated opening of 10 was accompanied by the desired epimerization of the ternary center, leading to 2.

The enol ether of 2 was hydrolyzed, and the more exposed of the two ketones was selectively reacted with methylene triphenylphosporane, leading to 11. The remaining ketone was reduced to the axial alcohol, that was cyclized with acid. The alcohol was then deprotected, leading to euphoranginol C (3).

The preparation of 1 outlined here emphasizes the importance of both the asymmetric epoxidation and the asymmetric dihydroxylation developed by Sharpless. The single stereogenic center of 6 set the absolute configuration of the pentacyclic 3.

D. F. Taber, Org. Chem. Highlights 2021, September 6.