Free-Radical-Mediated Conjugate Additions. Enantioselective Synthesis of Butyrolactone Natural Products: (−)-Enterolactone, (−)-Arctigenin, (−)-Isoarctigenin, (−)-Nephrosteranic Acid, and (−)-Roccellaric Acid

Abstract

Lewis acid-mediated conjugate addition of alkyl radicals to a differentially protected fumarate 10 produced the monoalkylated succinates with high chemical efficiency and excellent stereoselectivity. A subsequent alkylation or an aldol reaction furnished the disubstituted succinates with syn configuration. The chiral auxiliary, 4-diphenylmethyl-2-oxazolidinone, controlled the stereoselectivity in both steps. Manipulation of the disubstituted succinates obtained by alkylation furnished the natural products (-)-enterolactone, (-)-arctigenin, and (-)-isoarctigenin. The overall yields for the target natural products were 20-26% over six steps. Selective functionalization of the disubstituted succinates obtained by aldol condensation gave the paraconic acid natural products (-)-nephrosteranic acid (8) and (-)-roccellaric acid (9). The overall yield of the natural products 8 and 9 over four steps was 53% and 42%, respectively.