The total synthesis of (±) jaconecic acid

Abstract

Jaconecic acid (6) is a cyclic diacid produced when the pyrrolizidine alkaloid jacobine (5) is subjected to base hydrolysis. The first total synthesis of jaconecic acid was accomplished in 8 steps in an overall yield of 7% from 3,4-dichlorofuroic acid (59). Control of the stereochemistry of the tetrahydrofuran ring of 6 was accomplished through the intramolecular Diels-Alder reaction of furfuryl allyl sulfide 69. The double bond of cycloadduct 70 was cleaved by ozone and the sulfur removed with Raney nickel to give a 2.5:1 mixture of dimethyl jaconate and its C-6 epimer. The tricyclic alcohol 72 was oxidized to tricyclic ketone 80. This ketone was reduced with L-Selectride and the resulting alcohol subjected to ozonation-Raney nickel desulfurization to give a 5:1 mixture of dimethyl jaconate and its C-6 epimer. This synthesis shows that methodology involving the intramolecular Diels-Alder reaction of a furfuryl allyl sulfide, followed by bond cleavage can produce α α' tetra-substituted tetrahydrofurans with excellent control of stereochemistry. A more modest amount of stereochemical control was also achieved at the exocyclic chiral center of jaconecic acid when an extremely bulky protecting group was used. Somewhat better selectivity was seen by reducing tricyclic ketone 80 with sodium borohydride or L-Selectride. The precise reasons for this selectivity, are not well understood.