1. A formal total synthesis of dysiherbaine. 2. Asymmetric total synthesis of ceratopicanol

Abstract

Dysiherbaine and Neodysiherbaine are a novel neurotoxic amino acid isolated from marine sponge Dysidea herbacea by Sasaki in 1997. Pharmacologically, Dysiherbaine is considerably valuable since it was found to be an agonist for glutamate receptors and more potent than domoic acid or kainic acid, so this could be one of major medicinal candidate for epilepsy, Huntington’s disease, and Alzheimer’s diseases. Dysiherbaine / Neodysiherbaine has unique skeletal structure of cis-fused hexahydrofuraopyran ring substituted with alanine amino side chain. By now 6 groups have been researched for synthesis of these compounds and showed difficulties for construction of congested stereocenters at C-4, 6, and 7 position. We designed a new strategy in view of the efficiency for setup these stereocenters utilizing diene metathesis pathway. Exploring the model compound we disclosed this could be the straightforward route, wherein the meta-substituted allyloxy oxabicyclo[2,2,1]heptene was transformed to cis-fused hexahydrofuraopyran structure through Grubb’s ROCM (ring opening-cross metathesis) route. With this satisfactory result we undertook the asymmetric formal synthesis of Dysiherbaine. The enantiopure allyloxy oxabicyclo[2,2,1]heptene structure was synthesized from Diels-Alder reaction between substituted furan and 1,2-trans-bis(phenylsulfonyl) ethylene, and followed by resolution of those diastereomers from O-acetyl-L-mandelic acid. The chirally pure meta-substituted allyloxy oxabicyclo[2,2,1]heptene was subjected to domino metathesis with vinyl acetate and Hoveyda-Grubb’s II catalyst to produce stereocontrolled hexahydrofuropyran core structure of Dysiherbaine and Neodysiherbaine. Side chain manipulation of vinyl acetate and double bond afforded Sasaki’s intermediate for 16 steps, 2.3% overall yield. In 1988, Hanssen and Abraham reported the isolation of a novel triquinane sesquiterpene (+)-Ceratopicanol in agar cultures of the Ascomycete Ceratosystis piceae Ha 4/82, and...