Collective Synthesis of Aromadendrane Sesquiterpenoids via Intramolecular Allylic Alkylation & C-Acyl Transfer Reaction

Abstract

Aromadendrane which belongs to a class of sesquiterpenes, used worldwide in the pharmaceutical industries, were isolated from essential oils and various plants. It had widely used in the flavor, perfumery and pharmaceutical industries. Structurally, Aromadendrane is characterized by a dimethyl cyclopropane ring fused to a hydroazulene skeleton. In addition, among aromadendrane compounds which the hydroazulene skeleton is cis-fused is termed alloaromadendrane. Because Aromadendrane has many different kinds of bioactivities such as antifungal, antibacterial, antivirial, antifeedant, repellent, piscicidal, cytotoxic and anticancer activities, it has great value in the research of synthesis. Dysodensiol F, which has a cis-fused hydroazulene skeleton, was isolated from the EtOH extract of the twigs and leaveds of Dysoxylum densiflorum in 2008. It has structural features of a ketone at C-3 and a diol at C-10, biological activities and synthesis of Dysodensiol F have not been reported recently. Our research group reported the total synthesis of Dysodensiol F. (+)-10β, 14-Dihydroxy-alloaromadendrane which has a similar structure to Dysodensiol F except for a ketone at C-3, was isolated from Pulicaria paludosa in 1989 and Duguetia glabriuscula in 1997. Also it was reported that (+)-10β, 14-Dihydroxy-alloaromadendrane had an antibacterial activity. It was possible to synthesize with the structural feature comparing with Dysodensiol F. Dendroside C, has a glycoside at C-14, was isolated from the stem of Dendrobium nobile Lindl(Chinese name Jin-Chai-Shi-Hu) which is famous traditional Chinese medicine used as tonic. Although Dendrobium nobile Lindl and Dendroside A had known for immunomodulatory activity, Dendroside C has not been reported its biological activity yet. Our research group synthesized 3 natural compounds of aromadendrane sesquiterpenoid class with structural similarity via common intermediate to raise effectivity in the synthesis. First, stereogenic centers were introduced in bicyclic system through intramolecular allylic alkylation. Next, after cis-fused hydroazulene skeleton was obtained by intramolecular C-acyl transfer reaction, the common intermediate possessing hydroazulene skeleton was produced over a series of reactions. Followed by stereoselective cyclopropanation and Rh-catalyzed cyclopropanation from the common intermediate, finally we could complete the total synthesis of aromadendrane compounds in an efficient strategy.