A Facile Total Synthesis of (±)‐Acoragermacrone by Titanium‐Induced Keto Ester Cyclization

Abstract

A B S T R A C T (i)-Acoragermacrone, a natural occurring germacrane-type sesquiter-penoid. was synthesized from geranyl acetate via eight steps by employing titanium -induced intramolecular keto a,p-unsaturated ester coupling as key step.The synthesis of medium rings by direct methodology continues to be an attractive challenge for organic synthetic chemists. Several approaches by direct intramoleular carbon-carbon bond formation have been reported and another indirect approach is also known".Among these methods, the titanium-induced intramolecular coupling of a dicarbonyl precursor is an extraordinarily general and effective means of preparing carbocyclic rings of all sizes, by which total syntheses of some natural cembrenoids and sesquiterpenes have been accomplishedm. The titanium-induced intramolecular keto ester coupling was reported as a novel method for cycloalkanone synthesis by McMurry and his co-workers"', and has been used in the syntheses of two hydrocarbon sesquiterpenes capnellene'" and isocaryophyllene-.However, the intramolecular keto a.p-unsaturated ester coupling catalyzed by low valent titanium has not been investigated. Employing this COUPling as macrocyclization key step, herein we wish to report the total synthesis of (f)-acoragernacrone ( L ) , a chemically and thermally labile natural sesquiterpenoid possessing a 1,5-cyclodecadiene ring and a conjugated carbonyl group. It was first isolated from the plant Acorus calamus L . growing in Japan"' which exhibits insect attractant"' (on Female melon flies) and pheromone activitym (on American cockroach). Two syntheses of 1 have been described by S u ' " and Takahashi'" respectively.Our syhthetic strategy involves the titanium-induced macrocyclization of the keto a,p-unsaturated ester precursor which was prepared by the alkylation of the lithium enolate of methyl isopropyl ketone with the corresponding allylic iodide of alcohol 3. The synthetic route outlined in the following Scheme Geranyl acetate 2 was exposed to 75% m -b u t y l hydroperoxide in the presence of catalytic amount of selenium dioxide methylene chloride at room temperature and followed by reduction with sodium borohydride in methanol at OC to give the terminal allylic alcohol 3 in 64% yield (based on the consumed starting material), which then was converted to the corresponding iodide by standard methodology'" (Ph,P/Imidazole, 1.) quantitatively. Alkylation of the lithium enolate of methyl isopropyl ketone (formed by treatment of the ketone with LDA at -78C in THF) with the crude labile iodide (at -78C t o room temperature) afforded the ketone in 78% yield, which was subjected to solvolysis with potassium carbonate in methanol, followed by oxidation with active manganese dioxide in the presence of anhydrous -503.