Analogues ofα-Campholenal (= (1R)-2,2,3-Trimethylcyclopent-3-ene-1-acetaldehyde) as Building Blocks for (+)-β-Necrodol (= (1S,3S)-2,2,3-Trimethyl-4-methylenecyclopentanemethanol) and Sandalwood-like Alcohols

Abstract

To complete our panorama in structure-activity relationships (SARs) of sandalwood-like alcohols derived from analogues of a-campholenal (= (1R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde), we isomerized the epoxy-isopropyl-apopinene (À)-2d to the corresponding unreported a-campholenal analogue (+)-4d (Scheme 1). Derived from the known 3-demethyl-a-campholenal (+)-4a, we prepared the saturated analogue (+)-5a by hydrogenation, while the heterocyclic aldehyde (+)-5b was obtained via a Bayer-Villiger reaction from the known methyl ketone (+)-6. Oxidative hydroboration of the known acampholenal acetal (À)-8b allowed, after subsequent oxidation of alcohol (+)-9b to ketone (+)-10, and appropriate alkyl Grignard reaction, access to the 3,4-disubstituted analogues (+)-4f,g following dehydration and deprotection. (Scheme 2). Epoxidation of either (+)-4b or its methyl ketone (+)-4h, afforded stereoselectively the trans-epoxy derivatives 11a,b, while the minor cis-stereoisomer (+)-12a was isolated by chromatography (trans/cis of the epoxy moiety relative to the C 2 or C 3 side chain). Alternatively, the corresponding trans-epoxy alcohol or acetate 13a,b was obtained either by reduction/esterification from trans-epoxy aldehyde (+)-11a or by stereoselective epoxidation of the a-campholenol (+)-15a or of its acetate (À)-15b, respectively. Their cis-analogues were prepared starting from (+)-12a. Either (+)-4h or (À)-11b, was submitted to a Bayer-Villiger oxidation to afford acetate (À)-16a. Since isomerizations of (À)-16 lead preferentially to b-campholene isomers, we followed a known procedure for the isomerization of (À)-epoxyverbenone (À)-2e to the norcampholenal analogue (+)-19a. Reduction and subsequent protection afforded the silyl ether (À)-19c, which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)-20c. Further oxidation and epimerization furnished the trans-ketone (À)-17a, a known intermediate of either (+)-b-necrodol (= (+)-(1S,3S)-2,2,3-trimethyl-4methylenecyclopentanemethanol; 17c) or (+)-(Z)-lancifolol (= (1S,3R,4Z)-2,2,3-trimethyl-4-(4-methylpent-3-enylidene)cyclopentanemethanol). Finally, hydrogenation of (+)-4b gave the saturated cis-aldehyde (+)-21, readily reduced to its corresponding alcohol (+)-22a. Similarly, hydrogenation of b-campholenol (= 2,3,3-trimethylcyclopent-1-ene-1-ethanol) gave access via the cis-alcohol rac-23a, to the cis-aldehyde rac-24.

Synthesis and Bioassay of Racemic and Chiral trans-α-Necrodyl Isobutyrate, the Sex Pheromone of the Grape Mealybug Pseudococcus maritimus

“…Pamingle et al reported an efficient method of isomerizing the exocyclic double bond of β-necrodol to the endocyclic double bond of R-necrodol (8), but their synthesis of β-necrodol was inefficient (9). However, β-necrodol has been synthesized by several other routes (10)(11)(12)(13)(14)(15), with that reported by Monti et al being both short and proceeding with complete 1,3-diastereoselection (14). Here, we describe a convenient synthesis of the racemic grape mealybug sex pheromone by combination and further optimization of elements from several of these syntheses.…”