Analogues of α-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

Article abstract of DOI:10.1002/hlca.200690236

To complete our panorama in structure-activity relationships (SARs) of sandalwood-like alcohols derived from analogues of α-campholenal (=(1R)-2,2,3-trimethylcyclopent-3-ene-1-acetaldehyde), we isomerized the epoxy-isopropyl-apopinene (-)-2d to the corresponding unreported α-campholenal analogue (+)-4d (Scheme 1). Derived from the known 3-demethyl-α-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 α-campholenal acetal (-)-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 C₂ or C₃ 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 α-campholenol (+)-15a or of its acetate (-)-15b, respectively. Their cis-analogues were prepared starting from (+)-12a. Either (+)-4h or (-)-11b, was submitted to a Bayer-Villiger oxidation to afford acetate (-)-16a. Since isomerizations of (-)-16 lead preferentially to β-campholene isomers, we followed a known procedure for the isomerization of (-)-epoxyverbenone (-)-2e to the norcampholenal analogue (+)-19a. Reduction and subsequent protection afforded the silyl ether (-)-19c, which was stereoselectively hydroborated under oxidative condition to afford the secondary alcohol (+)-20c. Further oxidation and epimerization furnished the trans-ketone (-)-17a, a known intermediate of either (+)-β-necrodol (=(+)-(1S,3S)-2,2,3-trimethyl-4-methylenecyclopentanemethanol; 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 β-campholenol (=2,3,3-trimethylcyclopent-1-ene- 1-ethanol) gave access via the cis-alcohol rac-23a, to the cis-aldehyde rac-24.