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

• Published in: Helvetica chimica acta 2006-11, Vol.89 (11), p.2638-2653
• Main Authors: Chapuis, Christian, Barthe, Michel, Cantatore, Carole, Saint-Léger, Christine, Wyss, Patrick
• Format: Article
• Language: English
• Subjects: (+)-β-Necrodol; Epoxides; Sandalwood; α-Campholenal
• ISSN: 0018-019X; 1522-2675
• 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.