Total Synthesis and Olfactory Evaluation of (1R*,3S*,6S*,7S*,8S*)- 3-Hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undecan-2-one: A New Synthetic Route to the Patchoulol Skeleton

Autor: Christophe Weymuth, Cornelius Nussbaumer, Philip Kraft
Rok vydání: 2006
Předmět:
Zdroj: European Journal of Organic Chemistry. 2006:1403-1412
ISSN: 1099-0690
1434-193X
Popis: The superposition analysis of (–)-patchoulol (1), the odorous principle of patchouli oil, with the recently discoveredhigh-impact spirocyclic patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5]decan-2-one (2) resulted in the question as to whether a patchoulolderivative in which the gem-dimethyl group is replacedby a carbonyl function would be a powerful patchouliodorant. The total synthesis of the racemic superstructure (1R*,3S*,6S*,7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undecan-2-one (3) was accomplished in 13 steps from the inexpensive commercial odorant Cyclal C (7) with a total yield of 7 %. Conversion of 7 to the corresponding enamine 8 and subsequent copper-catalyzed oxidative degradation afforded 2,4-dimethylcyclohex-3-enone (6), which was subjected to a Robinson annulation with 1,4-dimethoxybutan-2-one (9). The carbonyl function of the resulting annulation product 10 was removed by LAH reduction, acylation with Ac2O, and dissolving metal reduction. The deoxygenated methyl enol ether 12 thus obtained was then cleaved by mild hydrolysis with oxalic acid, and the resulting 2,9-dimethyl-Δ1-octalin-5-one (5) was hydroxymethylenated by Claisen ester condensation with ethyl formate to provide thecis-configured (2Z)-2,3,4,4a,8,8a-hexahydro-2-(hydroxymethylene)-4a,6-dimethylnaphthalen-1(7H)-one (4). In a novel intramolecular Prins reaction with an equimolar amount of p-toluenesulfonic acid monohydrate, the ideally preformed precursor 4 cyclized to (1R*,2R*,3S*,7R*,8S*)-2-hydroxy-4,8-dimethyltricyclo[5.3.1.03,8]undec-4-en-11-one (13), comprising the complete carbon framework of the target compound 3. A Barton–McCombie deoxygenation of the corresponding O-phenoxythiocarbonyl derivative, followed by oxidation of the lithium enolate of the resulting ketone 14 with the molybdenum peroxide reagent MoO5–pyridine–DMPU, and the face-selective hydrogenation of the obtained(1R*,3S*,7S*,8S*)-3-hydroxy-6,8-dimethyltricyclo[5.3.1.03,8]undec-5-en-2-one (15) concluded the synthesis of the target molecule 3, which was accompanied by its odorless C-6 epimer epi-3 in the ratio 84:16. Both the target structure 3 and its unsaturated precursor 15 possessed pronounced patchouli odors, albeit slightly weaker in threshold than (–)-patchoulol (1). This proved the superposition analysis of the templates 1 and 2 to be correct and provided novel insight into the structural requirements of patchouli odorants. As 3 was an intermediate in a total synthesis of rac-1, the synthesis also constitutes a new formal total synthesis of racemic patchoulol (rac-1). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)
Databáze: OpenAIRE
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