944111-07-3Relevant academic research and scientific papers
Ring reversal of a spirocyclic patchouli odorant: Molecular modeling, synthesis, and odor of 6-hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one
Kraft, Philip,Bruneau, Audrey
, p. 2257 - 2267 (2008/02/06)
Molecular modeling calculations on the recently discovered high-impact patchouli odorant (+)-(1S,4R,5R,9S)-1-hydroxy-1,4,7,7,9-pentamethylspiro[4.5] decan-2-one (1) indicated that ring reversal of the spirocyclic system should lead to molecules in which two of the five methyl substituents could be spared without significantly affecting the overall shape or conformational equilibrium. Intramolecular ene reactions promised simple access to the desired target compound, (5R*,6R*)-6-hydroxy-1,1,6-trimethylspiro[4.5]decan-7-one (2), but all attempts failed utterly. The elaborated alternative six-step synthesis of target structure 2 commenced with the addition of HCl gas to 5-bromo-2-methyl-2-pentene (16), giving 1-bromo-4-chloro-4-methylpentane (15). Spiroannulation of cyclohexanone with this building block by TiCl 4-mediated alkylation of the TMS enolate 14 and subsequent cyclization by means of tBuOK afforded 1,1-dimethylspiro[4.5]decan-6-one (12). The reaction of this spirocyclic ketone with MeLi furnished the corresponding tertiary alcohol 17, which was dehydrated by Appel-Lee bromination with concomitant dehydrohalogenation. The resulting alkene mixture containing 1,1,6-trimethylspiro[4.5]dec-6-ene (4) as the major component was subjected to the ketohydroxylation method developed by Plietker to provide, after repeated chromatography, target compound 2 in 33 % yield. To study the influence of the gem-dimethyl position on the olfactory properties, the analogous spirocyclic 2,2,6-trimethylketone 22 was also synthesized. Spiroannulation of cyclohexanone with 1,4-dibromo-2,2-dimethylbutane (18), with the use of 2.2 equiv. tBuOK as base, furnished 2,2-dimethylspiro[4.5]decan-6-one (19). The reaction of 19 with MeLi and subsequent Appel-Lee bromination/dehydrohalogenation led to an isomeric mixture containing 2,2,6-trimethylspiro[4.5]dec-6-ene (21) as the main component. The ketohydroxylation method according to the protocol of Plietker concluded the synthesis of the second target structure 22. In contrast to methyl carbinol 17, which has a typical woody-earthy patchouli odor, the odor of target molecule 2 was displaced towards the camphoraceous and minty side. The 2,2,6-trirnethylalcohol 20 emanated a camphoraceous and vetiver-type note, while the second target molecule, 22, was only weakly woody, cedar-like, and powdery in smell. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.
