Ring Reversal of a Spirocyclic Patchouli Odorant: Molecular Modeling, Synthesis, and Odor of 6‐Hydroxy‐1,1,6‐trimethylspiro[4.5]decan‐7‐one

Abstract

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 TiCl4‐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‐trimethylalcohol 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, 69451 Weinheim, Germany, 2007)

Synthesis and odour evaluation of double‐bond isomers of DAMASCENOLIDE, 4‐(4‐methylpent‐3‐en‐1‐yl)‐2(5H)‐furanone, which has a citrus‐like odour

“…The ynoate 18 was converted to an enoate 20 ( Z : E ≥ 99:1) by the conjugate addition of cuprate prepared from known bromide 19 in the presence of magnesium and copper(I) bromide dimethyl sulphide complex (Scheme ). Removal of EE (ethoxyethyl) group using aqueous HCl was smoothly followed by lactonization in one‐pot to give compound 7 in good yield.…”

New Musk Odorants: (3E)‐4‐(2′‐Alkyl‐5′,5′‐dimethylcyclopent‐1′‐enyl)but‐3‐en‐2‐ones and (3E)‐1‐Acetyl‐3‐alkylidene‐4,4‐dimethylcyclohexenes

“…The required diene precursor was synthesized starting by the Grignard reaction of the vinylogous ester 24 with ethylmagnesium bromide, according to the method of Woods and co‐workers 17,14b. After acidic hydrolysis and chromatographic purification, the 3‐ethylcyclohex‐2‐enone ( 25 ) was obtained in 90 % yield.…”

Heiße Luft oder cooler Duft? Die Trends der letzten 20 Jahre in der Riechstoffchemie

“…Inversion des spirocyclischen Ringsystems von 210 lag dem Design von 211 zu Grunde,d as campherartige,h olzige und erdige Aspekte aufwies. [183] Mit 17.2 ng L À1 Luft besaß 211 allerdings einen ziemlich hohen Schwellenwert. Eine bifunktionelle Donor/Acceptor-Einheit kann dennoch eine charakteristische Patchouli-Note vermitteln, wie die mit Theaspiran verwandten Tetrahydrofuranylalkohole 212 [184] und 213 beweisen (Abbildung 19).…”