3-Alkyl-p-menthan-3-ol derivatives: synthesis and evaluation of their physiological cooling activity

Different 3-alkyl-p-methan-3-ol derivatives provide a strong physiological cooling effect with potential application as food and cosmetic additives. In order to investigate the influence of the chemical structure on the cooling sensation, the stereoselective syntheses of 29 different 3-alkyl-p-methan-3-ol derivatives were accomplished. All the compounds obtained are odorless and were evaluated by taste, considering two sensations: a cooling effect and bitterness. The results of this structure–activity relationship study highlight that compounds with a (1R,4S)-configuration are the isomers with the more intense cooling effect and lower bitterness. In addition, the structure of the 3-alkyl chain affected the latter properties. Increasing the chain length over two carbon atoms does not change the cooling power, but enhances the bitterness with the additional feature that the branched isomers are considerably more bitter than the linear ones. Overall, the 3-alkyl-p-menthan-3-ol isomers with the best quality in terms of high cooling power and low bitterness are (1R,4S)-3-(hydroxymethyl)-p-menthan-3-ol diastereoisomers (−)-38 and (−)-42.

Graphical abstractTwenty-nine different isomers and derivatives were stereoselectively synthesized and evaluated.Figure optionsDownload full-size imageDownload as PowerPoint slide

(1R,3R,4S)-3-Ethoxycarbonylmethyl-p-menthan-3-olC14H26O3[α]D20=-14.8 (c 1, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3S,4S)-3-Ethoxycarbonylmethyl-p-menthan-3-olC14H26O3[α]D20=-17.4 (c 1, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1S,3R,4S)-3-Ethoxycarbonylmethyl-p-menthan-3-olC14H26O3[α]D20=-25.1 (c 2, CHCl3)Source of chirality: (−)-isomenthoneAbsolute configuration: (1S,3R,4S)

(1R,3R,4S)-3-(2′-Hydroxyethyl)-p-menthan-3-olC12H24O2[α]D20=-16 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3S,4S)-3-(2′-Hydroxyethyl)-p-menthan-3-olC12H24O2[α]D20=-33.4 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1S,3R,4S)-3-(2′-Hydroxyethyl)-p-menthan-3-olC12H24O2[α]D20=-28.6 (c l, CHCl3)Source of chirality: (−)-isomenthoneAbsolute configuration: (1S,3R,4S)

(1R,3R,4S)-3-(2′-Acetoxyethyl)-p-menthan-3-olC14H26O3[α]D20=-2.9 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3R,4S)-3-(2′-Acetoxyethyl)-p-menthan-3-ol acetateC16H28O4[α]D20=+10.9 (c 1.5, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3R,4S)-3-(2′-Carboxypropionyloxy-ethyl)-p-menthan-3-olC16H28O5[α]D20=-4.2 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3S,4S)-3-(Hydroxymethyl)-p-menthan-3-ol acetateC13H24O3[α]D20=-4.8 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1R,3S,4S)-3-(Hydroxymethyl)-p-menthan-3-olC11H22O2[α]D20=-6.7 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1R,3S,4S)-3-(Hydroxymethyl)-3-(2′-Hydroxyethoxyl)-p-menthaneC13H26O3[α]D20=-3.3 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1R,3R,4S)-3-(Hydroxymethyl)-p-menthan-3-olC11H22O2[α]D20=-19.6 (c l, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3S,4S)-3-(3′-Hydroxypropyl)-p-menthan-3-olC13H26O2[α]D20=+4.2 (c 1, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1R,3S,4S)-3-(4′-Hydroxybutyl)-p-menthan-3-olC14H28O2[α]D20=+5.9 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3S,4S)

(1R,3R,4S)-3-(2′-Hydroxy-2′-methylpropyl)-p-menthan-3-olC14H28O2[α]D20=-45.0 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S)

(1R,3R,4S,2′S)-3-(2′-Hydroxy-3′-methoxypropyl)-p-menthan-3-olC14H28O3[α]D20=-15.8 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′S)

(1R,3R,4S,2′R)-3-(2′-Hydroxy-3′-methoxypropyl)-p-menthan-3-olC14H28O3[α]D20=-10.1 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′R)

(1R,3R,4S,2′R)-3-(2′-Hydroxypropyl)-p-menthan-3-olC13H26O2[α]D20=-29.7 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′R)

(1R,3R,4S,2′S)-3-(2′-Hydroxypropyl)-p-menthan-3-olC13H26O2[α]D20=+9.4 (c 2, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′S)

(1R,3R,4S,2′S)-3-(2′,3′-Dihydroxypropyl)-p-menthan-3-olC13H26O3[α]D20=-17.0 (c l, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′S)

(1R,3R,4S,2′R)-3-(2′,3′-Dihydroxypropyl)-p-menthan-3-olC13H26O3[α]D20=-4.3 (c l, CHCl3)Source of chirality: (−)-menthoneAbsolute configuration: (1R,3R,4S,2′R)