J. Agric. Food Chem. 2011, 59, 677–683
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DOI:10.1021/jf103989j
Hemisynthesis of Dihydroumbellulols from Umbellulone: New Cooling Compounds CHRISTIAN STARKENMANN,* ISABELLE CAYEUX, ROBERT BRAUCHLI, AND FABIENNE MAYENZET Corporate R&D Division, Firmenich SA, P.O. Box 239, CH-1211 Geneva 8, Switzerland
Although menthol is a common ingredient used in food products, other molecules also evoke coolness through stimulation of the somatosensory system. To discover new molecules having cooling properties, we virtually screened the chemical structures of terpenes and sesquiterpenes to find structures that are similar to (-)-menthol. We realized that dihydroumbellulols could be good candidates. Although their occurrence was reported in Hyptis pectinata Poit, we were unable to obtain these molecules from the plant or to prove their natural occurrence. Therefore, we extracted (-)-(R)umbellulone from Umbellularia californica Nutt. The (-)-(R)-umbellulone was reduced to prepare (1R,2R/S)-1-isopropyl-4-methylbicyclo[3.1.0]hex-3-en-2-ol, (1R,4R/S)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-2-one, and (1R,2RS,4RS)-1-isopropyl-4-methylbicyclo[3.1.0]hexan-2-ols, named dihydroumbellulols. Sensory analysis suggested that (1R,2R,4S)-dihydroumbellulol has a pleasant, trigeminal cooling effect, about 2-3 times less cooling than (-)-menthol, with a weak odor slightly reminiscent of eucalyptol. In addition, a previously unreported compound was discovered, (-)-(1R)1-isopropyl-4-methylenebicyclo[3.1.0]hexan-2-one. KEYWORDS: Trigeminal; cooling; umbellulone; dihydroumbellulols; Umbellularia californica Nutt
*Author to whom correspondence should be addressed (phone þ41 22 780 34 77; fax þ41 22 780 33 34; e-mail christian.starkenmann@ firmenich.com).
of chemical structures. We noticed a structure similarity between dihydroumbellulols and menthol. Unfortunately, the occurrence of these molecules was described only in Hyptis pectinata Poit by Malan et al. (15). We obtained this plant to isolate the dihydroumbellols, but it did not contain these molecules. However, the similarity between menthol and dihydroumbellol can also be seen in (-)-menthone (4) and umbellulone 10; therefore, we searched for a natural occurrence of umbellulone 10. The presence of (-)-(R)-umbellulone (10) in Umbellularia essential oil was reported by Power and Lees in 1904 (16). The natural occurrence of (-)-(R)-umbellulone (10) is frequently mentioned from many different plants, such as cold-pressed mandarin peel oil from Cuba (17), Lippia sidoides Cham. (18, 19), Cupressus lusitanica Mill. (20), Tanacetum cadmeum (Boiss.) Heywood (21-23), Daucus gingidium L. subsp. gingidium (24), and Cymbopogon jwarancusa (Jones) Schultz (25). (-)-(R)Umbellulone (10) is also present in the bark of Umbellaria californica (Hook. & Arn.) Nutt (26). Umbellulols 13 and 14 are also reported to be present in nature in C. lusitanica Mill. (27 ), Salvia officinalis L. (28), Zanthoxylum simulans Hance fruits (29 ), and Eucalyptus camaldulensis var. brevirostris (Miq.) Blakely (30), but most investigators have not discussed which stereoisomer was present or have indicated that the assignment was only tentative. The first preparation of dihydroumbellulols from umbellulone was reported in a paper by Wienhaus and Todenhofer in 1929, in which they described an odor resembling isomenthol, but no taste characteristics were discussed (31). The present paper describes the preparation of dihydroumbellulols, clarifies data about their
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INTRODUCTION
A cooling effect can be produced by several molecules, mainly derived from terpenes and sesquiterpenes (1, 2). The coolest natural molecule is apparently (-)-menthol (1). Other structural analogues bearing an oxygen atom in position 3 of the p-menthane framework have cooling activity. (-)-Isopulegol (2) has one-fifth as much cooling power as (-)-menthol and is used commercially in combination with (þ)-cis- and (-)-trans-p-menthane-3,8-diol (3). Another natural cooling molecule is (-)-menthone (4), which is weakly cooling and comparable to (()-piperitone (5) (2). Several other terpenes, such as verbenol (6) and eucalyptol (7), are slightly cooling (Figure 1), and only one sesquiterpene is described as cooling, cubebol (8) (3). Many artificial cooling compounds are menthol derivatives (e.g., esters, ethers, ketals) (4-10) or have very different chemical structures (11-14). Such compounds are not discussed in this paper. The flavor industry is intent on finding new molecules that produce trigeminal effects. Two approaches are followed to discover new natural molecules: high-throughput screening of plant extracts, with the help of cell-based assays, or a traditional method that consists of focusing only on botanical species having specific taste properties. The question is how to find these plants. Undertaking a botanical trek is an option, as in having discussions with ethnobotanists or chefs. The approach presented in this paper is quite different, however, because the idea came from investigations
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Starkenmann et al. H NMR: δ 0.94 (3H, q, J = 6.8 Hz, H-9), 0.96 (3H, q, J = 6.8 Hz, H-8), 1.11 (1H, dd, 4.8, 4.0 Hz, H-6), 1.31 (1H, ddd, J = 7.8, 4.8, 2.0, H-60 ), 2.09 (1H, sept, J = 6.8 Hz, H-7), 2.46 (1H, dd, J = 7.8, 4.0, H-5), 2.68 (1H, ddd, J = 21.2, 1.4 1.4 Hz, H-3), 2.92 (1H, dddd, J = 21.2, 2.4, 2.4, 2.0 Hz, H-30 ), 4.76 (1H, br s, H-10), 5.01 (1H, br s, H-100 ); 13C NMR δ 18.4 (t, C6), 19.6 (q, C8), 19.6 (q, C9), 26.2 (d, C7), 33.5 (d, C5), 40.7 (t, C3), 46.7 (s, C1), 105.8 (t, C10), 142.9 (s, C4), 211.4 (s, C2); GC retention indices LRISPB-1 1113 and LRISPWAX 1567; MS, 150 (M•þ), 135 (15), 108 (100), 107 (80), 91 (65), 83 (45), 79 (70), 77 (55). Isolation of (-)-(1R,5S)-1-Isopropyl-4-methylbicyclo[3.1.0]hex3-en-2-one, (R)-Umbellulone (10). Fraction 2 (2.97 g) was also chromatographed on SiO2 (270 g) by using the same solvent system. We obtained (-)-(1R,5S)-1-isopropyl-4-methylbicyclo[3.1.0]hex-3-en-2-one (10) (1.675 g, 98% purity by GC-TIC). Analyses were in agreement with published data (37). GC retention indices: LRISPB-1 1143 and LRISPWAX 1637, [R]D = -29° (c 1) EtOH. Preparation of (1R,2R)-1-Isopropyl-4-methylbicyclo[3.1.0]hex3-en-2-ol (13) and (1R,2S)-1-Isopropyl-4-methylbicyclo[3.1.0]hex3-en-2-ol (14). (-)-(R)-Umbellulone (10) (545 mg) was reduced with LiAlH4 (39 mg) in Et2O at 22 °C for 90 min. The reaction was poured on 1 M HCl at 0 °C. The compound was extracted twice with Et2O, and the organic phases were dried on anhydrous Na2SO4, filtered, and concentrated. We obtained 0.412 mg of crude oil (yield = 75%), a mixture of isomers 13 (24%) and 14 (76%). Both isomers were separated by chromatography on SiO2 (54 g) by using cyclohexane, EtOAc, and THF in a ratio of 93:6:1. (1R,2R)-Umbellulol (13) (114 mg, yield = 21%) and (1R,2S)-umbellulol (14) (152 mg, yield = 28%) were obtained. Analyses were in agreement with published data (37) (Table 1). GC retention indices: (1R,2R)-umbellulol (13), LRISPB-1 1094 and LRISPWAX 1596; (1R,2S)-umbellulol (14), GC LRISPB-1 1103 and LRISPWAX 1607. Preparation of (1R,4S)-1-Isopropyl-4-methylbicyclo[3.1.0]hexan-2one (11) and (1R,4R)-1-Isopropyl-4-methylbicyclo[3.1.0]hexan-2-one (12; Trivial Name, Thujanone). (-)-(R)-Umbellulone (10) (1369 mg) was reduced in EtOH in the presence of Pd/C 5% (100 mg) with H2 (148 mL, volume absorbed) at atmospheric pressure. The catalyst was filtered off on Celite and the solvent distilled. We obtained 0.662 g (yield 65%) of (1R,4S)dihydroumbellulone (1R,4S)-2-thujanone (11); isomer 12 was also formed, but it represented
