Flavor Chemistry - American Chemical Society

Chapter 12

Downloaded by UNIV OF ARIZONA on December 11, 2012 | http://pubs.acs.org Publication Date: February 21, 1989 | doi: 10.1021/bk-1989-0388.ch012

Enantioselectivity in Odor Perception W. Pickenhagen Research Laboratories, Firmenich SA, Case Postale 239, CH-1211, Geneva, Switzerland The first molecular event in odor perception is an interaction of an odorant with a receptor. Evidence exists that these receptors are proteins, i.e. chiral, so this first interaction should be enantioselective, meaning that these receptors react differently with the two enantiomeric forms of a chiral odorant leading to differences in odor strength and quality. In many cases, this fact has beenobserved.This paper describes the enantioselective syntheses of some known odorants of multiple chemical classes and discusses the differences of the organoleptic properties of their enantiomeric forms. The mechanism of odor perception is very complicated and the least understood of all our senses. It is well accepted that the perception of an odor, meaning the actual recognition by the brain, goes through a cascade of events.

^STIMULUS

- »

RECEPTOR

- »

TRANSDUCTION

• »

PROCESSING^

Of all these different steps, the very first one, namely the interaction of a stimulus, i.e. molecules that "have a smell", with the actual receptor is not at all u nderstood. These receptors are supposed to be located in the membrane of the cilia cells, because these cilia are the furthest out of the antennae of the olfactory system, and they have been shown to be excitable by chemical stimuli. In analogy toother-betterunderstood-receptor systems like some hormone and opiate receptors it is generally accepted that the olfactory receptors are proteins, and there are some facts known that support this hypothesis. One of these arguments is that, sometimes, slight modification of the chemical structure of a stimulus molecule can lead to big changes in the odor impression; this might be qualitative or quantitative. Proteins are chiral, so they should interact differently with the two enantiomeric forms of a chiral molecule, which should eventually translate into a difference of the odor impression of these mirror images of the molecules. A more detailed knowledge of the relations between the chemical structure of a molecule, including its absolute configuration, and its odor properties will contribute to the elucidation of the receptor mechanism. Actually there are many examples known where the two enantiomeric forms of chiral compounds have different odors. Table I shows some of them without being exhaustive. Enantioselective synthesis have become very fashionable in preparative chemistry, and a considerable effort is devoted to their methodology. 0097-6156/89/0388-O151$06.00/0 « 1989 American Chemical Society

In Flavor Chemistry; Teranishi, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

152

FLAVOR CHEMISTRY: TRENDS AND

DEVELOPMENTS

Table 1 Enantiomeric Forms of Chiral Compounds and Their Odors

Odor impression

Compound

(+)-Linalool

sweet, petitgrain

(-)-Linalool

lavender notes, Ho oil, woody

(+)-Carvone

caraway

(-)-Carvone

spearmint

(+) -cis-Rose oxide

sweet

(-)-c/s-Rose oxide

powerful, fruity

(+)-Hydroxycitronellal

sweet, powerful

(-)-Hydroxycitronellal

minty


CHj OH

^CKa OH

OH Ο CH,

OH

Η

CH3


12.

PICKENHAGEN

153

Enantioselectivity in Odor Perception Table 1. Continued

Compound

oX^O

^


O^^C/^^

\

J

-Nootk.tone

JL

H

J

Lit.

t s 0.8 ppm grapefruit, strong

[5]

(-)-Nootlcatone

t = 600 ppm very weak, no grapefruit

(-)-Patchoulol

natural patchouli, earthy, cellary

16]

(+)-Patchoulol

weak, not reminiscent of patchouli

(-)"Androstenone

sweaty, urine musky, strong

m

όψο»

J

Odor impression

Η

I

J

(+)-Androstenone

odorless

[8]

1

(+)- c/"s-2-methyl-4 propyl-1,3-oxathiane

t s 2 ppb sulfury, rubbery, tropical fruit

[9]

(-)- c/s-2-methyl-4propyl-1,3-oxathiane

t = 4 ppb flat, estery, camphoracious

Η

1^ Η

J ^ ^ ^ ^ ^


[10]

154

FLAVOR CHEMISTRY: TRENDS AND

DEVELOPMENTS

In our continuous interest in the relation of molecular structure and organoleptic activity, we synthesized the enantiomers of some well-known aroma chemicals, and evaluated their odor. For the preparation different synthetic approaches were used, i.e. a)

starting with the same material employing reagents of opposite chirality that can either be recovered after use or are lost during the synthesis;

b)

starting with natural products of known antipodal configuration.


Muscone 1 was discovered in 1906 [H]; its structure [12] and absolute configuration [IS] were determined later to be (7?>3-methylcyclopentadecanone.

3 It is, in its racemic form, a highly appreciated ingredient in fine perfumery. Because of its value a number of syntheses have been described [14]. Enantioselective syntheses of the (-)(R) 1 and the (+)-fS>form 2 have been developed [15], however no olfactive description of the two compounds could be found. Following the synthesis of Nelson and Mash, both enantiom eric forms of muscone were prepared. The optical purity, determined by 360 MHz NM R, using Pr (hfbc) as chiral shift agent was 95.5% for the (-)-(R) and 97.7% for the (+HS>form. The two products show distinct differences in their odor. The natural 1 is described by a panel of perfumers as "very nice musky note, rich and powerful", whereas 2 is "poor and less strong". Thresholds, determined in water, using Guadagni's procedure [1£], with a panel of 18 - 20 members, show values of 61 and 233 ppb respectively, giving a calculated threshold of 97 ppb for the racemic mixture, in good accordance with the experimental value of 103 ppb. 3

4

5

6

From these results, one could deduce that the methyl group in 2 somehow hinders easy access of the molecule to its receptor. This hypothesis is supported by the fact that 3,3dimethylcyclopentadecanone 3 is nearly odorless. The tricyclic ether AMBROX 4, first synthezised in 1950 [12], was later found as a constituent of ambergris [13], oriental tobacco (Demole, Ε., Firmenich SA. unpublished data), clary sage (Renold, W.; Keller, U.; Ohloff.G. Firmenich SA. unpublished data) and ciste labdanum (Renold, W.; Wuffli, F.; Ohloff, G. Firmenich SA. unpublished data). The absolute configuration of the natural (-)-form is determined by the configuration of the starting material (-)-sclareol 5.


12.

Enantioselectivity in Odor Perception

PICKENHAGEN

155

For the synthesis of the (+) enantiomer, eperuric acid 6 extracted from Wallaba wood (Eperura falcata) was converted to 7 following the method of Dey and Wolf [12]. The ketone 7 was then transformed into (+) Ambrox ent-4, following scheme 1 [20]. Optical purity, determined by 360 Mhz HNMR using Eu (hfbc) as chiral shift agent, is more than 98%, confirmed also by capillary gas chromatography using Ni(hfbc) in OV101 as chiral stationary phase. 3

2


Scheme 1

10 Reagents:

enhA a) 0 , t-BuOK, dry glyme (distilled over LiAIH ); b) LiAIH , Etp/reflux/1 h; c) CH N0 , TsOH/ref lux/100°/1 h. 2

4

4

3

2

Organoleptic comparison of the two forms shows that the (+) enantiomer has a dominant woody note and lacks the warm animal note of the (-)-form. Thresholds in water [16] were measured to 0.3 ppb for (-) 4 and 2.6 ppb for the (+). The racemic mixture was determined to be 0.6 ppb, corresponding well to the calculated threshold of 0.54 ppb.

11

12

(+) fl-12

(-) S-12

The rose ketones 11, first discovered in1970 [21] in Bulgarian rose oil, and named damascenes, show unique organoleptic properties. Because of this they have elicited great interest, also as target molecules for new synthetic methods. a-Damascone 12 possesses a quite unique fruity odor, and its utilization allows the creation of perfumistic notes otherwise difficult to achieve. Treatment of (+)-epoxy-a-dihydroionone OH with hydrazine hydrate gives as one of the reaction products alcohol 13, which was transformed by oxidation with Mn0 to (+)-(7?>-a-damascone 12 in 65% e. e., thus establishing its absolute configuration [22]· 3 2

1


156

FLAVOR CHEMISTRY: TRENDS AND DEVELOPMENTS

A new access to α-damascone by selective kinetic protonation of α-ketone enolate, formed by reaction of an ester enolate with nucleophiles, has recently been described by Fehr and Galindo [22] (scheme 2). Scheme 2


OLi

12

The same authors found that the prochiral enolate 16 can, under certain conditions, be protonated enantioselectively, using ephedrine derivatives as proton sources [23]. These compounds are available in their optically pure forms, thus both enantiomers of a-damascone can be prepared in about 70% optical yield starting with the same ketone enolate and using the appropriate optical form of the proton source. Enantiomerically pure α-damascones (-)-(S)~ 12, (+)-(fî>12 have been obtained by repeated recrystallization. The organoleptic properties of the two compounds are distinct. Striking is the difference in perception thresholds, which were found to be 1.5 ppb for the (-)-fS>, and 100 ppb for the (+)-(R)-iorm. Qualitatively, the (-)-(S) is described as more floral, reminiscent of rose petals, also having a winy character without the "cork" and the green apple note that are the characteristics of the (+)-(7?>form as well as of the racemic mixture. These examples that add to the existing list show to what extent modification of the chemical structure of a molecule can alter the perceived odor. The fact that two enantiomeric forms of odorants show distinct differences in their organoleptic properties supports the hypothesis that the initial event, the interaction of the stimulus with the receptor is enantioselective, leading to diastereoisomeric stimulus-receptor complexes; and these events are transduced to give rise to different odor impressions, the mechanism of which remains to be discovered.

Literature Cited 1. Ohloff, G.; Klein, E. Tetrahedron, 1981, 18, 37. 2. a) Friedmann, L.; Müller, J.G. Science, 1971, 172, 1044. b) Russel, G.F.; Hills, J.I. Science, 1971, 172, 1043. c) Leitereg, T.J.; Guadagni, D.G.; Harris, J.; Mon, T.R.; Teranishi, R. Nature, 1971, 230, 455. d) Leitereg, T.J.; Guadagni, D.G.; Harris, J.; Mon, T.R.; Teranishi, R. J. Agric. Food Chem.1971,19,785.



12. PICKENHAGEN

Enantioselectivity in Odor Perception

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3. Ohloff, G. In Olfaction & TasteIV;D. Schneider, Ed.; Wiss. Verlagsges.: Stuttgart, 1972, p 156. 4. Skorianetz, W.; Giger, H.; Ohloff, G. Helv. Chim. Acta, 1971, 54, 1797. 5. Haring, H.G.; Rijkens, F.; Boelens, H. v. d. Gen A. J. Agric. Food Chem., 1972, 20, 1018. 6. Näf, F.; Decorzant, R.; Giersch; W.;Ohloff,G. Helv. Chim. Acta, 1986,64,1387. 7. Prelog, V.; Ruzicka, L.; Wieland, P. Helv. Chim.Acta,1944, 27, 66. 8. Ohloff, G.; Maurer, B.; Winter, B.; Giersch, W. Helv. Chim. Acta, 1983,66,192. 9. Pickenhagen, W.; Brönner-Schindler, H. Helv. Chim. Acta, 1984,67,947. 10. Heusinger, G.; Mosandl, A. Liebigs Ann. Chem. 1985, 1185. 11 Walbaum, H. J.Prakt. Chem.II,1906,73,488. 12. Ruzicka, L. Helv. Chim. Acta, 1926,9,715, 1008. 13. Ställberg-Stenhagen, S. Ark. Kemi, 1951, 3, 517. 14. For a review see Mookherjee, B.; and Wilson, R.A. In Fragrance Chemistry; Theimer, E.T., Ed.; Academic Press Inc.: New York, 1982, p 433; and Wood, T.F. In Chemistry of SyntheticMusks,Ibid.p495. 15. Branca, Q.; Fischli, A. Helv. Chim. Acta, 1977,60,925. Nelson, K.A.; Mash, E.A., J. Org. Chem., 1986, 33, 2171. 16. Schwimmer, J.; Guadagni, D.G. J. Food Sci., 1962, 27, 94. 17. Hinder, M.; Stoll, M. Helv. Chim. Acta, 1950,33,1308. 18. Mookherjee, B.D.; Patel, R.R. Proc. of the VIIth Int. Cong. of Ess. Oils, 1977, p 479. 19. Dey, A.K.; Wolf, H.R. Helv. Chim. Acta, 1978,61,1004. 20. Ohloff, G.; Giersch, W.; Pickenhagen, W.; Furrer, Α.; Frei, B. Helv. Chim. Acta, 1985,68,2022. 21. Demole, E.; Enggist, P.; Säuberli; U.; Stoll, M. Helv. Chim. Acta, 1970, 55, 541. 22. Ohloff, G.; Uhde, G. Helv. Chim. Acta, 1970, 55, 531. 23. Fehr, C.; Galindo, J. J. Org. Chem., 1988, 53, 1828. 24. Fehr, C.; Galindo, J. Submitted to J. Am. Chem. Soc. RECEIVED September 12, 1988


Flavor Chemistry - American Chemical Society

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