The Enantioselectivity of Odor Sensation: Some ... - ACS Publications

In the Classroom

The Enantioselectivity of Odor Sensation: Some Examples for Undergraduate Chemistry Courses Philip Kraft Givaudan Schweiz AG, Fragrance Research, CH-8600 D€ ubendorf, Switzerland Albrecht Mannschreck* Department of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany *[email protected]

Within university curricula, elementary stereochemistry is often taught in the second year of organic chemistry, either in a dedicated course on stereochemistry or within the context of a natural products or bioorganic chemistry course. For this level of education, a few selected odorants are proposed as characteristic examples for the enantioselectivity of substance properties. To benefit the most from these examples, the student should be familiar with the basic notions of introductory organic stereochemistry (1, 2, 3a). Several recent reviews about chirality and odor sensation are available, most of which are general in scope (4-8), while musks (9) and woody odorants (10, 11) have been addressed in a specific manner. However, there is no literature on this subject matter under the aspect of teaching. The link between the receptor-mediated activity of chiral fragrance, pesticide, and drug molecules has been treated in an earlier publication (12); in this context, a few fragrance materials were addressed with a view to the classroom, but no use of these will be made in the present article. Methods for the analysis of chiral odorants were also reviewed (8, 13), of which enantioselective gas chromatography on different chiral stationary phases with odor detection by smelling at a sniffing port is the most important. The olfactory properties of the enantiomers of seven odorants particularly suited as teaching examples are detailed, together with their occurrence in nature, their industrial production, and their practical application in perfumery. Before presenting these, the biochemistry of the odorant-receptor binding and the code of olfaction are discussed to build a solid foundation for the understanding of these phenomena. Odorant-Receptor Interaction The sensory neurons of the olfactory epithelium at the back of each nasal passage of the human nose, about 7 cm (2.75 in.) up from the nostril, possess hair-like cilia, protruding into the mucus covering the olfactory epithelium. The membranes of these cilia contain the olfactory receptors (Figure 1), which are seven transmembrane (7TM) proteins. This means they possess seven helical domains that span the cell membrane to form a tunnellike cavity in which the odorants are bound as noncovalent association complexes (14). This process can be described as a 1:1 equilibrium (15), for which attractive and repulsive van der Waals interactions, hydrogen bonds, and the steric stress of the protein as well of the odorant in the bound state are responsible (16). Although the hydrogen bonds of the receptor with the most polar functional group of the odorant (the so-called osmophore) orient the molecule on the binding site, the nonbonding 598

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Figure 1. The biochemistry of odorant-receptor binding. A free odorant molecule of (R)-carvone forms a 1:1 association complex with a receptor coupled to a seven transmembrane (7TM) G protein. For details see the text.

through-space interactions of the hydrophobic parts are key to the specificity of the odorant-receptor interaction and, thus, mainly responsible for the array of receptors an odorant can bind to. Coupled with the receptor protein is a G protein, abbreviation for guanine nucleotide-binding protein, which consists of three subunits R, β, and γ (Figure 1). Binding of an odorant to the receptor causes the R-subunit of the G protein to dissociate and to activate adenyl cyclase, which catalyzes the conversion of adenosine-50 -triphosphate (ATP) to 30 ,50 -cyclic adenosine monophosphate (cAMP) and pyrophosphate. As a second messenger, cAMP binds to ion channels and opens them. Thus, Naþ and Ca2þ ions enter the cell, and the negative membrane potential (ca. -70 mV at rest) is decreased. Above a certain threshold (-50 mV), this analog sensor potential is converted into a digital action-potential frequency, which is conducted along the axon of the olfactory neuron into the respective glomerulus in the olfactory bulb, a spherical conglomerate where

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In the Classroom Table 1. Different Cases of Relative Odor Activities for Enantiomers Case

Relative Olfactory Properties

A

Only one enantiomer smells and the antipode is weak to odorless

B

Enantiomers smell similar but possess different intensities

C

Enantiomers smell similar and possess similar intensities

D

Enantiomers smell different

all axons of one receptor type end (17). The receptor releases the odorant again and returns to the unbound state. Similar to other natural proteins, odor receptors are composed of (S)-configured amino acids and are chiral molecules. Consequently, the binding pocket formed by a receptor protein is chiral and can discriminate two enantiomers (R) and (S) of a chiral odorant molecule. As the most potent ligand for a given receptor should be completely complementary to the binding pocket, the odor of a powerful chiral odorant is likely due to one enantiomer only, whereas its antipode is weak to odorless (Table 1, case A) (9). Far more common is that neither enantiomer is perfectly complementary to the receptor binding site, but that both enantiomers interact with the same receptor, yet with different affinities. In such a case, both enantiomers possess qualitatively similar main odors, but of quantitatively different intensities (Table 1, case B). If both enantiomers are not perfectly complementary to the binding site, and the stereogenic element is not differentiated by the receptors (i.e., the stereogenic element is situated outside the binding pocket), then both enantiomers are expected to emanate similar odors of similar, but not very high, intensity (Table 1, case C). The rarest case is when both enantiomers of an odorant are principally complementary to two different receptors and, as a consequence, possess completely different odor profiles (Table 1, case D). The Combinatorial Code of Olfaction Even in case D when two enantiomers possess seemingly different odor notes, it is likely that they interact with a few common receptors (18, 19). Generally, one odorant almost never activates only one receptor, but rather a set of odorant receptors, and to a different degree as well. The low substrate specificity of the odorant receptors allows for a maximum of differentiation. This is in contrast to receptors regulating biochemical processes where a specific response is essential. All axons of the ∼50,000 receptors of one type terminate in one corresponding glomerulus. With about 391 receptor types, humans have the same quantity of glomeruli in the olfactory bulb, the activation pattern of which is interpreted by the brain as an olfactory impression. Even if a glomerulus could only be on or off, and in reality many intermediate activation states are possible, this would already results in 2391 = 510117 potential combinations or odor impressions. So with training, we can distinguish almost every odorant or enantiomer. But the difference is sometimes too small to describe. Figure 2 schematically demonstrates the combinatorial code of olfaction for the case of the Celery Ketone enantiomers; the (S)-isomer smells like licorice, whereas the (R)-antipode has an odor reminiscent of celery leaves (Table 1, case D) and is stronger (i.e., possesses a lower threshold value). The large outer circle symbolizes a cut through a layer of glomeruli in the olfactory bulb. The information content of each glomerulus is indicated by a letter, which makes up the word of the respective overall odor impression. Though different E glumeruli are used in the

r 2010 American Chemical Society and Division of Chemical Education, Inc.

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Figure 2. Schematic model of the combinatorial code of olfaction. In the olfactory bulb, represented as the large outer circle, every receptor type is represented by a glomerulus, depicted as a smaller circle bearing a letter. Each molecule, including the enantiomers of Celery Ketone (2), activates an array of receptors, that is read by the brain as the respective odor. For details see the text.

example in Figure 2 to spell out LICORICE and CELERY, the L, R, and C glomeruli used are the same for both. Likewise, even in the case of enantiomers with completely different odors, a few common receptors may still be addressed. This may even be necessary for a well-defined odor impression. It must be emphasized that generally a set of odorant receptors is involved, although for simplification we often treat this receptor set as if it was only one receptor. Even untrained humans can distinguish many enantiomers just by their smell, and this direct way of chiral recognition is impressive, especially in the classroom. The senses of olfaction and taste are called the chemical senses, but owing to their discriminative power, they may well be called stereochemical senses. In the next section, a few selected cases are detailed, which, in our opinion, are most instructive (Figure 3 and Table 2). Selected Examples of Chiral Odorants Carvone The enantiomers of carvone (1, Figure 3) are the most prominent and impressive case for the enantioselectivity of odor sensation. In the past, (R)-(-)- and (S)-(þ)-carvone have been isolated by fractional distillation of spearmint and caraway oil, respectively (20, 21). Because both enantiomers are closely reminiscent of the respective natural oil they were isolated from, it remained possible that this similarity was due to trace impurities from the essential oils. By an elegant chemical interconversion of the (R)- to the (S)-enantiomer of 1 and vice versa, Friedman and Miller (22) demonstrated that the (R)-(-)-enantiomer smells of spearmint and (S)-(þ)-carvone smells of caraway (Table 2). Today, both enantiomers of 1 are prepared industrially from nonracemic natural (R)- or (S)-limonene (23). Because the carvone enantiomers are easily available, they are used in laboratory experiments to demonstrate the application of analytical methods to chiral compounds (24-26). In perfumery, the

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C) is believed to lie in the spherical shape of the molecule and its rigid structure (29). Possibly, neither enantiomer perfectly fills out the binding pocket(s), so that the receptor(s) cannot discriminate them. Thus, both seem to fit the receptor(s) equally poorly; the rather high odor threshold of ca. 50 ng/L for both enantiomers would support this assumption. Both enantiomers of 3 smell characteristically camphoraceous, that is, warm-minty, medicinal, and somewhat ethereal. Whereas both enantiomers and the racemate occur in nature, (1R,4R)(þ)-camphor is far more abundant and, for instance, the main component of the essential oil of the wood of the camphor tree Cinnamomum camphora L. (indigenous to Japan and China), after which it was named (27b). (1R,4R)-(þ)-Camphor can be isolated by distillation from camphor oil, but because the olfactory properties do not justify the production of enantiopure material, a more economic process is employed; that is, the synthesis from R-pinene of turpentine oils, via camphene and isobornyl acetate. This industrial synthesis makes camphor available for below $10/kg, a price that makes it attractive for applications in functional perfumery, that is, the perfumery of soaps and detergents. Here the medicinal aspects in the odor of camphor are even desirable to emphasize its hygienic properties. Figure 3. The seven sample odorants selected. For simplicity, only one enantiomer is depicted for each example, in the case of methyl jasmonate one enantiomer of each diastereomer.

stronger (R)-(-)-carvone (threshold 0.88 ng/L air) with its natural spearmint odor is utilized, especially to perfume dentalcare cosmetics, whereas the weaker caraway-like (S)-(þ)carvone serves as flavor material for foods and beverages. Celery Ketone In some respect Celery Ketone (2, Figure 3) is structurally similar to the naturally occurring carvone, a monoterpene (27a). However, Celery Ketone does not consist of isoprene units and therefore is not a terpene. It does not occur in nature and is neither close in odor to spearmint nor to caraway. The name is a Givaudan trademark coined for the commercial racemic material from its characteristic celery odor. Only recently (28) it was found that Celery Ketone, like carvone, is another rare case for completely different odor profiles of enantiomers. The odor of the racemate 2 is determined by the stronger (R)-enantiomer (threshold 9.1 ng/L air), which is reminiscent of celery leaves. The antipode (S)-Celery Ketone (threshold 45 ng/L air) is 5 times weaker in odor and reminiscent of licorice, anise, and fennel (Table 2). Both enantiomers have recently become available via an organocatalytic enantioselective intramolecular aldolization from the same starting material, 4-propylheptane-2,6-dione (28). Racemic Celery Ketone serves in perfumery as a modifier of basil and tarragon top notes and as a nuanceur to provide more naturalness to jasmine complexes. Camphor Owing to steric constraints, only two of the theoretically four stereoisomers of the monoterpenoid camphor (3, Figure 3) with two stereocenters exist: (1R,4R)-(þ)-camphor and its antipode (1S,4S)-(-)-camphor. These cannot be distinguished by their odors (29). The reason for this rare case (Table 1, case 600


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Florhydral Florhydral (4, Figure 3) is a prominent representative of the family of modern synthetic lily of-the-valley odorants that shaped today's perfumery. Other members of this odorant family include cyclamen aldehyde [2-methyl-3-(4-prop-2-ylphenyl)propanal], Lilial [3-(4-tert-butylphenyl)-2-methylpropanal], and silvial {2-methyl-3-[4-(2-methylpropyl)phenyl]propanal}. These latter perfumery materials are more closely reminiscent of lily of the valley and cyclamen, whereas Florhydral, as the name indicates, is floral and fresh aquatic in rather general terms. While the other aldehydes bear an R-methyl substituent that is prone to racemization by enolization, the methyl group of Florhydral is situated in β-position and cannot racemize via the aldehyde enol form. It was thus important to see whether an enantioselective approach would be interesting from the olfactory point of view. For this purpose, (S)-(þ)-Florhydral (4, Figure 3) and its (R)-(-)-configured antipode were prepared by an enzymemediated synthesis (30). The (S)-(þ)-4 enantiomer is about 25 times more potent (odor threshold 0.035 ng/L air) than the (R)-(-)-4 enantiomer (threshold 0.88 ng/L air, Table 2), but overall, the odor characters were similar. Both (S)-(þ)- and (R)-(-)-4 smell floral, aquatic, somewhat reminiscent of lily of the valley (5, 6, 30); a typical example of case B (Table 1), which is most common for enantiomeric odorants. At 25 times the intensity of the antipode, the odor of the racemate is completely determined by the (S)-(þ)-4 enantiomer. Impressive as this difference is, it does not necessarily justify an industrial enantioselective approach. Even if one enantiomer has a strong odor and the other is completely odorless (case A, Table 1), the active enantiomer would be diluted in half only by the inactive enantiomer in the racemic mixture, so an enantioselective approach can cost only about 2 times the expense of the synthesis of the racemate. In this case, (S)-(þ)-4 would exceed twice the price of racemic Florhydral by far, as the latter is accessible on a short and elegant industrial route by hydroformylation of the symmetric starting material 1,3-bis(1-methylethenyl)benzene and subsequent hydrogenation (31).


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In the Classroom Table 2. Sensory Properties of the Seven Chiral Sample Odorants Enantiomer Character Rel. Intensity Threshold

Odorant Carvone (1)

Celery Ketone (2)

Camphor (3)

Florhydral (4)

Antipode Character Rel. Intensity Threshold

(R)-(-)

(S)-(þ)

spearmint

caraway

stronger

weaker

0.88 ng/L air

7.6 ng/L air

(R)

(S)

celery leaves

licorice

stronger

weaker

9.1 ng/L air

45 ng/L air

(1R,4R)-(þ)

(1S,4S)-(-)

camphor

camphor

similar

similar

ca. 50 ng/L air

ca. 50 ng/L air

(S)-(þ)

(R)-(-)

floral, aquatic

floral, aquatic

stronger

weaker

0.035 ng/L air

0.88 ng/L air

3-Methyl-

(S)

(R)

3-sulfanyl-

onion

grapefruit

hexan-1-ol (5) Muscone (6)

intense

intense

ca. 0.001 ng/L air

ca. 0.001 ng/L air

(R)-(-)

(S)-(þ)

musky

musky

stronger

weaker

0.43 ng/L air

9.5 ng/L air

Methyl

(1R,2S)-cis

(1S,2R)-cis

jasmonate (7)

jasmine

odorless

Case (Table1)

Occurrence in Nature

Application in Perfumery and Flavorings

D

(R), (S), (RS)

(R), (S)

D

-

(RS)

C

(þ), (-), (()

(()

B

-

(RS)

D

(S)/(R)

-

ca. 3:1

B

(R)

(RS), (R)

A

(1R,2S)

(1RS,2RS)/ (1RS,2SR)

stronger

ca. 95:5

0.012 ng/L air (1R,2R)-trans

(1S,2S)-trans

jasmine

odorless

A

(1R,2R)

(1RS,2RS)/ (1RS,2SR)

weaker

ca. 95:5

0.24 ng/L air

3-Methyl-3-sulfanylhexan-1-ol As incredible as this may seem, fresh human sweat is completely odorless. Only by action of skin bacteria, predominantly the two genera Staphylococcus and Corynebacteria, malodorants are formed. An important malodorant of these bacteria is 3-methyl-3-sulfanylhexan-1-ol (5) that occurs in minute quantities as a ∼3:1 [(S)/(R)] enantiomeric mixture (32-35) and contributes to the pungent, lingering, repulsive malodor of sweat. The enantiomers of 5 differ considerably in odor character (case D, Table 1). Whereas the main (S)-configured thiol (S)-5 (Figure 3) emanates an aggressive onion-like sweaty note, its antipode (R)-5 possesses a sulfury, grapefruit-like odor (Table 2) (33, 34). Both enantiomers of 5 were prepared with considerable expenditure by two different routes (32, 33). Their odor intensities are extremely high with an odor threshold of ca.


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0.001 ng/L air for each (35). At these low concentrations, the determination of reliable data becomes difficult, but it seems that the minor (R)-configured thiol (R)-5 is slightly more potent than its antipode (S)-5. However, as this is determined only tentatively, a threshold value of ca. 0.001 ng/L air was given in Table 2 for both. As thiol 5 and related malodorants are released upon the reaction of specific enzymes with the odorless axilla secretion, several possibilities for new, highly efficient deodorants come within reach (36). Muscone Musk is the dried secretion from an internal pouch found between the hind legs of the Himalayan musk deer (37). As ca. 30-50 animals had to be killed to produce 1 kg of musk grains, the musk deer became an endangered species and could only be protected from extinction by international trading conventions


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and national laws. Since 1979, natural musk tinctures are not allowed for use in perfumery. Though the odor of natural musk tinctures is extremely complex, its warm, sensual, sweet-powdery dry-down was most valued by perfumers, and this is mainly due to (R)-(-)-muscone (6, Figure 3), which occurs in musk grains at ∼0.5-2%. Considering the highly flexible macrocyclic ring of muscone (6) that can adopt several conformations, especially with respect to the methyl group, it is perhaps not surprising that the odor discrimination of the enantiomers is not high and that both (R)-(-)- and (S)-(þ)-muscone smell musky, albeit the musk character of the natural (R)-(-)-enantiomer is somewhat more pronounced (38). Rather surprising is, however, that the difference in intensity is close to that of the Florhydral enantiomers. With an odor threshold of 0.43 ng/L air, the natural (R)-(-)-muscone enantiomer is about 22 times more intense than its (S)-(þ)-antipode (threshold 9.5 ng/L air) (38), a classical representative of case B (Table 1). Although the racemic (RS)-(()-muscone is still widely used, different from the case of Florhydral (4), an industrially feasible route via enantioselective hydrogenation of 3-methyl-2-cyclopentadecen-1-one (39) made (R)-(-)-muscone recently available at competitive cost. Time will tell if (R)-6 will gain market share against the racemic material 6 and other macrocyclic musks, among which the racemic (Z)-5-muscenone (38) is perhaps the most fierce competitor of (R)-(-)-muscone. Methyl Jasmonate Next to carvone, methyl jasmonate (7, Figure 3) is perhaps the second most prominent example for chiral odor recognition (9) that was originally reported by Acree, Nishida, and Fukami (40). Though present at about only 0.8% in jasmine absolute (Jasminium grandiflorum L.), methyl jasmonate is essential for its delicate and typical jasmine odor. Its occurrence is, however, not limited to jasmine absolute; methyl jasmonate occurs in many species in nature (41). As expected for two chiral centers, 7 forms four stereoisomers [all natural methyl jasmonate stereoisomers have double bonds with (20 Z)-stereochemistry]; the (1R,2S)-cis and the (1R,2R)-trans configured diastereoisomers are shown in Figure 3. Both of the (1R)-diastereomers emanate a typical floral, jasminic, slightly fruity scent, whereas both (1S)-configured enantiomers are odorless (Table 2) (40, 9). So with respect to the enantiomers two rare cases A (Table 1) are stated, which would indicate the (1R)-species to be almost perfectly complementary to the jasmine receptor(s). Interestingly, however, the diastereoisomers (1R,2S)-cis-7 (odor threshold 0.012 ng/L air) and (1R,2R)-trans-7 (threshold 0.24 ng/L air) are in a case B relationship to one another, with the (1R,2S)-cis-7 being 20 times more intense than its (1R,2R)-trans-7 diastereoisomer. So in this case, the diastereomers are in closer olfactory proximity than the enantiomers. All four stereoisomers of 7 were isolated from the commercial mixture by column-chromatographic separation of the diastereoisomes, esterification of the corresponding acid chlorides with (-)-borneol, preparative HPLC of the resulting bornyl jasmonates, subsequent saponification, and reaction with diazomethane (40). Commercially available is only the mixture of all stereoisomers with a thermodynamic trans/ cis-ratio of 95:5 [(1RS,2RS)/(1RS,2SR)-7]. The industrial synthesis of this mixture consists of aldol condensation of 3-oxocyclopentyl acetate with formaldehyde, and subsequent 1,4-addition of lithium di-(1Z)-but-1-en-1-yl cuprate (23). The resulting 602


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Figure 4. Prominent examples for odorants manufactured industrially via enantioselective synthetic routes and used in perfumery. In the case of (R)-9 and (-)-11 nonracemic starting materials from nature, that is, (-)-Rpinene and (-)-sclareol, respectively, are employed.

perfumery material 7 is used mainly in fine fragrances to provide naturalness and richness to floral compositions. Far more widely employed in perfumery than methyl jasmonate (7) is its dihydro derivative, which is known as Hedione, and is available at considerably lower cost. Hedione is more transparent than 7, and its jasmine character is besides reminiscent of magnolia and citrus fruits. For the analogous four stereoisomers of Hedione, olfactory activities similar to methyl jasmonate are observed, and in this case, the (1R,2S)-cis-8, known as Paradisone (8, Figure 4), is produced in an enantioselective approach (4). Some Practical Aspects of Chirality and Odor Whether a material is produced industrially via an enantioselective route depends on the price-performance ratio in comparison with the racemic material. Most often, in cases A-C in Table 1, the weaker enantiomer only reduces the intensity by a maximum factor of 2. The price of the enantiopure material has to reflect this. For example, for Hedione, the (1R,2S)-cis-8 (Paradisone, Figure 4) is produced enantioselectively in industry; however, for the related methyl jasmonate (7), this is uneconomical. In the sandalwood domain (10), many odorants such as Sandalmysore Core (9, Figure 4) derive from R-campholenic aldehyde. As (R)-(þ)-R-campholenic aldehyde is available from natural (-)-R-pinene in high enantiomeric purity, an enantioselective approach to the most potent stereoisomer can be established at almost no extra cost. Other examples for nonracemic substances industrially produced in the flavor and fragrance industry are (10 R,3S,60 S)-(þ)-Dextro Norlimbanol [(10 R,3S,60 S)10, Figure 4] and (-)-ambrox [(-)-11, Figure 4], the latter manufactured from natural (-)-sclareol (5, 42); (R)-muscone was already mentioned above and is another example. Summary The sense of smell offers a direct entry to the molecular world, and the enantioselectivity of odor sensation teaches that this world is chiral. It can be assumed that the presented examples turn out to be more attractive for students than compounds of mere academic interest. The chiral odorant molecules in Figure 3 are thus proposed as examples for use in either a dedicated course on stereochemistry or within the context of a natural products or bioorganic chemistry course. Depending on the time frame


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In the Classroom

available, these can be accompanied by brief information on the odorant-receptor interaction and the code of olfaction. As an industrial outlook, the substances in Figure 4 can lead the way into the discussion of asymmetric synthesis versus synthesis from the pool of available chiral starting materials. In addition, the structures of the odorants presented are rather simple, easy to memorize, and because both carvone enantiomers are available from the major chemicals suppliers one can even open up this topic with an impressive smelling session. Literature Cited 1. Vollhardt, K. P. C.; Shore, N. E. Organic Chemistry: Structure and Functions, 4th ed.; Freeman: New York, 2003; pp 163-182. 2. Bruice, P. Y. Organic Chemistry, 5th ed.; Person: London, 2007; pp 202-229. 3. Eliel, E. L.; Wilen, S. H.; Doyle, M. P. Basic Organic Stereochemistry; Wiley-Interscience: New York, 2001; (a) pp 4, 108, 142-143; (b) pp 136-137. 4. Kraft, P.; Bajgrowicz, J. A.; Denis, C.; Frater, G. Angew. Chem,. Int. Ed. 2000, 39, 2980–3010. 5. Brenna, E.; Fuganti, C.; Serra, S. Tetrahedron: Asymmetry 2003, 14, 1–42. 6. Abate, A.; Brenna, E.; Fuganti, C.; Gatti, F. G.; Serra, S. Chem. Biodiversity 2004, 1, 1888–1898. 7. Sell, C. S. Chem. Biodiversity 2004, 1, 1899–1920. 8. Bentley, R. Chem. Rev. 2006, 106, 4099–4112. 9. Kraft, P.; Frater, G. Chirality 2001, 13, 388–394. 10. Bajgrowicz, J. A.; Frater, G. Enantiomer 2000, 5, 225–234. 11. Leffingwell, J. C. Chimica Oggi 2006, 24 (4, Suppl.), 36–38. 12. Mannschreck, A.; Kiesswetter, R.; von Angerer, E. J. Chem. Educ. 2007, 84, 2012–2018. 13. Koenig, W. A.; Hochmuth, D. H. J. Chromatogr. Sci. 2004, 42, 423–439. 14. Koenig, W. A.; Chirality in the Natural World—Odours and Tastes. In Chirality in Natural and Applied Science; Lough, W. J., Wainer, I. W., Eds.; Blackwell: Oxford, 2002; pp 261-284. 15. Getz, W. M.; Lansky, P. Chem. Senses 2001, 26, 95–104. 16. Murthy, P. S. J. Chem. Educ. 2006, 83, 1010–1013. 17. Hatt, H. Chem. Biodiversity 2004, 1, 1857–1869. 18. Malnic, B.; Hirono, J.; Sato, T.; Buck, L. B. Cell 1999, 96, 713–723. 19. Wolfe, J. M.; Kluender, K. R.; Levi, D. M.; Bartoshuk, L. M.; Herz, R. S.; Klatzky, R. L.; Lederman, S. J. Sensation and Perception; Sinauer Associates: Sunderland, MA, 2006.


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The Enantioselectivity of Odor Sensation: Some ... - ACS Publications

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