Musk Odorants Research Articles

Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (R)‐Muscone and (R,Z)‐5‐Muscenone

Enantioselective Intramolecular Aldol Addition/Dehydration Reaction of a Macrocyclic Diketone: Synthesis of the Musk Odorants (<i>R</i>)‐Muscone and (<i>R</i>,<i>Z</i>)‐5‐Muscenone

Preparation and characterization of inclusion complexes containing fixolide, a synthetic musk fragrance and cyclodextrins

AHTN (7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene), commercially known as fixolide or tonalide, is a synthetic fragrance widely used in replace of natural musk odor which is more expensive. It is a popular fragrance material added in the manufacturing of personal care and household products, such as perfumes, soaps, shampoos, detergents, and fabric softeners. AHTN is semivolatile and is degraded under light exposure and high temperature. This work focuses on the complexation of AHTN with cyclodextrins in the effort to stabilize the fragrance material. AHTN was complexed with β-cyclodextrin, methyl (MβCD), and hydroxypropyl (HPβCD) derivatives in the mole ratio 1:1, 1:2, and 1:3 guest:host, and the complexes formed by physical mixing, co-precipitation, kneading, and freeze-drying were analyzed by DSC and FTIR. Percent AHTN included in the complex was also determined by hexane extraction and GC analysis. It was found that no inclusion complex was formed in the physical mixture. When co-precipitation method was performed, only βCD could form inclusion complex with AHTN, while the other two derivatives could not. Using 1:2 AHTN:βCD, no free AHTN was left in the complex as evidenced by DSC and FTIR spectrum. In kneading and freeze-drying methods, complexes could be formed with all CDs tested. However, co-precipitation method with 1:2 AHTN:βCD and kneading method with 1:2 AHTN:MβCD provided the highest complex yield with highest amount of AHTN included in the complex. AHTN in the complex form was more stable against high temperature and UV exposure than its free form.

Silicon Analogues of the Musk Odorant Versalide

Twofold sila-substitution (C/Si exchange) of the musk odorant Versalide (1a) provides Disila-versalide (1b). The silicon compound 1b and its derivatives 2b (Et/Me exchange) and 3b (Et/H exchange) were synthesized by starting from 1,2-bis(ethynyldimethylsilyl)ethane. The silicon compounds 1b−3b and their carbon analogues 1a−3a were studied for their olfactory properties and their biodegradability.

An alternative stereoselective synthesis of the macrocyclic fragrances ( R)-12-methyltridecanolide and ( S)-muscolide by means of an asymmetric catalytic conjugate addition/Baeyer–Villiger oxidation

We show herein an alternative catalytic, highly enantioselective approach to ( R)-12-methyltridecanolide and ( S)-muscolide, that is, chiral macrocyclic lactones which are good musk odorants. In fact, they can be efficiently prepared by a sequence of reactions consisting of a catalytic asymmetric conjugated addition of dimethylzinc to suitable α,β-unsaturated enones followed by a Baeyer–Villiger oxidation. Interestingly, high enantiomeric excesses (up to 92%) are obtained in the asymmetric conjugate addition by means of the ‘tropos’ phosphoramidite L1.

Synthetic Musk Compounds: Luckenbach Responds

In his letter on our recent article in EHP (Luckenbach and Epel 2005), Salvito raises important questions about effects of the synthetic musk fragrances regarding a) human and environmental health effects, b) environmental concentrations of the musks, and c) uniqueness of inhibition of efflux transporters to the musks, the effect we described in our article. a) Regarding health issues, we agree with Salvito that the available evidence indicates minimal direct affects of most synthetic musks on the health of humans and aquatic organisms. However, our data expand the definition of toxicity and detrimental effects to indirect and unanticipated consequences of these chemicals, even if the chemical itself might be nontoxic. The major point of our article (Luckenbach and Epel 2005) was that the musks inhibit efflux (drug) transporters, which act as first lines of defense to pump potentially toxic substances out of cells. These efflux transporters are ubiquitous and are found in bacteria, fungi, plants, and animals, including humans. The transporters have wide substrate specificity, and this binding to many compounds can result in inhibition of activity by competing substrates. As a consequence of transporter inhibition, cells and organisms can therefore become exposed to toxicants normally kept out of their cells. An unexpected finding was not only that the musks inhibit these transporters in marine mussels but that the effect is long-term and persists up to 24–48 hr after removal of the musk compounds. These indirect and long-term toxicity effects are of particular concern because these chemicals are stable and bioaccumulate; for example, musk xylene has a half-life of 70 days in human tissue (Riedel and Dekant 1999). Effects on human transporters by the musks cannot be inferred from our results, but they do point to the possibility of an interaction, considering the general property of the transporters to recognize a wide array of substrates. Therefore—and in light of accumulation of the musks in human tissue—research is needed to determine if the musks similarly inhibit the human efflux transporters, thereby compromising this defense against toxicants. b) The musks are of environmental concern because they enter the water column from incomplete degradation in sewage plants. We agree with Salvito that the reported levels in surface waters are extremely low (picomolar range) but disagree with his conclusion that such levels indicate that musks are not a problem. In spite of these low environmental levels, there is significant bioaccumulation of these chemicals in tissues of mussels and fish, and just several months ago Nakata (2005) reported significant bioaccumulation in cetaceans. The concentrations in aquatic organisms can become quite high, being on the order of nanograms per gram fresh weight, which translates to about 0.1 μM final concentration in tissue (Nakata 2005; Rimkus 1999; Yamagishi et al. 1983). According to Salvito, worldwide production of synthetic musks are only about one-half of the amount we cite. These lower numbers are even more worrisome because because this means that the potency of the musks to bioaccumulate is even higher. c) Salvito points out that the inhibition of transporters is not unique to the musks. We agree and note that the observed inhibition of efflux transporter activity by the musks may be the tip of the iceberg. As with the musks, there may be many chemicals that by themselves are not toxic but similarly inhibit the efflux transporters and thereby expose the organism to normally excluded toxicants. In summary, the available data suggest that efflux transporter inhibition could be a significant indirect, negative, and unappreciated effect of environmental chemicals. Several questions need to be answered: Do these chemicals inhibit human transporters? Are there other anthropogenic and natural products that inhibit these transporters in aquatic organisms and also in humans? Should anthropogenic chemicals be screened for inhibitory activity? If so, should there be voluntary or governmental regulations to ensure that such chemicals do not affect the health of exposed populations through these indirect actions?

‘Brain Aided’ Musk Design

This brief review, including new experimental results, is the summary of a talk at the RSC/SCI conference flavours & fragrances 2004 in Manchester, United Kingdom, 12-14 May, 2004. Musk odorants have been a classical domain for computer aided structure-odor relationship (SOR) studies, but, contrary to sandalwood or amber odorants, they belong to structurally very different substance classes, e.g., macrocycles, aromatic polycycles, and nitro arenes. Most SOR computer models are restricted to one class, excluding structural diversity to increase predictability. But even within a musk family, structural similarities are often due to a common synthetic access, and do not reflect binding requirements for the musk receptor. Beyond that, the importance of structural key features can be missed, which is discussed on the example of the (4S)-Me group of Galaxolide. By synthesis and olfactory evaluation of Galaxolide-like shaped macrobicycles as model compounds for conformationally constrained (12R)-12-methyltridecano-13-lactone, it was investigated how likely there is more than one musk receptor. Finally, the new family of so-called linear musks is discussed, especially with respect to the conformational importance of the gem-2',2'-dimethyl moiety in Helvetolide and the additional 2'-carbonyl group of Romandolide--structural features that strongly diminish the musk odor of macrocycles. On the example of 2-methyl-2-[(E)-1,2,4-trimethylpent-2-enyloxy]propyl esters, the 'brain-aided' design and conformational analysis of musk odorants is illustrated. The overview concludes with the synthesis, odor evaluation, and conformational discussion of the new musk odorant 2-(3,3-dimethylcyclohexyl)propanoic acid ethoxycarbonylmethyl ester.

New Alicyclic Musks: The Fourth Generation of Musk Odorants

Musk odorants are one of the most important classes of fragrances in perfumery because they impart sensuality to perfume-oil compositions. Among the three well-known classes of musks, a new and very exciting generation of musk odorants, the so-called alicyclic musks, was discovered recently, of which Helvetolide (2) and Romandolide (3) are the most popular representatives so far. To find new, structurally related alicyclic musks, we have synthesized a library of 114 unique alicyclic molecules with modified cyclohexyl moieties. The olfactory properties of all compounds were evaluated to identify the structural requirements to be met for a musk odorant.

Synthesis of Macrocyclic Carbonates with Musk Odor by Ring‐Closing Olefin Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diradical‐Promoted Two‐Carbon Ring‐Expansion Reactions by Thermal Isomerization: Synthesis of Functionalized Macrocyclic Ketones

AbstractA new method for the smooth and highly efficient preparation of functionalized macrocyclic ketones has been developed. Pyrolysis of medium‐ and large‐ring 3‐vinylcycloalkanones by dynamic gas‐phase thermo‐isomerization (DGPTI) at 600–630° yielded, under insertion of a previously attached vinyl side chain by means of a 1,3‐C shift, the corresponding γ,δ‐unsaturated cycloalkanones. The yield of the two‐carbon ring‐expanded ketones greatly depended on the relative ring strains of substrate and product (5–87%, cf. Table 5). The formation of minor amounts of one‐carbon ring‐expanded cycloalkenes (&lt;10%) can be ascribed to a subsequent decarbonylation step. A reaction mechanism involving initial cleavage of the weakest single bond in the molecule has been established (cf. Scheme 6). Recombination within the generated diradical intermediate in terminal vinylogous position led to the observed products, while reclosure gave recovered starting material. Substituents on the vinyl moiety were transferred locospecifically into the ring‐expanded products. An isopropenyl group did not significantly affect the isomerization process, whereas substrates bearing a prop‐1‐enyl group in β‐position enabled competing intramolecular H‐abstraction reactions, leading to acyclic dienones (cf. Schemes 9–11). DGPTI of the 13‐membered analogue directly yielded 4‐muscenone, which, upon hydrogenation, led to the valuable musk odorant (±)‐muscone. Increasing the steric hindrance on the vinyl moiety gave rise to diminishing amounts of the desired γ,δ‐unsaturated cycloalkanones. This novel two‐carbon ring‐expansion protocol was also successfully applied to 3‐ethynylcycloalkanones, giving rise to the corresponding ring‐expanded cyclic allenes (cf. Scheme 13).

Synthesis of Macrocyclic Carbonates with Musk Odor by Ring‐Closing Olefin Metathesis

AbstractThis study shows the efficiency of modern well‐defined ruthenium catalysts for the formation of musk‐odored macrocyclic carbonates with ring sizes between 15−23 atoms. It also reveals that, in these cases, geometric factors are very important and that smaller ring carbonates are difficult to access by ring closing metathesis, even with highly active second‐generation ruthenium catalysts. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

An Efficient Enantioselective Synthesis of (+)‐(R,Z)‐5‐Muscenone and (−)‐(R)‐Muscone − An Example of a Kinetic Resolution and Enantioconvergent Transformation

AbstractAn efficient catalytic kinetic resolution by CBS reduction and an original enantioconvergent transformation involving a PdII‐catalyzed position‐selective cyclization are the key steps for the synthesis of the exceptional musk odorant (R,Z)‐5muscenone [(R)‐1] and (R)‐muscone [(R)‐3]. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

Olfactory study on optically active citronellyl derivatives

AbstractOdour threshold concentrations, determined in agueous‐ethanol solution, and odour qualities are reported for 18 enantiomeric and diastereomeric pairs of citronellyl derivatives [13 linear monoterpene compounds and five monocyclic α‐damascone and α‐ionone‐related compounds (trans‐2,2,6‐trimethylcyclohexyl derivatives)] (98%ee). Fairly large differences in both odour strength and odour qualities were found between the monocyclic diastereomeric pairs. In four of the five cyclic compounds, the (1R, 6S)‐form was found to be stronger and more sensorily active than the antipode. On the other hand, the linear enantiomeric pairs showed only small differences in both odour strength (half of them showed the same threshold values) and odour character. However, all the (3S)‐forms showed milder, cleaner and a much preferable top note than the (3R)‐forms except for citronellyl nitrile and the diester (citronellyl ethyl oxalate), whose (3R)‐form showed a characteristic floral musk odour, although the (3S)‐form showed a rose floral odour. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Synthesis and Odor of Aliphatic Musks: Discovery of a New Class of Odorants

AbstractTo find new aliphatic musks, we synthesized the propionates of 2‐[1′‐(3′′,3′′‐dimethylcyclohex‐1′′‐enyl)ethoxy]‐2‐methylpropanol (8), of 2‐[1′‐(5′′,5′′‐dimethylcyclohex‐1′′‐enyl)ethoxy]‐2‐methylpropanol (11), of hydroxyacetic acid 1‐(3′,3′‐dimethylcyclohex‐1′‐enyl)ethyl ester (12), and of hydroxyacetic acid 1‐(5′,5′‐dimethylcyclohex‐1′‐enyl)ethyl ester (13) starting from 1‐(3′,3′‐dimethylcyclohex‐1′‐enyl)ethanone (5) and 1‐ethynyl‐3,3‐dimethylcyclohexanol (9). We found that the 3,3‐dimethylcyclohexenyl derivatives 8 (odor threshold 0.2 ng/air) and 12 (odor threshold 0.6 ng/air) are superior musk odorants, and, thus, we constructed 1,2,4‐trimethylpent‐2‐enyloxy analogues as seco versions. The synthesis of the esters 17−26 commenced with a Wittig−Horner− Emmons reaction of isobutyric aldehyde (14), followed by saponification, alkylation with methyllithium, LAH reduction, etherification with isobutylene oxide, and Steglich esterification. (2′′E)‐2′‐Methyl‐2′‐(1′′,2′′,4′′‐trimethylpent‐2′′‐enyloxy)propyl cyclopropanecarboxylate [(2′′E)‐19], which has a powerful and sweet musk odor and slightly fruity nuances, was found to be a typical representative of this new class of musk odorants, was subjected to conformational analysis. In addition, we report the synthesis and olfactory properties of the related ketones 28−30, the 2‐methyl‐2‐(1′,4′,4′‐trimethylpent‐2′‐enyloxy)propyl esters 31−33, and the 2‐(1′,4′‐dimethylpent‐2′‐enyloxy)‐2‐methylpropyl esters 35 and 36. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)

Synthesis of Macrocyclic Ketones by Repeatable Two-Carbon Ring Expansion Reactions

A novel and short method for the synthesis of macrocyclic alkanones has been developed: medium- and large-ring 1-vinylcycloalkanols can be transformed directly and efficiently into the isomeric, ring-expanded bishomologous macrocyclic ketones by a thermal 1,3-C shift rearrangement reaction in the gas phase, carried out under dynamic conditions in a flow reactor system at high temperatures. This two-carbon ring enlargement protocol involves only two steps and is easily repeatable, since the obtained cyclic ketones can directly be used as starting materials for the subsequent analogous two-carbon ring insertion reactions. Alkyl substituents at the vinylic side chain are transferred to the ring-expanded ketone as corresponding ?- and ?-substituents, respectively. Therefore, this thermo-isomerization process provides not only a short route to cycloalkanones but also to many alkyl-substituted macrocyclic ketones, such as, e.g. the musk odorant (±)-muscone. A reaction mechanism via alkyl hydroxyallyl biradical intermediates is proposed.

1,4-Dioxamacrolides: Preparation and Sensory Properties

The synthesis of 3-methyl-1,4-dioxacylopentadecan-2-one (12c) and 3-methyl-1,4-dioxacylohexadecan-2-one (12d), two new musk odorants, is described starting from methyl 2-bromopropionic acid (6b) and allylic alcohol, respectively. The key step of the synthesis is the ring-closing olefin metathesis (RCM) to the unsaturated 1,4-dioxamacrolides. Insight into the structure-odor relationship (SOR) is provided by the synthesis of ten related unsubstituted or methyl substituted oxamacrolides. Finally, a four step enantioselective synthesis of both (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclopentadecan-2-one as well as (3R)-(+)- and (3S)-(-)-3-methyl-1,4-dioxacyclohexadecan-2-one reveals that mainly the (3R)-(+) enantiomers are responsible for the powerful musky odor characteristic. Their synthesis starts from ethyl (2S)-2-hydroxypropanoate (14) or isobutyl (2R)-2-hydroxypropanoate (15) which were treated under acidic conditions with allyl trichloroacetimidate (16), followed by titanate mediated transesterification, ring-closing olefin metathesis and hydrogenation.

Asymmetric catalysis in fragrance chemistry: a new synthesis of Galaxolide®

A new synthesis of the olfactorally active stereoisomers of the musk odorant Galaxolide® is reported. The key step is the ruthenium-catalysed asymmetric hydrogenation of an α-aryl acrylic acid: asymmetric inductions up to 89% have been achieved using a catalytic system prepared in situ by mixing [Ru(benzene)Cl 2] 2 with ( S)-BINAP.

Transformation of Carotol into the Hydroindane-Derived Musk Odorant

Ozonolysis of carotol (1) gives dihydroxy ketone 2 (63% yield), the absolute configuration of which was established by X-ray crystallography. An acidic dehydration of 2 delivers a mixture of isomeric ketones 3 and 4 (3:1) that, catalysed by Pd/C in cyclohexene, yields a 1:1 thermodynamic mixture of 3 and 6. Ketone 6 exhibits an intensive musk odour. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of (-)-Vulcanolide by enantioselective protonation.

Two efficient enantioselective syntheses of the more active (S,S)-enantiomer of the powerful musk odorant Vulcanolide are described. In both syntheses, the key step is an enantioselective protonation of a ketone enolate. A third enantioselective protonation, of a thiol ester enolate, was applied for the determination of the absolute configuration of Vulcanolide by comparison with a known compound.

Syntheses of the Enantiomers ofVulcanolide®

The synthesis of the enantiomers of Vulcanolide ® ((±)-7) is described, the strongest musk odorant among hundreds of structurally related analogues, by resolution of an intermediate. To this end, we devised a new route which involves the temporary introduction of a modulable functional group in the vicinity of the stereogenic centers (Scheme 2). The resolution is based on the chromatographic separation of two diastereoisomeric camphanic acid esters. The strong and characteristic note of racemic Vulcanolide ® is almost entirely due to the (−)-enantiomer. This synthesis has allowed the preparation of new, structurally related musk odorants.

A Novel, Short and Repeatable Two-Carbon Ring Expansion Reaction by Thermo-Isomerization: Easy Synthesis of Macrocyclic Ketones

A novel two-carbon ring enlargement procedure, in which medium- and large-ring 1-vinylcycloalkanols are thermoisomerized in a flow reactor system at temperatures of 600 °C to about 650 °C, produces the isomeric ring-expanded cycloalkanones directly and efficiently. This two-step ring expansion protocol can easily be applied several times successively. For e.g., the musk odorant cyclopentadecanone (Exaltone ® ) is prepared from cycloundecanone in two repetitive cycles. Thermo-isomerization of the corresponding ethynylic cycloalkanols gives in moderate yields the bishomologous α,β-unsaturated macrocyclic (E)-2-cycloalkenones. A reaction mechanism via alkyl hydroxyallyl biradical intermediates is proposed.