DOI: 10.1002/ejoc.201501338 Full Paper

Fragrances

Synthesis and Olfactory Properties of Silicon-ContainingAnalogs of Rosamusk, Romandolide, and Applelide: Insightsinto the Structural Parameters of Linear Alicyclic MusksJunhui Liu,*[a] Yue Zou,[b] Wu Fan,[a] Jian Mao,[a] Guobi Chai,[a] Peng Li,[a] Zhan Qu,[a]

Yongli Zong,[a] Jianxun Zhang,*[a] and Philip Kraft*[c]

Abstract: A series of silicon-containing derivatives of linear ali-cyclic musks comprising sila-Rosamusk (3b), sila-Romandolide(5b), sila-Applelide (11b), and the corresponding dehydro deriv-atives was synthesized from sila-analogs of Artemone and Her-bac, respectively, by means of sodium borohydride reductionand subsequent esterification with the corresponding acidchlorides in the presence of triethylamine. The olfactory proper-ties of the new sila-odorants 3b–13b are reported in compari-

Introduction

Musk odorants are indispensable classic perfumery ingredientsthat impart volume, diffusivity, and sensuality to a fragrance.[1]

Five main classes of musk odorants are known at present: nitromusks, polycyclic aromatic musks (PCM), macrocyclic musks, lin-ear musks, and dienone musks. The last of these has, however,not yet found its way to the market. Due to the phototoxicityof nitro musks, and the limited biodegradability of polycyclicmusks in standard tests, the most interesting musk families to-day are those of macrocyclic and linear musks. The commer-cially important linear musks, the so-called fourth generation ofmusks, include Rosamusk (3a), Helvetolide, Romandolide (5a),Serenolide, Applelide (11a), and Sylkolide (Figure 1). Their muskodors have been rationalized with a conformational space richin horseshoe-shaped molecules that could thus mimic macro-cyclic musks in binding to the respective odorant receptors.[1,2]

This hypothesis was substantiated by a common olfactophoremodel of macrocyclic and linear musks that gave a correlation

[a] Key Laboratory of Tobacco Flavor Basic Research, Zhengzhou TobaccoResearch Institute of CNTC,No. 2 Fengyang Street High-Tech Zone, Zhengzhou 450001, ChinaE-mail: ljhpku@outlook.com

jxzh258@sina.com[b] Givaudan Fragrances (Shanghai) Ltd,

298 Li Shi Zhen Road, Shanghai 201203, China[c] Givaudan Schweiz AG,Fragrance Research,

Überlandstrasse 138, 8600 Dübendorf, SwitzerlandE-mail: philip.kraft@givaudan.comhttps://www.givaudan.comSupporting information and ORCID(s) from the author(s) for this articleare available on the WWW under http://dx.doi.org/10.1002/ejoc.201501338.

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son with their carba-analogs 3a–13a, and quantitativethreshold data allowed the generation of an improved muskolfactophore model featuring a correlation of 80.5 % with anull-cost distance of 244. This olfactophore model shows thatit is likely that linear and macrocyclic musks address the sameodorant receptors, and it should facilitate the design of newmusks.

of 54 %.[2a] In this paper, we report the synthesis of sila-analogsof Rosamusk (3a), Romandolide (5a), and Applelide (11a), anduse their olfactory properties for the generation of an improved

Figure 1. The building blocks Cyclademol (1a) and its Δ2′′-analog 2a, as wellas the most important linear alicyclic musk odorants derived from 1a, andSylkolide, which can be seen as a seco derivative of Δ2′′-Cyclademol (2a).

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olfactophore model that makes it even more plausible thatthese two families of musk odorants address the same olfactoryreceptors.

Rosamusk (3a) is prepared by the reaction of 3,7-dimethyl-octa-1,6-diene with acetic acid using sulfuric acid as catalyst.[1a]

It displays an unusual combination of floral rosy-geranium char-acter with musky, fruity pear, and violet aspects.[3] It was re-cently used as a nuanceur by Nicolas Beaulieu in “Aromatics inWhite” (Clinique, 2014), but it is commercially less important.[1]

Helvetolide (odor threshold, th = 1.1 ng/L air, activ = 3.87 pM),discovered in 1990 by Giersch and Schulte-Elte,[4a] was the firstcommercially successful member of the family of linear musks.It has a modern musk note with a fruity, pear aspect situatedolfactorily in between Ambrettolide and ethylene brassylate.[4b]

In combination with Habanolide [(12E)-oxacyclohexadec-12-en-2-one], it has become eponymous for white musk accords sincethe time it was used at 8.8 % in “Emporio White Her” (Armani,2001) by Alberto Morillas. Romandolide[4c] (5a; th = 0.4 ng/L air,activ = 1.48 pM) was discovered by Alvin Williams by substitut-ing the gem-dimethyl moiety of Helvetolide with a carbonylgroup to create a more easily synthesizable molecule. It has afruity musk odor of agrestic tonality, and is somewhat less fruitythan Helvetolide. Romandolide (5a) was recently featured byDaphne Bugey and Fabrice Pellegrin in “Valentina Pink” (Valen-tion, 2015), in which it was set against a fruity strawberry–black-berry accord. Applelide (11a; th = 1.5 ng/L air) is even easier tosynthesize, and has a powdery fruity musk odor with a distinctfruity green apple note, which somewhat restricts its use. Incertain contexts, however, this green apple note of Applelide(11a) brings a desirable signature, as for instance in the spicyoriental “Spicebomb Extreme” (Viktor & Rolf, 2015), where itgoes well with the cinnamic tones on top. Sylkolide[4d] is sofar the only commercial linear musk that does not derive fromCyclademol (1a), but rather can be seen as a seco derivative ofits Δ2′′-analog 2a. It has a radiant musk note with red fruitsaspects that, due to the volatility of the compound, unveils al-ready from the top notes. And yet Sylkolide also enhanceswoody facets, as was recently nicely demonstrated by AurelienGuichard with a hinoki wood accord in “Ever Bloom” (Shiseido,2015).

Silicon is the second most abundant element, and the mostsimilar to carbon. The Si–C bond is, however, about 20 % longerthan the analogous C–C bond, which significantly increases themolecular volume upon sila-substitution. This makes sila-ana-logs interesting test probes for olfactophore and pharmaco-phore models. Upon sila-substitution, the molecular weight in-creases by 16 atomic mass units, and together with the polari-zation of the Si–C bond, this leads to a decreased vapor pres-sure, and an increased substantivity of sila-odorants in func-tional applications.[5–10]

Although a variety of methods have been developed to pre-pare open-chain organosilanes, the incorporation of silicon at-oms into ring systems remains relatively unexplored.[9,10] Withthe aim of improving the olfactophore model of musk odorantsby structure–odor correlations and threshold data, we report inthis paper the synthesis and olfactory properties of new silicon-containing linear alicyclic musks.

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Results and DiscussionSix-membered silacyclic compounds have recently been synthe-sized for the probe and imaging applications.[11,12] The ring-expansion of four-membered silacycles with activated alkynesmediated by transition-metal catalysts is an efficient approachto these systems,[13] and has been used to synthesize the sila-analogs of Artemone and Herbac in good yields (Scheme 1).[13h]

These two compounds are the oxidation products of Cycla-demol (1a) and its Δ2′′-analog 2a. Cyclademol (1a) has a cam-phoraceous, borneol- and terpineol-type odor without muchinterest for perfumery. Its main importance is as building blockfor the synthesis of linear musks. The sila-analogs of Cyclademol(1a)[1a] and its dehydro derivative 2a (Figure 1) should be acces-sible by simple hydride reduction of sila-Artemone and sila-Herbac. This would then give access to sila-Rosamusk (3b), sila-Romandolide (5b), and sila-Applelide (11b), and also to theircorresponding dehydro derivatives (Figure 2).

Scheme 1. Ring-expansion reactions to give sila-Artemone and sila-Her-bac.[13h]

Figure 2. Odor descriptions, detection thresholds in ng L–1 air, activity in pM

air, and calculated activity in pM air of the sila-analog of Rosamusk (3a), Ro-mandolide (5a), and Applelide (11a) according to the generated olfactophoremodel in Figure 3. For the threshold data and the measured and calculatedactivities of the other musk odorants in the data set, see the SupportingInformation.

As shown in Scheme 2, treatment of sila-Herbac with an ex-cess of NaBH4 at room temperature in MeOH gave, after a reac-tion time of 1 h, sila-Cyclademol (1b) in 95 % isolated yield. Thecorresponding dehydro derivative (i.e., 2b) was also preparedin 98 % isolated yield by the same procedure (Scheme 2).

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Scheme 2. Preparation of sila-Rosamusk (3b) and its dehydro derivative 4bfrom sila-Herbac and sila-Artemone by carbonyl reduction and esterification.

With 1b and 2b in hand, our first synthetic targets were thesila-analog of Rosamusk (3a) and its dehydro derivative (i.e.,3b), by acylation. As shown in Scheme 2, sila-Rosamusk (3b)was prepared in 85 % isolated yield by the reaction of 1b withacetyl chloride in the presence of an excess of Et3N. The reac-tion of 2b with acetyl chloride also proceeded smoothly to give4b in excellent yield. Surprisingly, the dominant odor charactersof 3b and 4b were woody and herbal, with no musk, floral, orrosy tonalities being present.

Next, we tackled the synthesis of linear silacyclic musks 5b–10b. Sila-Romandolide (5b) was prepared as shown inScheme 3. Acylation of hydroxyacetic acid with propionyl chlo-ride gave 2-(propionyloxy)acetic acid (14) (R = Et). Without puri-fication, this compound was then transformed into 2-chloro-2-oxoethyl propionate (15) (R = Et) by treatment with SOCl2 atreflux. Subsequent reaction of 15 with 1b in the presence ofEt3N then gave sila-Romandolide (5b) in 74 % isolated yieldafter flash chromatography. Compounds 6b–10b were also syn-thesized in high yields following the same procedure(Scheme 3).

Scheme 3. Preparation of linear silacyclic musks 5b–10b.

All attempts to synthesize the sila-analogs of Helvetolide andSerenolide were unsuccessful due to the decomposition of 1band 2b in the presence of the required Lewis acids, such asBF3, AlCl3, and MeAlCl2.[2b] However, sila-Applelide (11b) and itsdehydro derivative 12b were easily prepared in good yields bythe condensation of 1b and 2b, respectively, with 3-ethoxy-3-oxopropanoic acid in the presence of N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (EDC) and DMAP (4-dimethylaminopyridine) (Scheme 4).

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Scheme 4. Preparation of sila-Applelide (11b), its 2′′-dehydro derivative 12b,and 2′,2′-gem-dimethyl analog 13b.

Generally, the presence of a dimethyl carbinol moiety on theCyclademol (1a) building block destabilizes horseshoe-shapedconformations, and for silacyclic musk 13b, the first nonhorse-shoe conformation appears already at 0.4 kcal mol–1 above theglobal energy minimum; and yet its conformational space isstill largely in a horseshoe shape. The Grignard reaction of sila-Artemone with methylmagnesium bromide provided the corre-sponding dimethyl carbinol (i.e., 16) in 86 % yield. This was thensubjected to esterification with 2-chloro-2-oxoethyl propionateto give target structure 13b in 57 % yield. Due to steric hin-drance in the esterification, the reaction of the homologousdialkyl carbinol failed completely, however (Scheme 4).

Structure–Odor Correlation and a Refined MuskOlfactophore Model

The odor descriptions, odor thresholds, and activity values ofthe sila-analogs of Rosamusk (3a), Romandolide (5a), andApplelide (11a) are compiled in Figure 2. In comparison withRomandolide (5a, th = 0.4 ng/L air, activ = 1.48 pM), sila-Romandolide (5b, th = 2.21 ng/L air, activ = 7.71 pM) is noticea-bly weaker, especially on blotter, where the lower vapor pres-sure comes into full effect. The odor character of 5b is also lessmusky and more woody, although the fruity aspects of Roman-dolide (5b) are clearly discernible. In the corresponding cyclo-propanoate (i.e., 7b), the musk character is clearly more promi-nent, so as a result it is closer to Romandolide (5a). The odorthresholds of 5b and 7b were, however, both determined to be2.21 ng L–1 air. Interestingly, Δ2′′-unsaturated sila-Romandolide(6b) is, with an odor threshold of 4.41 ng L–1 air, twice as weakas 5b and 7b, while its cyclopropanoate 8b is, with an odorthreshold of 0.28 ng L–1 air, eight times as strong as sila-Romandolide (5b) or its cyclopropanoate 7b. Thus, 2-[1′-(1′′,1′′-dimethyl-1′′,4′′,5′′,6′′-tetrahydrosilin-3′′-yl)ethoxy]-2-oxoethylcyclopropanoate (8b) is the most potent odorant of the series

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investigated, and it is also the most musky, with a pleasantpowdery tonality and some green side aspects.

Not surprisingly, saturated 9b and unsaturated 10b cyclo-pentanoates are both much weaker than 8b, especially the sat-urated compound (i.e., 9b), for which we measured an odorthreshold of 12.5 ng L–1 air. Due to its high molecular weight ofMr = 326.51, 9b appears even weaker on blotter, and it is mainlywoody and fruity in smell, with only a slight hint of musk. Theunsaturated analog (i.e., 10b), however, is a genuine musk odor-ant, with the typical fruity aspects of linear musks, and a distinctanimalic facet. With an odor threshold of 1.13 ng L–1 air and amolecular weight of Mr = 324.49 (C17H28O4Si), it is on a par withthe cyclopentanoate of Helvetolide (C20H36O3, Mr = 324.50),which is the highest molecular weight odorant known todate.[1a,1c] With an odor threshold of 17.7 ng L–1 air, the sila-analog of Applelide (11a) is the weakest odorant of the series,and has a mainly fruity, woody odor, though a musk inflectionis clearly perceivable. This musk character becomes more pro-nounced in Δ2′′-unsaturated derivative 12b, which is, with anodor threshold value of 3.13 ng L–1 air, over five times strongerthan the parent saturated compound (i.e., 11b). The introduc-tion of a second 2′-methyl group into 6b to give 2′,2′-gem-dimethyl-substituted analog 13b has no influence on the odorthreshold, but it does shift the odor more towards a woody andwaxy side. And yet Δ2′′-2′-methyl-sila-Romandolide 13b still hasto be considered a musk odorant, with an odor threshold of3.13 ng L–1 air.

It does appear at first sight that the Δ2′′ double bond has asignificant influence on the musk character, and though it ispositioned in same relative spatial geometry as the Δ3′′ doublebond in Sylkolide (Figure 1), the significant difference in theodor threshold between 8b (th = 0.28 ng L–1 air) and 6b (th =4.41 ng L–1 air) clearly indicates that this is due to conforma-tional rather than electronic effects. Thus, we were very inter-ested in using the quantitative threshold data in Figure 2 forthe refinement of our musk olfactophore model.[2a] Combiningthese data with the published threshold values of linear andmacrocyclic musks,[2a] the olfactophore model shown in Fig-ure 3 was generated using the Discovery Studio 4.1 softwarepackage[14] with a conformational space of 10 kcal mol–1. Whilethe odor thresholds were used as such in ng L–1 air for theprevious model,[2a] this time the activity (activ) was specified inpicomoles per liter of air (pM). In this way, the molecular weightis taken into consideration, and so the number of moleculesinteracting on the receptor level is reflected.

As detailed in the Supporting Information, the olfactophoremodel consists of two hydrogen-bond acceptors (HBA) at a dis-tance of 6.96 Å from one another; this explains why CPD ketone(1-oxacyclohexadecane-2,13-dione, ketodecanolide) also bindsand smells musky. Two aliphatic hydrophobes are situated at adistance of 7.51 Å from one another, and one of these is rightin front of one of the hydrogen-bond acceptors at a distanceof only 0.91 Å. As one of the features can be omitted in thedocking to the refined musk olfactophore, both a polar hydro-gen-bond acceptor and an aliphatic hydrophobe bind equallywell in that region. For Serenolide (gold, Figure 3), the gem-dimethyl group on the cyclohexyl ring binds in this aliphatic

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Figure 3. The refined musk olfactophore model with Romandolide (5a; black,activ = 1.48 pM, calcd. 2.95 pM), sila-Romandolide (5b; silver, activ = 7.71 pM,calcd. 5.29), and Serenolide (gold activ = 0.714 pM, calcd. 4.99 pM) bound toit. Due to the lack of threshold data for compounds with absolute configura-tion, the model contains no stereoinformation, and arbitrary enantiomers ofthe compounds are depicted. The reported threshold values represent theracemates, so medians of the individual enantiomers.

hydrophobe in front of the HBA; yet, for Romandolide (5a;black) it is the propionate tail. For sila-Romandolide (5b; silver),it is also the nonpolar propionate tail that docks to this aliphatichydrophobe. For sila-Romandolide (5b), the second aliphatichydrophobe is addressed by the 1,1-dimethylsilinanyl ring,while in the case of Romandolide (5a), the methyl group of theethoxy moiety is bound. This accounts for the lower calculatedactivity of 2.95 pM for 5a (activ = 1.48 pM) in comparison withsila-Romandolide (5b; calcd. 5.29 pM, activ = 7.71 pM). Thus, themodel differentiates the activities of the parent compound andits sila-analog quite well. However, Serenolide is, at 0.714 pM,

almost twice as potent as Romandolide, yet its calculated activ-ity is, at 4.99 pM, around 70 % less than the calculated activityfor Romandolide (5a; 2.95 pM). In line with the significant differ-ence in threshold between 8b and 6b, and the opposite varia-tion of intensities for 6b compared with 5b, vs. 8b in compari-son with 7b, the model features no additional double-bond-specific electronic binding site(s), and attempts to explain theseeffects by conformational preferences alone. Yet, as can be seenfrom the comparison between measured and calculated activi-ties in Figure 2, this constitutes an oversimplification that is notfully supported by the experimental data.

Still the correlation improved from 54 % for the previousmodel[2a] to 80.5 % for the refined model, and since the linearmusks are arranged alongside the perimeter of a macrocyclicring (Figure 3), with a convincing null-cost distance of 244, itmakes it even more likely that linear alicyclic and macrocyclicmusks address the same odorant receptor(s).

To account for the different activities of the linear musk in-vestigated and macrocyclic musks of the training set (see Sup-porting Information), four excluded volumes were placed bythe Discovery Studio 4.1 software. These form an irregular tetra-hedron with edges of 10.21, 8.79, 7.92, 7.85, 7.72, and 4.35 Å

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that slices through the plane defined by the imaginary macro-cyclic perimeter in Figure 3.

Interestingly, the cyclopropyl analog (i.e., 7b) of sila-Roman-dolide (5b) binds to the refined musk olfactophore model withthe opposite orientation compared to both Romandolide (5a)and sila-Romandolide (5b), with the gem-dimethyl group in thealiphatic hydrophobe in front of the HBA. This explains itssomewhat better activity, but while the tendency is correct, thecalculated value of 2.92 pM is far better than the 5.29 pM for5b, and both are lower than the experimental values of 7.40and 7.71 pM, respectively. The dimethyl tetrahydrosiline ring of6b binds less well and in a different conformation compared tothe isolated aliphatic hydrophobe, and this explains the calcu-lated and observed lessening of its activity on the musk recep-tor(s). In 8b, with the cyclopropyl moiety being bound to thealiphatic hydrophobe in front of the HBA, the fit of the dimethyltetrahydrosiline unit into the other aliphatic hydrophobe is,however, quite good. This explains the better calculated activityof 3.24 pM (Figure 2), which is, however, not as good as theexperimental value of 0.93 pM. In 9b and 10b, the binding ofthe cyclopentyl ring to the hydrophobe in front of the HBAdisplaces the fit of the sila-substituted six-membered ring tothe other aliphatic hydrophobe. But in this case it also becomesclear that the double bond of 10b must have some additionalinfluence not predicted by the refined olfactophore model.

Similarly to cyclopropanoate 7b, sila-Applelide (11b) bindsin the opposite orientation, with the 1,1-dimethylsilinanyl sub-stituent outside both of the hydrophobes, and this is also truefor its Δ2′′-unsaturated counterpart 12b. Instead, in both casesthe methyl group in the position α to the ring is bound to thehydrophobe in front of the HBA, leading to overly low predic-tions for their activity of 4.06 and 4.21 pM, respectively, andlittle differentiation due to the double bond. Finally, 2′,2′-gem-dimethyl-substituted analog 13b is again bound to the im-proved musk olfactophore in the conventional way, with a verygood prediction of its activity (9.64 pM) compared to the meas-ured value (10.5 pM).

ConclusionsThe refined musk olfactophore model is certainly not the lastword on the subject, but it still represents a major advancementthat should inspire further work in the areas of linear and mac-rocyclic musks. Sila-substitution has proved to be an interestingway to gain additional insight and refine the quantitative struc-ture–odor correlations to improve olfactophore models.

Experimental SectionGeneral Remarks: Sila-Artemone and sila-Herbac were preparedaccording to the published procedure.[13h] Unless otherwise stated,all other chemicals were commercially available, and were usedwithout further purification. Column chromatography was carriedout with silica gel (100–200 mesh, J & K Scientific). 1H (300 or400 MHz) and 13C (75.5 or 100 MHz) NMR spectra were recordedusing CDCl3 or [D6]DMSO as the solvent. Chemical shifts (ppm) werecalibrated using internal CHCl3/CDCl3 (1H, δ = 7.26 ppm; 13C, δ =77.00 ppm), internal [D5]/[D6]DMSO (1H, δ = 2.50 ppm; 13C, δ =

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39.50 ppm), or external tetramethylsilane (29Si, δ = 0.00 ppm). HRMSwas carried out with a VG-ZAB-HS instrument. The sensory proper-ties of all odorants were determined by six expert perfumers usingsolutions of the respective compounds (10 % in ethanol) applied tothe smelling blotters. The odor thresholds were determined by GC-olfactometry: different dilutions of the sample substances were in-jected into a gas chromatograph in descending order until threepanelists evaluating in blind, failed to detect the odor impressionat the correct retention time.

Carbonyl Reduction of Sila-Herbac and Sila-Artemone: NaBH4

(152 mg, 4.0 mmol) was added to a solution of sila-Herbac or sila-Artemone (4.0 mmol) in MeOH (5 mL) at 0 °C. The mixture waswarmed to room temp., and stirred for 1 h. The reaction was thenquenched with water (10 mL), and the mixture was extracted withEtOAc (3 × 20 mL). The combined organic phase was washed withbrine, and dried with Na2SO4. The solvent was removed under re-duced pressure, and the resulting residue was purified by flash col-umn chromatography (petroleum ether/EtOAc, 10:1) to give the de-sired compound (i.e., 1b/2b).

1b: Colorless oil (653 mg, 95 %). 1H NMR (CDCl3): δ = 0.010 (s, 3 H),0.033 (s, 3 H), 0.17–0.28 (m, 1 H), 0.34–0.44 (m, 1 H), 0.64–0.75 (m,2 H), 0.84–0.98 (m, 1 H), 1.12 (d, J = 8.0 Hz, 3 H), 1.35–1.50 (m, 2 H),1.60 (br., 1 H), 1.67–1.85 (m, 1 H), 1.98–2.06 (m, 1 H), 3.50–3.60 (m,1 H) ppm. 13C NMR (CDCl3): δ = –4.11, –4.10, –1.56, 13.85, 15.03,15.33, 19.32, 19.35, 23.62, 23.66, 31.68, 31.70, 43.28, 43.42, 73.62,73.76 ppm. HRMS: calcd. for C9H20OSi [M]+ 172.1283; found172.1287. C9H20OSi (172.34): calcd. C 62.72, H 11.70; found C 62.70,H 11.74.

2b: Colorless oil (666 mg, 98 %). 1H NMR ([D6]DMSO): δ = 0.016 (s,3 H), 0.021 (s, 3 H), 0.60 (t, J = 8.0 Hz, 2 H), 1.08 (d, J = 8.0 Hz, 3 H),1.64–1.76 (m, 2 H), 1.89–1.99 (m, 1 H), 2.01–2.11 (m, 1 H), 3.87–3.96(m, 1 H), 4.70 (d, J = 8.0 Hz, 1 H), 5.57 (s, 1 H) ppm. 13C NMR([D6]DMSO): δ = –1.36, 11.76, 21.34, 22.38, 29.25, 71.73, 115.93,164.43 ppm. HRMS: calcd. for C9H18OSi [M]+ 170.1127; found170.1130. C9H18OSi (170.32): calcd. C 63.47, H 10.65; found C 63.45,H 10.69.

Acetylation of 1b/2b: A solution of acetyl chloride (3.0 mmol) inCH2Cl2 (2 mL) was added to a solution of 1b/2b (3.0 mmol) inCH2Cl2 (10 mL) and Et3N (1 mL). The reaction mixture was stirredat 20 °C for 18 h, and then the solvent was removed under reducedpressure. CH2Cl2 (30 mL) and water (30 mL) were added to theresulting residue. The organic layer was separated, washed withbrine (10 mL), and dried with Na2SO4. The solvent was removed invacuo. The resulting residue was further purified by silica gel col-umn chromatography (petroleum ether/EtOAc, 10:1) to give the de-sired compound (i.e., 3b/4b).

3b: Colorless oil (546 mg, 85 %). 1H NMR (CDCl3): δ = 0.01 (s, 3 H),0.04 (s, 3 H), 0.20–0.29 (m, 1 H), 0.34–0.44 (m, 1 H), 0.65–0.75 (m, 2H), 0.79–0.97 (m, 1 H), 1.13–1.16 (m, 3 H), 1.30–1.44 (m, 1 H), 1.56–1.66 (m, 1 H), 1.67–1.77 (m, 1 H), 1.95–2.05 (m, 4 H), 4.64–4.75 (m,1 H) ppm. 13C NMR (CDCl3): δ = –4.11, –1.58, –1.55, 9.29, 9.30, 13.82,15.75, 15.81, 16.00, 23.50, 23.54, 28.01, 31.42, 40.97, 41.00, 75.94,75.97, 174.16, 174.18 ppm. HRMS: calcd. for C11H22O2Si [M]+

214.1389; found 214.1386.

4b: Colorless oil (522 mg, 82 %). 1H NMR (CDCl3): δ = 0.03 (s, 3 H),0.04 (s, 3 H), 0.60–0.65 (m, 2 H), 1.28 (d, J = 8.0 Hz, 3 H), 1.73–1.81(m, 2 H), 2.01–2.06 (m, 5 H), 5.15 (q, J = 6.7 Hz, 1 H), 5.60 (s, 1 H)ppm. 13C NMR (CDCl3): δ = –1.73, –1.70, 11.74, 19.28, 21.33, 21.51,30.02, 75.25, 120.05, 158.22, 170.23 ppm. HRMS: calcd. forC11H20O2Si [M]+ 212.1233; found 212.1232.

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Typical Procedure for the Synthesis of Linear Silacyclic Musks5b–10b: A mixture of propionyl chloride (2.10 g, 22.7 mmol) andhydroxyacetic acid (610 mg, 8.0 mmol) was heated at 40 °C until thehydroxyacetic acid was completely dissolved. The excess propionylchloride was then distilled off to give crude compound 14 as acolorless oil, which was used immediately without purification.

A mixture of 14 (310 mg, 2.3 mmol) and SOCl2 (3 mL) was heatedunder reflux for 3 h. The excess SOCl2 was then removed undervacuum to give 15 as a pale yellow oil.

Compound 15 was dissolved in CH2Cl2 (2 mL), and the solution wasadded to a solution of 1b/2b (2.0 mmol) in CH2Cl2 (10 mL) andEt3N (1 mL). The mixture was stirred at 20 °C for 18 h. After thistime, the solvent was removed under reduced pressure, and CH2Cl2(30 mL) and water (30 mL) were added to the resulting residue. Theorganic layer was separated, washed with brine (10 mL), and driedwith Na2SO4. The solvent was removed in vacuo. The resulting resi-due was purified by silica gel column chromatography (petroleumether/EtOAc, 10:1) to give the desired compound (i.e., 5b–10b).

5b: Colorless oil (423 mg, 74 %). 1H NMR (CDCl3): δ = 0.01–0.04 (m,6 H), 0.21–0.29 (m, 1 H), 0.34–0.43 (m, 1 H), 0.65–0.72 (m, 2 H), 0.79–0.97 (m, 1 H), 1.17–1.21 (m, 6 H), 1.31–1.43 (m, 1 H), 1.60–1.74 (m,2 H), 1.96–2.06 (m, 1 H), 2.44 (q, J = 8.0 Hz, 2 H), 4.59 (s, 1 H), 4.60(s, 1 H), 4.75–4.85 (m, 1 H) ppm. 13C NMR (CDCl3): δ = –4.17, –4.15,–1.63, –1.61, 8.96, 13.67, 13.73, 15.65, 15.83, 16.25, 23.41, 23.43,27.16, 31.29, 31.62, 40.83, 40.89, 60.82, 77.71, 77.75, 167.59, 167.64,173.76 ppm. HRMS: calcd. for C14H26O4Si [M]+ 286.1600; found286.1604.

6b: Colorless oil (471 mg, 83 %). 1H NMR (CD3OD): δ = 0.04 (s, 3 H),0.05 (s, 3 H), 0.63–0.69 (m, 2 H), 1.15 (t, J = 8.0 Hz, 2 H), 1.31 (d, J =6.4 Hz, 3 H), 1.75–1.86 (m, 2 H), 2.05–2.11 (m, 2 H), 2.43 (q, J =8.0 Hz, 2 H), 4.63 (s, 2 H), 5.18 (q, J = 6.7 Hz, 2 H), 5.64 (s, 1 H) ppm.13C NMR (CDCl3): δ = –1.81, –1.78, 8.95, 11.66, 19.14, 21.45, 27.14,29.82, 60.76, 76.61, 121.07, 157.30, 167.15, 173.71 ppm. HRMS: calcd.for C14H24O4Si [M]+ 284.1444; found 284.1440.

7b: Colorless oil (470 mg, 79 %). 1H NMR (CDCl3): δ = 0.01 (s, 3 H),0.03 (s, 3 H), 0.19–0.31 (m, 1 H), 0.32–0.45 (m, 1 H), 0.63–0.75 (m, 2H), 0.88–0.99 (m, 3 H), 1.04–1.11 (m, 2 H), 1.14–1.20 (m, 3 H), 1.31–1.40 (m, 1 H), 1.60–1.78 (m 3 H), 1.94–2.06 (m, 1 H), 4.590 (s, 1 H),4.599 (s, 1 H), 4.73–4.86 (m, 1 H) ppm. 13C NMR (CDCl3): δ = –4.16,–4.14, –1.62, –1.60, 8.82, 12.59, 13.68, 13.74, 15.60, 15.65, 15.82,16.26, 23.42, 23.44, 31.30, 31.59, 40.82, 40.88, 60.91, 77.70, 77.74,167.62, 167.66, 174.20 ppm. HRMS: calcd. for C15H26O4Si [M]+

298.1600; found 298.1597.

8b: Colorless oil (515 mg, 87 %). 1H NMR (CDCl3): δ = 0.04 (s, 3 H),0.05 (s, 3 H), 0.60–0.66 (m, 2 H), 0.90–0.96 (m, 2 H), 1.05–1.10 (m, 2H), 1.32 (d, J = 8.0 Hz, 3 H), 1.70–1.82 (m 3 H), 2.01–2.07 (m 2 H),4.616 (s, 1 H), 4.621 (s, 1 H), 5.23 (q, J = 6.7 Hz, 1 H), 5.62 (s, 1 H)ppm. 13C NMR (CDCl3): δ = –1.82, –1.80, 8.78, 11.63, 12.55, 19.12,21.42, 29.78, 60.80, 76.56, 121.01, 157.29, 167.12, 174.11 ppm.HRMS: calcd. for C15H24O4Si [M]+ 296.1444; found 296.1442.

9b: Colorless oil (528 mg, 81 %). 1H NMR (CDCl3): δ = 0.00–0.04 (m,6 H), 0.20–0.29 (m, 1 H), 0.34–0.44 (m, 1 H), 0.64–0.74 (m, 2 H), 0.78–0.96 (m, 1 H), 1.15–1.17 (m, 3 H), 1.20–1.40 (m, 1 H), 1.56–1.75 (m,6 H), 1.84–2.04 (m, 5 H), 2.79–2.87 (m, 1 H), 4.58 (s, 1 H), 4.59 (s, 1H), 4.75–4.85 (m, 1 H) ppm. 13C NMR (CDCl3): δ = –4.19, –4.17, –1.65,–1.64, 13.65, 13.71, 15.60, 15.66, 15.80, 16.25, 23.39, 23.40, 25.81,29.84, 29.85, 29.88, 29.90, 31.25, 31.63, 40.80, 40.86, 43.28, 43.31,60.73, 77.61, 77.67, 167.67, 167.71, 175.99 ppm. HRMS: calcd. forC17H30O4Si [M]+ 326.1913; found 326.1918.

10b: Colorless oil (544 mg, 84 %). 1H NMR (CDCl3): δ = 0.04 (s, 3 H),0.05 (s, 3 H), 0.61–0.65 (m, 2 H), 1.32 (d, J = 8.0 Hz, 3 H), 1.56–1.62

Eur. J. Org. Chem. 0000, 0–0 www.eurjoc.org © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim6

(m, 2 H), 1.70–1.82 (m, 4 H), 1.87–1.94 (m, 4 H), 2.01–2.06 (m, 2 H),2.80–2.90 (m, 1 H), 4.611 (s, 1 H), 4.615 (s, 1 H), 5.24 (q, J = 6.7 Hz,1 H), 5.62 (s, 1 H) ppm. 13C NMR (CDCl3): δ = –1.80, –1.78, 11.66,19.13, 21.45, 25.82, 29.85, 29.88, 29.90, 43.31, 60.71, 76.52, 121.06,157.28, 167.25, 176.01 ppm. HRMS: calcd. for C17H28O4Si [M]+

324.1757; found 324.1755.

Synthesis of 11b/12b: 3-Ethoxy-3-oxopropanoic acid (264 mg,2.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-chloride (EDC·HCl; 384 mg, 2.0 mmol), and DMAP (306 mg,2.5 mmol) were added to a solution of 1b/2b (2.0 mmol) in CH2Cl2(5 mL) at 0 °C. The reaction mixture was warmed to room temp.,and stirred for 1 h. Then the mixture was diluted with CH2Cl2(20 mL), and subsequently washed with water and brine. The or-ganic phase was dried over Na2SO4, and the solvent was removedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography (petroleum ether/EtOAc, 30:1) to give thedesired compound (i.e., 11b/12b, respectively).

11b: Colorless oil (331 mg, 58 %). 1H NMR (CDCl3): δ = 0.01–0.04(m, 6 H), 0.19–0.30 (m, 1 H), 0.32–0.45 (m, 1 H), 0.64–0.78 (m, 2 H),0.80–0.99 (m, 1 H), 1.15–1.21 (m, 3 H), 1.25–1.32 (m, 3 H), 1.32–1.46(m, 1 H), 1.60–1.80 (m, 2 H), 1.94–2.07 (m, 1 H), 3.33–3.37 (m, 2 H),4.14–4.26 (m, 2 H), 4.60 (s, 1 H), 4.70–4.83 (m, 1 H) ppm. 13C NMR(CDCl3): δ = –4.14, –1.59, 13.70, 13.77, 14.08, 15.67, 15.74, 15.82,16.29, 23.42, 23.47, 31.32, 31.62, 40.82, 40.88, 42.11, 61.41, 61.50,166.25, 166.75 ppm. HRMS: calcd. for C14H26O4Si [M]+ 286.1600;found 286.1601.

12b: Colorless oil (392 mg, 69 %). 1H NMR (CDCl3): δ = 0.02 (s, 3 H),0.03 (s, 3 H), 0.61 (t, J = 8.0 Hz, 2 H), 1.26 (t, J = 8.0 Hz, 3 H), 1.29(d, J = 8.0 Hz, 3 H), 1.70–1.82 (m, 2 H), 1.99–2.05 (m, 2 H), 3.35 (s, 2H), 4.14–4.22 (m, 2 H), 5.19 (q, J = 6.7 Hz, 1 H), 5.61 (s, 1 H) ppm.13C NMR (CDCl3): δ = –1.84, –1.81, 11.63, 14.01, 19.01, 21.42, 29.80,41.93, 61.35, 76.55, 120.79, 157.39, 165.68, 166.50 ppm. HRMS: calcd.for C14H24O4Si [M]+ 284.1444; found 284.1449.

Synthesis of 16 by Grignard Reaction: At –20 °C under a nitrogenatmosphere, MeMgBr (1.0 M in THF; 3 mL, 3.0 mmol) was added toa solution of sila-Artemone (504 mg, 3.0 mmol) in THF (10 mL). Themixture was stirred for 1 h, and then it was poured into satd. NH4Cl(30 mL) at –20 °C. At ambient temp., the reaction mixture was ex-tracted with diethyl ether (30 mL). The organic layer was separated,washed with water (30 mL) and brine (10 mL), and dried withNa2SO4. The solvent was removed under reduced pressure. The re-sulting residue was purified by flash column chromatography (pe-troleum ether/EtOAc, 1:1) to give the desired compound (i.e., 16).

16: Colorless oil (475 mg, 86 %). 1H NMR (CDCl3): δ = 0.05 (s, 6 H),0.61–0.64 (m, 2 H), 1.31 (s, 6 H), 1.50 (br., 1 H), 1.75–1.79 (m, 2 H),2.10–2.14 (m, 2 H), 5.69 (s, 1 H) ppm. 13C NMR (CDCl3): δ = –1.50,11.79, 22.34, 28.67, 29.72, 74.42, 115.80, 165.67 ppm. HRMS: calcd.for C10H20OSi [M]+ 184.1283; found 184.1279.

Synthesis of 13b: 2-Chloro-2-oxoethyl propionate was prepared ac-cording to the procedure used for the synthesis of 15. A solutionof 2-chloro-2-oxoethyl propionate (300 mg, 2.0 mmol) in CH2Cl2(2 mL) was added to a solution of 16 (2.0 mmol) in CH2Cl2 (10 mL)and Et3N (1 mL). The resulting mixture was stirred at 20 °C for 18 h.The solvent was then removed under reduced pressure, and CH2Cl2(30 mL) and water (30 mL) were added. The organic layer was sepa-rated, washed with brine (10 mL), and dried with Na2SO4. The sol-vent was removed under reduced pressure. The resulting residuewas purified by silica gel column chromatography (petroleumether/EtOAc, 10:1) to give the desired compound (i.e., 13b).

13b: Colorless oil (340 mg, 57 %). 1H NMR (CDCl3): δ = 0.04 (s, 6 H),0.60–0.64 (m, 2 H), 1.18 (t, J = 8.0 Hz, 3 H), 1.52 (s, 6 H), 1.72–1.79

Full Paper

(m, 2 H), 2.02–2.06 (m, 2 H), 2.44 (q, J = 8.0 Hz, 2 H), 4.53 (s, 2 H),5.58 (s, 1 H) ppm. 13C NMR (CDCl3): δ = –1.62, 8.94, 11.65, 22.17,26.25, 27.14, 28.78, 60.92, 86.01, 118.74, 160.95, 166.35, 173.69 ppm.HRMS: calcd. for C15H26O4Si [M]+ 298.1600; found 298.1598.

AcknowledgmentsThe authors thank Joos Kiener for help with the data acquisitionfor the generation of the refined musk olfactophore model, andDr. Lijun Zhou for the odor-threshold determination. The Na-tional Natural Science Foundation of China (NSFC) (grant num-bers 21102178 and 21402239) is acknowledged for funding.

Keywords: Fragrances · Silicon · Silanes · Molecularmodeling · Structure–activity relationships

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Received: October 19, 2015Published Online: ■

Full Paper

Fragrances Sila-Rosamusk, sila-Romandolide, sila-Applelide, and their dehydro derivati-J. Liu,* Y. Zou, W. Fan, J. Mao,ves were synthesized from sila-analogsG. Chai, P. Li, Z. Qu, Y. Zong,of Artemone and Herbac byJ. Zhang,* P. Kraft* ............................ 1–8hydride reduction and subsequent es-

Synthesis and Olfactory Properties terification. The olfactory properties ofof Silicon-Containing Analogs of these compounds allowed a refinedRosamusk, Romandolide, and Ap- musk olfactophore model to be deve-plelide: Insights into the Structural loped. The model shows that it is likelyParameters of Linear Alicyclic Musks that linear and macrocyclic musks ad-

dress the same odorant receptors.

DOI: 10.1002/ejoc.201501338

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Eur. J. Org. Chem. 2016 · ISSN 1099–0682

SUPPORTING INFORMATION

DOI: 10.1002/ejoc.201501338

Title: Synthesis and Olfactory Properties of Silicon-Containing Analogs of Rosamusk, Romandolide, and Applelide:

Insights into the Structural Parameters of Linear Alicyclic Musks

Author(s): Junhui Liu,* Yue Zou, Wu Fan, Jian Mao, Guobi Chai, Peng Li, Zhan Qu, Yongli Zong, Jianxun

Zhang,* Philip Kraft*

1

Table of Contents

1. Olfactophore Model 2

2. NMR Spectra of New Compounds 5

2

1. Olfactophore Model

Definition: HBA (hydrogen bond acceptor) – HBA – HYDROPHOBIC – HYDROPHOBIC – 4 EXCLUDED VOLUMES

Weights: 3.31204; 3.31204; 3.31204; 3.31204; 3.31204.

Spacing: 50. Variable Weight: No. Variable Tolerance: No. Olfactophore Space: 9215.84

Fixed Cost: 245.412. Null Cost: 644.308. Null Cost Distance: 243.55.

Geometric features:

Figure S1. Geometric features of the refined musk olfactophore model.

3

Figure S2. Graphical representation of the correlation of the model in logarithmic scale.

Figure S3. Odor thresholds and comparative calculation of activities for the musk odorants features the Supporting Information of

ref.[2a]

using the refined musk olfactophore model depicted in Figure 3.

4

Figure S3, contd. Odor thresholds and comparative calculation of activities for the musk odorants features the Supporting Information

of ref.[2a]

using the refined musk olfactophore model depicted in Figure 3.

5

2. NMR Spectra of New Compounds

1H NMR-1b

6

13C NMR-1b

7

1H NMR-2b

8

13C NMR-2b

9

1H NMR-3b

10

13C NMR-3b

11

1H NMR-4b

12

13C NMR-4b

13

1H NMR-5b

14

13C NMR-5b

15

1H NMR-6b

16

13C NMR-6b

17

1H NMR-7b

18

13C NMR-7b

19

1H NMR-8b

20

13C NMR-8b

21

1H NMR-9b

22

13C NMR-9b

23

1H NMR-10b

24

13C NMR-10b

25

1H NMR-11b

26

13C NMR-11b

27

1H NMR-12b

28

13C NMR-12b

29

1H NMR-13b

30

13C NMR-13b

31

1H NMR-16

32

13C NMR-16