Fluorinated Musk Fragrances: The CF2Group as a Conformational Bias Influencing the Odour of Civetone and (R)-Muscone

Article abstract of DOI:10.1002/chem.201600519

The difluoromethylene (CF₂) group has a strong tendency to adopt corner over edge locations in aliphatic macrocycles. In this study, the CF₂group has been introduced into musk relevant macrocyclic ketones. Nine civetone and five muscone analogues have been prepared by synthesis for structure and odour comparisons. X-ray studies indeed show that the CF₂groups influence ring structure and they give some insight into the preferred ring conformations, triggering a musk odour as determined in a professional perfumery environment. The historical conformational model of Bersuker and co-workers for musk fragrance generally holds, and structures that become distorted from this consensus, by the particular placement of the CF₂groups, lose their musk fragrance and become less pleasant.

Full text of DOI:10.1002/chem.201600519

DOI: 10.1002/chem.201600519
Full Paper
&
Organic Chemistry
Fluorinated Musk Fragrances: The CF2 Group as a Conformational
Bias Influencing the Odour of Civetone and (R)-Muscone
Ricardo Callejo+,[a] Michael J. Corr+,[a] Mingyan Yang,[a, b] Mingan Wang,[b] David B. Cordes,[a]
Alexandra M. Z. Slawin,[a] and David O’Hagan*[a]
Abstract: The difluoromethylene (CF2) group has a strong
tendency to adopt corner over edge locations in aliphatic
macrocycles. In this study, the CF2 group has been intro-
duced into musk relevant macrocyclic ketones. Nine cive-
tone and five muscone analogues have been prepared by
synthesis for structure and odour comparisons. X-ray studies
indeed show that the CF2 groups influence ring structure
and they give some insight into the preferred ring confor-
mations, triggering a musk odour as determined in a profes-
sional perfumery environment. The historical conformational
model of Bersuker and co-workers for musk fragrance gener-
ally holds, and structures that become distorted from this
consensus, by the particular placement of the CF2 groups,
lose their musk fragrance and become less pleasant.
Introduction
There has been a long interest in the molecular basis of per-
fumes and fragrances, and particularly, the relationship be-
tween molecular shape and the olfactory response.[1] Some of
the most iconic fragrances are the musk odorants, a large
family of natural and synthetic aliphatic macrocycles that have
been widely used for their olfactory and fixative properties.[2]
For instance, macrocyclic ketones (1 and 2) and lactones (3),
aromatic nitro derivatives (4) or fused bi- and poly(hetero)cy-
clic compounds (5) all produce a well-defined musk odour, de-
spite their structural diversity (Figure 1). This has complicated
a rational understanding of structure–odour relationships.[3] In
addition, it has been proposed that more than one musk re-
ceptor is involved in the recognition of these molecules.[4]
Natural macrocyclic musk odorants, such as 1–3, are
medium-sized ring lactones and ketones, which are highly ali-
phatic and display significant conformational freedom. At-
tempts to constrain such compounds have resulted in limited
success in deducing the optimal conformation for maximum
odour effect. For example, bridging bonds have been intro-
duced to achieve more rigid structures,[5] but this approach to
constrain conformational freedom has resulted in weaker fra-
Figure 1. Structures of diverse musk odorants. Macrocycles 1–3 are natural
products whereas 4 and 5 are synthetic.
grances and has failed to identify clear musk-related conforma-
tions.
The replacement of hydrogen for fluorine is a strategy used
for altering the properties of organic compounds, which has
been widely practiced in pharmaceuticals research.[6] We have
been exploring the role of the CF2 group[7] in influencing ali-
phatic macrocyclic ring conformations.[8] For example, X-ray
crystal structure analyses of cyclododecanes 6–8, which each
contain two CF2 groups at different locations around the 12-
membered ring, have shown that the CF2 groups only occupy
corner positions of these rings in the solid state (Figure 2). For
cyclododecanes 6 and 7, the CF2 groups stabilise a [3333][9]
square conformation, as the fluorine atoms are located at
either adjacent or opposite corners of the square. However, in
the case of cyclododecane 8, where the CF2 groups are posi-
tioned 1,6 to each other, this results in considerable distortion
of the ring. A square structure for 8 would force one of the
[a] Dr. R. Callejo,+ Dr. M. J. Corr,+ M. Yang, Dr. D. B. Cordes,
Prof. A. M. Z. Slawin, Prof. D. O’Hagan
School of Chemistry, University of St. Andrews
North Haugh, St. Andrews KY16 9ST (UK)
E-mail: do1@st-andrews.ac.uk
[b] M. Yang, Prof. M. Wang
Department of Applied Chemistry, College of Science
China Agricultural University, No.2 Yuanmingyuan West Road
Haidian District, Beijing 100193 (China)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201600519.
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CF2 groups to an edge position, however, this is avoided and
the ring distorts to create a new corner and a pseudorectangu-
lar conformation. This behaviour can be explained by two fac-
tors; the fluorine atoms avoid edge locations because they are
slightly larger than hydrogen and there is a steric cost to be
paid in projecting a fluorine into the ring, as the fluorine will
sterically impact in transannular interactions with internal
methylene hydrogen atoms. Also, the C-CF2-C angle (ꢀ1188) is
significantly wider than the C-CH2-C angle (ꢀ1128). This angle
widening is a general phenomenon which can be rationalised
both by Bent’s rule[10] and valence shell electron pair repulsions
(VSEPR) theory.[11] The angle widening relaxes 1,4-H-H intra-an-
nular interactions across the corner sites. These two factors
mutually reinforce a preference for the fluorine atoms to adopt
corner locations. The behaviour extends to larger C14 and C16
rings, where various placements of CF2 groups dictate the pre-
ferred ring conformation as determined by X-ray structure
analyses.[12]
Figure 3. Structures of monofluorinated odorants.
Results and Discussion
1. Civetone
Civetone (1; Figure 1) is a natural pheromone, which was first
isolated from the African civet over a hundred years ago by
Sack.[16] Civetone (1) has a musk scent and this pleasant olfac-
tory property has made the natural product desirable. Howev-
er, ethical and conservation concerns have led to protection of
the African civet and as a consequence, the macrocycle has re-
ceived significant synthesis attention.[17] Regarding structure
and conformation, cis-civetone (1) is a solid at room tempera-
ture (m.p. 328C),[16] but the conformationally labile nature of
the molecule has precluded successful X-ray crystallography.
Odd-membered rings, in this case C17, are more difficult to
crystallise than their even-membered homologues. For cive-
tone (1), a 2,4-dinitrophenyl hydrazone (DNP) derivative was
required to successfully crystallise the macrocycle, and this re-
solved as two conformers 1a and 1b (Figure 4).[18] In each
case, the macrocycle adopts a pseudo-rectangular conforma-
tion with the hydrazone located at the head of the longer axis
(Figure 4). A “straight” alignment of six methylenes defined by
a corner at C7 is notable in each polymorph.
Figure 2. X-ray crystal structures of 1,1,4,4-(6), 1,1,7,7-(7) and 1,1,6,6-(8) tetra-
fluorocyclododecanes.
There are very few reports on the outcome of replacing hy-
drogen for fluorine in flavour and fragrance compounds.
Schlosser and Michel reported that the smell (and taste) of the
raspberry ketone 9a was not significantly affected by the pres-
ence of a fluorine at specific locations (9b–e), but that the
smell was profoundly altered by methyl groups incorporated
at the same positions (Figure 3).[13] Also, Schlosser and Michel
reported that the musk odour of exaltone 10a was significant-
ly changed in compound 10b when an a-hydrogen of the
macrocyclic ketone was replaced by a fluorine (Figure 3).[14]
The authors suggested that the fluorine may induce a deleteri-
ous change in ring conformation, although being adjacent to
the ketone it may also have altered the electronic properties
of the carbonyl group and its interactions with a receptor.
These observations have led us to explore the impact of the
incorporation of CF2 groups into natural musk macrocycles,
with the substituent remote from the carbonyl. We have re-
cently reported such analogues of the 14-membered musk lac-
tone 3[15] and in that study, a preference for the CF2 groups to
dictate corner positions was obvious in the preferred ring con-
formations. In order to extend the scope of this study we now
describe the synthesis and structure of a range of CF2 contain-
ing analogues of the natural musk ketones, civetone (1) and
(R)-muscone (2). These macrocyclic ketones are among the
most widely recognised natural fragrances.
The corresponding DNP-hydrazone derivative of the non-
natural trans-1 isomer shows a less ordered overall conforma-
tion (Figure 4). The linear arrangement of the six methylenes
observed in conformers 1a and 1b is distorted and the
“straight” edge is now composed of seven methylene groups
(Figure 4).[19] On the other hand, the natural product dihydroci-
vetone 11, with the double bond saturated (Scheme 1), is also
a solid compound (m.p. 638C),[20] but there is no crystallo-
graphic information available. In this study, we prepared a syn-
thetic sample of dihydrocivetone 11 by a ring closing metathe-
sis (RCM)-hydrogenation sequence (Scheme 1), and a suitable
crystal of the dihydrocivetone DNP-hydrazone derivative was
subjected to X-ray crystallographic analysis. The resultant struc-
ture also had two different conformers within the same unit
cell, suggesting that they are close in energy (Figure 4). The
first, 11 a, has a similar conformation to the corresponding un-
saturated counterparts, 1a and 1b, with an edge of six methyl-
enes and corner locations at C7 and C10. The second, 11 b,
shows a wider pentagonal shape, with C1 located in a longer
edge and with corners at C8 and C11 (Figure 4).
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Figure 4. Solid state (X-ray) conformers of DNP-hydrazone derivatives of cis- and trans-civetone (1), and dihydrocivetone (11).
Scheme 1. Synthesis of civetone (1) and dihydrocivetone (11). Reagents and conditions: a) Grubbs’ 1st generation catalyst (5 mol%), DCM, reflux, 2 h, 33%;
b) H2, Pd(C) (10 mol%), EtOH, RT, overnight, 60%.
With these structural insights in place, we then addressed
CF2-containing analogues. The fluorinated targets 13–21
emerged as candidate compounds for synthesis (Figure 5).
They were designed on the assumption that the CF2 groups
would prefer corner locations and that the preferred conforma-
tion in the crystalline state will be a low energy conformer. Fur-
thermore, our working hypothesis assumes that the low
energy conformers will be relevant in contributing to odour.[21]
Some of the analogues 13–19 were designed to reinforce the
consensus structures that emerged from the crystallography
(Figure 4), whereas 20 and 21 were designed to be distorted
relative to the consensus structures. It was envisaged that the
selective replacement of the CH2 groups next to the cis-double
bond of the civetone, by two CF2 groups could reinforce or
mimic the ring constraint induced by the olefin moiety in com-
pounds 13–16. The influence of the carbonyl group location
on conformation might also be addressed by the preparation
of the regioisomer pairs 13/15 and 14/16. Compounds 17–19
should reinforce some of the crystallographic conformations
by inducing corners in the macrocycle at C7 and C9. Converse-
ly, fluorine substitution of compounds 20 and 21 should lead
to distorted conformations by the creation of corners at posi-
tions not observed in the structures in Figure 4.
Synthesis
The introduction of the 1,4-di-CF2 groups during the prepara-
tion of 13–16 was carried out by difluorination of propargylic
ketones[22] and then RCM as the key synthesis steps
(Scheme 2). The route started with a 2-iodoxybenzoic acid
(IBX) oxidation of commercially available alcohols 22 and 23 to
afford aldehydes 24 and 25, respectively. Addition of ethynyl-
magnesium bromide to 24, followed by oxidation of the inter-
mediate alcohol 26, gave propargylic ketone 27. The first gem-
difluoromethylene group was introduced in a reaction with di-
ethylaminosulfur trifluoride (DAST)[23] at 508C. The coupling of
volatile alkyne 28 with previously prepared aldehyde 25, and
subsequent oxidation of the intermediate alcohol, gave the
second propargylic ketone 30, which was fluorinated under
the same DAST conditions to give tetrafluoro-hydrocarbon 31.
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Figure 5. Target civetone analogue structures containing CF2 groups.
Macrocyclisation was carried out by a RCM reaction with the
Grubbs’ 1st generation catalyst. The resultant 17-membered
macrocycle 32 was obtained in good yield as a mixture of dia-
stereoisomers (E/Z, 2:1). A hydroboration–oxidation sequence
afforded a 1:1 inseparable mixture of regioisomeric alcohols.
Fortunately, direct oxidation of this mixture generated ketones
33 and 34, which were readily separated by column chroma-
tography. Interestingly, hydroboration occurred exclusively to
the double bond, presumably because the four fluorine atoms
deactivated the triple bond to borane attack. Acetylenic ke-
tones 33 and 34 might be considered to be civetone ana-
logues, however, they had no detectable odour. Finally, fluori-
nated targets 13 and 15 were prepared by partial hydrogena-
tion of 33 and 34 under Lindlar conditions. The saturated dihy-
drocivetones 14 and 16 were obtained by complete catalytic
hydrogenation of 33 and 34, respectively. Compounds 13–16
possessed a faint musk odour relative to our synthetic refer-
ence samples of civetone (1) and dihydrocivetone 11.
dation/oxidation sequence of cyclic olefin 36 gave the desired
macrocyclic ketone 17. Symmetry dictates that a single isomer
was generated. A pleasant musk odour was observed for dihy-
drocivetone analogue 17.
The syntheses of the mono-CF2 targets 18 and 19 were ach-
ieved following a similar strategy to that of 13–16 described
above (Scheme 4). Initially, mono-protection of heptane-1,7-
diol 38 with the p-methoxybenzyl (PMB) group was carried out
to generate alcohol 39, which was then oxidised to aldehyde
40. Treatment of 40 with allylmagnesium bromide, followed by
oxidation of alcohol 41 with IBX afforded homoallylic ketone
42. This ketone was then treated with DAST to give the di-
fluoro-olefin 43. Deprotection, followed by oxidation of the re-
leased alcohol 44 gave aldehyde 45. The open chain ketone
47 was then prepared by addition of an in situ generated
Grignard reagent, followed by oxidation of the resultant alco-
hol 46. RCM of 47 afforded the desired difluorinated civetone
18 as an inseparable mixture of diastereoisomers (E/Z, 3:1). Fi-
nally, catalytic hydrogenation of the double bond generated
mono-CF2 macrocyclic ketone 19. Both fluorinated compounds
18 and 19 were musk odorants, showing a comparable odour
intensity to reference compounds 1 and 11, respectively.
Analogue 20 was prepared as illustrated in Scheme 4, fol-
lowing the same strategy employed for 19. Compound 20 dis-
Mono-CF2 civetone analogue 17 was readily synthesised
from nonadeca-1,18-dien-10-one 12[17b] in four steps
(Scheme 3). The open chain hydrocarbon 35 was obtained in
modest yield, by treatment of 12 with DAST. Diene 35 was
then subject to an RCM reaction to afford macrocycle 36 as
a 1:8 mixture of cis/trans isomers. Finally, a hydroboration–oxi-
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Scheme 2. Synthesis of fluorinated civetone analogues containing the 1,4-di-CF2 motif. Reagents and conditions: a) IBX, DMSO, RT, overnight, 97% (n=5),
87% (n=6); b) ethynylmagnesium bromide, THF, 08C!RT, 3 h, 66%; c) IBX, DMSO, RT, overnight, 85%; d) DAST, 508C, overnight, 63%; e) 1) nBuLi, THF,
À788C!08C, 1 h; 2) 25, 08C!RT, 1 h, 71%; f) IBX, DMSO, RT, overnight, 82%; g) DAST, 508C, overnight, 69%; h) Grubbs’ 1st generation catalyst (5 mol%),
DCM, reflux, 24 h, 83%; i) 1) BH3·SMe2, THF, 08C!RT, overnight; 2) EtOH, NaOH, H2O2, RT, 4 h; 3) IBX, DMSO, RT, overnight, 36%; j) H2, Pd/BaSO4 (10 mol%),
quinoline, Py, RT, overnight, 96%; k) H2, Pd/BaSO4 (10 mol%), quinoline, Py, RT, overnight, 81%; l) H2, Pd(C) (10 mol%), EtOH, RT, overnight, 86%; m) H2, Pd(C)
(10 mol%), EtOH, RT, overnight, 79%.
Scheme 3. Synthesis of the fluorinated civetone analogue containing a CF2 group at C9. Reagents and conditions: a) DAST, 508C, 3 days, 27%; b) Grubbs’ 1st
generation catalyst (10 mol%), DCM, reflux, 3 h, 38%; c) 1) BH3·SMe2, THF, 08C!RT, overnight; 2) EtOH, NaOH, H2O2, RT, 4 h; 85%; d) IBX, DMSO, RT, overnight,
61%.
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Scheme 4. Synthesis of fluorinated civetone analogues containing a CF2 group at C7 and C5. Reagents and conditions: a) NaH, PMBCl, TBAI, THF, 08C!608C,
overnight, 41% (n=5), 45% (n=3); b) (COCl)2, DMSO, Et3N, DCM, À788C!08C, 1 h, 98% (n=5, 3); c) allylmagnesium bromide, THF, 0 8C!RT, overnight, 58%
(n=5), 46% (n=3); d) IBX, DMSO, RT, overnight, 85% (n=5), 79% (n=3); e) DAST, 508C, overnight, 43% (n=5), 34% (n=3); f) DDQ, DCM/H2O, RT, overnight,
74% (n=5), 78% (n=3); g) IBX, DMSO, RT, overnight, 98% (n=5), 72% (n=3); h) 1) 9-bromonon-1-ene (for n=5) or 11-bromoundec-1-ene (for n=3), Mg
(turnings), I2 (trace), THF, reflux, 6 h; 2) 45 (n=5) or 55 (n=3), RT, overnight, 62% (n=5), 49% (n=3); i) IBX, DMSO, RT, overnight, 93% (n=5), 81% (n=3);
j) Grubbs’ 1st generation catalyst (5 mol%), DCM, reflux, 3 h, 46% (n=5), 64% (n=3); k) H2, Pd(C) (10 mol%), EtOH, RT, overnight, 91% (n=5), 87% (n=3).
played a distinct floral odour, but without the characteristic
musk notes of 1 and 11.
vetone 11, musk notes were not recognised at all for 19. The
odour was significantly modified, having a non-pleasant sol-
vent character (see the Supporting Information).[25] The dis-
tinctly different olfactory outcome for 20 and 21, relative to
civetone (1), is consistent with the general hypothesis that
these compounds were designed to adopt a distorted macro-
cyclic ring structure.
The final dihydrocivetone target 21 was addressed, using di-
thiane chemistry by the route shown in Scheme 5. Bis-dithiane
60 was prepared using two equivalents of lithiated 1,3-dithiane
59 and 1,3-dibromopropane. This was followed by a double al-
kylation using n-butyllithium and then two equivalents of 7-
bromoheptene, to generate diene 61. Macrocyclisation of 61
by RCM gave the cyclic bis-dithiane 62 (E/Z, 2:1) in a relatively
Structure–odour relationships
good yield for such
a reaction, perhaps promoted by
a Thorpe–Ingold type effect associated with the dithiane mo-
tifs.[7c] A hydroboration–oxidation sequence was successfully
achieved to obtain the non-symmetrical alcohol 63. Direct di-
fluorination[24] of 63 with N-iodosuccinimide (NIS) and hydro-
gen fluoride in pyridine (HF·Py), was rather inefficient (14%
yield), but afforded the tetrafluorinated alcohol 64. In an at-
tempt to improve this fluorination step, a number of protec-
tion strategies for the alcohol were explored, but this was un-
productive, giving only very complex reaction mixtures. Finally,
oxidation of 64 with IBX gave the desired tetrafluorinated cive-
tone 21. In contrast to the parent civetone (1) and dihydroci-
The X-ray structures of all of the synthesis targets were ac-
quired, where possible, either as ketones or as their DNP deriv-
atives. Macrocycles 12–17, and 21 were crystalline and X-ray
crystal structures were obtained directly for these ketones.
Meanwhile, compounds 18–20 had to be derivatised to obtain
X-ray crystal structure data. The structures for all of these com-
pounds are shown in Figure 6.
As anticipated, the CF2 groups occupy corner locations in all
cases but one (structure DNP-20), and the group clearly influ-
ences the overall conformation of the macrocycles. The C-CF2-
C angles are significantly wider (114.58–118.98) than those usu-
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Scheme 5. Synthesis of the fluorinated civetone analogue containing the 1,5-di-CF2 motif. Reagents and conditions: a) 1) nBuLi, THF, À308C, 2 h; 2) 1,3-dibro-
mopropane, À308C!RT, overnight, 62%; b) 1) nBuLi, THF, À308C!08C, 2 h; 2) 7-bromohept-1-ene, À308C!RT, overnight, 60%; c) Grubbs’ 1st generation
catalyst (5 mol%), DCM, reflux, 2 h, 58%; d) 1) BH3·SMe2, THF, 08C!RT, overnight; 2) EtOH, NaOH, H2O2, RT, 4 h, 97%; e) NIS, HF·Py, DCM, À788C!RT, over-
night, 14%; f) IBX, DMSO, RT, overnight, 59%.
ally found in aliphatic chains,
a
feature previously ob-
Strikingly, a very regular, symmetric pentagonal conforma-
tion was obtained for the DNP-derivative of 20 (Figure 6). How-
ever, the unexpected observation in this case is that the struc-
ture locates the CF2 group at an edge and the carbonyl group
(hydrazone) at a corner, a reversal of all other situations so
far.[27] It must be assumed that conformations of 20 with the
CF2 at a corner location will impact negatively on an appropri-
ate location for the carbonyl and the ring conformation rear-
ranges as observed. Macrocyclic ketone 20 has no observable
musk odour, which is again consistent with not being able to
access ring conformations observed for 1 and 11.
A very different and distinctive conformation in the solid
state was found for compound 21 (Figure 6). The presence of
the 1,5-di-CF2 motif was designed to induce a C5 edge into
the ring and this has imposed a distorted rectangular structure,
quite different from the structures described so far. It is per-
haps not surprising that ketone 21 is absent of a detectable
musk note.
served.[7,8,12] Macrocyclic ketones 13 and 15 display almost
identical ring conformations (Figure 6) and are very similar to
that of civetone (1). The cis double bond is now located direct-
ly between the two corners, which are defined by the CF2
groups at C8 and C11, instead of lying in the arch created by
C7–C11 as in cis-1a and cis-1b (Figure 4). The main difference
between both regioisomers is the location of the carbonyl
group in 13 (similar to civetone, 1) and for 15, displaced to the
adjacent carbon on the top edge and pointing in the opposite
direction. Dihydrocivetone derivatives 14 and 16 also mimic
very closely the dihydrocivetone structure 11 a (Figure 4). The
presence of the fluorine atoms at corners C7–C10 in regioiso-
mer 16 reinforces the overall conformation observed for dihy-
drocivetone 11. Despite the very clear similarities in the confor-
mation of these four analogues, relative to civetone (1) and di-
hydrocivetone 11, only a faint musk odour was observed for all
of these compounds. Musk odours were retained but other pa-
rameters may impact on odour intensity, such as increasing
the molecular mass and reducing volatility with the introduc-
tion of four fluorine atoms.[26]
Some general conclusions on the civetone ring structure, rel-
ative to odour can be made. Excluding compounds 20 and 21,
the fluorinated analogues fit with the olfactophore model for
musk activity described by Bersuker and co-workers.[28] This
model proposed that a musk note requires a pseudo-rectangu-
lar structure with a slightly shorter horizontal axis (5–6 Š),
a slightly longer vertical axis (6.2–7.2 Š) and the carbonyl (C=
O) centred on a horizontal edge (Figure 7). Whilst the confor-
mation of analogues 13–19 fits this model well, the distorted
conformations of macrocycles 20 and 21 do not.
The more intense odour found in the mono-CF2 derivatives
17–19 versus the weak musk character observed for the 1,4-di-
CF2 compounds 13–16 could reasonably be due to volatility. A
comparative GC experiment was carried out (see the Support-
ing Information) in order to establish the relative volatility of
the civetone macrocycles, and there was a tendency towards
In the case of macrocycle 17 (Figure 6), the CF2 group rein-
forces a corner at C9 and has the same overall shape found for
dihydrocivetone 11 a (Figure 4). Ketone 17 retains an intense
musk odour. Although compound 17 was a crystalline solid
and an X-ray structure was obtained, the DNP-derivative of 17
was also analysed by X-ray to explore the influence of the hy-
drazone motif on ring conformation. These structures are
shown in Figure 6. Very different ring conformations are found.
The CF2 groups occupy different corners relative to the long
edge of six methylene groups, closer to structure 11 b
(Figure 4), suggesting that there is a relatively low energy bar-
rier between these two ring arrangements, however, they
retain a similar overall shape.
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Figure 6. Preferred solid-state conformations of fluorinated civetone derivatives.
2. Muscone
longer retention times for the tetrafluoro analogues, particular-
ly the olefins, although the correlation was less distinct for the
saturated macrocycles.
(R)-Muscone (2; Figure 1) was first discovered in 1906, isolated
from the male musk deer, Moschus moschiferus.[29] The S enan-
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Figure 7. Proposed structural features for macrocyclic musk odorants and ellipsoid-like shape of fluorinated targets 19 and 21 (DNP fragment was omitted to
simplify the Figure).
tiomer is described as having a poorer musk odour.[30] As a key
perfumery component, (R)-2 has been the target of a number
of total syntheses;[31] however, little work has been carried out
on assessing muscone ring conformation and odour. (R)-Mus-
cone (2) is a liquid at room temperature, and no X-ray crystal-
lography of the parent macrocycle has been recorded. In 1982,
Bernardinelli and Gerdil prepared the DNP-derivative of mus-
cone (2).[32] X-ray crystal analysis revealed significant disorder,
not unexpected for a 15-membered ring. Deconvolution of the
diffraction data led to the conclusion that up to eight closely
related, but different ring conformations were adopted by the
(R)-muscone macrocycle in the solid state (Figure 8), indicative
of a very flexible ring system.
As a start point to this study, a sample of (R)-muscone (2)
was prepared by the route illustrated in Scheme 6, to reinvesti-
gate the X-ray crystal structure analysis. This involved RCM of
65 and then hydrogenation of the resultant olefin 66, follow-
ing a previously described protocol.[31f] Crystallography of the
DNP derivative of (R)-2 gave a well resolved structure, as illus-
trated in Scheme 6.
Figure 8. Proposed ring conformations 2a–2h of (R)-muscone from Bernar-
dinelli and Gerdil’s X-ray study of the (R)-muscone-DNP derivative.
methyl group of the stereogenic centre at corner locations.
The earlier predictions had corner locations at C7/C12 rather
than C6/C13 as is observed in the new crystallographic data. In
overview, it may be that all of these structures are close in
energy and different crystallographic studies will find various
conformations.
In this structure the macrocycle has a regular pentagonal
conformation with corners at the carbonyl group, the stereo-
genic centre and carbons C6, C9 and C13. Interestingly, none
of the predicted structures of Bernardinelli and Gerdil[31f] maps
onto this structure, although all have a corner located at C-9
and conformers 2b, 2e, 2g and 2h (Figure 8) locate the
It was attractive to explore the incorporation of CF2 groups
into (R)-muscone (2) at different locations, but particularly cov-
ering C6 to C10, as a strategy to influence and limit the confor-
Scheme 6. Synthesis of (R)-muscone (2) and crystal structure of its DNP-hydrazone derivative. Reagents and conditions: a) Grubbs’ 2nd generation catalyst
(8 mol%), DCM, reflux, overnight, 30%; b) H2, Pd(C) (10 mol%), MeOH, RT, overnight, 95%.
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mational flexibility of the ring. To this end, the difluorinated
muscone derivatives 67–71 were chosen as synthetic targets
(Figure 9). The early X-ray data[32] indicated a corner at C9, thus
68 was selected as a target to stabilise this feature. Structures
67 and 69 were selected to move this corner by one methyl-
ene group in each direction, to assess disruption of this fea-
ture. Many of the predicted conformations in Figure 8 have
one edge which adopts a linear chain of five methylene
groups from C-3 (the stereogenic centre) to C-7. For this
reason, a CF2 group was engineered into the design of 70 at
C7 to try to stabilise this aspect. In a similar manner, by placing
the CF2 group at the C-6 position in 71, it should be possible
to mimic the conformation of the X-ray structure of the DNP
derivative of (R)-2 as shown in Scheme 6, where only four
carbon atoms form the “side” of the structure from C-3 to C-6.
The synthesis of muscone 68 was addressed as illustrated in
Scheme 8. The previously synthesised alcohol 44 (Scheme 4)
was converted to bromide 85 by an Appel reaction, and was
then used to prepare the corresponding Grignard reagent for
condensation with aldehyde 81. This coupling gave alcohol 86
as a 1:1 mixture of diastereoisomers. Oxidation to ketone 87
and then a RCM reaction gave macrocyclic ketone 88 as an E/Z
mixture (2:1). Finally, catalytic hydrogenation of 88 afforded
muscone 68. This compound had a weak musk note relative to
our synthetic sample of muscone (2).
8,8-Difluoromuscone 69 was prepared by coupling fluorinat-
ed aldehyde 96 with the enantiopure alkyl bromide 97,[33] as il-
lustrated in Scheme 9. Aldehyde 96 was obtained in a similar
manner to 45 (Scheme 4), but starting from the nonadiol 89. A
Grignard reaction between these entities generated 98, which
was then oxidised to ketone 99. RCM of 99 with the Hoveyda–
Grubbs’ 2nd generation catalyst generated macrocycle 100 as
an E/Z mixture (9:1). Finally, hydrogenation of the olefin gave
muscone 69, which had a good musk profile. The unsaturated
precursor 100 (E/Z, 9:1) had a nice musky odour too and the
perfumers also detected an exaltone aspect with compound
69.
The synthesis of difluoromuscone derivatives 70 and 71 re-
quired modification of the chiral fragment. The preparation of
70 from (R)-citronellal 72 is shown in Scheme 10. (R)-Citronellol
101[31b] was PMB protected to give 102, then ozonolysis fol-
lowed by a Wittig reaction gave terminal alkene 103. A hydro-
boration–oxidation sequence afforded primary alcohol 104,
which was sequentially oxidised and treated with a Grignard
reagent derived from 4-bromo-1-butene to give alcohol 106.
This alcohol was oxidised and fluorinated using DAST to gener-
ate 108. Ketone 112 was prepared after PMB deprotection fol-
lowed by the sequence of reactions used to convert 104 to
107. Finally, macrocyclisation of 112 by RCM afforded a separa-
ble mixture of E/Z isomers (5:2) 113 that were hydrogenated
to generate the target muscone 70. This ketone had only
a very faint musk odour.
Figure 9. Structures of synthetic (R)-muscone targets containing CF2 groups.
Synthesis
In order to prepare the targets, a ring closing metathesis ap-
proach was again adopted, a strategy that has previously been
employed for the synthesis of (R)-muscone (2).[31a–f] The stereo-
genic centre can usefully be contributed from commercially
available (+)-citronellal 72.
The last compound prepared in this series was muscone 71
as illustrated in Scheme 11. Alkene 102 was subjected to ozo-
nolysis, and the resultant aldehyde was treated with a Grignard
reagent derived from 4-bromo-1-butene, to generate alcohol
114. This alcohol was oxidised to ketone 115 and was then flu-
orinated with DAST. Deprotection gave alcohol 117, which was
progressed by an oxidation, Grignard reaction, oxidation se-
quence to give ketone 119. An RCM reaction generated macro-
cycle 120 (E/Z, 3:2) and then hydrogenation gave the target
muscone 71. This molecule had a pleasant musky odour, very
similar to synthetic (R)-muscone (2).
The synthesis of analogue 67 containing a CF2 group at C10
was carried out as illustrated in Scheme 7. A key early reaction
involved the conversion of alcohol 79 to bromide 80 by an
Appel reaction. Bromide 80 was then converted into the corre-
sponding Grignard reagent for condensation with aldehyde
81, itself derived from (+)-citronellal 72 as previously descri-
bed.[31b] Alcohol 82 was generated as a 1:1 mixture of diaste-
reoisomers, and then oxidation gave ketone 83. This ketone
was subject to a RCM reaction to afford 84 as a separable E/Z
mixture (1:1). To conclude this synthesis, macrocycles (E)-84
and (Z)-84 were independently hydrogenated to generate di-
fluoro-muscone derivative 67. Ketone 67 exhibited a weak
musk odour but, perhaps surprisingly, the trans-olefin precur-
sor, (E)-84 displayed stronger musky notes. It was interesting
to note a total absence of a musk odour when the cis-isomer
(Z)-84 was assessed, indicating that the configuration of the
double bond has a significant influence on the olfactory prop-
erties.
Structure–odour relationships
With muscones 67–71 in hand, it was of interest to obtain X-
ray structural data where possible. Suitable crystals of ketones
67 and 70 were forthcoming, and DNP derivatives of ketones
68 and 69 were successfully prepared. Some of the unsaturat-
ed RCM products, such as (Z)-84, (E)-100 and (Z)-113 also
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Scheme 7. Synthesis of fluorinated muscone analogue containing a CF2 group at C10. Reagents and conditions: a) NaH, PMBCl, TBAI, THF, 08C!608C, over-
night, 55%; b) DMP, DCM, RT, overnight; c) 1) 4-Bromo-1-butene, Mg (turnings), I2 (trace), Et2O, reflux, 2 h; 2) 75, 08C!RT, overnight, 52% (three steps);
d) DMP, DCM, RT, 2 h; e) DAST, 508C, overnight, 67% (two steps); f) DDQ, DCM/H2O, RT, 1 h, 81%; g) CBr4, PPh3, DCM, 08C!RT, overnight, 75%; h) 1) 80, Mg
(turnings), I2 (trace), Et2O, reflux, 2 h; 2) 81, 08C!RT, overnight, 43%; i) DMP, DCM, RT, 1 h; j) Grubbs’ 1st generation catalyst (6 mol%), DCM, reflux, overnight,
52% (two steps); k) H2, Pd(C) (10 mol%), MeOH, RT, overnight, 59% from (Z)-84; 79% from (E)-84.
Scheme 8. Synthesis of fluorinated muscone analogue containing a CF2 group at C9. Reagents and conditions: a) CBr4, PPh3, DCM, 08C!RT, overnight, 67%;
b) 1) 85, Mg (turnings), I2 (trace), THF, reflux, 6 h; 2) 81, RT, overnight, 40%; c) DMP, DCM, RT, 1 h; d) Grubbs’ 1st generation catalyst (6 mol%), DCM, RT, reflux,
overnight, 94% (two steps); e) H2, Pd(C) (10 mol%), MeOH, RT, overnight, 41%.
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Scheme 9. Synthesis of fluorinated muscone analogue containing a CF2 group at C8. Reagents and conditions: a) NaH, PMBCl, TBAI, THF, 08C!608C, over-
night, 46%; b) IBX, DMSO, RT, overnight, 80%; c) allylmagnesium bromide, THF, 08C!RT, overnight, 44%; d) IBX, DMSO, RT, overnight, 83%; e) DAST, 508C,
overnight, 63%; f) DDQ, DCM/H2O, RT, 1 h, 69%; g) IBX, DMSO, RT, overnight, 80%; h) 1) 97, Mg (turnings), I2 (trace), THF, reflux, 4 h; 2) 96, RT, overnight, 60%;
i) IBX, DMSO, RT, overnight, 95%; j) Hoveyda–Grubbs’ 2nd generation catalyst (6 mol%), toluene, reflux, overnight, 56%; k) H2, Pd(C) (10 mol%), MeOH, RT,
overnight, 93%.
Scheme 10. Synthesis of fluorinated muscone analogue containing a CF2 group at C7. Reagents and conditions: a) NaH, PMBCl, TBAI, THF, 08C!608C, over-
night, 82%; b) 1) O3, DCM, À788C, 30 min; 2) PPh3, À788C!RT, overnight; 3) nBuLi, PMe(Ph)3Br, THF, À788C!RT, overnight, 36%; c) 1) 9-BBN dimer, THF, RT,
overnight; 2) EtOH, NaOH, H2O2, 08C, 4 h, 99%; d) DMP, DCM, RT, 2 h; e) 4-bromo-1-butene, Mg (turnings), I2 (trace), THF, reflux, 6 h; 2) 105, RT, 16 h, 65% (two
steps); f) DMP, DCM, RT, 2 h; g) DAST, 508C, overnight, 70% (two steps); h) DDQ, DCM/H2O, RT, 1 h, 74%; i) DMP, DCM, RT, 1 h, 97%; j) 1) 6-bromo-1-hexene,
Mg (turnings), I2 (trace), THF, reflux, 30 min; 2) 110, 08C!RT, overnight, 72%; k) DMP, DCM, RT, 1 h, 99%; l) Grubbs’ 1st generation catalyst (6 mol%), DCM,
reflux, 46 h, 58%; m) H2, Pd(C) (10 mol%), MeOH, RT, overnight, 72%.
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Scheme 11. Synthesis of fluorinated muscone analogue containing a CF2 group at C6. Reagents and conditions: a) 1) O3, DCM, À788C, 15 min; 2) PPh3, À788C
!RT, overnight; 3) 4-bromo-1-butene, Mg (turnings), I2 (traces), Et2O, reflux, 2 h; 4) aldehyde, 08C!RT, overnight, 58%; b) DMP, DCM, RT, 2 h, 96%; c) DAST,
508C, overnight, 64%; d) DDQ, DCM/H2O, RT, 1 h, 88%; e) 1) DMP, DCM, RT, 1 h; 2) 7-bromo-1-heptene, Mg (turnings), I2 (trace), Et2O, reflux, 2 h; 3) aldehyde,
08C!RT, 4 h, 60%; f) DMP, DCM, RT, 1 h; g) Grubbs’ 1st generation catalyst (6 mol%), DCM, reflux, overnight, 50% (two steps); h) H2, Pd(C) (10 mol%), MeOH,
RT, overnight, 65%.
proved amenable to crystallisation. The resultant solid state
structures are shown in Figure 10.
reogenic centre. The overall structure is strikingly similar to the
rectangular civetone structures 13–19 in Figure 6, although
the six methylenes forming the long edge in those compounds
is shortened to five in this structure. Ketone 69 exhibits a very
good musk profile. The trans isomer (E)-100 was also analysed
by X-ray and two different conformers (E)-100a and (E)-100b
are observed in the unit cell, with a CF2 corner at C8 as shown
in Figure 10. The overall rectangular shape is conserved in (E)-
100a, and in (E)-100b the corner has moved from C11 to C12,
defining a longer five carbon edge. Curiously, both structures
have the stereogenic centre at an edge rather than a corner
possibly dictated by the trans double bond.
It is again clear that the CF2 groups adopt corner locations
and induce some predictable order into the structures. Regard-
ing muscone 67, a pseudo-rectangular conformation is appar-
ent with corners at C10 (CF2) and C7 and the methyl group-
stereogenic centre is at a corner (Figure 10) similar to the con-
formers described by Bernardinelli and Gerdil (Figure 8).[31f] This
feature is also found in the DNP structure of synthetic mus-
cone (2; Scheme 6). These compounds all have weak musk
odours. The RCM product cis-olefin 84 is interesting in that it
has a regular rectangular structure; however, the carbonyl is
unusually pointing into the ring suggesting some significance
with respect to its lack of odour. On the other hand, the trans
olefin (E)-84 has a good musk profile and presumably does not
have this endo preference for the carbonyl.
It was interesting to find “exaltone” notes described by the
perfumers for compound 69. Exaltone 10a (cyclopentanodeca-
none) is a natural 15-membered ketone structurally related to
muscone (2), but without the stereogenic methyl group at C3
(Figure 11). The X-ray structure of the DNP derivative of 10a
was solved by Fronczek and co-workers in 2008 and is shown
in Figure 11.[34] There is clearly a high level of homology be-
tween this conformation of exaltone 10a and the DNP deriva-
tive of 69 consistent with their odour relationship. These struc-
tures relate to the civetones 13–19 in Figure 6 too, with a five,
rather than six, carbon long edge, due to the smaller ring size.
Presumably, this overall shape could be close to a relevant bio-
active conformation for 15-membered musk ketones.
Ketone 70 has a similar conformation to that of 67, with
a corner defined at C7. The carbonyl locates in the middle of
an edge. Two conformers 70a and 70b were observed in the
crystal structure, which differ only around the C10–C11 corner.
Conformer 70b is very similar to that of the unsaturated mac-
rocycle (Z)-113. The common features between saturated and
unsaturated muscones fluorinated at C10 or C7, and the ab-
sence of a defined musky character in these derivatives, sug-
gest this squareoid shape is less relevant than that of the more
rectangular conformation for olfactory stimulation.
On the other hand, the structure of DNP-68 showed the cor-
responding CF2-corner at C9. This conformation is virtually
identical to 2d proposed by Bernardineli,[32] with the methyl
group at an edge. A hint of musk was recognised with ketone
68.
The structure of the DNP-derivative 69, has a distorted rec-
tangular conformation as shown in Figure 10, with well defined
corners at C11 and C8, and a corner formed at C3 by the ste-
Conclusions
In summary, a set of fluorinated civetone and muscone ana-
logues with one or more CF2 groups placed at strategic posi-
tions of the ring have been prepared by synthesis. The confor-
mation of all these molecules can be significantly influenced
by the location of CF2 groups. Our study demonstrates that
this motif has a clear preference for occupying corner locations
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Figure 10. X-ray structures of fluorinated muscone derivatives.
class. These compounds clearly have a distorted conformation
relative to the parent compounds. Compound (Z)-84 of the
muscone class, was also devoid of any distinctive scent, but
conspicuously it has a carbonyl group pointing into the ring,
the only such example in all of the X-ray structures. Also, there
is a tendency for weaker muscone notes as the ring structures
deviate from rectangular to square conformations comparing,
for example, muscones 69 with 70. These observations offer
structural information which contributes to our understanding
of musk odorants. It follows that the utility of this conforma-
tional tool could be extended to other macrocycles in order to
influence properties in other arenas.
Figure 11. X-ray crystal structure of exaltone DNP-derivative[34]
.
across a wider range of more complex and functionalised mac-
rocycles. The majority of the civetone and muscone analogues, Acknowledgements
and some of the olefin precursors which result from RCM reac-
tions, retain a muskoid scent, as the structures reinforce the
conformation of the natural ketones and fit the generalized
Bersuker model. However, some structures emerged that do
not retain a musk scent, such as 20 and 21 of the civetone
This work was supported by the Engineering and Physical Sci-
ences Research Council (EPSRC) and the European Research
Council (ERC). We are grateful to Prof. Paul N. Davey and Domi-
nique Leli›vre (Givaudan, Schweiz AG, Dübendorf, Switzerland)
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[19] G. Bernardinelli, R. Gerdil, Helv. Chim. Acta 1982, 65, 730.
for the olfactory evaluation of the compounds. The authors ac-
knowledge the EPSRC National Mass Spectrometry Facility
(Swansea) and Mrs. Caroline Horsburgh (University of St. An-
drews) for analytical assistance. M.Y. thanks the China Scholar-
ship Council for financial support. D.O’H. thanks the Royal Soci-
ety for a Wolfson Research Merit Award.
[20] M. Stoll, J. Huistkamp, A. RouvØ, Helv. Chim. Acta 1948, 31, 543.
[21] Z. Peterlin, Y. Li, G. Sun, R. Shah, S. Firestein, K. Ryan, Chem. Biol. 2008,
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[22] Propargylic ketones have proved very reliable for the incorporation of
the CF2 group. For selected examples of this methodology, see: a) P.
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Keywords: conformation analysis
fragrances organofluorine chemistry
relationships
·
macrocycles
· musk
structure–activity
·
·
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Published online on May 6, 2016
Chem. Eur. J. 2016, 22, 8137 – 8151
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