Fluorine in fragrances: Exploring the difluoromethylene (CF2) group as a conformational constraint in macrocyclic musk lactones

Article abstract of DOI:10.1039/c5ob02023a

The CF₂ group is incorporated into specific positions within the lactone ring of the natural musk lactone, (12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The approach is taken as it was antici

Full text of DOI:10.1039/c5ob02023a

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Fluorine in fragrances: exploring the
difluoromethylene (CF2) group as a conformational
constraint in macrocyclic musk lactones†
Cite this: DOI: 10.1039/c5ob02023a
Michael J. Corr,a Rodrigo A. Cormanich,b Cortney N. von Hahmann,a Michael Bühl,a
David B. Cordes,a Alexandra M. Z. Slawina and David O’Hagan*a
The CF2 group is incorporated into specific positions within the lactone ring of the natural musk lactone,
(12R)-(+)-12-methyl-13-tridecanolide, a constituent of Angelica root oil, Angelica archangelica L. The
approach is taken as it was anticipated that CF2 groups would dictate corner locations in the macrocycle
and limit the conformational space available to the lactone. Three fluorine containing lactones are pre-
pared by organic synthesis. One (8) has CF2 groups located at the C-6 and C-9 positions, another (9) with
CF2 groups at the C-5 and C-9 positions, and a third (10) with a CF2 group at C-8. Two of the fluorine
containing lactones (8 and 10) were sufficiently crystalline to obtain X-ray crystal structures which
revealed that the CF2 groups do adopt corner locations. All three lactones were subject to computational
analysis at the B3LYP-D3/6-311+G** level to assess the relative energies of different conformers. In all
cases, the global minima and most of the lowest energy minima have squared/rectangular geometries
and located the CF2 groups at the corners. The lowest energy structures for 8 and 10 closely approxi-
mated the observed X-ray structures, suggesting good convergence of theory and experiment in deter-
mining relevant low energy conformations. All three compounds retained a pleasant odour suggesting
the rings retained sufficient conformational flexibility to access relevant olfactory conformations.
Received 28th September 2015,
Accepted 4th November 2015
DOI: 10.1039/c5ob02023a
www.rsc.org/obc
square like conformation. However, in the case of cyclodode-
cane 3, incorporation of the difluoromethylene group 1,6 to
Introduction
The selective replacement of a hydrogen for a fluorine atom is each other results in considerable distortion of the ring confor-
a powerful method for altering the properties of organic com- mation as the CF2 group avoids an unfavourable edge location.
pounds, and a strategy that is widely used in bio-organic and
Natural musks are large conformationally flexible macro-
medicinal chemistry.1–3 Generally, this replacement has only a cyclic lactones and we were interested to evaluate if the CF2
moderate steric effect, but the high electronegativity of the fluo- group might limit this conformational flexibility as a tool for
rine can have significant electronic influences.4 The difluoro- exploring preferred conformations responsible for scent. (12R)-
methylene (CF2) group has received considerably less attention (+)-12-Methyl-13-tridecanolide 4 is a natural constituent of
as a group for modifying the properties of organic molecules Angelica root oil, Angelica archangelica L.9 The (R)-enantiomer
relative to the –F and –CF3 groups.5 However, we have recently is described as having “a clean, crystal-clear musk top note with
reported6–8 that incorporation of a CF2 group can influence strong, elegant woody accents”.10,11 Macrocycle 4 possesses a
the conformation of organic molecules. In particular, cyclo- high degree of conformational flexibility and could be expected
dodecanes 1–3 were prepared with varied locations of two to adopt a wide variety of conformations, not all of which are
difluoromethylene groups (Fig. 1). X-ray crystal structure analy- likely to be active musk odorants. Several syntheses of (R)-4 have
sis showed that the CF2 groups only occupied corner positions. been reported,10,12–14 but little work has been carried out on
In the case of cyclododecanes 1 and 2, this stabilises the determining the active conformations of the musk lactone that
contribute to its scent. One such study by Kraft and Cadalbert15
calculated the six lowest-energy conformations of (R)-4 (Fig. 3),
all of which were within 0.9 kcal mol−1 of each other. In order
to impart conformational restriction, they synthesised three
musk lactone derivatives 5–7 (Fig. 2), featuring bridging methyl-
ene groups. Musk derivatives 5–7 were weaker odorants than the
parent (R)-4, as the authors predicted, but did modify the olfac-
tory properties resulting in slightly differing smell descriptions.
aSchool of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST,
UK. E-mail: do1@st-andrews.ac.uk
bChemistry Institute, University of Campinas, Campinas, SP 13083-970, Brazil
†Electronic supplementary information (ESI) available. CCDC 1427901–1427903.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c5ob02023a. For access to research data and metadata see DOI:
10.17630/f6dc25c1-c693-4c59-a164-3ccce6e7ef15
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Fig. 1 X-ray crystal structures of 1,1,4,4-(1), 1,1,7,7-(2) and 1,1,6,6-(3) tetrafluorocyclododecanes.6a The CF2 groups conspicuously adopt corner
locations either reinforcing square like structures for 1 and 2 or a inducing a distorted ring for structure 3.
Fig. 2 (12R)-(+)-12-Methyl-13-tridecanolide
lactones 5–7.
4
and bridged musk
Fig. 4 Target musk lactone analogues 8–10 incorporating CF2
moieties.
In this respect lactones 8, 9 and 10 (Fig. 4) were selected for
synthesis. In each case we anticipated that they would adopt
different Kraft and Cadalbert conformations (Fig. 3). Con-
formation [3434]-4 has a four carbon edge running along the
top of the ring which should be reinforced by the 1,4-CF2
groups in structure 8. Conformation [3434]-1, the lowest
energy Kraft and Cadalbert structure should be reproduced by
lactone 9 if the hypothesis holds. Finally the Kraft and
Cadalbert structure [3344]-1, which is 0.74 kcal mol−1 above
the ground state structure, is an asymmetric rectangular struc-
ture, with a methyl at a corner location, a conformation which
should be preferred by lactone 10, which will locate a corner at
C-8 of the lactone ring.
Fig. 3 The six lowest-energy conformations of musk lactone (R)-4 as
reported by Kraft and Cadalbert (MM3 force field).15
Results and discussion
Synthesis
In order to prepare the CF2 containing musk lactones 8–10, a
synthesis was devised that would allow their assembly from a
common enantiomerically pure chiral fragment (Scheme 1).
(R)-Olefin 11 was chosen as it could be progressed in three sep-
arate directions to aldehyde 12, epoxide 13 and aldehyde 14,
respectively. It was envisaged that intermediates 12–14 could
then be progressed to the individual musk lactones 8–10.
A key strategy for incorporating the CF2 groups would exploit
Grée’s method of diethyaminosulfur trifluoride (DAST)
treatment of propargylic ketones to generate propargylic
difluoromethylene.16
As a continuation of the observation that difluoromethylene
groups can influence macrocyclic ring conformation, we
decided to investigate the synthesis of CF2 analogues of (12R)-
(+)-12-methyl-13-tridecanolide 4. The predicted lower energy
conformers shown in Fig. 3 are largely rectangular structures
with linear edges of four or five methylene groups. It was
envisaged that strategic incorporation of CF2 groups into the
macrolide would allow different ground state conformations to
be more highly populated, and then different conformations
could be assessed for their musk/odour properties.
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Scheme 1 Planned routes to target lactones 8–10 from (R)-olefin 11.
Scheme 2 Synthesis of chiral fragments 11 and 12. Reagents and conditions: (a) (i) H2O2, MeOH, 30 min. (ii) FeSO4·7H2O, CuSO4·5H2O, H2O, 20%;
(b) (i) Oxazolidinone 20, nBuLi, THF, −78 °C, 30 min. (ii) Pivaloyl chloride, NEt3, THF, 0 °C, 30 min, r.t., 1.5 h, 93%; (c) NaHMDS, MeI, THF, −78 °C, 3 h,
92%, dr >98 : 2; (d) LiAlH4, Et2O, 0 °C, 2 h, 66%; (e) NaH, BnBr, DME, r.t.-reflux, 20 h, 94%; (f) (i) O3, DCM, −78 °C. (ii) PPh3, −78 °C–r.t., 55%.
(R)-Olefin 11 was prepared as shown in Scheme 2. Firstly
hexenoic acid 19 was obtained from cyclohexanone 18 by the
method reported by Ogibin et al.17 Carboxylic acid 19 was then
activated as a mixed anhydride and coupled18 to (R)-oxazolidi-
none 20 19 to generate 21. Asymmetric methylation with iodo-
methane gave 22 as
a single diastereoisomer and the
stereochemistry was established by X-ray crystallographic ana-
lysis as shown in Fig. 5. Oxazolidinone 22 was then progressed
to aldehyde 12 by a sequence of lithium aluminium hydride
(LiAlH4) reduction to give alcohol 23, benzyl ether formation20
to give (R)-alkene 11 and then ozonolysis.
Fig. 5 X-ray crystal structure of compound 22.
Attention turned to the synthesis of the propargylic
difluoromethylene fragments 28a and 28b in Scheme 3. Diols (DMP)23 oxidation gave propargyl ketones 27, which were
24a and 24b were mono-protected21 as their 4-methoxybenzyl treated with DAST in methodology developed by Grée16,24,25 to
ethers to give alcohol 25a and 25b by modification of a pre- give the required difluoromethylene acetylenes 28a and 28b.
vious procedure.5 Oxidation to the corresponding aldehydes,22
With the appropriate fragments in hand, attention turned
followed by reaction with ethynylmagnesium bromide gave to the synthesis of lactone 8 (Scheme 4). Lithiation of alkyne
propargylic alcohols 26a and 26b. Dess–Martin periodinane 27b with n-butyllithium, and then treatment with, aldehyde 12
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Scheme 3 Synthesis of difluoro-alkyne fragments 28a and 28b. Reagents and conditions: (a) NaH, PMB–Cl, TBAI, THF, 0 °C-reflux, 19 h, 25a 85%,
25b 55%; (b) 25a: DMP, DCM, r.t., 18 h, 100%; 25b: oxalyl chloride, DMSO, NEt3, DCM, −78 °C–0 °C, 3 h, 100%; (c) ethynylmagnesium bromide, THF,
−78 °C–r.t., 18 h, 26a 71%, 26b 77%; (d) DMP, DCM, r.t., 2 h, 27a 85%, 27b 71%; (e) DAST, 50 °C, 18 h, 28a 61%, 28b 51%.
Scheme 4 Synthesis of musk lactone 8. Reagents and conditions: (a) (i) nBuLi, THF, −78 °C, 30 min. (ii) Aldehyde 12, THF, −78 °C–r.t., 20 h, 61%;
(b) DMP, DCM, r.t., 2 h, 89%; (c) DAST, 50 °C, 18 h, 71%; (d) DDQ, DCM, H2O, r.t., 2 h, 78%; (e) BAIB, TEMPO, CH3CN, H2O, r.t., 7 h, 58%; (f) palladium
on carbon (10 wt%), H2, MeOH, r.t., 18 h, 65%; (g) LiOH, THF, H2O, r.t., 3 h, 94%; (h) 2,4,6-trichlorobenzoyl chloride, NEt3, THF, r.t., 2.5 h. (ii) 4-DMAP,
toluene, r.t., 3.5 h, 54%.
gave alcohol 15 as a 1 : 1 mixture of diastereoisomers. After oxi- proved amenable to X-ray crystal structure analysis and the
dation,23 ketone 29 was converted to alkyne 30 with DAST. structure is shown in Fig. 6.
4-Methoxybenzyl cleavage26 and then oxidation with bis-
For the synthesis of lactone 9, alkene 11 was oxidised with
(acetoxy)iodobenzene (BAIB)/TEMPO27 generated carboxylic meta-perbenzoic acid (mCPBA) to give epoxide 13 as
a
acid 32. Benzyl deprotection could not be achieved under 1 : 1 mixture of diastereoisomers. Ring opening addition of
standard conditions, proving resistant to hydrogenation in lithiated alkyne 28a 29 to epoxide 13 gave alcohol 16 in 60%
either ethyl acetate or THF. Hydrogenation in methanol was yield. The acetylene could be selectively reduced to the (Z)-
successful but ester formation occurred to give the saturated alkene with a poisoned palladium catayst,30 and this gave
methyl ester 33. This proved satisfactory and then finally ester alkene 35 in 82% yield. This partial reduction was necessary as
hydrolysis and macrolactonisation28 of seco-acid 34 gave fluorinations of the ketone from the oxidised acetylene 16 lead
lactone 8 as a white waxy semi crystalline solid. Lactone 8 to decomposition in reactions with DAST. From here, a similar
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sequence of reactions as describe for the conversion of 14 to 8
was used to convert alcohol 35 to lactone 9. This lactone was
an oil at room temperature and it was not possible to obtain
an X-ray structure.
For the synthesis of lactone 10, (R)-olefin 11 was again used
as a starting material but this time converted to aldehyde 14.
This was achieved by hydroboration,31 followed by oxidation
with DMP (Scheme 6). The terminal acetylene 43 was prepared
by protection of 6-heptyn-1-ol 42. A coupling of alkyne 43 and
aldehyde 14 gave alcohol 16 in good yield. Following a similar
sequence to the conversions in Scheme 4 and Scheme 5,
alcohol 17 was converted to seco-acid 48, without having to
progress through the corresponding methyl ester. Macrolacton-
isation28 of seco-acid 48 gave lactone 10 as a white solid. This
lactone was also a wax but a suitable crystal was grown which
proved amenable to X-ray structure analysis, and the resultant
structure is shown in Fig. 6.
Fig. 6 X-ray crystal structure of musk lactones 8 (two conformers 8’
and 8’’ are obvious in the unit cell) and 10.
Scheme 5 Synthesis of musk lactone 9. Reagents and conditions: (a) mCPBA, DCM, r.t., 18 h, 55%; (b) (i) nBuLi, THF, −78 °C, 15 min. (ii) BF3·OEt2,
15 min. (iii) Epoxide 13, THF, −78 °C–r.t., 20 h, 60%; (c) palladium (5% on barium sulfate), quinoline, pyridine, H2 (1 atm), 22 h, 82% (d) DMP, DCM, r.t.,
2 h, 57%; (e) DAST, 50 °C, 18 h, 27%; (f) DDQ, DCM, H2O, r.t., 2 h, 70%; (g) BAIB, TEMPO, CH3CN, H2O, r.t., 18 h, 49%; (h) palladium on carbon
(10 wt%), H2, MeOH, r.t., 18 h, 59%; (i) LiOH, THF, H2O, r.t., 3 h, 70%; ( j) 2,4,6-Trichlorobenzoyl chloride, NEt3, THF, r.t., 2.5 h. (ii) 4-DMAP, toluene,
r.t., 3.5 h, 52%.
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Scheme 6 Synthesis of musk lactone 10. Reagents and conditions: (a) (i) 9-BBN dimer, THF, 0 °C–r.t., 23 h. (ii) EtOH, NaOH (2 N), H2O2, 0 °C–r.t.,
3 h, 59%; (b) DMP, DCM, r.t., 1 h, 100%; (c) NaH, PMBCl, DMF, 0 °C–r.t., 18.5 h, 87%; (d) (i) nBuLi, THF, −78 °C, 30 min. (ii) Aldehyde 14, THF, −78 °C–
r.t., 20 h, 80%; (e) DMP, DCM, r.t., 2 h, 61%; (f) DAST, 50 °C, 18 h, 62%; (g) DDQ, DCM, H2O, r.t., 2 h, 88%; (h) BAIB, TEMPO, CH3CN, H2O, r.t., 7 h,
48%; (i) palladium hydroxide on carbon (20 wt%), H2, THF, r.t., 18 h, 46%; ( j) (i) 2,4,6-trichlorobenzoyl chloride, NEt3, THF, r.t., 2.5 h. (ii) 4-DMAP,
toluene, r.t., 3.5 h, 67%.
X-ray structures
that there was no significant change in taste or smell when a
hydrogen was replaced by a fluorine. For example, for the rasp-
berry ketone 49 a systematic fluorine scan generated analogues
49a–d, however this resulted in little change to the smell,
whereas the same systematic replacement by a methyl has a
much more profound effect on the organoleptic properties.33
They concluded that the fluorine did not induce a significant
conformational or steric/shape change in this case, whereas
the methyl analogues do. In the case of musk lactone 50 and
analogue 50a, the fluorine located alpha to the ketone made a
significant difference in the smell. This was attributed to a
conformational change induced by the fluorine, although no
conformational analysis was carried out.34
Lactone 8 has two conformers 8′ and 8″, which are present in a
1 : 1 ratio within the unit cell. It is immediately apparent that
the CF2 groups locate at corner positions, thus the anticipated
role of the CF2 group is as predicted. Also for X-ray structures
8′ and 10 adopt the anticipated Kraft and Cadalbert confor-
mations (Fig. 3). Structure 8′ corresponds to the [3434]-4 struc-
ture which has the methyl group at an edge position, and
structure 8″ corresponds to the [3344]-1 structure with the
methyl group at a corner. Presumably they are close in energy.
For lactone 10 the predicted Kraft and Cadalbert [3344]-1 struc-
ture is also observed. Lactone 9 is a liquid at room temperature
and we could not obtain any X-ray structural data, although we
predict that the Kraft and Cadalbert structure [3434]-1, will be
relevant (see theory study below).
Lactones 8–10 all smell rather similar and all retain a plea-
sant muskoid odour, with the additional descriptors, ‘weak
hint of green, powdery’.32 A distinct smell differential between
the compounds proved difficult to discern even for compound
8 despite its having four fluorine atoms. So we could not draw
any significant conclusions from the smell analysis, except to
conclude that they retained a pleasant odour.
Michel and Schlosser report33,34 the only other examples
that we are aware of where fluorine substitutions for hydrogen
have been used as a probe to examine fragrance. They explored
several flavour and fragrance compounds and in general found
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Fig. 7 The calculated lowest energy geometries for 8, 9 and 10. Relative Gibbs free energies calculated at the B3LYP-D3/6-311+G** level in kcal
mol−1 are given between parenthesis. For full details see ESI.†
Computational studies
phase matches the experimental X-ray structure 8′ (Fig. 6) and
was the anticipated Kraft and Cadalbert structure at the outset.
Theory calculations have been carried out on the three lac- Conformer 8–27, which emerges as a higher energy conformer
tones 8–10 in order to explore their conformations further. (1.35 kcal mol−1) in this study, matches the experimental X-ray
Minimum energy conformers of the lactones in the gas phase structure 8″. That only two calculated conformers, 8–14 and
were located through a Monte Carlo conformational search at 8–27, were observed experimentally can be attributed to order
the MMFF level with the Spartan 14 program,35 and using an and packing in the crystal, where a range of conformers is not
initial temperature of 5000 K in the simulated-annealing algor- expected. Similarly lactone 10 emerges from this study with
ithm. This procedure found 9650 conformers for lactone 8, many low energy conformers, all with square/rectangular ring
9714 conformers for lactone 9 and 7948 conformers for geometries. Most of them have the CF2 groups locating at
lactone 10. The 30 lowest energy minima in the gas phase for corner locations. Indeed, both the calculated global minimum
each compound were optimised at the B3LYP-D3/6-311+G** 10-5 (0.00 kcal mol−1) and the second lowest energy conformer
level and frequency calculations were carried out at the same 10-7 have squared carbon ring geometries with CF2 groups at
level by using the Gaussian 09 program, Revision D.01.36 No corners (Fig. 7). Conformer 10-7 has a geometry which
negative harmonic vibrational frequencies were observed and, matches the observed X-ray structure of 10. Taking structures 8
hence the conformers are true energy minima. The same fre- and 10 together, the outcomes suggest that the computational
quency calculations were used to obtain thermodynamic cor- analysis was able to identify the experimental structures, as
rections affording enthalpies and Gibbs free energies at low energy stable conformers. These outcomes give some con-
ambient, standard pressure and temperature for all confor- fidence that the calculated lowest energy geometries are rele-
mers of 8–10 in the gas phase.
vant experimentally. For lactone 9 we have to rely on theory
The lowest energy conformers of lactones 8–10 in the gas only. It emerges as a very flexible structure, with many calcu-
phase, calculated at the B3LYP-D3/6-311+G** level corrected by lated low energy conformers, however it is noteworthy that the
Gibbs free energies, are shown in Fig. 7. The 30 lowest energy lowest energy conformer, 9-6 is almost identical to the antici-
conformers for each lactone are detailed in the ESI (see pated Kraft and Cadalbert [3434]-1 structure for musk lactone.
Fig. S1–S3 and Tables S1–S3†). The lowest energy conformers Thus the predictive power of the CF2/corner hypothesis holds
for 8 all have square/rectangular ring shapes and all but con- well.
former 8-1 have their CF2 groups located at corner positions.
In summary we have carried out a synthesis and structural
Notably, the calculated global minimum conformer in the gas study on three CF2 containing analogues of musk lactone 4.
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Acknowledgements
We thank EPSRC for a grant and we thank the EPSRC National
Mass Spectrometry Service, Swansea and Mrs Caroline
Horsburgh (University of St Andrews) for mass spectrometery
analysis. CNvH also thanks the Fluorine Division of the Ameri-
can Chemical Society for a Moissan Summer Undergraduate
Fellowship. RAC thank FAPESP for a fellowship (#2015/00975-
7) and MB thanks EaStCHEM and the University of St Andrews
for support access to a computing facility managed by
Dr H. Fruchtl. We thank Prof. Paul Davey and Dominique
Lelievre of Givaudan, Schweiz AG, Dübendorf, Switzerland, for
faciliting the olfactive assessments.
21 Using
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