Efficient macrocyclization by a novel oxy-oxonia-cope reaction: Synthesis and olfactory properties of new macrocyclic musks

Article abstract of DOI:10.1002/chem.201200882

Musk made to odor: A new oxy-oxonia-Cope macrocyclization to (3Z)-configured cycloalk-3-en-1-yl formates is reported, which is useful in the synthesis of unsaturated and saturated macrocyclic ketones (see scheme). The synthesized structures provide new insight into the structure-odor correlation of musks, making it likely for macrocyclic and linear alicyclic musks to address the same olfactory receptors.

Full text of DOI:10.1002/chem.201200882

COMMUNICATION
DOI: 10.1002/chem.201200882
Efficient Macrocyclization by a Novel Oxy-Oxonia-Cope Reaction:
Synthesis and Olfactory Properties of New Macrocyclic Musks
Yue Zou,[a, b] Halima Mouhib,[c] Wolfgang Stahl,[c] Andreas Goeke,[b]
Quanrui Wang,*[a] and Philip Kraft*[d]
Dedicated to Dr. Roman Kaiser
Musk odorants are indispensable in perfumery to lend
sensuality to fine fragrances, a nourishing effect to cosmet-
ics, and a comforting feeling to laundry.[1] Due to a certain
phototoxicity of nitro musks, and the lack of biodegradation
of polycyclic musks,[1] the two most important musk families
at present are macrocycles 1–5 (Figure 1), derived from the
natural lead muscone (1), and linear alicyclic musks such as
6–7, the odor of which has been attributed to horseshoe-
shaped conformers that mimic macrocyclic rings on the
odorant receptors.[1]
Both musk families, linear[1c] as well as macrocyclic,[2]
comprise highly flexible structures, which make double
bonds and methyl groups ideal design elements to rigidify
and conformationally constrain them. The two most power-
ful macrocyclic musks, (+)-(3R,5Z)-5-muscenone (2)[3] and
Figure 1. Macrocyclic musks 1–5, and linear musk structures 6 and 7.
(13R,10Z)-Nirvanolide (3) both feature a double bond and
a methyl substituent, and Cosmone (4) can be regarded as
a “nor-muscenone”. By introduction of two double bonds
such as in 5, the conformational freedom can be further re-
stricted, enabling a targeted design of potent musk odor-
ants.[4] Methyl substituents determine the conformational
space of linear musks to a great extend; yet, as apparent
from the two dehydro-derivatives 6 and 7 of Serenolide
(Figure 1), a shift of a double bond can change the odor
threshold by a factor of over 150.[5]
The synthesis of further unsaturated macrocyclic musks
can shed light upon similarities in the structure–odor corre-
lation of these two musk families, and to this purpose we
herein report on the intramolecular application of a new re-
action[6] of b,g-unsaturated aldehydes with different alde-
hydes in the presence of Lewis acids. The projected macro-
cyclization can be regarded as an oxy-version of the estab-
lished 2-oxonia Cope rearrangement,[7,8] but as illustrated in
Scheme 1, could as well proceed through compound 11 in
a Prins-type[9,10] manner by coordination of the Lewis acid
to the opposite formyl function. Both pathways would how-
ever lead to the same macrocyclic alk-3-en-1-yl formates 10.
Hydride reduction and subsequent oxidation of 10 should
provide b,g-unsaturated macrocyclic ketones, which could
then be hydrogenated to the saturated macrocycles; thus,
could then also open up a new route to (ꢀ)-muscone (1).[11]
As delineated in Scheme 2, the dicarbonyl substrates 8a–g
were prepared from commercial bromo alcohols 12a–g by
protection as tert-butyldiphenylsilyl (TBDPS) ethers 13a–g,
and subsequent Finkelstein reaction[12] with KI in acetone to
afford iodides 14a–g in excellent yields. Deconjugated a-al-
kylation[13] of the Weinreb amide 15[14] with 14a–g afforded
alkylated amides 16a–g in 39–60% yield, with unreacted
14a–g being recovered. Deprotection of the Weinreb amides
16a–g with tetrabutylammonium fluoride (TBAF) in THF
[a] Dr. Y. Zou, Prof. Dr. Q. Wang
Department of Chemistry, Fudan University
220 Handan Road, Shanghai, 200433 (P.R. China)
Fax : (+86)216-564-1740
E-mail: qrwang@fudan.edu.cn
[b] Dr. Y. Zou, Dr. A. Goeke
Givaudan Fragrances (Shanghai) Ltd
298 Li Shi Zhen Road, Shanghai, 201203 (P.R. China)
[c] Dr. H. Mouhib, Prof. Dr. W. Stahl
RWTH Aachen University, 52056 Aachen (Germany)
Institute of Physical Chemistry
[d] Dr. P. Kraft
Givaudan Schweiz AG, Fragrance Research
ꢀberlandstrasse 138, 8600 Dꢁbendorf (Switzerland)
Fax : (+41)44-8242926
E-mail: philip.kraft@givaudan.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200882.
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Scheme 3. Effect of the dilution on the macrocyclization of 8c.
By using a syringe pump at 1.0 mm on a preparative scale,
compound 10c was isolated in 45% yield with a Z/E ratio
of 99:1. As summarized in Table 1, the yield and Z/E ratio
of this new macrocyclization strongly depended upon the
ring size, with 8a and 8b affording no cyclization products.
Scheme 1. The two possible pathways of the new macrocyclization.
Table 1. Correlation of ring size and yield for the cyclization of the di-
AHCTUNGTRENNUNG
aldehydes 8a–g to cycloalk-3-en-1-yl formates 10a–g.[a]
Entry
n
Ring size
[n+6]
Product
Z/E
Yield
[%][c]
N
ratio[b]
a
b
c
d
e
f
6
7
8
9
10
11
12
12
13
14
15
16
17
18
10a
10b
10c
10d
10e
10 f
10g
–
–
0
0
99:1
82:18
95:5
98:2
85:15
45
43
91
35
90
g
[a] Reaction conditions: BF3·OEt2 (5 equiv), syringe pump, c=1.0 mm in
1,2-dichloroethane at RT. [b] Determined by GC and NMR spectroscopy.
[c] Isolated product yields after flash chromatography.
Yields for the 16- and 18-membered rings both reached
90%, whereas those for 14-, 15- and 17-membered rings
were in the 40% region.
Scheme 2. Synthetic route to the dicarbonyl substrates 8a–g, and macro-
cyclization to large-ring cycloalk-3-en-1-yl formates 10a–g.
Next, it was envisaged to further constrain the conforma-
tional freedom of the smallest attainable ring by introduc-
tion of another Z-configured double bond, thereby con-
structing a double-unsaturated structural isomer 25 of (5Z)-
Cosmone (4). The synthesis of 25 by reaction of the Wittig
salt 19 of 5-bromopentanol with 6-chlorohexanal, TBDPS
protection, Finkelstein trans halogenation, alkylation of the
Weinreb amide 15, hydride reduction/PCC oxidation, BF3-
mediated cyclization, and concluding hydride reduction/PCC
oxidation is summarized in Scheme 4. Due to the additional
ring strain of 24, the yield of the macrocyclization was 33%
(slightly lower than that for the cyclization of 10c); howev-
er, both double bonds were exclusively Z-configured.
As in the synthesis of 25, the cycloalk-3-en-1-yl formates
10a–g are transformed to the corresponding unsaturated
macrocyclic ketones by simple hydride reduction/PCC oxi-
dation. This is exemplified in Scheme 5 for the synthesis of
3-muscenone (26) from 10d. Catalytic hydrogenation of 26
completes a straightforward synthesis of (ꢀ)-muscone (1).[11]
provided the corresponding hydroxyamides 17a–g, free of
any a,b-double-bond isomers. Hydride reduction of 17a–g,
and subsequent pyridinium chlorochromate (PCC) oxidation
then furnished the dicarbonyl substrates 8a–g in yields of
40–64%.
2-(Prop-1-en-2-yl)tridecanedial (8c) was chosen as the
test substrate for the projected macrocyclization; however,
treatment with BF3OEt2 (0.3 equiv) in dichloroethane af-
forded 10c in trace amounts only. As delineated in
Scheme 3, the dimer 18 was the major isolated product. Di-
merization was suppressed under high-dilution conditions
(Scheme 3), with the best yield of 10c (52%) being obtained
at 0.4 mm by slow addition of 8c to the BF3OEt2 solution
through a syringe pump. All attempts to increase the yields
by use of other Lewis acids or Amberlyst 15 were unsuccess-
ful.
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Synthesis and Olfactory Properties of New Macrocyclic Musks
COMMUNICATION
Scheme 4. Synthesis of the double-unsaturated structural isomer 25 of
(5Z)-Cosmone (4).
Figure 2. Overview of the olfactory properties of the compounds with
measured odor thresholds. The thresholds calculated according to the ol-
factophore model in Figure 3 are given in brackets.
Scheme 5. Synthesis of (ꢀ)-muscone (1) from 10d.
The olfactory data of the b,g-unsaturated macrocyclic ke-
tones synthesized are summarized in Figure 2, together with
their detection thresholds (th) as determined by GC-olfac-
tometry. In contrast to a (5Z)-double bond of 2,[11f] the b,g-
double bond generally decreases the musk character and in-
tensity of these macrocyclic ketones. Within their respective
series, the 16-membered rings 28 and 29 turned out to be
the most potent and the most musky, which also indicates
that a b,g-double bond does rather populate inactive con-
formers. Usually only observed for unsubstituted 13-mem-
bered rings,[15] woody facets prevail in the 3-methyl-substi-
tuted 14-membered rings 25 and 27, whereas the molecular
dimensions of the musk receptors are reached with the
faint-to-odorless 18-membered analogues. The (10Z)-double
bond in 25 also has a negative influence on the odor thresh-
old, and makes the musk facets in the odor of 27 almost dis-
appear, indicating a negative but critical influence.
This critical influence makes the macrocyclic odorants 25–
30 ideal candidates for the generation of an olfactophore
model to test whether or not macrocyclic and linear alicyclic
musks could bind to the same set of receptors. The respec-
tive musk olfactophore model, derived with the Discovery
Studio 3.0 software package,[16] is depicted in Figure 3, and
albeit with a correlation of 0.54 it is not entirely convincing,
it still suggests that both families indeed should address the
same receptor sets. In Figure 3a, one can recognize how 25
(gold color) sticks out from the binding pocket that is nicely
filled up by macrolide 5. The estimated 10 ngLꢁ1 threshold
for 25 still is too optimistic, but goes in the right direction.
On the other hand, Figure 3b convincingly illustrates how
the linear musk 6 mimics the shape of the Nirvanolide ste-
reoisomer 3 on the olfactophore model, both constituting
potent musks. However, 6 is only about five times more in-
tense than 7 in the model, far less than in reality. Yet, while
in reality the hydrophobes are polarizable, in the olfacto-
phore model the double bond shift can only be accounted
for by the respective difference in conformational space. A
further comparison of the experimental data with the calcu-
lated values, as well as the geometric parameters for the ol-
factophore model, can be found in the Supporting Informa-
tion.
Finally, it remains to decide on the mechanistic path for
the BF3-catalyzed macrocyclization of 8 (Scheme 1). There-
fore, the reaction was investigated by density functional
theory at the B3LYP/6-31G(d) level using the Gaussian 03
program package.[17] The transition states (TS) were opti-
mized using the Berny algorithm,[18] whereas harmonic fre-
quency calculations were carried out to verify the nature of
the stationary points. Altogether, 16 TS were obtained and
energetically compared in Figure 4a, differentiated into
those yielding (Z)-10c [TS-(Z)] and (E)-10c [TS-(E)], re-
spectively, with the oxy-oxonia-Cope TS depicted in red,
and the Prins-type TS in blue. The lowest TS for the oxy-
oxonia-Cope TS-9-(Z)-1 (Figure 4b, 44.80 kJmolꢁ1) and the
Prins-type case TS-11-(Z)-1 (Figure 4c, 87.49 kJmolꢁ1) are
shown as well, both leading to the Z-configured product
(Z)-10c.
In accordance with the experimental results (Z/E, 99:1),
the three lowest energy TS all afford the Z-configured prod-
uct (Z)-10c. The lowest transition state affording the E-con-
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Q. Wang, P. Kraft et al.
Figure 4. a) Gas-phase relative energies (using the sum of electronic and
zero-point energies in kJmolꢁ1) for the oxy-oxonia-Cope (red) and the
Prins (blue) macrocyclization of 8c at the B3LYP/6-31G(d) level.
b) Lowest oxy-oxonia-Cope TS [TS-9-(Z)-1], and c) lowest Prins-type TS
[TS-11-(Z)-1] for the macrocyclization of 8c to 10c.
figured product (E)-10c is 67.29 kJmolꢁ1 higher in energy
than the lowest transition state TS-9-(Z)-1, with both pro-
ceeding according to an oxy-oxonia-Cope mechanism. Both,
the lowest oxy-oxonia-Cope TS-9-(Z)-1 (Figure 4b) and the
lowest Prins TS-11-(Z)-1 (Figure 4c) are in a chair-type con-
formation, with the chair necessarily occupying gauche-
corner positions. In TS-9-(Z)-1, the macrocyclic ring adapts
a rectangular [3434] diamond-lattice conformation[19] of all-
trans edges, and as one would expect to be energetically
most favorable, the chair is situated in the gauche-corner of
the longest all-trans edge. Such a favorable position is not
possible for the Prins case, in which the 14-membered mac-
rocyclic ring is forced into a [23333] conformation.[19] This
additionally favors the oxy-oxonia-Cope path over the Prins
path, especially for even-membered ring systems. We cannot
completely rule out the existence of further transition states
with slightly different conformations of the macrocyclic ring
system, but this should not change the overall picture. These
calculations are, however, only valid in the gas phase, and
solvent effects can exert some influence. But even then, one
would expect complete Z-selectivity at room temperature,
Figure 3. Musk olfactophore model derived with the Discovery Studio 3.0
software package,[16] featuring three aliphatic hydrophobes (cyan) and
two hydrogen-bond acceptors (green), with a) macrocycles 5 (steel, calcd
detection threshold (th) 0.21 ngLꢁ1) and 25 (gold), and b) linear musk 6
(gold, calcd th 0.52 ngLꢁ1) and macrolide 3 (steel, calcd th 0.06 ngLꢁ1).
as according to simple Boltzmann statistics N
NACHTUNGTRENNUNG
ACHTUNGTREN[NGNU TS-9c-(E)-1)]/
[TS-9c-(Z)-1)]=1.56ꢃ10ꢁ12, or 1 in 2/3 trillion transition
states would lead to (E)-10c only, whereas 1 in 30 million
reactions would run according to the Prins-type mechanism.
It therefore seems likely that the observed E isomers of
10c–g resulted from a subsequent isomerization reaction. To
verify this hypothesis, 10d (Z/E=82:18) was reduced, the
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resulting Z- and E-isomeric cyclopent-3-en-1-ols separated
by flash chromatography, and transformed into isomerically
pure formates (Z)-10d and (E)-10d that were then treated
separately with BF3·OEt2 in dichloroethane under exactly
the same conditions as in the cyclization reaction. After 24 h
of stirring, (Z)-10d partially isomerized to (E)-10d, whereas
(E)-10d did not isomerize to (Z)-10d. Thus, it is indeed
most likely that the (E)-10c–g isomers result from a subse-
quent isomerization reaction. The new macrocyclization 8!
(Z)-10 accordingly proceeds almost exclusively on an oxy-
oxonia-Cope path.
We have reported on a new efficient macrocyclization of
2-isopropenyl dialdehydes 8 to (3Z)-configured cycloalk-3-
en-1-yl formats (Z)-10 in the presence of Lewis acids. These
findings proved useful in the synthesis of several unsaturat-
ed and saturated macrocyclic ketones, including (ꢀ)-mus-
cone (1), and allowed additional insight into the structure–
odor correlation of musks, resulting in an olfactophore
model, which makes it likely that macrocyclic and linear ali-
cyclic musks address the same set of olfactory receptors.
[11] Selected more recent syntheses of (ꢀ)-muscone (1): a) K. H.
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Experimental Section
General procedure: Cyclization of 2-(prop-1-en-2-yl)heptadecanedial (8g)
to (3Z)-3-methylcyclooctadec-3-enyl formate (10g): At room temperature,
under N2 atmosphere, and with the aid of a syringe pump, a solution of
dialdehyde 8g (308 mg, 1.00 mmol) in 1,2-dichloroethane (200 mL) was
added at a rate of 2 mLhꢁ1 to a vigorously stirred solution of BF3·OEt2
(710 mg, 5.0 mmol) in 1,2-dichloroethane (800 mL). After 100 h, the addi-
tion was complete, and the reaction mixture was stirred at room tempera-
ture for another 1 h, prior to quenching by addition of saturated aq.
NaHCO3 (10 mL). The organic layer was separated and dried with
MgSO4, the solvent evaporated under reduced pressure, and the crude
product purified by flash chromatography (hexane/MTBE, 25:1, Rf =
0.30) to furnish 10g (277 mg, 90%).
[12] H. Finkelstein, Ber. Dtsch. Chem. Ges. 1910, 43, 1528–1532.
[13] For examples of deconjugated a-alkylation of amides, see: a) G. E.
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[14] For examples of a-alkylation of Weinreb amides, see: a) A. N. Cher-
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[16] Discovery Studio 3.0–advanced software package for life science re-
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Acknowledgements
We thank Dr. G. Brunner for NMR experiments, Dr. F. Kuhn and Dr. J.
Schmid for MS data, K. Grman for odor-threshold determinations, and
A. E. Alchenberger as well as D. Lelievre for olfactory evaluations. The
Center for Computing and Communication at the RWTH Aachen Uni-
versity is acknowledged for free computational time, and the state of
North Rhine-Westphalia for additional funding.
[17] Gaussian 03, Revision E. 01, M. J. Frisch, G. W. Trucks, H. B. Schle-
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Keywords: fragrances
reaction · rearrangement · structure–odor relationship
· ketones · macrocycles · Prins
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Published online: && &&, 2012
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Synthesis and Olfactory Properties of New Macrocyclic Musks
COMMUNICATION
Macrocycles
Y. Zou, H. Mouhib, W. Stahl,
A. Goeke, Q. Wang,*
P. Kraft* ....................... &&&& — &&&&
Efficient Macrocyclization by a Novel
Oxy-Oxonia-Cope Reaction:
Synthesis and Olfactory Properties of
New Macrocyclic Musks
Musk made to odor: A new oxy-
synthesized structures provide new
oxonia-Cope macrocyclization to (3Z)-
configured cycloalk-3-en-1-yl formates
is reported, which is useful in the syn-
thesis of unsaturated and saturated
macrocyclic ketones (see scheme). The
insight into the structure–odor correla-
tion of musks, making it likely for mac-
rocyclic and linear alicyclic musks to
address the same olfactory receptors.
No More Musk Suicides!
A poem by Shangyin Li (813–858)
from the late Tang Dynasty
reported the tragic case of a musk
deer that committed suicide rather
than let his hunters have his musk
pods. On page && ff., P. Kraft
and co-workers report a versatile
macrocyclization, which utilizes an
unprecedented oxy-oxonia-Cope
reaction. This novel macrocycliza-
tion can also be employed for
a new synthesis of muscone. The
book featuring the ancient drawing
is held by a Tibetan Alchi Lama
Monk.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!