(4E,8Z)-12-methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue: Conformationally constrained double-unsaturated macrocyclic musks by ring-closing alkyne metathesis

Article abstract of DOI:10.1055/s-2008-1032135

The double-unsaturated macrocyclic lactones (4E,8Z)-12- methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue (4E,9Z)-13- methyloxacyclopentadeca-4,9-dien-2-one, designed as new potent musk odorants by molecular modeling, were synthesized by ring-closing alkyne metathesis in the presence of 10 mol% of Schrock's alkylidyne catalyst, and subsequent Lindlar hydrogenation. Demethylation of citronellol, induced by nitrous acid, afforded the 3-methyloct-6-yn-1-ol building block. The substrates for the alkyne metathesis were prepared by Steglich esterification of citronellol with the 3E-configured non-3-en-7-ynoic and dec-3-en-8-ynoic acids, accessible by β,γ-selective Knoevenagel condensation from the corresponding alkynals hept-5-ynal and oct-6-ynal, which were synthesized by Eschenmoser-Ohloff fragmentation of the epoxide of 2-methylcyclohex-2-enone, and methylation of hex-5-yn-1-ol, respectively. Both target structures, (4E,8Z)-12-methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue, emanated most pleasant and powerful musk odors. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032135

PAPER
543
(
4E,8Z)-12-Methyloxacyclotetradeca-4,8-dien-2-one and Its 7a-Homologue:
Conformationally Constrained Double-Unsaturated Macrocyclic Musks by
Ring-Closing Alkyne Metathesis
M
P
acrocyclic
M
h
usks by
M
et
i
athesi sl ip Kraft,* Carola Berthold1
Givaudan Schweiz AG, Fragrance Research, Überlandstrasse 138, 8600 Dübendorf, Switzerland
Fax +41(44)8242926; E-mail: philip.kraft@givaudan.com
Received 5 October 2007; revised 19 November 2007
4Z
8E
10Z
Abstract: The double-unsaturated macrocyclic lactones (4E,8Z)-
2-methyloxacyclotetradeca-4,8-dien-2-one and its 7a-homologue
4E,9Z)-13-methyloxacyclopentadeca-4,9-dien-2-one, designed as
4E/Z
3
1
(
1
5
15
16
1
3
new potent musk odorants by molecular modeling, were synthe-
sized by ring-closing alkyne metathesis in the presence of 10 mol%
of Schrock’s alkylidyne catalyst, and subsequent Lindlar hydroge-
nation. Demethylation of citronellol, induced by nitrous acid, af-
forded the 3-methyloct-6-yn-1-ol building block. The substrates for
the alkyne metathesis were prepared by Steglich esterification of
citronellol with the 3E-configured non-3-en-7-ynoic and dec-3-en-
O
O
O
O
Nirvanolide® (2)
muscenone (1)
3
O
strong musky,
erogenous
8E/Z
6Z
3E
1
6
15
8
-ynoic acids, accessible by b,g-selective Knoevenagel condensa-
O
10Z
tion from the corresponding alkynals hept-5-ynal and oct-6-ynal,
which were synthesized by Eschenmoser–Ohloff fragmentation of
the epoxide of 2-methylcyclohex-2-enone, and methylation of hex-
O
O
4
5
musky, soapy,
pear, mushroom
musky, greasy,
waxy
5
-yn-1-ol, respectively. Both target structures, (4E,8Z)-12-methyl-
oxacyclotetradeca-4,8-dien-2-one and its 7a-homologue, emanated
most pleasant and powerful musk odors.
Figure 1 The most powerful macrocyclic musks muscenone (1) and
Nirvanolide (2) in comparison with the known double-unsaturated
macrocyclic musks 3–5
“
Key words: odorants, macrocycles, metathesis, musks, ring clo-
sure
Double bonds constitute electronegative elements that can
intensify the binding of an odorant to a complementary re-
ceptor site, but they are also of major importance in re-
stricting the conformational space of the macrocycles.
However, as long as only one double bond is present, the
ring remains quite flexible. This situation changes when
two double bonds are introduced, especially if one of
these is E-configured.
By providing a sweet, warm, and erogenous sensation,
musk odorants confer on perfumes that certain sensuality
that distinguishes them from being merely floral bouquets
or potpourris. Consequently, there is probably not a single
fragrance on the market that does not contain any musk
2
2
odorant. Macrocycles constitute the only class of musks
that occurs in nature: as ketones in the animal and as lac-
tones in the plant kingdom. Despite a relatively high price, As shown in Figure 1 for macrocycles 3–5, the odor of
their authenticity and natural character makes them highly double-unsaturated macrocycles changes dramatically
3
appreciated in perfumery. Today, the ketone muscenone with the position and configuration of the double bonds.
4
®
2
(
1) and the lactone Nirvanolide (2), both of which bear The strong, very erogenous animal musk note with sweet,
6
a methyl substituent and one double bond, constitute the warm sandalwood accents that (4E/Z,8E)-oxacyclohexa-
most efficient macrocyclic musks used in perfumery deca-4,8-dien-2-one (3) emanates becomes soapy with
(
Figure 1). Their musk odors depend critically on both the unpleasant pear- and mushroom-like undertones in the
2
,5
7
position and configuration of the double bond and that (3E,8E/Z)-isomer 4 (Figure 1). Only one other double-
3
of the methyl substituent. Most decisive is the latter, and unsaturated macrocyclic musk has been reported in the lit-
the methyl group is best be situated on a different trans- erature, the 6Z,10Z-configured cyclopentadeca-6,10-di-
8
configured edge than is the carbonyl osmophore, which enone (5) (Figure 1), which Fehr et al. obtained elegantly
acts as the hydrogen-bond acceptor on the receptor bind- upon iterative fragmentation of a 1,3,5-functionalized tri-
ing site. Placed that way, a methyl substituent will not cyclic system. However, its greasy, waxy, relatively weak
hinder the receptor interaction, but will instead imitate a musk odor was rather disappointing.
larger ring, without lowering the vapor pressure as much
To avoid transannular interactions, the gauche atoms in a
macrocyclic ring tend to be separated as far as possible
from one another. They form the corners of a regular poly-
gon, the edges of which consist of trans-configured ali-
phatic chains. An ester moiety tends to be accommodated
in the middle of such a zigzag chain, just where an E-con-
as would result from a correspondingly large perimeter.3
SYNTHESIS 2008, No. 4, pp 0543–0550
x
x
.
x
x
.2
0
0
8
9
Advanced online publication: 11.01.2008
DOI: 10.1055/s-2008-1032135; Art ID: T15807SS
Georg Thieme Verlag Stuttgart · New York
©

5
44
P. Kraft, C. Berthold
PAPER
figured double bond would prefer to be situated. Both fa- Retrosynthetic analysis suggested the introduction of the
vor the longest edge, but an E-configured double bond Z-configured double bond by Lindlar hydrogenation of
wins energetically over an ester function. Whenever pos- the corresponding oxacycloalkenynones, which could be
sible, a Z-configured double bond will replace one gauche accessible by ring-closing alkyne metathesis as, for in-
corner and thereby reduce the overall torsional (Pitzer) stance, applied by Fürstner and Seidel in their elegant
strain in the ring. In the minimum-energy conformer of civetone synthesis.10 There are quite a few examples for
“
Nirvanolide (2), delineated in Figure 2, the 10Z-double the compatibility of alkyne metathesis with double bonds
1
1,12
bond thus defines one corner, the ester moiety a trans- such as those present in 1,3-enynes,
terminal
configured edge of three bonds, and the methyl substitu- alkenes,1 styrenes, enoates, non-conjugated exocyclic
ent comes to lie on an all-trans side situated in between, alkenes, and b,g-unsaturated esters. In the synthesis of
imitating a larger ring on the receptor, even if the corner prostaglandin-E -1,15-lactone and various analogues
3,14
15
1
6
15
17
18
2
19
atoms move by one position. According to the Dale by alkyne metathesis, Fürstner et al. even employed sub-
9
system, these configurations of macrocyclic rings are strates with a 1,6-enyne moiety. Therefore, the mechanis-
designated by stating the number of bonds between the tic differences between alkyne and enyne metathesis20
corner atoms in square brackets, starting with the shortest seemed sufficiently pronounced to allow alkyne metathe-
trans-configured methylene chain and moving in the di- sis on substrates with a 1,5- or 1,6-enyne relation, even
rection of the next shortest. The sum of the numbers in without the double bond being deactivated by conjugation
square brackets thus corresponds to the respective ring with a carbonyl function. So, this synthetic plan seemed to
size (Figure 2).
us a promising approach.
The 4E-configured double bond on the corresponding car-
boxylic acid building block should be accessible by
Knoevenagel condensation of hept-5-ynal (12) and oct-6-
ynal (13) with malonic acid in the presence of piperidinium
8
Z
9Z
10Z
4E
4E
1
5
14
15
21
1
3
1
2
13
acetate (Scheme 1). This latter reagent catalyzes the de-
hydration of the intermediate hydroxymalonic acid and
the subsequent isomerization to the b,g-unsaturated
dicarboxylic acid, which then decarboxylates. Under stan-
dard reaction conditions, the a,b-unsaturated dicarboxylic
acid cannot decarboxylate, so that the equilibrium is shift-
O
O
O
O
O
O
Nirvanolide® (2)
6
7
10Z
9Z
8Z
2
1
[
123242]
13
ed towards the b,g-unsaturated system. The other re-
13
[123342]
13
[
23424]
4E
4E
O
O
H2O2,
NaOH, MeOH
H2NNHTs,
AcOH, CH2Cl2
O
O
O
O
O O
n
n
O
Figure 2 Minimum-energy conformation (PM3) of Nirvanolide“
2), and the two target structures 6 and 7 with their respective global
energy minima (PM3)
58%,
53%,
25%
6
9%
(
8
9
(n = 1)
(n = 2)
10 (n = 1)
11 (n = 2)
CH2(COOH)2,
C5H10NH2 AcO ,
DMSO
+
–
To maximize the latitudinal dimensions, it was desired to
fix the 13-methyl group by further restricting the flexi-
bility of the macrocyclic ring. Introducing a 4E-double bond
in the edge adjacent, and a Z-double bond opposite to the
carbonyl group should force the methyl substituent to pro-
trude from the side opposite to the E-configured double
bond, thereby imitating a larger ring (Figure 2). To take
full advantage of this effect, a high vapor pressure must,
however, be ensured. Consequently, the target structures
should possess a 14- or 15-membered ring, which are the
smallest to occur in macrocyclic musks. These reflections
led to the design of (4E,8Z)-12-methyloxacyclotetradeca-
O
n
n
3E
43%,
42%
O
OH
1
1
2 (n = 1)
3 (n = 2)
14 (n = 1)
15 (n = 2)
1. DHP, PTSA,
CH2Cl2
. BuLi, MeI, THF
2
OH
3. PPTS, MeOH
OH
6
1%
1
6
17
4
,8-dien-2-one (6) and (4E,9Z)-13-methyloxacyclopenta-
1
2
. MsCl,
Et3N, Et2O
1. DIBAL-H,
THF
deca-4,9-dien-2-one (7) as target molecules (Figure 2).
And indeed, in accord with these conformational consid-
erations, PM3 calculations confirmed that the 13-methyl
substituent extends the latitudinal dimensions of both
macrocyclic rings in the [123242] and [23424] conforma-
tions that were found to be the global energy minima of
the target structures 6 and 7, respectively (Figure 2).
. KCN, DMF
69%
2. H2O
83%
O
N
1
8
13
Scheme 1 Synthesis of the 3E-configured alk-3-en-(w–2)-ynoic
acids 14 and 15 from alkynals 12 and 13, obtained by Eschenmoser–
Ohloff fragmentation of 10, and elongation of hex-5-yn-1-ol (16), re-
spectively
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

PAPER
Macrocyclic Musks by Metathesis
545
quired building block should, for instance, be accessible nolysis of the monoterpene alcohol 19 furnished the cor-
from citronellol (19, Scheme 2) by ozonolysis and Corey– responding aldehyde in 96% yield after reductive workup
2
8
Fuchs reaction.
with dimethyl sulfide. Corey–Fuchs reaction in the pres-
ence of an eightfold excess of triethylamine, with quench-
ing by addition of iodomethane, then provided 3-
methyloct-6-yn-1-ol (20) in 41% overall yield after depro-
tection. The eightfold excess of triethylamine was neces-
sary to prevent cleavage of the THP protecting group,
which would otherwise lead to the corresponding bromide
by Appel–Lee reaction with the reactants present. How-
ever, independent of carrying out the methylation step in
the Corey–Fuchs reaction or separately on the terminal
alkyne, the 3-methyloct-6-yn-1-ol (20) isolated was
always accompanied by an additional 10% yield of
As outlined in Scheme 1, the synthesis of the 3E-config-
ured non-3-en-7-ynoic acid (14) commenced with the
2
2
Weitz–Scheffer epoxidation of commercially available
-methylcyclohex-2-enone (8), which afforded the 2,3-
epoxy ketone 10 in 58% yield. We obtained hept-5-ynal
12) in a good 53% yield from 10 by employing the stan-
dard conditions of the Eschenmoser–Ohloff fragmenta-
2
(
2
3,24
tion (Scheme 1).
The alkynal 12, however, turned out
to be very sensitive to even traces of acids, and decom-
posed partly upon chromatographic purification on silica
gel or alumina. Upon storage it also underwent slow rear-
rangement into the corresponding allene, and thus was
later directly employed, as crude material, in the next step.
3
-methylhept-6-yn-1-ol from incomplete methylation. It
turned out to be impossible to remove this terminal alkyne
completely by all means tried, also not as the THP ether
In analogy to the synthesis of 12, it was first attempted to
prepare the homologous oct-6-ynal (13) from 2-methylcy-
clohept-2-enone (9), which was accessible by a-methyla-
29
or on the following ester stage. Coutelier and Mortreux
had reported that alkyne metathesis of terminal alkynes
was possible in the presence of quinuclidine, but in our
hands this did not work. Thus, the Corey–Fuchs route to
alkynol 20 was abandoned.
2
5
tion of suberone (77%), bromination (73%), and
subsequent dehydrohalogenation with lithium carbonate
2
6
(
60%). The Weitz–Scheffer epoxidation of 9, followed
by an analogous Eschenmoser–Ohloff fragmentation of
the 2,3-epoxy ketone 11 gave, however, a poor 17% total
yield for oct-6-ynal (13) from 9 (Scheme 1), which corre-
sponds to a yield of only 6% from suberone.
1
4 or 15
NaNO2,
AcOH, H2O
OH
DCC, DMAP,
Et2O
OH
2
6%
31%,
It was therefore decided to follow the alternative synthetic
4
7%
2
7
scheme of Herndon and co-workers, which was modi-
fied by protection of the hydroxy function during the
methylation step. Commercially available hex-5-yn-1-ol
2
0
citronellol (19)
(
16) was protected as a tetrahydropyran-2-yl (THP) ether
by reaction with 3,4-dihydro-2H-pyran (DHP) and then
W(Ot-Bu)3
n
methylated with iodomethane to furnish hept-5-yn-1-ol
PhCl
(
17) in 61% yield after cleavage (Scheme 1). Cyanation
via the mesylate afforded the corresponding nitrile 18 in
9% yield, which after reduction with diisobutylalumi-
num hydride and aqueous workup provided oct-6-ynal
13) in 83% yield (Scheme 1). With a total yield of 36%
7
4
8%,
2%
O
O
6
2
1 (n = 1)
22 (n = 2)
(
8
9
Z,
Z
H2,
from hex-5-yn-1-ol (16), this route was thus far more ef-
ficient for preparing the homologous aldehyde 13. In ad-
dition, oct-6-ynal (13) proved to be significantly more
stable than hept-5-ynal (12), and thus could be stored for
a prolonged period of time.
[
Pd/BaSO4],
quinoline,
EtOH
n
n
4E
8
9
6%,
2%
O
O
O
O
2
2
3 (n = 1)
4 (n = 2)
6 (n = 1) 2.4 ng/L air
musky, warm, metallic
7 (n = 2) 0.42 ng/L air
musky, powdery, floral
The Knoevenagel condensation of the alkynals 12 and 13
with malonic acid in the presence of catalytic amounts of
piperidinium acetate (Scheme 1) took the expected
2
1
course and provided the desired b,g-unsaturated acids 14
Scheme 2 Synthesis of 3-methyloct-6-yn-1-ol (20) from citronellol
and 15 in good to excellent D /D selectivities of 98:2 (19), and completion of the synthesis of the target structures 6 and 7
3
2
(
14) and 70:30 (15) for the crude materials. The undesired
conjugated isomers were removed by chromatography,
which furnished 14 and 15 in 43% and 42% yield, respec-
tively (Scheme 1).
An alternative access to 3-methyloct-6-yn-1-ol (20), free
from any terminal alkyne, was found in the nitrous acid
induced demethylation of the isopropylidene group dis-
30
covered by Abidi, which allowed the direct conversion
For the synthesis of the required alcohol component 20, it
of citronellol (19) into 3-methyloct-6-yn-1-ol (20)
was originally intended to make use of a Corey–Fuchs
0a
2
8
(
Scheme 2).3 Although we were not able to reproduce
reaction starting from rac-citronellol (19) (Scheme 2) as
an inexpensive perfumery raw material of prominent rose
odor. After THP protection of the hydroxy function, ozo-
30a
the reported 95% yield of Abidi, the reaction provided
a direct access to the desired compound 20. In accordance
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

5
46
P. Kraft, C. Berthold
PAPER
3
1
with the 25–33% yield Corey et al. and the 10–15% of many other double- or possibly even triple-unsaturated
3
2
yield Zard and co-workers had obtained in their mecha- macrocycles with interesting properties and not only in
nistic studies of the reaction, we isolated 3-methyloct-6- the domain of fragrance chemistry.
yn-1-ol (20) in 26% yield after chromatographic purifica-
tion (Scheme 2). The mechanism of this unusual de-
methylation is believed to involve an N-hydroxypyrazole
N-oxide, which is further nitrosated. Tautomerization and or N atmosphere. Unless otherwise stated, reagents and solvents
All reactions involving chemicals sensitive to H O or O were car-
ried out in flame-dried glassware with magnetic stirring under argon
2
2
2
cleavage then leads to a pyrazolone di-N-oxide, which is (puriss. or purum) were purchased from SAFC or Acros, and used
without further purification. rac-Citronellol (19) was used as sup-
plied by Givaudan (Vernier, Switzerland) in perfumery-grade qual-
ity. Schrock’s alkylidyne catalyst and other metathesis catalysts
were purchased from Strem Chemicals, Newburyport. Flash chro-
matography was carried out on Brunschwig silica gel (particle size
prone to open hydrolytically with subsequent loss of car-
bon dioxide and nitrous oxide to afford the desired
3
2
33
alkynol 20. Steglich esterification of 3-methyloct-6-
yn-1-ol (20) with the 3E-configured alk-3-en-(w–2)-ynoic
acids 14 and 15 afforded the diyne esters 21 and 22, re-
0
.032–0.063 mm). TLC analyses were performed on precoated
spectively (Scheme 2). Although GC monitoring indicat- Polygram Sil G/UV 254 foils (Macherey & Nagel, Düren) with UV
ed complete conversion, the yields of esters 21 and 22 detection (254 nm) under a UV lamp, and subsequent treatment
with aq KMnO (0.5%). Melting points were determined on a Büchi
were only 31% and 47%, respectively. It is believed that
decomposition occurred during chromatography or even
upon esterification.
4
melting point apparatus B-545 and are uncorrected. Attenuated-
total-reflection (ATR) IR spectroscopic data were recorded on a
Bruker VECTOR 22 instrument with a Harrick SplitPea unit (Si).
Ring-closing metathesis employing 10 mol% of NMR experiments, of samples in CDCl or benzene-d , as indicat-
3
6
3
4
ed, were performed on Bruker Avance DPX-400 or Bruker Avance
Schrock’s alkylidyne catalyst [t-BuC≡W(Ot-Bu) ] in re-
3
1
3
5
DPX-500 (TCI) spectrometers. H NMR chemical shifts are given
fluxing chlorobenzene furnished 23 and 24 in spot-to-
spot reactions in 78% and 42% yield, respectively. Nota-
bly, enyne metathesis on (3E,6¢E/Z)-3¢-methyl-7¢-phenyl-
hept-6¢-enyl dec-3-en-8-ynoate and (3E)-3¢-methylhept-
1
3
relative to TMS (d = 0), and C NMR chemical shifts are given rel-
ative to CDCl (d = 77) or benzene-d (d = 128 ppm). The multi-
3
6
plicities were assigned by DEPT experiments. MS data were
collected on Finnigan MAT 95 or HP Chemstation 6890 GC-5973
6
¢-enyl dec-3-en-8-ynoate in the presence of Grubbs’ Mass Sensitive Detector equipment. Elemental analyses were per-
first-generation (5–10 mol%) or second-generation cata- formed by the Mikroanalytisches Laboratorium Ilse Beetz,
6301 Kronach, Germany. Olfactory evaluations of samples in
9
lyst (5–25 mol%) under an argon or ethene
2
0,36
10% soln in EtOH and 10% soln in dipropylene glycol (DPG) on
smelling blotters were performed by expert perfumers. The odor
thresholds were determined by GC–olfactometry. Different dilu-
tions of the sample substances were injected into a gas chromato-
graph in descending order until the panelist failed to detect an odor
at the correct retention time. The reported values are geometrical
means of the individual odor thresholds of different panelists.
atmosphere
did not provide 7 or other macrocyclic
products. This, indeed, confirms the different mechanistic
pathways proposed for alkyne and enyne metathesis.37
The synthesis of the target compounds 6 and 7 was com-
pleted by standard Lindlar hydrogenations in ethanol in
the presence of the Cram–Allinger catalyst system. The
3
8
4
2
E,8Z-configured 12-methyloxacyclotetradeca-4,8-dien-
-one (6) and its 7a-homologue 7 were isolated in 86%
1
-Methyl-7-oxabicyclo[4.1.0]heptan-2-one (10)
At r.t., 2 N aq NaOH (7.00 mL, 14.0 mmol), followed by
30% aq H O (11.0 mL, 112 mmol) were added to a stirred soln of
and 92% yield, respectively.
2
2
commercially available 2-methylcyclohex-2-enone (8; 2.20 g,
0.0 mmol) in MeOH (250 mL), upon which the resulting red color
of the soln faded within 10 min. After stirring at r.t. for 24 h, the re-
While the cycloalkenynones 23 and 24 were only very
weak and uncharacteristic in smell, both target com-
pounds 6 and 7 emanated pronounced pleasant and very
2
action mixture was diluted with H O (200 mL) and extracted with
2
powerful musk notes. In the case of (4E,8Z)-12-methyl- CH Cl (3 × 150 mL). The combined organic extracts were washed
2
2
oxacyclotetradeca-4,8-dien-2-one (6), the powdery musk with H O (200 mL) and dried (Na SO ). The solvent was removed
2
2
4
under reduced pressure, and the resulting residue was purified by
scent was accompanied by a warm-metallic hot-iron note
as well as herbaceous and floral facets. The musk tonality
of its 7a-homologue 7 was also powdery, but sweeter, and
more distinct, while at the same time also containing floral
facets in the direction of jasmine, with slightly green as-
chromatography (silica gel, 40 g, pentane–Et O, 9:1); this furnished
2
1
0.
Yield: 1.18 g (47%); colorless liquid; R = 0.29 (pentane–Et O,
f
2
9
:1).
pects being more apparent. With a GC–odor threshold of IR (neat): 1703 (C=O), 1439, 1378 (CH ), 1276, 891, 811 (C–O–C)
3
–
1
cm .
0
.42 ng/L air it was clearly stronger than 6, for which a
1
threshold of 2.4 ng/L air was measured.
H NMR (400 MHz, CDCl ): d = 1.40 (s, 3 H, 2-Me), 1.68 (m, 1 H,
3
5
-H ), 1.97–2.12 (m, 3 H, 4-H , 5-H ), 2.22 (m, 1 H, 6-H ), 2.56
ax 2 eq eq
Thus, the olfactory properties of both potent musks 6 and
(
m, 1 H, 6-H ), 3.41 (dd, J = 3.5, 3.5 Hz, 1 H, 3-H).
ax
7
confirmed the design principles conceived in the begin-
1
3
C NMR (100 MHz, CDCl ): d = 15.4 (q, 2-Me), 18.3 (t, C-5), 23.3
3
ning. Most importantly, however, ring-closing alkyne
metathesis proved chemoselective in the presence of dou-
ble bonds, even if those were not deactivated by conjuga-
tion with a carbonyl function. The presented methodology
should thus be applicable for the E/Z-selective synthesis
(
t, C-4), 36.4 (t, C-6), 59.4 (s, C-2), 62.7 (d, C-3), 206.6 (s, C-1).
+
+
MS (EI, 70 eV): m/z (%) = 43 (100) [C H O ], 55 (50) [C H O ], 71
2
3
3
3
+
+
+
(
[
58) [C H O ], 82 (26) [M – C H O], 98 (3) [M – CO], 108 (1)
M – H O], 111 (3) [M – CH ], 126 (27) [M ].
4 7 2 4
+
+
+
2
3
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

PAPER
Macrocyclic Musks by Metathesis
547
Hept-5-ynal (12)
lation product (19.0 g) in DMF (250 mL), and the resulting suspen-
sion was refluxed for 3.5 h. After the mixture had cooled, the
At –10 °C, H NNHTs (6.14 g, 33.0 mmol) was added portionwise
2
to a stirred soln of the 2,3-epoxy ketone 10 (3.78 g, 30.0 mmol) in
precipitate was dissolved by the addition of H O; then brine (20
2
AcOH–CH Cl (1:1, 80 mL). The reaction mixture was allowed to
mL) was added, and the mixture was extracted with Et O
2
2
2
warm up slowly. At 10 °C, GC monitoring indicated complete con-
version, whereupon crushed ice (20 g) was added and the layers
were separated. The aqueous layer was extracted with CH Cl
(5 × 200 mL). The combined organic extracts were washed with
brine (200 mL) and sat. aq FeSO (200 mL), dried (Na SO ), and
4
2
4
concentrated under reduced pressure. Chromatography of the re-
2
2
(
2 × 50 mL), and the combined organic solns were neutralized with
sulting residue (silica gel, 150 g, pentane–Et O, 5:1) provided oct-
6-ynenitrile (18).
2
ice-cold sat. aq NaHCO . After drying (Na SO ) and removal of the
3
2
4
solvent under reduced pressure, chromatography of the resulting
Yield: 7.90 g (69%); colorless liquid; R = 0.35 (pentane–Et O,
f
2
residue (silica gel, 50 g, pentane–Et O–Et N, 3:1:0.01) afforded 12.
2
3
4
:1).
Yield: 1.74 g (53%); colorless liquid; R = 0.48 (pentane–Et O,
f
2
A 1 M soln of DIBAL-H in hexane (97.8 mL, 97.8 mmol) was add-
ed dropwise to a stirred soln of nitrile 18 (7.90 g, 65.2 mmol) in
THF (150 mL) at 0 °C. The cooling bath was removed and the mix-
ture was stirred overnight at r.t., prior to being poured into ice-cold
sat. aq tartaric acid (50 mL). Further tartaric acid was added with
stirring until the precipitate dissolved completely, and the product
5
:1).
–
1
IR (neat): 1723 (HC=O), 1437 (CH ), 1352 (CH ) cm .
3
3
1
H NMR (400 MHz, CDCl ): d = 1.77 (t, J = 2.5 Hz, 3 H, 7-H ),
3
3
1
.80 (quin, J = 7.0 Hz, 2 H, 3-H ), 2.20 (qt, J = 2.5, 7.0 Hz, 2 H, 4-
2
H ), 2.57 (dt, J = 1.5, 7.0 Hz, 2 H, 2-H ), 9.80 (t, J = 1.5 Hz, 1 H, 1-
2
2
was extracted with Et O (3 × 200 mL). After drying of the mixture
2
H).
(
Na SO ), the solvent was removed under reduced pressure; this
2 4
1
3
C NMR (100 MHz, CDCl ): d = 3.4 (q, C-7), 18.5 (t, C-4), 21.4 (t,
3
provided alkynal 13 without further purification being necessary
GC).
C-3), 42.8 (t, C-2), 75.9 (s, C-6), 78.6 (s, C-5), 202.1 (s, C-1).
(
+
+
MS (EI, 70 eV): m/z (%) = 44 (5) [C H O ], 53 (62) [C H ], 66
2
4
4
5
Yield: 6.70 g (83%); colorless liquid.
+
+
+
(
[
63) [C H ], 68 (100) [M – C H O], 82 (27) [M – CO], 95 (10)
M – CH ], 109 (2) [M – H], 110 (1) [M ].
5 6 2 2
) cm–1.
+
+
+
IR (neat): 1723 (HC=O), 1439 (CH ), 1356 (CH
3 3
3
1
H NMR (400 MHz, benzene-d ): d = 1.21 (quin, J = 7.0 Hz, 2 H,
6
Oct-6-ynal (13)
4-H ), 1.38 (quin, J = 7.0 Hz, 2 H, 3-H ), 1.55 (t, J = 2.5 Hz, 3 H, 8-
2
2
Alkynal 13 was synthesized as follows, according to a synthetic
scheme of Herndon and co-workers, with additional THP protec-
H ), 1.73 (dt, J = 1.5, 7.0 Hz, 2 H, 2-H ), 1.94 (qt, J = 2.5, 7.0 Hz,
3
2
2
7
2 H, 5-H ), 9.25 (t, J = 1.5 Hz, 1 H, 1-H).
2
tion during the methylation step. PTSA·H O (300 mg, 1.58 mmol)
was added to a stirred soln of commercially available hex-5-yn-1-ol
13
2
C NMR (100 MHz, benzene-d ): d = 3.1 (q, C-8), 18.5 (t, C-5),
6
2
2
1.1 (t, C-3), 28.4 (t, C-4), 43.0 (t, C-2), 75.7 (s, C-7), 78.6 (s, C-6),
00.2 (s, C-1).
(
(
16, 15.2 g, 155 mmol) and DHP (29.8 mL, 232 mmol) in CH Cl
150 mL) at 0 °C. The cooling bath was removed and stirring con-
2 2
+
+
MS (EI, 70 eV): m/z (%) = 44 (5) [C H O ], 53 (100) [C H ], 79
tinued for 5 h, prior to addition of H O (100 mL) and separation of
2
4
4
+
5
2
+
+
(
84) [M – C H O], 91 (33) [M – H O – CH ], 106 (7) [M – H O],
the layers. The organic layer was washed with H O (50 mL) and
2
+
5
2
3
2
2
+
+
1
09 (32) [M – CH ], 123 (7) [M – H], 124 (2) [M ].
brine (50 mL), and the combined aqueous solns were re-extracted
with CH Cl (100 mL). The combined organic extracts were dried
3
2
2
(
3E)-Non-3-en-7-ynoic Acid (14)
(
Na SO ) and concentrated under reduced pressure. The crude
2 4
A piperidinium acetate soln, freshly prepared by mixing of piperi-
dine (35.0 mL, 0.354 mmol) and AcOH (19.0 mL, 0.332 mmol) in
DMSO (1.00 mL), was injected into a stirred soln of aldehyde 12
brownish product (40.2 g) was taken up in THF (500 mL), and
1
–
.6 M BuLi in THF (136 mL, 218 mmol) was added dropwise at
78 °C. After the mixture had stirred for 2 h at –40 °C, it was cooled
(
1.50 g, 13.6 mmol) and malonic acid (2.83 g, 27.2 mmol) in
DMSO (50 mL) at r.t. After the reaction mixture had refluxed for
h, H O (10 mL) and Et O (20 mL) were added at r.t., and the lay-
to –78 °C, and MeI (15.4 mL, 248 mmol) was added. The cooling
bath was removed, and stirring continued overnight at r.t. After
4
quenching of the mixture with H O (500 mL), the product was ex-
2
2
2
ers were separated. The aqueous layer was extracted with Et O
tracted with Et O (2 × 500 mL). The combined organic extracts
2
2
(
3 × 25 mL), and the combined organic extracts were washed with
were washed with sat. aq NH Cl (500 mL), dried (Na SO ), and
4
2
4
H O (25 mL), dried (Na SO ), and concentrated under reduced
concentrated under reduced pressure, and the resulting brownish
residue was dissolved in MeOH (250 mL). PPTS (370 mg, 1.47
mmol) was added, and the reaction mixture was stirred at r.t. over-
2
2
4
pressure. Kugelrohr distillation (149 °C/14 mbar) furnished acid
4.
1
night; then sat. aq NH Cl (150 mL) was added, and the mixture was
3
2
4
Yield: 902 mg (44%); D /D = 98:2 (GC); colorless crystals; mp 43–
45 °C.
extracted with Et O (4 × 400 mL). The combined organic extracts
2
were washed with sat. aq NH Cl (400 mL) and dried (Na SO ). Af-
4
2
4
IR (neat): 2916 (O–H), 1691 (C=O), 1335 (CH ), 969 (C=C, trans)
cm .
1H NMR (400 MHz, CDCl
3
ter removal of the solvent under reduced pressure, chromatography
–
1
of the resulting residue (silica gel, 400 g, pentane–Et O, 4:1) afford-
2
ed hept-5-yn-1-ol (17).
3
): d = 1.77 (t, J = 2.5 Hz, 3 H, 9-H
3
),
2
5
.18–2.24 (m, 4 H, 5-, 6-H ), 3.10 (dd, J = 1.0, 6.0 Hz, 2 H, 2-H ),
.54–5.70 (m, 2 H, 3-, 4-H), 11.36 (br s, 1 H, OH).
2
2
Yield: 10.6 g (61%); colorless liquid; R = 0.06 (pentane–Et O,
f
2
4
:1).
1
3
C NMR (100 MHz, CDCl ): d = 3.4 (q, C-9), 18.8 (t, C-6), 32.0 (t,
3
MsCl (9.50 mL, 123 mmol) was added dropwise to a stirred soln of
C-5), 37.7 (t, C-2), 76.1 (s, C-8), 78.3 (s, C-7), 122.0 (d, C-3), 133.6
d, C-4), 178.5 (s, C-1).
alkynol 17 (10.6 g, 94.5 mmol) and Et N (19.8 mL, 142 mmol) in
3
(
Et O (150 mL) at 0 °C. The cooling bath was removed, and the re-
2
+
+
action mixture was stirred overnight. H O (150 mL) was added, and
MS (EI, 70 eV): m/z (%) = 45 (20) [CO
(89) [C
CH CO
[M – CO
– H], 152 (1) [M ].
2
H ], 53 (100) [C
4
H
5
], 57
2
+
+
+
+
the organic layer was separated and washed with H O (2 × 100 mL)
4
H
9
], 60 (7) [CH
3
CO
2
H ], 79 (33) [C
6
H
7
], 92 (42) [M –
2
+
+
and sat. aq NH Cl (50 mL). The combined aqueous solns were re-
3
2
H], 93 (97) [M – CH
3
CO
H], 124 (2) [M – CO], 137 (3) [M – CH ], 151 (7) [M
3
2 4 5
], 99 (3) [M – C H ], 107 (68)
4
+
+
+
+
extracted with Et O (100 mL), and the organic extracts were com-
2
2
+
bined, dried (Na SO ), and concentrated under reduced pressure.
2
4
KCN (9.23 g, 142 mmol) was added to the soln of the crude mesy-
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

5
48
P. Kraft, C. Berthold
PAPER
(
3E)-Dec-3-en-8-ynoic Acid (15)
In analogy to the synthesis of 14 from 12, acid 15 was prepared from
3 (6.70 g, 54.0 mmol), malonic acid (11.2 g, 108 mmol), DMSO
200 mL), and freshly prepared piperidinium acetate (160 mg,
of the residue from the filtrate (silica gel, 50 g, pentane–Et O, 20:1)
afforded 21.
2
1
(
1
Yield: 470 mg (31%); colorless liquid; R = 0.65 (pentane–Et O,
f
2
5
:1).
3
.10 mmol) in DMSO (5.00 mL). The crude material [D /
–
1
2
IR (neat): 1734 (OC=O), 967 (C=C, trans) cm .
D = 70:30 (GC)] was purified by chromatography (silica gel, 200
g, pentane–Et O, 4:1) and subsequent Kugelrohr distillation
(
1
2
H NMR (400 MHz, benzene-d ): d = 0.70 (d, J = 6.5 Hz, 3 H, 3¢-
6
160 °C/13 mbar) to afford 15.
Me), 1.14–1.26 (m, 2 H, 2¢-, 4¢-H ), 1.36–1.52 (m, 2 H, 2¢-, 4¢-H ),
1
b
a
.55 (m, 1 H, 3¢-H), 1.56 (t, J = 2.5 Hz, 3 H, 8¢-H ), 1.59 (t,
3
Yield: 3.79 g (42%); colorless crystalline solid; mp 40–43 °C;
R = 0.24 (pentane–Et O, 5:1).
J = 2.5 Hz, 3 H, 9-H ), 1.97–2.14 (m, 6 H, 5-, 5¢-, 6-H ), 2.88 (dd,
3
2
f
2
J = 1.0, 6.0 Hz, 2 H, 2-H ), 4.01 (m, 2 H, 1¢-H ), 5.47 (ttd, J = 1.0,
2
2
IR (neat): 2937, 2860 (O–H), 1689 (C=O), 1347 (CH ), 964 (C=C,
trans) cm .
3
6
.5, 15.5 Hz, 1 H, 4-H), 5.64 (ttd, J = 1.0, 6.0, 15.5 Hz, 1 H, 3-H).
–
1
1
3
C NMR (100 MHz, benzene-d ): d = 3.1 (2q, C-9, -8¢), 16.5 (t, C-
1
6
H NMR (400 MHz, CDCl ): d = 1.56 (quin, J = 7.0 Hz, 2 H, 6-H ),
3
2
6
(
7
), 18.7 (q, 3¢-Me), 19.0 (t, C-5¢), 29.1 (d, C-3¢), 32.2 (t, C-5), 35.2
1
.78 (t, J = 2.5 Hz, 3 H, 10-H ), 1.99–2.18 (m, 4 H, 5-, 7-H ), 3.08
3
2
t, C-2¢), 36.1 (t, C-4¢), 38.0 (t, C-2), 62.5 (t, C-1¢), 75.4 (s, C-7¢),
(
1
ddd, J = 1.0, 1.0, 6.0 Hz, 2 H, 2-H ), 5.50–5.63 (m, 2 H, 3-, 4-H),
2
5.8 (s, C-8), 78.5 (s, C-7), 79.0 (s, C-6¢), 123.3 (d, C-3), 132.6 (d,
1.34 (br s, 1 H, OH).
C-4), 170.8 (s, C-1).
1
3
C NMR (100 MHz, CDCl ): d = 3.4 (q, C-10), 18.1 (t, C-7), 28.3
+
+
3
MS (EI, 70 eV): m/z (%) = 41 (55) [C H ], 53 (76) [C H ], 60 (2)
3
5
4
5
(
1
t, C-6), 31.5 (t, C-5), 37.8 (t, C-2), 75.7 (s, C-9), 78.8 (s, C-8),
+
+
+
+
[
1
CH CO H ], 67 (50) [C H ], 81 (100) [C H ], 93 (60) [C H ],
3 2 5 7 6 9 7 9
21.5 (d, C-3), 134.4 (d, C-4), 178.8 (s, C-1).
+
+
+
07 [C H O – CO H], 121 (44) [C H ], 124 (34) [C H O
–
1
0
16
2
2
9
13
+
10 14
2
+
+
+
+
MS (EI, 70 eV): m/z (%) = 41 (100) [C H ], 45 (24) [CO H ], 53
(
9
(
1
(
C H ], 147 (7) [C H O ], 207 (1) [M – C H ], 259 (1) [M –
3
5
2
3
6
9
11
5
7
+
+
+
+
+
68) [C H ], 60 (7) [CH CO H ], 66 (39) [C H ], 70 (40) [C H ],
CH ], 274 (1) [M ].
4
5
3
2
+
5
6
5
+
10
3
+
9
3 (68) [C H ], 106 (59) [M – CH CO H], 112 (9) [C H O ], 121
7
3
2
6
8
2
Anal. Calcd for C H O (274.40): C, 78.79; H, 9.55. Found: C,
+
+
+
18 26
2
28) [M – CO H], 133 (3) [M – H O – CH ], 138 (2) [M – C H ],
2 2 3 2 4
7
8.82; H, 9.48.
+
+
+
47 (1) [M – H – H O], 151 (5) [M – CH ], 165 (2) [M – H], 166
2 3
+
1) [M ].
(
3E)-3¢-Methyloct-6¢-ynyl Dec-3-en-8-ynoate (22)
In analogy to the synthesis of 21 from 14 and 20, ester 22 was pre-
3
-Methyloct-6-yn-1-ol (20)
pared from 15 (1.66 g, 9.99 mmol), 20 (1.40 g, 9.99 mmol), DMAP
Alkynol 20 was synthesized as follows, according to ref. 30a.
(
122 mg, 1.00 mmol), and DCC (2.27 g, 11.0 mmol) in Et O
2
NaNO (93.2 g, 135 mmol) was added portionwise, within 90 min,
to a vigorously stirred soln of rac-citronellol (19; 7.81 g,
5
2
(
30 mL). Chromatography (silica gel, 50 g, pentane–Et O, 20:1) af-
2
forded 22.
0.0 mmol) in AcOH–H O (5:2, 210 mL) at 0–6 °C; this resulted in
2
Yield: 1.34 g (47%); colorless liquid; R = 0.50 (pentane–Et O,
a large amount of gas (NO ) and lather being produced. The reaction
f
2
x
1
0:1).
mixture was stirred for 1 h at 0 °C, then the cooling bath was re-
moved, and stirring continued at r.t. for 1 d. The reaction mixture
was then heated to 54 °C for 1 d, and again stirred for 1 d at r.t., after
which it was poured into H O (500 mL), and extracted with EtOAc
(
H O (200 mL) and brine (50 mL), dried (Na SO ), and concentrated
under reduced pressure. Chromatography (silica gel, 250 g, pen-
tane–Et O, 2:1) provided alkynol 20.
IR (neat): 1735 (OC=O), 968 (C=C, trans) cm–1.
1
H NMR (500 MHz, benzene-d ): d = 0.49 (d, J = 7.0 Hz, 3 H, 3¢-
6
2
Me), 1.17 (m, 1 H, 4¢-H ), 1.20 (m, 1 H, 2¢-H ), 1.40 (m, 1 H, 4¢-H ),
1
J = 2.5 Hz, 3 H, 8¢-H ), 1.56 (m, 1 H, 3¢-H), 1.57 (t, J = 2.5 Hz, 3 H,
1
H ), 2.86 (dd, J = 1.0, 7.0 Hz, 2 H, 2-H ), 4.01 (m, 2 H, 1¢-H ), 5.31
(ttd, J = 1.0, 7.0, 15.5 Hz, 1 H, 4-H), 5.61 (ttd, J = 1.0, 7.0, 15.5 Hz,
b
b
a
2 × 200 mL). The combined organic extracts were washed with
.44 (m, 1 H, 2¢-H ), 1.46 (quin, J = 7.0 Hz, 2 H, 6-H ), 1.55 (t,
a
2
2
2
4
3
0-H ), 1.99 (m, 2 H, 5-H ), 2.02 (m, 2 H, 5¢-H ), 2.04 (m, 2 H, 7-
3
2
2
2
2
2
2
Yield: 1.80 g (26%); colorless liquid; R = 0.25 (pentane–Et O,
2
f
2
:1).
1
H, 3-H).
–
1
IR (neat): 3337 (O–H), 1378 (CH ) cm .
13
3
C NMR (125 MHz, benzene-d ): d = 3.3 (q, C-10), 3.4 (q, C-8¢),
6
1
16.7 (t, C-7), 18.4 (t, C-5¢), 18.9 (q, 3¢-Me), 28.8 (t, C-6), 29.3 (d,
C-3¢), 31.8 (t, C-5), 35.4 (t, C-2¢), 36.3 (t, C-4¢), 38.3 (t, C-2), 62.8
H NMR (400 MHz, CDCl ): d = 0.91 (d, J = 6.5 Hz, 3 H, 3-Me),
3
1
.29–1.47 (m, 2 H, 2-, 4-H ), 1.48–1.63 (m, 2 H, 2-, 4-H ), 1.70 (m,
b
a
(
1
t, C-1¢), 75.6 (s, C-7¢), 75.8 (s, C-9), 79.1 (s, C-8), 79.2 (s, C-6¢),
1
3
H, 3-H), 1.77 (t, J = 2.5 Hz, 3 H, 8-H ), 2.11–2.25 (m, 2 H, 5-H ),
3
2
23.2 (d, C-3), 133.5 (d, C-4), 171.2 (s, C-1).
.70 (m, 2 H, 1-H ), 6.51 (br s, 1 H, OH).
2
+
+
1
3
MS (EI, 70 eV): m/z (%) = 41 (80) [C H ], 55 (80) [C H ], 60 (1)
C NMR (100 MHz, CDCl ): d = 3.4 (q, C-8), 16.3 (t, C-5), 19.1 (q,
3
5
4
7
3
+
+
+
+
[
1
CH CO H ], 67 (69) [C H ], 81 (100) [C H ], 93 (59) [C H ],
3
(
-Me), 20.7 (d, C-3), 36.2 (t, C-2), 39.3 (t, C-4), 60.9 (t, C-1), 75.4
3 2 5 7 6 9 7 9
+
+
21 (44) [C H ], 124 (34) [C H O – C H ], 149 (7)
9 13 10 14 2 3 6
s, C-7), 79.1 (s, C-6).
+
+
+
[
C H O ], 166 (7) [C H O ], 273 (1) [M – CH ].
+
+
10 13 10 14 2 3
MS (EI, 70 eV): m/z (%) = 31 (23) [CH O ], 41 (100) [C H ], 67
(
H O], 125 (6), [M – CH ], 140 (1) [M ].
3
3
5
+
7
+
+
+
Anal. Calcd for C H O (288.43): C, 79.12; H, 9.78. Found: C,
19 28 2
79.13; H, 9.77.
75) [C H ], 68 (67) [C H ], 95 (54) [C H ], 107 (67) [M –
5
5
8
7
11
+
+
2
3
(
4E)-12-Methyloxacyclotetradec-4-en-8-yn-2-one (23)
(
3E)-3¢-Methyloct-6¢-ynyl Non-3-en-7-ynoate (21)
DMAP (68.4 mg, 0.559 mmol) was added to a stirred soln of acid
4 (850 mg, 5.59 mmol) and alcohol 20 (790 mg, 5.59 mmol) in
A soln of 21 (350 mg, 1.28 mmol) in absolute PhCl (120 mL) was
degassed with argon for 15 min, prior to the addition of Schrock’s
alkylidyne catalyst [t-BuC≡W(Ot-Bu) ] (60.5 mg, 0.128 mmol).
With a slow flow of argon bubbling through, the resulting mixture
was refluxed for 24 h and then allowed to cool to r.t. The solvent
was removed under reduced pressure, and the resulting residue was
purified by chromatography (silica gel, 50 g, pentane–Et O, 1:1);
this provided 23.
1
3
4
Et O (20 mL) at r.t. At 0 °C, DCC (1.27 g, 6.14 mmol) was added,
3
2
and the reaction mixture was stirred for 5 min at this temperature,
upon which a colorless precipitate formed. This insoluble material
was removed by suction filtration on a sintered-glass funnel, and the
filtrate was concentrated under reduced pressure. Chromatography
2
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

PAPER
Macrocyclic Musks by Metathesis
549
Yield: 220 mg (78%); colorless liquid; R = 0.55 (pentane–Et O,
6.5, 6.5 Hz, 1 H, 12-H), 1.90 (td, J = 7.0, 7.0, 2 H, 6-H ), 1.94 (td,
f
2
2
5
:1).
J = 7.0, 7.5 Hz, 2 H, 10-H ), 1.99 (td, J = 7.0, 7.5, 2 H, 7-H ), 2.74
2
2
–
1
(d, J = 6.5 Hz, 2 H, 3-H
2
), 4.01 (ddd, J = 3.0, 9.5, 11.5 Hz, 1 H, 14-
IR (neat): 1731 (OC=O), 966 (C=C, trans) cm .
H ), 4.10 (ddd, J = 3.0, 5.5, 11.5 Hz, 1 H, 14-H ), 5.21 (ttd, J = 1.0,
b
a
1
H NMR (400 MHz, CDCl ): d = 0.90 (d, J = 6.5 Hz, 3 H, 12-Me),
3
7.5, 11.0 Hz, 1 H, 8-H), 5.31 (ttd, J = 1.0, 6.5, 15.5 Hz, 1 H, 4-H),
5.37 (ttd, J = 1.0, 7.5, 11.0 Hz, 1 H, 9-H), 5.48 (ttd, J = 1.0, 7.0, 15.5
Hz, 1 H, 5-H).
1
1
3
1
7
.19 (m, 1 H, 13-H ), 1.29–1.47 (m, 2 H, 11-H , 13-H ), 1.68 (m,
b
b
a
H, 11-H ), 2.02 (m, 1 H, 12-H), 2.13–2.33 (m, 6 H, 6-, 7-, 10-H ),
.00 (ddd, J = 1.5, 7.0, 14.0 Hz, 1 H, 3-H ), 3.05 (ddd, J = 1.5, 7.0,
a
2
b
13
C NMR (125 MHz, benzene-d ): d = 19.9 (q, 12-Me), 24.9 (t, C-
6
4.0 Hz, 1 H, 3-H ), 4.21–4.24 (m, 2 H, 14-H ), 5.56 (ttd, J = 1.5,
a
2
1
0), 27.9 (t, C-7), 29.1 (d, C-12), 31.8 (t, C-6), 35.3 (t, C-13), 36.7
.0, 15.0 Hz, 1 H, 5-H), 5.64 (ttd, J = 1.5, 7.0, 15.0 Hz, 1 H, 4-H).
(
t, C-11), 38.6 (t, C-3), 62.2 (t, C-14), 122.9 (d, C-4), 129.6 (d, C-
1
3
C NMR (100 MHz, CDCl ): d = 16.0 (t, C-7), 18.1 (t, C-10), 18.5
q, 12-Me), 25.3 (d, C-12), 31.4 (t, C-6), 34.6 (t, C-13), 35.2 (t, C-
1), 39.4 (t, C-3), 61.2 (t, C-14), 79.8 (s, C-9), 80.0 (s, C-8), 123.7
3
8), 131.0 (d, C-9), 134.1 (d, C-5), 170.8 (s, C-2).
(
1
+
+
MS (EI, 70 eV): m/z (%) = 41 (41) [C H ], 54 (62) [C H ], 60 (2)
3
5
4
6
+
+
+
+
[
1
CH CO H ], 67 (58) [C H ], 81 (100) [C H ], 95 (17) [C H ],
3 2 5 7 6 9 7 11
(d, C-4), 132.5 (d, C-5), 171.6 (s, C-2).
+
+
+
+
07 (16) [C H ], 123 (15) [C H ], 149 (6) [C H ], 162 (7) [M
8 11 9 15
11 17
+
+
+
MS (EI, 70 eV): m/z (%) = 41 (39) [C H ], 60 (1) [CH CO H ], 99
2) [C H ], 160 (2) [M – C H O ], 178 (100) [M – C H O], 205
+
3
5
3
2
– CH COOH], 194 (1) [M – CO], 204 (1) [M – H O], 222 (2)
3
2
+
+
+
(
(
+
7
+
15
2
4
2
2
2
[M ].
+
1) [M – CH ], 220 (1) [M ].
3
Anal. Calcd for C H O (222.33): C, 75.63; H, 9.97. Found: C,
1
4
22
2
7
5.67; H, 9.96.
(
4E)-13-Methyloxacyclopentadec-4-en-9-yn-2-one (24)
In analogy to the synthesis of 23 from 21, macrocycle 24 was pre-
pared from 22 (435 mg, 1.51 mmol) and Schrock’s alkylidyne cat-
(
4E,9Z)-13-Methyloxacyclopentadeca-4,9-dien-2-one (7)
3
4
In analogy to the synthesis of 6 from 23, macrocyclic diene lactone
7
4
(
sion. Purification by chromatography (silica gel, 20 g, pentane–
Et O, 10:1) furnished 7.
alyst [t-BuC≡W(Ot-Bu) ] (71.3 mg, 0.151 mmol) in absolute
3
was prepared from 24 (48.2 mg, 206 mmol), quinoline (4.86 mL,
PhCl (80 mL). Purification by chromatography (silica gel, 50 g,
1.1 mmol), and 10% Pd/BaSO (0.88 mg, 8.24 mmol) in EtOH
4
pentane–Et O, 50:1) provided 24.
2
2.0 mL). After 3.5 h, GC monitoring indicated complete conver-
Yield: 150 mg (42%); colorless liquid; R = 0.44 (pentane–Et O,
f
2
5
:1).
2
–
1
IR (neat): 1733 (OC=O), 968 (C=C, trans) cm .
Yield: 44.8 mg (92%); colorless, odoriferous liquid; R = 0.78 (pen-
tane–Et O, 5:1).
f
1
H NMR (400 MHz, CDCl ): d = 0.92 (d, J = 6.5 Hz, 3 H, 13-Me),
2
3
1
.24 (m, 1 H, 12-H ), 1.35 (m, 1 H, 14-H ), 1.41–1.61 (m, 3 H, 7-
b
b
Odor description: intense, pleasant, sweet, aromatic-powdery musk
odor with floral facets in the direction of jasmine and slightly green
aspects; odor threshold: 0.42 ng/L air.
IR (neat): 1733 (OC=O), 968 (C=C, trans), 696 (C=C, cis) cm–1.
H , 12-H ), 1.72 (ttd, J = 3.5, 10.5, 14.5 Hz, 1 H, 14-H ), 1.93 (m,
2
a
a
1
2
H, 13-H), 2.09–2.31 (m, 6 H, 6-, 8-, 11-H ), 3.03 (ddd, J = 1.5,
2
.5, 6.5 Hz, 2 H, 3-H ), 4.19 (dd, J = 3.5, 10.5 Hz, 1 H, 15-H ), 4.23
2
b
(
dd, J = 3.5, 10.5 Hz, 1 H, 15-H ), 5.50 (ttd, J = 1.5, 7.0, 15.0 Hz,
a
1
1
H, 5-H), 5.67 (ttd, J = 1.5, 7.0, 15.0 Hz, 1 H, 4-H).
H NMR (400 MHz, CDCl ): d = 0.92 (d, J = 6.5 Hz, 3 H, 13-Me),
3
1
3
1.20–1.44 (m, 2 H, 12-, 14-H ), 1.46–1.63 (m, 3 H, 7-H , 12-H ),
b
2
a
C NMR (100 MHz, CDCl ): d = 16.4 (t, C-11), 17.0 (t, C-8), 18.5
3
1
(
.72 (m, 1 H, 14-H ), 1.95–2.12 (m, 7 H, 6-, 8-, 11-H , 13-H), 3.03
a 2
(
q, 13-Me), 25.5 (t, C-7), 26.7 (d, C-13), 30.3 (t, C-6), 35.7 (t, C-14),
ddd, J = 1.0, 1.0, 6.5 Hz, 2 H, 3-H ), 4.12 (ddd, J = 3.0, 9.5, 11.5
2
3
5.9 (t, C-12), 39.0 (t, C-3), 62.0 (t, C-15), 79.7 (s, C-10), 80.2 (s,
Hz, 1 H, 15-H ), 4.21 (ddd, J = 3.0, 6.0, 11.5 Hz, 1 H, 15-H ), 5.28
(
1 H, 4-H), 5.41–5.53 (m, 2 H, 9-, 10-H).
13C NMR (100 MHz, CDCl
2
1
(
b
a
C-9), 123.8 (d, C-4), 132.5 (d, C-5), 171.7 (s, C-2).
ttd, J = 1.0, 6.5, 11.0 Hz, 1 H, 5-H), 5.38 (ttd, J = 1.0, 6.5, 11.0 Hz,
+
+
MS (EI, 70 eV): m/z (%) = 41 (91) [C H ], 60 (1) [CH CO H ], 91
3
5
3
2
+
+
+
+
(
100) [C H ], 99 (6) [C H ], 178 (11) [C H ], 192 (66) [M –
7 7 7 15 13 22
+
+
+
3
): d = 20.7 (q, 13-Me), 24.2 (t, C-11),
5.6 (t, C-7), 27.4 (t, C-8), 29.9 (d, C-13), 30.1 (t, C-6), 34.8 (t, C-
4), 36.5 (t, C-12), 39.2 (t, C-3), 62.9 (t, C-15), 123.1 (d, C-4), 129.7
C H O], 206 (16) [M – CO], 219 (2) [M – CH ], 234 (1) [M ].
2
2
3
(
4E,8Z)-12-Methyloxacyclotetradeca-4,8-dien-2-one (6)
d, C-9), 130.8 (d, C-5), 133.9 (d, C-10), 172.0 (s, C-2).
Quinoline (27.5 mL, 0.232 mmol) and 10% Pd/BaSO (4.90 mg,
0
1
4
+
+
.0461 mmol) were added to a stirred soln of 23 (256 mg,
.16 mmol) in EtOH (20 mL). The reaction flask was flushed with
MS (EI, 70 eV): m/z (%) = 41 (72) [C H ], 60 (2) [CH CO H ], 67
(89) [C H ], 81 (100) [C H ], 176 (5) [M – CH COOH], 203 (1)
[M – H O – CH ], 208 (1) [M – CO], 218 (1) [M – H O], 236 (2)
2 3 2
[M ].
3
5
3
2
+
+
+
5 7 6 9 3
+
+
+
argon followed by H , and the reaction mixture was stirred under an
2
+
H atmosphere at r.t. and ambient pressure. After 5 h, GC monitor-
2
ing indicated complete conversion, upon which the catalyst was re-
moved by filtration of the mixture through a pad of Celite , which
was washed with EtOH. The solvent was removed from the filtrate
under reduced pressure, and the resulting residue was purified by
Anal. Calcd for C H O (236.35): C, 76.23; H, 10.23. Found: C,
®
15 24
2
7
6.30; H, 10.30.
chromatography (silica gel, 30 g, pentane–Et O, 20:1) to furnish 6.
2
Acknowledgment
Yield: 223 mg (86%); colorless, odoriferous liquid; R = 0.60 (pen-
f
We are grateful to Professor James W. Herndon, New Mexico State
University, Las Cruces, NM 88003-8001, for supplementary mate-
tane–Et O, 5:1).
2
2
7a
Odor description: powerful, warm-metallic, powdery musk odor
with herbaceous and floral facets as well as a strong hot-iron incli-
nation; odor threshold: 2.4 ng/L air.
rial to his publication as well as copies from the PhD thesis of Ju-
2
7b
lius J. Matasi. Thanks are also due to Dr. Fabian Kuhn for the
mass spectrometry data, Dr. Gerhard Brunner for multidimensional
NMR experiments, Katarina Grman for the determination of odor
thresholds, Alain E. Alchenberger for the olfactory evaluations, and
Dr. Samuel Derrer, Tony McStea, and Dr. Markus Gautschi for ca-
reful proofreading of the manuscript.
–
1
IR (neat): 1732 (OC=O), 967 (C=C, trans), 714 (C=C, cis) cm .
1
H NMR (500 MHz, benzene-d ): d = 0.77 (d, J = 6.5 Hz, 3 H, 12-
6
Me), 1.07 (dddd, J = 3.0, 5.5, 6.5, 10.5 Hz, 1 H, 13-H ), 1.09 (dt,
b
J = 6.5, 7.0 Hz, 1 H, 11-H ), 1.28 (dt, J = 6.5, 7.0 Hz, 1 H, 11-H ),
b
a
1
.40 (dddd, J = 3.0, 6.5, 9.5, 10.5 Hz, 1 H, 13-H ), 1.48 (ttq, J = 6.5,
a
Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York

5
50
P. Kraft, C. Berthold
PAPER
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Synthesis 2008, No. 4, 543–550 © Thieme Stuttgart · New York