An efficient route to the musk odorant (R,Z)-5-muscenone via base-metal-catalysis

Article abstract of DOI:10.1016/j.tet.2012.05.085

Muscenone is a valuable perfume ingredient consisting of a mixture of the E- and Z-isomers of 1 in racemic form as the major constituents. Among them, it is the (R,Z)-isomer, which exhibits the most favorable musk character and by far the lowest threshold; for these superior olfactory properties, pure (R,Z)-1 has recently been commercialized too. We present an efficient route to this precious compound based on an iron-catalyzed cross coupling reaction, a molybdenum-catalyzed alkyne metathesis for the formation of the macrocyclic ring, and a nickel-catalyzed semi-hydrogenation.

Full text of DOI:10.1016/j.tet.2012.05.085

Tetrahedron 68 (2012) 7695e7700
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient route to the musk odorant (R,Z)-5-muscenone via
base-metal-catalysis
Konrad Lehr, Alois F u€ rstner *
Max-Planck-Institut f u€ r Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 M u€ lheim/Ruhr, Germany
a r t i c l e i n f o
a b s t r a c t
MuscenoneÒ is a valuable perfume ingredient consisting of a mixture of the E- and Z-isomers of 1 in
racemic form as the major constituents. Among them, it is the (R,Z)-isomer, which exhibits the most
favorable musk character and by far the lowest threshold; for these superior olfactory properties, pure
Article history:
Received 23 February 2012
Received in revised form 4 May 2012
Accepted 22 May 2012
(
R,Z)-1 has recently been commercialized too. We present an efficient route to this precious compound
Available online 28 May 2012
based on an iron-catalyzed cross coupling reaction, a molybdenum-catalyzed alkyne metathesis for the
formation of the macrocyclic ring, and a nickel-catalyzed semi-hydrogenation.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Manfred T. Reetz, an
outstanding scholar, a generous mentor and
a dear friend, on receipt of the Tetrahedron
Prize
Keywords:
Alkynes
Iron catalysis
Macrocycles
Metathesis
Molybdenum
1
. Introduction
fragmentation of (þ)-5, which in turn was accessed either by ki-
5
netic resolution of (ꢁ)-5 via a CBS-reduction (35%, 97% ee), or by an
(
R)-Muscone (2), which was originally isolated from the scent
enantioselective transannular aldol condensation of diketone 3
using an excess (8 equiv) of sodium ephedrinate (4) as the base
gland of the male musk deer Moshus moshiferus, has a long and
interesting history and continues to play an important role in
perfume industry.1 Its unsaturated cousin (R,Z)-1 is equally
valuable, as it exhibits a strong and elegant odor with a desirable
nitromusk note and gentle animal undertones. Moreover, this
compound is distinguished by an outstandingly low threshold
6
(ꢂ76% ee). A related approach generates (R,Z)-1 by Grob frag-
,2
mentation of tosylate 9. This compound derives from aldol 8, which
was formed from 3, albeit in low yield (21% with 70% ee; 10% with
ꢃ98% ee after recrystallization), with the aid of stoichiometric
3
amounts of TiCl
drine (7).
4
in combination with (ꢀ)-N,N-dibutylnorephe-
ꢀ1 4
7
value of 0.027 ng L
R,Z)-1 has recently been commercialized as a fragrance in-
gredient, after a mixture comprising racemic Z-1 and racemic E-1
,
and is therefore highly sought after. Pure
(
These three fragmentation-based routes have the distinct ad-
8
vantage of delivering the desired Z-isomer only, whereas an al-
(
together with several positional isomers) had already been suc-
ternative RCM-based synthesis furnished a mixture of cycloalkenes
Ò
cessful on the market under the trade name Muscenone (Fir-
menich SA).
The excellent olfactory characteristics of (R,Z)-1 make a practical
synthesis of this particular isomer a highly desirable task. Two of
the published approaches (Scheme 1) rely on an Eschenmoser
in modest yield, in which the undesired E-olefin prevailed (53%,
9
,10
E/Z¼7:2) (Scheme 2).
11
Our longstanding interest in odoriferous compounds let us
pursue an alternative synthesis of (R,Z)-1. Not only should this new
route deliver the desired product in optically and isomerically pure
form, but also avoid recourse to precious metal catalysts altogether.
12,13
We believe that the use of ‘cheap metals for noble tasks’
defines
a challenging goal for contemporary organic synthesis, which is
more often missed than met. The results of our work along these
lines are summarized below.
*
Corresponding author. Tel.: þ49 208 306 2342; fax: þ49 208 306 2994; e-mail
address: fuerstner@kofo.mpg.de (A. F u€ rstner).
0
040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.085

7696
K. Lehr, A. F u€ rstner / Tetrahedron 68 (2012) 7695e7700
Scheme 3. (a) (i) Pig liver esterase, NaOH (1 M), MeOH, pH
ii) (ꢀ)-cinchonidine, aq acetone, then aq HCl (ꢃ98% ee); (b) (i) aq LiOH; (ii) LiBH
THF; (iii) aq HCl, 92%; (c) CCl , PPh , THF, reflux, 92%; (d) MeLi, Et O, RT, 90%; (e) (i)
TEMPO cat., aq NaOCl, KBr cat., CH Cl , aq NaHCO ; (ii) NaClO , NaH PO , t-BuOH, H O,
-methyl-2-butene, 91%; (f) oxalyl chloride, CH Cl , DMF cat.; (g) Fe(acac) (5 mol %),
7 buffer, 78%;
(
4
,
4
3
2
2
2
3
2
2
4
2
2
2
2
3
ꢄ
THF, ꢀ78 C, 79%.
Scheme 1. Fragmentation-based approaches to (R,Z)-1 reported in the literature, cf.
Ref. 5e7; diketone 3 is derived from cyclododecanone.
Oxidation of 20 under standard conditions furnished the re-
quired acid segment 21 in optically pure form. The derived acid
chloride was amenable to an iron-catalyzed cross coupling re-
18,19
20
action
with 10-dodecynylmagnesium bromide 23 to give
ketone 24 as the required substrate for the subsequent macro-
21,22
cyclization via ring closing alkyne metathesis (RCAM).
Alter-
natively, 24 can be formed from the Grignard reagent 23 and the
2
3
corresponding Weinreb-amide derived from 21.
The excellent track record of RCAM encompasses several ap-
plications to the stereoselective synthesis of olfactory compounds,
2
4
25,26
including ambrettolide and civetone.
However, fairly high
2
7
28
loadings (10 mol %) of the then used standard catalysts 25 or 26
were necessary, both of which are highly sensitive to air and
moisture (Scheme 4). Recently, we disclosed a new generation of
alkyne metathesis catalyst with a significantly improved applica-
tion profile. Specifically, it was shown that triarylsilanolates as
ancillary ligands impart exceptional reactivity as well as an un-
rivaled functional group tolerance on molybdenum alkyli-
Scheme 2. RCM-based approach, delivering an E,Z-mixture of 1, cf. Ref. 9,10.
2
. Results and discussion
2
9,30
dynes.
Complexes, such as 27 and 28 are readily prepared on
Dimethyl 3-methylglutarate 14 was deemed an appropriate
starting material, because it can be readily desymmetrized by a pig
liver esterase catalyzed saponification (Scheme 3). Recrystallization
of the cinchonidine salt of the resulting crude mono-acid (89e93%
ee) furnished optically pure 15 on large scale (ꢃ98% ee, 20 g single
largest batch).14 Subsequent reduction with LiBH
followed by an
4
acidic work-up gave lactone 16, which was converted into the gem-
15
4 3
dichloro-olefin 17 on treatment with CCl and PPh . Although this
material can be stored at low temperature for a couple of days, it
was best transformed without delay into the desired non-terminal
16
2
alkyne 20 upon reaction with MeLi in Et O, as recently described.
Although the scope and mechanism of this high-yielding alkylative
elimination are subject to ongoing investigations in this laboratory,
it is believed that an initial metal/halogen exchange generates the
vinylidene intermediate 18. Literature evidence suggests that such
carbenoids are highly electrophilic in nature;17 therefore, it is as-
sumed that 18 rapidly intercepts a second equivalent of MeLi to give
Scheme 4. Established and recent (pre)catalysts for alkyne metathesis; Ar¼C
p-MeOC
e; phen¼1,10-phenanthroline.
6 5
H e,
1
9, which eventually collapses to the methyl-capped alkyne 20.16
6 4
H

K. Lehr, A. F u€ rstner / Tetrahedron 68 (2012) 7695e7700
7697
a multigram scale from cheap precursors and can be rendered air-
3. Experimental section
3.1. General
stable upon complexation with 1,10-phenanthroline. Although the
resulting adduct 29 itself is inactive, the catalytically competent
molybdenum species can be conveniently regenerated in solution
upon mixing with either ZnCl
2
or MnCl
2
, which are capable of
Unless stated otherwise, all reactions were carried out in flame-
dried glassware under Argon. All solvents were purified by distil-
lation over the indicated drying agents and were stored and
pulling the stabilizing phenanthroline ligand off this bench-stable
2
9
precatalyst (Scheme 4).
The cyclization of diyne 24 to cycloalkyne 6 bears witness of the
excellent reactivity of these new catalysts. Although a full optimi-
zation of the reaction conditions was not intended, we showed that
transferred under Argon: THF (Mg-anthracene), Et
2
O (Mg-anthra-
cene), CH Cl , CHCl (CaH ), MeOH (Mg), hexanes, pentanes (Na/K),
2
2
3
2
toluene (Na/K). Flash chromatography: Merck silica gel 60
1
mol % of the ate-complex 27 (Ar¼p-MeOC
6
H
4
e) in toluene suf-
(230e400 mesh). IR: Nicolet FT-7199 spectrometer, wavenumbers
ꢀ1
ficed to ring-close this particular substrate within 30 min at am-
bient temperature, when the reaction was performed in the
presence of MS 5 A (Scheme 5). The remarkable rate of macro-
cyclization is best appreciated when compared with the long re-
action time of the analogous RCM reaction of diene 12 with the aid
in cm . MS (EI): Finnigan MAT 8200, MS (CI): Finnigan MAT 95, MS
(ESI) ESQ 3000, accurate mass determinations: Bruker APEX III FT-
MS (7 T magnet). NMR: Spectra were recorded on a Bruker DPX
ꢀ
31
1
300, AV 400 or AV 600 spectrometer in the solvents indicated; H
1
3
and C chemical shifts (
TMS, coupling constants (J) in Hertz (Hz). The solvent signals were
used as references (CDCl ¼77.00 ppm; C
¼7.26 ppm,
d) are given in parts per million relative to
9
of the first generation Grubbs catalyst 13 (Scheme 2).
3
:
d
H
d
C
6 6
D :
d
H
¼7.15 ppm,
d
C
¼128.02 ppm) and the chemical shifts converted to
the TMS scale. All commercially available compounds (ABCR, Acros,
Aldrich, Fluka, Lancaster, Strem) were used as received.
3.2. (R)-5-Methoxy-3-methyl-5-oxopentanoic acid (15)
2
Scheme 5. (a) See Table 1; (b) P2eNi cat., H (1 atm), EtOH, 94%.
A three necked, 2 L cylindrical reactor with a cooling mantle
connected to a cryostat was charged with KH
2 4 2 4
PO /Na HPO buffer
Moreover, it was possible to increase the substrate concentra-
tion from 0.003 M, as initially used, by one order of magnitude
without a dramatic loss in yield, provided that the cyclization was
performed at elevated temperatures (Table 1). Under these condi-
tions, the substrate initially converts into a product mixture com-
(1.0 L, 0.1 M, pH 7), MeOH (250 mL) and dimethyl 3-
methylglutarate 14 (45.0 g, 258 mmol). The mixture was cooled
ꢄ
to ꢀ10 C before pig liver esterase (1.81 g, 36,290 U, E.C.3.1.1.1) was
added. The necks of the reactor were closed with rubber septa;
through one of them aq NaOH (1.0 M, 260 mL, 260 mmol) was
injected via syringe pump through a steel cannula at such a rate as
to maintain the pH as close to 7 as possible. After 63 h the NaOH
feed was complete. The cold, light brown emulsion was filtered
through a pad of Celite (diameter¼10 cm, height¼5 cm), which was
carefully rinsed with water (500 mL). The pH of the combined fil-
trates was adjusted to 3 with HCl (2 M) and the mixture separated
in two equal parts, both of which were extracted with diethyl ether
prising
6 and several dimeric and oligomeric compounds.
Gratifyingly though, the latter largely converge to the cyclic
ꢄ
monomer 6 upon stirring of the mixture at 60e80 C for several
hours (compare the outcome of entries 5 and 6). Macrocyclizations
ꢄ
in 0.02 M solution at 80 C seem to be a good compromise between
rate, yield and the necessary catalyst loading (entry 4).
Cycloalkyne 6 thus obtained was identical to the material pre-
viously formed by an Eschenmoser fragmentation of 5 (Scheme 1).5,6
(
6ꢅ100 mL each). The combined organic phases were dried over
Its semi-hydrogenation over Lindlar catalyst has already been de-
5
Na SO , filtered through a sintered glass filter, and evaporated to
2
4
scribed in the literature. In our hands, however, the use of P2-nickel
3
2
give the crude product, which was purified by flash chromatogra-
phy (hexanes/ethyl acetate, 4:1) to give monoester 15 as a colorless
oil (32.1 g, 78%, 93% ee). The corresponding diacid (1.1 g) and a small
amount of the starting material (350 mg) were isolated as minor
by-products.
(
formed from Ni(OAc)
2
$4H
2
O and NaBH
4
)
gave better and more
reliable results than the sample of commercial Lindlar catalyst
available to us. The nickel catalyst furnished (R,Z)-1 in essentially
3
3
quantitative yield and consistently high purity.
In summary, the new generation of alkyne metathesis catalyst
(
ꢀ)-Cinchonidine (59.0 g, 200 mmol) was added to a solution of
exemplified by complex 27 proved highly adequate for the forma-
3
4
the enantioenriched monoester 15 in acetone (580 mL) and the
resulting suspension heated to 40 C. Water (z60 mL) was then
tion of the 15-membered cycloalkyne 6, which is the key in-
ꢄ
termediate for the production of optically and isomerically pure
introduced under vigorous stirring until a clear yellowish solution
had formed. The solution was then allowed to rest overnight at 8 C
to give a cake of off-white amorphous material, which was filtered
off through a sintered glass filter, washed with ice-cold acetone
(R,Z)-1, a valuable musk component used in fragrance industry.
ꢄ
Although other routes to the required diyne precursor 24 can be
envisaged, the convergent sequence presented herein allows cheap
substrates to be effectively converted into a valuable perfume in-
gredient with base-metal-catalysis (Fe, Mo, Ni) only.
(100 mL) and dried under reduced pressure. The dried material was
dissolved in aq HCl (2 M, 100 mL), the acidic layer was extracted
Table 1
with diethyl ether (5ꢅ40 mL) and the combined extracts were
a
Formation of cycloalkyne 6 by RCAM
2 4
dried over Na SO , filtered, and evaporated to give product 15 as
ꢄ
Yieldb
Entry
27 (mol %)
c (M)
T ( C)
t (h)
a colorless oil (19.3 g, 60%), From the mother liquor, additional
crops of the product can be obtained. The optical purity (98% ee)
1
2
3
4
5
6
5
1
1
1
1
0.003
0.003
0.003
0.02
0.03
0.03
20
20
60
80
60
80
0.5
0.5
0.5
2.0
0.5
4.0
86%
89%
91%
84%
44%
75%
was determined by GC (HP 6890 514 instrument, 2511 Hydrodex
ꢄ
BTBAC G 534 column, 0.4 bar H
2
, 115 C (isotherm) FID-detector:
20
D
retention times: 78 min (major), 82 min (minor)). ½
a
ꢆ
ꢀ0.6 (c
1
c
1.4, CHCl
m, 3H), 2.33e2.24 (m, 2H), 1.05 ppm (d, J¼6.5 Hz, 3H); C NMR
(100 MHz, CDCl ):
); H NMR (400 MHz, CDCl
):
d
¼3.68 (s, 3H), 2.50e2.38
2ꢅ1
3
3
13
(
a
All reactions were performed in toluene using complex 27 (Ar¼p-MeOC
6 4
H e) in
ꢀ
3
d¼177.9, 172.7, 51.5, 40.5, 40.4, 27.2, 19.8 ppm; IR
the presence of MS 5 A.
b
(film): ~
n
Isolated yields.
2959, 1733, 1704, 1437, 1414, 1371, 1287, 1203, 1158, 1082,
1007, 876, 854, 697 cm ; MS (70 eV) m/z (%): 161 (1), 142 (30), 129
c
ꢀ1
The second portion of the catalyst was added after 2 h reaction time.

7698
K. Lehr, A. F u€ rstner / Tetrahedron 68 (2012) 7695e7700
(
(
C
92), 114 (84), 101 (83), 87 (19), 82 (25), 74 (72), 69 (77), 59 (100), 55
(60 mL) and the resulting mixture stirred for 2 d at ambient tem-
perature. The reaction was quenched with water (80 mL) and the
mixture extracted with diethyl ether (3ꢅ80 mL). The combined
39), 43 (59), 41 (36), 29 (17); HRMS (CI) m/z: calcd for
þ
7 12
H O
4
þH : 161.0815; found: 161.0814.
2 4
organic phases were dried over Na SO , filtered, and evaporated,
3
.3. (S)-4-Methyltetrahydro-2H-pyran-2-one (16)
and the residue was purified by flash chromatography (pentane/
diethyl ether, 1:1) to give alcohol 20 as a colorless oil (750 mg, 90%).
2
0
1
Aqueous LiOH (0.2 M, 93.7 mL, 18.7 mmol) was slowly added to
½
a
ꢆ
þ3.2 (c 0.5, CHCl
3
); H NMR (400 MHz, CDCl
3
):
d
¼3.71 (dt,
D
a solution of compound 15 (3.00 g, 18.7 mmol) in water (5 mL) at
0
J¼10.9, 6.5 Hz, 1H), 3.67 (dt, J¼10.9, 6.5 Hz, 1H), 2.12e2.07 (m, 2H),
ꢄ
C. The mixture was stirred for 1 h before the solvent was evap-
1.84e1.65 (m, 2H), 1.78 (t, J¼2.6 Hz, 3H), 1.55e1.42 (m, 2H),
ꢄ
ꢀ3
ꢄ
13
orated (50 C, 20 mbar). Drying (3ꢅ10 mbar, 90 C) of the residue
0.98 ppm (d, J¼6.6 Hz, 3H); C NMR (100 MHz, CDCl
3
):
3339, 2970,
2956, 2920, 2875, 1738, 1455, 1434, 1375, 1366, 1229, 1217, 1206,
d¼77.5,
for 4 h gave the corresponding lithium salt as a white solid.
77.2, 61.0, 38.8, 29.6, 26.1, 19.7, 3.4 ppm; IR (film): ~
n
4
THF (240 mL) and LiBH (2.0 M in THF, 16 mL, 31 mmol) were
ꢀ
1
added to this salt and the resulting mixture refluxed for 5 h under
Ar with vigorous stirring. The suspension was cooled to room
temperature before MeOH (48 mL) was added. The mixture was
then stirred under reflux for 1 h. After reaching ambient temper-
ature, the reaction was quenched with water (120 mL) and the
organic solvents were evaporated. The aqueous solution was acid-
ified with HCl (2 M) to pH 2; chloroform (100 mL) was added and
the biphasic mixture stirred overnight. The layers were separated
and the aqueous phase was extracted with chloroform (3ꢅ50 mL).
1092, 1053, 1006, 962, 888, 842 cm ; MS (70 eV) m/z (%): 111 (31),
98 (65), 97 (13), 93 (33), 91 (22), 84 (24), 83 (11), 82 (100), 81 (14),
80 (20), 79 (38), 77 (31), 71 (19), 67 (46), 55 (85), 54 (36), 53 (44), 43
þ
(58), 41 (43); HRMS (CI): m/z calcd for C
127.1123.
8
H
14OþH : 127.1124, found
3.6. (R)-3-Methylhept-5-ynoic acid (21)
TEMPO (6 mg, 0.04 mmol) and aq NaOCl (z0.1 M, 10 mL,
ꢄ
The combined organic phases were dried over Na
evaporated, and the residue was purified by flash chromatography
pentanes/diethyl ether, 1:1), affording lactone 16 as a colorless
2
SO
4
, filtered, and
1.4 mmol) were successively added at 0 C to a biphasic mixture
comprising a solution of alcohol 20 (90 mg, 0.71 mmol) in CH
(5 mL), satd aq NaHCO (15 mL), and KBr (4 mg, 0.04 mmol). After
stirring for 1 h, the reaction was quenched with satd aq Na
2 2
Cl
(
3
liquid (1.96 g, 92%). The optical purity (98% ee) was determined by
2 2 3
S O
GC (AT 6890 N instrument, 2511 Hydrodex TBDAc column, 0.5 bar
(10 mL) and the mixture allowed to warm to ambient temperature.
The aqueous phase was extracted with methyl tert-butyl ether
(3ꢅ10 mL) and the combined organic phases were evaporated.
ꢄ
H
2
, 145 C (isotherm) FID-detector: retention times: 29 min (ma-
20
1
jor), 32 min (minor)). ½
a
ꢆ
ꢀ22.6 (c 1.0, CHCl
3
); H NMR (400 MHz,
¼4.41 (ddd, J¼11.4, 4.9, 4.0 Hz, 1H), 4.26 (ddd, J¼11.3, 10.6,
.8 Hz, 1H), 2.71e2.63 (m, 1H), 2.14e2.03 (m, 2H), 1.93e1.88 (m,
D
CDCl
3
1
(
(
3
):
d
2 4
2-Methyl-2-butene (7 mL), water (10 mL), NaH PO (300 mg,
2
3.4 mmol), and NaClO (300 mg, 2.5 mmol) were successively
13
H), 1.56e1.47 (m, 1H), 1.06 ppm (d, J¼6.4 Hz, 3H); C NMR
):
¼171.2, 68.5, 38.2, 30.6, 26.5, 21.4 ppm; IR
2959, 2931, 2876, 1724, 1457, 1401, 1255, 1224, 1153, 1088,
added to a solution of the resulting crude aldehyde in tert-butanol
(15 mL). The suspension was stirred for 4 h before it was diluted
with water (10 mL). The aqueous phase was extracted with methyl
tert-butyl ether (3ꢅ20 mL), the combined organic layers were dried
100 MHz, CDCl
film): ~
062, 994, 912, 823, 780, 690 cm ; MS (70 eV) m/z (%): 114 (49), 84
4), 70 (26), 55 (91), 53 (4), 42 (100), 39 (20), 29 (17); HRMS (CI): m/
z calcd for C : 114.0680, found 114.0681.
3
d
n
ꢀ
1
1
(
2 4
over Na SO , filtered, and evaporated. Purification of the residue by
6
10
H O
2
flash chromatography (pentane/methyl tert-butyl ether 8:2) gave
2
0
1
acid 21 as a colorless oil (91 mg, 91%). ½
a
ꢆ
þ3.5 (c 1.5, CHCl
3
); H
D
3
.4. Dichloroolefin 17
NMR (400 MHz, C
m, 4H), 1.49 (t, J¼2.5 Hz, 3H), 0.88 ppm (d, J¼6.4 Hz, 3H); C NMR
(100 MHz, C ):
¼179.5, 77.5, 76.9, 40.1, 30.0, 26.0, 19.4, 3.2 ppm;
IR (film): ~
2962, 2923, 1707, 1435, 1412, 1287, 1232, 1179, 1083, 932,
6 6
D ): d
¼2.36 (dd, J¼15.2, 5.5 Hz, 1H), 2.12e1.90
13
(
CCl
solution of lactone 16 (750 mg, 6.57 mmol) and PPh
6.3 mmol) in THF (130 mL). After complete addition, the dark so-
lution was cooled to room temperature and the reaction quenched
with water (150 mL). The aqueous phase was extracted with CH Cl
3ꢅ100 mL), the combined organic phases were washed with satd aq
NaHCO (100 mL) and dried over Na SO . The solution was con-
4
(15 mL, 24 g, 160 mmol) was added over 4 h to a refluxing
6
D
6
d
3
(6.89 g,
n
ꢀ
1
2
720, 695 cm ; MS (70 eV) m/z (%): 140 (2), 125 (4), 11 (7), 98 (100),
95 (21), 79 (68), 69 (18), 53 (42), 41 (39), 27 (48); HRMS (EI): m/z
2
2
8 12 2
calcd for C H O : 140.0837, found 140.0836.
(
3
2
4
3.7. 12-Bromododec-2-yne
centrated to a volume of about 10 mL before pentane (z100 mL) was
added under vigorous stirring, causing the formation of a precipitate,
which was filtered off. This cycle was repeated three times until no
more precipitate formed. Purification of the then remaining residue
by flash chromatography (pentanes/diethyl ether 100:0/98:2) gave
PPh
3
(2.16 g, 8.23 mmol) and N-bromosuccinimide (1.46 g,
ꢄ
8.23 mmol) were successively added at 0 C to a solution of dodec-
10-yn-1-ol (1.00 g, 5.49 mmol) in CH Cl (40 mL). The mixture was
2 2
stirred at ambient temperature overnight before all volatile mate-
rials were evaporated under reduced pressure. Purification of the
residue by flash chromatography (pentanes) gave the desired
product as a colorless oil (1.29 g, 96%). H NMR (400 MHz, CDCl
2
0
compound 17 as a colorless oil (1.11 g, 92%). ½
a
ꢆ
þ128 (c 1, CHCl
3
);
¼3.73 (ddd, J¼11.0, 4.6, 2.9 Hz, 1H), 3.21
td, J¼11.2, 3.1 Hz, 1H), 2.52 (ddd, J¼14.7, 4.5, 1.7 Hz, 1H), 1.35 (dd,
J¼14.7, 11.4 Hz, 1H), 1.18e1.04 (m, 1H), 0.96e0.89 (m, 1H), 0.88e0.76
D
1
H NMR (400 MHz, C
6 6
D ):
d
1
(
3
):
d
¼3.40 (t, J¼6.9 Hz, 2H), 2.11 (tdd, J¼7.2, 2.5, 2.5 Hz, 2H), 1.85 (tt,
13
(
m, 1H), 0.52 (d, J¼6.5 Hz, 3H); C NMR (100 MHz, C
04.2, 69.0, 33.8, 32.5, 28.2, 21.3 ppm; IR (film): ~
2956, 2874, 1737,
629, 1456, 1434, 1381, 1310, 1259, 1230, 1084, 1053, 996, 936, 843,
43, 695 cm ; MS (70 eV) m/z (%): 182 (18), 180 (27), 145 (7), 112
21),110 (47), 81 (12), 70 (20), 55 (100), 41 (27); HRMS (CI): m/z calcd
for C 10OCl : 180.0109, found 180.0109.
6 6
D ):
d¼150.0,
J¼7.0, 7.0 Hz, 2H), 1.78 (t, J¼2.6, 2.6 Hz, 3H), 1.56e1.22 ppm (m,
13
1
n
12H); C NMR (100 MHz, CDCl
3
):
d
¼79.3, 75.3, 34.0, 32.8, 30.0, 29.0
1
7
(2C), 28.8, 28.7, 28.1, 18.7, 3.5 ppm; IR (film): ~
1436, 1351, 1331, 1261, 1244, 723 cm ; MS (70 eV) m/z (%): 215 (4),
123 (6), 109 (41), 95 (100), 81 (53), 67 (51), 55 (41), 41 (40); HRMS
(EI): m/z calcd for C12H21Br: 244.0827, found 244.0827.
n
2926, 2854, 1460,
ꢀ1
ꢀ1
(
7
H
2
3
.5. Alcohol 20
3.8. Ketone 24
Dichloroolefin 17 (1.20 g, 6.63 mmol) was added to a solution of
MeLi (1.6 M in diethyl ether, 21 mL, 33 mmol) in diethyl ether
Magnesium turnings (400 mg, 16 mmol) were covered with THF
(2 mL) and etched with iodine. A solution of 12-bromododec-2-yne

K. Lehr, A. F u€ rstner / Tetrahedron 68 (2012) 7695e7700
7699
(
1.0 g, 4.1 mmol) in THF (25 mL) was added over ca. 20 min to the
CDCl
3
):
d
¼5.45e5.40 (m, 2H), 2.50e2.20 (m, 4H), 2.16e1.88 (m, 5H),
suspension, which was stirred under reflux for 1 h once the addi-
tion was complete. The solution of the resulting Grignard reagent
2
1.62 (tt, J¼6.7, 6.5 Hz, 2H), 1.46e1.20 (m, 12H), 0.99 ppm (d,
13
J¼6.7 Hz, 3H); C NMR (100 MHz, CDCl
49.1, 42.0, 33.1, 29.4, 27.6, 26.7, 26.6, 26.1, 26.1, 25.9, 25.8, 22.5,
19.9 ppm; IR (film): ~
2925, 2855, 1710, 1457, 1405, 1368, 1274,
3
):
d
¼211.5, 131.6, 126.7,
ꢄ
3 was stored at 8 C under Ar. Its concentration was checked be-
3
5
fore use according to a literature procedure.
n
ꢀ
1
Oxalyl chloride (24
mL, 36 mg, 0.28 mmol) and dimethylforma-
720 cm ; MS (70 eV) m/z (%): 236 (92), 178 (26), 122 (20), 109 (28),
95 (59), 81 (100), 68 (83), 55 (75), 41 (92), 29 (21); HRMS (EI): m/z
calcd for C16H28O: 236.2140, found 236.2141.
mide (about 5
0
m
L) were added to a solution of acid 21 (38 mg,
ꢄ
.27 mmol) in CH
2
Cl
2
(2 mL) at 0 C, and the resulting mixture
stirred for 1 h at ambient temperature. Evaporation of all volatile
ꢄ
materials (15 mbar, 35 C) gave acid chloride 22, the purity of which
Acknowledgements
1
was checked by H NMR spectroscopy.
A solution of the Grignard reagent 23 (0.13 M in THF, 3.25 mL,
Generous financial support by the Max-Planck-Gesellschaft, the
Fonds der Chemischen Industrie, and SusChemSys (Ziel 2 Pro-
gramm NRW 2007e2013) is gratefully acknowledged. We thank Dr.
A. Kondoh for samples of the alkylidyne catalyst 27.
0
.41 mmol) was slowly added to a solution of the crude acid
ꢄ
chloride 22 and Fe(acac)
3
(4.8 mg, 14
m
mol) in THF (5 mL) at ꢀ78 C.
The mixture was stirred for 15 min at this temperature before the
reaction was quenched with satd aq NH Cl (10 mL). After reaching
4
ambient temperature, the mixture was extracted with methyl tert-
butyl ether (3ꢅ10 mL). The combined organic phases were dried
Supplementary data
2 4
over Na SO , filtered, and evaporated, and the residue purified by
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.085.
flash chromatography (pentane/methyl tert-butyl ether 95:5) to
2
0
give ketone 24 as a colorless wax-like material (62 mg, 79%). ½ ꢆ
a
D
1
þ12 (c 0.5, CHCl
.9 Hz, 1H), 2.38 (t, J¼7.2 Hz, 2H), 2.29e2.00 (m, 6H), 1.77 (t,
J¼2.5 Hz, 3H), 1.77 (t, J¼2.6 Hz, 3H), 1.64e1.20 (m, 14H), 0.95 ppm
3
); H NMR (300 MHz, CDCl
3
):
d
¼2.56 (dd, J¼15.5,
References and notes
4
1. Walbaum, H. J. Prakt. Chem. (Leipzig) 1906, 73, 488e493; (b) Ruzicka, L. Helv.
Chim. Acta 1926, 9, 715e729.
13
(
d, J¼6.3 Hz, 3H); C NMR (75 MHz, CDCl
7.1, 75.3, 48.5, 43.4, 29.4, 29.3, 29.2, 29.1, 29.0, 28.8, 28.7, 25.8, 23.8,
9.6, 18.7, 3.5 ppm (2C); IR (film): ~
2922, 2855, 1712, 1456, 1435,
3
):
d
¼210.8, 79.3, 77.2,
2
. (a) Ohloff, G. Riechstoffe und Geruchsinn: die molekulare Welt der D u€ fte;
Springer: Berlin, 1990; (b) Williams, A. S. Synthesis 1999, 1707e1723; (c) Fr aꢁ ter,
G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633e7703.
7
1
1
n
ꢀ
1
409, 1372, 1110, 1029, 945, 720 cm ; MS (70 eV) m/z (%): 288 (33),
73 (20), 193 (11), 147 (20), 138 (31), 123 (58), 109 (36), 95 (100), 81
87), 80 (80), 79 (61), 67 (83), 55 (100), 41 (86); HRMS (EI): m/z
calcd for C20 32O: 288.2453, found 288.2452.
3. Demole, E.; Mahaim, C.; Blanc, P.-A. EP 584477 (Firmenich SA) (prior. July 30,
1992) Chem. Abstr. 1994, 120, 253101.
2
(
4
. The threshold of (R,Z)-1 is z100 times lower than that of its enantiomer (S,Z)-1
and more than an order or magnitude lower than that of natural muscone (2),
cf. Ref. 6.
H
5
6
. Fehr, C.; Galindo, J.; Etter, O. Eur. J. Org. Chem. 2004, 1953e1957.
. Knopff, O.; Kuhne, J.; Fehr, C. Angew. Chem., Int. Ed. 2007, 46, 1307e1310.
3
.9. Cycloalkyne 6
7
8
9
. Fehr, C.; Buzas, A. K.; Knopff, O.; de Saint Laumer, J.-Y. Chem.dEur. J. 2010, 16,
2487e2495.
. Fora classicalsynthesis of rac-1 and thedevelopment of the fragmentation method,
see: Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta 1967, 50, 708e713.
. Fujimoto, S.; Yoshikawa, K.; Itoh, M.; Kitahara, T. Biosci. Biotechnol. Biochem.
2002, 66, 1389e1392.
A solution of complex 27 (Ar¼p-MeOC
6 4
H ) (5.4 mg, 3.1 mmol) in
toluene (1 mL) was added to a mixture of ketone 24 (88 mg,
ꢀ
0
(
.31 mmol) and powdered molecular sieves (5 A, 90 mg) in toluene
90 mL). The suspension was stirred for 30 min at 60 C before it was
ꢄ
10. According to Ref. 5, the E/Z-ratio of the RCM product was erroneously assigned
as 2:7, but is in fact 7:2.
filtered through a pad of Celite and the filtrate evaporated. Purifica-
tion of the residue by flash chromatography (pentane/diethyl ether
1
1. (a) F u€ rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942e3943; (b) F u€ rstner,
A.; Langemann, K. Synthesis 1997, 792e803; (c) F u€ rstner, A.; M u€ ller, T. Synlett
2
0
€
9
CHCl
2
8
5:5)gavecycloalkyne6asacolorlessoil(65mg,91%).½
a
ꢆ
ꢀ18 (c0.5,
1997, 1010e1012; (d) Furstner, A.; Leitner, A. Angew. Chem., Int. Ed. 2003, 42,
308e311; (e) F u€ rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012e3043.
D
1
3
); H NMR (400 MHz, CDCl ¼2.93 (dd, J¼17.8, 4.5 Hz, 1H),
.46 (ddd, J¼14.6, 9.2, 3.9 Hz,1H), 2.40e2.14 (m, 6H),1.98 (ddt, J¼16.3,
.7, 2.5 Hz, 1H), 1.87e1.75 (m, 1H), 1.67e1.55 (m, 1H), 1.53e1.20 (m,
3
):
d
1
2. F u€ rstner, A.; Majima, K.; Martín, R.; Krause, H.; Kattnig, E.; Goddard, R.; Leh-
mann, C. W. J. Am. Chem. Soc. 2008, 130, 1992e2004.
13. Catalysis without Precious Metals: Bullock, R. M., Ed.; Wiley-VCH: Weinheim,
2010.
13
1
8
2
2H), 0.94 ppm (d, J¼6.5 Hz, 3H); C NMR (100 MHz, C
6
D
6
):
d¼209.3,
1
4. (a) Lam, L. K. P.; Hui, R. A. H. F.; Jones, J. B. J. Org. Chem. 1986, 51, 2047e2050; (b)
Poppe, L.; Novak, L.; Kolonits, P.; Bata, A.; Szantay, C. Tetrahedron 1988, 44,
1477e1487.
1.8, 79.1, 49.1, 41.3, 28.4, 28.3, 27.7, 27.1, 26.7, 26.6, 26.4, 25.7, 24.9,
ꢁ
ꢁ
ꢁ
ꢀ
1
0.2,18.7ppm;IR(film):~
n
2929, 2857,1711,1457,1371,1110,698cm ;
1
1
5. Lakhrissi, M.; Chapleur, Y. J. Org. Chem. 1994, 59, 5752e5757.
6. Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B.; F u€ rstner, A. Angew. Chem., Int. Ed.
011, 50, 11373e11377.
MS (70 eV) m/z (%): 234 (20), 219 (14), 177 (16), 149 (12), 137 (23), 135
23), 121 (34), 107 (43), 93 (65), 67 (52), 55 (74), 41 (100); HRMS (EI):
m/z calcd for C16 26O: 234.1984, found 234.1981.
(
2
H
17. (a) K o€ brich, G.; Ansari, F. Chem. Ber. 1967, 100, 2011e2020; (b) Duraisamy, M.;
Walborsky, H. M. J. Am. Chem. Soc. 1984, 106, 5035e5037; (c) Topolski, M.;
Duraisamy, M.; Rachon, J.; Gawronski, J.; Gawronska, K.; Goedken, V.; Wal-
borsky, H. M. J. Org. Chem. 1993, 58, 546e555.
3
.10. Musceonone (R,Z-1)
1
8. (a) Scheiper, B.; Bonnekessel, M.; Krause, H.; F u€ rstner, A. J. Org. Chem. 2004, 69,
943e3949; (b) F u€ rstner, A.; De Souza, D.; Turet, L.; Fenster, M. D. B.; Parra-Ra-
pado, L.; Wirtz, C.; Mynott, R.; Lehmann, C. W. Chem.dEur. J. 2007, 13, 115e134.
9. (a) Sherry, B. D.; F u€ rstner, A. Acc. Chem. Res. 2008, 41, 1500e1511; (b) F u€ rstner,
3
NaBH
.50 mmol) were added to a solution of Ni(OAc)
.34 mmol) in EtOH (technical grade, 10 mL) before H
4
(13 mg, 0.34 mmol) and ethylenediamine (33
$4H O (85 mg,
was bubbled
mL,
0
0
2
2
1
2
A. Angew. Chem., Int. Ed. 2009, 48, 1364e1367.
2
0. 10-Dodecynyl bromide was prepared on large scale from nonane-1,9-diol in
analogy to the procedures described in: Banaszak, E.; Xu, L.-W.; Bardeau, J.-F.;
Castanet, A.-S.; Mortier, J. Tetrahedron 2009, 65, 3961e3966.
through the resulting black suspension for 20 min.
An aliquot (z0.8 mL) of this catalyst suspension was added to
a solution of cycloalkyne 6 (36 mg, 0.15 mmol) in EtOH (technical
grade, 4 mL). Hydrogen was bubbled through the mixture for 1 min
21. F u€ rstner, A.; Davies, P. W. Chem. Commun. 2005, 2307e2320.
22. F
u€ rstner, A.; Seidel, G. Angew. Chem., Int. Ed. 1998, 37, 1734e1736.
2
2
3. This route furnished 24 in 65% yield over both steps.
2
before it was vigorously stirred for 1 h under an atmosphere of H .
4. F u€ rstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121,
The catalyst was filtered off through a plug of silica, which was
carefully rinsed with pentanes/methyl tert-butyl ether (95:5).
Evaporation of the combined filtrates gave pure (R,Z)-1 as a color-
11108e11113.
25. F u€ rstner, A.; Seidel, G. J. Organomet. Chem. 2000, 606, 75e78.
2
2
6. See also: Kraft, P.; Berthold, C. Synthesis 2008, 543e550.
7. (a) Freudenberger, J. H.; Schrock, R. R.; Churchill, M. R.; Rheingold, A. L.; Ziller, J.
W. Organometallics 1984, 3, 1563e1573; (b) Schrock, R. R. Chem. Rev. 2002, 102,
145e179.
2
0
20
D
less oil (34 mg, 94%). ½
a
ꢆ
þ2.8 (c 0.5, CHCl ), ½
3
a
ꢆ
þ10.5 (c 0.4,
D
2
0
1
MeOH) [Ref. 7: ½
a
ꢆ
þ11.6 (c 1.12, MeOH)]; H NMR (400 MHz,
D

7700
K. Lehr, A. F u€ rstner / Tetrahedron 68 (2012) 7695e7700
2
2
3
8. (a) F u€ rstner, A.; Mathes, C.; Lehmann, C. W. Chem.dEur. J. 2001, 7, 5299e5317; (b)
F u€ rstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 9453e9454.
9. Heppekausen, J.; Stade, R.; Goddard, R.; F u€ rstner, A. J. Am. Chem. Soc. 2010, 132,
32. Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38, 2226e2230.
33. The samples contained ꢂ2% of the over-reduced product 2.
34. For other advanced applications of this and related catalysts, see: (a)
Micoine, K.; F u€ rstner, A. J. Am. Chem. Soc. 2010, 132, 14064e14066; (b)
Hickmann, V.; Kondoh, A.; Gabor, B.; Alcarazo, M.; F u€ rstner, A. J. Am.
11045e11057.
0. Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard, R.; F u€ rstner, A. J. Am.
Chem. Soc. 2009, 131, 9468e9470.
1. MS 5 A is added to bind the 2-butyne formed as the generic by-product in
alkyne metathesis reactions of methyl-capped alkyne substrates. For the dra-
matic effect of this additive, see Ref. 29.
Chem. Soc. 2011, 133, 13471e13480; (c) Benson, S.; Collin, M.-P.; Arlt, A.;
Gabor, B.; Goddard, R.; Furstner, A. Angew. Chem., Int. Ed. 2011, 50,
8739e8744.
ꢀ
€
3
35. Krasovskiy, A.; Knochel, P. Synthesis 2006, 890e891.