Enantioselective routes to (-)-(R)-muscone

Article abstract of DOI:10.1055/s-2006-939069

The macrocyclic ring of muscone was prepared by Pd-catalyzed cyclization of hexadeca-1,15-diyne, which was converted to cyclopentadec-2-enone. The stereogenic center was introduced by enantioselective Cu-catalyzed conjugate addition of dimethylzinc. Because the ee in this step was only moderate, a new route via cyclopentadeca-2,14-dienone was developed. Enantioselective conjugate addition to this substrate led to 14-methylcylodec-2-enone, which was hydrogenated to give (-)-(R)-muscone in high overall yield with up to 98% ee. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939069

LETTER
1031
Enantioselective Routes to (–)-(R)-Muscone
Enantioselective
r
t
u
(
–)-(
R
)-Mu
n
scone o Bulic, Ulrich Lücking, Andreas Pfaltz*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671103; E-mail: andreas.pfaltz@unibas.ch
Received 1 February 2006
toluene was slowly added to a 0.25 mM solution of 5
mol% of ligand 2a and 2.5 mol% of Pd(OAc)2 in toluene
at 80 °C over 24 hours using a syringe pump, the desired
enyne 5 was isolated in 70% yield after a reaction time of
Abstract: The macrocyclic ring of muscone was prepared by Pd-
catalyzed cyclization of hexadeca-1,15-diyne, which was converted
to cyclopentadec-2-enone. The stereogenic center was introduced
by enantioselective Cu-catalyzed conjugate addition of dimethyl-
zinc. Because the ee in this step was only moderate, a new route via three days. Even better results were obtained in cyclo-
cyclopentadeca-2,14-dienone was developed. Enantioselective con-
jugate addition to this substrate led to 14-methylcylodec-2-enone,
which was hydrogenated to give (–)-(R)-muscone in high overall
yield with up to 98% ee.
hexane with faster rates and yields of up to 85% after 12
hours. Ligand 2b gave somewhat lower yields (61% in
toluene).
The macrocyclic enyne 5 possesses the proper carbon
Key words: macrocycles, copper, palladium, asymmetric catalysis,
skeleton of muscone and a reactive enyne system, offering
several options for converting this precursor to the target
molecule (R)-1. The most direct way would be water
addition to the triple bond with concomitant isomerization
to the enone 8. Enantioselective hydrogenation of this
compound with 98% ee has recently been reported.6 As
expected, conversion of enyne 5 to the corresponding b-
methyl-substituted enone 8 proved to be difficult. Under
acidic conditions, the a-methyl-substituted isomer 9 was
formed as the main product via a Rupe rearrangement
(Scheme 1), whereas with HgSO4/H2SO4 the a-methylene
ketone 10 was obtained (Scheme 2).
muscone
(–)-(R)-Muscone, the principal odorous component of the
male musk deer, is an important ingredient of perfumes.1,2
In contrast to the natural R-enantiomer, the S-enantiomer
has a much weaker, less pronounced musk odor.2,3 There-
fore, great efforts have been made to develop industrially
feasible enantioselective routes to (R)-muscone.4 Al-
though numerous enantioselective syntheses have been
reported, none of them meets the stringent requirements
of a commercial process.
Therefore alternative routes were investigated. Mono-
epoxidation of the methylene group of enyne 5 with
MCPBA and subsequent reductive epoxide opening with
LiBH(Et)2 led to the corresponding tertiary alcohol in
high yield. However, attempts to rearrange the alcohol to
the desired enone gave unsatisfactory results [30% 8 in
addition to 30% 12 with Mo(acac)2]. Hydroboration of the
enyne 5 with subsequent oxidation produced the unsatur-
ated enones 8 and 11 in 60% total yield with enyne 12 as
a side product (Scheme 2). However, enones 8 and 11
were formed as E/Z-mixtures, which were difficult to
separate, making this route unpractical. Therefore, the
reaction sequence via enone 7, shown in Scheme 1, was
chosen.
O
(R)
O
Ph2P
N
R2
R1
2a R1 = t-Bu, R2 = H
2b R1 = Me, R2 = Me
1
Figure 1
We have recently found that palladium complexes with
phosphinooxazoline ligands such as 2a or 2b (Figure 1)
are efficient catalysts for the homo- and heterocoupling of
alkynes to enynes.5 This method was applied to the in-
tramolecular coupling of hexadeca-1,15-diyne 4 to give
the macrocyclic enyne 5, which we thought would be an
attractive precursor for the synthesis of muscone
(Scheme 1).
Selective oxidative cleavage of the methylene group in 5
was achieved by ozonolysis in 57% yield. Trimethyl
phosphite as reducing agent proved to be superior to dim-
ethylsulfide (53% yield).7 Oxidation with sodium perio-
date in the presence of catalytic amounts of ruthenium(III)
chloride8 gave unsatisfactory yields (39%). Treatment of
ynone 6 with an aqueous solution of chromium(II) sulfate
in DMF9 led to the desired trans-enone 7 in 84% yield.
The trans geometry was assigned by 1H NMR spectrosco-
py, based on the chemical shift of the olefinic b-CH signal
at d = 6.78 ppm (CDCl3; cis isomer d = 6.20 ppm).10
The starting diyne 4 was readily prepared from 1,12-di-
bromododecane and the Li-acetylide-1,2-ethylenedi-
amine complex. When a 0.1 M solution of diyne 4 in
SYNLETT 2006, No. 7, pp 1031–1034
0
3.
0
5.
2
0
0
6
Advanced online publication: 24.04.2006
DOI: 10.1055/s-2006-939069; Art ID: D02906ST
© Georg Thieme Verlag Stuttgart · New York

1032
B. Bulic et al.
LETTER
Scheme 1
Several methods have been reported for the conversion of Similar results were obtained with valine-derived phos-
enone 7 to (R)-muscone by enantioselective 1,4-addi- phine-imine ligands of type 13.14 The catalysts were pre-
tion.4a,11 The highest ee so far was achieved by Tanaka et pared from [Cu(II)(OTf)2] and one equivalent of 13 in
al. using MeLi and a copper complex with a chiral amino dichloromethane and isolated as green solids by precipita-
alcohol (96% ee).12 However, more than 0.3 equivalents tion with pentane. With the catalyst derived from 13a 58%
of the copper complex had to be used, making this method ee was obtained at 23 °C. A major problem was the low
unpractical for large-scale reactions. Higher turnover reactivity of the enone, resulting in only 60% conversion
numbers were observed with dimethylzinc and copper at ambient temperature. At 50 °C, conversion was high,
catalysts derived from chiral phosphites or phosphor- but addition of the resulting zinc enolate to the starting
amidites, but the enantioselectivities did not exceed 85% enone was observed as a side reaction, which lowered the
ee.4a,11
yield considerably. The corresponding (Z)-cyclopentade-
cenone was found to be more reactive. However, the
enantioselectivities were also modest (50% ee at 23 °C
and 58% ee at 0 °C with 13a, Figure 2).
We also tested various other chiral ligands for this trans-
formation, including binaphthol-derived phosphite-ox-
azolines, which are efficient ligands for the 1,4-addition
of dialkylzinc reagents to five-, six-, and seven-membered
ring cycloalkenones.13 However, only moderate yields
and enantioselectivities of up to 63% ee were achieved.
H
N
N
R
O
PPh2
O
13a R = t-Bu; 13b R = 1-Adamantyl
HgSO4, H2SO4
Figure 2
5
CH2Cl2, 40 °C
60%
We thought that the lower enantioselectivity of enone 7
compared to cyclohexenone might be attributable to the
greater flexibility of the large ring and the presence of
both the s-cis and the s-trans isomer, which are expected
to react with different enantioselectivity. Therefore, we
decided to examine the corresponding cyclopentadeca-
2,14-dienone (15) as substrate, because we expected this
compound to be conformationally more rigid due to the
additional C=C bond and more reactive than enone 7,
allowing lower reaction temperatures with fewer side
reactions.
10
1) Br2BH⋅SMe2, CH2Cl2, r.t
2) H2O2, NaOH
O
O
+
+
(E)-11 (Z)-11
18% 6%
(E)-8 (Z)-8
30% 6%
Starting from commercially available cyclopentade-
canone (14), double dehydrogenation with IBX [1-hy-
droxy-1,2-benziodoxol-3(1H)-one-1-oxide] following a
12
Scheme 2
Synlett 2006, No. 7, 1031–1034 © Thieme Stuttgart · New York

LETTER
Enantioselective Routes to (–)-(R)-Muscone
1033
O
O
A temperature of –30 °C was found optimal with respect
to both yield and enantioselectivity. Using the adamantyl-
substituted ligand 13b, a very high ee of 98% was ob-
tained, slightly higher than the value recorded for the tert-
butyl derivative 13a (95% ee). Hydrogenation of product
(R)-16 over Pd/C led to (R)-muscone 1 in essentially
quantitative yield.
3 equiv IBX
DMSO–PhF
80 °C, 24 h
60%
14
15
In summary, we have shown that the macrocyclic ring
system of muscone is readily prepared by Pd-catalyzed
cyclization of hexadeca-1,15-diyne. The cyclization prod-
uct could also be of interest for the synthesis of macro-
cyclic products other than muscone, as the reactive enyne
system should allow transformation to a variety of func-
tionalized products. The second route to (R)-muscone via
conjugate addition to dienone 15 as the key step gives
access to this important perfume ingredient in very high
enantiomeric purity.
5 mol% 13b/Cu(OTf)2
2 equiv Me2Zn
toluene, –30 °C
98% yield
98% ee
O
O
H2, Pd/C
EtOH
99%
Acknowledgment
(R)-16
(R)-1
Financial support by the Swiss National Science Foundation is
gratefully acknowledged.
Scheme 3
procedure by Nicolaou et al.15 gave the desired cyclopen-
tadeca-2,14-dienone (15) in 60% yield (Scheme 3).16 At
80 °C, ketone 14 was completely consumed. As a major
by-product the mono-unsaturated cyclopentadec-2-enone
(7) was formed, which could be separated by chromatog-
raphy on silica gel and reused. Yields were found to de-
pend on the reaction temperature, substrate concentration,
and solvent.
References and Notes
(1) (a) Walbaum, H. J. J. Prakt. Chem. 1906, 73, 488.
(b) Ruzicka, L. Helv. Chim. Acta 1926, 9, 715. (c) Ruzicka,
L. Helv. Chim. Acta 1926, 9, 1008.
(2) Pickenhagen, W. In Flavour Chemistry: Trends and
Developments; Teranishi, R.; Butery, R. G.; Shahidi, F.,
Eds.; ACS Symposium Series No. 388: Washington DC,
1989, 151.
(3) Fehr, C.; Galindo, J.; Etter, O. Eur. J. Org. Chem. 2004, 9,
1953.
Enantioselective copper-catalyzed conjugate addition to
dienone 15 was conducted with
5
mol% of
(4) (a) Fuchs, N.; d’Augustin, M.; Humam, M.; Alexakis, A.;
Taras, R.; Gladiali, S. Tetrahedron: Asymmetry 2005, 16,
3143. (b) Morita, M.; Mase, N.; Yoda, H.; Takabe, K.
Tetrahedron: Asymmetry 2005, 16, 3176. (c) Fehr, C.;
Galindo, J.; Farris, I.; Cuenca, A. Helv. Chim. Acta 2004, 87,
1737; and references cited therein.
(5) Lücking, U.; Pfaltz, A. Synlett 2000, 1261.
(6) Ogura, M.; Kanisawa, T.; Yamamoto, T. Tetrahedron 2002,
58, 9209.
(7) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Willard, P. G.; Zutter, U. J. Am.
Chem. Soc. 1986, 108, 1039.
(8) Sharpless, K. B.; Martin, V. S.; Katsuki, T.; Carlson, P. H. J.
J. Org. Chem. 1981, 46, 3936.
[Cu(13)](OTf)2 as catalyst and 2 equivalents of dimethyl-
zinc.17 As expected the reaction was much faster than with
enone 7 and went to completion even at –30 °C. No trace
of 3,14-dimethyl-cyclopentadecanone, resulting from a
second addition of dimethylzinc, was detected by gas
chromatography. Apparently, conjugate addition leads to
a stable zinc dienolate, which does not react further with
dimethylzinc. However, at ambient temperature addition
of the dienolate to the starting dienone was observed as a
side reaction, resulting in somewhat lower yields than at
–30 °C (Table 1, entry 1).
Table 1 Cu-Catalyzed 1,4-Addition of Dimethylzinc to Dienone 15a
Entry
Ligand
13a
Temp (°C)
25
Time (h)
Conversion (%)b Yield (%)c
ee of 16 (%)d
70 (R)
1
2
3
16
48
48
99
98
98
85
97
98
13a
–30
95 (R)
13b
–30
98 (R)
a Reactions were carried out under argon using 5 mol% of [Cu(13)](OTf)2 in toluene.
b Determined by GC using tridecane as internal standard.
c Yields of purified products.
d Determined by HPLC (Daicel AS).
Synlett 2006, No. 7, 1031–1034 © Thieme Stuttgart · New York

1034
B. Bulic et al.
LETTER
(9) Smith, A. B.; Levenberg, P. A.; Suits, J. Z. Synthesis 1986,
184.
27.3, 27.6, 27.8, 32.2, 130.2, 148.7, 193.4. MS (EI): m/z
(%) = 220 (7.5) [M+], 205 (1), 191 (2), 179 (11), 163 (7), 149
(13), 135 (14), 109 (19), 95 (55), 81 (67), 67 (54), 55 (81),
41 (100). Rf = 0.45 (hexane–EtOAc, 9:1).
(10) Zountsas, J.; Meier, H. Liebigs Ann. Chem. 1982, 7, 1366.
(11) (a) Alexakis, A.; Benhaim, C.; Fournioux, X.; Heuvel, A.;
Leveque, J. M.; March, S.; Rosset, S. Synlett 1999, 1811.
(b) Scafato, P.; Labano, S.; Cunsolo, G.; Rosini, C.
Tetrahedron: Asymmetry 2003, 14, 3873.
(12) Tanaka, K.; Ushio, H.; Kawabata, Y.; Suzuki, H. J. Chem.
Soc., Perkin Trans. 1 1991, 1445.
(13) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(14) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem.
Soc. 2002, 124, 13362.
(17) Synthesis of 14-Methyl-cyclopentadec-2-enone (16).
The copper complex of ligand 13b (17.6 mg, 0.02 mmol, 5
mol%) was placed under argon in an ampoule equipped with
a magnetic stirring bar and a Young® valve, and dissolved in
3 mL of degassed toluene. The ampoule was sealed under
argon and the mixture stirred for 30 min at –30 °C. To this
green solution 2 equiv of 1.0 M dimethylzinc solution in
heptane (0.8 mL, 0.8 mmol) were added dropwise under an
argon stream (color change to yellow), followed by cyclo-
pentadeca-2,14-dienone (88 mg, 0.4 mmol). After stirring at
–30 °C for 48 h, the reaction was quenched with 3 mL of sat.
aq NH4Cl solution. After addition of 5 mL of n-tridecane as
internal standard and extraction with 5 mL of Et2O, the
organic layer was filtered and analyzed by GC and GCMS.
The solvents were evaporated and the reaction mixture
purified by column chromatography on silica gel eluting
with hexane–EtOAc 9:1 to give 16 as a colorless oil (93.7
mg, 98% yield). 1H NMR (400 MHz, CDCl3): d = 0.89 (d,
J = 6.8, 3 H), 1.10–1.30 (m, 18 H), 2.00–2.15 (m, 1 H), 2.20–
2.35 (m, 2 H), 2.35 (d, 2 H, J = 10.0 Hz), 6.11 (dt, 1 H, 1.6,
15.6 Hz), 6.74 (m, 1 H). 13C NMR (100 MHz, CDCl3): d =
20.5, 24.5, 26.9, 27.0, 27.1, 27.2, 27.3, 27.5, 30.6, 31.7, 34.3,
49.2, 131.4, 148.2, 201.3. MS (EI): m/z (%) = 236 (22) [M+],
221 (6.5), 178 (6), 151 (4), 135 (8), 123 (14), 109 (29), 81
(57), 67 (41), 55 (100), 41 (98). Rf = 0.55 (hexane–EtOAc,
9:1). HPLC (250 mm × 4.6 mm, Daicel, Chiracel AS,
detection at 223 nm, hexane–i-PrOH 98.5:1.5, 0.5 mL/min,
293K): 21.1 min (R), 24.1 min (S).
(15) (a) Nicolaou, K. C.; Gray, D. L. F.; Montagnon, T.;
Harrison, S. T. Angew. Chem. Int. Ed. 2002, 41, 996.
(b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.
L. J. Am. Chem. Soc. 2002, 124, 2245.
(16) Synthesis of Cyclopentadeca-2,14-dienone (15).
Cyclopentadecanone (1.8 g, 8.0 mmol) was treated with IBX
(6.7 g, 24.0 mmol) in 30 mL of DMSO and 10 mL of fluoro-
benzene at 80 °C for 24 h (formation of a white precipitate
was observed). The reaction was quenched by slow addition
of 100 ml of 5% aq NaHCO3 solution at 0 °C, followed by
filtration over a Celite® pad (7 × 3 cm) eluting with CH2Cl2
(150 mL). The organic phase was collected and the aqueous
phase extracted with CH2Cl2 (2 × 150 mL) and Et2O (150
mL). The organic phases were combined and the solvents
removed under reduced pressure. The residue was purified
by silica gel column chromatography (hexane–EtOAc, 9:1)
affording 1.1 g (60%) of 15 as a colorless oil. 1H NMR (400
MHz, CDCl3): d = 1.18–1.35 (m, 12 H), 1.51 (m, 4 H), 2.23
(m, 4 H), 6.20 (dt, 2 H, J = 1.6, 15.6 Hz), 6.63 (dt, 2 H,
J = 8.0, 15.6 Hz). 13C NMR (100 MHz, CDCl3): d = 26.7,
Synlett 2006, No. 7, 1031–1034 © Thieme Stuttgart · New York