Stereoselective synthesis of musclides A1, A2 and B

Article abstract of DOI:10.1016/S0957-4166(03)00120-4

An expedient method for the stereoselective preparation of musclide A1, A2 and B, cardiotonic-potentiating principles from musk, has been achieved. The key step is the addition of the O-benzyl ethers of prop-2-yn-1-ol and (R)-but-3-yn-2-ol to aldehydes me

Full text of DOI:10.1016/S0957-4166(03)00120-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1127–1131
Stereoselective synthesis of musclides A1, A2 and B
Jordi Ortiz, Xavier Ariza* and Jordi Garcia*
Departament de Qu´ımica Orga`nica, Universitat de Barcelona, Mart´ı i Franque`s 1, 08028 Barcelona, Catalonia, Spain
Received 16 December 2002; accepted 28 January 2003
Abstract—An expedient method for the stereoselective preparation of musclide A1, A2 and B, cardiotonic-potentiating principles
from musk, has been achieved. The key step is the addition of the O-benzyl ethers of prop-2-yn-1-ol and (R)-but-3-yn-2-ol to
aldehydes mediated by zinc triflate, Et3N, and (+)- or (−)-N-methylephedrine. In some cases, the partial reduction of the resulting
alkynols to Z-olefins has allowed us to remove the minor stereoisomer easily by chromatography to afford highly stereoenriched
precursors of musclides. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
study, the structure of musclide B was assigned as
(1S,4R)-4-hydroxy-1-(2-methylpropyl)pentyl hydrogen
sulphate 2 by comparison of the natural product with
the 1R,4S and 1R,4R stereoisomers obtained from ethyl
(S)-leucinate. Shortly after, the same research group
also confirmed that musclide A1 is a 7:3 mixture of
(1R,4R)- and (1S,4R)-4-hydroxy-1-isopropylpentyl
hydrogen sulphate [(1R,4R)-3 and (1S,4R)-3].5 Despite
the doubtless interest of such compounds and the
difficulty of their isolation from natural sources, syn-
thetic studies aimed at preparing musclides and their
precursors are limited to the aforementioned works.3–5
Musk, a dried secretion from the preputial follicles of
the male musk deer (Moschus moschiferus L.), has been
used not only as a precious perfume component but
also as a traditional Chinese medicine since ancient
times. Modern research has demonstrated that musk
displays extensive pharmacological actions, including
cardiotonic,
sedative
and
anti-inflammatory
properties.1,2
Kikuchi et al. have reported that the cardiotonic activ-
ity is due to the presence of three aliphatic 1,4-diol
monosulfates, musclide A1, A2 and B.3 Very recently,
Tezuka et al. have established that the natural musclide
A2 is the hydrogen sulphate 1 (Fig. 1).4 In the same
In 2000, Carreira et al. reported the enantioselective
addition of Zn–alkynylides to aldehydes using
Zn(OTf)2, (+)- or (−)-N-methylephedrine and Et3N to
afford highly enantioenriched propargylic alcohols.6
Based on these studies, we have very recently extended
this methodology to the stereoselective preparation of
chiral monoprotected syn- or anti-2-alkyne-1,4-diols.7
As a part of a project addressed to the application of
this approach to the synthesis of natural products,8 we
wish to report herein the first stereoselective synthesis
of musclides.
2. Results and discussion
In the light of our previous work, we envisaged that the
required 1,4-diol motif present in musclides could be
attainable through the stereoselective addition of 3-ben-
zyloxyprop-1-yne 4 or (R)-3-benzyloxybut-1-yne 5 to
the appropriate aldehyde.
Figure 1.
* Corresponding author. Tel.: +34 93 4021247; fax: +34 93 3397878;
e-mail: jgarcia@qo.ub.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00120-4

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J. Ortiz et al. / Tetrahedron: Asymmetry 14 (2003) 1127–1131
Our first efforts were directed to the preparation of
monoprotected propargylic diol 6 (Scheme 1). The
addition of alkyne 4 to 3-methylbutanal in the presence
of Zn(OTf)2, (+)-N-methylephedrine and Et3N (65°C, 1
h) afforded 6 in 85% yield (91:9 R/S ratio).9 Remark-
ably, when the reaction was performed at rt only a
slight improvement in the enantioselectivity was noted
but at the expense of longer reaction times and/or lower
yields (e.g. 41% yield, 92:8 R/S ratio, 4 h). Subsequent
hydrogenation of 6 cleanly afforded the known alcohol
7, which, in turn, can be readily transformed into
musclide A2.4
rated diol 10. The efficient transformation of 10 into
musclide B has been described previously.4
We then turned our attention to the synthesis of
musclide A1. Our previous experience7 suggested that
either (3R,6R)-11 or (3S,6R)-11, precursors of both
constituents of musclide A1 [i.e. (1R,4R)-3 and
(1S,4R)-3] could be selectively obtained simply by
switching from (+)- to (−)-N-methylephedrine in the
alkynylation step (see Scheme 3). To our delight, the
addition of the alkynylzinc reagent derived from 5 and
(+)-N-methylephedrine to isobutyraldehyde readily
afforded the desired monoprotected diol (3R,6R)-11
with excellent stereochemical control (75%, 97:3 (R,R)/
(R,S) ratio, matched case). As expected, when (−)-N-
methylephedrine was used in a similar protocol, the
3S,6R isomer was obtained as the major product with
good stereoselectivity (70%, 13:87 (R,R)/(S,R) ratio,
mismatched case).10 As in the case of musclide B,
transformation of 11 in (Z)-12 allowed us to remove
the minor stereoisomer, improving in this way the
stereochemical purity. Finally, hydrogenation of
(3R,6R)-12 and (3S,6R)-12 afforded pure (3S,6R)-13
and (3R,6R)-13, respectively. Since an efficient transfor-
mation of 13 into 3 has been described,5 this approach
constitutes a formal stereoselective synthesis of both
components of musclide A1.
Scheme 1. Reagents and conditions: (a) Zn(OTf)2 (1.1 equiv.),
(+)-N-methylephedrine (1.2 equiv.), Et3N (1.2 equiv.), 3-
methylbutanal (1.1 equiv.), toluene, 65°C; (b) H2 (1 atm),
Pt/C cat., EtOAc, rt; (c) Ref. 4.
In a similar way, we examined the asymmetric alkynyl-
ation of 3-methylbutanal with the alkyne 5, easily
obtained from commercially available, inexpensive (R)-
but-3-yn-2-ol. The slow addition of the aldehyde to the
Zn–alkynylide derived from 5 in the presence of (+)-N-
methylephedrine afforded the monoprotected diol 8 as
a
90:10 (R,R)/(R,S) inseparable mixture of
diastereomers (see Scheme 2).10 Although the direct
hydrogenation of 8 to 10 is obviously feasible, the
partial reduction to 9 allowed us to remove the minor
R,S stereoisomer by flash chromatography, increasing
in this way the purity of the monoprotected diol.11
Finally, hydrogenation of pure 9 gave the known satu-
Scheme 2. Reagents and conditions: (a) Zn(OTf)2 (1.1 equiv.),
(+)-N-methylephedrine (1.2 equiv.), Et3N (1.2 equiv.), 3-
methylbutanal (1.1 equiv.), toluene, 65°C; (b) H2 (1 atm.),
Lindlar cat., EtOAc, rt; (c) H2 (1 atm), Pt cat., EtOAc, rt; (d)
Ref. 4.
Scheme 3. Reagents and conditions: (a) Zn(OTf)2 (1.1 equiv.),
(+)- or (−)-N-methylephedrine (1.2 equiv.), Et3N (1.2 equiv.),
isobutyraldehyde (1.1 equiv.), toluene, 65°C; (b) H2 (1 atm),
Lindlar cat., EtOAc, rt; (c) H2 (1 atm), Pt cat., EtOAc, rt; (d)
Ref. 5.

J. Ortiz et al. / Tetrahedron: Asymmetry 14 (2003) 1127–1131
1129
3. Conclusion
3033, 3294. Anal. calcd for C11H12O: C, 82.46; H, 7.55.
Found: C, 82.64; H, 7.37.
In conclusion, we have disclosed herein a straightfor-
ward, stereoselective preparation of musclide A1, A2
and B from commercially available, low-cost starting
materials. This formal synthesis of musclides explores
and exemplifies the usefulness of the very recently
described alkynylation of aldehydes in the synthesis of
natural products.
4.3. General procedure for the addition of alkynes to
aldehydes. Preparation of (R)-1-benzyloxy-6-methyl-
hept-2-yn-4-ol, 6
A slurry mixture of dry Zn(OTf)2 (408 mg, 1.1 mmol),
(+)-N-methylephedrine (220 mg, 1.2 mmol), alkyne 5
(147 mg, 1 mmol), dry toluene (300 mL), and Et3N (167
mL, 1.2 mmol) were vigorously stirred under Ar at rt.
After 30 min, 3-methylbutanal (118 mL, 1.1 mmol) was
added dropwise (ca. 5–10 min) by syringe to the mix-
ture at 65°C. The reaction was monitored by TLC and,
after completion (1 h), the mixture was poured directly
into a silica gel column and purified by flash chro-
matography (9:1, hexane:EtOAc) to afford 197 mg
(0.85 mmol, 85%) of 6: colourless oil; Rf 0.23 (CH2Cl2);
[h]2D0=+10.7 (c 1.16, CHCl3); 1H NMR: l 0.92 (d,
J=6.6 Hz, 3H), 0.94 (d, J=6.9 Hz, 3H), 1.60 (m, 2H),
1.85 (m, 1H), 2.15 (br s, 1H, OH), 4.20 (d, J=1.4 Hz,
2H), 4.45 (td, J=7.2, 1.4 Hz, 1H), 4.59 (s, 2H), 7.25–
7.37 (m, 5H); 13C NMR: l 22.4, 22.5, 24.7, 46.7, 57.3,
60.9, 71.5, 80.5, 88.0, 127.8, 128.0, 128.4, 137.3; IR
(neat): 698, 1028, 1071, 1111, 2871, 2958, 3033, 3405;
HRMS calcd for C15H21O2 (M++1) 233.1542, found
233.1549. Anal. calcd for C15H20O2: C, 77.55; H, 8.68.
Found: C, 77.49; H, 8.88. The HPLC analysis (Chiral-
cel OD-H column, 9:1 hexane/PriOH, 0.9 mL/min,
tR(S)=13.2 min, tR(R)=16.9 min) revealed a 91:9 S/R
ratio.
4. Experimental
4.1. General methods
All the solvents were distilled from an appropriate
drying agent and stored under nitrogen atmosphere.
The crude products were purified by column chro-
matography on silica gel of 230–400 mesh (flash chro-
matography).
Thin-layer
chromatograms
were
performed on HF254 silica gel plates (using CH2Cl2,
CH2Cl2/MeOH, hexane/EtOAc or CH2Cl2/hexane as
the eluents, as indicated after the Rf values). NMR
spectra were recorded in CDCl3 at 300 or 400 MHz for
1H, 50.3 MHz for 13C, and 282.2 MHz for 19F. Chemi-
cal shifts are given in ppm with respect to internal
TMS. Infrared spectra were measured on a Perkin–
Elmer 681 on NaCl plates (neat); only the most signifi-
cant absorptions, in cm−1, are indicated. Microanalyses
were performed by the Serveis Cient´ıfico-Te`cnics (Uni-
versitat de Barcelona). Optical rotations were measured
at 20 2°C. HRMS (FAB+) were obtained at the
CACTI (Universidad de Vigo). Zn(OTf)2 was dried
overnight at 120°C under vacuum prior use. Acetylenic
4.3.1. (4R,7R)-7-Benzyloxy-2-methyloct-5-yn-4-ol, 8.
Alkynylation was performed according to the general
procedure described in Section 4.3, to afford 73% yield
of 8: colourless oil; Rf 0.14 (9:1, hexane:EtOAc); [h]2D0=
ether
4 was prepared according to a published
procedure.12
1
+100.4 (c 0.57, CHCl3); H NMR: l 0.94 (d, J=6.6 Hz,
4.2. (R)-3-Benzyloxybut-1-yne, 5
3H), 0.96 (d, J=6.6 Hz, 3H), 1.46 (d, J=6.6 Hz, 3H),
1.61 (m, 2H), 1.86 (m, 1H), 4.25 (qd, J=6.6, 1.6 Hz,
2H), 4.47 (td, J=7.2, 1.6 Hz, 1H), 4.50 (A of an AB
system, J=11.7 Hz, 1H), 4.76 (B of an AB system,
J=11.7 Hz, 1H), 7.26–7.38 (m, 5H); 13C NMR: l 22.2,
22.5, 22.6, 24.8, 46.9, 61.1, 64.5, 70.6, 84.6, 86.5, 127.7,
128.0, 128.4, 138.0; IR (neat): 699, 1028, 1053, 1086,
1106, 1162, 1328, 1455, 2871, 2935, 2958, 3066. Anal.
calcd for C16H22O2: C, 78.01; H, 9.00. Found: C, 77.83;
H, 9.12. An analytical sample was transformed into the
corresponding Mosher ester derived from Mosher’s
(R)-acid. 19F NMR analysis of the sample revealed as
composition (2R,5R)/(2R,5S)=9:1.
A solution of 890 mg (12.70 mmol) of (R)-but-3-yn-2-ol
in 2 mL of dry THF was carefully added via cannula to
a suspension of NaH (671 mg of 60% dispersion in
mineral oil, 16.78 mmol), previously washed with dry
hexane, containing
a catalytic amount of tetra-
butylammonium iodide, in 30 mL of dry THF. The
mixture was stirred for 45 min and then 3.39 mL (28.50
mmol) of neat benzyl bromide were added dropwise
and the resulting suspension was stirred at rt overnight.
Fifteen hours later, TLC showed that the starting alco-
hol had almost disappeared and the reaction mixture
was poured into CH2Cl2 and pH 7 phosphate buffer.
The organic layer was separated and washed with brine.
After drying (Na2SO4), the solvent was eliminated in
vacuo and the crude product was purified by flash
chromatography (99:1, hexane:EtOAc) to yield 1.694 g
(83%) of (R)-3-benzyloxybut-1-yne, 5: colourless oil; Rf
0.08 (1:1, hexane:CH2Cl2); [h]2D0=+110.5 (c 0.96,
4.3.2.
(3R,6R)-6-Benzyloxy-2-methylhept-4-yn-3-ol,
(3R,6R)-11. Alkynylation was performed according to
the general procedure described in Section 4.3, to
afford 75% yield of (3R,6R)-11: colourless oil; Rf 0.25
1
(85:15, hexane:EtOAc); [h]2D0=+94.2 (c 1.6, CHCl3); H
NMR: l 1.01 (d, J=6.3 Hz, 3H), 1.03 (d, J=6.3 Hz,
3H), 1.47 (d, J=6.6 Hz, 3H), 1.88 (m, 1H), 4.22–4.30
(m, 2H), 4.50 (A of an AB system, J=11.7 Hz, 1H),
4.77 (B of an AB system, J=11.7 Hz, 1H), 7.22–7.31
(m, 5H); 13C NMR: l 17.5, 18.1, 22.2, 34.6, 64.5, 67.9,
70.5, 84.9, 85.4, 127.7, 128.0, 128.4, 137.9; IR (neat):
698, 737, 1028, 1105, 1160, 1328, 1372, 1455, 2873,
1
CHCl3); H NMR: l 1.48 (d, J=6.6 Hz, 1H), 2.45 (d,
J=2.1 Hz, 1H), 4.20 (qd, J=6.6, 2.1 Hz, 1H), 4.50 (A
of an AB system, J=11.8 Hz, 1H), 4.79 (B of an AB
system, J=11.8 Hz, 1H), 7.30–7.38 (m, 5H); 13C NMR:
l 22.0, 64.2, 70.5, 73.1, 83.7, 127.7, 128.0, 128.4, 137.7;
IR (neat): 698, 739, 1065, 1098, 1455, 1719, 2939, 2989,

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J. Ortiz et al. / Tetrahedron: Asymmetry 14 (2003) 1127–1131
1
2933, 2964, 3421; HRMS calcd for C15H21O2 (M++1)
233.1542, found 233.1531. Anal. calcd for C15H20O2: C,
77.55; H, 8.68. Found: C, 77.60; H, 8.76. An analytical
sample was transformed into the corresponding Mosher
ester derived from Mosher’s (R)-acid. 19F NMR analy-
sis of the sample revealed as composition (3R,6R)/
(3S,6R)=97:3.
+6.2 (c 0.40, CHCl3); H NMR: l 0.89 (d, J=6.3 Hz,
3H), 0.91 (d, J=6.0 Hz, 3H), 1.32 (d, J=6.6 Hz, 3H),
1.42–1.58 (m, 2H), 1.64–1.80 (m, 1H), 4.30–4.47 (m,
2H), 4.37 (part A of an AB system, J=11.7 Hz), 4.53
(part B of an AB system, J=11.7 Hz), 5.46–5.58 (m,
2H), 7.23–7.34 (m, 5H); 13C NMR: 21.8, 22.2, 23.3,
24.4, 46.9, 66.1, 70.1, 70.7, 127.6, 128.4, 134.1, 134.8,
138.5; IR (neat): 697, 733, 1028, 1057, 1098, 1368, 1457,
2869, 2956, 3406. Anal. calcd for C16H24O2: C, 77.38;
H, 9.74. Found: C, 77.17; H, 9.65%.
4.3.3.
(3S,6R)-6-Benzyloxy-2-methylhept-4-yn-3-ol,
(3S,6R)-11. Alkynylation was performed according to
the general procedure described in Section 4.3, to
afford 70% yield of (3S,6R)-11: colourless oil; Rf 0.25
(85:15, hexane:EtOAc); [h]2D0=+118.5 (c 1.32, CHCl3);
1H NMR: l 1.01 (d, J=6.3 Hz, 3H), 1.03 (d, J=6.3
Hz, 3H), 1.47 (d, J=6.6 Hz, 3H), 1.88 (m, 1H), 4.22–
4.31 (m, 2H), 4.50 (A of an AB system, J=11.7 Hz,
1H), 4.77 (B of an AB system, J=11.7 Hz, 1H), 7.22–
7.30 (m, 5H). 13C NMR: l 17.5, 18.2, 22.3, 34.5, 64.5,
67.9, 70.6, 84.9, 85.4, 127.6, 127.9, 128.3, 137.9; IR
(neat): 699, 737, 1028, 1106, 1160, 1328, 1372, 1455,
2873, 2933, 2964, 3421; HRMS calcd for C15H21O2
(M++1) 233.1542, found 233.1553. Anal. calcd for
C15H20O2: C, 77.55; H, 8.68. Found: C, 77.61; H, 8.45.
An analytical sample was transformed into the corre-
sponding Mosher ester derived from Mosher’s (R)-acid.
19F NMR analysis of the sample revealed as composi-
tion (3R,6R)/(3S,6R)=13:87.
(4S,5Z,7R)-7-Benzyloxy-2-methyloct-5-en-4-ol: colour-
less oil; Rf 0.26 (85:15, hexane/EtOAc); [h]2D0=−14.6 (c
1.21, CHCl3); 1H NMR: l 0.88 (d, J=6.6 Hz, 6H), 1.27
(d, J=6.3 Hz, 3H), 1.22 (m, 1H), 1.44–1.72 (m, 2H),
4.27–4.42 (m, 2H), 4.44 (part A of an AB system,
J=11.7 Hz), 4.58 (part B of an AB system, J=11.7
Hz), 5.40–5.58 (m, 2H), 7.23–7.34 (m, 5H); 13C NMR:
21.5, 22.4, 23.0, 24.4, 46.6, 65.9, 70.0, 127.6, 127.7,
128.4, 133.1, 135.3, 138.5; IR (neat): 698, 737, 1028,
1057, 1098, 1368, 1455, 2871, 2930, 2957, 3422.
4.5.1. (3R,4Z,6R)-6-Benzyloxy-2-methylhept-4-en-3-ol,
(3R,6R)-12. Reduction was performed according to the
general procedure described in Section 4.5, to afford
78% yield of (3R,6R)-12: colourless oil; Rf 0.25 (85:15,
hexane/EtOAc); [h]2D0=−21.8 (c 0.76, CHCl3); 1H
NMR: l 0.91 (d, J=6.9 Hz, 3H), 0.97 (d, J=6.9 Hz,
3H), 1.31 (d, J=6.3 Hz, 3H), 1.69 (m, 1H), 4.02–4.07
(m, 1H), 4.35–4.42 (m, 2H, CHOBn plus the part A of
an AB system, OCH2Ph), 4.54 (part B of an AB system,
J=11.7 Hz, OCH2Ph), 7.26–7.34 (m, 5H, ArH); 13C
NMR: l 17.9, 18.3, 21.8, 34.2, 70.2, 70.9, 72.8, 127.5,
127.6, 128.4, 132.6, 135.7, 138.5; IR (neat): 698, 1028,
1072, 1369, 1455, 1498, 2873, 2929, 2961, 3432. HRMS
calcd for C15H23O2 (M++1) 235.1698, found 235.1710.
Anal. calcd for C15H22O2: C, 76.88; H, 9.46. Found: C,
76.72; H, 9.45%.
4.4. (S)-1-Benzyloxy-6-methylheptan-4-ol, 74
To a solution of 100 mg (0.43 mmol) of 6 (91:9 S/R
ratio) in 5 mL of EtOAc, 30 mg of 5% Pt/C were added
and the suspension was shaken under 1 atm of hydro-
gen for 4 h. Afterwards, the mixture was filtered
through a pad of Celite®, the solvent was eliminated in
vacuo and the residue was purified by flash chromatog-
raphy through a short pad of silica gel (98:2, CH2Cl2/
MeOH) to yield 85 mg (83%) of 7: colourless oil; Rf
0.15 (CH2Cl2); [h]D20=+3.7 (c 3.98, CHCl3) [lit.4 [h]2D0
1
+4.6 (c 0.92, CHCl3) for the R isomer]; H NMR: l
4.5.2. (3S,4Z,6R)-6-Benzyloxy-2-methylhept-4-en-3-ol,
(3S,6R)-12. Reduction was performed according to the
general procedure described in Section 4.5, to afford
80% yield of (3S,6R)-12: colourless oil; Rf 0.35 (85:15,
0.92 (d, J=6.6 Hz, 3H), 0.94 (d, J=6.6 Hz, 3H),
1.21–1.84 (m, 7H), 3.52 (t, J=6.0 Hz, 2H), 3.69 (m,
1H), 4.53 (s, 2H), 7.27–7.39 (m, 5H, ArH); 13C NMR:
l 22.1, 23.4, 24.6, 26.2, 35.2, 46.8, 69.5, 70.5, 73.0,
127.6, 127.7, 128.4, 138.2; IR (neat): 698, 735, 1028,
1099, 1366, 1455, 2869, 2927, 2954, 3423.
1
hexane/EtOAc); [h]D20=+7.4 (c 0.96, CHCl3); H NMR:
l 0.83 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.26
(d, J=6.6 Hz, 3H), 1.64 (m, 1H), 1.76 (bs, 1H, OH),
3.99 (dd, J=7.0, 7.0 Hz, 1H), 4.26–4.35 (m, 1H), 4.42
(part A of an AB system, J=12.2 Hz), 4.57 (part B of
an AB system, J=12.2 Hz), 7.25–7.35 (m, 5H, ArH);
13C NMR: l 18.0, 18.1, 21.3, 34.0, 69.9, 70.0, 72.6,
127.6, 127.7, 128.3, 133.2, 134.1, 138.6; IR (neat): 698,
1028, 1073, 1094, 1370, 1457, 1498, 2873, 2930, 2962,
3448. HRMS calcd for C15H23O2 (M++1) 235.1698,
found 235.1705. Anal. calcd for C15H22O2: C, 76.88; H,
9.46. Found: C, 76.63; H, 9.53%.
4.5. General procedure for the partial hydrogenation of
alkynols. Preparation of (4R,5Z,7R)-7-Benzyloxy-2-
methyloct-5-en-4-ol, 9
To a solution of 8 (112 mg, 0.45 mmol) in EtOAc (3
mL), 5% Pd on calcium carbonate poisoned with lead
(Lindlar catalyst, 30 mg) and quinoline (9 mL) were
added and the suspension was shaken under 1 atm of
hydrogen. The reaction was monitored by TLC. After 1
h, the mixture was filtered through a pad of Celite®
using more EtOAc and CH2Cl2. The organic layer was
washed with aq. HCl (5 mL, 0.1 M) and then dried over
MgSO4 and filtered. The solvent was eliminated in
vacuo and the residue was purified by flash chromatog-
raphy (96:4, hexane/EtOAc) to yield 102 mg (90%) of 9:
colourless oil; Rf 0.16 (85:15, hexane/EtOAc); [h]2D0=
4.6. General procedure for the hydrogenation of Z
alkenols to alkanols. Preparation of (4S,7R)-2-benzyl-
oxy-7-methyloctan-5-ol, 104
To a solution of 9 (100 mg, 0.40 mmol) in EtOAc (4
mL), 5% Pt/C (30 mg) were added and the suspension
was shaken under 1 atm of hydrogen for 1 h. The

J. Ortiz et al. / Tetrahedron: Asymmetry 14 (2003) 1127–1131
1131
mixture was filtered through a pad of Celite® and the
References
solvent was eliminated in vacuo. Column chromatogra-
phy (hexane:EtOAc, 92:8) of the residue gave 81 mg
(82%) of (4S,7R)-2-benzyloxy-7-methyloctan-5-ol, 10:
colourless oil; Rf 0.16 (85:15, hexane/EtOAc); [h]2D0=
−15.1 (c 0.68, CHCl3) [lit.4 [h]D=+9.9 (c 0.95, CHCl3)
1. (a) Kimura, M. Trends Pharmacol. Sci. 1980, 1, 341–343;
(b) Tokunaga, S.; Kimura, M.; Kimura, I. J. Med.
Pharm. Soc. Wakan-Yaku 1987, 4, 276–277; (c) Kimura,
M.; Kimura, I.; Uwano, T.; Isoi, Y.; Kadota, S.; Kikuchi,
T. Phytoter. Res. 1991, 5, 159–162; (d) Kimura, I.; Taka-
mura, Y.; Uwano, T.; Hata, Y.; Kimura, M.; Kikuchi, T.
Phytoter. Res. 1995, 9, 16–20.
2. Musk is a important component of Rokushingan, a com-
mercial cardiotonic sold in Japan.
3. Kadota, S.; Orito, T.; Kikuchi, T.; Uwano, T.; Kimura,
I.; Kimura, M. Tetrahedron Lett. 1991, 32, 1733–1736.
4. Tezuka, Y.; Kudoh, M.; Hatanaka, Y.; Kadota, S.;
Kikuchi, T. Nat. Prod. Lett. 1997, 9, 297–304.
5. Tezuka, Y.; Kudoh, M.; Hatanaka, Y.; Kadota, S.;
Kikuchi, T. Wakan Iyakugaku Zasshi 1998, 15, 168–175.
6. (a) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira,
E. M. Acc. Chem. Res. 2000, 33, 373–381; (b) Frantz, D.
E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 1806–1807; (c) Anand, N. K.; Carreira, E. M. J. Am.
Chem. Soc. 2001, 123, 9687–9688; (d) El-Sayed, E.;
Anand, N. K.; Carreira, E. M. Org. Lett. 2001, 3, 3017–
3020; (e) Boyall, D.; Frantz, D. E.; Carreira, E. M. Org.
Lett. 2002, 4, 2605–2606.
7. Amador, M.; Ariza, X.; Garcia, J.; Ortiz, J. Tetrahedron
Lett. 2002, 43, 2691–2694. See also: Sans, R.; Adger, B.;
Carreira, E. M. Tetrahedron 2002, 58, 8341–8344.
8. Reported applications of Carreira’s alkynylation to total
syntheses are still scarce. See for instance: (a) Bode, J.
W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611–
3612; (b) Bode, J. W.; Carreira, E. M. J. Org. Chem.,
2001, 66, 6410–6424; (c) Maezaki, N.; Kojima, N.; Asai,
M.; Tominaga, H.; Tanaka, T. Org. Lett. 2002, 4, 2977–
2980.
1
for (4R,7S) isomer]; H NMR: l 0.90 (d, J=6.9 Hz,
3H), 0.91 (d, J=6.9 Hz, 3H), 1.21 (d, J=6.0 Hz, 3H),
1.34–1.81 (m, 7H), 3.52–3.70 (m, 2H), 4.45 (part A of
an AB system, J=11.9 Hz), 4.59 (part B of an AB
system, J=11.9 Hz), 7.23–7.35 (m, 5H, ArH); 13C
NMR: l 19.5, 22.1, 23.5, 24.7, 32.8, 33.8, 46.8, 69.9,
70.3, 74.8, 127.5, 127.7, 128.3, 138.8; IR (neat): 697, 735
1028, 1065, 1090, 1374, 1455, 2869, 2929, 2956, 3423.
HRMS calcd for C16H27O2 (M++1) 251.2011, found
251.2002.
4.6.1.
(3S,6R)-2-Benzyloxy-6-methylheptan-5-ol,
(3S,6R)-135. Reduction was performed according to the
procedure described in Section 4.6, to afford 66% yield
of (3S,6R)-13: colourless oil; Rf 0.60 (65:35, hexane/
EtOAc); [h]2D0=−28.5 (c 0.89, CHCl3) [lit.5 [h]D=−35.5
1
(c 0.93, CHCl3]; H NMR: l 0.90 (d, J=6.9 Hz, 6H),
1.21 (d, J=6.0 Hz, 3H), 1.42–1.73 (m, 5H), 3.30–3.35
(m, 1H), 3.51–3.61 (m, 1H), 4.45 (part A of an AB
system, J=11.7 Hz), 4.59 (part B of an AB system,
J=11.7 Hz), 7.26–7.34 (m, 5H); 13C NMR: l 17.3, 18.8,
19.5, 29.9, 33.1, 33.6, 70.3, 74.7, 76.6, 127.5, 127.7,
128.3, 138.8; IR (neat): 697, 735, 1028, 1063, 1090,
1370, 1454, 2873, 2930, 2974, 3448. HRMS calcd for
C15H25O2 (M++1) 237.1855, found 237.1855.
4.6.2.
(3R,6R)-2-Benzyloxy-6-methylheptan-5-ol,
(3R,6R)-135. The reduction was performed according to
the procedure described in Section 4.6, to afford 71%
yield of (3R,6R)-13: colourless oil; Rf 0.60 (65:35, hex-
ane/EtOAc); [h]D20=−8.3 (c 0.89, CHCl3) [lit.5 [h]D=
9. R/S ratio of 6 was directly determined by HPLC analysis
on a chiral column. The absolute configuration of the
major enantiomer was assumed to be R on the basis of
the work of Carreira et al. (Ref. 6) and confirmed later by
chemical correlation with the known monoprotected diol
7.
1
–8.3 (c 0.75, CHCl3]; H NMR: l 0.91 (d, J=6.9 Hz,
6H), 1.22 (d, J=6.3 Hz, 3H), 1.39–1.45 (m, 1H), 1.57–
1.70 (m, 4H), 1.88 (bs, 1H), 3.30–3.36 (m, 1H), 3.52–
3.62 (m, 1H), 4.46 (part A of an AB system, J=11.9
Hz), 4.59 (part B of an AB system, J=11.9 Hz),
7.26–7.34 (m, 5H); 13C NMR: l 17.4, 18.8, 19.5, 30.0,
33.1, 33.6, 70.4, 75.1, 76.7, 127.5, 127.7, 128.3, 138.8;
IR (neat): 697, 735, 1028, 1063, 1090, 1373, 1454, 2873,
2931, 2963, 3448. HRMS calcd for C15H25O2 (M++1)
237.1855, found 237.1850.
10. Stereoselectivities were determined by 19F analysis of the
corresponding Mosher esters. The configuration of the
newly formed stereogenic centers was first determined by
the Kakisawa method (Ohtani, I.; Kusumi, T.; Kashman,
Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092–
4096) and it always agreed with that expected (Ref. 6). In
addition, it should be noted that the absolute configura-
tions were further confirmed by correlation with those of
the known, saturated monoprotected diols 7, 10 and 13.
11. We found that the chromatographic separation of (R,R)-
and (R,S)-9 was more convenient than that of their
corresponding E isomers, also accessible by LiAlH4
reduction of 8 (see Ref. 7).
Acknowledgements
This work has been supported by the Ministerio de
Educacio´n y Cultura (PB98-1272, DGESIC) and Direc-
cio´ General de Recerca, Generalitat de Catalunya
(2000SGR021). We also thank to Universitat de
Barcelona for a doctorate studentship to J.O., and
Professor J. Vilarrasa for reading the draft.
12. Manzocchi, A.; Fiecchi, A.; Santaniello, E. Synthesis
1987, 1007–1009.