Stereoselective approach to alk-2-yne-1,4-diols. Application to the synthesis of musclide B

Article abstract of DOI:10.1016/S0040-4039(02)00395-7

An expedient method for the stereoselective preparation of alk-2-yne-1,4-diols has been achieved, based on the addition of chiral alk-1-yn-3-ols (or their protected derivatives) to aldehydes mediated by zinc triflate, Et₃N, and (+)- or (-)-N-me

Full text of DOI:10.1016/S0040-4039(02)00395-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2691–2694
Stereoselective approach to alk-2-yne-1,4-diols. Application to
the synthesis of musclide B
Marta Amador, Xavier Ariza,* Jordi Garcia* and Jordi Ortiz
Departament de Qu´ımica Orga`nica, Universitat de Barcelona, Mart´ı i Franque`s 1, 08028 Barcelona, Catalonia, Spain
Received 25 January 2002; accepted 25 February 2002
Abstract—An expedient method for the stereoselective preparation of alk-2-yne-1,4-diols has been achieved, based on the addition
of chiral alk-1-yn-3-ols (or their protected derivatives) to aldehydes mediated by zinc triflate, Et3N, and (+)- or (–)-N-
methylephedrine. In general, the configuration observed at the emergent stereocenter depends on the N-methylephedrine employed
resulting in good to excellent diastereoselectivities. This strategy has been applied to the enantioselective synthesis of musclide B,
a bioactive metabolite from musk. © 2002 Elsevier Science Ltd. All rights reserved.
Achieving stereocontrol in the construction of acyclic
systems is of considerable interest in organic synthesis.
In particular, the efficient construction of chiral alk-2-
yne-1,4-diols (1) and/or (E)-alk-2-ene-1,4-diols (2) is a
challenging goal not only because these substructures
are often present in natural products,1 but also due to
the fact that such compounds are amenable to conver-
sion into saturated diols and other useful chiral
synthons.2
suffers from some limitations: (i) unsymmetrical start-
ing diketones 3 or 4 (R"R%) are not as easy to obtain
as the symmetrical ones;6 (ii) the reduction of diketones
with a chiral reagent obviously tends to give rise to two
stereocenters with the same configuration, leading to
the syn products rather than the anti isomers (meso
compounds when R=R%). In addition, if any derivative
with one protected hydroxyl group is required, an
additional, sometimes troublesome regioselective
monoprotection step has to be achieved.
In this connection, we have recently described a route
(Scheme 1) to chiral C2-symmetrical unsaturated 1,4-
diols through the oxazaborolidine-mediated reduction
of the parent acetylenic3 (3) or ethylenic diketones (4).4
Moreover, we have applied these diols to the syntheses
of (–)-methylenolactocin and (–)-phaseolinic acid.5
Nonetheless, this approach to compounds 1 and 2
Very recently, Carreira et al. reported the enantioselec-
tive addition of Zn-alkynylides to aldehydes using com-
mercially available zinc trifluoromethanesulphonate
(zinc triflate), (+)- or (–)-N-methylephedrine and Et3N
to afford highly enantioenriched propargylic alcohols.7
Based on these studies, we envisioned that addition of a
chiral O-protected propargylic alcohol, 5, to an alde-
hyde could provide a ready access to the syn- or anti-
propargylic diols 1 in a predictable way by using Car-
reira’s methodology. This would be the case if, as
expected, the stereochemical course of the addition was
ruled by the chiral auxiliary rather than by substrate
control (see Scheme 2).8 Since chiral compounds 5 are,
in turn, available in both configurations by different
ways, including the enantioselective reduction of the
parent ketone9 or the aforementioned addition of Zn-
alkynylides to aldehydes, this strategy could constitute
a flexible, modular approach to any stereoisomer of 1
(or their monoprotected derivatives 6). We wish to
report here our findings in this connection.
Scheme 1.
In order to assess the viability of this strategy, we
launched the study of the addition of some representa-
* Corresponding authors. Tel.: 34 93 4021247; fax: 34 93 3397878;
e-mail: jgarcia@qo.ub.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00395-7

2692
M. Amador et al. / Tetrahedron Letters 43 (2002) 2691–2694
Scheme 2.
tive protected, highly enantioenriched alk-1-yn-3-ols
(5)10 with a few aldehydes in the presence of zinc
triflate, (+)- or (–)-N-methylephedrine and Et3N.11 With
regard to the results summarised in Table 1 some
remarks should be noted:
ethers (5–12 h at 65°C).14 This fact can be attributed
to the higher acidity of propargylic esters 5b and 5d–f
in comparison with propargylic ethers 5a and 5c,
which probably favours the formation of the Zn-
alkynylide intermediate in the reaction media.
(i) Reactions worked well in the absence of solvent
or, even better, with a very small amount of dry
toluene. Although not pointed out in Table 1 for the
sake of simplicity, lower yields or longer reaction
times were observed in a number of preliminary
experiments using 0.3–0.5 M toluene solutions of
terminal alkynes 5 (for instance, 6a was obtained in
24% yield besides a 55% of recovered starting 5a,
after 1 day at 65°C, entry 1 in Table 1).
(ii) In general, good to excellent yields were noted in
all the cases. With regard to the stereochemical con-
trol, the use of (+)- or (–)-N-methylephedrine mainly
determined the configuration of the new stereocenter.
Monoprotected diols were formed in excellent
diastereoselectivities12 in the matched cases (entries 2,
4, 6, 8–10, 12 and 14) but also good in the mis-
matched ones (entries 3, 5, 7, 11 and 13).
(iii) The process is tolerant with a range of protective
groups (benzyl, benzoyl, acetyl, and tert-
butyldimethylsilyl groups). However, faster reactions
and, in general, better stereoselectivities were noted
for alkynes with the hydroxyl protected as benzoate
or acetate (2–4 hours at 20°C)13 than for alkynes
protected as silyl ethers (overnight at 20°C) or benzyl
We then attempted to expand the scope of this reaction
to simpler, unprotected alk-1-yn-3-ols. Although the
successful addition to aldehydes of the Zn-alkynylide
derived from 2-methylbut-3-yn-2-ol, which bears a free
tertiary alcohol, has been recently reported by Carrei-
ra’s group,10 related additions with substrates contain-
ing a less hindered, unprotected alcohol were still
undocumented. Since in a series of preliminary experi-
ments using representative propargylic alcohols in the
absence of solvents, we observed moderate yields of the
expected unprotected diols 1,15 we turned our attention
to toluene solutions. To our satisfaction, the expected
diols were obtained in useful yields and good to excel-
lent selectivities, as shown in Table 2.16
These goods results prompted us to apply this strategy
to an enantioselective synthesis of musclide B, a car-
diotonic potentiating principle present in musk. Musk,
a dried secretion from the preputial follicles of a male
musk deer (Moschus moschiferus L.), has been pre-
scribed traditionally in Chinese medicines, based upon
its three pharmacological actions, cardiotonic, sedative
and anti-inflammatory properties. Kikuchi et al. have
Table 1. Addition of O-protected (S)-1-alkyn-3-ols (5) to aldehydes
Entry
Alkyne
R% in R%-CHO
N-Methylephedrine
T (°C)
Product
Yield (%)
syn/anti
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
5a
5a
5a
5a
5a
5b
5b
5b
5c
5d
5d
5e
5e
5f
Cyclohexyl
Cyclohexyl
Cyclohexyl
Isopropyl
Isopropyl
Isopropyl
Isopropyl
tert-Butyl
Isopropyl
tert-Butyl
tert-Butyl
Isopropyl
Isopropyl
Cyclohexyl
(−)
(−)
(+)
(−)
(+)
(−)
(+)
(−)
(−)
(−)
(+)
(−)
(+)
(−)
65
65
65
65
65
rt
rt
rt
rt
rt
6a
6a
6a
6b
6b
6c
6c
6d
6e
6f
24
70
81
75
70
97
90
64
85
72
78
84
72
76
–
94:6
6:94
93:7
13:87
98:2
7:93
99:1
96:4
99:1
7:93
95:5
10:90
98:2
rt
rt
rt
rt
6f
6g
6g
6h
a Reaction performed in a 0.3 M toluene solution.

M. Amador et al. / Tetrahedron Letters 43 (2002) 2691–2694
2693
Table 2. Addition of unprotected (S)-1-alkyn-3-ols to cyclohexanecarbaldehyde
Entry
Alkyne (R)
N-Methylephedrine
Time (h)
Yield (%)
syn/anti
1
2
3
4
Methyl
Methyl
Cyclohexyl
Cyclohexyl
(−)
(+)
(−)
(+)
3
4
40
40
82
99
68
60
95:5
17:83
99:1
3:97
reported that the cardiotonic activity is due to the
presence of three aliphatic 1,4-diol monosulfates,
musclides A1, A2 and B.17 Very recently, Tezuka et al.
have determined the structure of musclide B to be
(2R,5S)-2-hydroxy-7-methyloct-5-yl hydrogen sulphate
(7) (Fig. 1) by comparison of the natural product with
the 2S,5R and the 2R,5R stereoisomers obtained from
(S)-(–)-ethyl leucate.18
tected derivatives) to aldehydes mediated by zinc
triflate, Et3N, and (+)- or (–)-N-methylephedrine consti-
tutes an efficient, modular way to prepare chiral syn- or
anti-2-alkyne-1,4-diols (or their monoprotected deriva-
tives). This strategy has been applied to the synthesis of
musclide B, a bioactive metabolite from musk. It
extends the scope of the enantioselective alkynylation
of aldehydes recently described by Carreira’s group.
Our approach to musclide B is summarised in Scheme
3. The slow addition of 3-methylbutanal to the Zn-
alkynylide derived from ent-5a in the presence of (+)-
N-methylephedrine afforded the monoprotected diol 6i
in a 90:10 (R,R)/(R,S) ratio.19 After reduction of 6i
with LiAlH4 in THF, the minor R,S stereoisomer was
separated by chromatography (MPLC, hexane/ethyl
acetate 98:2) to obtain diol 8. Finally, hydrogenation of
8 on Pt afforded the known saturated diol 9.20 Since an
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
(2000SGR00021). We also thank the Universitat de
Barcelona for a doctorate studentship to J.O., and
Professor J. Vilarrasa for reading the draft.
efficient transformation of
9
into
7
has been
a formal,
described,18 this approach constitutes
stereoselective synthesis of musclide B.
References
In summary, we have demonstrated that the stereose-
lective addition of chiral 1-alkyn-3-ols (or of their pro-
1. For example, see: (a) Grabley, S.; Granzer, E.; Huetter,
K.; Ludwig, D.; Mayer, M.; Thiericke, R.; Till, G.;
Phillipps, S.; Wink, J.; Zeeck, A. J. Antibiot. 1992, 45,
56–65; (b) Nagle, D. G.; Gerwick, W. H. J. Org. Chem.
1994, 59, 7227–7237; (c) Arnone, A.; Nasini, G.; de Pava,
O. V. Phytochemistry, 2000, 53, 1087–1090.
2. Ethylenic diols 2 or their Z isomers are easily obtainable
from 1 by LiAlH4 reduction and partial hydrogenation,
respectively. These substrates are potentially amenable to
transformation into other functionalities in a stereoselec-
tive way (see, for instance, Refs. 3–5). For a review on
substrate-directable chemical reactions, see: Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93,
1307–1370.
3. Bach, J.; Berenguer, R.; Garcia, J.; Loscertales, T.; Man-
zanal, J.; Vilarrasa, J. Tetrahedron Lett. 1997, 38, 1091–
1094.
Figure 1.
Scheme 3. Reagents and conditions: (a) Zn(TfO)2 (1.1 equiv.), (+)-N-methylephedrine (1.2 equiv.), Et3N (1.2 equiv.), 3-methylbu-
tanal (1.1 equiv.), toluene (0.3 mL), 65°C, overnight, 73%; (b) LiAlH4, THF, rt, 80%; (c) H2 (1 atm.), Pt cat., rt, 85%; (d) Ref.
18.

2694
M. Amador et al. / Tetrahedron Letters 43 (2002) 2691–2694
4. Bach, J.; Berenguer, R.; Garcia, J.; Lo´pez, M.; Manzanal,
13C NMR (CDCl3): 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. Compound
anti-6b: 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.
J.; Vilarrasa, J. Tetrahedron 1998, 54, 14947–14962.
5. Ariza, X.; Garcia, J.; Lo´pez, M.; Montserrat, L. Synlett
2001, 120–122.
6. Symmetrical alk-2-yne-1,4-diols, obtained as mixtures of
stereoisomers by one-pot double addition of dilithium (or
magnesium) acetylide to aldehydes can be transformed
into symmetrical diketones 3 by Jones oxidation in good
yields. See: Sudweeks, W. B.; Broadbent, H. S. J. Org.
Chem. 1975, 40, 1131–1136. See also: Choi, T.-L.; Lee, C.
W.; Chaterjee, A. K.; Grubbs, R. H. J. Am. Chem. Soc.
2001, 123, 10417–10418.
7. (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.
12. Stereoselectivities were determined by 19F analysis of the
corresponding Mosher esters. The configuration of the
new stereocenters were determined by the Kakisawa
method (Ohtani, I.; Kusumi, T.; Kashman, Y.; Kak-
isawa, H. J. Am. Chem. Soc. 1991, 113, 4092–4096) and it
always agreed with those expected on the basis of Carrei-
ra’s work.
13. A few experiments performed at 65°C showed lower
stereoselectivities (for example, reaction of 5b with isobu-
tyraldehyde gave 6c in 92% yield but only in a 83:17
syn/anti ratio).
8. Carreira and co-workers have very recently reported the
addition of the Zn-alkynylide derived from propargyl
acetate to (S)-2-(tert-butyldimethylsilyloxy)propanal
mediated by (+)- or (–)-N-methylephedrine (Ref. 7d). In
that case, the stereochemical outcome observed was pro-
vided by the chiral amino alcohol employed. To the best
of our knowledge, other exemples using chiral alkynes or
other a-substituted chiral aldehydes are unpublished.
9. For leading references on enantioselective reduction of
acetylenic ketones, see: (a) Noyori, R.; Tomino, I.;
Yamada, M.; Nishizawa M. J. Am. Chem. Soc. 1984, 106,
6717–6725; (b) Ramachandran, P. V.; Teodorovic, A. V.;
Rangaishenvi, M. V.; Brown, H. C. J. Org. Chem. 1992,
57, 2379–2386; (c) Parker, K. A.; Ledeboer, M. W. J.
Org. Chem. 1996, 61, 3214–3217; (d) Bach, J.; Berenguer,
R.; Garcia, J.; Loscertales, T.; Vilarrasa, J. J. Org. Chem.
1996, 61, 9021–9025; (e) Helal, C. J.; Magriotis, P. A.;
Corey, E. J. J. Am. Chem. Soc. 1996, 118, 10938–10939;
(f) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori,
R. J. Am. Chem. Soc. 1997, 119, 8738–8739.
10. Protected alcohols 5a–d were obtained from the commer-
cially available (S)-but-3-yn-2-ol or (S)-oct-1-yn-3-ol by
standard procedures. Compounds 5e–f were obtained
according to: Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz,
D.; Carreira, E. M. Org. Lett. 2000, 2, 4233–4236.
11. General procedure for alkynes 5a–f: To a mixture of
Zn(OTf)2 (dried overnight at 120°C under vacuum, 1.1
mmol), (+)- or (–)-N-methylephedrine (1.2 mmol) and
alkyne 5 (1 mmol), Et3N (1.2 mmol) was added under Ar
at rt. In most cases, a small amount (ꢀ0.3 mL) of dry
toluene was also added in order to obtain an almost
homogeneous mixture. After vigorous stirring for 30 min
at rt, the aldehyde (1.2 mmol) was added in one portion
by syringe, and the mixture was stirred at 20°C or 65°C.
The reaction was monitored by TLC and, after comple-
tion, the mixture was poured directly into a silica gel
column and purified by flash chromatography to afford
the desired diol 6. NMR data for syn-6b: 1H NMR
(CDCl3): 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).
14. A few experiments performed at higher temperatures (i.e.
100°C) gave less satisfactory yields due to the formation
of by-products (detected by TLC).
15. The reversible formation of ketals or/and hemiketals
between the free hydroxyl groups and the aldehyde in the
presence of Zn salts can be assumed, especially in a
solvent-free mixture.
16. General procedure for unprotected alkynes: A mixture of
Zn(OTf)2 (dried overnight at 120°C under vacuum, 1.1
mmol), (+)- or (–)-N-methylephedrine (1.2 mmol) and
Et3N (1.2 mmol) in 2 mL of dry toluene was stirred under
Ar at rt for 2 h. The alkyne (1 mmol) was then added and
the mixture was vigorously stirred for additional 15 min
before the aldehyde (1.2 mmol) was added in one portion
by syringe. The reaction was stirred at 60–70°C until
TLC revealed the disappearance of the starting alkyne,
and then quenched by addition of saturated aqueous
NH4Cl (3 mL). The mixture was poured into a separatory
funnel containing diethyl ether (20 mL) and the aqueous
layer was washed with more diethyl ether (2×10 mL). The
combined organic layers were dried (MgSO4) and concen-
trated. The crude was purified by flash chromatography
to afford the desired diol 1. NMR data for syn-1-cyclo-
1
hexylpent-2-yne-1,4-diol: H NMR (CDCl3): l 1.00–1.35
(m, 6H), 1.45 (d, J=6.3 Hz, 3H), 1.65–1.90 (m, 5H), 4.17
(d, J=5.7 Hz, 1H), 4.57 (q, J=6.3 Hz, 1H). 13C NMR
(CDCl3): l 24.2, 25.8, 26.3, 28.1, 28.6, 43.9, 58.0, 66.9,
84.0, 87.5. anti Isomer: 1H NMR: l 1.00–1.35 (m, 6H),
1.45 (d, J=6.7 Hz, 3H), 1.65–1.90 (m, 5H), 4.16 (dd,
J=6.5, 1.2 Hz, 1H), 4.56 (qd, J=6.7, 1.2 Hz, 1H). 13C
NMR: l 24.3, 25.9, 26.3, 28.1, 28.5, 43.9, 58.1, 67.0, 84.0,
87.6.
17. Kadota, S.; Orito, T.; Kikuchi, T.; Uwano, T.; Kimura,
I.; Kimura, M. Tetrahedron Lett. 1991, 32, 1733–1736.
18. Tezuka, Y.; Kudoh, M.; Hatanaka, Y.; Kadota, S.;
Kikuchi, T. Nat. Prod. Lett. 1997, 9, 297–304.
19. The fact that a-unbranched aldehydes, like 3-methylbu-
tanal, give products with lower yields and stereoselectivi-
ties has been previously reported (see Ref. 7a).
20. Spectral data of 9 fully agree with those reported in Ref.
18.