A short enantioselective synthesis of (R)-nostrenol

Article abstract of DOI:10.1016/j.tetasy.2004.02.014

The catalytic asymmetric synthesis of (-)-(R)-nostrenol is described in five steps starting from commercially available 1-pentyne. The key steps are a Noyori catalytic and asymmetric hydrogen transfer and a Cp₂TiCl ₂ catalyzed hydroalumination.

Full text of DOI:10.1016/j.tetasy.2004.02.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1199–1201
A short enantioselective synthesis of (R)-nostrenol
Nicolas P ꢀe try, Arnaud Parenty and Jean-Marc Campagne*
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 11 February 2004; accepted 12 February 2004
Abstract—The catalytic asymmetric synthesis of ())-(R)-nostrenol is described in five steps starting from commercially available
-pentyne. The key steps are a Noyori catalytic and asymmetric hydrogen transfer and a Cp TiCl catalyzed hydroalumination.
2004 Elsevier Ltd. All rights reserved.
1
2
2
ꢀ
1. Introduction
2. Results and discussion
Insects semiochemicals, including pheromones and
allelochemicals, play an important role in the chemical
Starting from commercially available 1-pentyne, prop-
argylic ketone 4 was obtained in 79% yield using butyl
lithium and acetic anhydride (Scheme 2). Catalytic
asymmetric hydrogen transfer, under NoyoriÕs condi-
1;2
communications between organisms. From a struc-
tural point of view, insect semiochemicals are usually
constituted with an unsaturated/saturated hydrocarbon
chain with some chiral branching (alkyl chain or oxygen
functionality). (R)-Nostrenol [())-(R)-(Z)-undec-6-en-2-
ol] 1 is the major semiochemical isolated from ant-lions
7
tions, led to the corresponding propargylic alcohol 5 in
5
60% yield. As previously described, the enantiomeric
excess was determined to be greater than 95% ee by
13
C
and natural abundance deuterium (NAD) D NMR
2
3;4
8
(
developed a rapid access to chiral building block 2, and
Euroleon nostras and Grocus bore). We have recently
5
spectroscopy in a chiral liquid crystal. Finally a chiral
building block 2 was obtained in 68% yield using a
6
5
2
a Cp
2
TiCl
2
catalyzed (Z)-selective reduction of internal
racemization-free (determined by NAD D NMR)
9
KAPA reaction.
alkynes. In our retrosynthetic analysis, we sought to
combine these two methodologies to develop a rapid
and efficient access to (R)-nostrenol (Scheme 1).
BuLi/Ac2O
THF
C3H7
79%
O
4
C H9
4
iPrOH/KOH
(R ,R)-Noyori's cat 1%
60%
C H9
4
OH
OH
3
1
Li(0), tBuOK
diaminopropane
C3H7
OH
68%
OH
2
5
OH
2
Scheme 2.
Scheme 1.
The free acetylenic compound was then alkylated with
butyl iodide, in the presence of HMPA, leading to
1
0
*
0
Corresponding author. Tel.: +33-01-69-82-30-73; fax: +33-01-65-07-
2-47; e-mail: jean-marc.campagne@icsn.cnrs-gif.fr
25
desired alkyne 3 in 75% yield with ½aŠ ¼ )10.9 (c 0.92,
7
D
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.02.014

1200
N. P ꢀe try et al. / Tetrahedron: Asymmetry 15 (2004) 1199–1201
CHCl
3
), which can be compared with the previously
4
ene)chlororuthenium(II)] (STREM, 275 mg; 0.45 mmol;
23
D
reported value ½aŠ ¼ )8.0( c 0.84, CHCl
3
) (Scheme 3).
0.5 mol %) was added propan-2-ol (20 mL). The solution
was degassed three times using the Schlenk procedure
and warmed to 80 ꢁC. After 1 h, the solution was cooled
to room temperature and flame-dried potassium
hydroxide (126 mg; 2.25 mmol; 2.5 mol %) added. The
red solution then turned to purple. After 5 min, a solu-
tion of ketone 3 (10g; 90.9 mmol) in propan-2-ol
(480mL) was added through a cannula. After stirring for
BuLi, THF-HMPA
o
o
-
78 C to0 C
o
thenC4H9I 0 C
2
7
5%
C4H9
OH
3
4
8 h under argon at room temperature, the solvent was
LiAl H4 4eq
Cp2TiCl2 10%
THF reflux
removed under vacuum at room temperature and the
residue purified (pentane/diethyl ether 9:1). The desired
alcohol was obtained in 60% yield as a light yellow oil.
85%
1
TLC: SiO
2
/(heptane/ethyl acetate 8:2) R
3
f
¼ 0.33.
H
C4H9
NMR (CDCl
300 MHz): 4.50 (qt, 6.5, 1.9, 1H); 2.16 (td,
.0, 1.9, 2H); 1.95 (br, 1H); 1.51 (ꢀsext, 2H); 1.42 (d, 6.5,
7
3
8
1
3
H); 0.96 (t, 7.0, 2H). C NMR (CDCl
3
75 MHz): 84.4;
¼
OH
13
25
D
2.4; 58.5; 24.7; 22.1; 20.5; 13.4. Rotation: lit. : ½aŠ
1
25
D
þ14:8 (c 0.662, CHCl ; ee ¼ 78%), Found: ½aŠ ¼ þ30.7
3
Scheme 3.
(c 1.01, CHCl
previously reported data.
3
; ee >95%). Data are in agreement with
13
The final reduction of the alkyne to the (Z)-alkene was
6
2 2
carried out by using our previously reported Cp TiCl
11
4.3. (R)-Hept-6-yn-2-ol, 2
catalyzed hydroalumination. ())-(R)-Nostrenol was
thus obtained in 85% yield with a (Z)-selectivity higher
13
According to the general procedure described by
9
than 95% [determined by comparison ( C NMR) with
an (E)-sample obtained using the Rossi and Carpita
Abrams and Shaw, in a flame dried tricol, and under
argon, containing lithium (0.89 g; 130 mmol; 6 equiv)
was added diaminopropane (distilled over BaO and
12
methodology ].
ꢁ
stored over 4 A MS) (80mL). The solution was stirred
for 30min at room temperature and then at 70 ꢁC for 4 h
(
until the total disappearance of the blue color). After
3
. Conclusion
cooling to room temperature, tBuOK (9.6 g; 84 mmol)
was added to the reaction mixture and the resulting
yellow solution stirred for a further 30min. The prop-
argylic alcohol 4 (2.4 g, 21.4 mmol) was then added
dropwise. After stirring for 30min, the reaction was
poured into crushed ice/water (250mL). The reaction
mixture was then extracted with diethyl ether (four
times, 125 mL). The combined organic layers were
In conclusion we have developed a short (five steps, 20%
overall yield, from commercially available 1-pentyne)
catalytic asymmetric total synthesis of the ant-lion
semiochemical ())-(R)-nostrenol, highlighting the ver-
satility of 2 as a chiral building block and the efficiency
of the Cp TiCl2 catalyzed (Z)-selective reduction of
2
internal alkynes.
washed twice with 1 M HCl (50mL), saturated NaHCO
50mL), brine (50mL), dried over MgSO , and the
3
(
4
solvent removed under vacuum. Pure alcohol (1.63 g;
8%) was obtained after chromatography (pentane/
6
1
4. Experimental
diethylether 8:2). R ¼ 0.33 Heptane/ethyl acetate 7:3. H
f
3
NMR (CDCl 300 MHz): 3.83 (m, 1H); 2.23 (td, 6.7, 2.6,
4
.1. General methods
2H); 1.96 (t, 2.6, 1H); 1.82 (br, 1H); 1.75–1.45 (m, 4H);
1
1
3
.19 (d, 6.2, 3H). C NMR (CDCl 75 MHz): 84.2; 68.4;
3
14
25
67.5; 38.1; 24.6; 23.5; 18.3. Rotation: lit. : ½aŠ ¼ )13.6
Unless otherwise specified, the reactions were carried
out in oven-dried glassware under an argon atmosphere.
D
25
(c 0.404, CHCl
CHCl ; ee >95%). Data are in agreement with the pre-
3
viously reported data.
3
; ee >95%); found: ½aŠ ¼ )14.5 (c 1.01,
D
1
13
H and C NMR spectra were recorded at 300 and
5 MHz, respectively, or at 250and 63 MHz, in CDCl 3
14
7
as solvent: chemical shifts are given in ppm. Column
chromatography was performed on silica-gel 230–400
mesh. THF was distilled from sodium/benzophenone.
Optical rotations were determined operating at the
sodium D line.
4.4. (R)-Undec-6-yn-2-ol, 3
To a solution of 2 (79 mg; 0.70 mmol) in THF (2 mL), at
)
78 ꢁC and under argon, was added dropwise n-butyl-
lithium (1.50mL; 1.6 M solution in hexane; 2.40mmol;
3.4 equiv). After 20min, the temperature was allowed to
warm up to 0 ꢁC and HMPA (0.75 mL; 4.3 mmol;
6 equiv) added to the reaction mixture. A solution of
1-iodobutane (193 mg; 1.03 mmol; 1.5 equiv) in dry THF
4
.2. (R)-Hept-3-yn-2-ol, 5
In a flask containing (R,R)-tosyldiphenylethylendiamine
333 mg; 0.9 mmol; 1 mol %) and di-l-chlorobis[(p-cym-
(

N. P ꢀe try et al. / Tetrahedron: Asymmetry 15 (2004) 1199–1201
1201
(
1 mL) was then added and the reaction mixture stirred
0.91, CHCl
reported data.
3
). Data are in agreement with the previously
4b
overnight with the temperature being allowed to rise to
the ambient. The reaction was quenched by the addition
of 1 M HCl and the mixture poured into water (20mL).
It was then extracted with diethyl ether (4 · 15 mL) and
the combined extracts washed with water and brine,
Acknowledgements
dried over MgSO
4
, and evaporated under vacuum.
We thank Dr. P. Lesot for the determination of the
enantiomeric excess and the CNRS for financial sup-
port.
Chromatographic purification of the crude residue on
silica (heptane/ethyl acetate 8:2) gave 90mg (75%) of
pure 3 as a light yellow oil. TLC: SiO /(heptane/ethyl
2
1
acetate 7:3) R
f
¼ 0.35; H NMR (CDCl
3
300 MHz): 3.84
(
1
q, J ¼ 5.8, 1H); 2.18–2.12 (m, 4H); 1.58–1.36 (m, 9H);
References and notes
13
.20(d, J ¼ 6.4, 3H); 0.90 (t, 3H, J ¼ 7.0, 3H); C NMR
, 75 MHz) 80.7; 79.8; 67.7; 38.4; 31.2; 25.3; 23.5;
1
. Mori, K. Eur. J. Org. Chem. 1998, 1479–1489, and
references cited therein.
2. Mori, K. Chem. Commun. 1997, 1153–1158.
(
CDCl
3
4b
25
D
2
1.9; 18.7; 18.4; 13.6. Rotation: lit. : ½aŠ ¼ )8.0( c 0.84,
25
CHCl ; ee >95%); Found: ½aŠ ¼ )10.9 (c 0.92, CHCl ).
3
D
Data are in agreement with the previously reported
3
3
. Baeckstr o€ m, P.; Bergstr o€ m, G.; Bj o€ rkling, F.; Hui-Zhu,
H.; H o€ gberg, H.; Jacobsson, U.; Guo-Qiang, L.; L o€ fquist,
J.; Norin, T.; Wassgren, A. J. Chem. Ecol. 1989, 15, 61–80.
. Previous synthesis: (a) Chow, S.; Kitching, W. Chem.
Commun. 2001, 1040–1041; (b) Chow, S.; Kitching, W.
Tetrahedron: Asymmetry 2002, 13, 779–793.
4b
data.
4
4
.5. (R)-Nostrenol, 1
5
6
7
. Parenty, A.; Campagne, J.-M.; Aroulanda, C.; Lesot, P.
Org. Lett. 2002, 4, 1663–1666.
. Parenty, A.; Campagne, J.-M. Tetrahedron Lett. 2002, 43,
To a suspension of LiAlH
in dry THF (3 mL) was added Cp
4
(95 mg; 2.4 mmol; 4 equiv)
2
TiCl
solution of
2
(15 mg;
(103 mg;
1
231–1233.
0
0
.06 mmol; 0.1 equiv).
.6 mmol; 1 equiv) in dry THF (3 mL) was then added
A
3
. (a) Matsumara, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1997, 119, 8738–8739; (b) Buisine, O.;
Aubert, C.; Malacria, M. Synthesis 2000, 985–989.
. Sarfati, M.; Lesot, P.; Merlet, D.; Courtieu, J. Chem.
Commun. 2000, 21, 2069–2081.
and the mixture heated to reflux for 16 h. After cooling
to rt, the mixture was diluted with diethyl ether and
neutralized with 1 M HCl. The aqueous phase was
extracted with diethyl ether and the combined organic
extracts washed with 1 M HCl, saturated aqueous
8
9
. (a) Abrams, S. R.; Shaw, A. C. Organic Synthesis 1993, 8,
146–152; (b) Midland, M. M.; Halterman, R. L. Tetra-
hedron Lett. 1981, 22, 4171–4172.
hydrogen carbonate and brine, dried over MgSO and
4
the solvent removed under vacuum. The crude residue
was purified by column chromatography on silica
10. (a) Mori, K.; Qian, Z.-H. Liebigs Ann. Chem. 1994, 35–39;
b) Cossy, J.; Pete, J.-P. Bull. Soc. Chim. Fr. 1988, 989–
94.
(
9
(
(
heptane/ethyl acetate 9:1 to 7:3) to give (R)-nostrenol
86 mg; 85%) as a light yellow oil. TLC: SiO /(heptane/
1
13
24
1
1. H and C NMR and ½aŠ )4.9 (c 0.91, CHCl
3
) are in
)5.5 (c
D
2
4b
23
D
1
agreement with the previously reported data : ½aŠ
ethyl acetate 7:3) R
5
9
NMR (CDCl
2
f
¼ 0.43; H NMR (CDCl
3
300 MHz):
0
2. Rossi, R.; Carpita, A. Synthesis 1977, 561–562.
3
.78, CHCl ).
.37 (m, 2H); 3.81 (m, 1H); 2.05 (m, 4H); 1.48–1.27 (m,
C
1
1
13
H); 1.20(d, J ¼ 6.1, 3H); 0.89 (t, J ¼ 7.0, 3H);
3. Marx, K.-H.; Raddatz, P.; Winterfeldt, E. Liebigs Ann.
Chem. 1984, 474–482.
14. Millar, J. G.; Oehlschager, A. C. J. Org. Chem. 1984, 49,
3
75 MHz): 130.3; 129.3; 68.0; 38.9; 31.9;
4b
25
D
7.1; 26.9; 25.9; 23.5; 22.3; 14.0. Rotation: lit. : ½aŠ
¼
25
ꢁ
5:5 (c 0.78, CHCl ; ee >95%); found: ½aŠ ¼ )4.9 (c
2332–2338.
3
D