Enantioselective synthesis of (+)-gossonorol and related systems using organozinc reagents

Article abstract of DOI:10.1016/j.tetasy.2012.04.003

The sesquiterpene (+)-gossonorol is prepared in only three synthetic steps in 60% overall yield and 82% ee from commercially available reagents. The key asymmetric step is the catalytic enantioselective addition of dimethylzinc to 5-methyl-1-(2-methylphen

Full text of DOI:10.1016/j.tetasy.2012.04.003

Tetrahedron: Asymmetry 23 (2012) 611–615
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of (+)-gossonorol and related systems using
organozinc reagents
⇑
Susana González-López, Miguel Yus, Diego J. Ramón
Instituto de Síntesis Orgánica (ISO), and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, E-03080-Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The sesquiterpene (+)-gossonorol is prepared in only three synthetic steps in 60% overall yield and 82% ee
from commercially available reagents. The key asymmetric step is the catalytic enantioselective addition
of dimethylzinc to 5-methyl-1-(2-methylphenyl)hex-4-en-1-one catalyzed by chiral isoborneolsulfona-
mide ligands in the presence of titanium tetraisopropoxide. The modular approach allows the synthesis
not only of the aforementioned natural product but also other products arising from the corresponding
processes of ethylation, phenylation, and ethynylation, just by changing the final nucleophilic reagent
and using the same isoborneol type ligand.
Received 2 April 2012
Accepted 5 April 2012
Available online 10 May 2012
Dedicated to Professor Dr. Lutz F. Tietze on
occasion of his 70th birthday
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
processes. This seven-steps synthesis rendered the final product 1a
in a 17% yield and 97% ee.11 Besides, this is a long reaction se-
The sesquiterpene gossonorol 1a was first isolated in 1984 from
the cotton plant.1 Since then, it has been found in many other plant
species, including Artemisia sieberi,2 Chamomilla recutita,3 Laurencia
tristicha,4 Hypericum linarioides,5 Croton flavens,6 Ferula orientalis,7
Teucrium,8 Pleurospermun austriacum,9 and it presents some inter-
esting biological properties, among others antifungal, anticancer
and antioxidant activities, biochemical communicator, and floral
scent.
quence, a large amount of waste is generated and the use of chro-
mium species makes this approach non-environmentally friendly.
The second approach involved the kinetic resolution of the corre-
sponding racemic acetate derivative by several esterases with
enantiomeric excesses lower than 10%,12 with this low enantiose-
lectivity hampering its practical use.
Recently, we have developed a new class of chiral isoborneol
sulfonamides,13 which have been successfully used in the enantio-
selective addition of various zinc reagents to simple ketones14 cat-
alyzed by titanium alkoxides,15 yielding the expected tertiary
alcohols with excellent enantioselectivities.16 Herein we report
the enantioselective synthesis of compound 1a through a catalytic
addition of dimethylzinc to 5-methyl-1-(2-methylphenyl)hex-4-
en-1-one as the key asymmetric step. This approach permitted
the synthesis of related compounds with similar results and in a
routine way.
OH
(+)-(R)-Gossonorol 1a
2. Results and discussion
Despite the widespread occurrence of alcohol 1a in the plant
kingdom and its use as a starting material for the synthesis of sev-
eral natural products,10 there are only two published approaches to
its asymmetric synthesis. The first one involved the enantioselec-
tive deprotonation of a benzyl ether chromium complex derivative
using excess of butyllithium and stoichiometric amounts of a chiral
diamine and methylation of the prepared benzyllithium intermedi-
ate, as the key step, performing other synthetic steps such as ben-
zylic deprotonation and alkylation, and finally double deprotection
The synthesis started with the preparation of amide 3 from the
commercially available carboxylic acid 2 using the classical stan-
dard protocols17 with an excellent yield (Scheme 1). Then, the lith-
iation of 5-bromo-2-methylpent-2-ene using lithium powder and a
substoichiometric amount of naphthalene18 under Barbier condi-
tions rendered the expected ketone 4,19 with an overall yield of
74%.
Once ketone 4 was prepared, we addressed the problem of the
enantioselective addition of dialkylzinc reagents 5 (Table 1).
The study started using the first generation chiral isoborneol
ligands 6.20 The enantioselective addition of dimethylzinc 5a to
⇑
Corresponding author. Tel.: +34 965903986; fax: +34 965903549.
E-mail address: djramon@ua.es (D.J. Ramón).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.003

612
S. González-López et al. / Tetrahedron: Asymmetry 23 (2012) 611–615
O
O
i) SOCl2, PhMe, 80 ºC, 15 h
ii) HN O , Et3N, CH2Cl2,
0 to 25 ºC, 15 h
OH
N
O
2
3
(95%)
Br
O
Li, C10H8(10 mol%), THF,
-78 ºC, 3 h
4 (78%)
Scheme 1. Synthesis of starting ketone 4.
ketone 4 in the presence of substoichiometric amounts of the
benzyl ligand 6a gave the expected (+)-gossonorol 1a after more
than seven days with modest yield and enantioselectivity (Table 1,
entry 1). The increase of the hindrance of the ligand from the
phenyl derivative to the related 1-naphthyl one 6b showed an
important increase in the enantiomeric excess of the natural prod-
uct 1a (entry 2 in Table 1). The above result prompted us to use a
more crowded 9-anthracenyl derivative ligand 6c.21 However, the
result obtained was practically the same as that obtained in the
naphthyl case (compare entries 2 and 3 in Table 1). Next, we
repeated the reaction but using the second generation22 chiral
ligand HOCSAC 7, obtaining the expected product 1a in a good
chemical yield and enantioselectivity (Table 1, entry 4). It should
be pointed out that the addition failed using the third generation
ligands 8,23 recovering the starting ketone 4 being recovered un-
changed after more than 11 days (entries 5 and 6 in Table 1). When
the reaction was performed using diethylzinc 5a with the HOCSAC
ligand 7, the related gossonorol product 1b was obtained in a mod-
erate yield, due to difficulty in its purification (Table 1, entry 7).
After proving that this modular approach was effective for the
synthesis of gossonorol, we tried to expand the possibilities with
other reagents of a different nature. Recently, the preparation of
ethyl phenyl zinc reagent has been described by transmetallation
of diethylzinc with triphenylboron,24 and this intermediate
showed a higher reactivity and enantioselectivity compared with
the related diethyl or diphenylzinc reagents.25 The corresponding
ethyl phenyl zinc intermediate was obtained starting from com-
mercially available triphenyl boron and diethylzinc by heating in
toluene at 70 °C. This intermediate was reacted in situ with the ke-
tone 4 in the presence of substoichiometric amounts of ligand 7
and a small excess of titanium tetraisopropoxide, giving the ex-
pected diaryl ethanol derivative 9 with good chemical yield and
enantioselectivity, with the absolute configuration being proposed
according to the outcome of the reaction for the methylation pro-
cess (Scheme 2).
Table 1
Catalytic enantioselective addition of dialkyllzincs to ketone 4
Ti(OPri)4 (110 mol%)
R
O
+ R2Zn
OH
PhMe, 25 ºC
Ligand (5 mol%)
4
5
1a: R = Me
1b: R = Et
OH
OH
SO2
NH
SO2
NH
OH
SO2
NH
NH
NH
Ar
SO2
SO2
6a: Ar = Ph
OH
6b: Ar = 1-naphthyl
R
6c: Ar = 9-anthracenyl
8a: R = OMe
8b: R = CF3
7
(HOCSAC)
Time (h)
Entry
Ligand
Product
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
6a
6b
6c
7
8a
8b
7
1a
1a
1a
1a
1a
1a
1b
180
180
280
180
280
280
180
60
59
48
81
26
72
70
82
—
Ph OH
0
0
i, PhMe, 70 ºC, 16 h
Ph3B+Et2Zn
—
64
25 (45)c
ii, 7 (10 mol%),
a
Ti(OPri)4(110 mol%),
4, 25 ºC, 10 d
Isolated yield based on the starting ketone 4 after column chromatography
(hexane/ethyl acetate).
9
(79%, 64% ee)
b
Enantiomeric excess determined by HPLC using a Chiralcel AD column.
Estimated yield by CG-analysis using Mesitylen as internal standard.
c
Scheme 2. Phenylation process.

S. González-López et al. / Tetrahedron: Asymmetry 23 (2012) 611–615
613
Finally, we studied the alkynylation process following the
4.1.1. N-(Anthracenyl-9-ylmethyl)-1-[(1S-,2R,4R)-2-hydroxy-
Chan’s copper protocol26 since the use of titanium tetraisopropox-
ide failed for simple ketones.22e,23a Thus, the reaction of phenyl-
acetylene, dimethylzinc, and the ketone 4 in the presence of
substoichiometric amounts of copper(II) triflate and ligand 6b gave
the expected tertiary alcohol 10 with moderate yield and enanti-
oselectivity (Scheme 3), with the absolute configuration being pro-
posed according to that obtained for simple ketones.21
7,7-dimethylbicyclo[2.2.1]-heptan-1-yl]methanesulfonamide
6c21
To a solution of 9-aminomethylanthracene (0.265 g, 1.3 mmol,
1.3 equiv) (previously synthesized as reported in the literature27
)
and triethylamine (0.181 mL, 1.3 mmol, 1.3 equiv) in acetonitrile
(10 mL) was added dropwise a solution of (S)-(+)-camphorsulfonyl
chloride (0.25 g, 1 mmol, 1.0 equiv) in acetonitrile (10 mL) at 0 °C.
The reaction mixture was allowed to rise to room temperature and
stirred for 8 h. Then, it was hydrolyzed with 2 M NaOH (20 mL) and
extracted with ethyl acetate (3 ꢀ 15 mL). The resulting organic lay-
ers were washed with 2 M HCl (30 mL), dried over anhydrous
Mg2SO4, filtered, and concentrated under vacuum to give 0.360 g
of the corresponding ketone. This ketone (0.360 g, 0.87 mmol,
1.0 equiv) was treated with sodium borohydride (0.132 g,
3.48 mmol, 4.0 equiv) in EtOH (10 mL) at 0 °C and the reaction
mixture was allowed to rise to room temperature and stirred for
8 h. Then, it was hydrolyzed with 2 M HCl (10 mL), extracted with
ethyl acetate (3 ꢀ 10 mL), and washed with saturated NaCl solu-
tion (30 mL), dried over anhydrous Mg2SO4, filtered, and concen-
trated under vacuum. The residue was purified by flash column
chromatography (using as solvents from hexane until hexane/ethyl
acetate: 9.5/0.5) to give 0.080 g (22% yield) of a white solid.
Rf = 0.53 (hexane/ethyl acetate: 9.5/0.5); mp 192–196 °C (from
Ph
i, Cu(OTf)2(10 mol%),
6b (10 mol%), CH2Cl2,
0 ºC, 30 min
H
OH
+Me2Zn
ii, 4, 25 ºC, 14 d
Ph
10
(51%, 62% ee)
Scheme 3. Alkynylation process.
3. Conclusion
The synthesis of (+)-gossonorol was accomplished in 60% over-
all yield by a three-step process and 82% ee from commercially
available reagents, which permits its easy multigram scale-up,
avoiding the economical and environmental problems associated
with other reported synthesis. The key asymmetric step was the
catalytic enantioselective addition of dimethyzinc to 5-methyl-1-
(2-methylphenyl)hex-4-en-1-one catalyzed by substoichiometric
amounts of chiral isoborneolsulfonamide ligands in the presence
of titanium tetraisopropoxide. The modular approach permitted
the synthesis not only of the (+)-gossonorol (methylation process)
but other related products arising from processes of ethylation,
phenylation, and ethynylation, just by changing the final nucleo-
philic reagent and using in all processes the same isoborneol type
ligand
ethyl acetate/hexane) (lit:21 167–169 °C);
CH2Cl2) [lit:
½
a 2D0
ꢁ
¼ ꢂ35:6 (c 1,
21
ꢂ34.5 (c 1, CH2Cl2)]; 1H NMR (300 MHz, (CD3)2SO)
d = 8.66 (br s, 1H), 8.53 (d, J = 9.0 Hz, 2H), 8.14 (d, J = 7.70 Hz,
2H), 7.65–7.55 (m, 5H), 5.30–5.15 (m, 2H), 4.41 (br s, 1H), 3.96–
3.92 (m, 1H), 3.5 (d, J = 14.0 Hz, 1H), 2.84 (d, J = 14.0 Hz, 1H),
1.71–1.61 (m, 5H), 1.40–1.35 (m, 1H), 1.05–0.95 (m with a s at
0.95, 4H), 0.66 (s, 3H); 13C NMR [75 MHz, (CD3)2SO], d = 20.74,
21.12, 27.88, 30.08, 39.60, 41.13, 44.70, 49.05, 50.57, 51.20,
75.61, 125.50 (2C), 126.12 (2C), 127.18 (2C), 128.69, 129.51,
129.77 (2C), 130.89 (2C), 131.97 (2C); Ms (DIP): m/z (%) 423 [M]+
(33), 271 (12), 208 (15), 207 (100), 206 (58), 205 (72), 204 (64),
192(13), 191 (56), 189 (11), 179(34), 178 (33), 176 (10).
4.2. Synthesis of starting ketone 4
4. Experimental
To a suspension of 4-methylbenzoic acid 2 (1.94 g, 14.25 mmol,
1.0 equiv) in toluene (15 mL), was added SOCl2 (6.25 mL,
85.5 mmol, 6.0 equiv) and some drops of DMF. The reaction mixture
was stirred at 80 °C for 15 h. Then the temperature was allowed to
rise to room temperature, and the solvent evaporated under vac-
uum. The residue was solved in toluene (20 mL) and it was evapo-
rated again to eliminate the excess of SOCl2. The 4-methylbenzoic
acid chloride was obtained as yellow oil and was used in the next
step without further purification. To a solution of 4-methylbenzoic
acid chloride (2.20 g, 14.25 mmol, 1.0 equiv) in dichloromethane
(25 mL) were added morpholine (2.5 mL, 28.5 mmol, 2.0 equiv)
and triethylamine (2 mL, 14.25 mmol, 1.0 equiv) at 0 °C. The reac-
tion mixture was allowed to rise to room temperature and stirred
for 15 h. Then, 2 M NaOH (30 mL) was added to the reaction mix-
ture, and extracted with ethyl acetate (2 ꢀ 30 mL). The resulting or-
ganic layers were washed with 2 M HCl (30 mL), and saturated NaCl
solution (30 mL), dried over anhydrous Mg2SO4, filtered, and con-
centrated under vacuum to yield 2.78 g of (4-methylphenyl)-mor-
pholin-4-ylmethanone 328 (95% yield) as a pale yellow solid.
Rf = 0.52 (hexane/ethyl acetate: 7/3); mp 74.1–76.3 °C; 1H NMR
(300 MHz, CDCl3) d = 2.38 (s, 3H), 3.69 (br s, 8H), 7.21 (d,
J = 7.8 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3)
d = 21.6, 43.0, 48.5, 67.1 (2C), 127.5 (2C), 129.4 (2C), 132.6, 140.3,
170.90; Ms (EI): m/z (%) 205 [M]+ (15), 204 (33), 119 (100), 91 (27).
To a suspension of lithium powder (0.168 g, 24 mmol, 6.0 equiv)
and naphthalene (0.051 g, 0.4 mmol, 0.1 equiv) in dry THF (10 mL)
under argon atmosphere at ꢂ78 °C were successively added
The reactions carried out under argon atmosphere were per-
formed with flame dried Schlenk glassware. Me2Zn (2.0 M in tolu-
ene) and Et2Zn (1.1 M in toluene) were purchased from Aldrich.
Dichloromethane was distilled from P2O5. Phenylacetylene was
purified by bulb-to-bulb distillation. The other chemicals were
used without further purifications. Column Chromatography was
carried out using Silica Gel 60, 40–63 microns RE, thin layer
chromatography TLC with Machery-Nagel Silica Gel 60, 0.20 mm.
Compounds were visualized by UV and phosphomolybdic acid
staining. NMR spectra were recorded on Bruker AC-300 (300 and
75 MHz, respectively) or a Bruker Avance-400 (400 and 101 MHz,
respectively) using CDCl3 and (CD3)2SO as solvent. Chemical shift
values are reported in ppm with TMS as the internal standard, pro-
ton chemical shift (d) and coupling constants (J) are given in ppm
and Hz. Spin multiplicities are given as s (singlet), d (doublet), t
(triplet), and m (multiplet) as well as br (broad). Optical rotations
were measured on a Perkin Elmer instruments (Model 341) with a
5 cm cell (c given in g/100 mL). Melting points were measured in a
Reichtert Thermovar hot plate apparatus. Enantioselectivities were
determined by HPLC analysis (Agilent 1100 Series HPLC) equipped
with a G1315B diode array detector and a Quat Pump G1311A.
4.1. Synthesis of chiral ligands
The ligands 6a,20a 6b,20a 7,22e 8a,22e and 8b20d were synthesized
following the protocol describe by us.

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S. González-López et al. / Tetrahedron: Asymmetry 23 (2012) 611–615
dropwise 5-bromo-2-methyl-2-pentene (0.588 mL, 4.4 mmol,
1.1 equiv) and (4-methylphenyl)-morpholine-4-ylmethanone
phenylborane (0.097 g, 0.4 mmol, 1.6 equiv) at 0 °C under argon
atmosphere. The resulting solution was warmed up to 70 °C, and
stirred for 16 h. After that, it was cooled to 0 °C and poured into
a Schlenk tube charged with the ligand HOCSAC (7) (0.011 g,
0.02 mmol, 0.1 equiv) the reaction mixture was stirred, allowed
3
(0.821 g, 4 mmol, 1.0 equiv). The reaction mixture was stirred for
3 h at the same temperature, quenched by addition of saturated
NH4Cl (15 mL), and extracted with ethyl acetate (3 ꢀ 10 mL). The
organic layers were dried over anhydrous Mg2SO4, filtered, and con-
centrated under vacuum. The residue was purified by flash chroma-
tography (using as solvents from hexane until hexane/ethyl
acetate: 9/1) to give 0.637 g of 5-methyl-1-(4-methylphenyl)hex-
4-en-1-one 419 (78% yield) as a white solid. Rf = 0.43 (hexane/ether:
9/1); mp 46.3–46.8 °C; 1H NMR (300 MHz,CDCl3) d = 1.63 (s, 3H),
1.69 (d, J = 1.1 Hz, 3H), 2.35–2.45 (m with a s at 2.41, 5H), 2.96 (t,
J = 7.26 Hz, 2H), 5.15–5.20 (m, 1H), 7.25, 7.86 (2d, J = 7.32 Hz, 2H
each); 13C NMR (75 MHz,CDCl3) d = 18.0, 22.0, 23.4, 26.0, 39.0,
123.4, 128.5 (2C), 129.5 (2C), 133.0, 134.9, 144.0, 200.0; Ms (EI):
m/z (%): 202 [M]+ (15), 134 (60), 119 (100), 91 (37), 65 (12).
to warm to room temperature and, then, Ti(OiPr)4 (65 lL,
0.22 mmol, 1.1 equiv) was added. After 15 min, the ketone 4
(40 mg, 0.2 mmol, 1.0 equiv) was added. The resulting mixture
was stirred at the same temperature for 10 d and finally quenched
by the successive addition of methanol (1 mL) and a saturated
solution of NH4Cl (10 mL). The mixture was extracted with EtOAc
(3 ꢀ 5 mL). The organic layers were washed with a saturated solu-
tion of NaHCO3 (15 mL), dried over anhydrous Mg2SO4, filtered,
and concentrated under vacuum. The residue was purified by flash
chromatography (using as solvents from hexane until hexane/ethyl
acetate: 9.5/0.5) to give 0.033 g (79% yield) of 9 as a colorless oil.
Rf = 0.42 (hexane/ethyl acetate: 9/1); ½a D20
¼ ꢂ1:2 (c 1, CHCl3);
ꢁ
4.3. General procedure for the enantioselective addition of
commercially available diorganozinc reagents to ketone 4
HPLC (OJ Chiralcel, UV 210 nm, hexane/2-propanol 99:1, flow
1 mL/min): tr = 13.2 min (major) tr = 16.3 min (minor), 64% ee; 1H
NMR (300 MHz, CDCl3) d = 1.47, 1.66 (2s, 3H each), 1.95–2.05 (m,
2H), 2.25–2.35 (m with a s at 2.30, 6H), 5.15–5.20 (m, 1H), 7.10
(d, J = 8.0 Hz, 2H), 7.20–7.15 (m, 1H), 7.28 (t, J = 7.5 Hz, 4H), 7.41
(dd, J = 8.2, 1.0 Hz,); 13C NMR (75 MHz, CDCl3) d = 18.0, 21.3, 23.2,
26.1, 42.1, 78.7, 124.5, 126.2 (4C), 127.0, 128.4 (2C), 129.2 (2C),
132.8, 136.6, 144.5, 147.5; HMRS calcd for C10H24O 280.1827,
found 280.1486.
To a solution of the corresponding chiral ligand 6a, 6b, 6c, 7, 8a,
8b, (0.02 mmol, 0.1 equiv) and the diorganozinc reagent in toluene
(5a or 5b, 2.4 mmol, 12.0 equiv) was added Ti(OiPr)4 (65 lL,
0.22 mmol, 1.1 equiv) at 25 °C and under argon atmosphere. The
reaction mixture was stirred at 25 °C (in case of diethylzinc at
0 °C) for 15 min and after that the ketone 4 (40 mg, 0.2 mmol,
1.0 equiv) was added. The reaction mixture was stirred for several
days (see Table 1) at the same temperature and finally quenched
by the successive addition of methanol (1 mL) and a saturated solu-
tion of NH4Cl (15 mL). The mixture was extracted with EtOAc
(3 ꢀ 5 mL) and the resulting organic layers were washed with a sat-
urated solution of NaHCO3 (5 mL), dried over anhydrous Mg2SO4,
filtered, and concentrated under vacuum. The residue was purified
by flash column chromatography (using as solvents from hexane
until hexane/ethyl acetate: 9/1) for 1a, and purified by bulb-to-bulb
distillation for 1b. Yields and ee are included in Table 1.
4.5. Enantioselective synthesis of (R)-7-methyl-3-(4-methyl-
phenyl)-1-phenyl-oct-6-en-1-yn-3-ol 10
A
solution of copper(II) triflate (14.47 mg, 0.04 mmol,
0.1 equiv), and the chiral ligand 6b (14.94 mg, 0.04 mmol,
0.1 equiv) in dry dichloromethane (2 mL) was stirred at 25 °C
for 30 min under argon atmosphere. A solution of Me2Zn (1 mL,
1.2 M, 1.2 mmol, 3.0 equiv) and phenylacetylene (114 lL,
1.04 mmol, 2.6 equiv) was stirred at 0 °C under argon atmosphere
for 15 min. Then, the previous formed copper solution was added
to the solution of Me2Zn at 0 °C for 30 min under argon atmo-
sphere. After that, the ketone 4 (0.080 g, 0.4 mmol, 1.0 equiv)
was added, and the reaction mixture was stirred for 14 days at
the same temperature. The mixture was hydrolyzed with 2 M
HCl (5 mL) and was extracted with EtOAc (3 ꢀ 5 mL). The result-
ing organic layers were washed with a saturated solution of NaH-
CO3 (15 mL), dried over anhydrous Mg2SO4, filtered, and
concentrated under vacuum. The residue was purified by flash
chromatography to give compound 10 0.061 g (51% yield) as a
4.3.1. (+)-(R)-6-Methyl-2-(4-methylphenyl)hept-5-en-2-ol, (+)-
Gossonorol, 1a11
Colorless oil Rf = 0.53 (hexane/ether: 3/2); ½a D20
¼ þ15:3 (c 1,
ꢁ
CHCl3); HPLC (AD Chiralpak, UV 210 nm, hexane/2-propanol
98:2, flow 0.5 mL/min): tr = 20.6 min (major) tr = 23.9 min (minor),
82% ee; 1H NMR (300 MHz,CDCl3) d = 1.49, 1.52 (2s, 3H each), 1.65
(s, 3H), 1.80–1.95 (m, 5H), 2.34 (s, 3H), 5.05–5.10 (m, 1H), 7.15,
7.31 (2d, J = 8.2 Hz, 2H each); 13C NMR (75 MHz,CDCl3) d = 18.0,
21.3, 23.3, 26.0, 30.9, 44.0, 75.2, 124.6, 125.0 (2C), 129.1 (2C),
132.5, 136.3, 145.2; Ms (EI): m/z (%) 218 [M]+ (<1%), 200 [Mꢂ18]+
(15), 85 (16), 158 (14), 157 (100), 143 (16), 142 (16), 135 (13),
132 (13), 129 (16), 128 (15), 115 (21), 105 (11), 90(16), 69(25).
yellow oil. Rf = 0.56 (hexane/ethyl acetate: 8.5/1.5); ½a D20
¼ ꢂ3:7
ꢁ
(c 1, CHCl3); HPLC (OJ Chiralcel, UV 210 nm, hexane/2-propanol
99:1, flow 1 mL/min): tr = 12.9 min (major) tr = 16.4 min (minor),
62% ee, 1H NMR (300 MHz, CDCl3) d = 1.53, 1.59 (2s, 3H each),
2.19–1.84 (m, 3H), 2.4–2.17 (m with a s at 2.4, 4H), 2.57 (s,
1H), 5.13–5.16 (m, 1H), 7.18 (d, J = 7.93 Hz, 2H), 7.30–7.35 (m,
3H) 7.45–7.50 (m, 2H), 7.58 (d, J = 8.19 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d = 17.7, 21.1, 23.9, 25.7, 45.2, 73.7, 86.1, 91.5,
122.7, 123.6, 125.4 (2C), 128.3, 128.4, 128.9 (2C), 131.7 (2C),
132.5, 137.4, 141.8; HMRS calcd for C22H24O 304.1827, found
304.1828.
4.3.2. (R)-7-Methyl-3-(4-methylphenyl)loct-6-en-3-ol 1b
Colorless oil. Rf = 0.42 (hexane/ethyl acetate: 9/1)); ½a D20
¼ þ6 (c
ꢁ
0.3, CHCl3); HPLC (AD Chiralpak, UV 210 nm, hexane/2-propanol
98:2, flow 0.5 mL/min): tr = 19.9 min (major) tr = 26.5 min (minor),
64% ee; 1H NMR (300 MHz,CDCl3) d = 0.75 (t, J = 9 Hz, 3H), 1.47,
1.65 (2s, 3H each), 1.85–1.75 (m, 7H), 2.34 (s, 3H), 5.05–5.15 (m,
1H), 7.15, 7.25 (2d, J = 9 Hz, 2H each); 13C NMR (75 MHz,CDCl3)
d = 8.1, 18.0, 21.3, 22.9, 26.0, 36.1, 42.4, 77.5, 124.7, 125.7 (2C),
129.0 (2C), 132.5, 136.0, 143.2; HMRS calcd for
232.1827, found 232.1825.
C
16H24
O
Acknowledgments
This work was supported by the Spanish Ministerio de Ciencia y
Tecnología (Consolider Ingenio 2010 CSD2007-00006, CTQ2007-
65218/BQU and CTQ2011-24151) and the Generalitat Valenciana
(PROMETEO 2009/03, FEDER). S.G.-L. thanks the Consolider Ingenio
program for a fellowship. We gratefully acknowledge the polishing
of our English by Mrs. Oriana C. Townley.
4.4. Enantioselective synthesis of (S)-5-methyl-1-(4-methyl-
phenyl)-1-phenylhex-4-en-1-ol 9
A
solution of Et2Zn (1.1 M in toluene, 1.6 mL, 1.8 mmol,
7.2 equiv) was slowly added to a pressure tube charged with tri-

S. González-López et al. / Tetrahedron: Asymmetry 23 (2012) 611–615
615
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