An enantioselective synthesis of (S)- and (R)-curcuphenol

Article abstract of DOI:10.1016/j.tetasy.2005.03.005

The enantioselective synthesis of the phenolic sesquiterenses (S)- and (R)-curcuphenol is reported. The key step in this synthesis is the asymmetric conjugate addition using a readily available enantiomerically pure sulfoxide as the chiral auxiliary.

Full text of DOI:10.1016/j.tetasy.2005.03.005

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1435–1438
An enantioselective synthesis of (S)- and (R)-curcuphenol
a,
Jiangping Lu,a Xingang Xie,a Bo Chen,a Xuegong Shea,b, and Xinfu Pan
*
*
aDepartment of Chemistry, State Key Lab of Applied Organic Chemistry, Lanzhou University, Lanzhou, PRChina
bState Key Lab for Oxo Synthesis and selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PRChina
Received 10 December 2004;revised 3 March 2005;accepted 3 March 2005
Abstract—The enantioselective synthesis of the phenolic sesquiterenses (S)- and (R)-curcuphenol is reported. The key step in this
synthesis is the asymmetric conjugate addition using a readily available enantiomerically pure sulfoxide as the chiral auxiliary.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
LDA followed by treatment of the mixture with excess
sodium hydride and methyl iodide in one pot, afforded
(R)-(+)-3 in 78% yield.9 Acid hydrolysis of (R)-(+)-3
gave (R)-(+)-4 in 95% yield. a-Lithiation followed by
carboxylation and cyclization10 produced enantiomeri-
cally pure (S)-(+)-3-(p-tolylsulfinyl)-7-methyl-2H-chro-
men-2-one 6 in 90% yield.
(S)-(+)-Curcuphenol 1a, which was isolated from the
marine sponges Didiscus flavus, shows potent antifungal
and antitumor activity,1 while the (R)-(ꢀ)-curcuphenol
1b, isolated from the gorgonian coral Pseudopterogorgia
rigida shows antibacterial activity (Fig. 1).2 Due to their
diverse biological activities arise, some methods have
been adapted to synthesize them,3 such as enzymatic
resolution of racemic intermediates,3b bakerÕs yeast
reduction,3d,e sparteine-mediated lateral metallation-
substitution reaction,3f and intramolecular Michael
addition reaction.3g
The key intermediate (S)-(+)-6 was treated with 2 equiv
of MeCuCNMgI at ꢀ78 ꢁC, then sodium-amalgam
reductive cleavage of the carbon–sulfur bond of the
resultant conjugate adduct followed by LiAlH4 reduc-
tion gave the expected (S)-7a in 50% yield (88% ee) over
three steps (Scheme 2). However, in the absence of
CuCN, mixed MeMgI11 and (S)-(+)-6 in THF at
ꢀ78 ꢁC ultimately gave (R)-methyl 7b in 45% yield
(74% ee) over three steps. Iodization of (S)-7a and
(R)-7b afforded (S)-8a (in 98% yield) and (R)-8b (in
96% yield). The coupling of iodides 8a and 8b with Grig-
nard reagent 9 catalyzed by Li2CuCl4 generated curcu-
phenol 1a and 1b in 40% and 41% yield, respectively.
OH
OH
1a: (S)-(+)-curcuphenol
1b: (R)-(-)-curcuphenol
Figure 1.
Herein, we report a new and effective synthetic route to
both 1a and 1b, based on the asymmetric conjugate
addition using an enantiomerically pure sulfoxide as
the chiral auxiliary.4–7
Rationalization of these results involves two different
transition states (Fig. 2).11 Reaction of MeMgI with
(S)-6 at ꢀ78 ꢁC via TS 1 led to the (R)-adduct. However,
when adding cold (S)-6 to MeCuCNMgI at ꢀ78 ꢁC, the
(S)-adduct was obtained probably because a metal ion
chelate was formed first (TS 2).
2. Results and discussion
As shown in Scheme 1, the reaction of aldehyde 2 with
(R)-(+)-methyl p-tolyl sulfoxide8 in the presence of
3. Conclusion
In summary we report a facile route to asymmetric syn-
thesis of 1a and 1b. The advantage of this method is that
using one route can obtain 1a and 1b, respectively.
*
Corresponding authors. Tel.: +86 (0)931 891 2407;fax: +86 (0)931
891 2582;e-mail: shexg@lzu.edu.cn
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.03.005

1436
J. Lu et al. / Tetrahedron: Asymmetry 16 (2005) 1435–1438
H
O
S
OH
OMOM
O
S
O
a
b
OMOM
4
2
3
OH
O
S
O
S
c
d
O
OH
O
O
5
6
Scheme 1. Reagents and conditions: (a) 1.5 equiv LDA, (R)-1-methyl-4-(methylsulfinyl)benzene, THF, ꢀ78 ꢁC, 30 min then excess of NaH and MeI,
rt, 2 h, 78%;(b) 4-methylbenzenesulfonic acid, THF, reflux, 6 h, 95%;(c) 3 equiv LDA, CO 2, THF, ꢀ78 ꢁC;(d) 4-methylbenzenesulfonic acid,
CHCl3, reflux, 20 min, 90% (two steps).
OH
OH
OH
e,g,h
f,g,h
j
j
OH
OH
i
i
I
I
6
6
7a
1a
8a
8b
MgBr
MgBr
9
9
OH
OH
OH
7b
1b
Scheme 2. Reagents and conditions: (e) MeCuCNMgI, THF, ꢀ78 ꢁC;(f) MeMgI, THF, ꢀ78 ꢁC;(g) Na 2HPO4, Na(Hg), MeOH, rt;(h) LiAlH
,
4
THF, rt, 7a (50%, over three steps), 7b (45%, over three steps);(i) PPh 3, C3H4N2, I2, CH2Cl2, rt, 8a (98%), 8b (96%);(j) 9, Li2CuCl4, THF, ꢀ40 to
0 ꢁC, 24 h, 1a (40%), 1b (41%).
60% NaH (0.84 g, 21.00 mmol). The mixture was stirred
for 10 min and then methoxymethyl chloride (1.54 mL,
20 mmol) was added slowly via syringe. The reaction
mixture was stirred for 15 min and used directly in the
next step.
MeCuCNMgI
p-Tol
MeMgI
O
S
S
O
M
p-Tol
O
O
O
O
TS 1
TS 2
To a cold (ꢀ78 ꢁC) 30 mmol THF solution of 1.5 equiv
of LDA, previously formed at 0 ꢁC, was added under
argon 1 equiv of (R)-(+)-methyl p-tolyl sulfoxide
(3.08 g, 20 mmol) in THF (3 mL/mmol). After stirring
for 15 min, the above solution 2 in THF was slowly
added via pressure-equalizing dropping funnel. The
mixture was treated with excess of MeI after warmed
up to room temperature, and then with excess of
NaH. The reaction mixture was quenched after 2 h of
stirring with a saturated NH4Cl solution. The aqueous
phase was extracted with Et2O (3 · 50 mL). The com-
bined organic extracts were washed with a saturated
NaCl solution, dried over anhydrous Na2SO4 and the
solvent evaporated in vacuo. The crude products were
purified by column chromatography using petroleum
Figure 2.
4. Experimental
4.1. General
Melting points were measured on a Kofler apparatus
and are uncorrected. The H and 13C NMR data were
1
recorded in CDCl3 solution with Bruker AM-200 or
AM-300 spectrometer. The chemical shifts are reported
in ppm relative to TMS. Optical rotations were deter-
mined on a JASCO J-20C polarimeter with a 0.2 dm
tube. Mass spectra were measured with an EI (70 eV)
technique. Chiral analysis was performed on Varian
Dynamax SD-300 using (chiralcel) column CDMPC
(150 · 4.6 mm /) with hexane/isopropyl alcohol as elu-
ent. Column chromatographs were generally performed
on silica gel (200–300 mesh) eluting with petroleum
ether/ethyl acetate or chloroform/ethyl acetate.
ether and acetate (4:1, v/v) to afford (R)-3 (4.93 g,
25
D
78%), ½aŠ ¼ þ59 (c 2.56, CHCl3). 1H NMR
(200 MHz, CDCl3): d 2.27 (s, 3H), 2.33 (s, 3H), 3.41
(s, 3H), 5.17 (s, 2H), 6.73 (d, 1H, J = 7.6 Hz), 6.85
(d, 1H, J = 15.8 Hz), 6.91 (s, 1H), 7.27 (d, 3H,
J = 7.6 Hz), 7.53 (d, 2H, J = 7.6 Hz), 7.60 (d, 1H,
J = 15.8 Hz). 13C NMR (50 MHz, CDCl3): d 21.1,
21.4, 56.0, 94.2, 115.1, 120.3, 122.5, 124.5, 128.3,
129.7, 131.9, 132.6, 141.1, 141.5, 155.3. MS (EI): m/z
316 (M+, 1), 300 (3), 268 (23), 255 (4), 223 (13), 195
(6), 163 (5), 139 (6), 132 (19), 123 (12), 91 (7), 77 (9),
4.2. 1-((R)-(E)-2-(p-Tolylsulfinyl)vinyl)-2-(methoxymeth-
oxy)-4-methylbenzene, 3
To a solution of 2-hydroxy-4-methylbenzaldehyde 2
(2.72 g, 20.00 mmol) in dry THF (50 mL) was added

J. Lu et al. / Tetrahedron: Asymmetry 16 (2005) 1435–1438
1437
45 (100). Anal. Calcd for C18H20O3S: C, 68.33;H, 6.37;
S, 10.13. Found: C, 68.21;H, 6.43;S, 10.30.
(d, 2H, J = 7.5 Hz), 8.42 (s, 1H). 13C NMR (75 MHz,
CDCl3): d 21.4, 21.9, 116.1, 116.9, 125.6, 126.3, 128.6,
129.9, 132.7, 139.4, 139.7, 142.5, 144.9, 154.1, 157.0.
MS (EI): m/z 298 (M+, 25), 282 (4), 250 (100), 222
(29), 187 (10), 163 (17), 147 (27), 91 (30), 77 (42), 43
(58). Anal. Calcd for C17H14O3S: C, 68.44;H, 4.73;S,
10.75. Found: C, 68.50;H, 4.80;S, 10.61.
4.3. 2-(R)-(E)-2-(p-Tolylsulfinyl)vinyl-5-methylphenol, 4
To a solution of (R)-3 (4.9 g, 15.5 mmol) in THF
(60 mL) was added 4-methylbenzenesulfonic acid
(3 mmol). The mixture was heated under refluxing for
6 h. After being cooled, the solution was poured into
water (10 mL) and neutralized with Na2CO3 to pH 7–
8. The aqueous phase was extracted with EtOAc
(3 · 40 mL). The combined organic extracts were
washed with a saturated NaCl solution, dried over anhy-
drous Na2SO4, and the solvent was evaporated in vacuo.
The crude products were purified by column chromato-
graphy using CHCl3 and EtOAc (10:1, v/v) to afford
4.6. 2-((S)-4-Hydroxybutan-2-yl)-5-methylphenol, 7a
To a cold (ꢀ78 ꢁC) solution of the organocuprate re-
agent [formed from 2 equiv CuCN and 2 equiv of MeMgI
(1.4 M in THF)] in THF (10 mL) was added dropwise
(S)-6 (0.596 g, 2.0 mmol) in THF (40 mL) under argon
with vigorous stirring. After 30 min at ꢀ78 ꢁC, the reac-
tion mixture was allowed to warm up to room tempera-
ture over 30 min after which time a saturated NH4Cl
solution was added. The aqueous layer was extracted
with ether (3 · 20 mL), and the combined organic ex-
tracts were washed with a saturated solution of Na2S2O3
and brine. After quickly drying over MgSO4 and con-
centration under reduced pressure, the crude conjugate
adduct was used directly in the next step.
(R)-4 (4.0 g, 95%) as a white solid. Mp 172–174 ꢁC,
25
½aŠ ¼ þ187 (c 0.40, CHCl3). 1H NMR (300 MHz,
D
CDCl3): d 2.24 (s, 3H), 2.39 (s, 3H), 6.63 (d, 1H,
J = 7.8 Hz), 6.76 (s, 1H), 7.13 (d, 1H, J = 7.8 Hz), 7.27
(d, 2H, J = 7.5 Hz), 7.40 (s, 2H), 7.57 (d, 2H,
J = 7.5 Hz), 9.18 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 20.7, 116.7, 117.1, 120.0, 124.3, 129.3, 130.2, 130.7,
136.0, 139.6, 140.8, 141.4, 156.2. FAB: M+1, 273.1.
MS (EI): m/z 256 (23), 224 (38), 179 (10), 165 (8), 135
(100), 121 (34), 105 (55), 91 (87), 77 (70), 65 (46), 45
(34), 39 (38). Anal. Calcd for C16H16O2S: C, 70.56;H,
5.92;S, 11.77. Found: C, 70.41;H, 5.80;S, 11.95.
The above crude conjugate adduct was dissolved in
dry MeOH (40 mL), cooled to 0 ꢁC, and treated with
Na2HPO4 (1.99 g, 15.0 mmol) and Na(Hg) (7.73 g,
20.0 mmol). After 2 h of vigorous stirring at 0 ꢁC, the
reaction mixture was quenched with a saturated NH4Cl
solution. The product was extracted into ether, dried
with anhydrous Na2SO4, concentrated under reduced
pressure. The product was used directly in the next step.
4.4. (S)-2-(p-Tolylsulfinyl)-3-(2-hydroxy-4-methylphen-
yl)acrylic acid, 5
To a cold (ꢀ78 ꢁC) 42 mmol THF solution of 3.0 equiv
of LDA, previously formed at 0 ꢁC, was added under
argon 1 equiv of (R)-4 (3.81 g, 14.0 mmol) in THF (5 mL/
mmol). After stirring for 15 min, excess of solid dry ice
was added in portion. The reaction mixture was allowed
to warm up to room temperature over 2 h after which
time water was added. The aqueous layer was acidified
with 6 M HCl pH 2–3 and then extracted with Et2O
(3 · 50 mL). The combined organic extracts were
washed with a saturated NaCl solution, dried over anhy-
drous Na2SO4, and the solvent evaporated in vacuo.
The acid 5 was used directly in the next step.
The above crude product was dissolved in dry THF, and
treated with LiAlH4 (76 mg, 2.0 mmol). The reaction
mixture was stirred at room temperature for 1 h. The
reaction mixture was quenched first with wet diethyl
ether and then with dil. aq HCl. It was then extracted
with diethyl ether (3 · 12 mL) and the combined organic
extracts were washed successively with a saturated solu-
tion of NaHCO3 and NaCl, dried over anhydrous
Na2SO4, and the solvent was evaporated in vacuo. The
crude products were purified by column chromatogra-
phy using petroleum ether and acetate (4:1, v/v) to afford
15
D
(S)-7a (180 mg, 50%) as a colorless oil. ½aŠ ¼ þ23 (c
1
4.5. (S)-(+)-3-(p-Tolylsulfinyl)-7-methyl-2H-chromen-2-
one, 6
1.30, CHCl3, ee 88%). H NMR (300 MHz, CDCl3): d
1.32 (d, 3H, J = 7.2 Hz), 1.49–1.59 (m, 1H), 1.94–2.07
(m, 1H), 2.30 (s, 3H), 3.30–3.42 (m, 2H), 3.65–3.69 (m,
1H), 6.67 (s, 1H), 6.75 (d, 1H, J = 7.8 Hz), 7.06 (d,
1H, J = 7.8). 13C NMR (75 MHz, CDCl3): d 20.9,
26.7, 40.8, 60.7, 116.6, 121.8, 126.5, 128.8, 136.9,
153.6. MS (EI): m/z 180 (M+, 16), 162 (2), 147 (19),
135 (100), 121 (11), 115 (16), 91 (40), 77 (30), 65 (12),
51 (16). Anal. Calcd for C11H16O2: C, 73.30;H, 8.95.
Found: C, 73.41;H, 9.01.
The above crude product was dissolved in CHCl3
(50 mL), and treated with 4-methylbenzenesulfonic acid
(1.0 mmol). The mixture was heated under refluxing for
20 min. After being cooled, the solution was poured into
water (10 mL) and neutralized with Na2CO3. The aque-
ous phase was extracted with CHCl3 (3 · 40 mL). The
combined organic extracts were washed with a saturated
NaCl solution, dried over anhydrous Na2SO4, and the
solvent was evaporated in vacuo. The crude products
were purified by column chromatography using chloro-
4.7. 2-((R)-4-Hydroxybutan-2-yl)-5-methylphenol, 7b
form and ethyl acetate (50:1, v/v) to afford (S)-6 (3.75 g,
Following the above procedure, (R)-7b was obtained
from MeMgI as the conjugate reagent in the absence
22
D
90%) as white solid. Mp 219–220 ꢁC, ½aŠ ¼ þ18 (c 2.00,
1
CHCl3). H NMR (300 MHz, CDCl3): d 2.35 (s, 3H),
2.45 (s, 3H), 7.12 (s, 1H), 7.15 (d, 1H, J = 7.8 Hz),
7.26 (d, 2H, J = 7.5 Hz), 7.52 (d, 1H, J = 7.8 Hz), 7.72
of CuCN. The overall chemical yield over three steps
15
D
was 45%, 162 mg, ee 74%, ½aŠ ¼ ꢀ19 (c 1.32, CHCl3).
1H NMR (300 MHz, CDCl3):
d
1.31 (d, 3H,

1438
J. Lu et al. / Tetrahedron: Asymmetry 16 (2005) 1435–1438
J = 7.2 Hz), 1.48–1.56 (m, 1H), 1.93–2.07 (m, 1H), 2.29
(s, 3H), 3.31–3.42 (m, 2H), 3.62–3.68 (m, 1H), 6.67 (s,
1H), 6.75 (d, 1H, J = 7.8 Hz), 7.06 (d, 1H, J = 7.8).
13C NMR (75 MHz, CDCl3): d 20.9, 26.7, 40.8, 60.7,
116.6, 121.8, 126.4, 128.8, 136.9, 153.6. MS (EI): m/z
180 (M+, 16), 162 (2), 147 (18), 135 (100), 121 (11),
115 (17), 91 (40), 77 (31), 65 (12), 51 (16). Anal. Calcd
for C11H16O2: C, 73.30;H, 8.95. Found: C, 73.47;H,
8.87.
J = 6.9 Hz), 1.50–1.76 (m, 2H), 1.56 (s, 3H), 1.70 (s,
3H), 1.92–1.99 (m, 2H), 2.29 (s, 3H), 2.93–3.05 (m, 1
H), 4.73 (s, 1H), 5.15 (t, 1H, J = 6.9 Hz), 6.60 (s, 1H),
6.74 (d, 1H, J = 7.8 Hz), 7.05 (d, 1H, J = 7.8 Hz). 13C
NMR (75 MHz, CDCl3): d 17.7, 20.9, 21.1, 25.7, 26.0,
31.3, 37.2, 116.1, 121.7, 124.6, 126.8, 129.9, 132.0,
136.5, 152.8. MS (EI): m/z 218 (M+, 16), 203 (1), 175
(1), 161 (7), 148 (32), 135 (100), 121 (21), 107 (5),91
(20), 77 (7), 69 (7), 55 (7), 41(13). Anal. Calcd for
C15H22O: C, 82.52;H, 10.16. Found: C, 82.61;H, 10.10.
4.8. 2-((S)-4-Iodobutan-2-yl)-5-methylphenol, 8a
4.11. (R)-(ꢀ)-Curcuphenol, 1b
Alcohol (S)-7a (180 mg, 2.0 mmol) as a solution in dry
CH2Cl2 (5 mL), was cooled to 0 ꢁC and treated under
argon with PPh3 (629 mg, 2.4 mmol), imidazole
[C3H4N2 (163 mg, 2.4 mmol)], I2 (610 mg, 2.4 mmol).
After 2 h of vigorous stirring at 0 ꢁC, the reaction mix-
ture was quenched with a 2 M Na2S2O3 solution
(5 mL). The product was extracted into ether, dried over
Na2SO4, concentrated under reduced pressure. The lat-
ter was purified by chromatography with petroleum
ether and acetate (95:5, v/v) to afford (S)-8a (284 mg,
Following the above procedure, (R)-1b was obtained
from (R)-8b (240 mg) in 41% chemical yield (74 mg),
15
½aŠ ¼ ꢀ18 (c 2.50, CHCl3) (Lit.1 ent-1b [a]D
=
D
+24.6 2). 1H NMR (300 MHz, CDCl3): d 1.25 (d,
3H, J = 6.9 Hz), 1.49–1.75 (m, 2H), 1.56 (s, 3H), 1.70
(s, 3H), 1.93–1.99 (m, 2H), 2.29 (s, 3H), 2.94–3.06 (m,
1 H), 4.74 (s, 1H), 5.15 (t, 1H, J = 6.9 Hz), 6.60 (s, 1H),
6.74 (d, 1H, J = 7.8 Hz), 7.05 (d, 1H, J = 7.8 Hz). 13C
NMR (75 MHz, CDCl3): d 17.7, 20.9, 21.1, 25.7, 26.1,
31.4, 37.3, 116.1, 121.7, 124.6, 126.8, 129.9, 132.0,
136.5, 152.8. MS (EI): m/z 218 (M+, 16), 203 (1), 175
(1), 161 (7), 148 (32), 135 (100), 121 (21), 107 (5),91
(20), 77 (7), 69 (7), 55 (7), 41(13). Anal. Calcd for
C15H22O: C, 82.52;H, 10.16. Found: C, 82.39;H, 10.00.
15
1
98%) as a colorless oil. ½aŠ ¼ þ36 (c 1.25, CHCl3). H
D
NMR (300 MHz, CDCl3): d 1.26 (d, 3H, J = 7.2 Hz),
2.05–2.25 (m, 2H), 2.28 (s, 3H), 3.04–3.21 (m, 3H),
4.76 (b, 1H), 6.58 (s, 1H), 6.73 (d, 1H, J = 7.8 Hz),
7.03 (d, 1H, J = 7.8 Hz). 13C NMR (75 MHz, CDCl3):
d 5.5, 20.3, 20.9, 33.6, 40.8, 116.4, 121.9, 127.3, 128.0,
137.1, 152.9. MS (EI): m/z 290 (M+, 15), 163 (0.4), 162
(0.4), 147 (4), 135 (100), 121 (8), 107 (6), 91 (19), 77
(8), 65 (3), 51 (3), 39 (5). Anal. Calcd for C11H15OI:
C, 45.54;H, 5.21. Found: C, 45.44;H, 5.09.
Acknowledgements
This work was supported by the Special Doctorial
Program Funds of the Ministry of Education of China
(20040730008), A hundred talents program of CAS,
NSFC (QT program), and SRF for ROCS SEM.
4.9. 2-((R)-4-Iodobutan-2-yl)-5-methylphenol, 8b
Following the above procedure, (R)-8b was obtained
from (R)-7b (162 mg) in 96% chemical yield (251 mg),
References
15
D
½aŠ ¼ ꢀ31 (c 1.50, CHCl3). 1H NMR (300 MHz,
CDCl3): d 1.26 (d, 3H, J = 7.2 Hz), 2.02–2.25 (m, 2H),
2.28 (s, 3H), 3.04–3.20 (m, 3H), 4.67 (b, 1H), 6.58 (s,
1H), 6.73 (d, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 7.8 Hz).
13C NMR (75 MHz, CDCl3): d 5.5, 20.3, 20.9, 33.6,
40.8, 116.4, 121.9, 127.3, 128.0, 137.1, 152.9. MS (EI):
m/z 290 (M+, 15), 163 (0.4), 162 (0.4), 147 (4), 135
(100), 121 (8), 107 (6), 91 (20), 77(8), 65 (3), 51 (3), 39
(5). Anal. Calcd for C11H15OI: C, 45.54;H, 5.21. Found:
C, 45.38;H, 5.34.
1. Wright, A.;Pomponi, S.;McConnel, O. J.;Komoto, S.;
McCarthy, P. J. J. Nat. Prod. 1987, 50, 976–978.
2. McEnroe, F. J.;Fenical, W. Tetrahedron 1978, 34, 1661–
1664.
3. (a) Ghisalberti, E. L.;Jefferies, P. R.;Stuart, A. D. Aust. J.
Chem. 1979, 32, 1627;(b) Ono, M.;Oguta, Y.;Hatogai,
K.;Akita, H. Tetrahedron: Asymmetry 1995, 6, 1829;(c)
Sugahara, T.;Ogasawara, K. Tetrahedron: Asymmetry
1998, 9, 2215–2217;(d) Fuganti, C.;Serra, S. Synlett 1998,
1252;(e) Fuganti, C.;Serra, S.
J. Chem. Soc., Perkin
Trans. 1 2000, 3758–3764;(f) Kimachi, T.;Takemoto, Y.
J. Org. Chem. 2001, 66, 2700;(g) Harmata, M.;Hong, X.;
Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261–7264.
4. Posner, G. H. Acc. Chem. Res. 1987, 20, 72–79.
5. Posner, G. H.;Hulce, M. Tetrahedron Lett. 1984, 25, 379–
382.
6. Posner, G. H.;Kogan, T. P.;Hulce, M. Tetrahedron Lett.
1984, 25, 383–386.
7. Posner, G. H.;Kogan, T. P.;Haines, S. R.;Frye, L. L.
Tetrahedron Lett. 1984, 25, 2627.
4.10. (S)-(+)-Curcuphenol, 1a
Iodide (S)-8a (261 mg, 0.9 mmol) as a solution in dry
THF (2 mL) was cooled to ꢀ40 ꢁC and treated under
argon with Li2CuCl4 (0.18 mmol) and Grignard 9
(3.6 mmol, 0.5 M in THF). The reaction mixture was
allowed to warm to 0 ꢁC and stirred at this temperature
for 24 h. Work-up with a saturated NH4Cl solution,
extraction with diethyl ether, and concentration of the
dried over Na2SO4 organic phase gave the crude
product. This was purified by chromatography with
petroleum ether and acetate (95:5, v/v) to afford
´
8. Solladie, G.;Hutt, J.;Girardin, A. Synthesis 1987, 173.
9. Tsuchihashi, G.;Mitamura, S.;Inoue, S.;Ogura, K.
Tetrahedron Lett. 1973, 4, 323–326.
10. Posner, G. H.;Weitzberg, M.;Hamill, T. G.;Asirvatham,
E.;Cun-Heng, H.;Clardy, J. Tetrahedron 1986, 42, 2919.
11. Posner, G. H.;Mallamo, J. P.;Hulce, M.;Frye, L. L.
J. Am. Chem. Soc. 1982, 104, 4180–4185.
(S)-(+)-curcuphenol 1a (78 mg, 40%) as colorless oil.
15
D
½aŠ ¼ þ21 (c 1.50, CHCl3), (Lit.1 [a]D = +24.6 2).
1H NMR (300 MHz, CDCl3):
d
1.25 (d, 3H,