Improved asymmetric synthesis of dopamine D1 full agonist, dihydrexidine, employing chiral ligand-controlled asymmetric conjugate addition of aryllithium to a nitroalkene

Article abstract of DOI:10.1016/j.tet.2004.03.039

Asymmetric conjugate addition of 2-trityloxymethylpheyllithium to a nitroalkene was mediated by a chiral ligand to give the key intermediate for dopamine D1 full agonist dihydrexidine 1. The shortcut of both Curtius rearrangement and Pictet-Spengler type

Full text of DOI:10.1016/j.tet.2004.03.039

Tetrahedron 60 (2004) 4237–4242
Improved asymmetric synthesis of dopamine D1 full agonist,
dihydrexidine, employing chiral ligand-controlled asymmetric
conjugate addition of aryllithium to a nitroalkene
*
Mitsuaki Yamashita, Ken-ichi Yamada and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 23 February 2004; revised 13 March 2004; accepted 15 March 2004
Abstract—Asymmetric conjugate addition of 2-trityloxymethylpheyllithium to a nitroalkene was mediated by a chiral ligand to give the key
intermediate for dopamine D1 full agonist dihydrexidine 1. The shortcut of both Curtius rearrangement and Pictet–Spengler type cyclization,
which were the drawback of the previously reported synthesis involving asymmetric conjugate addition of phenyllithium to an enoate, was
realized by the newly developed asymmetric reaction. Short and efficient synthetic way gave optically pure dihydrexidine in 45% overall
yield via eight steps. Improved synthesis of the best chiral ligand 13 was realized under the Buchwald conditions.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
metric conjugate addition of phenyllithium to a BHA enoate
4 as a key step (Fig. 1). However, the drawbacks of this
synthesis are the Curtius rearrangement of a carboxylic acid
moiety of 3 to an amine functionality of 2 and the following
Pictet–Spengler type cyclization of inactivated phenyl
group for the construction of a requisite arene-fused-
piperidine motif. The shortcut of the Curtius reaction relies
on the conjugate addition of phenyllithium to a nitroalkene 6
instead of an enoate 4 (Fig. 2). Further shortcut is possible
by the conjugate addition of ortho-substituted phenyllithium
to 6 giving 8 and reduction of a nitro group to an amine 7
that avoids tedious procedure for the Pictet–Spengler type
cyclization (Fig. 2). We have already succeeded in the
development of the chiral ligand-controlled asymmetric
ortho-substituted aryllithium addition to 6 and further
Nitrogen-containing heterocyclic compounds are abundant
in nature. Among them chiral arene-fused-piperidine is one
of the representative structural motifs often observed in
biologically active phenanthridine and isoquinoline alka-
loids1,2 as well as artificial pharmaceuticals.3 We have
previously reported the asymmetric synthesis of a phenan-
thridine class of compounds, dihydrexidine 14 being
characterized by dopamine D1 full agonist activity.5 The
synthesis is featured by a chiral ligand-mediated asym-
Figure 1. Asymmetric phenylation of 4, Curtius rearrangement, and
Pictet–Spengler cyclization for the synthesis of (þ)-dihydrexidine 1.
Keywords: Asymmetric synthesis; Alkaloid; Piperidine; Agonist;
Dopamine.
*
Corresponding author. Tel.: þ81757534553; fax: þ81757534604;
Figure 2. Asymmetric arylation of 6, reduction to an amine, and Pictet–
Spengler reaction or alkylation for the short synthesis of 1.
e-mail address: tomioka@pharm.kyoto-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.039

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M. Yamashita et al. / Tetrahedron 60 (2004) 4237–4242
be 22% ee by a chiral stationary phase HPLC. ortho-TMS-
Substituted phenyllithium, prepared from (2-bromophenyl)-
trimethylsilane,15 was not a good nucleophile, giving the
product 5a (R¼TMS) in low chemical yield (entry 2). The
bidentate Box ligand 11 mediated the reaction at 278 8C for
0.5 h to give 5 in 68% yield. However, enantioselectivity
was only 14% ee (entry 4). A tridentate aminodiether ligand
12 was also not a good mediator, giving 5 in 19% ee and
58% yield (entry 5). Fortunately, (2)-sparteine 10 was
found to be the best ligand, at 278 8C for 1 h affording ent-5
in 88% yield and 44% ee (entry 3).
Epimerization of the cis-5 to the requisite trans-5 was easily
carried out by treating a trans:cis 62:38-mixture of ent-5
(entry 3) with triethylamine in acetonitrile at room
temperature for 18 h, giving the trans:cis 86:14-mixture in
98% yield (Fig. 4). Recrystallization of the mixture three
times from methanol gave optically and diastereomerically
pure nitro compound ent-5 in 27% recovery yield. The
following treatment with zinc in 6 N HCl and ethanol at
room temperature for 2.5 h gave the amine ent-2 in 86%
yield. The spectroscopic and analytical data excepting
the sign of specific rotation were identical with those of
2 prepared previously. Thus, the asymmetric synthesis
of (2)-dihydrexidine 1 is possible in 11% overall yield
from 6.
Figure 3. The bidentate and tridentate chiral ligands 9-13.
construction of an arene-fused piperidine motif.6 We
describe herein full detail for the approach toward the
improved synthesis of dihydrexidine 1.
2. Results and discussion
2.1. Chiral ligand-mediated asymmetric conjugate
addition of phenyllithium to a nitroalkene
The first chiral ligand-mediated asymmetric alkyllithium
addition to nitroalkenes was developed by Seebach, giving
the corresponding substituted nitroalkanes in moderate
enantioselectivity.7 The impressive recent successes were
the catalytic asymmetric addition of dialkylzinc8 and
arylboronic acid.9 The sparteine-mediated conjugate
addition of the lithiated N-Boc allylic and benzylic amines
to nitroalkenes was also a great success, which provided an
efficient way to the synthesis of simple piperidines in high
enantioselectivities.10 As a challenge to this end,11,12 we
began our study with examination of a chiral ligand-
mediated asymmetric conjugate addition of phenyllithium
to a cyclic nitroalkene 6.13
The reaction of phenyllithium with 614 in toluene was
examined in the presence of a chiral diether ligand 9 that
gave a nice stereoselection in the reaction of an enoate 4
(Fig. 3). However, the reaction was not smooth at 220 8C
for 0.5 h to give ent-5 as a trans/cis mixture in 33% yield
(Table 1, entry 1). The enantioselectivity was determined to
Figure 4. Synthesis of the key intermediate ent-2.
Table 1. Chiral ligand-mediated asymmetric reaction of a nitroalkene 6 with aryllithium
Entry
Chiral ligand
R
Temperature (8C)
Product 5
Yield (%)
trans/cis
ee (%)
1
2
3
4
5
9
9
10
11
12
H
TMS
H
H
H
220
278
278
278
278
ent-5
5a
ent-5
5
33
10
88
68
58
52:48
49:51
62:38
41:59
71:29
22
27
44
14
19
5
The chiral ligand of 1.4–2.0 equiv./ArLi was used. ee of trans-5. ee of cis isomer is nearly same with that of trans-5.

M. Yamashita et al. / Tetrahedron 60 (2004) 4237–4242
4239
2.2. 2-Trityloxymethylphenyllithium as the key
nucleophile for the efficient asymmetric synthesis of (1)
dihydrexidine (1)
carbonate in refluxing tert-butanol for 1 h provided a fused
piperidine 14 in 86% three step overall yield. Further
demethylation with boron tribromide and hydrochloride
formation completed the total synthesis of (þ)-dihydrexi-
dine 1 in 45% overall yield via 8 steps from a nitroalkene 6.
A straightforward synthetic way toward 1 is the conjugate
addition of 2-hydroxymethylphenyllithium to nitroalkene 6
and subsequent reduction of the nitro group of 8 to an amino
group of 7 and cyclization to construct piperidine motif 1
(Fig. 2). The chiral ligand 12 controlled the asymmetric
addition of 2-trityloxymethylphenyllithium16 to 6 at 295 8C
for 1 h to afford the adduct 8 as a trans/cis mixture in 86%
ee. Subsequent treatment with sodium bicarbonate in
refluxing ethanol for 4 h and following detritylation with
conc. HCl in THF-methanol at room temperature for 18 h
gave 8a (R¼CH2OH) of 86% ee in 86% yield (Fig. 5).
2.3. Improved synthesis of a chiral tridentate
aminodiether ligand (13)
The chiral ligand 13 was prepared in much more
sophisticated way than the previous synthesis12e (Fig. 6).
Treatment of a chiral amino alcohol with 2-iodoanisole
under the Buchwald’s conditions,17 copper(I) iodide,
cesium carbonate in butyronitrile at 125 8C for 1 day,
gave 13 in 82% yield. Production of 13 over 10 g was
possible under the conditions. It is also important to note
that both enantiomers of 13 are available from the
corresponding chiral amino alcohols.
Figure 6. One step synthesis of 13.
3. Conclusion
Improvement of the previously reported synthetic route to
dihydrexidine 1 was realized by employing chiral ligand-
mediated asymmetric conjugate addition of aryllithium to a
nitroalkene 6. Shortcut of both Curtius rearrangement and
Pictet–Spengler type cyclization enabled an efficient and
short step synthesis of optically pure target. The asymmetric
reaction to a nitroalkene becomes the fundamental for the
synthesis of the related candidates of pharmaceuticals.
4. Experimental
4.1. General
1H and 13C NMR spectra were taken in CDC13 unless
otherwise noted. Chemical shift values are expressed in ppm
relative to internal tetramethylsilane. Abbreviations are as
follows: s, singlet; d, doublet; t, triplet; m, multiplet. IR was
expressed in cm21. The extract was dried over Na2SO4
unless otherwise noted. Purification was carried out using
silica gel column chromatography. All reactions were
carried out under an argon atmosphere unless otherwise
stated.
Figure 5. Efficient asymmetric total synthesis of 1.
Much more improvement was possible by the mediation of a
chiral ligand 13 to afford, after epimerization and detrityl-
ation, 8a (R¼CH2OH) of 95% ee in 83% overall yield
(Fig. 5).6 Recrystallization from toluene gave back optically
pure 8a (R¼CH2OH) in 87% yield.
4.1.1. (1S,2S)-6,7-Dimethoxy-2-nitro-1-phenyl-1,2,3,4-
tetrahydronaphthalene (ent-5) (Table 1, entry 3). To a
solution of (2)-sparteine 10 (984 mg, 4.2 mmol) in toluene
(25 mL) was added phenyllithium (1.7 mL, 1.8 M in
cyclohexane-ether, 3.0 mmol) at 278 8C over 1 min. After
0.5 h stirring, nitroalkene 614 (235 mg, 1.0 mmol) in toluene
(5.0 mL) was added over 2 min, and the mixture was stirred
for additional 1 h. The mixture was quenched with MeOH
(2.0 mL) and then satd NH4Cl (30 mL), and extracted with
AcOEt. The extract was washed with 10% HCl, satd
The zinc reduction of a nitro group of 8a in a mixture of
conc. HCl and ethanol at room temperature for 10 min,
chlorination of the resulting alcohol with HCl in refluxing
dioxane for 2.5 h, and then cyclization with potassium

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M. Yamashita et al. / Tetrahedron 60 (2004) 4237–4242
NaHCO3, and brine, and then dried. Concentration and
chromatography (hexane/AcOEt¼10/1) gave a mixture of
62/38 trans- and cis-ent-5 (277 mg, 88% yield) as pale
yellow amorphous of [a]D25¼þ75.3 (c 1.0, CHCl3). The ratio
of the stereoisomers was determined to be (1S,2S)/
(1R,2R)¼72:28 and (1S,2R)/(1R,2S)¼71:29 by a chiral
HPLC analysis (Daicel Chiralcel OD-H, hexane/i-PrOH¼
9/1, 1.0 mL/min, 254 nm, 14.5 min for (1S,2S), 18.6 min
for (1R,2R), 25.2 min for (1R,2S), and 30.1 min for
yield as a 70/30 trans/cis mixture of pale yellow needles of
mp 71–74 8C by using a chiral ligand 13.6
4.1.4. {2-[(1S,2R)-6,7-Dimethoxy-2-nitro-1,2,3,4-tetra-
hydronaphthalen-1-yl]phenyl}methanol (8a). A mixture
of above 8 (289 mg, 0.49 mmol) and NaHCO3 (414 mg,
4.9 mmol) in EtOH (5.0 mL) was heated under reflux for
4 h. The mixture was filtered and the filtrate was concen-
trated to give a 98:2 trans/cis mixture. The solution of the
residue in MeOH (1.9 mL), THF (1.9 mL), and 12 N HCl
(0.6 mL, 7.4 mmol) was stirred at rt for 18 h, and then
diluted with AcOEt. The organic layer was washed with satd
NaHCO3 and brine, and then dried. Concentration and
chromatography (hexane/AcOEt¼4:1) gave 8a (109 mg,
85% yield) as colorless prisms of mp 47–49 8C and
[a]2D5¼2147 (c 0.90, CHCl3) for 95% ee (HPLC: Daicel
Chiralpak AD; hexane/i-PrOH¼4:1, 1.0 mL/min; 254 nm,
major 12.8 min and minor 16.7 min). 1H NMR: 1.89
(1H, brs), 2.41–2.51 (2H, m), 2.94–3.06 (2H, m), 3.58
(3H, s), 3.86 (3H, s), 4.77 (1H, s), 5.08–5.10 (1H, m),
6.20 (1H, s), 6.62 (1H, s), 6.96 (1H, d, J¼6.1 Hz), 7.23–
7.40 (2H, m), 7.42 (1H, d, J¼7.4 Hz). 13C NMR: 26.3,
26.5, 44.6, 55.8, 63.3, 88.5, 110.8, 112.3, 126.7, 127.6,
127.7, 128.6, 129.6, 129.9, 138.8, 140.0, 147.9, 148.0. IR
(neat): 3487, 1547, 1516, 1462, 1404, 1369, 1254. EIMS
m/z: 343 (Mþ), 326, 296, 278, 265. Anal. Calcd for
C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.16;
H, 6.17; N, 3.93.
1
(1S,2R)). H NMR: 2.17–2.21 (0.38H, m, cis), 2.29–2.49
(1.62H, m, trans and cis), 2.90–3.11 (2H, m, trans and cis),
3.61 (1.86H, s, trans), 3.71 (1.14H, s, cis), 3.87 (1.86H, s,
trans), 3.89 (1.14H, s, cis), 4.72 (0.62H, d, J¼7.9 Hz, trans),
4.82 (0.38H, d, J¼5.8 Hz, cis), 4.85–4.88 (0.62H, m, trans),
4.98–5.02 (0.38H, m, cis), 6.24 (0.62H, s, trans), 6.40
(0.38H, s, cis), 6.62 (0.62H, s, trans), 6.66 (0.38H, s, cis),
6.93 (0.76H, dd, J¼3.7, 7.1 Hz, cis), 7.12 (1.24H, d,
J¼7.7 Hz, trans), 7.23–7.33 (3H, m, trans and cis).
A solution of the above mixture of ent-5 (230 mg,
0.74 mmol) and Et3N (0.10 mL, 0.74 mmol) in MeCN
(3.0 mL) was stirred for 18 h at rt. The mixture was
concentrated, and the resulting residue was dissolved in
AcOEt. The solution was washed with 10% HCl, satd
NaHCO3, and brine, and then dried. Concentration gave a
86:14 trans/cis mixture of ent-5 (226 mg, 98% yield), whose
recrystallization 3 times from methanol afforded the
enantiomerically and diastereomerically pure trans-ent-5
(77 mg, 27% yield) as colorless needles of mp 139.5–
140.5 8C and [a]2D5¼þ93.6 (c 1.0, CHCl3). 1H NMR: 2.37–
2.49 (2H, m), 2.92–3.05 (2H, m), 3.61 (3H, s), 3.87 (3H, s),
4.72 (1H, d, J¼8.3 Hz), 4.84–4.88 (1H, m), 6.24 (1H, s),
6.62 (1H, s), 7.11 (2H, d, J¼7.7 Hz), 7.26–7.33 (3H, m).
13C NMR: 26.7, 26.9, 48.8, 55.8, 55.9, 89.8, 110.7, 112.4,
126.7, 127.3, 127.6, 128.9, 129.0, 141.4, 147.8, 148.0. IR
(KBr): 1554, 1512. EIMS m/z: 313 (Mþ), 280, 265, 235,
176, 165, 91. Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11;
N, 4.47. Found: C, 68.91; H, 6.03; N, 4.21.
Recrystallization from toluene afforded the enantiomeric-
ally and diastereomerically pure 8a (77 mg, 87% yield) as
colorless prisms of mp 52–53 8C and [a]2D5¼2154 (c 0.81,
CHCl3) for .99% ee.
4.1.5. (6aR,12bS)-10,11-Dimethoxy-5,6,6a,7,8,12b-hexa-
hydrobenzo[a]phenanthridine (14). A suspension of the
above 8a (31 mg, 0.09 mmol) and Zn (59 mg, 0.90 mmol) in
EtOH (3.0 mL) and 6 N HCl (0.5 mL, 3.0 mmol) was stirred
for 10 min at rt. The mixture was filtered, and the filtrate
was concentrated. A solution of the resulting amine in
1,4-dioxane (1.3 mL) and 12 N HCl (0.8 mL) was heated
under reflux for 2.5 h. Concentration gave the intermediate
chloride, which was immediately dissolved in t-BuOH
(2.5 mL). To the solution was added K2CO3 (500 mg,
3.6 mmol), and the mixture was heated under reflux for 1 h.
The mixture was cooled to rt, poured into water, and
extracted with CHCl3. The organic layer was washed with
brine and dried over K2CO3. Concentration and chroma-
tography (AcOEt/MeOH¼9:1) gave 14 (23 mg, 86% yield)
as colorless prisms of mp 155–156 8C (.99% ee) and
[a]2D5¼2222 (c 1.1, CHCl3). 1H NMR: 1.69–1.75 (2H, m),
2.14–2.21 (1H, m), 2.71 (1H, ddd, J¼6.7, 10.7, 10.7 Hz),
2.78–2.84 (1H, m), 2.90–2.95 (1H, m), 3.77 (3H, s), 3.83
(1H, d, J¼10.7 Hz), 3.88 (3H, s), 4.03 (1H, d, J¼15.6 Hz),
4.11 (1H, d, J¼15.6 Hz), 6.74 (1H, s), 6.91 (1H, s), 7.16
(1H, d, J¼7.4 Hz), 7.21–7.29 (2H, m), 7.47 (1H, d, J¼
7.4 Hz). 13C NMR: 27.4, 28.9, 44.6, 49.1, 56.0, 56.1, 58.8,
110.0, 111.9, 126.0, 126.1, 126.8, 128.5, 130.7, 130.9,
136.1, 137.7, 146.6, 147.1. IR (KBr): 3294, 1504. EIMS
m/z: 295 (Mþ), 278, 263, 165. The hydrochloride: colorless
needles of mp .236 8C (dec) (.99% ee). [a]2D5¼þ123
(c 0.75, EtOH). Anal. Calcd for C19H22ClNO2: C, 68.77; H,
6.68; N, 4.22. Found: C, 68.53; H, 6.69; N, 4.16.
4.1.2. (1S,2S)-6,7-Dimethoxy-1-phenyl-1,2,3,4-tetrahydro-
naphthalen-2-amine (ent-2). To a solution of ent-5 (31 mg,
0.10 mmol) in EtOH (1.0 mL) and 6 N HCl (0.3 mL,
1.8 mmol) was added Zn (65 mg, 1.0 mmol). After stirred
for 2.5 h at rt the mixture was filtered, and the filtrate
was concentrated. The residue was dissolved in CHCl3,
and the solution was washed with satd NaHCO3 and brine,
and then dried. Concentration and recrystallization from
AcOEt gave ent-2 (24 mg, 86% yield) as colorless needles
of mp 101.0–102.5 8C and [a]2D5¼220.6 (c 1.3, CHCl3).
1H NMR: 1.27 (2H, s), 1.73 (1H, m), 2.04 (1H, m), 2.87 (1H,
ddd, J¼4.3, 4.9, 16.5 Hz), 2.97 (1H, ddd, J¼4.9, 5.5,
6.1 Hz), 3.18 (1H, m), 3.58 (3H, s), 3.68 (1H, d, J¼7.9 Hz),
3.86 (3H, s), 6.18 (1H, s), 6.62 (1H, s), 7.16–7.33 (5H,
m). 13C NMR: 27.7, 30.7, 54.5, 55.5, 55.7, 55.8, 110.9,
113.0, 126.6, 128.4, 129.9, 128.5, 130.3, 144.5,
147.2,147.4. IR (KBr): 3400, 3100, 1610, 1510. EIMS
m/z: 283 (Mþ), 266, 251. Anal. Calcd for C18H21NO2·
1/10H2O: C, 75.81; H, 7.49; N, 4.91. Found: C, 75.79; H,
7.43; N, 4.68.
4.1.3. (1S,2S)- and (1S,2R)-6,7-Dimethoxy-2-nitro-1-(2-
trityloxymethylphenyl)-1,2,3,4-tetrahydronaphthalene
(cis- and trans-8). The title compound was prepared in 98%

M. Yamashita et al. / Tetrahedron 60 (2004) 4237–4242
4241
Academic: New York, 1987; Vol. 30, pp 251–376.
(b) Grundon, M. F. Nat. Prod. Rep. 1989, 6, 79–84.
(c) Lewis, J. R. Nat. Prod. Rep. 1995, 12, 339–345.
(d) Hoshino, O. The alkaloids; Cordell, G. A., Ed.; Academic:
San Diego, 1998; Vol. 51, pp 323–424.
The absolute configuration was determined to be (6aR,12bS)
by comparison of the specific rotation with that reported
([a]2D5¼þ106 (c 0.75, EtOH) for .99% ee).18
4.1.6. (6aR,12bS)-10,11-Dihydroxy-5,6,6a,7,8,12b-hexa-
hydrobenzo[a]phenanthridine hydrochloride (1). To a
solution of 14 (20 mg, 0.06 mmol) in CH2Cl2 (3.0 mL) was
added BBr3 (0.3 mL, 1.0 M in hexane, 0.3 mmol) over
10 min at 278 8C, and the mixture was stirred at rt for 12 h.
The mixture was quenched with MeOH (3.0 mL), stirred for
0.5 h, and then concentrated. The residue was dissolved in
water, and the pH was adjusted to 9–10 with NaHCO3
under Ar atmosphere. The mixture was extracted with
CHCl3, and the combined organic layers were dried and
concentrated to give 20 mg of a pale yellow powder. A
solution of the powder in EtOH (1 mL) and EtOH–HCl
(3 mL) was stirrer at rt for 0.5 h and concentrated. The
residue was azeotoropically dried with benzene (3 mL) and
recrystallized from AcOEt/isopropanol to give 1 (15 mg,
73% yield) as pale yellow powder of mp .122 8C (dec) and
[a]2D5¼þ85.5 (c 0.24, EtOH). 1H NMR (DMSO): 1.98 (1H,
m), 2.23 (1H, m), 2.70–2.85 (2H, m), 3.00 (1H, m), 4.22
(1H, d, J¼11.0 Hz), 4.41 (1H, d, J¼15.8 Hz), 4.44 (1H, d,
J¼15.8 Hz), 6.68 (1H, s), 6.78 (1H, s), 7.35–7.50 (4H, m),
8.93 (1H, m), 8.95 (1H, m), 9.67 (1H, s), 9.95 (1H, s). 13C
NMR (DMSO): 25.3, 26.3, 40.3, 43.9, 56.6, 114.6, 115.9,
124.3, 126.3, 126.8, 127.5, 127.7, 127.8, 130.5, 143.2,
144.0. IR (nujol): 3000–3700, 1610, 1510. CIMS m/z:
268 (Mþþ1). HRMS-CI (m/z): [MþH]þ Calcd for
[C17H19NO2]þ, 268.1337. Found, 268.1135.
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4.1.7. (1S,2S)-1-Dimethylamino-2-(2-methoxyphenoxy)-1,
2-diphenylethane (13). A mixture of CuI (7.80 g, 33.3
mmol, 67 mol %), cesium carbonate (41.5 g, 133 mmol),
(1S,2S)-2-(dimethylamino)-1,2-diphenylethanol19 (12.1 g,
50 mmol), and 2-iodoanisole (23.5 g, 100 mmol) in butyro-
nitrile (60 mL) was stirred at 125 8C for 1 day.17 The reac-
tion mixture was cooled to rt and filtered, and the filter cake
was washed well with AcOEt. The combined filtrate and the
washings were extracted with 10% HCl (3£100 mL) and the
acid extracts were cooled at 0 8C for 1 h. The resulting
precipitates were filtered and washed with AcOEt. The
collected precipitates were dissolved in 5 M NaOH (200 mL),
and the solution was extracted with Et2O several times. The
extracts were washed with brine and dried over K2CO3.
Concentration and recrystallization from hexane gave 13
(14.3 g, 82% yield) as colorless needles of mp 72–73 8C.12e
9. (a) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc.
2000, 122, 10716–10717. (b) Hayashi, T. Synlett 2001,
879–887. (c) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003,
103, 2829–2844.
10. Johnson, T. A.; Jang, D. O.; Slafer, B. W.; Curtis, M. D.; Beak,
P. J. Am. Chem. Soc. 2002, 124, 11689–11698.
11. (a) Tomioka, K. Synthesis 1990, 541–549. (b) Tomioka, K.;
Nagaoka, Y. Comprehensive asymmetric catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. III, Chapter 31. (c) Tomioka, K. In Modern carbonyl
chemistry; Otera, J., Ed.; Wiley: Weinheim, 2000; Chapter 12.
(d) Iguchi, M.; Yamada, K.; Tomioka, K. In Organolithiums in
enantioselective synthesis; Hodgson, D. M., Ed.; Springer:
Berlin, 2003; pp 37–59.
12. (a) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc.
1989, 111, 8266–8268. (b) Shindo, M.; Koga, K.; Tomioka,
K. J. Org. Chem. 1998, 63, 9351–9357. (c) Taniyama, D.;
Hasegawa, M.; Tomioka, K. Tetrahedron Lett. 2000, 41,
5533–5536. (d) Tomioka, K.; Shioya, Y.; Nagaoka, Y.;
Yamada, K. J. Org. Chem. 2001, 66, 7051–7054.
(e) Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67,
431–434. (f) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa,
Y.; Taga, T.; Tomioka, K. J. Am. Chem. Soc. 2002, 124,
8932–8939. (g) Doi, H.; Sakai, T.; Iguchi, M.; Yamada, K.;
Tomioka, K. J. Am. Chem. Soc. 2003, 125, 2886–2887.
13. Unfortunately, rhodium-catalyzed phenylation with phenyl-
boronic acid was unsuccessful under Hayashi (Ref. 9) and our
conditions: Kuriyama, M.; Tomioka, K. Tetrahedron Lett.
2001, 42, 921–923, and Ref. 12f.
Acknowledgements
This research was supported by the 21st Century Center of
Excellence Program ‘Knowledge Information Infrastructure
for Genome Science’ and a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-
Element Cyclic Molecules’, from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
References and notes
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