Facile one-pot procedure for Et3Al-promoted asymmetric pinacol-type rearrangement

Article abstract of DOI:10.1055/s-2003-36266

A facile procedure for the synthesis of enantiomerically pure α-substituted ketones is described. The pinacol-type 1,2-shift of sec-tert 1,2-diols could be effected by performing the following two processes in a one pot procedure, (1) regioselective methanesulfonylation, and (2) direct treatment of the resulting mesylate with Et₃Al. This procedure allowed 1,2-shift reactions of various groups, including vinyl, aryl, and heteroaromatic groups, giving enantiomerically pure ketones in high yields.

Full text of DOI:10.1055/s-2003-36266

FEATURE ARTICLE
141
Facile One-Pot Procedure for Et3Al-Promoted Asymmetric Pinacol-Type
Rearrangement
O
ne-Pot Proced
o
ure for
E
t
A
3 ml-PromotedAsymm
o
etric Pinacol
i
R
c
earrangem
h
ent i Shionhara, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and CREST, Japan Science and Technology Corporation (JST), O-okayama,
Meguro-ku, Tokyo 152-8551, Japan
E-mail: ksuzuki@chem.titech.ac.jp
Received 25 September 2002; revised 4 November 2002
pheromone of an ant species,2a eldanolide,2b and protomy-
Abstract: A facile procedure for the synthesis of enantiomerically
cinolide IV2c (Figure 1).
pure -substituted ketones is described. The pinacol-type 1,2-shift
of sec-tert 1,2-diols could be effected by performing the following
two processes in a one pot procedure, (1) regioselective methane-
O
sulfonylation, and (2) direct treatment of the resulting mesylate with
O
Et3Al. This procedure allowed 1,2-shift reactions of various groups,
including vinyl, aryl, and heteroaromatic groups, giving enantio-
merically pure ketones in high yields.
OH
H
alarm pheromone of ant2a
Key words: -chiral ketone, diols, Lewis acids, rearrangements,
triethylaluminum
O
O
O
O
protomycinolide IV2c
(+)-eldanolide2b
Previously, we reported an enantiospecific access to
-
chiral ketones via Et3Al-promoted stereospecific pinacol-
Figure 1
type 1,2-shift of 1,2-diols (Scheme 1).1
Prior to this work, a two-step protocol was employed as
outlined in Scheme 1. The first step (1 2) was the meth-
anesulfonylation of sec-tert 1,2-diol 1, which proceeded
regioselectively under sulfene generating conditions
(MsCl, Et3N, CH2Cl2, 0 °C).3 After simple extractive
workup to remove triethylamine hydrochloride, drying
and evaporation, the crude mesylate 2 was dissolved in
CH2Cl2 and treated with Et3Al at –78 °C to effect the 1,2-
shift, thereby obtaining chiral ketones 3 in an enantio-
specific manner.
OH
R
OH
R
CH3SO2Cl, Et3N
CH2Cl2
R'
R'
HO
MsO
1
2
R
R'
O
O
Et3Al
R'
AlEt2
O
CH2Cl2
O
S
R
O
3
A
This protocol has been generally satisfactory as long as
the intermediary mesylate 2 is tractable. We have experi-
enced, however, some occasions where mesylate 2 was
extremely unstable. Recognizing that such unstable mesy-
lates share a structural feature that one of the potential mi-
grating groups, R, had a high migratory aptitude, we
reasoned that the instability could be due to the side reac-
tions triggered by minute amounts of CH3SO3H, which
may be formed by neighboring group participation of R.
We recently encountered such a case in the attempted 1,2-
shift of an N-methylindolyl group4 (Scheme 2). When diol
1a was sulfonylated by the above-stated procedure, the
colorless crude mesylate 2a, obtained by extraction–evap-
oration, suddenly changed to a black oil. Although many
by-products were present (TLC assay), we dared to treat
the black material with Et3Al. Not surprisingly, the yield
of 3a was low, but fortunately the enantiomeric purity was
preserved.
Scheme 1
Et3Al is a particularly effective Lewis acid, with the
mechanism proceeding through unstable intermediate A,
activating the mesyloxy leaving group, and also serving as
an acid scavenger. The salient features are, (1) the migra-
tion proceeds stereospecifically with inversion of the pre-
existing sec-alcohol center, (2) among the two potential
migrating groups, the one with higher migratory aptitude
selectively undergoes 1,2-shift, without regard to the
stereochemistry of the tert-alcohol due to the flexibility of
the 7-membered chelate intermediate, and (3) the reaction
conditions are mild enough to allow the preparation of la-
bile ketones, such as , -unsaturated ketones. This reac-
tion has been successfully applied to enantioselective
syntheses of several natural products, including an alarm
Since simple modification of the workup procedure failed
to solve the problem, we endeavoured to carry out the me-
sylation–rearrangement sequence in one pot, despite the
Synthesis 2003, No. 1, Print: 30 12 2002.
Art Id.1437-210X,E;2003,0,01,0141,0146,ftx,en;T10402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

142
T. Shionhara, K. Suzuki
FEATURE ARTICLE
the outcome as summarized in Table 1. When Et3Al was
used roughly stoichiometrically (1.1 equiv relative to the
starting diol 4), the yield of 6 was only 24%. Methyl ke-
tone 7 was obtained as a side product in 31% yield, and
28% yield of unreacted mesylate 5 remained. The yield of
6 increased to 70% when 2 equivalents of Et3Al were
used, although the reaction was still incomplete, and the
same by-products were again obtained. In sharp contrast,
an excellent result was attained when 3 equivalents of
Et3Al were used. The yield of 6 was 86%, and the enan-
tiomeric purity was 99% ee.6
OH
OH
Ph
Ph
CH3SO2Cl, Et3N
HO
MsO
NMe
NMe
CH2Cl2
0 °C, 10 min
1a
2a
O
Ph
Et3Al
NMe
CH2Cl2
–78 → –20 °C
10 min
Table 1 One-Pot conversion of Diol 4 to Ketone 6
OH
OH
MsCl (1.05 equiv)
Et3N (1.1 equiv)
39%
Ph
Ph
Ph
Ph
3a
CH2Cl2
0 °C, 10 min.
Scheme 2
MsO
OH
4
5
O
Ph
OH
Et3Al
Ph
Ph
presence of triethylamine hydrochloride, which may in-
terfere with the Et3Al-mediated 1,2-shift process. We re-
port herein that the one-pot procedure indeed provides a
nice solution to this issue.
+
+
Ph
Ph
conditions
Ph
O
OMs
Entry
Et3Al (equiv)
6 (%)
24
7 (%)
5 (%)
As an initial feasibility study, we examined the one-pot
conversion of diol 45 into ketone 6. Diol 4 was converted
to mesyloxy alcohol 5 by treatment with CH3SO2Cl (1.05
equiv) and Et3N (1.1 equiv) at 0 °C in CH2Cl2. After stir-
ring for 10 min, when completion of the reaction was ver-
ified by silica-gel TLC, the mixture was cooled to –78 °C,
and Et3Al was added. It was found that the desired 1,2-
shift was feasible, but the amount of Et3Al was critical to
1a
2a
3b
1.1
2.0
3.0
31
4
28
5
70
86
–
–
a Reaction was carried out at –78 0 °C for 20 min.
b Reaction was carried out at –78 –20 °C for 10 min.
Biographical Sketches
Tomoichi Shinohara was medicinal chemistry depart- under the direction of Pro-
born in 1965 in Ehime (Ja- ment at Otsuka Pharmaceu- fessor K. Suzuki to study
pan) and obtained his MSc tical Co., Ltd. (Tokushima, new methods for asymmet-
degree in Chemistry in 1990 Japan), and then joined the ric synthesis. Recently, he
at the Ehime University of Doctorate Program for restarted drug discovery re-
Japan. He worked for ten Company Employees at To- search at Otsuka Pharma-
years (1990–1999) in the kyo Institute of Technology ceutical.
Keisuke Suzuki was born Assistant Professor (1986), for Young Chemists, 1986,
in 1954 at Chigasaki, Kana- Associate Professor (1989), Takasago Award of the Syn-
gawa Pref. Japan. He re- and then to Professor (1994) thetic Organic Chemical So-
ceived BSc (1978), MSc at Keio University. In 1996, ciety of Japan (1994), Japan
(1980) and PhD (1983) de- he moved to his present po- IBM Award (1994), Teshi-
grees from the University of sition at Tokyo Institute of ma Award (1996), and
Tokyo under the guidance Technology. He spent a sab- Nagoya
Silver
Medal
of Prof. Teruaki Mukaiya- batical as a visiting Profes- (1999). His research inter-
ma. In 1983 he became a sor at ETH, Zürich, ests lies in the exploitation
Research Associate (with Switzerland (with Prof. Di- of new synthetic methods
the late Prof. Gen-ichi eter Seebach, 1990–1991). for selective synthesis of
Tsuchihashi) at Keio Uni- He received the Japan natural products.
versity. He was promoted to Chemical Society Award
Synthesis 2003, No. 1, 141–146 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Procedure for Et3Al-Promoted Asymmetric Pinacol-Type Rearrangement
143
Having identified the effective protocol for the one-pot the yields obtained by the two-pot procedure are shown in
conversion, we applied it to the aforementioned conver- parentheses in Table 2. Thus, the one-pot procedure en-
sion of diol 1a7 into ketone 3a, and we were pleased to ables the 1,2-shift reactions otherwise difficult due to in-
find that it was indeed effective. By applying exactly the stability of the intermediary mesylates, which is featured
same reaction conditions stated above for diol 1a, the in- by much improved yields by the one-pot procedure in runs
dolyl group underwent smooth 1,2-shift, giving chiral ke- 2 and 3 in comparison with the two-pot procedure.
tone 3a in 85% yield in enantiomerically pure form as
evidenced by the chiral HPLC analysis (Table 2, Entry 1).
The sequence proved to be effective also for other diols8 erally applicable to the 1,2-rearrangement of various
containing other various hetero-aromatics, and the corre- groups such as phenyl group (entry 6) and vinyl group
sponding chiral ketones were obtained in good yields with (entries 7 and 8) to afford chiral ketones, which were pre-
high enantiomeric purities (entries 2–5). For comparison, viously prepared by the two-pot sequence.1
Furthermore, this one-pot procedure is not restricted to the
case where intermediate mesylate was unstable, but gen-
In conclusion, the pinacol-type 1,2-shift of 1,2-diols can
be performed in one pot by consecutive treatment of diols
with methanesulfonyl chloride and triethylamine at 0 °C
followed by Et3Al at –78 °C. The protocol is especially ef-
fective in cases where the diol substrate has a potentially
high migrating group and/or an acid labile substructure,
such as entries 1 and 3 in Table 2.
Table 2 One-Pot Conversion of Various Diols 1 to Ketones 3
OH
OH
CH3SO2Cl, Et3N
Ph
Ph
CH2Cl2
0 °C, 10 min
R
R
HO
MsO
1
2
O
Et3Al
All 1H NMR spectra were taken with JEOL Lambda 400 (400 MHz)
spectrometer using tetramethylsilane as internal standard, and cou-
pling constants were given in Hz. All 13C NMR were taken on the
same instrument at 100 MHz, using the 13C signal of the deuterated
solvent as internal reference for CDCl3 ( = 77.0, central signal).
The signals of the major component of a product mixture are
marked with an asterisk (*). IR spectra were recorded on a Perkin
Elmer 1600 FT-IR spectrometer. Elemental analyses were carried
out using a Perkin Elmer Series II 2400 CHNS/O Analyzer. Optical
rotations were measured on a JASCO DIP-1000 instrument. HPLC
analyses were performed with a JASCO PU-1580 using a JASCO
CD-1595 detector (column, DAICEL CHIRALCEL OD-H,
25 0.46 cm; detection 254 nm light). Silica-gel chromatography
was performed using Merck Silicagel 60.
Ph
–78 → –20 °C
10 min
R
3
Entry
1
R
Product
Yield (%)a % ee
3a
85 (39)
99b
N
Me
2
3b
90 (76)
99b
N
SO2Ph
3
4
3c
96 (21)
90 (89)
99b
99b
OH
Li
O
O
S
Ph
N
9a
Me
PPTS
HO
3d
NMe
Ph
THF
–78 °C, 10 min
EtOH
40 °C, 0.5 h
EEO
8
1a
5
6
3e
3f
93 (90)
92 (86)
>98c
>98d
Scheme 3
S
Preparation of Diols 1 (Scheme 3); Typical Procedure
To a solution of 1-methylindole (0.60 mL, 4.7 mmol) and TMEDA
(0.60 mL, 4.0 mmol) in anhyd Et2O (10 mL) was added BuLi (1.58
M in hexane, 2.5 mL, 4.0 mmol) at –78 °C. After stirring at 0 °C for
30 min, the reaction mixture was cooled to –78 °C, and (S)-2-(1-
ethoxyethoxy)-5-phenylpentan-3-one1a (0.834 g, 3.33 mmol) was
added. After stirring for 10 min, the reaction mixture was poured
into water (20 mL), and the products were extracted with EtOAc (3
20 mL). The combined extracts were washed with brine (20 mL),
dried (MgSO4), and solvents were removed in vacuo. The crude oil,
thus obtained, was dissolved in EtOH (10 mL), to which was added
pyridinium p-toluenesulfonate (167 mg, 0.666 mmol) at r.t. After
stirring for 20 min, the reaction mixture was poured into water (20
mL), and products were extracted with EtOAc (3 20 mL). The
combined organic extracts were washed with brine (20 mL), dried
(MgSO4), and evaporated. The residue was purified by silica-gel
column chromatography (hexane–EtOAc, 10:1 3:1) to give a
7
8
3g
3h
89 (75)
95 (75)
>98d
>98d
Me3Si
a The numbers in parentheses refer to the yields in a two-pot protocol.
b Ee’s were determined by the chiral HPLC analysis (DAICEL
CHIRALCEL OD-H, i-PrOH–n-hexane, 1:9).
c The ee was determined by 1H NMR analysis of the (R)-MTPA9 ester
of the corresponding alcohol, which was prepared by treatment of 3e
with DIBAL.
d Ee’s were determined by comparison with [ ]D values and those re-
ported previously.1a,b See experimental section.
Synthesis 2003, No. 1, 141–146 ISSN 0039-7881 © Thieme Stuttgart · New York

144
T. Shionhara, K. Suzuki
FEATURE ARTICLE
53:47 diastereomeric mixture of diol 1a as a colorless oil (0.920 g,
89%).
13C NMR (CDCl3): = 16.3*, 17.9, 29.8, 29.9*, 39.5*, 41.6, 74.4*,
77.2, 79.1*, 120.5, 121.1*, 122.2, 122.3*, 123.3*, 123.4, 124.1*,
124.0, 124.4*, 125.9*, 128.3*, 128.38, 128.42*, 128.5, 139.6*,
139.8*, 139.9, 142.0*, 124.3, 149.7*.
(2S, 3RS)-3-(1-Methyl-1H-indol-2-yl)-5-phenyl-2,3-pentane-
diol (1a)
Anal. Calcd for C19H20O2S (312.43): C, 73.04; H, 6.45; S, 10.26.
Found: C, 72.74; H, 6.59; S, 10.23.
IR (neat): 3412, 2942, 1466, 751 cm–1.
1H NMR (CDCl3): = 1.12 (1.59 H, d, J = 6.3 Hz), 1.24 (1.41 H, d,
J = 6.3 Hz), 1.91 (0.53 H, d, J = 6.3 Hz), 2.16 (0.47 H, d, J = 2.7
Hz), 2.18–2.39 (2 H, m), 2.47 (0.53 H, s), 2.98 (0.47 H, s), 2.50–
2.74 (2 H, m), 3.96 (1.59 H, s), 4.00 (1.41 H, s), 4.10 (0.53 H, quin-
tet, J = 6.3 Hz), 4.37 (0.47 H, dq, J = 2.7, 6.3 Hz), 6.42 (0.53 H, s),
6.49 (0.47 H, s), 7.09–7.38 (8 H, m), 7.51–7.65 (1 H, m).
13C NMR (CDCl3): = 15.7, 18.0*, 30.2, 30.3*, 32.3, 32.5*, 37.3,
40.3*, 71.2, 73.1*, 77.8*, 78.7, 101.1, 101.4*, 109.2*, 109.3, 119.8,
119.6*, 120.3*, 120.4, 121.4*, 121.8, 125.9*, 126.0, 126.9*, 127.1,
128.2*, 128.3, 128.5*, 138.4*, 138.8, 139.9, 140.2*, 141.7, 142.0*.
1e
Yield: 98%: colorless oil; dr 70:30.
IR (neat): 3430, 2930, 1496, 1452, 1085, 701 cm–1.
1H NMR (CDCl3): = 1.09 (0.9 H, d, J = 6.3 Hz), 1.22 (2.1 H, d,
J = 6.3 Hz), 1.80 (0.3 H, d, J = 6.3 Hz), 1.87 (0.7 H, d, J = 3.8 Hz),
1.97–2.33 (2 H, m), 2.42 (0.7 H, dt, J = 4.6, 12.8 Hz), 2.54 (0.3 H,
dt, J = 4.6, 12.8 Hz), 2.74 (1 H, dt, J = 4.6, 12.8 Hz), 2.87 (0.3 H, s),
2.91 (0.7 H, s), 3.90 (0.3 H, quintet, J = 6.3 Hz), 4.00 (0.7 H, dq,
J = 3.8, 6.3 Hz), 6.92–7.70 (2 H, m), 7.12–7.32 (6 H, m).
Anal. Calcd for C20H23NO2 (309.41): C, 77.64; H, 7.49; N, 4.53.
Found: C, 77.67; H, 7.68; N, 4.30.
13C NMR (CDCl3): = 16.3*, 17.7, 29.8, 29.9*, 39.4*, 41.6, 74.2,
74.6*, 78.97*, 79.02, 123.7, 123.9*, 124.4, 127.7*, 125.8*, 127.0,
127.1*, 128.32*, 128.35, 128.4*, 142.1*, 146.9, 149.0*.
1b
Anal. Calcd for C15H18O2S (262.37): C, 68.67; H, 6.91; S, 12.22.
Found: C, 68.94; H, 6.85; S, 12.26.
Yield: 88%; colorless amorphous solid; dr 69:31.
IR (KBr): 3430, 1630, 1447, 1368, 1174 cm–1.
1H NMR (CDCl3): = 0.93 (2.07 H, d, J = 6.5 Hz), 1.21 (0.93 H, d,
J = 6.3 Hz), 1.65 (0.31 H, d, J = 3.9 Hz), 1.77 (0.69 H, d, J = 6.0
Hz), 2.09–2.43 (3 H, m), 2.49 (0.69 H, s), 2.79 (0.31 H, s), 2.56–
2.70 (1 H, m), 4.12 (0.69 H, dq, J = 6.0, 6.5 Hz), 4.17 (0.31 H, dq,
J = 3.9, 6.3 Hz) 6.93–7.03(2 H, m), 7.10–7.43 (7 H, m), 7.45–7.53
(1 H, m), 7.59 (0.69 H, d, J = 8.2 Hz), 7.70 (0.31 H, d, J = 8.2 Hz),
7.61 (0.69 H, s), 7.63 (0.31 H, s), 7.84–7.91(2 H, m), 8.06 (1 H, d,
J = 8.2 Hz).
13C NMR (CDCl3): = 16.2, 18.1*, 30.0*, 30.1, 37.3, 39.8*, 72.1,
72.8*, 77.6, 77.7*, 114.2, 114.3*, 121.0*, 123.51, 123.54*, 124.7*,
124.8*, 124.9, 125.1, 125.3*, 125.8*, 125.9, 126.6, 126.7*, 128.2,
128.3*, 128.36, 128.39*, 128.5*, 129.12, 129.16*, 133.8*, 133.9,
136.1*, 136.2, 137.8, 138.0*, 141.9, 142.0*.
1f1a
Yield: 87%; colorless oil; dr 70:30.
IR (neat) 3415, 2980, 1497, 1453, 1000, 699cm–1.
1H NMR (CDCl3): = 0.93 (2.1 H, d, J = 6.3 Hz), 1.22 (0.9 H, d,
J = 6.3 Hz), 1.50–2.75 (6 H, m), 3.95 (0.7 H, q, J = 6.3 Hz), 4.02
(0.3 H, q, J = 6.3 Hz), 7.08–7.54 (10 H, m).
13C NMR (CDCl3): = 16.2, 17.9*, 29.8*, 38.4, 40.9*, 74.2*,
78.9*, 79.2, 125.7*, 125.8*, 126.0, 126.8*, 127.2, 128.2*, 128.3*,
128.5, 128.4*, 142.1*, 142.4*.
1g1a
Yield: 92%; colorless oil; single diastereomer.
IR (neat) 3438, 2934, 1496, 1448, 1013, 700 cm–1.
Anal. Calcd for C25H25NO4S (435.55): C, 68.94; H, 5.79; N, 3.22;
S, 7.36. Found: C, 68.96; H, 5.88; N, 3.06; S, 7.59.
1H NMR (CDCl3): = 1.19 (3 H, d, J = 6.3 Hz), 1.71 (1 H, ddd,
J = 4.8, 12.1, 13.5 Hz), 1.94 (1 H, ddd, J = 5.3, 12.1, 13.5 Hz), 2.00
(1 H, br), 2.20 (1 H, br), 2.57 (1 H, ddd, J = 4.8, 13.5, 18.3 Hz), 2.70
(1 H, ddd, J = 5.3, 13.5, 18.3 Hz), 3.68 (1 H, q, J = 6.3 Hz), 5.36 (1
H, dd, J = 1.2, 10.6 Hz), 5.44 (1 H, dd, J = 1.2, 17.4 Hz), 5.89 (1 H,
dd, J = 10.6, 17.4 Hz), 7.14–7.31 (5 H, m).
1c
Yield: 85%; colorless oil; dr 62:38.
IR (neat) 3432, 2936, 1452, 746 cm–1.
1H NMR (CDCl3): = 1.07 (1.86 H, d, J = 6.3 Hz), 1.25 (1.14 H, d,
J = 6.3 Hz), 1.90 (0.38 H, d, J = 3.6 Hz), 1.94 (0.62 H, d, J = 6.3
Hz), 2.13–2.47 (3 H, m), 2.62 (0.62 H, s), 2.83 (0.38 H, s), 2.66–
2.80 (1 H, m), 4.12 (0.62 H, quintet, J = 6.3 Hz), 4.18 (0.38 H, dq,
J = 3.6, 6.3 Hz), 7.03–7.37 (7 H, m), 7.47–7.74 (3 H, m).
13C NMR (CDCl3): = 16.2, 18.1*, 30.1*, 30.2, 37.4, 39.7*, 72.4,
73.1*, 77.2*, 111.9*, 112.0, 120.9*, 122.6*, 122.7*, 122.8, 123.7,
124.3*, 124.5, 125.5, 125.9, 125.6*, 125.8*, 128.3*, 128.4*,
142.06, 142.14*, 143.0*, 143.5, 156.0*, 156.2.
13C NMR (CDCl3): = 16.2, 29.7, 36.7, 72.7, 77.8, 115.8, 125.8,
128.3, 128.4, 141.1, 142.4.
1h1a
Yield: 93%; colorless oil; dr 63:37.
IR (neat) 3442, 2953, 1244, 1030, 838 cm–1.
1H NMR (CDCl3): = 0.19 (5.67 H, s), 0.20 (3.33 H, s), 1.12 (1.89
H, d, J = 6.3 Hz), 1.18 (1.11 H, d, J = 6.5 Hz), 1.77–1.94 (2.37 H,
m), 2.05–2.16 (1.26 H, m), and 2.42–2.74 (2.37 H, m), 3.74 (0.63
H, dq, J = 6.1, 6.3 Hz), 3.84 (0.37 H, dq, J = 3.6, 6.5 Hz), 5.62 (0.63
H, d, J = 1.7 Hz), 5.73 (0.37 H, d, J = 1.7 Hz), 5.66 (0.63 H, d,
J = 1.7 Hz), 5.82 (0.37 H, d, J = 1.7 Hz), 7.11–7.30 (5 H, m).
Anal. Calcd for C19H20O3 (296.37): C, 77.00; H, 6.80. Found: C,
77.15; H, 7.08.
1d
13C NMR (CDCl3): = 0.0*, 0.1, 15.5, 17.5*, 29.7*, 37.4, 41.1*,
72.1, 73.2*, 81.6*, 124.6*, 125.2*, 125.3, 126.1, 127.9*, 128.0*,
142.2*, 142.4, 155.4*, 156.1.
Yield: 88%: colorless oil; dr 71:29.
IR (neat) 3423, 2921, 1456, 1072, 740 cm–1.
1H NMR (CDCl3): = 1.14 (0.87 H, d, J = 6.3 Hz), 1.27 (2.13 H, d,
J = 6.3 Hz), 1.87 (0.29 H, d, J = 6.3 Hz), 1.92 (0.71 H, d, J = 3.4
Hz), 2.02–2.62 (3 H, m), 2.73–2.86 (1 H, m), 2.92 (0.29 H, s), 3.05
(0.71 H, s), 3.95 (0.29 H, quintet, J = 6.3 Hz), 4.09 (0.71 H, dq,
J = 3.4, 6.3 Hz), 7.12–7.42 (8 H, m), 7.76 (1 H, d, J = 7.5 Hz), 7.84
(1 H, d, J = 7.5 Hz).
41b
Yield: 85%; white solid; single diastereomer.
IR (neat) 3448, 2984, 2936, 1492, 1448, 995, 700cm–1.
Synthesis 2003, No. 1, 141–146 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
One-Pot Procedure for Et3Al-Promoted Asymmetric Pinacol-Type Rearrangement
145
1H NMR (CDCl3): = 1.11 (3 H, d, J = 6.3 Hz), 1.83 (1 H, d, J = 3.6
Hz), 2.98 (1 H, s), 4.83 (1 H, dq, J = 3.6, 6.3 Hz), 7.15–7.47 (8 H,
m), 7.61 (2 H, dd, J = 1.5, 8.0 Hz).
13C NMR (CDCl3): = 16.6, 71.6, 79.9, 125.5, 126.2, 126.8, 127.3,
128.1, 128.6, 145.6 (2 C).
3d
The ee was determined to be 99% by the chiral HPLC analysis [i-
PrOH–hexane, 1:9 at 0.7 mL/min; tR (major enantiomer) 9.9 min, tR
(minor enantiomer) 10.7 min].
Yield: 90%; colorless oil; [ ]D24 +65 (c 0.67, CHCl3).
IR (neat): 2932, 1713, 1451, 740 cm–1.
(S)-4-(1-Methyl-1H-indol-2-yl)-1-phenyl-3-pentanone (3a)
To a solution of diol 1a (100 mg, 0.323 mmol) in anhyd CH2Cl2 (2.0
mL) was added Et3N (50 L, 0.36 mmol) and MsCl (26 L, 0.34
mmol) at 0 °C for 10 min. The completion of the reaction was ver-
ified by silica-gel TLC (EtOAc–hexane, 1:1, 2a, Rf 0.55, cf. 1a Rf
0.46), the reaction was cooled to –78 °C, and Et3Al was added (0.93
M in hexane, 1.0 mL, 0.97 mmol). After 10 min, the reaction mix-
ture was poured into aq KHSO4, and the products were extracted
with EtOAc (3 20 mL). The combined extracts were washed with
water (20 mL) and brine (20 mL), dried (MgSO4), and concentrated.
The residue was purified by silica-gel column chromatography
(hexane–EtOAc, 20:1) afforded 3a as a colorless oil (80.0 mg,
85%). The ee was determined to be 99% by chiral HPLC analysis
[i-PrOH–hexane, 1:9 at 0.7 mL/min; tR (the major
enantiomer) = 34.2 min, tR (the minor enantiomer) = 17.1 min];
[ ]D24 –38 (c 0.65, CHCl3).
1H NMR (CDCl3): = 1.51 (3 H, d, J = 7.0 Hz), 2.72–2.94 (4 H, m),
4.02 (1 H, q, J = 7.0 Hz), 7.02 (1 H, s), 7.06–7.38 (7 H, m), 7.67 (1
H, d, J = 7.3 Hz), 7.77 (1 H, dd, J = 0.7, 7.5 Hz).
13C NMR (CDCl3): = 17.8, 29.9, 42.1, 48.7, 121.7, 122.2, 123.3,
124.1, 124.4, 126.1, 128.3, 128.4, 139.4, 139.7, 140.8, 143.7, 208.1.
Anal. Calcd for C19H18OS (294.42): C, 77.51; H, 6.16; S, 10.89.
Found: C, 77.70; H, 6.38; S, 10.64.
3e
The ee was determined to be 99% by 1H NMR analysis as follows.
Ketone 3e was reduced with DIBAL (CH2Cl2, –78 °C, 10 min) to
give a 56:44 mixture of diastereomeric alcohols 10a in 96% yield,
which was converted to the (R)-(+)- -methoxy- -(trifluorometh-
yl)phenylacetic acid9 esters 11a quantitatively (pyridine, r.t., 6 h).
For comparison, the alcohols derived from ( )-ethyl lactate were
converted to the (R)-(+)- -methoxy- -(trifluoromethyl)phenylace-
tic acid esters 11b.
IR (neat): 2931, 1713, 1462, 745 cm–1.
1H NMR (CDCl3): = 1.49 (3 H, d, J = 7.0 Hz), 2.61–2.87 (4 H, m),
3.49 (3 H, s), 3.86 (1 H, q, J = 7.0 Hz), 6.30 (1 H, d, J = 0.8 Hz),
6.98–7.05 (2 H, m), 7.05–7.29 (6 H, m), 7.51–7.59 (1 H, m).
13C NMR (CDCl3): = 15.8, 29.6, 29.7, 40.3, 46.2, 100.0, 109.1,
119.6, 120.3, 121.4, 126.0, 127.6, 128.3, 128.3, 137.7, 138.6, 140.7,
209.0.
Yield: 93%; pale yellow oil; [ ]D19 +85 (c 0.69, CHCl3).
IR (neat): 2981, 1708, 1641, 1452, 696 cm–1.
1H NMR (CDCl3): = 1.45 (3 H, d, J = 7.0 Hz), 2.65–2.95 (4 H, m),
3.98 (1 H, q, J = 7.0 Hz), 6.83 (1 H, d, J = 3.4 Hz), 6.94 (1H, dd,
J = 3.4, 5.1 Hz), 7.06–7.29 (6 H, m).
13C NMR (CDCl3): = 18.1, 29.9, 41.7, 47.9, 124.5, 125.0, 126.0,
127.0, 128.2, 128.3, 140.9, 142.8, 208.4.
Anal. Calcd for C20H21NO (291.40): C, 82.44; H, 7.26; N, 4.81.
Found: C, 82.27; H, 7.54; N, 4.56.
Anal. Calcd for C15H16OS (244.36): C, 73.73; H, 6.60; S, 13.12.
Found: C, 73.64; H, 6.71; S, 12.88.
3b
The ee was determined to be 99% by the chiral HPLC analysis [i-
PrOH–hexane, 1:9 at 0.5 mL/min; tR (major enantiomer) 16.9 min,
tR (minor enantiomer) 18.1 min].
Yield: 90%; colorless oil; [ ]D18 +40 (c 0.64, CHCl3).
10a
IR (neat): 3422, 3030, 2943, 1490, 1452, 1033, 690 cm–1.
1H NMR (CDCl3): = 1.35 (1.32 H, d, J = 7.0 Hz), 1.36 (1.68 H, d,
J = 7.0 Hz), 1.59–1.90 (3 H, m), 2.60–2.75 (1 H, m), 2.79–2.91 (1
H, m), 3.07–3.22 (1 H, m), 3.59–3.68 (0.56 H, m), 3.69–3.78 (0.44
H, m), 6.83–6.90 (1 H, m), 6.93–7.00 (1 H, m), 7.15–7.31 (6 H, m).
IR (neat): 2938, 1714, 1446, 1369, 1169, 746 cm–1.
1H NMR (CDCl3): = 1.45 (3H, d, J = 7.2 Hz), 2.54–2.86 (4 H, m),
3.86 (1 H, q, J = 7.2 Hz), 6.95–7.03 (2H, m), 7.100–7.53 (10 H, m),
7.83 (2 H, d, J = 7.5 Hz), 7.98 (1 H, d, J = 8.5 Hz).
13C NMR (CDCl3): = 16.0, 29.8, 41.4, 44.3, 113.8, 119.7, 122.1,
123.5, 123.6, 125.1, 126.0, 126.6, 128.1, 128.3, 129.2, 129.6, 133.8,
135.4, 138.0, 140.7, 209.2.
11a
IR (neat): 2954, 1741, 1453, 1256, 1169, 1016, 695 cm–1.
1H NMR (CDCl3): = 1.29 (1.32 H, d, J = 7.0 Hz), 1.33 (1.68 H, d,
J = 7.2 Hz) 1.79–1.96 (2 H, m), 2.40–2.71 (2 H, m), 3.35 (0.44 H,
dq, J = 6.8, 7.0 Hz), 3.40–3.56 (3.56 H, m), 5.26–5.40 (1 H, m),
6.70 (0.44 H, d, J = 3.4 Hz), 6.83 (0.56 H, d, J = 3.4 Hz), 6.87 (0.44
H, dd, J = 3.4, 5.1 Hz), 6.92 (0.56 H, dd, J = 3.4, 5.1 Hz), 6.95–7.29
(6 H, m), 7.33–7.58 (5 H, m).
Anal. Calcd for C25H23NO3S (417.53): C, 71.92; H, 5.55; N, 3.35;
S, 7.68. Found: C, 71.94; H, 5.64; N, 3.17; S, 7.79.
3c
The ee was determined to be 99% by the chiral HPLC analysis [i-
PrOH–hexane, 1:9 at 0.7 mL/min; tR (major enantiomer) 10.6 min,
tR (minor enantiomer) 11.3 min].
Yield: 96%; colorless oil; [ ]D25 +86 (c 0.57, CHCl3).
11b
1H NMR (CDCl3): = 1.19 (0.84 H, d, J = 7.2 Hz), 1.29 (0.66 H, d,
J = 7.0 Hz), 1.33 (0.84 H, d, J = 7.2 Hz) 1.36 (0.66 H, d, J = 7.0
Hz), 1.78–1.98 (2 H, m), 2.40–2.72 (2 H, m), 3.31–3.57 (4 H, m),
5.27–5.39 (1 H, m), 6.68–7.58 (13 H, m).
IR (neat): 2978, 1716, 1453, 1103, 747 cm–1.
1H NMR (CDCl3): = 1.47 (3 H, d, J = 7.0 Hz), 2.65–2.92 (4 H, m),
3.87 (1 H, q, J = 7.0 Hz), 7.05 (2 H, d, J = 7.5 Hz), 7.09–7.33 (5 H,
m), 7.40–7.51 (3 H, m).
13C NMR (CDCl3): = 16.0, 29.8, 41.8, 43.2, 111.6, 119.6, 119.8,
122.7, 124.6, 126.0, 126.6, 128.2, 128.4, 140.8, 141.9, 155.4, 209.4.
3f
Yield: 92%; colorless oil; [ ]D +135 (c 1.02, CHCl3) {lit.1a
25
[ ]D29+138 (c 0.42, CHCl3)}.
IR (neat): 2931, 1712, 1495, 1453, 752, 700 cm–1.
1H NMR (CDCl3): = 1.37 (3 H, d, J = 7.0 Hz), 2.58–2.92 (4 H, m),
3.69 (1 H, q, J = 7.0 Hz), 7.01–7.38 (10 H, m).
Anal. Calcd for C19H18O2 (278.35): C, 81.99; H, 6.52. Found: C,
81.80; H, 6.71.
Synthesis 2003, No. 1, 141–146 ISSN 0039-7881 © Thieme Stuttgart · New York

146
T. Shionhara, K. Suzuki
FEATURE ARTICLE
13C NMR (CDCl3): = 17.3, 29.9, 42.5, 53.1, 126.0, 127.1, 127.8,
128.2, 128.3, 128.9, 140.4, 141.0, 209.8.
13C NMR (CDCl3): = 19.5, 47.9, 126.9, 127.7, 128.5, 128.7,
129.0, 132.7, 136.4, 141.4, 200.3.
3g
Yield: 89%; colorless oil; [ ]D26+140 (c 1.16, CHCl3) {lit.1a [ ]D
References
27+135 (c 0.34, CHCl3)}.
(1) (a) Suzuki, K.; Katayama, E.; Tsuchihashi, G. Tetrahedron
Lett. 1983, 24, 4997. (b) Suzuki, K.; Katayama, E.;
IR (neat): 2976, 1716, 1453, 945, 921, 700 cm–1.
Tsuchihashi, G. Tetrahedron Lett. 1984, 25, 1817.
(2) (a) Tsuchihashi, G.; Tomooka, K.; Suzuki, K. Tetrahedron
Lett. 1984, 25, 4253. (b) Suzuki, K.; Ohkuma, T.;
1H NMR (CDCl3): = 1.15 (3 H, d, J = 7.0 Hz), 2.67–2.93 (4 H, m),
3.17 (1 H, dq, J = 8.2, 7.0 Hz), 5.11 (1 H, d, J = 10.0 Hz), 5.13 (1
H, d, J = 17.2 Hz), 5.77 (1 H, ddd, J = 8.2, 10.0, 17.2 Hz), 7.13–7.22
(3 H, m), 7.23–7.32 (2 H, m).
13C NMR (CDCl3): = 15.6, 29.7, 42.3, 51.4, 116.9, 126.0, 128.3,
128.4, 137.3, 141.1, 210.4.
Tsuchihashi, G. Tetrahedron Lett. 1985, 26, 861.
(c) Suzuki, K.; Tomooka, K.; Katayama, E.; Matsumoto, T.;
Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 5221.
(3) King, J. F.; Lee, T. W. S. J. Am. Chem. Soc. 1969, 91, 6524.
(4) Shinohara, T.; Suzuki, K. Tetrahedron Lett. 2002, 43, 6937.
(5) Diol 41a was prepared by the reaction of (S)-ethyl lactate
with phenyllithium at –78 °C as shown in Scheme 4.
3h
25
Yield: 95%; colorless oil; [ ]D +131 (c 1.17, CHCl3) {lit.1b
[ ]D24+131 (c 1.2, CHCl3)}.
IR (neat): 2955, 1712, 1455, 1249, 839, 699 cm–1.
OH
CO2Et
PhLi
Ph
1H NMR (CDCl3): = 0.00 (9 H, s), 1.01 (3 H, d, J = 6.8 Hz), 2.50
(1 H, ddd, J = 6.5, 8.2, 15.2 Hz), 2.58–2.84 (3 H, m), 3.17 (1 H, q,
J = 6.8 Hz), 5.35 (1 H, d, J = 1.4 Hz), 5.42 (1 H, d, J = 1.4 Hz),
7.01–7.09 (3 H, m), 7.11–7.19 (2 H, m).
13C NMR (CDCl3): = –1.4, 17.0, 30.1, 42.7, 51.4, 125.9, 126.9,
128.3, 128.4, 141.2, 151.2, 210.1.
Ph
THF
HO
–78 °C, 5 min
HO
(S)-ethyl lactate
4
Scheme 4
(6) The ee was determined by comparison with the [ ]D value
reported in ref 1a.
6
(7) Diol 1a was readily prepared by introduction of 1-methyl-2-
indolyl group to chiral ketone 8,1a followed by removal of
the ethoxyethyl group as shown in Scheme 3.
(8) Diols 1b–h were also prepared in a similar manner shown in
Scheme 3.
Yield: 85%; colorless oil; [ ]D19+196 (c 1.10, CHCl3) {lit.1a
[ ]D25+200 (c 1.1, CHCl3)}.
IR (neat): 2975, 1682, 1597, 1448, 1220, 952, 758, 689 cm–1.
1H NMR (CDCl3): = 1.53 (3 H, d, J = 6.8 Hz), 4.68 (1 H, q, J = 6.8
Hz), 7.15–7.52 (8 H, m), 7.95 (2 H, d, J = 8.2 Hz).
(9) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
Synthesis 2003, No. 1, 141–146 ISSN 0039-7881 © Thieme Stuttgart · New York