Resolution of nitrogen-centered chiral tetraalkylammonium salts: application to [1,2] Stevens rearrangements with N-to-C chirality transmission

Article abstract of DOI:10.1016/j.tetasy.2009.10.025

The resolution of N-chiral, amino acid-derived quaternary ammonium salts is demonstrated by using chiral BINOL as a complexing agent. Determination of the enantiopurities and absolute configurations of the resolved N-chiral tetraalkylammonium salts are described. The [1,2] Stevens rearrangement of N-chiral ammonium salts is shown to proceed with N-to-C chirality transmission to afford optically active 3-substituted morpholin-2-one derivatives.

Full text of DOI:10.1016/j.tetasy.2009.10.025

Tetrahedron: Asymmetry 20 (2009) 2600–2608
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Resolution of nitrogen-centered chiral tetraalkylammonium salts:
application to [1,2] Stevens rearrangements with N-to-C chirality transmission
*
Eiji Tayama , Seijun Otoyama, Hiroyuki Tanaka
Department of Chemistry, Faculty of Science, Niigata University, Niigata 950-2181, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolution of N-chiral, amino acid-derived quaternary ammonium salts is demonstrated by using chi-
ral BINOL as a complexing agent. Determination of the enantiopurities and absolute configurations of the
resolved N-chiral tetraalkylammonium salts are described. The [1,2] Stevens rearrangement of N-chiral
ammonium salts is shown to proceed with N-to-C chirality transmission to afford optically active
3-substituted morpholin-2-one derivatives.
Received 7 September 2009
Accepted 14 October 2009
Available online 24 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Ph
Ph
1. Introduction
(1) (R)-BINOL
N
N
OH
OH
(2) dissociation
The asymmetric Stevens rearrangement1 of ammonium ylides,
in which chirality is transmitted from a nitrogen to a carbon center,
is a potentially interesting transformation for organic synthesis;
however, preparative methods for nitrogen-centered chiral (N-chi-
ral) tetraalkylammonium salts have been limited. The diastereose-
lective quaternarization of tertiary amines bearing a stereogenic
Br
Br
rac
(S)
97%, 82% ee
Scheme 1. Previously reported resolution of nitrogen-centered chiral tetraalkyl-
ammonium salts.
carbon (e.g., L-proline derivatives) to prepare enantio-enriched
treated with (S)-BINOL (0.50 equiv) at room temperature for 24 h.
Unfortunately, no precipitation was observed, and the resolution of
1a consequently failed (entry 1). However, treatment of its chloride
salt 1b under the same conditions afforded the corresponding 1:1
complex 2b as colorless crystals. The complex 2b was isolated by
filtration in 90% yield, as determined from the amount of (S)-BINOL
(entry 2). Then, complex 2b was dissociated in a mixture of diethyl
ether and water. Following extractive separation and the evapora-
tion of solvent, enantio-enriched 1b was obtained in 84% yield
from the aqueous solution. The enantiomeric excess (ee) of
C- and N-chiral diastereomers is known as a common preparative
method.2 Another method, the resolution of N-chiral tetraalkylam-
monium salts by fractional crystallization, was reported by Pope,3
Jones,4 and Torbeev.5 However, these methods have limited
practical value because they cannot be applied to several types of
N-chiral tetraalkylammonium salts.
Recently, we described the efficient and direct resolution of
racemic, N-centered chiral tetraalkylammonium salts by complex-
ation with (R)-1,10-bi-2-naphthol (BINOL) (Scheme 1).6 Herein, we
report that N-chiral tetraalkylammonium salts resolved by this
method undergo asymmetric [1,2] Stevens rearrangements to
afford optically active rearrangement products via N-to-C chirality
transmission.
resolved 1b was determined to be 89% ee by a comparison of the
23
589
specific rotation {½
aꢀ
¼ þ17:0 (c 1.00, EtOH)} with the highest
23
589
value of specific rotation {½
aꢀ
¼ þ19:1} obtained after three res-
olutions as the standard value (details: see Section 4).
To define the scope and limitations of the present resolution
method, we prepared a series of substrates 1c–1l and carried out
their resolution by complexation with (S)-BINOL (entries 3–12).
Enantio-enriched N-(2-methylbenzyl)ammonium bromide 1c was
obtained in lower yield with excellent selectivity (entry 3, 45%
yield, 94% ee) because the corresponding 1:1 complex 2c proved
somewhat soluble in dichloromethane, however, its chloride salt
1d was obtained in good yield with almost perfect selectivity
(entry 4, 79% yield, 98% ee). N-(2-Methoxybenzyl)- 1e, 1f, and
N-[2-(trifluoromethyl)benzyl]- 1g derivatives were also resolved
by the same general procedure with similar enantioselectivities
2. Results and discussion
First, we attempted the resolution of the N-racemic, amino acid-
derived tetraalkylammonium salt 1, which we hoped to subject to
a base-induced [1,2] Stevens rearrangement (Table 1). A solution of
N-benzyl-N-(tert-butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methylammonium bromide 1a (1.0 equiv) in dichloromethane was
* Corresponding author. Tel./fax: +81 25 262 7741.
E-mail address: tayama@chem.sc.niigata-u.ac.jp (E. Tayama).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.025

E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
2601
Table 1
configuration of 1l was determined as (R) on the nitrogen atom by
a single crystal X-ray diffraction (Fig. 1).7
Resolution of N-centered chiral tetraalkylammonium salt 1 by diastereoselective
complexation with (S)-BINOL
Next, we carried out the [1,2] Stevens rearrangement of the re-
solved N-chiral tetraalkylammonium salt (R)-1c. In preliminary
experiments, we found that the use of potassium tert-butoxide as a
base afforded the rearrangement product in reasonable yields.8
Treatment of (R)-1c (94% ee) with potassium tert-butoxide
(1.0 equiv) in THF at ꢁ20 °C for 6 h gave (S)-4-methyl-3-(2-methyl-
benzyl)morpholin-2-one 4c in 41% yield as the corresponding [1,2]
Stevens rearrangement product (Table 2, entry 1). The non-lacton-
ized derivative 3c could not be detected. The enantiopurity of 4c
was determined to be 48% ee by chiral HPLC analysis; thus, the effi-
ciency of N-to-C chirality transmission from (R)-1c to 4c was 51%
(94% ee to 48% ee). The absolute configuration of 4c was assigned
as (S) by comparison with an (S)-authentic sample.9
HO
HO
(S)-BINOL
CO2R
X
CO2R
(0.50 equiv)
OH
OH
N
N
CH2Cl2
rt, 24 h
X
Ar
rac-1
Ar
1:1 complex 2
HO
CO2R
extraction
Et2O−H2O
N
X
Ar
(R)-1a
Table 2
Asymmetric [1,2] Stevens rearrangement of (R)-1c with N-to-C chirality transmission
Entry
Ar
R
X
Yield (%)b
ee (%)
2
1 (two steps)
1
HO
CO2But
Br
HO
O
N
O
CO2But
1
2
3
4
5
6
7
8
9
Ph
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Me
Br
Cl
Br
Cl
Br
Cl
Br
Br
Cl
Br
Cl
Br
a
b
c
d
e
f
g
h
i
0c
—
—
t-BuOK
90
49
84
76
69
85
84
45
79
72
66
77
—
—
—
—
77
89d
94e
98e
79e
93e
80e
—
(1.0 equiv)
N
N
2-Me–Ph
2-Me–Ph
2-MeO–Ph
2-MeO–Ph
2-CF3–Ph
4-Me–Ph
4-Me–Ph
4-CF3–Ph
4-CF3–Ph
2-Me–Ph
+
solvent
temp, time
0c
3c (0%)
(S)-4c
(R)-1c
0c
0c
0c
—
—
—
94% ee
10
11
12
j
k
l
Entry Solvent
Temp, time (°C, h) Yield of 4ca (%) eeb,c (%)
82
81d (R)f
1
2
3
4
5
THF
ꢁ20, 6
ꢁ20, 6
ꢁ30, 6
ꢁ30, 6
ꢁ40, 15
41
55
57
62
22
48 (51)
52 (55)
55 (59)
60 (64)
67 (71)
a
b
c
Tentatively assigned configuration determined by analogy with (R)-1l.
Isolated yield. Determined from the amount of (S)-BINOL.
Not precipitated.
CH2Cl2–THF (10:1)
CH2Cl2–THF (10:1)
CH3CN–THF (10:1)
CH3CN–THF (10:1)
d
Determined by specific rotation, using the highest specific rotation obtained
after three resolutions as the standard value. The results include ca. 5% errors.
e
a
b
c
Determined by HPLC analysis.
The absolute configuration was determined by a single crystal X-ray diffraction.
Isolated yield.
Determined by HPLC analysis.
The parentheses are the rate of N-to-C chirality transmission.
f
(entries 5–7). The ee of the resolved 1c–1g could be determined by
chiral HPLC analysis (Daicel Chiralcel OD-H column, n-hexane/eth-
anol/trifluoroacetic acid/diethylamine = 95:5:0.1:0.1 as eluent). No
precipitations were observed using 4-substituted tetraalkylammo-
nium salts 1h–1k (entries 8–11). Methyl ester derivative 1l could
also be resolved under the same resolution conditions (entry 12,
77% yield, 81% ee). The yield of 1l was better than the tert-butyl
derivative 1c (entry 3, 45% yield) because the 1:1 complex 2l
proved to be less soluble in dichloromethane than 2c. The absolute
To improve the yield of (S)-4c and the transmission of N-to-C
chirality during the [1,2] Stevens rearrangement, we examined
the reactions of (R)-1c under different conditions. When the reac-
tion was carried out in dichloromethane–THF10 (10:1) as a solvent
at ꢁ20 or ꢁ30 °C, (S)-4c was obtained with better yields and selec-
tivities (entry 2: 55% yield, 52% ee; entry 3: 57% yield, 55% ee). The
use of acetonitrile–THF (10:1) as a solvent afforded (S)-4c with
moderate yield and chirality transmission (entry 4: 62% yield,
60% ee).11 Using the same solvent blend at a lower temperature
(ꢁ40 °C), the rate of N-to-C chirality transmission reached over
70% (entry 5); however, the reaction proceeded very slowly. The
rearrangement product (S)-4c was obtained in only 22% yield,
but with 67% ee (71% N-to-C chirality transmission). Although
the solvent effect is presently unclear, it was reported that the rate
of chirality transmission in the [1,2] Stevens rearrangement is
changeable by a variety of solvents.12
With the optimized conditions in hand (Table 2, entry 4), we
carried out the rearrangement of other N-chiral tetraalkylammo-
nium salts (R)-1 (Table 3). The rearrangement of N-benzyl ammo-
nium chloride (R)-1b (entry 1, >95% ee) gave (S)-4b in lower yield
(39%) with a similar level of N-to-C chirality transmission (56%).
The reaction of (R)-1d, 1e, 1f, or the methyl ester derivative (R)-
1l afforded the corresponding rearrangement products (S)-4 with
similar levels of chirality transmission (entries 2–5, 45–65%),
respectively. The absolute configurations of the rearrangement
products 4 were assigned by analogy with (S)-4c.
While an exact mechanism cannot be advanced at present, it is
safe to say that in the reaction from (R)-1 to (S)-4, the lactonization
Figure 1. Molecular structure of the 1:1 complex 2l (hydrogen atoms are omitted
for clarity).

2602
E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
yield (Scheme 3).14 The non-lactonized derivative 5e was obtained
as the major product without chirality transmission (55%, 11% ee)
along with lactone 6g with moderate chirality transmission (24%,
56% ee).15 The Sommelet–Hauser rearrangement from the corre-
sponding linear ammonium ylide might proceed more smoothly
than lactonization because of the concerted [2,3] sigmatropic
process.
Table 3
Rearrangement of N-chiral tetraalkylammonium salts (R)-1
HO
CO2R2
O
N
O
N
t-BuOK (1.0 equiv)
CH3CN−THF (10:1)
−30 ºC, 6 h
X
R1
R1
HO
CO2But
t-BuOK
(R)-1
(S)-4
(1.0 equiv)
N
3g or 4g
Br
Entry
R1
H
R2
X
ee of (R)-1 (%)
Yielda (%)
eeb,c (%)
CH3CN−THF (10:1)
−30 ºC, 6 h
0%
1
2
3
4
5
t-Bu
t-Bu
t-Bu
t-Bu
Me
Cl
Cl
Br
Cl
Br
b
d
e
f
>95
98
79
93
>95
39
76
52
53
60
56 (56)
44 (45)
50 (63)
49 (53)
65 (65)
CF3
HO
O
N
O
Me
CO2But
OMe
OMe
Me
(R)-1g
(93% ee)
N
l
+
+
a
b
c
Isolated yield.
Determined by HPLC analysis.
The parentheses are the rate of N-to-C chirality transmission.
CF3
CF3
5g
6g
55%, 11% ee
24%, 56% ee
of 1 proceeds first to form the corresponding cyclic ammonium salt
C (Scheme 2). Treatment of (R)-1 with potassium tert-butoxide
affords an equilibrium mixture of alkoxide A and ylide B. The alk-
oxide A is easily lactonized to the corresponding cyclic ammonium
salt C because the ester carbonyl of 1 is activated toward the nucle-
12% N-to-C
60% N-to-C
chirality transmission
chirality transmission
Sommelet−Hauser
Scheme 3. Sommelet–Hauser rearrangement of (R)-1g.
ophilic attack by an
a-electron-withdrawing substituent (ammo-
nium cation). Then, the [1,2] Stevens rearrangement with N-to-C
chirality transmission proceeds via radical cleavage and recombi-
nation to afford the 3-substituted morpholin-2-one (S)-4. If the
rearrangement proceeded without lactonization of A, the product
3 derived by [1,2] rearrangement of linear ammonium ylide B
should be formed; however, any detectable amount of 3 was not
obtained.
3. Conclusion
In conclusion, we have reported the resolution of N-chiral, ami-
no acid-derived quaternary ammonium salts using chiral BINOL as
a complexing agent. The resulting products undergo a [1,2] Stevens
rearrangement with N-to-C chirality transmission to afford the
optically active 3-substituted morpholin-2-one analogues. This
work is likely to stimulate further advances in the rapidly develop-
ing asymmetric chemistry of N-centered chiral molecules.
HO
O
N
OR
X
O
O
N
4. Experimental
4.1. General
Ar
Ar
(R)-1
(S)-4
t-BuOK
Infrared (IR) spectra were recorded on a HITACHI Infrared Spec-
trometer Model 270–30. 1H and 13C NMR spectra were measured
on a JEOL 270 MHz (1H: 270 MHz, 13C: 68 MHz) spectrometer.
Splitting patterns are indicated as follows: s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; br, broad peak. Specific rotations
were recorded on a JASCO Polarimeter P-1010. Elemental analyses
were recorded on a Yanaco CHN Corder MT-3. For thin layer chro-
matography (TLC) analysis throughout this work, Merck TLC plates
(Silica Gel 60F254) were used. The products were purified by pre-
parative column chromatography on silica gel (Silica Gel 60N,
spherical neutral, KANTO Chemical Co., Inc., Japan). (S)-BINOL
was purified by recrystallization from ethanol. A 1.0 M THF solu-
tion of potassium tert-butoxide was purchased from Aldrich, and
fresh bottles were used for as many reactions as possible.
O
O
N
OR
OR
O
N
O
O
N
O
O
O
N
OR
Ar
Ar
(A)
Ar
Ar
(C)
HO
O
N
HO
O
OR
HO
O
N
OR
Ar
N
Ar
(B)
3
Ar
0%
4.2. Resolutions and reactions
Scheme 2. Rearrangement of N-chiral tetraalkylammonium salts (R)-1.
4.2.1. Representative procedure for the resolution of N-chiral
tetraalkylammonium salt 1c
To a solution of 1c (2.13 g, 5.56 mmol) in dichloromethane
(5.6 mL) was added (S)-BINOL (795 mg, 2.78 mmol), and the mix-
ture was stirred for 24 h at room temperature. The precipitate
On the other hand, in the reaction of N-2-(trifluoromethyl)ben-
zyl derivative (R)-1g (93% ee),13 the [1,2] Stevens products 3g and
4g were not obtained. Instead, the Sommelet–Hauser rearrange-
ment proceeded to exclusively afford 5g and 6g in 79% combined

E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
2603
was isolated by filtration and washed with a small amount of the
mother liquid. The solid was dried under reduced pressure to af-
ford the corresponding 1:1 complex 2c as colorless crystals
[901 mg, 49% yield from the amount of (S)-BINOL]. The 1:1 com-
plex 2c (901 mg, 1.36 mmol) was dissolved in small amounts of
methanol, and the solution was transferred to a separatory funnel.
Diethyl ether (ca. 20 mL) and water (ca. 20 mL) were added to the
separatory funnel, and it was shaken at room temperature. The two
phases were then separated. From the diethyl ether solution,
(S)-BINOL was recovered as colorless crystals (369 mg, 95% recov-
ery) after solvent evaporation. From the aqueous solution, wet (R)-
1c was obtained after evaporation. The wet (R)-1c was dissolved in
dichloromethane and dried over sodium sulfate. Evaporation of the
solvent gave (R)-1c as a white solid (480 mg, 45% yield from
racemic 1c). The enantiomeric excess (ee) was determined to be
94% ee by HPLC analysis [Daicel Chiralcel OD-H column,
n-hexane/ethanol/trifluoroacetic acid/diethylamine = 95:5:0.1:0.1
as eluent, flow rate = 0.50 mL/min, tR = 20.9 min for the (S)-1c
and 23.7 min for (R)-1c].
(270 MHz, CDCl3) d 7.63 (2H, d, J = 7.6 Hz, Ph), 7.54–7.39 (3H, m,
Ph), 5.95 (1H, s, OH), 5.30 (1H, d, J = 12.4 Hz, CH2COO), 5.17 (1H,
d, J = 12.4 Hz, CH2COO), 4.65 (1H, d, J = 17.4 Hz, CH2Ph), 4.56 (1H,
d, J = 17.4 Hz, CH2Ph), 4.19 (2H, s, CH2CH2OH), 4.04–3.70 (2H, m,
CH2CH2OH), 3.48 (3H, s, NCH3), 1.48 (9H, s, t-Bu); 13C NMR
(68 MHz, CDCl3) d 164.0, 133.2, 130.6, 129.1, 126.9, 84.8, 66.9,
62.5, 58.8, 55.6, 48.8, 27.8; IR (film) 3204, 2960, 1732, 1628,
1452, 1392, 1368, 1240, 1146, 1086, 882, 834, 700 cmꢁ1; Anal.
Calcd for C16H28ClNO4: C, 57.56; H, 8.45; N, 4.20. Found: C,
57.40; H, 8.16; N, 4.16.
4.2.6. (R)-N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-
N-methyl-N-(2-methylbenzyl)ammonium chloride, 1.5 hydrate
(R)-1d
24
589
White solid; ½
a
ꢀ
¼ þ17:5 (c 1.00, EtOH); 98% ee [determined
by HPLC analysis: Daicel Chiralcel OD-H column, n-hexane/etha-
nol/trifluoroacetic acid/diethylamine = 95:5:0.1:0.1 as eluent, flow
rate = 0.50 mL/min, tR = 28.6 min for the (S)-1d and 32.4 min for
(R)-1d]; 1H NMR (270 MHz, CDCl3) d 7.56 (1H, d, J = 7.6 Hz, Ar-H),
7.44–7.23 (3H, m, Ar-H), 5.93 (1H, br, OH), 5.25 (1H, d,
J = 13.5 Hz, CH2COO), 5.19 (1H, d, J = 13.5 Hz, CH2COO), 4.74 (2H,
s, CH2Ar), 4.30–4.05 (3H, m, CH2CH2OH), 3.77–3.62 (1H, m,
CH2CH2OH), 3.44 (3H, s, NCH3), 2.56 (3H, s, ArCH3), 1.50 (9H, s,
t-Bu); 13C NMR (68 MHz, CDCl3) d 164.3, 140.3, 134.5, 131.9,
130.7, 126.3, 125.5, 84.8, 64.9, 62.3, 59.1, 55.6, 48.5, 27.8, 20.4;
IR (film) 3232, 2964, 1726, 1448, 1368, 1236, 1146, 834,
722 cmꢁ1; Anal. Calcd for C17H31ClNO4.5: C, 57.21; H, 8.76; N,
3.92. Found: C, 57.22; H, 8.63; N, 3.62.
4.2.2. (R)-N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-
N-methyl-N-(2-methylbenzyl)ammonium bromide, 0.5 hydrate
(R)-1c
26
589
White solid; ½
a
ꢀ
¼ þ13:3 (c 1.00, EtOH); 94% ee (determined
by HPLC); 1H NMR (270 MHz, CDCl3) d 7.57 (1H, d, J = 7.3 Hz, Ar-
H), 7.44–7.20 (3H, m, Ar-H), 5.22 (2H, s, CH2COO), 5.09 (1H, br,
OH), 4.62 (1H, d, J = 17.3 Hz, CH2Ar), 4.54 (1H, d, J = 17.3 Hz,
CH2Ar), 4.30–4.04 (3H, m, CH2CH2OH), 3.86–3.68 (1H, m,
CH2CH2OH), 3.43 (3H, s, NCH3), 2.55 (3H, s, ArCH3), 1.51 (9H, s,
t-Bu); 13C NMR (68 MHz, CDCl3) d 164.1, 140.3, 134.5, 131.9,
130.8, 126.4, 125.3, 84.9, 65.0, 62.3, 59.2, 55.5, 48.7, 27.8, 20.5;
IR (film) 3272, 2960, 1734, 1602, 1454, 1392, 1368, 1240, 1148,
1088, 832, 724 cmꢁ1; Anal. Calcd for C17H29BrNO3.5: C, 53.27; H,
7.63; N, 3.65. Found: C, 53.57; H, 7.48; N, 3.59.
4.2.7. (R)-N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-
N-(2-methoxybenzyl)-N-methylammonium bromide, 0.5
hydrate (R)-1e
26
589
White solid; ½
aꢀ
¼ þ4:2 (c 1.00, EtOH); 79% ee [determined by
HPLC analysis: Daicel Chiralcel OD-H column, n-hexane/ethanol/
trifluoroacetic acid/diethylamine = 95:5:0.1:0.1 as eluent, flow
rate = 0.50 mL/min, tR = 17.1 min for the (S)-1e and 22.7 min for
(R)-1e]; 1H NMR (270 MHz, CDCl3) d 7.66 (1H, dd, J = 7.6, 1.8 Hz,
Ar-H), 7.49 (1H, ddd, J = 8.4, 7.6, 1.8 Hz, Ar-H), 7.05 (1H, dd,
J = 7.6, 7.6 Hz, Ar-H), 7.00 (1H, d, J = 8.4 Hz, Ar-H), 5.27–4.93 (1H,
br, OH), 5.14 (1H, d, J = 12.4 Hz, CH2COO), 5.02 (1H, d, J = 12.4 Hz,
CH2COO), 4.51 (1H, d, J = 17.1 Hz, CH2Ar), 4.43 (1H, d, J = 17.1 Hz,
CH2Ar), 4.30–4.13 (2H, m, CH2CH2OH), 4.13–3.99 (1H, m,
CH2CH2OH), 3.99–3.78 (1H, m, CH2CH2OH), 3.89 (3H, s, OCH3),
3.40 (3H, s, NCH3), 1.52 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d
163.8, 158.7, 135.6, 132.8, 121.1, 115.1, 111.6, 84.7, 63.2, 62.3,
59.1, 55.7, 55.6, 49.4, 27.9; IR (film) 3268, 2956, 1734, 1600,
1458, 1392, 1368, 1246, 1148, 1086, 1018, 836, 724 cmꢁ1; Anal.
Calcd for C17H29BrNO4.5: C, 51.13; H, 7.32; N, 3.51. Found: C,
51.20; H, 7.21; N, 3.54.
4.2.3. Resolution of 1b, 1d, 1e, 1f, 1g, and 1l
Resolutions of 1b, 1d, 1e, 1f, 1g, and 1l were carried out using
the procedure described for 1c. The ee for (R)-1b and (R)-1l were
determined by specific rotation, using the highest specific rotations
obtained after three optical resolutions as standard values. These
procedures are described in detail within the next section. The ee
of (R)-1d, (R)-1e, (R)-1f, and (R)-1g were determined by HPLC
analysis.
4.2.4. Determination of the highest specific rotation of (R)-1b
and (R)-1l
The highest specific rotation of (R)-1b was obtained after three
23
589
successive resolutions. Initially resolved (R)-1b {½
a
ꢀ
¼ þ17:0
(c 1.00, EtOH)} was subjected to second and third resolution under
similar conditions [1.0 equiv of (S)-BINOL was used in the second
and third resolutions]. After a second resolution, (R)-1b was
4.2.8. (R)-N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-
N-(2-methoxybenzyl)-N-methylammonium chloride, 1.5
obtained in 78% yield, and the specific rotation value was
24
589
½aꢀ
¼ þ18:9. After a third resolution, (R)-1b was obtained in
hydrate (R)-1f
23
589
23
589
94% yield, and the specific rotation value was ½
aꢀ
¼ þ19:1. This
White solid; ½
a
ꢀ
¼ þ12:6 (c 1.00, EtOH); 93% ee [determined
highest specific rotation value was assigned as an enantiopure
by HPLC analysis: Daicel Chiralcel OD-H column, n-hexane/etha-
nol/trifluoroacetic acid/diethylamine = 96.5:3.5:0.1:0.1 as eluent,
flow rate = 0.50 mL/min, tR = 63.4 min for the (S)-1f and 74.4 min
for (R)-1f]; 1H NMR (270 MHz, CDCl3) d 7.63 (1H, dd, J = 7.6,
1.6 Hz, Ar-H), 7.49 (1H, ddd, J = 8.6, 7.6, 1.6 Hz, Ar-H), 7.06 (1H,
dd, J = 7.6, 7.6 Hz, Ar-H), 7.00 (1H, d, J = 8.6 Hz, Ar-H), 5.12 (1H, d,
J = 12.4 Hz, CH2COO), 4.99 (1H, d, J = 12.4 Hz, CH2COO), 4.54 (1H,
d, J = 17.4 Hz, CH2Ar), 4.46 (1H, d, J = 17.4 Hz, CH2Ar), 4.27–4.11
(2H, m, CH2CH2OH), 4.11–3.97 (1H, m, CH2CH2OH), 3.94–3.73
(1H, m, CH2CH2OH), 3.89 (3H, s, OCH3), 3.39 (3H, s, NCH3), 2.28
(1H, br, OH), 1.52 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d 164.0,
158.7, 135.7, 132.8, 121.2, 115.3, 111.5, 84.6, 63.4, 62.3, 59.1,
(R)-1b. The ee of (R)-1b includes ca. 5% error. The highest specific
rotation of (R)-1l was obtained through largely identical proce-
22
589
dures, with ½
aꢀ
¼ þ8:3 (c 1.00, EtOH) after one resolution,
22
589
24
589
½aꢀ
¼ þ10:1 after a second resolution, and ½
a
ꢀ
¼ þ10:3 after a
third resolution.
4.2.5. (R)-N-Benzyl-N-(tert-butoxycarbonylmethyl)-N-(2-hydro-
xyethyl)-N-methylammonium chloride, monohydrate (R)-1b
23
589
White solid; ½
aꢀ
¼ þ17:0 (c 1.00, EtOH); 89% ee (determined
by specific rotation, using triply-resolved material to give a stan-
dard specific rotation, ½
23
a
ꢀ
¼ þ19:1 with ca. 5% error); 1H NMR
589

2604
E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
55.8, 55.7, 49.4, 27.9; IR (film) 3336, 2968, 1726, 1600, 1440, 1366,
1238, 1146, 1018, 832, 724 cmꢁ1; Anal. Calcd for C17H31ClNO5.5: C,
54.76; H, 8.38; N, 3.76. Found: C, 54.71; H, 8.31; N, 3.48.
solution of potassium tert-butoxide (0.15 mL, 0.15 mmol). The
mixture was stirred for 6 h at the same temperature under an ar-
gon atmosphere. The resulting mixture was added to a stirred,
ice-cold solution of saturated aqueous ammonium chloride, and
the mixture was extracted with ether. The combined extracts were
washed with saturated aqueous sodium hydrogen carbonate and
brine, dried over sodium sulfate, and concentrated. Purification of
the residue by chromatography on silica gel (hexane/ethyl ace-
tate = 1:1 as eluent) gave 4c (20.7 mg, 62% yield) as a colorless
oil. The ee was determined to be 60% ee by HPLC analysis [Daicel
Chiralpak AD-H column, n-hexane/ethanol = 95:5 as eluent, flow
rate = 0.50 mL/min, tR = 20.9 min for the (S)-isomer and 27.6 min
for (R)-isomer].
4.2.9. (R)-N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-
N-methyl-N-[2-(trifluoromethyl)benzyl]ammonium bromide
(R)-1g
25
589
White solid; ½
a
ꢀ
¼ þ6:2 (c 1.00, EtOH); 80% ee [determined by
HPLC analysis: Daicel Chiralcel OD-H column, n-hexane/ethanol/
trifluoroacetic acid/diethylamine = 95:5:0.1:0.1 as eluent, flow
rate = 0.50 mL/min, tR = 17.9 min for the (S)-1g and 21.5 min for
(R)-1g]; 1H NMR (270 MHz, CDCl3) d 8.15 (1H, d, J = 7.6 Hz, Ar-H),
7.84 (1H, d, J = 7.6 Hz, Ar-H), 7.76 (1H, dd, J = 7.6, 7.6 Hz, Ar-H),
7.68 (1H, dd, J = 7.6, 7.6 Hz, Ar-H), 5.51 (1H, d, J = 13.6 Hz,
CH2COO), 5.41 (1H, dd, J = 13.6 Hz, CH2COO), 5.05 (1H, br, OH),
4.85 (1H, d, J = 17.0 Hz, CH2Ar), 4.61 (1H, d, J = 17.0 Hz, CH2Ar),
4.35–4.11 (3H, m, CH2CH2OH), 3.75–3.60 (1H, m, CH2CH2OH),
3.49 (3H, s, NCH3), 1.52 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d
163.3, 136.8, 132.4, 131.2, 131.0 (q, J = 30 Hz), 127.7 (q, J = 5 Hz),
124.6, 123.5 (q, J = 275 Hz), 85.0, 63.4, 63.1, 60.2, 55.3, 49.4, 27.6;
IR (film) 3300, 2960, 1732, 1602, 1580, 1450, 1392, 1368, 1300,
1242, 1146, 1120, 1036, 894, 832, 724 cmꢁ1; Anal. Calcd for
C17H25BrF3NO3: C, 47.67; H, 5.88; N, 3.27. Found: C, 47.69; H,
6.09; N, 3.22.
4.2.13. (S)-4-Methyl-3-(2-methylbenzyl)morpholin-2-one (S)-4c
and (S)-4l
22
589
Colorless oil; ½
aꢀ
¼ þ4:0 (c 1.00, EtOH); 60% ee (determined
by HPLC); 1H NMR (270 MHz, CDCl3) d 7.34–7.08 (4H, m, Ar-H),
4.23 (1H, ddd, J = 10.9, 3.0, 3.0 Hz, 6-H), 4.11 (1H, ddd, J = 10.9,
10.2, 3.0 Hz, 6-H), 3.45 (1H, dd, J = 5.8, 4.9 Hz, 3-H), 3.22 (1H, dd,
J = 14.5, 4.9 Hz, CH2Ar), 3.14 (1H, dd, J = 14.5, 5.8 Hz, CH2Ar), 2.89
(1H, ddd, J = 12.9, 3.0, 3.0 Hz, 5-H), 2.64 (1H, ddd, J = 12.9, 10.2,
3.0 Hz, 5-H), 2.37 (3H, s, NCH3 or ArCH3), 2.31 (3H, s, NCH3 or
ArCH3); 13C NMR (68 MHz, CDCl3) d 170.5, 136.9, 136.1, 130.11,
130.07, 126.5, 125.6, 67.22, 67.16, 50.3, 43.5, 34.5, 19.8; IR (film)
2940, 2848, 2788, 1726, 1488, 1452, 1402, 1368, 1334, 1288,
1184, 1146, 1056, 932, 740 cmꢁ1; Anal. Calcd for C13H17NO2: C,
71.21; H, 7.81; N, 6.39. Found: C, 71.12; H, 7.84; N, 6.46.
4.2.10. (R)-N-(2-Hydroxyethyl)-N-(methoxycarbonylmethyl)-N-
methyl-N-(2-methylbenzyl)ammonium bromide, 0.5 hydrate
(R)-1l
22
589
White solid; 8:2 mixture of rotamers; ½
a
ꢀ
¼ þ8:3 (c 1.00,
EtOH); 81% ee (determined by specific rotation, using triply-re-
solved material to give a standard specific rotation with ca. 5% er-
ror); 1H NMR (270 MHz, CDCl3) d 7.74 (0.2H, d, J = 7.4 Hz, Ar-H),
7.58 (0.8H, d, J = 7.4 Hz, Ar-H), 7.45–7.23 (3H, m, Ar-H), 5.52
(0.2H, d, J = 13.1 Hz, CH2COO), 5.44 (0.2H, d, J = 13.1 Hz, CH2COO),
5.26 (1.6H, s, CH2COO), 5.14 (0.8H, d, J = 17.4 Hz, CH2Ar), 5.03
(0.8H, d, J = 17.4 Hz, CH2Ar), 4.97–4.49 (1.4H, m, CH2Ar and OH),
4.42–4.03 (3H, m, CH2CH2OH), 3.79 (3H, s, OCH3 or NCH3), 3.69–
3.55 (1H, m, CH2CH2OH), 3.52 (0.6H, s, OCH3 or NCH3), 3.46
(2.4H, s, OCH3 or NCH3), 2.63 (0.6H, s, ArCH3), 2.56 (2.4H, s, ArCH3);
13C NMR (68 MHz, CDCl3) d 165.2 (0.8C), 160.4 (0.2C), 140.0 (0.2C),
139.9 (0.8C), 134.3 (0.2C), 134.1 (0.8C), 131.6 (0.2C), 131.5 (0.8C),
130.8 (0.2C), 130.5 (0.8C), 126.2 (0.2C), 126.1 (0.8C), 124.8 (0.8C),
123.8 (0.2C), 66.0 (0.2C), 64.8 (0.8C), 62.4 (0.2C), 61.5 (0.8C), 58.9
(0.8C), 58.5 (0.2C), 54.9 (1.0C), 53.7 (0.2C), 52.6 (0.8C), 48.1
(0.8C), 47.4 (0.2C), 20.2 (0.2C), 20.1 (0.8C); IR (film) 3280, 2948,
1742, 1602, 1438, 1262, 1222, 1086, 1000, 886, 722 cmꢁ1; Anal.
Calcd for C14H23BrNO3.5: C, 49.28; H, 6.79; N, 4.10. Found: C,
49.12; H, 6.56; N, 4.04.
4.2.14. (S)-3-Benzyl-4-methylmorpholin-2-one (S)-4b
25
589
Colorless oil; ½
a
ꢀ
¼ þ6:1 (c 1.00, EtOH); 56% ee [determined
by HPLC analysis: Daicel Chiralpak AD–H column, n-hexane/etha-
nol = 95:5 as eluent, flow rate = 0.50 mL/min, tR = 20.4 min for the
(S)-4b and 28.4 min for (R)-4b]; 1H NMR (270 MHz, CDCl3) d
7.35–7.17 (5H, m, Ph), 4.13 (1H, ddd, J = 10.8, 2.7, 2.7 Hz, 6-H),
3.96 (1H, ddd, J = 10.8, 10.8, 2.7 Hz, 6-H), 3.38 (1H, dd, J = 4.6,
4.3 Hz, 3-H), 3.26 (1H, dd, J = 14.3, 4.3 Hz, CH2Ph), 3.13 (1H, dd,
J = 14.3, 4.6 Hz, CH2Ph), 2.82 (1H, ddd, J = 12.6, 2.7, 2.7 Hz, 5-H),
2.63 (1H, ddd, J = 12.6, 10.8, 2.7 Hz, 5-H), 2.42 (3H, s, NCH3); 13C
NMR (68 MHz, CDCl3) d 170.1, 137.4, 129.9, 128.0, 126.5, 68.0,
67.4, 50.6, 43.1, 36.4; IR (film) 3020, 2944, 2844, 2788, 1726,
1600, 1490, 1450, 1402, 1368, 1334, 1290, 1180, 1144, 1056,
934, 746, 696 cmꢁ1; Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37;
N, 6.82. Found: C, 69.92; H, 7.31; N, 6.79.
4.2.15. (S)-3-(2-Methoxybenzyl)-4-methylmorpholin-2-one (S)-
4e and (S)-4f
25
589
Colorless oil; ½
a
ꢀ
¼ þ12:0 (c 1.00, EtOH); 50% ee [determined
by HPLC analysis: Daicel Chiralpak AD–H column, n-hexane/etha-
nol = 95:5 as eluent, flow rate = 0.50 mL/min, tR = 25.8 min for the
(S)-isomer and 31.0 min for (R)-isomer]; 1H NMR (270 MHz, CDCl3)
d 7.28–7.16 (2H, m, Ar-H), 6.93–6.81 (2H, m, Ar-H), 4.30–4.15 (2H,
m, 6-H), 3.81 (3H, s, OCH3), 3.41–3.24 (2H, m, 3-H and CH2Ar), 3.18
(1H, dd, J = 14.2, 6.6 Hz, CH2Ar), 2.83 (1H, ddd, J = 12.8, 3.0, 3.0 Hz,
5-H), 2.61 (1H, ddd, J = 12.8, 8.4, 5.0 Hz, 5-H), 2.33 (3H, s, NCH3);
13C NMR (68 MHz, CDCl3) d 170.6, 157.7, 131.0, 127.7, 126.2,
120.2, 110.0, 67.3, 66.3, 54.8, 50.5, 43.1, 31.9; IR (film) 2940,
2828, 2784, 1722, 1598, 1584, 1488, 1452, 1402, 1334, 1290,
1238, 1182, 1146, 1110, 1026, 932, 804, 746 cmꢁ1; Anal. Calcd
for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C, 66.15; H,
7.41; N, 5.92.
4.2.11. Determination of the absolute configuration of 1l
The absolute configuration of 1l was determined as (R) on the
nitrogen atom by a single crystal X-ray diffraction of a 1:1 complex
2l (Fig. 1). Recrystallization of 2l from methanol–diethyl ether gave
a single crystal which was suitable for crystallographic analysis.7
Crystal data of 2l: C34H36BrNO5, MW = 618.57; monoclinic; space
group P21 (#4); a = 9.1803(2) Å, b = 13.3010(4) Å, c = 12.6018(4) Å,
b = 101.267(2)°; V = 1509.11(8) Å3; Z = 2; Dcalcd = 1.361 g/cm3;
l
= 14.08 cmꢁ1; 2hmax = 60.1°; T = 296 K; R1 (I > 2
r(I)) = 0.045; wR2
(all data) = 0.102; GOF = 1.16 for 8210 reflections and 370 parame-
ters. The absolute structure was determined based on Flack param-
eter, 0.001(7), refined using 3823 Friedel pairs.
4.2.12. Representative procedure for the rearrangement of N-
chiral tetraalkylammonium salt (R)-1c
A solution of (R)-1c (58.6 mg, 0.153 mmol, 94% ee) in acetoni-
trile (1.5 mL) was cooled to ꢁ30 °C and treated with a 1.0 M THF
4.2.16. 2-[N-(2-Hydroxyethyl)-N-methylamino]-2-[2-methyl-3-
(trifluoromethyl)phenyl]acetic acid tert-butyl ester 5g
23
589
Colorless oil; ½
aꢀ
¼ þ5:8 (c 1.00, EtOH); 11% ee [determined by
HPLC analysis: Daicel Chiralpak AD-H column, n-hexane/isopropanol =

E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
2605
99.5:0.5 as eluent, flow rate = 0.50 mL/min, tR = 39.3 min for the
minor isomer and 46.0 min for the major isomer]; 1H NMR
(270 MHz, CDCl3) d 7.62 (1H, d, J = 7.6 Hz, Ar-H), 7.61 (1H, d,
J = 7.6 Hz, Ar-H), 7.29 (1H, dd, J = 7.6, 7.6 Hz, Ar-H), 4.53 (1H, s, NCH-
COO), 3.68–3.46 (2H, br, NCH2CH2OH), 2.84–2.58 (3H, m, NCH2CH2OH),
2.52 (3H, s, NCH3 or ArCH3), 2.30 (3H, s, NCH3 or ArCH3), 1.41 (9H, s, t-
Bu); 13C NMR (68 MHz, CDCl3) d 171.0, 137.4, 136.1, 131.7, 129.7 (q,
J = 29 Hz), 125.6, 125.5 (q, J = 5 Hz), 124.4 (q, J = 274 Hz), 81.9, 68.8,
58.7, 55.6, 38.3, 27.8, 14.7; IR (film) 3436, 2964, 2872, 2796, 1722,
1588, 1450, 1390, 1366, 1308, 1248, 1204, 1120, 1022, 946, 784,
722 cmꢁ1; Anal. Calcd for C17H24F3NO3: C, 58.78; H, 6.96; N, 4.03.
Found: C, 59.05; H, 6.93; N, 4.00.
(44 lL, 0.38 mmol) were added to the solution at 0 °C. After stirring
for 2 h at room temperature, the resulting mixture was quenched
with saturated aqueous ammonium chloride and extracted with
ethyl acetate. The combined extracts were washed with saturated
aqueous sodium hydrogen carbonate and brine, dried over sodium
sulfate and concentrated. The residue was purified by chromatog-
raphy on silica gel (hexane/ethyl acetate = 5:1 as eluent) to
afford N-(2-benzoyloxyethyl)-N-[2-benzoyloxy-1-(2-methylben-
zyl)]ethylmethylamine 7 (54 mg, 66% yield) as a colorless oil. The
ee was determined to be 60% ee by chiral HPLC analysis [Daicel
Chiralcel OD-H, hexane/isopropanol = 90:10, 0.50 mL/min, tR =
15.1 min for the (S)-isomer and 18.3 min for the (R)-isomer]. The
absolute configuration of 7 thus obtained was determined to be
(S) by comparison with the (S)-authentic sample (S)-7.
4.2.17. N-(2-Hydroxyethyl)-N-methyl-3-[2-(trifluoromethyl)-
phenyl]morpholin-2-one 6g
23
589
Colorless oil; ½
aꢀ
¼ þ42:3 (c 1.00, EtOH); 56% ee [determined
4.2.18.2. Preparation of the authentic sample of (S)-7. (Step 1)
To a mixture of tert-butyl 2-(diphenylmethyleneamino)acetate
(89 mg, 0.30 mmol), 2-methylbenzyl bromide (48 lL, 0.36 mmol),
by HPLC analysis: Daicel Chiralpak AS-H column, n-hexane/etha-
nol = 90:10 as eluent, flow rate = 0.50 mL/min, tR = 14.3 min for
the minor isomer and 16.5 min for the major isomer]; 1H NMR
(270 MHz, CDCl3) d 7.62 (1H, d, J = 7.8 Hz, Ar-H), 7.56 (1H, d,
J = 7.8 Hz, Ar-H), 7.28 (1H, dd, J = 7.8, 7.8 Hz, Ar-H), 4.70 (1H, ddd,
J = 11.9, 11.0, 3.2 Hz, 6-H), 4.45 (1H, ddd, J = 11.0, 3.2, 1.4 Hz,
6-H), 4.13 (1H, s, 3-H), 3.03 (1H, ddd, J = 12.8, 3.2, 1.4 Hz, 5-H),
2.78 (1H, ddd, J = 12.8, 11.9, 3.2 Hz, 5-H), 2.53 (3H, s, NCH3), 2.13
(3H, s, ArCH3); 13C NMR (68 MHz, CDCl3) d 167.9, 137.9, 136.3,
133.6, 130.0 (q, J = 29 Hz), 126.0 (q, J = 5 Hz), 125.7, 124.5 (q,
J = 275 Hz), 70.5, 68.2, 51.4, 43.5, 15.3; IR (film) 2948, 2900,
2840, 2792, 2708, 1722, 1636, 1586, 1450, 1404, 1366, 1306,
(R,R)-bis(2-naphthyl)-NAS bromide (Maruoka catalyst)16 (5 mg,
0.006 mmol) in toluene (1.5 mL) was added 50 wt % potassium
hydroxide aqueous solution (1 mL) at 0 °C under an air atmosphere.
The mixture was stirred for 1 h at the same temperature and
quenched with saturated aqueous ammonium chloride. The mixture
was extracted with ethyl acetate and the combined extracts were
washed with brine, dried over sodium sulfate, and concentrated.
The residue was purified by chromatography on silica gel (hexane/
ethyl acetate = 7:1–5:1 as eluent) to obtain (S)-tert-butyl 2-(diphe-
nylmethyleneamino)-3-(2-methylphenyl)propanoate (S)-8 (112
mg, 93% yield) as a colorless oil. The ee was determined to be 94%
ee by chiral HPLC analysis [Daicel Chiralcel OD-H, hexane/etha-
nol = 99.5:0.5, 0.50 mL/min, tR = 12.2 min for the (R)-isomer and
15.4 min for the (S)-isomer]. The absolute configuration was
assigned as (S) by analogy with the previous examples of (R,R)-
bis(2-naphthyl)-NAS bromide-catalyzed asymmetric alkylation of
Schiff-base protected glycine tert-butyl ester. (Step 2) A solution of
(S)-8 (163 mg, 0.41 mmol) in THF (2 mL) was treated with a
10 wt % citric acid aqueous solution (2 mL) and stirred for 2 h at
room temperature. The resulting mixture was diluted with diethyl
ether and extracted with a 10 wt % citric acid aqueous solution
(two times). The combined aqueous extracts were treated with a
15 wt % sodium hydroxide aqueous solution and extracted with
diethyl ether (three times). The combined ethereal extracts were
washed with brine, dried over sodium sulfate, and concentrated.
The residual oil was dissolved in methanol (1 ml) and treated with
1104, 1024, 928, 884, 840, 794, 724 cmꢁ1
C13H14F3NO2: C, 57.14; H, 5.16; N, 5.13. Found: C, 57.30; H, 5.21;
N, 5.00.
; Anal. Calcd for
4.2.18. Determination of the absolute configuration of [1,2]
Stevens rearrangement product 4
The (S)-configuration of 4 was assigned as follows. The [1,2] Ste-
vens rearrangement product 4c was converted to the corresponding
dibenzoyl derivative 7; this compound was then chromatographi-
cally correlated with the (S)-authentic sample (S)-7. Compound
(S)-7 was prepared from Schiff-base protected glycine tert-butyl
ester via phase-transfer catalyzed asymmetric alkylation using (R,
R)-bis(2-naphthyl)-NAS bromide (Maruoka catalyst).16 The config-
urations of 4b, 4d, 4e, 4f, and 4l were determined by analogy
with 4c.
diisopropylethylamine (61
lL, 0.35 mmol) and methyl bromoace-
LiAlH4
BzCl
4c
BzO
OBz
Ar
tate (30 L, 0.32 mmol) at room temperature. After stirring for 4 h
l
(Ar = 2-Me-Ph)
at the same temperature, the resulting mixture was diluted with sat-
urated aqueous sodium hydrogen carbonate. The mixture was ex-
tracted with diethyl ether and the combined extracts were washed
with brine. The organic layer was dried over sodium sulfate and
evaporated. The residue was purified by chromatography on silica
gel (hexane/ethyl acetate = 2:1–1:1 as eluent) to obtain tert-butyl
2-(2-methoxy-2-oxoethylamino)-3-(2-methylphenyl)propanoate
10 (41 mg, 42% yield) as a colorless oil. (Step 3) A mixture of 10
(41 mg, 0.13 mmol), palladium on carbon (loading: 10 wt %, 7 mg),
and 37 wt % formaldehyde aqueous solution (0.10 mL) in ethanol
(1.3 mL) was stirred for 12 h at room temperature under a hydrogen
atmosphere. The resulting mixture was filtered through a pad of Cel-
ite and the filtrate was concentrated. The residue (44 mg) was dis-
solved in THF (1.3 mL) and the solution was added to a suspension
of lithium aluminum hydride (25 mg, 0.66 mmol) in THF (1.3 mL)
at 0 °C. The mixture was allowed to warm to room temperature
and stirred for 2 h. The resulting mixture was diluted with diethyl
CO2But
CO2But
N
Ph2C
N
Ph2C
N
(S)-7
Ar
(S)-8
4.2.18.1. Preparation of dibenzoyl derivative 7 from 4c. A solu-
tion of 4c (41 mg, 0.19 mmol) in THF (1.0 mL) was added to a sus-
pension of lithium aluminum hydride (9 mg, 0.24 mmol) in THF
(1.1 mL) at 0 °C and the mixture was stirred at room temperature
for 2 h. The resulting mixture was diluted with diethyl ether and
the reaction was quenched with water (9
l
L), 15% aqueous sodium
lL) at 0 °C. The mixture
hydroxide solution (9 L), and water (27
l
was stirred for 1 h at room temperature and filtered through a
pad of Celite. The residual solids in the flask and/or on the pad of
Celite were washed with hot ethanol and filtered. The filtrate
was concentrated and the residue was dissolved in dichlorometh-
ane (1.5 ml). Triethylamine (0.11 mL, 0.79 mmol), 4-dimethylami-
nopyridine (DMAP) (2 mg, 0.02 mmol), and benzoyl chloride
ether and quenched with water (25
hydroxide solution (25 L), and water (75
was stirred for 2 h at room temperature and filtered through a pad
l
L), 15% aqueous sodium
l
lL) at 0 °C. The mixture

2606
E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
of Celite. The residual solids in the flask and/or on the pad of Celite
were washed with hot ethanol and filtered. The filtrate was concen-
trated and the residue (27 mg) was dissolved in dichloromethane
4.3.3. N-Benzyl-N-(tert-butoxycarbonylmethyl)-N-(2-hydroxy-
ethyl)-N-methylammonium chloride, monohydrate 1b
Prepared in 95% yield (two steps) by similar procedures with 1c.
In step 2, the reaction was carried out without solvent using an ex-
cess amount of benzyl chloride (5 equiv) instead of 2-methylben-
zyl bromide.
(1.3 mL). Triethylamine (91
lL, 0.65 mmol), 4-dimethylamino-pyri-
dine (DMAP) (2 mg, 0.02 mmol), and benzoyl chloride (36
lL,
0.31 mmol) were added to the solution at 0 °C. After stirring for 1 h
at 0 °C and 2.5 h at room temperature, the resulting mixture was
quenched with saturated aqueous ammonium chloride and ex-
tracted with ethyl acetate. The combined extracts were washed with
saturated aqueous sodium hydrogen carbonate and brine, dried over
sodium sulfate, and concentrated. The residue was purified by chro-
matography on silica gel (hexane/ethyl acetate = 5:1–3:1 as eluent)
to afford (S)-7 (32 mg, 57% yield) as a colorless oil. The ee was deter-
mined to be 94% ee by chiral HPLC analysis [Daicel Chiralcel OD-H,
4.3.4. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-(2-methylbenzyl)ammonium chloride, 1.5 hydrate 1d
Prepared in 84% yield (two steps) by similar procedures with 1c.
In step 2, the reaction was carried out without solvent using an
excess amount of 2-methylbenzyl chloride (1.5 equiv) instead of
2-methylbenzyl bromide.
hexane/isopropanol = 90:10, 0.50 mL/min, tR = 14.9 min for the (S)-
4.3.5. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-(2-
methoxybenzyl)-N-methylammonium bromide, 0.5 hydrate 1e
23
isomer and 19.1 min for the (R)-isomer]: ½
aꢀ
¼ 4:8 (c 1.00, EtOH);
589
1H NMR (270 MHz, CDCl3) d 8.05–7.91 (4H, m, Ar-H), 7.57–7.46 (2H,
m, Ar-H), 7.43–7.31 (4H, m, Ar-H), 7.19–7.00 (4H, m, Ar-H), 4.49 (1H,
dd, J = 11.7, 7.4 Hz, NCHCH2O), 4.33 (2H, t, J = 5.7 Hz, NCH2CH2O),
4.28 (1H, dd, J = 11.7, 4.6 Hz, NCHCH2O), 3.36–3.22 (1H, m,
NCHCH2O), 3.04 (2H, t, J = 5.7 Hz, NCH2CH2O), 2.92 (1H, dd,
J = 13.6, 5.5 Hz, CH2Ar), 2.76 (1H, dd, J = 13.6, 8.2 Hz, CH2Ar), 2.55
(3H, s, NCH3), 2.32 (3H, s, ArCH3); 13C NMR (68 MHz, CDCl3) d
166.4, 166.3, 137.3, 135.9, 132.8, 132.7, 130.3, 130.1, 130.0, 129.9,
129.4 (4C), 128.3 (2C), 128.2 (2C), 126.3, 125.9, 63.9, 63.4, 62.9,
53.1, 37.9, 32.3, 19.4; IR (film) 3056, 2944, 1710, 1598, 1582, 1448,
1368, 1310, 1266, 1172, 1110, 1066, 1024, 968, 704 cmꢁ1; Anal.
Calcd for C27H29NO4: C, 75.15; H, 6.77; N, 3.25. Found: C, 75.43; H,
6.97; N, 3.23.
(Step 1) A mixture of ethanolamine (604 lL, 10.0 mmol) and o-
anisaldehyde (1.22 mL, 10.0 mmol) in trimethyl orthoformate
(15 mL) was stirred for 18 h at room temperature. The resulting
mixture was concentrated and the residue was dissolved in meth-
anol (10 mL). The solution was treated with sodium borohydride
(378 mg, 10.0 mmol) at 0 °C and stirred for 4 h at room tempera-
ture. The solution was diluted with saturated aqueous sodium
hydrogen carbonate and extracted with ethyl acetate. The com-
bined extracts were washed with brine, dried over sodium sulfate,
and concentrated. The residue was purified by chromatography on
silica gel (dichloromethane/methanol = 10:1–3:1 as eluent) to af-
ford N-(2-hydroxyethyl)-N-(2-methoxylbenzyl)amine 12 (1.81 g,
quant.) as a colorless oil. (Step 2) A mixture of 12 (1.81 g,
10.0 mmol), 37 wt % formaldehyde aqueous solution (1.1 mL,
14 mmol), and formic acid (0.52 mL, 14 mmol) was heated at
100 °C for 2 h. The resulting mixture was cooled to room tempera-
ture, diluted with water, and treated with saturated aqueous so-
dium hydrogen carbonate. The mixture was extracted with ethyl
acetate and the combined extracts were washed with saturated
aqueous sodium hydrogen carbonate and brine. The organic layer
was dried over sodium sulfate and concentrated. Purification of
the residue by chromatography on silica gel (dichloromethane/
methanol = 10:1 as eluent) gave N-(2-hydroxyethyl)-N-(2-meth-
oxylbenzyl)methylamine 13 (1.67 g, 86% yield) as a colorless oil.
(Step 3) A mixture of 13 (750 mg, 3.84 mmol) and bromoacetic acid
tert-butyl ester (0.85 mL, 5.8 mmol) in acetonitrile (7.7 mL) was
stirred for 48 h at room temperature. The resulting mixture was
concentrated by evaporation and the residue was purified by chro-
matography on silica gel (dichloromethane/methanol = 10:1–5:1
as eluent) to afford 1e (1.15 g, 75% yield) as a white solid.
4.3. Preparation of substrates
4.3.1. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-(2-methylbenzyl)ammonium bromide, 0.5 hydrate 1c
(Step 1)
A mixture of N-methylethanolamine (0.92 mL,
11.5 mmol), tert-butyl bromoacetate (1.48 mL, 10.0 mmol), and tri-
ethylamine (1.39 mL, 10.0 mmol) in methanol (20 mL) was stirred
for 4 h at room temperature. The resulting mixture was diluted
with water and extracted with ethyl acetate. The combined ex-
tracts were washed with brine, dried over sodium sulfate, and con-
centrated. The residue was purified by chromatography on silica
gel (dichloromethane/methanol = 10:1 as eluent) to afford
N-(tert-butoxycarbonylmethyl)-N-(2-hydroxyethyl)methyl-amine
11 (1.78 g, 94% yield) as a colorless oil. (Step 2) A mixture of 11
(261 mg, 1.38 mmol) and 2-methylbenzyl bromide (0.22 mL,
1.6 mmol) in acetonitrile (2.7 mL) was stirred for 48 h at room
temperature. The resulting mixture was concentrated by evapora-
tion and the residue was purified by chromatography on silica gel
(dichloromethane/methanol = 10:1–5:1 as eluent) to afford 1c
(507 mg, 96% yield) as a white solid.
4.3.6. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-(2-
methoxybenzyl)-N-methylammonium chloride, 1.5 hydrate 1f
Prepared in 81% yield (two steps) by similar procedures with 1c.
In step 2, the reaction was carried out without solvent using excess
amount of 2-methoxybenzyl chloride (1.5 equiv) instead of
2-methylbenzyl bromide.
4.3.2. N-Benzyl-N-(tert-butoxycarbonylmethyl)-N-(2-
hydroxyethyl)-N-methylammonium bromide 1a
Prepared in 94% yield (two steps) by the same procedures with
1c using benzyl bromide instead of 2-methylbenzyl bromide in
step 2: white solid; 1H NMR (270 MHz, CDCl3) d 7.67–7.59 (2H,
m, Ph), 7.55–7.41 (3H, m, Ph), 5.30 (1H, d, J = 12.7 Hz, CH2COO),
5.16 (1H, d, J = 12.7 Hz, CH2COO), 5.10 (1H, t, J = 5.1 Hz, OH), 4.57
(1H, d, J = 17.1 Hz, CH2Ph), 4.49 (1H, d, J = 17.1 Hz, CH2Ph),
4.29–4.16 (2H, m, CH2CH2OH), 4.05–3.84 (2H, m, CH2CH2OH),
3.49 (3H, s, NCH3), 1.50 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d
164.0, 133.3, 130.8, 129.2, 126.7, 85.0, 67.0, 62.5, 58.9, 55.5, 49.0,
27.8; IR (film) 3280, 2968, 1734, 1622, 1452, 1392, 1368, 1240,
1148, 1086, 898, 834, 702 cmꢁ1; Anal. Calcd for C16H26BrNO3: C,
53.34; H, 7.27; N, 3.89. Found: C, 53.52; H, 7.57; N, 3.73.
4.3.7. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-[2-(trifluoromethyl)benzyl] ammonium bromide 1g
Prepared in 88% yield (two steps) by the same procedures with
1c using 2-(trifluoromethyl)benzyl bromide instead of 2-methyl-
benzyl bromide in step 2.
4.3.8. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-(4-methylbenzyl)ammonium bromide 1h
(Step 1)
A mixture of N-methylethanolamine (0.18 mL,
2.2 mmol) and sodium hydrogen carbonate (0.50 g, 6.0 mmol) in
THF (4 mL) was treated with p-toluoyl chloride (0.26 mL,
2.0 mmol) at 0 °C and the mixture was stirred for 2 h at room

E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
2607
temperature. The resulting mixture was diluted with water and ex-
4.3.11. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
tracted with ethyl acetate. The combined extracts were washed
with brine, dried over sodium sulfate, and concentrated. The resi-
due was dissolved in THF (2.0 mL) and the solution was added to
a suspension of lithium aluminum hydride (114 mg, 3.0 mmol) in
THF (4 mL) at 0 °C. The mixture was allowed to warm to room tem-
perature and stirred for 3 h. The resulting mixture was diluted with
diethyl ether and quenched with water (0.11 mL), 15% aqueous so-
dium hydroxide solution (0.11 mL), and water (0.33 mL) at 0 °C.
The mixture was stirred for 1 h at room temperature and filtered
through a pad of Celite. The filtrate was concentrated and the res-
idue was purified by chromatography on silica gel (dichlorometh-
ane/methanol = 10:1 as eluent) to afford N-(2-hydroxyethyl)-N-(4-
methylbenzyl)methylamine 14 (319 mg, 89% yield) as a colorless
oil. (Step 2) A mixture of 14 (305 mg, 1.70 mmol) and bromoacetic
acid tert-butyl ester (0.30 mL, 2.0 mmol) in acetonitrile (3.4 mL)
was stirred for 48 h at room temperature. The resulting mixture
was concentrated by evaporation and the residue was purified by
chromatography on silica gel (dichloromethane/methanol = 10:1–7:1
as eluent) to afford 1h (606 mg, 95% yield) as a white solid: 1H
NMR (270 MHz, CDCl3) d 7.48 (2H, d, J = 8.0 Hz, Ar-H), 7.25 (2H,
d, J = 8.0 Hz, Ar-H), 5.30–4.95 (1H, br, OH), 5.21 (1H, d,
J = 12.6 Hz, CH2COO), 5.08 (1H, d, J = 12.6 Hz, CH2COO), 4.46 (2H,
s, CH2Ar), 4.21 (2H, t, J = 4.2 Hz, CH2CH2OH), 3.98 (1H, dt, J = 13.9,
4.2 Hz, CH2CH2OH), 3.88 (1H, dt, J = 13.9, 4.2 Hz, CH2CH2OH), 3.46
(3H, s, NCH3), 2.38 (3H, s, ArCH3), 1.50 (9H, s, t-Bu); 13C NMR
(68 MHz, CDCl3) d 164.0, 141.1, 133.1, 129.9, 123.6, 84.9, 66.9,
62.4, 58.7, 55.6, 48.9, 27.8, 21.2; IR (film) 3272, 2952, 1728,
1610, 1448, 1390, 1368, 1240, 1148, 1082, 802, 722 cmꢁ1; Anal.
Calcd for C17H28BrNO3: C, 54.55; H, 7.54; N, 3.74. Found: C,
54.28; H, 7.70; N, 3.55.
methyl-N-(4-trifluoromethylbenzyl)ammonium chloride,
monohydrate 1k
Prepared in 86% yield (two steps) by similar procedures with 1c.
In step 2, the reaction was carried out without solvent using an ex-
cess amount of 4-(trifluoromethyl)benzyl chloride (1.5 equiv) in-
stead of 2-methylbenzyl bromide: white solid; 1H NMR
(270 MHz, CDCl3) d 7.89 (2H, d, J = 8.0 Hz, Ar-H), 7.71 (2H, d,
J = 8.0 Hz, Ar-H), 5.93 (1H, br, OH), 5.48 (1H, d, J = 12.3 Hz,
CH2COO), 5.38 (1H, d, J = 12.3 Hz, CH2COO), 4.74 (1H, d,
J = 17.1 Hz, CH2Ar), 4.56 (1H, d, J = 17.1 Hz, CH2Ar), 4.20 (2H, s,
CH2CH2OH), 4.03–3.80 (2H, m, CH2CH2OH), 3.50 (3H, s, NCH3),
1.48 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d 164.0, 134.1, 132.8
(q, J = 33 Hz), 131.0 (q, J = 1 Hz), 126.0 (q, J = 3 Hz), 123.4 (q,
J = 273 Hz), 85.3, 65.9, 62.7, 59.2, 55.7, 49.1, 27.8; IR (film) 3220,
2968, 1728, 1390, 1368, 1320, 1238, 1124, 1066, 824, 724 cmꢁ1
Anal. Calcd for C17H27ClF3NO4: C, 50.81; H, 6.77; N, 3.49. Found:
C, 50.89; H, 6.93; N, 3.35.
;
4.3.12. N-(2-Hydroxyethyl)-N-(methoxycarbonylmethyl)-N-
methyl-N-(2-methylbenzyl)ammonium bromide, 0.5 hydrate 1l
(Step 1) 2-Methylbenzyl bromide (0.27 mL, 2.0 mmol) was
added to a solution of N-methylethanolamine (0.46 mL, 5.7 mmol)
in methanol (4 mL) at 0 °C and the mixture was stirred for 2 h at
room temperature. The resulting mixture was concentrated and di-
luted with water. The mixture was extracted with ether and the
combined extracts were washed with brine, dried over sodium sul-
fate, and concentrated. The residue was purified by chromatogra-
phy on silica gel (dichloromethane/methanol = 10:1–5:1 as
eluent) to afford N-(2-hydroxyethyl)-N-(2-methylbenzyl)methyl-
amine 15 as a colorless oil (308 mg, 86% yield). (Step 2) A mixture
of 15 (300 mg, 1.67 mmol) and methyl bromoacetate (0.19 mL,
2.0 mmol) in acetonitrile (3.3 mL) was stirred for 48 h at room
temperature. The resulting mixture was concentrated by evapora-
tion and the residue was purified by chromatography on silica gel
(dichloromethane/methanol = 10:1–5:1 as eluent) to afford 1l as a
white solid (489 mg, 86% yield).
4.3.9. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-(4-methylbenzyl)ammonium chloride, monohydrate
1i
Prepared in 78% yield (two steps) by similar procedures with 1c.
In step 2, the reaction was carried out without solvent using excess
amount of 4-methylbenzyl chloride (1.5 equiv) instead of 2-meth-
ylbenzyl bromide: white solid; 1H NMR (270 MHz, CDCl3) d 7.48
(2H, d, J = 7.8 Hz, Ar-H), 7.24 (2H, d, J = 7.8 Hz, Ar-H), 6.40–5.50
(1H, br, OH), 5.21 (1H, d, J = 12.6 Hz, CH2COO), 5.09 (1H, d,
J = 12.6 Hz, CH2COO), 4.51 (2H, s, CH2Ar), 4.18 (2H, s, CH2CH2OH),
4.02–3.78 (2H, m, CH2CH2OH), 3.45 (3H, s, NCH3), 2.38 (3H, s,
ArCH3), 1.49 (9H, s, t-Bu); 13C NMR (68 MHz, CDCl3) d 164.1
141.0, 133.1, 129.8, 123.8, 84.7, 66.9, 62.5, 58.7, 55.7, 48.8, 27.8,
21.1; IR (film) 3256, 2964, 1726, 1612, 1388, 1366, 1234, 1146,
802, 722 cmꢁ1; Anal. Calcd for C17H30ClNO4: C, 58.69; H, 8.69; N,
4.03. Found: C, 58.87; H, 8.74; N, 3.73.
Acknowledgments
This work was supported by Grant-in-Aid for Young Scientists
(19750029) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan and The Asahi Glass Foundation.
References
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(b) Sweeney, J. B. Chem. Soc. Rev. 2009, 38, 1027; (c) Vanecko, J. A.; Wan, H.;
West, F. G. Tetrahedron 2006, 62, 1043.
2. (a) Wu, H.-F.; Lin, W.-B.; Xia, L.-Z.; Luo, Y.-G.; Chen, X.-Z.; Li, G.-Y.; Zhang, G.-L.;
Pan, X.-F. Helv. Chim. Acta 2009, 92, 677; (b) Tayama, E.; Nanbara, S.; Nakai, T.
Chem. Lett. 2006, 35, 478; (c) Shimomoto, A.; Yonezawa, K.; Takizawa, S.; Sasai,
H. Jpn. Kokai Tokkyo Koho JP 2006076911 A 20060323, 2006.; (d) Tayama, E.;
Tanaka, H.; Nakai, T. Heterocycles 2005, 66, 95; (e) Hirnschall, M.; Treu, M.;
Mereiter, K.; Hametner, C.; Fröhlich, J.; Jordis, U. Tetrahedron: Asymmetry 2003,
14, 675; (f) Arboré, A. P. A.; Cane-Honeysett, D. J.; Coldham, I.; Middleton, M. L.
Synlett 2000, 236; (g) Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1, 31; (h)
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4.3.10. N-(tert-Butoxycarbonylmethyl)-N-(2-hydroxyethyl)-N-
methyl-N-(4-trifluoromethylbenzyl)ammonium bromide,
monohydrate 1j
Prepared in 99% yield (two steps) by the same procedures with
1c using 4-(trifluoromethyl)benzyl bromide instead of 2-methyl-
benzyl bromide in step 2: white solid; 1H NMR (270 MHz, CDCl3)
d 7.91 (2H, d, J = 7.8 Hz, Ar-H), 7.72 (2H, d, J = 7.8 Hz, Ar-H), 5.44
(1H, d, J = 12.4 Hz, CH2COO), 5.36 (1H, d, J = 12.4 Hz, CH2COO),
5.10 (1H, br, OH), 4.56 (1H, d, J = 17.1 Hz, CH2Ar), 4.41 (1H, d,
J = 17.1 Hz, CH2Ar), 4.22 (2H, s, CH2CH2OH), 4.10–3.87 (2H, m,
CH2CH2OH), 3.52 (3H, s, NCH3), 1.50 (9H, s, t-Bu); 13C NMR
(68 MHz, CDCl3) d 163.7, 134.0, 132.7 (q, J = 33 Hz), 130.7, 126.0,
123.3 (q, J = 273 Hz), 85.3, 65.7, 62.7, 59.2, 55.5, 49.1, 27.8; IR (film)
3272, 2964, 1728, 1616, 1454, 1418, 1392, 1368, 1320, 1242, 1148,
1066, 1018, 822, 722 cmꢁ1; Anal. Calcd for C17H27BrF3NO4: C,
45.75; H, 6.10; N, 3.14. Found: C, 45.88; H, 5.81; N, 3.27.
7. CCDC-735959 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

2608
E. Tayama et al. / Tetrahedron: Asymmetry 20 (2009) 2600–2608
8. We attempted to use inorganic bases such as KOH or CsOH to improve the rate
of N-to-C chirality transmission, as described by our previous report (Ref.2b);
however, the yield and ee of the product 4c were lowered.
12. (a) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Perkin Trans. 1 1983,
1009; (b) Ollis, W. D.; Rey, M.; Sutherland, I. O. J. Chem. Soc., Chem. Commun.
1975, 543.
9. The compound 4c was converted to the O,O-dibenzoyl protected amino diol 7
by LiAlH4 reduction and dibenzoylation; this material was then
chromatographically correlated with the (S)-authentic sample. The
compound (S)-7 was prepared from Schiff-base protected glycine tert-butyl
ester via phase transfer catalyzed asymmetric alkylation. Details: see
Section 4.2.18.
13. Preparation: Treatment of (R)-1g (80% ee) with (S)-BINOL (1.0 equiv) in
dichloromethane afforded the 1:1 complex 2g. Adduct 2g was recrystallized
from dichloromethane–hexane; then the crystals were dissociated in diethyl
ether–water to give (R)-1g (93% ee).
14. Recently, our group reported that an electron-withdrawing group on N-
benzylic substituent enhanced the rate of Sommelet–Hauser rearrangement:
(a) Tayama, E.; Orihara, K.; Kimura, H. Org. Biomol. Chem. 2008, 6, 3673; (b)
Tayama, E.; Kimura, H. Angew. Chem., Int. Ed. 2007, 46, 8869.
10. THF was added as a 1.0 M THF solution of t-BuOK.
11. When the product (S)-4c (60% ee) was treated with t-BuOK (0.2 equiv) in
CH3CN–THF (10:1) at ꢁ30 °C for 30 min, (S)-4c was recovered in 74% yield
without racemization (60% ee). Use of excess amount of t-BuOK (over
1.0 equiv) in the rearrangement of (R)-1c decreased the chemical yield.
15. The absolute configurations of 5g and 6g were not determined.
16. (a) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139; (b) Ooi,
T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519.