Atropisomeric lactam chemistry: catalytic enantioselective synthesis, application to asymmetric enolate chemistry and synthesis of key intermediates for NET inhibitors

Article abstract of DOI:10.1016/j.tet.2009.10.095

In the presence of (R)-SEGPHOS-Pd(OAc)₂ catalyst, the intramolecular N-arylation of ortho-tert-butyl-NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89-98% ee) to give optically active atropisomeric lac

Full text of DOI:10.1016/j.tet.2009.10.095

Tetrahedron 66 (2010) 288–296
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Atropisomeric lactam chemistry: catalytic enantioselective synthesis,
application to asymmetric enolate chemistry and synthesis of key
intermediates for NET inhibitors
Masashi Takahashi y, Hajime Tanabe z, Tsuyoshi Nakamura, Daisuke Kuribara,
*
Toshiyuki Yamazaki, Osamu Kitagawa
Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of (R)-SEGPHOS-Pd(OAc)2 catalyst, the intramolecular N-arylation of ortho-tert-butyl-
NH-anilides possessing an iodophenyl group proceeded in a highly enantioselective manner (89–98% ee)
to give optically active atropisomeric lactams having an N–C chiral axis. MPLC purification of the enantio-
enriched lactam products using an achiral silica gel column led to a further increase in the enantiomeric
purity (>99% ee). The reaction of the lithium enolate prepared from the optically active atropisomeric
Received 7 October 2009
Received in revised form
23 October 2009
Accepted 27 October 2009
Available online 31 October 2009
lactam with various alkyl halides gave
diastereoselectivity. -Alkylated lactam derivatives were efficiently converted to key intermediates for
the synthesis of an NET inhibitor.
a-substituted and a,a-disubstituted lactam products with high
a
Keywords:
Atropisomerism
Lactams
Ó 2009 Elsevier Ltd. All rights reserved.
Palladium
Enantioselective
Diastereoselective
Enolate
Alkylation
5.0 mol%
1. Introduction
O
(R)-DTBM-SEGPHOS
3.3 mol% Pd(OAc)2
1.4 eq. Cs2CO3
O
Ar
Recently, atropisomeric compounds having an N–C chiral axis
have received much attention as novel chiral molecules.1
N-Substituted ortho-tert-butylanilide derivatives are typical
examples of such stable atropisomeric compounds due to the
rotational restriction around the N-Ar bond.2 In 2005, we
succeeded in the highly enantioselective synthesis of atropisomeric
ortho-tert-butylanilides and (N-ortho-tert-butylphenyl)lactams
through chiral Pd-catalyzed inter- and intra-molecular N-arylation
(catalytic asymmetric Buchwald–Hartwig amination3) of achiral
NH-anilides (Schemes 1 and 2).4,5 These reactions are the first
practical catalytic asymmetric synthesis of N–C axially chiral
compounds as well as the first example of catalytic asymmetric
Buchwald–Hartwig amination using achiral substrates.6,7 Further-
R1
N
R1
NH
t-Bu
Ar-I
+
t-Bu
toluene, 80 °C
R2 = t-Bu (91-95% ee)
R2
R2
"axially chiral"
R
2 = H (88-96% ee)
"achiral"
Ar = 4-nitrophenyl
O
N
O
OH
NHPh
1) n-BuLi
R3
Ph
t-Bu
Ph
2) R3-X
N
LAH
+
R3
t-Bu
t-Bu
THF
(R1 = Et)
(R2 = H)
more, highly diastereoslective a-alkylation using lithium enolates
Scheme 1. Catalytic enantioselective synthesis of atropisomeric anilides and their
application to asymmetric enolate chemistry.
prepared from anilide and lactam products was also found
(Schemes 1 and 2).4
* Corresponding author. Tel.: þ81 3 5859 8161; fax: þ81 3 5859 8101.
E-mail address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
y
In the intramolecular reaction of Scheme 2, the use of NH-ani-
Present address: Takeda Pharmaceutical Company Ltd, Osaka, Japan.
z
Present address: Daicel Chemical Industries Ltd, Niigata, Japan.
lides (R1¼t-Bu) prepared from expensive 2,5-di-tert-butylaniline
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.095

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
289
O
7.5 mol% ligand
5.0 mol% Pd(OAc)2
2 eq. Cs2CO3
O
5.0 mol% (S)-BINAP
3.3 mol% Pd(OAc)2
1.4 eq. Cs2CO3
O t-Bu
(II)
Pd
NH
NH
N
N
O
t-Bu
I
t-Bu
t-Bu
I
P
toluene 80 °C, 24 h
P
toluene, 80 °C
*
R1
1 "achiral"
R1
R1 = t-Bu (96% ee)
1a
R1 = H (70% ee)
2 "axially chiral"
(1)
R3
R2
R2
N
O
t-Bu
1) Li-TMP
*
2) R2-X
THF
N
O
N
O
2a
t-Bu
(?)
NET inhibitor
Ph
I [R2 = (CH2)3NHMe,
O
R1
R3 = H or Me]
O
O
PAr2
PAr2
PPh2
PPh2
Scheme 2. Catalytic enantioselective synthesis of atropisomeric lactams and their
Ar = 3,5-di-t-Bu-4-
application.
methoxyphenyl
was required for high enantioselectivity. The reaction with an
anilide (R1¼H) from the less expensive 2-tert-butylaniline resulted
in a considerable decrease in enantioselectivity, which is in contrast
to the intermolecular reaction in Scheme 1. Thus, the highly
enantioselective synthesis of atropisomeric N-(2-tert-butylphenyl)-
lactam has not been established yet.
N-(2-Tert-butylphenyl)lactam should be a better chiral molecule
than N-(2,5-di-tert-butylphenyl)lactam from the viewpoint of not
only cost performance but also synthetic utility. That is, a-alkyl-
ation with an N-(2,5-di-tert-butylphenyl)lactam may bring about
a decrease in diastereoselectivity in comparison with that of an
N-(2-tert-butylphenyl)lactam. This is due to the meta-tert-butyl
group, which shows an opposite stereocontrol from the ortho-tert-
butyl group. In addition, although the removal of the tert-butyl
O
(R)-DTBM-SEGPHOS
(R)-BINAP
(95%, 70% ee)
(12%, 0% ee)
O
O
O
O
F
F
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
O
O
O
F
O
F
O
(R)-SYNPHOS
(93%, 93% ee)
(R)-SEGPHOS
(95%, 93% ee)
(R)-DIFLUORPHOS
(93%, 90% ee)
group from
a-alkylated atropisomeric lactam (conversion to
1), which proceeded with poor enantioselectivity (23% ee) in the
presence of an (R)-SEGPHOS ligand.4b
a
-alkylated N-phenyl lactam) provides a key synthetic intermediate
for NET (norepinephrine transporter) inhibitors I (Scheme 2 and
Eq. 4),8 such a conversion from an N-(2,5-di-tert-butylphenyl)-
lactam may be troublesome as the meta-tert-butyl group is more
difficult to remove than an ortho-tert-butyl group.9
In this paper, we report on the highly enantioselective synthesis
of atropisomeric N-(2-tert-butylphenyl)lactam derivatives through
(R)-SEGPHOS-Pd(OAc)2 catalyzed intramolecular Buchwald–Hart-
wig amination.10 Furthermore, MPLC purification of the enantio-
enriched lactam products using achiral silica gel column was found
to bring about a further increase in enantiomeric purity (>99% ee).
Under the present conditions, the reactions with several
substrates were further examined (Table 1). With 2,5-di-tert-butyl-
NH-anilide 1b, excellent enantioselectivity better than that of
BINAP, was also observed (entry 2, SEGPHOS: 98% ee, BINAP: 96%
ee). The reactions of 1c having a 2-tert-butyl-4-methoxy phenyl
group and 1d having nitrogen-containing tether also proceeded
with higher enantioselectivities than those of BINAP (entries 3 and
4, SEGPHOS: 93% ee and 89% ee, BINAP: 71%ee and 67% ee).
Highly diastreodivergent synthesis of an
a
-alkylated lactam using
Table 1
Catalytic enantioselective N-arylation of several NH-anilides
asymmetric enolate chemistry and efficient conversion to key
intermediate for synthesis of the NET inhibitor are also described.
X
7.5 mol% (R)-SERGPHOS
5.0 mol% Pd(OAc)2
2 eq. Cs2CO3
O
X
I
NH
R2
N
O
t-Bu
2. Results and discussion
t-Bu
toluene 80 °C, 6-24 h
2.1. Highly catalytic enantioselective synthesis of
atropisomeric lactam derivatives
R1
R1
2
1
R2
Initially, highly enantioselective synthesis of atropisomeric N-(2-
tert-butylphenyl)lactam was investigated. In intramolecular Buch-
wald–Hartwig amination with an NH-anilide having an iodophenyl
group, re-screening of chiral phosphine ligands was performed
under previously reported conditions [5.0 mol % Pd(OAc)2, 7.5 mol %
chiral phosphine, 2.0 equiv Cs2CO3 in toluene at 80 ꢀC].4
c
Entry
1
X
R1
R2
2
Yielda (%)
eeb (%)
[a]
D
1
2
3
4
1a
1b
1c
1d
CH2
CH2
CH2
NBn
H
t-Bu
H
H
H
OMe
H
2a
2b
2c
2d
95
95
98
72
93
98
93
89
ꢁ77.1
ꢁ83.7
ꢁ101.5
ꢁ25.3
H
a
Isolated yield.
It was found that the use of (R)-SEGPHOS11 led to a remarkable
increase in enantioselectivity in comparison with previously used
BINAP (SEGPHOS: 93% ee, BINAP: 70% ee, Eq. 1). In the reaction with
(R)-DIFLUORPHOS12 and (R)-SYNPHOS13, a similar high enantiose-
lectivity was also observed (93% ee and 90% ee, Eq. 1). These results
are in striking contrast to that of intermolecular reaction (Scheme
b
c
The ee was determined by HPLC analysis using a chiral column.
D value was measured in CHCl3 (c=1).
[a]
The absolute configuration of the axial chirality in lactam
product 2a (93%ee, Eq. 1) was confirmed to be a (R)-configuration
by comparison of -methylation product 4a in Table 2 (entry 1)
a

290
M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
NH2
These results indicate that the excess enantiomer of 2a was
Pd (OAc)2
rac-BINAP
Cs2CO3
efficiently separated by MPLC using an achiral silica gel column. The
separation of excess enantiomer by achiral chromatography has
been already found by several groups,15 while as far as we know, in
an N–C axially chiral compound, such separation has yet to have
been reported.
As shown in Figure 2, the separation by MPLC was also observed
in other lactam substrates such as 2b and 2c. Similar to 2a (73% ee),
2b (73% ee) and 2c (80% ee) were isolated in almost optically pure
form by separation at the point marked by an arrow. On the other
hand, such separation remarkably depends on the eluent. For
example, MPLC chart of 2a using hexane-i-PrOH (50:1) as an eluent
showed one sharp peak, and the separation of an excess enantio-
mer was not observed.
O
O
(S)
I
(S)
I
t-Bu
OMe
Me3Al
NH
t-Bu
toluene
80 °C
(88% ee)
3a (92%)
Ha
Me
(S)
Me
(S)
N
O
N
O
ent-4a
(R)
(S)
+
4a'
(28%)
t-Bu
t-Bu
(30%, 88% ee)
[α]D = +14.9
(c=0.52, CHCl3)
t-Bu - Me (NOE)
t-Bu - Ha (no NOE)
2.3. Highly selective diastereodivergent synthesis of
alkylated and -dialkylated atropisomeric lactams
a-
a,a
Scheme 3. Stereochemical assignment of lactam product.
with ent-4a prepared in accordance with Scheme 3.14 The config-
We have already reported on highly diastereoselective a-alkyl-
ation using lithium enolate prepared from 2,5-di-tert-butyl lactam
2b.4 In this reaction, since the meta-tert-butyl group may show an
opposite stereocontrol from the ortho-tert-butyl group, the reaction
with mono-tert-butyl lactam 2a was expected to proceed with
higher diastereoselectivity. Indeed, the reaction of the lithium
enolate from 2a with iodomethane led to a further increase in
diastereoslectivity (Table 2, entry 1, dr¼31:1) in comparison with
that of 2b, which was previously reported (2b: dr¼13:1).4b In the
reaction of 2a with an allyl bromide and a benzyl bromide, almost
complete diastereoslectivity was observed (entries 2 and 3, dr of
allylaion and benzylation with 2b¼38:1 and 48:1). The reaction
with a less reactive halide such as n-propyl iodide also proceeded
with high diastereoslectivity (entry 4, dr¼32:1). The attack of alkyl
halides to the lactam enolate preferentially occurs from the
opposite site of the ortho-tert-butyl group to afford products 4a–
urations of 2c and 2d, which have negative [a] values such as 2a
D
and 2b, were also tentatively assigned to be the (R)-configuration.14
2.2. Enantiomer enrichment by MPLC using achiral silica
gel column
During purification of lactam products 2a by MPLC using silica
gel column (SiO2 10
mm, 30ꢂ4 cm i. d.), we found that the peak of 2a
shows different shape depending on optical purity. That is, the
MPLC chart of racemic- and optically pure 2a showed one clear
peak, while 2a of 70% ee, which was obtained by a reaction using
BINAP, gave an MPLC chart suggesting an overlap of two peaks
(Fig. 1, eluent: hexane/AcOEt¼10). 2a with 73% ee (41 mg) was
separated into two fractions at the point marked by an arrow
(Fig. 2), and the ee of each fraction was measured by HPLC analysis
using a CHIRALPAC AS column. The ee of the first (less polar, 17 mg,
41%) and second fractions (more polar, 24 mg, 59%) was determined
to be 99.5% and 59%, respectively (Fig. 2).
d possessing an a
-chiral carbon of the (R)-configuration.16
Table 2
Diastereoselective a-alkylation with atropisomeric lactam 2a
R
2a
(99%ee)
2a
(racemic)
2a
(70%ee)
Li-TMP
THF
R-X
N
O
t-Bu
N
OLi
t-Bu
2a
(93% ee)
4 (93% ee)
Entry
R-X
4
Yielda (%)
82
drb
1
Me-l
4a
31/1 [
a
]D¼ꢁ17.0
(c=0.92, CHCl3)
>50/1
2
3
4
Allyl-Br
PhCH2-Br
n-Pr-l
4b
4c
4d
83
85
86
retention time
retention time
retention time
>50/1
32/1
Figure 1. MPLC chart of 2a (70% ee, racemic and 99% ee, eluent: hexane/AcOEt¼10).
a
Isolated yield.
The diastereomer ratio was determined by 400 MHz 1H NMR.
b
less polar
fraction
99.4%ee
more polar
fraction
more polar
fraction
51.5%ee
(43.8%)
more polar
fraction
Subsequently, the further reaction of the
product with some electrophiles was investigated (Table 3).17
Protonation of the lithium enolate prepared from -allylated and
-propylated lactams 4b and 4d resulted in the inversion of the
-chiral carbon to give lactams 4b0 and 4d0 corresponding to the
a-alkylated lactam
less polar
fraction
99.7%ee
(31.8%)
62.9%ee
(67.0%)
less polar
fraction
99.5%ee
(41.0%)
59.5%ee
(59.0%)
(56.2%)
a
a
a
diastereomer of 4b and 4d with high stereoselectivity, respectively
(entries 1 and 2, dr¼21:1 and 26:1). Thus, the highly selective
diastereodivergent synthesis of
was achieved.
a-alkylated atropisomeric lactam
The present reaction can be also applied to the highly selective
diastereodivergent synthesis of -disubstituted lactams. -Ally-
lation of -methylated lactam 4a and -allylated
lactam 4b gave diastereomeric -allyl-
-methyl lactams 5a and 5a0
retention time
2c (80%ee)
retention time
2a (73%ee)
retention time
a
,a
a
2b (73%ee)
a
a
a
-methylation of a
Figure 2. MPLC separation of enantio-enriched 2a (73% ee), 2b (73% ee) and 2c (80% ee).
a

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
291
Table 3
As tert-butylphenyl group was difficult to remove, we next in-
vestigated the conversion to N-phenyl- -substituted dihy-
Highly selective diastereodivergent synthesis of
lactams
a
-alkylated and a,a-dialklated
a
droquinolin-2-one derivatives I having potent norepinephrine
transporter (NET) inhibitory activity, which has been reported by
Camp and his co-workers.8 Camp et al. found that an enantiomer of
IA (R¼H) was 20-fold more NET active than the antipode, while the
absolute configurations were not determined. We expected that the
efficient synthesis of key intermediates III for NET inhibitors I
would be achieved through the removal of the ortho-tert-butyl
group from lactams 4 and 5 by trans-tert-butylation (retro-Friedel–
Crafts reaction) (Eq. 4).
R
E
R
E-X
Li-TMP
THF
N
O
t-Bu
N
O
t-Bu
4 (93% ee)
4 or 5 (93% ee)
Entry
4
R
E-X
4 or 5
R
E
Yielda (%)
drb
1
2
3
4
5
6
4b
4d
4a
4b
4a
4d
Allyl
n-pr
Me
Allyl
Me
HCl aq
HCl aq
Allyl-Br
Me-l
n-Pr-l
Me-l
4b0
4d0
5a
5a0
5d
5d0
Allyl
n-pr
Me
allyl
Me
H
H
Allyl
Me
n-Pr
Me
85
94
91
70
46
70
21
26
>50
>50
>50
>50
allyl
R
(CH2)3NHMe
allyl
R
R
*
*
*
(4)
N
O
t-Bu
N
O
N
O
n-Pr
n-Pr
trans-tert-
butylation
a
Isolated yield.
b
The diastereomer ratio was determined by 400 MHz 1H NMR.
4 or 5
IA (R = H)
III
IB (R = Me)
with almost complete stereoslectivity, respectively (entries 3 and 4).
Similarly, both diastereomers 5d and 5d0 of the
-methyl-
propyl lactams were also obtained with complete stereo-
selectivity through -propylation of 4a and -methylation of 4d
a
a-
inhibitors of norepinephrine
transporter (NET inhibitors)
a
a
(entries 5 and 6). The configurations of these products show
that the protonation and second alkylation also selectively occur
from the opposite site of the ortho-tert-butyl group.16
For conversion to synthetic intermediates III (Eq. 4), the removal
of the ortho-tert-butyl group in
-allylated lactams 4b (R¼H) and 5a
a
(R¼Me) was investigated. In accordance with the procedure of
trans-tert-butylation reported by Simpkins et al.17 although 4b and
5a were treated with AlCl3 (10 equiv) in C6H6 at 80 ꢀC, the desired
N-phenyl lactams were not obtained. In these reactions, the for-
mation of complex mixtures accompanied by the disappearance of
the alkene part was observed. The tert-butyl group was removed by
trans-tert-butylation of the resulting hydroxy lactams 6b and 6a
after anti-Markovnikov hydration of 4b and 5a (Scheme 4). The
obtained N-phenyl lactams 7b and 7a are also synthetic
intermediates for NET inhibitors, which have been reported by
Camp et. al.8
2.4. Synthesis of key intermediates for the NET inhibitor
Although atropisomeric compounds having an N–C chiral axis
have been recently investigated by many groups, there have been
very few reports on the synthesis of natural productsand biologically
active compounds using these N–C axially chiral compounds.18
Meanwhile, various biological active compounds possessing a dihy-
droquinolin-2-one skeleton have been found so far.19 We thus
attempted the conversion of optically active atropisomeric lactam
products to biologically active dihydroquinolin-2-one derivatives.
Although the conversion to known synthetic intermediate II for
argatroban (an anticoagulant agent) 20 was initially investigated, all
attempts were unsuccessful (Eq. 2 and 3). For example, the attempt
R
R
(CH2)3-OH
to remove the tert-butylphenyl group from a-methylated lactam 4a
AlCl3
1) 9-BBN
N
O
t-Bu
N
O
t-Bu
by Birch-reduction gave complex mixtures, and the desired
NH-lactam II was not obtained. Oxidative treatment (CAN and
RuO4) of 6c, which was obtained with high diastereoselectivity
C6H6, 80 °C
2) NaOH, H2O2
(93% ee)
through a-methylation of atropisomeric lactam 2c having 2-tert-
6b (89 %)
6a (99 %)
4b (R = H)
5a (R = Me)
buty-4-methoxyphenyl group, also resulted in a complex mixture
due to oxidation of the dihydroquinolinone ring.
R
R
Me
(CH2)3-OH
Me
(CH2)3-NHMe
O
Birch
reduction
complex
mixture
(2)
(3)
N
O
t-Bu
N
O
N
N
H
O
II (not detected)
(93% ee)
4a
7b (57 %)
7a (53 %)
NET inhibitor
Scheme 4. Conversion to synthetic intermediates for NET inhibitors.
Me
CAN or
1) Li-TMP
2) Me-I
RuO4
N
O
t-Bu
complex
mixture
N
O
t-Bu
3. Conclusion
THF
(64%)
We succeeded in the highly enantioselective synthesis of atro-
pisomeric N-(2-tert-butylphenyl)lactam derivatives through (R)-
SEGPHOS-Pd(OAc)2 catalyzed intramolecular Buchwald–Hartwig
amination. The obtained enantio-enriched lactam products were
6c
(dr =33/1)
2c
OMe
OMe

292
M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
efficiently converted to almost enantiomerically pure form through
MPLC separation using an achiral silica gel column. Furthermore,
highly selective diastreodivergent synthesis of a-alkylated and a,a-
dialkylayed lactams using asymmetric enolate chemistry, and
efficient conversion to a key intermediate for the synthesis of an
NET inhibitor, were also found.
80 ꢀC. The mixture was poured into 2% HCl. Insoluble materials
were removed by filtration with a Celite pad, and the filtrate was
extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt¼5) gave 1d
(1.70 g, 71%). 1d: white solid; mp 110–111 ꢀC; IR (KBr) 3332,
1691 cmꢁ1
;
1H NMR (CDCl3)
d
: 8.59 (1H, br s), 7.93 (1H, dd, J¼1.5,
4. Experimental
4.1. General
7.9 Hz), 7.39 (1H, dt, J¼1.8, 7.3 Hz), 7.31–7.33 (6H, m), 7.20 (1H, dt,
J¼2.2, 7.6 Hz), 7.16 (1H, dt, J¼1.9, 7.6 Hz), 7.06 (1H, dd, J¼1.5,
7.9 Hz), 6.90–6.96 (2H, m), 4.25 (2H, s), 3.84 (2H, s), 1.33 (9H, s);
13C NMR (CDCl3)
d: 169.2, 150.5, 145.7, 140.4, 135.5, 134.7, 130.3,
Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on a 300 MHz spectrometer. In 1H and 13C NMR spectra,
129.6, 129.5, 128.5, 128.0, 127.3, 127.2, 126.8, 126.8, 124.3, 99.2,
60.5, 56.6, 34.9, 31.0; MS (m/z) 499 (MHþ); Anal. Calcd for
C25H27IN2O: C, 60.25; H, 5.46; N, 5.62. Found: C, 60.43; H, 5.64; N,
5.47.
chemical shifts were expressed in
d (ppm), using chloroform as an
internal reference. Mass spectra were recorded by electron impact
or chemical ionization. Column chromatography was performed on
silica gel (75–150 mm). Medium-pressure liquid chromatography
(MPLC) was performed on a 30ꢂ4 cm i. d. prepacked column (silica
gel, 50 mm) with a UV detector. High-performance liquid chro-
matography (HPLC) was performed on a 25ꢂ0.4 cm i. d. chiral
column with a UV detector.
4.3. General procedure of catalytic asymmetric
intramolecular N-arylation
Under Ar atmosphere, to 1a (407 mg, 1.0 mmol) in toluene
(3.0 mL) was added Cs2CO3 (651 mg, 2.0 mmol). After being stir-
red for 5 min at rt, the suspension of Pd(OAc)2 (11.2 mg,
0.05 mmol) and (R)-SEGPHOS (45.8 mg, 0.075 mmol) in toluene
(2.0 mL) was added to the mixture, and then the reaction mixture
was vigorously stirred for 24 h at 80 ꢀC (When the reaction mix-
ture was heated for several hours, some solids adhered to the
flask’s walls above the solution. The solids, including active cat-
alyst, had to be resuspended in the reaction solution by shaking
the flask). The mixture was poured into 2% HCl solution and
extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt¼10) gave 2a
(267 mg, 95%). The ee (93%ee) of 2a was determined by HPLC
analysis using a CHIRALPACK AD-H column [25 cmꢂ0.46 cm i.d.;
3% i-PrOH in hexane; flow rate, 1.0 mL/min; (-)-2a (major);
4.2. NH-Anilides 1a–d
NH-Anilides 1a and 1b were prepared in accordance with the
procedure described in our previous paper.4b Anilides 1c and 1d
were prepared in accordance with following procedure.
4.2.1. N-(2-tert-Butyl-4-methoxyphenyl)-3-(2-iodophenyl)propana-
mide (1c). Under Ar atmosphere, to 2-tert-butyl-4-methoxyani-
line17 (538 mg, 3.0 mmol) in toluene (5.0 mL) was added 1 M
hexane solution of Me3Al (4.5 mL, 4.5 mmol) at 0 ꢀC. After being
stirred for 20 min at 0 ꢀC, ethyl 3-(2-iodophenyl)propanoate21
(821 mg, 2.7 mmol) was added to the mixture, and then the
reaction mixture was stirred for 18 h at 80 ꢀC. The mixture was
poured into 2% HCl. Insoluble materials were removed by filtration
with a Celite pad, and the filtrate was extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt¼5) gave 1c (716 mg, 61%). 1c:
tR¼11.3 min, (þ)-2a (minor); tR¼12.6 min]. 2a: [ ]D¼ꢁ77.1 (c 1.0,
a
CHCl3); 1H and 13C NMR of lactam 2a coincided with that reported
in our previous paper (see copies of NMR chart in Supplementary
data).4b
white solid; mp 122–124 ꢀC; IR (KBr) 3262, 1645 cmꢁ1
;
1H NMR
: 7.83 (1H, dd, J¼0.9, 8.0 Hz), 7.23–7.36 (3H, m), 6.82–6.97
4.3.1. (R)-1-(2,5-di-tert-Butylphenyl)-3,4-dihydro-1H-quinoline-2-
one (2b). 2b was prepared from 1b (139 mg, 0.3 mmol) in accor-
dance with the general procedure for the synthesis of 2a (80 ꢀC,
24 h). Purification by column chromatography (hexane/AcOEt¼10)
gave 2b (96 mg, 95%). The ee (98%ee) of 2b was determined by
HPLC analysis using a CHIRALPACK AD-H column [25 cmꢂ0.46 cm
i.d.; 1% i-PrOH in hexane; flow rate, 1.0 mL/min; (þ)-2b (minor);
tR¼8.2 min, (ꢁ)-2b (major); tR¼9.9 min]. 2b (98%ee): white solid;
(CDCl3)
d
(3H, m), 6.74 (1H, dd, J¼2.9, 8.6 Hz), 3.79 (3H, s), 3.19 (2H, t,
J¼8.0 Hz), 2.68 (2H, t, J¼8.0 Hz), 1.32 (9H, s); 13C NMR (CDCl3)
d:
170.6, 157.5, 146.2, 143.0, 139.2, 130.7, 129.7, 128.3, 127.9, 127.6,
113.3, 110.1, 100.2, 55.0, 36.9, 36.2, 34.5, 30.4; MS (m/z) 438 (MHþ);
Anal. Calcd for C20H24INO2: C, 54.93; H, 5.53; N, 3.20. Found: C,
55.13; H, 5.53; N, 3.17. In 1H- and 13C NMR, the minor signals, which
may be due to the existence of the amide rotamer were also
observed.
[
a
]D¼ꢁ83.3 (c 1.0, CHCl3); 1H and 13C NMR of lactam 2b coincided
with that reported in our previous paper (see copies of NMR chart
in Supplementary data).4b
4.2.2. 2-[Benzyl-(2-iodophenyl)amino]-N-(2-tert-butylphenyl)aceta-
mide (1d). Under Ar atmosphere, to N-benzyl-2-iodoaniline22
(4.54 g, 14.7 mmol) and K2CO3 (5.08 g, 36.8 mmol) in acetonitrile
(12 mL) was added ethyl iodoacetate (3.5 mL, 29.4 mmol) at rt, and
then the reaction mixture was stirred for 47 h at 90 ꢀC. After
evaporation of acetonitrile, the mixture was poured into water and
extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt¼150) gave
ethyl N-benzyl-N-(2-iodophenyl)aminoacetate (2.25 g, 39%). Un-
der Ar atmosphere, to 2-tert-butylaniline (942 mg, 6.3 mmol) in
toluene (8.0 mL) was added 1 M hexane solution of Me3Al (7.3 mL,
7.3 mmol) at 0 ꢀC. After being stirred for 20 min at 0 ꢀC, N-benzyl-
N-(2-iodophenyl)aminoacetate (1.92 g, 4.9 mmol) was added to
the mixture, and then the reaction mixture was stirred for 17 h at
4.3.2. 1-(2-tert-Butyl-4-methoxyphenyl)-3,4-dihydro-1H-quinoline-
2-one (2c). 2c was prepared from 1c (137 mg, 0.31 mmol) in
accordance with the general procedure for the synthesis of 2a
(80 ꢀC, 24 h). Purification by column chromatography (hexane/
AcOEt¼3) gave 2c (95 mg, 98%). The ee (93%ee) of 2c was
determined by HPLC analysis using a CHIRALPACK AD-H column
[25 cmꢂ0.46 cm i.d.; 10% i-PrOH in hexane; flow rate, 1.0 mL/min;
(þ)-2c (minor); tR¼8.6 min, (ꢁ)-2c (major); tR¼12.1 min]. 2c
(93%ee): white solid; [
a
]D¼ꢁ101.5 (c 1.0, CHCl3); mp 146 ꢀC; IR
(KBr) 1685 cmꢁ1; 1H NMR (CDCl3)
d: 7.21 (1H, d, J¼8.0 Hz), 7.14 (1H,
d, J¼2.6 Hz), 7.05 (1H, dt, J¼1.4, 8.0 Hz), 6.97 (1H, dt, J¼1.4, 8.0 Hz),
6.91 (1H, d, J¼8.5 Hz), 6.86 (1H, dd, J¼2.6, 8.5 Hz), 6.29 (1H, d,
J¼8.0 Hz), 3.85 (3H, s), 3.11 (1H, ddd, J¼6.0, 11.8, 15.6 Hz), 2.99 (1H,
td, J¼6.0, 15.6 Hz), 2.86 (1H, td, J¼6.0, 16.0 Hz), 2.78 (1H, ddd, J¼6.0,

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
293
11.8, 16.0 Hz), 1.21 (9H, s); 13C NMR (CDCl3)
d
: 171.2, 159.1, 149.0,
with that of the product obtained by
infra).
a
-methylation of 2a (vide
142.5, 132.9, 128.6, 127.7, 127.0, 125.1, 122.6, 117.0, 115.6, 112.1, 55.2,
35.7, 32.3, 31.3, 25.2; MS (m/z) 310 (MHþ); Anal. Calcd for
C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.55; H, 7.38; N,
4.45.
4.5. Experimental procedure for diastereoselective
alkylation of lactam 2a
a-
4.3.3. 4-Benzyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quinoxaline-
2-one (2d). 2d was prepared from 1d (150 mg, 0.3 mmol) in
accordance with the general procedure for the synthesis of 2a
(80 ꢀC, 6 h). Purification by column chromatography (hexane/
AcOEt¼10) gave 2d (81 mg, 72%). The ee (89% ee) of 2d was
determined by HPLC analysis using a CHIRALCEL OD-H column
[25 cmꢂ0.46 cm i.d.; 5% i-PrOH in hexane; flow rate, 1.0 mL/min;
(ꢁ)-2d (major); tR¼13.0 min, (þ)-2d (minor); tR¼14.6 min]. 2d
Under Ar atmosphere, to 2,2,6,6-tetramethylpiperidine
(0.086 mL, 0.42 mmol) in THF (2.0 mL) was added 1.57 M hexane
solution of n-BuLi (0.23 mL, 0.36 mmol) at 0 ꢀC. After being stirred
for 30 min at 0 ꢀC, lactam (R)-2a (84 mg, 0.3 mmol) was added to
the mixture, and then the reaction mixture was stirred for 1 h at
0 ꢀC. CH3I (26
m
L, 0.42 mmol) was added at ꢁ78 ꢀC, and the mixture
was stirred for 20 min at ꢁ78 ꢀC. The mixture was poured into
NH4Cl solution and extracted with AcOEt. The AcOEt extracts were
washed with brine, dried over MgSO4, and evaporated to dryness.
Purification of the residue by column chromatography (hexane/
AcOEt¼10) and subsequent MPLC (hexane/AcOEt¼10) gave 4a0
(2.3 mg, 2.6%, less polar) and 4a (72 mg, 81%, more polar).
(89% ee): colorless oil; [
a
]D¼ꢁ25.3 (c 1.0, CHCl3); IR (neat)
: 7.67 (1H, dd, J¼1.5, 8.0 Hz), 7.45
1687 cmꢁ1 1H NMR (CDCl3)
;
d
(1H, dt, J¼1.5, 8.0 Hz), 7.31–7.39 (6H, m), 7.08 (1H, dd, J¼1.5,
7.7 Hz), 6.97 (1H, dt, J¼1.2, 8.0 Hz), 6.85 (1H, d, J¼8.0 Hz), 6.69 (1H,
dt, J¼1.2, 8.0 Hz), 6.29 (1H, dd, J¼1.2, 8.0 Hz), 4.62 (1H, d,
J¼14.9 Hz), 4.31 (1H, d, J¼14.9 Hz), 3.99 (1H, d, J¼15.3 Hz), 3.89
4.5.1. (R,R) and (S,R)-1-(2-tert-Butylphenyl)-3-methyl-3,4-dihydro-
(1H, d, J¼15.3 Hz), 1.30 (9H, s); 13C NMR (CDCl3)
d
:167.3, 147.9,
1H-quinoline-2-one (4a and 4a0). 4a (93%ee): white solꢁid1;
136.7, 136.5, 134.8, 132.1, 129.6, 129.0, 128.8, 127.73, 127.70, 127.6,
123.8, 119.2, 117.3, 112.6, 53.8, 53.6, 35.9, 31.5; MS (m/z) 371
(MHþ); HRMS. Calcd for C25H27N2O (MHþ): 371.2123, Found:
371.2118.
[
a
]D¼ꢁ17.0 (c 0.922, CHCl3); mp 150–151 ꢀC; IR (KBr) 1672 cm
;
1H NMR (CDCl3)
d
: 7.63 (1H, dd, J¼1.6, 8.0 Hz), 7.39 (1H, dt, J¼1.6,
7.6 Hz), 7.30 (1H, dt, J¼1.6, 7.6 Hz), 7.20 (1H, dd, J¼1.2, 7.2 Hz), 7.04
(1H, dt, J¼1.6, 7.8 Hz), 6.97 (1H, dt, J¼1.2, 7.2 Hz), 6.89 (1H, dd, J¼1.6,
7.6 Hz), 6.19 (1H, dd, J¼1.2, 8.0 Hz), 3.18 (1H, m), 2.78–2.89 (2H, m),
4.4. Stereochemical assignment of lactam product
1.29 (3H, d, J¼6.7 Hz), 1.26 (9H, s); 13C NMR (CDCl3)
d: 173.3, 148.0,
142.1, 136.2, 131.8, 129.7, 128.6, 128.3, 127.8, 127.1, 124.1, 122.7, 117.2,
36.1, 36.0, 33.1, 31.7, 15.7; MS (m/z) 294 (MHþ); Anal. Calcd for
C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found: C, 81.47; H, 7.92; N, 4.59.
4a0: white solid; mp 89–91 ꢀC; IR (KBr) 1680 cmꢁ1; 1H NMR (CDCl3)
4.4.1. (S)-N-(2-tert-Butylphenyl)-3-(2-iodophenyl)-2-methyl-
propanamide (3a). Under Ar atmosphere, to 2-tert-butyl-aniline
(102 mg, 0.68 mmol) in toluene (1.0 mL) was added 1 M hexane
solution of Me3Al (1.0 mL, 1.0 mmol) at 0 ꢀC. After being stirred for
20 min at 0 ꢀC, ethyl (S)-methyl 3-(2-iodophenyl)-2-methyl-
propanoate 4b (173 mg, 0.57 mmol) was added to the mixture, and
then the reaction mixture was stirred for 18 h at 80 ꢀC. The mixture
was poured into 2% HCl. Insoluble materials were removed by
filtration with a Celite pad, and the filtrate was extracted with
AcOEt. The AcOEt extracts were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification of the residue by
column chromatography (hexane/AcOEt¼10) gave 3a (221 mg,
d
: 7.62 (1H, dd, J¼1.6, 8.0 Hz), 7.40 (1H, dt, J¼1.7, 7.5 Hz), 7.33 (1H,
dt, J¼1.7, 7.5 Hz), 7.22 (1H, d, J¼7.0 Hz), 7.04 (1H, dt, J¼1.5, 7.9 Hz),
6.95–7.02 (2H, m), 6.21 (1H, dd, J¼1.2, 7.9 Hz), 3.01 (1H, dd, J¼6.2,
14.9 Hz), 2.90 (1H, dd, J¼12.9, 14.9 Hz), 2.78 (1H, quint-d, J¼6.2,
12.9 Hz), 1.39 (3H, d, J¼6.2 Hz), 1.21 (9H, s); 13C NMR (CDCl3)
d:
173.7, 147.6, 142.4, 136.6, 132.5, 129.4, 128.6, 127.68, 127.67, 127.1,
125.3, 122.6, 116.8, 36.1, 35.8, 33.5, 31.5, 15.8; MS (m/z) 294 (MHþ);
HRMS. Calcd for C20H24NO (MHþ): 294.1858, Found: 294.1844.
92%). 3a: white solid; [
a
]D¼þ97.6 (c 0.35, CHCl3); mp 90 ꢀC; IR (KBr)
4.5.2. (R,R)-3-Allyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quino-
line-2-one (4b). 4b was prepared from (R)-2a (140 mg, 0.5 mmol)
in accordance with the general procedure for the synthesis of 4a.
Purification by column chromatography (hexane/AcOEt¼30) and
subsequent MPLC (hexane/AcOEt¼20) gave 4b (133 mg, 83%). 4b
3250,1649 cmꢁ1; 1H NMR (CDCl3)
d
: 7.82 (1H, d, J¼7.6 Hz), 7.50 (1H,
d, J¼7.6 Hz), 7.34 (1H, d, J¼7.6 Hz), 7.08–7.30 (5H, m), 6.90 (1H, dt,
J¼1.7, 7.4 Hz), 3.23 (1H, dd, J¼10.2, 15.3 Hz), 2.80–2.90 (2H, m), 1.33
(3H, d, J¼6.2 Hz),1.29 (9H, s); 13C NMR (CDCl3)
d: 173.3,142.2, 142.0,
139.6, 135.1, 131.4, 128.49, 128.47, 127.5, 126.8, 126.5, 126.0, 100.4,
44.7, 42.8, 34.5, 30.7, 17.5; MS (m/z) 422 (MHþ); HRMS. Calcd for
C20H25INO (MHþ): 422.0981, Found: 422.0992.
(93% ee): white solid; [
(KBr) 1683 cmꢁ1
a
]D¼ꢁ58.4 (c 1.0, CHCl3); mp 78–82 ꢀC; IR
;
1H NMR (CDCl3)
d
: 7.63 (1H, dd, J¼1.5, 8.1 Hz),
7.39 (1H, dt, J¼1.5, 8.1 Hz), 7.30 (1H, dt, J¼1.5, 7.6 Hz), 7.19 (1H, d,
J¼7.0 Hz), 7.04 (1H, dt, J¼1.5, 7.6 Hz), 6.97 (1H, dt, J¼1.2, 7.6 Hz),
6.88 (1H, dd, J¼1.5, 7.6 Hz), 6.19 (1H, dd, J¼1.0, 8.0 Hz), 5.84 (1H,
dddd, J¼6.1, 8.1, 10.2, 17.0 Hz), 5.10 (1H, d, J¼10.2 Hz), 5.06 (1H, qd,
J¼1.6, 17.0 Hz), 3.15 (1H, dd, J¼5.4, 15.6 Hz), 2.89 (1H, dd, J¼6.7,
15.6 Hz), 2.81 (1H, m), 2.61 (1H, m), 2.23 (1H, td, J¼8.1,14.0 Hz),1.25
4.4.2. (S,R) and (S,S)-1-(2-tert-Butylphenyl)-3-methyl-3,4-dihydro-
1H-quinoline-2-one (ent-4a and 4a0). Under Ar atmosphere, to 3a
(126 mg, 0.3 mmol) in toluene (0.5 mL) was added Cs2CO3 (137 mg,
0.42 mmol). After being stirred for 5 min at rt, the suspension of
Pd(OAc)2 (2.2 mg, 0.01 mmol) and rac-BINAP (9.3 mg, 0.015 mmol)
in toluene (1.0 mL) was added to the mixture, and then the reaction
mixture was vigorously stirred for 43 h at 80 ꢀC. The mixture was
poured into 2% HCl solution and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over MgSO4, and evapo-
rated to dryness. Purification of the residue by column chroma-
tography (hexane/AcOEt¼10) and subsequent MPLC (hexane/
AcOEt¼10) gave 4a0 (24.4 mg, 28%, less polar) and ent-4a (26.2 mg,
30%, more polar). The ee (88% ee) of ent-4a was determined by
HPLC analysis using a CHIRALPACK AD-H column [25 cmꢂ0.46 cm
i.d.; 3% i-PrOH in hexane; flow rate, 1.0 mL/min; (ꢁ)-ent-4a
(9H, s); 13C NMR (CDCl3)
d: 172.6, 147.9, 141.9, 136.1, 135.3, 132.0,
129.6, 128.6, 128.4, 127.7, 127.0, 123.6, 122.8, 117.5, 116.9, 40.8, 35.9,
33.8, 31.6, 29.6; MS (m/z) 320 (MHþ); Anal. Calcd for C22H25NO: C,
82.72; H, 7.89; N, 4.38. Found: C, 82.75; H, 7.94; N, 4.47.
4.5.3. (R,R)-3-Benzyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quino-
line-2-one (4c). 4c was prepared from (R)-2a (84 mg, 0.3 mmol)
and benzyl bromide (50 mL, 0.42 mmol) in accordance with the
general procedure for the synthesis of 4a. Purification by column
chromatography (hexane/AcOEt¼10) and subsequent MPLC (hex-
ane/AcOEt¼10) gave 4c (93 mg, 84%). 4c (93% ee): white solid;
(minor); tR¼7.2 min, (þ)-ent-4a (major); tR¼8.6 min]. 4a:
[
a
]D¼ꢁ93.0 (c 1.04, CHCl3); mp 74–78 ꢀC; IR (KBr) 1684 cmꢁ1
;
1H
1
[
a
]D¼þ14.9 (c 0.52, CHCl3). H NMR of ent-4a and 4a0 coincided
NMR (CDCl3)
d
: 7.66 (1H, dd, J¼1.4, 8.0 Hz), 7.42 (1H, dt, J¼1.4,

294
M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
8.0 Hz), 7.19–7.37 (6H, m), 7.15 (1H, d, J¼7.0 Hz), 7.07 (1H, dt, J¼1.4,
7.5 Hz), 7.00 (1H, dt, J¼1.2, 7.5 Hz), 6.95 (1H, dd, J¼1.5, 7.5 Hz), 6.24
(1H, d, J¼7.9 Hz), 3.27 (1H, dd, J¼3.9, 13.5 Hz), 2.98–3.08 (2H, m),
2.72 (1H, dd, J¼7.5, 17.3 Hz), 2.66 (1H, dd, J¼10.4, 13.5 Hz), 1.27 (9H,
J¼7.2 Hz), 6.95–6.99 (2H, m),, 6.20 (1H, d, J¼8.0 Hz), 3.03 (1H, dd,
J¼5.7, 15.3 Hz), 2.87 (1H, t, J¼15.3 Hz), 2.65 (1H, m), 2.07 (1H, m),
1.44–1.61 (3H, m), 1.21 (9H, s), 0.98 (3H, t, J¼7.2 Hz); 13C NMR
(CDCl3) d: 173.3, 147.7, 142.2, 136.7, 132.5, 129.3, 128.5, 127.8, 127.6,
s); 13C NMR (CDCl3)
d
: 172.8, 147.9, 142.0, 138.7, 136.1, 132.0, 129.7,
127.0, 125.3, 122.6, 116.8, 40.7, 35.8, 31.8, 31.5, 30.6, 20.1, 14.1; MS
(m/z) 322 (MHþ); Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N,
4.36. Found: C, 81.83; H, 8.38; N, 4.18.
129.3, 128.70, 128.68, 128.55, 127.8, 127.1, 126.5, 123.4, 122.9, 117.0,
43.1, 35.9, 35.2, 31.6, 28.8; MS (m/z) 370 (MHþ); Anal. Calcd for
C26H27NO: C, 84.51; H, 7.37; N, 3.79. Found: C, 84.20; H, 7.52; N,
3.70.
4.7. Diastereoselective a-alkylation of a-substituted lactam
4.5.4. (R,R)-1-(2,5-di-tert-Butylphenyl)-3-propyl-3,4-dihydro-1H-
quinoline-2-one (4d). 4d was prepared from (R)-2a (559 mg,
2.0 mmol) and propyl iodide (0.27 mL, 2.8 mmol) in accordance
with the general procedure for the synthesis of 4a. Purification by
column chromatography (hexane/AcOEt¼30) and subsequent
MPLC (hexane/AcOEt¼20) gave 4d (553 mg, 86%) including trace
4.7.1. (R,R)-3-Allyl-1-(2-tert-butylphenyl)-3-methyl-3,4-dihydro-1H-
quinoline-2-one (5a). Under Ar atmosphere, to 2,2,6,6-tetrame-
thylpiperidine (0.12 mL, 0.7 mmol) in THF (2.0 mL) was added
1.65 M hexane solution of n-BuLi (0.36 mL, 0.60 mmol) at 0 ꢀC. After
being stirred for 30 min at 0 ꢀC, lactam 4a (147 mg, 0.5 mmol) was
added to the mixture, and then the reaction mixture was stirred for
amount of 4d0. 4d (93% ee): white solid; [
a
]D¼ꢁ97.4 (c 0.5,
1 h at 0 ꢀC. Allyl bromide (59
m
L, 0.7 mmol) was added at ꢁ78 ꢀC,
CHCl3); mp 112–113 ꢀC; IR (KBr) 1685 cmꢁ1
;
1H NMR (CDCl3)
d
:
and the mixture was stirred for 5 min at ꢁ78 ꢀC. The mixture was
poured into NH4Cl solution and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over MgSO4, and evapo-
rated to dryness. Purification of the residue by column chroma-
tography (hexane/AcOEt¼30) and subsequent MPLC (hexane/
AcOEt¼20) gave 5a (152 mg, 91%). 5a (93% ee): colorless oil;
7.62 (1H, dd, J¼1.5, 8.1 Hz), 7.39 (1H, dt, J¼1.6, 7.2 Hz), 7.31 (1H, dt,
J¼1.6, 7.2 Hz), 7.20 (1H, d, J¼7.0 Hz), 7.03 (1H, dt, J¼1.4, 7.7 Hz),
6.97 (1H, dt, J¼1.2, 7.2 Hz), 6.88 (1H, dd, J¼1.6, 7.7 Hz), 6.17 (1H,
dd, J¼1.0, 8.0 Hz), 3.21 (1H, dd, J¼5.3, 15.5 Hz), 2.84 (1H, dd, J¼5.6,
15.5 Hz), 2.77 (1H, m), 1.78 (1H, m), 1.40–1.54 (3H, m), 1.24 (9H, s),
0.94 (3H, t, J¼7.2 Hz),; 13C NMR (CDCl3)
d
: 173.4, 147.9, 141.9,
[
a
]D¼ꢁ122.6 (c 1.0, CHCl3); IR (neat) 1682 cmꢁ1; 1H NMR (CDCl3)
d:
136.2, 132.0, 129.6, 128.6, 128.4, 127.7, 126.9, 123.8, 122.6, 116.7,
40.9, 35.9, 31.6, 30.2, 20.2, 13.9; MS (m/z) 322 (MHþ); Anal. Calcd
for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 81.99; H, 8.45;
N, 4.05.
7.60 (1H, dd, J¼1.6, 8.0 Hz), 7.38 (1H, dt, J¼1.6, 7.3 Hz), 7.31 (1H, dt,
J¼1.6, 7.3 Hz), 7.16 (1H, d, J¼7.1 Hz), 7.03 (1H, dt, J¼1.2, 7.5 Hz), 6.97
(1H, dt, J¼1.2, 7.3 Hz), 6.87 (1H, dd, J¼1.6, 7.5 Hz), 6.15 (1H, dd,
J¼1.0, 8.0 Hz), 5.80 (1H, tdd, J¼7.4, 10.0, 17.0 Hz), 5.10 (1H, qd, J¼1.0,
10.0 Hz), 4.99 (1H, qd, J¼1.0, 17.0 Hz), 2.96 (1H, d, J¼15.8 Hz), 2.86
(1H, d, J¼15.8 Hz), 2.29 (1H, dd, J¼7.1, 14.6 Hz), 2.21 (1H, dd, J¼7.8,
4.6. Diastereoselective a-protonation of lactam 2a
14.6 Hz), 1.32 (3H, s), 1.22 (9H, s); 13C NMR (CDCl3)
d: 174.8, 147.7,
4.6.1. (S,R)-3-Allyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quino-
line-2-one (4b0). Under Ar atmosphere, to 2,2,6,6-tetramethyl-
piperidine (0.2 mL, 1.17 mmol) in THF (2.0 mL) was added 1.57 M
hexane solution of n-BuLi (0.61 mL, 1.0 mmol) at 0 ꢀC. After being
stirred for 30 min at 0 ꢀC, lactam 4b (160 mg, 0.5 mmol) was
added to the mixture, and then the reaction mixture was stirred
for 1 h at 0 ꢀC. 2% HCl (0.5 mL) was added at ꢁ78 ꢀC, and the
mixture was stirred for 5 min at ꢁ78 ꢀC. The mixture was poured
into NH4Cl solution and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane/AcOEt¼30) and subsequent MPLC (hexane/AcOEt¼20)
gave 4b0 (130 mg, 81%, less polar) and 4b (6.2 mg, 4%, more polar).
142.0, 136.6, 133.0, 132.3, 129.4, 128.5, 128.3, 127.6, 126.9, 123.7,
122.7, 118.7, 116.5, 40.8, 40.0, 37.2, 35.8, 31.5, 22.3; MS (m/z) 334
(MHþ); Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found:
C, 82.53; H, 8.10; N, 3.98.
4.7.2. (S,R)-3-Allyl-1-(2-tert-butylphenyl)-3-methyl-3,4-dihydro-
1H-quinoline-2-one (5a0). 5a0 was prepared from 4b (160 mg,
0.5 mmol) and methyl iodide (43 mL, 0.7 mmol) in accordance with
the experimental procedure for the synthesis of 5a. Purification by
column chromatography (hexane/AcOEt¼30) and subsequent
MPLC (hexane/AcOEt¼20) gave 5a0 (117 mg, 70%). 5a0 (93% ee):
colorless oil; [
NMR (CDCl3)
a
]D¼ꢁ116.5 (c 1.0, CHCl3); IR (neat) 1681 cmꢁ1
;
1H
d
: 7.61 (1H, dd, J¼1.6, 8.0 Hz), 7.38 (1H, dt, J¼1.6,
4b0 (93% ee): colorless oil; [
a
d
]D¼ꢁ200.4 (c 1.0, CHCl3); IR (neat)
7.3 Hz), 7.32 (1H, dt, J¼1.6, 7.3 Hz), 7.19 (1H, d, J¼7.3 Hz), 7.02 (1H, t,
J¼7.3 Hz), 6.97 (1H, dt, J¼1.3, 7.3 Hz), 6.89 (1H, dd, J¼1.6, 7.6 Hz),
6.14 (1H, dd, J¼1.3, 8.0 Hz), 5.93 (1H, m), 5.12–5.18 (2H, m), 3.17 (1H,
d, J¼15.7 Hz), 2.72 (1H, dd, J¼6.6, 13.6 Hz), 2.59 (1H, d, J¼15.7 Hz),
2.35 (1H, dd, J¼8.3, 13.6 Hz), 1.21 (9H, s), 1.15 (3H, s); 13C NMR
1684 cmꢁ1 1H NMR (CDCl3)
;
: 7.62 (1H, dd, J¼1.6, 8.0 Hz), 7.39
(1H, dt, J¼1.6, 7.3 Hz), 7.33 (1H, dt, J¼1.6, 7.3 Hz), 7.22 (1H, d,
J¼7.3 Hz), 7.04 (1H, dt, J¼1.3, 7.7 Hz), 6.96–6.99 (2H, m), 6.19 (1H,
dd, J¼0.9, 8.0 Hz), 5.91 (1H, tdd, J¼7.6, 10.2, 17.0 Hz), 5.17 (1H, d,
J¼17.0 Hz), 5.13 (1H, d, J¼10.2 Hz), 2.99 (1H, dd, J¼5.9, 15.3 Hz),
2.89 (1H, t, J¼15.3 Hz), 2.69–2.86 (2H, m), 2.42 (1H, td, J¼8.0,
(CDCl3)
d: 175.0, 147.7, 141.6, 136.6, 134.3, 132.3, 129.4, 128.50,
128.47, 127.6, 126.8, 124.0, 122.7, 118.6, 116.5, 42.2, 40.8, 36.5, 35.7,
31.5, 22.3; MS (m/z) 334 (MHþ); Anal. Calcd for C23H27NO: C, 82.84;
H, 8.16; N, 4.20. Found: C, 82.51; H, 8.10; N, 4.00.
14.0 Hz), 1.21 (9H, s); 13C NMR (CDCl3)
d: 172.5, 147.6, 142.1, 136.5,
135.7, 132.4, 129.3, 128.6, 127.8, 127.6, 127.0, 125.1, 122.7, 117.4,
116.8, 40.5, 35.7, 34.2, 31.5, 30.1; MS (m/z) 320 (MHþ); Anal. Calcd
for C22H25NO: C, 82.72; H, 7.89; N, 4.38. Found: C, 82.55; H, 7.84;
N, 4.18.
4.7.3. (R,R)-1-(2-tert-Butylphenyl)-3-methyl-3-propyl-3,4-dihydro-
1H-quinoline-2-one (5d). 5d was prepared from 4a (147 mg,
0.5 mmol) and propyl iodide (70 mL, 0.7 mmol) in accordance with
4.6.2. (S,R)-1-(2-tert-Butylphenyl)-3-propyl-3,4-dihydro-1H-quino-
line-2-one (4d0). 4d0 was prepared from 4d (161 mg, 0.5 mmol) in
accordance with the experimental procedure for the synthesis of
4b0. Purification by column chromatography (hexane/AcOEt¼30)
and subsequent MPLC (hexane/AcOEt¼20) gave 4d0 (145 mg, 90%,
less polar) and 4d (5.6 mg, 3.5%, more polar) 4d0 (93% ee): white
the experimental procedure for the synthesis of 5a. Purification by
column chromatography (hexane/AcOEt¼30) and subsequent
MPLC (hexane/AcOEt¼20) gave 5d (77 mg, 46%). 5d (93% ee): col-
orless oil; [
(CDCl3)
a
]D¼ꢁ155.3 (c 1.0, CHCl3); IR (neat) 1682 cmꢁ1; 1H NMR
d: 7.61 (1H, dd, J¼1.4, 8.0 Hz), 7.38 (1H, dt, J¼1.4, 7.6 Hz),
7.32 (1H, dt, J¼1.4, 7.6 Hz), 7.18 (1H, d, J¼7.2 Hz), 7.03 (1H, t,
J¼7.6 Hz), 6.97 (1H, t, J¼7.6 Hz), 6.87 (1H, dd, J¼1.6, 7.6 Hz), 6.15
(1H, d, J¼8.0 Hz), 3.02 (1H, d, J¼15.7 Hz), 2.83 (1H, d, J¼15.7 Hz),
1.54 (1H, m), 1.27–1.44 (3H, m), 1.33 (3H, s), 1.22 (9H, s), 0.85 (3H, t,
solid; [
a
]D¼ꢁ143.6 (c 0.7, CHCl3); mp 94–97 ꢀC; IR (KBr) 1684 cmꢁ1
;
1H NMR (CDCl3)
d
: 7.61 (1H, dd, J¼1.3, 8.0 Hz), 7.38 (1H, dt, J¼1.5,
7.6 Hz), 7.32 (1H, dt, J¼1.5, 7.6 Hz), 7.22 (1H, d, J¼7.2 Hz), 7.03 (1H, t,

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
295
J¼6.8 Hz); 13C NMR (CDCl3)
d
: 175.3, 147.7, 142.0, 136.7, 132.3, 129.3,
30.9, 30.1, 26.1; MS (m/z) 338 (MHþ); Anal. Calcd for C22H27NO2: C,
78.30; H, 8.06; N, 4.15. Found: C, 78.16; H, 7.90; N, 3.98.
128.4, 128.2, 127.6, 126.8, 123.9, 122.5, 116.2, 40.9, 38.2, 38.0, 35.8,
31.5, 22.6, 17.1, 14.6; MS (m/z) 336 (MHþ); Anal. Calcd for C23H29NO:
C, 82.34; H, 8.71; N, 4.18. Found: C, 82.04; H, 8.84; N, 4.45.
4.9.2. (R,R)-1-(2-tert-Butylphenyl)-3-(3-hydroxypropyl)-3-methyl-
3,4-dihydro-1H-quinoline-2-one (6a). 6a was prepared from 5a
(116 mg, 0.35 mmol) in accordance with the experimental
procedure for the synthesis of 6b. Purification of the residue by
column chromatography (hexane/AcOEt¼2) gave 6a (122 mg, 99%).
4.7.4. (S,R)-1-(2-tert-Butylphenyl)-3-methyl-3-propyl-3,4-dihydro-
1H-quinoline-2-one (5d0). 5d0 was prepared from 4d (147 mg,
0.5 mmol) and methyl iodide (43 mL, 0.7 mmol) in accordance with
the experimental procedure for the synthesis of 5a. Purification by
column chromatography (hexane/AcOEt¼30) and subsequent
MPLC (hexane/AcOEt¼20) gave 5d0 (118 mg, 70%). 5d0 (93% ee):
6a (93% ee): colorless oil; [
a
]D¼ꢁ145.7 (c 0.2, CHCl3); IR (neat)
: 7.60 (1H, dd, J¼1.5, 8.1 Hz),
3443, 1668 cmꢁ1 1H NMR (CDCl3)
;
d
7.37 (1H, dt, J¼1.5, 7.6 Hz), 7.30 (1H, dt, J¼1.5, 7.6 Hz), 7.17 (1H, d,
J¼7.1 Hz), 7.03 (1H, t, J¼7.6 Hz), 6.96 (1H, dt, J¼1.0, 7.3 Hz), 6.85 (1H,
dd, J¼1.5, 7.6 Hz), 6.15 (1H, d, J¼8.0 Hz), 3.55 (2H, t, J¼5.8 Hz), 3.01
(1H, d, J¼15.8 Hz), 2.86 (1H, d, J¼15.8 Hz), 1.50–1.67 (5H, m), 1.33
white solid; [
a
]D¼ꢁ124.7 (c 1.0, CHCl3); mp 110–112 ꢀC; IR (KBr)
1677 cmꢁ1
;
1H NMR (CDCl3)
d
: 7.60 (1H, dd, J¼1.5, 8.0 Hz), 7.37
(1H, dt, J¼1.5, 7.3 Hz), 7.31 (1H, dt, J¼1.5, 7.3 Hz), 7.19 (1H, d,
J¼7.1 Hz), 7.02 (1H, dt, J¼1.1, 7.5 Hz), 6.96 (1H, dt, J¼1.1, 7.3 Hz),
6.88 (1H, dd, J¼1.4, 7.5 Hz), 6.14 (1H, d, J¼8.0 Hz), 3.17 (1H, d,
J¼15.5 Hz), 2.65 (1H, d, J¼15.5 Hz), 1.87 (1H, ddd, J¼5.3, 12.0,
13.4 Hz), 1.62 (1H, m), 1.37–1.46 (2H, m), 1.22 (9H, s), 1.14 (3H, s),
(3H, s), 1.21 (9H, s); 13C NMR (CDCl3)
d: 175.0, 147.8, 141.8, 136.6,
132.2, 129.4, 128.5, 128.3, 127.7, 127.0, 123.7, 122.7, 116.5, 63.0, 40.6,
38.1, 35.9, 32.2, 31.5, 27.3, 22.5; MS (m/z) 352 (MHþ); HRMS Calcd
for C23H30NO2 (MHþ): 352.2277. Found: 352.2288.
0.96 (3H, t, J¼7.3 Hz); 13C NMR (CDCl3)
d: 175.6, 147.7, 141.8, 136.8,
132.3, 129.2, 128.40, 128.36, 127.6, 126.8, 124.2, 122.6, 116.4, 40.9,
39.9, 36.6, 35.8, 31.6, 22.6, 17.3, 14.8; MS (m/z) 336 (MHþ); Anal.
Calcd for C23H29NO: C, 82.34; H, 8.71; N, 4.18. Found: C, 82.18; H,
8.55; N, 3.92.
4.9.3. (R)-3-(3-Hydroxypropyl)-1-phenyl-3,4-dihydro-1H-quinoline-
2-one (7b). Under Ar atmosphere, to 6b (40.5 mg, 0.12 mmol) in
benzene (12 mL) was added AlCl3 (160 mg, 1.2 mmol) at rt. The
reaction mixture was stirred for 10 h at 80 ꢀC. The mixture was
poured into water and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane/AcOEt¼2) and subsequent MPLC (hexane/AcOEt¼1) gave
7b (19 mg, 57%). The ee (93% ee) of 7b was determined by HPLC
analysis using a CHIRALCEL OD-H column [25 cmꢂ0.46 cm i.d.; 20%
i-PrOH in hexane; flow rate, 1.0 mL/min; (ꢁ)-7b (minor);
tR¼6.2 min, (þ)-7b (major); tR¼7.3 min]. 7b (93% ee): white solid;
4.8. (R,R)-1-(2-tert-Butyl-4-methoxyphenyl)-3-methyl-3,4-
dihydro-1H-quinoline-2-one (6c)
6c was prepared from 2c (93 mg, 0.3 mmol) and methyl iodide
(26 mL, 0.42 mmol) in accordance with the general procedure for
the synthesis of 4a. Purification by column chromatography (hex-
ane/AcOEt¼5) and subsequent MPLC (hexane/AcOEt¼5) gave
diastereomer of 6c (1.8 mg, 2%, less polar) and 6c (60 mg, 62%, more
[
a
]D¼þ15.6 (c 0.4, CHCl3); mp 106–108 ꢀC; IR (KBr) 3420,
1682 cmꢁ1
;
1H NMR (CDCl3)
d
: 7.50 (2H, t, J¼7.6 Hz), 7.41 (1H, tt,
polar). 6c (93%ee): colorless gel; [
a
]D¼ꢁ30.0 (c 1.20, CHCl3); IR
J¼1.2, 7.6 Hz), 7.18–7.22 (3H, m), 7.04 (1H, dt, J¼1.5, 7.6 Hz), 6.99
(1H, dt, J¼1.2, 7.6 Hz), 6.34 (1H, dd, J¼1.2, 7.8 Hz), 3.62–3.72 (2H, m),
3.13 (1H, dd, J¼5.4, 15.4 Hz), 2.92 (1H, dd, J¼9.8, 15.4 Hz), 2.80 (1H,
(KBr) 1684 cmꢁ1; 1H NMR (CDCl3)
d
: 7.19 (1H, d, J¼7.4 Hz), 7.14 (1H,
dd, J¼0.6, 2.4 Hz), 7.05 (1H, dt, J¼1.6, 7.4 Hz), 6.96 (1H, dt, J¼1.2,
7.4 Hz), 6.85 (1H, dd, J¼2.4, 8.6 Hz), 6.81 (1H, dd, J¼0.6, 8.6 Hz), 6.25
(1H, dd, J¼1.2, 8.1 Hz), 3.85 (3H, s), 3.18 (1H, dd, J¼4.6, 14.3 Hz),
2.76–2.90 (2H, m), 1.27 (3H, d, J¼6.8 Hz), 1.24 (9H, s); 13C NMR
m), 1.98 (1H, m), 1.58–1.82 (4H, m); 13C NMR (CDCl3)
d: 172.7, 141.1,
138.6, 129.8, 129.0, 128.1, 128.1, 127.1, 124.9, 123.0, 116.8, 62.4, 40.7,
31.3, 30.2, 25.9; MS (m/z) 304 (MNaþ); HRMS Calcd for
C18H19NO2Na (MNaþ): 304.1313. Found: 304.1305.
(CDCl3) d:173.8, 159.1, 149.2, 142.2, 132.7, 129.0, 128.3, 126.9, 123.9,
122.5, 117.1, 115.7, 112.2, 55.3, 36.1, 35.9, 32.9, 31.5, 15.6; MS (m/z)
294 (MHþ); Anal. Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33.
Found: C, 77.69; H, 7.80; N, 4.16.
4.9.4. (R)-3-(3-Hydroxypropyl)-1-methyl-1-phenyl-3,4-dihydro-1H-
quinoline-2-one (7a). 7a was prepared from 6a (131 mg,
0.37 mmol) in accordance with the experimental procedure for the
synthesis of 7b. Purification of the residue by column chromatog-
raphy (hexane/AcOEt¼2) gave 7a (58 mg, 53%). The ee (93% ee) of
7a was determined by HPLC analysis using a CHIRALPAK AD-H
column [25 cmꢂ0.46 cm i.d.; 20% i-PrOH in hexane; flow rate,
1.0 mL/min; (þ)-7a (minor); tR¼7.6 min, (-)-7a (major);
4.9. Synthesis of NET inhibitors
4.9.1. (R,R)-1-(2-tert-Butylphenyl)-3-(3-hydroxypropyl)-3,4-dihydro-
1H-quinoline-2-one (6b). Under Ar atmosphere, to 0.5 M THF solu-
tion of 9-BBN (1.44 mL, 0.72 mmol) was added 4b (94 mg,
0.29 mmol) at rt. After being stirred for 2 h at rt, EtOH (0.21 mL), 3 M
NaOH aq (2.8 mL) and 30% H2O2 aq (0.39 mL) were added to the
mixture, and then the reaction mixture was stirred for 1 h at 60 ꢀC.
tR¼10.7 min]. 7a (93% ee): white solid; [
a
;
]D¼ꢁ12.8 (c 1.0, CHCl3);
mp 82–85 ꢀC; IR (KBr) 3435, 1680 cmꢁ1
1H NMR (CDCl3)
d
: 7.50
(2H, t, J¼7.5 Hz), 7.40 (1H, t, J¼7.5 Hz), 7.16–7.20 (3H, m), 7.03 (1H,
dt, J¼1.5, 7.5 Hz), 6.98 (1H, dt, J¼1.0, 7.5 Hz), 6.28 (1H, dd, J¼1.0,
8.0 Hz), 3.59 (2H, t, J¼5.7 Hz), 3.02 (1H, d, J¼15.7 Hz), 2.88 (1H, d,
CH3I (26
m
L, 0.42 mmol) was added at ꢁ78 ꢀC, and the mixture was
stirred for 20 min at ꢁ78 ꢀC. The mixture was poured into water and
extracted with AcOEt. The AcOEt extracts were washed with brine,
dried over MgSO4, and evaporated to dryness. Purification of the
residue by column chromatography (hexane/AcOEt¼2) gave 6b
J¼15.7 Hz), 1.63–1.78 (5H, m), 1.27 (3H, s); 13C NMR (CDCl3)
d: 174.7,
140.8,138.8,129.8,129.0,128.4,128.0,127.0,124.0,122.9,116.2, 62.8,
40.6, 37.8, 32.6, 27.5, 22.5; MS (m/z) 296 (MHþ); HRMS Calcd for
C19H22NO2 (MHþ): 296.1651. Found: 296.1678.
(87 mg, 89%). 6b (93% ee): white solid; [
a
]D¼ꢁ44.0 (c 1.0, CHCl3);
mp 91–92 ꢀC; IR (KBr) 3420,1681 cmꢁ1; 1H NMR (CDCl3)
d
: 7.63 (1H,
dd, J¼1.5, 8.1 Hz), 7.39 (1H, dt, J¼1.5, 7.6 Hz), 7.31 (1H, dt, J¼1.5,
7.6 Hz), 7.20 (1H, d, J¼7.0 Hz), 7.04 (1H, dt, J¼1.5, 7.6 Hz), 6.98 (1H,
dt, J¼1.2, 7.3 Hz), 6.87 (1H, dd, J¼1.5, 7.6 Hz), 6.19 (1H, d, J¼7.6 Hz),
3.60–3.70 (2H, m), 3.21 (1H, dd, J¼5.1, 15.3 Hz), 2.88 (1H, dd, J¼6.8,
15.3 Hz), 2.82 (1H, m), 2.01 (1H, br s),1.88 (1H, m),1.55–1.82 (3H, m),
Acknowledgements
We gratefully acknowledge Takasago International Corporation
for supplying (R)-SEGPHOS. This work was partly supported by
a Grant-in-Aid from The Research Foundation for Pharmaceutical
Sciences, and a Grant-in-Aid [(C) Grant No. 18590018] for Scientific
1.25 (9H, s); 13C NMR (CDCl3)
128.7, 128.4, 127.8, 127.1, 123.8, 122.9, 117.0, 62.4, 40.8, 35.9, 31.6,
d: 173.3, 147.9, 141.7, 136.0, 131.8, 129.7,

296
M. Takahashi et al. / Tetrahedron 66 (2010) 288–296
6. After publication of our paper (Ref. 4a), catalytic asymmetric syntheses of
similar N–C axially chiral compounds were also reported by other groups: (a)
Brandes, S.; Bella, M.; Kjoersgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2006, 45, 1147; (b) Tanaka, K.; Takeishi, K.; Noguchi, K. J. Am. Chem. Soc. 2006,
128, 4586; (c) Brandes, S.; Niess, B.; Bella, M.; Prieto, A.; Overgaard, J.; Jor-
gensen, K. A. Chem.d Eur. J. 2006, 12, 6039; (d) Duan, W.; Imazaki, Y.; Shintani,
R.; Hayashi, T. Tetrahedron 2007, 63, 8529; (e) Oppenheimer, J.; Hsung, R. P.;
Figueroa, R.; Johnson, W. L. Org. Lett. 2007, 9, 3969; (f) Tanaka, K.; Takahashi, Y.;
Suda, T.; Hirano, M. Synlett 2008, 1724; (g) Clayden, J.; Turner, H. Tetrahedron
Lett. 2009, 50, 3216; (h) Oppenheimer, J.; Johnson, W. L.; Figueroa, R.; Hayashi,
R.; Hsung, R. P. Tetrahedron 2009, 65, 5001.
Research and the Ministry of Education, Science, Sports and Culture
of Japan.
Supplementary data
Copies of 1H- and 13C NMR spectra of key compounds and new
compounds. Supplementary data associated with this article can be
found in online version, at doi:10.1016/j.tet.2009.10.095.
7. Quite recently, catalytic asymmetric Buchwald–Hartwig amination using achi-
ral substrates was also reported by other groups. (a) Takenaka, K.; Itoh, N.;
Sasai, H. Org. Lett. 2009, 11, 1483; (b) Ishibashi, K.; Tsue, H.; Takahashi, H.;
Tamura, R. Tetrahedron: Asymmetry 2009, 10, 375; (c) Porosa, L.; Viirre, R. D.
Tetrahedron Lett. 2009, 50, 4170.
8. Beadle, C. D.; Boot, J.; Camp, N. P.; Dezutter, N.; Findlay, J.; Hayhurst, L.; Masters,
J. J.; Penariol, R.; Walter, M. W. Bioorg. Med. Chem. Lett. 2005, 15, 4432.
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Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42, 6543.
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Taguchi, T. Tetrahedron Lett. 2008, 49, 471.
11. (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumo-
bayashi, H. Adv. Synth. Catal. 2001, 343, 264; (b) Sumi, K.; Kumobayashi, K. Top.
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N.; Dellis, P. Tetrahedron Lett. 2003, 44, 823.
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14. The absolute configuration of 2b was determined in accordance with similar
method to 2a (see ref. 4b).
15. (a) Cundy, K. C.; Crooks, P. A. J. Chromatogr. 1983, 281, 17; (b) Charles, R.; Gil-Av,
E. J. Chromatogr. 1984, 298, 516; (c) Dobashi, A.; Motoyama, Y.; Kinoshita, K.;
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Shogase, Y.; Kitahara, Y. J. Chem. Soc., Perkin Trans. 1 1998, 935; (h) Ernholt, B. V.;
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References and notes
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Mino, T.; Fujita, T. J. Org. Chem. 2003, 68, 942; (j) Sakamoto, M.; Utsumi, N.;
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bata, T.; Jiang, C.; Hyashi, K.; Tsubaki, K.; Yoshimura, T.; Majumdar, S.; Sasamori,
T.; Tokitoh, N. J. Am. Chem. Soc. 2009, 131, 54.
2. Typical papers on atropisomeric ortho-tert-butylanilides: (a) Curran, D. P.; Qi,
H.; Geib, S. J.; DeMello, N. C. J. Am. Chem. Soc. 1994, 116, 3131; (b) Kishikawa, K.;
Tsuru, I.; Kohomoto, S.; Yamamoto, M.; Yamada, K. Chem. Lett. 1994, 1605; (c)
Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org. Chem.
1998, 63, 2634; (d) Hughes, A. D.; Price, D. A.; Simpkins, N. S. J. Chem. Soc.,
Perkin Trans. 1 1999, 1295; (e) Bach, T.; Schro¨der, J.; Harms, K. Tetrahedron Lett.
1999, 40, 9003; (f) Kondo, K.; Iida, T.; Fujita, H.; Suzuki, T.; Yamaguchi, K.;
Murakami, Y. Tetrahedron 2000, 56, 8883; (g) Ates, A.; Curran, D. P. J. Am. Chem.
Soc. 2001,123, 5130; (h)Dantale, S.; Reboul, V.; Metzner, P.;Philouze,C. Chem.dEur.
J. 2002, 8, 632.
3. (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995,
34, 1348; (b) Hartwig, J. F.; Loue, J. Tetrahedron Lett. 1995, 36, 3609; (c) Yin, J.;
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Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley-Interscience: New York, NY, 2002; p 1051; (h) Jiang, L.; Buchwald, S. L.
In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; De Meijere, A., Diederich,
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kahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923.
5. Although the enantioselectivity is not high (30–50% ee), first catalytic asym-
metric synthesis of N–C axially chiral compounds through enatioselective N-
16. Configuration of
hydrogen or -alkyl group on the lactam ring and ortho- tert-butyl group.
17. Similar stereoselective -mono-alkylation with racemic atropisomeric N-(or-
a-carbon was determined on the basis of NOE between a-
a
a
tho- tert-butylphenyl)-5,6-dehydropiperidin-2-one has been reported: Bennett,
D. J.; Blake, A. J.; Cooke, P. A.; Godfrey, C. R. A.; Pickering, P. L.; Simpkins, N. S.;
Walker, M. D.; Wilson, C. Tetrahedron 2004, 60, 4491.
18. Bennett, D. J.; Pickering, P. L.; Simpkins, N. S. Chem. Commun. 2004, 1392.
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Rosauer, K. G.; Ogawa, A. K.; Willoughby, C. A.; Ellsworth, K. P.; Geissler, W. M.;
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allylation using chiral
p-allyl-Pd catalyst was independently reported by us and
Curran’s group. (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002,
67, 8682; (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003, 14, 587.