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

Tetrahedron 66 (2010) 288–296

Contents lists available at ScienceDirect

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: Received 7 October 2009 Received in revised form 23 October 2009 Accepted 27 October 2009 Available online 31 October 2009

In the presence of (R)-SEGPHOS-Pd(OAc)2 catalyst, the intramolecular N-arylation of ortho-tert-butylNH-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 enantioenriched 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 lactam with various alkyl halides gave a-substituted and a,a-disubstituted lactam products with high diastereoselectivity. a-Alkylated lactam derivatives were efficiently converted to key intermediates for the synthesis of an NET inhibitor. Ó 2009 Elsevier Ltd. All rights reserved.

Keywords: Atropisomerism Lactams Palladium Enantioselective Diastereoselective Enolate Alkylation

1. Introduction O

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 Furthermore, highly diastereoslective a-alkylation using lithium enolates

R1

NH

t-Bu

+ Ar-I R2 "achiral"

O N

Ph t-Bu

(R1 = Et) (R2 = H)

5.0 mol% (R)-DTBM-SEGPHOS 3.3 mol% Pd(OAc)2 1.4 eq. Cs2CO3

O N

R1

Ar t-Bu

toluene, 80 °C R2 = t-Bu (91-95% ee) R2 = H (88-96% ee) Ar = 4-nitrophenyl

"axially chiral"

O

1) n-BuLi 2) R3-X

OH N

R3 THF

R2

Ph LAH t-Bu

R3 +

NHPh

t-Bu

Scheme 1. Catalytic enantioselective synthesis of atropisomeric anilides and their application to asymmetric enolate chemistry.

* Corresponding author. Tel.: þ81 3 5859 8161; fax: þ81 3 5859 8101. E-mail address: [email protected] (O. Kitagawa). y Present address: Takeda Pharmaceutical Company Ltd, Osaka, Japan. z Present address: Daicel Chemical Industries Ltd, Niigata, Japan. 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.10.095

prepared from anilide and lactam products was also found (Schemes 1 and 2).4 In the intramolecular reaction of Scheme 2, the use of NH-anilides (R1¼t-Bu) prepared from expensive 2,5-di-tert-butylaniline

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296

O NH t-Bu

I

1 "achiral" 1) Li-TMP 2) R2-X THF

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

N

NH

O

t-Bu

t-Bu I

toluene, 80 °C R1

289

R1 = t-Bu (96% ee) R1 = H (70% ee)

2 "axially chiral"

R2

R3

O

1a

R1

(1) N

R2

t-Bu

N

O

Ph

NET inhibitor

(?) R1

O t-Bu 2a

I [R2 = (CH2)3NHMe, R3 = H or Me]

O

O (R)-DTBM-SEGPHOS (12%, 0% ee)

(95%, 70% ee) O O

PPh2 PPh2

O

PAr2 PAr2 Ar = 3,5-di-t-Bu-4methoxyphenyl

O

(R)-BINAP

O

F

O

F

O

(R)-SEGPHOS

O

O

O (R)-SYNPHOS

(R)-DIFLUORPHOS

(95%, 93% ee)

PPh2 PPh2

O O

PPh2 PPh2

O

F F

(93%, 93% ee)

(93%, 90% ee)

1), which proceeded with poor enantioselectivity (23% ee) in the presence of an (R)-SEGPHOS ligand.4b Under the present conditions, the reactions with several substrates were further examined (Table 1). With 2,5-di-tert-butylNH-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). Table 1 Catalytic enantioselective N-arylation of several NH-anilides

O X

NH

2. Results and discussion

t-Bu

I

2.1. Highly catalytic enantioselective synthesis of atropisomeric lactam derivatives Initially, highly enantioselective synthesis of atropisomeric N-(2tert-butylphenyl)lactam was investigated. In intramolecular Buchwald–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 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 enantioselectivity was also observed (93% ee and 90% ee, Eq. 1). These results are in striking contrast to that of intermolecular reaction (Scheme

O

PPh2 PPh2

Scheme 2. Catalytic enantioselective synthesis of atropisomeric lactams and their application.

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-alkylation 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-tertbutyl group. In addition, although the removal of the tert-butyl group from a-alkylated atropisomeric lactam (conversion to 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–Hartwig amination.10 Furthermore, MPLC purification of the enantioenriched lactam products using achiral silica gel column was found to bring about a further increase in enantiomeric purity (>99% ee). Highly diastreodivergent synthesis of an a-alkylated lactam using asymmetric enolate chemistry and efficient conversion to key intermediate for synthesis of the NET inhibitor are also described.

O t-Bu

P P *

toluene 80 °C, 24 h

* N

(II)

Pd N

1

X

7.5 mol% (R)-SERGPHOS 5.0 mol% Pd(OAc)2 2 eq. Cs2CO3

N

O t-Bu

toluene 80 °C, 6-24 h R1

2

R1

R2

R2

Entry

1

X

R1

R2

2

Yielda (%)

eeb (%)

[a]Dc

1 2 3 4

1a 1b 1c 1d

CH2 CH2 CH2 NBn

H t-Bu H 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

a b c

Isolated yield. The ee was determined by HPLC analysis using a chiral column. [a]D value was measured in CHCl3 (c=1).

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 a-methylation product 4a in Table 2 (entry 1)

290

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296

NH2 O t-Bu

(S)

OMe

Pd (OAc)2 rac-BINAP Cs2CO3

O (S)

Me3Al

NH t-Bu

I (88% ee)

I 3a (92%) Ha

Me (S)

N (S)

t-Bu

toluene 80 °C

Me

(S)

N

O ent-4a

(R)

+

O t-Bu

(30%, 88% ee) [α]D = +14.9

4a' (28%)

t-Bu - Me (NOE) t-Bu - Ha (no NOE)

(c=0.52, CHCl3)

Scheme 3. Stereochemical assignment of lactam product.

with ent-4a prepared in accordance with Scheme 3.14 The configurations of 2c and 2d, which have negative [a]D values such as 2a 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, 304 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).

These results indicate that the excess enantiomer of 2a was 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 enantiomer was not observed. 2.3. Highly selective diastereodivergent synthesis of aalkylated and a,a-dialkylated atropisomeric lactams We have already reported on highly diastereoselective a-alkylation 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– d possessing an a-chiral carbon of the (R)-configuration.16 Table 2 Diastereoselective a-alkylation with atropisomeric lactam 2a

R

2a (racemic)

2a (70%ee)

2a (99%ee)

Li-TMP 2a (93% ee) THF

N

OLi t-Bu

R-X

N

O t-Bu

4 (93% ee)

retention time

retention time

retention time

Figure 1. MPLC chart of 2a (70% ee, racemic and 99% ee, eluent: hexane/AcOEt¼10).

Entry

R-X

4

Yielda (%)

drb

1

Me-l

4a

82

2 3 4

Allyl-Br PhCH2-Br n-Pr-l

4b 4c 4d

83 85 86

31/1 [a]D¼17.0 (c=0.92, CHCl3) >50/1 >50/1 32/1

a b

more polar fraction 59.5%ee (59.0%)

less polar fraction 99.5%ee (41.0%)

retention time 2a (73%ee)

more polar fraction 62.9%ee (67.0%)

less polar fraction 99.7%ee (31.8%)

retention time 2b (73%ee)

more polar fraction 51.5%ee (43.8%)

less polar fraction 99.4%ee (56.2%)

retention time 2c (80%ee)

Figure 2. MPLC separation of enantio-enriched 2a (73% ee), 2b (73% ee) and 2c (80% ee).

Isolated yield. The diastereomer ratio was determined by 400 MHz 1H NMR.

Subsequently, the further reaction of the a-alkylated lactam product with some electrophiles was investigated (Table 3).17 Protonation of the lithium enolate prepared from a-allylated and a-propylated lactams 4b and 4d resulted in the inversion of the a-chiral carbon to give lactams 4b0 and 4d0 corresponding to the 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 a-alkylated atropisomeric lactam was achieved. The present reaction can be also applied to the highly selective diastereodivergent synthesis of a,a-disubstituted lactams. a-Allylation of a-methylated lactam 4a and a-methylation of a-allylated lactam 4b gave diastereomeric a-allyl-a-methyl lactams 5a and 5a0

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296 Table 3 Highly selective diastereodivergent synthesis of a-alkylated and a,a-dialklated lactams

R R O t-Bu

N

Li-TMP

E-X

N

Entry 1 2 3 4 5 6 a b

4

R

4b 4d 4a 4b 4a 4d

E-X

Allyl n-pr Me Allyl Me n-Pr

O t-Bu

THF

4 (93% ee)

HCl aq HCl aq Allyl-Br Me-l n-Pr-l Me-l

E

4 or 5 (93% ee) 4 or 5 0

4b 4d0 5a 5a0 5d 5d0

R

E

Yielda (%)

drb

Allyl n-pr Me allyl Me n-Pr

H H Allyl Me n-Pr Me

85 94 91 70 46 70

21 26 >50 >50 >50 >50

291

As tert-butylphenyl group was difficult to remove, we next investigated the conversion to N-phenyl-a-substituted dihydroquinolin-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). (CH2)3NHMe R * N

N

O

IA (R = H)

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 products and biologically active compounds using these N–C axially chiral compounds.18 Meanwhile, various biological active compounds possessing a dihydroquinolin-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 to remove the tert-butylphenyl group from a-methylated lactam 4a 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 through a-methylation of atropisomeric lactam 2c having 2-tertbuty-4-methoxyphenyl group, also resulted in a complex mixture due to oxidation of the dihydroquinolinone ring.

Me N

O t-Bu

R

R

(CH2)3-OH 1) 9-BBN

N

O t-Bu 2) NaOH, H2O2

N

AlCl3 O t-Bu C6H6, 80 °C

(93% ee) 4b (R = H)

6b (89 %)

5a (R = Me)

6a (99 %)

(2) N O H II (not detected)

N

O

(64%)

N

CAN or complex O RuO4 mixture (3) t-Bu 6c

OMe (dr =33/1)

R (CH2)3-NHMe N

O

(93% ee) 7b (57 %) 7a (53 %)

1) Li-TMP O 2) Me-I t-Bu THF 2c

For conversion to synthetic intermediates III (Eq. 4), the removal of the ortho-tert-butyl group in a-allylated lactams 4b (R¼H) and 5a (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 formation 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

(CH2)3-OH

Me

OMe

IB (R = Me) inhibitors of norepinephrine transporter (NET inhibitors)

Me complex mixture

(4) O t-Bu

4 or 5

III

R

Birch reduction

4a

N

N

O trans-tertbutylation

Isolated yield. The diastereomer ratio was determined by 400 MHz 1H NMR.

with almost complete stereoslectivity, respectively (entries 3 and 4). Similarly, both diastereomers 5d and 5d0 of the a-methyl-apropyl lactams were also obtained with complete stereoselectivity through a-propylation of 4a and a-methylation of 4d (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

allyl R *

allyl R *

NET inhibitor

Scheme 4. Conversion to synthetic intermediates for NET inhibitors.

3. Conclusion We succeeded in the highly enantioselective synthesis of atropisomeric N-(2-tert-butylphenyl)lactam derivatives through (R)SEGPHOS-Pd(OAc)2 catalyzed intramolecular Buchwald–Hartwig amination. The obtained enantio-enriched lactam products were

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,adialkylayed lactams using asymmetric enolate chemistry, and efficient conversion to a key intermediate for the synthesis of an NET inhibitor, were also found. 4. Experimental 4.1. General Melting points were uncorrected. 1H and 13C NMR spectra were recorded on a 300 MHz spectrometer. In 1H and 13C NMR spectra, 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 304 cm i. d. prepacked column (silica gel, 50 mm) with a UV detector. High-performance liquid chromatography (HPLC) was performed on a 250.4 cm i. d. chiral column with a UV detector. 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)propanamide (1c). Under Ar atmosphere, to 2-tert-butyl-4-methoxyaniline17 (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: white solid; mp 122–124  C; IR (KBr) 3262, 1645 cm1; 1H NMR (CDCl3) d: 7.83 (1H, dd, J¼0.9, 8.0 Hz), 7.23–7.36 (3H, m), 6.82–6.97 (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. 4.2.2. 2-[Benzyl-(2-iodophenyl)amino]-N-(2-tert-butylphenyl)acetamide (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%). Under 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-benzylN-(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

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 cm1; 1H NMR (CDCl3) d: 8.59 (1H, br s), 7.93 (1H, dd, J¼1.5, 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); 13 C NMR (CDCl3) d: 169.2, 150.5, 145.7, 140.4, 135.5, 134.7, 130.3, 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. 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 stirred 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 mixture was heated for several hours, some solids adhered to the flask’s walls above the solution. The solids, including active catalyst, 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 cm0.46 cm i.d.; 3% i-PrOH in hexane; flow rate, 1.0 mL/min; (-)-2a (major); tR¼11.3 min, (þ)-2a (minor); tR¼12.6 min]. 2a: [a]D¼77.1 (c 1.0, 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 4.3.1. (R)-1-(2,5-di-tert-Butylphenyl)-3,4-dihydro-1H-quinoline-2one (2b). 2b was prepared from 1b (139 mg, 0.3 mmol) in accordance 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 cm0.46 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; [a]D¼83.3 (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 4.3.2. 1-(2-tert-Butyl-4-methoxyphenyl)-3,4-dihydro-1H-quinoline2-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 cm0.46 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]D¼101.5 (c 1.0, CHCl3); mp 146  C; IR (KBr) 1685 cm1; 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, 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.

with that of the product obtained by a-methylation of 2a (vide infra).

4.3.3. 4-Benzyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quinoxaline2-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 cm0.46 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 (89% ee): colorless oil; [a]D¼25.3 (c 1.0, CHCl3); IR (neat) 1687 cm1; 1H NMR (CDCl3) d: 7.67 (1H, dd, J¼1.5, 8.0 Hz), 7.45 (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 (1H, d, J¼15.3 Hz), 1.30 (9H, s); 13C NMR (CDCl3) d:167.3, 147.9, 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.

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 mL, 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).

4.4. Stereochemical assignment of lactam product 4.4.1. (S)-N-(2-tert-Butylphenyl)-3-(2-iodophenyl)-2-methylpropanamide (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-methylpropanoate 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, 92%). 3a: white solid; [a]D¼þ97.6 (c 0.35, CHCl3); mp 90  C; IR (KBr) 3250, 1649 cm1; 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. 4.4.2. (S,R) and (S,S)-1-(2-tert-Butylphenyl)-3-methyl-3,4-dihydro1H-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 evaporated to dryness. Purification of the residue by column chromatography (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 cm0.46 cm i.d.; 3% i-PrOH in hexane; flow rate, 1.0 mL/min; ()-ent-4a (minor); tR¼7.2 min, (þ)-ent-4a (major); tR¼8.6 min]. 4a: [a]D¼þ14.9 (c 0.52, CHCl3). 1H NMR of ent-4a and 4a0 coincided

4.5. Experimental procedure for diastereoselective aalkylation of lactam 2a

4.5.1. (R,R) and (S,R)-1-(2-tert-Butylphenyl)-3-methyl-3,4-dihydro1H-quinoline-2-one (4a and 4a0 ). 4a (93%ee): white solid; [a]D¼17.0 (c 0.922, CHCl3); mp 150–151  C; IR (KBr) 1672 cm1; 1 H 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), 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 cm1; 1H NMR (CDCl3) 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. 4.5.2. (R,R)-3-Allyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quinoline-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 (93% ee): white solid; [a]D¼58.4 (c 1.0, CHCl3); mp 78–82  C; IR (KBr) 1683 cm1; 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 (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-quinoline-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 (hexane/AcOEt¼10) gave 4c (93 mg, 84%). 4c (93% ee): white solid; [a]D¼93.0 (c 1.04, CHCl3); mp 74–78  C; IR (KBr) 1684 cm1; 1H 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, s); 13C NMR (CDCl3) d: 172.8, 147.9, 142.0, 138.7, 136.1, 132.0, 129.7, 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.

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, 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.

4.5.4. (R,R)-1-(2,5-di-tert-Butylphenyl)-3-propyl-3,4-dihydro-1Hquinoline-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 amount of 4d0 . 4d (93% ee): white solid; [a]D¼97.4 (c 0.5, CHCl3); mp 112–113  C; IR (KBr) 1685 cm1; 1H NMR (CDCl3) d: 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, 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.

4.7.1. (R,R)-3-Allyl-1-(2-tert-butylphenyl)-3-methyl-3,4-dihydro-1Hquinoline-2-one (5a). Under Ar atmosphere, to 2,2,6,6-tetramethylpiperidine (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 1 h at 0  C. Allyl bromide (59 mL, 0.7 mmol) 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 5a (152 mg, 91%). 5a (93% ee): colorless oil; [a]D¼122.6 (c 1.0, CHCl3); IR (neat) 1682 cm1; 1H NMR (CDCl3) d: 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, 14.6 Hz), 1.32 (3H, s), 1.22 (9H, s); 13C NMR (CDCl3) d: 174.8, 147.7, 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.

4.6. Diastereoselective a-protonation of lactam 2a 4.6.1. (S,R)-3-Allyl-1-(2-tert-butylphenyl)-3,4-dihydro-1H-quinoline-2-one (4b0 ). Under Ar atmosphere, to 2,2,6,6-tetramethylpiperidine (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). 4b0 (93% ee): colorless oil; [a]D¼200.4 (c 1.0, CHCl3); IR (neat) 1684 cm1; 1H NMR (CDCl3) d: 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, 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. 4.6.2. (S,R)-1-(2-tert-Butylphenyl)-3-propyl-3,4-dihydro-1H-quinoline-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 solid; [a]D¼143.6 (c 0.7, CHCl3); mp 94–97  C; IR (KBr) 1684 cm1; 1 H 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,

4.7. Diastereoselective a-alkylation of a-substituted lactam

4.7.2. (S,R)-3-Allyl-1-(2-tert-butylphenyl)-3-methyl-3,4-dihydro1H-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; [a]D¼116.5 (c 1.0, CHCl3); IR (neat) 1681 cm1; 1H NMR (CDCl3) d: 7.61 (1H, dd, J¼1.6, 8.0 Hz), 7.38 (1H, dt, J¼1.6, 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 (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. 4.7.3. (R,R)-1-(2-tert-Butylphenyl)-3-methyl-3-propyl-3,4-dihydro1H-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 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): colorless oil; [a]D¼155.3 (c 1.0, CHCl3); IR (neat) 1682 cm1; 1H NMR (CDCl3) 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,

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296

J¼6.8 Hz); 13C NMR (CDCl3) d: 175.3, 147.7, 142.0, 136.7, 132.3, 129.3, 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. 4.7.4. (S,R)-1-(2-tert-Butylphenyl)-3-methyl-3-propyl-3,4-dihydro1H-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): white solid; [a]D¼124.7 (c 1.0, CHCl3); mp 110–112  C; IR (KBr) 1677 cm1; 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), 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. 4.8. (R,R)-1-(2-tert-Butyl-4-methoxyphenyl)-3-methyl-3,4dihydro-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 (hexane/AcOEt¼5) and subsequent MPLC (hexane/AcOEt¼5) gave diastereomer of 6c (1.8 mg, 2%, less polar) and 6c (60 mg, 62%, more polar). 6c (93%ee): colorless gel; [a]D¼30.0 (c 1.20, CHCl3); IR (KBr) 1684 cm1; 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 (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. Synthesis of NET inhibitors 4.9.1. (R,R)-1-(2-tert-Butylphenyl)-3-(3-hydroxypropyl)-3,4-dihydro1H-quinoline-2-one (6b). Under Ar atmosphere, to 0.5 M THF solution 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. CH3I (26 mL, 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 (87 mg, 89%). 6b (93% ee): white solid; [a]D¼44.0 (c 1.0, CHCl3); mp 91–92  C; IR (KBr) 3420, 1681 cm1; 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), 1.25 (9H, s); 13C NMR (CDCl3) d: 173.3, 147.9, 141.7, 136.0, 131.8, 129.7, 128.7, 128.4, 127.8, 127.1, 123.8, 122.9, 117.0, 62.4, 40.8, 35.9, 31.6,

295

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. 4.9.2. (R,R)-1-(2-tert-Butylphenyl)-3-(3-hydroxypropyl)-3-methyl3,4-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%). 6a (93% ee): colorless oil; [a]D¼145.7 (c 0.2, CHCl3); IR (neat) 3443, 1668 cm1; 1H NMR (CDCl3) d: 7.60 (1H, dd, J¼1.5, 8.1 Hz), 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 (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. 4.9.3. (R)-3-(3-Hydroxypropyl)-1-phenyl-3,4-dihydro-1H-quinoline2-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 cm0.46 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; [a]D¼þ15.6 (c 0.4, CHCl3); mp 106–108  C; IR (KBr) 3420, 1682 cm1; 1H NMR (CDCl3) d: 7.50 (2H, t, J¼7.6 Hz), 7.41 (1H, tt, 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, 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. 4.9.4. (R)-3-(3-Hydroxypropyl)-1-methyl-1-phenyl-3,4-dihydro-1Hquinoline-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 chromatography (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 cm0.46 cm i.d.; 20% i-PrOH in hexane; flow rate, 1.0 mL/min; (þ)-7a (minor); tR¼7.6 min, (-)-7a (major); tR¼10.7 min]. 7a (93% ee): white solid; [a]D¼12.8 (c 1.0, CHCl3); mp 82–85  C; IR (KBr) 3435, 1680 cm1; 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, 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.

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

296

M. Takahashi et al. / Tetrahedron 66 (2010) 288–296

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. References and notes 1. Typical examples of atropisomeric compounds having an N-C chiral axis: (a) Bock, L. H.; Adams, R. J. Am. Chem. Soc. 1931, 53, 374; (b) Kashima, C.; Katoh, A. J. Chem. Soc., Perkin Trans. 1 1980, 1599; (c) Roussel, C.; Adjimi, M.; Chemlal, A.; Djafri, A. J. Org. Chem. 1988, 53, 5076; (d) Kawamoto, T.; Tomishima, M.; Yoneda, F.; Hayami, J. Tetrahedron Lett. 1992, 33, 3169; (e) Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63, 2597; (f) Curran, D. P.; Liu, W.; Chen, C. H. J. Am. Chem. Soc. 1999, 121, 11012; (g) Hata, T.; Koide, H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2, 1907; (h) Shimizu, K. D.; Freyer, H. O.; Adams, R. D. Tetrahedron Lett. 2000, 41, 5431; (i) Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino, T.; Fujita, T. J. Org. Chem. 2003, 68, 942; (j) Sakamoto, M.; Utsumi, N.; Ando, M.; Saeki, M.; Mino, T.; Fujita, T.; Katoh, A.; Nishio, T.; Kashima, C. Angew. Chem., Int. Ed 2003, 42, 4360; (k) Tetrahedron symposium-in-print on axially chiral amides (Atropisomerism). Clayden, J., Ed. Tetrahedron 2004, 60, 4325– 4558; (l) Betson, M. S.; Clayden, J.; Helliwell, M.; Mitjans, D. Org. Biomol. Chem. 2005, 3, 3898; (m) Bringmann, G.; Gulder, T.; Reichert, M.; Meyer, F. Org. Lett. 2006, 8, 1037; (n) Kamikawa, K.; Kinoshita, S.; Matsuzaka, H.; Uemura, M. Org. Lett. 2006, 8, 1097; (o) Tokitoh, T.; Kobayashi, T.; Nakada, E.; Inoue, T.; Yokoshima, S.; Takahashi, H.; Natsugari, H. Heterocycles 2006, 70, 93; (p) Kawabata, 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.d Eur. 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.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043; (d) Shen, Q.; Shashank, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2005, 44, 1371; For reviews: (e) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046; (f) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041; (g) Hartwig, J. F. In 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, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; p 699. 4. (a) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem. Soc. 2005, 127, 3676; (b) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923. 5. Although the enantioselectivity is not high (30–50% ee), first catalytic asymmetric synthesis of N–C axially chiral compounds through enatioselective Nallylation 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.

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.; Jorgensen, 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. 7. Quite recently, catalytic asymmetric Buchwald–Hartwig amination using achiral 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. 9. (a) Tashiro, M. Synthesis 1979, 921; (b) Bigi, F.; Conforti, M. L.; Maggi, R.; Mazzacani, A.; Sartori, G. Tetrahedron Lett. 2001, 42, 6543. 10. Preliminary communication: Kitagawa, O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi, T. Tetrahedron Lett. 2008, 49, 471. 11. (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264; (b) Sumi, K.; Kumobayashi, K. Top. Organomet. Chem. 2004, 6, 63. 12. Duprat de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P. Tetrahedron Lett. 2003, 44, 823. 13. Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N. Angew. Chem., Int. Ed. 2004, 43, 320. 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.; Hara, S.; Fukasaku, N. Anal. Chem. 1987, 59, 2209; (d) Diter, P.; Taudien, S.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1994, 59, 370; (e) Takahata, H. Yuki Gosei Kagaku Kyokaishi 1996, 54, 708; (f) Kosugi, H.; Abe, M.; Hatsuda, R.; Uda, H.; Kato, M. Chem. Commun. 1997, 1857; (g) Tanaka, K.; Osuga, H.; Suzuki, H.; Shogase, Y.; Kitahara, Y. J. Chem. Soc., Perkin Trans. 1 1998, 935; (h) Ernholt, B. V.; Thomsen, I. B.; Lohse, A.; Plesner, I. W.; Jensen, K. B.; Hazell, R. G.; Liang, X.; Jacobsen, A.; Bols, M. Chem.d Eur. J. 2000, 6, 278; (i) Suchy, M.; Kutschy, P.; Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla, M.; Balentova, E. J. Org. Chem. 2001, 66, 3940; (j) Soloshonok, V. A. Angew. Chem., Int, Ed. 2006, 45, 766. 16. Configuration of a-carbon was determined on the basis of NOE between ahydrogen or a-alkyl group on the lactam ring and ortho- tert-butyl group. 17. Similar stereoselective a-mono-alkylation with racemic atropisomeric N-(ortho- 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. 19. Typical examples of biologically active dihydroquinolin-2-one derivatives. (a) Rosauer, K. G.; Ogawa, A. K.; Willoughby, C. A.; Ellsworth, K. P.; Geissler, W. M.; Myers, R. W.; Deng, Q.; Chapman, K. T.; Harris, G.; Moller, D. E. Bioorg. Med. Chem. Lett. 2003, 13, 4385; (b) Iyobe, A.; Uchida, M.; Kamata, K.; Hotei, Y.; Kusama, H.; Harada, H. Chem. Pharm. Bull. 2001, 49, 822; (c) Tzeng, C.; Chen, I.; Chen, Y.; Wang, T.; Chang, Y.; Teng, C. Helv. Chim. Acta 2000, 83, 349; (d) Beard, R. L.; Teng, M.; Colon, D. F.; Duong, T. T.; Thacher, S. M.; Arefieg, T.; Chandraratna, A. S. Bioorg. Med. Chem. Lett. 1997, 7, 2373. 20. Brundish, D.; Bull, A.; Donovan, V.; Fullerton, J. D.; Garman, S. M.; Hayler, J. F.; Janus, D.; Kane, P. D.; McDonnell, M.; Smith, G. P. J. Med. Chem. 1999, 42, 4584. 21. Ciufolini, M.; Browene, M. E. Tetrahedron Lett. 1987, 28, 171. 22. Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000, 2239.