Synthesis of optically active α-aminobenzolactam via an oxidative-cyclization reaction

Article abstract of DOI:10.1016/S0957-4166(03)00408-7

A convergent pathway for the asymmetric synthesis of (-)-α-aminobenzolactam 1 is described. For the first time, the key intermediate N-methoxybenzolactam 8 was prepared from L-homophenylalanine ethyl ester hydrochloride (LHPE·HCl) 5 by employing an oxidat

Full text of DOI:10.1016/S0957-4166(03)00408-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2081–2085
Synthesis of optically active a-aminobenzolactam via an
oxidative–cyclization reaction
Ching-Yao Chang and Teng-Kuei Yang*
Department of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan, ROC
Received 21 April 2003; accepted 14 May 2003
Abstract—A convergent pathway for the asymmetric synthesis of (−)-a-aminobenzolactam 1 is described. For the first time, the
key intermediate N-methoxybenzolactam 8 was prepared from -homophenylalanine ethyl ester hydrochloride (LHPE·HCl) 5 by
employing an oxidative cyclization in the presence of trifluoroacetic acid (TFA). © 2003 Elsevier Science Ltd. All rights reserved.
L
1. Introduction
Numerous reports related to the synthesis of (−)-a-
aminobenzolactam 1 have been reported. These meth-
ods mainly consist of the resolution of racemates by
fractional crystallization of diastereomeric tartaric acid
salts4a or enantioselective synthesis employing catalytic
hydrogenation in the presence of an external chiral
ligand.4b On the other hand, a synthesis of (−)-a-
aminobenzolactam 1 was recently published in which
an organozinc reagent of N-protected g-halo-a-amino
ester was used to react with 2-iodoaniline followed by
cyclization and hydrogenation to give compound 1.5
Herein we report a more convenient synthesis of enan-
tiopure compound 1 based on the oxidative cyclization
of N-methoxyamide 7 by employing the commercially
(3S)-3-Amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one
[(−)-a-aminobenzolactam] 1 is a key intermediate in the
total synthesis of Benazepril·HCl 2,1 an angiotensin
converting enzyme (ACE) inhibitor which has recently
become a blockbuster antihypertensive drug. Com-
pound 1 is also an important precursor for the new
class of antithrombotic agent 32 as derivatives of CVS-
1778, as well as for the nonpeptidyl growth hormone
secretagogue 4, L-6924283 (Fig. 1).
and readily available L-homophenylalanine ethyl ester
hydrochloride (LHPE·HCl) 5 as a starting material.
2. Results and discussion
As part of our studies towards the development of an
asymmetric synthesis of Benazepril·HCl 2, we discov-
ered an oxidative cyclization procedure for the prepara-
tion
of
N-methoxybenzolactam
8
from
N-methoxyamide 7. The readily available LHPE·HCl 5
suggested that an effective asymmetric synthesis of (−)-
a-aminobenzolactam 1 could be achieved.
The synthetic strategy for (−)-a-aminobenzolactam 1 is
illustrated in Scheme 1. The synthesis began with the
protection of the amino group of LHPE using benzyl
chloroformate to give compound 6 in 99% yield.6 The
N-methoxyamide 7 was produced in a 70% yield overall
through amidation of benzyloxycarbonyl LHPE 6 by
Figure 1.
* Corresponding author. Tel.: +886 (4)22856603; fax: +886
(4)22856597; e-mail: tkyang@mail.nchu.edu.tw
0957-4166/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00408-7

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C.-Y. Chang, T.-K. Yang / Tetrahedron: Asymmetry 14 (2003) 2081–2085
Scheme 1. Reagents and conditions: (a) CBzCl, NaHCO3, THF/H2O (99%); (b) HONH2HCl, KOH, CH3OH, 0°C, then CH3I
(70%); (c) PIFA, TFA, CH2Cl2, 0°C (8, 40%; 9, 45%); (d) BF3·Et2O/THF/reflux (75%); (e) H2, Pd(OH)2/C, C2H5OH, rt (97%).
hydroxylamine followed by an in-situ methylation of
hydroxamic acid using iodomethane as the methylating
agent.7
N-methoxybenzolactam 8. In another related report,
Romero et al.9 observed a dramatic increase in yield
during a cyclization reaction in the presence of protic
acids. Therefore various protic acids were used in our
investigation to obtain the N-methoxybenzolactam 8
and the results obtained are summarised in Table 1.
The key step in our synthetic strategy is the generation
of N-methoxybenzolactam 8 through the acid induced
cyclization of N-methoxyamide 7. When we employed a
literature procedure8 for the treatment of N-
methoxyamide 7 in dichloromethane with [bis(trifl-
uoroacetoxy)iodo]benzene (PIFA) at 0°C for 15 min it
afforded the cyclized N-methoxybenzolactam 8 in a
disappointingly low yield of 22%. Therefore, we under-
took a comprehensive investigation to circumvent the
low yield in the cyclization of N-methoxyamide 7 to
To date, the overall yield has reached 74% for the
cyclization of N-methoxyamide 7 to the desired N-
methoxybenzolactam 8. We found that the treatment of
N-methoxyamide 7 with 3 equiv. of trifluoroacetic acid
in dichloromethane at 0°C produced 40% of N-
methoxybenzolactam 8 and 45% of hydroxyl compound
9 (Table 1, entry 4). The mechanism of this cyclization
Table 1. Study for oxidative–cyclization reaction of N-methoxyamide 7
Entry
Solvent
Acid catalyst
Acid equiv.
Temperature (°C)
8a yield (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CHCl3
CH3CN
CH3CN
Toluene
Toluene
–
–
0
0
0
0
0
0
−15
rt
0
0
0
rt
rt
Reflux
rt
Reflux
57
64
69
74
72
71
54
72
56
61
67
65
57
63
70
61
TFA
TFA
TFA
TFA
TFA
TFA
TFA
PTSA
–
TFA
TFA
TFA
TFA
TFA
TFA
0.2
1.0
3.0
6.0
10.0
3.0
3.0
0.2
–
3.0
3.0
3.0
3.0
3.0
3.0
9
10
11
12
13
14
15
16
a The yield of N-methoxybenzolactam 8 was reported according to combined yields of oxidative–cyclization of 7 and dehydration of 9.

C.-Y. Chang, T.-K. Yang / Tetrahedron: Asymmetry 14 (2003) 2081–2085
2083
process is illustrated in Scheme 2. The cationic interme-
4. Experimental
diate 12 generated in the acidic cyclization would pro-
duce not only the desired N-methoxybenzolactam 8 but
also hydroxyl compound 9, because the anion of trifl-
uoroacetic acid eliminated from PIFA during the reac-
Starting materials were obtained from commercial sup-
pliers and used without further purification unless oth-
erwise stated. All reactions were performed in
flame-dried apparatus under nitrogen at room tempera-
ture unless otherwise stated. THF was distilled from
sodium/benzophenone under nitrogen. Flash chro-
matography was carried out using Merck silica gel 60,
70–230 mesh ASTM. Melting points are uncorrected.
Optical rotations were measured on a Perkin–Elmer
241 polarimeter. Infrared spectra were recorded on a
Hitachi 270-30 infrared spectrophtometer. NMR spec-
tra were recorded on a Varian Mercury 400 or Varian
Inova 600. The chemical shifts are reported as l value
in ppm relative to TMS (l=0), which was used as the
tion, would act as
a
nucleophile to generate
trifluoroacetate 13 which was then hydrolyzed during
aqueous work-up to give alcohol 9.10 The hydroxyl
compound 9 would gain back its aromaticity by treat-
ment with BF3·Et2O to give compound 8 in 75% yield.
The overall yield of the desired N-methoxybenzolactam
8 was 74%.
Subsequent treatment of N-methoxybenzolactam 8 by
hydrogenation in the presence of Pearlman%s catalyst at
100 psi hydrogen pressure produced the target com-
pound 1 in a 97% yield.9 The HPLC analysis demon-
1
internal standard in CDCl3 for H NMR spectra and
strated
that
the
enantiomeric
purity
of
the center peak of CDCl3 (l=77.0 ppm), which was
used as the internal standard in 13C NMR spectra.
FAB-mass spectra were collected on a JMS-700 double-
focusing mass spectrometer. Elemental analyses were
collected on a Foss Heraeus CHN-O-Rapid elemental
analyzer.
(−)-a-aminobenzolactam 1 was greater than 98% e.e.
which indicated there was almost no racemization dur-
ing the whole synthetic process.11
3. Conclusion
4.1. (2S)-2-Benzyloxycarbonylamino-4-phenylbutyric
acid ethyl ester, 6
We have accomplished a novel chiral synthesis of (−)-a-
aminobenzolactam
1 through a unique oxidative
cyclization of N-methoxyamide 7. Our synthesis
demonstrated the first example by employing commer-
cially available LHPE·HCl 5 from the chiral pool to
prepare (−)-a-aminobenzolactam 1. Further condition
optimization of the synthesis and application of this
To a solution of the LHPE·HCl 5 (4.87 g, 20 mmol)
and sodium bicarbonate (3.53 g, 42 mmol) in 1:1
THF:water (100 ml), benzyl chloroformate (3.58 g, 21
mmol) was added dropwisely at 0°C. The solution was
allowed to slowly warm to ambient temperature and
stirred overnight. The THF was removed in vacuo,
after which water (50 ml) was added, and the aqueous
important chiral synthon
investigation.
1 are currently under
Scheme 2.

2084
C.-Y. Chang, T.-K. Yang / Tetrahedron: Asymmetry 14 (2003) 2081–2085
solution extracted with ethyl acetate (3×50 ml). The
combined organic layers were washed with brine and
dried over magnesium sulphate. The solvent was
removed in vacuo and purified by flash chromatogra-
phy (hexane/ethyl acetate=10:1) to afford 6 (6.75 g,
99%) as a white solid: [h]D=+25.1 (c 1.08, CHCl3); mp
55–56°C; IR (neat): 3364, 2968, 1728, 1528, 1212 cm−1;
1H NMR (400 MHz, CDCl3) l 7.40–7.12 (m, 10H,
magnesium sulphate. The solvent was removed in
vacuo and purified by flash chromatography (hexane/
ethyl acetate=3:1) to obtain the desired 8 (0.68 g, 40%)
as a white solid and hydroxyl compound 9 (0.81 g,
45%) as a viscous liquid.9 The hydroxyl compound 9
was dissolved in THF (20 ml) with BF3·Et2O (0.96 g,
6.75 mmol) being added and the reaction solution being
allowed to reflux for 4 h. The mixture was vaporized in
vacuo and purified by flash chromatography (hexane/
ethyl acetate=3:1) to get more 8 (0.57 g, 75%) as a
white solid. Therefore the total yield of the desired
compound 8 was 74%: [h]D=−120.7 (c 1.03, CHCl3);
mp 151–152°C; IR (neat): 3336, 1724, 1690, 1530, 1488,
CH
4.45–4.40 (m, 1H, CH
CO2CH2CH3), 2.75–2.60 (m, 2H, CCH2
1H, CH2CH), 2.06–1.94 (m, 1H, CH2
J=7.0 Hz, 3H, CO2CH2CH3
); 13C NMR (100 MHz,
6
), 5.37 (br, 1H, NH
NHCBz), 4.18 (q, J=7.0 Hz, 2H,
), 2.24–2.14 (m,
CH), 1.28 (t,
6 CBz), 5.13 (s, 2H, CO2CH6 2Ph),
6
6
6
6
6
6
CDCl3) l 172.2, 155.8, 140.6, 136.2, 128.5, 128.4, 128.3,
128.1, 128.0, 126.1, 66.9, 61.4, 53.6, 34.2, 31.4, 14.1; MS
(FAB): m/z 342 (MH+), 298, 224, 117, 91 (100%), 77.
Anal. calcd for C20H23NO4: C, 70.36; H, 6.79; N, 4.10;
O, 18.75. Found: C, 70.38; H, 6.85; N, 4.25; O, 18.99.
1
1256, 1240 cm−1; H NMR (400 MHz, CDCl3) l 7.42–
7.24 (m, 9H, CH
5.05 (s, 2H, CO2CH2
CHNHCBz), 3.83 (s, 3H, OCH3
CCH2), 2.70–2.62 (m, 2H, CH2CH2
CH2
CH); 13C NMR (100 MHz, CDCl3) l 166.7, 155.3,
6
), 5.74 (d, J=7.6 Hz, 1H, NH
Ph), 4.22–4.15 (m, 1H,
), 2.94–2.82 (m, 1H,
), 2.05–1.97 (m, 1H,
6 CBz),
6
6
6
6
6
6
6
4.2. (1S)-(1-Methoxycarbamoyl-3-phenylpropyl)-
carbamic acid benzyl ester, 7
137.4, 136.2, 133.7, 129.3, 128.4, 128.1, 128.0, 128.0,
127.9, 122.6, 66.8, 62.3, 50.8, 36.2, 28.3; MS (FAB):
m/z 341 (MH+), 297, 265, 175, 154, 91 (100%), 77.
Anal. calcd for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23;
O, 18.80. Found: C, 66.74; H, 5.80; N, 8.13; O, 18.96.
To a solution of N-protected LHPE 6 (3.41 g, 10
mmol) and hydroxylamine hydrochloride (2.08 g, 30
mmol) in methanol (20 ml) was cooled to 0°C and a
methanolic solution of potassium hydroxide (3.95 g,
85%, 60 mmol) was added dropwisely. The solution was
stirred at 0°C for 6 h, after which iodomethane (2.13 g,
15 mmol) was added. The solution was allowed to
slowly warm to ambient temperature and stirred
overnight. The methanol was removed in vacuo, where-
upon water (50 ml) was added, and the aqueous solu-
tion extracted with ethyl acetate (3×50 ml). The
combined organics were washed with brine and dried
over magnesium sulphate. The solvent was removed in
vacuo and purified by flash chromatography (hexane/
ethyl acetate=2:1) to obtain 7 (2.40 g, 70%) as a white
solid: [h]D=−29.5 (c 1.03, CHCl3); mp 140–141°C; IR
4.4. (3S)-3-Amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-
one, (−)-a-aminobenzolactam, 1
To a solution of N-methoxybenzolactam 8 (0.68g,
2mmol) and 20% palladium hydroxyl on carbon (0.14
g) in absolute ethanol (20 ml) was shaken in a Parr
apparatus under hydrogen pressure of 100 psi for 6 h.
The mixture was filtered through Celite and the filtered
cake washed with methanol (30 ml). The solvent was
then removed in vacuo to afford 1 (0.34 g, 97%) as pale
yellow solid with e.e.=98% based on the HPLC analy-
sis on the chiral column: [h]D=−447.0 (c 1.02, CH3OH)
[lit.5 [h]D=−446.0 (c 1.0, CH3OH)]; mp 150–151°C (lit.5
mp 147–149°C); IR (neat): 1670, 1588, 1492, 1416, 1292
1
(neat): 3304, 1690, 1664, 1536, 1250 cm−1; H NMR
(400 MHz, CDCl3) l 8.99 (br, 1H, NH
7.12 (m, 10H, CH), 5.31 (br, 1H, NHCBz), 5.14–5.05
(m, 2H, CO2CH2Ph), 4.04–3.94 (m, 1H, CHNHCBz),
3.74 (s, 3H, NHOCH3), 2.72–2.64 (m, 2H, CCH2),
2.20–2.10 (m, 1H, CH2CH), 2.02–1.92 (m, 1H,
CH2
CH); 13C NMR (100 MHz, CDCl3) l 169.1, 156.4,
6 OCH3), 7.38–
1
cm−1; H NMR (400 MHz, CD3OD) l 7.28–7.23 (m,
6
6
2H, CH
1H, CH
1H, CCH2
1H, CH2CH), 2.01–1.92 (m, 1H, CH2
6
), 7.17–7.13 (m, 1H, CH
), 3.44–3.39 (m, 1H, CH
), 2.72–2.65 (m, 1H, CCH2
6
), 7.02 (d, J=8.0 Hz,
6
6
6
6
NH2), 2.90–2.83 (m,
6
6
6
6
), 2.53–2.42 (m,
6
6
6
CH); 13C NMR
6
140.5, 135.9, 128.5, 128.4, 128.3, 128.2, 127.9, 126.1,
67.1, 64.1, 52.0, 33.8, 31.6; MS (FAB): m/z 343 (MH+),
307, 289, 224, 154 (100%), 136, 91. Anal. calcd for
C19H22N2O4: C, 66.65; H, 6.48; N, 8.18; O, 18.69.
Found: C, 66.65; H, 6.26; N, 8.05; O, 19.16.
(150 MHz, CD3OD) l 176.2, 138.3, 135.4, 130.6, 128.7,
127.1, 123.3, 51.9, 38.9, 29.6; MS (FAB): m/z 177
(MH+), 154 (100%), 136, 132, 107, 89. Anal. calcd for
C10H12N2O: C, 68.16; H, 6.86; N, 15.90; O, 9.08.
Found: C, 68.28; H, 6.93; N, 15.98; O, 9.36.
4.3. (3S)-(1-Methoxy-2-oxo-2,3,4,5-tetrahydro-1H-ben-
zo[b]azepin-3-yl)carbamic acid benzyl ester, 8
Acknowledgements
To a solution of N-methoxyamide 7 (1.71 g, 5 mmol) in
dichloromethane (40 ml) was cooled to 0°C, and trifl-
uoroacetic acid (1.71 g, 15 mmol) was added. PIFA
(2.25 g, 5.25 mmol) was added in portions over 10 min,
and the mixture was stirred at 0°C for 15 min. Cooled
water (5 ml) was then added, and the aqueous solution
extracted with dichloromethane (2×50 ml). The com-
bined organics were washed with brine and dried over
Support from the National Science Council of the
Republic of China (NSC 91-2113-M-005-008) is grate-
fully acknowledged. We thank Wisdom Technology
Co. Ltd., Taiwan, for the gift sample of L-homophenyl-
alanine ethyl ester hydrochloride 5. We thank Ms. Lin
Ping-Yu for analyzing mass spectra. Also we thank Dr.
Chaudhari, B. A. for advise before publication.

C.-Y. Chang, T.-K. Yang / Tetrahedron: Asymmetry 14 (2003) 2081–2085
2085
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10. The compound 9 was identified by mass spectroscopy,
C19H22N2O5 MS (FAB): m/z 359.2 (MH+); HRMS (FAB):
m/z calcd for C19H22N2O5 MH+ 359.1607, found MH+
359.1608.
11. The e.e. of 1 was determinated by high-performance liquid
chromatography equipped with a Daicel CROWNPAK
CR(+) column, 150×4.0 mm, eluted (0.8 ml/min) with aq.
HClO4 (pH 2) and detected by a UV lamp at u=254 nm.
The retention times of the R- and S-forms were 9.4 min
and 11.6 min, respectively.