Novozyme 435 lipase mediated enantioselective kinetic resolution: A facile method for the synthesis of chiral tetrahydroquinolin-4-ol and tetrahydro-1H-benzo[b]azepin-5-ol derivatives

Article abstract of DOI:10.1016/j.tet.2015.05.066

Vinyl 2-chloroacetate was used as an efficient acyl donor for enantioselective acylation of racemic 1,2,3,4-tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ols with Novozyme 435 lipase. Two enantiocomplimentary tetrahydroquinolin-4-ol

Full text of DOI:10.1016/j.tet.2015.05.066

Tetrahedron 71 (2015) 4738e4744
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Tetrahedron
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Novozyme 435 lipase mediated enantioselective kinetic resolution:
a facile method for the synthesis of chiral tetrahydroquinolin-4-ol
and tetrahydro-1H-benzo[b]azepin-5-ol derivatives
*
Xiaojian Zhou, Daijun Zheng, Baodong Cui, Wenyong Han, Yongzheng Chen
School of Pharmacy, Zunyi Medical University, Zunyi 563000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 April 2015
Received in revised form 16 May 2015
Accepted 18 May 2015
Available online 22 May 2015
Vinyl 2-chloroacetate was used as an efficient acyl donor for enantioselective acylation of racemic 1,2,3,4-
tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ols with Novozyme 435 lipase.
Two enantiocomplimentary tetrahydroquinolin-4-ol or tetrahydro-1H-benzo[b]azepin-5-ol derivatives
could be smoothly obtained in good to excellent yields and ee values at the same time. Noteworthily,
large scale preparation experiment was also demonstrated when amplified the reaction system to 10 g
scale experiment, and products were obtained with high yields and ee values.
Keywords:
Novozyme 435 lipase
Kinetic resolution
Ó 2015 Elsevier Ltd. All rights reserved.
Biocatalytic processes
Tetrahydroquinolin-4-ol
Tetrahydro-1H-benzo[b]azepin-5-ol
1. Introduction
asymmetric centre in the molecular are usually appropriate to
be used in their optically active form instead of in racemic
Chiral benzylic alcohols and their derivatives are important
building blocks for the synthesis of chemical materials, pharma-
ceuticals, and agrochemicals, which can be attributed to hydroxyl
group could be readily converted to versatile intermediates.1
Among these, enantiopure tetrahydroquinolin-4-ols and tetrahy-
dro-1H-benzo[b]azepin-5-ols are attractive targets due to their
promising biological activities and wide-ranging use as synthetic
intermediates for drug candidates.2 Accordingly, there has been
a powerful inner impetus to quest efficient routes to this type of
fascinating structures.
In the last few years, different methodologies for the synthesis
of 1,2,3,4-tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-
benzo[b]azepin-5-ols have been established.3e7 However, these
strategies mainly rely on the chemical synthesis methods, and most
of studies mainly focused on the synthesis of these two classes of
compounds in their racemic form. In contrast, the methodologies
to access chiral 1,2,3,4-tetrahydroquinolin-4-ols and 2,3,4,5-
tetrahydro-1H-benzo-[b]azepin-5-ols are still limited.2a,3,4a,4c
Meanwhile, from the view point of intended side-effects and
pharmacological activities, pharmaceutical compounds having an
form. Therefore, it is much desired to develop novel and
efficient methods for the synthesis of optically active 1,2,3,4-
tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-5-ols.
Biocatalytic processes have been intensely studied and have
become a useful and green alternative in stereoselective synthesis
due to their multiple advantages.8 Among them, lipase mediated
kinetic resolution has been broadly applied in the synthesis of
chiral benzylic alcohol derivatives.2a,9 Noteworthily, the bio-
catalytic kinetic resolution of racemic N-Ts-substituted 2,3,4,5-
tetrahydro-1H-benzo[b]azepin-5-ol was reported by Matsubara
and co-workers.2a However, there were no examples of highly
enantioselective and efficient synthesis of chiral 1,2,3,4-
tetrahydroquinolin-4-ols and 2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-5-ols via the enzymatic process except for only one trans-
formation of N-substituted-1,2,3,4-tetrahydroquinoline into
corresponding benzyl alcohol with 5.4e9.4% yield and unknown ee
using the fungus Cunninghamella elegans.10 Moreover, even though
we have discovered that Pseudomonas plecoglossicidas ZMU-T02
and ZMU-T06 could smoothly catalyzed the reaction for synthesis
of (R)-1,2,3,4-tetrahydroquinolin-4-ol and 2,3,4,5-tetrahydro-1H-
benzo[b]azepin-5-ol with 82% yield in 99% ee and 99% yield in 98%
ee, respectively, the substrate concentration (2 mM) and substrate
scope were also the main bottle neck for practical preparation.11
* Corresponding author. Tel.: þ86 851 28642336; fax: þ86 851 28609726; e-mail
address: yzchen@zmc.edu.cn (Y. Chen).
http://dx.doi.org/10.1016/j.tet.2015.05.066
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
4739
In this context, as a continuation of our studies on the enzymatic
reactions,11,12 we found that (rac)-N-Boc-1,2,3,4-tetrahydro
quinolin-4-ol (1a) could be chosen as a suitable substrate for the
lipase mediated enantioselective kinetic resolution, which was
easily synthesized from 1,2,3,4-tetrahydroquinoline. Protection of
the NeH group of 1,2,3,4-tetrahydroquinoline followed by oxida-
tion and reduction gave (rac)-1a in 35% total yield (Scheme 1).13
Moreover, a series of enantiocomplimentary 1,2,3,4-tetrahydro
quinolin-4-ols, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ols, and
the corresponding esters can be obtained in excellent results with
Novozyme 435 as biocatalyst and vinyl 2-chloroacetate as a novel
acyl donor via highly enantioselective acylation process. It is
worthwhile to note that this work represents the first example
regarding vinyl 2-chloroacetate serving as highly efficient acyl
donor for biocatalytic asymmetric transformation. Herein, we wish
to report the results of our endeavours on this subject.
on the activity and enantioselectivity of the resolution of (rac)-1a
(Table 2). This decision was also based on the wide application of
Novozyme 435 as biocatalyst for kinetic resolution and dynamic
kinetic resolution of amines15 and alcohols.9b-e,15a,16 As shown in
Table 2, it was found that the reactions were proceed smoothly to
offer the desired compounds (S)-1a and (R)-3aec in good conver-
sions with excellent enantioselectivities using 2aec as acyl donors
(Table 2, entries 1e3), but the acyl donors 2d and 2e gave poor ee
for (S)-1a (Table 2, entries 4 and 5). To our great surprise, the
enantioselective acylation could not occur when the R group of acyl
donor was tBu, which may be attributed to the steric effect (Table 2,
entry 6). Undoubtedly, 2b was selected as the best acyl donor to be
applied in the following studies in terms of the enantiomeric ratio
(>200 E value) and ee (99% and 99%) for the (S)-1a and (R)-3b
(Table 2, entry 2).
Table 2
Evaluation of acyl donors of enantioselective acylation of racemic 1aa
Scheme 1. Synthesis of (rac)-1a.
2. Results and discussion
Our initial studies started with the reaction of compound (rac)-
1a and vinyl acetate (2a) in MeOtBu at 30 ꢀC for the screening of
a series of lipases (Table 1). There is no activity with the substrate
(rac)-1a in the presence of Amano Type VII (Table 1, entry 1). When
the reaction was performed using CAL-A as biocatalyst, the (rac)-1a
was completely transformed into the racemic ester 3a (Table 1,
entry 2). Further investigations into several other lipases, including
Amano lipase A, Novozyme 435, lipase RM IM, and lipase TL IM,
revealed that (S)-1a and (R)-3a could be obtained in good to ex-
cellent results (Table 1, entries 3e6). Particularly, the lipase Novo-
zyme 435 provided the highest enantioselectivity (98% and 97% ee,
>200 E value) for the (S)-1a and (R)-3a (Table 1, entry 4).
Entry
2
ee (%)b
c (%)c
Ed
(S)-1a
(R)-3
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
98
99
71
23
20
d
(R)-3a/97
(R)-3b/99
(R)-3c/99
(R)-3d/99
(R)-3e/99
d
50
50
42
19
17
d
>200
>200
>200
>200
>200
d
a
Unless otherwise noted, the reaction mixtures of racemic 1a (0.05 mmol,
12.5 mg), 2 (0.25 mmol) and Novozyme 435 (5.0 mg) in 0.5 mL MeOtBu were shaken
in orbital shaker at 300 rpm at 30 ꢀC for 8 h.
b
Determined by HPLC analysis.
c
Conversion: c¼eeS/(eeSþeeP).
d
Encouraged by these excellent results, we employed Novozyme
435 as biocatalyst to investigate the influence of various acyl donors
E¼{ln[eeP(1ꢁeeS)]/(eePþeeS)}/{ln [eeP(1þeeS)]/(eePþeeS)}.
To further optimize the reaction efficiency, various solvents
were then examined. As shown in Table 3, kinetic resolution of
racemic 1a run in (iPr)2O and CH3CN gave the similar results as that
performed in MeOtBu (Table 3, entries 2 and 3 vs entry 1). How-
ever, (S)-1a was obtained with dramatically decreased enantiose-
lectivity using toluene and n-hexane as solvents, though both of
the enantioselectivities of the ester (R)-3b were excellent (Table 3,
entries 4 and 5). Moreover, the target compounds were not ob-
tained with added water under the reaction conditions (Table 3,
entry 6). Additionally, the probe into the concentration effects of
Novozyme 435 revealed that a low concentration did lead to an
obvious decrease in enantioselectivity and conversion (Table 3,
entry 7). Thus, the above studies provided the optimal reaction
conditions: the reaction mixtures of racemic 1a (0.05 mmol), vinyl
2-chloroacetate 2b (0.25 mmol) and Novozyme 435 (5.0 mg) in
0.5 mL MeOtBu were shaken at 300 rpm at 30 ꢀC for 8 h (Table 3,
entry 1).
After the establishment of the optimal conditions (Table 3, entry
1), substrate scope of Novozyme 435-mediated enantioselective
acylation of racemic 1 was explored. As shown in Table 4, for the
substrate racemic 1, whether the substituent group is electro-
nedeficient or erich on the phenyl ring, the reactions proceeded
smoothly and gave the corresponding alcohols (S)-1bed and esters
(R)-3feh in excellent results (up to 48% yield, >99% ee, and >200 E
Table 1
Lipase-catalyzed acetylation of racemic 1a with vinyl acetatea
Entry
Lipase
ee (%)b
c (%)c
Ed
(S)-1a
(R)-3a
1
Amano Type VII
CAL-A
Amano lipase A
Novozyme 435
lipase RM IM
lipase TL IM
d
d
53
98
58
99
d
0
99
97
99
48
d
d
2e
3
100
35
50
37
67
d
>200
>200
>200
13
4
5
6
a
Unless otherwise noted, the reaction mixtures of racemic 1a (0.05 mmol,
12.5 mg), vinyl acetate 2a (0.25 mmol, 23.0 m
L) and lipase (5.0 mg) in 0.5 mL MeOtBu
were shaken in orbital shaker at 300 rpm at 30 ꢀC for 8 h.
b
Determined by HPLC analysis.
c
Conversion: c¼eeS/(eeSþeeP).14
E¼{ln[eeP(1ꢁeeS)]/(eePþeeS)}/{ln[eeP(1þeeS)]/(eePþeeS)}.14
d
e
The (rac)-1a was completely transformed into the racemic ester 3a.

4740
X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
Table 3
It was noteworthy that single crystal suitable for X-ray crystal-
lographic analysis was fortunately obtained from optically pure 3j.
As shown in Fig. 1, it was determined as (R) configuration.17 So it
was natural that the absolute configuration of compound 1f could
be assigned as (S) configuration according to the absolute config-
uration of compound 3j. The stereochemistry of other products in
this work was assigned by analogy.
Screening of solvents for Novozyme 435 catalyzed enantioselective acylation of
racemic 1aa
Entry
Solvent
ee (%)b
c (%)c
Ed
(S)-1a
(R)-3b
1
2
3
4
MeOtBu
(iPr)2O
CH3CN
Toluene
n-Hexane
MeOtBu
MeOtBu
99
99
92
78
33
d
99
95
99
99
99
d
50
51
48
44
25
d
>200
>200
>200
>200
>200
d
5
6e
7f
73
99
42
>200
a
Unless otherwise noted, the reaction mixtures of racemic 1a (0.05 mmol,
12.5 mg), vinyl 2-chloroacetate 2b (0.25 mmol, 25.3 mL) and Novozyme 435 (5.0 mg)
in 0.5 mL solvent were shaken in orbital shaker at 300 rpm at 30 ꢀC for 8 h.
b
Determined by HPLC analysis.
c
Fig. 1. X-ray crystallographic structure of optically pure 3j.
Conversion: c¼eeS/(eeSþeeP).
d
E¼{ln[eeP(1ꢁeeS)]/(eePþeeS)}/{ln[eeP(1þeeS)]/(eePþeeS)}.
e
Water (0.55 mmol, 10.0 mL) was used.
f
Novozyme 435 (2.0 mg) was used.
The excellent results of enantioselective acylation of racemic
1,2,3,4-tetrahydroquinolin-4-ols (rac)-1 mediated by the lipase
Novozyme 435 (Table 4) prompted us to test another chiral reso-
lution with respect to the racemic 2,3,4,5-tetrahydro-1H-benzo[b]
azepin-5-ols (rac)-4 by using the previously optimized reaction
conditions (Table 3, entry 1),18 and the results were summarized in
Table 5. Different substitutions on the N1 position of the racemic 4,
such as Bz, 2-furoyl and Cbz, were all well tolerated to smoothly
supply the corresponding alcohols (S)-4 and esters (R)-5 in excel-
lent yields (up to 44%) with enantioselectivities (up to 98% ee and
>200 E value) (Table 5, entries 1e3).
Table 4
Substrate scope of Novozyme 435-mediated enantioselective acylation of racemic
1aeka
Table 5
Substrate scope of Novozyme 435-mediated enantioselective acylation of racemic
4aeca
Entry
(Rac)-1
(S)-1/Yield (%)b/ee (%)c
(R)-3/Yield (%)b/ee (%)c
Ed
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
(S)-1a/45/94
(S)-1b/48/98
(S)-1c/29/>99
(S)-1d/38/>99
(S)-1e/46/96
(S)-1f/35/95
(S)-1g/44/>99
(S)-1h/34/>99
(S)-1i/40/99
(S)-1j/34/>99
(S)-1k/nr/d
(R)-3b/42/99
(R)-3f/42/>99
(R)-3g/47/96
(R)-3h/42/92
(R)-3i/43/94
(R)-3j/37/>99
(R)-3k/40/95
(R)-3l/49/97
(R)-3m/46/99
(R)-3n/40/>99
(R)-3o/nr/d
>200
>200
>200
126
127
>200
>200
>200
>200
>200
d
9
Entry
(Rac)-4
(S)-4/Yield (%)b/ee (%)c
(R)-5/Yield (%)b/ee (%)c
Ed
10
1j
1k
1
2
3
4a
4b
4c
(S)-4a/40/98
(S)-4b/39/96
(S)-4c/44/90
(R)-5a/42/97
(R)-5b/43/98
(R)-5c/41/93
>200
>200
85
11e
a
Unless otherwise noted, reaction mixtures of racemic 1 (5.00 mmol), vinyl 2-
chloroacetate 2b (25.00 mmol) and Novozyme 435 (0.50 g) in MeOtBu (50 mL)
were shaken in orbital shaker at 300 rpm at 30 ꢀC for 8 h.
a
Unless otherwise noted, reaction mixtures of racemic 4 (0.50 mmol), vinyl 2-
chloroacetate 2b (2.50 mmol) and Novozyme 435 (0.05 g) in MeOtBu (5 mL) were
shaken in orbital shaker at 300 rpm at 30 ꢀC for 8 h.
b
Isolated yield.
Determined by HPLC analysis.
c
b
Isolated yield.
Determined by HPLC analysis.
E¼{ln[eeP(1ꢁeeS)]/(eePþeeS)}/{ln[eeP(1þeeS)]/(eePþeeS)}.
d
E¼{ln[eeP(1ꢁeeS)]/(eePþeeS)}/{ln[eeP(1þeeS)]/(eePþeeS)}.
c
e
Run for 24 h nr¼No reaction.
d
value) (Table 4, entries 2e4). On the other hand, upon changing the
protected group of N1 to other groups, such as CO2Ph, Cbz, Ac, Bz,
furoyl, and SO2Ph, the corresponding reaction also provided the
expected products in up to 49% yield with up to >99% ee and
>200 E value (Table 4, entries 5e10). However, substrate 1k bearing
benzyl group at the N1 position did not provide the desired prod-
ucts under the standard conditions (Table 4, entry 11).
To evaluate the practicability of the above methodology, the
enantioselective acylation process of the racemic compound 1g was
conducted on a large more than tenfold scale with the lipase
Novozyme 435 as biocatalyst. As outlined in Scheme 2, the 10 g-
scale enantioselective acylation proceeded smoothly to afford the
corresponding products (S)-1g and (R)-3k in the same isolated
yields almost without any loss of enantioselectivities (Scheme 2, a).

X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
4741
4.2. Representative procedure for the synthesis of (S)-1,2,3,4-
tetrahydroquinolin-4-ol (1) and (R)-1,2,3,4-tetrahydroquinolin-
4-yl 2-chloroacetate (3)
To
a
solution of (rac)-1,2,3,4-tetrahydroquinolin-4-ol (1)
(5.00 mmol, 1 equiv) in 50 mL MeOtBu, vinyl 2-chloroacetate
(25.00 mmol, 5 equiv) and Novozyme 435 (0.50 g) were consecu-
tively added. The reaction mixture was shaken in orbital shaker at
300 rpm at 30 ꢀC for 8 h. After that, the mixture was filtered and
concentrated, and the residue was purified by column chromatog-
raphy (EtOAc/petroleum¼1:5) to give (S)-1 and (R)-3, respectively.
4.2.1. (S)-tert-Butyl 4-hydroxy-3,4-dihydroquinoline-1(2H)-carbox-
ylate (1a). Gray solid, yield 45%; 94% ee, [
a
]
D
25 ꢁ24.1 (c 1.00, CHCl3);
mp 129.1e130.8 ꢀC. HPLC analysis Chiralpak OD-H (hexane/i-
PrOH¼95/5; 0.3 mL/min,
l
¼254 nm; tminor¼35.0 min,
tmajor¼32.2 min); 1H NMR (300 MHz, DMSO-d6):
7.63 (d, J¼8.1 Hz,
d
Scheme 2. Large scale experiment and the transformation of (S)-1g to chiral amine 7.
1H), 7.35 (d, J¼6.6 Hz, 1H), 7.20e7.15 (m, 1H), 7.06e7.00 (m, 1H),
5.36 (s, 1H), 4.56 (s, 1H), 3.83e3.76 (m, 1H), 3.60e3.53 (m, 1H),
1.98e1.93 (m,1H),1.80e1.76 (m,1H),1.47 (s, 9H); 13C NMR (75 MHz,
Additionally, the enantioenriched secondary alcohol (S)-1g could
be transformed to (R)-1,2,3,4-tetrahydroquinolin-4-amine 7 with
a complete inversion of stereochemistry in 58% total yield with 96%
ee by treatment with diphenyl phosphorazidate, and followed by
catalytic hydrogenation (Scheme 2, b).
DMSO-d6):
d 152.9, 137.1, 132.5, 127.8, 126.7, 122.9, 122.7, 80.2, 64.1,
40.9, 32.1, 27.9; HRMS (ESI-TOF): calcd for C14H19NNaO3 [MþNa]þ,
272.1257; found: 272.1269.
4.2.2. (R)-tert-Butyl
1(2H)-carboxylate (3b). Yellow oil, yield 42%; 99% ee, [
4-(2-chloroacetoxy)-3,4-dihydroquinoline-
25
a
]
87.2 (c
D
1.04, CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼95/5,
¼254 nm, tminor¼25.4 min, tmajor¼26.6 min); 1H NMR
3. Conclusion
0.3 mL/min,
l
(300 MHz, CDCl3):
d
7.83 (d, J¼8.7 Hz, 1H), 7.31e7.26 (m, 2H),
In summary, we have developed a practical and efficient
methodology for the construction of enantiocomplimentary
1,2,3,4-tetrahydroquinolin-4-ols, 2,3,4,5-tetrahydro-1H-benzo[b]
azepin-5-ols and its corresponding esters through kinetic resolu-
tion. With the Novozyme 435 as efficient biocatalyst and vinyl 2-
chloroacetate as a novel acyl donor, the enantioselective acylation
of the racemic 1,2,3,4-tetrahydroquinolin-4-ols and 2,3,4,5-
tetrahydro-1H-benzo[b]azepin-5-ols proceeded smoothly to give
the corresponding chiral alcohols and esters in high yields with
excellent enantioselectivities (up to 49% yield, >99% ee, and >200 E
value). Furthermore, the usefulness of this protocol was demon-
strated by the investigation into the 10 g-scale enantioselective
acylation of the racemic 1,2,3,4-tetrahydroquinolin-4-ol, as well as
the transformation of the chiral 1,2,3,4-tetrahydroquinolin-4-ol
into chiral 1,2,3,4-tetrahydroquinolin-4-amine. Further biological
evaluation of chiral tetrahydroquinolin-4-ol and tetrahydro-1H-
benzo[b]azepin-5-ol derivatives are currently underway in our
laboratory.
7.08e7.03 (m, 1H), 6.03 (t, J¼3.9 Hz, 1H), 4.18e4.11 (m, 1H), 4.06 (s,
2H), 3.60e3.50 (m, 1H), 2.17e2.12 (m, 2H), 1.54 (s, 9H); 13C NMR
(75 MHz, CDCl3):
d 166.8, 153.4, 138.8, 129.5, 128.9, 125.1, 123.6,
123.4, 81.5, 70.0, 41.1, 40.3, 29.2, 28.3; HRMS (ESI-TOF): calcd for
C
16H20ClNNaO4 [MþNa]þ, 348.0973; found: 348.0985.
4.2.3. (S)-tert-Butyl
1(2H)-carboxylate (1b). White solid, yield 48%; 98% ee, [
(c 0.71, CHCl3); mp 132.2e133.5 ꢀC. HPLC analysis Chiralpak OJ-H
6-Chloro-4-hydroxy-3,4-dihydroquinoline-
25
a
]
ꢁ17.2
D
(hexane/i-PrOH¼95/5, 0.8 mL/min,
l
¼254 nm, tminor¼15.2 min,
tmajor¼16.7 min); 1H NMR (400 MHz, DMSO-d6):
7.65 (d, J¼9.2 Hz,
d
1H), 7.35 (d, J¼2.0 Hz, 1H), 7.20 (dd, J¼9.0 Hz, 2.6 Hz, 1H), 5.55 (d,
J¼5.5 Hz, 1H), 4.55e4.50 (m, 1H), 3.77e3.71 (m, 1H), 3.57e3.51 (m,
1H), 1.98e1.93 (m, 1H), 1.75e1.70 (m, 1H), 1.44 (s, 9H); 13C NMR
(100 MHz, DMSO-d6): d 153.2, 136.3, 135.3, 127.4, 127.1, 127.0, 125.1,
81.1, 64.3, 41.6, 32.1, 28.3; HRMS (ESI-TOF): calcd for C14H18ClNNaO3
[MþNa]þ, 306.0867; found: 306.0872.
4.2.4. (R)-tert-Butyl-4-(2-chloroacetoxy)-3,4-dihydroquinoline-
1(2H)-carboxylate (3f). White solid, yield 42%; >99% ee [
a]
25 76.5 (c
D
4. Experimental section
4.1. General
0.71, CHCl3); mp 139.8e141.2 ꢀC. HPLC analysis Chiralpak OJ-H
(hexane/i-PrOH¼97/3, 0.5 mL/min, ¼254 nm, tminor¼30.6 min,
l
tmajor¼24.5 min); 1H NMR (400 MHz, CDCl3):
d
7.81 (d, J¼8.8 Hz,
1H), 7.27e7.22 (m, 2H), 5.94 (t, J¼4.2 Hz, 1H), 4.19e4.09 (m, 1H),
Reagents were purchased from commercial sources and were
used as received unless mentioned otherwise. Reactions were
monitored by TLC. 1H NMR (300 MHz or 400 MHz) and 13C NMR
(75 MHz or 100 MHz) spectra were recorded in CDCl3 and DMSO-
d6. 1H NMR chemical shifts are reported in parts per million (ppm)
relative to tetramethylsilane (TMS) with the solvent resonance
employed as the internal standard (CDCl3 at 7.26 ppm, DMSO-d6 at
2.50 ppm). Data are reported as follows: chemical shift, multiplicity
(s¼singlet, br s¼broad singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet), coupling constants (Hz) and integration. 13C NMR
chemical shifts are reported in ppm from tetramethylsilane (TMS)
with the solvent resonance as the internal standard (CDCl3 at
77.20 ppm, DMSO-d6 at 39.51 ppm).
4.08 (s, 2H), 3.56e3.49 (m, 1H), 2.14e2.10 (m, 2H), 1.54 (s, 9H); 13
NMR (100 MHz, CDCl3): 166.7, 153.1, 137.3, 128.9, 128.4, 126.6,
C
d
124.9, 81.9, 69.3, 41.0, 40.3, 28.9, 28.3; HRMS (ESI-TOF): calcd for
C
16H19Cl2NNaO4 [MþNa]þ, 382.0583; found: 382.0574.
4.2.5. (S)-tert-Butyl
6-bromo-4-hydroxy-3,4-dihydroquinoline-
1(2H)-carboxylate (1c). White solid, yield 29%; >99% ee, [
a
]
D
25 ꢁ11.2
(c 0.64, CHCl3); mp 174.8e176.4 ꢀC. HPLC analysis Chiralpak OJ-H
(hexane/i-PrOH¼97/3, 0.5 mL/min, ¼254 nm, tminor¼20.8 min,
l
tmajor¼22.7 min); 1H NMR (400 MHz, DMSO-d6):
7.60 (d, J¼9.2 Hz,
d
1H), 7.48 (d, J¼2.8 Hz, 1H), 7.33 (dd, J¼9.2 Hz, 2.8 Hz, 1H), 5.55 (d,
J¼5.6 Hz, 1H), 4.55e4.51 (m, 1H), 3.77e3.70 (m, 1H), 3.56e3.50 (m,
1H), 1.99e1.93 (m, 1H), 1.73e1.70 (m, 1H), 1.44 (s, 9H); 13C NMR

4742
X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
(100 MHz, DMSO-d6):
d
153.1, 136.8, 135.7, 130.3, 129.8, 125.5, 115.2,
J¼5.2 Hz, 1H), 5.18 (s, 2H), 4.58e4.56 (m, 1H), 3.90e3.85 (m, 1H),
3.67e3.65 (m, 1H), 1.99e1.96 (m, 1H), 1.80e1.78 (m, 1H); 13C NMR
(100 MHz, DMSO-d6): d 154.2, 137.1, 136.9, 133.3, 128.9, 128.4, 128.3,
81.1, 64.3, 41.6, 32.1, 28.3; HRMS (ESI-TOF): calcd for C14H18BrNNaO3
[MþNa]þ, 350.0362; found: 350.0351.
128.2, 127.4, 123.6, 123.1, 67.3, 64.5, 41.6, 32.4; HRMS (ESI-TOF):
4.2.6. (R)-tert-Butyl 6-bromo-4-(2-chloroacetoxy)-3,4-
calcd for C17H17NNaO3 [MþNa]þ, 306.1101; found: 306.1108.
dihydroquinoline-1(2H)-carboxylate (3g). Brown solid, yield 47%;
96% ee, [
a
]
25 55.1 (c 1.16, CHCl3); mp 149.2e150.8 ꢀC. HPLC analysis
4.2.12. (R)-Benzyl 4-(2-chloroacetoxy)-3,4-dihydroquinoline-1(2H)-
D
Chiralpak OJ-H (hexane/i-PrOH¼97/3, 0.5 mL/min,
l¼254 nm,
carboxylate (3j). White solid, yield 37%; >99% ee, [
a]
25 88.3 (c 1.05,
D
tminor¼32.9 min, tmajor¼26.4 min); 1H NMR (400 MHz, CDCl3):
CHCl3); mp 90.1e91.3 ꢀC. HPLC analysis Chiralpak AY-H (hexane/i-
d
7.75 (d, J¼8.8 Hz, 1H), 7.41e7.36 (m, 2H), 5.94 (t, J¼4.0 Hz, 1H),
PrOH¼90/10, 0.8 mL/min,
l
¼254 nm, tminor¼21.4 min,
4.14e4.08 (m, 3H), 3.54e3.50 (m, 1H), 2.14e2.10 (m, 2H), 1.53 (s,
tmajor¼18.4 min); 1H NMR (400 MHz, CDCl3):
d
7.92 (d, J¼8.8 Hz,
9H); 13C NMR (100 MHz, CDCl3):
d
166.7, 153.1, 137.8, 131.9, 131.8,
1H), 7.42e7.26 (m, 7H), 7.11e7.07 (m,1H), 6.03 (t, J¼3.8 Hz,1H), 5.26
126.9, 125.3, 115.9, 81.9, 69.3, 41.0, 40.3, 28.8, 28.3; HRMS (ESI-TOF):
(s, 2H), 4.25e4.20 (m, 1H), 4.05 (s, 2H), 3.69e3.61 (m, 1H),
calcd for C16H19BrClNNaO4 [MþNa]þ, 426.0078; found: 426.0072.
2.19e2.14 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
166.8, 154.2, 138.3,
136.0, 129.7, 129.3, 128.6, 128.3, 128.1, 125.2, 123.9, 123.4, 69.8, 67.9,
4.2.7. (S)-1-(4-Hydroxy-6-methoxy-3,4-dihydroquinolin-1(2H)-yl)
41.1, 40.5, 28.9; HRMS (ESI-TOF): calcd for C19H18ClNNaO4
ethanone (1d). Colorless oil, yield 38%; >99% ee, [
a
]
D
25 ꢁ189.7 (c 1.0,
[MþNa]þ, 382.0817; found: 382.0823.
CHCl3); HPLC analysis Chiralpak AD-H (hexane/i-PrOH¼90/10,
1.0 mL/min,
(400 MHz, DMSO-d6):
l
¼254 nm, tminor¼19.1 min, tmajor¼16.6 min); 1H NMR
4.2.13. (S)-1-(4-Hydroxy-3,4-dihydroquinolin-1(2H)-yl)ethanone
25
d
7.20e7.19 (br s, 1H), 6.97e6.96 (m, 1H),
(1g). Yellow oil, yield 44%; >99% ee, [
a
]
D
ꢁ96.1 (c 1.09, CHCl3);
6.79e6.76 (m, 1H), 5.47e5.46 (d, J¼4.0 Hz, 1H), 4.50 (dd, J¼12.0 Hz,
HPLC analysis Chiralpak AY-H (hexane/i-PrOH¼90/10, 0.8 mL/min,
8.0 Hz,1H), 3.85 (br s,1H), 3.73 (s, 3H), 3.43e3.41 (m,1H), 2.09e2.05
l
¼254 nm, tminor¼18.3 min, tmajor¼14.6 min); 1H NMR (300 MHz,
(m, 4H),1.67 (br s,1H); 13C NMR (100 MHz, DMSO-d6):
d
169.4,156.6,
DMSO-d6): d 7.50e7.41 (m, 2H), 7.24e7.19 (m, 1H), 7.16e7.11 (m,
130.8,125.6,112.7,111.7, 64.8, 55.6, 33.4, 23.5; HRMS (ESI-TOF): calcd
1H), 5.43e5.42 (d, J¼7.3 Hz, 1H), 4.58e4.53 (m, 1H), 3.91e3.84 (m,
for C12H15NNaO3 [MþNa]þ, 244.0944; found: 244.0952.
1H), 3.54e3.50 (m, 1H), 2.16 (s, 3H), 2.13e2.04 (m, 1H), 1.78e1.71
(m, 1H); 13C NMR (75 MHz, DMSO-d6):
d 169.3, 137.3, 127.0, 126.7,
4.2.8. (R)-1-Acetyl-6-methoxy-1,2,3,4-tetrahydroquinolin-4-yl 2-
124.1, 123.9, 64.2, 32.9, 23.3; HRMS (ESI-TOF): calcd for
C
25
chloroacetate (3h). White solid, yield 42%; 92% ee, [
a
]
D
71.2 (c
11H13NNaO2 [MþNa]þ, 214.0838; found: 214.0846.
1.0, CHCl3); mp 151.2e152.9 ꢀC. HPLC analysis Chiralpak AD-H
(hexane/i-PrOH¼90/10, 1.0 mL/min,
l
¼254 nm, tminor¼22.1 min,
4.2.14. (R)-1-Acetyl-1,2,3,4-tetrahydroquinolin-4-yl 2-chloroacetate
tmajor¼19.5 min); 1H NMR (400 MHz, CDCl3):
d
7.06 (br s, 1H),
(3k). White solid, yield 40%; 95% ee, [a]
25 78.2 (c 1.07, CHCl3); mp
D
6.87e6.85 (m, 2H), 5.93 (t, J¼4.0 Hz, 1H), 4.05 (s, 2H), 3.97e3.94 (m,
89.7e91.3 ꢀC. HPLC analysis Chiralpak AY-H (hexane/i-PrOH¼90/10,
1H), 3.77e3.71 (m, 4H), 2.21 (s, 3H), 2.19e2.16 (m, 2H); 13C NMR
0.8 mL/min,
l
¼254 nm, tminor¼39.3 min, tmajor¼45.0 min); 1H NMR
(100 MHz, CDCl3):
d
170.2, 168.9, 166.8, 157.0, 132.0, 125.8, 114.8,
(400 MHz, CDCl3): d 7.33 (m, 3H), 7.20e7.16 (m, 1H), 6.00
113.4, 69.9, 55.6, 41.0, 39.4, 30.1, 23.0; HRMS (ESI-TOF): calcd for
C
(t, J¼4.4 Hz, 1H), 4.07e4.01 (m, 3H), 3.79e3.69 (m, 1H), 2.26 (s, 3H),
14H16ClNNaO4 [MþNa]þ, 320.0660; found: 320.0663.
2.23e2.18 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
169.9, 166.8, 139.0,
129.1, 129.0, 125.3, 124.5, 69.9, 41.0, 39.8, 30.1, 23.4; HRMS (ESI-
4.2.9. (S)-Phenyl 4-hydroxy-3,4-dihydroquinoline-1(2H)-carboxylate
TOF): calcd for
290.0567.
C
13H14ClNNaO3 [MþNa]þ, 290.0554; found:
(1e). White solid, yield 46%; 96% ee, [
a
]
25 ꢁ37.6 (c 1.07, CHCl3); mp
D
126.1e127.3 ꢀC. HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/
10, 0.8 mL/min,
NMR (400 MHz, DMSO-d6):
l
¼254 nm, tminor¼37.0 min, tmajor¼14.6 min); 1H
4.2.15. (S)-(4-Hydroxy-3,4-dihydroquinolin-1(2H)-yl) (phenyl)meth-
25
d
7.74 (d, J¼8.4 Hz, 1H), 7.43e7.39 (m,
anone (1h). White solid, yield 34%; >99% ee, [
a
]
ꢁ59.9 (c 1.10,
D
3H), 7.26e7.20 (m, 4H), 7.12e7.08 (m, 1H), 5.47 (d, J¼4.8 Hz, 1H),
CHCl3); mp 200.7e201.9 ꢀC. HPLC analysis Chiralpak OJ-H (hexane/i-
4.66e4.62 (m,1H), 4.02e3.97 (m, 1H), 3.79e3.77 (m,1H), 2.14e2.09
PrOH¼90/10, 1.0 mL/min,
l
¼254 nm, tminor¼27.4 min,
(m, 1H), 1.89e1.86 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d
152.9,
tmajor¼33.5 min); 1H NMR (400 MHz, DMSO-d6):
d 7.42e7.37 (m, 2H),
151.4, 136.8, 133.8, 129.8, 128.3, 127.5, 126.0, 124.1, 123.3, 122.4, 64.5,
7.33e7.30 (m, 4H), 7.06e7.02 (m, 1H), 6.95e6.91 (m, 1H), 6.79e6.77
(m, 1H), 5.51 (d, J¼5.6 Hz, 1H), 4.71e4.67 (m,1H), 3.92e3.85 (m, 1H),
3.67e3.60 (m, 1H), 2.18e2.10 (m, 1H), 1.86e1.78 (m, 1H); 13C NMR
42.1, 32.5; HRMS (ESI-TOF): calcd
292.0944; found: 292.0949.
C
16H15NNaO3 [MþNa]þ,
(100 MHz, DMSO-d6): d 169.8, 137.9, 136.9, 134.6, 130.5, 128.6, 128.5,
4.2.10. (R)-Phenyl 4-(2-chloroacetoxy)-3,4-dihydroquinoline-1(2H)-
127.8, 126.9, 124.8, 124.5, 64.5, 42.2, 33.3; HRMS (ESI-TOF): calcd for
C
25
carboxylate (3i). Yellow oil, yield: 43%; 94% ee; [
a]
70.7 (c 1.11,
16H15NNaO2 [MþNa]þ, 276.0995; found: 276.0998.
D
CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/10,
0.8 mL/min,
(400 MHz, CDCl3):
l
¼254 nm, tminor¼28.7 min, tmajor¼35.6 min); 1H NMR
4.2.16. (R)-1-Benzoyl-1,2,3,4-tetrahydroquinolin-4-yl 2-
25
d
7.96 (d, J¼8.4 Hz, 1H), 7.43e7.33 (m, 4H),
chloroacetate (3l). Yellow oil, yield 49%; 97% ee, [
a
]
51.0 (c 1.03,
D
7.27e7.23 (m,1H), 7.19e7.12 (m, 3H), 6.10 (t, J¼4.0 Hz,1H), 4.14e4.11
CHCl3); HPLC analysis Chiralpak OJ-H (hexane/i-PrOH¼90/10,
(m,1H), 4.10 (s, 2H), 3.84e3.77 (m,1H), 2.31e2.26 (m, 2H); 13C NMR
1.0 mL/min,
l
¼254 nm, tminor¼24.0 min, tmajor¼21.9 min); 1H NMR
(100 MHz, CDCl3):
d
166.9, 153.0, 150.8, 137.9, 129.7, 129.5, 129.4,
(400 MHz, CDCl3): d 7.43e7.39 (m, 3H), 7.36e7.30 (m, 3H),
125.9,125.6,124.4,123.5,121.7, 69.7, 41.1, 40.6, 29.1; HRMS (ESI-TOF):
7.08e7.05 (m, 2H), 6.92e6.91 (m, 1H), 6.12 (t, J¼4.2 Hz, 1H),
calcd for C18H16ClNNaO4 [MþNa]þ, 368.0684; found: 368.0675.
4.16e4.11 (m, 1H), 4.09 (s, 2H), 3.90e3.85 (m, 1H), 2.31e2.26 (m,
2H); 13C NMR (100 MHz, CDCl3):
d 170.5, 166.9, 139.1, 135.6, 130.6,
4.2.11. (S)-Benzyl 4-hydroxy-3,4-dihydroquinoline-1(2H)-carboxyl-
129.2, 128.7, 128.5, 128.3, 126.5, 125.1, 124.8, 69.8, 41.3, 41.0, 29.9;
HRMS (ESI-TOF): calcd for C18H16ClNNaO3 [MþNa]þ, 352.0717;
found: 352.0717.
ate (1f). White solid, yield 35%; 95% ee, [
a
]
D
25 ꢁ24.9 (c 1.05, CHCl3);
mp 110.2e111.5 ꢀC. HPLC analysis Chiralpak AY-H (hexane/i-
PrOH¼90/10, 0.8 mL/min,
l
¼254 nm, tminor¼14.8 min,
tmajor¼12.2 min); 1H NMR (400 MHz, DMSO-d6):
d
7.71 (d, J¼8.0 Hz,
4.2.17. (S)-Furan-2-yl(4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)
25
1H), 7.41e7.31 (m, 6H), 7.19e7.16 (m,1H), 7.07e7.03 (m,1H), 5.42 (d,
methanone (1i). Yellow oil, yield 40%; 99% ee, [
a
]
D
ꢁ59.2 (c 0.60,

X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
4743
CHCl3); HPLC analysis Chiralpak AY-H (hexane/i-PrOH¼90/10,
1.97e1.90 (m, 1H), 1.73e1.62 (m, 1H), 1.50e1.54 (m, 1H); 13C NMR
(100 MHz, DMSO-d6): 168.4, 142.9, 140.5, 136.7, 129.8, 128.4, 128.1,
0.8 mL/min,
l
¼254 nm, tminor¼25.4 min, tmajor¼20.3 min); 1H NMR
d
(400 MHz, DMSO-d6):
d
7.71e7.44 (m, 2H), 7.13e7.06 (m, 2H), 6.96
127.9, 127.3, 127.2, 125.4, 70.1, 46.6, 36.0, 26.3; HRMS (ESI-TOF):
(d, J¼7.6 Hz, 1H), 6.82 (d, J¼3.6 Hz, 1H), 6.56e6.55 (m, 1H), 5.51 (d,
J¼5.6 Hz, 1H), 4.65e4.60 (m, 1H), 4.02e3.94 (m, 1H), 3.70e3.64 (m,
1H), 2.14e2.10 (m, 1H), 1.81e1.77 (m, 1H); 13C NMR (100 MHz,
calcd for C17H17NNaO2 [MþNa]þ, 290.1151; found: 290.1151.
4.3.2. (R)-1-Benzoyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 2-
25
DMSO-d6):
d
159.6, 147.9, 145.4, 137.4, 134.5, 127.8, 127.1, 124.7,
chloroacetate (5a). Colorless oil, yield 42%; 97% ee, [
a
]
78.6 (c
D
123.5, 116.8, 112.0, 64.3, 42.1, 33.3; HRMS (ESI-TOF): calcd for
C
1.00, CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/10,
14H13NNaO3 [MþNa]þ, 266.0788; found: 266.0794.
0.8 mL/min,
l
¼201 nm, tminor¼43.1 min, tmajor¼30.1 min); 1H NMR
(400 MHz, CDCl3):
d 7.31e7.12 (m, 7H), 7.02e6.94 (m, 1H),
4.2.18. (R)-1-(Furan-2-carbonyl)-1,2,3,4-tetrahydroquinolin-4-yl 2-
6.65e6.62 (m, 1H), 6.25e6.11 (m, 1H), 5.12e4.84 (m, 1H), 4.25 (s,
1H), 4.05e3.91 (m, 1H), 2.85 (t, J¼12.0 Hz, 1H), 2.27e2.12 (m, 2H),
25
chloroacetate (3m). White solid, yield 46%; >99% ee, [
a]
81.6 (c
D
1.07, CHCl3); mp 110.6e112.1 ꢀC. HPLC analysis Chiralpak AY-H
1.82e1.79 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 169.6, 166.3, 135.4,
(hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼254 nm, tminor¼45.0 min,
131.3, 129.8, 129.4, 128.7, 128.2, 127.8, 127.6, 127.2, 123.6, 74.7, 46.4,
41.0, 31.7, 25.4; HRMS (ESI-TOF): calcd for C19H18ClNNaO3 [MþNa]þ,
366.0867; found: 366.0866.
tmajor¼41.0 min); 1H NMR (400 MHz, CDCl3):
d 7.39e7.37 (m, 2H),
7.21e7.13 (m, 2H), 7.08e7.06 (m, 1H), 6.86 (d, J¼3.6 Hz, 1H),
6.45e6.43 (m, 1H), 6.09 (t, J¼4.2 Hz, 1H), 4.23e4.18 (m, 1H), 4.06 (s,
2H), 3.92e3.85 (m, 1H), 2.30e2.26 (m, 2H); 13C NMR (100 MHz,
4.3.3. (S)-Furan-2-yl(5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]aze-
25
CDCl3):
d
166.8, 159.9, 147.5, 144.5, 138.8, 129.3, 128.9, 126.8, 125.1,
pin-1-yl)methan-one(4b). Brown solid, yield 39%; 96% ee, [a]
D
123.9, 117.4, 111.6, 69.6, 41.0, 40.6, 30.0; HRMS (ESI-TOF): calcd for
ꢁ24.9 (c 0.84, CHCl3); mp 227.4e228.9 ꢀC. HPLC analysis Chiralpak
C
16H14ClNNaO4 [MþNa]þ, 342.0504; found: 342.0503.
OJ-H
(hexane/i-PrOH¼90/10,
0.8
mL/min,
l¼201
nm,
tminor¼27.2 min, tmajor¼23.0 min); 1H NMR (400 MHz, DMSO-d6):
4.2.19. (S)-1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-ol
d 7.67e7.63 (m, 2H), 7.40e7.37 (m, 1H), 7.19e7.17 (m, 1H), 7.00e6.98
(1j). White solid, yield 34%; >99% ee, [
a
]
25 37.3 (c 1.04, CHCl3); mp
(m, 1H), 6.34 (s, 1H), 5.63 (s, 1H), 5.51 (d, J¼4.0 Hz, 1H), 4.70e4.67
(m, 1H), 4.61e4.58 (m, 1H), 2.64e2.58 (m, 1H), 2.04e2.01 (m, 1H),
1.89e1.85 (m, 1H), 1.71e1.68 (m, 1H), 1.50e1.45 (m, 1H); 13C NMR
D
118.1e119.7 ꢀC. HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/
10, 0.5 mL/min,
NMR (400 MHz, DMSO-d6):
l
¼254 nm, tminor¼22.6 min, tmajor¼20.2 min); 1H
d
7.66e7.60 (m, 4H), 7.55e7.51 (m, 2H),
(100 MHz, DMSO-d6): d 157.3, 147.0, 145.4, 143.9, 140.0, 128.4, 127.9,
7.34e7.32 (m, 1H), 7.24e7.20 (m, 1H), 7.12e7.08 (m, 1H), 5.37 (d,
J¼5.2 Hz, 1H), 4.22e4.19 (m, 1H), 4.00e3.93 (m, 1H), 3.75e3.68 (m,
1H), 1.72e1.67 (m, 1H), 1.62e1.58 (m, 1H); 13C NMR (100 MHz,
127.6, 125.6, 115.9, 111.6, 69.8, 46.6, 36.1, 26.3; HRMS (ESI-TOF):
calcd for C15H15NNaO3 [MþNa]þ, 280.0944; found: 280.0945.
DMSO-d6):
d
139.2, 135.7, 133.9, 133.4, 129.9, 129.5, 128.0, 127.2,
4.3.4. (R)-1-(Furan-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b]aze-
25
124.7, 122.5, 63.6, 43.2, 30.9; HRMS (ESI-TOF): calcd for
pin-5-yl 2-chloroacetate (5b). White solid, yield 43%; 98% ee, [a]
D
C
15H15NNaO3S [MþNa]þ, 312.0665; found: 312.0672.
37.0 (c 0.84, CHCl3); mp 196.4e197.9 ꢀC. HPLC analysis Chiralpak
OD-H (hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼201 nm,
4.2.20. (R)-1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-4-yl 2-
chloroacetate (3n). Yellow oil, yield 40%; >99% ee, [
tminor¼40.9 min, tmajor¼27.3 min); 1H NMR (400 MHz, CDCl3):
25
a
]
51.9 (c
d
7.52e7.41 (m, 1H), 7.37e7.26 (m, 2H), 7.08 (d, J¼8.0 Hz, 1H), 6.20
D
1.12, CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/10,
(s, 1H), 5.92 (d, J¼8.0 Hz, 1H), 5.72 (d, J¼4.0 Hz, 1H), 4.98e4.95 (m,
1H), 4.23e3.28 (m, 2H), 2.86e2.83 (m, 1H), 2.44e2.31 (m, 2H),
0.5 mL/min,
l
¼254 nm, tminor¼35.5 min, tmajor¼33.5 min); 1H NMR
(400 MHz, CDCl3):
d
7.91 (d, J¼8.4 Hz, 1H), 7.64e7.54 (m, 3H),
1.84e1.71 (m, 3H); 13C NMR (100 MHz, CDCl3):
d 166.5, 157.8, 147.1,
7.45e7.32 (m, 3H), 7.26e7.12 (m, 2H), 5.76 (t, J¼3.6 Hz, 1H),
4.26e4.20 (m, 1H), 3.88 (d, J¼4.0 Hz 2H), 3.69e3.61 (m, 1H),
1.92e1.82 (m, 1H), 1.81e1.73 (m, 1H); 13C NMR (100 MHz, CDCl3):
144.4, 142.4, 135.8, 131.5, 129.8, 129.0, 128.2, 116.3, 111.1, 74.7, 47.8,
40.6, 30.1, 23.1; HRMS (ESI-TOF): calcd for C17H16ClNNaO4
[MþNa]þ, 356.0660; found: 356.0670.
d
166.6, 139.1, 136.9, 133.2, 130.4, 129.8, 129.2, 127.0, 125.6, 125.0,
123.6, 68.8, 42.2, 40.6, 27.1; HRMS (ESI-TOF): calcd for
C
4.3.5. (S)-Benzyl 5-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine-
25
17H16ClNNaO4S [MþNa]þ, 388.0381; found: 388.0375.
1-carboxylate (4c). Colorless oil, yield 44%; 90% ee, [
a
]
ꢁ18.0 (c
D
1.00, CHCl3); HPLC analysis Chiralpak OJ-H (hexane/i-PrOH¼90/10,
4.3. Representative procedure for the synthesis of (S)-2,3,4,5-
tetrahydro-1H-benzo[b]azepin-5-ol (4) and (R)-2,3,4,5-
tetrahydro-1H-benzo[b]azepin-5-yl 2-chloroacetate (5)
0.8 mL/min,
(400 MHz, DMSO-d6):
l
¼201 nm, tminor¼37.5 min, tmajor¼41.9 min); 1H NMR
d 7.61e7.59 (m, 1H), 7.42e7.40 (m, 1H),
7.30e7.15 (m, 7H), 5.48 (s, 1H), 5.18e5.11 (m, 1H), 5.02e4.99 (m,
1H), 4.63 (d, J¼12.0 Hz, 1H), 4.21 (d, J¼12.0 Hz, 1H), 2.64e2.61 (m,
1H), 2.04e2.01 (m, 1H), 1.90e1.86 (m, 1H), 1.67e1.63 (m, 1H),
To a solution of (rac)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-ol
(4) (0.50 mmol, 1 equiv) in 5 mL MeOtBu, vinyl 2-chloroacetate
(2.50 mmol, 5 equiv) and Novozyme 435 (0.05 g) were consecu-
tively added. The reaction mixture was shaken in orbital shaker at
300 rpm at 30 ꢀC for 8 h. After that, the mixture was filtered and
concentrated, and the residue was purified by column chromatog-
raphy (EtOAc/petroleum¼1:5) to give (S)-4 and (R)-5, respectively.
1.46e1.41 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d 154.1, 143.2,
138.9, 137.3, 128.9, 128.7, 128.3, 128.1, 127.4, 127.1, 125.3, 70.0, 66.6,
48.0, 36.1, 26.4; HRMS (ESI-TOF): calcd for C18H19NNaO3 [MþNa]þ,
320.1257; found: 320.1261.
4.3.6. (R)-Benzyl 5-(2-chloroacetoxy)-2,3,4,5-tetrahydro-1H-benzo
25
[b]azepine-1-carboxylate (5c). White solid, yield 41%; 93% ee, [a]
D
4.3.1. (S)-(5-Hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)
40.3 (c 1.00, CHCl3); mp 104.6e105.8 ꢀC. HPLC analysis Chiralpak
25
(phenyl)methanone (4a). White solid, yield 40%; 98% ee, [
a
]
OD-H (hexane/i-PrOH¼90/10, 0.8 mL/min,
l
¼201 nm,
D
ꢁ139.1 (c 1.08, CHCl3); mp 143.3e144.6 ꢀC. HPLC analysis Chiralpak
tminor¼28.8 min, tmajor¼18.2 min); 1H NMR (400 MHz, CDCl3):
OJ-H
(hexane/i-PrOH¼90/10,
0.8
mL/min,
l¼201
nm,
d 7.47e7.34 (m, 3H), 7.29e7.19 (m, 6H), 6.00e5.92 (m, 1H),
tminor¼24.0 min, tmajor¼18.8 min); 1H NMR (400 MHz, DMSO-d6):
5.31e5.02 (m, 2H), 4.48e4.09 (m, 1H), 3.73e3.50 (m, 2H),
d
7.59e7.40 (m, 1H), 7.28e7.05 (m, 6H), 6.93e6.90 (m, 1H),
2.88e2.74 (m, 1H), 2.36e2.13 (m, 2H), 1.74e1.65 (m, 2H); 13C NMR
6.64e6.54 (m, 1H), 5.56 (d, J¼4.0 Hz, 1H), 4.93 (d, J¼12.0 Hz, 1H),
(100 MHz, CDCl3):
128.5, 128.4, 128.0, 127.7, 127.3, 67.3, 66.9, 48.9, 40.6, 30.0, 23.0;
d 166.3, 154.5, 141.6, 136.6, 135.3, 130.7, 129.4,
4.66 (d, J¼16.0 Hz, 1H), 2.67e2.61 (m, 1H), 2.13e2.10 (m, 1H),

4744
X. Zhou et al. / Tetrahedron 71 (2015) 4738e4744
HRMS (ESI-TOF): calcd for C20H20ClNNaO4 [MþNa]þ, 396.0973;
QKHRZ-2013-47 and QKHRCTD-2014-4002), National Natural Sci-
ence Foundation of China (NSFC 21162047 and 21262051) and New
Century Excellent Talent of the Ministry of Education (NCET-13-
1069). Special thanks are expressed to Zeli Yuan and Dabing
Shi (Zunyi Medical University) for their help of single crystal
analysis.
found: 396.0971.
4.4. Large scale experiment for enzyme kinetic resolution of
racemic 1g
To a solution of racemic alcohol 1g (52.33 mmol, 10.00 g,
1.0 equiv) in 523.0 mL MeOtBu, vinyl 2-chloroacetate (78.50 mmol,
1.5 equiv) and Novozyme 435 (5.23 g) were consecutively added.
The reaction mixture was shaken at 300 rpm at 30 ꢀC for 2 h. After
that, the mixture was filtered and concentrated, and the residue
was purified by column chromatography (EtOAc/petroleum¼1:1)
to give (S)-1g (4.42 g, 44% yield, 99% ee) and (R)-3k (5.64 g, 40%
yield, 96% ee), respectively.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.05.066.
References and notes
1. (a) Ebner, D. C.; Bagdanoff, J. T.; Ferreira, E. M.; McFadden, R. M.; Caspi, D. D.;
Trend, R. M.; Stoltz, B. M. Chem.dEur. J. 2009, 15, 12978e12992; (b) Khan, I. A.;
Saxena, A. K. J. Org. Chem. 2013, 78, 11656e11669; (c) Caswell, J. M.; O’Neill, M.;
Taylor, S. J.; Moody, T. S. Curr. Opin. Chem. Biol. 2013, 17, 271e275.
2. (a) Matsubara, J.; Kitano, K.; Otsubo, K.; Kawano, Y.; Ohtani, T.; Bando, M.; Kido,
M.; Uchida, M.; Tabusa, F. Tetrahedron 2000, 56, 4667e4682; (b) Uchida, R.;
Imasato, R.; Shiomi, K.; Tomoda, H.; Ohmura, S. Org. Lett. 2005, 7, 5701e5704;
(c) Scherlach, K.; Hertweck, C. Org. Biomol. Chem. 2006, 4, 3517e3520; (d) Neff,
S. A.; Lee, S. U.; Asami, Y.; Ahn, J. S.; Oh, H.; Baltrusaitis, J.; Gloer, J. B.; Wicklow,
D. T. J. Nat. Prod. 2012, 75, 464e472.
4.5. Procedure for the synthesis of (R)-1-(4-azido-3,4-
dihydroquinolin-1(2H)-yl)ethanone (6)
To a solution of (S)-1g (4.00 mmol, 764.4 mg, 1.0 equiv) in
40.0 mL Et2O were consecutively added diphenyl phosphorazidate
(6.00 mmol, 1.3 mL, 1.5 equiv) and DBU (0.9 mL, 1.5 equiv) at 0 ꢀC
under N2 atmosphere. After 30 min, the reaction mixture was
warmed to room temperature and continued to stir for 24 h. After
quenching with water, the organic phase was separated, and the
aqueous phase was extracted with EtOAc (5ꢂ10.0 mL). Then the
combined organic layers were dried over anhydrous Na2SO4, con-
centrated, and the residue was purified by flash column chroma-
tography (EtOAc/petroleum¼1:1) to give the compound 6.
3. Masaki, O.; Akira, S.; Yoshikazu, M.; Muneki, K. European Patent, EP1944291A1,
2008.
4. (a) Noriyuki, U.; Kunihiko, T.; Masahiko, W.; Kunihiko, M.; Noriyoshi, A.; No-
buhito, K.; Takeshi, O. Heterocycles 2010, 80, 141e147; (b) Tokuyama, T.; Senoh,
S.; Sakan, T.; Brown, K. S.; Witkop, B. J. Am. Chem. Soc. 1967, 89, 1017e1021; (c)
Mosberg, H. I.; Yeomans, L.; Harland, A. A.; Bender, A. M.; Sobczyk-Kojiro, K.;
Anand, J. P.; Clark, M. J.; Jutkiewicz, E. M.; Traynor, J. R. J. Med. Chem. 2013, 56,
2139e2149.
ꢀ
ꢀ
ꢀ
5. (a) Sole, D.; Vallverdu, L.; Peidro, E.; Bonjoch, J. Chem. Commun. 2001,
4.5.1. (R)-1-(4-Azido-3,4-dihydroquinolin-1(2H)-yl)ethanone
ꢀ
ꢀ
1888e1889; (b) Sole, D.; Vallverdu, L.; Solans, X.; Font-Bardía, M.; Bonjoch, J. J.
Am. Chem. Soc. 2003, 125, 1587e1594; (c) Kobayashi, Y.; Igarashi, J.; Feng, C.;
Tojo, T. Tetrahedron Lett. 2012, 53, 3742e3745; (d) Sole, D.; Mariani, F.;
(6). Colorless oil, 709.2 mg, yield 82%; 96% ee, [a]
25 152.3 (c 1.00,
D
ꢀ
CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼90/10,
ꢀ
Fernandez, I.; Sierra, M. A. J. Org. Chem. 2012, 77, 10272e10284.
1.0 mL/min,
(400 MHz, CDCl3):
l
¼254 nm, tminor¼15.6 min, tmajor¼12.7 min); 1H NMR
6. (a) Kumar, N. N. B.; Mukhina, O. A.; Kutateladze, A. G. J. Am. Chem. Soc. 2013, 135,
9608e9611; (b) Cronk, W. C.; Mukhina, O. A.; Kutateladze, A. G. J. Org. Chem.
2014, 79, 1235e1246.
7. Wang, J.-F.; Liao, Y.-X.; Kuo, P.-Y.; Gau, Y.-H.; Yang, D.-Y. Synlett 2006,
2791e2794.
d 7.35e7.30 (m, 3H), 7.22e7.18 (m, 1H), 4.58 (t,
J¼4.0 Hz, 1H) 3.97e3.92 (m, 1H), 3.80e3.75 (m, 1H), 2.25 (s, 3H),
2.21e2.08 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
170.1, 138.3, 128.6,
128.3, 128.1, 125.3, 124.7, 57.3, 40.4, 29.9, 23.4; HRMS (ESI-TOF):
8. (a) Caner, H.; Groner, E.; Levy, L.; Agranat, I. Drug Discov. Today 2004, 9,
105e110; (b) Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.;
Sturmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788e824; (c) Schmid,
calcd for C20H20ClNNaO4 [MþNa]þ, 239.0903; found: 239.0908.
€
A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B. Nature 2001,
409, 258e268.
9. (a) Traff, A.; Bogar, K.; Warner, M.; Backvall, J.-E. Org. Lett. 2008, 10, 4807e4810;
(b) Ou, L.; Xu, Y.; Ludwig, D.; Pan, J.; Xu, J. Org. Process Res. Dev. 2008, 12,
192e195; (c) Andrade, L. H.; Barcellos, T. Org. Lett. 2009, 11, 3052e3055; (d)
4.6. Procedure for the synthesis of (R)-1-(4-amino-3,4-
dihydroquinolin-1(2H)-yl)ethanone (7)
€
ꢀ
€
The compound 6 (709.2 mg, 3.28 mmol) was dissolved in MeOH
(50.0 mL), and Pd/C (10%) (145.0 mg) was added into the solution at
room temperature. Then the reaction mixture was stirred under H2
atmosphere (1.0 atm) for 12 h. After completion of the reaction, as
indicated by TLC, Pd/C was removed by filtration, the filtrate was
concentrated under reduced pressure, and the residue was purified
by flash column chromatography on silica gel (MeOH/dichloro-
methane/Et3N¼1:10:0.2) to give the product 7.
ꢀ
€
Krumlinde, P.; Bogar, K.; Backvall, J.-E. J. Org. Chem. 2009, 74, 7407e7410; (e)
ꢀ
Mendiola, J.; García-Cerrada, S.; de Frutos, O.; de la Puente, M. L. Org. Process
Res. Dev. 2012, 16, 1312e1316.
10. Crabb, T. A.; Soilleux, S. L. J. Chem. Soc., Perkin Trans. 1 1985, 1381e1385.
11. Zheng, D.; Yang, M.; Zhuo, J.; Li, K.; Zhang, H.; Yang, J.; Cui, B.; Chen, Y. J. Mol.
Catal. B: Enzym. 2014, 110, 87e91.
12. (a) Chen, Y.; Tang, W.; Mou, J.; Li, Z. Angew. Chem., Int. Ed. 2010, 49,
5278e5283; (b) Chen, Y.; Lie, F.; Li, Z. Adv. Synth. Catal. 2009, 351, 2107e2112;
(c) Chen, Y.; Lin, H.; Xu, X.; Xia, S.; Wang, L. Adv. Synth. Catal. 2008, 350,
426e430; (d) Chen, Y.; Zhuo, J.; Zheng, D.; Tian, S.; Li, Z. J. Mol. Catal. B: Enzym.
2014, 106, 100e104.
13. For details about the preparation of (rac)-tetrahydroquinolin-4-ol (1) see: Chen,
Y.; Zheng, D.; Liu, X.; Xu, K.; Chin, J. Synth. Chem. 2014, 22, 687e690.
14. The selectivity ratio (E) is an inherent property of the enzyme that, unlike the
enantiomeric excesses of product (eep) and substrate (ees), is independent of
the degree of conversion of the reaction (c). For details, see:Enzyme Catalysis in
4.6.1. (R)-1-(4-Amino-3,4-dihydroquinolin-1(2H)-yl)ethanone
25
(7). Colorless oil, 442.9 mg, yield 71%; 96% ee, [
a]
53.0 (c 0.80,
D
CHCl3); HPLC analysis Chiralpak OD-H (hexane/i-PrOH¼98/2,
1.0 mL/min,
NMR (400 MHz, CDCl3):
l
¼254 nm, tminor¼206.1 min, tmajor¼180.2 min); 1H
€
Organic Synthesis, 3rd Completely Revised and Enlarged; Drauz, K., Groger, H.,
May, O., Eds.; Wiley-VCH: Weinheim, Germany, 2012; pp 43e48.
d
7.33 (d, J¼4.0 Hz, 1H), 7.16e7.09 (m, 3H),
15. For reviews, see: (a) Ahn, Y.; Ko, S.-B.; Kim, M.-J.; Park, J. Coord. Chem. Rev. 2008,
3.86e3.83 (m, 2H), 3.56e3.53 (m, 1H), 2.31 (s, 2H), 2.15e2.12 (m,
ꢀ
252, 647e658; (b) Gotor-Fernandez, V.; Busto, E.; Gotor, V. Adv. Synth. Catal.
1H), 2.12 (s, 3H), 1.61e1.59 (m, 1H); 13C NMR (100 MHz, CDCl3):
2006, 348, 797e812.
d
169.9, 137.6, 136.6, 126.9, 125.7, 125.2, 124.3, 47.6, 41.0, 33.9, 23.2;
16. (a) Marr, A. C.; Pollock, C. L.; Saunders, G. C. Organometallics 2007, 26,
HRMS (ESI-TOF): calcd for
found: 213.1004.
C
11H14N2NaO [MþNa]þ, 213.0998;
ꢀ
€
3283e3285; (b) Martin-Matute, B.; Edin, M.; Bogar, K.; Kaynak, F. B.; Backvall,
ꢀ
J.-E. J. Am. Chem. Soc. 2005, 127, 8817e8825; (c) Bogar, K.; Vidal, P. H.;
Alcantara Leon, A. R.; Backvall, J.-E. Org. Lett. 2007, 9, 3401e3404; (d) Millet,
R.; Traff, A. M.; Petrus, M. L.; Backvall, J.-E. J. Am. Chem. Soc. 2010, 132,
15182e15184; (e) Hapǎu, D.; Brem, J.; Zaharia, V. Tetrahedron: Asymmetry
2011, 22, 2165e2171.
ꢀ
ꢀ
€
€
€
Acknowledgements
17. See Supplementary data for the details of X-ray structures of product 3j.
18. The method for the synthesis of (rac)-tetrahydro-1H-benzo[b]azepin-5-ol (4)
was similar to that of (rac)-tetrahydroquinolin-4-ol (1).
We are grateful for financial support from Science and Tech-
nology Foundation of Guizhou Province (No. QKHSZ-2012-3078,