2404
L. Qin et al. / Tetrahedron Letters 57 (2016) 2403–2405
investigated. Unfortunately, both decrease and increase of the cell
O
O
concentration could not furnish preferable resolution results
(Table 1, entries 10 and 11). To our delight, increasing of the sub-
strate concentration of (rac)-1a from 2 mM to 4 mM, the ee of
(R)-1a could be significantly increased from 70% to 90%, and the
conversion of (rac)-1a to 2-methyl-quinoline 2a was also increased
from 41% to 47% (Table 1, entry 12).
N
CH3
N
CH3
(-)-Angustureine
(-)-Galipinine
F
N
After establishment of reaction conditions (Table 1, entry 12),
substrate scope of the whole cell of Pseudomonas monteilii ZMU-
T01 strains mediated oxidative resolution of (rac)-2-substituted
1,2,3,4-tetrahydroquinolines 1 was following tested. As indicated
in Table 2, both racemic substrates 1c and 1d containing the linear
alkyl substituent (n-Pr and n-Bu) at C2 position could give the
desired corresponding products (R)-1c and (R)-1d with high enan-
tioselectivities (up to >99% ee) and 50% conversion of (rac)-1c to
(R)-2c (Table 2, entries 3 and 4). Exceptionally, relatively low ee
of (R)-1b was obtained when using (rac)-1b with ethyl group at
the C2 position as the substrate (Table 2, entry 2). Besides, chang-
ing substituent at C2 position of (rac)-2-substituted 1,2,3,4-
tetrahydroquinolines into the branched alkyl group (i-Pr and
i-Bu) showed the excellent results as well (Table 2, entries 5 and
6). It is noteworthy that substrates 1g and 1h with unsaturated
substituent (allyl and cyclopropyl) at C2 position also could be
applied to the whole cell catalyzed resolution process, giving the
corresponding products (S)-1g and (S)-1h with >99% ee and >99%
ee, respectively (Table 2, entries 7 and 8). Unfortunately, (R)-1i
and 1j compounds were not obtained by using the racemic sub-
strates 1i and 1j bearing a methyl or methoxy substitution on
the phenyl ring of tetrahydroquinoline (Table 2, entries 9 and 10).
The practical application of the whole cell of Pseudomonas
monteilii ZMU-T01 strain mediated oxidative resolution of (rac)-
2-substituted 1,2,3,4-tetrahydroquinolines 1 could be illustrated
by the transformation of resolution product (R)-1c into the anti-
malarial reagent 31,2a according to the literature reported method
(Scheme 1).12
OMe
OMe
N
CH3
O
CO2H
(-)-Cuspareine
(S)-Flumequine
Figure 1. Selective examples of pharmacologically relevant therapeutic agents
derived from chiral 2-substituted 1,2,3,4-tetrahydroquinolines.
lower enantioselectivities of (R)-1a (Table 1, entries 2–4). The
ZMU-T18 and ZMU-T19 strains, by contrast, showed unsatisfactory
resolution activities (Table 1, entries 5 and 6). The pH effect on the
oxidative resolution of (rac)-1a was next evaluated. When the
reaction was conducted under the weak acidic conditions
(pH = 6), similar resolution results were obtained with that con-
ducted at pH of 7 (Table 1, entry 1 vs. entry 7). Adjustment of
the pH from 7 to 8 or 9 indicated that weak basic reaction condi-
tions were beneficial for the oxidative resolution of (rac)-1a, and
pH of 8 provided relatively high enantioselectivity of (rac)-1a (up
to 69% ee) (Table 1, entry 8 vs. entries 1 and 9). In order to further
improve the enantioselectivity of the oxidative resolution, cell con-
centration of Pseudomonas monteilii ZMU-T01 strains was also
Table 1
Screening of reaction conditionsa
reaction conditions
+
N
H
N
N
H
(rac)-1a
(R)-1a
2a
Entry Strains
pH Cell concentration (R)-1a/
2a/cd
(%)
(cdw g/L)
eeb,c (%)
Table 2
Substrate scope for the bio-mediated oxidative resolution of racemic 2-methyl-
1
Pseudomonas
monteilii ZMU-T01
Pseudomonas
monteilii ZMU-T02
Pseudomonas
monteilii ZMU-T04
Pseudomonas
monteilii ZMU-T15
Pseudomonas
monteilii ZMU-T18
Pseudomonas
monteilii ZMU-T19
Pseudomonas
monteilii ZMU-T01
Pseudomonas
monteilii ZMU-T01
Pseudomonas
monteilii ZMU-T01
Pseudomonas
monteilii ZMU-T01
Pseudomonas
monteilii ZMU-T01
Pseudomonas
7
7
7
7
7
7
6
8
9
8
8
8
30
60
38
14
24
37
17
0
1,2,3,4-tetrahydroquinolines 1a
2
30
30
30
30
30
30
30
30
10
50
50
16
32
58
20
0
R1
whole cell from Pseudomonas
monteilii ZMU-T01 strains
R1
R1
+
3
R2
N
H
R2
Na2HPO4-KH2PO4 buffer
(50 mM, pH = 8)
30 οC, 24 h
N
R2
N
H
(rac)-1
(R/S)-1
4
2
5
Entry
(rac)-1
(R/S)-1/eeb,c (%)
2/cd (%)
6
1
2
3
4
5
6
7
8
9
10
R1 = H, R2 = Me (1a)
R1 = H, R2 = Et (1b)
(R)-1a/90e
(R)-1b/89f
(R)-1c/>99
(R)-1d/95g
(S)-1e/>99h
(S)-1f/>99
(S)-1g/>99g
(S)-1h/>99g
(R)-1i/0
2a/47
2b/47
2c/50
2d/49
2e/50
2f/50
2g/50
2h/50
2i/trace
2j/trace
7
59
69
64
22
70
90e
37
41
39
18
41
47
R1 = H, R2 = n-Pr (1c)
R1 = H, R2 = n-Bu (1d)
R1 = H, R2 = i-Pr (1e)
R1 = H, R2 = i-Bu (1f)
R1 = H, R2 = allyl (1g)
R1 = H, R2 = cyclopropyl (1h)
R1 = Me, R2 = Me (1i)
R1 = OMe, R2 = Me (1j)
8
9
10
11
12
(R)-1j/0
a
Unless otherwise noted, mixtures of (rac)-1 (2 mM), cell suspension (50 cdw g/
L), Na2HPO4–KH2PO4 buffer (50 mM, pH = 8.0) in 5.0 mL reaction system were
shaken at 250 rpm at 30 °C for 24 h.
monteilii ZMU-T01
b
Determined by chiral HPLC analysis.
The absolute configuration of the chiral products were assigned by comparison
a
c
Unless otherwise noted, mixtures of (rac)-1a (2 mM), cell suspension, Na2-
HPO4–KH2PO4 buffer (50 mM) in 5.0 mL reaction system were shaken at 250 rpm
and 30 °C for 24 h.
of the specific optical rotation with literature report.4b
d
Conversion of (rac)-1 to 2: c = [(R/S)-1/ee]/[1 + (R/S)-1/ee]. The conversion was
b
Determined by chiral HPLC analysis.
determined with the premise that ee value was high and no other side reaction was
detected.
c
The absolute configuration of the chiral product was assigned by comparison of
e
the specific optical rotation with literature report.4b
4 mM (rac)-1a was used.
4 mM (rac)-1b was used.
pH = 9.0.
pH = 7.0.
d
f
Conversion of (rac)-1a to 2a: c = [(R)-1a/ee]/[1 + (R)-1a/ee]. The conversion was
determined with the premise that no other side reaction was detected.
g
e
h
4 mM of (rac)-1a was used.