Stereoselective synthesis of optically active cyclic α- And β-amino esters through lipase-catalyzed transesterification or interesterification processes

Article abstract of DOI:10.1016/j.tetasy.2010.08.002

A series of cyclic α- and β-amino esters belonging to a family of indolines and quinolines have been efficiently synthesized to study their behavior in lipase-mediated kinetic resolution reactions. The influence of the fused ring structure to the benzene ring and the position of the ester functionality relative to the amino group have been demonstrated, finding excellent values of enantiodiscrimination in the transesterification reaction of methyl indoline-3-carboxylate with n-butanol catalyzed by Candida antarctica lipase B being observed. On the other hand, low to moderate selectivities have been found when using a wide panel of lipases toward methyl indoline-2- carboxylate or 1,2,3,4-tetrahydroquinoline derivatives in alkoxycarbonylation, transesterification or interesterification reactions.

Full text of DOI:10.1016/j.tetasy.2010.08.002

Tetrahedron: Asymmetry 21 (2010) 2307–2313
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of optically active cyclic
a- and b-amino esters
through lipase-catalyzed transesterification or interesterification processes
⇑
⇑
Sergio Alatorre-Santamaría, Vicente Gotor-Fernández , Vicente Gotor
Departamento de Química Orgánica e Inorgánica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33071 Oviedo, Asturias, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Accepted 4 August 2010
Available online 15 September 2010
A series of cyclic a- and b-amino esters belonging to a family of indolines and quinolines have been effi-
ciently synthesized to study their behavior in lipase-mediated kinetic resolution reactions. The influence
of the fused ring structure to the benzene ring and the position of the ester functionality relative to the
amino group have been demonstrated, finding excellent values of enantiodiscrimination in the transeste-
rification reaction of methyl indoline-3-carboxylate with n-butanol catalyzed by Candida antarctica lipase
B being observed. On the other hand, low to moderate selectivities have been found when using a wide
panel of lipases toward methyl indoline-2-carboxylate or 1,2,3,4-tetrahydroquinoline derivatives in alk-
oxycarbonylation, transesterification or interesterification reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
evant systems and are useful building blocks for the preparation of
many valuable products. On the other hand, amino esters are very
Amino acid derivatives are central to chemistry because of their
presence in biologically active compounds and pharmaceuticals,1
in addition to their possibilities as organic chiral building blocks
for the generation of ligands or catalysts with applications in asym-
metric synthesis.2 For these reasons, the development of practical
synthetic routes to render this type of compounds in a stereoselec-
tive fashion has received very much attention in recent years.3 In
particular, the preparation of enantiopure cyclic amino esters has
been the focus of a number of investigations,4 mainly on those
compounds with structures similar to proline and pipecolic acid,
and amino acids that play a crucial role both in the structural
and in the biological properties of peptides.5
attractive compounds due to their intrinsic bifunctionality. Thus,
concerning lipase catalysis, while the nucleophilic amino group is
susceptible to acylation or alkoxycarbonylation, the electrophilic
ester functionality allows the preparation of amides, carboxylic
acids, and related compounds by means of a typical addition–elim-
ination mechanism.10
Herein we report the chemical synthesis of methyl indoline and
1,2,3,4-tetrahydroquinoline carboxylates bearing the ester group at
the 2- or 3-position, and studied their behavior in different lipase-
mediated reactions directed toward the production of optically ac-
tive compounds. Thus, alkoxycarbonylation, transesterifcation, and
interesterification processes have been undertaken.
Nowadays, enzyme-mediated processes are considered elegant
and useful methodologies for enantioselective transformations.6
From the wide set of enzymatic classes, lipases have gained much
attention over the last two decades due to their ease of manipula-
tion, low cost, and wide substrate tolerance.7 Traditionally, most of
the lipase-catalyzed enantioselective reactions have efficiently
mediated the acylation of alcohols or hydrolysis of esters, whereas
the preparation of chiral amides or carbamates has been much less
investigated, in spite of the fact that mild reaction conditions are
required for the formation of these nitrogenated compounds.8
There are few examples of enzymatic kinetic or dynamic kinetic
resolutions of cyclic secondary amines described in the literature,9
even though they are present in a large number of biologically rel-
2. Results and discussion
Recently we have described the enzymatic kinetic resolution of
methyl indoline-2-carboxylate using an alkoxycarbonylation reac-
tion, where Candida antarctica lipase A (CAL-A) showed excellent
levels of activity and stereodiscrmination.9o This research contin-
ued a previous study from our research group on the enzymatic
resolution of a family of 2- and 3-alkyl and 2-phenyl indoline
derivatives.9l In this case, CAL-A gave the best activity toward the
2-substituted derivatives, while Candida antarctica lipase B (CAL-
B) was found to be the best catalyst for the kinetic resolution of
the 3-methyl indoline. These results encouraged us to test the
enzymatic resolution of racemic methyl indoline-3-carboxylate 3.
Initially, the synthesis of ( )-3 was performed from indole-3-
carboxylic acid 1 in a two-step sequence (Scheme 1). Chemical
reduction of the internal C–C double bond of the five-membered
⇑
Corresponding authors.
E-mail addresses: vicgotfer@uniovi.es (V. Gotor-Fernández), vgs@uniovi.es (V.
Gotor).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.08.002

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S. Alatorre-Santamaría et al. / Tetrahedron: Asymmetry 21 (2010) 2307–2313
CO2Me
CO2H
CO2H
CO2Me
SOCl2, MeOH
Allyl chloroformate
N
Na, BuOH
O
CH2Cl2, rt
6 h (91%)
65 ºC, 12 h
(74%)
120 ºC, 16 h
N
N
N
O
H
H
H
1
2
3
4
CO2Me
CO2Me
CO2Me
Diallyl carbonate
Lipase
O
N
O
+
+
O
Organic solvent
30 ºC, 250 rpm
N
H
N
H
O
N
H
3
3
4
5
Scheme 1. Chemical synthesis of racemic methyl indoline-3-carboxylate 3 and our attempts at enzymatic kinetic resolution by a lipase-mediated alkoxycarbonylation
procedure.
ring using sodium and n-butanol (BuOH) as solvent at 120 °C,11 fol-
lowed by esterification with MeOH of the obtained racemic amino
acid 2 in the presence of thionyl chloride (SOCl2) gave the desired
methyl ester in an overall 74% isolated yield. For the study of the
enzymatic alkoxycarbonylation reaction, the corresponding allyl
carbamate 4 was first prepared chemically, in order to develop
adequate chiral HPLC methods for the determination of the enan-
tiomeric excesses of both substrate and product of the enzymatic
reaction (see Section 4).
We tested the enzymatic resolution with both types of C. ant-
arctica lipases (Scheme 1). As expected, CAL-A has a limited selec-
tivity toward this substrate (56% conversion, 71% eeS, 56% eeP after
10 days), while CAL-B presented a high stereoselectivity toward
the formation of carbamate 4. Unfortunately, a lipase-mediated
transesterification process also occurred, giving considerable
amounts of the allylic ester 5 in the reaction media. The appear-
ance of both amino esters 3 and 5 led to serious problems in the
purification step, hence we decided at this point to study other
known enzymatic approaches, such as transesterification12 or
interesterification lipase-catalyzed processes.13 Thereby the
transesterification with n-butanol was tested with two lipases,
CAL-B and Pseudomonas cepacia lipase (PSL-C I, also known as Burk-
holderia cepacia lipase). Despite the poor selectivity of the latter en-
zyme, CAL-B displayed both a great activity and enantiopreference
toward the enantiomers of this particular substrate, giving sub-
strate 3 and product 6 at 50% conversion in enantiopure form after
a short timespan (Scheme 2).
reaction.14 These successful results in the study of the transesteri-
fication reaction of methyl ester 3 encouraged us to study the
behavior of lipases toward methyl indoline-2-carboxylate 8a using
the same experimental conditions, both to compare the reactivity
of compounds with the same substitutions in different positions
of the five-membered ring, but also using the alkoxycarbonylation
reaction.9o
In this manner racemic methyl ester 8a and butyl ester 8b were
prepared in excellent yields by simple chemical transesterification
of indoline-2-carboxylic acid using MeOH and BuOH, respectively
(Scheme 3). The lipase-mediated transesterification reaction of
racemic methyl ester 8a using n-butanol as a nucleophile and
PSL-C I and CAL-B as biocatalysts was then examined exhaustively
(Table 1, entries 1–4).
ROH, SOCl2
COOH
COOR
N
H
N
H
65 °C, 5 h
( )-8a R= Me (90%)
( )-8b R= Bu (97%)
( )-7
BuOH or PrCO2Bu
(R)-8b
+
(S)-8a
( )-8a
Lipase
Organic solvent
T, 250 rpm
Scheme 3. Chemical synthesis of amino esters 8a–b and lipase-mediated esteri-
fication and transesterification reactions of 8a.
CO2Bu
CO2H
Initially the use of BuOH as a donor and solvent was tested,
observing that while the PSL-C I showed a low selectivity (entry
1), CAL-B reacted with great selectivity for the substrate although
the reaction rate was quite high (entry 2). In order to find better
selectivities, we decided to test THF as solvent with just two equiv-
alents of BuOH (entries 3 and 4). Even though the data from PSL-C I
got better, the enantioselectivity was still low (entry 3). On the
other hand, CAL-B was almost equal in terms of enantioslectivity
(E = 7), reaching 50% conversion values with a moderate enantio-
meric excess for both the substrate and product after 7 h (entry
4). Finding that the transesterification process was not as synthet-
ically useful as it was with the 3-substituted derivative ( )-3, we
decided to explore another enzymatic approach such as the inter-
esterification reaction, employing butyl butanoate and screening
different lipases: Rhizomucor miehei (RM), C. antarctica type-A
(CAL-A), Candida rugosa (CRL) and from porcine pancreatic (PPL).
No reactivity toward the substrate was found except for the RM
(entries 5–8), which showed no great improvement from the oth-
ers. While PSL-C I double the previous E value (entries 3 and 9), it
1) Na, BuOH, 120 ºC, overnight
2) SOCl2, BuOH, 120º C, 6 h
(71%)
N
N
H
H
1
6
CO2Me
CO2Bu
CO2Me
CAL-B
+
BuOH, 4 h
N
N
N
H
30 ºC, 250 rpm
(50% conv.)
H
H
3
(S)-6
(>99% ee)
(R)-3
(>99% ee)
Scheme 2. Chemical synthesis of amino ester
resolution by an esterification reaction.
6
and CAL-B mediated kinetic
The absolute configuration of the remaining methyl aminoester
(R)-3 was confirmed by comparison of its specific rotation value,
½
a 2D0
ꢀ
¼ ꢁ94:7 (c 0.88, CH2Cl2), with the one obtained in the enzy-
matic kinetic resolution of ( )-3 by a CAL-B-mediated hydrolysis

S. Alatorre-Santamaría et al. / Tetrahedron: Asymmetry 21 (2010) 2307–2313
2309
Table 1
Lipase-catalyzed transesterification or interesterification of methyl 2-indoline-carboxylate 8a
b
b
Entry
Solvent
Enzyme
Resolving agenta
T (°C)
t (h)
eeS (%)
eeP (%)
cc (%)
Ed
1
2
3
4
5
6
7
8
9
BuOH
BuOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
PSL-C I
CAL-B
PSL-C I
CAL-B
RM
CAL-A
CRL
PPL
BuOH (110)
BuOH (110)
BuOH (2)
30
30
30
30
30
30
30
30
30
30
20
23
8
20
7
21
21
21
21
92
2
10
>99
9
61
11
0
0
0
78
76
77
8
57
88
10
50
34
0
0
0
50
49
48
1
6
10
7
2
—
—
—
20
18
30
13
81
60
21
—
—
—
50
78
86
BuOH (2)
PrCO2Bu (2)
PrCO2Bu (2)
PrCO2Bu (2)
PrCO2Bu (2)
PrCO2Bu (2)
PrCO2Bu (2)
PrCO2Bu (2)
PSL-C I
CAL-B
CAL-B
10
11
2
a
b
c
Number of equivalents in brackets.
Determined by HPLC.
c = eeS/(eeS+eep).
d
E = ln[(1 ꢁ c) ꢂ (1 ꢁ eeP)]/ln[(1 ꢁ c) ꢂ (1 + eeP)].15
Table 2
should be noted that the reaction time was higher and the selectiv-
ity value was still low (entry 9). Again CAL-B was the biocatalyst
that gave a higher stereodiscrimination with a faster reaction rate
(entry 10). Finally, we tested the process by decreasing the temper-
ature to 20 °C in order to determine a better stereodiscrimination
(entry 11), and although the enantioselectivity increased, this
was poor in comparison with previous results achieved using the
alkoxycarbonylation approach.9o
Next, we decided to study the enzymatic synthesis of related
cyclic aminoesteres with similar structures, such as methyl quino-
line carboxylates substituted at the 2-position (11) or at the 3-po-
sition (15). For the chemical synthesis of racemic methyl-1,2,3,
4-tetrahydroquinoline-2-carboxylate 11, 2-quinoline carboxylic
acid 9 was selected as the ideal starting material, which was chem-
ically esterified to obtain methyl 2-quinoline carboxylate. Selective
reduction of the pyridine ring using sodium cyanoborohydride
(NaBH3CN) in acidic media, allowed the isolation of 11 in good
overall yield (Scheme 4).16
Similar to the enzymatic alkoxycarbonylation reaction of indo-
line 3, a mixture of products were found in the CAL-B-mediated
process; we attempted to overcome this issue by focusing on the
study of the transesterification reaction of ( )-11 using the same
pool of enzymes that were used for the indoline ester 8a (Table 2).
As was seen before, CAL-A, CRL, and PPL showed no activity toward
the substrate (entries 1–3), while RM, CAL-B, and PSL-C I displayed
moderate to high activities (entries 4–6), with only PSL-C I showing
good selectivity for the transesterification of the (R)-enantiomer. In
this process, the butyl ester 12 was isolated in 91% ee and 40% con-
version after 30 h at 30 °C (entry 6).17
Finally we studied the chemical preparation and lipase-medi-
ated kinetic resolution of the racemic quinoline analogue bearing
an ester group at the 3-position. Methyl-1,2,3,4-tetrahydroquino-
line-3-carboxylate 15 was prepared in very high yield from 3-quin-
oline carboxylic acid 13 following an analogous sequence than
with the 2-substituted derivative, esterification with MeOH fol-
Enzymatic transesterification of methyl 1,2,3,4-tetrahydroquinoline-2-carboxylate 11
in THF at 30 °C
cb (%)
Ec
a
a
Entry
Enzyme
t (h)
eeS (%)
eeP (%)
1
2
3
4
5
6
CAL-A
CRL
PPL
RM
CAL-B
PSL-C I
30
72
30
30
30
30
0
0
0
40
70
63
—
—
—
16
31
91
0
0
0
72
70
40
—
—
—
2
4
39
a
b
c
Determined by HPLC.
c = eeS/(eeS+eep).
E = ln[(1 ꢁ c) ꢂ (1 ꢁ eeP)]/ln[(1 ꢁ c) ꢂ (1 + eeP)].15
lowed by reduction with NaBH3CN (Scheme 5). As occured with
the 2-methyl-1,2,3,4-tetrahydroquinoline analogue, when the
transesterification reactions were carried out in THF as solvent
and 2 equivalents of BuOH, no reaction was observed with some
enzymes (CAL-A or PSL-C I, Table 3, entries 1 and 2); R. Miehei
lipase showed slightly better stereodiscrimination than CAL-B
although with a very modest value (entries 3 and 4). In order to im-
prove the results we attempted the interesterification process with
Table 3
Enzymatic transesterification of 1,2,3,4-tetrahydroquinoline-3-carboxylate 15 using
BuOH in THF at 30 °C at 250 rpm after 34 h
cb (%)
Ec
a
a
Entry
Enzyme
eeS (%)
eeP (%)
1
2
3
4
CAL-A
PSL-C I
RM
0
0
56
63
—
—
69
11
0
0
45
70
—
—
9
CAL-B
2
a
b
c
Determined by HPLC.
c = eeS/(eeS + eep).
E = ln[(1 ꢁ c) ꢂ (1 ꢁ eeP)]/ln[(1 ꢁ c) ꢂ (1 + eeP)].15
MeOH, SOCl2
NaBH3CN, HCl
N
H
CO2Me
65
°
C, 12 h
THF-MeOH
rt, overnight
(87%)
N
CO2H
N
CO2Me
(80%)
9
10
( )-11
BuOH, SOCl2
BuOH, Lipase
( )-11
(R)-12
+ (S)-11
120 °C, overnight
(62%)
N
CO2Bu
THF, 30 °C
250 rpm
H
( )-12
Scheme 4. Chemical synthesis of racemic methyl and butyl 1,2,3,4-tetrahydroquinoline esters 11 and 12, and study of the enzymatic kinetic resolution of the methyl ester.

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S. Alatorre-Santamaría et al. / Tetrahedron: Asymmetry 21 (2010) 2307–2313
CO2Me
CO2H
CO2Me
CO2Bu
MeOH, SOCl2
NaBH3CN, HCl
BuOH, SOCl2
N
65 °C, 12 h
(83%)
THF-MeOH
rt, overnight
(90%)
120 °C, overnight
(70%)
N
N
N
H
( )-16
H
13
14
( )-15
CO2Me
CO2Bu
CO2Me
*
BuOH, Lipase
*
+
N
H
THF, 30 °C
34 h, 250 rpm
N
N
H
H
( )-15
16
15
Scheme 5. Chemical synthesis of quinoline derivative 15 and attempts of lipase-mediated kinetic resolutions by using a transesterification reaction.
butyl butanoate and RM lipase and slightly improved upon the ste-
reodiscrimination shown by the enzyme (46% conversion, 50% eeS,
67% eeP after 34 h). Finally, much better results were attained
when the transesterification reaction was carried out with the
same lipase, but in neat butanol as solvent and resolving agent,
reaching 54% conversion after 24 h and recovering the substrate
in 91% ee and the product in 76% ee.
4.2. Synthesis of indoline-3-carboxylic acid 211
To a heated suspension of indole-3-carboxylic acid (1.0 g,
6.2 mmol) in butanol (30 mL), metallic Na (1.9 g, 82.2 mmol) was
carefully added in batches of 200–250 mg every 10 min. After all
the sodium was added, the mixture was refluxed at 120 °C over-
night. After this time, the mixture was left cool to room tempera-
ture and 15 mL of distilled water were added to assure no more
sodium was left in the reaction medium. The mixture was then
concentrated on a rotary evaporator and in a high-vacuum pump
until none of the butanol was present. The solid was redissolved
in water (10 mL), neutralized with concentrated HCl, and later
acidified to pH 4–5 with an aqueous AcOH solution. The suspen-
sion was put on an ice-bath, and after a solid started to precipitate,
the formed suspension was filtrated and the mother liquor was
saturated with solid NH4Cl. The solid formed was filtrated and both
resulting solids were combined and used without further purifica-
tion for the synthesis of compounds 3 and 6.
3. Conclusions
In conclusion, we have developed the chemical synthesis of a
series of racemic cyclic a- and b-amino esters to study their behav-
ior in lipase-catalyzed alkoxycarbonylation, transesterification, or
interesterification processes. The production of enantiomerically
pure alkyl indoline-3-carboxylates has been successfully achieved
via the kinetic resolution of methyl indoline-3-carboxylate using
C. antarctica lipase B as a biocatalyst and butanol for the transeste-
rification reaction. Lipases have shown lower enantiopreferences
toward the homologous 2-substituted ester and also 1,2,3,4-tetra-
hydroquinoline derivatives bearing the ester group at the 2- or 3-
position, leading to optically active amino esters with low to high
enantiomeric excesses depending on the substrate structure and
the choice of transesterification or interesterification process.
4.3. Typical procedure for the esterification of indoline-3-
carboxylic acid (synthesis of esters 3 and 6)
Carboxylic acid 2 (100 mg, 0.61 mmol) was dissolved in the cor-
responding alcohol (MeOH or n-BuOH, 12 mL) and placed in an ice-
bath. Then SOCl2 (61 lL, 0.80 mmol) was added dropwise and the
4. Experimental
4.1. General
corresponding mixture refluxed overnight (67 °C, for methanol;
120 °C, for n-butanol) until no starting material was detected on
TLC (10% MeOH/CH2Cl2). After that, the mixture was concentrated
under reduced pressure, resuspended in water (10 mL), slightly
alkalinized until pH 8.0 with an aqueous solution of NaOH 1 M,
and extracted with CH2Cl2 (3 ꢂ 10 mL). The resulting esters were
purified by column chromatography (10–30% EtOAc/hexane),
obtaining a yellowish oil both for 3 (74%) and 6 (71%).
C. antarctica lipase type B (CAL-B, Novozyme 435, 7300 PLU/g)
and R. miehei lipase (Lipozyme RM IM, <15% in weight) were a gift
from Novozymes (Denmark). C. antarctica lipase type A was ac-
quired from Codexis (2.6 U/mg using tributyrin). P. cepacia lipase
type I (PSL-C I, Amano, 1061 U/g), porcine pancreas lipase (PPL)
type II (30–90 U/mg of protein using triacetin), and C. rugosa lipase
(965 U/mg of solid using olive oil) were purchased from Sigma–Al-
drich. All other reagents were purchased from Acros Organics or
Sigma–Aldrich and used without further purification. Solvents
were distilled over an adequate desiccant under nitrogen. Flash
chromatography was performed using Silica Gel 60 (230–240
mesh). High performance liquid chromatography (HPLC) analyses
were carried out at 30 °C in a Hewlett Packard 1100 chromato-
graph under the conditions specified for each substrate and with
UV monitoring at 210 and 215 nm. IR spectra were recorded using
NaCl plates or KBr pellets in a Perkin–Elmer 1720-X FT. 1H, 13C
NMR and DEPT experiments were carried out using AC-300 (1H,
300.13 MHz and 13C, 75.5 MHz) or DPX-300 (1H, 300.13 MHz and
13C, 75.5 MHz) Bruker spectrometers. The chemical shifts are given
in delta (d) values and the coupling constants (J) in Hertz (Hz).
HP1100 chromatograph mass detector was used to record mass
spectra experiments (MS) through ESI+ or APCI+ mass experiments.
The measurement of the specific rotation was carried out in a Per-
kin–Elmer 241 polarimeter.
4.3.1. Methyl indoline-3-carboxylate 3
Rf (30% EtOAc/hexane): 0.26; IR (NaCl):
1732, 1606, 1532, 1488, 1465, 1436, 1317, 1254, 1200, 1173,
1051, 751 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 3.46 (br s, 1H, NH),
m 3378, 2952, 2282,
;
3.74–3.83 (m, 4H, H2, 3H11), 3.96 (t, 2H, J = 8.44, H2), 4.22 (dd,
1H, J = 7.90, 9.20 Hz, H3), 6.70 (d, 1H, J = 7.68 Hz, H4), 6.74 (t, 1H,
J = 7.45, H5), 7.11 (t, 1H, J = 6.19, H6), 7.33 (d, 1H, J = 7.45 Hz,
H
4,7); 13C NMR (CDCl3, 75.5 MHz): 47.1 (C3), 49.1 (C2), 52.2 (C12),
110.0 (C7), 118.8 (C5), 125.0 (C6), 125.9 (C9), 128.6 (C4), 150.9
(C8), 172.6 (C10). MS (APCI+, m/z): 178.1 [(M+H)+, 100]. HPLC: Chi-
ralcel OJ-H column, hexane/propan-2-ol (90:10), 30 °C, and 0.8 mL/
min flow.
4.3.2. Butyl indoline-3-carboxylate 6
Rf (30% EtOAc/hexane): 0.60; IR (NaCl):
m
3378, 2960, 2934,
1H
2874, 1732, 1607, 1533, 1488, 1465, 1256, 1180, 748 cmꢁ1
;
NMR: (CDCl3, 300 MHz): 0.98 (t, 3H, J = 7.35 Hz, H15), 1.38–1.50
(m, 2H, H14), 1.65–1.74 (qt, 2H, H13), 3.59 (s, 1H, NH), 3.74 (t, 1H,

S. Alatorre-Santamaría et al. / Tetrahedron: Asymmetry 21 (2010) 2307–2313
2311
J = 9.65 Hz, H2), 3.96 (dd, 1H, J = 7.67, 7.68 Hz, H2), 4.18–4.23 (m,
4.6. Typical procedure for the lipase-mediated
transesterification or interesterification reactions of amino
esters 3, 8a, 11 and 15
3H, 2H12+H3), 6.67 (d, 1H, J = 7.89 Hz, H4), 6.77 (t, 1H, J = 7.46 Hz,
H5), 7.11 (t, 1H, J = 7.57 Hz, H6), 7.33 (d, 1H, J = 7.46 Hz, H7); 13C
NMR (CDCl3, 75.5 MHz): 13.5 (C15), 19.0 (C14), 30.5 (C13), 47.1
(C3), 49.0 (C2), 64.9 (C12), 109.9 (C7), 118.7 (C5), 124.9 (C6), 126.0
(C9), 128.5 (C4), 150.9 (C8), 172.1 (C10). MS (APCI+, m/z): 220.1
[(M+H)+, 100]. HPLC: Chiralcel OJ-H column, hexane/propan-2-ol
(90:10), 30 °C, and 0.8 mL/min flow.
To a mixture of the corresponding substrate (0.10 mmol) and
the lipase (1:1 in weight) was added the corresponding solvent
(1 mL) under a nitrogen atmosphere. At this point, n-BuOH or
PrCO2Bu (0.20 mmol) was added. The resulting suspension was
shaken at the given temperature and 250 rpm in an orbital shaker,
following the time course of the reactions by HPLC analysis (Chiral-
cel OJ-H column, hexane/propan-2-ol 90:10, 30 °C, and 0.8 mL/min
flow for 3 and 8a; Chiralcel OD column, hexane/propan-2-ol 90:10,
30 °C, and 0.8 mL/min flow for 11 and 15). After the indicated time
the reaction was stopped, and the enzyme filtered off and washed
with 5 mL of CH2Cl2. The solvent was evaporated under reduced
pressure and the reaction crude purified by flash chromatography
on silica gel using different gradients of EtOAc/hexane as eluent
(10% EtOAc/hexane for the indoline derivative and 30% EtOAc/hex-
ane for the quinoline derivatives) to afford the desired amino es-
ters, which were injected in the HPLC for measurement of their
4.4. Synthesis of compound 4 by chemical alkoxycarbonylation
reaction
In a similar approach to the one previously described,9o to a
solution of racemic aminoester 2 (30 mg, 0.17 mmol) and pyridine
(14.5
lL, 0.18 mmol) in dry CH2Cl2 (1.13 mL) placed into an ice
bath under a nitrogen atmosphere, allyl chloroformate (15.3
lL,
0.18 mmol) was added dropwise. The solution was allowed to
warm to room temperature and the reaction mixture stirred for
6 h until no starting material was detected by TLC analysis (40%
EtOAc/hexane). Then, the solvent was evaporated under reduced
pressure, and the resulting residue was purified by flash chroma-
tography (10–20% EtOAc/hexane), yielding carbamate 4 (91% iso-
lated yield) as a yellow oil.
enantiomeric excesses. ½a D20
¼ ꢁ94:7 (c 0.88, CH2Cl2) for (R)-3 in
ꢀ
>99% ee, ½a 2D0
¼ þ78:3 (c 0.60, CH2Cl2) for (S)-6 in >99% ee; and
ꢀ
½
a 2D0
ꢀ
¼ ꢁ47:3 (c 0.28, CH2Cl2) for (R)-8a in >99% ee (Scheme 5).
4.4.1. 3-Methyl 1-prop-2-en-1-yl 2,3-dihydro-1H-indole-1,3-
dicarboxylate 4
4.7. Enzymatic kinetic resolution of racemic compounds 3 and
11 by alkoxycabonylation reactions
Rf (40% EtOAc/hexane): 0.65; IR (NaCl):
1732, 1606, 1532, 1488, 1465, 1436, 1317, 1254, 1200, 1173,
1051, 751 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 3.79 (s, 3H, H11),
4.14–4.24 (m, 2H, H2), 4.50 (dd, 1H, J = 4.84, 4.84 Hz, H3), 4.74 (br
s, 2H, H14), 5.34 (dd, 2H, J = 17.07, 10.25, H16), 5.94–6.11 (m, 1H,
m 3378, 2952, 2282,
To a suspension of the amino ester 3 or 11 (50 mg, 0.28 mmol)
and the corresponding lipase (100 mg, 2:1 in weight relative to
the starting material) in TBME or THF (1.9 mL) under a nitrogen
atmosphere, the corresponding carbonate (allyl carbonate or 3-
methoxyphenyl allyl carbonate, 0.70 mmol) was added. The mix-
ture was shaken at 30 °C and 250 rpm and the reaction course
followed by HPLC. At the desired time, the reaction mixture was fil-
tered off and the filtrate was concentrated under reduced pressure.
The reaction crude was purified by flash chromatography (eluent
gradient 10–30% EtOAc/hexane).
;
H
15), 7.01 (t, 1H, J = 7.54, H5), 7.27 (t, 1H, J = 7.54, H6), 7.39 (d,
1H, J = 7.69 Hz, H4), 7.91 (br s, 1H, H7); 13C NMR (CDCl3,
75.5 MHz): 44.8 (C2), 49.4 (C3), 52.6 (C11), 65.9 (C14), 114.9 (C7),
122.7 (C5), 125.0 (C6), 127.4 (C9), 129.0 (C4), 132.3 (C15), 142.2
(C8), 152.2 (C12), 171.6 (C10). MS (APCI+, m/z): 262.1 [(M+H)+, 10].
HPLC: Chiralcel OD column, hexane/propan-2-ol (90:10), 20 °C,
and 0.8 mL/min flow.
4.8. Synthesis of methyl indoline-2-carboxylate 8a and butyl
indoline-2-carboxylate 8b
4.5. Synthesis of allyl indoline-3-carboxylate 5
Indoline-3-carboxylic acid 2 (50 mg, 0.6 mmol) was dissolved in
allylic alcohol (12 mL) by gentle heating and magnetic stirring.
After a solution was formed, it was placed in an ice-bath. Then
To a solution of commercially available 2-indoline carboxylic
acid 7 (100 mg, 0.61 mmol) in MeOH or n-BuOH (12.2 mL), was
carefully added SOCl2 (67.1 lL, 0.91 mmol) at 0 °C. The mixture
SOCl2 (61
l
L, 0.8 mmol) was added dropwise and the correspond-
was then heated at reflux (65 °C or 120 °C, respectively) for 5 h,
after which none of the starting material could be detected by
TLC (30% EtOAc/hexane). The reaction was concentrated on a ro-
tary evaporator, resuspended in water, slightly alkalinized until
pH 8.0 with an aqueous solution of NaOH 1 M, and extracted with
CH2Cl2 (4 ꢂ 10 mL). The resulting esters were purified by column
chromatography (10% EtOAc/hexane), to give 8a (90%) and 8b
(97%) as colorless oils.
ing mixture heated overnight (75 °C), until no starting material
was detected on TLC (60% EtOAc/hexane). After that, the mixture
was concentrated under reduced pressure, resuspended in water
(10 mL), slightly alkalinized until pH 8.0 with an aqueous solution
of NaOH 1 M, and extracted with CH2Cl2 (3 ꢂ 10 mL). The resulting
esters were purified by column chromatography (20% EtOAc/hex-
ane), to give 5 (42%) as a yellowish oil.
Spectroscopic data for 8a are already described.9o HPLC: Chiral-
cel OJ-H column, hexane/propan-2-ol (90:10), 30 °C, and 0.8 mL/
min flow.
4.5.1. Allyl indoline-3-carboxylate 5
Rf (40% hexane/EtOAc): 0.55; IR (NaCl):
1732, 1606, 1532, 1488, 1465, 1436, 1317, 1254, 1200, 1173,
1051, 751 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 3.77 (t, 1H, J = 9.99,
m 3378, 2952, 2282,
;
4.8.1. Butyl indoline-2-carboxylate 8b
H2), 3.98 (t, 1H, J = 8.43, H3), 4.24 (t, 1H, J = 8.58 Hz, H2), 4.69 (dd,
2H, J = 1.23, 1.26, H11), 5.26–5.39 (m, 2H, H13), 5.91–6.04 (m, 1H,
H12), 6.69 (d, 1H, J = 7.80, H4), 6.77 (t, 1H, J = 7.49, H6), 7.11 (t,
1H, J = 7.64 Hz, H5), 7.34 (d, 1H, J = 7.48 Hz, H7); 13C NMR (CDCl3,
75.5 MHz): 47.1 (C2), 49.1 (C3), 65.7 (C11), 110.0 (C7), 118.4 (C13),
118.8 (C5), 125.1 (C6), 125.8 (C9), 128.7 (C4), 131.9 (C12), 151.0
(C8), 171.8 (C10). MS (APCI+, m/z): 204.1 [(M+H)+, 100]. HPLC: Chi-
ralcel OD column, hexane/propan-2-ol (90:10 or 95:5), 20 °C, and
0.8 mL/min flow.
Rf (30% EtOAc/hexane): 0.57; IR (NaCl):
2934, 2874, 1733, 1610, 1531, 1486, 1467, 1396, 1308, 1244,
1198, 1076, 1019, 738 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 0.98 (t,
3H, J = 7.35 Hz, H14), 1.36–1.48 (m, 2H, H13), 1.63–1.72 (qt, 2H,
12), 3.31–3.48 (m, 2H, H3), 4.19 (t, 2H, J = 6.69 Hz, H11) 4.34–4.43
overlap (m, 1H, H2; br s, 1H, NH), 6.73–6.81 (m, 2H, H5+H7), 7.06–
7.13 (m, 2H, H4+H6); 13C NMR (CDCl3, 75.5 MHz): 13.4 (C14), 18.9
(C13), 30.4 (C12), 33.5 (C3), 59.7 (C2), 65.0 (C11), 109.9 (C7), 119.2
(C5), 124.2 (C6), 126.5 (C9), 127.4 (C4), 150.0 (C8), 174.0 (C10). MS
m 3373, 3055, 2961,
;
H

2312
S. Alatorre-Santamaría et al. / Tetrahedron: Asymmetry 21 (2010) 2307–2313
(ESI+, m/z): 242.1 [(M+Na)+, 100]. HPLC: Chiralcel OJ-H column, hex-
ane/propan-2-ol (90:10), 30 °C, and 0.8 mL/min flow.
25.6 (C3), 52.2 (C2), 53.8 (C12), 114.4 (C8), 117.5 (C6), 120.4 (C10),
126.9 (C7), 129.0 (C5), 142.8 (C9), 173.6 (C11). MS (APCI+, m/z):
192.1 [(M+H)+, 100]. HPLC: Chiralcel OD column, hexane/propan-
2-ol (90:10), 30 °C, and 0.8 mL/min flow.
4.9. Typical procedure for the methyl esterification of the 2- and
3-quinaldic acid derivatives (synthesis of 10 and 14)
4.10.2. Methyl-1,2,3,4-tetrahydroquinoline-3-carboxylate 15
The corresponding quinoline derivative
2.90 mmol) was dissolved in MeOH (57.8 mL) and the solution
was cooled on an ice-bath. Then SOCl2 (291.4 L, 3.90 mmol) was
9
or 13 (500 mg,
Rf (30% EtOAc/hexane): 0.32; IR (NaCl):
1608, 1500, 1439, 1379, 1311, 1267, 1197, 1169, 1121, 1071,
738 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 2.94–3.00 (m, 1H, H4),
m 3409, 3055, 2855, 1734,
l
;
carefully added and the mixture refluxed overnight until no more
starting material was detected by TLC (30% EtOAc/hexane). At this
point the reaction was left to cool to room temperature and the
solvent evaporated under reduced pressure. The crude was resus-
pended in water and slightly alkalinized until pH 8.0 with an aque-
ous solution of NaOH 1 M and extracted with CH2Cl2 (3 ꢂ 15 mL).
The crude was finally purified by column chromatography (30%
EtOAc/hexane), to give amino esters 10 (432 mg, 80%), and 14
(446 mg, 83%) as white solids.
3.03–3.06 (m, 2H, H3+H4), 3.39 (dd, 1H, J = 8.99, 8.99 Hz, H2), 3.56–
3.61 (m, 1H, H2), 3.76 (br s, 4H, NH+H12), 6.55 (d, 1H, J = 8.11 Hz,
H5), 6.68 (t, 1H, J = 6.0 Hz, H6), 7.02 (t, 2H, H7+H8); 13C NMR (CDCl3,
75.5 MHz): 24.5 (C4), 25.6 (C3), 52.2 (C2), 53.8 (C12), 114.4 (C8), 117.5
(C6), 120.4 (C10), 126.9 (C7), 129.0 (C5), 142.8 (C9), 173.6 (C11). MS
(APCI+, m/z): 192.1 [(M+H)+, 100]. HPLC: Chiralcel OD column, hex-
ane/propan-2-ol (90:10), 30 °C, and 0.8 mL/min flow.
4.11. Typical procedure for the transesterification with n-
butanol of 11 and 15 (synthesis of 12 and 16)
4.9.1. Methyl quinoline-2-carboxylate 10
Rf (30% EtOAc/hexane): 0.24; mp 87–89 °C; IR (KBr):
2954, 1725, 1463, 1320, 1266, 1212, 1138, 1108, 846, 779,
736 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 4.09 (s, 3H, CH3), 7.65 (t,
J = 7.1 Hz, 1H, arom), 7.79 (t, J = 8.5 Hz, 1H, H7), 7.88 (d,
J = 8.1 Hz, 1H, H5), 8.20 (d, J = 8.56 Hz, 1H, H2), 8.31 (d,
J = 8.56 Hz, 2H, H4+H8); 13C NMR (CDCl3, 75.5 MHz): 53.1 (C13),
120.9 (C3), 127.4 (C5), 128.6 (C6), 129.3 (C10), 130.3 (C8), 130.6
(C7), 137.3 (C4), 147.4 (C9), 147.8 (C2), 165.9 (C12); MS (ESI+, m/z):
187 (M+, 90), 156 [(MꢁCH4O)+, 100%].
m
3054,
The corresponding quinoline methyl ester derivative 11 or 15
(30 mg, 0.16 mmol) was dissolved in BuOH (3.1 mL) and the solu-
tion was cooled on an ice-bath. Then SOCl2 (15.7 lL, 0.22 mmol)
;
H
was carefully added and the mixture refluxed overnight until no
more starting material was found on TLC (30% EtOAc/hexane). At
this point the reaction was left to cool to room temperature and
the solvent evaporated under reduced pressure. The crude product
was resuspended in water and slightly alkalinized until pH 8.0
with an aqueous solution of NaOH 1 M and extracted with CH2Cl2
(3 ꢂ 5 mL). The crude was finally purified by column chromatogra-
phy (10–20% EtOAc/hexane), to give aminobutyl esters 12 (23 mg,
62%), and 16 (26 mg, 70%) as white semi-solids.
4.9.2. Methyl quinoline-3-carboxylate 14
Rf (30% EtOAc/hexane): 0.32; mp 87–89 °C; IR (KBr):
2954, 1725, 1463, 1320, 1266, 1212, 1138, 1108, 846, 779,
736 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 4.02 (s, 3H, H12), 7.59–
m 3054,
;
4.11.1. Butyl-1,2,3,4-tetrahydroquinoline-2-carboxylate 12
7.65 (m, 1H, H7), 7.80–7.84 (m, 1H, H6), 7.93 (t, J = 8.33, 1H, H5),
8.16 (d, J = 8.33, 1H, H8), 8.84 (d, J = 1.53, 1H, H4), 9.45 (d,
J = 1.97, 1H, H2); 13C (CDCl3, 75.5 MHz): 53.4 (C12), 122.9 (C3),
126.7 (C5), 127.4 (C6), 129.0 (C10), 129.4 (C7), 131.8 (C8), 138.7
(C4), 149.1 (C9), 149.9 (C2), 165.7 (C11); MS (ESI+, m/z): 187 (M+,
90), 156 [(MꢁCH4O)+, 100%].
Rf (30% EtOAc/hexane): 0.56; IR (NaCl): m 3414, 3054, 2963, 2874,
1735, 1608, 1587, 1491, 1390, 1343, 1299, 1211, 1139, 738 cmꢁ1; 1H
NMR: (CDCl3, 300 MHz): 0.97 (t, 3H, J = 7.34 Hz, H15), 1.35–1.48 (m,
2H, H14), 1.63–1.72 (m, 2H, H13), 2.27–2.37 (m, 1H, H4), 2.73–2.92
(m, 1H, H4), 4.03–4.06 (dd, 1H, J = 3.73, 3.73 Hz, H2), 4.14–4.27 (m,
2H, H12), 6.61–6.70 (m, 1H, H6+H8), 6.97–7.06 (m, 2H, H5+H7); 13C
NMR (CDCl3, 75.5 MHz): 13.6 (C15), 19.0 (C14), 24.7 (C4), 25.8 (C3),
30.5 (C13), 53.9 (C2), 65.0 (C12), 114.5 (C8), 117.5 (C6), 120.5 (C10),
126.9 (C7), 129.0 (C5), 142.9 (C9), 173.2 (C11). MS (APCI+, m/z):
234.1 [(M+H)+, 100]. HPLC: Chiralcel OD column, hexane/propan-
2-ol (90:10), 30 °C, and 0.8 mL/min flow.
4.10. Typical procedure for the hydrogenation of methyl
quinoline carboxylates 10 and 14 (synthesis of 11 and 15)
To a solution of the corresponding quinoline ester 10 or 14
(250 mg, 1.30 mmol) in THF (4.7 mL) and MeOH (2.3 mL) under a
nitrogen atmosphere, NaBH3CN (355 mg, 5.50 mmol) was added.
Once the entire solid had dissolved, a small amount of bromocresol
green (pH indicator) was added, and the solution acquired a bluish
color (alkaline). Then, a 4 M HCl solution in dioxane was added
dropwise onto the reaction mixture from time to time, till the mix-
ture maintained a yellowish color (acid). After that, the beaker was
put on an ice-bath and the proper volume of a saturated aqueous
solution of NaHCO3 was added to neutralize the medium. The mix-
ture was extracted with EtOAc (3 ꢂ 10 mL) and the organic phases
combined and concentrated under reduced pressure. The crude
was purified by column chromatography (10–20% EtOAc/hexane),
to give 11 (87%) and 15 (90%) both as yellowish oils.
4.11.2. Butyl-1,2,3,4-tetrahydroquinoline-3-carboxylate 16
Rf (30% EtOAc/hexane): 0.54; IR (NaCl):
2873, 1728, 1608, 1587, 1500, 1467, 1375, 1310, 1267, 1186,
1120, 738 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 0.96 (t, 3H,
m 3407, 3055, 2961,
;
J = 7.26 Hz, H15), 1.34–1.46 (m, 2H, H14), 1.60–1.69 (m, 2H, H3),
2.93–2.99 (m, 1H, H4), 3.04 (d, 2H, J = 7.26 Hz, H3+H4), 3.39 (t,
1H, J = 10.26 Hz, H2), 3.59 (dd, 1H, J = 2.67, 3.63 Hz, H2), 4.15 (t,
2H, J = 6.63 Hz, H12), 6.58 (d, 1H, J = 8.37 Hz, H8), 6.70 (t, 1H,
J = 7.41 Hz, H6), 7.02 (t, 2H, J = 7.11 Hz, H7+H5); 13C NMR (CDCl3,
75.5 MHz): 13.6 (C15), 19.0 (C14), 29.5 (C4), 30.6 (C13), 38.3 (C3),
43.5 (C2), 64.5 (C12), 114.6 (C8), 117.9 (C6), 120.0 (C10), 127.0 (C7),
129.5 (C5), 143.1 (C9), 173.6 (C11). MS (ESI+, m/z): 234.1 [(M+H)+,
100]. HPLC: Chiralcel OD column, hexane:IPA (90:10), 30 °C, and
0.8 mL/min flow.
4.10.1. Methyl-1,2,3,4-tetrahydroquinoline-2-carboxylate 11
Rf (30% EtOAc/hexane): 0.40; IR (NaCl):
2844, 1739, 1608, 1497, 1437, 1343, 1301, 1247, 1171, 1019,
749 cmꢁ1 1H NMR: (CDCl3, 300 MHz): 1.98–2.10 (m, 1H, H3),
m 3400, 3017, 2951,
References
;
2.27–2.36 (m, 1H, H3), 2.73–2.92 (m, 2H, H4), 3.81 (s, 3H, OCH3),
4.07 (dd, J = 3.95, 3.73 Hz, 1H, H2), 6.61–6.71 (m, 2H, H6+H8),
6.98–7.07 (m, 2H, H5+H7); 13C NMR (CDCl3, 75.5 MHz): 24.5 (C4),
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