Lipase-catalyzed kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-acetic acid esters

Article abstract of DOI:10.1016/j.tetasy.2008.11.032

The enantiomers of 1,2,3,4-tetrahydroisoquinoline- and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acids were prepared via Burkholderia cepacia lipase (lipase PS-D)-catalyzed kinetic resolution of the corresponding ethyl and 2-methoxyethyl esters using enantioselective (E > 200) hydrolysis in DIPE. The (S)-acids were produced enzymatically, whereas the (R)-acids were obtained via the chemical hydrolysis of the unreacted (R)-esters. The solvent and its water content had major effects on both reactivity and enantioselectivity. The methoxyethyl moiety of the ester had a key role concerning the reactivity of the substrates.

Full text of DOI:10.1016/j.tetasy.2008.11.032

Tetrahedron: Asymmetry 19 (2008) 2784–2788
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Lipase-catalyzed kinetic resolution of 1,2,3,4-tetrahydroisoquinoline-1-acetic
acid esters
b
b,
a
a,
Tihamér A. Paál a,b, Eniko Forró , Ferenc Fülöp , Arto Liljeblad , Liisa T. Kanerva
*
*
}
a Department of Pharmacology, Drug Development and Therapeutics/Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku,
Lemminkäisenkatu 5C, FIN-20250, Turku, Finland
b Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös 6, H-6720 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiomers of 1,2,3,4-tetrahydroisoquinoline- and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-
1-acetic acids were prepared via Burkholderia cepacia lipase (lipase PS-D)-catalyzed kinetic resolution
of the corresponding ethyl and 2-methoxyethyl esters using enantioselective (E > 200) hydrolysis in DIPE.
The (S)-acids were produced enzymatically, whereas the (R)-acids were obtained via the chemical hydro-
lysis of the unreacted (R)-esters. The solvent and its water content had major effects on both reactivity
and enantioselectivity. The methoxyethyl moiety of the ester had a key role concerning the reactivity
of the substrates.
Received 1 October 2008
Accepted 20 November 2008
Available online 10 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
tive, large-scale applicable and sustainable methods for the kinetic
resolution of b-amino acid derivatives and precursors.10,14 An
Interesting results obtained in the study of b-peptides during
the last decade have given chemical and therapeutic importance
enzymatic method for the resolution of cyclic b-amino acids has
recently been developed, using CAL-B-catalyzed hydrolysis of the
corresponding esters.15
to b-amino acids. Resembling
nizing, capable of self-association, and some of them exert similar
biological effects as antimicrobial -peptides and cyclic -peptide
hormones.1–3 In some cases, it is useful to replace an
-amino acid
with a b-analogue in biologically active -peptides in order to
modulate their therapeutic effects by stabilizing secondary
structures, such as
-turn sequences.4,5 1,2,3,4-Tetrahydroisoquin-
a-peptides, b-peptides are self-orga-
In addition to being the sterically constrained analogue of
b3-phenylalanine, 1,2,3,4-tetrahydroisoquinoline-1-acetic acid is
a benzene-fused (piperidin-2-yl)acetic acid (Fig. 1). In our previous
work, we had demonstrated the lipase-catalyzed kinetic and dy-
namic kinetic resolution of various 2-piperidyl-based amino acid
derivatives.16–20 Herein, we report the lipase-catalyzed kinetic res-
olution of 1,2,3,4-tetrahydroisoquinoline-1-acetic acid esters ( )-
1–( )-4 (Scheme 1). It should be mentioned that the N-acylation
of (piperidin-2-yl)acetic acid derivatives is unsuccessful although
the N-acylation of pipecolic acid methyl ester proceeds nicely with
Candida antarctica lipase A (CAL-A).16–18 On the other hand, the ki-
netic resolution of N-protected (piperidin-2-yl)acetic acid methyl
ester with Burkholderia cepacia lipase (lipase PS) was reported to
be successful through interesterification18 and hydrolysis,21 that
is, through reactions directed to the ester function. Enantioselec-
tive hydrolysis of b3-phenylalanine ethyl ester was also previously
accomplished with lipase PS.22 The kinetic resolution of the pres-
a
a
a
a
c
oline-1-acetic acid is a sterically constrained analogue of b3-phen-
ylalanine. As b3-phenylalanine itself, the title compounds are
valuable building blocks, which can be used in the synthesis of
melanocortin receptor agonists,6 integrin inhibitors7, or bradyki-
nin-1 antagonists.8 Driven by increasing needs for enantiopure
b-amino acids, a large number of resolutions of racemic mixtures
and enantioselective syntheses have been developed.9,10 Methods
for the preparation of enantiopure 1,2,3,4-tetrahydroisoquino-
line-1-acetic acid derivatives are mostly based on metal complex
catalysis, employing chiral ligands. These methods comprise the
enantioselective hydrogenation of the corresponding 3,4-dihydro-
isoquinolines (with a chiral Ru complex)11 and the addition of
ketene silyl acetals12 or vinyl ethers13 to 3,4-dihydroisoquinoline
N-oxide (catalyzed by Ti or Al complexes with chiral BINOL ligands,
respectively). As previously reviewed, lipase catalysis offers effec-
NH
NH
A.
B.
CO2H
CO2H
* Corresponding authors. Tel.: +36 62 455 564; fax: +36 62 420 604 (L.T.K.).
E-mail addresses: fulop@pharm.u-szeged.hu (F. Fülöp), lkanerva@utu.fi (L.T.
Kanerva).
Figure 1. b3-Phenylalanine (A) and piperidylacetic acid (B) skeletons of 1,2,3,4-
tetrahydroisoquinoline-1-acetic acid.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.11.032

T. A. Paál et al. / Tetrahedron: Asymmetry 19 (2008) 2784–2788
2785
R1
R1
NH
NH
R1
CO2Et
CO2R2
Lipase
Lipase
H2O
1
1 4
(R)-
(R)-( - )
NH
PrCO2Bu
R1
+
+
Interesterification
R1
R1
Hydrolysis
COOR2
(±)-1: R1=H, R2=Et
2:
(±)- R =H, R =CH2CH2OMe
3:
(±)- R =OMe, R =Et
NH
NH
1
2
1
2
CO2Bu
CO2H
(S)- R =H
(S)-7: R1=OMe
1
1
2
6:
4:
(S)-5
(±)- R =OMe, R =CH2CH2OMe
Scheme 1.
ent substrates ( )-1–( )-4 has been studied using lipase-catalyzed
interesterification and hydrolysis reactions (Scheme 1).
in the mixture of DIPE/PrCOOBu [1:1 (v/v)], all the lipases used
were inactive with no measurable conversion in 24 h.
Hydrolysis of ( )-1 in aqueous buffer (at pH 8, in 0.1 M Tris–HCl,
room temperature) was studied next. Unfortunately, very low
enantioselectivity was detected in the presence of various lipases,
lipase PS-D showing the highest enantioselectivity (E = 7). The pre-
viously reported enantioselective hydrolysis22 of b3-phenylalanine
ethyl ester with lipase PS in DIPE encouraged us to turn our atten-
tion to the hydrolysis of ( )-1 with 0.5–4 equiv of added H2O in
DIPE with lipase PS-D and lipase PS-C II preparations (Table 2).
Reactivities with both preparations were generally low. However,
there was a remarkable increase in reactivity (time needed to reach
50% conversion) with increasing water contents, the increase being
more pronounced with lipase PS-D compared to lipase PS-C II.
More importantly, enantioselectivity also increased, becoming
excellent (E > 200) for lipase PS-D when 2 equiv or more H2O
was added. The highly enantioselective and economical lipase PS-
D was selected for further studies.
2. Results and discussion
2.1. Preparation of racemic substrates
3,4-Dihydroisoquinolines were prepared using the Bischler–
Napieralski cyclization of the corresponding N-phenethylforma-
mides (formed in situ from 2-arylethylamine and formic acid).23
The addition of ethyl hemimalonate to the 3,4-dihydroisoquino-
lines followed by decarboxylation furnished compounds ( )-1
and ( )-3.24 Alkyl-activated ( )-2 and ( )-4 were prepared from
the corresponding ethyl esters ( )-1 and ( )-3 using acid-catalyzed
transesterification with 2-methoxyethanol.
2.2. Lipase-catalyzed kinetic resolution
Lipase screening with CAL-A on Celite,25 Candida antarctica li-
pase B (CAL-B as Novozym 435), lipase PS as lipase PS-C II (Amano
preparation on Toyonite 200M) and lipase PS-D (Amano lipase PS
on Celite) preparations were started using ( )-1 as a model
substrate for interesterification with butyl butanoate in tert-
butylmethyl ether (TBME) and diisopropyl ether (DIPE) (Scheme
1). CAL-A did not catalyze the reaction, while CAL-B provided no
enantioselectivity in the terms of enantiomer ratio (E = 2). With
lipase PS preparations, relatively good initial enantioselectivities
started to drop during the reaction, indicating that interesterifica-
tion was not the only reaction taking place (Table 1). Competing
alcoholyses (interesterification is basically an alcoholysis reaction
with BuOH which competes with EtOH) can spoil an initially effec-
tive kinetic resolution, while also enzymatic hydrolysis of the butyl
ester (S)-5 may also have an effect on E values even if the propor-
tion of hydrolysis is minimal. When N-Boc- and N-formyl-pro-
tected ( )-1 were subjected under interesterification conditions
Table 2
The effect of the added H2O on the hydrolysis of ( )-1 (0.05 M) with lipase PS
preparations (50 mg mLꢀ1) in DIPE, at room temperature
Entry Lipase Added H2O Time (h) ee(R)-1a (%) ee(S)-6a (%) Conv. (%)
(equiv)
E
1
2
3
PS-CII 0.5
192
68
48
91
95
95
94
94
95
49
50
50
103
121
146
2
4
4
5
6
PS-D
0.5
2
504
96
78
96
95
94
95
97
97
50
49
49
154
>200
>200
4
a
Determined by GC.
Compound ( )-1 (0.05 M) was subjected to hydrolysis with 2–
4 equiv of added H2O in Et2O, TBME, DIPE, toluene, and 2-
methyl-THF (Table 3). DIPE with 4 equiv of added H2O (corre-
sponds to 0.2 M H2O in DIPE, where DIPE is saturated with H2O
at 23 °C) proved to be the best solvent concerning both the reactiv-
ity and the enantioselectivity (Table 3, entry 6). The reactivity still
stayed low. When the reaction was performed at elevated temper-
ature (47 °C), the reactivity was enhanced while enantioselectivity
was notably decreased (Table 3, entry 7). Another way to increase
reactivity is to increase the electrophilic character of the carbonyl
carbon in the ester substrate. Accordingly, 2-methoxyethyl ester
( )-2 was prepared and subjected to hydrolysis under the reaction
conditions described above (Table 4). Substantial reactivity
enhancement was evident (Table 4, entry 2 vs entry 1) without a
change in the excellent enantioselectivity. The same trend was ob-
served when the enzymatic hydrolyses of ( )-3 and ( )-4 were per-
Table 1
Lipase PS-D-catalyzed interesterification of ( )-1 (0.05 M) in the mixture of solvent/
PrCO2Bu [1:1 (v/v)] in the presence of lipase PS-D (75 mg mLꢀ1) at room temperature
Solvent
TBME
Time (h)
ee(R)-1a (%)
ee(S)-5a (%)
Conv.a (%)
‘E’
12
36
60
32
59
81
96
92
87
25
39
48
67
44
36
DIPE
12
36
60
29
69
88
97
92
87
23
43
50
87
50
42
a
Determined by GC.

2786
T. A. Paál et al. / Tetrahedron: Asymmetry 19 (2008) 2784–2788
Table 3
3. Conclusions
Solvent and temperature effects on the hydrolysis of ( )-1 (0.05 M) with lipase PS-D
(50 mg mLꢀ1
)
The enantiomers of 1,2,3,4-tetrahydroisoquinoline- and 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-acetic acids were
prepared via Burkholderia cepacia lipase (lipase PS-D)-catalyzed ki-
netic resolution of the corresponding ethyl and 2-methoxyethyl es-
ters using enantioselective hydrolysis in DIPE. The enzymatic
hydrolysis in aqueous buffer was not enantioselective. Also N-acyl-
ation and interesterification were studied. The reactivity was
remarkably improved when the alkyl part of the ester was changed
from ethyl to 2-methoxyethyl, and when 2–4 equiv of water was
added to the reaction mixture. The preparative scale kinetic resolu-
tions provided the enantiomeric products in good yields (46–49%
the theoretical yields of each enantiomer being 50%) and with high
enantiopurities (96–98%).
Entry Solvent
Added H2O Time
(equiv)
ee(R)-1c ee(S)-6c Conv. (%)
(days) (%) (%)
E
1
2
3
4
5
6
7
2-Methyl-THFa
4
4
21
21
35
22
35
3
82
94
73
93
75
94
92
94
94
96
96
97
97
93
47
50
43
49
44
49
50
83
Et2Oa
115
108
168
149
>200
91
Et2Oa
Saturated
Saturated
0.65
4
TBMEa
Toluenea
DIPEa
DIPEb
4
1
a
b
c
Reaction at room temperature.
Reaction temperature 47 oC.
Determined by GC.
Table 4
4. Experimental
Hydrolysis of ( )-1–4 (0.05 M) with lipase PS-D (50 mg mLꢀ1) in DIPE with 4 equiv of
added H2O at room temperature
4.1. Materials and methods
Entry
Substrate
Time (h)
ee(S)-1–4 (%)
ee(R)-6/7 (%)
Conv. (%)
E
1
2
3
4
5
( )-1
( )-2
( )-2a
( )-3
( )-4
78
16
37
32
18
94b
97b
98b
89c
97c
97b
98b
97b
98c
96c
49
50
50
48
50
>200
>200
>200
>200
>200
Lipase PS (Burkholderia cepacia lipase) preparations (lipase PS-D
and PS-C II) and CAL-A and CAL-B (lipase A and lipase B from Can-
dida antarctica) were purchased from Amano Pharmaceuticals and
Novo Nordisk, respectively. CAL-A was used after immobilization
on Celite in the presence of sucrose as previously described, and
the preparation contained 20% (w/w) of lipase.25 Solvents were of
highest analytical grade.
0.1 M substrate and 2 equiv of added H2O in DIPE; lipase PS-D 25 mg mLꢀ1
Determined by GC.
Determined by HPLC.
.
a
b
c
In a typical small-scale experiment, lipase was added to ( )-1
(0.05 M) in organic solvent/PrCO2Bu [1:1 (v/v)] or in an organic sol-
vent containing small amount (0.5–4 equiv) of added H2O (1–
2 mL). The reactions were performed at room temperature
(23 °C) if not otherwise stated. The reactions were followed by tak-
ing samples from the reaction mixture at intervals and analyzing
them. In the case of compounds ( )-1 and ( )-2, GC analyses were
performed on a CP Chirasil-DEX CB-coated chiral capillary column,
containing permethylated b-cyclodextrin (manufactured by Var-
ian). For the reactions of ( )-3 and ( )-4, analyses were performed
by HPLC using a Chiralcel OD-H chiral HPLC column (manufactured
by Daicel).
Compounds 1 and the corresponding methyl esters 1a, 2, and 5
were analyzed by GC after derivatization with trifluoroacetic anhy-
dride in the presence of N,N-dimethylaminopyridine (DMAP) in
pyridine. Amino acid 6 was analyzed by GC after derivatization
with diazomethane, followed by a second derivatization with
trifluoroacetic anhydride in the presence of DMAP in pyridine.
Compounds 3 and 4 were analyzed by HPLC, eluting with EtOH/
n-hexane (contained 0.1% Et2NH) [15:85 (v/v)]; 0.5 mL minꢀ1 flow,
25 °C. Amino acid 7 was analyzed in a similar way after derivatiza-
tion with diazomethane.
formed (Table 4, entries 4 and 5). Methoxy substitutions on the
benzene ring clearly enhanced the reactivity of ( )-3 compared
to the unsubstituted case, ( )-1, whereas alkyl-activated ( )-2
and ( )-4 reacted in similar ways.
To this end, the preparative scale resolutions of ( )-1–( )-3
were performed, as shown in Section 4. In order to use more eco-
nomical conditions, the resolutions were performed with 0.1 M
substrate in DIPE with 2 equiv of added H2O (corresponds to
0.2 M H2O in DIPE) and with the lipase PS-D content of
25 mg mLꢀ1. Accordingly, we reduced the enzyme content at the
expense of reactivity (Table 4, entry 2 vs entry 3). The gram-scale
resolutions resulted in excellent yields (46–49% for the separated
enantiomers, the theoretical yields in racemic mixtures being
50%) and high enantiopurities (ee 96–98%, Table 5). The absolute
configurations of the enantiomers were assigned comparing the
measured specific rotation data with the literature, which justifies
that the lipase PS-catalyzed hydrolysis is (S)-selective in all cases.
There is a discrepancy between the ½a D25
ꢁ
value observed in the
present work for (R)-1 (Table 5, entry 1) and the literature value11
{½a 2D5
¼ ꢀ12:5 (c 0.2, CHCl3; ee 99%)} for the (S)-enantiomer. In or-
ꢁ
der to show that the kinetic resolution of ( )-1 produced the unre-
acted ethyl ester as an (R)-enantiomer and that our compound was
correct, the unreacted ethyl ester was transformed into the methyl
ester (R)-1a by refluxing with methanolic HCl solution and by the
successive release of (R)-1a with K2CO3 treatment. Indeed, the ob-
Optical rotations were measured with a Perkin–Elmer 341
polarimeter. 1H NMR spectra were recorded on a Bruker Avance
DRX 400 spectrometer. The water concentrations of the solvents
were determined using a coulometric Karl Fischer instrument.
Melting points were determined on a Kofler apparatus.
tained ½a 2D5
¼ þ92 (c 1.0, CHCl3; ee > 99%) is in accordance with the
ꢁ
literature value26
½
a 2D5
ꢁ
¼ þ95 (c 1.0, CHCl3; ee 95%) for (R)-1a.
4.2. Preparation of the racemic substrates
Table 5
4.2.1. ( )-2-Methoxyethyl 1,2,3,4-tetrahydroisoquinoline-1-
acetate ( )-2
Data for the prepared enantiomers
Sub-strate
(R)-1–(R)-3ee (%)/½a D25
ꢁ
(S)-6ee (%)/½a 2D5
ꢁ
(S)-7ee (%)/½a 2D5
ꢁ
Compound ( )-1 (2.0 g, 9.12 mmol) was dissolved in
2-methoxyethanol (15 mL, 152.19 mmol), and sulfuric acid
(1.0 mL) was added. The mixture was refluxed for 4 h before the
solvent was evaporated. The residue was neutralized with ice-cold
aqueous K2CO3, and the free amino ester extracted with Et2O. The
crude product was purified as ( )-2ꢂHCl by crystallization from
(c 0.2, CHCl3)
(c 0.25, H2O)
(c 0.25, H2O)
( )-1
( )-2
( )-3
96/+81
97/+64
98/+52a
>99/ꢀ46
>99/ꢀ46
—
—
—
>99/+51
a
c 1.0, CHCl3.

T. A. Paál et al. / Tetrahedron: Asymmetry 19 (2008) 2784–2788
2787
2-methoxyethanol/Et2O and subsequent treatment with ice-cold
4.3.3. Kinetic resolution of ( )-3
( )-3 (1.0 g, 3.58 mmol) was dissolved in DIPE (freshly distilled,
35.8 mL), followed by the addition of H2O (128.9 L, 7.16 mmol)
aqueous K2CO3, followed by extraction with Et2O to give ( )-2 as
a
light yellow oil (1.6 g, 6.48 mmol, 71% yield). 1H NMR
l
(400 MHz, CDCl3) d (ppm): 1.44–2.27 (br s, 1H, NH), 2.72–2.98
(overlapping multiplets, 4H, CH2–COO and CH2–CH2–NH), 3.00–
3.10 (m, 1H, CH2–CHH–NH), 3.17–3.28 (m, 1H, CH2–CHH–NH),
3.41 (s, 3H, OCH3), 3.55–3.68 (t, 2H, J = 4.7 Hz, CH2–CH2–OCH3),
4.23–4.39 (m, 2H, CH2–CH2–OCH3), 4.46–4.56 (dd, 1H, J = 9.8,
2.9 Hz, Ar-CH–NH), 7.06-7.23 (m, 4H, Ar).
and lipase PS-D (895 mg) as above. The reaction was stopped by fil-
tering off the enzyme and the DIPE insoluble (S)-7 at 50% conver-
sion after 160 h. The work-up produced (R)-3, which readily
crystallized as a light yellow crystalline mass {483 mg, 1.73 mmol,
48% yield, mp 85–88 °C (described previously as an oil11,12), ee 98%,
½
a 2D5
ꢁ
¼ þ52 (c 1.0 CHCl3) and ½a D25
¼ þ46:5 (c 1.22 EtOH); for (S)-3
ꢁ
lit.13
½
a 2D5
ꢁ
¼ ꢀ10:2 (c 1.0 CHCl3, ee 58%) lit.12
½
a 2D5
ꢁ
¼ ꢀ30:5 (c 1.22
4.2.2. ( )-2-Methoxyethyl 6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline-1-acetate ( )-4
EtOH, ee 99%)}. 1H NMR (400 MHz, CDCl3) d (ppm): 1.23–1.37 (t,
3H, J = 7.1 Hz, O–CH2–CH3), 1.67–2.03 (br s, 1H, NH), 2.66–2.88
(overlapping multiplets, 4H, CH2–COO and CH2–CH2–NH), 2.98–
3.09 (m, 1H, CH2–CHH–NH), 3.16–3.27 (m, 1H, CH2–CHH–NH),
3.79–3.97 (br s, 6H, CH3O–Ar-OCH3) 4.24–4.38 (q, 2H, J = 7.1 Hz,
O–CH2–CH3), 4.37–4.48 (dd, 1H, J = 9.5, 3.5 Hz, Ar-CH–NH), 6.61
(s, 2H, Ar).
Compound ( )-4 was prepared by a method similar to ( )-2, and
( )-4 (710 mg, 2.29 mmol, 32% yield) was isolated as a light yellow
oil. 1H NMR (400 MHz, CDCl3) d (ppm): 1.67–2.15 (br s, 1H, NH),
2.59–2.93 (overlapping multiplets, 4H, CH2–COO and CH2–CH2–
NH), 2.94–3.07 (m, 1H, CH2–CHH–NH), 3.09–3.13 (m, 1H, CH2–
CHH–NH), 3.37 (s, 3H, CH2–CH2–OCH3), 3.53–3.67 (t, 2H,
J = 4.7 Hz, CH2–CH2–OCH3), 3.75 and 3.93 (s, 6H, H3CO–Ar-OCH3),
4.20-4.34 (m, 2H, CH2–CH2–OCH3), 4.34-4.46 (dd, J = 9.6, 3.3 Hz,
1H, Ar-CH–NH), 6.51 (s, 2H, Ar).
(S)-7 was washed with water from the solid residue, and the
water was evaporated under vacuum. After recrystallization from
water, (S)-7 was obtained as a white crystalline powder {413 mg,
1.64 mmol, 46% yield, mp 225–227 °C, ee P 99%, ½a D25
¼ ꢀ53:5 (c
ꢁ
0.25 H2O}. 1H NMR (400 MHz, DMSO-d6) d (ppm): 2.37–2.47 (dd,
1H, J = 16.3, J = 10.4, CHH–COO), 2.53–2.62 (dd, 1H, J = 16.3,
J = 4.1, CHH–COO), 2.65–2.83 (m, 2H, CH2–CH2–NH), 3.03–3.23
(m, 2H, CH2–CH2–NH), 3.61 and 3.82 (s, 6H, CH3O–Ar-OCH3),
4.21-4.34 (dd, 1H, J = 10.3, 3.9 Hz, Ar-CH–NH), 6.68 (s, 1H, Ar),
6.80 (s, 1H, Ar).
4.3. Gram-scale kinetic resolutions
4.3.1. Kinetic resolution of ( )-1
Compound ( )-1 (0.50 g, 2.28 mmol) was dissolved in DIPE
(freshly distilled, 20 mL), and H2O (73.8 lL, 4.1 mmol) and lipase
PS-D (0.5 g) were added. The mixture was shaken at room temper-
ature. The reaction was stopped by filtering off the enzyme and the
DIPE insoluble (S)-6 at 50% conversion after 17 days. The organic
phase was dried on Na2SO4, and evaporated to yield (R)-1 as a light
4.3.4. Transformation of (R)-1 into the methyl ester (R)-1a
Compound (R)-1 (290 mg, 1.16 mmol) was dissolved in metha-
nol (15 mL), after which HCl in methanol (20 g HCl/100 mL meth-
anol, 0.48 mL) was added. The solution was refluxed for 4 h before
evaporation. (R)-1aꢂHCl was recrystallized from methanol/Et2O,
and the colorless crystals were treated with aqueous K2CO3 under
cooling. Extraction with Et2O followed by evaporation of the sol-
vent produced ( )-1a as an almost colorless oil {138 mg,
yellow oil {238 mg, 1.09 mmol, 48% yield, ee 96%, ½a D25
¼ þ81 (c 0.2
ꢁ
CHCl3), for (S)-1 lit.11
½
a 2D5
ꢁ
¼ ꢀ12:5 (c 0.2 CHCl3, ee 99%)}. 1H NMR
(400 MHz, CDCl3) d (ppm): 1.16–1.36 (t, 3H, J = 7.1 Hz, O–CH2–
CH3), 1.95–2.17 (br s, 1H, NH), 2.67–2.93 (overlapping multiplets,
4H, CH2–COO and CH2–CH2–NH), 2.96–3.09 (m, 1H, CH2–CHH–
NH), 3.13–3.27 (m, 1H, CH2–CHH–NH), 4.09–4.27 (q, 2H,
J = 7.1 Hz, O–CH2–CH3), 4.40–4.53 (dd, 1H, J = 9.7, 3.1 Hz, Ar-CH–
NH), 7.01–7.22 (m, 4H, Ar).
0.67 mmol, 58% yield, ee P 99%, ½a D25
ꢁ
¼ þ92:0 (c 1.0 CHCl3), lit.26
½
a 2D5
ꢁ
¼ þ95 (c 1.0 CHCl3, ee 95%)]. (R)-1aꢂHCl 1H NMR (400 MHz,
D2O) d (ppm): 3.12–3.36 (overlapping multiplets, 4H, CH2–COO
and CH2–CH2–NH), 3.40–3.56 (m, 1H, CH2–CHH–NH), 3.57–3.79
(m, 1H, CH2–CHH–NH), 3.70–3.86 (br s, 3H, O–CH3), 4.94–5.12
(m, 1H, Ar-CH–NH), 7.18–7.47 (m, 4H, Ar).
Compound (S)-6 was dissolved in water, filtered, and the water
was evaporated under vacuum. After recrystallization from water,
(S)-6 was obtained as
a white crystalline powder {204 mg,
1.07 mmol, 47% yield, mp 226–228 °C, ee P 99%, ½a D25
¼ ꢀ46 (c
ꢁ
0.25 H2O)}. 1H NMR (400 MHz, D2O) d (ppm): 2.82–2.98 (m, 2H,
CH2–COO), 3.02–3.23 (m, 2H, CH2–CH2–NH), 3.35–3.49 (m, 1H,
CH2–CHH–NH) 3.53–3.68 (m, 1H, CH2–CHH–NH), 4.77–4.83 (m,
1H, Ar-CH–NH), 7.20–7.41 (m, 4H, Ar).
4.3.5. (R)-1,2,3,4-Tetrahydroisoquinoline-1-acetic acid, (R)-6
Compound (R)-1 (250 mg, 1.00 mmol) was mixed with H2O
(10 mL), and the mixture was refluxed for 4 h. The water was
evaporated off, the crystalline residue was washed with acetone,
and recrystallized from water/acetone. (R)-6 {120 mg, 0.63 mmol,
4.3.2. Kinetic resolution of ( )-2
Compound ( )-2 (1.0 g, 4.01 mmol) was dissolved in DIPE
(freshly distilled, 40 mL), followed by the addition of H2O
63% yield, mp 226–228 °C, ee P 99%, ½a D25
¼ þ46:0 (c 0.25 H2O)}
ꢁ
was obtained as colorless crystals. 1H NMR spectrum similar to
(S)-6.
(147.6 lL, 8.2 mmol) and lipase PS-D (1.0 g) as above. The reaction
was stopped by filtering off the enzyme and the DIPE insoluble (S)-
4.3.6. (R)-6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-
acetic acid, (R)-7
6 at 50% conversion after 37 h. The work-up produced (R)-2 as an or-
ange oil {486 mg, 1.95 mmol, 49% yield, ee 97%, ½a D25
¼ þ64 (c 0.2
ꢁ
CHCl3)}. 1H NMR (400 MHz, CDCl3) d (ppm): 1.78–2.09 (br s, 1H,
NH), 2.70–2.96 (overlapping multiplets, 4H, CH2–COO and CH2–
CH2–NH), 2.97-3.08 (m, 1H, CH2–CHH–NH), 3.13–3.26 (m, 1H,
CH2–CHH–NH), 3.38 (s, 3H, OCH3), 3.52–3.67 (t, 2H, J = 4.7 Hz,
CH2–CH2–OCH3), 4.20–4.35 (m, 2H, CH2–CH2–OCH3), 4.42–4.52
(dd, 1H, J = 9.8, 2.9 Hz, Ar-CH–NH), 7.01–7.18 (m, 4H, Ar).
Compound (R)-3 (200 mg, 0.72 mmol) was mixed with H2O
(10 mL), and the mixture was refluxed for 4 h. The work-up pro-
duced (R)-7 as colorless crystals {107 mg, 0.43 mmol, 60% yield,
mp 224–226 °C, ee P 99%, ½a D25
ꢁ
¼ þ51 (c 0.25 H2O)}. 1H NMR spec-
trum similar to (S)-7.
Acknowledgments
Compound (S)-6 was dissolved in water, filtered, and the water
was evaporated under vacuum. After recrystallization from water,
(S)-6 was obtained as a white crystalline powder {357.6 mg,
The Hungarian authors acknowledge the receipt of OTKA Grants
T 046440 and T 049407. T.A.P. is grateful for a fellowship awarded
by the Center for International Mobility (CIMO) in Finland.
1.87 mmol, 47% yield, mp 226–228 °C, ee P 99%, ½a D25
¼ ꢀ46 (c
ꢁ
0.25 H2O}.

2788
T. A. Paál et al. / Tetrahedron: Asymmetry 19 (2008) 2784–2788
13. Jensen, K. B.; Roberson, M.; Jørgensen, A. K. J. Org. Chem. 2000, 65, 9080–9084.
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