Efficient dynamic kinetic resolution method for the synthesis of enantiopure 6-hydroxy- and 6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid

Article abstract of DOI:10.1016/j.tetasy.2016.10.011

Enantiomeric 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (ee >99%), useful in the synthesis of modulators of nuclear receptors, including liver X receptor and its analogue 6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (ee >99%), a source of the above enantiomer was synthesized through Candida antarctica lipase B-catalysed dynamic kinetic hydrolysis of the corresponding 1,2,3,4-tetrahydroisoquinoline-1-carboxylic esters (±)-4·HCl and (±)-5. (R)-Selective hydrolysis in both organic solvents and an aqueous NH₄OAc buffer at pH 8.5 was observed and the amino acids were obtained in good chemical yields (>87%).

Full text of DOI:10.1016/j.tetasy.2016.10.011

Tetrahedron: Asymmetry 27 (2016) 1213–1216
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Efficient dynamic kinetic resolution method for the synthesis of
enantiopure 6-hydroxy- and 6-methoxy-1,2,3,4-
tetrahydroisoquinoline-1-carboxylic acid
⇑
⇑
}
Eniko Forró , Rita Megyesi, Tihamér A. Paál, Ferenc Fülöp
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, Eötvös u 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomeric 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (ee >99%), useful in the syn-
thesis of modulators of nuclear receptors, including liver X receptor and its analogue 6-methoxy-
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (ee >99%), a source of the above enantiomer was synthe-
sized through Candida antarctica lipase B-catalysed dynamic kinetic hydrolysis of the corresponding
1,2,3,4-tetrahydroisoquinoline-1-carboxylic esters ( )-4ÁHCl and ( )-5. (R)-Selective hydrolysis in both
organic solvents and an aqueous NH4OAc buffer at pH 8.5 was observed and the amino acids were
obtained in good chemical yields (>87%).
Received 8 September 2016
Revised 21 October 2016
Accepted 21 October 2016
Available online 4 November 2016
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
tetrahydroisoquinoline-1-carboxylic esters,9 and the Seaprose
S-catalysed hydrolysis of methyl ( )-N-tert-Boc-6-hydroxy-3,4-
Isoquinolines are an important class of compounds from both
biological1 and chemical2 aspects. Some of them, for example
1-tetrahydroisoquinoline carboxylic acid can be used in the
synthesis of promising matrix metalloproteinase inhibitors,3
while 6,7-dimethoxy-1-tetrahydroisoquinoline carboxylic acid
has been successfully applied in the synthesis of b-site amyloid
precursor protein-cleaving enzyme inhibitors, which are useful
for Alzheimer’s disease.4 Significant antitumor activity was
reported for 8-methoxy-4,5-dihydropirrolo[2,1-a]isoquinolines
with 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid
as a key intermediate in its synthesis.5 (R)-2-tert-Butyl-1-methyl-
6-(3-chloro-2,6-difluorobenzyloxy)-3,4-dihydroisoquinoline-1,2
(1H)-dicarboxylate, prepared from (R)-2-tert-butyl-1-methyl-6-
hydroxy-3,4-dihydroisoquinoline-1,2(1H)-dicarboxylate, is useful
as a modulator of nuclear receptors, including liver X receptor.6
Only a few enzymatic methods have been developed for the
synthesis of valuable enantiopure isoquinolines,7–10 such as
chemoenzymatic kinetic resolution for the preparation of Crispine
A,7a calicotomine7b and homocalicotomine7c enantiomers, the
kinetic resolution for the preparation of enantiomeric
1-tetrahydroisoquinoline carboxylic acid,8 the directed (R)- or
(S)-selective dynamic kinetic enzymatic hydrolysis of 1,2,3,4-
dihydro-1H-isoquinoline-1-carboxylate.10
Over last few years, a large number of dynamic kinetic resolu-
tion methods for the preparation of enantiomeric compounds,
important in terms of both biological and chemical aspects have
been published and most of them reviewed.11
Herein our aim was to develop a dynamic kinetic resolution
strategy for the synthesis of enantiopure 6-hydroxy-1,2,3,4-
tetrahydroisoquinoline-1-carboxylic acid, with the appropriate
(1R)-absolute configuration, essential for the biological activity of
the above-mentioned (R)-2-tert-butyl-1-methyl-6-(3-chloro-2,
6-difluorobenzyloxy)-3,4-dihydroisoquinoline-1,2(1H)-dicarboxy-
late. Our earlier extensive investigations of the CAL-B-catalysed
dynamic kinetic resolution of 1-tetrahydroisoquinoline car-
boxylic acid8 and 6,7-dimethoxy-1-tetrahydroisoquinoline car-
boxylic acid9 prompted us to explore the possibility of the
dynamic kinetic hydrolysis of ( )-4 and ( )-5 catalyzed by CAL-B.
2. Results and discussion
Racemic 6-methoxy-1-tetrahydroisoquinoline carboxylic acid
ethyl ester ( )-4 was synthesized via Bischler–Napieralski cyclisa-
tion of 3-methoxyphenethylamine hemioxalamide ethyl ester 2
(formed by heating 3-methoxyphenethylamine 1 and diethyl oxa-
late at reflux) and subsequent hydrogenation of compound 3
(Scheme 1).12 Demethylation13 of ( )-4 followed by esterification
furnished ( )-5.
⇑
Corresponding authors. Tel.: +36 62 54 5564; fax: +36 62 54 5705.
E-mail addresses: forro.eniko@pharm.u-szeged.hu (E. Forró), fulop@pharm.
u-szeged.hu (F. Fülöp).
http://dx.doi.org/10.1016/j.tetasy.2016.10.011
0957-4166/Ó 2016 Elsevier Ltd. All rights reserved.

1214
E. Forró et al. / Tetrahedron: Asymmetry 27 (2016) 1213–1216
COOEt
MeO
MeO
MeO
MeO
HO
H2
POCl3
COOEt
1. HBr
N
NH
NH2
HN
O
NH
Δ
Δ
Pt/C
2. EtOH/SOCl2
COOEt
COOEt
COOEt
COOEt
( )-4
( )-5
1
2
3
Scheme 1. Synthesis of ( )-4 and ( )-5.
The resolution of ( )-5 (Scheme 2) was first attempted in the
presence of CAL-B (20 mg mLÀ1) with H2O (1 equiv) in toluene/
MeCN (4:1) at 25 °C (Table 1, entry 1).
were observed, when using either CAL-B or
the enzyme (Table 2, entries 1 and 6).
a-chymotrypsine as
In order to improve the eep, the reaction was carried out at 3 °C
(Table 2, entry 2) without much success (the eep did not change,
the reaction became slower). An increase in reaction temperature
to 45 °C resulted in a significant increase in reaction rate with
the concomitant drop of the ee value (entry 3). A slight increase
in the reaction rate was observed when using an increased amount
of enzyme (Table 2, entries 4 and 5 vs entry 1).
HO
HO
HO
enzyme
H2O
NH
NH
NH
COOH
COOEt
COOEt
As an alternative strategy to prepare (R)-6 (Scheme 3), ( )-4 was
subjected to enzymatic resolution. When the CAL-B-catalysed
hydrolysis of ( )-4 was performed under the above optimized con-
ditions for ( )-5 [2 equiv of H2O, 0.25 equiv of Pr2NH, iPr2O/MeCN
(3:2), 25 °C], only traces of enantiomeric 7 were formed (ee of 91%,
conversion of 35%, 2 days).
Hydrolysis of ( )-4 in aqueous NH4OAc buffer at pH 8.5, at 25 °C
gave amino acid 7 (only traces) with an ee of 66% (90% conversion,
2 days). The major part of the starting amino ester underwent
degradation (Table 2, entry 7).
In order to overcome the above-mentioned degradation, ( )-
4ÁHCl rather than ( )-4 was subjected to CAL-B-catalysed hydroly-
sis (Table 2, entry 8). Compound (R)-7 was obtained as the sole
product with an excellent ee value of >99%. This may be due to
the relatively slow in situ liberation of basic amino ester from its
( )-5
Scheme 2. Enzymatic dynamic kinetic resolution of ( )-5.
(R)-6
In an attempt to increase the reaction rate, preliminary experi-
ments were performed with higher amounts of added H2O (Table 1,
entries 2 and 3). As the amount of H2O was increased, only slightly
faster reactions were observed, without a drop in eep (entries 2 and
3 vs entry 1).
Increasing the proportion of MeCN in the reaction medium, led
to only slight differences in the reaction rates (entries 1 and 4–6).
Next, iPr2O/MeCN was used instead of toluene/MeCN (3:2) afford-
ing a marginally faster reaction (entry 7 vs 5). Nevertheless,
because of toxicity reasons, iPr2O/MeCN (3:2) was selected for fur-
ther reactions.
hydrochloric salt followed by
hydrolysis.
a relatively fast enzymatic
When the CAL-B-catalysed hydrolysis of ( )-5 was performed
with 2 equiv of H2O together with Pr2NH (0.25 equiv) as a basic
additive (base-catalysed racemisation of the unreacted amino ester
enantiomer), a considerable enhancement in the reaction rate was
observed (entry 8 vs entry 7) in accordance with our earlier
observation.9
Hoping to further enhance the reaction rate and, at the same
time, preserve the (R)-selectivity, the hydrolysis of ( )-5 was per-
formed in an aqueous NH4OAc buffer at pH 8.5, at 25 °C. Much fas-
ter (R)-selective reactions, but lower ee values for the amino acid
The preparative-scale dynamic kinetic resolution of ( )-4ÁHCl14
and ( )-515 was performed under the optimised conditions (foot-
notes of Table 3), and the results are summarized in Table 3.
Demethylation of (R)-7 with 48% aqueous HBr16 resulted in the
desired (R)-6ÁHBr with a significant decrease in ee (80%).
The analysed chromatograms indicated that the corresponding
enantiomers of both compounds ( )-4 and ( )-5 reacted preferen-
tially on CAL-B catalysis similar to ethyl 1,2,3,4-tetrahydroiso-
Table 1
Conversion and enantiomeric excess values (ee) of the hydrolysis of ( )-5 in organic solventsa
b
c
Entry
1
Solvent mixtures (V:V)
H2O (equiv)
1
Reaction time (day)
Conversion (%)
eeS (%)
eeP (%)
Toluene:MeCN (4:1)
2
7
2
7
2
7
2
7
2
7
2
7
2
7
2
22
35
20
37
30
37
16
32
16
38
20
33
14
32
87
15
27
15
27
19
29
9
19
9
17
6
>99
>99
>99
>99
>99
>99
>99
>99
2
3
4
5
6
7
8
Toluene:MeCN (4:1)
Toluene:MeCN (4:1)
Toluene:MeCN (7:3)
Toluene:MeCN (3:2)
Toluene:MeCN (1:1)
iPr2O:MeCN (3:2)
2
4
1
1
1
1
2
14
10
20
nd
iPr2O:MeCN (3:2)
Pr2NH (0.25 equiv)
a
20 mg mLÀ1 CAL-B, at 25 °C.
b
According to HPLC on a Chiralpak IA chiral column, (a 3,5-dimethylphenylcarbamate derivative of amylose, immobilized onto silica), eluent n-Hex/EtOH (80:20), Et2NH
(0.1%), flow: 1 mL minÀ1, 25 °C, 232 nm {retention times [min], (R)-5: 7.62 and (S)-5: 23.09.
c
According to HPLC by using a Chiralpak IA column (for N-Boc-protected derivative), eluent: n-Hex/iPA (90:10), TFA (0.1%), flow: 0.5 mL minÀ1, 25 °C, 232 nm {retention
times [min], (R)-6: 25.52 and (S)-6: 28.26}.

E. Forró et al. / Tetrahedron: Asymmetry 27 (2016) 1213–1216
1215
Table 2
Conversion and enantiomeric excess values (ee) of the hydrolysis in aqueous NH4OAc buffer at pH 8.5
Entry
1a
Substrate
Enzyme (mg mLÀ1
CAL-B (30)
)
Temperature (°C)
Time (h)
eeS (%)
eeP (%)
( )-5
25
3
8b
—
80c
81c
—
24 (conv. >99%)
2a
3a
4a
5a
6a
( )-5
( )-5
( )-5
( )-5
( )-5
CAL-B (30)
CAL-B (30)
CAL-B (50)
CAL-B (90)
3
45
25
25
25
3
168 (conv. >99%)
3
24 (conv. >99%)
3
18 (conv. >99%)
3
14 (conv. >99%)
3
24b
—
81c
—
5b
—
67c
76c
82c
78c
81c
—
14b
—
19b
—
a-Chymotrypsine (10)
—
50 (conv. >99%)
48 (conv. = 90%)
3 (conv. = 89%)
—
84c
66e,f
>99%e
7a
8g
( )-4
( )-4ÁHCl
CAL-B (30)
CAL-B (30)
25
25
27d
5d
a
b
c
Racemic amino ester in aqueous NH4OAc buffer at pH 8.5.
According to HPLC (footnote of Table 1).
According to HPLC (footnote of Table 1).
d
According to HPLC on a Chiralpak IA chiral column, eluent: n-Hex/iPA (90:10), DEA (0.1%), flow: 0.5 mL minÀ1, 25 °C, 232 nm {retention times [min], (R)-4: 26.6 and (S)-4:
28.17}.
e
According to HPLC by using a Chiralpak IA column (for N-Boc-protected derivative), eluent: n-Hex/iPA (90:10), TFA (0,1%), flow: 0.5 mL minÀ1, 25 °C, 232 nm {retention
times [min], (R)-7: 19.37 and (S)-7: 21.29}.
f
Only trace amounts of amino acid.
( )-4ÁHCl in aqueous NH4OAc buffer at pH 8.5.
g
MeO
HO
MeO
MeO
48% HBr
130 °C
CAL-B
H2O
NH.HBr
NH
NH
NH
COOH
COOH
(R)-6.HBr
COOEt
COOEt
( )-4
(R)-7
ee > 99%, yield = 91% after optimisation14
Scheme 3. Preparation of (R)-6ÁHBr through enzymatic dynamic kinetic resolution of ( )-4.
Table 3
Preparative-scale hydrolysis of ( )-4ÁHCla and ( )-5b
Substrate
Time (h)
Product amino acid
25
Yield (%)
Isomer
ee (%)
[
a
]
H2O
D
( )-4ÁHCl
( )-5
3
48
91
87
(R)-7
(R)-6
>99c
>99d
À58 (c 0.2)
À51 (c 0.3)
a
b
c
100 mg (0.37 mmol) substrate, 25 mL aqueous NH4OAc buffer at pH 8.5 (NH4OH), 750 mg CAL-B (30 mg mLÀ1), 25 °C.
200 mg (0.9 mmol) substrate, 2 equiv of H2O, 0.25 equiv Pr2NH, 25 mL iPr2O/MeCN (3:2), 25 °C, 600 mg CAL-B (20 mg mLÀ1), 25 °C.
According to HPLC (footnote of Table 1).
d
According to HPLC (footnote of Table 2).
quinoline carboxylate8 and ethyl 6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline carboxylate.9 Thus the enantiomer hydrolysing
with higher reactivity has the (R)-absolute configuration; conse-
quently, the (S)-configuration was assigned to the racemizing
enantiomer (S)-4 and (S)-5.
Acknowledgement
The authors acknowledge the receipt of OTKA Grants K-108943
and K115731 for financial support.
References and notes
3. Conclusion
1. (a) Li, J. J.; Tino, J. A. PCT Int. Appl. WO 2001085695, 2001.; (b) Scott, J. D.;
Williams, R. M. Chem. Rev. 2002, 102, 1669–1730; (c) Kesteren, C.; Vooght, M.
M.; Lopez-Lazaro, L.; Mathot, R. A. A.; Schellens, J. H. M.; Jimeno, J. M.; Beijnen,
J. H. Anti-Cancer Drugs 2003, 14, 487–502; (d) Carter, N. J.; Keam, S. J. Drugs
2007, 67, 2257–2276.
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Chem. 2008, 43, 2211–2219.
3. Hofmeister, A.; Schudok, M.; Matter, H.; Breitschopf, K.; Ugolini, A. PCT Int.
Appl. WO 2006002763, 2006.
4. Mjalli, A.; Jones, D.; Gohimmukkula, D. R. PCT Int. Appl. WO 2006099379, 2006.
5. Anderson, W. K.; McPherson, H. L., Jr.; New, J. S.; Rick, A. C. J. Med. Chem. 1984,
27, 1321–1325.
In conclusion, an efficient dynamic kinetic resolution technique
was carried out for the preparation of (1R)-6-hydroxy- and (1R)-6-
methoxy-subsituted 1,2,3,4-tetrahydroisoquinoline-1-carboxylic
acids (ee >99%, chemical yields >87%), which are useful in the
synthesis of modulators of nuclear receptors. The (R)-selective
hydrolysis of the corresponding 1,2,3,4-tetrahydroisoquinoline-1-
carboxylates took place with Candida antarctica lipase B as the
catalyst and the reactions were performed in either organic sol-
vents or aqueous NH4OAc buffer at pH 8.5. It is important to note
that the present dynamic kinetic resolution using the hydrochloric
salt as starting racemate might provide an extra possibility for the
resolution of such racemates, which are stable only as salts.
6. Yang, W.; Wang, Y.; Kick, E. K.; PCT Int. Appl. WO 2007047991, 2007.
7. (a) Forró, E.; Schönstein, L.; Fülöp, F. Tetrahedron: Asymmetry 2011, 22, 1255–
1260; (b) Schönstein, L.; Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2013, 24,
1059–1062; (c) Schönstein, L.; Forró, E.; Fülöp, F. Tetrahedron: Asymmetry 2013,
24, 202–206.

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8. Paál, T. A.; Forró, E.; Liljeblad, A.; Kanerva, L. T.; Fülöp, F. Tetrahedron:
Asymmetry 2007, 18, 1428–1433.
9. Paál, T. A.; Liljeblad, A.; Kanerva, L. T.; Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008,
5269–5276.
CH3), 4.94 (s, 1H, H-1), 6.82–7.55 (m, 3H, Ph) ppm. Elemental analysis for
C11H13NO3 (207.09): calcd. C 63.76, H 6.32, N 6.76; found C 63.74, H 6.20, N
6.79.
15. (R)-Selective preparative-scale dynamic kinetic resolution of ( )-5: Compound
10. Gill, I. S.; Kick, E.; Richlin-Zack, K.; Yang, W.; Wang, Y.; Patel, R. N. Tetrahedron:
Asymmetry 2007, 18, 2147–2154.
( )-5 (200 mg, 0.9 mmol), dipropylamine (30.84
l
L, 0.23 mmol), water
(32.46
l
L, 1.8 mmol) and CAL-B (600 mg, 20 mg mLÀ1
)
were added to
a
11. (a) Kamal, A.; Azhar, M. A.; Krishnaji, T.; Malik, M. S.; Azeeza, S. Coord. Chem.
Rev. 2008, 252, 569–592; (b) Kamaruddin, A. H.; Uzir, M. H.; Aboul-Enein, H. Y.;
Halim, H. N. A. Chirality 2009, 21, 449–467; (c) Pellissier, H. Tetrahedron 2011,
67, 3769–3802; (d) Pellissier, H. Tetrahedron 2016, 72, 3133–3150.
12. Zalán, Z.; Martinek, T. A.; Sillanpää, R.; Fülöp, F. Tetrahedron 2006, 62, 2883–
2891.
mixture of iPr2O:MeCN (3:2) (30 mL). The mixture was shaken at 25 °C for
2 days, then the enzyme was filtered off at a conversion of 87%. A wash with
iPr2O and then with H2O, followed by evaporation of the aqueous phase
resulted in amino acid (R)-6 as a yellowish oil (151 mg, 87% yield), [
a
]
25 = À51
D
(c 0.3, H2O), ee >99%. 1H NMR for (R)-6ÁHBr (400 MHz, D2O): d = 3.04–3.20 (t,
J = 6.5 Hz, 2H, H-4), 3.51–3.76 (m, 2H, H-3), 5.20 (s, 1H, H-1), 6.82–7.00 (m, 2H,
Ph) 7.47–7.57 (d, J = 8.4 Hz, 1H, Ph) ppm. Elemental analysis for C10H12BrNO3
(274.11): calcd. C 43.82, H 4.41, N 5.11; found C 43.66, H 4.33, N 5.00.
13. Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J. Org. Chem. 1980, 45, 4275–4277.
14. (R)-Selective preparative-scale dynamic kinetic resolution of ( )-4ÁHCl:
Compound ( )-4ÁHCl (100 mg, 0.37 mmol) was dissolved in an aqueous
16. Demethylation of (R)-7: Compound (R)-7 (20 mg, 0.09 mmol, ee = 98%) was
dissolved in 48% HBr (5 ml) and kept at reflux temperature for 4 h. The solvent
was then evaporated and the product was recrystallized from EtOH and Et2O to
afford beige crystals of (R)-6ÁHBr (18 mg, 58% yield), M.p. 257-258 °C,
solution of NH4OAc (0.1 M, 25 mL), after which CAL-B (750 mg, 30 mg mLÀ1
)
was added. The pH was set to 8.5 (with 25% aqueous NH4OH at the start of the
reaction). The mixture was shaken at 25 °C for 3 h to attain a conversion of
>99%. The enzyme was filtered off and washed with warm H2O. The solvent
and NH4OAc were evaporated under vacuum, and after a wash of the residue
with Me2CO (R)-7 was isolated (69 mg, 91% yield). M.p. 247–250 °C,
[
a
]
25 = À47 (c 0.1, H2O), ee = 80%.
D
The 1H NMR (400 MHz, D2O) data were similar to those given in the
literature.14 Elemental analysis calcd. for C10H12BrNO3: C 43.82, H 4.41, N
5.11; found C 43.78, H 4.60, N 5.11.
(recrystallised from H2O/Me2CO), [
(400 MHz, D2O): d = 3.09–3.12 (m, 2H, H-4), 3.39–3.70 (m, 2H, H-3), 3.86 (s, 3H,
a
]
25 = À58 (c 0.2, H2O), ee > 99%. 1H NMR
D