Continuous-flow enzymatic resolution strategy for the acylation of amino alcohols with a remote stereogenic centre: Synthesis of calycotomine enantiomers

Article abstract of DOI:10.1016/j.tetasy.2013.01.006

Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmetric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3, 4-tetrahydroisoquinolin-1-yl)methanol [(±)-3)]. The optimum conditions for the enzymatic resolution were determined under continuous-flow conditions, while the preparative-scale resolution of (±)-3 was performed as a batch reaction with high enantioselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5 (ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetrahydroisoquinoline amino alcohol homologues (±)-1 to (±)-3 containing a remote stereogenic centre.

Full text of DOI:10.1016/j.tetasy.2013.01.006

Tetrahedron: Asymmetry 24 (2013) 202–206
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Continuous-flow enzymatic resolution strategy for the acylation of amino
alcohols with a remote stereogenic centre: synthesis of calycotomine
enantiomers
⇑
⇑
}
László Schönstein, Eniko Forró , Ferenc Fülöp
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6701 Szeged, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Both enantiomers of calycotomine (R)-5 and (S)-5 were prepared through the CAL-B-catalysed asymmet-
ric O-acylation of N-Boc-protected (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)methanol [( )-3)].
The optimum conditions for the enzymatic resolution were determined under continuous-flow condi-
tions, while the preparative-scale resolution of ( )-3 was performed as a batch reaction with high enanti-
oselectivity (E >200). The resulting amino alcohol (S)-3 and amino ester (R)-4, obtained with high
enantiomeric excess (ee = 99%), were transformed into the desired calycotomine (S)-5 and (R)-5
(ee = 99%). A systematic study was carried out in a continuous-flow system on the O-acylation of tetra-
hydroisoquinoline amino alcohol homologues ( )-1 to ( )-3 containing a remote stereogenic centre.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 26 November 2012
Accepted 4 January 2013
Available online xxxx
1. Introduction
The continuous-flow technique is currently gaining popularity12
due to its many advantages, including reproducibility, safer sol-
The tetrahydroisoquinoline skeleton is a key structural unit in a
large number of naturally-occurring alkaloids.1 8,9-Dimethoxy-
1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline (crispine A)
has been isolated from the plant Carduus crispus,2 while some other
tetrahydroisoquinoline derivatives have been detected in the hu-
man brain, such as (ꢀ)-salsolinol.3 The tetrahydroisoquinoline
alkaloids are utilized as important building blocks in the synthesis
of several drugs, such as the expectorant emetin,4 the antitussive
noscapin5 and the antitumour agent trabectedin (as YondelisÒ).6
1-Methyl- and 1-phenyl-tetrahydroisoquinoline play significant
roles in the prevention of Parkinson’s disease and other neurolog-
ical diseases.7 (S)-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-
1-yl)methanol [(S)-calycotomine] is a natural alkaloid, isolated
from Calycotome spinosa8 and some other plants.9
vents, short reaction times, rapid heating and compression.13 The
continuous-flow techniques are widely applied in heterogeneous
catalysis procedures such as catalysis with metals or metals on
activated charcoal,14 peptide catalysis15 and enzyme catalysis.16
We therefore set out to perform small-scale enzymatic O-acylation
reactions using a continuous-flow technique.
Our earlier results on the enzyme-catalysed O-acylation of race-
mic N-Boc-protected 1-(3-hydroxypropyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline ( )-1 in an organic solvent, the key step
in the total synthesis of both enantiomers of crispine A,17 led us
to focus on the development of an adequate enzymatic strategy
for the preparation of both enantiomers of calycotomine, through
asymmetric O-acylation of the corresponding primary alcohol
( )-3, in a continuous-flow system.
A few syntheses of enantiopure compounds containing a tetra-
hydroisoquinoline skeleton have recently been reported. For exam-
ple, an asymmetric synthesis of (S)-calycotomine was achieved via
catalytic hydrogenation with an iridium(I)-(R)-BINAP-phthalimide
complex.10 An efficient dynamic kinetic resolution technique has
also been described for the synthesis of (R)-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, an intermediate
in the synthesis of (R)-calycotomine.11
Additionally, we planned a systematic study on the effects of
the remote stereogenic centre on the enantioselectivity and con-
version through lipase-catalysed kinetic resolutions of ( )-1, ( )-2
and ( )-3 (Scheme 1) in a continuous-flow system under the opti-
mized conditions.
2. Results and discussion
Racemic starting compounds ( )-1 to ( )-3 were prepared
according to known methods.17,18 The few literature articles deal-
ing with the possibility of the enzymatic acylation of primary alco-
hols have reported only low to moderate selectivity (E ꢁ 20) and
enantiomeric excess values.19 Our recent total synthesis of the
⇑
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).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.01.006

L. Schönstein et al. / Tetrahedron: Asymmetry 24 (2013) 202–206
203
MeO
MeO
MeO
MeO
MeO
MeO
NBoc
NBoc
OH
NBoc
OH
OH
( )-1
( )-2
( )-3
Scheme 1. Amino alcohols with a remote stereogenic centre.
Table 1
crispine A enantiomers via the lipase PS-catalysed enantioselective
acylation of a primary hydroxy group at a three-carbon-atom dis-
tance from the stereogenic centre ( )-1 resulted in relatively high
enantioselectivity (E = 68) after a long optimization phase for
O-acylation with vinyl decanoate in the presence of Et3N and
Na2SO4 in t-BuOMe at 45 °C.17 In the frame of enzymatic continu-
ous-flow reactions, the lipase-catalysed kinetic resolution of sec-
ondary alcohols through O-acylation has been reported to afford
excellent enantioselectivity (E usually >200).20
Enzyme screening for the acylation of ( )-3a
b
b
Entry
Enzyme
ees (%)
eep (%)
Conversion (%)
E
1
2
3
4
5
PPL
No reaction
rac
4
6
52
CAL-Ac
rac
50
54
99
14
7
10
35
1
3
3
Lipase AYc
Lipase PS-IM
CAL-B
>200
a
0.012 M substrate, 2 equiv vinyl acetate, 80 bar, 60 °C, 0.1 mL minꢀ1 flow, n-
hexane.
The aforementioned results led us to study the possibility of
O-acylation of the corresponding ( )-3 (Scheme 2).
b
According to HPLC.
c
Contains 20% (w/w) lipase adsorbed on Celite in the presence of sucrose.21
Preliminary enzyme screening was performed in a flow reactor
system (H-Cube), using a 70-mm-long heat- and pressure-resistant
stainless-steel CatCart, charged with different enzymes. The acyla-
tion reactions involved 2 equiv of vinyl acetate as the acyl donor in
n-hexane at 60 °C (Table 1). As recommended for the enzymatic
resolution of secondary alcohols in a continuous-flow system,16,20
Table 2
Effects of the solvent on E and the conversion in the acylation of ( )-3a
b
b
Entry
Solvent
ees (%)
eep (%)
Conversion (%)
E
80 bar and
parameters.
a
0.1 mL minꢀ1 flow were used as operational
1
2
3
t-BuOMe
n-Hexane
Toluene
15
52
99
95
99
99
14
35
50
45
>200
>200
PPL (porcine pancreatic lipase) (295 mg/CatCart) did not cata-
lyse the reaction (no product was detected) (entry 1); CAL-A (Can-
dida antarctica lipase A) (350 mg/CatCart) catalysed the reaction,
but no enantioselectivity was observed (entry 2); low selectivities
were detected with lipase AY (from Candida rugosa) (344 mg/Cat-
Cart) and lipase PS-IM (from Burkholderia cepacia) (250 mg/Cat-
Cart) (entries 3 and 4); the best enantioselectivity (E >200) was
attained in the presence of CAL-B (Candida antarctica lipase B)
(270 mg/CatCart) (entry 5). Consequently CAL-B was chosen as
the optimum enzyme for further preliminary reactions.
a
0.012 M substrate, CAL-B, 2 equiv vinyl acetate, 80 bar, 60 °C, 0.1 mL minꢀ1
flow.
b
According to HPLC.
ee
Conversion (%)
(%)
110
100
90
In order to improve the reaction rate without a decrease in
enantioselectivity, several solvents were tested (Table 2). In n-hex-
ane, E remained excellent (>200) and the conversion reached 35%
(entry 2); in t-BuOMe, E and the conversion were considerably
lower (entry 1); in toluene, the conversion was improved signifi-
cantly and no decrease in enantioselectivity (E >200) was observed
(entry 3). Thus, toluene proved to be the best of the solvents tested,
which was in good agreement with the data on the O-acylation of
N-hydroxymethylated b-lactam.22
80
70
(%)
60
50
40
30
20
Since the use of a continuous-flow system allows the possibility
of testing the effects of pressure on the conversion and E, the reac-
tions were performed at different pressures.
1
20
40
60
80
100
Pressure (bar)
As the pressure was increased in 20 bar steps from atmospheric
pressure to 100 bar, the conversion increased, reaching 50% at
approximately 60 bar (Fig. 1). At all of these pressures, E was >200.
With regard to temperature variation (Table 3), when the tem-
perature was lowered from 60 °C (entry 1) to 40 °C (entry 2) and
Figure 1. Dependence of conversion and ee on pressure.
then 25 °C (entry 3), the conversion decreased from 50% to 48%
and then 42%, respectively, but E remained >200.
MeO
MeO
MeO
+
MeO
MeO
vinyl acetate
NBoc
OH
NBoc
NBoc
OH
MeO
lipase
organic solvent
H-Cube
OCOMe
( )-3
(R)-3
(S)-4
Scheme 2. Enzymatic acylation of ( )-3.

204
L. Schönstein et al. / Tetrahedron: Asymmetry 24 (2013) 202–206
Table 3
The absolute configurations of the product enantiomers were
Effects of temperature on E and the conversion in the acylation of ( )-3a
proven by comparing the literature23 specific rotation of (S)-calyc-
otomine, ½a 2D5
¼ ꢀ13:1 (c 0.38, CHCl3), with those of the product
ꢂ
b
b
Entry
Temperature (°C)
ees (%)
eep (%)
Conversion (%)
E
(S)-5 calycotomine, ½a D25
¼ ꢀ15 (c 0.18, CHCl3), and (R)-5 calycoto-
ꢂ
1
2
3
60
40
25
99
92
71
99
99
99
50
48
42
>200
>200
>200
mine, ½a 2D5
¼ þ16 (c 0.165, CHCl3). Accordingly, the absolute con-
ꢂ
figuration of the resulting ester was (S), while that of the
unreacted alcohol was (R). Thus, CAL-B catalysed the O-acetylation
of ( )-3 with (S)-selectivity. It is noteworthy that the same stereo-
chemical demands are fulfilled around the asymmetric centres of
all the amino alcohols tested ( )-1 to ( )-3 for the O-acylation reac-
tions; only the sequence of priority of the substituents on the sub-
strates differed.
a
0.012 M substrate, CAL-B, 2 equiv vinyl acetate, toluene, 80 bar, 0.1 mL minꢀ1
flow.
b
According to HPLC.
In an attempt to increase the efficiency of the method, experi-
ments were also performed with more concentrated solutions of
substrate: 20 mg mLꢀ1 (0.06 M) and 40 mg mLꢀ1 (0.12 M), the lat-
ter being the maximum concentration attainable by dissolution of
the substrate. The conversion reached 50% even at 40 mg mLꢀ1
substrate, while E remained excellent (>200).
In order to verify that the optimum conditions obtained in the
continuous-flow system were also valid in a batch reaction, a
small-scale enzymatic reaction of ( )-3 (0.012 M) was performed
with vinyl acetate (2 equiv) in the presence of CAL-B (30 mg/mL)
in toluene (1 mL) at 60 °C, in an incubator shaker. Since the enanti-
oselectivity of the reaction proved to be excellent (E >200), further
optimization was not necessary. The gram-scale resolution of ( )-3
was therefore performed in an incubator shaker under the afore-
mentioned conditions. The reaction was stopped at 50% conversion
by filtering off the enzyme, and the products of the enzymatic res-
olution were separated by column chromatography.
A systematic study was next performed to assess the effects of
the remote stereogenic centre on E and the conversion in the cases
of ( )-1 to ( )-3 (Scheme 4).
The reactions were carried out in the continuous-flow system
under the best conditions observed in the acylation of ( )-3; in
the presence of CAL-B, with vinyl acetate as acyl donor in toluene,
at 80 bar, 60 °C and a flow rate of 0.1 mL minꢀ1 after one run
(Table 4).
At a distance of one carbon atom between the stereogenic cen-
tre and the active hydroxy group [n = 1, ( )-3], CAL-B demonstrated
excellent E and the acylation gave 50% conversion in one run (Ta-
Table 4
Enzymatic acylation of ( )-1 to ( )-3a after one run
b
b
Entry
Substrate
ees (%)
eep (%)
Conversion (%)
E
1
2
3
( )-3, n = 1
( )-2, n = 2
( )-1, n = 3
99
34
rac
99
88
rac
50
28
ꢁ64
>200
21
ꢁ1
The resulting (S)-4 (ee = 99%, yield = 43%) and (R)-3 (ee = 99%,
yield = 46%) were further transformed into the desired calycoto-
mine enantiomers (S)-5 (ee = 99%, yield = 76%) and (R)-5 calycoto-
mine (ee = 99%, yield = 73%) through a two-step reaction utilizing
18% HCl and then 5% NaOH solution (Scheme 3, Section 4).
a
0.012 M substrate, CAL-B, 2 equiv vinyl acetate, toluene, 80 bar, 0.1 mL minꢀ1
flow.
b
According to HPLC.
MeO
MeO
MeO
MeO
MeO
MeO
vinyl acetate
+
NBoc
OH
NBoc
NBoc
OH
CAL-B
toluene
incubator shaker
OCOMe
3
( )-
4
(S)-
3
(R)-
1. 18% HCl
1. 18% HCl
2. 5% NaOH
2. 5% NaOH
MeO
MeO
NH
OH
NH
MeO
MeO
OH
(S)-5-calycotomine
(R)-5-calycotomine
Scheme 3. Preparation of calycotomine enantiomers.
MeO
MeO
MeO
MeO
vinyl acetate
CAL-B
toluene
H-Cube
+
NBoc
NBoc
NBoc
MeO
MeO
n
n
n
OH
OCOMe
OH
(R)-3, n = 1
(S)-2, n = 2
(S)-1, n = 3
4,
(S)- n = 1
(R)-6, n = 2
(R)-7, n = 3
( )-3, n = 1
( )-2, n = 2
1,
( )- n = 3
Scheme 4. Enzymatic acylation of ( )-1 to ( )-3.

L. Schönstein et al. / Tetrahedron: Asymmetry 24 (2013) 202–206
205
MeO
MeO
MeO
NBoc
NBoc
MeO
(S)-4
(R)-3
ee=99%
OCOMe
ee=99% OH
E > 200
MeO
MeO
MeO
MeO
NBoc
OH
NBoc
OCOMe
(R)-6
(S)-2
ee=88%
ee=34%
E = 21
MeO
MeO
MeO
MeO
NBoc
NBoc
( )-7
( )-1
OCOMe
OH
= 1
E
Figure 2. Progress of acylations of ( )-1 to ( )-3 under the same conditions.
ble 4, entry 1). As the distance increased [n = 2, ( )-2], both the
reaction rate and E decreased considerably (entry 2). When the
separation involved three carbon atoms [n = 3, ( )-1], the reaction
was fastest, but E was virtually one (entry 3).
The acylation reactions were followed by HPLC (see Section 4);
chromatograms are presented in Figure 2.
the distance between the hydroxy group and the stereogenic centre
increased from one carbon atom ( )-3 to three carbon atoms ( )-1.
4. Experimental
4.1. Materials and methods
3. Conclusion
CAL-B (lipase B from Candida antarctica) immobilized on acrylic
resin (L47777) was purchased from Sigma, while PPL (lipase from
porcine pancreas) (L-3126, Type II) and lipase PS IM (Burkholderia
cepacia immobilized on diatomaceous earth) were from Amano En-
zyme Europe Ltd. CAL-A (lipase A from Candida antarctica) was
from Novo Nordisk and lipase AY (Candida rugosa) from Fluka. Be-
fore enzymatic reactions, lipase AY and CAL-A (5 g) were dissolved
in Tris–HCl buffer (0.02 M; pH 7.8) in the presence of sucrose (3 g),
followed by adsorption on Celite (17 g).21 The lipase preparation
thus obtained contained 20% (w/w) lipase. All solvents were of
the highest analytical grade. For column chromatography, Merck
silica gel 60 (0.063–0.200 mm) mesh was used. The preliminary
reactions in the continuous-flow technique were performed in an
H-Cube system in ‘No H2’ mode, equipped with a stainless-steel
enzyme-charged cartridge (70 mm total length, 4 mm inside diam-
eter). The cartridges were charged with enzymes under laboratory
conditions. Optical rotations were measured with a Perkin–Elmer
341 polarimeter. 1H NMR spectra were recorded on a Bruker
A new enzymatic method in a continuous-flow system was
established for the enantioselective O-acylation of the primary
hydroxy group in racemic N-Boc-protected 6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline-1-yl)methanol ( )-3. High enanti-
oselectivity (E >200) was observed when the preparative-scale
batch reaction was performed with CAL-B as the enzyme, and
2 equiv of vinyl acetate as acyl donor in toluene at 60 °C. The
resulting enantiomers, ester (S)-4 and unreacted alcohol (R)-3
(ee = 99%), were further transformed into the desired calycotomine
enantiomers, (S)-5 and (R)-5, with high ee (=99%) and good chem-
ical yields (P73%).
Additionally, a systematic study in the continuous-flow system
was performed on the O-acylation of amino alcohols ( )-1 to ( )-3
with a remote stereogenic centre. Under the optimized conditions
(0.012 M amino alcohol, CAL-B, toluene, 2 equiv vinyl acetate,
80 bar, 60 °C, 0.1 mL minꢀ1 flow), E decreased from 200 to 1 when

206
L. Schönstein et al. / Tetrahedron: Asymmetry 24 (2013) 202–206
Avance DRX 400 spectrometer. Melting points were determined on
a Kofler apparatus.
dried on Na2SO4, filtered and evaporated. Both enantiomers were
obtained as white crystalline products: (S)-5 calycotomine
(23 mg, 76%), mp 139–140 °C, Ref. 24 mp 138 °C ½a D25
¼ ꢀ15 (c
ꢂ
4.2. Small-scale enzymatic reactions
0.18, CHCl3), Ref. 23 ½a D25
¼ ꢀ13:1 (c 0.38, CHCl3) ee = 99% [(deter-
ꢂ
mined after derivatization with Boc2O in the presence of DMAP/Py
The preliminary small-scale experiments were carried out in a
continuous-flow system. The racemic N-Boc-protected amino alco-
hol ( )-3 (0.012 M, 3.9 mg mLꢀ1) and vinyl acetate (0.024 M,
2.06 mg mLꢀ1) were dissolved in toluene (1 mL), and the solution
was then pumped through the heated and compressed enzyme-
charged cartridge at a flow rate of 0.1 mL minꢀ1. In order to follow
the progress of the reactions and to determine the ee values of the
products, HPLC with a chiral column was used. The ee values for
the unreacted amino alcohols (R)-3, (S)-2 and ( )-1 and the product
amino esters (R)-6 and ( )-7 were determined on a Chiralpak IA
column (4.6 ꢃ 250 mm); eluent: n-hexane/iPA (85:15); flow rate:
0.5 mL minꢀ1; detection at 260 nm; retention time (min) for (R)-
3: 25.9, for (S)-3: 18.7, for (R)-6: 16.8, for (S)-6: 18.4, for (S)-2:
35.1, for (R)-2: 24.1, for ( )-7: 15.2 and 20.8, and for ( )-1: 24.1
and 40.6. The ee value for the amino ester (S)-4 was determined
on a Chiralcel OD-H column (4.6 ꢃ 250 mm); eluent: n-hexane/
iPA (95:5); flow rate: 0.5 mL minꢀ1; detection at 260 nm; retention
time (min) for (R)-4: 30.1, and for (S)-4: 25.2.
(1:9)]; (R)-5 calycotomine (25 mg, 73%), mp 140–141 °C,
½
a 2D5
ꢂ
¼ þ16 (c 0.165, CHCl3), ee = 99%. 1H NMR (400 MHz, CDCl3)
data for (S)-5 were identical to those of (R)-5: d = 1.81–2.18 (br s,
2H, OH, NH), 2.68–2.73 (m, 2H, CH2–CH2–NH), 3.07–3.11 (m, 2H,
CH2–CH2–NH), 3.62–3.67 (m, 1H, CH–CH2–OH), 3.76–3.80 (dd,
J = 4.3 Hz, J = 4.3 Hz, 1H, CH–CHH–OH), 3.87 (s, 6H, 2 ꢃ CH3O–Ar),
3.98–4.00 (dd, J = 4.4 Hz, J = 4.2 Hz, 1H, CH–CHH–OH), 6.61 (s, 1H,
Ar), 6.62 (s, 1H, Ar) ppm. 13C NMR (400 MHz, CDCl3) data for (S)-
5 were identical to those of (R)-5: d = 29.5, 39.2, 56.2, 56.4, 64.5,
64.6, 109.6, 112.5, 127.6, 128.1, 147.9, 148.1 ppm. C12H17NO3
(223.27): Calcd C, 64.55; H, 7.67; N, 6.27. Found: C, 64.41; H,
7.52; N, 6.21.
Acknowledgments
We are grateful to the Hungarian Research Foundation (T
049407). Thanks are also due to TÁMOP-4.2.2/A-11/1/KONV-
2012-0052 for financial support.
4.3. Gram-scale resolution of ( )-3
References
1. (a) Herbert, R. B. In The Chemistry and Biology of Isoquinoline Alkaloids; Philips, J.
D., Roberts, M. F., Zenk, M. H., Eds.; Springer Verlag: Berlin, Heidelberg, New
York, Tokyo, 1985; p 231; (b) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev.
2004, 104, 3341–3370; (c) Miyazaki, M.; Ando, N.; Sugai, K.; Seito, Y.; Fukuoka,
H.; Kanemitsu, T.; Nagata, K.; Odanaka, Y.; Nakamura, K. T.; Itoh, T. J. Org. Chem.
2011, 76, 534–542.
2. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798.
3. Tóth, B. E.; Bodnár, I.; Homicskó, K. G.; Fülöp, F.; Fekete, M. I. K.; Nagy, G. M.
Neurotoxicol. Teratol. 2002, 24, 655–666.
Compound ( )-3 (500 mg, 1.55 mmol) was dissolved in toluene
(40 mL). CAL-B (1 g) and vinyl acetate (266.88 mg, 3.1 mmol) were
added and the mixture was shaken in an incubator shaker at 60 °C
for 1 h. The reaction was stopped at 50% conversion (eep = 99% and
ees = 99%) by filtering off the enzyme, and the solvent was evapo-
rated off. The products were separated by column chromatography
on silica, with elution with n-hexane/EtOAc (5:1), affording ester
4. Boyd, E. M.; Knight, L. M. J. Pharm. Pharmacol. 1964, 16, 118–124.
5. Al-Yahya, M. A.; Hassan, M. M. A. Anal. Profiles Drug Subst. 1982, 11, 407–461.
6. (a) Ortín, I.; González, J. F.; Cuesta, E.; Manguan-García, C.; Perona, R.;
(S)-4 {241 mg, 43%; ½a D25
¼ ꢀ103 (c 0.24, CHCl3) as a white crystal-
ꢂ
line product; mp 72–74 °C, ee = 99%} and amino alcohol (R)-3
{230 mg, 46%, ½a 2D5
¼ þ82 (c 0.255, CHCl3) as a light-yellow oil;
ꢂ
´
Avendano, C. Bioorg. Med. Chem. 2008, 16, 9065–9078; (b) Cuevas, C.;
Francesch, A. Nat. Prod. Rep. 2009, 26, 322–337; (c) Schwartsmann, G.;
Schwartsmann, G.; Brondani da Rocha, A.; Mattei, J.; Lopes, R. Expert Opin.
Investig. Drugs 2003, 12, 1367–1383.
ee = 99%}. 1H NMR (400 MHz, CDCl3) for (S)-4: d = 1.51 [s, 9H,
C(CH3)3], 2.04–2.15 (m, 3H, OCOCH3), 2.63–2.73 (m, 1H, Ar–CHH),
2.78–2.97 (m, 1H, Ar–CHH), 3.17–3.40 (m, 1H, CH2–CHH–NBoc),
3.88 (s, 6H, 2 ꢃ CH3O–Ar), 3.99–4.42 (m, 3H, CH2–OCOCH3, CH2–
CHH–NBoc), 5.21–5.46 (br s, 1H, CH–CH2–OCOCH3), 6.64 (s, 1H,
Ar), 6.72 (s, 1H, Ar) ppm. 13C NMR (400 MHz, CDCl3) for (S)-4:
d = 20.3, 27.5, 27.8, 38.0, 55.2, 55.4, 64.7, 79.2, 109.7, 111.1,
124.1, 126.7, 147.0, 147.7, 154.1, 169.9 ppm. C19H27NO6 (365.42):
Calcd C, 62.45; H, 7.45; N, 3.83. Found: C, 62.29; H, 7.41; N, 3.69.
1H NMR (400 MHz, CDCl3) for (R)-3: d = 1.53 [s, 9H, C(CH3)3],
2.67–2.75 (m, 1H, Ar–CHH), 2.80–2.91 (m, 1H, Ar–CHH), 3.31–
3.47 (br s, 1H, CH2–CHH–NBoc), 3.78–3.91 (m, 2H, CH2–OH over-
lapping with s, 6H, 2 ꢃ CH3O-Ar), 3.95–4.09 (m, 1H, CHH–NBoc),
5.10–5.27 (br s, 1H, CH–CH2–OH), 6.65 (s, 1H, Ar), 6.71 (s, 1H, Ar)
ppm. 13C NMR (400 MHz, CDCl3) for (R)-3: d = 28.5, 28.8, 40.0,
56.3, 56.4, 56.7, 62.0, 80.8, 110.7, 111.9, 125.8, 127.6, 148.0,
148.5, 154.0 ppm. C17H25NO5 (323.38): Calcd C, 63.14; H, 7.79; N,
4.33. Found: C, 63.26; H, 7.84; N, 4.21.
7. Taniyama, D.; Hasegawa, M.; Tomioka, T. Tetrahedron: Asymmetry 1999, 10,
221–223.
8. White, E. P. N.Z. J. Sci. Technol. 1944, 25B, 137–162.
9. Loy, G.; Cottiglia, F.; Garau, D.; Deidda, D.; Pompei, R.; Bonsignore, L. II Farmaco
2001, 56, 433–436.
10. Morimoto, T.; Suzuki, N.; Achiwa, K. Tetrahedron: Asymmetry 1998, 9, 183–187.
11. Paál, T. A.; Liljeblad, A.; Kanerva, L. T.; Forró, E.; Fülöp, F. Eur. J. Org. Chem. 2008,
5269–5276.
12. Wegner, J.; Ceylan, S.; Kirschning, A. Chem. Commun. 2011, 47, 4583–4592.
13. Wiles, C.; Watts, P. Green Chem. 2012, 14, 38–54.
14. Falus, P.; Boros, Z.; Hornyánszky, G.; Nagy, J.; Darvas, F.; Ürge, L.; Poppe, L.
Tetrahedron Lett. 2011, 52, 1310–1312.
15. Ötvös, S. B.; Mándity, I. M.; Fülöp, F. ChemSusChem 2012, 5, 266–269.
16. Tomin, A.; Hornyánszky, G.; Kupai, K.; Dorkó, Zs.; Ürge, L.; Darvas, F.; Poppe, L.
Process Biochem. 2010, 45, 859–865.
17. Forró, E.; Schönstein, L.; Fülöp, F. Tetrahedron: Asymmetry 2011, 22, 1255–1260.
18. (a) Lázár, L.; Fülöp, F.; Bernáth, G.; Mattinen, J. Org. Prep. Proc. Int. 1993, 25, 91–
97; (b) Fülöp, F.; Forró, E.; Martinek, T.; Günther, G.; Sillanpää, R. J. Mol. Struct.
2000, 554, 119–125; (c) Kóbor, J.; Fülöp, F.; Bernáth, G. Heterocycles 1986, 24,
2227–2231; (d) Zalán, Z.; Martinek, T. A.; Lázár, L.; Sillanpää, R.; Fülöp, F.
Tetrahedron 2006, 62, 2883–2891.
19. Sabbani, S.; Hedenström, E.; Andersson, J. Tetrahedron: Asymmetry 2007, 18,
1712–1720.
20. Csajági, C.; Szatzker, G.; Toke, E. R.; Ürge, L.; Darvas, F.; Poppe, L. Tetrahedron:
4.4. Preparation of (S)- and (R)-(6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinolin-1-yl)methanol (S)-5 and (R)-5
}
Asymmetry 2008, 19, 237–246.
21. Kanerva, L. T.; Sundholm, O. J. Chem. Soc., Perkin Trans. 1 1993, 2407–2410.
22. Li, X.-G.; Kanerva, L. T. Adv. Synth. Catal. 2006, 348, 197–205.
23. Pedrosa, R.; Andrés, C.; Iglesias, J. M. J. Org. Chem. 2001, 66, 243–250.
24. Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett 2006, 1595–1597.
At first, (S)-4 (50 mg, 0.137 mmol) or (R)-3 (50 mg, 0.155 mmol)
was refluxed for 5 h in 18% HCl (10 mL). The solvent was then
evaporated off, and 5% NaOH was added until pH = 10. The residue
was extracted with CH2Cl2 (3 ꢃ 30 mL). The organic layer was