A new chemoenzymatic approach to the synthesis of chiral 4-aryl-1,4-dihydro-2H-isoquinolines via the enzymatic resolution of 2-acetyl-4-phenyl-1,4-dihydro-2H-isoquinolin-3-one

Article abstract of DOI:10.1016/j.tetasy.2012.07.013

A new chemoenzymatic method is proposed for the synthesis of enantiomerically pure 4-phenyl-1,4-dihydro-2H-isoquinolines based on the enzymatic kinetic resolution of 2-acetyl-4-phenyl-1,4-dihydro-2H-isoquinolin-3- one. For the enzymatic resolution of the racemic substrate, readily available 'home made' animal liver acetone powders (LAPs) were used. Excellent enantioselectivity, exceeding 500, was achieved in a short reaction time upon application of turkey liver acetone powder as the biocatalyst. Reduction of obtained product led to the formation of amine (R)-1, which is hardly available using standard procedures. These results show that N-acetyl lactams are a new type of substrate for enzymatic biotransformations.

Full text of DOI:10.1016/j.tetasy.2012.07.013

Tetrahedron: Asymmetry 23 (2012) 1256–1261
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Tetrahedron: Asymmetry
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A new chemoenzymatic approach to the synthesis of chiral
4-aryl-1,4-dihydro-2H-isoquinolines via the enzymatic resolution of
2-acetyl-4-phenyl-1,4-dihydro-2H-isoquinolin-3-one
Dominik Koszelewski a, Malgorzata Cwiklak a, Ryszard Ostaszewski a,b,
⇑
a Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
b Industrial Chemistry Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A new chemoenzymatic method is proposed for the synthesis of enantiomerically pure 4-phenyl-1,4-
dihydro-2H-isoquinolines based on the enzymatic kinetic resolution of 2-acetyl-4-phenyl-1,4-dihydro-
2H-isoquinolin-3-one. For the enzymatic resolution of the racemic substrate, readily available ‘home
made’ animal liver acetone powders (LAPs) were used. Excellent enantioselectivity, exceeding 500, was
achieved in a short reaction time upon application of turkey liver acetone powder as the biocatalyst.
Reduction of obtained product led to the formation of amine (R)-1, which is hardly available using stan-
dard procedures. These results show that N-acetyl lactams are a new type of substrate for enzymatic
biotransformations.
Received 28 June 2012
Accepted 27 July 2012
Available online 17 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The reported syntheses of target compound 1 are based on the
reductive amination of substituted benzaldehydes with respective
A large number of bioactive molecules possessing a chiral tetra-
hydroisoquinoline (THIP) scaffold 1–3 and their asymmetric syn-
theses are reported in the literature.1–5 For instance, nomifensine
ethanolamines, followed by acid catalyzed cyclization of product
obtained with methanesulfonic acid.10 However, the arylethanol-
amines required for the first reaction are hardly available. Another
method for the synthesis of 1 via cis- and trans-phenantridine is a
time consuming multistep reaction and requires a chiral auxil-
iary.11 Bourguignon et al. proposed a highly selective protonation
of chiral lactam enolates of 4-substituted-1,4-dihydroisoquinolin-
3-ones, which are obtained from isochroman-3-ones. However,
this method demands deuterated ethanol.12
In recent years the use of hydrolytic enzymes for the resolution
of different racemic compounds has been growing continu-
ously.13,14 The kinetic resolution of amides is a well-known
procedure.15 In order to enhance the reactivity of lactam 2, its
N-acetylated derivatives can be used. A literature search indicated
that N-acetyl lactam esters were slowly hydrolyzed by esterases,
which reduced its skin permeation.16 This suggests, that they can
be good substrates for enzymatic hydrolysis reactions.
4
6,7 and dichlorofensine 58 are of considerable interest due to their
ability to inhibit the uptake of important central neurotransmitters
such as serotonine, norepinephrine, or dopamine at postsynaptic
receptors (Fig. 1). In most cases, only one enantiomer of these com-
pounds demonstrates pharmacological activity. However, they are
synthesized as racemic mixtures, and thus require an additional
step for resolution into enantiomers.9
Cl
Cl
X
1
R
NH
N
N
R2
CH3
O
NH2
2. Results and discussion
1: X=H2, R1=R2=H
: X=O, R =R =H
3: X=O, R1=H, R2=COCH3
4
5
1
2
2
We were interested in a general synthetic method which could
be applied for the synthesis of enantiomerically pure N–H and
N-alkyl tetrahydroisoquinoline scaffolds. This scaffold can be
obtained by the reduction of amides 2, themselves available
via stereoselective Friedel–Craft cyclization of optically active
Figure 1. Bioactive compounds possessing the THIP scaffold.
⇑
Corresponding author. Tel.: +48 22 343 2120; fax: +48 22 632 66 81.
E-mail address: rysza@icho.edu.pl (R. Ostaszewski).
a-acetoxyamides. In Scheme 1, we propose a new synthetic route
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.07.013

D. Koszelewski et al. / Tetrahedron: Asymmetry 23 (2012) 1256–1261
1257
R1
amides (R)-9, (R)-10, and (R)-11 were prepared according to stan-
dard procedures. The application of Lewis acid catalysts for the
cyclization provided the respective lactams in good yield but mod-
erate ee (Table 1, entries 5–7).
H2N
a
+
OH
NH
AcO
AcO
c
Functionalization of the acetoxy group in order to obtain a hy-
droxyl group did not influence the stereochemical course of the
cyclization, and the product was obtained in 31% enantiomeric ex-
cess (Table 1, entry 4). After many trials we found that compound 2
could be obtained in good yield but the enantiomeric excess did
not exceed 47% (Table 1, entry 5). Due to the fact that the target
compound racemized under the cyclization conditions, we turned
our attention to methods based on kinetic enzymatic kinetic reso-
lution procedures, which nowadays are commonly used in organic
laboratories. Experiments dedicated to the resolution of lactams 2
and 12 were completely unsuccessful. None of the commercially
available protease catalyzed this reaction. Enantiomerically pure
lactam 2 could be obtained upon application of the acetylated
derivative 2-acetyl-4-phenyl-1,4-dihydro-2H-izochinolin-3-one 3
as a substrate to the enzymatic reactions. To the best of our knowl-
edge, this approach has not been investigated before. Model
compound rac-3 was prepared by acetylation of 4-phenyl-1,4-
dihydro-2H-isoquinolin-3-one rac-2, using acetyl chloride, in 85%
yield. No attempts were made to optimize this reaction. This
compound was used as a new type of substrate for the enzymatic
kinetic resolution (Scheme 2).
After the screening of commercially available enzymes in a
phosphate buffer (pH 7) and acetone, we chose two enzymes
(lipase from wheat germ and lipase from Pseudomonas cepacia),
which converted substrate 3 into the product. The influence of or-
ganic cosolvents (acetone, t-butylmethyl ether, ethyl ether) on the
stereochemical course of reaction was then investigated (Table 2,
entries 1–6). The product was obtained in excellent enantioselec-
tivity in t-butylmethyl ether and diethyl ether in reaction catalyzed
by Pseudomonas cepacia (Table 2, entries 5 and 6). However, the
formation of an emulsion was observed, which strongly limited
the use of the native lipase from Pseudomonas cepacia. In reactions
catalyzed by the lipase from wheat germ, the increase in enanti-
oselectivity was insubstantial (Table 2, entries 1–3). In order to
avoid the formation of the emulsion in two phase system, we
prepared a set of immobilized lipases from Pseudomonas cepacia.
Immobilization was conducted in three ways: covalent
R1
O
O
R1 = H
(R)-6: R1 = H
R1 = OMe
(R)-7: R1 = OMe
b
R1
d
c
O
NH
R2
HN
HN
R1
O
(R)-8: R1 = H, R2 = OH
(R)- : R1 = H
(R)-13: R1 = OMe
1
(R)-2: R1 = H
(R)-12: R1 = OMe
(R)-9: R1 = H, R2 = CH3SO2O
(R)-10: R1 = H, R2 = Cl
(R)-11: R1 = OMe, R2 = Cl
Scheme 1. Synthesis of non-racemic 4-aryl-1,4-dihydro-2H-isoquinolines 1 and 13.
Reagents and conditions: (a) DCC / HOBt, CH2Cl2, 0 °C, rt, 24 h; (b) [(R)-1 in (R)-3,
NaOHaq/MeOH, ultrasounds], [(R)-1 in (R)-4, CH3SO2Cl/Et3N, CH2Cl2, reflux, 6 h],
[(R)-1 in (R)-5 and (R)-2 in (R)-6 SOCl2, CH2Cl2, rt, 2 h]; (c) Table 1, (d) B2H6, THF.
to obtain optically active lactam 2 and its derivative 12. Enatiomer-
ically pure amides (R)-6 and (R)-7 were prepared in a condensation
reaction between (R)-acetoxymandelic acid with the appropriate
benzylamine in 68% and 76% yields, respectively.
We applied the literature procedure to the cyclization of the al-
ready prepared amides (R)-6 and (R)-7 to obtain the corresponding
lactams (R)-2 and (R)-12 (Table 1, entries 1 and 2). However, while
both reactions proceeded in good chemical yield, racemization oc-
curred and lactam 12 was obtained in 21% ee (Table 1, entry 2). For
substrate (R)-6, the racemic product was obtained (Table 1, entry
1). Since racemization occurred upon cyclization the influence of
the leaving group on the stereochemical course of the cyclization
was studied (Table 1, entries 3–7). Using
a-hydroxyamide (R)-8
as the substrate and performing the reaction at ꢀ20 °C increased
the yield, but again a racemic product was obtained (Table 1, entry
3). The use of polyphosphoric acid as a catalyst provided the
desired product (R)-2 in 51% yield and 31% enantiomeric excess
(Table 1, entry 4). For the next set of experiments,
a-substituted
Table 1
Conditions of cyclization (c from Scheme 1)
b
Entry
Sub.
Cat.
Solvent
T (°C)
Prod.
Y (%)
[
a
]
D
eea (%)
1
2
3
4
5
6
7
(R)-6
(R)-7
(R)-8
(R)-8
(R)-9
(R)-10
(R)-11
H2SO4
H2SO4
H2SO4
PPA
AlCl3
ZnCl3
ZnCl3 (3 equiv)
CH2Cl2
CH2Cl2
CH2Cl2
—
CH2Cl2
ClCH2CH2Cl
ClCH2CH2Cl
0
0
2
12
2
50
43
85
51
16
44
54
—
—
2 (R)
21
ꢀ20
ꢀ1.3
2 (R)
31 (R)
47 (R)
14 (R)
11
40
ꢀ8.2
40
80
80
ꢀ10.2
ꢀ3.2
ꢀ0.5
12
a
Ee determined by HPLC on a Chiralcel OD-H column.
Solvent: CHCl3, 22 °C, c 1.0.
b
AcCl
Et3N
reflux
enzyme
+
O
O
N
O
O
NH
N
NH
(R)-(+)-2
COCH3
COCH3
rac-3
(S)-3
rac-2
Scheme 2. Enzymatic kinetic resolution of compound 3.

1258
D. Koszelewski et al. / Tetrahedron: Asymmetry 23 (2012) 1256–1261
Table 2
Conditions of the enzymatic kinetic resolution of 3
Entry
Substrate
Enzyme
Solvent
t (h)
ca (%)
eeb (%)
E
1
2
3
4
5
6
7
8
rac-3
Lipase from wheat germ
Lipase from wheat germ
Lipase from wheat germ
Lipase from P. cepacia (PcL)
Lipase from P. cepacia
Lipase from P. cepacia
PcL-CelitÒ545
Me2CO
TBME
Et2O
Me2CO
TBME
Et2O
6
20
24
4
24
24
5
5
5
4
4
50
46
42
26
36
28
17
47
41
44
70
46
28
86
19(R)
47(R)
43(R)
77(S)
>99(S)
>99(S)
45
80
81
9
41
2
4
3
10
350
290
3
19
17
1
TBME
PcL-chitosan, EDC
9
PcL-chitosan, EDC, GA
PcL-silica gel, cyanuric chloride
PcL-Zol-Gel AK, Sigma product
PcL-Zol-Gel, PTMS, TweenÒ80
PcL-Zol-Gel, PTMS, PVA
PcL-Zol-Gel, L-Ph-O
10
11
12
13
14
8
5
5
5
75
>99
15
13
290
3
a
Determined by HPLC on a reverse phase column. Isolated yield in brackets.
Ee determined by HPLC on a Chiralcel OD-H column. E-values calculated according to Chen et al.24
b
immobilization on chitosan, adsorption on CeliteÒ545, and inclu-
sion of a zole–gel matrix. Application of immobilized PcL with
EDC hydrochloride and zole–gel matrix gave product (R)-2 in mod-
erate enantioselectivity (Table 2, entries 8, 9, and 12). However, the
reaction time was substantially shorter when conducted with
unimmobilized PcL. Immobilization of PcL with zole–gel matrix
supported with polyvinyl acetate and propyl trimethoxysilane
triggered enantioselectivity on level of 290 (Table 2, entry 13).
From an economical point of view, biotransformations using
home made liver acetone powders (LAP)17 are very important, be-
cause these biocatalysts are readily available and when used as
substrates, accept a broad range of compounds.18–20 For the next
set of experiments, liver acetone powders (LAPs) were prepared
according to a previously published protocol.22 Fast TLC screening
showed that crude powders obtained from pig (PLAP), rabbit
(RLAP), chicken (CLAP), turkey (TLAP), and bovine (BLAP) livers
are good biocatalysts for this enzymatic reaction. These enzymes
were used for the model enzymatic kinetic resolution of rac-3 per-
formed in phosphate buffer (pH 8) containing 20% (v/v) of acetone.
The progress of the enzymatic reactions was monitored by HPLC.
The product obtained was separated and its enantiomeric excess
was determined using HPLC. The results are summarized in
Table 3.
The liver acetone powders obtained from pig, chicken, and bo-
vine LAPs were moderate biocatalysts and showed fair enantiose-
lectivity (19–60% ee; Table 3, entries 1, 2, and 4). Better results
were achieved when rabbit acetone liver powder was used and
product was obtained in good yield and enantiomeric excess
(Table 3, entry 5).
It is noteworthy that in this case, the obtained product pos-
sessed the opposite absolute configuration. The best result was
reached when turkey LAP was used. In this case very good yield
and excellent enantiomeric excess (E >500) were achieved (Table 3,
entry 3). The absolute configuration of compound 2 was assigned
B2H6
O
NH
(R)-(–)-2
NH
(R)-(+)-1
[α]D = +1.2
Scheme 3. Reduction of lactam 2 leading to amine 1.
by chemical correlation after reduction to 4-phenyl-1,2-dihydro-
2H-isoquinolin 1 (Scheme 3). The positive value of the specific
rotation was compared to the published data23 and confirmed its
(R)-configuration.
3. Conclusion
Studies on the synthesis of enantiopure THIP scaffold 1 based on
a stereoselective Friedel–Crafts cyclization were performed and
proved to be completely inefficient. Therefore, a new approach
was proposed based on the enzymatic kinetic resolution of
a
-acetoxyamides which are readily available from their respective
lactams. Our results clearly indicate that 2-acetyl-4-aryl-1,4-dihy-
dro-2H-isoquinolin-3-ones are good substrates for hydrolases and
the target compounds were obtained in excellent enantioselectiv-
ity upon application of native and immobilized enzymes. The
procedure presented is simple, efficient, and can be readily
extended to other substrates. This is a new and parallel approach
to already known protease hydrolysis protocols.
4. Experimental
The HPLC analyses were performed on a Chiralcel OD-H column
(4.6 mm ꢁ 250 mm, from Diacel Chemical Ind., Ltd) equipped with
a pre-column (4 mm ꢁ 10 mm, 5 m) using an LC-6A Shimadzu
apparatus with UV SPD-6A detector and Chromatopac C-R6A
analyser. The elemental analyses were performed on CHN
Perkin-Elmer 240 apparatus. All the reactions were monitored by
TLC on Merck silica gel Plates 60 F254. The acetone powders were
prepared in our laboratory.13 All the chemicals were obtained from
commercial chemical sources. The solvents were of analytical grade.
Table 3
Enzymatic kinetic resolution of 3
Entry
Enzyme
ca (%)
eeb (%)
Conf.
E
1
2
3
4
5
PLAP
CLAP
TLAP
BLAP
RLAP
62
62
45
58 (53)
41
47
60
99
19
84
(S)
(S)
(R)
(R)
(R)
6.1
17
>500
2
4.1. Immobilization of enzymes on CeliteÒ 545
21
a
Determined by HPLC on a reverse phase column. Isolated yield in brackets.
b
Ee determined by HPLC on
a Chiralcel OD-H column. E-values calculated
To a solution of supernatant (0.2 ml) in 50 mM of phosphate
buffer (pH 7.4, 0.8 ml) was added CeliteÒ 545 and stirred for
according to Chen et al.24

D. Koszelewski et al. / Tetrahedron: Asymmetry 23 (2012) 1256–1261
1259
30 min at room temperature and dried over vacuum. The dry
4.4.3. N-Benzyl-2-hydroxy-2-phenylethanamide rac-8
immobilizate was preserved at 4 °C.
Procedure 2. To a solution of 2-(benzylamino)-2-oxo-1-phenyl-
ethyl acetate rac-6 (1.4 mmol) in methanol (1 ml), sodium hydrox-
ide (2 M, 1.5 ml) was added. The mixture was placed in an
ultrasonic washer for 30 min. The alcohol was evaporated under
vacuum, and the residue was acidified with hydrochloric acid
(10%) to pH 7. The aqueous phase was extracted with chloroform
(3 ꢁ 10 ml). The combined organic phases were dried over anhy-
drous magnesium sulfate and the solvent was evaporated under
vacuum. The crude product was purified by crystallization from
ethyl acetate/n-hexane to obtain 0.4 g of the product in 90% yield;
4.2. Immobilization of enzymes in sol–gel matrix
Supernatant with appropriate addition: TweedÒ 80 (0.18 ml)
and
L
-phenylalanine (20 mg) were mixed and then added to a solu-
l, 4% v/v), sodium fluoride (50 l,
tion of polyvinyl alcohol (100
l
l
1 M), and isopropyl alcohol (0.1 ml) and stirred. Next, alkyl silane
(PTMS or i-BTMS) (2.5 mmol) and tetramethoxysilane (0.5 mmol,
75 ll) were added and stirred for 15 s. The mixture was left to
dry in an open tube at room temperature. The obtained gel was
washed with water (10 ml), isopropyl alcohol 10 ml), and n-pen-
tane (10 ml). The gel was crumbled and the immobilizate was left
to dry in an open tube at room temperature.
mp 95 °C, 1H NMR (200 MHz, CDCl3):
d 3.90 (s, 1H), 4.52
(d, J = 5.8 Hz, 2H), 5.13 (s, 1H), 6.75 (br s, 1H), 7.20–7.60 (m, 10H);
13C NMR (50 MHz, CDCl3): d 43.8, 74.5, 127.1, 127.9, 128.9, 129.0,
129.1, 137.9, 139.7, 172.4; IR (cmꢀ1): 1620 (C@O), 3215, 3277; HPLC
analysis: chiral column Chiralcel OD-H; n-hexane/i-propanol; 6/4;
v/v; 0.8 ml/min; 223 nm; Rt(R) = 6.03 min.; Rt(S) = 6.43 min.
4.3. Immobilization of enzymes on chitosan with 1-ethyl-3-(3-
dimethylaminopropyl)-carbodiimide chlorohydride (EDC)
4.4.4. (2R)-N-Benzyl-2-hydroxy-2-phenylethanamide (R)-8
Prepared according to procedure 2. Product (R)-8 was isolated
in 91% yield; mp 94–96 °C; 1H NMR (200 MHz, CDCl3): d 3.90 (s,
1H), 4.52 (d, J = 5.8 Hz, 2H), 5.13 (s, 1H), 6.75 (br s, 1H), 7.20–
To the solution of 1 M sodium hydroxide containing 26% (v/v)
ethyl alcohol was added dropwise chitosan 3% (v/v) in 1% (v/v) ace-
tic acid and stirred. The mixture was then left for 3 h in room tem-
perature. Chitosan was filtered and washed with water (500 ml).
Dry chitosan (114 mg) was placed in 3 ml of a 0.75% (v/v) solu-
tion of EDC in 25 °C. After 10 min the bed was separated, washed
with water, and added to supernatant (0.8 ml) at room tempera-
ture for 1 h. The catalyst was then separated and washed with
water (10 ml).
7.60 (m, 10H); IR (cmꢀ1): 1622 (C@O), 3220, 3281; ½a 2D2
¼ ꢀ76:9
ꢂ
(c 1.0, CHCl3)26; HPLC analysis: chiral column Chiralcel OD-H,
n-hexane/i-propanol; 6/4; 0.8 ml/min; 223 nm; Rt(R) = 6.03 min.
4.4.5. (1R)-2-(Benzylamino)-2-oxo-1-phenylethyl methanesulf-
onate (R)-9
N-Benzyl-(2R)-hydroxyphenylacetamide
(R)-8
(568 mg,
2.35 mmol) was dissolved in anhydrous dichloromethane (5 ml)
after which triethylamine (1.3 ml, 9 mmol) was added. The mix-
ture was cooled to 0 °C and methane sulfonyl chloride (0.3 ml,
3.10 mmol) was added. The mixture was stirred at reflux, then
the solvent was evaporated under vacuum. The crude product
was purified by gel chromatography (n-hexane/ethyl acetate) to
obtain 743 mg of the product in 99% yield; AE: calculated
4.4. Preparation of cyclisation precursors
4.4.1. (1R)-2-(Benzylamino)-2-oxo-1-phenylethyl acetate (R)-6
Procedure 1. To
a solution of (R)-O-acetoxymandelic acid
(200 mg, 1 mmol) in anhydrous dichloromethane (4 ml) 1-hydroxy-
benztriazole (153 mg, 1.1 mmol) and 1,3-dicyclohexylcarbodiimide
(233 mg, 1.1 mmol) were added. The mixture was cooled to 10 °C,
C
16H17NO4S: C, 60.17; H, 5.37; N, 4.39, obtained: C, 60.09; H,
5.41; N, 4.25; 1H NMR (200 MHz, CDCl3): d 2.88 (s, 3H), 4.42–
4.68 (m, 2H), 6.00 (s, 1H), 6.86 (br s, 1H), 7.25–7.60 (m, 10H);
13C NMR (50 MHz, CDCl3): d 39.7, 43.9, 81.8, 128.1, 128.1, 129.2,
then
a solution of benzylamine or 4-methoxybenzylamine
(1.1 mmol) in dichloromethane (1 ml) was added. The mixture
was then stirred for 24 h at 20 °C. Dichloromethane (10 ml) was
added and the residue of the carbamide was separated. The organic
phase was washed with citric acid (10%, 3 ꢁ 10 ml), saturated
sodium bicarbonate (3 ꢁ 10 ml), and brine (3 ꢁ 10 ml). The organic
phase was dried over anhydrous magnesium sulfate and solvent
was evaporated under vacuum. The crude was purified by crystalli-
zation from ethyl acetate/n-hexane. Product (R)-6 was isolated in
68% yield; mp 90oC (ethyl acetate/n-hexane); 1H NMR (200 MHz,
CDCl3): d 1.28 (t, J = 7.2 Hz, 3H), 2.20 (s, 3H), 4.06 (d, J = 5.3 Hz,
2H), 4.22 (q, J = 7.1 Hz, 2H), 6.13 (s, 1H), 6.72 (s, 1H), 7.30–7.52
(m, 5H); 13C NMR (50 MHz, CDCl3): d 14.5, 21.4, 41.6, 62.1, 75.7,
129.5, 130.3, 134.3, 167.0, 202.9; ½a D22
¼ ꢀ108:8 (c 0.6, CHCl3);
ꢂ
HPLC analysis: chiral column Chiralcel OD-H, n-hexane/i-PrOH;
6/4; v/v; 0.8 ml/min; 223 nm; Rt(R) = 8.48 min.
4.4.6. rac-N-Benzyl-2-chloro-2-phenylethanamide rac-10
Procedure 3. To a solution of N-benzyl-2-hydroxyphenylaceta-
mide rac-8 (1.045 g, 4.33 mmol) in anhydrous dichloromethane
(5 ml) cooled to 0 °C, thionyl chloride (1 ml, 13 mmol) was added.
The mixture was then stirred for 1.5 h at room temperature. The
solvent was evaporated under vacuum. The crude product was
purified by crystallization from n-hexane/ethyl acetate to obtain
1.125 g of in 85% yield; mp 95 °C (ethyl acetate/n-hexane) [Lit.
94.5–96.5]; 1H NMR (200 MHz, CDCl3): d 4.59 (d, J = 5.6 Hz, 2H),
5.50 (s, 1H), 7.10 (br s, 1H), 7.20–7.60 (m, 10H); 13C NMR
(50 MHz, CDCl3): d 44.3, 62.0, 128.0, 128.1, 129.1, 129.2, 129.4,
137.3, 137.7, 167.6; IR (KBr) cmꢀ1: 1537, 1650 (C@O), 3336.
127.8, 129.0, 129.4, 168.7, 169.3, 169.7; ½a D22
¼ ꢀ112:9 (c 1.0,
ꢂ
CHCl3)26 >99% ee (HPLC Chiralcel OD-H); enantiomeric excess was
defined by HPLC with a chiral column; n-hexane/i-propanol; 6/4;
v/v; 0.8 ml/min; 223 nm; RtR = 6.32 min.
4.4.2. (1R)-2-[(4-Methoxybenzyl)amino]-2-oxo-1-phenylethyl
acetate (R)-7
Prepared according to procedure 1. Product (R)-7 was isolated
in 76% yield; 1H NMR (200 MHz, CDCl3): d 2.15 (s, 3H), 3.79
(s, 3H), 4.30–4.50 (m, 2H), 6.09 (s, 1H), 6.40 (br s, 1H), 7.00
(d, J = 8.6 Hz, 4H), 7.30–7.50 (m, 5H); 13C NMR (50 MHz, CDCl3):
d 21.3, 43.2, 55.6, 75.8, 114.4, 127.7, 129.1, 129.3, 129.4, 130.0,
4.4.7. (2R)-N-Benzyl-2-chloro-2-phenylethanamide (R)-10
Prepared according to procedure 3. Product was obtained in 83%
yield; mp 91–93 °C (ethyl acetate/n-hexane); AE: calculated
C
15H14ClNO: C, 69.37; H, 5.43; N, 5.39, obtained: C, 69.15; H,
5.55; N, 5.16; 1H NMR (200 MHz, CDCl3): d 4.59 (d, J = 5.6 Hz,
135.8, 159.4, 168.4; ½a D22
¼ ꢀ101:5 (c 1.0, CHCl3) >99% e.e. (HPLC
ꢂ
2H), 5.50 (s, 1H), 7.10 (br s, 1H), 7.20–7.60 (m, 10H);
½
a 2D2
ꢂ
¼ ꢀ59:9 (c 0.55, CHCl3); HPLC analysis: chiral column Chiral-
Chiralcel OD-H); Parametres of HPLC analysis: chiral column
Chiralcel OD-H; n-hexane/i-propanol; 6/4; v/v; 0.8 ml/min;
223 nm; RtR = 8.07 min.
cel OD-H, n-hexane/i-propanol; 6/4; v/v; 0.8 ml/min; 223 nm;
Rt(R) = 6.35 min.

1260
D. Koszelewski et al. / Tetrahedron: Asymmetry 23 (2012) 1256–1261
4.4.8. 2-Chloro-N-(4-methoxybenzyl)-2-phenylethanamide rac-
11
6.90-7.450 (m, 8H); 13C NMR (50 MHz, CDCl3): d 25.2, 34.2, 52.9,
113.6, 113.7, 126.9, 127.5, 128.2, 128.6, 129.0, 136.8, 138.6,
159.5, 172.8; HPLC analysis: chiral column Chiralcel OD-H; n-
hexane/i-propanol; 6/4; v/v; 0.8 ml/min; 223 nm; Rt(R) = 13.73 min.;
Prepared according to procedure 3. Product rac-11 was obtained
in 90% yield; AE: calculated C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83,
obtained: C, 66.41; H, 6.02; N, 5.82; 1H NMR (200 MHz, CDCl3): d
3.8 (s, 3H), 4.43 (d, J = 5.6 Hz, 2H), 5.40 (s, 1H), 6.90 (br s, 1H),
7.10 (dd, J = 8.6 Hz, 4H), 7.30–7.50 (m, 5H); 13C NMR (50 MHz,
CDCl3): d 43.9, 55.6, 62.1, 114.5, 128.0, 129.2, 129.4, 157.6.
Rt(S) = 15.00 min.; IR (KBr) cmꢀ1
: 1629, 3251; HR EI-MS m/z
C
16H15NO2 [M]+ꢃ: calculated 253.110; measured: 253.109.
4.4.13. (4R)-7-Methoxy-4-phenyl-1,4-dihydroisoquinolin-3(2H)-
one (R)-12
4.4.9. (2R)-2-Chloro-N-(4-methoxybenzyl)-2-phenylethanamide
(R)-11
To a solution of (2R)-(ꢀ)-chloro-N-(4-methoxybenzyl)-2-phen-
ylethanamide (R)-11 (174 mg, 0.6 mmol) in 1,2-dichloroethane
(10 ml) cooled to 0 °C, zinc chloride(II) (3 equivalents) was added
(Table 1, entry 7). The mixture was stirred at 80 °C, then it was
cooled to 0 °C and hydrochloric acid was added (10%, 10 ml). The
aqueous phase was extracted with chloroform (3 ꢁ 5 ml). The
combined organic phases were dried over anhydrous magnesium
sulfate and the solvent was evaporated under vacuum. The product
was purified by gel chromatography with n-hexane/ethyl acetate.
HPLC analysis: chiral column Chiralcel OD-H; n-hexane/
i-propanol; 6/4; v/v; 0.8 ml/min; 223 nm; Rt(R) = 13.73 min.
Prepared according to procedure 3. Product (R)-11 was obtained
in 83% yield; AE: calculated C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83,
obtained: C, 66.41; H, 5.82; N, 4.82; 1H NMR (200 MHz, CDCl3): d
3.8 (s, 3H), 4.43 (d, J = 5.6 Hz, 2H), 5.40 (s, 1H), 6.90 (br s, 1H),
7.10 (dd, J = 8.6 Hz, 4H), 7.30–7.50 (m, 5H); 13C NMR (50 MHz,
CDCl3): d 43.9, 55.6, 62.1, 114.5, 128.0, 129.2, 129.4, 157.6;
½
a 2D2
ꢂ
¼ ꢀ66:4 (c 0.55, CHCl3); HPLC analysis: chiral column Chiral-
cel OD-H; n-hexane/i-propanol; 6/4; v/v; 0.8 ml/min; 223 nm;
Rt(R) = 5.89 min.
4.4.10. 4-Phenyl-1,4-dihydroisoquinolin-3(2H)-one rac-2
To a solution of N-benzyl-2-chlorophenylethanamide rac-10
(500 mg, 1.2 mmol) in anhydrous 1,2-dichoroethane (5 ml) cooled
to 0 °C, zinc chloride(II) (981 mg, 7.2 mmol) was added. The mix-
ture was stirred at reflux for 36 h and then cooled to 0 °C. Next, dis-
tilled water (10 ml) was added. The mixture was extracted with
chloroform. The combined organic phases were dried over anhy-
drous magnesium sulfate and the solvent was evaporated under
vacuum. The crude product was purified by gel chromatography
with benzene to obtain 267 mg of rac-2 in 65% yield; mp 198 °C
(benzene) [Lit. 199–201]21 AE: calculated C15H13NO + 0.5 H2O: C,
77.56; H, 6.08; N, 6.03, obtained: C, 77.63; H, 5.83; N, 6.10%; 1H
NMR (200 MHz, CDCl3): d 4.55 (dd, J = 5.6 Hz, 2H), 4.88 (s, 1H),
7.10 (br s, 1H), 7.12–7.50 (m, 9H); 13C NMR (50 MHz, CDCl3): d
45.4, 52.8, 125.8, 127.4, 127.5, 128.2, 129.2, 131.9, 173.0; HPLC
analysis: chiral column Chiralcel OD-H; n-hexane/i-propanol;
6/4; 0.8 ml/min; 223 nm; Rt(S) = 11.22 min.; Rt(R) = 12.25 min.; IR
(KBr) cmꢀ1: 1633, 3251; HR EI-MS m/z C15H13NO [M]+ꢃ: calculated
223.099; obtained: 223.099.
4.4.14. 2-Acetyl-4-phenyl-1,4-dihydro-2H-izoquinolin-3-one
rac-3
To a solution of 4-phenyl-1,4-dihydro-2H-izoquinolin-3-one
rac-2 (100 mg, 0.45 mmol) in dichloromethane (3 ml) were added
potassium carbonate (100 mg) and 4-dimethylaminepyridine
(10 mg) at room temperature. Next, acetyl chloride was added
(0.1 ml, 1.35 mmol) and the solution was stirred at reflux for 3 h.
The mixture was cooled to 0 °C, quenched with HCl (5%) to pH 1.
The aqueous phase was extracted with chloroform (3 ꢁ 5 ml).
The combined organic phase was dried over magnesium sulfate
and the solvent was removed under reduced pressure. The crude
product was purified by gel chromatography by n-hexane/ethyl
acetate as eluent. The product was isolated in 77% yield (92 mg).
Rf = 0.48 (n-hexane/ethyl acetate; 1/1; v/v); Elemental analysis:
calculated C17H15NO2 + 1.3 H2O: C, 70.72; H, 6.14; N, 4.85, mea-
sured: C, 70.67; H, 6.20; N, 4.35; 1H NMR (200 MHz, CDCl3): d
2.68 (s, 3H), 4.92 (dd, J = 16.2 Hz, 2H), 5.11 (s, 1H), 7.15–7.53 (m,
9H); 13C NMR (50 MHz, CDCl3): d 27.7, 45.6, 56.5, 126.6, 128.1,
128.2, 128.3, 128.4, 128.8, 129.2, 132.9, 134.9, 135.4, 172.6,
173.2; HR EI-MS m/z for C17H15NO2 [M]+ꢃ: calculated 265.110;
measured:265.109.
4.4.11. (4R)-4-Phenyl-1,4-dihydroisoquinolin-3(2H)-one (R)-2
To a solution of appropriate amide (0.72 mmol) in anhydrous
dichloromethane (1 ml) cooled to the appropriate temperature,
sulfuric acid (1 ml) was added. The mixture was stirred for 4 h,
then poured into crushed ice, neutralized with potassium carbon-
ate, and extracted with chloroform (3 ꢁ 5 ml). The combined
organic phases were dried over anhydrous magnesium sulfate
and the solvent was evaporated under vacuum. The product was
purified by gel chromatography with n-hexane/ethyl acetate. HPLC
analysis: chiral column Chiralcel OD-H; n-hexane/i-propanol; 6/4;
0.8 ml/min; 223 nm; Rt(R) = 12.25 min.
4.4.15. 4-Phenyl-1,4-dihydro-2H-isoquinoline (R)-1
To a solution of 4-phenyl-1,4-dihydro-2H-izochinolin-3-one
(R)-2 (206 mg, 0.924 mmol, 47% ee) in dry tetrahydrofurane was
added a solution of diborane complex in tetrahydrofuran (1 M,
4 ml, 1.84 mmol). The mixture was stirred at reflux for 6 h. HCl
(6 M, 10 ml) was added, and the solvent was evaporated. The aque-
ous phase was washed with chloroform (3 ꢁ 5 ml), then basified
with sodium hydroxide (6 M), and ethyl acetate was added
(10 ml). The organic phase was dried over magnesium sulfate
and the solvent was evaporated under reduced pressure. The crude
product was purified by gel chromatography with methylene chlo-
ride/methanol (24/1 = v/v) to obtain 70 mg of (R)-1 in 36% yield as
a pale yellow oil. 1H NMR (200 MHz, CDCl3): d 1.85 (s, 1H), 3.13
(dd, J = 12.8, 6.5 Hz, 1H), 3.44 (dd, J = 12.8, 5.3 Hz, 1H), 4.00–4.20
(m, 3H), 6.88 (d, J = 7.0 Hz, 1H), 7.10–7.30 (m, 8H); HR EI-MS m/z
for C15H15N [M]+ꢃ: calculated 209.120; measured 209.119; IR
4.4.12. 7-Methoxy-4-phenyl-1,4-dihydroisoquinolin-3(2H)-one
rac-12
To a solution of 2-chloro-N-(4-methoxybenzyl)-2-phenyleth-
antamide rac-11 (180 mg, 0.61 mmol) in anhydrous 1,2-dichloro-
ethane (10 ml) cooled to 0 °C, zinc chloride (244 mg, 1.8 mmol)
was added. The mixture was stirred at reflux for 7 h. Next, it was
cooled to 0 °C, and distilled water (10 ml) was slowly added. The
aqueous phase was extracted with chloroform (3 ꢁ 5 ml). The
combined organic phases were dried over anhydrous magnesium
sulfate and the solvent was evaporated under vacuum. The product
was purified by gel chromatography with n-hexane/ethyl acetate
to obtain 55 mg in 36% yield; 1H NMR (200 MHz, CDCl3): d 3.76
(s, 3H), 4.35 (dd, J = 5.6 Hz, 2H), 4.78 (s, 1H), 6.80 (br s, 1H),
(film): 1450, 2808, 3222;
[a]
½
a 2D2
ꢂ
¼ þ1:2 (c 1.0, CH3OH) {Lit.
D = +11.1 (c 1.0, CH3OH) for the (R)-enantiomer}.25
4.4.16. (4R)-7-Methoxy-4-phenyl-1,2,3,4-tetrahydroisoquino-
line (R)-13
Thirty-one grams of (R)-13 in 16% yield as a yellow oil was ob-
tained; 1H NMR (200 MHz, CDCl3): d 1.80 (s, 1H), 3.13 (d, J = 6.5 Hz,

D. Koszelewski et al. / Tetrahedron: Asymmetry 23 (2012) 1256–1261
1261
Wuenschen, B.; Nerdinger, S. Eur. J. Org. Chem. 1999, 503–517; (e) Ruchirawat,
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2H), 3.44 (dd, J = 12.8, 5.3 Hz, 2H), 3.73 (s, 3H), 4.00–4.13 (m, 1H),
7.00 (d, J = 7.0 Hz, 1H), 7.20–7.65 (m, 7H); 13C NMR (50 MHz,
CDCl3): d 45.4, 48.1, 52.3, 55.5, 113.7, 114.3, 126.7, 126.8, 127.1,
127.2, 127.3, 128.1, 128.7, 129.1, 129.4; HR EI-MS m/z dla
C
16H18NO [M]+ꢃ: calculated 240.139; measured 240.138.
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To a solution of 2-acetyl-4-phenyl-1,4-dihydro-2H-izoquinolin-
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mixture (10 ml, 1/4 = v/v), the enzyme was added. The mixture
was then stirred for 2 h at room temperature. The enzyme was
separated and washed with chloroform (3 ꢁ 2 ml) and phosphate
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This work was supported by the State Committee for Scientific
Research, KBN Grant PBZ-MIN-007/P04/2003 and by project
‘Biotransformations for pharmaceutical and cosmetics industry’
No. POIG.01.03.01-00-158/09-01 part-financed by the European
Union within the European Regional Development Fund.
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