Noscapine Derivatives as New Chiral Catalysts in Asymmetric Synthesis: Highly Enantioselective Addition of Diethylzinc to Aldehydes

Article abstract of DOI:10.1055/s-0037-1609224

Noscapine, a natural alkaloid, has never been used as a parent scaffold in chiral induction. The first examples of noscapinoid compounds as efficient catalysts in asymmetric synthesis are now reported. Three derivatives of noscapine were synthesized from its reaction with different Grignard reagents. Asymmetric addition of diethylzinc to aldehydes was performed in the presence of these catalysts in high yields and good to excellentees.

Full text of DOI:10.1055/s-0037-1609224

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
M. Mohebbi et al.
Paper
Synthesis
Noscapine Derivatives as New Chiral Catalysts in Asymmetric
Synthesis: Highly Enantioselective Addition of Diethylzinc to
Aldehydes
Maryam Mohebbia
Morteza Bararjaniana
Samad N. Ebrahimia
Martin Smieškob
O
O
O
O
(R)
O
O
(S)
(R)
O
Peyman Salehi*a
0
0
0
0
0-
0
0
1
5-
7
7
4
3-
3
7
2
O
O
O
H
1.88Å
O
O
N
O
H
a Department of Phytochemistry, Medicinal Plants and Drugs
Research Institute, Shahid Beheshti University, G. C., Evin,
1983963113 Tehran, Iran
O
MgBr
N
Et2Zn
+
benzaldehyde
noscapine
p-salehi@sbu.ac.ir
b Division of Molecular Modeling, Department of Pharmaceuti-
cal Sciences, University of Basel, Klingelbergstrasse 50, 4056
Basel, Switzerland
O
H
O
Zn
(R)
OH
O
O
O
H
Zn
O
N
O
O
+ 9 other examples
up to 99% ee
up to 99% yield
Received: 01.01.2018
Accepted after revision: 09.01.2018
Published online: 05.02.2018
scaffolds such as pinenes,7 camphor,8 etc. Catalysts with an
alkaloidal backbone are among the most favorite organo-
catalysts because of their high efficiency in chiral induc-
tion. The natural structural complexity of alkaloids derived
from nature can help us in approaching the synthesis of
complex structures. The most famous structures of these
groups are cinchona alkaloids with high potency, which
have been used in many asymmetric reactions such as
Sharpless asymmetric dihydroxylation,9 asymmetric Bay-
lis–Hillman,10 aldol,11 and Mannich reactions.12 Despite the
high potency of organocatalysts with alkaloidal backbones,
high prices, adverse effects on health, and their sparse
availability negatively counterbalance their advantages.
Therefore, finding new alkaloids as potent catalysts to over-
come the drawbacks of the previously reported catalysts, is
a challenging issue in this field.
Noscapine is a benzylisoquinoline alkaloid and the sec-
ond most abundant alkaloid in opium. Noscapine has been
used as an antitussive agent since 1963 and in recent years
it is being used as an anticancer lead compound (Figure
1).13 The main advantages of noscapine are low toxicity and
commercial availability. Despite numerous studies on bio-
logical activities of noscapine derivatives, their application
as a chiral catalyst has not been reported in the literature so
far. In continuation of our research on the application of
natural-based catalysts in asymmetric reactions,14 we re-
port here the synthesis of novel derivatives from noscapine
and their utilization as efficient catalysts in asymmetric ad-
dition of diethylzinc to aldehydes.
DOI: 10.1055/s-0037-1609224; Art ID: ss-2017-n0571-op
Abstract Noscapine, a natural alkaloid, has never been used as a par-
ent scaffold in chiral induction. The first examples of noscapinoid com-
pounds as efficient catalysts in asymmetric synthesis are now reported.
Three derivatives of noscapine were synthesized from its reaction with
different Grignard reagents. Asymmetric addition of diethylzinc to
aldehydes was performed in the presence of these catalysts in high
yields and good to excellent ees.
Key words noscapine, asymmetric reaction, diethylzinc, alkaloids,
MacroModel
Chirality is one of the most elegant features of creation.
This feature can cause significant differences in biological
function of enantiomers. Nature has always been inspiring
for the enantioselective synthesis of chiral molecules.
Asymmetric addition of dialkylzinc to aldehydes is a
noteworthy reaction because the produced chiral second-
ary alcohols are attractive intermediates in organic synthe-
sis and also this is a standard reaction for benchmarking the
efficiency of new chiral catalysts.1
In recent years, many catalysts with different back-
bones such as, amino alcohols,2 diols,3 and diamines4 have
been reported for this reaction, but synthesis of new cata-
lysts with novel structures is still in demand.
In many reactions, amino alcohols are powerful cata-
lysts. The majority of these are derived from natural com-
pounds such as amino acids,5 alkaloids,6 or other natural
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
M. Mohebbi et al.
Paper
Synthesis
reagent to 12 equivalents and the temperature to 60 °C, no
difference in the pattern of the products was observed. A
probable explanation for this behavior could be the forma-
tion of a strong complex between O–Mg–N after addition of
the Grignard reagent, which locks the molecule in a way
that no further progress to the corresponding ketone is pos-
sible. This effect was reflected in the downfield chemical
shift of hydrogen-bonded OH equal to 7.55 ppm.
O
O
H
N
(R)
O
(S)
O
H
O
O
O
1
Figure 1 Noscapine structure
In spite of the predicted formation of two diastereo-
mers, NMR spectra of the crude reaction mixture showed
only one stereoisomer. This obviously can be explained by
examining the structure of noscapine, which is crowded in
the Re-face of the carbonyl group for the nucleophilic attack
(Figure 2). X-ray crystal structure analysis on a single crys-
tal of the product 7a confirmed the hemiacetal structure
with 1R,3S,5R-configuration. Its ORTEP view is depicted in
Figure 3. The strong hydrogen bond between the OH and
the amine was obvious. Conformational analysis of 7a with
MacroModel in solution and the structure of more stable
conformer (Figure 3) showed a shorter O–H–N distance
(1.88 Å) than in the crystal structure (1.92 Å) (for details of
the X-ray crystal structures, see the Supporting Informa-
tion).
Although we did not synthesize the targeted structure
(β-amino alcohol), the short distance between the OH and
amine N atom of the group in 7a aroused our curiosity and
prompted us to examine the catalytic potency of this mole-
cule (Table 1). Efficiency of this compound in asymmetric
addition of Et2Zn was amazing. At room temperature, excel-
lent enantioselectivity (99% ee) was observed for the for-
mation of R-enantiomer with 10 mol% of the catalyst in 99%
yield after 3 hours (Table 1, entry 4).
The masked functional groups of noscapine caught our
attention for the design and synthesis of various derivatives
for different catalytic roles. One of the active sites of nos-
capine available for modification and synthesis of new de-
rivatives is the lactone ring. Our main strategy was based
on nucleophilic opening of lactone ring by a Grignard re-
agent to form the golden β-amino alcohol moiety. Accord-
ing to the literature, three different products could be
formed by the reaction of the Grignard reagent with γ-lac-
tones, namely, a ketone 3a, a tertiary alcohol 3b, or a hemi-
acetal 3c (Scheme 1).
OH
OH
R
RMgBr
O
O
R
+
+
R
R
O
OH
O
OH
3c
3b
3a
2
Scheme 1 Three possible products from the reaction of Grignard
reagent with a γ-lactone ring
By the reaction of 2 equivalents of t-BuMgCl with nos-
capine at room temperature, only the hemiacetal 7a was
obtained (Scheme 2). By increasing the amount of Grignard
O
O
O
O
O
H
H
N
N
N
O
O
H
O
O
OH
HO
O
THF
THF
OH
H
MgCl
+
H
H
4a
O
O
O
O
O
O
O
O
5a
1
6a
THF
H
O
N
O
(R)
O
(S)
O
H
OH
(R)
O
O
7a
Scheme 2 Expected and isolated products for Grignard reaction with noscapine
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
M. Mohebbi et al.
Paper
Synthesis
Table 1 Optimization of Diethylzinc Addition Reaction Catalyzed by
7a–c
O
OH
ligand
H
Et2Zn
+
toluene
9a
Entry
Ligand mol%
Temp (°C) Time (h) Conv. (%)a ee (%)-b
(Config.)c
1
2
7a
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
7b
7b
7b
7c
7c
7c
2
5
r.t.
r.t.
r.t.
r.t.
40
0
3
nrd
84
65
99
99
80
80
96
97
97
98
93
96
94
43
96
98
–
Figure 2 Crystal structure of noscapine
3
39 (R)
95 (R)
99 (R)
80 (R)
98 (R)
6 (R)
3
7
3
4
10
10
10
2
3
5
3
6
3
7
r.t.
r.t.
r.t.
r.t.
r.t.
40
0
3
8
5
3
44 (R)
70 (R)
91 (R)
84 (R)
88 (R)
96 (R)
96 (R)
64 (R)
92 (R)
99 (R)
9
7
3
10
11
12
13
14
15
16
17
10
12
10
10
10
10
10
10
3
3
3
1.5
–10
–20
r.t.
0
16
16
2
2
a Measured as % conversion by GC.
b Determined by capillary chiral GC.
c Absolute configuration was determined by comparing the sign of specific
rotations with those reported in the literature.
d No reaction.
Figure 3 a) ORTEP view of compound 7a, b) structure of more stable
conformer of 7a in solution
In parallel, we also synthesized two other noscapine de-
rivatives with benzyl 7b and phenyl groups 7c by the same
Grignard reaction (Scheme 3). The efficiency of new cata-
lysts was also examined by adding of diethylzinc to benz-
aldehyde in toluene as solvent with different mol% of 7b
and 7c (Table 1, entries 7–17). The best enantioselectivity
for 7b was obtained with 10 mol% of the catalyst at 0 °C in
96% yield and 96% ee in 1.5 hours (entry 13).
The optimum conditions for 7c used 10 mol% of the cat-
alyst at 0 °C in 2 hours with 99% ee and in 98% yield (Table
1, entry 17). With the optimized conditions in hand for 7a–
c, the asymmetric addition of diethylzinc to other aromatic
and aliphatic aldehydes was investigated. The results are
summarized in Table 2.
Excellent ees were observed for p-substituted benzalde-
hydes in almost quantitative yields (Table 2, entries 4–12,
19–21). A slight decrease in enantioselectivities was
observed for o-substituted benzaldehydes (entries 13–18).
1-Naphthaldehyde has also undergone the asymmetric re-
actions in high yields and enantioselectivities with all three
catalysts (entries 22–24). The reaction of 3-phenylpropanal
as an aliphatic aldehyde ended up with 76% ee in the pres-
ence of 7a after 16 hours at room temperature (entry 28).
To investigate the role of OH group in asymmetric in-
duction of the catalysts, dehydration reaction of 7b was
carried out by heating it in the presence of p-toluenesulfon-
ic acid (Scheme 4). Interestingly, we observed that asym-
O
HO
HO
H
H
H
N
O
N
O
1) THF
O
MgBr
+
O
R
2) H3O+
O
H
OH
4a R = t-Bu
4b R = Bz
4c R = Ph
R
O
O
O
O
O
7a R = t-Bu
7b R = Bz
7c R = Ph
1
Scheme 3 Synthesis of ligands 7a–c
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
M. Mohebbi et al.
Paper
Synthesis
Figure 4 Schematic description and 3D structure of four possible diastereomeric complexes of 9a with calculated energies
metric addition of diethylzinc to benzaldehyde did not pro-
ceed at all in the presence of 8 under different conditions.
This showed that the oxygen of hydrofuran ring did not
participate in the reaction and the presence of OH group in
the right position was vital for the success of this reaction.
To gain insight into the conformational analysis of chiral
active species in this reaction, DFT calculations of mixed
complexes of 7a, diethylzinc, and benzaldehyde (9a) were
conducted. Combination of R or S configurations of nitrogen
group and syn or anti arrangements of the amino alkoxide
ring with C=O bond, resulted in four diastereomeric com-
plexes (Figure 4). Comparison of the optimized energies for
different structures indicate that stability decreases in the
order anti-(R)-N-9a > syn-(R)-N-9a > anti-(S)-N-9a > syn-
(S)-N-9a. The anti-(R)-N-9a and syn-(R)-N-9a are stabilized
by a coulombic interaction between Zn2 (1.23 au) and O3
(–0.55 au), which is shorter (2.44 Å) in the anti complex
than in the syn (2.59 Å).
O
O
O
O
H
H
N
O
N
O
toluene, p-TsOH
O
O
reflux
H
H
OH
O
O
O
O
7b
8
Scheme 4 Dehydration of ligand 7b
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
M. Mohebbi et al.
Paper
Synthesis
Table 2 Enantioselective Addition of Diethylzinc Addition to Various
Aldehydes Catalyzed by Ligands 7a–ca,b
In summary, we have reported the synthesis of three
derivatives of noscapine and their applications as chiral cat-
alysts in the asymmetric addition of diethylzinc to alde-
hydes in high yields and with good to excellent enantio-
selectivities. To the best of our knowledge, this is the first
report on the application of noscapine derivatives as chiral
catalysts in asymmetric synthesis. Noscapine could be con-
sidered as a parent alkaloid for the synthesis of new
organocatalysts, which can be used in other asymmetric re-
actions.
Entry
Aldehyde
Ligand
Time (h) Yield (%)c
ee (%)d
1
2
PhCHO
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
3
99
99
99
99
99
99
99
99
99
99
99
99
99
93
93
99
97
97
96
98
96
99
99
99
60
75
74
93
80
90
99
96
98
98
98
97
98
97
97
96
97
98
88
93
96
89
90
84
98
97
97
95
96
94
85
85
80
76
53
44
PhCHO
1.5
2
3
PhCHO
4
p-FC6H4CHO
3
5
p-FC6H4CHO
1.5
2
6
p-FC6H4CHO
7
p-MeC6H4CHO
p-MeC6H4CHO
p-MeC6H4CHO
p-ClC6H4CHO
p-ClC6H4CHO
p-ClC6H4CHO
o-ClC6H4CHO
o-ClC6H4CHO
o-ClC6H4CHO
o-MeOC6H4CHO
o-MeOC6H4CHO
o-MeOC6H4CHO
p-F3CC6H4CHO
p-F3CC6H4CHO
p-F3CC6H4CHO
1-naphthaldehyde
1-naphthaldehyde
1-naphthaldehyde
4-pyridylCHO
4-pyridylCHO
4-pyridylCHO
PhCH2CH2CHO
PhCH2CH2CHO
PhCH2CH2CHO
3
Melting points were measured on an Electrothermal 9200 instru-
ment. HR-ESIMS spectra were recorded on a Bruker microTOF ESI-MS
system. IR spectra were recorded on a Bruker Tensor 27 spectropho-
tometer. 1H and 13C NMR spectra were recorded on a Bruker Ascend
600 spectrometer at 600.15 and 150.92 MHz, respectively, in CDCl3
using TMS as internal standard and reported in ppm. Et2Zn was pur-
chased from Sigma-Aldrich Co. LLC. Noscapine was purchased from
Temad Co. Silica gel (70–230 mesh) used for column chromatography
and pre-coated silica gel F254 (20 × 20 cm) plates for TLC were pur-
chased from Merck Co. The enantiomeric ratios of the optically active
products were determined by gas chromatoghraphy (GC) analysis. GC
analysis was performed on an Agilent 4890 D instrument equipped
with a Supelco β-DEXTM 120 fused silica capillary column (0.25
nm/0.25 μm, 30 m).
8
1.5
2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
3
1.5
2
3
1.5
2
3
1.5
2
Grignard Reaction Noscapine; General Procedure
1.5
2
To a 1 M solution of the respective Grignard reagent in THF (15 mmol,
15 mL) was added a solution of noscapine (1; 4.2 g, 10 mmol) in THF
(15 mL) dropwise at r.t. The reaction mixture was stirred for 2 h, then
quenched with sat. aq NH4Cl, and extracted with EtOAc (3 × 30 mL).
The combined organic layers were washed with brine and dried (Mg-
SO4). The solvent was removed using a rotary evaporator under re-
duced pressure. The crude product was purified by column chroma-
tography (n-hexane/EtOAc).
3
1.5
2
3
1.5
2
(1R,3S)-1-tert-Butyl-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-
5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-1,3-dihydro-
2-benzofuran-1-ol (7a)
3
16
Yield: 3.7 g (78%); white crystals; mp 178–179 °C.
16
16
FTIR (KBr): 3445, 2943, 1621, 1479, 1263, 1086, 1045 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.55 (br s, 1 H, OH), 6.57 (d, J = 8.1 Hz,
1 H, HAr), 6.25 (s, 1 H, HAr), 5.93 (d, J = 1.3 Hz, 1 H, OCH2O), 5.90 (d,
J = 1.3 Hz, 1 H, OCH2O), 5.70 (d, J = 8.1 Hz, 1 H, HAr), 5.45 (d, J = 4.8 Hz,
1 H, CHO), 4.07 (s, 3 H, OCH3), 4.05 (d, J = 4.8 Hz, 1 H, CHN), 3.80 (s, 3
H, OCH3), 3.78 (s, 3 H, OCH3), 2.48–2.54 (m, 1 H, CH2N), 2.43 (s, 3 H,
NCH3), 2.17–2.20 (m, 1 H, CH2N), 1.75 (dt, J = 16, 4.02 Hz, 1 H, CH2),
1.52–1.57 (m, 1 H, CH2) 1.14 [s, 9 H, C(CH3)3].
13C NMR (150 MHz, CDCl3): δ = 153.0 (C), 148.0 (C), 144.2 (C), 140.8
(C), 137.7 (C), 134.1 (C), 133.3 (C), 129.6 (C), 117.3 (CH), 116.2 (C),
113.6 (C), 112.2 (CH), 102.4 (CH), 100.6 (CH2), 81.6 (CH), 62.0 (CH),
60.7 (CH3), 59.4 (CH3), 56.2 (CH3), 45.6 (CH2), 44.5 (CH3), 38.8 (C), 26.2
(CH3), 22.9 (CH2).
a Ligand 7a (10 mol%), r.t.
b Ligand 7b (10 mol%), 0 °C. Ligand 7c (10 mol%), 0 °C.
c Isolated yield.
d The ee was determined by chiral GC or HPLC.
The lower stability of the syn-(R)-N-9a could be related
to the steric repulsion between one of the ethyl groups on
Zn2 and the phenyl ring of the aldehyde. In addition, in the
anti-(R)-N-9a the benzaldehyde molecule has a tight con-
tact with the catalyst and the carbonyl carbon atom is posi-
tioned closer to one of the ethyl groups (3.79 Å) than in the
syn-(R)-N-9a (4.38 Å). This facilitated the alkylation reac-
tion leading to R-configured alcohols.
HRMS (ESI): m/z [M + H]+ calcd for C26H34NO7: 472.2335; found:
472.2343.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
M. Mohebbi et al.
Paper
Synthesis
(1R,3S)-1-Benzyl-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-
5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-1,3-dihydro-
2-benzofuran-1-ol (7b)
J = 3.8 Hz, 1 H, CHO), 4.39 (d, J = 3.8 Hz, 1 H, CHN), 3.92 (s, 3 H, OCH3),
3.89 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 2.79–2.83 (m, 1 H, CH2N), 2.50
(s, 3 H, NCH3), 2.45–2.49 (m, 1 H, CH2N), 2.39–2.43 (m, 1 H, CH2),
2.20–2.24 (m, 1 H, CH2).
Yield: 4.3 g (85%); pale yellow solid; mp 99–100 °C.
13C NMR (150 MHz, CDCl3): δ = 154.1 (C), 152.3 (C), 148.0 (C), 13.6 (C),
140.6 (C), 137.4 (C), 135.4 (C), 133.7 (C), 131.7 (C), 129.1 (CH), 128.1
(CH), 128.0 (CH), 124.8 (CH), 117.8 (C), 117.5 (CH), 113.1 (CH), 102.5
(CH), 100.4 (CH2), 100.1 (CH), 87.3 (CH), 62.5 (CH), 60.0 (CH3), 59.1
(CH3), 56.4 (CH3), 49.6 (CH2), 45.8 (CH3), 27.9 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C29H31NO6: 488.2073; found:
488.2039.
FTIR (KBr): 3450, 2939, 1618, 1483, 1265, 1030 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.80 (br s, 1 H, OH), 7.31 (d, J = 7.38 Hz,
2 H, HAr), 7.08–7.10 (m, 2 H, HAr), 7.01–7.03 (m, 1 H, HAr), 6.49 (d,
J = 8.1 Hz, 1 H, HAr), 6.26 (s, 1 H, HAr), 5.89 (d, J = 1.3 Hz, 1 H, OCH2O),
5.88 (d, J = 1.3 Hz, OCH2O), 5.59 (d, J = 8.1 Hz, 1 H, HAr), 5.35 (d, J = 3.9
Hz, 1 H, CHO), 4.09 (d, J = 3.9 Hz, 1 H, CHN), 4.03 (s, 3 H, CH3), 3.97 (s,
3 H, CH3), 3.75 (s, 3 H, CH3), 3.71 (d, J = 13.9 Hz, 1 H, CH2), 3.49 (d,
J = 13.9 Hz, 1 H, CH2), 2.51–2.57 (m, 1 H, CH2N), 2.45 (s, 3 H, CH3),
2.21–2.25 (m, 1 H, CH2N), 1.81–1.85 (m, 1 H, CH2), 1.69–1.74 (m, 1 H,
CH2).
Enantioselective Addition of Diethylzinc to Aldehydes; General
Procedure
13C NMR (150 MHz, CDCl3): δ = 152.3 (C), 148.1 (C), 143.8 (C), 140.8
(C), 137.3 (C), 136.9 (C), 134.1 (C), 132.4 (C), 130.5 (CH), 129.5 (C),
127.4 (CH), 125.6 (CH), 117.4 (CH), 116.1 (C), 112.7 (CH), 108.1 (C),
102.3 (CH), 100.6 (CH2), 82.8 (CH), 61.5 (CH), 61.3 (CH3), 59.4 (CH3),
56.1 (CH3), 45.6 (CH2), 44.4 (CH3), 42.9 (CH2), 22.7 (CH2).
HRMS (ESI): m/z [M + H]+ calcd for C29H33NO7: 506.2179; found:
506.2149.
The ligand 7 (0.10 mmol) was dissolved in anhyd toluene (1 mL) in a
test tube. The solution was stirred for 5 min. A 1.0 M solution of Et2Zn
in n-hexane (2.0 mmol, 2.0 mL) was then added, and after the mix-
ture had been stirred for 5 min at the appropriate temperature, a
solution of aldehyde (1.0 mmol) in anhyd toluene (1 mL) was added
by syringe. The mixture was stirred for the time reported in Table 2.
Sat. aq NH4Cl (10 mL) was added and the mixture was extracted with
EtOAc (3 × 10 mL). The collected organic phases were combined,
washed with H2O, dried (Na2SO4), and concentrated.
(1R,3S)-6,7-Dimethoxy-3-[(5R)-4-methoxy-6-methyl-5,6,7,8-tetra-
hydro[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-1-phenyl-1,3-dihydro-
2-benzofuran-1-ol (7c)
GC or HPLC analysis was done after suitable dilution. General method
for GC analysis: TInj: 260 °C, TDet: 260 °C (FID), H2: 1 mL/min, split
100:1.
Yield: 3.9 g (80%); yellow solid; mp 67–69 °C.
FTIR (KBr): 3445, 2943, 1621, 1479, 1263, 1086, 1045 cm–1
.
1-Phenylpropan-1-ol
1H NMR (600 MHz, CDCl3): δ = 8.54 (br s, 1 H, OH), 7.66 (dd, J = 7.2,
1.14 Hz, 2 H, HAr), 7.31 (m, 2 H, HAr), 7.25 (m, 1 H, HAr), 6.61 (d, J = 8.1
Hz, 1 H, HAr), 6.34 (s, 1 H, HAr), 5.94 (d, J = 1.4 Hz, 1 H, OCH2O), 5.91 (d,
J = 1.4 Hz, 1 H, OCH2O), 5.86 (d, J = 8.1 Hz, 1 H, HAr), 5.77 (d, J = 3.8 Hz,
1 H, CHO), 4.17 (d, J = 3.8 Hz, 1 H, CHN), 4.06 (s, 3 H, OCH3), 3.72 (s, 3
H, OCH3), 3.24 (s, 3 H, OCH3), 3.23 (s, 3 H, NCH3), 2.56–2.62 (m, 1 H,
CH2N), 2.49 (s, 3 H), 2.30–2.33 (m, 1 H, CH2N), 1.90–1.94 (m, 1 H,
CH2), 1.83–1.87 (m, 1 H, CH2).
13C NMR (150 MHz, CDCl3): δ = 152.9 (C), 148.2 (C), 143.8 (C), 142.2
(C), 140.8 (C), 139.2 (C), 134.1 (C), 132.1 (C), 129.5 (C), 127.6 (CH),
127.5 (CH), 126.7 (CH), 117.1 (CH), 116.0 (C), 113.3 (CH), 106.4(C),
102.5 (CH), 100.6 (CH2), 83.45 (CH), 61.5 (CH), 59.9 (CH3), 59.4 (CH3),
56.2 (CH3), 45.6 (CH2), 44.3 (CH3), 22.6 (CH2).
Yield: 0.134 g (99%); colorless oil; [α]D20 +41.5 (c 1.0, CHCl3) {Lit.15
[α]D20 +46.90 (c 1.0, CHCl3)}.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 90 → 110 °C (1.5 °C/min)]. tR = 24.3 min (R); tR = 25.1 min
(S).
FTIR (neat): 3360, 2963, 1490, 1450, 1377, 1200, 974 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.26–7.40 (m, 5 H, HAr), 4.59 (t, J = 6.6
Hz, 1 H, CHOH), 1.69–1.91 (m, 2 H, CH2), 0.93 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 144.7, 128.5, 127.6, 126.1, 75.9, 31.9,
10.1.
HRMS (ESI): m/z [M + Na]+ calcd for C9H12ONa: 159.0786; found:
159.0780.
HRMS (ESI): m/z [M + H]+ calcd for C28H31NO7: 492.2022; found:
492.1991.
1-(4-Fluorophenyl)propan-1-ol
Yield: 0.152 g (99%); colorless oil; [α]D20 +38.5 (c 1.0, CHCl3) {Lit.16
(5R)-5-[(1R)-4,5-Dimethoxy-3-[(Z)-phenylmethylidene]-2-benzo-
furan-1(1H)-yl]-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]diox-
olo[4,5-g]isoquinoline (8)
[α]D37 +37.0 (c 1.0, CHCl3)}.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 90 → 110 °C (1.5 °C/min)]. tR = 14.5 min (R); tR = 15.5 min
(S).
Ligand 7b (1 g, 2 mmol) and p-TsOH (70 mg, 0.4 mmol) were dis-
solved in toluene (50 mL) in a 2-necked round-bottomed flask
equipped with a Dean–Stark apparatus and refluxed for 3 h. After
completion of the reaction, the solvent was evaporated, and the resi-
due was purified by column chromatography on silica gel with n-hex-
ane/EtOAc as eluent to afford 8; yield: 0.78 g (80%); pale yellow crys-
tals; mp 188–190 °C.
FTIR (neat): 3358, 2965, 1605, 1509, 1458 1379, 1223, 1157 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.34 (m, 2 H, HAr), 7.01–7.07 (m,
2 H, HAr), 4.59 (t, J = 6.6 Hz, 1 H, CHOH), 2.01 (br s, 1 H, OH), 1.65–1.86
(m, 2 H, CH2), 0.91 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 140.3, 127.6, 127.5, 115.3, 1149, 75.2,
31.9, 10.0.
FTIR (KBr): 2945, 1645, 1619, 1492, 1270, 1033, 1003 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 7.70 (d, J = 7.4 Hz, 1 H, HAr), 7.26–7.29
(m, 2 H, HAr), 7.1 (t, J = 7.3 Hz, 1 H, HAr), 6.72 (d, J = 8.2 Hz, 1 H, HAr),
6.37 (s, 1 H, C=CH), 6.29 (s, 1 H, HAr), 6.20 (d, J = 8.2 Hz, 1 H, HAr), 5.87
(d, J = 1.5 Hz, 1 H, OCH2O), 5.84 (d, J = 1.5 Hz, 1 H, OCH2O), 5.71 (d,
HRMS (ESI): m/z [M + Na]+ calcd for C9H11FONa: 177.0692; found:
177.0689.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

G
M. Mohebbi et al.
Paper
Synthesis
1-(p-Tolyl)propan-1-ol
13C NMR (75 MHz, CDCl3): δ = 156.6, 132.4, 128.1, 127.0, 110.5, 75.1,
Yield: 0.148 g (99%); colorless oil; [α]D20 +31.5 (c 1.0, CHCl3) {Lit.16
55.2, 30.2, 10.4.
[α]D32 +31.5 (c 1.0, C6H6)}.
HRMS (ESI): m/z [M + Na]+ calcd for C10H14O2Na: 189.0891; found:
189.0889.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 80 → 110 °C (1.0 °C/min)]. tR = 24.3 min (R); tR = 25.7 min
(S).
1-[4-(Trifluoromethyl)phenyl]propan-1-ol
Yield: 0.174 g (99%); colorless oil; [α]D20 +24.2 (c 1, CHCl3) {Lit.17
FTIR (neat): 3361, 2962, 1450, 1377, 1200, 1042, 973 cm–1
.
[α]D25 +20.02 (c 1.1, CHCl3)}.
1H NMR (300 MHz, CDCl3): δ = 7.25 (d, J = 7.8 Hz, 2 H, HAr), 7.17 (d,
J = 7.8 Hz, 2 H, HAr), 4.54 (t, J = 6.7 Hz, 1 H, CHOH), 2.37 (s, 3 H, CH3),
2.05 (br s, 1 H, OH), 1.66–1.87 (m, 2 H, CH2), 0.92 (t, J = 7.5 Hz, 3 H,
CH3).
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 100 → 140 °C (1.5 °C/min)]. tR = 15.6 min (R); tR = 16.5 min
(S).
FTIR (neat): 3357, 2968, 1619, 1458, 1418, 1018, 975 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 141.7, 129.1, 127.6, 125.9, 75.8, 31.9,
1H NMR (300 MHz, CDCl3): δ = 7.58 (d, J = 8.2 Hz, 2 H, HAr), 7.42 (d,
J = 8.2 Hz, 2 H, HAr), 4.55 (t, J = 6.7 Hz, 1 H, CHOH), 1.65–1.83 (m, 2 H,
CH2), 0.90 (t, J = 7.5 Hz, 3 H, CH3).
21.1, 10.1.
HRMS (ESI): m/z [M + Na]+ calcd for C10H14ONa: 173.0942; found:
173.0945.
13C NMR (75 MHz, CDCl3): δ = 148.5, 126.2, 125.3, 75.3, 32.0, 9.9.
1-(4-Chlorophenyl)propan-1-ol
HRMS (ESI): m/z [M + H]+ calcd for C10H12F3O: 205.8400; found:
205.8360.
Yield: 0.168 g (99%); colorless oil; [α]D30.1 +39.2 (c 1.2, CHCl3) {Lit.16
[α]D37 +38.9 (c 1.2, CHCl3)}.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
1-(Naphthalen-1-yl)propan-1-ol
Yield: 0.184 g (99%); colorless oil; [α]D20 +53.5 (c 0.5, CHCl3) {Lit.17
umn [Oven 100 → 130 °C (1.0 °C/min)]. tR = 22.0 min (R); tR = 21.3 min
(S).
[α]D25 +24.5 (c 4, C6H6)}.
FTIR (neat): 3358, 2965, 1460, 1410, 1198, 1013, 975 cm–1
.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
1H NMR (300 MHz, CDCl3): δ = 7.31 (d, J = 8.8 Hz, 2 H, HAr), 7.23 (d,
J = 8.8 Hz, 2 H, HAr), 4.55 (t, J = 6.7 Hz, 1 H, CHOH), 2.31 (br s, 1 H, OH),
1.65–1.83 (m, 2 H, CH2), 0.89 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 143.0, 133.0, 128.4, 127.4, 75.2, 31.8,
10.0.
umn [Oven 120 °C (40 °C/min)]. tR 32.1 min (R); tR 33.9 min (S).
FTIR (neat): 3385, 2963, 1590, 1509, 1376, 1094, 970 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.12 (d, J = 9.0 Hz, 1 H, HAr), 7.89–7.92
(m, 1 H, HAr), 7.81 (d, J = 8.2 Hz, 1 H, HAr), 7.65 (d, J = 7.1 Hz, 1 H, HAr),
7.28–7.54 (m, 3 H, HAr), 5.39 (t, J = 6.7 Hz, 1 H, CHOH), 2.38 (br s, 1 H,
OH), 1.88–2.38 (m, 2 H, CH2), 1.05 (t, J = 7.5 Hz, 3 H, CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H11ClONa: 193.0396; found:
13C NMR (75 MHz, CDCl3): δ = 140.3, 133.8, 130.6, 128.9, 128.5, 127.8,
193.0392.
127.0, 125.9, 125.5, 123.3, 123.0, 72.5, 31.1, 10.5.
1-(2-Chlorophenyl)propan-1-ol
HRMS (ESI): m/z [M + Na]+ calcd for C13H14ONa: 209.0942; found:
209.0937.
Yield: 0.168 g (99%); colorless oil; [α]D20 +45.2 (c 3, CHCl3) {Lit.17
[α]D25 +42.2 (c 3.2, CHCl3)}.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
1-(Pyridin-4-yl)propan-1-ol
Yield: 0.113 g (60%); colorless oil; [α]D20 +50.4 (c = 0.5, CHCl3).
umn [Oven 100 → 140 °C (1.5 °C/min)]. tR = 15.6 min (R); tR = 16.5 min
(S).
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 150 °C (20 °C/min)]. tR = 13.7 min (R); tR = 14.1 min (S).
FTIR (neat): 3358, 2963, 1595, 1460, 1437, 1260, 1012 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.53 (d, J = 8.1 Hz, 1 H, HAr), 7.21–7.32
(m, 2 H, HAr), 5.05 (t, J = 6.7 Hz, 1 H, CHOH), 2.87 (br s, 1 H, OH), 1.67–
1.87 (m, 2 H, CH2), 0.98 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 142.0, 132.5, 129.2, 128.6, 127.0, 126.9,
71.8, 30.5, 10.0.
FTIR (neat): 3218, 2963, 1604, 1458, 1414, 1120, 1093, 984 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.42 (d, J = 5.3 Hz, 1 H, HAr), 7.28 (d,
J = 5.3 Hz, 1 H, HAr), 4.55 (t, J = 6.7 Hz, 1 H, CHOH), 2.28 (br s, 1 H, OH),
1.65–1.83 (m, 2 H, CH2), 0.89 (t, J = 7.5 Hz, 3H, CH3).
13C NMR (75 MHz, CDCl3): δ = 153.6, 149.5, 121.0, 74.0, 31.7, 9.7.
HRMS (ESI): m/z [M + H]+ calcd for C8H11NO: 138.0919; found:
HRMS (ESI): m/z [M + Na]+ calcd for C9H11ClONa: 193.0396; found:
193.0391.
138.0910.
1-(2-Methoxyphenyl)propan-1-ol
1-Phenylpentan-3-ol
Yield: 0.164 g (99%); colorless oil; [α]D20 +48.1 (c 1, CHCl3) {Lit.18
Yield: 0.152 g (93%); colorless oil; [α]D20 –22.5 (c 1, CHCl3) {Lit.19
[α]D20.4 +31.0 (c 1.35, CHCl3)}.
[α]D20 –22.5 (c 1.0, EtOH)}.
Enantiomeric excess determined by GC using Chiralsil-Dex CB col-
umn [Oven 100 → 180 °C (10 °C/min)]. tR = 10.6 min (R); tR = 11.5 min
(S).
FTIR (neat): 3360, 2963, 1487, 1459, 1378, 1290, 1008 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.23–7.33 (m, 2 H, HAr), 7.00–6.89 (m,
2 H, HAr), 4.80 (t, J = 6.7 Hz, 1 H, CHOH), 3.86 (s, 3 H, CH3), 2.67 (br s, 1
H, OH), 1.81–1.89 (m, 2 H, CH2), 0.97 (t, J = 7.5 Hz, 3 H, CH3).
Enantiomeric excess was determined by HPLC analysis: Chiralcel OD-
H, hexane/i-PrOH (95:5), flow rate 1.0 mL/min. tR = 11.02 min (R); tR =
16.13 min (S).
FTIR (neat): 3357, 2926, 1603, 1496 1377, 1030, 965 cm–1
.
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
M. Mohebbi et al.
Paper
Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.19–7.36 (m, 5 H, HAr), 3.56–3.65 (m,
1 H, CHOH), 2.67–2.90 (m, 2 H, CH2), 1.76–1.86 (m, 2 H, CH2), 1.45–
1.67 (m, 2 H, CH2), 1.00 (t, J = 7.5 Hz, 3 H, CH3).
13C NMR (75 MHz, CDCl3): δ = 142.5, 128.5, 125.8, 72.6, 38.7, 32.2,
30.3, 10.0.
Q.; Aoki, T.; Zhang, G.; Kaneko, T.; Teraguchi, M.; Zhang, C.;
Wang, Y. Chirality 2015, 27, 454. (d) Zhang, A.-l.; Yang, L.-w.;
Yang, N.-f.; Liu, Y.-l. Tetrahedron: Asymmetry 2014, 25, 289.
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3375. (b) Anderson, J. Chem. Commun. 1998, 393.
(4) (a) Celik, S.; Cakici, M.; Kilic, H.; Sahin, E. Tetrahedron: Asymme-
try 2015, 26, 152. (b) Gök, Y.; Kekeç, L. Tetrahedron Lett. 2014,
55, 2727.
HRMS (ESI): m/z [M + Na]+ calcd for C11H16ONa: 187.1099; found:
187.1097.
(5) Csillag, K.; Szakonyi, Z.; Fülöp, F. Tetrahedron: Asymmetry 2013,
24, 553.
Computational Methods
The optimization of structures was carried out using the density
function theory (DFT) with the B3LYP functional and the 6-31G(d,p)
basis-set as implemented with the Gaussian 09 program package in
toluene using the ‘self-consistent reaction field’ method (SCRF) with
the conductor-like polarizable calculation model (CPCM). As Macro-
Model does not contain parametrization for zinc–carbon bonds, the
initial structures of feasible complexes (catalyst + reactant) were gen-
erated using silicon instead of zinc and constraining the Si–C and Si–O
bond lengths to 2.0 ± 0.1 Å.
(6) (a) Yao, Y.; Xu, L. Mini. Rev. Org. Chem. 2016, 13, 184.
(b) Marcelli, T.; Hiemstra, H. Synthesis 2010, 1229. (c) Jarvo, E.
R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (d) Wang, T.; Han, X.;
Zhong, F.; Yao, W.; Lu, Y. Acc. Chem. Res. 2016, 49, 1369. (e) Xu,
L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047.
(7) (a) El Alami, M. S. I.; El Amrani, M. A.; Agbossou-Niedercorn, F.;
Suisse, I.; Mortreux, A. Chem. Eur. J. 2015, 21, 1398. (b) Brown,
H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992, 25, 16.
(8) (a) Groselj, U. Curr. Org. Chem. 2015, 19, 2048. (b) Chuo, T. H.;
Boobalan, R.; Chen, C. ChemistrySelect 2016, 1, 2174. (c) Ričko,
S.; Svete, J.; Štefane, B.; Perdih, A.; Golobič, A.; Meden, A.;
Grošelj, U. Adv. Synth. Catal. 2016, 358, 3786.
Funding Information
(9) (a) Bui, T.; Borregan, M.; Barbas, C. F. III. J. Org. Chem. 2009, 74,
8935. (b) Chadha, A. W. B. Y. L.; Davis, W. J. Org. Chem. 1993, 58,
844.
The authors would like to thank the Iran National Science Foundation
(INSF, grant number 94-S-43569) for financial support of the work.arIn
N
oaitn
a
l
Secince
F
o
u
n
d
o
i
n
9
4
S--4
3
5
6
9)
(10) Brzezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119,
4317.
Acknowledgment
(11) (a) Lou, L.-L.; Zhang, J.; Du, H.; Zhao, B.; Li, S.; Yu, W.; Yu, K.; Liu,
S. Catal. Today 2016, 264, 109. (b) Machajewski, T. D.; Wong, C.
H. Angew. Chem. Int. Ed. 2000, 39, 1352.
(12) (a) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
2005, 127, 11256. (b) Cui, X. Y.; Duan, H. X.; Zhang, Y.; Wang, Y.
Q. Chem. Asian J. 2016, 11, 3118.
The authors would like to thank the Shahid Beheshti University
Research Council for the facilitation of the process to conduct this
study.
(13) (a) Chen, X.; Dang, T.-T. T.; Facchini, P. J. Phytochemistry 2015,
111, 7. (b) Segal, M. S.; Goldstein, M. M.; Attinger, E. O. Chest J.
1957, 32, 305.
(14) (a) Salehi, P.; Dabiri, M.; Kozehgary, G.; Baghbanzadeh, M. Tetra-
hedron: Asymmetry 2009, 20, 2609; Highlighted in Synfacts
2010, 203. (b) Dabiri, M.; Salehi, P.; Kozehgary, G.; Heydari, S.;
Heydari, A.; Esfandyari, M. Tetrahedron: Asymmetry 2008, 19,
1970.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609224.
S
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ortioInfgrmoaitn
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p
ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H