A convergent approach towards the synthesis of the 2-alkyl-substituted tetrahydroquinoline alkaloid (?)-cuspareine

Article abstract of DOI:10.1016/j.tetasy.2017.10.023

A convergent approach towards the synthesis of the 2-alkyl-substituted tetrahydroquinoline alkaloid (?)-cuspareine via enantiospecific construction of the (R)-benzyl 2-formyl-3,4-dihydroquinoline-1(2H)-carboxylate. We have achieved an efficient enantiospe

Full text of DOI:10.1016/j.tetasy.2017.10.023

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A convergent approach towards the synthesis of the 2-alkyl-
substituted tetrahydroquinoline alkaloid (À)-cuspareine
a
a
a
a
a
a
M. V. Madhubabu , R. Shankar , T. Krishna , Y. Satish Kumar , Y. Chiranjeevi , Ch. Muralikrishna ,
a
a
b,
⇑
a,
⇑
H. Rama Mohan , Satish S. More , M. V. Basaveswara Rao , Raghunadh Akula
a
Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, India
b
Department of Chemistry, Krishna University, Machilipatnam, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent approach towards the synthesis of the 2-alkyl-substituted tetrahydroquinoline alkaloid
Received 9 October 2017
Revised 23 October 2017
Accepted 25 October 2017
Available online xxxx
(
À)-cuspareine via enantiospecific construction of the (R)-benzyl 2-formyl-3,4-dihydroquinoline-1(2H)-
carboxylate. We have achieved an efficient enantiospecific synthesis of (À)-cuspareine starting from
known key starting materials. The reactions employed for individual transformations are simple and high
yielding, and the strategy could potentially be easily extended.
Ó 2017 Elsevier Ltd. All rights reserved.
1
. Introduction
Galipinine 1, Galipeine 2, Angustureine 3 and cuspareine 4 con-
2. Results and discussion
Herein, we describe the synthesis of (À)-cuspareine 4 from
enantiomerically pure (R)-benzyl 2-formyl-3,4-dihydroquinoline-
1(2H)-carboxylate 5, obtained by the coupling of two key starting
stitute a family of anti-malaria and tetrahydroquinoline alkaloids
isolated by Jacquemond-Collet from the bark of Galipea officinalis
Hancock (Fig. 1). This shrub is indigenous to the mountains of
1
10
materials (2-nitrobenzyl)triphenylphosphonium bromide 7 and
1
1
Venezuela and belongs to the genus Galipea aublet. The biological
activity of an ethanolic extract of Galipea officinalis bark against
mycobacterium tuberculosis was initially tested by Houghton
et al.,2 which consists of approximately 20 species that are found
in northern South America. Preparations from Galipea officinalis
have been used in folk medicine for the treatment of various disor-
ders such as dysentery and fever.2 Over the years numerous syn-
thetic routes have been developed for the preparation of this
type of 2-substituted tetrahydroquinolines.3
(R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 6. The retrosyn-
thetic disconnection strategy for enantiospecific intermediate 5 is
depicted in Scheme 1. Wittig and intramolecular Mitsunobu
12
cyclization reactions are the key steps for the synthesis (R)-ben-
zyl 2-formyl-3,4-dihydroquinoline-1(2H)-carboxylate 5.
Wittig reaction between the two key starting materials
(2-nitrobenzyl)triphenylphosphonium bromide
7
and (R)-2,
2-dimethyl-1,3-dioxolane-4-carbaldehyde 6 yielded the interme-
diate 8. Reduction of the nitro to an amine under Pd/C in methanol
to obtain the amino dimethyl-1,3-dioxolane intermediate, which
on further CBZ protection of amine group with CBZ chloride and
diisopropylethylamine in dichloromethane followed by the selec-
tive cleavage of oxazolidine group with oxalic acid in acetonitrile
and water yielded the intermediate 11. The selective protection
of primary alcohol with tert-butyldimethylsilyl chloride in THF to
get the desired unprotected secondary alcohol 12 with 95% yield.
The intramolecular Mitsunobu reaction of 12 between the amide
and secondary alcohol was then attempted. Initially, the reaction
was performed with 12 using diisopropyl azodicarboxylate (DIAD),
The majority of the strategies towards the synthesis of (À)-cus-
pareine 4 are based on asymmetric hydrogenations of 2-alkyl
quinolines, which also include transfer-hydrogenations. Previous
strategies used for the synthesis of tetrahydroquinoline alkaloids
in general are enantioselective aza-michael reactions.
4
5
Asymmetric hydroamination,6 enantioselective petasis-type
7
8
reaction, asymmetric aza Diels–Alder reactions, and conjugate
addition of chiral lithium amides.9
3
triphenyl phosphine (Ph P) and the catalytic amount of pyridine
provided 2-substituted tetrahydroquinoline 13 by the cyclization
of amide with secondary alcohol under the Mitsunobu reaction
conditions. Then the selective deprotection of the alcohol with
tin(II) chloride in ethanol and water mixture followed by the
⇑
Corresponding authors.
E-mail address: raghunadha@drreddys.com (R. Akula).
https://doi.org/10.1016/j.tetasy.2017.10.023
957-4166/Ó 2017 Elsevier Ltd. All rights reserved.
0
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2
M. V. Madhubabu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
of (2-nitrobenzyl)triphenylphosphonium bromide (7) (10.0 g, 20.9
mmol) and potassium carbonate (5.8 g, 41.8 mmol) in acetonitrile
(100.0 mL) under nitrogen atmosphere. After completion of the
reaction (by TLC), distilled acetonitrile under vacuum & diluted
with water (100.0 mL). Extracted the product with ethyl acetate
(2 Â 50.0 mL) and washed with 10% aq sodium chloride solution.
The organic layer was concentrated under vacuum and the crude
product was purified column chromatography using ethyl acetate
hexanes mixture (90:10) yielded the (S,E)-2,2-dimethyl-4-(2-
nitrostyryl)-1,3-dioxolane 8 in 4.8 g (94%) as a pale yellow colour
N
N
OH
O
OMe
O
(
-)-Galipinine
(-)-Galipeine
1
2
2
5
À1
liquid. [
a
]
D
= À79.4 (c 1.37, EtOH); IR (neat, cm ): 3567, 2987,
N
1
2
862, 2374, 1717, 1523, 1374, 860, 767; H NMR (400 MHz, CDCl
3
)
N
OMe
d (ppm): 8.07 (dd, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 7.59–7.64 (m, 1H,
ArH), 7.42–7.49 (m, 2H, ArH), 6.99 (d, J = 11.6 Hz, 1H, @CHAAr),
5.84 (dd, J = 11.6 Hz, 9.2 Hz, 1H, @CHACH), 4.52–4.58 (m, 1H,
OMe
(
-)-Angustureine
(-)-Cuspareine
3
4
CHAO), 4.02 (dd, J = 8.2 Hz, 6.0 Hz, 1H, CH
.2 Hz, 1H, CH AO), 1.33 (s, 3H, CH AC), 1.44 (s, 3H, CH
NMR (100 MHz, CDCl ) d (ppm): 147.9 (ArCANO ), 133.1, 131.9,
31.6, 130.7, 130.2, 128.6 (@CHAAr), 124.7 (@CHACH), 109.5
CA(CH ), 72.2 (CHAO), 69.5 (CH AO), 26.8 (CH AC), 25.8 (CH
AC); GCMS (C.I): m/z (%) = 250.2 [M+H].
2
O), 3.67 (dd, J = 8.0 Hz,
7
2
3
3
AC); 13
C
Figure 1. Examples of natural products which contain tetrahydroquinoline
skeleton.
3
2
1
(
3
)
2
2
3
3
-
primary hydroxyl group in 14 was oxidized to the corresponding
aldehyde by using Dess Martin periodinane in dichloromethane
yielded the key intermediate (R)-benzyl 2-formyl-3,4-dihydro-
quinoline-1(2H)-carboxylate 5 with 30% yield in 8 linear steps as
shown in Scheme 2.
4.2. Synthesis of (S)-2-(2-(2,2-dimethyl-1,3-dioxolan-4-yl) ethyl)
aniline 9
Wittig reaction between (R)-benzyl 2-formyl-3,4-dihydro-
quinoline-1(2H)-carboxylate 5 and (3,4-dimethoxy benzyl)triph-
enylphosphonium bromide 1513 yielded the olefin 16 with 87%
yield, which was further subjected to hydrogenation using Pd/C
and ammonium formate in methanol to yield the CBZ deprotected
and double bond reduced 2-alkyl tetrahydroquinoline intermedi-
ate 17 with 87% yield. Finally, N-alkylation of the secondary amine
with methyl iodide and di-isopropyl ethylamine in DMF yielded
A mixture of 10% Pd/C catalyst (0.45 g) and (S,E)-2,2-dimethyl-
4-(2-nitrostyryl)-1,3-dioxolane 8 (4.5 g, 18.0 mmol) were charged
into a hydrogenator containing methanol (22.5 mL) and applied
hydrogen gas (80 psi) at 25–35 °C After completion of the reaction
(by TLC), catalyst was then filtered. Concentrated, the crude was
further purified by column chromatography yielded 9 with 95%
2
5
À1
yield. [
a
]
D
= À12.4 (c 1.06, EtOH); IR (neat, cm ): 3464, 3373,
1
3008, 2936, 2873, 1894, 1624, 1380, 1056, 937, 753, 475;
H
(
À)-cuspareine 4 from 17 in 90% yield (Scheme 3).
NMR (400 MHz, CDCl
6.74 (m, 2H, ArH), 4.08–4.15 (m, 1H, CHAO), 4.03 (dd, J = 7.8 Hz,
5.6 Hz, 1H, CH AO), 3.77 (br, 2H, NH ), 3.53 (t, J = 8.0 Hz, 1H, CH
AO), 2.56–2.70 (m, 2H, CH AAr), 1.77–1.94 (m, 2H, CH AC), 1.44
(s, 3H, CH AC), 1.37 (s, 3H, CH AC); C NMR (100 MHz, CDCl ) d
(ppm): 144.4 (ArCAN), 129.5, 127.1, 125.6, 118.6, 115.5, 108.7
(CA(CH ), 75.1 (CHAO), 69.2 (CH AO), 33.0 (CH AC), 27.1 (CH
AC), 26.9 (CH AC), 25.6 (CH AAr); MS: m/z (%) = 222.20 [M+H];
3
) d (ppm): 7.02–7.25 (m, 2H, ArH), 6.66–
This enantiospecific strategy employed for the synthesis of (À)-
Cuspareine 4 starting from (R)-2,2-dimethyl-1,3-dioxolane-4-car-
baldehyde 6 is efficient and is completed with an overall yield of
2
thesis of related natural products by choosing suitable Wittig
reagents.
2
2
2
-
2
2
1
3
2% in eleven steps. The methodology can be extended to the syn-
3
3
3
3
)
2
2
2
3
-
3
2
2
HRMS: m/z [M+H] calcd for C13H20NO [M+H]; 222.1494 [M+H];
found: 222.1493 [M+H].
3
. Conclusion
In conclusion, we have achieved enantiospecific synthesis of
4
.3. Synthesis of benzyl (S)-(2-(2-(2,2-dimethyl-1,3-dioxolan-4-
(
À)-cuspareine starting from the known key starting materials.
yl)ethyl)phenyl)carbamate 10
The strategy could be extended for the synthesis of other 2-
alkyltetrahydroquinolines.
Benzyl chloroformate (Cbz-Cl) (2.83 g, 16.6 mmol) was added to
the mixture of (S)-2-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)ani-
line 9 (3.5 g, 15.8 mmol) and di-isopropyl ethylamine (DIPEA, 3.06
g, 23.7 mmol) in DCM (35.0 mL) at 0–5 °C. Reaction was monitored
by TLC and quenched with water (17.5 mL). Separated the layers
and extracted the product with DCM (5.0 vol). Combined both
the organic layers and washed with water twice (2 Â 17.5 mL)
concentrated the organic layer and crude product was purified by
4
4
. Experimental
.1. Synthesis of (S,E)-2,2-dimethyl-4-(2-nitrostyryl)-1,3-
dioxolane 8
(R)-2,2-Dimethyl-1,3-dioxolane-4-carbaldehyde or (R)-glycer-
aldehyde acetonide 6 (2.6 g, 19.8 mmol) was added to the mixture
Br
PPh
N
O
O
3
OMe
OMe
N
CHO
NO2
Cbz
O
(
-)-Cuspareine 4
5
6
7
Scheme 1. Retrosynthetic scheme for the synthesis of 5.
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M. V. Madhubabu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Br
PPh3
O
O
O
O
O
O
K CO
2 3
10 % Pd/C
Cbz-Cl, DIPEA
DCM, 0-5 °C 1 h,
NO2
ACN, rt
NO
2
H
2
(~80 psi), MeOH
rt, 4 h, 95 %
O
12 h, 94 %
NH2
6
7
8
9
8
6 %
O
OH
OH
O
OTBDMS
OH
TBDMSCl
Oxalic acid
ACN, H O rt, 14 h,
Imidazole, THF
NHCbz
0-5 °C, 2 h, 94 %
NHCbz
2
9
NHCbz
1 %
12
10
11
DIAD,PPh3
SnCl2
Ethanol, H
DMP,DCM
OTBDMS
OH
Pyridine,THF,
N
2
O rt,
12 h, 78 %
N
rt, 2 h, 76 %
N
Cbz
5
CHO
Cbz
1
5-20 °C, 2 h, 78 %
Cbz
1
3
1
4
Scheme 2. Synthesis of 2-formyl-3,4-dihydroquinoline-1(2H)-carboxylate 5.
Br
MeO
MeO
PPh3
K CO
2
3
N
Cbz
N
CHO
Cbz
ACN, rt
OMe
5
15
12 h, 87 %
16
OMe
1
0 % Pd/C,MeOH
MeI, DIPEA
N
H
N
NH HCO , 60-65 °C
DMF, 0-5 °C
16 h, 89 %
4
2
1
6h, 93 %
OMe
OMe
(
-)-Cuspareine
1
7
OMe
4
OMe
Scheme 3. Synthesis of Cuspareine 4.
2
5
25
column chromatography yielded the 10 with 86% yield. [
a]
D
=
the product 11 with 91% yield. Melting point: 108–110 C; [
a]
D
=
À1
À1
+
97.5 (c 1.7, EtOH); IR (Neat, cm ): 3309, 3032, 2985, 2878,
952, 1732, 1538, 1371, 1048, 754, 698; H NMR (400 MHz, CDCl
+13.5 (c 1.19, Chloroform); IR (KBr, cm ): 3686, 3310, 3019,
2400, 1731, 1591, 1453, 1216, 1052, 929, 770; H NMR (400
1
1
1
3
)
d (ppm): 7.82 (br, 2H, ArH and NH), 7.32–7.42 (m, 5H, ArH), 7.03–
.24 (m, 3H, ArH), 5.19 (s, 2H, OACH AAr), 3.97 (t, J = 7.6 Hz, 1H,
CH AO), 3.89–3.94 (m, 1H, CHAO), 3.50 (t, J = 7.2 Hz, 1H, CH AO),
.71–2.79 (m, 2H, CH AAr), 1.75–1.84 (m, 2H, CH AC), 1.36 (s, 3H,
CH AC), 1.27 (s, 3H, CH ) d (ppm):
AC); 13C NMR (100 MHz, CDCl
54.2 (C@O), 136.3, 136.0, 131.1, 129.8, 128.5 (2C), 128.3 (2C),
28.2, 127.0, 124.2, 122.1, 109.2 (CA(CH ), 73.8 (CHAO), 69.2
AC), 26.8 (CH AC), 26.7
AAr); MS: m/z (%) = 356.30 [M+H]; HRMS: m/z
[M+H]; 356.1862 [M+H]; found:
MHz, CDCl
5H, ArH), 7.14–7.23 (m, 2H, ArH), 7.04–7.08 (m, 1H, ArH), 5.20 (s,
2H, OACH AAr), 3.53–3.61 (m, 2H, CH AO), 3.39–3.43 (m, 1H,
CHAO), 2.69–2.81 (m, 2H, CH AAr), 1.61–1.78 (m, 4H, CH AC
and 2 Â OH); C NMR (100 MHz, CDCl ) d (ppm): 154.5 (C@O),
136.4, 136.0, 131.9, 129.7 (2C), 128.5 (4C), 128.2 (2C), 127.0,
124.6, 70.3 (CHAO), 66.9 (OACH AAr), 66.7 (CH AO), 33.0 (CH
AC), 26.3 (CH AAr); MS: m/z (%) = 316.30 [M+H]; HRMS: m/z [M
3
) d (ppm): 7.82 (br, 2H, ArH and NH), 7.32–7.42 (m,
7
2
2
2
2
2
2
2
2
2
2
13
3
3
3
3
1
1
3
)
2
2
2
2
-
(
(
[
CH
CH
2
3
AO), 66.8 (OACH
AC), 25.2 (CH
2
AAr), 34.1 (CH
2
3
2
2
+H] calcd for
316.1563 [M+H].
C
18
H
22NO
4
[M+H]; 316.1549 [M+H]; found:
M+H] calcd for C21H26NO
4
3
56.1866 [M+H].
4
.5. Synthesis of benzyl (S)-(2-(4-((tert-Butyldimethylsilyl)oxy)-
4
.4. Synthesis of benzyl (S)-(2-(3,4-dihydroxybutyl)phenyl)
3-hydroxybutyl)phenyl)carbamate 12
carbamate 11
A solution of tert-butylchlorodimethylsilane (TBDMS-Cl, 1.5 g,
10.0 mmol) in THF (18.0 mL) was added drop wise to the reaction
mixture containing (S)-(2-(3,4-dihydroxybutyl)phenyl)carbamate
(11) (3.0 g, 9.5 mmol) and Imidazole (1.0 g, 14.2 mmol) in THF
(18.0 mL) at 0–5 °C. After completion of the reaction, slowly
quenched with water (30.0 mL) at 0–5 °C and extracted the
A mixture of oxalic acid (2.4 g, 26.6 mmol) and water (4.5 mL)
charged into the reaction mixture containing (S)-(2-(2-(2,2-
dimethyl-1,3-dioxolan-4-yl)ethyl)phenyl)carbamate 10 (4.5 g,
1
2.7 mmol) and acetonitrile (40.5 mL) under stirring at 25–35 °C.
After completion of the reaction, add water (90.0 mL) and filter
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4
M. V. Madhubabu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
product with n-heptane (2 Â 30.0 mL). The combined organic layer
(ppm): 156.3 (C@O), 136.5, 136.1, 133.3, 128.5, 128.4, 128.1,
127.9, 127.5, 127.4, 126.3, 125.9, 124.8, 67.8 (CH-N), 65.2 (OACH
Ar), 56.1 (CH AO), 25.7 (CH AC), 22.0 (CH Ar); HRMS: m/z [M+H]
[M+H]; 298.1443 [M+H]; found: 298.1438
2
5
concentrated to give 12 with 94% yield. [
a]
D
= À4.2 (c 1.01, EtOH);
2
-
À1
IR (neat, cm ): 3686, 3304, 3019, 2400, 1729, 1591, 1452, 1215,
2
2
2
1
1
124, 669, 467; H NMR (400 MHz, CDCl
OH), 7.84 (br, 1H, NH), 7.31–7.44 (m, 5H, ArH), 7.15–7.26 (m, 3H,
ArH), 7.04–7.07 (m, 1H, ArH), 5.72 (s, 2H, OACH AAr), 3.56–3.59
m, 1H, CH AOSi), 3.47–3.52 (m, 1H, CHAO), 3.35–3.39 (m, 1H,
CH AOSi), 2.80–2.88 (m, 1H, CH AAr), 2.69–2.76 (m, 1H, CH AAr),
.70–1.78 (m, 1H, CH AC), 1.60–1.66 (m, 1H, CH AC), 0.89 (s, 9H, C
CH ), 0.06 (s, 3H, CH Si), 0.05 (s, 3H, CH
Si); 13C NMR (100 MHz,
CDCl ) d (ppm): 154.4 (C@O), 136.6, 136.4, 129.8, 128.5 (2C), 128.3
2C), 128.1, 128.1, 126.9, 124.1, 122.1, 69.7 (CHAO), 67.1 (CH OSi),
), 25.9 (3C, (CH ),
Si); HRMS: m/z [M+H] calcd
3
) d (ppm): 8.08 (br, 1H,
calcd for C18
[M+H].
H20NO
3
2
(
2
4.8. Synthesis of benzyl (R)-2-formyl-3,4-dihydroquinoline-1
(2H)-carboxylate 5
2
2
2
1
(
2
2
3
)
3
3
3
Dess-Martin periodinane (2.78 g, 6.6 mmol) was charged lot
wise into the reaction mixture containing (R)-2-(hydrox-
ymethyl)-3,4-dihydroquinoline-1(2H)-carboxylate 14 (0.75 g, 2.5
mmol) and DCM (15.0 mL) at 10–15 °C. Allowed the mass to 25–
30 °C and stirred until reaction completion. After completion of
the reaction, filtered the mass and concentrated and the crude pro-
duct was further purified by column chromatography yielded 5
3
(
6
1
2
6.6 (OACH
2
Ar), 33.1 (CH
2
CH), 26.2 (CA(CH
3
)
3
3 3
)
8.3 (CH
2
Ar), À5.4 (CH
3
Si), À5.4 (CH
3
for C24
H
4
36NO Si [M+H]; 430.2414 [M+H]; found: 430.2416 [M+H].
2
5
4
.6. Synthesis of benzyl (R)-2-(((tert-butyldimethylsilyl)oxy)
with76% yields as a pale yellow colour liquid. [
a
]
D
= 69.3 (c 0.78,
À1
methyl)-3,4-dihydroquinoline-1(2H)-carboxylate 13
EtOH); IR (neat, cm ): 3683, 3020, 2958, 2852, 2400, 1700,
585, 1215, 1141, 1027, 767, 463; H NMR (400 MHz, CDCl ) d
3
1
1
To a solution of benzyl (S)-(2-(4-((tert-butyldimethylsilyl)oxy)-
-hydroxybutyl)phenyl)carbamate 12 (3.5 g, 8.2 mmol) in THF
(ppm): 9.55 (s, 1H, HAC@O), 7.72 (m, 1H, ArH), 7.31–7.37 (m,
5H, ArH), 7.20 (t, J = 7.6 Hz, 1H, ArH), 7.02–7.09 (m, 2H, ArH),
3
(
70.0 mL), under nitrogen atmosphere was added triphenyl phos-
5.31 (d, J = 12.4 Hz, 1H, OACH
OACH AAr), 4.82 (t, J = 7.2 Hz, 1H, CHAN), 2.68–2.72 (m, 2H, CH
Ar), 2.26–2.30 (m, 1H, CH AC), 1.96–2.05 (m, 1H, CH
AC); 13C NMR
(100 MHz, CDCl ) d (ppm): 199.9 (HAC@O), 154.9 (NAC@O), 136.5,
135.7, 128.6, 128.6 (2C), 128.3, 128.2 (2C), 128.1, 127.5, 126.7,
124.4, 68.2 (CHAN), 62.8 (OACH Ar), 25.4 (CH AC), 24.8 (CH Ar);
[M+H]; 296.1287 [M+H];
2
AAr), 5.21 (d, J = 12.4 Hz, 1H,
phine (4.3 g, 16.3 mmol) and pyridine (0.35 mL), and cooled the
reaction mixture to below 15–20 °C. A solution of Di isopropyl
aza dicarboxylate (DIAD, 3.3 g, 16.3 mmol) in THF (35.0 mL) was
added into the reaction mixture at 15–20 °C for 5–10 min, and stir-
red for 4 h. After reaction completion, RM was quenched with
water (140.0 mL) and extracted the product with hexanes (2 Â
2
2
-
2
2
3
2
2
2
HRMS: m/z [M+H] calcd for C18H18NO
3
3
5.0 mL). The organic layer concentrated and purified by column
found: 296.1294 [M+H].
25
D
chromatography yielded the 13 with 78% yield. [a] = +86.0 (c
0
1
.78, EtOH); IR (neat): 3685, 3019, 2956, 2400, 1695, 1472, 1215,
025, 757, 669, 454; H NMR (400 MHz, CDCl ) d (ppm): 7.53 (d,
3
4.9. Synthesis of (R,E)-benzyl 2-(3,4-dimethoxystyryl)-3,4-
dihydroquinoline-1(2H)-carboxylate 16
1
J = 7.6 Hz, 1H, ArH), 7.27–7.39 (m, 4H, ArH), 7.13–7.19 (m, 2H,
ArH), 7.08 (d, J = 6.0 Hz, 1H, ArH), 6.99–7.04 (m, 1H, ArH), 5.29
(R)-Benzyl 2-formyl-3,4-dihydroquinoline-1(2H)-carboxylate 5
(1.0 g, 3.4 mmol) was added to the mixture of (3,4-dimethoxyben-
zyl)triphenylphosphonium bromide 15 (1.75 g, 3.5 mmol) and
anhydrous potassium carbonate (0.9 g, 6.8 mmol) in anhydrous
acetonitrile (10.0 mL) under nitrogen atmosphere. After comple-
tion of the reaction (by TLC), distilled acetonitrile under vacuum
and diluted with water (100.0 mL). Extracted the product with
ethyl acetate (2 Â 10.0 mL) and washed with 10% aq. Sodium chlo-
ride solution. The organic layer was concentrated under vacuum
and the crude product was purified by column chromatography
yielded 16 with 87% yield as an off-white colour solid. Melting
(
d, J = 12.4 Hz, 1H, OACH
2
AAr), 5.17 (d, J = 12.8 Hz, 1H, OACH
AOSi),
AAr), 2.19–
AC), 0.80 (s, 9H, C
Si); 13C NMR (100
) d (ppm): 154.9 (C@O), 137.3, 136.5, 128.5 (2C),
28.0, 127.9 (2C), 127.4, 126.0 (2C), 125.4, 124.1, 67.4 (CHAN),
3.8 (OACH Ar), 55.0 (CH AOSi), 25.8 (CA(CH ), 25.7 (3C,
), 25.4 (CH CH), 18.1 (CH Si); HRMS: m/z
Ar), À5.5 (2C, CH
M+H] calcd for C24 Si [M+H]; 412.2308 [M+H]; found:
2
-
AAr), 4.57–4.62 (m, 1H, CHAN), 3.65–3.69 (m, 1H, CH
2
3
.49–3.53 (m, 1H, CH
.27 (m, 1H, CH AC), 1.74–1.80 (m, 1H, CH
), À0.04 (s, 3H, CH Si), À0.06 (s, 3H, CH
MHz, CDCl
2 2
AOSi), 2.61–2.68 (m, 2H, CH
2
(
2
2
3
CH )
3
3
3
3
1
6
(
[
2
2
3 3
)
3
CH )
3
2
2
3
H34NO
3
2
5
À1
4
12.2292 [M+H].
point: 125–127 °C; [
a]
D
= +67.5 (c 0.44, EtOH); IR (KBr, cm ):
1
3
370, 3029, 2918, 1693, 1317, 1157, 755, 667, 458; H NMR
4
.7. Synthesis of benzyl (R)-2-(hydroxymethyl)-3,4-dihydro
(400 MHz, CDCl
(m, 5H, ArH), 7.12–7.19 (m, 3H, ArH), 6.99–7.05 (m, 3H, ArH),
.59 (dd, J = 14.4 Hz, 1.2 Hz, 1H, @CHAAr), 6.23 (dd, J = 12.0 Hz,
3
) d (ppm): 7.67 (d, J = 8.4 Hz, 1H, ArH), 7.29–7.39
quinoline-1(2H)-carboxylate 14
6
A mixture of stannous chloride (SnCl
2
, 0.46 g, 2.4 mmol) and
5.2 Hz, 1H, @CHAC), 5.16–5.24 (m, 3H, CH-N and OACH
2
AAr),
AAr),
water (2.0 mL) charged into the reaction mixture containing ((R)-
-(((tert-butyldimethylsilyl)oxy)methyl)-3,4-dihydroquinoline-1
2H)-carboxylate 13 (2.0 g, 4.9 mmol) and ethanol (18.0 mL) under
3.75 (s, 3H, OCH
2.22–2.29 (m, 1H, CH
(100 MHz, CDCl
3
), 3.73 (s, 3H, OCH
3
), 2.64–2.75 (m, 2H, CH
2
2
(
2
AC), 1.79–1.84 (m, 1H, CH
2
AC); 13C NMR
3
) d (ppm): 154.7 (C@O), 149.2 (ArCAOMe), 148.4
stirring at 25–35 °C. After completion of the reaction, diluted with
water (40.0 mL) and extracted the product with Methyl tertiary
butyl ether (MTBE, 2 Â 10.0 mL). The combined organic Layer con-
centrated and crude product was purified by column chromatogra-
(ArCAOMe), 136.8, 136.3, 131.5 (@CHAAr), 129.8 (@CHAC),
129.4, 128. 128.5 (2C), 128.0 (2C), 128.0 (2C), 126.2, 125.1, 124.1,
115.2, 114.3, 109.0, 67.6 (CHAN), 56.1 (CH
55.5 (OACH AAr), 30.0 (CH AC), 25.3 (CH AAr); MS: m/z (%) =
430.30 [M+H].
3 3
AO), 56.0 (CH AO),
2
2
2
25
phy yielded the 14 with 78% yield as a colorless liquid. [
a
]
D
= 86.1
À1
(
c 0.99, CHCl
3
); IR (neat, cm ): 3677, 3426, 3018, 2954, 2401,
1
1
690, 1398, 1050, 758, 697, 468; H NMR (400 MHz, CDCl
3
) d
4.10. Synthesis of (S)-2-(3,4-dimethoxyphenethyl)-1,2,3,4-
(
ppm): 7.43 (d, J = 8.0 Hz, 1H, ArH), 7.28–7.37 (m, 4H, ArH), 7.15–
tetrahydroquinoline 17
7
1
.20 (m, 2H, ArH), 7.04–7.11 (m, 2H, ArH), 5.31 (d, J = 12.0 Hz,
H, OACH AAr), 5.15 (d, J = 12.0 Hz, 1H, OACH AAr), 4.62–4.69
AO), 3.50–3.55 (m, 1H, CH
AAr and CH AC), 2.26–2.34 (m, 1H,
AC), 1.49–1.56 (m, 1H, OH); C NMR (100 MHz, CDCl ) d
2
2
A mixture of 10% Pd/C catalyst (0.2 g) and (R,E)-benzyl
(
m, 1H, CH-N), 3.59–3.63 (m, 1H, CH
AO), 2.59–2.69 (m, 3H, CH
CH
2
2
-
2-(3,4-dimethoxystyryl)-3,4-dihydroquinoline-1(2H)-carboxylate 16
(1.0 g, 2.4 mmol) were charged into the round bottom flask
containing methanol (22.5 mL) and ammonium formate (2.0 g).
2
2
1
3
2
3
Please cite this article in press as: Madhubabu, M. V.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.023

M. V. Madhubabu et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Warmed the reaction mass to 60–65 °C and stirred. After comple-
A. Supplementary data
tion of the reaction (by TLC), catalyst was then filtered off under
vacuum. Filtrate was concentrated and the crude was purified by
column chromatography yielded 17 with 93% yield as a pale yellow
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetasy.2017.10.023.
2
5
À1
colour liquid. [
a
]
D
= À65.9 (c 0.96, Chloroform); IR (neat, cm ):
3
389, 3018, 2954, 2400, 1697, 1489, 1215, 1042, 939, 755, 471;
References
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H NMR (400 MHz, CDCl
3
) d (ppm): 6.95–6.99 (m, 2H, ArH),
.74–6.80 (m, 3H, ArH), 6.61 (td, J = 13.6 Hz, 1.6 Hz, 1H, ArH),
.45 (d, J = 8.4 Hz, 1H, ArH), 3.88 (s, 3H, OCH ), 3.87 (s, 3H,
), 3.72 (br, 1H, NH), 3.30–3.34 (m, 1H, CHAN), 2.73–2.83
m, 2H, CH AAr), 2.68–2.72 (m, 2H, CH AAr), 1.97–2.04 (m, 1H,
AC), 1.80–1.86 (m, 2H, CH AC), 1.65–1.74 (m, 1H, CH AC);
NMR (100 MHz, CDCl (ppm): 148.9 (ArCAO), 147.3
ArCAO), 144.5 (ArCAN), 134.5, 129.2, 126.7, 121.3, 120.1, 117.1,
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14.1, 111.7, 111.3, 56.0 (CH
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2
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2
m/z (%) = 298.20 [M+H].
6
5
55–666; (i) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem. Commun. 2007, 504–
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.11. Synthesis of (À)-Cuspareine 4
Methyl iodide (MeI) (2.83 g, 16.6 mmol) was added to the mix-
4
.
(a) Wang, W. B.; Lu, S. M.; Yang, P. Y.; Han, X. W.; Zhou, Y. G. J. Am. Chem. Soc.
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Vidal, V. Synlett 2007, 2743; (e) Wang, D. W.; Zeng, W.; Zhou, Y. G. Tetrahedron:
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ture of (S)-2-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroquino-
line 17 (0.5 g, 1.7 mmol) and di-isopropyl ethylamine (DIPEA, 0.5
g, 3.7 mmol) in DMF (5.0 mL) at 0–5 °C. After completion of the
reaction, RM was quenched with water (10.0 mL) and extracted
with methyl tertiary butyl ether (MTBE, 5.0 vol) and organic layer
washed with water (2 Â 17.5 mL), organic layer was concentrated
and crude product was purified by column chromatography
5
2
640; (g) Gou, F. R.; Li, W.; Zhang, X.; Liang, Y. M. Adv. Synth. Catal. 2010, 352,
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5
.
2
5
14
yielded pure (À)-Cuspareine 4 with 89% yield. [
a
]
D
= À20.6 (c
À1
1
1
.24, Chloroform); IR (neat, cm ): 3685, 3390, 3020, 2937, 2400,
6. Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577.
7. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686.
601, 1500, 1260, 1028, 625, 479; 1H NMR (400 MHz, CDCl
3
) d
8
9
.
.
a) Ishitani, H.; Kobayashi, S. Tetrahedron 2003, 59, 6785.
Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Thomson, J. E. Org. Lett.
(
ppm): 7.08 (t, J = 8.0 Hz, 1H, ArH), 6.98 (d, J = 8.0 Hz, 1H, ArH),
.78 (d, J = 8.4 Hz, 1H, ArH), 6.71–6.74 (m, 2H, ArH), 6.59 (t, J =
6
7
3
2
2
1
1
1
2011, 13, 2544.
.2 Hz, 1H, ArH), 6.53 (d, J = 8.4 Hz, 1H, ArH), 3.87 (s, 3H, OCH
.85 (s, 3H, OCH ), 3.27–3.30 (m, 1H, CHAN), 2.91 (s, 3H, NCH
.81–2.85 (m, 1H, CH AAr), 2.63–2.72 (m, 2H, CH
.57 (m, 1H, CH AAr), 1.88–1.96 (m, 3H, CH AC and CH
AC); 1 C NMR (100 MHz, CDCl
.73–1.76 (m, 1H, CH ) d (ppm):
3
),
10. Nguyen, V. H.; Vendier, L.; Etienne, M.; Despagnet-Ayoub, E.; Breuil, P. A. R.;
Magna, L.; Proriol, D.; Olivier-Bourbigou, H.; Lorber, C.; Eur, J. Org. Chem 2011,
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1. Chavan, S. P.; Khairnar, L. B.; Pawar, K. P.; Chavan, P. N.; Kawale, S. A. RSC Adv.
3
3
),
4, 6877.
2
2
AAr), 2.51–
AAr),
1
2015, 5, 50580.
2
2
2
3
12. (a) Theeraladanon, C.; Arisawa, M.; Nakagawa, M. Tetrahedron: Asymmetry
005, 16, 827; (b) Jae-Sang, R. Bull. Korean Chem. Soc. 2006, 27, 631; (c) Yuvraj,
2
3
2
48.9 (ArCAO), 147.2 (ArCAO), 145.3 (ArCAN), 134.6, 128.7,
27.1, 121.7, 120.0, 115.4, 111.6, 111.3, 110.6, 58.4 (CHAN), 55.9
G.; Suraksha, G.; Satyendra Kumar, P. RSC Adv. 2015, 5, 38846; (d) Munoz, G. D.;
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3. (a) Alonso, F.; Riente, P.; Yus, M.; Eur, J. Org. Chem 2009, 34, 6034; (b) Zheng, Y.;
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Crisenza, G. E. M.; Dauncey, E. M.; Bower, J. F. Org. Biol. Chem. 2016, 14, 5820.
(
(
[
[
CH
CH
3
AO), 55.9 (CH
AAr), 24.4 (CH
3
AO), 38.1 (CH
3 2
AN), 33.1 (CH AC), 31.9
2
2
AC), 23.5 (CH AAr); MS: m/z (%) = 312.30
2
1
2
M+H]; HRMS: m/z [M+H] calcd for C20H26NO [M+H]; 312.1964
M+H]; found: 312.1961 [M+H].
Please cite this article in press as: Madhubabu, M. V.; et al. Tetrahedron: Asymmetry (2017), https://doi.org/10.1016/j.tetasy.2017.10.023