Enantiospecific Synthesis of (-)-Cuspareine and (-)-Galipinine

Article abstract of DOI:10.1002/jhet.2112

An enantiospecific route to the synthesis of tetrahydroquinoline alkaloids (-)-cuspareine and (-)-galipinine is reported. Coupling of an iodide derivative of D-serine with aromatic dithianes and Pd-catalyzed intramolecular C-N coupling are the key steps in the synthesis.

Full text of DOI:10.1002/jhet.2112

1
902
Enantiospecific Synthesis of (–)-Cuspareine and (–)-Galipinine
Vol 52
Shibin Chacko and Ramesh Ramapanicker*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, India 208016
*
E-mail: rameshr@iitk.ac.in
Received June 12, 2013
DOI 10.1002/jhet.2112
Published online 16 December 2014 in Wiley Online Library (wileyonlinelibrary.com).
An enantiospecific route to the synthesis of tetrahydroquinoline alkaloids (–)-cuspareine and (–)-galipinine
is reported. Coupling of an iodide derivative of D-serine with aromatic dithianes and Pd-catalyzed intramo-
lecular C–N coupling are the key steps in the synthesis.
J. Heterocyclic Chem., 52, 1902 (2015).
INTRODUCTION
–)-Cuspareine (1a) and (–)-galipinine (1b) are among the
RESULTS AND DISCUSSION
(
We have recently demonstrated the use of an iodide deriv-
ative of serine 2, for the synthesis of unusual amino acid de-
rivatives [11]. Similarly, an umpolung reaction between 2,
prepared from D-serine and aromatic dithianes (3a or 3b)
was carried out (n-BuLi, THF, À20°C) to get 4 (Scheme 2).
The reaction proceeded smoothly and the coupled products
were isolated in very good yields. These reactions do not lead
to stereo randomization of 3, and the stereochemistry of the
iodide derivative is retained in 4 [11]. The dithiane group
was then reduced to get the corresponding oxazolidine deriv-
atives 5 using a recently reported procedure, employing
NiCl ·6H O/NaBH (CH OH, THF, r. t.) [12]. 5 was care-
tetrahydroquinoline alkaloids isolated from the bark of
Galipea officinalis Hancock, a Venezuelan tree [1]. The po-
tential utility of extracts from these trees as antimalarials and
cytotoxic substances [2] has spurred interest in their chemical
synthesis. Most of the strategies towards their synthesis are
based on asymmetric hydrogenations of 2-alkyl quinolines,
which also include transfer-hydrogenations [3]. Other strate-
gies used for the synthesis of tetrahydroquinoline alkaloids in
general are asymmetric hydroamination [4], asymmetric aza
Diels–Alder reactions [5], enantioselective Petasis-type reac-
tion [6], enantioselective aza-Michael reactions [7], and con-
jugate addition of chiral lithium amides [8], and there are
reports on their racemic synthesis [9].
All of the syntheses available for these compounds are
based on asymmetric transformations, which do not always
proceed with good selectivity. Enantiospecific strategies
based on asymmetric starting materials are available for a
related compound (+)-angustureine, but are based on un-
common starting materials, which are not easily available
and are difficult to make [10]. We report here an
enantiospecific synthesis of 1a and 1b starting from an
iodide derivative 2, derived from D-serine (Scheme 1).
An umpolung reaction between 2-aryl dithianes as the ini-
tial step and a Pd-catalyzed intramolecular C–N coupling
later are the key steps (Scheme 1). The strategy is quite
general and could potentially be used for the synthesis
of related molecules.
2
2
4
3
fully treated with TFA (7% in CH OH, r. t.) to selectively
3
cleave the oxazolidine group. Under the conditions used,
the Boc group remained intact, and the amino alcohols 6
were obtained in very good yields. The primary hydroxyl
group in 6 was oxidized to the corresponding aldehydes
using IBX (1.5 equiv, DMSO, r. t.) to obtain the amino
aldehyde derivatives 7. Upon Wittig reaction using the ylide
derived from (2-bromobenzyl)triphenylphosphonium bro-
mide (t-BuOK, CH Cl , À10°C), 7 yielded the olefin 8 as a
2
2
mixture of cis–trans isomers. The diastereomers of 8 were
purified as a mixture and were subjected to hydrogenation
using Rh/Al O (C H OH, H , r. t.), which yielded the Boc
2
3
2
5
2
protected amine 9 in very good yields. The reduction of
8 to 9 could be carried out only using Rh; the use of Pd/C
resulted in the debromination of the aromatic ring. Com-
pound 9 was then subjected to an intramolecular C–N
©
2014 HeteroCorporation

November 2015
Synthesis of (–)-Cuspareine and (–)-Galipinine
1903
Scheme 1. Retrosynthetic strategy for 1a and 1b.
individual transformations are simple and high yielding.
The strategy could be extended for the synthesis of other
2
-alkyltetrahydroquinolines.
EXPERIMENTAL
General.
All the chemicals were purchased from
commercial sources and were used without further purification.
1
13
H and C NMR spectra were recorded either on a 400 MHz
13
13
(
100 MHz for C) or on a 500 MHz (125 MHz for C) JEOL-
1
Lambda NMR spectrometer at 25°C. The H NMR signals are
13
referenced to TMS (δ = 0.00 ppm) and the C NMR peaks are
referenced to the residual CHCl3 signal (δ = 77.0 ppm). The
chemical shifts are reported in parts per million and coupling
constants in Hz. The multiplicities are assigned as s (singlet), d
(
doublet), t (triplet), bs (broad singlet), dd (double doublet), and
coupling using Pd(OAc) as a catalyst (rac-BINAP, Cs CO ,
toluene, reflux) to get the tetrahydroquinoline derivative 10 in
very high yields. Reduction of the N-Boc group to an N-
2
2
3
m (multiplet). High-resolution mass spectra were obtained using
a Waters Q/Tof Premier micromass HAB 213 spectrometer with
an ESI source. IR spectra were recorded on a Bruker Vector 22
FTIR instrument, and melting points were recorded on a DBK
Automatic Programmable digital instrument. Column
chromatography was performed using 100–200 mesh silica gel,
and appropriate mixtures of petroleum ether (PE) and EtOAc
were used as eluent.
Synthesis of 4a and 4b. Aromatic dithiane 3 (1.200 g of 3a
or 1.280 g of 3b, 5 mmol) was dissolved in dry THF (10 mL) and
was cooled to À20°C; n-BuLi (3.4 mL of 1.6 M solution in
hexane, 5.5 mmol) was added to the above solution drop wise.
The reaction mixture turned orange indicating the formation
of the anion, which was stirred for 40 min at À20°C and
the iodide 2 (1.023 g, 3 mmol) in THF (3 mL) was added
over a period of 15 min and the stirring continued. The
reaction was monitored with TLC, until the complete
disappearance of the iodide (1 to 1.5 h). The reaction was
methyl group using LiAlH (7 equiv. in THF, reflux) yielded
4
1
from 10 in excellent yields. This enantiospecific strategy
employed for the synthesis of 1a and 1b starting from 2 is very
efficient and is completed in eight steps with an overall yield
of 32% for 1a and 33% for 1b. The methodology can be
extended to the synthesis of other 2-alkyltetrahydroquinoline
derivatives by choosing suitable dithiane derivatives.
CONCLUSION
In conclusion, we have achieved a very efficient
enantiospecific synthesis of 1a and 1b starting from
readily available materials. The reactions employed for
Scheme 2. Synthesis of 1a and 1b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
904
S. Chacko and R. Ramapanicker
Vol 52
13
quenched with a saturated solution of NH Cl (10 mL) and
ppm; C NMR (CDCl , 125 MHz): δ = 156.5, 148.9, 147.3,
4
3
was extracted with EtOAc (3 × 50 mL). The organic layers
134.1, 120.2, 111.7, 111.3, 93.7, 79.7, 65.9, 57.9, 55.9, 55.8, 33.5,
were pooled, dried over anhydrous Na
removed under vacuum. The crude product (3) was purified by
column chromatography.
N-Boc-(S)-4-((2-(benzo[d][1,3]dioxol-5-yl)-1,3-dithian-2-yl)
methyl)-2,2-dimethyloxazolidine, 4a.
2
SO
4
, and the solvent was
32.4, 31.0, 28.4 ppm; HRMS (ES): m/z calcd for C20
[M+Na ]: 388.2100; found: 388.2101.
H
31NO
5
+
Acidolysis of 5 to 6.
The oxazolidine (0.349 g of 5a or
0
.365 g of 5b, 1 mmol) was cooled to 0°C and a solution of
Clear oil (1.046 g,
trifluoroacetic acid (7%) in methanol (3 mL) was added drop
wise. The reaction was monitored through TLC, until the
complete disappearance of the starting material and was
7
2
7%). [α]D = 21.9 (c = 0.86, CHCl ); IR (thin film): 2977,
927, 1694, 1490, 1389, 1365, 1245, 1039 cm
3
À1
1
; H NMR
(
3
CDCl , 500 MHz), mixture of rotamers: δ = 7.46–7.43 (m,
3
neutralized with NaHCO (0.500 g). The solution was diluted
2
3
2
1
H), 6.78–6.77 (m, 1H), 5.96 (s, 2H), 4.16–3.98 (m, 1H),
.55–3.46 (m, 1H), 3.07–2.92 (m, 1H), 2.72–2.47 (m, 4H),
.49–2.26 (m, 1H), 2.16–2.03 (m, 1H), 1.95–1.87 (m, 2H),
with methanol (5 mL) and filtered; the filtrate was concentrated
under vacuum and the crude N-protected amino alcohols (6)
were purified by column chromatography.
1
3
3
.48,1.33 (2 bs, 15H) ppm; C NMR (CDCl , 125 MHz),
(
S)-2-(tert-Butyloxycarbonylamino)-amino-4-(benzo[d][1,3]
mixture of rotamers: δ = 151.5, 148.5, 148.4, 146.8, 135.4,
dioxol-5-yl)butan-1-ol, 6a. White solid (0.281 g, 91%). Mp
1
9
2
35.0, 122.7, 122.4, 109.4, 109.2, 108.3, 101.4, 101.3, 93.2,
2.6, 80.4, 80.1, 67.4, 57.6, 57.3, 54.2, 53.9, 48.1, 47.4, 28.8,
8
2
8–89°C. [α]D = 42.8 (c = 0.58, CHCl ); IR (KBr): 3395,
3
1
À1
975, 2926, 1686, 1503, 1489, 1245, 1169, 1039 cm
, 500 MHz): δ = 6.70 (d, J = 7.75 Hz, 1H), 6.66
s, 1H), 6.61 (d, J = 7.75 Hz, 1H), 5.90 (s, 2H), 4.69 (d, J =
7.4 Hz, 1H), 3.64–3.54 (m, 3H), 2.65–2.53 (m, 2H), 1.80–1.74
; H
8.5, 27.6, 27.5, 26.9, 24.9, 24.4 ppm; HRMS (ES): m/z calcd
NMR (CDCl
(
3
+
for C22
H
31NO
5
S
2
[M+H ]: 454.1722; found: 454.1726.
N-Boc-(S)-4-((2-(3,4-dimethoxyphenyl)-1,3-dithian-2-yl)
methyl)-2,2-dimethyloxazolidine, 4b. Clear oil (1.154 g,
); IR (thin film): 2931, 1695,
H NMR (CDCl , 500 MHz), mixture of
1
3
(m, 1H), 1.72–1.64 (m, 1H), 1.44 (s, 9H) ppm; C NMR
82%). [α]
D
= 20.0 (c = 0.20, CHCl
3
(CDCl , 125 MHz): δ = 156.5, 147.7, 145.8, 135.3, 121.1,
3
À1
1
1387, 1026 cm
;
108.8, 108.3, 100.8, 79.7, 65.9, 52.4, 33.5, 32.2, 28.4 ppm;
3
+
rotamers: δ = 7.50–7.47 (m, 2H), 6.85–6.84 (m, 1H), 4.15–4.01 (m,
HRMS (ES): m/z calcd for C H NO [M+Na ]: 332.1474;
1
6
23
5
1H), 3.87 (s, 6H), 3.50–3.44 (m, 1H), 2.99–2.89 (m, 1H), 2.72–
found: 332.1472.
2
.52 (m, 4H), 2.17–2.09 (m, 1H), 1.92–1.90 (m, 2H), 1.49, 1.33 (2
(S)-2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)
13
bs, 15H) ppm; C NMR (CDCl
δ = 151.5, 149.3, 149.2, 148.2, 133.6, 133.5, 121.6, 121.2, 112.1,
3
, 125 MHz), mixture of rotamers:
butan-1-ol, 6b. Clear oil (0.283 g, 87%). [α] = 36.8 (c = 0.51,
D
À1
1
CHCl ); IR (thin film): 3360, 2927, 1687, 1516 cm ; H NMR
3
1
11.8, 111.2, 111.1, 111.0, 93.0, 92.6, 80.4, 80.1, 67.4, 57.0, 57.2,
(CDCl , 500 MHz): δ = 6.78–6.70 (m, 3H), 3.85 (s, 3H), 3.83
3
56.1, 55.9, 54.3, 54.0, 48.1, 47.2, 29.7, 28.8, 28.5, 27.7, 25.0 ppm;
(s, 3H), 3.69–3.63 (m, 2H), 3.56–3.53 (m, 1H), 2.68–2.56 (m,
+
13
HRMS (ES): m/z calcd for C23
H
35NO
5
S
2
[M+Na ]: 492.1854;
2H), 1.84–1.69 (m, 2H), 1.43 (s, 9H) ppm; C NMR (CDCl3,
found: 492.1856.
125 MHz): δ = 156.3, 148.0, 147.1, 133.9, 120.1, 111.7, 79.7,
6
6.0, 56.0, 55.9, 52.4, 33.5, 32.0, 28.4 ppm; HRMS (ES): m/z
Reduction of 4 to 5. To a stirred solution of the dithiane
0.453 g of 4a or 0.469 g of 4b, 1 mmol) in MeOH:THF (8:2,
+
calcd for C H NO [M+Na ]: 348.1787; found: 348.1780.
(
17 27
5
1
0 mL), NiCl
2
·6H
2
O (1.66 g, 7 mmol) was added at 0°C and
(0.76 g, 20 mmol) was
Oxidation of 6 to 7. The N-protected amino alcohol (0.309
g of 6a or 0.325 g of 6b, 1 mmol) was dissolved in DMSO (5 mL)
and IBX (0.420 g, 1.5 mmol) was added at r. t. (30°C). The
reaction mixture was stirred for 5 h and was quenched with
was vigorously stirred for 5 min; NaBH
4
added to this mixture in small portions over a period of 5 min.
The temperature was allowed to attain r. t. (30°C) and the
progress of the reaction was monitored through TLC. On
complete disappearance of the starting material, reaction was
saturated NaHCO solution (10 mL). The aldehyde was extracted
3
from the crude solution with ethyl acetate (3 × 15 mL); the
quenched by the addition of saturated NaHCO
3
(10 mL) and the
organic layers were pooled together and washed with brine
crude product was extracted with dichloromethane (3 × 15 mL).
The crude solution containing the product was dried by passing
(2 × 15 mL), dried over anhydrous Na SO4 and concentrated
under reduced pressure. The crude products were purified by
2
through a bed of anhydrous Na
2
SO
4
and the oxazolidine
column chromatography.
derivatives (5) were further purified by column chromatography.
N-Boc-(S)-4-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-2,2-
(S)-2-(tert-Butyloxycarbonylamino)-4-(benzo[d][1,3]dioxol-
5-yl)butanal, 7a. Clear oil (0.236 g, 77%). [α]D = 17.7 (c =
dimethyloxazolidine, 5a. Clear oil (0.314 g, 90%). [α] = 49.1 (c
0.45, CHCl ); IR (thin film): 3376, 2976, 2919, 1702, 1503,
D
3
À1
1
=
0.55, CHCl ); IR (thin film): 2977, 2918, 2850, 1694, 1481, 1387,
1490, 1246, 1166, 1039 cm ; H NMR (CDCl , 500 MHz): δ
3
3
À1
1
1
3
237, 1038 cm ; H NMR (CDCl , 500 MHz): δ = 6.68–6.58 (m,
= 9.52 (s, 1H), 6.71 (d, J = 7.75 Hz, 1H), 6.65 (s, 1H), 6.61
3
H), 5.88 (s, 2H), 3.91–3.71 (m, 3H), 2.58–2.42 (m, 2H), 2.07–1.90
(d, J = 7.75 Hz, 1H), 5.91 (s, 2H), 5.08 (bs, 1H), 4.21–4.20
(m, 1H), 2.61 (t, J = 6.9 Hz, 2H), 2.20–2.13 (m, 1H), 1.85–
13
(m, 1H), 1.82–1.70 (m, 1H), 1.58, 1.42 (bs, 15H) ppm; C NMR
1
3
(CDCl , 125 MHz): δ = 152.2, 151.8, 147.7, 147.6, 145.8, 145.7,
1.78 (m, 1H), 1.44 (s, 9H) ppm; C NMR (CDCl , 125
3
3
1
6
2
3
35.5, 135.2, 121.0, 108.9, 108.2, 100.8, 93.7, 93.2, 80.1, 79.5,
MHz): δ = 199.6, 155.6, 147.8, 146.1, 134.3, 121.3, 108.9,
6.8, 66.7, 57.5, 56.8, 35.5, 34.9, 32.5, 28.5, 27.6, 26.8, 24.5,
100.9, 80.2, 59.5, 31.2, 28.3 ppm; HRMS (ES): m/z calcd for
+
+
3.3 ppm; HRMS (ES): m/z calcd for C19
H
27NO
5
[M+Na ]:
C H NO [M+Na ]: 330.1317; found: 330.1317.
1
6
21
5
72.1787; found: 372.1789.
(S)-2-(tert-Butyloxycarbonylamino)-4-(3,4-dimethoxyphenyl)
N-Boc-(S)-4-(3,4-dimethoxyphenethyl)-2,2-dimethyloxazolidine,
butanal, 7b. Clear oil (0.265 g, 82%). [α]D = 25.7 (c = 0.16,
5
b. Clear oil (0.325 g, 89%). [α] = 9.0 (c = 0.08, CHCl ); IR (thin
CHCl ); IR (thin film): 3356, 2934, 2836, 1707, 1516, 1261,
D
3
3
À1 1
À1
1
film): 2927, 1693, 1515, 1029 cm ; H NMR (CDCl
3
, 500 MHz): δ
1159, 1028 cm ; H NMR (CDCl , 500 MHz): δ = 9.53 (s, 1H),
3
=
6.78–6.66 (m, 3H), 3.86 (s, 3H), 3.83 (s, 3H), 3.92–3.76 (m, 3H),
6.78–6.76 (m, 1H), 6.71–6.67 (m, 2H), 5.08 (bs, 1H), 4.24–4.23
2.60–2.46 (m, 2H), 1.93–1.77 (m, 2H), 1.47 (s, 9H), 1.42 (s, 6H)
(m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.64 (t, J = 7.47 Hz, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2015
Synthesis of (–)-Cuspareine and (–)-Galipinine
1905
1
3
2
(
.21–2.15 (m, 1H), 1.87–1.79 (m, 1H), 1.44 (s, 9H) ppm; C NMR
2.49 (m, 2H), 2.21–2.17 (m, 1H), 1.82–1.75 (m, 1H), 1.68–1.56
13
CDCl , 125 MHz): δ = 199.7, 155.6, 149.0, 147.5, 133.1, 120.3,
(m, 2H), 1.49 (s, 9H) ppm; C NMR (CDCl , 125 MHz): δ =
3
3
1
11.8, 111.3, 80.2, 59.5, 55.9, 55.9, 31.1, 31.1, 28.3 ppm; HRMS
154.1, 147.5, 145.6, 137.0, 135.8, 130.9, 128.1, 125.9, 125.8,
+
(ES): m/z calcd for C17
H25NO
5
[M+Na ]: 346.1630; found:
123.8, 121.0, 108.9, 108.1, 100.7, 80.6, 52.0, 34.9, 32.3, 28.5,
+
3
46.1647.
28.4, 24.5 ppm; HRMS (ES): m/z calcd for C23
04.1838; found: 404.1830.
Boc-(S)-2-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroquinoline,
0b. Clear oil (0.345 g, 87%). [α] = 29.3 (c = 0.71, CHCl ); IR
thin film): 2928, 2852, 1692, 1515, 1332, 1258, 1159, 1030 cm
H27NO
4
[M+Na ]:
4
Conversion of 7 to 9 through 8. Amino aldehyde (0.368 g
of 7a or 0.388 g of 7b, 1.2 mmol) in anhydrous DCM (4 mL) was
added drop wise to a precooled (to À10°C) solution of (2-
bromobenzyl)triphenylphosphonium bromide (1.229 g, 2.4
mmol) and t-BuOK (0.171 g, 1.4 mmol) in dry DCM (20 mL)
under nitrogen atmosphere. After completion of reaction as
observed in TLC, the mixture was quenched with saturated
sodium bicarbonate solution (10 mL) and extracted with DCM
1
(
D
3
À1
;
1
H NMR (CDCl , 400 MHz): δ = 7.43–7.41 (m, 1H), 7.16–6.94 (m,
3
3H), 6.71–6.59 (m, 3H), 4.56–4.50 (m, 1H), 3.78 (2 bs, 6H), 2.68–
2
.65 (m, 2H), 2.57–2.51 (m, 2H), 2.21–2.12 (m, 1H), 1.83–1.73 (m,
13
1
H), 1.68–1.58 (m, 2H), 1.45 (s, 9H) ppm; C NMR (CDCl
MHz): δ = 154.1, 148.8, 147.1, 137.0, 134.7, 131.0, 128.1, 126.0,
25.7, 123.9, 120.1, 111.7, 111.2, 80.6, 56.0, 55.8, 52.2, 34.9, 32.1,
3
, 125
(
2 × 15 mL). The product 8 was isolated as a mixture of
1
diastereomers by passing through a silica bed and was taken to
the next step without further purification.
2
8.6, 28.4, 24.6 ppm; HRMS (ES): m/z calcd for C H NO [M
24 31
4
+
+
Na ]: 420.2151; found: 420.2155.
Reduction of 10 to 1. LiAlH
portion wise to a solution of 10 (0.381 g of 10a or 0.397 g of 10b,
mmol) in dry THF (20 mL) at r. t. and refluxed until the
To a stirred solution of 8 (as obtained from the previous step),
4
(0.266 g, 7 mmol) was added
in ethanol (25 mL) Rh on alumina (5%, 100 mg) was added. The
reaction mixture was stirred for 2 h at r. t. (30°C) under H atmo-
2
sphere (1 atm). On completion of the reaction, the inorganic
residues were removed by filtration through a celite pad and the
solvent evaporated under vacuum and the crude product was
purified by column chromatography.
1
complete disappearance of 10 on TLC. After the completion,
reaction mixture was cooled to 0°C and was quenched by the
drop wise addition of water and the solution was basified with
1
(
0% NaOH solution. The mixture was extracted with diethyl ether
3 × 15 mL) and the combined organic layer was dried over
anhydrous Na SO and the solvent was removed under vacuum.
(
S)-1-(Benzo[d][1,3]dioxol-5-yl)-5-(2-bromophenyl)-3-(tert-
butyloxycarbonylamino)pentane, 9a. White solid (0.499 g,
0% after two steps). Mp: 84–85°C. [α]D = 12.5 (c = 0.40,
9
2
4
The crude products were purified by column chromatography.
3
CHCl ); IR (KBr): 3349, 2922, 2852, 1697, 1503, 1489, 1244,
1
7
À1
1
(
–)-Cuspareine (1a). Clear oil (0.244 g, 83%). [α]
D
= –22.4
169, 1040 cm ; H NMR (CDCl
3
, 500 MHz): δ = 7.50 (d, J =
[1b]
(
1
c = 1.33, CHCl
3
), lit: –22.8; IR (thin film): 2926, 1602, 1500,
.7 Hz, 1H), 7.28–7.15 (m, 2H), 7.06–7.02 (m, 1H), 6.71- 6.61
À1
1
489, 1244, 1039 cm ; H NMR (CDCl , 500 MHz): δ = 7.08 (t,
(
2
m, 3H), 5.90 (s, 2H), 4.40–4.33 (m, 1H), 3.72–3.64 (m, 1H),
.84–2.78 (m, 1H), 2.74–2.53 (m, 3H), 1.81–1.58 (m, 4H), 1.46
3
J = 7.5 Hz, 1H), 6.97 (d, J = 7.15 Hz, 1H), 6.73–6.71 (m, 1H),
.68 (s, 1H), 6.64–6.63 (m, 1H), 6.59 (t, J = 7.15 Hz, 1H), 6.52
d, J = 8.3 Hz, 1H), 5.91 (s, 2H), 3.29–3.24 (m, 1H), 2.9 (s,
13
6
(
(
s, 9H), ppm; C NMR (CDCl
3
, 125 MHz): δ = 155.7, 147.6,
45.7, 135.8, 132.9, 130.5, 128.4, 128.4, 127.6, 127.6, 121.1,
08.9, 108.2, 100.8, 79.2, 50.4, 37.8, 35.9, 32.8, 32.2, 28.5 ppm;
1
1
3
1
1
1
2
H), 2.87–2.80 (m, 1H), 2.70–2.60 (m, 2H), 2.53–2.47 (m, 1H),
13
+
.97–1.84 (m, 3H), 1.73–1.66 (m, 1H) ppm; C NMR (CDCl3,
25 MHz): δ = 147.6, 145.6, 145.3, 135.9, 128.7, 127.2, 121.7,
21.0, 115.0, 110.7, 108.8, 108.2, 100.8, 58.3, 38.1, 33.2, 32.1,
HRMS (ES): m/z calcd for C H BrNO [M+Na ]: 484.1099;
found: 484.1090.
S)-1-(2-Bromophenyl)-5-(3,4-dimethoxyphenyl)-3-(tert-
butyloxycarbonylamino)pentane, 9b.
g, 94% after two steps). Mp: 80–81°C. [α]
2
3
28
4
(
2
4.4, 23.6 ppm; HRMS (ES): m/z calcd for C19H21NO [M
White solid (0.538
D
= 18.0 (c = 0.16,
+
+
H ]: 296.1651; found: 296.1655.
–)-Galipinine (1b). Yellow oil (0.242 g, 72%). [α] = –33.9
(
CHCl
3
); IR (KBr): 3363, 2931, 1685, 1519, 1240, 1155, 1030
D
[1b]
À1
1
3
(c = 1.38, CHCl ), lit: –33.4; IR (thin film): 2924, 2853, 1515,
cm ; H NMR (CDCl , 400 MHz): δ = 7.43 (d, J = 8.0 Hz, 1H),
7
3
À1
1
1463 cm ; H NMR (CDCl
3
, 400 MHz): δ = 7.01 (t, J = 9.3 Hz,
.14–7.08 (m, 2H), 6.99–6.95 (m, 1H), 6.72–6.64 (m, 3H), 4.35
1H), 6.91 (d, J = 8.85 Hz, 1H), 6.72–6.70 (m, 1H), 6.66–6.63
(
(
bs, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.67–3.63 (m, 1H), 2.79–2.48
m, 4H), 1.78–1.52 (m, 4H), 1.39 (s, 9H) ppm; C NMR (CDCl ,
3
1
3
(m, 2H), 6.54–6.50 (m, 1H), 6.45 (d, J = 9.7 Hz, 1H), 3.79 (s, 3H),
3
.78 (s, 3H), 3.23–3.20 (m, 1H), 2.84 (s, 3H), 2.82–2.73 (m, 1H),
.64–2.56 (m, 2H), 2.49–2.41 (m, 1H), 1.98–1.78 (m, 4H) ppm;
1
1
3
25 MHz): δ = 155.8, 148.9, 147.2, 141.3, 134.6, 132.8, 130.5,
28.4, 127.7, 127.6, 120.2, 111.8, 111.3, 79.2, 56.0, 55.9, 50.3,
2
1
3
C NMR (CDCl
128.7, 127.2, 121.7, 121.7, 120.1, 115.4, 111.2, 110.6, 58.2, 55.7,
5.7, 37.9, 32.9, 31.8, 24.3, 23.5 ppm; HRMS (ES): m/z calcd for
3
, 125 MHz): δ = 148.9, 147.2, 145.3, 134.7,
7.8, 36.0, 32.8, 32.0, 28.5 ppm; HRMS (ES): m/z calcd for
+
C
24
H
32BrNO
4
[M+Na ]: 502.1392; found: 502.1386.
5
Cyclization of 9 to 10. A solution of 9 (0.461 g of 9a or
.477 g of 9b, 1 mmol), Pd(OAc) (0.022 g, 0.1 mmol), rac-
BINAP (0.075 g, 0.12 mmol), and Cs CO (0.456 g, 1.4 mmol)
+
C H NO [M+H ]: 312.1964; found: 312.1967.
20
25
2
0
2
2
3
Acknowledgments. The authors thank the Department of Science
and Technology (India) for financial support. S. C. thanks the
Council of Scientific and Industrial Research (CSIR), New
Delhi for a Senior Research Fellowship.
in dry toluene (15 mL) was refluxed for 6 h. After completion
of the reaction, solvent was removed under reduced pressure
and the residue purified through column chromatography.
Boc-(S)-2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-1,2,3,4-
tetrahydroquinoline, 10a. Clear oil (0.342 g, 90%). [α] = 24.7
D
(
1
c = 0.56, CHCl ); IR (thin film): 2919, 2850, 1691, 1490, 1331,
245, 1167, 1039 cm ; H NMR (CDCl , 500 MHz): δ = 7.47
3
3
À1
1
REFERENCES AND NOTES
(
7
(
d, J = 7.75 Hz, 1H), 7.15–7.12 (m, 1H), 7.07–7.06 (m, 1H),
.01–6.99 (m, 1H), 6.69–6.67 (m, 1H), 6.60–6.56 (m, 2H), 5.88
s, 2H), 4.53 (q, J = 6.3 Hz, 1H), 2.70 (t, J = 6.3 Hz, 2H), 2.60–
[1] (a) Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.;
Fourasté, I.; Moulis, C. Phytochemistry 1999, 51, 1167; (b) Rakotoson, J. H.;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
906
S. Chacko and R. Ramapanicker
Vol 52
[
5] (a) Ishitani, H.; Kobayashi, S. Tetrahedron Lett 1996, 37, 7357; (b)
Fabre, N.; Jacquemond-Collet, I.; Hannedouche, S.; Fouraste, I.; Moulis, C.
Planta Med 1998, 64, 762; (c) Jacquemond-Collet, I.; Bessiere, J. M.;
Hannedouche, S.; Bertrand, C.; Fouraste, I.; Moulis, C. Phytochem Anal
Akiyama, T.; Morita, H.; Fuchibe, K. J Am Chem Soc 2006, 128, 13070; (c)
Avemaria, F.; Vanderheiden, S.; Bräse, S. Tetrahedron 2003, 59, 6785.
[
6] Yamaoka, Y.; Miyabe, H.; Takemoto, Y. J Am Chem Soc
007, 129, 6686.
7] (a) Fustero, S.; Moscardó, J.; Jiménez, D.; Pérez-Carrión, M. D.;
2
001, 12, 312.
2] Jacquemond-Collet, I.; Benoit-Vical, C.; Mustofa; Valentin, A.;
Stanislas, E.; Mallie, M.; Fouraste, I. Planta Med 2002, 68, 68.
3] (a) Wang, W. B.; Lu, S. M.; Yang, P. Y.; Han, X. W.; Zhou, Y. G.
2
[
[
Sánchez-Roselló, M.; del Pozo, C. Chem Eur J 2008, 14, 9868; (b) Taylor, L. L.;
Goldberg, F. W.; Hii, K. K. Org Biomol Chem 2012, 10, 4424.
[
J Am Chem Soc 2003, 125, 10536; (b) Lu, S. M.; Wang, Y. Q.; Han, X. W.;
Zhou, Y. G. Angew Chem Int Ed 2006, 45, 2260; (c) Rueping, M.;
Antonchick A. P.; Theissmann, T. Angew Chem Int Ed 2006, 45,
[
8] Bentley S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.;
Thomson, J. E. Org Lett 2011, 13, 2544.
9] (a) Shahane, S.; Louafi, F.; Moreau, J.; Hurvois, J. P.; Renaud,
[
3
683; (d) Deport, C.; Buchotte, M.; Abecassis, K.; Tadaoka, H.; Ayad, T.;
Ohshima, T.; Genet, J. P.; Mashima, K.; Ratovelomanana-Vidal, V. Synlett
007, 2743; (e) Wang, D. W.; Zeng, W.; Zhou, Y. G. Tetrahedron: Asymme-
try 2007, 18, 1103; (f) Wang, X. B.; Zhou, Y. G. J Org Chem 2008, 73,
J. L.; van de Weghe, P.; Roisnel, T. Eur J Org Chem 2008, 4622;
(b) O’Byrne, A.; Evans, P. Tetrahedron 2008, 64, 8067.
[10] (a) Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida, A.
Tetrahedron: Asymmetry 2005, 16, 827; (b) Ryu, J. S. Bull Korean
Chem Soc 2006, 27, 631; (c) Lin, X. F.; Li, Y.; Ma, D. W. Chin J Chem
2004, 22, 932.
2
5
2
640; (g) Gou, F. R.; Li, W.; Zhang, X.; Liang, Y. M. Adv Synth Catal
010, 352, 2441; (h) Wang, T.; Zhuo, L. G.; Li, Z.; Chen, F.; Ding, Z.;
He, Y.; Fan, Q. H.; Xiang, J.; Yu, Z. X.; Chan, A. S. C. J Am Chem
Soc 2011, 133, 9878.
[11] Chacko, S.; Ramapanicker, R. Eur J Org Chem 2012, 7120.
[12] Khurana, J. M.; Magoo, D. Synth Commun 2010, 40, 2908.
[4] Patil, N. T.; Wu, H.; Yamamoto, Y. J Org Chem 2007, 72, 6577.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet