A facile biogenetic synthesis of pulcheotine A

Article abstract of DOI:10.1055/s-2008-1067162

Starting from homopiperonylamine and 4-methoxyphenylacetic acid, a facile biogenetic route to naturally occurring pulcheotine A has been demonstrated via Pictet-Spengler cyclization and two different air oxidation processes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067162

SHORT PAPER
2321
A Facile Biogenetic Synthesis of Pulcheotine A
B
iogenetic Sy
r
nthesis
o
a
f
Pulcheotin
s
e
A
ad B. Wakchaure, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory, Pune 411008, India
E-mail: np.argade@ncl.res.in
Received 31 March 2008; revised 21 April 2008
that herein both the oxidation processes, viz. methylene to
carbonyl and dihydroisoquinoline to isoquinoline, occur
by the base-catalyzed formation of corresponding peroxy
linkages.
Abstract: Starting from homopiperonylamine and 4-methoxyphe-
nylacetic acid, a facile biogenetic route to naturally occurring pul-
cheotine A has been demonstrated via Pictet–Spengler cyclization
and two different air oxidation processes.
Key words: homopiperonylamine, 4-methoxyphenylacetic acid,
Pictet–Spengler cyclization, regioselective air oxidations, pulcheo-
tine A
O
O
O
O
N
NH
O
i
Pulcheotine A (1) has been isolated from Ocotea pulchel-
la.1 Pulcheotine and its congeners have been synthesized
from the coupling reaction of an appropriate amine with
vicinal tricarbonyl compounds,2 a-chloro-a-phenyl
thioketones,3 or phenylglyoxal.4 The air oxidation of the
benzylic methylene group to the corresponding carbonyl
compound in the presence of platinum-on-charcoal is
known in the literature.5 We reasoned and proposed that
4-methoxyphenylacetic acid would be the best biogenetic
precursor for the synthesis of 1. Herein we report the di-
rect and stepwise synthesis of 1 via Pictet–Spengler cy-
clization and two very regioselective air oxidation
reactions (Scheme 1).
3
2
OMe
OMe
iv
77%
ii
78%
O
O
O
iii
N
N
O
86%
O
O
OMe
OMe
1
4
Scheme 1 Reagents and conditions: (i) POCl3, benzene, 80 °C, 2 h;
(ii) DBU, CH2Cl2, r.t., 2 h, 78%; (iii) DBU, CH2Cl2, r.t., 24 h, 86%;
(iv) POCl3, benzene, 80 °C, 2 h, then DBU, CH2Cl2, r.t., 24 h, 77%.
The carbodiimide-induced dehydrative coupling reaction
of homopiperonylamine with 4-methoxyphenylacetic
acid furnished the required amide 2 in 86% yield. The
amide 2, on treatment with phosphorus oxychloride, gave
the desired intermediate dihydroisoquinoline 3 via dehy-
drative intramolecular cyclization. Herein, we confirmed
the formation of 3 only by thin layer chromatography; we
did not isolate 3 because of its instability to silica gel col-
umn chromatography. We proposed that the doubly acti-
vated (allylic and benzylic) methylene will undergo a
rapid air oxidation process proving that the simple 4-
methoxyphenylacetic acid is the better precursor for the
synthesis of 1. As expected the dihydroisoquinoline 3 on
treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene at 25
°C for two hours, almost exclusively furnished the expect-
ed ketone 4 in 78% yield via a facile regioselective base-
catalyzed air oxidation process. The dihydroisoquinoline
4 again on treatment with 1,8-diazabicyclo[5.4.0]undec-
7-ene at 25 °C for 24 hours, underwent a smooth second
air oxidation process and gave the expected natural prod-
uct pulcheotine A (1) in 86% yield. The repetition of both
In summary, we have completed the direct and stepwise
efficient synthesis of pulcheotine A by taking advantage
of two facile air oxidations. We feel that the present ap-
proach is general in nature and it will be useful for the de-
sign of focused combinatorial libraries of natural and
unnatural isoquinoline analogues and congeners for the
study of structure–activity relationships.
1H NMR spectra were recorded on a Bruker AC 200 (200 MHz)
spectrometer using TMS as an internal standard. 13C NMR spectra
were recorded on a Bruker AC 200 (50 MHz) spectrometer. FT-IR
spectra were recorded on a Shimadzu FT-IR-8300 spectrophotome-
ter. Column chromatographic separations were carried out on silica
gel (60–120 mesh); PE = petroleum ether (bp 60–80 °C).
N-[2-(1,2-Benzodioxol-5-yl)ethyl]-2-(4-methoxyphenyl)acet-
amide (2)
To a stirred soln of 4-methoxyphenylacetic acid (1 g, 6.02 mmol) in
CH2Cl2 (15 mL) at 0 °C was added EDCI (1.26 g, 6.66 mmol) and
the Pictet–Spengler cyclization and two air oxidation a catalytic amount of DMAP (20 mg). The mixture was stirred un-
der an inert atmosphere for 20 min. Homopiperonylamine (993 mg,
6.02 mmol) in CH2Cl2 (7 mL) was added to this mixture in a drop-
wise fashion over 10 min and it was further stirred at 25 °C for 4 h.
The mixture was diluted with H2O (25 mL) and extracted with
EtOAc (3 × 25 mL). The organic layer was washed with H2O and
brine and dried (Na2SO4). Concentration of the organic layer in
steps in one pot also furnished 1 in 77% yield. We surmise
SYNTHESIS 2008, No. 15, pp 2321–2322
x
x.
x
x
.
2
0
0
8
Advanced online publication: 08.07.2008
DOI: 10.1055/s-2008-1067162; Art ID: Z07108SS
© Georg Thieme Verlag Stuttgart · New York

2322
P. B. Wakchaure, N. P. Argade
SHORT PAPER
vacuo followed by column chromatographic purification of the ob-
tained residue (silica gel, PE–EtOAc, 1:1) gave 2 as a white crystal-
line solid (1.61 g, 86%); mp 86–88 °C.
IR (Nujol): 3248, 1641, 1610 cm–1.
stirred at 25 °C for 24 h. The mixture was concentrated in vacuo and
the obtained residue was purified by column chromatography (silica
gel, PE–EtOAc, 7:3) to give 1 as a yellow crystalline solid (256 mg,
86%).
Method B: Compound 1 can also be directly synthesized in 77%
yield by repeating the above imine preparation and air oxidation
procedures in one pot; mp 150–151 °C (Lit.1a 152–153 °C).
IR (CHCl3): 1661, 1599 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.64 (t, J = 6 Hz, 2 H), 3.41 (q,
J = 6 Hz, 2 H), 3.51 (s, 2 H), 3.81 (s, 3 H), 5.62 (br s, 1 H), 5.92 (s,
2 H), 6.45 (dd, J = 8, 2 Hz, 1 H), 6.53 (d, J = 2 Hz, 1 H), 6.66 (d,
J = 8 Hz, 1 H), 6.85 (d, J = 8 Hz, 2 H), 7.09 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 35.0, 40.8, 42.6, 55.2, 100.8, 108.2,
1H NMR (200 MHz, CDCl3): d = 3.81 (s, 3 H), 6.06 (s, 2 H), 6.88
(d, J = 8 Hz, 2 H), 7.11 (s, 1 H), 7.38 (s, 1 H), 7.62 (d, J = 6 Hz, 1
H), 7.84 (d, J = 8 Hz, 2 H), 8.38 (d, J = 6 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = 55.5, 101.8, 102.1, 102.7, 113.7,
121.8, 123.7, 129.4, 133.1, 135.6, 139.9, 149.3, 151.2, 154.4, 164.0,
193.2.
108.9, 114.3, 121.5, 126.4, 130.5, 132.2, 146.0, 147.6, 158.8, 171.6.
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
69.11; H, 6.04; N, 4.39.
(7,8-Dihydro-1,3-dioxolo[4,5-g]isoquinolin-5-yl)(4-methoxy-
phenyl)methanone (4)
Anal. Calcd for C18H13NO4: C, 70.35; H, 4.26; N, 4.55. Found: C,
70.42; H, 4.17; N, 4.42.
To a stirred soln of amide 2 (750 mg, 2.39 mmol) in benzene (25
mL) at 25 °C was added POCl3 (1.37 mL, 14.37 mmol) in a drop-
wise fashion. The mixture was heated at 80 °C for 2 h under N2. The
mixture was then cooled to 25 °C and excess POCl3 and solvent
were removed in vacuo. The thus formed yellow-colored residue
was dissolved in CH2Cl2 (20 mL) and DBU (1.00 mL, 7.17 mmol)
was added, the mixture was stirred at 25 °C for 2 h, and it then was
concentrated in vacuo. The obtained residue was purified by col-
umn chromatography (silica gel, PE–EtOAc, 3:2) to provide 4 as a
yellow crystalline solid (580 mg, 78%); mp 130–132 °C.
Acknowledgement
P.B.W. thanks CSIR, New Delhi, for the award of a research fel-
lowship.
References
IR (Nujol): 1651, 1599 cm–1.
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M.; Gottlieb, O. R. Phytochemistry 1993, 32, 1331.
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F. D. A. M. Phytochemistry 1980, 19, 995.
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Soc., Perkin Trans. 1 1982, 2163.
1H NMR (200 MHz, CDCl3): d = 2.90 (dd, J = 8, 8 Hz, 2 H), 3.88
(s, 3 H), 3.95 (dd, J = 8, 8 Hz, 2 H), 6.00 (s, 2 H), 6.77 (s, 1 H), 6.85
(s, 1 H), 6.96 (d, J = 8 Hz, 2 H), 7.98 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 25.8, 46.5, 55.5, 101.5, 107.2,
108.3, 113.9, 120.2, 128.0, 132.7, 133.2, 146.6, 150.3, 164.4, 165.0,
191.8.
Anal. Calcd for C18H15NO4: C, 69.89; H, 4.88; N, 4.52. Found: C,
69.70; H, 4.99; N, 4.38.
(1,3-Dioxolo[4,5-g]isoquinolin-5-yl)(4-methoxyphenyl)metha-
none (Pulcheotine A, 1)
Method A: To a stirred soln of 4 (300 mg, 0.97 mmol) in CH2Cl2 (10
mL) was added DBU (0.44 mL, 2.91 mmol) and the mixture was
Synthesis 2008, No. 15, 2321–2322 © Thieme Stuttgart · New York