Determination of the absolute configuration of picrasidine Y, a naturally occurring β-carboline alkaloid

Article abstract of DOI:10.1016/j.tetlet.2015.07.079

Abstract The absolute configuration of picrasidine Y, a β-carboline alkaloid isolated from Picrasma quassioides (Simaroubaceae), has not been determined. To determine the absolute configuration of picrasidine Y, we synthesized stereoisomers of picrasidine Y through 7-step chemical reactions using tartaric acid as a starting material. Moreover, we extended the scope of application of this synthetic method to canthin-5,6-dione compounds. The absolute configuration of natural picrasidine Y was elucidated based on comparisons of chemically synthesized isoforms with the naturally occurring compound in ¹H and ¹³C NMR spectra, specific optical rotation, HPLC analysis with chiral columns, computational molecular simulation, and analysis with the CD exciton chirality method.

Full text of DOI:10.1016/j.tetlet.2015.07.079

Tetrahedron Letters 56 (2015) 5306–5308
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Determination of the absolute configuration of picrasidine Y,
a naturally occurring b-carboline alkaloid
a,
⇑
a
b
a
a
Kazuo Koike , Hiroshi Yoshino , Hong-yu Li , Tatsunori Sasaki , Wei Li
a
Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan
College of Pharmacy, Department of Pharmacology and Toxicology, The University of Arizona, Tucson, AZ 85721, USA
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The absolute configuration of picrasidine Y, a b-carboline alkaloid isolated from Picrasma quassioides
Simaroubaceae), has not been determined. To determine the absolute configuration of picrasidine Y,
Received 26 June 2015
Accepted 29 July 2015
Available online 1 August 2015
(
we synthesized stereoisomers of picrasidine Y through 7-step chemical reactions using tartaric acid as
a starting material. Moreover, we extended the scope of application of this synthetic method to
canthin-5,6-dione compounds. The absolute configuration of natural picrasidine Y was elucidated based
Keywords:
Absolute configuration
Picrasidine Y
b-Carboline alkaloid
Canthin-5,6-dione
Picrasma
1
13
on comparisons of chemically synthesized isoforms with the naturally occurring compound in H and
C
NMR spectra, specific optical rotation, HPLC analysis with chiral columns, computational molecular
simulation, and analysis with the CD exciton chirality method.
Ó 2015 Elsevier Ltd. All rights reserved.
Picrasma quassioides and other plants in the Picrasma genus of
the Simaroubaceae family are used as bitter stomachics for gastritis,
loss of appetite, and indigestion in Chinese and Japanese traditional
medicine. In addition to limonoids, a large number of b-carboline
and canthinone alkaloids have been isolated from these
L-tartaric acid (2a) was treated with acetic anhydride to yield
the O-protected acid anhydride 3a in one step, which was then
converted to the half-ester 4a with methanol. The carboxylic acid
was converted to the acid chloride 5a with thionyl chloride. The
1
production of 5a was monitored by H NMR spectroscopy.
1
–19
plants.
Furthermore, these alkaloids have been reported to
Specifically, after the 2 h reaction, a broad signal at d
two doublet signals at d 5.72 and 5.75 assignable, respectively,
to the carboxylic acid and two methine protons in 4a disappeared,
and the new methine proton signals shifted to lower field (d 5.83
and 5.91) were observed. Next, 5a was allowed to react with bub-
bling hydrogen in the presence of 5% Pd-BaSO in a xylene reflux to
H
9.84 and
have a variety of biological activities, including PTP1B-inhibition,
anti-inflammatory activity, cAMP-phosphodiesterase inhibition,
H
6
,14,17–19
and cytotoxicity.
Picrasidine
Y
(1) isolated from
H
P. quassioides is a b-carboline alkaloid, and the absolute configura-
tion of the propionic acid side chain at position 1 of the backbone
structure has not been determined (Fig. 1).16 In the present study,
we synthesized stereoisomers of picrasidine Y through 7-step
chemical reactions using tartaric acid as a starting material. We
then determined the absolute configuration of natural picrasidine
Y (1) by comparing chemically synthesized isoforms with the
4
obtain aldehyde 6a through the Rosenmund reduction. The struc-
ture of 6a was confirmed by the appearance of a low-field signal
1
at d
H
9.45 for the aldehyde moiety in the H NMR spectrum and
C
the downfield shift of a carbonyl signal at d C
194.7 in the 13
NMR spectrum.
1
13
naturally occurring compound in H and C NMR spectra, specific
optical rotation, HPLC analysis with chiral columns, computational
molecular simulation, and analysis with the CD exciton chirality
method.
Next, 6a was treated with tryptamine in the presence of triflu-
oroacetic acid (TFA) to construct the b-carboline backbone through
Stereoisomers of picrasidine Y were synthesized from
acid (2R,3R, 2a), -tartaric acid (2S,3S, 2b), and meso-tartaric acid
2c) (Scheme 1). The synthetic methods for these compounds are
L-tartaric
D
N
N
H
HO
1
(
1'
2'
COOH
explained using the one starting from
representative.
L-tartaric acid (2a) as a
OH
Picrasidine Y (1)
⇑
Corresponding author. Tel.: +81 47 4721396; fax: +81 47 4721404.
E-mail address: koike@phar.toho-u.ac.jp (K. Koike).
Figure 1. Chemical structure of natural occurring picrasidine Y.
http://dx.doi.org/10.1016/j.tetlet.2015.07.079
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

K. Koike et al. / Tetrahedron Letters 56 (2015) 5306–5308
5307
O
AcO
AcO
AcO
COOH
AcO
AcO
COCl
AcO
AcO
CHO
HO
HO
COOH
COOH
Ac O
MeOH
rt
SOCl2
60 o
2
5
% Pd-BaSO , H2
4
O
8
0 o
C
C
Xylene, 120 o
AcO
COOMe
COOMe
C
COOMe
O
2a: 2R,3R
2b: 2S,3S
2c: meso
3
a - 3c
4a - 4c
5a - 5c
6a - 6c
1
) 1N NaOH, 10 min
) 1N HCl
2
DDQ
THF, 5 - 10 o
Tryptamine, TFA
CH Cl , -50 oC
NH
COOMe
OAc
N
3) ODS CC
N
N
H
AcO
N
H
AcO
N
H
HO
C
1'
2
2
COOMe
OAc
2' COOH
OH
1'S, 2'R
b:1'R, 2'S
c:1'S, 2'S and 1'R, 2'R
7
a - 7c
8a - 8c
9a
9
9
:
1
N NaOH
rt. 24 hr
NH
N
O
O
11
Scheme 1.
0
0
0
0
(
1 S,2 S and 1 R,2 R) were compared with those of the natural picra-
sidine Y (1). The spectra of the natural picrasidine Y (1) were com-
pletely identical to those of 9c, but were slightly different from
N
N
O
H H
AcO
0
0
0
0
those of 9a (1 S,2 R) and 9b (1 R,2 S). While the specific rotation
OAc
25
D
for the natural compound was [a] -30°, the values for 9a and 9b
were +104° and -104°, respectively, revealing large differences. The
natural picrasidine Y (1) was also chromatographically compared
with synthesized optical isomers 9a (1 S,2 R), 9b (1 R,2 S), and 9c
1
0a - 10b
0
0
0
0
Figure 2. Chemical structure of 10a and 10b, and ORTEP structure of compound
0a.
0
0
0
0
1
(1 S,2 S and 1 R,2 R) using chiral HPLC analysis (CHIRAL PAK AD-RH
CN/H O = 2:3, flow rate:
0
.46 ꢁ 15 cm, mobile phase CH
3
2
the Pictet–Spengler reaction. When this reaction was carried out at
room temperature, the carbonyl part of the methyl ester group of
a reacted with the amino group at position 2 to release methanol
and form an amide bond, and thereby compound 10a containing a
-membered ring was produced in a large amount (Fig. 2).
0.5 mL/min) (Fig. 3). The analytical peak of the natural compound
1 was similar in retention time (3.55 min) to one of the peaks
detected for the racemic 9c synthesized from meso-tartaric acid,
but differed from 9a and 9b. These data indicate that the absolute
6
0
0
0
0
5
configuration of picrasidine Y (1) is either 1 S,2 S or 1 R,2 R in 9c,
and have ruled out the possibility that 9a or 9b has the same config-
uration as 1.
However, when the reaction was carried out at ꢀ50 °C, the produc-
tion of the by-product 10a was suppressed and the desired 1,2,3,
4
-tetrahydro-b-carboline 7a was obtained.
Compound 7a was an epimer as a new chiral center was created
at position 1 of b-carboline. DDQ oxidation of 7a at or below 10 °C
yielded compound 8a containing the aromatized C ring. Finally,
the deprotective deacetylation of compound 8a yielded
0
0
1
S,2 R-picrasidine Y (9a).
It is worth noting that the compound 8a was converted to a
highly-fluorescent canthin-5,6-dione compound (11) by a 24 h agi-
tation in MeOH at 50 °C or in 1 N NaOH at room temperature
(Scheme 1). The mechanism underlying production of compound
1
1 presumably involves lactam ring formation through the indole
NH and the carbonyl group, followed by dehydration to yield com-
pound 11. Canthin-5,6-dione derivatives represent a major group
of alkaloids found in P. quassioides and have been reported to show
the potent anticancer cytotoxicity and PTP1B inhibitory activ-
1
8,19
ity.
Using the synthetic method described here, it may be pos-
sible to synthesize chemical derivatives with longer alkyl chains or
other substituting groups after constructing the canthin-5,6-dione
backbone.
0
0
0
0
1
R,2 S-picrasidine Y (9b) and a mixture of enantiomers 1 S, 2 S-
0
0
and 1 R,2 R-picrasidine Y (9c) were synthesized from D-tartaric
acid (2S,3S, 2b) and meso-tartaric acid (2c), respectively, with
methods similar to those described above. H and C NMR data
Figure 3. Chiral HPLC. HPLC chromatograms of natural and synthetic picrasidine Y.
Daicell AD-RH 4.6 mm l.d ꢁ 150 mm, and an isocratic mode of 40% MeCN (aq) in
15 min was used with detection at 254 nm.
1
13
0
0
0
0
of optical isomers synthesized, 9a (1 S,2 R), 9b (1 R,2 S), and 9c

5
308
K. Koike et al. / Tetrahedron Letters 56 (2015) 5306–5308
N
N
N
N
O
HO
H
OH
H
H
O
H
OH
OH
HO
HO
H
H
1
'S, 2'R (9a)
1
'R, 2'S (9b)
N
N
H
N
H
N
H
H
O
O
H
H
OH
HO
HO
OH
HO
HO
1
'S, 2'S (9c)
0
0
Figure 4. CD spectra of picrasidine Y (1) and synthetic compounds (1 S,2 R form
1
'R, 2'R (9c)
Natural product (1)
0
0
(9a), 1 R,2 S form (9b), and alcohol form of 9a (12)).
Figure 6. CD exciton chirality of picrasidine Y.
show positive chirality. By applying this estimated result to the
N
N
H
HO
natural compound 1, the configuration of 1 was determined to be
0
0
OH
1 S,2 S.
In summary, to determine the absolute configurations of picra-
OH
12
sidine Y, enantiomers of picrasidine Y were successfully synthe-
sized by constructing the b-carboline backbone from tryptamine
and using enantiomers of tartaric acid as sources of the asymmet-
ric carbon at position 1. Furthermore, the scope of application of
this synthetic method was extended to canthin-5,6-dione com-
pounds. In the meanwhile, the absolute configuration of the natu-
Figure 5. Chemical structure of 12.
It is plausible that two chromophores of picrasidine Y,
b-carboline backbone, and the carbonyl group, produce the
2
0
0
0
0
0
ral picrasidine Y was suggested to be either 1 S,2 S or 1 R,2 R, based
Cotton effect via exciton interactions. Therefore, the absolute
configuration of picrasidine Y was finally determined by the CD
exciton chirality method. Although picrasidine Y compounds
showed a complex exciton-split Cotton effect, we focused on major
transition moments at 370 nm and 290 nm (Fig. 4). For 9a (1 S,2 R),
a weak negative Cotton effect and a positive Cotton effect were
observed at 370 nm and 290 nm, respectively. Compound 12
1
13
on comparisons of H and C NMR spectral data and specific opti-
cal rotation values, and HPLC analysis using chiral columns. Finally,
its absolute configuration was determined to be 1 S,2 S using
molecular computational methods and the CD exciton chirality
method.
0
0
0
0
(Fig. 5), an alcohol obtained by reducing the carbonyl group of 9a
Supplementary data
with LiAlH , showed no Cotton effect at 270–390 nm, suggesting
4
that exciton interactions between the two chromophores of picra-
sidine Y compounds, the b-carboline backbone and carbonyl group,
underlie the Cotton effect. In other words, the natural compound 1
and 9a (1 S,2 R) showed negative chirality, whereas 9b (1 R,2 S)
showed positive chirality.
Supplementary data (experimental and spectroscopic data)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.07.079.
0
0
0
0
References and notes
Conformation that could yield such chirality was examined by
molecular computation with Discovery 4.1 software. For computa-
tion, a state satisfying small J values of positions 1 and 2 was esti-
mated, when a hydrogen bond between the carbonyl group and the
indole NH was taken into consideration. Namely, an angle of
1
2
3
.
.
.
Ohmoto, T.; Koike, K.; Sakamoto, Y. Chem. Pharm. Bull. 1981, 29, 390.
Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1982, 30, 1204.
Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1983, 31, 3198.
0
0
4. Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1984, 32, 170.
5
6
.
.
Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1984, 32, 3579.
Sung, Y.; Koike, K.; Nikaido, T.; Ohmoto, T.; Sankawa, U. Chem. Pharm. Bull.
ꢀ
1 H, 2 H
67.8° gave the calculated J = 2.1 Hz by Karplus model for
0 0
1872, 1984, 32.
0
0
9
a
(1 S,2 R), an angle of +64.5° gave J
1
0
H,2
0
H
= 2.4 Hz for 9b
7. Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1985, 33, 3356.
8. Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1985, 33, 3847.
9. Ohmoto, T.; Koike, K. Chem. Pharm. Bull. 1985, 33, 4901.
0
0
0
0
(
1 R,2 S), an angle of ꢀ52.6° gave J
1 H,2 H
0
0
= 3.6 Hz for 9c (1 S,2 S),
0
0
21
and an angle of +52.8° gave J
1
0
H,2
0
H
= 3.6 Hz for 9c (1 R,2 R).
1
0. Koike, K.; Ohmoto, T. Chem. Pharm. Bull. 1986, 34, 2090.
11. Koike, K.; Ohmoto, T. Chem. Pharm. Bull. 1987, 35, 3305.
12. Ohmoto, T.; Koike, K.; Ikeda, K. Chem. Pharm. Bull. 1988, 36, 578.
These computed values do not contradict the observed values.
These results suggest that a pseudo-octacyclic ring structure is
formed by hydrogen bonding between the carbonyl group and
1
1
3. Koike, K.; Ohmoto, T. Phytochemistry 1988, 27, 3029.
4. Ohmoto, T.; Nikaido, T.; Koike, K.; Kohda, K.; Sankawa, U. Chem. Pharm. Bull.
0
the indole NH in a solution state, allowing protons at position 1
1988, 36, 4588.
0
and 2 to be arranged in a gauche conformation and stabilized.
15. Koike, K.; Ohmoto, T.; Ikeda, K. Phytochemistry 1990, 29, 3060.
1
1
1
6. Li, H.; Koike, K.; Ohmoto, T. Chem. Pharm. Bull. 1807, 1993, 41.
7. Yoshino, H.; Koike, K.; Nikaido, T. Heterocycles 1999, 51, 281.
8. Koike, K.; Yoshino, H.; Nikaido, T. Heterocycles 1999, 51, 315.
Figure 6 recapitulates estimation of the torsion axis between two
electric transition moments in the carbonyl group and the
b-carboline backbone of the picrasidine Y compounds (four enan-
19. Sasaki, T.; Li, W.; Higai, K.; Koike, K. Bioorg. Med. Chem. Lett. 1979, 2015, 25.
20. Albinsson, B.; Norden, B. J. Phys. Chem. 1992, 96, 6204.
0
0
tiomers). Specifically, it could be estimated that 1 S,2 R (9a) and
21. Karplus, M. J. Chem. Phys. 1959, 30, 11.
0
0
0
0
0
0
1
S,2 S show negative chirality, whereas 1 R,2 S (9b) and 1 R,2 R