Isolation and structure elucidation of two new alkaloids, pandamarilactonine-C and -D, from Pandanus amaryllifolius and revision of relative stereochemistry of pandamarilactonine-A and -B by total synthesis

Article abstract of DOI:10.1248/cpb.50.1303

Two new pyrrolidine alkaloids, pandamarilactonine-C and -D, were isolated from Pandanus amaryllifolius. Based on the total synthesis of pandamarilactonine-C and its related alkaloid, pandamarilactonine-A, the relative stereochemistry of pandamarilactonine-A and -B, which was previously proposed by spectroscopic analysis, was revised.

Full text of DOI:10.1248/cpb.50.1303

September 2002
Communications to the Editor
Chem. Pharm. Bull. 50(9) 1303—1304 (2002)
1303
isomers of coexisting alkaloids, pandamarilactonine-A and
Isolation and Structure Elucidation of
Two New Alkaloids,
1
B.5) The UV, H- and 13C-NMR spectra of pandamarilacto-
nine-C and -D were very similar to those of pandamarilacto-
nine-A and B, which comprised g-butylidene-a-methyl a,b-
unsaturated g-lactone and pyrrolidinyl a,b-unsaturated g-
lactone residues, indicating that these four alkaloids are
stereoisomers. Unambiguous assignment of all the carbons
Pandamarilactonine-C and -D, from
Pandanus amaryllifolius and Revision
of Relative Stereochemistry of
Pandamarilactonine-A and -B by Total
Synthesis
1
and protons in 18) and 29) was realized using H–1H corre-
lated spectroscopy (COSY), heteronuclear multiple quantum
coherence (HMQC), and heteronuclear multiple bond corre-
lation (HMBC) spectra. Comparing the 13C-NMR data of 1
and 2 with those of 3 and 4,5) a significant difference was ob-
served in the chemical shifts at the C-4 position. The signals
of 1 (d 130.3) and 2 (d 133.9) appeared in the higher field
than those of 3 (d 137.7) and 4 (d 137.7), which can be rea-
sonably interpreted in terms of the g-gauche effect due to the
E configuration in the g-alkylidene-g-lactone moiety of both
1 and 2. Differential nuclear Overhauser effect (NOE) exper-
iments on 1 and 2, i.e., observation of a clear peak enhance-
ment from H-4 to H-7, also demonstrated the E configuration
of the g-alkylidenebutenolide moiety. All of the above find-
ings enabled us to elucidate the molecular structures of the
new alkaloids (1, 2) except for the stereochemistry of the
vicinal asymmetric center at the C-14 and C-15 positions.
To confirm the structures and the relative stereochemistry
at the C-14 and C-15 positions in the new alkaloids, we at-
tempted the total synthesis of pandamarilactonines. The
lower part of the alkaloids, i.e., the pyrrolidinyl a,b-unsatu-
rated g-lactone residue, was synthesized according to the
procedure of Martin et al.10) as follows. Compound (7),
whose stereochemistry at the vicinal positions was estab-
lished to be threo by X-ray analysis,10) was prepared by viny-
logous Mannich coupling reaction of 5 and 6. The protecting
group on the nitrogen in 7 was removed by treatment with
TMSI in CH3CN to give 8 in 94% yield. The iodide (13) cor-
responding to the upper part of pandamarilactonines was pre-
pared by a three-step operation: i) condensation of the alde-
Hiromitsu TAKAYAMA, ,a Tomotake ICHIKAWA,a
*
Mariko KITAJIMA,a Maribel G. NONATO,b and
a
Norio AIMI
a Graduate School of Pharmaceutical Sciences, Chiba University;
b
1–33 Yayoi-cho, Inage-ku, Chiba 263–8522, Japan: and Research
Center for the Natural Sciences, University of Santo Tomas;
Espana, Manila 1008, Philippines.
Received July 8, 2002; accepted July 30, 2002; published online
July 31, 2002
Two new pyrrolidine alkaloids, pandamarilactonine-C and
-D, were isolated from Pandanus amaryllifolius. Based on the
total synthesis of pandamarilactonine-C and its related alkaloid,
pandamarilactonine-A, the relative stereochemistry of pan-
damarilactonine-A and -B, which was previously proposed by
spectroscopic analysis, was revised.
Key words pyrrolidine alkaloid; Pandanus; pandamarilactonine; total
synthesis; structure elucidation; structure revision
The genus Pandanus (Pandanaceae) comprises approxi-
mately 600 species that are widely distributed in tropical and
subtropical regions. Several Pandanus species are used as a
remedy for toothache and rheumatism, and as diuretic, car-
diotonic, etc.1) In a recent pharmacological screening, the hy-
poglycemic effect of an extract of P. odorus was noted.2—4) In
our continuing search for structurally unique and biologically
active Pandanus alkaloids, new pyrrolidine alkaloids were
found in P. amaryllifolius ROXB.5—7) Further investigation of
the minor constituents in the fresh leaves of this plant re-
sulted in the isolation of two new alkaloids, pandamarilacto-
nine-C and -D (1, 2). In this communication, we describe the
structure elucidation of these alkaloids as well as the total
synthesis of pandamarilactonine-C (1) and its related alka-
loid, pandamarilactonine-A (3), which resulted in the revi-
sion of the relative stereochemistry of pandamarilactonine-A
and -B (3, 4), which was previously proposed based on the
results of spectroscopic analysis.
The crude alkaloid fraction (1.10 g), which was obtained
from young leaves of P. amaryllifolius,5) was initially sepa-
rated by SiO2 column chromatography using MeOH/CHCl3
gradient, and then the 2—5% MeOH/CHCl3 eluate was sub-
jected to SiO2 medium pressure liquid chromatography using
2% EtOH/CHCl3 to give 20 mg of pandamarilactonine-C and
4 mg of pandamarilactonine-D.
The two new compounds, pandamarilactonine-C (1)8) and
pandamarilactonine-D (2),9) gave respectively m/z 318.1691
[MϩH]ϩ and m/z 318.1704 [MϩH]ϩ by high-resolution
FAB-MS, which established the molecular formulas of the
two compounds as C18H23NO4, and indicated that these are
To whom correspondence should be addressed. e-mail: htakayam@p.chiba-u.ac.jp
© 2002 Pharmaceutical Society of Japan

1304
Vol. 50, No. 9
Chart 1. Total Synthesis of (Ϯ)-Pandamarilactonine-A and -C
N., Nonato M. G., J. Am. Chem. Soc., 122, 8635—8639 (2000).
6) Takayama H., Ichikawa T., Kitajima M., Aimi N., Lopez D., Nonato
M. G., Tetrahedron Lett., 42, 2995—2996 (2001).
7) Takayama H., Ichikawa T., Kitajima M., Nonato M. G., Aimi N., J.
Nat. Prod., 64, 1224—1225 (2001).
hyde (9) with the siloxyfuran (10) in the presence of
BF3·Et2O; ii) dehydration of the resultant aldol adduct (11)
with trifluoromethanesulfonic anhydride and pyridine11)
(48% overall yield); and iii) halogen exchange of (12) with
NaI in acetone (47% yield). The thus-obtained C9 unit (13)
consisted of Z and E isomers in the ratio of 4.6 : 1, and was
then condensed with secondary amine (8) in acetonitrile in
the presence of K2CO3 to give two pandamarilactonines in
33% and 7% yields, both of which possessed the threo form
at the C-14 and C-15 positions. The major synthetic product
having the Z configuration was completely identical with nat-
ural pandamarilactonine-A and the minor one having the E
configuration was identical with natural pandamarilactonine-
C, respectively, by direct comparison of their chromato-
8) Pandamarilactonine-C (1): An amorphous powder, [a]D23 ϩ26.2° (cϭ
0.99, CHCl3), UV (MeOH) lmax nm (log e): 275 (4.23), 220 (sh), 201
(3.67). IR (neat) nmax cmϪ1: 1758 (lactone). FAB-MS (NBA) m/z; 318
[MϩH]ϩ. HR-FAB-MS (NBA): Calcd for C18H23NO4: 318.1704,
Found 318.1691. 1H-NMR (500 MHz, CDCl3) d: 7.31 (1H, dd, Jϭ0.9,
1.5 Hz, H-4), 7.04 (1H, d-like, Jϭ1.5 Hz, H-16), 5.64 (1H, dd, Jϭ8.2,
8.5 Hz, H-6), 4.80 (1H, ddd, Jϭ1.8, 1.8, 5.5 Hz, H-15), 3.12 (1H, dd-
like, Jϭ6.7, 7.3 Hz, H-11), 2.91 (1H, ddd, Jϭ7.9, 8.2, 11.9 Hz, H-9),
2.78 (1H, m, H-14), 2.45 (1H, ddd, Jϭ5.8, 7.0, 11.9 Hz, H-9), 2.35
(1H, ddd, Jϭ7.0, 8.2, 14.7 Hz, H-7), 2.25 (2H, m, H-7 and H-11), 2.02
(3H, d, Jϭ0.9 Hz, H3-21), 1.94 (3H, d-like, Jϭ1.8 Hz, H3-20), 1.71—
1.82 (2H, m, H-12, H-13), 1.62—1.68 (3H, m, H2-8, H-13), 1.45 (1H,
m, H-12). 13C-NMR (125 MHz, CDCl3) d: 174.2 (C-18), 171.0 (C-2),
148.7 (C-5), 146.7 (C-16), 131.3 (C-17), 130.3 (C-4), 129.1 (C-3),
113.4 (C-6), 83.8 (C-15), 65.6 (C-14), 55.2 (C-9), 54.2 (C-11), 29.1
(C-8), 26.1 (C-12), 24.2 (C-7), 23.8 (C-13), 10.8 (C-20, C-21).
9) Pandamarilactonine-D (2): An amorphous powder, [a]D25 0° (cϭ0.21,
CHCl3), UV (MeOH) lmax nm (log e): 276 (4.38), 234 (sh), 203 (4.30).
IR (neat) nmax cmϪ1: 1760 (lactone). FAB-MS (NBA) m/z; 318 [Mϩ
H]ϩ. HR-FAB-MS (NBA): Calcd for C18H23NO4: 318.1704, Found
318.1704. 1H-NMR (500 MHz, CDCl3) d: 7.35 (1H, m, H-4), 6.99
(1H, dd, Jϭ1.5, 1.7 Hz, H-16), 5.60 (1H, dd, Jϭ8.3, 8.8 Hz, H-6), 4.74
(1H, m, H-15), 3.08 (1H, m, H-11), 2.77 (1H, m, H-9), 2.72 (1H, m,
H-14), 2.42 (1H, m, H-9), 2.29 (2H, m, H2-7), 2.25 (1H, m, H-11),
2.01 (3H, m, H3-21), 1.94 (3H, dd-like, Jϭ1.5, 2.0 Hz, H3-20), 1.78—
1.92 (4H, m, H2-12, H2-13), 1.63 (2H, m, H2-8). 13C-NMR (125 MHz,
CDCl3) d: 174.3 (C-18), 171.0 (C-2), 149.0 (C-5), 147.1 (C-16), 131.0
(C-17), 133.9 (C-4), 130.3 (C-3), 113.3 (C-6), 83.0 (C-15), 65.9 (C-
14), 55.1 (C-9), 54.0 (C-11), 28.7 (C-8), 26.3 (C-12), 24.0 (C-7), 23.9
(C-13), 10.8 (C-20), 10.7 (C-21).
1
graphic behavior, as well as their mass, and H- and 13C-
NMR spectra. Based on the results of this synthetic study, the
structures of pandamarilactonine-C, -D, -A, and -B were un-
ambiguously established to be formulas 1 to 4, respectively.
The stereochemistry at the vicinal centers in pandamarilacto-
nine-A and -B was analyzed by spectroscopic methods and
the structures having the erythro-form for pandamarilacto-
nine-A and the threo-form for B have been proposed.5) How-
ever, they should be revised as above.
Acknowledgments This work was supported in part by a Grant-in-Aid
(No. 14370718) for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
Rerefercnes and Notes
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chemistry and Pharmacology,” AKAP, Quezon City, 1980.
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19, 364—366 (1996).
3) Peungvicha P., Thirawarapan S. S., Watanabe H., Jpn. J. Pharmacol.,
78, 395—398 (1998).
4) Peungvicha P., Temsiririrkkul R., Prasain J. K., Tezuka Y., Kadota S.,
Thirawarapan S. S., Watanabe H., J. Ethnopharmacol., 62, 79—84
(1998).
10) Martin S. F., Barr K. J., Smith D. W., Bur S. K., J. Am. Chem. Soc.,
121, 6990—6997 (1999).
11) Bruckner R., Chem. Commun., 2001, 141—152 (2001), and references
cited therein.
12) Note added in proof: After submission of the paper, a total synthesis of
pandamarilactonine-A and -B was published, Busque F., March P.,
Figueredo M., Font J., Sanfeliu E., Tetrahedron Lett., 43, 5583—5585
(2002).
5) Takayama H., Ichikawa T., Kuwajima T., Kitajima M., Seki H., Aimi