Structure and total synthesis of (-)-myrionidine and (-)-schoberine, antimalarial alkaloids from Myrioneuron nutans

Article abstract of DOI:10.1021/jo801046j

(Chemical Equation Presented) Two new alkaloids, (5S,9S,10R)-myrionidine (1) and (5S,9S,10R,13S)-myrionamide (2), along with the known schoberine (3), were isolated from the leaves of Myrioneuron nutans (Rubiaceae), and their structures were determined fr

Full text of DOI:10.1021/jo801046j

Structure and Total Synthesis of (-)-Myrionidine and
(-)-Schoberine, Antimalarial Alkaloids from Myrioneuron nutans
Van Cuong Pham,*,†,| Akino Jossang,† Philippe Grellier,‡ Thierry Se´venet,§ Van Hung Nguyen,|
and Bernard Bodo*,†
Laboratoire de Chimie et Biochimie des Substances Naturelles - UMR 5154 CNRS, Muse´um National
d’Histoire Naturelle, 63 rue Buffon, 75005 Paris, France, Laboratoire de Biologie des Protozoaires
Parasites - Muse´um National d’Histoire Naturelle, 61 rue Buffon, 75005 Paris, France, Institut de Chimie
des Substances Naturelles, CNRS - 91198 Gif-sur-YVette cedex, France, and Institute of Chemistry,
Vietnamese Academy of Science and Technology, 18 Hoang Quoc Viet road, Hanoi, Vietnam
bodo@mnhn.fr; phamVc@ich.ncst.ac.Vn
ReceiVed May 20, 2008
Two new alkaloids, (5S,9S,10R)-myrionidine (1) and (5S,9S,10R,13S)-myrionamide (2), along with the
known schoberine (3), were isolated from the leaves of Myrioneuron nutans (Rubiaceae), and their
structures were determined from spectral analysis, including mass spectrometry and 2D NMR. The total
asymmetric syntheses of (-)-myrionidine (1), (-)-schoberine (3), their enantiomers as well as their
9-epimers derivatives were performed, allowing the determination of their absolute configuration together
with that of myrionamide (2). (-)-Myrionidine (1) and its synthetic enantiomer (18) showed a significant
antimalarial activity on Plasmodium falciparum.
Introduction
An ongoing research interest in our group is the identification
of alkaloids from Myrioneuron nutans, a small shrub of North-
Vietnam. We have previously isolated from this plant several
novel alkaloid skeletons,1a-d containing the cis-decahydroquino-
line (cis-DHQ) motif which is rare in plant source,2 but
characterized from some neotropical frogs3a-d and ants.4 The
plants known to produce DHQs derivatives are restricted to
several Lycopodium5a-e and Nitraria species.6a,b Analysis of
the alkaloidal fraction of M. nutans has led to the isolation of
two new tetracyclic alkaloids, (-)-myrionidine (1) and (+)-
myrionamide (2), along with the known (-)-schoberine (3).7a-c
Previous reported papers on schoberine isolated from several
Nitraria species, described it as a mixture of enantiomers.7a-c
In addition, the schoberine skeleton has not been synthesized
yet. In this paper, we described the structure elucidation by
spectral methods, and the total asymmetric syntheses of (-)-
myrionidine (1) and (-)-schoberine (3), together with the
syntheses of their enantiomers and their epimers at C-9.
Furthermore, the absolute configuration of (+)-myrionamide (2)
was determined by its transformation into (-)-schoberine (3),
the absolute stereochemistry of which has been established by
its total synthesis. The cytotoxic and antimalarial activities of
all the natural and synthetic compounds were evaluated.
(-)-Myrionidine (1) and its synthetic enantiomer (18) showed
an important antimalarial activity on Plasmodium falciparum
with IC50 of 0.3 and 0.5 µg/mL, respectively. Finally, a plausible
† Laboratoire de Chimie et Biochimie des Substances Naturelles.
‡ Laboratoire de Biologie des Protozoaires Parasites.
§ Institut de Chimie des Substances Naturelles.
| Vietnamese Academy of Science and Technology.
10.1021/jo801046j CCC: $40.75
Published on Web 09/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7565–7573 7565

Pham et al.
TABLE 1. NMR Data for (-)-Myrionidine (1) and (+)-Myrionamide (2) (1H: 400.13 MHz, 13C: 75.47 MHz, CDCl3, 298 K)
(-)-myrionidine (1) (+)-myrionamide (2)
δH m (J, Hz) δH m (J, Hz)
Cn°
δC
Cn°
δC
2
40.3
-
21.2
-
19.5
-
29.0
28.8
-
19.1
-
27.4
-
29.5
58.6
54.6
-
160.1
27.2
-
3.62 ddd (14.2,7.1, 1.3)
3.38 m
1.83 m
1.68 m
1.55 m
1.38 m
2.33 m
1.55 m
1.55 m
1.43 m
1.27 m
1.72 m
0.88 dddd (13.0, 13.0, 13.0, 3.9)
1.97 ddddd (13.0, 12.5, 10.7, 5.4, 3.9)
3.50 dd (10.7, 6.1)
3.25 dd (12.5, 5.4)
3.16 dd (12.5,12.5)
2
168.1
-
3
4
3
4
32.7
-
21.7
-
32.5
30.3
-
20.3
-
29.8
-
34.7
54.9
52.8
-
68.2
23.1
-
24.1
-
2.44 ddd (17.5, 5.4, 1.7)
2.29 ddd (17.5, 12.6, 6.5)
1.90 dddd (13.3, 13.3, 12.6, 5.4)
1.41 m
5
6
5
6
2.03 ddddd (13.3, 5.2, 5.2,5.2, 2.6)
1.68 m
1.65 m
1.48 m
1.35 m
1.53 m
1.04 m
1.75 m
3.29 dd (11.0, 5.2)
2.68 dd (11.3, 8.7)
2.49 dd (11.3, 5.6)
5.07 dd (11.4, 2.9)
1.78 m
1.43 m
1.79 m
1.52 m
1.55 m
7
8
7
9
10
11
9
10
11
13
14
-
13
14
2.74 br. d (17.1)
2.65 ddd (17.1, 8.1, 8.1)
1.88 m
15
16
17
18.7
-
20.9
-
51.3
-
15
16
17
1.71 m
1.81 m
1.70 m
3.42 m
19.9
-
53.6
-
1.22 m
2.81 ddd (13.3, 3.8, 1.8)
2.75 ddd (13.3, 12.3, 3.0)
3.33 m
biosynthesis pathway was proposed for these alkaloids based
on their structure.
and 3.42) indicated that C-13 was linked to CH2-14 and both
N-1 and N-12 and methylene CH2-11 was connected to CH2-
17 through N-12. Further HMBC correlations between H-10
(δH 3.50) and carbon C-2 (δC 40.3) established the presence of
a DHQ motif. The structure of 1 was thus determined to be an
iminium salt, in which the double bond could be delocalized
on the N1-C13-N12 system (Figure 1A).
Results and Discussion
1. Isolation and Structure Elucidation of (-)-Myrionidine
(1), (+)-Myrionamide (2), and (-)-Schoberine (3). The crude
alkaloid fraction (29.5 g) obtained from the dried leaves of M.
nutans (5.5 kg) was purified by repeated open column chro-
matography over silica gel eluted with CH2Cl2/MeOH gradient
to afford (-)-myrionidine (1, 3.7 g), (+)-myrionamide (2, 55
mg), and (-)-schoberine (3, 24 mg).
(-)-Myrionidine (1) was obtained as an optically active
20
colorless crystalline solid, [R]D -60 (c 1, MeOH). The ESI-
MS showed the molecular ion at m/z 233.2003 (calcd. 233.2018
for C15H25N2). The IR spectrum indicated the presence of an
imine (1626 cm-1) functionality. The 1D-NMR (1H and 13C)
spectra indicated 11 methylenes, 3 methines, and 1 quaternary
carbon at δC 160.1 (C-13). The five degrees of unsaturation were
thus assigned to one double bond and four rings. In the 1H-1H
COSY spectrum, connections were depicted from CH2-2 (δH
3.38 and 3.62) to CH-10 (δH 3.50), which was then correlated
to CH-5 (δH 2.33), and the correlations between CH-9 (δH 1.97)
FIGURE 1. Selected HMBC and NOE correlations for (-)-myrionidine
(1).
1
and CH2-11 (δH 3.16 and 3.25) were also observed. The H
The relative stereochemistry of the ring junctions at C-5,
C-9, and C-10 was determined from 3J 1H-1H coupling
constants and NOESY data. The three large coupling constants
(10.7, 12.5, and 13.0 Hz), characteristic of trans-diaxial
couplings and the two gauche interactions (3.9 and 5.4 Hz)
observed for H-9, indicated its trans-diaxial relationship with
H-10. In addition, the signal for H-10 was a doublet of doublet
(JH10-H9 ) 10.7 Hz and JH10-H5 ) 6.1 Hz), corresponding to a
gauche relationship between H-10 and H-5. This relative
stereochemistry was confirmed from the NOESY experiment
in which spatial interactions of H-10 with H-5, H-6ax, and H-8ax,
together with those of H-9 with H-4ax and H-7ax, were observed
(Figure 1B). These data indicated the cis-fused junction for the
and 13C chemical shifts of CH2-2 and CH-10 (Table 1) suggested
their direct linkage to a nitrogen atom. All of these data defined
the substructure I, marked with bold bonds in Figure 1A. On
the other hand, a set of connections from CH2-17 (δH 3.33 and
3.42) to CH2-14 (δH 2.65 and 2.74), via CH2-16 (δH 1.70 and
1.81) and CH2-15 (δH 1.71 and 1.88), formed a -(CH2)4- system
(substructure II), in which CH2-17 was linked to a nitrogen atom,
in agreement with its 1H and 13C chemical shifts (δC 51.3). The
planar structure of 1 was then established from HMBC data:
cross peaks of sp2 quaternary carbon C-13 (δC 160.1) with
CH2-2 (δH 3.38 and 3.62), CH-10 (δH 3.50), CH2-11 (δH 3.16
and 3.25), CH2-15 (δH 1.71 and 1.88), and CH2-17 (δH 3.33
7566 J. Org. Chem. Vol. 73, No. 19, 2008

Antimalarial Alkaloids from Myrioneuron nutans
FIGURE 3. Structure of (-)-schoberine (3).
protonated molecular [M+H]+ ion at m/z 235.2141 (calcd.
235.2174 for C15H27N2) was observed in the ESI mass spectrum.
The 1D NMR spectra (1H and 13C) were close to those of 2,
except for the presence of one additional methylene in the sp3
region and the disappearance of the carbonyl group. The planar
structure of 3 was determined from 2D NMR and its relative
configuration was further established from 1H-1H vicinal
coupling constants and NOESY experiment (Figure 3). All of
these data indicated that 3 was identical to schoberine, which
has been previously isolated from several Nitraria species.7a-c
It is important to note that the schoberine previously isolated
from Nitraria species was described as racemic form, and it
was suggested to be biosynthesized by a nonenzymatic way.7a-c
However, the sample of (-)-schoberine (3) that we isolated from
FIGURE 2. Key HMBC (A) and NOE (B) correlations for (+)-
myrionamide (2).
a/b-rings and the trans-junction for the b/c-rings. The relative
configuration of this new tetracyclic iminium alkaloid 1 which
was named myrionidine, was thus 5S*, 9S*, 10R*.
(+)-Myrionamide (2) was isolated as a colorless solid (mp.
20
154-155 °C, MeOH), optically active ([R]D +17.0, c 1,
MeOH). In its ESI mass spectrum, the protonated molecular
ion [M+H]+ at m/z 249.1965 (calcd. 249.1967 for C15H25N2O)
was in agreement with the molecular formula C15H24N2O. The
IR absorption band at 1637 cm-1 was characteristic of an amide
carbonyl. The five degrees of unsaturation were distributed into
one double bond and four rings. The 1D NMR (1H and 13C)
spectra of 2 were nearly similar with those of 1, except the
presence of the methine CH-13 (δH 5.07 and δC 68.2) instead
of a sp2 quaternary carbon (C-13), and that of a carbonyl in
place of a methylene. 1H-1H COSY and HSQC analyses
determined the two fragments (I and II) shown in bold bonds
in Figure 2A. The gross planar structure of 2 was established
from HMBC cross-peaks of CH2-4 (δH 1.41 and 1.90), H-10
(δH 3.29) and H-13 (δH 5.07) with C-2 (δC 168.1), and those
of H-10, CH2-11 (δH 2.49 and 2.68) and CH2-17 (δH 2.75 and
2.81) with C-13 (δC 68.2) allowed linking the two fragments I
and II.
20
M. nutans was optically active, as discussed above ([R]D
-12.2), suggesting it was a single enantiomer. This point was
further confirmed by its total asymmetric synthesis yielding a
20
unique compound having the same rotatory power ([R]D
-12.6) as described below.
2. Synthesis of (-)-Myrionidine (1), (-)-Schoberine (3),
and their Enantiomers and 9-Epimers. Schoberine (3) was
isolated for the first time in 19897a and no synthesis has been
reported yet. To confirm the structures of (-)-myrionidine (1),
(+)-myrionamide (2), and (-)-schoberine (3) and also to
determine their absolute configuration, we attempted their total
synthesis, as well as those of their enantiomers and epimers at
C-9. Retrosynthesis analysis of 1 and 3 suggested that they could
be obtained from the tetrahydroquinoline (R)-7 (Scheme 1).
The two enantiomers (R)-7 and (S)-7 were separated from
the racemic mixture 41,9 via the two diastereoisomers 5 and 6,
respectively. These diastereoisomers 5 and 6 were obtained by
The relative configuration of 2 was deduced from the
observed NOE correlations and the values of the 1H-1H vicinal
coupling constants. A trans-diaxial (JH10-H9 ) 11.0 Hz) and a
gauche (JH10-H5 ) 5.2 Hz) couplings were depicted for H-10,
suggesting the relative stereochemistry at C-5, C-9, and C-10
to be identical with that of (-)-myrionidine (1). Finally, the
coupling constants of H-13 (JH13-H14eq ) 2.9 Hz and JH13-H14ax
) 11.4 Hz) pointed its axial disposition on the d-ring. This
agreed with the observed NOE correlations of H-10 with H-6ax,
H-11ax, H-8ax, and H-13, which are all on the same side (Figure
2B), and furthermore of H-9 with both H-4ax and H-7ax, which
are on the opposite side. The 1,3-diaxial relationship of H-13
with H-10 on the c-ring was depicted and the data indicated
the relative configuration for 2 as 5S*, 9S*, 10R*, 13S*. This
original tetracyclic alkaloid is named myrionamide.
(1) (a) Pham, V. C.; Jossang, A.; Chiaroni, A.; Se´venet, T.; Bodo, B.
Tetrahedron Lett. 2002, 43, 7565. (b) Pham, V. C.; Jossang, A.; Chiaroni, A.;
Se´venet, T.; Nguyen, V. H.; Bodo, B. Org. Lett. 2007, 9, 3531. (c) Pham, V. C.;
Jossang, A.; Se´venet, T.; Nguyen, V. H.; Bodo, B. Tetrahedron 2007, 63, 11244.
(d) Pham, V. C.; Jossang, A.; Se´venet, T.; Nguyen, V. H.; Bodo, B. J. Org.
Chem. 2007, 72, 9826.
(2) Banner, E. J.; Stevens, E. D.; Trudell, M. L. Tetrahedron Lett. 2004, 45,
4411.
(3) (a) Ozawa, T.; Aoyagi, S.; Kibayashi, C. Org. Lett. 2000, 2, 2955. (b)
Kubanek, J.; Williams, D. E.; Dilip de Silva, E.; Allen, T.; Andersen, R. J.
Tetrahedron Lett. 1995, 36, 6189. (c) Steffan, B. Tetrahedron 1958, 47, 8729.
(d) Tokuyama, T.; Nishimori, N.; Karle, I. L.; Edwards, M. W.; Daly, J. W.
Tetrahedron 1986, 42, 3453. (e) Bonin, M.; Besselie`vre, R.; Grierson, D. S.;
Husson, H. P. Tetrahedron Lett. 1983, 24, 1493. (f) Hart, D. J.; Kanai, K. I.
J. Am. Chem. Soc. 1983, 105, 1255. (g) Daly, J. W.; Witkop, B. HelV. Chim.
Acta 1977, 60, 1128.
(4) Spande, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; yeh, H. J. C.;
Daly, J. W.; Fukumoto, S.; Imamura, K.; Tokuyama, T.; Torres, J. A.; Snelling,
R. R.; Jones, T. H. J. Nat. Prod. 1999, 62, 5.
The upfield chemical shifts of H-8ax (Table 1) of both
myrionidine (1) and myrionamide (2) were characteristic of
N-outside conformation for the decahydroquinoline system (a-
and b-ring). This N-outside conformation was constrained by
the c-ring.
(5) (a) Hirasawa, Y.; Morita, H.; Kobayashi, J. Org. Lett. 2004, 6, 3389. (b)
Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org. Chem. 1999, 64,
2184. (c) Morita, H.; Hirasawa, Y.; Shinzato, T.; Kobayashi, J. Tetrahedron
2004, 60, 7015. (d) Hirasawa, Y.; Morita, H.; Kobayashi, J. Tetrahedron 2003,
59, 3567. (e) Tori, M.; Shimoji, T.; Shimura, E.; Takaoka, S.; Nakashima, K.;
Sono, M.; Ayer, W. A. Phytochemistry 2000, 53, 503.
(6) (a) Joseph, P. M. Nat. Prod. Rep. 2003, 20, 476. (b) Tulyaganov, T. S.;
Allaberdiev, F. K. Chem. Nat. Compd. 2001, 37, 556 Engl. transl. of Khim.
Prir. Soedin., 2001, 476.
(-)-Schoberine (3) was obtained as microcrystals (mp. 62-63
20
°C, MeOH), optically active ([R]D -12.2, c 1, MeOH). The
J. Org. Chem. Vol. 73, No. 19, 2008 7567

Pham et al.
SCHEME 1. Retrosynthesis of (-)-Myrionidine (1) and (-)-Schoberine (2)
SCHEME 2. Synthesis of 9-Methanol-DHQsa
a Reagents and conditions: (a) (1S)-(-)-camphanoyl chloride, Et3N, CH2Cl2, 25 °C, 12 h, 48% for 5 and 46% for 6. (b) Aq. NaOH/MeOH, 50 °C, 3 h,
20
20
20
97% for (R)-7 and 95% for (S)-7. (c) H2/PtO2, AcOH, 25 °C, 15 h, (-)-8 (59%, [R]D -2.1), (+)-9 (18%, [R]D +33.2), (+)-8 (63%, [R]D +1.8), and
20
(-)-9 (19%, [R]D -33.8).
SCHEME 3. Synthesis of (-)-Schoberine and Its (+)-9-Epimera
a Reagents and conditions: (a) BnBr, CH2Cl2/aq. NaHCO3, 25 °C, 12h, (-)-10 (93%) and (+)-13 (82%). (b) i. MsCl, CH2Cl2, -5 °C, 1 h. ii. 2-piperidinone,
20
20
KH, DMF, -5 to 25 °C, 12h, (-)-11 (75%), and (+)-14 (75%). (c) H2/Pd-C, AcOH, 25 °C, 3 h, (-)-12 (90%, [R]D -16.8), and (-)-15 (89%, [R]D
-21.8). (d) i. POCl3, toluene, reflux, 12 h. ii. Aq. NaOH/MeOH, 1 (97%, [R]D20 -60.1), and (-)-16 (92%, [R]D20 -53.2). (e) LiAlH4, THF, 0 to 25 °C, 12 h,
20
20
3 (87%, [R]D -12.6), and (+)-17 (90%, [R]D +32.4).
esterification of the racemic compound 4 with the chiral, (1S)-
(-)-camphanoyl chloride, followed by basic hydrolysis. X-ray
analysis of the ester 5 allowed determining of the absolute
stereochemistry at C-9 chiral center as R and it was thus S in
the ester 6.1 Catalytic hydrogenation of (R)-7 and (S)-7 gave
the two pairs of diastereoisomers (-)-8/(+)-9 and (+)-8/(-)-
9, respectively (Scheme 2).10a,b The resulting diastereoisomers
were successfully separated by column chromatography.
The relative configurations at C-10 and C-5 of (-)-8 [or (+)-
characterized the DHQ moiety. The absolute stereochemistry
at C-5 and C-10 of (+)- and (-)-8 and (+)- and (-)-9 was
then established on the basis of the known absolute configuration
at C-9 of (R)-7 and (S)-7. The amino group of (-)-8 was then
protected with a benzyl group (Scheme 3).11 The resulting
benzyl protected (-)-10 was first transformed into its mesyl
derivative with MsCl and then coupled with 2-piperidinone in
(7) (a) Tashkhodzhaev, B.; Ibragimov, A. A.; Ibragimov, B. T.; Yunusov,
S. Y. Khim. Prir. Soedin. 1989, 32, 30. (b) Tulyagalov, T. S. Chem. Nat. Compd.
1993, 29, 31 Engl. transl. of Khim. Prir. Soedin 1993, 1, 39. (c) Shen, M. Y.;
Zuanazzi, J. A.; Kan, C.; Quirion, J. C.; Husson, H. P.; Bick, I. R. C. Nat. Prod.
Lett. 1995, 6, 119.
(8) Ogawa, A. K.; Abou-Zied, O. K.; Tsui, V.; Jimenez, R.; Case, D. A.;
Romesberg, F. E. J. Am. Chem. Soc. 2000, 122, 9917.
(9) Crabb, T. A.; Turner, C. H. J. Chem. Soc., Perkin Trans. 2 1980, 1778.
(10) (a) Adams, R.; Voorhees, V.; Shriner, R. L. Org. Synth. Collect. Vol.
1932, 1, 463. (b) Adams, R.; Shriner, R. L. J. Am. Chem. Soc. 1923, 45, 2171.
(11) Yamazaki, N.; kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396.
8] and for (+)-9 [or (-)-9] were determined from J H-1H
coupling constants analysis of H-10 which in 8, showed a strong
(J1 ) 10.6 Hz) and a small (J2 ) 2.8 Hz) coupling constants
with H-9 and H-5, respectively, while it had two small ones (J1
) J2 ) 2.7 Hz) for 9. This indicated that H-10 and H-9 were
in a trans-diaxial relationship in (+)- and (-)-8 and in a cis-
disposition in (+)- and (-)-9, and that a cis-fused junction
3
1
7568 J. Org. Chem. Vol. 73, No. 19, 2008

Antimalarial Alkaloids from Myrioneuron nutans
SCHEME 4. Reduction of (+)-Myrionamide (2) into
(-)-Shoberine (3)
FIGURE 4. Stereochemistry of (+)-9-epi-schoberine [(+)-17].
the presence of KH to afford (-)-11. Benzyl deprotection of
(-)-11 by catalytic hydrogenation (H2/Pd-C) in methanol,12a,b
provided (-)-myrionine, (-)-12. Intramolecular cyclization of
(-)-12 carried out with POCl3 in toluene at reflux, followed by
treatment with NaOH in methanol gave the iminium 1 in good
yield (97%).13a,b Reduction of 1 by NaBH4 in methanol afforded
3 in poor yield (50%), however higher yield (87%) was obtained
when using LiAlH4 in THF for the reduction of 1.14a,b
The following isomers, (-)-9-epi-myrionine [(-)-15], (-)-
9-epi-myrionidine [(-)-16] and (+)-9-epi-schoberine [(+)-17],
were subsequently synthesized from (-)-9 by similar procedure
as above. Interestingly, the reduction of the iminiums 1 and
(-)-16 by LiAlH4 selectively afforded (-)-shoberine 3 and (+)-
17, respectively. No formation of the 13-epimer of the two last
compounds was observed.
M. nutans suggested that they are oligomeric (dimeric and
trimeric) ∆2-piperideines. They could thus arise from lysine Via
piperideine as previously proposed for alkaloids of Nicotiana16
and Nitraria17 as well as for Lupin alkaloids such as matrine
(23).18 The intermediate 20, a precursor for many alkaloid
types,19 could be on one hand hydrolyzed, affording the
quinolizidine derivative 21 which is then condensed with a third
∆2-piperideine unit to provide 22. Cyclization of 22 yields
matrine 23 (route A).18 On the other hand, the intermediate 20
could be hydrolyzed to form the aldehyde 24 (route B) which,
as demonstrated by Wanner and Koomen, affords 25 by addition
of a third ∆2-piperideine unit. Then, an intramolecular 1,4-
addition cyclization of 25 provides the DHQ system 26.
Selective reduction of 26 results in the formation of 27 which
can be cyclized into (-)-schoberine (3)17c or oxidized to form
the (-)-myrionine [(-)-12]. Intramolecular cyclization of myri-
onine provides (-)-myrionidine (1). In fact, (-)-myrionidine
(1) was the main alkaloid of M. nutans (0.07% from dry leaves),
suggesting that (-)-schoberine (3) could be also obtained from
hydrogenation of (-)-myrionidine (1). Finally, oxidation of 1
can yield (+)-myrionamide (2) (Scheme 5). On the other hand,
compound 26 could be hydrolyzed to yield the amino aldehyde
28, the reduction of which, followed by condensation with
formaldehyde and cyclization, could afford myrioxazine A (30).
It is important to note that the 9-epimers of (-)-myrionine,
(-)-myrionidine, and (-)-schoberine were not found in the
extracts of M. nutans. The presence of myrioxazine B, 33 (9-
epimer of myrioxazine A) in the plant should be thus explained
by tautomerisation of the aldehyde function of 28, and the
resulting enol 31 is reduced, condensed with formaldehyde and
then cyclized affording myrioxazine B (Scheme 5). Hence, the
difference of the biosynthesis pathways of myrionidine and
matrine concerns the intermediate 20, which can evolve ac-
cording to two possible routes: either the formation of quino-
lizidine 21 (route A) to yield matrine or the formation of the
cis-decahydroquinoline derivative 26 (route B) to afford (-)-
myrionidine.
In the 1H NMR spectrum of (+)-17, the signal for H-13 was
a doublet of doublet (J1 ) 11.8; J2 ) 3.1 Hz), indicating its
axial disposition on the d-ring and its 1,3-diaxial relationship
with H-10 on the c-ring (Figure 4). This was confirmed by the
strong NOE between H-10 with both H-13 and H-11ax.
The enantiomers, (+)-myrionine [(+)-12], (+)-9-epi-myri-
onine [(+)-15], (+)-9-epi-myrionidine [(+)-16], (+)-myrioni-
dine (18), (+)-9-epi-myrionidine [(-)-17], and (+)-schoberine
(19) were also synthesized according to the above procedure:
(+)-myrionidine (18) and (+)-schoberine (19) were prepared
from (+)-8, and (+)-9-epi-myrionidine, (+)-16 and (-)-9-epi-
schoberine (-)-17 from (+)-9 (Figure 5). Comparison of the
NMR data and the optical rotations of the natural compounds
with those of synthetic ones, revealed that the absolute config-
uration of (-)-myrionidine (1) was 5S, 9S, 10R, and that of
(-)-schoberine (3) was 5S, 9S, 10R, 13S.
3. Absolute Configuration of (+)-Myrionamide (2). As
discussed above, the relative configuration of (+)-myrionamide
(2) was identical to that of (-)-schoberine (3). With the absolute
stereochemistry of (-)-schoberine (3) in hand, the absolute
configuration of (+)-myrionamide (2) could be deduced from
its transformation into (-)-schoberine (3) as shown in Scheme
15
4. Exposure of 2 to LiAlH4 in THF afforded (-)-schoberine
(3) which was determined by comparison of their NMR data
and optical activity of the natural (-)-schoberine and the
5. Cytotoxic and Antimalarial Activities. All of the syn-
thetic and natural compounds were tested for their cytotoxic
20
synthetic one under the same condition ([R]D -12.9 for the
synthetic (-)-schoberine and [R]D20 -12.2 for the natural (-)-
schoberine). Thus, (+)-myrionamide (2) and (-)-schoberine (3)
have the same absolute configuration 5S, 9S, 10R, 13S at the
asymmetric centers.
(16) Leete, E. J. Am. Chem. Soc. 1969, 91, 1697.
(17) (a) Gravel, E.; Poupon, E.; Hocquemiller, R. Tetrahedron 2006, 62,
5248. (b) Wanner, M. J.; Koomen, G. J. J. Org. Chem. 1995, 60, 5634. (c)
Wanner, M. J.; Koomen, G. J. Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1994; Vol. 14, p 731. (d) Wanner, M. J.;
Koomen, G. J. Tetrahedron 1992, 48, 3935.
4. Plausible Biosynthesis Pathway of Myrioneuron Alka-
loids. Analysis of the structures of the alkaloids isolated from
(18) (a) Golebiewski, W. M.; Spenser, I. D. J. Am. Chem. Soc. 1976, 98,
6726. (b) Leeper, F. J.; Grue-Sorensen, G.; Spenser, I. D. Can. J. Chem. 1981,
59, 106.
(12) (a) Felix, A. M.; Heimer, E. P.; Lambros, T. J.; Tzougraki, C.;
Meienhofer, J. J. Org. Chem. 1978, 43, 4194. (b) ElAmin, B.; Anantharamaiah,
G. M.; Royer, G. P.; Means, G. E. J. Org. Chem. 1979, 44, 3442.
(13) (a) Fordor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279. (b) Whaley,
W. M.; Govindachari, T. R. Org. Reactions 1951, VI, 74.
(19) (a) Golebiewski, W. M.; Spenser, I. D. J. Am. Chem. Soc. 1984, 106,
7925. (b) Fraser, A. M.; Robins, D. J. J. Chem. Soc., Chem. Commun. 1984,
1477.
(20) Frappier, F.; Jossang, A.; Soudon, J.; Calvo, F.; Rasoanaivo, P.;
Rastimamanga-Urveg, S.; Saez, J.; Schrevel, J.; Grellier, P. Antimicrob. Agents
Chemother. 1996, 6, 1476.
(21) Desjardins, R. E.; Candfield, C. J.; Haynes, J. D.; Chulay, J. D.
Antimicrob. Agents Chemother. 1979, 16, 710.
(22) T. Mosmann., J. Immunol. Meth. 1983, 65, 55.
(14) (a) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley: New York,
1992; p 918. (b) Finholt, A. E.; Bond, A. C.; Schlesinger, H. I. J. Am. Chem.
Soc. 1947, 69, 1199.
(15) Micovic, V.; Mihailovic, M. J. Org. Chem. 1953, 18, 1190.
J. Org. Chem. Vol. 73, No. 19, 2008 7569

Pham et al.
FIGURE 5. Synthetic enantiomers and 9-epimers of Myrioneuron alkaloids.
SCHEME 5. Proposed Biosynthesis Pathway for the Myrioneuron Alkaloids
activity against KB cell and antimalarial activity against P.
falciparum (FcB1 strain) according to the previously described
procedure20-22 (Table 2). The results showed that most of these
compounds were more active on P. falciparum than on KB cell
lines, indicating the antiplasmodial activity could not be due to
their cytotoxicity. The most potent compounds were the
enantiomeric (-) and (+)-myrionidines (1 and 18), whereas their
9-epimers, (+)- and (-)-16, had weaker activity on both target
cell lines. This suggested that the stereochemistry at C-9 in
myrionidine played an important role in the bioactivity.
Furthermore, as schoberine showed much lower cytotoxic and
antimalarial activities than myrionidine, the iminium function
probably is a significant factor for the biological activities of
myrionidine.
Conclusion
This paper illustrates the structural determination, including
absolute configuration, of a special class of original alkaloids
from M. nutans. Presumably, these alkaloids are biosynthesized
from L-lysine via ∆-piperideine, as described for Lycopodium
and Lupin alkaloids. However, the bioformation of DHQ
alkaloids of M. nutans was different from that of the Lupin
alkaloids which are characterized by a quinolizidine skeleton.
Furthermore, the pure enantiomers of alkaloids of M. nutans
were obtained indicating their stereoselective biosynthesis,
whereas, schoberine and nitraramine isolated from several
Nitraria species were described as racemic mixtures. We
propose the name Myrioneuron alkaloids for this original class
of alkaloids isolated from M. nutans.
7570 J. Org. Chem. Vol. 73, No. 19, 2008

Antimalarial Alkaloids from Myrioneuron nutans
TABLE 2. Cytotoxic and Antimalarial Activities Expressed by IC50 (µg/mL)
Sample
KB cell
P. falciparum
Sample
KB cell
P. falciparum
crude alkaloid (M. nutans)
(-)-myrionidine (1)
30
6
3
>50
20
82
50
>100
-
0.3
0.5
91
4
39
10
8
39
4
20
2
6
(R)-7
(S)-7
>100
42
45
44
10
13
10
9
16
34
0.8
12
0.7
44
13
2
(+)-myrionidine (18)
>100
>100
>100
>100
>100
23
(+)-myrionamide (2)
(-)-8
(-)-schoberine (3)
(+)-8
(+)-schoberine (19)
(-)-9
(-)-myrionine [(-)-12]
(+)-myrionine [(+)-12]
(-)-9-epi-myrionine [(-)-15]
(+)-9-epi-myrionine [(+)-15]
(-)-9-epi-myrionidine [(-)-16]
(+)-9-epi-myrionidine [(+)-16]
(-)-9-epi-schoberine [(-)-17]
(+)-9-epi-schoberine [(+)-17]
chloroquine
(+)-9
(-)-10
(+)-10
(-)-11
(+)-11
(-)-13
(+)-13
(-)-14
(+)-14
25
87
11
6
57
>100
24
26
3
8
42
44
3
0.03
-
>100
-
0.01
22
4
vinblastine
diminished pressure and the residue purified by chromatography
on silica gel, eluted with n-hexane/Et2O/EtOH (10:1:0.5) to yield
the two diastereoisomers 5 (15.2 g, 48%) and 6 (14.5 g, 46%).
In order to confirm the structures of (-)-myrionidine (1) and
(-)-schoberine (3) and to determine their absolute configuration,
the first total asymmetric synthesis of the schoberine skeleton
was performed. The absolute stereochemistry of C-9 in the
intermediate 7 was deduced from X-ray analysis of its (1S)-
(-)-camphanoyl ester 5.
20
5: White solid, mp. 110-110.5 °C; [R]D -45 (c 2, MeOH);
1H (400.13 MHz, CDCl3, 298 K): 8.33 (m, 4.7, 1.7, 1H, H-2), 7.33
(m, 7.7, 1.7, 1H, H-4), 7.0 (dd, 7.7, 4.7, 1H, H-3), 4.63 (dd, 10.7,
8.1, 1H, H-11a), 4.61 (dd, 10.7, 3.5, 1H, H-11b), 3.25 (m, 1H, H-9),
2.72 (m, 2H, H-6), 2.32 (ddd, 13.3, 10.8, 4.3, 1H, H-21a), 2.03 (m,
1H, H-8a), 1.95 (m, 1H, H-21b), 1.90 (m, 1H, H-7a), 1.84 (m, 1H,
H-20a), 1.83 (m, 1H, H-8b), 1.71 (m, 1H, H-7b), 1.61 (ddd, 13.1,
9.3, 4.2, 1H, H-20b), 1.03 (s, 3H, CH3-25), 0.94 (s, 3H, CH3-24),
0.74 (s, 3H, CH3-23); 13C (CDCl3, 75.47 MHz): 178.2 (C-17), 167.3
(C-13), 155.4 (C-10), 146.9 (C-2), 136.8 (C-4), 133.2 (C-5), 121.5
(C-3), 91.2 (C-15), 68.4 (C-11), 54.6 (C-19 or C-22), 53.9 (C-22
or C-19), 40.0 (C-9), 30.4 (C-24), 28.8 (C-6, C-20), 26.1 (C-8),
20.1 (C-7), 16.6 (CH3-21), 16.4 (CH3-23), 9.6 (CH3-25); ESI-MS
(TOF): 344.1864 [M+H]+, (calcd. 344.1862 for C20H26NO4).
Experimental Section
(-)-Myrionidine (1). Colorless crystals, mp. 154-155 °C
20
(MeOH), [R]D -60.0 (c 1, MeOH); IR (KBr) νcm-1: 3217, 3035,
2940, 2874, 1626, 1517, 1392, 1316, 1245, 980, 971, 830. ESI-
MS (TOF): 233.2003 (calcd. 233.2018 for C15H25N2). ESI-MSMS
on [M]+: 205, 191, 177, 163, 151, 149, 135, 123, 111, 110. NMR
see Table 1.
(+)-Myrionamide (2). Colorless crystals, mp. 151-152 °C
20
(MeOH), [R]D +17.0 (c 1, MeOH); IR (KBr) νcm-1: 2936, 2863,
20
1
6: Colorless oil, [R]D +23 (c 2, MeOH); H (400.13 MHz,
CDCl3, 298 K): 8.33 (m, 4.7, 1.8, 1H, H-2), 7.33 (m, 7.7, 1.8, 1H,
H-4), 7.0 (dd, 7.7, 4.7, 1H, H-3), 4.61 (d, 5.9, 2H, CH2-11), 3.23
(dddd, 6.2, 6.2, 6.1, 6.0, 1H, H-9), 2.72 (dd, 6.1, 6.1, 2H, H-6),
2.30 (ddd, 13.4, 10.7, 4.3, 1H, H-21a), 2.01 (m, 1H, H-8a), 1.92
(m, 1H, H-21b), 1.90 (m, 1H, H-7a), 1.81 (m, 2H, H-20a, and H-8b),
1.71 (m, 1H, H-7b), 1.59 (ddd, 13.1, 9.3, 4.3, 1H, H-20b), 1.02 (s,
3H, CH3-25), 0.84 (s, 3H, CH3-24), 0.81 (s, 3H, CH3-23); 13C (75.47
MHz, CDCl3, 298 K): 178.0 (C-17), 167.1 (C-13), 155.3 (C-10),
146.8 (C-2), 136.8 (C-4), 133.1 (C-5), 121.4 (C-3), 91.1 (C-15),
68.3 (C-11), 54.5 (C-19 or C-22), 53.8 (C-22); ESI-MS (TOF):
344.1859 [M+H]+, (calcd. 344.1862 for C20H26NO4).
1637, 1465, 1450, 1424, 1370, 1292, 1215, 1195, 1181; ESI-MS
(TOF): 249.1965 [M+H]+ (calcd. 249.1967 for C15H25N2O); ESI-
MSMS on [M+H]+: 98, 96, 84, 70, 55. NMR see Table 1.
(-)-Schoberine (3). Colorless crystals, mp. 62-63 °C (MeOH),
[R]D20 -12.2 (c 1, MeOH); IR (KBr) νcm-1: 2929, 2863, 2808, 2749,
1626, 1497, 1447, 1362, 1275, 1245, 1181, 1125, 1096, 1041, 967,
850, 815, 777, 672, 605; ESI-MS (TOF): 235.2141 [M+H]+ (calcd.
235.2174 for C15H27N2); ESI-MSMS on [M+H]+: 205, 192, 184,
1
178, 163, 150, 136, 124, 110, 98, 83. H NMR (400.13 MHz,
CDCl3, 298 K): 2.83 (dd, 9.5, 4.0, 1H, H-13), 2.81 (m, 1H, H-2b),
2.76 (dd, 11.1 and 3.9 Hz, 1H, H-11b), 2.73 (m, 1H, H-17b), 2.68
(ddd, 11.5, 11.5 and 2.8 Hz, 1H, H-2a), 2.49 (dd, 11.0 and 4.7 Hz,
1H, H-10), 2.15 (ddddd, 11.1, 11.1, 11.0, 3.9 and 3.3 Hz, 1H, H-9),
1.88 (m, 1H, H-5), 1.85 (ddd, 11.9, 11.9 and 3.4 Hz, 1H, H-17a),
1.78 (m, 1H, H-16b), 1.72 (m, 1H, H-6b), 1.68 (dd, 11.1 and 11.1
Hz, 1H, H-11a), 1.61 (m, 2H, CH2-15), 1.57 (m, 1H, H-4b), 1.52
(m, 2H, CH2-14), 1.51 (m, 1H, H-3b), 1.48 (m, 1H, H-8b), 1.47
(m, 1H, H-6a), 1.43 (m, 1H, H-3a), 1.37 (m, 2H, CH2-7), 1.30 (m,
2H, H-4a and H-16a), 0.79 (m, 1H, H-8a); NMR 13C (75.47 MHz,
CDCl3, 298 K): 82.5 (C-13), 65.0 (C-10), 63.7 (C-11), 56.3 (C-
17), 39.8 (C-2), 35.2 (C-5), 31.5 (C-14), 30.2 (C-8), 30.0 (C-15),
27.0 (C-9), 26.3 (C-6), 25.4 (C-3), 24.6 (C-16 and C-4), 20.2 (C-
7).
9R-(1S-Camphanic acid)-6,7,8,9-tetrahydroquinolin-9-yl Methyl
Ester (5) and (9S)-((1S)-Camphanic acid)-6,7,8,9-tetrahydroquino-
lin-9-yl Methyl Ester (6). To a solution of racemic 4 (15 g, 92 mmol)
in dry CH2Cl2 (150 mL) was slowly added (1S)-(-)-camphanoyl
chloride (20 g, 92.6 mmol) in dry CH2Cl2 (100 mL) and EtN3 (20
mL) at 0 °C. The reaction mixture was then warmed to rt and stirred
for 12 h. Ice water (200 mL) was added and the organic layer was
separated. The aqueous solution was washed with CH2Cl2 (2 ×
100 mL). The combined organic extracts were washed with aqueous
5% NaHCO3 and then with water. The solvent was removed under
(R)-(6,7,8,9-Tetrahydroquinolin-9-yl)methanol [(R)-7]. A solution
of 5 (8.0 g, 23.3 mmol) in MeOH (10 mL) was treated with aqueous
30% NaOH (30 mL). The reaction mixture was stirred at 50 °C
for 3 h. The methanol was evaporated under diminished pressure
and the aqueous solution was extracted with CH2Cl2 (3 × 30 mL).
The combined organic extracts were washed with saturated aqueous
solution of NH4Cl, then with water and dried over MgSO4. The
solvent was removed under diminished pressure and the crude
extract chromatographed on silica gel to afford (R)-7 as colorless
20
1
oil (3.9 g, 97%). [R]D -61.5 (c 2, MeOH); H (400.13 MHz,
CDCl3, 298 K): 8.29 (d, 4.4 Hz, 1H), 7.39 (d, 7.6 Hz, 1H), 7.05
(dd, 7.6 and 4.4 Hz, 1H), 5.58 (br.s, 1H, OH), 3.75 (br.d, 7.8 Hz,
2H), 3.01 (m, 1H), 2.72 (m, 2H), 1.95 (m, 2H), 1.71 (m, 2H); 13
C
(75.47 MHz): 154.5, 146.8, 137.0, 133.3, 121.7, 62.9, 40.4, 28.7,
25.5, 20.2; ESI-MS (TOF): 164.1076 [M+H]+, (calcd. 164.1075
for C10H14NO).
Details for compound (S)-7 see the Supporting Information
section.
[(5S,9R,10R)-Decahydroquinolin-9-yl]methanol [(-)-8] and [(5R,
9R,10S)-Decahydroquinolin-9-yl]methanol [(+)-9]. A solution of
(R)-7 (2 g, 12.27 mmol) in acetic acid (8 mL) was treated with
J. Org. Chem. Vol. 73, No. 19, 2008 7571

Pham et al.
PtO2 (100 mg) under hydrogen atmosphere at rt for 15 h. The solid
was removed by filtration through Celite and then washed with
MeOH. Methanol was eliminated by evaporation under diminished
pressure and the remaining was neutralized with 10% NaOH
aqueous solution to pH 8. The mixture was extracted with CH2Cl2
(3 × 15 mL) and the combined organic extracts were washed with
saturated aqueous solution of NH4Cl, water and dried over MgSO4.
The solvent was removed under reduced pressure and the crude
extract was chromatographed on silica gel column (CH2Cl2/MeOH/
20% NH4OH: 8/1/0.5) to provide (-)-8 (1.3 g, 59%) and (+)-9
(0.4 g, 18%).
mixture was stirred for 1 h and the solid was removed by filtration
then washed with dry CH2Cl2. The filtrate was evaporated under
diminished pressure at temperature below 25 °C. To this resulting
residue was added 2-piperidinone (202 mg, 2.04 mmol) in DMSO
(5 mL) and KH (90 mg, 2.25 mmol) at -5 °C. The solution mixture
was stirred at at -5 °C for 3 h and then warmed to rt and stirred
for additional 15 h. The reaction solution was cooled to 0 °C and
ice water (20 mL) was added then the mixture was extracted with
CH2Cl2 (3 × 30 mL). The combined organic extracts were washed
with a saturated aqueous solution of NH4Cl, then water and dried
over MgSO4. The solvent was removed under diminished pressure.
The resulting crude extract was chromatographed on silica gel (2
to 20% MeOH in CH2Cl2) to afford (-)-11 as colorless oil (260
20
(-)-8: White solid, mp. 110-111 °C (n-hexane/Et2O); [R]D
1
-2.1 (c 2, MeOH); H (400.13 MHz, CDCl3, 298 K): 3.58 (dd,
20
mg, 75%). [R]D -18.4 (c 2, MeOH); NMR spectra of (-)-11 at
10.6, 3.6, 1H, H-11a), 3.45 (dd, 10.6, 10.6, 1H, H-11b), 2.79 (m,
1H, H-2eq), 2.77 (dd, 10.6, 2.8, 1H, H-10), 2.74 (m, 1H, H-2ax),
2.10 (m, 1H, H-9), 1.73, (m, 1H, H-4ax), 1.68 (m, 1H, H-5), 1.68
(m, 1H, H-3eq), 1.52 (m, 1H, H-8eq), 1.44 (m, 2H, H-6ax and H-6eq),
1.39 (m, 2H, H-7ax and H-7eq), 1.38 (m, 1H, H-4eq), 1.36 (m, 1H,
H-3ax), 0.79 (m, 1H, H-8ax); 13C (75.47 MHz, CDCl3, 298 K): 70.6
(C-11), 60.9 (C-10), 40.0 (C-2), 37.4 (C-5), 33.4 (C-9), 31.3 (C-
6), 28.3 (C-8), 27.7 (C-3), 25.1 (C-4), 19.9 (C-7); ESI-MS (TOF):
170.1533 [M+H]+, (calcd. 170.1545 for C10H20NO); ESI-MS/MS
on [M+H]+ ion: 170, 153, 135, 121, 107, 97, 93, 83, 79, 69, 67,
57, 43.
298 K showed broad signals, caused by conformational equilibrium,
1
then spectra were recorded at 338 K. H (400.13 MHz, C5D5N):
3.89 (d, 13.7, 1H, H-18a), 3.82 (dd, 13.5, 4.6, 1H, H-11a), 3.81 (m,
1H, H-18b), 3.50 (dd, 13.5 and 9.7 Hz, 1H, H-11b), 3.24 (m, 1H,
H-17), 3.11 (m, 1H, H-17), 2.99 (ddd, 13.8, 11.1 and 3.0 Hz, 1H,
H-2ax), 2.50 (m, 1H, H-9), 2.46 (m, 1H, H-2eq), 2.4 (m, 2H, CH2-
14), 2.35 (m, 1H, H-10), 2.09 (m, 1H, H-5), 1.88 (m, 1H, H-4eq),
1.70 (m, 1H, H-3ax), 1.69 (m, 1H, H-7eq), 1.60 (m, 4H, CH2-15,
CH2-16), 1.59 (m, 1H, H-8eq), 1.42 (m, 1H, H-6ax), 1.39 (m, 1H,
H-6eq), 1.35 (m, 2H, H-3eq, H-8ax), 1.30 (m, 1H, H-7ax), 1.09 (m,
1H, H-4ax); 13C (75.47 MHz, C5D5N, 338 K): 169.2 (C-13), 141.5
(C-19), 129.3 (C-20, C-24), 128.7 (C-21, C-23), 127.2 (C-22), 64.2
(C-10), 58.0 (C-18), 50.9 (C-11), 49.0 (C-17), 46.2 (C-2), 33.0 (C-
14), 32.9 (C-9), 31.2 (C-8), 30.2 (C-5), 29.1 (C-4), 27.1 (C-3), 23.8
(C-16), 21.9 (C-15), 21.1 (C-6), 20.9 (C-7); ESI-MS (TOF):
341.2578 [M+H]+ (calcd. 341.2593 for C22H33N2O); ESI-MSMS
on [M+H]+ ion: 341, 249, 242, 234, 222, 150, 135, 112, 107, 100,
91, 84, 65, 56.
(+)-9: White solid, mp. 125-126 °C (EtO2); [R]D20 +33.2 (c 2,
MeOH); 1H (400.13 MHz, CDCl3, 298 K): 3.79 (m, 1H, H -11a),
3.52 (dd, 2.7 and 2.7 Hz, 1H, H-11b), 3.01 (ddd, 13.0, 4.1 and 1.9
Hz, 1H, H-2eq), 2.96 (dd, 2.7 and 2.7 Hz, 1H, H-10), 2.54 (ddd,
13.0, 13.0 and 3.3 Hz, 1H, H-2ax), 1.78 (m, 1H, H-7eq), 1.66 (m,
2H, H-4ax and H-6ax), 1.55 (m, 1H, H-4eq), 1.48 (m, 1H, H-3ax),
1.47 (m, 1H, H-5), 1.42 (m, 1H, H-9), 1.41 (m, 2H, H-8ax and
H-8eq), 1.29 (m, 1H, H-3eq), 1.28 (m, 1H, H-6eq), 1.26 (m, 1H,
H-7ax); 13C (75.47 MHz): 67.3 (C-11), 59.1 (C-10), 47.1 (C-2), 42.5
(C-9), 35.6 (C-5), 30.3 (C-4), 25.6 (C-7), 24.3 (C-6), 23.2 (C-8),
21.9 (C-3), ESI-MS (TOF): 170.1537 [M+H]+, (calcd. 170.1545
for C10H20NO), ESI-MS/MS on [M+H]+ ion: 170, 163, 158, 149,
140, 135, 128, 123, 121, 119, 111, 107.
Details for compound (+)-11 see the Supporting Information
section.
(-)-Myrionine [(-)-12]. To a solution of (-)-11 (100 mg, 0.29
mmol) in AcOH (2 mL) was added 10% Pd/C (10 mg) under
hydrogen atmosphere and the mixture was stirred at rt for 3 h. The
solid was filtered-off and washed with MeOH. The filtrate was
concentrated under diminished pressure and the residue was
chromatographed on silica gel (CH2Cl2/MeOH: 9/1) to afford (-)-
Details for compounds (+)-8 and (-)-9 see the Supporting
Information section.
[(5S,9R,10R)-N-Benzyl-decahydroquinolin-9-yl]methanol [(-)-
10]. To a solution of (-)-8 (250 mg, 1.48 mmol) in a mixture of
CH2Cl2/ sat. Na2CO3 (1:1, 10 mL) was added benzyl bromide (0.26
mL, 2.22 mmol). The reaction mixture was stirred for 12 h at rt.
Water (15 mL) was added and the mixture solution was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with water and dried over MgSO4. The solvent was removed
under diminished pressure and the crude extract purified by
chromatography over silica gel column (CH2Cl2/MeOH 98/2) to
20
1
12 (66 mg, 90%) as oil. [R]D -16.8 (c 1, MeOH). H (400.13
MHz, C5D5N, 328 K): 3.62 (dd, 13.4, 8.1, 1H, H-11b), 3.53 (dd,
13.4, 8.1, 1H, H-11a), 3.19 (m, 2H, CH2-17), 2.98 (ddd, 12.0, 6.5
and 4.0 Hz, 1H, H-2b), 2.69 (m, 1H, H-2a), 2.68 (dd, 6.2 and 3.1
Hz, 1H, H-10), 2.38 (m, 2H, CH2-14), 2.18 (ddddd, 8.1, 6.4, 6.2,
5.7 and 5.7 Hz, 1H, H-9), 1.90 (m, 1H, H-5), 1.85 (m, 1H, H-8b),
1.79 (m, 1H, H-6b), 1.67 (m, 1H, H-3b), 1.63 (m, 2H, CH2-16),
1.61 (m, 2H, CH2-15), 1.57 (m, 1H, H-4b), 1.55 (m, 1H, H-7b),
1.46 (m, 1H, H-7a), 1.41 (m, 1H, H-4a), 1.35 (m, 1H, H-3a), 1.29
(m, 1H, H-6a), 1.20 (dddd, 12.8, 7.0, 5.7, 3.7, 1H, H-8a); 13C (75.47
MHz, C5D5N, 328 K): 57.9 (C-10), 49.1 (C-11), 48.3 (C-17), 44.2
(C-2), 35.6 (C-9), 33.8 (C-5), 32.8 (C-14), 29.7 (C-4), 28.3 (C-6),
26.5 (C-8), 24.2 (C-3), 23.7 (C-16), 21.7 (C-15), 21.6 (C-7); ESI-
MS (TOF): 251.2136 [M+H]+, (calcd. 251.2123 for C15H27N2O);
ESI-MS/MS (TOF) on [M+H]+ ion: 251 [M+H]+, 234, 152, 135,
112, 107, 100, 93, 84, 79, 67.
20
give 356 mg of (-)-10 as colorless oil (93% yield). [R]D -21.8
(c 2, MeOH); 1H (400.13 MHz): 7.3 (m, 4H, H-14,15,17,18), 7.23
(m, 1H, H-16), 3.89 (s, 2H, H-12), 3.50 (dd, 10.4 and 3.2 Hz, 1H,
H-11a), 3.32 (dd, 10.4 and 104 Hz, 1H, H-11b), 3.01 (ddd, 13.7,
13.7 and 3.1 Hz, 1H, H-2ax), 2.58 (m, 1H, H-2eq), 2.55 (dd, 11.1
and 4.4 Hz, 1H, H-10), 2.17 (m, 1H, H-9), 2.13 (m, 1H, H-5), 1.79
(m, 1H, H-3ax), 1.76 (m, 1H, H-4ax), 1.48 (m, 1H, H-6eq), 1.46 (m,
1H, H-8eq), 1.39 (m, 1H, H-4eq), 1.38 (m, 2H, H-7ax and H-7eq),
1.33 (m, 1H, H-3eq), 1.32 (m, 1H, H-6ax), 0.68 (m, 1H, H-8ax). 13
C
Details for compound (+)-12 see the Supporting Information
section.
(75.47 MHz): 129.0 (C-14, C-18), 128.4 (C-15, C-17), 127.2 (C-
16), 138.6 (C-13), 70.7 (C-11), 66.3 (C-10), 57.1 (C-12), 44.4 (C-
2), 33.7 (C-9), 31.2 (C-6), 28.7 (C-8), 28.5 (C-5), 25.4 (C-4), 19.9
(C-7), 19.7 (C-3); ESI-MS (TOF): 260.2023 [M+H]+ (calcd.
260.2014 for C17H26NO); ESI-MS/MS (TOF) on [M+H]+ ion: 260,
242, 168, 152, 135, 107, 91, 79, 65.
Details for compound (+)-10 see the Supporting Information
section.
1-{[(5S,9S,10R)-N-Benzyl-decahydroquinolin-9-yl]methyl}piperidin-
2-one [(-)-11]. A solution containing (-)-10 (264 mg, 1.02 mmol)
in dry CH2Cl2 (4 mL) was treated with Et3N (0.2 mL) and MsCl
(80 µL, mmol) at -5 °C under argon atmosphere. The reaction
[(5S,9S,10R)-N-benzyl-decahydroquinolin-9-yl]methanol [(+)-
13]. According to the procedure used for (-)-10, compound (+)-
13 (314 mg) was obtained as an oil from (-)-9 (250 mg, 1.48 mmol)
20
and benzyl bromide (0.27 mL, 2.22 mmol) in 82% yield. [R]D
+41.8 (c 2, MeOH). Due to conformational equilibrium at rt, the
spectra were recorded at 318 K. H (400.13 MHz, CDCl3): 7.31
1
(m, 2H, H-17 and 15), 7.27 (m, 2H, H-18 and H-14), 7.20 (m, 1H,
H-16), 3.89 (dd,10.5 and 6.7 Hz, 1H, H-11a), 3.88 (d, 13.0 Hz,
1H, H-12a), 3.69 (dd, 10.5 and 7.1 Hz, 1H, H-11b), 3.22 (d, 13.0
Hz, 1H, H-12b), 2.78 (dd, 3.8 and 3.8 Hz, 1H, H-10), 2.68 (ddd,
11.8, 4.1 and 4.1 Hz, 1H, H-2eq), 2.13 (ddd, 11.8, 11.8 and 3.5 Hz,
7572 J. Org. Chem. Vol. 73, No. 19, 2008

Antimalarial Alkaloids from Myrioneuron nutans
1H, H-2ax), 1.96 (m, 1H, H-9), 1.95 (m, 1H, H-6ax), 1.88 (m, 1H,
H-5), 1.73 (m, 1H, H-7eq), 1.69 (m, 1H, H-3ax), 1.64 (m, 1H, H-8ax),
1.58 (m, 2H, H-4ax and H-4eq), 1.50 (m, 1H, H-8eq), 1.38 (m, 2H,
H-3eq and H-7ax), 1.37 (m, 1H, H-6eq); 13C (75.47 MHz, CDCl3):
139.8 (C-13), 128.7 (C-17 and 15), 128.3 (C-18 and 14), 126.8
(C-16), 67.7 (C-11), 63.9 (C-10), 59.3 (C-12), 50.3 (C-2), 45.2 (C-
9), 36.8 (C-5), 28.6 (C-4), 28.3 (C-6), 25.7 (C-8), 23.5 (C-7), 20.7
(C-3); ESI-MS (TOF): 260.1990 [M+H]+ (calcd. 260.2014 for
C17H26NO); ESI-MS/MS on [M+H]+ ion: 260, 242, 168, 152, 150,
135, 121, 107, 96, 91, 79, 65.
(c 1, MeOH). NMR data were identical with those of the natural
(-)-myrionidine (1).
Details for compound 18 see the Supporting Information section.
(-)-9-Epi-myrionidine [(-)-16]. According to the procedure
described above for (-)-myrionidine (1), (-)-9-epi-myrionine [(-)-
15] (87 mg, 0.34 mmol) and POCl3 (49 µL, 0.4 mmol) gave [(-)-
20
16] (74 mg, 92%). Mp 162-164 °C; [R]D -53.2 (c 2, MeOH);
1H (400.13 MHz, CDCl3, 298 K): 4.21 (br.d, 13.1, 1H, H-11a),
3.90 (m, 2H, H-2eq and H-10), 3.56 (ddd, 13.3, 5.5 and 5.4 Hz,
1H, H-17eq), 3.37 (ddd, 13.2, 13.2 and 2.7 Hz, 1H, H-2ax), 3.26
(ddd, 13.3, 9.0 and 4.7 Hz, 1H, H-17ax), 2.99 (ddd, 17.4, 8.3 and
8.3 Hz, 1H, H-14ax), 2.86 (dd, 13.1 and 1.9 Hz, 1H, H-11b), 2.52
(ddd, 17.4, 4.8 and 4.8 Hz, 1H, H-14eq), 2.05 (m, 1H, H-9), 2.01
(m, 1H, H-15eq), 1.99 (m, 1H, H-16ax), 1.78 (m, 3H, H-5, H-7eq
and H-16eq), 1.74 (m, 1H, H-4ax), 1.68 (m, 1H, H-3ax), 1.63 (m,
1H, H-15ax), 1.57 (m, 2H, H-3eq and H-8eq), 1.55 (m, 1H, H-4eq),
1.36 (m, 1H, H-7ax), 1.31 (m, 2H, CH2-6), 1.09 (m, 1H, H-8ax);
13C (75.47 MHz, CDCl3, 298 K): 161.7 (C-13), 55.8 (C-10), 54.0
(C-11), 52.4 (C-17), 47.6 (C-2), 35.0 (C-5), 32.2 (C-9), 27.2 (C-
14), 25.1 (C-8), 24.9 (C-6), 24.3 (C-7), 20.8 (C-16), 19.5 (C-3),
18.5 (C-15), 18.2 (C-4); ESI-MS (TOF): 233.2016 [M]+ (calcd.
233.2014 for C15H25N2); ESI-MS/MS on [M]+ ion: 233, 151, 123,
111, 93, 81, 79, 67, 55, 41.
Details for compound (-)-13 see the Supporting Information
section.
1-{[(5S,9R,10R)-N-Benzyl-decahydroquinolin-9-yl]methyl}piperidin-
2-one [(+)-14]. By using the similar procedure as (-)-11, (+)-13
(253 mg, 0.97 mmol), MsCl (75 µL, 0.97 mmol), 2-piperidinone
(144 mg, 1.45 mmol) and KH (39 mg, 0.97 mmol) afforded 247
mg of (+)-14 as an oil (75% yield). [R]D20 +9.6 (c 2, MeOH); 1H
(400.13 MHz, C5D5N, 338 K): 7.51 (br.d, 7.4 Hz, 2H, H-20 and
H-24), 7.39 (m, 7.4, 7.3 and 1.5 Hz, 2H, H-21 and H-23), 7.29
(ddt, 7.3, 7.3 and 1.4 Hz, 1H, H-22), 4.10 (d, 13.0 Hz, 1H, H-18a),
3.91 (dd, 13.1 and 9.8 Hz, 1H, H-11a), 3.52 (dd, 13.1 and 3.5 Hz,
1H, H-11b), 3.35 (d, 13.0 Hz, 1H, H-18b), 3.27 (m, 1H, H-17ax),
3.19 (m, 1H, H-17eq), 2.81 (ddd, 11.7, 4.4 and 4.4 Hz, 1H, H-2eq),
2.75 (dd, 3.0 and 3.0 Hz, 1H, H-10), 2.41 (m, 2H, CH2-14), 2.12
(m, 1H, H-6ax), 2.09 (m, 1H, H-9), 2.08 (ddd, 11.7, 11.7, 3.7 Hz,
1H, H-2ax), 1.90 (m, 1H, H-7eq), 1.81 (m, 1H, H-8ax), 1.65 (m, 2H,
CH2-16), 1.63 (m, 2H, CH2-15), 1.60 (m, 1H, H-3ax), 1.58 (m, 1H,
H-8eq), 1.51 (m, 2H, CH2-4), 1.39 (m, 1H, H-7ax), 1.27 (m, 1H,
H-6eq), 1.25 (m, 1H, H-3eq); 13C (75.47 MHz, C5D5N, 338 K): 169.2
(C-13), 141.6 (C-19), 129.0 (C-20 and -24), 128.7 (C-21 and -23),
127.1 (C-22), 65.0 (C-10), 59.0 (C-18), 52.7 (C-11), 52.5 (C-2),
48.8 (C-17), 44.3 (C-9), 39.8 (C-5), 33.0 (C-14), 30.7 (C-4), 28.2
(C-6), 26.3 (C-8), 25.3 (C-7), 23.9 (C-16), 22.3 (C-3), 21.9 (C-
15); ESI-MS (TOF): 341.2597 [M+H]+ (calcd. 341.2593 for
C22H33N2O); ESI-MS/MS on [M+H]+ ion: 341, 265, 251, 214, 205,
199, 183, 163, 158, 149, 140, 135, 128, 121, 111.
Details for compounds (+)-16 and 19 see the Supporting
Information section.
(+)-9-Epi-schoberine [(+)-17]. To a solution of (-)-9-epi-
myrionidine (-)-16 (50 mg, 0.2 mmol) in dry THF (4 mL) was
treated with LiAlH4 (10 mg, 0.26 mmol) at -5 °C. The reaction
solution was stirred for 30 min at this temperature then warmed to
rt and stirred for additional 12 h. Aqueous solution of NaOH (5%,
5 mL) was added and the solution was extracted with CH2Cl2 (5 ×
10 mL). The combined organic extracts were washed with water
and dried over MgSO4. The solvent was removed under diminished
pressure and the residue was purified by chromatography on silica
gel (CH2Cl2/MeOH 95/5) to afford (+)-17 as colorless solid (51
mg, 90%). Mp 71-72 °C; [R]D20 +32.4 (c 1, MeOH); 1H (400.13
MHz, CDCl3, 298 K): 3.15 (dd, 10.7, 3.3 and 3.3 Hz, 1H, H-2eq),
2.66 (m, 1H, H-17eq), 2.58 (dd 11.1 and 1.8 Hz, 1H, H-11eq), 2.18
(dd, 11.1, 3.7, 1H, H-11ax), 2.05 (m, 2H, H-8ax and H-10), 2.03
(m, 1H, H-14eq), 1.90 (dd, 11.8 and 3.1 Hz, 1H, H-13), 1.89 (m,
1H, H-17ax), 1.86 (m, 1H, H-6ax), 1.78 (m, 1H, H-7eq), 1.77 (m,
1H, H-15eq), 1.73 (m, 1H, H-3ax), 1.57 (m, 1H, H-2ax), 1.55 (m,
1H, H-16ax), 1.52 (m, 1H, H-5), 1.46 (m, 1H, H-16eq), 1.40 (m,
1H, H-9), 1.38 (m, 1H, H-3eq), 1.32 (m, 1H, H-8eq), 1.29 (m, 1H,
H-7ax), 1.24 (m, 1H, H-14ax), 1.20 (m, 1H, H-15ax), 1.14 (m, 1H,
H-6eq); 13C (75.47 MHz, CDCl3, 298 K): 85.7 (C-13), 64.1 (C-10),
61.9 (C-11), 56.3 (C-17), 50.3 (C-2), 37.7 (C-5 and 9), 30.5 (C-4),
28.9 (C-14), 27.0 (C-8), 26.5 (C-7), 25.9 (C-6), 25.0 (C-16), 24.1
(C-15), 21.5 (C-3); ESI-MS (TOF): 235.2179 [M+H]+ (calcd.
235.2174 C15H27N2); ESI-MS/MS, on [M+H]+ ion: 235, 152, 150,
121, 98, 79, 70, 67, 55, 41.
Details for compound (-)-14 see the Supporting Information
section.
(-)-9-Epi-myrionine [(-)-15]. By applying the procedure de-
scribed above for (-)-myrionine [(-)-12], (+)-14 (165 mg, 0.48
mmol) and 10% Pd/C (15 mg) provided (-)-15 as an oil (107 mg,
20
1
89%). [R]D -21.8 (c 2, MeOH); H (400.13 MHz, CDCl3, 298
K): 4.03 (dd, 14.3 and 11.4 Hz, 1H, H-11a), 3.33 (m, 1H, H-2eq),
3.31 (m, 1H, H-17eq), 3.17 (ddd, 12.2, 8.0 and 5.1 Hz, 1H, H-17ax),
2.59 (br.s, 1H, H-10), 2.55 (dd, 14.4 and 4.6 Hz, 1H, H-11b), 2.46
(ddd, 13.0, 13.0 and 3.1 Hz, 1H, H-2ax), 2.35 (m, 2H, CH2-14),
1.93 (dddd, 12.2, 12.2, 12.2 and 4.0 Hz, 1H, H-6ax), 1.83 (m, 1H,
H-7eq), 1.81 (m, 1H, H-3ax), 1.78 (m, 2H, CH2-16), 1.75 (m, 1H,
H-9), 1.74 (m, 2H, CH2-15), 1.59 (m, 1H, H-8ax), 1.58 (m, 1H,
H-5), 1.55 (m, 1H, CH2-4), 1.39 (br.d, 14.1 Hz, 1H, H-3eq), 1.26
(m, 3H, H-6eq, H-7ax, H-8eq); 13C (75.47 MHz, CDCl3, 298 K): 171.0
(C-13), 55.3 (C-10), 49.2 (C-11), 48.4 (C-17), 46.3 (C-2), 39.3 (C-
9), 35.3 (C-5), 31.7 (C-14), 29.8 (C-4), 25.6 (C-7), 24.6 (C-6), 24.3
(C-8), 23.0 (C-16), 21.0 (C-15), 19.5 (C-3); ESI-MS (TOF):
251.2129 [M+H]+ (calcd. 251.2123 C15H27N2O); ESI-MS/MS on
[M+H]+ ion: 251, 152, 135, 121, 112, 107, 100, 96, 93, 91, 84,
81, 79, 67, 56, 44, 41.
Details for compound (-)-17 see the Supporting Information
section.
Acknowledgment. We thank Mr A. Gramain and Mr D. C.
Dao (Institute of Chemistry - VAST - Vietnam) for plant
collection and botanical determination, Dr A. Blond and Mr.
Lionel Dubost (MNHN - France) for recording 2D NMR spectra
and ESI-MS measurement, respectively. The CNRS is gratefully
acknowledged for doctoral fellowship supporting (V. C. Pham).
Details for compound (+)-15 see the Supporting Information
section.
(-)-Myrionidine (1). To a solution of (-)-myrionine [(-)-12]
(75 mg, 0.3 mmol) in dry toluene (4 mL) was added POCl3 (33
µL, 0.36 mmol) and heated at reflux for 12 h. The volatile layer
was removed under diminished pressure. To this residue, 10%
NH4OH (5 mL) was added and the solution was concentrated under
diminished pressure to dryness. The residue was purified by repeated
chromatography on Sephadex (LH-20) eluted with MeOH to afford
1 as colorless solid (72 mg, 97%). Mp 155-156 °C; [R]D20 -60.5
Supporting Information Available: ESI-MS and NMR
spectra of all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO801046J
J. Org. Chem. Vol. 73, No. 19, 2008 7573