Asymmetric synthesis of myrioxazines A and B, novel alkaloids of Myrioneuron nutans

Article abstract of DOI:10.1016/S0040-4039(02)01771-9

Two new epimeric tricyclic alkaloids, myrioxazines A and B were isolated from the leaves of Myrioneuron nutans and their structures elucidated by spectral analysis (mass spectrometry and 2D NMR). Absolute configurations were determined by total asymmetric synthesis.

Full text of DOI:10.1016/S0040-4039(02)01771-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7565–7568
Asymmetric synthesis of myrioxazines A and B, novel alkaloids
of Myrioneuron nutans
Van Cuong Pham,a Akino Jossang,a Ange`le Chiaroni,b Thierry Se´venetb and Bernard Bodoa,*
aLaboratoire de Chimie des Substances Naturelles-ESA 8041 CNRS, Muse´um National d’Histoire Naturelle,
63 rue Buffon, 75005 Paris, France
bInstitut de Chimie des Substances Naturelles, CNRS-91198 Gif-sur-Yvette cedex, France
Received 20 August 2002; revised 21 August 2002; accepted 22 August 2002
Abstract—Two new epimeric tricyclic alkaloids, myrioxazines A and B were isolated from the leaves of Myrioneuron nutans and
their structures elucidated by spectral analysis (mass spectrometry and 2D NMR). Absolute configurations were determined by
total asymmetric synthesis. © 2002 Elsevier Science Ltd. All rights reserved.
The Rubiaceae is a large family containing various and
important alkaloid classes, such as purine (caffeine),1
pyrrolidinoindoline (psychotridine),2,3 indole (yohim-
bine), quinolizidine (emetine) and quinoline (quinine,1
camptothecin4) alkaloids.
Compound 1 was isolated as an optically active colour-
less oil, [h]2D0 +21 (c 1, MeOH). Its ESI-MS showed the
protonated molecular [M+H]+ ion at m/z 182.1559
(calcd 182.1545 for C11H20NO), indicating the molecu-
lar formula C11H19NO. The 13C NMR spectrum pre-
sented eight methylene and three methine groups.
Analysis of 1H–1H COSY spectrum showed complex
connections, starting from the methylene at l 2.55 and
3.09 (CH2-2) to methine at l 2.73 (CH-10) and also
those of the methine at l 2.13 (H-9) to the methylene at
We report here, the first chemical study on Myrioneu-
ron nutans Drake (Rubiaceae). Two tricyclic alkaloids,
with a new natural skeleton were isolated from the
leaves and named myrioxazines A (1) and B (2). Fur-
thermore, the absolute configurations of the natural
compounds were established by the total asymmetric
syntheses of 1, 2 and their enantiomers.
1
l 3.13 and 3.80 (CH2-11). The H and 13C chemical
shifts (Table 1) suggested that the CH2-2 and the
CH-10 were linked to nitrogen atom and the CH2-11
linked to oxygen atom. In the HMBC spectrum, the
proton at l 2.73 (H-10) was correlated to the methylene
carbons at l 73.1 (C-11), 44.7 (C-2), 23.7 (C-4) and 31.0
(C-6), thus depicting a decahydroquinoline substituted
skeleton. The methylene CH2-13, linked to both oxygen
and nitrogen atoms (-O-CH2-N<) as indicated by its
chemical shifts (lC 86.2 and lH 4.42 and 4.36), was
correlated to the protons of two methylenes CH2-2 and
CH2-11, forming an 1,3-oxazine ring system. From
further HMBC analysis, the structure perhydroquino
[1,8-cd] [1,3] oxazine was assigned to myrioxazine A (1).
The relative configuration of 1 was determined from
vicinal 1H–1H coupling constants and NOESY data.
The proton H-9 displayed three trans-diaxial coupling
constants with H-11ax, H-10 and H8ax (11.1 Hz), and
two gauche-coupling ones with H-11eq and H-8eq (4.3
and 3.3 Hz), indicating that it was axial on both b and
c-rings.
The dried leaves (5 kg) of M. nutans, collected in North
Vietnam were extracted with CH2Cl2 at pH
9
(NH4OH). The crude alkaloid obtained by acid–base
purification was separated by cc on SiO2 eluted with
CH2Cl2/MeOH gradient to yield compounds 1 (25 mg)
and 2 (40 mg).
* Corresponding author. Tel.: +33(0)140793129; fax: +33(0)
140793135; e-mail: bodo@mnhn.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01771-9

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V. C. Pham et al. / Tetrahedron Letters 43 (2002) 7565–7568
1
Table 1. NMR data for 1 and 2, (CDCl3); H (400.13 MHz), 13C (75.47 MHz)
1
2
Cn°
lC
lH
m (J, Hz)
lC
lH
m (J, Hz)
2
–
3
–
4
–
5
6
–
7
–
8
–
9
44.7
–
25.9
–
23.7
–
34.8
31.0
–
20.2
–
27.5
–
27.8
62.3
73.1
–
86.2
–
3.09 (ax)
2.56 (eq)
1.71 (eq)
1.50 (ax)
1.50 (ax)
1.26 (eq)
1.79
1.51
1.51
1.34
1.34
ddd (11.9; 11.9; 2.8)
ddd (11.9; 3.8; 2.2)
m
m
m
m
ddddd (12.0; 4.0; 4.0; 4.0; 4.0)
m
m
m
m
m
dddd (12.2; 12.2; 11.1; 4.3)
ddddd (11.1; 11.1; 11.1; 4.3; 3.3)
dd (11.1; 4.8)
dd (10.8; 4.3; 1.0)
dd (11.1; 10.8)
50.0
–
20.3
–
30.1
–
36.2
25.4
–
26.0
–
25.2
–
37.0
63.3
73.4
–
87.7
–
2.57 (eq)
1.73 (ax)
1.76 (ax)
1.38 (eq)
1.47
d (8.2)
m
m
m
m
m
m
m
1.47
1.49
1.80 (ax)
1.16 (eq)
1.78 (eq)
1.27 (ax)
1.95 (ax)
1.35 (eq)
1.33
m
m
m
1.33 (eq)
0.71 (ax)
2.13
dddd (13.6; 13.6; 13.6; 3.6)
m
m
br.s
dd (11.1; 0.9)
dd (11.1; 2.7)
d (7.6)
10
11
–
13
–
2.73
2.16
3.80 (eq)
3.13 (ax)
4.42 (ax)
4.36 (eq)
3.70 (ax)
3.56 (eq)
4.26 (eq)
3.38 (ax)
d (10.4)
dd (10.4; 1.0)
d (7.6)
On the other hand, H-10 showed an additive gauche-
coupling constant with H-5 (4.8 Hz). These results
indicated the cis-a/b and trans-b/c rings junctions for
compound 1. Finally, the relative configuration 5S*,
9R* and 10R* was confirmed by the NOESY spectrum,
in which strong interactions of H-10 with H-5, H-8ax,
H-11ax and H-13ax, and of H-9 with both H-2ax and
H-11eq were observed (Fig. 1). Complete analysis of
NOE interactions determined that the three a, b and
c-rings were in the chair conformation and that H-10
was equatorial in a-ring with cis-a/c rings junction.
COSY spectrum of 1 indicated the same spin systems
for a decahydroquinoline derivative. In the HMBC
spectrum, the proton at l 2.16 (H-10) showed correla-
tions to the methylene carbons at l 87.7 (C-13), 73.4
(C-11), 30.1 (C-4), 25.4 (C-6) and 25.2 (C-8). Further-
more, the methylene at l 73.4 (C-11) correlated to the
two methylenes CH2-8 and CH2-13 at l 1.35, 1.95 and
3.38, 4.26, respectively. These results indicated that
compound 2 has the same plane structure as compound
1. In comparison with 1, the stereochemical inversion at
chiral carbon C-9 of 2 was depicted by the broad singlet
signal for proton H-10 at l 2.16, indicating small
coupling constants between H-10 and both H-9 and
H-5. These results showed cis-relationship of H-10 with
both H-5 and H-9, defining thus cis-a/b and b/c ring
fusions. Furthermore, the strong interactions observed
in the NOESY spectrum of H-10 with H-2ax, H-4ax,
H-5, H-9 and H-13ax, and of H-9 with H-5, H-7ax and
CH2-11 determined that the three a, b, c-rings were in
Myrioxazine
A (1) was a cis-decahydroquinoline
derivative, for which the N-out (N-outside)5 conforma-
tion was constrained by the -O-CH2- bridge.
Figure 1. Selected NOE and HMBC correlations for myriox-
azine A (1).
Compound 2 was obtained as a colourless oil, [h]2D0 +9
(c 1, MeOH). The ESI-MS showed the protonated
molecular [M+H]+ ion at m/z 182.1549, and the H and
1
13C NMR (J-modulated) spectra were similar to those
of 1, suggesting 1 and 2 to be isomers. The 1H–1H
Figure 2. Selected NOE and HMBC correlations for myriox-
azine B (2).

V. C. Pham et al. / Tetrahedron Letters 43 (2002) 7565–7568
7567
chair conformation and that H-10 was axial in the a
and c-rings and equatorial in b-ring; the two a and
c-ring were thus in trans-fusion. From foregoing stud-
ies, the relative stereochemistry 5S*, 9S* and 10R* was
assigned to myrioxazine B (2), a cis-decahydroquinoline
derivative, possessing the N-in (N-inside)5 structure,
which was also locked by the -O-CH2- bridge (Fig. 2).
In order to determine the absolute configurations of 1
and 2, their total asymmetric syntheses were performed
as described in Fig. 3. Tetrahydroquinoline 46–8 was
prepared by Michael addition of acroleine with the
enamine of cyclohexanone, followed by cyclisation with
hydroxylamine hydrochloride. Compound 4 reacted
with paraformaldehyde at 90°C for 48 h, to give a
racemic mixture of 8-hydroxymethyl tetrahydro-
quinoline 5 with 37% yield (50% of 4 recovered). This
reaction was previously reported by Crabb et al.,9
but with lower yield because of the formation of bis-
substituted compounds. The two diastereoisomers 610
and 711 were obtained via esterification of the racemate
5 with (1S)-(−)-camphanyl chloride followed by SiO2 cc
(n-hexane/Et2O/EtOH 10/1/0.5). Compound 6 ([h]D20
+23; c 2, MeOH) was an oil and 7 ([h]2D0 −45; c 2,
MeOH) was crystallised from n-hexane/Et2O mixture.
Figure 4. X-Ray crystallographic structure of compound 7
(ORTEP drawing with 30% probability ellipsoids).
diastereoisomers
6 (S) and 7 (R) were further
hydrolysed to give two enantiomers 8 (9-S) ([h]2D0 +60; c
2, MeOH) and 13 (9R) ([h]2D0 −61; c 2, MeOH), respec-
tively. Catalytic hydrogenation (H2/PtO2, AcOH) of 8
provided two stereoisomers 913 ([h]D20 −34; c 2, MeOH)
and 1014 ([h]2D0 +2; c 1, MeOH): similarly, compound 13
yielded two stereoisomers 1413 ([h]D20 +33; c 2, MeOH)
and 1514 ([h]2D0 −2, c 1, MeOH), in ratio 4:1 for 9:10 and
14:15. Finally, compounds 1115 ([h]D20 −19; c 1, MeOH),
1216 ([h]2D0 +10; c 1, MeOH), 1615 ([h]2D0 +19; c 1,
MeOH) and 1716 ([h]D20 −9; c 1, MeOH) were obtained
respectively from cyclisation of 10, 9, 15 and 14 with
HCHO 30% at rt for 1 h.
The X-ray diffraction12 analysis of 7 indicated that the
absolute configuration of the chiral carbon C-9 was (R)
(Fig. 4), and that of 6 was thus (S). The two
Figure 3. Reagents and conditions: (a) 1. Piperidine, toluene, p-TsOH, 110°C, 12 h; (2) acroleine, THF, 3 h; HCl 2N, 4 h, 35%
overall. (b) NH2OH–HCl, EtOH, 80°C, 3 h, 77%. (c) Paraformaldehyde, 90°C, 48 h, 37%. (d) (1S)-(−)-camphanic chloride,
CH2Cl2/Py, 15 h, 91%. (e) NaOH 30%, 60°C, 5 h, 97%. (f) H2/PtO2, AcOH, 12 h, 82%. (g) HCHO 30%, 1 h, 95%.

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V. C. Pham et al. / Tetrahedron Letters 43 (2002) 7565–7568
Comparison of NMR data and optical activities of the
natural myrioxazines A (1) and B (2) with the synthetic
11, 12, 16 and 17 revealed that they were identical to 16
and 12, respectively. The absolute configurations 5S,
9R and 10R were thus assigned to myrioxazine A (1),
and 5S, 9S and 10R for myrioxazine B (2).
or C-19); 39.9 (C-9); 30.4 (C-21); 28.8 (C-6; C-20); 26.0
(C-8); 20.0 (C-7); 16.4 (CH3-24); 16.3 (CH3-23); 9.5 (CH3-
25).
11. Compound 7: mp 110–110.5°C; [h]2D0 −45 (c 2, MeOH);
1H (CDCl3, 400.13 MHz): 8.33, 1H (m, 4.7; 1.7, H-2);
7.33, 1H (m, 7.7; 1.7, H-4); 7.00, 1H (dd, 7.7, 4.7, H-3);
4.63, 1H (dd, 10.7; 8.1, H-11a); 4.61, 1H (dd, 10.7; 3.5,
H-11b); 3.25, 1H (m, H-9); 2.72, 2H (m, H-6); 2.32, 1H
(ddd, 13.3; 10.8; 4.3, H-21a); 2.03, 1H (m, H-8a); 1.95,
1H (m, H-21b); 1.90, 1H (m, H-7a); 1.84, 1H (m, H-20a);
1.83, 1H (m, H-8b); 1.71, 1H (m, H-7b); 1.61, 1H (ddd,
13.1; 9.3; 4.2, H-20b); 1.03, 3H (s, CH3-25); 0.94, 3H (s,
CH3-24); 0.74, 3H (s, 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).
12. Structure solved with SHELXS-86 and refined with
SHELXL-93. H atoms treated riding. Refinement con-
verged to R(F)=0.0548 for the 3379 observed reflections
and wR(F2)=0.1310 for all the 4227 data, goodness-of-fit
S=1.083. Residual electron density between −0.17 and
Acknowledgements
We thank Dr V. H. Nguyen for the supporting of the
program ‘Research for Flora of Vietnam’. The CNRS
is gratefully acknowledged for doctoral fellowship sup-
porting (V.C.P.), and the ‘Re´gion Ile de France’ for the
distribution of NMR 400 MHz and the mass spec-
trometry equipment. We thank also Dr. J. P. Brouard
and Mr. L. Dubost for the mass spectra, Mrs. C. Caux
for the NMR spectra, and Mr. D. C. Dao and Mr. A.
Gramain for the collect of plant materials.
References
0.28 e A−3. Full crystallographic results have been
,
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deposited as Supplementary Material (CIF file), at the
Cambridge Crystallographic Data Centre, UK. Displace-
ment ellipsoids are shown at the 30% probability level.
13. Compound 9: mp 125–125.5°C; [h]2D0 −34 (c 2, MeOH).
Compound 14: [h]2D0 +33 (c 2, MeOH); 1H (CDCl3, 400.13
MHz): 3.79, 1H (m, H -11a); 3.52, 1H (dd, 2.7; 2.7,
H-11b); 3.01, 1H (ddd, 13.0; 4.1; 1.9, H-2eq); 2.96, 1H
(dd, 2.7; 2.7, H-10); 2.54, 1H (ddd, 13.0; 13.0; 3.3,
H-2ax); 1.78, 1H (m, H-7eq); 1.66, 2H (m, H-4ax and
H-6ax); 1.55, 1H (m, H-4eq); 1.48, 1H (m, H-3ax); 1.47,
1H (m, H-5); 1.42, 1H (m, H-9); 1.41, 2H (m, CH2-8);
1.29, 1H (m, H-3eq); 1.28, 1H (m, H-6eq); 1.26, 1H (m,
H-7ax); 13C (CDCl3, 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).
6. Cope, A. C.; Nealy, D. L.; Scheiner, P.; Wood, G. J. Am.
Chem. Soc. 1965, 87, 3130–3135.
7. Allan, R. D.; Cordiner, G. B.; Wells, R. J. Tetrahedron
Lett. 1968, 58, 6055–6056.
14. Compound 10: mp 110–111°C [h]2D0 +2 (c 1, MeOH).
8. Jones, J.; Jones, R. K.; Robinson, M. J. J. Chem. Soc.,
1
Compound 15: mp 110–111°C [h]2D0 −2 (c 1, MeOH); H
Perkin 1 1973, 968–972.
(CDCl3, 400.13 MHz): 3.58, 1H (dd, 10.6; 3.6, H-11a);
3.45, 1H (dd, 10.6; 10.6, H-11b); 2.79, 1H (m, H-2eq);
2.77, 1H (dd, 10.6; 2.8, H-10); 2.74, 1H (m, H-2ax); 2.10,
1H (m, H-9); 1.73, 1H (m, H-4ax); 1.68, 1H (m, H-5);
1.68, 1H (m, H-3eq); 1.52, 1H (m, H-8eq); 1.44, 2H (m,
CH2-6); 1.39, 2H (m, CH2-7); 1.38, 1H (m, H-4eq); 1.36,
1H (m, H-3ax); 0.79, 1H (m, H-8ax); 13C (CDCl3, 75.47
MHz): 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).
9. Crabb, T. A.; Turner, C. H. J. Chem. Soc., Perkin 2 1980,
1778–1782.
1
10. Compound 6: [h]2D0 +23 (c 2, MeOH); H (CDCl3, 400.13
MHz): 8.33, 1H (m, 4.7; 1.8, H-2); 7.33, 1H (m, 7.7; 1.8,
H-4); 7.00, 1H (dd, 7.7; 4.7, H-3); 4.61, 2H (d, 5.9,
CH2-11); 3.23, 1H (dddd, 6.2; 6.2; 6.1; 6.0; H-9); 2.72, 2H
(dd, 6.1; 6.1, H-6); 2.30, 1H (ddd, 13.4; 10.7; 4.3, H-21a);
2.01, 1H (m, H-8a); 1.92, 1H (m, H-21b); 1.90, 1H (m,
H-7a); 1.81, 2H (m, H-20a and H-8b); 1.71, 1H (m,
H-7b); 1.59, 1H (ddd, 13.1; 9.3; 4.3, H-20b); 1.02, 3H (s,
CH3-25); 0.84, 3H (s, CH3-24); 0.81, 3H (s, CH3-23); 13C
(CDCl3, 75.47 MHz): 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
15. Compound 11: [h]2D0 −19 (c 1, MeOH). Compound 16:
[h]2D0 +19 (c 1, MeOH).
16. Compound 12: [h]2D0 +10 (c 1, MeOH). Compound 17:
[h]2D0 −9 (c 1, MeOH).