Solution and crystal conformations of myrionine, a new 8β-Alkyl-cis- decahydroquinoline of Myrioneuron nutans

Article abstract of DOI:10.1021/ol071393a

Myrionine (1), a new 8β-alkyl-cis-decahydroquinoline, was isolated from Myrloneuron nutans. Its structure was determined by spectral methods and then confirmed by X-ray analysis and total synthesis. In solution, 1 gives rise to an N-in/N-out equilibrium.

Full text of DOI:10.1021/ol071393a

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3531-3534
Solution and Crystal Conformations of
Myrionine, a New
8â-Alkyl-cis-decahydroquinoline of
Myrioneuron nutans
Van Cuong Pham,†,‡ Akino Jossang,† Ange`le Chiaroni,§ Thierry Se´venet,§
Van Hung Nguyen,‡ and Bernard Bodo*,†
Laboratoire de Chimie des Substances Naturelles - UMR 5154 CNRS, Muse´um
National d’Histoire Naturelle, 63 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
Received June 13, 2007
ABSTRACT
Myrionine (1), a new 8â-alkyl-cis-decahydroquinoline, was isolated from Myrioneuron nutans. Its structure was determined by spectral methods
and then confirmed by X-ray analysis and total synthesis. In solution, 1 gives rise to an N-in/N-out equilibrium. The solvent has weak influence
on the N-in/N-out ratio for myrionine (1), whereas together with the anions, it plays an important role for myrionine hydrochloride (9) and
hydroiodide (10). The two N-in and N-out conformations obtained separately by crystallization of 9 and 10, respectively, were analyzed by
X-ray diffraction.
As part of our program on alkaloids from plants of Vietnam,
we have selected Myrioneuron nutans, a small tree belonging
to the Rubiaceae family. Herein, we describe the isolation,
structure determination, and asymmetric synthesis of a new
alkaloid, myrionine (1), a cis-decahydroquinoline derivative
(cis-DHQ). Its conformation in solution was studied by NMR
and in the solid state by X-ray crystallography. In fact, due
to ring inversion, cis-DHQs can occur in two chair-chair
forms termed N-inside (N-in) and N-outside (N-out) and are
biconformational molecules as cis-decalins. Conformational
equilibrium of cis-DHQs has attracted a great deal of
attention1a-k as the conformation of flexible biomolecules
is important for their biological properties. An understanding
of the factors determining the conformer equilibrium is
needed in order to control the conformer populations. The
preferred conformation depends upon a number of factors
such as solvent, pH, or substituents on the ring framework.2a,b
(1) (a) Ganguly, B.; Freed, D. A.; Kozlowski, M. C. J. Org. Chem. 2001,
66, 1103. (b) Xu, Z.; Kozlowski, M. C. J. Org. Chem. 2002, 67, 3072. (c)
Xie, X.; Freed, D. A.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 6451.
(d) Santos, A. G. O.; Klute, W.; Torode, J.; Bohm, V. P. W.; Cabrita, E.;
Runsink, J.; Hoffmann, R. W. New J. Chem. 1998, 993. (e) Onan, K. D.;
Vierhapper, F. W. Tetrahedron. Lett. 1984, 25, 799. (f) Booth, H.; Griffths,
D. V. J. Chem. Soc., Perkin Trans. 2 1973, 842. (g) Booth, H.; Griffths, D.
V. J. Chem. Soc., Perkin Trans. 2 1975, 111. (h) Booth, H.; Griffths, D. V.
J. Chem. Soc., Chem. Commun. 1973, 666. (i) Booth, H.; Bostock, A. H.
J. Chem. Soc., Perkin Trans. 2 1972, 615. (j) Brown, K.; Kartritzky, A. R.;
Warning, A. J. J. Chem. Soc. B 1967, 487. (k) Gerig, J. T.; Roberts, J. D.
J. Am. Chem. Soc. 1966, 88, 2791.
† Muse´um National d’Histoire Naturelle.
‡ Vietnamese Academy of Science and Technology.
§ Institut de Chimie des Substances Naturelles.
(2) (a) Vierhapper, F. W.; Eliel, E. L. J. Org. Chem. 1977, 42, 51. (b)
Phuan, P. W.; Kozlowski, M. C. J. Org. Chem. 2002, 67, 6339.
10.1021/ol071393a CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/11/2007

Previous conformational studies on cis-DHQs only deal with
the solution structures of the N-in and N-out equilibrium
analyzed by various methods, especially by NMR. To our
knowledge, no study deals with the solid structure of the
two conformers obtained and analyzed individually. We
report here for the first time the X-ray structure of the two
conformers, N-in and N-out of one cis-DHQ derivative
(myrionine). Generally, natural cis-DQHs have been reported
from animal sources, such as amphibians or tunicates, but
rarely from plants.3a,b
Scheme 1. Synthesis of 1 and Its 8-Epimer (8)
the resulting 3 coupled with 2-piperidinone after hydroxyl
activation with mesyl chloride in the presence of KH to
afford synthetic 1 ([R]20D -16.8 (c 1, MeOH)) (Scheme 1).
Myrionine (1) was isolated from the leaves of M. nutans
as an optically active oil ([R]20 -16.1 (c 1, MeOH)). The
D
ESI-MS showed the protonated molecular [M + H]+ ion at
m/z 251.2129 (calcd 251.2123 for C15H27N2O), indicating
the molecular formula C15H26N2O. The IR spectrum depicted
an amide bond at 1634 cm-1. The 1H and 13C NMR spectra
of 1 in CDCl3 at 298 K as well as in C5D5N showed broad
signals, suggesting a conformational equilibrium. The gross
structure of 1 in C5D5N was elucidated from its NMR spectra
at 328 K in which all of the signals were present and sharp.
By using the same procedure, 8-epi-myrionine (8; [R]20
D
-21.8 (c 2, MeOH)) was synthesized starting from 8R,9R,-
10S-8R-methanol-DHQ (5)4a,b via benzyl-protected com-
pounds 6 and 7. Comparison of NMR data and optical
activities of the synthetic compounds with myrionine (1)
under the same conditions revealed that they were identical.
The absolute configuration of the chiral centers was thus
established as 8S,9R,10S, with H9 and H10 in a cis-
relationship.
1
The H-1H COSY data allowed the determination of an
8-substituted DHQ and a 2-piperidinone moiety, which were
further connected as indicated in structure 1 from the
observed HMBC correlations between the carbonyl at C13
and the protons of both methylenes CH2-11 and CH2-17.
Proton H9 had two coupling consants with H10 (3.1 Hz)
and H8 (6.2 Hz) indicating that H9 and H10 were in a cis-
relative disposition. In addition, the NOE interaction between
H9 and H10 confirmed the cis-fused junction for the a/b-
rings of 1, and the NOEs between methylene CH2-11 and
H10 indicated the 8-substituent to be in â-disposition on the
cyclohexane b-ring. However, at 328 K, as the observed
conformation was an average, no definitive stereochemistry
for C8 could be deduced. To confirm its structure and
establish its absolute configuration, myrionine (1) was
synthesized (Scheme 1).
The conformational equilibrium of 1 observed by NMR
resulted from the ring inversion of the cis-DHQ motif to
form the two chair-chair conformers 1a and 1b. To
determine the 1a/1b ratio, 1 was analyzed in CDCl3 at low
temperature (233 K) and the 1H NMR spectrum then
displayed two sets of sharp signals. The signal for H9
appeared as a broad singlet in 1a, whereas it was a doublet
of doublet (J ) 4.7 and 14.5 Hz) in 1b. Complete assignment
for the two conformers by 2D-NMR indicated that H9 was
in a gauche- and anti-relationship with H8 in 1b and 1a,
respectively. The 70:30 ratio for 1a/1b was determined from
the 1H NMR spectrum. When analyzed either in CD3COCD3
or in CD3OD at 233 K, no significant change in the 1a/1b
ratio was observed.
To ascertain if the conformational equilibrium resulted
from the ring inversion and not from inversion of the
pyramidal nitrogen N1, myrionine hydrochloride (9) and
myrionine hydroiodide (10) were prepared by treatment of
1 with HCl and HI, respectively, and analyzed by NMR.
Synthon 2 (8S,9R,10S) was prepared in four steps from
cyclohexanone according to the previously reported method.4a,b
The amino group of 2 was protected by benzylation5 and
(3) (a) Spende, T. F.; Jain, P.; Garraffo, H. M.; Pannell, L. K.; Yeh, H.
J. C.; Daly, J. W. J. Nat. Prod. 1999, 62, 5. (b) Tori, M.; Shimura, E.;
Takaoka, S.; Nakashima, K.; Sono, M.; Ayer, W. A. Phytochemistry 2000,
53, 503.
(4) (a) Pham, V. C.; Jossang, A.; Chiaroni, A.; Se´venet, T.; Bodo, B.
Tetrahedron Lett. 2002, 43, 7565. (b) Crabb, T. A.; Turner, C. H. J. Chem.
Soc., Perkin Trans. 2 1980, 1778.
1
Broad signals were observed in the H NMR spectra of 9
and 10 in CD3OD at 298 K, confirming that the conforma-
tional equilibrium was still observable and not due to
pyramidal inversion. To determine the N-in/N-out ratio for
each of them, 9 and 10 were analyzed at low temperature in
(5) Yamazaki, N.; Kibayashi, C. J. Am. Chem. Soc. 1989, 111, 1396.
3532
Org. Lett., Vol. 9, No. 18, 2007

Figure 2. (A) 1,4-Hydrogen-lone pair interactions in the N-in
form of â-alkyl-cis-DHQs. (B) syn-Pentane interaction between
equatorial N-methyl- and 1-methyl-2-piperidinone groups in the
N-out form of N,N-dimethylmyrionine (13).
cis-fused along the C9/C10 bond, with atoms H9 and H10
in the â-position. A slight flattening was noted at C9 in 9.
In this structure, H8 and H9 were in the gauche position,
while they were in the trans-diaxial position in 10, with
respective torsion angles H8-C8-C9-H9 ) 78.9 (9) and
176.7° (10). The conformation of the two molecules differed
notably, resulting in an inversion of rings, as shown by the
full equivalent torsion angle values with opposite signs. In
9, the 1-methyl-2-piperidinone group fixed at C8 was in an
axial position, avoiding interactions with the six-membered
rings, while it was equatorial in 10. Furthermore, in 9, the
piperidinone ring exhibited a perfect half-chair conformation
(with atoms C15 and C16, respectively, deviated by -0.402
and 0.379 Å from the mean plane of the four other atoms),
while in 10, this ring with disordered atoms C15 and C16
exhibited a nearly envelope conformation, either in C15 or
in C17.
Figure 1. X-ray structures of myrionine salts: 9 (A) and 10 (B)
drawn by ORTEP. (Displacement ellipsoids are shown at the 30%
probability level.)
The molecular packing of 9 showed that the two hydrogen
atoms of nitrogen N1 were hydrogen bonded to two Cl-
anions. In fact, the chloride ions bridged together the two
molecules of the cell, linking in chains the different cells
along the b-axis. In the molecular packing of 10, each of
the four molecules per cell beared a positive charge on the
nitrogen atom N1. Electroneutrality in the unit cell was
therefore ensured by the presence of four iodide counterions
CD3OD and in CDCl3. At 233 K in CD3OD, two sets of
sharp signals were observed for 9 and 10. Each set of signals
was identified from 2D-NMR. Then the N-in/N-out ratios
1
measured from the H NMR spectra were 65:35 for 9 and
1
55:45 for 10. Surprisingly, the N-in/N-out ratio for 10 in
CDCl3 at 233 K was 20:80, whereas it was 70:30 for 9 under
the same conditions. This corroborated that the solvent and
the nature of the counterion played an important role in the
conformational equilibrium of the two salts, 9 and 10.
Myrionine hydrochloride (9) was crystallized in EtOAc/
EtOH (8:2) and myrionine hydroiodide (10) in MeOH to give
suitable crystals for X-ray diffraction (Figure 1).6 Attempts
to crystallize 9 in MeOH and 10 in EtOAc/EtOH (8:2) were
unsuccessful. Analysis confirmed the configuration C8(S),
C9(R), C10(S) for both molecules. In each molecule, the two
rings of the DHQ moieties were in a chair conformation,
in special positions with a weight of /2, plus four triiodide
linear anions, all with an occupancy factor refined to 1/2. The
two hydrogen atoms of nitrogen N1 were hydrogen bonded,
one with the iodide of the molecule, the other one with O18
realizing an intramolecular hydrogen bond. Surprisingly in
the crystals, the pure N-in form was obtained for 9, whereas
in the case of 10, only the pure N-out conformer was present.
Comparison of various cis-DHQs substituted at C8 permit-
ted understanding of the factors which control the distribution
of the N-in and N-out isomers in this series. The unsubsti-
tuted cis-DHQ (11) was previously reported to be in the 90:
10 ratio, in favor of the N-in conformer.1g An explanation
referred to the possibility that the NH could be equatorial,
leading to two 1,4 hydrogen-lone pair interactions for the
N-in conformer (Figure 2A). These interactions are consider-
ably smaller than the corresponding 1,4 hydrogen-hydrogen
ones in the N-out conformer.1g Another possible explanation
(6) CCDC 619064 and CCDC 619065 contain the supplementary
crystallographic data for the respective compounds 9 and 10. These data
can be obtained free of charge at www.ccdc.cam.ac.uk /conts/retrieving.html
[or from the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB 1EZ, UK; fax / (internat.) +44-1223/336-033; E-mail :
deposit@ccdc.cam.ac.uk].
Org. Lett., Vol. 9, No. 18, 2007
3533

is the stronger stereoelectronic interactions (nitrogen lone
pair and σ* acceptors, C-H and C-C bonds; σ-donor C-H
and σ*-acceptor C-N bonds) in the N-in over the N-out
conformers.1b,d,7
between the equatorial N-methyl and the 1-methyl-2-piperi-
dinone group, which destabilizes the N-out conformer (Figure
2B). Thus, for the 8â-alkyl-cis-DHQ series, the distribution
of the conformers is controlled by competition between two
types of 8â-alkyl group interactions with either the DHQ
nitrogen or the axial H10 and H-6ax on the cyclohexane b-ring
(Figure 3).
Vierhapper and Eliel have demonstrated that the N-out
conformer slightly predominated (N-out/N-in ratio 59:41) for
8â-methyl-cis-DHQ (12).2a The equilibrium thus shifted to
the N-out conformer by introducing a methyl group at the
8â-position. In addition, for the synthetic 8â-hydroxymethyl-
cis-DHQ (2), the sharp signals observed at 298 K in the 1H
NMR spectrum (CDCl3) suggested the presence of only one
conformer (>95%) according to NMR sensitivity. The
coupling constants of H9 (dd, 10.6 and 2.8 Hz) allowed
assigning its trans-diaxial relationship with H8. The pre-
dominant conformation of 2 was thus N-out. This could be
explained by the intermolecular hydrogen bonding between
the NH and the oxygen atom that stabilizes the N-out form.
This effect was also observed in the 5-hydroxy-cis-DHQ
derivatives.2b The intramolecular hydrogen bonding was also
observed in the N-out conformer of myrionine salt 10.
However, the N-in conformer of 1 was preferred. This
observation suggested that such an intramolecular hydrogen
bond was not a predominant stabilizing factor in the case of
myrionine. The preference of 1a over 1b could be then
explained by the strong gauche interaction between the
1-methyl-2-piperidinone and the nitrogen of the cis-DHQ in
1b. Such an interaction was previously proposed for 8â-tert-
butyl-cis-DHQ in which the ratio of 93:7 in favor of the N-in
conformer was observed.8 To verify the role of these
interactions, N,N-dimethylmyrionine (13) was prepared by
methylation of 1 with methyl iodide and analyzed by NMR.
The sharp signals were observed in the 1D NMR spectra at
298 K, 13 was presumably conformationally homogeneous.
As anticipated, 13 adopted the N-in conformation character-
ized by a broad doublet (JH9-H8 ) 5.1 Hz, JH9-H10 < 1 Hz)
for H9, indicating its gauche-couplings with H8 and H10.
The shifting (from N-out to N-in), by introducing methyl
groups on the DHQ nitrogen atom of myrionine (1), could
be clearly explained by the strong syn-pentane interaction
Figure 3. Distribution of the N-in/N-out conformers for various
8â-alkyl-cis-DHQ in CDCl3. *Results taken from ref 2a.
It is important to note that myrionine (1) is in a conformer
equilibrium, whereas the 8-alkyl-cis-DHQ derivatives, myri-
oxazines A and B previously isolated from M. nutans, are
N-out and N-in conformers, respectively. This is explained
by the fact that these two forms are constrained by the
O-CH2-N bridge.4a
Acknowledgment. We thank Mr. A. Gramain and Mr.
D. C. Dao (Institute of Chemistry, VAST, Vietnam) for plant
collection and botanical identification, Mr. L. Dubost and
Dr. A. Blond (MNHN, France) for ESI-MS measurements
and recording 2D-NMR spectra, respectively, and Dr. C.
Riche (ICSN, CNRS, France) for fruitful discussions on
X-ray data analysis.
Supporting Information Available: Crystallographic
data for 9 and 10, NMR spectra, and experimental proce-
dures. This material is available free of charge via the Internet
at http://pubs.acs.org.
(7) Wiberg, K. B.; Rablen, P. R. J. Am. Chem. Soc. 1993, 115, 614.
(8) Vierhapper, F. W. Tetrahedron Lett. 1981, 22, 5161.
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