Stereochemistry of the aza-michael reaction with natural alantolactones

Article abstract of DOI:10.1007/s10593-012-1047-6

Hydrogenated 3-aminomethylnaphtho[2,3-b]furan-2-ones were synthesized by the reaction of natural alantolactones with pharmacophoric amines. Determination of the newly formed asymmetric center configuration by two-dimensional NMR data is presented. The str

Full text of DOI:10.1007/s10593-012-1047-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 5, August, 2012 (Russian Original Vol. 48, No. 5, May, 2012)
STEREOCHEMISTRY OF THE AZA-MICHAEL REACTION
WITH NATURAL ALANTOLACTONES
S. G. Klochkov1*, I. V. Anan'ev2, S. A. Pukhov1, and S. V. Afanas'eva1
Hydrogenated 3-aminomethylnaphtho[2,3-b]furan-2-ones were synthesized by the reaction of natural
alantolactones with pharmacophoric amines. Determination of the newly formed asymmetric center
configuration by two-dimensional NMR data is presented. The structure of the obtained compounds was
proved by X-ray structural analysis.
Keywords: alantolactones, 3-aminomethyldecahydronaphtho[2,3-b]furan-2-ones, aza-Michael reaction,
stereochemistry, two-dimensional NMR, X-ray structural analysis.
Isoalantolactone (1) and alantolactone (2) belong to the class of sesquiterpene lactones (secondary
metabolites of plants of the Compositae family Asteraceae), which exhibit various types of physiological
activity [1, 2]. The use of natural compounds and of sesquiterpene lactones in particular is one of the shortest
ways of creating optically active molecules with novel biological properties. The presence of the α-methylene-
γ-lactone ring in the structure of compounds 1 and 2 makes it possible to modify them easily, e.g.,
H
Me
H
Me
8
1
O
9
O
7
2
9a
R1R2NH
O
O
4a
3a
6
3
5
4
H
H
H
H
CH2
CH2
NR1R2
CH2
1
3a,b
Me
H
CO2Et
O
Me
H
H
O
O
HN
O
H
N
Me
CH2
CO2Et
Me
4
2
OH
3 a R1 = H, R2 = 3,4-(MeO)2C6H3CH2; b NR1R2 =
N
Cl
_______
*To whom correspondence should be addressed, e-mail: klochkov@ipac.ac.ru.
1Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severnyi Ave.,
Chernogolovka 142432, Russia.
2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 119991, Russia; e-mail: i.ananyev@gmail.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 750-756, May, 2012. Original
article submitted February 29, 2012.
698
0009-3122/12/4805-0698©2012 Springer Science+Business Media, Inc.

by means of the Michael reaction [3]. If chiral molecules are brought into this reaction the stereochemical result
is of great significance. Under the conditions of such a transformation the chiral centers contained in the
molecule are preserved, and a new asymmetric carbon atom C-3 appears, presenting a fairly difficult task of
determining its stereo configuration.
The room temperature reaction of the lactones 1 and 2 with primary and secondary amines in methanol
proceeds regioselectively, giving the products from addition at the exocyclic double bond of the lactone ring –
the hydrogenated 3-aminomethylnaphtho[2,3-b]furan-2-ones 3 and 4, respectively. The yields were high, and in
all cases only one diastereomer was found in the reaction mixture.
The structure of the obtained compounds was established by spectral methods, including homo- and
1
heterocorrelation H–1H COSY and 13C–1H HSQC methods. The stereo configuration of the C-3 atom was
determined by means of the two-dimensional 1H–1H NOESY spectroscopy, which made it possible to reveal the
closely located protons. In this article, the spectral characteristics of the aminomethyl derivatives 3a,b and 4 are
considered, for which it was possible to grow single crystals and confirm the obtained results by X-ray
structural analysis.
Thus, the empirical formula C24H33NO4 was established for compound 3a on the basis of the protonated
molecular ion [M+H]+ peak at m/z 400.2471 in the high-resolution mass spectrum with electrospray ionization
(ESI). The data from the 1H and 13 C NMR spectra confirm the presence of the isoalantolactone fragment in the
1
molecule. The H NMR spectrum contains the exocyclic methylene group signals at 4.40 and 4.77 ppm in the
form of doublets with a spin-spin coupling constant of 1.2 Hz, a signal from the methyl protons at the C-8a atom
in the form of a singlet at 0.80 ppm, a characteristic downfield signal from the proton at the C-9a atom at 4.49
ppm in the form of a doublet of doublets of doublets (SSCC 6.0, 4.5, and 1.4 Hz), and also the signals from the
amine fragment – the aromatic protons and two methoxy groups. The stereo configuration of the C-3 atom of
this compound was established on the basis of correlation analysis of the vicinal interactions of the protons and
NOE correlations in the NOESY experiment (Fig. 1).
It is known that the H-9a proton in the molecule of isoalantolactone (1) has the α-orientation, like the
proton at the C-3a atom, which is confirmed experimentally by the small spin-spin coupling constant (J3a,9a = 6.0
Hz) and indicates cis coupling of the lactone and decahydronaphthalene rings [4]. In the NOESY spectrum of
compound 3a, there are clear NOE correlations between the H-9a and H-3a, the H-9a and H-3, the H-9a and
Heq-9, and the H-9a and Hax-9 protons. For the proton at the C-3a atom, there are conspicuous correlations with
the α-oriented proton at the position 4a, and with the proton at the C-3 atom, formed after addition of the amine.
On the basis of these data, it can be concluded that the H-9a, H-4a, H-3a, and H-3 protons are located on one
side of the hydrogenated naphtho[2,3-b]furan-2-one system, i.e., the formed aminomethyl substituent has a β-
configuration (stereodescriptor R). Analogous relationships were revealed by analyzing the spectra of products
3b and 4.
b
H
a
H
Me
H
Me
H
H
9
O
3
O
9
9a
3a
9a
3a
H
O
O
4a
3
H
H
H
H
H
Me
N
NR1R2
CH2
3a,b
4
CO2Et
Fig. 1. Structurally significant NOE correlations for compounds 3a,b (a) and 4 (b).
699

The aforementioned structural data of all the obtained compounds were additionally confirmed by X-ray
structural analysis of single crystals. Figure 2a-c shows the three-dimensional structure of all the obtained
compounds 3a,b and 4, with the non-hydrogen atoms represented by thermal vibration ellipsoids with 50%
probability.
It should be noted that the investigated aminomethyl derivatives crystallize in non-centrosymmetric
space groups as pure stereoisomers. Since Kα radiation of a molybdenum anode (0.71073 Å) was used in the
experiments, the absolute configuration was determined with allowance for the anomalous scattering of the
X-ray radiation by the chlorine atom in compound 3b by means of Flack parameter (0.02(4)) [5]. However, all
the compounds are formed under similar synthesis conditions, and this makes it possible to interpolate the
obtained data on the absolute configuration onto compounds 3a and 4.
The data from X-ray structural analysis also confirm the cis relationship of the lactone and
tetrahydronaphthalene rings (the C-3a and C-9a carbon atoms have the (R)-configuration). Here the lactone ring
retains its geometry irrespective of the nature of the substituent at the N(1) nitrogen atom and in all cases has the
“envelope” conformation, in which the deviation of the C-3a atom from the plane is dictated by the nature of the
fused ring: 0.574(2) and 0.592(2) Å for the compounds 3a and 3b, and 0.464(1) Å in the case of the
alantolactone derivative 4. Finally, analysis of the molecular structure shows that the asymmetric carbon atom
C-3 has the (R)-configuration, while the atoms C-4a (C-5 in the compound 4) and C-8a obviously retain their
configuration in the course of reaction (stereodescriptors S and R, respectively), which fully agrees with the
NMR spectroscopy data.
The three-dimensional structure of the aminomethyl derivatives 3a,b and 4 allows to reach a conclusion
about the aza-Michael reaction stereochemistry in the series of natural lactones 1 and 2. The N-nucleophile adds
to the activated double bond of the lactone at the exocyclic carbon atom, generating an enolate. Protonation of
the latter takes place exclusively on the exo-side, and leads to the diastereomer, in which the hydrogen atom at
position 3 occupies a pseudo-axial position and is in cis configuration with the H-3a atom in relation to the five-
member ring. Only one compound with a pseudo-equatorial aminomethyl substituent is formed as a result of
this transformation, while the chiral C-3 atom acquires an (R)-configuration due to the stereochemical features
of the starting molecule.
OH
O
O
O
O
O
R1R2NH
MeOH
H
H
H
CH2
NR1R2
H
H
H
NR1R2
H
The reaction of natural optically active α-methylene-γ-lactones with primary and secondary amines has
been elucidated through this data. It was established that this reaction results in the addition products at the
exocyclic double bond. The stereo configuration of the formed asymmetric center was determined through
analysis of NMR spectra and X-ray structural data.
EXPERIMENTAL
1
The IR spectra were recorded in KBr pellets on a Bruker ZFS-113 spectrometer. The H and 13C ,
1
NOESY, H-1H COSY, and 13C-1H HSQC NMR spectra were recorded on a Bruker Avance III instrument
(working frequency 500 MHz and 125 MHz respectively, for the NOESY experiment mixing time 1 sec, delay
between pulses 2 sec) in CDCl3 solution with the residual signal of the solvent (δH 7.27 and δC 77.2 ppm) as a
standard. In the interpretation of the 1H NMR spectra the indices α and β refer to the non-equivalent protons at
one carbon atom. The high-resolution mass spectra were recorded on a Thermo Fisher Exactive mass
700

spectrometer with ORBITRAP mass analyzer and electrospray ionization source. Solutions of the starting
substances in acetonitrile with concentrations of ~10-5 M were used for ionization, and the m/z values
correspond to the peak of the protonated molecular ion. The specific rotation was determined on a Perkin Elmer
Model 341 polarimeter in CHCl3 solution; the rotation values are expressed in (deg·ml)/(g·dm), while the
concentrations are in g per 100 ml of solution.
Fig. 2. The general view of compounds 3a (a), 3b (b), and 4 (c). Only the hydrogen atoms at the stereo centers
and heteroatoms are shown.
701

TABLE 1. Basic Crystallographic Data of Compounds 3a,b and 4
Compound
Parameters
3а
3b
4
T, K
100
100
100
Crystal system
Monoclinic
P21
Monoclinic
P21
Rhombic
P21212
4
Space group
Z
2
2
a, Å
11.1974(7)
8.2102(5)
12.3374(8)
109.2220(10)
1070.98(12)
1.239
5.7663(4)
13.6039(10)
14.6585(11)
92.1920(14)
1149.03(14)
1.283
9.948(5)
28.013(14)
7.611(4)
—
b, Å
c, Å
Β, deg
V, Å3
2120.9(19)
1.220
Dcalc, g·cm–3
μ, cm–1
0.83
1.94
0.82
F(000)
432
476
848
2θmax, deg
63
61
55
Number of measured reflections
Number of independent reflections
Number of reflections with I > 2σ(I)
Number of refined parameters
R1
15139
14962
7726
3815
6950
2890
3584
5713
2756
266
282
256
0.0344
0.0953
1.038
0.0384
0.0894
0.991
0.0319
0.0852
1.014
wR2
GOOF
Residual electron density, e·Å–3(dmin/dmax
)
0.368/–0.170
0.279/–0.186
0.271/–0.177
X-ray Diffraction Investigation of Compounds 3a,b and 4. The investigation was conducted on a
SMART APEX II CCD diffractometer (MoKα radiation, graphite monochromator, ω-scan). The structures were
interpreted by the direct method and refined by the least-squares method in anisotropic full-matrix
approximation in Fhkl2. The hydrogen atoms at the heteroatoms were located from electron density Fourier
difference syntheses and refined in isotropic approximation. The positions of the hydrogen atoms bonded to
carbon were calculated geometrically and were refined by the “rider” model. All the calculations were
performed by SHELXTL PLUS software [6]. The main crystallographic data and the refinement parameters are
presented in the table. The crystallographic data for all the compounds were deposited at the Cambridge
Crystallographic Data Center (CCDC 868314-868316).
The starting isoalantolactone (1) and alantolactone (2) were isolated as a mixture from the roots of the
plant Inula helenium L. (fam. Asteraceae); the isomers were separated on a column impregnated with silver
nitrate, as described in [7], and the purity was monitored by GLC.
Reaction of (Iso)alantolactone with Amines (General Method). A mixture of the lactone 1 or 2
(0.232 g, 1.0 mmol) and the corresponding amine (1.1 mmol) was dissolved with stirring in MeOH and left at
room temperature. At the end of the reaction (12-24 h), compounds 3a,b and 4 precipitated from the solution,
and the crystals were collected by filtration, washed with a small amount of MeOH and dried in vacuum.
(3R,3aR,4aS,8aR,9aR)-3-[(3,4-Dimethoxybenzylamino)methyl]-8a-methyl-5-methylidenedecahydro-
naphtho[2,3-b]furan-2-one (3a). Yield 0.264 g (66%); mp 96-96°C. [α]D +34° (c 0.1). IR spectrum, ν, cm-1:
20
1
1027 and 1236 (MeО), 1761 (O–C=O), 3461 (NH). H NMR spectrum, δ, ppm (J, Hz): 0.80 (3H, s, 8а-CH3);
1.19 (1H, q, J = 12.6, 4-СHα); 1.25-1.28 (1H, m, 8-СHα); 1.46 (1H, dd, J = 15.5, J = 4.6, 9-СHα); 1.50-1.54
(1H, m, 4-СHβ); 1.54-1.56 (1H, m, 8-СHβ); 1.56-1.62 (2H, m, 7-СН2); 1.77 (1H, d, J = 12.6, H-4a); 1.99 (1H,
td, J = 12.6, J = 6.2, 6-СHα); 2.17 (1H, dd, J = 15.5, J = 1.4, 9-CHβ); 2.33 (1H, d, J = 12.6, 6-CHβ); 2.49 (1H,
tdd, J = 12.6, J = 6.0, J = 1.6, H-3a); 2.77 (1H, dd, J = 11.8, J = 7.3) and 3.05 (1H, dd, J = 11.8, J = 7.2,
CHСН2N); 2.94 (1H, q, J = 6.9, H-3); 3.75 (1H, d, J = 12.9) and 3.83 (1H, d, J = 12.9, NCH2Ar); 3.88 (3Н, s,
OCH3) and 3.89 (3H, s, OCH3); 4.40 (1H, d, J = 1.2, (E)-СH=С); 4.49 (1H, ddd, J = 6.0, J = 4.5, J = 1.4, H-9a);
4.77 (1H, d, J = 1.2, (Z)-СH=С); 6.83 (1H, d, J = 8.1, H-5'); 6.87 (1H, dd, J = 8.1, J = 1.7, H-6'); 6.90 (1H, d,
702

J = 1.7, H-2'). 13C NMR spectrum, δ, ppm: 17.8 (8а-CH3); 21.1 (C-4); 22.7 (C-7); 34.8 (C-8a); 36.8 (C-6); 39.2
(C-3a); 41.5 (C-9); 42.3 (C-8); 44.7 (3-CH2); 46.6 (C-4a); 47.6 (C-3); 54.0 (NCH2); 55.9 and 56.0 (OCH3); 78.3
(C-9a); 106.5 (5-CH2); 111.1 (C-5'); 111.4 (C-2'); 120.3 (C-6'); 132.5 (C-1'); 148.2 (C-4'); 149.1 (C-5); 149.3
(C-3'); 178.2 (C-2). Found, m/z: 400.2471 [М+H]+. С24H33NO4. Calculated, m/z: 400.2488.
(3R,3aR,4aS,8aR,9aR)-3-[4-(4-Chlorophenyl)-4-hydroxypiperidin-1-ylmethyl]-8a-methyl-5-meth-
20
ylidenedecahydronaphtho[2,3-b]furan-2-one (3b). Yield 0.369 g (83%); mp 137-138°C. [α]D +42° (c 0.1).
IR spectrum, ν, cm−1: 1106 (Ph–Cl), 1762 (O–C=O), 3590 (ОН). 1H NMR spectrum, δ, ppm (J, Hz): 0.82 (3H,
s, 8а-CH3); 1.18 (1H, q, J = 13.0, 4-СHα); 1.26 (1H, t, J = 12.1, 8-СHα); 1.49 (1H, dd, J = 15.6, J = 3.5,
9-СHα); 1.56 (1H, d, J = 12.1, 8-СHβ); 1.58-1.65 (2H, m, 7-СH2); 1.69-1.78 (2H, m, 5'-СНax, 4-СНβ); 1.83
(1H, d, J = 12.7, H-4a); 1.97-2.07 (3H, m, 3′-СHax, 5′-СHeq, 6-СHα); 2.12 (1H, td, J = 13.6, J = 3.8, 3'-СHeq);
2.19 (1H, dd, J = 15.6, J = 1.3, 9-СHβ); 2.36 (1H, d, J = 12.1, 6-СHβ); 2.48 (1H, t, J = 11.0, 6'-CHax); 2.55
(1H, tdd, J = 13.0, J = 5.5, J = 1.5, H-3a); 2.64 (1H, t, J = 11.5, 2'-CHax); 2.70–2.76 (2H, m, СНCHαN,
2'-CHeq); 2.83-2.89 (2H, m, CHCHβN, 6'-CHeq); 2.96-3.04 (1H, m, H-3); 4.50 (2H, br. s, (Z)-СH=С, H-9a);
4.80 (1H, s, (E)-СH=С); 7.32 (2H, d, J = 8.4, H-5",3"); 7.45 (2H, d, J = 8.4, H-6",2"). 13C NMR spectrum, δ,
ppm: 17.9 (8а-CH3); 21.1 (C-4); 22.7 (C-7); 34.9 (C-8a); 36.8 (C-6); 38.5 (C-3'); 38.5 (C-5'); 39.5 (C-3a); 41.6
(C-9); 42.3 (C-8); 45.7 (C-3); 46.6 (C-4a); 48.6 (C-6'); 50.6 (C-2'); 53.2 (3-СH2); 70.9 (C-4'); 78.3 (C-9a); 106.5
(5-CH2); 126.1 (C-6"); 126.1 (C-2"); 128.4 (C-5"); 128.5 (C-3"); 132.9 (C-4"); 146.9 (C-1"); 149.5 (C-5); 177.9
(C-2). Found, m/z: 444.2289 [М+H]+. С26H34ClNO3. Calculated, m/z: 444.2305.
(3R,3aR,5S,8aR,9aR)-Ethyl-1-(5,8a-dimethyl-2-oxo-3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]-
furan-3-ylmethyl)piperidine-4-carboxylate (3c). Yield 0.312 g (80%); mp 135-137°C. [α]D20 +42° (c 0.1). IR
1
spectrum, ν, cm−1: 1722 and 1756 (O–C=O). H NMR spectrum, δ, ppm (J, Hz): 1.11-1.15 (1H, m, 8-СHα);
1.16 (3H, d, J = 7.5, 5-CH3); 1.26 (3H, s, 8а-CH3); 1.29 (3H, t, J = 7.1, OCH2CH3); 1.46 (1H, dquint, J = 13.9,
J = 3.5, 7-СHα); 1.56 (1H, dd, J = 14.7, J = 2.5, 9-СHα); 1.58-1.69 (3H, m, 6-СH2, 8-СHβ); 1.69-1.83 (2H, m,
3'-СН2); 1.83-1.89 (1H, m, 7-СHβ); 1.91-1.97 (2H, m, 5'-СН2); 2.02 (1H, td, J = 11.4, J = 2.0, 6'-CHax); 2.14
(1H, dd, J = 14.7, J = 3.2, 9-СHβ); 2.25 (1H, td, J = 11.4, J = 2.3, 2'-CHax); 2.33 (1H, tt, J = 11.3, J = 4.0,
H-4'); 2.53 (1H, td, J = 7.5, J = 2.3, H-5); 2.62 (1H, dd, J = 13.0, J = 11.3) and 2.69 (1H, dd, J = 13.0, J = 4.6,
CHCH2N); 2.83 (1H, dt, J = 10.7, J = 3.5, 2'-CHeq); 3.01 (1H, dt, J = 11.3, J = 4.0, 6'-CHeq); 3.07 (1H, ddd,
J = 11.3, J = 8.4, J = 4.3, H-3); 3.16 (1H, ddd, J = 8.5, J = 5.5, J = 3.3, H-3a); 4.17 (2H, q, J = 7.1, OCH2CH3);
4.76 (1H, dt, J = 5.4, J = 2.6, H-9a); 5.36 (1H, d, J = 2.9, H-4). 13C NMR spectrum, δ, ppm: 14.2 (OCH2CH3);
16.9 (C-7); 23.1 (5-CH3); 28.3 (C-3'); 28.6 (C-5'); 28.7 (8a-CH3); 33.0 (C-6); 33.2 (C-8a); 38.1 (C-3a); 38.7 (C-
5); 41.2 (C-4'); 42.4 (C-8); 42.9 (C-9); 43.8 (C-3); 51.6 (C-2'); 54.4 (C-6'); 54.5 (3-СH2); 60.3 (OCH2CH3); 77.4
(C-9a); 115.8 (C-4); 150.9 (C-4a); 175.2 (C=O); 177.6 (C-2). Found, m/z: 390.2654 [М+H]+. С23H35NO4.
Calculated, m/z: 390.2644.
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