, 2005, 15(1), 27–29
three alkyl substituents at the α-carbon atom of the oxime
fragment, just as in camphor oxime. Isosteviol (ent-16-oxo-
beyeran-19-oic acid), a diterpenoid of the beyeran (shachen)
series,8,9 is obtained by acid hydrolysis of the glycoside
extracted from the plant Stevia rebaudiana Bertoni.10–12
Me
N
OH
1
We found that, under conditions of the Beckmann rearrange-
ment, 16-E-oxime isosteviol 113 reacts differently from camphor
oxime. After heating with concentrated hydrochloric acid or
25% H2SO4 for 10 h, oxime 1 unexpectedly afforded lactone 2†
(Scheme 1) as the main reaction product in 53% yield (after
chromatography on silica and recrystallization from AcOEt).
The co-product of this reaction is isosteviol8–12 formed as a
result of hydrolysis of oxime 1. No traces of lactam 3 were
observed. It should be noted that we did not find in the litera-
ture any examples of lactone formation either under Beckmann
rearrangement conditions or as the result of Beckmann frag-
mentation reactions. Lactone 2 was synthesised earlier by the
oxidation of isosteviol with peracetic acid.9
H+
H+
– H2O
– H2O
Me
Me
Me
N
C
CN
A
C
H2O
– H+
H2O
– H+
Me
O
N
NH
B
OH
Me
O
i
Me
ii
Me
H2O
OH
O
– NH3
3
1
2
4
18
9
12
O
O
11
10
17
2
Me
5
13
Me
iii
iv
7
14
15 16
Me
Me
6
19
8
2
+
3
O
Me
OH
20
O
NH
N
Me
O
Me
1
O
O
OH
Me
2
3
OH
NH
Scheme 2
3
One can assume that carbocation C (Scheme 2) is also formed
under conditions (iii) and undergoes usual transformation2,3,5
into lactam 3.
Scheme 1 Reagents and conditions: i, 0.15 g (0.4 mmol) of oxime 1 and
3 ml of conc. HCl, 110 °C, 10 h; ii, 0.1 g (0.3 mmol) of oxime 1 and 3 ml
of 25% H2SO4, 110 °C, 10 h; iii, 0.15 g (0.45 mmol) of oxime 1 and 2.5 ml
of conc. HCl, ampoule, 180 °C, 10 h; iv, 0.08 g (0.6 mmol) of SOCl2 was
added to 0.1 g (0.3 mmol) of oxime 1 in 6 ml of CHCl3, 60 °C, 10 h.
X-ray data‡ observed for lactone 2 (Figure 1) and lactam 3
(Figure 2) demonstrate that the reactions proceed stereoselec-
tively with cleavage of the C13–C16 bond of cyclopentane ring
D of the isosteviol framework, which is in the anti position in
respect to the OH group of the oxime moiety (Scheme 2).
This reaction under conditions (iii) provides approximately
equal quantities of lactone 2 and lactam 3 (30% yield each after
chromatography on silica). As expected, under mild conditions
of the Beckmann rearrangement (iv), lactam 3† was isolated as
the main reaction product in 70% yield (after chromatography
on silica and recrystallization from methanol). The following
explanation of the formation of lactone 2 can be proposed
according to published data.3,5,7 Nitrile carbocation A (Scheme 2)
is formed as in the Beckmann fragmentation reaction of
camphor oxime,3,7 norcamphor oxime5 or fenchone oxime.3
However, it is further stabilised not by losing α-proton but
by attaching a hydroxyl group and subsequent cyclization in
imidate B, which, as well as other imidates,3 is unstable under
conditions (i), (ii) and (iii) and easily hydrolyses to lactone 2.
C(2A)
C(12A)
C(1A)
C(9A)
C(3A)
C(11A)
C(17A)
C(13A)
C(10A)
C(19A)
C(7A)
C(14A)
C(8A)
C(4A)
O(1A)
C(5A)
N(17A)
C(6A)
C(18A)
H(17A)
C(20A)
C(16A)
O(16A)
H(1A)
C(15A)
O(2A)
Figure 2 Molecular geometry of lactam 3 according to X-ray data (only
the hydrogen atoms of carboxylic and amide groups are shown).
‡
X-Ray crystallography of 2 and 3: C20H30O4 2, orthorhombic, space
C(1A)
C(2A)
C(12A)
C(17A)
group P212121, a = 12.139(4), b = 14.029(3) and c = 20.890(10) Å, V =
= 3559(2) Å3, Z = 8, dcalc = 1.253 g cm–3, 4081 independent reflections,
final residues R1 = 0.068 and wR2 = 0.143.
C20H31N1O3 3, monoclinic, space group P21, a = 11.728(2), b =
= 13.997(2) and c = 12.385(2) Å, b = 116.91(2)°, V = 1813(1) Å3, Z = 8,
dcalc = 1.22 g cm–3, 3767 independent reflections (710 reflections with
F2 ³ 3s), final residues R1 = 0.064 and wR2 = 0.053.
Cell parameters and intensities of reflections were measured on an
Enraf-Nonius CAD-4 diffractometer in the w/2q-scan mode (q £ 22.76°,
MoKα radiation with a graphite monochromator). The structure was
solved by a direct method using the SIR program and refined by the full
matrix least-squares using the MOLEN program package. All non-
hydrogen atoms were refined anisotropically. The hydrogen atoms were
solved from difference Fourier maps, and the contribution of structural
factors was included with fixed positional and thermal parameters in the
last cycles.
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference numbers 242202 and 242203. For details, see ‘Notice
to Authors’, Mendeleev Commun., Issue 1, 2005.
C(3A)
C(11A)
C(9A)
C(5A)
C(13A)
C(14A)
C(8A)
C(18A)
C(4A)
C(6A)
C(19A)
C(7A)
O(1A)
O(17A)
C(16A)
O(16A)
C(20A)
C(15A)
H(1A)
O(2A)
Figure 1 Molecular geometry of lactone 2 according to X-ray data (only
the hydrogen atom of the carboxylic group is shown).
†
2: mp 272 °C (from AcOEt) (lit.,9 mp 262–264 °C). 1H NMR (CDCl3)
d: 0.87 (s, 3H, 20-H3), 1.25 (s, 3H, 17-H3), 1.35 (s, 3H, 18-H3), 2.17
(d, 1H, 3-H, J 12.9 Hz), 3.12 (dd, 1H, 15-H, J 18.56 and 2.2 Hz). IR
(mineral oil, n/cm–1): 1156 (C–O), 1690 (CO2H), 1722 (lactone). EIMS,
m/z: 334.2162 [calc. for C20H30O4 (M+) m/z 334.2144]. Found (%): C,
72.03; H, 9.50. Calc. for C20H30O4 (%): C, 71.82; H, 9.04.
3: mp 377 °C (from MeOH). 1H NMR (CD3OD) d: 0.82 (s, 3H,
20-H3), 1.10 (s, 3H, 17-H3), 1.21 (s, 3H, 18-H3), 2.79 (d, 1H, 15-H,
J 18.24 Hz). IR (mineral oil, n/cm–1): 1633 (O=C–NH), 1713 (CO2H).
EIMS, m/z: 333.2307 [calc. for C20H31O3N (M+) m/z 333.2304]. Found
(%): C, 72.05; H, 9.78; N, 4.22. Calc. for C20H31O3N (%): C, 72.02;
H, 9.39; N, 4.2.
28 Mendeleev Commun. 2005