20-hydroxyecdysone oximes and their rearrangement into lactams

Article abstract of DOI:10.1134/S1070428009100066

(E)-Oximes derived from 20-hydroxyecdysone diacetonides and 7,8-dihydro analog were converted into the corresponding lactams (6-oxo-5a-aza-5a-homo derivatives) via Beckmann rearrangement. 14,15-Anhydro-20-hydroxyecdysone (Z)-oxime under analogous conditio

Full text of DOI:10.1134/S1070428009100066

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 10, pp. 1456–1463. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © R.V. Shafikov, Ya.R. Urazaeva, S.R. Afon’kina, R.G. Savchenko, L.M. Khalilov, V.N. Odinokov, 2009, published in Zhurnal
Organicheskoi Khimii, 2009, Vol. 45, No. 10, pp. 1473–1478.
20-Hydroxyecdysone Oximes and Their Rearrangement
into Lactams
R. V. Shafikov, Ya. R. Urazaeva, S. R. Afon’kina, R. G. Savchenko,
L. M. Khalilov, and V. N. Odinokov
Institute of Petroleum Chemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: ink@anrb.ru
Received April 9, 2009
Abstract—(E)-Oximes derived from 20-hydroxyecdysone diacetonides and 7,8-dihydro analog were converted
into the corresponding lactams (6-oxo-5a-aza-5a-homo derivatives) via Beckmann rearrangement. 14,15-An-
hydro-20-hydroxyecdysone (Z)-oxime under analogous conditions (reaction with p-toluenesulfonyl chloride in
acetone in the presence of Na2CO3) gave rise to 20-hydroxyecdisone 20,22-acetonide (Z)-O-tosyloxime which
did not undergo Beckmann rearrangement.
DOI: 10.1134/S1070428009100066
Oximes are widely used in organic synthesis, and
they exhibit diverse biological activity [1]. In the
recent years, interest in oximes of the steroid series
considerably increased [2, 3]. This interest was stimu-
lated primarily by the isolation of steroidal oximes
from the marine sponges Cynachyrella alloclada and
S. apion [4]. which, like their synthetic analogs [5],
turned out to effectively inhibit aromatase (the key
enzyme in the biosynthesis of estrogens) and attracted
attention as potential antitumor agents [6]. Ecdysteroid
oximes and their chemical properties have been
studied poorly. We previously reported on the syn-
thesis of 20-hydroxyecdisone oxime and the corre-
sponding diacetonide [7].
sium hydroxide in ethanol, we obtained 14,15-an-
hydro-7,8-dihydro-20-hydroxyecdysone diacetonide
(E)-oxime VI. An attempt to reduce the latter into
7,8-dihydro-14-deoxy-20-hydroxyecdysone diaceto-
nide oxime by catalytic hydrogenation over Raney
nickel resulted in the formation of 7,8-dihydro-
stachysterone B diacetonide VII (Scheme 3). The 13C
NMR spectrum of VII was fairly similar to the spec-
trum of 7,8-dihydrostachysterone B 20,22-acetonide
[9], and some differences were related to the presence
of an additional O,O′-isopropylidene protective group
at positions 2 and 3 of compound VII.
The structure of oximes V and VI was confirmed
1
by the H and 13C NMR spectra. The signals were as-
In the present work we succeeded in effecting
Beckmann rearrangement of (E)-oximes II and V
derived from 20-hydroxyecdysone and its 7,8-dihydro
analog with a view to transform the ecdysteroid B ring
into seven-membered lactam ring, a fragment intrinsic
to azabrassinosteroids [8].
signed using one- (1H, 13C, APT) and two-dimensional
correlation techniques (COSY, HSQC, HMBC). In the
13C NMR spectra of oximes V and VI, the α-meth-
ylene carbon atom (C7) resonated in a stronger field
(δC 26.18 and 26.16 ppm, respectively) than the C5
atom (CH, δC 42.28 and 42.48 ppm), indicating their
syn (C7) and anti (C5) orientation with respect to the
N–OH group. This means that oximes V and VI have
E configuration [7, 10].
By treatment of 20-hydroxyecdysone diacetonide I
with hydroxylamine hydrochloride in pyridine we
obtained a mixture of the corresponding (E)- and
(Z)-oximes II and III (Scheme 1) [7]. The oximation
of 7,8-dihydro-20-hydroxyecdysone diacetonide IV
under analogous conditions gave (E)-oxime V
(Scheme 2). When the oximation product of 7,8-di-
hydro analog IV was treated with a solution of potas-
Oximes of the ecdysteroid series did not undergo
Beckmann rearrangement under conditions of acid
catalysis. Instead of rearrangement, boron trifluoride–
ether complex in methylene chloride promoted depro-
tection of the hydroxy groups in positions 2 and 3 of
1456

20-HYDROXYECDYSONE OXIMES AND THEIR REARRANGEMENT INTO LACTAMS
1457
Scheme 1.
Me
O
Me
O
Me
Me
O
O
21
22
Me
Me
Me
24
18 Me
20
26
Me
25
23
Me
OH
12
17
16
15
19
Me
11
9
13
14
27
Me
H
Me
Me
OH
8
O
O
O
O
1
4
Me
Me
Me
Me
2
3
10 H
6
OH
H
N
OH
5
7
H
O
OH
I
II
Me
O
Me
O
Me
Me
Me
OH
+
Me
H
Me
O
Me
Me
H
N
OH
O
HO
III
Scheme 2.
Me
Me
O
O
Me
Me
i
Me
OH
Me
Me
H
H
Me
Me
O
Me
O
O
H
N
OH
Me
Me
Me
O
Me
OH
OH
Me
H
H
Me
O
O
Me
Me
V
H
OH
Me
O
Me
O
O
Me
Me
IV
ii
Me
OH
Me
H
H
Me
O
O
Me
Me
H
N
OH
VI
i: NH2OH·HCl–pyridine, 70°C; ii: (1) NH2OH·HCl–pyridine, 70°C; (2) KOH–EtOH.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

SHAFIKOV et al.
1458
Scheme 3.
Me
O
Me
O
Me
Me
iii
Me
OH
VI
Me
H
H
Me
O
O
Me
Me
H
O
VII
iii: H2–Raney nickel, 96% EtOH.
downfield shift (ΔδC = 13.2 and 8.6 ppm, respectively)
of the signal from C6 in IX and X. The existence
of a correlation (15N–1H HMBC) between 5-H
(δ 3.26 ppm) and nitrogen nucleus (δN 120.1 ppm; this
value is typical of nitrogen atom in an amide group
[11]) unambiguously indicates that the NHCO group is
located between C5 and C7 in the B ring of compound
IX. An additional support is provided by the presence
of a cross peak from 7-H (δ 5.85 ppm) and nitrogen
atom. Conservation of β-configuration of the 5-H atom
in the initial oximes and their rearrangement products
IX and X is ensured by stereospecificity of the Beck-
mann rearrangement [12].
(E)-oxime II, 14,15-dehydration, and E/Z-isomeriza-
tion with formation of 14,15-anhydro-20-hydroxyec-
dysone 20,22-acetonide (Z)-oxime VIII (Scheme 4).
1
The H and 13C NMR spectra of compound VIII were
similar to those of previously described compound III
[7] (with small differences related to the lack of aceto-
nide protection at C2 and C3 in VIII). Treatment of
oximes II and V with phosphoric anhydride, phos-
phorus pentachloride, thionyl chloride, or p-toluene-
sulfonyl chloride resulted in the formation of mixtures
of products. We succeeded in effecting rearrangement
of oximes II and V with transformation of the B ring
into seven-membered lactam fragment by the action of
p-toluenesulfonyl chloride in acetone in the presence
of sodium carbonate (Schemes 4, 5) [1]. The structure
of lactams IX and X was determined by analysis of
Unlike (E)-oximes II and V, no Beckmann rear-
rangement occurred with (Z)-oxime III having a diene
fragment. Under analogous conditions, compound III
was converted into (Z)-O-tosyloxime XI in which the
hydroxy groups in positions 2 and 3 were deprotected
(Scheme 5). As a result, the C2 and C3 signals in the
13C NMR spectrum of XI are displaced upfield (∆δC =
4.6 ppm), and signal typical of 2,3-O-isopropylidene
group (δC 108.0 ppm) disappears, whereas the signal at
1
their H and 13C NMR spectra. All proton and carbon
signals were assigned using one- (1H, 13C, DEPT 135°)
and two-dimensional homo- (COSY, NOESY) and het-
eronuclear correlation techniques (13C–1H and 15N–1H
HSQC and HMBC). The transformation of oximes II
and V into the corresponding lactams followed from
Scheme 4.
Me
Me
Me
O
Me
O
O
O
21
22
Me
Me
Me
24
18 Me
20
26
Me
25
v
iv
23
Me
12
Me
Me
17
16
15
19Me
II
11
9
13
14
27
O
Me
Me
OH
Me
OH
1
8
2
HO
3
O
5
H
10 H
OH
4
7
5a
HO
6
N
H
H
N
H
O
HO
VIII
IX
iv: BF3 ·Et2O, CH2Cl2; v: TsCl–Na2CO3, Me2CO.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

20-HYDROXYECDYSONE OXIMES AND THEIR REARRANGEMENT INTO LACTAMS
1459
Scheme 5.
Me
Me
O
O
Me
Me
v
Me
OH
Me
Me
V
O
Me
H
Me
O
H
OH
N
H
H
O
X
Me
O
Me
O
Me
Me
v
Me
OH
III
Me
Me
HO
HO
H
N
H
O
4-MeC6H4SO2
XI
v: TsCl–Na2CO3, Me2CO.
δC 106.9 ppm from the 20,22-O-isopropylidene frag-
ment remains almost unchanged. All signals in the
1H and 13C NMR spectra of XI were assigned using
one- (1H, 13C, DEPT 135°) and two-dimensional cor-
relation techniques (COSY, HSQS, HMBC). Protons in
the 18-methyl group (δ 0.98 ppm) gave a cross peak
with the carbon signal at δC 149.17 ppm in the HMBC
spectrum, indicating that the latter belongs to quater-
nary (DEPT 135°) sp2-hybridized carbon atom at the
double bond (C14). The latter showed a correlation with
the signal at δ 6.16 ppm, which was therefore assigned
to 7-H. The 7-H proton was coupled (HSQC) with
a carbon nuclei resonating at δC 113.78 ppm; this
signal arises from tertiary (DEPT 135°) sp2-carbon
atom (C7). Approximately similar chemical shifts of C5
in compound XI (δC 37.17 ppm) and initial (Z)-oxime
III (δC 37.82 ppm) [7] indicate conservation of Z con-
figuration of the oxime moiety. The large vicinal
coupling constant (J = 13.2 Hz) for 5-H (δ 3.27 ppm),
corresponding to its interaction with the axial 4-H
proton suggests axial orientation of 5-H in the A ring,
i.e., cis-junction of the A and B rings. Aromatic carbon
atoms in the p-tolylsulfonyl group resonated (DEPT
135°) as singlets at δ 132.64 (C4′) and 144.90 ppm (C1′)
and doublets at δC 128.81 (C3′, C5′) and 129.59 ppm
(C2′, C6′). The most downfield signal in the 13C NMR
spectrum of XI was located at δC 167.17 ppm (DEPT
135°); it was assigned to C6.
It is known [13, 14] that not oximes themselves but
products of their reaction with the acid catalyst under-
go Beckmann rearrangement. Stereospecific Beck-
mann rearrangement always involves that group which
is located in the anti position with respect to the
hydroxy group [12]. The corresponding group in
(Z)-O-tosyloxime XI is C7H with sp2-hybridized
carbon atom, which is not capable of migrating (as in
menth-4-en-3-one oxime [15]). Therefore, (Z)-O-tosyl-
oxime XI remains unchanged under the above condi-
tions. Presumably, the stability of oxime XI and spatial
proximity of the sulfonate group (which forms com-
plex A with hydrogen chloride [13]) to the A ring
promote deprotection of the hydroxy groups on C2 and
C3 (Scheme 6).
(E)-Oxime II (or V) gives rise to hydrogen chloride
complex B, and Beckmann rearrangement in
(E)-O-tosyloxime involves migration of C5H (in the
anti position with respect to the hydroxy group in the
initial oxime) to the nitrogen atom. Complex B decom-
poses with formation of intermediate C whose hydrol-
ysis gives lactam IX (or X), and liberated hydrogen
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

SHAFIKOV et al.
1460
Scheme 6.
Me
Me
H
HO
HO
Na2CO3
TsCl
III
XI
–NaCl, –CO2, –Me2CO
H
Ts
N
Cl–
O
H
A
Me
Me
OH
Me
Me
O
Me
Me
H2O
TsCl
O
O
Me
Me
II
IX
O
–HCl
H
–TsOH
H
N
OH
Ts
Na2CO3
N
H
H
Cl–
OTs
O
NaCl + H2O + CO2
B
C
chloride is neutralized with sodium carbonate, thus
preventing deprotection of the hydroxy groups in
the A ring.
stirring to a solution of 0.40 g (0.7 mmol) of com-
pound IV (mp 275–277°C; prepared according to the
procedure described in [9]) in 6 ml of freshly distilled
pyridine, and the mixture was heated for 3 days at
70°C and evaporated on a rotary evaporator. The
residue was treated with 20 ml of water, the product
was extracted into ethyl acetate (3×30 ml), the extract
was dried over MgSO4 and evaporated, and the residue
was subjected to column chromatography on silica gel
(30 g) using chloroform–methanol (30:1) as eluent.
Yield 0.4 g (98%), Rf 0.47 (CHCl3–MeOH, 10:1),
mp 90–92°C, [α]D18 = 19.8° (c = 12.7, CHCl3). 1H NMR
spectrum (CDCl3), δ, ppm: 1.05 s (3H, C18H3), 1.08 s
(3H, C21H3), 1.18 s (6H, C26H3, C27H3), 1.21 s (3H,
C19H3); 1.27 s, 1.28 s, 1.37 s, and 1.50 s (12H, Me2C);
EXPERIMENTAL
The IR spectra were recorded on a Specord 75IR
spectrometer from samples dispersed in mineral oil.
The UV spectra were measured from solutions in
chloroform on a Specord M-40 spectrophotometer. The
1H and 13C NMR spectra were obtained on a Bruker
Avance-400 spectrometer at 400.13 and 100.62 MHz,
1
respectively, using CDCl3 as solvent. The H and
13C NMR spectra of compound V in CDCl3 were
recorded on a Bruker AM-300 instrument (300.13 and
75.46 MHz, respectively). Homo- and heteronuclear
DEPT-135°, COSY, HSQC, and HMBC experiments
were performed on a Bruker Avance-400 spectrometer
according to standard procedures. The melting points
were determined on a Boetius melting point apparatus.
The optical rotations were measured on a Perkin–
Elmer 141 polarimeter. Thin-layer chromatography
was performed on Silufol plates; spots were visualized
by treatment with a solution of vanillin in ethanol
acidified with sulfuric acid.
1.53–2.17 m (19H, CH, CH2), 2.32 m (1H, 9-H, w1/2
20.8 Hz), 3.27 m (1H, 5-H, w1/2 = 21.4 Hz), 3.63 m
(1H, 22-H, w1/2 = 14.0 Hz), 4.23 m (1H, 3-H, w1/2
=
=
13.0 Hz), 4.63 m (1H, 2-H, w1/2 = 15.5 Hz). 13C NMR
spectrum (CDCl3), δC, ppm: 17.87 t (C11), 18.45 q
(C18), 20.91 q (C21), 21.32 t (C16), 23.46 t (C23),
25.89 q (C19), 26.18 t (C4), 26.18 t (C7), 26.65 q (C26),
26.65 q (C27), 26.65 q and 29.50 q (20,22-Me2C),
28.34 q and 28.90 q (2,3-Me2C), 31.28 t (C12), 33.46 t
(C15), 36.82 t (C1), 36.82 s (C10), 41.24 t (C24), 41.48 d
(C9), 41.80 d (C8), 42.28 d (C5), 46.74 s (C13), 49.75 d
(C17), 70.27 s (C25), 71.46 d (C3), 73.95 d (C2), 81.81 d
(C22), 84.48 s (C20), 85.53 s (C14), 106.74 s (20,22-
Me2C), 107.38 s (2,3-Me2C), 158.57 s (C6).
(6E)-2,3:20,22-Di-O-isopropylidene-7,8α-dihy-
dro-20-hydroxyecdysone oxime (V). Hydroxylamine
hydrochloride, 0.39 g (5.6 mmol), was added under
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

20-HYDROXYECDYSONE OXIMES AND THEIR REARRANGEMENT INTO LACTAMS
1461
(6E)-2,3:20,22-Di-O-isopropylidene-14,15-anhy-
dro-7,8α-dihydro-20-hydroxyecdysone oxime (VI).
Hydroxylamine hydrochloride, 0.29 g (4.0 mmol), was
added under stirring to a solution of 0.30 g (0.5 mmol)
of diacetonide IV in 3 ml of freshly distilled pyridine,
and the mixture was heated for 3 days at 70°C. The
mixture was cooled to 0°C, a solution of 0.023 g
(5.0 mmol) of potassium hydroxide in 2.3 ml of an-
hydrous ethanol was added, and the mixture was
evaporated on a rotary evaporator. The residue was
treated with 25 ml of water, the product was extracted
into ethyl acetate (3×25 ml), and the extract was dried
over MgSO4 and evaporated. Yield 0.07 g (23%),
mp 123–125°C, [α]D20 = –1.4° (c = 3.7, CHCl3).
1H NMR spectrum, δ, ppm: 1.13 s (3H, C18H3), 1.14 s
(3H, C21H3), 1.18 s (3H, C19H3), 1.25 m (1H, 9-H),
1.26 s (6H, C26H3, C27H3), 1.29 s and 1.38 s (3H each,
2,3-Me2C), 1.31 s and 1.50 s (3H each, 20,22-Me2C),
1.32 m and 2.12 m (2H, 24-H), 1.37 m and 1.56 m
(2H, 23-H), 1.51 m and 1.68 m (2H, 7-H), 1.52 m and
1.89 m (2H, 1-H), 1.57–1.77 m (2H, 11-H), 1.62 m and
2.38 m (2H, 4-H), 1.77 m (1H, 17-H), 1.99 d.d (1H,
7α-H, J7α,8 = 4.4, J7α,7β = 14.8 Hz), 2.07 m and 2.46 m
(2H, 16-H), 2.16 m and 2.46 m (2H, 12-H), 2.28 m
1H NMR spectrum, δ, ppm: 1.17 s (3H, C18H3), 1.19 s
(3H, C21H3), 1.22 s (6H, C26H3, C27H3), 1.29 s (3H,
C19H3); 1.39 s, 1.41 s, and 1.50 s (12H, Me2C), 1.54–
2.23 m (17H, CH, CH2), 2.48 d.d (1H, 17-H, J =
7.5 Hz), 2.75 t (1H, 7β-H, J = 3.6 Hz), 3.09 d.t (1H,
8-H, J = 18.0, 4.8 Hz), 3.73 m (1H, 22-H, w1/2
=
9.9 Hz), 4.22 m (1H, 2-H, w1/2 = 9.0 Hz), 4.50 m (1H,
3-H, w1/2 = 10.5 Hz), 5.37 m (1H, 15-H, w1/2 = 5.4 Hz).
13C NMR spectrum, δC, ppm: 17.85 (C11), 20.98 (C18),
21.02 (C21), 23.71 (C23), 25.23 (C16), 25.96 (C19),
26.03 and 28.55 (2,3-Me2C), 26.55 and 28.88 (20,22-
Me2C), 29.05 (C27), 29.66 (C26), 30.47 (C4), 33.94
(C1), 37.97 (C9), 39.82 (C10), 41.29 (C24), 42.32 (C12),
44.57 (C7), 46.83 (C13), 47.59 (C8), 50.81 (C5), 59.40
(C17), 70.31 (C25), 70.94 (C3), 71.51 (C2), 81.69 (C22),
83.45 (C20), 106.82 (20,22-Me2C), 107.71 (2,3-Me2C),
122.56 (C15), 150.98 (C14), 211.50 (C6).
(6Z)-20,22-O-Isopropylidene-14,15-anhydro-20-
hydroxyecdysone oxime (VIII). Freshly distilled
boron trifluoride–ether complex, 0.02 ml, was added
under stirring to a solution of 0.10 g (0.17 mmol) of
(6E)-oxime II in 3 ml of anhydrous methylene
chloride, and the mixture was stirred for 16 h at 20°C.
The mixture was cooled to 0°C, 5 ml of water was
added under stirring, the product was extracted into
ethyl acetate (3×10 ml), the extract was dried over
MgSO4, the combined extracts were evaporated under
reduced pressure, and the residue was subjected to
chromatography on 4 g of silica gel using chloroform–
methanol (30:1) as eluent. Yield 0.04 g (45%), Rf 0.43
(1H, 5-H, w1/2 = 11.2 Hz), 2.79 m (1H, 8-H, w1/2
20.4 Hz), 3.13 d.d (1H, 7β-H, J7β,7α = 14.8, J7β,8
=
=
13.0 Hz), 3.71 m (1H, 22-H, w1/2 = 14.3 Hz), 4.25 m
(1H, 2-H, w1/2 = 13.6 Hz), 4.66 m (1H, 3-H, w1/2
=
19.2 Hz), 5.37 m (1H, 15-H, w1/2 = 8.0 Hz). 13C NMR
spectrum, δC, ppm: 17.77 (C11), 21.08 (C18), 21.17
(C21), 23.90 (C23), 26.22 (C19), 26.89 (C4), 26.16 (C7),
26.88 (C26), 26.92 (C27), 28.65 and 29.05 (2,3-Me2C),
29.11 and 29.87 (20,22-Me2C), 30.64 (C12), 30.64
(C16), 33.34 (C1), 36.05 (C8), 37.20 (C10), 42.48 (C5),
42.77 (C24), 47.04 (C13), 48.15 (C9), 59.65 (C17), 70.56
(C25), 71.80 (C3), 74.19 (C2), 81.89 (C20), 83.73 (C22),
107.03 (20,22-Me2C), 107.71 (2,3-Me2C), 122.40
(C15), 152.48 (C14), 158.69 (C6).
(CHCl3–MeOH, 10 : 1), mp 155–157°C, [α]D20
=
1
–115.0° (c = 1.0, CHCl3). H NMR spectrum, δ, ppm:
0.88 s (3H, C19H3), 1.01 s (3H, C18H3), 1.20 s (3H,
C21H3), 1.24 s (3H, C26H3), 1.25 s (3H, C27H3), 1.31 s
and 1.43 s (6H, 20,22-Me2C), 1.52–2.36 m (19H, CH,
CH2), 2.58 m (1H, 9-H, w1/2 = 27.0 Hz), 3.21 d.d (1H,
5-H, J = 16.2 Hz), 3.74 m (1H, 22-H, w1/2 = 18.6 Hz),
3.74 m (1H, 2-H, w1/2 = 18.6 Hz), 4.03 m (1H, 3-H,
w1/2 = 12.3 Hz), 5.77 br.s (1H, 15-H, w1/2 = 7.8 Hz),
7,8a-Dihydrostachysterone B 2,3:20,22-diaceto-
nide (VII). Gaseous hydrogen was passed at room tem-
perature through a suspension of 0.07 g (0.32 mmol) of
(6E)-oxime VI and 0.7 g of Raney nickel (prepared
according to the procedure described in [16] from
powdered Ni–Al alloy from Acros Organics) in 4 ml of
ethanol until the substrate disappeared completely
(~30 h, according to the TLC data). The catalyst was
filtered off, the filtrate was evaporated, and the residue
was subjected to column chromatography on 5 g of
silica gel using chloroform–methanol (30:1) as eluent.
Yield 0.04 g (59%), Rf 0.61 (CHCl3–MeOH, 10:1),
mp 233–235°C, [α]D20 = –8.6° (c = 2.20, CHCl3).
13
6.21 d (1H, 7-H, 4J = 6.3 Hz). C NMR spectrum, δC,
ppm: 18.83 (C18), 20.78 (C11), 21.24 (C19), 23.66 (C21),
23.83 (C23), 26.83 (C16), 28.90 (C26), 29.24 and 29.68
(20,22-Me2C), 29.45 (C27), 30.20 (C12), 31.21 (C4),
35.40 (C10), 36.36 (C9), 37.97 (C5), 39.97 (C1), 41.23
(C24), 47.27 (C13), 57.52 (C17), 67.88 (C3), 68.20 (C2),
70.56 (C25), 81.80 (C22), 83.53 (C20), 106.92 (20,22-
Me2C), 116.29 (C7), 123.34 (C15), 140.82 (C8), 149.64
(C14), 159.64 (C6).
(20R,22R)-14α,25-Dihydroxy-2β,3β:20,22-di-O-
isopropylidene-5a-aza-5a-homo-5β-cholest-7-en-6-
one (IX). Oxime II, 0.143 g (0.25 mmol), was dis-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009

SHAFIKOV et al.
1462
solved in 10 ml of freshly distilled acetone, 0.027 g
(0.25 mmol) of sodium carbonate and 0.096 g
(0.5 mmol) of p-toluenesulfonyl chloride were added
under stirring, and the mixture was stirred for 24 h at
20°C. The mixture was cooled to 0°C, 6 ml of water
was added under stirring, the product was extracted
into ethyl acetate (3×20 ml), the combined extracts
were dried over MgSO4 and evaporated under reduced
pressure, and the residue was subjected to chromatog-
raphy on 5 g of silica gel using chloroform–methanol
(20:1) as eluent. Yield 0.068 g (48%), Rf 0.43 (CHCl3–
MeOH, 10:1), mp 165–167°C, [α]D20 = 45.5° (c = 3.8,
CHCl3). IR spectrum, ν, cm–1: 3420–3280, 2980–2900,
1680, 1620, 1470, 1390, 1230, 1160, 1080, 890. UV
pressure, and the residue was subjected to chromatog-
raphy on 3 g of silica gel using chloroform–methanol
(20:1) as eluent. Yield 0.015 g (21%), Rf 0.40 (CHCl3–
MeOH, 10:1), mp 152–154°C, [α]D20 = 5.2° (c = 1.7,
1
CHCl3). H NMR spectrum, δ, ppm: 0.93 s (3H,
C18H3), 1.11 s (3H, C21H3), 1.14 s (3H, C19H3), 1.20 m
and 2.12 m (2H, 15-H), 1.23 m and 2.11 m (2H, 4-H),
1.24 s (6H, C26H3, C27H3); 1.32 s, 1.41 s, and 1.50 s
(12H, 2,3-Me2C, 20,22-Me2C); 1.46 m and 1.60 m
(2H, 24-H), 1.50 m and 1.65 m (2H, 23-H), 1.53 m and
1.70 m (2H, 25-H), 1.60 m (2H, 11-H), 1.70 m (2H,
12-H), 2.03 m (1H, 17-H), 2.36 m (1H, 9-H, w1/2
=
18.0 Hz), 2.55 m (1H, 8-H, w1/2 = 36.8 Hz), 2.47 d
(1H, 7α-H, J7α, 8 = 14.0 Hz), 2.75 d.d (1H, 7β-H,
1
spectrum: λmax 259 nm (ε = 11567). H NMR spec-
J7β,7α = 14.0, J7β,8 = 16.0 Hz), 3.45 m (1H, 5-H, w1/2
=
trum, δ, ppm: 0.80 s (3H, C18H3), 0.98 s (3H, C19H3),
1.11 s (3H, C21H3), 1.20 s and 1.39 s (3H each,
2,3-Me2C), 1.21 s and 1.46 s (3H each, 20,22-Me2C),
1.23 s and 1.24 s (3H, C27H3), 1.26 m and 2.17 m (2H,
24-H), 1.40 m and 1.70 m (2H, 12-H), 1.44 m and
2.11 m (2H, 4-H), 1.50 m and 1.70 m (2H, 16-H),
1.56 s and 1.72 s (3H, C26H3), 1.57 m and 1.71 m (2H,
1-H), 1.58 m and 1.64 m (2H, 23-H), 1.80 m and
1.94 m (2H, 15-H), 1.81 m and 2.08 m (2H, 11-H),
2.21 m (1H, 17-H), 2.92 m (1H, 9-H, w1/2 = 18.0 Hz),
3.26 m (1H, 5-H, w1/2 = 16.8 Hz), 3.64 m (1H, 22-H,
w1/2 = 13.2 Hz), 4.26 m (1H, 2-H, w1/2 = 18.0 Hz),
4.36 m (1H, 3-H, w1/2 = 9.0 Hz), 5.85 m (1H, 7-H,
20.8 Hz), 3.66 m (1H, 22-H, w1/2 = 14.4 Hz), 4.30–
4.39 m (2H, 2-H, 3-H, w1/2 = 31.0 Hz), 5.85 m (1H,
7-H, w1/2 = 16.8 Hz), 5.67 s (1H, NH, J = 29.2 Hz).
13C NMR spectrum, δC, ppm: 17.17 (C18), 18.27 (C11),
21.05 (C16), 21.49 (C21), 23.56 (C23), 25.57 (C19),
26.81 and 28.96 (2,3-Me2C), 28.24 and 29.22 (20,22-
Me2C), 28.96 (C26), 29.59 (C27), 31.94 (C12), 31.98
(C4), 32.05 (C15), 36.10 (C7), 39.90 (C10), 41.17 (C9),
41.20 (C1), 41.20 (C8), 41.40 (C24), 46.62 (C13), 49.81
(C17), 51.03 (C5), 70.34 (C25), 70.34 (C2), 72.18 (C3),
81.90 (C22), 84.39 (C20), 86.14 (C14), 106.95 (20,22-
Me2C), 108.41 (2,3-Me2C), 176.13 (C6).
w
1/2 = 16.8 Hz), 6.40 s (1H, NH, J = 9.8 Hz). 13C NMR
20,22-O-Isopropylidene-14,15-anhydro-20-hy-
droxyecdysone (Z)-O-(4-methylphenylsulfonyl)-
oxime (XI). Sodium carbonate, 0.019 g (0.18 mmol),
and p-toluenesulfonyl chloride, 0.069 g (0.36 mmol),
were added under stirring to a solution of 0.1 g
(0.18 mmol) of oxime III (mp 148–150°C; prepared
according to the procedure described in [7]*) in 7 ml
of freshly distilled acetone, and the mixture was stirred
for 24 h at 20°C. The mixture was cooled to 0°C, 5 ml
of water was added, the product was extracted into
ethyl acetate (3×15 ml), the extract was dried over
MgSO4 and evaporated, and the residue was subjected
to chromatography on silica gel (4 g) using chloro-
form–methanol (30:1) as eluent. Yield 0.075 g (59%),
spectrum, δC, ppm: 17.10 (C18), 21.07 (C11), 21.76
(C21), 22.25 (C19), 23.15 (C16), 23.55 (C23), 26.33 and
26.88 (2,3-Me2C), 28.46 and 28.95 (20,22-Me2C),
29.29 (C26), 29.50 (C27), 29.95 (C12), 32.21 (C15),
32.89 (C4), 38.98 (C9), 39.65 (C10), 41.35 (C1), 42.41
(C24), 48.04 (C13), 49.28 (C17), 55.95 (C5), 70.42 (C25),
71.82 (C2), 73.99 (C3), 81.93 (C22), 84.39 (C20), 87.77
(C14), 106.92 (20,22-Me2C), 108.35 (2,3-Me2C), 120.07
(C7), 154.48 (C8), 168.78 (C6). Found, %: C 68.66;
H 9.70; N 2.59. C33H53NO7. Calculated, %: C 68.84;
H 9.28; N 2.43.
(20R,22R)-14α,25-Dihydroxy-2β,3β:20,22-di-
O-isopropylidene-5a-aza-5a-homo-5β,8α-cholestan-
6-one (X). Oxime V, 0.07 g (0.12 mmol), was dis-
solved in 5 ml of freshly distilled acetone, 0.013 g
(0.12 mmol) of sodium carbonate and 0.046 g
(0.24 mmol) of p-toluenesulfonyl chloride were added
under stirring, and the mixture was stirred for 24 h at
20°C. The mixture was cooled to 0°C, 3 ml of water
was added under stirring, the product was extracted
into ethyl acetate (3×10 ml), the combined extracts
were dried over MgSO4 and evaporated under reduced
Rf 0.51 (CHCl3–MeOH, 10:1), mp 121–123°C, [α]D20
=
–95.6° (c = 0.63, CHCl3). IR spectrum, ν, cm–1: 3500–
3300, 3020–2900, 1600, 1510, 1450, 1380, 1230,
1190. UV spectrum: λmax 300 nm (ε = 15 284).
1H NMR spectrum, δ, ppm: 0.79 s (3H, C19H3), 0.98 s
(3H, C18H3), 1.18 s (3H, C21H3), 1.23 s (3H, C26H3),
* According to the refined data (HSQC), the C7 and C15 signals, as
well as the C8 and C14 signals, in the 13C NMR spectrum of XI
given in [7] should be swapped.
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20-HYDROXYECDYSONE OXIMES AND THEIR REARRANGEMENT INTO LACTAMS
1463
1.24 s (3H, C27H3), 1.30 s and 1.45 s (6H, 20,22-
Me2C), 1.41 m and 1.87 m (2H, 23-H), 1.42 m and
2.18 m (2H, 12-H), 1.44 m and 1.83 m (2H, 1-H),
1.46 m and 1.61 m (2H, 16-H), 1.52 m and 1.71 m
(2H, 24-H), 1.60 m and 1.71 m (2H, 11-H), 1.94 m
(1H, 17-H), 2.26 m and 2.57 m (2H, 4-H), 2.36 m (1H,
3. Kovganko, N.V. and Chernov, Yu.G., Khim. Prirodn.
Soedin., 2001, p. 218.
4. Rodrigues, J., Nunez, L., Peixinho, S., and Jimenez, C.,
Tetrahedron Lett., 1997, vol. 38, p. 1833.
5. Holland, H.L., Kumaresan, S., Tan, L., and Njar, V.C.O.,
J. Chem. Soc., Perkin Trans. 1, 1992, p. 585.
6. Zeelen, F.J., Medicinal Chemistry of Steroids,
9-H), 2.44 s (3H, C7′H3), 3.27 d.d (1H, 5-H, J4α,5
13.2, J4β,5 = 4.4 Hz), 3.69–3.71 m (1H, 22-H, w1/2
=
=
Amsterdam: Elsevier, 1990.
7. Galyautdinov, I.V., Ves’kina, N.A., Afon’kina, S.R.,
Khalilov, L.M., and Odinokov, V.N., Russ. J. Org.
Chem., 2006, vol. 42, p. 1333.
13.2 Hz), 3.69–3.73 m (1H, 3-H, w1/2 = 9.2 Hz),
4.03 m (1H, 2-H, w1/2 = 9.2 Hz), 5.81 m (1H, 15-H,
w1/2 = 6.8 Hz), 6.16 s (1H, 7-H), 7.31 m (2H, 2′-H,
8. Baron, D.L., Luo, W., Yanzen, L., Pharis, R.P., and
6′-H, w1/2 = 8.4 Hz), 7.87 m (2H, 3′-H, 5′-H, w1/2
=
8.4 Hz). 13C NMR spectrum, δC, ppm: 18.90 (C18),
20.65 (C11), 21.16 (C21), 21.69 (C7′), 23.52 (C19), 23.68
(C16), 26.49 (C26), 26.79 and 28.86 (20,22-Me2C),
29.19 (C27), 29.63 (C12), 30.95 (C23), 31.32 (C4), 36.56
(C10), 36.61 (C1), 37.13 (C5), 38.06 (C9), 41.21 (C24),
47.38 (C13), 57.44 (C17), 67.50 (C2), 67.50 (C3), 70.46
(C25), 81.73 (C22), 83.39 (C20), 106.99 (20,22-Me2C),
113.47 (C7), 125.62 (C15), 128.80 (C3′, C5′), 129.59
(C2′, C6′), 132.64 (C4′), 144.90 (C1′), 146.41 (C8),
149.17 (C14), 167.17 (C6). Found, %: C 66.08; H 7.80;
N 2.03; S 4.24. C37H53NO8S. Calculated, %: C 66.14;
H 7.95; N 2.08; S 4.77.
Back, T.G., Phytochemistry, 1998, vol. 49, p. 1849.
9. Odinokov, V.N., Afon’kina, S.R., Shafikov, R.V., Sav-
chenko, R.G., Galyautdinov, I.V., Khalilov, L.M., and
Shashkov, A.S., Russ. J. Org. Chem., 2007, vol. 43,
p. 825.
10. Afonin, A.V., Ushakov, I.A., Tarasova, O.A.,
Shmidt, E.Yu., Mikhaleva, A.I., and Voronov, V.K.,
Russ. J. Org. Chem., 2000, vol. 36, p. 1777.
11. Levy, G.C. and Lichter, R.L., Nitrogen-15 Nuclear
Magnetic Resonance Spectroscopy, New York: Wiley,
1979.
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dia), Moscow: Sovetskaya Entsiklopediya, 1988, vol. 1.
13. Vinchik, M.I. and Zarakhani, N.G., Usp. Khim., 1967,
This study was performed under financial support
by the Academy of Sciences of Bashkortostan Repub-
lic and by the President of the Russian Federation
(project no. NSh-6079.2008.3).
vol. 36, p. 167.
14. Huitric, A.C. and Nelson, S.D., J. Org. Chem., 1969,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 10 2009