A short way to invert configuration of the 2,3-hydroxy groups in ecdysteroids

Article abstract of DOI:10.1134/S1070428013070063

3-epi-2-Dehydro-20-hydroxyecdysone and its 20,22-acetonide were reduced with lithium tris(secbutyl) hydridoborate selectively at the 2-oxo group with formation of 2β,3β-dihydroxy derivatives and the corresponding 2α,3α epimers which were separated by chromatography.

Full text of DOI:10.1134/S1070428013070063

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 7, pp. 995–998. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © R.G. Savchenko, S.A. Kostyleva, V.V. Kachala, L.M. Khalilov, V.N. Odinokov, 2013, published in Zhurnal Organicheskoi Khimii,
2013, Vol. 49, No. 7, pp. 1011–1014.
A Short Way to Invert Configuration of the 2,3-Hydroxy
Groups in Ecdysteroids
R. G. Savchenkoa, S. A. Kostylevaa, V. V. Kachalab, L. M. Khalilova, and V. N. Odinokova
a Institute of Petrochemistry and Catalysis, Russian Academy of Sciences,
pr. Oktyabrya 141, Ufa, 450075 Bashkortostan, Russia
e-mail: odinokov@anrb.ru
b Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia
Received December 26, 2012
Abstract—3-epi-2-Dehydro-20-hydroxyecdysone and its 20,22-acetonide were reduced with lithium tris(sec-
butyl)hydridoborate selectively at the 2-oxo group with formation of 2β,3β-dihydroxy derivatives and the
corresponding 2α,3α epimers which were separated by chromatography.
DOI: 10.1134/S1070428013070063
Ecdysteroids are hormones responsible for moult-
ing, metamorphosis, and reproduction of insects and
other arthropods. They are also produced by plants
even at much higher concentrations (up to 2–2.5% of
the air-dry weight of some plant species) [1–4]. The
hydroxy groups in the A ring of ecdysteroids are
usually 2β,3β-configured; however, some plant species
contain minor ecdysteroid components with α-oriented
hydroxy groups in the A ring [5–8]. The most prom-
ising way of synthesis of such minor ecdysteroids and
their analogs is 2,3-epimerization of one of the most
widely known ecdysteroid, 20-hydroxyecdysone, and
its derivatives. However, the known methods for epi-
merization of ecdysteroids include many steps [9, 10].
We previously reported on a one-step synthesis of
3-epi-2-dehydro-20-hydroxyecdysone (I) and its
20,22-acetonide (II) via ozonation in pyridine [11].
Selective reduction of the 2-oxo group in compounds I
Scheme 1.
OR'
OR'
OR
OR
Me
Me
Me
Me
H
H
Me
OH
Me
OH
[HB(CHMeEt)3] Li+
THF
Me
H
Me
H
Me
Me
O
HO
HO
H
O
OH
H
O
OH
HO
I, II
III, IV
OR'
OR
Me
Me
H
Me
OH
30% H2O2
Me
H
Me
+
HO
HO
V
VII
H
O
OH
V–VII
I, III, VII, R = R′ = H; II, IV, VI, RR′ = Me2C; V, RR′ = MeEtCHB.
995

SAVCHENKO et al.
996
Scheme 2.
Me
H
Me
HO
Me
H
O
HO
O
H
O
H
H
O
HO
HO
H
O
A
B
L-Selectride
L-Selectride
Me
H
Me
H
HO
HO
HO
HO
H
O
H
O
2α,3α
2β,3β
OH
OH
Me
Me
Et
Me
H
Li+
Li+
O
H
B
Me
Me
Me
OH
I
+
B(CHMeEt)3
H
O
OH
HO
H
C
Me
B
Et
O
OH
OH
O
Me
Me
Me
Me
H2O
30% H2O2
H
H
Me
Me
OH
–2MeCH2Et
–LiOH
Me
H
Me
Me
Me
OH
HO
HO
HO
H
O
OH
H
O
OH
HO
H
V
VII
and II could provide the shortest way to 2,3-di-epi-20-
hydroxyecdysone (III) and its 20,22-acetonide IV.
isolated from the reaction mixtures by column
chromatography on silica gel 20-hydroxyecdysone
20,22-(sec-butyl)boronate (V) and 20-hydroxyec-
dysone 20,22-acetonide (VI), respectively. Removal of
the boronate group from V by treatment with 30% hy-
drogen peroxide afforded 20-hydroxyecdysone (VII)
(Scheme 1).
The reduction of diketones I and II with alkali
metal hydride complexes (LiAlH4, NaBH4, NaBH4–
CeCl3) involved both oxo groups in positions 2 and 6.
Treatment of I and II with 9-bora[3.3.1]bicyclononane
ensured selective reduction of the 2-oxo group, but
the products were 20-hydroxyecdysone and its
20,22-acetonide, respectively.
2,3-Di-epi-ecdysteroids III and IV were obtained
by reaction of diketones I and II with lithium tris(sec-
butyl)hydridoborate (L-Selectride) in THF at –10°C.
However, apart from 2α,3α-epimers III and IV, we
Thus the final products of the hydride reduction of
3-epi-2-dehydroecdysteroids I and II with L-Selectride
are the corresponding 2α,3α- and 2β,3β-dihydroxy
derivatives III, IV and VI, VII, respectively, at a ratio
of ~30:70. With account taken of the number of steps
in the synthesis of 3-epi-2-dehydro-20-hydroxyecdy-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

A SHORT WAY TO INVERT CONFIGURATION
997
sone [11], we have proposed a two-step procedure for
the inversion of configuration of the 2,3-hydroxy
groups in 20-hydroxyecdysone; the known synthesis of
2,3-di-epi-20-hydroxyecdysone includes six steps [10].
parameters of V are fairly similar to those observed
for 20-hydroxyecdysone 20,22-acetonide (VI) [10, 16,
17]. Some differences are determined by the presence
of 20,22-O-(sec-butyl)boronate moiety in molecule V
instead of 20,22-O-isopropylidene group in VI. The
result is that there is no acetal carbon signal
(δC 106 ppm) in the 13C NMR spectrum of V. The
1H NMR spectrum of V contained a triplet at
δ 1.03 ppm (J = 8 Hz) and a doublet at δ 1.05 ppm (J =
10 Hz) from the methyl protons in the MeCHCH2Me
fragment instead of two Me2C singlets (δ 1.26 and
1.33 ppm) present in the spectrum of VI. Compound V
displayed ion peaks with m/z 569 [M + Na]+ and 585
[M + K]+ in the MALDI-TOF mass spectrum.
Presumably, the formation of 2β,3β epimers in the
examined reactions is the result of keto–enol tauto-
merism known for α-hydroxy ketones. Intermediate
α,β-enediol A is likely to occur in equilibrium with
initial 2-oxo-3α-hydroxy derivative I and its 3-oxo-2β-
hydroxy isomer B, and their reduction with L-Selec-
tride yields 2α,3α and 2β,3β epimers, respectively
(Scheme 2). Boronic ester V is formed due to the
known ability of trialkylboranes to react with hydroxy
compounds; this reaction is used to protect hydroxy
groups [12], e.g., in the synthesis of shidasterone [13]
and viticosterone E [14]. In keeping with the generally
accepted mechanism of the reduction of ketones with
L-Selectride [15], addition of hydride ion to the car-
bonyl group releases tris(sec-butyl)borane which reacts
with vicinal hydroxy groups to produce 20-hydroxyec-
dysone 20,22-(sec-butyl)boronate (V) (Scheme 2). The
corresponding boronic acid ester derived from 2,3-di-
epi-20-hydroxyecdysone is likely to be less stable, so
that it undergoes hydrolysis during chromatography on
silica gel to give 2,3-di-epi-20-hydroxyecdysone (III).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded from
solutions in pyridine-d5. The homo- and heteronuclear
DEPT-135°, COSY, HSQC, and HMBC spectra were
1
measured on Bruker Avance-400 (400.13 MHz for H
and 100.62 MHz for 13C) and Bruker Avance II 600
1
(600.13 MHz for H and 150.76 MHz for 13C) instru-
ments equipped with an inverse broad-band probe. The
chemical shifts were determined relative to tetra-
methylsilane as internal reference. The melting points
were measured using a Boetius micro-hot stage. The
optical rotations were measured on a Perkin Elmer-141
polarimeter. Analytical TLC was performed on Silufol
plates; spots were developed with a solution of vanillin
in ethanol acidified with sulfuric acid.
1
The H and 13C NMR spectra of 2α,3α epimers III
and IV, as well as of ecdysteroids VI and VII, were
identical to those reported previously [10, 16, 17].
1
Signals in the H and 13C NMR spectra of III and IV
were assigned with the aid of homo- and heteronuclear
shift correlation techniques (HSQC, HMBC, COSY,
ROESY).
2,3-Di-epi-20-hydroxyecdysone (III) and
(20R,22R)-2β,3β,14α,25-tetrahydroxy-20,22-(butan-
2-yl)boranediyldioxy-5β-cholest-7-en-6-one
[V, 20-hydroxyecdysone 20,22-(sec-butyl)boronate].
A solution of 0.15 g (0.31 mmol) of compound I
{mp 136–138°C, [α]D20 = +13.05° (c = 2.18, CHCl3)
[11]} in 10 ml of anhydrous THF was cooled to –10°C,
0.56 ml (0.47 mmol) of a 1 M solution of L-Selectride
in THF was added under argon, and the mixture was
stirred until the initial compound disappeared (2 h,
TLC). The mixture was evaporated, and the residue
was subjected to chromatography on 4.5 g of silica gel
(gradient elution with chloroform to chloroform–meth-
anol, 10:1) to isolate 0.025 g (20%) of compound III,
The configuration of the 2,3-dihydroxy fragment in
III was confirmed by the coupling constants observed
for 2-H and 3-H and the neighboring protons (1-H and
1
4-H) in the H NMR spectrum recorded at 323 K.
Small coupling constants between 2-H (δ 4.33 ppm)
and the axial and equatorial protons on C1 (δ 1.22 and
3
3
2.42 ppm, J2,1-ax = J2,1-eq = 2.4 Hz) indicated equato-
rial orientation (β-configuration) of 2-H. Correspond-
ingly, the 2-hydroxy group in III is axial (α-con-
figuration). The coupling constant of 3-H (δ 3.90 ppm)
with the axial proton on C4 (δ 1.85 ppm) is equal to
10.6 Hz, indicating its axial orientation (β-configura-
tion). This means that the hydroxy group on C3
occupies equatorial position (α-configuration).
1
Rf 0.46 (CHCl3–MeOH, 3:1), whose H and 13C NMR
spectra were identical to those reported in [10], and
0.07 g (60%) of boronate V, Rf 0.45 (CHCl3–MeOH,
5 : 1), mp 136–138°C, [α]D20 = +63.8° (c = 0.58,
The structure of boronic ester V was determined on
1
the basis of spectral data. Signals in the H and 13C
1
NMR spectra of V were assigned using JMOD, HSQC,
HMBC, COSY, and ROESY techniques. The spectral
MeOH). H NMR spectrum, δ, ppm: 0.99 s (3H,
C18H3), 1.03 t (3H, CH3CH2CHB, J = 8.0 Hz), 1.05 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013

SAVCHENKO et al.
998
(3H, CH3CHB, J = 10.0 Hz), 1.12 s (3H, C19H3),
1.38 s (9H, C21H3, C26H3, C27H3), 1.66 m and 2.09 m
(2H, 1-H), 2.72 m (1H, 17-H), 3.00 br.d (1H, 5-H, J =
3.9 Hz), 3.52 br.s (1H, 9-H, w1/2 = 7.2 Hz), 4.12 m
(1H, 2-H), 4.18 m (1H, 22-H), 4.21 m (1H, 3-H),
6.20 s (1H, 7-H). 13C NMR spectrum, δC, ppm: 13.15
(CH3CH2CHB), 14.66 (CH3CHB), 18.17 (C18), 19.90
(C11), 20.86 (C16), 21.74 (C21), 23.37 (C19), 25.65 (C23),
29.53 and 29.64 (C26, C27), 30.46 (C12, C15), 31.38
(C4), 33.26 (C9), 36.89 (C1), 37.65 (C24), 40.87 (C10),
46.47 (C13), 50.33 (C5), 53.78 (C17), 64.32 (C8), 67.68
(C2, C3), 68.24 (C25), 83.08 (C14), 83.86 (C22), 85.00
(C20), 120.85 (C7), 202.38 (C6). Mass spectrum: m/z
569 [M + Na]+ and 585 [M + K]+. Found, %: C 68.12;
H 9.41. C31H51BO7. Calculated, %: C 68.38; H 9.04.
REFERENCES
1. Akhrem, A.A. and Kovganko, N.V., Ekdisteroidy:
khimiya i biologicheskaya aktivnost’ (Ecdysteroids:
Chemistry and Biological Activity), Minsk: Nauka i
Tekhnika, 1989, p. 325.
2. Rees, H.H., Ecdysone: From Chemistry to Mode of
Action, Koolman, J., Ed., Stuttgart: Georg Thieme,
1989, p. 28.
3. Lafont, R. and Horn, D.N.S., Ecdysone: From Chem-
istry to Mode of Action, Koolman, J., Ed., Stuttgart:
Georg Thieme, 1989, p. 39.
4. Camps, F., Ecological Chemistry and Biochemistry of
Plant Terpenoids, Harborne, J.B. and Tomas-
Barberan, F.A., Eds., Oxford: Clarendon, 1991, p. 331.
5. Lafont, R., Harmatha, J., Marion-Poll, F., Dinan, L., and
Wilson, I.D., The Ecdysone Handbook, 2002, 3rd ed.;
http://ecdybase.org
Deprotection of 20-hydroxyecdysone 20,22-
(sec-butyl)boronate (V). Compound V, 0.07 g
(0.12 mmol), was dissolved in 5 ml of aqueous THF
(THF–H2O, 9:1), 0.003 ml (0.10 mmol) of 30% hy-
drogen peroxide was added, and the mixture was
stirred until the initial compound disappeared (10 min,
TLC). The mixture was treated with 0.015 ml of
Na2S2O3 and extracted with butan-1-ol (3×5 ml), the
combined extracts were evaporated, and the residue
was subjected to chromatography on 3 g of silica gel
(gradient elution with chloroform to chloroform–meth-
anol, 10:1) to isolate 0.034 g (58%) of compound VII,
6. Vokac, K., Budesinsky, M., and Harmatha, J., Collect.
Czech. Chem. Commun., 2002, vol. 67, p. 124.
7. Thompson, M.J., Kaplanis, J.N., Robbins, W.E.,
Dutky, S.R., and Nigg, H.N., Steroids, 1974, vol. 24,
p. 359.
8. Odinokov, V.N., Galyautdinov, I.V., Nedopekin, D.V.,
Khalilov, L.M., Shashkov, A.S., Kachala, V.V.,
Dinan, L., and Lafont, R., Insect Biochem. Mol. Biol.,
2002, vol. 32, p. 161.
9. Charoensuk, S., Yingyongnarongkul, B., and Suksam-
1
13
rarn, A., Tetrahedron, 2000, vol. 56, p. 9313.
Rf 0.45 (CHCl3–MeOH, 3:1), whose H and C NMR
10. Homvisasevongsa, S., Chuaynugul, A., Chimnoi, N.,
and Suksamrarn, A., Tetrahedron, 2004, vol. 60,
p. 3433.
spectra were identical to those reported previously [5].
2,3-Di-epi-20-hydroxyecdysone 20,22-acetonide
(IV) and 20-hydroxyecdysone 20,22-acetonide (VI).
A solution of 0.12 g (0.23 mmol) of compound II
{mp 100–102°C, [α]D20 = +24.2° (c = 3.8, CHCl3) [11]}
in 10 ml of anhydrous THF was cooled to –10°C,
0.42 ml (0.35 mmol) of a 1 M solution of L-Selectride
in THF was added under argon, and the mixture was
stirred until the initial compound disappeared (2 h,
TLC). The mixture was evaporated, and the residue
was subjected to chromatography on 4 g of silica gel
(gradient elution with chloroform to chloroform–
methanol, 20:1) to isolate 0.03 g (30%) of compound
IV, Rf 0.46 (CHCl3–MeOH, 5:1), and 0.06 g (60%) of
11. Savchenko, R.G., Urmanova, Y.R., Shafikov, R.V.,
Afon’kina, S.R., Khalilov, L.M., and Odinokov, V.N.,
Mendeleev Commun., 2008, vol. 18, p. 191.
12. Mikhailov, B.M. and Bubnov, Yu.N., Bororganicheskie
soedineniya v organicheskom sinteze (Organoboron
Compounds in Organic Synthesis), Moscow: Nauka,
1977, p. 204.
13. Roussel, P.G., Sik, V., Turner, N.Y., and Dinan, L.N.,
J. Chem. Soc., Perkin Trans. 1, 1997, p. 2237.
14. Politova, N.K., Punegov, V.V., Volodin, V.V., and Igna-
tov, A.V., Khim. Prirodn. Soedin., 1997, vol. 33, p. 74.
15. Kuding, E.P. and Enriques-Garsia, A., Beilst. J. Org.
Chem., 2008, vol. 4, no. 37.
1
VI, Rf 0.47 (CHCl3–MeOH, 5 :1). The H and 13C
NMR spectra of compounds IV and VI were identical
to those reported previously [10].
16. Darwish, F.M.M. and Reinecke, M.G., Phytochemistry,
2003, vol. 62, p. 1179.
This study was performed under financial support
by the Academy of Sciences of Bashkortostan
Republic.
17. Odinokov, V.N., Galyautdinov, I.V., Nedopekin, D.V.,
and Khalilov, L.M., Izv. Akad. Nauk, Ser. Khim., 2003,
p. 220.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 7 2013