Synthesis of Hoodigogenin A, aglycone of natural appetite suppressant glycosteroids extracted from Hoodia gordonii

Article abstract of DOI:10.1016/j.steroids.2011.03.014

14β-hydroxy pregnane glycosides extracted from Hoodia gordonii, a succulent plant isolated from Apocynaceae are suggested to have appetite suppressant properties in animals and humans. However, limited reports on biological studies concerning the appetite suppressant properties are available in the open literature. One reason for that is the poor availability of these glycosteroids because H. gordonii is a protected plant and the yield of extraction lies between 0.003% and 0.02%. Starting from 3α,12α- diacetoxy-pregnanone 1, we disclose in this report the synthesis of Hoodigogenin A, the aglycone of the natural 14β-hydroxy pregnane glycosides extracted from H. Gordonii.

Full text of DOI:10.1016/j.steroids.2011.03.014

Steroids 76 (2011) 702–708
Contents lists available at ScienceDirect
Steroids
journal homepage: www.elsevier.com/locate/steroids
Synthesis of Hoodigogenin A, aglycone of natural appetite suppressant
glycosteroids extracted from Hoodia gordonii
a
a
b
a,∗
Philippe Geoffroy , Blandine Ressault , Eric Marchioni , Michel Miesch
a
Université de Strasbourg-Institut de Chimie, UMR 7177-Laboratoire de Chimie Organique Synthétique-1, rue Blaise Pascal, BP 296/R8, 67008 Strasbourg-Cedex, France
Université de Strasbourg, Faculté de Pharmacie, IPHC, UMR 7178, Laboratoire de Chimie Analytique et de Science de l’Aliment, 74 route du Rhin, 67640 Illkirch Graffenstaden, France
b
a r t i c l e i n f o
a b s t r a c t
Article history:
14ˇ-hydroxy pregnane glycosides extracted from Hoodia gordonii, a succulent plant isolated from Apoc-
ynaceae are suggested to have appetite suppressant properties in animals and humans. However, limited
reports on biological studies concerning the appetite suppressant properties are available in the open
literature. One reason for that is the poor availability of these glycosteroids because H. gordonii is
a protected plant and the yield of extraction lies between 0.003% and 0.02%. Starting from 3˛,12˛-
diacetoxy-pregnanone 1, we disclose in this report the synthesis of Hoodigogenin A, the aglycone of
the natural 14ˇ-hydroxy pregnane glycosides extracted from H. Gordonii.
Received 31 January 2011
Received in revised form 24 March 2011
Accepted 25 March 2011
Available online 5 April 2011
Keywords:
Obesity
Norrish type I reaction
Prins reaction
Hoodia gordonii
©
2011 Elsevier Inc. All rights reserved.
1
4ˇ-hydroxy pregnane glycosides
Appetite suppressant properties
1
. Introduction
developed an original synthesis of Hoodigogenin A starting from
commercially available reagents. The main reason for our interest
in the synthesis of the Hoodigogenin A is because there is limited
access to the active compounds which are a priori responsable for
the appetite suppressant properties. According to the literature, the
yield of extraction of the oxypregnane glycosides from H. gordonii
lies between 0.003% and 0.02% [7–10]. In addition, H. gordonii is
a protected plant and therefore of limited access. Furthermore, to
the best of our knowledge, no synthesis of Hoodigogenin A has been
reported in the open literature [11]. We report herein the synthe-
sis of Hoodigogenin A, the key step being a Norrish type I – Prins
reaction.
Obesity is one of the major health concerns in the 21st cen-
tury. Worldwide, more than 300 million people are obese and one
billion are overweight [1]. The increase of childhood obesity is a
worrisome problem [2,3]. Obesity is also associated with several
health problems such as diabetes, heart diseases and dyslipidemia,
and glucose intolerance. Obesity is a disease that requires careful
attention and pragmatic treatment. Lifestyle changes, exercising,
dieting and weight loss are needed for a complete treatment and
prevention of relapse. However, diet pills can help in fighting obe-
sity. In this context, there is a growing interest for Hoodia gordonii,
a succulent plant isolated from Apocynaceae (previously Asclepi-
adaceae) which grows in South Africa and Namibia [4]. It is claimed
that this plant presents appetite suppressant properties. However,
only limited reports on biological studies concerning the appetite
suppressant properties are available in the open literature [5–7].
The extraction of H. gordonii provided numerous oxypregnane gly-
cosides, for example P57AS3, characterized by a common aglycone
called Hoodigogenin A (12-O-ˇ-tigloyl-3ˇ, 14ˇ-dihydroxy-pregn-
2. Experimental
2.1. General
Melting points were measured on a Stuart Scientific melting
point apparatus (SMP 3) and are uncorrected. Reactions were car-
ried out under argon with magnetic stirring and degassed solvents.
5
-ene-20-one) (Fig. 1) [8–10].
Et O and THF were distilled from Na/benzophenone. Thin layer
2
In the frame of a collaborative study concerning the synthesis,
chromatography (TLC) was carried out on silica gel plates (Merck
the extraction and the biological evaluation of Hoodigogenin A, we
6
3
0F254) and the spots were visualized under UV lamp (254 or
65 nm) and sprayed with phosphomolybdic acid solution (25 g
phosphomolybdic acid, 10 g cerium sulfate, 60 mL H SO , 940 mL
2
4
∗ Corresponding author. Tel.: +33 0 368851752; fax: +33 0 68851754.
E-mail address: m.miesch@unistra.fr (M. Miesch).
H O) followed by heating on a hot plate. For column chromatogra-
phy, silica gel (Merck Si 60 40–60 ␮m) was used. IR spectra were
2
0
039-128X/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2011.03.014

P. Geoffroy et al. / Steroids 76 (2011) 702–708
703
O
O
O
O
O
O
H
H
OH
OH
O
O
O
O
HO
HO
O
O
O
OH
O
P57AS3
HoodigogeninA
O
Fig. 1.
1
recorded on Bruker Alpha (ATR) spectrophotomer. H NMR spectra
were recorded at 300 MHz (Bruker AC-300) and 13C NMR spectra
at 75 MHz (Bruker AC-300) using the signal of the residual non-
deuterated solvent as internal reference. Significant 1H NMR data
are tabulated in the following order: chemical shift (ı) expressed
in ppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet), coupling constants in hertz, number of protons. High-
resolution mass spectra (HRMS) were performed on a Agilent 6520
Accurate Mass Q-TOF.
2.4. 4ˇ-bromo,12˛-acetoxy-5Hˇ-pregnan-3,20-dione (3)
To a solution of compound 2 (2.14 g, 5.71 mmol) in AcOH
(60 mL), was added dropwise over 45 min a solution of Br2 (0.29 mL,
5.65 mmol) in AcOH (25 mL). The solution was stirred for an
additional 30 min and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (50 mL) and washed with water
(3 × 30 mL). The combined aqueous layers were extracted with
CH2Cl2 (2 × 50 mL). The combined organic layers were washed with
sat. NaHCO3 (3 × 30 mL), dried over Na SO , filtered and concen-
2
4
2.2. 3˛-hydroxy,12˛-acetoxy-5Hˇ-pregnan-20-one (1a)
trated under reduced pressure to yield compound 3 as a white
◦
solid (2.89 g, quant., mp 167.4–169.9 C) which was used directly
for the next step. IR (ATR, cm ): 1726, 1698. 1H NMR (CDCl3) ı:
5.16 (t, 1H, J = 2.4 Hz, H-12ˇ); 4.92 (d, 1H, J = 11.7 Hz, H-4˛); 2.92
(t, 1H, J = 9.3 Hz, H-17˛); 2.47 (dt, 1H, J = 3.9–14.4 Hz); 2.35–0.60
(17H, m); 2.11 (s, 3H, CH3, H-21); 2.00 (s, 3H, CH3, Ac); 0.88 (s,
3H, CH3); 0.71 (s, 3H, CH3). 13C NMR (CDCl3) ı: 208.5 (C O); 201.8
(C O); 170.2 (C O, OAc); 74.1 (CH, C-12); 59.5 (CH); 55.4 (CH);
53.9 (CH); 49.4 (CH); 46.6 (C); 37.6 (C); 36.3 (CH2); 36.2 (CH2);
35.8 (CH); 35.4 (CH); 31.1(CH); 26.0 (CH2); 25.4 (CH2); 24.7 (CH2);
23.6 (CH ); 2.9 (CH ); 22.4 (CH ); 21.3 (CH ); 13.9 (CH ). HRMS
−
1
To a solution of compound 1 (3.37 g, 8.05 mmol) in MeOH
(
80 mL) was added K CO3 (1.00 g, 7.24 mmol). The reaction mix-
2
ture was stirred for 1 h at r.t. and treated with water (50 mL).
The aqueous layer was extracted with Et O (3 × 60 mL). The com-
2
bined organic layers were washed with brine (1 × 50 mL), dried
over Na SO , filtered and concentrated under reduced pressure.
2
4
The white residue was purified by column chromatography (30 g
silica gel, petroleum ether–ethyl acetate, 3:7), to afford compound
◦
−1
1
3
1
a as a white solid (2.48 g, 83%, mp 201.5–203.8 C). IR (ATR, cm ):
2
3
2
3
3
1
(ESI) m/z: C23H33BrNaO [M+Na]+ calcd. 477.1437, found 477.1445.
472, 1714, 1696. H NMR (CDCl ) ı: 5.12 (t, 1H, J = 2.7 Hz, H-
2ˇ); 3.63 (tt, 1H, J = 10.9–4.6 Hz, H-3ˇ); 2.95 (t, 1H, J = 9.3 Hz,
4
3
20
[˛] D: +151 (c 0.01, CHCl3).
H-17˛); 2.20–2.05 (1H, m); 2.14 (s, 3H, H-21); 2.01 (s, 3H, CH , Ac);
3
13
1
.95–0.85 (m, 20H); 0.89 (s, 3H, CH ); 0.67 (3H, s, CH ). C NMR
2.5. 12˛-acetoxy-pregn-4-ene-3,20-dione (4)
3
3
(
CDCl ) ı: 208.9 (C O, C-20); 170.5 (C O, OAc); 74.5 (CH, C-3); 71.6
3
(
(
CH, C-12);55.6 (CH); 49.6(CH); 46.7(C); 41.9(CH); 36.2(CH ); 35.6
To a solution of the crude compound 3 (2.60 g, 5.73 mmol) in
DMF (65 mL), was added LiCl (1.20 g, 28.24 mmol). The reaction
mixture was refluxed for 1 h and the medium was concentrated
under reduced pressure. The orange residue was dissolved in AcOEt
(50 mL) and washed with water (3 × 30 mL). The combined aque-
ous layers were extracted with AcOEt (3 × 30 mL). The combined
organic layers were washed with brine (1 × 30 mL), dried over
Na SO , filtered and concentrated under reduced pressure. The
2
CH); 35.0 (CH ); 34.5 (CH); 34.1 (C); 31.1 (CH ); 30.4 (CH ); 27.0
2
3
2
(
CH ); 26.0 (CH ); 25.6 (CH ); 23.7 (CH ); 23.0 (CH ); 22.3 (CH );
2 2 2 2 3 2
+
2
3
1.4 (CH ); 13.8 (CH ). HRMS (ESI) m/z: C23H36NaO [M+Na] calcd.
3 3 4
20
99.2506, found 399.2518; [˛] D: +154 (c 0.01, CHCl ).
3
2
.3. 12˛-acetoxy-5Hˇ-pregnan-3,20-dione (2)
2
4
A solution of compound 1a (1.00 g, 2.66 mmol) in acetone
60 mL) at 0 C was treated dropwise with Jones reagent (2.7 mL).
The orange solution was stirred for 1 h at r.t. and treated with water
crude material was purified by column chromatography (60 g sil-
ica gel, petroleum ether–ethyl acetate, 8:2) to afford compound
◦
(
◦
4 as a slightly yellow solid (1.43 g, 67%, mp 147.4–151 C). IR (ATR,
−
1
1
(
50 mL). The aqueous layer was extracted with Et O (3 × 50 mL).
cm ): 1729, 1700, 1665, 1618. H NMR (CDCl3) ı: 5.71 (s, 1H, H-4);
5.15 (t, 1H, J = 2.7 Hz, H-12ˇ); 2.91 (t, 1H, J = 9 Hz, H-17˛); 2.40–0.60
(m, 17H); 2.16 (s, 3H, CH3, H-21); 2.00 (s, 3H, CH3, Ac); 1.14 (s, 3H,
CH3); 0.72 (s, 3H, CH3). 13C NMR (CDCl3) ı: 208.5 (C O, C-20); 199.1
(C O, C-3); 170.2 (C C, C-5); 170.0 (C O, OAc); 124.1 (CH, C-4);
74.3 (CH, C-12); 55.3 (CH, C-17); 48.7 (CH);47.9 (CH); 46.4 (C); 38.0
(C); 35.7 (CH); 35.6 (CH2); 33.8 (CH2); 32.6 (CH2); 31.6 (CH2); 31.1
(CH3); 25.6 (CH2); 23.6 (CH2); 22.2 (CH2); 21.2 (CH3); 17.1 (CH3);
2
The combined organic layers were washed with sat. NaHCO3
(
1 × 50 mL) and then with brine (1 × 50 mL), dried over Na SO ,
2
4
filtered and concentrated under reduced pressure to afford com-
◦
pound 2 as a white solid (1.034 g, quant., mp 124–125.7 C) which
was used directly for the next step. IR (ATR, cm ): 1714–1699. 1
−
1
H
NMR (CDCl ) ı: 5.16 (t, 1H, J = 2.7 Hz, H-12ˇ); 2.93 (t, 1H, J = 9 Hz,
3
H-17˛); 2.63 (dd, 1H, J = 13.5–15.3 Hz); 2.30–1.05 (m, 19H); 2.11
+
(
(
s, 3H, CH , H-21); 2.00 (s, 3H, CH , Ac); 0.98 (3H, s, CH ); 0.70
13.7 (CH3). HRMS (ESI) m/z: C23H32NaO4 [M+Na] calcd. 395.2193,
3
3
3
1
3
20
3H, s, CH ). C NMR (CDCl ) ı: 212.6 (C O, C-3); 208.6 (C O, C-
found 395.2202. [˛] D: +217 (c 0.01, CHCl3).
3
3
2
0); 170.3 (C O, OAc); 74.3 (CH, C-12); 55.5 (CH); 49.5 (CH); 46.7
(
(
(
C); 43.8 (CH); 42.1 (CH ); 36.8 (CH ); 36.5 (CH ); 35.3 (CH); 34.7
2 2 2
2.6. 3,12˛-diacetoxy-pregna-3,5-diene-20-one (5)
CH); 34.3 (C); 31.1 (CH ); 26.3 (CH ); 25.9 (CH ); 25.7 (CH ); 23.6
3
2
2
2
CH ); 22.3 (CH ); 22.3 (CH ); 21.3 (CH ); 13.9 (CH ). HRMS (ESI)
2
2
3
3
3
A solution of compound 4 (2.80 g, 3.73 mmol) in Ac O (18 mL)
was treated with AcCl (30 mL) and heated under reflux for 1 h.
After cooling to r.t., the reaction mixture was concentrated under
2
+
20
m/z: C23H34NaO [M+Na] calcd. 397.2349, found 397.2357. [˛] D:
+
4
146 (c 0.01, CHCl ).
3

7
04
P. Geoffroy et al. / Steroids 76 (2011) 702–708
◦
−2
reduced pressure without heating (25 C, 10 mbar). The orange
material was purified by column chromatography (100 g silica gel,
petroleum ether–ethyl acetate, 9:1), to afford compound 5 as a
49.7 (CH); 48.5 (CH); 48.4 (C); 44.4 (CH2); 38.6 (CH2); 36.8 (C); 36.2
(CH2); 29.6 (CH); 29.1 (CH2); 25.2 (CH2); 24.0 (CH3); 23.0 (CH2);
22.3 (CH2); 21.4 (CH3); 21.2 (CH3); 13.5 (CH3). HRMS (ESI) m/z:
◦
−1
C25H39O5 [M+H]+ calcd. 419.2680, found 419.2745. [˛] D:+58 (c
20
white solid (2.69 g, 85%, mp 134.7–137.5 C). IR (ATR, cm ): 1745,
726, 1700, 1667. H NMR (CDCl ) ı: 5.69 (d, 1H, J = 1.8 Hz, H-4);
.39 (d, 1H, J = 3.6 Hz, H-6); 5.18 (t, 1H, J = 3, H-12ˇ); 2.94 (t, 1H,
1
1
5
0.01, CHCl3).
3
J = 8.7, H-17˛); 2.50–1.45 (m, 11H); 2.13 (s, 3H, CH , H-21); 2.11
2.9. 3ˇ,12˛-dihydroxy, cyclic 20-(ethylene acetal) pregn-5-ene
(6)
3
(
s, 3H, CH , Ac); 2.03 (s, 3H, CH , Ac); 1.45–0.80 (m, 4H); 0.98 (s,
3
3
13
3
1
1
4
H, CH3); 0.74 (3H, s, Me). C NMR (CDCl ) ı: 208.7 (C O, C-20);
3
70.4 (C O, OAc); 169.4 (C O, OAc); 147.1 (C C); 139.2 (C C);
32.4 (CH, C CH); 116.8 (CH, C CH); 74.3 (CH, C-12); 55.4 (CH);
A solution of compound 5b (330 mg, 1.15 mmol) in MeOH
(15 mL) was treated with KOH (83 mg, 1.48 mmol) and refluxed for
1 h. After cooling to r.t., water (20 mL) was added and the aqueous
layer was extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried over Na2SO4, filtered and concentrated under
reduced pressure to afford compound 6 as a white solid (266 mg,
9.5 (CH); 46.5 (C); 42.4 (CH); 34.4 (CH ); 33.7 (C); 31.5 (CH); 31.4
2
(
CH ); 31.1 (CH ); 25.7 (CH ); 24.6 (CH ); 23.6 (CH ); 22.9 (CH );
2 3 2 2 2 2
2
1.3 (CH ); 21.1 (CH ); 18.6 (CH ); 13.8 (CH ). HRMS (ESI) m/z:
3 3 3 3
+
20
C25H34NaO5 [M+Na] calcd. 437.2298, found 437.2302. [˛] D: +2
c 0.01, CHCl ).
◦
(
85%, mp 133.0–135.2 C) which was used directly for the next step.
3
IR (ATR, cm ): 3460, 1733. 1H NMR (C D ) ı: 5.34 (m, 1H, H-6);
−
1
6
6
4
.01 (t, 1H, J = 3 Hz, H-12ˇ); 3.55–3.25 (m, 5H, OCH + H-3˛); 2.37
2
2
.7. 3,12˛-diacetoxy, cyclic 20-(ethylene
(t, 1H, J = 9.96 Hz, H-17˛); 2.30–2.20 (m, 3H); 2.05–0.80 (m, 16H);
acetal)-pregna-3,5-diene (5a)
13
1
.021 (s, 3H, CH , H-21); 0.92 (s, 3H, CH ); 0.87 (s, 3H, CH ). C NMR
3 3 3
(
(
4
(
C D ) ı: 140.6 (C C, C-5); 121.6 (C CH, C-6); 112.2 (C, C-20); 72.7
6 6
To a solution of compound 5 (635 mg, 1.53 mmol) in toluene
CH, C-12); 71.7 (CH, C-3); 64.0 (OCH ); 63.7 (OCH ); 49.7 (CH);
2 2
(
25 mL), were added ethylene glycol (1.10 mL, 20.03 mmol) and
PPTS (catalytic amount). The reaction mixture was refluxed
Dean Stark trap) for 3.5 h. The solvent was evaporated under
8.0 (CH); 45.8 (C); 44.2 (CH); 42.3 (CH ); 37.0 (CH ); 36.1 (C); 31.6
2 2
CH); 31.3 (CH ); 31.2 (CH ); 27.6 (CH ); 23.8 (CH ); 23.1 (CH );
2 2 2 3 2
(
2
[
2.9 (CH ); 19.2 (CH ); 13.9 (CH ). HRMS (ESI) m/z: C23H36NaO4
2 3 3
reduced pressure and the residue dissolved in CH Cl2 (20 mL) was
2
M+Na]+ calcd. 399.2506, found 399.2518, [˛] D: −25 (c 0.0075,
20
washed with water (2 × 20 mL). The combined aqueous layers were
CHCl ).
3
extracted with CH Cl (2 × 20 mL). The combined organic layers
2
2
were washed with sat. NaHCO3 (1 × 20 mL), dried over Na SO , fil-
2
4
2
.10. 3ˇ-acetoxy,12˛-hydroxy, cyclic 20-(ethylene acetal)
tered and concentrated under reduced pressure. The crude material
was purified by column chromatography (30 g silica gel, petroleum
ether–ethyl acetate, 9:1) to afford compound 5a as a yellow solid
pregn-5-ene (7)
To a solution of compound 6 (564 mg, 1.51 mmol) in CH Cl2
◦
−1
1
2
(
(
700 mg, quant., mp 68–69 C). IR (ATR, cm ): 1733–1680. H NMR
(25 mL), were added Ac O (0.17 mL, 1.81 mmol), pyridine (0.24 mL,
2
CDCl ) ı: 5.69 (s, 1H, H-6); 5.40 (d, 1H, J = 3.0 Hz, H-4); 5.14 (t, 1H,
3
3
.02 mmol) and DMAP (catalytic amount). The reaction mixture
J = 2.4 Hz, H-12ˇ); 4.00–3.80 (m, 4H, OCH ); 2.50–1.90 (m, 4H); 2.13
2
was stirred at r.t. for 3 h and treated with water (20 mL). The
(
s, 3H, CH , Ac); 2.04 (s, 3H, CH , Ac); 1.90–1.40 (m, 10H); 1.40–0.90
3
3
aqueous layer was extracted with CH Cl2 (3 × 20 mL). The com-
2
(
m, 2H); 1.22 (s, 3H, CH , H-21); 0.99 (s, 3H, CH ); 0.88 (s, 3H, CH ).
3 3 3
bined organic layers were washed with 10% HCl (1 × 20 mL), with
sat. NaHCO3 (1 × 20 mL), dried over Na SO , filtered and concen-
1
3
C NMR (CDCl ) ı: 170.6 (C O, OAc); 169.4 (C O, OAc); 147.0
3
2
4
(
7
4
(
2
C
C); 139.3 (C C); 123.7 (C CH); 116.7 (C CH); 111.4 (C, C-2);
trated under reduced pressure. The crude material was purified
by column chromatography (30 g silica gel, petroleum ether–ethyl
acetate, 9:1) to afford compound 7 as a white solid (505 mg, 80%,
5.3 (CH, C-12); 64.9 (OCH ); 63.3 (OCH ); 49.7 (CH); 49.2 (CH);
2
2
4.3 (C, 13-C); 42.5 (CH); 34.4 (CH ); 33.7 (10-C); 31.4 (CH ); 31.0
2
2
CH); 25.4 (CH ); 24.7 (CH ); 24.0 (CH); 23.1 (CH ); 22.3 (CH );
2 2 2 2
mp 158.8–160.6 C). IR (ATR, cm ): 3417, 1733. 1H NMR (C D )
◦
−1
6
6
1.4 (CH ); 21.1 (CH ); 18.6 (CH ); 13.5 (CH ). HRMS (ESI) m/z:
3 3 3 3
ı: 5.40–5.33 (m, 1H, H-6); 4.81 (tt, 1H, J = 4.8–11.3 Hz, H-3˛); 4.01
t, 1H, J = 2.4 Hz, H-12ˇ); 3.48 (s, 4H, OCH ); 2.60–2.30 (m, 3H);
+
20
C27H38NaO [M+Na] calcd. 481.2561, found 481.2569. [˛] D: +61
6
(
2
0
2
(
c 0.02, MeOH).
.00–0.80 (m, 16H); 1.75 (s, 3H, CH , Ac); 1.22 (s, 3H, CH , H-21);
3
3
13
.89 (s, 3H, CH ); 0.86 (s, 3H, CH ). C NMR (C D ) ı: 169.3 (C O,
3
3
6
6
2
.8. 3ˇ hydroxy, 12˛-acetoxy, cyclic 20-(ethylene acetal)
OAc); 139.5 (C C, C-5); 122.5 (C CH, C-6); 111.9 (C, C-20); 73.6
(CH, C-12); 72.2 (CH, C-3); 64.0 (OCH ); 63.2 (OCH ); 49.6 (CH);
pregn-5-ene (5b)
2
2
4
7.8 (CH); 45.8 (C, 13-C); 43.9 (CH); 38.3 (CH ); 36.7 (CH ); 36.1
2 2
To a suspension of NaBH4 (860 mg, 22.7 mmol) in a mixture of
MeOH (6 mL) and THF (6 mL), was added a solution of compound
(C, 10-C); 31.5 (CH ); 31.2 (CH); 27.8 (CH ); 23.6 (CH ); 23.1 (CH );
2 2 3 2
22.7 (CH ); 20.7 (CH ); 18.8 (CH ); 13.8 (CH ). HRMS (ESI) m/z:
2
3
3
3
+
20
5
a (540 mg, 1.18 mmol) in THF (5 mL). The reaction mixture was
stirred for 1.5 h at r.t. and treated with 10% HCl until neutral pH.
CH Cl (15 mL) was added and the layers were separated. The aque-
C25H38NaO5 [M+Na] calcd. 441.2611, found 441.2608, [˛] D: −31
(c 0.006, CHCl ).
3
2
2
ous layer was extracted with CH Cl2 (3 × 15 mL). The combined
2.11. 3ˇ-acetoxy,12-keto, cyclic 20-(ethylene acetal)
pregn-5-ene (8)
2
organic phase were dried over Na SO , filtered and concentrated
2
4
under reduced pressure. The crude material was purified by column
chromatography (30 g silica gel, petroleum ether–ethyl acetate,
To a solution of compound 7 (143 mg, 0.34 mmol) in CH Cl
2
2
◦
7
1
1
4
:3), to afford compound 5b as a white solid (333 mg, 70%, mp
(3 mL) at 0 C, was added the Dess Martin reagent (174 mg,
0.41 mmol). The reaction mixture was stirred for 1 h at r.t., then
was treated with sat. Na S O (8 mL) and the reaction mixture was
◦
−1
1
66–167 C). IR (ATR, cm ): 3446, 1699; H NMR(CDCl ) ı: 5.55 (s,
3
H, H-6); 5.11 (t, 1H, J = 2.7 Hz, H-12ˇ); 4.24 (t, 1H, J = 2.4 Hz, H-3˛);
2
2
3
.00–3.70 (m, 4H, OCH ); 2.28 (t, 1H, J = 9.9 Hz, H-17˛); 2.10–1.90
stirred for 5 min. To the medium was added sat. NaHCO (8 mL) and
2
3
(
m, 3H); 2.04 (s, 3H, CH , Ac); 1.90–0.70 (m, 15H); 1.23 (s, 3H, CH ,
the reaction mixture was stirred for 5 min. The layers were sepa-
3
3
13
H-21); 1.20 (s, 3H, CH ); 0.88 (s, 3H, CH ). C NMR (CDCl ) ı: 170.5
rated and the aqueous layer was extracted with CH Cl (3 × 10 mL).
3
3
3
2
2
(
C
O, OAc); 147.1 (C C, C-5); 129.0 (C CH, C-6); 111.4 (C, C-20);
The combined organic layers were dried over Na SO , filtered and
2 4
7
5.2 (CH, C-3); 74.0 (CH, C-12); 67.8 (CH); 64.9 (OCH ); 63.3 (OCH );
concentrated under reduced pressure. The crude material was puri-
2
2

P. Geoffroy et al. / Steroids 76 (2011) 702–708
705
fied by column chromatography (5 g silica gel, cyclohexane–ethyl
J = 6.3 Hz, H-17˛); 3.35 (dd, 1H, J = 4.2–11.7 Hz, H-12˛); 2.40–2.15
acetate, 7:3) to afford compound 8 as a white solid (140 mg, 99%,
(m, 3H); 2.27 (s, 3H, CH , H-21); 2.10–0.80 (m, 16H); 2.03 (s, 3H,
3
mp 150–151 C). IR (ATR, cm ): 1722, 1700. 1H NMR (CDCl ) ı:
◦
−1
CH , Ac); 1.01 (s, 3H, CH , H-18); 0.92 (s, 3H, CH , H-19). C NMR
13
3
3 3 3
13
5
4
.40 (m, 1H, H-6); 4.58 (tt, 1H, J = 4.6–1.4 Hz, H-3˛); 4.05–3.65 (m,
(CDCl ) ı: C NMR (CDCl ): 218.0 (C O, C-20); 170.6 (C O, OAc);
3 3
H, OCH ); 2.80–2.55 (m, 2H); 2.45–1.95 (m, 4H); 2.3 (s, 3H, CH ,
137.8 (C C, C-5); 123.1 (C CH, C-6); 85.5 (C, C-14); 73.6 (CH, C-12);
73.4 (CH, C-3); 56.9 (CH, C-17); 55.0 (C, C-13); 43.3 (CH, C-9); 37.8
(CH , C-1); 37.0 (CH , C-4); 36.8 (C, C-10); 35.6 (CH , C-21); 34.5
2
3
Ac); 1.95–1.10 (m, 12H); 1.25 (s, 3H, CH , H-21); 1.15 (s, 3H, CH );
3
3
1
3
1
.12 (s, 3H, CH ). C NMR (CDCl ) ı: 214.0 (C O, C-12); 170.4
3 3
2
2
3
(
C
O, OAc); 139.4 (C C, C-5); 122.3 (C CH, C-6); 111.2 (C, C-20);
(CH , C-15); 33.1 (CH, C-8); 29.9 (CH , C-11); 27.6 (CH , C-2); 27.
2
2
2
7
5
3.5 (CH, C-3); 65.5 (OCH ); 62.9 (OCH ); 58.3 (CH); 56.6 (C, C-13);
(CH , C-7); 24.4 (CH , C-16); 21.4 (CH , Ac); 19.3 (CH , C-19); 8.3
2 2 3 3
2
2
+
3.6 (CH); 49.1 (CH); 37.9 (CH ); 37.7 (CH ); 37.5 (C, C-10); 36.7
(CH , C-18). HRMS (ESI) m/z: C23H34NaO5 [M+Na] calcd. 413.2298,
2
2
3
20
(
CH ); 31.4 (CH); 31.3 (CH ); 27.5 (CH ); 4.4 (CH ); 24.0 (CH );
found 413.2308, [˛] D: +14 (c 0.01, CHCl ).
2
2
2
3
2
3
2
2.0 (CH ); 21.4 (CH ); 18.9 (CH ); 12.9 (CH ). HRMS (ESI) m/z:
2 3 3 3
+
20
C25H36NaO5 [M+Na] calcd. 439.2455, found 439.2496, [˛] D: +12
c 0.01, CHCl ).
2.16. 12-O-ˇ-tigloyl-3ˇ-acetoxy,
14ˇ-hydroxy-pregn-5-ene-20-one (13)
(
3
2.12. Synthesis of compounds 10, 11 and 12
To a solution of compound 12 (40 mg, 0.10 mmol) in CH Cl2
2
(5 mL), were added tigloyl chloride (0.12 mL, 1.09 mmol), pyridine
A solution of compound 8 (895 mg, 2.15 mmol) in CH Cl2
280 mL) was degassed with argon for 15 min and then was irradi-
(0.14 mL, 1.74 mmol) and DMAP (catalytic amount). The reaction
mixture was heated under reflux for 7 h and stirred for 15 h at
r.t. Water (10 mL) was added and the layers were separated. The
2
(
ated with a high pressure mercury lamp Philips HPK 125 for 15 min
in a quartz vessel. The solvent was then evaporated under reduced
pressure, to afford the crude seco aldehyde 9 (931 mg, 100%).
To a solution of crude seco aldehyde (931 mg, max. 2.15 mmol)
in THF (4.0 mL), was added a solution of AcOH/H O/CF COOH
aqueous layer was extracted with CH Cl2 (2 × 10 mL). The com-
2
bined organic layers were washed with 10% HCl (1 × 10 mL), with
sat. NaHCO3 (1 × 10 mL), dried over Na SO , filtered and concen-
2
4
trated under reduced pressure. The crude material was purified by
column chromatography (5 g silica gel, cyclohexane–ethyl acetate,
95:5) to afford compound 13 as a white solid (38 mg, 80%, mp
2
3
(
2/1/0.6, 20.0 mL). The reaction mixture was stirred 1.5 h at r.t.
The reaction mixture was then diluted with CH Cl2 (30 mL) and
2
◦
−1
1
washed with water (2 × 30 mL), with sat. NaHCO (3 × 30 mL), dried
70–72 C). IR (ATR, cm ): 3434, 1730, 1696, 1650; H NMR (CDCl )
3
3
over Na SO , filtered and concentrated under reduced pressure.
ı: 6.93 (dq, 1H, J = 1.5–7.2 Hz, H-tig); 5.44 (m, 1H, H-6); 4.65 (dd,
1H, J = 4.5–11.7 Hz, H-12˛); 4.65–4.55 (m, 1H, H-3˛); 4.29 (s, 1H,
2
4
The crude material was purified by flash column chromatography
(
30 g, silica gel, petroleum ether–ethyl acetate, 8:2–6:4) afford-
OH); 3.15 (m, 1H, H-17˛); 2.50–2.05 (m, 3H); 2.21 (s, 3H, CH , H-
3
◦
ing compound 10 (153 mg, 19%, mp 192–194 C), compound 11
(
1
21); 2.05–0.90 (m, 13H); 2.03 (s, 3H, CH , Ac); 1.89 (s, 3H, CH ,
3
3
◦
118 mg, 15%, mp 116–117 C) and compound 12 (210 mg, 25%, mp
H-tig); 1.84 (dd, 3H, CH , J = 0.9–6.3 Hz, H-tig); 1.07 (s, 3H, CH ,
3
3
◦
13
40–142 C).
H-18); 1.02 (s, 3H, CH , H-19). C NMR (CDCl ) ı: 217.0 (C O,
3 3
C-20); 170.5 (C O, OAc); 167.7 (C O, C-tig); 137.8 (C CH, C-tig);
123.0 (C CH, C-6); 85.7 (C, C-14); 75.9 (CH, C-3); 73.9 (CH, C-12);
2.13. 3ˇ-acetoxy,pregn-5-ene-12,20-dione (10)
5
7.2 (CH, C-17); 53.7 (C, C-13); 42.9 (CH, C-9); 37.8 (CH , C-1);
2
−1
IR (ATR, cm ): 1729, 1703. 1H NMR (CDCl ): 5.42–5.40 (m,
36.9 (CH , C-4); 36.9 (C, C-10); 35.6 (CH , C-21); 34.4 (CH , C-
3
2
3
2
1
H, H-6); 4.59 (tt, 1H, J = 4.6–11.4 Hz, H-3˛); 3.34 (t, 1H, J = 9.6 Hz,
15); 33.2 (CH, C-8); 27.6 (CH , C-2); 27.3 (CH , C-7); 26.0 (CH ,
2 2 2
H-17˛); 2.62 (t, 1H, J = 13.2 Hz, H-11); 2.50–2.00 (m, 4H); 2.26 (s,
C-11); 24.4 (CH , C-16); 21.4 (CH , Ac); 19.3 (CH , C-19); 14.5
2 3 3
3
3
H, CH , H-21); 2.03 (s, 3H, CH , Ac); 2.00–0.80 (m, 12H); 1.12 (s,
(CH , C-tig); 12.2 (CH , C-tig); 9.9 (CH , C-18). HRMS (ESI) m/z:
3 3 3
3
3
C28H40NaO6 [M+Na]+ calcd. 495.2717, found 495.2693, [˛] D: +5
20
H, CH ); 0,98 (s, 3H, CH ). 13C NMR (CDCl3): 213.0 (C O); 209.4
3
3
(
C
O); 170.2 (C O, OAc); 139.2 (C C, C-5); 121.9 (C CH, C-6); 73.1
(c 0.01, CHCl ).
3
(
CH, C-3); 57.6 (C, C-13); 57.4 (CH); 54.0 (CH); 527 (CH); 52.7 (CH);
3
2
7.6 (CH ); 37.4 (CH ); 37.2 (C, C-10); 36.4 (CH ); 31.1 (2CH + CH );
2.17. 12-O-ˇ-tigloyl-3ˇ, 14ˇ-dihydroxy-pregn-5-ene-20-one
(Hoodigonenin A)
2
2
2
2
7.3 (CH ); 24.0 (CH ); 22.4 (CH ); 21.2 (CH ); 18.7 (CH ); 13.2
2
2
2
3
3
2
0
(
CH ). [˛] D: +55 (c 0.009, CHCl ).
3
3
A solution of compound 13 (42 mg, 0.09 mmol) in MeOH (5 mL)
2.14. 3ˇ-acetoxy,12˛-hydroxy-12,14˛-cyclo-12,13-secopregna-
was treated with K CO3 (33 mg, 0.24 mmol). The reaction mixture
2
5,13(17)-diene-20-one
was stirred for 2 h at r.t. Water (10 mL) was added and the aque-
(
11)
ous layer was extracted with CH Cl2 (3 × 10 mL). The combined
2
organic layers were dried over Na SO , filtered and concentrated
2
4
IR (ATR, cm 1): 3430, 1729, 1666, 1608. 1H NMR (CDCl ): 5.36
−
under reduced pressure. The residue was purified by column chro-
matography (5 g silica gel, cyclohexane–ethyl acetate, 6:4) to afford
3
(
d, 1H, J = 4.8 Hz, H-6); 4.58 (tt, 1H, J = 4.8–11.4 Hz, H-3˛); 4.14 (dt,
◦
1
2
3
H, J = 8.2–9.7 Hz, H-12ˇ); 2.80–0.80 (m, 17H); 2.22 (s, 3H, CH , H-
1); 2.02 (s, 3H, CH , Ac); 1.96 (t, 3H, J = 2.1 Hz, CH , H-18); 1.04 (s,
H, CH , H-19). C NMR (CDCl ): 198.7 (C O, C-20); 170.5 (C O,
Hoodigogenin A as a white solid (26 mg, 69%, mp 151–153 C).
3
IR (ATR, cm ) 3535, 3471 1698, 1682, 1651 1H NMR (CDCl ) ı:
−
1
3
3
3
1
3
6.91 (dq, 1H, J = 1.6–7.2 Hz, H-tig); 5.40 (m, 1H, H-6); 4.63 (dd, 1H,
J = 4.4–12.0 Hz, H-12˛); 4.26 (s, 1H, OH); 3.51 (tt, 1H, J = 4.6–11.2 Hz,
H-3˛); 3.12 (m, 1H, H-17˛); 2.40–2.15 (m, 3H); 2.10 (s, 3H, CH3,
3
3
OAc); 153.7 (C C); 140.5 (C C); 137.9 (C C); 122.6 (C CH); 76.5
(
(
CH, C-12); 73.7 (CH, C-3); 65.7 (C, C-14); 48.3 (CH); 39.9 (CH); 37.9
CH ); 37.7 (CH ); 37.2 (C, C-10); 32.4 (CH ); 30.5 (CH); 30.3 (CH );
H-21); 2.10–0.90 (m, 14H); 1.88 (s, 3H, CH , H-tig); 1.83 (dd, 3H,
2
2
2
2
3
2
7.4 (CH ); 25.9 (CH ); 21.8 (CH ); 21.4 (CH ); 18.0 (CH ); 12.1
CH , J = 0.8–6.8 Hz, H-tig); 1.06 (s, 3H, CH , H-18); 0.99 (s, 3H,
2
2
2
2
3
3
3
3
0
13
(
CH ). [˛] D: −12 (c 0.006, CHCl ).
CH , H-19). C NMR (CDCl ) ı: 217.1 (C O, C-20); 167.7 (C O,
3
3
3
3
C-tig); 139.0 (C C, C-5); 137.8 (C C, C-tig); 128.7 (C CH, C-tig);
122.0 (C CH, C-6); 85.7 (C, C-14); 75.9 (CH, C-3); 71.5 (CH, C-
2.15. 3ˇ-acetoxy,12ˇ,14ˇ-dihydroxy pregn-5-ene-20-one (12)
1
2); 57.2 (CH, C-17); 53.8 (C, C-13); 43.1 (CH, C-9); 42.0 (CH2,
IR (ATR, cm 1): 3399, 1730, 1686; 1H NMR (CDCl ) ı: 5.42 (m,
−
C-4); 37.2 (CH , C-1); 36.9 (C, C-10); 35.8 (CH, C-8); 34.5 (CH ,
3
2
2
1
H, H-6); 4.65–4.50 (m, 1H, H-3˛); 4.37 (s, 1H OH); 3.61 (t, 1H,
C-15); 33.2 (CH , C-21); 31.4 (CH , C-2); 27.4 (CH , C-7); 26.1
3 2 2

7
06
P. Geoffroy et al. / Steroids 76 (2011) 702–708
3. Results and discussion
The synthesis started from the commercially available com-
pound 1. After a regioselective deprotection of the 3˛-acetoxy
group and oxidation of the resulting hydroxy group, a regioselective
˛-bromination of the diketo derivative 2 yielded stereospecifi-
cally the ˇ-bromoketo derivative 3. The structure of the latter was
confirmed by X-ray analysis, which clearly indicated the absolute
configuration for carbons 4 (ˇ-Br), 12 (˛-acetoxy) and 17 (ˇ-acetyl)
as well as the A–B fused cis ring junction (Fig. 2) [12]. A dehydro-
bromination reaction led to the ˛, ˇ-unsaturated keto derivative 4
[
13]. The latter was treated with acetic anhydride and acetyl chlo-
ride to give readily the dienol acetate 5 [14]. After protection of the
carbonyl group with ethyleneglycol, the dienol acetate was reduced
in the presence of NaBH4 [15] followed by a KOH promoted depro-
tection of the 12˛-acetate group, allowing the introduction of the
double bond in the B ring and yielding the unstable diol 6. A regios-
elective protection of the 3ˇ-hydroxyl group gave compound 7,
which was subjected to a Dess Martin periodane oxidation [16] to
afford the keto derivative 8 (Scheme 1).
Fig. 2. ORTEP drawing of bromo derivative 3 with thermal ellipsoids at the 30%
probability level.
(
CH , C-11); 24.4 (CH , C-16); 19.4 (CH , C-19); 14.5 (CH , C-tig);
2 2 3 3
1
2.2 (CH , C-tig); 9.9 (CH , C-18). HRMS (ESI) m/z: C26H38NaO5
3 3
+
20
[
M+Na] calcd. 453.2611, found 453.2576, [˛] D: +1.13 (c 0.006,
CHCl ).
3
AcO
AcO
O
AcO
O
O
a
b
8
3%
H
H
H
AcO
O
O
O
H
H
H
3
1
2
Br
67%
b+c)
c
(
O
OH
AcO
AcO
O
O
O
d
e
6
0%
85%
H
H
H
HO
AcO
6
5
4
O
O
O
OH
O
f
g
O
80%
99%
H
H
AcO
AcO
7
8
◦
◦
◦
Scheme 1. Reagents and reaction conditions: (a) i: K2CO3, MeOH, 25 C 1 h (83%, formation of compound 1a); ii: CrO3, acetone, 25 C, 1 h (quant.); (b): Br2, AcOH, 25 C, 1.5 h;
(
1
◦
◦
c): LiCl, DMF, reflux, 1 h (67% for the 2 steps); (d) AcCl, Ac2O, reflux 50 C, 1 h (85%); (e): i: ethylene glycol, toluene, reflux, 3 h (quant.); ii: NaBH4, MeOH/THF (1/1), 25 C,
◦ ◦ ◦
.5 h; iii: KOH, MeOH, reflux, 1 h (ii + iii: 60%); (f): Ac2O, pyridine, DMAP, CH2Cl2, 25 C, 2.5 h (80%); (g): Dess Martin reagent, CH2Cl2, 0 C–>25 C, 1 h (99%).
O
O
O
O
O
O
a
b
H
AcO
O
8
AcO
9
OH
O
OH
O
O
+
+
H
OH
1
0
11
12
AcO
AcO
AcO
◦
◦
Scheme 2. Reagents and reaction conditions: (a): hꢀ, CH2Cl2, 25 C, 30 min (quant.); (b) AcOH/H2O/TFA (2.5/1/0.6), THF, 25 C, 1.5 h [10 (19%), 11 (15%), 12 (25%)].

P. Geoffroy et al. / Steroids 76 (2011) 702–708
707
O
O
OH
O
O
O
O
O
a
b
OH
OH
OH
HoodigogeninA
Scheme 3. Reagents and reaction conditions: (a) tigloyl chloride, pyridine, DMAP, CH2Cl2, reflux, 7 h (80%); (b) K2CO3, MeOH, 25 C, 2 h (69%).
1
2
13
AcO
AcO
HO
◦
our method. Biological SAR studies with highly pure compounds
are currently underway.
Acknowledgements
Support for this work was provided by Université de Stras-
◦
bourg, CNRS and ANR (N 07-PCVI-0016). B.R. thanks Région Alsace
and CNRS for a research fellowship. The authors thank Dr. Jennifer
Wytko for her assistance in preparing this manuscript.
Fig. 3. ORTEP drawing of spiro derivative 11 with thermal ellipsoids at the 30%
probability level.
References
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[
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(
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Compound 8 was then suitable to undergo a Norrish type I
reaction [17]. However, the photochemical ring opening of preg-
nenolone derivatives was never reported in the literature. We were
pleased to see that the photolysis of compound 8, which was car-
ried out in a quartz apparatus with a 125 W high pressure mercury
lamp, led readily to the formation of aldehyde 9. The latter proved
to be instable; therefore the subsequent Prins reaction was directly
carried out on the crude mixture of the photolysis reaction. Under
these reactions conditions, three compounds were isolated: com-
pound 10 that resulted from a deprotection of the dioxolane 8,
the spiro derivative 11 and the desired compound 12, which was
isolated in 25% yield (Scheme 2) [18]. The structure of the spiro
derivative 11 was secured by X-ray analysis (Fig. 3) [19].
[
[7] van Heerden FR, Marthinus Horak R, Maharaj VJ, Vleggaar R, Senabe JV,
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[
[
8] Shukla YJ, Pawar RS, Ding Y, Li X-C, Ferreira D, Khan IA. Pregnane glycosides
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007;72:524–34.
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11] There is only one patent which describes the synthesis of digipurpurogenin II
3ˇ, 12ˇ, 14ˇ-trihydroxy derivative corresponding to Hoodigogenin A) which
Finally, the protection of the 12ˇ-hydroxy group with tigloyl
chloride in the presence of pyridine and DMAP afforded compound
2
[
[
1
3 [20]. Deprotection of the 3ˇ-acetate group gave Hoodigogenin
(
1
13
A, whose structure was confirmed by H and C NMR analysis [21]
and by X-ray analysis [22] (Scheme 3 and Fig. 4).
was isolated in 0.1% overall yield; see Ref. [5a].
12] CCDC-770179 contains the supplementary crystallographic data for bromo
derivative 3. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data request/cif.
[13] Just IG, Engel ChR. Steroids and related products. IX Introduction of type ꢁ11
-
4
. Conclusion
double bond. J Org Chem 1958;23:12–5.
[
14] Wendler NL, Reichstein T. 3␤,12␣-dioxy-5-cholen säure. Helv Chim Acta
948;31:1713–9.
[15] (a) Villoti R, Djerassi C, Ringold HL. Steroids. CXXIII. 19-nor-6-
methylandrostane derivatives. Am Chem Soc 1959;81:4566–
0;
b) Jiang X, Covey DF. Total synthesis of ent-cholesterol via a steroid C D-ring
side-chain synthon. J Org Chem 2002;67:4893–900.
To overcome the limited availability of Hoodigogenin A, we have
1
disclosed an original synthetic route that affords the latter in 3%
overall yield [23]. This synthesis represents a very interesting alter-
native to the extraction methods for which the yields are 100 times
lower. Moreover, analogs of Hoodigogenin A are now accessible by
J
7
(

7
08
P. Geoffroy et al. / Steroids 76 (2011) 702–708
[
[
16] Dess DB, Martin JC. Readily accessible 12-I-5 oxidant for the conversion
of primary and secondary alcohols to aldehydes and ketones. J Org Chem
[19] CCDC-817804 contains the supplementary crystallographic data for the spiro-
derivative 11. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data request/cif.
[20] Van Heerden et al. (see Ref. [5a]) reported the NMR data for isoramanone
(3ˇ, 12ˇ, 14ˇ-trihydroxy-pregn-5-en-20-one; 17-H˛: 3.598 ppm) and for
ramanone (17-Hˇ: 3.339 ppm). Compound 12 corresponds to the 3ˇ-acetoxy
derivative of isoramanone (17-H: 3.61 ppm): thus, it is reasonable to postulate
that compound 12 and isoramanone present the same configuration at posi-
tion 17, that is H˛. For compound 13, the chemical shift for H-17 is 3.15 ppm
and for Hoodigogenin, H˛-17 is 3.12 ppm (configuration secured by X-ray anal-
ysis): thus, it is reasonable to postulate that compound 13 present the same
configuration as Hoodigogenin, that is H˛-17.
1
983;48:4155–6.
17] (a) Welzel P, Janssen B, Duddeck H. 14ˇ-Hydroxy steroids II. Prins reaction of
lumihecogenin acetate. Liebigs Ann Chem 1981:546–64;
(
b) Welzel P, Stein H. 14ˇ-Hydroxy steroids III. Synthesis of digoxigenin from
deoxycholic acid. Tetrahedron Lett 1981;22:3385–8;
c) Milkova T, Stein H, Ponty A, Boettger D, Welzel P. 14ˇ-Hydroxy steroids VI.
Synthesis of digitoxigenin. Tetrahedron Lett 1982;23:413–4;
d) Welzel P, Moschner R, Ponty A, Pommerenk U, Sengewein H. 14␤-
(
(
Hydroxysteroids. V. Synthesis of digipurpurogenin I and II derivatives. Liebigs
Ann Chem 1982:564–78;
1
13
(
e) Welzel P, Stein H, Milkova T. 14ˇ-Hydroxy steroids VII. Synthesis of
digoxigenin and digitoxigenin from deoxycholic acid. Liebigs Ann Chem
982:2119–34;
f) LaCour TG, Guo C, Bhandaru S, Fuchs PL, Boyd MR. Interphylal product
[21] The H and C NMR spectra of Hoodigogenin A were fully described in Refs.
[7] and [9] and our data are in full agreement with the reported data.
1
(
[22] CCDC-795873 contains the supplementary crystallographic data for Hoodi-
gogenin A. These data can be obtained free of charge from The Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data request/cif.
[23] Geoffroy P, Ressault B, Miesch M. Procédé de synthèse de stéroides. French
splicing: the first total syntheses of cephalostatin 1, the north hemisphere of
Ritterazine G, and the highly active hybrid analog, Ritterostatin GN1N. J Am
Chem Soc 1998;120:692–707.
◦
Patent Application N 10/03194, 29/07/2010.
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18] Geoffroy P, Ressault B, Marchioni E, Miesch M. Norrish-Prins reaction as a key
5,6
step in the synthesis of 14␤-hydroxy-5H␣ (or 5H␤ or ꢁ )-pregnane deriva-
tives, Steroids, submitted.