Selective ring-opening carbonylation of epoxy-steroids

Article abstract of DOI:10.1016/j.steroids.2004.02.003

Ring-opening alkoxycarbonylation of epoxy-steroids has been carried out with a Co₂(CO)₈/3-hydroxypyridine catalytic system. High chemo- and regioselectivities were obtained under the reaction conditions applied. Structural analysis of the products proved their high stereochemical purity in each case, accompanied by inversion of the original configuration. No carbonylation took place for sterically hindered steranic epoxides.

Full text of DOI:10.1016/j.steroids.2004.02.003

Steroids 69 (2004) 271–277
Selective ring-opening carbonylation of epoxy-steroidsଝ
a
b
c
a,∗
"
Attila Balázs , Csilla Benedek , Gábor Szalontai , Szilárd Torös
a
Department of Organic Chemistry, University of Veszprém, H-8201 Veszprém, P.O. Box 158, Hungary
b
Chemical Institute of the Hungarian Customs and Finance Guard, H-1163 Budapest, 20-22 Ho´´sök Fasora, Hungary
c
University of Veszprém, NMR Laboratory, H-8201 Veszprém, P.O. Box 158, Hungary
Received 8 April 2003; received in revised form 9 February 2004; accepted 17 February 2004
Abstract
Ring-opening alkoxycarbonylation of epoxy-steroids has been carried out with a Co2(CO)8/3-hydroxypyridine catalytic system. High
chemo- and regioselectivities were obtained under the reaction conditions applied. Structural analysis of the products proved their high
stereochemical purity in each case, accompanied by inversion of the original configuration. No carbonylation took place for sterically
hindered steranic epoxides.
© 2004 Elsevier Inc. All rights reserved.
Keywords: Epoxy-steroid; Cobalt; Homogeneous catalysis; Alkoxycarbonylation; Asymmetric ring-opening
1. Introduction
with BF3·Et2O was tested with good results in transforma-
tion of simple and functionalized epoxides to ␤-lactones
[12]. It was Drent who reported first selective catalytic
carbonylation of epoxides using Co2(CO)8 as catalyst with
3-hydroxypyridine as co-catalyst [13]. Based on this report
and their own previous results, Jacobsen’s team transformed
a series of terminal, enantiomerically pure epoxides regio-
and enantioselectively into ␤-hydroxy esters [6]. Consider-
ing the reaction above as a starting point, we investigated
its application to non-terminal steroidal epoxides (Fig. 1) as
rather complex molecules of obvious biological importance.
Our goal was also to screen the optimal reaction conditions,
catalyst composition, and substrate-selectivity interdepen-
dence, as well as the influence of the nucleophilic reagent.
The new compounds prepared were then to be isolated and
fully characterized, especially from the point of view of
stereochemistry.
Stereospecific nucleophilic substitution reactions of chi-
ral carbon atoms represent a challenging, fast developing
area of asymmetric catalysis. Such transformations have
already been applied in successful desymmetrization of
meso-substrates, kinetic resolution of racemic compounds
and stereospecific reactions of enantiopure compounds ([1]
and references therein).
The development of asymmetric ring-opening (ARO) re-
actions of epoxides has advanced rapidly since the discovery
of Jacobsen’s metal–salen catalyst complexes. Applied suc-
cessfully in asymmetric epoxidation, these catalysts have
proven to be efficient in ring-opening reactions as well ([1]
and references therein). Available either by classical meth-
ods [2] or by transition metal-catalyzed oxidation [3,4],
epoxides are valuable sources leading to a wide range of
products, such as ␤-amino alcohols [5], ␤-hydroxy esters
[6], ␣-aryloxy alcohols [7], ␤-hydroxy mercaptans [8], and
diols [9].
2. Experimental
As far as ring-opening carbonylation is concerned, some
authors found that alkynyl oxiranes can be carbomethoxy-
lated in presence of palladium catalysts to yield axially
chiral 5-hydroxy-penta-2,3-dienoates [10,11]. Also, a tri-
dentate ligand-containing (P,P,N)-Co(CO)4 catalyst together
Tetrahydrofuran (THF) was dried over sodium and dis-
tilled under argon in presence of benzophenone prior to
use. Anhydrous alcohols and solvents were purchased from
Sigma-Aldrich. The starting steroids were received from the
Chemical Works of Gedeon Richter Ltd. Crude Co2(CO)8
was prepared at our site by a well-known method [14]. After
recrystallization from dichloromethane and pentane its pu-
rity was checked by IR spectroscopy [15]. 1H and 13C NMR
spectra were recorded in CDCl3 on a Varian Unity 300
ଝ
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.steroids.2004.02.003
∗
Corresponding author. Tel.: +36-88-442-022; fax: +36-88-427-492.
E-mail address: toros@almos.vein.hu (S. To"rös).
0039-128X/$ – see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2004.02.003

272
A. Bala´zs et al. / Steroids 69 (2004) 271–277
O
O
CH3
CH3
CH3
CH3
O
O
H
H
1
2
O
CH3
CH3
O
H
CH3
CH3
H
H
HO
O
H
3
4
H3C
H3C
CH3
O
O
CH3
O
O
CH3
CH3
H
H
HO
AcO
5
6
Fig. 1. Structures of the starting steroids.
spectrometer (Palo Alto, CA, USA) at 300 and 75.5 MHz,
respectively. Proton chemical shifts were referenced to resid-
ual CHCl3 (δ = 7.24), and 13C NMR chemical shifts were
20 mL stainless steel autoclave containing the epoxy-steroid
1 (1 mmol, 288 mg), Co2(CO)8 (0.05 mmol, 17.4 mg), and
0.3 mmol (19.2 mg) 3-hydroxypyridine. The autoclave was
pressurized to 100 atm with CO, placed into an oil bath,
heated to 75 ◦C, and stirred magnetically for 72 h at this tem-
perature. The reaction was followed by GLC and TLC. Chro-
matography on neutral alumina with ethyl acetate/hexane
(1:1), ethyl acetate/hexane (3:1), and ethyl acetate yielded
the desired compound, ethyl ester 7b (307 mg, 85%) which
was then characterized by GC–MS and various NMR tech-
niques.
1
referenced to the solvent CDCl3 (δ = 77.0). H and 13C
assignments were based on DEPT, COSY, CYCLENOE,
and NOESY experiments. GLC analyses were performed
on a Hewlett-Packard 5917 gas chromatograph fitted with
a 10 m HP-1 column. GC–MS measurements were run on
a Hewlett Packard 5971A GC-MSD with a 25 m HP-1 col-
umn. TLC analyses were performed on silica gel TLC-cards
with fluorescent indicator at 254 nm (0.2 mm, Fluka), the
chromatograms were developed in an iodine chamber. FT-IR
spectra were obtained with Avatar 330 Thermo Nicolet
spectrophotometer in KBr pellets. All manipulations were
performed under argon using standard inert techniques.
2.2. Characterization of the products
2.2.1. Methyl 3α-hydroxy-17-keto-5α-androstan-
2β-carboxylate (7a)
White powder (isolated yield: 132 mg, 38%), mp =
2.1. Preparation procedure
112 ◦C; [␣]D = 58 (c = 1 in chloroform); TLC: Rf
=
In a typical procedure a solution of 1.5 mL of THF and
20 mmol (1.1 mL) ethanol was transferred under argon into a
0.38 [ethyl acetate/hexane (2:3) as eluting solvent]; 1H
NMR (δ, CDCl3): 0.65 (s, 3H, C19H3), 0.80 (s, 3H,

A. Bala´zs et al. / Steroids 69 (2004) 271–277
273
C18H3), 0.68−2.43 (m, 20H, ring protons), 2.62 (m,
2.2.5. Isopropyl 2β-hydroxy-17-keto-5α-androstan-
3α-carboxylate (10c)
1H, C2H), 3.63 (s, 3H, –OCH3), 4.38 (m, 1H, C3H);
13C NMR (δ, CDCl3): 11.87, 13.77, 20.20, 21.67,
27.75, 30.66, 31.47, 33.31, 34.74, 35.13, 35.77, 36.45,
39.05, 44.64, 47.75, 51.33, 51.47, 54.6, 65.89, 175.13,
221.35; MS (m/z/relative intensity): 348/64 [M+], 330/23,
271/25, 218/63, 147/40, 105/100; IR (KBr, ν [cm−1]):
White powder (isolated yield: 315 mg, 84%), mp =
174 ◦C; [␣]D = 112 (c = 1 in chloroform); TLC: Rf = 0.6
[ethyl acetate/hexane (2:3) as eluting solvent]; 1H NMR (δ,
CDCl3): 0.67 (m, 1H,), 0.82 (s, 3H, C18H3), 1.01 (s, 3H,
C19H3), 0.78–2.44 (m, ring protons), 1.19 (d, J = 6.1 Hz,
3H, –CH(CH3)2), 1.22 (d, J = 6.1 Hz, 3H, –CH(CH3)2),
2.65 (m, 1H, C3H), 4.39 (q, 1H, J = 3.1 Hz, C2H), 5.0
(septet, 1H, J = 6.1 Hz); 13C NMR (δ, CDCl3): 13.8, 14.64,
20.09, 21.66, 21.71, 21.79, 26.05, 27.99, 30.61, 31.48,
34.38, 35.72, 35.77, 43.34, 42.54, 46.76, 47.78, 51.29,
55.26, 67.54, 67.94, 173.25, 221.25; MS (m/z/relative in-
tensity): 376/1 [M+], 335/3, 316/8, 231/12, 213/10, 173/11,
149/15, 121/22, 107/34, 93/48, 67/70, 55/100; IR (KBr, ν
=
1736 (C O).
2.2.2. Ethyl 3α-hydroxy-17-keto-5α-androstan-
2β-carboxylate (7b)
White powder (isolated yield: 307 mg, 85%), mp =
119 ◦C; [␣]D = 60 (c = 1 in chloroform); TLC: Rf = 0.42
[ethyl acetate/hexane (2:3) as eluting solvent]; 1H NMR
(δ, CDCl3): 0.68 (s, 3H, C19H3), 0.89 (s, 3H, C18H3),
0.94–2.15 (m, 20H, ring protons), 1.24 (t, J = 7 Hz, 3H,
–OCH2CH3), 2.6 (m, 1H, C2H), 4.14 (q, J = 7 Hz, 2H,
–OCH2CH3), 4.42 (m, 1H, C3H); 13C NMR (δ, CDCl3):
12.06, 13.8, 14.1, 20.16, 21.68, 27.75, 30.66, 31.48, 33.36,
34.75, 35.14, 35.77, 36.5, 39.06, 44.83, 47.72, 51.36, 54.61,
60.34, 65.99, 174.58, 221.27; MS (m/z/relative intensity):
362/26 [M+], 344/30, 270/12, 218/33, 147/30, 105/100; IR
[cm−1]): 1722, 1736 (C O).
=
2.2.6. Methyl 17α-hydroxyandrostane-16α-
carboxylate (13a)
White powder (isolated yield: 94 mg, 28%), mp = 109 ◦C;
[␣]D < 1 (c = 1 in chloroform); TLC: Rf = 0.45 [ethyl ac-
etate/hexane (1:4) as eluting solvent]; 1H NMR (δ, CDCl3):
0.66 (s, 3H, C18H3), 0.76 (s, 3H, C19H3), 0.6–1.88 (m, 22H,
ring protons), 2.01 (m, 1H, C15H), 2.68 (m, 1H, C16H), 3.68
(s, 3H, –OCH3), 3.98 (d, 1H, J = 1.4 Hz, C17H); 13C NMR
(δ, CDCl3): 12.18, 16.84, 20.07, 22.13, 26.71, 28.88, 28.96,
29.25, 31.74, 32.31, 35.29, 36.23, 38.67, 45.08, 46.89, 49.64,
51.83, 52.57, 54.25, 82.8, 175.43; MS (m/z/relative inten-
sity): 334/6 [M+], 306/32, 288/19, 274/34, 256/25, 233/100,
217/48, 149/53, 109/54, 95/51; IR (KBr, ν [cm−1]): 1736
(KBr, ν [cm−1]): 1701, 1733 (C O).
=
2.2.3. Isopropyl 3α-hydroxy-17-keto-5α-androstan-
2β-carboxylate (7c)
White powder (isolated yield: 330 mg, 88%), mp =
183–187 ◦C; [␣]D = 62 (c = 1 in chloroform); TLC: Rf =
0.47 [ethyl acetate/hexane (2:3) as eluting solvent]; 1H NMR
(δ, CDCl3): 0.69 (s, 3H, C19H3), 0.82 (s, 3H, C18H3), 1.20
(d, J = 6.1 Hz, 3H, –CH(CH3)2), 1.24 (d, J = 6.1 Hz, 3H,
–CH(CH3)2), 0.91–2.45 (m, 20H, ring protons), 2.58 (m, 1H,
J1 = 8.7 Hz, J2 = 2.7 Hz, C2H), 4.39 (q, 1H, J = 2.7 Hz,
C3H), 5.0 (septet, 1H, J = 6.1 Hz, –COCH(CH3)2); 13C
NMR (δ, CDCl3): 12.19, 13.81, 20.11, 21.65, 21.68, 21.75,
27.75, 30.67, 31.49, 33.34, 34.75, 35.1, 35.78, 36.53, 39.04,
45.03, 47.76, 51.36, 54.61, 66.03, 67.70, 174.04, 221.34;
MS (m/z/relative intensity): 376/32 [M+], 358/18, 333/21,
315/100, 218/33, 147/30, 105/10; IR (KBr, ν [cm−1]):
=
(C O).
2.2.7. Ethyl 17α-hydroxyandrostane-16α-
carboxylate (13b)
White powder (isolated yield: 285 mg, 82%), mp =
113–115 ◦C; [␣]D < 1 (c = 1 in chloroform); TLC:
Rf = 0.46 [ethyl acetate/hexane (1:4) as eluting solvent];
1H NMR (δ, CDCl3): 0.66 (s, 3H, C18H3), 0.76 (s, 3H,
C19H3), 0.66–1.75 (m, 22H, ring protons), 1.21 (t, 3H,
J = 7.1 Hz, –OCH2CH3), 2.01 (m, 1H, C15H), 2.67 (dt,
1H, J1 = 8.7 Hz, J2 = 1.5 Hz, C16H), 3.98 (d, 1H, J =
1.5 Hz, C17H), 4.13 (q, 2H, J = 7.1 Hz, –OCH2CH3); 13C
NMR (δ, CDCl3): 12.18, 14.22, 16.82, 20.09, 22.13, 26.72,
28.89, 28.96, 29.25, 31.76, 35.28, 35.30, 36.27, 38.67,
45.06, 46.88, 49.63, 52.79, 54.20, 60.54, 82.78, 174.98;
MS (m/z/relative intensity): 348/1 [M+], 274/16, 256/35,
233/100, 217/31, 149/21, 109/14, 95/11; IR (KBr, ν [cm−1]):
=
1722 (C O).
2.2.4. Ethyl 2β-hydroxy-17-keto-5α-androstan-3α-
carboxylate (10b)
White powder (isolated yield: 288 mg, 80%), mp =
122–125 ◦C; [␣]D = 115 (c = 1 in chloroform); TLC: Rf =
0.54 [ethyl acetate/hexane (2:3) as eluting solvent]; 1H
NMR (δ, CDCl3): 0.83 (s, 3H, C18H3), 0.99 (s, 3H, C19H3),
0.94–2.47 (m, 20H, ring protons), 1.24 (t, J = 7 Hz, 3H,
–OCH2CH3), 2.6 (m, 1H, C2H), 4.14 (q, J = 7 Hz, 2H,
–OCH2CH3), 4.42 (m, 1H, C3H); 13C NMR (δ, CDCl3):
13.8, 14.18, 14.62, 20.09, 21.66, 26.0, 27.94, 30.55, 31.48,
34.36, 35.72, 35.76, 42.33, 42.52, 46.66, 47.78, 51.31,
55.18, 60.35, 67.91, 173.78, 221.27; MS (m/z/relative inten-
sity): 362/2 [M+], 345/5, 270/10, 231/20, 213/10, 147/18,
121/25, 107/65, 79/75, 67/80, 55/100; IR (KBr, ν [cm−1]):
=
1729 (C O).
2.2.8. Isopropyl 17α-hydroxyandrostane-16α-
carboxylate (13c)
White powder (isolated yield: 304 mg, 84%), mp =
77–83 ◦C; [␣]D < 1 (c = 1 in chloroform); TLC: Rf = 0.46
[ethyl acetate/hexane (1:4) as eluting solvent]; 1H NMR
(δ, CDCl3): 0.66 (s, 3H, C18H3), 0.77 (s, 3H, C19H3),
0.66–1.7 (m, 22H, ring protons), 1.2 (d, 6H, J = 6.4 Hz,
=
1726, 1734 (C O).

274
A. Bala´zs et al. / Steroids 69 (2004) 271–277
–CH(CH3)2), 2.01 (m, 1H, C15H), 2.66 (dt, J1 = 8.5 Hz,
J2 = 1.4 Hz, 1H, C16H), 3.98 (d, J = 1.4 Hz, 1H, C17H),
5.00 (septet, 1H, J = 6.4 Hz, –OCH(CH3)2); 13C NMR (δ,
CDCl3): 12.18, 16.77, 20.09, 21.76, 22.13, 26.72, 28.89,
28.97, 29.22, 31.74, 32.31, 35.28, 35.31, 36.29, 38.67,
45.05, 46.89, 49.61, 53.01 54.22, 67.69, 82.78, 174.45; MS
(m/z/relative intensity): 362/1 [M+], 334/4, 301/10, 274/14,
256/14, 233/100, 217/33, 149/20, 109/20, 95/13; IR (KBr,
2.2.14. 16 (or 17)-Isopropyloxy-17 (or 16)-
hydroxyandrostane (14c)
MS (m/z/relative intensity): 334/5, 306/40, 274/45,
256/30, 233/100, 217/32, 149/14, 109/5, 55/4.
3. Results and discussion
ν [cm−1]): 1724 (C O).
=
3.1. Alkoxycarbonylation of 2α,3α- and
2β,3β-epoxy-5α-androstan-17-ones (1 and 2)
2.2.9. 2 (or 3)-Hydroxy-3 (or 2)-methyoxy-17-
ketoandrostane (9a)
MS (m/z/relative intensity): 320/5, 270/5, 230/12, 215/5,
108/22, 97/90, 84/100, 67/50, 55/66.
Screening for the optimal reaction conditions, catalyst
composition, and influence of nucleophilic reagent was car-
ried out using epoxide 1 as a model substrate. The progress
of the reaction (Fig. 2) was monitored by GC, GC–MS, and
TLC.
2.2.10. 2 (or 3)-Hydroxy-3 (or 2)-ethyoxy-17-
ketoandrostane (9b)
MS (m/z/relative intensity): 334/25, 270/8, 218/100,
190/80, 161/92, 147/50, 105/100, 91/85, 55/50.
The conditions described by Jacobsen for simple oxiranes
with methanol resulted in only moderate conversion and low
yield (Table 1). As side-reactions, water elimination from
the substrate and direct nucleophilic attack of the alcohol
on the substrate were detected, this latter resulting in ether
9a–c formation which were identified by GC–MS analysis
of the reaction mixture. Compound 9a was further charac-
terized also by 1H NMR from chromatographically enriched
samples in mixture with 7a.
2.2.11. 2 (or 3)-Hydroxy-3 (or 2)-isopropyloxy-17-
ketoandrostane (9c)
MS (m/z/relative intensity): 348/6, 326/8, 281/14, 270/16,
231/18, 214/5, 161/10, 107/60, 91/45, 55/100.
Both reaction time and temperature were increased to
reach an almost complete conversion (Table 1); however, hy-
droxy ester yield remained still unsatisfactory. In EtOH bet-
ter results were obtained. While further temperature increase
shifts the product composition towards undesired side-reac-
tions, higher pressure proved to be beneficial. Since product
yields were only moderate, we changed the co-catalyst/Co
molar ratio, which was determinant for our reaction.
The effect of nucleophilic reagent was studied as well
(Table 2). At similar conversions the chemo- and regiose-
lectivity increased with an increasing bulkiness of the alco-
hol. The main side-reaction, ether formation, is facilitated
especially in the case of methanol.
2.2.12. 16 (or 17)-Methyoxy-17 (or 16)-
hydroxyandrostane (14a)
MS (m/z/relative intensity): 306/60, 274/32, 259/28,
243/55, 217/100, 189/50, 149/48, 109/85, 95/82, 67/80,
55/72.
2.2.13. 16 (or 17)-Ethyoxy-17 (or 16)-
hydroxyandrostane (14b)
MS (m/z/relative intensity): 320/44, 305/3, 274/20,
259/24, 243/80, 231/75, 217/100, 203/64, 189/65, 149/35,
109/26, 55/16.
CH3
HO
RO
HO
ROOC
Co2(CO)8, THF
1 + CO + ROH
+
+
3-hydroxypyridine
ROOC
HO
a: R =Me
7a...c
8a...c
9a...c
b: R = Et
CH3
c: R =iPr
ROOC
HO
HO
RO
HO
Co2(CO)8, THF
+
+
2 + CO + ROH
3-hydroxypyridine
ROOC
10b, c
Fig. 2. Alkoxycarbonylation of 2,3-epoxy-steroids.
11b, c
12b, c

A. Bala´zs et al. / Steroids 69 (2004) 271–277
275
Table 1
Determination of the optimal reaction conditions in alkoxycarbonylation of 1a
Run
Alcohol
Base/Co
ratio(mol/mol)
Reaction time(h)
Reaction
temperature (◦C)
PCO (atm)
Conversionb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
2
2
2
2
2
2
2
6
9
72
9
72
144
72
72
72
65
75
75
75
75
105
75
75
45
45
45
45
45
45
100
100
51
97
77
90
93
74
95
95
24
27
20
43
46
24
49
91
a General conditions: 1 mmol substrate 1; 0.05 mmol Co2(CO)8 catalyst; 3-hydroxypyridine; 1 mL THF; 20 mmol alcohol; CO atmosphere.
b [(1 mmol unreacted 1/1 mmol starting 1)] × 100.
c [mmol (7b + 8b)/mmol 1] × 100 based on GC.
It should be mentioned that a control experiment was car-
ried out during which a pure sample of 7c was reacted under
the standard reaction conditions in order to check its stabil-
ity. After 72 h the hydroxy ester was recovered unchanged,
ial vicinal couplings which gave sufficiently strong cross
peaks. Based on these spectra, we could identify isopropyl
3-hydroxy-17-ketoandrostan-2-carboxylate as the main
product. The minor amount of isomeric ␤-hydroxy ester 8c
1
1
as verified by GC–MS and H NMR.
was identified on the base of the H spectrum of a sample
containing esters 7c and 8c, chromatographically enriched
in the latter. Two signal pairs with similar fine structure at
4.46 and 4.38 ppm and at 2.96 and 2.58 ppm indicate the
presence of two possible regioisomers.
3.1.1. Structure elucidation
The structure and configuration of the new molecules
were determined from their 1H NMR spectra (for all spectra
referred to see Supporting information). Detailed measure-
ments have been carried out on pure samples of 7c and 10c.
There are two distinct one-proton signals in the spec-
trum of 7c at 4.46 and 2.58 ppm, corresponding to the
protons of –OH- and –COOR-substituted methylene
groups, respectively. To decide between the two possi-
ble regioisomers (3-hydroxy, 2-carboxylate, or 2-hydroxy,
3-carboxylate), one has to identify unambiguously the cou-
pling partners and the magnitude of the relevant scalar
couplings. This was possible by routine two-dimensional
(2D) (COSY 90-45 spectra) and one-dimensional (1D)
1H techniques. Good use was made of the large diax-
Concerning the ␣ or ␤ position of the substituents on the
1
A ring, the fine structures of the H signals gave important
clues. The small coupling values observed for both signals
exclude the existence of diaxial relations between the pro-
tons involved. Assuming the usual chair conformation for
the A ring, this predicts C2H␣ and C3H␤ position for the
protons, i.e. 2␤ and 3␣ positions for the –COOR and –OH
substituents, respectively [16,17]. These configurations were
confirmed further by steady-state 1D NOE difference and
2D transient NOE (NOESY) experiments [17].
The same measurements have been carried out for 10c
when the product was found to be isopropyl 2␤-hydroxy-5␣-
androstan-17-one-3␣-carboxylate. Comparison of the 1H
NMR spectra of 7c and 10c revealed a low-frequency
(upfield) shift of the C19H3 protons for 7c, indicating the
spatial proximity of –COOR and the angular methyl group
as an other evidence for the configuration deduced.
As obvious from the various NMR measurements, the
stereochemistry of the starting materials 1 and 2 has not been
preserved, as the configuration of the carbon atoms bear-
ing –COOR substituents has changed. This seems to be in
agreement with those observed by other authors for simple,
non-terminal epoxides, where inversion of configuration oc-
curs at the supposed site of attack [18,19].
Table 2
Alkoxycarbonylation of epoxy-steroids 1, 2, and 3 with different alcoholsa
Product
Conversionb
(%)
Chemoselectivityc
(%)
Regioselectivityd
(%)
7a
7b
7c
10b
10c
13a
13b
13b
99
98
96
98
98
96
98
96
70
91
95
90
96
68
89
91
93
95
97
96
97
99
99
99
3.2. Alkoxycarbonylation of 16α,17α-epoxy-
5α-androstane (3)
a General conditions: 1 mmol steroid 1, 2, or 3; 0.3 mmol
3-hydroxypyridine; 0.05 mmol Co2(CO)8; 1.5 mL THF; 20 mmol alcohol;
100 atm CO; 75 ◦C.
b [(1 mmol unreacted 1, 2, or 3/1 mmol starting 1, 2, or 3) × 100],
Likewise the 2,3-epoxy-derivatives discussed above,
unhindered 16,17-epoxide 3 underwent efficient alkoxy-
carbonylation in the Co-catalyzed process (Fig. 3). The
conditions of the reaction were analogous to the former,
based on GC.
c [(mmol esters/mmol products) × 100], based on GC.
d [(mmol major ester/mmol major + minor esters) × 100], based on
GC.

276
A. Bala´zs et al. / Steroids 69 (2004) 271–277
OH
OH
CH3
CH3
Co2(CO)8, THF
COOR
OR
3 + CO + ROH
+
3-hydroxypyridine
13a...c
14a...c
R = -Me, -Et, -iPr
Fig. 3. Alkoxycarbonylation of 16␣,17␣-epoxy-steroids.
H3C
CH3
O
CH3
Co2(CO)8, THF
5 or 6 + CO + EtOH
3-hydroxypyridine
H
15 R = -H
RO
16 R = -Ac
Fig. 4. Alkoxycarbonylation of 16␣,17␣-epoxy-17-substituted epoxy-pregnenes.
and high chemo- and regioselectivities were observed in
the main product 13a (Table 2, lines 4–6). The same ten-
dencies were observed also when the alcohol was varied.
The high regioselectivities are attributed to the steric ef-
fect of the angular C18H3 methyl group [20,21]. Losses in
chemoselectivity are due again to ether (14a–c) formation.
1D NOE measurements indicate that C17H is ␤, therefore,
C16H must be ␣, so the original configuration of the C16
carbon atom involved was not preserved during the reaction
(like in the 2,3-epoxy cases).
3.3. Alkoxycarbonylation of sterically hindered
epoxy-steroids
3.2.1. Structure elucidation
Pregnenolones with sterically hindered 16,17-epoxides (5
and 6) were subjected to alkoxycarbonylation in presence of
EtOH under the same conditions. No ester could be detected
by GC–MS analyses. TLC screening of the mixture showed
one dominant product, which remained the same if reacting
The relevant NMR spectra (see Supporting information)
were obtained on a chromatographically purified sample
of 13c. In the 1H NMR spectrum there is only one sig-
nal at 3.98 ppm (doublet with a small coupling value of
1.4 Hz) and with an integral value of one proton and an other
one-proton signal at much lower frequency (2.66 ppm). This
latter has, however, double-triplet fine structure, indicating
almost identically strong (∼8–9 Hz) couplings to two other
protons and a small one (1.4 Hz) to the signal at 3.98 ppm.
Based on their chemical shift values, we can safely assume
that these are the C17H and C16H ring protons attached to
carbon atoms bearing –OH and –COOR groups, respectively.
Since the signal at 3.98 ppm shows only a small coupling,
the isopropyl 16-hydroxyandrostane-17-carboxylate regioi-
somer can be excluded, the main structure being isopropyl
17-hydroxyandrostane-16-carboxylate.
1
the substrate with MeOH. The H NMR spectrum of the
product revealed the formation of a pregnadiene as a result
of a reductive elimination reaction (Fig. 4). The 5,6-double
bond was left intact under the conditions applied.
The other sterically hindered substrate 4 was reacted with
ethanol for as long as 96 h. As TLC analyses showed, a
rather complex reaction mixture was formed. The GC–MS
and 1H NMR spectra of the components showed that no car-
bonylation took place, and only unsaturated steroids were
detectable. This is in agreement with our former results ob-
tained in carbonylation of sterically hindered unsaturated
steroids [21].
Concerning the ␣ or ␤ position of the substituents on
the conformationally more flexible D ring, the answer is
less obvious (in comparison with the A ring), since the ring
conformation is always perturbed by the substituents them-
4. Conclusion
1
selves. Nevertheless, fine structures of the H signals give
Homogeneous catalytic ring-opening alkoxycarbonyla-
tion of various epoxy-steroids has been carried out suc-
cessfully in presence of Co2(CO)8/3-hydroxypyridine as
catalyst precursor. The reactions took place in a highly
chemo- and regioselective manner with unhindered 2,3- and
16,17-epoxides.
again important clues. The very small coupling [22] (1.4 Hz)
between C17H and C16H (although smaller than the typi-
cal three-bond equatorial–axial couplings obtained from the
generalized Karplus equation [23] and experimental data
[24]) suggests 16␣,17␤ or 17␣,16␤ arrangement for them.

A. Bala´zs et al. / Steroids 69 (2004) 271–277
277
Conversion and selectivity depended on the suitable
choice of the conditions and the Co/base ratio, as well
as the bulkiness of the nucleophilic reagent. Even more
important is the accessibility and position of the epox-
ide moiety. No carbonylation took place with 5,6- and
16,17-epoxides where a C–O bond belongs to a tertiary
carbon atom.
The resulting steroidal ␤-hydroxy esters were ob-
tained as isomerically pure compounds. The new com-
pounds were isolated and characterized in pure form.
Both 2␣,3␣- and 2␤,3␤-epoxy-5␣-androstan-17-one and
16␣,17␣-epoxy-androstane underwent alkoxycarbonylation
with configuration inversion at the carbon atoms bearing
the –COOR moiety.
[8] Wu J, Hou X-L, Dai L-X, Xia LJ, Tang MH. Enantioselective
ring opening of meso-epoxides with thiols, catalyzed by chiral
(salen)Ti(IV) complex. Tetrahedron Asymmetry 1998;9:3431–6.
[9] Furrow ME, Schaus SE, Jacobsen EN. Practical access to highly
enantioenriched C-3 building blocks via hydrolytic kinetic resolution.
J Org Chem 1998;63:6776–7.
[10] Piotti ME, Alper H. Carbonylation of alkynyl epoxides: synthesis of
5-hydroxy-2,3-dienoate esters and 2,3-dihydrofuran-3-ol derivatives.
J Org Chem 1997;62:8484–9.
[11] Knight JG, Ainge SW, Baxter CA, Eastman TP, Harwood SJ.
Synthesis of ␦-lactones from 2-alkynyl epoxides and 4-alkynyl-1,3-
dioxolan-2-ones by palladium catalyzed carbonylation and conjugate
nucleophilic addition. J Chem Soc Perkin Trans 2000;1:3188–90.
[12] Lee JT, Thomas PJ, Alper H. Synthesis of ␤-lactones by
regioselective cobalt and Lewis acid catalyzed carbonylation of
simple and functionalized epoxides. J Org Chem 2001;66:5424–6.
[13] Drent E, Kragtwijk E. Eur Pat Appl 577206 (1994 March 30). Chem
Abstr 1994;120:191517c.
[14] Szabó P, Markó L, Bor G. Einfache Laboratoriumsmethode zur
Herstellung von kristallinem Dicobaltoctacarbonyl. Chem Techn
(Berlin) 1961;13:549–50.
Acknowledgements
[15] Bor G. Infrared spectroscopic studies on metal carbonyl compounds-
III. Spectrochim Acta 1963;19:1209–24.
The authors thank Z. Tuba and S. Mahó (Chemical Works
of Gedeon Richter Ltd.) for the steroids and Prof. B. Heil for
helpful discussions. This work was supported by the Hun-
garian National Science Foundation (OTKA Grant T034328
and T34355).
[16] Sedee AGJ, Vanhenegouwen GMB, Guijt W, Haasnoot CAG.
Assignment of the H-1 and C-13 nuclear magnetic-resonance spectra
of norethisterone using two-dimensional nuclear magnetic-resonance
spectroscopy. J Chem Soc Perkin Trans II 1984;11:1755–9.
[17] Croasmun WR, Carlson RMK. Two-dimensional NMR spectroscopy.
Weinheim: VCH Publishers, Inc.; 1987. p. 387–424.
[18] Brandes BD, Jacobsen EN. Regioselective ring opening of enantiome-
rically enriched epoxides via catalysis with chiral (salen)Cr(III)
complexes. Synlett 2001;1013–16.
References
[19] Mahadevan V, Getzler YDY, Coates GW. [Lewis acid]+[Co(CO)4]−
complexes: a versatile class of catalysts for carbonylative ring
expansion of epoxides and aziridines. Angew Chem Int Ed 2002;
41:2781–4.
[1] Jacobsen EN. Asymmetric catalysis of epoxide ring-opening
reactions. Acc Chem Res 2000;33:421–31.
[2] Bartók M, Lang KL. Small ring heterocycles, Part 3. Hassner A,
editor. New York: Wiley; 1985. p. 15–57.
[3] Jörgensen KA. Transition-metal-catalyzed epoxidations. Chem Rev
1989;89:431–58.
[4] Jacobsen EN. Transition metal catalyzed oxidations: asymmetric
epoxidation. In: Wilkinson G, Stone FGA, Abel EW, Hegedus LS,
editors. Comprehensive organometallic chemistry II, vol. 12. New
York: Pergamon; 1995. p. 1097–135.
[5] Hou X-L, Wu J, Dai L-X, Xia LJ, Tang MH. Desymmetric
ring-opening of meso-epoxides with anilines: a simple way to chiral
␤-amino-alcohols. Tetrahedron Asymmetry 1998;9:1747–52.
[6] Hinterding K, Jacobsen EN. Regioselective carbomethoxylation of
chiral epoxides: a new route to enantiomerically pure ␤-hydroxy
esters. J Org Chem 1999;64:2164–5.
[7] Ready JM, Jacobsen EN. Asymmetric catalytic synthesis of
␤-aryloxy alcohols: kinetic resolution of terminal epoxides via
highly enantioselective ring opening with phenols. J Am Chem Soc
1999;121:6086–7.
[20] To"rös Sz, Gémes-Pécsi I, Heil B, Mahó S, Tuba Z. Synthesis of
new formyl and aminomethyl steroids via homogeneous catalysis. J
Chem Soc Chem Commun 1992;11:858–9.
[21] To"rös Sz, Heil B, Gálik G, Tuba Z. Hydroalkoxycarbonylation of
androstene derivatives. Tetrahedron Lett 1992;33:3667–8.
[22] Scönecker B, Tresselt D, Draffehn J, Ponsold K, Engelhardt G,
Zeigan D, et al. 1H-NMR-Untersuchungen. Konfigurationszuordnung
von 16-Substituierten 17-Hydroxy-Steroiden. J Prakt Chem 1977;
319:419–31.
[23] Haasnoot CAG, de Leeuw FAA, Altona C. The relationship between
proton–proton NMR coupling constants and substituent electro-
negativities. I. An empirical generalization of the Karplus equation.
Tetrahedron 1980;36:2783–92.
[24] Sedee AGJ, van Henegouwen GMJ, Guijt W, Haasnot CAG. Confor-
mational analysis of steroids in solution. J Org Chem 1985;50:4182–
7.