Diastereoselective hydroformylation of Δ4-steroids with rhodium-phosphite catalysts

Article abstract of DOI:10.1016/S0957-4166(01)00191-4

The hydroformylation of two steroidal substrates, namely 17β-acetoxyandrost-4-ene 1 and 3β,17β-diacetoxyandrost-4-ene 2, with a rhodium tris(O-tert-butylphenyl)phosphite catalyst was investigated. In both cases, the major reaction product was 4β-formyl-17β-acetoxy-5β-androstane 3, which was isolated and characterized by X-ray diffraction and NMR techniques. This reaction is the first example of catalytic carbonylation to the β face of a steroid backbone. The effect of reaction temperature, the pressure at which the reaction was completed and the ligand:Rh ratio on the regio- and stereoselectivity of the reaction is also discussed.

Full text of DOI:10.1016/S0957-4166(01)00191-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1083–1087
Diastereoselective hydroformylation of D4-steroids with
rhodium–phosphite catalysts
Zoraida Freixa,a Mariette M. Pereira,a,* J. Carles Bayo´n,b,* Artur M. S. Silva,c
Jorge A. R. Salvador,d Ana Matos Beja,e Jose´ A. Paixa˜oe and Manuela Ramose
aDepartamento de Qu´ımica, Rua Larga, Universidade de Coimbra, 3049 Coimbra, Portugal
bDepartament de Qu´ımica, Universitat Auto`noma de Barcelona, Bellaterra, 08193 Barcelona, Spain
cDepartamento de Qu´ımica, Universidade de Aveiro, 3810-193 Aveiro, Portugal
dFaculdade de Farma´cia, Universidade de Coimbra, Coimbra, Portugal
eDepartamento de F´ısica, Universidade de Coimbra, Coimbra, Portugal
Received 26 March 2001; accepted 25 April 2001
Abstract—The hydroformylation of two steroidal substrates, namely 17b-acetoxyandrost-4-ene 1 and 3b,17b-diacetoxyandrost-4-
ene 2, with a rhodium tris(O-tert-butylphenyl)phosphite catalyst was investigated. In both cases, the major reaction product was
4b-formyl-17b-acetoxy-5b-androstane 3, which was isolated and characterized by X-ray diffraction and NMR techniques. This
reaction is the first example of catalytic carbonylation to the b face of a steroid backbone. The effect of reaction temperature, the
pressure at which the reaction was completed and the ligand:Rh ratio on the regio- and stereoselectivity of the reaction is also
discussed. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
double bond at the six-membered B ring remained
intact.7 The only two reports dealing with the car-
bonylation of a double bond on a six-membered ring
of a steroid were published in the 1950s. These pio-
neering works describe the reaction of 3b-acetoxy-
pregn-5-ene-20-one and 3b,20b-diacetoxy-pregn-5-ene
under quite drastic conditions with syn-gas in the
presence of cobalt catalysts. In both cases, the corre-
sponding 6a-hydroxymethylpregnanes were obtained
in 60% yield. Also, a trans-fusion of rings A and B
was observed, which is the expected one for cis-addi-
tion of the formyl group and hydrogen to the a face
of the steroid.9,10 Since these works were reported, a
number of very efficient hydroformylation catalysts
have been developed, most of them based on
rhodium and P-donor ligands.11 Of these catalysts,
tris(O-tert-butylphenyl)phosphite has been shown to
form active rhodium catalysts for the hydroformyla-
tion of hindered olefins.12–14
There is an increasing interest in developing new
strategies to introduce functional groups into specific
positions of steroidal nuclei in order to modulate
their biological properties.1,2 Hydroformylation is now
a well established process in the production of fine
chemicals for the introduction of an aldehyde func-
tionality into complex molecules containing a car-
bonꢀcarbon double bond.3 However, the catalytic
carbonylation of unsaturated steroids has been only
scarcely reported compared with the equivalent reac-
tion on other substrates. Recent work in this area
used steroidal substrates containing an exocyclic
olefin4,5 or unsaturation at the D ring (the five-mem-
bered ring).6–8 The stereochemistry of the major prod-
ucts revealed addition occurred from the a face of the
steroid backbone. Furthermore, in the hydroformyl-
ation of 3b,17b-dihydroxyandrosta-5,16-diene, con-
taining double bonds in both the D and B rings, only
the D ring was carbonylated, while the more hindered
We report herein the low pressure rhodium/tris(O-
tert-butylphenyl)phosphite-catalyzed hydroformylation
of two D4-steroids, 17b-acetoxyandrost-4-ene 1 and
3b,17b-diacetoxyandrost-4-ene 2. Both substrates con-
tain a double bond at the same position of the A
ring, for which carbonylation has not been previously
explored.
* Corresponding authors. E-mail: mmp@ci.uc.pt; bayon@cc.uab.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00191-4

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Z. Freixa et al. / Tetrahedron: Asymmetry 12 (2001) 1083–1087
2. Results and discussion
Homogenous17,18 and heterogenous19,20 catalytic reac-
tions involving D4-steroids have been widely investi-
gated. For these substrates, products of both the a and
the b attack are obtained, depending on the catalyst
and the substituents on the steroid. The existence of a
stable conformation with a partially folded structure
along the A and B ring-fusion bond has previously been
invoked to explain formation of the b products.21 This
is probably the reason for the stereochemistry of the
major product from the hydroformylation of 1.
2.1. Catalytic reactions
Substrate 1 was prepared in 80% yield by reduction of
testosterone acetate with NaBH4 in CF3COOH/AcOH/
CH3CN.15 Substrate 2 was synthesized in two steps
from the same material: reduction with NaBH4 in
MeOH afforded 3b-hydroxy-17b-acetoxyandrost-4-
ene15 (74% yield), followed by acetylation with Ac2O/py
(60% yield).16
For substrate 1, the cis-addition of the hydrogen and
the formyl group over the double bond, with the formyl
group in a 4b-position, produces the cis-fusion of rings
A and B (i.e. 5b-H). Both, the formation of a cis-addi-
tion product, and the fact that only one further alde-
hyde product is observed (likely the 4a-formyl
derivative), suggests that the reaction takes place by
direct hydroformylation of D4 double bond and not
through previous isomerization of the substrate, for
which a more complicated mixture of products would
be expected. Furthermore, analysis of the reaction mix-
ture at intervals through the catalytic process reveals
the formation of variable amounts of isomers of sub-
strate 1. These isomeric products are hydroformylated
only at the end of the reaction, with concomitant
formation of small amounts of other aldehyde side
products. The overall effect is a decrease in the regiose-
lectivity of the reaction. It should be noted, however,
that the ratio of the two initially formed aldehydes
remains practically constant (ca. 7/3) throughout the
reaction and that the hydroformylation of the isomer-
ized products does not change the output of aldehyde 3.
The catalyst was prepared in situ by reaction of [Rh2(m-
OMe)2(cod)2] and tris(O-tert-butylphenyl)phosphite
under CO/H2 atmosphere. The hydroformylation of
substrates 1 and 2 with this catalyst was then examined
and the results of the study are collected in Table 1.
For substrate 1, the major aldehyde product was found
to be 4b-formyl-17b-acetoxy-5b-androstane 3 (Scheme
1). The product 3 was purified by chromatography on
silica gel using dichloromethane/petroleum ether as elu-
ent (1:1). Crystals suitable for X-ray diffraction were
obtained by recrystallization from petroleum ether with
a few drops of dichloromethane. The product was
characterized by X-ray diffraction and NMR
techniques.
Aldehyde 3 is the expected regioisomer (i.e. the formyl
group addition to the less substituted carbon) and it is
formed by the reaction of the catalyst with the double
bond to the b face of the steroidal skeleton. This is in
contrast to that reported for the hydroformylation of
D5-steroids, which afforded a addition products.9,10
Table 1. Hydroformylation of steroids 1 and 2 with the [Rh2(m-OMe)2(cod)2]/P(O-o-tBuC6H4)3 catalytic systema
Entry
Substrate
Temp. (°C)
Pressure (bar)
L:Rh
Time (h)
Conv.b (%)
Chem.c (%)
Aldehyde 3d (%)
1
2
3
4
5
6
7e
1
1
1
1
1
2
1
70
100
100
100
100
100
100
20
20
10
20
40
20
20
2.5
2.5
10
48
48
48
48
48
48
48
44
89
80
89
89
97
60
34
85
60
85
77
70
78
64
61
65
61
68
58
60
10
2.5
2.5
2.5
a Reaction conditions: Substrate (1.26×10−3 mol) and Rh (1.26×10−4 mol) dissolved in toluene (6 mL).
b Calculated as a percentage of converted substrate.
c [Total aldehydes]/[olefin converted].
d [Aldehyde 3]/[total aldehydes].
e S/Rh=50.
Scheme 1.

Z. Freixa et al. / Tetrahedron: Asymmetry 12 (2001) 1083–1087
1085
The best yields of aldehyde 3 were obtained at 100°C
and 20–40 bar pressure (entries 2, 4 and 5). At 120°C
the reaction lacks reproducibility and no apparent
improvement in the conversion was obtained, these
observations are a result of catalyst decomposition
under the reaction conditions. No significant effect on
the activity or selectivity was observed when either the
pressure or the molar ratio of ligand to metal was
changed, except for a pressure of 10 bar, at which the
chemoselectivity of the reaction decreased (entry 3).
It is noteworthy that hydroformylation of substrate 2 at
100°C and 20 bar pressure also produced the aldehyde
3 as the major component of the reaction mixture
(entry 6). The isolated yield was similar to that
obtained with substrate 1. The formation of 3 could
arise from the elimination of acetic acid after the
hydroformylation, followed by the stereoselective
hydrogenation of the unsaturated aldehyde at the a face
of the steroid. A similar situation has been previously
reported for allylic acetates derived from carbohy-
drates.22 However, a path involving the formation of
Rh-p-allyl intermediate cannot be completely
excluded.23 Studies to elucidate the mechanism of this
reaction are underway.
Figure 1. X-Ray structure of aldehyde 3.
1
Table 2. 13C and H NMR data for aldehyde 3
C
13C (l)
1H (l)
b
b
C1
C2
36.9 or 37.0a
23.4
C(3)
C(4)
C(5)
C(8)
C(9)
C(10)
C(13)
C(14)
C(17)
26.9
48.2
42.4
35.3
41.6
35.0
42.7
50.7
1.70–1.80 (m) CH2
2.66–2.77 (m) CH
1.53–1.59 (m) CH
6
6
6
b
1.20–1.40 (m) CH
–
–
1.00–1.20 (m) CH
4.6 (dd, J=9, J=7.9) CH
6
6
2.2. X-Ray crystal structure of aldehyde 3
82.8
6
OC
OCOC
CH3 (18)
CH3 (19)
CHO
6
OCH3
H3
171.2
21.2
12.1
23.9
205.5
–
Fig. 1 shows the molecular structure of aldehyde 3
obtained by X-ray analysis.24 Rings A and B have a
cis-junction typical of a 5b epimer. This is revealed by
the torsion angles C(19)ꢀC(10)ꢀC(5)ꢀC(4)=166.8(4)°
and C(1)ꢀC(10)ꢀC(5)ꢀC(6)=176.2(3)°. As expected, the
other ring junctions are trans-orientated. A twist
around the C(13)ꢀC(14) bond can also be seen in the
five-membered ring. The distance between the two more
6
2.04 (s) CH3
0.77 (s) CH3
1.01 (s) CH3
9.41 (d, J=4.4) CH6 O
6
6
a These resonances can be interchangeable
b These 1H resonances were not assigned.
,
distant terminal atoms, 0(1) and C(17B), is 12.03 A.
2.3. NMR analysis of aldehyde 3
The assignment of most of the proton and carbon
1
signals in the H and 13C NMR spectra of aldehyde 3
was achieved by using two-dimensional techniques. The
results are collected in Table 2.
Figure 2. Correlations found in the COSY and HETCOR
spectrum of 3 around the formyl group.
The proton correlations observed in the COSY spec-
trum between the aldehydic proton, methylene protons
and a methynic proton are in agreement with the
presence of a 4-formyl group on the androstane
nucleus. These results and the analysis of the HETCOR
spectrum allow assignment of the C(3), C(4) and C(5)
carbon resonances (Fig. 2).
In the HMBC spectrum, the aldehydic proton shows
connectivity with C(4) (l=48.2) and also a weak corre-
lation with the carbon resonance of another methylene
group (l=23.4), which has then been assigned to C(2).
The signal for C(4)H shows connectivities with C(3)
(l=26.9) and C(5) (l=42.4). The 19-methyl group
shows connectivities with C(1) (l=36.9 or 37.0), C(9)
(l=41.6), C(10) (l=35.0) and also with C(5) (l=42.4)
(Fig. 3).
Figure 3. Main connectivity found in the HMBC spectrum of
3.

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Z. Freixa et al. / Tetrahedron: Asymmetry 12 (2001) 1083–1087
The HMBC connectivities found for both the C(18)-CH3
and C(17)H allowed the assignment of the majority of
their neighboring carbon resonances. In the NOESY
spectrum of aldehyde 3, intense NOE cross peaks were
observed between the resonances of the 19-methyl group
and C(5)H, as well as between C(5)H and the aldehydic
proton. This suggests that the three groups are on the
same (b) face of the steroid plane, as is corroborated by
the X-ray analysis. The absence of NOE cross peaks of
C(4)H with C(5)H and the 19-methyl group, reinforces
this hypothesis.
mmol) in CH2Cl2 (200 mL) and the reaction mixture was
refluxed overnight. Montmorillonite was removed by
filtration and the resulting filtrate was washed twice with
saturated aqueous NaHCO3. The organic layer was dried
over MgSO4 and then evaporated. The crude product
was recrystallized from CH2Cl2–petroleum ether–ethanol
to produce a white crystalline material (1.66 g, 72%); mp
139–141°C (Lit.,26 139–140°C); 1H NMR: l 0.80 (s, 3H,
C(18)Me), 1.15 (s, 3H, C(19)Me), 2.1 (s, 3H, CH3COO),
4.56 (dd, J=8.7 Hz, J=8.0 Hz, 1H, C(17)H), 5.69 (s, 1H,
C(4)H); 13C NMR: l 82.4 (C17), 123.9 (C4), 125.8 (C5),
171.1 (OC6 OCH3), 199.4 (C3).
4.3. 17-b-Acetoxyandrost-4-ene 115
3. Conclusion
The system Rh-tris(O-tert-butylphenyl)phosphite cata-
lyzes the hydroformylation of D4 double bond of sub-
strates 1 and 2. The system is 68% selective in
4b-formyl-17b-acetoxy-5b-androstane 3. This product
was isolated from the reaction mixture in 50% yield and
characterized by single crystal X-ray diffraction and
double resonance NMR techniques. The hydroformyla-
tion reaction occurred preferentially at the b face of the
steroid nucleus forming a new steroid with cis-fusion of
A and B rings.
A mixture of CF3COOH (1.8 mL), CH3COOH (1.8 mL)
and CH3CN (1.8 mL), and NaBH4 (0.30 g, 7.93 mmol)
were added to an ice-cooled solution of 17b-acetoxyan-
drost-4-ene-3-one (0.50 g, 1.51 mmol) in CH2Cl2 (10 mL).
After stirring for 10 h, aqueous NaHCO3 was added
dropwise until the pH of the mixture was 7. The mixture
was extracted with CH2Cl2 and the organic layer washed
with H2O and dried over MgSO4. The white solid
obtained after evaporation of the solvent was recrystal-
lized from CH2Cl2–petroleum ether–ethanol to afford the
product as a crystalline material (0.38 g, 80%); mp
95–97°C (Lit.,15 97°C); 1H NMR: l 0.80 (s, 3H,
C(18)Me), 1.02 (s, 3H, C(19)Me), 2.05 (s, 3H, CH3COO),
4.58 (dd, J=9, J=7.7 Hz, 1H, C(17)H,), 5.30 (m, 1H,
C(4)H); 13C NMR: 82.8 (C17), 119.3 (C4), 144.7 (C5),
4. Experimental
1H and 13C NMR spectra were recorded in CDCl3
solutions on a Bruker AMX 300 spectrometer. 1H
assignments were made using 2D COSY and NOESY
(mixing time of 800 ms) experiments, while 13C assign-
ments were made using HETCOR and HMBC (delays
for long-range J C/H couplings were optimized for 7 Hz)
experiments. GC and GC–MS were carried out on
HP-5890 and HP-G1800A apparatus, both equipped
with capillary HP5 columns. Reported melting points are
not corrected.
171.0 (OC6
OCH3); MS-EI: m/z 316 (M+, 26%), 301 (4%),
256 (14%), 241 (34%), 146 (34%), 133 (24%), 93 (54%),
91 (45%), 79 (39%), 55 (23%), 43 (100%).
4.4. 17b-Acetoxy-3b-hydroxyandrost-4-ene15
A solution 17b-acetoxyandrost-4-ene-3-one (4.00 g, 12.1
mmol) in methanol (50 mL) was treated with NaBH4
(3.00 g, 79.3 mmol) at 0°C for 2 h. AcOH (2.0 mL) was
then added to destroy the excess of NaBH4 and the
mixture was poured into water. The product was
extracted with ethyl acetate. The combined extracts were
washed with water and dried over Na2SO4. The solvent
was evaporated under vacuum and the crude was recrys-
tallized to give white needles of 3b-hydroxy-17b-acet-
oxyandrost-4-ene (2.95 g, 74%); mp 135–136°C (Lit.,15
135–136°C); 1H NMR: l 0.77 (s, 3H, C(18)Me), 1.02 (s,
3H, C(19)Me), 2.01 (s, 3H, CH3COO), 4.12 (m, 1H,
C(3)H), 4.54 (dd, J=7.9 Hz, J=10.0 Hz, 1H, C(17)H),
5.25 (m, 1H, C(4)H); 13C NMR: l 67.8 (C3), 82. 7 (C17),
[Rh2(m-OMe)2(cod)2] and tris-(O-tert-butylphenyl)phos-
phite were synthesized by slightly modified procedures
with respect to those described in the literature.12,25
4.1. General procedure for hydroformylation reactions
The appropriate quantities of substrate, tris-(O-tert-
butylphenyl)phosphite, [Rh2(m-OMe)2(cod)2] and a stir-
ring bar were introduced in a glass vessel. This was then
closed in the autoclave, and the system was purged by
three cycles of vacuum and syn-gas. Being the reactor in
vacuum, toluene was introduced through the inlet can-
nula. The reactor was pressurized with syn-gas at 40 bar
at the working temperature for 45 minutes. After this
incubation period, the autoclave was set to the desired
pressure. Conversions and selectivities were determined
throughout the reaction by gas chromatography analysis
of aliquots of the mixture.
123.5 (C4), 147.1 (C5), 171.2 (OC6 OCH3).
4.5. 3b,17b-Diacetoxyandrost-4-ene 216
3b-Hydroxy-17b-acetoxyandrost-4-ene (0.50 g, 1.51
mmol) was dissolved in a mixture of freshly distilled
pyridine (1.0 mL, 12 mmol) and Ac2O (2.5 mL, 26
mmol). After the complete disappearance of starting
material (as indicated by TLC), the reaction mixture
was washed with an aqueous saturated solution of
CuCl2, until no color change in the aqueous layer was
observed, then with 10% HCl (aq.), a saturated solution
4.2. 17b-Acetoxyandrost-4-ene-3-one26
Montmorillonite (10 g) and Ac2O (6.0 mL, 63 mmol)
were added to a solution of testosterone (2.00 g, 6.93

Z. Freixa et al. / Tetrahedron: Asymmetry 12 (2001) 1083–1087
1087
of NaHCO3, and finally with water. The organic layer
was dried over MgSO4 and the solvent evaporated
under vacuum. The resulting white solid was recrystal-
lized from CH2Cl2–petroleum ether–ethanol to afford
the crystalline product (0.34 g, 60%); mp 110–113°C
Metals for Organic Synthesis; Beller, M.; Bolem, C., Eds.;
Wiley-VCH: New York, 1998; pp. 26–48.
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1
(Lit.,16 101–102°C); H NMR: l 0.81 (s, 3H, 18-Me),
1.07 (s, 3H, C(19)Me), 2.04 (s, 3H, CH3COO), 2.05 (s,
3H, CH3COO), 4.58 (dd, 1H, C(17)H, J=9 Hz, J=7.8
Hz), 5.23 (m, 1H, C(4)H), 5.22 (m, 1H, C(3)H); 13C
NMR: l 70.8 (C3), 82.7 (C17), 119.2 (C4), 149.1 (C5),
6. To¨ro¨s, S.; Heil, B.; Ga´lik, G.; Tuba, Z. Tetrahedron Lett.
1992, 33, 3667–3668.
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11. van Leeuwen, P. W. N. M.; Claver, C. Rhodium Cata-
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171.0 (OC6 OCH3), 171.2 (OC6 OCH3); MS-EI: m/z 374
(M+), 314 (36%), 239 (19%), 146 (33%), 106 (52%), 91
(74%), 81 (30%), 55 (22%), 43 (100%).
4.6. 4b-Formyl-17b-acetoxy-5b-androstane 3
This product was synthesized by catalytic hydroformyl-
ation using the general procedure described above. The
autoclave was charged with 1 (0.40 g, 1.26 mmol),
tris-(O-tert-butylphenyl)phosphite (0.031 g, 0.063
mmol) and (0.006 g, 0.025 mmol) of [Rh2(m-
OMe)2(cod)2] and toluene (6 mL). When the catalytic
reaction was stopped, the reactor was cooled and
depressurized. After evaporation of the toluene, the
mixture of aldehydes was isolated by preparative chro-
matography (silica, petroleum ether–CH2Cl2 1:1).
Finally, the aldehyde 3 was crystallized from a solution
of petroleum ether–CH2Cl2 to give a white crystalline
material (0.22 g, 50%); mp 112–114°C; 1H and 13C
NMR are collected in Table 2; MS-EI: m/z 346 (M+,
29%), 286 (13%), 201 (43%), 149 (27%), 105 (43%), 95
(43%), 43 (100%); [h]D=+20 (c 1, CHCl3). Anal. calcd
for C22H34O3: C, 76.37; H, 9.90. Found: C, 76.59; H,
9.70%.
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Acknowledgements
The authors are grateful to FCT, PRAXIS-XXI (QUI-
1008/98), Chymiotechnon and DGCYT (PB98-0913)
for financial support. Z.F. would also like to thank
PRAXIS-XXI for a grant (QUI-1008/98).
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