Synthesis and photochemical trasformations of 19-phenylsulfonyl provitamin D analogue

Article abstract of DOI:10.1135/cccc19981597

The synthesis of provitamin D analogue 19-(phenylsulfonyl)androsta-5,7-diene-3β, 17β-diyl 3-acetate 17-pivalate (20) has been accomplished from 19-hydroxyandrost-5-ene-3β,17β-diyl 3-acetate 17-pivalate. 19-(Phenylsulfonyl)androst-5-ene-3β,17β-diyl 3-acetate 17-pivalate (10), a precursor of 20, was first obtained in low yield in the nucleophilic displacement reactions of 19-halogenated-5-ene steroids with sodium benzenesulfinate. Then a more efficient method has been used, which involves protection of the double bond as an epoxide. Introduction of the C(7)-C(8) double bond into olefin 10 has been also achieved in two ways. The first involved bromination-dehydrobromination and the other consisted of an allylic oxidation of olefin 10 leading to enone and the Bamford-Stevens reaction of its tosylhydrazone. UV irradiation of 5,7-diene 20 resulted in formation of a complex mixture of products. The structures of five isolated compounds were established on the basis of their ¹H NMR spectra and mechanistic rationale.

Full text of DOI:10.1135/cccc19981597

19-Phenylsulfonyl Provitamin D Analogue
1597
SYNTHESIS AND PHOTOCHEMICAL TRASFORMATIONS
OF 19-PHENYLSULFONYL PROVITAMIN D ANALOGUE
a1
a
b
Piotr GRZEGORZEWSKI , Izabela KOLADKIEWICZ , Jacek W. MORZYCKI
and Rafal R. SICINSKI
a2,
*
a Department of Chemistry, University of Warsaw, 02-093 Warszawa, Pasteura 1, Poland;
e-mail: 1 benu@chem.uw.edu.pl, 2 rasici@chem.uw.edu.pl
b Institute of Chemistry, University of Warsaw, Bialystok Branch, Pilsudskiego 11/4,
15-443 Bialystok, Poland; e-mail: morzycki@noc.uwb.edu.pl
Received May 22, 1998
Accepted July 4, 1998
Dedicated to Dr Jan Fajkos on the occasion of his 75th birthday.
The synthesis of provitamin D analogue 19-(phenylsulfonyl)androsta-5,7-diene-3β,17β-diyl 3-acetate
17-pivalate (20) has been accomplished from 19-hydroxyandrost-5-ene-3β,17β-diyl 3-acetate 17-piva-
late. 19-(Phenylsulfonyl)androst-5-ene-3β,17β-diyl 3-acetate 17-pivalate (10), a precursor of 20, was
first obtained in low yield in the nucleophilic displacement reactions of 19-halogenated-5-ene ste-
roids with sodium benzenesulfinate. Then a more efficient method has been used, which involves
protection of the double bond as an epoxide. Introduction of the C(7)–C(8) double bond into olefin
10 has been also achieved in two ways. The first involved bromination–dehydrobromination and the
other consisted of an allylic oxidation of olefin 10 leading to enone and the Bamford–Stevens reac-
tion of its tosylhydrazone. UV irradiation of 5,7-diene 20 resulted in formation of a complex mixture
of products. The structures of five isolated compounds were established on the basis of their 1H
NMR spectra and mechanistic rationale.
Key words: 5,7-Androstadienes; Steroids; Photochemistry; Sulfones; Provitamin D; Vitamines.
The main photoisomerization path in the vitamin D series was established by Velluz1 in
1955. It has been deduced that the main photochemical processes consist of the conro-
tatory electrocyclic ring B opening in the steroidal 5,7-diene (provitamin D) to form the
9,10-seco-5(10),6,8-triene (previtamin D) which can be subsequently isomerized to its
6E-form (tachysterol). Previtamin D also undergoes a thermally induced [1,7]-sigma-
tropic rearrangement to the 5,7,10(19)-triene system characteristic of vitamin D com-
pounds. The intramolecular nature of this antarafacial migration of hydrogen was
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1598
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
determined by Havinga2 in 1964. Thermodynamics and kinetics of photochemical and
thermal interconversions of pro- and previtamin D compounds have been intensively
studied during the last four decades3–6. However, very few studies have been reported
examining electronic effects of the C-19 substituents on these processes7–9. Considering
the fact that 19-methyl group in provitamin D is attached directly to a C(9)–C(10) bond
which undergoes photolytic opening and that rehybridization at C-19 occurs during
previtamin–vitamin rearrangement, we initiated studies on 19-functionalized provit-
amin D analogues. In our previous papers10,11, we reported the synthesis of provitamin
D in androstane series (1a), and its analogues substituted at C-19: homologue 1b, ace-
tate 1c and methyl ether 1d (Scheme 1). It turned out that ultraviolet irradiation of
dienes 1a–1d produces a similar distribution of photoproducts, previtamins 2a–2d and
tachysterol analogues11,12 3a–3d. It has also been found that in the case of thermal
previtamin–vitamin conversion, the equilibrium mixture of 19-unsubstituted analogue
consisted of 2a and 4a in a 1 : 3 ratio whereas for all 19-functionalized compounds, the
equilibrium of thermal reaction lies far towards the side of the vitamin D forms 4b–4d.
OPiv
OPiv
OAc
R
hν
1
2
AcO
∆
R
hν
Piv = C(O)C(CH )
3 3
OPiv
OPiv
In formulae 1-4:
a, R = H
b, R = CH
3
c, R = OAc
d, R = OCH
3
R
R
4
OAc
AcO
3
SCHEME 1
We explained this phenomenon by postulating that all of the 19-substituents studied
(methyl, acetoxy and methoxy), which exert positive mesomeric effect, stabilize the
vitamin D triene system. It was therefore of interest to perform further studies on
photochemical and thermal isomerizations of the analogues substituted at position 19
with a group that can withdraw electrons by both inductive and mesomeric effects. The
present paper deals with the synthesis and photochemistry of a compound which fulfils
this condition, i.e., androsta-5,7-diene bearing 19-phenylsulfonyl substituent.
In our earlier work13, we described the transformation of androst-5-ene-3β,17β-diyl
3-acetate 17-pivalate (5) into 19-alcohol 6 (Scheme 2). Its tosyl derivative14 7 was used
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1599
now to obtain the corresponding 19-bromo and 19-iodo compounds 8 and 9 by the
modified Counsell procedure15. As expected, no significant homoallylic rearrangement
was observed and both 19-halogeno compounds were formed in high yields. Then a
direct nucleophilic displacement of the halogen atom in 8 and 9 by PhSO−2 was at-
tempted. It could be anticipated16 that this reactive nucleophile might also form product
with unrearranged carbon skeleton, i.e., 19-phenylsulfonyl derivative 10. However, the
desired compound 10 was only a minor product (10% yield) of the iodo derivative 9
OPiv
RO
AcO
(i)
5
6, R = H
AcO
Br
7, R = Ts
(ii)
(iii)
I
PhSO
2
AcO
AcO
AcO
(iv)
9
8
10
(iv)
AcO
RO
RO
SO Ph
SO Ph
2
2
11
14, R = Ac
15, R = H
12, R = Ac
13, R = H
(v)
(v)
(vi)
Piv = C(O)C(CH )
3 3
(vi)
o
(i) TsCl/pyridine; (ii) LiBr/propan-2-ol, reflux; (iii) NaI/propan-2-ol, reflux; (iv) PhSO Na/DMF, 65 C;
2
o
(v) K CO /MeOH, H O, 40 C; (vi) Ac O/pyridine
2
3
2
2
SCHEME 2
reaction with sodium phenylsulfinate. The polar fraction of the reaction consisted of the
isomeric 5β,19-cyclo compounds, 12 and 14 (1 : 1.4, 38% yield) substituted at C-6 with
phenylsulfonyl group. These compounds could be separated chromatographically only
after their hydrolysis to the respective 3β-alcohols 13 and 15 which were then reacetyl-
1
ated for further identification. The analysis of 13C and H NMR spectra of both pro-
ducts 12 and 14, showing no olefinic protons, the presence of high-field signals of the
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1600
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
cyclopropyl protons at C-19 and the presence of the methine proton signals at ca 3.4
ppm clearly demonstrated their rearranged structure. Analysis of the coupling constants
of the latter signals allowed one to establish the configuration of C-6 substituents. In
order to determine the preferred conformation of compounds 12 and 14, molecular
mechanics calculations were employed*. The torsional angles between the C-6 proton
and the vicinal 7α- and 7β-protons in the energy-minimized structures (173.0° and
52.9° for 12; 42.1° and –73.9° for 14) were used to calculate the expected 1H–1H coup-
ling constants. The respective vicinal couplings for compounds 12 and 14 were calcu-
lated on the basis of Altona’s modified Karplus relationship17. The experimental
coupling constants for the C-6 methine proton (brd, J = 8.3 Hz) in the major isomer
were in agreement with the values calculated for 6β-phenylsulfonyl compound 14
(J(6α,7α) = 6 Hz, J(6α,7β) = 1 Hz), whereas the observed couplings of H-6 in the
minor isomer (dd, J = 10.3, 5.4 Hz) provided a better match with those calculated** for
epimeric 6α-substituted compound 12 (J(6β,7α) = 12 Hz, J(6β,7β) = 4 Hz). It should
be added that blank experiments performed with compounds 12 and 14 revealed that
these isomers were unchanged during a prolonged treatment with PhSO2Na in DMF or
with K2CO3 in methanol. Thus, the possibility of their interconversion due to epimeri-
zation process at C-6, occurring during the displacement reaction or hydrolysis, has
been excluded. Reaction of 19-bromo-5-ene 8 with the sodium phenylsulfinate pro-
ceeded similarly as in the case of the iodo compound 9 but the yield of the desired
product 10 was lower. It was established that a major product of the reaction was
5β,19-cyclo-6-ene compound 11; this rearranged olefin was also formed by the elimi-
nation of a 4-methylbenzene sulfonic acid from the tosylate 7. The predominant forma-
tion of the 5β,19-cyclo compounds in these processes confirmed that the displacement
of 19-halogenated steroidal 5-enes with PhSO−2 occurs mainly with the concomitant
homoallylic rearrangement.
Low yields of the 19-phenylsulfonyl olefin 10 formed in the displacement reactions
examined, encouraged us to seek for an alternative method of its preparation. In order
to prevent the participation of the homoallylic double bond in the nucleophilic substitu-
tion at C-19, we decided to epoxidize the double bond in the B ring. Thus, 19-bromo
* Molecular modelling was performed using the MM+ algorith (an enhanced version of MM2) included
in the HyperChem (release 4.0) software package (Autodesk, Inc. 1994) The least energy
conformers were further subjected to rotations (30°) of angles: H–C(6)–S–O, C(6)–S–C′(1)–C′(2) and
C(5)–C(6)–C(7)–C(8) using the conformational search option of ChemPlus (release 1.5) software
package.
**Some of the discrepancies between the calculated and observed couplings may stem from the
electronegativity of the C-6 substituent. Since the electronegativity of the phenylsulfonyl group, to
our knowledge, has not been described in literature, we used in our calculations a value of 2.60
corresponding to the electronegativity of a sulfur atom.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1601
olefin 8 was treated with 3-chloroperoxybenzoic acid in dichloromethane and the re-
sulting mixture of 5α- and 5β-epoxides 16 and 18 (4.9 : 1) was separated by crystal-
lization and column chromatography (Scheme 3). Both epoxides were next subjected to
the reaction with PhSO2Na. It was found that only α-epoxide 16 underwent the sub-
stitution to yield the 19-phenylsulfonyl derivative 17 as the sole product, whereas the
isomeric compound 18 was remained unchanged. Therefore, it was also possible to use
a mixture of epoxides 16 and 18 for the substitution reaction with subsequent easy
separation of the product 17. The remarkable difference in reactivity between the
isomeric 19-bromo-5,6-epoxides was rationalized in terms of molecular mechanics cal-
culations of the preferred conformations of an angular C(10)–CH2Br arrangement in
both compounds 16 and 18. The rotation of this bulky group is restricted by the axial
substituents of the A, B and C rings, situated on the β-face of the molecules. Energy
minimization of structures 16 and 18 was first done using the MM+ force field. Then,
three conformers of each epoxide were generated by 120° increment rotation around
the C(10)–C(19) bond and energy was minimized for all of the conformers involved.
Finally, the geometry optimization of the resulting structures was performed using the
semi-empirical AM1 method. Comparison of the structures and energies of all six con-
formers (Fig. 1) indicates that the orientations of the CH2Br group in the least-energy
conformers (a and b) of the α-epoxide 16 favour an SN2 displacement reaction,
whereas in the case of the third conformer (c), access of the nucleophile would be
hindered severely by an angular methyl group at C-13 and the axial hydrogens at C-8
a
b
c
0
+0.6 kcal/mol
+2.1 kcal/mol
d
e
f
+1.8 kcal/mol
0
+0.4 kcal/mol
FIG. 1
Schematic top view of the energy-minimized conformers of the 19-bromo-5α,6-epoxide 16 (a, b, c)
and its 5β,6-isomer 18 (d, e, f) resulting from rotation of bromomethyl group around the C(10)–C(19)
bond. The steric energy differences between the preferred conformers and the corresponding rotamers
are given
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1602
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
and C-11. On the contrary, an attack of the nucleophile on the CH2Br group in β-epox-
ide 18 could take place only for the conformer of the highest energy (d).
OPiv
Br
Br
AcO
(iv)
(i)
O
AcO
R
8
18
PhSO
PhSO
2
2
(iii)
AcO
(ii)
AcO
Br
AcO
O
19
10
16, R = Br
17, R = SO Ph
(v)
2
(vi)
PhSO
PhSO
2
PhSO
2
2
(viii)
(vii)
AcO
O
AcO
RO
NNHTs
20
21
22
Piv = C(O)C(CH )
3 3
o
(i) 3-chloroperoxybenzoic acid/CH Cl ; (ii) PhSO Na/DMF, 65 C; (iii) AlI /benzene, MeCN;
2
2
2
3
(iv) 1,3-dibromo-5,5-dimethylhydantoin, NaHCO /benzene, hexane, reflux; (v) tetrabutylammonium
3
fluoride, 2,4,6-trimethylpyridine/THF; (vi) CrO -(pyridine) complex/CH Cl ; (vii) TSNHNH /MeOH,
3
2
2
2
2
o
65 C; (viii) LiH/toluene, reflux
SCHEME 3
Reduction of epoxide 17 with aluminium triiodide18 regenerated the C(5)=C(6)
double bond providing the expected product 10 in 50% yield. The next synthetic step
involved the introduction of an additional C(7)=C(8) double bond into olefin 10. This
goal was achieved by two methods. First, the well-known procedure of allylic bromina-
tion–dehydrobromination19 was examined. Compound 10 was treated with 1,3-di-
bromo-5,5-dimethylhydantoin in refluxing benzene–hexane and the resulted allylic
bromides 19 were subjected to the fluoride-promoted dehydrobromination20. However,
the overall yield of the desired 5,7-diene 20 was not acceptable (9% based on 10). An
alternative method of the synthesis of diene 20 consisted of allylic oxidation of 10 with
chromium(VI) oxide–(pyridine)2 complex in dichloromethane providing 7-oxo com-
pound 21 in 61% yield. This was converted quantitatively to tosylhydrazone 22 which,
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1603
in turn, was subjected to a modified Bamford–Stevens reduction (lithium hydride in
refluxing toluene) to give diene 20 in 67% yield.
Ultraviolet irradiation of diene 20 was carried out in benzene–ether (1 : 4) solution at
0 °C and the resulting complex mixture of products (Scheme 4) was separated by re-
peated column chromatography on silica. The following compounds were isolated (in
the elution order): isomeric 8α- and 8β-phenyl-5-enes 23 and 24 (4.5 : 1), 5α-phe-
nylsulfonyl-9,10-seco-6,8,10(19)-triene 25 and isomeric 7S- and 7R-phenylsulfonyl-
9,10-seco-5,8,10(19)-trienes 26 and 27 (1.9 : 1). The structural assignments were based
on spectral data and mechanistic rationale. The presence of only one olefin proton sig-
1
nal in the H NMR spectrum of 23 practically excluded the possibility of the 9,10-seco
structure and suggested that this product might have a normal steroidal tetracyclic
1
skeleton. Comparison of the H NMR spectra of the product 23 and olefin 10 indicated
that the compounds might contain the same structural moiety consisting of A ring,
19-phenylsulfonyl group and a double bond C(5)=C(6). The signals of aromatic protons
at 7.13, 7.19 and 7.28 ppm indicated the presence of an additional phenyl ring attached
to an alkyl fragment. Taking into account that 23 was the main reaction product formed
from diene 20, it was reasonable to place the phenyl ring at 8α-position. An alternative
1
position at C-7 was excluded because of lack, in the H NMR spectrum of 23, of the
deshielded signal of H-7 coupled with olefinic H-6. The minor isomer 24, with the
protons at C-18 and C-19 considerably more shielded owing to the presence of the
8β-phenyl substituent, would result from the attack of the phenyl radical at C-8 of the
5,7-diene system in 20, occurring from the more shielded β-face of the molecule. The
phenyl radical attack at C-8 gives an allylic radical that can abstract hydrogen from
benzene. This begins the free radical relay. The stronger secondary C-H bond at C-7
(rather than the weaker tertiary bond at C-5) is preferentially formed without allylic
rearrangement. The process of the formation of 23 and 24 could be initiated by photo-
lytic decomposition of the phenylsulfonyl substituent leading to phenyl radical, SO2
and alkyl radical21. The next photoproduct was very unstable undergoing decomposi-
tion soon after its isolation. Therefore, structure 25 can be proposed on the basis of the
1H NMR spectrum only. The presence of the signals of five olefinic protons indicated
strongly the 9,10-seco system, whereas the characteristic coupling constant (J = 16.3 Hz)
between the protons resonating at 5.47 and 6.08 ppm suggested a tachysterol-like struc-
ture. The third olefinic proton, resonating as a multiplet at 5.71 ppm was therefore
ascribed to H-9. Its chemical shift as well as the chemical shift of methyl group at C-13
closely resembled those observed for the tachysterol compounds prepared by us pre-
viously11 (e.g., 3c). Since the two remaining olefinic protons, resonating at 5.33 and
5.79 ppm as singlets, come from the exomethylene group at C-10, the phenylsulfonyl
substituent the most likely is attached to C-5. Thus, analysis of the olefinic protons
pattern seems to be sufficient for elucidation of the structure 25. Such a product is
probably derived from the intermediate tachysterol analogue. Its 19-phenylsulfonyl group,
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1604
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
being in allylic position to the triene system, underwent 1,3-migration occurring at the
less hindered α-face of the ring A. It is very likely that analogous 1,5-migration of
19-phenylsulfonyl substituent in previtamin and/or tachysterol intermediates was also
responsible for the formation of the remaining photoproducts 26 and 27. Both com-
1
pounds show very similar H NMR spectra, indicating the presence of four olefinic
protons. The signals of protons at 4.75, 4.97 and 5.69 ppm are very similar to the
corresponding signals of some 9,10-seco-5,10(19)-diene steroids22,23. The latter signal
derives from the olefinic proton at C-6 which is coupled with a methine proton at C-7
(δ 4.34, d, J = 10.7 Hz), bearing the phenylsulfonyl substituent. The chemical shift of
the proton resonating at δ 5.86 is similar to the shifts of the corresponding olefinic
1
protons at C-9 in closely related systems24. Analysis of the H NMR spectra did not
allow to establish the configuration at C-7 in both isomers 26 and 27. However, ana-
lysis of the Dreiding models of the previtamin and tachysterol analogues derived from
diene 20 reveals that among the conformers suitable for 1,5-migration of the phenylsul-
fonyl group, those leading to the 7S-substituted compound are less crowded. Therefore,
7S-configuration of the phenylsulfonyl substituent has been tentatively ascribed to the
predominant isomer 26.
From the present study it is evident that ultraviolet light irradiation of 19-phenylsul-
fonyl substituted provitamin D analogue 20 caused the ring B opening, resulting in
formation of the corresponding 19-substituted previtamin and tachysterol analogues.
hν
20
23
24
25
26
27
+
+
+
+
OPiv
OPiv
PhSO
PhSO
2
2
Ph
Ph
AcO
AcO
23
24
OPiv
OPiv
OPiv
SO Ph
SO Ph
2
2
SO Ph
2
OAc
AcO
AcO
25
26
27
Piv = C(O)C(CH )
3 3
SCHEME 4
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1605
These photoproducts, however, underwent further transformations, consisting mainly in
1,3- and 1,5-migration of the 19-phenylsulfonyl group, being in the allylic position in
respect to the triene systems. The studies on the photochemistry of other 19-substituted
provitamin D analogues are in progress.
EXPERIMENTAL
Melting points were measured on a Kofler type (Boetius) hot-stage apparatus and are given without
corrections. Optical rotations were measured in chloroform using a Perkin–Elmer 241 automatic po-
larimeter at 22 °C, [α]D values are given in 10–1 deg cm2 g–1. Ultraviolet spectra (λmax, nm; ε) were
measured on a Beckman Acta M VI apparatus in hexane solutions. Infrared spectra (wavenumbers in
cm–1) were recorded on a Zeiss UR-20 spectrometer in KBr pellets unless stated otherwise. 1H and
13C NMR spectra were recorded at 500 and 125 MHz with a Bruker AM-500 spectrometer using
CDCl3 as a solvent and tetramethylsilane as an internal standard. Chemical shifts are given in ppm (δ
scale), coupling constants (J) and half-width of multiplets (W) in Hz. For 13C NMR spectra, the number
of directly bonded hydrogen atoms was determined from the proton-decoupled “attached proton test”.
Mass spectra were determined with an AMD-604 instrument at 70 eV. High-resolution data were
obtained by peak matching.
Thin-layer chromatography (TLC) was carried out on precoated aluminium silica sheets from
Merck, column chromatography on silica gel Macherey–Nagel (100–200 mesh) and flash chromato-
graphy on silica gel 60 (230–400 mesh, Merck No. 9385).
Androst-5-ene-3β,17β,19-triyl 3-Acetate 17-Pivalate 19-Tosylate11 (7)
A solution of 19-alcohol 6 (21.63 g, 0.05 mol) and tosyl chloride (19.07 g, 0.1 mol) in anhydrous
pyridine (70 ml) was allowed to react for 4 days at room temperature. The mixture was poured into
ice/water and extracted with benzene. The organic phase was washed with water, saturated CuSO4,
again water, dried (Na2SO4) and evaporated. The crystalline residue was washed twice with cold
methanol and the solvent was decanted. The colourless residue was filtered and air dried to give 22.1 g
(76%) of 19-tosylate 7, m.p. 136.5–140.5 °C, [α]D –71 (c 1.3), which was sufficiently pure to be
used in the following synthetic steps without further purification.
19-Bromoandrost-5-ene-3β,17β-diyl 3-Acetate 17-Pivalate (8)
A solution of tosylate 7 (11.74 g, 0.02 mol) and LiBr (8.68 g, 0.1 mol) in propan-2-ol (525 ml) was
gently refluxed for 4 h. The solution was concentrated to a small volume in vacuo, poured into water
and extracted with dichloromethane. The extract was washed with water and dried (Na2SO4). The
solvent was evaporated to give a colourless solid residue which was crystallized from acetone to ob-
tain 6.44 g (65%) of pure 19-bromo steroid 8. The mother liquor was chromatographed on silica gel
column. Elution with dichloromethane–hexane (80 : 20 →95 : 5) gave additional 1.39 g of crystalline 8
(total yield 7.83 g; 79%), 160–162 °C; [α]D –71 (c 1.3). IR spectrum: 1 735, 1 483, 1 373, 1 292, 1 252,
1 170, 1 034. 1H NMR spectrum: 0.90 s, 3 H (3 × H-18); 1.20 s, 9 H ((CH3)3CCOO); 2.04 s, 3 H
(CH3COO); 3.50 d, 1 H, J = 11.1 (H-19); 3.78 d, 1 H, J = 11.1 (H-19); 4.64 brm, 2 H (H-3α and
H-17α); 5.69 m, 1 H (H-6). For C26H39BrO4 (495.5) calculated: 63.03% C, 7.93% H; found: 63.19% C,
8.00% H.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1606
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
19-Iodoandrost-5-ene-3β,17β-diyl 3-Acetate 17-Pivalate (9)
The title compound 9 was prepared in 90% yield from tosylate 7 and NaI by a method analogous to
that described above for compound 8. Crystallization from hexane–acetone afforded the pure product 9,
m.p. 144–148 °C, [α]D –84 (c 1.0). IR spectrum: 1 732, 1 482, 1 293, 1 254, 1 175, 1 036. 1H NMR
spectrum: 0.92 s, 3 H (3 × H-18); 1.20 s, 9 H ((CH3)3CCOO); 2.03 s, 3 H (CH3COO); 3.30 d, 1 H,
J = 11.0 (H-19); 3.59 d, 1 H, J = 11.0 (H-19); 4.58 brm, 2 H (H-3α and H-17α); 5.66 m, 1 H (H-6).
For C26H39IO4 (542.5) calculated: 57.57% C, 7.25% H; found: 57.49% C, 7.15% H.
Reaction of 19-Bromo and 19-Iodo Olefins 8 and 9 with Sodium Phenylsulfinate
Olefin 9 (995 mg, 1.83 mmol) and PhSO2Na (398 mg, 2.43 mmol) in anhydrous DMF (5 ml) were
heated at 65 °C for 24 h. The reaction mixture was poured into water and extracted three times with
dichloromethane. The combined extracts were washed with saturated NaHCO3 and water, dried and
evaporated to give a dark yellow oily residue which was subjected to column chromatography on
silica. Elution with benzene and benzene–ether (99 : 1) gave a mixture (212 mg) of starting material
and some elimination products. Further elution with benzene–ether (99 : 1) yielded slightly impure
fractions (120 mg) of 19-phenylsulfonyl olefin 10 which after rechromatography in the same solvent
system yielded pure and crystalline product 10 (103 mg, 10%). Elution with benzene–ether (99 : 1
and 98 : 2) afforded a mixture of polar 5β,19-cyclo compounds 12 and 14 (391 mg, 38%) in a 1 : 1.4
ratio.
19-(Phenylsulfonyl)androst-5-ene-3β,17β-diyl 3-acetate 17-pivalate (10): m.p. 175–177 °C (hexane–
acetone), [α]D –99.1 (c 1.0). IR spectrum (CCl4): 1 730, 1 480, 1 447, 1 369, 1 326, 1 308, 1 285, 1 241,
1
1 164, 1 155, 1 033. H NMR spectrum: 1.04 s, 3 H (3 × H-18); 1.21 s, 9 H ((CH3)3CCOO); 2.03 s,
3 H (CH3COO); 3.13 d, 1 H, J = 14.8 (H-19); 3.49 d, 1 H, J = 14.8 (H-19); 4.62 brm, 2 H (H-3α
and H-17α); 5.63 d, 1 H, J = 5.5 (H-6); 7.57 m, 2 H (2 × Hm-Ar); 7.65 m, 1 H (Hp-Ar); 7.93 m, 2 H
(2 × Ho-Ar). 13C NMR spectrum: 12.3 (q), 21.3 (q), 22.2 (t), 23.4 (t), 27.3 (q), 27.6 (t), 27.7 (t), 30.8 (t),
31.5 (d), 37.4 (t), 38.5 (t), 38.6 (t), 38.9 (s), 41.5 (s), 43.0 (s), 51.0 (d), 52.6 (d), 57.7 (t), 73.2 (d),
82.2 (d), 126.6 (d), 127.5 (d), 129.3 (d), 133.4 (d), 133.8 (s), 142.0 (s), 170.4 (s), 178.7 (s). Mass
spectrum, m/z (%): 496 (21, M – AcOH), 354 (37, 496 – PhSO2H), 341 (38), 239 (87), 57 (100). For
C32H44O6S (556.8) calculated: 69.03% C, 7.97% H; found: 69.09% C, 7.87% H.
An analogously performed reaction of 19-bromo compound 8 (551 mg, 1.11 mmol) with sodium
benzenesulfinate (251 mg, 1.53 mmol) in DMF (2.5 ml), followed by standard work-up and column
chromatography, afforded unreacted substrate, some nonpolar products (290 mg) consisting mainly of
5β,19-cyclo olefin 11, and 19-phenylsulfonyl olefin 10 (32 mg, 5%).
5β,19-Cycloandrost-6-ene-3β,17β-diyl 3-Acetate 17-Pivalate (11)
A solution of tosylate 7 (500 mg, 0.85 mmol) in anhydrous pyridine (10 ml) was refluxed for 18 h.
The mixture was poured into water and extracted with benzene. The extract was washed with water,
5% HCl, again water and saturated NaHCO3, dried (Na2SO4) and evaporated. The residue was crys-
tallized from a small volume of hexane to yield 187 mg of pure 5β,19-cyclo olefin 11. The mother
liquor was chromatographed on silica. Elution with benzene gave additional 109 mg of crystalline 11
(total yield 296 mg, 84%), m.p. 145–147 °C (hexane), [α]D +1.3 (c 1.2). IR spectrum (KBr): 1 727,
1
1 482, 1 370, 1 286, 1 251, 1 167, 1 032. H NMR spectrum: 0.55 d, 1 H, J = 4.7 (H-19); 0.81 s, 3 H
(3 × H-18); 1.15 d, 1 H, J = 4.7 (H-19); 1.20 s, 9 H ((CH3)3CCOO); 2.01 s, 3 H (CH3COO); 4.60 dd,
1 H, J = 9.1, J′ = 7.7 (H-17α); 4.63 brm, 1 H (H-3α); 5.22 dd, 1 H, J = 9.8, J′ = 1.6 (H-6); 5.72 dd,
1 H, J = 9.8, J′ = 3.0 (H-7). For C26H38O4 (414.6) calculated: 75.33% C, 9.24% H; found: 75.23% C,
9.07% H.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1607
Hydrolysis of 3β-Acetoxy Group in 5β,19-Cyclo Compounds 12 and 14
A mixture of polar 5β,19-cyclo compounds 12 and 14 (390 mg), obtained in the experiment de-
scribed above (reaction of 9 with PhSO2Na), was dissolved in warm (40 °C) methanol (35 ml) and a
solution of K2CO3 (1 g) in water (3.5 ml) was added. After 30 min of stirring at 40 °C, the reaction
mixture was poured into water and extracted three times with dichloromethane. The combined ex-
tracts were washed with water, dried (Na2SO4) and evaporated to give a crystalline residue which
was subjected to column chromatography on silica. Elution with benzene–ether (90 : 10) gave crystalline
3β-alcohol 13 (128 mg). Subsequent elution with benzene–ether (80 : 20) afforded the isomeric com-
pound 15 (182 mg) as colourless crystals. Both products were recrystallized from hexane–acetone.
3β-Hydroxy-6α-(phenylsulfonyl)-5β,19-cycloandrostan-17β-yl pivalate (13): m.p. 124–127 °C
(hexane–acetone), [α]2D2 +26.7 (c 1.0). IR spectrum (KBr): 1 725, 1 444, 1 304, 1 292, 1 173, 1 154,
1 137, 1 084, 1 042. 1H NMR spectrum: 0.69 d, 1 H, J = 5.6 (H-19); 0.70 d, 1 H, J = 5.6 (H-19);
0.72 s, 3 H (3 × H-18); 1.17 s, 9 H ((CH3)3CCOO); 3.06 dd, 1 H, J = 14.0, J′ = 5.8 (H-4α); 3.41 dd,
1 H, J = 8.6, J′ = 6.8 (H-6β); 3.92 brm, 1 H (H-3α); 4.54 dd, 1 H, J = 9.0, J′ = 7.9 (H-17α); 7.56 m,
2 H (2 × Hm-Ar); 7.64 m, 1 H (Hp-Ar); 7.88 m, 2 H (2 × Ho-Ar). 13C NMR spectrum: 12.2 (q), 20.9 (s),
22.9 (t), 23.3 (t), 24.7 (t), 27.0 (s), 27.2 (q), 27.3 (t), 28.0 (t), 28.1 (t), 29.1 (t), 33.9 (d), 36.7 (t),
38.5 (t), 43.4 (s), 46.7 (d), 49.0 (d), 51.1 (s), 67.3 (d), 68.6 (d), 81.9 (d), 128.2 (d), 129.1 (d), 133.4 (d),
140.4 (s), 178.4 (s). For C30H42O5S (514.7) calculated: 70.01% C, 8.22% H; found: 70.09% C,
8.11% H.
3β-Hydroxy-6β-(phenylsulfonyl)-5β,19-cycloandrostan-17β-yl pivalate (15): m.p. 191–194 °C
(hexane–acetone), [α]2D2 +49.4 (c 1.0). IR spectrum (KBr): 1 732, 1 479, 1 444, 1 290, 1 167, 1 142,
1 083, 1 042. 1H NMR spectrum: 0.49 d, 1 H, J = 5.6 (H-19); 0.82 s, 3 H (3 × H-18); 1.19 s, 9 H
((CH3)3CCOO); 1.63 d, 1 H, J = 5.6 (H-19); 3.47 d, 1 H, J = 8.3 (H-6α); ca 3.48 brm, 1 H (H-3α);
4.57 dd, 1 H, J = 9.1, J′ = 7.6 (H-17α); 7.57 m, 2 H (2 × Hm-Ar); 7.66 m, 1 H (Hp-Ar); 7.94 m, 2 H
(2 × Ho-Ar). 13C NMR spectrum: 12.3 (q), 18.0 (t), 18.8 (s), 23.1 (t), 24.5 (t), 26.4 (s), 27.1 (t), 27.2 (q),
27.4 (t), 28.9 (t), 29.5 (t), 30.7 (d), 36.7 (t), 38.9 (s), 43.2 (s), 46.8 (t), 48.4 (d), 49.2 (d), 67.7 (d),
68.4 (d), 82.1 (d), 129.08 (d), 129.14 (d), 133.7 (d), 139.4 (s), 178.6 (s). For C30H42O5S (514.7)
calculated: 70.01% C, 8.22% H; found: 69.95% C, 8.14% H.
Acetylation of 3β-Hydroxy Compounds 13 and 15
Samples of alcohols 13 and 15 (50 mg) were acetylated in the mixture pyridine–acetic anhydride (2 : 1,
1 ml) at room temperature overnight. After standard isolation procedure, the crude acetylation pro-
ducts (single spots on TLC) were crystallized from hexane–acetone.
6α-(Phenylsulfonyl)-5β,19-cycloandrostane-3β,17β-diyl 3-acetate 17-pivalate (12): m.p. 167–168 °C
(hexane–acetone), [α]2D2 +15.1 (c 0.7). IR spectrum (KBr): 1 732, 1 479, 1 445, 1 363, 1 303, 1 287, 1 247,
1 167, 1 140, 1 084, 1 025. 1H NMR spectrum: 0.65 d, 1 H, J = 5.3 (H-19); 0.73 s, 3 H (3 × H-18); 0.77 d,
1 H, J = 5.3 (H-19); 1.17 s, 9 H ((CH3)3CCOO); 2.00 s, 3 H (CH3COO); 2.95 dd, 1 H, J = 14.6, J′ = 6.1
(H-4α); 3.34 dd, 1 H, J = 10.3, J′ = 5.4 (H-6β); 4.54 dd, 1 H, J = 9.0, J′ = 7.8 (H-17α); 4.99 brm, 1 H
(H-3α); 7.56 m, 2 H (2 × Hm-Ar); 7.63 m, 1 H (Hp-Ar); 7.90 m, 2 H (2 × Ho-Ar). 13C NMR spectrum:
12.2 (q), 20.6 (s), 21.4 (q), 22.8 (t), 22.9 (t), 24.6 (t), 25.8 (t), 26.8 (s), 27.2 (q), 27.2 (t), 27.3 (t),
28.3 (t), 33.4 (t), 34.1 (d), 36.7 (t), 38.8 (s), 43.5 (s), 46.9 (d), 48.9 (d), 68.6 (d), 69.8 (d), 81.9 (d),
128.3 (d), 129.1 (d), 133.4 (d), 140.3 (s), 170.2 (s), 178.4 (s). For C32H44O6S (556.8) calculated:
69.03% C, 7.97% H; found: 69.15% C, 7.90% H.
6β-(Phenylsulfonyl)-5β,19-cycloandrostane-3β,17β-diyl 3-acetate 17-pivalate (14): m.p. 156–157 °C
(hexane–acetone), [α]2D2 +11.7 (c 1.0). IR spectrum (KBr): 1 729, 1 479, 1 444, 1 361, 1 297, 1 283,
1 245, 1 167, 1 137, 1 082, 1 031. 1H NMR spectrum: 0.58 d, 1 H, J = 5.7 (H-19); 0.82 s, 3 H (3 × H-18);
1.19 s, 9 H ((CH3)3CCOO); 1.66 d, 1 H, J = 5.7 (H-19); 1.97 s, 3 H (CH3COO); 3.46 d, 1 H, J = 8.3
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1608
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
(H-6α); 4.56 dd, 1 H, J = 9.1, J′ = 7.7 (H-17α); 4.60 brm, 1 H (H-3α); 7.57 m, 2 H (2 × Hm-Ar); 7.65 m,
1 H (Hp-Ar); 7.91 m, 2 H (2 × Ho-Ar). 13C NMR spectrum: 12.3 (q), 17.9 (t), 18.3 (s), 21.3 (q), 23.1 (t),
24.5 (t), 25.8 (t), 26.1 (s), 27.2 (q), 27.4 (t), 28.3 (t), 29.7 (t), 30.4 (d), 36.7 (t), 38.9 (s), 42.4 (t), 43.2 (s),
48.0 (d), 49.0 (d), 67.8 (d), 70.0 (d), 82.0 (d), 128.9 (d), 129.1 (d), 133.6 (d), 139.2 (s), 170.6 (s), 178.6 (s).
For C32H44O6S (556.8) calculated: 69.03% C, 7.97% H; found: 68.85% C, 7.89% H.
19-Bromo-5α,6-epoxy-5α-androstane-3β,17β-diyl 3-Acetate 17-Pivalate (16) and
19-Bromo-5β,6-epoxy-5β-androstane-3β,17β-diyl 3-Acetate 17-Pivalate (18)
A solution of 19-bromo olefin 8 (2.0 g, 4.0 mmol) in dichloromethane (50 ml) was treated with
3-chloroperoxybenzoic acid (80–85%, 2.3 g) added in portions. The temperature of the reaction mix-
ture was maintained below 25 °C. After addition of all reagent, the mixture was allowed to stand at
room temperature for 24 h with occasional shaking. The aromatic acids were removed by extraction
with 5% NaOH, and the organic layer was washed with water and dried. The solvent was evaporated
to give a colourless solid residue (2.1 g) consisting of 5α,6- and 5β,6-epoxides 16 and 18 in 4.9 : 1
ratio (established from 1H NMR spectrum). The epoxide mixture was repeatedly crystallized from
hexane–acetone to obtain 1.06 g of pure compound 16. The mother liquor was chromatographed on
silica gel column. Elution with benzene–ether (99 : 1) gave an additional 0.3 g of crystalline 16 (total
yield 1.36 g, 66%). Further elution afforded a mixture of the epoxides (0.4 g) and pure isomeric
5β,6-oxide 18, which was crystallized from acetone–hexane (yield 0.25 g, 12%).
19-Bromo-5α,6-epoxide 16: m.p. 190–192 °C, [α]2D2 –74.1 (c 1.0). IR spectrum (KBr): 1 732, 1 483,
1
1 448, 1 369, 1 298, 1 288, 1 249, 1 168, 1 037. H NMR spectrum: 0.81 s, 3 H (3 × H-18); 1.18 s,
9 H ((CH3)3CCOO); 2.02 s, 3 H (CH3COO); 3.07 d, 1 H, J = 3.4 (H-6β); 3.71 s, 2 H (2 × H-19);
4.53 dd, 1 H, J = 9.3, J′ = 7.3 (H-17α); 4.96 brm, 1 H (H-3α). For C26H39BrO5 (511.5) calculated:
61.05% C, 7.69% H; found: 61.18% C, 7.79% H.
19-Bromo-5β,6-epoxide 18: m.p. 154–156 °C, [α]2D2 –31.9 (c 0.9). IR spectrum (KBr): 1 735, 1 485,
1 460, 1 369, 1 288, 1 253, 1 171, 1 036. 1H NMR spectrum: 0.83 s, 3 H (3 × H-18); 1.18 s, 9 H
((CH3)3CCOO); 2.04 s, 3 H (CH3COO); 3.05 narrm, 1 H (H-6α); 3.64 s, 2 H (2 × H-19); 4.53 dd, 1 H,
J = 9.8, J′ = 7.3 (H-17α); 4.83 brm, 1 H (H-3α). For C26H39BrO5 (511.5) calculated: 61.05% C,
7.69% H; found: 60.88% C, 7.80% H.
Reaction of 19-Bromo Epoxides 16 and 18 with Sodium Phenylsulfinate
19-Bromo-5α,6-epoxide 16 (102 mg, 0.20 mmol) and PhSO2Na (44.5 mg, 0.27 mmol) in anhydrous
DMF (1 ml) were heated at 65 °C for 24 h. The reaction mixture was poured into water and extracted
three times with methylene chloride. The combined extracts were washed with saturated NaHCO3
and water, dried and evaporated to give a dark yellow oily residue which was subjected to column
chromatography on silica. Elution with benzene–ether (98 : 2) yielded unreacted substrate (16 mg)
and pure product 17.
19-(Phenylsulfonyl)-5α,6-epoxy-5α-androstane-3β,17β-diyl 3-acetate 17-pivalate (17) (90.1 mg,
79%; 93% based on recovered 16), m.p. 172–175 °C (hexane–acetone), [α]2D2 –83.2 (c 0.5). IR spectrum
1
(KBr): 1 727, 1 481, 1 447, 1 368, 1 322, 1 309, 1 288, 1 244, 1 170, 1 147, 1 090, 1 037. H NMR
spectrum: 0.94 s, 3 H (3 × H-18); 1.19 s, 9 H ((CH3)3CCOO); 2.01 s, 3 H (CH3COO); 3.19 d, 1 H,
J = 3.9 (H-6β); 3.29 d, 1 H, J = 14.7 (H-19); 3.48 d, 1 H, J = 14.7 (H-19); 4.57 dd, 1 H, J = 9.0, J′ = 7.6
(H-17α); 5.02 brm, 1 H (H-3α); 7.63 m, 2 H (2 × Hm-Ar); 7.70 m, 1 H (Hp-Ar); 7.97 m, 2 H (2 × Ho-Ar).
For C32H44O7S (572.8) calculated: 67.11% C, 7.74% H; found: 67.01% C, 7.79% H.
An analogous reaction of the isomeric 19-bromo-5β,6-epoxide 18 resulted in an isolation of the
unchanged substrate only.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1609
Reduction of Epoxide 17 with Aluminium Triiodide
To a solution of epoxide 17 (14.3 mg, 0.025 mmol) in anhydrous acetonitrile (0.4 ml), a freshly pre-
pared 0.35 M benzene solution of AlI3 (1 ml) was added. The reaction mixture was stirred at room
temperature for 20 h, quenched with cold water, diluted with dichloromethane and poured into water.
The water layer was extracted with dichloromethane and the combined organic extracts were washed
with 5% NaHSO3 and water, dried and evaporated. The residue was subjected to flash chromato-
graphy. Elution with hexane–ethyl acetate (80 : 20) afforded 19-phenylsulfonyl olefin 10 (6.9 mg,
50%) identical with product described above.
Preparation of 19-(Phenylsulfonyl)androsta-5,7-diene-3β,17β-diyl 3-Acetate 17-Pivalate (20) by
Bromination–Dehydrobromination
A mixture of olefin 10 (38.4 mg, 0.07 mmol) and NaHCO3 (30 mg, 0.33 mmol) in benzene–hexane
(1 : 1, 1 ml) was heated under reflux, and the hot solution was treated with 1,3-dibromo-5,5-di-
methylhydantoin (14 mg, 0.05 mmol). The mixture was refluxed for 30 min, cooled and filtered. The
solution was evaporated and the residue containing the allylic bromides 19 was redissolved in anhy-
drous THF (0.5 ml). Tetrabutylammonium bromide (2 mg) was added and the mixture was stirred for
30 min at room temperature. Then, it was treated with 2,4,6-trimethylpyridine (20 ml) and a 1 M THF
solution of tetrabutylammonium fluoride (400 ml). The mixture was stirred at room temperature for
3 h. The solution was diluted with ether, washed with water, cold 5% HCl, and saturated NaHCO3,
dried and evaporated. The residue was chromatographed on a silica gel column. Elution with ben-
zene–ether (99 : 1) yielded slightly impure 19-phenylsulfonyl diene 20 which after rechromatography
in the same solvent system gave analytically pure oily product (3.4 mg, 9%), [α]2D2 –60.0 (c 0.5). UV
spectrum: 287 (9 500), 275 (10 100), 267 (9 200), 223 (7 900). 1H NMR spectrum: 0.83 s, 3 H (3 × H-18);
1.21 s, 9 H ((CH3)3CCOO); 2.05 s, 3 H (CH3COO); 3.29 d, 1 H, J = 14.7 (H-19); 3.43 d, 1 H, J = 14.7
(H-19); 4.70 brm, 2 H (H-3α and H-17α); 5.45 m, 1 H (H-7); 5.66 d, 1 H, J = 5.9 (H-6); 7.49–7.68 brm,
3 H (2 × Hm-Ar and 1 × Hp-Ar); 7.89 m, 2 H (2 × Ho-Ar). For C32H42O6S (554.7) calculated: 69.29% C,
7.63% H; found: 69.19% C, 7.52% H.
7-Oxo-19-(phenylsulfonyl)androst-5-ene-3β,17β-diyl 3-Acetate 17-Pivalate (21)
Olefin 10 (516 mg, 0.93 mmol) in dry dichloromethane (6 ml) was added to a solution of CrO3–(py-
ridine)2 complex, prepared from CrO3 (2.2 g, 22 mmol) and pyridine (3.5 ml, 44 mmol) in CH2Cl2
(44 ml), and the mixture was stirred for 48 h at room temperature. The solution was poured into
saturated NaHCO3. A black tarry precipitate was dissolved in saturated NaHCO3 and extracted with
CH2Cl2. The combined organic layers were washed several times with saturated NaHCO3, 5% HCl,
5% NaHCO3 and brine, dried and evaporated. The residue was subjected to flash chromatography.
Elution with hexane–ethyl acetate (6 : 4) gave pure enone 21 (323 mg, 61%) as a glass: m.p. 108–110 °C,
[α]2D2 –113.3 (c 0.8). IR spectrum (KBr): 1 728, 1 669, 1 480, 1 447, 1 364, 1 323, 1 309, 1 291, 1 241, 1 164,
1
1 151, 1 089, 1 033. H NMR spectrum: 1.04 s, 3 H (3 × H-18); 1.21 s, 9 H ((CH3)3CCOO); 2.05 s,
3 H (CH3COO); 3.24 dd, 1 H, J = 12.2, J′ = 10.7 (H-8β); 3.32 d, 1 H, J = 14.7 (H-19); 3.55 d, 1 H,
J = 14.7 (H-19); 4.64 dd, 1 H, J = 8.8, J′ = 7.8 (H-17α); 4.74 brm, 1 H (H-3α); 5.96 s, 1 H (H-6);
7.61 m, 2 H (2 × Hm-Ar); 7.70 m, 1 H (Hp-Ar); 7.94 m, 2 H (2 × Ho-Ar). For C32H42O7S (570.7)
calculated: 67.34% C, 7.42% H; found: 67.21% C, 7.34% H.
Conversion of Enone 21 into Tosylhydrazone 22
A solution of enone 21 (171 mg, 0.3 mmol) and tosylhydrazide (223 mg, 1.2 mmol) in anhydrous
methanol (3.6 ml) was heated at 55 °C for 14 h. The mixture was cooled and poured into 5% HCl.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1610
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
The white precipitate was filtered off washed on the filter with water and air dried. After drying
overnight in the desiccator (over P2O5), the crude product was sufficiently pure (a single spot on
TLC) to be used for the next step without any further purification. Yield of tosylhydrazone 22 was
217 mg (98%), m.p. 132–137 °C. IR spectrum (KBr): 3 210, 1 726, 1 666, 1 480, 1 448, 1 324, 1 306,
1 292, 1 241, 1 169, 1 154, 1 088, 1 036. 1H NMR spectrum: 1.03 s, 3 H (3 × H-18); 1.21 s, 9 H
((CH3)3CCOO); 2.06 s, 3 H (CH3COO); 2.44 s, 3 H (CH3-Ar); 3.14 dd, 1 H, J = 12.2, J′ = 10.3
(H-8β); 3.22 d, 1 H, J = 14.7 (H-19); 3.49 d, 1 H, J = 14.7 (H-19); 4.61 brm, 2 H (H-3α and H-
17α); 6.22 s, 1 H (H-6); 7.28–7.93 brm, 10 H (9 × H-Ar and 1 × H-N).
Reduction of Tosylhydrazone 22
The crude tosylhydrazone 22 (185 mg, 0.25 mmol) was dissolved in dry toluene (6 ml) and lithium
hydride (52 mg, 6.5 mmol) was added. The mixture was refluxed for 45 min under argon atmos-
phere. Fast filtration of the cooled reaction mixture into ice-cold 2% H2SO4 followed by washing of
the organic layer with saturated NaHCO3 solution and water, drying and concentration in vacuo
yielded an oily residue which was subjected to flash chromatography. Elution with hexane–ethyl ace-
tate (80 : 20) gave oily diene 20 (93 mg, 67%), identical with the product described above.
Photochemical Reaction of 19-Phenylsulfonyl Diene 20
A solution of diene 20 (33 mg, 0.06 mmol) in benzene–ether (1 : 4, 300 ml) was cooled to 0 °C and
degassed by an argon purge for 30 min. The mixture was irradiated for 15 min through a water-
cooled (0 °C) quartz inner well with a 350 W Hanau S 81 lamp. The solvents were evaporated and
the complex mixture of irradiation products was initially separated by column chromatography on
silica using benzene–ethyl acetate (99 : 1) as an eluent. The first chromatographical separation pro-
vided the mixture of 23 and 24, mixture of 25 and 26, and impure 27. Further separation and purifi-
cation of these photoproducts were achieved by repeated chromatography on silica using
benzene–ethyl acetate (199 : 1 → 99 : 1) solvent systems. Yields and RF (benzene–ethyl acetate, 9 : 1)
of the analytically pure compounds were as follows: 23 (6.7 mg, RF 0.51), 24 (1.5 mg, RF 0.49), 25
(0.8 mg, RF 0.47), 26 (2.8 mg, RF 0.44), 27 (1.5 mg, RF 0.37).
19-(Phenylsulfonyl)-8α-phenyl-8α-androst-5-ene-3β,17β-diyl 3-acetate 17-pivalate (23): m.p. 135–138 °C
(hexane–acetone). IR spectrum (CHCl3): 1 719, 1 480, 1 448, 1 370, 1 324, 1 317, 1 308, 1 289, 1 251,
1
1 171, 1 152, 1 033. H NMR spectrum: 1.11 s, 3 H (3 × H-18); 1.23 s, 9 H ((CH3)3CCOO); 2.02 s,
3 H (CH3COO); 2.96 dd, 1 H, J = 12.5, J′ = 3.8 (H-9α?); 3.17 d, 1 H, J = 14.9 (H-19); 3.53 d, 1 H, J
= 14.9 (H-19); 4.64 brm, 1 H (H-3α); 4.69 dd, 1 H, J = 9.0, J′ = 6.9 (H-17α); 5.40 d, 1 H, J = 5.2 (H-6);
7.13 m, 2 H (2 × Ho-Ar); 7.19 m, 1 H (Hp-Ar); 7.28 m, 2 H (2 × Hm-Ar); 7.55 m, 2 H (2 × Hm-Ar′); 7.63 m,
1 H (Hp-Ar′); 7.91 m, 2 H (2 × Ho-Ar′). Mass spectrum, m/z (%): 495 (58, M – AcOH – Ph), 393 (16,
495 – Me3CCOOH), 353 (100, 495 – PhSO2H), 251 (35, 353 – Me3CCOOH), 57 (56). For
C38H48O6S (632.9) calculated: 72.12% C, 7.65% H; found: 72.56% C, 8.16%.
19-(Phenylsulfonyl)-8β-phenylandrost-5-ene-3β,17β-diyl 3-acetate 17-pivalate (24): IR spectrum
1
(CHCl3): 1 718, 1 480, 1 378, 1 307, 1 288, 1 253, 1 175, 1 151, 1 036. H NMR spectrum: 1.05 s,
3 H (3 × H-18); 1.22 s, 9 H ((CH3)3CCOO); 2.00 s, 3 H (CH3COO); 2.89 d, 1 H, J = 14.7 (H-19);
3.00 d, 1 H, J = 14.7 (H-19); 3.05 dd, 1 H, J = 13.2, J′ = 2.9 (H-9α?); 4.56 ≈ tt, 1 H, J = 11.5, J′ = 4.5
(H-3α); 4.63 dd, 1 H, J = 9.3, J′ = 7.3 (H-17α); 5.37 narrm, 1 H (H-6); 7.05 m, 2 H (2 × Ho-Ar);
7.14 m, 1 H (Hp-Ar); 7.19 m, 2 H (2 × Hm-Ar); 7.59 m, 2 H (2 × Hm-Ar′); 7.67 m, 1 H (Hp-Ar′);
7.89 m, 2 H (2 × Ho-Ar′). Mass spectrum, m/z (%): 495 (41, M – AcOH – Ph), 393 (19, 495 –
Me3CCOOH), 353 (100, 495 – PhSO2H), 251 (40, 353 – Me3CCOOH), 57 (55).
(6E)-5α-(Phenylsulfonyl)-9,10-secoandrosta-6,8,10(19)-triene-3β,17β-diyl 3-acetate 17-pivalate (25):
1H NMR spectrum: 0.83 s, 3 H (3 × H-18); 1.19 s, 9 H ((CH3)3CCOO); 2.02 s, 3 H (CH3COO); ca
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

19-Phenylsulfonyl Provitamin D Analogue
1611
4.7 brm, 2 H (H-3α and H-17α); 5.33 s, 1 H (H-19); 5.47 d, 1 H, J = 16.3 (H-7); 5.71 m, 1 H (H-9);
5.79 s, 1 H (H-19); 6.08 d, 1 H, J = 16.3 (H-6); 7.49 m, 2 H (2 × Hm-Ar); 7.62 m, 1 H (Hp-Ar); 7.77 m,
2 H (2 × Ho-Ar).
(5Z,7S)-7-(Phenylsulfonyl)-9,10-secoandrosta-5,8,10(19)-triene-3β,17β-diyl 3-acetate 17-pivalate (26):
1
IR spectrum (CCl4): 1 729, 1 462, 1 447, 1 378, 1 320, 1 307, 1 286, 1 240, 1 162, 1 151, 1 032. H
NMR spectrum: 0.75 s, 3 H (3 × H-18); 1.19 s, 9 H ((CH3)3CCOO); 2.02 s, 3 H (CH3COO); 4.34 d,
1 H, J = 10.7 (H-7); 4.65 dd, 1 H, J = 9.3, J′ = 7.3 (H-17α); 4.70 ≈ tt, 1 H, J = 10, J′ = 4.5 (H-3α);
4.75 brs, 1 H (H-19); 4.97 brs, 1 H (H-19); 5.69 dd, 1 H, J = 10.7, J′ = 1.0 (H-6); 5.86 m, 1 H, W = 9
(H-9); 7.52 m, 2 H (2 × Hm-Ar); 7.62 m, 1 H (Hp-Ar); 7.82 m, 2 H (2 × Ho-Ar). Mass spectrum, m/z
(%): 554 (4, M+), 412 (2, M+ – PhSO2H), 353 (72, M+ – AcOH - PhSO2), 251 (41, 353 –
Me3CCOOH), 57 (100). HR-MS, for C32H42O6S calculated: 554.2702; found: 554.2729.
(5Z,7R)-7-(Phenylsulfonyl)-9,10-secoandrosta-5,8,10(19)-triene-3β,17β-diyl 3-acetate 17-pivalate (27):
IR spectrum (CCl4): 1 730, 1 480, 1 447, 1 377, 1 321, 1 308, 1 286, 1 242, 1 161, 1 151, 1 036. 1H NMR
spectrum: 0.75 s, 3 H (3 × H-18); 1.20 s, 9 H ((CH3)3CCOO); 1.96 s, 3 H (CH3COO); 4.36 d, 1 H,
J = 10.7 (H-7); 4.44 ≈ tt, 1 H, J = 6.4, J′ = 3.2 (H-3α); 4.69 dd, 1 H, J = 9.3, J′ = 7.3 (H-17α); 4.73 d,
1 H, J = 1.1 (H-19); 4.94 brs, 1 H (H-19); 5.73 d, 1 H, J = 10.7 (H-6); 5.88 m, 1 H, W = 9 (H-9);
7.52 m, 2 H (2 × Hm-Ar); 7.63 m, 1 H (Hp-Ar); 7.81 m, 2 H (2 × Ho-Ar). Mass spectrum, m/z (%):
554 (5, M+), 494 (1, M+ – AcOH), 412 (2, M+ – PhSO2H), 353 (100, M+ – AcOH – PhSO2), 251 (66,
353 – Me3CCOOH), 57 (41). HR-MS, for C32H42O6S calculated: 554.2702; found: 554.2730.
The authors gratefully acknowledge financial support from the University of Warsaw. The work was
supported in part by grants No. BW-1343/40/96 and No. BW-1383/40/97.
REFERENCES
1. Velluz L., Amiard G., Goffinet B.: Bull. Soc. Chim. Fr. 1955, 1341.
2. Schlatmann J. L. M. A., Pot J., Havinga E.: Rec. Trav. Chim. Pays-Bas 1964, 83, 1173.
3. Hanewald K. H., Rappoldt M. P., Roborgh J. R.: Rec. Trav. Chim. Pays-Bas 1961, 80, 1003.
4. Havinga E.: Experientia 1973, 29, 1181.
5. Okamura W. H., Elnagar H. Y., Ruther M., Dobreff S.: J. Org. Chem. 1993, 58, 600.
6. Jacobs H. J. C.: Pure Appl. Chem. 1995, 67, 63.
7. Paaren H., Moriarty R. M., Flippen J.: J. Chem. Soc., Chem. Commun. 1976, 114.
8. Sialom B., Mazur Y.: J. Org. Chem. 1980, 45, 2201.
9. Moriarty R. M., Paaren H.: J. Org. Chem. 1981, 46, 970.
10. Jaszczynski J. R., Sicinski R. R., Rodewald W. J.: Pol. J. Chem. 1984, 58, 711.
11. Sicinski R. R.: Acta Chim. Hung. 1992, 129, 191.
12. Rodewald W. J., Sicinski R. R.: Pol. J. Chem. 1983, 57, 1267.
13. Rodewald W. J., Jaszczynski J. R., Sicinski R. R.: Pol. J. Chem. 1978, 52, 501.
14. Sicinski R. R., Szczepek W. J.: Tetrahedron Lett. 1987, 28, 5729.
15. Counsell R. E.: Steroids 1970, 16, 317.
16. Wright J. N., van Leersum P. T., Chamberlin S. G., Akhtar M.: J. Chem. Soc., Perkin Trans. 1
1989, 1647.
17. Haasnoot C. A. G., de Leeuw F. A. A. M., Altona C.: Tetrahedron Lett. 1980, 36, 2783.
18. Sarmah P., Barua N. C.: Tetrahedron Lett. 1988, 29, 5815.
19. Hunziker F., Mullner F. X.: Helv. Chim. Acta 1958, 41, 70.
20. Rappoldt M. P., Hoogendoorn J., Pauli L. F.: Vitamin D. Chemical, Biological and Clinical
Endocrinology of Calcium Metabolism., p. 1133. Walter de Gruyter, Berlin 1982.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)

1612
Grzegorzewski, Koladkiewicz, Morzycki, Sicinski:
21. Durr H. in: Methoden der organischen Chemie (Houben–Weyl) (E. Muller and O. Bayer, Eds),
Vol. IV/5b, p. 1027. Thieme, Stuttgart 1975.
22. Paaren H. E., Schnoes H. K., DeLuca H. F.: J. Org. Chem. 1983, 48, 3819.
23. Nakayama K., Yamada S., Takayama H., Nawata Y., Itaka Y.: J. Org. Chem. 1984, 49, 1537.
24. Kocienski P. J., Lythgoe B.: J. Chem. Soc., Perkin Trans. 1 1980, 1400.
Collect. Czech. Chem. Commun. (Vol. 63) (1998)