Radical oxidation of 17-functionalized 14α-hydroxy steroids

Article abstract of DOI:10.1135/cccc20011764

The radical oxidation of 14α-hydroxy steroids with various functional groups at C-17 was studied. Lead tetraacetate and ceric ammonium nitrate were used as oxidizing agents. It was shown that reactions of this type afforded complex mixtures of compounds.

Full text of DOI:10.1135/cccc20011764

1764
Khripach et al.:
RADICAL OXIDATION OF 17-FUNCTIONALIZED
14α-HYDROXY STEROIDS
a3
Vladimir A. KHRIPACHa1,*, Vladimir N. ZHABINSKIIa2, Anna I. KOTYATKINA
,
a
a
a4
Galina P. FANDO , Yuliya Y. ZHIBURTOVICH , Alexander S. LYAKHOV
,
a
b
Alla A. GOVOROVA , Marinus B. GROENb1, Jaap van der LOUW
c
and AededeG ROOT
a
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich Str. 5/2,
1
2
220141 Minsk, Belarus; e-mail: khripach@iboch.bas-net.by, vz@iboch.bas-net.by,
3
4
kotyatkina@yahoo.com, lyakhov@bsu.by
b
c
Scientific Development Group, N. V. Organon, P.O. Box 20, 5340 BH Oss, Netherlands;
e-mail: 1 m.groen@organon.oss.akzonobel.nl
Wageningen University, Laboratory of Organic Chemistry, Dreijenplein 8, 6703 HB Wageningen,
Netherlands; e-mail: aede.degroot@bio.oc.wau.nl
Received October 10, 2001
Accepted Decem ber 11, 2001
Dedicated to the memory of Dr VáclavČerný.
Th e radical oxidation of 14α-h ydroxy steroids with various fun ction al groups at C-17 was
studied. Lead tetraacetate an d ceric am m on ium n itrate were used as oxidizin g agen ts. It was
sh own th at reaction s of th is type afforded com plex m ixtures of com poun ds. However, th e
radical oxidation of 14α-h ydroxy-17-oxo steroid (lead tetraacetate version of th e h ypoiodite
reaction ) proceeded sm ooth ly with form ation of th e 13,14-secosteroid in up to 85% yield.
Th e structure an d con form ation of th e form ed 13α-iodo-3α,5-cyclo-13,14-seco-5α-an drost-
5-en e-14,17-dion e was determ in ed by X-ray an alysis.
Keyw ord s: Steroids; Secosteroids; Radical oxidation s; Lead tetraacetate; Ceric am m on ium n i-
trate; Fragm en tation ; Con form ation an alysis.
Radical oxidation of steroids with h ydroxy group at C-5 h as been exten -
sively studied for th e preparation of various steroidal com poun ds with a
m odified AB rin gs. Th e reaction can be effected by treatm en t of 5α/5β-alco-
h ols with lead tetraacetate1 (LTA) or 5α-alcoh ols with ceric am m on ium n i-
trate2 (CAN) an d leads m ain ly to 5,10-secosteroids. It was assum ed th at
th ese com poun ds would differ sign ifican tly from n orm al steroids by con -
form ation of th e basic carbon skeleton 3,4 an d th at a n ew set of biological
properties m igh t be expected. Th is was th e case in acetylen ic 5,10-seco-
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doi:10.1135/cccc20011764

14α-Hydroxy Steroids
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steroids wh ich were foun d5–7 to be irreversible in h ibitors of ∆5-3-ketosteroid
isom erase.
We were in terested in studyin g sim ilar tran sform ation s of 14α-alcoh ols as
possible precursors of steroids with an un usual CD cyclic part. Th e
13,14-secosteroidal m oiety is also ch aracteristic of som e n atural com poun ds
like carolin oside8 or with aph ysalin s9. It was assum ed th at treatm en t of
14α-h ydroxy derivatives 1 with CAN or LTA would result in th e form ation
of radical 2 (Sch em e 1). β-Fission of th e latter sh ould lead to radical 3,
wh ich can produce a n um ber of products with m odified carbon skeleton s
depen din g on th e substituen t R.
R
R
R
CAN
or LTA
product(s)
O
OH
O
2
1
3
SCHEME 1
In vestigation s usin g th is approach h ave th us far been con ducted for de-
rivatives con tain in g oxo group10 or a ch olestan e side ch ain 11 at C-17. In th e
first case th e form ation of 13-iodo-13,14-secosteroids was observed usin g
LTA/I2; h owever, th e stereoch em istry at C-13 rem ain ed to be un deter-
m in ed. Oxidation with LTA of 14α-h ydroxy steroids with a ch olestan e side
ch ain un der th erm al or ph otolytic con dition s resulted also in fragm en ta-
tion of th e C13–C14 bon d to give th e correspon din g ∆12- an d ∆13(18)-13,14-
seco derivatives11. In addition , form ation of com poun ds with a pyran cycle
an d oth er cyclization products was observed. An oth er result of radical oxi-
dation of 14α-alcoh ols with HgO/I2 was deh ydration to th e ∆14-alken es.
We decided to exten d th e n um ber of 14α-h ydroxy steroids as substrates
for th e radical oxidation an d to pay m ore atten tion to th e stereoch em istry
an d con form ation of th e form ed products.
EXPERIMENTAL
Meltin g poin ts were taken on a Boetius m eltin g poin t m icroapparatus an d are un corrected.
IR spectra (waven um bers in cm –1) were recorded on a UR-20 spectroph otom eter. 1H an d
13C NMR spectra were, un less oth erwise stated, taken on a Bruker AC-200 (200 MHz for 1H,
50 MHz for 13C) spectrom eter usin g TMS as an in tern al stan dard. Ch em ical sh ifts are given
in δ (ppm ), couplin g con stan ts (J) in Hz. MS an d HRMS data were obtain ed with a Fin n igan
MAT95 spectrom eter. X-Ray data collection (Nicolet R3m diffractom eter) was perform ed via
th e ω/2θ scan m ode. Th e structure was solved by direct m eth ods (SIR97)12 an d refin ed by
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Khripach et al.:
full-m atrix least squares (SHELXL97)13. Position s of h ydrogen atom s were calculated, an d re-
fin ed by usin g th e ridin g m odel. All ch em icals were of an alytical grade. 3β-Acetoxy-
14α-h ydroxyan drost-5-en -17-on e was obtain ed from Organ on N.V. (Akzo Nobel, Neth er-
lan ds). Reaction s were m on itored by TLC usin g alum in ium or plastic sh eets with silica gel
60 F254 precoated (Merck Art. 5715). Colum n ch rom atograph y was carried out on Kieselgel 60
(Merck Art. 7734). Usual work-up in cludes wash in g of th e organ ic layer with water followed
by dryin g (an h ydrous Na2SO4) an d evaporation in vacuo.
Oxidation of 4 with CAN
To a stirred solution of h ydroxy keton e 4 (200 m g, 0.58 m m ol) in CH3CN (3 m l), a solution
of CAN (1.112 g, 2.03 m m ol) in water (0.5 m l) was added at 75 °C. Th e solution becam e
colorless in 0.5 m in . After th e usual work-up, th e residue was ch rom atograph ed on SiO2
to give:
a) (13S)-3β-Acetoxy-13-hydroxy-13,14-secoandrost-5-ene-14,17-dione 13-nitrate (5) (50 m g,
40% based on used 4). MS, m/z (rel.%): 347 (12), 301 (54), 159 (71), 158 (31), 157 (64), 145
(85), 105 (41), 81 (39). HRMS: calculated for C19H25NO5: 347.1733 (M+ – AcOH), foun d:
347.1735; calculated for C19H25O3: 301.1804 (M+ – AcOH – NO2), foun d: 301.1804.
b) Startin g ketol 4 (75 m g).
An drost-5-en e-3β,14α-diol (6)
A solution of ketol 4 (200 m g, 0.58 m m ol), KOH (325 m g, 5.8 m m ol), an d N2H4·H2O (0.5 m l,
11.6 m m ol) in dieth ylen e glycol (3 m l) was h eated at 185 °C for 2 h . Th e reaction m ixture
was cooled, diluted with water, an d extracted with EtOAc an d toluen e. Th e com bin ed
extracts were evaporated to give diol 6 (160 m g, 95%) as wh ite crystals, m .p. 172–174 °C
(h exan e). 1H NMR: 0.90 s, 3 H (3 × 18-H), 1.04 s, 3 H (3 × 19-H); 3.52 m , 1 H (3-H); 5.40 m ,
1 H (6-H). 13C NMR: 19.2, 19.3, 19.8, 21.9, 26.1, 30.6, 31.6, 33.7, 34.5, 36.4, 36.6, 37.3,
42.2, 43.8, 44.8, 71.6, 83.5, 121.7, 140.2.
3β-Acetoxyan drost-5-en -14α-ol (7)
To a solution of diol 6 (150 m g, 0.52 m m ol) in pyridin e (2 m l), acetic an h ydride (0.5 m l,
5.2 m m ol) was added. Th e reaction m ixture was left at room tem perature for 16 h , th en di-
luted with water, an d extracted with EtOAc. Th e extract was dried (an h ydrous Na2SO4) an d
th e solven t was evaporated. Th e residue was crystallized from h exan e to give th e acetate 7
(2.6 g, 76%) as wh ite crystals, m .p. 109–110 °C. 1H NMR: 0.90 s, 3 H (3 × 18-H); 1.06 s, 3 H
(3 × 19-H); 2.04 s, 3 H (OAc); 4.60 m , 1 H (3-H); 5.44 brs, 1 H (6-H). IR (KBr): 1 730, 1 470,
1 440, 1 385, 1 260,1 040.
Oxidation of 7 with CAN
To a stirred solution of 7 (200 m g, 0.60 m m ol) in CH3CN (3 m l) at 55 °C, a solution of CAN
(825 m g, 1.5 m m ol) in water (0.4 m l) was added. Th e solution becam e dark-brown an d th en
in 30 s colorless. Th e reaction m ixture was diluted with eth er an d wash ed with water. Th e
organ ic layer was dried (an h ydrous Na2SO4) an d evaporated. Th e residue was
ch rom atograph ed on SiO2 to give 3β-acetoxyan drosta-5,14-dien e (8) (28 m g, 15%), m .p.
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14α-Hydroxy Steroids
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105–107 °C (h exan e). 1H NMR: 0.98 s, 3 H (3 × 18-H); 1.02 s, 3 H (3 × 19-H); 2.02 s, 3 H
(OAc); 4.60 m , 1 H (3-H); 5.14 brs, 1 H (15-H); 5.44 brs, 1 H (6-H).
3β-Acetoxyan drost-5-en e-14α,17β-diol (9)
To a solution of ketol 4 (2.0 g, 5.7 m m ol) in EtOAc (30 m l) an d MeOH (7.5 m l), NaBH4
(430 m g, 11 m m ol) was added portion wise durin g 0.5 h . Th e m ixture was stirred for 1 h an d
th en dilute AcOH was added. Th e solven t was evaporated, th e residue was dissolved in
CHCl3 an d water was added. Th e organ ic layer was separated, wash ed with brin e, dried (an -
h ydrous Na2SO4) an d evaporated. Th e residue was ch rom atograph ed on silica gel (toluen e–
EtOAc 5 : 1 an d 1 : 1) to give diol 9 (1.8 g, 89%), m .p. 147–150 °C (h exan e–EtOAc). 1H NMR:
0.90 s, 3 H (3 × 18-H); 1.06 s, 3 H (3 × 19-H); 2.04 s, 3 H (OAc); 4.30 dd, 1 H, J1 = 11, J2 = 7
(17-H); 4.58 m , 1 H (3-H); 5.40 brs, 1 H (6-H).
Oxidation of 9 with CAN
To a solution of diol 9 (100 m g, 0.28 m m ol) in CH3CN (1.5 m l), CAN (798 m g, 1.42 m m ol)
dissolved in water (0.4 m l) was added at room tem perature. Th e solution becam e dark-
brown , an d th en in 30 s its color ch an ged to yellow. Th e reaction m ixture was diluted with
eth er an d th e organ ic layer was wash ed with brin e, dried (an h ydrous Na2SO4), an d evapo-
rated. Th e residue was ch rom atograph ed on silica gel (h exan e–EtOAc 3 : 1 an d 1 : 1) to give:
a) 3β-Acetoxy-13,14-dioxo-13,14:13,17-disecoandrost-5-en-17-al (10) (35 m g, 38%) as a
colorless oil. 1H NMR: 1.04 s, 3 H (3 × 19-H); 2.04 s, 3 H (OAc); 2.10 s, 3 H (3 × 18-H); 4.60 m ,
3 H (3-H); 5.40 brs, 1 H (6-H); 9.80 s, 1 H (-CHO). 13C NMR: 18.6, 21.4, 22.8, 27.4, 30.0,
30.4, 36.0, 36.7, 37.2, 37.7, 38.2, 44.8, 46.7, 49.0, 75.4, 120.9, 139.7, 170.5, 200.1, 208.8,
213.1. IR (KBr): 1 730, 1 710, 1 440, 1 370, 1 250, 1 040.
b) 3β-Acetoxy-14-oxo-des-D-androst-5-ene 13-carbaldehyde (11) (12 m g, 14%) as a colorless
oil. 1H NMR: 1.00 s, 3 H (3 × 19-H); 1.20 s, 3 H (3 × 18-H); 2.04 s, 3 H (OAc); 4.58 m , 1 H
(3-H); 5.40 d, 1 H, J = 6 (6-H); 9.86 s, 1 H (-CHO). 13C NMR: 18.4, 21.4, 23.7, 25.2, 27.4,
27.8, 33.6, 36.9, 37.4, 37.5, 48.9, 52.8, 55.7, 73.8, 122.5, 140.5, 170.4, 200.9, 213.8. IR (KBr):
1 740, 1 705, 1 625, 1 470, 1 445, 1 370, 1 250, 1 040.
c) Startin g diol 9 (20 m g).
3β,17β-Diacetoxyan drost-5-en -14α-ol (12)
To a solution of diol 9 (2.0 g, 5.7 m m ol) in Py (5 m l), Ac2O (2 m l, 21 m m ol) was added. Th e
reaction m ixture was left at room tem perature for 16 h , th en diluted with water an d ex-
tracted with EtOAc. Th e extract was dried (an h ydrous Na2SO4) an d th e solven t was evapo-
rated. Th e residue was crystallized from h exan e–EtOAc to give 17β-acetate 12 (1.92 g, 86%)
as wh ite crystals, m .p. 174–177 °C. 1H NMR: 0.94 s, 3 H (3 × 18-H); 1.06 s, 3 H (3 × 19-H);
2.06 s, 3 H (OAc); 2.08 s, 3 H (OAc); 4.60 m , 1 H (3-H); 5.20 dd, 1 H, J1 = 16, J2 = 4 (17-H);
5.42 brs, 1 H (6-H). 13C NMR: 15.7, 19.2, 19.4, 21.2, 21.4, 25.0, 27.0, 27.7, 28.9, 32.3, 34.8,
36.7, 37.0, 38.0, 43.5, 46.8, 73.8, 81.3, 82.5, 122.2, 139.2, 170.5, 171.2. IR (KBr): 1 740, 1 470,
1 450, 1 380, 1 250, 1 040.
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3β,17β-Diacetoxyan drosta-5,14-dien e (13)
To a solution of 17β-acetate 12 (160 m g, 0.41 m m ol) in CH3CN (1.0 m l), CAN (562 m g,
1.03 m m ol) in water (0.2 m l) was added at 80 °C. Th e solution becam e dark-brown an d th en
its color ch an ged to pale-yellow in 30 s. Th e reaction m ixture was cooled an d diluted with
eth er. Th e organ ic layer was wash ed with brin e, dried (Na2SO4), an d evaporated. Th e residue
was ch rom atograph ed on silica gel (h exan e–EtOAc 3 : 1) to give dien e 13 (100 m g, 65%),
m .p. 150–152 °C (h exan e–EtOAc). 1H NMR: 1.00 s, 3 H (3 × 18-H); 1.06 s, 3 H (3 × 19-H);
2.04 s, 3 H (OAc); 2.08 s, 3 H (OAc); 2.58–2.66 m , 1 H (16-H); 4.60 m , 1 H (3-H); 4.88 t, 1 H,
J = 8 (17-H); 5.16 brs, 1 H (15-H); 5.46 brs, 1 H (6-H). 13C NMR: 16.7, 19.0, 21.2, 21.4, 27.6,
29.3, 31.2, 35.3, 36.7, 37.0, 38.0, 39.1, 47.2, 50.0, 73.7, 83.4, 116.0, 122.1, 138.9, 151.5,
170.4, 171.
14α-Hydroxy-6β-m eth oxy-3α,5-cyclo-5α-an drostan -17-on e (16)
To a suspen sion of 3β-acetoxy-14α-h ydroxyan drost-5-en -17-on e 4 (17 g) in MeOH (200 m l),
a solution of MeONa (prepared from 1.5 g of Na an d 50 m l of MeOH) was added. Th e m ix-
ture was stirred for 30 m in an d th e solven t was partly evaporated. Th e m ixture was diluted
with water an d th e precipitated wh ite crystals were filtered off, wash ed with water, an d
dried in air to give 3β,14α-dih ydroxyan drost-5-en -17-on e 14 (14 g, 94%).
To a suspen sion of keton e 14 (14 g) in pyridin e (200 m l), tosyl ch loride (21 g) was added.
Th e m ixture was stirred for 1 h un til it becam e h om ogen eous an d left at room tem perature
for 20 h . Th en it was diluted with water, th e precipitated crystals were filtered off an d dried
in air to give 14α-h ydroxy-3β-tosyloxyan drost-5-en -17-on e 15 (19.4 g, 92%).
A suspen sion of tosylate 15 (19.4 g) in MeOH (300 m l) an d pyridin e (20 m l) was refluxed
for 3 h . Th e reaction m ixture was cooled an d th e solven t was evaporated. Th e residue was
dissolved in EtOAc–h exan e (1 : 2) an d left for crystallization . Th e precipitated crystals were
wash ed with h exan e an d dried to give 7.5 g of eth er 16. Th e m oth er liquor was evaporated
an d subjected to colum n ch rom atograph y (h exan e–EtOAc 1 : 1) to give an addition al 3 g of
eth er 16. Total yield was 10.5 g (78%). 1H NMR: 1.06 s, 3 H (3 × 18-H); 1.07 s, 3 H (3 ×
19-H); 2.90 m , 1 H (6-H); 3.37 s, 3 H (OMe). 13C NMR: 13.3, 18.2, 19.3, 20.6, 21.3, 24.9,
25.1, 29.4, 30.1, 32.9, 33.3, 33.4, 34.9, 41.1, 43.7, 53.0, 56.7, 81.6, 82.1, 218.9. MS, m/z
(rel.%): 318 (73), 303 (32), 300 (18), 286 (100), 268 (40), 263 (69), 245 (63), 243 (20), 227
(50), 213 (46), 94 (66). HRMS: calculated for C20H30O3: 318.2195 (M+); foun d: 318.2193.
6β-Meth oxy-3α,5-cyclo-5α-an drostan e-14α,17β-diol (17)
To a suspen sion of ketol 16 (500 m g, 1.57 m m ol) an d CaCl2 (200 m g, 2 m m ol) in eth an ol
(5 m l), a solution of NaBH4 (90 m g, 2.36 m m ol) in water (0.2 m l) was added. Th e m ixture
was stirred for 30 m in an d th en excess of NaBH4 was destroyed with dilute AcOH. Th e usual
work-up an d colum n ch rom atograph y gave diol 17 (400 m g, 80%), m .p. 176–178 °C (h exan e–
EtOAc). 1H NMR: 0.94 s, 3 H (3 × 18-H); 1.06 s, 3 H (3 × 19-H); 2.85 t, 1 H, J = 3 (6-H); 3.34 s,
3 H (OMe); 4.31 dd, 1 H, J1 = 8, J2 = 4 (17-H). IR (KBr): 1 460, 1 380, 1 100, 1 040, 920.
14α-Hydroxy-6β-m eth oxy-3α,5-cyclo-5α-an drostan -17-on e O-Meth yloxim e (20)
To a solution of ketol 16 (200 m g, 0.63 m m ol) in pyridin e (5 m l), NH2OMe·HCl (105 m g,
1.26 m m ol) was added. Th e reaction m ixture was h eated at 50 °C for 8 h . Th en it was di-
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14α-Hydroxy Steroids
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luted with water an d extracted with EtOAc. Th e extract was dried an d evaporated. Th e resi-
due was ch rom atograph ed on SiO2 to give oxim e 20 (240 m g, 73%), m .p. 75–78 °C
(h exan e–EtOAc). 1H NMR: 1.04 s, 3 H (3 × 18-H); 1.08 s, 3 H (3 × 19-H); 2.85 t, 1 H, J = 3
(6-H); 3.33 s, 3 H (6-OMe); 3.81 s, 3 H (=NOMe). 13C NMR: 13.3, 19.2, 20.9, 21.3, 21.8, 23.8,
24.9, 27.3, 30.3, 31.4, 33.4, 35.0, 40.9, 43.7, 49.1, 56.6, 61.2, 82.3, 82.9, 169.1. IR (KBr): 1 470,
1 385, 1 100, 1 060, 950.
Oxidation of 20 with LTA
A suspen sion of oxim e 20 (1.3 g, 3.75 m m ol), LTA (2.87 g, 6.62 m m ol), an d CaCO3 (562 m g,
5.62 m m ol) was refluxed for a sh ort tim e. Upon coolin g, iodin e (714 m g, 5.62 m m ol) was
added an d th e m ixture was refluxed for 15 m in . Th e usual work-up an d colum n ch rom ato-
graph y on SiO2 gave 700 m g of 21 an d 22 as wh ite crystals. Crystallization of th is m ixture from
eth an ol afforded pure (13S)-13-acetoxy-6β-methoxy-3α,5-cyclo-13,14-seco-5α-androstane-
13,17-dione 17-(O-methyloxime) (21) (150 m g, 11%), m .p. 199–202 °C. MS, m/z (rel.%): 405
(9.8), 390 (1.7), 375 (23), 374 (100), 346 (10), 345 (10), 314 (33), 105 (20), 43 (59). HRMS:
calculated for C23 H35NO5: 405.2515 (M+); foun d: 405.2510. Th e m oth er liquor was treated
with Ca(BH4)2 to decom pose th e rest of 21 an d to allow ch rom atograph ic separation of 22.
To a suspen sion of NaBH4 (49 m g, 1.3 m m ol) in dry EtOH (2 m l), CaCl2 (71 m g,
0.64 m m ol, dried at 250 °C for 2 h ) was added at –10 °C. Th e suspen sion was stirred for
20 m in an d th e m ixture of 21 an d 22 (130 m g, 0.32 m m ol, from m oth er liquor) was added
dropwise at th e sam e tem perature. Th e reaction m ixture was stirred for 15 m in , an d th en
several drops of aceton e were added an d th e m ixture was worked up in a usual way. Ch ro-
m atograph y on SiO2 gave 14-acetoxy-13,14-epoxy-6β-methoxy-3α,5-cyclo-13,14-seco-5α-androstan-
17-one O-methyloxime (22) (38 m g, 32%). IR (KBr): 1 760, 1 470, 1 450, 1 370, 1 255, 1 220,
1 095, 1 060. MS, m/z (rel.%): 405 (6.9), 374 (15), 346 (27), 345 (100), 314 (37), 313 (42),
300 (20), 282 (31), 137 (32), 105 (26). HRMS: calculated for C23H35NO5: 405.2515 (M+),
foun d: 405.2517; calculated for C21H31NO3: 345.2303 (M+ – AcOH), foun d: 345.2303.
Oxidation of 4 with LTA an d I2
A suspen sion of ketol 4 (400 m g, 1.2 m m ol), LTA (786 m g, 1.54 m m ol), an d CaCO3 (154 m g,
1.65 m m ol) was sh ortly h eated un der reflux. Upon coolin g, iodin e (196 m g, 1.54 m m ol) was
added an d th e suspen sion was h eated un der reflux with stirrin g for 20 m in . Th e reaction
m ixture was cooled an d filtered. Th e filtrate was wash ed with a solution of Na2S2O3 an d
with H2O, dried (an h ydrous Na2SO4), an d evaporated. Th e residue was ch rom atograph ed on
SiO2 to give (13S)-3β-acetoxy-13-iodo-13,14-secoandrost-5-ene-14,17-dione (24) (85 m g, 16%), m .p.
128–131 °C (h exan e–EtOAc). IR (KBr): 1 730, 1 705, 1 480, 1 445, 1 375, 1 250, 1 040.
Oxidation of 16 with LTA an d I2
A su spen sion of ketol 16 (200 m g, 0.63 m m ol), LTA (482 m g, 0.94 m m ol), an d CaCO3
(94 m g, 0.94 m m ol) was refluxed for a sh ort tim e. Upon coolin g, iodin e (119 m g, 0.94 m m ol)
was added an d th e suspen sion was refluxed for 15 m in . Th e m ixture was cooled an d filtered.
Th e filtrate was wash ed with a solution of Na2S2O3, an d with H2O, dried (an h ydrous
Na2SO4), an d evaporated. Th e residue was ch rom atograph ed on SiO2 to give (13S)-13-iodo-
6β-methoxy-3α,5-cyclo-13,14-seco-5α-androstane-14,17-dione (25) (237 m g, 85%), m .p. 161–163 °C
(eth an ol). 1H NMR: 0.99 s, 3 H (3 × 19-H); 1.95 s, 3 H (3 × 18-H); 3.32 s, 3 H (OMe); 3.86 t,
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Khripach et al.:
1 H, J = 11 (16α-H). 13C NMR: 13.0, 18.1, 21.1, 24.5, 27.6, 27.8, 32.6, 32.8, 34.2, 34.3, 41.8,
42.2, 45.5, 48.1, 48.7, 49.5, 56.8, 81.1, 206.8, 218.1. IR (KBr): 1 705, 1 475, 1 450, 1 385, 1 280,
1 185, 1 110, 1 085. MS, m/z (rel.%): 444 (0.8), 429 (3), 389 (14), 318 (23), 317 (100), 299
(12), 191 (9), 137 (9), 125 (15), 105 (10). HRMS: calculated for C20H29IO3: 444.1161 (M+);
foun d: 444.1156.
RESULTS AND DISCUSSION
First experim en ts were carried out on com poun ds with a 3β-acetoxy-5-en e
system in rin gs A an d B (Sch em e 2). Th e reaction of 17-oxo steroid 4 with
CAN produced th e 13,14-secosteroid 5 in a m oderate 40% yield. Sim ilar
tran sform ation of 17-un substituted 14α-h ydroxy steroid 7 was studied as
well. Th is com poun d was obtain ed by Wolf–Kish n er reduction 14 of h ydroxy
keton e 4 followed by reacetylation . However, form ation of a rath er com -
plex m ixture of com poun ds was observed again , an d on ly on e product h as
been iden tified as th e 14-en e steroid 8.
O
NH2NH2
KOH, DEG
OH
OH
RO
AcO
6, R = H
4
Ac2O/Py
7, R = Ac
CAN
CAN
ONO2
O
O
AcO
AcO
5
8
SCHEME 2
Next, th e oxidation of th e 17β-h ydroxy derivative 9 an d its correspon d-
in g acetate 12 with CAN was studied (Sch em e 3). In th e case of diol 9, oxi-
dative fragm en tation of th e C an d D rin gs took place with th e form ation of
two m ain products 10 an d 11. Un der sim ilar con dition s, 17β-acetate 12 un -
derwen t deh ydration to th e 14-en e 13.
Sim ilar to th e reaction with CAN, practically all experim en ts with LTA
led to form ation of rath er com plex m ixtures. Th us, treatm en t of 6 with LTA
in th e presen ce of iodin e gave 13-iodo-14,17-dioxo steroid 24 in 16% yield
on ly. At least partly th ese m ixtures resulted from decom position in A an d B
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

14α-Hydroxy Steroids
1771
OAc
OH
NaBH4
Ac2O/Py
4
OH
OH
AcO
AcO
9
12
CAN
CAN
OAc
CHO
CHO
O
+
O
O
AcO
AcO
AcO
10
13
11
SCHEME 3
rin gs, an d th erefore th e m ore stable 6β-m eth oxy-3α,5-cyclo derivatives
16–20 were in vestigated. Th ese com poun ds were prepared as in dicated in
Sch em e 4. Th e keton e 16 was obtain ed from th e startin g m aterial 4 via
deacetylation , tosylation , an d i-steroidal rearran gem en t. Th e h ydride reduc-
tion of 16 gave th e 17β-alcoh ol 17. Ester 18 an d eth er 19 were prepared
from 17 usin g stan dard m eth ods. Treatm en t of 16 with NH2OMe furn ish ed
oxim e 20.
O
O
MeOH/Py
OH
OH
RO
4, R = Ac
16
OMe
MeONa
TsCl/Py
14, R = H
15, R = Ts
NaBH4
NH2OMe
N OMe
OR
OH
OH
OH
20
OH
18, R = Ac
19, R = Bn
17
SCHEME 4
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1772
Khripach et al.:
Th e radical oxidation of th e m eth oxyim in e 20 with LTA led to form ation
of a m ixture of two com poun ds, wh ich could n ot be separated by colum n
ch rom atograph y. Crystallization of th e m ixture gave th e secosteroid 21
(Sch em e 5). Treatm en t of th e m oth er liquor with NaBH4 gave two products,
on e with th e sam e m obility as th e startin g m ixture an d a m ore polar prod-
uct. Th e less polar product separated by colum n ch rom atograph y was iden -
tified as com poun d 22.
OAc
N OMe
N OMe
N OMe
O
LTA/I2
+
OH
O
OAc
OMe
22
OMe
OMe
20
21
SCHEME 5
It is eviden t th at form ation of com poun d 22 con tain in g a tran san n ular
epoxy bridge in volves th e tran sform ation of radical 3 in to 23 (Sch em e 6).
Th e subsequen t reaction with acetoxy radical m ay produce product 22. A
sim ilar tran sform ation h as been described for 5-h ydroxy-7-n orsteroids15.
R
R
N OMe
+ OAc
O
O
O
OAc
22
3
23
SCHEME 6
Th e m ost prom isin g results with respect to th e syn th esis of 13,14-seco-
steroids were obtain ed with LTA/I2 oxidation of th e 14α-h ydroxy-17-oxo
com poun ds (Sch em e 7). Th us, th e radical oxidation of com poun d 16 led to
O
I
LTA/I2
16%
LTA/I2
85%
4
16
O
AB
24, AB =
25, AB =
AcO
OMe
SCHEME 7
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

14α-Hydroxy Steroids
1773
th e desired product 25 in 85% yield. In th e case of th e 17-un substituted
14α-alcoh ol, diol 17 an d its derivatives 18 an d 19, all attem pts to get an in -
dividual com poun d failed.
Th e stereoch em ical assign m en t of th e m eth yl group an d iodin e at C-13
1
was don e by X-ray an alysis of com poun d 25 (Fig. 1). Th e H an d 13C ch em i-
cal sh ifts of secosteroids 5, 21, 22, an d 24 were establish ed usin g stan dard
COSY tech n iques (Table I), an d a com parative con form ation al study of
TABLE I
13C an d 1H NMR sh ifts (ppm ) of com poun ds 5, 21, 22, an d 24 at 150 an d 600 MHz, respec-
tively
5
21
1H
22
1H
24
1H
Position
13C
1H
13C
13C
13C
1
2
35.6
1.07/1.9
1.9/1.6
4.58
33.4
0.91/1.44
1.80/1.59
0.97
34.0
0.93/1.64
1.75/1.57
0.97
35.6
1.05/1.9
1.9/1.58
4.59
27.7
73.3
37.9
138.7
121.5
29.0
51
25.0
21.7
13.4
34.7
81.5
33.4
49.3
48.6
45.7
23.4
36.5
84.2
221.1
41.5
22.2
160.1
20
25.3
23.0
13.2
36.7
82.1
30.4
41.4
48.1
45.9
24.4
41.2
75.1
107.5
25.4
19.0
161.0
25.6
19.7
27.7
74
3
4
2.37/2.24
0.49/0.65
0.46/0.63
38.0
138.6
122
2.36/2.23
5
6
5.41
2.80
2.80
5.42
7
2.41/1.87
2.77
1.77/1.80
3.08
1.20/2.06
2.94
28.3
50.1
50.9
38.9
26.6
41.3
2.5/1.86
2.73
8
9
52
1.31
1.23
1.03
10
11
12
13
14
15
16
17
18
19
38.7
21.1
31.1
93.5
218.3
43.1
33.1
207.6
17.2
18.1
1.6/0.87
1.6/1.77
1.45/1.03
1.45/1.97
1.67/1.6
1.6/1.9
1.87/0.7
2.3/2.3
217.5
42.5
34.7
207.4
18.6
18.0
3.38/2.27
2.62/3.01
2.42/3.02
2.3/2.8
1.90/2.06
2.84/2.71
2.82/2.63
2.53/3.94
1.52
0.97
2.03
1.54
1.02
1.96
1.40
1.05
2.02
1.95
0.97
2.03
18.9
20.6/
170.9
22.3/
170
23/
168.8
21.3/
170.9
AcO
–OMe
57.1
62.4
3.32
3.95
56.4
61.9
=NOMe
3.86
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1774
Khripach et al.:
com poun ds 5 an d 24 was don e usin g n uclear Overh auser effect experi-
m en ts (Fig. 2). It is in terestin g th at th e con form ation of th e n in e-
m em bered rin g of 5 differs very stron gly from th at of com poun d 24.
Am on g possible reason s for con form ation al differen ces, steric factors (io-
din e bein g larger th an n itrate prefers to be in equatorial position ) an d di-
pole in teraction of n itrate an d C-17 carbon yl groups can be con sidered.
C1
C2
C18
C3
C12
I1
C10
C4
C13
C17
C11
C9
C5
C6
C19
C7
O14
O17
C8
C16
C14
O6
C15
C20
FIG. 1
ORTEP view of (13S)-13-iodo-6β-m eth oxy-3α,5-cyclo-13,14-seco-5α-an drost-5-en e-14,17-dion e
(25) (displacem en t ellipsoids are drawn at th e 30% probability level)
5
24
FIG. 2
CD-Rin gs con form ation of secosteroids 5 an d 24 on NMR data
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

14α-Hydroxy Steroids
1775
Com parison of th e data obtain ed from th e X-ray (Table II) an d NMR studies
sh ow th at th e con form ation of th e n in e-m em bered rin g iodides 24 an d 25
in th e solid state correspon ds with th at in solution .
TABLE II
Crystal data an d structure refin em en t for (13S)-13-iodo-6β-m eth oxy-3α,5-cyclo-13,14-seco-
5α-an drost-5-en e-14,17-dion e (25)
Em pirical form ula
Form ula weigh t
C20H29IO3
444.33
293(2)
Tem perature, K
Wavelen gth , Å
0.71069
Mon oclin ic
P21
Crystal system
Space group
Un it cell dim en sion s, Å an d °
a = 10.969(2); α = 90
b = 7.680(2); β = 96.960(10)
c = 11.9430(10); γ = 90
Volum e, Å3
998.7(3)
Z
2
Den sity (calculated), Mg m –3
Absorption coefficien t, m m –1
F(000)
1.478
1.617
452
Crystal size, m m 3
0.32 × 0.22 × 0.16
1.87 to 27.56
–10≤h≤14, –9≤k≤9, –15≤l≤15
4 293
θ ran ge for data collection , °
In dex ran ges
Reflection s collected
In depen den t reflection s
Com pleten ess to θ = 27.56°
Refin em en t m eth od
Data/restrain ts/param eters
Goodn ess-of-fit on F2
Fin al R in dices [I > 2σ(I)]
R in dices (all data)
4 039 [Rin t = 0.0139]
99.9%
Full-m atrix least-squares on F2
4 039/1/220
1.055
R1 = 0.0425, wR2 = 0.1159
R1 = 0.0526, wR2 = 0.1271
–0.04(3)
Absolute structure param eter
Largest diff. peak an d h ole, e Å–3
0.895 an d –1.081
Crystallograph ic data for th e structure reported in th is paper h ave been deposited with th e
Cam bridge Crystallograph ic Data Cen tre as supplem en tary publication n um ber
CCDC-171299. Copies of th e data can be obtain ed free of ch arge on application to CCDC,
e-m ail: deposit@ccdc.cam .ac.uk.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1776
Khripach et al.:
The authors are indebted to Organon International for financial support of this research. We thank
Dr N. B. Khripach and E. V. Skorodumov (Minsk) for recording of NMR spectra, and Dr M. A. Posthumus
(Wageningen) for the mass spectral measurements.
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