Pd-catalyzed cross-coupling reaction of sterically hindered vinyl iodides and organozinc reagents. Synthesis of vitamin D analogues with an aromatic ring attached at C-17

Article abstract of DOI:10.1135/cccc20021658

Palladium-catalyzed coupling of steroid 17-iodo-6β-methoxy-3α,5-cyclo-5α-androst-16-ene (4) 17-iodoandrosta-5,16-dien-3β-ol (5), and structurally similar (3aS,7R,7aR)-benzenesulfonyl-3-iodo-3a-methyl-3a,4,5,6,7,7a-hexahydro-1H- indene (6) with various ary

Full text of DOI:10.1135/cccc20021658

1658
Przezdziecka, Kurek-Tyrlik, Wicha:
Pd -CATALYZED CROSS-COUPLING REACTION OF STERICALLY
HINDERED VINYL IODIDES AND ORGANOZINC REAGENTS.
SYNTHESIS OF VITAMIN D ANALOGUES WITH AN AROMATIC
RING ATTACHED AT C-17
1
2,
Agnieszka PRZEZDZIECKA, Alicja KUREK-TYRLIK and Jerzy WICHA *
Institute of Organic Chemistry, Polish Academy of Sciences, POB 58, 01-224 Warszawa 42,
1
2
Poland; e-mail: alicja@ichf.edu.pl, jwicha@icho.edu.pl
Received February 25, 2002
Accepted July 24, 2002
This paper is dedicated to the memory of Dr Václav Černý.
Palladium -catalyzed couplin g of steroid 17-iodo-6β-m eth oxy-3α,5-cyclo-5α-an drost-16-en e
(4) 17-iodoan drosta-5,16-dien -3β-ol (5), an d structurally sim ilar (3aS,7R,7aR)-ben zen e-
sulfon yl-3-iodo-3a-m eth yl-3a,4,5,6,7,7a-h exah ydro-1H-in den e (6) with various arylzin c
ch lorides, wh ich were gen erated from aryl brom ides 8 [1-brom om eth ylben zen e (8a ),
O-(trieth ylsilyl-2-brom oph en yl)propan -2-ol (8b), 2-(4-brom oph en yl)propan -2-ol (8c), 4-bro-
m oben zon itrile (8d ), 4-brom oben zoic acid m eth yl ester (8e), 4-brom oben zoic acid tert-butyl
ester (8f) an d 3-brom opyridin e (8g)] via aryllih ium derivatives (th e Negish i couplin g) was
exam in ed. Th e respective cross-couplin g products were obtain ed in good yields for all aryl
brom ides except of 8c an d 8e. Buildin g blocks for syn th esis of certain vitam in D an alogues
h ave been prepared.
Keyw ord s: Negish i cross-couplin g; Organ ozin c reagen ts; Steroids; Vin yl iodides; Palladium ;
Vitam in s.
17-Iodoan drost-16-en e an d 17-iodoestr-16-en e derivatives, easily accessible
from th e correspon din g 17-on es1,2, h ave em erged as m ajor in term ediates in
steroid syn th esis due to progress in th e tran sition -m etal-m ediated couplin g
reaction s of vin yl iodides3. Th us, an approach to 17-pyridyl an drostan e de-
rivatives utilizin g dieth yl(3-pyridyl)boran e an d th e Suzuki couplin g4, Stille
couplin g in volvin g a furan e derivative5, an d carbon ylation in th e presen ce
of organ otin reagen ts6 or h ydroxam ic acid derivatives7,8 h ave been recen tly
reported. Th e Heck reaction of 17-iodo-16-en e steroids with eth yl vin yl
eth ers h as also been exam in ed9. In certain cases en ol triflates gen erated
from 17-on es provide a plausible altern ative to th e iodides10–13; h owever,
th ese in term ediates are operation ally less con ven ien t an d th eir preparation
requires m ore expen sive reagen ts.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021658

Synthesis of Vitamin D Analogues
1659
In con jun ction with th e syn th esis of an alogues of 1α,25-dih ydroxy-
vitam in D3 (1) on goin g in our laboratory, we were in terested in palladium -
catalyzed couplin g of 17-iodo-16-en e steroids with arom atic organ ozin c
com poun ds (th e Negish i couplin g reaction 14). Th is reaction was th ough t
particularly suited for our purposes because organ ozin c reagen ts are easy to
prepare, capable to accom m odate fun ction al groups useful for furth er elab-
oratin g of th e couplin g products (as th e cyan o group an d, possibly, th e
alkoxycarbon yl group), an d toleran t to un protected h ydroxy groups15. Th e
effect of steric h in dran ce on th e efficien cy of th e Negish i couplin g could
n ot be apprised. However, literature reports on th e couplin g of represen ta-
tive 17-iodo-16-en e steroids an d trifluoroisopropen ylzin c reagen ts16 an d on
som e experim en ts with attach m en t of 2- an d 4-brom opyridin e to th e ste-
roid rin g system 11 were en couragin g. Now, we presen t a scrutin y of reaction
of vin yl iodides 4, 5 an d 6 with a variety of aryl brom ides an d th e syn th esis
17
of key buildin g blocks for con struction of vitam in D an alogues 2 an d 3
.
OH
OH
H
OH
H
H
H
H
H
PhSO2
HO
OH
HO
2
1
3
I
I
I
O
H
H
H
H
H
H
H
H
PhSO2
PhSO2
HO
OMe
6
4
5
7
RESULTS AND DISCUSSION
1
Iodides 4 an d 5 were prepared from th e correspon din g keton es via h ydra-
zon es usin g th e origin al Barton procedure1. Iodide 6 was obtain ed from
keton e 7 wh ich was syn th esized in an an alogous way as described earlier
for its en an tiom er18
.
4-Brom otoluen e (8a) (Sch em e 1), in THF at –78 °C, was treated with
butyllith ium (1.1 m olar equivalen t, in h exan es) an d th en with zin c ch lo-
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1660
Przezdziecka, Kurek-Tyrlik, Wicha:
ride solution (1.5 m olar equivalen t, in THF). Th e obtain ed solution of
tolylzin c ch loride was allowed to react with a pre-form ed m ixture of iodide
4 an d tetrakis(triph en ylph osph in e)palladium (0) [Pd(PPh 3)4], th e latter be-
in g gen erated in situ from palladium (II) acetate, 10 m ole %, an d triph en yl-
ph osph in e, 40 m ole %. Th e tolyl derivative 9a was obtain ed in 78% yield.
TLC an alysis of th e crude product sh owed th at 9a was con tam in ated with
on ly traces of a m ore m obile product wh ich was iden tified as 6β-m eth -
oxy-3,5-cyclo-5α-an drost-16-en e; n o oth er side products could be detected.
Th e reaction of th e organ ozin c derivative gen erated from a brom ide bearin g
th e silyloxy group 8b sm ooth ly afforded product 9b. Un der an alogous con -
dition s, th e respective free alcoh ol 8c 19 failed to afford an y product, pre-
sum ably due to in solubility of th e organ om etalic in term ediate. Couplin g of
iodide 4 with 4-brom oben zon itrile (8d ) gave 9d in an excellen t yield.
R
X
R
R
4
1) BuLi
2) ZnCl2
Pd(OAc)2, PPh3
X
X
THF/hexanes
–78 oC
Br
ZnCl
8
9
OMe
R
X
Aryl bromide
Product
9a
Yield, %
Me
CH
8a
8b
8c
8d
8e
8f
78
CMe2OSiEt3
CMe2OH
CN
CH
CH
CH
CH
CH
N
9b
88
9c
-
9d
89
CO2Me
CO2C(CH3)3
H
9e
-
9f
59, 69a
8g
9g
78
a The reaction was carried out at –96 oC.
SCHEME 1
Th e above discussed results an d th e reported application of eth yl 2-
an d 3-brom oben zoates in th e zin c-m ediated couplin g with prim ary alkyl
iodides20, prom pted us to exam in e also brom oben zoic acid derivatives.
Wh en m eth yl 4-brom oben zoate (8e) was used n o couplin g product could
be obtain ed. However, tert-butyl 4-brom oben zoate21 (8f) afforded th e de-
sired product 9f in 59% yield un der stan dard con dition s (–78 °C) an d in
69% yield wh en h alogen –lith ium an d lith ium –zin c exch an ge reaction s
were carried out at –96 °C.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Vitamin D Analogues
1661
It was of in terest to exam in e, en route, th e reaction of iodide 4 with a
3-pyridyl organ ozin c derivative wh ich could lead to 17-(3-pyridyl)an drostan e
derivatives th at appear to h ave poten tial th erapeutic value22. 3-Brom o-
pyridin e (8g) was tran sform ed in to th e correspon din g lith ium an d th en
zin c derivative wh ich was used in th e Negish i couplin g reaction . Pyridyl-
an drostan e derivative 9g was obtain ed in a 78% yield as, virtually, th e on ly
reaction product. Th e h igh yield of th is preparation is n oteworth y sin ce
an alogous pyridylan drostan e derivatives were obtain ed in on ly ca 10%
yield by th e reaction of 17-oxoan drostan es with 3-lith iom pyridin e, fol-
lowed by deh ydration 23,24 an d sin ce th e afore m en tion ed Suzuki couplin g
em ployin g th e respective vin yl iodide an d dieth yl(3-pyridyl)boran e4 af-
forded th e product con tam in ated with a steroid dim er, wh ich required te-
dious purification 4,11
.
Wh en vin yl iodide with an un protected h ydroxy group 5 was treated
with an excess of organ ozin c reagen t prepared from 8d , in th e presen ce of
10 m ole % of Pd(PPh 3)4, th e cross-couplin g product 10 (Sch em e 2) was ob-
1) BuLi
2) ZnCl2
CN
CN
3) 5, Pd(OAc)2, PPh3
Br
R
In formulae 10, 11 R =
71%
8d
10
OSiEt3
1) BuLi
2) ZnCl2
3) 5, Pd(OAc)2, PPh3
HO
R
11
OSiEt3
85%
OSiEt3
Br
1) BuLi
2) ZnCl2
8b
3) 6, Pd(OAc)2, PPh3
H
PhSO2
12
82%
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1662
Przezdziecka, Kurek-Tyrlik, Wicha:
tain ed in 71% yield. Un der th e sim ilar con dition s, couplin g of 5 with th e
silyloxy derivative 8b gave 11 in 85% yield. Fin ally, iodide 6 with th e
ph en ylsulfon yl group an d th e adjacen t acidic proton sm ooth ly un derwen t
couplin g with silyloxy brom ide 8b to afford 12 in 82% yield.
Th e required ch olesterol derivative 2 was gen erated by desilylation of 11
(Sch em e 3). It could be also con ven ien tly syn th esized from n itrile 9d . Th e
reaction of 9d with m eth ylm agn esium iodide followed by h ydrolysis af-
forded th e acetoph en on e derivative 13. At th is stage th e i-steroid protective
system was cleaved an d th e resultin g keto alcoh ol 14 was treated with ex-
COCH3
R
H
H
TsOH/dioxane
H
H
H
H
HO
OMe
9d, R = CN
14
MeMgI
THF
13, R = COCH3
MeMgBr
THF
OSiEt3
OH
H
TBAF/THF
H
H
H
H
H
HO
HO
11
2
OSiEt3
OH
H
TBAF/THF
H
H
H
H
H
OMe
OMe
9b
15
SCHEME 3
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Vitamin D Analogues
1663
cess of th e Grign ard reagen t. Th e th us obtain ed acid-sen sitive diol 2 was
purified by ch rom atograph y an d crystallization . Desilylation of 9b afforded
15 wh ich is an oth er precursor of 2.
In con clusion , it was sh own th at 17-iodo-16-en e steroids sm ooth ly react
with arom atic organ ozin c reagen ts in th e presen ce of a palladium catalyst.
Com parison of our results with th ose of oth er cross-couplin g reaction s re-
ported in th e literature in dicates th at th e Negish i cross-couplin g reaction is
particularly well suited for th e vin yl iodide m oiety located in a sterically
h in dered en viron m en t.
EXPERIMENTAL
Meltin g poin ts were determ in ed on a h ot-stage apparatus an d are un corrected. NMR spectra
were recorded in CDCl3 solution s at 200 MHz with Varian Gem in i in strum en t. Ch em ical
sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. IR spectra (waven um bers in
cm –1) were recorded on Perkin –Elm er 1670 FT un it. Mass spectra (electron im pact, 70 eV)
were taken on AMD 604 (AMD In tectra Gm bH, Germ an y). Reaction s in volvin g organ o-
m etallic reagen ts were carried out in flam e-dried glassware un der an alytical grade argon
(con tain in g less th an 0.5 ppm of oxygen an d less th an 1.4 ppm of water). THF was dried
over Na-K alloy an d distilled un der argon . Organ ic extracts were dried over an h ydrous
MgSO4 an d th e solven ts were rem oved on a rotary evaporator un der reduced pressure. Merck
silica gel, 230–400 m esh , was used for colum n ch rom atograph y. Butyllith ium (2.0–2.3
M
solution in h exan es), zin c ch loride (0.5
(99.98%), were purch ased from Aldrich .
M solution in THF) an d palladium (II) acetate
17-Iodo-6β-m eth oxy-3α,5-cyclo-5α-an drost-16-en e (4)
To a solution of 6β-m eth oxy-3α,5-cyclo-5α-an drostan -17-on e (1.6 g, 5.3 m m ol) in eth an ol
(98%, 45 m l) con tain in g trieth ylam in e (25 m l), h ydrazin e h ydrate (50%, 22 m l) was added.
Th e m ixture was h eated un der reflux for 1.5 h , cooled an d th e bulk of th e solven t was re-
m oved. Th e residue was diluted with ch loroform , wash ed with water an d dried. Th e solven t
was evaporated an d th e crude h ydrazon e (2.3 g) was dissolved in THF (50 m l) an d tri-
eth ylam in e (20 m l). To th is solution , vigorously stirred an d cooled with cold water, a solu-
tion of iodin e (6.0 g, 23.6 m m ol) in THF (15 m l) was added dropwise un til brown color
persisted. After con sum ption of th e h ydrazon e (TLC), th e m ixture was extracted with tolu-
en e. Th e com bin ed extracts were wash ed with water, dried an d th e solven t was evaporated.
Th e residue (2.2 g) was ch rom atograph ed on silica gel (100 g, h exan es–eth er 99.6:0.4) to
give 4 as an oil (1.2 g, 55%). M.p. 72–73 °C (aceton e–H2O). 1H NMR: 0.47 dd, 1 H, J = 8.0,
5.1 (H-4α); 0.68 t, 1 H, J = 4.5 (H-4β); 0.79 s, 3 H (3 × H-18); 1.06 s, 3 H (3 × H-19); 2.80 t, 1 H,
J = 2.7 (H-6); 3.35 s, 3 H (OCH3); 6.13 dd, J = 3.1, 1.8 (H-16). EI-MS, m/z (%): 412 (22) [M+],
397 (57) [M+ – CH3], 380 (44) [M+ – H3COH], 357 (95) [M+ – C4H7], 91 (100). For C20H29IO
(412.4) calculated: 58.26% C, 7.09% H; foun d: 58.29% C, 7.10% H.
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1664
Przezdziecka, Kurek-Tyrlik, Wicha:
(3aS,7R,7aR)-Ben zen esulfon yl-3-iodo-3a-m eth yl-3a,4,5,6,7,7a-h exah ydro-1H-in den e (6)
Th is com poun d was prepared by th e procedure described above, usin g th e (3aR,4R,7aS)-4-
ben zen esulfon yl-7a-m eth yloctah ydroin den -1-on e18 (7; 110 m g, 0.38 m m ol), eth an ol (8 m l),
trieth ylam in e (1.4 m l) an d h ydrazin e h ydrate (2.8 m l). Th e h ydrazon e was isolated with
m eth ylen e ch loride an d th e crude product in THF (7.5 m l) an d trieth ylam in e (0.75 m l) was
treated with iodin e (200 m g, 0.79 m m ol) in THF (2 m l). Th e product was isolated with di-
ch lorom eth an e an d purified by ch rom atograph y on silica gel (14 g, h exan es–aceton e 95:5)
to give iodide 6 as an oil (101 m g, 70%). M.p. (decom p.) 172–184 °C (aceton e–h exan e).
1H NMR: 0.78 s, 3 H (3a-CH3); 2.01 td, 1 H, J = 11.3, 6.6 (H-7a); 2.36 an d 2.61 AB part of
ABXY system , 2 H, J1A,1B = 15.7, J2A,7a = 11.0, J1A,2 = 1.7, J1B,7a = 6.6, J1B,2 = 3.3 (H-2);
3.22 td, 1 H, J = 11.6, 3.4 (H-7a); 6.18 dd, 1 H, J = 3.3, 1.6 (H-2); 7.52–7.72 m , 3 H (H-Ph );
7.84–7.92 m , 2H (H-Ph ). EI-MS, m/z (%): 402 (14) [M+], 261 (29) [M+ – SO2Ph ], 134 (100)
[M+ – SO2Ph – I]. For C16H19IO2S (402.3) calculated: 47.76% C, 4.77% H, 7.97% S; foun d:
47.81% C, 4.68% H, 8.05% S.
Gen eral Procedure for th e Couplin g Reaction
To a solution of aryl h alide in THF, stirred at –78 °C, butyllith ium (2.3 M solution in
h exan es, 0.24 m l, 0.55 m m ol) an d th en , after 7 m in , zin c ch loride (0.5 M solution in THF,
1.5 m l, 0.75 m m ol) were added. Th e m ixture was stirred for 10 m in at th e in itial tem pera-
ture, th e coolin g bath was rem oved an d stirrin g was con tin ued for 30–35 m in (solution A).
In parallel, palladium (II) acetate an d triph en ylph osph in e were placed in a flask, dried an d
de-oxygen ated by con secutive application of vacuum an d argon , th en dissolved in THF an d
stirred at room tem perature for 1 h . Th e resultin g clear brigh t-yellow solution was added by
a syrin ge to th e dried an d de-oxygen ated 4, 5, or 6 an d th e wh ole was im m ediately taken
in to th e syrin ge an d added to th e solution A. Th e m ixture was stirred for 18 h , aqueous am -
m on ium ch loride solution was added, an d th e m ixture was diluted with dich lorom eth an e.
Th e organ ic layer was wash ed with water, dried an d th e solven t was evaporated.
6β-Methoxy-17-(4-methylphenyl)-3α,5-cyclo-5α-androst-16-ene (9a ). p-Tolylbrom ide (8a ;
86 m g, 0.50 m m ol) in THF (0.7 m l), butyllith ium (2.3 M solution , 0.24 m l, 0.55 m m ol) zin c
ch loride (0.5 M solution , 1.5 m l, 0.75 m m ol) an d palladium (II) acetate (2.7 m g, 0.012 m m ol)
an d triph en ylph osph in e (12.6 m g, 0.048 m m ol) in THF, an d iodide 4 (50 m g, 0.12 m m ol).
Th e residue (70 m g) was ch rom atograph ed on silica gel (7 g, h exan es–dich lorom eth an e 8:2)
to give 9a as an oil (36 m g, 78%). 1H NMR: 0.46 dd, 1 H, J = 8.0, 5.1 (H-4α); 0.67 t, 1 H, J =
4.4 (H-4β); 1.07 s, 6 H (3 × H-18 an d 3 × H-19); 2.33 s, 3 H (Ar-CH3); 2.82 t, 1 H, J = 2.6
(H-6); 3.37 s, 3 H (OCH3); 5.85 dd, 1 H, J = 3.1, 1.8 (H-16); 7.15 an d 7.27 AA′BB′ system ,
4 H, J = 8.1 (4 × H-Ar). EI-MS, m/z (%): 376 (100) [M+], 361 (20) [M+ – CH3], 329 (56) [M+
–
CH3 – H3COH], 321 (32) [M+ – C4H7]. HR-MS: for C27H36O calculated: 376.27662; foun d:
376.27643. TLC an alysis of th e crude reaction product sh owed th at 9a was con tam in ated by
traces of a m ore m obile com pon en t to wh ich structure of 6β-m eth oxy-3α,5-cyclo-5α-
an drost-16-en e was ascribed.
6β-Methoxy-17-(4-{2-[(triethylsilyl)oxy]propan-2-yl}phenyl)-3α,5-cyclo-5α-androst-16-ene (9b).
19
O-Trieth ylsilyl 2-(4-brom oph en yl)propen -2-ol (8b), prepared from 8c
in th e usual way
(380 m g, 1.15 m m ol) in THF (5 m l), butyllith ium (2.0 M solution , 0.57 m l, 1.15 m m ol), zin c
ch loride (0.5 M solution , 3 m l, 1.5 m m ol) an d palladium (II) acetate (5 m g, 0.022 m m ol),
triph en ylph osph in e (23.5 m g, 0.090 m m ol), THF (2.5 m l), an d iodide 4 (80 m g, 0.19 m m ol).
Th e crude product (397 m g) was ch rom atograph ed on silica gel (10 g, h exan es–eth er
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of Vitamin D Analogues
1665
99.6:0.4) to give 9b (92 m g, 88%) as an oil. 1H NMR: 0.47 dd, 1 H, J = 8.1, 5.1 (H-4α);
0.52–0.72 m , 6 H (Si(CH2CH3)3) an d 1 H (H-4β); 0.95 t, 9 H, J = 7.8 (Si(CH2CH3)3); 1.09 s,
6 H (3 × H-18 an d 3 × H-19); 1.56 s, 6 H (Et3SiOC(CH3)2); 2.82 t, 1 H, J = 2.6 (H-6); 3.37 s,
3 H (OCH3); 5.90 dd, 1 H, J = 3.1, 1.8 (H-16); 7.32 an d 7.37 ABq, 4 H, J = 8.6 (4 × H-Ar).
EI-MS, m/z (%): 534 (18) [M+], 519 (100) [M+ – CH3], 505 (18) [M+ – CH2CH3], 403 (18)
[M+ – OSiEt3]. HR-MS: for C35H54O2Si calculated: 534.38931; foun d: 534.39020.
17-(4-Cyanophenyl)-6β-methoxy-3α,5-cyclo-5α-androst-16-ene (9d ). 4-Brom oben zon itrile (8d ;
455 m g, 2.5 m m ol) in THF (15 m l), butyllith ium (2.3 M solution , 1.05 m l, 2.41 m m ol),
zin c ch loride (0.5
M solution , 5.4 m l, 2.7 m m ol) an d palladium (II) acetate (13.5 m g,
0.060 m m ol), triph en ylph osph in e (63 m g, 0.24 m m ol) in THF (11 m l), an d iodide 4
(259 m g, 0.63 m m ol). Th e crude product (550 m g) was ch rom atograph ed on silica gel (11 g,
h exan es–eth er 99.5:0.5) to give 9d as an oil (216 m g, 89%). IR: 2226 (CN). 1H NMR:
0.48 dd, 1 H, J = 7.9, 5.4 (H-4α); 0.69 t, 1 H, J = 4.4 (H-4β); 1.08 an d 1.10 2 s, 6 H (3 × H-18
an d 3 × H-19); 2.83 t, 1 H, J = 2.9 (H-6); 3.37 s, 3 H (OCH3); 6.07 dd, 1 H, J = 3.2, 1.8
(H-16); 7.57 an d 7.45 ABq, 4 H, J = 8.6 (H-Ar). EI-MS, m/z (%): 387 (42) [M+], 372 (65) [M+
–
CH3], 355 (39) [M+ – H3COH], 340 (42) [M+ – CH3 – H3COH], 332 (100) [M+ – C4H7].
HR-MS: for C27H33NO calculated: 387.25621; foun d: 387.25625.
17-[4-(tert-Butoxycarbonyl)phenyl]-6β-methoxy-3α,5-cyclo-5α-androst-16-ene (9f). Th e reaction
was carried out as described above but at –96 °C, usin g tert-butyl 4-brom oben zoate25 (8f;
167 m g, 0.65 m m ol) in THF (2.7 m l), butyllith ium (2.0 M solution , 0.33 m l, 0.66 m m ol),
zin c ch loride (0.5
M solution , 1.7 m l, 0.85 m m ol) an d palladium (II) acetate (2.4 m g,
0.011 m m ol), triph en ylph osph in e (11.2 m g, 0.042 m m ol) in THF (1.3 m l), an d iodide 4
(44 m g, 0.11 m m ol). Th e crude product (145 m g) was ch rom atograph ed on silica gel (3.5 g,
h exan es–eth er 99.4:0.6) to give a m ixture of 4 an d 6β-m eth oxy-5α-an drost-16-en e (8 m g),
an d th en 9f (34 m g, 69%). M.p. 152–157 °C (aceton e). IR: 1709 (COOt-Bu). 1H NMR:
0.47 dd, 1 H, J = 8.0, 5.0 (H-4α); 0.68 t, 1 H, J = 4.9 (H-4β); 1.08 an d 1.10 2 s, 6 H (3 × H-18
an d 3 × H-19); 1.59 s, 9 H (COOC(CH3)3); 2.83 t, 1 H, J = 2.7 (H-6); 3.37 s, 3 H (OCH3);
6.01 dd, 1 H, J = 3.0, 1.8 (H-16); 7.40 an d 7.90 ABq, 4 H, J = 8.2 (H-Ar). EI-MS, m/z (%): 462
(100) [M+], 447 (36) [M+ – CH3], 415 (38) [M+ – CH3 – H3COH], 407 (49) [M+ – C4H9], 389
(25) [M+ – t-BuO], 359 (32) [M+ – HCOOt-Bu – H]. For C31H42O3 (462.7) calculated:
80.48% C, 9.15% H; foun d: 80.43% C, 9.11% H. An an alogous reaction carried out at –78 °C
gave 9f in a 59% yield.
6β-Methoxy-17-(3-pyridyl)-3α,5-cyclo-5α-androst-16-ene (9g). 3-Brom opyridin e (8g; 100 m g,
0.63 m m ol) in THF (2.2 m l), butyllith ium (2.1 M solution , 0.30 m l, 0.63 m m ol), zin c ch lo-
ride (1.8 m l solution , 0.9 m m ol), an d palladium (II) acetate (2.7 m g, 0.012 m m ol), tri-
ph en ylph osph in e (12.6 m g, 0.048 m m ol) in THF (1.8 m l), an d iodide 4 (52 m g, 0.126 m m ol).
Th e crude product was ch rom atograph ed on silica gel (3 g, h exan es–aceton e 98:2) to give 9g
(36 m g, 78%). 1H NMR: 0.47 dd, 1 H, J = 8.1, 5.1 (H-4α); 0.69 t, 1 H (H-4β); 1.08 s, 6 H (3 ×
H-18 an d 3 × H-19); 2.83 t, 1 H, J = 2.7 (H-6); 3.37 s, 3 H (OCH3); 5.98 dd, 1 H, J = 3.1, 1.8
(H-16); 7.21 dd, 1 H, J = 7.9, 4.8 (H-5′); 7.64 dt, 1 H, J = 7.9, 1.9 (H-4′); 8.45 d, 1 H, J = 4.5
(H-6′); 8.62 brs, 1 H (H-2′). EI-MS, m/z (%): 363 (92) [M+], 348 (75) [M+ – CH3], 331 (42)
[M+ – H3COH], 316 (79) [M+ – CH3 – H3COH], 308 (100) [M+ – C4H7]. For C25H33NO (363.5)
calculated: 82.60% C, 9.15% H, 3.85% N; foun d: 82.45% C, 9.16% H, 3.69% N.
17(4-{2-[(Triethylsilyl)oxy]propan-2-yl}phenyl)androsta-5,16-dien-3β-ol (11). Brom ide 8b
(254 m g, 0.77 m m ol), THF (3 m l), butyllith ium (2.5 M solution , 310 µl, 0.77 m m ol), zin c
ch loride (0.5 M solution , 1.8 m l, 0.9 m m ol), palladium (II) acetate (3 m g, 0.013 m m ol) an d
triph en ylph osph in e (15.3 m g, 0.058 m m ol), THF (1.8 m l), iodide 5 (45 m g, 0.11 m m ol). Th e
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1666
Przezdziecka, Kurek-Tyrlik, Wicha:
crude product was ch rom atograph ed on silica gel (7.5 g, h exan es–aceton e 95:5) to give 11 as
a crystallin e m ass (50 m g, 85%). 1H NMR: 0.50–0.66 m , 6 H (Si(CH2CH3)); 0.95 t, 9 H, J =
8.2 (Si(CH2CH3)); 1.06 an d 1.07 2 s, 6 H (3 × H-18 an d 3 × H-19); 1.56 s, 6 H (Et3SiO(CH3)2);
3.44–3.65 m , 1 H (H-3); 5.39 brd, 1 H, J = 4.8 (H-6); 5.91 dd, 1 H, J = 3.1, 1.8 (H-16); 7.31
an d 7.37 ABq, 4 H, J = 8.7 (H-Ar). EI-MS, m/z (%): 520 (16) [M+], 505 (100) [M+ – CH3], 491
(23) [M+ – CH2CH3], 389 (27) [M+ – OSiEt3], 371 (13) [M+ – OSiEt3 – H2O]. HR-LSIMS for
C
34H52NaO2Si calculated: 543.36343; foun d: 543.36593.
O-Triethylsilyl-(3aR,4R,7aS)-2-[4-(4-benzenesulfonyl-7a-methyl-3a,4,5,6,7,7a-hexahydro-3H-
inden-1-yl)phenyl]propan-2-ol (12). Brom ide 8b (208 m g, 0.63 m m ol), butyllith ium (2.5 M so-
lution , 255 µl, 0.64 m m ol), zin c ch loride (0.5 M solution , 1.6 m l, 0.8 m m ol), palladium (II)
acetate (2.7 m g, 0.012 m m ol) an d triph en ylph osph in e (12.6 m g, 0.048 m m ol) in THF
(1.8 m l), an d iodide 6 (42 m g, 0.10 m m ol). Th e crude product was ch rom atograph ed on
silica gel (7 g, h exan es–aceton e 95:5) to give 12 as an oil (45 m g, 82%). 1H NMR: 0.51–
0.66 m , 6 H, (Si(CH2CH3)3); 0.94 t, 9 H, J = 7.8 (Si(CH2CH3)3); 1.07 s, 3 H (7a-CH3); 1.55 s,
6 H (Et3SiOC(CH3)2); 2.39 an d 2.65 AB part of ABXY system , 2 H, J15A,15B = 16.2, J15A,14
=
11.1, J15A,16 = 1.7, J15B,14 = 6.6, J15B,16 = 3.3 (H-3); 3.31 td, 1 H, J = 11.6, 3.2 (H-4); 5.88 dd,
1 H, J = 3.2, 1.8 (H-2); 7.25 an d 7.37 ABq, 4 H, J = 8.6 (H-Ar); 7.57–7.71 m , 3 H (H-Ph );
7.85–7.95 m , 2 H (H-Ph ). EI-MS, m/z (%): 524 (8) [M+], 509 (76) [M+ – CH3], 495 (14) [M+
–
CH2CH3], 393 (23) [M+ – OSiEt3], 251 (100) [M+ – OSiEt3 – Ph SO2 – H]. HR-MS: for
C
31H44O3SSi calculated: 524.27805; foun d: 524.27505.
17-(4-Cyanophenyl)androsta-5,16-dien-3β-ol (10)
a) 4-Brom oben zon itrile (8d ; 128 m g, 0.70 m m ol) in THF (3 m l), butyllith ium (2.1 M solu-
tion , 0.34 m l, 0.71 m m ol), zin c ch loride (0.5 M solution , 1.8 m l, 0.9 m m ol) an d palla-
dium (II) acetate (3.7 m g, 0.016 m m ol) an d triph en ylph osph in e (16.9 m g, 0.064 m m ol) in
THF (2.5 m l), an d iodide
5 (36 m g, 0.09 m m ol). Th e crude product (107 m g) was
ch rom atograph ed on silica gel (3.5 g, h exan es–aceton e 95:5) to give 10 (24 m g, 71%). M.p.
197–199 °C (aceton e). IR: 3616 (OH), 2221 (CN). 1H NMR: 1.07 s, 6 H (3 × H-18 an d 3 ×
H-19); 1.57 s (OH an d H2O); 3.43–3.65 m , 1 H (H-3); 5.39 brd, 1 H, J = 5.4 (H-6); 6.08 dd, 1
H, J = 3.3, 1.9 (H-16); 7.46 an d 7.57 ABq, 4 H, J = 8.6 (H-Ar). EI-MS, m/z (%): 373 (96) [M+],
358 (71) [M+ – CH3], 355 (37) [M+ – H2O], 340 (100) [M+ – CH3 – H2O]. HR-MS: for
C
26H31NO calculated: 373.24056; foun d: 373.24107.
b) i-Eth er 9d (87 m g, 0.22 m m ol) was dissolved in dioxan e (36 m l) con tain in g water (1.2
m l) an d 4-toluen esulfon ic acid m on oh ydrate (ca 7 m g, 0.037 m m ol) an d th e m ixture was
stirred at 68 °C for h . Th e product was isolated with dich lorom eth an e an d
6
ch rom atograph ed on silica gel to give 10 (66 m g, 78%), iden tical with th e sam ple described
above.
17-(4-Acetylph en yl)-6β-m eth oxy-3α,5-cyclo-5α-an drost-16-en e (13)
To a solution of n itrile 9d (86 m g, 0.22 m m ol) in THF (3.2 m l) m eth ylm agn esium iodide
(2.5 M solution in eth er, 3.2 m l, 8 m m ol) was added an d th e m ixture was stirred at 50 °C for
2 h . After coolin g, th e m ixture was diluted with toluen e, th e reaction was quen ch ed by care-
ful addition of water an d th en aqueous NH4Cl was added. Th e organ ic layer was separated,
wash ed with water an d th e solven t was rem oved. Th e residue was ch rom atograph ed on sil-
ica gel (3.5 g, h exan es–aceton e 99.2:0.8) to give 13 as an oil (62 m g, 69%). IR: 1679 (con ju-
gated COCH3); 1601, 1554 (double bon ds). 1H NMR: 0.47 dd, 1 H, J = 7.9, 5.1 (H-4α); 0.69 t,
1 H, J = 4.4 (H-4β); 1.09 an d 1.12 2 s, 6 H (3 × H-18 an d 3 × H-19); 2.59 s, 3 H (CH3CO);
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Synthesis of Vitamin D Analogues
1667
2.80 t, 1 H, J = 2.7 (H-6); 3.38 s, 3 H (OCH3); 6.06 dd, 1 H, J = 3.3, 2.0 (H-16); 7.46 an d
7.89 ABq, 4 H, J = 8.6 (H-Ar). EI-MS, m/z (%): 404 (96) [M+], 389 (81) [M+ – CH3], 372 (35)
[M+ – H3COH], 357 (85) [M+ – CH3 – H3COH], 349 (92) [M+ – C4H7], 43 (100). For C28H36O2
(404.6) calculated: 83.12% C, 8.97% H; foun d: 83.35% C, 8.89% H.
17-(4-Acetylph en yl)an drosta-5,16-dien -3β-ol (14)
A solution of i-eth er 13 (37 m g, 0.09 m m ol) an d 4-toluen esulfon ic acid m on oh ydrate (3 m g,
0.016 m m ol) in dioxan e (1.2 m l) con tain in g water (0.4 m l) was stirred at 65 °C. After 5 h ,
th e m ixture was diluted with dich lorom eth an e an d wash ed with water. Th e solven t was
evaporated an d th e residue was ch rom atograph ed on silica gel (1.5 g, h exan es–aceton e
90:10). Alcoh ol 14 (24 m g, 67%) was obtain ed. M.p. 218–219 °C (aceton e). IR: 3408, 1666
(con jugated COCH3); 1601, 1553. 1H NMR: 1.08 an d 1.09 2 s, 6 H (3 × H-18 an d 3 × H-19);
1.56 s (OH an d H2O); 2.59 s, 3 H (COCH3); 3.43–3.65 m , 1 H (H-3); 5.40 brd, 1 H (H-6);
6.08 dd, 1 H, J = 3.3, 1.9 (H-16); 7.46 an d 7.89 ABq, 4 H, J = 8.6 (H-Ar). EI-MS, m/z (%): 390
(68) [M+], 375 (53) [M+ – CH3], 372 (11) [M+ – H2O], 357 (48) [M+ – H2O – CH3]; 43 (100).
For C27H34O2 (390.5) calculated: 83.03% C, 8.77% H; foun d: 83.03% C, 8.59% H.
17-[4-(2-Hydroxypropan -2-yl)ph en yl]an drosta-5,16-dien -3β-ol (2)
a) To a solution of keton e 14 (15 m g, 0.04 m m ol) in THF (1 m l), m eth ylm agn esium
iodide (2.5 Msolution in eth er, 1 m l, 2.5 m m ol) was added an d th e m ixture was stirred at
60–65 °C for 1 h . After coolin g, th e m ixture was diluted with dich lorom eth an e an d water,
an d aqueous NH4Cl was added. Th e organ ic layer was separated, wash ed with water an d
evaporated to give a crystallin e residue (14 m g). Th is product was ch rom atograph ed on silica
gel (1.5 g, h exan es–aceton e 90:10) to give 2 (6 m g, 38%) wh ich was recrystallized from di-
ch lorom eth an e. M.p. 214–217 °C. 1H NMR: 1.06 an d 1.59 2 s, 6 H (3 × H-18 an d 3 × H-19);
1.57 s (OH an d H2O); 1.59 s, 6 H (ArC(CH3)2OH); 3.42–3.65 m , 1 H (H-3); 5.39 brd, 1 H, J =
5.7 (H-6); 5.92 dd, 1 H, J = 3.2, 1.9 (H-16); 7.36 an d 7.42 ABq, 4 H, J = 8.8 (H-Ar). EI-MS,
m/z (%): 406 (100) [M+], 391 (98) [M+ – CH3], 373 (26) [M+ – CH3 – H2O], 355 (10) [M+
–
CH3 – H2O – H2O]. For C28H38O2 (406.6) calculated: 82.71% C, 9.42% H; foun d: 82.70% C,
9.39% H.
b) A solution of crude silyl eth er 11 (44 m g, 0.085 m m ol) an d tetrabutylam m on ium fluo-
ride trih ydrate (110 m g, 0.35 m m ol) in THF (3 m l) was stirred at room tem perature for 4 h .
Th e product was crystallized from dich lorom eth an e to give 2 (26 m g, 76%) iden tical with
th e sam ple described above.
17-[4-(2-Hydroxypropan -2-yl)ph en yl]-6β-m eth oxy-3α,5-cyclo-5α-an drost-16-en e (15)
A solution of 8b (51 m g, 0.095 m m ol) an d tetrabutylam m on ium fluoride trih ydrate
(104 m g, 0.33 m m ol) in THF (3 m l) was set aside at room tem perature for 3 days. Th e m ix-
ture was diluted with dich lorom eth an e, wash ed with water an d th e solven t was evaporated.
Th e crystallin e residue (45 m g) was ch rom atograph ed on silica gel (6 g, h exan es–aceton e
97:3) to give 15 (37 m g, 93%). M.p. 188–190 °C (aceton e). 1H NMR: 0.46 dd, 1 H, J = 7.9,
4.9 (H-4α); 0.68 t, 1 H, J = 4.5 (H-4β); 1.08 s, 6 H (3 × H-18 an d 3 × H-19); 1.58 s, 6 H
(ArC(CH3)2OH); 2.82 t, 1 H, J = 2.7 (H-6); 3.36 s, 3 H (OCH3); 5.90 dd, 1 H, J = 3.1, 1.8
(H-16); 7.36 an d 7.40 ABq, 4 H, J = 8.8 (H-Ar). EI-MS, m/z (%): 420 (100) [M+], 405 (52)
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

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Przezdziecka, Kurek-Tyrlik, Wicha:
[M+ – CH3], 373 (33) [M+ – CH3 – H3COH], 365 (22) [M+ – C4H7]. For C29H40O2 (420.6) cal-
culated: 82.81% C, 9.59% H; foun d: 82.76% C, 9.61% H.
Financial support from the State Committee for Scientific Research, Grant No. 3 T09A 134 18 is
gratefully acknowledged.
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