Stereochemistry of cuprate-mediated conjugate additions of a 17-iodoandrost-16-ene to E- and Z-6-methylhept-2-en-4-one

Article abstract of DOI:10.1135/cccc20011797

(3S,15R)-15-(Benzyloxy)-3-[(tert-butyldimethylsilyl)oxy]-17-iodoandrosta -5, 16-diene (3) was prepared from the corresponding 17-hydrazone 9 with iodine in the presence of tetramethylguanidine. The vinyl iodide 3 was converted into the corresponding organ

Full text of DOI:10.1135/cccc20011797

Cuprate-Mediated Conjugate Additions
1797
STEREOCHEMISTRY OF CUPRATE-MEDIATED CONJUGATE
ADDITIONS OF A 17-IODOANDROST-16-ENE TO E- AND
Z-6-METHYLHEPT-2-EN-4-ONE
1
2,
Denise L. ANDERSEN and Thomas G. BACK *
Department of Chemistry, University of Calgary, Calgary, Alberta, T2N 1N4, Canada;
1
2
e-mail: danderse@chem.ubc.ca, tgback@ucalgary.ca
Received October 1, 2001
Accepted Decem ber 6, 2001
Dedicated to the memory of Dr Václav Černý, DrSc., a pioneer of steroid chemistry.
(3S,15R)-15-(Ben zyloxy)-3-[(tert-butyldim eth ylsilyl)oxy]-17-iodoan drosta-5,16-dien e (3) was
prepared from th e correspon din g 17-h ydrazon e 9 with iodin e in th e presen ce of tetra-
m eth ylguan idin e. Th e vin yl iodide 3 was con verted in to th e correspon din g organ ocuprate
an d con jugate addition s of th e latter were perform ed with both (E)- an d (Z)-6-m eth yl-
h ept-2-en -4-on e (4a an d 4b, respectively). In each case, th e resultin g adduct 5a was obtain ed
exclusively with th e un n atural 20S con figuration . (3S,15R)-15-(Ben zyloxy)-3-[(tert-butyl-
dim eth ylsilyl)oxy]an drosta-5,16-dien e (13) an d th e correspon din g 17,17′ h om ocouplin g
product 14 were obtain ed as byproducts. Wh en th e addition to th e E-en on e was repeated in
th e presen ce of ch loro(trim eth yl)silan e, th e yield of th e con jugate addition product im -
proved, but th e stereoch em istry at C-20 rem ain ed th e sam e.
Keyw ord s: Vin yl iodides; Cuprates; Con jugate addition s; Steroids; Total syn th eses; An ti-
biotics; A25822 B.
Steroids con tain in g a wide ran ge of side ch ain s at C-17 h ave been reported
an d th e n ature of th e side ch ain plays an im portan t role in determ in in g bio-
logical activity1. Con sequen tly, con siderable effort h as been expen ded in
devisin g n ew m eth ods for th e elaboration of steroid side ch ain s from a vari-
ety of precursors2. Th e m ajority of strategies reported to date in volve tran s-
form ation s or exten sion s of existin g side ch ain s, or th e use of 17-oxo
derivatives for th e in stallation of n ew on es. Alth ough several 17-iodo-
∆
16-steroids h ave been prepared in th e an drostan e3, estran e3g–3i,4 an d
4-azaan drostan e series3h ,3i, on ly a few exam ples of th eir use in th e
co n struction of steroid side chains have been reported, usually em ploying
palladium -catalyzed coupling reactions3f–3i,4c. In gen eral, vin yl iodides can be
con ven ien tly prepared from th e correspon din g keton es by treatm en t of
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi:10.1135/cccc20011797

1798
Andersen, Back:
th eir h ydrazon es with iodin e an d a base such as tetram eth ylguan idin e via
th e procedure of Barton an d coworkers5.
In th e course of our work directed toward th e syn th esis6 of th e an ti-
m ycotic agen t an tibiotic A25822 B (ref.7), we observed th e in adverten t
cyclization of th e keto lacton e 1 to 2 via an in tram olecular aldol con den sa-
tion durin g an attem pted Wittig reaction (Sch em e 1). Sim ilar aldol con den -
O
Base
(Ph3P=CH2)
O
O
H
O
O
t-BuMe2SiO
H
H
1
2
H
OH
H
H
N
H
H
O
HO
OH
HO
H
H
OH
Antibiotic A25822 B
Xestobergsterol A
SCHEME 1
sation s of 15,23-dioxo steroids were recen tly em ployed by Jun g8 an d Krafft9
an d th eir coworkers in syn th eses of th e com plex m arin e sterol xesto-
bergsterol A (ref.10) an d related com poun ds. Prom pted by th ese preceden ts,
we wish ed to in vestigate th e possibility of usin g a 17-iodo-∆16 sterol con -
tain in g an appropriate oxygen fun ction at C-15 for th e purpose of in troduc-
in g a suitably fun ction alized side ch ain at C-17. We n ow report th e
preparation of th e n ovel steroidal vin yl iodide 3 an d our first attem pts at its
cuprate-m ediated con jugate addition to en on e 4 to afford adduct 5 via
Sch em e 2. Of particular in terest was th e determ in ation of th e effect of th e
E,Z geom etry of th e en on e upon th e stereoch em istry at C-20 in th e product.
I
20
O
O
+
OBn
t-BuMe2SiO
OBn
4a (E)
4b (Z)
3
5a (20S)
and/or 5b (20R)
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Cuprate-Mediated Conjugate Additions
1799
RESULTS AND DISCUSSION
Th e E-isom er 4a was con ven ien tly obtain ed by a literature m eth od from
th e aldol con den sation of keton e 6 with acetaldeh yde, followed by deh y-
dration 11 (Sch em e 3). Sin ce an earlier syn th esis of th e Z-isom er 4b required
th e separation of an E,Z-m ixture by preparative gas ch rom atograph y12, we
developed a stereoselective m eth od for its preparation (Sch em e 3). Th us, 4b
was obtain ed by th e copper(I)-catalyzed couplin g of (Z)-prop-1-en yl-
1-m agn esium brom ide with 3-m eth ylbutan oyl ch loride by m ean s of th e
gen eral procedure of Koch etkov et al.13. Both products were obtain ed as es-
sen tially pure (>95%) geom etrical isom ers.
1. MsCl, Py
2. Et3N
1. LDA
2. CH3CHO
O
OH
O
O
6
4a (45% overall; >95% E)
1. Mg
2. CuI, Me2S
O
Br
O
Me2CHCH2CCl
3.
4b (58% overall; >95% Z)
SCHEME 3
Th e vin yl iodide 3 was prepared by th e gen eral m eth od of Barton et al.5b
.
Th us, th e kn own epoxy keton e 7 (ref.14) was first reduced to th e corre-
spon din g 15β-h ydroxy derivative 8 with diph en yl diselen ide an d sodium
boroh ydride in eth an ol15. Th e latter steroid was con verted to its h ydrazon e
9 an d subjected to th e Barton protocol, th ereby providin g 10 an d a sm all
am oun t of th e rearran ged product 11 (ref.16). Fin ally, th e O-ben zylation of
10 afforded th e desired 15β-ben zyloxy vin yl iodide 3 (Sch em e 4).
Th e vin yl iodide 3 was th en con verted to th e correspon din g cuprate 12
by lith iation with tert-butyllith ium an d addition to copper(I) iodide–
tributylph osph in e com plex17. Wh en th e cuprate was added to th e (E)-en on e
4a, th e con jugate addition product 5a was obtain ed in relatively poor yield,
alon g with th e alken e 13 an d th e dim er 14, th e latter two products result-
in g from h ydrolysis an d h om ocouplin g of th e cuprate, respectively. Sin ce
ch loro(trim eth yl)silan e is kn own to affect th e rate an d th e stereoch em istry
of con jugate addition s of cuprates18,19, th e reaction was repeated in th e
presen ce of th e ch lorosilan e. Th is resulted in a sign ifican t im provem en t in
th e yield of adduct 5a, but h ad n o effect on th e stereo- ch em istry at C-20.
We th en perform ed th e cuprate addition to th e Z-isom er 4b in order to de-
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1800
Andersen, Back:
O
PhSeSePh
NaBH4
EtOH
NH2
N
O
O
NH2NH2
H
t-BuMe2SiO
H
H
7
OH
OH
8 (96%)
9 (98%)
I2, (Me2N)2C=NH
I
I
Me
OH
1. NaH
2. BnBr
+
H
H
H
OBn
OH
3 (98%)
10 (64%)
11 (18%)
SCHEME 4
term in e wh eth er th e com plem en tary epim er at C-20 would be produced.
However, th e sam e adduct 5a was obtain ed as in th e reaction of cuprate 12
with en on e 4a. We were un able to detect an y sign ifican t am oun t of th e
C-20 epim er 5b in an y of th ese experim en ts. Th ese results are sum m arized
in Sch em e 5.
I
CuLi
1. t-BuLi (2 equiv)
2
2. CuI (0.5 equiv)
OBn
H
12
OBn
t-BuMe2SiO
3
BnO
H
H
O
O
12
12
+
+
4a
H
H
OBn
5a (37%)
OBn
13 (30%)
H
OBn
14 (14%)
O
5a (62%) + 13 (37%) + 14 (1%)
5a (33%) + 13 (30%) + 14 (4%)
Me3SiCl
4a
O
12
4b
SCHEME 5
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Cuprate-Mediated Conjugate Additions
1801
In order to con firm th e C-20 con figuration of th e adduct 5a, it was sub-
jected to acid-catalyzed elim in ation of th e ben zyloxy group to afford trien e
15. Th e latter com poun d was iden tical to th e product of deh ydration of th e
kn own allylic alcoh ol 17, in turn produced from th e epoxy alken e 16 by
th e m eth od of Tsuji et al.14 (Sch em e 6). Th us, it was establish ed th at th e
O
O
TsOH
H
OBn
91%
t-BuMe2SiO
15
5a
95%
TsOH
O
ref. 14
O
H
H
OH
t-BuMe2SiO
16
17
SCHEME 6
product of cuprate addition to eith er geom etrical isom er of th e en on e (4a
or 4b) con tain ed th e “un n atural” 20S con figuration . Attem pts to con vert
5a to th e kn own allylic alcoh ol 17 by h ydrogen olysis or Birch reduction of
th e ben zyl group resulted in sim ultan eous h ydrogen ation at ∆5 an d reduc-
tion of th e 23 oxo group, respectively. Th e observed form ation of th e sam e
C-20 epim er from both en on e isom ers can be explain ed (Sch em e 7) by as-
sum in g th at th e four possible in itial d–π* com plexes 18a–18d (form ed re-
spectively from attack of th e cuprate upon eith er face of eith er en on e
isom er) are in equilibrium an d th at product form ation en sues from th e
preferen tial irreversible reductive elim in ation of th e copper(III) in term edi-
ate 19b in stead of 19a (refs19,20).
In con clusion , a sim ple procedure for th e preparation of th e vin yl iodide
3 was developed, alon g with on e for obtain in g th e (Z)-en on e 4b stereo-
selectively. Surprisin gly, th e con jugate addition s of cuprate 12, derived
from iodide 3, to eith er geom etrical isom er of en on e 4 afforded th e sam e
adduct 5a, possessin g th e 20S con figuration . Th us, wh ile th e m eth od pro-
vides access to un n atural 20S sterols, it is n ot viable as a n ew approach to
xestobergsterol A an d related com poun ds.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1802
Andersen, Back:
(20R)
O
R
X
Li
Li
Li
Li
R2Cu
O
R2Cu
O
O
H
18a
19a
R2Cu
R2Cu
18b
Li
Li
O
O
O
H
R2Cu
R2Cu
18c
19b
18d
(20S)
R
O
R=
H
OBn
t-BuMe2SiO
SCHEME 7
EXPERIMENTAL
Meltin g poin ts were obtain ed on an A. H. Th om as h ot-stage apparatus an d are un corrected.
IR spectra (waven um bers in cm –1) were recorded on a Mattson 4030 spectrom eter. Proton
an d carbon spectra were obtain ed on a Bruker ACE 200 (1H, 200 MHz; 13C, 50 MHz), a Bruker
AM 400 (1H, 400 MHz; 13C, 100 MHz) or a Bruker DRX 400 (1H, 400 MHz; 13C, 100 MHz)
spectrom eter. Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz.
Deuterioch loroform was used as th e solven t an d residual ch loroform or tetram eth ylsilan e
were used as th e in tern al stan dards, un less oth erwise n oted. 13C NMR sign als were assign ed
as C, CH, CH2 or CH3 by DEPT experim en ts21. Low- an d h igh -resolution m ass spectra were
obtain ed on a VG 7070 or a Kratos MS80 m ass spectrom eter. All m ass spectra were obtain ed
by electron im pact at 70 eV with direct probe sam ple in troduction . Ch rom atograph y refers
to flash ch rom atograph y22 perform ed on Merck 230–400 m esh silica gel.
(Z)-Prop-1-en yl-1-m agn esium brom ide23, epoxide 7 (ref.14) an d (E)-6-m eth ylh ept-2-en -
4-on e11 (4a) were prepared accordin g to literature m eth ods. (Z)-Prop-1-en yl-1-m agn esium
brom ide an d tert-butyllith ium were titrated usin g 1 M sec-butyl alcoh ol in xylen es an d
1,10-ph en an th rolin e as th e in dicator24
.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Cuprate-Mediated Conjugate Additions
1803
(Z)-6-Meth ylh ept-2-en -4-on e (4b)
A precooled (ca –45 °C) solution of (Z)-prop-1-en yl-1-m agn esium brom ide (10 m l of a 1.0
M
solution in THF, 10 m m ol) was added to copper(I) brom ide–dim ethyl sulfide com plex (10 m m ol)
in 10 m l of THF an d 10 m l of dim eth yl sulfide at –45 °C. Th e black solution was stirred for
10 m in , an d 2 m l of h exam eth ylph osph oram ide was added. Th e m ixture was stirred for an
addition al 10 m in , 3-m eth ylbutan oyl ch loride (830 m g, 6.91 m m ol) in 2 m l of THF was
added, an d th e m ixture was stirred for 4 h at –25 °C. Th e reaction was quen ch ed with
NH4Cl solution an d partition ed between 10% aqueous NH4OH solution an d eth er. Th e re-
sultin g h eterogen eous solution was filtered th rough Celite an d extracted with eth er. Th e
eth er layer was wash ed with 10% aqueous NH4OH solution , water, NaCl solution , dried (an -
h ydrous MgSO4), an d evaporated at reduced pressure. Th is gave 500 m g (58%) of 4b as a
colourless oil. IR (n eat): 1 697, 1 673, 1 633, 1 058, 972. 1H NMR (400 MHz): 6.19–6.12 (m ,
2 H); 2.32 (d, J = 7.0, 2 H); 2.12 (m , 1 H); 2.11 (dd, J = 5.5, 0.5, 3 H); 0.94 (d, J = 6.6, 6 H).
13C NMR (100 MHz): 202.3, 142.7, 128.4, 53.7, 25.3, 23.1, 16.2. MS, m/z (rel.%): 126 (M+,
11), 111 (12), 84 (14), 69 (100). Exact m ass calculated for C8H14O: 126.1045; foun d:
126.1054.
(3S,15R)-3-[(tert-Butyldim eth ylsilyl)oxy]-15-h ydroxyan drost-5-en -17-on e (8)
Sodium boroh ydride (582 m g, 15.4 m m ol) was slowly added to a solution of diph en yl
diselen ide (2.4 g, 7.7 m m ol) in 70 m l of absolute eth an ol. Th e in itial yellow color faded an d
th e m ixture was stirred for 5 m in . Acetic acid (60 µl, 1.0 m m ol) was added, followed by
epoxy keton e 7 (2.07 g, 4.97 m m ol) an d th e solution was stirred for 2 h . Th e reaction was
diluted with NH4Cl solution an d extracted several tim es with eth er. Th e com bin ed eth er ex-
tracts were wash ed with 10% HCl solution , NaHCO3 an d NaCl solution s, dried (an h ydrous
MgSO4), an d th e solven t was evaporated. Th e residue was purified by ch rom atograph y (elu-
tion with 0–20% eth yl acetate–h exan es) to afford 1.45 g (60%) of recovered diph en yl
diselenide and 2.00 g (96%) of hydroxy ketone 8 as a white solid, m .p. 180–182 °C (chloroform –
h exan es). IR (KBr): 3 499, 1 734, 1 254, 1 166, 1 156, 1 130, 1 098. 1H NMR (200 MHz): 5.35
(m , 1 H); 4.55 (m , 1 H); 3.49 (m , 1 H); 1.19 (s, 3 H); 1.07 (s, 3 H); 0.89 (s, 9 H); 0.067 (s, 3 H);
0.065 (s, 3 H). 13C NMR (100 MHz): 220.0 (C), 142.1 (C), 119.9 (CH), 72.4 (CH), 67.3 (CH),
56.0 (CH), 50.6 (CH), 47.0 (C), 46.7 (CH2), 42.7 (CH2), 37.3 (CH2), 36.8 (C), 32.8 (CH2), 32.0
(CH2), 30.4 (CH2), 27.6 (CH), 25.9 (CH3), 20.3 (CH2), 19.3 (CH3), 18.2 (C), 17.4 (CH3), –4.6
(CH3). MS, m/z (rel.%): 361 (M+ – t-Bu, 1), 251 (28), 75 (100). For C25H42O3Si calculated:
71.72% C, 10.11% H; foun d: 71.63% C, 9.98% H.
(3S,15R)-3-[(tert-Butyldim eth ylsilyl)oxy]-15-h ydroxy-17-iodoan drosta-5,16-dien e (10) an d
(3S,15R)-3-[(tert-Butyldim eth ylsilyl)oxy]-15-h ydroxy-17-h om o-18-n oran drosta-5,17-dien e (11)
Hydroxy keton e 8 (9.03 g, 21.6 m m ol), h ydrazin e h ydrate (6.5 m l of a 55% aqueous solu-
tion , 0.12 m ol), an d trieth ylam in e (6.5 m l, 47 m m ol) were stirred in 70 m l of absolute
eth an ol for 12 h . Th e solven t was evaporated to give 9.17 g (98%) of th e correspon din g
h ydrazon e 9, wh ich was used directly in th e n ext step.
A solution of 1,1,3,3-tetram eth ylguan idin e (6.9 m l, 55 m m ol) in 160 m l of THF was
added over 15 m in to iodin e (4.2 g, 17 m m ol) dissolved in 100 m l of THF. Th e solution was
cooled to 0 °C, an d th e above h ydrazon e (3.40 g, 7.86 m m ol) in 60 m l of THF was added
dropwise. Th e m ixture was stirred for 30 m in an d th en th e THF was evaporated in vacuo.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

1804
Andersen, Back:
Th e residue was diluted with eth er, wash ed with 10% aqueous HCl solution , NaHCO3,
Na2S2O3 an d NaCl solution s, dried (an h ydrous MgSO4), an d th e solven t was evaporated.
Ch rom atograph y with 0–3% eth er–ben zen e gave two fraction s. Th e first con tain ed 2.67 g
(64%) of th e desired vin yl iodide 10 as a wh ite solid, m .p. 140–141 °C (m eth an ol). IR (KBr):
3 420, 1 575, 1 256, 1 101, 1 012, 1 001, 836. 1H NMR (200 MHz): 6.34 (d, J = 2.9, 1 H);
5.35 (m , 1 H); 4.47 (dd, J = 4.9, 3.0, 1 H); 3.50 (m , 1 H); 1.10 (s, 3 H); 1.08 (s, 3 H); 0.90 (s,
9 H); 0.07 (s, 6 H). 13C NMR (50 MHz): 142.0 (C), 139.0 (CH), 121.2 (C), 120.3 (CH), 74.6
(CH), 72.5 (CH), 58.2 (CH), 50.9 (CH), 50.6 (C), 42.7 (CH2), 37.2 (CH2), 36.9 (C), 36.3
(CH2), 32.0 (CH2), 30.7 (CH2), 28.1 (CH), 25.9 (CH3), 22.0 (CH3), 20.7 (CH2), 19.2 (CH3),
18.2 (C), –4.6 (CH3). MS, m/z (rel.%): 513 (M+ – CH3, 2), 510 (M+ – H2O, 2), 471 (M+ – t-Bu,
51), 453 (15), 252 (25), 75 (100). For C25H41IO2Si calculated: 56.81% C, 7.82% H; foun d:
57.01% C, 7.96% H.
Th e secon d fraction con tain ed 560 m g (18%) of th e rearran ged product 11 as a solid
foam . IR (KBr): 3 557, 1 252, 1 223, 1 195, 1 086, 838. 1H NMR (400 MHz): 5.34 (m , 1 H);
4.30 (t, J = 5.4, 1 H); 3.51 (m , 1 H); 1.64 (s, 3 H); 0.95 (s, 3 H); 0.90 (s, 9 H); 0.07 (s, 6 H).
13C NMR (100 MHz): 140.8 (C), 133.4 (C), 125.3 (C), 120.8 (CH), 72.6 (CH), 70.2 (CH), 58.4
(CH), 48.3 (CH), 47.7 (CH2), 42.7 (CH2), 37.4 (CH2), 36.7 (C), 32.7 (CH2), 32.0 (CH2), 30.6
(CH), 25.9 (CH3), 25.5 (CH2), 25.2 (CH2), 19.3 (CH3), 18.2 (C), 13.3 (CH3), –4.6 (CH3). MS,
m/z (rel.%): 345 (M+ – t-Bu, 23), 327 (78), 312 (25), 253 (100). Exact m ass calculated for
C
21H33O2Si (M+ – t-Bu): 345.2250; foun d: 345.2255.
(3S,15R)-15-(Ben zyloxy)-3-[(tert-butyldim eth ylsilyl)oxy]-17-iodoan drosta-5,16-dien e (3)
Alcoh ol 10 (452 m g, 0.854 m m ol) was dissolved in 25 m l of THF. Sodium h ydride (170 m g
of a 60% dispersion in m in eral oil, 4.27 m m ol) was added slowly an d th e solution was
stirred for 1 h at room tem perature. Ben zyl brom ide (0.51 m l, 4.3 m m ol) an d tetrabutyl-
am m on ium iodide (16 m g, 0.043 m m ol) were added an d th e m ixture was stirred for a fur-
th er 17 h before water was added. Th e m ixture was extracted several tim es with eth er, dried
(an h ydrous MgSO4), an d th e solven t was evaporated. Th e crude product was subjected to
kugelroh r distillation , 100 °C at 13 Pa, to rem ove th e excess ben zyl brom ide. Th e residue
con tain ed 516 m g (98%) of ben zyl eth er 3 as a wh ite solid, m .p. 112–113 °C (eth er). IR
(KBr): 1 572, 1 248, 1 096, 1 070, 838. 1H NMR (200 MHz): 7.37–7.22 (m , 5 H); 6.42 (d, J =
2.6, 1 H); 5.31 (m, 1 H); 4.54 (d, J = 11.8, 1 H); 4.38 (d, J = 11.8, 1 H); 4.11 (dd, J = 5.1, 2.6, 1 H);
3.48 (m , 1 H); 1.09 (s, 3 H); 1.06 (s, 3 H); 0.89 (s, 9 H); 0.06 (s, 6 H). 13C NMR (50 MHz):
141.8 (C), 138.8 (C), 137.3 (CH), 128.2 (CH), 127.4 (2 CH), 121.9 (C), 120.7 (CH), 80.7
(CH), 72.5 (CH), 71.0 (CH2), 58.3 (CH), 50.9 (CH), 50.8 (C), 42.7 (CH2), 37.3 (CH2), 36.9
(C), 36.3 (CH2), 32.0 (CH2), 30.6 (CH2), 28.3 (CH), 25.9 (CH3), 20.8 (CH3), 20.7 (CH2), 19.2
(CH3), 18.2 (C), –4.6 (CH3). MS, m/z (rel.%): 618 (M+, 0.2), 603 (M+ – CH3, 1), 561 (M+ – t-Bu,
78), 453 (14), 379 (9), 252 (19), 91 (100). For C32H47IO2Si: 62.12% C, 7.66% H; foun d:
61.77% C, 8.06% H.
Con jugate Addition of Cuprate 12 to En on e 4a
tert-Butyllith ium (0.45 m l of a 1.8 M solution in pen tan e, 0.80 m m ol) was added to a solu-
tion of iodide 3 (233 m g, 0.377 m m ol) in 2 m l of eth er at –78 °C, an d th e m ixture was
stirred for 1 h . Th is solution was added to copper(I) iodide–tributylph osph in e com plex17,25
(74 m g, 0.19 m m ol) in 2 m l of eth er. Th e solution was stirred for 1 h at –78 °C, followed by
th e addition of en on e 4a (24 m g, 0.19 m m ol) in 1 m l of eth er, an d th e m ixture was warm ed
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Cuprate-Mediated Conjugate Additions
1805
from –78 to 0 °C over 3 h . It was quen ch ed with (NH4)2SO4 solution , extracted several tim es
with eth er, wash ed with NaCl solution , dried (an h ydrous MgSO4), an d th e solven t was evap-
orated. Ch rom atograph y with 50% ben zen e–h exan es afforded th ree fraction s.
Th e first fraction con tain ed 55 m g (30%) of (3S,15R)-15-(benzyloxy)-3-[(tert-butyl-
dimethylsilyl)oxy]androsta-5,16-diene (13) as a white solid, m.p. 109–111 °C (methanol–petroleum
eth er). IR (KBr): 1 601, 1 589, 1 141, 1 119, 1 094, 1 058. 1H NMR (200 MHz): 7.38–7.23
(m , 5 H); 6.20 (d, J = 5.8, 1 H); 5.98 (dd, J = 5.6, 2.2, 1 H); 5.33 (m , 1 H); 4.57 (d, J = 12.0,
1 H); 4.42 (d, J = 12.0, 1 H); 4.21 (dd, J = 5.2, 2.1, 1 H); 3.48 (m , 1 H); 1.14 (s, 3 H); 1.09 (s,
3 H); 0.91 (s, 9 H); 0.08 (s, 6 H). 13C NMR (50 MHz): 149.1 (CH), 141.6 (C), 139.4 (C), 128.8
(CH), 128.1 (CH), 127.3 (CH), 127.1 (CH), 121.0 (CH), 80.8 (CH), 72.6 (CH), 70.8 (CH2),
59.2 (CH), 51.4 (CH), 46.0 (C), 42.8 (CH2), 37.3 (CH2), 36.9 (C), 35.7 (CH2), 32.0 (CH2), 30.9
(CH2), 27.7 (CH), 25.9 (CH3), 22.1 (CH3), 20.7 (CH2), 19.3 (CH3), 18.2 (C), –4.6 (CH3). MS,
m/z (rel.%): 492 (M+, 3), 477 (M+ – CH3, 15), 435 (M+ – t-Bu, 75), 91 (100). For C32H48O2Si
calculated: 77.99% C, 9.82% H; foun d: 77.80% C, 10.06% H.
Th e secon d fraction con tain ed 25 m g (14%) of 17,17′-bis{(2S,15R)-15-(benzyloxy)-
3-[(tert-butyldimethylsilyl)oxy]androsta-5,16-diene} (14) as a wh ite solid, m .p. 116–117 °C
(m eth an ol–petroleum eth er). IR (KBr): 1 560, 1 254, 1 149, 1 096. 1H NMR (400 MHz):
7.36–7.23 (m , 5 H); 5.99 (m , 1 H); 5.34 (m , 1 H); 4.54 (d, J = 12.0, 1 H); 4.46 (d, J = 12.0,
1 H); 4.20 (dd, J = 5.1, 2.4, 1 H); 3.49 (m , 1 H); 1.30 (s, 3 H); 1.08 (s, 3 H); 0.89 (s, 9 H); 0.06
(s, 6 H). 13C NMR (100 MHz): 153.9 (C), 141.7 (C), 139.6 (C), 128.2 (CH), 127.4 (CH), 127.2
(CH), 126.5 (CH), 121.1 (CH), 79.9 (CH), 72.6 (CH), 71.0 (CH2), 59.9 (CH), 51.0 (CH), 48.0
(C), 42.9 (CH2), 39.3 (CH2), 36.8 (C), 35.9 (CH2), 32.1 (CH2), 30.8 (CH2), 27.5 (CH), 25.9
(CH3), 22.2 (CH3), 21.0 (CH2), 19.2 (CH3), 18.2 (C), –4.6 (CH3). MS, m/z (rel.%): 759 (39),
108 (89), 69 (100). For C64H94O4Si2 calculated: 78.09% C, 9.63% H; foun d: 77.95% C, 9.78% H.
Th e th ird fraction con tain ed 43 m g (37%) of (3S,15R,20S)-15-(benzyloxy)-3-[(tert-butyl-
dimethylsilyl)oxy]cholesta-5,16-dien-23-one (5a) as a gum : IR (KBr): 1 713, 1 616, 1 291, 1 252,
1 090, 1 067. 1H NMR (400 MHz): 7.37–7.21 (m , 5 H); 5.62 (d, J = 1.8, 1 H); 5.33 (m , 1 H);
4.51 (d, J = 12.1, 1 H); 4.41 (d, J = 12.1, 1 H); 4.13 (dd, J = 5.1, 2.4, 1 H); 3.48 (m , 1 H); 2.81
(m , 1 H); 2.53 (dd, J = 16.0, 5.0, 1 H); 1.17 (s, 3 H); 1.09 (d, J = 6.8, 3 H); 1.08 (s, 3 H); 0.90
(d, J = 7.1, 6 H); 0.89 (s, 9 H); 0.06 (s, 6 H). 13C NMR (100 MHz): 209.8 (C), 166.2 (C), 141.7
(C), 139.7 (C), 128.1 (CH), 127.3 (CH), 127.1 (CH), 121.9 (CH), 121.1 (CH), 79.6 (CH), 72.6
(CH), 70.6 (CH2), 60.1 (CH), 52.4 (CH2), 51.2 (CH), 50.5 (CH2), 47.6 (C), 42.8 (CH2), 37.3
(CH2), 36.9 (C), 34.9 (CH2), 32.1 (CH2), 30.8 (CH2), 27.6 (CH), 27.4 (CH), 25.9 (CH3), 24.5
(CH), 22.59 (CH3), 22.56 (CH3), 21.1 (CH3), 21.2 (CH3), 20.6 (CH2), 19.2 (CH3), 18.2 (C),
–4.6 (CH3). MS, m/z (rel.%): 618 (M+, 0.4), 603 (M+ – CH3, 0.8), 561 (M+ – t-Bu, 21), 510
(16), 453 (22), 279 (26), 91 (100). Exact m ass calculated for C36H53O3Si (M+ – t-Bu):
561.3764; foun d: 561.3763.
Con jugate Addition of Cuprate 12 to En on e 4a in th e Presen ce of Ch loro(trim eth yl)silan e
tert-Butyllith ium (0.38 m l of a 1.78 M solution in pen tan e, 0.68 m m ol) was added to iodide
3 (211 m g, 0.341 m m ol) in 2 m l of eth er at –78 °C, an d th e m ixture was stirred for 1 h . A
h om ogen eous solution of copper(I) iodide–tributylph osph in e com plex25 (67 m g, 0.17 m m ol)
in 2 m l of eth er was added, th e m ixture was stirred for 1 h at –78 °C, an d a solution of
en on e 4a (22 m g, 0.17 m m ol) an d ch loro(trim eth yl)silan e (43 µl, 0.34 m m ol) in 1 m l of
eth er was added. Th e m ixture was warm ed from –78 to 0 °C over 4 h . Th e reaction was
quen ch ed with (NH4)2SO4 solution , extracted several tim es with eth er, wash ed with NaCl
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solution , dried (an h ydrous MgSO4), evaporated, an d purified by ch rom atograph y (elution
with 50% ben zen e–h exan es). Th is gave th ree fraction s. Th e first con tain ed 62 m g (37%) of
13, th e secon d con tain ed 2 m g (1%) of dim er 14, an d th e th ird fraction con tain ed 66 m g
(62%) of 5a. Th ese products were iden tical (TLC an d 1H NMR) with th ose obtain ed in th e
absen ce of ch loro(trim eth yl)silan e.
Con jugate Addition of Cuprate 12 to En on e 4b
Iodide 3 (275 m g, 0.444 m m ol) in 2 m l of eth er at –78 °C was reacted with tert-butyllith ium
(0.66 m l of a 1.35 M solution in pen tan e, 0.89 m m ol) for 15 m in . A h om ogen eous m ixture
of copper(I) iodide (43 m g, 0.23 m m ol) an d dim eth yl sulfide25 (65 µl, 0.88 m m ol) in 2 m l of
THF was added, an d th e solution was stirred for 30 m in at –40 °C. En on e 4b (28 m g, 0.22
m m ol) in 1 m l of THF was added an d th e m ixture was stirred for 2 h , durin g wh ich th e re-
action m ixture was warm ed from –78 °C to room tem perature. Th e reaction was quen ch ed
with NH4Cl solution , diluted with eth er, wash ed with NaCl solution , dried (MgSO4), an d th e
solven t was rem oved in vacuo. Ch rom atograph y with 50% ben zen e–h exan es gave th ree frac-
tion s: 64 m g (30%) of 13, 10 m g (4%) of dim er 14, an d 45 m g (33%) of 5a. Th e 1H NMR
spectra of th ese com poun ds were iden tical to th ose obtain ed from en on e 4a.
(3S,20S)-3-[(tert-Butyldim eth ylsilyl)oxy]ch olesta-5,14,16-trien -23-on e (15)
Th e epoxide 16 was prepared an d con verted in to th e allylic alcoh ol 17 by th e m eth od of
Tsuji et al.14. Th e latter com poun d was refluxed in m eth ylen e ch loride in th e presen ce of a
catalytic am oun t of 4-m eth ylben zen e-1-sulfon ic acid for 3 h to afford trien e 15 in 95%
yield, after ch rom atograph y (elution with 50% ben zen e–h exan es). Th e sam e product was ob-
tain ed in 91% yield wh en 5a was subjected to sim ilar con dition s. Product 15 was a wh ite
solid, m .p. 97–98 °C (m eth an ol–petroleum eth er). IR (KBr): 1 712, 1 256, 1 079, 1 018, 889.
1H NMR (400 MHz): 6.04 (d, J = 1.9, 1 H); 5.82 (d, J = 1.9, 1 H); 5.41 (m , 1 H); 3.49 (m , 1 H);
2.97 (m , 1 H); 2.61 (dd, J = 16.1, 5.5, 1 H); 2.44 (dd, J = 16.4, 8.5, 1 H); 1.12 (d, J = 7.2, 3 H);
1.11 (s, 3 H); 1.05 (s, 3 H); 0.91 (d, J = 6.9, 6 H); 0.90 (s, 9 H); 0.07 (s, 6 H). 13C NMR (100 MHz):
210.1 (C), 162.7 (C), 158.4 (C), 140.9 (C), 122.2 (CH), 120.9 (CH), 118.5 (CH), 72.6 (CH),
53.8 (CH), 53.7 (C), 52.7 (CH2), 51.5 (CH2), 42.8 (CH2), 37.7 (CH2), 37.3 (C), 35.7 (CH2),
32.0 (CH2), 31.7 (CH), 29.1 (CH2), 27.1 (CH), 25.9 (CH3), 24.5 (CH), 22.62 (CH3), 22.59
(CH3), 22.4 (CH2), 21.1 (CH3), 19.5 (CH3), 18.2 (C), –4.6 (CH3). MS, m/z (rel.%): 510 (M+,
15), 411 (17), 353 (11), 279 (23), 207 (100), 158 (51), 75 (85). Exact m ass calculated for
C
33H54O2Si: 510.3893; foun d: 510.3872.
We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial
support. D. L. A. is grateful to NSERC, the Izaak Walton Killam Foundation and the Alberta Heritage
Foundation for Fellowships. We also thank Dr R. Yamdagni, Ms D. Fox and Ms Q. Wu for assistance
in obtaining NMR and mass spectra, and elemental analyses.
REFERENCES AND NOTES
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1807
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25. When the cuprate in the conjugate addition to 4a was prepared from CuI and dimethyl
sulfide, with or without chlorotrimethylsilane, a poorer yield of 5a was obtained than
with the tributylphosphine complex. Attempts at utilizing mixed cuprates failed to
produce significant amounts of conjugate addition products and returned 13 as the
principal product. However, we did not observe the formation of the 20R epimer 5b in
any of these experiments.
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