A new approach toward the synthesis of C,D-cis coupled steroid and C,D-cis coupled D-homosteroid skeletons

Article abstract of DOI:10.1016/S0040-4020(03)00629-X

A short and efficient procedure has been developed for the synthesis of C,D-cis coupled steroid and D-homo steroid skeletons. A Mukaiyama reaction with transfer of the silyl group of the starting silyl enol ether to the enol of the adduct followed by addition of vinyl magnesium bromide to the unprotected carbonyl group leads to adducts which can be cyclized with ZnBr₂. The synthesis of functionalized steroid skeletons in overall yields of about 50% in four steps can be achieved in this way.

Full text of DOI:10.1016/S0040-4020(03)00629-X

Tetrahedron 59 (2003) 4287–4295
A new approach toward the synthesis of C,D-cis coupled steroid
and C,D-cis coupled D-homosteroid skeletons
a
a
Svetlana Dratch,a,b Tanya Charnikhova,a,b Florence C. E. Saraber, Ben J. M. Jansen
`
and Aede de Groota
,
*
aLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
bInstitute of Bioorganic Chemistry, National Academy of Sciences of Belarus, Kuprevich str. 5/2, 220141 Minsk, Belarus
Received 10 February 2003; revised 27 March 2003; accepted 16 April 2003
Abstract—A short and efficient procedure has been developed for the synthesis of C,D-cis coupled steroid and D-homo steroid skeletons. A
Mukaiyama reaction with transfer of the silyl group of the starting silyl enol ether to the enol of the adduct followed by addition of vinyl
magnesium bromide to the unprotected carbonyl group leads to adducts which can be cyclized with ZnBr2. The synthesis of functionalized
steroid skeletons in overall yields of about 50% in four steps can be achieved in this way. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
which the silyl group of the silyl enol ether of methoxy
tetralone is transferred to the carbonyl group of the
receiving enone e.g. carvone or methyl cyclopentenone. A
selective Grignard reaction of vinyl magnesium bromide
with the unprotected carbonyl group of methoxy tetralone
becomes possible, leading to a Torgov type intermediate.
This can be converted easily into a carbocation, which than
reacts with the silyl enol ether to close ring C, thus
completing the synthesis of the (homo)steroid skeleton.
The construction of ring C as the final step in total syntheses
of steroid skeletons is well known because of the good
results that have been obtained using the Torgov reac-
tion.1–12 In this approach the formation of the 8–14 bond
completes the synthesis of the steroid skeleton. Many other
methods, based on other reaction types for the closing of
ring C have been employed in later steroid syntheses, but to
the best of our knowledge only one report has been
published in which the construction the 12–13 bond was
the final step in the closure of ring C.13–16 We now report a
second example of such an approach, which is depicted in
Scheme 1.
It is clear that the use of cyclopentenone as receptor in the
Mukaiyama–Michael reaction will lead to racemic reaction
products in which equilibration at C14 will not be
straightforward. For this reason R-carvone was investigated
as receptor, which should lead to enantiomerically pure
products with the natural steroid configuration at C14.
The strategy relies on a Mukaiyama–Michael reaction in
Scheme 1.
Keywords: Mukaiyama–Michael addition; homo-steroid synthesis; C,D-cis steroids; carvone.
*
Corresponding author. Tel.: þ31-317-482370; fax: þ31-317-484914; e-mail: aede.degroot@wur.nl
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00629-X

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S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
Scheme 2.
Starting from R-carvone, D-homo steroids will be obtained
as end products but handles are available in ring D for ring-
contraction to a normal steroid skeleton. The D-homo
steroids may also have interesting biological properties.
Since both enantiomers of carvone are available from
nature, it is possible to determine the configuration of C14
by choosing the correct enantiomer as starter, thus making
the normal 14-a D-homo steroids and their 14-b isomers
accessible. The D9,11 double bond in the ring-closed
products, will allow an easy functionalization of C11. In
this paper we would like to report on this approach and on
aspects of its scope and stereochemistry.
mixtures of diastereomers of the new silyl enol ether. To
minimize these complications in product separation and
identification, our efforts were concentrated first on carvone
as acceptor in the Mukaiyama–Michael reaction. It was
expected that the asymmetric center in carvone would direct
the addition to the enone from the least hindered side,
opposite to the isopropenyl group, thus leading to just one
adduct. It appears that diastereomeric mixtures of adducts
are formed, which differ in configuration at C8.19 This
stereoselectivity proved to be dependent on the nature of the
starting silyl enol ether. When the trimethyl silyl enol ether
2 was used, a 3:2 ratio of diastereomers 5a and 5b was
obtained in 56% yield. With the tert-butyl dimethyl silyl
enol ether 3, the ratio of 6a:6b could be improved to 4:1 and
the yield was quantitative. When the triethyl silyl enol ether
4 was the starting compound a 7:1 ratio of diastereomers
was obtained in 88% yield (Scheme 2). The yields of these
reactions were influenced by the stoichiometry of the
reagents, a 2:1 molar ratio of enol ether and carvone gave
the best results. Several Lewis acids and reaction conditions
were tried out but ultimately tritylantimonyhexachloride
(TrSbCl6) as catalyst and methylene chloride as solvent at
278 to 2408C were used for all the Mukaiyama–Michael
reactions.
2. Results and discussion
The silyl enol ether of methoxy tetralone has been used
before to generate the corresponding enolate for a Michael
reaction with cyclopentenone.17 The resulting enolate has
been reacted further with suitable electrophilic reagents,
with the ultimate purpose of constructing steroid skeletons.
Silyl dienol ethers have been reacted with methyl
cyclopentenone, with transfer of the silyl group to form a
new silyl enol ether of the accepting enone.18 This new silyl
enol ether has been used as a substrate for further alkylation
to give ultimately steroid skeletons.
Since the diastereomeric mixtures of 5a and 5b and of 6a
and 6b could be separated only with difficulties or not at all,
further reactions were first carried out with the pure major
diastereomer of triethyl silyl enol ether 7a (see Scheme 3).
The addition of vinyl magnesium bromide to 7 proceeded in
a reasonable 70% yield to give only one stereoisomer of the
adduct 8, which tentatively was assigned the indicated
configuration13 (vide infra). About 10% of non-converted
To the best of our knowledge no Mukaiyama–Michael
reaction of the silyl enol ether of methoxy tetralone with
methyl cyclopentenone, accompanied by transfer of the silyl
group to the carbonyl group of methyl cyclopentenone, has
been reported. Preliminary results showed that such a
reaction can proceed in high yield, leading to inseparable
Scheme 3.

S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
4289
starting material could be recovered. Complete conversion
of 7 proved to be difficult to achieve, probably because of
competing enolization. Unfortunately enol ether 7 and
adduct 8 could not be separated by column chromatography
in our hands. Therefore cyclization of the mixture of 8 and 7
with ZnBr220 was undertaken and went smoothly to give 9 in
good yield, together with the desilylated diketone 10. In a
separate reaction it was shown that desilylation of 7 to 10
indeed takes place with ZnBr2 under the applied reaction
conditions.
75% yield (see Scheme 4). The ratio of the diastereomers
varied slightly with the enol ether that was used, and again
the reaction was not complete after one run but a good yield
could be achieved by performing several repetitions of the
reaction without purification of the intermediate mixtures.
The ratio of the unreacted silyl enol ethers 5 and 6 and the
ratio of the corresponding adducts 13 and 14, respectively,
differed from that of the starting mixture of silyl enol ethers
5 and 6, which can be explained either by different rates of
enolization and reprotonation of the enols, or by different
rates of adduct formation.
The yield of the vinyl magnesium bromide addition could be
improved by repeating the addition twice or three times after
workup and drying of the mixture of 7 and 8. This worked
well for the TES and TBDMS silyl enol ethers because these
are stable compounds. The TMS silyl enol ether is less
stable and some decomposition leading to desilylated
product 10 and its stereoisomers, was observed.
The adducts 13 and 14 could be cyclized to a mixture of 9
and its C8 epimer 15 with ZnBr2. The fact that the two
compounds in the mixture were epimeric at C8 was proven
again by acid catalyzed isomerization of the mixture to one
compound 11.
The reactions with methyl cyclopentenone as acceptor also
proceeded smoothly, this was performed with silyl enol
ether 4. In this case the Mukaiyama–Michael reaction also
gave diastereomeric mixtures of the new silyl enol ether 16.
The addition of vinyl magnesium bromide also went
smoothly and again the reaction was not complete after
one run. A good yield could be achieved by performing
several repetitions of the reaction without purification of the
intermediate mixtures. The cyclization of the adducts 17
with ZnBr2 gave a lower yield of the cyclised dia-
stereomeric mixture of the steroid skeleton 18. Dehydration
was a major side reaction in these cases. Finally acid
catalyzed isomerization of this mixture gave the known
racemic 1923 in about 30% overall yield starting from 4
(Scheme 5).
The cyclization of pure 8 with ZnBr2 proceeded in 66%
yield, and in this way D-homo steroid 9 was obtained as an
enantiopure product in just four steps starting from methoxy
tetralone in 40% overall yield. It is known that the D9,11
double bond in steroids like 9 can be isomerized easily by
treatment with mild acid.21 It indeed proved to be the case
that 9 could be converted smoothly into its D8,9 isomer 11 by
treatment with hydrochloric acid at room temperature in
quantitative yield. All compounds were obtained as oils, but
the oxime 12, derived from 11, could be obtained in
crystalline form, so an X-ray became possible.22 In this way
the stereochemistry of 12 was determined unambiguously,
and turned out to be as indicated in Scheme 3. This
stereochemistry can be explained by a selective approach of
the bulky triethyl silyl enol ether 4 to R-(2)-carvone from
the top face, opposite to the isopropenyl group. The carvone
substituent ends up in a favorable axial position next to the
carbonyl group in the tetralone portion of the molecule and
consequently the addition of vinyl magnesium bromide
occurs from the top face.14 The closure of ring C then leads
to a cis fused CD-ring system in the steroid skeleton.
3. Conclusions
A short and efficient synthesis has been developed of CD cis
coupled steroid and CD cis coupled D-homo steroid
skeletons. A Mukaiyama–Michael reaction with transfer
of the silyl group of the starting silyl enol ether to the enol of
the adduct is the key feature in this approach. Addition of
vinyl magnesium bromide to the unprotected carbonyl
group followed by cyclization of the adduct with ZnBr2
completes the synthesis of the (homo)steroid skeleton.
The reaction of the mixture of TMS silyl enol ethers 5a and
5b with vinyl magnesium bromide gave a mixture of two
adducts 13a and 13b in good yield, and in a similar way the
mixture of 6a and 6b could be converted into 14a and 14b in
Scheme 4.

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S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
Scheme 5.
Overall yields of about 50% in four steps leading to
functionalized steroid skeletons, make this approach easy
and attractive.
0.21 (3q); 22.20 (t); 28.66 (t); 55.14 (q); 102.86 (d); 110.68
(d); 113.18 (d); 123.10 (d); 126.61 (s); 138.91 (s); 147.95
(s); 158.94 (s). HRMS: Mþ, found 248.1229. C14H20O2Si
requires 248.1233. MS m/e (%) 248 (Mþ, 100), 247 (64),
233 (30), 217 (13), 73 (21).
4. Experimental
4.1. General
4.1.2. [(6-Methoxy-3,4-dihydro-1-naphthalenyl)oxy](di-
methyl-tert-butyl)silane (3). To a solution of 10 g
(56.8 mmol) of 6-methoxytetralone in 90 ml of acetonitrile
were added 6.9 ml (68.2 mmol) of triethylamine, 10.3 g
(68.2 mmol) of chlorodimethyl-tert-butylsilane and 10.2 g
(68.2 mmol) of sodium iodide. The reaction mixture was
stirred overnight at room temperature. Then 100 ml of
petroleum ether and 50 ml of a saturated solution of sodium
bicarbonate were added. After separation the petroleum
ether solution was dried over Na2SO4. After evaporation of
the solvent, bulb to bulb distillation afforded silyl enol ether
3 (16.55 g, 100%).
All reagents were purchased from Aldrich or Arcos, except
for carvone which was donated by Quest, and were used
without further purification unless otherwise stated. Melting
points are uncorrected. Infrared spectra were recorded on a
FTIR Biorad FTS7 spectrometer and only characteristic
absorptions are reported. NMR experiments were conducted
with Bruker AC-E 200 or DPX 400 instruments; signals are
reported in ppm (d), referenced to CHCl3. HRMS data were
obtained with a Finnigan MAT 95 spectrometer. Solvents
were freshly distilled by common practice. Product
solutions were dried over MgSO4 prior to evaporation of
the solvent under reduced pressure by using a rotary
evaporator. Reactions were monitored by GC with a DB-17
column (30 m£0.25 mm i.d.) or by TLC on silica gel plate
and visualization of compounds was accomplished by UV
detection and by spraying with a molybdate solution and
subsequent heating.
1H NMR d: 0.21 (s, 6H), 1.02 (s, 9H), 2.30 (m, 2H), 2.74 (t,
J¼7.8 Hz, 2H), 3.80 (s, 3H), 5.06 (t, J¼4.6 Hz, 1H), 6.72
(m, 2H), 7.40 (d, J¼8.2 Hz, 1H). 13C NMR d: 24.43 (2q),
18.36 (s), 22.27 (t), 25.95 (3q), 28.74 (t), 55.22 (q), 102.58
(d), 110.68 (d), 113.24 (d), 123.19 (d), 126.81 (s), 139.04
(s), 148.16 (s), 158.92 (s). HRMS: Mþ, found 290.1704.
C17H26O2Si requires 290.1702. MS m/e (%) 290 (Mþ, 54),
275 (5), 234 (28), 233 (100), 203 (38), 73 (8).
4.1.1. [(6-Methoxy-3,4-dihydro-1-naphthalenyl)oxy](tri-
methyl)silane (2).24 To a solution of 8.8 g (50 mmol) of
6-methoxytetralone in 60 ml of acetonitrile were added
6.1 g (60 mmol) of triethylamine, 6.5 g (60 mmol) of
chlorotrimethylsilane and 9 g (60 mmol) of sodium iodide.
The reaction mixture was stirred overnight at room
temperature. Then 100 ml of petroleum ether and 50 ml of
a saturated solution of sodium bicarbonate were added.
After extraction the petroleum ether solution was dried over
Na2SO4. After evaporation of the solvent, bulb to bulb
distillation afforded silyl enol ether 2 (11.4 g, 92%).
4.1.3. [(6-Methoxy-3,4-dihydro-1-naphthalenyl)oxy]-
(triethyl)silane (4). To a solution of 8.8 g (50 mmol) of
6-methoxytetralone in 60 ml of acetonitrile were added
8.3 ml (60 mmol) of triethylamine, 9.1 g (60 mmol) of
chlorotriethylsilane and 9 g (60 mmol) of sodium iodide.
The reaction mixture was stirred overnight at room
temperature. Then 100 ml of petroleum ether and 50 ml of
a saturated solution of sodium bicarbonate were added.
After extraction the petroleum ether solution was dried over
Na2SO4. After evaporation of the solvent, bulb to bulb
distillation afforded silyl enol ether 4 (12.0 g, 83%).
1
IR (CCl4) 2958, 2835, 1683, 1639, 1607, 1252 cm21. H
IR (CCl4) 2956, 2877, 1682, 1600, 1271 cm21. 1H NMR d:
0.78 (q, J¼7.6 Hz, 6H); 1.06 (t, J¼7.6 Hz, 9H); 2.30–2.38
(m, 2H); 2.73–2.81 (t, J¼7.8 Hz, 2H), 3.81 (s, 3H); 5.11 (t,
NMR d: 0.31 (s, 9H); 2.24–2.35 (m, 2H); 2.79 (t, J¼7.8 Hz,
2H); 3.83 (s, 3H); 5.12 (t, J¼4.6 Hz, 1H); 6.74 (s, 1H); 6.76
(d, J¼8.6 Hz, 1H); 7.41 (d, J¼8.2 Hz, 1H). 13C NMR d:

S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
4291
J¼4.2 Hz, 1H); 6.72–6.77 (m, 2H); 7.45 (d, J¼8.2 Hz, 1H).
13C NMR d: 5.15 (3t); 6.85 (3q); 22.31 (t); 28.74 (t);
55.14 (q); 102.18 (d); 110.71 (d); 113.22 (d); 123.11 (d);
126.79 (s); 138.98 (s); 148.19 (s); 158.99 (s). HRMS: Mþ,
found 290.1707. C17H26O2Si requires 290.1702. MS m/e
(%) 290 (Mþ, 100); 261 (81); 233 (9); 232 (9); 231 (38); 159
(8).
1H); 6.71 (dd, J¼8.7, 2.4 Hz, 1H); 7.29 (d, J¼8.7 Hz, 1H).
13C NMR d: 5.45 (3t); 6.63 (3q); 14.24 (q); 19.88 (t); 20.85
(q); 28.92 (t); 31.04 (t); 34.34 (t); 37.53 (d); 38.32 (d); 43.71
(d); 55.02 (q); 104.78 (s); 108.33 (t); 112.24 (d); 112.57 (d);
113.06 (s); 113.57 (t); 129.25 (d); 133.77 (s); 137.92 (s);
143.56 (d); 144.50 (s); 148.93 (s); 158.60 (s). HRMS: Mþ,
found 468.3062. C29H44O3Si requires 468.3060. MS m/e
(%) 468 (Mþ, 4.5); 450 (10); 336 (10); 265 (100); 115 (6);
87 (17).
4.1.4. 2-{(1R,5S)-5-Isopropenyl-2-methyl-3-[(triethyl-
silyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-3,4-dihydro-
1(2H)-naphthalenone (7a and 7b). To a solution of 2.03 g
(7 mmol) of triethylsilylenol ether 4 and 0.525 g (3.5 mmol)
of R-carvone in 15 ml CH2Cl2 was added 0.035 g
(0.06 mmol) of TrSbCl6 at 2788C and the reaction mixture
was allowed to warm to 2408C. After 1 h some drops of
pyridine were added to destroy the catalyst, and the yellow
color of the reaction mixture immediately disappeared. The
reaction mixture was allowed to warm to room temperature,
washed with brine, dried (Na2SO4), and the solvent was
evaporated. The adducts 7a and 7b (1.36 g, ratio 7:1) were
isolated by chromatography on SiO2 (light petroleum/ethyl
acetate/pyridine, 98:1:1) as an oil in 88% yield.
4.1.6. (3R,4aS,4bS,12aR)-3-Isopropenyl-8-methoxy-12a-
methyl-3,4,4a,4b,5,6,12,12a-octahydro-1(2H)-chryse-
none (9). A suspension 0.47 g (1 mmol) of adduct 8 and
0.22 g (1 mmol) of ZnBr2 in 20 ml of dry CH2Cl2 was
stirred under nitrogen for 1 h at 2788C. Then the reaction
mixture was allowed to warm to room temperature and the
solution became clear and green. After 2 h the mixture was
poured into 50 ml of saturated sodium bicarbonate solution.
The organic solution was separated and the aqueous solution
was washed three times with 50 ml of CH2Cl2. The
combined organic solution was dried over Na2SO4 and the
solvent was carefully evaporated. The residue was chro-
matographed over silica gel (light petroleum/ethyl acetate,
9:1) to give 0.22 g (66%) of 9 as a colorless oil.
1H NMR d: 0.69 (q, J¼7.9 Hz, 6H); 1.00 (t, J¼7.9 Hz, 9H);
1.61 (s, 3H); 1.67 (s, 3H); 1.50–2.40 (m, 7H); 2.76 (dt,
J¼13.0, 3.7 Hz, 1H), 2.92 (m, 2H); 3.22 (br s, 1H); 3.83 (s,
3H); 4.66 (d, J¼5.6 Hz, 2H); 6.66 (d, J¼2.4 Hz, 1H); 6.82
(dd, J¼8.6, 2.4 Hz, 1H); 8.02 (d, J¼8.6 Hz, 1H).
13C NMR (main isomer) d: 5.66 (3t); 6.84 (3q); 13.99 (q);
20.76 (q); 25.45 (t); 29.39 (t); 30.54 (t); 35.07 (t); 36.46 (d);
39.46 (d); 50.60 (d); 55.40 (q); 109.10 (t); 111.10 (s); 112.46
(d); 112.96 (d); 126.97 (s); 129.87 (d); 145.33 (s); 146.58
(s); 148.61 (s); 163.32 (s); 198.60 (s). (Minor isomer): 5.77
(3t); 6.59 (3q); 16.24 (q); 20.45 (q); 27.09 (t); 29.88 (t);
30.47 (t); 35.00 (t); 36.15 (d); 38.49 (d); 53.59 (d); 55.31 (q);
108.88 (t); 110.50 (s); 112.12 (d); 112.88 (d); 126.27 (s);
130.03 (d); 144.75 (s); 144.89 (s); 146.11 (s); 163.24 (s);
198.10 (s). HRMS: Mþ, found 440.2749. C27H40O3Si
requires 440.2747. MS m/e (%) 440 (Mþ, 10); 290 (8);
265 (100); 223 (5); 176 (7); 115 (8); 87 (21).
IR (CCl4) 2935, 2837, 1711, 1644, 1608, 1571, 1234,
1
1177 cm21. H NMR d: 1.35 (s, 3H); 1.82 (s, 3H); 1.65–
2.85 (m, 13H); 3.76 (s, 3H); 4.81 (s, 2H); 6.11 (m, 1H); 6.56
(d, J¼2.6 Hz, 1H); 6.71 (dd, J¼8.6, 2.4 Hz, 1H); 7.50 (d,
J¼8.6 Hz, 1H). 13C NMR d: 20.58 (q); 26.85 (t); 27.14 (q);
29.16 (t); 30.42 (t); 33.24 (t); 36.01 (d); 41.31 (d); 41.75 (t);
46.74 (d); 47.15 (s); 55.23 (q); 109.93 (t); 112.53 (d); 112.93
(d); 116.59 (d); 125.21 (d); 127.89 (s); 133.54 (s); 136.81
(s); 147.59 (s); 158.37 (s); 213.32 (s). HRMS: Mþ, found
336.2096. C23H28O2 requires 336.2089. MS m/e (%) 336
(Mþ, 100); 321 (11); 239 (14); 225 (29); 187 (17); 186 (44);
174 (14).
4.1.7. (3R,4aS,12aR)-3-Isopropenyl-8-methoxy-12a-
methyl-3,4,4a,5,6,11,12,12a-octahydro-1(2H)-chryse-
none (11). Compound 9 (0.08 g, 0.24 mmol) was stirred in
12 ml of 5:1 MeOH/10N HCl for 1 h. The MeOH was
removed and the remaining aqueous suspension was diluted
with 12 ml NaH2PO4 buffer (pH 4) and extracted three times
with 30 ml of ethyl acetate. The combined extracts were
dried over Na2SO4, and the solvent was evaporated to give
0.08 g (100%) of 11 as a colorless oil.
4.1.5. (1R,2S)-2-{(1R,5S)-5-Isopropenyl-2-methyl-3-
[(triethylsilyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-1-
vinyl-1,2,3,4-tetrahydro-1-naphthalenol (8). To a solution
of 15 mmol of 1 M vinyl magnesium bromide in THF was
added slowly a solution of 1.32 g (3 mmol) of ketone 7 in
15 ml of THF at 08C. The reaction mixture was stirred under
these conditions for 1 h and then at room temperature for
4–5 h. Then 25 ml of a saturated solution of NH4Cl was
added and the mixture was extracted with ethyl acetate
(3£75 ml). The ethyl acetate solution was dried (Na2SO4)
and the solvent was evaporated. The residue was purified by
chromatography on SiO2 (light petroleum/ethyl acetate,
grad., with 1% of pyridine) to give 0.95 g (68%) of 8 as a
colorless oil.
1
IR (CCl4) 2937, 2834, 1705, 1608, 1500, 1283 cm21. H
NMR d: 1.19 (s, 3H); 1.74 (s, 3H); 2.05–2.73 (m, 14H);
3.78 (s, 3H); 4.68 (s, 1H); 4.80 (s, 1H); 6.69 (s, 1H); 6.73 (d,
J¼8.2 Hz, 1H); 7.10 (d, J¼8.1 Hz, 1H). 13C NMR d: 21.11
(q); 22.96 (t); 24.48 (q); 26.61 (t); 28.93 (t); 30.34 (t); 40.14
(d); 43.15 (t); 45.99 (d); 47.13 (s); 55.28 (q); 110.60 (t);
110.89 (d); 113.20 (d); 123.17 (d); 128.25 (s); 129.47 (s);
131.53 (s); 136.89 (s); 147.33 (s); 158.12 (s); 215.60 (s).
HRMS: Mþ, found 336.2090. C23H28O2 requires 336.2089.
MS m/e (%) 336 (Mþ, 100), 321 (16), 240 (18), 239 (16),
226 (36), 225 (43), 211 (14), 150 (10).
IR (CCl4) 3616, 2957, 2914, 2878, 1677, 1604, 1575, 1498,
1
1460, 1245, 1177 cm21. H NMR d: 0.69 (q, J¼7.9 Hz,
6H); 1.00 (t, J¼7.8 Hz, 9H); 1.56 (s, 3H); 1.72 (s, 3H),
1.50–2.85 (m, 11H); 3.77 (s, 3H); 4.69 (d, J¼5.2 Hz, 2H);
5.40 (dd, J¼10.2, 2.3 Hz, 1H); 5.62 (dd, J¼17.1, 2.4 Hz,
1H); 5.84 (dd, J¼17.1, 10.2 Hz, 1H); 6.61 (d, J¼2.4 Hz,
4.1.8. (1E,3R,4aS,12aR)-3-Isopropenyl-8-methoxy-12a-
methyl-3,4,4a,5,6,11,12,12a-octahydro-1(2H)-chryse-
none oxime (12). To a stirred solution of 11 (0.67 g,

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2.0 mmol)inEtOHwasaddedahydroxylaminehydrochloride
(1.39 g, 20 mmol) and anhydrous sodium acetate (1.64 g,
20 mmol) in portions, and the suspension was refluxed.
After 30 min, TLC showed the reaction to be complete. The
mixture was filtered and solvent was removed under
vacuum. The residue was dissolved in CHCl3 (100 ml)
and extracted with H2O (3£30 ml). Drying (Na2SO4),
removal of solvent under vacuum, and column chromato-
graphy over silica gel (light petroleum/ethyl acetate, 9:1)
provided 0.53 g (75%) of 25 as white crystals, mp 1128C
(from hexane/Et2O).
drops of pyridine were added to destroy the catalyst, and the
yellow color of the reaction mixture immediately dis-
appeared. The reaction mixture was allowed to warm to
room temperature, washed with brine, dried (Na2SO4), and
the solvent was evaporated. The residue was purified by
chromatography on SiO2 (light petroleum/ethyl acetate/
pyridine, 98:1:1). A mixture of two isomers 5a and 5b in the
ratio of 3:2 was obtained (2.6 g, 56%) as white crystals (mp
55–568C from pentane).
IR (CCl4) 2939, 1680, 1602, 1252 cm21. 1H NMR d: 0.15,
0.19 (s, s, 9H); 1.39, 1.58 (s, s, 3H); 1.68, 1.73 (s, s, 3H);
1.45–2.65 (m, 6H); 2.75 (dt, J¼13.0, 3.7 Hz, 1H), 2.92 (m,
2H); 3.23, 3.35 (br s, br s, 1H); 3.83 (s, 3H); 4.73 (m, 2H);
6.67 (br s, 1H); 6.80 (dd, J¼8.7, 2.5 Hz, 1H); 8.02 (d, d,
J¼8.7 Hz, 1H). 13C NMR (isomer 1) d: 1.35 (3q); 11.90 (q);
21.38 (q); 25.53 (t); 27.24 (t); 28.11 (t); 34.36 (d); 40.63 (d);
42.16 (t); 46.60 (d); 55.43 (q); 77.05 (s); 111.70 (t); 112.35
(d); 113.36 (d); 125.88 (s); 129.88 (d); 145.63 (s); 146.73
(s); 163.50 (s); 198.95 (s); 213.78 (s). (Isomer 2) 1.95 (3q);
12.23 (q); 21.07 (q); 26.83 (t); 29.06 (t); 29.50 (t); 36.51 (d);
42.41 (d); 44.11 (t); 47.99 (d); 55.43 (q); 77.69 (s); 111.04
(t); 112.35 (d); 113.22 (d); 125.18 (s); 130.05 (d); 145.77
(s); 147.03 (s); 163.50 (s); 198.85 (s); 213.78 (s). HRMS:
Mþ, found 398.2275. C24H34O3Si requires 398.2277. MS
m/e (%) 398 (Mþ, 12), 329 (3), 248 (31), 223 (100), 222
(49), 176 (21), 73 (33).
IR (CCl4) 3602, 3267, 3086, 2936, 2833, 1645, 1608, 1573,
1
1500, 1284 cm21. H NMR d:1.24 (s, 3H), 1.55 (m, 1H),
1.77 (s, 3H), 1.93 (t, J¼5.8 Hz, 2H), 2.23 (m, 6H), 2.74 (m,
5H), 3.81 (s, 3H), 4.80 (s, 2H), 6.73 (m, 2H), 7.15 (d,
J¼8.0 Hz, 1H), 9.20 (br s, 1H). 13C NMR d: 21.37 (q), 22.88
(t), 25.50 (t), 25.90 (q), 26.78 (t), 28.99 (t), 29.31 (t), 31.38
(t), 38.63 (d), 39.06 (s), 45.23 (d), 55.25 (q), 110.21 (t),
110.87 (d), 113.16 (d), 123.05 (d), 127.04 (s), 129.42 (s),
132.09 (s), 136.93 (s), 147.35 (s), 157.97 (s), 163.95 (s).
HRMS: Mþ, found 351.2191. C23H29NO2 requires
351.2198. MS m/e (%) 351 (Mþ, 100), 334 (57), 306 (4),
226 (12), 225 (19), 143 (16).
4.1.9. (2S)-2-[(1R,5R)-Isopropenyl-2-methyl-3-oxocyclo-
hexyl]-6-methoxy-3,4-dihydro-1(2H)-naphthalenone
(10). A suspension 0.22 g (0.5 mmol) of enol ether 7 and
0.11 g (0.5 mmol) of ZnBr2 in 15 ml of dry CH2Cl2 was
stirred under nitrogen for 1 h at 2788C. Then the reaction
mixture was allowed to warm to room temperature and the
solution became clear and green. After 2.5 h the mixture
was poured into 25 ml of saturated sodium bicarbonate
solution. The organic solution was separated and the
aqueous solution was washed three times with 30 ml of
CH2Cl2. The combined organic solution was dried over
Na2SO4 and the solvent was evaporated. The residue was
chromatographed over silica gel (light petroleum/ethyl
acetate, 4:1) to give 0.168 g (100%) of two isomers (in
ratio 15:1) of diketone 10 as white crystals (mp 118–1198C
for main isomer).
4.1.11. 2-{(1R,5S)-5-Isopropenyl-2-methyl-3-[(dimethyl-
tert-butylsilyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-3,4-
dihydro-1(2H)-naphthalenone (6a and 6b). To a solution
of 3.48 g (12 mmol) of dimethyl-tert-butylsilylenol ether 3
and 1.5 g (10 mmol) of R-carvone in 25 ml CH2Cl2 was
added 0.24 g (0.4 mmol) of TrSbCl6 at 2788C. After 0.5 h
some drops of pyridine were added to destroy the catalyst,
the yellow color of the reaction mixture immediately
disappeared. The reaction mixture was allowed to warm to
room temperature, washed with brine, dried (Na2SO4), and
the solvent was evaporated. The residue was purified by
chromatography on SiO2 (light petroleum/ethyl acetate/
pyridine, 98:1:1). A mixture of two isomers 6a and 6b in the
ratio of 4:1 was obtained (4.4 g, 100%) as white crystals
(mp 72–738C from pentane).
Main isomer: IR (CCl4) 2938, 1712, 1678, 1601, 1476,
1252, 1177 cm21
.
1H NMR d: 1.02 (d, J¼6.5 Hz, 3H);
1.50–1.72 (m, 1H), 1.80 (s, 3H); 1.82–2.71 (m, 9H);
2.93–2.98 (m, 2H); 3.81 (s, 3H); 4.73 (s, 1H); 4.89 (s,
1H); 6.66 (d, J¼2.4 Hz, 1H); 6.77 (dd, J¼8.6, 2.4 Hz,
1H); 7.96 (d, J¼8.6 Hz, 1H). 13C NMR d: 11.71 (q);
22.04 (q); 22.85 (t); 28.90 (t); 29.97 (t); 37.52 (d); 40.70
(d); 44.57 (t); 46.72 (d); 48.67 (d); 55.44 (q); 112.42
(d); 112.47 (t); 113.15 (d); 126.67 (s); 129.81 (d); 146.13
(s); 146.54 (s); 163.48 (s); 197.38 (s); 212.55 (s).
HRMS: Mþ, found 326.1879. C21H26O3 requires
326.1882. MS m/e (%) 326 (Mþ, 6); 176 (100); 161 (4);
150 (15); 135 (3).
IR (CCl4) 2931, 2858, 1678, 1602, 1253 cm21. 1H NMR d:
0.11, 0.14 (s, s, 6H), 0.92, 0.94 (s, s, 9H), 1.42, 1.60 (s, s,
3H), 1.68, 1.72 (s, s, 3H), 1.50–2.40 (m, 7H), 2.74 (dt,
J¼13.0, 3.8 Hz, 1H), 2.90 (m, 2H), 3.22, 3.32 (br s, br s,
1H), 3.82 (s, 3H), 4.70 (m, 2H), 6.66 (d, J¼2.2 Hz, 1H),
6.77 (dd, J¼8.7, 2.2 Hz, 1H), 8.00 (d, d, J¼8.8 Hz, 1H). 13C
NMR (main isomer) d: 23.66 (2q), 14.25 (q), 18.25 (s),
20.80 (q), 25.44 (t), 25.93 (3q), 29.33 (t), 30.51 (t), 35.22 (t),
36.56 (d), 39.40 (d), 50.56 (d), 55.37 (q), 109.15 (t), 111.20
(s), 112.45 (d), 112.99 (d), 126.97 (s), 129.85 (d), 145.28 (s),
146.56 (s), 148.50 (s), 163.33 (s), 198.51 (s). (Minor
isomer): 23.74 (2q), 16.54 (q), 20.98 (q), 22.64 (s), 25.78
(3q), 27.29 (t), 28.83 (t), 29.99 (t), 34.86 (t), 36.34 (d), 38.57
(d), 53.60 (d), 55.24 (q), 110.00 (t), 110.63 (s), 112.28 (d),
113.09 (d), 126.41 (s), 130.13 (d), 144.85 (s), 146.11 (s),
148.68 (s), 158.56 (s), 198.03 (s). HRMS: Mþ, found
440.2746. C27H40O3Si requires 440.2747. MS m/e (%) 440
(Mþ, 8), 383 (2), 266 (22), 265 (100), 264 (31), 233 (6), 176
(7), 73 (28).
4.1.10. 2-{(1R,5S)-5-Isopropenyl-2-methyl-3-[(trimethyl-
silyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-3,4-dihydro-
1(2H)-naphthalenone (5a and 5b). To a solution of 5.7 g
(23 mmol) of trimethylsilylenol ether
2 and 1.7 g
(11.5 mmol) of R-carvone in 50 ml CH2Cl2 was added
0.11 g (0.2 mmol) of TrSbCl6 at 2788C and the reaction
mixture was allowed to warm to 2408C. After 1 h some

S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
4293
4.1.12. 2-{(1R,5S)-5-Isopropenyl-2-methyl-3-[(trimethyl-
silyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-1-vinyl-1,2,3,4-
tetrahydro-1-naphthalenol (13a and 13b). To a solution
of 3.5 mmol of 1 M vinyl magnesium bromide in THF was
added slowly a solution of 0.28 g (0.7 mmol) of the mixture
of 5a and 5b in 15 ml of THF at 08C. The reaction mixture
was stirred under these conditions for 1 h and at the room
temperature for 4–5 h. Then 10 ml of a saturated solution of
NH4Cl was added and the mixture was extracted with ethyl
acetate (3£25 ml). The ethyl acetate solution was dried
(Na2SO4) and the solvent was evaporated. The residue was
purified by chromatography on SiO2 (light petroleum/ethyl
acetate, with 1% of pyridine) to give 0.18 g (62%) of a
mixture of two isomers 13a and 13b in the ratio of 3:2 as a
colorless oil.
18.29 (s), 20.05 (t), 21.12 (q), 25.98 (3q), 29.13 (t), 31.31 (t),
34.83 (t), 37.82 (d), 38.92 (d), 43.92 (d), 55.23 (q), 76.78 (s),
108.63 (t), 112.49 (d), 112.91 (s), 113.35 (d), 113.82 (t),
129.50 (d), 134.07 (s), 138.17 (s), 143.83 (d), 144.75 (s),
149.08 (s), 158.85 (s). (Minor isomer): 24.26 (s), 17.19 (q),
17.55 (s), 22.13 (q), 23.40 (t), 25.89 (3q), 27.83 (t), 31.31 (t),
35.60 (t), 37.29 (d), 38.07 (d), 43.62 (d), 55.41 (q), 75.30 (s),
108.87 (t), 111.86 (t), 112.61 (d), 113.16 (d), 130.44 (d),
132.66 (s), 138.45 (s), 143.56 (d), 148.77 (s), 149.48 (s),
155.00 (s). HRMS: Mþ, found 468.3066. C29H44O3Si
requires 468.3060. MS m/e (%) 468 (Mþ, 3), 450 (11),
336 (12), 265 (100), 263 (27), 223 (7), 186 (11), 75 (14), 73
(48).
4.1.14. (3R,4aS,4bS,12aR)-3-Isopropenyl-8-methoxy-
12a-methyl-3,4,4a,4b,5,6,12,12a-octahydro-1(2H)-
chrysenone (9) and (3R,4aS,4bR,12aR)-3-isopropenyl-8-
methoxy-12a-methyl-3,4,4a,4b,5,6,12,12a-octahydro-
1(2H)-chrysenone (15). A suspension 0.3 g (0.7 mmol) of
the mixture of adducts 13a and 13b and 0.16 g (0.7 mmol)
of ZnBr2 in 15 ml of dry CH2Cl2 was stirred under nitrogen
for 1 h at 2788C. Then the reaction mixture was allowed to
warm to room temperature and the solution became clear
and green. After 4 h the mixture was poured into 30 ml of
saturated sodium bicarbonate solution. The organic solution
was separated and the aqueous solution was extracted three
times with 30 ml of CH2Cl2. The combined organic solution
was dried over Na2SO4 and the solvent was carefully
evaporated. The residue was chromatographed over silica
gel (light petroleum/ethyl acetate, 9:1) to give 0.16 g (68%)
of a mixture of 9 and 15 in the ratio 1:1.
IR (CCl4) 3617, 2936, 1678, 1643, 1607, 1499, 1277,
1175 cm21. 1H NMR d: 0.20 (m, 9H); 1.63, 1.64 (s, s, 3H);
1.70, 1.72 (s, s, 3H); 1.40–2.85 (m, 11H); 3.77 (s, 3H); 4.69
(d, J¼5.6 Hz, 2H); 5.35, 5.39 (dd, J¼10.3, 2.4 Hz; dd,
J¼9.8, 2.4 Hz, 1H), 5.62 (dd, J¼17.1, 2.4 Hz, 1H); 5.81,
5.84 (dd, J¼17.1, 10.3 Hz; dd, J¼17.1, 9.8 Hz, 1H); 6.62 (br
s, 1H); 6.72 (dd, J¼8.6, 2.4 Hz, 1H); 7.29 (m, 1H). 13C
NMR (main isomer) d: 0.89 (3q); 14.56 (q); 20.01 (t); 21.13
(q); 29.09 (t); 31.30 (t); 34.64 (t); 37.67 (d); 38.84 (d); 43.90
(d); 55.24 (q); 76.78 (s); 108.62 (t); 112.50 (d); 113.36 (d);
113.83 (t); 114.36 (s); 129.45 (d); 134.09 (s); 138.16 (s);
143.78 (d); 144.68 (s); 149.03 (s); 158.86 (s). (Minor
isomer): 0.81 (3q); 17.37 (q); 20.41 (q); 23.37 (t); 31.35 (t);
35.46 (t); 37.06 (d); 37.86 (t); 38.01 (d); 49.84 (d); 55.25 (q);
75.31 (s); 108.86 (t), 112.63 (d); 113.15 (d); 113.37 (s);
113.48 (t); 130.43 (d); 132.63 (s); 138.45 (s); 143.54 (d);
144.48 (s); 149.47 (s); 158.86 (s). HRMS: Mþ, found
426.2590. C26H38O3Si requires 426.2590. MS m/e (%) 426
(Mþ, 51), 411 (5), 408 (10), 281 (24), 223 (100), 186 (31),
73 (28).
1H NMR d (9þ15): 1.15, 1.35 (s, s, 3H), 1.74, 1.78 (s, s,
3H), 1.68–2.90 (m, 13H), 3.76, 3.78 (s, s, 3H), 4.68, 4.80,
4.88 (s, s, s, 2H), 6.09, 6.17 (m, m, 1H), 6.58 (dd, J¼10.0,
2.6 Hz, 1H), 6.69, 6.73 (dd, dd, J¼8.6, 2.6 Hz, 1H), 7.48,
7.59 (d, d, J¼8.6 Hz, 1H). 13C NMR d (15): 19.64 (q), 22.10
(q), 23.80 (t), 27.44 (t), 31.23 (t), 32.72 (t), 35.29 (d), 39.94
(d), 39.98 (d), 40.63 (t), 47.75 (s), 55.25 (q), 112.46 (t),
112.83 (d), 113.36 (d), 123.17 (d), 124.34 (d), 126.63 (s),
131.95 (s), 138.07 (s), 146.89 (s), 158.45 (s), 215.55 (s).
HRMS: Mþ, found 336.2083. C23H28O2 requires 336.2089.
MS m/e (%) 336 (Mþ, 100), 239 (18), 225 (30), 224 (19),
187 (33), 186 (57), 171 (16).
4.1.13. 2-{(1R,5S)-5-Isopropenyl-2-methyl-3-[(dimethyl-
tert-butylsilyl)oxy]-2-cyclohexen-1-yl}-6-methoxy-1-
vinyl-1,2,3,4-tetrahydro-1-naphthalenol (14a and 14b).
To a solution of 25 mmol of 1 M vinyl magnesium bromide
in THF was added slowly a solution of 2.2 g (5 mmol) of a
mixture of ketones 6a and 6b in 20 ml of THF at 08C. The
reaction mixture was stirred under these conditions for 1 h
and at the room temperature for 4–5 h. Then 100 ml of a
saturated solution of NH4Cl was added and the mixture was
extracted with ethyl acetate (3£75 ml). The ethyl acetate
solution was dried (Na2SO4) and the solvent was evapor-
ated. This residue was treated two times again with 15 mmol
of 1 M vinyl magnesium bromide as described above and
worked up as described above. The residue was purified by
chromatography on SiO2 (light petroleum/ethyl acetate,
grad., with 1% of pyridine) to give 1.75 g (75%) of a
mixture of 14a and 14b in the ratio of 5:1 as a colorless oil.
4.1.15. (3R,4aS,4bS,12aR)-3-Isopropenyl-8-methoxy-
12a-methyl-3,4,4a,4b,5,6,12,12a-octahydro-1(2H)-
chrysenone (9) and (3R,4aS,4bR,12aR)-3-isopropenyl-8-
methoxy-12a-methyl-3,4,4a,4b,5,6,12,12a-octahydro-
1(2H)-chrysenone (15). A suspension 0.35 g (0.75 mmol)
of a 4:1 mixture of adducts 14a and 14b and 0.17 g
(0.75 mmol) of ZnBr2 in 50 ml of dry CH2Cl2 was stirred
under nitrogen for 1 h at 2788C. Then the reaction mixture
was allowed to warm to room temperature and the
solution became clear and green. After 1 h the mixture
was poured into 15 ml of saturated sodium bicarbonate
solution. The organic solution was separated and the
aqueous solution was washed three times with 50 ml of
CH2Cl2. The combined organic solution was dried over
Na2SO4 and the solvent was carefully evaporated. The
residue was chromatographed over silica gel (light
petroleum/ethyl acetate, 9:1) to give 0.18 g (72%) of a
mixture of 9 and 15 in the ratio 5:3.
IR (CCl4) 3617, 2931, 2859, 1676, 1607, 1558, 1256,
1167 cm21. 1H NMR d: 0.15 (s, 6H), 0.97 (s, 9H), 1.55, 1.58
(s, s, 3H), 1.71, 1.74 (s, s, 3H), 1.80–2.95 (m, 11H), 3.77 (s,
3H), 4.68, 4.72 (d, d, J¼6.3 Hz, 2H), 5.35, 5.41 (dd, dd,
J¼10.2, 2.2 Hz, 1H), 5.63 (dd, J¼17.1, 2.2 Hz, 1H), 5.82,
5.85 (dd, dd, J¼17.1, 10.2 Hz, 1H), 6.61 (d, J¼2.6 Hz, 1H),
6.72 (dd, J¼8.6, 2.6 Hz, 1H), 7.27, 7.30 (d, d, J¼8.6 Hz,
1H). 13C NMR (main isomer) d: 23.63 (2q), 14.73 (q),

4294
S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
4.1.16. (3R,4aS,12aR)-3-Isopropenyl-8-methoxy-12a-
methyl-3,4,4a,5,6,11,12,12a-octahydro-1(2H)-chryse-
none (11). A mixture (5:3 or 1:1) of compounds 9 and 15
(0.13 g, 0.38 mmol) was stirred in 30 ml of 5:1 MeOH/10N
HCl for 1 h. The MeOH was removed and the remaining
aqueous suspension was diluted with 30 ml NaH2PO4 buffer
(pH 4) and extracted three times with 30 ml of ethyl acetate.
The combined extract was dried over Na2SO4, and the
solvent was evaporated to give 0.13 g (100%) of 11 as a
colorless oil.
2.2 Hz, 1H), 5.58 (dd, J¼17.1, 2.2 Hz, 1H), 5.80 (dd,
J¼17.1, 10.4 Hz, 1H), 6.60 (d, J¼2.2 Hz, 1H), 6.71 (dd,
J¼8.6, 2.2 Hz, 1H), 7.28 (d, J¼8.6 Hz, 1H). 13C NMR d:
5.42 (3t), 6.71 (3q), 10.14 (q), 18.06 (t), 22.64 (t), 31.01 (t),
33.71 (t), 44.04 (d), 44.07 (d), 55.17 (q), 76.44 (s), 112.47
(d), 113.22 (d), 113.38 (t), 114.40 (s), 130.09 (d), 133.30 (s),
1
138.61 (s), 144.37 (d), 147.73 (s), 158.73 (s). H NMR
(minor isomer) d: 0.65 (q, J¼7.9 Hz, 6H), 0.99 (t, J¼8.0 Hz,
9H), 1.63 (s, 3H), 1.40–2.9 (m, 10H), 3.77 (s, 3H), 5.30 (dd,
J¼10.4, 1.8 Hz, 1H), 5.50 (dd, J¼17.1, 10.4 Hz, 1H), 5.84
(dd, J¼17.1, 10.4 Hz, 1H), 6.60 (d, J¼2.6 Hz, 1H), 6.71 (dd,
J¼8.6, 2.6 Hz, 1H), 7.30 (d, J¼8.6 Hz, 1H). 13C NMR d:
6.32 (3t), 7.11 (3q), 13.12 (q), 21.48 (t), 25.33 (t), 31.11 (t),
32.51 (t), 43.95 (d), 50.39 (d), 55.21 (q), 75.42 (s), 111.58
(d), 112.56 (d), 113.05 (t), 115.54 (s), 130.16 (d), 133.04 (s),
138.40 (s), 144.72 (d), 149.00 (s), 158.68 (s). HRMS: Mþ,
found 414.2590. C25H38O3Si requires 414.2590. MS m/e
(%) 414 (Mþ, 8), 385 (7), 300 (8), 227 (11), 211 (16), 186
(100), 176 (11), 171 (6).
4.1.17. (1R)-6-Methoxy-2-{2-methyl-3-[(triethylsilyl)-
oxy]-2cyclopenten-1-yl}-3,4-dihydro-1(2H)-naphthale-
none (16). To
a solution of 2.03 g (7 mmol) of
triethylsilylenol ether 4 and 0.5 g (5.25 mmol) methyl
cyclopentenone in 30 ml CH2Cl2 was added 0.03 g
(0.07 mmol) of TrSbCl6 at 2788C. After 1 h some drops
of pyridine were added to destroy the catalyst, and the
yellow color of the reaction mixture immediately dis-
appeared. The reaction mixture was allowed to warm to
room temperature, washed with brine, dried (Na2SO4), and
the solvent was evaporated. A mixture of two diastereomers
16a and 16b in the ratio of 3:2 was obtained (2.02 g, 100%)
as a colorless oil.
4.1.19. 3-Methoxyestra-1(10),2,4,9(11)-tetraen-17-one
(18). A suspension 0.36 g (0.9 mmol) of the mixture of
adducts 17 and 0.2 g (0.9 mmol) of ZnBr2 in 15 ml of dry
CH2Cl2 was stirred under nitrogen for 1 h at 2788C. Then
the reaction mixture was allowed to warm to room
temperature and the solution became clear and green.
After 2 h the mixture was poured into 25 ml of saturated
sodium bicarbonate solution. The organic solution was
separated and the aqueous solution was extracted three
times with 30 ml of CH2Cl2. The combined organic solution
was dried over Na2SO4 and the solvent was carefully
evaporated. The residue was chromatographed over silica
gel (light petroleum/ethyl acetate, 9:1) to give 0.1 g (40%)
of a diastereomeric mixture of 18 in the ratio of 4:1 as white
crystals (mp 94–958C from ethyl acetate/pentane).
IR (CCl4) 2957, 2877, 1679, 1601, 1250 cm21. 1H NMR d:
0.62 (m, 6H), 0.94 (m, 9H), 1.29, 1.51 (s, s, 3H), 1.30–2.35
(m, 6H), 2.53–2.65 (m, 1H), 2.86–2.92 (m, 2H), 3.43–3.70
(m, 1H), 3.81 (s, 3H), 6.65 (d, J¼2.2 Hz, 1H), 6.77 (dd,
J¼8.8, 2.2 Hz, 1H), 7.98 (dd, J¼8.8, 2.2 Hz, 1H). 13C NMR
(main isomer) d: 5.39 (3t), 6.68 (3q), 10.02 (q), 22.36 (t),
22.91 (t), 29.92 (t), 33.19 (t), 43.90 (d), 49.68 (d), 55.34 (q),
112.31 (d), 112.81 (s), 112.93 (d), 127.05 (s), 129.62 (d),
146.78 (s), 148.07 (s), 163.31 (s), 198.96 (s). (Minor
isomer): 5.36 (3t), 6.68 (3q), 11.68 (q), 23.62 (t), 25.02 (t),
29.79 (t), 32.98 (t), 43.26 (d), 52.15 (d), 55.34 (q), 112.36
(d), 113.01 (d), 113.87 (s), 126.55 (s), 129.94 (d), 146.48 (s),
148.26 (s), 163.26 (s), 197.79 (s). HRMS: Mþ, found
386.2273. C23H34O3Si requires 386.2277. MS m/e (%) 386
(Mþ, 8), 290 (10), 270 (12), 211 (100), 176 (27), 87 (15).
IR (CCl4) 2961, 2934, 2836, 1742, 1608, 1499, 1252 cm21
.
1H NMR d: 1.09 (s, 3H), 1.4–2.4 (m, 10H), 2.84 (m, 2H),
3.77, 3.79 (s, s, 3H), 6.06, 6.11 (m, m, 1H), 6.60 (d,
J¼2.1 Hz, 1H), 6.70 (dd, J¼8.6, 2.7 Hz, 1H), 7.45, 7.55 (d,
d, J¼8.6 Hz, 1H). 13C NMR d: 23.05 (q), 25.12 (t), 29.72 (t),
29.85 (t), 30.63 (t), 34.70 (t), 37.97 (d), 47.17 (s), 47.88 (d),
55.24 (q), 112.61 (d), 113.12 (d), 115.53 (d), 124.96 (d),
128.16 (s), 135.17 (s), 137.47 (s), 158.58 (s), 221.69 (s).
HRMS: Mþ, found 282.1618. C19H22O2 requires 282.1620.
MS m/e (%) 282 (Mþ, 100), 267 (16), 225 (24), 186 (51).
4.1.18. (1R)-6-Methoxy-2-{(1R)-2-methyl-3-[(triethyl-
silyl)oxy]-2-cyclopenten-1-yl}-1-vinyl-1,2,3,4-tetra-
hydro-1-naphthalenol (17). To a solution of 15 mmol of
1 M vinyl magnesium bromide in THF was added slowly a
solution of 1.16 g (3 mmol) of the diastereomeric mixture of
16 in 15 ml of THF at 08C. The reaction mixture was stirred
under these conditions for 1 h and at the room temperature
for 4–5 h. Then 25 ml of a saturated solution of NH4Cl was
added and the mixture was extracted with ethyl acetate
(3£75 ml). The ethyl acetate solution was dried (Na2SO4)
and the solvent was evaporated. This residue was treated
again with 10 mmol of 1 M vinyl magnesium bromide as
described above and worked up as described above (this
procedure was repeated once more). The residue was
purified by chromatography on SiO2 (light petroleum/ethyl
acetate, grad.) to give 0.93 g (75%) of a diastereomeric
mixture of 17 in the ratio of 10:1 as a colorless oil.
4.1.20. 3-Methoxyestra-1(10),2,4,8-tetraen-17-one (19).21
The diastereomeric mixture of compounds 18 (0.07 g,
0.25 mmol) was stirred at the room temperature in 12 ml
of 5:1 MeOH/10N HCl for 1 h. The MeOH was evaporated
and the remaining aqueous suspension was diluted with
15 ml NaH2PO4 buffer (pH 4) and extracted three times with
30 ml of ethyl acetate. The combined extracts were dried
over Na2SO4, the solvent was evaporated to give 0.07 g
(100%) of the enantiomeric mixture of 19 as white crystals,
mp 85–878C (from ethyl acetate/pentane), lit.21 mp 88–
908C (from ether/hexane).
1
1
IR (CCl4) 3617, 2956, 2876, 1609, 1498, 1240 cm21. H
IR (CCl4) 2935, 2835, 1740, 1608, 1500, 1251 cm21. H
NMR (main isomer) d: 0.68 (q, J¼7.9 Hz, 6H), 1.00 (t,
J¼7.9 Hz, 9H), 1.47 (s, 3H), 1.50–1.91 (m, 4H), 2.21–2.26
(m, 2H), 2.7–2.95 (m, 4H), 3.76 (s, 3H), 5.35 (dd, J¼10.4,
NMR d: 1.07 (s, 3H), 1.51 (m, 1H), 1.77 (m, 2H), 2.05–2.39
(m, 8H), 2.71 (t, J¼8.2 Hz, 2H), 3.79 (s, 3H), 6.69 (s, 1H),
6.71 (d, J¼7.4 Hz, 1H), 7.10 (d, J¼7.4 Hz, 1H). 13C NMR

S. Dratch et al. / Tetrahedron 59 (2003) 4287–4295
4295
9. Magriotis, P. A.; Johnson, F. J. Org. Chem. 1984, 49, 1460.
10. Groen, M. B.; Zeelen, F. J. Recl. Trav. Chim. 1986, 105, 465,
and references cited therein.
d: 20.63 (q), 21.98 (t), 25.47 (t), 26.88 (t), 27.48 (t), 28.86
(t), 36.79 (t), 47.22 (s), 48.64 (d), 55.29 (q), 110.92 (d),
113.49 (d), 123.08 (d), 126.40 (s), 129.04 (s), 131.84 (s),
137.08 (s), 158.13 (s), 223.40 (s). HRMS: Mþ, found
282.1620. C19H22O2 requires 282.1620. MS m/e (%) 282
(Mþ, 100), 254 (7), 226 (25), 225 (20), 211 (9).
´
11. Gauthier, V.; Cazes, B.; Gore, J. Tetrahedron Lett. 1991, 32,
915.
´
12. Gauthier, V.; Cazes, B.; Gore, J. Bull. Soc. Chim. Fr. 1996,
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13. Gilchrist, T. L.; Stanford, J. E. J. Chem. Soc., Perkin Trans. 1
1987, 225.
Acknowledgements
14. Gilchrist, T. L.; Summersell, R. J. Tetrahedron Lett. 1987, 28,
1469.
The authors gratefully acknowledge financial support from
the Dutch Technology Foundation (Grant CW/STW-project
790.35.215) and from Organon International. The authors
thank A. van Veldhuizen for NMR and IR spectroscopic
data, and M. A. Posthumus for mass spectroscopic
measurements.
15. Gilchrist, T. L.; Summersell, R. J. J. Chem. Soc., Perkin Trans.
1 1988, 2203.
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1998, 39, 7047.
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