Synthesis of a chiral steroid ring D precursor starting from carvone

Article abstract of DOI:10.1016/j.tet.2005.11.057

A chiral five-membered, silyl enol ether containing, steroid ring D precursor has been synthesized from carvone. This silyl enol ether has been applied in the synthesis of a chiral C17 functionalized steroid skeleton using the addition of a carbocation, g

Full text of DOI:10.1016/j.tet.2005.11.057

Tetrahedron 62 (2006) 1743–1748
Synthesis of a chiral steroid ring D precursor starting
from carvone
a
a
a,
Serghei Pogrebnoi,a,b Florence C. E. Saraber, Ben J. M. Jansen and Aede de Groot
*
`
aLaboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
bInstitute of Chemistry, Academy str. 3, MD-2028 Kishinev, Republic of Moldova
Received 20 May 2005; accepted 24 November 2005
Available online 20 December 2005
Abstract—A chiral five-membered, silyl enol ether containing, steroid ring D precursor has been synthesized from carvone. This silyl enol
ether has been applied in the synthesis of a chiral C17 functionalized steroid skeleton using the addition of a carbocation, generated with
ZnBr2 from a Torgov reagent, followed by cyclization of the adduct by treatment with acid.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
material obtained through biotransformation has been
applied.6,7
An ultimate goal in steroid synthesis is the development of
short and efficient routes to enantiomerically pure
compounds. The encouraging results obtained in the
coupling reactions of the Torgov reagent 6 with silyl
enol ether derivatives of five-membered ring D precursors,1
seems to offer a good prospect for a chiral approach. On
the other hand, suitably functionalised optically active five-
membered ring ketones or their silyl enol ethers, with the
right configuration for steroid synthesis, are not over-
abundant. Most efforts were developed to obtain ring D
precursors for the synthesis of vitamin D analogs2–10 and
some for steroids.9–13 Three such routes starting from a
chiral natural product have been published,3,8–10,14,15 next
to several routes using a chiral auxiliary during
synthesis.2,4,5,11,16–19 In one route a chiral starting
Compounds from the chiral pool seemed to offer good
opportunities to access a chiral steroid ring D precursor and
based on our experience it was decided to explore a
synthesis starting from carvone (1). A sequence involving a
ring contraction of carvone using a Favorskii rearrangement
has been reported in the literature and leads, in five steps, to
the selectively protected diol 3 in 36% overall yield.20
Further transformation could lead in a few more steps to
silyl enol ether 5 as the chiral steroid ring D precursor.
Coupling with the Torgov reagent 6 and ring closure should
lead to the chiral steroid skeleton 8 with a functionalised
substituent at C17 (see Scheme 1). To obtain the correct
stereochemistry at C17 in the final steroid skeleton, C5 in
carvone 1 should have the S configuration.
O
O
CH2OTBDMS
CH2OH
CH2OTBDMS
O
TMSO
O
THPO
4
1
5
2
3
CH2OTBDMS
CH2OH
OH
5
O
MeO
MeO
MeO
7
8
6
Scheme 1.
Keywords: Mukaiyama–Michael addition; Carvone; Chiral silyl enol ethers; C,D-trans steroid synthesis.
*
Corresponding author. Tel.: C31 317482370; fax: C31 317484914; e-mail: aede.degroot@wur.nl
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.057

1744
S. Pogrebnoi et al. / Tetrahedron 62 (2006) 1743–1748
2. Results and discussion
alcohol in 3 and then selectively remove the THP group
using MgBr2 gave only 24% of 13, and treatment with
26
Epoxidation of the double bond of the enone in carvone
using hydrogenperoxide in basic solution, leads to epoxide 2
in 88% yield, and in principle this epoxide should be a
substrate for the required Favorskii rearrangement. Unfortu-
nately, this rearrangement does not give only the desired
ring contraction product, but also a regioisomer and opening
of the epoxide.20–23 For a more selective result, the epoxide
ring has to be opened first stereoselectively to compound 9b
and then converted to THP ether 10 (Scheme 2). In the
literature an opening of epoxide 2 to the silylated alcohol 9a
was reported using TMSCl.20 In our hands better results
were obtained using LiCl in combination with trifluoro-
acetic acid,24 giving directly the free alcohol 9b. Protection
of the alcohol as a diastereomeric mixture of THP ethers 10
was necessary for complete stereo- and regioselectivity in
the Favorskii rearrangement,20,24 the use of silyl protecting
groups on the alcohol moiety did not give as good results.25
Coordination of the oxygen in the THP ring with the alcohol
that donates its proton during the rearrangement could be a
possible explanation for the desired regioselective opening
of the cyclopropane ring.
Et2AlCl27 failed completely. Diol 13, with a protected
primary hydroxyl group, was obtained in a better 65% yield
via deprotection to diol 14, followed by selective
reprotection of the primary alcohol. Although this yield
is still not very high, the remaining products consist
of unreacted diol 14 (21%) and the double protected
diol (12.5%), which can be separated easily from 13 and
used again.
Oxidation of the secondary hydroxyl group in 13 opens up
the possibility for regioselective elimination of the
isopropenyl group to compound 17 (Scheme 3). Ozono-
lysis followed by Criegee rearrangement, using triethyl-
amine, aceticanhydride and DMAP in methanol,28,29 was
troublesome in our hands and usually gave diketone 16, in
which normal ozonolysis of the double bond to the ketone
had taken place. Only with the use of FeSO4 and CuSO4
salts for decomposition of the intermediate a fair yield
(50%) of the desired enone 17 could be obtained.30
Catalytic reduction of the double bond to 18 and
regioselective formation of the silyl enol ether, both in
near quantitative yields, finally led to the desired chiral
steroid ring D precursor 5 in 10% overall yield starting
from (S)-(C)-carvone.
Reduction of the rearranged ester 11 gave the selectively
protected diol 3.24 Our attempts to first protect the primary
O
O
COOMe
Cl
Cl
THPO
LiCl, CF3CO2H
74%
NaOMe
96%
H2O2, NaOH
88%
DHP, pTsOH
85%
2
1
RO
THPO
10
9a R = TMS
9b R = H
11
CH2OTBDMS
TBDMSCl,
imidazole
THPO
MgBr
2
12
14
24%
66%
CH2OTBDMS
CH2OH
LiAlH4
11
TBDMSCl,
imidazole
HO
THPO
83%
PPTS
80%
3
CH2OH
13
65%
HO
Scheme 2.
(a) O3;
(b) Ac2O, Et3N,
DMAP,MeOH
CH2OTBDMS
CH2OTBDMS
CH2OTBDMS
O
PCC
88%
HO
O
O
16
13
15
50%
(a) O3;
(b) FeSO4 . 7H2O,
Cu(OAc)2 . H2O
CH2OTBDMS
CH2OTBDMS
CH2OTBDMS
H2, Pd/C
TMSI, HMDS
TMSO
O
O
98%
99%
5
18
17
Scheme 3.

S. Pogrebnoi et al. / Tetrahedron 62 (2006) 1743–1748
1745
CH2OTBDMS
CH2OTBDMS
CH2OH
ZnBr2, CH2Cl2,
20oC -5oC
-
pTsOH
C6H6
+
+
5
6
O
82%
MeO
MeO
MeO
19 (47%)
8 (35%)
7
81%de
Scheme 4.
Silyl enol ether 5 was put into reaction with the Torgov
reagent 6, which yielded secosteroid 7 in 82% yield as a
mixture of two C13 diastereomers, with a diastereomeric
excess of 81% (Scheme 4). No crystals could be obtained to
prove the configuration of the main product using X-ray
crystallography, and also NOE experiments failed to show
any effect between the C13 methyl group or the C12
methylene group with the hydrogen atom on C17 or the
methylene group bearing the OTBDMS group. However,
based on experience with similar reactions,1 it may be
assumed that this main product has the desired S-configur-
ation on C13.
(m, 2H), 3.37 (d, JZ2.8 Hz, 1H), 4.63 (br s, 1H), 4.70 (br s,
1H); 13C NMR (C6D6) d: 15.2 (q), 20.5 (q), 28.6 (t), 34.9 (d),
41.7 (t), 58.6 (s), 61.2 (d), 110.4 (d), 146.3 (s), 205.3 (s).
To an ice-cooled solution of 2 (4.3 g, 26 mmol) in dry THF
(100 ml), LiCl (1.8 g, 43 mmol) and CF3COOH (4.9 g,
43 mmol) were added. The mixture was stirred for 20 min at
0 8C and during 2 h at room temperature. Water (500 ml)
was added and the reaction mixture was extracted with
diethyl ether (3!100 ml). The combined organic layers
were washed with a saturated solution of NaHCO3 (100 ml),
water (100 ml) and brine (100 ml), dried (MgSO4) and
evaporated under reduced pressure. The crude product
(5.2 g) was used without any further purification in the next
step. 1H NMR (C6D6) d: 1.63 (s, 3H), 1.73 (s, 3H), 1.87 (ddt,
J1Z2.1 Hz, J2Z3.6 Hz, J3Z14.2 Hz, 1H), 2.28–3.10 (m,
5H), 4.23 (dd, J1Z3.7 Hz, J2Z6.3 Hz, 1H), 4.75 (br s, 1H),
4.78 (br s, 1H); 13C NMR (C6D6) d: 20.3 (q), 22.1 (q), 32.8
(t), 38.9 (d), 41.1 (t), 67.9 (s), 76.8 (d), 110.6 (t), 146.4 (s),
205.3 (s).
Subsequent cyclisation of 7 gave the steroidal diene 19 in
47% yield, next to the deprotected compound 8, in 35%
yield. The protected diene 19 appeared to be unstable upon
storage, decomposing to a complex mixture of products,
even when kept at K18 8C. Better results were obtained
with diene 8, which remained stable upon storage and
complete deprotection of the alcohol moiety in the side
chain (e.g., using TBAF in THF) directly after the
cyclisation, is therefore the best procedure. Selective
reduction (e.g., using H2, Pd/CaCO3) then can be carried
out to afford the C,D trans coupled steroid skeleton.
A solution of product 9b (5.2 g) from the former reaction in
dry CH2Cl2 (100 ml) was cooled on ice and DHP
(dihydropyran, 6.4 g, 76 mmol) was added, followed by a
catalytic amount of pTsOH (50 mg). The mixture was
stirred for 2 h during, which the temperature was allowed to
rise to room temperature (the reaction mixture became
green). After evaporation of CH2Cl2 under reduced
pressure, the residue was dissolved in light petroleum and
purified over a short plug of silica (5 g), yielding 4.7 g of
crude product 10 as a mixture of diastereomers, which were
used without any further purification in the next step.
Although the overall yield of optically active steroid ring D
precursor 5 from (S)-(C)-carvone is only 10% and requires
11 steps, the applicability of this approach for the
preparation of enantiomerically pure steroid skeletons has
been shown. The development of straightforward, easy and
high yielding syntheses for chiral steroid ring D precursors
is, however, essential to make this route to a good method
for the synthesis of optically active steroid skeletons.
To 20 ml of an ice-cooled solution of NaOMe (1.2 M) in
methanol, 4.7 g of 10, from the former experiment, in 10 ml
of dry methanol was added drop wise over a period of
10 min. During the addition, a precipitate started to form
and it appeared necessary to keep the temperature of the
reaction below 15 8C. The reaction mixture was stirred for a
further 15 min before water (300 ml) was added. The
mixture was extracted with diethyl ether (3!100 ml). The
combined organic layers were washed with brine, dried
(MgSO4) and evaporated under reduced pressure, yielding
4.43 g of crude product 11 as a slightly yellow oil as a
mixture of two diastereomers. The crude product was used
without any further purification in the next step.
3. Experimental
3.1. General procedure. See31
3.1.1. 3-Hydroxymethyl-4-isopropenyl-2-methyl-cyclo-
pentanol (14). To a cooled solution (at K15 8C) of (S)-
(C)-carvone (10 g, 0.066 mol) in methanol (66 ml) and
22 ml of H2O2 (30%, 0.198 mol), 5 ml of 6.6 M NaOH
solution in H2O was added dropwise over a period of 5 min.
During the addition the temperature was carefully kept
below 0 8C. The mixture was stirred for 2 h at 0 8C and then
the solution was allowed to warm to room temperature over
a period of 1 h. The reaction mixture was poured in water
(400 ml) and the water solution was extracted four times
with diethyl ether (100 ml). The combined organic layers
were washed with brine, dried (MgSO4) and evaporated
under reduced pressure, yielding 9.8 g of crude product 2,
which was used without any further purification in the
To an ice-cooled mixture of LiAlH4 (1 g, 26 mmol) in dry
diethyl ether (20 ml) was added drop wise a solution of 11
(4.43 g) in dry diethyl ether (10 ml), over a period of
10 min. The reaction mixture was stirred for a 2 h at room
temperature. Then 1 ml of water was carefully added under
cooling with ice, followed by 4 ml of a 4 M NaOH solution
and again 4 ml of water. After stirring for 30 min
1
next step. H NMR (C6D6) d: 1.31 (s, 3H), 1.62 (s, 3H),
1.75–2.05 (m, 2H), 2.28 (br d, JZ14.6 Hz, 1H), 2.38–2.75

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S. Pogrebnoi et al. / Tetrahedron 62 (2006) 1743–1748
the reaction mixture was filtered to remove the inorganic
precipitate, which was carefully washed with ether (20 ml).
The filtrate was dried (MgSO4) and evaporated under
reduced pressure. The crude product 3 (3.31 g, slightly
yellow oil) was used without any further purification in
4.09–4.13 (m, 1H), 4.62 (s, 1H), 4.77 (s, 1H); 13C NMR
(C6D6) d: K5.4 (2q), K4.7 (q), K4.6 (q), 15.5 (q), 18.2 (s),
23.9 (q), 25.9 (6q), 39.5 (t), 43.2 (d), 43.7 (d), 47.5 (d), 64.2
(t), 74.8 (d), 109.7 (t), 145.7 (s).
1
the next step. H NMR (C6D6) d: 0.98 and 1.09 (2d, JZ
3.1.3. 3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-isopro-
penyl-2-methyl-cyclopentanone (15). To a solution of 13
(4.1 g, 14.4 mmol) in dry CH2Cl2 (120 ml), to which 4 g of
6.6 Hz, 3H), 1.30–2.15 (m, 10H), 2.78–3.10 (m, 1H), 3.47
(q, JZ5.5 Hz, 2H), 3.80–3.93 (m, 1H), 4.00–4.15 (m, 1H),
m 4.52–4.67 (m, 1H), 4.76 (br s, 1H), 4.85 (br s, 1H).24
˚
molecular sieves (3 A) were added, 4.5 g of pyridinium
chlorochromate (PCC, 21.6 mmol) was added in three
portions over a period of 3 h. The reaction mixture was
stirred for 2 h more, filtered over a short plug of silica and
evaporated under reduced pressure. The residue was
dissolved in Et2O (200 ml) washed with water and brine,
dried (MgSO4) and evaporated again under reduced
pressure. The crude product was purified by flash
chromatography (PE/EtOAc 15:1), yielding 3.6 g of 15
(88%), next to some minor unidentified products. [a]2D0 21.2
(c 1.25 in CHCl3); IR (CCl4 sol.) cmK1: 2958, 2931, 2859,
The crude product 3 from the former experiment (3.1 g) in
35 ml of methanol and a catalytic amount of pyridinium
para-toluenesulfonic acid (PPTS, 10 mol%) were stirred at
50 8C during 2 h. After evaporation of the methanol under
reduced pressure, the residue (2.35 g) was purified by rapid
column chromatography (PE/EtOAc 10:1), yielding 1.5 g of
pure 14 (32% overall yield from (S)-(C)-carvone). [a]D20
13.6 (c 12.0 in CHCl3); IR (film) cmK1: 3356 (br), 3081,
1
2957, 2932, 1646, 1453, 1375, 1080, 1041, 891; H NMR
1
(CDCl3) d: 1.01 (d, JZ6, 7 Hz, 3H), 1.65–2.23 (m, 9H),
2.94–3.04 (m, 1H), 3.44 (d, JZ5 Hz, 2H), 4.11 (m, 1H),
4.72 (s, 1H), 4.82 (s, 1H); 13C NMR (CDCl3) d: 14.0 (q),
23.83 (q), 38.8 (t), 41.6 (d), 44.8 (d), 49.0 (d), 63.6 (t), 74.47
(d), 110.6 (t), 147.0 (s). HRMS: MC, found 170.1308.
C10H18O2 requires 170.1307. MS m/e (%) 170 (MC, !1),
155 (3), 152 (4), 121 (81), 99 (55), 81 (100), 72 (64), 71
(66), 55 (69), 43 (56).
1743, 1471, 1254, 1091; H NMR (CDCl3) d: 0.01 (s, 6H),
0.83 (s, 9H), 1.13 (d, JZ7.5 Hz, 3H), 1.77 (s, 3H), 2.05–
2.60 (m, 5H), 2.97 (br q, JZ8.0 Hz, 1H), 3.57 (d, JZ7.9 Hz,
2H), 4.69 (s, 1H), 4.88 (s, 1H); 13C NMR (CDCl3) d: K5.7
(2q), 15.9 (q), 18.1 (s), 22.6 (q), 25.7 (3q), 41.7 (t), 42.6 (d),
45.6 (d), 47.9 (d), 62.8 (t), 111.5 (t), 143.9 (s), 221.2 (s).
HRMS: [MKCH3]C, found 267.1782. C15H27O2Si requires
267.1780. MS m/e (%) 282 (MC, 0.03), 267 (2.7), 225
(100), 195 (8), 133 (20), 131 (15), 75 (59), 73 (22).
3.1.2. 3-(tert-Butyl-dimethyl-silanyloxymethyl)-4-isopro-
penyl-2-methyl-cyclopentanol (13). A solution of 14
(3.8 g, 22 mmol) in dimethylformamide (DMF, 70 ml)
was cooled to 5 8C and TBDMSCl (3.7 g, 24 mmol) in
DMF (20 ml) was added by rapid dropping (5 min),
followed by a solution of imidazole (3.8 g, 56 mmol) in
DMF (10 ml). The reaction mixture was stirred for 20 min at
5 8C and then for 3 h at 30 8C. Water was added (500 ml)
and the water layer was extracted with Et2O (4!100 ml).
The combined organic layers were washed with brine, dried
(MgSO4) and evaporated under reduced pressure. The crude
product was purified by column chromatography (PE/EA
15:1), yielding 4.15 g of 13 (65%) as a colourless oil, 1.1 g
of the diprotected compound (12.5%) as a colourless oil,
and 0.46 g of unreacted material 14 (12%).
3.1.4.
4-(tert-Butyl-dimethyl-silanyloxymethyl)-5-
methyl-cyclopent-2-enone (17). A stirred solution of 15
(1.0 g, 3.54 mmol) in CH2Cl2 (24 ml) and MeOH (20 ml)
was cooled to K78 8C and purged with ozone until a pale
blue colour appeared (w15 min). Nitrogen was then
bubbled through for 30 min to remove the excess of ozone
and FeSO4$7H2O (0.98 g, 3.54 mmol) and Cu(OAc)2$H2O
(1.4 g, 7.10 mmol) were added. The reaction mixture was
allowed to warm to room temperature overnight, after which
the solvents were evaporated under reduced pressure.
The residue was dissolved in water and extracted with
Et2O (4!100 ml). The combined organic layers were
washed with brine, dried (MgSO4) and evaporated under
reduced pressure. The crude product was purified by column
chromatography (PE/EtOAc 15:1), yielding 0.43 g of 17
(50%), next to some unidentified products and 16. [a]D20
Compound 13. [a]D20 K3.1 (c 5.0 in CHCl3); IR (CCl4
sol.) cmK1: 3631, 3491 (br), 3083, 2951, 2894, 2858, 1647,
1471, 1459, 1255, 1093, 1003, 889; 1H NMR (C6D6) d: 0.16
(s, 6H), 0.86 (s, 9H), 1.08 (d, JZ6.9 Hz, 3H), 1.75 (s, 3H),
1.64–2.04 (m, 5H), 2.89–2.98 (m, 1H), 3.28 (dd, J1Z
7.6 Hz, J2Z10.1 Hz, 1H), 3.47 (dd, J1Z5.3 Hz, J2Z
10.1 Hz, 1H), 4.17 (dd, J1Z3.6 Hz, J2Z4.4 Hz, 1H), 4.62
(s, 1H), 4.77 (s, 1H); 13C NMR (C6D6) d: K5.5 (2q), 14.7
(q), 18.2 (s), 23.8 (q), 25.9 (3q), 38.8 (t), 42.5 (d), 44.8
(d), 47.5 (d), 64.1 (t), 74.6 (d), 110.1 (t), 145.2 (s). HRMS:
[MKtBu]C, found 227.1470. C12H23O2Si requires
227.1467. MS m/e (%) 251 ([MKCH3–H2O]C, 2), 227
(32), 209 (76), 185 (20), 95 (18), 93 (14), 75 (100), 73 (29).
1
122.4 (c 6.6 in CHCl3); H NMR (CDCl3) d: 0.02 (s, 6H),
0.75 (s, 9H), 1.17 (d, JZ7.4 Hz, 3H), 2.09 (dq, J1Z2.5 Hz,
J2Z7.5 Hz, 1H), 2.65 (m, 1H), 3.68 (m, 2H), 6.15 (dd, J1Z
2.0 Hz, J2Z5.8 Hz, 1H) 7.56 (dd, J1Z2.3 Hz, J2Z5.8 Hz,
1H); 13C NMR (CDCl3) d: K5.5 (2q), 14.9 (q), 18.9 (s),
25.8 (3q), 43.2 (d), 52.9 (d), 64.3 (t), 133.7 (d), 163.9 (d),
212.1 (s). HRMS: [MKCH3]C, found 225.1311.
C12H21O2Si requires 225.1311. [MKC4H9]C, found
183.00842, C9H15O2Si requires 183.0841. MS m/e (%)
225 (MKCHC3 , 3), 210 (2), 183 (MKC4HC9 , 100), 153 (15),
139 (15), 126 (9), 75 (32).
3.1.5.
3-(tert-Butyl-dimethyl-silanyloxymethyl)-2-
1
Diprotected compound. H NMR (C6D6) d: 0.07 (s, 6H),
methyl-cyclopentanone (18). To a solution of 17
(200 mg, 0.83 mmol) in tBuOMe (10 ml) was added Pd on
C (10%, 20 mg) had the suspension was shaken under
hydrogen atmosphere pressure (50 psi [3.45 bar]) during
1 h. The reaction mixture was filtered over a short plug of
0.09 (s, 6H), 0.89 (s, 18H), 1.02 (d, JZ6.6 Hz, 3H), 1.60
(dd, J1Z6.4 Hz, J2Z12.4 Hz, 1H), 1.77 (s, 3H), 1.70–1.97
(m, 3H), 2.89–3.02 (m, 1H), 3.28 (dd, J1Z7.1 Hz, J2Z
10.0 Hz, 1H), 3.47 (dd, J1Z5.1 Hz, J2Z10.0 Hz, 1H),

S. Pogrebnoi et al. / Tetrahedron 62 (2006) 1743–1748
1747
Hyflo, which was then carefully washed with ether. The
filtrate was dried (MgSO4) and the solvent was removed
under reduced pressure yielding pure 18 (198 mg, 98%),
which needed no further purification. [a]2D0 K46.3 (c 1.7 in
CHCl3); IR (CCl4 sol.) cmK1: 2957, 2925, 2876, 2858,
1743, 1470, 1255, 1107; 1H NMR (CDCl3) d: 0.03 (s, 6H),
0.88 (s, 9H), 1.16 (d, JZ7 Hz, 3H), 1.61–2.44 (m, 6H), 3.7
(m, 2H); 13C NMR (CDCl3) d: K5.1 (2q), 12.8 (q), 23.6
(t), 25.8 (3q), 37.2 (t), 46.2 (d), 46.8 (d), 64.3 (t). HRMS:
[MKCH3]C, found 227.1471. C12H23O2Si requires
227.1467. MS m/e (%) 227 ([MKCH3]C, 2.6), 185 (100),
141 (13), 129 (18), 75 (58), 73 (11).
requires 428.2747. MS m/e (%) 428 (MC, 8.1), 187 (100),
174 (3.2), 161 (3.1), 159 (3.5), 75 (2.6), 73 (3.4).
3.1.8. tert-Butyl-(3-methoxy-13-methyl-7,11,12,13,16,17-
hexahydro-6H-cyclopenta[a]-phenanthren-17-ylmeth-
oxy)-dimethyl-silane (19) and (3-methoxy-13-methyl-7,
11,12,13,16,17-hexahydro-6H-cyclopenta[a]phenanthren-
17-yl)-methanol(8).Compound 7 (108 mg, 0.25 mmol) was
dissolved in benzene (5 ml) and a crystal of para-toluene
sulfonic acid (pTsOH) was added. The reaction mixture was
stirred at 40 8C for 6 h, then the reaction mixture was diluted
with Et2O (15 ml) and washed with saturated NaHCO3
solution and brine. The organic layer was dried (MgSO4)
and the solvent was removed under reduced pressure.
The crude product was purified by column chromatography
(PE/EtOAc 9:1) yielding 47% of 19 (48 mg) and 35% of 8
(26 mg).
3.1.6.
3-(tert-Butyl-dimethyl-silanyloxymethyl)-2-
methyl-1-trimethylsilanyloxy-cyclopentene (5). Com-
pound 18 (174 mg, 0.72 mmol) was dissolved in CH2Cl2
(5 ml) and hexamethyl disilazane (HMDS, 0.550 ml,
2.6 mmol) was added, followed by TMSI (312 ml,
2.2 mmol). The reaction mixture was stirred overnight at
room temperature, diluted with Et2O (15 ml) and washed
with a saturated solution of NaHCO3 and brine. After drying
(Na2SO4) the solvent was evaporated under reduced
pressure. The crude product was purified by column
chromatography (PE:Et2O/Et3N 98:1:1) giving 225 mg of
pure product 5 (99%). [a]2D0 15.4 (c 5.5 in n-C6H12); IR
(CCl4 sol.) cmK1: 2958, 2924, 2898, 2857, 1685, 1329,
1253, 1205, 1107, 1065, 1006, 920; 1H NMR (C6D6) d: 0.03
(s, 6H), 0.14 (s, 9H), 0.97 (s, 9H), 1.67 (s, 3H), 1.64–1.93
(m, 2H), 2.15–2.34 (m, 2H), 2.50–2.67 (m, 1H), 3.44 (dd,
J1Z6.3 Hz, J2Z9.7 Hz, 1H), 3.59 (dd, J1Z4.8 Hz, J2Z
9.7 Hz, 1H); 13C NMR (C6D6) d: K5.4 (2q), 0.6 (3q), 10.8
(q), 18.4 (s), 24.0 (t), 26.0 (3q), 32.8 (t), 47.9 (d), 66.1 (t),
113.4 (s), 148.3 (s). HRMS: MC, found 314.2095.
C16H34O2Si2 requires 314.2097. MS m/e (%) 314 (MC,
2), 299 (2), 257 (2), 169 (100), 147 (2), 73 (20).
Compound 19. [a]D20 K9.3 (c 2.89 in CHCl3); IR (CCl4
1
sol.) cmK1: 2957, 2931, 2858, 1607, 1464, 1255; H NMR
(C6D6) d: 0.10 (s, 6H), 1.00 (s, 3H), 1.02 (s, 9H), 1.20–1.38
(m, 1H), 1.55–1.78 (m, 2H), 2.10–2.80 (m, 8H), 3.38 (s,
3H), 3.65–3.88 (m, 2H), 5.53 (br s, 1H), 6.68–6.79 (m, 2H),
7.19 (d, JZ9.3 Hz, 1H); 13C NMR (C6D6) d: K5.5 (2q),
16.1 (q), 18.2 (s), 23.8 (t), 24.0 (t), 25.9 (3q), 28.8 (t), 33.8
(t), 36.1 (t), 44.9 (s), 53.6 (q), 54.5 (d), 63.7 (t), 111.2 (d),
113.6 (d), 119.3 (d), 124.2 (d), 125.7 (s), 129.1 (s), 129.5 (s),
138.0 (s), 149.8 (s), 158.8 (s). HRMS: MC, found 410.2639.
C26H38O2Si requires 410.2641. MS m/e (%) 410 (MC, 100),
395 (4), 353 (8), 278 (43), 263 (33), 89 (9), 75 (17), 73 (23).
Compound 8. [a]2D0 K34.0 (c 1.08 in CHCl3); IR (CCl4
sol.) cmK1: 2933, 2835, 1606, 1561, 1498, 1248, 1216,
1044; 1H NMR (C6D6) d: 0.91 (s, 3H), 1.01 (br, 1H),
1.50–1.70 (m, 1H), 1.95–2.73 (m, 10H), 3.37 (s, 3H),
3.45–3.70 (m, 2H), 5.50 (br s, 1H), 6.68–6.75 (m, 2H), 7.17
(d, JZ9.8 Hz, 1H); 13C NMR (C6D6) d: 16.1 (q), 23.8 (t),
24.0 (t), 28.8 (t), 34.1 (t), 35.9 (t), 44.8 (s), 53.7 (d), 54.5 (q),
63.2 (t), 111.3 (d), 113.6 (d), 119.3 (d), 124.3 (d), 125.7 (s),
129.1 (s), 129.5 (s), 138.1 (s), 149.7 (s), 158.8 (s). HRMS:
MC, found 296.1774. C20H24O2 requires 296.1776. MS m/e
(%) 296 (MC, 100), 265 (7), 263 (9), 249 (3), 225 (3), 165
(4), 139 (3).
3.1.7. 3-(tert-Butyl-dimethyl-silanyloxymethyl)-2-[2-(6-
methoxy-3,4-dihydro-2H-naphthalen-1-ylidene)-ethyl]-
2-methyl-cyclopentanone (7). 6-Methoxy-1-vinyl-1,2,3,4-
tetrahydro-naphthalen-1-ol (6, 68 mg, 0.33 mmol) and
compound 5 (314 mg, 1 mmol) were dissolved in CH2Cl2
(20 ml) and cooled to K20 8C. ZnBr2 (a few crystals,
approx. 20 mg) was added as the catalyst and the reaction
mixture was stirred for 4 h at K5 8C. When all of compound
6 had disappeared (TLC), EtOAc (25 ml) was added and the
reaction mixture was washed with saturated NaHCO3
solution and brine, dried (MgSO4) and the solvent was
evaporated under reduced pressure. The crude product was
purified by column chromatography (PE/EtOAc 9:1)
yielding compound 7 as a colourless oil in 82% yield
(116 mg). [a]2D0 K16.5 (c 2.34 in CHCl3); IR (CCl4
sol.) cmK1: 2953, 2932, 2896, 2859, 1740, 1606, 1496,
1464, 1255, 1100; 1H NMR (C6D6) d: 0.02 (s, 6H), 0.94 (s,
9H), 0.97 (s, 3H), 1.10–1.34 (m, 1H), 1.60–1.95 (m, 4H),
2.05–2.26 (m, 2H), 2.30–2.64 (m, 6H), 3.33 (s, 3H), 3.35–
3.62 (m, 2H), 6.00 (br t, JZ7.8 Hz, 1H), 6.57 (d, JZ2.7 Hz,
1H), 7.72 (dd, J1Z2.7 Hz, J2Z8.7 Hz, 1H), 7.60 (d, JZ
8.7 Hz, 1H); 13C NMR (C6D6) d: K5.7 (2q), 17.2 (q), 18.1
(s), 22.8 (t), 23.5 (t), 25.8 (q), 26.9 (t), 30.8 (t), 35.9 (t), 36.8
(t), 44.6 (d), 51.1 (s), 54.5 (q), 64.4 (t), 112.7 (d), 113.3 (d),
117.3 (d), 125.3 (d), 129.3 (s), 136.6 (s), 138.6 (s), 159.0 (s),
220.1 (s). HRMS: MC, found 428.2755. C26H40O3Si
Acknowledgements
The authors gratefully acknowledge financial support from
the Dutch Technology Foundation (Grant CW/STW-project
790.35.215), from Organon International and from WICC
Wageningen. The authors thank B. van Lagen for NMR and
IR spectroscopic data, and M.A. Posthumus for mass
spectroscopic measurements.
References and notes
1. Saraber, F. C. E.; de Groot, A. Tetrahedron Lett. 2004, 45,
9431.
2. Pan, L. R.; Tokoroyama, T. Tetrahedron Lett. 1992, 33, 1473.
3. Daniewski, A. R.; Warchol, T. Liebigs Ann. Chem. 1992, 965.

1748
S. Pogrebnoi et al. / Tetrahedron 62 (2006) 1743–1748
4. Nagasawa, K.; Matsuda, N.; Noguchi, Y.; Yamanashi, M.;
20. Lee, E.; Yoon, C. H. J. Chem. Soc., Chem. Commun. 1994,
479.
Zako, Y.; Shimizu, I. J. Org. Chem. 1993, 58, 1483.
5. He, M.; Tanimori, S.; Ohira, S.; Nakayama, M. Tetrahedron
1997, 53, 13307.
21. Kametani, T.; Suzuki, Y.; Ban, C.; Honda, T. Heterocycles
1987, 26, 1491.
6. Stepanenko, W.; Wicha, J. Tetrahedron Lett. 1998, 39, 885.
7. Gorobets, E.; Urbanczyk-Lipowska, Z.; Stepanenko, V.;
Wicha, J. Tetrahedron Lett. 2001, 42, 1135.
22. Kametani, T.; Honda, T.; Ishizone, H.; Kanada, K.; Naito, K.;
Suzuki, Y. J. Chem. Soc., Chem. Commun. 1989, 646.
23. Asaka, Y.; Kamikawa, T.; Kubota, T. Tetrahedron 1974, 30,
3257.
8. Taber, D. F.; Malcolm, S. C. J. Org. Chem. 2001, 66, 944.
9. Suzuki, T.; Sato, E.; Unno, K.; Kametani, T. J. Chem. Soc.,
Chem. Commun. 1988, 724.
¨
24. Oliver, S. F.; Hogenauer, K.; Simic, O.; Antonello, A.;
Smith, M. D.; Ley, S. V. Angew. Chem., Int. Ed. 2003, 42, 5996.
25. A lower yield and selectivity was reported in the literature for
the TBDPS-protected alcohol [Ref. 22]. In our case, the
Favorskii rearrangement was also attempted with the TMS-
protected alcohol, but this yielded a mixture of several
products, which were not identified.
10. Suzuki, T.; Sato, E.; Unno, K. Chem. Pharm. Bull. 1993, 41,
244.
11. Quinkert, G.; Schwartz, U.; Stark, H.; Weber, W. D.;
Adam, F.; Baier, H.; Frank, G.; Du¨rner, G. Liebigs Ann.
Chem. 1982, 1999.
12. Trudeau, S.; Deslongchamps, P. J. Org. Chem. 2004, 69, 832.
13. Jiang, X.; Covey, D. F. J. Org. Chem. 2002, 67, 4893.
14. Taber, D. F.; Raman, K. J. Am. Chem. Soc. 1983, 105, 5935.
15. Suzuki, T.; Sato, E.; Unno, K.; Kametani, T. J. Chem. Soc.,
Perkin Trans. 1 1986, 2263.
26. Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439.
27. Ogava, J.; Shibasaki, M. Tetrahedron Lett. 1984, 25, 663.
28. Schreiber, S. L.; Liew, W. F. Tetrahedron Lett. 1983, 24, 2363.
29. Daniewski, A. R.; Garofalo, L. M.; Hutchings, S. D.;
Kabat, M. M.; Liu, W.; Okabe, M.; Radinov, R.;
Yiannikouros, G. P. J. Org. Chem. 2002, 67, 1580.
16. Pan, L. R.; Tokoroyama, T. Tetrahedron Lett. 1992, 33, 1469.
17. Shimizu, I.; Matsuda, N.; Noguchi, Y.; Zako, Y.; Nagasawa, K.
Tetrahedron Lett. 1990, 31, 4899.
´
18. Hanessian, S.; Gomtsyan, A.; Payne, A.; Herve, Y.; Beaudoin, S.
J. Org. Chem. 1993, 58, 5032.
19. Tanaka, K.; Ohta, Y.; Fuji, K. J. Org. Chem. 1995, 60, 8036.
30. Schreiber, S. L. J. Am. Chem. Soc. 1980, 102, 6165.
`
31. Saraber, F.C.E.; Drach, S.; Bosselaar, G.; Jansen, B.J.M.; de
Groot, A. Tetrahedron 2005, 62, see doi: 10.1016/
j.tet.2005.11.056.