Dialkylation of various butane-2,3-diacetals using allylsilane and 1,8-bis(trimethylsilyl)-2,6-octadiene

Article abstract of DOI:10.1002/ejoc.200400042

We report in this paper a greatly improved procedure for the formation of a range of 1-acetyl-1-methyl-2,5-divinylcyclopentanes from 1,8- bis(trimethylsilyl)octa-2,6-diene (BISTRO) and 1,2-diacetals prepared directly from biacetyl. These 1-acetyl-1-methyl

Full text of DOI:10.1002/ejoc.200400042

FULL PAPER
Dialkylation of Various Butane-2,3-diacetals Using Allylsilane and
1,8-Bis(trimethylsilyl)-2,6-octadiene
[a]
[a]
[a]
[a]
´ `
Natacha Mariet, Helene Pellissier, Malika Ibrahim-Ouali, and Maurice Santelli*
Keywords: Asymmetric synthesis / Chiral pool / Electrophilic substitution / Oxygen heterocycles / Steroids
We report in this paper a greatly improved procedure for the
formation of a range of 1-acetyl-1-methyl-2,5-divinylcyclo-
pentanes from 1,8-bis(trimethylsilyl)octa-2,6-diene (BISTRO)
and 1,2-diacetals prepared directly from biacetyl. These
1-acetyl-1-methyl-2,5-divinylcyclopentanes are building
blocks for the synthesis of 2- and 3-methoxy-12-oxo-17β-vin-
ylestranes.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
In the course of a program directed towards the develop-
ment of new steroids that might exhibit improved thera-
peutic actions over existing drugs, we have adopted a con-
vergent steroid synthesis,[1] based on the approach A ϩ D
Ǟ AD Ǟ ABCD, which involves the use of the intramol-
ecular cycloaddition of o-xylylenes that was developed inde-
pendently by Oppolzer[2] and Kametani[3] for the generation
of the BC ring system (Scheme 1).
Scheme 1
Scheme 2
The required substituted divinylcyclopentanes result from
the addition of 1,8-bis(trimethylsilyl)octa-2,6-diene (BI-
STRO, 1) to various electrophilic reagents (anhydrides,[4]
ethyleneketals,[5] benzaldehyde,[6] and acyl chlorides[7]). The
reaction of BISTRO with the ketal 3 (derived from 2),
which leads to 5 via 4 through a pinacol-type rearrange-
ment (Scheme 2), has attracted much current interest.[8]
Our past studies have shown that divinylcyclopentanes 5
can lead to 12-oxo-17β-vinylsteroids in good yields.[9] This
present account describes the synthesis of ten steroids ob-
tained in three steps from 5a or 5b, as outlined in Scheme 3.
The trans-anti-trans steroids, obtained from 5a, are of
prime interest. To enhance the selectivity of the reactions
of both BISTRO and allylsilane[10] with the ketals, we stud-
ied the reactivity of some ketals of the 2,3-butanedione
other than 3. In particular, we investigated the mixed ketals
obtained from methanol and optically active diols, such as
(ϩ)-trans-1,2-cyclohexanol,
(ϩ)-1-phenyl-1,2-ethanediol,
and -(ϩ)-dimethyl tartrate, or triols, such as glycerol pro-
tected by the Ley procedure.[11] Thus, 15 was prepared from
2 in 80% yield; the reaction of -(ϩ)-dimethyl tartrate with
2 in methanol in the presence of trimethyl orthoformate
gave the dioxane derivative (Ϫ)-16 in 93% yield.[12,13] The
same procedure led to (Ϫ)-17 (95% yield) from (ϩ)-trans-
1,2-cyclohexanol,[11b] (Ϫ)-18 (98% yield) from (ϩ)-1-phe-
nyl-1,2-ethanediol,[14] and 19 (98% yield) from glycer-
ol[14,15] (Scheme 4).
[a]
`
Laboratoire de Synthese Organique, UMR n° 6180,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
Fax: (internat.) ϩ33-4-91983865
E-mail: m.santelli@univ.u-3mrs.fr
Eur. J. Org. Chem. 2004, 2679Ϫ2691
DOI: 10.1002/ejoc.200400042
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2679

N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
Scheme 3
Results and Discussion
First, we studied the generally clean TiCl4-mediated ad-
dition of allylsilanes to the acetals using CH2Cl2 as solvent
and 4 equiv. of nitromethane.[16] Compound 20 was pro-
duced from 15, in the presence of 3 equiv. of allylsilane, in
43% yield and from (Ϫ)-16 in 60% yield. The structure of
20 was established by its ring closing metathesis using the
Grubbs catalyst[17] to form (1R,2S)-1,2-dimethyl-1,2-di-
methoxycyclohex-4-ene (21) in 90% yield. As indicated in
Scheme 5, the chirality of the (Ϫ)-16 moiety is lost.
Scheme 4
2680
Scheme 5
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Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
FULL PAPER
In the case of (Ϫ)-17, substitution of the methoxyl groups methoxyl group assisting the departure of the other so that
was observed and the optically active dioxadecalin (Ϫ)-22 the first substitution occurs with retention. The anomer-
was obtained in 68% yield as the sole product (Ͼ 98% de, ically assisted ionization[22] of the second methoxyl group
1
Ͼ 99% ee). Analysis of the H and 13C NMR spectra pro- in accordance with the lone-pair-electron hypothesis[23] then
ved that the C2 axis of symmetry is maintained. Only two leads to an oxocarbenium species that is attacked axially by
structures having such a C2-axis of symmetry, 22 and 22Ј, allylsilane, as shown in Scheme 7.[24]
are possible. Nevertheless, the NOESY spectrum of 22
We have investigated the structure of the oxocarbenium
shows two diagnostic cross peaks between the H(5) or H(6) ion at the B3LYP/6-311G (d,p) level by using Gaussian 98,
protons and the allylic protons. Moreover, all attempts to revision A.11.4.[25] These calculations indicate that the oxy-
apply ring closing metathesis to 22 failed,[11] leading us to gen atom of the methoxyl group contributes to the stabiliz-
propose that structure 22 results from a substitution that ation of the positive charge. In particular, the
occurs with retention of configuration (Scheme 6).
C(2)ϪC(3)ϪO(7) angle is reduced to 100.4° and the O(7)
atom is positioned nearer to the C(2) center than to either
the C(10) or O(4) atoms (Figure 1).
Figure 1. Optimized geometry of the oxocarbenium ion at the
˚
B3LYP/6.311G (d,p) level; selected bond lengths (A): O(1)ϪC(2),
1.258; O(1)ϪC(6), 1.530; C(2)ϪC(3), 1.549; C(2)ϪC(9), 1.475;
C(3)ϪO(4), 1.404; C(3)ϪO(7), 1.406; O(4)ϪC(5), 1.437;
C(5)ϪC(6), 1.506; O(7)ϪC(8), 1.445; C(2)ϪO(7), 2.27; O(4)ϪO(7),
2.34; C(10)ϪO(7), 2.48; selected bond angles (°): O(1)ϪC(2)ϪC(3),
121.9; O(1)ϪC(2)ϪC(9), 116.9; C(3)ϪC(2)ϪC(9), 121.2;
Scheme 6
The Lewis acid-mediated addition of carbon nucleophiles
to acetals is a common reaction in organic synthesis; it is
used widely for the formation of carbonϪcarbon bonds.[18]
The HosomiϪSakurai allylation of acetals is a seminal ex-
ample of these reactions.[19]
Mechanistic hypotheses involving either synchronous
(SN2-like) or dissociative (SN1-like) substitution processes
have been proposed, as well as the involvement of equilib-
rating ion pairs.[20]
C(2)ϪC(3)ϪO(7),
100.4;
O(4)ϪC(3)ϪO(7),
112.9;
O(7)ϪC(3)ϪC(10), 115.2; selected dihedral angle (°):
O(1)ϪC(2)ϪC(3)ϪO(4), Ϫ5.0; O(1)ϪC(2)ϪC(3)ϪO(7), 114.9;
C(2)ϪC(3)ϪO(7)ϪC(8), 173.3; C(9)ϪC(2)ϪC(3)ϪO(7), Ϫ64.2;
selected total atomic charges: O(1), 0.175; C(2), 0.398; C(9),
Ϫ0.468; C(3), Ϫ0.709; O(4), 0.127; O(7), 0.001; C(8), Ϫ0.173; the
HOMO (MO, 54; E ϭ Ϫ11.76 eV) is centered on O(7) and the
LUMO (MO, 55; E ϭ Ϫ6.98 eV) is centered on C(2); total energy:
Ϫ656.201(90) hartrees
Similarly, the dioxane (Ϫ)-23 was obtained in 60% yield
from (Ϫ)-18; again, no ring closing metathesis was observed
when using the Grubbs catalyst. NOESY data allowed us
to confirm the identity of structure 23. We observed two
cross peaks in the NOESY spectrum of 23 that reveal an
NOE between H(5) and both protons of the proximal allylic
group. In contrast, the NOESY spectrum does not shown
any NOE between H(5) and the distal allylic moiety or the
two methyl groups. Again, we note that the allylic substi-
tution occurs with a double retention of configuration. All
attempts to observe the monoallylation failed; we obtained
23 only when we used one equiv. of allylsilane (Scheme 8).
With regard to the use of asymmetric acetals in organic
synthesis, a general view has emerged that a reaction
mechanism continuum exists with its extremes being an
SN2-type invertive displacement and a dissociative SN1-type
process proceeding via a free oxocarbenium ion and fol-
lowed by rapid nucleophilic attack.[21]
The double retention of configuration observed in the
case of (Ϫ)-17 could result from the participation of one
Scheme 7
Scheme 8
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N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
We studied the coordination of the two methoxyl groups the coordination of titanium tetrachloride to the oxygen
of 18 in the presence of 0.25 equiv. of titanium tetrachloride atom of the bridge is postulated to induce the substitution
by 400-MHz 1H NMR spectroscopy at room tempera- occurring with inversion. In each case, the more reactive
ture;[26] the spectra revealed that the ratio of the one doubly CϪO bond is in an axial position (Scheme 10).
and two singly coordinated species [i.e., through either the
C(2) methoxyl or C(3) methoxyl groups] to the free ketal
was ca. 2.1:1.6:1.15:1.
Two oxocarbenium ions A and B could result from the
departure of the methoxyl group of 18. Our calculations
indicated that the departure of the C(3) methoxyl group led
to the more-stable oxocarbenium ion A (Figure 2).
Figure 2. Optimized geometry of the oxocarbenium ions at the
B3LYP/6.31G(d,p) level; total energy (hartrees): A, Ϫ731.060(41);
B, Ϫ731.056(84); energy difference: 2.24 kcal/mol; A, selected bond
˚
lengths (A): O(4)ϪC(3), 1.26; C(2)ϪO(2Ј), 1.41; C(3)ϪO(2Ј), 2.27;
selected
bond
angles
(°):
C(3)ϪC(2)ϪO(2Ј),
100.5;
Scheme 10
O(1)ϪC(2)ϪO(2Ј), 113.1; O(2Ј)ϪC(2)ϪC(2Ј), 115.5
1
For the asymmetric dioxane 19, in the presence of one
equiv. of allylsilane, the first reaction is a substitution of
the methoxyl group with overall retention of configuration
followed by an invertive (‘‘SN2-like’’) substitution on the
mixed ketal moiety.
Again, the stereochemistry of 25 has been confirmed by
performing a ring closing metathesis using the Grubbs cata-
lyst; it led to a cis ring junction dioxadecalin, 26. Moreover,
NOESY experiments were in agreement with the proposed
structure (Scheme 9).
A 400-MHz H NMR spectroscopy study of the coordi-
nation of titanium tetrachloride with 19 showed that the
Lewis acid is bound mainly to the methoxyl group. When
0.25 equiv. of titanium tetrachloride was added to a solu-
tion of 19 in deuterated chloroform at room temperature,
the signal of the methoxyl group shifts from δ ϭ 3.27 to
4.63 ppm (broad singlet, W1/2 ϭ 27 Hz). In the 13C NMR
spectra, the number of signals doubled [δ, ppm: C(1), 106.8
and 107.5; C(1Ј), 18.2 and 19.1; C(2), 99.0 and 104.0; C(2Ј),
18.5 and 27.4; C(6), 64.2 and 66.5].
We have investigated the structure of the oxocarbenium
ion C at the B3LYP/6-311G (d,p) level. These calculations
indicate that the oxygen atom of the bridge contributes to
the stabilization of the positive charge. In particular, the
O(7)ϪC(1)ϪC(2) angle is reduced to 90.7° and the O(7)
atom is positioned near the C(2) center (Figure 3).
Figure 3. Optimized geometry of the oxocarbenium ion at the
˚
B3LYP/6.311G (d,p) level; selected bond lengths (A): C(1)ϪO(8),
1.400; C(1)ϪO(7), 1.429; C(1)ϪC(2), 1.542; C(1)ϪC(1Ј), 1.505;
C(2)ϪO(3), 1.270; C(2)ϪC(2Ј), 1.471; O(3)ϪC(4), 1.498;
C(2)ϪO(7), 2.27; selected bond angles (°): O(7)ϪC(1)ϪC(2), 90.7;
Scheme 9
O(8)ϪC(1)ϪC(2),
O(7)ϪC(1)ϪC(1Ј),
108.6;
112.7;
O(7)ϪC(1)ϪO(8),
C(1)ϪC(2)ϪO(3),
107.0;
119.3;
C(1)ϪC(2)ϪC(2Ј), 123.8; C(2Ј)ϪC(2)ϪO(3), 116.8; selected di-
For the substitution occurring with retention of configu-
ration, the most reasonable interpretation is that, after co-
ordination of titanium tetrachloride to the oxygen atom of
the methoxyl group, an oxygen atom participation occurred
to give an oxonium ion C, which was attacked by allylsilane
hedral
angles
(°):
O(8)ϪC(1)ϪC(2)ϪO(3),
30.3;
C(1Ј)ϪC(1)ϪC(2)ϪC(2Ј), Ϫ27.3; C(1)ϪC(2)ϪO(3)ϪC(4), Ϫ3.0;
selected total atomic charges: C(1), Ϫ1.078; C(1Ј), Ϫ0.577; C(2),
0.770; C(2Ј), Ϫ0.686; O(3), 0.104; O(7), 0.063; O(8), 0.018; the
HOMO (MO, 38; E ϭ Ϫ12.36 eV) is centered on O(7) and the
LUMO (MO, 39; E ϭ Ϫ7.42 eV) is centered on C(2); total energy:
to give an overall retention of configuration. Subsequently, Ϫ498.883(61) hartrees
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Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
FULL PAPER
The addition of BISTRO to various mixed ketals 15Ϫ19
was less stereoselective than the addition of allylsilane. In
most cases, we obtained a mixture of 5a and 5b, but, inter-
estingly, in some cases, 5a or 5b was the major product.
At first, we added BISTRO to biacetyl, which led to the
creation of a 1:1 mixture of 27a and (Ϯ)-27b in 50% yield.
We note that these compounds could result from the ad-
dition of a chelated biacetyl, but the use of a large excess
of TiCl4 should exclude the formation of chelated com-
plexes (Scheme 11).
As is evident from Table 1, the best yields of 5 were ob-
tained from the more-common ketal 15, which also gave the
highest proportion of 5a (70%).
The stereochemistries of the dioxanes 28a and 28b were
confirmed by NOESY analyses (Figure 5).
Scheme 11
The structure of 27 was established by analysis of the
NOESY spectra; it was confirmed by X-ray crystallo-
graphic analysis of (Ϯ)-27b (Figure 4). Unfortunately, we
were unable to rearrange 27, obtained in fair yields, into
the corresponding acetylcyclopentanes 5.
Figure 5. NOESY analyses of 28a, 28b, and 29
We have determined that the dioxanes 28a or 28b, when
treated with TiCl4, rearrange to acetylcyclopentanes 5a and
(Ϫ)-(S,S)-5b, respectively.
A more interesting result was observed with the dioxane
(Ϫ)-18, obtained from (S)-(ϩ)-1-phenyl-1,2-ethanediol
(98% ee), which led mainly to (ϩ)-(R,R)-5b (98% ee).[27]
Using 3 equiv. of TiCl4, we obtained mainly the non-
racemic dioxane 29. The 13C NMR spectra of 29 reveals a
conformationally mobile system at room temperature,
which is in accordance with a cis ring junction (signals
duplicated so that 35 resonances appear instead of the 20
expected). According to semi-empirical calculations under-
taken using the PM3-method,[28] conformation b is slightly
more stable than that of a [∆Hf (kcal molϪ1), a: Ϫ4915.70;
b: Ϫ4916.04].[29] The structure was established by a series
of 1D NMR spectroscopy and NOESY experiments (Fig-
ure 5).
Figure 4. ORTEP diagram of diol (Ϯ)-27b
Next, we examined the addition of BISTRO to the ketals
15Ϫ19 (Table 1).
Table 1. Addition of BISTRO to ketals 15Ϫ19
The use of 4 equiv. of TiCl4 led directly to (ϩ)-(R,R)-5b
and (S)-(ϩ)-1-phenyl-1,2-ethanediol (35% isolated yield).
The enantiomeric excess of the recovered diol was deter-
mined by its transformation into (Ϫ)-18 (Scheme 12). Com-
parison with the starting material showed that no racemiz-
ation occurred during either the BISTRO addition or the
pinacol-like rearrangement. In either case, the OϪC and
CϪC bonds that are involved have the antiperiplanar re-
lationship required for 1,2-migration (Scheme 13).[30]
The reaction of BISTRO with 19 occurred with poor
stereoselectivity; 30 was formed as a mixture of dia-
stereoisomers.
Ketals TiCl4
Temp.
Dioxane
yield (%)
5
equiv. (°C)
yield (%)
15
15
3
4
4
3
3
3
4
2
4
Ϫ90 Ǟ Ϫ60
Ϫ90 Ǟ Ϫ60
Ϫ90 Ǟ Ϫ60
Ϫ90 Ǟ Ϫ10
Ϫ90 Ǟ Ϫ60 28a, 15; 28b, 36 trace
Ϫ90 Ǟ rt
Ϫ90 Ǟ Ϫ60
Ϫ90 Ǟ Ϫ60 29 (28)
Ϫ90 Ǟ Ϫ60 30 (9)
Ϫ
Ϫ
Ϫ
Ϫ
5a, 55; (Ϯ)-5b, 23
5a, 45; (Ϯ)-5b, 19
5a, 42; (Ϯ)-5b, 28
5a, 45; (Ϯ)-5b, 30
(Ϫ)-16
(Ϫ)-16
(Ϫ)-17
(Ϫ)-17
(ϩ)-18
(ϩ)-18
19
28a, 4; 28b, 10
Ϫ
5a, 13; (Ϫ)-(S,S)-5b, 31
5a, 7; (ϩ)-(R,R)-5b, 60
5a, 8; (ϩ)-(R,R)-5b, 32
5a, 45; (Ϯ)-5b, 19
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N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
Scheme 12
Figure 7. ORTEP diagram of steroid 9ad
Scheme 13
Starting from 5a, we have prepared five new steroids ac-
cording to procedures we have reported previously
(Scheme 3). Compound 5a was acylated and the resulting
compound, 6a, was alkylated with 7c (R1 ϭ MeO, R2 ϭ H)
or 7d (R1 ϭ H, R2 ϭ MeO).[4e] Interestingly, we obtained
only one racemic stereoisomer 8ac or 8ad. Upon heating at
215 °C, 8ac was converted into steroids 9ac (40%) and 10ac
(40%) and 8ad into steroids 9ad (40%) and 11ad (40%). In
the latter case, and as already mentioned,[9] heating at 215
°C leads to an in situ demethoxycarbonylation of 10ad and
the formation of 11ad (40%). Upon heating at 200 °C, 8ad
was converted into steroids 9ad (40%) and 10ad (40%). The
structures of 10ac, 9ad, and 11ad have been confirmed un-
ambiguously by X-ray diffractometry (see Figure 6, Fig-
ure 7, Figure 8, Figure 9).
Figure 8. ORTEP diagram of steroid 11ad
Figure 9. ORTEP diagram of steroid 14bc
°C led to 13bd (25%) and 14bd (55%). The structure of 14bc
was confirmed by X-ray diffractometry (Figure 9). The en-
antiomeric excesses of 14bc (93%) and 14bd (98%) corre-
spond to the optical purity of the -(ϩ)-mandelic acid used
for the preparation of (Ϫ)-18.
Figure 6. ORTEP diagram of steroid 10ac
From the structures of the various steroids, it was easy
Heating of 8bc or 8bd led to five steroids that exhibit a to predict the structures of the transition states of the
cis C/D ring junction. Upon heating at 215 °C, 8bc was DielsϪAlder reactions. Steroids bearing a cis B/C ring junc-
cyclized into 12bc (27%) and 14bc (63%) and 8bd into 12bd tion, such as 9ac, 9ad, 14bc, and 14bd, arise from an endo
(25%) and 14bd (55%). In contrast, heating of 8bd at 200 transition state involving the formation of an E-o-xylylene.
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Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
FULL PAPER
In contrast, 10ac, 10ad, 11ad, 12bc, 12bd, and 13bd, each Experimental Section
of which exhibits a trans B/C ring junction, result from exo
General: All reactions were performed under argon in oven-dried
transition states, which imply, again, the formation of an
(E)-o-xylylene (Scheme 14).
glassware. TLC was performed on silica gel 60 F254
.
1H and 13C
NMR spectra were recorded in CDCl3 solutions at 500, 400, and
300 and 125, 100, and 75 MHz, respectively. CarbonϪproton coup-
lings were determined by DEPT sequence experiments. Mass spec-
tra (electron impact ionization, 70 eV) were recorded by GC/MS
(VarianϪSaturn 2100 T; Chrompack column, CP-Sil 8CB, 30 m ϫ
0.25 mm, DF ϭ 0.25 µm). THF was distilled before use from so-
dium/benzophenone; CH2Cl2 from P2O5. The enantiomeric ex-
cesses of ketals and ketones were determined by GC (Chrompack
CP7502 WCOT fused silica column and CP-Chirasil-Dex CB as
the stationary phase) and those of the steroids by chiral HPLC
(Daicel, 250 ϫ 4.6 mm; 14bc: Chiralcel OD-H [cellulose tris(3,5-
dimethylphenylcarbamate)], mobile phase: hexane/2-PrOH, 95:5;
14bd: Chiralpak AD [amylose tris(3,5-dimethylphenylcarbamate)],
mobile phase: hexane/ethanol, 95:5). Flash chromatography was
performed on silica gel (230Ϫ400 mesh) obtained from
MachereyϪNagel & Co.
For the preparation of iodobenzocyclobutenes 7, see ref.[4e]; for
compounds 8 and steroids 9Ϫ11 (R1 ϭ R2 ϭ H), see ref.[9]
General Procedure for the Formation of trans Acetals: Camphorsul-
fonic acid (0.1 equiv.) was added to a solution of diol (0.9 equiv.),
2,3-butanedione (1 equiv.), and trimethyl orthoformate (3 equiv.) in
dry methanol (1.75 mL/mmol of biacetyl). The mixture was heated
under reflux for 72 h. The reaction was neutralized by the addition
of triethylamine and then the solvents were evaporated under re-
duced pressure. The residue was purified by flash chromatography
to give the diacetals 16, 17, 18, and 19.
Scheme 14
General Procedure for the Condensation of Silylated Derivatives on
Ketals: A 250-mL flask equipped with a thermometer, septum cap,
magnetic stirring bar, and argon outlet was charged with anhydrous
CH2Cl2 (100 mL) and anhydrous nitromethane (4.4 mL, 80 mmol).
The solution was cooled to Ϫ70 °C; TiCl4 (11.4 g, 6.6 mL,
60 mmol) was added, followed by the slow addition of the ketal
(20 mmol) in CH2Cl2 (10 mL). The mixture was stirred 0.5 h. at
this temperature, then cooled to Ϫ90 °C; a solution of allyltrimeth-
ylsilane (6.9 g, 9.6 mL, 60 mmol) or BISTRO (10.2 g, 40 mmol) in
CH2Cl2 (30 mL) was then added over 15 min. The mixture was
stirred for 2 h. at Ϫ90 °C. When BISTRO was used, the solution
was slowly warmed to Ϫ60 °C. After a certain time, the reaction
was quenched by addition of saturated aqueous NH4Cl and then
the mixture was stirred for 0.5 h. before being extracted with
CH2Cl2. The organic layer was washed with water, dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was subjected to flash chromatography.
As an illustration of the possibility of functionalizing the
17β position, we performed the oxidation of the vinyl group
by the Wacker process.[4e,31] The corresponding 17β-acetyl
steroid (ϩ)-31 was obtained in 55% yield (Scheme 15).
Scheme 15
(4R,5S)-4,5-Dimethoxyocta-4,5-dimethyl-1,7-diene (20): Synthe-
sized from 15 (3.56 g) or 16 (5.84 g) and allyltrimethylsilane (2 h. at
Ϫ90 °C). The crude product was purified by flash chromatography
(petroleum ether/Et2O, 98:2) to give 20 [1.70 g from 15 (43%) or
Conclusion
1
2.40 g from 16 (60%)] as an oil. H NMR (CDCl3, 300 MHz): δ ϭ
We have shown that allylsilane and BISTRO can react
with ketals with high stereoselectivity. In fact, the formation
of discrete oxocarbenium ions, stabilized by the anomeric
effect and the proximal methoxyl group, seems to be the
major process of the various allylic substitution reac-
tions.[32] The high stereoselectivities of these reactions allow
the synthesis of divinylacetylcyclopentanes 5, which are key
molecules for the stereoselective synthesis of various 12-
oxosteroids.
5.88 (ddt, J ϭ 16.9, 10.9, 7.1 Hz, 2 H), 4.97 (m, 4 H), 3.25 (s, 6 H),
2.49 (1/2AB, br. d, J ϭ 14.7, 7.1 Hz, 1 H), 2.24 (1/2AB, dt, J ϭ
14.7, 7.6, 1.2 Hz, 1 H), 1.14 (s, 6 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 136.0 (d), 116.3 (t), 81.9 (s), 51.0 (q), 39.6 (t), 18.0
(q) ppm. MS: m/z (%) ϭ 157 (44, Mϩ Ϫ allyl), 125 (25), 116 (22),
101 (34), 99 (100), 98 (22), 89 (55), 73 (21), 67 (45), 43 (30), 41 (29).
(؊)-(2S,3S,5S,6S)-2,3-Diallyl-2,3-dimethoxyoctahydrobenzo[1,4]-
dioxine (22): Synthesized from (Ϫ)-17 (4.61 g) and allyltrimethylsil-
ane (2 h at Ϫ90 °C). The crude product was purified by flash chro-
Eur. J. Org. Chem. 2004, 2679Ϫ2691
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2685

N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
matography (petroleum ether/Et2O, 98:2) to give 22 (3.40 g, 68%)
(1/2AB, d, J ϭ 16.3 Hz, 2 H), 1.96 (1/2AB, d, J ϭ 16.3 Hz, 2 H),
as an oil; ee Ͼ 99%. [α]2D5 ϭ Ϫ108.4 (CHCl3, 0.92). 1H NMR 1.13 (s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 124.8 (d), 78.0
(CDCl3, 300 MHz): δ ϭ 5.77 (dddd, J ϭ 16.6, 10.8, 8.0, 5.9 Hz, 2
H), 5.11 (br. d, J ϭ 10.8 Hz, 2 H), 5.10 (br. d, J ϭ 16.6 Hz, 2 H),
3.29 (m, 2 H), 3.16 (1/2AB, d, J ϭ 14.8, 5.8 Hz, 2 H), 1.97 (1/2AB,
d, J ϭ 14.8, 8.0 Hz, 2 H), 1.72 (m, 4 H), 1.25 (m, 4 H), 1.0 (s, 6
H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 133.8 (d), 117.8 (t), 77.4
(s), 72.7 (d), 35.5 (t), 30.2 (t), 24.4 (t), 21.1 (q) ppm. MS: m/z (%) ϭ
210 (17), 209 (100, Mϩ Ϫ allyl), 153 (10), 123 (11), 111 (28), 93
(14), 83 (24), 81 (32), 69 (15), 67 (36), 43 (70), 41 (16). C16H26O2
(250.38): calcd. C 76.75, H 10.47; found C 76.82, H 10.32.
(s), 49.8 (q), 33.8 (t), 17.8 (q) ppm. MS: m/z (%) ϭ 170 (14, Mϩ),
111 (100), 81 (30), 79 (33), 73 (21).
(1S*,3S*,6R*)-3-(Hydroxymethyl)-1,6-dimethyl-2,5-dioxabicyclo-
[4.4.0]dec-8-ene (26): Oil. 1H NMR (CDCl3, 500 MHz): δ ϭ 5.65
(m, 1 H), 5.45 (m, 1 H), 4.07 (dddd, J ϭ 11.7, 4.8, 4.4, 3.4 Hz, 1
H), 3.82 (1/2AB, d, J ϭ 11.9, 11.7 Hz, 1 H), 3.62 (1/2AB, d, J ϭ
11.7, 3.4 Hz, 1 H), 3.53 (1/2AB, d, J ϭ 11.9, 4.4 Hz, 1 H), 3.49 (1/
2AB, d, J ϭ 11.7, 4.8 Hz, 1 H), 3.13 (1/2AB, J ϭ 17.2 Hz, 1 H),
2.23 (br. s, 1 H), 2.00 (br. s, 1 H), 1.73 (1/2AB, d, J ϭ 17.2, 5.2 Hz,
1 H), 1.34 (s, 3 H), 1.06 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 124.5 (d), 122.5 (d), 74.4 (s), 73.1 (s), 67.3 (d), 62.8 (t), 61.2
(t), 39.3 (t), 30.8 (t), 24.0 (q), 19.1 (q) ppm. MS: m/z (%) ϭ 144
(100, Mϩ Ϫ 1,3-butadiene), 43 (53).
(Ϫ)-(2S,3S,5S)-2,3-Diallyl-2,3-dimethyl-5-phenyl-1,4-dioxane (23):
Synthesized from (ϩ)-18 (5.05 g) and allyltrimethylsilane (2 h. at
Ϫ90 °C). The crude product was purified by flash chromatography
(petroleum ether/Et2O, 98:2) to give 23 (3.27 g, 60%) as an oil; ee
Ͼ 99%. [α]2D5 ϭ Ϫ77.9 (CHCl3, 1.05). 1H NMR (CDCl3, 300 MHz):
δ ϭ 7.21 (m, 5 H), 5.75 (m, 2 H), 5.05 (m, 4 H), 4.70 (dd, J ϭ 9.9, (1S*,2R*,3R*,6S*)-1,2-Dimethyl-3,6-divinylcyclohexan-1,2-diol
5.1 Hz, 1 H), 3.48 (m, 2 H), 3.20 (1/2AB, d, J ϭ 14.9, 5.9 Hz, 2 (27a) and (1S*,2R*,3S*,6S*)-1,2-Dimethyl-3,6-divinylcyclohexan-
H), 1.99 (1/2AB, d, J ϭ 14.9, 7.7 Hz, 2 H), 0.99 (s, 3 H), 0.95 (s, 3 1,2-diol [(؎)-27b]: Compounds were synthesized from biacetyl
H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 139.0 (s), 133.8 (d), (20 mmol, 1.72 g) and BISTRO (12 h. at room temp.) according
133.6 (d), 128.5 (d, 2C), 128.0 (d), 126.4 (d, 2C), 118.2 (t), 118.0 to the general procedure. The crude product was purified by flash
(t), 77.4 (s), 76.0 (s), 70.2 (t), 65.6 (t), 35.3 (t), 35.0 (t), 21.3 (q), chromatography (petroleum ether/Et2O, 98:2 to 80:20) to give 27a
20.8 (q) ppm. MS: m/z (%) ϭ 231 (18, Mϩ Ϫ allyl), 188 (11), 104
(100), 78 (19), 43 (29). C18H24O2 (272.38): calcd. C 79.37, H 8.88;
found C 79.28, H 9.02.
(1.02 g, 26%) and then (Ϯ)-27b (0.98 g, 25%).
27a: Oil. 1H NMR (CDCl3, 500 MHz): δ ϭ 5.89 (ddd, J ϭ 17.3,
10.5, 8.4 Hz, 2 H), 5.09 (br. d, J ϭ 10.5 Hz, 2 H), 5.06 (br. d, J ϭ
17.3 Hz, 2 H), 2.42 (ddd, J ϭ 11.9, 8.4, 3.2 Hz, 2 H), 1.63 (m, 3
H), 1.43 (m, 3 H), 1.21 (s, 6 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 139.9 (d), 116.4 (t), 74.8 (s), 45.9 (d), 26.7 (t), 21.9 (q) ppm.
MS: m/z (%) ϭ 168 (17), 153 (12), 135 (21), 109 (34), 93 (23), 88
(30), 69 (31), 43 (100).
(1S*,2R*,5R*)-2-Allyl-1,2-dimethyl-3,7,8-trioxabicyclo[3.2.1]octane
(24): Synthesized from 19 (3.48 g) and allyltrimethylsilane (3.2 mL,
0.2 mmol) (2 h. at Ϫ90 °C). The crude product was purified by
flash chromatography (petroleum ether/Et2O, 95:5 to 70:30) to give
1
24 (0.74 g, 21%) and 25 (1.18 g, 26%). 24, oil. H NMR (CDCl3,
300 MHz): δ ϭ 5.81 (dddd, J ϭ 16.9, 10.3, 7.7, 6.6 Hz, 1 H), 5.09
(m, 1 H), 5.08 (m, 1 H), 4.39 (br. t, J ϭ 6.6 Hz, 1 H), 4.11 (d, J ϭ (؎)-27b: White crystals, m.p. 64Ϫ65 °C (hexane). 1H NMR
6.6 Hz, 1 H), 3.99 (br 1/2AB, J ϭ 11.6 Hz, 1 H), 3.86 (td, J ϭ 6.0,
(CDCl3, 300 MHz): δ ϭ 5.90 (m, 2 H), 5.11 (m, 2 H), 5.04 (m, 2
1.3 Hz, 1 H), 3.41 (1/2AB, d, J ϭ 11.6, 1.2 Hz, 1 H), 3.00 (1/2AB, H), 2.54 (ddd, J ϭ 11.7, 7.5, 3.6 Hz, 1 H), 2.09 (ddd, J ϭ 11.9, 8.2,
d, J ϭ 14.6, 6.6 Hz, 1 H), 1.97 (1/2AB, d, J ϭ 14.6, 7.7 Hz, 1 H),
1.32 (s, 3 H), 1.10 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
3.8 Hz, 1 H), 1.67 (m, 2 H), 1.39 (m, 1 H), 1.32 (dq, J ϭ 4.0, 0.9
Hz, 1 H), 1.16 (s, 3 H), 1.05 (s, 3 H) ppm. 13C NMR (CDCl3,
133.2 (d), 117.6 (t), 109.2 (s), 78.6 (s), 74.8 (d), 67.7 (t), 65.1 (t), 75 MHz): δ ϭ 139.4 (d), 139.3 (d), 116.6 (t), 116.0 (t), 75.8 (s), 75.4
29.8 (t), 21.3 (q), 19.6 (q) ppm.
(s), 48.3 (d), 46.8 (d), 27.3 (t), 27.1 (t), 22.4 (q), 17.8 (q) ppm. MS:
m/z (%) ϭ 168 (28), 153 (15), 135 (35), 109 (38), 95 (29), 88 (44),
69 (22), 43 (100).
(2R*,3S*,5S*)-2,3-Diallyl-5-(hydroxymethyl)-2,3-dimethyl-1,4-
dioxane (25): Synthesized from 20 (3.48 g) and allyltrimethylsilane
(2 h at Ϫ90 °C). The crude product was purified by flash chroma-
tography (petroleum ether/Et2O, 95:5 to 80:20) to give 25 (3.26 g,
(1R,3S,8S,10S,11S,14R)-1,10-Dimethyl-11,14-divinyl-2,9-dioxatri-
cyclo[8.4.0.03,8]tetradecane (28a) and (1R,3S,8S,10S,11S,14S)-1,10-
Dimethyl-11,14-divinyl-2,9-dioxatricyclo[8.4.0.03,8]tetradecane (28b):
Synthesized from 17 (4.61 g) and BISTRO (12 h. at Ϫ60 °C) ac-
cording to the general procedure. The crude product was purified
by flash chromatography (petroleum ether/Et2O, 100:0 to 98:2) to
give 28b (2.00 g, 36%) and then 28a (0.83 g, 15%).
1
72%) as an oil. H NMR (CDCl3, 500 MHz): δ ϭ 5.86 (m, 2 H),
5.17 (m, 2 H,), 5.10 (m, 2 H), 3.90 (m, 1 H), 3.70 (1/2AB, d, J ϭ
11.6, 11.4 Hz, 1 H,), 3.59 (m, 1 H), 3.95 (m, 1 H), 3.53 (1/2AB, d,
J ϭ 11.6, 3.6 Hz, 1 H), 3.48 (m, 1 H), 3.20 (1/2AB, d, J ϭ 14.7,
6.2 Hz, 1 H), 2.26 (1/2AB, d, J ϭ 13.9, 5.6 Hz, 1 H), 2.04 (m, 2
H), 1.32 (s, 3 H), 1.06 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ 133.9 (d), 133.6 (d), 118.1 (t), 117.6 (t), 76.9 (s), 76.8 (s), 68.1
(d), 62.8 (t), 61.0 (t), 41.8 (t), 35.0 (t), 21.6 (q), 17.6 (q) ppm. MS:
m/z (%) ϭ 185 (37, Mϩ Ϫ allyl), 117 (17), 85 (10), 84 (11), 83 (13),
69 (19), 55 (15), 43 (100). C13H22O3 (226.31): calcd. C 68.99, H 9.8;
found C 68.84, H 10.01.
28a: Oil. 1H NMR (CDCl3, 200 MHz): δ ϭ 5.98 (m, 2 H), 5.06 (m,
4 H), 3.50 (m, 2 H), 2.36 (m, 1 H), 2.07 (m, 1 H), 1.78 (m, 4 H),
1.50 (m, 4 H), 1.32 (s, 3 H), 1.29 (m, 4 H), 0.93 (s, 3 H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ 139.4 (d), 138.9 (d), 116.7 (t), 114.4
(t), 78.2 (s), 78.1 (s), 73.4 (d), 71.5 (d), 51.3 (d), 38.8 (d), 30.7 (t),
30.5 (t), 26.2 (t), 24.6 (t, 2C), 23.5 (t), 19.4 (q), 18.9 (q) ppm.
General Procedure for the RCM Reaction: Cl2(PCy3)2RuϭCHPh
(124 mg, 0.151 mmol) was added to a solution of 20 (300 mg,
1.51 mmol) or 25 (342 mg, 1.51 mmol) in dry CH2Cl2 (18 mL). The
mixture was stirred at room temp. (for 20: 1.15 h; for 25: 24 h). The
solution was concentrated and the residue was purified by flash
chromatography (21: petroleum ether/Et2O, 100:0 to 90:10; 26:
90:10 to 60:40) to give 21 (231 mg, 90%) or 26 (263 mg, 88%).
28b: Oil. 1H NMR (CDCl3, 500 MHz): δ ϭ 6.15 (ddd, J ϭ 17.5,
10.7, 5.7 Hz, 1 H), 5.98 (ddd, J ϭ 17.2, 10.2, 9.0 Hz, 1 H), 5.14 (d,
J ϭ 10.7 Hz, 1 H), 5.06 (d, J ϭ 17.5 Hz, 1 H), 5.01 (m, 2 H), 3.89
(td, J ϭ 10.1, 4.0 Hz, 1 H), 3.80 (td, J ϭ 10.1, 4.0 Hz, 1 H), 2.66
(m, 1 H), 2.03 (m, 2 H), 1.97 (m, 1 H), 1.75 (m, 2 H), 1.69 (m, 2
H), 1.35 (m, 2 H), 1.25 (s, 3 H), 1.23 (m, 2 H), 1.21 (m, 2 H), 1.01
(s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 139.6 (d), 139.5
(1R,2S)-1,2-Dimethoxy-1,2-dimethylcyclohex-4-ene (21): Oil. 1H
NMR (CDCl3, 300 MHz): δ ϭ 5.53 (br. s, 2 H), 3.23 (s, 6 H), 2.44 (d), 115.0 (t), 114.6 (t), 79.2 (s), 77.4 (s), 74.8 (2C, d), 52.1 (d), 49.3
2686  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 2679Ϫ2691

Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
FULL PAPER
(d), 33.4 (t), 32.8 (t), 28.0 (t), 27.3 (q), 26.8 (t), 24.2 (t, 2C), 19.2 Methoxycarbonylation of 5: A 250-mL flask equipped with a ther-
(q) ppm. MS: m/z (%) ϭ 169 (16), 168 (100, Mϩ Ϫ C8H12), 99 (15),
mometer, septum cap, magnetic stirring bar, and argon outlet was
81 (28), 79 (15), 67 (24), 43 (23), 41 (10). C18H28O2 (276.41): calcd. charged with anhydrous THF (100 mL), NaH (55% dispersion in
C 78.21, H 10.21; found C 78.27, H 10.17.
oil, 587 mg, 13.5 mmol), and dimethyl carbonate (1 mL,
11.8 mmol). The mixture was heated under reflux and then 5
(800 mg, 4.49 mmol) was added. The solution was heated under
reflux for 12 h and then cooled to room temp.; acetic acid (4 mL)
was added slowly, followed by water (13.2 mL). After extraction
with diethyl ether (3 ϫ 10 mL), the organic phases were washed
with water (2 ϫ 5 mL) and brine (5 mL), dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The residue was
subjected to flash chromatography (petroleum ether/Et2O, 100:0 to
98:2) to give 6a and then 6b (827 mg, 78% of overall yield).
(1S,3S,6R,7R,10R)-1,6-Dimethyl-3-phenyl-7,10-divinyl-2,5-dioxabi-
cyclo[4.4.0]decane (29): Synthesized from (Ϫ)-18 (5.05 g) and BI-
STRO (1 h. at Ϫ60 °C) according to the general procedure using 2
equiv. of TiCl4 (7.6 g, 4.4 mL). The crude product was purified by
flash chromatography (petroleum ether/Et2O, 100:0 to 98:2) to give
29 (1.67 g, 28%) and then 5 (1.43 g, 40%).
1
29: Oil. H NMR (CDCl3, 400 MHz): δ ϭ 7.48 (d, J ϭ 7.3 Hz, 1
H), 7.44 (d, J ϭ 7.3 Hz, 1 H), 7.33 (d, J ϭ 7.3 Hz, 1 H), 7.31 (d,
J ϭ 7.3 Hz, 1 H), 7.25 (m, 1 H), 6.04 (m, 1 H), 5.96 (m, 1 H), 5.04
(m, 4 H), 4.85 (m, 1 H), 4.14 (m, 2 H), 3.19 (m, 1 H), 2.83 (m, 1
H), 2.05 (m, 2 H), 1.74 (m, 2 H), 1.43 (s, 3 H), 1.05 (s, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ 142.3 (s), 141.4 (s), 139.5 (d), 139.1
(d), 138.9 (d), 128.4 (d), 128.3 (d), 127.8 (d), 127.7 (d), 127.2 (d),
127.0 (d), 115.5 (t), 115.3 (t), 115.0 (t), 114.3 (t), 79.3 (s), 77.4 (s),
77.1 (s), 76.4 (s), 71.6 (d), 70.9 (d), 64.1 (t), 61.4 (t), 51.8 (d), 51.4
(d), 46.0 (d), 42.8 (d), 28.0 (t), 27.5 (t), 26.73 (t), 26.66 (t), 25.0 (q),
(2S,5R)-1-[2-(Methoxycarbonyl)ethan-1-on-1-yl]-1-methyl-2,5-
divinylcyclopentane (6a): Synthesized from 5a. 6a: 1H NMR
(CDCl3, 300 MHz): δ ϭ 5.66 (ddd, J ϭ 16.5, 10.8, 7.9 Hz, 2 H),
5.0 (m, 4 H), 3.69 (s, 3 H), 3.48 (s, 2 H), 2.91 (br. q. J ϭ 6.8 Hz, 2
H), 1.94 (m, 2 H), 1.64 (m, 2 H), 0.95 (s, 3 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ ϭ 206.7 (s), 168.2 (s), 137.3 (d, 2C), 116.9
(t, 2C), 62.1 (s), 52.3 (q), 51.6 (t, 2C), 46.0 (t), 27.8 (t, 2C), 11.0
(q) ppm.
24.0 (q), 18.9 (q), 18.2 (q) ppm. MS: m/z (%) ϭ 190 (21, Mϩ
Ϫ
(؉)-(2R,5R)-1-[2-(Methoxycarbonyl)ethan-1-on-1-yl]-1-methyl-2,5-
divinylcyclopentane (6b): Synthesized from (ϩ)-5b. (ϩ)-6b: [α]2D5
ϭ
C8H12), 163 (10), 120 (21), 109 (14), 104 (100), 91 (25), 78 (29), 43
(52). C20H26O2 (298.42): calcd. C 80.50, H 8.78; found C 80.46,
H 8.83.
1
ϩ33.1 (CHCl3, 1.16). H NMR (CDCl3, 300 MHz): δ ϭ 5.65 (m,
2 H), 5.00 (m, 4 H), 3.68 (s, 3 H), 3.49 (1/2AB, J ϭ 16.0 Hz, 1 H),
3.36 (1/2AB, J ϭ 16.0 Hz, 1 H), 3.14 (br. q, J ϭ 8.0 Hz, 1 H), 2.43
(br. q, J ϭ 8.5 Hz, 1 H), 1.94 (m, 2 H), 1.57 (m, 2 H), 1.12 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 205.5 (s), 168.0 (s),
138.5 (d), 138.1 (d), 115.7 (t), 115.67 (t), 61.6 (s), 55.7 (q), 52.0 (d),
47.0 (t), 46.9 (d), 29.8 (t), 28.3 (t), 19.3 (q) ppm.
(؉)-(2R,5R)-1-Acetyl-1-methyl-2,5-divinylcyclopentane (5b): Syn-
thesized from (Ϫ)-18 (5.05 g) and BISTRO according to the general
procedure using 4 equiv. of TiCl4 (15.2 g, 8.8 mL); the reaction mix-
ture was stirred 12 h. at Ϫ60 °C. The crude product was purified
by flash chromatography (petroleum ether/Et2O, 100:0 to 98:2) to
give 5 (2.40 g, 67%) as a mixture of 5a and 5b (10:90).[9] 5b: ee Ͼ
98%. [α]2D5 ϭ ϩ13.1 (CHCl3, 1.1). 1H NMR (CDCl3, 300 MHz):
δ ϭ 5.68 (m, 2 H), 4.97 (m, 4 H), 3.17 (br. q, J ϭ 9.1 Hz, 1 H),
2.44 (br. q, J ϭ 7.4 Hz, 1 H), 2.01 (s, 3 H), 1.80 (m, 2 H), 1.55 (m,
2 H), 1.11 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 212.5
(s), 139.6 (d), 138.7 (d), 115.3 (t), 114.8 (t), 61.6 (s), 46.6 (d), 45.5
(d), 29.8 (t), 28.2 (t), 28.2 (q), 19.7 (q) ppm.
General Procedure for the Alkylation of 6: Cesium carbonate
(2.44 g, 7.5 mmol) and 4- or 5-methoxy-1-iodobenzocyclobutene
(1.95 g, 7.5 mmol) were added to a solution of 6 (1.18 g, 5 mmol)
in anhydrous acetone (25 mL). The mixture was stirred vigorously
and then heated under reflux for 24 h. After cooling, the mixture
was filtered through Celite. The filtrate was concentrated under
reduced pressure and the residue was subjected to flash chromatog-
raphy.
(2S,5R)-1-Acetyl-1-methyl-2,5-divinylcyclopentane (5a): Synthesized
from 15 (3.56 g) and BISTRO according to the general procedure
using 3 equiv. of TiCl4 (11.4 g, 6.6 mL); the reaction mixture was
stirred 12 h. at Ϫ60 °C. Compound 5 (2.78 g, 78%) was obtained
as a mixture of 5a and 5b (70:30). 5a: Oil. 1H NMR (CDCl3,
300 MHz): δ ϭ 5.64 (ddd, J ϭ 16.8, 10.6, 7.8 Hz, 2 H), 4.99 (br.
d, J ϭ 10.6 Hz, 2 H), 4.97 (br. d, J ϭ 16.8 Hz, 2 H), 2.87 (q, J ϭ
7.2 Hz, 2 H), 2.09 (s, 3 H), 1.91 (m, 2 H), 1.62 (m, 2 H), 0.93 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 212.7 (s), 137.8 (d),
116.2 (t), 62.0 (s), 52.0 (d), 27.9 (t), 27.1 (q), 11.1 (q) ppm.
1-[2-(5-Methoxybenzocyclobuten-1-yl)-2-(methoxycarbonyl)-1-oxo-
ethyl]-1-methyl-2,5-divinylcyclopentane (8ac): 1H NMR (CDCl3,
300 MHz): δ ϭ 6.88 (d, J ϭ 8.1 Hz, 1 H), 6.69 (dd, J ϭ 8.1, 2.1
Hz, 1 H), 6.45 (d, J ϭ 2.1 Hz, 1 H), 5.63 (ddd, J ϭ 17.4, 10.6, 7.0
Hz, 1 H), 5.54 (ddd, J ϭ 17.2, 10.2, 8.1 Hz, 1 H), 4.94 (m, 2 H),
4.79 (dd, J ϭ 10.3, 0.9 Hz, 1 H), 4.54 (d, J ϭ 17.0 Hz, 1 H), 3.98
(1/2AB, dd, J ϭ 11.0, 5.0, 2.1 Hz, 1 H), 3.85 (1/2AB, J ϭ 11.0 Hz,
1 H), 3.66 (s, 3 H), 3.63 (s, 3 H), 3.19 (1/2AB, d, J ϭ 13.9, 5.0 Hz,
1 H), 3.16 (m, 1 H), 2.89 (1/2AB, d, J ϭ 13.9, 2.1 Hz, 1 H), 2.69
(br. q, J ϭ 8.4 Hz, 1 H), 1.85 (m, 2 H), 1.56 (m, 2 H), 0.93 (s, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 207.5 (s), 168.8 (s),
159.0 (s), 147.0 (s), 137.2 (d), 134.5 (s), 123.8 (d), 116.8 (t), 115.9
(t), 115.1 (d, 2C), 108.6 (d), 61.9 (s), 59.8 (q), 55.3 (q), 52.6 (d),
52.2 (d), 50.2 (d), 41.8 (d), 33.3 (t), 28.2 (t), 26.8 (t), 11.0 (q) ppm.
4-Hydroxymethyl-1,6-dimethyl-7,10-divinyl-2,5-dioxabicyclo-
[4.4.0]decane (30): Synthesized from 19 (3.48 g) and BISTRO (12 h.
at Ϫ60 °C) according to the general procedure using 4 equiv. of
TiCl4 (15.2 g, 8.8 mL). The crude product was purified by flash
chromatography (petroleum ether/Et2O, 100:0 to 98:2 then 70:30)
to give 5 (2.28 g, 64%) and then 30 (0.45 g, 9%; inseparable mixture
of two diastereoisomers). 30: Oil. 1H NMR (CDCl3, 300 MHz):
1-[2-(4-Methoxybenzocyclobuten-1-yl)-2-(methoxycarbonyl)-1-oxo-
ethyl]-1-methyl-2,5-divinylcyclopentane (8ad): 1H NMR (CDCl3,
300 MHz): δ ϭ 6.85 (1/2AB, J ϭ 8.1 Hz, 1 H), 6.69 (1/2AB, d, J ϭ
δ ϭ 6.30Ϫ5.1 (m, 2 H), 5.1Ϫ5.8 (m, 4 H), 4.2Ϫ3.9 (m, 2 H), 8.1, 1.7 Hz, 1 H), 6.61 (br. s, 1 H), 5.69Ϫ5.59 (m, 2 H), 4.96 (m, 4
3.7Ϫ3.5 (m, 3 H), 2.80Ϫ2.70 (m, 2 H), 1.8 (m, 2 H), 1.5 (m, 2 H), H), 4.03 (1/2AB, dd, J ϭ 10.6, 5.1, 1.9 Hz, 1 H), 3.89 (1/2AB, J ϭ
1.30Ϫ1.28 (m, 3 H), 0.89Ϫ0.86 (m, 3 H) ppm. MS: m/z (%, first/ 10.6 Hz, 1 H), 3.70 (s, 3 H), 3.67 (s, 3 H), 3.29 (1/2AB, d, J ϭ 14.4,
second eluted isomer) ϭ 178 (12/3, Mϩ Ϫ C3H6O2), 163 (34/27),
135 (78/36), 124 (31/47), 119 (21/9), 109 (90/100), 107 (61/47), 91
(67/48), 79 (97/66), 43 (100).
5.1 Hz, 1 H), 3.12 (br. q, J ϭ 7.9 Hz, 1 H), 2.85 (br. q, J ϭ 7.9 Hz,
1 H), 2.60 (1/2AB, J ϭ 14.4 Hz, 1 H), 1.88 (m, 2 H), 1.59 (m, 2
H), 0.99 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 207.2 (s),
Eur. J. Org. Chem. 2004, 2679Ϫ2691
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2687

N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
168.6 (s), 160.2 (s), 143.5 (s), 137.3 (d), 137.0 (d), 123.6 (d), 116.6 (؎)-(8β,9β,14α)-3-Methoxy-17β-vinylestra-1,3,5(10)-trien-12-one
(t), 116.0 (t), 113.6 (d), 108.6 (d), 62.0 (s), 59.0 (q), 55.2 (q), 53.2 (9ad): Obtained by heating 8ad at 215 °C (40% yield); white crys-
(d), 52.0 (d), 51.2 (d), 41.9 (d), 35.6 (t), 28.3 (t), 27.0 (t), 10.8 (q) tals, m.p. 163 °C (acetonitrile). H NMR (CDCl3, 300 MHz): δ ϭ
1
ppm.
7.20 (d, J ϭ 8.7 Hz, 1 H), 6.70 (dd, J ϭ 8.7, 2.4 Hz, 1 H), 6.60 (br.
d, J ϭ 2.4 Hz, 1 H), 6.00 (ddd, J ϭ 18.2, 9.7, 5.9 Hz, 1 H), 5.04
(m, 2 H), 3.74 (s, 3 H), 3.42 (br. q, J ϭ 5.7 Hz, 1 H), 2.88 (1/2AB,
d, J ϭ 15.2, 6.1 Hz, 1 H), 2.78 (1/2AB, d, J ϭ 15.2, 5.4 Hz, 1 H),
2.67 (m, 2 H), 2.55 (m, 1 H), 2.34 (sext. J ϭ 5.5 Hz, 1 H),
1.94Ϫ1.40 (m, 7 H), 1.00 (s, 3 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ 214.2 (s), 157.7 (s), 139.1 (d), 138.7 (s), 129.3 (s),
128.5 (d), 115.1 (t), 113.8 (d), 112.1 (d), 55.3 (s), 55.26 (q), 48.7 (d),
46.6 (d), 42.3 (t), 39.1 (d), 34.1 (d), 27.1 (t), 25.6 (t), 24.7 (t), 24.1
(t), 13.1 (q) ppm. MS: m/z (%) ϭ 310 (100) [Mϩ], 292 (15), 267
(15), 199 (31), 160 (21), 115 (13), 91 (18).
1-[2-(5-Methoxybenzocyclobuten-1-yl)-2-(methoxycarbonyl)-1-oxo-
ethyl]-1-methyl-2,5-divinylcyclopentane (8bc): 1H NMR (CDCl3,
300 MHz): δ ϭ 7.02 (1/2AB, J ϭ 7.7 Hz, 1 H), 6.86 (br. s, 1 H),
6.85 (1/2AB, J ϭ 7.7 Hz, 1 H,), 5.69Ϫ5.58 (m, 2 H), 5.05Ϫ4.74 (m,
4 H), 3.76 (s, 3 H), 3.68 (s, 3 H), 3.51 (1/2AB, d, J ϭ 13.6, 4.7 Hz,
1 H), 3.23 (br. d, J ϭ 13.6 Hz, 1 H), 2.95 (m, 2 H), 1.86 (m, 2 H),
1.62 (m, 2 H), 0.76 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
173.8 (s), 166.0 (s), 159.5 (s), 146.2 (s), 137.7 (d), 134.0 (s), 124.2
(d), 117.0 (d), 116.8 (d), 115.7 (t, 2C), 109.1 (d), 79.7 (d), 55.6 (q),
55.2 (s), 51.1 (d), 50.2 (d), 39.6 (t), 27.0 (t), 26.7 (t), 12.7 (q) ppm.
(؎)-(8β,9α,14α)-3-Methoxy-17β-vinylestra-1,3,5(10)-trien-12-one
(11ad): Obtained by heating 8ad at 215 °C (40% yield); white crys-
tals, m.p. 146 °C (acetonitrile). H NMR (CDCl3, 300 MHz): δ ϭ
1-[2-(4-Methoxybenzocyclobuten-1-yl)-2-(methoxycarbonyl)-1-oxo-
ethyl]-1-methyl-2,5-divinylcyclopentane (8bd): 1H NMR (CDCl3,
300 MHz): δ ϭ 7.14 (d, J ϭ 8.3 Hz, 1 H), 6.74 (d, J ϭ 8.3 Hz, 1
H), 6.69 (br. s, 1 H), 5.87Ϫ5.57 (m, 2 H), 5.26Ϫ4.71 (m, 4 H), 3.75
(s, 3 H), 3.67 (s, 3 H), 3.55 (1/2AB, d, J ϭ 14.6, 4.1 Hz, 1 H), 3.28
(1/2AB, J ϭ 14.6 Hz, 1 H), 2.95 (m, 2 H), 1.85 (m, 2 H), 1.60 (m,
2 H), 0.74 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 206.7
(s), 169.2 (s), 160.2 (s), 143.8 (s), 139.3 (s), 138.6 (d), 124.0 (d),
115.6 (t), 115.5 (t), 113.6 (d), 113.5 (d), 108.5 (d), 61.6 (s), 56.7 (q),
55.3 (q), 52.1 (d), 51.9 (d), 48.4 (d), 41.5 (d), 35.4 (t), 30.8 (t), 28.4
(t), 19.1 (q) ppm.
1
7.02 (d, J ϭ 8.5 Hz, 1 H), 6.70 (br. d, J ϭ 8.5 Hz, 1 H), 6.65 (br.
s, 1 H), 5.98 (ddd, J ϭ 17.4, 10.6, 5.8 Hz, 1 H), 5.14 (d, J ϭ 17.4
Hz, 1 H), 5.11 (m, 1 H), 3.76 (s, 3 H), 2.90 (m, 3 H), 2.68 (1/2AB,
J ϭ 12.9 Hz, 1 H), 2.61 (1/2AB, J ϭ 12.9 Hz, 1 H), 2.00Ϫ1.40 (m,
8 H), 0.93 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 213.7
(s), 158.0 (s), 139.0 (d), 137.8 (s), 131.2 (s), 126.0 (d), 115.3 (t),
114.1 (d), 111.7 (d), 56.8 (s), 55.3 (q), 54.8 (d), 46.4 (d), 45.5 (d),
42.8 (t), 38.3 (d), 29.8 (t), 27.3 (t), 24.9 (t), 23.6 (t), 13.1 (q) ppm.
MS: m/z (%) ϭ 310 (100) [Mϩ], 292 (62), 277 (64), 238 (12), 199
(11), 159 (31), 115 (16), 91 (31).
General Procedure for the Thermolysis of 8: A solution of 8 in anhy-
drous 1,2,4-trichlorobenzene (10 mL/mmol) was heated at 200 °C
or 215 °C for 6 h (the progress of the reaction was followed by TLC
analysis). The solvent was evaporated under reduced pressure and
the residue was subjected to flash chromatography (petroleum
ether/Et2O, 98:2 to 95:5) to give the corresponding steroid.
(؎)-(8β,9α,14α)-3-Methoxy-11α-methoxycarbonyl-17β-vinylestra-
1,3,5(10)-trien-12-one (10ad): Obtained by heating 8ad at 200 °C
(40% yield); white crystals, m.p. 196 °C (acetonitrile). 1H NMR
(CDCl3, 300 MHz): δ ϭ 6.80 (d, J ϭ 8.3 Hz, 1 H), 6.67 (br. s, 1
H), 6.65 (dd, J ϭ 8.3, 2.6 Hz, 1 H), 5.89 (ddd, J ϭ 17.3, 10.4, 6.3
Hz, 1 H), 5.1 (d, J ϭ 17.3 Hz, 1 H), 5.06 (d, J ϭ 10.4 Hz, 1 H),
3.90 (d, J ϭ 11.9 Hz, 1 H), 3.82 (s, 3 H), 3.74 (s, 3 H), 3.20 (br. d,
J ϭ 11.9, 9.8 Hz, 1 H), 2.88 (m, 3 H), 2.00Ϫ1.40 (m, 8 H), 0.93 (s,
3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 209.0 (s), 172.0 (s),
158.1 (s), 138.5 (s), 138.2 (d), 131.6 (s), 124.4 (d), 115.8 (t), 114.4
(d), 111.1 (d), 57.8 (d), 56.4 (s), 55.2 (q), 53.8 (d), 52.5 (q), 47.2 (d),
46.7 (d), 37.4 (d), 28.4 (t), 27.1 (t), 25.0 (t), 25.0 (t), 24.0 (t), 12.4
(؎)-(8β,9β,14α)-2-Methoxy-17β-vinylestra-1,3,5(10)-trien-12-one
(9ac): Obtained by heating 8ac at 215 °C (40% yield); white crystals,
1
m.p. 109 °C (acetonitrile). H NMR (CDCl3, 300 MHz): δ ϭ 6.97
(d, J ϭ 8.1 Hz, 1 H), 6.82 (br. s, 1 H), 6.66 (br. d, J ϭ 8.1 Hz, 1
H), 6.02 (ddd, J ϭ 18.1, 9.80, 5.9 Hz, 1 H), 5.04 (m, 2 H), 3.76 (s,
3 H), 3.45 (br. q, J ϭ 5.9 Hz, 1 H), 2.89 (1/2AB, d, J ϭ 15.4,
6.1 Hz, 1 H), 2.79 (1/2AB, d, J ϭ 15.4, 5.9 Hz, 1 H), 2.62 (m, 3
H), 2.33 (br. sext, J ϭ 5.6 Hz, 1 H), 1.93Ϫ1.60 (m, 6 H), 1.45 (m,
1 H), 1.01 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 214.1
(s), 158.1 (s), 139.0 (d), 138.4 (s), 129.6 (d), 129.5 (s), 115.1 (t),
112.8 (d), 112.0 (d), 55.3 (q), 55.2 (s), 48.9 (d), 46.6 (d), 42.4 (t),
39.5 (d), 33.9 (d), 26.1 (t), 25.9 (t), 24.8 (t), 24.1 (t), 13.1 (q) ppm.
MS: m/z (%) ϭ 310 (100) [Mϩ], 292 (29), 267 (18), 159 (21).
C21H26O2 (310.43): calcd. C 81.25, H 8.44; found C 81.32, H 8.34.
(q) ppm. MS: m/z (%) ϭ 368 (1) [Mϩ], 310 (26), 309 (100, Mϩ
Ϫ
CO2Me), 292 (23), 266 (18), 159 (38), 91 (30).
(؎)-(8α,9β,14β)-2-Methoxy-17β-vinylestra-1,3,5(10)-trien-12-one
(12bc): Obtained by heating 8bc at 215 °C (27% yield); oil. 1H
NMR (CDCl3, 300 MHz): δ ϭ 6.98 (d, J ϭ 8.3 Hz, 1 H), 6.68 (dd,
J ϭ 8.3, 2.5 Hz, 1 H), 6.62 (d, J ϭ 2.5 Hz, 1 H), 5.71 (ddd, J ϭ
17.6, 9.6, 8.1 Hz, 1 H), 5.01 (m, 2 H), 3.75 (s, 3 H), 3.35 (m, 1 H),
3.03 (dt, J ϭ 8.1, 7.0 Hz, 1 H), 2.74 (m, 2 H), 2.66 (m, 2 H), 2.04
(m, 1 H), 1.99Ϫ1.82 (m, 2 H), 1.82 (m, 1 H), 1.58 (m, 1 H), 1.25
(m, 1 H), 0.98 (s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
215.0 (s), 157.8 (s), 140.2 (s), 138.3 (d), 130.1 (d), 128.0 (s), 115.6
(t), 112.8 (d), 112.7 (d), 56.2 (s), 55.3 (q), 52.5 (d), 50.0 (d), 42.6
(t), 38.2 (d), 37.4 (d), 30.3 (t), 29.0 (t), 27.9 (t), 26.0 (t), 21.1 (q)
ppm. MS: m/z (%) ϭ 310 (100) [Mϩ], 292 (23), 266 (18), 159 (38),
91 (30). C21H26O2 (310.43): calcd. C 81.25, H 8.44; found C 81.48,
H 8.39.
(؎)-(8β,9α,14α)-2-Methoxy-11α-methoxycarbonyl-17β-vinylestra-
1,3,5(10)-trien-12-one (10ac): Obtained by heating 8ac at 215 °C
(40% yield); white crystals, m.p. 168Ϫ169 °C (acetonitrile). 1H
NMR (CDCl3, 300 MHz): δ ϭ 7.03 (d, J ϭ 8.3 Hz, 1 H), 6.70 (dd,
J ϭ 8.3, 2.2 Hz, 1 H), 6.49 (br. d, J ϭ 2.2 Hz, 1 H), 5.89 (ddd, J ϭ
17.3, 10.6, 6.2 Hz, 1 H), 5.12 (dt, J ϭ 17.3, 1.0 Hz, 1 H), 5.07 (d,
J ϭ 10.6 Hz, 1 H), 3.94 (d, J ϭ 11.7 Hz, 1 H), 3.84 (s, 3 H), 3.72
(s, 3 H), 3.25 (t, J ϭ 10.9 Hz, 1 H), 2.85 (m, 3 H), 1.97 (m, 1 H),
1.89 (m, 1 H), 1.85 (m, 1 H), 1.76 (m, 1 H), 1.64 (m, 1 H), 1.58
(m, 1 H), 1.45 (m, 2 H), 0.94 (s, 3 H) ppm. 13C NMR (CDCl3,
(؊)-(8α,9α,14β)-2-Methoxy-11-methoxycarbonyl-17β-vinylestra-
75 MHz): δ ϭ 209.0 (s), 172.0 (s), 157.9 (s), 140.6 (s), 138.2 (d), 1,3,5(10),11-tetraen-12-ol (14bc): Obtained by heating 8bc at 215
129.6 (d), 129.1 (s), 115.9 (t), 111.8 (d), 109.7 (d), 57.6 (d), 56.4 (s),
55.2 (q), 54.0 (d), 52.6 (q), 47.8 (d), 46.8 (d), 37.1 (d), 27.3 (t), 27.2
°C (63% yield); white crystals, m.p. 112 °C (acetonitrile). [α]2D5
ϭ
1
Ϫ21.9 (CHCl3, 1.0). H NMR (CDCl3, 300 MHz): δ ϭ 12.91 (s, 1
(t), 25.1 (t), 24.1 (t), 12.5 (q) ppm. MS: m/z (%) ϭ 368 (16) [Mϩ], H), 6.99 (d, J ϭ 8.2 Hz, 1 H), 6.66 (dd, J ϭ 8.2, 2.2 Hz, 1 H), 6.48
310 (21), 309 (100, Mϩ Ϫ CO2Me), 200 (17), 109 (12).
(br. s, 1 H), 6.19 (ddd, J ϭ 17.1, 10.6, 6.6 Hz, 1 H), 5.04 (m, 1 H),
2688
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 2679Ϫ2691

Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
FULL PAPER
5.01 (d, J ϭ 17.1 Hz, 1 H), 3.75 (s, 3 H), 3.72 (s, 3 H), 2.68 (m, 3
H), 2.07 (sext., J ϭ 6.8 Hz, 1 H), 1.91 (m, 3 H), 1.72 (m, 1 H), 1.65
(%) ϭ 368 (3) [Mϩ], 311 (24), 310 (100, Mϩ Ϫ CO2CH2), 292 (25),
267 (29), 187 (30), 160 (75), 115 (21), 91 (34). C23H28O4 (368.47):
(m, 1 H), 1.55 (m, 2 H), 1.43 (m, 1 H), 0.86 (s, 3 H) ppm. 13C calcd. C 74.97, H 7.66; found C 74.82, H 7.54.
NMR (CDCl3, 75 MHz): δ ϭ 181.0 (s), 173.8 (s), 157.9 (s), 141.4
(8α,9β,14β)-3-Methoxy-11α-methoxycarbonyl-17β-vinylestra-
(s), 139.6 (d), 129.7 (s), 128.3 (d), 114.5 (t), 113.5 (d), 110.3 (d),
98.3 (s), 55.3 (q), 51.7 (q), 50.5 (d), 48.9 (s), 47.7 (d), 37.8 (d), 37.2
(d), 28.6 (t), 27.5 (t), 26.2 (t), 25.5 (t), 21.8 (q) ppm. MS: m/z (%) ϭ
310 (100, Mϩ Ϫ CO2Me), 292 (22), 267 (21), 159 (34), 109 (29).
1,3,5(10)-trien-12-one (13bd): Obtained by heating 8bd at 200 °C
(25% yield); oil. 1H NMR (CDCl3, 300 MHz): δ ϭ 6.81 (d, J ϭ
8.5 Hz, 1 H), 6.65 (m, 2 H), 5.90 (ddd, J ϭ 17.4, 10.5, 6.2 Hz, 1
H), 5.11 (d, J ϭ 17.4 Hz, 1 H), 5.01 (d, J ϭ 10.5 Hz, 1 H), 3.90
(d, J ϭ 11.9 Hz, 1 H), 3.83 (s, 3 H), 3.74 (s, 3 H), 3.20 (t, J ϭ 10.8
Hz, 1 H), 2.95Ϫ2.75 (m, 3 H), 2.25Ϫ1.35 (m, 8 H), 0.93 (s, 3 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 209.1 (s), 172.1 (s), 158.2
(s), 138.6 (s), 138.2 (d), 131.7 (s), 124.5 (d), 115.9 (t), 114.4 (d),
111.1 (d), 57.9 (d), 56.5 (s), 55.3 (d), 53.9 (d), 52.6 (d), 47.2 (d),
46.8 (d), 37.5 (d), 28.5 (t), 27.1 (t), 25.1 (t), 24.0 (t), 12.5 (q) ppm.
MS: m/z (%) ϭ 310 (24), 309 (100, Mϩ Ϫ CO2Me), 109 (10).
C23H28O4 (368.47): calcd. C 74.97, H 7.66; found C 75.02, H 7.64.
(؎)-(8α,9β,14β)-3-Methoxy-17β-vinylestra-1,3,5(10)-trien-12-one
(12bd): Obtained by heating 8bd at 215 °C (25% yield); oil. 1H
NMR (CDCl3, 300 MHz): δ ϭ 7.01 (d, J ϭ 8.5 Hz, 1 H), 6.68 (dd,
J ϭ 8.5, 2.6 Hz, 1 H), 6.61 (d, J ϭ 2.6 Hz, 1 H), 5.70 (ddd, J ϭ
15.9, 11.5, 7.9 Hz, 1 H), 5.01 (br. d, J ϭ 11.5 Hz, 1 H), 4.98 (br.
d, J ϭ 15.9 Hz, 1 H), 3.75 (s, 3 H), 3.34 (m, 1 H), 3.03 (dt, J ϭ
7.9, 7.7 Hz, 1 H), 2.80 (m, 2 H), 2.74 (m, 1 H), 2.66 (1/2AB, d, J ϭ
15.9, 6.4 Hz, 1 H), 2.10Ϫ1.80 (m, 6 H), 1.65Ϫ1.55 (m, 2 H), 0.95
(s, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ 215.0 (s), 157.9
(s), 138.3 (d), 137.3 (s), 131.2 (s), 129.0 (d), 115.6 (t), 113.9 (d),
112.1 (d), 56.3 (s), 55.2 (q), 52.3 (d), 50.0 (d), 42.7 (t), 37.6 (d), 37.5
(d), 30.1 (t), 28.9 (t), 28.8 (t), 25.7 (t), 20.8 (q) ppm. MS: m/z (%) ϭ
310 (100) [Mϩ], 292 (20), 277 (25), 187 (22), 174 (39), 160 (74), 115
(21), 91 (27).
Wacker-Type Oxidation of 14bc: Water (1.5 mL) and HClO4 (70%;
0.3 mL) were added successively to a solution of Pd(OAc)2
(22.4 mg, 0.1 mmol, 0.1 equiv.) and benzoquinone (97 mg,
0.9 mmol, 0.9 equiv.), in acetonitrile (10 mL). The mixture was
stirred for 1 h at room temp. under argon. A solution of 14bc
(368 mg, 1 mmol) in acetonitrile (2 mL) was then added and the
mixture was stirred at room temp. for 5 h [(the progress of the reac-
tion was followed by TLC analysis (petroleum ether/Et2O, 50:50)].
The mixture was poured into diethyl ether and washed with 30%
aqueous NaOH. The aqueous layer was extracted with diethyl
ether. The combined organic layers were dried over MgSO4, fil-
tered, and concentrated under reduced pressure. The crude product
was purified by flash chromatography (petroleum ether/Et2O, 95:5)
to give 31 (211 mg, 55%).
(؊)-(8α,9α,14β)-3-Methoxy-11-methoxycarbonyl-17β-vinylestra-
1,3,5(10),11-tetraen-12-ol (14bd): Obtained by heating 8bd at 215
°C (55% yield); white crystals, m.p. 111 °C (hexane/ethanol, 95:5).
[α]2D5 ϭ Ϫ62.1 (CHCl3, 1.3). 1H NMR (CDCl3, 300 MHz): δ ϭ
12.87 (s, 1 H), 6.79 (d, J ϭ 8.1 Hz, 1 H), 6.64 (d, J ϭ 8.1 Hz, 1
H), 6.62 (br. s, 1 H), 6.18 (ddd, J ϭ 16.9, 11.0, 6.5 Hz, 1 H), 5.02
(m, 1 H), 4.99 (d, J ϭ 16.9 Hz, 1 H), 3.74 (br. s, 6 H), 3.72 (m, 1
H), 2.72 (m, 3 H), 2.06 (sext., J ϭ 6.9 Hz, 1 H), 1.9 (m, 3 H), 1.75
(m, 1 H), 1.69Ϫ1.58 (m, 4 H), 1.41 (m, 1 H), 0.82 (s, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 180.8 (s), 174.0 (s), 157.6 (s),
(؉)-(8α,9α,14β)-17β-Acetyl-2-methoxy-11-(methoxycarbonyl)estra-
139.7 (d), 138.4 (s), 132.1 (s), 128.1 (d), 114.5 (t), 113.0 (d), 111.3 1,3,5(10),11-tetraen-12-ol (31): Oil. [α]2D5 ϭ ϩ4.7 (CHCl3, 1.1). H
1
(d), 98.9 (s), 55.2 (q), 51.7 (q), 50.5 (d), 48.9 (d), 47.2 (d), 37.6 (d),
37.0 (d), 28.6 (t), 27.6 (t), 26.5 (t), 25.9 (t), 22.0 (q) ppm. MS: m/z
NMR (CDCl3, 300 MHz): δ ϭ 12.91 (s, 1 H), 6.98 (br. d, J ϭ
8.1 Hz, 1 H), 6.64 (br. d, 1 Hd, J ϭ 8.1, 2.7 Hz), 6.45 (br. d, J ϭ
Table 2. Crystal data and structure refinement for 27b, 10ac, 9ad, 11ad, and 14bc
27b
10ac
9ad
11ad
14bc
Empirical formula
Formula mass
Crystal color
C12H20O2
196.29
colorless
0.3 ϫ 0.2 ϫ 0.1
monoclinic
P21/c
12.6130 (7)
12.2233 (5)
7.5992 (3)
99.860 (2)
1154.3(1)
4
C23H28O4
368.47
colorless
0.5 ϫ 0.5 ϫ 0.5
monoclinic
P21/c
12.0682(7)
17.0040 (5)
9.6948 (5)
96.795 (4)
1975.5(2)
4
C21H26O2
310.43
colorless
0.3 ϫ 0.15 ϫ 0.05 0.4 ϫ 0.3 ϫ 0.3
orthorhombic
P212121
7.8381 (3)
12.4579 (8)
17.1470 (10)
C21H26O2
310.43
colorless
C23H28O4
368.47
colorless
0.4 ϫ 0.4 ϫ 0.3
monoclinic
P21/c
10.9790 (3)
9.8450 (4)
18.2470 (7)
90.274 (2)
1972.3(1)
4
Crystal size/mm3
Crystal system
Space group
orthorhombic
P212121
7.9300 (4)
12.536 (1)
17.203 (1)
˚
a (A)
˚
b (A)
˚
c (A)
β (°)
V [A3]
1674.3(2)
4
1.23
0.8
1856
208
1710.2(2)
4
1.205
0.78
1915
208
Z
Dc/g·cmϪ3
1.13
0.7
2245
1.24
0.9
3757
244
1.24
0.84
3909
244
µ(Mo-Kα)/cmϪ1
Number of unique data
Number of parameters refined 127
Number of refl. in refinement
R
wR
1630
2620
1611
1900
3728
0.049 [F2 Ͼ 4.5σF2] 0.051 [F2 Ͼ 3σF2] 0.05 [F2 Ͼ 3σF2]
0.084 [F2 Ͼ 3σF2] 0.053 [F2 Ͼ 3σF2]
0.061[a]
0.066[a]
0.048[a]
0.24[b]
0.149[c]
Goodness of fit
Residual Fourier/e A
1.561
Ϫ0.21; 0.21
1.387
Ϫ0.19; 0.21
1.373
Ϫ0.21; 0.21
1.17
Ϫ0.254; 0.23
1.15
Ϫ0.335; 0.302
Ϫ3
˚
[a]
2
2
[b]
2
2
2
2
[c]
2
w ϭ 1/[σ2(Fo ) ϩ (0.03Fo ].
w ϭ 1/[σ2(Fo ) ϩ (0.094P)2 ϩ 2.8716P] where P ϭ (Fo ϩ 2Fc )/3. w ϭ 1/[σ2(Fo ) ϩ (0.08684P)2 ϩ
2
0.5489P] where P ϭ (Fo ϩ2Fc )/3.
Eur. J. Org. Chem. 2004, 2679Ϫ2691
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2689

N. Mariet, H. Pellissier, M. Ibrahim-Ouali, M. Santelli
FULL PAPER
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2.7 Hz, 1 H), 3.80 (s, 3 H), 3.80 (m, 1 H), 3.75 (s, 3 H), 3.09 (dd,
J ϭ 8.9, 7.5 Hz, 1 H), 2.71 (t, J ϭ 6.9 Hz, 2 H), 2.28 (s, 3 H), 2.09
(m, 1 H), 2.02Ϫ1.82 (m, 6 H), 1.58 (m, 1 H), 0.93 (s, 3 H) ppm.
13C NMR (CDCl3, 75 MHz): δ ϭ 210.9 (s), 179.0 (s), 173.7 (s),
158.0 (s), 140.9 (s), 129.5 (s), 128.4 (d), 113.5 (d), 110.5 (d), 98.8
(s), 56.7 (q), 55.3 (q), 51.9 (d), 51.2 (s), 48.4 (d), 37.7 (d), 36.7 (d),
32.8 (q), 28.0 (t), 27.6 (t), 26.1 (t), 25.4 (t), 22.8 (q) ppm. C23H28O5
(384.47): calcd. C 71.85, H 7.34; found C 71.80, H 7.44.
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H. W. M. Priepke, S. L. Warriner, Synlett 1996, 793Ϫ795.
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Trans. 1 1999, 1631Ϫ1634.
D. Haag, H.-D. Sharf, J. Org.
X-ray Crystallography: CCDC-225808 [for (Ϯ)-27b], -225809 (for
10ac), -225810 (for 9ad), -225811 (for 11ad), and -225812 (for 14bc)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: (in-
ternat.) ϩ44-1223-336-033; or E-mail: deposit@ccdc.cam.ac.uk].
A summary of the crystal data, data collection, and refinements is
given in Table 2.
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N. M. is grateful to the ‘‘Region Provence-Alpes-Cote dЈAzur’’ and
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ray crystallographic data and Prof. C. Roussel and Dr. N. Van-
thuyne for the measurements of the enantiomeric excesses. We are
indebted to Dr. B. Vacher (Pierre Fabre Medicaments, Castres,
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2690
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 2679Ϫ2691

Application to the Enantioselective Synthesis of 12-Oxo-estrane Derivatives
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Received January 22, 2004
Eur. J. Org. Chem. 2004, 2679Ϫ2691
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2691