Lactone kinetic resolution by acylation - Application to the enantioselective synthesis of estrane derivatives

Article abstract of DOI:10.1002/ejoc.200500380

The acylation of an excess of racemic spirolactone 1 (6,9-divinyl-1- oxaspiro[4.4]nonan-2-one) enolate by protected methyl (S)-lactate or (-)-bornyl carbonate occurs with a kinetic resolution. The resulting lactones were alkylated with 1-iodobenzocyclobut

Full text of DOI:10.1002/ejoc.200500380

FULL PAPER
Lactone Kinetic Resolution by Acylation – Application to the Enantioselective
Synthesis of Estrane Derivatives
Serge Wilmouth,[a,c] Anne-Catherine Durand,[a] Sarah Goretta,[a] Christophe Ravel,[a]
Delphine Moraleda,[a] Michel Giorgi,[b] Hélène Pellissier,[a] and Maurice Santelli*[a]
Keywords: Steroids / Acylation / Kinetic resolution / Asymmetric synthesis / Chiral pool
The acylation of an excess of racemic spirolactone 1 (6,9-divi-
nyl-1-oxaspiro[4.4]nonan-2-one) enolate by protected methyl
(S)-lactate or (–)-bornyl carbonate occurs with a kinetic reso-
lution. The resulting lactones were alkylated with 1-iodoben-
zocyclobutenes to afford compounds that serve as precursors
to nonracemic steroids such as 11α-alkyloxycarbonyl-
11β,13β-(γ-carbolactone)-17β-vinylgonatri-1,3,5(10)-enes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
In the course of a program directed towards the develop-
ment of new steroids that might exhibit improved thera-
peutic action over existing drugs[1] we have reported a
convergent
steroid
synthesis[2]
based
on
the
A+DǞADǞABCD approach, involving the use of intra-
molecular cycloaddition of o-xylylenes developed indepen-
dently by Oppolzer[3] and by Kametani[4] for generation of
the BC ring system.
Our strategy was based on the use of spirolactone 1, aris-
ing in 78% yield from the addition of 1,8-bis(trimethylsilyl)-
octa-2,6-diene (Bistro) to succinic anhydride. Indeed, com-
pound 1 is an easily available and a very cheap reagent.[1i]
With the aim of expanding the scope of this strategy[1i] to
the synthesis of optically active steroids, we investigated the
possibility of preparing enantiomerically enriched spirolac-
tones by kinetic resolution. In recent years this methodol-
ogy has proved to be one of the most efficient methods for
asymmetric synthesis.[5] Kinetic resolution could indeed be
observed in the course of acylation of racemic spirolactone
1 enolate, thus providing an efficient route to various op-
tically active steroids (Scheme 1).
Scheme 1.
Results and Discussions
In a first investigation, the protected methyl (–)-(S)-lac-
tate derivative 3 was chosen as acylating agent. The tert-
butyldimethylsilyl (TBDMS) group was found to be the
largest protecting group possible to introduce.[6] When one
equivalent of protected methyl lactate 3 was added at
–78 °C to a THF solution of three equivalents of racemic
lactone 1 enolate, a 4:1 mixture of two products, (R,R)-4
and (S,S)-4, was obtained in 73% yield, along with reco-
vered spirolactone 1 in ca. 26% enantiomeric excess. Vari-
ous conditions – such as the use of pentane as solvent, a
lower reaction temperature (–100 °C), the addition of
MgBr2 and the use of HMPA or TMEDA as co-solvent –
were tested in order to improve the reaction, but without
success. Unfortunately, separation of the diastereomers
(R,R)-4 and (S,S)-4 was impossible because of the existence
of a tautomeric equilibrium in each case (Scheme 2).
[a] Laboratoire de Synthèse Organique, UMR 6180 CNRS: “Chir-
otechnologies: Catalyse et Biocatalyse”,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
Fax: +33-4-91983865
E-mail: m.santelli@univ.u-3mrs.fr
[b] Laboratoire de Cristallochimie, Université Paul Cézanne (Aix-
Marseille III), Faculté de St-Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
[c] Present address: Organon S.A.; Centre de Développement
Préclinique,
20–22 rue Henri Goudier, BP 140, 63203 Riom Cedex, France
4806
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500380
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Lactone Kinetic Resolution by Acylation
FULL PAPER
The assignment of the configuration of 7 was made in
accordance with the ORTEP diagram (Figure 1). As dem-
onstrated in previous works,[7] the stereoselectivity of the
alkylation was such that the attack took place at the face
of the enolate bearing the vinyl group anti to the lactone
ring-oxygen linkage [Si face of the enolate of (R,R)-4].[8]
The unexpected formation of 7 could be explained by the
sequence summarised in Scheme 4. Addition of a hydroxide
anion to the ketone function in compound 6 could give the
corresponding hydrate anion, which could then add to the
silicon atom of the protected group. Opening of the thus
formed cyclic siliconate anion would result in the formation
of both an alkoxide anion and a monoprotected ketone hy-
drate.[9] The latter hydrate could eliminate silanolate anion
to regenerate the ketone function, whereas alkoxide anion
could undergo acylation with the lactone, leaving a new alk-
oxide anion, which could finally add to the ketone to afford
product 7.[10]
Scheme 2.
The next step of the strategy involved the alkylation of a
stabilised enolate of 4 [in the form of a diastereomeric mix-
ture of unseparated (R,R)-4 and (S,S)-4] with racemic iodo-
benzocyclobutene 5b in the presence of cesium carbonate
and potassium iodide according to Claisen’s procedure. Af-
ter chromatography on silica gel, the major polar product
7 was isolated in 57% yield along with the expected steroid
precursor 6 in 33% yield. Unfortunately, this latter com-
pound was contaminated with other diastereomers and
could not be purified. In contrast, product 7 was obtained
in such high purity that it was possible to isolate crystals
suitable for X-ray analysis (Scheme 3).
Scheme 3.
Scheme 4.
Figure 1. ORTEP diagram of compound 7.[11]
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M. Santelli et al.
FULL PAPER
The fact that one diastereomer was obtained in more
Claisen condensation of the protected methyl (S)-lactate
than 50% yield was due to iodide-induced racemization of with the racemic mixture of spirolactone 1 enolate could
the more slowly reacting enantiomer (S)-5b to produce the occur through eight transition states, as summarised below:
more rapidly reacting enantiomer (R)-5b in a dynamic kin- Si-face or Re-face of methyl (S)-lactate with the Re-face of
etic resolution [the racemization of the enantiomer (S)-5b the (R,R)-1 enolate,
could be rapid enough with respect to the alkylation reac- Si-face or Re-face of methyl (S)-lactate with the Si-face of
tion].[12] In recent years, dynamic kinetic resolution has the (R,R)-1 enolate,
been noted as one of the most efficient methods for asym- Si-face or Re-face of methyl (S)-lactate with the Re-face of
metric synthesis.[13]
the (S,S)-1 enolate, or
Si-face or Re-face of methyl (S)-lactate with the Si-face of
the (S,S)-1 enolate.
The results clearly show that the reaction occurs mainly
on the enolate of the enantiomer (R,R)-1. If we assume that
the acylation is the result of an attack on the Re face of the
enantiomer (R,R)-1 enolate as the alkylation reaction,[7] we
can conclude that the kinetic approach involves the Si face
of the lactate according to a Felkin–Anh-type approach,[14]
Scheme 5.
Scheme 6.
Scheme 7.
4808
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Lactone Kinetic Resolution by Acylation
FULL PAPER
anti to the silyloxy group. Scheme 5 represents the struc- which provokes a strong interaction between the two methyl
tures of the four transition states A–D according to the groups of the lactate moiety.
Zimmerman–Traxler aldol reaction model.[15,16] In the pro-
As the protection of methyl lactate was too labile under
cess, the (R,R)-1 enolate is relatively free to react through the reaction conditions allowing the preparation of steroid
the Re-face as depicted in transition state A. In contrast, in precursor 6, it was decided, in a second investigation, to use
the case of attack on the Si-face, a strong interaction be- optically active carbonates possessing a C2-axis of sym-
tween the vinyl group and the methyl group of the lactate metry – such as carbonates 8 [from (–)-menthol], 9 [from
moiety occurs (transition state B), whilst a similar interac- (–)-methyl lactate] and 10 [from (–)-borneol] (Scheme 6) –
tion occurs in the transition state involving the (S,S)-1 enol- as acylating agents.
ate (transition state C). Moreover, the transition states B
Interestingly, we found that diastereomeric mixtures of
and D also involve attack on the Re-face of the lactate, the two expected lactones 11 were obtained in up to 80%
Figure 2. ORTEP diagram of steroid 13b.[11,18]
Figure 3. ORTEP diagram of steroid 14b.[11,18]
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M. Santelli et al.
FULL PAPER
yields and with diastereoselectivities ranging from 75:25 to
The lactone bridge of the main steroid 13b could be
80:20 when an excess of racemic spirolactone 1 enolate opened cleanly by methanolysis in a neutral medium to give
(3 equiv.) was acylated with carbonic acid dibornyl ester 10. the corresponding compound 16 (Scheme 8).
Unfortunately, the use either of menthyl carbonate 8 or of
methyl lactate carbonic ester 9 did not give better diastereo-
selectivities.
Conclusions
Since diastereomers (R,R)-11 and (S,S)-11 were insepa-
rable due to the presence of an enolisable centre, we decided
to alkylate 11 (as the crude mixture) with benzocyclobutene
iodides 5a and 5b, which yielded 12a and 12b, respectively.
These latter compounds were then thermolysed in trichloro-
benzene at reflux, providing a mixture of steroids 13–15. In
particular, thermolysis of 12a afforded a mixture of steroids
13a and 14a in 88% combined yield (13a:14a = 70:30). On
the other hand, cyclisation of 12b gave a mixture of 13b
and 14b in 80% combined yield (13b:14b = 80:20), along
with steroid 15b isolated in 12% yield (Scheme 7). After
extensive recrystallisation and chromatography, steroids 13b
and 14b were separated. The structures of 13b–15b were
confirmed by X-ray crystallographic analysis (Figure 2, Fig-
ure 3 and Figure 4). Steroids 13b and 15b arose from (R,R)-
11, whereas steroids 14b arose from (S,S)-11. Consequently,
the stereoselectivity of the acylation reaction providing 11
was 76:16 = 4.75, corresponding to a ΔG‡ = 0.78 kcalmol–1
(at –20 °C).
We have described an expeditious synthesis of the tricyclic
core of C-11 functionalised steroids in a few steps (four steps
for the preparation of iodobenzocyclobutene 5b, two steps
for the synthesis of 1, and three steps for the elaboration of
steroids) from very cheap reagents (Scheme 9). Moreover, use
of a chiral auxiliary such as (–)-borneol allowed nonracemic
products to be obtained with fair selectivity by kinetic resolu-
tion during the Claisen condensation step.
Scheme 9.
Experimental Section
General: All reactions were run under argon in oven-dried glass-
1
ware. TLC was performed on silica gel 60 F254. H and 13C NMR
spectra were recorded in CDCl3 solutions at 400 and 300, and 100
and 75 MHz respectively. Chemical shifts are reported in ppm rela-
tive to CDCl3 [signals for residual CHCl3 in the CDCl3: 7.24 for 1H
NMR and 77.16 (central) for 13C NMR]. Carbon–proton couplings
were determined by DEPT sequence experiments. THF was dis-
tilled before use from sodium-benzophenone. For the preparation
of spirolactone 1 and iodobenzocyclobutenes 5, see ref.[1i]
.
3-[2(S)-(tert-Butyldimethylsilyloxy)propanoyl]-6,9-divinyl-1-oxa-
spiro[4.4]nonan-2-one (4): Lactone 1 (25 g, 130 mmol) in THF
(20 mL) was added slowly at –90 °C to a solution of lithium hexa-
methyldisilazide (21.75 g, 130 mmol) in anhydrous THF (200 mL).
The solution was stirred for 1 hour, and a solution of protected
methyl lactate 3 (9.47 g, 43 mmol) in THF (20 mL) was then slowly
added. The solution was stirred for 6 h at –90 °C and the mixture
was then allowed to stand at –60 °C for 15 h. The reaction was
Figure 4. ORTEP diagram of steroid 15b.[19]
Steroids 13 or 14, each containing a trans B/C ring junc- quenched by the addition of a saturated aqueous NH4Cl solution
and the mixture was then extracted with diethyl ether. The organic
layer was dried (MgSO4) and the solvents were evaporated. The oil
was flash chromatographed on silica gel with elution with petro-
tion, are the results of a Diels–Alder reaction involving an
exo transition state, whereas steroid 15b, with a cis B/C ring
junction, arises from an endo transition state.[17]
1
leum ether/diethyl ether (PE/DE) (97:3) to give 4 (12 g, 73%). H
NMR (300 MHz, CDCl3): δ = 5.81–5.53 (m, 2 H), 5.22–5.07 (m, 4
H), 4.54 (q, J = 10.0 Hz, 1 H), 4.34 (d, J = 7.6 Hz, 1 H), 2.42 (m,
2 H), 2.25–1.46 (m, 6 H), 1.31 (d, J = 10.0 Hz, 3 H), 0.89 (s, 9 H),
0.06 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 205.9 (s), 171.7
(s), 137.3 (d), 135.4 (d), 118.6 (t), 117.2 (t), 95.6 (s), 72.9 (d), 52.9
(t), 52.2 (t), 47.4 (t), 47.4 (d), 29.6 (d), 28.1 (d), 25.5 (q) (3C), 20.9
(q), 17.6 (s), –5.4 (q, 2C) ppm. C21H34O4Si (378.6): C 66.62, H 9.05;
found C 66.69, H 9.09.
Scheme 8.
4810
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Lactone Kinetic Resolution by Acylation
FULL PAPER
(3S,6R,9R)-3-[2(S)-(tert-Butyldimethylsilyloxy)propanoyl]-3-[(1S)-
5-methoxybenzocyclobuten-1-yl]-6,9-divinyl-1-oxaspiro[4.4]nonan-2-
CDCl3): δ = 5.07 (q, J = 7.2 Hz, 1 H), 3.69 (s, 3 H), 1.49 (d, J =
7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.0 (s), 150.3
one (6) and Compound 7: A mixture of spirolactone 4 (11.7 g, (s), 75.1 (d), 52.7 (t), 16.6 (q) ppm. IR (CH Cl ): ν = 1792,
˜
2
2
31 mmol), 1-iodobenzocyclobutene 5b (9.88 g, 38 mmol), cesium
carbonate (dried by heating at 100 °C under vacuum; 15.35 g,
47 mmol) and potassium iodide (5 g, 30 mmol) in anhydrous ace-
tone (250 mL) was heated at reflux for 120 h. The mixture was
filtered through Celite®, the solid was washed with diethyl ether,
and the organic phase was concentrated under reduced pressure.
The crude product was flash chromatographed on silica gel with
elution with PE/DE [elution order: 6 (mixture) with PE/DE = 97:3
(4.1 g, 33%); 7, with PE/DE = 87:13; (6.7 g, 57%)].
Compound 6: Major isomer, 1H NMR (300 MHz, CDCl3): δ = 7.2–
6.88 (m, 2 H), 6.79 (d, J = 1.7 Hz, 1 H), 5.57–5.48 (m, 2 H), 5.36
(q, J = 6.5 Hz, 1 H), 5.18–4.98 (m, 4 H), 4.67 (d, J = 10.2 Hz, 1
H), 4.16–4.02 (m, 1 H), 3.73–3.68 (m, 1 H), 3.71 (s, 3 H), 2.96 (dd,
J = 14.4, 5.2 Hz, 1 H), 2.78–2.70 (m, 1 H), 2.68–2.53 (m, 1 H), 2.50
(½AB, J = 14.4 Hz,1 H), 2.40–2.20 (m, 2 H), 2.15–2.0 (m, 1 H),
1.93 (½AB, J = 14.4 Hz, 1 H), 1.90–1.55 (m, 2 H), 1.22 (d, J =
6.5 Hz, 3 H), 0.87 (s, 9 H), 0.09 (s, 6 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 203.8 (s), 175.6 (s), 160.0 (s), 143.3 (s), 137.2 (s), 135.1
(d), 134.9 (d), 124.4 (d), 119.6 (t), 117.5 (t), 116.5 (d), 107.9 (d),
94.8 (s), 68.7 (d), 63.3 (s), 55.8 (q), 53.2 (d), 53.1 (d), 52.7 (d), 46.5
(q), 31.7 (t), 29.5 (t), 27.6 (t), 27.2 (t), 25.9 (q) (3C), 21.7 (s), –4.4
(q, 2C) ppm.
1758 cm–1.
Bis[(1S)-bornyl] Carbonate (10):[22] This compound was synthesized
from (–)-borneol (46.2 g) to give 10 [42.6 g (85%)]. [α]2D0 = –27.8
1
(CH2Cl2, c = 0.01). H NMR (300 MHz, CDCl3): δ = 4.77 (ddd, J
= 9.9, 3.4, 1.9 Hz, 2 H), 2.32 (m, 2 H), 1.96 (m, 2 H), 1.80–1.70
(m, 2 H), 1.68–1.64 (m, 2 H), 1.33–1.21 (m, 4 H), 1.06 (dd, J =
13.8, 3.4 Hz, 2 H), 0.88 (s, 6 H), 0.86 (s, 6 H), 0.85 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 156.2 (s), 83.6 (d), 49.0 (s), 48.1
(s), 44.9 (d), 36.6 (t), 28.1 (t), 27.0 (t), 19.9 (q), 19.0 (q), 13.7
(q) ppm. IR (CH Cl ): ν = 1772, 1728, 1162 cm–1.
˜
2
2
3-[endo-(1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yloxycarbonyl]-
6,9-divinyl-1-oxaspiro[4,4]nonan-2-one (11): Lactone 1 (36.5 g,
190 mmol) in THF (150 mL) was slowly added at –20 °C to a solu-
tion of lithium hexamethyldisilazide (43 g, 257 mmol) in anhydrous
THF (400 mL). The solution was stirred for 1 hour, and a solution
of bornyl carbonate 10 (28.4 g, 85 mmol) in THF (250 mL) was
then slowly added. The solution was stirred for 12 h at –20 °C and
the mixture was then allowed to stand at –20 °C for 5 days. The
reaction was quenched by the addition of a saturated aqueous
NH4Cl solution and the mixture was then extracted with diethyl
ether. The organic layer was dried (MgSO4) and the solvents were
evaporated. The oil was flash chromatographed on silica gel, with
elution with petroleum ether/diethyl ether (PE/DE) (elution order:
borneol with PE/DE = 99:1; 11, with PE/DE = 97:3; 1, with PE/
DE = 97:3).
Compound 7: White crystals, m.p. 187 °C. [α]2D0 = 2.0 (CH2Cl2, c =
1
0.01). H NMR (300 MHz, CDCl3): δ = 6.93 (d, J = 8.1 Hz, 1 H),
6.79 (d, J = 2.1, 1 H), 6.77 (dd, J = 8.1, 2.1 Hz, 1 H), 5.84 (ddd, J
= 17.4, 10.2, 8.1 Hz, 1 H), 5.53 (ddd, J = 18.6 13.9, 8.9 Hz, 1 H),
5.26 (dd, J = 10.4, 1.8 Hz, 1 H), 5.15 (dd, J = 17.4, 1.3 Hz, 1 H),
5.05 (m, 2 H), 4.55 (q, J = 6.5 Hz, 1 H), 3.75 (s, 3 H), 3.64 (dd, J
= 5.2, 2.7 Hz, 1 H), 3.29 (½ABX, J = 13.8, 2.8 Hz,1 H), 3.18
(½ABX, J = 13.8, 5.2 Hz, 1 H), 2.57 (½AB, J = 13.8 Hz, 1 H),
2.52–2.30 (m, 3 H), 2.15–1.90 (2H), 1.87 (½AB, J = 13.8 Hz, 1 H),
1.39 (d, J = 6.5 Hz, 3 H), 0.87 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 176.8 (s), 159.5 (s), 144.7 (s), 138.9 (d), 138.4 (d), 135.4
(s), 123.9 (d), 118.2 (t), 117.3 (t), 115.2 (d), 109.4 (d), 109.2 (s), 97.0
(s), 79.0 (d), 58.8 (s), 55.6 (q), 53.2 (d), 50.7 (d), 42.8 (d), 34.4 (t),
31.6 (t), 28.0 (t), 27.6 (t), 12.8 (q) ppm. C24H28O5 (396.5): C 72.70,
H 7.12; found C 72.76, H 7.15.
Compound 11: 1H NMR (300 MHz, CDCl3): δ = 5.83–5.53 (m, 2
H), 5.22–5.08 (m, 4 H), 4.97–4.88 (m, 1 H), 3.62 (t, J = 9.6 Hz, 1
H) (major isomer), 3.59 (td, J = 11.3, 1.7 Hz, 1 H) (minor isomer),
2.83–2.65 (m, 2 H), 2.54–2.24 (m, 3 H), 2.22–2.15 (m, 2 H), 2.0–
1.85 (m, 1 H), 1.83–1.76 (m, 1 H), 1.66–1.64 (m, 1 H), 1.58 (d, J
= 1.7 Hz, 3 H), 1.33–1.17 (m, 1 H), 1.06–0.96 (m, 1 H), 0.87 (s, 3
H), 0.85 (s, 3 H), 0.81 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3)
(major/minor): δ = 171.4/171.2 (s), 168.3/167.8 (s), 137.5/138.1 (d),
135.4/135.3 (d), 119.0/118.6 (t), 117.6/117.4 (t), 96.0/95.4 (s), 81.6/
81.8 (d), 53.5/53.2 (d), 53.0/52.4 (d), 49.1/48.9 (s), 47.9 (s), 47.7/
47.6 (d), 44.8 (d), 36.4/36.6 (t), 30.9–30.8 (t), 28.9/29.0 (t), 28.4/28.6
(t), 27.95/27.9 (t), 27.05/27.0 (t), 19.7 (q), 18.8 (q), 13.42 (q) ppm.
General Procedure for the Formation of Carbonate Esters 8–10:
Phosgene is a hazardous compound and all the operations should
be performed under an efficient hood. The alcohol (0.30 mol) in
CH2Cl2 (50 mL) and molecular sieves (60 g) were added to a phos-
gene solution in toluene (ca. 20%, 200 mL, 0.20 mol). The solution
was stirred at room temperature for 48 h (monitored by TLC). The
reaction mixture was filtered and the solution was stirred for
30 min. with saturated aqueous NaHCO3 solution. The organic
layer was dried (MgSO4) and the solvents were evaporated. The
yellow oil was flash chromatographed on silica gel with elution with
a PE/DE (10:1) to affording dialkyl carbonate.
IR (CH Cl ): ν = 3078, 1766, 1675, 1639 cm–1. C H O (372.5):
˜
2
2
23 32
4
C 74.16, H 8.66; found C 74.26, H 8.59.
3-[endo-(1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yloxycarbonyl]-
3-(benzocyclobuten-1-yl)-6,9-divinyl-1-oxaspiro[4,4]nonan-2-one
(12a) or 3-[endo-(1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yloxy-
carbonyl]-3-(5-methoxybenzocyclobuten-1-yl)-6,9-divinyl-1-oxa-
spiro[4,4]nonan-2-one (12b): A mixture of spirolactone 11 (7.57 g,
20 mmol), 1-iodobenzocyclobutene 5a (6.00, 26 mmol) or 5b
(6.76 g, 26 mmol), cesium carbonate (dried by heating at 100 °C
under vacuum, 9.8 g, 30 mmol) and potassium iodide (2.72 g,
16 mmol) in anhydrous acetone (250 mL) was heated at reflux for
120 h. The mixture was filtered, the solid was washed with diethyl
ether, and the organic phase was concentrated under reduced pres-
Bis[(1R)-menthyl] Carbonate (8):[20] This compound was synthe-
1
sized from (–)-menthol (56.8 g) to give 8 [43.1 g (85%)]. H NMR
(300 MHz, CDCl3): δ = 4.71 (td, J = 10.9, 4.5 Hz, 2 H), 2.11 (dq, sure. The crude product was flash chromatographed on silica gel
J = 11.7, 1.6 Hz, 2 H), 1.92 (sept.d, J = 7.0, 2.7 Hz, 2 H), 1.67 (m,
4 H), 1.45 (m, 8 H), 1.12 (m, 2 H), 0.92 (d, J = 7.0 Hz, 6 H), 0.89
(d, J = 7.0 Hz, 6 H), 0.78 (d, J = 7.0 Hz, 6 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 157.1 (s), 74.9 (d), 47.3 (d), 41.3 (d), 34.3
(d), 31.3 (t), 26.3 (t), 23.5 (t), 22.0 (q), 20.7 (q), 16.5 (q) ppm.
Dimethyl O,O’-Carbonylbis[(S)-lactate] (9):[21] This compound was
synthesized from (–)-methyl l-lactate (31.2 g) to give 9 [29.8 g
(85%)]. [α]2D0 = –42.7 (CH2Cl2, c = 0.01). 1H NMR (300 MHz,
with elution with pentane/diethyl ether (95:5), affording 12a
(6.92 g, 14.6 mmol, 73%) or 12b (9.07 g, 18 mmol, 90%).
1
Compound 12a: H NMR (300 MHz, CDCl3): δ = 7.17 (m, 2 H),
7.02 (m, 2 H), 5.67 (m, 2 H), 5.05 (m, 4 H), 4.66 (dd, J = 10.2,
1.6 Hz, 1 H), 4.15 (dd, J = 4.7, 2.3 Hz, 1 H), 3.21 (m, 1 H), 2.96
(m, 1 H), 2.27 (m, 3 H), 1.99 (m, 4 H), 1.80–1.10 (m, 8 H), 0.84 (s,
3 H), 0.82 (s, 3 H), 0.80 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 172.9 (s), 169.7 (s), 143.7 (s), 142.8 (s), 137.2 (d), 134.8 (d),
Eur. J. Org. Chem. 2005, 4806–4814
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4811

M. Santelli et al.
FULL PAPER
128.5 (d), 127.1 (d), 123.0 (d), 122.6 (d), 118.5 (t), 117.3 (t), 93.5 (8β,9α,14α)-11β-[endo-(1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-
(s), 81.7 (d), 57.3 (d), 53.3 (d), 52.8 (d), 52.4 (t), 48.7 (s), 47.6 (s), yloxycarbonyl]-11α,13α-(γ-carbolactone)-17α-vinylgonatri-1,3,5(10)-
1
47.0 (s), 44.5 (d), 36.1 (t), 33.1 (t), 27.7 (t), 26.9 (t), 26.8 (t), 26.6 ene (14a): H NMR (400 MHz, CDCl3): δ = as 13a, except for the
(t), 19.3 (q), 18.5 (q), 13.3 (q) ppm. IR (CH Cl ): ν = 1775, 1569,
following signals: 5.73 (ddd, J = 17.0, 10.1, 8.3 Hz, 1 H), 4.89 (dt,
J = 9.0, 2.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.7
(s), 170.1 (s), 142.2 (s), 137.7 (s), 135.2 (d), 128.5 (d), 126.1 (d),
125.6 (d), 121.8 (d), 117.1 (t), 93.2 (s), 82.0 (d), 55.4 (s), 53.5 (d),
50.8 (d), 49.1 (s), 47.6 (s), 44.8 (d), 43.4 (d), 42.7 (d), 35.5 (t), 35.0
(t), 31.9 (t), 30.8 (t), 27.5 (t), 27.3 (t), 27.1 (t), 26.1 (t), 19.6 (q),
18.9 (q), 13.2 (q) ppm.
˜
2
2
1264, 1094, 1033, 812, 739 cm–1.
1
Compound 12b: H NMR (300 MHz, CDCl3): δ = 6.94–6.86 (m, 1
H), 6.79–6.71 (m, 1 H), 6.59–6.51 (m, 1 H), 5.76–5.30 (m, 2 H),
5.26–5.03 (m, 4 H), 4.92–4.61 (t, 4 H), 4.25 (d, J = 7.0 Hz, 1 H),
4.09 (br. s, 1 H), 3.69 (s, 3 H), 3.27–3.13 (m, 1 H), 2.95–2.81 (m, 1
H), 2.39–2.28 (m, 3 H), 2.16–1.63 (m, 5 H), 1.29–1.13 (m, 2 H),
0.87 (s, 3 H), 0.85 (s, 3 H), 0.81 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 173.5 (s), 170.0 (s), 159.8 (s), 143.7 (s), 137.3 (d), 135.3
(8β,9α,14α)-2-Methoxy-11β-[endo-(1S)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-yloxycarbonyl]-11α,13α-(γ-carbolactone)-17α-vinyl-
1
(s), 135.2 (d), 124.1 (d), 118.84 (t), 117.4 (t), 116.3 (d), 107.9 (d), gonatri-1,3,5(10)-ene (14b): H NMR (300 MHz, CDCl3): δ = 7.02
93.8 (s), 81.9 (d), 57.7 (s), 55.5(q), 53.2 (d), 52.8 (d), 49.1 (s), 48.0
(s), 46.4 (d), 44.9 (d), 37.0 (t), 36.5 (t), 32.4 (t), 30.1 (t), 28.0 (t),
(d, J = 8.1 Hz, 1 H), 6.61 (dd, J = 8.2, 2.5 Hz, 1 H), 6.51 (d, J =
2.5 Hz, 1 H), 5.87 (ddd, J = 17.0, 10.2, 8.1 Hz, 1 H), 5.11 (d, J =
27.7 (t), 27.2 (t), 19.7 (q), 18.9 (q), 13.7 (q) ppm. IR (CH Cl ): ν = 17.0 Hz, 1 H), 5.09 (d, J = 10.1 Hz, 1 H), 4.88 (dt, J = 8.7, 2.6 Hz,
˜
2
2
1776, 1566, 1262, 1096, 813, 736 cm–1.
1 H), 3.67 (s, 3 H), 3.07 (d, J = 11.2 Hz, 1 H), 2.85–2.72 (m, 1 H),
2.68 (½AB, J = 12.2 Hz, 1 H), 2.46 (dt, J = 11.8, 7.3 Hz, 1 H),
2.22 (½AB, J = 12.1 Hz, 1 H), 2.03 (quint., J = 6.0 Hz, 1 H), 1.88
(m, 4 H), 1.71–1.45 (m, 6 H), 1.27–1.19 (m, 2 H), 1.07 (m, 1 H),
0.83 (s, 3 H), 0.75 (s, 3 H), 0.33 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.5 (s), 169.8 (s), 157.6 (s), 143.2 (s), 135.1 (d), 129.4
(s), 129.1 (d), 117.0 (t), 110.4 (d), 108.9 (d), 92.9 (s), 81.8 (d), 55.2
(q), 55.2 (s), 53.4 (d), 50.8 (d), 48.9 (s), 47.6 (s), 44.8 (d), 43.2 (d),
35.8 (t), 35.0 (t), 31.6 (t), 30.6 (t), 27.5 (t), 27.1 (t), 26.3 (t), 22.6 (t)
19.4 (q), 18.7 (q), 13.0 (q) ppm.
General Procedure for the Thermolysis of 12: Compound 12a
(8.54 g, 18 mmol) or 12b (9.1 g, 18 mmol) in anhydrous 1,2,4-trich-
lorobenzene (150 mL) was heated at 215 °C for 36 h (the progress
of the reaction was followed by TLC analysis). The solvent was
removed under reduced pressure and the residue was flash chro-
matographed (PE/DE 93:7) to give steroid analogues. From 12a:
13a + 14a, crystallised from petroleum ether, 7.5 g (88%), white
crystals, m.p. 153 °C (13a:14a = 70:30). From 12b: 13b + 14b, 7.27 g
(14.4 mmol, 80 %, 80:20 mixture), crystallised from petroleum
ether, white crystal, m.p. 170 °C; 15b, 1.28 g, 2.5 mmol, 12%.
(8α,9α,14β)-2-Methoxy-11α-[endo-(1S)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-yloxycarbonyl]-11β,13β-(γ-carbolactone)-17β-vinyl-
gonatri-1,3,5(10)-ene (15b): [α]2D0 = 24.5 (CH2Cl2, c = 0.01). 1H
NMR (300 MHz, CDCl3): δ = 6.89 (d, J = 8.5 Hz, 1 H), 6.82 (d,
J = 2.3 Hz, 1 H), 6.64 (dd, J = 8.5, 2.3 Hz, 1 H), 5.86 (ddd, J =
17.6, 9.6, 8.1 Hz, 1 H), 5.09 (d, J = 17.4 Hz, 1 H), 5.08 (d, J =
10.1 Hz, 1 H), 4.31 (br. d, J = 6.4 Hz, 1 H), 3.71 (s, 3 H), 2.72 (q,
J = 8.1 Hz, 1 H), 2.56–2.34 (m, 5 H), 2.51 (d, J = 8.3 Hz, 1 H),
2.19–2.09 (m, 3 H), 1.94–1.86 (m, 4 H), 1.77–1.58 (m, 3 H), 1.34–
1.17 (m, 3 H), 1.02 (dd, J = 13.8, 3.4 Hz, 1 H), 0.93 (s, 3 H), 0.91
(s, 3 H), 0.87 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.0
(s, 2C), 157.3 (s), 135.6 (d), 134.2 (s), 129.8 (d), 128.7 (s), 116.8 (t),
115.3 (d) 113.9 (d), 91.3 (s), 82.0 (d), 57.5 (s), 55.4 (q), 51.7 (d),
49.4 (s), 48.2 (s), 45.9 (d), 45.0 (d), 41.3 (t), 40.0 (d), 36.8 (t), 35.2
(d), 31.6 (t), 30.4 (t), 28.2 (t), 27.2 (t), 25.2 (t), 24.0 (t), 19.8 (q),
19.1 (q), 13.6 (q) ppm.
(8α,9β,14β)-11α-[endo-(1S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-
yloxycarbonyl]-11β,13β-(γ-carbolactone)-17β-vinylgonatri-1,3,5(10)-
ene (13a): 1H NMR (400 MHz, CDCl3): δ = 7.11 (m, 3 H), 6.92
(d, J = 6.4 Hz, 1 H), 5.88 (ddd, J = 17.0, 10.1, 8.3 Hz, 1 H), 5.12
(br. d, J = 17.0 Hz, 1 H), 5.10 (br. d, J = 10.1 Hz, 1 H), 4.74 (dt,
J = 9.0, 2.2 Hz, 1 H), 3.10 (d, J = 11.0 Hz, 1 H), 2.90–2.82 (m, 2
H), 2.80–2.75 (m, 2 H), 2.71 (½AB, J = 12.1 Hz, 1 H), 2.47 (td, J
= 7.2, 11.7 Hz, 1 H), 2.23 (m, 2 H), 2.21 (½AB, J = 12.3 Hz, 1 H),
2.03 (dt, J = 11.7, 6.1 Hz, 1 H), 1.98–1.82 (m, 4 H), 1.75–1.48 (m,
6 H), 1.23 (m, 1 H), 1.07 (m, 1 H), 0.81 (s, 3 H), 0.75 (s, 3 H), 0.29
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.7 (s), 170.2
(s), 142.2 (s), 137.6 (s), 135.2 (d), 128.5 (d), 126.0 (d), 125.8 (d),
121.7 (d), 117.1 (t), 93.0 (s), 82.2 (d), 55.2 (s), 53.5 (d), 50.8 (d),
48.6 (s), 47.7 (s), 44.9 (d), 43.2 (d), 42.8 (d), 35.9 (t), 35.5 (t), 31.9
(t), 30.7 (t), 27.6 (t), 27.4 (t), 27.2 (t), 26.1 (t), 19.6 (q), 18.9 (q),
12.9 (q) ppm. IR (CH Cl ): ν = 1610, 1582, 1271, 745 cm–1
.
(8α,9β,14β)-2-Methoxy-11α-[endo-(1S)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-yloxycarbonyl]-11β-methoxycarbonyl-17β-vinylgona-
tri-1,3,5(10)-en-13β-ol (16): Compound 13b (1 g, 2 mmol) was
heated at reflux in anhydrous methanol (20 mL) for 36 h (the pro-
gress of the reaction was followed by TLC analysis). The solvent
was removed under reduced pressure and the residue was flash
chromatographed (PE/DE 93:7) to give 13b and then 16.
˜
2
2
C31H38O4 (474.6): C 78.45, H 8.07; found C 78.40, H 8.09.
(8α,9β,14β)-2-Methoxy-11α-[endo-(1S)-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-yloxycarbonyl]-11β,13β-(γ-carbolactone)-17β-vinyl-
1
gonatri-1,3,5(10)-ene (13b): H NMR (300 MHz, CDCl3): δ = 7.01
(d, J = 8.2 Hz, 1 H), 6.62 (dd, J = 8.2, 2.5 Hz, 1 H), 6.50 (d, J =
2.5 Hz, 1 H), 5.87 (ddd, J = 17.0, 10.2, 8.1 Hz, 1 H), 5.11 (d, J =
17.0 Hz, 1 H), 5.09 (d, J = 10.1 Hz, 1 H), 4.76 (dt, J = 8.7, 2.6 Hz,
1 H), 3.68 (s, 3 H), 3.07 (d, J = 11.2 Hz, 1 H), 2.85–2.72 (m, 1 H),
2.68 (½AB, J = 12.2 Hz, 1 H), 2.46 (dt, J = 11.8, 7.3 Hz, 1 H),
2.22 (½AB, J = 12.1 Hz, 1 H), 2.03 (quint., J = 6.0 Hz, 1 H), 1.88
Compound 16: White crystals, m.p. 137 °C. [α]2D0 = –29.0 (CH2Cl2,
c = 0.046). 1H NMR (300 MHz, CDCl3): δ = 7.01 (s, 1 H), 6.84
(d, J = 8.3 Hz, 1 H), 6.55 (dd, J = 8.3, 2.5 Hz, 1 H), 5.75 (ddd, J
= 17.4, 10.4, 7.5 Hz, 1 H), 5.14 (br. s, J = 10.4 Hz, 1 H), 5.10 (d,
(m, 4 H), 1.71–1.45 (m, 6 H), 1.27–1.19 (m, 2 H), 1.07 (m, 1 H), J = 17.4 Hz, 1 H), 4.44 (dt, J = 9.1, 2.5 Hz, 1 H), 3.79 (s, 3 H),
0.82 (s, 3 H), 0.75 (s, 3 H), 0.33 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 175.4 (s), 170.0 (s), 157.8 (s), 143.0 (s), 135.1 (d), 129.4
3.61 (s, 3 H), 2.77 (½ AB, J = 14.0 Hz, 1 H), 2.67 (m, 3 H), 2.19–
1.96 (m, 4 H), 2.05 (½ AB, J = 14.0 Hz, 1 H), 1.80–1.63 (m, 3 H),
(s), 129.1 (d), 117.0 (t), 110.9 (d), 108.5 (d), 92.8 (s), 82.0 (d), 55.2 1.62–1.50 (m, 4 H), 1.45 (m, 2 H), 1.30–1.15 (m, 4 H), 0.7 (s, 3 H),
(q), 55.2 (s), 53.4 (d), 50.8 (d), 48.5 (s), 47.6 (s), 44.8 (d), 43.1 (d),
0.67 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.7 (s), 172.2
43.0 (d), 35.8 (t), 35.6 (t), 31.8 (t), 30.6 (t), 27.5 (t), 27.2 (t), 26.4 (s), 157.6 (s), 138.2 (s), 136.4 (d), 129.9 (s), 129.6 (d), 118.2 (t),
(t), 22.6 (t), 19.5 (q), 18.8 (q), 12.8 (q) ppm. IR (CH Cl ): ν = 3051, 113.8 (d), 112.8 (d), 81.3 (d), 79.2 (s), 59.8 (s), 55.9 (q), 55.1 (q),
˜
2
2
1774, 1716, 1263, 895, 727 cm–1. C32H40O5 (504.7): C 76.16, H 7.99; 52.8 (d), 48.4 (s), 47.4 (s), 44.6 (d), 44.4 (d), 42.2 (t), 40.6 (d), 34.5
found C 76.28, H 8.03. (t), 31.0 (t), 30.3 (d), 29.9 (t), 29.4 (t), 28.6 (t), 27.6 (t), 27.3 (t),
4812
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4806–4814

Lactone Kinetic Resolution by Acylation
FULL PAPER
Table 1. Crystal data and structure refinement for 7, 13b + 14b and 15b.
7
13b + 14b
15b
Empirical formula
Formula mass
Crystal colour
Crystal size [mm]3
Crystal system
Space group
a [Å]
C24H28O5
396.46
colourless
0.4×0.4×0.3
monoclinic
P21/c
9.0960(2)
12.8020(6)
18.4210(9)
97.924(3)
2124.59(15)
4
C128H160O20
2018.56
colourless
0.5×0.3×0.3
monoclinic
P21
11.3903(1)
23.5785(3)
21.8713(3)
104.7571(5)
5680.03(12)
2
C32H40O5
504.64
colourless
0.4×0.15×0.15
monoclinic
P21
10.7630(8)
11.5830(4)
11.5950(8)
99.541(3)
1425.53(15)
2
b [Å]
c [Å]
β [°]
V [A3]
Z
Dc [g·cm–3]
1.239
0.086
3884
262
1.18
0.078
16154
1333
1.176
0.078
2786
332
M (Mo-Kα) [mm–1]
No. of unique data
No. parameters refined
No. refl. in refinement
R
3889 [F2 Ͼ 4σF2]
0.0481
10716 [F2 Ͼ 4σF2]
0.0852
2414 [F2 Ͼ 4σF2]
0.0556
wR [all reflections]
Goodness of fit
Residual Fourier [e·Å–3]
0.1389[a]
1.188
0.2031[b]
1.091
0.1251[c]
1.072
–0.233; 0.238
–0.214; 0.315
–0.206; 0.217
2
2
2
[a] w = 1/[σ2(Fo2) + (0.0692P)2 + 0.5517P] where P = (Fo + 2Fc )/3. [b] w = 1/[σ2(Fo2) + (0.0943P)2 + 1.92366P] where P = (Fo
+
2Fc )/3. [c] w = 1/[σ2(Fo2) + (0.0545P)2 + 0.5135P] where P = (Fo + 2Fc )/3.
2
2
2
[3]
a) W. Oppolzer, J. Am. Chem. Soc. 1971, 93, 3833–3834; W.
Oppolzer, J. Am. Chem. Soc. 1971, 93, 3834–3835; b) W. Op-
polzer, K. Keller, J. Am. Chem. Soc. 1971, 93, 3836–3837; c)
W. Oppolzer, Tetrahedron Lett. 1974, 15, 1001–1004; d) W. Op-
polzer, Angew. Chem. Int. Ed. Engl. 1977, 16, 10–22; e) W. Op-
polzer, M. Petrzilka, K. Bättig, Helv. Chim. Acta 1977, 60,
2964–2967; f) W. Oppolzer, K. Bättig, M. Petrzilka, Helv.
Chim. Acta 1978, 61, 1945–1947.
a) T. Kametani, K. Fukumoto, Heterocycles 1975, 3, 29–56; b)
T. Kametani, Y. Kato, T. Honda, K. Fukumoto, Heterocycles
1976, 4, 241–246; c) T. Kametani, H. Nemoto, H. Ishikawa, K.
Shiroyama, K. Fukumoto, J. Am. Chem. Soc. 1976, 98, 3378–
3379; d) T. Kametani, H. Matsumoto, H. Nemoto, K. Fukum-
oto, J. Am. Chem. Soc. 1978, 100, 6218–6220.
For excellent discussions of kinetic resolution, see: a) S. El-
Baba, J.-C. Poulin, H. B. Kagan, Tetrahedron 1984, 40, 4275;
b) H. B. Kagan, J. C. Fiaud, Topics Stereochem. 1988, 18, 249.
D. Kim, J. Lee, P. J. Shim, J. I. Lim, T. Doi, S. Kim, J. Org.
Chem. 2002, 67, 772–781.
H. Pellissier, P.-Y. Michellys, M. Santelli, J. Org. Chem. 1997,
62, 5588–5591.
O. I. Kolodiazhnyi, Tetrahedron 2003, 59, 5953–6018.
Loss of TBDMS groups during LiAlH4 reductions has been
observed in cases in which an adjacent hydroxy group is pres-
ent, see: E. F. J. De Vries, J. Brussee, A. van der Gen, J. Org.
Chem. 1994, 59, 7133–7137.
For similar structures from treatment of ethanediol derivatives
with l-ascorbic acid, see: M. N. Preobrazhenskaya, E. I.
Lazhko, A. M. Korolev, Tetrahedron: Asymmetry 1996, 7, 641–
644.
ORTEP view showing 20% probability displacement ellipsoids.
For similar results, see: K. Koh, T. Durst, J. Org. Chem. 1994,
59, 4683–4686.
H. Pellissier, Tetrahedron 2003, 59, 8291–8327.
E. L. Eliel, S. H. Wilen, Stereochemistry of Organic Compounds,
John Wiley & Sons: New York, 1994, pp. 876–880.
19.5 (q), 18.6 (q), 13.6 (q) ppm. IR (CH Cl ): ν = 1738, 1719, 1264,
˜
2
2
910 cm–1. C33H44O6 (536.7): C 73.85, H 8.26; found C 73.95, H
8.19.
X-ray Crystallography: CCDC-273092 (for 7), CCDC-273093 (for
13b+14b) and CCDC-273094 (for 15b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[4]
[5]
A summary of the crystal data, data collection, and refinements is
given in Table 1.
Acknowledgments
S. W. is grateful to the MEN for a grant. We are indebted to Dr.
B. Vacher (Pierre Fabre Médicaments, Castres, France) for helpful
comments.
[6]
[7]
[1] a) H. Pellissier, M. Santelli, Tetrahedron 1996, 52, 9093–9100;
b) S. Wilmouth, H. Pellissier, M. Santelli, Tetrahedron 1998,
54, 10079–10088; c) G. Burtin, H. Pellissier, M. Santelli, Tetra-
hedron 1998, 54, 4913–4922; d) G. Burtin, H. Pellissier, M. San-
telli, Tetrahedron 1998, 54, 8065–8074; e) S. Wilmouth, H. Pel-
lissier, M. Santelli, Tetrahedron 1998, 54, 10079–10088; f) S.
Wilmouth, H. Pellissier, M. Santelli, Tetrahedron 1998, 54,
13805–13812; g) F. Cachoux, M. Ibrahim-Ouali, M. Santelli,
Tetrahedron Lett. 2000, 41, 1767–1769; h) F. Cachoux, M. Ib-
rahim-Ouali, M. Santelli, Synlett 2000, 3, 418–420; i) P.-Y.
Michellys, P. Maurin, L. Toupet, H. Pellissier, M. Santelli, J.
Org. Chem. 2001, 66, 115–122; j) P. Maurin, M. Ibrahim-Ouali,
M. Santelli, Eur. J. Org. Chem. 2002, 151–156; k) N. Mariet,
H. Pellissier, M. Ibrahim-Ouali, M. Santelli, Eur. J. Org. Chem.
2004, 2679–2691.
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[2] a) A. A. Akhrem, Y. A. Titov, Total Steroid Synthesis, Plenum
Press: New York, 1970; b) R. T. Blickenstaff, A. C. Ghoosh,
G. C. Wolf, Total Steroid Synthesis, Academic Press: New
York, 1974; c) F. J. Zeelen, Medicinal Chemistry of Steroids,
Elsevier: Amsterdam, 1990.
[15]
[16]
a) H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957,
79, 1920–1923; b) Ref.[14], pp. 914–920.
F. A. Davis, A. Kumar, J. Org. Chem. 1992, 57, 3337–3339.
Eur. J. Org. Chem. 2005, 4806–4814
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4813

M. Santelli et al.
FULL PAPER
[17] For a discussion explaining the stereochemical course of the
refined on two sites with occupancies equal to 0.5. Only one
site for the disordered vinyl group is shown for clarity.
[20] R. B. Woodward, T. P. Kohman, G. C. Harris, J. Am. Chem.
Soc. 1941, 63, 120–124.
[21] P. D. Ritchie, J. Chem. Soc. 1935, 1054–1061.
[22] M. Hanack, Chem. Ber. 1961, 94, 1082–1088.
Received: May 26, 2005
intramolecular Diels–Alder cycloaddition involving an o-xylyl-
ene, see ref.[1k]
.
[18] Steroids 13b and 14b crystallised as a tetramer with the two
isomers as symmetrically unrelated dimers in the asymmetric
unit.
[19] ORTEP view showing 30% probability displacement ellipsoids.
The vinyl group was found to be disordered and was split and
Published Online: September 21, 2005
4814
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4806–4814