Synthesis of novel 5α,9α-bridged steroids by a boron trifluoride-diethyl ether induced rearrangement

Article abstract of DOI:10.1002/ejoc.200400117

A stereoselective and synthetically useful rearrangement reaction of 5α,8α-bridged 9,11α-epoxy steroids induced by boron trifluoride-diethyl ether is presented, in the preparation of a new class of 5α,9α-bridged 11α-hydroxy steroid derivatives in high yields. Lactones were prepared from several of the rearranged 11α-hydroxy compounds. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400117

FULL PAPER
Synthesis of Novel 5α,9α-Bridged Steroids by a Boron Trifluoride؊Diethyl
Ether Induced Rearrangement
Lidija Bondarenko,*[a] Ljubinka Lorenc,[b] Dieter Bläser,[c] and Roland Boese[c]
Keywords: Steroids / Epoxides / Lewis acids / Rearrangements / Lactones
A stereoselective and synthetically useful rearrangement re-
rivatives in high yields. Lactones were prepared from several
action of 5α,8α-bridged 9,11α-epoxy steroids induced by
of the rearranged 11α-hydroxy compounds.
boron trifluoride−diethyl ether is presented, in the prepara- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
tion of a new class of 5α,9α-bridged 11α-hydroxy steroid de- Germany, 2004)
Introduction
produce a 6,8(14)-dien-11α-ol as the only product, in high
yield (B, Scheme 1).
In our continuing studies of steroid transformations, we
This is not so surprising since it is known that treatment
have been attempting to prepare an 11-oxo derivative of
of epoxides with boron trifluorideϪdiethyl ether can give,
some 5,8-bridged steroids (C, Scheme 1). Opening of differ-
in some cases, other rearrangement products besides ke-
ent steroidal epoxides to give ketones using boron
tones,[2] especially in natural product chemistry.[3] For some
trifluorideϪdiethyl ether is a well-investigated and high-
synthetic rearrangement reactions,[3a,4] various Lewis acids
yield reaction.[1] However, in the case of our bridged epox-
have been investigated, and it has been found that BF3·Et2O
ide A, the bridge had migrated from position C-8 to C-9 to
gives the best results. However, since there has been no
comprehensive structure-dependency studies of these re-
arrangement reactions, we decided to prepare several easily
accessible steroidal epoxy adducts to investigate the influ-
ence of the neighboring double bond on bridge migration.
The preparation of new steroid structures with useful bio-
logical activities is also of interest.[5] New derivatives are
prepared by functional group transformations, functionaliz-
ation of different nonactivated positions[6] and modification
of the steroidal skeleton, as in seco-steroids,[6a,7] or homo-
and aza-steroids.[6a,8] Different positions in steroids have
been bridged by heteroatoms or other functions (lactones).
Furthermore, in the past 20 years, steroids with small car-
bon bridges have been studied as potential therapeutic ag-
ents.[5] The most thoroughly investigated are: 6,19-bridged
for antiherpes virus activity, anticonvulsant and other un-
usual activities,[9] 2,19-bridged as aromatase inhibitors,[10]
10,11-bridged as gestagens and antigestagens,[11] and
Scheme 1. Reaction of epoxides with boron trifluorideϪdiethyl
ether
7α,15α-bridged steroids as antihypercholesterolemics.[12]
Substitution in the position C-9 in steroids is not very
[a]
Institut für Organische Chemie, Technische Universität
common. Halogen, hydroxy, methyl and cyano substituents
Braunschweig,
at position C-9 are known in corticosteroids and in estrone
derivatives, where this is a benzylic activated position.[6a]
Only three carbon-bridged rings at the 8,9-position in ster-
oids are known.[13] To the best of our knowledge, in steroid
chemistry the presented work is the only known case where
a carbocyclic ring is introduced between the two tertiary
carbon atoms at the 5α,9α-positions.
Hagenring 30, 38106 Braunschweig, Germany
Fax: (internat.) ϩ 49-531-391-5388
E-mail: lidijabondarenko@netscape.net
Faculty of Chemistry, University of Belgrade,
Studentski trg 12Ϫ16, P. O. Box 158, 11001 Belgrade, Serbia
and Montenegro
Fachbereich Chemie der Universität Duisburg-Essen, Campus
Essen
Universitätstr. 3, 45117 Essen, Germany
[b]
[c]
3526
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400117
Eur. J. Org. Chem. 2004, 3526Ϫ3534

Synthesis of Novel 5α,9α-Bridged Steroids
FULL PAPER
Results and Discussion
Table 2. Products and yields in the synthesis of epoxides 3
The epoxy adducts were prepared using a method which
is similar to those described previously.[14] The DielsϪAlder
reaction of 5,7,9(11)-cholestatriene[15] 1 with different di-
enophiles gave the corresponding adducts 2[16] together with
some unstable ene adducts in the case of acetylenedicarbox-
ylate, as indicated by NMR spectroscopy (Scheme 2,
Table 1).
[a]
[b]
All yields refer to isolated, purified products.
tion.
90% consump-
Scheme 2. The DielsϪAlder reaction of 5,7,9(11)-cholestatriene
acetate (1)
Table 1. Products and yields in the synthesis of 5α,8α-adducts 2
Scheme 4. Hydrogenation of epoxy adducts 3a and 3c
[a]
[b]
All yields refer to isolated, purified products.
18% of an
Scheme 5. Rearrangement of 5α,8α-bridged 9,11α-epoxy steroids
[c]
unstable 7-ene adduct was isolated.
adduct was isolated.
30% of an unstable 7-ene
Table 3. Products and yields of the rearrangement of 5α,9α-bridged
11α-epoxysteroids
Treatment of adducts 2 with m-CPBA in dichloro-
methane solution at room temperature yielded the 9,11α-
epoxides 3 (Scheme 3, Table 2).
Entry Adduct Solvent
Conditions
Products/Yields [%][a]
1
2
3
4
6
7
8
9
10
11
12
13
2a
3a
3a
3b
3b
4a
3c
3c
3c
4c
3d
3d
Et2O
20 °C/72 h
2a/95
5a/90
benzene 20 °C/0.1 h
Et2O
benzene 20 °C/0.1 h
Et2O
benzene 20 °C/0.2 h
Et2O
benzene 20 °C/6 h
CH2Cl2 20 °C/12 h
benzene 20 °C/3 h
benzene 80 °C/4 h
benzene 40 °C/36 h
20 °C/200 h 5a/80
5b/86
20 °C/200 h 5b/85
5aЈ/80
20 °C/100 h 3c/98
5c/88 ϩ 6c/2Ϫ5
5c/80 ϩ 6c/5
5cЈ/60 ϩ 6cЈ/32
5d/18[b]
Scheme 3. Epoxidation of adducts 2
The epoxidation takes place selectively at the 9,11-double
bond, since the other two double bonds are sterically more
hindered.[17] Finally, the 6,7-double bond in adducts 3a, 3c
were hydrogenated[16] in the presence of PtO2 in ethyl acet-
ate at atmospheric pressure (Scheme 4).
5d/35[b]
[a]
[b]
All yields refer to isolated, purified products.
The remaining
complex mixture was not investigated.
All epoxides 3aϪd, 4a, 4c were then allowed to react with
The best solvents for the boron trifluorideϪdiethyl ether
BF3·Et2O under different reaction conditions (Scheme 5), rearrangement reaction are benzene and dichloromethane
and the results are presented in Table 3.
because of the stabilization of the Lewis acid π-complex by
Eur. J. Org. Chem. 2004, 3526Ϫ3534
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3527

L. Bondarenko, Lj. Lorenc, D. Bläser, R. Boese
FULL PAPER
the solvent. Diethyl ether lowers the reaction rate (Entries
All compounds of type 5 have the same molecular for-
1
3, 6, 8, Table 3). The 6,7-double bond does not influence mula as the starting epoxide. In the H NMR spectra the
the reaction (Entry 7). However, while the double bond on observed change noted for 11-H in the epoxide was regis-
the migrating bridge enhances the isomerisation reaction, tered at δ ϭ 2.8Ϫ3.5 ppm and in 5 at δ ϭ 3.6Ϫ4.0 ppm
its absence increases the rate of the competing epoxide- (see Exp. Sect.) together with an IR signal at 3500 cmϪ1
,
opening reaction, which forms a ketone (Entries 9, 10, which indicates a hydroxy group at C-11. The angular
Table 3), especially in the case of the completely saturated methyl groups have a pattern typical for 8,14-unsaturated
epoxide 4d (Entry 11). The rearrangement of the triazoline steroids with very similar chemical shifts.[19] The AB system
epoxide 3d can be explained by the participation of the elec- of olefinic protons 6-H and 7-H were unchanged. In the
tron pair on the nitrogen atom, while it is known from the 13C NMR spectra signals of two new quaternary olefin car-
literature that boron trifluorideϪdiethyl ether can cleave the bon atoms appear, indicating a conjugated 6,8(14)-diene
triazoline, immediately regenerating the diene system.[18] system, which was supported by an absorption maximum
The adduct 2a does not react, thus proving that the Lewis at ca. 312 nm in the UV spectra (pale yellow color). All
acid opening of the epoxide is the initial reaction step.
compounds of type 5 are oils (resins), and only 5a gave
A plausible mechanistic route, which is essentially based single crystals suitable for X-ray analysis. The structure pre-
on the proposed mechanism for a similar acid-catalyzed re- sented in Figure 1, clearly shows the new five-membered
arrangement of epoxides,[3] is shown in Scheme 6. The coor- ring containing the bridge at the α-side.
dination-activation of the Lewis acid to the epoxide oxygen
Compounds of type 6 were easily identified by disappear-
1
atom leads to the C-9 carbocation intermediate, which can ance of the 11-H signal in the H NMR spectra and the
be stabilized in two ways. The usual 1,2-hydride shift from appearance of a new signal for the C-11 oxo group in the
C-11 to C-9 with formation of the C-11 ketone 6 (Scheme 6) 13C NMR spectrum at δ ϭ 212 ppm, the remainder of the
is not favored and the bridge at C-8 is migrating to C-9, molecule having resonances at about the same positions as
with formation of an intermediate carbocation at C-8. This the starting epoxide.
subsequently forms the 8,14-double bond by base abstrac-
Furthermore, we prepared lactones 7a,b and 8a,b from
tion of the proton at C-14. The bridge migrates to the α-side alcohols 5a and 5b by acid-catalyzed[20] and thermal trans-
with retention of configuration at C-10. This rearrangement esterification reactions (Scheme 7, Table 4). The bridge ester
pathway is favored by an electron-rich double bond on the group reacts with the sterically close 11α-hydroxy group
migrating bridge, and is stereocontrolled without further di-
ene migration, resulting in a single product.
Scheme 6. The proposed mechanism of the epoxide-opening re-
arrangement
Scheme 7. Lactonization of 5α,9α-bridged 11α-hydroxy steroid
Figure 1. Structure and solid-state conformation of 5a
3528
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3526Ϫ3534

Synthesis of Novel 5α,9α-Bridged Steroids
FULL PAPER
formed on PLC plates Silica gel 60 F254ϩ366, 2 mm from Merck.
Elemental analysis: Faculty of Chemistry, University of Belgrade.
Table 4. Yields of 5α,9α-bridged steroidal lactones
Entry Alcohol Catalyst
Conditions Products/Yields [%][a] Cholesta-5,7,9(11)-trien-3β-yl Acetate (1): A solution of cholesta-
5,7-dien-3β-yl acetate (4.6 g) in ethanol (270 mL), was heated to
1
2
3
4.
5
6
5a
5a
5a
5b
5b
3b
pTsOH
pTsOH
none
pTsOH
none
20 °C/24 h 5a/95
reflux, and then mercuric acetate (10 g), dissolved in a mixture of
ethanol (160 mL) and acetic acid (5.5 mL), was added. The reac-
tion mixture was refluxed for 30 min. The solvents were evaporated
to dryness, and after addition of chloroform (80 mL), the solution
was filtered through Celite, and the filtrate was concentrated. Crys-
tallization from methanol gave cholesta-5,7,9(11)-trien-3β-yl acet-
ate (1) [2.27 g (50%)] which was used without further purification.
An analytical sample was dissolved in CH2Cl2, the solution filtered
again through Celite, concentrated and the residue recrystallized
from methanol and a little CH2Cl2 to give white crystals. M.p.
80 °C/3 h
7a/64, 8a/11
80 °C/24 h 7a/42, 8a/0, 5a/33
80 °C/10 h 7b/65, 8b/20
140 °C/150 h 7b/95, 8b 0
pTsOH/BF3·Et2O20 °C/36 h 5b/80
[a]
All yields refer to isolated, purified products.
with elimination of methanol or ethanol. The acid catalysis
increases the transesterification reaction rate (Entries 2 and
4), but it also causes the isomerisation of the 6,8(14)-diene
1
87Ϫ88 °C (ref.[15] 91Ϫ94 °C). H NMR (400 MHz): δ ϭ 0.61 (s, 3
H, 18-Me), 0.90 (d, J ϭ 1.9 Hz, 3 H, 26-Me), 0.92 (d, J ϭ 1.9 Hz,
3 H, 27-Me), 0.96 (d, J ϭ 6.5 Hz, 3 H, 21-Me), 1.30 (s, 3 H, 19-
Me), 2.08 (s, 3 H, AcO), 4.70 (m, 3 H, 3-H), 5.44 (dd, J ϭ 2.6,
2.6 Hz, 1 H, 6-H), 5.55 (dd, J ϭ 2.0, 4.4 Hz, 1 H, 7-H), 5.74 (dd,
1
to the 7,14-diene unit, indicated in the H NMR spectra by
signals of the two uncoupled olefinic protons instead of the
AB system of the 6,8(14)-diene. The acid-catalyzed mi- J ϭ 1.7, 6.0 Hz, 1 H, 11-H) ppm. 13C NMR (100 MHz): δ ϭ 11.4
gration of steroid dienes has been investigated previously[19]
(q), 18.4 (q), 21.4 (q), 22.6 (q), 22.8 (2 ϫ q), 23.9 (t), 28.0 (d), 28.3
(t), 28. 5 (t), 30.2 (d), 35.9 (d), 36.1 (t), 37.4 (t), 38.1 (t), 39.3 (s),
and those results differ from ours, presumably because of
39.5 (t), 42.3 (s), 43.1 (t), 50.9 (d), 53.7 (s), 56.4 (d), 74.0 (d), 115.6
the bridge position. The thermal lactonization only pro-
duced the lactone 7a,b, but harsher conditions are needed.
In both thermal and acid-catalyzed transesterification, the
(d), 119.1 (d), 122.6 (d), 135.7 (s), 140.0 (s), 144.0 (s), 170.4 (s)
ppm. MS (EI): m/z ϭ 424(8) [Mϩ], 364 (100) [Mϩ Ϫ AcOH], 349
(38) [Mϩ Ϫ AcOH Ϫ Me], 209 (50). HRMS (EI) [Mϩ] (C29H44O2):
methyl ester is more reactive than its ethyl analogue. The
calcd. 424.3341; found 424.3333.
one-pot rearrangement/lactonization of epoxide 3b failed at
General Procedure for the Diels؊Alder Addition: A solution of the
diene [cholesta-5,7,9(11)-trien-3β-yl acetate] in dry xylene and a
large excess of dienophile (6Ϫ10 equiv.) was refluxed under nitro-
gen for 24 h. In the case of maleic anhydride, the benzene solution
was refluxed for 6 h. The solvent was evaporated to dryness, and
the residue was chromatographed on silica gel.
room temperature.
In summary, we have developed a simple and efficient
synthesis of a new class of 5α,9α-bridged steroid derivatives.
The key step is a Lewis acid induced rearrangement, which
was investigated and could be applied to other similar sys-
tems. Further cyclization/lactonization reactions produced
several new steroidal lactones.
5α,8α-[1Ј,2Ј-cis-Bis(methoxycarbonyl)etheno]cholesta-6,9(11)-dien-
3β-yl Acetate (2a): Elution with CH2Cl2/Et2O (96:4) afforded crude
(2a) [2.7 g (50%)] which was crystallized from ethanol to give 1.43 g
(26%) of pure product. M.p. 194Ϫ195 °C (ref.[16a] 192Ϫ194 °C). [α]
Experimental Section
20
ϭ Ϫ40.00 (c ϭ 1.00, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ
D
1739 (s), 1725 (s), 1715 (s), 1267 (s), 1247 (s), 1217 (s), 1195 (m),
1
General: H and 13C NMR spectra were recorded using a Bruker
1023 (m) cmϪ1 1H NMR (400 MHz): δ ϭ 0.68 (s, 3 H, 18-Me),
.
AC 200, 1H NMR (200.1 MHz), 13C NMR (50.3 MHz) and Bruker
DRX-400, 1H NMR (400.1 MHz), 13C NMR (100.6 MHz) spec-
trometer. Chemical shifts (δ) are expressed in ppm downfield from
tetramethylsilane using the residual nondeuterated solvent as in-
0.86 (d, J ϭ 1.09 Hz, 3 H 26-Me), 0.89 (d, J ϭ 1.04 Hz, 3 H, 27-
Me), 0.92 (d, J ϭ 5.90 Hz, 3 H 21-Me), 1.14 (s, 3 H 19-Me), 2.04
(s, 3 H AcO), 2.62 (dd, J ϭ 11.5, ca. 4.5 Hz, 1 H, 4-H), 2.88 (dd,
J ϭ 8.6, 4.8 Hz, 1 H, 12-H), 3.71 (s, 3 H, COOMe), 3.80 (s, 3 H,
COOMe), 4.77 (m, 1 H, 3-H), 5.37 (d, J ϭ 4.8 Hz, 1 H, 11-H),
6.13 (d, J ϭ 7.3 Hz, 1 H, 7-H), 6.46 (d, J ϭ 7.4 Hz, 1 H, 6-H)
ppm.13C NMR (100 MHz): δ ϭ 12.5 (q, 18-Me), 18.4 (q, 21-Me),
21.3 (q, OAc), 22.4 (t), 22.6 (q, 26-Me), 22.8 (q, 27-Me), 23.8 (t),
26.5 (q, 19-Me), 26.7 (t), 27.9 (t), 28.0 (d), 29.8 (t), 35.4 (d), 35.7
(t), 36.0 (s), 39.5 (t), 41.2 (t), 41.7 (s), 45.1 (s), 46.0 (d), 51.8 (s),
52.1 (s), 52.2 (q, COOMe), 52.5 (q, COOMe), 55.8 (d, 17-C), 69.8
(d, 3-C), 118.2 (d, 11-C), 132.4 (d, 6-C), 139.3 (d, 7-C), 144.2 (s),
145.3 (s), 146.2 (s), 166.7 (s, COOMe), 167.0 (s, COOMe), 170.1 (s,
AcO) ppm. MS (EI): m/z ϭ 566 (10) [Mϩ], 534 (18) [Mϩ Ϫ MeOH],
506 (100) [Mϩ Ϫ AcOH]. C35H50O6 (566.36): calcd. C 74.17, H
8.99; found C 74.41, H 8.19.
ternal standard (CDCl3: H: δ ϭ 7.26 ppm; 13C: δ ϭ 77.00 ppm).
1
Coupling constants are expressed in Hz. The degree of substitution
of the carbon atoms was determined by employing the DEPT-135
technique. Other signal assignments were done by using H,H-
COSY and C,H-correlation by HSQC/HMQC. IR spectra were re-
corded using a Nicolet 320 FT-IR spectrometer or Bruker Tensor
27. UV/Vis spectra were recorded using a Beckman UV 8452A Di-
ode Array Spectrophotometer. Mass spectra were recorded using a
Finnigan MAT 90 spectrometer (EI, 70 eV). Optical rotations were
measured using
a Propol-Digital Automatic Polarimeter, Dr.
Kernchen. Melting points were determined using a Büchi 510 melt-
ing point apparatus and are uncorrected. Dry benzene, absolute
puriss. over molecular sieves, was used as obtained, while dichloro-
methane and Et2O were distilled from CaH2 under nitrogen prior
5α,8α-[1Ј,2Ј-cis-Bis(ethoxycarbonyl)etheno]cholesta-6,9(11)-dien-3β-
to use. Thin layer chromatography was performed using precoated yl Acetate (2b): Elution with CH2Cl2/Et2O (97:3) afforded (2b)
plastic plates, polygram Sil G/ UV254 MachereyϪNagel & Co.
(Düren), while column chromatography was performed on Silica
gel 60 (70Ϫ230 mesh) from Merck. Preparative TLC was per-
[666 mg (30%)], crystallization from methanol gave 385 mg (17%).
M.p. 135 °C. [α]2D0 ϭ Ϫ41.0 (c ϭ 0.485, CHCl3). IR (KBr): nu
(tilde) ϭ 1735 (s), 1720 (s), 1260Ϫ1240 (m) cmϪ1
.
1H NMR
Eur. J. Org. Chem. 2004, 3526Ϫ3534
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3529

L. Bondarenko, Lj. Lorenc, D. Bläser, R. Boese
FULL PAPER
(200 MHz): δ ϭ 0.69 (s, 3 H, 18-Me), 0.86 (d, J ϭ 1.0 Hz, 3 H, 27-
General Procedure for the Epoxidation: A solution of the adduct in
Me), 0.89 (s, J ϭ 1.1 Hz, 3 H, 26-Me), 0.93 (d, J ϭ 5.9 Hz, 3 H, CH2Cl2 was added to an excess (for PTAD adduct a large excess)
21-Me), 1.15 (s, 3 H, 19-Me), 1.26 (t, J ϭ 7.14 Hz, 3 H, EtOCO), of 70% m-chloroperbenzoic acid, and was left at room temperature
1.29 (t, J ϭ 7.08 Hz, 3 H, EtOCO), 2.02 (s, 3 H, AcO), 2.90 (dd, until full consumption of the starting material. The reaction was
J ϭ 4.7, 13.3 Hz, 1 H, 4-H), 2.60 [dd, J ϭ 8.6, 11.7 Hz, 1 H, monitored by TLC in CH2Cl2/Et2O (9:1).The organic solution was
HϪC(12)] 4.21 (m, 4 H, 2 ϫ EtOCO), 4.81 (m, 1 H, 3-H), 5.36 (d, washed with solutions of NaHSO3, NaHCO3, NaCl, and dried
J ϭ 4.8 Hz, 1 H, 11-H), 6.13 (d, J ϭ 7.3 Hz, 1 H, 7-H), 6.46 (d, with anhydrous MgSO4 and the solvents were evaporated to dry-
J ϭ 7.4 Hz, 1 H 6-H) ppm. 13C NMR (50 MHz): δ ϭ 12.4(q, 18- ness. The residue was chromatographed on silica gel when neces-
Me), 13.9 (q, COOEt), 14.0 (q, COOEt), 18.4 (q, 21-Me), 21.2 (q,
AcO), 22.4 (t), 22.5 (q), 22.8(q), 23.7 (t), 26.5 (q), 26.7 (t), 27.9 (t),
28.0(d), 29.8 (t), 35.3(d), 35.6 (t), 35.9 (t), 39.5 (t), 41.2(t), 41.6 (s),
45.1 (s), 45.8(d), 51.7(s), 52.1 (s), 55.8 (d), 61.0 (t, COOEt), 61.6 (t,
COOEt), 69.8 (d, 3-C), 117.9 (d, 11-C), 132.3 (d, 6-C), 139.2(d, 7-
C), 143.7 (s), 145.0(s), 146.3 (s), 166.2 (s, COOEt), 166.6 (s, CO-
OEt), 170.0 (s, AcO) ppm. C37H54O6 (594.83): calcd. C 74.71, H
10.15; found C 74.84, H 9.14.
sary.
5α,8α-[1Ј,2Ј-cis-Bis(methoxycarbonyl)etheno]-9α,11α-epoxycholest-
6-en-3β-yl Acetate (3a): M.p. 158 °C (from ether). [α]2D0 ϭ Ϫ94.3
(c ϭ 1.00, CHCl3). IR (KBr): nu (tilde) ϭ 2955 (s), 2870 (m), 1731
(s), 1241 (s) cmϪ1. 1H NMR (400 MHz): δ ϭ 0.81 (s, 3 H, 18-Me),
0.86 (d, J ϭ 2.2 Hz, 3 H, 27-Me), 0.88 (d, J ϭ 2.3 Hz, 3 H, 26-
Me), 0.91 (d, J ϭ 6.3 Hz, 3 H, 21-Me), 1.05 (s, 3 H, 19-Me), 2.03
(s, 3 H, AcO), 3.06 (d, J ϭ 5.5 Hz, 1 H, 11-H), 3.71 (s, 3 H, CO-
OMe), 3.82 (s, 3 H, COOMe), 4.75 (m, 1 H, 3-H), 6.29 (d, J ϭ
7.5 Hz, 1 H, 6-H, 6.38 (d, J ϭ 6.9 Hz, 1 H, 7-H) ppm. 13C NMR
(100 MHz): δ ϭ 16.1 (q, 18-Me), 18.4 (q, 21-Me), 21.2 (q, AcO),
21.8 (t), 22.5 (q, 19-Me), 22.8 (q, 26-Me), 22.8 (q, 27-Me), 23.6 (t),
25.6 (t), 27.8 (t), 28.0 (d), 30.7 (t), 31.7 (t), 35.0 (d), 35.8 (t), 39.4
(t), 40.3 (d), 40.4 (t), 41.5 (s), 42.0 (s), 50.8 (s), 51.3 (s), 52.1 (q,
COOMe), 52.5 (q, COOMe), 55.3 (d), 56.0 (d), 69.4 (s, 9-C), 73.1
(d, 3-C), 132.2 (d, 7-C), 142.1 (d), 145.7 (s), 145.8 (s), 165.9 (s),
167.0 (s), 170.0 (s) ppm. MS (EI): m/z ϭ 582.6 (19) [Mϩ], 550.6
5α,8α-(3,5-Dioxo-4-oxacyclopentane-1,2-diyl)cholesta-6,9(11)-dien-
3β-yl Acetate (2c): M.p. 178Ϫ179 °C (ref.[16a] 181Ϫ182 °C). IR (Di-
amant-ATR): nu (tilde) ϭ 1859 (s), 1771 (s), 1730 (s), 1252 (s), 1092
1
(m), 1078 (m), 1027 (s), 953 (m), 930 (s), 915 (s) cmϪ1. H NMR
(400 MHz): δ ϭ 0.61 (s, 3 H, 18-Me), 0.86 (d, J ϭ 2.1 Hz, 3 H, 26-
Me), 0.88 (d, J ϭ 2.1 Hz, 3 H, 27-Me), 0.92 (d, J ϭ 6.5 Hz, 3 H,
21-Me), 1.08 (s, 3 H, 19-Me), 2.07 (s, 3 H, AcO), 2.79 (d, J ϭ
8.8 Hz, 1 H, 1Ј-H), 2.85 (m, 1 H, 4-Hα), 3.49 (d, J ϭ 8.7 Hz, 1 H,
2Ј-H), 5.44 (dd, J ϭ 7.2, 1.7 Hz, 1 H, 11-H), 5.94 (d, J ϭ 8.6 Hz,
1 H, 7-H), 6.32 (d, J ϭ 8.6 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz): δ ϭ 12.1 (q, 18-Me), 18.6 (q, 21-Me), 21.3 (q, AcO),
22.1 (t), 22.6 (q, 26-Me), 22.8 (q, 27-Me), 23.8 (t), 26.4 (q, 19-Me),
26.8 (t), 28.0 (d), 28.1 (t), 30.1 (t), 32.8 (t), 35.9 (t), 39.5 (t), 40.7
(t), 41.2 (s), 42.5 (s), 44.0 (d), 45.3 (s), 45.5 (s), 52.2 (d), 54.9 (d),
68.9 (d, 3-C), 119.5 (d, 11-C), 130.1 (d, 6-C), 136.5 (d, 7-C), 147.4
(s), 170.3 (s,), 170.5 (s), 171.3 (s,) ppm. MS (EI): m/z ϭ 424 (5) [Mϩ
Ϫ maleic anhydride (C4H2O3)], 364 (100) [Mϩ Ϫ maleic anhydride
(C4H2O3) Ϫ AcOH].
(60) [Mϩ Ϫ CH4O], 522.6 (38) [Mϩ Ϫ AcOH], 490.5 (100) [Mϩ
Ϫ
AcOH Ϫ CH4O], 458.5 (58) [Mϩ Ϫ AcOH Ϫ 2 ϫ CH4O]. HRMS
(EI) [Mϩ] (C35H50O7): calcd. 582.3557; found 582.3546.
5α,8α-[1Ј,2Ј-cis-Bis(ethoxycarbonyl)etheno]-9α,11α-epoxycholest-6-
en-3β-yl Acetate (3b): M.p. 132Ϫ133 °C (from methanol). [α]2D0
ϭ
Ϫ87.3 (c ϭ 0.795, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 1720
(s), 1255 (s), 1236 (s), 1030 (s) cmϪ1 1H NMR (400 MHz): δ ϭ
.
0.77 (s, 3 H, 18-Me), 0.86 (d, J ϭ 2.2 Hz, 3 H, 26-Me), 0.88 (d,
J ϭ 2.2 Hz, 3 H, 27-Me), 0.91 (d, J ϭ 6.3 Hz, 3 H, 21-Me), 1.26
(t, J ϭ 7.1 Hz, 3 H, COOEt), 1.31 (t, J ϭ 7.2 Hz, 3 H, COOEt),
2.02 (s, 3 H, AcO), 2.10 (m, 1 H, 12-H), 2.80 (m, 1 H, 2-H), 2.88
(m, 1 H, 4-H), 3.05 (d, J ϭ 5.5 Hz, 1 H, 11-H), 4.17 (q, J ϭ 7.0 Hz,
2 H, COOEt), 4.23 (m, 1 H, COOEt), 4.33 (m, 1 H, COOEt), 4.78
(m, 1 H, 3-H), 6.29 (d, J ϭ 7.5 Hz, 1 H, 7-H), 6.39 (d, J ϭ 7.6 Hz,
1 H, 6-H) ppm. 13C NMR(100 MHz): δ ϭ 13.8 (q, COOEt), 13.9
(q, COOEt), 16.1 (q, 18-Me), 18.4 (q, 21-Me), 21.2 (q, AcO), 21.8
(t), 22.5 (q, 26-Me), 22.7 (q, 27-Me), 22.8 (q, 19-Me), 23.6 (t), 25.6
(t), 27.8 (t), 27.9 (d), 30.6 (t), 31.6 (t), 35.0 (d), 35.8 (t), 39.4 (t),
40.2 (d), 40.5 (t), 41.5 (s), 42.0 (s), 50.6 (s), 51.2 (s), 55.2 (d), 56.1
(d), 61.1 (t, COOEt), 61.6 (t, COOEt), 69.5 (d), 73.1 (s), 132.2
[d,C(7)], 142.1 [d, C(8)], 145.3 (s), 145.4 (s), 165.5 (s), 166.6 (s),
5α,8α-(3,5-Dioxo-4-phenyl-1,2,4-triazolidine-1,2-diyl)cholesta-
6,9(11)-dien-3β-yl Acetate (2d): A solution of 4-phenyl-1,2,4-triazo-
line-3,5-dione (ca. 300 mg) in dry acetone (10 mL) was added drop-
wise to a stirred and cooled (Ϫ10 °C) solution of cholesta-
5,7,9(11)-trien-3β-yl acetate (758 mg, 1.34 mmol) in CH2Cl2 (10
mL, abs.) until the solution remained pink. The solution was fil-
tered through neutral Al2O3, concentrated and chromatographed.
Recrystallization from methanol gave the pure product. M.p.
134Ϫ135 °C. [α]2D0 ϭ ϩ16.0 (c ϭ 1.00, CHCl3). IR (Diamant-ATR):
nu (tilde) ϭ 1761 (m), 1731 (m), 1702 (s), 1399 (s), 1364 (s), 1240
(s), 1024 (s) cmϪ1. 1H NMR (400 MHz): δ ϭ 0.69 (s, 3 H, 18-Me),
0.86 (d, J ϭ 1.8 Hz, 3 H, 26-Me), 0.87 (d, J ϭ 1.9 Hz, 3 H, 27-
Me), 0.93 (d, J ϭ 6.0 Hz, 3 H, 21-Me), 1.17 (s, 3 H, 19-Me), 2.02
(s, 3 H, AcO), 2.33Ϫ2.45(m, 2 H, 12-H), 2.75 (dd, J ϭ 7.4, 12.0 Hz,
1 H, 4-H), 5.40 (m, 1 H, 3-H), 5.60 (dd, J ϭ 1.7, 6.9 Hz, 1 H, 11-
H), 6.22 (d, J ϭ 8.3 Hz, 1 H, 7-H), 6.53 (d, J ϭ 8.4 Hz, 1 H, 6-H),
169.9 (s) ppm. MS (EI): m/z ϭ 610 (18) [Mϩ], 564 (64) [Mϩ
Ϫ
C2H6O], 550 (25) [Mϩ Ϫ AcOH], 504 (100) [Mϩ Ϫ AcOH Ϫ
C2H6O], 458 (68) [Mϩ Ϫ AcOH Ϫ 2 ϫ C2H6O]. C37H54O7 (610.83):
calcd. C 72.74, H 8.93; found C 73.13, H 9.10.
5α,8α-[1Ј,2Ј-cis-Bis(ethoxycarbonyl)etheno]-6,7β,9α,11α-diepoxy-
7.27Ϫ7.34 (m, 1 H Ph), 7.37Ϫ7.47 (m, 4 H, Ph) ppm. 13C NMR cholest-3β-yl Acetate (3b’):[16] M.p. 146 °C. [α]2D0 ϭ Ϫ72.0 (c ϭ 1.00,
(100 MHz): δ ϭ 12.5 (q, 18-Me), 18.6 (q, 21-Me), 21.3 (q, AcO), CHCl3). IR (ATR): nu (tilde) ϭ 1737 (m), 1714 (s), 1382 (m), 1365
1
22.5 (q, 26-Me), 22.8 (q, 27-Me), 22.9 (t), 23.7 (t), 25.2 (q, 19-Me),
(m), 1256 (s), 1020 (s) cmϪ1. H NMR (200 MHz): δ ϭ 0.87 (d, 3
26.7 (t), 27.6 (t), 28.0 (d), 30.7 (t), 32.3 (t), 35.3 (d), 35.8 (t), 39.5 H, 26-Me), 0.90 (d, 3 H, 27-Me), 0.90 (d, 3 H, 21-Me), 0.90 (s, 3
(t), 40.5 (t), 41.4 (s), 43.3 (s), 47.5 (d), 54.9 (d), 64.3 (s), 65.8 (t), H, 18-Me), 1.25Ϫ1.34 (m, 7 H, 19-Me), 2 ϫ COOEt), 2.60 (m, 1
66.0 (s), 70.4 (d, 3-C), 122.0 (d, 11-C), 126.0 (d, Ph), 127.8 (d, Ph), H, 12-H), 3.10 (m, 1 H, 4-H), 3.08 (d, J ϭ 5.4 Hz, 1 H, 11-H), 3.15
128.8 (d, Ph), 129.3 [d, C(6)], 131.6 (s, PhϪN), 133.9 (d, 7-C), 141.7
(d, J ϭ 4.0 Hz, 1 H, 7-H), 3.58 (d, J ϭ 4.1 Hz, 1 H, 6-H), 4.12Ϫ4.39
(s, 9-C), 150.3 (s, CO), 151.4 (s, CO), 170.0 (s, AcO) ppm. MS
(m, 4 H, COOEt), 4.60(m, 1 H, 3-H) ppm. 13C NMR (50 MHz):
(EI): m/z ϭ 424 (10) [Mϩ Ϫ C8H5N3O2 (PTAD)], 364 (100) [Mϩ δ ϭ 13.9 (q), 13.9 (q), 17.7 (q), 18.3 (q), 19.9 (q), 21.2 (q), 21.6 (t),
Ϫ C8H5N3O2 (PTAD) Ϫ AcOH]. C37H49N3O4 (599.75): calcd. C
74.08, H 8.25, N 7.00; found C 74.00, H 8.31, N 7.19.
22.5 (q), 22.8 (q), 23.6 (t), 25.8 (t), 27.6 (t), 28.0 (d), 31.5 (t), 34.9
(d), 35.7 (t), 39.4 (t), 39.6 (s), 40.1 (t), 40.2 (d), 41.7 (s), 45.4 (d),
3530
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3526Ϫ3534

Synthesis of Novel 5α,9α-Bridged Steroids
FULL PAPER
47.4 (s), 47.9 (s), 52.1 (d), 55.6(d), 55.9 (d), 61.3 (t), 61.6 (t), 69.4 51.1 (q, COOMe), 52.3 (q, COOMe), 56.2 (d), 56.2 (d), 56.3 (d, 3-
(d), 70.1 (s), 134.7 (s), 137.2 (s), 164.7 (s), 166.0 (s), 169.9 (s) ppm. C), 70.1 (d, 11-C), 70.8 (s, 9-C), 141.8 (s), 142.3 (s), 166.0 (s), 167.2
MS(EI): m/z ϭ 626.5 (11) [Mϩ], 610.5 (10) [Mϩ Ϫ O], 598.5 (45) (s), 170.0 (s) ppm. MS (EI): m/z ϭ 584 (5) [Mϩ], 552 (35) [Mϩ
Ϫ
[Mϩ Ϫ CO] 581.4 (100) [Mϩ Ϫ C2H5O]. HRMS (EI) [Mϩ] MeOH], 492 (50) [Mϩ Ϫ MeOH Ϫ AcOH], 460 (70) [Mϩ Ϫ 2 ϫ
(C37H54O8): calcd. 626.3819; found 626.3804.
MeOH Ϫ AcOH]. HRMS (EI) [Mϩ] (C35H52O7): calcd. 584.3713;
found 584.3717.
5α,8α-(3,5-Dioxo-4-oxacyclopentane-1,2-diyl)-9α,11α-epoxycholest-
6-en-3β-yl Acetate (3c): M.p. 170 °C (from methanol). [α]2D0
ϭ
5α,8α-(3,5-Dioxo-4-oxacyclopentane-1,2-diyl)-9α,11α-epoxychol-
estan-3β-yl Acetate (4c): M.p. 186 °C (from methanol). [α]2D0 ϭ ϩ6.8
ϩ98.9 (c ϭ 1.00, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 1846
(w), 1780 (s), 1736 (s), 1720 (s), 1240 (s), 1209 (m) cmϪ1. 1H NMR (c ϭ 1.00, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 1778 (s), 1735
(400 MHz): δ ϭ 0.69 (s, 3 H, 18-Me), 0.86 (d, J ϭ 1.9 Hz, 3 H, 26-
Me), 0.87 (d, J ϭ 1.9 Hz, 3 H, 27-Me), 0.91 (d, J ϭ 6.5 Hz, 3 H,
21-Me), 1.04 (s, 3 H, 19-C), 2.06 (s, 3 H AcO), 2.76 (m, 1 H, 4-
Hα), 3.12 (d, J ϭ 5.9 Hz, 1 H, 11-H), 3.48 (d, J ϭ 8.5 Hz, 1 H, 1Ј-
(s), 1721 (s), 1241 (s), 1213 (s), 1026 (s), 939 (s) cmϪ1 1H NMR
.
(200 MHz): δ ϭ 0.82 (s, 3 H, 18-Me), 0.83 (s, 3 H, 27-M), 0.86 (s,
3 H, 26-Me), 0.86 (d, J ϭ 10.7 Hz, 3 H, 21-Me), 1.24 (s, 3 H, 19-
Me), 2.01 (s, 3 H, AcO), 3.14 (d, J ϭ 5.8 Hz, 1 H, 11-H), 3.26 (d,
H), 3.57 (d, J ϭ 8.5 Hz, 1 H, 2Ј- H), 5.10 (m, 1 H, 3-H), 5.97 (d, J ϭ 10.1 Hz, 1 H, 1Ј-H), 3.52 (d, J ϭ 10.1 Hz, 1 H, 2Ј-H), 4.94 (m,
J ϭ 8.6 Hz, 1 H, 7-H), 6.35 (d, J ϭ 8.7 Hz, 1 H, 6-H) ppm. 13C 1 H, 3-H) ppm. 13C NMR (50 MHz): δ ϭ 16.3 (q), 18.5 (q), 20.7
NMR (100 MHz): δ ϭ 15.0 (q, 18-Me), 18.7 (q, 21-Me), 21.3 (q, (q), 21.1 (t), 21.3 (q), 22.5 (q), 22.7 (q), 23.7 (t), 26.3 (t), 26.4 (t),
AcO), 21.6 (t), 21.9 (q, 19-Me), 22.5 (q, 26-Me), 22.8 (q, 27-Me),
26.9 (t), 27.4 (t), 27.9 (d), 34.1 (t), 35.1 (d), 35.7 (t), 37.3 (s), 38.4
23.7 (t), 25.8 (t), 27.4 (t), 28.0 (t), 30.9 (t), 34.9 (d), 35.8 (t), 39.1 (s), 39.4 (t), 39.6 (t), 39.6 (s), 42.7 (s), 45.0 (d), 48.3 (d), 50.8 (d),
(s), 39.4 (t), 39.6 (t), 42.8 (s), 43.3 (d), 44.6 (s), 45.4 (s), 46.0 (d), 55.5 (d), 57.2 (d), 68.5 (s), 69.0 (d), 170.1 (s), 171.3 (s), 171.7 (s)
50.6 (d), 55.3 (d), 57.5 (d), 68.7 (d, 3-C), 70.1 (s, 9-C), 130.7 (d, 7-
ppm. MS (EI): m/z ϭ 540 (37) [Mϩ], 480 (10) [Mϩ Ϫ AcOH], 442
C), 136.1 (d, 6-C), 170.2 (s), 170.7 (s), 170.9 (s) ppm. MS (EI): (100) [Mϩ Ϫ maleic anhydride (C4H2O3)]. HRMS (EI): m/z ϭ [Mϩ]
m/z ϭ 538 (100) [Mϩ], 520 (68) [Mϩ Ϫ H2O], 505 (63) [Mϩ Ϫ H2O
Ϫ CH3]. HRMS (EI) [Mϩ] (C33H46O6): calcd. 538.3294; found
538.3282.
(C33H48O6): calcd. 540.3451; found 540.3451.
General Procedure for the Rearrangement: About 0.5 mmol of the
adduct was dissolved in a dry solvent (benzene, CH2Cl2 or Et2O;
5α,8α-(3,5-Dioxo-4-phenyl-1,2,4-triazolidine-1,2-diyl)-9α,11α- Table 2) (25 mL) and BF3·Et2O (0.5 mL) was added under nitrogen
epoxycholest-6-en-3β-yl Acetate (3d): M.p. 150Ϫ152 °C (from
or argon and the mixture left at room temp. In benzene solution a
ether). [α]2D0 ϭ ϩ77.4 (c ϭ 1.00, CHCl3). IR (Diamant-ATR): nu fast color change from pink-violet to blue was observed. The reac-
1
(tilde) ϭ 1762 (m), 1731 (m), 1701 (s), 1399 (s), 1239 (s) cmϪ1. H
tion was monitored by TLC in CH2Cl2/Et2O (9:1). Following com-
NMR (400 MHz): δ ϭ 0.79 (s, 3 H, 18-Me), 0.88 (d, J ϭ 1.8 Hz, pletion, ice was added and the mixture extracted with diethyl ether.
3 H, 26-Me), 0.90 (d, J ϭ 1.9 Hz, 3 H, 27-Me), 0.95 (d, J ϭ 6.2 Hz, The organic solution was washed with solutions of NaHCO3,
3 H, 21-Me), 1.13 (s, 3 H, 19-Me), 2.04 (s, 3 H, AcO), 3.28 (d, J ϭ NaCl, and dried with anhydrous MgSO4. The solution was filtered
5.4 Hz, 1 H, 11-H), 5.44 (m, 1 H, 3-H), 6.32 (d, J ϭ 8.3 Hz, 1 H, and the solvents evaporated to dryness. The residue was chromato-
7-H), 6.58 (d, J ϭ 8.4 Hz, 1 H, 6-H), 7.30Ϫ7.34 (m, 1 H, Ph),
7.40Ϫ7.50 (m, 4 H, Ph) ppm. 13C NMR (100 MHz): δ ϭ 15.9 (q,
18-Me), 18.6 (q, 21-Me), 21.2 (q, AcO), 21.4 (q, q, 19-Me), 22.2
(t), 22.5 (q, 26-Me), 22.7 (q, 27-Me), 23.6 (t), 25.3 (t), 27.4 (t), 27.6
(t), 27.9 (d), 31.5 (t), 34.8 (d), 35.7 (t), 39.3 (t), 39.4 (t), 40.3 (s),
42.2 (d), 43.4 (s), 55.3 (d), 57.9 (d, 11-C), 63.9 (s), 66.4 (s), 68.4 (s),
70.1 (d, 3-C), 126.1 (d, Ph), 127.7 (d, Ph), 128.7 (d, Ph), 129.4 (d,
6-C), 131.6 (s, Ph), 134.5 (d, 7-C), 148.4(s, CO), 150.3(s, CO), 169.7
graphed on silica gel if necessary (CH2Cl2/Et2O, 95:5).
5α,9α-[1Ј,2Ј-cis-Bis(methoxycarbonyl)etheno]-11α-hydroxycholesta-
6,8(14)-dien-3β-yl Acetate (5a): M.p. 128 °C (from methanol/pen-
tane). [α]2D0 ϭ ϩ272.4 (c ϭ 1.00, CHCl3). UV (ethanol): λmax. (log
ε) ϭ 238 (4.23), 312 (3.70). IR (KBr): nu (tilde) ϭ 3501 (m), 1734
1
(s), 1725 (s), 1707 (s), 1620 (w), 1265 (m), 1244 (s), 1222 (m). H
NMR (400 MHz): δ ϭ 0.86 (s, 3 H, 27-Me), 0.87 (s, 3 H, 26-Me),
0.92 (s, 3 H, 19-Me), 0.95 (d, J ϭ 6.4 Hz, 3 H, 21-Me), 0.96 (s, 3
H, 18-Me), 2.01 (s, 3 H, AcO), 2.21 (m, 2 H, 12α-H), 2.37 (t, J ϭ
6.7 Hz, 2 H), 2.45 (m, 1 H, 4α-H), 3.73 (d, J ϭ 12 Hz, 1 H, 11α-
OH), 3.74 (s, 3 H, COOMe), 3.80 (s, 3 H, COOMe), 3.95 (dt, J ϭ
4.4, 12.1 Hz, 1 H, 11β-H), 4.60 (m, 1 H, 3-H), 5.61 (d, J ϭ 9.5 Hz,
1 H, 7-H), 5.98 (d, J ϭ 9.4 Hz, 1 H, 6-H) ppm. 13C NMR
(400 MHz): δ ϭ 14.7 (q, 19-Me), 18.7 (q, 21-Me), 19.6 (q, 18-Me),
21.3 (q, AcO), 22.5 (q, COOMe), 22.7 (q, COOMe), 23.8 (t), 25.2
(t), 27.2 (t), 27.7 (t), 27.9 (d), 31.2 (t), 31.5 (t), 34.7 (d), 35.7 (t),
39.4 (t), 43.8 (t), 45.7 (s), 51.2 (s), 52.1 (d), 52.7 (d), 54.3 (s), 56.1
(d), 63.0 (s), 65.7 (d, 11-C), 71.1 (d, 3-C), 120.6 (s), 123.6 (d, 6-C),
131.3 (d, 7-C), 134.9 (s), 148.1 (s), 154.3 (s), 164.9 (s), 169.2 (s),
(s, AcO) ppm. MS (EI): m/z ϭ 615 (2) [Mϩ], 440 (8) [Mϩ
Ϫ
C8H5N3O2], 380 (59) [Mϩ Ϫ C8H5N3O2 Ϫ AcOH], 365 (100) [Mϩ
Ϫ C8H5N3O2 Ϫ AcOH Ϫ CH3]. HRMS (EI) [Mϩ] (C37H49N3O5):
calcd. 615.3672; found 615.3643.
General Procedure for the Hydrogenation:[15] The adduct (0.5 g) was
dissolved in EtOAc (30 mL) and PtO2 (50 mg) was added followed
by hydrogenation at room temp. and atmospheric pressure. The
reaction of the acetylenic adduct 4a was complete after 3 h, and
the maleic anhydride adduct 4c was to 90% hydrogenated after
50 h, and was recrystallized from ether, CH2Cl2, and methanol.
5α,8α-[1Ј,2Ј-cis-Bis(methoxycarbonyl)etheno]-9α,11α-epoxycholest-
3β-yl Acetate (4a): M.p. 65 °C (from methanol). [α]2D0 ϭ Ϫ70.0 (c ϭ
0.60, CHCl3). IR (Diamant.ATR): nu (tilde) ϭ 1724 (s), 1247 (s),
170.1 (s) ppm. MS (EI): m/z ϭ 582.6 (18) [Mϩ], 550.6 (95) [Mϩ
Ϫ
MeOH], 518.5 (55) [Mϩ Ϫ 2 ϫ MeOH], 490.5 (27) [Mϩ Ϫ 2 ϫ
MeOH Ϫ CO], 458.5 (45) [Mϩ Ϫ 2 ϫ MeOH Ϫ AcOH], 431.5 (65)
[Mϩ Ϫ 2 ϫ MeOH Ϫ AcOH Ϫ C2H3]. HRMS (EI) [Mϩ]
(C35H50O7): calcd. 582.3557; found 582.3547.
1
1032 (m), 1018 (m) cmϪ1. H NMR (200 MHz): δ ϭ 0.63 (s, 3 H
27-Me), 0.66 (s, 3 H, 26-Me), 0.66 (s, 3 H, 18-Me), 0.68 (s, 3 H,
21-Me), 0.95 (s, 3 H, 19-Me), 1.79 (s, 3 H, AcO), 2.86 (d, J ϭ
5.1 Hz, 1 H, 11-H), 3.50 (s, 3 H, COOMe), 3.56 (s, 3 H, COOMe), 5α,9α-[1Ј,2Ј-cis-Bis(ethoxycarbonyl)etheno]-11α-hydroxycholesta-
4.41 (m, 1 H, 3-H) ppm. 13C NMR (50 MHz): δ ϭ 17.8 (q), 18.2 6,8(14)-dien-3β-yl Acetate (5b): Pale yellow oil (resin). [α]2D0
(q), 20.6 (t), 21.2 (q), 21.3 (q), 21.5 (t), 22.5 (q), 22.8 (q), 23.7 (t), ϩ219.7 (c ϭ 1.00, CHCl3). UV (ethanol): λmax. (log ε) ϭ 238 (4.12),
26.1 (t), 27.3 (t), 27.9 (d), 30.9 (t), 31.1 (t), 33.4 (t), 35.2 (d), 35.6 316 (3.64). IR (KBr): nu (tilde) ϭ 3468 (w), 1734 (s), 1702 (s), 1617
(t), 38.2 (s), 39.4 (t), 40.2 (t), 41.3 (s), 41.5 (d), 43.1 (s), 44.3 (s), (w), 1280 (s), 1266 (s), 1242 (s), 1054 (s), 1030 (s) cmϪ1. H NMR
ϭ
1
Eur. J. Org. Chem. 2004, 3526Ϫ3534
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3531

L. Bondarenko, Lj. Lorenc, D. Bläser, R. Boese
FULL PAPER
(400 MHz): δ ϭ 0.85 (d, J ϭ 0.94 Hz, 3 H, 27-Me), 0.87 (d, J ϭ (s), 1697 (s), 1275 (s), 1241 (s), 1062 (m), 1031 (s). 1H NMR
0.94 Hz, 3 H, 26-Me), 0.93 (s, 3 H 19-Me), 0.95 (d, J ϭ 6.32 Hz, 3 (400 MHz): δ ϭ 0.86 (d, J ϭ 1.5 Hz, 3 H, 26-Me), 0.87 (d, J ϭ
H, 21-Me), 0.96 (s, 3 H, 18-Me), 1.25 (t, J ϭ 7.1 Hz, 3 H, COOEt), 1.5 Hz, 3 H, 27-Me), 0.88 (s, 3 H, 19-Me) 0.93 (s, 3 H, 18-Me),
1.30 (t, J ϭ 7.2 Hz, 3 H, COOEt), 2.01 (s, 3 H, AcOH), 2.16Ϫ2.30
0.95 (d, J ϭ 6.7 Hz, 3 H, 21-Me), 1.99 (s, 3 H, AcO), 3.62 (d, J ϭ
(m, 2 H, 12-H), 2.37 (t, J ϭ 6.5 Hz, 2 H), 2.46 (m, 1 H, 4α-H), 11.0 Hz, 1 H, 11-OH), 3.75 (s, 3 H, COOMe), 3.82 (s, 3 H, CO-
3.81 (d, J ϭ 11.7 Hz, 1 H, 11α-OH), 3.94 (dt, J ϭ 4.2, 12.0 Hz, 1 OMe), 3.96 (dt, J ϭ 4.5, 11.8 Hz, 1 H, 11-H), 4.65 (m, 1 H, 3-H)
H, 11-H), 4.13Ϫ4.31 (m, 4 H, COOEt), 4.63 (m, 1 H, 3-H), 5.61
ppm. 13C NMR (100 MHz): δ ϭ 15.4 (q, 18-Me), 18.6 (q, 19-Me),
18.8 (q, 21-Me), 21.3 (q, AcO), 22.5 (q, 26-Me), 22.8 (q, 27-Me),
22.8 (t), 23.8 (t), 26.0 (t), 27.2 (t), 27.9 (t), 28.0 (d), 28.4 (t), 31.1
(t), 34.0 (t), 34.5 (d), 35.8 (t), 39.5 (t), 44.5 (s), 45.4 (t), 50.2 (s),
52.0 (q, COOMe), 52.7 (q, COOMe), 53.3 (s), 57.2 (d), 63.6 (s),
66.1 (d, 11-C), 71.3 (d, 3-C), 120.0 (s), 139.3 (s), 146.2 (s), 146.6
(d, J ϭ 9.5 Hz, 1 H, 7-H), 5.97 (d, J ϭ 9.4 Hz, 1 H, 6-H) ppm. 13
C
NMR (100 MHz): δ ϭ 13.9 (q, COOEt), 14.0 (q, COOEt), 14.7 (q,
19-Me), 18.7 (q, 21-Me), 19.6 (q, 18-Me), 21.2(q, AcO), 22.5 (q,
27-Me), 22.7 (q, 26-Me), 23.6 (t), 25.2 (t), 27.2 (t), 27.8 (t), 27.9
(d), 31.2 (t), 31.5 (t), 34.6 (d), 35.7 (t), 39.4 (t), 43.9 (t), 45.7 (s),
51.1 (s), 54.3 (s), 56.0 (d), 61.1 (t, COOEt), 61.9 (t, COOEt), 63.1 (s), 165.9 (s), 168.3 (s), 170.1 (s) ppm. MS (EI): m/z ϭ 584 (5) [Mϩ]
(s), 65.7 (d, 11-C), 71.1 (d, 3-C), 120.8 (s), 123.6 (d, 6-C), 131.4 (d, 566 (20) [Mϩ Ϫ H2O], 552 (50) [Mϩ Ϫ MeOH], 534 (22) [Mϩ
7-C), 134.8 (s), 147.6 (s), 153.9 (s), 164.5 (s), 168.9 (s), 170.0 (s) MeOH Ϫ H2O], 506 (30) [Mϩ Ϫ H2O Ϫ AcOH], 474 (45) [Mϩ
Ϫ
Ϫ
ppm. MS (EI): m/z ϭ 610 (15) [Mϩ], 564 (85) [Mϩ Ϫ EtOH], 518
(35) [Mϩ Ϫ 2 ϫ EtOH], 504 (22) [Mϩ Ϫ EtOH ϪAcOH], 458 (40)
MeOH Ϫ H2O Ϫ AcOH], 460 (50) [Mϩ Ϫ 2 ϫ MeOH Ϫ AcOH],
446 (100) [Mϩ Ϫ MeOH Ϫ H2O Ϫ AcOH Ϫ CO]. HRMS (EI)
[Mϩ Ϫ 2 ϫ EtOH Ϫ AcOH], 431 (55) [Mϩ Ϫ 2 ϫ EtOH Ϫ AcOH [Mϩ] (C33H48O6): calcd. 584.3713; found 584.3712.
Ϫ C2H3]. HRMS (EI) [Mϩ] (C37H54O7): calcd. 610.3870; found
5α,8α-(3,5-Dioxo-4-oxacyclopentan-1,2-diyl)-11-oxocholestan-3β-yl
610.3873.
Acetate (6cЈ): M.p. 201 °C (from ether). [α]2D0 ϭ ϩ60.4 (c ϭ 1.00,
5α,9α-[3,5-Dioxo-4-oxacyclopentane-1,2-diyl]-11α-hydroxycholesta-
6,8(14)-dien-3β-yl Acetate (5c): Pale yellow oil (resin). [α]2D0 ϭ ϩ34.6
(c ϭ 1.00, CHCl3). UV (ethanol): λmax. (log ε) ϭ 260 (4.13). IR
CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 1859 (w), 1833 (w), 1773
1
(s), 1716 (s), 1257 (s), 1222 (s), 1022 cmϪ1. H NMR (400 MHz):
δ ϭ 0.88 (d, J ϭ 5.9 Hz, 3 H, 21-Me), 0.89 (d, J ϭ 2.3 Hz, 3 H,
(Diamant-ATR): nu (tilde) ϭ 1856 (w), 1773 (s), 1721 (m), 1242 (s) 26-Me), 0.89 (s, 3 H, 18-Me), 0.90 (d, J ϭ 2.3 Hz, 3 H, 27-Me),
cmϪ1. 1H NMR (400 MHz): δ ϭ 0.89 (d, J ϭ 2.1 Hz, 3 H 27-Me),
0.90 (d, J ϭ 2.1 Hz, 3 H, 26-Me), 0.97 (s, 3 H, 19-Me), 0.98 (s, 3
1.21 (s, 3 H, 19-Me), 2.05 (s, 3 H, AcO), 2.60 (d, J ϭ 17.4 Hz, 1
H, 12-H), 2.88 (dd, J ϭ 1.9, 10.3 Hz, 1 H, 1Ј-H), 3.13 (s, 1 H, 9-
H, 18-Me), 1.00 (d, J ϭ 5.8 Hz, 3 H, 21-Me), 2.08 (s, 3 H, AcO), H), 3.60 (dd, J ϭ 2.5, 10.3 Hz, 1 H, 2Ј-H), 5.08 (m, 1 H, 3-H) ppm.
2.29Ϫ2.45 (m, 3 H, 2-H, 4-H), 3.86 (d, J ϭ 10.0 Hz, 1 H, 1Ј-H), 13C NMR (100 MHz): δ ϭ 17.3 (q, 19-Me), 18.1 (q, 21-Me ϩ18-
4.05 (dd, J ϭ 3.7, 12.1 Hz, 1 H, 11-H), 4.32 (d, J ϭ 10.0 Hz, 1 H, Me), 21.2 (q, AcO), 21.5 (t), 22.5 (q, 26-Me), 22.8 (q, 27-Me), 23.7
2Ј-H), 5.08 (m, 1 H, 3-H), 5.39 (d, J ϭ 9.6 Hz, 1 H, 7-H), 6.24 (d,
(t), 25.2 (t), 25.5 (d), 26.2 (t), 26.4 (t), 27.8 (t), 28.0 (d), 28.9 (t),
J ϭ 9.6 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz): δ ϭ 16.2 (q, 32.0 (t), 35.3 (t), 37.9 (s), 38.0 (s), 39.3 (s), 43.7 (d), 45.4 (s), 48.7
19-Me), 18.7 (q, 21-Me), 19.6, (q, 18-Me), 21.2 (q, AcO), 22.5 (q,
26-Me), 22.8 (q, 27-Me), 23.9 (t), 25.3 (t), 27.0 (t), 27.4 (t), 27.9
(d), 52.3 (d), 57.3 (d), 57.9 (t), 58.3 (d), 68.6 [d, C(3)], 170.2 (s),
171.9 (s), 212.1 (s, 11-C) ppm. MS (EI): m/z ϭ 540 (4) [Mϩ], 522
(d), 30.5 (t), 32.3 (t), 34.6 (d), 35.6 (t), 39.4 (t), 43.5 (t), 45.1 (s), (2) [Mϩ Ϫ H2O], 480 (100) [Mϩ Ϫ AcOH]. HRMS (EI) [Mϩ]
47.1 (d), 50.3 (s), 50.9 (s), 54.5 (d), 55.1 (d), 59.6 (s), 64.9 (d, 11-
C), 69.1 (d, 3-C), 124.4 (s, 8-C), 127.3 (d, 6-C), 130.9 [d, C(7)],
152.0 [s, C(14)], 170.4 (s), 171.9 (s), 172.6 (s) ppm. MS (EI): m/z ϭ
538 (100) [Mϩ], 520 (95) [Mϩ Ϫ H2O], 505 (90) [Mϩ Ϫ H2O Ϫ
(C33H48O6): calcd. 540.3451; found 540.3452.
5α,9α-(3,5-Dioxo-4-oxacyclopentane-1,2-diyl)-11α-hydroxycholest-
8(14)-en-3β-yl Acetate (5cЈ): Colorless oil (resin). [α]2D0 ϭ ϩ75.5
(c ϭ 1.02, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 3454 (w), 1853
CH3], 460 (20) [Mϩ ϪH2O
Ϫ
AcOH]. HRMS (EI) [Mϩ]
(w), 1773 (s), 1718 (s), 1238 (s), 1210 (s), 1027 (s) cmϪ1. H NMR
1
(C33H46O6): calcd. 538.3294; found 538.3292.
(400 MHz): δ ϭ 0.89 (d, J ϭ 2.2 Hz, 3 H, 27-Me), 0.91 (d, J ϭ
2.2 Hz, 3 H, 26-Me), 0.93 (s, 3 H, 19-Me), 0.98 (d, J ϭ 6.9 Hz, 3
H, 21-Me), 0.99 (s, 3 H, 18-Me), 2.06 (s, 3 H AcO), 3.74 (d, J ϭ
11.5 Hz, 1 H, 1Ј-H), 4.03 (t, J ϭ 8.1 Hz, 1 H, 11-H), 4.42 (d, J ϭ
5α,8α-(3,5-Dioxo-4-oxacyclopentane-1,2-diyl)-11-oxocholest-6-en-
3β-yl Acetate (6c): M.p. 223 °C (from ether). [α]2D0 ϭ ϩ40.0 (c ϭ
1.00, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 1861 (w), 1835 (w),
1776 (s), 1720 (s), 1261 (s), 1222 (s), 1027 (s) cmϪ1 1H NMR 11.5 Hz, 1 H, 2Ј-H), 5.00 (m, 1 H, AcO) ppm. 13C NMR
.
(400 MHz): δ ϭ 0.86 (d, J ϭ 2.4 Hz, 3 H, 27-Me), 0.86 (d, J ϭ (100 MHz): δ ϭ 17.2 (q, 18-Me), 18.7 (q, 21-Me), 19.0 (q, 19-Me),
6.0 Hz, 3 H, 21-H), 0.88 (d, J ϭ 2.3 Hz, 3 H, 26-Me), 1.06 (s, 3 H, 21.2 (q, AcO), 22.2 (t), 22.5 (q, 26-Me), 22.8 (q, 27-Me), 23.9 (t),
18-Me), 1.15 (s, 3 H, 19-Me), 2.05 (s, 3 H, AcO), 2.34 (d, J ϭ 26.1 (t), 27.0 (t), 27.6 (t), 27.9 (d), 29.9 (t), 31.1 (t), 34.6 (d), 35.7
7.3 Hz, 1 H), 2.56 (d, J ϭ 7.29 Hz, 1 H 12-H), 2.86 (s, 1 H, 9-H), (t), 36.0 (t), 39.4 (t), 44.2 (s), 44.7 (t), 46.5 (d, 2Ј-C), 49.1 (s), 49.7
2.89 (d, J ϭ 8.8 Hz, 1 H, 1Ј-H), 3.58 (d, J ϭ 8.7 Hz, 1 H, 2Ј-H),
(d. 1Ј-C)), 50.4 (s), 56.0 (d), 60.1 (s), 65.2 (d, 11-C), 69.3 (d, 3-C),
5.16 (m, 1 H, 3-H), 6.02 (d, J ϭ 8.6 Hz, 1 H, 7-H), 6.42 (d, J ϭ 122.0 (s, 8-C), 146.9 (s, 14-C), 170 (s), 172.6 (s), 172.9 (s) ppm. MS
8.6 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz): δ ϭ 17.3 (q), 18.3
(q), 21.3 (q), 22.5 (q), 22.7 (t), 22.8 (q), 23.8 (t), 26.5 (t), 27.5 (q),
28.0 (d), 28.4 (t), 28.9 (t), 30.0 (t), 35.4 (t), 35.5 (d), 38.5 (s), 39.4
(t), 43.9 (d), 44.2 (s), 44.7 (s), 45.6 (s), 47.7 (d), 51.7 (d), 57.9 (d),
58.9 (d), 59.0 (t), 68.3 (d, 3-C), 130.6 (d, 6-C), 137 (d, 7-C), 170.2
(s), 170.8 (s), 170.9 (s), 211.4 (s, 11-C) ppm. MS (EI): m/z ϭ 538
(4) [Mϩ], 478 (35) [Mϩ Ϫ AcOH], 380 (100) [Mϩ Ϫ AcOH Ϫ
maleic anhydride (C4H2O3)]. HRMS (EI) [Mϩ] (C33H46O6): calcd.
538.3294; found 538.3276.
(EI): m/z ϭ 540 (10) [Mϩ], 522 (36) [Mϩ Ϫ H2O], 447 (100) [Mϩ
Ϫ H2O Ϫ AcOH Ϫ CH3]. HRMS (EI) [Mϩ] (C33H48O6): calcd.
540.3451; found 540.3447.
5α,9α-(3,5-Dioxo-4-phenyl-1,2,4-triazolidine-1,2-diyl)-11α-hydroxy-
cholest-6,8(14)-dien-3β-yl Acetate (5d): Colorless oil (resin). [α]2D0
ϭ
ϩ404.0 (c ϭ 0.85, CHCl3). UV (ethanol): λmax. (log ε) ϭ 204 (5.28),
222 (4.29), 270 (4.17). IR (Diamant-ATR): nu (tilde) ϭ 3478 (w),
1762 (m), 1710 (s), 1398 (s), 1362 (m), 1238 (s) cmϪ1 1H NMR
.
(400 MHz): δ ϭ 0.85 (d, J ϭ 1.9 Hz, 3 H, 26-Me), 0.87 (d, J ϭ
5α,9α-[1Ј,2Ј-cis-Bis(methoxycarbonyl)etheno]-11α-hydroxycholest- 1.9 Hz, 3 H, 27-Me), 0.93 (s, 3 H, 19-Me), 0.98 (d, J ϭ 0.98 Hz, 3
8(14)-en-3β-yl Acetate (5aЈ): Colorless oil (resin). [α]2D0 ϭ ϩ197.9
H, 21-Me), 1.03 (s, 3 H, 18-Me), 2.04 (s, 3 H, AcO), 2.92-2-97 (m,
(c ϭ 1.00, CHCl3). IR (Diamant-ATR): nu (tilde) ϭ 3441 (w), 1729 1 H, 4-H), 4.04 (dd, J ϭ 4.7, 12.2 Hz, 1 H, 11-H), 5.26 (m, 1 H, 3-
3532
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3526Ϫ3534

Synthesis of Novel 5α,9α-Bridged Steroids
FULL PAPER
H), 5.28 (d, J ϭ 16.6 Hz, 1 H, 11-OH), 5.60 (d, J ϭ 9.6 Hz, 1 H,
Ϫ AcOH], 458.4 (40) [Mϩ Ϫ AcOH Ϫ EtOH], 431.4 (100) [Mϩ
Ϫ
7-H), 6.30 (d, J ϭ 9.5 Hz, 1 H, 6-H), 7.30Ϫ7.37 (m, 1 H, Ph), AcOH Ϫ EtOH Ϫ C2H3]. C35H48O6 (564.35): calcd. C 74.44, H
7.38Ϫ7.45 (m, 4 H, Ph) ppm. 13C NMR(100 MHz): δ ϭ 15.0 (q, 8.57; found C 74.60, H 8.57.
18-Me), 18.7 (q, 21-Me), 18.8 (q, 19-Me), 21.2 (q, AcO), 22.5 (q,
26-Me), 22.8 (q, 27-Me), 23.9 (t), 25.5 (t), 26.9 (t), 27.7 (t), 28.0
(d), 29.6 (t), 32.8 (t), 34.5 (d), 35.7 (t), 39.4 (t), 42.5 (t), 45.0 (s),
49.2 (s), 55.5 (d), 64.4 [d, C(11)], 68.7 (s, 5-C), 70.0 (d, 3-C), 71.8
5α,9α-[1Ј-cis-Bis(ethoxycarbonyl)etheno]-11α,2Ј-lactonocholesta-
7,14-dien-3β-yl Acetate (8b): Pale yellow oil. IR (KBr): nu (tilde) ϭ
1
1771 (s), 1734 (s), 1266 (s), 1242 (s) cmϪ1. H NMR (400 MHz):
δ ϭ 0.79 (d, J ϭ 2.4 Hz, 3 H, 27-Me), 0.81 (d, J ϭ 2.4 Hz, 3 H,
26-Me), 0.83 (s, 3 H, 19-Me), 0.88 (d, J ϭ 6.6 Hz, 3 H, 21-Me),
1.12 (s, 3 H, 18-Me), 1.27 (t, J ϭ 7.1 Hz, 3 H, COOEt), 1.95 (s, 3
H, AcO), 2.08 (dd, J ϭ 3.1, 20.0 Hz, 1 H, 6-H), 2.45 (dd, J ϭ 3.8,
(s, 9-C), 121.6 (s), 125.6 (d, 7-C), 125.7 (d, Ph), 128.0 (d, 6-C),
128.2 (d, Ph), 129.0 (d, Ph), 131.6 (s, Ph), 153.3 (s), 155.3 (s, CO),
155.7 (s, CO), 170.1 (s, AcO) ppm. MS (EI): m/z ϭ 615 (75) [Mϩ],
379 (62) [Mϩ
Ϫ AcOH Ϫ
C8H6N3O2]. HRMS (EI) [Mϩ]
19.9 Hz, 1 H, 6-H), 2.29Ϫ2.39 (m, 2 H 16-H), 2.43Ϫ2.58 (m, 2 H,
12-H), 4.23 (dq, J ϭ 1.7, 7.1 Hz, 2 H, COOEt), 4.54Ϫ4.64 (m, 2
H, 11-H, 3-H), 5.53 (d, J ϭ 1.7 Hz, 1 H, 15-H), 5.60 (dd, J ϭ 3.4,
3.7 Hz 1 H, 7-H) ppm. 13C NMR (100 MHz): δ ϭ 14.0 (q, CO-
OEt), 15.8 (q, 18-Me), 18.7 (q, 21-Me), 21.2 (q, AcO), 22.5 (q, 26-
Me), 22.8 (q, 27-Me), 23.1 (q, 19-Me), 23.9 (t), 28.0 (d), 28.1 (t),
30.2 (t), 33.3 (t), 34.1 (t), 34.4 (d), 35.6 (t), 35.8 (t), 39.5 (t), 39.7
(t), 43.6 (s), 47.4 (s), 58.1 (d), 59.4 (s), 61.5 (s), 62.4 (t,
CH3CH2OCO), 70.5 (d), 77.0 (d, 11-C), 120.7 (d), 123.6 (d), 134.3
(s), 135.9 (s), 146.4 (s), 150.1 (s), 161.8 (s), 162.9 (s), 170.0 (s) ppm.
MS (EI): m/z ϭ 564 (25) [Mϩ], 458 (24) [Mϩ Ϫ AcOH Ϫ EtOH,],
411 (100). HRMS (EI) [Mϩ] (C35H48O6): calcd. 564.3451; found
(C37H49N3O5): calcd. 615.3672; found 615.3666.
General Procedure for the Lactonization: A solution of the alcohol
adduct was heated at reflux in benzene or xylene with or without
addition of a catalytic amount of p-toluenesulfonic acid (Table 3).
The reaction was monitored by TLC in CH2Cl2/Et2O (9:1). After
completion of the reaction, diethyl ether was added to the mixture
resulting solution was washed with water, solutions of NaHCO3
and NaCl, and dried with anhydrous MgSO4. The mixture was
purified by preparative TLC developing several times in CH2Cl2/
Et2O (95:5).
5α,9α-[1Ј-cis-Bis(methoxycarbonyl)etheno]-11α,2Ј-lactono- 564.3424.
cholesta-6,8(14)-dien-3β-yl Acetate (7a): M.p. 129Ϫ130 °C (pale
X-ray Crystallography Data Collection and Structure Refinement for
yellow crystals from ethanol/pentane). [α]2D0 ϭ ϩ5.7 (c ϭ 0.92,
CHCl3). UV (ethanol): λmax. (log ε) ϭ 210 (4.01), 244 (4.38), 348
(3.30). IR (KBr): nu (tilde) ϭ 1765 (s), 1737 (s), 1716 (s), 1244 (s),
5a: A colorless single crystal (0.28 ϫ 0.22 ϫ 0.14 mm) of C35H50O7
(582.75) was measured at 203(2) K with a Siemens SMART CCD
1 K system. Cell dimensions: a ϭ 7.709(2), b ϭ 8.647(3), c ϭ
1
1231 (s), 1099 (s), 1076 (m), 1030 (s) cmϪ1. H NMR (400 MHz):
12.797(4), α ϭ 73.939(6), β ϭ 85.231(6), γ ϭ 82.784(6), V ϭ
δ ϭ 0.86 (d, J ϭ 1.3 Hz, 3 H, 27-Me), 0.88 (d, J ϭ 1.4 Hz, 3 H,
26-Me), 089 (s, 3 H, 19-Me), 0.97 (d, J ϭ 6.5 Hz, 3 H, 21-Me),
1.04 (s, 3 H, 18-Me), 2.02 (s, 3 H, AcO), 2.33Ϫ2.50 (m, 3 H, 2-H,
4-H), 2.64 (q, J ϭ 7.0 Hz, 1 H, 12-H), 3.89 (s, 3 H, COOMe), 4.68
(m, 1 H, 3-H), 4.76 (dd, J ϭ 7.0, 8.9 Hz, 1 H, 11-H), 5.64 (d, J ϭ
9.5 Hz, 1 H, 7-H), 6.01 (d, J ϭ 9.4 Hz, 1 H, 6-H) ppm. 13C NMR
(100 MHz): δ ϭ 17.1 (q, 18-Me), 18.9 (q, 21-Me), 19.0 (q, 19-Me),
21.2 (q, AcO), 22.5 (q, 27-Me), 22.8 (q, 26-Me), 23.7 (t), 25.7 (t),
27.0 (d), 27.3 (t), 28.0 (d), 28.7 (t), 31.3 (t), 34.5 (d), 35.8 (t), 39.4
(t), 43.2 (s), 43.7 (t), 52.5 (d), 55.2 (d), 58.1 (s), 60.6 (s), 60.8 (s),
70.4 [d, C(3)], 74.3 (d, 11-C), 120.9 (s), 123.9 (d, 6-C), 130.5 (d, 7-
C), 139.3 (s), 148.3 (s), 152.6 (s), 162.8 (s), 163.1 (s), 170.0 (s) ppm.
MS (EI): m/z ϭ 550 (33) [Mϩ], 518 (60) [Mϩ Ϫ MeOH], 431 (100)
[Mϩ Ϫ MeOH Ϫ MeOCOHCH2]. HRMS (EI) [Mϩ] (C34H46O6):
calcd. 550.3294; found 550.3287.
3
812.3(4) A , ρ ϭ 1.191 g·cmϪ3. Triclinic space group P1, 9776
˚
intensities collected (θmax. ϭ 28.46°), 7012 unique (Rint ϭ 0.0196),
6108 observed [I Ͼ 2σ(I)], empirical absorption correction (Bruker
AXS SADABS program multiscan V2.03) max/min transmission
1.00/0.91, Rmerg before/after correction 0.0926/0.0293, absorption
coefficient 0.081 mmϪ1, structure solution with direct methods and
refinement on F2 with Bruker AXS SHELXTL Vers. 5.10 DOS/
WIN95/NT, 379 parameters, GOF ϭ 1.118, R1 ϭ 0.0472, wR2 ϭ
0.1188, all data: R1 ϭ 0.0557, wR2 ϭ 0.1300, w ϭ 1/[σ2(F2o) ϩ
(0.0842·P)2], where P ϭ (F2o ϩ 2F2c)/3, absolute structure parameter
0.1(7) (absolute structure not reliably determined), residual electron
density 0.370 and Ϫ0.200 e·AϪ3, hydrogen treatment: riding model
˚
based on idealized geometries with the 1.2-fold (1.5-fold for methyl
and hydroxy groups) isotropic displacement parameters of the
equivalent Uij values of the corresponding carbon atom. CCDC-
5α,9α-[1Ј-cis-Bis(ethoxycarbonyl)etheno)]-11α,2Ј-lactonocholesta- 231711 contains the supplementary crystallographic data
6,8(14)-dien-3β-yl Acetate (7b): M.p. 147Ϫ148 °C (pale yellow crys-
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
tals from ethanol/pentane). [α]2D0 ϭ ϩ7.8 (c ϭ 0.42, CHCl3).UV
(ethanol): λmax. (log ε) ϭ 212 (2.96), 244 (3.34), 350 (2.31). IR Crystallographic Data Centre, 12 Union Road, Cambridge CB2
(KBr): nu (tilde) ϭ 1763 (s), 1739 (s), 1710 (s), 1295 (s), 1245 (s),
1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; or E-mail:
1
1091 (s), 1076 (s), 1027 (s) cmϪ1. H NMR (400 MHz): δ ϭ 0.79 deposit@ccdc.cam.ac.uk].
(d, J ϭ 1.4 Hz, 3 H, 27-Me), 0.81 (d, J ϭ 1.4 Hz, 3 H, 26-Me),
0.82 (s, 3 H, 19-Me), 0.91 (d, J ϭ 6.5 Hz, 3 H, 21-Me), 0.97 (s, 3
H, 18-Me), 1.29 (t, J ϭ 7.1 Hz, 3 H, COOEt), 1.94 (s, 3 H, AcO),
Acknowledgments
Financial support of this work by the Deutsche Forschungsgemein-
schaft (fellowship to L. B.) and Prof. H. Hopf is gratefully acknowl-
edged.
2.26Ϫ2.43 (m, 3 H, 2-H, 4-H), 2.56 (q, J ϭ 7.0 Hz, 1 H, 12-H),
4.28 (q, J ϭ 7.1 Hz, 2 H, COOEt), 4.64 (m, 1 H, 3-H), 4.68 (dd,
J ϭ 7.0, 8.8 Hz, 1 H, 11-H), 5.57 (d, J ϭ 9.5 Hz, 1 H, 7-H), 5.93
(d, J ϭ 9.4 Hz, 1 H, 6-H) ppm. 13C NMR (100 MHz): δ ϭ 14.0
(q, COOEt), 17.1 (q, 18-Me), 18.9 (q, 21-Me), 19.1 (q, 19-Me), 21.2
(q, AcO), 22.5(q, 27-Me), 22.7 (q, 26-Me), 23.7 (t), 25.7 (t), 27.0
(t), 27.3 (t), 27.9 (d), 28.6 (t), 31.3 (t), 34.5 (d), 35.7 (t), 39.4 (t),
43.1 (s), 43.6 (t), 55.1 (d), 57.9 (s), 60.6 (s), 60.7 (s), 61.7 (t), 70.4
(d, 3-C), 74.2 (d, 11-C), 120.9 (s), 123.8 (d), 130.6 (d), 139.0 (s),
148.6 (s), 152.4 (s), 162.6 (s), 162.7 (s), 169.9 (s) ppm. MS (EI):
m/z ϭ 564.4 (50) [Mϩ], 518.4 (58) [Mϩ Ϫ EtOH], 504.4 (30) [Mϩ
[1]
H. B. Henbest, T. I. Wrigley, J. Chem. Soc. 1957, 4596Ϫ4604.
[2] [2a]
V. Cornel, in Handbook of Reagents for Organic Synthesis:
Acidic and Basic Reagents (Ed.: J. Reich, J. H. Rigby), Wiley,
Chichester 2000, p. 50Ϫ59.
Organic Synthesis (Ed.: H. Yamamoto),Wiley-VCH, Weinheim,
[2b]
K. Ishihara, in: Lewis Acid in
[2c]
2000, vol. 1, p. 101Ϫ104.
629Ϫ656.
J. G. Smith, Synthesis 1984,
[3] [3a]
M. Nakatani, M. Nakamura, A. Suzuki, M. Inoue, T. Ka-
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3533
Eur. J. Org. Chem. 2004, 3526Ϫ3534
www.eurjoc.org

L. Bondarenko, Lj. Lorenc, D. Bläser, R. Boese
FULL PAPER
[3b]
toh, Org. Lett. 2002, 4, 4483Ϫ4486.
Q. Cheng, T. Oritani,
Neef, E. Ottow, K. Schollkopf, Steroids 1998, 63, 166Ϫ177. [11c]
W. Halfbrodt, A. Clewe, K. Schoellkopf, W. Schwede, K.-H.
T. Horiguchi, Tetrahedron 1999, 55, 12099Ϫ12108. [3c] H. Hide-
yuki, S. Jun’ichi Kobayashi, Tetrahedron Lett. 1999, 40,
Fritzemier, C. Hegele-Hartung, H.-P. Muhn-Seipoldy, DE
[3d]
[11d]
2149Ϫ2152.
F. J. Parodi, N. H. Fischer, J. Chem. Soc.,
4337416, 1995; Chem. Abstr. 1995, 123, 83834.
E. Ottow,
Chem. Commun. 1986, 1405Ϫ1405. [3e] M. Taran, B. Delmond,
J. Chem. Soc., Cem. Commun. 1984, 716Ϫ718.
R. Wiechert, G. Neef, S. Beier, W. Elger, D. A. Henderson, US
[3f]
T. Nakano,
5095129, 1992; Chem. Abstr. 1992, 117, 131435.
[12]
[12a]
´
A. C. Spinelli, A. Martın, A. Usubillaga, A. T. McPail, K. D.
Onan, Tetrahedron Lett. 1982, 23, 3627Ϫ3630.
J. Wölfling, E. Frank, G. Schneider, L. F. Tietze, Eur. J. Org.
Chem. 2004, 90Ϫ100.
The 7α,15α-bridges:
U. Egner, K.-H. Fritzmeier, W. Half-
brodt, N. Heinrich, J. Kuhnke, A. Muller-Fahrnow, G. Neef,
[4]
[12b]
Tetrahedron 1999, 55, 11267Ϫ11274.
W. K. Chong, W.-R.
Chao, D. M. Yasuda, D. M. Johansson, M. A. Avery, M.
[5] [5a]
[5b]
J. F. Zeelen, Princ. Med. Biol. 1997, 8B, 427Ϫ463.
J. F.
Tanabe, WO 93/255,568, 1993; Chem. Abstr. 1994, 121, 57783.
[12c]
Zeelen, Medicinal Chemistry of Steroids, Elsevier, Amsterdam,
L. G. Bondarenko-Gheorghiu, Lj. B. Lorenc, M. Lj.
[5c]
´
Mihailovic, J. Serb. Chem. Soc. 2000, 65, 147Ϫ156.
[13] [13a]
1990.
R. T. Blickenstaff, Antitumor Steroids, Academic
Press, New York, 1992.
V. Dave, R. Farwaha, P. de Mayo, J. B. Stothers, Can. J.
[6] [6a]
[13b]
J. Fried, J. A. Edwards, Organic Reactions in Steroid Chem-
Chem. 1985, 63, 2401Ϫ2405.
J. F. Blount, G. D. Gray, K.
istry, Van Nostrand Reinhold Company, New York, 1972, vol.
S. Atwal, T. Y. R. Tsai, K. Wiesner, Tetrahedron Lett. 1980,
[6b]
´
R. Skoda-Földes, L. Kollar, Chem. Rev. 2003, 103,
1Ϫ2.
21, 4413Ϫ4416.
[14]
4095Ϫ4129.
J. P. Connolly, S. F. O Muircheartaigh, J. B. Thomson, J. Chem.
Soc. C 1970, 508Ϫ513.
[7] [7a]
S. Bäurle, T. Blume, A. Mengel, C. Parchmann, W. Skub-
alla, S. Bäsler, M. Schäfer, D. Sülzle, H-P. Wrona-Metzinger,
[15] [15a]
F. Ramirez, J. Marecek, S. S. Yemul, J. Org. Chem. 1983,
[7b]
[15b]
Angew. Chem. 2003, 115, 4091Ϫ4094.
E. Winterfeldt, Chi-
Lj. Lorenc, L. Bondarenko-
Gheorghiu, N. Krstic, H. Fuhrer, J. Kalvoda, M. Lj. Mihai-
48, 1417Ϫ1420.
A. van der Gen, J. Lakeman, M. A. M. P.
[7c]
[15c]
mia 1993, 47, 39Ϫ45.
Gras, H. O. Huisman, Tetrahedron 1964, 20, 2521Ϫ2530.
[15d]
´
M. Inhoffen, Chem. Ber. 1954, 87, 146Ϫ159.
M. Deppe, C. Roosen-Runge, Justus Liebigs Ann. Chem. 1939,
537, 1Ϫ10.
A. Windaus,
[7d]
´
lovic, Helv. Chim. Acta 1995, 78, 891Ϫ898.
Lj. Lorenc, L.
´
Bondarenko, V. Pavlovic, H. Fuhrer, G. Rihs, J. Kalvoda, M.
[16] [16a]
´
Lj. Mihailovic, Helv. Chim. Acta 1989, 72, 608Ϫ623.
A. van der Gen, W. A. Zunnebeld, U. K. Pandit, Tetra-
[8]
[9]
J. W. Morzyeki, Pol. J. Chem. 1995, 69, 321Ϫ340.
The 6,19-bridges:
hedron 1965, 21, 3651Ϫ3659. [16b] D. W. Guest, D. H. Williams,
[9a]
[16c]
E. Petrera, M. Joselevich, A. Ghini, G.
J. Chem. Soc., Perkin Trans. 1 1979, 1695Ϫ1697.
A. Abra-
Burton, C. E. Coto, Antiviral Chem. Chemother. 2003, 14,
243Ϫ248. [9b] M. Joselevich, A. Ghini, G. Burton, Org. Biomol.
Chem. 2003, 1, 939Ϫ943.
movitch, P. W. Le Quesne, J. Org. Chem. 1974, 39, 2197Ϫ2201
The use of 77% mCPBA gave also some 9,11:6,7-diepoxides
(3bЈ) causing purification problems. With 70% mCPBA monoe-
poxide is the only product.
[17]
[10]
The 2,19-bridges: [10a] N. P. Peet, J. O. Johnston, J. P. Burkhart,
[10b]
[18]
[19]
US 5491136, 1996; Chem. Abstr. 1996, 124, 289995.
N. P.
J. Brynjolffssen, A. Emke, D. Hands, J. M. Midgley, W. Basil
Whalley, J. Chem. Soc., Chem. Commun. 1975, 633Ϫ633.
H. Seto, S. Fujioka, H. Koshino, S. Takatsuto, S. Yoshida, J.
Chem. Soc., Perkin Trans. 1 2000, 1697Ϫ1703.
Peet, J. O. Johnston, J. P. Burkhart, L. C. Wright, J. Steroid
J. P. Burkhart, E.
W. Huber, F. M. Laskovics, N. P. Peet, J. Org. Chem. 1992, 57,
[10c]
Biochem. Mol. Biol. 1993, 44, 409Ϫ420.
[10d]
5150Ϫ5154.
J. O. Johnston, N. P. Peet, J. P. Burkhart, EP
[20] [20a] Gregory S. Hamilton, in Handbook of Reagents for Organic
488383, 1992; Chem. Abstr. 1992, 117, 131436.
Synthesis: Acidic and Basic Reagents (Ed.: J. Reich, J. H.
[11]
[20b]
The 10,11-bridges: [11a] W. Schewede, W. Halfbrodt, J. Kuhnke,
Rigby), Wiley, Chichester, 2000, p. 402Ϫ405.
E. J. Cory,
R. Krattenmacher, H.-P. Muhn, K.-H. Fritzemier, DE 4413184,
D. J. Brunelle, K. C. Nicolaou, J. Am. Chem. Soc. 1977, 99,
[11b]
1995; Chem. Abstr. 1996, 124, 56404.
W. Schwede, K.-H.
7359Ϫ7360.
Fritzemeier, W. Halfbrodt, R. Krattenmacher, P. Muhn, G.
Received February 23, 2004
3534
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3526Ϫ3534