Diversity-oriented synthesis of enantiomerically pure steroidal tetracycles employing stille/diels-alder reaction sequences

Article abstract of DOI:10.1002/chem.200800601

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0

Full text of DOI:10.1002/chem.200800601

DOI: 10.1002/chem.200800601
Diversity-Oriented Synthesis of Enantiomerically Pure Steroidal Tetracycles
Employing Stille/Diels–Alder Reaction Sequences
Hans Wolf Sünnemann,[a] Martin G. Banwell,[b] and Armin de Meijere*[a]
Abstract: Various steroid analogues
were synthesized by Stille coupling of
N
to promote the relevant cycloaddition
with trans-19 to furnish several stereo-
isomeric forms of trans-28 and trans-29
in significantly lower yields (31–45%).
The selected steroid analogues trans-22
and trans-23 were deprotected in two
steps by using acid catalysis to provide
trans-31 and trans-33 (91 and 80% over
two steps). Cyclopropanation of trans-
30 yielded the cyclopropasteroid ana-
logue 34 (74%), treatment of which
with trifluoroacetic acid furnished the
cyclopropasteroid 35 and the 2-methyl-
substituted steroid analogue 36 in 40
and 12% yield, respectively. Aromatic
B-ring steroids 38 (69%) and 39 (5%)
were accessed by dehydrogenation of
trans-24 with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone.
bicyclo
A
cis-/
trans-8 and 14 with cyclohexenol tri-
flates 17 and 18 and subsequent Diels–
Alder reactions of the resulting dienes.
The enantiomerically pure bicyclo-
A
were prepared in good yields via the
enol triflates cis- and trans-7, obtained
from the bicyclo[4.3.0]non-2-en-3-one
G
5. The alkenylstannane 14 was ob-
tained from the [2+2] cycloadduct 10a
produced from addition of dichloroke-
tene to the enantiomerically pure and
protected bishydroxycyclohexadiene 9a
(65%). Treatment of 10a with diazo-
methane, reduction of the dichloro-
methylene group, and trapping with
tributyltin chloride after lithium-for-
bromine exchange, yielded the bicyclo-
Introduction
application of steroidal compounds is sometimes accompa-
nied by undesired physiological side effects.[4]
Natural steroids and many of their analogues are important
substances with a wide spectrum of biological activities in-
cluding pharmacologically relevant ones.[1] Exploiting both
natural and novel synthetic steroids for use as potential
pharmaceuticals is, therefore, a highly promising research
area in medicinal chemistry.[2,3] However, the therapeutic
Appropriate structural modifications to steroids can lead
to improved therapeutic indices and, therefore, fewer or less
intense physiological side effects.[5] To develop a deeper un-
derstanding of the structure–activity relationships within the
class, a larger number of structurally diverse steroids would
have to be investigated. These can be best obtained by total
synthesis. Interestingly, many classical steroid syntheses are
highly target-oriented and often only lead to single com-
pounds.[5] In view of the demands of pharmaceutical re-
search, an efficient, diversity-oriented steroid synthesis
would be of considerable interest. Therefore, a new ap-
proach to the tetracyclic steroidal framework following a
convergent A+CD!ACD!ABCD synthetic strategy was
designed (Scheme 1). The retrosynthetic concept for this is
based on three building blocks for the A-, C,D-, and B-rings
which, by permutation, allows for a high degree of diversity.
[a] Dr. H. W. Sünnemann, Prof. Dr. A. de Meijere
Institut für Organische und Biomolekulare Chemie der
Georg-August-Universität Gçttingen, Tammannstrasse 2
37077 Gçttingen (Germany)
Fax : (+49)551-399475
E-mail: Armin.deMeijere@chemie.uni-goettingen.de
[b] Prof. Dr. M. G. Banwell
Research School of Chemistry, Institute of Advanced Studies
The Australian National University
Canberra ACT 0200 (Australia)
7236
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FULL PAPER
Scheme 1. Retrosynthetic depiction of a new approach to the steroid
skeleton.
The C,D-rings would be linked to the A-ring by a Stille
cross-coupling reaction, and the B-ring finally completed by
using a Diels–Alder reaction. This approach would lead to
steroidal compounds with substituents at C-6 and C-7, a sub-
stitution type that has rarely been achieved,[6] but neverthe-
less appears to be a particularly interesting one.[7]
Results and Discussion
The necessary building blocks resembling the C,D-ring
Scheme 2. Bicyclo[4.3.0]nonenylstannanes cis-/trans-8 as basic building
blocks for the new steroid synthesis. DIBALH=diisobutylaluminum hy-
dride; HMPT=hexamethylphosphoric triamide.
A
system of the final steroid are bicyclo[4.3.0]non-2-enylstan-
R
nanes of type cis-8 and trans-8. The syntheses of these start
from the readily available and enantiomerically pure Hajos–
Parrish–Wichert–Sauer ketone 5 (Scheme 2).[8] Reduction
with lithium in liquid ammonia and THF as a cosolvent, fol-
lowed by trapping of the so-formed lithium enolate with
chlorotrimethylsilane provided the enol silyl ether cis-6 with
a cis-ring junction in 84% yield.[9]
generated dichloroketene[15] to 9a,b led to the oligofunction-
alized bicycles 10a,b. The iodocyclohexadiene 9b partially
decomposed under the reaction conditions, which resulted
in compound 10b being obtained in only 12% yield. How-
ever, under optimized conditions, the bromodiene 9a fur-
nished the desired bicycle 10a in 65% yield along with the
product of a [4+2] cycloaddition (Scheme 3). At tempera-
tures below 08C, the [2+2] cycloaddition did not take place
at an observable rate. Reductive removal of only one of the
chlorine substituents from 10a under established conditions
(Zn–Cu, MeOH, NH4Cl, RT)[16] could not be achieved, in-
stead some of the fully dehalogenated bicycle 16 was ob-
tained among several other unidentified products. However,
ring-enlargement of the dichlorocyclobutanone moiety
within 10a with diazomethane in the presence of methanol
proceeded smoothly to provide the tetrahydroindanone de-
rivative 11 in 57% yield.[17] The two chlorine atoms were
then cleanly removed with zinc and acetic acid in the pres-
ence of tetramethylethylenediamine to provide the tetrahy-
droindanone 12 (83%).[18] Interestingly, treatment of 11 with
zinc and ammonium chloride selectively furnished the mon-
ochlorotetrahydroindanone 15 as a single diastereomer of
undetermined configuration at the chlorinated carbon
center. The carbonyl group within 12 was protected as the
corresponding 1,3-dioxolane 13, which was obtained by
treatment of 12 with ethylene glycol under p-toluenesulfonic
acid catalysis. To achieve acceptable yields (65%), the reac-
tion had to be performed by using low concentrations of 12,
The corresponding trans-isomer (trans-6) was obtained by
reduction of compound 5 with a copper hydride complex
generated in situ from cuprous bromide–dimethyl sulfide
complex, diisobutylaluminum hydride, and tert-butyllithium.
Trapping of the resulting enolate with chlorotrimethylsilane
then gave trans-6.[10] For optimal diastereoselectivity, the
hexahydroindenone 5 had to be added very slowly. After
cleavage of the enol silyl ethers cis-6 and trans-6 with meth-
yllithium in the presence of 4,4’-bipyridyl and trapping of
the resulting enolates with N,N-bis(trifluoromethanesulfony-
l)aniline,[11] the bicyclo
[4.3.0]nonenol triflates cis-7 and
U
trans-7, respectively, were obtained in excellent yields of 95
and 97%, respectively.[9] The enol triflates cis-7 and trans-7
reacted smoothly with dilithium bis(tri-n-butylstannyl)cya-
nocuprate[12]
to
[4.3.0]nonenylstannanes cis-8 and trans-8 in 92 and 85%
yield, respectively (Scheme 2).
yield
the
tri-n-butylbicyclo-
ACHTREUNG
To extend this methodology so as to be able to access cor-
ticosteroid analogues, the enantiomerically pure bicyclo-
[4.3.0]nonenylstannane 14 was synthesized from the protect-
ed 1-halo-5,6-dihydroxycyclohexa-1,3-dienes 9a,b, which are
readily accessible by microbial oxidation[13] of the corre-
sponding halobenzene and subsequent protection of the re-
sulting diol (Scheme 3).[14] [2+2]-Cycloaddition of in situ
Chem. Eur. J. 2008, 14, 7236 – 7249
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7237

A. de Meijere et al.
(Table 1, entry 2). To achieve such yields, the solvent N-
methylpyrrolidone had to be completely anhydrous. The
yields, based on the starting enol triflate 17 (Scheme 4),
Table 1. Stille couplings of cyclohexenol triflates 17 and 18 with bicyclo-
AHCTREUNG
T [8C]/t Product Yield
[h]
[%][b]
[c]
1
2
3
4
5
6
trans-8
trans-8
trans-8
cis-8
14
17
17
17
17
18
18
trans-19 –
A (5) 90/12
A (5) 90/12
A (5) 90/12
A (5) 65/12
B (5) 65/12
trans-19 57
trans-19 77[d]
cis-19
20
73[d]
[c]
–
14
20
34
[a] A: [Pd2dba3]·CHCl3, CuI, LiCl, NMP; B: as in A, plus 1.00 equiv CuI;
C: as in A, plus AsPh3. [b] Isolated yields. [c] Complete decomposition of
the starting material. [d] The vinylstannane was used in 20% excess.
Scheme 3. A novel protected 4,5-dihydroxy-8-oxobicyclo
A
3-ylstannane 14 as building block for corticosteroid analogues.
a
TMEDA=N,N,N’,N’-tetramethylethylenediamine; pTs=p-toluenesulfon-
yl.
otherwise a significant fraction underwent cleavage of the
acetonide moiety. The lithium-for-bromine exchange on 13
with tert-butyllithium was relatively slow, and for this to go
to completion, the reaction mixture had to be warmed to
ꢀ208C and eventually to 08C to destroy excess tert-butyl-
lithium. The alkenyllithium species was trapped with tri-n-
Scheme 4. Stille coupling reactions leading to tricyclic dienes cis-19 and
trans-19 as well as 20. dba=dibenzylideneacteone; NMP=N-methylpyr-
rolidone.
butyltin chloride to yield the bicyclo[4.3.0]nonenylstannane
U
14 (70%) (Scheme 3).
The necessary Stille-coupling substrates representing the
A-rings in the targeted steroidal skeletons, specifically the
enol triflates 17 and 18,[19] were prepared from cyclohexane-
1,4-dione monoethylene acetal and cyclohexanone, respec-
tively, according to a modified protocol employing sodium
bis(trimethylsilyl)amide (prepared from inexpensive sodium
hydride[20] and bis(trimethylsilyl)amine) to generate the re-
spective enolate, and trifluoromethanesulfonic acid (triflic)
anhydride in diethyl ether to trap the enolate. Unlike THF,
diethyl ether turned out to be stable towards the triflic an-
hydride at ꢀ208C. Thus, the enol triflate 17 was obtained in
96% yield.
could be further improved to 77 and 73% for trans-19 and
cis-19,
respectively,
by
employing
the
bicyclo-
AHCTREUNG
tries 3,4). It is noteworthy that the addition of triphenylar-
sine, which is known to enhance the transmetallation rate in
Stille couplings,[22] led, in the case of trans-8 and 17, to a
rapid decomposition of the starting material and/or the
product (entry 1).
This optimized catalyst system was not able to bring
about the coupling of cyclohexenyl triflate 18 with the novel
bicyclo[4.3.0]nonenylstannane 14. This outcome can be ex-
R
plained by the presence of the sterically demanding aceto-
nide unit adjacent to the reacting alkenyltin moiety. Appa-
rently, there is no rate acceleration induced by coordination
effects of the neighboring oxygen atom towards the metals
involved, namely palladium and copper. However, after the
addition of one equivalent of CuI, the reactants could not
be detected anymore and the tricyclic diene 20 was isolated
in 34% yield, which proved to be sufficient for testing 20 in
Diels–Alder reactions. As for the coupling of the alkenyl-
stannane trans-8, after addition of AsPh3 to the reaction
Stille couplings[21] of the enol triflates 17 and 18 with the
bicyclo[4.3.0]nonenylstannanes cis-8, trans-8, and 14 yielded
A
the tricyclic 1,3-dienes cis-19, trans-19, and 20. Tetrakis-(tri-
phenylphosphine)palladium proved to be inefficient as a cat-
alyst for the Stille coupling of 17 with trans-8. The supposed-
ly more-reactive catalyst based on dipalladiumtris(dibenzyli-
deneacetone)·chloroform decomposed prematurely. Howev-
er, with added cuprous iodide and lithium chloride, the tri-
cyclic diene trans-19 could be obtained in 57% yield
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Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
mixture, significant decomposi-
tion of the starting material was
observed.
The abovementioned and
previously unreported tricyclic
dienes 19 and 20 are reasonably
well set up for subsequent
Diels–Alder reactions to fur-
nish compounds embodying the
steroid framework.
Upon treatment with maleic
anhydride in benzene at 1008C,
trans-19 cleanly furnished the
steroid analogue trans-21 in
80% yield, and with N-methyl-
maleimide at 1008C the cyclo-
adduct trans-23 was obtained in
79% yield. Both cycloadditions
followed the endo rule of Alder
and gave single diastereomers.
The absolute configuration of
trans-21 was established by an
Scheme 5. Diels–Alder reactions yielding novel enantiomerically pure steroidal compounds.
X-ray crystal structure analy-
sis[19] (see Figure 1), and the
same was done for the single
diastereomer trans-22 that was formed in 84% yield upon
cycloaddition of fumaronitrile onto trans-19 which occurred
in toluene at 1108C (Scheme 5).[23]
4-Phenyl-1,2,4-triazoline-3,5-dione, which is well known
for its high dienophilicity, reacted with trans-19 in methylene
chloride at ambient temperature to yield trans-26 (77%),
also as a single diastereomer. The less reactive dimethyl ace-
tylenedicarboxylate (DMAD), like the other dienophiles
employed, required heating in benzene and gave trans-24
(65% yield), a steroidal compound with a 1,4-diene moiety
in the B-ring. It is noteworthy that the yield of trans-24 was
only 23% when toluene was used as solvent. On the other
hand, heating of trans-19 with DMAD in chlorobenzene as
an electron-deficient aromatic solvent did not furnish trans-
24 in better yield.[24] The unsymmetrically substituted dieno-
phile 2-chloroacrylonitrile gave a mixture of two regioiso-
meric cycloadducts of trans-25 in a yield of 67%.
Unlike trans-19, the diene cis-19 did not react diastereose-
lectively with N-methylmaleimide. Due to the bent molecu-
lar shape, the directing effects of the methyl group at C-13
and the tert-butoxy substituent at C-17 apparently are not as
dominant so that both diastereomers cis-23a and cis-23b can
be formed by approach of the dienophile to either face of
the molecule with comparable ease (1:1.5). Nevertheless,
both diastereomers (62%) are again endo-Diels–Alder ad-
ducts (Scheme 6).
The diastereoselectivity was slightly more pronounced
(3.8:1) in the cycloaddition of N-phenylmaleimide onto the
more highly functionalized diene 20, which also has a cis-
junction at its bicyclo[4.3.0]nonene core. The two diastereo-
G
meric adducts 27a and 27b were isolated in a combined
yield of 53%.
The less-reactive dienophiles dimethyl maleate and 6,6-di-
methyl-4,8-dioxaspiro[2.5]oct-1-ene required heating at
G
1308C for their cycloadditions onto trans-19 to occur at rea-
sonable rates and the products trans-28 and trans-29, (3 1
and 45% yields, respectively) were each mixtures of several
diastereomers (Scheme 7).[25]
Attempts to accelerate the Diels–Alder reaction of
methyl acrylate with trans-19 by adding ethylaluminum di-
chloride were not successful, as no reaction occurred at low
Figure 1. X-ray crystal structure analyses of the steroid analogues trans-
21 and trans-22.[24]
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A. de Meijere et al.
To demonstrate the capability of the new steroid synthesis
to provide samples for biological testing, the protecting
groups within compounds trans-22 and trans-23 were re-
moved in two steps. The 1,3-dioxolane moieties were cleanly
cleaved with p-toluenesulfonic acid in aqueous acetone to
furnish the oxosteroids trans-30 (99%) and trans-32 (85%).
On the other hand, the tert-butyl ether moieties were best
cleaved with trifluoroacetic acid in methylene chloride.
Thus, the steroid analogues trans-31 and trans-33 were ob-
tained, with conservation of the original configuration, in 91
and 94% yield, respectively (Scheme 8).[26]
Scheme 6. Diels–Alder reactions of the tricyclic dienes cis-19 and 20 with
N-methyl- and N-phenylmaleimide, respectively.
Scheme 8. Deprotection of selected steroid analogues.
Attempts were made to cyclopropanate the tetrasubstitut-
ed double bond in trans-30 with the trifluoroacetoxy-activat-
ed zinc carbenoid generated from diiodomethane and dieth-
ylzinc according to Shi et al.[27] However, the central double
bond remained untouched and, instead, the methoxycyclo-
propane-annelated derivative trans-34 was obtained in 74%
yield. Apparently, the initially formed iodomethylzinc tri-
fluoroacetate reacted with the enol of trans-30 to form the
zinc-substituted enol methyl ether trans-37, and this was
subsequently cyclopropanated by an excess of the zinc car-
benoid to furnish, after hydrolysis, the diastereomerically
pure steroidal hexacycle trans-34. Attempts to cleave the
tert-butyl ether within trans-34 provided the cyclopropaste-
roid trans-35[28] as the major product (40%), but this was ac-
companied by trans-36, the a-methyl derivative of trans-30
Scheme 7. Diels–Alder reactions of the tricyclic diene trans-19 with a cy-
clopropane acetal and dimethyl maleate.
temperatures (ꢀ788C), while decomposition of the sub-
strates was observed at ambient temperature.
Due to the stereoselectivity of the Diels–Alder reaction,
the resulting steroidal frameworks do not have a naturally
occurring configuration. Instead, one carbon atom or anoth-
er always has the inverted configuration. Therefore, the
novel approach described here provides access to different
epimers of the natural steroid skeleton. As such, they
should be interesting subjects for biological investigations
(Schemes 5–7).
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Chem. Eur. J. 2008, 14, 7236 – 7249

Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
resulting from cyclopropane ring opening,[29] as a single dia-
stereomer in 12% yield. 2,3-Cyclopropane-annelated steroid
analogues of type trans-35 have been found to act as irrever-
sible inhibitors of cholesterol oxidase,[30] and the minor
product trans-36 is structurally similar to anabolic-androgen-
ic steroids (Scheme 9).[31]
and without any possible racemization of the preset stereo-
genic centers.
Conclusion
A sequence of Stille cross-coupling reactions of cyclohexe-
nol triflates with enantiomerically pure bicyclo-
[4.3.0]nonenylstannanes and subsequent Diels–Alder reac-
tions of the resulting tricyclic 1,3-dienes leads efficiently to
novel steroid analogues with interesting functionalities for
further elaboration. The thus obtained steroidal tetracycles
with a trans-C,D-ring junction were single diastereomers,
whereas the analogues with a cis-C,D-ring junction were
mixtures of two diastereomers each. With less-reactive dien-
ophiles, the steroid analogues so-formed were mixtures of
several diastereomers. Overall, a spectrum of new steroid
analogues, which includes examples with an aromatic B-ring
and with a cyclopropane-annelated A-ring, are accessible in
good yields. Removal of protecting groups could be readily
achieved and provided sufficiently large samples for biologi-
cal testing. As this new access to the steroid skeleton is
based on three variable building blocks, the diversity of ob-
tainable steroidal compounds is of particular interest.
Experimental Section
Scheme 9. Attempted cyclopropanation of the tetrasubstituted double
bond within trans-30.
General remarks: 1H NMR: Bruker AM 250 (250 MHz). Chemical shifts
in CDCl3 are reported as d values relative to chloroform (d=7.26 ppm)
or benzene (d=7.20 ppm) as internal reference. 13C NMR: Bruker AW
250 (62.9 MHz). Chemical shifts in CDCl3 are reported as d values rela-
tive to chloroform (d=77.0 ppm) or benzene (d=128 ppm); the multi-
plicities of the signals were determined by the DEPT (62.9 MHz) tech-
nique and are quoted as (+) for CH3 and CH groups, (ꢀ) for CH2 groups
and (Cquat) for quaternary carbon atoms. IR spectra: Bruker IFS 66. Low-
resolution EI mass spectra: Finnigan MAT 95, ionizing voltage 70 eV.
High-resolution mass spectra: Finnigan MAT 95; preselected ion peak
matching at Rꢁ10000 to be within ꢂ2 ppm of the exact masses. Elemen-
tal analyses: Mikroanalytisches Labor des Instituts für Organische und
Biomolekulare Chemie der Universität Gçttingen (Germany). Melting
points are uncorrected. Solvents for extraction and chromatography were
of technical grade and were distilled before use. All reactions were car-
ried out under an atmosphere of dry nitrogen in oven- and/or flame-
dried glassware. Benzene, THF, and diethyl ether were distilled from
sodium. Dichloromethane was distilled from CaH2.
Dehydrogenation of the steroidal diene trans-24 with
DDQ,[32] afforded a mixture of the B-ring aromatic tetracy-
cle trans-38 (69% yield) as the major product[33] and trans-
39 with an additional double bond in the D-ring as the
minor product (5%; Scheme 10).[34]
General
[4.3.0]nonenylstannanes (GP 1): n-Butyllithium (2.60 equiv, 2.36m in
hexane) was added at ꢀ788C to solution of diisopropylamine
procedure
for
the
preparation
of
the
bicyclo-
AHCTREUNG
a
(2.60 equiv) in THF, and the mixture was stirred for 30 min. Tri-n-butyl-
tin hydride (2.20 equiv) was added to the resulting solution, and stirring
was continued for 30 min before copper(I) cyanide (1.10 equiv) was
added in one portion. The reaction mixture was warmed to ꢀ508C until
a yellow solution had formed, which was treated with the relevant enol
triflate (1.00 equiv) in THF. The resulting solution was warmed to ꢀ258C
and stirred for an additional 2 h. The reaction mixture was poured into
pentane and washed with 10% NH3 solution, water, and brine. After
drying over MgSO4 and concentration in vacuo, the residue was taken up
in ethyl acetate and the solution, contained in an unsealed vessel, was
treated with silver(I) acetate (3.00 equiv) at ambient temperature for 2 h.
The reaction mixture was filtered through Celite, washed with water,
brine, and dried over MgSO4. After concentration in vacuo, the residue
Scheme 10. New steroid analogues with an aromatic B-ring obtained by
dehydrogenation of the steroidal diene trans-24 with DDQ. DDQ=2,3-
dichloro-5,6-dicyano-1,4-benzoquinone.
All of the new steroidal products described herein ought
to be enantiomerically pure because the bicyclo-
A
were enantiomerically pure starting materials; almost all the
transformations occurred with complete diastereoselectivity
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A. de Meijere et al.
was purified by column chromatography on neutral aluminum oxide (de-
activated with 5% water).
6-(3S,3aS,7aR)-3-tert-Butoxy-3a-methyl-3a,4,5,7a-tetrahydroindanyltri-
n-butylstannane (cis-8): Following GP 1, diisopropylamine (1.69 g,
16.5 mmol) in THF (100 mL) was treated with n-butyllithium (7.00 mL,
16.5 mmol, 2.36m). Tri-n-butyltin hydride (4.07 g, 14.0 mmol) and cop-
per(I) cyanide (626 mg, 6.99 mmol) were added, followed by bicyclic enol
triflate cis-7 (2.26 g, 6.35 mmol) in THF (5 mL). Workup with pentane
(100 mL), NH3 solution (30 mL, 10%), water (2”30 mL), and brine
(25 mL) yielded, after treatment of the crude product with silver(I) ace-
tate (3.18 g, 19.1 mmol) in ethyl acetate (80 mL) and column chromatog-
raphy on neutral aluminum oxide (40 g, pentane), cis-8 as a colorless oil
(2.92 g, 92%). Rf =0.5, pentane/diethyl ether 20:1; IR (film): n˜ =2957,
2925, 2871, 1609, 1464, 1418, 1387, 1376, 1361, 1292, 1198, 1072, 1020,
General procedure for [2+2] cycloadditions of dichloroketene (GP 2):
Powdered zinc (2.00 equiv) was added to a solution of the relevant halo-
cyclohexadiene (1.00 equiv) in diethyl ether, and the resulting suspension
was treated in an ultrasonic bath at 15–208C for 30 min. Trichloroacetic
acid chloride (1.50 equiv) in diethyl ether was then added within 3h
under continuous ultrasonication. The reaction mixture was diluted with
diethyl ether and filtered through Celite. The filtrate was washed with
sat. NaHCO3 solution and water. After extraction of the combined aque-
ous phases with diethyl ether, washing of the combined organic layers
with brine, drying over MgSO4, and concentration in vacuo, the residue
was subjected to column chromatography on silica gel.
902, 874, 689 cmꢀ1
;
1H NMR (250 MHz, C6D6): d=0.82–1.04 (m, 15H;
ꢀ
ꢀ
nBu CH3, nBu CH2), 1.13(s, 3H; CH 3), 1.15 (s, 9H; C(CH3)3), 1.24–
1.79 (m, 16H), 1.89–2.16 (m, 2H), 2.18–2.27 (m, 1H), 2.33 (mc, 2H), 3.66
AHCTREUNG
General procedure for Stille couplings of bicyclo[4.3.0]nonenylstannanes
A
with 2-bromocyclohexenol triflates (GP 3): A Pyrex bottle containing a
magnetic stirring bar was charged with a solution of the relevant enol tri-
(t, 3J=6.8 Hz, 1H; 3-H), 5.85–5.95 ppm (m, 1H; 7-H); 13C NMR
ꢀ
(62.9 MHz, C6D6, add. DEPT): d=9.26 (ꢀ, 3 C,nBu CH2), 14.0 (+, 3 C,
flate (1.00 equiv) and the bicyclo
in NMP. After purging the solution with argon in an ultrasonic bath for
5 min, [Pd2(dba)3]·CHCl3 (2.00–5.00 mol%), LiCl (3.00 equiv), and CuI
A
ꢀ
ꢀ
(CH3)3), 28.9 (ꢀ, 3 C,nBu
nBu CH3), 21.8 (+, CH3), 27.8 (+, 3 C, C
G
ꢀ
CH2), 29.1 (ꢀ, CH2), 29.3( ꢀ, CH2), 29.7 (ꢀ, 3 C,nBu CH2), 31.1 (ꢀ,
CH2), 32.8 (ꢀ, CH2), 42.2 (Cquat, C-3a), 46.2 (+, C-7a), 72.4 (Cquat, C-
ACHTREUNG
(2.00–5.00 mol%) were added. Before carefully sealing the bottle with a
screw cap, the mixture was purged again with argon in an ultrasonic bath
for 5 min. The reaction mixture was stirred vigorously with heating at
908C for 12 h. After cooling down to ambient temperature, the reaction
mixture was poured into diethyl ether and the mixture washed with NH3
solution (5%) and water. The combined aqueous phases were extracted
with diethyl ether, and the combined organic layers were vigorously
stirred with sat. KF solution for 45 min. The combined organic phases
were dried over MgSO4 and concentrated in vacuo. If necessary, the resi-
due was adsorbed onto silica gel and purified by column chromatography
on silica gel.
(CH3)3), 76.7 (+, C-3), 137.4 (Cquat, C-6), 142.7 ppm (+, C-7); MS
(70 eV): m/z (%): 443/442/441/440/439/438/437 (16/24/100/44/83/33/46)
[M+ꢀC4H9],
387/386/385/384/383/382/381
(1/2/13/5/16/5/6)
[M+
ꢀC4H9ꢀ2”C4H8], 331/330/329/327/326/325/324 (2/1/12/4/11/4/5) [M+
ꢀC4H9ꢀ2”C4H8], 293/292/291/290/289/288/287 (1/1/6/3/5/2/3) [SnBu3+],
237/236/235/234/233/232/231 (1/1/4/2/3/2/1) [SnBu2H+], 179/178/177/176/
175 (2/1/4/1/2) [SnBuH+], 136 (2) [M+ꢀSnBu3ꢀC4H8ꢀCH3], 122/121/
120/119/118/117 (1/5/2/4/2/3) [SnH+], 91 (3), 57 (21) [tBu+], 41 (3); ele-
mental analysis calcd (%) for C26H50OSn (497.4): C 62.78, H 10.13; found
C 62.83, H 10.17.
(2aS,4aS,7aS,7bR)-4-Bromo-2,2-dichloro-6,6-dimethyl-2a,4a,7a,7b-tet-
rahydro-2H-5,7-dioxacyclobuta[e]inden-1-one (10a): Following GP 2,
bromocyclohexadiene 9a (4.80 g, 20.8 mmol) in diethyl ether (50 mL)
was treated with trichloroacetic acid chloride (5.67 g, 31.2 mmol) and
powdered zinc (2.72 g, 41.5 mmol). Workup with diethyl ether (100 mL),
sat. NaHCO3 solution (50 mL), water (50 mL), extraction with diethyl
ether (2”40 mL), and brine (30 mL) provided, after column chromatog-
raphy (50 g of silica gel, pentane/diethyl ether/triethylamine 1:1:0.01), the
product 10a as a yellow wax (4.45 g, 65%). Rf =0.3; IR (film): n˜ =2988,
2936, 2881, 1809, 1751, 1648, 1472, 1454, 1382, 1370, 1347, 1306, 1236,
General procedure for Diels–Alder reactions of tricyclic dienes (GP 4):
A Pyrex bottle, containing a magnetic stirring bar, was charged with a so-
lution of the tricyclic diene and the relevant dienophile in the specified
solvent. The resulting solution was purged with argon in an ultrasonic
bath for 5 min. The bottle was carefully sealed with a screw cap and,
after heating at the specified temperature for the stated time, the volatile
components were removed in vacuo, and the residue was purified by
column chromatography.
(+)-6-(3S,3aS,7aS)-3-tert-Butoxy-3a-methyl-3a,4,5,7a-tetrahydroindanyl-
tri-n-butylstannane (trans-8): Following GP 1, diisopropylamine (3.69 g,
36.5 mmol) in THF (150 mL) was treated with n-butyllithium (15.1 mL,
36.5 mmol, 2.42m). Tri-n-butyltin hydride (8.98 g, 30.9 mmol) and cop-
per(I) cyanide (1.38 g, 15.4 mmol) were added, followed by a solution of
the bicyclic enol triflate trans-7 (5.00 g, 14.0 mmol) in THF (15 mL).
Workup with pentane (200 mL), 10% NH3 solution (50 mL), water (2”
50 mL), and brine (40 mL) yielded, after treatment of the crude product
with silver(I) acetate (6.50 g, 39.0 mmol) in ethyl acetate (100 mL) and
column chromatography on neutral aluminum oxide (100 g, pentane),
trans-8 as a colorless oil (5.90 g, 85%). Rf =0.5, pentane/diethyl ether
20:1; IR (film): n˜ =2976, 2956, 2928, 2872, 2847, 1606, 1461, 1419, 1383,
1359, 1337, 1290, 1251, 1195, 1117, 1070, 1021, 958, 897, 836, 689,
1165, 1072, 1044, 994, 965, 931, 871, 855, 786 cmꢀ1 1H NMR (300 MHz,
;
CDCl3): d=1.09 (s, 3H; CH3), 1.28 (s, 3H; CH3), 2.75 (ddd, 3J=9.6, 3J=
3
3
4.4, J=1.7 Hz, 1H; 2a-H), 3.84 (dd, 3J=9.6, J=2.5 Hz, 1H; 7b-H), 4.02
(d, 3J=5.7 Hz, 1H; 4a-H), 4.19 (dd, 3J=5.7, 3J=2.5 Hz, 1H; 7a-H),
3
3
5.80 ppm (dt, J=4.4, J=1.1 Hz, 1H; 3-H); 13C NMR (75.7 MHz, CDCl3
add. APT): d=26.15 (+, CH3), 27.57 (+, CH3), 45.24 (ꢀ, CH), 53.35 (ꢀ,
CH), 70.76 (+, CHOC), 72.75 (+, CHOC), 87.07 (ꢀ, Cquat, C-2), 110.16
(ꢀ, Cquat, C-6), 125.28 (+, CH, C-3), 128.60 (ꢀ, Cquat, C-4), 190.95 ppm
(ꢀ, Cquat, C-1); MS (70 eV): m/z (%): 346/344/342/340 (4/27/57/37) [M+],
331/329/327/325 (4/26/56/35) [M+ꢀCH3], 288/286/284/282 (3/20/40/25),
272 (14), 248 (11), 246/244/242/240 (4/26/56/36), 221 (22), 205 (71), 203
(100), 179/177/175/173 (10/53/98/36), 167 (8), 146 (21), 133 (23), 121 (27),
111 (32), 94 (47), 85 (73), 77 (39), 65 (64), 63 (29); elemental analysis
calcd (%) for C11H11BrCl2O3 (342.0): C 40.48, H 3.68; found C 40.24, H
3.66.
659 cmꢀ1 1H NMR (250 MHz, CDCl3): d=0.73(s, 3H; CH 3), 0.82–1.01
;
ꢀ
ꢀ
(m, 14H; nBu CH3, nBu CH2), 1.14 (s, 9H; C(CH3)3), 1.22–1.40 (m,
G
ꢀ
7H; nBu CH2), 1.42–1.58 (m, 7H; nBu-CH2), 1.65–1.83(m, 2H), 1.89–
2.16 (m, 2H), 2.20–2.41 (m, 4H), 3.43 (dd, 3J=6.8, J=8.0 Hz, 1H; 3-H),
3
(2aS,4aS,7aS,7bR)-4-Iodo-2,2-dichloro-6,6-dimethyl-2a,4a,7a,7b-tetra-
hydro-2H-5,7-dioxacyclobuta[e]inden-1-one (10b): Following GP 2, the
iodocyclohexadiene 9b (2.50 g, 9.00 mmol) in diethyl ether (25 mL) was
treated with powdered zinc (1.18 g, 18.0 mmol) and trichloroacetic acid
chloride (2.45 g, 13.5 mmol) in diethyl ether (13 mL). Workup with dieth-
yl ether (100 mL), sat. NaHCO3 solution (50 mL), water (50 mL), and
brine (30 mL) yielded, after column chromatography (30 g of silica, pen-
tane/diethyl ether 2:1), product 10b as a colorless solid (434 mg, 12%).
Rf =0.4; 1H NMR (300 MHz, C6D6): d=1.04 (s, 3H; CH3), 1.24 (s, 3H;
CH3), 2.61 (ddd, 3J=9.3, 3J=4.4, 3J=1.7 Hz, 1H; 2a-H), 3.78 (dd, 3J=
5.72 ppm (mc, 1H; 7-H); 13C NMR (62.9 MHz, CDCl3, add. DEPT): d=
ꢀ
ꢀ
8.89 (ꢀ, 3 C,nBu CH2), 10.99 (+, CH3), 13.74 (+, 3 C,nBu CH3), 24.60
ꢀ
(ꢀ, CH2), 27.40 (ꢀ, 3 C,nBu CH2), 28.72 (+, 3 C, C
ACHTREUNG
ꢀ
AHCTREUNG
C-3), 138.30 (Cquat, C-6), 141.72 ppm (+, CH, C-7); MS (70 eV): m/z (%):
443/442/441/440/439/438/437 (16/24/100/44/83/33/46) [M+ꢀC4H9], 293/292/
291/290/289/288/287 (1/1/6/3/5/2/3) [SnBu3+], 239/237/236/235/234/233/
232/231 (15/12/11/99/32/76/26/42) [SnBu2H+], 180/179/178/177/176/175
(11/88/83/53/26/12) [SnBu+], 135 (5) [M+ꢀSnBu3ꢀC4H9ꢀCH3], 122/121/
120/119/118/117 (1/5/26/20/12/10) [SnH+], 91 (3), 57 (84) [Bu+], 41 (22);
elemental analysis calcd (%) for C26H50OSn (497.37): C 62.78, H 10.13;
found C 62.86, H 10.01.
3
9.3, 3J=2.5 Hz, 1H; 7b-H), 3.91 (d, J=5.5 Hz, 1H; 4a-H), 4.09 (dd, 3J=
5.5, 3J=2.5 Hz, 1H; 7a-H), 6.03ppm (dt, 3J=4.4, 3J=0.6 Hz, 1H; 3-H);
13C NMR (75.6 MHz, CDCl3 add. APT): d=26.16 (+, CH3), 27.53( +,
CH3), 45.79 (+, CH), 52.96 (+, CH), 69.91 (+, CHOC), 74.40 (+,
7242
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7236 – 7249

Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
CHOC), 90.74 (ꢀ, Cquat, C-2), 109.84 (ꢀ, Cquat, C-6), 132.76 (+, CH, C-3),
149.90 (ꢀ, Cquat, C-4), 204.98 ppm (ꢀ, Cquat, C-1); MS (70 eV): m/z (%):
column chromatography (40 g of silica, pentane/diethyl ether 2:1) yielded
compound 13 as
a
colorless oil (821 mg, 65%). Rf =0.4; 1H NMR
297/295/293/
(4/17/26), 265/263/261 (3/15/22/) [M+ꢀI], 251/249/247 (8/23/
(300 MHz, C6D6): d=1.30 (s, 3H; CH3), 1.47 (s, 3H; CH3), 1.49–1.75 (m,
3H), 1.92 (dd, 3J=14.2, 3J=8.0 Hz, 1H), 2.50–2.69 (m, 2H), 3.32–3.52
(m, 4H; 2’-H, 3’-H), 3.99 (dd, 3J=5.2, 3J=3.3 Hz, 1H; 8b-H), 4.25 (dd,
3J=5.2, 3J=1.7 Hz, 1H; 3a-H), 5.76 ppm (d, 3J=2.7 Hz, 1H; 5-H);
13C NMR (75.6 MHz, CDCl3 add. APT): d=27.04 (+, CH3), 28.21 (+,
CH3), 36.59 (+, CH), 38.15 (+, CH), 38.15 (ꢀ, CH2), 42.38 (ꢀ, CH2),
63.87 (ꢀ, CH2O), 64.46 (ꢀ, CH2O), 74.79 (+, CHOC), 76.15 (+,
CHOC), 109.08 (ꢀ, Cquat, C-2), 116.48 (ꢀ, Cquat, C-7), 121.94 (ꢀ, Cquat, C-
4), 134.21 ppm (+, CH, C-5); MS (70 eV): m/z (%): 332/330 (5/6) [M+],
317/315 (58/59) [M+ꢀCH3], 275/273 (13/14), 257/253 (10/9), 231/229 (12/
12), 213/211 (10/10), 193 (30), 169 (10), 165 (8), 137 (5), 132 (12), 128
(55), 87 (82), 86 (100), 77 (26), 65 (22), 55 (10), 52 (6); HRMS: m/z:
calcd for C14H19BrO4 (331.2): 332.0445 (correct HRMS).
33), 209/207/205 (2/9/14), 176 (13), 169 (35), 166/164/162 (25/77/100), 143
(27), 127 (29) [I+], 125 (56), 111 (17), 99 (28), 95 (55), 85 (32), 77 (53),
66 (41), 61 (15); elemental analysis calcd (%) for C11H11Cl2IO3 (389.0): C
33.96, H 2.85; found C 34.25, H 2.85.
(3aR,5aR,8aR,8bS)-4-Bromo-6,6-dichloro-2,2-dimethyl-3a,5a,6,8,8a,8b-
hexahydro-1,3-dioxa[a,s]indacen-7-one (11): A solution of the bicyclooc-
C
tenone 10a (1.99 g, 4.90 mmol) in diethyl ether (40 mL) and methanol
(11 mL) was treated with diazomethane in diethyl ether (46 mL,
46 mmol, ca. 1.0m) added at ꢀ158C over 45 min. After continued stirring
at ꢀ158C for 15 min, excess diazomethane was quenched with acetic
acid. Workup with sat. NaHCO3 solution (2”50 mL), drying over
MgSO4, and column chromatography (45 g of silica, pentane/diethyl
ether 2:1) yielded the indenone 11 as a yellow wax (1.00 g, 57%). Rf =
0.6; IR (film): n˜ =2988, 2934, 1771, 1644, 1454, 1404, 1382, 1371, 1322,
1309, 1231, 1170, 1144, 1128, 1070, 1049, 1014, 982, 905, 867, 829,
(3aR,5aR,8aR,8bS)-Tributyl
5a,6,7,8,8a,8b-hexahydro-3aH-1’,4’-dioxaspiro
[a,s]indacene-4-yl)]}stannane (14): tert-Butyllithium (3.59 mL, 5.38 mmol
A
N
AHCTREUNG
AHCTREUNG
783cm ꢀ1 1H NMR (300 MHz, C6D6): d=1.21 (s, 3H; CH3), 1.31 (s, 3H;
;
1.50m in hexane) was added dropwise to a solution of bicyclononenylbro-
mide 13 (810 g, 2.54 mmol) in THF (30 mL) at ꢀ788C, and the mixture
was stirred for 1 h. The reaction mixture was warmed to 08C and stirred
for 30 min at this temperature. After cooling to ꢀ788C, tri-n-butyltin
chloride (1.19 g, 3.67 mmol) was added dropwise, and the reaction mix-
ture was warmed to 08C within 4 h. The reaction mixture was then
poured into diethyl ether (100 mL) and washed with NH4Cl solution
(35 mL, 1.0m). After drying over MgSO4, concentration in vacuo, and
column chromatography (35 g of silica, pentane/diethyl ether 2:1), the
CH3), 1.33–1.48 (m, 1H), 1.89 (dd, 3J=19.5, 3J=8.2 Hz, 1H; 5a-H), 2.70
(mc, 1H; 8-H), 2.97 (mc, 1H; 8a-H), 3.65 (t, 3J=4.9 Hz, 1H; 8b-H), 3.93
(dd, 3J=4.9, 3J=2.2 Hz, 1H; 3a-H), 6.07 ppm (d, 3J=2.7 Hz, 1H; 5-H);
13C NMR (75.5 MHz, CDCl3 add. APT): d=26.65 (+, CH3), 27.82 (+,
CH3), 32.30 (+, CH), 32.89 (ꢀ, CH2), 50.61 (+, CH), 74.00 (+, CHOC),
74.58 (+, CHOC), 87.05 (ꢀ, Cquat, C-6), 110.24 (ꢀ, Cquat, C-2), 125.44 (+,
CH, C-5), 127.60 (ꢀ, Cquat, C-4), 197.34 ppm (ꢀ, Cquat, C-8); MS (70 eV):
m/z (%): 345/343/341/339 (10/64/100/79) [M+ꢀCH3], 305 (3) 299 (9), 270
(7), 263 (15), 243/241/239/237 (22/22/45/30), 217 (13), 212 (4), 191 (7), 184
(12), 182 (15), 172 (10), 161 (7), 133 (10), 127 (17), 125 (35), 112 (12), 101
(8), 89 (23), 75 (13), 65 (17), 61 (25); HRMS: m/z: calcd for
C12H13BrCl2O3ꢀCH3 (341.0): 340.9160 (correct HRMS).
bicyclo[4.3.0]nonenylstannane 14 was obtained as a colorless oil (923mg,
E
70%). Rf =0.7; IR (film): n˜ =2956, 2927, 2871, 1614, 1463, 1430, 1376,
1366, 1333, 1312, 1293, 1221, 1147, 1104, 1069, 1044, 960, 945, 905, 874,
1
3
788 cmꢀ1; H NMR (300 MHz, C6D6): d=0.98 (t, J=7.2 Hz, 9H; nBuSn)
1.39 (s, 3H; CH3), 1.40–1.48 (m, 9H; nBuSn), 1.50 (s, 3H; CH3), 1.63–
1.93(m, 12H), 2.18 (dd, 3J=13.7, 3J=8.8 Hz, 1H), 2.67–2.83(m, 2H),
3.36–3.51 (m, 4H; 2’-H, 3’-H), 4.20 (dd, 3J=5.2, 3J=3.3 Hz, 1H; 8b-H),
4.47 (dt, 3J=5.2, 3J=1.1 Hz, 1H; 3a-H), 5.75 ppm (d, 3J=1.4 Hz, 1H; 5-
H); 13C NMR (75.6 MHz, CDCl3 add. APT): d=9.88 (+, CH3, 3 C,
nBuSn), 13.93 (ꢀ, CH2, 3 C,nBuSn), 27.72 (ꢀ, CH2, 3 C,nBuSn), 28.12
(+, CH3), 28.57 (+, CH3), 29.43( ꢀ, CH2, 3 C,nBuSn), 35.19 (+, CH),
38.55 (+, CH), 38.89 (ꢀ, CH2), 43.56 (ꢀ, CH2), 63.81 (ꢀ, CH2, CH2O),
64.32 (ꢀ, CH2, CH2O), 74.52 (+, CHOC), 74.86 (+, CHOC), 108.26 (ꢀ,
Cquat, C-2), 116.86 (ꢀ, Cquat, C-7), 138.84 (ꢀ, Cquat, C-4), 141.36 ppm (+,
CH, C-5); MS (70 eV): m/z (%): 530/529/528/527/526/525/524 (6/16/12/28/
12/18) [M+ꢀCH3], 487/486/485/484/483/482/481 (20/28/100/52/84/30/52),
429/428/427/426/425/424/423 (15/21/88/40/61/30/34), 385/384/383/382/381/
380/379 (4/4/17/10/21/8/12), 339 (2), 327 (5), 291 (4), 270/269/268/267/266/
265/264 (6/5/26/10/22/7/12), 252 (6), 235 (5), 212 (10), 178/177/176/175/
174/173/172 (20/5/23/6/17/4/5), 160 (1), 133 (11), 119 (6), 105 (10), 91 (21),
87 (14), 77 (7), 59 (2); elemental analysis calcd (%) for C26H46O4Sn
(541.2): C 57.69, H 8.56; found C 57.32, H 8.68.
(3aR,5aR,8aR,8bS)-4-Bromo-2,2-dimethyl-3a,5a,6,8,8a,8b-hexahydro-
1,3-dioxa[a,s]indacene-7-one (12): Powdered zinc (660 mg, 10.1 mmol)
U
was added to a solution of acetic acid (586 mg, 9.75 mmol) and tetrame-
thylethylenediamine (992 mg, 8.53mmol) in ethanol (6.0 mL), and the
mixture was stirred at 238C for 20 min. After addition of the dichloroin-
denone 11 (620 mg, 1.74 mmol) in ethanol (3.0 mL), the mixture was
stirred at 238C for 3h. The reaction mixture was poured into diethyl
ether (75 mL), and the solution was filtered through Celite. The filtrate
was washed with water (30 mL) and sat. NaHCO3 solution (25 mL).
After extraction of the combined aqueous phases with diethyl ether (2”
50 mL), the combined organic layers were dried over MgSO4. After con-
centration in vacuo, the residue was purified by column chromatography
(35 g of silica, pentane/diethyl ether 2:1) to yield the hexahydroindenone
12 as a yellow oil (415 mg, 83%). Rf =0.5; 1H NMR (300 MHz, C6D6):
d=1.26 (s, 3H; CH3), 1.36 (s, 3H; CH3), 1.42–1.58 (m, 1H), 1.66–1.82 (m,
3H), 2.30 (m c, 1H; 5a-H), 2.49 (mc, 1H; 8a-H), 3.83 (dd, 3J=4.9, 3J=
3
3
3.6 Hz, 1H; 8b-H), 4.11 (dd, J=5.2, J=2.2 Hz, 1H; 3a-H), 5.46 ppm (d,
3J=2.7 Hz, 1H; 5-H); 13C NMR (75.6 MHz, CDCl3 add. APT): d=26.77
(+, CH3), 27.89 (+, CH3), 35.15 (+, CH), 36.34 (ꢀ, CH2), 38.27 (ꢀ,
CH2), 44.27 (+, CH), 74.11 (+, CHOC), 75.54 (+, CHOC), 109.68 (ꢀ,
(2aS,4aS,7aS,7bR)-4-Bromo-2-chloro-6,6-dimethyl-2a,4a,7a,7b-tetrahy-
dro-2H-5,7-dioxacyclobuta[e]inden-1-one (15): A solution of the dichlor-
obicyclooctene 11 (0.500 g, 1.53mmol) in methanol (1.20 mL) and THF
(5.00 mL) was treated with powdered zinc (401 mg, 6.13mmol) and
NH4Cl (328 mg, 6.13 mmol) at 238C for 2 h in an ultrasonic bath. After
this time, the reaction mixture was poured into diethyl ether (75 mL),
and the solution was filtered through Celite. The filtrate was washed with
water (30 mL) and brine (25 mL). After drying over MgSO4 and concen-
tration in vacuo, column chromatography (30 g of silica, pentane/diethyl
ether 1:1) yielded the product 15 as a colorless wax (83.1 mg, 18%). Rf =
0.6; 1H NMR (300 MHz, CDCl3): d=1.13(s, 3H; CH 3), 1.34 (s, 3H;
CH3), 2.47 (mc, 1H; 2a-H), 3.19 (mc, 1H; 2-H), 3.93 (mC, 1H; 7b-H),
4.21–4.28 (m, 1H; 7a-H), 4.33 (dd, 3J=5.8, 3J=2.7 Hz, 1H; 4a-H),
5.97 ppm (dt, 3J=4.1, 3J=0.83Hz, 1H; 3- H); 13C NMR (75.5.9 MHz,
CDCl3 add. APT): d=26.25 (+, CH3), 27.55 (+, CH3), 31.79 (ꢀ, CH),
53.14 (ꢀ, CH), 63.77 (+, CH, C-2), 71.03( +, CHOC), 73.20 (+,
CHOC), 109.95 (ꢀ, Cquat, C-6), 125.90 (+, CH, C-3), 127.34 (ꢀ, Cquat, C-
4), 196.16 ppm (ꢀ, Cquat, C-1); MS (70 eV): m/z (%): 310/308/306 (2/7/5)
[M+], 295/293/291 (7/25/20) [M+ꢀCH3], 252/250/248 (5/19/15), 240/238/
236 (31/100/85), 221 (8), 217 (26), 215 (28), 185 (20), 173 (98), 169 (63),
C
C
quat, C-2), 123.96 (ꢀ, Cquat, C-4), 132.55 (+, CH, C-5), 213.07 ppm (ꢀ;
quat, C-8); MS (70 eV): m/z (%): 288/286 (12/13) [M+], 273/271 (100/99)
[M+ꢀCH3], 231/229 (56/61) [M+ꢀC
(CH3)2], 213/211 (35/37) [M+
ꢀHOCH
A
(5), 150 (7), 149 (20), 132 (27), 121 (14), 107 (25), 104 (32), 91 (42), 77
(47), 65 (39), 59 (13); HRMS: m/z: calcd for C12H15BrO3 (287.1):
286.0204 (correct HRMS).
(3aR,5aR,8aR,8bS)-4-Bromo-2,2-dimethyl-spiro(1’,3’-dioxolane
A
3a,5a,6,8,8a,8b-hexahydro-1,3-dioxa[a,s]indacene (13): A solution of the
AHCTREUNG
hexahydroindenone 12 (1.10 g, 3.83 mmol), ethylene glycol (1.34 g,
21.6 mmol), and triethyl orthoformate (1.30 g, 8.78 mmol) in dichlorome-
thane (40.0 mL) was treated with p-toluenesulfonic acid (10.0 mg,
0.160 mmol) at 238C for 23h. After this time, the reaction mixture was
poured into diethyl ether (50 mL) and the mixture washed with sat.
NaHCO3 solution (20 mL) and water (20 mL). After extraction of the
combined aqueous phases with diethyl ether (2”35 mL), the combined
organic layers were dried over MgSO4. Concentration in vacuo and
Chem. Eur. J. 2008, 14, 7236 – 7249
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7243

A. de Meijere et al.
159 (30), 141 (39), 129 (33), 112 (16), 101 (44), 99 (98), 94 (71), 89 (21),
77 (96), 65 (67), 63 (39), 59 (31).
(3aR,5aR,8aR,8bS)-4’-Cyclohex-1-enyl-2,2-dimethyl-spiro(1’,3’-
dioxolane[2’,7]-3a,5a,6,8,8a,8b-hexahydro-1,3-dioxa[a,s]indacene) (20):
Following GP 3, a solution of the enol triflate 18 (348 mg, 1.48 mmol)
and the bicyclo[4.3.0]nonenylstannane 14 (400 mg, 0.739 mmol) in NMP
(7.0 mL) was treated with [Pd2(dba)3]·CHCl3 (81.7 mg, 78.9 mmol), LiCl
G
ACHTREUNG
1,4-Dioxaspiro
bis(trimethylsilyl)amide solution (13.4 mL, 26.8 mmol, 2.00m in THF)
was added to solution of 1,4-dioxaspiro[4.5]decan-8-one (4.00 g,
[4.5]dec-7-en-8-yl trifluoromethanesulfonate (17): Sodium
AHCTREUNG
AHCTREUNG
a
ACHTREUNG
(188 mg, 4.43mmol), and CuI (281 mg, 1.88 mmol) at 65 8C for 13h.
Workup with diethyl ether (80 mL) and water (2”25 mL), extraction
with diethyl ether (2”40 mL), treatment with sat. KF solution (35 mL),
and column chromatography (22 g of silica gel, pentane/diethyl ether 2:1)
yielded the tricyclic butadiene 20 as a colorless oil (84.0 mg, 34%). Rf =
0.3; IR (film): n˜ =2972, 2934, 2873, 1462, 1453, 1382, 1352, 1250, 1184,
25.6 mmol) in diethyl ether (300 mL) at ꢀ208C. After 60 min at this tem-
perature, the solution was treated with trifluoromethanesulfonic acid an-
hydride (4.52 mL, 26.9 mmol). After stirring for 16 h, during which time
the temperature was raised to 228C, the reaction mixture was washed
with sat. NaHCO3 solution (50 mL) and water (50 mL). The aqueous
phases were re-extracted with diethyl ether (2”50 mL), and the com-
bined organic phases were dried over MgSO4. After removal of the vola-
tile components in vacuo, the residue was purified by column chromatog-
raphy on silica gel (25 g, pentane/diethyl ether 5:1) to yield the title com-
pound 17 (Rf =0.4) as a colorless oil (7.08 g, 96%), the analytical data for
which were consistent with those reported previously.[15]
1052, 1010, 981, 936, 858, 732 cmꢀ1 1H NMR (300 MHz, CDCl3): d=1.33
;
(s, 3H; CH3), 1.40 (s, 3H; CH3), 1.69–1.81 (m, 4H), 1.85–1.97 (m, 2H),
2.00–2.22 (m, 5H), 2.52–2.84 (m, 3H), 3.33–3.57 (m, 4H; 2’’-H, 3’’-H),
4.21 (t, 3J=6.1 Hz, 1H; 8a-H), 4.61 (d, 3J=5.2 Hz, 1H; 3a-H), 5.57 (d,
3J=3.3 Hz, 1H; 5-H), 6.23ppm (m C, 1H; 2’-H); 13C NMR (75.6 MHz,
CDCl3, add. APT): d=22.82 (ꢀ, CH2), 24.61 (ꢀ, CH2), 26.99 (+, CH3),
28.43( +, CH3), 33.92 (ꢀ, CH2), 34.03 (+, CH), 36.73 (ꢀ, CH2), 38.45 (ꢀ,
CH2), 39.23 (+, CH), 43.58 (ꢀ, CH2), 63.85 (ꢀ, OCH2CH2O), 64.46 (ꢀ,
OCH2CH2O), 72.11 (+, CH, CHOC), 74.83( +, CH, CHOC), 108.61 (ꢀ,
Cquat, C-2), 116.98 (ꢀ, Cquat, C-7), 119.90 (+, CH, C-2’), 130.82 (+, CH,
C-5), 137.83 (ꢀ, Cquat), 137.83 ppm (ꢀ, Cquat); MS (70 eV): m/z (%): 332
(10) [M+], 317 (14) [M+ꢀCH3], 309 (27), 292 (31), 273 (100), 258 (11),
229 (34), 201 (28), 189 (19), 167 (8), 141 (17), 126 (22), 99 (15), 91 (21),
87 (41), 83 (33), 73 (10), 67 (17); HRMS: m/z: calcd for C20H28O4 (332.4):
332.1987 (correct HRMS).
(1’S,3a’S,7a’S)-8-(1’-tert-Butoxy-7a’-methyl-2’,3’,3a’,6’,7’,7a’-hexahydro-
1’H-inden-5’-yl)-1,4-dioxaspiro
enol triflate 17 (288 mg, 1.00 mmol) and bicyclo
trans-8 (597 mg, 1.20 mmol) in NMP (5 mL) were treated with [Pd2-
(dba)3]·CHCl3 (54.0 mg, 52.2 mmol), LiCl (127 mg, 3.00 mmol), and CuI
ACHTREUNG
AHCTREUNG
ACHTREUNG
(30.0 mg, 158 mmol). Workup with diethyl ether (50 mL), water (2”
25 mL), extraction with diethyl ether (2”30 mL), treatment with sat. KF
solution (30 mL), and column chromatography (27 g of silica gel, pen-
tane/diethyl ether 10:1) yielded the tricyclic butadiene trans-19 as a color-
less wax (265 mg, 77%). Rf =0.4; IR (film): n˜ =2975, 2930, 2873, 1465,
1457, 1388, 1377, 1362, 1341, 1252, 1197, 1165, 1118, 1059, 1015, 982, 946,
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-tert-Butoxy-9a-methyl-
spiro(1’,3’dioxolane
hydro-3aH-2-oxadicyclopenta
Following GP 4, solution of the tricyclic diene trans-19 (100 mg,
ACHTREUNG
907, 859, 734, 701 cmꢀ1
;
1H NMR (250 MHz, CDCl3): d=0.69 (s, 3H;
(CH3)3), 1.22–1.62 (m, 3H), 1.75–2.21 (m, 6H), 2.24–
AHCTREUNG
CH3), 1.17 (s, 9H; C
ACHTREUNG
a
2.33 (m, 6H), 3.49 (dd, 3J=11.4, 3J=8.0 Hz, 1H; 1’-H), 3.98 (s, 4H; 2-H,
3-H), 5.22–5.76 ppm (m, 2H; 4’-H, 7-H); 13C NMR (75.5 MHz, CDCl3,
add. APT): d=10.95 (+, CH3), 24.46 (ꢀ, CH2), 24.77 (ꢀ, 2C, CH2), 28.68
0.289 mmol) and maleic anhydride (35.4 mg, 0.361 mmol) in benzene
(2.0 mL) was stirred at ambient temperature for 12 h. Column chroma-
tography (32 g of silica gel, diethyl ether/pentane 1:1) provided the title
product trans-21 as a colorless wax (103mg, 80%). Rf =0.4; [a]2D0 =ꢀ13.5
(c=1.23in MeOAc); IR (film): n˜ =2973, 2882, 1717, 1700, 1653, 1635,
1557, 1506, 1447, 1417, 1388, 1363, 1288, 1238, 1197, 1118, 1092, 1060,
(+, 3 C, C
(ꢀ, CH2), 41.96 (ꢀ, Cquat
OCH2CH2O), 64.40 (ꢀ, OCH2CH2O), 72.17 (ꢀ, Cquat, C
(CH3)3), 31.18 (ꢀ, CH2), 31.70 (ꢀ, CH2), 34.15 (ꢀ, CH2), 35.96
,
C-7a’), 44.36 (+, CH, C-3’), 64.35 (ꢀ,
AHCTREUNG
946, 910, 734 cmꢀ1
;
1H NMR (300 MHz, C6D6): d=0.64 (s, 3H; CH3),
(CH3)3), 1.58–1.73(m, 5H), 1.82–2.19 (m, 10H), 2.21–2.38
(+, CH, C-1’), 108.02 (ꢀ, Cquat, C-5), 118.51 (ꢀ, Cquat), 123.81 (ꢀ, Cquat),
135.29 (ꢀ, Cquat), 135.82 ppm (ꢀ, Cquat); MS (70 eV): m/z (%): 346 (10)
[M+], 316 (1), 290 (100) [M+ꢀC4H8], 289 (55) [M+ꢀC4H9], 272 (5), 228
(26), 203(22), 185 (10), 171 (6), 159 (9), 131 (12), 105 (11), 91 (10), 86
(22), 79 (4), 57 (38) [C4H9+], 41 (9); HRMS: m/z: calcd for
C22H34O3+H+ (347.5): 347.25814 (correct HRMS).
1.07 (s, 9H; C
AHCTREUNG
(m, 3H), 2.68 (t, 3J=17.5 Hz, 1H), 3.34 (t, 3J=7.2 Hz, 1H; 17-H), 3.43–
3.60 ppm (m, 4H; OCH2CH2O); 13C NMR (75.5 MHz, C6D6, add. APT):
d=11.06 (+, CH3), 23.78 (ꢀ, CH2), 24.87 (ꢀ, CH2), 25.10 (ꢀ, CH2), 28.92
(+, 3 C, C
(CH3)3), 31.54 (ꢀ, CH2), 33.53 (ꢀ, CH2), 33.71 (+, CH), 34.17
(ꢀ, CH2), 34.90 (ꢀ, CH2), 39.29 (+, CH), 42.00 (+, CH), 42.77 (ꢀ, Cquat
,
(1’S,3a’R,7a’S)-8-(1’-tert-Butoxy-7a’-methyl-2’,3’,3a’,6’,7’,7a’-hexahydro-
C-13), 43.04 (+, CH), 44.91 (+, CH), 64.26 (ꢀ, 2C, OCH2CH2O), 72.32
1’H-inden-5’-yl)-1,4-dioxaspiro
enol triflate 17 (288 mg, 1.00 mmol) and bicyclo
cis-8 (599 mg, 1.20 mmol) in NMP (5 mL) were treated with [Pd2-
(dba)3]·CHCl3 (54.1 mg, 52.2 mmol), LiCl (127 mg, 3.00 mmol) and CuI
ACHTREUNG
(ꢀ, Cquat, C
(ꢀ, Cquat
(CH3)3), 80.44 (+, CH, C-17), 109.43( ꢀ, Cquat, C-5), 130.38
AHCTREUNG
ꢀ
ꢀ
,
C=C), 131.80 ( , Cquat, C=C), 171.85 ( , Cquat, OC=O),
172.21 ppm ( , Cquat, OC=O); MS (70 eV): m/z (%): 444 (18) [M+], 416
(59), 388 (76) [M+ꢀC4H8], 360 (100), 342 (30), 315 (15), 297 (56), 286
(10), 253(12), 203(7), 169 (6), 155 (11), 131 (15), 99 (41), 86 (64), 57
(100) [C4H9+], 41 (24); HRMS: m/z: calcd for C26H36O6+H+ (445.6):
445.25847 (correct HRMS); the X-ray crystal structure analysis of trans-
21 has been published elsewhere.[23]
ꢀ
ACHTREUNG
(30.0 mg, 158 mmol). Workup with diethyl ether (45 mL), water (2”
25 mL), extraction with diethyl ether (2”30 mL), treatment with sat. KF
solution (30 mL), and column chromatography (25 g of silica gel, pen-
tane/diethyl ether 10:1) yielded the tricyclic butadiene cis-19 as a color-
less wax (253mg, 73%). Rf =0.4; IR (film): n˜ =2971, 2929, 2873, 1621,
1493, 1463, 1447, 1433, 1422, 1387, 1362, 1303, 1255, 1224, 1198, 1140,
(6S,7S,5R,8S,13R,14S,17S)-17-tert-Butoxy-13-methyl-spiro(1’,3’-
dioxolane[2’,3]-2,3,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-cyclo-
R
1117, 1061, 1058, 1040, 1017, 994, 950, 897, 875, 861 cmꢀ1
;
1H NMR
penta[a]phenanthrene-6,7-dicarbonitrile) (trans-22): Following GP 4, a
solution of the tricyclic diene trans-19 (350 mg, 1.01 mmol) and fumaroni-
trile (117 mg, 1.50 mmol) in toluene (2.00 mL) was heated at 1108C for
16 h. Column chromatography (25 g of silica gel, pentane/diethyl ether
1:1) provided the title compound trans-22 (357 mg, 84%) as colorless
crystals. Crystals suitable for X-ray diffraction were grown from pentane/
diethyl ether 1:1 by slow evaporation of the solvent. M.p.: 183–1848C;
Rf =0.4; [a]2D0 =+36.5 (c=1.06 in MeOAc); IR (film): n˜ =2973, 2931,
2882, 2296, 1700, 1653, 1635, 1472, 1457, 1394, 1362, 1246, 1196, 1143,
(250 MHz, C6D6): d=1.15 (s, 9H, C(CH3)3), 1.17 (s, 3H, CH3), 1.21–1.48
AHCTREUNG
(m, 2H), 1.58–1.78 (m, 3H), 1.87 (mc, 2H), 1.93–2.20 (m, 3H), 2.23 (mc,
4H), 2.24–2.33 (m, 1H), 3.53–3.62 (m, 5H, 1’-H, 2-H, 3 -H), 5.69 (mc, 1H,
7’-H), 5.39 ppm (mc, 1H, 4’-H); 13C NMR (75.5 MHz, CDCl3 add. APT):
d=21.51 (+, CH3), 22.79 (ꢀ, CH2), 25.37 (ꢀ, CH2), 28.82 (+, 3 C, C-
A
36.62 (ꢀ, CH2), 42.15 (ꢀ, Cquat, C-7a’), 44.92 (+, CH, C-3a’), 64.28 (ꢀ,
(CH3)3), 76.86 (+, CH, C-1’),
CH2, 2C, OCH2CH2O), 72.36 (ꢀ, Cquat, C
1
1107, 1094, 1068, 1041, 1017, 982, 946, 906, 881 cmꢀ1; H NMR (250 MHz,
108.22 (ꢀ, Cquat, C-5), 119.23( +, CH), 126.76 (+, CH), 133.88 (ꢀ, Cquat),
136.43 ppm (ꢀ, Cquat); MS (70 eV): m/z (%): 346 (3) [M+], 321 (1), 306
(3), 290 (100) [M+ꢀC4H8], 289 (46) [M+ꢀC4H9], 245 (4), 228 (30), 203
(9), 185 (9), 159 (11), 145 (13), 131 (20), 97 (19), 91 (22), 86 (42), 79 (10),
57 (88) [C4H9+], 41 (26); ESI-HRMS: calcd for C22H34O3+H+ (347.5):
347.25807 (correct HRMS).
CDCl3): d=0.86 (s, 3H; CH3), 1.16 (s, 9H; C(CH3)3), 1.32–2.13 (m,
N
13H), 2.29 (mc, 1H), 2.55 (mc, 1H), 2.71–2.86 (m, 2H), 3.00–3.14 (m,
2H), 3.46 (t, 3J=8.3Hz, 1H; 17-H), 3.98 ppm (m c, 4H; OCH2CH2O);
13C NMR (75.6 MHz, CDCl3, add. APT): d=10.77 (+, CH3), 23.62 (ꢀ,
CH2), 24.13( ꢀ, CH2), 26.78 (ꢀ, CH2), 28.67 (+, 3 C, C
A
7244
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7236 – 7249

Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
CH), 30.89 (ꢀ, CH2), 31.89 (+, CH2), 35.44 (ꢀ, CH2), 36.12 (+, CH),
36.12 (ꢀ, CH2), 37.62 (+, CH), 42.54 (ꢀ, CH2), 42.64 (ꢀ, CH2), 47.13( +,
CH), 64.46 (ꢀ, OCH2CH2O), 64.57 (ꢀ, OCH2CH2O), 72.54 (ꢀ, Cquat, C-
1066, 983, 944, 912, 883, 862 cmꢀ1
;
1H NMR (250 MHz, CDCl3, distin-
guishable signals of the individual diastereomers are marked by #): d=
0.86 (s, 3H; CH3), 0.86 (s, 3H; CH3)#, 1.15 (s, 9H; C
AHCTREUNG
C
(CH3)3)#, 1.22–1.63 (m, 11H), 1.71–2.82 (m, 8H), 3.38–3.47 (m, 1H),
G
U
,
3.99 ppm (mc, 4H; OCH2CH2O); 13C NMR (75.5 MHz, CDCl3, add.
APT): d=11.26 (+, CH3), 11.37 (+, CH3), 24.75 (ꢀ, CH2), 25.13( ꢀ,
CH2), 25.59 (ꢀ, CH2), 25.74 (ꢀ, CH2), 25.94 (ꢀ, CH2), 26.80 (ꢀ, CH2),
CN), 119.37 (ꢀ, Cquat, CN), 127.54 (ꢀ, Cquat), 128.06 ppm (ꢀ, Cquat); MS
(70 eV): m/z (%): 424 (29) [M+], 396 (6), 368 (51), 350 (31), 323 (26),
305 (14), 279 (42), 262 (14), 235 (6), 194 (2), 180 (8), 168 (4), 129 (4), 99
(10), 86 (56), 57 (100) [C4H9+], 41 (14); HRMS: m/z: calcd for
C26H36O3N2+H+ (425.6): 425.280358 (correct HRMS); the X-ray crystal
structure analysis of trans-22 has previously been published.[23]
28.67 (+, 3 C, C
A
34.45 (+, CH), 35.13 (ꢀ, CH2), 35.48 (ꢀ, CH2), 35.66 (ꢀ, CH2), 37.40 (ꢀ,
CH2), 40.79 (ꢀ, CH2), 41.42 (ꢀ, CH2), 41.56 (ꢀ, CH2), 41.82 (ꢀ, CH2),
42.70 (ꢀ, Cquat), 43.41 (ꢀ, Cquat), 45.55 (+, CH), 45.78 (+, CH), 46.72 (+,
CH), 47.71 (+, CH), 58.54 (ꢀ, Cquat), 58.96 (ꢀ, Cquat), 60.36 (ꢀ, Cquat),
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-tert-Butoxy-2,9a-dimethyl-
spiro(1’,3’-dioxolane
ACHTREUNG
64.36 (ꢀ, OCH2CH2O), 72.42 (ꢀ, Cquat, C
(CH3)3), 79.92 (+, CH, C-17),
dro-3aH,4H-2-azadicyclopenta
AHCTREUNG
79.98 (+, CH, C-17), 108.29 (ꢀ, Cquat, C-3), 108.44 (ꢀ, Cquat, C-3), 119.45
(ꢀ, Cquat), 120.73( ꢀ, Cquat), 127.37 (ꢀ, Cquat), 128.28 (ꢀ, Cquat), 129.19 (ꢀ,
Cquat), 129.54 (ꢀ, Cquat), 129.69 ppm (ꢀ, Cquat); MS (70 eV): m/z (%): 435/
433 (1/4) [M+], 397 (1), 379/377 (4/11) [M+ꢀC4H8], 341 (8), 315 (2), 289/
287 (3/10), 252 (36), 246 (15), 208 (6), 166 (2), 155 (100), 133 (8), 111
(14), 96 (21), 84 (25), 57 (27) [C4H9+], 41 (9); HRMS: m/z: calcd for
C25H36ClNO3+H+ (436.0): 434.24565 (correct HRMS).
Following GP 4, a solution of the tricyclic diene trans-19 (80.4 mg,
0.232 mmol) in benzene (1.00 mL) and N-methylmaleimide (42.9 mg,
0.348 mmol) was heated at 908C for 15 h. Column chromatography (15 g
of silica, pentane/diethyl ether/methanol 1:1:0.04) provided the title com-
pound trans-23 as a colorless wax (83.9 mg, 79%). Rf =0.3; IR (film): n˜ =
2974, 2936, 2874, 1718, 1653, 1457, 1437, 1391, 1368, 1249, 1196, 1153,
1
1048, 957, 903, 845, 754 cmꢀ1; H NMR (250 MHz, C6D6): d=0.78 (s, 3H;
(3bS,9aS,10S,12aS,12bR)-10-tert-Butoxy-9a-methyl-2-phenyl-spiro(1’,3’-
CH3), 0.80–1.00 (m, 2H), 1.09 (s, 9H; C(CH3)3), 1.13–1.38 (m, 3H), 1.52–
E
dioxolane
ACHTREUNG
1.79 (m, 3H), 1.82–2.27 (m, 4H), 2.30–2.58 (m, 6H), 2.61 (s, 3H; NCH 3),
2.99 (t, 3J=13.6 Hz, 1H), 3.39 (t, 3J=8.3 Hz, 1H; 10-H), 3.52–3.68 ppm
(m, 4H; OCH2CH2O); 13C NMR (62.9 MHz, C6D6, add. DEPT): d=
11.30 (+, CH3), 23.86 (ꢀ, CH2), 24.28 (ꢀ, CH2), 24.77 (+, CH), 25.31 (ꢀ,
2,3a,12c-triazadicyclopenta
AHCTREUNG
lowing GP 4,
0.289 mmol)
a
0.434 mmol) in dichloromethane (2.0 mL) was stirred at ambient temper-
ature for 12 h. Column chromatography (32 g of silica gel, diethyl ether/
pentane 1:2) provided the title product trans-26 as a colorless wax
(116 mg, 77%). Rf =0.3; [a]2D0 =+60.3( c=1.09 in MeOAc); IR (film):
n˜ =3067, 2973, 2931, 1768, 1714, 1685, 1646, 1559, 1503, 1457, 1419, 1362,
CH2), 28.86 (+, CH, 3C, C
A
(+, CH), 34.47 (ꢀ, CH2), 40.36 (ꢀ, CH2), 41.55 (+, CH), 42.25 (+, CH),
42.78 (+, CH), 42.82 (Cquat
C-9a), 43.99 (+, CH), 64.12 (ꢀ, 2C,
OCH2CH2O), 72.16 (Cquat, C(CH3)3), 80.79 (+, CH, C-10), 109.99 (Cquat
C-5), 130.09 (Cquat), 131.43 (Cquat), 177.43(C quat, NC=O), 177.67 ppm
(Cquat, NC=O); MS (70 eV): m/z (%): 457 (2) [M+], 401 (20) [M+
ꢀC4H8], 400 (6) [M+ꢀC4H9], 356 (2), 339 (8), 289 (2), 227 (1), 155 (1),
112 (2), 99 (7), 78 (100), 52 (10), 45 (5); HRMS: m/z: calcd for
C27H39O5N+H+ (458.6): 458.29005 (correct HRMS).
1299, 1267, 1244, 1194, 1143, 1092, 1073, 945, 911, 733 cmꢀ1
(300 MHz, CDCl3): d=1.02 (s, 3H; CH3), 1.10 (s, 9H; C(CH3)3), 1.42–
;
1H NMR
AHCTREUNG
1.73(m, 6H), 1.79–2.21 (m, 7H), 2.77 (m c, 2H), 3.08 (mc, 1H), 3.39 (t,
3J=7.3Hz, 1H; 10-H), 3.90–4.08 (m, 5H), 7.27–7.53ppm (m, 5H; Ph);
13C NMR (75.5 MHz, CDCl3, add. APT): d=11.75 (+, CH3), 23.90 (ꢀ,
Dimethyl(5R,8S,13S,14S,17S)-17-tert-butoxy-13-methyl-
CH2), 24.65 (ꢀ, CH2), 25.59 (ꢀ, CH2), 28.76 (+, 3C, C(CH3)3), 31.00 (ꢀ,
H
spiro(1’,3’dioxolane[2’,3]-2,3,4,5,8,11,12,13,14,15,16,17-dodecahydro-1H-
R
CH2), 35.87 (ꢀ, CH2), 38.85 (ꢀ, CH2), 41.28 (ꢀ, Cquat, C-13), 45.03 (ꢀ,
CH2), 52.52 (+, CH), 54.76 (+, CH), 55.50 (+, CH), 64.47 (ꢀ, 2C, CH2,
cyclopenta[a]phenanthrene-6,7-dicarboxylate) (trans-24): Following GP
4, a solution of the tricyclic diene trans-19 (100 mg, 0.289 mmol) and di-
methyl acetylenedicarboxylate (103mg, 0.726 mmol) in benzene
(1.00 mL) was heated at 908C for 14 h. Column chromatography (30 g of
silica gel, pentane/diethyl ether 1:1) provided the title product trans-24 as
OCH2CH2O), 72.53( ꢀ, Cquat, C(CH3)3), 79.63( +, CH, C-10), 107.49 (ꢀ,
G
Cquat, C-5), 123.57 (ꢀ, Cquat), 125.26 (+, CH), 127.63( +, CH, 2C, Ph),
129.18 (+, CH, 2C, Ph), 129.75 (ꢀ, Cquat), 131.42 (ꢀ, Cquat), 149.76 (ꢀ,
Cquat, NC=O), 153.49 ppm (ꢀ, Cquat, NC=O); MS (70 eV): m/z (%): 521.4
(100) [M+], 465 (62) [M+ꢀC4H8], 420 (5), 354 (8), 345 (2), 289 (16), 289
(2), 231 (2), 178 (9), 119 (4), 99 (21), 786 (6), 57 (21) [C4H9+], 41 (4);
HRMS: m/z: calcd for C30H39N3O5+H+ (522.7): 522.29631 (correct
HRMS).
a
colorless wax (91.8 mg, 65%). Rf =0.4; [a]2D0 =+79.5 (c=1.17 in
MeOAc); IR (film): n˜ =2972, 2845, 1739, 1652, 1635, 1464, 1419, 1387,
1374, 1250, 1224, 1191, 1109, 1090, 1014, 923, 858 cmꢀ1 1H NMR
(300 MHz, CDCl3): d=0.92 (s, 3H; CH3), 1.09 (s, 9H; C(CH3)3), 1.13–
;
AHCTREUNG
1.60 (m, 3H), 1.65–1.99 (m, 5H), 2.42–2.76 (m, 7H), 3.00–3.11 (m, 1H),
3.19–3.25 (m, 1H), 3.31 (dd, 3J=8.7, 3J=6.3Hz, 1H; 17- H), 3.72 (s, 3H;
OCH3), 3.77 (s, 3H; OCH3), 3.91–4.05 ppm (m, 4H; OCH2CH2O);
13C NMR (75.6 MHz, CDCl3, add. APT): d=11.68 (+, CH3), 23.35 (ꢀ,
(9aS,10S,12aR)-10-tert-Butoxy-2,9a-dimethyl-spiro(1’,3’-dioxolane
3b,6,7,8,9,9a,10,11,12,12a,12b,12c-dodecahydro-3aH,4H-2-
[2’,5]-
azadicyclopenta[a,l]phenanthrene-1,3-dione) (cis-23a,b): Following GP
A
4, a solution of the tricyclic diene cis-19 (416 mg, 1.20 mmol) and N-
methylmaleimide (187 mg, 1.50 mmol) in benzene (2.00 mL) was heated
at 1108C for 14 h. Column chromatography (25 g of silica gel, pentane/di-
ethyl ether/methanol 1:1:0.02) provided the title compounds cis-23a,b as
CH2), 24.75 (ꢀ, CH2), 26.12 (ꢀ, CH2), 28.66 (+, 3C, C(CH3)3), 31.26 (ꢀ,
G
CH2), 37.41 (ꢀ, CH2), 38.65 (+, CH), 39.32 (ꢀ, CH2), 40.26 (+, CH),
43.81 (ꢀ, CH2), 44.10 (ꢀ, Cquat, C-13), 51.98 (+, CH), 52.09 (+, CH),
54.41 (+, CH), 64.37 (ꢀ, OCH2CH2O), 64.39 (ꢀ, OCH2CH2O), 72.36 (ꢀ,
a
colorless wax (341 mg, 62%). Rf =0.3; [a]2D0 =+3.20 (c=1.53in
C
quat, C
A
MeOAc); IR (film): n˜ =2969, 2881, 1772, 1744, 1700, 1653, 1617, 1457,
Cquat), 130.80 (ꢀ, Cquat), 135.56 (ꢀ, Cquat), 149.03( ꢀ, Cquat), 168.44 (ꢀ,
1436, 1383, 1363, 1327, 1287, 1246, 1198, 1121, 1091, 1048, 979, 948, 902,
C
quat, C=O), 169.01 ppm (ꢀ, Cquat, C=O); MS (70 eV): m/z (%): 488 (6)
871, 844 cmꢀ1 1H NMR (250 MHz, CDCl3, distinguishable signals of the
;
[M+], 456 (100), 428 (3), 399 (54), 341 (6), 301 (5), 288 (9), 275 (12), 230
(4), 203(1), 143(2), 115 (4), 99 (15), 86 (12), 57 (52) [C 4H9+], 41 (12);
HRMS: m/z: calcd for C28H40O7+H+ (489.6): 489.28468 (correct HRMS).
individual diastereomers are marked by #): d=0.83(s, 3H; CH 3), 1.00 (s,
3H; CH3)#, 1.16 (s, 9H; C (CH3)3)#, 1.22–2.05 (m,
A
ACHTREUNG
7H), 2.12–2.58 (m, 10H), 2.72 (mc, 1H), 2.90 (s, 3H; NCH3), 2.98 (s, 3H;
NCH3)#, 3.04 (mC, 1H), 3.52 (dd, 3J=9.5, 3J=8.0 Hz, 1H; 10-H), 3.52–
3.68 ppm (m, 4H; OCH2CH2O); 13C NMR (75.5 MHz, CDCl3, add.
APT): d=22.08 (+, CH3), 23.00 (+, CH3)#, 23.37 (ꢀ, CH2), 23.71 (ꢀ,
CH2)#, 24.52 (+, CH), 24.84 (+, CH)#, 25.76 (ꢀ, CH2), 25.97 (ꢀ, CH2)#,
(5R,8S,13S,14S,17S)-Spiro(1’,3’-dioxolane-[2’,3]-17-tert-butoxy-6-chloro-
13-methyl-2,3,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopen-
ta[a]phenanthrene-6-carbonitrile) (trans-25): Following GP 4, the tricy-
clic diene (trans-19) (100 mg, 0.289 mmol) and 2-chloroacrylonitrile
(0.200 mL) in benzene (1.0 mL) were heated at 908C for 14 h. Column
chromatography (35 g of silica gel, pentane/diethyl ether 3:1) provided
the title compound trans-25 as a mixture of isomers and as a colorless
wax (84.0 mg, 67%). Rf =0.4; IR (film): n˜ =2973, 2931, 1717, 1675, 1635,
1617, 1472, 1457, 1437, 1419, 1389, 1363, 1249, 1198, 1142, 1118, 1092,
26.33 (ꢀ, CH2), 28.72 (+, 3 C, C
U
G
Chem. Eur. J. 2008, 14, 7236 – 7249
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7245

A. de Meijere et al.
64.07 (ꢀ, CH2, 2C, OCH2CH2O), 64.40 (ꢀ, CH2, 2C, OCH2CH2O)#,
129.79 ppm (ꢀ, Cquat); ESI-MS (NH3): m/z (%): 990 (31), 487 (100) [M+
+H]; HRMS: m/z: calcd for C30H46O5+H+ (487.6): 487.34180 (correct
HRMS).
72.29 (ꢀ, Cquat, C
(CH3)3), 72.55 (ꢀ, Cquat, C
(CH3)3]#, 76.19 (+, CH, C-10),
80.36 (+, CH, C-10)#, 108.15 (ꢀ, Cquat, C-5), 109.91 (ꢀ, Cquat, C-5)#,
125.94 (ꢀ, Cquat), 127.97 (ꢀ, Cquat)#, 129.77 (ꢀ, Cquat), 134.04 (ꢀ, Cquat)#,
177.71 (ꢀ, Cquat, C=O), 177.89 (ꢀ, Cquat, C=O), 179.73( ꢀ, Cquat, C=O)#,
179.83ppm ( ꢀ, Cquat, C=O)#; MS (70 eV): m/z (%): 457 (1) [M+], 412
(1), 401 (64) [M+ꢀC4H8], 400 (22) [M+ꢀC4H9], 383 (10), 356 (7), 339
(22), 321 (9), 305 (4), 290 (1), 155 (2), 112 (3), 86 (5), 78 (6), 74 (26), 57
(9) [C4H9+], 43(100); HRMS: m/z: calcd for C27H39NO5+H+ (458.6):
458.29044 (correct HRMS).
Dimethyl (13S,14S,17S)-17-tert-Butoxy-13-methyl-spiro(1’,3’-dioxolane-
A
phenanthrene-6,7-dicarboxylate) (trans-29): Following GP 4, a solution
of the tricyclic diene trans-19 (100 mg, 0.289 mmol) and dimethyl maleate
(62.6 mg, 0.434 mmol) in benzene (1.5 mL) was stirred at 1308C for 12 h.
Column chromatography (25 g of silica gel, pentane/diethyl ether 1:1)
provided a mixture of two diastereoisomers of trans-29 as a colorless wax
(63.8 mg, 45%). IR (film): n˜ =2975, 1735, 1684, 1653, 1472, 1457, 1436,
(8aR,9S,9aR,12aR)-10,10-dimethyl-spiro(1’,3’-dioxolane
2,3b,4,5,6,7,8,12,12a,13,14,15,15a,15b,15c-tetradecahydro-3aH-2-phenyl-
9,14-dioxa-[c]-2-azadicyclopenta[a,l]phenanthrene-1,3-dione) (27a,b):
[2’,12])-
1388, 1362, 1262, 1197, 1124, 1081, 1033 cmꢀ1 1H NMR (250 MHz,
;
CDCl3, distinguishable signals of the individual diastereomers are
AHCTREUNG
Following GP 4, a solution of the tricyclic diene 20 (60.0 mg, 0.181 mmol)
and N-phenylmaleimide (156 mg, 0.962 mmol) in toluene (2.0 mL) was
stirred at 808C for 20 h. Column chromatography (19 g of silica gel, pen-
tane/diethyl ether 2:1) provided the title products 27a,b as a colorless
wax (48.5 mg, 53%). Rf =0.3; IR (film): n˜ =3064, 2963, 2874, 1742, 1705,
1650, 1627, 1448, 1373, 1354, 1320, 1292, 1257, 1199, 1121, 1091, 1066,
marked by #): d=0.73(s, 3H; CH 3), 0.73(s, 3H; CH 3), 0.86 (s, 3H;
CH3)#, 0.90 (s, 3H; CH3)#, 1.07 (s, 9H; C
A
N
1.13–2.16 (m, 3H), 2.35–2.81 (m, 9H), 2.92–3.04 (m, 6H), 3.23–3.39 (m,
1H), 3.60 (s, 3H; OCH3), 3.61 (s, 3H; OCH3)#, 3.63 (s, 3H; OCH3), 3.67
(s, 3H; OCH3)#, 3.68 (s, 3H; OCH3)#, 3.88–4.03 ppm (m, 4H;
OCH2CH2O); 13C NMR (75.5 MHz, CDCl3, add. APT): d=10.14 (s,
CH3)#, 11.99 (s, CH3), 22.45 (ꢀ, CH2)#, 23.60 (ꢀ, CH2), 24.10 (ꢀ, CH2)#,
25.60 (ꢀ, CH2)#, 25.83( ꢀ, CH2), 26.10 (ꢀ, CH2)#, 26.48 (ꢀ, CH2)#, 28.71
994, 944, 912, 845 cmꢀ1 1H NMR (300 MHz, CDCl3, distinguishable sig-
;
nals of the individual diastereomers are marked with “#”): d=1.29 (s,
3H; CH3), 1.42 (s, 3H; CH3), 1.40 (s, 3H; CH3)#, 1.49 (s, 3H; CH3)#,
1.60–1.73(m, 2H) #, 1.82–2.01 (m, 2H), 2.04–2.20 (m, 2H), 2.28–2.49 (m,
5H), 2.51–2.69 (m, 2H), 2.73(dd, 3J=8.8, 3J=6.9 Hz, 1H), 3.34–3.60 (m,
4H; 2’’-H, 3’’-H), 4.05 (dd, 3J=6.9, 3J=2.2 Hz, 1H; 9-H), 4.83(d, 3J=
(+, 3 C, C
A
(+, CH), 35.07 (+, CH)#, 35.42 (ꢀ, CH2)#, 35.75 (ꢀ, CH2)#, 36.07 (ꢀ,
CH2), 36.95 (+, CH)#, 38.60 (+, CH), 39.06 (ꢀ, CH2), 39.41 (+, CH),
39.73 (ꢀ, CH2), 39.83 (+, CH), 41.11 (+, CH)#, 41.76 (ꢀ, CH2)#, 42.56
(ꢀ, CH2), 43.03 (+, CH)#, 43.79 (ꢀ, Cquat), 44.37 (+, CH), 44.76 (+,
CH), 44.99 (+, CH)#, 45.26 (+, CH)#, 49.22 (+, CH)#, 51.45 (+, OCH3),
51.68 (+, OCH3), 51.82 (+, 2C, OCH3)#, 64.14 (ꢀ, 2C, OCH2CH2O)#,
6.6 Hz, 1H; 8-H), 6.94–7.03(m, 3H; Ph) #, 7.10–7.24 (m, 3H; Ph), 7.43–
#
7.51 (m, 2H; Ph), 7.58–7.63ppm (m, 2H; Ph)
;
13C NMR (75.5 MHz,
CDCl3 add. APT): d=20.94 (ꢀ, CH2), 21.52 (ꢀ, CH2), 23.47 (ꢀ, CH2),
23.69 (ꢀ, CH2), 25.24 (+, CH3), 27.27 (+, CH3), 30.38 (+, CH)#, 32.52
(+, CH), 37.67 (+, CH), 39.87 (ꢀ, CH2), 42.65 (+, CH), 43.37 (+, CH),
44.06 (ꢀ, CH2), 45.08 (+, CH), 63.88 (ꢀ, OCH2CH2O), 64.35 (ꢀ,
64.29 (ꢀ, OCH2CH2O), 64.35 (ꢀ, OCH2CH2O), 72.30 (ꢀ, Cquat, C
79.54 (+, CH, C-17)#, 80.19 (+, CH, C-17), 108.10 (ꢀ, Cquat, C-3)#, 108.50
(ꢀ, Cquat, C-3), 125.93 (ꢀ, Cquat)#, 126.23( ꢀ, Cquat)#, 126.99 (ꢀ, 2C, Cquat),
131.97 (ꢀ, Cquat), 135.29 (ꢀ, Cquat), 173.54 (ꢀ, C=O)#, 173.81 (ꢀ, C=O),
174.26 (ꢀ, C=O)#, 175.98 ppm (ꢀ, C=O); ESI-MS (NH3): m/z (%): 1020
(67), 998 (77), 529 (38), 513 (19), 508 (92) [M+NH4+], 491 (100) [M+H+
], 431 (30), 375 (18); HRMS: m/z: calcd for C28H42O7+H+ (491.6):
491.30033 (correct HRMS).
OCH2CH2O), 69.02 (+, CH, C-9), 74.34 (+, CH, C-8), 107.54 (ꢀ, Cquat
,
C-11), 117.02 (ꢀ, Cquat, C-2’), 119.63( +, CH, Ph), 123.99 (ꢀ, Cquat)#,
125.02 (ꢀ, Cquat), 125.84 (ꢀ, Cquat)#, 127.77 (+, CH, 2C, Ph), 127.87 (+,
CH, 2C, Ph)#, 128.60 (+, CH, 2C, Ph), 128.79 (+, CH, 2C, Ph)#, 133.42
(ꢀ, Cquat, Ph), 143.80 (ꢀ, Cquat), 175.82 (ꢀ, Cquat, C=O), 176.51 ppm (ꢀ,
Cquat, C=O); MS (70 eV): m/z (%): 505 (100) [M+], 490 (7) [M+ꢀCH3],
447 (11), 403 (24), 385 (16), 361 (7), 345 (96), 318 (11), 273 (5), 199 (26),
171 (13), 157 (10), 129 (22), 99 (17), 91 (24), 87 (40), 77 (12), 67 (10);
HRMS: m/z: calcd for C30H35O6N (505.6): 505.2463(correct HRMS).
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-tert-Butoxy-2,9a-dimethyl-
3b,6,7,8,9,9a,10,11,12,12a,12b,12c-dodecahydro-3aH,4H-2-aza-
dicyclopenta[a,l]phenanthrene-1,3,5-trione (trans-30): p-Toluenesulfonic
N
acid (93.0 mg, 0.489 mmol) was added to a solution of the steroid ana-
logue trans-23 (700 mg, 1.53mmol) in acetone (30 mL) and water
(0.100 mL). The resulting solution was stirred at 238C for 24 h. The reac-
tion mixture was concentrated in vacuo, and the residue was taken up in
diethyl ether (75 mL). After washing with sat. NaHCO3 solution (20 mL),
the organic layer was dried over MgSO4. After removal of the volatile
components in vacuo, the residue was purified by column chromatogra-
phy on silica gel (30 g, pentane/diethyl ether 1:2) to yield the product
trans-30 as a colorless wax (626 mg, 99%). Rf =0.4; IR (film): n˜ =2967,
2930, 2871, 1768, 1695, 1653, 1457, 1436, 1385, 1362, 1336, 1288, 1268,
(13S,14S,17S)-17-tert-Butoxy-13-methyl-spiro(1’’,3’’-dioxolane
2,3,4,5,6,7,8,11,23,13,14,15,16,17-tetradecahydro-1H-(6’,6’dimethyl-4’,8’-
dioxaspiro)[6’,3]cyclopropa[6,7]cyclopenta[a]phenanthrene) (trans-28):
Following GP 4, solution of the tricyclic diene trans-19 (100 mg,
0.289 mmol) and 6,6-dimethyl-4,8-dioxaspiro[2.5]oct-1-ene (60.8 mg,
A
G
ACHTREUNG
a
AHCTREUNG
0.434 mmol) in benzene (1.5 mL) was stirred at 1308C for 12 h. Column
chromatography (27 g of silica gel, pentane/diethyl ether 1:1) provided a
mixture of two diastereoisomers of trans-28 as a colorless wax (43.6 mg,
31%). Rf =0.5; IR (film): n˜ =2965, 2872, 1653, 1635, 1472, 1393, 1363,
1267, 1220, 1193, 1108, 1078, 1036, 962, 948, 898, 823, 794 cmꢀ1 1H NMR
;
1226, 1198, 1131, 1095, 1081, 1064, 980, 963, 900, 839 cmꢀ1
;
1H NMR
(300 MHz, C6D6, distinguishable signals of the single diastereomers are
(250 MHz, CDCl3): d=0.69 (s, 3H; CH3), 1.16 (s, 9H; C(CH3)3), 1.21–
AHCTREUNG
marked by #): d=0.73(s, 3H; CH 3), 0.88 (s, 6H; CH3)#, 0.98 (s, 3H;
1.73(m, 8H), 1.93–2.13(m, 1H), 2.19–2.52 (m, 5H), 2.56–2.73(m, 2H),
2.96–3.09 (m, 2H), 2.90 (s, 3H; NCH3), 3.49 (mC, 1H), 3.58 ppm (t, 3J=
8.7 Hz, 1H; 10-H); 13C NMR (75.5 MHz, C6D6, add. APT): d=11.56 (+,
CH3), 22.88 (ꢀ, CH2), 23.18 (ꢀ, CH2), 24.28 (+, CH), 25.25 (ꢀ, CH2),
CH3), 1.03(s, 3H; CH 3), 1.10 (s, 9H; C
N
N
1.14–1.25 (m, 2H), 1.32–2.22 (m, 11H), 2.38–2.70 (m, 5H), 3.33 (t, 3J=
7.0 Hz, 1H; 17-H), 3.42–3.57 (m, 5H), 3.90–4.05 ppm (m, 4H;
OCH2CH2O); 13C NMR (75.5 MHz, CDCl3, add. APT): d=11.53( +,
CH3), 15.69 (+, CH3)#, 21.41 (+, CH, Cp), 22.07 (+, CH, Cp)#, 22.23( +,
CH, Cp), 22.44 (+, CH, Cp)#, 22.74 (ꢀ, CH2), 23.33 (+, CH)#, 23.68 (ꢀ,
CH2), 24.52 (ꢀ, CH2)#, 25.03( +, CH), 25.32 (ꢀ, CH2)#, 25.70 (ꢀ, CH2),
28.53( +, 3 C; C
A
38.15 (ꢀ, CH2), 40.69 (+, CH), 40.77 (+, CH), 41.42 (ꢀ, CH2), 42.02 (+,
CH), 42.82 (Cquat, C-9a), 43.75 (+, CH), 72.21 (Cquat, C(CH3)3), 80.78 (+,
CH, C-10), 130.60 (ꢀ, Cquat), 131.01 (ꢀ, Cquat), 177.08 (ꢀ, Cquat, NC=O),
177.45 (ꢀ, Cquat, NC=O), 209.33 ppm (ꢀ, Cquat, C=O); MS (70 eV), m/z
(%): 413(5) [ M+], 371 (6), 357 (100) [M+ꢀC4H8], 356 (21) [M+ꢀC4H9],
339 (82), 312 (20), 300 (17), 295 (11), 246 (28), 227 (20), 201 (6), 166 (12),
122 (4), 113 (13), 61 (8), 57 (38) [C4H9+], 43(29); HRMS: m/z: calcd for
C25H35NO4+H+ (414.6): 414.26393 (correct HRMS).
27.07 (ꢀ, CH2), 27.32 (+, CH), 27.41 (+, CH)#, 28.70 (+, 3 C, C
A
28.83( +, 3 C, C
G
CH2), 31.13 (ꢀ, CH2), 31.80 (ꢀ, CH2), 32.03 (+, CH), 34.26 (ꢀ, CH2),
35.67 (ꢀ, CH2), 36.79 (ꢀ, CH2), 38.99 (ꢀ, CH2), 41.92 (ꢀ, CH2), 42.37
(+, CH)#, 42.60 (ꢀ, Cquat), 43.44 (ꢀ,Cquat)#, 45.29 (ꢀ, Cquat), 52.05 (+,
CH), 64.07 (ꢀ, OCH2CH2O)#, 64.30 (ꢀ, 2C, OCH2CH2O), 64.42 (ꢀ,
OCH2CH2O)#, 71.17 (ꢀ, Cquat, C
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-Hydroxy-2,9a-dimethyl-
3b,6,7,8,9,9a,10,11,12,12a,12b,12c-dodecahydro-3aH,4H-2-aza-
(ꢀ, CH2)#, 75.65 (ꢀ, CH2), 75.77 (ꢀ, CH2)#, 76.43( ꢀ, CH2), 80.32 (+,
CH), 81.43( +, CH)#, 89.03( ꢀ, Cquat), 89.94 (ꢀ, Cquat)#, 108.92 (ꢀ, Cquat),
109.07 (ꢀ, Cquat), 126.24 (ꢀ, Cquat), 127.87 (ꢀ, Cquat), 127.97 (ꢀ, Cquat),
dicyclopenta
A
acid (3.00 mL) was added to a solution of the oxosteroid analogue trans-
7246
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 7236 – 7249

Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
30 (237 mg, 0.573 mmol) in methylene chloride (27.0 mL), and the mix-
ture was stirred at 238C for 2.0 h. After this time, the reaction mixture
was concentrated in vacuo, and the residue was taken up in diethyl ether
(30 mL), washed with sat. NaHCO3 solution (10 mL), and dried over
MgSO4. After concentration in vacuo, the residue was purified by
column chromatography (25 g of silica gel, diethyl ether+3% methanol)
7.2 Hz, 1H; 17-H); 13C NMR (75.6 MHz, CDCl3, add. APT): d=10.20
(+, CH3), 23.22 (ꢀ, CH2), 24.27 (ꢀ, CH2), 27.32 (ꢀ, CH2), 29.15 (ꢀ,
CH2), 30.25 (ꢀ, CH2), 31.30 (+, CH), 35.35 (ꢀ, CH2), 36.20 (+, CH),
38.27 (+, CH), 40.50 (ꢀ, CH2), 42.94 (ꢀ, CH2), 46.90 (+, CH), 47.42 (ꢀ,
C
quat, C-13), 80.85 (+, CH, C-17), 117.94 (ꢀ, Cquat), 118.60 (ꢀ, Cquat),
126.00 (ꢀ, Cquat), 129.78 (ꢀ, Cquat), 207.15 ppm (ꢀ, Cquat, C=O); MS
(70 eV): m/z (%): 324 (100) [M+], 291 (11), 265 (15), 252 (9), 226 (11),
195 (8), 129 (9), 111 (10), 84 (18), 55 (12), 41 (17); HRMS: m/z: calcd for
C20H24N2O2+H+ (325.4): 325.19113 (correct HRMS).
to yield the product trans-31 as
a colorless solid. M.p. 169–1738C
(186 mg, 91%). Rf =0.3; [a]2D0 =ꢀ16.1 (c=0.981 in MeOAc); IR (film):
n˜ =3370, 2955, 2876, 1768, 1684, 1653, 1559, 1437, 1382, 1371, 1286, 1265,
1138, 1046, 1034, 983, 911, 881, 844 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-tert-Butoxy-5-methoxy-2,9a-di-
methyl-3b,6,7,8,9,9a,10,11,12,12a,12b,12c-dodecahydro-3aH,4H-2-
d=0.67 (s, 3H; CH3), 1.18–1.78 (m, 6H), 2.01–2.27 (m, 4H), 2.28–2.51
(m, 3H), 2.54–2.70 (m, 4H), 2.85 (s, 3H; NCH 3), 2.90–3.05 (m, 2H), 3.46
(dd, 3J=20, 3J=12 Hz, 1H), 3.82 ppm (t, 3J=8.0 Hz, 1H; 10-H);
13C NMR (75.6 MHz, CDCl3 add. H,H-COSY, APT, HSQC, HMBC,
NOESY): d=11.39 (+, CH3), 22.86 (ꢀ, CH2), 23.44 (ꢀ, CH2), 24.28 (ꢀ,
CH2), 24.69 (+, CH3, NCH3), 30.64 (ꢀ, CH2), 33.12 (ꢀ, CH2), 34.36 (+,
CH), 38.11 (ꢀ, CH2), 40.63( +, CH), 40.66 (ꢀ, CH2), 41.19 (ꢀ, Cquat, C-
9a), 41.91 (+, CH), 42.71 (+, CH), 43.69 (+, CH), 81.50 (+, CH, C-10),
130.00 (ꢀ, Cquat), 131.27 (ꢀ, Cquat), 177.33 (ꢀ, Cquat), 177.83( ꢀ, Cquat),
211.88 ppm (ꢀ, Cquat, C=O); MS (70 eV): m/z (%): 357 (100) [M+], 354
(46), 337 (10), 298 (14), 283 (10), 246 (100), 221 (82), 185 (11), 167 (15),
azacyclopropa
N
N
tion of diethylzinc (2.24 mL, 2.24 mmol, 1.00m in hexane) in CH2Cl2
(10 mL) was carefully treated with trifluoroacetic acid (255 mg,
2.24 mmol) at 08C. The resulting mixture was stirred for 20 min. After
dropwise addition of diiodomethane (600 mg, 2.24 mmol), the reaction
mixture was stirred until a homogeneous solution had formed. The oxos-
teroid analogue trans-30 (92.9 mg, 0.224 mmol) was added as a solution
in diethyl ether (2.0 mL), and the resulting solution was stirred at 08C
for 1 h, and at 228C for 12 h. After his time, the reaction mixture was
poured into sat. NH4Cl solution and extracted with diethyl ether
(35 mL). The organic layer was washed with water (20 mL) and dried
over MgSO4. After concentration in vacuo, the residue was purified by
column chromatography on silica gel (15 g, pentane/diethyl ether 1:2) to
yield the title compound 34 as a colorless wax (73.1 mg, 74%). Rf =0.6;
[a]2D0 =ꢀ4.7 (c=0.68 in MeOAc); IR (film): n˜ =2973, 2931, 1700, 1653,
143(14), 129 (20), 113(62), 79 (18), 55 (03); HRMS:
m/z: calcd for
C21H27NO4+H+ (358.4): 358.20123 (correct HRMS).
(5R,6S,7S,8S,13S,14S,17S)-17-tert-Butoxy-13-methyl-3-oxo-
2,3,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenan-
threne-6,7-dicarbonitrile (trans-32): p-Toluenesulfonic acid (80.0 mg,
0.402 mmol) was added to a solution of the steroid analogue trans-22
(330 mg, 777 mmol) in acetone (15.0 mL) and water (0.050 mL). The re-
sulting solution was stirred at 238C for 24 h. After this time, the reaction
mixture was concentrated in vacuo, and the residue was taken up in di-
ethyl ether (55 mL). After washing the solution with sat. NaHCO3 solu-
tion (15 mL), the organic layer was dried over MgSO4. After removal of
the volatile components in vacuo, the residue was purified by column
chromatography (30 g of silica gel, pentane/diethyl ether 1:2) to yield the
product trans-32 as a colorless wax (252 mg, 85%). Rf =0.3; IR (film):
n˜ =2974, 2931, 2874, 2267, 1715, 1637, 1508, 1461, 1444, 1389, 1363, 1337,
1635, 1457, 1437, 1419, 1387, 1363, 1288, 1255, 1195, 1080, 1034, 901 cmꢀ1
;
1H NMR (250 MHz, CDCl3): d=0.52 (t, 3J=5.8 Hz 1H; c-Pr-H), 0.60 (s,
3H; CH3), 0.80 (dd, 3J=11.0, 3J=5.9 Hz, 1H; cPr-H), 1.11 (s, 9H; C-
A
(mc, 1H), 2.84 (s, 3H; NCH3), 2.93(dd, 3J=8.9, 3J=5.7 Hz, 1H), 3.11
(dd, 3J=9.0, 3J=6.3 Hz, 1H), 3.34 (s, 3H; OCH3), 3.53 ppm (t, 3J=
7.1 Hz, 1H; 10-H); 13C NMR (75.6 MHz, CDCl3 add. APT, HSQC): d=
10.76 (+, CH3), 12.21 (ꢀ, CH2, cPr), 21.68 (+, CH, cPr), 22.71 (ꢀ, CH2),
23.03 (ꢀ, CH2), 23.22 (ꢀ, CH2), 24.56 (+, NCH3), 25.02 (ꢀ, CH2), 28.71
(+, 3 C, C
A
1294, 1253, 1196, 1137, 1099, 1082, 1058, 1016, 969, 942, 832 cmꢀ1
1H NMR (250 MHz, CDCl3): d=0.87 (s, 3H; CH3), 1.15 (s, 9H; C-
(CH3)3), 1.18–1.26 (m, 1H), 1.31–1.64 (m, 3H), 1.73 (mc, 1H), 1.80–1.89
;
(+, CH), 40.68 (+, CH), 42.04 (+, CH), 42.18 (ꢀ, Cquat, C-9a), 45.91 (+,
CH), 53.78 (+, OCH3), 61.93( ꢀ, Cquat, C-5), 72.31 (Cquat, C
ACHTREUNG
(+, CH, C-10), 127.79 (ꢀ, Cquat), 131.82 (ꢀ, Cquat), 177.54 (ꢀ, Cquat, C=O),
178.19 ppm (ꢀ, Cquat, C=O); MS (70 eV): m/z (%): 441 (75) [M+], 426
(5) [M+ꢀCH3], 409 (14) [M+ꢀCH3OH], 384 (12) [M+ꢀC4H9], 353 (15),
337 (20), 330 (100), 320 (26), 308 (9), 273 (82), 255 (9), 223 (4), 192 (8),
162 (13), 123 (8), 112 (18), 91 (9), 57 (74) [C4H9+], 41 (21); HRMS: m/z:
calcd for C27H39NO4+H+ (442.6): 442.29560 (correct HRMS).
(m, 1H), 1.92–2.05 (m, 1H), 2.18 (mc, 2H), 2.32–2.43 (m, 1H), 2.49–2.63
(m, 3H), 2.71–2.89 (m, 2H), 2.96–3.06 (m, 2H), 3.11–3.19 (m, 2H),
3.44 ppm (t, 3J=7.5 Hz, 1H, 17-H); 13C NMR (75.6 MHz, CDCl3, add.
APT): d=10.70 (+, CH3), 23.63 (ꢀ, CH2), 24.34 (ꢀ, CH2), 27.33 (ꢀ,
CH2), 28.63( +, 3 C; C
A
CH), 35.75 (ꢀ, CH2), 36.19 (+, CH), 38.31 (+, CH), 40.58 (Cquat, C-13),
(3aR,3bS,9aS,10S,12aS,12bR,12cS)-10-Hydroxy-2,9a-dimethyl-
3b,6,7,8,9,9a,10,11,12,12a,12b12c-dodecahydro-3aH,4H-2-azacyclopropa-
42.46 (ꢀ, CH2), 46.85 (+, CH), 47.48 (ꢀ, CH2), 72.58 (ꢀ, Cquat, C(CH3)3],
79.88 (ꢀ, Cquat, CO2C
C
A
N
S,9aS,10S,12aS,12bR,12cS)-10-Hydroxy-2,6,9a-trimethyl-
3b,6,7,8,9,9a,10,11,12,12a,12b,12c-dodecahydro-3aH,4H-2-
azadicyclopenta[a,l]phenanthrene-1,3,5-trione (36): Trifluoroacetic acid
U
41 (14); HRMS: m/z: calcd for C24H32O2N2+NH4 (398.5): 398.28020
(0.500 mL) was added to a solution of the cyclopropasteroid analogue 34
(40.2 mg, 0.0910 mmol) in methylene chloride (5.00 mL), and the mixture
was stirred at 238C for 2 h. After this time, the reaction mixture was con-
centrated in vacuo, and the residue was taken up in diethyl ether
(30 mL), washed with sat. NaHCO3 solution (10 mL), and dried over
MgSO4. After concentration in vacuo, the residue was purified by
column chromatography (20 g of silica gel, diethyl ether) to yield the
products 35 (14.1 mg, 40%) and 36 (4.2 mg, 12%) as colorless waxes.
(correct HRMS).
(6S,7S,5R,8S,13S,14S,17S)-17-Hydroxy-13-methyl-3-oxo-
2,3,4,5,6,7,8,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenan-
threne-6,7-dicarbonitrile (trans-33): Trifluoroacetic acid (1.00 mL) was
added to
a solution of the oxosteroid analogue trans-32 (150 mg,
0.395 mmol) in methylene chloride (10.0 mL), and the mixture was
stirred at 238C for 2 h. After this time, the reaction mixture was concen-
trated in vacuo, and the residue was taken up in diethyl ether (35 mL),
washed with sat. NaHCO3 solution (10 mL), and dried over MgSO4.
After concentration in vacuo, the residue was purified by column chro-
matography (25 g of silica gel, diethyl ether+1% methanol) to yield the
product trans-33 as a colorless solid. M.p. 188–1908C (120 mg, 94%);
Rf =0.3; [a]2D0 =ꢀ4.80 (c=1.02 in MeOAc); IR (film): n˜ =3410, 2955,
2878, 2253, 1734, 1669, 1635, 1472, 1457, 1437, 1371, 1339, 1254, 1133,
Compound 35: Rf =0.5; IR (film): n˜ =3403, 2924, 2865, 1695, 1653, 1636,
1465, 1436, 1383, 1336, 1287, 1266, 1213, 1169, 1131, 1081, 1054, 1033,
973, 917, 734 cmꢀ1 1H NMR (250 MHz, CDCl3): d=0.54 (t, 3J=6.6 Hz,
;
3
3
1H; cPr-H), 0.63(s, 3H; CH 3), 0.82 (dd, J=10.9, J=6.0 Hz, 1H; cPrH),
1.16–1.40 (m, 3H), 1.42–1.76 (m, 4H), 1.97–2.29 (m, 8H), 2.37–2.44 (m,
1H), 2.53(m c, 1H), 2.87 (s, 3H; NCH3), 2.95 (dd, 3J=9.1, 3J=6.0 Hz,
3
1H), 3.11 (dd, 3J=9.0, J=6.1 Hz, 1H), 3.38 (s, 3H; OCH3), 3.80 ppm (t,
1072, 1047, 981, 942, 915, 845, 736 cmꢀ1; H NMR (300 MHz, CDCl3): d=
0.89 (s, 3H; CH3), 1.22 (mc, 1H), 1.35–1.71 (m, 3H), 1.77 (mc, 1H), 1.90
(mc, 1H), 2.08–2.27 (m, 3H), 2.30–2.46 (m, 1H), 2.49–2.60 (m, 3H), 2.72–
2.93 (m, 3H), 2.97–3.08 (m, 2H), 3.11–3.20 (m, 2H), 3.76 ppm (t, 3J=
1
3J=7.8 Hz, 1H; 10-H); 13C NMR (75.6 MHz, CDCl3, add. APT): d=
10.49 (+, CH3), 12.23( ꢀ, CH2, cPr), 21.66 (+, CH, cPr), 22.72 (ꢀ, CH2),
23.03 (ꢀ, CH2), 23.05 (ꢀ, CH2), 24.51 (ꢀ, CH2), 24.61 (+, CH3, NCH3),
Chem. Eur. J. 2008, 14, 7236 – 7249
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7247

A. de Meijere et al.
30.67 (ꢀ, CH2), 33.23 (ꢀ, CH2), 37.01 (+, CH), 40.48 (+, CH), 40.75 (+,
CH), 42.01 (+, CH), 42.62 (ꢀ, Cquat, C-13), 45.87 (+, CH), 53.83 (+,
OCH3), 61.92 (ꢀ, Cquat, C-6), 81.44 (+, CH, C-10), 128.14 (ꢀ, Cquat),
131.46 (ꢀ, Cquat), 177.46 (ꢀ, Cquat, C=O), 178.03ppm ( ꢀ, Cquat, C=O); MS
(70 eV): m/z (%): 385 (48) [M+], 353 (21) [M+ꢀCH3OH], 294 (1), 283
(2), 274 (100), 259 (10), 215 (3), 162 (4), 129 (4), 112 (6), 77 (2), 43 (2);
HRMS: m/z: calcd for C23H31NO4+H+ (386.5): 386.23258 (correct
HRMS).
Acknowledgements
This work was supported by the Land Niedersachsen and the companies
BASF AG, Schering AG, and Chemetall GmbH (Chemicals). H.W.S. is
indebted to the German Merit Foundation (Studienstiftung des deut-
schen Volkes) for a graduate student fellowship. The authors are grateful
to S. Beusshausen, Gçttingen, for his technical support in preparing the
final manuscript.
Compound 36: Rf =0.6; IR (film): n˜ =3432, 2967, 2874, 1684, 1653, 1457,
1436, 1419, 1384, 1339, 1287, 1265, 1215, 1163, 1133, 1088, 1058, 1038,
912, 732 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=0.64 (s, 3H; CH3), 1.23
3
(d, J=6.0 Hz, 3H; CH3), 1.28–1.77 (m, 4H), 1.62 (mc, 2H), 2.01–2.21 (m,
5H), 2.22–2.80 (m, 4H), 2.69 (mc, 1H), 2.86 (s, 3H; NCH3), 3.00 (dd, J=
[1] L. Träger, Steroid-Hormone, Springer Verlag, Berlin, Heidelberg,
1977.
3
9.1, 3J=6.0 Hz, 1H), 3.20 (dd, 3J=9.3, 3J=5.4 Hz, 1H), 3.58 (q, 3J=
5.9 Hz, 1H; 6-H), 3.82 ppm (t, 3J=7.2 Hz, 1H; 10-H); 13C NMR
(75.6 MHz, CDCl3, add. APT): d=11.52 (+, CH3), 11.67 (+, CH3), 22.62
(ꢀ, CH2), 23.33 (ꢀ, CH2), 24.23( ꢀ, CH2), 24.67 (+, NCH3), 30.72 (ꢀ,
CH2), 33.09 (ꢀ, CH2), 37.84 (ꢀ, CH2), 40.39 (+, CH), 40.64 (+, CH),
41.25 (+, CH), 41.82 (+, CH), 41.95 (+, CH), 42.72 (ꢀ, Cquat, C-13),
42.80 (+, CH), 81.61 (+, CH, C-10), 130.45 (ꢀ, Cquat), 131.02 (ꢀ, Cquat),
[2] a) C. R. Engel, D. Mukherjee, M. N. Chowdhury, G. S. Ramani, J.
Steroid Biochem. 1975, 6, 585–597; b) J. van der Vies, J. Steroid Bio-
chem. 1975, 6, 215–220; c) W. L. Duax, C. M. Weeks, D. C. Rohrer,
Y. Osawa, J. Steroid Biochem. 1975, 6, 195–200; d) A. Poletti, A.
Coscarella, P. Negri-Cesi, A. Colciago, F. Celotti, L. Martini, Ste-
roids 1998, 63, 246–251.
[3] a) G. Schneider, J. Woelfling, Current Organic Chemistry 2004, 8,
1381–1403; b) V. Piironen, D. G. Lindsay, T. A. Miettinen, J. L.
Toivo, J. Sci. Food Agric. 2000, 80, 939–966; c) D. I. Thurnham, Br.
J. Nutr. 1999, 82, 255–256; d) J. W. Farquhar, Handbook of Lipids in
Human Nutrition 1996, pp. 101–105; e) C. Djerassi, N. Theobald,
W. C. M. Kokke, C. S. Pak, R. M. K. Carlson, Pure Appl. Chem.
1979, 51, 1815–1828; f) C. Descoteaux, J. Provencher-Mandeville, I.
Mathieu, V. Perron, S. Mandal, E. Asselin, G. Berube, Bioorg. Med.
Chem. Lett. 2003, 13, 3927–3931.
177.38 (ꢀ, Cquat, NC=O), 177.58 (ꢀ, Cquat, NC=O), 213.50 ppm (ꢀ, Cquat
,
C=O); DCI-MS (NH3): m/z (%): 389 (100) [M++NH4], 372 (3) [M+
+H], 266 (2); HRMS: m/z: calcd for C22H29NO4+H+ (371.5): 372.21696
(correct HRMS).
Dimethyl (13R,14S,17S)-17-tert-Butoxy-13-methyl-spiro(1’,3’-dioxolane-
ACHTREUNG
AHCTREUNG
[4] D. Refojo, A. C. Liberman, F. Holsboer, E. Arzt, Immunol. Cell
Biol. 2001, 79, 385–394.
1H-cyclopenta[a]phenanthrene-6,7-dicarboxylate) (39): A solution of the
aromatic steroid analogue trans-24 (50.0 mg, 0.102 mmol) and DDQ
(24.3mg, 0.107 mmol) in dioxane (1.50 mL) was stirred at 100 8C for 1 h.
After his time, the reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography (20 g of silica gel, pen-
tane/diethyl ether 1:1) to yield the products 38 (34.2 mg, 69%) and 39
(2.5 mg, 5%) as colorless waxes:
[5] a) S. N. Anachenko, I. V. Torgov, Tetrahedron Lett. 1963, 1553–1558;
b) N. Cohen, B. L. Banner, W. F. Eichel, D. R. Parrish, G. Saucy,
J. M. Cassal, W. Meier, A. Fürst, J. Org. Chem. 1975, 40, 681–685;
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5625–5631; h) C. D. Dzierba, K. S. Zandi, T. Mçllers, K. J. Shea, J.
Am. Chem. Soc. 1996, 118, 4711–4712; i) K. C. Nicolaou, D. Vour-
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Angew. Chem. Int. Ed. 2000, 39, 44–122; j) L. Funk, K. P. C. Voll-
hardt, J. Am. Chem. Soc. 1980, 102, 5253–5261; k) K. P. C. Voll-
hardt, J. Am. Chem. Soc. 1979, 101, 215–217; l) Y. Zang, E. I. Ne-
gishi, J. Am. Chem. Soc. 1989, 111, 3454–3456; m) E. Negishi, Pure
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Negishi, J. Am. Chem. Soc. 1990, 112, 8590–8592; o) L. F. Tietze, S.
Petersen, Eur. J. Org. Chem. 2001, 1619–1624; p) F. Aulenta, M.
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2007, 13, 6047–6062.
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1745; b) L. Bondarenko, L. Lorenc, D. Bläser, R. Boese, Eur. J. Org.
Chem. 2004, 3526–3534; c) P. Allevi, A. Longo, M. Anastasia, Tetra-
hedron 1999, 55, 4167–4176; d) P. Allevi, P. Ciuffreda, M. Anastasia,
J. Org. Chem. 1997, 62, 8218–8220.
[7] a) D. C. Labaree, J. X. Zhang, H. A. Harris, C. OꢁConnor, T. Y. Rey-
nolds, R. B. Hochberg, J. Med. Chem. 2003, 46, 1886–1904; b) R. M.
Weier, L. M. Hofmann, J. Med. Chem. 1975, 18, 817–821.
[8] a) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492–
493; Angew. Chem. Int. Ed. Engl. 1971, 10, 496–497; b) Z. G. Hajos,
D. R. Parrish, J. Org. Chem. 1974, 39, 1612–1614; c) Z. G. Hajos,
D. R. Parrish, Org. Synth. 1985, 63, 26–36.
Compound 38: Rf =0.4; IR (film): n˜ =3064, 2970, 2928, 1702, 1650, 1472,
1445, 1410, 1373, 1302, 1244, 1180, 1106, 1066, 944, 915, 854 cmꢀ1
;
1H NMR (300 MHz, CDCl3): d=0.60 (s, 3H; CH3), 1.16 (s, 9H; C-
(CH3)3), 1.22–1.71 (m, 3H), 1.88–2.05 (m, 4H), 2.59–2.88 (m, 7H), 3.21
ACHTREUNG
3
3
(d, J=15.9 Hz, 1H), 3.55 (t, J=6.9 Hz, 1H; 17-H), 3.78 (s, 3H; OCH3),
3.83 (s, 3H; OCH3), 3.98 ppm (mC, 4H; OCH2CH2O); 13C NMR
(75.6 MHz, CDCl3, add. APT): d=11.35 (+, CH3), 23.62 (ꢀ, CH2), 25.56
(ꢀ, CH2), 26.16 (ꢀ, CH2), 28.69 (+, 3 C; C(CH3)3), 31.22 (ꢀ, CH2), 31.42
G
(ꢀ, CH2), 33.36 (ꢀ, CH2), 37.27 (ꢀ, CH2), 42.33 (+, CH), 45.44 (ꢀ, Cquat
,
C-13), 52.45 (+, 2C, OCH3), 64.52 (ꢀ, 2C, OCH2CH2O), 72.52 (Cquat, C-
(CH3)3), 79.33 (+, CH, C-17), 107.38 (ꢀ, Cquat, C-3), 129.20 (ꢀ, Cquat),
129.78 (ꢀ, Cquat), 129.98 (ꢀ, Cquat), 135.04 (ꢀ, Cquat), 135.83 (ꢀ, Cquat),
138.74 (ꢀ, Cquat), 168.95 (ꢀ, Cquat, C=O), 170.50 ppm (ꢀ, Cquat, C=O);
ESI-MS (NH3): m/z (%): 990 (49), 504 (100) [M++NH4], 455 (75), 397
+
(11); HRMS: m/z: calcd for C28H38O7+NH4 (504.6): 504.29604 (correct
HRMS).
Compound 39: Rf =0.4; IR (film): n˜ =3073, 2972, 2931, 1734, 1653, 1635,
1472, 1437, 1419, 1388, 1362, 1302, 1252, 1198, 1172, 1109, 1078, 1062,
1035, 947, 908, 856 cmꢀ1 1H NMR (300 MHz, CDCl3): d=0.93(s, 3H;
;
CH3), 1.18 (s, 9H; C
(CH3)3), 1.60–1.81 (m, 2H), 1.86 (t, 3J=6.3Hz, 2H),
N
2.30–2.40 (m, 1H), 2.43–2.97 (m, 6H), 3.21 (d, 3J=17.4 Hz, 1H), 3.76 (s,
3
3H; OCH3), 3.82 (s, 3H; OCH3), 3.84 (t, J=6.6 Hz, 1H; 17-H), 3.99 (mc,
4H; OCH2CH2O), 5.58 ppm (mc, 1H; 15-H); 13C NMR (75.6 MHz,
CDCl3, add. APT): d=16.82 (+, CH3), 24.65 (ꢀ, CH2), 26.14 (ꢀ, CH2),
28.71 (+, 3 C, C
A
39.51 (ꢀ, Cquat, C-13), 46.39 (ꢀ, CH2), 52.29 (+, OCH3), 52.37 (+,
OCH3), 64.37 (ꢀ, OCH2CH2O), 64.39 (ꢀ, OCH2CH2O), 72.69 (ꢀ, Cquat
C
A
[9] H. W. Sünnemann, A. Hofmeister, J. Magull, A. de Meijere, Chem.
Eur. J. 2007, 13, 3739–3756.
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15), 128.53( ꢀ, Cquat), 129.07 (ꢀ, Cquat), 129.58 (ꢀ, Cquat), 131.42 (ꢀ, Cquat),
135.42 (ꢀ, Cquat), 138.33 (ꢀ, Cquat), 142.59 (ꢀ, Cquat), 168.40 (ꢀ, Cquat, C=
O), 170.31 ppm (ꢀ, Cquat, C=O); DCI-MS (NH3): m/z (%): 502 (100)
[M+NH4+], 446 (3), 428 (1), 296 (1); HRMS: m/z: calcd for
C28H36O7+NH4 (502.6): 502.28030 (correct HRMS).
7248
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Chem. Eur. J. 2008, 14, 7236 – 7249

Synthesis of Enantiomerically Pure Steroidal Tetracycles
FULL PAPER
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Received: April 1, 2008
Published online: July 14, 2008
Chem. Eur. J. 2008, 14, 7236 – 7249
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7249