Azasteroids. Reaction of chiral N,N-maleoyl amino acids with 1-(1-trimethylsiloxyvinyl)-3,4-dihydronaphthalene

Article abstract of DOI:10.1007/s00706-005-0406-8

The cycloaddition between N,N-maleoyl amino acid esters and 1-(1-trimethylsiloxyvinyl)-3,4-dihydronaphthalene gave 11-(trimethylsiloxy) derivatives of 16-azaestra-1,3,5(10)-trienes. These were transformed by desilylation into the parent 11-oxo-derivatives

Full text of DOI:10.1007/s00706-005-0406-8

Monatshefte f€ur Chemie 137, 83–103 (2006)
DOI 10.1007/s00706-005-0406-8
Azasteroids. Reaction of Chiral
N,N-Maleoyl Amino Acids
with 1-(1-Trimethylsiloxyvinyl)-3,4-
dihydronaphthalene
Anja Bodtke1, Milton T. Stubbs2, and Hans-Hartwig Otto1;ꢀ
1
Department of Pharmaceutical=Medicinal Chemistry (PMC), Institute of Pharmacy,
Ernst-Moritz-Arndt-University, 17487 Greifswald, Germany
2
Institute of Physical Biotechnology, University of Halle, 06099 Halle, Germany
Received April 11, 2005; accepted (revised) May 11, 2005
Published online January 5, 2006 # Springer-Verlag 2006
Summary. The cycloaddition between N,N-maleoyl amino acid esters and 1-(1-trimethylsiloxyvinyl)-
3,4-dihydronaphthalene gave 11-(trimethylsiloxy) derivatives of 16-azaestra-1,3,5(10)-trienes. These
were transformed by desilylation into the parent 11-oxo-derivatives, which reacted with hydroxyl-
amines to 11-hydroxyimino derivatives. The stereochemistry of the products was elucidated using
different NMR methods, HPLC, CD, X-ray structure analysis, and calculations. It was found that
mixtures of diastereoisomers were obtained from these cycloadditions. Reactions using chiral maleoyl
amino acid derivatves did not change this result. The chiral center did not provoke stereoselectivity,
probably caused by the flexibility of the chiral side chain. A directing influence of the side chain was
found only in reactions with derivatives of phenylalanine. This might be explained as an interaction
between the aromatic system and the carbonyl groups of the imide moiety. This interaction kept the
aromatic ring in its position in the final product, and was found in the X-ray crystallographic analysis,
and agreed with results of calculations.
Keywords. Azasteroids; 2-Trialkylsiloxy-1,3-diene; Maleimides, chiral; Diels-Alder reaction;
Crystallographic structure analysis.
Introduction
Natural steroids with 8ꢀ, 9ꢁ, 13ꢀ, and 14ꢁ configuration, halogenated and par-
tially modified derivatives, and azaderivatives like the 5ꢁ-reductase inhibitor fina-
steride or the C-11 phenyl substituted antigestagene mifepristone are used as highly
potent drugs [1, 2]. These derivatives are characterized either by unusual substi-
tuents, like mifepristone, or by an azasteroid structure like finasteride. There are
ꢀ
Corresponding author. E-mail: ottoha@pharmazie.uni-greifswald.de

84
A. Bodtke et al.
many syntheses described for azasteroids containing the nitrogen atom either in
ring A or in ring B of the steroid skeleton [3]. In preceding papers we have
described a synthesis route to azasteroids by Diels-Alder reactions between 1-(1-
siloxyvinyl)olefines and dienophiles like maleimides, citraconimide, and triazoli-
dinones [4], and reactions between cyclopentadiene and maleimides [5]. Here we
report about our experiments to use chiral N-substituted maleimides bearing the
chiral center in the substituent [5] as chiral inductors in Diels-Alder reactions with
1-(1-siloxyvinyl)-3,4-dihydronaphthalene derivatives.
Results and Discussion
The synthesis of the siloxydiene 1 was done following a literature procedure, and it
is reported that the reaction between 1 and maleimide (2a) or alkyl=aryl substituted
maleimides in toluene yielded 3-methoxy-11-(trialkylsiloxy)-18-nor-16-azaestra-
1,3,5(10),9(11)-tetraene-15,17-dione derivatives [6]. We tried to use this synthesis
for the reaction between 1 and substituted maleimides, mainly chiral N,N-maleoyl
amino acid derivatives [5], to study if the chiral center in the dienophiles could
induce an enantioselective cycloaddition. To find the optimum conditions the reac-
tions were performed in CH2Cl2, THF, benzene, toluene, or without any solvent at
different temperatures (20, 40, 60, 80, 100ꢁC), and with reaction times of 4–16 h.
Performing the reaction without any solvent was in many examples the best
way. From the reaction between 1 and the maleoyl glycinate 2b at 60ꢁC for 6 h, we
isolated after addition of a mixture from n-hexane and Et2O two fractions: I, mp
Scheme 1

Azasteroids
85
142–143ꢁC (3bI), and II, mp 120–125ꢁC (3bII), and from the residue a small
amount of 4bII. From the reaction between 1 and the maleoyl L-asparaginate
20
2c we obtained one crystalline product 3c (26%), mp 132.5–134ꢁC, and ½ꢁꢂD ¼
ꢃ38.0ꢁ cmꢃ2 gꢃ1 (c ¼ 2, CH2Cl2) (Scheme 1).
Reactions between 1 and the maleoyl amino acid derivatives 5a–5i, 7a–7c, and
10 done under these conditions yielded highly viscous residues, which we could
not transform into pure crystalline materials. Neither crystallization nor CC
with silica-gel or Al2O3 were successful, and TLC and HPLC experiments (Et2O=
n-hexane 1=1) showed mixtures of at least four products.
Looking for more appropriate conditions we tried reactions catalyzed by Lewis
acids. Using EtAlCl2, ZnCl2ꢄEt2O, or TiCl4 at low temperatures failed completely.
From most experiments we isolated after hydrolytic work-up only 1-acetyl-3,4-
dihydronaphthalene (from 1). Finally, we tried a reaction catalyzed by LiClO4 [7]
using 3 equivalents LiClO4 in reactions between 1 and 2b, and 2c in CH2Cl2,
and indeed, after work-up we obtained 3bI=3bII (52%), and 3c (33%). The ob-
tained products 3bI and 3bII were identical with those from the ‘dry’ reaction
20
(mp, HPLC, spectroscopy, ½ꢁꢂD ), and in HPLC experiments with the crude mixture
of 3bI and 3bII a ratio 87:13 was found. In the not purified mixture of 3bI and 3bII
obtained from a ‘dry’ reaction, 60ꢁC, 3 h, the ratio was 66:34.
Unfortunately, the analogous reaction between 1 and the L-phenylalanine deriv-
ative 5e gave a highly viscous material, which could not be purified.
The IR spectra of 3a, 3bI, 3bII, and 3c were characterized by the carbonyl
bands of the imide moiety at ca. 1770 and 1700 cmꢃ1, whereas the carbonyl bands
of the ester functions were found at 1750–1760 cmꢃ1. The asymmetrically sub-
stituted double bond at C-9(11) caused intensive bands at 1605–1630 cmꢃ1.
Considering that the cycloaddition had occured as an endo addition we had to
discuss at least 2 possible configurations, each racemic: Structure I syn-cis (8ꢀ,
13ꢀ, 14ꢀ), and structure II anti-cis (8ꢁ, 13ꢀ, 14ꢀ) (Scheme 2)y. In compounds with
a chiral R at position 16, diastereoisomers had to be considered.
The 1H NMR spectra showed the characteristic resonance signals of the protons
of the functional groups, trimethylsilyl, methoxy, ester, etc. As each functional
group gave only one clear signal we excluded mixtures of diastereoisomers. The
Scheme 2
y
So far reactions yielded racemic compounds; thus, we use in this paper the ꢁ=ꢀ nomenclature as
common in steroid chemistry; the R=S nomenclature is used only when the absolute configuration is
known

86
A. Bodtke et al.
spectra of 3bI and 3bII differed in two aspects: In the spectra of 3bII the signal of
14-H at ꢂ ¼ 2.73 ppm (dd) was shifted highfield compared with that of 3bI found at
ꢂ ¼ 3.18 ppm (dd). The coupling constant J13-H=14-H wasꢅ9 Hz in both spectra, but
J
8-H=14-H was found to be 10.5 Hz in the spectra of 3bII, and 5.7 Hz in the spectra
of 3bI. Interpreting these values following the modified Karplus rules [8] we es-
timated a torsion angle ꢃ8-H=14-Hꢅ48ꢁ in 3bI, while the value in 3bII was ꢃ ꢅ 154ꢁ.
Therefore we postulate for 3bI the structure I and for 3bII structure II. More
difficult to interprete were the spectra of 3c. Most protons showed 2 signals, and
13C NMR spectra confirmed a mixture of diastereoisomers, but we were unable
to separate the isomers. HPLC experiments showed for 3a, 3bI, and 3bII each
one peak using a RP-18 phase, and two peaks on a (S,S)-Whelk-O1 phase (chiral).
Scheme 3

Azasteroids
87
Although the spectroscopic data of 3c looked like from a mixture of diastereo-
isomers we found with RP-18 and Chiracel OJ-R phase only one peak (k0 ¼ 4.18
resp. k0 ¼ 3.38).
The desilylation of 3a, 3bI, and 3bII was successful using MeOH and HCl [9]
yielding 4a, mp 205–210ꢁC [6], 4bI, mp 160–165ꢁC, and 4bII, mp 160–168ꢁC.
The reaction of 3c in boiling MeOH with conc. HCl gave 4c (44%).
As from the reaction between 1 and the maleoyl amino acid derivatives 5a–5i
no defined trimethylsiloxy derivatives were obtained, the viscous residues of these
reactions were treated with MeOH and HCl, whereby the crystalline products 6a
(23%), 6b (15%), 6c (10%), 6d (6%), 6e (40%), 6f (39%), and 6g (31%) were
obtained. Using similar conditions made the products 6h–8c available (Scheme 3).
In some reactions the desilylation occurred at room temperature, in some when
warmed or refluxed, in some other reactions no acid was necessary, and 8b and 8c
were obtained using AcOH (see Exp.).
The IR spectra of all 11-oxo derivatives showed two intensive carbonyl bands
at 1770–1780 and 1700–1710 cmꢃ1, representing the C¼O groups of the imide
part and the 11-oxo group. The C¼O bands of the ester moiety were found at
1730–1750 cmꢃ1, and the intensive bands between 1585 and 1610 cmꢃ1 repre-
sented the imide groups.
By cleavage of the siloxy group forming the 11-oxo derivatives a new chiral
center was formed at C-9. Considering that the stereochemical properties at C-8,
C-13, and C-14 were not influenced (changed) by the cleavage reaction at
C-11 we had to discuss four stereoisomers (Scheme 4): Structure III cis-syn-cis
(8ꢀ, 9ꢀ, 13ꢀ, 14ꢀ), structure IV trans-anti-cis (8ꢁ, 9ꢀ, 13ꢀ, 14ꢀ), structure V
trans-syn-cis (8ꢀ, 9ꢁ, 13ꢀ, 14ꢀ), and structure VI cis-anti-cis (8ꢁ, 9ꢁ, 13ꢀ, 14ꢀ).
1H NMR data of 4a (R¼H) were congruent with the reported data [6]. The
spectra of 4bI (R¼CH2CO2CH3) showed signals of the protons 1-H, 4-H, and 2-H
at ꢂ ¼ 7.24 (d), 6.61 (dd), and 6.77 (d) ppm. Two singlets were found from the
protons of the methoxy group at C-3 and from the ester group, at ꢂ ¼ 3.79 and
Scheme 4

88
A. Bodtke et al.
3.77 ppm. The spectra of the other 11-oxo derivatives showed the analogous signals
in the same range. Differences were found concerning the substituent at position 16
and the protons at C-7, C-8, C-9, C-12, C-13, and C-14.
The data show nearly analogous shift values for 4bI–6d with an aliphatic
substituent in position 16, and for compounds 6e–6i with a phenyl ring part of
the substituent at position 16 exhibiting that the aromatic system in the side chain
influenced the shift values of the steroidal skeleton. A significant difference was
noticed between the values of 4bI with 8ꢀ-configuration, and its 8ꢁ isomer 4bII.
3
4
5
5
1
From the cross signals J8,9, J1,9, J2,9, J4,9 found in the H,1H-COSY spectrum
3
of 4bI the doublet of 9-H was located at ꢂ ¼ 3.44 ppm, J8,9 ¼ 8.4 Hz, and using
the Karplus-Garbisch relation the torsion angle was estimated as ꢃ ꢆ 36ꢁ indicat-
ing a cis orientation, that means III with 8ꢀ-H and 9ꢀ-H. The spectra of 4bII
contained two separated double doublets of 12-H at ꢂ ¼ 2.77 and 2.98 ppm with
3
Jgem ¼ 17.3 Hz, and J12,13 ¼ 7.3 and 11.0 Hz, and one doublet of a doublet at
3
ꢂ ¼ 3.10 ppm for 14-H. The coupling J13,14 ¼ 9.0 Hz indicated the cis orientation,
3
13ꢀ-H, 14ꢀ-H, and from the coupling J8,14 ¼ 11.4 Hz resulted a torsion angle
ꢃ ꢆ 160ꢁ indicating a trans orientation. As we could not resolve the multiplets
of 9-H and 13-H we optimized and calculated the structure of 4bII (PM3,
HYPERCHEM [10]), and compared the experimental spectrum with the spec-
trum of the optimized structure [11]. This gave for 9-H ꢂ ¼ 3.44 ppm, for 13-H
ꢂ ¼ 3.47 ppm, and the coupling constants 3J12,13 ¼ 7.4 and 10.9 Hz, 3J13,14 ¼ 9.0 Hz,
and 3J8,9 ¼ 12.8 Hz. The last value indicated a trans orientation, and thereby 8ꢁ-H
and 9ꢀ-H (IV) for 4bII.
The data of the analogous isopropyl ester 6a and the benzyl ester 6b were
similar to those of the methyl ester 4bII. Therefore, these compounds should have
the same relative stereochemistry, 8ꢁ, 9ꢀ, 13ꢀ, and 14ꢀ (structure IV). In contrast,
the spectra of 4c, prepared from maleoyl L-asparaginate, showed for most protons
of the steroidal skeleton and for the protons of the substituent at position 16
two sets of signals. One 12-H was registered as 2 double doublets (ꢀꢂ ¼ 4.7 Hz)
with 2J12,12 ¼ 17.4 Hz, and 3J12,13 ¼ 7.1 and 7.6 Hz, confirmed by an 1H,1H-COSY
spectrum. Even 14-H showed 2 double doublets at ꢂ ¼ 3.04–3.12 ppm, with
3J13,14 ¼ 9.1 Hz, 3J8,14 ¼ 2.0 Hz (ꢀꢂ ¼ 11.4 Hz), 3J13,14 ¼ 9.1 Hz, and 3J8,14 ¼ 11.4 Hz
with ꢀꢂ ¼ 2.0 Hz. One set agreed with the syn-cis (8ꢀ, 13ꢀ, 14ꢀ) conformation, the
1
other one with the anti-cis (8ꢁ, 13ꢀ, 14ꢀ) conformation. From the H,1H-COSY
3
3
spectra 2 double doublets of 8-H were found with J7,8 ¼ 2.6 Hz, and J7,8 and
3J8,14 ꢆ 11.9 Hz. These values would fit to the anti-cis isomer. From the cross
3
signal of 8-H and 9-H 2 doublets for 9-H at ꢂ ¼ 3.43 and 3.44 ppm, J8,9 ¼ 11.5,
12.8 Hz were found, and from the Karplus-Garbisch relation a torsion angle
ꢃ ꢆ 160ꢁ or 173ꢁ resulted, both speaking for the trans orientation of 8-H und
9-H supporting the structure IV of 4c. Therefore, the observed two sets of signals
might be explained by two diastereoisomers formed by two enantiomeric steroidal
skeletons with the (S)-configuration in the side chain at position 16.
There is no difference between the 1H NMR spectra of the isomeric 2-substituted
propionates 6c obtained from maleoyl L-alaninate and 6d from maleoyl D-alaninate.
A partial definitive correlation of the signals was possible using the data of the
1H,1H-COSY spectra. For 1-H, 9-H, 12-H, 13-H, and 14-H, each two signals with
ꢀꢂ ¼ 5–8 Hz were registered. Furthermore, the signals of the ꢁ-H and of the methyl

Azasteroids
89
Scheme 5
group of the side chain showed two sets of signals ꢀꢂ ꢆ 1 Hz. The signals of 14-H
(dd) with 3J13,14 ¼ 9.0 Hz and 3J8,14 ¼ 4.7 Hz (ꢀꢂ ¼ 11.4 Hz), or with 3J13,14 ¼ 9.0 Hz
and 3J8,14 ¼ 11.4 Hz (ꢀꢂ ¼ 4.7 Hz) might be explained as in the spectra of 4c. The
3
first group with J8,14 ¼ 4.7 Hz looked like the syn-cis form (8ꢀ, 13ꢀ, 14ꢀ),
3
the second group with J8,14 ¼ 11.4 Hz like the anti-cis orientation (8ꢁ, 13ꢀ,
14ꢀ). We could not detect the coupling between 8-H and 14-H in the multiplet
1
of 8-H. In the H,1H-COSY spectrum of 6c we found long-range couplings of
1-H, 2-H, and 4-H with 9-H. From this fact, and from the cross signal of 8-H with
9-H the trans orientation of 8-H and 9-H (8ꢁ, 9ꢀ, structure IV) was deduced.
Furthermore, as the 13C NMR spectra of 6c showed double signals for the C-atoms
1, 7, 8, 10, 11, 13, and 17, we propose for 6c a mixture of 2 diastereoisomers with
(S)-configuration in the side chain as shown in Scheme 5.
As the spectral data of 6d were similar, we propose for 6d the analogous
structure with (R)-configuration in the side chain. The H NMR data of the 3
1
isomeric compounds 6e–6g obtained from reactions with the isomers of maleoyl
phenylalaninate, L-, D,L-, and D- (Table 1), showed no significant differences.
Between ꢂ ¼ 6.61 ppm and ꢂ ¼ 7.28 ppm the signals of 1-H, 2-H, and 4-H, and
the signals of the phenyl ring were recorded. ꢁ- and ꢀ-protons of the substituent
at position 16 caused an ABX-system at ꢂ ¼ 5.10, 3.48, and 3.51 ppm with
3
3
2JAB ¼ 14.1 Hz, JAX ¼ 12.3 Hz, and JBX ¼ 4.7 Hz. Protons of 3-OMe and ester
OMe were found at ꢂ ¼ 3.78 and 3.81 ppm. Using 1H,1H-COSY and 13C,1H-COSY
1
Table 1. Selected H NMR data of 6e, and torsion angles ꢃ (a Karplus, b Karplus-Garbisch)
ꢂ=ppm
J=Hz
ꢃ=ꢁ, a
ꢃ=ꢁ, b
8-H
1.31 (dd)
3J8,9 ¼ 12.2
150–180
169.5
3J8,14 ¼ 11.3
3J8,9 ¼ 12.2
145–180
159.0
9-H
3.28 (dd)
2.78 (dd)
150–180
165.9
12-H
2J12,12 ¼ 17.0
3J12,13 ¼ 8.1
10–45=135–160
37.7=142.2
12-H
13-H
2.46 (dd)
3.22 (dd)
2J12,12 ¼ 17.0
3J12,13 ¼ 9.3
0–40=135–175
31.9=147.9
3J12,13 ¼ 17.2, 9.3
3J12,13 ¼ 8.1
0–40=135–175
10–45=135–160
0–38=135–165
0–38=135–165
145–189
31.9=147.9
37.7=142.2
3J13,14 ¼ 8.8, 8.8
3J13,14 ¼ 8.8
34.4=145.4
34.4=145.4, 159.0
14-H
2.85 (dd)
3J8,14 ¼ 11.3

90
A. Bodtke et al.
data the signals of protons of the steroidal skeleton were determined. The relevant
data obtained for 6e are collected in Table 1.
Using the Karplus and the Karplus-Garbisch rules we calculated from the
3
3
relevant coupling constants J8,9 and J8,14 the torsion angles ꢃ ꢆ 150–180ꢁ and
145–180ꢁ, 165.9ꢁ and 159.0ꢁ resp. Considering the cycloaddition was a cis addi-
tion, from 3J13,14 ¼ 8.8 Hz followed torsion angles of 0–38ꢁ, 34.4ꢁ resp., and from
this results a trans-anti-cis orientation of 8-H, 9-H, 13-H, and 14-H (structure IV).
This conclusion was partially supported by NOE experiments. Irradiation at
ꢂ ¼ 1.31 ppm (8-H) caused weak positive effects on the signals of 9-H, 12-H,
and 14-H, irradiation at ꢂ ¼ 3.28 ppm (9-H) resulted in weak positive effects on
the signals of 8-H, 12-H, and a strong effect on 14-H, irradiation at ꢂ ¼ 3.22 ppm
(13-H) gave strong effects on the signals of 12-H and 14-H, and finally irradiation
at ꢂ ¼ 2.85 ppm (14-H) caused strong effects on the signals of 9-H and 13-H.
Spectral data of the ethyl ester 6h and the isopropyl ester 6i, both obtained from
reactions with the parent L-Phe derivative were congruent to those of 6e, and
therefore we postulate analogous structures.
The 1H NMR spectra of 8a obtained from the N,N-maleoyl ꢀ-Ala derivative 7a,
8b from the maleoyl carbamate 7b (alternative from 4a and methyl chloroformi-
ate), and 8c from N-(2-phenylethyl)maleimide (7c) and 1, showed the signals of the
substituent at position 16, and similar patterns for the steroidal part as all other
derivatives. The signals of 13-H and 14-H supported the cis addition, but as an
exact resolution of the signals of 8-H and 9-H was not possible, we described the
relative configuration as 8ꢄ, 9ꢄ, 13ꢀ, and 14ꢀ.
All 11-oxo derivatives were proved by HPLC experiments using mixtures
from MeCN and H2O as the mobile phase and RP-18 (achiral) and Chiracel
OJ-R or (S,S)-Whelk-O1 (chiral) columns. As expected, 4a, 4bI, 4bII, 6a, 6b,
8a, 8b, and 8c having no chiral center in the substituent at position 16, gave one
peak on the achiral RP-18 phase, but showed as racemates two peaks on the chiral
(S,S)-Whelk-O1 or Chiralcel OJ-R phase. The result of 4c seemed to be not clear,
only one peak was found on both phases. The HPLC data of 6c and 6d supported
the interpretation of their NMR data. The isolated compounds existed as two iso-
mers, which caused one peak on the RP-18 phase. On Chiracel OJ-R each com-
pound caused two peaks (ratio 1:1) with identical ꢅ values.
Surprising observations were made when the compounds 6e, 6f, and 6g,
obtained from reactions with the isomers of N,N-maleoyl phenylalaninate, were
examined by HPLC. 6e and 6g, derivatives of L-Phe and D-Phe, showed each only
one peak on the RP-18 and on the Chiracel OJ-R phase. The derivative of D,L-Phe,
6f, gave 2 peaks on the RP-18 phase (ratio 1:1), and 4 peaks on the Chiracel OJ-R
phase. This indicated that 6f was isolated as a mixture of two racemic diastereoi-
somers, a result congruent with the results from NMR spectroscopy. On the other
hand, from the reaction between 1 and N,N-maleoyl-L-Phe-OMe (5e) we isolated
the pure enantiomer 6e, and from the reaction between 1 and N,N-maleoyl-D-Phe-
OMe (5g) we isolated the pure enantiomer 6g.
As the isolated yields from these reactions were not higher than 40%, we
proved the reaction between 1 and the L-Phe derivative by following the reaction
course at 50ꢁC over 6 h by analyzing probes on RP-18 phase at the beginning and
then after 1, 2, 4, and 6 h. After 1 h the turn-over was 52%, and after 6 h 66%, and

Azasteroids
91
Fig. 1. CD spectra of 6e (a) and 6g (b) in CH2Cl2
we detected after 1 h two compounds, ratio 1:5.8, and after 6 h ratio 1:5.5. The
major compound was the silylenol ether of the isolated 6e (anti-cis), and the
minor compound was the syn-cis isomer. When similar experiments were done
with hydrolytic work-up we detected 2 products, the 11-oxo derivatives 6e and
6g, and we found, that the anti-cis adduct was much faster hydrolyzed than the
syn-cis adduct. These results demonstrated that the reaction between 1 and 5e was
stereoselective.
For proving the enantiomeric character of 6e and 6g we recorded the CD
ꢀ
spectra in CH2Cl2 (Fig. 1). The spectrum of 6e showed Cotton effects for n ! ꢆ
ꢀ
and ꢆ ! ꢆ at ꢅ ¼ 298 nm (þ9), 249 nm (þ13), 230 nm (ꢃ14.8), and 221 nm
(þ8.5). As the spectrum of 6g was the mirror image, 6e and 6g should be enan-
tiomers [12].
Structures of 6e and 6g were calculated using HYPERCHEM. We report here
the data and results for 6g. Optimization with MMþ resulted in a minimum
energy ꢀꢂEpot for the chair-boat (ring B, ring C) and the chair-chair conformation,
in which the phenyl ring of the side chain is located over ring D. A similar con-
formation was favored when we used a PM3 calculation. The X-ray crystallo-
graphic analysis of 6g gave a very similar result (Fig. 2), and the analysis of 6e
established the enantiomers.

92
A. Bodtke et al.
Fig. 2. Superposition of the X-ray analysis structure of 6g with the calculated, MMþ optimized,
conformation of 6g
Comparing the calculated conformation of 6g with the phenyl ring of the side-
chain at position 16 above the steroidal skeleton resulted for MMþ a RMS gra-
dient of 0.3, and for PM3 a RMS gradient of 0.6. The superposition of the MMþ
optimized conformation with the structure of the X-ray analysis is given in Fig. 2.
Only small differences are visible concerning the orientation of the ester group and
of the methoxy group. The benzyl group is fixed above the steroidal skeleton in
both structures.
Compounds 3bI, 3c, 6c, and 6h were transformed by standard procedures into
the 11-hydroxyimino or the 11-methoxyimino derivatives 9a–9e with satisfactory
yields up to 90% (Scheme 3).
Compound 11 (Scheme 6) was obtained as a crystalline product from the crude
reaction mixture of the reaction between 1 and N,N-maleoyl-L-Val-OMe (10), with-
out isolation of the 11-oxo derivative from this reaction.
The IR spectra of 9a–11 showed the expected 3 carbonyl bands around 1775
and 1710 cmꢃ1 from the CO groups in positions 15 and 17, and the CO bands of the
ester groups around 1730 cmꢃ1. Compounds 9a and 9b were formed as E=Z mix-
tures (ꢆ1:1), which could be seen from HPLC experiments and from the two signals
of the hydroxyl proton or the methoxy group in their 1H NMR spectra. Compounds
9c-11 gave in all HPLC experiments only one peak, either their isomers were not
separated, or each existed only as one stereoisomer. Detailed studies of the NMR
Scheme 6

Azasteroids
93
spectra showed that the stereochemistry (trans-anti-cis) of the steroidal skeleton
was not changed by the transformation of the 11-oxo derivatives into the oximes.
Summarizing our experiments we observed that the cycloaddition between 1
and maleimides bearing a chiral substituent at the nitrogen did not occur stereo-
selectively. This might be caused by the flexibility of the chiral side chain. A
mixture of diastereoisomers was formed in all reactions as in reactions with ma-
leimides bearing an achiral side chain. The ratio of diastereoisomers was influenced
by the substituents at the chiral center, the ꢁ-position of the parent amino acid. If
this substituent was a small aliphatic group like methyl, the ratio was about 1:1. If
the substituent was a benzyl group from phenylalanine, the ratio rose to 6:1, and we
isolated after workup the major isomer. The effect of the phenyl (benzyl) group in
the side chain might be explained as an interaction between the aromatic system
and the carbonyl groups of the imide moiety during the cycloaddition. This inter-
action kept the phenyl ring in its position in the final product, and was found in the
X-ray crystallographic analysis of 6g (Fig. 2) and 6e.
Experimental Part
1
Mp: Mikroheiztisch PHMX 80=2778. IR spectra (KBr): Perkin-Elmer IR 1310. H NMR spectra:
Bruker DPX 200 (200 MHz), Bruker DPX 300 (300 MHz), 13C NMR spectra: Bruker DPX 300
1
(75.43 MHz). Internal standard TMS, ꢂTMS ¼ 0.00 ppm. H=13C values from 300=75.43 MHz spectra
in CDCl3, if not otherwise noted. Optical rotation: Polartronic D. Elementary analyses: Institute of
Pharmacy (Perkin-Elmer Elemental Analyzer 2400 CHN), or Institute of Chemistry, University of
Greifswald. All compounds gave satisfactory elemental analyses. Dimethoxyethane (DME) and tetra-
hydrofuran (THF) were stored with KOH, then refluxed with Na and benzophenone, and distilled prior
to use. Other solvents were dried=purified according to literature procedures. LDA (lithium diisopro-
pylamide) was freshly prepared by mixing equimolar amounts of (i-Pr)2NH and BuLi (n-butyl lithium,
15% in n-hexane) in THF at ꢃ78ꢁC. HPLC: System LaChrom, series 7000 Merck Hitachi. Columns:
LiChrospher 250-4, RP-18, 5mm; (S,S)-Whelk-O1, 250-4, 5mm; Chiraspher, 250-4, 5 mm, Chirobiotic
T. Molecular modeling: Hyperchem+ 4.0, Hypercube, Inc.; HyperchemTM 6.0 (Demo version), Hyper-
cube, Inc.
Abbreviations: CC¼column chromatography (silica gel 60, Merck 7734, 0.040–0.063mm);
AcOEt¼ ethyl acetate; tlc ¼ thin layer chromatography (pre-coated plates, silica gel 60 F254, Merck
5554); al¼ aliphatic; ar¼ aromatic.
6-Methoxy-1-(1-trimethylsiloxyvinyl)-3,4-dihydronaphthaline (1) [6], and N,N-maleoyl amino acid
derivatives [5] were prepared according to literature.
(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-18-nor-16-azaestra-1,3,5(10),9(11)-
tetraene-15,17-dione (3a, C20H25NO4Si) [6]
Compound 1 (6g, 23.2mmol) and 2a (2.23 mg, 23mmol) in 60 cm3 toluene were refluxed for
3 h. Yield 7.95 g (98%); colorless crystals; mp 196–201ꢁC (dec, acetone); IR: ꢇꢁ¼ 3167 (NH),
3066 (C¼CH, ar CH), 2958, 2837 (al CH), 1776, 1702 (CO), 1629, 1606 (C¼CH) cmꢃ1
;
2
1H NMR (200 MHz): ꢂ ¼ 0.12 (s, SiMe3), 1.98–2.11 (m, 7-H), 2.23 (dddd, J7,7 ¼ 12.3 Hz,
3J7,8 ¼ 12.3 Hz, J6,7 ¼ 12.3Hz, J6,7 ¼ 3.4 Hz, 7-H), 2.46–2.74 (m, 2 6-H, 8-H, 12-H), 2.80 (dd,
3
3
3
3
3
2J12,12 ¼ 15.4Hz, J12,13 ¼ 1.6 Hz, 12-H), 3.12 (dd, J8,14 ¼ 5.6 Hz, J13,14 ¼ 8.9 Hz, 14-H), 3.24
3
3
3
5
(ddd, J12,13 ¼ 6.8 Hz, J12,13 ¼ 1.6 Hz, J13,14 ¼ 9.0 Hz, 13-H), 3.78 (s, OMe), 6.61 (d, J2,4 ¼ 2.5 Hz,
3
5
3
4-H), 6.66 (dd, J1,2 ¼ 8.6 Hz, J2,4 ¼ 2.8 Hz, 2-H), 7.85 (d, J1,2 ¼ 8.5 Hz, 4-H), 7.93 (s, H–N) ppm;
0
0
HPLC: k0 ¼ 4.86, t0 ¼ 2.22min (RP-18, MeCN=H2O 6=4); k1 ¼ 2.07, k2 ¼ 2.34, t0 ¼ 2.16min ((S,S)-
Whelk-O1 n-hexane=AcOEt 8=2).

94
A. Bodtke et al.
Reaction of 1 with Methyl N,N-Maleoylglycinate
Method a: A mixture from 1 (1.8g, 5.7 mmol) and N,N-maleoyl-Gly-OMe (2b, 0.96 g, 5.7mmol) was
heated for 4 h to 80ꢁC. After cooling to room temperature, and dropwise addition of 50cm3
n-hexane=Et2O (1=1) first 3bI (830 mg, 33%), and then a mixture from 3bI and 3bII (825 mg,
33%) were obtained as colorless precipitates. Pure 3bII was isolated after fractionizing crystallization
from MeOH. Keeping the mother liquor for 1 h at room temperature, gave additional 4bII (80 mg, 4%).
Method b: LiClO4 (1.33 g, 12.5mmol) was added with stirring to a suspension of 2b (423mg,
2.5 mmol) in 20 cm3 CH2Cl2, and after 20 min 1 (0.8g, 2.5 mmol) in 10 cm3 CH2Cl2 was dropwise
added, stirring was continued for 3 h at room temperature, then the mixture was diluted with 20cm3 of
a saturated solution of NaCl, and extracted with 100cm3 AcOEt. The organic layer was separated,
dried (Na2SO4), and evaporated in vacuo. After addition of a few cm3 of Et2O, the precipitate was
separated. Yield 572 mg (52%) of a mixture of 3bI and 3bII.
Methyl 2-[(8ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10),9(11)-tetraen-16-yl]acetate (3bI, C23H29NO6Si)
Yield 1.23g (49%); colorless crystals; mp 142–143ꢁC; IR: ꢇꢁ¼ 3012 (ar CH), 2951, 2940, 2873, 2838
1
(al CH), 1759, 1704 (CO), 1623, 1605 (C¼C) cmꢃ1; H NMR: ꢂ ¼ 0.12 (s, SiMe3), 2.08 (dddd,
3
3
3
2
2J7,7 ¼ 12.7 Hz, J6,7 ¼ 5.8 Hz, J6,7 ¼ 3.6 Hz, J7,8 ¼ 3.4 Hz, 7-H), 2.24 (dddd, J7,7 ¼ 12.6 Hz,
3
3
2
3J6,7 ¼ 12.6 Hz, J6,7 ¼ 3.2 Hz, J7,8 ¼ 12.6 Hz, 70-H), 2.49–2.57 (m, 8-H), 2.55 (ddd, J12,12
¼
3
2
15.4Hz, J12,13 ¼ 6.8 Hz, J ¼ 1.7 Hz, 12-H), 2.66–2.74 (m, 6-H, 60-H), 2.83 (dd, J12,12 ¼ 15.4Hz,
3J12,13 ¼ 1.7 Hz, 120-H), 3.18 (dd, J13,14 ¼ 8.9 Hz, J8,14 ¼ 5.7Hz, 14-H), 3.28 (ddd, J13,14 ¼ 8.9 Hz,
3
3
3
3
3J12,13 ¼ 6.9 Hz, J12,13 ¼ 1.7 Hz, 13-H), 3.63 (s, OMe), 3.77 (s, OMe), 4.16 (s, NCH2), 6.61
4
3
4
(d, J2,4 ¼ 2.8 Hz, 4-H), 6.65 (ddd, J1,2 ¼ 8.6 Hz, J2,4 ¼ 2.8 Hz, J ¼ 0.4 Hz, 2-H), 7.84
(d, J1,2 ¼ 8.6 Hz, 1-H) ppm; 13C NMR: ꢂ ¼ 0.62 (SiMe3), 25.23 (C-7), 31.07, 31.13 (C-6, CH2),
3
37.99 (C-13), 39.54 (C-12), 41.28 (C-8), 43.54 (C-14), 52.53 (OMe), 55.08 (OMe), 111.17 (C-2),
112.54 (C-4), 113.08 (C-10), 125.46 (C-11), 129.93 (C-1), 139.72 (C-5), 143.68 (C-9), 157.17 (C-3),
166.87 (CO), 176.68 (C-15), 178.33 (C-17) ppm; HPLC: k0 ¼ 3.53, t0 ¼ 1.76min (RP-18, MeCN=H2O
0
0
7=3); k0 ¼ 2.97, t0 ¼ 2.09min (Chiralcel OJ-R, MeCN=H2O 1=1); k1 ¼ 1.32, k2 ¼ 1.74, t0 ¼ 1.98 min
((S,S)-Whelk-O1, n-hexane=EtOH 1=1).
Methyl 2-[(8ꢁ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10),9(11)tetraen-16-yl]acetate (3bII, C23H29NO6Si)
Yield 425 mg (17%); colorless crystals; mp 120–125ꢁC (MeOH); 1H NMR: ꢂ ¼ 0.14 (s, SiMe3), 1.70
2
3
(m, 7-H), 2.42 (dd, J12,12 ¼ 15.2 Hz, J12,13 ¼ 11.5 Hz, 12-H), 2.48–2.71 (m, 6-H, 60-H, 70-H, 8-H),
2.73 (dd, 3J8,14 ¼ 10.5Hz, 3J13,14 ¼ 9.5 Hz, 14-H), 2.74 (dd, 2J12,12 ¼ 15.2Hz, 3J12,13 ¼ 7.2 Hz, 120-H),
3
3
3
3.20 (ddd, J12,13 ¼ 11.4 Hz, J12,13 ¼ 7.2 Hz, J13,14 ¼ 9.4 Hz, 13-H), 3.78 (s, OMe), 3.80 (s, OMe),
4
3
4
4.28 (s, NCH2), 6.65 (d, J2,4 ¼ 2.7 Hz, 4-H), 6.72 (dd, J1,2 ¼ 8.7 Hz, J2,4 ¼ 2.8 Hz, 2-H), 7.98 (d,
3J1,2 ¼ 8.7Hz, 1-H) ppm; 13C NMR: ꢂ ¼ 0.61 (s, SiMe3), 27.89 (C-7), 30.04, 31.51 (C-6, CH2), 37.65
(C-13), 39.12 (C-12), 41.29 (C-8), 45.86 (C-14), 52.72 (OMe), 55.13 (OMe), 111.38 (C-2), 112.58
(C-4), 114.53 (C-10), 125.40 (C-11), 130.02 (C-1), 139.83 (C-5), 145.02 (C-9), 157.20 (C-3), 167.26
(CO), 177.57 (C-15), 177.76 (C-17) ppm; HPLC: k0 ¼ 5.42, t0 ¼ 1.76 min (RP-18, MeCN=H2O 7=3);
k0 ¼ 4.28, 4.67, t0 ¼ 1.77min (Chiralcel OJ-R, MeCN=H2O 1=1).
Dimethyl (S)-2-[(8ꢄ,13ꢀ,14ꢀ)-3-Methoxy-11-(trimethylsiloxy)-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10),9(11)tetraen-16-yl]succinate (3c, C26H33NO8Si)
Method a: A mixture from 1 (1.5g, 4.7 mmol) and N,N-maleoyl-L-Asp(OMe)2 (2c, 1.13 g, 4.7mmol)
was heated to 70ꢁC for 22h. After cooling to room temperature, the mixture was diluted with Et2O,
and the precipitate was separated. Yield 618mg (26%).
Method b: From LiClO4 and 2c (603mg, 2.5 mmol) as described for 3bI=3bII. Yield 425 mg
20
(33%); colorless needles; mp 132.5–134ꢁC (MeOH); ½ꢁꢂD ¼ ꢃ38.0ꢁ cmꢃ2 gꢃ1 (c ¼ 2, CH2Cl2);
1
IR: ꢇꢁ¼ 2955, 2836 (al CH), 1773, 1751, 1704 (CO), 1623, 1606 (C¼C) cmꢃ1; H NMR: ꢂ ¼ 0.14

Azasteroids
95
2
3
(s, SiMe3), 1.70–1.74 (m, 7-H), 2.36, 2.40 (2dd, J12,12 ¼ 15.3 Hz, J12,13 ¼ 6.7Hz, 12-H), 2.33–2.74
(m, 6-H, 60-H, 70-H, 8-H, 14-H), 2.69, 2.72 (2dd, 2J12,12 ¼ 15.3Hz, 3J12,13 ¼ 1.8 Hz, 120-H), 3.07, 3.08
2
3
3
3
(2AMX, JAM ¼ 16.6Hz, JAX ¼ 9.3 Hz, ꢀ-HAsp), 3.14, 3.18 (2ddd, J12,13 ¼ 1.8 Hz, J12,13 ¼ 7.2 Hz,
3J13,14 ¼ 9.5 Hz, 13-H), 3.27 (AMX, 2JAM ¼ 16.6Hz, 3JMX ¼ 5.7 Hz, ꢀ0-HAsp), 3.69, 3.69 (2s, 2 OMe),
3.76 (s, OMe), 3.80 (s, OMe), 5.21 (AMX, 3JAX ¼ 9.3 Hz, 3JMX ¼ 5.6 Hz, ꢁ-H), 6.65 (d, 4J2,4 ¼ 2.8 Hz,
3
4
3
4-H), 6.72 (dd, J1,2 ¼ 8.8 Hz, J2,4 ¼ 2.8Hz, 2-H), 7.97 (d, J1,2 ¼ 8.8Hz, 1-H) ppm; 13C NMR:
ꢂ ¼ 0.59 (SiMe3), 27.76, 27.85 (C-7), 29.91 (C-6), 31.26, 31.36 (CH2), 32.78, 32.82 (C-12), 37.46,
37.48 (C-13), 40.95, 41.06 (C-8), 45.41, 45.54 (C-14), 48.50 (C-ꢁ), 52.05 (OMe), 53.12 (OMe),
55.08 (OMe), 111.33 (C-2), 112.53 (C-4), 114.41 (C-10), 125.37 (C-11), 129.98 (C-1), 139.78
(C-5), 144.86, 144.91 (C-9), 157.18 (C-3), 168.08 (CO), 177.29, 177.42, 177.43, 177.50 (C-15,
C-17) ppm; HPLC: k0 ¼ 4.18, t0 ¼ 1.76min (RP-18, MeCN=H2O 7=3); k0 ¼ 3.38, t0 ¼ 1.81min
(Chiralcel OJ-R, MeCN=H2O 1=1).
(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-16-azaestra-1,3,5(10)-triene-
11,15,17-trione (4a, C17H17NO4) [6]
Compound 3a (0.9g, 2.4 mmol) and 1.5 cm3 conc. HCl in 30 cm3 MeOH were refluxed for 30min.
After cooling, the precipitate was separated. Yield 580 mg (91%); colorless crystals; mp 205–210ꢁC
(MeOH); IR: ꢇꢁ¼ 3167 (NH), 3054 (ar CH), 2929 (al CH), 1774, 1705 (CO), 1612, 1580, 1503 (C¼C)
cmꢃ1; 1H NMR: ꢂ ¼ 0.88 (m, 7-H), 1.44–1.54 (m, 70-H), 1.98–2.04 (m, 6-H), 2.82–2.92 (m, 6-H, 8-H,
12-H, 120-H), 3.43–3.50 (m, 9-H, 13-H, 14-H), 3.77 (s, OMe), 6.62 (d, 4J2,4 ¼ 2.5 Hz, 4-H), 6.77 (dd,
4
3
3J1,2 ¼ 8.5 Hz, J2,4 ¼ 2.5 Hz, 2-H), 7.22 (d, J2,4 ¼ 8.7 Hz, 1-H), 7.80 (s, H–N) ppm; HPLC: k0 ¼ 0.2,
0
0
t0 ¼ 1.85min (RP-18, MeCN=H2O 1=1); k1 ¼ 11.86, k2 ¼ 16.57, t0 ¼ 2.59min ((S,S)-Whelk-O1,
n-hexane=i-PrOH=MeCN 7=2.5=0.5).
Methyl 2-[(8ꢀ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]acetate (4bI, C20H21NO6)
Some (ca. 5) drops of conc. HCl were added to 3bI (726mg, 1.64 mmol) dissolved in 30cm3 boiling
MeOH, the mixture was refluxed for 1–2 min, and slowly cooled to room temperature. Yield 205 mg
(34%); colorless needles; mp 160–165ꢁC (MeOH); IR: ꢇꢁ¼ 3008 (ar CH), 2960, 2934, 2857, 2839
1
(al CH), 1778, 1750, 1707 (CO), 1606 (C¼C) cmꢃ1; H NMR: ꢂ ¼ 1.36–1.57 (m, 7-H), 2.03–2.09
(m, 70-H), 2.83–2.94 (m, 6-H, 60-H, 8-H, 12-H, 120-H), 3.37–3.53 (m, 9-H, 13-H, 14-H), 3.77 (s, OMe),
4
3
4
3.79 (s, OMe), 4.32 (s, NCH2), 6.61 (d, J2,4 ¼ 2.5 Hz, 4-H), 6.77 (dd, J1,2 ¼ 8.5 Hz, J2,4 ¼ 2.7 Hz,
3
2-H), 7.24 (d, J2,4 ¼ 8.8 Hz, 1-H) ppm; HPLC: k0 ¼ 0.79, t0 ¼ 1.76min (RP-18, MeCN=H2O 7=3);
0
0
k1 ¼ 2.08, k2 ¼ 2.49, t0 ¼ 1.75 min (Chiralcel OJ-R, MeCN=H2O 4=6).
Methyl 2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]acetate (4bII, C20H21NO6)
Obtained as a by-product from the synthesis of 3bII. Yield 80mg (4%); colorless crystals; mp
160–168ꢁC (MeOH); IR: ꢇꢁ¼ 3035 (ar CH), 2993, 2950, 2916, 2848 (al CH), 1782, 1748, 1709.5
1
2
(CO), 1608, 1584 (C¼C) cmꢃ1; H NMR: ꢂ ¼ 1.58–1.74 (m, 7-H), 2.21 (dddd, J8,14 ¼ 11.7Hz,
3J7,8 ¼ 11.7 Hz, J7,8 ¼ 2.3 Hz, J8,9 ¼ 11.7Hz, 8-H), 2.77 (dd, J12,12 ¼ 17.3 Hz, J12,13 ¼ 11.1Hz,
3
3
2
3
2
3
12-H), 2.79–2.90 (m, 6-H, 60-H, 70-H), 2.98 (dd, J12,12 ¼ 17.3Hz, J12,13 ¼ 7.3 Hz, 120-H), 3.10
3
3
3
3
(dd, J13,14 ¼ 9.0 Hz, J8,14 ¼ 11.4Hz, 14-H), 3.47 (ddd, J12,13 ¼ 7.4 Hz, J12,13 ¼ 10.9 Hz,
3J13,14 ¼ 9.0 Hz, 13-H), 3.44 (d, J8,9 ¼ 12.8Hz, 9-H), 3.77 (s, OMe), 3.78 (s, OMe), 4.29 (s, NCH2),
3
6.63 (d, 4J2,4 ¼ 2.7 Hz, 4-H), 6.78 (dd, 3J1,2 ¼ 8.7 Hz, 4J2,4 ¼ 2.7 Hz, 2-H), 7.37 (d, 3J1,2 ¼ 8.8 Hz, 1-H)
ppm; 13C NMR: ꢂ ¼ 28.08 (C-7), 29.53 (C-6), 37.95 (CH2), 38.02, 38.07 (C-13, C-8), 39.31 (C-12),
45.48 (C-14), 52.24 (C-9), 52.82 (OMe), 55.18 (OMe), 111.89 (C-2), 113.60 (C-4), 121.43 (C-10),
131.47 (C-1), 138.44 (C-5), 158.34 (C-3), 166.96 (CO), 176.44 (C-15), 176.52 0(C-17), 204.66 (C-11)
0
ppm; HPLC: k0 ¼ 0.82, t0 ¼ 1.76min (RP-18, MeCN=H2O 7=3); k1 ¼ 1.04, k2 ¼ 1.15, t0 ¼ 2.09min
(Chiralcel OJ-R, MeCN=H2O 1=1).

96
A. Bodtke et al.
Dimethyl (S)-3-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-tetraen-16-yl]succinate (4c, C23H25NO8)
From 3c (250 mg, 0.48 mmol), as described for 4bI. Yield 95mg (44%); colorless crystals; mp
20
145–148ꢁC (AcOEt); ½ꢁꢂD ¼ ꢃ46.4ꢁ cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 2954 (al CH), 1778, 1741, 1711
(CO), 1610 (C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.66 (m, 7-H), 2.12–2.26 (2dddd, 3J7,8 ¼ 2.6 Hz, 3J7,8 ¼ 11.9Hz,
2
3J8,9 ¼ 11.9Hz, 3J8,14 ¼ 11.9 Hz, 8-H), 2.74 (dd, J12,12 ¼ 17.4Hz, 3J12,13 ¼ 11.4Hz, 12-H), 2.79–2.88
2
3
(m, 6-H, 60-H, 70-H), 2.94, 2.96 (2dd, J12,12 ¼ 17.4Hz, J12,13 ¼ 7.1, 7.6 Hz, 120-H), 3.08, 3.09 (2dd,
3
2
3
3J13,14 ¼ 9.1 Hz, J8,14 ¼ 11.4Hz, 14-H), 3.14, 3.14 (2AMX, JAM ¼ 16.6 Hz, JAX ¼ 9.7 Hz, ꢀ-HAsp),
2
3
3.24, 3.24 (2AMX, JAM ¼ 16.6 Hz, JMX ¼ 5.5 Hz, ꢀ0-HAsp), 3.39–3.51 (m, 13-H), 3.43, 3.44 (2d,
3J8,9 ¼ 11.5, 12.8Hz, 9-H), 3.66, 3.67 (2s, OMe), 3.76 (s, OMe), 3.78 (s, OMe), 5.18 (AMX,
3JAX ¼ 9.7 Hz, JMX ¼ 5.5 Hz, ꢁ-HAsp), 6.64 (d, J2,4 ¼ 2.4 Hz, 4-H), 6.78, 6.79 (dd, J1,2 ¼ 8.6 Hz,
3
4
3
4J2,4 ¼ 2.6 Hz, 2-H), 7.35, 7.38 (2d, 3J1,2 ¼ 8.6Hz, 1-H) ppm; HPLC: k0 ¼ 1.44, t0 ¼ 1.76min (RP-18,
0
0
MeCN=H2O 7=3); k1 ¼ 1.12, k2 ¼ 1.29, t0 ¼ 1.87min (Chiralcel OJ-R, MeCN=H2O 1=1).
Isopropyl 2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]acetate (6a, C22H25NO6)
From 1 (1.36 g, 4.3 mmol) and N,N-maleoyl-Gly-OiPr (5a) (0.84 g, 4.3 mmol) for 6 h at 50ꢁC, as
described for 3bI (a). After cooling to room temperature, the mixture was diluted with 100cm3
acetone=Et2O (1=10). Yield 398 mg (23%); colorless crystals; mp 170–172ꢁC (AcOEt); IR: ꢇꢁ¼ 2984,
2950, 2840 (al CH), 1781, 1737, 1707 (CO), 1608, 1584 (C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.25 (d, 3J ¼ 6.3 Hz,
2 Me), 1.67 (m, 7-H), 2.14–2.26 (m, 8-H), 2.72-2.87 (m, 6-H, 60-H, 70-H, 12-H), 2.98 (dd,
2J12,12 ¼ 17.6Hz, 3J12,13 ¼ 7.3 Hz, 120-H), 3.10 (dd, 3J8,9 ¼ 11.2Hz, 3J13,14 ¼ 9.1 Hz, 14-H), 3.46 (ddd,
3J12,13 ¼ 7.3 Hz, 3J12,13 ¼ 10.9Hz, 3J13,14 ¼ 8.8 Hz, 13-H), 3.43 (d, 3J8,9 ¼ 12.3 Hz, 9-H), 3.78 (s, OMe),
3
4
3
4.24 (s, NCH2), 5.04 (spt, J ¼ 6.3 Hz, CH), 6.64 (d, J2,4 ¼ 2.6 Hz, 4-H), 6.78 (dd, J1,2 ¼ 8.5 Hz,
4J2,4 ¼ 2.6 Hz, 2-H), 7.37 (d, J1,2 ¼ 8.5 Hz, 1-H) ppm; HPLC: k0 ¼ 5.05, t0 ¼ 1.89min (RP-18,
3
0
0
MeCN=H2O 1=1); k1 ¼ 1.77, k2 ¼ 2.09, t0 ¼ 1.80min (Chiralcel OJ-R, MeCN=H2O 1=1).
Benzyl 2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]acetate (6b, C26H25NO6)
From 1 (1.89 g, 5.9 mmol) and N,N-maleoyl-Gly-OBn (5b) (1.46 g, 5.9 mmol) for 6 h at 50ꢁC, as
described for 3bI (a). After hydrolysis with 0.5 N HCl the organic layer was diluted with AcOEt,
washed with a saturated solution of NaHCO3, dried (MgSO4), and evaporated. 20cm3 MeOH were
added, and after 12–24h the precipitate was collected. Yield 320 mg (15%); mp 153–156ꢁC (dec,
MeOH); IR: ꢇꢁ¼ 3066, 3035 (ar CH), 2994, 2950, 2915, 2839 (al CH), 1780, 1741, 1708 (CO), 1608,
1584 (C¼C), 749, 696 (ar C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.56–1.71 (m, 7-H), 2.12 (dddd, 3J7,8 ¼ 2.1 Hz,
3
3
2
3
3J7,8 ¼ 11.7 Hz, J8,9 ¼ 11.7Hz, J8,14 ¼ 11.7Hz, 8-H), 2.68 (dd, J12,12 ¼ 17.3Hz, J12,13 ¼ 11.2Hz,
2
3
12-H), 2.75–2.82 (m, 6-H, 60-H, 70-H), 2.94 (dd, J12,12 ¼ 17.3Hz, J12,13 ¼ 7.3 Hz, 120-H), 3.08 (dd,
3
3
3
3J13,14 ¼ 9.1 Hz, J8,14 ¼ 11.3Hz, 14-H), 3.41 (d, J8,9 ¼ 12.3Hz, 9-H), 3.44 (ddd, J12,13 ¼ 7.6 Hz,
3J12,13 ¼ 10.8Hz, J13,14 ¼ 8.8 Hz, 13-H), 3.78 (s, OMe), 4.33 (s, NCH2), 5.16 (s, OCH2), 6.63 (d,
3
4J2,4 ¼ 2.6Hz, 4-H), 6.78 (dd, J1,2 ¼ 8.8 Hz, J2,4 ¼ 2.6 Hz, 2-H), 7.27–7.33 (m, 5 ar H), 7.36 (d,
3
4
3
0
J1,2 ¼ 8.8Hz, 1-H) ppm; HPLC: k0 ¼ 10.70, t0 ¼ 2.20min (RP-18, MeCN=H2O 1=1); k1 ¼ 15.47,
0
k2 ¼ 17.00, t0 ¼ 1.81 min (Chiralcel OJ-R, MeCN=H2O 4=6).
Methyl (S)-2-[(8ꢄ,9ꢄ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]propionate (6c, C21H23NO6)
N,N-Maleoyl-L-Ala-OMe (5c, 1.35 g, 7.4 mmol) in 10 cm3 toluene was dropwise added with stirring to
a solution of 1 (2.3g, 7.4 mmol) in 10 cm3 toluene. Stirring was continued for 6 h at 60ꢁC, then the
solvent was evaporated, and the residue was purified by CC (n-hexane=Et2O 1=1), elution with
20
CH2Cl2. Yield 270 mg (10%); colorless crystals; mp 152–159ꢁC (MeOH); ½ꢁꢂD ¼ ꢃ36.0ꢁ cmꢃ2 gꢃ1
(c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 3000 (ar CH), 2952, 2930, 2867 (al CH), 1774, 1735, 1707 (CO), 1610
1
3
(C¼C) cmꢃ1; H NMR: ꢂ ¼ 1.59–1.74 (m, 7-H), 1.62, 1.62 (2d, J ¼ 7.3 Hz, MeAla), 2.16 (m, 8-H),

Azasteroids
97
2
3
2.71 (dd, J12,12 ¼ 17.4Hz, J12,13 ¼ 11.4Hz, 12-H), 2.74–2.88 (m, 6-H, 60-H, 70-H), 2.95, 2.98 (2dd,
3
3
2J12,12 ¼ 17.4Hz, J12,13 ¼ 1.5 Hz, 120-H), 3.04, 3.08 and 3.06, 3.07 (2dd, J8,14 ¼ 11.4 Hz,
3J13,14 ¼ 9.0 Hz, 14-H), 3.39–3.50 (m, 9-H, 13-H), 3.74 (s, OMe), 3.78 (s, OMe), 4.83 (2q, 3J ¼ 7.3 Hz,
Hz, ꢁ-HAla), 6.64 (d, J2,4 ¼ 2.7Hz, 4-H), 6.79 (dd, 3J1,2 ¼ 8.7 Hz, J2,4 ¼ 2.8 Hz, 2-H), 7.35, 7.37 (d,
3J1,2 ¼ 8.7 Hz, 1-H) ppm; 13C NMR: ꢂ ¼ 14.25 (MeAla), 28.12, 28.23 (C-7), 29.57 (C-6), 37.84, 37.95
(C-13), 37.98 (C-12), 38.24, 38.32 (C-8), 45.37 (C-14), 48.16 (C-9), 52.28 (C-ꢁAla), 52.91 (OMe),
55.21 (OMe), 111.93 (C-2), 113.64 (C-4), 121.42, 121.47 (C-10), 131.50, 131.54 (C-1), 138.45 (C-5),
158.38 (C-3), 169.39 (COAla), 176.35, 176.46, 176.49 (C-15, C-17), 204.74, 204.81 (C-11) ppm;
4
4
0
0
HPLC: k0 ¼ 3.10, t0 ¼ 1.98 min (RP-18, MeCN=H2O 1=1); k1 ¼ 1.96, k2 ¼ 2.34, t0 ¼ 1.83 min (Chi-
ralcel OJ-R, MeCN=H2O 45=55).
Methyl (R)-2-[(8ꢄ,9ꢄ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)- trien-16-yl]propionate (6d, C21H23NO6)
From N,N-maleoyl-D-Ala-OMe (5d, 1.35 g, 7.4 mmol) as described for 6c. Yield 165 mg (6%); colorless
20
crystals; mp 154–159ꢁC (MeOH); ½ꢁꢂD ¼ þ32.7 cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 3000 (ar CH), 2952,
2930, 2868 (al CH), 1774, 1735, 1707 (CO), 1611 (C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.58–1.73 (m, 7-H), 1.62,
1.62 (2d, 3J ¼ 7.3 Hz, MeAla), 2.16 (m, 8-H), 2.71 (dd, 2J12,12 ¼ 17.4Hz, 3J12,13 ¼ 11.3 Hz, 12-H), 2.79–
2.82 (m, 6-H, 60-H, 70-H), 2.96, 2.96 (2dd, 2J12,12 ¼ 17.2Hz, 3J12,13 ¼ 1.3 Hz, 120-H), 3.04, 3.08 and 3.05,
3.07 (2dd, 3J8,14 ¼ 11.4Hz, 3J13,14 ¼ 9.0Hz, 14-H), 3.39–3.47 (m, 9-H, 13-H), 3.74 (s, OMe), 3.78 (s,
4
3
OMe), 4.85 (2q, 3J ¼ 7.4 Hz, ꢁ-HAla), 6.64 (d, J2,4 ¼ 2.6 Hz, 4-H), 6.78 (dd, J1,2 ¼ 8.6 Hz,
4J2,4 ¼ 2.5 Hz, 2-H), 7.34, 7.36 (d, J1,2 ¼ 8.7 Hz, 1-H) ppm; HPLC: k0 ¼ 3.90, t0 ¼ 1.75 min (RP-18,
3
0
0
MeCN=H2O 1=1); k1 ¼ 3.65, k2 ¼ 4.23, t0 ¼ 1.75min (Chiralcel OJ-R, MeCN=H2O 4=6).
Methyl (S)-2-[(8S,9R,13S,14R)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (6e, C27H27NO6)
A mixture from N,N-maleoyl-L-Phe-OMe (5e) (1.54 g, 5.9 mmol) and 1 (1.9g, 5.9 mmol) was warmed
without any solvent for 6 h to 60ꢁC. After cooling to room temperature, 50cm3 MeOH were added
with stirring, later the precipitate was separated. Yield 1.1 g (40%); colorless needles; mp 202–207ꢁC
20
(MeOH); ½ꢁꢂD ¼ ꢃ134.6ꢁ cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 3029, 3007 (ar CH), 2950, 2934, 2914,
2894 (al CH), 2856 (OMe), 1775, 1740, 1705 (CO), 1610, 1506 (C¼C), 755, 706 (ar C¼C) cmꢃ1; 1H
3
3
3
3
NMR: ꢂ ¼ 1.31 (dddd, J8a,14a ¼ 11.8 Hz, J7a,8a ¼ 11.8 Hz, J7e,8a ¼ 2.6 Hz, J8a,9a ¼ 11.8Hz, 8-Ha),
2
3
3
3
1.49 (dddd, J7,7 ¼ 12.2Hz, J6a,7a ¼ 12.2Hz, J6e,7a ¼ 5.1 Hz, J7a,8a ¼ 12.2Hz, 7-Ha), 2.46 (dd,
2J12,12 ¼ 17.0Hz, J12,13 ¼ 9.3 Hz, 12-H), 2.43–2.50 (m, J ¼ 2.5 Hz, J ¼ 5.0 Hz, 7-He), 2.59 (ddd,
3
2J6,6 ¼ 16.7 Hz, J6a,7a ¼ 12.3Hz, J6a,7e ¼ 5.0 Hz, 6-Ha), 2.69 (ddd, J6,6 ¼ 16.7Hz, J6e,7a ¼ 4.9 Hz,
3
3
2
3
3J6e,7e ¼ 2.5 Hz, 6-He), 2.78 (dd, 2J12,12 ¼ 17.0Hz, 3J12,13 ¼ 8.1 Hz, 120-H), 2.85 (dd, 3J13,14a ¼ 8.8 Hz,
3J8a,14a ¼ 11.3Hz, 14-Ha), 3.22 (ddd, J13,14a ¼ 8.8 Hz, J12,13 ¼ 9.3 Hz, J12,13 ¼ 8.1 Hz, 13-H), 3.28
(d, 3J8a,9a ¼ 12.2Hz, 9-Ha), 3.78 (s, OMe), 3.81 (s, OMe), 3.48 (ABX, 2JAB ¼ 14.1Hz, 3JAX ¼ 12.3Hz,
ꢀ-H), 3.51 (ABX, 2JAB ¼ 14.1 Hz, 3JBX ¼ 4.7 Hz, ꢀ0-H), 5.10 (ABX, 3JAX ¼ 12.3Hz, 3JBX ¼ 4.7 Hz, ꢁ-
H), 6.61 (d, 4J2,4 ¼ 2.7Hz, 4-H), 6.76 (dd, 3J1,2 ¼ 8.7 Hz, 4J2,4 ¼ 2.7 Hz, 2-H), 7.10–7.28 (m, 5 ar H, 1-
H) ppm; 13C NMR: ꢂ ¼ 27.57 (C-7), 29.27 (C-6), 33.67 (CH2(Phe)), 37.60 (C-12), 37.93 (C-13), 38.68
(C-8), 45.36 (C-14), 52.31 (C-9), 52.76 (C-ꢁ), 53.00 (OMe), 55.20 (OMe), 111.86 (C-2), 113.58 (C-4),
121.54 (C-10), 127.26 (C-40), 128.63 (C-30, C-50), 129.11 (C-20, C-60), 131.34 (C-1), 136.07 (C-10),
138.35 (C-5), 158.33 (C-3), 168.53 (COPhe), 176.06 (C-15), 176.54 (C-17), 204.98 (C-11) ppm; HPLC:
k0 ¼ 7.99, t0 ¼ 1.89 min (RP-18, MeCN=H2O 1=1); k0 ¼ 8.34, t0 ¼ 1.85min (Chiralcel OJ-R,
MeCN=H2O 45=55); k0 ¼ 4.20, t0 ¼ 1.96min ((S,S)-Whelk-O1, n-hexane=EtOH 1=1).
3
3
3
Methyl (S)-2-[(8S,9R,13S,14R)-3-Methoxy-18-nor-11,15,17-trioxo-16-azaestra-1,3,5(10)-
trien-16-yl]-3-phenylpropionate and Methyl (R)-2-[(8R,9S,13R,14S)-3-Methoxy-18-
nor-11,15,17-trioxo-16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (6f, C27H27NO6)
From 1 (1g, 3.7 mmol) and N,N-maleoyl-L,D-Phe-OMe (5f, 1 g, 3.7mmol) as described for 6e.
20
Yield 0.67g (39%); colorless crystals; mp 178–184ꢁC (MeOH); ½ꢁꢂD ¼ 0ꢁ cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2);

98
A. Bodtke et al.
IR: ꢇꢁ¼ 3003 (ar CH), 2950 (al CH), 2861 (OMe), 1775, 1741, 1706 (CO), 1609, 1506 (C¼C), 755,
1
3
3
3
747, 703 (ar C¼C) cmꢃ1; H NMR: ꢂ ¼ 1.30 (dddd, J8a,14a ¼ 11.8 Hz, J7a,8a ¼ 11.8Hz, J7e,8a
¼
3
2
3
3
2.5 Hz, J8a,9a ¼ 11.8Hz, 8-Ha), 1.49 (dddd, J7,7 ¼ 12.1Hz, J6a,7a ¼ 12.1Hz, J6e,7a ¼ 5.1 Hz,
3J7a,8a ¼ 12.1Hz, 7-Ha), 2.46 (dd, 2J12,12 ¼ 17.0Hz, 3J12,13e ¼ 9.3 Hz, 12-H), 2.42–2.50 (m, J ¼ 2.5 Hz,
J ¼ 5.0 Hz, 7-He), 2.53–2.73 (m, 6-Ha, 6-He), 2.77 (dd, 2J12,12 ¼ 16.9Hz, 3J12,13 ¼ 8.1 Hz, 120-H), 2.85
3
3
3
3
(dd, J13,14a ¼ 8.9 Hz, J8a,14a ¼ 11.3 Hz, 14-Ha), 3.22 (ddd, J13,14a ¼ 9.0 Hz, J12,13 ¼ 9.3 Hz,
3J12,13 ¼ 8.1 Hz, 13-H), 3.28 (d, J8a,9a ¼ 12.3Hz, 9-Ha), 3.80 (s, OMe), 3.81 (s, OMe), 3.47 (ABX,
3
2JAB ¼ 14.1Hz, JAX ¼ 12.3 Hz, ꢀ-H), 3.51 (ABX, JAB ¼ 14.1Hz, JBX ¼ 4.7 Hz, ꢀ0-H), 5.09 (ABX,
3
2
3
3JAX ¼ 12.3Hz, JBX ¼ 4.7 Hz, ꢁ-H), 6.61 (d, J2,4 ¼ 2.6Hz, 4-H), 6.76 (dd, J1,2 ¼ 8.7 Hz,
4J2,4 ¼ 2.7Hz, 2-H), 7.09–7.28 (m, 5 ar H, 1-H) ppm; 13C NMR: ꢂ ¼ 27.55 (C-7), 29.26 (C-6),
33.65 (CH2(Phe)), 37.58 (C-12), 37.90 (C-13), 38.65 (C-8), 45.35 (C-14), 52.30 (C-9), 52.74 (C-ꢁ),
53.01 (OMe), 55.20 (OMe), 111.84 (C-2), 113.55 (C-4), 121.48 (C-10), 127.26 (C-4Phe), 128.62
(C-3Phe, C-5Phe), 129.09 (C-2Phe, C-6Phe), 131.34 (C-1), 136.04 (C-1Phe), 138.34 (C-5), 158.32 (C-3),
168.51 (COPhe), 176.04 (C-15), 176.53 (C-17), 204.97 (C-11) ppm; HPLC: k0 ¼ 7.99, t0 ¼ 1.89min
(RP-18, MeCN=H2O 1=1); k0 ¼ 7.88, 8.35, t0 ¼ 1.85min (Chiralcel OJ-R MeCN= H2O 45:55).
3
4
3
Methyl (R)-2-[(8R,9S,13R,14S)-3-Methoxy-18-nor-11,15,17-trioxo-16-azaestra-
1,3,5(10)-trien-16-yl]-3-phenylpropionate (6g, C27H27NO6)
From 1 (1g, 3.7 mmol) and N,N-maleoyl-D-Phe-OMe (5g, 1 g, 3.7 mmol), as described for 6e. Yield
20
0.53g (31%); colorless needles; mp 202–206ꢁC (MeOH); ½ꢁꢂD ¼ þ132.0ꢁcmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2);
IR: ꢇꢁ¼ 3029, 3008 (ar CH), 2951, 2934, 2914, 2895 (al CH), 2856 (OMe), 1775, 1740, 1706 (CO),
3
1611, 1506 (C¼C), 755, 706 (ar C¼C) cmꢃ1
;
1H NMR: ꢂ ¼ 1.31 (dddd, J8a,14a ¼ 11.8 Hz,
3J7a,8a ¼ 11.8Hz, J8a,9a ¼ 11.8Hz, J7e,8a ¼ 2.5 Hz, 8-Ha), 1.49 (dddd, J7,7 ¼ 12.2Hz, J6a,7a
¼
3
3
2
3
3
3
2
3
12.2Hz, J6e,7a ¼ 5.2 Hz, J7a,8a ¼ 12.2Hz, 7-Ha), 2.46 (dd, J12,12 ¼ 17.0 Hz, J12,13 ¼ 9.3 Hz, 12-H),
2
3
3
2.43–2.50 (m, J ¼ 2.5 Hz, J ¼ 5.0Hz, 7-He), 2.59 (ddd, J6,6 ¼ 16.7Hz, J6a,7a ¼ 12.2Hz, J6a,7e
¼
¼
2
3
3
2
5.2 Hz, 6-Ha), 2.69 (ddd, J6,6 ¼ 16.7Hz, J6e,7a ¼ 4.9 Hz, J6e,7e ¼ 2.5 Hz, 6-He), 2.78 (dd, J12,12
2
3
3
17.0Hz, J12,13 ¼ 8.1 Hz, 120-H), 2.85 (dd, J13,14a ¼ 8.8 Hz, J8a,14a ¼ 11.3Hz, 14-Ha), 3.22 (ddd,
3J13,14a ¼ 8.9 Hz, J12,13e ¼ 9.3 Hz, J12,13 ¼ 8.1Hz, 13-H), 3.28 (d, J8a,9a ¼ 12.1Hz, 9-Ha), 3.48
3
3
3
2
3
2
3
(ABX, JAB ¼ 14.1Hz, JAX ¼ 12.3 Hz, ꢀ-H), 3.51 (ABX, JAB ¼ 14.1Hz, JBX ¼ 4.7 Hz, ꢀ0-H), 3.78
3
3
4
(s, OMe), 3.81 (s, OMe), 5.10 (ABX, JAX ¼ 12.3Hz, JBX ¼ 4.7 Hz, ꢁ-H), 6.61 (d, J2,4 ¼ 2.7 Hz,
4-H), 6.76 (dd, J1,2 ¼ 8.7 Hz, J2,4 ¼ 2.8Hz, 2-H), 7.10–7.29 (m, 5 ar H, 1-H) ppm; 13C NMR:
ꢂ ¼ 27.56 (C-7), 29.26 (C-6), 33.65 (CH2(Phe)), 37.59 (C-12), 37.90 (C-13), 38.65 (C-8), 45.35
(C-14), 52.31 (C-9), 52.74 (C-ꢁ), 53.02 (OMe), 55.20 (OMe), 111.85 (C-2), 113.56 (C-4), 121.50
(C-10), 127.27 (C-4Phe), 128.63 (C-3Phe, C-5Phe), 129.10 (C-2Phe, C-6Phe), 131.35 (C-1), 136.05
(C-1Phe), 138.35 (C-5), 158.30 (C-3), 168.52 (COPhe), 176.06 (C-15), 176.54 (C-17), 204.98 (C-11)
ppm; HPLC: k0 ¼ 8.01, t0 ¼ 1.89 min (RP-18, MeCN=H2O 1=1); k0 ¼ 7.88, t0 ¼ 1.85min (Chiralcel
OJ-R, MeCN=H2O 45=55).
3
4
X-Ray Crystallographic Analysis of 6g
A clear prism crystal of C27H27NO6 of 0.35ꢄ0.15ꢄ0.15mm was mounted on a glass fiber. All
measurements were made on a Rigaku AFC5R diffractometer with graphite monochromated
Cu–Kꢁ radiation and a rotating anode generator. Cell constants and an orientation matrix for data collec-
tion, obtained from a least-squares reꢁfinement using the setting angles of 24 carefully centered reflec-
˚
tions in the range 42.71<2ꢈ<59.04 corresponded to a primitive monoclinic cell with a ¼ 8.668(5) A,
3
ꢁ
˚
˚
˚
b ¼ 9.098(8)A, ꢀ ¼ 96.37(3) , c ¼ 14.710(4)A, and V ¼ 1153(1) A . For Z ¼ 2 and FW¼ 461.51, the
calculated density is 1.33 g=cm3. Based on the systematic absences of: 0k0: k ¼ 2n packing considera-
tions, a statistical analysis of intensity distribution, and the successful solution and refinement of the
structure, the space group was determined to be P21 (#4). The data were collected at 23 ꢇ 1ꢁC using
the !-2ꢈ scan technique to a maximum 2ꢈ value of 120.1ꢁ. Omega scans of several intense reflections,
made prior to data collection, had an average width at half-height of 0.30ꢁ with a take-off angle of 6.0ꢁ.
Scans of (1.26 þ 0.30 tanꢈ)ꢁ were made at a speed of 8.0ꢁ=min (in omega). The weak reflections

Azasteroids
99
(I<10.0ꢉ(I)) were rescanned (maximum of 4 scans) and the counts were accumulated to ensure good
counting statistics. Stationary background counts were recorded on each side of the reflection. The
ratio of peak counting time to background counting time was 2:1. The diameter of the incident beam
collimator was 1.0 mm, the crystal to detector distance was 400 mm, and the detector aperture was
9.0ꢄ13.0mm2 (horizontalꢄvertical). Of the 1980 reflections which were collected, 1844 were unique
(Rint ¼ 0.047). The intensities of three representative reflection were measured after every 150 reflec-
tions. No decay correction was applied. The linear absorption coefficient, m, for Cu–Kꢁ radiation is
7.7 cmꢃ1. An empirical absorption correction based on azimuthal scans of several reflections was
applied which resulted in transmission factors ranging from 0.97 to 1.00. The data were corrected
for Lorentz and polarization effects.
The structure was solved by direct methods [13] and expanded using Fourier techniques [14]. The
non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included but not refined. The
final cycle of full-matrix least-squares refinement was based on 1586 observed reflections (I>3.00ꢉ(I))
and 307 variable parameters and converged (largest parameter shift was 0.06 times its esd) with
unweighted and weighted agreement factors. The standard deviation of an observation of unit weight
was 2.18. The weighting scheme was based on counting statistics and included a factor (p ¼ 0.012) to
P
2
downweight the intense reflections. Plots of
wðjFoj ꢃ jFcjÞ versus jFoj, reflection order in data
collection, sin (ꢈ=ꢅ), and various classes of indices showed no unusual trends. The maximum and
3
ꢃ
˚
minimum peaks on the final difference Fourier map corresponded to 0.16 and ꢃ0.20 e =A . Neutral
atom scattering factors were taken from Ref. [15]. Anomalous dispersion effects were included in Fcalc
[16]; the values for ꢀf 0 and ꢀf 00 were those of Ref. [17]. The values for the mass attenuation coefficients
were those of Ref. [18]. All calculations were performed using the teXsan [19] software package of
Molecular Structure Corporation. Compound 6e was also measured, and proved to be enantiomeric to 6g.
The results of the X-ray analysis were deposited at the CDC, deposition number ##.
Ethyl (S)-2-[(8S,9R,13S,14R)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (6h, C28H29NO6)
From 1 (2.3g, 7.4 mmol) and N,N-maleoyl-L-Phe-OEt (5h) (2.0g, 7.4mmol), as described for 6e.
20
Yield 1.38 g (40%); colorless crystals; mp 182–186ꢁC (dec, EtOH); ½ꢁꢂD ¼ ꢃ130.0ꢁ cmꢃ2 gꢃ1 (c ¼ 5,
CH2Cl2); IR: ꢇꢁ¼ 3005 (ar CH), 2949, 2931, 2891, 2836 (al CH), 1776, 1739, 1705 (CO), 1610
(C¼C), 1268, 1256 (C–O–C), 754, 705 (ar C¼C) cmꢃ1; 1H NMR (200MHz): ꢂ ¼ 1.40 (t, 3J ¼ 7.1 Hz,
Me), 1.31–1.68 (m, 7-H, 8-H), 2.57 (dd, 2J12,12 ¼ 16.9Hz, 3J12,13 ¼ 9.3 Hz, 12-H), 2.51–2.64 (m, 70-H),
2
3
2.69–2.83 (m, 6-H, 60-H), 2.89 (dd, J12,12 ¼ 16.9Hz, J12,13 ¼ 8.1 Hz, 120-H), 2.95 (dd,
3J13,14 ¼ 9.0 Hz, J8,14 ¼ 10.7Hz, 14-H), 3.32 (ddd, J13,14 ¼ 8.9 Hz, J12,13 ¼ 9.3 Hz, J12,13 ¼ 8.1 Hz,
3
3
3
3
3
13-H), 3.39 (d, J8,9 ¼ 11.9Hz, 9-Ha), 3.49–3.61 (ABX, ꢀ-H, ꢀ0-H), 3.88 (s, OMe), 4.37 (q,
3J ¼ 7.1 Hz, OCH2), 5.18 (ABX, ꢁ-H), 6.71 (d, J2,4 ¼ 2.4 Hz, 4-H), 6.86 (dd, J1,2 ¼ 8.6 Hz,
4J2,4 ¼ 2.5Hz, 2-H), 7.20–7.39 (m, 5 ar H, 1-H) ppm; HPLC: k0 ¼ 8.59, t0 ¼ 1.98 min (RP-18,
MeCN=H2O 1=1); k0 ¼ 4.77, t0 ¼ 1.8 min (Chiralcel OJ-R, MeCN=H2O 1=1).
4
3
Isopropyl (S)-2-[(8S,9R,13S,14R)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (6i, C29H31NO6)
From 1 (1.2g, 4.5mmol) and N,N-maleoyl-L-Phe-OiPr (5i) (1.3g, 4.5mmol) as described for 6e. Yield
20
270 mg (12%); mp 160–164ꢁC (i-PrOH); ½ꢁꢂD ¼ ꢃ137ꢁ cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 3061, 3027
(ar CH), 2986, 2954, 2931, 2890, 2859, 2837 (al CH), 1779, 1727, 1709 (CO), 1610 (C¼C) cmꢃ1; 1H
3
3
NMR (200 MHz): ꢂ ¼ 1.24–1.55 (m, 7-H, 8-H), 1.26 (d, J ¼ 6.2 Hz, Me), 1.29 (d, J ¼ 6.2 Hz, Me),
2
3
2.42–2.55 (m, 70-H), 2.48 (dd, J12,12 ¼ 17.0 Hz, J12,13 ¼ 9.4 Hz, 12-H), 2.59–2.66 (m, 6-H, 60-H),
2.75 (dd, 2J12,12 ¼ 17.0Hz, 3J12,13 ¼ 8.9 Hz, 120-H), 2.85 (dd, 3J13,14 ¼ 8.9 Hz, 3J8a,14a ¼ 11.3 Hz, 14-H),
3
3
3
3
3.20 (ddd, J13,14 ¼ 8.9 Hz, J12,13 ¼ 9.4 Hz, J12,13 ¼ 8.9 Hz, 13-H), 3.29 (d, J8,9 ¼ 11.7Hz, 9-H),
3
3.44–3.54 (ABX, ꢀ-H, ꢀ0-H), 3.78 (s, OMe), 5.07 (ABX, ꢁ-H), 5.09 (spt, J ¼ 6.1 Hz, CH), 6.61 (d,
4J2,4 ¼ 2.5Hz, 4-H), 6.76 (dd, 3J1,2 ¼ 8.5 Hz, 4J2,4 ¼ 2.7 Hz, 2-H), 7.09–7.78 (m, 5 ar H, 1-H) ppm; 13
C
NMR: ꢂ ¼ 21.73, 21.79 (2 Me), 27.63 (C-7), 29.32 (C-6), 33.72 (CH2(Phe)), 37.68 (C-12), 37.95 (C-13),

100
A. Bodtke et al.
38.71 (C-8), 45.33 (C-14), 52.34 (C-9), 53.10 (C-ꢁ), 55.15 (OMe), 70.00 (CH), 111.88 (C-2), 113.60
(C-4), 121.60 (C-10), 127.18 (C-4Phe), 128.61 (C-3Phe, C-5Phe), 129.14 (C-2Phe, C-6Phe), 131.40 (C-1),
136.35 (C-1Phe), 138.37 (C-5), 158.37 (C-3), 167.50 (COPhe), 176.14 (C-15), 176.53 (C-17), 205.00
(C-11) ppm; HPLC: k0 ¼ 16.98, t0 ¼ 1.98min (RP-18, MeCN=H2O 1=1); k0 ¼ 12.63, t0 ¼ 1.85min
(Chiralcel OJ-R, MeCN=H2O 45=55).
Methyl 3-[(8ꢄ,9ꢄ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]propionate (8a, C21H23NO6)
A mixture from N,N-maleoyl-ꢀ-Ala-OMe (7a, 1.24 g, 6.74 mmol) and 1 (2.16 g, 6.74mmol) was
heated to 70ꢁC for 22h. After cooling to room temperature the mixture was dissolved in Et2O=PE
1=1. After cooling to 0ꢁC for 2–4 d the precipitate was collected. Yield 545mg (21%); colorless
crystals; mp 169–173ꢁC (MeOH=AcOEt); IR: ꢇꢁ¼ 3007 (ar CH), 2944, 2834 (al CH), 1772, 1725,
1701 (CO), 1611, 1576 (C¼C) cmꢃ1
;
1H NMR: ꢂ ¼ 1.39, 1.82–1.88 (2m, 7-H, 8-H), 2.68 (t,
3J ¼ 7.1 Hz, 2 ꢁ-H), 2.79–2.92 (m, 6-H, 60-H, 70-H, 12-H, 120-H), 3.33–3.43 (m, 9-H, 13-H, 14-H),
3.69 (s, OMe), 3.77 (s, OMe), 3.87 (dt, 3J ¼ 7.1 Hz, J ¼ 1 Hz, 2 ꢀ-H), 6.60 (d, 4J2,4 ¼ 2.6 Hz, 4-H), 6.76
3
4
3
(dd, J1,2 ¼ 8.5 Hz, J2,4 ¼ 2.7 Hz, 2-H), 7.21 (d, J1,2 ¼ 8.6 Hz, 1-H) ppm; HPLC: k0 ¼ 2.26,
0
0
t0 ¼ 1.75min (RP-18, MeCN=H2O 1=1); k1 ¼ 4.91, k2 ¼ 5.22, t0 ¼ 1.77 min (Chiralcel OJ-R,
MeCN=H2O 3=7).
Methyl [(8ꢄ,9ꢄ,13ꢀ,14ꢀ)-3-Methoxy-18-nor-11,15,17-trioxo-
16-azaestra-1,3,5(10)-trien-16-yl]formiate (8b, C19H19NO6)
Method a: At 0ꢁC, methyl chloroformiate (47 mm3, 0.62mmol) was dropwise added to a solution of 4a
(186 mg, 0.62mmol) and N-methylmorpholine (62.5 mg, 0.62mmol) in AcOEt (20 cm3). After stirring
for 4 h at 0ꢁC, the precipitate was separated, washed with AcOEt, and the combined AcOEt was
evaporated in vacuo. A few cm3 of MeOH were added to the residue, and after some h the precipitate
was collected.
Method b: A mixture from 1 (1.5g, 5.3mmol) and N-(methoxycarbonyl)maleimide (7b, 0.83 g,
5.3 mmol) in 10 cm3 toluene was stirred for 5 h at 50ꢁC. Then the solvent was evaporated, the residue
was dissolved in a few cm3 of MeOH, 3 drops of conc. HCl were added, and after addition (with
stirring) of 50 cm3 Et2O the precipitate was collected. Yield (a) 63mg (28%); (b) 0.91g (48%);
colorless crystals; mp 153–155.5ꢁC (AcOEt); IR: ꢇꢁ¼ 2931, 2844 (al CH), 1812, 1769, 1716 (CO),
1610 (C¼C) cmꢃ1; 1H NMR (200 MHz): ꢂ ¼ 1.33–1.55 (m, 7-H), 1.90–1.96 (m, 70-H), 2.79–3.08 (m,
6-H, 60-H, 8-H, 12-H, 120-H), 3.48–3.50 (m, 9-H, 13-H, 14-H), 3.77 (s, OMe), 4.03 (s, OMe), 6.61 (d,
4
3
3
4J2,4 ¼ 2.4Hz, 4-H), 6.70 (dd, J2,4 ¼ 2.6 Hz, J1,2 ¼ 8.5 Hz, 2-H), 7.16 (d, J1,2 ¼ 8.4 Hz, 1-H) ppm;
13C NMR: ꢂ ¼ 22.60 (C-7), 28.88 (C-6), 34.65 (C-12), 36.97 (C-13), 38.27 (C-8), 43.43 (C-14), 50.79
(C-9), 55.17 (OMe), 77.23 (OMe), 112.43 (C-2), 113.42 (C-4), 123.24 (C-10), 131.94 (C-1), 136.17
(C-5), 148.62 (CO), 159.14 (C-3), 172.73 (C-15), 174.10 (C-17), 205.12 (C-11) ppm; HPLC: k0 ¼ 1.60,
0
0
t0 ¼ 1.98min (RP-18, MeCN=H2O 1=1); k1 ¼ 5.13, k2 ¼ 10.64, t0 ¼ 1.98 min ((S,S)-Whelk O1,
n-hexane=EtOH 1=1 þ 2% MeCN).
(8ꢄ,9ꢄ,13ꢀ,14ꢀ)-3-Methoxy-16-(2-phenylethyl)-18-nor-16-azaestra-1,3,5(10)-trien-
11,15,17-trione (8c, C25H25NO4)
A mixture of N-(2-phenylethyl)maleimide (7c, 1 g, 5 mmol) and 1 (1.6g, 5 mmol) was heated for 2 h
to 60ꢁC. After cooling to room temperature, a mixture of AcOEt and Et2O (100 cm3, 1=10) was added
with stirring, and then the precipitate was collected. Yield 270 mg (13%); colorless crystals; mp
153–156ꢁC (AcOEt); IR: ꢇꢁ¼ 3064, 3028.2 (ar CH), 2937, 2866, 2840 (al CH), 1766, 1691 (CO), 1612
(C¼C), 702 (ar C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.28–1.80 (m, 7-H, 70-H), 2.67–3.39 (m, 6-H, 60-H, 8-H,
12-H, 120-H, CH2), 3.65–3.87 (m, 9-H, 13-H, 14-H, CH2), 3.76–3.77 (3s, OMe), 6.61 (d, 4J2,4 ¼ 2.6 Hz,
4-H), 6.75 (dd, 4J2,4 ¼ 2.6 Hz, 3J1,2 ¼ 8.7Hz, 2-H), 7.19–7.37 (m, 5 ar H), 7.39 (d, 3J1,2 ¼ 8.7 Hz, 1-H)
0
0
0
0
ppm; HPLC: k1 ¼ 4.66, k2 ¼ 5.66, k3 ¼ 8.13, t0 ¼ 1.75min (RP-18, MeCN=H2O 1=1); k1 ¼ 3.73,
k2 ¼ 8.35, k3 ¼ 9.27, k4 ¼ 11.51, k5 ¼ 13.15, t0 ¼ 1.75 min (Chiralcel OJ-R MeCN=H2O 4:6).
0
0
0
0

Azasteroids
101
Ethyl (S)-2-[(E=Z,8S,9R,13S,14R)-11-Hydroxyimino-3-methoxy-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (9a, C28H30N2O6)
A solution of AcONa (0.9g, 11mmol) and H2NOH ꢈ HCl (0.8g, 11mmol) in 30 cm3 H2O was added
to a solution of 6h (476 mg, 1 mmol) in 20cm3 THF with stirring, and MeOH was added until a
clear solution was formed. The mixture was stirred for 16h, H2O was added, and the precipitate was
20
collected. Yield 440 mg (90%); colorless crystals; mp 178–182ꢁC (MeOH); ½ꢁꢂD ¼ ꢃ176.7ꢁ cmꢃ2 gꢃ1
(c ¼ 0.5, MeCN); IR: ꢇꢁ¼ 3464 (OH), 3005 (ar CH), 2949, 2891, 2836 (al CH), 1776, 1729, 1705
1
(CO), 1610, 1584 (C¼C), 754, 705 (ar C¼C) cmꢃ1; H NMR (DMSO-d6, 200 MHz): ꢂ ¼ 0.95–1.41
(m, 7-H, 8-H), 1.17 (t, 3J ¼ 7.1 Hz, Me), 2.09–3.63 (m, 6-H, 60-H, 70-H, 9-H, 12-H, 120-H, 13-H, 14-H),
3.70 (s, OMe), 4.15 (m, CH2), 5.01–5.08 (m, ꢁ-HPhe), 6.61–6.73 (m, 2-H, 4-H), 7.11–7.21 (m, 5 ar H,
0
1-H), 10.69 (s, H–O) ppm; HPLC: k0 ¼ 1.93, 2.67, t0 ¼ 1.76 min (RP-18, MeCN=H2O 7=3); k1 ¼ 3.57,
0
k2 ¼ 4.90, t0 ¼ 2.09min (Chiralcel OJ-R, MeCN=H2O 1=1).
ꢀ
16-azaestra-1,3,5(10)-trien-16-yl]acetate (9b, C20H22N2O6)
Methyl 2-[(E=Z,8ꢀ,9ꢀ,13ꢀ,14ꢀ)-11-Hydroxyimino-3-methoxy-18-nor-15,17-dioxo-
From 3bI (222 mg, 0.5 mmol) as described for 9a. Yield 138 mg (71%); colorless crystals; mp
203–206ꢁC (MeOH); IR: ꢇꢁ¼ 3254 (OH), 2998, 2955, 2899, 2837 (al CH), 1779, 1751, 1712 (CO),
1610, 1585 (C¼C) cmꢃ1; 1H NMR (DMSO-d6): ꢂ ¼ 1.21 (m, 7-H), 1.71–1.75 (m, 70-H), 2.46–2.57
3
(m, 8-H), 2.62–2.90 (m, 6-H, 60-H, 12-H, 120-H), 3.26–3.46 (m, 13-H), 3.54 (dd, J8,14 ¼ 7.1 Hz,
3
3J13,14 ¼ 9.3 Hz, 14-H), 3.66 (d, J8,9 ¼ 3.6 Hz, 9-H), 3.68, 3.69 (2s, 2 OMe), 4.18, 4.24 (AB, each
5
3
2JAB ¼ 17.3 Hz, 2 ꢁ-HGly), 6.60 (d, J2,4 ¼ 2.5 Hz, 4-H), 6.65 (dd, J1,2 ¼ 8.4 Hz, 2-H), 7.00, 7.24
3
0
0
(2d, each J1,2 ¼ 8.4 Hz, 2 1-H), 10.67, 10.80 (2s, H–O) ppm; HPLC: k1 ¼ 1.57, k2 ¼ 1.77,
0
0
0
t0 ¼ 1.75 min (RP-18, MeCN=H2O 1=1); k1 ¼ 3.11, k2 ¼ 6.34, k3 ¼ 6.64, t0 ¼ 1.77 min (Chiralcel
OJ-R, MeCN=H2O 3=7).
Ethyl (S)-2-[(8S,9R,13S,14R)-3-Methoxy-11-methoxyimino-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-phenylpropionate (9c, C29H32N2O6)
A mixture from 0.86 g AcONa and 2.05 cm3 of a solution of H2N–OMe ꢈ HCl (25% in 10% HCl) in
30cm3 H2O was dropwise added with stirring to a solution of 6h (476mg, 1 mmol) in 30cm3 THF.
MeOH was added until a homogeneous mixture was formed, which was stirred for 12h. Then 150cm3
H2O were added, and the precipitate was collected. Yield 404 mg (80%); colorless crystals; mp
20
153–156ꢁC (AcOEt); ½ꢁꢂD ¼ ꢃ175.0ꢁ cmꢃ2 gꢃ1 (c ¼ 1, CH2Cl2); IR: ꢇꢁ¼ 2998, 2978, 2927 (al CH),
1775, 1730, 1709 (CO), 1608, 1583 (C¼C), 701 (ar C¼C) cmꢃ1
;
1H NMR: ꢂ ¼ 1.16 (dddd,
3
3
3
3
3J7,8 ¼ 3.1 Hz, J7,8 ¼ 11.7Hz, J8,9 ¼ 11.7Hz, J8,14 ¼ 11.7Hz, 8-H), 1.27 (t, J ¼ 7.2 Hz, Me), 1.46
(dddd, 3J6,7 ¼ 6.6 Hz, 2J7,7 ¼ 11.7Hz, 3J6,7 ¼ 11.7Hz, 3J7,8 ¼ 11.7 Hz, 7-H), 2.28–2.35 (m, 70-H), 2.45
2
3
3
3
(dd, J12,12 ¼ 15.7 Hz, J12,13 ¼ 9.1 Hz, 12-H), 2.61 (dd, J13,14 ¼ 8.6 Hz, J8,14 ¼ 11.6Hz, 14-H),
3
3
3
2.68–2.74 (m, 6-H, 60-H), 2.95 (ddd, J13,14 ¼ 8.6 Hz, J12,13 ¼ 8.6 Hz, J12,13 ¼ 8.6Hz, 13-H), 3.10
2
3
3
(dd, J12,12 ¼ 15.6Hz, J12,13 ¼ 8.0 Hz, 120-H), 3.24 (d, J8,9 ¼ 11.7Hz, 9-H), 3.39–3.51 (ABX, ꢀ-H,
ꢀ0-H), 3.78 (s, NOMe), 3.87 (s, OMe), 4.10–4.33 (m, CH2), 5.01 (ABX, ꢁ-H), 6.61 (d, 4J2,4 ¼ 2.6 Hz,
4-H), 6.70 (dd, 3J1,2 ¼ 8.5 Hz, 4J2,4 ¼ 2.6Hz, 2-H), 7.05–7.18 (m, 5 ar H), 7.35 (d, 3J1,2 ¼ 8.5 Hz, 1-H)
ppm; HPLC: k0 ¼ 4.73, t0 ¼ 1.76 min (RP-18, MeCN=H2O 7=3); k0 ¼ 13.00, t0 ¼ 1.89 min (Chiralcel
OJ-R, MeCN=H2O 45=55).
Methyl (S)-2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-methoxyimino-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10)-trien-16-yl]propionate (9d, C22H26N2O6)
From 6c (280 mg, 0.73mmol) as described for 9c. Yield 71mg (23%); colorless crystals; mp
20
182–185ꢁC (AcOEt); ½ꢁꢂD ¼ þ98.9ꢁ cmꢃ2 gꢃ1 (c ¼ 0.9, CH2Cl2); IR: ꢇꢁ¼ 2996, 2945, 2852, 2815 (al
CH), 1776, 1754, 1706 (CO), 1612 (C¼C) cmꢃ1; 1H NMR: ꢂ ¼ 1.58 (d, 3J ¼ 7.3 Hz, MeAla), 1.61 (dddd,
2
3
3
3
3J6,7 ¼ 6.1 Hz, J7,7 ¼ 11.7Hz, J6,7 ¼ 11.7Hz, J7,8 ¼ 11.7 Hz, 7-H), 1.94 (dddd, J7,8 ¼ 3.0 Hz,
3
3
2
3
3J7,8 ¼ 11.7 Hz, J8,9 ¼ 11.7 Hz, J8,14 ¼ 11.7 Hz, 8-H), 2.53 (ddd, J12,12 ¼ 16.6Hz, J12,13 ¼ 10.6Hz,
3
3
J ¼ 0.8 Hz, 12-H), 2.62–2.82 (m, 6-H, 60-H, 7-H), 2.86 (dd, J8,14 ¼ 11.4Hz, J13,14 ¼ 8.8 Hz, 14-H),

102
A. Bodtke et al.
3
3
3
2
3.16 (ddd, J12,13 ¼ 7.5 Hz, J12,13 ¼ 10.7Hz, J13,14 ¼ 8.8Hz, 13-H), 3.34 (dd, J12,12 ¼ 16.7 Hz,
3J12,13 ¼ 7.4 Hz, 120-H), 3.43 (d, 3J8,9 ¼ 11.8Hz, 9-H), 3.73 (s, OMe), 3.78 (s, OMe), 3.85 (s, NOMe),
4.80 (q, J ¼ 7.3 Hz, ꢁ-H), 6.63 (d, J2,4 ¼ 2.7Hz, 4-H), 6.73 (dd, 3J1,2 ¼ 8.7 Hz, J2,4 ¼ 2.8 Hz, 2-H),
7.43 (d, 3J1,2 ¼ 8.7 Hz, 1-H) ppm; HPLC: k0 ¼ 2.31, t0 ¼ 1.76 min (RP-18 MeCN=H2O 7=3); k0 ¼ 6.16,
t0 ¼ 1.80min (Chiralcel OJ-R, MeCN=H2O 4=6).
3
4
4
Dimethyl (S)-2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-methoxyimino-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10)-trien-16-yl]succinate (9e, C24H28N2O8)
From 3c (270 mg, 0.52mmol) as described for 9c. Yield 41 mg (17%); colorless crystals; mp 190–
20
193ꢁC (AcOEt); ½ꢁꢂD ¼ þ35.6ꢁ cmꢃ2 gꢃ1 (c ¼ 0.7, CH2Cl2); IR: ꢇꢁ¼ 3005 (ar CH), 2952, 2903, 2854,
2830 (al CH), 1779, 1743, 1711 (CO), 1612, 1575 (C¼C) cmꢃ1
;
1H NMR: ꢂ ¼ 1.61 (dddd,
2
3
3
3
3J6,7 ¼ 6.0 Hz, J7,7 ¼ 11.6Hz, J6,7 ¼ 11.6Hz, J7,8 ¼ 11.6 Hz, 7-H), 1.97 (dddd, J7,8 ¼ 2.9 Hz,
3
3
2
3
3J7,8 ¼ 11.6 Hz, J8,9 ¼ 11.6Hz, J8,14 ¼ 11.6Hz, 8-H), 2.54 (dd, J12,12 ¼ 16.6Hz, J12,13
¼
3
3
10.6Hz, 12-H), 2.66–2.89 (m, 6-H, 60-H, 70-H), 2.88 (dd, J8,14 ¼ 11.4Hz, J13,14 ¼ 9.1 Hz, 14-H),
2
3
2
3.07 (AMX, JAM ¼ 16.6Hz, JAX ¼ 9.5 Hz, ꢀ-H), 3.13–3.22 (m, 13-H), 3.24 (AMX, JAM
¼
3
2
3
16.6Hz, JMX ¼ 5.6 Hz, ꢀ0-H), 3.34 (dd, J12,12 ¼ 16.6 Hz, J12,13 ¼ 7.4 Hz, 120-H), 3.43 (d,
3J8,9 ¼ 11.7 Hz, 9-H), 3.67, 3.74, 3.78 (3s, 3 OMe), 3.85 (s, NOMe), 5.18 (AMX, JAX ¼ 9.5 Hz,
3
3JMX ¼ 5.6 Hz, ꢁ-H), 6.63 (d, J2,4 ¼ 2.6 Hz, 4-H), 6.73 (dd, J1,2 ¼ 8.6 Hz, J2,4 ¼ 2.6 Hz, 2-H), 7.44
4
3
4
(d, J1,2 ¼ 8.6 Hz, 1-H) ppm; 13C NMR: ꢂ ¼ 23.15, 23.50 (CH2), 27.77, 27.99 (C-7), 29.70 (C-6),
3
32.66, 32.71 (C-12), 38.03, 38.38 (C-13), 39.16, 39.44 (C-8), 44.52, 44.68 (C-14), 45.46, 45.54
(C-9), 48.57 (C-ꢁ), 52.11 (OMe), 53.18 (OMe), 55.13 (OMe), 61.74 (NOMe), 111.48 (C-2),
113.36, 113.41 (C-4), 124.32, 124.47 (C-10), 131.31, 131.55 (C-1), 138.34, 138.40 (C-5), 155.00
(C-11), 158.00 (C-3), 167.97, 170.27 (CO), 176.64, 176.71, 176.85, 177.07 (C-15, C-17) ppm;
HPLC: k0 ¼ 2.13, t0 ¼ 1.76 min (RP-18, MeCN=H2O 7=3); k0 ¼ 5.85, t0 ¼ 1.80min (Chiralcel OJ-R,
MeCN=H2O 4=6).
Methyl (S)-2-[(8ꢁ,9ꢀ,13ꢀ,14ꢀ)-3-Methoxy-11-methoxyimino-18-nor-15,17-dioxo-
16-azaestra-1,3,5(10)-trien-16-yl]-3-methylbutyrate (11, C24H30N2O6)
A mixture from 1 (2 g, 4.6 mmol) and N,N-maleoyl-L-Val-OMe (10, 1.36 g, 4.6 mmol) was heated
to 70ꢁC for 22 h. Then 10 cm3 THF were added, and a solution of AcONa (3.95 g) and 9.3 cm3
H2N–OMe ꢈ HCl (25% in 10% HCl) in 130 cm3 H2O was added. Stirring was continued for 12 h, and
after addition of H2O the precipitate was collected. Yield 1.37 g (37%); colorless crystals; mp
20
209–214ꢁC (AcOEt); ½ꢁꢂD ¼ þ77.8ꢁ cmꢃ2 gꢃ1 (c ¼ 2, CH2Cl2); IR: ꢇꢁ¼ 2993, 2962, 2940, 2900,
2853, 2830 (al CH), 1777, 1752, 1705 (CO), 1613 (C¼C) cmꢃ1
;
1H NMR: ꢂ ¼ 0.83, 1.12 (2d,
3
2
3
3
3J ¼ 8.7 Hz, 2 Me), 1.63 (dddd, J6,7 ¼ 6.4 Hz, J7,7 ¼ 11.8Hz, J6,7 ¼ 11.8Hz, J7,8 ¼ 11.8Hz, 7-H),
3
3
3
3
1.93 (dddd, J7,8 ¼ 3.0 Hz, J7,8 ¼ 11.7 Hz, J8,9 ¼ 11.7Hz, J8,14 ¼ 11.7 Hz, 8-H), 2.51 (ddd,
2J12,12 ¼ 16.6Hz, J12,13 ¼ 10.7 Hz, J ¼ 0.8 Hz, 12-H), 2.59–2.85 (m, 6-H, 60-H, 7-H, ꢀ-H), 2.87 (dd,
3
3J8,14 ¼ 11.4Hz, 3J13,14 ¼ 8.9 Hz, 14-H), 3.19 (ddd, 3J12,13 ¼ 7.5 Hz, 3J12,13 ¼ 10.6Hz, 3J13,14 ¼ 8.8 Hz,
13-H), 3.35 (dd, 2J12,12 ¼ 16.6Hz, 3J12,13 ¼ 7.5 Hz, 120-H), 3.44 (d, 3J8,9 ¼ 11.7Hz, 9-H), 3.70 (s, OMe),
3.78 (s, OMe), 3.85 (s, NOMe), 4.39 (d, 3J ¼ 8.5 Hz, ꢁ-H), 6.63 (d, J2,4 ¼ 2.7 Hz, 4-H), 6.73
4
3
4
3
(dd, J1,2 ¼ 8.7 Hz, J2,4 ¼ 2.8 Hz, 2-H), 7.44 (dd, J1,2 ¼ 8.7 Hz, J ¼ 0.4 Hz, 1-H) ppm; HPLC:
k0 ¼ 2.99, t0 ¼ 1.81 min (RP-18, MeCN=H2O 7=3); k0 ¼ 4.74, t0 ¼ 1.81 min (Chiralcel OJ-R,
MeCN=H2O 1=1).
Acknowledgements
We thank Degussa AG, for generous support with chemicals, E. Merck KGaG, Darmstadt, for con-
tinuous support with chromatography materials and biological tests, the ‘‘Fonds der Chemischen
Industrie’’ for financial support, Dr. M. Kindermann, Chemistry Dept., University of Greifswald, for
the COSY experiments, and PD Dr. T. Jira, PMC Greifswald, for the CD spectra.

Azasteroids
103
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