Synthesis and stereochemistry of 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives

Article abstract of DOI:10.1016/S0039-128X(98)00011-7

From the condensation reaction of O-methylbutyrolactim (2), O-methylvalerolactim (3), O-methylcaprolactim (4) and O-methyl-4-t-butylcaprolactim (5) with ethyl 6,7-dimethoxy-α-<1,2,3,4-tetrahydro-isoquinoyl)>acetate (1), 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one (6) D-homo-derivatives (7-9), and medium sized ring cyclic diamides (10,11) were obtained.The stereoselective reduction of compounds 6-9 by Adam's platinum catalyst afforded 8,13-diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-one (12) and its D-homo derivatives (13-15).The structures of thecompounds obtained were established by NMR and X-ray crystallographic analyses. - Keywords: 8,13-diazasteroids; stereochemistry; X-ray structure analysis

Full text of DOI:10.1016/S0039-128X(98)00011-7

Papers
Synthesis and stereochemistry of
8,13-diaza-2,3-dimethoxygona-
1,3,5(10),9(11)-tetraen-12-one and
D-homo derivatives
Gyo¨rgy Go¨ndo¨s,* Lajos Gera,* Ga´bor To´th,† Alajos Ka´lma´n,‡ and John Bridson§
*Department of Organic Chemistry, Jo´zsef Attila University,
Szeged, Do´m te´r 8, H-6720, Hungary; †Technical Analytical Research Group of the Hungarian
Academy of Sciences, Technical University, H-1111, Budapest, St. Gelle´rt te´r 4, Hungary;
‡Central Research Institute for Chemistry Hungarian Academy of Sciences, 1525
Budapest, Hungary; and §Department of Chemistry, Memorial University of Newfoundland,
St. John’s, NF, Canada A1C 5S7
From the condensation reaction of O-methylbutyrolactim (2), O-methylvalerolactim (3), O-methylcaprolactim (4)
and O-methyl-4-t-butylcaprolactim (5) with ethyl 6,7-dimethoxy-␣-[1-(1,2,3,4-tetrahydro-isoquinolyl)]acetate
(1), 8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one (6) D-homo-derivatives (7–9), and medium-
sized ring cyclic diamides (10,11) were obtained. The stereoselective reduction of compounds 6–9 by Adam’s
platinum catalyst afforded 8,13-diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-one (12) and its D-homo derivatives
(13–15). The structures of the compounds obtained were established by NMR and X-ray crystallographic
analyses. (Steroids 63:375–382, 1998) © 1998 by Elsevier Science Inc.
Keywords: 8,13-diazasteroids; stereochemistry; X-ray structure analysis
both in crystalline form and in solution, despite the fact that
there are nitrogen atoms at both bridgehead positions.1
A new method for the synthesis of 8,13-diazasteroids
worked out by Yamazaki et al14 is both stereochemically
specific and pharmacologically useful. In this method, the
ethyl 6,7-dimethoxy-␣-[1-(1,2,3,4,-tetrahydroisoquinolyl)]-
acetate (1) is reacted with two molar equivalents of the
lactim ether [e.g., (2)] without solvent, and the tetracyclic
immonium salt is obtained as an intermediate. Reduction of
the intermediate with sodium borohydride or Adam’s plat-
inum catalyst gives the 8,13-diaza-2,3-dimethoxygona-
1,3,5(10)-triene-12-one. These compounds and their salts
possess analgesic and antiinflammatory15 activity.
Two products are usually obtained from the condensa-
tion reactions of ␤-aminoesters (1) with lactim ethers.16–19
This could be attributed to the presence of both tautomeric
forms (imine and enamine)18 of the lactim ethers. However,
only a single product was formed from the reaction of
␤-aminoester (1) and methyl-butyrolactime (2), the imine-
type product. Although the reported14 synthesis of 8,13-
diazasteroids is very attractive method, unfortunately under
the same reaction conditions the expected D-homo-
derivatives of 8,13-diazasteroids were not formed.
Introduction
Azasteroids were first synthesized some time ago1–5 and
have been shown recently to have significant biological
activity.6–9 The synthesis of diazasteroids1 has also been
accomplished, including some containing bridgehead nitro-
gens. The first synthesis of the 8,13-diazasteroid system was
accomplished by Burckhalter et al.,10 and the structures
were confirmed by X-ray11 analysis. It has been found that
the hydrogens at positions H-9 and H-14 are both ␣ in
orientation. Later, Redeuilh and Viel12 studied 8,13-
diazaestrone derivatives by IR and NMR methods. The
structures of these compounds have been defined, particu-
larly the trans configurations of the B/C and C/D ring
junctions. The position of the hydrogens when compared to
H-9 to H-14, were cis and ␣, the same configuration found
in the natural estrone. This finding was supported by inves-
tigations13 with 13C NMR. A general conclusion that can be
drawn from the spectroscopic data of the 8,13-diazasteroids
is that the compounds are stereochemically homogeneous
Address reprint requests to Dr. Gyo¨rgy Go¨ndo¨s, Department of Organic
Chemistry, Jo´zsef Attila University, 6720 Szeged, Do´m te´r 8, Hungary.
Received July 2, 1997; accepted January 20, 1998.
In the present, work we report a more convenient and
Steroids 63:375–382, 1998
© 1998 by Elsevier Science Inc. All rights reserved.
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Papers
more highly selective method for synthesis of the 8,13-
diazasteroid system than previously14 described. Condensa-
tion of the ethyl 6,7-dimethoxy-␣-[1-(1,2,3,4-tetrahydroiso-
quinolyl)]acetate (1) with different ring-sized lactim ether
(2–5) led to the formation of 8,13-diazasteroid systems.
Herein, we discuss the stereochemistry of the products on
the basis of spectroscopic and X-ray data.
Experimental
General methods
1H NMR spectra were obtained on Brucker AC-250 and JEOL
FX-100 spectrometers at room temperature. Chemical shifts were
given on the (⌬)-scale. In the ID, measurements 32 K data points
were used for FID. For homonuclear 1H NOE experiments, a delay
1
time of 3 s was applied. H NOE difference assessments and two-
dimensional carbon-proton correlated experiments were performed
2
using the Brucker DISNMR software package. In the H experi-
mental, 1KX1K data matrices were transformed. Mass spectra
were recorded on a Finningan-MAT 8230 mass spectrometer.
X-Ray crystallographic data were collected on a Rigaku AFC6S
diffractometer with a graphite monochromator and with Mo-K␣
(␭ ϭ 0.710 69 A) radiation. Elemental analyses were obtained with
a KOVO (Czechoslovakia) CHN automatic analyzer.
Thin-layer chromatography (TLC) was performed with glass
plates (0.25 mm) precoated with silica gel G, which were pur-
chased form Merck (Darmstadt). Spots were visible under short-
wavelength UV light or made visible by spraying with EtOH-
H2SO4 (1:1) and heating the plates to 100°C. Reaction components
were visualized under UV light, in an iodine chamber, or by
spraying with Dragendorff’s reagent. Lactim ethers (2–5) were
prepared by the method of Peterson and Titze.20
General procedure for the preparation of 8,13-diaza-
2,3-dimethoxygona-1,3,5(10)9(11)-tetraen-12-one
and D-homo derivatives (6–9) as well as medium
ring-size diamides (10–11) and compound (17)
Scheme 1 Synthesis and reduction products of 8,13 diazaster-
oid and D-homo-derivatives with cyclic diamides (Numbers in-
side the rings corresponds to the steroid; numbers outside the
rings indicate the heterocyclic numbering conventions. Number-
ing in Tables 1 through 6 and compounds 6 and 12 follow the
steroid convention, while in the Experimental section, for 7–11 and
13–15 the heterocyclic numbering convention was followed).
Lactim ether (2–5) (11 mmol) was added to a stirred suspension of
ethyl 6,7-dimethoxy-␣-[1-(1,2,3,4-tetrahydroisoquinolyl)]acetate
(1) (2.8 g 10 mmol) in xylene (25 mL). The mixtures were allowed
to warm to reflux and were kept there for 80–140 h. Subsequently,
they were concentrated in vacuo to give dark brown oil products.
The residues were purified by column chromatography on silica
gel (EtOAc:CHCl3 ϭ 2:1 and/or benzene:EtOH ϭ 4:1). Eluting
with EtOAc:CHCl3 initially afforded the 6–9 8,13-diazagona com-
pounds, then the 10,11 cyclic diamides, and finally compound 17
(2,3,15b,15c-tetramethoxy-15,16-benzo-8,13-diaza-D-homogona-
1,3,5(10)trien-12-one). The greatest amount of compound 17 pre-
cipitated from the solution of xylene during the reaction.
9,10-Dimethoxy-1,2,3,4,4a,6,7,13-
octahydroisoquino[1,2-f]pyrido[2,1-b]pyrimidin-13-
one (7)
Ratio of products: 21% (7), 34% (10), and 8% (17), remainder was
unchanged compound (1). Analysis calculated for C18H22N2O3: C,
68.76; H, 7.05; N, 8.91. Found: C, 68.64; H, 6.93; N, 8.78.
The chromatographic fractions were analyzed by TLC (ben-
zene:EtOH ϭ 4:1). The 6–9 diazasteroids showed higher Rf values
than the 10–11 cyclic diamides. Compounds 6–9 became visible
as dark brown spots in an iodine chamber much faster than
compounds 10–11, which appeared later as pale yellow spots. The
Rf values of the compounds will be published in a separate paper.
The obtained diazasteroids 6–9 had a yellow color, and the cyclic
diamides 10,11 were white crystalline compounds. The physical,
1H NMR, and MS data are summarized in Table 1; 13C NMR data
are summarized in Table 2.
10,11-Dimethoxy-1,2,3,4,5,5a,7,8-octahydro-14H-
isoquino[1,2-f]azepino[2,1-b]pyrimidin-14-one (8)
Ratio of products: 17% (8), 43% (11), and 10% (17); the remainder
was unchanged compound (1). Analysis calculated for C19H24N2O3:
C, 69.48; H, 7.36; N, 8.53. Found: C, 69.34; H, 7.22; N, 8.47.
10,11-Dimethoxy-1,2,3,4,5,5a,7,8-octahydro-14H-3-tert-
butyl-isoquino[1,2-f]azepino[2,1-b]pyrimidin-14-one (9)
8,13-Diaza-2,3-dimethoxygona-1,3,5(10)-9(11)-
tetraen-12-one (6)
Ratio of products: 14% (9), the corresponding cyclic diamide was
not isolated, 11% (17), the remainder was unchanged compound
(1). Analysis calculated for C23H32N2O3: C, 71.84; H, 8.39; N,
7.28. Found: C, 71.73; H, 8.22; N, 7.18.
Analysis calculated for C17H20N2O3: C, 67.97; H, 6.71; N, 9.33.
Found: C, 67.74; H, 6.59; N, 9.18.
376 Steroids, 1998, vol. 63, July/August

8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives: Go¨ ndo¨ s et al.
Scheme 2 Synthesis of 2,3,15b,15c-tetramethoxy-15,16-benzo-8,13-diaza-D-homogona-1,3,5(10)-trien-12-one.
1-(1,5-Diaza-2,6-dioxocyclodecanyl)-6,7-dimethoxy-
Conversion of compound 10 to compound 7
1,2,3,4-tetrahydroisoquinoline (10)
A solution of compound 10 (0.33 g, 1 mmol) in 50 mL of xylene
and a solution of methylvalerolactim (3) (0.11 g, 1 mmol) dis-
solved in 5 mL of xylene were mixed and placed in a 100-mL
round-bottomed flask. The mixture was heated under reflux for
48 h. Evaporation of the solvent and purification of the residue by
chromatography on silica gel (EtOH:CHCl3 ϭ 3:1) provided
0.27 g (87%) of 7 as a pale yellow crystalline solid: m.p. 216–
218°C. The 1H NMR and 13C NMR data were the same as the
compound obtained by another procedure.
Analysis calculated for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43.
Found: C, 64.92; H, 7.11; N, 8.32.
1-(1,5-Diaza-2,6-dioxocycloundecanyl)-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (11)
Analysis calculated for C19H26N2O4: C, 65.87; H, 7.56; N, 8.08.
Found: C, 65.91; H, 7.44; N, 8.11.
Preparation of compound 17
Reduction of the 8,13-diaza-2,3-dimethoxygona-
1,3,5(10)-9(11)-tetraen-12-one and D-homo
derivatives (6–9): General procedure
A solution of 6,7-dimethoxy-3,4-dihydroisoquinoline (16) (0.36 g,
1.8 mmol) in 25 mL xylene and a solution of 1 (0.53 g, 1.8 mmol)
in 20 mL xylene were combined, and the resulting mixture was
heated under reflux for 54 h. The conversion of starting material
was followed by TLC (benzene:EtOH ϭ 4:1; under UV light or an
iodine chamber) and resulted in 17 with Rf 0.61. The reaction
mixture was cooled, and compound 17 was precipitated as a pale
yellow crystalline product (0,12 g, 16%): m.p. 247–50°C. Recrys-
tallization of the product from xylene gave a solid, m.p. 251–
252°C. Analysis calculated for C24H28N2O5: C, 67.90; H, 6.65; N,
A stirring suspension of Adam’s PtO2 catalyst (0.1 g) in EtOH (15
mL) at room temperature was prehydrogenated for 2 h under an
atmosphere of hydrogen, and then a solution of the 8,13-
diazasteroids (6–9) in 50–130 mL of EtOH was added to the
suspension. The reaction mixtures were hydrogenated at 1 atm for
6 h, subsequently filtered, and the solvents were evaporated from
the filtrate. Removal of the solvent gave solid residues, which were
recrystallized from the proper solvents (see Table 1) to give the
pure products 12–15. The yields and physical data of compounds
12–15 are summarized in Table 1.
6.60. Found C, 67.78; H, 6.61; N, 6.38. MS H NMR, and 13C
NMR data (see Tables 1 and 2).
1
X-ray diffraction
Crystal and molecular structures of the azasteroids 6 and 8 were
determined by direct methods using diffractometer data. Both
compounds crystallized in a monoclinic system with space
group P21/c. Crystal data and experimental details are listed in
Table 3. Intensity data were collected at 298–299(1) K with a
Rigaku AFC6S diffractometer using graphite monochromated
Mo K␣ radiation and a 2kW sealed tube generator. Lattice
parameters were refined by least squares fit of 21/23 reflections
in a 2␪ range of 35.03–40.66° for 6 and 20.19–33.52° for 8. For
both crystals, three standard reflections were measured after
every 150 reflections. They remained constant throughout data
collection, indicating crystal and electronic stability. Thus, no
decay correction was applied in either case. Data were then
corrected against Lorentz and polarization effects. An empirical
absorption correction based on azimuthal scans of several re-
flections was applied for 6, which resulted in the transmission
factors ranging from 0.98 to 1.00. No need for absorption
correction was indicated by a similar azimuthal scan for 8. A
total of 3003 and 3281 reflections were collected from the thin
crystal plates of 6 and 8, respectively. 2853 reflections were
8,13-Diaza-2,3-dimethoxygona-1,3,5(10)-trien-12-
one (12)14
Analysis calculated for C17H22N2O3: C, 67.52; H, 7.33; N, 9.26.
Found: C, 67.63; H, 7.38; N, 9.30.
9,10-Dimethoxy-1,2,3,4,4a,6,7,11b,12,13,-
decahydroisoquino[1,2-f]pyrido[2,1-b]pyrimidin-13-
one (13)
Analysis calculated for C18H24N2O3: C, 68.32; H, 7.64; N, 8.85.
Found: C, 68.24; H, 7.49; N, 8.58.
10,11-Dimethoxy-1,2,3,4,5,5a,7,8,12b,13,14-
undecahydroisoquino[1,2-f]azepino[2,1-]pyrimidin-
14-one (14)
Analysis calculated for C19H26N2O3: C, 69.06; H, 7.93; N, 8.48.
Found: C, 68.92; H, 8.02; N, 8.27.
10,11-Dimethoxy-1,2,3,4,5,5a,7,8,12b,13,14-
undecahydro-3-tert-butyl-isoquino[1,2f]azepino[2,1-
b]pyrimidin-14-one (15)
unique and nonzero (Rint ϭ 0.234) for 6 and 3103 (Rint
ϭ
0.037) for 8. Intensities with I Ն 2␴ (I) were used to solve the
structures by direct methods (using programs MITHRIL21 and
DIRDIF22) and to refine the structures by using full-matrices
Analysis calculated for C23H34N2O3: C, 71.46; H, 8.86; N, 7.25.
Found: C, 71.32; H, 8.72; N, 7.12.
2
least-squares to minimize the function ⌺w(Fo-k͉Fc͉) . Weights
Steroids, 1998, vol. 63, July/August 377

Papers
Table 1 Physical and Spectral Data of Compoundsa 6–15 and 17
Compound Yield (%)
m.p. (°C)/(cryst solvent)
264–268, (DMF)
1H NMR and MS spectral data
6
7
81
21
NMR (CDCl3), 100 MHz; 7.12 (s, 1, H-1), 6.62 (s, 1H, H4), 2.70–3.05 (m, 3H, H2-6,
Heq-15), (2H, H2-17), 1.80–2.50 (m, 5H, Hax-15, H2-16, H2-16a), 3.86 (s, 3H,
MeO), 3.88 (s, 3H, MeO); MS (FAB) m/z 299 [M-H]Ϫ
218–219, (EtOH)
NMR (CDCl3), 250 MHz; 7.08 (s, 1H, H-1), 6.61 (s, 1H, H-1), 2.75–3.00 (m, 2H,
H2-6), 3.25 (t, 2H, H2-7), 5.18 (s, 1H, H-1), 4.68 (dd, 1H, J ϭ 10.0 Hz, 3 Hz, Hax
14), 1.80–2.15 (m, 2H, H-15), 1.40–1.80 (m, 4H, H2-16, H2-16a), 2.55 (m, 1H,
Hax-17), 4.58 (dt, 1H, J ϭ 12.0 Hz, 2.5 Hz, Heq-17), 3.84 (s, 3H, MeO), 3.87 (s,
3H, MeO); MS (FAB) m/z 313 [M-H]Ϫ
-
8
9
17
14
34
165–167, (Aceton/Ether)
225–228, (EtOH)
NMR (CDCl3), 100 MHz; 7.07 (s, 1H, H-1), 6.63 (s, 1H, H-4), 2.88 (m, 2H, H2-7),
5.30 (s, 1H, H-11), 4.60 (dd, 1H, J ϭ 10.8 Hz, 2.8 Hz, H-14), 1.90–2.30 (m, 2H,
H2-15), 1.40–1.90 (m, 4H, H2-16, H2-16a), 2.75 (m, 1H, Hax-17), 4.43 (ddd, 1H,
J ϭ 13.5 Hz, 7 Hz, 5 Hz, Heq-17), 3.86 (s, 3H, MeO), 3.88 (s, 3H, MeO); MS
(FAB) m/z 327 [M-H]Ϫ
NMR (CDCl3), 100 MHz; 7.09 (s, 1H, H-1), 6.61 (s, 1H, H-4), 2.87 (m, 2H, H2-6),
3.31 (t, 2H, H2-7), 5.28 (s, 1H, H-11), 4.57 (dd, 1H, J ϭ 11.0 Hz, 3 Hz, H-14),
1.00–2.60 (m, 6H, H2-15, H2-16, H2-16a), 2.75 (m, 1H, Hax-17), 4.40 (m, 1H,
Heq-17), 3.86 (s, 3H, MeO), 3.88 (s, 3H, MeO, 0.85 (s, 9H, Me3C); MS (FAB)
m/z 383 [M-H]Ϫ
NMR (CDCl3), 250 MHz; 6.73 (s, 1H, H-1), 6.61 (s, 1H, H-4), 5.23 (dd, 1H, J ϭ 9.5
Hz, 3 Hz, Hax-9), 2.60 (m, 2H from decoupling experiment H2-11), 3.86 (s, 3H,
MeO), 3.88 (s, 3H, MeO), 4.92 (m, 1H, Heq-7), 3.85 (m, 1H from decoupling
experiment, H-17), 5.47 (dd, 1H, J ϭ 9 Hz, 2 Hz, NH), 1.5–31 (m, 13 H, other
skeleton protons); MS (FAB) m/z 331 [M-H]Ϫ
NMR (CDCl3), 100 MHz; 6.72 (s, 1H, H-1), 6.57 (s, 1H, H-4), 5.26 (dd, 1H, J ϭ 9
Hz, 4.5 Hz, Hax-9) 2.60 (m, 2H, from decoupling experiment, H2-11), 3.83 (s,
3H, MeO) 3.85 (s, 3H, MeO, 4.87 (m, 1H, Heq-7) 3.65 (m, 1H, H-17), 6.24 (t,
1H, J ϭ 6 Hz, NH); MS (FAB) m/z 345 [M-H]Ϫ
NMR (CDCl3), 250 MHz; 6.56 (s, 1H, H-1), 6.60 (s, 1H, H-4), 3.76 (dd, 1H, J ϭ
11.5 Hz, 5 Hz, Hax-9), 2.48 (dd, 1h, J ϭ 17.5 Hz, 11.5 Hz, Hax-11), 3.04 (dd, 1H,
J ϭ 17.5 Hz, 5.0 Hz, Heq-11), 3.98 (dd, 1H, J ϭ 9.0 Hz, 5.0 Hz, Hax-14), 3.82 (s,
3H, MeO), 3.84 (s, 3H, MeO), 1.75–2.04 (m, 4H, H2-15, H2-16), (1.85 m, from
decoupling experiment, Hax-15), 2.54 ddd (1H, J ϭ 11.0 Hz, 9.0 Hz, 5.0 Hz,
Hax-17), 2.70–3.80 (m, 5H, H2-6, H2-7, Heq-17); MS (FAB) m/z 301 [M-H]Ϫ
NMR (CDCl3), 100 MHz; 6.55 (s, 1H, H-1), 6.58 (s, 1H, H-4), 3.78 (dd, 1H, J ϭ
10.5 Hz, 5 Hz, Hax-9), 2.48 (dd, 1H, J ϭ 17.5 Hz, 10.5 Hz, Hax-11), 2.92 (dd, 1H,
J ϭ 17.5 Hz, 5 Hz, Heq-11), 3.7–3.9 (m, 1H, in overlapping H-14) 3.80 (s, 3H,
MeO), 3.83 (s, 3H, MeO), 1.20–3.40 (m, 11H, other skeleton protons, 2.48 m,
from decoupling experiment, Hax-17), 4.82 (ddd, 1H, J ϭ 12.0 Hz, 3.5 Hz, 2.0
Hz, Heq-17); MS (FAB) m/z 315 [M-H]Ϫ
10
202–205, (EtOH)
11
12
43
98
262–265, (EtOH)
212–214, (EtOH/ether)b
13
99
193–194, (EtOH)
14
15
17
97
99
8
162–165, (ether/hexane) NMR (CDCl3), 100 MHz; 6.55 (s, 1H, H-1), 6.60 (s, 1H, H-4), 3.97 (dd, 1H, J ϭ
11.0 Hz, 4.0 Hz, Hax-9), 2.55 (dd, 1H, J ϭ 17.5 Hz, 11.0 Hz, Hax-11), 2.85 (dd,
1H, J ϭ 17.5 Hz, 4.0 Hz), 4.29 (t, 1H, J ϭ 4 Hz, Heq-14), 3.82 (s, 3H, MeO),
1.40–3.40 (m, 13H, other skeleton protons), 3.70–4.10 (m, 1H, Heq-17); MS
(FAB) m/z 329 [M-H]Ϫ
183–184 (MeOH/ether)
NMR (CDCl3), 10 MHz; 6.52 (s, 1H, H-1), 6.61 (S, 1H, H-4), 3 (dd, 1H, J ϭ 11.0
Hz, 5.0 Hz, Hax-9), 2.70 (m, 1H, from decoupling experiments, Hax-11), 2.95,
(1H, from decoupling experiments, Heq-11), 4.24, (dd, 1H, J ϭ 9.5 Hz, 2.5 Hz,
Hax-14), 3.84 (s, 3H, MeO), 1.00–3.50, (m, 12H, other skeleton protons), 3.9–
4.3 (m, 1H, Heq-17), 0.87 (s, 9H, Me3C); MS (FAB) m/z 385 [M-H]Ϫ
251–253 (EtOH)
NMR (CDCl3), 250 MHz; 6.58 (s, 2H, 4, -15d), 6.50 (s, 1H, H-1), 6.98 (s 1H broad,
H-15a), 5.75 (s, 1H, Hax-14, 4.86 (m, 1H, Heq-17), 4.45 (t, 1H, J ϭ 8.5 Hz, H-9,
2.45–2.90 (m, 9H other skeleton protons, from decoupling experiment and
C/H correlation 2.68 Hax-7, 2.85 Hax-17), 3.85 (s, 3H, MeO), 3.82 (s, 3H, MeO),
3.80 (s, 3H, MeO), 3.97 (s, 3H, MeO); MS (FAB) m/z 423 [M-H]Ϫ
aThe steroid skeleton numbering convention was followed in compounds (6–15) and (17).
bLit m.p. 219–240°C.
assigned to individual observations were w ϭ 4Fo2/␴2(Fo2),
the bonded partner. The final R values together with maximum
2
where ␴2(Fo2) ϭ [S2(C ϩ R2B) ϩ (pFo2)]/Lp with the param-
and minimum peaks in the final difference Fourier maps are
given in Table 3. Neutral atomic scattering factors were taken
from Cromer and Waber.23 All calculations were performed
using the TEXSAN24 crystallographic software package (Mo-
lecular Structure Corporation). The sample of 6 was poorly
crystalline; its peaks were wide and, in some cases, rather
unsymmetrical. This resulted in a limited data set of low inten-
sities (Table 3). Although the data/parameter ratio is lower than
eters: S, scan rate; C, total integrated peak count; R, ratio of
scan time to background counting time; B, total background
count; and Lp, Lorentz polarization factors. For both data sets,
the fudge factor was p ϭ 0.01. For each hydrogen, positions
were generated from assumed geometry but were not refined.
They were only included in the final rounds of least squares
with isotropic displacement parameters set to 20% greater than
378 Steroids, 1998, vol. 63, July/August

8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives: Go¨ ndo¨ s et al.
Table 2 13C NMR Chemical Shifts of Products 6–15 and 17 (␦ppm; CDCl3/TMS)
Compound C1
C2
C3
C4
C5
C6
C7
C9
C10
C11 C12
C14
C15
C16
C16a C16b C17 CH3O
6
7
107.4 147.9 150.2 110.2 128.5 28.3 43.9a 153.1 119.9 91.4 164.8 74.9 32.8
108.2 148.2 149.1 110.5 128.1 28.8 44.3 151.1 121.0 85.7 166.2 77.9 24.5
21.5
—
—
—
43.4a
—
—
25.8 24.1
44.0 56.0
56.0
8
107.7 147.9 148.6 110.3 128.0 28.9 45.3 150.7 121.0 87.1 165.0 78.6 28.7a 25.1b 25.3b 28.2b 43.6 55.9
55.9
107.7 147.9 148.7 110.3 128.0 28.2 45.2 150.7 121.0 86.6 165.2 78.5 28.9
9
26.3 46.6 28.9 43.0 55.9
55.9
23.9
10
11
12
13
14
15
17
109.7 148.0a 148.2a 111.2 126.7b 28.3 39.5
109.7 147.9 147.9 111.1 126.4a 28.6 41.7
107.9 147.5 147.5 111.0 125.6 28.3 46.3
108.3 147.6 147.7 111.2 126.0 29.1 44.8
108.1 147.6 147.7 111.2 125.7 28.9 43.5
108.6 147.6 147.6 111.6 125.6 29.0 42.6
108.9 147.2 147.7 111.7 125.3 28.6 35.3
54.5 126.9b 35.2 172.5 170.5 28.6
54.3 127.8a 35.1 171.9 170.9 28.0
58.8 128.0 31.9 166.6 79.0 24.2
55.7 128.2 39.6 167.3 77.1 31.2
56.4 128.7 37.9 168.1 77.9 33.3
56.0 129.2 37.6 168.4 79.0 34.1
—
—
—
—
—
25.6 55.9
55.9
25.1 55.9
56.2
44.6 55.7
55.7
41.7 55.7
55.7
22.7 24.3
20.7
—
23.5a 24.0a
23.5 27.3a 28.9a 43.2 55.8
55.8
27.2a 49.6 27.3a 41.4 56.0
56.0
55.3 129.7 35.2 167.9 74.4 124.3c 128.9 28.0
—
37.7 55.7
55.8
c
a,bTentative assignment; C15a 109.4; C15b 148.1; C15c 148.3; C15d 110.6.
ideal, the refinement proceeded well resulting in a structure
comparable to that of 8. At any rate, the ring puckering and
general conformation of the diazasteroid skeletons in the solid
state could be characterized and compared.
Results and discussion
Synthesis
The reaction of a 1.1 molar equivalent of methyl butyrolac-
tim (2) with 1 in xylene at 137–144°C for 80 h gave only the
imine-type product 8,13-diaza-2,3-dimethoxygona-1,3,
5(10),9(11)-tetraen-12-one (6) in 81% yield (Table 1). This
product, when reduced with Adam’s catalyst in ethanol, fur-
nished a pale yellow crystalline compound (12, m.p. 212–
214°C, Table 1). This differed from the m.p. reported in the
literature (219–240°C).14 The previously reported product was
obtained by reduction of the quaternary immonium iodide of
8,13-diazasteroid with Adam’s catalyst in acetic acid. Presum-
ably, the latter compound was a mixture of configurational
isomers. The basis of this conclusion is the observed broad
range of the melting point; our product seems to be stereoho-
mogeneous, as judged by 1H NMR and 13C NMR data.
Similar reaction of lactim ethers 3–5 with 1 gave the
imine-type D-homo-8,13-diazagonane derivatives 7–9 and
provided the medium-sized ring cyclic diamides 10,11. The
same diamide formation was not observed when lactim
ether 2 was reacted with 1. The probable reason is that the
nine-membered ring diamide was very strained. The ratio of
the two kinds of products strongly depends on the ring size
of the lactim ethers, as shown in Table 1. The major prod-
ucts were cyclic diamides; 10,11 and the D-homo-8,13-
diazagona derivatives 7–9 were the minor products when
lactim ethers 3 and 4 were used in the annelation reactions.
The corresponding cyclic diamides were not isolated from
the reaction of lactim ether 5 with ␤-aminoester 1. The
Table 3 Crystal Data and Experimental Details
Compound 6
C17H20N2O3
300.36
Monoclinic
P21/c
11.427 (3)
6.905 (3)
19.192 (3)
101.92 (2)
1481.6 (7)
4
Compound 8
C19H24N2O3
328.41
Monoclinic
P21/c
10.921 (2)
15.282 (3)
10.239 (2)
99.06 (2)
1687 (1)
4
Molecular formula
M
Crystal system
Space group
´
a (L)
´
b (L)
´
c (L)
b (deg)
3
´
V (L )
Z
Dc (g.cmϪ3
)
1.346
0.87
640
1.293
0.82
704
␮(mmϪ1
)
F(000)
Crystal dimensions
(mm)
0.40 ϫ 0.30 ϫ 0.08 0.40 ϫ 0.15 ϫ 0.10
Maximum 2␪ (deg)
50.1
Mo K␣, 0.71069
␻/2␪
50.0
Mo K␣, 0.71069
␻/2␪
´
Radiation (L)
Scan mode
Scan width (deg)
Temperature (K)
Number of reflections:
unique
With I Ն 2␴(I)
No. of parameters
refined
1.84 ϩ 0.30tan␪
298 (1)
1.00 ϩ 0.30tan␪
299 (1)
2853
3103
919
199
1320
218
Goodness-of-fit on F
R
2.03
0.061
0.046
0.24
1.65
0.052
0.039
0.20
1
physical and H NMR data are shown in Table 1, and the
13C NMR data are summarized in Table 2.
Rw
r
r
Ϫ3
´
max in ⌬F map (eL
)
)
Ϫ3
When the ␤-aminoester 1 was reacted with lactim ether
3, the imine-type product 7 and the cyclic diamide 10 were
´
min in ⌬F map (eL
Ϫ0.25
Ϫ0.18
Steroids, 1998, vol. 63, July/August 379

Papers
Table 5 Results of the 1H NOE Difference Measurements of
Compound 17
accompanied by an unexpected pentacyclic compound:
2,3,15b,15c-tetramethoxy-15,16-benzo-8,13-diaza-D-
homogona-1,3,5(10)trien-12-one (17). The structure of this
compound was determined by MS, 1H NMR (Table 1), and
13C NMR (Table 2). Results of COLOC25 analysis are
shown in Table 4, and one-dimensional 1H NOE difference
measurements are given in Table 5. Evaluations of the
spectroscopic data are presented in the section titled “As-
signment of Structure”. The spectral studies were in com-
plete accordance with the structure of 17.
In the present studies, we proposed to form the com-
pound 17. Under basic conditions, the ␤-aminoester 1 un-
derwent a retro-Mannich reaction to form 6,7-dimethoxy-
3,4-dihydroisoquinoline (16). The opposite reaction was
observed by Pelletier and Cava.26 When 16 was condensed
with diethyl malonate to form ␤-aminoester 1, we presume
compound 16 reacted with ␤-aminoester 1 to afford 17 in a
slow reaction. When compound 16 reacted with ␤-aminoester
1 in xylene at 75°C for 54 h, compound 17 was formed in
8% yield. At higher temperature (138°C) in xylene for 54 h,
the yield of compound 17 was 16%. In both cases after
removal of the precipitated compound 17 by filtration, the
reactions were continued. Compound 17 was detected in the
reaction of the ␤-aminoester 1 with lactim ethers 4 and 5,
but was not observed in the reaction with lactim ether 2. The
lack of formation of compound 17 can be explained by the
fact that the reaction with lactim ether 2 was much faster
than that with lactim ethers, 3–5 and the 8,13-diazasteroid
(6) was formed in good yield (81%), with no starting
material from the retro-Mannich reaction remaining. It was
observed that subjecting the cyclic diamide 10 to the same
reaction conditions under which 8,13-diazasteroids were
formed, produced the diazasteroid 7.
Irradiate
H-1
Observe
% NOE
H-9
H2-11
8.1
3.2
MeO-2
H-1
Heq-11/Hax-7
H-14
H2-7
H-9
H-15a
H-14
MeO-15b
15.7
8.4
H-9
4.7
17.2
3.2
15.2
5.5
4.8
10.2
H-14
H-15a
Assignment of structures of compounds 6–15 and 17
by NMR spectroscopy
The dd multiplicity of the H-9 signal and its couplings (9.5
Hz/3.0 Hz and 9.0 Hz/4.5 Hz) indicate that, in the case of
the ten- and eleven-membered ring compounds (10 and 11),
a conformer is predominant in which the dihedral angles of
H-9 and protons of H-11 are approximately 180° and 60°.
It is well known that in solution a trans º cis-1 º cis-2
equilibrium can be formed in isoquinoline-type nitrogen
bridgehead compounds.27 In compounds 6–9, the bridge-
head N-8 atom is part of an enamine moiety and has a planar
or nearly planar geometry; consequently, in this peculiar
case, the formation of the above mentioned conformational
equilibrium does not take place. The dd multiplicity of the
H-14 signal and the couplings of 10 Hz and 3 Hz support the
axial position of this proton. The triplet multiplicity of the
signal of the H-7 methylene protons is indicative of the fast
interconversion of the two possible half-chair conformers of
the flexible B ring.
In the reduced 8,13-diazasteroids (12–15), the proton at
H-9 is axial, as follows from the bond coupling constants of
11 Hz and 5 Hz between the H-9 and H-11 methylene
proton measurements. Similar multiplicity of the H-14 pro-
ton and the coupling constants of 9.5 Hz and 4.0 Hz in
compounds 12, 13 and 15 indicate that the H-14 proton is
also axial. The stereochemistry of these compounds was
also supported by NOE measurements. Significant NOE
was detected between H-14 and H-9 protons, which indi-
cates a cis-diaxial position for the two hydrogens; in other
words, the ring junctions of B/C and C/D are trans as in the
natural steroids. This finding was consistent with the 13C
NMR chemical shifts measured for these compounds. A
noteworthy change was observed in the conformation of the
seven-membered ring by the introduction of a tert-butyl
group. In compound 14, the triplet multiplicity of the H-14
proton and coupling constants of 4 Hz indicated that in this
compound, H-14 is equatorial. However, the same com-
pound with a bulky tert-butyl group in ring-D (15), resulted
in an axial H-14 proton, which exhibited a doublet of
doublets resonance with J ϭ 9.5 and 2.5 Hz.
The lactam 11 did not convert to the 8,13-diazasteroid
homolog 8. As we proposed on the basis of the stereochem-
ical model of 11, in this structure, it is impossible for the
N-CAO and -NH-CAO groups to approach close enough
for ring closure to occur.
The hydrogenation of compounds 7–9 was carried out as
for compound 6, giving 13–15. The conformation of the
B/C ring was similar to that of compound 12. The catalytic
hydrogenation carried out by the stereospecific pathway
1
does not depend on the ring-member of ring D. The H
NMR and 13C NMR data of compounds 13–15 are summa-
rized in Tables 1 and 2.
Table 4 Determination of Carbon–Proton Connectivity over
Two and Three Bonds for Compound 17 by the COLOC Method
(Jopt ϭ 7 Hz)
Proton
Carbon
H-1
H-4/H-15d
H-9
C(3), C(5), C(9)
C(2), C(10), C(15, C(15b)
C(1), C(10)
In compound 17, the elucidation of the relative stereochem-
istries of protons H-9 and H-14 required a more detailed
examination. However, the signal of H-9 appeared separately
H-14
C(7), C(9), C(15), C(15h), C(16)
C(15c), C(16)
H-15a
H-eq-17
C(12), C(16), C(16a)
1
in the H NMR spectrum of the vicinal H-11 protons, which
380 Steroids, 1998, vol. 63, July/August

8,13-diaza-2,3-dimethoxygona-1,3,5(10),9(11)-tetraen-12-one and D-homo derivatives: Go¨ ndo¨ s et al.
Table 6 Relevant Torsion Angles for 6 and 8
Ring B
C5-C6-C7-N8
6
8
45 (1)
Ϫ48 (1)
24.4 (9)
1.9 (9)
Ϫ3 (1)
Ϫ20 (1)
Ϫ54.8 (5)
46.1 (5)
Ϫ11.4 (6)
Ϫ14.0 (6)
1.2 (6)
C6-C7-N8-C9
C7-N8-C9-C10
N8-C9-C10-C5
C9-C10-C5-C6
C10-C5-C6-C7
33.3 (6)
Ring C
N8-C9-C11-C12
C9-C11-C12-N13
C11-C12-N13-C14
C12-N13-C14-N8
N13-C14-N8-C9
C14-N8-C9-C11
0 (1)
3 (1)
7.4 (6)
Ϫ14.6 (6)
Ϫ11.7 (5)
40.7 (5)
Ϫ47.3 (5)
25.2 (6)
16 (1)
Ϫ36 (1)
36 (1)
Ϫ20 (1)
Ring D
C17-N13-C14-C15
C19-N13-C14-C15
N13-C14-C15-C16
C14-C15-C16-C17
C15-C16-C17-N13
C15-C16-C17-C18
C16-C17-N13-C14
C16-C17-C18-C19
C17-C18-C19-N13
C18-C19-N13-C14
Exocyclic torsion
angles
24.9 (9)
—
Ϫ28.7 (9)
22.5 (9)
Ϫ8.8 (9)
—
Ϫ9.5 (9)
—
—
—
—
87.6 (4)
Ϫ70.7 (5)
51.3 (7)
—
Figure 2 Molecular structure of compound 8. ORTEP diagram
with atomic labeling and thermal ellipsoids with 50% probability
level. The hydrogen atoms are shown but not labeled.
Ϫ62.5 (8)
—
74.9 (8)
Ϫ33.8 (7)
Ϫ40.6 (6)
For a complete assignment of 13C NMR signals, the two-
dimensional C/H correlation measurement was used, while for
the assignment of quaternary carbon atoms, especially in the
cases where the CH-signals were overlapped, the COLOC25
method was used. This measurement was optimized for J(C,H)
ϭ 7 Hz long-range couplings. The detected proton-carbon
connectivities over two and three bonds, for compound 17 are
summarized in Table 4.
C9-C11-C12-O12
C14-N13-C12-O12
C1-C2-O2-C2Ј
Ϫ173.2 (8)
Ϫ167.8 (8)
Ϫ1 (1)
161.2 (4)
172.5 (4)
4.0 (7)
C4-C3-O2-C3Ј
1 (1)
0.2 (6)
C7-N8-C14-N13
N8-C14-N13-C19
N8-C14-N13-C17
178.1 (7)
—
160.0 (6)
163.0 (3)
Ϫ147.1 (4)
—
X-ray diffraction
Crystallographic data and experimental details for 6 and 8
are listed in Table 3. Selected torsion angles are given in
Table 6. Racemates of the diazasteroids crystallized in the
monoclinic space group P21/c. Due to the aromatic ring A,
the double bond between C9–C11, and the N-8 and N-13
atoms sitting in the B/C and C/D ring junctions, only one
chiral center, C-14, was retained. Figures 1 and 2 show the
C-14(S) enantiomers for both structures with thermal ellip-
soidal plots and numbering schemes. The stereoscopic rep-
resentation of molecule 6 (Figure 3) revealed a practically
coplanar skeleton; only C-7 and C-14 were visibly out of the
least squares plane in the ␣-position at a distance of
Ϫ0.576(6) and Ϫ0.385(7)Å, respectively. Both B/C and
C/D rings junctions are trans like. The puckering parame-
ters28 [Q ϭ 0.387(8), 0.285(9)Å, ␸ ϭ 121(1), 113(2)°, ␪ ϭ
123(1), 123(2)°] showed that the B and C heterorings
equally assume envelope conformation with C-7 and C-14
on the flaps (the corresponding asymmetry factors29 fCs ϭ
0.9 pm and 2.9 pm), while the five membered hetero ring is
in half-chair [Q ϭ 0.268(9)Å, ␸ ϭ 235(2°)] conformation
were strongly coupled, and their signals were overlapped,
prohibiting an adequate spectral analysis. The H-14 signal
appeared as a singlet; thus, from the coupling constants, the
stereochemistry of compound 17 could not be concluded. The
1
1,3-diaxial position of H-9 and H-14 was confirmed by H
1
NOE difference spectroscopy. The results of the H NOE
difference measurements of compound 17 (summarized in
Table 5) contributed to the assignment of other proton signals.
Figure 1 Molecular structure of compound 6. ORTEP diagram
with atomic labeling and thermal ellipsoids with 50% probability
level. The hydrogen atoms are shown but not labeled.
Figure 3 Stereoscopic view of molecule 6 showing its basically
flattened comformation. To fix the enantiomer with the chirality
of C-14(S), the C-14 hydrogen atom is also presented.
Steroids, 1998, vol. 63, July/August 381

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tramolecular Friedel-Crafts cyclization of nitrogen heterocycles. An
expeditious approach to the aza-phenantrene skeleton. J Org Chem
58:700–704.
7.
8.
Catsoulacos P, Catsoulacos D (1994). Conjugated system of homo-
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2525–2528.
Williams JM, Marchesini G, Reamer RA, Dolling U-H, Grabowski
EJJ (1995). Sequential dehydrogenation of 3-keto-4-azasteroids.
The reaction of ene-lactams with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ). J Org Chem 60:5337–5340.
Figure 4 Stereoscopic view of molecule 8 showing its twisted
conformation. To fix the enantiomer with the chirality of C-14(S),
the C-14 hydrogen atom is also presented.
9.
Meyers AI, Elworthy TR (1992). Chiral formamidines. The total
asymmetric synthesis of (Ϫ)-8-azaestrone and related (Ϫ)-8aza-12-
oxo-17-desoxoestrone. J Org Chem 57:4732–4740.
Burckhalter JH, Abramson HN (1966). Total synthesis of 8,13-
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the 8,13-diaza-steroids. J Chem Soc Chem Commun 1274–1275.
Redeuilh G, Viel C (1975). Hetero steroids II. Configuration of
8,13-diazaestrone. Tetrahedron 31:1443–1448.
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Matoba K, Isomura K, Nagata M, Yamazaki T, Castle RN (1972).
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2,3-dimethoxygona-1,3,5(10)triene and its mercuric acetate oxida-
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Isomura K, Yamazaki T, Nagata M, Matoba K, inventors; Nihon
Izakuhin Kogyo Co., Ltd., assignee. Diazasteroid derivative. Japan
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lactim ethers with carbethoxymethyl piperidines. Hererocycles
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Takahata H, Ishikura M, Yamazaki T (1980). The chemistry of
lactim ethers. II. Reaction of lactim ethers with 2-carbethoxymethyl
piperidines. Chem Pharm Bull 28:220–226.
Takahata H, Tomoguchi A, Yamazaki T (1980). Chemistry of
lactim ethers, Part III. Reaction of lactim thioethers with
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Bull 28:1000–1002.
Takahata H, Ishikura M, Nagai K, Nagata M, Yamazaki T (1981).
The chemistry of lactim ethers. IV. Synthesis of 1,9- and 5,9-
diazasteroid systems. Chem Pharm Bull 29:366–369.
Peterson S, Titze E (1957). Reaktionen cyclischer lactimather mit
acylierten hydrazin-derivaten. Chem Ber 90:909–921.
Gilmore CJ (1984). MITHRIL-an integrated direct-methods com-
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Beurkens PT (1984). Program DIRDIF, Direct Methods for Differ-
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TEXSAN–TEXRAY (1985). Structure Analysis Package, Molecu-
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with a twofold axis [fC2 ϭ 0.4 pm] bisecting atom C-17.
The pyramidality of the nitrogen atoms result from their
distance from the plane of the three atoms bonded by N-C
multiple bonds: ⌬N-8 ϭ 0.288(8) and ⌬N-13 ϭ 0.117(7)Å.
(An alternative measurement of pyramidality is suggested
by Dunitz and Winkler30 calculated from properly chosen
pairs of endo- and exocyclic torsion angles (cf Table 6)
10.
11.
12.
13.
pertaining to the nitrogen atoms: ␹ ϭ 0.21, ␹
ϭ 0.09
rad). In contrast, molecule 8, as depicted in FNig13ure 4, is
twisted approximately around the axis defined by atoms
C-10 and C-18. The seven-membered ring exhibits distorted
twist-chair (TC) conformation with endocyclic torsion an-
gles close to those of the canonical form.31 Their discrep-
ancies were measured by the asymmetry factor of fC2 ϭ 6.2
pm calculated24 for the twofold axis, which bisects atom
C-19 and bond C15–C16. Ring D is cis-like and fused to
ring C which, instead of the envelope shape found in 6, has
a skewed form [Q ϭ 0.481(5)Å, ␸ ϭ 280(1)°, ␪ ϭ 63(1)°].
The twist of ring C is propagated further onto ring B,
which also assumes a skewed form [Q ϭ 0.409(5)Å, ␸ ϭ
287(1)°, ␪ ϭ 66(1)°]. But, similarly to 6, the out-of-plane
atoms are again C-7 and C-14. These features of the mol-
ecule and, in particular the cis-C/D junction, give rise to the
N8
14.
15.
16.
17.
18.
very low pyramidality of N-13 [⌬N-13 ϭ Ϫ0.056(4)Å, ␹
N13
19.
ϭ 0.04 rad]. Similarly, the out-of-plane amplitude of N-8 is
less [⌬N-8 ϭ Ϫ0.231(5).Å, ␹ ϭ 0.17 rad] than that of
N8
compound 6. Finally, it is worth noting that the enantiomers
assigned C-14(S) chirality exhibit torsion angles with op-
posite signs for rings B and C, which is due to the difference
in their C/D ring junctions (trans versus cis).
20.
21.
22.
Acknowledgments
23.
24.
25.
Financial support from the Ministry of Education, Hungary
(Grant No. MKM-224) and from the Hungarian National
Science Foundation (Grant No. OTKA-T 014978) is grate-
fully acknowledged.
References
26.
27.
1.
2.
3.
4.
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