Stereochemical issues related to the synthesis of 7,10-dimethyl- 7,10,16,16a-tetrahydro-11H-quinazolino[2',3':3,4]pyrazino-[1,2-b]β- carboline-5,8-diones

Article abstract of DOI:10.1016/S0957-4166(98)00315-2

Condensation reactions between anthranilic acid and iminoethers derived from 2,3,6,7,12,12a-hexahydropyrazino[1,2-b]β-carboline-1,4-diones 3-8 to give the title hexacyclic compounds were studied from a stereochemical point of view. The configuration was r

Full text of DOI:10.1016/S0957-4166(98)00315-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3115–3123
Stereochemical issues related to the synthesis of 7,10-dimethyl-
7,10,16,16a-tetrahydro-11H-quinazolino[20,30:3,4]pyrazino-
[1,2-b]β-carboline-5,8-diones
Antonio Madrigal, Mercedes Grande and Carmen Avendaño ∗
Departamento de Química Orgánica y Farmacéutica, F. de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 22 July 1998; accepted 4 August 1998
Abstract
Condensation reactions between anthranilic acid and iminoethers derived from 2,3,6,7,12,12a-
hexahydropyrazino[1,2-b]β-carboline-1,4-diones 3–8 to give the title hexacyclic compounds were studied
from a stereochemical point of view. The configuration was retained in the formation of iminoethers, but inversion
of the tryptophan sterocenter C-16a took place in the condensation process. Epimerization also occurred in an
alternative procedure that involves acylation at N-2 with o-azidobenzoyl chloride, followed by intramolecular
aza-Wittig reaction. © 1998 Published by Elsevier Science Ltd. All rights reserved.
1. Introduction
Our current interest in multi drug resistance (MDR) reversal agents, designed as analogs of the
fungal metabolite N-acetylardeemin (1),1,2 moved us to study the dehydro-C-homo analogs 2, in which
rings A–C have been modified to a 1,2,3,4-tetrahydro-β-carboline system. These compounds could be
potentially used in combination with antitumor drugs to avoid resistances related to the overexpression of
the membrane glycoprotein P-170, that lowers the intracellular concentrations of several antitumor agents
below their therapeutic levels.3 Their synthesis was planned through condensation with anthranilic acid of
the tetracyclic piperazinediones containing the A–D fragment, with special concern given to the possible
epimerization of stereogenic centers, especially of C-16a (Scheme 1).
Condensation with anthranilic acid of iminoethers with one or two stereocenters derived from proline
dipeptide anhydrides may affect the proline stereocenter. Thus, epimerization took place in the reactions
of anthranilic acid with iminoethers derived from cyclo-L-Pro-Gly and cyclo-L-Val-L-Pro, but not in
those of cyclo-D-Val-L-Pro and cyclo-Sar-L-Ala.4
∗
Corresponding author.
0957-4166/98/$ - see front matter © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00315-2
tetasy 2464 Article

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A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
Scheme 1.
We have recently studied the fate of the tryptophan stereocenter in the acylation at the N-2 position of
3,5a,6,10b,11,11a-hexahydro-2H-pyrazino[20 ,10-5,1]pyrrolo[2,3-b]indole-1,4-diones to give compounds
A, which are precursors of N-acetylardeemin,5a and in the condensation of the corresponding iminoethers
with anthranilic acid,5b to obtain analogs B.
In the first case, we observed epimerization at C-11a in compounds with a syn-relationship between H-
3 and H-11a hydrogen atoms. In the second case, the stereochemistry of all stereocenters was retained in
compounds with an anti-relationship between H-7 and H-15a protons when R=H or R=Me, while partial
epimerization at C-15a was observed for derivatives with R=Me and with a syn-relationship between
H-7 and H-15a protons. These observations were explained taking into account the steric compression
between the N-2 acyl, the C-1 oxygen and the C-3 methyl groups or between the C-7 methyl and the C-5
and C-8 carbonyl groups in the most probable conformation of ring D in the A or B systems.
2. Results and discussion
We study here the stereochemistry of these transformations in the tetracyclic piperazinediones 3–8
(Scheme 1), which were prepared from (1S,3S), (1R,3R) and (1R,3S) methyl 1-methyl-1,2,3,4-tetrahydro-
β-carboline-3-carboxylates through their reaction with glycine, or L or D-alanine, followed by cycliza-
tion of the dipeptides thus obtained to the corresponding cyclic anhydrides.6
Activation of the amide function in compounds 3–8 by transformation into the iminoethers 9–147
was required to achieve the hexacyclic compounds in the subsequent reaction with anthranilic acid.
The alternative procedure to obtain 4-quinazolones from amides by direct reaction with anthranilic acid
and thionyl chloride, which has been exploited by Kametani and coworkers for the synthesis of natural
products,8 did not work in our case (Scheme 2).
This process took place with retention of the configuration of all stereocenters, according to 1H-NMR

A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
3117
Scheme 2.
experiments. For instance, the syn-relationship between H-3, H-6 and H-12a protons in enantiomers 9
and 10 was confirmed by the NOE effects shown for compound 9 and by the homoallylic coupling (J=2.6
Hz) between H-3 and H-12a protons, which was confirmed by COSY experiments. This coupling was
absent in compounds 11 and 12.9
Treatment of iminoethers 9–14 with excess anthranilic acid gave the hexacycles 15–20 with inversion
of the stereocenter C-16a during the cyclization (Scheme 3). This was confirmed in all compounds
by NOE experiments (see for instance those of diagnostic value for compounds 15 and 16). The high
chemical shift value of the H-7 proton (δ H-7=5.28–5.46 ppm, Table 1) confirms that it is coplanar
with the C-5 carbonyl group, as it occurs in simpler pyrazinoquinazolinediones containing the D–F
fragment.2,4 This means that ring D is anchored by the C-7 methyl substituent into a pseudoaxial
configuration. On the other hand, the H-10 hydrogen atom is also nearly coplanar with the C-8 carbonyl
group, being highly deshielded (δ H-10=6.02–6.07 ppm).
Due to the nearly planar chair conformation that can be assumed for ring C10 and the coplanarity of
H-7 and H-10 with C5_O and C8_O groups, respectively, it could be argued that with the epimerization
of the tryptophan stereocenter in compounds 15, 16 and 19, important steric interactions between the
methyl group at C-7 and the C16a–C16 bond were released (Fig. 1),11 while the epimerization found

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A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
Scheme 3.
Fig. 1.
in the case of compounds 17, 18 and 20 was not expected, a possible factor being the interaction
between the methyl substituent at C-10 and the carbonyl group at C-8, which may be prevented. The
enantiomeric relationships between compounds 3–4, 5–6, 9–10, 11–12, 15–16 and 17–18 were reflected
in their experimental optical rotations.
To explore the stereochemistry of the alternative route to the hexacycles previously mentioned,12,13
we assayed the reaction of piperazinedione 6 with o-azidobenzoyl chloride in the presence of KHMDS.
These reaction conditions permitted the benzoylation at N-2 of pyrazino[20,10-5,1]pyrrolo[2,3-b]indole-
1,4-diones with retention of stereochemistry, even in compounds with a syn-relationship between the two
CH protons of the piperazinedione ring.1c,5a,b However compound 6 gave as the only reaction product
the ortho-azidobenzoyl derivative 21, with epimerization of the tryptophan sterocenter according to NOE
experiments. As expected, treatment of this intermediate with tributylphosphine afforded hexacycle 18
through an intramolecular aza-Wittig coupling (Scheme 4).
To rationalize the stereochemistry of compound 21, we can assume that the steric compression between
the N2–acyl, the C1_O and the C3–methyl groups is relieved by epimerization of C12a.
3. Experimental
All reagents were of commercial quality (Aldrich, Fluka, SDS, Probus) and were used as received.
Solvents (SDS, Scharlau) were dried and purified using standard techniques. The expression ‘petroleum
ether’ refers to the fraction boiling at 40–60°C. Reactions were monitored by thin layer chromatography,
on aluminum plates coated with silica gel with a fluorescent indicator (Macherey-Nagel Alugram Sil

A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
3119
Scheme 4.
G/UV254). Separations by flash chromatography were performed on silica gel (SDS 60 ACC, 230–400
mesh). Catalytic hydrogenations were carried out using a Parr 3920 shaking reactor. Melting points were
measured on a Reichert 723 hot stage microscope, and are uncorrected. Infrared spectra were recorded
on a Perkin–Elmer Paragon 1000 FT-IR spectrophotometer, with solid compounds compressed into KBr
pellets and liquid compounds placed (neat or dissolved in the minimum amount of bromoform) between
NaCl plates. NMR spectra were obtained on a Bruker AC-250 spectrometer (250 MHz for 1H, 63 MHz for
13C) spectrometer (Servicio de Espectroscopía, Universidad Complutense), with CDCl3 or DMSO-d6 as
solvents. When necessary, assignments were aided by DEPT, COSY and 13C–1H correlation experiments.
Optical rotations were determined at 25°C on a 1 ml cell, using a Perkin–Elmer 240 polarimeter operating
at the emission wavelength of a sodium lamp; concentrations are given in g/100 ml. Combustion
elemental analyses were determined by the Servicio de Microanálisis, Universidad Complutense, on a
Perkin–Elmer 2400 CHN microanalyzer.
3.1. Synthesis of piperazinedione 8
N-Boc-Glycine (3.68 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (5.44
mmol) were added to methyl (1S,3S) 1-methyl-β-carboline-3-carboxylate6 (3.68 mmol). The reaction
was protected with an anhydrous calcium chloride tube and was magnetically stirred in the dark for 24
h. After concentration to dryness at low pressure, the residue was extracted with a mixture of chloroform
(15 ml) and 1 N hydrochloric acid (16 ml). The separated organic phase was washed with 1 N sodium
bicarbonate (15 ml), dried and concentrated. Purification of the residue by column chromatography
with chloroform gave methyl (1S,3S) 1,2,3,4-tetrahydro-1-methyl-2-tert-butoxyglycyl-β-carboline-3-
carboxylate, 1.05 g (71%) as a white solid. Mp 109–110°C. IR (KBr): 3330, 1740, 1692 and 1655 cm−1
.
1H-NMR (CDCl3) δ: 8.14 (br. s, 1H); 7.49 (d, 1H, J=7.3 Hz); 7.30 (d, 1H, J=8.1 Hz); 7.15 (m, 2H); 5.72
(s, 1H); 5.57 (q, 1H, J=6.5 Hz); 4.13 (d, 1H, J=5.9 Hz); 4.10 (m, 2H); 3.62 (s, 3H); 3.50 (m,1H); 1.49
(m, 6H); 1.45 (s, 9H) ppm. 13C-NMR (CDCl3) δ: 171.8; 170.9; 168.6; 156.2; 136.4; 133.0; 126.5; 122.3;
119.8; 118.5; 111.0; 104.7; 52.9; 49.9; 47.8; 43.3; 42.9; 28.5; 19.5 ppm. Anal. calcd for C21H27N3O5:
C, 62.83; H, 6,78; N, 10.47. Found: C, 62.90; H, 6.85; N, 10.25.
Heating the above dipeptide (1.2 g, 3.12 mmol) at 200°C for 2 h, under a stream of argon, followed
by purification by column chromatography on silica gel (ethyl acetate:chloroform=1:2), afforded 0.8 g
(90.4% yield) of compound 8. Mp 228–229°C. IR (KBr): 3334; 1720 and 1656 cm−1. 1H-NMR (DMSO-
d6) δ: 11.03 (s, 1H); 8.31 (s, 1H); 7.5 (d, 1H; J=7.1 Hz); 7.27 (d, 1H; J=7.5 Hz); 7.01 (m, 2H); 5.23 (q,
1H, J=5.9 Hz); 4.17 (d, 1H, J=9.5 Hz); 3.8 (dd, 2H, J=64.4 and 17.02 Hz); 2.74 (dd, 1H, J=14.6 and 12.8
Hz); 1.37 (d, 3H, J=5.9 Hz) ppm. 13C-NMR (DMSO-d6) δ: 170.4; 169.4; 137.6; 137.4; 127.7; 122.7;

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A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
120.5; 113; 119.6; 106.3; 56.7; 49.5; 46.5; 25.1; 23.9 ppm. [α]D25=+382 (c 0.1, EtOH). Anal. calcd for
C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.91; H, 5.66; N, 15.75.
3.2. Activation of piperazinediones. General method. Synthesis of iminoethers 9–14
To a solution of the starting piperazinedione (0.35 mmol) and triethyloxonium tetrafluoroborate
(3 equiv.) in dry dichloromethane (50 ml), was added anhydrous sodium carbonate (5 equiv.). The
suspension was stirred at room temperature under a stream of argon for 16 h, and was then poured onto
ice water. The combined organic layers were dried over sodium sulfate and evaporated under reduced
pressure. The residue was used in the next reaction without further purification.
Data for 9 and 10: 1H-NMR (CDCl3) δ: 8.97 (s, 1H); 7.56 (d, 1H, J=7.1 Hz); 7.37 (d, 1H, J=7.0 Hz);
7.15 (m, 2H); 5.44 (q, 1H, J=6.0 Hz); 4.16 (m, 3H); 3.92 (m, 1H); 3.50 (dd, 1H, J=15.5 and 4.0 Hz);
2.94 (dd, 1H, J=15.5 and 11.8 Hz); 1.62 (d, 3H, J=6.0 Hz); 1.50 (d, 3H, J=7.1 Hz); 1.37 (t, 3H, J=6.8
Hz) ppm. 13C-NMR δ: 173.4; 160.9; 136.0; 135.7; 126.1; 121.7; 119.6; 117.9; 111.3; 62.1; 55.4; 54.3;
48.6; 23.3; 23.0; 14.1 ppm.
Data for 11 and 12: 1H-NMR (CDCl3) δ: 9.04 (s, 1H); 7.50 (d, 1H, J=6.9 Hz); 7.37 (d, 1H, J=7.1 Hz);
7.17 (m, 2H); 5.42 (q, 1H, J=6.5 Hz); 4.19 (m, 3H); 3.94 (m, 1H); 3.57 (dd, 1H, J=15.2 and 4.2 Hz);
3.10 (dd, 1H, J=15.2 and 11.8 Hz); 1.68 (d, 3H, J=6.2 Hz); 1.58 (d, 3H, J=6,5 Hz); 1.25 (t, 3H, J=7.0
Hz) ppm.
Data for 13: 1H-NMR (CDCl3) δ: 9.24 (s, 1H); 7.57 (d, 1H, J=7.0 Hz); 7.37 (d, 1H, J=6.9 Hz); 7.08
(m, 2H); 5.40 (q, 1H, J=6.1 Hz); 4.22 (m, 3H); 3.90 (m, 1H); 3.50 (dd, 1H, J=15.4 and 3.7 Hz); 2.90 (dd,
1H, J=15.4 and 12.0 Hz); 1.62 (d, 3H, J=6.1 Hz); 1.38 (d, 3H, J=6.8 Hz); 1.22 (t, 3H, J=7.1 Hz) ppm.
Data for 14: 1H-NMR (CDCl3) δ: 9.42 (s, 1H); 7.55 (d, 1H, J=7.2 Hz); 7.38 (d, 1H, J=6.9 Hz); 7.12
(m, 2H); 5.44 (q, 1H, J=6.2 Hz); 4.02 (m, 1H); 3.90 (m, 1H); 3.48 (dd, 1H, J=14.7 and 4.1 Hz); 2.95 (dd,
1H, J=14.7 and 11.6 Hz); 1.67 (d, 3H, J=4.4 Hz); 1.50 (d, 3H, J=6.2 Hz); 1.38 (t, 3H, J=7.1 Hz) ppm.
3.3. Synthesis of 7,10,16,16a-tetrahydroquinazolino[20 ,30:3,4]pyrazino[1,2-b]β-carboline-5,8-diones.
General method
A mixture of the corresponding iminoether (0.22 mmol) and anthranilic acid (0.68 mmol) was melted
at 130°C under a stream of argon for 2 h. The melt was cooled and triturated with 20% aqueous
ammonium hydroxide (2 ml), and the mixture was extracted with chloroform. The combined organic
layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue
was chromatographed on silica gel, eluting with dichloromethane.
Data for 15: Mp: 211–212°C. IR (KBr): 3308, 1688, 1634 and 1646. [α]D25=+240 (c 0.8, EtOH).
Anal. calcd for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C, 72.04; H, 5.08; N, 14.52.
Data for 16 were identical to those of compound 15. [α]D25=−232 (c 0.8, EtOH).
Data for 17: Mp: 201–202°C. IR (KBr): 3290, 1667, 1622 and 1610. [α]D25=+205 (c 0.2, EtOH).
Anal. calcd for C23H20N4O2: C, 71.86; H, 5.24; N, 14.57. Found: C, 72.17; H, 5.07; N, 14.50.
Data for 18 were identical to those of compound 17. [α]D25=+186 (c 0.2, EtOH).
Data for 19: Mp: 257–258°C. [α]D25=+182.85 (c 0.07, CHCl3). Anal. calcd for C23H20N4O2: C, 71.86;
H, 5.24; N, 14.57. Found: C, 71.17; H, 5.07; N, 14.10.
Data for 20: Mp: 266–267°C. [α]D25=+407 (c 0.1, CHCl3). Anal. calcd for C22H18N4O2: C, 71.34; H,
4.9; N, 15.13. Found: C, 71.38; H, 4.95 N; 15.05.
NMR data for compounds 15–20 are given in Tables 1 and 2.

A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
3121
Table 1
1H-NMR data of compounds 15–20
Table 2
13C-NMR data of compounds 15–20

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A. Madrigal et al. / Tetrahedron: Asymmetry 9 (1998) 3115–3123
3.4. (3S,6R,12aR)-2-(o-Azidobenzoyl)-3,6-dimethyl-2,3,6,7,12,12a-hexahydropyrazino[1,2-b]-β-
carboline-1,4-dione 21
o-Azidobenzoyl chloride was prepared by heating at 80°C for 3 h, under an argon atmosphere, a
solution of o-azidobenzoic acid (326 mg, 6.0 mmol) in thionyl chloride (2.18 ml, 90 mmol). The excess
of thionyl chloride was evaporated under reduced pressure. Dry benzene (2×5 ml) was added to the
residue and evaporated. The crude o-azidobenzoyl chloride was inmediately used for the acylation step,
which was performed as follows. To a cooled (−78°C) solution of compound 66 (100 mg, 0.35 mmol) in
dry THF (20 ml) was dropwise added a 0.5 M solution of potassium hexamethyldisilazide in toluene (1.5
ml, 2.3 equiv.). The solution was stirred at −78°C for 15 min, becoming intensely yellow, and was then
treated with a solution of the crude o-azidobenzoyl chloride in THF (10 ml). The solution was stirred at
−78°C for 3 h, was left to warm to room temperature over 20 h and then poured over saturated aqueous
ammonium chloride (10 ml), which was extracted with dichloromethane (6×10 ml). The combined
dichloromethane layers were dried over sodium sulfate and the residue was chromatographed on silica
gel eluting with dichloromethane. Yield, 80 mg (53%) of compound 21.
Data for 21: Mp: 109–110°C. IR (KBr): 3368, 2130, 1722, 1655 and 1621 cm−1. 1H-NMR (CDCl3)
δ: 8.66 (s, 1H); 8.17 (d, 1H, J=8 Hz); 7–7.6 (m, 8H); 5.53 (q, 1H, J=6.4 Hz); 5.22 (q, 1H, J=7.3 Hz);
4.30 (dd, 1H, J=6.6 and 12.2 Hz); 3.61 (dd, 1H, J=4.7 and 15.6 Hz); 2.96 (dd, 1H, J=15.6 and 12.2 Hz);
1.57 (d, 3H, J=7.3 Hz); 1.52 (d, 3H, J=7.3 Hz) ppm. 13C-NMR (CDCl3) δ: 168.9; 168.8; 166.3; 137.5;
136.0; 134.9; 131.9; 129.2; 125.9; 125.2; 125.1; 123.9; 122.2; 120.0; 118.4; 118.1; 111.4; 105.8; 56.3;
53.9; 48.3; 23.4; 22.9; 17.1. [α]D25=−167 (c 0.10, CHCl3). Anal. calcd for C23H20O3N6: C, 64.48; H,
4.71; N,19.61. Found: C, 64.59; H, 4.76; N, 19.51.
3.5. Alternative synthesis of compound 18 by intramolecular aza-Wittig reaction of compound 21
To a solution of compound 21 (81 mg, 0.187 mmol) in dry toluene (8 ml) was added tributylphosphine
(80 µl, 0.35 mmol). The solution was stirred at room temperature for 2 h. The solvent was evaporated
and the residue was chromatographed on silica gel, eluting with petroleum ether:dichloromethane (1:1)
and then with ethyl acetate. Yield, 15 mg (21%) of compound 18.
Acknowledgements
We thank CICYT for financial support (projects SAF-94-01517 and SAF-97-0143).
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