A New Route toward 4-Substituted Pyrazino[2,1-b]quinazoline-3,6-dione Systems. Total Synthesis of Glyantrypine

Article abstract of DOI:10.1021/jo991626e

Treatment of sodium N-(o-azidobenzoyl)aminoacylglycinates 8 with acetic anhydride afforded 1-acetyl-4-(o-azidobenzoyl)-2,5-piperazinediones 7, with complete retention of the stereochemistry. The intramolecular aza Wittig reactions of compounds 7 in the pr

Full text of DOI:10.1021/jo991626e

J . Org. Chem. 2000, 65, 1743-1749
1743
A New Rou te tow a r d 4-Su bstitu ted
P yr a zin o[2,1-b]qu in a zolin e-3,6-d ion e System s. Tota l Syn th esis of
Glya n tr yp in e
Pilar Cledera, Carmen Avendan˜o,* and J . Carlos Mene´ndez*
Departamento de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia,
Universidad Complutense, 28040 Madrid, Spain
Received October 18, 1999
Treatment of sodium N-(o-azidobenzoyl)aminoacylglycinates 8 with acetic anhydride afforded
1-acetyl-4-(o-azidobenzoyl)-2,5-piperazinediones 7, with complete retention of the stereochemistry.
The intramolecular aza Wittig reactions of compounds 7 in the presence of tributylphosphine
followed by deacetylation gave 1,2-unsubstituted pyrazino[2,1-b]quinazoline-3,6-diones 1. This route
was adapted to the synthesis of both enantiomers of the alkaloid glyantrypine.
In tr od u ction
tion of 1,2-unsubstituted derivatives 1 because of their
potential role as starting materials for the synthesis of
more complex derivatives with additional rings fused to
the 1-2 bond and also to study their anti-MDR proper-
ties.
The pyrazino[2,1-b]quinazoline-3,6-dione system can be
considered as a costrained peptidomimetic and is present
in several families of natural products such as the
fiscalins,1 the fumiquinazolines,2 glyantrypine,3 and N-
acetylardeemin.4 Other natural products, like the asper-
licins,5 vasicinone,6 and the luotonins,7 among many
others, contain related heteroareno[2,1-b]quinazoline
substructures. Some of these compounds exhibit very
interesting biological properties. For instance, N-acety-
lardeemin is one of the most potent known inhibitors of
multidrug resistance to antitumor compounds (MDR),
which can be considered as the most important single
factor that prevents the success of antitumor chemo-
therapy in many cancer patients.8 Because the anti-MDR
activity of N-acetylardeemin can be ascribed to its
pyrazino[2,1-b]quinazoline fragment,9 we became inter-
ested in developing new synthetic entries to this ring
system. We were particularly interested in the prepara-
* Phone: 34-91-394 18 21/40. Fax: 34-91-394 18 22. E-mail:
josecm@eucmax.sim.ucm.es.
(1) (a) Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.; Gillum,
A. M.; Cooper, R. J . Antibiotics 1993, 46, 545. (b) Fujimoto, H.; Negishi,
E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm. Bull. 1996,
44, 1843.
(2) (a) Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.;
Kawai, K.; Usami, Y.; Matsumura, E.; Inoue, M.; Ohishi, H.; Shingu,
T. Tetrahedron Lett. 1992, 33, 1621. (b) Takahashi, C.; Matsushita,
T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda, Y.; Numata A. J . Chem.
Soc., Perkin Trans. 1 1995, 2345.
(3) Penn, J .; Mantle, P. G.; Bilton, J . N.; Sheppard, R. N. J . Chem.
Soc., Perkin Trans. 1 1992, 1495.
(4) (a) Karwowski, J . P.; J ackson, M.; Rasmussen, R. R.; Humphrey,
P. E.; Poddig, J . B.; Kohl, W. L.; Scherr, M. H.; Kadam, S.; McAlpine,
J . B. J . Antibiot. 1993, 46, 374. (b) Hochlowski, J . E.; Mullally, M. M.;
Spanton, S. G.; Whittern, D. N.; Hill, P.; McAlpine, J . B. J . Antibiot.
1993, 46, 380.
(5) Liesch, J . M.; Hensens, O. D.; Springer, J . P.; Chang, R. S. L.;
Lotti, V. J . J . Antibiot. 1985, 58, 1638.
(6) (a) Isolation and structure: Mehta, D. R.; Naravane, J . S.; Desai,
R. M. J . Org. Chem. 1963, 28, 445. (b) Absolute configuration: J oshi,
B. S.; Newton, M. G.; Lee, D. W.; Barber, A. D.; Pelletier, S. W.
Tetrahedron: Asymmetry 1996, 7, 25.
(7) (a) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J . Heterocycles 1997,
46, 541. (b) Ma, Z. Z.; Hano, Y.; Nomura, T.; Chen, Y. J . Heterocycles
1999, 51, 1883.
The currently known syntheses of pyrazino[2,1-b]-
quinazoline-3,6-dione derivatives can be grouped as
follows: (a) Transformation of 4-substituted 2,5-pipera-
zinediones into the corresponding iminoethers10 or thio-
iminoethers,11 followed by cyclocondensation with an-
thranilic acid or methyl anthranilate. (b) Acylation of
4-substituted 2,5-piperazinediones with o-azidobenzoyl
chloride, followed by Staudinger reaction with a phos-
phine to yield the corresponding λ5-phosphazene and
(8) (a) Molecular and Cellular Biology of Multidrug Resistance in
Tumor Cells; Roninson, I. B., Ed.; Plenum Press: New York, 1991. (b)
Kane, S. E. Adv. Drug Res. 1996, 28, 181.
(9) Me´ndez-Vidal, C.; Rodr´ıguez de Quesada, A. Cancer Lett. 1998,
132, 45.
(10) (a) Rajappa, S.; Advani, B. G. Tetrahedron 1973, 29, 1299. (b)
Rajappa, S.; Advani, B. G. J . Chem. Soc., Perkin Trans. 1 1974, 2122.
(11) Bock, M. G.; DiPardo, R. M.; Pitzenberger, S. M.; Homnick, C.
F.; Springer, J . P.; Freidinger, R. M. J . Org. Chem. 1987, 52, 1644.
10.1021/jo991626e CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/24/2000

1744 J . Org. Chem., Vol. 65, No. 6, 2000
Cledera et al.
Sch em e 1
Sch em e 2
subsequent intramolecular aza Wittig cyclization of the
latter intermediate.12,13 These methods lead to 2-substi-
tuted derivatives of the desired ring system, and there-
fore their application to the synthesis of 1 requires
troublesome14 protection and deprotection steps of the
starting 2,5-piperazinediones. (c) Cyclization of 4-imino-
4H-3,1-benzoxazines,15,16 prepared through cyclodehy-
dration of suitable o-acylanthranylamides in the presence
of iodine-triphenylphosphine.17
Our route to 1 involves the novel retrosynthetic ap-
proach summarized in Scheme 1, which is based on the
double cyclization of open-chain “tripeptides” 2, where
the anthranilic acid unit is the N-terminal residue and
bears an azido group as a masked amino function. This
strategy allows the use of unprotected glycine derivatives
as starting materials and hence leads directly to the
target compounds 1.
spheric pressure,19 yielding compounds 4, which were
immediately acylated with o-azidobenzoyl chloride to give
compounds 2 in good overall yields.
The double cyclization of compounds 2 to the target
structures 1 was carried out in two stages, starting from
their transformation into 2,5-piperazinedione derivatives.
This transformation involves the acylation of an amide
group to give an imide, and therefore difficulties were
anticipated.20 Thus, all attempts to cyclize compound 2c
in the presence of a variety of bases, under thermal
conditions and under other literature conditions,21 were
unsuccessful. In one of the experiments, exposure of 2c
to an excess of triethylamine in the presence of 4-(di-
methylamino)pyridine (DMAP) afforded a small amount
(9%) of compound 5, but this result could not be repro-
duced. We decided therefore to hydrolyze compounds 2
to the corresponding carboxylic acids 6 and try to activate
the carboxylic function. After several failed attempts
under varied literature methods,22-24 we finally achieved
moderate success by activation of the carboxylic group
through formation of a mixed anhydride in the presence
of acetic anhydride at 80 °C. These conditions led also to
acetylation of the free nitrogen of the 2,5-piperazinedione
structure, affording compounds 7 in ca. 30% yield. During
our efforts to improve this result, we found that the
sodium salts 8 are soluble in acetic anhydride under our
reaction conditions. Their use instead of 6 improved the
activation of the carboxylic group and allowed the isola-
tion of compounds 7a -c in 81-97% yields. The efficiency
and mildness of the method was confirmed by applying
Resu lts a n d Discu ssion
Starting materials were prepared as shown in Scheme
2. Dipeptides 3 were obtained from ethyl glycinate and
the appropriate N-Cbz amino acids, using ethyl chloro-
formate or EDC18 as the coupling reagent. They were
deprotected by catalytic hydrogenation under atmo-
(12) (a) Takeuchi, H.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989,
45, 6375. For some applications of this method to the synthesis of
natural products, see: (b) Marsden, S. P.; Depew, K. M.; Danishefsky,
S. J . J . Am. Chem. Soc. 1994, 116, 11143 (total synthesis of N-
acetylardeemin). (c) He, F.; Snider, B. B. Synlett 1997, 483 (total
synthesis of ent-fumiquinazoline G). (d) He, F.; Foxman, B. M.; Snider,
B. B. J . Am. Chem. Soc. 1998, 120, 6417 (total synthesis of asperlicin
and asperlicin C).
(13) Related method: (a) Molina, P.; Alajar´ın, M.; Vidal, A.; Foces-
Foces, M. C.; Herna´ndez-Cano, F. Tetrahedron 1989, 45, 4263. (b)
Villalgordo, J . M.; Obrecht, D.; Chucholowsky, A. Synlett 1998, 1405.
(14) For problems found in this type of deprotection, see: Buenadicha,
F. L.; Bartolome´, M. T.; Aguirre, M. J .; Avendan˜o, C.; So¨llhuber, M.
Tetrahedron: Asymmetry 1998, 9, 483.
(19) Use of higher pressures (4 atm) favors the cyclization of
compounds 4 to the corresponding 2,5-piperazinediones.
(20) Bailey, P. D.; Collier, I. D.; Morgan, K. M. In Comprehensive
Functional Group Chemistry; Moody, C. J ., Ed.; Katritzky, A. R., Meth-
Cohn, O., Rees, C. W., General Eds.; Pergamon Press: Elmsforg, NY,
1995; chapter 5.04
(21) Pihko, P. M.; Koskinen, A. M. P. J . Org. Chem. 1998, 63, 92.
(22) Kometani, T.; Fitz, T.; Watt, D. S. Tetrahedron Lett. 1986, 27,
919.
(23) (a) Butler, D. E.; Leonard, J . D.; Caprathe, B. W.; L’Italien, Y.
J .; Pavia, M. R.; Hershenson, F. M.; Poschel, P. H.; Marriott, J . G. J .
Med. Chem. 1987, 30, 498. (b) Pavia, M. R.; Moos, W. H.; Hershenson,
F. M. J . Org. Chem. 1990, 55, 560.
(24) Gonza´lez-Mun˜iz, R.; Garc´ıa-Lo´pez, M. T.; Go´mez-Monterrey, I.;
Herranz, R.; J imeno, M. L.; Sua´rez-Gea, M. L.; J ohansen, N. L.;
Madsen, K.; Thøgersen, H.; Suzdak, P. J . Med. Chem. 1995, 38, 1015.
(15) Treatment with piperidine to give an amidine carboxamide,
followed by silica gel-induced cyclization to
a 2-aminomethyl-3-
carboxymethyl-3,4-dihydroquinazolin-4-one and then to the tricyclic
system: He, F.; Snider, B. B. J . Org. Chem. 1999, 64, 1397. For an
alternative method to achieve this cyclization, in the context of a
synthesis of the alkaloid (-)-alantrypinone, see: Hart, D. J .; Mago-
medov, N. Tetrahedron Lett. 1999, 40, 5429.
(16) These intermediates were initially assigned as 2-aminomethyl-
3-carboxymethyl-3,4-dihydroquinazolin-4-ones during the total syn-
thesis of fumiquinazoline G and fiscalin B: Wang, H.; Ganesan, A. J .
Org. Chem. 1998, 63, 2432.
(17) For the application of these conditions to the synthesis of
oxazole derivatives from â-ketoamides, see: Wipf, P.; Miller, C. P. J .
Org. Chem. 1993, 58, 3604.
(18) Sheehan, J . C.; Ledis, S. L. J . Am. Chem. Soc. 1973, 95, 875.

Total Synthesis of Glyantrypine
J . Org. Chem., Vol. 65, No. 6, 2000 1745
Sch em e 3
Sch em e 4
it to the synthesis of precursors to both enantiomers of
glyantripine, which contain a sensitive tryptophan unit.
Thus, treatment of the carboxylic salts 8d ,e with acetic
anhydride led to mixtures of the corresponding com-
pounds 7d ,e and 10d ,e, the latter of which was acetylated
at the indole nitrogen and was isolated in variable
proportions depending on the reaction time (Scheme 3).
The second cyclization to pyrazino[2,1-b]quinazoline-
3,6-dione derivatives was carried out through a Staud-
inger-aza Wittig sequence by treatment of compounds
7 with tributylphosphine, which afforded compounds 9
in 51-93% yields. Similarly, the diacetylated derivative
10d was transformed into compound 11 in 66% yield
(Scheme 4). Deacetylation of 9 or 11 to give the target
compounds 1 was achieved in good yield by addition
of hydrazine hydrate at room temperature. On the
other hand, treatment of compound 5 with tributylphos-
phine led directly to 1c in 83% yield. Both 1d and 1e
showed spectral properties identical to those previously
described for glyantrypine.3 Because of the absence of
reference data in the literature,3 we could not use the
optical rotation values of our synthetic samples to
establish the absolute configuration of natural gly-
antrypine.

1746 J . Org. Chem., Vol. 65, No. 6, 2000
Cledera et al.
valine and using method A, 4.61 g (86%) of 3c was obtained
as white crystals. Starting from 4.0 g (15.9 mmol) of N-
(benzyloxycarbonyl)-L-valine and using method B, 3.98 g (74%)
One final issue that needed to be addressed was the
integrity of the stereocenter during the series of trans-
formations, particularly during the cyclization step in the
presence of acetic anhydride. This was confirmed by the
absence of any splitting of the 1H NMR signals of
compounds 7d and 7e in the presence of 1 equiv of
Eu(hfc)3. In a control experiment, a racemic sample
prepared by mixing equimolecular amounts of 7d and 7e
showed a clear separation of most signals under the same
conditions.
of 3c was obtained: mp 143-145 °C; [R]25 ) +17.1 (c 0.07,
D
CHCl3); IR (KBr) ν 3290, 1748, 1689, 1652 cm-1; 1H NMR (250
MHz, CDCl3) δ 7.25-7.40 (m, 5H), 6.42 (br. s, 1H), 5.35 (br. d,
J ) 8.4 Hz, 1H), 5.05-5.20 (m, 2H), 4.21 (q, J ) 7.1 Hz, 2H),
3.90-4.15 (m, 3H), 2.17 (m, 1H), 1.27 (t, J ) 7.1 Hz, 3H), 0.98
and 0.93 (d, J ) 6.8 Hz, 3H and d, J ) 6.8 Hz, 3H); 13C NMR
(63 MHz, CDCl3) δ 171.6, 169.7 (2 signals), 128.6, 128.4, 128.3,
128.2, 67.2, 61.7, 58.2, 41.3, 31.1, 19.3, 14.2. Anal. Calcd for
C
17H24N2O5: C, 60.70; H, 7.19; N, 8.33. Found: C, 60.76; H,
7.22; N, 8.30.
Exp er im en ta l Section
E t h yl N-(Ben zyloxyca r b on yl)-D-t r yp t op h a n ylglyci-
n a te (3d ). Starting from 2.0 g (5.516 mmol) of N-(benzyloxy-
carbonyl)-D-tryptophan and using method B, 1.62 g (65%) of
All reagents were of commercial quality and were used as
received. Solvents were dried and purified using standard
techniques. “Petroleum ether” refers to the fraction boiling at
40-60 °C. Reactions were monitored by thin-layer chroma-
tography, on aluminum plates coated with silica gel with
fluorescent indicator. Separations by flash chromatography
were performed on silica gel. Melting points were measured
in a hot stage microscope and are uncorrected. Optical rotation
values were determined in a polarimeter equipped with a 1
mL cell measuring 10 cm and a thermostated bath, using the
emission wavelength of a sodium lamp; concentrations are
given in g/100 mL. Infrared spectra were recorded on a FT-IR
spectrophotometer, with solid compounds compressed into KBr
pellets and liquid compounds examined as films on NaCl disks.
NMR spectra were obtained at 250 MHz for 1H and 63 MHz
for 13C, with CDCl3 or DMSO-d6 as solvents (Servicio de
Espectroscop´ıa, Universidad Complutense). Elemental analy-
ses were determined by the Servicio de Microana´lisis, Uni-
versidad Complutense.
3d was obtained as pale yellow crystals: mp 70-72 °C; [R]25
D
) +2.9 (c 0.23, CHCl3); IR (KBr) ν 3314, 1704, 1666 cm-1; 1H
NMR (250 MHz, CDCl3) δ 8.29 (s, 1H), 7.60 (d, J ) 7.0 Hz,
1H), 7.06-7.34 (m, 9H), 7.01 (s, 1H), 6.33 (br. s, 1H), 4.95-
5.15 (m, 2H), 4.40-4.60 (m, 1H), 4.09 (q, J ) 7.1 Hz, 2H), 3.70-
4.95 (m, 2H), 3.25-3.40 (m, 1H), 3.17 (dd, J ) 14.4 and 7.2
Hz, 1H), 1.20 (t, J ) 7.1 Hz, 3H); 13C NMR (63 MHz, CDCl3)
δ 171.7, 169.5, 156.0, 136.3, 128.6, 128.4, 128.3, 128.2, 127.0,
123.5, 122.3, 119.8, 118.8, 111.4, 110.0, 67.1, 61.6, 55.5, 41.4,
28.5, 14.2. Anal. Calcd for C23H25N3O5: C, 65.24; H, 5.95; N,
9.92. Found: C, 64.89; H, 5.57; N, 9.93.
Eth yl N-(Ben zyloxyca r bon yl)-L-tr yp top h a n ylglycin a te
(3e). Starting from 0.25 g (0.74 mmol) of N-(benzyloxy-
carbonyl)-L-tryptophan and using method B, 0.25 g (80%) of
3e was obtained as pale yellow crystals: mp 70-72 °C; [R]25
D
) -3.1 (c 0.215, CHCl3). Anal. Calcd for C23H25N3O5: C, 65.24;
H, 5.95; N, 9.92. Found: C, 64.92; H, 5.86; N, 9.56. Spectral
data were identical to those of 3d .
Syn th esis of N-Cbz Dip ep tid es. Gen er a l P r oced u r es.
Meth od A. To a stirred solution of the suitable N-Cbz amino
acid and triethylamine (1 equiv) in dry CHCl3 (20 mL per g of
protected amino acid) was dropwise added ethyl chloroformate
(1 equiv) at 0 °C. The solution thus obtained was warmed to
room temperature, and a solution of ethyl glycinate hydro-
chloride (1 equiv) and triethylamine (1 equiv) in dry CHCl3
(20 mL per g of protected amino acid) was added over 30 min.
When the addition was complete, the solution was refluxed
for 10 min, cooled, and washed with water (3 × 10 mL). The
organic layer was dried (Na2SO4) and evaporated, yielding the
analytically pure dipeptides.
Meth od B. A solution of the N-Cbz amino acid, ethyl
glycinate hydrochloride (1.1 equiv), and EDC (1.1 equiv) in dry
CH2Cl2 (25 mL per g of protected amino acid) was stirred at
room temperature for 16 h. The suspension was washed
sequentially with 1 M aqueous HCl, 1 M aqueous NaHCO3,
and water, in volumes equal to that of the CH2Cl2 phase; dried
(Na2SO4); and evaporated, yielding the analytically pure
dipeptides.
Dep r otection of N-Cbz Dip ep tid es. Gen er a l P r oce-
d u r e. To a solution of the suitable N-Cbz dipeptide 3 in
methanol (100 mL) was added 10% Pd-C (0.2 times the weight
of protected dipeptide). The suspension was stirred at room
temperature for 16 h under a balloon filled with hydrogen. The
suspension was filtered through Celite and evaporated, and
the residue was crystallized from ethanol.
Eth yl L-Ala n ylglycin a te (4a ). Starting from 5.103 g (16.5
mmol) of 3a , 2.78 g (96%) of 4a was obtained as pale yellow
needles: mp 55-57 °C; [R]25 ) +8.2 (c 0.535, DMSO); IR
D
(KBr) ν 3329, 2977, 1741, 1661 cm-1
;
1H NMR (250 MHz,
CDCl3) δ 7.72 (br. s, 1H), 4.07 (q, J ) 7.3 Hz, 2H), 3.85-3.95
(m, 2H), 3.41 (q, J ) 6.8 Hz, 1H), 1.94 (br. s, 2H), 1.21 (d, J )
6.8 Hz, 3H), 1.15 (t, J ) 7.3 Hz, 3H); 13C NMR (63 MHz,
DMSO-d6) δ 176.0, 170.1, 61.5, 50.7, 41.09, 21.7, 14.6. Anal.
Calcd for C7H14N2O3: C, 48.26; H, 8.10; N, 16.08. Found: C,
48.60; H, 7.98; N, 15.81.
Eth yl D-Ala n ylglycin a te (4b). Starting from 2.0 g (6.5
mmol) of 3a , 1.01 g (89%) of 4b was obtained as pale yellow
needles: mp 55-57 °C; [R]25 ) -7.7 (c 0.535, DMSO). Anal.
D
Eth yl N-(Ben zyloxyca r bon yl)-L-a la n ylglycin a te (3a ).
Starting from 4.46 g (20 mmol) of N-(benzyloxycarbonyl)-L-
alanine and using method A, 6.16 g (100%) of 3a was obtained
as a colorless oil that crystallizes from 1:1 AcOEt/Et2O: mp
Calcd for C7H14N2O3: C, 48.26; H, 8.10; N, 16.08. Found: C,
48.35; H, 7.72; N, 16.03. Spectral data were identical to those
of 4a .
Eth yl L-Va lylglycin a te (4c). Starting from 4.61 g (13.7
mmol) of 3c, 2.73 g (100%) of 4c was obtained as white
96-98 °C; [R]25 ) +13.3 (c 0.325, CHCl3); IR (KBr) ν 3290,
D
1732, 1654 cm-1; 1H NMR (250 MHz, CDCl3) δ 7.30-7.40 (m,
5H), 6.52 (br. s, 1H), 5.33 (br. s, 1H), 5.10 (AB system, J )
11.7 Hz, 2H), 4.20.4.40 (m, 1H), 4.18 (q, J ) 7.0 Hz, 3H), 4.00
needles: mp 140-142 °C; [R]25 ) +31.6 (c 0.095, DMSO); IR
D
(KBr) ν 3308, 3074, 1746, 1660 cm-1
;
1H NMR (250 MHz,
DMSO-d6) δ 7.87 (br. s, 1H), 4.17 (q, J ) 7.0 Hz, 2H), 3.90-
4.15 (m, 2H), 3.25-3.35 (m, 1H), 2.20-2.40 (m, 1H), 1.59 (br.
s, 2H), 1.25 (t, J ) 7.0 Hz, 3H), 0.98 and 0.86 (d, J ) 6.8 Hz,
3H and d, J ) 6.8 Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ
167.2, 166.0, 59.7, 55.9, 44.0, 32.1, 18.5, 16.9. Anal. Calcd for
C9H18N2O3: C, 53.45; H, 8.97; N, 13.85. Found: C, 52.87; H,
8.81; N, 13.74.
(m, 2H), 1.39 (d, J ) 7.1 Hz, 3H), 1.28 (t, J ) 7.0 Hz, 3H); 13
C
NMR (63 MHz, CDCl3) δ 171.6, 169.7 (2 signals), 128.6, 128.4,
128.3, 128.2, 67.2, 61.7, 41.4, 17.3, 14.2 (2 signals). Anal. Calcd
for C15H20N2O5: C, 58.43; H, 6.54; N, 9.09. Found: C, 58.67;
H, 6.65; N, 9.03.
Eth yl N-(Ben zyloxyca r bon yl)-D-a la n ylglycin a te (3b).
Starting from 3.50 g (15.6 mmol) of N-(benzyloxycarbonyl)-D-
alanine and using method A, 3.74 g (77%) of 3b was obtained:
mp 95-97 °C; [R]25D ) -13.2 (c 0.325, CHCl3). Anal. Calcd for
Eth yl D-Tr yp top h a n ylglycin a te (4d ). Starting from 1.201
g (2.84 mmol) of 3d , 0.8 g (98%) of 4d was obtained as pale
pink needles: mp 90-92 °C; [R]25 ) +18.0 (c 0.5, DMSO); IR
D
(KBr) ν 3230, 3403, 1735, 1684 cm-1
;
1H NMR (250 MHz,
C
15H20N2O5: C, 58.43; H, 6.54; N, 9.09. Found: C, 58.15; H,
6.74; N, 8.71. Spectral data were identical to those of 3a .
E t h yl N-(Ben zyloxyca r b on yl)-L-va lylglycin a t e (3c).
Starting from 4.0 g (15.9 mmol) of N-(benzyloxycarbonyl)-L-
DMSO-d6) δ 11.05 (s, 1H), 9.12 (br. s, 1H), 8.15 (br. s, 2H),
7.70 (d, J ) 7.7 Hz, 1H), 7.35 (d, J ) 7.8 Hz, 1H), 7.23 (s, 1H),
6.97-7.15 (m, 2H), 4.00-4.15 (m, 3H), 3.80-4.00 (m, 2H),

Total Synthesis of Glyantrypine
J . Org. Chem., Vol. 65, No. 6, 2000 1747
was obtained as pale brown crystals: mp 57-59 °C; [R]25
-54.1 (c ) 0.2, CHCl3). Anal. Calcd for C22H22N6O4: C, 60.82;
H, 5.10; N, 19.34. Found: C, 60.57; H, 4.89; N, 19.57. Spectral
data were identical to those of 2d .
3.04-3.28 (m, partially overlapped with the water signal, 2H),
1.22 (t, J ) 7.1 Hz, 3H); 13C NMR (63 MHz, DMSO-d6) δ 169.3,
169.0, 136.2, 127.0, 125.0, 121.0, 118.0, 118.3, 111.3, 106.6,
60.6, 52.4, 40.7, 27.2, 14.0. Anal. Calcd for C15H19N3O3: C,
66.27; H, 6.62; N, 14.52. Found: C, 66.08; H, 6.48; N, 14.32.
Eth yl L-Tr yp top h a n ylglycin a te (4e). Starting from 1.045
g (2.47 mmol) of 3e, 0.694 g (97%) of 4e was obtained as pale
)
D
(3S)-4-(o-Azid ob e n zoyl)-3-isop r op yl-2,5-p ip e r a zin e -
d ion e (5). To a solution of 2c (0.17 g, 0.5 mmol) in dry THF
(25 mL) and under an argon atmosphere were added Et3N
(0.44 mL, 1.5 mmol) and DMAP (6 mg, 0.05 mmol). The
solution was stirred at 80 °C for 3 h and then at room
temperature for 16 h. The solvent was evaporated, and the
residue was chromatographed on silica gel, eluting with 6:1
petroleum ether/ethyl acetate to yield 0.014 g (9%) of com-
pound 5, as an oil: 1H NMR (250 MHz, CDCl3) δ 7.56 (t, J )
7.2 Hz, 1H), 7.15-7.30 (m, 4H), 4.13 and 3.68 (AB quartet, J
) 17.4 Hz, 2H), 3.54 (d, J ) 3.8 Hz, 1H), 2.15-2.34 (m, 1H),
1.05 (d, J ) 7.0 Hz, 3H), 0.95 (d, J ) 6.8 Hz, 3H).
H yd r olysis of Com p ou n d s (2). Gen er a l P r oced u r es.
P r ep a r a tion of Sod iu m Sa lts (8). To a solution of the
suitable compound 2 in MeOH (15 mL per g of 2) was added
0.5 N aqueous NaOH (1 equiv), and the solution was heated
at 50 °C for 2 h. Evaporation of the solvent afforded the sodium
salts 8.
pink needles: mp 91-93 °C; [R]25 ) -17.3 (c 0.5, DMSO).
Anal. Calcd for C15H19N3O3: C, 66.27; H, 6.62; N, 14.52.
Found: C, 66.14; H, 6.47; N, 14.26%. Spectral data were
identical to those of 4d .
D
Acyla tion of Dip ep tid es w ith o-Azid oben zoyl Ch lo-
r id e. Gen er a l P r oced u r e. To a solution of the suitable
dipeptide 4 in THF (30 mL) were added Et3N (1 equiv) and
DMAP (0.2 equiv). The solution was stirred at 80 °C for 15
min, under an argon atmosphere, and treated at the same
temperature with a solution of o-azidobenzoyl chloride25 (1.2
equiv) in THF (10 mL). The reacting mixture was maintained
at 80 °C for a further 3 h and then at room temperature for
16 h (in the case of the indole derivatives 4d ,e, the flask was
protected from light for the duration of the experiment). The
reacting mixture was then filtered and evaporated, and the
residue was chromatographed on silica gel, eluting with 6:1
petroleum ether/ethyl acetate.
Sod iu m N-(o-Azid ob en zoyl)-L-a la n ylglycin a t e (8a ).
Starting from 0.933 g (2.92 mmol) of 2a , 0.915 g (100%) of 8a
was obtained: mp 101-103 °C; [R]25 ) +17.3 (c 0.185,
D
Eth yl N-(o-Azid oben zoyl)-L-a la n ylglycin a te (2a ). Start-
ing from 3.044 g (17.5 mmol) of 4a , 3.118 g (56%) of 2a was
DMSO); IR (KBr) ν 3352, 2132, 1631, 1600 cm-1; 1H NMR (250
MHz, DMSO-d6) δ 8.69 (d, J ) 7.6 Hz, 1H), 7.60-7.51 (m, 3H),
7.34 (d, J ) 7.9 Hz, 1H), 7.23 (t, J ) 7.6 Hz, 1H), 4.31-4.50
(m, 1H), 3.38-3.33 (m, 2H), 1.27 (d, J ) 7,1 Hz, 3H); 13C NMR
(63 MHz, DMSO-d6) δ 172.1, 168.5, 164.9, 136.7, 131.6, 131.3,
124.8, 122.6, 116.0, 53.1, 43.9, 16.9. Anal. Calcd for C12H12N5O4-
Na: C, 46.01; H, 3.86; N, 22.36. Found: C, 46.12; H, 4.09; N,
21.99.
obtained as pale brown crystals: mp 88-90 °C; [R]25 ) +9.9
D
(c 0.21, CHCl3); IR (KBr) ν 3304, 2132, 1747, 1647 cm-1
.
1H
NMR (250 MHz, CDCl3) δ 8.91 (d, J ) 7.5 Hz, 1H), 7.94 (d, J
) 7.1 Hz, 1H), 7.49 (t, J ) 7.5 Hz, 1H), 7.15-7.30 (m, 2H),
6.92 (br. s, 1H), 4.70-4.85 (m, 1H), 4.17 (q, J ) 7.5 Hz, 2H),
3.95-4.05 (m, 2H), 1.50 (d, J ) 7.2 Hz, 3H), 1.24 (t, J ) 7.5
Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 172.5, 169.7, 164.7,
137.5, 132.8, 132.2, 125.2, 124.4, 118.5, 61.6, 49.5, 41.5, 18.2,
14.2. Anal. Calcd for C14H17N5O4: C, 52.66; H, 5.37; N, 21.93.
Found: C, 52.35; H, 5.24; N, 21.57.
Sod iu m N-(o-Azid ob en zoyl)-D-a la n ylglycin a t e (8b ).
Starting from 0.70 g (2.19 mmol) of 2b, 0.68 g (100%) of 8b
was obtained: mp 101-103 °C; [R]25 ) -17.8 (c 0.185,
D
DMSO). Anal. Calcd for C12H12N5O4Na: C, 46.01; H, 3.86; N,
22.36. Found: C, 45.96; H, 4.08; N, 21.93%. Spectral data were
identical to those of 8a .
Eth yl N-(o-Azid oben zoyl)-D-a la n ylglycin a te (2b). Start-
ing from 0.95 g (5.46 mmol) of 4b, 0.963 g (55%) of 2b was
obtained, as white crystals: mp 87-89 °C; [R]25 ) -10.2 (c
D
Sodiu m N-(o-Azidoben zoyl)-L-valylglycin ate (8c). Start-
ing from 1.026 g (2.95 mmol) of 2c, 1.00 g (100%) of 8c was
0.21, CHCl3); Anal. Calcd for C14H17N5O4: C, 52.66; H, 5.37;
N, 21.93. Found: C, 52.34; H, 5.25; N, 21.74. Spectral data
were identical to those of 2a .
obtained: mp 127-129 °C; [R]25 ) +50.0 (c 0.05, DMSO); IR
D
1
(KBr) ν 3299, 2132, 1632 cm-1; H NMR (250 MHz, DMSO-
Eth yl N-(o-Azid oben zoyl)-L-va lylglycin a te (2c). Start-
ing from 1.2 g (6.03 mmol) of 4c, 2.027 g (97%) of 2c was
obtained as pale brown crystals: mp 98-100 °C; [R]25D ) +1.4
d6) δ 8.42 (d, J ) 7.5 Hz, 1H), 8.31 (s, 1H), 7.55 (t, J ) 7.5 Hz,
1H), 7.42 (br. s, 1H), 7.34 (d, J ) 7.5 Hz, 1H), 7.23 (t, J ) 7.5
Hz, 1H), 4.25-4.38 (m, 1H), 3.26-3.36 (m, 2H), 2.05-2.25 (m,
1H), 0.89 (d, J ) 7.0 Hz, 6H); 13C NMR (63 MHz, DMSO-d6) δ
176.5, 171.6, 165.1, 136.6, 132.1, 131.8, 125.0, 124.0, 117.6,
59.8, 43.6, 30.6, 19.3, 18.3. Anal. Calcd for C14H16N5O4Na: C,
49.27; H, 4.73; N, 20.52. Found: C, 48.93; H, 4.89; N, 20.65.
Sod iu m N-(o-Azid oben zoyl)-D-tr yp top h a n ylglycin a te
(8d ). Starting from 1.02 g (2.35 mmol) of 2d , 1.00 g (100%) of
(c 0.12, CHCl3); IR (KBr) ν 3309, 2131, 1748, 1641 cm-1; H
1
NMR (250 MHz, CDCl3) δ 8.08 (d, J ) 7.2 Hz, 1H), 7.90 (d, J
) 8.2 Hz, 1H), 7.48 (t, J ) 8.2 Hz, 1H), 7.18-7.30 (m, 2H),
6.76 (br. s, 1H), 4.56 (t, J ) 7.0 Hz, 1H), 4.18 (q, J ) 7.2 Hz,
2H), 3.95-4.15 (m, 2H), 2.27-2.40 (m, 1H), 1.24 (t, J ) 7.2
Hz, 3H), 1.03 (d, J ) 6.8 Hz, 6H); 13C NMR (63 MHz, CDCl3)
δ 171.3, 169.6, 164.9, 137.3, 132.7, 132.2, 125.2, 124.5, 118.4,
61.5, 59.2, 41.4, 30.7, 19.4, 18.1, 14.1. Anal. Calcd for
8d was obtained: mp 108-110 °C; [R]25 ) +28.7 (c 0.115,
D
DMSO); IR (KBr) ν 3402, 2131, 1636 cm-1; 1H NMR (250 MHz,
DMSO-d6) δ 10.90 (s, 1H), 8.58 (d, J ) 7.9 Hz, 1H), 7.15-7.59
(m, 8H), 7.03 (t, J ) 6.9 Hz, 1H), 6.96 (t, J ) 6.9 Hz, 1H),
4.59-4.70 (m, 1H), 3.27-2.99 (m, 4H); 13C NMR (63 MHz,
DMSO-d6) δ 170.5, 169.9, 165.1, 136.7, 136.0, 131.5, 129.7,
127.4, 127.3, 124.6, 123.5, 120.7, 119.2, 118.2, 118.1, 111.2,
110.3, 54.4, 44.2, 27.3. Anal. Calcd for C20H17N6O4Na: C, 56.08;
H, 4.00; N, 19.62. Found: C, 55.73; H, 4.32; N, 19.73.
C
16H21N5O4: C, 55.32; H, 6.09; N, 20.16. Found: C, 55.67; H,
5.82; N, 19.81.
Eth yl N-(o-Azidoben zoyl)-D-tr yptoph an ylglycin ate (2d).
Starting from 0.86 g (2.97 mmol) of 4d , 1.02 g (79%) of 2d was
obtained as pale brown crystals: mp 57-59 °C; [R]25D ) + 56.3
(c 0.19, CHCl3); IR (KBr) ν 3406, 2131, 1736, 1644 cm-1; H
1
NMR (250 MHz, CDCl3) δ 8.42 (s, 1H), 8.00-8.15 (m, 2H), 7.66
(d, J ) 7.6 Hz, 1H), 7.41 (t, J ) 7.0 Hz, 1H), 7.31 (d, J ) 7.5
Hz, 1H), 7.00-7.20 (m, 4H), 6.60 (t, J ) 5.1 Hz, 1H), 4.97 (q,
J ) 7.0 Hz, 1H), 3.78-4.02 (m, 2H), 3.91 (t, J ) 5.2 Hz, 2H),
3.46 (dd, J ) 14.6 and 5.5 Hz, 1H), 3.27 (dd, J ) 14.6 and 7.1
Hz, 1H), 1.19 (t, J ) 7,0 Hz, 3H); 13C NMR (63 MHz, CDCl3)
δ 171.7. 169.5, 164.8, 137.5, 136.2, 132.8, 132.2, 127.6, 125.1,
124.2, 123.6, 122.3, 119.8, 118.9, 118.4, 111.3, 110.5, 61.6, 52.8,
41.6, 27.8, 14.2. Anal. Calcd for C22H22N6O4: C, 60.82; H, 5.10;
N, 19.34. Found: C, 60.65; H, 4.97; N, 19.04.
Sod iu m N-(o-Azid oben zoyl)-L-tr yp top h a n ylglycin a te
(8e). Starting from 0.367 g (0.84 mmol) of 2e, 0.360 g (100%)
of 8e was obtained: mp 110-112 °C. [R]25 ) -28.8 (c 0.115,
D
DMSO). Anal. Calcd for C20H17N6O4Na: C, 56.08; H, 4.00; N,
19.62. Found: C, 55.74; H, 4.40; N, 19.53. Spectral data were
identical to those of 8d .
P r ep a r a tion of Ca r boxylic Acid s (6).To a solution of the
suitable salt 8 in water (15 mL per g of salt) was added 1 N
aqueous HCl (1 equiv), and the solution was stirred at room
temperature for 15 min and then left to stand for 5 min. The
precipitated solid was filtered and dried in vacuo.
Eth yl N-(o-Azidoben zoyl)-L-tr yptoph an ylglycin ate (2e).
Starting from 0.673 g (2.32 mmol) of 4e, 0.956 g (94%) of 2e
N-(o-Azid oben zoyl)-L-a la n ylglycin e (6a ). Starting from
2.339 g (7.47 mmol) of 8a , 1.705 g (78%), of 6a was obtained:
(25) Prepared from anthranilic acid as described in Cledera, P.;
Avendan˜o, C.; Mene´ndez, J . C. Tetrahedron 1998, 54, 12349.
mp 105-107 °C; [R]25 ) +29.8 (c ) 0.205, DMSO); IR (KBr)
D

1748 J . Org. Chem., Vol. 65, No. 6, 2000
Cledera et al.
1
ν 3322, 2135, 1750, 1634 cm-1; H NMR (250 MHz, CDCl3) δ
10d : mp 59-61 °C; [R]25D ) -8.6 (c 0.145, CHCl3); IR (KBr)
1
8.58 (d, J ) 7.5 Hz, 1H), 8.25 (t, J ) 5.0 Hz, 1H), 7.64-7.50
(m, 2H), 7.36 (d, J ) 7.5 Hz, 1H), 7.24 (t, J ) 6.7 Hz, 1H),
4.39-4.57 (m, 1H), 3.70-3.95 (m, 2H), 1.31 (d, J ) 7.5 Hz,
3H) (the CO2H proton was not detected); 13C NMR (63 MHz,
CDCl3) δ 172.2, 171.0, 164.7, 136.7, 131.6, 129.9, 127.3, 124.7,
119.4, 48.6, 40.7, 18.2. Anal. Calcd for C12H13N5O4: C, 49.48;
H, 4.50; N, 24.04. Found: C, 49.55; H, 4.49; N, 24.04.
ν 2131, 1711 cm-1; H NMR (250 MHz, CDCl3) δ 8.45 (d, J )
7.1 Hz, 1H), 6.95-7.50 (m, 8H), 5.40-5.50 (m, 1H), 4.55 and
2.80 (AB quartet, J ) 19.5 Hz, 2H); 3.64 (dd, J ) 14.9 and 5.2
Hz, 1H), 3.49 (dd, J ) 14.9 and 6.1 Hz, 1H), 2.51 (s, 3H), 2.54
(s, 3H); 13C NMR (63 MHz, CDCl3) δ 170.9 (2 signals), 168.2,
167.3, 166.8, 163.5, 136.5, 135.5, 132.0, 129.3, 128.6 (2 signals),
126.1, 125.6, 125.1, 123.9, 118.3, 116.8, 114.8, 59.1, 46.0, 28.7,
26.9, 23.8. Anal. Calcd. for C24H20N6O5: C, 61.01; H, 4.27; N,
17.79. Found: C, 60.75; H, 4.23; N, 17.42.
N-(o-Azid oben zoyl)-L-va lylglycin e (6c). Starting from 0.3
g (0.88 mmol) of 8c, 0.219 g (73%) of 6c was obtained: mp
48-50 °C; [R]25 ) + 58.18 (c 0.055, DMSO); IR (KBr) ν 3307,
(3S)-1-Acet yl-4-(o-a zid ob en zoyl)-3-(3-in d olylm et h yl)-
2,5-p ip er a zin ed ion e (7e) a n d (3S)-1-Acetyl-4-(o-a zid o-
b en zoyl)-3-(1-a cet yl-3-in d olylm et h yl)-2,5-p ip er a zin ed i-
on e (10e). Starting from 0.203 g (0.5 mmol) of 8e, 0.057 g
(26%) of 7e and 0.029 g (12%) of 10e were obtained after a 4
h reaction followed by chromatography on silica gel, eluting
with 6:1 petroleum ether/ethyl acetate.
D
2131, 1743, 1632 cm-1; 1H NMR (250 MHz, CDCl3) δ 9.04 (br.
s, 1H), 8.18 (d, J ) 8.6 Hz, 1H), 7.92 (d, J ) 8.6 Hz, 1H), 7.35-
7.46 (m, 2H), 7.05-7.29 (m, 2H), 4.68 (t, J ) 7.3 Hz, 1H), 3.90-
4.18 (m, 2H), 2.13-2.32 (m, 1H), 0.99 (d, J ) 7.0 Hz, 6H); 13
C
NMR (63 MHz, CDCl3) δ 172.2, 171.9, 165.4, 137.6, 132.9,
132.2, 125.2, 124.3, 118.6, 59.3, 41.4, 31.3, 19.4, 18.3. Anal.
Calcd for C14H17N5O4: C, 52.66; H, 5.37; N, 21.93. Found: C,
53.01; H, 5.26; N, 21.70.
7e: mp 54-56 °C; [R]25 ) +39.6 (c 0.145, CHCl3). Anal.
D
Calcd for C22H18N6O4: C, 61.39; H, 4.22; N, 19.52. Found: C,
61.14; H, 4.35; N, 19.74. Spectral data were identical to those
of 7d .
Cycliza t ion s in t h e P r esen ce of Acet ic An h yd r id e.
Gen er a l P r oced u r e. A solution of the suitable carboxylic acid
6 or sodium salt 8 in acetic anhydride (2.5 mL per 0.1 g of
substrate) was stirred in a bath at 80 °C for 3 h. The solution
was evaporated, yielding the virtually pure 2,5-piperazinedione
derivatives. Analytical samples were obtained by chromatog-
raphy on silica gel, eluting with 6:1 petroleum ether/ethyl
acetate.
10e: mp 60-62 °C; [R]25 ) +8.9 (c 0.145, CHCl3). Anal.
D
Calcd for C24H20N6O5: C, 61.01; H, 4.27; N, 17.79. Found: C,
61.17; H, 4.22; N, 17.28. Spectral data were identical to those
of 10d .
Aza Wittig Cycliza tion s. Gen er a l P r oced u r e. A solution
of the suitable 2,5-piperazinedione derivative and tributyl-
phosphine (1.1 equiv) in dry toluene (20 mL) was stirred at
room temperature for 3 h. After evaporation, the residue was
chromatographed on silica gel, eluting with 2:1 petroleum
ether/ethyl acetate.
(3S)-1-Acet yl-4-(o-a zid ob en zoyl)-3-m et h yl-2,5-p ip er a -
zin ed ion e (7a ). Starting from 0.6 g (1.90 mmol) of 8a , 0.49 g
(82%) of 7a was obtained. Starting from 0.2 g (0.687 mmol) of
6a , 0.065 g (31%) of 7a was obtained: mp 76-78 °C; [R]25
)
D
-10.7 (c 0.055, CHCl3); IR (KBr) ν 2131, 1692 cm-1; 1H NMR
(250 MHz, CDCl3) δ 7.59-7.05 (m, 4H), 5.23 (q, 1H, J ) 7.2
Hz), 5.10 and 3.99 (AB quartet, 2H, J ) 17.5 Hz), 2.62 (s, 3H),
1.64 (d, J ) 7.2 Hz, 3H); 13C NMR (63 MHz, CDCl3) δ 171.6,
168.8, 167.4, 165.5, 141.9, 136.9, 132.3, 129.2, 125.2, 118.4,
55.2, 46.2, 27.1, 18.2. Anal. Calcd for C14H13N5O4: C, 53.33;
H, 4.16; N, 22.21. Found: C, 52.94; H, 4.16; N, 21.99.
(4S)-2-Acetyl-4-m eth yl-1,2,3,4-tetr a h yd r o-5H-p yr a zin o-
[2,1-b]qu in a zolin e-3,6-d ion e (9a ). Starting from 0.063 g (0.2
mmol) of 7a , 0.042 g (78%) of 9a was obtained: mp 126-128
1
°C; [R]25 ) -2.2 (c 0.135, CHCl3); IR (KBr) ν 1698 cm-1; H
D
NMR (250 MHz, CDCl3) δ 8.31 (d, J ) 7.5 Hz, 1H), 7.83-7.44
(m, 3H), 5.60-5.75 (m, 1H), 5.60 and 4.44 (AB quartet, J )
17.5 Hz, 2H), 2.60 (s, 3H), 1.71 (d, J ) 6.9 Hz, 3H); 13C NMR
(63 MHz, CDCl3) δ 173.7, 169.2, 168.0, 150.4 (2 signals), 135.7,
128.6, 127.6, 127.0, 120.4, 44.8, 31.0, 25.6, 19.6. Anal. Calcd
for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.60.
H, 4.79; N, 15.23.
(3R)-1-Acetyl-4-(o-a zid oben zoyl)-3-m eth yl-2,5-p ip er a -
zin ed ion e (7b). Starting from 0.58 g (1.85 mmol) of 8b, 0.47
g (81%) of 7b was obtained: mp 75-77 °C; [R]25 ) +10.9 (c
D
0.055, CHCl3). Anal. Calcd for C14H13N5O4: C, 53.33; H, 4.16;
N, 22.21. Found: C, 53.65; H, 4.38; N, 22.20. Spectral data
were identical to those of 7a .
(4R)-2-Acetyl-4-m eth yl-1,2,3,4-tetr a h ydr o-5H-p yr a zin o-
[2,1-b]qu in a zolin e-3,6-d ion e (9b). Starting from 0.200 g
(0.07 mmol) of 7b, 0.104 g (61%) of 9b was obtained: mp 127-
(3S)-1-Acet yl-4-(o-a zid ob en zoyl)-3-isop r op yl-2,5-p ip -
er a zin ed ion e (7c). Starting from 1.145 g (3.35 mmol) of 8c,
1.11 g (97%) of 7c was obtained. Starting from 0.2 g (0.626
mmol) of 6c, 0.065 g (31%) of 7c was obtained: mp 72-74 °C;
129 °C; [R]25 ) +2.2 (c 0.135, CHCl3). Anal. Calcd for
D
C
14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.64. H,
4.72; N, 15.16. Spectral data were identical to those of 9a .
(4S)-2-Acetyl-4-isop r op yl-1,2,3,4-tetr a h yd r o-5H-p yr a zi-
n o[2,1-b]qu in a zolin e-3,6-d ion e (9c). Starting from 0.150 g
(0.438 mmol) of 7c, 0.122 g (93%) of 9c was obtained: mp 62-
[R]25 ) -4.24 (c 0.165, CHCl3); IR (KBr) ν 2127, 1723 cm-1
;
D
1H NMR (250 MHz, CDCl3) δ 7.54-7.11 (m, 4H), 5.11 and 4.03
(AB quartet, J ) 20.0 Hz, 2H), 4.93 (d, J ) 10 Hz, 1H), 2.63
(s, 3H), 2.05-2.20 (m, 1H), 1.11 and 1.09 (2 d, 6H, J ) 7.0
Hz); 13C NMR (63 MHz, CDCl3) δ 171.6, 167.4, 167.3, 166.6,
136.8, 136.5, 132.1, 129.3, 125.3, 118.2, 64.0, 46.5, 31.9, 27.2,
19.7, 19.52. Anal. Calcd for C16H17N5O4: C, 55.97; H, 4.99; N,
20.40. Found: C, 56.25; H, 5.17; N, 20.21.
64 °C; [R]25 ) -7.3 (c 0.055, CHCl3); IR (KBr) ν 1688 cm-1
;
D
1H NMR (250 MHz, CDCl3) δ 8.26 (d, J ) 7.5 Hz, 1H), 7.85-
7.47 (m, 3H), 5.61 and 4.50 (AB quartet, J ) 17.5 Hz, 2H),
5.36 (d, J ) 10.0 Hz, 1H), 2.61 (s, 3H), 2.15-2.35 (m, 1H),
1.15 and 1.00 (d, J ) 6.5 Hz, 3H and d, J ) 6.5 Hz, 3H); 13C
NMR (63 MHz, CDCl3) δ 171.6, 167.3, 160.6, 148.1, 146.1,
135.1, 127.7, 127.3, 127.3, 120.3, 62.6, 45.4, 31.2, 27.3, 19.7,
19.6. Anal. Calcd for C16H17N3O3: C, 64.20; H, 5.72; N, 14.04.
Found: C, 63.91; H, 5.45; N, 14.40.
(3R)-1-Acet yl-4-(o-a zid ob en zoyl)-3-(3-in d olylm et h yl)-
2,5-p ip er a zin ed ion e (7d ) a n d (3R)-1-Acetyl-4-(o-a zid o-
b en zoyl)-3-(1-a cet yl-3-in d olylm et h yl)-2,5-p ip er a zin ed i-
on e (10d ). Starting from 0.195 g (0.452 mmol) of 8d , 0.150 g
(79%) of 7d was obtained after a 3 h reaction. Starting from
0.22 g (0.51 mmol) of 8d , 0,010 g (5%) of 7d and 0.063 g (38%)
of 10d were obtained after a 5 h reaction followed by chroma-
tography on silica gel, eluting with 6:1 petroleum ether/ethyl
acetate.
(4R)-2-Acet yl-4-(3-in d olylm et h yl)-1,2,3,4-t et r a h yd r o-
5H-p yr a zin o[2,1-b]qu in a zolin e-3,6-d ion e (9d ). Starting
from 0.035 g (0.081 mmol) of 7d , 0.019 g (61%) of 9d was
obtained: mp 56-58 °C; [R]25 ) -210 (c 0.02, CHCl3); IR
D
1
(KBr) ν 3399, 1708, 1684 cm-1; H NMR (250 MHz, CDCl3) δ
7d : mp 53-55 °C; [R]25 ) -39.2 (c 0.12, CHCl3); IR (KBr)
8.33 (d, J ) 7.5 Hz, 1H), 8.11 (s, 1H), 7.77 (t, J ) 7.1 Hz, 1H),
7.49-7.58 (m, 2H), 7.23-7.31 (m, 2H), 7.11 (t, J ) 6.9 Hz, 1H),
6.90 (t, J ) 7.1 Hz, 1H), 6.69 (d, J ) 2.5 Hz, 1H), 5.78-5.85
(m, 1H), 4.82 and 2.63 (AB quartet, J ) 17.5 Hz, 2H), 3.75
(dd, J ) 15.0 and 2.5 Hz, 1H), 3.63 (dd, J ) 15.0 and 7.5 Hz,
1H), 2.52 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 165.3, 164.4,
162.3, 148.3, 147.3, 137.0, 135.0, 126.0, 127.3, 127.1, 126.8,
123.0 (2 signals), 120.3, 120.1, 117.9, 111.5, 107.6, 58.6, 45.1,
27.9, 27.1. Anal. Calcd for C22H18N4O3: C, 68.38; H, 4.70; N,
14.50. Found: C, 68.33; H, 4.40; N, 14.41.
D
ν 3405, 2131, 1712 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.26 (s,
1H), 7.03-7.55 (m, 8H), 6.93 (s, 1H), 5.40-5.50 (m, 1H), 4.27
and 2.16 (AB quartet, J ) 19.5 Hz, 1H), 3.77 (dd, J ) 14.9
and 5.2 Hz, 1H), 3.57 (dd, J ) 14.9 and 5.1 Hz, 1H), 2.61 (s,
3H); 13C NMR (63 MHz, CDCl3) δ 171.3, 168.9, 167.9, 136.7,
136.1, 132.0, 128.8, 128.1, 126.7, 125.2, 123.2, 120.5, 118.5,
118.4, 111.7, 108.3, 60.3, 46.1, 29.4, 27.3. Anal. Calcd for
C
22H18N6O4: C, 61.39; H, 4.22; N, 19.52. Found: C, 61.09; H,
4.35; N, 19.33.

Total Synthesis of Glyantrypine
J . Org. Chem., Vol. 65, No. 6, 2000 1749
(4S)-2-Acet yl-4-(3-in d olylm et h yl)-1,2,3,4-t et r a h yd r o-
5H-pyr azin o[2,1-b]qu in azolin e-3,6-dion e (9e). Starting from
0.1 g (0.23 mmol) of 7e, 0.046 g (51%) of 9e was obtained: mp
mmol of 9b, 0.031 g (64%) of 1b was obtained, as an oil: [R]25
) -35.0 (c 0.185, DMSO). Anal. Calcd for C12H11N3O2: C,
62.87; H, 4.84; N, 18.33. Found: C, 62.66; H, 5.07; N, 18.35.
Spectral data were identical to those of 1a .
D
56-58 °C; [R]25 ) +206 (c 0.02, CHCl3). Anal. Calcd for
D
C22H18N4O3: C, 68.38; H, 4.70; N, 14.50. Found: C, 68.47; H,
5.01; N, 14.29. Spectral data were identical to those of 9d .
(4R)-2-Acet yl-4-(1-a cet yl-3-in d olylm et h yl)-1,2,3,4-t et -
r a h yd r o-5H -p yr a zin o[2,1-b]q u in a zolin e-3,6-d ion e (11).
Starting from 0.048 g (0.101 mmol) of 10d , 0.029 g (66%) of
11 was obtained: mp 62-64 °C; [R]25D ) - 30.0 (c 0.01, CHCl3);
IR (KBr) ν 1711 cm-1; 1H NMR (250 MHz, CDCl3) δ 8.32 (d, J
) 7.1 Hz, 1H), 8.28 (d, J ) 7.1 Hz, 1H), 7.78 (t, J ) 7.1 Hz,
1H), 7.53-7.63 (m, 2H), 7.23-7.36 (m, 2H), 7.13 (t, J ) 7.5
Hz, 1H), 7.04 (s, 1H), 5.82-5.92 (m 1H), 4.82 and 3.46 (AB
quartet, J ) 17.5 Hz, 2H), 3.10-3.50 (m, 2H), 2.52 (s, 3H),
2.41 (s, 3H); 13C NMR (63 MHz, CDCl3) δ 171.2, 168.1, 160.2
(2 signals), 147.6, 147.2, 135.8, 135.4, 124.4, 127.2, 126.9,
126.2, 124.2, 124.1, 120.2, 118.2, 117.9, 111.6, 107.3, 57.7, 40.9,
27.1, 24.0 and 23.9. Anal. Calcd for C24H20N4O4: C, 67.28; H,
4.71; N, 13.08. Found: C, 67.74; H, 4.76: N, 12.82.
(4R)-4-Isop r op yl-1,2,3,4-tetr a h yd r o-5H-p yr a zin o[2,1-b]-
qu in a zolin e-3,6-d ion e (1c). Starting from 0.014 g (0,046
mmol) of 5, 0.010 g (83%) of 1c was obtained, as an oil (see
data below).
Dea cetyla tion s w ith Hyd r a zin e. Gen er a l P r oced u r e.
80% Hydrazine hydrate (2 equiv) was added to a solution of
the starting acetyl derivative in DMF (20 mL). The solution
was stirred at room temperature for 3 h, poured on ice water
(20 mL), and extracted with CHCl3 (3 × 15 mL). The combined
organic layers were dried (Na2SO4) and evaporated.
(4S)-4-Isop r op yl-1,2,3,4-tetr a h yd r o-5H-p yr a zin o[2,1-b]-
qu in a zolin e-3,6-d ion e (1c). Starting from 0.166 g (0.56
mmol) of 9c, 0.100 g (71%) of 1c was obtained, as an oil. [R]25
D
) +50.0 (c 0.01, DMSO); IR (KBr) ν 3241, 1683 cm-1; 1H NMR
(250 MHz, CDCl3) δ 8.28 (d, J ) 7.5 Hz, 1H), 7.79-7.46 (m,
3H), 6.73 (br. s, 1H), 5.25 (d, J ) 7.5 Hz, 1H), 4.70 (d, J )
17.1 Hz, 1H), 4.43 (dd, J ) 17.1 and 5.3 Hz, 2H), 2.10-2.40
(m, 1H) 1.06 and 0.94 (d, J ) 7.5 Hz, 3H and d, J ) 6.7 Hz,
3H); 13C NMR (63 MHz, CDCl3) δ 169.1, 160.8, 148.6, 147.0,
134.9, 127.3, 127.2, 126.9, 120.3, 60.8, 45.4, 31.8, 19.9 and 18.9.
Anal. Calcd for C14H15N3O2: C, 65.36; H, 5.88; N, 16.33.
Found: C, 65.75; H, 5.71; N, 16.63.
(4R)-4-(3-In dolylm eth yl)-1,2,3,4-tetr ah ydr o-5H-pyr azin o-
[2,1-b]qu in azolin e-3,6-dion e (1d) [(-)-Glyan tr ypin e]. Start-
ing from 0.030 g (0.077 mmol) of 9d , 0.016 g (62%) of 1d was
obtained. Starting from 0.023 g (0.053 mmol) of 11d , 0.012 g
(65%) of 1d was obtained: mp 86-88 °C; [R]25 ) -150.5 (c
D
0.105, DMSO); IR (KBr) ν 3273, 1683 cm-1; 1H NMR (250 MHz,
CDCl3) δ 10.94 (s, 1H), 8.34 (s, 1H), 8.20 (d, J ) 10.0 Hz, 1H),
7.82 (t, J ) 7.5 Hz, 1H), 7.50-7,62 (m, 2H), 7.20-7.35 (m, 2H),
6.99 (t, J ) 7.5 Hz, 1H), 6.86 (d, J ) 2.5 Hz, 1H), 6.76 (t, J )
7.5 Hz, 1H), 5.25 (t, J ) 6.0 Hz, 1H), 3.80 (dd, J ) 17.2 and
5.1 Hz), 3.33-3.42 (m, 2H), 3.04 (d, J ) 17.2 Hz, 2H); 13C NMR
(63 MHz, CDCl3) δ 167.5, 159.8, 149.2, 146.9, 135.9, 134.6,
127.0, 126.6, 126.5, 126.2, 124.3, 121.1, 119.8, 118.5, 117.7,
111.3, 107.7, 56.4, 43.7, 26.4. Anal. Calcd for C20H16N4O2: C,
69.76; H, 4.68; N, 16.27. Found: C, 69.73; H, 4.94; N, 16.57.
(4S)-4-(3-In dolylm eth yl)-1,2,3,4-tetr ah ydr o-5H-pyr azin o-
[2,1-b]qu in azolin e-3,6-dion e (1e) [(+)-Glyan tr ypin e]. Start-
ing from 0.023 g (0.059 mmol) of 9e, 0.010 g (50%) of 1e was
(4S)-4-Met h yl-1,2,3,4-t et r a h yd r o-5H -p yr a zin o[2,1-b]-
qu in a zolin e-3,6-d ion e (1a ). Starting from 0.055 g (0.20)
mmol of 9a , 0.030 g (66%) of 1a was obtained, as an oil: [R]25
D
) +35.0 (c 0.185, DMSO); IR (KBr) ν 3281, 1682 cm-1; 1H NMR
(250 MHz, CDCl3) δ 8.27 (d, J ) 7.5 Hz, 1H), 7.90-6.90 (m,
4H), 5.40 (q, J ) 7.1 Hz, 1H), 4.63 (d, J ) 15.0 Hz, 1H) and
4.23 (dd, J ) 15.0 and 4.8 Hz, 2H), 1.62 (d, J ) 7.5 Hz, 3H);
13C NMR (63 MHz, CDCl3) δ 170.3, 160.3, 147.8, 147.2, 134.9,
127.4, 127.0 (2 signals), 120.3, 45.08, 29.2, 17.0. Anal. Calcd
for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.60;
H, 5.14; N, 18.54.
obtained: mp 86-87 °C; [R]25 ) +150.1 (c 0.105, DMSO).
D
Anal. Calcd for C20H16N4O2: C, 69.76; H, 4.68; N, 16.27.
Found: C, 69.55; H, 5.18; N, 16.93. Spectral data were
identical to those of 1d and those found in ref 3.
Ack n ow led gm en t. We thank CICYT for financial
support (project SAF-97-0143).
(4R)-4-Met h yl-1,2,3,4-t et r a h yd r o-5H -p yr a zin o[2,1-b]-
qu in a zolin e-3,6-d ion e (1b). Starting from 0.057 g (0.21)
J O991626E