Asymmetrically induced alkylation of 2-benzyl-4-isopropyl-2,4-dihydro- 1H-pyrazino [2,1-b] quinazoline-3,6-dione

Article abstract of DOI:10.1016/S0957-4166(98)00464-9

The substitution of the 4-methyl group by a 4-isopropyl group in the 2- benzyl-2,4-dihydro-1H-pyrazino[2,1b]quinazoline-3,6-dione system allows a notable improvement in the stereoselective alkylation at C-1. The configuration of the newly introduced stereogenic centre has been assigned on the basis of ¹H NMR data and NOE measurements.

Full text of DOI:10.1016/S0957-4166(98)00464-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 4275–4284
Asymmetrically induced alkylation of 2-benzyl-4-isopropyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Félix L. Buenadicha, Carmen Avendaño ∗ and Mónica Söllhuber
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 6 November 1998; accepted 11 November 1998
Abstract
The substitution of the 4-methyl group by a 4-isopropyl group in the 2-benzyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione system allows a notable improvement in the stereoselective alkylation at C-1. The
1
configuration of the newly introduced stereogenic centre has been assigned on the basis of H NMR data and
NOE measurements. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
By far the most popular and extensively studied glycine template among Schöllkopf’s bis-lactim ethers
used as anion precursors in the synthesis of optically active α-amino acids, is that derived from valine
and glycine.1 Its homologue derived from cyclo-Val-Ala has also been used for similar purposes.2
Anions derived from N,N0-disubstituted chiral piperazine-2,5-diones have been exploited to a much
lesser extent than the bis-lactim ethers. Intramolecular C–C bond-forming cyclizations,3 asymmetric
induction studies4 and enhancement of diastereocontrol by chiral relay auxiliary5 have been reported in
this context.
We have shown that, because of its locked pseudoaxial disposition, the 4-methyl substituent in
anions derived from 2-substituted (4S)-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones
(1a and 1b) induces the asymmetric alkylation at C-1, with the preferential formation of the 1,4-anti
isomers in kinetically controlled reactions. Under thermodynamic conditions, these isomers equilibrate to
the more stable syn-isomers through the corresponding anions.6,7 This tricyclic system can be considered
a β-turn template and attracted our attention because it contains three of the six rings of the fungal
metabolite N-acetylardeemin. This natural compound has been described as a potent reversal agent of
multiple drug resistance (MDR) in tumour cell lines8 by inhibiting the membrane glycoprotein Pgp-170,
which is thought to function by lowering the intracellular levels of many antineoplastic drugs.9 In our
∗
Corresponding author. E-mail: msollhub@eucmax.sim.ucm.es
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00464-9

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current work, aiming at the synthesis of analogues for structure–activity relationships, we have found
that some simple analogues, especially the C-1 alkylated derivatives of 1b, retain most of the biological
activity of N-acetylardeemin.10 Here we study, from a stereochemical point of view, the alkylation of
compound 2 derived from L-Val, Gly and anthranilic acid, expecting that the bulkier substituent at C-4
would induce the asymmetric alkylation at C-1 with better d.e. than those described for compound 1b.
2. Results and discussion
Compound 2 was prepared11 starting from ethyl N-benzylglycinate and Cbz-(L)-valine, cyclization of
the dipeptide to the piperazinedione, conversion to the corresponding iminoether and condensation with
anthranilic acid. The results obtained by treatment of 2 with LHMDS at −78°C, followed by addition
of 1.1 equivalents of the alkylating agent to give compounds 3–10, are summarized in Table 1. For
comparison purposes, the anti/syn ratios previously found in the same reactions on compound 1b6 have
been included in brackets. In the case of the 1-arylmethyl derivatives, both diastereomers could be clearly
1
distinguished by H NMR assignment. Similarly to the 1-alkyl derivatives of compound 1b, the anti-
isomers of compounds 5–10 show a upfield shift for H-4 of about 1 ppm (δ=5.4 to δ=4.4 ppm) with
respect to the syn-isomers. These data suggest that the piperazine ring adopts a boat conformation in the
syn-isomers, while this ring is more planar in the anti-isomers. The assignment in the case of 3 and 4,
where both isomers present the same chemical shift for H-4 (δ≈5.4 ppm), required NOE experiments,
which also corroborated the structure of isomers 5–9: see, for instance, the most significant NOEs for
1
both isomers of compound 5 in Fig. 1. The enantiomeric purity was determined by H NMR (addition
of europium(III) tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate] [(+)-Eu(HFC)3] as chiral
shift reagent).
The reactions with compound 2 are more diastereoselective than with compound 1b, as would be
expected from the greater steric interaction of the C-4 isopropyl substituent. In addition, ratios higher
than 8:2 in favour of the anti-isomers were found for compounds 5–9. Also noteworthy is the appearance
of significant amounts of the anti-isomer of compound 3 (since this isomer was not isolated when
compounds 1a or 1b were alkylated with methyl iodide), and the significant improvement of the
diastereoselection found in the alkylation of 2 with p-nitrobenzyl bromide.
According to the proposed mechanism, the reverse diastereoselectivity found with the earlier-
mentioned electrophiles and the anion derived from 1a and 1b (0:100 for 1 and 30:70 for 2) was explained
on the basis of the faster equilibration by epimerization at C-1 as a result of either a more favourable
alignment of H-1 for deprotonation in the 1-methyl derivatives, or the greater acidity of this proton in the
p-nitrobenzyl derivatives with respect to the C-1 arylmethyl substituted compounds.
The lower d.e. observed in these reactions in comparison with the d.e. described for derivatives of
cyclo-Val-Gly bis-lactim ethers1 can be explained by the easier equilibration of the kinetically favoured
anti-isomers to the more stable syn-isomers in compounds 3–9.

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Table 1
1-Alkylated derivatives of 2
Figure 1. Significant NOEs observed in anti- and syn-diastereomers of compound 5
A high-temperature molecular dynamics study of representative compounds derived from 1b and 2
was carried out using the HyperChem 3 program in order to explore their putative minimum energy
conformations. To avoid the risks inherent to this methodology, additional molecular dynamics was
used and, finally, the minimum energy conformers were minimized using MM calculations and the
Fletcher–Reeves algorithm (RMS gradient 0.01 kcal/Å mol) (Table 2).
It can be seen from Table 2 that the anti-isomers are less stable than the syn-isomers in all cases, and

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Table 2
Calculated energies (MM2, kcal/mol) for some representative compounds
that the calculated energy differences are greater in derivatives with a C-4 methyl substituent. According
to the more planar conformation for the piperazine ring, the replacement of the methyl group at C-4 by an
isopropyl group does not affect the minimum energy in the anti-isomers, but in the syn-isomers the boat
conformation presents a greater 1,4-steric interaction in the isopropyl derivatives, which could explain
the higher diastereoselectivity in the asymmetrically induced alkylation at C-1.
3. Experimental
3.1. General methods
Melting points are uncorrected. IR spectra were recorded with all solid compounds compressed into
KBr pellets and liquid compounds placed between NaCl plates. NMR spectra were recorded at 250 MHz
1
for H and 62.5 MHz for 13C in CDCl3, with TMS as the internal reference (Servicio RMN, U.C.M.).
Mass spectra were recorded at 70 eV, quadrupole detector, EI (Centro de Espectroscopía U.C.M).
Elemental analyses were obtained from the Servicio de Microanálisis, U.C.M. Optical rotations were
determined at 25°C in CHCl3 at 589 nm. Separations by chromatography were performed on silica gel
(35–70 µm). Tetrahydrofuran was freshly distilled from sodium-benzophenone. All commercial reagents
were used as received. The expression ‘petroleum ether’ refers to the fraction boiling at 40–60°C.
3.2. (4S)-2-Benzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 2
To a stirred solution of 4.35 g (22.4 mmol) of distilled ethyl N-benzylglycinate in 80 ml dry CH2Cl2, N-
Cbz-(L)-valine (5.65 g, 22.4 mmol) and DCC (5.1 g 24.6 mmol) were added, and stirring was continued
overnight. The reaction mixture was filtered, washed successively with HCl (1N), NaHCO3 (1N) and
water, dried over anhydrous Na2SO4 and evaporated. The syrupy residue (8.9 g, 20.1 mmol; yield 93%)
was hydrogenated at 35 psi for 14 h with 0.8 g of C/Pd (10%) in 150 ml of methanol, filtered (Celite),
and evaporated. The obtained syrup was recrystallized from toluene to give 4.76 g (98%) of (3S)-3-
isopropyl-1-benzylpiperazine-2,5-dione. Mp: 137–138°C. [α]D +2.15 (0.25, chloroform). IR (KBr) ν:
3329, 1684, 1641 cm−1. 1H NMR (CDCl3) δ: 7.29 (5H, m-ArH), 6.25 (1H, s, NH), 4.74 (1H, d, J=14.3
Hz, Ar–CH2–N), 4.43 (1H, d, J=14.3 Hz, Ar–CH2–N), 3.90 (1H, m, H-3), 3.86 (1H, d, J=17.7 Hz, H-6),
3.76 (1H, d, J=17.7 Hz, H-6), 2.44 (1H, sep, J=6.8 Hz, CH(CH3)2), 1.01 (3H, d, J=6.8 Hz, CH3), 0.86

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 4275–4284
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(3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 166.5, 166.5, 135.1, 128.8, 128.5, 128.1, 60.6, 49.5, 48.5,
33.1, 18.8, 16.1. Analysis calcd for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C, 68.34; H, 7.39;
N, 11.48.
A mixture of 2 g (8.1 mmol) of the earlier-described (3S)-1-benzyl-3-isopropylpiperazine-2,5-dione,
triethyloxonium tetrafluoroborate (4.6 g, 24.2 mmol) and anhydrous Na2CO3 (4.27 g, 40.3 mmol) in 75
ml dry CH2Cl2 was stirred overnight at room temperature, poured on ice water, extracted with CH2Cl2,
dried over anhydrous Na2SO4 and evaporated. Anthranilic acid (1.48 g, 10.8 mmol) was added to the
syrupy residue, the mixture was stirred vigorously at 120°C for 3 h under argon, dissolved in CH2Cl2,
extracted with diluted ammonium hydroxide, dried (Na2SO4) and concentrated. Column chromatography
(CH2Cl2:EtOAc 9:1) afforded 1.35 g (48%) of 2 as a syrup. [α]D +35.0 (0.25, chloroform). IR (KBr) ν:
1
1676, 1607 cm−1. H NMR (CDCl3) δ: 8.23 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.71 (1H, ddd, J=8.4, 7.2,
1.5 Hz, H-9), 7.54 (1H, dd, J=8.4, 1.1 Hz, H-10), 7.45 (1H, ddd, J=8.0, 7.2, 1.1 Hz, H-8), 7.32 (5H,
m, ArH), 5.25 (1H, d, J=7.8 Hz, H-4), 4.95 (1H, d, J=14.5 Hz, Ar–CH2–N), 4.49 (1H, d, J=17.2 Hz,
H-1), 4.31 (1H, d, J=14.5 Hz, Ar–CH2–N), 4.21 (1H, d, J=17.2 Hz, H-1), 2.14 (1H, m, CH(CH3)2),
0.99 (3H, d, J=7.2 Hz, CH3), 0.99 (3H, d, J=7.2 Hz, CH3). 13C NMR (CDCl3) δ: 165.5, 160.3, 148.4,
146.9, 135.3, 134.5, 128.9, 128.3, 128.1, 126.93, 126.90, 126.7, 120.2, 60.7, 49.7, 49.5, 31.9, 19.8, 18.7.
Analysis calcd for C21H21N3O2: C, 72,60; H, 6.09; N, 12.10. Found: C, 72.41; H, 6.32; N, 11.45.
3.3. General procedure for the alkylation of compound 2
To a cold (−78°C), magnetically stirred solution of compound 2 (0.5 mmol) in dry THF (10 ml)
was added, under argon, dropwise via syringe, a 1 M solution of lithium hexamethyldisilazide in THF
(0.7 ml), followed by the appropriate halide (0.7 mmol dissolved in 5 ml of THF) 10 min later. The
reaction mixture was maintained at −78°C for 10 min, and at 0°C for 10–30 min, quenched with
ice, and diluted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and evaporated.
Column chromatography of the residue on silica gel (toluene:ethyl acetate, 9:1 if not otherwise indicated)
afforded first the 1,1-dialkylated product, if any, followed by the anti-1-alkylated and the syn-alkylated
compounds. In some cases traces of the 1-hydroxy derivative of 2 were isolated. Yields are included in
Table 1; analytical and spectroscopic data follow.
3.4. (1R,4S)-2-Benzyl-4-isopropyl-1-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
anti-3
Yellow oil (petroleum ether:ethyl acetate 1:1). [α]D +15.3 (0.25, chloroform). IR (NaCl) ν: 1678, 1604
cm−1. 1H NMR (CDCl3) δ: 8.27 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.74 (1H, ddd, J=8.3, 7.0, 1.5 Hz, H-9),
7.64 (1H, dd, J=8.3, 1.2 Hz, H-10), 7.48 (1H, ddd, J=8.0, 7.0, 1.2 Hz, H-8), 7.30 (5H, m, ArH), 5.43
(1H, d, J=8.9 Hz, H-4), 5.39 (1H, d, J=15.7 Hz, Ar–CH2–N), 4.77 (1H, q, J=6.8 Hz, H-1), 4.31 (1H,
d, J=15.7 Hz, Ar–CH2–N), 2.26 (1H, m, CH(CH3)2), 1.74 (3H, d, J=6.8 Hz, CH3), 1.21 (3H, d, J=6.8
Hz, CH3), 1.02 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 167.4, 160.8, 151.7, 146.9, 137.0, 134.5,
128.8, 127.5, 127.4, 127.1, 127.0, 126.9, 120.3, 60.7, 52.9, 45.3, 31.0, 19.8, 19.3, 16.0. Analysis calcd
for C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C, 72.69; H, 6.52; N, 11.32.

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3.5. (1S,4S)-2-Benzyl-4-isopropyl-1-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione syn-
3
Yellow oil (petroleum ether:ethyl acetate 1:1). [α]D −0.8 (0.25, chloroform). IR (NaCl) ν: 1680, 1603
cm−1. 1H NMR (CDCl3) δ: 8.24 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.4, 7.1, 1.5 Hz, H-9),
7.53 (1H, dd, J=8.4, 1.1 Hz, H-10), 7.44 (1H, ddd, J=8.0, 7.1, 1.1 Hz, H-8), 7.27 (5H, m, ArH), 5.31
(1H, d, J=8.8 Hz, H-4), 5.22 (1H, d, J=14.8 Hz, Ar–CH2–N), 4.56 (1H, q, J=7.2 Hz, H-1), 4.22 (1H,
d, J=14.8 Hz, Ar–CH2–N), 2.16 (1H, m, CH(CH3)2), 1.68 (3H, d, J=7.2 Hz, CH3), 1.27 (3H, d, J=6.8
Hz, CH3), 0.99 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 165.8, 161.0, 152.1, 147.0, 135.7, 134.6,
128.9, 128.3, 128.0, 127.1, 126.9, 126.6, 119.9, 60.0, 55.9, 47.5, 34.0, 20.5, 20.4, 19.4. Analysis calcd
for C22H23N3O2: C, 73.11; H, 6.41; N, 11.63. Found: C, 72.87; H, 6.53; N, 11.23.
3.6. (1R,4S)-1-Allyl-2-benzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione anti-4
Oil (petroleum ether:ethyl acetate 6:4). [α]D +44.4 (0.25, chloroform). IR (NaCl) ν: 1679, 1601 cm−1
.
1H NMR (CDCl3) δ: 8.24 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.3, 7.2, 1.5 Hz, H-9), 7.58
(1H, dd, J=8.3, 1.1 Hz, H-10), 7.46 (1H, ddd, J=8.0, 7.2, 1.1 Hz, H-8), 7.33 (5H, m, ArH), 5.64 (1H, d,
J=15.1 Hz, Ar–CH2–N), 5.55 (1H, ddt, J=13.7, 9.6, 6.8 Hz, H-200), 5.31 (1H, d, J=5.1 Hz, H-4), 5.07
(1H, dd, J=9.63, 1.3 Hz, H-300), 5.04 (1H, dd, J=13.7, 1.3 Hz, H-300), 4.65 (1H, dd, J=4.3, 3.3 Hz, H-1),
4.09 (1H, d, J=15.1 Hz, Ar–CH2–N), 3.13 (1H, m, H-100), 3.00 (1H, m, H-100), 2.30 (1H, m, CH(CH3)2),
1.14 (3H, d, J=6.9 Hz, CH3), 0.87 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 165.8, 160.5, 150.6,
146.8, 135.6, 134.6, 131.1, 128.9, 128.4, 128.0, 126.9, 126.8, 120.2, 120.1, 60.1, 57.1, 45.7, 35.9, 33.4,
20.2, 17.7. Analysis calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84. Found: C, 74.21; H, 6.68; N,
10.51.
3.7. (1S,4S)-1-Allyl-2-benzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione syn-4
Oil (petroleum ether:ethyl acetate 6:4). [α]D +2.4 (0.25, chloroform). IR (NaCl) ν: 1681, 1603 cm−1
.
1H NMR (CDCl3) δ: 8.27 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.3, 7.2, 1.5 Hz, H-9), 7.55
(1H, dd, J=8.3, 1.0 Hz, H-10), 7.46 (1H, ddd, J=8.0, 7.2, 1.0 Hz, H-8), 7.24 (5H, m, ArH), 5.96 (1H, ddt,
J=17.0, 10.4, 7.0 Hz, H-200), 5.35 (1H, d, J=14.9 Hz, Ar–CH2–N), 5.31 (1H, d, J=9.2 Hz, H-4), 5.17 (2H,
m, H-300), 4.52 (1H, t, J=7.2 Hz, H-1), 4.20 (1H, d, J=14.9 Hz, Ar–CH2–N), 2.77 (2H, m, H-100), 2.20
(1H, m, CH(CH3)2), 1.37 (3H, d, J=6.6 Hz, CH3), 0.98 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ:
166.5, 161.2, 150.6, 146.8, 135.6, 134.6, 133.2, 128.9, 128.2, 128.0, 127.0, 126.9, 126.8, 120.0, 119.0,
60.2, 60.1, 48.5, 40.6, 34.2, 20.9, 19.1. Analysis calcd for C24H25N3O2: C, 74.39; H, 6.50; N, 10.84.
Found: C, 74.36; H, 6.67; N, 10.26.
3.8. (4S)-2-Benzyl-1,1-diallyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 10
Oil (petroleum ether:ethyl acetate 6:4). Yield: 18%. [α]D +17.3 (0.26, chloroform). IR (NaCl) ν: 1680,
1657, 1587 cm−1. 1H NMR (CDCl3) δ: 8.22 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.74 (1H, ddd, J=8.3, 7.0, 1.5
Hz, H-9), 7.64 (1H, dd, J=8.3, 1.3 Hz, H-10), 7.49 (2H, m, ArH), 7.46 (1H, ddd, J=8.0, 7.0, 1.3 Hz, H-8),
7.30 (3H, m, ArH), 5.48 (1H, m, H-200), 5.25 (1H, m, H-2000), 5.18 (1H, d, J=5.0 Hz, H-4), 5.16 (1H, d,
J=15.1 Hz, Ar–CH2–N), 4.88 (3H, m, 2H-300, H-3000), 4.70 (1H, dd, J=17.0, 1.6 Hz, H-3000), 4.50 (1H,
d, J=15.1 Hz, Ar–CH2–N), 3.24 (1H, dd, J=14.5, 8.0 Hz, H-100), 2.85 (3H, m, H-100, 2H-1000), 2.22 (1H,
m, CH(CH3)2), 1.09 (3H, d, J=6.9 Hz, CH3), 0.95 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 166.8,

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160.9, 152.1, 146.8, 138.1, 134.5, 132.1, 130.0, 128.8, 128.5, 127.5, 127.0, 126.72, 126.70, 120.8, 120.1,
119.9, 70.0, 59.5, 46.2, 45.7, 42.8, 34.3, 20.1, 18.6. Analysis calcd for C27H29N3O2: C, 75.85; H, 6.84;
N, 9.83. Found: C, 76.13; H, 7.22; N, 9.35.
3.9. (1R,4S)-1,2-Dibenzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione anti-5
Mp: 135–137°C (CH2Cl2:ethyl acetate 9:1). [α]D +79 (0.25, chloroform). IR (KBr) ν: 1688, 1651,
1597 cm−1. 1H NMR (CDCl3) δ: 8.17 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.75 (1H, ddd, J=8.3, 7.1, 1.5 Hz,
H-9), 7.60 (1H, dd, J=8.3, 1.2 Hz, H-10), 7.45 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.36 (5H, m, ArH),
7.12 (3H, m, ArH), 6.66 (2H, m, H-200,600), 5.75 (1H, d, J=14.7 Hz, Ar–CH2–N), 4.86 (1H, dd, J=3.9,
3.5 Hz, H-1), 4.38 (1H, d, J=3.3 Hz, H-4), 4.13 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.52 (1H, dd, J=14.1,
3.9 Hz, C1–CH2–Ar), 3.28 (1H, dd, J=14.1, 3.5 Hz, C1–CH2–Ar), 2.13 (1H, m, CH(CH3)2), 1.12 (3H, d,
J=7.0 Hz, CH3), 0.67 (3H, d, J=7.0 Hz, CH3). 13C NMR (CDCl3) δ: 165.0, 160.1, 150.5, 146.5, 135.1,
134.6, 133.7, 129.2, 129.0, 128.9, 128.6, 128.2, 127.7, 126.8, 126.7, 126.6, 120.3, 59.7, 58.5, 46.3, 39.0,
33.4, 20.3, 16.5. Analysis calcd for C28H27N3O2: C, 76.86; H, 6.22; N, 9.60. Found: C,77.05; H, 6.08;
N, 9.53.
3.10. (1S,4S)-1,2-Dibenzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione syn-5
1
Oil (CH2Cl2:ethyl acetate 9:1). [α]D −3.2 (0.19, chloroform). IR (NaCl) ν: 1682, 1601 cm−1. H
NMR (CDCl3) δ: 8.26 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.4, 7.1, 1.5 Hz, H-9), 7.52 (1H,
dd, J=8.4, 1.1 Hz, H-10), 7.46 (1H, ddd, J=8.0, 7.1, 1.1 Hz, H-8), 7.35 (3H, m, ArH), 7.18 (2H, m,
ArH), 7.35 (3H, m, ArH), 6.92 (2H, m, ArH), 6.66 (2H, m, H-200,600), 5.34 (1H, d, J=9.6 Hz, H-4),
5.26 (1H, d, J=14.9 Hz, Ar–CH2–N), 4.69 (1H, dd, J=9.2, 5.0 Hz, H-1), 3.48 (1H, dd, J=13.7, 5.0 Hz,
C1–CH2–Ar), 3.21 (1H, dd, J=13.7, 9.2 Hz, C1–CH2–Ar), 3.16 (1H, d, J=14.9 Hz, Ar–CH2–N), 2.12
(1H, m, CH(CH3)2), 1.38 (3H, d, J=6.7 Hz, CH3), 0.97 (3H, d, J=6.7 Hz, CH3). 13C NMR (CDCl3) δ:
166.5, 161.1, 150.9, 146.7, 136.4, 135.3, 134.6, 129.4, 129.0, 128.7, 128.2, 127.8, 127.6, 127.1, 127.0,
126.7, 119.9, 61.8, 60.1, 48.1, 42.5, 34.3, 20.9, 19.4. Analysis calcd for C28H27N3O2: C, 76.86; H, 6.22;
N, 9.60. Found: C, 76.82; H, 6.48; N, 9.71.
3.11. (4S)-4-Isopropyl-1,1,2-tribenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 11
White solid (toluene:ethyl acetate 85:15). Mp: 144–145°C. [α]D +10.6 (0.26, chloroform). IR (KBr)
1
ν: 1687, 1656, 1588 cm−1. H NMR (CDCl3) δ: 8.18 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.85 (1H, ddd,
J=8.4, 7.0, 1.5 Hz, H-9), 7.78 (1H, dd, J=8.2, 1.3 Hz, H-10), 7.50 (1H, ddd, J=8.0, 7.0, 1.3 Hz, H-8),
7.20 (5H, m, ArH), 7.00 (6H, m, ArH), 6.75 (2H, m, ArH), 6.55 (2H, m, ArH), 5.53 (1H, d, J=14.9 Hz,
Ar–CH2–N), 4.72 (1H, d, J=14.9 Hz, Ar–CH2–N), 4.39 (1H, d, J=5.4 Hz, H-4), 4.18 (1H, d, J=14.3 Hz,
C1–CH2–Ar), 3.67 (1H, d, J=13.9 Hz, C1–CH2–Ar), 3.56 (1H, d, J=13.9 Hz, C1–CH2–Ar), 3.50 (1H, d,
J=14.3 Hz, C1–CH2–Ar), 1.44 (1H, m, CH(CH3)2), 0.72 (3H, d, J=6.9 Hz, CH3), 0.39 (3H, d, J=6.9 Hz,
CH3). 13C NMR (CDCl3) δ: 167.0, 160.5, 151.9, 146.3, 138.2, 135.4, 134.6, 133.9, 131.2, 129.6, 129.0,
128.6, 128.2, 127.8, 127.7, 127.6, 126.9, 126.8, 126.7, 120.2, 72.7, 59.1, 48.7, 47.9, 43.8, 34.2, 20.1,
17.8. Analysis calcd for C35H33N3O2: C, 79.67; H, 6.30; N, 7.96. Found: C, 79.26; H, 6.16; N, 7.66.

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3.12. (1R,4S)-2-Benzyl-4-isopropyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione anti-6
1
Mp: 147–149°C. [α]D +68.8 (0.26, chloroform). IR (NaCl) ν: 1688, 1651, 1595 cm−1. H NMR
(CDCl3) δ: 8.18 (1H, dd, J=8.1, 1.5 Hz, H-7), 7.75 (1H, ddd, J=8.4, 7.1, 1.5 Hz, H-9), 7.60 (1H, dd,
J=8.4, 1.1 Hz, H-10), 7.46 (1H, ddd, J=8.1, 7.1, 1.1 Hz, H-8), 7.37 (5H, m, ArH), 6.90 (2H, d, J=7.9
Hz, H-30,50), 6.54 (2H, d, J=7.9 Hz, H-20,60), 5.75 (1H, d, J=14.7 Hz, Ar–CH2–N), 4.83 (1H, dd, J=4.0,
3.3 Hz, H-1), 4.40 (1H, d, J=3.2 Hz, H-4), 4.12 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.49 (1H, dd, J=14.1,
4.0 Hz, C1–CH2–Ar), 3.24 (1H, dd, J=14.1, 3.3 Hz, C1–CH2–Ar), 2.22 (1H, s, CH3Ar), 2.17 (1H, m,
CH(CH3)2), 1.13 (3H, d, J=6.9 Hz, CH3), 0.66 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 164.9,
160.1, 158.7, 146.6, 137.3, 135.1, 134.6, 130.4, 129.2, 129.0, 128.98, 128.93, 128.2, 126.8, 126.6, 120.3,
59.7, 58.6, 46.5, 38.3, 33.6, 21.2, 20.5, 16.7. Analysis calcd for C29H29N3O2: C, 77.14; H, 6.47; N, 9.31.
Found: C, 77.12; H, 6.52; N, 9.27.
3.13. (1S,4S)-2-Benzyl-4-isopropyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione syn-6
1
[α]D −5.8 (0.25, chloroform). IR (NaCl) ν: 1684, 1602 cm−1. H NMR (CDCl3) δ: 8.26 (1H, dd,
J=8.1, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.4, 7.1, 1.5 Hz, H-9), 7.53 (1H, dd, J=8.4, 1.1 Hz, H-10), 7.45
(1H, ddd, J=8.1, 7.1, 1.1 Hz, H-8), 7.20 (5H, m, ArH), 7.15 (4H, t, J=8.0 Hz, ArH), 5.38 (1H, d, J=9.6
Hz, H-4), 5.25 (1H, d, J=14.9 Hz, Ar–CH2–N), 4.66 (1H, dd, J=9.3, 4.9 Hz, H-1), 3.45 (1H, dd, J=13.8,
4.9 Hz, C1–CH2–Ar), 3.18 (1H, dd, J=13.8, 9.3 Hz, C1–CH2–Ar), 3.14 (1H, d, J=14.7 Hz, Ar–CH2–N),
2.37 (1H, s, CH3Ar), 2.11 (1H, m, CH(CH3)2), 1.38 (3H, d, J=6.8 Hz, CH3), 0.96 (3H, d, J=6.8 Hz,
CH3). 13C NMR (CDCl3) δ: 166.5, 161.2, 151.1, 146.8, 137.3, 135.4, 134.6, 133.2, 129.7, 129.3, 128.7,
128.2, 127.8, 127.1, 126.9, 126.7, 120.0, 61.9, 60.1, 48.1, 42.0, 34.2, 21.1, 20.9, 19.3. Analysis calcd for
C29H29N3O2: C, 77.14; H, 6.47; N, 9.31. Found: C, 77.39; H, 6.61; N, 9.28.
3.14. (1R,4S)-2-Benzyl-4-isopropyl-1-p-nitrobenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione anti-7
Mp: 114–116°C (yellow solid). [α]D +67 (0.25, chloroform). IR (NaCl) ν: 1680, 1602 cm−1. 1H NMR
(CDCl3) δ: 8.18 (1H, dd, J=8.0, 1.4 Hz, H-7), 7.95 (2H, d, J=8.7 Hz, H-300,500), 7.75 (1H, ddd, J=8.4,
7.1, 1.4 Hz, H-9), 7.57 (1H, dd, J=8.4, 1.2 Hz, H-10), 7.47 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.35 (5H,
m, ArH), 6.97 (2H, d, J=8.7 Hz, H-200,600), 5.72 (1H, d, J=15.1 Hz, Ar–CH2–N), 4.95 (1H, dd, J=4.9,
3.6 Hz, H-1), 4.80 (1H, d, J=4.9 Hz, H-4), 4.16 (1H, d, J=15.1 Hz, Ar–CH2–N), 3.66 (1H, dd, J=14.5,
4.9 Hz, C1–CH2–Ar), 3.56 (1H, dd, J=14.5, 3.6 Hz, C1–CH2–Ar), 2.19 (1H, m, CH(CH3)2), 1.09 (3H, d,
J=6.7 Hz, CH3),), 0.80 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 165.5, 160.1, 149.7, 146.9, 146.3,
142.8, 135.0, 134.9, 130.0, 129.1, 128.4, 128.3, 127.3, 126.9, 126.7, 59.9, 57.9, 46.4, 37.4, 33.0, 20.1,
17.2. Analysis calcd for C28H26N4O4: C, 69.70; H, 5.43; N, 11.61. Found: C, 69.66; H, 5.33; N, 11.43.
3.15. (1S,4S)-2-Benzyl-4-isopropyl-1-p-nitrobenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione syn-7
1
[α]D +12.2 (0.25, chloroform). IR (NaCl) ν: 1679, 1602 cm−1. H NMR (CDCl3) δ: 8.26 (1H, dd,
J=8.0, 1.5 Hz, H-7), 8.18 (2H, d, J=8.7 Hz, H-300,500), 7.70 (1H, ddd, J=8.5, 7.2, 1.5 Hz, H-9), 7.47 (1H,
ddd, J=8.0, 7.2, 1.2 Hz, H-8), 7.40 (1H, dd, J=8.5, 1.2 Hz, H-10), 7.35 (2H, d, J=8.7 Hz, H-200,600), 7.24

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4283
(3H, m, ArH), 7.07 (2H, m, ArH), 5.36 (1H, d, J=9.4 Hz, H-4), 5.16 (1H, d, J=14.9 Hz, Ar–CH2–N),
4.70 (1H, dd, J=7.0, 6.7 Hz, H-1), 3.76 (1H, d, J=14.9 Hz, Ar–CH2–N), 3.46 (1H, dd, J=13.8, 6.7 Hz,
C1–CH2–Ar), 3.29 (1H, dd, J=13.8, 7.0 Hz, C1–CH2–Ar), 2.18 (1H, m, CH(CH3)2), 1.33 (3H, d, J=6.6
Hz, CH3), 1.08 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 166.3, 161.0, 149.8, 147.2, 146.5, 144.1,
135.1, 134.8, 130.3, 129.0, 128.2, 128.1, 127.3, 127.1, 126.7, 123.9, 120.0, 61.7, 60.1, 48.6, 42.2, 34.4,
20.8, 19.3. Analysis calcd for C28H26N4O4: C, 69.70; H, 5.43; N, 11.61. Found: C, 69.99; H, 5.73; N,
11.30.
3.16. (1R,4S)-2-Benzyl-1-m-chlorobenzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione anti-8
1
[α]D +30.4 (0.25, chloroform). IR (NaCl) ν: 1679, 1599 cm−1. H NMR (CDCl3) δ: 8.20 (1H, dd,
J=8.0, 1.5 Hz, H-7), 7.75 (1H, ddd, J=8.4, 7.2, 1.5 Hz, H-9), 7.62 (1H, dd, J=8.4, 1.1 Hz, H-10), 7.47
(1H, ddd, J=8.1, 7.2, 1.1 Hz, H-8), 7.35 (2H, m, ArH), 7.20 (3H, m, ArH), 7.15 (1H, ddd, J=7.4, 2.0,
1.1 Hz, H-400), 7.06 (1H, t, J=7.4 Hz, H-500), 6.67 (1H, t, J=1.6 Hz, H-200), 6.66 (1H, dd, J=7.4, 1.6 Hz,
H-500), 5.73 (1H, d, J=14.9 Hz, Ar–CH2–N), 4.88 (1H, dd, J=4.2, 3.6 Hz, H-1), 4.64 (1H, d, J=4.0 Hz,
H-4), 4.14 (1H, d, J=14.9 Hz, Ar–CH2–N), 3.52 (1H, dd, J=14.2, 4.2 Hz, C1–CH2–Ar), 3.32 (1H, dd,
J=14.2, 3.6 Hz, C1–CH2–Ar), 2.20 (1H, m, CH(CH3)2), 1.14 (3H, d, J=7.0 Hz, CH3), 0.74 (3H, d, J=7.0
Hz, CH3). 13C NMR (CDCl3) δ: 165.1, 160.1, 150.2, 146.4, 136.4, 135.1, 134.7, 134.3, 129.7, 129.4,
129.1, 128.7, 128.2, 128.1, 127.6, 127.0, 126.9, 126.7, 120.3, 59.7, 58.3, 46.4, 38.2, 33.3, 20.2, 16.8.
Analysis calcd for C28H26ClN3O2: C, 71.25; H, 5.55; N, 8.90. Found: C, 71.18; H, 5.73; N, 8.65.
3.17. (1S,4S)-2-Benzyl-1-m-chlorobenzyl-4-isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione syn-8
1
[α]D −0.4 (0.26, chloroform). IR (NaCl) ν: 1683, 1601 cm−1. H NMR (CDCl3) δ: 8.26 (1H, dd,
J=8.0, 1.5 Hz, H-7), 7.73 (1H, ddd, J=8.4, 7.2, 1.5 Hz, H-9), 7.52 (1H, dd, J=8.4, 1.1 Hz, H-10), 7.48
(1H, ddd, J=8.0, 7.2, 1.1 Hz, H-8), 7.22 (5H, m, ArH), 7.14 (2H,m, ArH), 6.98 (2H, m, ArH), 5.50
(1H, d, J=9.5 Hz, H-4), 5.35 (1H, d, J=14.9 Hz, Ar–CH2–N), 4.68 (1H, dd, J=8.5, 5.3 Hz, H-1), 3.43
(1H, dd, J=13.8, 5.3 Hz, C1–CH2–Ar), 3.40 (1H, d, J=14.9 Hz, Ar–CH2–N), 3.18 (1H, dd, J=13.9,
8.5 Hz, C1–CH2–Ar), 2.08 (1H, m, CH(CH3)2), 1.37 (3H, d, J=6.6 Hz, CH3),), 0.97 (3H, d, J=6.8 Hz,
CH3). 13C NMR (CDCl3) δ: 166.4, 161.1, 150.5, 146.6, 138.5, 134.7, 134.6, 130.2, 129.5, 128.9, 128.2,
128.0, 127.7, 127.6, 127.1, 126.7, 120.2, 61.6, 60.1, 48.3, 42.1, 34.4, 20.8, 19.4. Analysis calcd for
C28H26ClN3O2: C, 71.25; H, 5.55; N, 8.90. Found: C, 71.11; H, 5.73; N, 8.55.
3.18. (1R,4S)-2-Benzyl-4-isopropyl-1-(2-naphthyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione anti-9
1
[α]D +86 (0.26, chloroform). IR (NaCl) ν: 1680, 1599 cm−1. H NMR (CDCl3) δ: 8.17 (1H, dd,
J=8.0, 1.5 Hz, H-7), 7.79 (1H, ddd, J=8.1, 7.0, 1.5 Hz, H-9), 7.72 (1H, m, ArH), 7.65 (1H, dd, J=8.1,
1.1 Hz, H-10), 7.57 (3H, m, ArH), 7.48 (1H, ddd, J=8.0, 7.0, 1.1 Hz, H-8), 7.30 (7H, m, ArH), 7.19
(1H, s, H-100), 6.78 (1H, dd, J=8.3, 1.6 Hz, H-300), 5.77 (1H, d, J=14.8 Hz, Ar–CH2–N), 4.98 (1H, dd,
J=3.8, 3.5 Hz, H-1), 4.42 (1H, d, J=3.8 Hz, H-4), 4.25 (1H, d, J=14.9 Hz, Ar–CH2–N), 3.71 (1H, dd,
J=14.2, 3.8 Hz, C1–CH2–Ar), 3.51 (1H, dd, J=14.2, 3.5 Hz, C1–CH2–Ar), 2.15 (1H, m, CH(CH3)2),
1.08 (3H, d, J=6.9 Hz, CH3),), 0.72 (3H, d, J=6.9 Hz, CH3). 13C NMR (CDCl3) δ: 165.1, 160.0, 150.7,
146.6, 135.3, 134.7, 133.0, 132.3, 131.5, 129.0, 128.9, 128.8, 128.3, 128.2, 128.17, 128.1, 127.6, 127.3,

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126.9, 126.8, 126.75, 126.7, 126.3, 126.0, 120.3, 59.7, 58.6, 46.4, 38.8, 33.2, 20.2, 16.7. Analysis calcd
for C32H29N3O2: C, 78.83; H, 5.99; N, 8.62. Found: C, 78.43; H, 6.19, N, 8.34.
3.19. (1S,4S)-2-Benzyl-4-isopropyl-1-(2-naphthyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione syn-9
1
[α]D +18.4 (0.25, chloroform). IR (NaCl) ν: 1684, 1600 cm−1. H NMR (CDCl3) δ: 8.27 (1H, dd,
J=8.0, 1.5 Hz, H-7), 7.85 (2H, m, ArH), 7.73 (1H, ddd, J=8.4, 7.1, 1.5 Hz, H-9), 7.69 (1H, s, ArH),
7.54 (1H, dd, J=8.4, 1.3 Hz, H-10), 7.48 (4H, m, ArH), 7.44 (1H, ddd, J=8.0, 7.1, 1.3 Hz, H-8), 7.18
(3H, m, ArH), 6.88 (2H, m, ArH), 5.36 (1H, d, J=9.6 Hz, H-4), 5.21 (1H, d, J=14.9 Hz, Ar–CH2–N),
4.83 (1H, dd, J=9.2, 4.8 Hz, H-1), 3.66 (1H, dd, J=13.8, 4.8 Hz, C1–CH2–Ar), 3.39 (1H, dd, J=13.8, 9.2
Hz, C1–CH2–Ar), 3.21 (1H, d, J=14.9 Hz, Ar–CH2–N), 2.21 (1H, m, CH(CH3)2), 1.39 (3H, d, J=6.6
Hz, CH3), 0.98 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 166.5, 161.2, 151.1, 146.7, 135.3, 134.7,
133.8, 133.4, 132.5, 128.8, 128.7, 128.2, 128.17, 127.8, 127.7, 127.6, 127.1, 127.08, 127.0, 126.7, 126.5,
126.1, 120.0, 61.8, 60.1, 48.3, 42.8, 34.3, 20.9, 19.3. Analysis calcd for C32H29N3O2: C, 78.83; H, 5.99;
N, 8.62. Found: C, 78.50; H, 6.23; N, 8.31.
Acknowledgements
We thank CICYT for financial support (Project SAF97-0143).
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