New findings in the alkylation and N-deprotection of (4S)-4-methyl-2- benzyl-2,4-dihydro-1H-pyrazino [2,1-b] quinazoline-3,6-diones

Article abstract of DOI:10.1016/S0957-4166(97)00629-0

Alkyl halides behave differently to benzyl halides in C-1 alkylation of the title compounds. The syn and anti 1,4-disubstituted diastereomers thus obtained show different regioselectivity by further alkylation leading to the 1,4,4-and 1,1,4-trisubstituted compounds, respectively. Alkylation is always directed anti with respect to the bulkier substituent at C-l or C-4. Debenzylation attempts on 2-benzyl-derivatives lb by treatment with HCOOH and C/Pd or H²/C-Pd/MeOH/H⁺ led to C-1 oxidised or 7,8,9,10-tetrahydro- derivatives. Deprotection of 2-p-methoxybenzyland 2-(2,4-dimethoxybenzyl)- derivatives with CAN and with TFA/anisole, respectively, was successful, but in the latter case epimerization at C-1 occurred.

Full text of DOI:10.1016/S0957-4166(97)00629-0

Pergamon
Tetrahedron: Asymmetry 9 (1998) 483–501
New findings in the alkylation and N-deprotection of (4S)-4-
methyl-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
diones
Félix L. Buenadicha, M. Teresa Bartolomé, M. Jesús Aguirre, Carmen Avendaño∗ and
Mónica Söllhuber
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040- Madrid,
Spain
Received 4 December 1997; accepted 10 December 1997
Abstract
Alkyl halides behave differently to benzyl halides in C-1 alkylation of the title compounds. The syn and anti 1,4-
disubstituted diastereomers thus obtained show different regioselectivity by further alkylation leading to the 1,4,4-
and 1,1,4-trisubstituted compounds, respectively. Alkylation is always directed anti with respect to the bulkier
substituent at C-1 or C-4. Debenzylation attempts on 2-benzyl-derivatives 1b by treatment with HCOOH and C/Pd
or H2/C–Pd/MeOH/H+ led to C-1 oxidised or 7,8,9,10-tetrahydro-derivatives.Deprotection of 2-p-methoxybenzyl-
and 2-(2,4-dimethoxybenzyl)-derivatives with CAN and with TFA/anisole, respectively, was successful, but in the
latter case epimerization at C-1 occurred. © 1998 Elsevier Science Ltd. All rights reserved.
The 2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione system C, is a fragment of the fungal
metabolite N-acetylardeemin A, (Fig. 1) which has been described as a potent reversal agent of multiple
drug resistance (MDR) in tumour cell lines.1 A variety of fungal metabolites, such as glyantrypine,2a
fumiquinazolines F and G2b,c or fiscalin B,2d are also derivatives of C, and a convergent synthetic route
to N-acetylardeemin analogues features the cyclization of compounds B (R1=3-indolylmethyl), which
can be prepared by alkylation of N-protected derivatives C (R1=H) as the key step.3a
N-Protection of B is required in its synthesis by condensation of piperazinedione bislactim ethers and
anthranilic acid, in order to avoid formation of compounds such as 2 in the synthesis of C-1 unsubstituted
1a (Scheme 1). Furthermore, N-arylmethyl groups allow an easy manipulation of the starting piperazine-
2,5-diones, because of their increased lipophilicity, being at the same time relatively stable towards
electrophilic substitution conditions.
We have recently reported3a that compounds 1b,c (Scheme 2) are regioselectively alkylated in base
at C-1 and that the asymmetric induction of the C-4 stereocentre directs the attack of benzyl halides to
∗
Corresponding author.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(97)00629-0

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Fig. 1.
Scheme 1.
give (1R,4S)-diastereomers with an anti-configuration for the alkyl groups at C-1 and C-4. Due to 1,2-
interactions of the pseudoequatorial C-1 and N-2 substituents, the (1R,4S) anti-isomers equilibrate to the
(1S,4S) syn-isomers, which are the thermodynamic products, by deprotonation at C-1. The diastereomeric
excess is dependant on the volume of the R2 substituent, being lower for 1c derivatives.
Scheme 2.
The syn- and anti-isomers can clearly be distinguished by NOE experiments. Irradiating the C4–CH3
(Fig. 2), NOE is registered on C1–H and R1–H in anti- and syn-isomers, respectively, which suggests
a boat conformation for both isomers, with the C4-methyl group in axial or pseudoaxial disposition.
1
Different δ values for the C-4 proton in the H NMR are observed, around 5.3 ppm in the syn-isomers
and around 4 ppm in the anti-isomers. This difference shows that the pyperazine ring adopts a boat
conformation in the syn-isomers with the C-1 and C-4 substituents in a pseudoaxial disposition, the C-4
proton being strongly deshielded by the C-6 carbonyl group, while this ring is more planar in the anti-
isomers, because of the previously mentioned 1,2 steric interactions (Fig. 2).3,4

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485
Fig. 2. Conformation of the piperazine ring in 1,4-dialkyl anti- and syn-isomers
Table 1
The exclusive isolation of the syn-isomers in the alkylation with methyl iodide (Scheme 2) was
supposed to be due to a slower SN2 mechanism, compared to the SN1 reactions that occur with most
benzyl halides,5 and to a faster equilibration of 1-methyl anti-isomers with respect to the 1-benzyl
derivatives due to steric effects.6 Different experiments also suggested that the formation of racemic
(1S*, 4S*)-compounds during long reaction times was due to deprotonation at C-4 and C-1.3a Thus,
benzylation of 1c with an excess of alkylating agent during prolonged reaction times (12 h) gave lower
yields of the anti-isomers in favour of the syn-isomers, which racemized (Table 1, entries 1 and 2).
From this reaction mixture 1,1- and 1,4-dialkylated derivatives were also isolated. On the other hand,
treatment of 1c with 2 equivalents of base, benzyl bromide and DMEU as cosolvent gave exclusively the
1,1-dibenzyl derivative 18c in good yields (Table 1, entry 3).
Since 1,1- and 1,4-dialkyl compounds derive from further alkylation of the initially formed anti- or
syn-1-alkyl-diastereoisomers, it can be supposed that the regioselectivity of the second reaction depends
on the anti or syn stereochemistry of the initially formed substrates. To confirm these assumptions and to
extend the understanding of this reaction, we first studied the alkylation of 1d (R2=p-MeOC6H4–CH2).
It can be seen in Table 2 that methyl and benzyl halides behaved as expected giving syn-3d and anti-
7d as exclusive or major products, respectively. Ethyl bromoacetate and n-butyl iodide, for which an
SN2 mechanism was supposed, gave the syn-isomers 4d and 5d in great d.e., while isopropyl iodide
gave racemic 6d.7 These results confirm that SN2 reactions give the thermodynamic products and that
racemization implies C-4 anions.
Again, syn- and anti- isomers mainly differ in their δ H-4 values (∆δ=1.3 ppm for 4d and 7d). In the
case of 5d the chemical shift of H-4 is similar in both isomers suggesting a similar boat conformation.
Traces of (1R,4S)-1-hydroxy derivative 19d were also obtained, showing the sensitivity of this system to
be oxidised at C-1 (see later).
The regioselectivity of the second alkylation step was studied next. Enantiopure syn-3d was treated

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Table 2
with LHMDS and either methyl iodide or p-methylbenzyl bromide. The stereochemistry of the 1,4,4-
trialkyl derivatives thus obtained (compounds 11d and 12d, Scheme 3) showed that the diastereoselection
is imposed by the C-1 centre. The stereochemistry of the 1,1,4,4-tetra-alkyl compound 20d also showed
that additional alkylation of 12d is controlled by the bulkier substituent at C-4. An additional reactivity
confirmation for the syn-1,4-disubstituted derivatives was obtained when syn-9c was alkylated with p-
methylbenzyl bromide and 13c was produced. The configuration of all compounds was determined by
NOE experiments (see Experimental and Fig. 3).
Scheme 3.
On the other hand, when the anti-isomers 9c and 10c (Scheme 4) were treated with LHMDS and p-
fluorobenzyl or p-methylbenzyl bromide, respectively, we got, instead of the 1,4-dialkyl derivatives, the
1,1-dialkylated compounds 14c and 15c, respectively.
In conclusion, syn-1,4-dialkyl-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones are
regioselectively alkylated at C-4 while the anti-isomers are alkylated at C-1. This behaviour differs
from that of the 2-methyl analogues where both, anti- and syn- 1,4-dialkyl isomers are regioselectively

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 483–501
487
Fig. 3. NOEs registered on 12d and 20d
Scheme 4.
alkylated at C-1.3b The greater 1,2-steric interaction at the planar C-1 anion in compounds c and d
(where R2=benzyl) than in compounds b (where R2=methyl) explains the different regioselectivity of
syn-isomers in 2-methyl and 2-benzyl series.
The difficulty that N-debenzylation of amides presents in some cases is well known.8 Steglich et al.9
have studied in particular the debenzylation of peptidic benzylamides in different media, but deprotection
of model compounds 1c–e presented some interesting problems. Attempts of reductive debenzylation of
1c or 1d by treatment with 95% formic acid under argon atmosphere at rt or 50°C10 were unsuccessful
being starting compounds recovered. The same result was obtained in the treatment of 1c with formic
acid and C/Pd at rt.11 When this reaction was performed at 50°C, oxidation compounds 21c, 21d and
syn-19d were obtained.
Furthermore catalytic hydrogenation of 1c was unsuccessful with recovery of the starting material,
while hydrogenation in acidic medium (methanol/formic acid 5%) at rt and 33 psi produced partial
hydrogenation of the fused benzene ring, giving compound 22 (Scheme 5) instead of the desired reductive
debenzylation. Finally, the reductive debenzylation of 1c with sodium and liquid ammonia in THF led to
decomposition.
Scheme 5.
Debenzylation with strong organic acids, which requires benzyl groups carrying electron donor
substituents, was investigated with 1e. After several experiments we found that treatment of 1e with

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trifluoroacetic acid and anisole as a cation captor12 gave 1a in 68% yield together with traces of
21a (Scheme 6). This procedure was successful when applied to the 1-alkyl compound anti-8e but,
unfortunately, epimerization of the C-1 stereocentre also took place,13 giving syn-8a quantitatively.
Similar isomerizations at C-1 in acid media have also been observed for fumiquinazolines.14,15
Scheme 6.
These results forced us to apply the oxidative debenzylation on 1d and 1e by using CAN8b,16,17 and
DDQ.18 Reaction of 1d with DDQ (Scheme 7) gave starting compound (38%) together with the syn- and
anti-1-hydroxy-derivatives13 19d (18% and 7%, respectively) and traces of ketone 21d.
Scheme 7.
The treatment of 1d with CAN (Scheme 8) allowed the oxidative debenzylation to the desired product
1a (38%) together with 19% of debenzylated hydroxy derivative syn-19a and 7% of syn-19d. Finally, the
application of this oxidative debenzylation to the 1-alkyl derivative 8d led to the debenzylated product
anti-8a, with retention of the configuration, in acceptable yields (72% over recovered starting material).13
1. Experimental
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
1
MHz for H and 62.5 MHz for 13C in CDCl3, with TMS as the internal reference (Servicio RMN,

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 483–501
489
Scheme 8.
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 Centro de Microanálisis, U. C. M. Optical
rotations were determined at 25°C in CHCl3 or EtOH 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.
1.1. (4S)-2-(2,4-Dimethoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 1e
To a stirred solution of 3.6 g (14.2 mmol) of distilled ethyl N-(2,4-dimethoxybenzyl)glycinate19 in
40 ml dry CH2Cl2, 3.17 (14.2 mmol) of N-Cbz-L-alanine and 3.22 g (15.7 mmol) of DCC were added
and stirring was continued overnight. The reaction mixture was filtered, washed successively with HCl
(1 N), NaHCO3 (1 N) and water, dried over anhydrous Na2SO4 and evaporated. The syrupy residue (6
g, 1.31 mmol; yield 92%) was hydrogenated at 35 psi during 14 h with 0.55 g of C/Pd (10%) in 100 ml
methanol, filtered (Celite) and evaporated. The obtained syrup was refluxed in 30 ml of methanol for 12
h, concentrated and recrystallized to give (3S)-3-methyl-1-(2,4-dimethoxybenzyl)piperazine-2,5-dione
(3.83 g, 78%). Mp: 115–117°C (toluene). [α]D: +5.6 (0.30, CHCl3). IR (KBr) ν: 1690, 1654 cm−1. 1H
NMR (CDCl3) δ: 7.20 (1H, d, J=8.3 Hz, H-60), 7.19 (1H, s, NH), 6.45 (1H, dd, J=8.3, 2.4 Hz, H-50),
6.43 (1H, d, J=2.4 Hz, H-30), 4.55 (1H, d, J=14.3 Hz, Ar–CH2–N), 4.48 (1H, d, J=14.3 Hz, Ar–CH2–N),
4.05 (1H, q, J=7 Hz, H-3), 3.88 (2H, s, H-6), 3.78 (3H, s, OCH3), 3.77 (3H, s, OCH3), 1.46 (3H, d, J=7
Hz, CH3). 13C NMR (CDCl3) δ: 166.9, 166.7, 161.0, 158.8, 131.8, 116.0, 104.6, 98.5, 55.5, 51.1, 49.4,
44.1, 20.1. Analysis calc. for C14H18N2O4: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.54; H, 6.42; N,
10.12.
A mixture of 5.25 g (18.9 mmol) of the above described (3S)-3-methyl-1-(2,4-dimethoxybenzyl)-
piperazine-2,5-dione, triethyloxonium tetrafluoroborate (15 g, 79 mmol) and anhydrous Na2CO3 (11.1
g, 105 mmol) in 100 ml of dry CH2Cl2 was stirred overnight at rt, poured on ice water, extracted with
CH2Cl2, dried (Na2SO4) and evaporated. Anthranilic acid (3.85 g, 28.1 mmol) was added to the syrupy

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residue, the mixture was stirred vigorously at 130–140°C for 2.5 h under argon, dissolved in CH2Cl2,
extracted with diluted ammonium hydroxide, dried (Na2SO4) and concentrated. Column chromatography
(EtOAc:MeOH 95:5) afforded 3.87 g (54%) of 1e as a white solid. Mp: 72–73°C (ethyl acetate:methanol).
[α]D: +24.7 (0.29, CHCl3). IR (KBr) ν: 1710, 1678 cm−1. 1H NMR (CDCl3) δ: 8.26 (1H, ddd, J=7.9,
1.5, 0.5 Hz, H-7), 7.73 (1H, ddd, J=8.2, 7.1, 1.5 Hz, H-9), 7.58 (1H, ddd, J=8.2, 1.2, 0.5 Hz, H-10),
7.46 (1H, ddd, J=7.9, 7.1, 1.2 Hz, H-8), 7.23 (1H, d, J=9 Hz, H-60), 6.45 (1H, dd, J=9, 2.2 Hz, H-50),
6.45 (1H, d, J=2.2 Hz, H-30), 5.47 (1H, q, J=7.2 Hz, H-4), 4.85 (1H, d, J=14.2 Hz, Ar–CH2–N), 4.49
(1H, J=14.2 Hz, Ar–CH2–N), 4.50 (1H, d, J=17.2 Hz, H-1), 4.41 (1H, d, J=17.2 Hz, H-1), 3.81 (3H, s,
OCH3), 3.78 (3H, s, OCH3), 1.56 (3H, d, J=7.2 Hz, CH3). 13C NMR (CDCl3) δ: 167.1, 160.9, 159.9,
158.7, 148.5, 147.2, 134.6, 131.7, 127.0, 126.8, 126,7, 120.4, 115.6, 104.4, 98.4, 55.3, 55.3, 52.1, 49.3,
44.4, 16.8. Analysis calc. for C21H21N3O4: C, 66.48; H, 5.58; N, 11.07. Found: C, 66.03; H, 5.64; N,
10.74.
1.2. (ꢀ)-4-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 1a and (ꢀ)-1-methyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 2
A mixture of 1 g (7.4 mmol) of (ꢀ)-3-methylpiperazine-2,5-dione, triethyloxonium tetrafluoroborate
(4 g, 22 mmol) and anhydrous Na2CO3 (3.9 g, 37 mmol) in 100 ml dry CH2Cl2 was stirred for 3
days at room temperature, poured on ice water, extracted with CH2Cl2, dried over anhydrous Na2SO4
and evaporated. Anthranilic acid (1.2 g, 8.7 mmol) was added to the syrupy residue, the mixture was
stirred vigorously at 130°C for 2.5 h under argon, dissolved in CHCl3, extracted with diluted ammonium
hydroxide, dried (Na2SO4) and concentrated. Column chromatography (EtOAc:MeOH 95:5) afforded
160 mg (9%) of (ꢀ)-1a and 250 mg (14%) of (ꢀ)-2.
1.2.1. Data for (ꢀ)-1a
Mp: 216–218°C (CHCl3:methanol:hexane). Spectral data identical to (+)-1a (see later). Analysis calc.
for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.98; H, 4.70; N, 18.46.
1.2.2. Data for (ꢀ)-2
Mp: 240–243°C (CHCl3:methanol:hexane). IR (KBr) ν: 1684 cm−1. 1H NMR (CDCl3:MeOD) δ: 7.95
(1H, ddd, J=7.9, 1.5, 0.6 Hz, H-7), 7.55 (1H, ddd, J=8.2, 7.1, 1.5 Hz, H-9), 7.40 (1H, ddd, J=8.2, 1.2,
0.6 Hz, H-10), 7.25 (1H, ddd, J=7.9, 7.1, 1.2 Hz, H-8), 4.52 (1H, d, J=18 Hz, H-4), 4.40 (1H, q, J=7 Hz,
H-1), 4.35 (1H, d, J=18.0 Hz, H-4), 1.45 (3H, d, J=7.0 Hz, CH3). 13C NMR (CDCl3:MeOD) δ: 166.5
(C-3), 160.8 (C-6), 151.8 (C-11a), 146.9 (C-10a), 134.8 (C-9), 127.2, 126.8 and 126.4 (C-7, 8 and 10),
119.6 (C-6a), 51.1 (C-4), 44.2 (C-1), 19.8 (CH3). Analysis calc. for C12H11N3O2: C, 62.87; H, 4.84; N,
18.33. Found: C, 63.09; H, 4.63; N, 18.57.
1.3. General alkylation procedures
Method A: To a cold (−78°C), magnetically stirred solution of 1 mmol of 1d20 (if not otherwise
indicated) in dry THF (15 ml) was added, under argon, drop wise via syringe a 1 M solution of lithium
hexamethyldisilazide in THF (1 ml), followed by the adequate halide (1.1 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 30 min
(if not indicated otherwise) quenched with a cold saturated ammonium chloride solution and diluted
with CH2Cl2. The separated aqueous layer was extracted with CH2Cl2 (3×20 ml) and the combined
organic layers were washed with water, dried and evaporated. Chromatography of the residue on silica

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491
gel provided first the 1,4-dialkylated and 1,1-dialkylated, if any, followed by the anti-1-alkylated and
syn-1-alkylated compounds.
Method B: To a cold (−78°C), magnetically stirred solution the corresponding 2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione (0.5 mmol) and 1,3-dimethylimidazolidin-2-one (DMEU) (0.5
mmol) in dry THF (15 ml) was added, under argon, drop wise via syringe a 1 M solution of lithium
hexamethyldisilazide in THF (0.6 ml), followed by the adequate halide (0.6 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 30 min and
worked up as indicated for Method A.
Method C: To a cold (−78°C), magnetically stirred solution of 1c3a (0.5 mmol) and 1,3-
dimethylimidazolidin-2-one (DMEU) (1 mmol) in dry THF (15 ml) was added, under argon, drop
wise via syringe a 1 M solution of lithium hexamethyldisilazide in THF (1.1 ml), followed by the
adequate halide (1.1 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 30 min and worked up as indicated for Method A.
1.4. (1S,4S)-1,4-Dimethyl-2-p-methoxybenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
(syn-3d) and (1S)-2-p-methoxybenzyl-1,4,4-trimethyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 11d
Method A: Column chromatography (ethyl acetate:petroleum ether 7:3) affords syn-3d and 11d.
Method B: Starting from syn-3d, 11d was obtained in 33% yield.
1.4.1. Data for syn-3d
Mp: 122–124°C (ethyl acetate:petroleum ether). [α]D: +23.0 (0.14, chloroform). IR (KBr) ν: 1684,
1659, 1602 cm−1. 1H NMR (CDCl3) δ: 8.21 (1H, dd, J=8.0, 1.1 Hz, H-7), 7.69 (1H, ddd, J=7.7, 7.1, 1.1
Hz, H-9), 7.51 (1H, dd, J=7.7, 1.2, H-10), 7.42 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.21 (2H, d, J=8.7
Hz, H-20 and 60), 6.81 (2H, d, J=8.7 Hz, H-30 and 50), 5.37 (1H, q, J=7.2 Hz, H-4), 5.23 (1H, d, J=14.7
Hz, Ar–CH2–N), 5.11 (1H, q, J=7.1 Hz, H-1), 4.07 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.73 (3H, s, OCH3),
1.72 (3H, d, J=7.2 Hz, CH3 (4)), 1.62 (3H, d, J=7.1 Hz, CH3). 13C NMR (CDCl3) δ: 167.1, 160.4, 159.6,
151.8, 147.4, 134.8, 130.0, 127.6, 127.1, 126.9, 126.8, 120.3, 114.5, 55.5, 55.4, 52.3, 47.1, 21.4, 18.5.
Analysis calc. for C21H21N3O3: C, 69.41; H; 5.82; N, 11.56. Found: C, 69.05; H, 6.05; N, 11.34.
1.4.2. Data for 11d
Mp: 61–62°C (ethyl acetate:petroleum ether). [α]D: −1.3 (0.35, dichloromethane). IR (KBr) ν: 1683,
1600 cm−1. 1H NMR (CDCl3) δ: 8.20 (1H, dd, J=8.0, 1.2 Hz, H-7), 7.68 (1H, ddd, J=8.5, 7.6, 1.2 Hz,
H-9), 7.48 (1H, dd, J=7.6, 1.1 Hz, H-10), 7.41 (1H, ddd, J=8.5, 8.0, 1.1 Hz, H-8), 7.20 (2H, d, J=8.7
Hz, H-20 and 60), 6.84 (2H, d, J=8.7 Hz, H-30 and 50), 5.31 (1H, d, J=14.7 Hz, Ar–CH2–N), 4.48 (1H, q,
J=6.7 Hz, H-1), 4.02 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.76 (3H, s, OCH3), 2.08 (3H, s, CH3), 2.04 (3H,
s, CH3), 1.53 (3H, d, J=6.7 Hz, CH3). 13C NMR (CDCl3) δ: 170.3, 162.2, 159.6, 151.8, 146.7, 134.6,
129.8, 127.7, 127.0, 126.9, 126.4, 121.8, 114.5, 64.4, 55.4, 55.0, 47.5, 25.3, 24.8, 22.3. Analysis calc. for
C22H23N3O3: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.83; H, 6.12; N, 10.99.
1.5. (1R,4S)-1-Ethoxycarbonylmethyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione (anti-4d) and (1S,4S)-1-ethoxycarbonylmethyl-2-p-methoxybenzyl-4-methyl-2,
4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (syn-4d)
Method A: Column chromatography: ethyl acetate:petroleum ether (7:3).

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1.5.1. Data for anti-4d
1H NMR (CDCl3) δ: 8.00 (1H, dd, J=8.0, 1.2 Hz, H-7), 7.76 (1H, ddd, J=7.6, 7.1, 1.2 Hz, H-9), 7.60
(1H, dd, J=7.6, 1.2 Hz, H-10), 7.48 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.20 (2H, d, J=8.7 Hz, H-20 and
60), 6.88 (2H, d, J=8.7 Hz, H-30 and 50), 5.60 (1H, d, J=15.5 Hz, Ar–CH2–N), 4.91 (1H, dd, J=6.2, 3.9
Hz, H-1), 4.08 (2H, q, J=7.1 Hz, O–CH2–CH3), 4.00 (1H, q, J=6.6 Hz, H-4), 3.88 (1H, d, J=15.5 Hz,
Ar–CH2–N), 3.79 (3H, s, OCH3), 3.27 (1H, dd, J=16.6, 3.9 Hz, H-α), 3.18 (1H, dd, J=16.6, 6.2 Hz, H-
α), 1.40 (3H, d, J=6.6 Hz, CH3), 1.18 (3H, J=7.1 Hz, OCH2–CH3). 13C NMR (CDCl3) δ: 169.9, 167.7,
159.7, 159.0, 145.5, 145.0, 135.6, 128.8, 128.1, 127.7, 126.8, 126.7, 120.2, 114.7, 61.7, 55.3, 54.3, 52.3,
46.4, 41.4, 18.5, 14.3.
1.5.2. Data for syn-4d
[α]D: +17.3 (0.45, chloroform). IR (NaCl) ν: 1732, 1684, 1610 cm−1. 1H NMR (CDCl3) δ: 8.21 (1H,
dd, J=8.0, 1.1 Hz, H-7), 7.68 (1H, ddd, J=7.6, 7.1, 1.1 Hz, H-9), 7.51 (1H, dd, J=7.6, 1.2 Hz, H-10),
7.42 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.24 (2H, d, J=8.7 Hz, H-20 and 60), 6.82 (2H, d, J=8.7 Hz,
H-30 and 50), 5.37 (1H, q, J=7.2 Hz, H-4), 5.19 (1H, d, J=14.6 Hz, Ar–CH2–N), 5.02 (1H, 0t0, J=6.4 Hz,
H-1), 4.33 (1H, d, J=14.6 Hz, Ar–CH2–N), 4.07 (2H, q, J=7.1 Hz, O–CH2–CH3), 3.73 (3H, s, OCH3),
2.86 (1H, dd, J=15.2, 6.6 Hz, H-α), 2.93 (1H, dd, J=15.2, 6.6 Hz, H-α), 1.73 (3H, d, J=7.2 Hz, CH3),
1.20 (3H, J=7.1 Hz, OCH2–CH3). NOE (δ; %): irradiate Me (1.73), observe H-α (2.93; 2.1) and H-4
(5.37; 8.9). 13C NMR (CDCl3) δ: 169.4, 167.2, 160.3, 159.6, 149.9, 147.2, 134.8, 130.1, 127.5, 127.3,
127.2, 126.8, 120.4, 114.4, 61.7, 56.7, 55.3, 52.2, 47.5, 41.4, 19.1, 14.2. Analysis calc. for C24H25N3O5:
C, 69.19; H, 5.79; N, 9.65. Found: C, 69.35; H, 5.71; N, 9.57.
1.6. (1R,4S)-1-n-Butyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-
3,6-dione (anti-5d), (1S,4S)-1-n-butyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino-[2,1-
b]quinazoline-3,6-dione (syn-5d) and (1R,4S)-1-hydroxy-4-methyl-2-p-methoxybenzyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione anti-19d
Method A: Reaction time: 2 h at −78°C and 4 h at 0°C; column chromatography (ethyl ac-
etate:petroleum ether 6:4).
1.6.1. Data for anti-5d
Mp: 129–131°C (ethyl ether). [α]D: +50 (0.18, chloroform). IR (KBr) ν: 1682, 1610 cm−1. 1H NMR
(CDCl3) δ: 8.24 (1H, dd, J=8.0, 1.2 Hz, H-7), 7.73 (1H, ddd, J=8.1, 7.9, 1.2 Hz, H-9), 7.57 (1H, dd,
J=7.9, 1.1 Hz, H-10), 7.45 (1H, ddd, J=8.1, 8.0, 1.1 Hz, H-8), 7.21 (2H, d, J=8.6 Hz, H-20 and 60), 6.87
(2H, d, J=8.6 Hz, H-30 and 50), 5.64 (1H, d, J=14.8 Hz, Ar–CH2–N), 5.36 (1H, q, J=6.7 Hz, H-4), 4.53
(1H, dd, J=4.7, 1.9 Hz, H-1), 3.86 (1H, d, J=14.8 Hz, Ar–CH2–N), 3.78 (3H, s, OCH3), 2.31–2.12 (2H,
m, H-α), 1.67 (3H, d, J=6.7 Hz, CH3), 1.22 (4H, m, H-β and γ), 1.22 (3H, m, H-δ). 13C NMR (CDCl3)
δ: 168.0, 160.5, 159.5, 150.3, 147.2, 134.8, 129.5, 127.6, 127.1, 127.0, 126.9, 120.4, 114.5, 57.1, 55.4,
52.0, 45.3, 31.8, 24.8, 22.6, 20.4, 14.0. Analysis calc. for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36.
Found: C, 70.86; H, 6.71; N, 10.22.
1.6.2. Data for syn-5d
Mp: 109–110°C (ethyl ether). [α]D: +3.4 (0.30, chloroform). IR (KBr) ν: 1668, 1603 cm−1. 1H NMR
(CDCl3) δ: 8.26 (1H, dd, J=8.0, 1.3 Hz, H-7), 7.72 (1H, ddd, J=7.6, 7.2, 1.3 Hz, H-9), 7.57 (1H, dd,
J=7.6, 1.2 Hz, H-10), 7.45 (1H, ddd, J=8.0, 7.2, 1.2 Hz, H-8), 7.18 (2H, d, J=8.7 Hz, H-20 and 60), 6.83
(2H, d, J=8.7 Hz, H-30 and 50), 5.37 (1H, q, J=7.2 Hz, H-4), 5.34 (1H, d, J=14.7 Hz, Ar–CH2–N), 4.35

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493
(1H, dd, J=8.8, J=5.1 Hz, H-1), 4.02 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.76 (3H, s, OCH3), 1.91 (2H, m,
H-α), 1.76 (3H, d, J=7.2 Hz, CH3), 1.50 (2H, m, H-β), 1.23 (2H, m, H-γ), 0.87 (3H, t, J=7.1 Hz, H-δ).
NOE (δ; %): irradiate Me-4 (1.76), observe H-α (1.91; 1.1) and H-4 (5.41; 6.9). 13C NMR (CDCl3) δ:
167.4, 160.6, 159.6, 150.6, 147.2, 134.7, 129.9, 127.6, 127.2, 127.1, 126.8, 120.5, 114.5, 59.7, 55.4, 52.6,
47.6, 35.8, 28.6, 22.5, 19.3, 13.9. Analysis calc. for C24H27N3O3: C, 71.09; H, 6.71; N, 10.36. Found: C,
70.93; H, 6.74; N, 10.18.
1.6.3. Data for anti-19d
Mp: 164–166°C (dichloromethane:ethyl acetate). [α]D: +45.9 (0.31, dichloromethane). IR (KBr) ν:
1682, 1609cm−1. 1H NMR (CDCl3) δ: 8.25 (1H, dd, J=8.0, 1.6 Hz, H-7), 7.72 (1H, ddd, J=8.2, 7.1, 1.6
Hz, H-9), 7.52 (1H, dd, J=8.2, 1.2 Hz, H-10), 7.48 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 7.22 (2H, d, J=8.7
Hz, H-20 and 60), 6.80 (2H, d, J=8.7 Hz, H-30 and 50), 5.72 (1H, s, H-1), 5.41 (1H, q, J=7.1 Hz, H-4),
5.25 (1H, s, OH), 5.05 (1H, d, J=15.6 Hz, Ar–CH2–N), 4.44 (1H, d, J=15.6 Hz, Ar–CH2–N), 3.71 (3H,
s, OCH3), 1.83 (3H, d, J=7.1 Hz, CH3). NOE (δ; %): irradiate Me-4 (1.83), observe H-4 (5.41; 6.1) and
H-1 (5.72; 3). 13C NMR (CDCl3) δ: 169,3, 159.7, 159.6, 149.7, 146.6, 134.9, 130.2, 127.6, 127.9, 127.0,
126.8, 120.8, 114.5, 79.5, 55.3, 52.8, 47.3, 19.5. Analysis calc. for C20H19N3O4: C, 65.74; H, 5.24; N,
11.50. Found: C, 65.22; H, 5.20; N, 11.60.
1.7. (1S*,4S*)-1-Isopropyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-
3,6-dione (ꢀ)-syn-6d
Method A: Reaction time 2 h at −78°C and 4 h at 0°C; column chromatography (ethyl ac-
1
etate:petroleum ether 7:3). Mp: 153–155°C (ethyl ether). IR (KBr) ν: 1682, 1604 cm−1. H NMR
(CDCl3) δ: 8.24 (1H, dd, J=8.0, 1.2 Hz, H-7), 7.71 (1H, ddd, J=7.6 Hz, 7.1, 1.2 Hz, H-9), 7.57 (1H,
dd, J=7.6, 1.1 Hz, H-10), 7.45 (1H, ddd, J=8.0, 7.1, 1.1 Hz, H-8), 7.12 (2H, d, J=8.6 Hz, H-20 and 60),
6.79 (2H, d, J=8.6 Hz, H-30 and 50), 5.56 (1H, d, J=14.8 Hz, Ar–CH2–N), 5.34 (1H, q, J=7.2 Hz, H-4),
4.11 (1H, d, J=9 Hz, H-1), 3.90 (1H, d, J=14.8 Hz, Ar–CH2–N), 3.72 (3H, s, OCH3), 2.24 (1H, m, H-α),
1.79 (3H, d, J=7.2 Hz, CH3), 1.24 (3H, d, J=6.8 Hz, CH(CH3)2), 1.05 (3H, d, J=6.7 Hz, CH(CH3)2).
NOE (δ; %): irradiate Me-4 (1.79), observe H-4 (5.34; 6.2) and H-α (2.24; 3.4). 13C NMR (CDCl3)
δ: 167.8, 160.6, 159.2, 150.1, 146.8, 134.5, 129.4, 127.3, 127.1, 126.9, 126.5, 120.2, 114.2, 65.5, 55.1,
52.9, 49.8, 35.9, 20.6, 20.3, 18.5. Analysis calc. for C23H25N3O3: C, 70.57; H, 6.44; N, 10.73. Found: C,
70.23; H, 6.39; N, 10.58.
1.8. (1R,4S)-1-Benzyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino-[2,1-b]quinazoline-3,
6-dione (anti-7d) and (1S,4S)-1-benzyl-2-p-methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino-[2,
1-b]quinazoline-3,6-dione (syn-7d)
Method A: Column chromatography (ethyl acetate:petroleum ether 7:3).
1.8.1. Data for anti-7d
[α]D: +6.8 (0.34, dichloromethane). IR (NaCl) ν: 1683, 1659, 1610 cm−1. 1H NMR (CDCl3) δ: 8.14
(1H, dd, J=8.0, 1.3 Hz, H-7), 7.65 (1H, ddd, J=7.6, 7.0, 1.3 Hz, H-9), 7.58 (1H, dd, J=7.6, 1.1, H-10),
7.41 (1H, ddd, J=8.0, 7.0, 1.0 Hz, H-8), 7.23 (2H, d, J=8.6 Hz, H-20 and 60), 7.09 (3H, m, Ph), 6.87 (2H,
d, J=8.6 Hz, H-30 and 50), 6.63 (2H, m, Ph), 5.67 (1H, d, J=14.7 Hz, Ar–CH2–N), 4.68 (1H, ‘t’, J=3.5
Hz, H-1), 4.03 (1H, q, J=6.7 Hz, H-4), 4.00 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.75 (3H, s, OCH3), 3.40
(1H, dd, J=13.8, 3.5 Hz, H-α), 3.22 (1H, dd, J=13.8 Hz, 3.5 Hz, H-α), 1.50 (3H, d, J=6.7 Hz, CH3).

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13C NMR (CDCl3) δ: 167.6, 160.2, 159.7, 149.9, 146.8, 134.8, 133.7, 129.9, 129.6, 128.7, 127.9, 127.3,
127.0, 126.8, 126.7, 120.5, 114.6, 59.8, 55.4, 52.1, 46.1, 39.8, 20.6. Analysis calc. for C27H25N3O3: C,
73.79; H, 5.73; N, 9.56. Found: C, 74.01; H, 5.80; N, 10.00.
1.8.2. Data for syn-7d
[α]D: +47.3 (0.66, chloroform). IR (NaCl) ν: 1684, 1662, 1610 cm−1. 1H NMR (CDCl3) δ: 8.18 (1H,
dd, J=8.0, 1.3 Hz, H-7), 7.68 (1H, ddd, J=7.6, 7.0, 1.3 Hz, H-9), 7.50 (1H, dd, J=7.6, 1.0 Hz, H-10),
7.41 (1H, ddd, J=8.0, 7.0, 1.0 Hz, H-8), 7.20 (2H, d, J=8.6 Hz, H-20 and 60), 7.05 (5H, m, Ph), 6.70 (2H,
d, J=8.6 Hz, H-30 and 50), 5.38 (1H, d, J=14.7 Hz, Ar–CH2–N), 5.25 (1H, q, J=7.2 Hz, H-4), 4.72 (1H,
dd, J=7.0, 4.9 Hz, H-1), 3.95 (1H, d, J=14.7 Hz, Ar–CH2–N), 3.66 (3H, s, OCH3), 3.38 (1H, dd, J=13.8,
4.9 Hz, H-α), 3.30 (1H, dd, J=13.8, 3.5 Hz, H-α), 1.18 (3H, d, J=7.2 Hz, CH3). 13C NMR (CDCl3) δ:
167.2, 160.1, 159.4, 150.4, 147.2, 135.7, 134.7, 130.0, 129.2, 128.9, 127.8, 127.2, 127.0, 126.9, 126.8,
120.3, 114.4, 60.7, 55.2, 52.3, 47.1, 41.4, 18.4. Analysis calc. for C27H25N3O3: C, 73.79; H, 5.73; N,
9.56. Found: C, 73.33; H, 5.71; N, 9.21.
1.9. (1R,4S)-2-(p-Methoxybenzyl)-4-methyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione (anti-8d)
Method A: Starting from 1d,20 syn- and anti-8d were obtained; column chromatography
(CH2Cl2:petroleum ether 9:1). Yield: 234 mg (52%). Mp: 167–168°C (CH2Cl2:petroleum ether).
[α]D: +97.2 (0.43, CH2Cl2). IR (KBr) ν: 1682, 1665 cm−1. 1H NMR (CDCl3) δ: 8.20 (1H, dd, J=8.0,
1.3 Hz, H-7), 7.77 (1H, ddd, J=8, 7.1, 1.3 Hz, H-9), 7.61 (1H, dd, J=8, 1.2 Hz, H-10), 7.47 (1H, ddd,
J=8.0, 7.1, 1.2 Hz, H-8), 7.27 (2H, d, J=8.5 Hz, H-20 and 60), 6.93 (2H, d, J=7.8 Hz, H-300 and 500),
6.91 (2H, d, J=8.5 Hz, H-30 and 50), 6.55 (2H, d, J=7.9 Hz, H-200 and 600), 5.72 (1H, d, J=14.6 Hz,
Ar–CH2–N), 4.80 (1H, ‘t’, J=3.5 Hz, H-1), 4.06 (1H, q, J=6.7 Hz, H-4), 4.02 (1H, d, J=14.6 Hz,
Ar–CH2–N), 3.81 (3H, s, OCH3), 3.42 (1H, dd, J=13.9, 3.9 Hz, H-α), 3.27 (1H, dd, J=13.8, 3.2 Hz,
H-α) 2.26 (3H, s, CH3–Ar), 1.55 (3H, d, J=6.6 Hz, CH3). 13C NMR (CDCl3) δ: 167.7, 160.3, 160.3,
159.7, 150.2, 146.9, 137.8, 134.8, 130.3, 129.6, 129.5, 129.5, 127.4, 127.0, 126.9, 120.6, 114.6, 59.0,
55.4, 52.2, 46.1, 39.5, 21.2, 20.8. Analysis calc. for C28H27N3O3: C, 74.15; H, 6.00; N, 9.26. Found: C,
74.31; H; 6.27; N; 9.48.
1.10. (1R,4S)-2-(2,4-Dimethoxybenzyl)-4-methyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione (anti-8e)
Method A: Starting from 1e, syn- and anti-8e were obtained; column chromatography (CH2Cl2:EtAcO
9:1). Yield: 361 mg (75%). Mp: 127–129°C (ethyl ether). [α]D: +85.6 (0.25, CH2Cl2). IR (KBr) ν: 1685,
1666 cm−1. 1H NMR (CDCl3) δ: 8.16 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.76 (1H, ddd, J=7.7, 7.2, 1.5 Hz,
H-9), 7.61 (1H, dd, J=7.7, 1.2 Hz, H-10), 7.45 (1H, ddd, J=8.0, 7.2, 1.2 Hz, H-8), 7.24 (1H, d, J=8.9 Hz,
H-60), 6.91 (2H, d, J=7.8 Hz, H-300 and 500), 6.53 (2H, d, J=7.8 Hz, H-200 and 600), 6.48 (1H, dd, J=8.9,
2.3 Hz, H-30), 6.48 (1H, d, J=2.3 Hz, H-50), 5.26 (1H, d, J=14.4 Hz, Ar–CH2–N), 4.82 (1H, ‘t’, J=3.9,
3.2 Hz, H-1), 4.24 (1H, d, J=14.4 Hz, Ar–CH2–N), 4.00 (1H, q, J=6.6 Hz, H-4), 3.46 (1H, dd, J=13.8,
3.9 Hz, H-α), 3.18 (1H, dd, J=13.8, 3.2 Hz, H-α) 3.82 (3H, s, OCH3), 3.80 (3H, s, OCH3), 2.32 (3H, s,
CH3–Ar), 1.48 (3H, d, J=6.6 Hz, CH3). 13C NMR (CDCl3) δ: 167.3, 161.1, 160.3, 159.1, 150.6, 146.9,
137.6, 134.7, 131.7, 130.6, 129.6, 129.4, 126.9, 126.8, 126.6, 120.5, 115.8, 104.7, 98.8, 59.3, 55.6, 55.6,
52.2, 41.6, 40.0, 21.2, 20.8. Analysis calc. for C29H29N3O4: C, 72.03; H, 6.04; N, 8.69. Found: C, 71.81;
H; 6.25; N; 8.48.

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1.11. (1S,4R)-1,4-Dimethyl-2-p-methoxybenzyl-4-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione 12d and (1S,4R)-1,4-bis(p-methylbenzyl)-1,4-dimethyl-2-p-methoxybenzyl-2,4-
dihydro-1H-pyrazino-[2,1-b]quinazoline-3,6-dione 20d
Method B: Starting from syn-3d, 12d and 20d were obtained; column chromatography (ethyl ac-
etate:petroleum ether 6:4).
1.11.1. Data for 12d
Mp: 138–140°C (ethyl acetate:petroleum ether). [α]D: −162.2 (0.29, chloroform). IR (KBr) ν: 1683,
1601 cm−1. 1H NMR (CDCl3) δ: 8.33 (1H, dd, J=7.9, 1.5 Hz, H-7), 7.72 (1H, ddd, J=8.2, 7.9, 1.5 Hz,
H-9), 7.49 (1H, ddd, J=8.2, 7.9, 1.1 Hz, H-8), 7.46 (1H, dd, J=7.9, 1.1 Hz, H-10), 6.77 (8H, m, Ar–H),
5.37 (1H, d, J=14.8 Hz, Ar–CH2–N), 4.39 (1H, d, J=13.8 Hz, H-α), 4.13 (1H, q, J=6.8 Hz, H-1), 3.88
(1H, d, J=14.8 Hz, Ar–CH2–N), 3.79 (3H, s, OCH3), 3.62 (1H, d, J=13.8 Hz, H-α), 2.22 (3H, s, CH3
(4)), 2.19 (3H, s, CH3), 1.48 (3H, d, J=6.8 Hz, CH3). NOE (δ; %): irradiate Me-4 (2.22), observe Me-1
(1.48; 4.2), H-α (3.62; 3.5) and H-α (3.79; 3.5). 13C NMR (CDCl3) δ: 168.6, 162.7, 159.4, 152.0, 146.5,
136.3, 134.6, 133.2, 129.7, 129.6, 129.0, 127.1, 127.0, 126.5, 126.9, 121.3, 114.2, 69.2, 55.4, 54.1, 46.9,
40.0, 24.9, 22.4, 21.1. Analysis calc. for C29H29N3O3: C, 74.50; H, 6.25; N, 8.99. Found: C, 74.04; H,
6.31; N, 8.87.
1.11.2. Data for 20d
[α]D: +48.7 (0.27, dichloromethane). IR (NaCl) ν: 1683, 1650, 1610 cm−1. 1H NMR (CDCl3) δ: 8.30
(1H, dd, J=7.9, 1.5 Hz, H-7), 7.80 (1H, ddd, J=7.9, 7.6, 1.5 Hz, H-9), 7.67 (1H, d, J=7.6, 1.3 Hz, H-10),
7.52 (1H, ddd, J=7.9, 7.9, 1.3 Hz, H-8), 7.30 (2H, d, J=8.7z, H-20 and 60), 6.90 (2H, d, J=8.0 Hz, H-3
and 5 Ar (1)), 6.85 (2H, d, J=8.7 Hz, H-30 and 50), 6.60 (2H, d, J=7.8 Hz, H-3 and 5 Ar (4)), 6.51 (2H,
d, J=8.0 Hz, H-2 and 6 Ar (1)), 6.40 (2H, d, J=7.8 Hz, H-2 and 6 Ar (4)), 5.13 (1H, d, J=14.6 Hz,
Ar–CH2–N), 4.35 (1H, d, J=14.6 Hz, Ar–CH2–N), 4.09 (1H, d, J=13.7 Hz, H-α4), 3.85 (3H, s, OCH3),
3.33 (1H, d, J=13.7 Hz, H-α1), 3.20 (2H, d, J=13.7 Hz, H-α and α0), 2.20 (3H, s, CH3), 2.13 (3H, s,
CH3), 1.54 (3H, s, CH3 (1)), 1.19 (3H, s, CH3 (4)). NOE (δ; %): irradiate Me-4 (1.19), observe H-α4
(3.20; 5), H-α4 (4.09; 4.7), H–Ar (1) (6.51; 2.8) and H–Ar (1) (6.90; 5.3), irradiate Me-1 (1.54), observe
H-α1 (3.20 and 3.33; 6.4), N–CH2–Ar (4.35; 4.9), H–Ar (4) (6.40; 4.2), H–Ar (4) (6.60; 2.2) and H-20
and 60 (7.30; 11.6). 13C NMR (CDCl3) δ: 168.8, 161.9, 158.6, 153.6, 146.2, 137.1, 135.8, 134.3, 133.3,
131.9, 130.9, 129.6, 129.5, 129.4, 129.3, 128.9, 126.8, 126.7, 121.1, 113.2, 67.5, 66.7, 55.4, 47.7, 47.6,
41.1, 30.4, 29.2, 23.9, 21.0. Analysis calc. for C37H37N3O3: C, 77.73; H, 6.52; N, 7.35. Found: C, 77.60;
H, 6.71; N, 7.70.
1.12. (1S,4R)-2-Benzyl-1,4-bis(p-methylbenzyl)-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-
3,6-dione 13c
Method A: Starting from syn-9c,3a 13c was obtained after column chromatography (ethyl ac-
1
etate:petroleum ether 8:2). [α]D: −137 (0.10, chloroform). IR (KBr) ν: 1684, 1648 cm−1. H NMR
(CDCl3) δ: 8.3 (1H, dd, J=8.1, 1.1, H-7), 7.7 (1H, ddd, J=8.1, 8.1, 1.5 Hz, H-9), 7.5 (1H, dd, J=8.1, 1.5
Hz, H-10), 7.5 (1H, ddd, J=8.1, 8.1, 1.1 Hz, H-8), 7.25 (3H, m, ArH), 7.0 (2H, d, J=8.3 Hz, H-300,500),
6.8 (2H, m, ArH), 6.7 (d, J=8.3 Hz, 2H, H-30,50), 6.6 (d, J=8.3 Hz, 2H, H-200,600), 6.6 (d, J=8.3 Hz,
2H, H-20,60), 5.62 (d, J=14.9 Hz, 1H, CH2–N), 4.36 (1H, t, J=4.2 Hz, H-1), 4.17 (1H, d, J=13.8 Hz,
CH2-4), 3.93 (1H, dd, J=14.9 Hz, CH2-N), 3.34 (1H, d, J=13.8 Hz, CH2-4), 3.17 (1H, dd, J=13.9, 4.1
Hz, CH2-1), 3.12 (1H, dd, J=13.9, 4.3 Hz, CH2-1), 2.23 (3H, s, CH3), 2.19 (3H, s, CH3), 1.42 (3H, s,

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CH3). 13C NMR (CDCl3) δ: 168.7, 162.2, 150.9, 146.4, 138.5, 137.6, 136.1, 134.4, 133.3, 131.3, 129.8,
129.6, 129.1, 129, 128.9, 127.1, 127, 126.4, 121.5, 68.8, 58.8, 47.3, 40.7, 39.8, 21.4, 21.2, 21.1. Analysis
calc. for C35H33N3O2: C, 79.67; H, 6.30; N, 7.96. Found C, 79.98; H, 6.55; N, 7.68.
1.13. (1R,4S)-2-Benzyl-4-methyl-1-p-methylbenzyl-1-p-fluorobenzyl-2,4-dihydro-1H-pyrazino[2,
1-b]quinazoline-3,6-dione 14c
Method A: Starting from anti-9c,3a 14c (1.2 h at 0°C) was obtained after column chromatography
(dichloromethane:ethyl acetate, 9:1). [α]D: +16.6 (0.25, chloroform). IR (NaCl) ν: 1683, 1662, 1609
cm−1. 1H NMR (CDCl3) δ: 8.17 (1H, dd, J=9.0, 1.4 Hz, H-7), 7.80 (1H, ddd, J=7.0, 8.2, 1.4 Hz, H-9),
7.77 (1H, dd, J=8.1, 1.1 Hz, H-10), 7.45 (1H, ddd, J=8.1, 7.0, 1.1 Hz, H-8), 7.37 (2H, m, ArH), 7.25
(3H, m, ArH), 6.78 (2H, d, J=7.9 Hz, H-3 and 5 ArMe), 6.51 (4H, m, ArF), 6.50 (2H, d, J=7.9 Hz, H-2
and 6 ArF), 5.08 (1H, d, J=15.4 Hz, Ar–CH2–N), 4.98 (1H, d, J=15.4 Hz, Ar–CH2–N), 4.55 (1H, q,
J=6.8 Hz, H-4), 3.90 (2H, d, J≈14.4 Hz, C1–CH2–Ar), 3.53 (1H, d, J=14.7 Hz, C1–CH2–Ar–F), 3.45
(1H, d, J=14.1 Hz, C1–CH2–Ar–Me), 2.13 (3H, s, CH3), 0.73 (3H, d, J=6.8 Hz). NOE (δ; %): irradiate
Me-4 (0.73), observe H-2 and 6 ArMe (6.50; 0.5) and H-4 (4.55; 7.7). 13C NMR (CDCl3) δ: 168.4, 161.5
(d, J=246 Hz), 159.9, 151.9, 146.6, 137.5, 137.0, 134.7, 131.7, 130.7 (d, J=8 Hz), 130.4 (d, J=3.5 Hz),
130.2, 129.1, 128.5, 127.5, 127.0, 126.9, 126.6, 119.9, 114.9 (d, J=21 Hz), 72.7, 51.1, 47.3, 45.7, 44.9,
20.7, 19.1. Analysis calc. for C34H30N3O2F: C, 76.81; H, 5.68; N, 7.90. Found: C, 76.77; H, 5.43; N,
7.56.
1.14. (1S,4S)-2-Benzyl-4-methyl-1-p-methylbenzyl-1-p-fluorobenzyl-2,4-dihydro-1H-pyrazino[2,
1-b]quinazoline-3,6-dione 15c
Method A: Starting from anti-10c,3a 15c was obtained after column chromatography
(dichloromethane:ethyl acetate, 9:1). [α]D: +38.8 (0.26, chloroform). IR (NaCl) ν: 1674, 1656,
1607 cm−1. 1H NMR (CDCl3) δ: 8.20 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.81 (1H, ddd, J=8.1, 7.1, 1.5 Hz,
H-9), 6.75 (1H, dd, J=8.1, 1.5 Hz, H-10), 7.48 (1H, ddd, J=8.0, 7.1, 1.5 Hz, H-8), 7.38 (2H, m, ArH),
7.28 (3H, m, ArH), 6.75 (2H, d, J=8.2 Hz, H-3 and 5 ArMe), 6.57 (2H, t, J=8.8 Hz, H-3 and 5 ArF),
6.49 (2H, d, J=8.2 Hz, H-2 and 6 ArMe), 6.42 (2H, dd, J=5.5, 8.8 Hz, H-2 and 6 ArF), 5.38 (1H, d,
J=15.1 Hz, Ar–CH2–N), 4.68 (1H, d, J=15.1 Hz, Ar–CH2–N), 4.65 (1H, q, J=6.8 Hz, H-4), 3.95 (1H,
d, J=14.2 Hz, C1–CH2–Ar–F), 3.89 (1H, d, J=14.3 Hz, C1–CH2–Ar–Me), 3.58 (1H, d, J=14.3 Hz,
C1–CH2–Ar–Me), 3.38 (1H, d, J=14.2 Hz, C1–CH2–Ar–F), 2.14 (3H, s, CH3), 0.89 (3H, d, J=6.8 Hz,
CH3). NOE (δ; %): irradiate Me-4 (0.89), observe H-2 and 6 ArF (6.42; 1), H-3 and 5 ArF (6.57; 1) and
H-4 (4.65; 8.1). 13C NMR (CDCl3) δ: 168.4, 161.6, 159.8, 151.8, 146.6, 137.7, 136.9, 134.7, 131.8 (d,
J=8.0 Hz), 131.1, 130.9 (d, J=3 Hz), 129.0, 128.7, 128.6, 127.6, 126.9, 126.6, 119.9, 114.9 (d, J=21
Hz), 72.9, 51.0, 47.1, 46.6, 44.2, 20.8, 19.9. Analysis calc. for C34H30N3O2F: C, 76.81; H, 5.68; N, 7.90.
Found: C, 76.69; H, 5.48; N, 7.58.
1.15. (4S)-2-Benzyl-1,1-diallyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 16c
Method A: Starting compound 1c, reaction time 1 h; column chromatography: dichloromethane:ethyl
acetate (9:1) affording 16c, besides both C-1 allyl isomers.3a [α]D=+8.7 (0.25, chloroform). IR ν: 1682,
1655 cm−1. 1H NMR (CDCl3) δ: 8.23 (1H, dd, J=8.1, 1.5 Hz, H-7), 7.74 (1H, ddd, J=8.1, 8.1, 1.5 Hz,
H-9), 7.63 (1H, dd, J=8.1, 1.2 Hz, H-10), 7.45 (1H, ddd, J=8.1, 8.1, 1.2 Hz, H-8), 7.44 (2H, m, ArH-3
and 5), 7.29 (3H, m, ArH-2, 4 and 6), 5.32 (1H, d, J=6.8 Hz, H-4), 5.3 (2H, m, Hβ and β0), 5.09 (1H, d,

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497
J=15.3 Hz, N–CH2–Ar), 4.89 (1H, dd, J=10.3, 1.7 Hz, Hγ0 ), 4.82 (1H, dd, J=10.6, 1.7 Hz, Hγc), 4.76
c
(1H, dd, J=17.1, 1.7 Hz, Hγ0 ), 4.73 (1H, dd, J=17.1, 1.1 Hz, Hγt), 4.60 (1H, d, J=15.3 Hz, N–CH2–Ar),
t
3.22 (1H, dd, J=14.5, 7.3 Hz, Hα0), 3.07 (1H, dd, J=14.1, 7.8 Hz, Hα), 2.88 (1H, dd, J=14.5, 6.8 Hz,
Hα0), 2.72 (1H, dd, J=14.1, 6.9 Hz, Hα), 1.69 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 168.3,
160.2, 151.9, 147.1, 137.8, 134.5, 131.5, 130.6, 128.5, 128.4, 127.5, 127.1, 126.8, 126.5, 120.8, 120.5,
119.8, 70.7, 51.2, 45.5, 44.6, 43.9, 21.4. Analysis calc. for C25H25N3O2: C, 75.16; H, 6.31; N, 10.52.
Found C, 75.29; H, 6.46; N, 10.20.
1.16. 2-Benzyl-1,1-bis(p-methylbenzyl)-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione, (ꢀ)-17c and (1S*,4R*)-2-benzyl-1,4-bis(p-methylbenzyl)-4-methyl-2,4-dihydro-1H-pyrazino[2,
1-b]quinazoline-3,6-dione (ꢀ)-13c
Method A: Starting compound 1c, reaction time 12 h; column chromatography: dichloromethane:ethyl
acetate (9:1) affording (ꢀ)-13c (12%), (ꢀ)-17c (7%), besides anti-9c3a and (ꢀ)-syn-9c.
1.16.1. Data for (ꢀ)-syn-9c
Mp: 157–160°C (ethyl ether). For spectroscopic data see Martín-Santamaría3a Analysis calc. for
C27H25O2N3: C, 76.57; H, 5.95; N, 9.92. Found C, 76.19; H, 6.26; N, 9.12.
1.16.2. Data for (ꢀ)-17c
IR (KBr) ν: 1684, 1648 cm−1. 1H NMR (CDCl3) δ: 8.19 (1H, dd, J=8.0, 1.0 Hz, H-7), 7.78 (1H, dd,
J=8.0, 1.5 Hz, H-10), 7.76 (1H, ddd, J=8.0, 8.0, 1.0 Hz, H-9), 7.5 (1H, ddd, J=8.0, 8.0, 1.5 Hz, H-8),
7.35 (2H, m, ArH), 7.25 (3H, m, ArH), 6.73 (2H, d, J=8.0 Hz, H-30,50), 6.72 (2H, d, J=8.0 Hz, H-300,500),
6.45 (2H, d, J=8.0 Hz, H-20,60), 6.41 (2H, d, J=8.0 Hz, H-200, 600), 5.21 (1H, d, J=15.0 Hz, N–CH2–Ar),
4.84 (1H, d, J=15.0 Hz, N–CH2–Ar), 4.79 (1H, q, J=6.8 Hz, H-4), 3.93 (1H, d, J=14.5 Hz, CH2-1), 3.92
(1H, d, J=14.1 Hz, CH2-1), 3.53 (1H, d, J=14.5 Hz, CH2-1), 3.4 (1H, d, J=14.1 Hz, CH2-1), 2.11 (6H, s,
2CH3–Ar), 0.8 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 168.6, 160.2, 152.3, 146.9, 137.7, 136.7,
136.6, 134.6, 131.9, 131.4, 130.2, 129.1, 129, 128.9, 128.4, 128.1, 127.9, 127.1, 126.8, 126.5, 120.2,
72.9, 51.3, 47.5, 46.6, 45.1, 21, 20.9, 19.6. Analysis calc. for C35H33N3O2: C, 79.67; H, 6.30; N, 7.96.
Found C, 79.82; H, 6.49; N, 7.63.
1.16.3. Data for (ꢀ)-13c
Mp: 137–140°C. Spectral data identical to (−)-13c described above. Analysis calc. for C35H33O2N3:
C, 79.67; H, 6.30; N, 7.96. Found C, 79.31; H, 6.60; N, 7.60.
1.17. (4S)-4-Methyl-1,1,2-tribenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione, 18c
Method C: Column chromatography: dichloromethane:ethyl acetate (9:1). [α]D=+19 (0.25, chloro-
form). IR (KBr) ν: 1687, 1660 cm−1. 1H NMR (CDCl3) δ: 8.17 (1H, dd, J=8.1, 1.5 Hz, H-7), 7.8 (1H,
ddd, J=8.1, 8.1, 1.5 Hz, H-9), 7.73 (1H, dd, J=8.1, 1.5 Hz, H-10), 7.48 (1H, ddd, J=8.1, 8.1, 1.5 Hz,
H-8), 7.35 (2H, m, ArH), 7.23 (3H, m, ArH), 6.95 (6H, m, ArH), 6.56 (4H, m, ArH), 5.18 (1H, d, J=15.1
Hz, N–CH2–Ar), 4.89 (1H, d, J=15.1 Hz,0N–CH2–Ar), 4.69 (1H, q, J=6.8 Hz, H-4), 3.98 (1H, d, J=14.2
0
Hz, CH2-1), 3.96 (1H, d, J=14.6 Hz, CH2 -1), 3.59 (1H, d, J=14.6 Hz, CH2 -1), 3.45 (1H, d, J=14.2 Hz,
CH2-1), 0.77 (3H, d, J=6.8 Hz, CH3). 13C NMR (CDCl3) δ: 168.4, 160.0, 151.9, 146.6, 137.5, 135.0,
134.6, 134.5, 130.3, 129.0, 128.9, 128.4, 128.3, 128.2, 127.5, 127.1, 127.0, 126.9, 126.8, 126.1, 119.9,

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72.4, 51.1, 47.3, 46.8, 45.3, 19.4. Analysis calc. for C33H29N3O2: C, 79.33; H, 5.85; N, 8.41. Found C,
79.07; H, 5.69; N, 8.36.
1.18. Oxidation of 1c or 1d with HCOOH–C/Pd. General procedure
Compound 1c or 1d (0.3 mmol), 10 mg C/Pd 10% and 5 ml of formic acid (95%) were maintained
at 50°C for 24 h (1c) or 6 h (1d) and filtered. After addition of 20 ml of CH2Cl2, the organic layer was
washed with water, dried over anhydrous Na2SO4 and concentrated. Recrystallization (1c) led to 21c and
column chromatography (1d) (ethyl acetate:methanol 95:5) afforded 41 mg (40%) 21d and 42 mg (41%)
syn-19d.
1.19. (4S)-2-Benzyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-1,3,6-trione 21c
Yield: 287 g (87%). Mp: 202–204°C (CHCl3:hexane 1:4). [α]D: −2.7 (0.25, CH2Cl2). IR (KBr) ν:
1
1742, 1685, 1590 cm−1. H NMR (CDCl3) δ: 8.28 (1H, dd, J=8.0, 1.5 Hz, H-7), 8.00 (1H, dd, J=8.0,
1.2 Hz, H-10), 7.85 (1H, ddd, J=8.0, 8.0, 1.5 Hz, H-9), 7.60 (1H, ddd, J=8.0, 8.0, 1.2 Hz, H-8), 7.45
(2H, m, Ph), 7.25 (3H, m, Ph), 5.58 (1H, q, J=7.0 Hz, H-4), 5.20 (1H, d, J=13.6 Hz, Ph–CH2–N), 5.10
(1H, d, J=13.6 Hz, Ph–CH2–N), 1.65 (3H, d, J=7.0 Hz, CH3). 13C NMR (CDCl3) δ: 168.4, 159.4, 157.0,
146.5, 138.6, 135.5, 135.3, 129.9, 129.7, 129.5, 128.8, 128.4, 127.0, 121.8, 52.7, 44.7, 21.1. MS (70 eV),
m/z (%): 334 ([M+1]+, 36), 333 (M+, 100), 305 (28), 304 (11), 214 (10), 171 (11), 146 (23), 145 (12),
132 (26), 129 (12), 117 (16), 106 (28), 102 (14), 91 (36), 77 (17), 70 (10), 65 (20). Analysis calc. for
C19H15N3O3: C, 68.46; H, 4.53; N, 12.60. Found: C, 68.32; H, 4.47; N, 12.67.
1.20. (4S)-2-p-Methoxybenzyl-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-1,3,6-trione 21d
Mp: 75°C (ethyl acetate:methanol). [α]D: +9.6 (0.25, CH2Cl2). IR (KBr) ν: 1741, 1687, 1610 cm−1
.
1H NMR (CDCl3) δ: 8.30 (1H, dd, J=8.3, 1.5 Hz, H-7), 8.01 (1H, dd, J=8.2, 1.2 Hz, H-10), 7.85 (1H,
ddd, J=8.2, 7.2, 1.5 Hz, H-9), 7.63 (1H, ddd, J=8.3, 7.2, 1.2 Hz, H-8), 7.43 (2H, d, J=8.8 Hz, H-20and 60),
6.81 (2H, d, J=8.8 Hz, H-30 and 50), 5.58 (1H, q, J=7.0 Hz, H-4), 5.15 (1H, d, J=13.6 Hz, Ar–CH2–N),
5.05 (1H, d, J=13.6 Hz, Ar–CH2–N), 3.75 (3H, s, OCH3), 1.66 (3H, d, J=7.0 Hz, CH3). 13C NMR
(CDCl3) δ: 168.4, 159.6, 159.4, 156.7, 146.5, 138.5, 135.4, 131.1, 129.9, 129.6, 127.5, 126.9, 121.7,
113.8, 55.5, 52.8, 44.4, 21.1. Analysis calc. for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C,
66.43; H, 4.51; N, 11.68.
1.21. (1S,4S)-1-Hydroxy-4-methyl-2-p-methoxybenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione (syn-19d)
Mp: 102–104°C (ethyl acetate:methanol). [α]D: +34.4 (0.34, CH2Cl2). IR (KBr) ν: 1682, 1611 cm−1
.
1H NMR (CDCl3) δ: 8.26 (1H, dd, J=8.1, 1.5 Hz, H-7), 7.77 (1H, ddd, J=8.3, 7.1, 1.5 Hz, H-9), 7.67
(1H, dd, J=8.3, 1.2 Hz, H-10), 7.51 (1H, ddd, J=8.1, 7.1, 1.2 Hz, H-8), 7.39 (2H, d, J=8.7 Hz, H-20 and
60), 6.84 (2H, d, J=8.7 Hz, H-30 and 50), 5.57 (1H, d, J=3.5 Hz, H-1), 5.42 (1H, q, J=7.2 Hz, H-4), 5.26
(1H, d, J=3.5 Hz, OH), 5.16 (1H, d, J=14.1 Hz, Ar–CH2–N), 4.47 (1H, d, J=14.1 Hz, Ar–CH2–N), 3.77
(3H, s, OCH3), 1.53 (3H, d, J=7.2 Hz, CH3). 13C NMR (CDCl3) δ: 166.3, 159.6, 159.3, 150.2, 146.0,
135.1, 130.5, 128.5, 128.0, 127.2, 127.1, 120.9, 114.0, 74.4, 55.5, 52.8, 44.1, 17.5. MS (70 eV), m/z (%):
365 (M+, 1), 364 (3), 363 (14), 349 (6), 335 (7), 258 (11), 230 (7), 229 (23), 228 (7), 214 (6), 201 (14),
191 (9), 162 (25), 146 (18), 136 (53), 135 (16), 129 (9), 121 (100), 102 (10), 91 (16), 78 (16), 77 (29),

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 483–501
499
65 (11), 60 (36), 57 (63). Analysis calc. for C20H19N3O4: C, 65.74; H, 5.24; N, 11.50. Found: C, 65.34;
H, 5.14; N, 11.69.
1.22. Catalytic hydrogenation of 1c in acidic medium: (4S)-2-benzyl-4-methyl-2,4,7,8,9,10-hexahydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 22
Compound 1c (350 mg, 1.1 mmol), 100 mg of C/Pd 10% and 1 ml of formic acid (95%) in methanol
(50 ml) were hydrogenated at 33 psi for 14 h. The reaction mixture was filtered and concentrated. Column
chromatography (ethyl acetate:methanol 95:5) afforded 192 mg (55%) of 22. Mp: 128–129°C (ethyl
1
acetate:methanol). [α]D: +31.8 (0.25, CH2Cl2). IR (KBr) ν: 1666, 1605 cm−1. H NMR (CDCl3) δ:
7.27 (5H, m, Ph), 5.37 (1H, q, J=7.1 Hz, H-4), 4.79 (1H, d, J=14.5 Hz, Ph–CH2–N), 4.70 (1H, d, J=14.5
Hz, Ph–CH2–N), 4.35 (1H, d, J=17.0 Hz, H-1), 4.15 (1H, d, J=17.0 Hz, H-1), 2.46 (4H, m, H-7 and 10),
1.70 (4H, m, H-8 and 9), 1.53 (3H, d, J=7.1 Hz, CH3). 13C NMR (CDCl3) δ: 167.2, 160.0, 159.3, 148.5,
134.9, 129.0, 128.2, 128.1, 120.4, 51.7, 49.4, 48.6, 31.2, 22.2, 21.9, 21.4, 16.9. MS (70 eV), m/z (%):
324 ([M+1]+, 71), 323 (M+, 91), 233 (16), 232 (100), 218 (25), 204 (17), 191 (10), 190 (35), 189 (30),
164 (46), 91 (56), 79 (16), 77 (13), 65 (20), 56 (11). Analysis calc. for C19H21N3O2: C, 70.56; H, 6.54;
N, 12.99. Found: C, 70.19; H, 6.42; N, 13.05.
1.23. (4S)-4-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 1a
Method A: 1e (100 mg, 0.26 mmol), 2.6 ml of TFA (0.1 M) and 0.1 ml of anisole were refluxed for
14 h at 80°C, extracted with CHCl3, dried (Na2SO4) and concentrated. Column chromatography (ethyl
acetate:methanol 95:5) afforded (+)-1a (41 mg; 68%) and traces of 21a (4 mg, 6%).
Method B: A solution of 1d (0.5 mmol) in 7 ml acetonitrile:water (5:2) and CAN (0.6 g, 1.1 mmol)
was stirred 30 min at rt. The reaction mixture was extracted with chloroform, dried (Na2SO4) and
concentrated. Column chromatography (ethyl acetate:methanol, 95:5) afforded syn-19d (10 mg, 7%),
(+)-1a (43 mg, 38%) and syn-19a (19 mg, 19%).
1.23.1. Data for (+)-1a
Mp: 207–210°C (ethyl acetate:methanol). [α]D: +42.8 (0.26, CHCl3). IR (KBr) ν: 1675, 1603 cm−1
.
1H NMR (CDCl3) δ: 8.26 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.74 (1H, ddd, J=8.1, 8.1, 1.5 Hz, H-9), 7.69
(1H, d, J=4.9 Hz, NH), 7.61 (1H, dd, J=8.1, 1.2 Hz, H-10), 7.47 (1H, ddd, J=8.1, 8.1, 1.2 Hz, H-8), 5.41
(1H, q, J=7.1 Hz, H-4), 4.66 (1H, d, J=16.8 Hz, H-1), 4.48 (1H, dd, J=16.8, 4.9 Hz, H-1), 1.63 (3H,
d, J=7.1 Hz, CH3). 13C NMR (CDCl3) δ: 170.6, 160.3, 147.7, 147.2, 135.0, 127.4, 127.1, 127.0, 120.5,
51.9, 45.1, 17.0. Analysis calc. for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.69; H, 4.82;
N, 18.50.
1.24. (4S)-4-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-1,3,6-trione 21a
1H NMR (CDCl3) δ: 8.31 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.87 (1H, ddd, J=8.2, 7.1, 1.5 Hz, H-9), 7.71
(1H, dd, J=8.2, 1.2 Hz, H-10), 7.59 (1H, ddd, J=8.0, 7.1, 1.2 Hz, H-8), 5.42 (1H, q, J=7.2 Hz, H-4), 1.7
(3H, d, J=7.2 Hz, CH3). (NH not observed). 13C NMR (CDCl3) δ: 169.3, 159.8, 148.7, 145.6, 135.2,
135.0, 127.4, 126.5. 125.6, 119.6, 51.8, 16.1.

500
F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 483–501
1.25. (1S,4S)-1-Hydroxy-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (syn-19a)
Mp: 200–203°C (ethyl acetate:methanol). [α]D: +80.3 (0.18, CH2Cl2:methanol (1:1)). IR (KBr) ν:
1698, 1670, 1610 cm−1. 1H NMR (CDCl3:CD3OD) δ: 8.07 (1H, dd, J=8.0, 1.5 Hz, H-7), 7.61 (1H, ddd,
J=8.0, 8.0, 1.5 Hz, H-9), 7.49 (1H, d, J=8.0 Hz, H-10), 7.35 (1H, ddd, J=8.0, 8.0, 1.2 Hz, H-8), 5.46
(1H, s, H-1), 5.06 (1H, q, J=7.1 Hz, H-4), 1.62 (3H, d, J=7.1 Hz, CH3). 13C NMR (CDCl3:MeOD) δ:
171.8, 160.3, 149.2, 146.6, 134.6, 127.4, 126.7, 126.3, 120.1, 75.5, 52.6, 18.5. MS (70 eV), m/z (%):
246 ([M+1]+, 11), 245 (M+, 30), 230 (14), 229 (92), 228 (22), 227 (M-18, 100), 175 (12), 174 (77),
173 (14), 172 (11), 171 (17), 146 (30), 145 (18), 144 (18), 132 (13), 131 (13), 130 (32), 129 (23), 121
(55), 118 (13), 117 (31), 116 (14), 90 (26), 77 (35), 76 (61), 75 (34), 63 (24), 60 (89). Analysis calc. for
C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.62; H, 4.50; N, 17.21.
1.26. Oxidation of 1d with DDQ. General procedure
Compound 1d (175 mg, 0.5 mmol) and 114 mg (0.5 mmol) of DDQ in 9.5 ml of CH2Cl2:water
(9:0.5) were stirred at rt for 3 h, filtered, washed with water, dried (Na2SO4) and concentrated. Column
chromatography (CH2Cl2:ethyl acetate, 9:1) gave 65 mg (38%) of recovered 1d, 20 mg (18%) of syn-19d,
8 mg (7%) of anti-19d and 4 mg (4%) of 21d.
1.27. (1S,4S)-4-Methyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (syn-
8a)
A mixture of compound anti-8e (48 mg, 0.1 mmol) in 1 ml of TFA (0.1 M) and 0.05 ml of anisole
was refluxed for 7 h at 80°C, dissolved in CH2Cl2, extracted with 1 N NaHCO3, dried (Na2SO4) and
concentrated. Column chromatography (ethyl acetate:petroleum ether 7:3) afforded syn-8a (32 mg; 96%).
Mp: 221–222°C (ether). [α]D: +23.4 (0.16, CH2Cl2). IR (KBr) ν: 1682, 1598 cm−1. 1H NMR (CDCl3)
δ: 8.30 (1H, dd, J=8.0, 1.0 Hz, H-7), 7.81 (1H, ddd, J=7.6, 7.1, 1.0 Hz, H-9), 7.70 (1H, dd, J=7.6,
1.1 Hz, H-10), 7.52 (1H, ddd, J=8.0, 7.1, 1.1 Hz, H-8), 7.16• (2H, d J=9.1 Hz, H-300 and 500), 7.13•
(2H, d, J=9.1 Hz, H-200 and 600), 6.62 (1H, d, J=2.8 Hz, NH), 5.26 (1H, q, J=7.1 Hz, H-4), 4.78 (1H,
dd, J=9.9, 3.7 Hz, H-1), 3.44 (1H, dd, J=13.5, 3.7 Hz, H-α), 3.11 (1H, dd, J=13.5, 9.9 Hz, H-α), 2,33
(3H, s, CH3–Ar), 1.50 (3H, d, J=7.1 Hz, CH3). 13C NMR (CDCl3) δ: 168.8, 160.6, 149.9, 147.3, 137.6,
135.0, 132.2, 130.0, 129.6, 127.3, 127.0, 126.9, 120.3, 58.2, 51.9, 43.9, 21.2, 19.0. Analysis calc. for
C20H19N3O2: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.72; H, 5.94; N, 12.25.
1.28. (1R,4S)-4-Methyl-1-p-methylbenzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione (anti-
8a)
A solution of anti-8d (80 mg, 0.18 mmol) in 7 ml acetonitrile:water (5:2) and CAN (210 mg, 0.4
mmol) was stirred for 20 min at rt. The reaction mixture was extracted with chloroform, dried (Na2SO4)
and concentrated. Column chromatography (ethyl acetate:petroleum ether, 6:4) afforded anti-8a (20 mg,
34%; 72% based on recovered starting compound. Mp: 187–188°C (ether). [α]D: +102.5 (0.04, CHCl3).
IR (KBr) ν: 1684 cm−1. 1H NMR (CDCl3) δ: 8.29 (1H, dd, J=8.1, 1.2 Hz, H-7), 7.80 (1H, ddd, J=8.0,
7.8, 1.2 Hz, H-9), 7.75 (1H, dd, J=7.8, 1.0 Hz, H-10), 7.53 (1H, ddd, J=8.0, 8.1, 1.0 Hz, H-8), 7.20 (4H,
d J=8.7 Hz, H–Ar), 5.84 (1H, s, NH), 5.47 (1H, q, J=7.1 Hz, H-4), 4.77 (1H, dd, J=10.5, 3.7 Hz, H-1),
4.08 (1H, dd, J=14.4, 3.7 Hz, H-α), 2.93 (1H, dd, J=14.4, 10.5 Hz, H-α), 2.37 (3H, s, CH3–Ar), 1.61
(3H, d, J=7.1 Hz, CH3). 13C NMR (CDCl3) δ: 168.9, 160.2, 149.6, 146.8, 137.5, 134.6, 132.0, 130.0,

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 9 (1998) 483–501
501
129.0, 127.4, 127.3, 126.8, 120.4, 53.9, 52.0, 37.5, 21.0, 16.8. Analysis calc. for C20H19N3O2: C, 72.05;
H, 5.74; N, 12.60. Found: C, 71.77; H, 5.56; N, 12.27.
Acknowledgements
We thank CICYT for financial support (Project SAF94-0517).
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