Cyclisation of (4S)-4-methyl-2-phenethyl-2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6- dione derivatives via N-acyliminium ions

Article abstract of DOI:10.1016/S0957-4166(01)00492-X

Enantiomerically pure 1-methylene and 1-oxo derivatives (compounds 4 and 10, respectively) of compounds 1 were obtained and studied as precursors of N-acyliminium ions. 1-Substituted-1-hydroxyderivatives, obtained by regioselective syn-addition of organom

Full text of DOI:10.1016/S0957-4166(01)00492-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2883–2889
Cyclisation of (4S)-4-methyl-2-phenethyl-2,4-
dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione derivatives via
N-acyliminium ions
Mar´ıa Luisa Heredia, Elena de la Cuesta and Carmen Avendan˜o*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 22 October 2001; accepted 1 November 2001
Abstract—Enantiomerically pure 1-methylene and 1-oxo derivatives (compounds 4 and 10, respectively) of compounds 1 were
obtained and studied as precursors of N-acyliminium ions. 1-Substituted-1-hydroxyderivatives, obtained by regioselective
syn-addition of organometallics to compounds 10 gave the desired species under acid treatment while compounds 4 did not.
N-Phenethyl substituted N-acyliminium ions gave isoquino[1%,2%:3,4]pyrazino[2,1-b]quinazoline-8,11-diones through a Pictet–Spen-
gler-type cyclisation. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
hydroxy derivatives, obtained by addition of
organometallic reagents to 1-oxo compounds 10. The
2-phenethyl derivatives deserve special interest as they
are model compounds able to trap the above-men-
tioned intermediates through Pictet–Spengler-type
reactions.
N-Acyliminium ions have highly versatile reaction
characteristics which are reflected in the impressive
scope of their synthetic applications. Both inter- and
intramolecular carbonꢀcarbon bond forming reactions
of these ions have been comprehensively reviewed, and
their application in cyclisations onto olefins or arenes is
in continuous expansion.1–6 System 1 is used in nature
as a scaffold for constrained peptidomimetics, as
demonstrated by the structure of several fungal
metabolites including glyantrypine,7 the fumiquinazoli-
nes,8 the fiscalins9 and N-acetylardeemin.10,11
2. Results and discussion
We have previously described17 that the 1-methylene-2-
methyl derivative (−)-4a dimerised to the self-coupling
product (−)-5 when treated with trifluoroacetic acid
through a process that implies the protonation at N(11)
to give the iminium ion III, but the 2-benzyl analogue
(−)-4b was recovered unaltered after this treatment.
This difference in behaviour could be explained if the
bulk of the benzyl substituent prevents the C–C cou-
pling reaction to give 5 (Scheme 2). Looking for more
adequate analogues to trap the alternative iminium ion
IV and thus form a six-membered ring,14 we studied
this reaction with the 2-phenethyl derivative (−)-4c.
We have previously shown that compounds 2 and 3,
obtained by oxidation with hypervalent iodine
reagents12–14 or radical bromination15 of compounds 1,
behave as glycine templates and generate N-
acyliminium ions I (Scheme 1a). Taking into account
that
N,N%-disubstituted-3-methylenepiperazine-2,5-
diones16 are efficient precursors of iminium ions such as
II by protonation of the double bond (Scheme 1b), we
report herein a study into the generation of tertiary
iminium cations from 1-methylene derivatives 4, which
are readily accessible through Mannich–Hofmann reac-
tions on compounds 1. We also report the formation of
these species by acid treatment of 1-substituted 1-
Compound (−)-4c could be quantitatively obtained in
the Mannich–Hofmann reaction of (−)-1c when the
unreacted Mannich product (−)-6c was submitted to
subsequent elimination (its enantiomeric purity was
corroborated by chiral HPLC on a Chiracel OD). How-
ever, on prolonged acid treatment of 4c in refluxing
trifluoroacetic or concentrated sulfuric acid at room
temperature, the expected cyclisation product was not
* Corresponding author. Fax: 34 91 394 18 22; e-mail:
avendano@farm.ucm.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00492-X

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M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
Scheme 1.
Scheme 2.
formed 7 and/or 8 and the unreacted starting material
was returned (7 and/or 8, Scheme 3). We concluded
that either the corresponding N-acyliminium ion IV did
not form or the rate of proton elimination was faster
than the rate of the Pictet–Spengler-type cyclisation.
PCC to 10a, this method was rejected because it is
tedious and time consuming. The treatment of 1a with
selenium dioxide in acetic anhydride21 gave a substan-
tial amount of the decomposition product 11a, while
the reaction in pyridine22 led to 10a in low yield.
Finally, 10a was obtained as the sole reaction product
in 95% yield by direct treatment of 1a with two equiva-
lents of PCC. This procedure was then applied to
obtain the desired compound 10c (78%) with e.e. >98%,
Since 1-hydroxy (alkoxy or tosyloxy) derivatives 2, as
other simpler N-(1-hydroxy alkyl)amides,18 generate N-
acyliminium species (I, Scheme 1), we extended this
chemistry to form tertiary N-acyliminium cations19
from 1-hydroxy-1-alkyl(aryl) derivatives. In order to
obtain the 1-oxo precursors, we studied different oxida-
tion methods with the model compound 1a. Thus, given
the easy oxidation of the 1-formyl derivative, as
observed in the attempted reductive N(2)-debenzylation
of compound 1b in formic acid,20 we treated 1a under
the same reaction conditions and obtained a 1:1 mix-
ture of 9a and 10a (Scheme 4). Although unreacted 1a
was easily recovered and 9a was further oxidised with
1
as determined by H NMR spectroscopy using euro-
pium(III) [tris(3-heptafluoropropyl hydroxymethylene-
(+)-camphorate] as a chiral reagent.
Organometallic additions to compounds 1 and 4 take
place at the C(3) carbonyl group,23 but in the case of
compounds 10 these reactions were expected to give
adducts on the more electrophilic C(1) carbonyl group.
In fact, addition of organolithium and Grignard
reagents to 10a was diastereoselective giving the 1-

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
2885
Scheme 3.
Scheme 4.
hydroxy derivatives 12–14 as 1,4-syn-isomers according
to NOESY experiments (Scheme 5). The syn-selectivity
of the Grignard additions to compounds 10 has no
precedent in the literature. First assays confirmed that
these compounds are effective precursors of tertiary
N-acyliminium ions in acid media. Thus, treatment of
12 with p-toluenesulfonic acid in methanol at room
temperature gave the solvolysis products (1R,4S)-15
and (1S,4S)-16 derivatives in a 8:1 relationship, show-
ing the asymmetric induction by the C(4)-substituent in
the addition of methanol as a nucleophile. Under the
same conditions, analogues 13 and 14 gave the 1-meth-
ylene compounds 4a and 17 by proton elimination.
We next followed the same protocol using the N-
phenethyl analogue 10c to obtain 18 (56%) and 19
(97%) through regio- and diastereoselective syn-addi-
tions (Scheme 6). Treatment of these compounds with
Scheme 5.

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M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
Scheme 6.
sulfuric acid at room temperature afforded the desired
cyclised products 7, 8, 20 and 21, whose stereochem-
istry were unequivocally assigned by NOESY experi-
ments. The enantiomeric purity of these compounds
was confirmed by chiral HPLC, in comparison with
racemic samples. In the case of 18, the syn-isomer was
the major product (diastereomeric ratio 7/8=4:1), while
for 19, the anti-isomer predominated (diastereomeric
ratio 20/21=3:2).
the Servicio de Microana´lisis, Universidad Com-
plutense on a Leco 932 microanalyzer. Optical rota-
tions were measured at 25°C on a 1 mL cell in CHCl3
or MeOH at 589 nm, using a Perkin Elmer 240 polar-
imeter; concentrations are given in g/100 mL. HPLC
analyses were performed using a Constametric 4100
system equipped with a chiral column (Chiracel OD)
and UV–vis detector. Mobile phase: hexane/2-propanol
(9:1).
In conclusion, PCC oxidation of compounds 1 with
adequate 2-aryl (or heteroaryl)alkyl substituents, fol-
lowed by organometallic addition and acid treatment,
could be used to generate tertiary N-acyliminium ions,
useful as intermediates in intramolecular p-nucleophilic
additions.
3.1. (−)-(4S)-4-Methyl-1-methylene-2-phenethyl-2,4-
dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione 4c
To a cold (−15°C), magnetically stirred anhydrous trifl-
uoroacetic acid (13 mmol), bis(dimethylamino)methane
(2.6 mmol) was added slowly and diluted with dry
CH2Cl2 (10 mL). The temperature of the resulting
solution was kept below −10°C and a solution of
compound 1c (2.6 mmol) in dry CH2Cl2 (10 mL) was
then added. The cooling bath was removed and the
solution was heated at 65°C for 3.5 h. To the cooled
solution, H2O (15 mL) was added and the separated
aqueous layer was extracted with CH2Cl2, the combined
organic layers were washed with water, dried over
Na2SO4, filtered and evaporated. Chromatography of
the residue in alumina (EtOAc/hexane, 1:1) provided
methylene compound 4c, together with 6c. 4c: white
solid; yield: 77% [found: C, 73.00; H, 5.65; N, 12.34.
C21H19N3O2 requires: C, 73.03; H, 5.54; N, 12.16%]; mp
93–95°C; [h]D25=−79 (c 0.12, CHCl3); wmax (KBr) 1684,
1619 cm−1; lH (250 MHz, CDCl3) 8.26 (dd, 1H, J=7.9
and 1.5 Hz), 7.77 (ddd, 1H, J=8.2, 7.5 and 1.5 Hz),
7.70 (dd, 1H, J=8.2 and 1.5 Hz), 7.48 (ddd, 1H,
J=7.9, 7.5 and 1.5 Hz), 7.31–7.16 (m, 5H), 6.24 (d, 1H,
J=1.7 Hz), 5.50 (q, 1H, J=7.0 Hz), 5.14 (d, 1H, J=1.7
Hz), 4.06 (m, 2H), 2.94 (m, 2H), 1.53 (d, 3H, J=7.0
Hz); lC (63 MHz, CDCl3) 165.6, 159.9, 147.5, 144.8,
137.9, 136.9, 134.9, 128.9, 128.8, 127.9, 127.5, 126.9,
126.7, 120.5, 103.4, 51.5, 45.8, 32.5, 19.1.
3. Experimental
All reagents were of commercial quality (Aldrich,
Fluka, SDS, Probus) and were used as received. Sol-
vents (SDS, Scharlau) were dried and purified using
standard techniques. Reactions were monitored by thin
layer chromatography on aluminium plates coated with
silica gel or aluminium oxide with fluorescent indicator
(Merck 60 F254). Separations by flash chromatography
were performed on silica gel (Merck 60, 230–400 mesh)
or aluminium oxide (Merck 90, 70–230 mesh). Melting
points were measured in open capillary tubes using a
Bu¨chi immersion apparatus or on a Reichert 723 hot
stage microscope, and are uncorrected. Infrared spectra
were recorded on a Perkin Elmer Paragon 1000 FT-IR
spectrophotometer, with solid compounds compressed
into KBr pellets. NMR spectra were obtained at 250 or
1
300 MHz for H and at 63 or 75 MHz for 13C NMR
(Servicio de Espectroscop´ıa, Universidad Com-
plutense). When necessary, assignments were aided by
DEPT, COSY, CH COLOC and 13C–1H correlation
experiments. Elemental analyses were determined by

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
2887
3.2. (−)-(1S,4S)-4-Methyl-1-dimethylaminomethyl-2-
phenethyl-2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-
3,6-dione 6c
3.5. Addition of RM. Preparation of 1-hydroxy-1-alkyl-
(aryl)-pirazino[2,1-b]quinalzolinones. General procedure
To a solution of 9 (0.39 mmol) in dry THF (7 mL)
was added, under nitrogen, a solution of RLi (0.5
mmol) at −30°C or a solution of RMgBr (0.5 mmol)
at −78°C. The resulting mixture was stirred for 3 h,
quenched by the addition of a saturated solution of
amonium chloride (1 mL), and allowed to warm to
20°C. Ethyl acetate was added (10 mL), the organic
layer was separated and the aqueous phase was
extracted with EtOAc (3×10 mL). The combined
organic extracts were dried (Na2SO4) and concentrated
in vacuo. Flash column chromatography (silica gel)
afforded pure products.
Compound 6c was obtained as a yellow solid (alu-
mina, EtOAc/hexane, 1:1); yield: 23% [found: C,
70.34; H, 6.58; N, 14.28. C23H26N4O2 requires: C,
70.75; H, 6.71; N, 14.35%]; mp 45–46°C; [h]2D5=−130
(c 0.12, CHCl3); wmax (KBr) 2933, 1685, 1586 cm−1; lH
(250 MHz, CDCl3) 8.28 (dd, 1H, J=8.0 and 1.5 Hz),
7.77 (ddd, 1H, J=8.2, 7.4 and 1.5 Hz), 7.69 (d, 1H,
J=8.2 Hz), 7.50 (ddd, 1H, J=8.0, 7.4 and 1.4 Hz),
7.23–7.11 (m, 5H), 5.92 (dd, 1H, J=8.0 and 4.2 Hz),
5.50 (q, 1H, J=7.1 Hz), 4.1 (m, 1H), 3.90 (m, 1H),
3.82 (dd, 1H, J=16.5 and 4.2 Hz), 3.52 (dd, 1H,
J=16.5 and 8.0 Hz), 3.0 (m, 2H), 2.27 (s, 6H), 1.50
(d, 3H, J=7.1 Hz); lC (63 MHz, CDCl3) 166.3, 159.8,
147.1, 144.9, 137.9, 134.7, 128.9, 128.7, 127.8, 127.7,
126.9, 126.8, 124.8, 120.4, 57.7, 51.7, 46.7, 45.7, 45.6,
33.3, 17.8.
3.6. (−)-(1R,4S)-1-Hydroxy-2,4-dimethyl-1-phenyl-2,4-
dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione 12
Compound 12 was obtained (EtOAc/hexane, 2:3) as a
white solid; yield: 95% [found: C, 67.83; H, 5.13; N,
12.75. C19H17N3O3 requires: C, 68.05; H, 5.11; N,
12.52%]; mp 68–69°C; [h]2D5=−18 (c 0.19, CHCl3); wmax
(KBr) 3380, 1669, 1607 cm−1; lH (250 MHz, CDCl3)
8.20 (d, 1H, J=8.2 Hz), 7.80–7.77 (m, 2H), 7.54–7.32
(m, 6H), 6.35 (s, 1H), 5.30 (q, 1H, J=7.2 Hz), 3.26 (s,
3H), 1.34 (d, 3H, J=7.2 Hz). lC (63 MHz, CDCl3)
167.4, 159.9, 152.6, 145.9, 140.4, 135.2, 129.6, 128.4,
127.9, 127.2, 126.6, 126.4, 120.7, 84.5, 53.2, 28.9, 17.6.
3.3. (−)-(4S)-4-Methyl-2-phenethyl-2,4-dihydropyrazino-
[2,1-b]quinazoline-1,3,6-trione 10c
A mixture of 1c (300 mg, 0.89 mmol) and PCC (388
mg, 1.8 mmol) in dry CH2Cl2 (15 mL) was stirred
under nitrogen at room temperature overnight. After
evaporation of the solvent in vacuo, the crude was
chromatographed in silica gel (EtOAc/hexane, 1:1)
yielding a white solid (69%) [found: C, 70.08; H, 4.71;
N, 12.23. C20H17N3O3 requires: C, 69.15; H, 4.93; N,
12.09%]; mp 66–68°C; [h]2D5=−0.5 (c 0.25, CHCl3);
wmax (KBr) 1741, 1686 cm−1; lH (250 MHz, CDCl3)
8.22 (dd, 1H, J=8.0 and 1.4 Hz), 7.94 (d, 1H, J=8.1
Hz), 7.81 (ddd, 1H, J=8.1, 7.5 and 1.4 Hz), 7.58
(ddd, 1H, J=8.0, 7.5 and 0.9 Hz), 7.26–7.11 (m, 5H),
5.44 (q, 1H, J=6.9 Hz), 4.3 (m, 1H), 4.06 (m, 1H),
2.96 (t, 2H, J=7.4 Hz), 1.49 (d, 3H, J=6.9 Hz); lC
(63 MHz, CDCl3) 168.4, 159.3, 156.9, 146.4, 138.6,
137.3, 135.4, 129.8, 129.7, 129.2, 128.7, 127.0, 126.8,
121.7, 52.6, 42.3, 33.5, 20.9.
3.7. (−)-(1R,4S)-1-Hydroxy-1,2,4-trimethyl-2,4-dihydro-
(1H)-pyrazino[2,1-b]quinazoline-3,6-dione 13
Compound 13 was obtained (EtOAc/hexane, 4:1) as a
white solid; yield: 73% [found: C, 61.75; H, 5.55; N,
15.14. C14H15N3O3 requires: C, 61.52; H, 5.53; N,
15.37%]; mp 167–168°C; [h]2D5=−46 (c 0.12 CHCl3);
wmax (KBr) 3157, 1693, 1655, 1609 cm−1; lH (250 MHz,
CDCl3) 8.24 (dd, 1H, J=8.0 and 1.5 Hz), 7.77 (ddd
1H, J=8.0, 7.5 and 1.5 Hz), 7.66 (d, 1H, J=8.0 Hz),
7.50 (ddd, 1H, J=8.0, 7.5 and 1.2 Hz), 5.29 (s, 1H),
5.26 (q, 1H, J=7.1 Hz), 3.13 (s, 3H), 1.78 (s, 3H),
1.69 (d, 3H, J=7.1 Hz). lC (63 MHz, CDCl3) 165.6,
159.7, 153.3, 145.9, 134.9, 127.6, 126.8, 126.7, 120.5,
82.3, 52.4, 29.2, 26.8, 18.4.
3.4. N-Methyl-4-oxo-3H-quinazoline-2-carboxamide
11a
Selenium oxide (505 mg, 4.55 mmol) was added to a
stirred suspension of 1a (300 mg, 1.3 mmol) in acetic
anhydride (0.25 mL). The reaction mixture was stirred
at 145°C overnight, filtered and the filtrate washed
with acetic acid and ethyl acetate. The combined
organic extracts were neutralised with NaOH 20%,
dried over Na2SO4 and concentrated to dryness.
Column chromatography (silica gel, EtOAc/hexane,
4:1) of the residue yielded 11a as a white solid (30%);
[found: C, 58.68; H, 4.63; N, 20.00. C10H9N3O2
requires: C, 59.1; H, 4.46; N, 20.67%]; mp 177–79°C;
wmax (KBr) 3348, 2930, 1622 cm−1; lH (250 MHz,
CDCl3) 8.99 (d, 1H, J=4.6 Hz), 8.15 (dd, 1H, J=7.9
and 1.4 Hz), 7.87 (dd, 1H, J=7.5 and 1.4 Hz), 7.75
(d, 1H, J=7.6 Hz), 7.54 (ddd, 1H, J=7.9, 7.5 and 1
Hz), 2.81 (d, 3H, J=4.6 Hz). lC (63 MHz, CDCl3)
159.8, 159.7, 145.7, 134.9, 134.7, 134.6, 127.9, 126.1,
115.2, 26.2.
3.8. (+)-(1R,4S)-1-Benzyl-1-hydroxy-2,4-dimethyl-2,4-
dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione 14
Compound 14 was obtained (CHCl3/EtOAc, 2:1) as a
white solid; yield: 73% [found: C, 68.43; H, 5.50; N,
12.10. C20H19N3O3 requires: C, 68.75; H, 5.48; N,
12.03%]; mp 48–49°C; [h]2D5=+90 (c 0.2, CHCl3); wmax
(KBr) 3326, 1684, 1594 cm−1; lH (250 MHz, CDCl3)
8.19 (dd, 1H, J=7.9 and 1.5 Hz), 7.8 (ddd, 1H, J=
8.2, 7.5 and 1.5 Hz), 7.72 (dd, 1H, J=8.2 and 1.3 Hz),
7.5 (ddd, 1H, J=7.9, 7.5 and 1.3 Hz), 7.15 (m, 1H),
7.06 (dt, 2H, J=7.4 and 1.5 Hz), 6.62 (dd, 2H, J=7.6
and 1.4 Hz), 5.02 (s, 1H), 4.06 (q, 1H, J=6.7 Hz),
3.50 (d, 1H, J=13.5 Hz), 3.39 (d, 1H, J=13.5 Hz),
3.28 (s, 3H), 1.48 (d, 3H, J=6.7 Hz). lC (63 MHz,
CDCl3) 166.9, 159.8, 151.5, 146.1 135.0, 133.2, 129.3,
128.8, 128.1, 127.7, 127.1, 127.0, 120.8, 86.7, 52.2,
48.1, 28.3, 20.2.

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M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
3.9. (+)-(1R,4S)-1-Hydroxy-1,4-dimethyl-2-phenethyl-
164–166°C; [h]D25=−59 (c 0.09, CHCl3); wmax (KBr)
1684, 1590 cm−1; lH (250 MHz, CDCl3) 8.23 (dd, 1H,
J=8.0 and 1.5 Hz), 7.68 (ddd, 1H, J=7.9, 7.6 and 1.5
Hz), 7.56 (dd, 1H, J=7.9 and 1.3 Hz), 7.45 (ddd, 1H,
J=8.0, 7.6 and 1.3 Hz), 7.40–7.25 (m, 5H), 5.48 (q, 1H,
J=6.8 Hz), 3.42 (s, 3H), 2.72 (s, 3H), 1.79 (d, 3H,
J=6.8 Hz). lC (63 MHz, CDCl3) 168.2, 160.4, 149.2,
146.9, 140.3, 134.8, 128.2, 128.0, 127.4, 127.2, 126.1,
125.5, 120.4, 92.8, 52.0, 51.9, 29.3, 20.9.
2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-dione
18
Compound 18 was obtained (EtOAc/hexane, 2:3) as a
white solid; yield: 56% [found: C, 69.51; H, 5.77; N,
11.65. C21H21N3O3 requires: C, 69.40; H, 5.82; N,
11.56%]; mp 108–109°C; [h]2D5=+43 (c 0.13, CHCl3);
wmax (KBr) 3398, 1689, 1668 cm−1; lH (250 MHz,
CDCl3) 8.28 (dd, 1H, J=7.9 and 1.5 Hz), 7.80 (ddd,
1H, J=8.1, 7.6 and 1.5 Hz), 7.69 (dd, 1H, J=8.1 and
1.2 Hz), 7.53 (ddd, 1H, J=7.9, 7.6 and 1.2 Hz), 7.28–
7.15 (m, 5H), 5.31 (q, 1H, J=7.1 Hz), 5.23 (s, 1H), 4.04
(m, 1H), 3.56 (m, 1H), 2.93 (m, 2H), 1.76 (s, 3H), 1.74
(d, 3H, J=7.1 Hz); lC (63 MHz, CDCl3) 165.4, 160.0,
153.5, 146.1, 139.1, 135.0, 128.9, 128.4, 127.7, 127.0,
126.4, 120.6, 82.7, 52.7, 43.6, 35.7, 30.6, 18.3.
3.12. Cyclisation reactions. Synthesis of isoquino-
[1%,2%:3,4]pyrazino[2,1-b]quinazolinones. General
procedure
A solution of (0.28 mmol) in concentrated sulfuric acid
(2 mL) was stirred at room temperature overnight, then
poured onto ice and the precipitate thus formed was
filtered and washed with water. The solid residue was
chromatographed in silica gel to afford the pure
products.
3.10. (−)-(1R,4S)-1-Hydroxy-4-methyl-2-phenethyl-1-
phenyl-2,4-dihydro-(1H)-pyrazino[2,1-b]quinazoline-3,6-
dione 19
3.13. (−)-(9S,16bS)-9,16b-Dimethyl-5,6,9,16b-tetra-
hydroisoquino[1%,2%:3,4]pyrazino[2,1-b]quinazoline-8-11-
dione 7
Compound 19 was obtained (EtOAc/hexane, 1:2) as a
white solid; yield: 97% [found: C, 73.52; H, 5.37; N,
9.62. C26H23N3O3 requires: C, 73.39; H, 5.45; N,
9.87%]; mp 76–78°C; [h]2D5=−64 (c 0.13, CHCl3); wmax
(KBr) 3413, 1690, 1669 cm−1; lH (250 MHz, CDCl3)
8.25 (d, 1H, J=7.8 Hz), 7.82–7.78 (m, 2H), 7.52 (m,
1H), 7.41–7.28 (m, 5H), 7.24–7.11 (m, 5H), 6.28 (s, 1H),
5.34 (q, 1H, J=7.2 Hz), 4.35 (m, 1H), 3.6 (m, 1H), 2.9
(m, 2H), 1.28 (d, 3H, J=7.2 Hz); lC (63 MHz, CDCl3)
167.1, 159.8, 152.5, 145.7, 140.8, 138.9, 134.9, 129.4,
128.9, 128.3, 127.8, 127.1, 126.9, 126.3, 126.2, 120.6,
85.0, 53.1, 45.4, 35.8, 17.3.
Compound 7 was obtained (EtOAc/hexane, 1:2) as a
white solid; yield: 75% [found: C, 72.94; H, 5.37; N,
12.08. C21H19N3O2 requires: C, 73.02; H, 5.54; N,
12.16%]; mp 76–78°C; [h]2D5=−30 (c 0.11, CHCl3); wmax
(KBr) 1684, 1589 cm−1; lH (250 MHz, CDCl3) 8.29 (dd,
1H, J=7.8 and 0.8 Hz), 7.82 (m, 1H), 7.79 (dd, 1H,
J=7.6 and 1.3 Hz), 7.52 (m, 1H), 7.32 (dd, 1H, J=7.9
and 0.9 Hz), 7.21 (ddd, 1H, J=7.2, 6.2 and 0.9 Hz),
7.14 (dd, 1H, J=7.2 and 0.9 Hz), 7.03 (ddd, 1H,
J=7.9, 7.2 and 0.9 Hz), 5.36 (q, 1H, J=7.0 Hz), 4.92
(dd, 1H, J=14.0 and 8.9 Hz), 3.66 (ddd, 1H, J=14.0,
8.9 and 6.5 Hz), 3.34 (dd, 1H, J=17.5 and 8.9 Hz), 2.89
(dd, 1H, J=17.5 and 6.5 Hz), 2.26 (s, 3H), 1.01 (d, 3H,
J=7.0 Hz); lC (63 MHz, CDCl3) 169.7, 160.5, 150.8,
146.8, 139.8, 134.8, 132.5, 130.6, 128.2, 128.0, 127.5,
126.8, 126.4, 124.1, 120.5, 63.3, 51.3, 37.1, 30.7, 25.9,
18.6.
3.11. (+)-(1R,4S)- and (−)-(1S,4S)-1-Methoxy-2,4-
dimethyl-1-phenyl-2,4-dihydro-(1H)-pyrazino[2,1-b]-
quinazoline-3,6-dione 15 and 16
A mixture of 12 (280 mg, 0.84 mmol) and p-toluenesul-
fonic acid (catalytic amount) in methanol (20 mL) was
refluxed for 2 h. The mixture was cooled, concentrated
in vacuo and the residue partitioned between CH2Cl2
and a saturated sodium bicarbonate solution. The
organic layer was dried over Na2SO4 and concentrated
to dryness. The residue was subjected to column chro-
matography (alumina, Et2O) yielding 15 (54%) and 16
(7%).
3.14. (−)-(9S,16bR)-9,16b-Dimethyl-5,6,9,16b-tetra-
hydroisoquino[1%,2%:3,4]pyrazino[2,1-b]quinazoline-8-11-
dione 8
Compound 8 was obtained (EtOAc/hexane, 1:2) as a
white solid; yield: 19% [found: C, 73.18; H, 5.26; N,
12.32. C21H19N3O2 requires: C, 73.02; H, 5.54; N,
12.16%]; mp 75–77°C; [h]2D5=−42 (c 0.33, CHCl3); wmax
(KBr) 1734, 1684, 1662 cm−1; lH (250 MHz, CDCl3)
8.22 (d, 1H, J=8.1 Hz), 8.18 (d, 1H, J=7.7 Hz), 7.69
(dd, 1H, J=8.1 and 6.9 Hz), 7.59 (d, 1H, J=8.1 Hz),
7.44 (dd, 1H, J=8.1 and 6.9 Hz), 7.35 (dd, 1H, J=7.7
and 7.5 Hz), 7.25 (d, 1H, J=7.5 Hz), 7.09 (d, 1H,
J=7.5 Hz), 5.45 (q, 1H, J=7.1 Hz), 5.04 (m, 1H), 2.98
(m, 2H), 2.74 (d, 1H, J=13.0 Hz), 2.12 (s, 3H), 1.82 (d,
3H, J=7.1 Hz); lC (63 MHz, CDCl3) 167.3, 160.9,
151.8, 146.5, 135.7, 135.3, 134.4, 132.9, 128.5, 127.8,
127.5, 127.3, 126.5, 125.1, 120.0, 63.0, 52.2, 37.4, 32.3,
29.9, 18.8.
15: [Found: C, 68.32; H, 5.39; N, 12.25. C20H19N3O3
requires: C, 68.75; H, 5.48; N, 12.03%.] mp 141–142°C;
[h]2D5=+112 (c 0.14, CHCl3); wmax (KBr) 1670, 1592
cm−1; lH (250 MHz, CDCl3) 8.21 (dd, 1H, J=7.9 and
0.9 Hz), 7.76–7.72 (m, 2H), 7.66–7.61 (m, 2H), 7.46 (m,
1H), 7.42–7.28 (m, 3H), 5.43 (q, 1H, J=7.0 Hz), 3.25
(s, 3H), 2.98 (s, 3H), 1.67 (d, 3H, J=7.0 Hz). lC (63
MHz, CDCl3) 168.3, 160.2, 148.8, 147.2, 138.7, 134.9,
129.5, 128.7, 128.1, 127.7, 127.0, 126.7, 120.4, 92.3,
52.0, 51.4, 20.0, 14.3.
16: white solid: [Found: C, 68.41; H, 5.02; N, 11.95.
C20H19N3O3 requires: C, 68.75; H, 5.48; N, 12.03%.] mp

M. L. Heredia et al. / Tetrahedron: Asymmetry 12 (2001) 2883–2889
2889
3.15. (−)-(9S,16bR)-9-Methyl-16b-phenyl-5,6,9,16b-tet-
rahydroisoquino[1%,2%:3,4]pyrazino[2,1-b]quinazoline-8-
11-dione 20
Additions to N-acyliminium ions; Pergamon Press:
Oxford, 1991; Vol. 2, pp. 1047–1082.
2. Heaney, H.; Shuhaibar, K. F. Synlett 1995, 47–48.
3. Lo¨gers, M.; Overman, L. E.; Welmaker, G. S. J. Am.
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4. Rigo, B.; El Ghammarti, S.; Couturier, D. Tetrahedron
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Compound 20 was obtained (CHCl3/EtOAc, 9:1) as a
white solid; yield: 54% [found: C, 76.19; H, 4.95; N,
10.17. C26H21N3O2 requires: C, 76.64; H, 5.19; N,
10.31%]; mp 111–113°C; [h]2D5=−236 (c 0.33, CHCl3);
wmax (KBr) 1671, 1596 cm−1; lH (250 MHz, CDCl3) 8.25
(dd, 1H, J=7.9 and 1.5 Hz), 7.70 (ddd, 1H, J=8.2, 7.6
and 1.5 Hz), 7.54 (d, 1H, J=8.2 Hz), 7.48 (ddd, 1H,
J=7.9, 7.5 and 1.2 Hz), 7.41 (m, 1H), 7.32–7.27 (m,
3H), 7.25–7.17 (m, 5H), 5.39 (q, 1H, J=7.2 Hz), 5.16
(m, 1H), 3.47 (m, 1H), 2.92 (m, 2H), 0.78 (d, 3H, J=7.2
Hz); lC (63 MHz, CDCl3) 169.9, 161.0, 151.3, 146.1,
145.1, 134.8, 134.3, 133.6, 133.0, 129.1, 128.5, 128.3,
127.5, 127.3, 126.4, 126.3, 125.2, 120.3, 68.2, 53.6, 41.3,
29.9, 15.0.
3.16. (−)-(9S,16bS)-9-Methyl-16b-phenyl-5,6,9,16b-tet-
rahydroisoquino[1%,2%:3,4]pyrazino[2,1-b]quinazoline-8-
11-dione 21
Compound 21 was obtained (CHCl3/EtOAc, 9:1) as a
white solid; yield: 34% [found: C, 76.39; H, 5.29; N,
10.19. C26H21N3O2 requires: C, 76.64; H, 5.19; N,
10.31%]; mp 104–105°C; [h]2D5=−166 (c 0.27, CHCl3);
wmax (KBr) 1684, 1590 cm−1; lH (250 MHz, CDCl3) 8.26
(dd, 1H, J=7.6 and 1.3 Hz), 7.68 (ddd, 1H, J=7.9, 7
and 1.5 Hz), 7.53–7.47 (m, 2H), 7.45 (m, 1H), 7.33 (m,
2H), 7.28–7.14 (m, 4H), 7.03–6.99 (m, 2H), 5.51 (q, 1H,
J=7.0 Hz), 4.59 (ddd, 1H, J=13.3, 8.2 and 2.3 Hz),
3.24 (dd, 1H, J=13.3 and 9.0 Hz), 2.98 (ddd, 1H,
J=14.9, 9 and 8.2 Hz), 2.56 (dd, 1H, J=14.9 and 6.5
Hz), 1.12 (d, 3H, J=7.0 Hz); lC (63 MHz, CDCl3)
169.3, 160.3, 146.6, 143.8, 136.1, 134.6, 134.5, 130.6,
129.0, 128.9, 128.2, 128.1, 128.0, 127.7, 127.4, 126.6,
126.5, 126.1, 120.0, 70.2, 51.4, 38.5, 26.2, 18.8.
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Acknowledgements
Financial support from CICYT (SAF-97-0143 and
SAF-2000-0130) and a MEC fellowship to M.L.H. are
gratefully acknowledged.
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