1-Alkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as glycine templates. Synthesis of fiscalin B

Article abstract of DOI:10.1016/S0957-4166(02)00027-7

An excess of base allows the regio- and diastereoselective alkylation at C(4) of the glycine templates 1-methyl(isopropyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones 9a and 9b without the need for N(2)-protecting groups. While the alkylation of

Full text of DOI:10.1016/S0957-4166(02)00027-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3387–3398
1-Alkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as
glycine templates. Synthesis of Fiscalin B
Fernando Herna´ndez, Fe´lix L. Buenadicha, Carmen Avendan˜o* and Mo´nica So¨llhuber*
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 14 December 2001; accepted 16 January 2002
Abstract—An excess of base allows the regio- and diastereoselective alkylation at C(4) of the glycine templates 1-methyl(iso-
propyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones 9a and 9b without the need for N(2)-protecting groups. While the
alkylation of 9a gave exclusively the 1,4-anti-isomers, the isopropyl derivative 9b required much longer reaction times and
occurred with lower diastereoselectivity. Fiscalin B 3 was obtained by alkylation of 9b with N-Boc-3-indolylmethyl bromide
followed by indole deprotection. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
have also shown that N-unsubstituted 3-arylmethyl-(6-
alkyl)-piperazine-2,5-diones can be regioselectively N-
acylated to give 2,4-dihydro-4-arylmethyl-(1-alkyl)-
pirazino[2,1-b]quinazoline-3,6-diones.21
Several fungal metabolites like compounds 1–51–7 are
4-alkyl or 1,4-dialkyl derivatives of the pyrazino[2,1-
b]quinazoline-3,6-dione system. They display significant
biological activities, the more complex N-acetyl
ardeemin 5 being an MDR-reversal agent which inhibits
the membrane transport glycoprotein Gp-170.
In this context, we have previously studied the alkylation
of anions derived from 2,4-dialkyl15–17 and 1,2-dialkyl-
pyrazino[2,1-b]quinazoline-3,6-diones,18 demonstrating
the behaviour of the starting N-substituted tricyclic
system as glycine template. Interestingly, some of these
alkyl derivatives retained most of the MDR reversal
activity showed by N-acetyl ardeemin.22
Up to now, metabolites 1–4 have been synthesised from
tripeptides containing
D- or L-tryptophan, L-alanine or
L
-valine or glycine and anthranilic acid, through initial
cyclodehydration to 4-imino-4H-3,1-benzoxazines8–12 or
piperazine-2,5-dione for 1.13 Related N-substituted com-
pounds are usually prepared from enantiomerically pure
1,3-dialkylpiperazine-2,5-diones14–17 via imino ethers by
condensation with anthranilic acid, or alternatively from
1,6-dialkyl-,18 and 1,3,6-trialkylpiperazine-2,5-diones19,20
through N-acylation with o-azidobenzoyl chloride fol-
lowed by an intramolecular Staudinger reaction. We
Approaches to N-unsubstituted compounds such as 2–4
through this chemistry, would require the N,C-dianions
of
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
diones and have not been reported to date. Herein, we
study the alkylation of these anions using their (1S)-1-
methyl and (1S)-1-isopropyl derivatives 9a and 9b as
starting materials.
* Corresponding authors.
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00027-7

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F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
2. Results and discussion
enantiomeric purity (e.e. >95%). Attempting the synthe-
sis of 9a with greater e.e. we followed Ganesan’s
strategy8,10 by starting from ethyl N-Fmoc-l-alanylan-
thranylglycinate (method C), but we obtained the same
e.e. (80%, Scheme 2). Since the enantiomeric purity of
9a could not be optimised, we concluded that epimer-
ization of the C(1)-methyl derivatives in such tricyclic
systems is easier than epimerization of the previously
studied C(4)-methyl analogues.15,16,18,28
Compounds 9a and 9b were prepared by two routes
(Scheme 1): firstly, oxidative debenzylation of (3S)-3-
methyl(isopropyl)-4-p-methoxybenzyl-1-o-azidobenzoyl-
piperazine-2,5-dione 7a, 7b with CAN23–26 followed by
intramolecular Staudinger reaction (method A), or sec-
ondly, by acylation with o-azidobenzoyl chloride of
(3S)-3-methyl(isopropyl)-2,5-bis(trimethylsilyloxy)-3,6-
dihydropyrazine 11a, 11b followed by treatment with
tributylphosphine (method B),27 which was less satisfac-
tory. Both methods gave the 1-methyl derivative 9a
with an e.e. of 80% which could not be optimised,
although both enantiomers were easily separated by
analytical chiral HPLC. This value is similar to that
found in the synthesis of 1-methyl-2-benzyl-
pyrazino[2,1-b]quinolizinedione.18 However, the 1-iso-
Several alkylation assays allowed us to establish good
reaction conditions for the use of 9a as a glycine
template. Thus, with THF as solvent, 10 equiv. of
lithium hexamethyldisilazide as base, 2 equiv. of the
alkyl halide, at low temperatures (−78°C), and with
long reaction times (16 h) we obtained the 1,4-anti
isomers regioselectively and with good diastereoselectiv-
ity (compounds 16a–16g, Table 1). In contrast to the
propyl derivative 9b always had
a
satisfactory
Scheme 1. Reagents and conditions: (i) 2 equiv. DMI, 1.5 equiv. KHMDS, 10 min, −78°C; 3 equiv. o-N3C6H4COCl, −78°C (15
min), 0°C (16 h); (ii) 4 equiv. CAN, H2O/MeCN 2:5, 0.5–1 h, rt; (iii) 1.1 equiv. Bu3P, dry toluene, rt, 16 h; (iv) 2 equiv. TMSCl,
2 equiv. Et3N, CH2Cl2, rt, 2.5 h; (v) 1 equiv. o-N3C6H4COCl, rt, 16 h.
Scheme 2. Reagents and conditions: (i) 1.2 equiv. Fmoc-
D-Ala-Cl, CH2Cl2/aq. Na2CO3, rt, 1 h; (ii) 5 equiv. Ph3P, 4.9 equiv. I2,
10.1 equiv. EtN(i-Pr)2, rt, 3 h; (iii) 20% piperidine in CH2Cl2, rt, 3 h.

F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
Table 1. Alkylation of compounds 9a and 9ba
3389
Entry
R1
R2
% anti compounds a
% syn compounds b
d.e.b (%)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH3
CH2CH=CH2
CH2C6H5
CH2C6H4-p-CH3
CH2C6H4-p-F
CH2C6H4-m-Cl
2-Naphthylmethyl
CH3
CH2CH=CH2
CH2C6H5
CH2C6H4-p-CH3
CH2C6H4-p-F
N-Boc-3-indolylmethyl
57 (16a)
28 (16b)
68 (16c)
64 (16d)
68 (16e)
59 (16f)
66 (16g)
24 (18a)
23 (18b)
63 (18c)
57 (18d)
48 (18e)
31 (18f)
Traces
Traces
Traces (17c)
Traces
Traces
\95
\95
\95
\95
\95
\95
\95
36c
Traces
Traces
41 (19a)
12 (19b)
15 (19c)
10 (19d)
8 (19e)
46 (19f)
9
32
62
70
10
11
12
13
72
19c
a General reaction conditions: THF as solvent, 10 equiv. LHMDS and 2 equiv. of alkyl halide, 16 h (entries 1–7), 3.5 days (entry 8) or 5 days
(entries 9–13) at −78°C.
b The ratios given are of the isolated products.
c Indicates a syn/anti ratio.
previously studied 1-methyl-2-benzyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione,18 even at higher
temperatures, only traces of the 1,4-syn-isomers were
formed and no dialkylation was observed. In this context
it was also notable that alkylation with iodomethane
(entry 1) afforded the 1,4-anti isomer and only traces of
the 1,4-syn-isomer, while in the 1-methyl-2-benzyl deriva-
tive the observed syn/anti ratio was 3/1. Since the
enantiomeric excess values of these compounds were
similar to that of the starting compound 9a (about 80%),
we concluded that the alkylation reaction does not affect
the stereogenic centre at C(1). The low epimerization rates
and the lack of alkylation at C(1) can be explained by
taking into account that under these reaction conditions
the negative charge of the amide anion makes the
neighbouring C(1) position virtually inert to the base.
configuration of both stereogenic centres and the boat
conformation of the piperazine ring in compounds 16a–
16g (Fig. 1). The C(4) substituent always adopts a
pseudoaxial disposition while the C(4) proton is shifted
to l=5.6 ppm in all compounds, showing the character-
istic anisotropic effect of the coplanar carbonyl group at
C(6) on the quasi-equatorial proton.15 As well as the
observed NOEs between the axial substituent at C(4) and
the C(1) proton in the anti-isomers, the chemical shift at
l=3.0–3.2 ppm for C(1)H in compounds 16c–16g indi-
cates folding of the C(4)-benzyl substituent over the
piperazine ring. In accordance, the syn-isomer 17c, which
could be purified, showed the shielding effect of the phenyl
group on the C(1) methyl group (l=0.69 ppm).
When alkylation of 9b was performed with benzyl
bromide under reaction conditions similar to those used
for9a, only8%oftheanti-isomer18cwasisolated. Longer
reaction times (5 days) improved the yields considerably,
1
NOESY experiments and H NMR chemical shifts of
significant protons were conclusive about the relative
Figure 1. Significant NOEs and chemical shifts for compounds 16a–16g and 17c.

3390
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
but also favoured epimerization at C(4) giving the
1,4-dialkyl derivatives with a diastereomeric excess
between 60 and 70% in favour of the anti-isomers
(Table 1, entries 9–12) or in favour of the syn-isomers
(Table 1, entry 8).29
performed on silica gel (Merck 60, 230–400 mesh).
Melting points were measured in a Reichert 723 hot
stage microscope and are uncorrected. NMR spectra
1
were obtained on Bruker AC–250 (250 MHz for H,
62.5 MHz for 13C) and Bruker Avance DPX–300 (300
1
MHz for H, 75 MHz for 13C) spectrometers, in CDCl3
Since 9b is a suitable starting material for the synthesis
of Fiscalin B, its alkylation with N-Boc-3-indolylmethyl
bromide30,31 was performed using the above conditions,
the syn-isomer 19f being the predominant product
(entry 13, Table 1). Subsequent deprotection of 18f with
boron tribromide32 gave Fiscalin B in 88% yield.
unless otherwise mentioned. (Servicio de RMN, Uni-
versidad Complutense). Protons were assigned accord-
ing to COSY, HMQC and/or 1D-NOE experiments;
carbons were assigned according to DEPT, HMQC,
and/or HMBC experiments. Optical rotation values
were determined using a Perkin–Elmer 241 polarimeter
equipped with a 1 mL cell measuring 10 cm at 25°C,
using the emission wavelength of a sodium lamp; con-
centrations are given in g/100 mL. The enantiomeric
purity was determined by 1H NMR (addition of europi-
um(III) tris[3-heptafluoropropylhydroxymethylene)-(+)-
camphorate] [(+)-Eu(HFC)3] as shift reagent) and by
chiral HPLC (comparison to racemic products),
employing a Constrometric 4100 system equipped with
a chiral column (Chiracel OD; 25 cm×0.25 mm) and
UV-detection at 254 nm; mobile phase:hexane/2-
propanol (9:1) at 1 mL/min. IR spectra were recorded
on a Perkin–Elmer Paragon 1000 FT–IR spectrophoto-
meter, with solid compounds compressed into KBr
pellets and liquid compounds placed as films on NaCl
disks. Elemental analyses were determined by the Servi-
cio de Microana´lisis, Universidad Complutense on a
Leco 932 microanalyser.
The boat conformation of the piperazine ring and the
axial disposition of the C(4) substituent in compounds
18 and 19 were also determined from NOESY experi-
1
ments and were supported by H NMR data: chemical
shift values of l=5.3–5.6 ppm for C(4)H in all com-
pounds and differences between the anti and syn iso-
mers for C(1)H. The anti-isomers showed different
C(1)H chemical shifts: lꢀ4.6 ppm in 18a and 18b and
lꢀ2.7–3.2 ppm in compounds 18c–18f (shielding by
the aromatic ring). In the syn-isomers the C(1) proton
resonated at l=4.0–4.3 ppm and the CH isopropyl
proton shifts differed between 19a, 19b (l=2.4 ppm)
and compounds 19c–19f (l=1.2–1.5 ppm) where an
aromatic ring shielding effect is present (see Fig. 2).
3. Conclusion
4.2. (6S)-6-Alkylpiperazine-2,5-diones 6a and 6b
We conclude that the 1-methyl(isopropyl)-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-diones 9a and 9b
allow regio- and diastereoselective alkylation at C(4)
without the need for N(2)-protecting groups showing
variations in the diastereoselectivity when compared
with the N(2)-alkylated systems.
To a stirred solution of of N-Cbz-glycine (4.5 g, 21.4
mmol) and DCC (4.8 g, 23 mmol) in dry CH2Cl2 (150
mL) freshly distilled ethyl N-(p-methoxybenzyl)-
alaninate33 (23 mmol) for 6a or ethyl N-(p-methoxy-
benzyl)-
-valinate33 for 6b was added, and stirring was
L-
L
continued at room temperature for 12 h. The reaction
mixture was filtered, washed successively with aqueous
HCl (1N), aqueous NaHCO3 (1N) and water, dried
over anhydrous Na2SO4 and evaporated. The syrupy
residue, was hydrogenated at 35 psi for 12 h with C/Pd
(10%, 1 g) in ethanol (120 mL), filtered (Celite) and
evaporated. The residue was heated under reflux in
toluene (50 mL) for 12 h affording 6a or 6b,
respectively.
4. Experimental
4.1. General methods
All reagents were of commercial quality and were used
as received. Solvents were dried and purified using
standard techniques. ‘Petroleum ether’ refers to the
fraction boiling at 40–60°C. TLC was carried out on
precoated plates (Merck Kieselgel 60 F254), spots visu-
alised with UV light. Column chromatography was
4.2.1. (6S)-6-Methyl-1-p-methoxybenzylpiperazine-2,5-
dione 6a. Yield 73%; mp: 145–146°C; [h]2D5=+11.0 (c
0.25; CHCl3); wmax (KBr) 2931, 1692, 1655 cm−1; lH
Figure 2. Significant NOEs and chemical shifts for compounds 18 and 19.

F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
3391
(250 MHz, CDCl3) 7.16 (d, 2H, J=8.6 Hz, H-2% and
H-6%), 6.83 (d, 2H, J=8.6 Hz, H-3% and H-5%), 6.53 (s,
1H, N-H), 5.11 (d, 1H, J=14.7 Hz, N-CH2ꢀAr), 4.07
(d, 1H, J=17.2 Hz, H-3), 3.98 (d, 1H, J=14.7 Hz,
N-CH2ꢀAr), 3.96 (d, 1H, J=17.2 Hz, H-3), 3.81 (q, 1H,
J=7.1 Hz, H-6), 3.77 (s, 3H, OCH3), 1.40 (d, 3H,
J=7.1 Hz, CH3); lC (62.5 MHz, CDCl3) 169.9, 163.9,
159.5, 129.8, 127.6, 114.4, 55.4, 54.8, 46.8, 45.0, 17.5.
C13H16N2O3 requires: C, 62.83; H, 6.44; N, 11.27.
Found: C, 62.57; H, 6.69; N, 11.10%.
4.3.2. (3S)-1-(o-Azidobenzoyl)-4-p-methoxybenzyl-3-iso-
propylpiperazine-2,5-dione 7b. Compound 7b was
obtained as an oily product; yield 86%; [h]2D5=−123.0 (c
0.27; CHCl3); wmax (NaCl) 2129, 1718, 1675, 1249 cm−1;
lH (250 MHz, CDCl3) 7.43 (ddd, 1H, J=1.5, 6.5 and
8.0 Hz, H-4%%), 7.34 (dd, 1H, J=1.5 and 7.7 Hz, H-6%%),
7.17 (d, 2H, J=8.9 Hz, H-3% and H-5%), 7.16 (ddd, 1H,
J=0.9, 6.5 and 7.7 Hz, H-5%%), 7.05 (dd, 1H, J=0.9 and
8.0 Hz, H-3%%), 6.85 (d, 2H, J=8.7 Hz, H-2% and H-6%),
5.51 (d, 1H, J=14.7 Hz, N-CH2ꢀAr), 4.86 (d, 1H,
J=17.8 Hz, H-6), 4.24 (d, 1H, J=17.8 Hz, H-6), 3.90
(d, 1H, J=14.7 Hz, N-CH2ꢀAr), 3.76 (s, 3H, OCH3),
3.69 (d, 1H, J=6.0 Hz, H-3), 2.25 (m, 1H, CH(CH3)2),
1.06 (d, 3H, J=6.8 Hz, CH3), 1.01 (d, 3H, J=6.8 Hz,
CH3); lC (62.5 MHz, CDCl3) 168.2, 167.3, 164.4, 159.6,
136.6, 131.9, 129.6, 129.2, 128.3, 127.2, 125.2, 118.0,
114.5, 65.4, 55.3, 47.8, 46.8, 32.4, 20.0, 18.6.
C22H23N5O4 requires: C, 62.64; H, 5.45; N, 16.60.
Found: C, 62.59; H, 5.28; N, 16.25%.
4.2.2.
(6S)-6-Isopropyl-1-p-methoxybenzylpiperazine-
2,5-dione 6b. Compound 6b was obtained as a syrup;
yield 76%; [h]D25=−9.0 (c 0.24; CHCl3); wmax (NaCl)
2963, 2932, 1654, 1245 cm−1; lH (250 MHz, CDCl3)
7.13 (d, 2H, J=8.6 Hz, H-2% and H-6%), 6.82 (d, 2H,
J=8.6 Hz, H-3% and H-5%), 6.61 (s, 1H, N-H), 5.34 (d,
1H, J=14.7 Hz, N-CH2ꢀAr), 4.10 (d, 1H, J=17.4 Hz,
H-3), 3.98 (d, 1H, J=14.7 Hz, N-CH2ꢀAr), 3.96 (d, 1H,
J=17.4 Hz, H-3), 3.77 (s, 3H, OCH3), 3.63 (d, 1H,
J=4.9 Hz, H-6), 2.22 (m, 1H, J=4.9 and 6.9 Hz,
CH(CH3)2), 1.08 (d, 3H, J=6.9 Hz, CH3), 1.40 (d, 3H,
J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3) 167.7, 164.5,
159.4, 129.7, 127.5, 114.4, 64.3, 55.4, 47.8, 45.4, 31.9,
19.9, 17.7. C15H20N2O3 requires: C, 65.13; H, 7.23; N,
10.13. Found: C, 64.90; H, 7.34; N, 10.34%.
4.4. (3S)-3-Alkyl-1-(o-azidobenzoyl)piperazine-2,5-
diones 8a and 8b
A solution of 7a or 7b (3.8 mmol) in acetonitrile:water
(5:2, 50 mL) and CAN (8.4 g, 15.3 mmol) was stirred
for 80 min (8a) or 35 min (8b) at room temperature.
The reaction mixture was extracted with CHCl3, dried
(Na2SO4) and evaporated. Column chromatography
(EtOAc:petroleum ether, 1:1) afforded 8a or 8b,
respectively.
4.3. (3S)-3-Alkyl-1-(o-azidobenzoyl)-4-p-methoxyben-
zylpiperazine-2,5-diones 7a and 7b
To a magnetically stirred solution of compound 6a or
6b (4.7 mmol) in dry THF (90 mL) at −78°C under
argon was added dropwise via syringe DMI (0.95 mL,
9.5 mmol) and a solution of potassium hexamethyldisi-
lazide in dry toluene (0.5 M, 14 mL), followed 10 min
later by addition of o-azidobenzoyl chloride (2 g, 14.1
mmol) in THF (5 mL). Stirring was continued for 15
min at −78°C, and then for a further 16 h at room
temperature. The reaction mixture was quenched with
ice and extracted with chloroform (3×10 mL). The
organic layer was dried over anhydrous Na2SO4, evapo-
rated and isolated by column chromatography
(petroleum ether:EtOAc 2:3 for 7a and petroleum
ether:EtOAc, 1:1 for 7b).
4.4.1. (3S)-1-(o-Azidobenzoyl)-3-methylpiperazine-2,5-
dione 8a. Yield: 67%; mp: 155–157°C; [h]2D5=−4.0 (c
0.25; CHCl3); wmax (NaCl) 3424, 2133, 1692 cm−1; lH
(250 MHz, CDCl3) 7.48 (ddd, 1H, J=1.6, 6.4 and 7.9
Hz, H-4%), 7.37 (dd, 1H, J=1.6 and 7.7 Hz, H-6%), 7.33
(s, 1H, N-H), 7.20 (ddd, 1H, J=1.0, 6.4 and 7.7 Hz,
H-3%), 7.15 (dd, 1H, J=1.6 and 7.9 Hz, H-5%), 4.64 (d,
1H, J=17.7 Hz, H-6), 4.38 (d, 1H, J=17.7 Hz, H-6),
4.20 (dq, 1H, J=1.4 and 6.9 Hz, H-3), 1.50 (d, 3H,
J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3) 168.6, 168.1,
166.8, 136.5, 131.7, 128.8, 128.0, 124.9, 118.1, 51.7,
46.6, 17.9. C12H11N5O3 requires: C, 52.74; H, 4.02; N,
25.64. Found: C, 52.59; H, 4.17; N, 25.29%.
4.3.1.
(3S)-1-(o-Azidobenzoyl)-4-p-methoxybenzyl-3-
methylpiperazine-2,5-dione 7a. Compound 7a was
obtained as an oily product; yield 76%; [h]2D5=−78.0 (c
0.25; CHCl3); wmax (NaCl) 2128, 1725, 1675 cm−1; lH
(250 MHz, CDCl3) 7.41 (ddd, 1H, J=1.6, 7.6 and 8.0
Hz, H-4%%), 7.35 (dd, 1H, J=1.3 and 8.1 Hz, H-6%%), 7.18
(d, 2H, J=8.6 Hz, H-2% and H-6%), 7.14 (ddd, 1H,
J=0.9, 7.6 and 8.0 Hz, H-5%%), 7.03 (d, 1H, J=8.0 Hz,
H-3%%), 6.84 (d, 2H, J=8.6 Hz, H-3% and H-5%), 5.21 (d,
1H, J=14.7 Hz, N-CH2ꢀAr), 4.90 (d, 1H, J=17.4 Hz,
H-6), 4.15 (d, 1H, J=17.4 Hz, H-6), 3.92 (q, 1H, J=7.2
Hz, H-3), 3.90 (d, 1H, J=14.7 Hz, N-CH2ꢀAr), 3.74 (s,
3H, OCH3), 1.38 (d, 3H, J=7.2 Hz, CH3); lC (62.5
MHz, CDCl3) 168.9, 167.7, 163.7, 159.3, 136.5, 131.9,
129.3, 129.2, 127.6, 127.1, 124.9, 117.9, 114.3, 55.7,
55.1, 46.1, 45.9, 16.9. C20H19N5O4 requires: C, 61.06; H,
4.86; N, 17.80. Found: C, 60.89; H, 4.77; N, 18.10%.
4.4.2. (3S)-1-(o-Azidobenzoyl)-3-isopropylpiperazine-2,5-
dione 8b. Yield: 84%; mp: 115–117°C; [h]2D5=−86.4 (c
0.25; CHCl3); wmax (NaCl) 2966, 2129, 1686 cm−1; lH
(250 MHz, CDCl3) 8.42 (d, 1H, J=4.3 Hz, N-H), 7.32
(ddd, 1H, J=1.5, 7.0 and 8.3 Hz, H-4%), 7.22 (dd, 1H,
J=1.5 and 7.8 Hz, H-6%), 7.04 (ddd, 1H, J=0.9, 7.0
and 7.8 Hz, H-5%), 7.01 (dd, 1H, J=0.9 and 8.3 Hz,
H-3%), 4.42 (d, 1H, J=17.9 Hz, H-6), 4.24 (d, 1H,
J=17.9 Hz, H-6), 3.80 (dd, 1H, J=4.3 and 6.8 Hz,
H-3), 2.20 (m, 1H, J=4.3 and 6.8 Hz, CH(CH3)2), 0.93
(d, 3H, J=6.8 Hz, CH3), 0.85 (d, 3H, J=6.8 Hz, CH3);
lC (62.5 MHz, CDCl3) 168.4, 168.0, 167.4, 136.5, 131.6,
128.6, 124.9, 118.2, 61.7, 46.2, 32.4, 20.9, 18.7.
C14H15N5O3 requires: C, 55.75; H, 4.97; N, 23.23.
Found: C, 55.46; H, 4.95; N, 23.08%.

3392
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
4.5. Synthesis of compounds 9 (method A)
4.6.1. (6S)-6-Methyl-6,14-dihydroquinazolino[2%,3%:5,4]-
pyrazino[2,1-b]quinazoline-8,16-dione 13a. Compound
13a was obtained as an oily product; [h]2D5=−90.5 (c
0.61; CHCl3); wmax (NaCl) 2932, 2859, 1683, 1610,
1470, 1320 cm−1; lH (250 MHz, CDCl3) 8.30 (dd, 2H,
J=1.4 and 8.1 Hz, H-1 and H-9), 7.79 (ddd, 2H,
J=1.4, 7.1 and 8.3 Hz, H-3 and H-11), 7.69 (dd, 2H,
J=1.3 and 8.3 Hz, H-4 and H-12), 7.52 (ddd, 2H,
J=1.3, 7.1 and 8.1 Hz, H-2 and H-10), 6.21 (q, 1H,
J=7.2 Hz, H-6), 6.06 (d, 1H, J=17.6 Hz, H-14), 4.76
(d, 1H, J=17.6 Hz, H-14), 1.77 (d, 3H, J=7.2 Hz,
CH3); lC (62.5 MHz, CDCl3) 160.2, 159.8, 151.1,
147.3, 147.2, 147.1, 134.9, 127.5, 127.4, 127.3, 126.9,
120.5, 120.1, 52.1, 43.9, 18.6. C19H14N4O2 requires: C,
69.08; H, 4.27; N, 16.96. Found: C, 69.13; H, 4.28; N,
16.94%.
To a stirred solution of 8a or 8b (3 mmol) in dry
toluene (10 mL) tributylphosphine (3.3 mmol) was
added via syringe. The mixture was stirred under
argon for 16 h at room temperature, and evaporated
under reduced pressure. The residue was purified by
column chromatography (ethyl acetate).
4.5.1.
(1S)-1-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 9a. Yield: 79%; mp: 240–243°C;
wmax (KBr) 3261, 2924, 1684, 1607 cm−1; lH (250 MHz,
CDCl3) 8.27 (dd, 1H, J=1.4 and 8.1 Hz, H-7), 7.77
(ddd, 1H, J=1.4, 7.1 and 8.3 Hz, H-9), 7.66 (dd, 1H,
J=1.3 and 8.3 Hz, H-10), 7.49 (ddd, 1H, J=1.3, 7.1
and 8.1 Hz, H-8), 7.00 (s, 1H, N-H), 4.74 (m, 2H,
H-4), 4.68 (dq, 1H, J=2.4 and 6.9 Hz, H-1), 1.71 (d,
3H, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3) 178.7,
166.4, 148.9, 147.0, 134.7, 127.3, 127.2, 126.7, 119.9,
51.4, 44.5, 20.3. C12H11N3O2 requires: C, 62.87; H,
4.84; N, 18.33. Found: C, 62.56; H, 4.88; N, 17.98%.
4.6.2.
(4S)-4-Methyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 12a. Compound 12a was
obtained as a solid; mp: 216–218°C; [h]2D5=+146.9 (c
0.28; DMSO); wmax (KBr) 3199, 3067, 2927, 1671, 1602
cm−1; lH (250 MHz, CDCl3) 8.21 (dd, 1H, J=1.5 and
8.1 Hz, H-7), 8.18 (s, 1H, N-H), 7.71 (ddd, 1H, J=
1.5, 7.1 and 8.2 Hz, H-9), 7.57 (dd, 1H, J=1.2 and 8.2
Hz, H-10), 7.44 (ddd, 1H, J=1.2, 7.1 and 8.1 Hz,
H-8), 5.38 (q, 1H, J=7.2 Hz, H-4), 4.64 (d, 1H, J=
16.9 Hz, H-1), 4.48 (dd, 1H, J=4.7 and 16.9 Hz,
H-1), 1.61 (d, 3H, J=7.2 Hz, CH3); lC (62.5 MHz,
CDCl3) 170.6, 160.3, 147.7, 147.2, 135.0, 127.4, 127.1,
127.0, 120.5, 51.9, 45.1, 17.0. C12H11N3O2 requires: C,
62.87; H, 4.84; N, 18.33. Found: C, 62.74; H, 4.68; N,
18.34%.
4.5.2. (1S)-1-Isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 9b. Yield: 80%; mp: 171°C;
[h]2D5=−26.0 (c 0.28; DMSO); wmax (KBr) 1667, 1604
cm−1; lH (250 MHz, CDCl3) 8.45 (s, 1H, N-H), 8.20
(dd, 1H, J=1.2 and 8.0 Hz, H-7), 7.72 (ddd, 1H,
J=1.2, 7.0 and 8.3 Hz, H-9), 7.62 (dd, 1H, J=1.2 and
8.3 Hz, H-10), 7.43 (ddd, 1H, J=1.2, 7.0 and 8.0 Hz,
H-8), 4.93 (d, 1H, J=18.9 Hz, H-4), 4.39 (t, 1H,
J=4.4 Hz, H-1), 4.31 (d, 1H, J=18.9 Hz, H-4), 2.39
(m, 1H, J=8.8 Hz, CH(CH3)2), 1.07 (d, 3H, J=6.8
Hz, CH3), 0.94 (d, 3H, J=6.8 Hz, CH3); lC (62.5
MHz, CDCl3) 166.6, 160.5, 150.1, 146.7, 134.8, 127.2,
126.9, 126.6, 119.6, 61.5, 44.6, 35.1, 19.1, 16.9.
C14H15N3O2 requires: C, 65.36; H, 5.88; N, 16.33.
Found: C, 65.21; H, 5.83; N, 16.42%.
4.6.3.
(6S)-6-Isopropyl-6,14-dihydroquinazolino[2%,3%-
5,4]pyrazino[2,1-b]quinazoline-8,16-dione 13b. Com-
pound 13b was obtained as an oily product;
[h]2D5=−155.6 (c 0.32; CHCl3); wmax (NaCl) 2970, 1684,
1608, 1568 cm−1; lH (250 MHz, CDCl3) 8.30 (m, 2H,
H-1 and H-9), 7.75 (m, 4H, H-3, H-4, H-11 and H-
12), 7.51 (ddd, 2H, J=1.5, 6.9 and 8.1 Hz, H-2 and
H-10), 6.00 (d, 1H, J=17.7 Hz, H-14), 5.90 (d, 1H,
J=10.1 Hz, H-6), 4.80 (d, 1H, J=17.7 Hz, H-14),
2.30 (m, 1H, J=6.7 and 10.1 Hz, CH(CH3)2), 1.14 (d,
3H, J=6.7 Hz, CH3), 1.06 (d, 3H, J=6.7 Hz, CH3);
lC (62.5 MHz, CDCl3) 160.5, 160.4, 149.6, 147.7,
146.9, 146.8, 134.9, 134.8, 127.6, 127.55, 127.5, 127.2,
127.1, 126.8, 120.4, 120.1, 61.0, 44.5, 32.3, 19.7, 19.6.
C21H18N4O2 requires: C, 70.38; H, 5.06; N, 15.63.
Found: C, 70.21; H, 4.98; N, 15.92%.
4.6. Synthesis of compounds 9, 12 and 13 (method B)
To
a suspension of the suitable piperazinedione
10a34,35 or 10b36,37 (7.7 mmol) in dry CH2Cl2 (50 mL)
were added trimethylsilyl chloride (2 mL, 15.4 mmol)
and NEt3 (1.0 mL, 7.7 mmol). The suspension was
vigorously stirred under argon at room temperature
until complete disolution. Then, a solution of o-azi-
dobenzoyl chloride (1.48 g, 7.7 mmol) in CH2Cl2 (10
mL) was added and the reaction was stirred for a
further 16 h at room temperature. The mixture was
washed with brine (3×25 mL). The organic layer
together with the CH2Cl2 layers coming from the
extraction of the brine with CH2Cl2 (3×10 mL), were
dried (Na2SO4), filtered, evaporated and dried. The
solid residue, which was a mixture of both N-acyl
piperazinediones plus N,N-diacyl derivative was used
without further purification in the next step. The acyl
derivatives and Bu3P (2 mL, 8 mmol) in dry toluene (8
mL) were stirred at room temperature under argon for
16 h. After evaporation, the residue was purified by
column chromatography (EtOAc:MeOH, 9:1) yielding
13a (10%), 9a (32%) and 12a (27%); or 13b (10%); 9b
(38%) and 12b (23%).
4.6.4. (4S)-4-Isopropyl-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 12b. Compound 12b was
obtained as a solid; mp: 203–204°C; [h]2D5=+132.0 (c
0.22; CHCl3); wmax (NaCl) 3214, 2969, 1685, 1606,
1469 cm−1; lH (250 MHz, CDCl3) 8.26 (dd, 1H, J=1.5
and 8.0 Hz, H-7), 7.75 (ddd, 1H, J=1.5, 7.0 and 8.4
Hz, H-9), 7.60 (dd, 1H, J=1.1 and 8.4 Hz, H-10),
7.48 (ddd, 1H, J=1.1, 7.0 and 8.0 Hz, H-8), 7.20 (s,
1H, N-H), 5.24 (d, 1H, J=7.9 Hz, H-4), 4.69 (d, 1H,
J=17.2 Hz, H-1), 4.42 (dd, 1H, J=5.2 and 17.2 Hz,
H-1), 2.27 (m, 1H, J=7.0 Hz, CH(CH3)2), 1.14 (d,
3H, J=6.8 Hz, CH3), 1.06 (d, 3H, J=6.8 Hz, CH3);
lC (62.5 MHz, CDCl3) 168.7, 160.8, 148.4, 147.0,

F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
3393
134.9, 127.3, 127.2, 126.9, 120.3, 60.8, 45.5, 31.8, 19.9,
18.9. C14H15N3O2 requires: C, 65.36; H, 5.88; N, 16.33.
Found: C, 65.21; H, 5.98; N, 16.12%.
4.9. Ethyl-N-{2-[(S)-1-N-[(9H-fluoren-9-ylmethoxy)-
carbonyl]aminoethyl]-4H-3,1-benzoxazin-4-ylidene}-
glycinate 15
To a solution of 14 (0.98 g, 1.9 mmol) in dry CH2Cl2
(30 mL) was added Ph3P (2.49 g, 9.5 mmol), I2 (2.38
g, 9.4 mmol) and N,N-diisopropylethylamine (3.5 mL,
19.9 mmol). The reaction mixture was stirred at room
temperature for 3 h, quenched with aqueous Na2CO3
(20 mL), then extracted with CH2Cl2, dried over
Na2SO4, filtered, and evaporated. The residue was
purified by column chromatography (EtOAc:hexane:
Et3N, 5:5:0.2) to give 15 (0.64 g, 68%). Mp: 100–
101°C; wmax (NaCl) 3339, 2927, 1681, 1605, 1523,
1450 cm−1; lH (250 MHz, CDCl3) 8.15 (dd, 1H, J=
1.3 and 7.9 Hz, H-5), 7.74 (d, 2H, J=7.4 Hz, H-4%
and H-5%), 7.61 (t, 2H, J=7.4 Hz, H-2% and H-7%),
7.55 (dt, 1H, J=1.5 and 8.1 Hz, H-7), 7.32 (m, 6H,
H-6, H-8, H-1%, H-3%, H-6% and H-8%), 5.73 (d, 1H,
J=7.7 Hz, NH-COO), 4.64 (qui, 1H, J=7.2 Hz, CH-
CH3), 4.41 (m, 3H, H-9% and O-CH2ꢀAr), 4.28 (s, 2H,
N-CH2-COO), 4.20 (q, 2H, J=7.2 Hz, O-CH2ꢀCH3),
1.52 (d, 3H, J=7.2 Hz, CH3), 1.29 (t, 3H, J=7.1 Hz,
O-CH2ꢀCH3); lC (62.5 MHz, CDCl3) 170.2, 159.4,
155.5, 148.6, 143.7, 141.2, 140.8, 133.4, 128.4, 127.6,
126.9, 126.2, 125.0, 124.9, 119.9, 119.0, 66.9, 61.0,
48.8, 48.2, 47.1, 19.1, 14.1. C29H27N3O5 requires: C,
70.01; H, 5.47; N, 8.45. Found: C, 69.91; H, 5.44; N,
8.52%.
4.7. Ethyl N-(2-aminobenzoyl)-glycinate
To a solution of glycine ethyl ester hydrochloride (1.0
g, 7.16 mmol) in dry CH2Cl2 (30 mL) was added Et3N
(1 mL, 7.2 mmol). To the filtered organic phase EDC
(1.5 g, 7.88 mmol) was added followed by anthranilic
acid (2 g, 14.32 mmol) in 10 portions over 1.5 h at
room temperature with stirring. After being stirred for
an additional 1.5 h, the organic phase was washed with
diluted ammonium hydroxide, dried (Na2SO4), filtered
and evaporated. The residue was purified by column
chromatography (EtOAc:CH2Cl2, 0.5:9.5) to yield 1.15
g (72%) of N-(2-aminobenzoyl)glycinate ethyl ester as a
white solid. Mp: 54–55°C; wmax (NaCl) 3359, 2983,
1733, 1644, 1585, 1531 cm−1; lH (250 MHz, CDCl3)
7.34 (dd, 1H, J=1.5 and 8.1 Hz, H-6), 7.10 (ddd, 1H,
J=1.5, 7.4 and 8.4 Hz, H-4), 6.89 (t, 1H, J=5.3 Hz,
CO-NH), 6.58 (dd, 1H, J=1.0 and 8.4 Hz, H-3), 6.53
(ddd, 1H, J=1.0, 7.4 and 8.1 Hz, H-5), 5.66 (s, 2H,
NH2), 4.13 (q, 2H, J=7.1 Hz, O-CH2ꢀCH3), 4.06 (d,
2H, J=5.3 Hz, NH-CH2-CO), 1.20 (t, 3H, J=7.1 Hz,
O-CH2ꢀCH3); lC (62.5 MHz, CDCl3) 170.2, 169.4,
148.7, 132.4, 127.5, 117.1, 116.4, 115.0, 61.4, 41.4, 14.0.
C11H14N2O3 requires: C, 59.45; H, 6.35; N, 12.60.
Found: C, 59.18; H, 6.18; N, 12.52%.
4.10. Synthesis of compound 9a from 15
4.8. Ethyl-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-
D
-
The oxazine 15 (638 mg, 1.3 mmol) in CH2Cl2 (30
mL) was treated with piperidine (8 mL) at room tem-
perature under argon for 3 h. The reaction mixture
was evaporated and purified by column chromatogra-
phy (EtOAc/MeOH, 9.5:0.5) to give 9a (176 mg,
61%).
alanyl-2-aminobenzoylglycinate 14
To a solution of ethyl N-(2-aminobenzoyl)glycinate
(1.15 g, 5.18 mmol) and DMAP (0.63 g, 5.18 mmol)
in dry CH2Cl2 (30 mL) was added Fmoc-L
-Ala-Cl38
(5.7 mmol). The mixture was stirred for 1 h at room
temperature, followed by addition of aqueous Na2CO3
solution (1 M, 30 mL). After stirring the reaction for
a total of 2 h, the mixture was extracted with CH2Cl2,
dried over Na2SO4, filtered, and evaporated. The
residue was purified by column chromatography
(EtOAc:hexane, 6:4) to give 14 as a white solid (0.98
g, 86%). Mp: 184–185°C; wmax (NaCl) 3326, 2922,
2855, 1725, 1643, 1590, 1522, 1446 cm−1; lH (250
MHz, CDCl3) 11.47 (s, 1H, NH-CO), 8.59 (d, 1H,
J=7.8 Hz, H-3), 7.74 (d, 2H, J=7.3 Hz, H-4% and
H-5%), 7.63 (t, 1H, J=8.3 Hz, H-4), 7.54 (d, 2H, J=
7.3 Hz, H-1% and H-8%), 7.48 (t, 1H, J=8.3 Hz, H-6),
7.31 (m, 4H, Ar), 7.12 (t, 1H, J=7.0 Hz, H-5), 6.72
(s, 1H, NH(Gly)), 5.52 (d, 1H, J=7.0 Hz, NH(Ala)),
4.42 (qui, 1H, J=7.0 Hz, CH-CH3), 4.33 (t, 1H, J=
7.2 Hz, H-9%), 4.26 (m, 2H, O-CH2ꢀAr), 4.21 (q, 2H,
J=7.2 Hz, O-CH2ꢀCH3), 4.09 (m, 2H, COꢀCH2ꢀN),
1.52 (d, 3H, J=7.0 Hz, CH3), 1.27 (t, 3H, J=7.2 Hz,
O-CH2ꢀCH3); lC (62.5 MHz, CDCl3):171.0, 169.6,
168.5, 156.4, 143.7, 141.1, 139.1, 133.0, 127.6, 126.9,
126.7, 125.2, 123.2, 121.4, 119.8, 119.6, 67.1, 61.8,
48.3, 47.1, 41.6, 19.1, 14.0. C29H29N3O6 requires: C,
67.56; H, 5.67; N, 8.15. Found: C, 67.61; H, 5.64; N,
8.19%.
4.11. General alkylation procedures
4.11.1. Alkylation of 9a. To a cold (−78°C), magneti-
cally stirred solution of 9a (0.5 mmol) in dry THF (10
mL) was added, under argon, dropwise via syringe a
solution of lithium hexamethyldisilazide in THF (1 M,
5.0 mL), followed after 10 min by a solution of the
appropriate halide (1.0 mmol dissolved in THF (5
mL)). The reaction mixture was stirred at –78°C for
16 h, quenched with drops of glacial acetic acid fol-
lowed by a saturated aqueous solution of ammonium
chloride (5 mL), and extracted with CHCl3. The
organic layer was dried over anhydrous Na2SO4 and
evaporated. Column chromatography of the residue
on silica gel (EtOAc:CH2Cl2, 2:3 unless otherwise
mentioned) afforded the anti-4-alkyl compounds 16a–
16g followed by traces of the syn-compounds 17.
4.11.1.1.
(1S,4R)-1,4-Dimethyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 16a. Compound
16a was obtained (EtOAc) as a solid; mp: 165°C;
yield 57%; wmax (NaCl) 3239, 2931, 1688, 1607 cm−1;
lH (250 MHz, CDCl3) 8.26 (dd, 1H, J=1.5 and 8.1
Hz, H-7), 7.75 (ddd, 1H, J=1.5, 7.0 and 8.2 Hz,

3394
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
H-9), 7.67 (dd, 1H, J=1.4 and 8.2 Hz, H-10), 7.48
(ddd, 1H, J=1.4, 7.0 and 8.1 Hz, H-8), 7.36 (s, 1H,
N-H), 5.47 (dq, 1H, J=1.0 and 7.2 Hz, H-4), 4.71 (q,
1H, J=6.6 Hz, H-1), 1.79 (d, 3H, J=6.6 Hz, C(1)-
CH3), 1.63 (d, 3H, J=7.2 Hz, C(4)-CH3); lC (62.5
MHz, CDCl3) 170.3, 160.3, 150.6, 146.9, 134.5, 127.4,
127.2, 126.7, 120.3, 52.3, 49.2, 17.4, 16.4. C13H13N3O2
requires: C, 64.19; H, 5.39; N, 17.27. Found: C, 63.98;
H, 5.34; N, 17.22%.
8.4 Hz, H-9), 7.63 (dd, 1H, J=1.2 and 8.4 Hz, H-10),
7.52 (ddd, 1H, J=1.2, 7.0 and 8.0 Hz, H-8), 7.42 (s,
1H, N-H), 6.97 (d, 2H, J=7.0 Hz, Ar), 6.83 (d, 2H,
J=7.0 Hz, Ar) 5.60 (‘t%, 1H, J=4.3 Hz, H-4), 3.43 (dd,
1H, J=4.3 and 15.0 Hz, CH2ꢀAr), 3.36 (dd, 1H, J=4.3
and 15.0 Hz, CH2ꢀAr), 3.04 (q, 1H, J=6.6 Hz, H-1),
2.26 (s, 3H, Ar-CH3), 1.47 (d, 3H, J=6.6 Hz, CH3); lC
(62.5 MHz, CDCl3) 169.0, 160.5, 151.5, 146.9, 137.4,
134.6, 131.7, 129.5, 129.4, 127.3, 127.0, 126.8, 120.0,
57.6, 48.8, 36.4, 21.0, 18.8. C20H19N3O2 requires: C,
72.04; H, 5.75; N, 12.61. Found: C, 71.91; H, 5.73; N,
11.87%.
4.11.1.2.
(1S,4R)-4-Allyl-1-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 16b. Compound
16b was obtained (EtOAc) as a solid; mp: 102–103°C;
yield 31%; wmax (NaCl) 3249, 2923, 1682, 1606 cm−1; lH
(250 MHz, CDCl3) 8.26 (dd, 1H, J=1.5 and 8.0 Hz,
H-7), 7.75 (ddd, 1H, J=1.5, 7.0 and 8.4 Hz, H-9), 7.66
(dd, 1H, J=1.3 and 8.4 Hz, H-10), 7.48 (ddd, 1H,
J=1.3, 7.0 and 8.0 Hz, H-8), 7.36 (s, 1H, N-H), 5.85
(ddt, 1H, J=7.5, 10.4 and 17.8 Hz, H-2%), 5.45 (t, 1H,
J=6.3 Hz, H-4), 5.08 (d, 1H, J=10.4 H-3%), 5.03 (dd,
1H, J=1.3 and 17.8 Hz, H-3%), 4.76 (q, 1H, J=6.6 Hz,
H-1), 2.85 (ddd, 1H, J=7.1, 7.5 and 14.1 Hz, H-1%),
2.80 (ddd, 1H, J=7.1, 7.5 and 14.1 Hz, H-1%), 1.75 (d,
3H, J=6.6 Hz, CH3); lC (62.5 MHz, CDCl3) 169.0,
160.4, 151.0, 146.8, 134.6, 131.3, 127.4, 127.2, 126.8,
120.2, 120.1, 55.9, 49.5, 39.5, 18.1. C15H15N3O2
requires: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.71;
H, 5.64; N, 15.52%.
4.11.1.6.
(1S,4R)-4-(p-Fluorobenzyl)-1-methyl-2,4-
16e.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Mp: 161°C; yield 68%; wmax (NaCl) 3230, 2923, 1684,
1601 cm−1; lH (250 MHz, CDCl3) 8.28 (dd, 1H, J=1.5
and 8.0 Hz, H-7), 7.76 (ddd, 1H, J=1.5, 7.1 and 8.3
Hz, H-9), 7.64 (s, 1H, N-H), 7.63 (dd, 1H, J=1.2 and
8.3 Hz, H-10), 7.50 (ddd, 1H, J=1.2, 7.1 and 8.0 Hz,
H-8), 6.90 (m, 4H, Ar), 5.59 (dd, 1H, J=4.2 and 5.5
Hz, H-4), 3.42 (dd, 1H, J=5.5 and 14.2 Hz, CH2ꢀAr),
3.36 (dd, 1H, J=4.2 and 14.2 Hz, CH2ꢀAr), 3.24 (q,
1H, J=6.6 Hz, H-1), 1.52 (d, 3H, J=6.6 Hz, CH3); lC
(62.5 MHz, CDCl3) 168.7, 162.2 (d, J=247.2 Hz),
160.5, 151.1, 146.9, 134.7, 131.1 (d, J=7.9 Hz), 130.7
(d, J=3.4 Hz), 127.4, 127.2, 126.7, 119.9, 115.7 (d,
J=21.2 Hz), 57.4, 48.9, 36.0, 18.6. C19H16FN3O2
requires: C, 67.65; H, 4.78; N, 12.46. Found: C, 67.41;
H, 4.65; N, 12.64%.
4.11.1.3. (1S,4R)-4-Benzyl-1-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 16c. Mp: 194–
195°C; yield 68%; wmax (NaCl) 2923, 1684, 1600 cm−1;
lH (250 MHz, CDCl3) 8.31 (dd, 1H, J=1.3 and 8.0 Hz,
H-7), 7.76 (ddd, 1H, J=1.3, 7.1 and 8.3 Hz, H-9), 7.63
(dd, 1H, J=1.1 and 8.3 Hz, H-10), 7.50 (ddd, 1H,
J=1.1, 7.1 and 8.0 Hz, H-8), 7.21 (m, 3H, Ph), 6.93 (m,
2H, Ph), 6.55 (s, 1H, N-H), 5.63 (t, 1H, J=4.6 Hz,
H-4), 3.48 (dd, 1H, J=5.1 and 14.0 Hz, CH2-Ph), 3.42
(dd, 1H, J=3.9 and 14.0 Hz, CH2-Ph), 3.00 (q, 1H,
J=6.6 Hz, H-1), 1.46 (d, 3H, J=6.6 Hz, CH3); lC (62.5
MHz, CDCl3) 168.8, 160.7, 151.5, 147.0, 135.0, 134.8,
129.8, 128.9, 127.9, 127.5, 127.3, 126.9, 120.1, 57.7,
49.0, 37.0, 18.9. C19H17N3O2 requires: C, 71.46; H, 5.37;
N, 13.16. Found: C, 71.61; H, 5.34; N, 13.22%.
4.11.1.7.
(1S,4R)-4-(m-Chlorobenzyl)-1-methyl-2,4-
16f.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Mp: 85–86°C; yield 59%; wmax (NaCl) 3253, 2926, 1686,
1599 cm−1; lH (250 MHz, CDCl3) 8.29 (dd, 1H, J=1.5
and 8.0 Hz, H-7), 7.77 (ddd, 1H, J=1.5, 7.1 and 8.4
Hz, H-9), 7.64 (dd, 1H, J=1.2 and 8.4 Hz, H-10), 7.51
(ddd, 1H, J=1.2, 7.1 and 8.0 Hz, H-8), 7.35 (s, 1H,
N-H), 7.21 (ddd, 1H, J=1.1, 1.6 and 7.8 Hz, H-4%),
7.13 (t, 1H, J=7.8 Hz, H-5%), 7.03 (dd, 1H, J=1.1 and
1.6 Hz, H-2%), 6.84 (dd, 1H, J=1.1 and 7.5 Hz, H-6%),
5.61 (t, 1H, J=4.8 Hz, H-4), 3.40 (dd, 1H, J=4.8 and
14.3 Hz, CH2ꢀAr), 3.39 (dq, 1H, J=2.6 and 6.6 Hz,
H-1), 3.34 (dd, 1H, J=4.8 and 14.3 Hz, CH2ꢀAr), 1.54
(d, 3H, J=6.6 Hz, CH3); lC (62.5 MHz, CDCl3) 168.4,
160.5, 150.9, 146.9, 136.9, 134.8, 134.5, 130.0, 129.6,
127.9, 127.7, 127.4, 127.2, 126.7, 119.9, 57.4, 49.2, 36.7,
18.9. C19H16ClN3O2 requires: C, 64.50; H, 4.56; N,
11.88. Found: C, 64.41; H, 4.73; N, 11.87%.
4.11.1.4. (1S,4S)-4-Benzyl-1-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 17c. Traces of 17c
were obtained as an oil; wmax (NaCl) 2923, 1684, 1600
cm−1; lH (250 MHz, CDCl3) 8.34 (dd, 1H, J=1.4 and
8.0 Hz, H-7), 7.79 (ddd, 1H, J=1.4, 7.1 and 8.4 Hz,
H-9), 7.62 (dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.52
(ddd, 1H, J=1.1, 7.1 and 8.0 Hz, H-8), 7.18 (m, 3H,
Ph), 6.93 (m, 2H, Ph), 6.11 (s, 1H, N-H), 5.52 (dd, 1H,
J=3.6 and 5.4 Hz, H-4), 4.52 (dq, 1H, J=3.2 and 7.2
Hz, H-1), 3.60 (dd, 1H, J=5.4 and 14.0 Hz, CH2-Ph),
3.47 (dd, 1H, J=3.6 and 14.0 Hz, CH2ꢀPh), 0.69 (d,
3H, J=7.2 Hz, CH3).
4.11.1.8. (1S,4R)-1-Methyl-4-(2-naphthylmethyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
16g.
Mp: 63–65°C; yield 66%; wmax (NaCl) 2923, 1684, 1600
cm−1; lH (250 MHz, CDCl3) 8.34 (dd, 1H, J=1.5 and
8.0 Hz, H-7), 7.79 (ddd, 1H, J=1.5, 7.1 and 8.4 Hz,
H-9), 7.75 (m, 1H, H-8%), 7.66 (d, 1H, J=8.5 Hz, H-4%),
7.62 (dd, 1H, J=1.2 and 8.4 Hz, H-10), 7.57 (m, 1H,
H-5%), 7.53 (ddd, 1H, J=1.2, 7.1 and 8.0 Hz, H-8), 7.44
(t, 1H, J=1.7 Hz, H-1%), 7.40 (m, 2H, H-6% and H-7%),
7.09 (dd, 1H, J=1.7 and 8.4 Hz, H-3%), 6.92 (s, 1H,
N-H), 5.71 (t, 1H, J=4.8 Hz, H-4), 3.66 (dd, 1H,
J=4.8 and 14.1 Hz, CH2ꢀAr), 3.56 (dd, 1H, J=4.8 and
14.1 Hz, CH2ꢀAr), 3.10 (q, 1H, J=6.6 Hz, H-1), 1.36
4.11.1.5.
(1S,4R)-1-Methyl-4-(p-methylbenzyl)-2,4-
16d.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Mp: 146–147°C; yield 64%; wmax (NaCl) 3253, 2926,
1686, 1599 cm−1; lH (250 MHz, CDCl3) 8.33 (dd, 1H,
J=1.3 and 8.0 Hz, H-7), 7.78 (ddd, 1H, J=1.3, 7.0 and

F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
3395
(d, 3H, J=6.6 Hz, CH3); lC (62.5 MHz, CDCl3) 168.7,
160.8, 151.4, 147.1, 134.9, 133.4, 132.6, 132.5, 128.7,
128.6, 127.8, 127.7, 127.6, 127.5, 127.3, 127.0, 126.5,
126.2, 120.3, 57.8, 49.2, 37.3, 18.9. C23H19N3O2
requires: C, 74.78; H, 5.18; N, 11.37. Found: C, 74.69;
H, 5.13; N, 11.37%.
MHz, CDCl3) 8.27 (dd, 1H, J=1.4 and 8.1 Hz, H-7),
7.76 (ddd, 1H, J=1.4, 7.2 and 8.3 Hz, H-9), 7.65 (dd,
1H, J=1.3 and 8.3 Hz, H-10), 7.49 (ddd, 1H, J=1.3,
7.2 and 8.1 Hz, H-8), 6.41 (s, 1H, N-H), 5.78 (ddt, 1H,
J=7.5, 10.1 and 17.5 Hz, H-2%), 5.47 (t, 1H, J=5.6 Hz,
H-4), 5.04 (dd, 1H, J=1.4 and 10.1 Hz, H-3%), 4.99 (dd,
1H, J=1.4 and 17.5 Hz, H-3%), 4.58 (d, 1H, J=2.4 Hz,
H-1), 3.10 (m, 1H, J=2.4 and 7.0 Hz, CH(CH3)2), 2.91
(ddd, 1H, J=6.2, 7.5 and 12.4 Hz, H-1%), 2.79 (ddd, 1H,
J=5.2, 7.5 and 12.4 Hz, H-1%), 1.17 (d, 3H, J=7.0 Hz,
CH3), 0.86 (d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz,
CDCl3) 168.2, 160.4, 149.6, 146.6, 134.6, 130.9, 127.0,
126.7, 120.5, 119.9, 58.6, 55.3, 36.1, 30.0, 19.1, 14.9.
C17H19N3O2 requires: C, 68.67; H, 6.44; N, 14.13.
Found: C, 68.06; H, 6.64; N, 13.77%.
4.11.2. Alkylation of 9b. To a magnetically stirred solu-
tion of 9b (0.5 mmol) in dry THF (10 mL) at −78°C
under argon, was added dropwise via syringe a solution
of lithium hexamethyldisilazide in THF (1 M, 5 mL)
followed by a solution of the appropriate halide (1
mmol) in THF (5 mL) 10 min later. The reaction
mixture was stirred at −78°C for 5 days (3.5 days for
18a and 19a), quenched by the dropwise addition of
glacial acetic acid followed by saturated aqueous
ammonium chloride (10 mL), and extracted with
CHCl3. The organic layer was dried over anhydrous
Na2SO4 and evaporated. Column chromatography of
the residue on silica gel (EtOAc:CH2Cl2, 3:7 unless
otherwise mentioned) afforded the 4-alkyl derivatives
18 and 19.
4.11.2.4. (1S,4S)-4-Allyl-1-isopropyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 19b. Compound
19b was obtained as an oily product; yield 12%; [h]2D5=
+134.4 (c 0.09; CHCl3); wmax (NaCl) 3257, 3215, 2962,
2934, 1684, 1608, 1472 cm−1; lH (250 MHz, CDCl3)
8.26 (dd, 1H, J=1.3 and 8.1 Hz, H-7), 7.79 (ddd, 1H,
J=1.3, 7.1 and 8.4 Hz, H-9), 7.68 (dd, 1H, J=1.3 and
8.4 Hz, H-10), 7.52 (ddd, 1H, J=1.3, 7.1 and 8.1 Hz,
H-8), 6.64 (s, 1H, N-H), 5.24 (ddt, 1H, J=7.3, 9.6 and
17.2 Hz, H-2%), 5.24 (dd, 1H, J=5.4 and 8.1 Hz, H-4),
5.10 (dd, 1H, J=1.4 and 17.2 Hz, H-3%), 5.10 (dd, 1H,
J=1.4 and 9.6 Hz, H-3%), 4.45 (m, 1H, H-1), 2.83 (m,
2H, H-1%), 2.43 (m, 1H, J=6.7 Hz, CH(CH3)2), 1.07 (d,
3H, J=6.7 Hz, CH3), 1.05 (d, 3H, J=6.7 Hz, CH3); lC
(62.5 MHz, CDCl3) 165.6, 160.4, 152.1, 145.7, 134.9,
132.3, 127.1, 126.9, 120.4, 118.3, 58.6, 56.4, 38.0, 30.9,
18.3, 16.5. C17H19N3O2 requires: C, 68.67; H, 6.44; N,
14.13. Found: C, 68.43; H, 6.19; N, 13.91%.
4.11.2.1.
(1S,4R)-1-Isopropyl-4-methyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 18a. Com-
pound 18a was obtained (EtOAc) as a solid; mp:
135–137°C; yield 25%; [h]2D5=−124.7 (c 0.09; CHCl3);
wmax (NaCl) 3197, 2968, 2930, 1733, 1682, 1608, 1496
cm−1; lH (250 MHz, CDCl3) 8.27 (dd, 1H, J=1.4 and
8.0 Hz, H-7), 7.75 (ddd, 1H, J=1.4, 7.1 and 8.2 Hz,
H-9), 7.65 (dd, 1H, J=1.3 and 8.2 Hz, H-10), 7.49
(ddd, 1H, J=1.3, 7.1 and 8.0 Hz, H-8), 6.37 (s, 1H,
N-H), 5.46 (q, 1H, J=7.2 Hz, H-4), 4.52 (d, 1H, J=2.3
Hz, H-1), 3.16 (m, 1H, J=2.3 and 7.1 Hz, CH(CH3)2),
1.62 (d, 3H, J=7.2 Hz, C(4)-CH3), 1.21 (d, 3H, J=7.4
Hz, CH3), 0.94 (d, 3H, J=6.8 Hz, CH3); lC (62.5 MHz,
CDCl3) 170.2, 160.6, 149.2, 147.1, 134.7, 127.5, 127.4,
126.9, 120.4, 58.4, 52.0, 29.0, 19.5, 15.3, 14.2.
C15H17N3O2 requires: C, 66.40; H, 6.32; N, 15.49.
Found: C, 66.29; H, 6.13; N, 15.37%.
4.11.2.5.
(1S,4R)-4-Benzyl-1-isopropyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 18c. Mp: 78–
80°C; yield 63%; [h]2D5=−225.0 (c 0.05; CHCl3); wmax
(NaCl) 3210, 2918, 2847, 1723, 1683, 1599, 1470 cm−1;
lH (250 MHz, CDCl3) 8.33 (dd, 1H, J=1.4 and 8.0 Hz,
H-7), 7.77 (ddd, 1H, J=1.4, 7.2 and 8.3 Hz, H-9), 7.60
(dd, 1H, J=1.1 and 8.3 Hz, H-10), 7.51 (ddd, 1H,
J=1.1, 7.2 and 8.0 Hz, H-8), 7.20 (m, 3H, Ph), 6.90 (m,
2H, Ph), 6.03 (s, 1H, N-H), 5.64 (dd, 1H, J=4.1 and
4.3 Hz, H-4), 3.49 (dd, 1H, J=4.3 and 14.5 Hz, CH2-
Ph), 3.43 (dd, 1H, J=4.1 and 14.5 Hz, CH2-Ph), 2.75
(m, 1H, J=2.2 and 6.9 Hz, CH(CH3)2), 2.69 (d, 1H,
J=2.2 Hz, H-1), 0.86 (d, 3H, J=6.9 Hz, CH3), 0.69 (d,
3H, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3) 168.5,
160.9, 150.0, 147.1, 135.0, 134.9, 130.0, 128.9, 128.0,
127.5, 127.3, 127.0, 120.1, 58.0, 57.2, 37.3, 29.5, 19.1,
15.0. C21H21N3O2 requires: C, 72.60; H, 6.09; N, 12.09.
Found: C, 72.54; H, 6.34; N, 12.27%.
4.11.2.2.
(1S,4S)-1-Isopropyl-4-methyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 19a. Com-
pound 19a was obtained (EtOAc) as an oily product;
yield 41%; [h]D25=+25.5 (c 0.17; CHCl3); wmax (NaCl)
3176, 3062, 2925, 1682, 1594, 1568, 1472 cm−1; lH (250
MHz, CDCl3) 8.27 (dd, 1H, J=1.4 and 8.1 Hz, H-7),
7.76 (ddd, 1H, J=1.4, 7.1 and 8.4 Hz, H-9), 7.64 (dd,
1H, J=1.2 and 8.4 Hz, H-10), 7.48 (ddd, 1H, J=1.2,
7.1 and 8.1 Hz, H-8), 6.96 (d, 1H, J=3.9 Hz, N-H),
5.25 (q, 1H, J=7.1 Hz, H-4), 4.29 (dd, 1H, J=3.9 and
7.0 Hz, H-1), 2.36 (m, 1H, J=7.1 Hz, CH(CH3)2), 1.74
(d, 3H, J=7.1 Hz, C(4)-CH3), 1.13 (d, 3H, J=7.0 Hz,
CH3), 1.07 (d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz,
CDCl3) 169.3, 160.6, 149.4, 146.8, 134.6, 127.0, 126.9,
126.6, 120.1, 62.1, 51.9, 35.6, 19.5, 19.2, 18.4.
C15H17N3O2 requires: C, 66.40; H, 6.32; N, 15.49.
Found: C, 66.38; H, 6.28; N, 15.41%.
4.11.2.6.
(1S,4S)-4-Benzyl-1-isopropyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 19c. Com-
pound 19c was isolated as an oily product; yield 15%;
[h]2D5=+154.4 (c 0.48; CHCl3); wmax (NaCl) 3196, 3063,
2968, 1683, 1596, 1570, 1473 cm−1; lH (250 MHz,
CDCl3) 8.30 (dd, 1H, J=1.3 and 8.0 Hz, H-7), 7.77
(ddd, 1H, J=1.3, 7.1 and 8.3 Hz, H-9), 7.63 (dd, 1H,
J=1.2 and 8.3 Hz, H-10), 7.57 (d, 1H, J=3.5 Hz,
N-H), 7.50 (ddd, 1H, J=1.2, 7.1 and 8.0 Hz, H-8), 7.18
4.11.2.3. (1S,4R)-4-Allyl-1-isopropyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 18b. Mp: 158–
159°C; yield 23%; [h]2D5=−285.0 (c 0.30; CHCl3); wmax
(NaCl) 2923, 2355, 2329, 1684, 1602 cm−1; lH (250

3396
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
(m, 5H, Ph), 5.41 (t, 1H, J=5.6 Hz, H-4), 4.02 (dd, 1H,
J=3.5 and 8.5 Hz, H-1), 3.45 (2dd, 2H, J=5.6 and 13.5
Hz, CH2ꢀPh), 1.16 (m, 1H, J=6.7 and 8.5 Hz,
CH(CH3)2), 0.94 (d, 3H, J=6.7 Hz, CH3), 0.84 (d, 3H,
J=6.7 Hz, CH3); lC (62.5 MHz, CDCl3) 167.7, 161.1,
149.3, 146.8, 136.0, 134.8, 129.9, 128.7, 127.3, 127.1,
126.7, 120.1, 61.9, 57.5, 38.1, 35.1, 20.0, 19.0.
C21H21N3O2 requires: C, 72.60; H, 6.09; N, 12.09.
Found: C, 72.73; H, 6.04; N, 12.10%.
(d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz, CDCl3) 168.2,
162.4 (d, J=247 Hz), 160.6, 149.6, 146.8, 134.8, 131.2
(d, J=8.0 Hz), 130.5 (d, J=3.3 Hz), 127.3, 127.1,
126.8, 119.9, 115.6 (d, J=21.3 Hz), 58.1, 56.8, 36.3,
29.7, 18.9, 14.8. C21H20FN3O2 requires: C, 69.03; H,
5.52; N, 11.50. Found: C, 68.98; H, 5.78; N, 11.35%.
4.11.2.10. (1S,4S)-4-(p-Fluorobenzyl)-1-isopropyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
19e.
Compound 19e was obtained as an oil; yield 8%; lH
(250 MHz, CDCl3) 8.30 (dd, 1H, J=1.4 and 8.0 Hz,
H-7), 7.79 (ddd, 1H, J=1.4, 7.2 and 8.4 Hz, H-9), 7.65
(dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.52 (ddd, 1H,
J=1.1, 7.2 and 8.0 Hz, H-8), 7.17 (m, 2H, Ar), 6.93 (m,
2H, Ar), 6.73 (d, 1H, J=3.7 Hz, N-H), 5.37 (dd, 1H,
J=4.5 and 6.9 Hz, H-4), 4.11 (dd, 1H, J=3.7 and 8.1
Hz, H-1), 3.44 (dd, 1H, J=4.5 and 13.9 Hz, CH2ꢀAr),
3.36 (dd, 1H, J=6.9 and 13.9 Hz, CH2ꢀAr), 1.54 (m,
1H, J=6.8 and 8.1 Hz, CH(CH3)2), 1.01 (d, 3H, J=6.8
Hz, CH3), 0.87 (d, 3H, J=6.8 Hz, CH3).
4.11.2.7. (1S,4R)-1-Isopropyl-4-(p-methylbenzyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
18d.
Mp: 75–77°C; yield 57%; [h]2D5=−340.0 (c 0.11; CHCl3);
wmax (NaCl) 3199, 3076, 2961, 2926, 1730, 1683, 1599,
1570 cm−1; lH (250 MHz, CDCl3) 8.33 (dd, 1H, J=1.4
and 8.1 Hz, H-7), 7.77 (ddd, 1H, J=1.4, 7.1 and 8.4
Hz, H-9), 7.61 (dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.51
(ddd, 1H, J=1.1, 7.1 and 8.1 Hz, H-8), 6.96 (d, 2H,
J=7.9 Hz, H-3% and H-5%), 6.78 (d, 2H, J=7.9 Hz, H-2%
and H-6%), 5.99 (s, 1H, N-H), 5.61 (t, 1H, J=4.2 Hz,
H-4), 3.42 (dd, 1H, J=4.2 and 13.7 Hz, CH2ꢀAr), 3.40
(dd, 1H, J=4.3 and 13.7 Hz, CH2ꢀAr), 2.76 (m, 1H,
J=2.4 and 7.0 Hz, CH(CH3)2), 2.72 (d, 1H, J=2.4 Hz,
H-1), 2.27 (s, 3H, ArCH3), 0.86 (d, 3H, J=7.0 Hz,
CH3), 0.69 (d, 3H, J=7.0 Hz, CH3); lC (62.5 MHz,
CDCl3) 168.6, 160.9, 150.1, 147.1, 137.4, 134.9, 131.8,
129.8, 129.5, 127.4, 127.2, 127.0, 120.1, 58.0, 57.3, 36.9,
29.6, 21.2, 19.1, 15.0. C22H23N3O2 requires: C, 73.11; H,
6.41; N, 11.63. Found: C, 72.84; H, 6.34; N, 11.57%.
4.11.2.11.
(1S,4R)-4-(N-Boc-3-indolylmethyl)-1-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 18f. Compound 18f was isolated (EtOAc:toluene,
1:1) as an oil; yield 31%; [h]2D5=−241.4 (c 0.62;
methanol); wmax (NaCl) 1734, 1685, 1601 cm−1; lH (250
MHz, CDCl3) 8.36 (dd, 1H, J=1.5 and 8.0 Hz, H-7),
8.07 (dd, 1H, J=0.8 and 8.3 Hz, H-7%), 7.78 (ddd, 1H,
J=1.5, 7.1 and 8.4 Hz, H-9), 7.57 (dd, 1H, J=1.0 and
8.4 Hz, H-10), 7.54 (ddd, 1H, J=1.0, 7.1 and 8.0 Hz,
H-8), 7.41 (dd, 1H, J=0.8 and 8.0 Hz, H-4%), 7.24 (dt,
1H, J=0.8 and 8.0 Hz, H-6%), 7.01 (dt, 1H, J=0.8 and
8.0 Hz, H-5%), 6.96 (s, 1H, H-2%), 6.19 (s, 1H, N-H), 5.67
(‘t’, 1H, J=5.4 Hz, H-4), 3.63 (dd, 1H, J=5.4 and 14.9
Hz, CH2ꢀAr), 3.57 (dd, 1H, J=5.4 and 14.9 Hz,
CH2ꢀAr), 3.20 (d, 1H, J=2.2 Hz, H-1), 2.73 (m, 1H,
J=2.2 and 6.9 Hz, CH(CH3)2), 1.49 (s, 9H, 3CH3), 0.79
(d, 3H, J=7.2 Hz, CH3), 0.69 (d, 3H, J=6.7 Hz, CH3);
lC (62.5 MHz, CDCl3) 168.8, 160.8, 149.7, 149.1, 146.9,
135.2, 134.6, 129.7, 127.1, 127.0, 126.7, 124.9, 124.7,
122.7, 120.0, 118.7, 115.0, 113.8, 86.3, 58.3, 56.0, 29.9,
27.9, 26.8, 18.8, 14.7. C28H30N4O4 requires: C, 69.05; H,
6.16; N, 11.50. Found: C, 69.45; H, 6.02; N, 11.24%.
4.11.2.8. (1S,4S)-1-Isopropyl-4-(p-methylbenzyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
19d.
Compound 19d was isolated as an oil; yield 10%;
[h]2D5=+161.7 (c 0.06; CHCl3); wmax (NaCl) 3208, 3064,
2958, 2928, 1682, 1597, 1472 cm−1; lH (250 MHz,
CDCl3) 8.31 (dd, 1H, J=1.4 and 8.1 Hz, H-7), 7.77
(ddd, 1H, J=1.4, 7.1 and 8.4 Hz, H-9), 7.63 (dd, 1H,
J=1.2 and 8.4 Hz, H-10), 7.51 (ddd, 1H, J=1.2, 7.1
and 8.1 Hz, H-8), 7.03 (m, 4H, Ar), 6.88 (d, 1H, J=3.8
Hz, N-H), 5.34 (dd, 1H, J=4.9 and 6.3 Hz, H-4), 4.03
(dd, 1H, J=3.8 and 8.5 Hz, H-1), 3.45 (dd, H, J=4.9
and 14.0 Hz, CH2ꢀAr), 3.38 (dd, H, J=6.3 and 14.0
Hz, CH2ꢀAr), 2.26 (s, 3H, ArCH3), 1.23 (m, 1H, J=6.6
Hz, CH(CH3)2), 0.94 (d, 3H, J=6.6 Hz, CH3), 0.83 (d,
3H, J=6.6 Hz, CH3); lC (62.5 MHz, CDCl3) 167.2,
161.0, 149.2, 146.7, 136.9, 134.7, 132.8, 129.6, 129.2,
127.0, 126.7, 120.1, 61.9, 57.6, 37.6, 34.8, 21.0, 19.8,
18.8. C22H23N3O2 requires: C, 73.11; H, 6.41; N, 11.63.
Found: C, 73.04; H, 6.39; N, 11.47%.
4.11.2.12.
(1S,4S)-4-(N-Boc-3-indolylmethyl)-1-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 19f. Compound 19f was isolated (EtOAc:toluene,
1:1) as an oil; yield 46%; [h]2D5=+173.5 (c 0.62;
methanol); wmax (NaCl) 3344 1735, 1684, 1595 cm−1; lH
(250 MHz, CDCl3) 8.33 (dd, 1H, J=1.5 and 8.0 Hz,
H-7), 8.05 (dd, 1H, J=0.8 and 8.2 Hz, H-7%), 7.78 (ddd,
1H, J=1.5, 7.2 and 8.4 Hz, H-9), 7.62 (dd, 1H, J=1.1
and 8.4 Hz, H-10), 7.60 (d, 1H, J=3.7 Hz, N-H), 7.51
(ddd, 1H, J=1.1, 7.2 and 8.0 Hz, H-8), 7.30 (s, 1H,
H-2%), 7.23 (dt, 1H, J=0.8 and 8.0 Hz, H6%), 7.12 (dt,
1H, J=0.8 and 8.2 Hz, H-5%), 5.50 (dd, 1H, J=4.2 and
7.4 Hz, H-4), 4.02 (dd, 1H, J=3.7 and 8.3 Hz, H-1),
3.61 (dd, 1H, J=4.2 and 14.5 Hz, CH2ꢀAr), 3.51 (dd,
1H, J=4.2 and 14.5 Hz, CH2ꢀAr), 1.55 (s, 9H, 3CH3),
1.45 (m, 1H, J=6.7 and 8.3 Hz, CH(CH3)2), 0.89 (d,
3H, J=6.7 Hz, CH3), 0.68 (d, 3H, J=6.7 Hz, CH3); lC
(62.5 MHz, CDCl3) 167.6, 161.1, 149.3, 149.1, 146.7,
135.1, 134.7, 130.4, 127.0, 126.6, 124.5, 122.7, 120.0,
4.11.2.9. (1S,4R)-4-(p-Fluorobenzyl)-1-isopropyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
18e.
Mp: 188–190°C; yield 48%; [h]2D5=−478.3 (c 0.06;
CHCl3); wmax (NaCl) 3200, 2967, 2921, 2857, 1684,
1601, 1508 cm−1; lH (250 MHz, CDCl3) 8.31 (dd, 1H,
J=1.3 and 8.1 Hz, H-7), 7.78 (ddd, 1H, J=1.3, 7.1 and
8.3 Hz, H-9), 7.61 (dd, 1H, J=1.1 and 8.3 Hz, H-10),
7.51 (ddd, 1H, J=1.1, 7.1 and 8.1 Hz, H-8), 6.85 (m,
4H, Ar), 6.33 (s, 1H, N-H), 5.61 (dd, 1H, J=4.3 and
4.6 Hz, H-4), 3.45 (dd, 1H, J=4.6 and 14.6 Hz,
CH2ꢀAr), 3.39 (dd, 1H, J=4.3 and 14.6 Hz, CH2ꢀAr),
2.96 (d, 1H, J=2.3 Hz, H-1), 2.81 (m, 1H, J=2.3 and
7.0 Hz, CH(CH3)2), 0.93 (d, 3H, J=7.0 Hz, CH3), 0.71

F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
3397
119.1, 115.0, 114.9, 83.5, 61.7, 56.2, 35.2, 28.0, 27.7,
19.4, 18.1. C28H30N4O4 requires: C, 69.05; H, 6.16; N,
11.50. Found: C, 68.68; H, 6.26; N, 11.45%.
3. Takahashi, C.; Matsishita, T.; Doi, M.; Minoura, K.;
Shingu, T.; Kumeda, Y.; Numata, A. J. Chem. Soc.,
Perkin Trans. 1 1995, 2345–2353.
4. Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.;
Gillum, A. M.; Cooper, R. J. Antibiot. 1993, 46, 545–
553.
4.12. Deprotection of 18f and 19f
5. Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.;
Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843–1848.
6. Karwowsky, J. P.; Jackson, M.; Rasmussen, R. R.;
Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr,
M. H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993,
46, 347–379.
7. Chou, T.-C.; Depew, K. M.; Zheng, Y.-H.; Safer, M.
L.; Chan, D.; Helfrich, B.; Zatorska, D.; Zatorski, A.;
Bornmann, W.; Danishefsky, S. J. Proc. Natl. Acad.
Sci. USA 1998, 95, 8369–8374.
To a cold (−78°C) magnetically stirred solution of 18f
or 19f (0.1 mmol) in dry CH2Cl2 (3 mL), boron tribro-
mide (0.5 mmol) was added and stirring was continued
for 40 min. The reaction mixture was extracted with
ethyl acetate (9 mL) and the organic layers were dried
over anhydrous Na2SO4, filtered, evaporated, and
purified by column chromatography (EtOAc:MeOH,
3:2).
4.12.1. Fiscalin B 3. Yield 88%; 1H and 13C NMR
spectra were identical to those previously reported.10,21
The enantiomeric purity was measured by chiral
HPLC.
8. Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432–
2433.
9. He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397–
1399.
10. Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022–
1030.
11. Hart, D. J.; Magomedov, N. Tetrahedron Lett. 1999,
40, 5429–5432.
12. Snider, B. B.; Zeng, H. Org. Lett. 2000, 2, 4103–
4106.
13. Cledera, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org.
Chem. 2000, 65, 1743–1749.
14. Rajapa, S.; Advani, B. G. J. Chem. Soc., Perkin Trans.
1 1974, 2122–2124.
15. Mart´ın-Santamar´ıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M.; Avendan˜o, C. J. Org. Chem. 1997, 62,
6424–6428.
16. Buenadicha, F. L.; Bartolome´, M. T.; Aguirre, M. J.;
Avendan˜o, C.; So¨llhuber, M. Tetrahedron: Asymmetry
1998, 9, 483–501.
17. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetra-
hedron: Asymmetry 1998, 9, 4275–4284.
4.12.2. (1S,4S)-4-(3-Indolylmethyl)-1-isopropyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 20. Com-
pound 20 was isolated as an oil; yield 44%;
[h]2D5=+255.0 (c 0.02; methanol); wmax (NaCl) 3283,
2925, 1679, 1594, 1472, 1332, 1219 cm−1; lH (250 MHz,
CDCl3) 8.35 (dd, 1H, J=1.5 and 8.0 Hz, H-7), 8.10 (s,
1H, N-Hi), 7.77 (ddd, 1H, J=1.5, 7.2 and 8.4 Hz, H-9),
7.61 (dd, 1H, J=1.1 and 8.4 Hz, H-10), 7.52 (ddd, 1H,
J=1.1 7.2 and 8.0 Hz, H-8), 7.48 (dd, 1H, J=0.9 and
8.0 Hz, H-4%), 7.23 (dd, 1H, J=0.9 and 8.0 Hz, H-7%),
7.13 (dt, 1H, J=0.9 and 8.0 Hz, H-6%), 6.97 (s, 1H,
N-H), 6.90 (dt, 1H, J=0.9 and 8.0 Hz, H-5%), 6.88 (d,
1H, J=2.0 Hz, H-2%), 5.49 (dd, 1H, J=4.1 and 6.0 Hz,
H-4), 3.93 (dd, 1H, J=3.4 and 8.4 Hz, H-1), 3.76 (dd,
1H, J=6.0 and 14.8 Hz, CH2ꢀAr), 3.68 (dd, 1H, J=4.1
and 14.8 Hz, CH2ꢀAr), 0.97 (m, 1H, CH(CH3)2), 0.73
(d, 3H, J=6.7 Hz, CH3), 0.47 (d, 3H, J=6.7 Hz, CH3);
lC (62.5 MHz, CDCl3) 167.9, 161.2, 149.4, 146.6, 135.9,
134.8, 127.1, 126.9, 126.8, 123.5, 122.2, 120.2, 119.8,
118.9, 110.9, 110.1, 61.7, 57.4, 34.9, 27.5, 19.5, 18.1.
C23H22N4O2 requires: C, 71.47; H, 5.74; N, 14.50.
Found: C, 71.54; H, 5.48; N, 14.17%.
18. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetra-
hedron: Asymmetry 2001, 12, 3019–3028.
19. He, F.; Snider, B. B. Synlett 1997, 483–484.
20. Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57,
3301–3307.
21. Herna´ndez, F.; Lumetzberger, A.; Avendan˜o, C.; So¨ll-
huber, M. Synlett 2001, 1387–1390.
Acknowledgements
22. Mene´ndez Vidal, C.; Quesada, A. R. Cancer Lett. 1998,
132, 45–50.
We thank CICYT for financial support (Project
SAF97–0143 and SAF2000-130). F. Herna´ndez would
like to thank UCM and CAM for the research
fellowships.
23. Overman, L. E.; Osawa, T. J. Am. Chem. Soc. 1985,
107, 1698–1701.
24. Williams, R. M.; Armstrong, R. W.; Dung, J. S. J.
Am. Chem. Soc. 1985, 107, 3253–3266.
25. Kawabata, T.; Kimura, Y.; Ito, S. Tetrahedron Lett.
1986, 27, 6241–6244.
26. Oxidative deprotection of the tricyclic pyrazinoquinazo-
line system usually gave mixtures of oxidation products
(see Ref. 16).
27. The synthesis of 9a starting from the iminoether
derived from 6a and anthranilic acid afforded a racemic
product as expected (see Ref. 18).
References
1. Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N.
J. Chem. Soc., Perkin Trans. 1 1992, 1495–1496.
2. Numata, A.; Takahashi, C.; Matsishita, T.; Miyamoto,
T.; Kawai, K.; Usam, Y.; Matsumura, E.; Inoue, M.;
Ohishi, H.; Shingu, T. Terahedron Lett. 1992, 33, 1621–
1624.
28. Sa´nchez, J. D.; Ramos, M. T.; Avendan˜o, C. J. Org.
Chem. 2001, 66, 5731–5735.

3398
F. Herna´ndez et al. / Tetrahedron: Asymmetry 12 (2001) 3387–3398
29. Evidence of epimerization at C(4) gives the alternative
synthesis of 19a starting from (3S,6S)-3-isopropyl-6-
methylpiperazine-2,5-dione and o-azidobenzoyl chloride
followed by intramolecular Staudinger reaction (Lumet-
zberger, A.; Diplomarbeit, U. Bonn, April 2000).
30. Scho¨llkopf, U.; Lonsky, R.; Lehr, P. Liebigs Ann. Chem.
1985, 413–417.
1963, 46, 327–333.
34. Chu, D. T. W.; Nordeen, C. W.; Hardy, D. J.; Swanson,
R. N.; Giardina, W. J.; Pernet, A. G.; Plattner, J. J. J.
Med. Chem. 1991, 34, 168–174.
35. Smith, G. G.; Baum, R. J. Org. Chem. 1987, 52, 2248–
2255.
36. Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321–327.
31. Venkatachalam, T. K.; Mzengeza, S.; Diksic, M. Org.
37. Deng, C.; Groth, U.; Scho¨llkopf, U. Angew. Chem., Int.
Ed. Engl. 1981, 21, 798–799.
38. Matsuda, F.; Itoh, S.; Hattori, N.; Yanagiya, M.; Mat-
Prep. Proc. Int. 1993, 25, 249–251.
32. Gan, T.; Cook, J. M. Tetrahedron Lett. 1997, 38, 1301–
1304.
sumoto, T. Tetrahedron 1985, 41, 3625–3631.
33. Quitt, P.; Hellerbach, J.; Vogler, K. Helv. Chim. Acta