A new stereocontrolled approach to fused polycyclic compounds containing a diketopiperazine ring

Article abstract of DOI:10.1016/j.tetasy.2005.08.034

Representative (1S)- and (4S)-alkyl-1,4-dihydropyrazino[2,1-b]quinazoline- 3,6-dione lactim ethers were regio- and diastereoselectively alkylated after metallation to give the corresponding 1,4-trans-isomers with retention of the stereocentres. The result

Full text of DOI:10.1016/j.tetasy.2005.08.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3160–3169
A new stereocontrolled approach to fused polycyclic
compounds containing a diketopiperazine ring
*
*
´
´
Fernando Hernandez, Carmen Avendano and Monica So¨llhuber
˜
Departamento de Quı´mica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 22 June 2005; accepted 25 August 2005
Abstract—Representative (1S)- and (4S)-alkyl-1,4-dihydropyrazino[2,1-b]quinazoline-3,6-dione lactim ethers were regio- and diaste-
reoselectively alkylated after metallation to give the corresponding 1,4-trans-isomers with retention of the stereocentres. The results
were compared with the previously studied lactams. The (1R,4S)-dialkyl derivatives obtained by C(1)-alkyation with bifunctional
reagents were lately cyclized to complex polycyclic compounds through a second N(2)-alkylation promoted by sodium iodide.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
or C(4)-protons in compounds 1.9–16 On the other hand,
bis-lactim ethers derived from chiral piperazine-2,5-
diones, which are known as Scho¨llkopf auxiliaries, have
been extensively used in the asymmetric synthesis of acy-
clic or cyclic amino acids in a process that implies their
regioselective metallation followed by a diastereoselec-
tive nucleophilic displacement and a final acid hydroly-
sis,17,18 but lactim ethers of fused diketopiperazines have
rarely been used.19 On this basis, we herein report the
alkylation of (1S)- and (4S)-pyrazino[2,1-b]quinazo-
line-3,6-dione lactim ethers 2–4.
In our work directed towards the synthesis of analogues
of the multi-drug resistance reversal agent to antitumour
drugs N-acetylardeemin,1,2 we focussed our attention on
the synthesis and reactivity of the 2,4-dihydro-1H-pyr-
azino[2,1-b]quinazoline-3,6-dione system 1,3 which con-
stitutes the pharmacophoric moiety of this natural
product (Fig. 1). This system is also the core of other
natural compounds such as glyantripine,4 fiscalins,5
fumiquinazolines,6 alantrypinone7 and spiroquinazo-
line.8 Part of this work showed that monosubstituted
compounds 1, where R1 or R4 are alkyl groups and R2
are hydrogen, alkyl or aryl substituents, behave as
nucleophilic glycine templates. In this way, we have
developed useful approaches to these products by regio-
and diastereoselective alkylation of metallated deriva-
tives generated by the elimination of either the C(1)-
2. Results and discussion
Compounds 2–4 were quantitatively obtained from the
corresponding starting materials 1 (R2 = H) after treat-
ment with MeerweinÕs reagent.20 When compounds 2
F
N
N
N
N
D
O
H
E
N
R1
R2
H3C
N
N
N
O
O
O
O
C
N
N
N
N
B
N
R4
R4
CH3
A
OEt
OEt
O
H
Ac
2, R4 = Me
3, R4 = iPr
1, R1 or R4 = alkyl
R2 = H, alkyl, aryl
5-Acetylardeemin
4
Figure 1.
*
Corresponding authors. Tel.: +34 91 394 18 21/39; fax: +34 91 394 18 22; e-mail addresses: avendano@farm.ucm.es; msollhub@farm.ucm.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.08.034

F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
3161
N
N
LHMDS, THF,
-78 oC 10 min,
R1X, 30 min
R1
R1
N
N
O
O
N
N
R4
R4
OEt
OEt
method
A
6a R1= R4 = Me; (19%)
5a R4 = Me; R1= Me; (57%)
N
5b R4 = Me; R1= Bn; (50%)
8a R4 =i Pr; R1= Me (14%)
7a R4 =i Pr; R1= Me; (52%)
7b R4 =i Pr; R1= Bn; (54%)
N
O
N
R4
OEt
method B
2 (R4 = Me)
3 (R4 =i Pr)
LHMDS,
DMI, THF
-78 oC 10 min,
PhCH2Br,
30 min
Ph
N
N
5b
+
Ph
N
O
(5%)
CH3
OEt
9 (30%)
Scheme 1.
and 3 were metallated with lithium hexamethyldisilazide
and the corresponding intermediates were trapped with
methyl iodide or benzyl bromide, the reactions gave
regio- and diastereoselectively the enantiomerically pure
1,4-trans-isomers 5 and 7 (method A, Scheme 1). The
yields obtained were similar to those reported for other
fused diketopiperazine lactim ethers,19 and could not be
further optimized either with longer reaction times or
with the addition of DMI as a cosolvent (method B).
This last alternative promoted instead the 1,1-dialkyl-
ation (see compound 9). The 1,4-trans-diastereoselecti-
vity was especially important for benzyl halides
(de > 98%), being in general the asymmetric trans-induc-
tion of compounds 2 and 3 almost similar to and better
than in their precursor-lactams 1.16 During the reaction,
the alkylated lactims 5 and 7 obtained were less prone to
epimerize, via enamine tautomers, to the 1,4-cis-isomers
than the previously studied lactams 1.9–16 However, more
care was needed during the chromatographic work-up to
avoid epimerization on contact with silica gel.
To prove that a double alkylation on C(1) and N(2) in
compounds 2 and 3 using bifunctional reagents would
lead to fused polycycles, we performed the reaction of
metallated 2 and 3 with bis-1,2-phenylenemethyl bro-
mides. Here the main products isolated were 1,4-trans
isomers 12 and 13. Only compound 2 gave small
amounts of 1,4-cis-isomer 14 and dimer 15 (Scheme 3).
1
According to H NMR experiments, in all 1,4-disubsti-
tuted compounds 5–15, the piperazine ring adopts a
boat conformation, with the alkyl chain at C(4) in an
axial disposition. The important NOEs observed in these
compounds between the H(1) and the C(4) alkyl protons
corroborate this conformation. In compound 10, an
additional shielding effect was observed on H(1), which
is produced by the C(4) phenyl ring (Fig. 2). The boat
conformation contrasts with the flat boat conformation
previously described for the alkylated lactam isomers of
1.9–16 This conformational difference explains the great-
er integrity of the C(1)-stereogenic centre in the 1,4-
trans-dialkyllactim ethers in comparison to 1,4-trans-
lactams 1, where the mobile proton H(1) is nearly copla-
nar to the whole ring system.9–16
As expected, the alkylation of the metallated 1-methyl-
lactim ether 4 with benzyl bromide (method A)
conduced regio- and diastereoselectively (de >98%) to
the 1,4-trans isomer 10. Attempts to improve the yields
by using DMI (method B) gave exclusively, in this
case, the C(1) alkylation product 11 instead of 10
(Scheme 2).
Cyclization of compounds 12 and 13 through a subse-
quent N(2)-alkylation to give stereoselectively the penta-
cyclic compounds 16 and 17, required the assistance of
sodium iodide, to promote a Finkelstein reaction. Only
N
N
N
LHMDS, DMI, THF
H3C
LHMDS, THF,
H3C
H3C
-78 oC 10 min,
PhCH2Br, 30 min
(method B)
N
-78 oC 10 min,
PhCH2Br, 30 min
(method A)
O
N
N
O
O
Ph
1
N
4
N
N
OEt
OEt
11 (45%)
OEt
Ph
4
10 ( 53%)
Scheme 2.

3162
F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
R1
N
1) LHMDS, THF,
-78 oC 10 min.
N
O
2 or 3
R1
N
R4
R1 Br OEt
Br
, 30 min
2)
12a R4 = Me, R1 = H, (47%)
12b R4 = Me, R1 = OMe, (31%)
13a R4 = iPr, R1 = H, (44%)
13b R4 = iPr, R1 = OMe, (48%)
Br
R1
(R1 = H, OMe)
N
N
O
OCH3
N
N
CH3
N
O
OEt
15 (11%)
N
N
CH3
N
CH3O
Br OEt
N
EtO
14 (16%)
CH3
O
Scheme 3.
Et
erazine bis-lactim ethers.21 The exclusive formation of
the didehydroderivatives 19 when compounds 12 were
treated with an excess of NaI is also noticeable. Accord-
ing to our experiences with related systems,22,23 com-
pounds 19 are probably formed through a radical
iodination of compounds 16 at the 15b-captodative
position followed by subsequent dehydrohalogenation.
The stereochemistry of the pentacyclic compounds 16
and 17 was confirmed by NOESY experiments [NOE
between H(15b)-proton and the methyl or isopropyl
substituent at C(8) confirms their syn relationship] and
their enantiomeric purity was measured by chiral
HPLC.
R4
H
N
O
4
N
C
N
H
R4
H
1
N
N
R1
N
4
1
N
O
N
H3C
R1
H
4
C
1
N
H
O
R2
H
Ph
Et
boat conformation
flat boat conformation
boat conformation
of 10
compounds 1
of 5 and 7
Figure 2. Conformation of the piperazine ring in 1,4-dialkyl anti- and
syn-isomers.
in 16a was the stereocentre C(15b), which was partially
epimerized, giving in part 18 during work-up (Scheme
4). This type of cyclization has previously been observed
by Davies et al. on a similar allylic system in diketopip-
In a similar protocol, 1-substituted lactim ether 4 was
dialkylated with tetramethylene bromide to give first,
R1
N
N
NaI, DMF,
1h
N
8
N
15b
O
O
15b
12, 13
8
N
N
R4
CH3
R1
____ R4_ R1_ Yield
16a Me H 65%
16b Me OMe 69%
17a iPr
71%
17b iPr OMe 76%
R1
O
O
18 (31%)
H
N
O
NaI (excess),
DMF, 1h
N
8
O
12
19a R1 = H (67%)
19b R1 = OMe (56%)
N
CH3
R1
Scheme 4.

F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
3163
1) LHMDS, DMI, THF,
-78 oC 10 min.
NaI, DMF, 1h
N
N
H3C
H3C
4
N
N
O
O
2)
Br
Br
N
N
16 h
O
OEt
20 (23%)
Br
21 (87%)
Scheme 5.
´
with DMI as a cosolvent, compound 20 and, finally, the
fused tetracycle 21 (Scheme 5).
de Microanalisis, Universidad Complutense on a Leco
932 microanalyzer.
4.2. (1S)-3-Ethoxy-1-(or 4-)alkyl-1,4-dihydropyrazino-
[2,1-b]quinazolin-6-ones 2–4: general procedure
3. Conclusion
Herein, we have reported a simple method for the diaste-
reocontrolled synthesis of different fused polycyclic sys-
tems containing a diketopiperazine ring by starting from
the so far unexplored lactim ethers.
The mixture of the corresponding 1- or 4-alkyl-1,4-
dihydropyrazino[2,1-b]quinazolin-3,6-dione 1 (1.0 mmol;
vacuum dried),14,16 triethyloxonium tetrafluoroborate
(0.57 g, 2.3 mmol) and anhydrous Na2CO3 (0.52 g,
4.5 mmol) in 10 mL dry CH2Cl2 was stirred for 24 h at
room temperature and then ice water was added. The
product was extracted with CH2Cl2, dried over anhy-
drous Na2SO4 and evaporated, yielding 95%, 93% and
95% of 2, 3 and 4, respectively, as oily products.
4. Experimental
4.1. General methods
All reagents were of commercial quality and used as
received. Solvents were dried and purified using stan-
dard techniques. ÔPetroleum etherÕ refers to the frac-
tion boiling at 40–60 ꢁC. TLC was carried out on
precoated plates (Merck Kieselgel 60 F254), spots visu-
alized with UV light. Column chromatography was
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
were obtained on Bruker AC-250, Bruker Avance
4.2.1. (+)-(4S)-3-Ethoxy-4-methyl-1,4-dihydropyrazino-
25
[2,1-b]quinazolin-6-one 2. ½aꢀD ¼ þ143:1 (c 0.16, CHCl3);
mmax (NaCl) 2981, 1679, 1604 cmꢁ1; dH (250 MHz,
CDCl3) 8.25 (1H, dd, J = 1.4 and J = 8.0 Hz, H-7),
7.74 (1H, ddd, J = 1.4, 7.0 and 8.4 Hz, H-9), 7.63 (1H,
dd, J = 1.2 and 8.4 Hz, H-10), 7.45 (1H, ddd, J = 1.2,
7.0 and 8.0 Hz, H-8), 5.29 (1H, dq, J = 1.1 and 7.0 Hz,
H-4), 4.80 (1H, d, J = 19.6 Hz, H-1), 4.65 (1H, dd,
J = 1.1 and 19.6 Hz, H-1), 4.19 (2H, q, J = 7.1 Hz,
O–CH2–CH3), 1.53 (3H, d, J = 7.0 Hz, O–CH2–CH3),
1.32 (3H, t, J = 7.1 Hz, CH3); dC (62.5 MHz, CDCl3)
164.1 (C-3), 160.3 (C-6), 150.7 (C-11a), 147.4 (C-10a),
134.6 (C-9), 126.7 (C-10), 126.6 (C-7), 126.5 (C-8), 120.1
(C-6a), 62.1 (O–CH2–CH3), 50.6 (C-1), 47.7 (C-4), 16.5
(CH3), 14.0 (O–CH2–CH3). C14H15O2N3 requires: C,
65.35; H, 5.88; N, 16.33. Found: C, 65.46; H, 5.83; N,
15.57.
1
250 (250 MHz for H, 62.5 MHz for 13C) and Bruker
Avance DPX-300 (300 MHz for 1H, 75 MHz for 13C
spectrometers, in CDCl3 unless otherwise mentioned
(Servicio de RMN, Universidad Complutense). Pro-
tons were assigned according to COSY, HMQC and/
or 1D NOE experiments; carbons were assigned
according to DEPT, HMQC and/or HMBC experi-
ments. NOE and NOESY experiments allowed the
assignation of the cis- and trans-diastereoisomers.
Optical rotation values were determined in a Perkin–
Elmer 241 polarimeter equipped with a 1 mL cell mea-
suring 10 cm at 25 ꢁC, using the emission wavelength
of a sodium lamp; concentrations are given in g/
100 mL. The enantiomeric purity was determined by
1H NMR {addition of europium (III) tris[3-hepta-
fluoropropylhydroxymethylene)-(+)-camphorate] [(+)-
Eu(HFC)3] as shift reagent} and/or by chiral HPLC
(comparison to racemic products), employing a Cons-
trometric 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 spectrophotometer, with
solid compounds compressed into KBr pellets and
liquid compounds placed as films on NaCl disks.
Elemental analyses were determined by the Servicio
4.2.2.
(+)-(4S)-3-Ethoxy-4-isopropyl-1,4-dihydropyr-
25
azino[2,1-b]quinazolin-6-one 3. ½aꢀD ¼ þ187:3 (c 0.15,
CHCl3); mmax (NaCl) 2927, 1678, 1600, 1472, 1328,
1028 cmꢁ1; dH (250 MHz, CDCl3) 8.25 (1H, dd,
J = 1.4 and 8.1 Hz, H-7), 7.74 (1H, ddd, J = 1.4, 7.1
and 8.3 Hz, H-9), 7.63 (1H, dd, J = 1.2 and 8.3 Hz, H-
10), 7.45 (1H, ddd, J = 1.2, 7.1 and 8.1 Hz, H-8), 5.20
(1H, d, J = 6.3 Hz, H-4), 4.77 (1H, d, J = 20.4 Hz, H-
1), 4.68 (1H, d, J = 20.4 Hz, H-1), 4.20 (2H, m, O–
CH2–CH3), 2.28 (1H, m, J = 6.8 Hz, CH3–CH–CH3),
1.33 (3H, t, J = 7.1 Hz, O–CH2–CH3), 1.08 (3H, d,
J = 6.8 Hz, CH3–CH–CH3), 0.97 (3H, d, J = 6.8 Hz,
CH3–CH–CH3); dC (62.5 MHz, CDCl3) 163.2 (C-3),
161.0 (C-6), 151.7 (C-11a), 147.5 (C-10a), 134.8 (C-9),
127.0 (C-10), 126.9 (C-7), 126.7 (C-8), 120.3 (C-6a),
62.0 (O–CH2–CH3), 57.0 (C-4), 51.7 (C-1), 32.5 (CH3–
CH–CH3), 21.2 (CH3–CH–CH3), 19.6 (CH3–CH–
CH3), 14.4 (O–CH2–CH3). C16H19O2N3 requires: C,

3164
F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
67.35; H, 6.71; N, 14.73. Found: C, 67.27; H, 6.63; N,
14.54.
7.1 and 8.3 Hz, H-9), 7.63 (1H, dd, J = 1.0 and 8.3 Hz,
H-10), 7.43 (1H, ddd, J = 1.0, 7.1 and 8.0 Hz, H-8),
5.11 (1H, q, J = 6.9 Hz, H-4), 4.86 (1H, q, J = 7.3 Hz,
H-1), 4.15 (2H, m, J = 7.1 and 10.6 Hz, O–CH2–CH3),
1.59 (6H, d, J = 7.1 Hz, CH3-1 and CH3-4), 1.28 (3H,
t, J = 7.1 Hz, O–CH2–CH3); dC (62.5 MHz, CDCl3)
162.0 (C-3), 160.8 (C-6), 154.7 (C-11a), 147.8 (C-10a),
134.7 (C-9), 126.9 (C-10), 126.7 (C-7), 126.5 (C-8),
120.2 (C-6a), 61.9 (O–CH2–CH3), 57.0 (C-1), 47.9 (C-
4), 24.4* (CH3-1), 19.5* (CH3-4), 14.2 (O–CH2–CH3).
C15H17O2N3 requires: C, 66.39; H, 6.32; N, 15.49.
Found: C, 66.13; H, 5.99; N, 15.29.
4.2.3. (+)-(1S)-3-Ethoxy-1-methyl-1,4-dihydropyrazino[2,1-b]-
quinazolin-6-one 4. Since the starting piperazine-
2,5-dione 1 could only be obtained with an ee =
80%,14 no specific rotation could be determined for
4
and its derivatives; mmax (NaCl) 2981, 1679,
1604 cmꢁ1; dH (250 MHz, CDCl3) 8.19 (1H, dd,
J = 1.5 and 8.0 Hz, H-7), 7.70 (1H, ddd, J = 1.5, 7.0
and 8.4 Hz, H-9), 7.60 (1H, dd, J = 1.2 and 8.4 Hz, H-
10), 7.40 (1H, ddd, J = 1.2, 7.0 and 8.0 Hz, H-8), 4.76
(1H, dq, J = 1,1 and 7.1 Hz, H-1), 4.71 (1H, dd,
J = 1.1 and 17.5 Hz, H-4), 4.31 (1H, d, J = 17.5 Hz,
H-4), 4.18 (2H, q, J = 7.1 Hz, O–CH2–CH3), 1.54 (3H,
d, J = 7.1 Hz, CH3), 1.29 (3H, t, J = 7.1 Hz, O–CH2–
CH3); dC (62.5 MHz, CDCl3) 161.1, 159.2, 154.2,
147.6, 134.7, 127.1, 126.7, 126.6, 119.8, 62.2, 56.7,
40.5, 21.9, 14.2. C14H15O2N3 requires: C, 65.35; H,
5.88; N, 16.33. Found: C, 65.09; H, 5.75; N, 16.48.
4.3.1.3. (+)-(1R,4S)-1-Benzyl-3-ethoxy-4-methyl-1,4-
dihydropyrazino[2,1-b]quinazolin-6-one
5b. Column
chromatography (CH2Cl2/triethylamine, 100:2) afforded
5b (yield 50%). Long chromatography times induce epi-
25
merization to the cis-isomer 6b. ½aꢀD ¼ þ159:3 (c 0.15,
CHCl3); mmax (NaCl) 2979, 2930, 1678, 1598 cmꢁ1; dH
(250 MHz, CDCl3) 8.24 (1H, dd, J = 1.5 and 8.1 Hz,
H-7), 7.77 (1H, dd, J = 1.1 and 8.2 Hz, H-10), 7.76
(1H, ddd, J = 1.5, 5.3 and 8.1 Hz, H-9), 7.45 (1H,
ddd, J = 1.1, 7.0 and 8.2 Hz, H-8), 7.38 (2H, m, Ar–
H0), 7.21 (3H, m, Ar–H0), 5.16 (1H, dq, J = 1.2 and
7.0 Hz, H-4), 4.73 (1H, dd, J = 3.9 and 7.9 Hz, H-1),
4.18 (2H, m, O–CH2–CH3), 3.83 (1H, dd, J = 3.9 and
13.5 Hz, CH2–Ar–H0), 3.32 (1H, dd, J = 7.9 and
13.5 Hz, CH2–Ar–H0), 1.47 (3H, d, J = 7.0 Hz, CH3),
1.28 (3H, t, J = 7.1 Hz, O–CH2–CH3); dC (62.5 MHz,
CDCl3) 162.4 (C-3), 160.6 (C-6), 152.4 (C-11a), 147.0
(C-10a), 138.8 (C-10), 134.4 (C-9), 130.5 (C-20 and 60),
127.7 (C-30 and 50), 127.2 (C-40), 126.6 (C-10), 126.5
(C-7), 126.1 (C-8), 120.1 (C-6a), 61.8 (O–CH2–CH3),
58.7 (C-1), 48.0 (C-4), 39.4 (CH2–Ar–H0), 16.4 (CH3),
14.0 (O–CH2–CH3). C21H21O2N3 requires: C, 72.60;
H, 6.09; N, 12.10. Found: C, 72.29; H, 5.76; N, 11.69.
4.3. General alkylation procedures
4.3.1. Alkylation of 2–4. To a cold (ꢁ78 ꢁC) magneti-
cally stirred solution of 2 (257 mg, 1.0 mmol) in dry
THF (10 mL) was added, under argon, a solution of
lithium hexamethyldisilazide in THF (1 M, 1.1 mL)
dropwise via syringe, followed by a solution of the
appropriate halide [1.0 mmol dissolved in THF (5 mL)]
after 10 min. The reaction mixture was stirred at
ꢁ78 ꢁC for 30 min for 2, 1 h for 3 or 16 h for 4,
quenched with ice and extracted with CH2Cl2. The
organic layer was dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was
purified by flash column chromatography to furnish
compounds 5–8 and 10 as white syrups.
4.3.1.1. (+)-(1R,4S)-1,4-Dimethyl-3-ethoxy-1,4-dihydro-
pyrazino[2,1-b]quinazolin-6-one 5a. Column chromato-
graphy (ethyl acetate/CH2Cl2/triethylamine, 1:1:0.02)
4.3.1.4. (+)-(1S,4S)-1-Benzyl-3-ethoxy-4-methyl-1,4-
dihydropyrazino[2,1-b]quinazolin-6-one 6b. ½aꢀD ¼ þ5:2
25
(c 0.16 CHCl3); mmax (NaCl) 2920, 2849, 1680, 1606,
1592 cmꢁ1; dH (250 MHz, CDCl3) 8.23 (1H, dd, J = 1.4
and 8.2 Hz, H-7), 7.77 (1H, ddd, J = 1.4, 6.9 and
8.4 Hz, H-9), 7.69 (1H, dd, J = 1.4 and 8.4 Hz, H-10),
7.45 (1H, ddd, J = 1.4, 6.9 and 8.2 Hz, H-8), 7.17 (3H,
m, Ar–H0), 7.05 (2H, m, Ar–H0), 5.13 (1H, ddd,
J = 1.4, 4.7 and 6.2 Hz, H-1), 4.88 (1H, dq, J = 1.4
and 6.9 Hz, H-4), 4.19 (2H, m, O–CH2–CH3), 3.47
(1H, dd, J = 6.2 and 13.2 Hz, CH2–Ar–H0), 3.36 (1H,
dd, J = 4.7 and 13.2 Hz, CH2–Ar–H0), 1.31 (3H, t,
J = 7.1 Hz, O–CH2–CH3), 0.79 (3H, d, J = 6.9 Hz,
CH3); dC (62.5 MHz, CDCl3) 161.0 (C-3), 160.5 (C-6),
152.8 (C-11a), 147.4 (C-10a), 136.9 (C-10), 134.5 (C-9),
130.0 (C-20 and 60), 128.2 (C-30 and 50), 126.8 (C-40),
126.7 (C-10), 126.5 (C-7), 126.3 (C-8), 120.1 (C-6a),
61.9 (C-1), 61.5 (O–CH2–CH3), 47.5 (C-4), 43.0 (CH2–
Ar–H0), 17.8 (CH3), 14.2 (O–CH2–CH3). C21H21O2N3
requires: C, 72.60; H, 6.09; N, 12.10. Found: C, 72.37;
H, 5.81; N, 11.75.
afforded 5a (yield 57%) followed by 6a (yield 19%).
25
½aꢀD ¼ þ253:5 (c 0.17, CHCl3); mmax (NaCl) 2983,
2938, 1684, 1595, 1569 cmꢁ1; dH (250 MHz, CDCl3)
8.22 (1H, ddd, J = 0.8, 1.4 and 8.1 Hz, H-7), 7.69 (1H,
ddd, J = 1.4, 6.7 and 8.2 Hz, H-9), 7.62 (1H, dd,
J = 1.6 and 8.2 Hz, H-10), 7.41 (1H, ddd, J = 1.6, 6.7
and 8.1 Hz, H-8), 5.30 (1H, dq, J = 0.8 and 7.0 Hz,
H-4), 4.55 (1H, dq, J = 0.8 and 6.9 Hz, H-1), 4.18
(2H, q, J = 7.2 Hz, O–CH2–CH3), 1.78 (3H, d, J =
6.9 Hz, CH3-1), 1.50 (3H, d, J = 7.0 Hz, CH3-4), 1.28
(3H, t, J = 7.2 Hz, O–CH2–CH3); dC (62.5 MHz,
CDCl3) 163.2 (C-3), 160.6 (C-6), 153.9 (C-11a), 147.4
(C-10a), 134.3 (C-9), 127.4 (C-10), 126.5 (C-8), 126.4
(C-7), 120.1 (C-6a), 61.9 (O–CH2–CH3), 53.4 (C-1),
48.5 (C-4), 20.3 (CH3-1), 15.8 (CH3-4), 14.1 (O–CH2–
CH3). C15H17O2N3 requires: C, 66.39; H, 6.32; N,
15.49. Found: C, 66.26; H, 6.29; N, 15.38.
4.3.1.2. (ꢁ)-(1S,4S)-1,4-Dimethyl-3-ethoxy-1,4-dihydro-
25
pyrazino[2,1-b]quinazolin-6-one 6a. ½aꢀD ¼ ꢁ13:7 (c
4.3.1.5. (+)-(1R,4S)-3-Ethoxy-4-isopropyl-1-methyl-
1,4-dihydropyrazino[2,1-b]quinazolin-6-one 7a. Column
chromatography (ethyl acetate/petroleum ether/triethyl-
amine, 4:6:0.2) afforded 7a (yield 52%) followed by 8a
0.26, CHCl3); mmax (NaCl) 2979, 2933, 1683, 1654,
1595 cmꢁ1; dH (250 MHz, CDCl3) 8.25 (1H, ddd,
J = 0.8, 1.5 and 8.0 Hz, H-7), 7.74 (1H, ddd, J = 1.5,

F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
3165
25
(yield 14%); ½aꢀD ¼ þ231:4 (c 0.29, CHCl3); mmax (NaCl)
C23H25O2N3 requires: C, 73.57; H, 6.71; N, 11.19.
Found: C, 73.39; H, 6.68; N, 11.08.
2974, 2936, 1684, 1654, 1595 cmꢁ1; dH (250 MHz,
CDCl3) 8.25 (1H, ddd, J = 0.6, 1.5 and 8.0 Hz, H-7),
7.74 (1H, ddd, J = 1.5, 6.7 and 8.2 Hz, H-9), 7.68 (1H,
dd, J = 1.6 and 8.2 Hz, H-10), 7.45 (1H, ddd, J = 1.6,
6.7 and 8.0 Hz, H-8), 5.24 (1H, d, J = 7.1 Hz, H-4),
4.64 (1H, q, J = 6.9 Hz, H-1), 4.21 (2H, m, O–CH2–
CH3), 2.32 (1H, m, J = 7.1 Hz, CH3–CH–CH3), 1.78
(3H, d, J = 6.9 Hz, CH3-1), 1.32 (3H, t, J = 7.2 Hz,
O–CH2–CH3), 1.05 (3H, d, J = 7.1 Hz, CH3–CH–
CH3), 1.02 (3H, d, J = 7.1 Hz, CH3–CH–CH3); dC
(62.5 MHz, CDCl3) 162.9 (C-3), 161.5 (C-6), 155.2 (C-
11a), 147.7 (C-10a), 134.8 (C-9), 127.7 (C-10), 127.2
(C-7), 127.0 (C-8), 120.5 (C-6a), 62.2 (O–CH2–CH3),
58.1 (C-4), 54.5 (C-1), 32.0 (CH3–CH–CH3), 21.2
(CH3-1), 20.7 (CH3–CH–CH3), 19.3 (CH3–CH–CH3),
14.6 (O–CH2–CH3). C17H21O2N3 requires: C, 68.20;
H, 7.07; N, 14.04. Found: C, 68.00; H, 7.09; N, 13.95.
4.3.1.8. (1S,4R)-4-Benzyl-3-ethoxy-1-methyl-1,4-dihydro-
pyrazino[2,1-b]quinazolin-6-one 10. Column chromato-
graphy [CH2Cl2/triethylamine (50:1)] afforded 187 mg
(53%) of 10. mmax (NaCl) 2930, 1677, 1593, 1472,
1415 cmꢁ1; dH (250 MHz, CDCl3) 8.30 (1H, dd,
J = 1.6 and 8.1 Hz, H-7), 7.75 (1H, ddd, J = 1.6, 7.1
and 8.3 Hz, H-9), 7.63 (1H, dd, J = 1.2 and 8.3 Hz, H-
10), 7.47 (1H, ddd, J = 1.2, 7.1 and 8.1 Hz, H-8), 7.18
(3H, m, Ar–H0), 6.87 (2H, m, Ar–H0), 5.49 (1H, ddd,
J = 1.5, 3.6 and 6,1 Hz, H-4), 4.16 (2H, dq, J = 0.6
and 7.1 Hz, O–CH2–CH3), 3.39 (1H, dd, J = 6.1 and
13.8 Hz, CH2–Ar–H0), 3.27 (1H, dq, J = 1.5 and
7.0 Hz, H-1), 3.23 (1H, dd, J = 3.6 and 13.8 Hz, CH2–
Ar–H0), 1.52 (3H, d, J = 7.0 Hz, CH3), 1.28 (3H, t,
J = 7.1 Hz, O–CH2–CH3); dC (62.5 MHz, CDCl3)
160.9 (C-3), 159.6 (C-6), 154.7 (C-11a), 147.4 (C-10a),
135.1 (C-10), 134.5 (C-9), 129.6 (C-20 and 60), 128.6
(C-30 and 50), 127.5 (C-10), 127.4 (C-40), 126.6
(C-8), 126.5 (C-7), 119.9 (C-6a), 61.6 (O–CH2–CH3),
53.8 (C-4), 53.5 (C-1), 36.4 (CH2–Ar–H0), 21.4
(CH3), 14.2 (O–CH2–CH3). C21H21O2N3 requires: C,
72.60; H, 6.09; N, 12.10. Found: C, 71.65; H, 6.26; N,
11.70.
4.3.1.6. (ꢁ)-(1S,4S)-3-Ethoxy-4-isopropyl-1-methyl-
25
1,4-dihydropyrazino[2,1-b]quinazolin-6-one 8a. ½aꢀD
¼
ꢁ26:8 (c 0.25, CHCl3); mmax (NaCl) 2977, 2937, 1681,
1594, 1568, 1473 cmꢁ1; dH (250 MHz, CDCl3) 8.26
(1H, ddd, J = 0.5, 1.5 and 8.1 Hz, H-7), 7.76 (1H,
ddd, J = 1.5, 7.0 and 8.3 Hz, H-9), 7.64 (1H, ddd,
J = 0.5, 1.3 and 8.3 Hz, H-10), 7.45 (1H, ddd, J = 1.3,
7.0 and 8.1 Hz, H-8), 5.12 (1H, dd, J = 1.1 and 6.1 Hz,
H-4), 4.91 (1H, dq, J = 1.0 and 7.4 Hz, H-1), 4.21
(2H, m, O–CH2–CH3), 2.17 (1H, m, J = 6.9 Hz, CH3–
CH–CH3), 1.73 (3H, d, J = 7.4 Hz, CH3-1), 1.35 (3H,
t, J = 7.1 Hz, O–CH2–CH3), 1.10 (3H, d, J = 6.9 Hz,
CH3–CH–CH3), 1.04 (3H, d, J = 6.9 Hz, CH3–CH–
CH3); dC (62.5 MHz, CDCl3) 161.6 (C-6), 160.8 (C-3),
155.4 (C-11a), 147.8 (C-10a), 135.0 (C-9), 127.2 (C-7),
127.0 (C-10), 126.7 (C-8), 120.4 (C-6a), 61.9 (O–CH2–
CH3), 57.4 (C-1), 56.5 (C-4), 34.2 (CH3–CH–CH3),
23.7 (CH3-1), 20.8 (CH3–CH–CH3), 19.7 (CH3–CH–
CH3), 14.6 (O–CH2–CH3). C17H21O2N3 requires: C,
68.20; H, 7.07; N, 14.04. Found: C, 67.72; H, 7.00; N,
13.89.
4.3.2. Alkylations with DMI as cosolvent. To a cold
(ꢁ78 ꢁC) magnetically stirred solution of 2 or 4
(1.0 mmol) and 2 equiv of DMI in dry THF (10 mL)
was added, under argon, a solution of lithium hexam-
ethyldisilazide in THF (1 equiv) dropwise via syringe,
followed by a solution of benzyl bromide or 1,4-dibro-
mobutane (1.0 equiv dissolved in THF) after 10 min.
The reaction mixture was stirred at ꢁ78 ꢁC for 1.5 h
for 2 or 16 h for 4, quenched with ice and extracted with
CH2Cl2. The organic layer was dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The
residue was purified by flash column chromatography
to furnish 9 or 11 as white syrups.
4.3.1.7. (+)-(1R,4S)-1-Benzyl-3-ethoxy-4-isopropyl-
1,4-dihydropyrazino[2,1-b]quinazolin-6-one 7b. Column
4.3.2.1. (+)-(4S)-1,1-Dibenzyl-3-ethoxy-4-methyl-1,4-
dihydropyrazino[2,1-b]quinazolin-6-one 9. Column chro-
matography [toluene/ethyl acetate (95:5)] afforded
chromatography (CH2Cl2/hexane/triethylamine, 9:1:0.2)
25
afforded 7b (yield 54%). ½aꢀD ¼ þ178:1 (c 0.11, CHCl3);
142 mg (30%) of
9
and 17 mg (5%) of 5b.
25
m
max (NaCl) 2925, 2853, 1735, 1681, 1595, 1471 cmꢁ1; dH
½aꢀD ¼ þ158:7 (c 0.15, CHCl3); mmax (NaCl) 3062,
3029, 2929, 1681, 1585 cmꢁ1; dH (250 MHz, CDCl3)
8.16 (1H, dd, J = 1.4 and 8.1 Hz, H-7), 7.91 (1H, dd,
J = 1.5 and 8.2 Hz, H-10), 7.84 (1H, ddd, J = 1.4, 6.8
and 8.2 Hz, H-9), 7.47 (1H, ddd, J = 1.5, 6.8 and
8.1 Hz, H-8), 6.98 (10H, m, Ar–H), 4.33 (3H, m, H-4
and O–CH2–CH3), 3.97 (1H, d, J = 12.4 Hz, CH2–Ar–
H0), 3.86 (1H, d, J = 12.4 Hz, CH2–Ar–H00), 3.23 (1H,
d, J = 12.4 Hz, CH2–Ar–H00), 3.22 (1H, d, J = 12.4 Hz,
CH2–Ar–H0), 1.35 (3H, t, J = 7.1 Hz, O–CH2–CH3),
0.32 (3H, d, J = 6.7 Hz, CH3); dC (62.5 MHz, CDCl3)
160.1 (C-6), 158.8 (C-3), 154.0 (C-11a), 146.7 (C-10a),
137.2 (C-10), 136.6 (C-100), 134.4 (C-9), 130.6 (C-20 and
60), 130.1 (C-200 and 600), 128.0 (C-300 and 500), 127.5
(C-30 and 50), 127.0 (C-400), 126.6 (C-10), 126.5 (C-40),
126.4 (C-7), 126.3 (C-8), 119.9 (C-6a), 68.5 (C-1),
60.9 (O–CH2–CH3), 50.4 (CH2–Ar–H00), 48.4 (CH2–
Ar–H0), 46.9 (C-4), 17.7 (CH3), 14.4 (O–CH2–CH3).
(250 MHz, CDCl3) 8.24 (1H, dd, J = 1.5 and 8.0 Hz, H-
7), 7.76 (1H, m, H-9), 7.73 (1H, m, H-10), 7.45 (1H, ddd,
J = 2.3, 5.9 and 8.1 Hz, H-8), 7.38 (2H, m, Ar–H0), 7.22
(3H, m, Ar–H0), 5.12 (1H, dd, J = 0.9 and 6.8 Hz, H-4),
4.76 (1H, dd, J = 4.0 and 7.9 Hz, H-1), 4.18 (2H, m, O–
CH2–CH3), 3.80 (1H, dd, J = 4.0 and 13.5 Hz, CH2–Ar–
H0), 3.29 (1H, dd, J = 7.9 and 13.5 Hz, CH2–Ar–H0),
2.21 (1H, m, J = 6.9 Hz, CH3–CH–CH3), 1.28 (3H, t,
J = 7.1 Hz, O–CH2–CH3), 1.02 (3H, d, J = 6.9 Hz,
CH3–CH–CH3), 0.92 (3H, d, J = 6.9 Hz, CH3–CH–
CH3); dC (62.5 MHz, CDCl3) 161.5 (C-3), 161.1 (C-6),
153.2 (C-11a), 147.0 (C-10a), 139.0 (C-10), 134.4 (C-9),
130.5 (C-20 and 60), 127.6 (C-30 and 50), 127.2 (C-10),
126.7 (C-7), 126.5 (C-8), 126.0 (C-40), 120.0 (C-6a),
61.6 (O–CH2–CH3), 59.3 (C-1), 57.0 (C-4), 39.8
(CH2–Ar–H0), 31.8 (CH3–CH–CH3), 20.1 (CH3–CH–
CH3), 18.6 (CH3–CH–CH3), 14.2 (O–CH2–CH3).

3166
F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
C28H27O2N3 requires: C, 76.86; H, 6.22; N, 9.60. Found:
C, 76.33; H, 6.36; N, 9.90.
4.3.3.1. (+)-(1R,4S)-1-(2-Bromomethylbenzyl)-3-eth-
oxy-4-methyl-1,4-dihydropyrazino[2,1-b]quinazolin-6-one
12a. Yield 47% of 12a and 11% of dimer 15.
25
4.3.2.2. ( )-1-Benzyl-3-ethoxy-1-methyl-1,4-dihydro-
pyrazino[2,1-b]quinazolin-6-one 11. Column chroma-
tography [CH2Cl2/petroleum ether (9:1)] afforded 45%
of 11. mmax (NaCl) 2977, 2929, 1682, 1610, 1589,
1566 cmꢁ1; dH (250 MHz, CDCl3) 8.18 (1H, dd,
J = 2.0 and 8.0 Hz, H-7), 7.76 (2H, m, H-9 and 10),
7.44 (1H, m, H-8), 7.08 (3H, m, Ar–H0), 6.79 (2H, m,
Ar–H0), 4.26 (2H, q, J = 7.1 Hz, O–CH2–CH3), 4.18
(1H, d, J = 18.6 Hz, H-4), 3.46 (1H, d, J = 12.7 Hz,
CH2–Ar–H0), 3.04 (1H, d, J = 12.7 Hz, CH2–Ar–H0),
2.78 (1H, d, J = 18.6 Hz, H-4), 1.86 (3H, s, CH3), 1.32
(3H, t, J = 7.1 Hz, O–CH2–CH3); dC (62.5 MHz,
CDCl3) 160.7 (C-3), 156.5 (C-6), 155.2 (C-11a), 147.3
(C-10a), 136.6 (C-10), 134.4 (C-9), 130.1 (C-20 and 60),
128.0 (C-30 and 50), 127.4 (C-10), 127.0 (C-40), 126.5
(C-8), 126.4 (C-7), 119.4 (C-6a), 63.5 (C-1), 61.4
(O–CH2–CH3), 50.3 (CH2–Ar–H0), 40.8 (C-4), 30.3
(CH3), 14.3 (O–CH2–CH3). C21H21O2N3 requires: C,
72.60; H, 6.09; N, 12.10. Found: C, 72.36; H, 6.60; N,
11.63.
½aꢀD ¼ þ52:8 (c 0.36, CHCl3); mmax (NaCl) 2980, 2928,
1676, 1597 cmꢁ1; dH (250 MHz, CDCl3) 8.26 (1H, ddd,
J = 0.8, 1.4 and 8.2 Hz, H-7), 7.77 (2H, m, H-9 and
H-10), 7.47 (1H, ddd, J = 1.2, 7.0 and 8.2 Hz, H-8),
7.45 (1H, dd, J = 1.4 and 7.5 Hz, H-60), 7.37 (1H, dd,
J = 1.4 and 7.5 Hz, H-30), 7.19 (2H, m, H-40 and 50),
5.28 (1H, dq, J = 1.1 and 7.1 Hz, H-4), 5.00 (1H, d,
J = 10.0 Hz, Ar–CH2–Br), 4.72 (1H, d, J = 10.0 Hz,
Ar–CH2–Br), 4.71 (1H, dd, J = 3.5 and 9.1 Hz, H-1),
4.10 (1H, dd, J = 3.5 and 14.1 Hz, C1–CH2–Ar–H0),
4.09 (2H, q, J = 7.1 Hz, O–CH2–CH3), 3.35 (1H, dd,
J = 9.1 and 14.1 Hz, C1–CH2–Ar–H0), 1.46 (3H, d,
J = 7.1 Hz, CH3), 1.24 (3H, t, J = 7.1 Hz, O–CH2–
CH3); dC (62.5 MHz, CDCl3) 163.3 (C-3), 160.6 (C-6),
152.2 (C-11a), 147.1 (C-10a), 138.7 (C-20), 137.2 (C-10),
134.4 (C-9), 131.5 (C-60), 130.3 (C-30), 128.5 (C-50),
127.4 (C-10), 126.9 (C-8), 126.7 (C-40), 126.7 (C-7),
120.1 (C-6a), 61.9 (O–CH2–CH3), 58.9 (C-1), 48.2 (C-
4), 35.3 (C1–CH2–Ar–H0), 33.0 (Ar–CH2–Br), 15.8
(CH3), 14.0 (O–CH2–CH3). C22H22O2N3Br requires: C,
60.01; H, 5.04; N, 9.54. Found: C, 60.12; H, 4.91; N,
9.45.
4.3.2.3. ( )-1-(4-Bromobutyl)-3-ethoxy-1-methyl-1,4-
20. Column
dihydropyrazino[2,1-b]quinazolin-6-one
chromatography [CH2Cl2/petroleum ether (8:2)] affor-
ded 23% of 20. mmax (NaCl) 2934, 1680, 1611, 1591,
1567 cmꢁ1; dH (250 MHz, CDCl3) 8.23 (1H, ddd,
J = 0.5, 1.5 and 8.0 Hz, H-7), 7.74 (1H, ddd, J = 1.5,
6.8 and 8.3 Hz, H-9), 7.66 (1H, ddd, J = 0.5, 1.4 and
8.3 Hz, H-10), 7.44 (1H, ddd, J = 1.4, 6.8 and 8.0 Hz,
H-8), 4.61 (1H, d, J = 18.6 Hz, H-4), 4.38 (1H, d,
J = 18.6 Hz, H-4), 4.24 (2H, m, O–CH2–CH3), 3.35
(2H, m, H-40), 2.34 (1H, m, H-10), 1.83 (3H, m, H-10
and 30), 1.54 (3H, s, CH3), 1.33 (3H, t, J = 7.1 Hz, O–
CH2–CH3), 1.25 (2H, m, H-20); dC (62.5 MHz, CDCl3)
161.3 (C-3), 156.4 (C-6), 155.4 (C-11a), 147.5 (C-10a),
134.5 (C-9), 127.4* (C-7), 126.5* (C-8), 126.4* (C-10),
119.5 (C-6a), 61.9 (C-1), 61.6 (O–CH2–CH3), 41.5* (C-
4), 41.0* (C-30), 33.6* (C-40), 32.8* (C-10), 29.5 (CH3),
23.0 (C-20), 14.2 (O–CH2–CH3). C18H22O2N3Br
requires: C, 55.10; H, 5.70; N, 10.70. Found: C, 55.26;
H, 5.61; N, 10.59.
4.3.3.2.
(1R,4S)-1,2-Bis-[(3-ethoxy-4-methyl-6-oxo-
1,4-dihydropyrazino[2,1-b]quinazolin-1-yl)methyl]benzene
15. dH (250 MHz, CDCl3) 8.23 (2H, dd, J = 1.5 and
8.0 Hz, H-7), 7.70 (2H, ddd, J = 1.5, 6.9 and 8.3 Hz,
H-9), 7.62 (2H, dd, J = 1.4 and 8.3 Hz, H-10), 7.43
(4H, m, H-8 and Ar–H0), 7.19 (2H, m, Ar–H0), 5.24
(2H, dq, J = 1.1 and 7.0 Hz, H-4), 4.69 (2H, dd,
J = 2.6 and 9.8 Hz, H-1), 4,16 (4H, dq, J = 7.1 and
10.8 Hz, O–CH2–CH3), 4.12 (2H, dd, J = 2.6 and
14.0 Hz, C1–CH2–Ar–H0), 3.55 (2H, dd, J = 9.8 and
14.0 Hz, C1–CH2–Ar–H0), 1.46 (6H, d, J = 7.0 Hz,
CH3), 1.26 (6H, t, J = 7.1 Hz, O–CH2–CH3); dC
(62.5 MHz, CDCl3) 162.9 (C-3), 160.9 (C-6), 153.0 (C-
11a), 147.4 (C-10a), 136.9 (C-10 and 20), 134.5 (C-9),
130.7 (C-30 and 60), 127.5* (C-10), 126.8* (C-8), 126.7*
(C-40 and 50), 126.2* (C-7), 120.3 (C-6a), 62.1 (O–
CH2–CH3), 59.8 (C-1), 48.4 (C-4), 36.5 (C1–CH2–Ar–
H0), 16.2 (CH3), 14.4 (O–CH2–CH3). C36H36O4N6
requires: C, 70.11; H, 5.88; N, 13.63. Found: C, 70.36
H, 5.79; N, 13.51.
4.3.3. (+)-(1R,4S)-1-(2-Bromomethylbenzyl)- and 1-(2-
bromomethyl-3,6-dimethoxybenzyl)-3-ethoxy-4-alkyl-1,4-
dihydropyrazino[2,1-b]quinazolin-6-ones 12 and 13: gen-
eral procedure. To a cold (ꢁ78 ꢁC) magnetically stirred
solution of 2 or 3 (1.0 mmol) in dry THF (10 mL) was
added, under argon, a solution of lithium hexamethyldi-
silazide in THF (1 M, 1.5 mL) dropwise via syringe.
After 10 min, the basic cold solution was transferred
with a double-tipped needle over a cold solution
(ꢁ78 ꢁC) of the corresponding 1,2-bisbromoxylene
(1.0 mmol) in THF (25 mL). The reaction mixture was
stirred at ꢁ78 ꢁC for 16 h, quenched with ice and
extracted with CH2Cl2. The organic layer was dried over
anhydrous Na2SO4 and evaporated under reduced pres-
sure. The residue was purified by flash column chroma-
tography [petroleum ether/ethyl acetate (9:1) for 12 and
petroleum ether/ethyl acetate/triethylamine (95:5:2) for
13] to furnish compounds 12–15 as oily products.
4.3.3.3. (+)-(1R,4S)-1-(2-Bromomethyl-3,6-dimeth-
oxybenzyl)-3-ethoxy-4-methyl-1,4-dihydropyrazino[2,1-b]-
quinazolin-6-one 12b. Yield 31% of 12b and 16% of 14.
25
½aꢀD ¼ þ48:7 (c 0.25, CHCl3); mmax (NaCl) 2937, 1681,
1599, 1568, 1468 cmꢁ1; dH (250 MHz, CDCl3) 8.25
(1H, td, J = 1.0 and 8.0 Hz, H-7), 7.77 (2H, m, H-9
and H-10), 7.45 (1H, m, H-8), 6.62 (1H, d, J = 9.0 Hz,
H-50), 6.76 (1H, d, J = 9.0 Hz, H-40), 5.30 (1H, dq,
J = 1.0 and 7.1 Hz, H-4), 4.98 (1H, d, J = 9.4 Hz, Ar–
CH2–Br), 4.89 (1H, d, J = 9.4 Hz, Ar–CH2–Br), 4.70
(1H, dd, J = 3.3 and 10.8 Hz, H-1), 4.27 (1H, dd,
J = 3.3 and 13.8 Hz, C1–CH2–Ar–H0), 3.99 (2H, m,
O–CH2–CH3), 3.86 (3H, s, OCH3-3), 3.77 (3H, s,
OCH3-6), 3.10 (1H, dd, J = 10.8 and 13.8 Hz, C1–
CH2–Ar–H0), 1.46 (3H, d, J = 7.1 Hz, CH3), 1.21 (3H,
t, J = 7.0 Hz, O–CH2–CH3); dC (62.5 MHz, CDCl3)

F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
3167
163.4 (C-3), 160.7 (C-6), 152.7 (C-11a), 151.9 (C-60),
151.7 (C-30), 147.4 (C-10a), 134.3 (C-9), 128.9 (C-20),
127.8 (C-10), 127.7 (C-10), 126.6 (C-8), 126.4 (C-7), 120.1
(C-6a), 110.8 (C-40), 109.3 (C-50), 61.7 (O–CH2–CH3),
56.8 (C-1), 56.1 (OCH3), 55.7 (OCH3), 48.5 (C-4), 29.9
(C1–CH2–Ar–H0), 27.3 (Ar–CH2–Br), 15.4 (CH3), 14.0
(O–CH2–CH3). C24H26O4N3Br requires: C, 57.61; H,
5.24; N, 8.40. Found: C, 57.45; H, 5.21; N, 8.37.
4.3.3.6. (+)-(1R,4S)-1-(2-Bromomethyl-3,6-dimeth-
oxybenzyl)-3-ethoxy-4-isopropyl-1,4-dihydropyrazino [2,1-b]-
25
quinazolin-6-one 13b. Yield 48%; ½aꢀD ¼ þ30:0 (c 0.05,
CHCl3); mmax (NaCl) 2969, 2361, 1678, 1598 cmꢁ1; dH
(250 MHz, CDCl3) 8.25 (1H, td, J = 1.0 and 8.0 Hz,
H-7), 7.77 (1H, dt, J = 1.4 and 8.2 Hz, H-9), 7.74 (1H,
dt, J = 1.3 and 8.2 Hz, H-10), 7.45 (1H, ddd, J = 1.3,
7.2 and 8.2 Hz, H-8), 6.85 (1H, d, J = 9.0 Hz, H-50),
6.75 (1H, d, J = 9.0 Hz, H-40), 5.20 (1H, d, J = 7.5 Hz,
H-4), 4.98 (1H, d, J = 9.4 Hz, Ar–CH2–Br), 4.89 (1H,
d, J = 9.4 Hz, Ar–CH2–Br), 4.70 (1H, dd, J = 3.3 and
10.8 Hz, H-1), 4.27 (1H, dd, J = 3.3 and 13.8 Hz, C1–
CH2–Ar–H0), 3.99 (2H, m, O–CH2–CH3), 3.86 (3H, s,
OCH3-3), 3.77 (3H, s, OCH3-6), 3.10 (1H, dd, J = 10.8
and 13.8 Hz, C1–CH2–Ar–H0), 2.16 (1H, m, CH3–CH–
CH3), 1.21 (3H, t, J = 7.0 Hz, O–CH2–CH3), 0.95
(3H, d, J = 7.1 Hz, CH3–CH–CH3), 0.85 (3H, d, J =
7.1 Hz, CH3–CH–CH3). C26H30O4N3Br requires: C,
59.09; H, 5.72; N, 7.95. Found: C, 61.43; H, 5.29; N,
8.86.
4.3.3.4. (+)-(1S,4S)-1-(2-Bromomethyl-3,6-dimeth-
oxybenzyl)-3-ethoxy-4-methyl-1,4-dihydropyazino[2,1-b]-
25
quinazolin-6-one 14. ½aꢀD ¼ þ54:0 (c 0.25, CHCl3);
mmax (NaCl) 2935, 1678, 1595, 1587, 1483, 1261
cmꢁ1; dH (250 MHz, CDCl3) 8.23 (1H, dd, J = 1.6 and
8.4 Hz, H-7), 7.66 (1H, ddd, J = 1.6, 7.2 and 8.0 Hz,
H-9), 7.40 (1H, ddd, J = 1.3, 7.2 and 8.4 Hz, H-8),
7.39 (1H, dd, J = 1.3 and 8.0 Hz, H-10), 6.69 (1H, d,
J = 9.0 Hz, H-50), 6.50 (1H, d, J = 9.0 Hz, H-40), 5.10
(1H, q, J = 7.0 Hz, H-4), 4.88 (1H, dd, J = 6.7 and
8.5 Hz, H-1), 4.87 (1H, d, J = 9.7 Hz, Ar–CH2–Br),
4.65 (1H, d, J = 9.7 Hz, Ar–CH2–Br), 4.12 (2H, q,
J = 7.1 Hz, O–CH2–CH3), 3.83 (3H, s, OCH3-3), 3.42
(1H, dd, J = 6.7 and 13.5 Hz, C1–CH2–Ar–H0), 3.26
(1H, dd, J = 8.5 and 13.5 Hz, C1–CH2–Ar–H0), 3.16
(3H, s, OCH3-6), 1.63 (3H, d, J = 7.0 Hz, CH3), 1.30
(3H, t, J = 7.1 Hz, O–CH2–CH3); dC (62.5 MHz,
CDCl3) 162.6 (C-3), 160.8 (C-6), 152.6 (C-11a), 152.1
(C-60), 151.7 (C-30), 147.4 (C-10a), 134.3 (C-9), 126.8
(C-8), 126.3 (C-7), 126.2 (C-10), 126.2 (C-10), 125.9
(C-20), 120.1 (C-6a), 110.2 (C-40), 109.8 (C-50), 61.8
(O–CH2–CH3), 61.3 (C-1), 56.1 (OCH3), 54.9 (OCH3),
48.3 (C-4), 34.2 (C1–CH2–Ar–H0), 26.2 (Ar–CH2–Br),
18.5 (CH3), 14.2 (O–CH2–CH3). C24H26O4N3Br re-
quires: C, 57.61; H, 5.24; N, 8.40. Found: C, 57.70; H,
5.12; N, 8.29.
4.4. Synthesis of (8S,15bR(S))-8-alkyl-15b,16-dihydro-
5H,8H-isoquinolino[20,30-4,3]pyrazino[2,1-b]quinazolin-
7,10-diones 16–18
A solution of compound 12 or compound 13 (0.1 mmol)
in 2 mL of dry dimethylformamide and 15 mg
(0.1 mmol) of NaI were refluxed for 1 h. Toluene was
added and the organic layer extracted with brine, dried
over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue was purified by flash column chro-
matography (petroleum ether/ethyl acetate [6:4 for 16,
18 and 7:3 for 17]).
4.4.1. (+)-(8S,15bR)-8-Methyl-15b,16-dihydro-5H,8H-iso-
quinolino[20,30-4,3]pyrazino[2,1-b]quinazoline-7,10-dione
16a. Chromatography yielded 65% of 16a and 34% of
4.3.3.5. (+)-(1R,4S)-1-(2-Bromomethylbenzyl)-3-eth-
oxy-4-isopropyl-1,4-dihydropyrazino[2,1-b]quinazolin-6-
18a. Mp: 178–179 ꢁC (petroleum ether/ethyl acetate);
25
25
one 13a. Yield 44%; ½aꢀD ¼ þ70:9 (c 1.60, CHCl3); mmax
½aꢀD ¼ þ24:0 (c 0.08, CHCl3); mmax (NaCl) 2922, 1670,
(NaCl) 2969, 2361, 1678, 1598 cmꢁ1; dH (250 MHz,
CDCl3) 8.26 (1H, td, J = 1.6 and 7.4 Hz, H-7), 7.77
(1H, dt, J = 1.6 and 8.2 Hz, H-9), 7.74 (1H, dd, J = 2.4
and 7.7 Hz, H-10), 7.47 (1H, ddd, J = 2.4, 6.9 and
8.1 Hz, H-8), 7.38 (2H, m, H-30 and 60), 7.24 (1H, dt,
J = 2.2 and 7.5 Hz, H-50), 7.20 (1H, dt, J = 2.4 and
7.5 Hz, H-40), 5.18 (1H, dd, J = 0.9 and 7.4 Hz, H-4),
4.99 (1H, d, J = 10.0 Hz, Ar–CH2–Br), 4.77 (1H, dd,
J = 3.4 and 9.1 Hz, H-1), 4.73 (1H, d, J = 10.0 Hz, Ar–
CH2–Br), 4.12 (2H, m, O–CH2–CH3), 4.07 (1H, dd,
J = 3.4 and 14.1 Hz, C1–CH2–Ar–H0), 3.31 (1H, dd,
J = 9.1 and 14.1 Hz, C1–CH2–Ar–H0), 2.21 (1H, m,
J = 6.9 Hz, CH3–CH–CH3), 1.25 (3H, t, J = 7.1 Hz,
O–CH2–CH3), 1.00 (3H, d, J = 6.9 Hz, CH3–CH–
CH3), 0.94 (3H, d, J = 6.9 Hz, CH3–CH–CH3); dC
(62.5 MHz, CDCl3) 162.5 (C-3), 161.1 (C-6), 153.0 (C-
11a), 147.0 (C-10a), 138.8 (C-20), 137.1 (C-10), 134.4
(C-9), 131.5 (C-60), 130.3 (C-30), 128.5 (C-50), 127.3 (C-
10), 126.8 (C-8), 126.7 (C-40), 126.6 (C-7), 120.1 (C-6a),
61.8 (O–CH2–CH3), 59.4 (C-1), 57.2 (C-4), 35.8 (C1–
CH2–Ar–H0), 33.0 (Ar–CH2–Br), 31.4 (CH3–CH–CH3),
20.1 (CH3–CH–CH3), 18.8 (CH3–CH–CH3), 14.1 (O–
CH2–CH3). C24H26O2N3Br requires: C, 61.64; H, 5.60;
N, 8.97. Found: C, 61.43; H, 5.29; N, 8.86.
1605 cmꢁ1; dH (250 MHz, CDCl3) 8.28 (1H, dd,
J = 1.4 and 8.1 Hz, H-11), 7.79 (1H, ddd, J = 1.4, 6.7
and 8.2 Hz, H-13), 7.73 (1H, dd, J = 1.6 and 8.2 Hz,
H-14), 7.51 (1H, ddd, J = 1.6, 6.7 and 8.1 Hz, H-12),
7.35 (4H, m, H-1, 2, 3 and 4), 5.69 (1H, q, J = 7.2 Hz,
H-8), 5.16 (1H, d, J = 16.0 Hz, H-5), 4.67 (1H, dd,
J = 4.1 and 10.7 Hz, H-15b), 4.42 (1H, d, J = 16.0 Hz,
H-5), 3.87 (1H, dd, J = 4.1 and 15.5 Hz, H-16), 3.34
(1H, dd, J = 10.7 and 15.5 Hz, H-16), 1.59 (3H, d,
J = 7.2 Hz, CH3); dC (62.5 MHz, CDCl3) 167.3 (C-7),
160.1 (C-10), 149.9 (C-15a), 147.0 (C-14a), 134.6 (C-
13), 134.1 (C-16a), 132.7 (C-4a), 127.9 (C-1), 127.7 (C-
3), 127.5 (C-14), 127.4 (C-2), 127.3 (C-11), 126.8 (C-
12), 126.4 (C-4), 120.5 (C-10a), 53.7 (C-8), 52.3 (C-
15b), 44.0 (C-5), 31.8 (C-16), 16.1 (CH3). C20H17O2N3
requires: C, 72.48; H, 5.17; N, 12.69. Found: C, 72.33;
H, 5.06; N, 12.48.
4.4.2. (ꢁ)-(8S,15bS)-8-Methyl-15b,16-dihydro-5H,8H-
isoquinolino[20,30-4,3]pyrazino[2,1-b]quinazoline-7,10-dione
18. Mp: 98–99 ꢁC (petroleum ether/ethyl acetate);
25
½aꢀD ¼ ꢁ40:0 (c 0.04, CHCl3); mmax (NaCl) 2928, 1671,
1600, 1474 cmꢁ1; dH (250 MHz, CDCl3) 8.30 (1H, dd,
J = 1.3 and 8.1 Hz, H-11), 7.79 (1H, ddd, J = 1.3, 7.2

3168
F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
and 8.4 Hz, H-13), 7.65 (1H, dd, J = 1.2 and 8.4 Hz,
H-14), 7.51 (1H, ddd, J = 1.2, 7.2 and 8.1 Hz, H-12),
7.20 (4H, m, H-1, 2, 3 and 4), 5.70 (1H, d, J = 16.7 Hz,
H-5), 5.40 (1H, q, J = 7.0 Hz, H-8), 4.93 (1H, dd,
J = 3.9 and 12.7 Hz, H-15b), 4.24 (1H, d, J = 16.7 Hz,
H-6), 3.54 (1H, dd, J = 3.9 and 16.0 Hz, H-16), 3.23
(1H, dd, J = 12.7 and 16.0 Hz, H-16), 1.67 (3H, d,
J = 7.0 Hz, CH3); dC (62.5 MHz, CDCl3) 165.3 (C-7),
160.1 (C-10), 149.3 (C-15a), 147.2 (C-14a), 134.8 (C-13),
131.7 (C-16a), 131.6 (C-4a), 129.1 (C-11a), 128.1 (C-1),
127.1 (C-3), 127.0 (C-12), 126.8 (C-4), 126.5 (C-14),
125.2 (C-2), 120.3 (C-10a), 57.4 (C-8), 51.6 (C-15b),
44.1 (C-5), 36.0 (C-16), 20.1 (CH3). C20H17O2N3 requires:
C, 72.48; H, 5.17; N, 12.69. Found: C, 72.51; H, 5.11; N,
12.39.
4.4.5. (+)-(8S,15bR)-1,4-Dimethoxy-8-isopropyl-15b,16-
dihydro-5H,8H-isoquinolino[20,30-4,3]pyrazino[2,1-b]qui-
nazoline-7,10-dione 17b. Mp: 191–192 ꢁC (petroleum
25
ether/ethyl acetate); ½aꢀD ¼ þ61:5 (c 0.07; CHCl3); mmax
(NaCl) 2956, 2927, 2841, 1669, 1606 cmꢁ1
;
dH
(250 MHz, CDCl3) 8.28 (1H, dd, J = 1.0 and 8.0 Hz,
H-11), 7.77 (1H, ddd, J = 1.0, 7.6 and 8.2 Hz, H-13),
7.76 (1H, dd, J = 1.4 and 8.2 Hz, H-14), 7.49 (1H,
ddd, J = 1.4, 7.6 and 8.0 Hz, H-12), 6.79 (1H, d,
J = 9.0 Hz, H-2), 6.74 (1H, d, J = 9.0 Hz, H-3), 5.38
(1H, d, J = 7.9 Hz, H-8), 5.17 (1H, d, J = 17.4 Hz, H-
5), 4.66 (1H, dd, J = 4.1 and 11.1 Hz, H-15b), 4.36
(1H, d, J = 17.4 Hz, H-5), 4.23 (1H, dd, J = 4.1 and
16.1 Hz, H-16), 3.86 (3H, s, OCH3-1), 3.80 (3H, s,
OCH3-4), 2.82 (1H, dd, J = 11.1 and 16.1 Hz, H-16),
2.22 (1H, m, J = 6.8 Hz, CH3–CH–CH3), 1.06 (3H,
d, J = 6.8 Hz, CH3–CH–CH3), 1.03 (3H, d, J =
6.8 Hz, CH3–CH–CH3), dC (62.5 MHz, CDCl3) 166.0
(C-7), 160.7 (C-10), 150.8 (C-15a), 150.1* (C-1), 149.6*
(C-4), 147.0 (C-14a), 134.5 (C-13), 127.4 (C-14), 127.1
(C-11), 126.9 (C-12), 123.4* (C-4a), 122.2* (C-16a),
120.4 (C-10a), 109.1* (C-3), 108.4* (C-2), 60.8 (C-8),
55.9 (OCH3), 55.5 (OCH3), 53.7 (C-15b), 39.1 (C-5),
31.7 (CH3–CH–CH3), 26.3 (C-16), 19.8 (CH3–CH–
CH3), 18.9 (CH3–CH–CH3). C24H25O4N3 requires: C,
68.72; H, 6.01; N, 10.02. Found: C, 68.43; H, 5.92; N,
10.35.
4.4.3.
(+)-(8S,15bR)-1,4-Dimethoxy-8-methyl-15b,16-
dihydro-5H,8H-isoquinolino[20,30-4,3]pyrazino[2,1-b]-
25
quinazoline-7,10-dione 16b. Yield 68%; ½aꢀD ¼ þ31:6
(c 0.06; CHCl3); mmax (NaCl) 2925, 1683, 1608 cmꢁ1
;
dH (250 MHz, CDCl3) 8.30 (1H, dd, J = 2.0 and
8.0 Hz, H-11), 7.80 (1H, m, H-12), 7.78 (1H, m,
H-11), 7.45 (1H, m, H-13), 6.82 (1H, d, J = 9.0 Hz,
H-2), 6.76 (1H, d, J = 9.0 Hz, H-3), 5.59 (1H, q,
J = 7.1 Hz, H-8), 5.29 (1H, d, J = 17.1 Hz, H-5), 4.62
(1H, dd, J = 4.1 and 11.1 Hz, H-15b), 4.34 (1H, d,
J = 17.1 Hz, H-5), 4.26 (1H, dd, J = 4.1 and 15.9 Hz,
H-16), 3.88 (3H, s, OCH3), 3.82 (3H, s, OCH3), 2.91
(1H, dd, J = 11.1 and 15.9 Hz, H-16), 1.53 (3H, d,
J = 7.1 Hz, CH3); dC (62.5 MHz, CDCl3) 167.4 (C-7),
160.2 (C-10), 151.0 (C-1), 150.3 (C-15a), 149.7 (C-4),
147.2 (C-14a), 134.6 (C-13), 127.5 (C-12), 127.3
(C-14), 126.8 (C-11), 123.5 (C-16a), 122.3 (C-4a),
120.6 (C-10a), 109.3 (C-2), 108.7 (C-3), 56.0 (OCH3),
55.7 (OCH3), 53.5 (C-15b), 52.2 (C-8), 39.2 (C-5),
26.0 (C-16), 16.9 (CH3). C22H21O4N3 requires: C,
67.50; H, 5.40; N, 10.70. Found: C, 67.38; H, 5.31;
N, 10.59.
4.5. Synthesis of (8S)-8-methyl-5H,8H-isoquinolino[20,30-
4,3]pyrazino[2,1-b]quinazolin-7,10-diones 19
A solution of compound 12 (0.1 mmol) in 2 mL of dry
dimethylformamide and a big excess of NaI was refluxed
for 1 h. Toluene was added and the organic layer
extracted with brine, dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The residue was
purified by flash column chromatography [petroleum
ether/ethyl acetate (6:4)].
4.4.4. (+)-(8S,15bR)-8-Isopropyl-15b,16-dihydro-5H,8H-
isoquinolino[20,30-4,3]pyrazino[2,1-b]quinazoline-7,10-
4.5.1. (ꢁ)-(8S)-8-Methyl-5H,8H-isoquinolino[20,30-4,3]-
pyrazino[2,1-b]quinazoline-7,10-dione 19a. White syr-
25
25
dione 17a. Yield 71%; ½aꢀD ¼ þ55:1 (c 0.10; CHCl3);
up; yield 67%; ½aꢀD ¼ ꢁ31:9 (c 0.16, CHCl3); mmax
mmax (NaCl) 2928, 1682, 1606, 1568 cmꢁ1
;
dH
(NaCl) 2928, 1684, 1629 cmꢁ1; dH (250 MHz, CDCl3)
8.28 (1H, dd, J = 1.6 and 8.2 Hz, H-11), 7.79 (1H,
ddd, J = 1.5, 6.7 and 8.2 Hz, H-13), 7.74 (1H, dd,
J = 1.5 and 8.2 Hz, H-14), 7.49 (1H, ddd, J = 1.6, 6.7
and 8.2 Hz, H-12), 7.46 (1H, s, H-16), 7.32–7.21 (4H,
m, H-1, 2, 3 and 4), 5.72 (1H, d, J = 15.9 Hz, H-5),
5.62 (1H, q, J = 7.0 Hz, H-8), 4.42 (1H, d, J =
15.9 Hz, H-5), 1.55 (3H, d, J = 7.0 Hz, CH3); dC
(62.5 MHz, CDCl3) 165.1 (C-7), 159.9 (C-10), 147.5
(C-14a), 144.0 (C-15a), 134.8 (C-13), 129.7 (C-16a),
129.5* (C-4), 128.3* (C-3), 128.1 (C-15b), 128.0 (C-4a),
127.4 (C-14), 127.1* (C-3 and 12), 126.8 (C-11), 126.0*
(C-1), 120.2 (C-10a), 115.7 (C-16), 51.7 (C-8), 43.7 (C-
5), 19.2 (CH3). C20H15O2N3 requires: C, 72.92; H,
4.59; N, 12.76. Found: C, 72.86; H, 4.76; N, 12.65.
(250 MHz, CDCl3) 8.28 (1H, dd, J = 1.5 and 8.1 Hz,
H-11), 7.79 (1H, ddd, J = 1.5, 6.8 and 8.2 Hz, H-13),
7.72 (1H, dd, J = 1.6 and 8.2 Hz, H-14), 7.50 (1H,
ddd, J = 1.6, 6.8 and 8.1 Hz, H-12), 7.34 (4H, m, H-
1, 2, 3 and 4), 5.48 (1H, d, J = 9.2 Hz, H-8), 5.10
(1H, d, J = 16.0 Hz, H-5), 4.74 (1H, dd, J = 4.2 and
10.5 Hz, H-15b), 4.42 (1H, d, J = 16.0 Hz, H-5), 3.85
(1H, dd, J = 4.2 and 15.4 Hz, H-16), 3.28 (1H, dd,
J = 10.5 and 15.4 Hz, H-16), 2.19 (1H, m, CH3–CH–
CH3), 1.12 (3H, d, J = 6.7 Hz, CH3–CH–CH3), 0.98
(3H, d, J = 6.7 Hz, CH3–CH–CH3); dC (62.5 MHz,
CDCl3) 166.1 (C-7), 160.7 (C-10), 150.7 (C-15a),
146.9 (C-14a), 134.5 (C-13), 134.2 (C-16a), 132.9
(C-4a), 127.8 (C-1), 127.7* (C-3), 127.4* (C-14), 127.3
(C-2), 127.2 (C-11), 127.1 (C-12), 126.4 (C-4), 120.4
(C-10a), 61.2 (C-8), 54.0 (C-15b), 44.0 (C-5), 32.2
(C-16), 30.8 (CH3–CH–CH3), 19.8 (CH3–CH–CH3),
19.4 (CH3–CH–CH3). C22H21O2N3 requires: C,
73.52; H, 5.89; N, 11.69. Found: C, 73.36; H, 5.78;
N, 11.55.
4.5.2. (ꢁ)-(8S)-1,4-Dimethoxy-8-methyl-5H,8H-isoquin-
olino[20,30-4,3]pyrazino[2,1-b]quinazoline-7,10-dione 19b.
Mp: 108–109 ꢁC (petroleum ether/ethyl acetate); yield
25
56%; ½aꢀD ¼ ꢁ212:0 (c 0.16; CHCl3); mmax (NaCl) 2928,
2851, 1725, 1684, 1634 cmꢁ1; dH (250 MHz, CDCl3)

F. Herna´ndez et al. / Tetrahedron: Asymmetry 16 (2005) 3160–3169
3169
8.25 (1H, dd, J = 1.4 and 8.4 Hz, H-11), 7.76 (1H, m,
References
1. For a review of MDR reversal agents see: Avendano, C.;
H-14), 7.75 (1H, m, H-12), 7.73 (1H, s, H-16), 7.45
(1H, ddd, J = 2.1, 6.0 and 8.1 Hz, H-13), 6.79* (1H, d,
J = 9.0 Hz, H-2), 6.72* (1H, d, J = 9.0 Hz, H-3), 5.93
(1H, d, J = 16.7 Hz, H-5), 5.60 (1H, q, J = 7.0 Hz,
H-8), 4.14 (1H, d, J = 16.7 Hz, H-5), 3.85 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 1.53 (3H, d, J = 7.0 Hz,
CH3); dC (62.5 MHz, CDCl3) 165.3 (C-7), 160.2
(C-10), 149.9* (C-1), 149.3* (C-4), 147.8 (C-14a), 144.5
(C-15a), 134.8 (C-13), 127.7* (C-14), 127.5 (C-15b),
127.1* (C-12), 126.9* (C-11), 120.4 (C-10a), 119.9*
(C-16a), 119.4 (C-4a), 112.3 (C-16), 111.0* (C-2),
110.1* (C-3), 56.1 (OCH3), 55.9 (OCH3), 51.9 (C-8),
39.4 (C-5), 19.2 (CH3). C22H19O4N3 requires: C,
67.84; H, 4.92; N, 10.80. Found: C, 67.74; H, 4.86; N,
10.66.
˜
´
Menendez, J. C. Curr. Med. Chem. 2002, 9, 159–193.
2. 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.
U.S.A. 1998, 95, 8369–8374 (and references cited therein).
3. For a review about the chemistry of pyrazino[2,1-b]qui-
´
nazoline-3,6-diones see: Avendano, C.; Menendez, J. C.
˜
Curr. Org. Chem. 2003, 7, 149–173.
4. Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N.
J. Chem. Soc., Perkin Trans. 1 1992, 1495–1496.
5. Fijimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.;
Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843–1848
(and references cited therein).
6. Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.;
Shingu, T.; Kumeda, Y.; Numata, A. J. Chem. Soc., Perkin
Trans. 1 1995, 2345–2353 (and references cited therein).
7. Larse, T. O.; Frydenvang, K.; Frisvad, J. C.; Christo-
phersen, C. J. Nat. Prod. 1998, 61, 1154–1157.
4.6. ( )-14b-Methyl-1,2,3,4-tetrahydro-7H,14bH-
pyrido[20,10-3,4]pyrazino[2,1-b]quinazoline-6,9-dione 21
8. Borrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471–476.
A solution of compound 20 (67 mg, 0.17 mmol) in 2 mL
of dry dimethylformamide and 26 mg (0.17 mmol) of
NaI were refluxed for 1 h. Toluene was added and the
organic layer extracted with brine, dried over anhydrous
Na2SO4 and evaporated under reduced pressure. The
residue was purified by flash column chromatography
(petroleum ether/ethyl acetate (1:1)) affording 42 mg
´
´
9. Martın-Santamarıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M.; Avendano, C. J. Org. Chem. 1997, 62,
˜
6424–6428.
´
´
10. Martın-Santamarıa, S.; Espada, M.; Avendano, C. Tetra-
˜
hedron 1997, 53, 16795–16802.
´
11. Buenadicha, F. L.; Bartolome, M. T.; Aguirre, M. J.;
Avendano, C.; So¨llhuber, M. Tetrahedron: Asymmetry
˜
1998, 9, 483–501.
(87%) of 21. mmax (NaCl) 2935, 1665, 1594, 1568 cmꢁ1
;
12. Buenadicha, F. L.; Avendano, C.; So¨llhuber, M. Tetra-
˜
dH (250 MHz, CDCl3) 8.27 (1H, ddd, J = 0.5, 1.4 and
8.0 Hz, H-10), 7.77 (1H, ddd, J = 1.5, 7.0 and 8.3 Hz,
H-12), 7.65 (1H, ddd, J = 0.5, 1.2 and 8.2 Hz, H-13),
7.48 (1H, ddd, J = 1.3, 7.0 and 8.0 Hz, H-11), 5.15
(1H, d, J = 19.3 Hz, H-7), 4.60 (1H, ddt, J = 2.0, 4.7
and 13.8 Hz, H-4), 4.27 (1H, dd, J = 1.0 and 19.3 Hz,
H-7), 2.95 (1H, d, J = 13.8 Hz, H-4), 2.90 (1H, m, H-
1), 2.60 (1H, ddt, J = 1.9, 3.2 and 13.0 Hz, H-1), 2.0–
1.6 (4H, m, H-1, 2 and 3), 1.45 (1H, m, H-3), 1.00
(3H, s, CH3); dC (62.5 MHz, CDCl3) 164.6 (C-6), 161.1
(C-9), 155.0 (C-14a), 147.7 (C-13a), 135.0 (C-12),
127.9* (C-13), 127.5* (C-11), 127.0 (C-10), 120.3 (C-
9a), 59.9 (C-14b), 44.7 (C-7), 38.8 (C-4), 36.9 (C-1),
24.2* (C-3), 23.7 (CH3), 20.0* (C-2). C16H17O2N3
requires: C, 67.83; H, 6.05; N, 14.83. Found: C, 66.91;
H, 6.14; N, 14.13.
hedron: Asymmetry 1998, 9, 4275–4284.
13. Buenadicha, F. L.; Avendano, C.; So¨llhuber, M. Tetra-
˜
hedron: Asymmetry 2001, 12, 3019–3028.
´
14. Hernandez, F.; Buenadicha, F.; Avendano, C.; So¨llhuber,
˜
M. Tetrahedron: Asymmetry 2001, 12, 3387–3398.
´
´
´
15. Martın-Santamarıa, S.; Corzo-Suarez, R.; Avendano, C.;
˜
´
Espada, M.; Gago, F.; Garcıa-Granda, S.; Rzepa, H. S.
J. Org. Chem. 2002, 67, 2013–2018.
´
16. Hernandez, F.; Morales, V.; Buenadicha, F. L.; So¨llhuber,
M.; Avendano, C. Tetrahedron: Asymmetry 2004, 15,
˜
3045–3058.
17. See for instance: Scho¨llkopf, U.; Groth, U.; Deng, C.
Angew. Chem., Int. Ed. Engl. 1981, 20, 798–799.
18. See for instance: Scho¨llkopf, U.; Hinrichs, R.; Lonsky, R.
Angew. Chem., Int. Ed. Engl. 1987, 26, 143–145.
19. Fukuyama, T.; Frank, R. K.; Laird, A. A. Tetrahedron
Lett. 1985, 26, 2955–2958.
20. Scho¨llkopf, U.; Groth, U.; Westphalen, K.; Deng, C.
Synthesis 1981, 969–971.
´
21. Bull, S. D.; Davies, S. G.; Parkin, R. M.; Sanchez-Sancho,
Acknowledgements
F. J. Chem. Soc., Perkin Trans. 1 1998, 2313–2320.
´
22. Gonzalez, J. F.; de la Cuesta, E.; Avendano, C. Tetra-
˜
Financial support from CICYT (SAF 2003-03141 and
SAF-2000-0130) and research fellowships for F.H.
(CAM) are gratefully acknowledged.
hedron Lett. 2003, 44, 4395–4398.
´
23. Gonzalez, J. F.; de la Cuesta, E.; Avendano, C. Tetra-
˜
hedron 2004, 60, 6319–6326.