Influence of N(2)-substitution in the alkylation of (4S)-alkyl-2,4-dihydro- 1H-pyrazino[2,1-b]quinazoline-3,6-diones

Article abstract of DOI:10.1016/j.tetasy.2004.07.034

1-Alkylation of O(3)-lactim, N(11)-azaenolate dilithium species derived from N(2)-H compounds 1a and 1b and the lithium azaenolates derived from the N(2)-phenyl and N(2)-(1-arylethyl) substituted compounds 2, 3 and 4 is studied. In 1 the trans-diastereose

Full text of DOI:10.1016/j.tetasy.2004.07.034

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3045–3058
Influence of N(2)-substitution in the alkylation of
(4S)-alkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones
´
´
Fernando Hernandez, Viviana Morales, Felix L. Buenadicha,
*
*
´
Monica So¨llhuber and Carmen Avendan˜o
´ ´ ´
Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense. 28040 Madrid, Spain
Received 10 June 2004; accepted 23 July 2004
Available online 16 September 2004
Abstract—1-Alkylation of O(3)-lactim, N(11)-azaenolate dilithium species derived from N(2)–H compounds 1a and 1b and the
lithium azaenolates derived from the N(2)-phenyl and N(2)-(1-arylethyl) substituted compounds 2, 3 and 4 is studied. In 1 the
trans-diastereoselectivity of 1-alkylation is controlled by 1,4-asymmetric induction, with some of these products precursors of
the ent-ardeemin framework. By contrast in compounds 2–4, the stabilization of the lithium azaenolate imposed by the phenyl sub-
stituent in 2, and the repulsive steric 1,2-interactions present in the initially formed 1,4-trans derivatives of 3 and 4, favour a C(1)-
epimerization to the 1,4-cis isomers.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
existence of repulsive interactions between the C(1)-
and N(2)-substituents in the 1,4-trans-isomers.2–7
In connection with the synthesis of the MDR reversal
agent1 N-acetylardeemin (Fig. 1) and other related nat-
ural products, we have extensively studied the reactivity
of homochiral N(2)-methyl and N(2)-arylmethyl-pyraz-
ino[2,1-b]quinazoline-3,6-diones as nucleophilic glycine
templates. In the alkylation of the corresponding base-
generated azaenolates, we have shown that the main
factors leading the 1,4-asymmetric induction are the
substituent size at the stereogenic centre (methyl or
iso-propyl groups at C-1 or C-4 positions) and the
According to these results, a greater diastereoselectiv-
ity was expected for N(2)–H compounds. In fact, the
O(3)-lactim, C(4)-dilithium species originated from
N(2)-unsubstituted-1-methylpyrazino[2,1-b]quinazoline-
3,6-diones and an excess of base, were alkylated at C-4
to give the 1,4-trans-isomers with de >95%. However,
when this method was applied to the less reactive 1-
iso-propyl analogues for the synthesis of fiscalin B, the
diastereomeric excess found was lower because of the
much longer reaction times required.8
In order to complete the stage, we study here the alkyl-
ation of O(3)-lactim, N(11)-azaenolate dilithium species
derived from compounds 1a and 1b. We also investigate
in the as yet unexplored N(2)-phenyl and N(2)-(1-phen-
ylethyl) lithium azaenolates derived from 2, 3 and 4,
whether the electronic effects in 2, or the presence of a
stereocentre in 3 and 4, have a diastereoselective influ-
ence on alkylation.
F
F
F
N
D
O
N
D
O
N
D
O
E
N
E
N
H
E
N
1
1
O
O
O
C
N
HN
N
4
R
4
CH3
R
B
CH3
A
N
H
2, R = Ph
Ac
1a, R = Me
1b, R = i
3, R = (1'R)-CH(CH3)Ph
Pr
5-Acetylardeemin
Figure 1.
4, R = (1'S)-CH(CH3)Ph
2. Results and discussion
Compounds 1 and 2 were obtained by N-acylation of the
corresponding piperazine-2,5-diones 5 and 6 with o-azi-
dobenzoyl chloride following the Eguchi aza-Wittig
*
Corresponding authors. Tel.: +34 91 394 18 21/39; fax: +34 91 394 18
22; e-mail addresses: msollhub@farm.ucm.es; avendano@farm.
ucm.es
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.034

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3046
protocol (method A),9 while compounds 3 and 4 were
prepared by condensation of anthranilic acid with the
lactim ether derivatives of piperazinediones 7 and 8
(method B, Scheme 1).10 In the case of 1a and 1b the
N-protected N-(4-methoxybenzyl)-N0-(2-azidobenzoyl)-
piperazinediones 9a and 9b were submitted to oxidative
cleavage before being cyclized to the corresponding pyr-
azino[2,1-b]quinazoline-3,6-diones.
N
O
N
R1
H
R1
H
i, ii
N
O
N
1
N
1a
O
1
N
4
4
CH3
CH3
O
R1= CH3
12a
15%
13a 54%
R1= CH2-CH=CH2
R1= CH2-C6H5
12b
12c
30%
44%
43%
36%
13b
13c
13d
2%
5%
7%
Method A:
R1= CH2-C6H4-p-CH3 12d
R1= CH2-C6H4-p-F
12e
13e ---
N
O
O
N3
O
i
ii
N
O
N
O
NH
R4
N
N
N
N
N
R2
R2
CH3
R1
R4
R1
N
O
i, iii
1
O
O
N
1b
O
1
4
N
4
9a, 9b, 10
2
N
5a, R2 = 4(CH3O)-C6H4-CH2,
CH3
H
CH3
H
R
4 = CH3
O
CH3
15a 46%
5b, R2 = 4(CH3O)-C6H4-CH2,
R4 = CH(CH3)2
O
CH3
---
iii
R1= CH3
14a
6, R2 = C6H5,
R
4 = CH3
R1= CH2-CH=CH2
R1= CH2-C6H5
14b
14c
32%
15b
15c
15d
15e
---
O
N3
N
O
50%
58%
48%
---
ii
R1= CH2-C6H4-p-CH3 14d
5%
3%
N
O
N
O
R1= CH2-C6H4-p-F
14e
N
N
H
H
R4
R4
Scheme 2. Reagents and conditions: (i) LHMDS (6equiv), THF,
À78ꢁC, 10min. (ii) R1X (2equiv), 16h. (iii) R1X (2equiv), 3d.
O
1a, 1b
11a, 11b
Method B:
tates the epimerization at C(1) in the kinetic products
12a and 14a. Although the activation barrier for the syn-
attack in the transition state might be lower for methyl
iodide than for other alkylating agents,7 the exclusive
isolation of 1,1-dialkylderivatives as trace products in
the alkylation of compounds 1, proves that the incorpo-
ration of the second electrophile takes place solely at C-
1, and also establishes the deprotonation/protonation
equilibrium at this position to give the thermodynamic
cis-products.
O
O
OEt
N
N
N
i
NH
ii
O
1'
1'
H3C
N
H3C
N
1'
H3C N
CH3
CH3
CH3
Ph
Ph
O
Ph
O
7 (1'-R)
8 (1'-S)
3
4
Scheme 1. Method A. Reagents and conditions: (i) KHMDS, THF,
DMI, À78ꢁC, 16h. (ii) Bu3P, PhMe, D. (iii) CAN (2equiv), MeCN/
H2O (4:1.5), 1h. Method B. Reagents and conditions: (i) (Et)3O+F4BÀ
(3equiv), Na2CO3 (5equiv), CH2Cl2, rt, overnight. (ii) Anthranilic acid
(1equiv), 130ꢁC, 3h.
At this point, introduction of a 3-indolylmethyl substit-
uent at the C(1)-position was specially interesting
because these compounds are potential ardeemin skele-
ton precursors. The alkylation of 1a and 1b with
N-Boc-3-indolylmethyl bromide (method A, Scheme 3)
Alkylation of compounds 1a and 1b was performed by
using a large excess of lithium hexamethyldisilazide.
Reaction with allyl bromide and arylmethyl bromides
gave the 1,4-trans-isomers 12 and 14 as the main or
exclusive products, while reaction with methyl iodide af-
forded compounds 13a and 15a as the major or exclusive
products (Scheme 2). In most cases small amounts of
1,1-dialkyl derivatives were also isolated. The diastereo-
meric ratio of the isolated products was in agreement
N
O
N
O
H
H
i, ii
N
O
N
O
1a, 1b
N
N
HN
HN
R
R
R1
R1
1
with that observed in the H NMR spectra of the crude
12f R= Me R1= Boc
7%
13f R= Me R1= Boc 28%
products. NOESY experiments allowed an easy assign-
ment of the cis- and trans-isomers. The enantiomeric
purity (>95%) was determined by chiral HPLC (see Sec-
tion 4).
14f R= iPr R1= Boc 20%
15f R= iPr R1= Boc 35%
12g R= Me R1= H
14g R= iPr R1= H
23%
24%
13g R= Me R1= H
15g R= iPr R1= H
11%
11%
Scheme 3. Reagents and conditions: (i) LHMDS (6equiv), THF,
À78ꢁC, 10min. (ii) Method A: N-Boc-3-indolylmethyl bromide, 6 h
(R = Me) or 72h (R = iPr). Method B: trimethyl-3-indolylmethyl
ammonium iodide, 16h (R = Me) or 72h (R = iPr).
The apparent diastereoselectivity discrepancy found
for the methyl derivatives 13a and 15a can be attributed
to the small volume of the methyl group, which facili-

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3047
gave mainly the cis-isomer, showing here again the
already reported cis/trans diastereomeric ratio for alkyl-
ation with N-Boc-3-indolylmethyl halides.7,8 The reac-
tions with trimethyl-3-indolylmethylammonium iodide
(method B, Scheme 3) gave instead a diastereomeric
ratio in favour of trans-isomers (see 12g and 14g vs
13g and 15g).
N
O
N
O
i, ii
R1
Ph
3
R1
H3C
N
O
N
O
1
N
1
N
4
4
H3C
CH3
CH3
Ph
R1= CH3
19a 76%
20a
20b
---
5%
R1= CH2 CH=CH2 19b 36%
Compounds 12g and 14g were submitted to acid-pro-
moted cyclization to give the de-ÔprenylÕ-ardeemin deriv-
atives 16a and 16b, while the 1,4-cis epimers 13g and 15g
failed to cyclize in all acid catalyzed attempts due to the
pseudoaxial disposition of the 3-indolylmethyl substitu-
ent (Scheme 4).11
R1= CH2 C6H5
19c 43%
20c 14%
R1= CH2 C6H4-p-F 19d 72%
20d
9%
N
N
i, ii
4
R1
R1
Ph
N
O
N
O
1
4
4
H3C
N1
H3C
N
CH3
CH3
Ph
O
O
22 R1= CH2 C6H5 14%
21 R1= CH2 C6H5 46%
N
H
TFA, r.t.
12g
14g
H
N
O
Scheme 6. Reagents and conditions: (i) LHMDS (1.2equiv), THF,
À78ꢁC, 10min. (ii) R1X (1.2equiv), 10min (À78ꢁC), then 30min at
0ꢁC.
N
R
N
H
H
O
experiments on N-benzyl analogues of compounds 17
and 18 showed that under basic conditions the 1,4-cis-
isomers are deprotonated at C-4, while the 1,4-trans-iso-
mers are deprotonated at C-1.4
16a (72%); 16b (48%)
N
H
TFA, r.t.
13g
15g
H
N
O
N
In spite of the precedents of the N-phenylethyl radical
acting as an asymmetric inductor,14 the benzyl bromide
alkylation of lithium azaenolates derived from 3 and 4
afforded the same diastereomeric ratio for both epimers
(Scheme 6). The observed predominance of the 1,4-cis-
isomers 19 and 21 is attributed to the destabilizing steric
interaction between the bulky N(2)-substituent and the
C(1)-alkyl group in the quasiplanar 1,4-trans-isomers
20 and 22, favouring the epimerization at C-1 as in pre-
ceding examples.4 The enantiomeric purity of com-
R
N
H
H
O
Scheme 4.
Alkylation of the lithium azaenolate derived from 2 re-
quired the use of DMI as a cosolvent12 as the yields were
very low in its absence (Scheme 5).13 These findings can
be explained taking into consideration that the N(2)-
phenyl group stabilizes the negative charge. In contrast
to all previously studied 4-alkyl-pyrazino[2,1-b]quinazo-
line-3,6-diones, the 1,4-cis-isomers 17 were the predom-
inant products here. Small amounts of the 1,4-trans-
isomers and traces of 1,1- and 1,4-dialkylated products
were also detected. We assume that the 1,4-trans-isomers
epimerize almost completely when formed, due to the
more acidic character of the C(1)-protons. Alkylation
1
pounds 17–22 (ee >95%) was determined by H NMR
experiments (see Section 4).
3. Conclusion
In conclusion, we have shown that the alkylation of
compounds 1 (N(2)–H) is diastereoselectively controlled
by 1,4-asymmetric induction and affords 1,4-trans-deriv-
atives as the main products, with some of them being
precursors of the ardeemin framework. By contrast,
the stabilization of the lithium azaenolate imposed by
a phenyl substituent in 2, as well as the repulsive steric
1,2-interactions present in the 1,4-trans isomers of the
2-(1-phenylethyl)-compounds 3 and 4, favour the epime-
rization at C(1) to give predominantly or almost exclu-
sively the corresponding 1,4-cis derivatives.
N
N
R1
R1
Ph
i, ii
2
N
O
N
O
1
1
4
4
N
N
Ph
CH3
CH3
O
O
R1= CH3
17a
17b
17c
42%
50%
57%
51%
56%
18a
18b
18c
18d
18e
---
R1= CH2 CH=CH2
R1 = CH2 C6H5
7%
1%
8%
---
4. Experimental
R1 = CH2 C6H4-p-CH3 17d
R1 = CH2 C6H4-p-F
17e
4.1. General methods
Scheme 5. Reagents and conditions: (i) LHMDS (1.2equiv), DMI
(1.2equiv), THF, À78ꢁC, 10min. (ii) R1X (1.2equiv), 10min (À78ꢁC),
then 30min at 0ꢁC.
All reagents were of commercial quality and were used
as received. Solvents were dried and purified using

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3048
standard techniques. ÔPetroleum etherÕ refers to the frac-
tion boiling at 40–60ꢁC. TLC was carried out on pre-
coated plates (Merck Kieselgel 60 F254) and spots
visualized 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 250
(250MHz for 1H, 62.5MHz for 13C) and Bruker Avance
J = 17,8Hz, H-6), 2.40 (1H, m, CH(CH3)2), 0.98 (3H,
d, J = 6.9Hz, CH3), 0.82 (3H, d, J = 6.9Hz, CH3); dC
(62.5MHz, CDCl3) 166.5, 165.4, 159.4, 129.9, 127.2,
114.2, 60.6, 55.2, 49.0, 48.4, 33.1, 18.8, 16.0.
C15H20N2O3 requires: C, 65.20; H, 7.30; N, 10.14.
Found: C, 64.79; H, 7.17; N, 10.06%.
4.2.2. (3S)-3-Methyl-1-phenylpiperazine-2,5-dione 6.
25
Mp: 148–150ꢁC (ethyl ether); yield 98%; ½aŠ ¼ À21:7
D
DPX-300 (300MHz for H, 75MHz for 13C) spectro-
(c 0.25, CHCl3); mmax (NaCl) 1689, 1646cmÀ1; dH
(250MHz, CDCl3) 7.42 (2H, m, Ar–H), 7.27 (3H, m,
Ar–H), 6.56 (1H, s, NH), 4.33 (2H, ÔtÕ, J = 17.4Hz, H-
6), 4.24 (1H, q, J = 7.0Hz, H-3), 1.58 (3H, d,
J = 7.0Hz, CH3); dC (62.5MHz, CDCl3) 166.8, 166.1,
140.1, 129.3, 127.5, 125.2, 52.7, 51.4, 19.5.
C11H12N2O2 requires: C, 64.69; H, 5.92; N, 13.72.
Found: C, 64.58; H, 5.86; N, 13.70%.
1
meters, in CDCl3 unless otherwise mentioned. (Servicio de
RMN, Universidad Complutense). Protons were as-
signed according to COSY, HMQC and/or 1D-NOE
experiments; carbons were assigned according to DEPT,
HMQC and/or HMBC experiments. 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 1mL cell measuring 10cm at 25ꢁC, using the
emission wavelength of a sodium lamp; concentrations
are given in g/100mL. The enantiomeric purity was
4.2.3. (10R,3S)-3-Methyl-1-(1-phenylethyl)piperazine-2,5-
dione 7. Mp: 114–115ꢁC (toluene); yield 98%;
25
½aŠ ¼ þ148 (c 0.25, CHCl3); mmax (NaCl) 3244, 1683,
D
1
determined by H NMR {addition of europium (III)
1636cmÀ1; dH (250MHz, CDCl3) 7.30 (5H, m, Ar–H),
6.80 (1H, s, NH), 5.98 (1H, q, J = 7.1Hz, Ha), 4.10
(1H, q, J = 6.9Hz, H-3), 3.74 (1H, d, J = 17.6Hz,
H-6), 3.42 (1H, d, J = 17.6Hz, H-6), 1.51 (3H, d,
J = 7.0Hz, CH3), 1.48 (3H, d, J = 7.0Hz, CH3); dC
(62.5MHz, CDCl3) 166.6, 135.5, 128.9, 128.1, 127.5,
51.2, 50.4, 44.2, 19.9, 15.2. C13H16N2O2 requires: C,
67.22; H, 6.94; N, 12.06. Found: C, 66.69; H, 6.80; N,
11.69%.
tris[3-heptafluoropropylhydroxymethylene)-(+)-campho-
rate] [(+)-Eu(HFC)3] as shift reagent} and/or by chiral
HPLC (comparison to racemic products), employing a
Constrometric 4100 system equipped with a chiral col-
umn (Chiracel OD; 25cm · 0.25mm) and UV-detection
at 254nm; mobile phase: hexane/2-propanol (9:1) at
1mL/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
4.2.4. (10S,3S)-3-Methyl-1-(1-phenylethyl)piperazine-2,5-
´
analyses were determined by the Servicio de Microanali-
Leco 932
dione 8. Mp: 126–128ꢁC (CH2Cl2/ether); yield 98%;
25
sis, Universidad Complutense on
microanalyser.
a
½aŠ ¼ À124 (c 0.25, CHCl3); mmax (NaCl) 3276, 2929,
D
1675, 1620cmÀ1; dH (250MHz, CDCl3) 7.30 (5H, m,
Ar–H), 6.66 (1H, s, NH), 5.99 (1H, q, J = 7.1Hz, Ha),
4.08 (1H, q, J = 6.9Hz, H-3), 3.75 (1H, d, J = 17.5Hz,
H-6), 3.43 (1H, d, J = 17.6Hz, H-6), 1.51 (3H, d,
J = 7.1Hz, CH3), 1.50 (3H, d, J = 6.9Hz, CH3); dC
(62.5MHz, CDCl3) 166.6, 138.4, 128.9, 128.2, 127.4,
51.3, 50.4, 44.1, 19.9, 15.2. C13H16N2O2 requires: C,
67.22; H, 6.94; N, 12.06. Found: C, 66.81; H, 7.36; N,
11.64%.
4.2. (3S)-3-Alkyl-1-arylalkyl-(aryl)-piperazine-2,5-diones
5–8. General procedure
To a stirred solution of freshly distilled ethyl N-(aryl-
alkyl or phenyl)-L-glycinate (20mmol), and Cbz–alanine
or Cbz–valine in dry CH2Cl2 (50mL) DCC (or EDC for
5b) (22mmol) was added, and stirring was continued at
room temperature for 16h. The reaction mixture was fil-
tered, washed successively with 1N HCl, 1N NaHCO3
and water, dried over anhydrous Na2SO4 and evapo-
rated. The syrupy residue was hydrogenated at 35psi
for 12h with C/Pd (10%, 1.8g) in ethanol (100mL), fil-
tered (Celite) and evaporated. Compounds 7 and 8 were
directly isolated. In case of 5 and 6 the residue was
heated under reflux in toluene (or methanol for 5b)
(25mL) for 12h affording the corresponding
piperazinedione.
4.3. (3S)-3-Alkyl-4-(o-azidobenzoyl)-1-p-methoxybenzyl-
(1-phenyl)-piperazine-2,5-diones 9 and 10
To a cold (À78ꢁC), magnetically stirred solution of
compounds 5a,4 5b or 6 (3mmol) in dry THF (30mL)
under argon was added dropwise via syringe, DMI
(0.6mL, 6mmol) and a solution of potassium hexa-
methyldisilazide in dry toluene (0.5M. 7.2mL,
3.6mmol), followed 10min later by addition of o-azi-
dobenzoyl chloride (0.55g, 3mmol) in THF (10mL).
Stirring was continued for 15min at À78ꢁC, and then
for a further 16h at room temperature. The reaction
mixture was quenched with ice, washed with brine
(3 · 15mL) and extracted with chloroform (3 · 10mL).
The organic layer was dried over anhydrous Na2SO4,
evaporated and isolated by column chromatography
(petroleum ether–EtOAc, 7:3) for compounds 9 (10
(97% yield) was used in the next step without further
purification).
4.2.1. (3S)-3-iso-Propyl-1-p-methoxybenzyl-piperazine-
25
D
2,5-dione 5b. Mp: 145ꢁC (EtOAc); yield 72%; ½aŠ
¼
þ11:9 (c 0.46, CHCl3); mmax (NaCl) 3236, 2962, 1684,
1654, 1612cmÀ1; dH (250MHz, CDCl3) 7.53 (1H, s,
NH), 7.17 (2H, d, J = 8.6Hz, H-20 and H-60), 6.83
(2H, d, J = 8.6Hz, H-30 and H-50), 4.68 (1H, d,
J = 14.2Hz, N–CH2–Ar), 4.32 (1H, d, J = 14.7Hz, N–
CH2–Ar) 3.86 (1H, t, J = 8.8Hz, H-3), 3.81 (1H, d,
J = 17,8Hz, H-6), 3.76 (3H, s, OCH3), 3.70 (1H, d,

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3049
25
D
4.3.1. (3S)-4-(o-Azidobenzoyl)-1-p-methoxybenzyl-3-meth-
ylpiperazine-2,5-dione 9a. Compound 9a was obtained
½aŠ ¼ À14:7 (c 0.09, CHCl3); mmax (NaCl) 3234, 2193,
1692cmÀ1; dH (250MHz, CDCl3) 7.62 (1H, s, N–H),
7.48 (1H, ddd, J = 1.7, 7.5 and 8.3Hz, H-40), 7.39 (1H,
dd, J = 1.5 and 8.4Hz, H-60), 7.20 (1H, ddd, J = 0.8,
7.5 and 8.4Hz, H-50), 7.14 (1H, dd, J = 0.8 and 8.3Hz,
H-30), 5.00 (1H, q, J = 7.2Hz, H-6), 4.14 (1H, d,
J = 18.4Hz, H-3), 4.06 (1H, d, J = 18.4Hz, H-6), 1.62
(3H, d, J = 7.2Hz, CH3); dC (62.5MHz, CDCl3) 170.0,
167.8, 166.1, 136.5, 131.9, 129.0, 127.9, 124.9, 118.1,
53.5, 45.7, 18.1. C12H11N5O3 requires: C, 52.74; H,
4.02; N, 25.64. Found: C, 52.45; H, 3.93; N, 25.41%.
25
as an oily product; yield 52%; ½aŠ ¼ À64:5 (c 0.33,
D
CHCl3); mmax (NaCl) 2129, 1720, 1676, 1610cmÀ1; dH
(250MHz, CDCl3) 7.44 (1H, dt, J = 1.6 and 8.0Hz, H-
40), 7.42 (1H, dd, J = 1.5 and 7.9Hz, H-60), 7.20 (2H,
d, J = 8.7Hz, H-200 and H-600), 7.19 (1H, dt, J = 0.9
and 7.9Hz, H-50), 7.10 (1H, dd, J = 8.1 and 0.9Hz, H-
30), 6.87 (2H, d, J = 8.7Hz, H-300 and H-500), 5.10 1H,
(q, J = 7.2Hz, H-3), 4.81 (1H, d, J = 14.1Hz, N–CH2–
Ar), 4.32 (1H, d, J = 14.1Hz, N–CH2–Ar), 3.98 (1H,
d, J = 18.8Hz, H-6), 3.88 (1H, d, J = 18.8Hz, H-6),
3.78 3H, (s, OCH3), 1.59 (3H, d, J = 7.2Hz, CH3); dC
(62.5MHz, CDCl3) 167.3, 167.1, 166.5, 159.5, 136.4,
131.9, 129.4, 127.7, 126.8, 125.0, 117.9, 114.4, 55.2,
53.9, 49.2, 48.2, 18.4. C20H19N5O4 requires: C, 61.06;
H, 4.86; N, 17.80. Found: C, 60.91; H, 4.98; N,
17.92%.
4.4.2.
(6S)-1-(o-Azidobenzoyl)-6-iso-propylpiperazine-
2,5-dione 11b. Yield: 45%; mp: 165–167ꢁC (EtOAc);
25
½aŠ ¼ þ14:3 (c 0.28, CHCl3); mmax (NaCl) 2969, 2129,
D
1689cmÀ1; dH (250MHz, CDCl3) 7.82 (1H, d, N-H),
7.45 (1H, dt, J = 1.5 and 8.0Hz, H-40), 7.35 (1H, dd,
J = 1.5 and 7.7Hz, H-60), 7.18 (1H, dt, J = 1.0 and
7.7Hz, H-50), 7.12 (1H, dd, J = 1.0 and 8.0Hz, H-30),
4.81 (1H, d, J = 7.4Hz, H-6), 4.15 (1H, d, J = 19.1Hz,
H-3), 4.05 (1H, d, J = 19.1Hz, H-3), 2.19 (1H, m,
J = 7.4 and 6.8Hz, CH(CH3)2), 1.13 (3H, d,
J = 6.8Hz, CH3), 1.12 (3H, d, J = 6.8Hz, CH3); dC
(62.5MHz, CDCl3) 168.9, 167.7, 167.4, 136.2, 131.6,
128.8, 128.0, 125.0, 118.0, 62.2, 46.0, 32.4, 19.5, 18.8.
C14H15N5O3 requires: C, 55.75; H, 4.97; N, 23.23.
Found: C, 55.38; H, 4.88; N, 23.11%.
4.3.2. (3S)-4-(o-Azidobenzoyl)-1-p-methoxybenzyl-3-iso-
propylpiperazine-2,5-dione 9b. Compound 9b was ob-
25
tained as an oily product; yield 54%; ½aŠ ¼ À38:8 (c
D
0.08, CHCl3); mmax (NaCl) 2129, 1729, 1674cmÀ1; dH
(250 MHz, CDCl3) 7.43 (1H, ddt, J = 0.5, 1.6 and
8.0Hz, H-40), 7.35 (1H, dd, J = 1.6 and 7.7Hz, H-60),
7.21 (2H, d, J = 8.9Hz, H-200 and H-600), 7.16 (1H, dt,
J = 0.9 and 7.7Hz, H-50), 7.04 (1H, dd, J = 0.9 and
8.0Hz, H-30), 6.86 (2H, d, J = 8.7Hz, H-300 and H-500),
4.92 (1H, d, J = 7.8Hz, H-3), 4.72 (1H, d, J = 14.4Hz,
N–CH2–Ar), 4.40 (1H, d, J = 14.4Hz, N–CH2–Ar),
4.00 (1H, d, J = 19.2Hz, H-6), 3.89 (1H, d,
J = 19.2Hz, H-6), 3.77 (3H, s, OCH3), 2.14 (1H, m,
J = 7.0Hz, CH(CH3)2), 1.08 (6H, d, J = 7.0Hz, 2CH3);
dC (62.5MHz, CDCl3) 167.6, 167.2, 165.5, 159.4,
135.9, 131.6, 129.7, 129.6, 127.9, 127.1, 125.0, 117.8,
114.4, 62.2, 55.2, 49.7, 48.3, 32.8, 19.5, 18.9.
C22H23N5O4 requires: C, 62.70; H, 5.50; N, 16.62.
Found: C, 62.59; H, 5.46; N, 16.41%.
4.5. Synthesis of compounds 1 and 2 (method A)
To a stirred solution of 11a, 11b or 10 (3mmol) in dry
toluene (10mL) tributylphosphine (3mmol) was added
with syringe. The mixture was stirred under argon for
16h at room temperature, and evaporated under re-
duced pressure. The residue was purified by column
chromatography (EtOAc (1) or EtOAc/petroleum ether
3:7 (2) yielding 60%, 45% and 68% of 1a,8 1b8 and 2,
respectively.
4.3.3. (3S)-4-o-Azidobenzoylmethyl-3-methyl-1-phenyl-
piperazine-2,5-dione 10. White solid, mp: 138–140ꢁC
4.5.1. (4S)-4-Methyl-2-phenyl-2,4-dihydro-1H-pyrazino-
[2,1-b]-quinazoline-3,6-dione 2. White solid, mp:
25
25
(EtOAc); yield 97%; ½aŠ ¼ þ10:8 (c 0.35, CHCl3); mmax
151–152ꢁC; ½aŠ ¼ þ11:4 (c 0.25, CHCl3); mmax
D
D
(KBr) 2193, 1692, 1596cmÀ1; dH (250MHz, CDCl3)
7.52–7.13 (9H, m, Ar–H), 5.24 (1H, q, J = 7.2Hz, H-
3), 4.63 (1H, d, J = 18.1Hz, H-6), 4.29 (1H, d,
J = 18.1Hz, H-6), 1,71 (3H, d, J = 7.2Hz, CH3), dC
(62.5MHz, CDCl3) 167.5, 166.9, 166.0, 139.4, 136.6,
132.0, 129.5, 129.1, 127.8, 127.6, 125.1, 124.9, 118.2,
54.5, 53.5, 18.2. C12H11O3N5 requires: C. 61,89; H,
4.33; N, 20.05. Found: C, 61.75; H, 4.20; N, 19.91%.
(KBr) 1679, 1608cmÀ1; dH (250MHz, CDCl3) 8.29
(1H, dd, J = 8.0Hz, J = 1.2Hz, H-7), 7.77 (1H, ddd,
J = 8.4, 7.1 and 1.5Hz, H-9), 7.63 (1H, dd, J = 8.4 and
1.1Hz, H-10), 7.50 (1H, ddd, J = 8.0, 7.1 and 1.1 Hz
H-8), 7.46–7.30 (5H, m, Ar–H), 5.66 (1H, q,
J = 7.3Hz, H-4), 5.15 (1H, d, J = 16.3Hz, H-1), 4.78
(1H, d, J = 16.3Hz, H-1), 1.72 (3H, d, J = 7.3Hz,
CH3), dC (62.5MHz, CDCl3) 167.1, 159.9, 147.8,
147,2, 139.9, 134.8, 129,4, 127.5, 127.1, 126.9, 124.8,
120.5, 52.6, 16.8. C18H15O2N3 requires: C, 70.81; H,
4.95; N, 13.76. Found: C, 70.72; H, 4.83; N, 13.68%.
4.4. (6S)-6-Alkyl-1-(o-azidobenzoyl)piperazine-2,5-diones
11a and 11b
A solution of 9a or 9b (3mmol) in 50mL acetonitrile–
water (5:2) and CAN 3.3g, 6mmol) was stirred for 1h
at room temperature. The reaction mixture was ex-
tracted with CH2Cl2, dried (Na2SO4) and evaporated.
Column chromatography (EtOAc–petroleum ether, 1:1
or 3:7) afforded 11a or 11b, respectively.
4.6. Synthesis of compounds 3and 4 (method B)
A mixture of 1g (4mmol) of the piperazine-2,5-dione 7
or 8, triethyloxonium tetrafluoroborate (2.6g, 12mmol)
and anhydrous Na2CO3 (2.3g, 20mmol) in 40mL dry
CH2Cl2 was stirred overnight at room temperature,
poured on ice water, extracted with CH2Cl2, dried over
anhydrous Na2SO4 and evaporated. Anthranilic acid
(0.74g, 5.4mmol) was added to the syrupy residue, the
4.4.1. (6S)-1-(o-Azidobenzoyl)-6-methylpiperazine-2,5-
dione 11a. Mp: 150–152ꢁC (EtOAc); yield: 60%;

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3050
mixture was stirred vigorously at 120ꢁC for 3h under
argon, dissolved in CH2Cl2, extracted with diluted
ammonium hydroxide, dried (Na2SO4) and concen-
trated. Column chromatography (EtOAc) afforded
0.72g of 3 and 0.84g of 4, respectively.
(250MHz, CDCl3) 8.26 (1H, dd, J = 1.5Hz,
J = 8.1Hz, H-7), 7.75 (1H, ddd, J = 1.5Hz, J = 7.0Hz,
J = 8.2Hz, H-9), 7.67 (1H, dd, J = 1.4Hz, J = 8.2Hz,
H-10), 7.48 (1H, ddd, J = 1.4Hz, J = 7.0Hz,
J = 8.1Hz, H-8), 7.36 (1H, sa, NH), 5.47 (1H, dq,
J = 1.0Hz, J = 7.2 Hz H-4), 4.71 (1H, q, J = 6.6 Hz H-
1), 1.79 (3H, d, J = 6.6Hz, CH3-1), 1.63 (3H, d,
J = 7.2Hz, CH3-4);dC (62.5MHz, 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. C13H13O2N3 requires: C, 64.19; H,
5.39; N, 17.27. Found: C, 63.91; H, 5.43; N, 17.04%.
4.6.1. (+)-(10R,4S)-4-Methyl-2-(10-phenylethyl)-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 3. White
solid, yield 48%; mp: 120–122ꢁC (ethyl ether);
25
½aŠ ¼ þ141 (c 0.26, CHCl3); mmax (KBr) 1693,
D
1654cmÀ1; dH (250MHz, CDCl3) 8.21 (1H, dd, J = 8.0
and 1.5Hz, H-7), 7.69 (1H, ddd, J = 8.5, 7.2 and
1.5Hz, H-9), 7.53 (1H, dd, J = 8.5 and 1.1Hz, H-10),
7.42 (1H, ddd, J = 8.0, 7.2 and 1.1Hz, H-8), 7.32 (5H,
m, Ar–H), 6.05 (1H, q, J = 7.0Hz, H-10), 5.48 (1H, q,
J = 7.1Hz, H-4), 4.15 (1H, d, J = 17.0Hz, H-1), 3.92
(1H, d, J = 17.0Hz, H-1), 1.54 (3H, d, J = 7.1Hz,
CH3), 1.53 (3H, d, J = 7.0Hz, CH3); dC (62.5MHz,
CDCl3) 167.2, 159.9, 148.5, 147.2, 138.4, 129.1, 128.3,
127.3, 126.9, 120.5, 52.3, 50.3, 44.8, 16.6, 15.3.
C20H19O2N3 requires: C, 72.05; H, 5.74; N, 12.60.
Found: C, 71.76; H, 5.68; N, 12.22%.
4.7.1.2. (+)-(1S,4S)-1,4-Dimethyl-2,4-dihydro-1H-pyr-
azino[2,1-b]quinazoline-3,6-dione 13a. Compound 13a
was obtained as a solid (EtOAc–MeOH, 9:1); mp:
25
205ꢁC (ethyl ether); yield 54%; ½aŠ ¼ þ110:5 (c 0.41,
D
CHCl3); mmax (NaCl) 3169, 3063, 2978, 1684, 1600,
1569, 1473cmÀ1; dH (250MHz, CDCl3) 8.25 (1H, dd,
J = 1.4Hz, J = 8.1Hz, H-7), 7.83 (1H, sa, NH), 7.75
(1H, ddd, J = 1.4Hz, J = 7.1Hz, J = 8.4Hz, H-9), 7.61
(1H, dd, J = 1.1Hz, J = 8.4Hz, H-10), 7.47 (1H, ddd,
J = 1.1Hz, J = 7.1Hz, J = 8.1Hz, H-8), 5.27 (1H, q,
J = 7.1Hz, H-4), 4.73 (1H, dq, J = 4.0Hz, J = 7.1 Hz
H-1), 1.74 (3H, d, J = 7.1Hz, CH3-1), 1.73 (3H, d,
J = 7.1Hz, CH3-4); dC (62.5MHz, CDCl3) 169.6,
160.4, 151.0, 147.1, 134.7, 127.0, 126.8, 126.7, 120.0,
52.3, 51.6, 24.8, 19.2. C13H13O2N3 requires: C, 64.19;
H, 5.39; N, 17.27. Found: C, 63.90; H, 5.38; N, 17.12%.
4.6.2. (À)-(10S,4S)-4-Methyl-2-(10-phenylethyl)-2,4-dihy-
25
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 4. White
oil, yield 59%, ½aŠ ¼ À38 (c 0.25, CHCl3); mmax (NaCl)
D
1672, 1608cmÀ1; dH (250MHz, CDCl3) 8.24 (1H, dd,
J = 8.0 and 1.5Hz, H-7), 7.70 (1H, ddd, J = 8.3, 6.9
and 1.4Hz, H-9), 7.50 (1H, dd, J = 8.3 and 1.1Hz, H-
10), 7.45 (1H, ddd, J = 8.0, 6.9 and 1.1Hz, H-8), 7.27
(5H, m, Ar–H), 6.02 (1H, q, J = 7.0Hz, H-10), 5.54
(1H, q, J = 7.1Hz, H-4), 4.45 (1H, d, J = 16.6Hz, H-
1), 4.14 (1H, d, J = 16.6Hz, H-1), 1.62 (3H, d,
J = 7.1Hz, CH3), 1.61 (3H, d, J = 7.0Hz, CH3); dC
(62.5MHz, CDCl3) 167.3, 160.0, 148.5, 147.2, 138.4,
129.1, 128.3, 127.3, 126.9, 120.5, 52.3, 50.3, 44.8, 16.6,
15.3. C20H19O2N3 requires: C, 72.05; H, 5.74; N,
12.60. Found: C, 72.50; H, 5.62; N, 12.32%.
4.7.1.3. (+)-(1R,4S)-1-Allyl-4-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 12b. Compound
12b was obtained as a solid (EtOAc–CH2Cl2, 1:1);
25
D
mp: 185–186ꢁC (ethyl ether); yield 30%; ½aŠ
¼
þ175:6 (c 0.25, CHCl3); mmax (NaCl) 3253, 2980, 2922,
1686, 1606, 1566, 1470cmÀ1; dH (250MHz, CDCl3)
8.26 (1H, dd, J = 1.4Hz, J = 8.1Hz, H-7), 7.75 (1H,
ddd, J = 1.4Hz, J = 7.1Hz, J = 8.3Hz, H-9), 7.65 (1H,
dd, J = 1.3Hz, J = 8.3Hz, H-10), 7.48 (1H, ddd,
J = 1.3Hz, J = 7.1Hz, J = 8.1Hz, H-8), 6.35 (1H, sa,
NH), 5.88 (1H, dddd, J = 5.7Hz, J = 8.9Hz,
J = 10.0Hz, J = 17.1Hz, H-20), 5.46 (1H, dq,
J = 0.9Hz, J = 7.2Hz, H-4), 5.33 (1H, dd, J = 0.9Hz,
J = 10.1Hz, H-30), 5.32 (1H, dd, J = 0.9Hz,
J = 17.2Hz, H-30), 4.60 (1H, dd, J = 3.6Hz, J = 8.9Hz,
H-1), 3.36 (1H, ddd, J = 3.6Hz, J = 5.7Hz,
J = 14.7Hz, H-10), 2.66 (1H, dt, J = 8.9Hz,
J = 14.7Hz, H-10), 1.62 (3H, d, J = 7.2Hz, CH3); dC
(62.5MHz, CDCl3) 169.2, 160.2, 149.2, 146.7, 134.6,
132.5, 127.4, 127.3, 126.7, 121.0, 120.3, 52.1, 51.6,
36.2, 16.7. C15H15O2N3 requires: C, 66.90; H, 5.61; N,
15.60. Found: C, 66.67; H, 5.47; N, 15.43%.
4.7. General alkylation procedures
4.7.1. Alkylation of 1a. To a cold (À78ꢁC), magneti-
cally stirred solution of 1a (0.5mmol) in dry THF
(10mL) was added, under argon, dropwise via syringe
a solution of lithium hexamethyldisilazide in THF
(1M, 3.0mL), followed after 10min by a solution of
the appropriate halide (1.0mmol dissolved in THF
(5mL)). The reaction mixture was stirred at À78ꢁC for
16h, quenched with drops of glacial acetic acid followed
by a saturated aqueous solution of ammonium chloride
(5mL), and extracted with CHCl3. The organic layer
was dried over anhydrous Na2SO4 and evaporated. Col-
umn chromatography of the residue on silica gel
(EtOAc–CH2Cl2, 3:7 unless otherwise mentioned)
afforded traces of 1,1-dialkylated compounds, followed
from the expected anti-1-alkyl compounds and small
amounts of syn-1-alkyl derivatives.
4.7.1.4. (+)-(1S,4S)-1-Allyl-4-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 13b. Compound
13b was obtained as an oil (EtOAc–CH2Cl2, 1:1); yield
25
2%; ½aŠ ¼ þ92:0 (c 0.05, CHCl3); mmax (NaCl) 3258,
D
2962, 2932, 1723, 1689, 1607cmÀ1; dH (250MHz,
CDCl3) 8.28 (1H, dd, J = 1.3Hz, J = 8.0Hz, H-7), 7.77
(1H, ddd, J = 1.3Hz, J = 7.1Hz, J = 8.4Hz, H-9), 7.64
(1H, dd, J = 1.1Hz, J = 8.4Hz, H-10), 7.49 (1H, ddd,
J = 1.1Hz, J = 7.1Hz, J = 8.0Hz, H-8), 6.57 (1H, sa,
NH), 5.88 (1H, dddd, J = 6.1Hz, J = 9.4Hz,
J = 10.3Hz, J = 16.8Hz, H-20), 5.30 (1H, q, J = 7.1Hz,
4.7.1.1. (+)-(1R,4S)-1,4-Dimethyl-2,4-dihydro-1H-pyr-
azino[2,1-b] quinazoline-3,6-dione 12a. Compound 12a
was obtained as a solid (EtOAc–MeOH, 9:1); mp: 89–
25
90ꢁC (ethyl ether); yield 15%; ½aŠ ¼ þ98:2 (c 0.28,
D
CHCl3); mmax (NaCl) 3239, 2931, 1688, 1607cmÀ1; dH

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3051
H-4), 5.27 (1H, ddd, J = 1.0Hz, J = 3.8Hz, J =
16.8Hz, H-30), 5.26 (1H, dd, J = 1.0Hz, J = 10.3Hz,
H-30), 4.60 (1H, dt, J = 3.8Hz, J = 10.3Hz, H-1), 2.94
(1H, ddd, J = 3.8Hz, J = 6.1Hz, J = 13.7Hz, H-10),
2.56 (1H, ddd, J = 9.4Hz, J = 10.3Hz, J = 13.7Hz,
H-10), 1.73 (3H, d, J = 7.1Hz, CH3); dC (62.5MHz,
CDCl3) 168.8, 160.4, 149.7, 147.0, 134.8, 131.7, 130.8,
126.8, 126.7, 120.9, 120.1, 56.1, 52.5, 42.7, 19.3.
C15H15O2N3 requires: C, 66.90; H, 5.61; N, 15.60.
Found: C, 66.71; H, 5.64; N, 15.52%.
CDCl3) 169.0, 160.2, 149.6, 146.8, 137.5, 134.6, 132.1,
130.1, 129.0, 128.1, 127.4, 127.3, 126.8, 120.4, 53.9,
52.1, 37.5, 20.9, 16.9. C20H19O2N3 requires: C, 72.05;
H, 5.74; N, 12.60. Found: C, 72.16; H, 5.64; N, 12.64%.
4.7.1.8. (+)-(1S,4S)-4-Methyl-1-(p-methylbenzyl)-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
13d.
25
D
Mp: 221–222ꢁC (ethyl ether); yield 7%; ½aŠ ¼ þ23:4
(c 0.16, CHCl3); mmax (NaCl) 3211, 2925, 1682, 1598,
1473, 1406, 1333, 1174cmÀ1; dH (250MHz, CDCl3)
8.30 (1H, dd, J = 1.0Hz, J = 8.0Hz, H-7), 7.81 (1H,
ddd, J = 1.0Hz, J = 7.1Hz, J = 7.6Hz, H-9), 7.70 (1H,
dd, J = 1.1Hz, J = 7.6Hz, H-10), 7.52 (1H, ddd,
4.7.1.5. (+)-(1R,4S)-1-Benzyl-4-methyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazolino-3,6-dione 12c. Mp: 204–
25
D
206ꢁC (ethyl ether); yield 44%; ½aŠ ¼ þ167:8 (c 0.14,
J = 1.1Hz, J = 7.1Hz, J = 8.0Hz, H-8), 7.16 (2H, d,
*
CHCl3); mmax (NaCl) 2920, 1684, 1605cmÀ1
; dH
J = 9.1Hz, H-30 y 50), 7.13 (2H, d, J = 9.1Hz, H-20 y
*
60), 6.62 (1H, da, J = 2.8Hz, NH), 5.26 (1H, q,
J = 7.1Hz, H-4), 4.78 (1H, dt, J = 3.7Hz, J = 9.9Hz,
H-1), 3.44 (1H, dd, J = 3.7Hz, J = 13.5Hz, CH2–Ar–
CH3), 3.11 (1H, dd, J = 9.9Hz, J = 13.5Hz, CH2–Ar–
CH3), 2.33 (3H, s, Ar–CH3), 1.50 (3H, d, J = 7.1Hz,
CH3); dC (62.5MHz, CDCl3) 168.8, 160.6, 149.9,
147.3, 137.6, 135.0, 132.2, 130.0, 129.6, 127.3, 127.0,
126.9, 120.3, 58.2, 51.9, 43.9, 21.2, 19.0. C20H19O2N3
requires: C, 72.05; H, 5.74; N, 12.60. Found: C, 71.72;
H, 5.94; N, 12.25%.
(250MHz, CDCl3) 8.28 (1H, dd, J = 1.3Hz, J = 8.1Hz,
H-7), 7.79 (1H, ddd, J = 1.3Hz, J = 6.9Hz, J = 8.2Hz,
H-9), 7.71 (1H, dd, J = 1.3Hz, J = 8.2Hz, H-10), 7.51
(1H, ddd, J = 1.3Hz, J = 6.9Hz, J = 8.1Hz, H-8), 7.35
(5H, m, Ar–H), 5.92 (1H, sa, NH), 5.42 (1H, q,
J = 7.2Hz, H-4), 4.80 (1H, dd, J = 3.6Hz, J = 10.4Hz,
H-1), 4.12 (1H, dd, J = 3.6Hz, J = 14.5Hz, CH2–Ar–
H), 2.96 (1H, dd, J = 10.4Hz, J = 14.5Hz, CH2–Ar–
H), 1.59 (3H, d, J = 7.2Hz, CH3); dC (62.5MHz, CDCl3)
169.1, 160.2, 149.5, 146.7, 135.3, 134.7, 129.4, 129.2,
128.1, 127.8, 127.4, 126.9, 120.4, 53.9, 52.1, 37.9, 16.9.
C19H17O2N3 requires: C, 71,46; H, 5,37; N, 13,16.
Found: C, 71,16; H, 5,64; N, 12,84%.
4.7.1.9. (+)-(1R,4S)-1-(p-Fluorobenzyl)-4-methyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazolino-3,6-dione
Mp: 168–171ꢁC (ethyl ether); yield 36%; ½aŠ
12e.
25
D
¼
4.7.1.6. (+)-(1S,4S)-1-Benzyl-4-methyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazolino-3,6-dione 13c. Mp: 71–
þ175:3 (c 0.31, CHCl3); mmax (NaCl) 3209, 3072, 2926,
1686, 1605, 1568, 1510cmÀ1; dH (250MHz, CDCl3)
8.26 (1H, dd, J = 1.4Hz, J = 8.1Hz, H-7), 7.78 (1H,
ddd, J = 1.4Hz, J = 7.0Hz, J = 8.2Hz, H-9), 7.69 (1H,
dd, J = 1.1Hz, J = 8.2Hz, H-10), 7.50 (1H, ddd,
J = 1.1Hz, J = 7.0Hz, J = 8.1Hz, H-8), 7.27 (2H, m,
JH–F = 9.5Hz, H-30 y 50), 7.04 (2H, m, JH–F = 5.2Hz,
H-20 y 60), 6,31 (1H, sa, NH), 5,40 (1H, q, J = 7.2Hz,
H-4), 4.78 (1H, dd, J = 3.8Hz, J = 9.6Hz, H-1), 4.01
(1H, dd, J = 3.8Hz, J = 14.9Hz, CH2–Ar–F), 3.04
(1H, dd, J = 9.6Hz, J = 14.9 Hz, CH2–Ar–F), 1.58
(3H, d, J = 7.2Hz, CH3); dC (62.5MHz, CDCl3) 169.3,
162.2 (d, J = 247.0 Hz), 160.2, 149.3, 146.6, 134.7,
131.1 (d, J = 3.4 Hz), 130.9 (d, J = 8.0 Hz), 127.4,
127.3, 126.8, 120.4, 116.1 (d, J = 21.4Hz), 54.0, 52.0,
37.0, 16.9. C19H16O2N3F requires: C, 67.65; H, 4.78;
N, 12.46. Found: C, 66.55; H, 4.84; N, 12.21%.
25
73ꢁC (ethyl ether); yield 5%; ½aŠ ¼ þ41:4 (c 0.15,
D
CHCl3); mmax (NaCl) 2926, 1682, 1597, 1567cmÀ1; dH
(250MHz, CDCl3) 8.29 (1H, dd, J = 1.2Hz,
J = 8.1Hz, H-7), 7.80 (1H, ddd, J = 1.2Hz, J = 7.1Hz,
J = 8.4Hz, H-9), 7.69 (1H, dd, J = 1.2Hz, J = 8.4Hz,
H-10), 7.51 (1H, ddd, J = 1.2Hz, J = 7.1Hz,
J = 8.1Hz, H-8), 7.33 (2H, m, Ar–H), 7.24 (3H, m,
Ar–H), 6.12 (1H, da, J = 3.7Hz, NH), 5.24 (1H, q,
J = 7.1Hz, H-4), 4.78 (1H, dt, J = 3.7Hz, J = 10.1Hz,
H-1), 3.47 (1H, dd, J = 3.7Hz, J = 13.5Hz, CH2–Ar–
H), 3.12 (1H, dd, J = 10.1Hz, J = 13.5Hz, CH2–Ar–
H), 1.53 (3H, d, J = 7.1Hz, CH3); dC (62.5MHz, CDCl3)
168.4, 160.4, 149.6, 147.1, 135.1, 134.8, 129.5, 129.2,
127.7, 127.1, 126.8, 126.7, 120.1, 58.0, 51.8, 44.8, 18.9.
C19H17O2N3 requires: C, 71,46; H, 5,37; N, 13,16.
Found: C, C, 71.23; H, 5.34; N, 13.04%.
4.7.1.10.
(+)-(1R,4S)-1-(N-Boc-3-indolylmethyl)-4-
4.7.1.7. (+)-(1R,4S)-4-Methyl-1-(p-methylbenzyl)-2,4-
12d.
methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazolino-3,6-di-
one 12f. Compound 12f was obtained as a solid
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Mp: 134–135ꢁC (ethyl ether); yield 43%; ½aŠ
25
D
¼
(CH2Cl2); mp: 108–110ꢁC (CH2Cl2); yield: 7%;
25
þ152:7 (c 0.15, CHCl3); mmax (NaCl) 3234, 2924, 1687,
½aŠ ¼ þ35:3 (c 0.09, CHCl3); mmax (NaCl) 3214, 2978,
D
1605cmÀ1
; dH (250MHz, CDCl3) 8.28 (1H, dd,
2929, 1732, 1689, 1606, 1570cmÀ1; dH (250MHz,
CDCl3) 8.30 (1H, dd, J = 1.5Hz, J = 8.0Hz, H-7), 8.19
(1H, da, J = 7.9Hz, H-70), 7.80 (1H, ddd, J = 1.5Hz,
J = 6.6Hz, J = 8.1Hz, H-9), 7.74 (1H, dd, J = 1.3Hz,
J = 8.1Hz, H-10), 7.59 (1H, dd, J = 1.0Hz, J = 7.9Hz,
H-40), 7.58 (1H, d, J = 2.4Hz, H-20), 7.53 (1H, ddd,
J = 1.5Hz, J = 6.6Hz, J = 8.0Hz, H-8), 7.38 (1H, dt,
J = 1.0Hz, J = 7.9Hz, H-60), 7.27 (1H, dt, J = 1.0Hz,
J = 7.9Hz, H-50), 5.97 (1H, sa, NH), 5.45 (1H, q,
J = 7.2Hz, H-4), 4.89 (1H, dd, J = 3.5Hz, J = 10.5Hz,
J = 1.3Hz, J = 8.1Hz, H-7), 7.78 (1H, ddd, J = 1.3Hz,
J = 6.9Hz, J = 8.1Hz, H-9), 7.70 (1H, dd, J = 1.2Hz,
J = 8.1Hz, H-10), 7.50 (1H, ddd, J = 1.2Hz,
J = 6.9Hz, J = 8.1Hz, H-8), 7.18 (4H, ÔtÕ, Ar–CH3),
5.89 (1H, sa, NH), 5.42 (1H, q, J = 7.3Hz, H-4), 4.76
(1H, dd, J = 4.0Hz, J = 10.5Hz, H-1), 4.06 (1H, dd,
J = 4.0Hz, J = 14.4Hz, CH2–Ar–CH3), 2.91 (1H, dd,
J = 10.5Hz, J = 14.4Hz, CH2–Ar–CH3), 2.34 (3H, s,
Ar–CH3), 1.58 (3H, d, J = 7.2Hz, CH3); dC (62.5MHz,

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3052
H-1), 4.21 (1H, ddd, J = 1.1Hz, J = 3.5Hz, J = 15.1Hz,
CH2–Ar), 3.09 (1H, dd, J = 10.5Hz, J = 15.1Hz, CH2–
Ar), 1.68 (9H, s, C(CH3)3), 1.58 (3H, d, J = 7.2Hz,
CH3); dC (62.5MHz, CDCl3) 168.9, 160.2, 149.4,
149.2, 146.8, 135.8, 134.7, 129.3, 127.4, 126.8, 125.2,
124.9, 122.9, 120.4, 118.4, 115.7, 114.1, 84.2, 52.2,
51.8, 28.1, 27.8, 16.8. C26H26O4N4 requires: C, 68.11;
H, 5.72; N, 12.22. Found: C, 68.43; H, 5.85; N, 12.09%.
1.74 (3H, d, J = 6.6Hz, CH3-(1)), 1.17 (3H, d,
J = 6.8Hz, CH3–CH–CH3), 1.04 (3H, d, J = 6.8Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 168.6, 160.9,
151.5, 146.9, 134.6, 127.4, 127.2, 127.1, 120.3, 61.4,
49.5, 31.3, 19.9, 19.1, 18.0. C15H17O2N3 requires: C,
66.40; H, 6.32; N, 15.49. Found: C, 66.38; H, 6.28; N,
15.41%.
4.7.2.2. (+)-(1R,4S)-1-Allyl-4-iso-propyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 14b. Com-
pound 14b was obtained (EtOAc–CH2Cl2, 3:7) as a
4.7.1.11.
(+)-(1S,4S)-1-(N-Boc-3-indolylmethyl)-4-
methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazolino-3,6-di-
one 13f. Compound 13f was obtained as a solid
solid; mp: 178–179ꢁC (EtOAc/CH2Cl2); yield 32%;
25
(CH2Cl2); mp: 189–191ꢁC (CH2Cl2); yield 28%;
½aŠ ¼ þ175:2 (c 0.23, CHCl3); mmax (NaCl) 3262,
D
25
½aŠ ¼ þ84:6 (c 0.24, CHCl3); mmax (NaCl) 3200, 2928,
2978, 1683, 1605, 1568, 1470, 1386, 1331cmÀ1; dH
(250MHz, CDCl3) 8.26 (1H, dd, J = 1.5Hz,
J = 8.0Hz, H-7), 7.76 (1H, ddd, J = 1.5Hz, J = 7.2Hz,
J = 8.3Hz, H-9), 7.65 (1H, dd, J = 1.2Hz, J = 8.3Hz,
H-10), 7.48 (1H, ddd, J = 1.2Hz, J = 7.2Hz,
J = 8.0Hz, H-8), 6.24 (1H, sa, NH), 5.85 (1H, dddd,
J = 5.6Hz, J = 8.9Hz, J = 10.2Hz, J = 17.0Hz, H-20),
5.30 (3H, m, H-4 y 30), 4.65 (1H, dd, J = 3.7Hz,
J = 8.9Hz, H-1), 3.35 (1H, ddd, J = 3.7Hz, J = 5.4Hz,
J = 14.9Hz, H-10), 2.61 (1H, dt, J = 8.9Hz, J =
14.9Hz, H-10), 2.28 (1H, m, J = 6.9Hz, CH3 –CH–
CH3), 1.13 (3H, d, J = 6.9Hz, CH3–CH–CH3), 1.04
(3H, d, J = 6.9Hz, CH3–CH–CH3); dC (62.5MHz,
CDCl3) 167.7, 160.9, 150.1, 147.6, 134.7, 132.6, 127.3,
127.2, 127.1, 121.0, 120.3, 61.1, 52.1, 36.6, 31.6, 19.9,
18.9. C17H19O2N3 requires: C, 68.67; H, 6.44; N,
14.13. Found: C, 68.74; H, 6.35; N, 14.26%.
D
1732, 1683, 1599, 1568cmÀ1; dH (250MHz, CDCl3)
8.28 (1H, dd, J = 1.5Hz, J = 8.1Hz, H-7), 8.14 (1H,
da, J = 8.2Hz, H-70), 7.80 (1H, ddd, J = 1.5Hz,
J = 7.0Hz, J = 8.3Hz, H-9), 7.72 (1H, dd, J = 1.3Hz,
J = 8.3Hz, H-10), 7.60 (1H, dd, J = 1.2Hz, J = 7.2Hz,
H-40), 7.56 (1H, s, H-20), 7.51 (1H, ddd, J = 1.2Hz,
J = 7.0Hz, J = 8.1Hz, H-8), 7.33 (1H, dt, J = 1.2Hz,
J = 8.2Hz, H-60), 7.24 (1H, dt, J = 1.2 Hz, J = 8.2Hz,
H-50), 6.48 (1H, da, J = 3.4Hz, NH), 5.26 (1H, q,
J = 7.1Hz, H-4), 4.87 (1H, dt, J = 3.5Hz, J = 10.6Hz,
H-1), 3.61 (1H, ddd, J = 1.0Hz, J = 3.5Hz, J =
14.2Hz, CH2–Ar), 3.16 (1H, dd, J = 10.6Hz,
J = 14.2Hz, CH2–Ar), 1.68 (3H, d, J = 7.1Hz, CH3),
1.65 (9H, s, C(CH3)3); dC (62.5MHz, CDCl3) 168.4,
160.4, 149.7, 149.3, 147.1, 135.5,134.8, 129.4, 127.1,
126.9, 126.7, 124.9, 124.8, 122.9, 120.1, 118.6, 115.5,
114.2, 84.1, 56.7, 51.7, 34.6, 28.1, 19.3. C26H26O4N4 re-
quires: C, 68.11; H, 5.72; N, 12.22. Found: C, 67.92; H,
5.63; N, 12.18%.
4.7.2.3. (+)-(1R,4S)-1-Benzyl-4-iso-propyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14c. Mp:
25
D
73–75ꢁC (CH2Cl2); yield 50%; ½aŠ ¼ þ138:4 (c
4.7.2. Alkylation of 1b. To a cold (À78ꢁC), magneti-
cally stirred solution of 1b (0.5mmol) in dry THF
(10mL) was added, under argon, dropwise via syringe
a solution of lithium hexamethyldisilazide in THF
(1M, 3.0mL), followed after 10min by a solution of
the appropriate halide (1.0mmol dissolved in THF
(5mL)). The reaction mixture was stirred at À78ꢁC for
3d, quenched with drops of glacial acetic acid followed
by a saturated aqueous solution of ammonium chloride
(5mL), and extracted with CHCl3. The organic layer
was dried over anhydrous Na2SO4 and evaporated. Col-
umn chromatography of the residue on silica gel
(CH2Cl2, unless otherwise mentioned) afforded traces
of 1,1-dialkylated compounds, followed from the ex-
pected anti-1-alkyl compounds and small amounts of
syn-1-alkyl derivatives.
0.32, CHCl3); mmax (NaCl) 3207, 2965, 2932, 1688,
1605, 1570cmÀ1; dH (250MHz, CDCl3) 8.28 (1H, ddd,
J = 0.8Hz, J = 1.5Hz, J = 8.1Hz, H-7), 7.76 (1H,
ddd, J = 1.5Hz, J = 6.9Hz, J = 8.3Hz, H-9), 7.74 (1H,
dd, J = 1.4Hz, J = 8.3Hz, H-10), 7.51 (1H, ddd,
J = 1.4Hz, J = 6.9Hz, J = 8.1Hz, H-8), 7.33 (5H, m,
Ar–H), 5.86 (1H, sa, NH), 5.28 (1H, dd, J = 1.1Hz,
J = 7.8Hz, H-4), 4.85 (1H, dd, J = 3.7Hz, J = 10.5Hz,
H-1), 4.11 (1H, dd, J = 3.7Hz, J = 14.5Hz, CH2–Ar–
H), 2.89 (1H, dd, J = 10.5Hz, J = 14.5Hz, CH2–Ar–
H), 2.26 (1H, m, CH3–CH–CH3), 1.07 (3H, d,
J = 6.9Hz, CH3–CH–CH3), 1.04 (3H, d, J = 6.9Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 167.5, 160.8,
150.4, 146.7, 135.5, 134.7, 129.5, 129.2, 127.8, 127.4,
127.3, 127.1, 120.4, 61.0, 54.4, 38.5, 31.7, 19.8, 18.8.
C21H21O2N3 requires: C, 72.60; H, 6.09; N, 12.09.
Found: C, 72.24; H, 6.29; N, 12.29%.
4.7.2.1. (+)-(1S,4S)-4-iso-Propyl-1-methyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15a. Com-
pound 15a was obtained (EtOAc) as a solid; mp: 161–
4.7.2.4. (+)-(1R,4S)-4-iso-Propyl-1-p-methylbenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14d.
25
25
D
163ꢁC (EtOAc); yield 46%; ½aŠ ¼ þ82:9 (c 0.25,
Mp: 79ꢁC (CH2Cl2); yield 58%; ½aŠ ¼ þ200:0 (c 0.06,
D
CHCl3); mmax (NaCl) 2956, 2928, 1685, 1608, 1472,
1388, 1327cmÀ1; dH (250MHz, CDCl3) 8.26 (1H, dd,
J = 1.3Hz, J = 8.1Hz, H-7), 7.75 (1H, ddd, J = 1.3Hz,
J = 7.0Hz, J = 8.2Hz, H-9), 7.66 (1H, dd, J = 1.3Hz,
J = 8.2Hz, H-10), 7.48 (1H, ddd, J = 1.3Hz, J =
7.0Hz, J = 8.1Hz, H-8), 6.77 (1H, sa, NH), 5.30 (1H,
dd, J = 1.2Hz, J = 8.5Hz, H-4), 4.76 (1H, q,
J = 6.6Hz, H-1), 2.29 (1H, m, CH3–CH–CH3),
CHCl3); mmax (NaCl) 3209, 3063, 2967, 2929, 1683,
1606, 1471, 1387, 1330cmÀ1; dH (250MHz, CDCl3)
8.28 (1H, dd, J = 1.3Hz, J = 8.1Hz, H-7), 7.79 (1H,
ddd, J = 1.3Hz, J = 7.0Hz, J = 8.3Hz, H-9), 7.70 (1H,
dd, J = 1.2Hz, J = 8.3Hz, H-10), 7.51 (1H, ddd,
J = 1.2Hz, J = 7.0Hz, J = 8.1Hz, H-8), 7.18 (4H, ÔtÕ,
J = 8.3Hz, Ar–CH3), 5.80 (1H, sa, NH), 5.28 (1H, dd,
J = 1.1Hz, J = 7.8Hz, H-4), 4.81 (1H, dd, J = 3.8Hz,

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3053
J = 10.6Hz, H-1), 4.06 (1H, dd, J = 3.8Hz, J = 14.4Hz,
CH2–Ar–CH3), 2.84 (1H, dd, J = 10.6Hz, J = 14.4Hz,
CH2–Ar–CH3), 2.35 (3H, s, Ar–CH3), 2.25 (1H, m,
J = 6.9Hz, CH3–CH–CH3), 1.07 (3H, d, J = 6.9Hz,
CH3–CH–CH3), 1.03 (3H, d, J = 6.9Hz, CH3–CH–
CH3); dC (62.5MHz, CDCl3) 167.5, 160.9, 150.5,
146.7, 137.6, 134.9, 132.3, 130.2, 129.1, 127.4, 120.4,
61.0, 54.4, 38.1, 31.8, 20.9, 19.8, 18.8. C22H23O2N3 re-
quires: C, 73.11; H, 6.41; N, 11.63.Found: C, 72.65; H,
6.57; N, 11.08%.
J = 8.1Hz, H-7), 7.79 (1H, ddd, J = 1.3Hz, J = 7.1Hz,
J = 8.5Hz, H-9), 7.67 (1H, dd, J = 1.3Hz, J = 8.5Hz,
H-10), 7.50 (1H, ddd, J = 1.3Hz, J = 7.1Hz,
J = 8.1Hz, H-8), 7.27 (2H, m, H-30 y 50), 7.08 (2H, m,
H-20 y 60), 5.95 (1H, sa, NH), 5.19 (1H, dd, J = 0.8Hz,
J = 7.5Hz, H-4), 4.71 (1H, dt, J = 3.7Hz, J = 11.4Hz,
H-1), 3.66 (1H, dd, J = 3.7Hz, J = 13.6Hz, CH2–Ar–
F), 3.05 (1H, dd, J = 11.4Hz, J = 13.6 Hz, CH2–Ar–
F), 2.25 (1H, m, J = 7.0Hz, CH3 –CH–CH3), 1.21
(3H, d, J = 7.0Hz, CH3–CH–CH3), 1.10 (3H, d,
J = 7.0Hz, CH3–CH–CH3).
4.7.2.5. (+)-(1S,4S)-4-iso-Propyl-1-p-methylbenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15d.
Mp: 82–84ꢁC (CH2Cl2); yield 5%; ½aŠ ¼ þ73:7 (c 0.18,
4.7.2.8. (+)-(1R,4S)-1-(N-Boc-3-indolylmethyl)-4-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
25
D
CHCl3); mmax (NaCl) 3246, 2954, 2824, 1686, 1607, 1471,
1389, 1329cmÀ1; dH (250MHz, CDCl3) 8.28 (1H, dd,
J = 1.3Hz, J = 8.1Hz, H-7), 7.79 (1H, ddd, J = 1.3Hz,
J = 7.1Hz, J = 8.3Hz, H-9), 7.68 (1H, dd, J =
1.3Hz, J = 8.3Hz, H-10), 7.49 (1H, ddd, J = 1.3Hz,
J = 7.1Hz, J = 8.1Hz, H-8), 7.18 (4H, ÔtÕ, J = 8.4Hz,
Ar–CH3), 5.96 (1H, da, J = 3.3Hz, NH), 5.21 (1H,
dd, J = 0.6Hz, J = 7.2Hz, H-4), 4.71 (1H, dt,
J = 3.7Hz, J = 11.6Hz, H-1), 3.65 (1H, dd, J = 3.7Hz,
J = 13.4Hz, CH2–Ar–CH3), 3.01 (1H, dd, J =
11.6Hz, J = 13.4Hz, CH2–Ar–CH3), 2.71 (1H, m,
CH3–CH–CH3), 2.34 (3H, s, Ar–CH3), 1.21 (3H, d,
J = 6.9Hz, CH3–CH–CH3), 1.10 (3H, d, J = 6.9Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 166.6, 161.1,
150.2, 146.9, 137.4, 134.9, 132.5, 129.9, 129.3, 127.1,
126.8, 120.1, 59.9, 58.3, 43.0, 33.7, 21.1, 19.9, 19.5.
C22H23O2N3 requires: C, 73.11; H, 6.41; N,
11.63.Found: C, 73.15; H, 6.38; N, 11.84%.
one 14f. Mp: 149–151ꢁC (CH2Cl2); yield 20%;
25
½aŠ ¼ þ56:7 (c 0.06, CHCl3); mmax (NaCl) 3240, 2971,
D
1734, 1685, 1606cmÀ1; dH (250MHz, CDCl3) 8.32
(1H, dd, J = 1.5Hz, J = 8.1Hz, H-7), 8.22 (1H, da,
J = 7.7Hz, H-70), 7.83 (1H, ddd, J = 1.5Hz, J = 6.7Hz,
J = 8.2Hz, H-9), 7.77 (1H, dd, J = 1.4Hz, J = 8.2Hz,
H-10), 7.63 (1H, d, J = 7.7Hz, H-40), 7.59 (1H, s, H-
20), 7.55 (1H, ddd, J = 1.4Hz, J = 6.7Hz, J = 8.1Hz,
H-8), 7.41 (1H, dt, J = 1.2Hz, J = 7.7Hz, H-60), 7.30
(1H, dt, J = 1.2Hz, J = 7.7Hz, H-50), 5.97 (1H, sa,
NH), 5.32 (1H, dd, J = 1.0Hz, J = 6.8Hz, H-4), 4.96
(1H, dd, J = 3.5Hz, J = 10.5Hz, H-1), 4.20 (1H, ddd,
J = 1.0Hz, J = 3.5Hz, J = 15.0Hz, CH2–Ar), 3.06 (1H,
dd, J = 10.5Hz, J = 15.0Hz, CH2–Ar), 2.25 (1H, m,
CH3–CH–CH3), 1.69 (9H, s, C(CH3)3), 1.07 (3H, d,
J = 6.5Hz, CH3–CH–CH3), 1.05 (3H, d, J = 6.5Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 167.4, 160.8,
150.3, 146.7, 135.9, 134.8, 129.5, 127.5, 127.4, 127.2,
125.2, 124.9, 123.0, 120.4, 118.5, 115.8, 114.3, 84., 61.1
(C-1), 52.3, 31.7, 29.2, 28.2, 19.8, 18.9. C28H30O4N4 re-
quires: C, 69.12; H, 6.21; N, 11.51.Found: C, 68.96; H,
6.12; N, 11.38%.
4.7.2.6.
(+)-(1R,4S)-1-p-Fluorobenzyl-4-iso-propyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14e.
Compound 14e was obtained (EtOAc–CH2Cl2, 3:7) as a
solid; mp: 64–66ꢁC (EtOAc/CH2Cl2); yield 48%;
25
½aŠ ¼ þ119:0 (c 0.20, CHCl3); mmax (NaCl) 3207,
D
2965, 1687, 1606cmÀ1; dH (250MHz, CDCl3) 8.28
(1H, dd, J = 1.3Hz, J = 8.1Hz, H-7), 7.79 (1H, ddd,
J = 1.3Hz, J = 7.0Hz, J = 8.3Hz, H-9), 7.70 (1H, dd,
J = 1.3Hz, J = 8.3Hz, H-10), 7.51 (1H, ddd, J =
1.3Hz, J = 7.0Hz, J = 8.1Hz, H-8), 7.26 (2H, m, H-20
y 60), 7.06 (2H, m, H-30 y 50), 5.91 (1H, sa, NH),
5.28 (1H, dd, J = 1.1Hz, J = 7.8Hz, H-4), 4.82 (1H,
dd, J = 3.7Hz, J = 10.2Hz, H-1), 4.05 (1H, dd,
J = 3.7Hz, J = 14.6Hz, CH2–Ar–F), 2.92 (1H, dd,
J = 10.2Hz, J = 14.6Hz, CH2–Ar–F), 2.26 (1H, m,
CH3–CH-CH3), 1.08 (3H, d, J = 6.9Hz, CH3–CH–
CH3), 1.04 (3H, d, J = 6.9Hz, CH3–CH–CH3); dC
(62.5MHz, CDCl3) 167.5, 162.3 (d, J = 246.9 Hz),
160.8, 150.1, 146.6, 134.8, 131.2 (d, J = 3.3 Hz), 130.8
(d, J = 8.1 Hz), 127.5, 127.3, 127.2, 120.4, 116.3 (d,
J = 21.5 Hz), 60.9, 54.4, 37.6, 31.7, 19.8, 18.8.
4.7.2.9. (+)-(1S,4S)-1-(N-Boc-3-indolylmethyl)-4-iso-
propyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
one 15f. Compound 15f was obtained (EtOAc–
CH2Cl2, 3:7) as a solid; mp: 111–113ꢁC (CH2Cl2); yield
25
35%; ½aŠ ¼ þ47:9 (c 0.14, CHCl3); mmax (NaCl) 3271,
D
2976, 1685, 1606cmÀ1; dH (250MHz, CDCl3) 8.29
(1H, dd, J = 1.5Hz, J = 8.2Hz, H-7), 8.17 (1H, da,
J = 7.6Hz, H-70), 7.81 (1H, ddd, J = 1.5Hz, J = 6.9Hz,
J = 8.3Hz, H-9), 7.73 (1H, dd, J = 1.3Hz, J = 8.3Hz,
H-10), 7.69 (1H, dd, J = 1.3Hz, J = 6.8Hz, H-40), 7.56
(1H, s, H-20), 7.51 (1H, ddd, J = 1.3Hz, J = 6.9Hz,
J = 8.2Hz, H-8), 7.37 (1H, dt, J = 1.3Hz, J = 7.4Hz,
H-60), 7.29 (1H, dt, J = 1.3Hz, J = 7.4Hz, H-50), 6.05
(1H, da, J = 3.6Hz, NH), 5.22 (1H, d, J = 6.4Hz, H-
4), 4.91 (1H, dt, J = 3.6Hz, J = 11.4Hz, H-1), 3.83
(1H, dd, J = 3.6Hz, J = 14.1Hz, CH2–Ar), 3.19 (1H,
dd, J = 11.4Hz, J = 14.1Hz, CH2–Ar), 2.29 (1H, m,
CH3–CH–CH3), 1.68 (9H, s, C(CH3)3 ), 1.21 (3H, d,
J = 6.9Hz, CH3–CH–CH3), 1.12 (3H, d, J = 6.9Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 166.3, 161.0,
150.2, 149.4, 147.0, 134.9, 129.4, 127.2, 126.8, 125.1,
124.8, 123.0, 120.1, 118.8, 115.7, 114.6, 84.2, 59.9,
56.5, 33.8, 33.7, 28.2, 19.9, 19.3. C28H30O4N4 requires:
C, 69.12; H, 6.21; N,11.51.Found: C, 69.01; H, 6.11;
N, 11.39%.
C21H20O2N3 F requires: C, 69.03; H, 5.52; N,
11.50.Found: C, 68.67; H, 5.81; N, 11.39%.
4.7.2.7. (+)-(1S,4S)-1-p-Fluorobenzyl-4-iso-propyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15e.
Compound 15e was obtained (EtOAc–CH2Cl2, 3:7) as a
25
D
solid; yield 3%; ½aŠ ¼ þ18:0 (c 0.20, CHCl3); mmax
(NaCl) 3221, 2965, 1687, 1601, 1510cmÀ1
(250MHz, CDCl3) 8.28 (1H, dd, J = 1.3Hz,
;
dH

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3054
4.7.3. Alkylation with gramine methiodide. To a cold
(À78ꢁC), magnetically stirred solution of 1a,b
(0.5mmol) in dry THF (10mL) was added, under argon,
dropwise via syringe a solution of lithium hexamethyl-
disilazide in THF (1M, 3.0mL). After 10min this solu-
tion was added dropwise over a solution of the
gramine methiodide (1.0mmol dissolved in THF
(15mL)). The reaction mixture was stirred at À78ꢁC
for 16h (1a) or for 3d (1b), quenched with drops of gla-
cial acetic acid followed by a saturated aqueous solution
of ammonium chloride (5mL), and extracted with
CHCl3. The organic layer was dried over anhydrous
Na2SO4 and evaporated. Column chromatography of
the residue on silica gel (EtOAc–CH2Cl2, 6:4 (1a) or
3:7 (1b)) afforded the expected anti-1-indolylmethyl
compounds and smaller amounts of its syn-isomers.
(c 0.07, CHCl3); mmax (NaCl) 3366, 1682cmÀ1; dH
(250MHz, CDCl3) 8.38 (1H, sa, NHi), 8.30 (1H, ddd,
J = 0.7Hz, J = 1.5Hz, J = 8.2Hz, H-7), 7.80 (1H,
ddd, J = 1.5Hz, J = 6.5Hz, J = 8.2Hz, H-9), 7.76 (1H,
dd, J = 1.9Hz, J = 8.2Hz, H-10), 7.65 (1H, d,
J = 7.9Hz, H-40), 7.52 (1H, ddd, J = 1.9Hz, J = 6.5Hz,
J = 8.2Hz, H-8), 7.42 (1H, d, J = 7.9Hz, H-70), 7.25
(1H, dt, J = 1.1Hz, J = 7.9Hz, H-60), 7.15 (1H, dt,
J = 1.1Hz, J = 7.9Hz, H-50), 7.13 (1H, d, J = 1.4Hz,
H-20), 5.98 (1H, sa, NH-2), 5.29 (1H, dd, J = 1.1Hz,
J = 7.9Hz, H-4), 4.94 (1H, dd, J = 3.7Hz, J = 10.5Hz,
H-1), 4.22 (1H, ddd, J = 0.8Hz, J = 3.7Hz, J =
15.0Hz, CH2–Ar), 3.09 (1H, dd, J = 10.5Hz, J =
15.0Hz, CH2–Ar), 2.24 (1H, hept, J = 6.8Hz, CH3–
CH–CH3), 1.05 (3H, d, J = 6.8Hz, CH3–CH–CH3),
1.03 (3H, d, J = 6.8Hz, CH3–CH–CH3); dC (62.5MHz,
CDCl3) 167.4, 160.9, 150.7, 146.8, 136.7, 134.7, 127.4,
127.3, 127.1, 126.8, 123.7, 122.9, 120.4, 120.1, 118.4,
111.7, 109.4, 61.1, 52.7, 31.7, 28.8, 19.8, 18.8.
C23H22O2N4 requires: C, 71.48; H, 5.74; N, 14.31.
Found: C, 71.25; H, 5.83; N, 14.31%.
4.7.3.1. (+)-(1R,4S)-1-(3-Indolylmethyl)-4-methyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
12g.
¼
25
D
Mp: 109–111ꢁC (EtOAc/CH2Cl2); yield 23%; ½aŠ
þ30:6 (c 0.16, CHCl3); mmax (NaCl) 3282, 1684cmÀ1
;
dH (250MHz, CDCl3) 8.17 (1H, dd, J = 1.4Hz,
J = 8.1Hz, H-7), 7.74 (1H, ddd, J = 1.4Hz, J = 6.9Hz,
J = 8.2Hz, H-9), 7.69 (1H, dd, J = 1.1Hz, J = 8.2Hz,
H-10), 7.52 (1H, d, J = 8.0Hz, H-40), 7.45 (1H, ddd,
J = 1.1Hz, J = 6.9Hz, J = 8.1Hz, H-8), 7.34 (1H, d,
J = 8.0Hz, H-70), 7.12 (1H, dt, J = 1.0Hz, J = 8.0Hz,
H-60), 7.11 (1H, s, H-20), 7.00 (1H, dt, J = 1.0Hz,
J = 8.0Hz, H-50), 5.24 (1H, q, J = 7.2Hz, H-4), 4.82
(1H, dd, J = 3.5Hz, J = 10.0Hz, H-1), 4.11 (1H, dd,
J = 3.5Hz, J = 14.9Hz, CH2–Ar), 3.10 (1H, dd,
J = 10.0Hz, J = 14.9Hz, CH2–Ar), 1.47 (3H, d,
J = 7.2Hz, CH3); dC (62.5MHz, CDCl3) 169.0, 160.5,
149.8, 146.8, 136.7, 134.8, 127.3, 126.5, 124.0, 122.2,
120.2, 119.4, 118.0, 111.6, 108.2, 52.4, 52.1, 28.2, 16.7.
C21H18O2N4 requires: C, 70.38; H, 5.06; N, 15.63.
Found: C, 70.38; H, 5.38; N, 15.89%.
4.7.3.4. (+)-(1S,4S)-1-(3-Indolylmethyl)-4-iso-propyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15g.
Mp: 97ꢁC (EtOAc/CH2Cl2); yield 11%; ½aŠ ¼ þ78:2
25
D
(c 0.17, CHCl3); mmax (NaCl) 3326, 3269, 2926, 1682,
1600cmÀ1; dH (250MHz, CDCl3) 8.48 (1H, sa, NHi),
8.29 (1H, dd, J = 1.5Hz, J = 8.2Hz, H-7), 7.80 (1H,
ddd, J = 1.5Hz, J = 6.9Hz, J = 8.2Hz, H-9), 7.74 (1H,
dd, J = 1.4Hz, J = 8.2Hz, H-10), 7.68 (1H, d,
J = 7.8Hz, H-40), 7.50 (1H, ddd, J = 1.4Hz, J = 6.9Hz,
J = 8.2Hz, H-8), 7.37 (1H, d, J = 7.8Hz, H-70), 7.20
(1H, dt, J = 1.1Hz, J = 7.8Hz, H-60), 7.12 (1H, dt,
J = 1.1Hz, J = 7.8Hz, H-50), 7.11 (1H, m, H-20), 6.24
(1H, da, J = 3.3Hz, NH-2), 5.20 (1H, dd, J = 0.7Hz,
J = 7.0Hz, H-4), 4.80 (1H, dt, J = 3.4Hz, J = 11.4Hz,
H-1), 3.84 (1H, dd, J = 3.4Hz, J = 14.3Hz, CH2–Ar),
3.22 (1H, dd, J = 11.4Hz, J = 14.3Hz, CH2–Ar), 2.27
(1H, hept, J = 6.9Hz, CH3–CH-CH3), 1.19 (3H, d,
J = 6.9Hz, CH3–CH–CH3), 1.09 (3H, d, J = 6.9Hz,
CH3–CH–CH3); dC (62.5MHz, CDCl3) 166.7,
161.2, 150.5, 147.0, 136.4, 134.8, 127.1, 127.0, 126.9,
126.7, 123.6, 122.6, 120.1, 120.0, 118.5, 111.5, 109.8,
59.9, 57.2, 33.8, 19.9, 19.5. C23H22O2N4 requires: C,
71.48; H, 5.74; N, 14.31. Found: C, 71.36; H, 5.66; N,
14.24%.
4.7.3.2. (+)-(1S,4S)-1-(3-Indolylmethyl)-4-methyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
13g.
25
D
Mp: 215ꢁC (EtOAc/CH2Cl2); yield 11%; ½aŠ ¼ þ6:9(c
0.13, CHCl3); mmax (NaCl) 3264, 2925, 1682,
1596cmÀ1; dH (250MHz, CDCl3) 8.29 (1H, sa, NHi),
8.28 (1H, dd, J = 1.3Hz, J = 8.0Hz, H-7), 7.81 (1H,
ddd, J = 1.3Hz, J = 6.8Hz, J = 8.2Hz, H-9), 7.74 (1H,
dd, J = 1.3Hz, J = 8.2Hz, H-10), 7.60 (1H, d,
J = 7.8Hz, H-40), 7.51 (1H, ddd, J = 1.3Hz, J = 6.8Hz,
J = 8.0Hz, H-8), 7.37 (1H, d, J = 8.1Hz, H-70), 7.20
(1H, dt, J = 1.0Hz, J = 7.2Hz, H-60), 7.12 (1H, d,
J = 2.2Hz, H-20), 7.09 (1H, dt, J = 1.0Hz, J = 7.9Hz,
H-50), 6.33 (1H, da, J = 3.2Hz, NH), 5.23 (1H, q,
J = 7.1Hz, H-4), 4.85 (1H, dt, J = 3.4Hz, J = 10.1Hz,
H-1), 3.65 (1H, dd, J = 3.4Hz, J = 14.3Hz, CH2–Ar),
3.28 (1H, dd, J = 10.1Hz, J = 14.3Hz, CH2–Ar), 1.54
(3H, d, J = 7.1Hz, CH3); dC (62.5MHz, CDCl3) 168.5,
160.4, 150.9, 147.2, 136.2, 134.7, 127.0, 126.9, 126.7,
123.6, 122.6, 120.1, 120.0, 118.5, 111.4, 109.4, 57.2,
51.8, 34.8, 19.0. C21H18O2N4 requires: C, 70.38; H,
5.06; N, 15.63. Found: C, 70.06; H, 5.31; N, 15.20%.
4.7.4. Alkylation of 2. To a cold (À78ꢁC), magnetically
stirred solution of 2 (0.5mmol) and 0.1mL (1mmol) of
DMI in dry THF (10mL) was added, under argon,
dropwise via syringe a solution of lithium hexamethyl-
disilazide in THF (1M, 0.6mL, 0.6mmol), followed
after 15min by a solution of the appropriate halide
(1.2mmol dissolved in THF (5mL)). The reaction mix-
ture was stirred at À78ꢁC for 10min (45min for p-tolyl-
bromide) and at 0ꢁC for 45min (90min for p-
fluorobenzyl bromide and 3h for p-tolyl bromide),
quenched with ice followed by a saturated aqueous solu-
tion of ammonium chloride (5mL), and extracted with
CHCl3. The organic layer was dried over anhydrous
Na2SO4 and evaporated. Column chromatography of
the residue on silica gel (toluene/EtOAc 8:2) afforded
traces of 1,1-dialkylated and 1,4-dialkylated com-
4.7.3.3. (+)-(1R,4S)-1-(3-Indolylmethyl)-4-iso-propyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14g.
25
D
Mp: 64ꢁC (EtOAc/CH2Cl2); yield 24%; ½aŠ ¼ þ66:2

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3055
pounds, followed by the anti-1-alkyl compounds (small
amounts) and the expected syn-1-alkyl derivatives.
Ar–H), 7.34 (3H, m, Ar–H), 7.16 (3H, m, Ar–H), 5.42
(1H, t, J = 5.7Hz, H-1), 5.26 (1H, q, J = 7.1Hz, H-4),
3.49 (1H, dd, J = 5.8 and 13.9Hz, CH2–Ar), 3.71 (1H,
dd, J = 5.6 and 13.9Hz, CH2–Ar), 1.18 (3H, d, J = 7.1
Hz, CH3); dC (62.5MHz, CDCl3) 166.3, 160.2, 149.9,
147.0, 138.8, 135.0, 134.7, 129.8, 129.4, 128.7, 127.8,
127.5, 127.1, 127.0, 126.9, 126.7, 120.2, 65.6, 52.7, 41.0,
18.5. C25H21N3O2 requires: C, 75.93; H, 5.35; N, 10.63.
Found: 75.68; H, 5.20; N, 10.45%.
4.7.4.1. (+)-(1S,4S)-1,4-Dimethyl-2-phenyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 17a. Mp:
25
84–85ꢁC (ethyl ether); yield 42%; ½aŠ ¼ þ12:4 (c 0.25,
D
CHCl3); mmax (KBr) 1686, 1606cmÀ1; dH (250MHz,
CDCl3) 8.30 (1H, dd, J = 1.5Hz, J = 8.0Hz, H-7), 7.76
(1H, ddd, J = 1.5Hz, J = 8.4Hz, J = 7.1Hz, H-9),
7.68 (1H, dd, J = 1.1Hz, J = 8.4Hz, H-10), 7.50 (1H,
ddd, J = 1.1Hz, J = 7.1Hz, J = 8.0Hz, H-8), 7.47–7.30
(5H, m, Ar–H), 5.48 (1H, q, J = 7.1Hz, H-4), 5.00
(1H, q, J = 7.1Hz, H-1), 1.85 (3H, d, J = 7.1Hz, CH3-
4), 1.73 (3H, d, J = 7.1Hz, CH3-1); dC (62.5MHz,
CDCl3) 166.8, 160.5, 151.8, 147,5, 138.9, 135.0, 129.9,
128.4, 127.6, 127.3, 127.0, 126.9, 120.4, 60.8, 52.7,
22.1, 19.5. C19H17O3N2 requires: C, 71.46; H, 5.37; N,
13.16. Found: C, 71.28; H, 5.34; N, 12.82%.
4.7.4.5. (+)-(1R,4S)-1-Benzyl-4-methyl-2-phenyl-2,4-
18c.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
25
Mp: 128–130ꢁC (ethyl ether); yield 1%; ½aŠ ¼ À38:2 (c
D
0.12, CHCl3); mmax (KBr) 2923, 1679, 1600cmÀ1; dH
(250MHz, CDCl3) 8.24 (1H, dd, J = 8.0 and 1.3Hz, H-
7), 7.77 (1H, ddd, J = 8.3, 7.0 and 1.3Hz, H-9), 7.69
(1H, dd, J = 8.3 and 1.0Hz, H-10), 7.44 (6H, m,
Ar–H), 7.17 (3H, m, Ar–H), 6.85 (2H, m, Ar–H), 5.48
(1H, t, J = 4,3Hz, H-1), 4.69 (1H, q, J = 6.9Hz, H-4),
3.42 (1H, dd, J = 14.3Hz, J = 4.3Hz, CH2–Ar), 3.27
(1H, dd, J = 14.3Hz, J = 4.3Hz, CH2–Ar), 1.65 (3H, d,
J = 6.9Hz, CH3); dC (62.5MHz, CDCl3) 167.7, 160.7,
150.3, 147.1, 138.6, 135.4, 134.2, 129.8, 129.7, 129.0,
128.5, 128.2, 127.8, 127.6, 127.5, 127.3, 121.0, 63.0,
52.9, 39.4, 19.7. C25H21N3O2 requires: C, 75.93; H,
5.35; N, 10.63. Found: C, 75.86; H, 5.28; N, 10.65%.
4.7.4.2.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
(+)-(1S,4S)-1-Allyl-4-methyl-2-phenyl-2,4-
17b.
25
D
Mp: 122–124ꢁC (ethyl ether); yield 50%; ½aŠ ¼ þ47:1
(c 0.23, CHCl3); mmax (KBr) 3249, 2923, 1682,
1606cmÀ1; dH (250MHz, CDCl3) 8.34 (1H, dd, J = 8.0
and 1.5Hz, H-7), 7.80 (1H, ddd, J = 8.2, 7.0 and
1.5Hz, H-9), 7.67 (1H, dd, J = 8.2 and 1.0Hz, H-10),
7.53 (1H, ddd, J = 8.0, 7.0 and 1.0Hz, H-8), 7.48-7.32
(5H, m, Ar–H), 5.73 (1H, ddt, J = 14.4, 9.8 and
7.3Hz, H-200), 5.45 (1H, q, J = 7.1Hz, H-4), 5.09 (3H,
m, 2H-30, H-1), 2.95 (1H, m, H-100), 2.75 (1H, m, H-
100), 1.92 (3H, d, J = 7.1Hz, CH3); dC (62.5MHz,
CDCl3) 166.6, 160.4, 149.9, 147.0, 138.9, 134.8, 132.0,
129.6, 128.2, 127.5, 127.2, 127.0, 126.8, 120.3, 119.7,
64.4, 52.7, 40,2, 19.8. C21H19N3O2 requires: C, 73.03;
H, 5.54; N, 12.17. Found: C, 72.98; H, 5.34; N, 12.22%.
4.7.4.6. (+)-(1S,4S)-4-Methyl-2-phenyl-1-(p-methyl-
benzyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 17d. Mp: 100–101ꢁC (ethyl ether); yield 51%;
25
½aŠ ¼ þ62:2 (c 0.50, CHCl3); mmax (KBr) 1677,
D
1596cmÀ1; dH (250MHz, CDCl3) 8.32 (1H, dd, J = 8.0
and 1.5Hz, H-7), 7.82 (1H, ddd, J = 8.3, 7.2 Hz and
1.5Hz, H-9), 7.66 (1H, dd, J = 8.3 and 1.0Hz, H-10),
7.57–7.35 (6H, m, ArH), 6,97 (2H, d, J = 7,9Hz, H-300,
H-500), 6,84 (2H, d, J = 7,9Hz, H-200, H-600), 5,42 (1H,
t, J = 5.5Hz, H-1), 5.28 (1H, q, J = 7.2Hz, H-4), 3.48
(1H, dd, J = 14,0 and 5.5Hz, CH2–Ar), 3.20 (1H, dd,
J = 14.0 and 5.5Hz, CH2–Ar), 2.26 (3H, s, CH3), 1.23
(3H, d, J = 7.2Hz, CH3); dC (62.5MHz, CDCl3) 166.4,
160.3, 150.1, 147.0, 138.9, 134.8, 131.9, 129.8, 129.5,
129.4, 127.8, 127.2, 127.1, 126.9, 126.8, 120.3, 65.7,
52.8, 40.5, 21.0, 18.5. C26H23O2N3 requires: C, 76.26;
H, 5.66; N, 10.26. Found: 76.22; H, 5.55; N, 9.81%.
4.7.4.3.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
(+)-(1R,4S)-1-Allyl-4-methyl-2-phenyl-2,4-
18b.
25
Mp: 136–138ꢁC (ethyl ether); yield 7%; ½aŠ ¼ þ32:2
D
(c 0.65, CHCl3); mmax (KBr) 1683cmÀ1; dH (250MHz,
CDCl3) 8.32 (1H, dd, J = 8.0 and 1.5Hz, H-7), 7.77
(1H, ddd, J = 8.4, 7.1 and 1.5Hz, H-9), 7.69 (1H, dd,
J = 8.4 and 1.2Hz, H-10), 7.53 (1H, ddd, J = 8.0, 7.1
and 1.2Hz, H-8), 7.52–7.30 (5H, m, Ar–H), 5.63 (1H,
ddt, J = 17.1, 10.3 and 7.0Hz, H-200), 5.53 (1H, q,
J = 7.0Hz, H-4), 5.22 (1H, t, J = 4.1Hz, H-1), 5.01
(1H, dd, J = 10.3 and 1.5Hz, H-300), 4.87 (1H, ddd,
J = 17.1, 2.5 and 1.5Hz, H-300), 2.98 (1H, m, H-100),
2.70 (1H, m, H-100), 1.74 (3H, d, J = 7.0Hz, CH3); dC
(62.5MHz, CDCl3) 167.8, 160.4, 149.5, 147.0, 137.8,
134.8, 131.2, 129.3, 128.3, 128.1, 127.3, 126.8, 120.4,
120.3, 60.3, 52.3, 36.1, 19.2. C21H19N3O2 requires: C,
73.03; H, 5.54; N, 12.17. Found: C, 72.79; H, 5.43; N,
12.02%.
4.7.4.7. (À)-(1R,4S)-4-Methyl-2-phenyl-1-(p-methyl-
benzyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 18d. Mp: 70–72ꢁC (ethyl ether); yield 8%;
25
½aŠ ¼ À15:4 (c 0.30, CHCl3); mmax (KBr) 1681,
D
1596cmÀ1; dH (250MHz, CDCl3) 8.27 (1H, dd, J = 8.0
and 1.5Hz, H-7), 7.81 (1H, ddd, J = 8.3, 7.1 and
1.5Hz, H-9), 7.71 (1H, dd, J = 8.3 and 1.1Hz, H-10),
7.52–7.38 (6H, m, Ar–H), 6.95 (2H, d, J = 7.8Hz, H-
300,H-500), 6.71 (2H, d, J = 7.8Hz, H-200, H-600), 5.45
(1H, ÔtÕ, J = 4.2Hz, H-1), 4.64 (1H, ÔqÕ, J = 6.8Hz, H-
4), 3.32 (1H, dd, J = 14.2 and 4.3Hz, CH2–Ar), 3.22
(1H, dd, J = 14.2 and 4.3Hz, CH2–Ar), 2.28 (3H, s,
CH3), 1.64 (3H, d, J = 6.8Hz, CH3); dC (62.5MHz,
CDCl3) 167.2, 160.3, 150.0, 146.7, 138.3, 137.2, 134.7,
131.5, 129.4, 129.3, 129.2, 128.0, 127.7, 127.2, 127.0,
126.8, 120.6, 62.8, 52.5, 38.9, 21.0, 19.4 Found: C,
75.97; H, 5,81; N, 10,02, C26H23O2N3 requires: C,
76.26; H, 5,66; N, 10,26%.
4.7.4.4. (+)-(1S,4S)-1-Benzyl-4-methyl-2-phenyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
17c.
25
Mp: 146–148ꢁC (ethyl ether); yield 57%; ½aŠ ¼ þ79:5
D
(c 0.15, CHCl3); mmax (KBr) 2923, 1679, 1600cmÀ1; dH
(250MHz, CDCl3) 8.29 (1H, dd, J = 1.5Hz, J = 8.0Hz,
H-7), 7.79 (1H, ddd, J = 1.5Hz, J = 7.2Hz, J = 8.5Hz,
H-9), 7.62 (1H, dd, J = 1.1 and 8.5Hz, H-10), 7.51 (1H,
dd, J = 1,1 and 7.2Hz, J = 8.0Hz, H-8), 7.42 (2H, m,

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3056
4.7.4.8. (+)-(1S,4S)-1(p-Fluorobenzyl)-4-methyl-2-
phenyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
(3H, d, J = 7.1Hz, CH3); dC (62.5MHz, CDCl3) 167.4,
160.7, 150.3, 147.0, 139.1, 134.7, 132.2, 129.0, 128.6,
128.5, 128.3, 128.0, 127.0, 126.7, 120.4, 118.5, 57.4,
52.9, 53.2, 51.9, 41.4, 18.9, 16.4. C23H23O2N3 requires:
C, 73.97; H, 6.21; N, 11.25. Found: C, 73.78; H, 6.41;
N, 11.45%.
one 17e. Mp: 77–78ꢁC (ethyl ether); yield 56%;
25
½aŠ ¼ þ52:8 (c 0.50, CHCl3); mmax (KBr) 1680,
D
1601cmÀ1; dH (250MHz, CDCl3) 8.28 (1H, dd, J = 8.1
and J = 1.5Hz, H-7), 7.76 (1H, ddd, J = 8.4, 7.2 and
1.5Hz, H-9), 7.59 (1H, dd, J = 8.4 and 1.0Hz, H-10),
7.51 (1H, ddd, J = 8.1, 7.2 and 1.0Hz, H-8), 7.45–7.26
(6H, m, F–Ar–H), 6.85 (3H, m, Ar–H), 5.36 (1H, t,
J = 5.9Hz, H-1), 5.32 (1H, q, J = 7.1Hz, H-4), 3.43
(1H, dd, J = 14.0 and 5.8Hz, CH2–Ar–F), 3.23 (1H,
dd, J = 14.0 and J = 5.9Hz, CH2–Ar–F), 1.38 (3H, d,
J = 7.1Hz, CH3); dC (62.5MHz, CDCl3) 167.2, 161.8
(d, J = 24,5Hz, C-400), 161.1, 150.6, 147.8, 139.7, 135.7,
132.2 (d, J = 8,0Hz, C-200, C-60), 127.7, 131.9 (d,
J = 3.5Hz, C-100), 130.5, 128.7, 128.1, 127.9, 127.7,
121.0, 116.5 (d, J = 21.4Hz, C-300,C-500), 66.0, 53.1,
40,9, 19,3. C25H20 FN3O2 requires: C, 72.63; H, 4.60;
N, 10.16. Found: C, 72.29; H, 4.57; N, 10.39%.
4.7.5.3. (+)-(10R,1R,4S)-1-Allyl-4-methyl-2-(10-phen-
ylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
25
dione 20b. White oil, yield 5%; ½aŠ ¼ þ102 (c 0.16,
D
CHCl3); mmax (NaCl) 1682, 1662cmÀ1; dH (250MHz,
CDCl3) 8.21 (1H, dd, J = 8.0 and 1.5Hz, H-7), 7.71
(1H, ddd, J = 8.4, 6.9 and 1.5Hz, H-9), 7.52 (1H, d,d,
J = 8.4 and 1.2Hz, H-10), 7.44 (1H, ddd, J = 8.0, 6.9
and 1.2, H-8), 7.37 (5H, m, Ar–H), 5.76 (1H, q,
J = 7.2Hz, H-10), 5.52 (1H, ddd, J = 17.0, 10.2 and
7.9Hz, H-200), 5.11 (1H, q, J = 6.6Hz, H-4), 5.01 (1H,
ddd, J = 10.2, 2.5 and 1.4Hz, H-300), 4.83 (1H, ddd,
J = 17.0, 2.5 and 1.4Hz, H-300), 4.46 (1H, dd, J = 4.9
and 3.1Hz, H-1), 2.76 (1H, ddd, J = 14.3, 6.0 and
4.9Hz, H-100), 2.64 (1H, ddd, J = 14.3, 7.9 and 3.1Hz,
H-200), 1.80 (3H, d, J = 7.2Hz, CH3), 1.73 (3H, d,
J = 6.6Hz, CH3); dC (62.5MHz, CDCl3) 167.8, 160.5,
150.7, 146.8, 138.5, 134.8, 129.8, 128.9, 128.2, 127.6,
126.9, 126.8, 126.6, 121.8, 120.4, 54.3, 53.1, 41.5, 21.0,
17.9. C21H21O2N3 requires: C, 73.97; H, 6.21; N,
11.25. Found: C, 73.69; H, 6.10; N, 11.30%.
4.7.5. Alkylation of 3and 4. To a cold (À78ꢁC), mag-
netically stirred solution of 3 or 4 (c 0.5mmol) in dry
THF (10mL) was added, under argon, dropwise via
syringe a solution of lithium hexamethyldisilazide in
THF (1M, 0.6mL), followed after 10min by a solution
of the appropriate halide (0.5mmol dissolved in THF
(5mL)). The reaction mixture was stirred at À78ꢁC for
10min and 30min at 0ꢁC (10min for methyl iodide
and 45min for 4), quenched with ice and extracted with
CH2Cl2. The organic layer was dried over anhydrous
Na2SO4 and evaporated. Column chromatography of
the residue on silica gel (toluene/EtOAc, 8:2 unless
otherwise mentioned) afforded the anti-1-alkyl and
syn-1-alkyl derivatives.
4.7.5.4. (+)-(10R,1S,4S)-1-Benzyl-4-methyl-2-(10-phen-
ylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
25
dione 19c. White oil, yield 43%; ½aŠ ¼ þ120 (c 0.27,
D
CHCl3); mmax (NaCl) 1684, 1661cmÀ1; dH (250MHz,
CDCl3) 8.23 (1H, dd, J = 8.0 and 1.2Hz, H-7), 7.66
(1H, ddd, J = 8.4, 6.9 and 1.5Hz, H-9), 7.58 (1H, d,
J = 8.4Hz, H-10), 7.40 (6H, m, Ar–H and H-8), 7.10
(3H, m, H-200, H-400, H-600), 6,50 (2H, dd, J = 7.4 and
1.2Hz, H-200, H-500), 6.02 (1H, q, J = 7.0Hz, H-10),
5.32 (1H, q, J = 7.2Hz, H-4), 4.65 (1H, dd, J = 9.4
and 4.5Hz, H-1), 2.68 (1H, dd, J = 13.5 and 9.4Hz,
CH2), 2.48 (1H, dd, J = 13.5 and 4.5Hz, CH2), 1.64
(3H, d, J = 7.0Hz, CH3), 1.62 (3H, d, J = 7.2Hz,
CH3); dC (62.5MHz, CDCl3) 167.5, 160.7, 149.7,
146.8, 139.2, 135.5, 134.7, 129.2, 129.0, 128.5, 128.2,
127.8, 126.9, 126.8, 126.4, 120.3, 59.3, 53.4, 52.7, 43.0,
18.5, 16.7. C27H25O2N3 requires: C, 76.57; H, 5.95; N,
9.92. Found: C, 76.68; H, 6.22; N, 10.21%.
4.7.5.1. (+)-(10R,1S,4S)-1,4-Dimethyl-2-(10-phenyl-
ethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
one 19a. White oil,(CH2Cl2/EtOAc, 95:5); yield 76%;
25
½aŠ ¼ þ120 (c 0.30, CHCl3); mmax (NaCl) 1682,
D
1660cmÀ1; dH (250MHz, CDCl3) 8.18 (1H, dd, J = 8.0
and 1.5Hz, H-7), 7.68 (1H, ddd, J = 8.4, 6.9 and
1.5Hz, H-9), 7.54 (1H, d, J = 7.7Hz, H-10), 7.36 (6H,
m, Ar–H and H-8), 6.05 (1H, q, J = 7.1Hz, H-4), 5.34
(1H, q, J = 7.2Hz, H-1), 4.61 (1H, q, J = 7.0Hz, H-7),
1.69 (3H, d, J = 7.1Hz, CH3), 1.55 (3H, d, J = 7.2Hz,
CH3), 0.92 (3H, d, J = 7.0Hz, CH3); dC (62.5MHz,
CDCl3) 167.2, 160.4, 152.7, 147.4, 139.4, 134.8, 128.9,
128.4, 128.2, 127.1, 126.9, 120.3, 53.1, 52.9, 51.3, 44.8,
23.3, 18.6, 16.2. C21H21O2N3 requires: C, 72.60; H,
6.09; N, 12.09. Found: C, 72.43; H, 6.21; N, 12.32%.
4.7.5.5. (+)-(10R,1R,4S)-1-Benzyl-4-methyl-2-(10-phen-
ylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
25
dione 20c. White oil, yield 14%; ½aŠ ¼ þ127 (c 0.20,
D
CHCl3); mmax (NaCl) 1684, 1660cmÀ1; dH (250MHz,
CDCl3) 8.14 (1H, dd, J = 8.0 and 1.5Hz, H-7), 7.73
(1H, ddd, J = 8.4, 6.9 and 1.5Hz, H-9), 7.55 (1H, d,
J = 8.4Hz, H-10), 7.44 (1H, ddd, J = 8.0, 6,9 and
1.1Hz, H-8), 7.38 (4H, m, Ar–H), 7.20 (2H, m,
ArH), 7.10 (2H, m, ArH), 6,65 (2H, m, ArH), 5.90
(1H, q, J = 7.2Hz, H-10), 4.71 (1H, t, J = 3.7Hz, H-1),
3.67 (1H, q, J = 6,6Hz, H-4), 3.31 (1H, dd, J = 13.6
and 3.8Hz, CH2), 3.16 (1H, dd, J = 13.6 and 3.6Hz,
CH2), 1.97 (3H, d, J = 7.2Hz, CH3), 1.51 (3H, d,
J = 6.6Hz, CH3); dC (62.5MHz, CDCl3) 168.3.4,
160.4, 150.4, 146.6, 139.5, 134.6, 133.6, 129.8, 129.0,
128.5, 128.2, 127.9, 127.4, 126.7, 126.6, 126.4, 120.7,
4.7.5.2. (+)-(10R,1S,4S)-1-Allyl-4-methyl-2-(10-phenyl-
ethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-di-
25
D
one 19b. White oil, yield 36%; ½aŠ ¼ þ109:4 (c
0.27, CHCl3); mmax (NaCl) 1682, 1662cmÀ1
; dH
(250MHz, CDCl3) 8.23 (1H, dd, J = 7.7 and 1.4Hz,
H-7), 7.73 (1H, ddd, J = 8.3, 6.8 and 1.4Hz, H-9), 7.63
(1H, d, J = 8.3Hz, H-10), 7.42 (6H, m, Ar–H and H-
8), 6.04 (1H, q, J = 7.1 Hz, H-10), 5.47 (1H, m, H-200),
5.34 (1H, q, J = 7.0Hz, H-4), 4.83 (1H, ddd, J = 10.2,
2.7 and 1.5Hz, H-30), 4.53 (1H, ddd, J = 17.2, 2.7 and
1.5Hz, H-30), 4.48 (1H, dd, J = 10.2 and 4.1Hz, H-1),
1.77 (3H, d, J = 7.1Hz, CH3), 1.72 (2H, m, CH2), 1.59

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3057
58.1, 54.3, 52.9, 44.0, 20.4, 18.7. C27H25O2N3 requires:
C, 76.57; H, 5.95; N, 9.92%. Found: C, 76.46; H, 5.78;
N, 10.13%.
4.7.5.9. (À)-(10S,1R,4S)-1-Benzyl-4-methyl-2-(10-phen-
25
ylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 22. White oil, yield 14%; ½aŠ ¼ À42:4 (c 0.25,
D
CHCl3); mmax (NaCl) 1686, 1657, 1599cmÀ1
; dH
4.7.5.6.
(+)-(10R,1S,4S)-1-p-Fluorophenylmethyl-4-
(250MHz, CDCl3) 8.15 (1H, dd, J = 8.0 and 1.2Hz,
H-7), 7.76 (1H, ddd, J = 8.3, 7.1 and 1.5Hz, H-9), 7.62
(1H, d, J = 7.7Hz, H-10), 7.43 (6H, m, Ar–H and H-
8), 7.15 (4H, m, Ar–H), 7.03 (2H, m, ArH), 6.42 (2H,
m, ArH), 6.08 (1H, q, J = 7.1Hz, H-10), 4.98 (1H, t,
J = 3.8Hz, H-1), 3.55 (1H, q, J = 6.6Hz, H-4), 2.73
(1H, dd, J = 13.6 and 3.6Hz, CH2), 2,24 (1H, dd,
J = 13.6 and 4.0Hz, CH2), 1.73 (3H, d, J = 7.1Hz,
CH3), 1.49 (3H, d, J = 6.6Hz, CH3); dC (62.5MHz,
CDCl3) 167.8, 160.5, 150.6, 146.6, 139.2, 134.7, 133.6,
129.9, 129.1, 128.9, 128.5, 128.3, 127.9, 126.9, 126.8,
126.6, 120.8, 57.7, 53.2, 53.1, 42.7, 20.1, 17.7.
C27H25O2N3 requires: C, 76.50; H, 5.90; N, 9.91. Found:
C, 76.15; H, 6.11; N, 10.01%.
methyl-2-(10-phenylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 19d. White oil, (ethyl ether/hex-
25
ane 8:2); yield 72%; ½aŠ ¼ þ123:7 (c 0.27, CHCl3);
D
mmax (NaCl) 1684, 1661cmÀ1; dH (250MHz, CDCl3)
8.24 (1H, dd, J = 8.0 and 1.4Hz, H-7), 7.67 (1H, ddd,
J = 8.6, 7.0 and 1.4Hz, H-9), 7.58 (1H, d, J = 8.6Hz,
H-10), 7.46 (6, m, Ar–H and H-8), 6.72 (2H, t,
J = 8.6Hz, H-300, H-500), 6.41 (2H, dd, J = 8.6 and
5.3Hz, H-200, H-600), 6.08 (1H, q, J = 7.1Hz, H-10),
5.34 (1H, q, J = 7.2Hz, H-4), 4.57 (1H, dd, J = 9.9
and 4.2Hz, H-1), 2.65 (1H, dd, J = 13.7 and 9.9Hz,
CH2), 2.39 (1H, dd, J = 13.7 and 4.2Hz, CH2), 1.71
(3H, d, J = 7.2Hz, CH3), 1.61 (3H, d, J = 7.1Hz,
CH3); dC (62.5MHz, CDCl3) 167.5, 165.2, 160.7,
149.3, 146.7, 139.1, 134.8, 131.3, 130.9, 129.1, 128.8,
128.1, 127.2, 127.0, 126.7, 120.1, 115.2, 59.0, 53.3,
52.3, 42.2, 18.7, 16.6. C27H24O2N3F requires: C, 73.45;
H, 5,48; N, 9,52. Found: C, 73.71; H, 5.71; N, 9.77%.
4.8. General procedure for cyclization to de-‘prenyl’-
ardeemin
The corresponding 1-(3-indolylmethyl) derivative 12g or
14g (0.21mmol) was added in one portion to TFA
(5mL). The solution was stirred for 20min (compound
12g) or 2.30h (compound 14g) and was poured onto
an externally ice cooled, vigorously stirred, two phase
system of CH2Cl2 (20mL) and 20% aqueous K2CO3
(20mL). The pH of the aqueous layer was adjusted to
7 and was extracted with CHCl3. The organic layers
were dried over Na2SO4 and evaporated. The residue
was purified by chromatography (ethyl acetate/petro-
leum ether, (8:2 for 12g and 6:4 for 14g)).
4.7.5.7.
(+)-(10R,1R,4S)-1-p-Fluorophenylmethyl-4-
methyl-2-(10-phenylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]-
quinazoline-3,6-dione 20d. White solid, (ethyl ether/
25
D
hexane, 8:2); mp: 118–120ꢁC; yield 9%; ½aŠ ¼ þ92 (c
0.25, CHCl3); mmax (KBr) 1671, 1658cmÀ1
;
dH
(250MHz, CDCl3) 8.15 (1H, dd, J = 8.0 and 1.4Hz,
H-7), 7.73 (1H, ddd, J = 8.4, 6.9 and 1.4Hz, H-9), 7.54
(1H, d, J = 8.4Hz, H-10), 7.44 (1H, ddd, J = 8.0, 6.9
and 1.1Hz, H-8), 7.38 (5H, m, Ar–H), 6.80 (2H, t,
J = 8.6Hz, H-300, H-500), 6.61 (2H, dd, J = 8.6 and
5.3Hz, H-200, H-600), 5.87 (1H, q, J = 7.2Hz, H-10),
4.69 (1H, t, J = 3.8Hz, H-30), 3.86 (1H, q, J = 6.6Hz,
H-4), 3.27 (1H, dd, J = 13.8 and 4.0Hz, CH2), 3.15
(1H, dd, J = 13.8 and 3.6Hz, CH2), 1.95 (3H, d,
J = 7.2Hz, CH3), 1.54 (3H, d, J = 6.6Hz, CH3); dC
(62.5MHz, CDCl3) 168.2, 162.4, 160.3, 150.1, 146.6,
139.4, 134.7, 131.5, 129.2, 128.4, 127.6, 127.0, 126.8,
126.7, 120.6, 115.8, 58.3, 54.5, 52.9, 43.0, 20.5, 18.7.
C27H24O2N3F requires: C, 73.45; H, 5.48; N, 9.52.
Found: C, 73.62; H, 5.63; N, 9.68%.
4.8.1. (+)-(5aR,8S,15bR,16aR)-8-Methyl-5,5a,8,15b,16,
16a-hexahydro-indolo[300,200-40,50]pyrrolo[20,10-3,4]pyraz-
ino[2,1-b]quinazoline-7,10-dione 16a. Solid, yield 72%;
25
D
mp: 193–195ꢁC; ½aŠ ¼ þ203:9 (c 0.17, CHCl3);
IR (NaCl) 3336, 1676, 1605, 1469cmÀ1
;
1H NMR
(CDCl3) d 8.25 (1H, dd, J = 1.3 and 8.1Hz, H-11),
7.75 (1H, ddd, J = 1.3, 7.1 and 8.3Hz, H-13), 7.64
(1H, dd, J = 1.2 and 8.3Hz, H-14), 7.48 (1H, ddd,
J = 1.2, 7.1 and 8.1Hz, H-12), 7.22 (1H, d, J = 7.7Hz,
H-1), 7.11 (1H, dt, J = 0.8 and 7.7Hz, H-3), 6.80 (1H,
dt, J = 0.8 and 7.7Hz, H-2), 6.65 (1H, d, J = 7.7Hz,
H-4), 5.79 (1H, d, J = 6.8Hz, H-5a), 5.46 (1H, q, J =
7.2Hz, H-8), 5.19 (1H, br s, N–Hi), 4.61 (1H, dd,
J = 6.3 and 10.5Hz, H-15b), 4.13 (1H, t, J = 7.0Hz,
H-16a), 3.08 (1H, dd, J = 6.3 and 13.2Hz, H-16), 2.75
(1H, ddd, J = 7.2, 10.5 and 13.2Hz, H-16), 1.51 (3H,
d, J = 7.2Hz, CH3); 13C NMR (CDCl3) d 166.7, 159.9,
150.7, 149.0, 147.0, 134.6, 128.7, 127.3, 127.2, 127.1,
126.8, 124.2, 120.4, 119.4, 109.3, 75.9, 57.2, 53.3, 44.5,
35.8, 16.7. C21H18N4O2 requires: C, 70.38; H, 5.06; N,
15.63. Found: C, 70.12; H, 5.13; N, 15.16%.
4.7.5.8. (+)-(10S,1S,4S)-1-Benzyl-4-methyl-2-(10-phen-
ylethyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
25
dione 21. White oil, yield 46%; ½aŠ ¼ þ27:3 (c 0.33,
D
CHCl3); mmax (NaCl) 1682, 1659cmÀ1; dH (250MHz,
CDCl3) 8.23 (1H, dd, J = 8.2 and 1.3Hz, H-7), 7.65
(1H, ddd, J = 8.2, 7.1 and 1.3Hz, H-9), 7.43 (1H, ddd,
J = 8.1, 7.1 and 1.1Hz, H-8), 7.35 (1H, d, J = 8.1Hz,
H-10), 7.26 (5H, m, Ar–H), 7.18 (3H, m, ArH), 6.98
(2H, m, ArH), 5.91 (1H, q, J = 7.2Hz, H-10), 5.32 (1H,
q, J = 7.2Hz, H-4), 4.54 (1H, dd, J = 7.7 and 4.8Hz,
H-1), 3.38 (1H, dd, J = 14.0 and 4.8Hz, CH2), 3.24
(1H, dd, J = 14.0 and 7.7Hz, CH2), 1.75 (3H, d,
J = 7.2Hz, CH3), 1.53 (3H, d, J = 7.2Hz, CH3); dC
(62.5MHz, CDCl3) 167.9, 160.6, 150.1, 147.0, 138.8,
135.8, 134.6, 129.6, 129.1, 128.8, 128.4, 128.3, 127.6,
127.0, 125.4, 120.3, 59.5, 53.6, 53.0, 44.1, 18.5, 18.3.
C27H25O2N3 requires: C, 76.50; H, 5.90; N, 9.91. Found:
C, 76.71; H, 6.14; N, 10.19%.
4.8.2. (+)-(5aR,8S,15bR,16aR)-8-iso-Propyl-5,5a,8,15b,
16,16a-hexahydro-indolo[300,200-40,50]pyrrolo[20,10-3,4]-
pyrazino[2,1-b]quinazoline-7,10-dione 16b. Solid, yield
25
D
48%; mp: 124–126ꢁC; ½aŠ ¼ þ135:4 (c 0.07, CHCl3); IR
(NaCl) 3346, 1715, 1682, 1605, 1467cmÀ1
;
1H NMR
(300MHz, CDCl3) d 8.25 (1H, dd, J = 1.5 and 8.1Hz,
H-11), 7.75 (1H, ddd, J = 1.5, 7.1 and 8.3Hz, H-13),

´
F. Hernandez et al. / Tetrahedron: Asymmetry 15 (2004) 3045–3058
3058
F. Il Farmaco 2002, 57, 385–415; (c) Kawase, M.;
Motohashi, N. Curr. Drug Targets 2003, 57, 385–415.
7.65 (1H, dd, J = 1.3 and 8.3Hz, H-14), 7.48 (1H, ddd,
J = 1.3, 7.1 and 8.1Hz, H-12), 7.21 (1H, d, J = 7.6Hz,
H-1), 7.10 (1H, dt, J = 0.9 and 7.6Hz, H-3), 6.80 (1H,
dt, J = 0.9 and 7.6Hz, H-2), 6.66 (1H, d, J = 7.6Hz,
H-4), 5.78 (1H, d, J = 6.8Hz, H-5a), 5.29 (1H, d,
J = 7.9Hz, H-8), 4.65 (1H, dd, J = 6.3 and 10.4Hz,
H-15b), 4.09 (1H, t, J = 7.0Hz, H-16a), 3.07 (1H, dd,
J = 6.3 and 13.2Hz, H-16), 2.68 (1H, ddd, J = 7.2,
10.4 and 13.1Hz, H-16), 2.68 (1H, m, CH(CH3 )2),
0.99 (3H, d, J = 6.9Hz, CH3), 0.99 (3H, d,
J = 6.9Hz, CH3). 13C NMR (75MHz, CDCl3) d 165.4,
160.6, 151.6, 149.1, 146.9, 134.7, 128.8, 127.4, 127.3,
127.2, 127.1, 124.2, 120.4, 119.5, 109.2, 75.8, 62.1,
57.8, 44.5, 36.0, 31.8, 19.9, 18.8. C23H22N4O2 requires:
C, 71.48; H, 5.73; N, 14.49. Found: C, 71.22; H, 5.43;
N, 14.26%.
´
´
2. Martın-Santamarıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M.; Avendan˜o, C. J. Org. Chem. 1997, 62,
6424–6428.
´
´
3. Martın-Santamarıa, S.; Espada, M.; Avendan˜o, C. Tetra-
hedron 1997, 53, 16795–16802.
´
4. Buenadicha, F. L.; Bartolome, M. T.; Aguirre, M. J.;
Avendan˜o, C.; So¨llhuber, M. Tetrahedron: Asymmetry
1998, 9, 483–501.
5. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetrahe-
dron: Asymmetry 1998, 9, 4275–4284.
6. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetrahe-
dron: Asymmetry 2001, 12, 3019–3028.
´
7. Martın-Santamarıa, S.; Corzo-Suarez, R.; Avendan˜o, C.;
Espada, M.; Gago, F.; Garcıa-Granda, S.; Rzepa, H. S.
´
´
´
J. Org. Chem. 2002, 67, 2013–2018.
´
8. Hernandez, F.; Buenadicha, F.; Avendan˜o, C.; So¨llhuber,
M. Tetrahedron: Asymmetry 2001, 12, 3387–3398.
9. Takeuchi, S.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989,
45, 6375–6386.
Acknowledgements
10. For a detailed comment of these methods see: Avendan˜o,
´
C.; Menendez, J. C. Curr. Org. Chem. 2003, 7, 149–
Financial support from CICYT (SAF 97-0143 and SAF-
2000-0130) and research fellowships for F.H. (CAM)
and V.M. [AECI (Mutis) and SENACYT–Beca 2003],
are gratefully acknowledged.
173.
11. See similar cyclizations in: Hernandez, F.; Avendan˜o, C.;
´
So¨llhuber, M. Tetrahedron Lett. 2003, 44, 3367–
3369.
12. Sakurai, H.; Kondo, F. J. Organomet. Chem. 1976, 117,
References
149.
13. Seebach, D. Angew. Chem., Int. Ed. Engl. 1989, 28,
1. For reviews about MDR reversal agents see: (a) Aven-
277–297.
14. Orena, M.; Porzi, G.; Sandri, S. J. Org. Chem. 1992,
6532–6541.
´
dan˜o, C.; Menendez, J. C. Curr. Med. Chem. 2002, 9,
159–193; (b) Teodori, E.; Dei, S.; Scapecchi, S.; Gualtieri,