Reactivity as glycine templates of 1,2-dialkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones

Article abstract of DOI:10.1016/S0957-4166(01)00515-8

The 1-methyl(iso-propyl)-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3, 6-diones 8 and 9 could be regio- and diastereoselectively alkylated at C(4) with retention of configuration at both stereocentres.

Full text of DOI:10.1016/S0957-4166(01)00515-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3019–3028
Reactivity as glycine templates of
1,2-dialkyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones
Fe´lix L. Buenadicha, Carmen Avendan˜o* and Mo´nica So¨llhuber
Departamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 1 November 2001; accepted 12 November 2001
Abstract—The 1-methyl(iso-propyl)-2-benzyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones 8 and 9 could be regio- and
diastereoselectively alkylated at C(4) with retention of configuration at both stereocentres. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
ally have anti-configuration at C(1) and C(4) and equi-
librate to the more stable syn-isomers under
thermodynamic conditions (to minimise the 1,2-interac-
tions between the C(1) and N(2) pseudoequatorial sub-
stituents). Thus, the bulk of the C(1) and C(4)
substituents influences the resultant diastereomeric
excess.18–21 In this context we study herein how 1,2-
dialkyl - 2,4 - dihydro - 1H - pyrazino[2,1 - b]quinazoline-
diones behave in the alkylation process.
Several fungal metabolites such as fumiquinazolines F 1
and 2,1,2 fiscalin B 3,3,4 and N-acetylardeemin 45,6 are
1,4-dialkyl derivatives of the 2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione system. A com-
mon strategy in the synthesis of compounds 1–3 uses
tripeptide starting materials bearing two residues with
the desired substituents at the final C(1) and C(4)
positions and anthranilic acid as the third residue.
These tripeptides give the target molecules through
cyclodehydration to 4-imino-4H-3,1-benzoxazines.7–14
Other alternatives generally start from appropriately
substituted piperazine-2,5-diones and either involve N-
acylation with o-azidobenzoyl chloride followed by an
intramolecular Staudinger reaction, or condensation of
their lactim derivatives with anthranilic acid.15–17
2. Results and discussion
Condensation of anthranilic acid with the iminoether
derived from 1-benzyl-6-methylpiperazine-2,5-dione 6
gave 8 as a racemate, while no cyclisation was observed
with the iso-propyl derivative 7 (Scheme 1). These
results contrast with those obtained with 1,3-
dialkylpiperazine-2,5-diones, which gave enantiomeri-
cally pure 5.18,20,21
In the synthesis of analogues of 4, our group has shown
that enantiomerically pure 2,4-dialkyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazolinediones 5 can be used as
glycine templates for regio- and diastereoselective alkyl-
ation at C(1). The kinetically controlled products usu-
The alternative route outlined in Scheme 2, which
involves the N-acylation of piperazinediones 6 and 7
* Corresponding author.
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00515-8

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F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
is in accordance with C(1) epimerisation observed by
Ganesan et al. in the synthesis of fumiquinazolines F
and G through the corresponding alanylanthranyltryp-
tophan.12 These stereochemical results allow us to con-
clude that while the synthesis of C(4)-alkylated tricyclic
systems always leads to enantiomerically pure com-
pounds, in C(1) methyl systems such as 8, epimerisation
at C(1) occurs. The C(1)-iso-propyl derivatives 9 are
exceptions to this general behaviour because epimerisa-
tion is prevented by the steric bulk of the C(1)
substituent.
Scheme 1.
followed by an intramolecular Staudinger reaction, was
more convenient in this case. Thus, 8 and 9 were
obtained in acceptable yields, but only the 1-iso-propyl
derivative 9 showed satisfactory enantiomeric purity
(e.e. >95%). In the case of the 1-methyl derivative 8 the
e.e. (80%) could not be optimised, although a very good
separation of both enantiomers by analytical chiral
HPLC was observed. It is significant that this e.e. value
The alkylations of compounds 8 and 9 were performed
under reaction conditions similar to those used for their
4-alkyl analogues,18,20,21 using THF as solvent and
lithium hexamethyldisilazide as a base. The obtained
results are summarised in Table 1.
To favour kinetic conditions and avoid possible dialkyl-
ation processes, alkylations of 8 were performed at
Scheme 2.
Table 1. Alkylation of compounds 8 and 9
Entry
R1
R2
% anti compounds a
% syn compounds b
D.e.a (%)
% 4,4-dialkyl
b
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3
CH3
25 (10a)
48 (11a)
72 (12a)
88 (13a)
62 (14a)
41 (19a)
47 (20a)
71 (21a)
70 (22a)
78 (23a)
85 (24a)
74 (10b)
5 (11b)
2 (12b)
7 (13b)
49
81
94
84
72
\99
\99
\99
\99
\99
\99
c
CH2CHꢀCH2
CH2C6H5
CH2C6H4-p-CH3
CH2C6H4-p-NO2
d
CH3
10 (14b)
9 (15)
50 (25)
21 (26)
b
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH3
–
–
–
–
–
–
CH2CHꢀCH2
CH2C6H5
CH2C6H4-p-CH3
CH2C6H4-p-F
CH2C6H4-p-NO2
9
10
11
General reaction conditions: THF as solvent, LHMDS (1.2 equiv.) and alkyl halide (1 equiv.), 20 min at −78°C (entries 1, 3, 4 and 11) or 10 min
at −78°C plus 40 min at 0°C (entries 6–10).
a The ratios given are of the isolated products.
b Excess iodomethane was employed.
c Reaction times: 10 min at −78°C plus 10 min at 0°C.
d Reaction times: 10 min at −78°C.

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
3021
Figure 1. Significant NOEs and chemical shifts for compounds a and b.
−78°C. Except in the reaction with iodomethane (com-
pounds 10, entry 1), the reactions were highly
diastereoselective in favour of the anti-isomers, with
d.e. values of about 80%. It is notable that although the
syn-isomer 10b was the main isomer in this case (d.e.
49%), methylation of the 4-methyl derivatives 5 only
gave the syn-isomer.18 In the reaction with p-nitroben-
zyl bromide (entry 5) small amounts of the 4,4-dialkyl
derivative 15 were also formed, even when short reac-
tion times were used. Since the enantiomeric excess of
compounds 10–14 (both isomers), was similar to that of
the starting compound 8 (about 80%), we concluded
that the alkylation process does not affect the stereo-
genic centre at C-(1).
Although the iso-propyl derivative 9 required longer
reaction times and higher temperatures than 8, alkyl-
ation was completely diastereoselective, giving the anti-
isomers 19a–24a exclusively in enantiomerically pure
form. The boat conformation of the piperazine ring and
the axial disposition of the C(4) substituent in com-
pounds 19a–24a (anti-isomers) were also deduced from
1
NOESY experiments and H NMR data: chemical shift
values l=5.5 ppm for H-4 in all compounds and
l=3.9 ppm for H-1, which is shielded by the phenyl
ring, in compounds 21a–24a.
3. Conclusion
The configuration and conformation of compounds
10–14 were determined by NOESY experiments and
were supported by the 1H NMR chemical shifts of
significant protons (Fig. 1). The piperazine ring adopts
a boat conformation in both diastereoisomers, the C(4)-
substituent always being in a pseudoaxial disposition.
The C(4) proton resonates at l=5.5 ppm in all com-
pounds showing the characteristic anisotropic effect of
the coplanar carbonyl group at C(6) on this quasi
equatorial proton.18 As well as the observed NOEs
between the axial substituents at C(1) and C(4) in the
syn-isomers, the chemical shift at l=0.8 ppm for the
C(1)-methyl group in compounds 12b and 13b indicates
folding of the C(4)-benzyl substituent over the piper-
azine ring. In accordance, the anti-isomers 12a and 13a
show a shielding effect of the phenyl ring on the C(1)
protons.
We conclude that, in contrast to their 2-benzyl-4-
methyl(iso-propyl) analogues 5, the 2-benzyl-1-
methyl(iso-propyl) derivatives 8 and 9 can be alkylated
to give the 1,4-anti-isomers with much greater
diastereoselectivity, the anti-isomer being the only
product that is obtained in the case of compounds 9.
4. Experimental
4.1. General methods
All reagents were of commercial quality and were used
as received. Solvents were dried and purified using
standard techniques. ‘Petroleum ether’ refers to the
fraction boiling at 40–60°C. TLC was carried out on
precoated plates (Merck Kieselgel 60 F254), spots visu-
alised with UV light. Column chromatography was
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
When alkylation of 8 was forced by using 2 equiv. of
base and 2 equiv. of p-methylbenzyl bromide (10 min at
−78°C plus 20 min at 0°C) the 4,4-dialkyl derivative 16
was obtained in quantitative yield, while addition of
DMI as co-solvent in this reaction also gave the 1,4-
dialkyl 1722 and the 1,4,4-trialkyl 18 derivatives.
1
were obtained on Bruker AC-250 (250 MHz for H,
62.5 MHz for 13C) and Bruker Avance DPX-300 (300
1
MHz for H, 75 MHz for 13C) spectrometers, in CDCl3

3022
F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
unless otherwise mentioned. (Servicio de RMN, Univer-
sidad Complutense). Protons were assigned according
to COSY, HMQC and/or 1D-NOE experiments; car-
bons were assigned according to DEPT, HMQC, and/
or HMBC experiments. Optical rotation values were
4.3. (1S)-2-Benzyl-1-methyl(iso-propyl)-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-diones 8 and 9
To a cold (−78°C), magnetically stirred solution of
compound 6 or 7 (2 mmol) in dry THF (40 mL) under
argon was added, dropwise via a syringe, DMI (0.4 mL,
4 mmol) and a solution of potassium hexamethyldisil-
azide in dry toluene (0.5 M, 6 mL), followed 15 min later
by addition of a solution of 2-azidobenzoyl chloride (5
mmol). Stirring was continued for 15 min at −78°C and
then for a further 18 h at room temperature. The reaction
mixture was quenched with ice and diluted with CHCl3.
The organic layer was dried over anhydrous Na2SO4
evaporated and isolated by column chromatography
(CH2Cl2:EtOAc 9:1 for 6 and petroleum ether:EtOAc 1:1
for 7).
determined in
a
Perkin–Elmer 241 polarimeter
equipped with a 1 mL cell measuring 10 cm at 25°C,
using the emission wavelength of a sodium lamp; con-
centrations are given in g/100 mL. The enantiomeric
purity was determined by 1H NMR (addition of
europium
(III)
tris[3-heptafluoropropylhydroxy-
methylene)-(+)-camphorate] [(+)-Eu(HFC)3] as shift
reagent) and by chiral HPLC (comparison to racemic
products), employing a Constrometric 4100 system
equipped with a chiral column (Chiracel OD; 25 cm×
0.25 mm) and UV-detection at 254 nm; mobil phase:
hexane/propan-2-ol (9:1) at 1 mL/min IR spectra were
recorded on a Perkin–Elmer Paragon 1000 FT-IR spec-
trophotometer, with solid compounds compressed into
KBr pellets and liquid compounds placed as films on
NaCl disks. Elemental analyses were determined by the
Servicio de Microana´lisis, Universidad Complutense on
a Leco 932 microanalyser.
(3S)-1-(o-Azidobenzoyl)-4-benzyl-3-methylpiperazine-
2,5-dione was obtained as a pale yellow oil; yield 84%;
[h]2D5=−78.8 (c 0.27, CHCl3); wmax (NaCl) 2129, 1726,
1674 cm−1; lH (250 MHz, CDCl3) 7.46 (1H, ddd, J=8.0
Hz, J=7.5 Hz, J=1.5 Hz, H-4%), 7.31 (1H, d, J=8.1 Hz,
H-6%), 7.30 (5H, m, ArH), 7.19 (1H, dt, J=7.6 Hz, J=1.8
Hz, H-5%), 7.08 (1H, d, J=8.3 Hz, H-3%), 5.32 (1H, d,
J=15.0 Hz, N-CH2-Ar), 4.96 (1H, d, J=17.5 Hz, H-6),
4.20 (1H, d, J=17.5 Hz, H-6), 4.00 (1H, d, J=15.0 Hz,
N-CH2-Ar), 3.96 (1H, q, J=7.2 Hz, CH), 1.43 (3H, d,
J=7.2 Hz, CH3); lC (62.5 MHz, CDCl3) 169.0, 168.0,
164.1, 136.8, 135.3, 131.9, 129.3, 129.0, 128.1, 127.9,
127.0, 125.2, 118.1, 56.2, 46.9, 46.1, 17.1. C19H17O3N5
requires: C, 62.80; H, 4.72; N, 19.27. Found: C, 62.89;
H, 4.77; N, 19.10%.
4.2. (6S)-1-Benzyl-6-alkylpiperazine-2,5-diones 6 and 7
To a stirred solution of Cbz–glycine (11.0 g, 52 mmol)
and DCC (10.9 g, 52 mmol) in dry CH2Cl2 (150 mL), 52
mmol of freshly distilled ethyl N-benzylalaninate (for 6)
or ethyl N-benzylvalinate (for 7) was added, and stirring
was continued overnight. The reaction mixture was
filtered, washed successively with HCl (1 N), NaHCO3
(1 N) and water, dried over anhydrous Na2SO4 and
evaporated. The syrupy residue was hydrogenated at 35
psi for 18 h with C/Pd (10%, 1.7 g) in ethanol (200 mL),
filtered (Celite) and evaporated. The obtained white solid
6 or syrup 7 was recrystallised from ether.
(3S)-1-(o-Azidobenzoyl)-4-benzyl-3-iso-propylpiperazine-
2,5-dione was obtained as a syrup; yield 70%; [h]2D5=
−108.3 (c 0.26, CHCl3); wmax (NaCl) 2129, 1724, 1676
cm−1; lH (250 MHz, CDCl3), 7.44 (1H, ddd, J=8.0 Hz,
J=7.6 Hz, J=1.5 Hz, H-4%), 7.33 (3H, m, ArH), 7.25
(3H, m, ArH), 7.18 (1H, ddd, J=7.6 Hz, J=7.5 Hz,
J=1.0 Hz, H-5%), 7.06 (1H, dd, J=8.1 Hz, J=0.5 Hz,
H-3%), 5.57 (1H, d, J=14.9 Hz, N-CH2-Ar), 4.89 (1H, d,
J=17.8 Hz, H-6), 4.26 (1H, d, J=17.8 Hz, H-6), 3.85
(1H, d, J=14.9 Hz, N-CH2-Ar), 3.70 (1H, d, J=6.0 Hz,
4.2.1. (6S)-1-Benzyl-6-methylpiperazine-2,5-dione 6.
Yield 88%; mp 175–176.5°C; [h]2D5=+30.0 (c 0.26,
CHCl3); wmax (KBr) 3246, 1696, 1654 cm−1; lH (250 MHz,
CDCl3) 7.29 (5H, m, ArH), 6.14 (1H, s, NH), 5.21 (1H,
d, J=14.8 Hz, N-CH2-Ar), 4.08 (1H, d, J=17.3 Hz,
H-5), 4.02 (1H, d, J=14.8 Hz, N-CH2-Ar), 3.98 (1H, dd,
J=17.3 Hz, J=3.5 Hz, H-5), 3.86 (1H, q, J=7.1 Hz,
H-2), 1.45 (3H, d, J=7.1 Hz, CH3); lC (62.5 MHz,
CDCl3) 169.8, 164.0, 135.6, 129.0, 128.3, 128.2, 55.1,
47.3, 44.9, 17.5. C12H14O2N2 requires: C, 66.04; H, 6.47;
N, 12.84. Found: C, 65.77; H, 6.55; N, 12.72%.
H-3), 2.27 (1H, sep, J=6.7 Hz, CH6 (CH3)2), 1.06 (3H, d,
J=6.9 Hz, CH3), 1.02 (3H, d, J=6.9 Hz, CH3); lC (62.5
MHz, CDCl3), 168.2, 167.2, 164.5, 136.6, 135.3, 131.9,
129.2, 128.4, 128.3, 128.1, 125.2, 118.0, 65.9, 48.4, 46.7,
32.4, 20.0, 18.6. C21H21O3N5 requires: C, 64.44; H, 5.41;
N, 17.89. Found: C, 64.03; H, 5.42; N, 17.75%.
To a solution of the corresponding 1-(o-azidobenzoyl)-4-
benzyl-3-alkylpiperazine-2,5-dione (1.9 mmol) in dry
toluene (10 mL) was added tributylphosphine (3.8
mmol). The mixture was stirred under argon for 48 h at
room temperature 8, or was heated under reflux for 4.5
h under argon 9, and evaporated under reduced pressure.
The residue was chromatographed on a silica gel column
(ether).
4.2.2. (6S)-1-Benzyl-6-iso-propylpiperazine-2,5-dione 7.
Yield 91%; mp: 84–85°C. [h]2D5=+12 (c 0.25, CHCl3); wmax
(KBr) 3210, 1671, 1647 cm−1; lH (250 MHz, CDCl3), 7.3
(5H, m, ArH), 6.83 (1H, s, NH), 5.41 (1H, d, J=15 Hz,
N-CH2-Ar), 4.11 (1H, d, J=17.5 Hz, H-5), 3.95 (1H, d,
J=17.5 Hz, H-5), 3.89 (1H, d, J=15 Hz, N-CH2-Ar),
3.64 (1H, d, J=4.7 Hz, H-1), 2.24 (1H, m, J=6.9, J=4.9
Hz, CH6 (CH3)2), 1.1 (3H, d, J=6.9 Hz, CH3), 1.02 (3H,
d, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3), 167.9, 164.6,
135.4, 128.8, 127.9, 127.9, 64.5, 48.1, 45.1, 38.0, 19.7,
17.6. C14H18O2N2 requires: C, 68.27; H, 7.37; N, 11.37.
Found: C, 68.16; H, 7.45; N, 11.25%.
4.3.1. (1S)-2-Benzyl-1-methyl-2,4-dihydro-1H-pyrazino-
[2,1-b]quinazoline-3,6-dione 8. Compound 8 was obtained
as a pale yellow solid; yield 73%; mp 136–137°C (ether);
wmax (KBr) 1667, 1610 cm−1; lH (250 MHz, CDCl3) 8.27

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
3023
(1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 7.74 (1H, ddd,
J=8.1 Hz, J=7.2 Hz, J=1.5 Hz, H-9), 7.56 (1H, dd,
J=8.1 Hz, J=1.0 Hz, H-10), 7.48 (1H, ddd, J=8.0 Hz,
J=7.2 Hz, J=1.0 Hz, H-8), 7.30 (5H, m, ArH), 5.36
(1H, d, J=18.3 Hz, H-4), 5.10 (1H, d, J=14.8 Hz,
N-CH2-Ar), 4.53 (1H, q, J=7.1 Hz, H-1), 4.33 (1H, d,
J=14.8 Hz, N-CH2-Ar), 4.16 (1H, d, J=18.3 Hz, H-4),
1.46 (3H, d, J=7.1 Hz, CH3); lC (62.5 MHz, CDCl3)
163.9, 160.2, 151.6, 147.1, 135.5, 134.6, 128.9, 128.3,
128.1, 127.1, 126.9, 126.7, 119.9, 56.3, 47.8, 44.4, 19.0.
C19H17O2N3 requires: C, 71.46; H, 5.37; N, 13.16.
Found: C, 71.21; H, 5.40; N, 13.00%.
72.05; H, 5.74; N, 12.60. Found: C, 71.95; H, 5.97; N,
12.32%.
4.4.1.2.
(1S,4S)-2-Benzyl-1,4-dimethyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 10b. Com-
pound 10b was obtained (toluene:EtOAc 8:2) as a pale
yellow oil; yield 74%; wmax (NaCl) 1684, 1659 cm−1; lH
(250 MHz, CDCl3) 8.22 (1H, dd, J=8.0 Hz, J=1.2 Hz,
H-7), 7.69 (1H, ddd, J=8.2 Hz, J=7.0 Hz, J=1.5 Hz,
H-9), 7.52 (1H, ddd, J=8.0 Hz, J=1.5 Hz, J=0.6 Hz,
H-10), 7.42 (1H, ddd, J=8.2 Hz, J=7.3 Hz, J=1.2 Hz,
H-8), 7.26 (5H, m, ArH), 5.39 (1H, q, J=7.0 Hz, H-4),
5.30 (1H, d, J=15.0 Hz, N-CH2-Ar), 4.53 (1H, q,
J=7.0 Hz, H-1), 4.13 (1H, d, J=15.0 Hz, N-CH2-Ar),
1.73 (3H, d, J=7.0 Hz, C(4)-CH3), 1.63 (3H, d, J=7.0
Hz, C(1)-CH3); lC (62.5 MHz, CDCl3) 167.2, 160.4,
151.7, 147.4, 135.6, 134.8, 128.9, 128.3, 128.1, 126.9,
126.7, 126.6, 120.1, 55.8, 52.2, 47.6, 21.4, 19.2.
C20H19O2N3 requires: C, 72.05; H, 5.74; N, 12.60.
Found: C, 71.90; H, 5.75; N, 12.72%.
4.3.2.
(1S)-2-Benzyl-1-iso-propyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione 9. Compound
9
was obtained as a yellow oil; yield 80%; [h]2D5=−82.5 (c
0.27, CHCl3); wmax (NaCl) 1676, 1608 cm−1; lH (250
MHz, CDCl3), 8.24 (1H, dd, J=8, J=1.4 Hz, H-7),
7.72 (1H, ddd, J=8.1, J=6.9, J=1.4 Hz, H-9), 7.57
(1H, dd, J=8.1, J=1.1 Hz, H-10), 7.46 (1H, ddd, J=8,
J=6.9, J=1.1 Hz, H-8), 7.21 (5H, m, ArH), 5.54 (1H,
d, J=15 Hz, N-CH2-Ar), 5.26 (1H, d, J=18.6 Hz,
H-4), 4.31 (1H, d, J=18.6 Hz, H-4), 4.20 (1H, d, J=7.1
Hz, H-1), 4.03 (1H, d, J=15 Hz, N-CH2-Ar), 2.28 (1H,
4.4.1.3.
(1S,4R)-4-Allyl-2-benzyl-1-methyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 11a. Com-
pound 11a was obtained (toluene:EtOAc 8:2 or
CH2Cl2:EtOAc 9:1) as a pale yellow oil; yield 48%; wmax
(NaCl) 1682, 1603 cm−1; lH (250 MHz, CDCl3) 8.26
(1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 7.74 (1H, ddd,
J=8.4 Hz, J=7.1 Hz, J=1.5 Hz, H-9), 7.62 (1H, dd,
J=8.4 Hz, J=1.2 Hz, H-10), 7.47 (1H, ddd, J=8.0 Hz,
J=7.1 Hz, J=1.2 Hz, H-8), 7.29 (5H, m, ArH), 5.76
(1H, ddt, J=16.2 Hz, J=10.8 Hz, J=7.4 Hz, H-2%),
5.60 (1H, t, J=6.0 Hz, H-4), 5.47 (1H, d, J=15.5 Hz,
N-CH2-Ar), 5.02 (1H, d, J=10.8 Hz, H-3%), 4.97 (1H,
dd, J=16.2 Hz, J=1.4 Hz, H-3%), 4.68 (1H, q, J=6.7
Hz, H-1), 4.25 (1H, d, J=15.5 Hz, N-CH2-Ar), 2.90
(1H, ddd, J=14.1 Hz, J=7.4 Hz, J=6.0 Hz, H-1%),
2.88 (1H, ddd, J=14.1 Hz, J=7.4 Hz, J=6.0 Hz,
H-1%), 1.77 (3H, d, J=6.7 Hz, CH3); lC (62.5 MHz,
CDCl3) 167.1, 160.4, 151.3, 147.0, 136.2, 134.5, 131.2,
128.8, 127.7, 127.5, 127.3, 127.1, 126.7, 120.2, 120.0,
55.4, 53.2, 45.8, 36.2, 17.4. C22H21O2N3 requires: C,
73.52; H, 5.89; N, 11.69. Found: C, 73.34; H, 5.99; N,
11.82%.
m, J=6.8 Hz, CH6 (CH3)2), 1.14 (3H, d, J=6.8 Hz,
CH3), 0.95 (3H, d, J=6.8 Hz, CH3); lC (62.5 MHz,
CDCl3), 164.3, 160.4, 149.5, 146.7, 135.2, 134.6, 128.8,
128.0, 127.9, 127.2, 127.1, 126.7, 119.8, 65.9, 49.5, 45.2,
33.7, 20.1, 18.9. C21H21O2N3 requires: C, 72.60; H, 6.09;
N, 12.10. Found: C, 72.65; H, 5.93; N, 11.98%.
4.4. General alkylation procedures
4.4.1. Monoalkylation of 8. To a cold (−78°C), magnet-
ically stirred solution of 8 (0.5 mmol) in dry THF (10
mL) was added, under argon, dropwise via syringe, a
solution of lithium hexamethyldisilazide in THF (1 M,
0.6 mL), followed by a solution of the appropriate
halide (0.5 mmol dissolved in THF (5 mL)) 10 min
later. The reaction mixture was stirred at −78°C for 20
min (10 min for 14; 10 min at −78°C and 10 min at 0°C
for 11), quenched with ice, and diluted with CH2Cl2.
The organic layer was dried over anhydrous Na2SO4
and evaporated. Column chromatography of the
residue on silica gel (toluene:EtOAc or CH2Cl2: EtOAc)
afforded first the dialkylated, if any, followed by the
anti-4-alkylated and the syn-4-alkylated compounds.
4.4.1.4.
(1S,4S)-4-Allyl-2-benzyl-1-methyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 11b. Com-
pound 11b was obtained (toluene:ethyl acetate 8:2 or
CH2Cl2:EtOAc 9:1) as a pale yellow oil; yield 5%; wmax
(NaCl) 1680, 1666 cm−1; lH (250 MHz, CDCl3) 8.25
(1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 7.72 (1H, ddd,
J=8.2 Hz, J=7.1 Hz, J=1.5 Hz, H-9), 7.54 (1H, dd,
J=8.2 Hz, J=1.2 Hz, H-10), 7.46 (1H, ddd, J=8.2 Hz,
J=7.1 Hz, J=1.2 Hz, H-8), 7.31 (5H, m, ArH), 5.94
(1H, ddt, J=14.6 Hz, J=10.2 Hz, J=7.3 Hz, H-2%),
5.47 (1H, t, J=7 Hz, H-4), 5.30 (1H, d, J=14.9 Hz,
N-CH2-Ar), 5.10 (1H, d, J=10.2 Hz, H-3%), 5.05 (1H,
d, J=14.6 Hz, H-3%), 4.57 (1H, q, J=7.1 Hz, H-1), 4.19
(1H, d, J=14.9 Hz, N-CH2-Ar), 2.84 (2H, t, J=7 Hz,
H-1%), 1.69 (3H, d, J=7.1 Hz, CH3), lC (62.5 MHz,
CDCl3) 165.5, 160.5, 151.8, 147.1, 135.4, 134.7, 132.5,
128.9, 128.3, 128.1, 126.9, 126.8, 126.7, 120.3, 119.1,
55.8, 55.6, 47.6, 38.4, 21.7. C22H21O2N3 requires: C,
73.52; H, 5.89; N, 11.69. Found: C, 73.60; H, 5.95; N,
11.72%.
4.4.1.1.
(1S,4R)-2-Benzyl-1,4-dimethyl-2,4-dihydro-
1H-pyrazino[2,1-b]quinazoline-3,6-dione 10a. Com-
pound 10a was obtained (toluene:EtOAc 8:2) as a pale
yellow oil; yield 25%; wmax (NaCl) 1682, 1602 cm−1; lH
(250 MHz, CDCl3) 8.27 (1H, dd, J=1.4 Hz, J=8.1 Hz,
H-7), 7.74 (1H, ddd, J=1.4 Hz, J=7.0 Hz, J=8.4 Hz,
H-9), 7.63 (1H, dd, J=1.3 Hz, J=8.4 Hz, H-10), 7.47
(1H, ddd, J=1.3 Hz, J=7.0 Hz, J=8.1 Hz, H-8), 7.33
(5H, m, ArH), 5.60 (1H, q, J=7.1 Hz, H-4), 5.45 (1H,
d, J=15.7 Hz, N-CH2-Ar), 4.67 (1H, q, J=6.7 Hz,
H-1), 4.30 (1H, d, J=15.7 Hz, N-CH2-Ar), 1.79 (3H, d,
J=6.7 Hz, CH3), 1.69 (3H, d, J=7.1 Hz, CH3); lC
(62.5 MHz, CDCl3) 168.8, 160.2, 150.8, 147.0, 136.5,
134.5, 128.9, 127.6, 127.4, 127.1, 127.0, 126.7, 120.4,
52.7, 51.9, 45.4, 17.1, 16.1. C20H19O2N3 requires: C,

3024
F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
4.4.1.5.
(1S,4R)-2,4-Dibenzyl-1-methyl-2,4-dihydro-
4.4.1.8. (1S,4S)-2-Benzyl-1-methyl-4-p-methylbenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 13b.
Compound 13b was obtained (toluene:EtOAc 9:1)
as an oil; yield 7%; wmax (NaCl) 1684 cm−1; lH (250
MHz, CDCl3) 8.30 (1H, dd, J=8.0 Hz, J=1.5 Hz,
H-7), 7.75 (1H, ddd, J=8.4 Hz, J=7.1 Hz, J=1.5 Hz,
H-9), 7.53 (1H, dd, J=8.4 Hz, J=1.1 Hz, H-10), 7.48
(1H, ddd, J=8.0 Hz, J=7.1 Hz, J=1.1 Hz, H-8), 7.27
(5H, m, ArH), 7.00 (2H, d, J=8.0 Hz, H-3%,5%), 6.90
(2H, d, J=8.0 Hz, H-2%,6%), 5.58 (1H, t, J=5.0 Hz,
H-4), 5.45 (1H, d, J=14.7 Hz, N-CH2-Ar), 4.35 (1H, q,
J=7.0 Hz, H-1), 3.90 (1H, d, J=14.7 Hz, N-CH2-Ar),
3.56 (1H, dd, J=14.3 Hz, J=5.2 Hz, C(4)-CH2), 3.49
(1H, dd, J=14.3 Hz, J=4.8 Hz, C(4)-CH2), 2.25 (3H,
s, CH3), 0.8 (3H, d, J=7.0 Hz, CH3); lC (62.5 MHz,
CDCl3) 164.8, 160.5, 151.8, 147.1, 137.1, 135.2, 134.7,
132.4, 129.9, 129.4, 128.8, 128.5, 128.0, 126.7, 126.6,
120.0, 57.3, 54.9, 46.6, 36.9, 20.9, 19.7. C27H25O2N3
requires: C, 76.57; H, 5.95; N, 9.92. Found: C, 76.71;
H, 5.98; N, 9.81%.
1H-pyrazino[2,1-b]quinazoline-3,6-dione 12a. Com-
pound 12a was obtained (toluene:EtOAc 8:2) as a wax;
yield 72%; wmax (KBr) 1682, 1595 cm−1; lH (250 MHz,
CDCl3) 8.31 (1H, dd, J=8.0 Hz, J=1.4 Hz, H-7), 7.75
(1H, ddd, J=8.0 Hz, J=7.0 Hz, J=1.4 Hz, H-9), 7.59
(1H, dd, J=8.0 Hz, J=1.0 Hz, H-10), 7.50 (1H, dd,
J=8.0 Hz, J=7.0 Hz, J=1.0 Hz, H-8), 7.29 (3H, m,
ArH), 7.15 (3H, m, ArH), 7.02 (2H, m, ArH), 6.79 (2H,
m, ArH), 5.73 (1H, dd, J=6.6 Hz, J=5.0 Hz, H-4),
4.84 (1H, d, J=15.4 Hz, N-CH2-Ar), 4.50 (1H, d,
J=15.4 Hz, N-CH2-Ar), 3.53 (1H, dd, J=5.0 Hz,
J=14.0 Hz, C(4)-CH2), 3.47 (1H, dd, J=14.0 Hz,
J=6.6 Hz, C(4)-CH2), 3.35 (1H, q, J=6.7 Hz, H-1),
1.52 (1H, d, J=6.7 Hz, CH3), lC (62.5 MHz, CDCl3)
166.8, 160.5, 151.6, 147.0, 136.3, 134.9, 134.7, 129.6,
128.5, 127.8, 127.5, 127.4, 127.2, 127.0, 126.7, 120.1,
56.7, 53.6, 46.7, 37.2, 18.6. C26H23O2N3 requires: C,
76.26; H, 5.66; N, 10.25. Found: C, 75.90; H, 5.42; N,
10.05%.
4.4.1.9.
(1S,4R)-2-Benzyl-1-methyl-4-p-nitrobenzyl-
4.4.1.6.
(1S,4S)-2,4-Dibenzyl-1-methyl-2,4-dihydro-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14a.
Compound 14a was obtained (toluene:EtOAc 9:1)
as a pale yellow solid; yield 62%; mp 82–84°C; wmax
(KBr) 1669, 1647, 1343 cm−1; lH (250 MHz, CDCl3)
8.28 (1H, dd, J=7.9 Hz, J=1.5 Hz, H-7), 7.82 (2H, d,
J=8.6 Hz, H-3%,5%), 7.76 (1H, ddd, J=8.0 Hz, J=7.1
Hz, J=1.5 Hz, H-9), 7.60 (1H, dd, J=8.0 Hz, J=1.0
Hz, H-10), 7.50 (1H, ddd, J=7.9 Hz, J=7.1 Hz, J=1.0
Hz, H-8), 7.30 (3H, m, ArH), 7.18 (2H, m, ArH), 6.95
(2H, d, J=8.6 Hz, H-2%,6%), 5.69 (1H, dd, J=5.9 Hz,
J=4.3 Hz, H-4), 5.24 (1H, d, J=15.2 Hz, N-CH2-Ar),
4.27 (1H, d, J=15.2 Hz, N-CH2-Ar), 3.92 (1H, q,
J=6.7 Hz, H-1), 3.57 (1H, dd, J=13.8 Hz, J=5.9 Hz,
C(4)-CH2), 3.48 (1H, dd, J=13.8 Hz, J=4.3 Hz, C(4)-
CH2), 1.67 (3H, d, J=6.7 Hz, CH3); lC (62.5 MHz,
CDCl3) 165.6, 160.5, 150.9, 147.1, 146.8, 142.7, 135.7,
135.0, 130.4, 128.7, 128.1, 128.0, 127.4, 127.3, 126.6,
123.5, 120.0, 56.2, 53.5, 46.2, 36.9, 18.9. C26H22O4N4
requires: C, 68.71; H, 4.88; N, 12.33. Found: C, 68.91;
H, 5.00; N, 12.61%.
1H-pyrazino[2,1-b]quinazoline-3,6-dione 12b. Com-
pound 12b was obtained (toluene:EtOAc 8:2) as a white
solid; yield 2%; mp 124–126°C; wmax (KBr) 1684, 1654
cm−1; lH (250 MHz, CDCl3) 8.30 (1H, dd, J=8.0 Hz,
J=1.3 Hz, H-7), 7.75 (1H, ddd, J=8.1 Hz, J=7.1 Hz,
J=1.3 Hz, H-9), 7.55 (1H, dd, J=8.1 Hz, J=1.0 Hz,
H-10), 7.48 (1H, ddd, J=8.0 Hz, J=7.1 Hz, J=1.0 Hz,
H-8), 7.25 (5H, m, ArH), 7.18 (3H, m, ArH), 7.03 (2H,
m, ArH), 5.59 (1H, t, J=5.0 Hz, H-4), 5.15 (1H, d,
J=14.8 Hz, N-CH2-Ar), 4.37 (1H, q, J=7.0 Hz, H-1),
3.93 (1H, d, J=14.8 Hz, N-CH2-Ar), 3.59 (1H, dd,
J=14.1 Hz, J=5.2 Hz, C(4)-CH2), 3.52 (1H, dd, J=
14.1 Hz, J=4.8 Hz, C(4)-CH2), 0.75 (3H, d, J=7.0 Hz,
CH3); lC (62.5 MHz, CDCl3) 164.7, 160.4, 151.9, 146.8,
135.5, 135.1, 134.8, 130.1, 128.8, 128.7, 128.5, 128.1,
127.5, 126.9, 126.8, 126.4, 119.8, 57.2, 54.8, 46.7, 37.2,
19.8. C26H23O2N3 requires: C, 76.26; H, 5.66; N, 10.25.
Found: C, 76.01; H, 5.74; N, 10.34%.
4.4.1.7. (1S,4R)-2-Benzyl-1-methyl-4-p-methylbenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 13a.
Compound 13a was obtained (toluene:EtOAc 9:1)
as an oil; yield 88%; wmax (NaCl) 1682 cm−1; lH (250
MHz, CDCl3) 8.32 (1H, dd, J=8.0 Hz, J=1.5 Hz,
H-7), 7.75 (1H, ddd, J=8.4 Hz, J=7.2 Hz, J=1.5 Hz,
H-9), 7.59 (1H, dd, J=8.4 Hz, J=1.1 Hz, H-10), 7.50
(1H, ddd, J=8.0 Hz, J=7.2 Hz, J=1.1 Hz, H-8), 7.28
(3H, m, ArH), 7.12 (2H, m, ArH), 6.86 (2H, d, J=8.0
Hz, H-3%,5%), 6.68 (2H, d, J=8.0 Hz, H-2%,6%), 5.71 (1H,
dd, J=6.6 Hz, J=5.0 Hz, H-4), 4.85 (1H, d, J=15.4
Hz, N-CH2-Ar), 4.51 (1H, d, J=15.4 Hz, N-CH2-Ar),
3.48 (1H, dd, J=14.2 Hz, J=5.0 Hz, C(4)-CH2), 3.42
(1H, dd, J=14.2 Hz, J=6.6 Hz, C(4)-CH2), 3.41 (1H,
q, J=6.7 Hz, H-1), 2.23 (3H, s, CH3), 1.52 (3H, d,
J=6.7 Hz, CH3); lC (62.5 MHz, CDCl3) 166.8, 160.5,
151.7, 147.0, 137.1, 136.3, 134.6, 131.7, 129.5, 129.2,
128.5, 127.7, 127.4, 127.2, 127.0, 126.7, 120.1, 56.8,
53.7, 46.7, 36.8, 21.0, 18.7. C27H25O2N3 requires: C,
76.57; H, 5.95; N, 9.92. Found: C, 76.65; H, 5.85; N,
9.79%.
4.4.1.10. (1S,4S)-2-Benzyl-1-methyl-4-p-nitrobenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 14b.
Compound 14b was obtained (toluene:EtOAc 9:1)
as a pale yellow oil; yield 10%; wmax (NaCl) 1682, 1602,
1346 cm−1; lH (250 MHz, CDCl3) 8.27 (1H, dd, J=8.0
Hz, J=1.5 Hz, H-7), 8.15 (2H, d, J=8.4 Hz, H-3%,5%),
7.77 (1H, ddd, J=8.1 Hz, J=7.0 Hz, J=1.5 Hz, H-9),
7.57 (1H, dd, J=8.1 Hz, J=1.0 Hz, H-10), 7.51 (1H,
ddd, J=8.0 Hz, J=7.0 Hz, J=1.0 Hz, H-8), 7.40 (2H,
d, J=8.4 Hz, H-2%,6%), 7.28 (5H, m, ArH), 5.56 (1H, dd,
J=7.5 Hz, J=4.2 Hz, H-4), 5.31 (1H, d, J=14.7 Hz,
N-CH2-Ar), 4.53 (1H, q, J=7.0 Hz, H-1), 4.07 (1H, d,
J=14.7 Hz, N-CH2-Ar), 3.55 (1H, dd, J=13.6 Hz,
J=4.2 Hz, C(4)-CH2), 3.45 (1H, dd, J=13.6 Hz, J=7.5
Hz, C(4)-CH2), 1.26 (1H, d, J=7.0 Hz, CH3); lC (62.5
MHz, CDCl3) 164.3, 163.3, 151.4, 147.2, 146.5, 143.6,
135.2, 135.0, 130.7, 129.0, 128.5, 128.3, 127.4, 126.8,
126.6, 123.8, 119.7, 56.7, 55.1, 47.4, 38.6, 21.7.
C26H22O4N4 requires: C, 68.71; H, 4.88; N, 12.33.
Found: C, 68.49; H, 4.63; N, 12.29%.

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
3025
4.4.1.11. (1S)-2-Benzyl-1-methyl-4,4-bis(p-nitrobenzyl-
2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 15.
Compound 15 was obtained (toluene:EtOAc 9:1) as an
oil; wmax (NaCl) 1681, 1653 cm−1; lH (250 MHz, CDCl3)
8.41 (1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 8.05 (2H, d,
J=8.7 Hz, H-3¦,5¦), 7.78 (1H, ddd, J=8.0 Hz, J=7.0
Hz, J=1.5 Hz, H-9), 7.63 (2H, d, J=8.7 Hz, H-3%,5%),
7.57 (1H, ddd, J=8.0 Hz, J=7.0 Hz, J=1.0 Hz, H-8),
7.43 (1H, d, J=8.0 Hz, H-10), 7.32 (2H, d, J=8.7 Hz,
H-2¦,6¦), 7.27 (3H, m, ArH), 7.00 (2H, m, ArH), 6.86
(2H, d, J=8.7 Hz, H-2%,6%), 5.35 (1H, d, J=14.5 Hz,
N-CH2-Ar), 4.85 (1H, d, J=13.2 Hz, C(4)-CH2), 4.50
(1H, d, J=13.5 Hz, C(4)-CH2), 3.95 (1H, q, J=6.8 Hz,
H-1), 3.88 (1H, d, J=13.2 Hz, C(4)-CH2), 3.84 (1H, d,
J=13.5 Hz, C(4)-CH2), 3.72 (1H, d, J=14.5 Hz, N-
CH2-Ar), 0.38 (3H, d, J=6.8 Hz, CH3); lC (62.5 MHz,
CDCl3) 165.4, 163.1, 151.2, 147.2, 146.9, 145.9, 143.6,
142.7, 135.4, 133.9, 131.3, 130.4, 128.8, 128.7, 128.1,
127.7, 126.9, 126.6, 123.8, 123.3, 120.6, 72.9, 53.7, 47.4,
40.9, 40.6, 21.4. C33H27O6N5 requires: C, 67.22; H, 4.62;
N, 11.88. Found: C, 67.35; H, 4.82; N, 11.93%.
hexamethyldisilazide in THF (1 M, 1.1 mL), followed
10 min later by addition of a solution of p-methylben-
zyl bromide (1 mmol) in THF (5 mL). The reaction
mixture was stirred at −78°C for 10 min and 15 min at
0°C, quenched with ice and diluted with CH2Cl2. The
organic layer was dried over anhydrous Na2SO4 and
evaporated. Column chromatography of the residue on
silica gel (toluene:EtOAc 9:1) afforded 18, 17, and 16 in
4, 19 and 30% yield, respectively.
4.4.3.1. 2-Benzyl-1,4,4-tris(p-methylbenzyl)-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 18. Com-
pound 18 was obtained (toluene:EtOAc 9:1) as a wax;
wmax (NaCl) 1681, 1651 cm−1; lH (250 MHz, CDCl3)
8.41 (1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 7.68 (1H,
ddd, J=8.5 Hz, J=7.2 Hz, J=1.5 Hz, H-9), 7.51 (1H,
ddd, J=8.0 Hz, J=7.2 Hz, J=1.2 Hz, H-8), 7.23 (3H,
m, ArH); 7.15 (5H, m, ArH, H-3%,5%,10), 6.98 (2H, d,
J=7.8 Hz, H-2%,6%), 6.75 (2H, d, J=7.7 Hz, H-3¦,5¦),
6.63 (2H, d, J=7.8 Hz, H-3§,5§), 6.48 (2H, d, J=7.8
Hz, H-2§,6§), 6.32 (2H, d, J=7.8 Hz, H-2¦,6¦), 4.80
(1H, d, J=15.2 Hz, N-CH2-Ar), 4.48 (1H, d, J=13.5
Hz, C(4)-CH2), 4.28 (1H, d, J=13.7 Hz, C(4)-CH2),
4.19 (1H, d, J=15.2 Hz, N-CH2-Ar), 3.73 (1H, d,
J=13.5 Hz, C(4)-CH2), 3.47 (1H, d, J=13.7 Hz, C(4)-
CH2), 2.25 (1H, d, J=13.8 Hz, C(1)-CH2), 2.18 (3H, s,
CH3), 2.10 (3H, s, CH3), 2.09 (3H, s, CH3), 1.56 (1H, d,
J=13.8 Hz, C(1)-CH2), 1.20 (3H, s, CH3); lC (62.5
MHz, CDCl3) 167.5, 163.3, 152.4, 145.6, 137.3, 136.8,
136.1, 135.9, 134.2, 133.8, 132.8, 132.6, 130.5, 130.2,
129.6, 129.1, 128.6, 128.5, 128.0, 127.9, 127.0, 126.9,
126.8, 126.7, 121.3, 73.5, 64.6, 48.2, 47.5, 40.9, 40.6,
25.6, 20.9, 20.8. C43H41O2N3 requires: C, 81.74; H, 6.54;
N, 6.65. Found: C, 81.83; H, 6.64; N, 6.75%.
4.4.2. 4,4-Dialkylation of 8. To a cold (−78°C), magnet-
ically stirred solution of 8 (0.5 mmol) in dry THF (10
mL) under argon was added, dropwise via syringe, a
solution of lithium hexamethyldisilazide in THF (1 M,
1.1 mL), followed 10 min later by the addition of a
solution of p-methylbenzyl bromide (1 mmol dissolved
in THF (5 mL)). The reaction mixture was stirred at
−78°C for 3 min and 20 min at 0°C, quenched with ice
and diluted with CH2Cl2. The organic layer was dried
over anhydrous Na2SO4 and evaporated. Column chro-
matography of the residue on silica gel (toluene:EtOAc
9:1) afforded 16 in quantitative yield.
4.4.2.1. (1S)-2-Benzyl-1-methyl-4,4-bis(p-methylben-
zyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
16. Compound 16 was obtained (toluene:EtOAc 9:1) as
an oil; wmax (NaCl) 1682, 1654 cm−1; lH (250 MHz,
CDCl3) 8.42 (1H, dd, J=8.0 Hz, J=1.5 Hz, H-7), 7.72
(1H, ddd, J=8.5 Hz, J=7.1 Hz, J=1.5 Hz, H-9), 7.51
(1H, ddd, J=8.0 Hz, J=7.1 Hz, J=1.1 Hz, H-8), 7.39
(1H, dd, J=8.5 Hz, J=1.1 Hz, H-10), 7.25 (3H, m,
ArH), 6.99 (2H, d, J=8.1 Hz, H-3%,5%), 6.94 (2H, d,
J=8.1 Hz, H-2%,6%), 6.78 (2H, m, ArH), 6.72 (2H, d,
J=8.2 Hz, H-3¦,5¦), 6.68 (2H, d, J=8.2 Hz, H-2¦,6¦),
5.47 (1H, d, J=14.9 Hz, N-CH2-Ar), 4.65 (1H, d,
J=13.4 Hz, C(4)-CH2), 4.39 (1H, d, J=13.7 Hz, C(4)-
CH2), 3.78 (1H, q, J=6.8 Hz, H-1), 3.68 (1H, d,
J=14.9 Hz, N-CH2-Ar), 3.66 (1H, d, J=13.4 Hz,
C(4)-CH2), 3.65 (1H, d, J=13.7 Hz, C(4)-CH2), 2.19
(3H, s, CH3), 2.17 (3H, s, CH3), 0.28 (3H, d, J=6.8 Hz,
CH3); lC (62.5 MHz, CDCl3) 166.4, 162.9, 152.5, 146.3,
136.7, 136.2, 134.6, 134.3, 133.4, 132.7, 130.2, 129.5,
129.2, 128.9, 128.5, 128.4, 127.7, 127.0, 126.7, 126.2,
121.2, 74.5, 53.2, 46.5, 40.5, 40.1, 20.9, 20.8, 20.3.
C35H33O2N3 requires: C, 79.67; H, 6.30; N, 7.96.
Found: C, 79.82; H, 6.42; N, 8.15%.
4.4.3.2. (1S,4R)-2-Benzyl-1-methyl-1,4-bis(p-methyl-
benzyl)-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-
dione 17. wmax (NaCl) 1680, 1655 cm−1; lH (250 MHz,
CDCl3) 8.26 (1H, dd, J=8 Hz, J=1.5 Hz, H-7), 7.81
(1H, ddd, J=8.3 Hz, J=7.1 Hz, J=1.5 Hz, H-9), 7.70
(1H, dd, J=8.3 Hz, J=1.2 Hz, H-10), 7.51 (1H, ddd,
J=8 Hz, J=7.1 Hz, J=1.2 Hz, H-8), 7.30 (5H, m,
ArH), 6.71 (2H, d, J=8 Hz, H-3%,5%), 6.63 (2H, d, J=8
Hz, H-3¦,5¦), 6.37 (2H, d, J=8 Hz, H-2%,6%), 6.28 (2H,
d, J=8 Hz, H-2¦,6¦), 5.28 (1H, d, J=14.8 Hz, N-CH2-
Ar), 4.61 (1H, dd, J=5 Hz, J=3 Hz, H-4), 4.28 (1H, d,
J=14.8 Hz, N-CH2-Ar), 3.37 (1H, dd, J=14.1 Hz,
J=5 Hz, C(4)-CH2), 3.23 (1H, d, J=13.7 Hz, C(1)-
CH2), 3.14 (1H, dd, J=14.1 Hz, J=3 Hz, C(4)-CH2),
3.11 (1H, d, J=13.7 Hz, C(1)-CH2), 2.20 (3H, s, CH3),
2.16 (3H, s, CH3), 1.42 (3H, s, CH3); lC (62.5 MHz,
CDCl3) 165.5, 160.2, 153.3, 146.8, 137.2, 136.9, 136.2,
134.5, 131.5, 131.2, 129.8, 129.3, 129.1, 128.9, 128.7,
128.0, 127.2, 127.1, 126.7, 126.6, 120.0, 67.0, 55.5, 47.8,
46.9, 36.5, 26.8, 20.9, 20.8. C35H33O2N3 requires: C,
79.67; H, 6.30; N, 7.96. Found: C, 79.35; H, 6.40; N,
7.90%.
4.4.4. Monoalkylation of 9. To a cold (−78°C), magnet-
ically stirred solution of 9 (0.5 mmol) in dry THF (10
mL) under argon was added, dropwise via syringe, a
solution of lithium hexamethyldisilazide in THF (1 M,
0.6 mL), followed 10 min later by a solution of the
4.4.3. Alkylation of 8 in presence of DMI. To a cold
(−78°C), magnetically stirred solution of 0.5 mmol of 8
in dry THF (10 mL) and DMI (1 mmol) under argon
was added, dropwise via syringe, a solution of lithium

3026
F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
appropriate halide (0.5 mmol) in THF (5 mL); in the
case of 19, excess iodomethane was employed). The
reaction mixture was maintained at −78°C for 10 min,
and at 0°C for 40 min, quenched with ice and diluted
with CH2Cl2. The organic layer was dried over anhy-
drous Na2SO4 and evaporated. Column chromatogra-
phy of the residue on silica gel (toluene:EtOAc or
CH2Cl2:EtOAc) afforded first the 4,4-dialkylated, if
any, followed by the anti-4-alkylated compound.
ddd, J=13.2 Hz, J=8.1 Hz, J=4.4 Hz, H-1%), 2.99
(1H, ddd, J=13.2 Hz, J=7 Hz, J=2.7 Hz, H-1%), 2.42
(1H, sepd, J=6.9 Hz, J=2.7 Hz, CH6 (CH3)2), 1.00 (3H,
d, J=6.9 Hz, CH3), 0.75 (3H, d, J=6.9 Hz, CH3); lC
(62.5 MHz, CDCl3), 165.9, 160.8, 148.6, 146.3, 135.2,
134.8, 130.5, 129.1, 128.9, 128.3. 127.1, 126.8, 120.7,
120.6, 63.5, 56.6, 47.7, 36.1, 33.8, 19.9, 16.4.
C24H25O2N3 requires: C, 74.39; H, 6.50; N, 10.84.
Found: C, 74.17; H, 6.65; N, 10.62%.
4.4.4.1. (1S,4R)-2-Benzyl-1-iso-propyl-4-methyl-2,4-
4.4.4.4.
(1S)-2-Benzyl-4,4-diallyl-1-iso-propyl-2,4-
26.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
19a.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Compound 19a was obtained (toluene:EtOAc 8:2) as a
yellow oil; yield 41%; [h]2D5=−122 (c 0.19, CHCl3); wmax
(NaCl) 1683, 1667 cm−1; lH (250 MHz, CDCl3), 8.23
(1H, dd, J=8, J=1.5 Hz, H-7), 7.72 (1H, ddd, J=8.2.
J=6.8, J=1.5 Hz, H-9), 7.5 (1H, dd, J=8.2, J=1.2
Hz, H-10), 7.45 (1H, ddd, J=8, J=6.8, J=1.2 Hz,
H-8), 7.3 (5H, m, ArH), 5.62 (1H, d, J=14.9 Hz,
N-CH2-Ar), 5.16 (1H, q, J=6.5 Hz, H-4), 4.34 (1H, d,
J=2.7 Hz, H-1), 3.96 (1H, d, J=14.9 Hz, N-CH2-Ar),
Compound 26 was obtained (toluene:EtOAc 9:1) as a
yellow oil; yield 21%; [h]2D5=−80 (c 0.25, CHCl3); wmax
(NaCl) 1685, 1656 cm−1; lH (250 MHz, CDCl3), 8.21
(1H, dd, J=8.2 Hz, J=1.5 Hz, H-7), 7.69 (1H, ddd,
J=8.2 Hz, J=7 Hz, J=1.2 Hz, H-8), 7.53 (1H, dd,
J=8.1 Hz, J=1.2 Hz, H-10), 7.43 (1H, ddd, J=8.1 Hz,
J=7 Hz, J=1.5 Hz, H-9), 7.29 (5H, m, ArH), 5.85 (1H,
dddd, J=17 Hz, J=10 Hz, J=8.2 Hz, J=7.9 Hz,
H-2%), 5.52 (1H, d, J=14.7 Hz, N-CH2-Ar), 5.2 (1H,
dd, J=17 Hz, J=2 Hz, H-3%), 5.06 (1H, dd, J=10 Hz,
J=2.0 Hz, H-3%), 5.03 (1H, dddd, J=17 Hz, J=10 Hz,
J=8.5 Hz, J=6.3 Hz, H-2¦), 4.72 (1H, dd, J=17.1 Hz,
J=2.1 Hz, H-3¦), 4.61 (1H, dd, J=10 Hz, J=2.1 Hz,
H-3¦), 4.18 (1H, d, J=6.9 Hz, H-1), 4.05 (1H, d,
J=14.8 Hz, N-CH2-Ar), 3.56 (1H, dd, J=13.8 Hz,
J=8.5 Hz, H-1¦), 3.53 (1H, dd, J=13.9 Hz, J=8.2 Hz,
H-1%), 3.33 (1H, dd, J=13.9 Hz, J=7.9 Hz, H-1%), 3.0
(1H, dd, J=13.8 Hz, J=6.3 Hz, H-1¦), 2.25 (1H, m,
2.42 (1H, sepd, J=6.9, J=2.7 Hz, CH6 (CH3)2), 1.74
(3H, d, J=6.5 Hz, CH3), 1.03 (3H, d, J=6.9 Hz, CH3),
0.73 (3H, d, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3),
167.7, 160.7, 147.9, 146.2, 135.4, 134.6, 129.0, 128.1,
128.0, 126.9, 126.8, 126.6, 120.6, 63.6, 53.3, 47.5, 34.1,
23.0, 19.8, 16.5. C22H23O2N3 requires: C, 73.11; H, 6.41;
N, 11.63. Found: C, 72.83; H, 6.14; N, 11.58%.
4.4.4.2. (1S)-2-Benzyl-1-iso-propyl-4,4-dimethyl-2,4-
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
25.
J=6.9 Hz, CH6 (CH3)2), 1.17 (3H, d, J=6.9 Hz, CH3),
Compound 25 was obtained (toluene:EtOAc 8:2) as a
pale yellow solid; yield 50%; mp 118–120°C; [h]2D5=−63
(c 0.26, CHCl3); wmax (KBr) 1674, 1654 cm−1; lH (250
MHz, CDCl3), 8.22 (1H, dd, J=8.0, J=1.5 Hz, H-7),
7.69 (1H, ddd, J=8.2. J=6.8, J=1.5 Hz, H-9), 7.53
(1H, dd, J=8.2. J=1.2 Hz, H-10), 7.42 (1H, ddd,
J=8.2, J=6.8, J=1.2 Hz, H-8), 7.24 (5H, m, ArH),
5.59 (1H, d, J=15 Hz, N-CH2-Ar), 4.25 (1H, d, J=5.5
Hz, H-1), 3.99 (1H, d, J=15 Hz, N-CH2-Ar), 2.29 (1H,
0.86 (3H, d, J=6.8 Hz, CH3); lC (62.5 MHz, CDCl3),
167.9, 162.5, 150.4, 145.8, 135.7, 134.6, 133.2, 133.0,
128.9, 128.7, 128.1, 127.1, 126.9, 126.8, 121.7, 120.2.
119.5, 71.2. 65.1, 51.0, 41.3, 40.5, 36.5, 21.2, 19.7.
C27H29O2N3 requires: C, 75.85; H, 6.84; N, 9.83.
Found: C, 75.69; H, 6.77; N, 9.67%.
4.4.4.5.
(1S,4R)-2,4-Dibenzyl-1-iso-propyl-2,4-dihy-
dro-1H-pyrazino[2,1-b]quinazoline-3,6-dione 21a. Com-
pound 21a was obtained (CH2Cl2:EtOAc 95:5) as a
colourless oil; yield 71%; [h]2D5=−357.6 (c 0.25, CHCl3);
wmax (NaCl) 1683. 1661 cm−1; lH (250 MHz, CDCl3),
8.33 (1H, dd, J=7.9 Hz, J=1.5 Hz, H-7), 7.75 (1H,
ddd, J=8.4 Hz, J=6.9 Hz, J=1.5 Hz, H-9), 7.54 (1H,
dd, J=8.4 Hz, J=1 Hz, H-10), 7.50 (1H, ddd, J=7.9
Hz, J=6.9 Hz, J=1 Hz, H-8), 7.19 (4H, m, ArH), 6.98
(2H, m, ArH), 6.8 (2H, m, ArH), 6.63 (2H, m, ArH),
5.49 (1H, t, J=3.7 Hz, H-4), 5.38 (1H, d, J=14.9 Hz,
N-CH2-Ar), 3.94 (1H, d, J=14.9 Hz, N-CH2-Ar), 3.85
(1H, d, J=2.6 Hz, H-1), 3.79 (1H, dd, J=14.0 Hz,
J=4.6 Hz, C(4)-CH2), 3.53 (1H, dd, J=14.0 Hz, J=3.0
Hz, C(4)-CH2), 2.25 (1H, sepd, J=6.9 Hz, J=2.6 Hz,
m, J=6.9 Hz, CH6 (CH3)2), 2.15 (3H, s, CH3), 1.98 (3H,
s, CH3), 1.15 (3H, d, J=6.9 Hz, CH3), 0.87 (3H, d,
J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3), 172, 162.2,
149.1, 146.0, 135.9, 134.6, 129.1, 129.0, 128.1, 128.0,
127.1, 126.9, 126.8, 64.8, 64.7, 49.7, 35.3. 26.8, 24.9,
20.7, 19.0. C23H25O2N3 requires: C, 73.58; H, 6.71; N,
11.19. Found: C, 73.49; H, 6.86; N, 10.96%.
4.4.4.3.
(1S,4R)-4-Allyl-2-benzyl-1-iso-propyl-2,4-
20a.
dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
Compound 20a was obtained (toluene:EtOAc 9:1) as a
pale yellow oil; yield 47%; [h]2D5=−220.4 (c 0.24,
CHCl3); wmax (NaCl) 1682, 1662 cm−1; lH (250 MHz,
CDCl3), 8.23 (1H, dd, J=8 Hz, J=1.5 Hz, H-7), 7.71
(1H, ddd, J=8.2 Hz, J=7.2 Hz, J=1.5 Hz, H-9), 7.56
(1H, dd, J=8.2 Hz, J=1.1 Hz, H-10), 7.45 (1H, ddd,
J=8 Hz, J=7.2 Hz, J=1.1 Hz, H-8), 7.25 (5H, m,
ArH), 5.66 (1H, d, J=14.8 Hz, N-CH2-Ar), 5.30 (1H,
dddd, J=16.2 Hz, J=10.8 Hz, J=8.1 Hz, J=7 Hz,
H-2%), 5.24 (1H, dd, J=4.4 Hz, J=2.7 Hz, H-4), 4.78
(1H, dd, J=10.8 Hz, J=1.8 Hz, H-3%), 4.75 (1H, dd,
J=16.2 Hz, J=1.8 Hz, H-3%), 4.32 (1H, d, J=2.7 Hz,
H-1), 3.97 (1H, d, J=14.8 Hz, N-CH2-Ar), 3.22 (1H,
CH6 (CH3)2), 0.87 (3H, d, J=6.9 Hz, CH3), 0.61 (3H, d,
J=6.9, CH3); lC (62.5 MHz, CDCl3), 165.1, 160.9,
148.2, 146.0, 134.8, 134.7, 134.1, 129.6, 128.7, 128.6,
128.4, 127.8, 127.0, 126.9, 126.7, 120.4, 62.5, 57.3. 47.0,
36.5, 33.0, 19.8, 16.0. C28H27O2N3 requires: C, 76.86; H,
6.22; N, 9.60. Found: C, 76.64; H, 5.95; N, 9.54%.
4.4.4.6. (1S,4R)-2-Benzyl-1-iso-propyl-4-p-methylben-
zyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
22a. Compound 22a was obtained (toluene:EtOAc 95:5)

F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
3027
as a yellow oil; yield 70%; [h]2D5=−389.6 (c 0.28,
CHCl3); wmax (NaCl) 1683, 1661 cm−1; lH (250 MHz,
CDCl3), 8.33 (1H, dd, J=8.0 Hz, J=1.5 Hz, H-7),
7.75 (1H, ddd, J=8.4 Hz, J=6.8 Hz, J=1.5 Hz, H-
9), 7.55 (1H, dd, J=8.4 Hz, J=1.1 Hz, H-10), 7.5
(1H, ddd, J=8.0 Hz, J=6.8 Hz, J=1.1 Hz, H-8),
7.20 (3H, m, ArH), 6.80 (2H, m, ArH), 6.78 (2H, d,
J=8 Hz, H-3%,5%), 6.50 (2H, d, J=8.0 Hz, H-2%,6%),
5.47 (1H, t, J=3.7 Hz, H-4), 5.38 (1H, d, J=14.9
Hz, N-CH2-Ar), 3.91 (1H, d, J=14.9 Hz, N-CH2-Ar),
3.85 (1H, d, J=2.6 Hz, H-1), 3.73 (1H, dd, J=14.1
Hz, J=4.4 Hz, C(4)-CH2), 3.48 (1H, dd, J=14.1 Hz,
J=3.1 Hz, C(4)-CH2), 2.26 (1H, sepd, J=6.9 Hz, J=
C(4)-CH2), 3.63 (1H, dd, J=13.8 Hz, J=3.0 Hz,
C(4)-CH2), 2.33 (1H, sepd, J=6.9 Hz, J=2.8 Hz,
CH6 (CH3)2), 0.93 (3H, d, J=6.9 Hz, CH3), 0.65 (3H,
d, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3), 164.5,
161.0, 147.7, 146.8, 145.8, 142.6, 135.1, 134.4, 130.4,
128.7, 128.6, 128.3, 127.4, 127.2. 126.6, 123.2, 120.2,
63.6, 57.1, 47.6, 36.4, 33.7, 19.6, 16.0. C28H26O4N4
requires: C, 69.70; H, 5.43; N, 11.61. Found: C,
69.57; H, 5.44; N, 11.46%.
Acknowledgements
2.6 Hz, CH6 (CH3)), 2.22 (3H, s, CH3), 1.29 (3H, d,
J=6.9 Hz, CH3), 0.59 (3H, d, J=6.9 Hz, CH3); lC
(62.5 MHz, CDCl3), 165.4, 161.1, 148.5, 146.2, 136.5,
134.7, 134.1, 131.6, 129.5, 129.0, 128.7, 128.6, 127.8,
126.9, 126.95, 126.7, 120.6, 62.5, 57.6, 47.1, 36.4,
33.1, 21.1, 19.7, 15.9. C29H29O2N3 requires: C, 77.14;
H, 6.47; N, 9.31. Found: C, 76.86; H, 6.40; N, 9.12%.
We thank CICYT for financial support (Project
SAF97-0143).
References
1. Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto,
T.; Kawai, K.; Usam, Y.; Matsumura, E.; Inoue, M.;
Ohishi, H.; Shingu, T. Tetrahedron Lett. 1992, 33,
1621–1624.
2. Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.;
Shingu, T.; Kumeda, Y.; Numata, A. J. Chem. Soc.,
Perkin Trans. 1 1995, 2345–2353.
3. Wong, S.-M.; Musza, L. L.; Kydd, G. C.; Kullnig, R.;
Gillum, A. M.; Cooper, R. J. Antibiot. 1993, 46, 545–
553.
4. Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.;
Yamazaki, M. Chem. Pharm. Bull. 1996, 44, 1843–1848.
5. Karwowsky, J. P.; Jackson, M.; Rasmussen, R. R.;
Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.; Scherr,
M. H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993,
46, 374–379.
6. Chou, T.-C.; Depew, K. M.; Zheng, Y.-H.; Safer, M.
L.; Chan, D.; Helfrich, B.; Zatorska, D.; Zatorski, A.;
Bornmann, W.; Danishefsky, S. J. Proc. Natl. Acad.
Sci. USA 1998, 95, 8369–8374.
7. Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973–
980.
8. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–
3606.
9. He, F.; Snider, B. B. J. Org. Chem. 1999, 64, 1397–
1399.
4.4.4.7. (1S,4R)-2-Benzyl-4-p-fluorobenzyl-1-iso-pro-
pyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
23a. Compound 23a was obtained (toluene:EtOAc
95:5) as a yellow solid; yield 78%; mp 91–93°C;
[h]2D5=−378 (c 0.27, CHCl3); wmax (KBr) 1678, 1659
cm−1; lH (250 MHz, CDCl3), 8.32 (1H, dd, J=8.2
Hz, J=1.3 Hz, H-7), 7.77 (1H, ddd, J=8.5 Hz, J=
7.0 Hz, J=1.3 Hz, H-9), 7.56 (1H, dd, J=8.5 Hz,
J=1.2 Hz, H-10), 7.52 (1H, ddd, J=8.2 Hz, J=7.0
Hz, J=1.2 Hz, H-8), 7.25 (3H, m, ArH), 6.84 (2H,
m, ArH), 6.60 (4H, m, ArF-H), 5.44 (1H, t, J=3.5
Hz, H-4), 5.39 (1H, d, J=14.3 Hz, N-CH2-Ar), 3.95
(1H, d, J=2.7 Hz, H-1), 3.92 (1H, d, J=14.3 Hz,
N-CH2-Ar), 3.75 (1H, dd, J=14.2 Hz, J=4.6 Hz,
C(4)-CH2), 3.5 (1H, dd, J=14.2 Hz, J=3.0 Hz, C(4)-
CH2), 2.31 (1H, sepd, J=6.9 Hz, J=2.7 Hz,
CH6 (CH3)2), 0.89 (3H, d, J=6.9 Hz, CH3), 0.62 (3H,
d, J=6.9 Hz, CH3); lC (62.5 MHz, CDCl3), 165.0,
164.1, 162.0 (d, J=244.3 Hz, C-4%), 160.9, 148.2,
145.9, 134.9, 134.3, 131.1 (d, J=7.8 Hz, C-2%,6%),
130.5 (d, J=3.3 Hz, C-1%), 128.7, 128.5, 128.0, 127.1,
126.9, 126.6, 120.3, 115.2 (d, J=21 Hz, C-3%,5%), 62.9,
57.5, 47.3, 35.8, 33.4, 19.7, 16.0. C28H26O2N3F
requires: C, 73.83; H, 5.75; N, 9.22. Found: C, 73.46;
H, 5.83; N, 9.09%.
4.4.4.8. (1S,4R)-2-Benzyl-1-iso-propyl-4-p-nitroben-
zyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-dione
24a. Compound 24a was obtained (CH2Cl2:EtOAc
95:5) as a yellow oil; yield 85%; [h]2D5=−322.5 (c 0.28,
CHCl3); wmax (NaCl) 1682, 1658, 1347 cm−1; lH (250
MHz, CDCl3), 8.32 (1H, dd, J=8.0 Hz, J=1.4 Hz,
H-7), 7.78 (1H, ddd, J=8.4 Hz, J=7.0 Hz, J=1.4
Hz, H-9), 7.69 (2H, d, J=8.7 Hz, H-3¦,5¦), 7.58 (1H,
dd, J=8.4 Hz, J=1.1 Hz, H-10), 7.53 (1H, ddd, J=
8.0 Hz, J=7.0 Hz, J=1.1 Hz, H-8), 7.22 (3H, m,
ArH), 6.94 (2H, d, J=8.1 Hz, ArH), 6.74 (2H, d,
J=8.7 Hz, H-2%,6%), 5.45 (1H, dd, J=4.8 Hz, J=3.0
Hz, H-4), 5.36 (1H, d, J=14.6 Hz, N-CH2-Ar), 4.03
(1H, d, J=2.8 Hz, H-1), 3.9 (1H, d, J=14.6 Hz,
N-CH2-Ar), 3.87 (1H, dd, J=13.8 Hz, J=4.8 Hz,
10. Hart, D. J.; Magomedov, N. Tetrahedron Lett. 1999,
40, 5429–5432.
11. Wang, H.; Ganesan, A. J. Org. Chem. 1998, 63, 2432–
2433.
12. Wang, H.; Ganesan, A. J. Org. Chem. 2000, 65, 1022–
1030.
13. Wang, H.; Ganesan, A. J. Comb. Chem. 2000, 2, 186–
194.
14. Snider, B. B.; Zeng, H. Org. Lett. 2000, 2, 4103–4106.
15. He, F.; Snider, B. B. Synlett 1997, 483–484.
16. Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57,
3301–3307.
17. Herna´ndez, F.; Lumetzberger, A.; Avendan˜o, C.; So¨ll-
huber, M. Synlett 2001, 1387–1390.

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F. L. Buenadicha et al. / Tetrahedron: Asymmetry 12 (2001) 3019–3028
18. Mart´ın-Santamar´ıa, S.; Buenadicha, F. L.; Espada, M.;
So¨llhuber, M.; Avendan˜o, C. J. Org. Chem. 1997, 62,
6424–6428.
1998, 9, 483–501.
21. Buenadicha, F. L.; Avendan˜o, C.; So¨llhuber, M. Tetra-
hedron: Asymmetry 1998, 9, 4275–4284.
22. The structure of 17 was established from NOESY
experiments: irradiation at l=1.42 ppm (C(1)-CH3)
showed significant NOEs at l=6.63 and 6.28 ppm
(C(4)-CH2-C6H4-p-CH3).
19. Mart´ın-Santamar´ıa, S.; Espada, M.; Avendan˜o, C. Tetra-
hedron 1997, 53, 16795–16802.
20. Buenadicha, F. L.; Bartolome´, M. T.; Aguirre, M. J.;
Avendan˜o, C.; So¨llhuber, M. Tetrahedron: Asymmetry