New development of Meyers' methodology: Stereoselective preparation of an axially chiral 5,7-fused bicyclic lactam related to circumdatins/benzomalvins and asperlicins

Article abstract of DOI:10.1016/j.tetasy.2005.12.019

The stereoselective preparation of a new Meyers' bicyclic lactam-bridged biaryl 1, highly structurally related to circumdatins, benzomalvins and asperlicins, is reported. Using the popular Meyers' diastereoselective lactamization, under dehydrating conditions (CH₂Cl ₂/reflux/MgSO₄), trans-(aS,R,S)-1 was obtained in a rather modest yield of 25% and an excellent diastereoselectivity >95%. An alternative procedure making use of the activating agents of carboxylic acid (Mukaiyama reagent and FEP) allowed the lactamization process to take place under milder conditions (CH₂Cl₂/20°C) affording trans-(aS,R,S)-1 in fairly good yields (50%-85%) and in up to 65% de.

Full text of DOI:10.1016/j.tetasy.2005.12.019

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 17 (2006) 281–286
New development of Meyers’ methodology: stereoselective
preparation of an axially chiral 5,7-fused bicyclic lactam
related to circumdatins/benzomalvins and asperlicins
Mael Penhoat, Pierre Bohn, Georges Dupas, Cyril Papamicael, Francis Marsais and
¨
¨
Vincent Levacher*
Laboratoire de Chimie Organique Fine et He´te´rocyclique, UMR 6014, IRCOF, CNRS, Universite´ et INSA de Rouen, B.P. 08 F-76131
Mont-Saint-Aignan Ce´dex, France
Received 19 November 2005; accepted 21 December 2005
Available online 23 January 2006
Abstract—The stereoselective preparation of a new Meyers’ bicyclic lactam-bridged biaryl 1, highly structurally related to circum-
datins, benzomalvins and asperlicins, is reported. Using the popular Meyers’ diastereoselective lactamization, under dehydrating
conditions (CH2Cl2/reflux/MgSO4), trans-(aS,R,S)-1 was obtained in a rather modest yield of 25% and an excellent diastereoselec-
tivity >95%. An alternative procedure making use of the activating agents of carboxylic acid (Mukaiyama reagent and FEP) allowed
the lactamization process to take place under milder conditions (CH2Cl2/20 ꢀC) affording trans-(aS,R,S)-1 in fairly good yields
(50%–85%) and in up to 65% de.
ꢁ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
from the fungus Aspergillus alliaceus.5 Interestingly,
with regards to the stereochemistry, most of these ben-
zodiazepine–quinazolinone alkaloids display two com-
mon configurational elements, that is, a stereogenic
centre incorporated into the diazepine framework and
an additional chiral axis due to restricted rotation
around the C–N biaryl bond, connecting both the ben-
zodiazepine and the quinazolone rings. This atropo-
isomerism is a feature of a number of natural
products, which should be considered, in respect to their
potential biological targets, as an important configura-
tional element of recognition.6 We recently extended
Meyers’ bicyclic lactam methodology7 to the highly ste-
reoselective construction of axially chiral 7,5-fused bicy-
clic lactams.8 This approach presents the advantage of
controlling in a single step both the stereogenic centre
and the biaryl chiral axis of these axially chiral bridged
biaryls. In this context, we became interested in explor-
ing the potential of this new extension by investigating
the stereoselective preparation of analogues of these
benzodiazepine–quinazolinone alkaloids. Herein we
report an efficient and straightforward stereoselective
synthesis of analogue 1, which may be considered as a
common precursor to most of these various alkaloids
(Fig. 1).
The benzodiazepine moiety is found in a large number
of natural products1 and has been considered for a while
as a privileged heterocyclic scaffold in lead generation
for many researchers involved in CNS research pro-
grammes. The benzodiazepines constitute a well-known
class of therapeutics displaying hypnotic, anxiolytic and
anticonvulsant effects and still represent a widely
prescribed class of psychoactive drugs.2 In 1999, a new
class of benzodiazepine alkaloids, circumdatins A–C
were isolated from a terrestrial isolate of the fungus
Aspergillus ochraceus3 and are considered as excellent
chemotaxonomic markers for this species. If any
methodical screening of the biological activities of these
circumdatins has been instigated, related benzomalvins
A–C alkaloids, isolated from a fungus Penicillium sp.,
have already shown inhibitory activity against substance
P at the guinea pig, rat and human neurokinin NK1
receptor.4 Finally, Asperlicins, which are known as
potent cholescystokinin antagonists have been isolated
*
Corresponding author. Tel.: +33 (0)2 3552 2485; fax: +33 (0)2 3552
2962; e-mail: vincent.levacher@insa-rouen.fr
0957-4166/$ - see front matter ꢁ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.12.019

282
M. Penhoat et al. / Tetrahedron: Asymmetry 17 (2006) 281–286
O
R
O
R
N
O
N
N
R
N
H
NH
N
O
N
H
Me
O
N
H
O
O
N
OMe
OH
R = OMe Circumdatin A
R'
MeO
R = H
CircumdatinB
R = OMe Circumdatin D
R = OH, R' = H Circumdatin C
R = H, R' = H CircumdatinF
R = H, R' = OH Circumdatin G
R = H
Circumdatin E
O
Ph
Ph
Ph
Me O
N
O
Me
N
N
R3
N
N
O
N
N
O
R1
N
O
N
R1=R2=
R3=H: 1
R2
O
O
BenzomalvinC
BenzomalvinA
H
O
N
Ph
O
Me
HO
NH
N
N
NH
N
H
O
N
N
N
N
N
O
HN
O
O
O
AsperlicinC
BenzomalvinB
Asperlicin
Figure 1. New axially chiral bridged biaryl benzodiazepine–quinazolinones. Potential analogues of circumdatins/benzomalvins and asperlicin.
2. Results and discussion
1b). Interestingly, as a result of the subordinate relation-
ship between the absolute configuration of this chiral
biaryl axis and that of the aminal centre incorporated
in the benzodiazepine ring, this stereoselective ring clo-
sure is accompanied by configurational control of the
chiral biaryl axis. The preparation of the key intermedi-
ates 2a and b is related to those employed for the prep-
aration of the natural alkaloids, changing the a-amino
acid for acetic anhydride (Scheme 1b).
Most of these alkaloids have been prepared over the
past 10 years.9 A brief synthetic analysis reveals that
they are formally accessible from two properly substi-
tuted anthranilic acid elements and one unit of a-amino
acid (Scheme 1a). Our synthetic approach is based on a
diastereoselective Meyers’ lactamization of benzodiaze-
pine–quinazolinone intermediates 2a and b (Scheme
R1
O
COOH
H2N
N
R2
R4
H2N
R2
NH2
(a)
N
COOH
HOOC
N
R3
O
R4
R3
O
Ac2O
R4, R3 = H
Ph
Ph
COOR
CHO
COOR
Me
H2N
Meyers'
lactamization
OH
N
O
H
N
(b)
N
N
N
N
N
O
O
O
2a: R = H
2b: R = Et
3a: R = H
3b: R = Et
1
Scheme 1. (a) Previous synthetic routes to circumdatins, benzomalvins and asperlicins; (b) new stereoselective access to an analogue 1 via Meyers’
lactamization of 2a–b.

M. Penhoat et al. / Tetrahedron: Asymmetry 17 (2006) 281–286
283
COOEt
(c)
COOR
COOR
Me
65%
NH2
CHO
N
(d)
N
N
95%
O
O
O
N
(b)
COOH
NH2
(a)
O
72%
Me
85%
N
2a: R = H (95%)
2b: R = Et (95%)
4
3a: R = H
3b: R = Et
Scheme 2. Preparation of the benzodiazepine–quinazolone intermediate 2a–b. Reagents and conditions: (a) Ac2O/reflux/2 h; (b) anthranilic acid/
AcOH/reflux/168 h; (c) ethyl orthoacetate (1.5 equiv)/180 ꢀC/sealed tube/7 days; (d) SeO2/dioxane/reflux/10 h.
Acetylanthranil 4 was prepared in 85% yield by treat-
ment of anthranilic acid with acetic anhydride according
to a literature procedure.10 The required 2-methyl-qui-
nazolinone 3a was obtained in 72% yield, by treatment
of 4 with a second equivalent of anthranilic acid.11 At
this stage, various attempts to convert 3a into the corre-
sponding ester 3b proved to be unfruitful, leading in
most cases to unidentified by-products. Alternatively,
3b could be prepared according to a one pot procedure
by reaction of ethyl o-aminobenzoate with ethyl ortho-
acetate. Ester 3b was isolated in a fairly good yield of
65%. Finally, the desired benzodiazepine–quinazolinone
intermediates 2a and 2b were obtained in 95% yields, in
both cases, by direct oxidation of 2-methyl-quinazoli-
nones 3a–b with selenium dioxide12 (Scheme 2).
suffered from the formation of unidentified by-products
furnishing lactam trans-(aS,R,S)-1 in a rather poor yield
of 25%.
We recently developed new lactamisation conditions14
of c-, d-, x-keto acids based on the activation of carbox-
ylic acid by means of Mukaiyama’s reagent15 (N-methyl-
2-chloropyridinium iodide). These new activated condi-
tions offer the advantage of accelerating the lactamisation
process providing bicyclic lactams in high yields at lower
temperatures. It was therefore speculated that these new
activated conditions should be especially suitable for the
heat-sensitive substrate 2a. Thus, the carboxylic acid of
benzodiazepine–quinazolidinone 2a was first activated
in the presence of Mukaiyama’s reagent and triethyl-
amine prior to reacting with (R)-phenylglycinol.
Meyers’ lactamisation of benzodiazepine–quinazolidi-
none 2a and b was first assessed under dehydrating con-
ditions in the presence of (R)-phenylglycinol at reflux in
toluene solution. These classical conditions proved to be
inappropriate, leading mainly to degradation of the
starting materials (Table 1, entries 1 and 2). Although
Meyers’ methodology, has been widely exploited with
various simple c-, d-keto acids, this failure points out
the serious limitation of these classical dehydrating con-
ditions when applied to heat-sensitive substrates. In
search of milder lactamisation conditions, benzodiaze-
pine–quinazolidinone 2a was reacted with (R)-phenyl-
glycinol in CH2Cl2 in the presence of MgSO4 as the
dehydrating agent (Table 1, entry 3). The desired lactam
trans-(aS,R,S)-1 was obtained as a single diastereoiso-
mer (de >95%).13 However, these new conditions still
Even if these conditions could improve to some extent
the conversion of 2a into bicyclic lactam 1 (50%), a sig-
nificant amount of by-products was still present in the
crude. Even more disappointing was the complete
absence of diatereoselectivity observed under these con-
ditions. Both diastereoisomers trans-(aS,R,S)-1 and syn-
(aR,R,R)-1 could be isolated by flash chromatography
(Scheme 3).
Given the modest results obtained with Mukaiyama’s
reagent, it was next decided to employ N-ethyl-2-fluoro-
pyridinium tetrafluoroborate (FEP), known to be more
reactive.16 On treating benzodiazepine–quinazolidinone
2a with FEP in the presence of DIEA in CHCl3 at
60 ꢀC, followed by the addition of (R)-phenylglycinol,
lactam trans-(aS,R,S)-1 was obtained in 70% yield and
a modest but still significant 20% de (Table 2, entry 1).
When carrying out the same procedure in CH2Cl2 at
40 ꢀC, both the yield and diastereoselectivity were nota-
bly enhanced providing lactam trans-(aS,R,S)-1 in 80%
yield and 51% de (Table 2, entry 2). The best results were
finally obtained at 0 ꢀC, affording lactam trans-(aS,R,S)-
1 in a satisfactory yield of 85% and 65% de (Table 2,
entry 4). Let us note that conducting the reaction at
lower temperatures (Table 2, entry 5) did not lead to
any significant improvement of the diastereoselectivity.
Table 1. Meyers’ lactamization of benzodiazepine–quinazolone inter-
mediates 2a–b under dehydrating conditions
R
Ph
Ph
O
S
H
OHC
ROOC
N
N
N
H2N
OH
O
N
N
S
a
Table 1
O
O
2a: R = H
2b: R = Et
trans-(aS,R,S)-1
Entry Substrate Conditions
Yield (%) dea (%)
1
2
3
2a
2b
2a
Toluene/reflux/24 h
Toluene/reflux/24 h
CH2Cl2/MgSO4/
reflux/132 h
0
0
25
—
—
>95
3. Conclusion
In summary, we have reported the stereoselective prep-
aration of an axially chiral 7,5-fused bicyclic lactam 1,
a Determined from 1H NMR spectrum of the crude reaction mixture.

284
M. Penhoat et al. / Tetrahedron: Asymmetry 17 (2006) 281–286
R
Ph
O
H
N
O
N
S
O
N
O
COOH
CHO
N+
Me
aS
O
CHO
trans -(aS,R,S)-1
(b)
(a)
N
+
N
Yield = 50%
de = 0%
N
O
N
R
Ph
O
O
H
N
O
N
R
O
2a
N
aR
syn-(aR,R,R)-1
Scheme 3. Meyers’ lactamization of benzodiazepine–quinazolone intermediate 2a activated by Mukaiyama’s reagent. Reagents and conditions: (a)
N-methyl-2-chloropyridinium iodide/NEt3/CH2Cl2/reflux/15 min; (b) (R)-phenylglycinol.
Table 2. Meyers’ lactamization of the benzodiazepine–quinazolone
intermediate 2a by activation with FEP
demonstrated promising results in broadening the scope
of Meyers’ methodology to heat-sensitive substrates.
R
Ph
O
O
S
H
N
O
N
4. Experimental
N
O
COOH
CHO
N+
Et
aS
O
CHO
trans-(a
Major
S
,
R
,
S
)-1
4.1. General
(b)
(a)
N
+
N
N
O
N
R
Ph
O
O
Chemicals and solvents were either purchased from
commercial suppliers or purified by standard tech-
H
N
O
N
R
O
niques. H NMR and 13C NMR spectra were recorded
1
2a
N
aR
1
on a Bruker Avance 300. H at 300 MHz and 13C at
syn-(a
Minor
R,R,R
)-1
75 MHz using CDCl3 as solvent and with the residual
1
solvent signal (d 7.26, H; d 77.0, 13C) as internal stan-
Entry
Conditions
Yield (%)
de (%)
dard unless otherwise indicated. The following abbrevi-
ations are used to describe peak pattern: s (singlet), d
(doublet), t (triplet), q (quartet). Melting points are
uncorrected. Infrared spectra were recorded on a Perkin-
Elmer Paragon 500 FT-IR spectrometer. Flash chroma-
tographies were performed with silica 60 (70–230 mesh
from Merck) and monitored by thin layer chromatogra-
phy (TLC) with silica plates (Merck, Kieselgel 60 F254).
1
2
3
4
5
CHCl3/60 ꢀC/8 h
CH2Cl2/40 ꢀC/8 h
CH2Cl2/20 ꢀC/8 h
CH2Cl2/0 ꢀC/8 h
CH2Cl2/ꢀ20 ꢀC/8 h
70
80
83
85
83
20
51
60
65
65
Reagents and conditions: (a) FEP (N-ethyl-2-fluoropyridinium tetra-
fluoroborate)/DIEA; (b) (R)-phenylglycinol.
an analogue of benzodiazepine–quinazolidinone alka-
loids. Attempts to apply Meyers’ lactamisation to 2a
and b under the classical dehydrating conditions
(CH2Cl2/reflux/MgSO4) resulted in formation of the
desired analogue trans-(aS,R,S)-1 in up to 95% de, how-
ever in a poor yield of 25%. This modest yield, mainly
due to the moderate stability of the starting material
2a–b, reveals the limits of these reaction conditions.
To circumvent this limitation, we decided to test out
whether activating agents for carboxylic acids could
promote the lactamisation under milder conditions.
Interestingly, whereas N-methyl-2-chloropyridinium
iodide (Mukaiyama’s reagent) furnished lactam 1 in 50%
yield and without diastereoselectivity, its analogue N-
ethyl-2-fluoropyridinium tetrafluoroborate (FEP) affor-
ded trans-(aS,R,S)-1 in up to 65% de (85% yield). These
results clearly showed the crucial role of the leaving
group of the carboxylic acid on both the yield and stereo-
selectivity of the reaction. Further investigations to gain
insight into the mechanism of bicyclic lactam formation
under these new activated conditions are under way in
our laboratory. Although the stereoselectivity remains
medium, these new activated conditions have already
4.2. 2-Methyl-3,1-benzoxazin-4-one 4
Compound 4 was prepared according to Ref. 10:
yield = 85%. Mp 81–82 ꢀC. 1H NMR (CDCl3,
300 MHz) d 7.86 (d, J = 7 Hz, 1H), 7.48 (td, J = 1.5
and 7 Hz, 1H), 7.20 (m, 2H), 2.16 (s, 3H). 13C NMR
(CDCl3, 75 MHz) d 160.5, 159.9, 146.7, 136.9, 128.7,
128.5, 126.7, 116.9, 21.7. IR mmax (KBr): 1756, 1645,
1472, 1266, 1195, 1053, 998, 961, 779, 691 cmꢀ1. Anal.
Calcd for C9H7NO2: C, 67.07; H, 4.38; N, 8.69. Found:
C, 67.01; H, 4.32; N, 8.71.
4.3. 2-(2-Methyl-4-oxo-4H-quinazolin-3-yl)-benzoic acid
3a
To a solution of acetylanthranyl 4 (5.8 g, 36 mmol) in
acetic acid (60 mL), was added anthranilic acid (5 g,
36.4 mmol). The resulting solution was refluxed for
168 h. After cooling to room temperature, the resulting
precipitate was filtered and dried to afford 3a as a white
solid. Yield = 72%. Mp 256–258 ꢀC. 1H NMR (DMSO-
D6, 300 MHz) d 13.11 (s, 1H), 8.10 (m, 2H), 7.82 (m,
2H), 7.67 (m, 2H), 7.57 (dd, J = 0.7 and 7.5 Hz, 1H),

M. Penhoat et al. / Tetrahedron: Asymmetry 17 (2006) 281–286
285
7.50 (td, J = 0.9 and 8.3 Hz, 1H), 2.10 (s, 3H). 13C NMR
(DMSO-D6, 75 MHz) d 166.1, 161.7, 154.6, 147.8, 137.9,
134.9, 134.1, 131.95, 130.6, 129.95, 129.2, 127.0, 126.65,
126.6, 120.7, 24.1. IR mmax (KBr): 1692, 1609, 1568,
1477, 1388, 1282, 1264, 1244, 1121, 779, 760,
696 cmꢀ1. MS IE (70 eV) calcd for C16H12N2O3:
m/z = 280. Found: (MH+) m/z = 281. Anal. Calcd for
C16H12N2O3: C, 68.56; H, 4.32; N, 9.99. Found: C,
68.51; H, 4.35; N, 10.01.
NMR (CDCl3, 75 MHz) d 186.4, 165.1, 162.0, 147.4,
146.9, 136.8, 135.4, 133.9, 132.4, 130.3, 130.2, 129.8,
129.2, 128.0, 127.9, 122.9, 61.7, 14.2. IR mmax (KBr):
1720, 1691, 1608, 1293, 1266, 1114, 775, 698. HRMS
IE (70 eV) calcd for C18H14N2O4: 322.0953; found:
322.0945.
4.7. Meyers’ lactamization by activation with FEP
(typical procedure)
4.4. 2-(2-Methyl-4-oxo-4H-quinazolin-3-yl)-benzoic acid
ethyl ester 3b
To a solution of 2a (2.52 g, 8.6 mmol) in CH2Cl2
(50 mL) was added DIEA (2.22 g, 17.2 mmol) and
FEP (1.83 g, 9.4 mmol). The resultant solution was
stirred at room temperature for 15 min, after which
(R)-phenylglycinol (1.18 g, 8.6 mmol) was added. The
solution was stirred for a further 8 h, filtered and the sol-
vent evaporated under vacuum. The diastereoselectivity
(de = 60% in favour of trans-(aS,R,S)-1) was deter-
mined from the 1H NMR of the crude reaction mixture.
The residue was purified by flash chromatography on
silica gel (AcOEt/CH2Cl2: 8/2) affording both diastereo-
isomers trans-(aS,R,S)-1 in 70% yield (Rf = 0.52) and
syn-(aR,R,R)-1 in 13% yield (Rf = 0.35). Selected data
for trans-(aS,R,S)-1: mp > 250 ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.29 (d, J = 7.9 Hz, 1H), 7.77 (m, 3H),
7.58–7.43 (m, 4H), 7.33–7.23 (m, 5H), 5.98 (s, 1H),
5.21 (d, J = 6.4 Hz, 1H), 5.02 (dd, J = 6.8 and 9.6 Hz,
1H), 4.31 (d, J = 9.7 Hz, 1H). 13C NMR (CDCl3,
75 MHz) d 161.8, 161.5, 151.5, 146.4, 140.3, 135.6,
132.7, 131.7, 130.3, 129.7, 129.3 (2·), 129.2, 128.5,
A solution of ethyl o-aminobenzoate (6.18 g, 37.4 mmol)
and ethyl orthoacetate ester (5.15 mL, 28.5 mmol) was
refluxed for 48 h. The resultant mixture was transferred
in a sealed tube and heated to 180 ꢀC for 110 h. Tritur-
ation of the crude product with cold ethanol afforded 3b
as a yellow solid in 65% yield. When precipitation did
not occur, the crude product could be purified by chro-
matography on silica gel (CH2Cl2/cyclohexane: 8/2) to
afford 3b as a yellow oil that crystallized under vacuum
1
(72%). Mp 152 ꢀC. H NMR (CDCl3, 300 MHz) d 8.16
(dd, J = 0.6 and 6.8 Hz, 2H), 7.66 (m, 3H), 7.53 (td,
J = 0.8 and 7.6 Hz, 2H), 7.38 (td, J = 1.1 and 8.3 Hz,
1H), 7.26 (dd, J = 1.1 and 7.9 Hz, 1H), 4.05 (q,
J = 7.1 Hz, 2H), 2.12 (s, 3H), 0.90 (t, J = 7.1 Hz, 3H).
13C NMR (CDCl3, 75 MHz) d 164.9, 162.8, 154.4,
148.0, 138.2, 135.0, 134.4, 133.0, 130.2, 130.0, 128.8,
127.4, 127.2, 126.9, 121.1, 61.9, 24.5, 14.0. IR mmax
(KBr): 1708, 1681, 1609, 1595, 1473, 1293, 1249,
787 cmꢀ1. Anal. Calcd for C18H16N2O3: C, 70.12; H,
5.23; N, 9.09. Found: C, 70.21; H, 5.12; N, 9.11.
128.45, 128.4, 128.0, 126.65 (2·), 122.0, 85.0, 76.1,
20
59.3. IR mmax (KBr): cmꢀ1. ½aꢁD ¼ ꢀ93:2 (c 3.4,
CH2Cl2). HRMS IE (70 eV) calcd for C24H17N3O3:
395.1270; found: 395.1265. Selected data for syn-
1
4.5. 2-(2-Formyl-4-oxo-4H-quinazolin-3-yl)-benzoic acid
2a
(aR,R,R)-1: mp 204 ꢀC. H NMR (CDCl3, 300 MHz) d
8.32 (d, J = 7.9 Hz, 1H), 7.97 (dd, J = 1.1 and 8.3 Hz,
1H), 7.83–7.60 (m, 2H), 7.58–7.45 (m, 4H), 7.12–7.08
(m, 5H), 5.86 (s, 1H), 5.19 (t, J = 7.5 Hz, 1H), 4.68
(dd, J = 7.5 and 9 Hz, 1H), 4.58 (t, J = 7.5 and 9 Hz,
1H). 13C NMR (CDCl3, 75 MHz) d 160.9, 160.3,
150.9, 144.8, 135.9, 134.3, 131.4, 130.8, 130.3, 129.4
To a solution of 3a (2.69 g, 9.6 mmol) in dioxane
(50 mL), was added freshly prepared SeO2 (1.06 g,
9.6 mmol), then the resulting mixture refluxed for 3 h.
The cooled solution was filtered through a plug of celite
545. The plug of celite was washed with dioxane
(2 · 15 mL) and the solvent was evaporated to afford
2a in 95% yield as a yellow oil. Recrystallization in tol-
(2·), 128.2, 128.0, 127.8, 127.1, 127.1, 127.0, 126.7,
20
125.7 (2·), 120.5, 84.1, 74.95, 59.4. ½aꢁD ¼ þ130:9 (c
7.15, CH2Cl2). HRMS IE (70 eV) calcd for
C24H17N3O3: 395.1270; found: 395.1274.
1
uene provided 2a as a yellow solid. Mp 80 ꢀC (dec). H
NMR (CDCl3, 300 MHz) d 9.44 (s, 1H), 8.83 (s, 1H),
8.22 (d, J = 7.6 Hz, 1H), 8.06 (d, J = 6.9 Hz, 1H), 7.78
(m, 2H), 7.64–7.46 (m, 4H), 7.17 (d, J = 6.4 Hz, 1H).
13C NMR (CDCl3, 75 MHz) d 186.2, 168.0, 162.1,
147.25, 146.6, 137.0, 135.2, 134.4, 132.8, 130.2, 129.0,
127.8, 127.3, 122.8, 121.6. IR mmax (KBr): 1724, 1693,
1601, 1288, 1236, 774, 695. HRMS IE (70 eV) calcd
for C16H10N2O4: 294.0640; found: 294.0638.
Acknowledgement
´
We thank the CNRS, the region Haute-Normandie, and
the CRIHAN for financial and technical support.
References
4.6. 2-(2-Formyl-4-oxo-4H-quinazolin-3-yl)-benzoic acid
ethyl ester 2b
1. (a) Tsuyoshi, K.; Yoshihiro, S.; Miwako, M. Tetrahedron
2004, 60, 9649–9657; (b) Langlois, N.; Rojas-Rousseau,
A.; Gaspard, C.; Werner, G. H.; Darro, F.; Kiss, R. J.
Med. Chem. 2001, 44, 3754–3757; (c) Langley, D. R.;
Thurston, D. E. J. Org. Chem. 1987, 52, 91–97.
2. Huang, Q.; He, X.; Ma, C.; Liu, R.; Yu, S.; Dayer, C. A.;
Wenger, G. R.; McKernan, R.; Cook, J. M. J. Med.
Chem. 2000, 43, 71–95.
Compound 2b was prepared from compound 3b accord-
ing to the procedure reported above. Yield = 95%. H
NMR (CDCl3, 300 MHz) d 9.51 (s, 1H), 8.27 (d,
J = 7.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.90–7.78
(m, 2H), 7.67–7.51 (m, 3H), 7.22 (d, J = 7.0 Hz, 1H),
4.06 (q, J = 7.2 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H). 13C
1

286
M. Penhoat et al. / Tetrahedron: Asymmetry 17 (2006) 281–286
3. (a) Rahbæk, L.; Breinholt, J.; Frisvad, J. C.; Christopher-
9. Total synthesis of asperlicins: (a) He, F.; Foxman, B. M.;
Snider, B. B. J. Am. Chem. Soc. 1998, 120, 6417–6418;
Total synthesis of Benzomalvins A and B: (b) Sugimori,
T.; Okawa, T.; Eguchi, S.; Kakehi, A.; Yashima, E.;
Okamoto, Y. Tetrahedron 1998, 54, 7997–8008; Total
synthesis of benzomalvin C: (c) Sun, H. H.; Barrow, C. J.;
Cooper, R. J. Nat. Prod. 1995, 58, 1575–1580; Total
synthesis of circumdatins F and C: (d) Witt, A.; Bergman,
J. J. Org. Chem. 2001, 66, 2784–2788; Total synthesis of
Sclerotigenin: (e) Harrison, D. R.; Kennewell, P. D.;
Taylor, J. B. J. Heterocycl. Chem. 1977, 14, 1191–1196;
Building block approach: (f) Grieder, A.; Thomas, A. W.
Synthesis 2003, 11, 1707–1711.
10. Errede, L. A. J. Org. Chem. 1976, 41, 1763–1765.
11. (a) Heller, G.; Fiesselman, G. Justus Liebigs Ann. Chem.
1902, 324, 134; (b) Bogert, M. T.; Chambers, V. J. J. Am.
Chem. Soc. 1905, 27, 649–658; (c) Patel, N. C.; Mehta,
A. G. J. Indian Council Chem. 2001, 18, 83–86.
12. For the preparation of SeO2 see: (a) Baker, R. H.;
Maxson, R. N. Inorg. Synth. 1939, 1, 119; (b) Organic
reaction; Wiley: London, 1952; Vol. V, pp 345–346.
13. The relative configuration in trans-(aS,R,S)-1 was deter-
mined by assuming the same sense of stereoselection as
observed previously with related substrates and under the
same reaction conditions, see Ref. 8.
sen, C. J. Org. Chem. 1999, 64, 1689–1692; (b) Rahbæk,
L.; Breinholt, J. J. Nat. Prod. 1999, 62, 904–905; (c) Dai,
´
J.-R.; Carte, B. K.; Sidebottom, P. J.; Yew, A. L. S.; Ng,
S.-B.; Huang, Y.; Butler, M. S. J. Nat. Prod. 2001, 64,
125–126.
4. (a) Sun, H. H.; Barrow, C. J.; Sedlock, D. M.; Gillum, A.
M.; Cooper, R. J. Antibiot. 1994, 47, 515–522; (b) Sun, H.
H.; Barrow, C. J.; Cooper, R. J. Nat. Prod. 1995, 58,
1575–1580.
5. (a) Goetz, M. A.; Lopez, M.; Monaghan, R. L.; Chang, R.
S. L.; Lotti, V. J.; Chen, T. B. J. Antibiot. 1985, 38, 1633–
1637; (b) Liesh, J. M.; Hensens, O. D.; Zink, D. L.; Goetz,
M. A. J. Antibiot. 1988, 41, 878–881; (c) Joshi, B. K.;
Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. J. Nat. Prod.
1999, 62, 650–652.
6. Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.;
¨
Tasler, S. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Falk, H., Kirby, G. W.,
Moore, R. E., Eds.; Springer: Wien, New York, 2001; 82,
pp 3–249.
7. For leading references on chiral bicyclic lactams see: (a)
Meyers, A. I.; Brengel, G. P. Chem. Commun. 1997, 1–8;
´
(b) Amat, M.; Canto, M.; Llor, N.; Ponzo, V.; Perez, M.;
Bosch, J. Angew. Chem., Int. Ed. 2002, 41, 335–338; (c)
Amat, M.; Canto, M.; Llor, N.; Escolano, C.; Molins, E.;
Espinosa, E.; Bosch, J. J. Org. Chem. 2002, 67, 5343–5351;
(d) Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch,
J. J. Org. Chem. 2003, 68, 1919–1928; (e) Ennis, M. D.;
Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney, P. A.
J. Org. Chem. 1996, 61, 5813–5817; (f) Allin, S. M.; James,
S. L.; Elsegood, M. R. J.; Martin, W. P. J. Org. Chem.
2002, 67, 9464–9467.
14. Penhoat, M.; Leleu, S.; Dupas, G.; Papamicae¨l, C.;
Marsais, F.; Levacher, V. Tetrahedron Lett. 2005, 46,
8385–8389.
15. (a) Saigo, K.; Usui, M.; Kikushi, K.; Shimada, E.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1977, 50, 1863–
1866; (b) Mukaiyama, T. Angew. Chem., Int. Ed. 1979,
18, 707–721; (c) Sutherland, J. K.; Widdowson, D. A.
J. Chem. Soc. 1964, 4650–4651; (d) Bald, E.; Saigo, K.;
Mukaiyama, T. Chem. Lett. 1975, 1163–1166.
8. Penhoat, M.; Levacher, V.; Dupas, G. J. Org. Chem. 2003,
68, 9517–9520.
16. Li, P.; Xu, J.-C. Tetrahedron 2000, 56, 8119–8131.