Traceless chirality transfer from a norbornene β-amino acid to pyrimido[2,1-a]isoindole enantiomers

Article abstract of DOI:10.1016/j.tetasy.2017.07.006

The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(?)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(?)-1] was successfully transfered to heterocycles (+)-9a, (+)-10a, (?)-9b, (?)-10b and (?)-10c.

Full text of DOI:10.1016/j.tetasy.2017.07.006

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Traceless chirality transfer from a norbornene b-amino acid to
pyrimido[2,1-a]isoindole enantiomers
Ferenc Miklós a, Kristóf Bozó a, Zsolt Galla a, Matti Haukka c, Ferenc Fülöp a,b,
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
c Department of Chemistry, University of Jyväskylä, FIN-40014 Jyväskylä, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of two enantiomeric pairs of pyrimidoisoindoles 9a, 9b and 10a, 10b is reported. During a
domino ring-closure reaction, followed by cycloreversion, the chirality of diendo-(À)-(1R,2S,3R,4S)-3-
aminobicyclo[2.2.1]hept-5-ene-2-carboxamide [(À)-1] was successfully transfered to heterocycles (+)-
9a, (+)-10a, (À)-9b, (À)-10b and (À)-10c.
Received 30 June 2017
Accepted 17 July 2017
Available online xxxx
Ó 2017 Published by Elsevier Ltd.
Dedicated to the Memory of Professor
Howard Flack
1. Introduction
cyclopentadiene in a retro Diels–Alder reaction to obtain pyrim-
ido[2,1-a]isoindole racemates and enantiomers.
Several pyrimido[2,1-a]isoindoles are well known for their
potential biological and pharmacological properties such as pro-
lactin-inhibition,1 antidepressant and diuretic,2 anxiolytic,3 vasore-
laxant,4 antiplasmodial5 and antifungal6 activity. In contrast to
these findings, derivatives of these heterocyles are still insuffi-
ciently studied, even less their enantiomers. To our best knowledge
so far, as single enantiomers, 1N-Me,7 -OMe,8 and -OBn8 substi-
tuted pyrimidoisoindole derivatives have been synthetized.
Compounds were prepared by the application of retro Diels–Alder
(rDA) reaction.9
Both racemic and enantiomeric diendo-3-aminonorbornene-2-
carboxamide for the synthesis of isoindolo-quinazolines were
prepared by a known literature protocol.12 A preparative-scale res-
olution of racemic ethyl diendo-3-aminocicyclo[2.2.1]hept-5-ene-
2-carboxylates was achieved by adopting the diastereomeric salt
formation with (R)-(À)-mandelic acid.13 The reaction afforded
ethyl
(À)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-ene-2-car-
boxylate applied in the synthesis of (À)-(1R,2S,3R,4S)-3-aminobi-
cyclo[2.2.1]hept-5-ene-2-carboxamide (À)-1.
In preliminary studies on the three-step domino reaction,14
racemic diendo-3-aminonorbornene-2-carboxamide ( )-1 was
reacted with 2-formylbenzoic acid (R = H), 2-acetylbenzoic acid
(R = Me) or 2-(4-methylbenzoyl)benzoic acid (R = 4-MeC6H4) in
toluene under reflux in the presence of p-toluenesulfonic acid (p-
TSA) as catalyst. The reaction mixture of ( )-1 (monitored by
TLC) was transferred to a neutral Al2O3 column and the cyclization
products ( )-2a–4b were eluted with EtOAc. The solvent was then
removed and diastereomeric ratios of ( )-2a–4a and ( )-2b–4b
were determined by the integration of 1H NMR spectra. The
diastereomerically pure isoindoloquinazolinones were readily sep-
arated by silica gel chromatography [n–hexane–EtOAc (2:1)]. The
structures of ( )-2a, ( )-2b, ( )-3a; and ( )-3b, ( )-4a and ( )-4b
were elucidated on the basis of spectroscopic data, in particular,
information acquired by 2D-NMR (Scheme 1). The relative config-
urations of diastereomeric pairs ( )-2a and ( )-2b as well as ( )-3a
and ( )-3b were determined by employing X-ray crystallographic
analysis (Fig. 1). In accordance with the literature data, mutual
NOEs were observed for ArH-2,6 and 12a-H (NCH), and also for
ArH-2,6 and 4a-H [CH(C@O)] in ( )-4b,15 while the structure of
2. Results and discussion
In an earlier paper,7 we described an enantioselective synthesis
of pyrimido[2,1-a]isoindoles by microwave-induced retro
Diels–Alder10 reaction. diexo-(À)-3-Amino-norbornene-2-car-
boxylic acid readily available through an enzymatic resolution
was used as a starting chiral source.11
The goal of the present work was to explore further extensions
of the above methodology that includes (i) the introduction of
diendo-(À)-ethyl-3-aminonorbornene-2-carboxylate as
a chiral
source, (ii) the use of 2-formyl-, 2-acetyl- and 2-(4-methylben-
zoyl)-benzoic acid for the preparation of isoindoloquinazolinone
intermediates, (iii) the investigation of the steric effect of the 2-for-
myl and 2-acyl groups on the diastereoselectivity of the ring-clo-
sure reaction, (iv) separation of diastereomers, and (v) removal of
⇑
Corresponding author.
E-mail address: fulop@pharm.u-szeged.hu (F. Fülöp).
http://dx.doi.org/10.1016/j.tetasy.2017.07.006
0957-4166/Ó 2017 Published by Elsevier Ltd.
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2
F. Miklós et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
( )-4a was supported by a strong NOE measured between ArH-2,6
and 3-H (olefinic) atoms.16
carboxamide (À)-1 was completely preserved during the stereo-
controlled three-step domino reaction to give epimeric pairs. The
effective separation of diastereomers followed by their racemiza-
tion-free retro Diels–Alder reaction allowed the formation of enan-
tiomerically pure pyrimidoisoindoles (+)-9a and (+)-10a, (À)-9b,
and (À)-10b and (À)-10c.
With the isoindoloquinazolinones in hand, considerable efforts
were made to accomplish their thermal decomposition under
microwave irradiation. On the basis of the optimized reaction con-
ditions shown in Scheme 1, pyrimidoisoindoles ( )-5a–5c were
obtained almost quantitatively and in high purity from both 2a–
4a and 2b–4b. Interestingly, in our earlier study,17 ( )-5a formed
directly on cyclization and thermolysis through the reaction of
diexo-3-amino-7-oxanorbornene-2-carboxamide with 2-formyl-
benzoic acid, when the non-isolated oxygen-bridged intermediate
decomposed via the loss of furan in a retro Diels–Alder reaction.
To establish the generality and synthetic potential of the
cyclization of ( )-1 with 2-formylbenzoic acid or 4-oxo acids
followed by the easy separation of the diastereomers and the
successful retro Diels–Alder reaction, the preparation of enan-
tiomerically pure pyrimido[2,1-a]isoindoles was attempted. By
the ammonolysis of ethyl (À)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]
hept-5-ene-2-carboxylate, the amorphous free base (À)-1 was
obtained with an ee value about 98%. To determine the physical
and optical properties of poorly crystallized (À)-1 its HCl salt
was prepared. In a stereocontrolled cyclization, (À)-1 was treated
with 2-formylbenzoic acid, 2-acetylbenzoic acid and 2-(4-toluoyl)
benzoic acid under reaction conditions similar to those presented
in Scheme 1. The reactions gave epimeric pentacycle pairs (À)-6a
and (+)-6b, (+)-7a and (À)-7b and 8a and (+)-8b (Scheme 2). The
presence of diastereomer 8a was observed only in the proton spec-
trum of the crude diastereomeric mixture, and a sufficient amount
of 8a was not available for further investigations. The purified iso-
mers were subjected to microwave-assisted retro Diels–Alder reac-
tion, resulting in the enantiomeric (+)-9a and (+)-10a from (À)-6a
and (+)-7b, respectively. Furthermore, the counterpart (À)-9b and
(À)-10b from (+)-6b and (À)-7b could also be obtained. The single
enantiomer (À)-10c was prepared by the thermolysis of (+)-8b.
The ready loss of cyclopentadiene afforded the expected enan-
tiomers in yields of 89–97% and with ee values of ꢀ99%.
4. Experimental
4.1. General
Melting points were determined on a Kofler apparatus and are
uncorrected. 1H NMR (400 Hz) and 13C NMR (100 MHz) spectra
were recorded on a Bruker Avance DRX 400 spectrometer, with
TMS as internal reference and DMSO-d6 or CDCl3 as solvent. FTIR
spectra were recorded on a Perkin-Elmer 100 FT-IR spectrometer.
Elemental analyses were carried out on a Perkin-Elmer 2400 ele-
mental analyser. Microwave-promoted reactions were performed
in sealed reaction vials (10 mL) by means of a CEM, Discover micro-
wave reactor. Optical rotations were measured on a Perkin-Elmer
341 polarimeter. Mass spectra were recorded on a Finnigan MAT
95S spectrometer.
The ee values of (+)-10a and (À)-10b were determined on a
Chiralpak IA column (4.6 Â 250 mm); detection at 332 nm; eluent:
n-hexane/Et2NH/i-PA (75/0.1/25); flow rate: 0.5 mL/min; retention
times (min) for (+)-10a: 23.96 (antipode, (À)-10b: 25.66).
Conditions for (+)-11a and (À)-11b: Chiralpak IA column
(4.6 Â 250 mm); detection at 236 nm; eluent: n–hexane/Et2NH/i-
PA (90/0.1/10); flow rate: 0.5 mL/min; retention times (min) for
(+)-11a: 41.26 (antipode, (À)-11b: 46.02). Data for (+)-9a and
(À)-9b: Chiralpak IA column (4.6 Â 250 mm); detection at
220 nm; eluent: n–hexane/Et2NH/i-PA (90/0.1/10); flow rate: 0.5
mL/min; retention times (min) for (+)-9a: 49.19 (antipode, (À)-
9b: 51.57). The ee value of (À)-1 was determined on a GC equipped
with a Chrompack Chirasil-Dex CB column after a simple derivati-
zation with Ac2O in the presence of 4-dimethylaminopyridine and
pyridine [120 °C for 4 min ? 170 °C (temperature rise 10 °C min-1;
140 kPa; retention times (min), (À)-1: 22.25 (antipode: 23.25)].
It should be noted that all spectroscopic data of the enantiopure
compounds were identical with those of the racemic samples.
3. Conclusions
4.1.1. X-ray structure determination
The crystals of 2a, 2b, 3a, and 3b were immersed in cryo-oil,
mounted in a MiTeGen loop, and measured at 120–170 K on a
Rigaku Oxford Diffraction Supernova or on a Bruker Kappa Apex
In conclusion, an efficient synthesis of pyrimidoisiondole ena-
tiomers has been accomplished. The chirality of parent b-amino
COOH
O
N
O
6
O
NH
NH
O
R
R
+
6a
R
N
NH2
1
12
p-TSA
NH2
O
O
toluene, reflux, 16 h
2b
(
(
(
)- : R = H (49%)
2a
(
(
(
)- : R = H (24%)
(
)-1
)-3b: R = Me (38%)
)-4b: R = 4-MeC6H6 (39%)
)-3a: R = Me (6%)
)-4a: R = 4-MeC6H6 (3%)
MW, 200 W
MW, 200 W
°
210 C, 15 min
°
210 C, 15 min
o-DCB
o-DCB
O
N
1
NH
R
10b
6
O
(
(
(
)-5a: R = H
5b
)- : R = Me
5c
(89–96%)
)- : R = 4-MeC6H4
Scheme 1. Preparation of pyrimidoisoindoles ( )-5a–5c by domino ring closure, followed by thermal cycloreversion.
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F. Miklós et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Figure 1. ORTEP views of diastereomeric pairs 2a–2b and 3a–3b.
O
N
O
N
COOH
O
NH
NH
O
R
R
R
+
NH2
NH2
p-TSA
toluene, reflux, 16 h
O
O
+
(
6b
)- : R = H (49%)
−
6a
(
)- : R = H (26%)
1
(–)-
(−)-7b: R = Me (41%)
(+)-7a: R = Me (5%)
8b
(+)- : R = 4-MeC6H6 (38%)
8a
: R = 4-MeC6H6 (≈0%)
MW, 200 W
210 °C, 15 min
o-DCB
MW, 200 W
210 °C, 15 min
o-DCB
O
O
NH
R
NH
R
N
O
N
O
9b
(–)- : R = H (96%)
(+)-9a: R = H (92%)
(–)-10b: R = Me (97%)
(+)-10a: R = Me (91%)
10c
(–)-
: R = 4-MeC6H4 (89%)
Scheme 2. Synthesis of antipode pairs [(+)-9a–(À)-9b and [(+)-10a–(À)-10b] and single enantiomeric pyrimidoisoindoles.
II diffractometer using Cu
K
a
(k = 1.54184 Å) or Mo
K
a
using SHELXL-2014.22 The high R-values and residual densities in
3a are due to the low data quality and possible twinning. How-
ever, not satisfactory twin model could be found and therefore
no twin model was used in the final refinement. In 2b and 3b
the NH hydrogen atoms were located from the difference Fourier
map and refined isotropically. Other hydrogen atoms were posi-
tioned geometrically and constrained to ride on their parent
(k = 0.71073) radiation. The CrysAlisPro18 or Denzo-Scalepack19
program packages were used for cell refinements and data reduc-
tions. Multi-scan absorption corrections (CrysAlisPro18 or
SADABS20) were applied to the intensities before structure solu-
tion. The structures were solved by charge flipping method using
the SUPERFLIP21 software. Structural refinements were carried out
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4
F. Miklós et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
atoms, with C–H = 0.95–1.00 Å, N–H = 0.88 Å and Uiso = 1.2–
1.5ÁUeq(parent atom). The crystallographic details are summarized
in Table XS1.
dd, J = 8.8 Hz, J = 4.1 Hz, H-4a), 3.26 (1H, s, H-4), 4.02 (1H, s, H-1),
4.36 (1H, dd, J = 8.8 Hz, J = 3.6 Hz, H-12a), 5.80 (1H, s, H-6a), 5.95
(1H, dd, J = 6.0 Hz, J = 2.9 Hz, H-2), 6.06 (1H, dd, J = 5.6 Hz,
J = 2.7 Hz, H-3), 7.51–7.74 (4H, m, H-Ar), 8.92 (1H, s, CONH). 13C
NMR (100 MHz, DMSO-d6) d (ppm) 44.7, 46.0, 46.1, 46.2, 54.9,
66.7, 123.5, 124.5, 130.3, 132.5, 133.5, 135.3, 137.7, 141.5, 165.4,
172.1. Anal. calcd. for C16H14N2O2 (%): C, 72.16; H, 5.30; N, 10.52.
Found: C, 72.15; H, 5.45; N, 10.45. MS: (ESI) m/z = 201.26 [M+rDAH]+
and 267.23 [M+H]+.
4.2. Synthesis of isoindolo[2,1-a]quinazolines ( )-2a, ( )-2b, ( )-
3a, ( )-3b, ( )-4a and ( )-4b
A
mixture of diendo-3-aminobicyclo[2.2.1]hept-5-ene-2-car-
boxamide ( )-1, (0.76 g, 5.0 mmol) 2-formylbenzoic acid, 2-
acetylbenzoic acid or 2-(4-methylbenzoyl)benzoic acid
(5.2 mmol) and p-TSA (0.05 g) in toluene (40 mL) was refluxed
for 16 h. The solvent was then evaporated off, the residue was
dissolved in EtOAc (15 mL) and the solution was transferred to
a neutral Al2O3 column and eluted with EtOAc. After evaporation,
a small amount (10 mg) of the residue was separated to deter-
mine the diastereomeric ratio by 1H NMR analysis. The major
fraction was transferred to a silica gel column and eluted with
a mixture of n-hexane–EtOAc (2:1).
4.2.3. (1S⁄,4R⁄,4aS⁄,6aR⁄,12aR⁄)-6a-Methyl-1,4,4a,6,6a,12a-
hexahydro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-
dione ( )-3a
Yield: 6%, colourless crystals, mp 297–299 °C (EtOAc). IR (KBr):
3170, 3047, 3023, 2985, 2978, 2902, 1701, 1655, 1466, 1347,
736 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm) 1.49 (1H, m, H-
.
13), 1.57–1.63 (4H, m, H-13 and CH3), 2.94 (1H, dd, J = 9.6 Hz,
J = 4.0 Hz, H-4a), 3.14 (1H, s, H-4), 3.28 (1H, s, H-1), 5.01 (1H, dd,
J = 9.7 Hz, J = 3.5 Hz, H-12a), 6.36 (2H, m, H-2 and H-3), 7.49–
7.85 (4H, m, H-Ar), 8.88 (1H, s, CONH). 13C NMR (100 MHz,
DMSO-d6) d (ppm) 34.1, 41.1, 47.1, 48.4, 49.5, 54.0, 74.4, 122.7,
123.8, 128.9, 130.1, 133.8, 137.3, 138.3, 150.8, 170.1, 170.5. Anal.
calcd. for C17H16N2O2 (%): C, 72.84; H, 5.75; N, 9.99. Found: C,
72.65; H, 5.95; N, 10.05 MS: (ESI) m/z = 281.45 [M+H]+.
4.2.1. (1S⁄,4R⁄,4aS⁄,6aR⁄,12aR⁄)-1,4,4a,6,6a,12a-Hexahydro-1,4-
methanoisoindolo[2,1-a]quinazoline-5,11-dione ( )-2a
Yield: 24%, colourless crystals, mp 302–304 °C (EtOH). IR
(KBr): 3218, 3112, 3062, 2969, 1683, 1665, 1654, 1470, 1398,
737 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm) 1.45 (1H, d,
.
J = 8.8 Hz, H-13), 1.62 (1H, d, J = 8.7 Hz, H-13), 2.90 (1H, dd,
J = 9.1 Hz, J = 4.1 Hz, H-4a), 3.17 (1H, s, H-4), 3.26 (1H, s, H-1),
5.03 (1H, dd, J = 9.1 Hz, J = 3.5 Hz, H-12a), 5.64 (1H, s, H-6a),
6.38 (1H, dd, J = 5.8 Hz, J = 2.8 Hz, H-2), 6.42 (1H, dd, J = 5.7 Hz,
J = 2.8 Hz, H-3), 7.53–7.79 (4H, m, H-Ar), 8.81 (1H, s, CONH). 13C
NMR (100 MHz, DMSO-d6) d (ppm) 42.1, 47.2, 48.8, 49.3, 51.1,
66.1, 123.8, 124.5, 130.4, 131.5, 133.0, 136.6, 137.6, 143.3,
4.2.4. (1S⁄,4R⁄,4aS⁄,6aS⁄,12aR⁄)-6a-Methyl-1,4,4a,6,6a,12a-
hexahydro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-
dione ( )-3b
Yield: 38%, colourless crystals, mp 264–266 °C (EtOAc). IR (KBr):
3246, 3165, 3064, 3014, 2970, 2930, 2890, 1707, 1683, 1666, 1655,
1468, 1383, 737 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm) 1.46
.
167.2, 171.5. Anal. calcd. for
C16H14N2O2 (%): C, 72.16; H,
(2H, m, H-13), 1.67 (3H, s, CH3), 3.17 (1H, dd, J = 8.6 Hz, J = 4.1 Hz,
H-4a), 3.25 (1H, s, H-4), 4.07 (1H, s, H-1), 4.35 (1H, dd, J = 8.6 Hz,
J = 3.6 Hz, H-12a), 5.92 (1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-2), 6.15
(1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-3), 7.48–7.79 (4H, m, H-Ar), 8.94
(1H, s, CONH). 13C NMR (100 MHz, DMSO-d6) d (ppm) 29.3, 44.1,
45.9, 46.0, 46.3, 53.1, 73.9, 123.1, 123.6, 130.2, 131.6, 132.8,
135.4, 137.6, 146.6, 164.7, 171.3. Anal. calcd. for C17H16N2O2 (%):
C, 72.84; H, 5.75; N, 9.99. Found: C, 72.69; H, 5.65; N, 9.75. MS:
(ESI) m/z = 215.48 [MrDA+H]+, 281.70 [M+H]+.
5.30; N, 10.52. Found: C, 72.03; H, 5.51; N, 10.65. MS: (ESI)
m/z = 267.32 [M+H]+.
4.2.2. (1S⁄,4R⁄,4aS⁄,6aS⁄,12aR⁄)-1,4,4a,6,6a,12a-Hexahydro-1,4-
methanoisoindolo[2,1-a]quinazoline-5,11-dione ( )-2b
Yield: 49%, colourless crystals, mp 263–265 °C (EtOAc). IR (KBr):
3244, 3045, 2968, 2870, 1673, 1661, 1466, 1348, 731 cmÀ1 1H
.
NMR (400 MHz, DMSO-d6) d (ppm) 1.46 (2H, m, H-13), 3.03 (1H,
Table XS1
Crystal data
2a
2b
3a
3b
Empirical formula
fw
Temp (K)
k (Å)
Cryst syst
Space group
a (Å)
C
16H14N2O2
C16H14N2O2
266.29
120(2)
1.54184
Monoclinic
P21/c
21.07531(12)
13.71333(7)
8.74579(5)
90
94.4336(5)
90
C17H16N2O2
280.32
120(2)
1.54184
Orthorhombic
Pca21
12.78094(14)
11.91104(12)
18.28733(19)
90
C17H16N2O2
280.32
170(2)
266.29
170(2)
0.71073
Monoclinic
P21/n
6.6492(6)
10.4134(11)
18.0859(14)
90
92.658(8)
90
1250.94(19)
4
0.71073
Triclinic
ꢀ
P1
9.3061(2)
11.8133(3)
13.0880(3)
98.2230(10)
98.7360(10)
90.9940(10)
1406.40(6)
4
b (Å)
c (Å)
a
(°)
b (°)
90
90
c
(°)
V (Å3)
2520.08(2)
8
1.404
2783.96(5)
8
1.338
Z
qcalc (Mg/m3)
1.414
0.095
1.324
0.088
l(K
a
) (mmÀ1
)
0.762
0.716
No. reflns.
4527
63286
33800
27156
Unique reflns.
GOOF (F2)
Rint
2572
1.053
0.0352
0.0535
0.1089
5306
1.028
0.0291
0.0355
0.0906
4893
1.415
0.2771
0.1254
0.2771
7258
1.110
0.0581
0.0702
R1a (I ꢀ 2
r
)
wR2b (I ꢀ 2
r
)
0.1112
a
R1 =
wR2 = [
R
||Fo| À |Fc||/
R|Fo|.
b
R
[w(F2o À F2c)2]/
R .
[w(F2o)2]]1/2
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F. Miklós et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
4.2.5. (1S⁄,4R⁄,4aS⁄,6aR⁄,12aR⁄)-6a-(p-Tolyl)-1,4,4a,6,6a,12a-
hexahydro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-
dione ( )-4a
C, 74.47; H, 4.86; N, 9.65. Found: C, 74.62; H, 5.00; N, 9.81; MS:
(ESI) m/z = 291.30 [M+H]+.
Yield: 3%, colourless crystals, mp 230–232 °C (EtOAc). IR (KBr):
3291, 3075, 3018, 2986, 2944, 2904, 1756, 1676, 1652, 1611, 1487,
4.4. Synthesis of (À)-(1R,2S,3R,4S)-3-aminobicyclo[2.2.1]hept-5-
ene-2-carboxamide (À)-1
1355, 1322, 738 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm) 1.38
.
(2H, m, H-13), 2.26 (3H, s, CH3), 2.34 (1H, dd, J = 8.8 Hz, J = 3.9 Hz,
H-4a), 2.94 (1H, d, J = 10.3 Hz, CONH), 3.04 (1H, s, H-4), 3.20 (1H, s,
H-1), 3.79 (1H, m, H-12a), 6.16 (1H, dd, J = 5.6 Hz, J = 2.9 Hz, H-2),
6.23 (1H, dd, J = 5.6 Hz, J = 2.8 Hz, H-3), 7.17–7.77 (8H, m, H-Ar).
13C NMR (100 MHz, DMSO-d6) d (ppm) 21.4, 46.3, 46.5, 46.7,
47.6, 57.8, 83.9, 124.2, 125.2, 126.2 (2 Â C), 128.7, 130.5, 130.9
(2 Â C), 135.4, 135.5, 138.5, 138.9, 139.4, 149.3, 165.9, 170.7. Anal.
calcd. for C23H20N2O2 (%): C, 77.51; H, 5.66; N, 7.86. Found: C,
77.68; H, 5.75; N, 7.75. MS: (ESI) m/z = 291.39 [MrDA+H]+ and
357.26 [M+H]+.
(À)-(1R,2S,3R,4S)-Ethyl-3-aminobicyclo[2.2.1]hept-5-ene-2-car-
boxylate13 (3.5 g, 19.3 mmol,) was left to stand at rt for 5 weeks in
a 26% ammoniaÀmethanol solution (200 mL). The solution was
then evaporated to dryness, the residue was dissolved in EtOAc
(20 mL), and the solution was transferred to a silica gel column
and eluted, first with EtOAc and then with EtOAc/MeOH (3:1).
The residue of the eluates afforded (À)-1 (1.41 g, 48%) as pale-
yellow semi-crystalline solid. 100 mg of (À)-1 was treated with
ethanolic hydrogen chloride to obtain crytalline (À)-1 Â HCl. Mp
239–241 °C (EtOH–Et2O); [
a
]
D
25=À14.8 (c 0.485, H2O), ee > 99%
(GC).
4.2.6. (1S⁄,4R⁄,4aS⁄,6aS⁄,12aR⁄)-6a-(p-Tolyl)-1,4,4a,6,6a,12a-
hexahydro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-
dione ( )-4b
4.5. Synthesis of isoindolo[2,1-a]quinazolines (À)-6a, (+)-6b,
(+)-7a, (À)-7b and (+)-8b enantiomers
Yield: 39%, colourless crystals, mp 265–267 °C (EtOAc) (lit. mp
270–271 °C)15 The NMR spectrum was identical with that of an
authentic sample.
A mixture of (À)-(1R,2S,3R,4S)-3-norbornene-2-carboxamide
(À)-1, (350 mg, 2.3 mmol), 2-formylbenzoic acid, 2-acetylbenzoic
acid or 2-(4-methylbenzoyl)benzoic acid (2.5 mmol), and p-TSA
(0.03 g) in toluene (25 mL) was refluxed for 16 h. The solvent
was then evaporated off, the residue was dissolved in EtOAc
(10 mL), and the solution was transferred to a neutral Al2O3 col-
umn and eluted with EtOAc. The residue of the eluates was trans-
ferred to a silica gel column and eluted with a mixture of n-
hexane–EtOAc (2:1). The 1H NMR spectra for optically active com-
pounds were in accordance with those reported for the racemates.
4.3. Synthesis of pyrimido[2,1-a]isoindole ( )-5a, ( )-5b and ( )-
5c by microwave-induced retro Diels–Alder reaction
All microwave-mediated reactions were carried out in reaction
vials sealed with a Teflon cap. Heterocycles ( )-2a, ( )-2b, ( )-3a,
( )-3b, ( )-4a or ( )-4b (25–100 mg) were placed in a microwave
test tube (10 mL) containing a magnetic stirrer and 1,2-DCB
(2 mL). The test-tube was placed in the cavity of the CEM Discover
microwave reactor. The solutions were irradiated during a period
of 15 min at 210 °C (power 250 W). The cooled solution diluted
with CHCl3 (6 mL) was then transferred to a SiO2 column and
eluted with n-hexaneÀEtOAc (1:1).
4.5.1. (1S,4R,4aS,6aR,12aR)-(À)-1,4,4a,6,6a,12a-Hexahydro-1,
4-methanoisoindolo[2,1-a]quinazoline-5,11-dione (À)-6a
Yield: 26%, colourless crystals, mp 262–264 °C (EtOH).
[a
]
D
25 = À100.5 (c 0.49, EtOH).
4.5.2. (1S,4R,4aS,6aS,12aR)-(+)-1,4,4a,6,6a,12a-Hexahydro-1,4-
methanoisoindolo[2,1-a]quinazoline-5,11-dione (+)-6b
Yield: 38%, colourless crystals, mp 254–256 °C (EtOAc).
4.3.1. 1,10b-Dihydropyrimido[2,1-a]isoindole-2,6-dione ( )- 5a
Yield: 89–95%, colourless crystals, mp 270À272 °C (EtOH) (lit.
mp 242–244 °C)17 Spectroscopic data were identical with that of
an authentic sample.
[a]
25 = +38.0 (c 0.50, EtOH).
D
4.5.3. (1S,4R,4aS,6aR,12aR)-(+)-6a-Methyl-1,4,4a,6,6a,12a-hexahy-
dro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-dione (+)-7a
Yield: 5%, colourless crystals, mp 258–259 °C (iPr2O–EtOAc).
4.3.2. 10b-Methyl-1,10b-dihydropyrimido[2,1-a]isoindole-2,
6-dione ( )-5b
[a]
25 = +10.0 (c 0.19, EtOH).
D
Yield: 91–94%, colourless crystals, mp 200–202 °C (EtOAc–
iPr2O). IR (KBr): 3425, 3178, 3043, 2974, 2899, 1724, 1657, 1617,
4.5.4. (1S,4R,4aS,6aS,12aR)-(À)-6a-Methyl-1,4,4a,6,6a,12a-hexahy-
dro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-dione (À)-7b
Yield: 41%, colourless crystals, mp 141–142 °C (EtOAc).
1472, 1310, 808 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm))
.
1.72 (3H, s, CH3-10b), 5.64 (1H, dd, J = 7.6 Hz, J = 2.0 Hz, H-3),
7.60–7.93 (5H, m, H-4 and H-Ar), 8.84 (1H, s, CONH). 13C NMR
(100 MHz, DMSO-d6) d (ppm) 27.7, 74.9, 107.4, 123.7, 125.3,
129.5, 130.9, 133.0, 135.0, 148.3, 164.8, 165.5. Anal. calcd. for
[a
]
D
25 = À27.0 (c 0.16, EtOH).
4.5.5. (1S,4R,4aS,6aS,12aR)-(+)-6a-(p-Tolyl)-1,4,4a,6,6a,12a-
hexahydro-1,4-methanoisoindolo[2,1-a]quinazoline-5,11-dione
(+)-8b
C
12H10N2O2 (%): C, 67.28; H, 4.71; N, 13.08. Found: C, 67.12; H,
5.95; N, 12.91. MS: (ESI) m/z = 215.35 [M+H]+.
Yield: 34%, colourless crystals, mp 265–267 °C (iPr2O–EtOAc).
[a]
25 = +106.8 (c 0.37, EtOH).
D
4.3.3. 10b-(p-Tolyl)-1,10b-dihydropyrimido[2,1-a]isoindole-2,6-
dione ( )-5c
Yield: 90–96%, colourless crystals, mp 268–270 °C (EtOAc–
iPr2O). IR (KBr): 3430, 3184, 3062, 2922, 1722, 1665, 1651, 1465,
4.6. Synthesis of enantiomeric pyrimido[2,1-a]isoindole (+)-9a,
(À)-9b, (+)-10a, (À)-10b and (À)-11b by microwave-induced
retro Diels–Alder reaction
1316, 822, 810 cmÀ1 1H NMR (400 MHz, DMSO-d6) d (ppm)) 1.99
.
(3H, s, p-CH3-Ar-10 b), 5.36 (1H, dd, J = 7.7 Hz, J = 2.1 Hz, H-3),
7.10–7.94 (9H, m, H-4 and H-Ar), 9.71 (1H, d, J = 1.8 Hz, CONH).
13C NMR (100 MHz, DMSO-d6) d (ppm) 21.4, 78.0, 108.7, 124.4,
125.4, 125.8 (2 Â C), 129.2, 130.2 (2 Â C), 130.9, 133.2, 135.3,
138.8, 140.0, 148.2, 165.6, 166.1. Anal. calcd. for C18H14N2O2 (%):
The reactions were performed as described for the racemates,
on 25–100 mg scale. All 1H NMR spectra recorded for the enan-
tiomeric substances were the same as those for the racemic
counterparts.
Please cite this article in press as: Miklós, F.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.07.006

6
F. Miklós et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.6.1. (R)-(+)-1,10b-Dihydropyrimido[2,1-a]isoindole-2,6-dione
(+)-9a
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D
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(À)-9b
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isoindole-2,6-dione (À)-10b
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[a
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4.6.5. (S)-(À)-10b-(p-Tolyl)-1,10b-dihydropyrimido[2,1-a]
isoindole-2,6-dione (À)-11b
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Acknowledgements
We are grateful to the Hungarian Research Foundation (OTKA
No. K 115731). The financial support of the GINOP-2.3.2-15-
2016-00014 project is acknowledged.
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A. Supplementary data
Supplementary data (Copies of the 1H and 13C NMR spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetasy.2017.07.006.
Please cite this article in press as: Miklós, F.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.07.006