Diexo-3-aminonorbornane-2-carboxylic acid as highly applicable chiral, source for the enantioselective synthesis of heterocycles

Article abstract of DOI:10.1055/s-2008-1077793

Diastereomers of tetracyclic pyrrolopyrimidine derivatives 2 and 3 were prepared in a three-step domino reaction from diexo-3-aminobicyclo[2.2.1]hept-5- ene-2-carboxamide with levulinic acid or p-toluoylpropionic acid. When subjected to a microwave-mediated retro-Diels-Alder reaction, these tetracycles furnished bicyclic pyrrolo[1,2-a]pyrimidines through the loss of cyclopentadiene. When enantiomeric diexo-3-aminobicyclo 2.2.1]hept-5-ene-2-carboxamide was used, the products were enantiomeric heterocycles with ee >99%, demonstrating that the title compound is an excellent chiral source. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077793

LETTER
1687
diexo-3-Aminonorbornane-2-carboxylic Acid as Highly Applicable Chiral
Source for the Enantioselective Synthesis of Heterocycles
C
hira
l
Source
e
for the
E
na
r
ntiosele
c
e
tive Synthe
n
sis of
H
etero
c
c
ycles Fülöp,*a,b Ferenc Miklós,a Enikő Forróa
a
Institute of Pharmaceutical Chemistry, Hungarian Academy of Sciences, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary
Fax +36(62)545705; E-mail: fulop@pharm.u-szeged.hu
b
Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, Eötvös utca 6, 6720 Szeged, Hungary
Received 12 March 2008
stereoselective reactions, the starting amino acid controls
the new stereogenic center(s) and the chirality of the ami-
no acid is transferred to the heterocycles. Since determi-
nation of the relative configuration of the intermediate
Abstract: Diastereomers of tetracyclic pyrrolopyrimidine deriva-
tives 2 and 3 were prepared in a three-step domino reaction from
diexo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxamide with le-
vulinic acid or p-toluoylpropionic acid. When subjected to a micro-
wave-mediated retro-Diels–Alder reaction, these tetracycles heterocycles is generally a routine process, the absolute
furnished bicyclic pyrrolo[1,2-a]pyrimidines through the loss of cy-
configuration of the final product will also be evident.
clopentadiene.
When
enantiomeric
diexo-3-aminobicyc-
lo[2.2.1]hept-5-ene-2-carboxamide was used, the products were
enantiomeric heterocycles with ee >99%, demonstrating that the ti-
tle compound is an excellent chiral source.
O
NH2
NH2
rac-1
Key words: asymmetric synthesis, b-amino acids, retro reactions,
ring closure, chiral source, chirality transfer, domino reactions
COOH
PTSA
toluene
reflux, 10 h
O
R
Cyclic b-amino acids have attracted great interest in the
past decade, and this has become a hot topic in synthetic
and medicinal chemistry. These compounds can be widely
applied as building blocks in peptide chemistry, in drug
research, and in heterocyclic and combinatorial chemis-
try.1–5
O
N
O
N
NH
NH
R
R
O
O
A new application of diendo- and diexo-3-aminobicyc-
lo[2.2.1]hept-5-ene-2-carboxylic acid (diendo- or diexo-
aminonorbornenecarboxylic acid) and their derivatives
was discovered by Stájer and coworkers: the construction
of saturated heterocycles based on them and the subse-
quent removal of cyclopentadiene in a mild thermal pro-
cess. This is a new strategy for the preparation of mono-
and bicyclic heterocycles (oxazoles, isoxazoles, pyra-
zoles, imidazoles, triazoles, pyrimidinones, oxazinones,
and pyridazinones) using a retro-Diels–Alder (RDA) re-
action.6–8
rac-2a: R = Me 84%
rac-2b: R = 4-MeC6H4 33%
rac-3a: R = Me ~0%
rac-3b: R = 4-MeC6H4 16%
MW
MW
250 °C
10 min
250 °C
10 min
O
NH
N
R
O
rac-4a: R = Me 98%
rac-4b: R = 4-MeC6H4 90–93%
A major goal of synthetic organic chemistry is the asym-
metric synthesis of biologically active compounds, and
especially heterocycles. The use of chirality transfer is a
powerful method to generate new stereogenic centers.9,10
Our present aim was to investigate the applicability of
diexo-3-aminonorbornane-2-carboxylic acid enantiomers
as chiral sources for the synthesis of several simple het-
erocycles. The most important elements of the strategy
are: i) synthesis of a heterocycle from a b-amino acid or
its derivative by generating a new asymmetric center(s);
ii) separation of the diastereomers, if necessary; iii) re-
moval of the cyclopentadiene in an RDA reaction. In dia-
Scheme 1 Synthesis of bicycles 4 by domino ring closure, followed
by retro-Diels–Alder reaction
Racemic diexo-3-aminobicyclo[2.2.1]hept-5-ene-2-car-
boxamide (rac-1) was prepared by known literature pro-
tocols. Bicyclo[2.2.1]hepta-2,5-diene underwent the 1,2-
dipolar cycloaddition of chlorosulfonyl isocyanate11 to
give the corresponding b-lactam, which was ring-opened
to afforded the amino acid ethyl ester with 20% ethanolic
HCl, and then amidated with methanolic ammonia.12 The
enantiomeric (–)-1 carboxamide was prepared from the
racemic lactam, which was selectively ring-opened to the
amino acid with water in the presence of Lipolase in diiso-
propyl ether at 70 °C.13 Opening of the enantiomerically
SYNLETT 2008, No. 11, pp 1687–1689
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.05.2008
DOI: 10.1055/s-2008-1077793; Art ID: G07808ST
© Georg Thieme Verlag Stuttgart · New York

1688
F. Fülöp et al.
LETTER
O
pure unreacted b-lactam with 20% ethanolic HCl gave the
enantiopure ethyl ester, which was amidated with metha-
nolic ammonia to yield (–)-1 carboxamide with ee >99%.
H2N
H2N
In preliminary experiments, levulinic acid or p-toluoyl-
propionic acid and racemic diexo-3-aminobicyc-
lo[2.2.1]hept-5-ene-2-carboxamide (rac-1) were reacted
in toluene under reflux with p-toluenesulfonic acid (PT-
SA) as catalyst. In the case of levulinic acid, only a single
diastereomer, pyrrolopyrimidine rac-2a, was formed.
When p-toluoylpropionic acid was reacted with rac-1,
two epimeric tetracycles, rac-2b and rac-3b, were formed
in a ratio 2:1 (Scheme 1). The diastereomers were easily
separable by column chromatography. The RDA reac-
tions can be performed without solvent in the melt phase,
or in high-boiling solvents. We recently discovered14 that
microwave heating accelerates the RDA reaction and the
products are formed in very clean procedures in high
yields. The RDA reaction was therefore performed in a
microwave reactor at 250 °C, in o-dichlorobenzene (o-
DCB), resulted in rac-4a from rac-2a and rac-4b from
both rac-2b and rac-3b, respectively, in yields of over
90%. Pyrroloquinazolinones are interesting compounds
from both synthetic and pharmacological apects.15,16
(–)-1
PTSA
toluene
reflux, 14 h
COOH
O
R
O
N
O
N
HN
R
HN
R
O
O
(+)-2a: R = Me 86%
(+)-3b: R = 4-MeC6H4 19%
(+)-2b: R = 4-MeC6H4 36%
MW
250 °C
10 min
MW
250 °C
10 min
O
O
HN
R
HN
R
N
N
O
O
(–)-4a: R = Me 96%
(–)-4b: R = 4-MeC6H4 91%
(+)-4b: R = 4-MeC6H4 93%
The formation of pyrroloquinazolines 2 and 3 is a typical
three-step domino reaction17 via a ring–chain tautomeric
protocol (Scheme 2). In the first step, Schiff base 5 is
formed, which undergoes cyclization to pyrimidine dias-
tereomers 6 and 7 by ring–chain tautomerism.18 The last
step is the formation of the lactam by nucleophilic attack
of the ring nitrogen. The diastereoselectivity of the reac-
tions results from the last step.18,19
Scheme 3 Synthesis of enantiomeric heterocycles 4a and 4b
from (+)-2b and the counterpart (+)-4b from (+)-3b, re-
spectively, in yields of over 90% and with ee >99%.23
In conclusion, a simple protocol was introduced to pre-
pare several nonracemic heterocycles using diexo-3-ami-
nonorbornane-2-carboxylic acid as chiral source. The
protocol is based on a domino ring-closure reaction where
the relative configuration of a new asymmetric center is
controlled by the stereochemistry of the amino acid, fol-
lowed by RDA reaction. Since determination of the rela-
tive configuration of the resulting heterocycles is routine,
the absolute configuration of the heterocycles formed in
the microwave-mediated RDA reaction is evident. In the
removal of the cyclopentadiene, only five carbon atoms
are lost; the reaction therefore has relatively good atom
economy.
O
O
NH
R
NH2
C
COOH
COOH
N
H
N
R
5
6
O
2
NH
R
COOH
3
N
H
Acknowledgment
7
We are grateful to the Hungarian Research Foundation (OTKA No.
T049407) for financial support.
Scheme 2 The mechanism of domino ring closure
When levulinic acid was reacted with (–)-1,20 the single
diastereomer (enantiomer) (+)-2a was formed in 86%
yield.21 The ready loss of cyclopentadiene resulted in the
enantiomeric (+)-4a in almost quantitative yield.22
References and Notes
(1) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.;
Soloshonok, V. A., Eds.; Wiley-Interscience: New York,
2005.
(2) Fülöp, F. Chem. Rev. 2001, 101, 2181.
(3) Davies, S. G.; Smith, A. D.; Price, P. D. Tetrahedron:
Asymmetry 2005, 16, 2833.
(4) Ortuno, R. M.; Moglioni, A. G.; Moltrasio, G. Y. Curr. Org.
Chem. 2005, 9, 237.
(5) Fülöp, F.; Martinek, T. A.; Tóth, G. K. Chem. Soc. Rev.
2006, 35, 323.
When carboxamide (–)-1 was reacted with p-toluoylpro-
pionic acid under the above conditions, epimeric tetracy-
cles (+)-2b and (+)-3b were formed21 in a ratio of 2:1
(Scheme 3). The diastereomers were separated by column
chromatography. The RDA reaction was performed by
microwave heating,22 resulting in the enantiomeric (–)-4b
Synlett 2008, No. 11, 1687–1689 © Thieme Stuttgart · New York

LETTER
Chiral Source for the Enantioselective Synthesis of Heterocycles
1689
(6) Stájer, G.; Csende, F.; Fülöp, F. Curr. Org. Chem. 2003, 7,
1423.
137.85, 169.96, 172.35. MS: m/z = 233 [M + H]+.
Compound (+)-2b: colorless crystals, mp 134–136 °C
(7) (a) Stájer, G.; Szabó, A. E.; Fülöp, F.; Bernáth, G. Synthesis
1984, 345. (b) Miklós, F.; Stájer, G.; Sohár, P.; Böcskei, Z.
Synlett 2000, 67. (c) Stájer, G.; Miklós, F.; Sohár, P.;
Sillanpää, R. Eur. J. Org. Chem. 2001, 4153. (d) Stájer, G.;
Szabó, A. E.; Sohár, P.; Csámpai, A.; Sillanpää, R. J. Mol.
Struct. 2006, 784, 239. (e) Stájer, G.; Miklós, F.; Kanizsai,
I.; Csende, F.; Sillanpää, R.; Sohár, P. Eur. J. Org. Chem.
2004, 3701.
(8) (a) Fülöp, F.; Huber, I.; Szabó, ; Bernáth, G.; Sohár, P.
Tetrahedron 1991, 47, 7673. (b) Fülöp, F.; Palkó, M.;
Bernáth, G.; Sohár, P. Synth. Commun. 1997, 27, 195.
(9) (a) Handbook of Chiral Chemicals, 2nd ed.; Ager, D., Ed.;
CRC Press/Taylor and Francis: Boca Raton, 2006.
(b) Asymmetric Synthesis – The Essentials; Christmann, M.;
Bräse, S., Eds.; Wiley-VCH: Weinheim, 2007.
(Et2O–n-hexane); [a]D25 +37 (c 0.25, MeOH). IR (KBr):
3178, 1705, 1661, 817 cm–1. 1H NMR (400 MHz, DMSO):
d = 9.48 (br s, NH), 7.23–7.07 (m, 4 ArH), 6.15 (dd, J = 2.9,
5.8 Hz, H-7), 6.11 (dd, J = 3.0, 5.6 Hz, H-8), 4.21 (br s, H-
9), 3.25 (br s, H-6), 3.13 (d, J = 7.9 Hz, H-9a), 2.54–2.35 (m,
2 H, H-2), 2.33–2.22 (m, H-3), 2.27 (s, 3 H, CH3-Ar), 2.04
(m, H-3), 1.62 (d, J = 7.7 Hz, H-5a), 1.33 (d, J = 8.8 Hz, H-
10), 1.27 (d, J = 8.8 Hz, H-10). 13C NMR (100 MHz,
DMSO): d = 20.43, 29.30, 34.67, 42.24, 42.63, 43.81, 44.86,
54,08, 77.14, 124.75 (2 × C), 129.56 (2 × C), 135.95, 137.23,
137.66, 140.45, 170.57, 173.36. MS: m/z = 309 [M + H]+.
Compound (+)-3b: colorless powder, mp 247–248 °C
(EtOAc); [a]D25 +40 (c 0.28, MeOH). IR (KBr): 3161, 1704,
1648, 815 cm–1. 1H NMR (400 MHz, DMSO): d = 9.58 (br
s, NH), 7.28–7.17 (m, 4 ArH), 6.26 (dd, J = 3.2, 5.4 Hz, H-
7), 6.20 (dd, J = 2.8, 5.6 Hz, H-8), 4.12 (d, J = 8.8 Hz, H-9a),
2.92 (br s, H-6), 2.62 (br s, H-9), 2.50–2.23 (m, 2 H, H-2),
2.30 (m, H-3a), 2.28 (s, 3 H, CH3-Ar), 2.20 (d, J = 8.8 Hz,
H-3), 2.00 (m, H-3), 0.78 (d, J = 9.1 Hz, H-10), 0.60 (d,
J = 9.1 Hz, H-10). 13C NMR (100 MHz, DMSO): d = 20.44,
28.05, 39.28, 39.70, 44.27, 46.45, 46.58, 50.95, 76.36,
123.76 (2 × C), 129.14 (2 × C), 136.73, 137.53, 137.79,
142.60, 168.98, 173.73. MS: m/z = 309 [M + H]+.
(10) (a) Anaya de Parrodi, C.; Juaristi, E. Synlett 2006, 2699.
(b) Gnas, Y.; Glorius, F. Synthesis 2006, 1899.
(11) Stájer, G.; Mód, L.; Szabó, A. E.; Fülöp, F.; Bernáth, G.;
Sohár, P. Tetrahedron 1984, 40, 2385.
(12) (a) Sohár, P.; Csámpai, A.; Szabó, A. E.; Stájer, G. J. Mol.
Struct. 2004, 694, 139. (b) Stájer, G.; Szabó, A. E.; Fülöp,
F.; Bernáth, G.; Sohár, P. Chem. Ber. 1987, 120, 259.
(13) (a) Forró, E.; Fülöp, F. Org. Lett. 2003, 5, 1209. (b) Forró,
E.; Fülöp, F. Tetrahedron: Asymmetry 2004, 15, 573.
(14) Miklós, F.; Stájer, G.; Fülöp, F. Lett. Org. Chem. 2006, 3,
915.
(22) Syntheses of Pyrrolo[1,2-a]pyrimidines by Microwave-
Induced Retro-Diels–Alder Reaction
All microwave-induced reactions were performed in sealed
reaction vials. Tetracycle 2a, 2b, or 3b (200 mg) was placed
in a microwave test tube (10 mL) subsequently sealed with a
Teflon cap, which contained a magnetic stirrer and o-DCB
(2 mL). The test tube was placed in the microwave (CEM,
Discover) cavity. The solutions were irradiated at 250 °C
(power 250 W) for 10 min then cooled to r.t., CHCl3 (6 mL)
was added, and the solution was transferred to a SiO2 column
and eluted with EtOAc.
Compound (–)-4a: synthesized from (+)-2a, colorless
crystals, mp 170–172 °C (i-Pr2O–EtOAc); [a]D25 –445 (c
0.23, MeOH), ee >99%. IR (KBr): 3182, 1734, 1667, 826
cm–1. 1H NMR (400 MHz, DMSO): d = 8.22 (br s, NH), 7.31
(d, J = 7.8 Hz, H-4), 5.25 (dd, J = 1.9, 7.8 Hz, H-3), 2.69–
2.40 (m, 2 H, H-7), 2.20–2.02 (m, 2 H, H-8), 1.41 (s, 3 H,
CH3). 13C NMR (100 MHz, DMSO): d = 24.03, 29.00, 33.37,
73.08, 105.05, 130.65, 163.03, 170.28. MS: m/z = 167 [M +
H]+.
(15) Gao, J.; Henry, R. F.; Pagano, T. G.; Duerst, R. W.; Souers,
A. J. Tetrahedron Lett. 2007, 48, 7395.
(16) (a) Mutz, M.; Fischer, R. WO 2007082946, 2007.
(b) Nakazato, A.; Okubo, T.; Nozawa, H.; Minda, T.;
Kenneth, L. E. JP 2007169216, 2007. (c) Haberg, A.; Qu,
H.; Hjelstuen, M. H.; Sonnewald, U. Neurochem. Int. 2007,
50, 932. (d) Ishikawa, T.; Miwa, K.; Seto, M.; Banno, H.;
Kawakita, Y. WO 2007064045, 2007. (e) Nagle, A.; Gray,
N. S. WO 2007053343, 2007.
(17) Tietze, L. F.; Brasche, G.; Kersten, G. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(18) Lázár, L.; Fülöp, F. Eur. J. Org. Chem. 2003, 3025.
(19) (a) Meyers, A. I.; Downing, S. W.; Weiser, M. J. J. Org.
Chem. 2001, 66, 1413. (b) Fülöp, F.; Pihlaja, K.
Tetrahedron 1993, 49, 6701.
(20) (1S,2S,3R,4R)-3-Aminobicyclo[2.2.1]hept-5-ene-2-
carboxamide [(–)-1]
Ethyl (1S,2S,3R,4R)-3-aminobicyclo[2.2.1]hept-5-ene-2-
carboxylate (2.5 g, 13.8 mmol) was left to stand at r.t. for 3
weeks in MeOH (50 mL) saturated with NH3. The solution
was then evaporated and the solid residue was crystallized
from MeOH–Et2O, which afforded (–)-1 (72%) as colorless
needles, mp 131–133 °C; [a]D25 –4.8 (c 0.51, MeOH).
(21) Synthesis of Pyrrolo[1,2-a]quinazolines 2 and 3
diexo-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxamide
[(–)-1, (0.76 g, 5 mmol], levulinic acid or p-toluoylpropionic
acid (5.2 mmol), and PTSA (0.05 g) in toluene (25 mL) was
refluxed for 14 h. The solvent was then evaporated off, and
the residue was dissolved in CHCl3 (10 mL) and the products
were separated on a SiO2 column with a mixture of n-
hexane–EtOAc–EtOH (5:4:1).
Compound (–)-4b: synthesized from (+)-2b, colorless
crystals, mp 198–200 °C (i-Pr2O–EtOAc); [a]D25 –311 (c
0.14, MeOH), ee >99%. IR (KBr): 3184, 1728, 1667, 817
cm–1. 1H NMR (400 MHz, DMSO): d = 9.17 (br s, NH), 7.49
(d, J = 7.7 Hz, H-4), 7.22–7.16 (m, 4 ArH), 5.21 (dd, J = 7.7,
1.9 Hz, H-3), 2.59–2.36 [m, 3 H, H-7 (2 H) and H-8 (1 H)],
2.28 (s, 3 H, CH3), 2.28–2.20 (m, 1 H, H-8). 13C NMR
(100.62 MHz, DMSO): d = 20.46, 28.54, 35.47, 76.14,
106.91, 124.33 (2×), 129.08 (2×), 131,62, 137.42, 139.98,
163.23, 171.26. MS: m/z = 243 [M + H]+.
Compound (+)-4b: synthesized from (+)-3b, colorless
crystals, mp 197–199 °C (i-Pr2O×EtOAc); [a]D25 +310 (c
0.11, MeOH), ee >99%. 1H NMR and 13C NMR data were
identical to the compound (–)-4b.
Compound (+)-2a: yield 86%, colorless crystals, mp 173–
175 °C (EtOAc–i-Pr2O); [a]D25 +49 (c 0.27, MeOH). IR
(KBr): 3173, 1701, 1659, 707 cm–1. 1H NMR (400 MHz,
DMSO): d = 8.69 (br s, NH), 6.29 (dd, J = 2.7, 5.5 Hz, H-7),
6.17 (dd, J = 2.7, 5.5 Hz, H-8), 4.05 (br s, H-9), 3.34 (d,
J = 7.8 Hz, H-8a), 3.27 (br s, H-6), 2.39–2.32 (m, 2 H, H-2),
2.29 (d, J = 7.8 Hz, H-5a), 2.02 (m, H-3), 1.87 (m, H-3), 1.37
(s, 3 H, CH3-3a), 1.27 (d, J = 8.7 Hz, H-10), 1.20 (d, J = 8.7
Hz, H-10). 13C NMR (100 MHz, DMSO): d = 26.12, 29.49,
32.28, 41.69, 43.11, 43.38, 45.23, 52.32, 73.14, 135.70,
(23) The ee value for pyrrolo[1,2-a]pyrimidine (–)-4a was
determined by GC on a Chromopack Chiralsil-Dex CB
column (25 m) [120 °C for 7 min → 190 °C (temperature
rise 20 °C min–1; 100 kPa; (–)-4a: tR = 23.25 min (antipode:
24.70)]. The ee values for pyrrolo[1,2-a]pyrimidine (–)-4b
and (+)-4b were determined by HPLC on a Chiralcel
OD-RH column (15 cm) [mobile phase, H2O–MeCN
(75:25), 205 nm, 0.5 mL min–1, 25 °C; (–)-4b: tR = 13.29
min; (+)-4b: tR = 16.85 min].
Synlett 2008, No. 11, 1687–1689 © Thieme Stuttgart · New York