Preparation of cycloalkane-fused dihydropyrimidin-4(3H)-one enantiomers

Article abstract of DOI:10.1016/S0957-4166(98)00069-X

Racemic cis-2-amino-1-cyclopentane- or -cyclohexane-1-carboxylic acid was reacted with (R)-α-methylbenzylamine to form homochiral amides 3, 4 and 8, 9. The ring closures of 3, 4 and 8, 9 with aryl imidates resulted in cyclopentane cis-fused and cyclohexane cis- and trans-fused dihydropyrimidin- 4-one enantiomers with loss of the N-substituent. The absolute configurations were determined by hydrolysis of 5, 6 and 10-13 to the corresponding amino acids.

Full text of DOI:10.1016/S0957-4166(98)00069-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 993–999
Preparation of cycloalkane-fused dihydropyrimidin-4(3H)-one
enantiomers†
Zsolt Szakonyi,a Ferenc Fülöp,a,∗ Gábor Bernáth,a Gabriella Törökb and Antal Péter b
aInstitute of Pharmaceutical Chemistry, Albert Szent-Györgyi Medical University, H-6701 Szeged, POB 121, Hungary
bDepartment of Inorganic and Analytical Chemistry, Attila József University, H-6701 Szeged, POB 440, Hungary
Received 12 January 1998; accepted 12 February 1998
Abstract
Racemic cis-2-amino-1-cyclopentane- or -cyclohexane-1-carboxylic acid was reacted with (R)-α-
methylbenzylamine to form homochiral amides 3, 4 and 8, 9. The ring closures of 3, 4 and 8, 9 with aryl
imidates resulted in cyclopentane cis-fused and cyclohexane cis- and trans-fused dihydropyrimidin-4-one
enantiomers with loss of the N-substituent. The absolute configurations were determined by hydrolysis of 5, 6 and
10–13 to the corresponding amino acids. © 1998 Published by Elsevier Science Ltd. All rights reserved.
In the past two decades, increased attention has been directed towards the synthesis of cycloalkane-
fused saturated heterocycles,1 but the methods applied have mostly involved racemic compounds.
However, besides their stereochemical and pharmacological interest,2–4 these heterocycles can also be
used for enantioselective syntheses.5,6
The aim of the present work was the preparation of the enantiomers of 2-aryl-substituted cycloalkane-
fused dihydropyrimidin-4(3H)-ones, and determination of their absolute configurations. These
compounds possess pronounced pharmacological activity; as an example, (ꢀ)-2-(m-chlorophenyl)-
3,4a,5,6,7,7a-hexahydrocyclopenta[d]pyrimidin-4(3H)-one (CHINOIN-143) has
a
strong anti-
inflammatory effect.7 CHINOIN-143 had been earlier resolved via diastereomeric salt formation
in two-phase systems by using half an equivalent of dibenzoyltartaric acid.8 The anti-inflammatory
activity of the (−)-enantiomer was twice that of the racemic mixture.7 The absolute configurations of
the enantiomers were not determined.
∗
†
Corresponding author. E-mail: Fulop@pharma.szote.u-szeged.hu
Saturated Heterocycles, Part 261. Part 260: Szakonyi, Z.; Fülöp, F.; Bernáth, G.; Evanics, F.; Riddell, F. G. Tetrahedron 1998,
54, 1013.
0957-4166/98/$19.00 © 1998 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00069-X

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Z. Szakonyi et al. / Tetrahedron: Asymmetry 9 (1998) 993–999
1. Results and discussion
The pathways for the syntheses of the desired cyclopentane-fused dihydropyrimidin-4-ones 5 and 6
are shown in Scheme 1. After protection of the racemic cis-2-amino-1-cyclopentanecarboxylic acid 1,
the Z-amino acid was treated with isobutyl chloroformate, and the resulting anhydride was reacted with
(+)-(R)-α-methylbenzylamine, resulting in 2.9 The protecting group of 2 was removed by treatment with
hydrogen bromide. The separation of racemic cis-2-amino-1-cyclopentanecarboxylic acid was accom-
plished by the procedure applied by Goodman et al. to Boc-trans-2-amino-1-cyclopentanecarboxylic
acid.10 The diastereomers 3 and 4 were separated by flash chromatography.
Scheme 1. i: 10% aq. NaOH, PhCH2OCOCl (yield: 95%); ii: TEA, ClCOOiBu, THF/−10°C, then
(+)-(R)-H2NCH(Me)Ph/−10°C, 5 h (yield: 81%); iii: cc. AcOH, HBr, 1 h, then 20% aq. NaOH (yield: 89%); iv: flash
chromatography (MeOH:EtOAc=4:1); v: ethyl m-chlorobenzimidate, cat. H+/EtOH, reflux for 5 days
When 3 and 4 were heated with ethyl m-chlorobenzimidate in ethanol in the presence of a catalytic
amount of acetic acid, 5 and 6 were obtained in high enantiomeric purity.
Racemic 2-(m-chlorophenyl)-3,4a,5,6,7,7a-hexahydrocyclopenta[d]pyrimidin-4(3H)-one and its ana-
logues were synthesized by reaction of the corresponding β-amino acid or its derivatives with ethyl ben-
zimidates, by reaction of orthoesters with 2-amino-1-cycloalkanecarboxamides, or by ring enlargement
of cycloalkane-fused azetidinones with imidates.1,11 In the reactions of the β-amino acid derivatives with
benzimidates, the first step is the formation of an amidine intermediate; the subsequent nucleophilic
attack of the imino group of the amidine on the carbonyl group results in the desired pyrimidin-
4(3H)-ones. The same mechanism was found in the ring enlargement of cycloalkane-fused azetidinones
on reaction with benzimidates.12 In the reaction of 3, the intermediate amidine 7 was isolated (mp:
218–221°C).
The absolute configurations of the prepared compounds were determined by hydrolysis of 5 and
6 to the corresponding amino acid, which was identified by HPLC.13–17 It is interesting that the
absolute configuration of the enantiomer with the higher anti-inflammatory activity corresponds to that of
cispentacin [(1R,2S)-2-amino-1-cyclopentanecarboxylic acid], an antibiotic isolated from Bacillus cereus
and Streptomyces setonii18–22 and enantioselectively prepared earlier.23–25

Z. Szakonyi et al. / Tetrahedron: Asymmetry 9 (1998) 993–999
995
In the ring-closure reaction of the cyclohexane-fused homologue, C-1 epimerization was observed
(Scheme 2). Separation of the epimers 10, 11 and 12, 13 resulted in all four possible enantiomers. It is
noteworthy that cis-→trans isomerization is also possible for the cyclopentane derivatives, but the trans
isomer (in accordance with earlier observations on trans-1,2-disubstituted 1,3-difunctional cyclopentane
derivatives) does not undergo hetero-ring formation.1
Scheme 2. i: Ethyl benzimidate, cat. H+/EtOH, 5 days; ii: flash chromatography (hexane:EtOAc=6:4)
The yields of the cyclohexane-fused pyrimidin-4(3H)-ones were relatively low, probably in conse-
quence of their ring opening to afford amidines26 in the course of the separation of the isomers on a silica
gel column. The absolute configurations of the prepared compounds were determined by hydrolysis of
10–13 to the corresponding amino acids, which were identified by HPLC.13–17
2. Experimental
The NMR spectra were recorded on a BRUKER AVANCE DRX 400 spectrometer, using a ‘5 mm
inverse Z gradient’ probehead. The samples were dissolved in CDCl3 containing 0.03% TMS as a
reference. The number of scans was usually 64 for 1H and 2K for 13C spectra. All NMR measurements
were carried out at 300 K.
HPLC measurements were performed on a Waters system consisting of an M-600 low-pressure
gradient pump, an M-996 photodiode array detector and a Millenium 2010 Chromatography Manager
data system (Waters Chromatography, Division of Millipore, Milford, MA, USA). The column used
for indirect separation was a Vydac 218TP54 C18 column (250×4.6 mm I.D.), 5 µm particle size (The
Separations Group, Hesperia, CA, USA), and for direct separation a CHIRAL-AGP column (100×4.0

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Z. Szakonyi et al. / Tetrahedron: Asymmetry 9 (1998) 993–999
mm I.D.), 5 µm particle size (ChromTech AB, HŠgersten, Sweden), and a cellulose triacetate column
(250×10 mm I.D.), 10 µm particle size (Merck, Darmstadt, Germany).
GC measurements were performed on a Crompack CP-9002 system consisting of a Flame Ionization
Detector 901A and Maestro II Chromatography data system (Chrompack International B.V., Middelburg,
The Netherlands). The column used for direct separation was a CHIRASIL-DEX CB column (2500×0.25
mm I.D.). Optical rotation values were obtained with a Perkin–Elmer 341 polarimeter.
Melting points were determined on a Kofler apparatus and are uncorrected.
2.1. Chemicals and reagents
2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosylisothiocyanate (GITC) was purchased from Aldrich (Stein-
heim, Germany); trifluoroacetic acid (TFA), NaH2PO4 and NaOH of analytical reagent grade and
HPLC-grade methanol, ethanol and 2-propanol were obtained from Merck (Darmstadt, Germany). A
0.1% aqueous solution of TFA was prepared with Milli-Q water purified further by filtering on a 0.45
µm Millipore filter, type HV (Molsheim, France). A 0.01 M NaH2PO4 buffer (pH=5.0) was prepared
with Milli-Q water. A Radelkis OP/20811 pH meter (Budapest, Hungary) equipped with a combined
glass–calomel electrode was employed for pH measurements. The mobile phases were prepared by
mixing a 0.1% aqueous solution of TFA or 0.01 M NaH2PO4 buffer or water with methanol, ethanol
or 2-propanol. The eluent was degassed in an ultrasonic bath, and during the analysis helium gas was
bubbled through the solution.
2.2. cis-2-Benzyloxycarbonylamino-1-cycloalkanecarbonyl-(+)-(R)-α-methylbenzylamines
A quantity (20 mmol) of cis-2-benzyloxycarbonylamino-1-cyclopentane- or -cyclohexanecarboxylic
acid was dissolved in dry THF (70 ml) and the solution was cooled to −10°C. Triethylamine (2.02 g,
20 mmol) and isobutyl chloroformate (2.73 g, 20 mmol) were added with vigorous stirring; after stirring
for another 10 minutes, (+)-(R)-α-methylbenzylamine (2.42 g, 20 mmol) dissolved in THF (20 ml) was
added dropwise at −10°C. Stirring was continued for 5 hrs, and the mixture was then allowed to stand
overnight at room temperature. After evaporation of the THF, the residue was dissolved in CHCl3 (200
ml) and extracted with a 5% solution of aqueous HCl (2×50 ml) and a 5% solution of NaOH (1×50
ml). The organic phase was dried over Na2SO4 and evaporated. The crude products were used for the
preparation of 3, 4, 8 and 9 without further purification.10
2.3. [(1R,2S)- and (1S,2R)-cis-2-Amino-1-cyclopentanecarbonyl]-(+)-(R)-α-methylbenzylamine (3 and
4), [(1R,2S)- and (1S,2R)-cis-2-amino-1-cyclohexanecarbonyl]-(+)-(R)-α-methylbenzylamine (8 and 9)
Five equivalents of HBr, as a 20% solution in glacial acetic acid, was added to a diastereomeric mixture
of 2-Z-amino-1-carboxamides (10 mmol) and the mixture was stirred for 50 minutes at room temperature.
The clarified solution was extracted with diethyl ether (2×60 ml). The aqueous phase was made alkaline
with a 20% solution of NaOH and extracted with CHCl3 (3×50 ml). The organic phase was dried over
Na2SO4 and evaporated, yielding the products as yellow oils. The diastereomeric mixtures were separated
by flash chromatography (CHCl3:MeOH=4:1) and the separated diastereomers were obtained as pale-
yellow crystalline products.
The fast-eluting isomer 3 [1.11 g, 48%; [α]20 = +108 (c=0.1, MeOH); ee>99%]: H NMR (400
1
D
MHz, CDCl3): δ 7.23–7.35 (m, 5H, Ph), 7.20 (bd, 1H, J=6.4 Hz, NH), 5.10 (m, 1H, PhCHN), 3.47 (m,

Z. Szakonyi et al. / Tetrahedron: Asymmetry 9 (1998) 993–999
997
1H, H–C2), 2.59 (m, 1H, H–C1), 1.52–1.96 (m, 6H, 3×CH2), 1.47 (d, 3H, J=6.9 Hz, Me). Analysis:
calculated for C14H20N2O: C, 72.38; H, 8.68; N, 12.06; found: C, 72.12; H, 8.49; N, 12.15.
The slow-eluting isomer 4 [0.95 g, 41%; [α]20 = +124 (c=0.1, MeOH); ee>99%]: H NMR (400
1
D
MHz, CDCl3): δ 7.22–7.33 (m, 5H, Ph), 7.16 (bd, 1H, J=6.4 Hz, NH), 5.14 (m, 1H, PhCHN), 3.51 (m,
1H, H–C2), 2.53 (m, 1H, H–C1), 1.50–2.00 (m, 6H, 3×CH2), 1.48 (d, 3H, J=6.9 Hz, Me). Analysis:
calculated for C14H20N2O: C, 72.38; H, 8.68; N, 12.06; found: C, 72.16; H, 8.79; N, 12.46.
The fast-eluting isomer 8 [1.06 g, 43%; [α]20 = +80 (c=0.1, MeOH); ee>99%]: H NMR (400
1
D
MHz, CDCl3): δ 8.68 (bd, 1H, J=6.8 Hz, NH), 7.20–7.34 (m, 5H, Ph), 5.11 (m, 1H, PhCHN), 3.29 (m,
1H, H–C2), 2.38 (m, 1H, H–C1), 1.33–1.87 (m, 8H, 4×CH2), 1.45 (d, 3H, J=6.9 Hz, Me). Analysis:
calculated for C15H22N2O: C, 73.13; H, 9.00; N, 11.37; found: C, 73.29; H, 8.69; N, 11.35.
The slow-eluting isomer 9 [0.98 g, 40%; [α]20 = +95 (c=0.1, MeOH); ee>99%]: H NMR (400
1
D
MHz, CDCl3): δ 8.76 (bd, 1H, J=6.5 Hz, NH), 7.20–7.31 (m, 5H, Ph), 5.12 (m, 1H, PhCHN), 3.28 (m,
1H, H–C2), 2.35 (m, 1H, H–C1), 1.34–1.91 (m, 8H, 4×CH2), 1.45 (d, 3H, J=6.9 Hz, Me). Analysis:
calculated for C15H22N2O: C, 73.13; H, 9.00; N, 11.37; found: C, 73.32; H, 8.88; N, 11.53.
To determine the enantiomeric purity, 3, 4 and 8, 9 were derivatized with GITC and subsequently
separated by HPLC on a Vydac column (a 0.1% aqueous solution of TFA:methanol=45:55 v/v; flow rate,
0.8 ml/min; detection at 250 nm).
2.4. (−)-(4aR,7aS)- and (+)-(4aS,7aR)-2-(m-Chlorophenyl)-3,4a,5,6,7,7a-hexahydrocyclopenta[d]-
pyrimidin-4(3H)-one (5 and 6)
To a solution of 3 or 4 (1.00 g, 4.3 mmol) in 40 ml of dry ethanol, ethyl m-chlorobenzimidate
(0.47 g, 4.3 mmol) and one drop of glacial acetic acid were added and the mixture was refluxed for
6 days. The solution was then evaporated to dryness, and the residue was dissolved in 50 ml of 3%
aqueous HCl solution and extracted with CHCl3 (2×20 ml). The aqueous phase was made alkaline with
saturated NaHCO3 solution and extracted with CHCl3 (3×30 ml). The combined organic phase was dried
(Na2SO4), and evaporated, and the crystalline residue was recrystallized from isopropyl ether.
1
Compound 5 (0.56 g, 52%): H NMR (400 MHz, CDCl3): δ 8.61 (bs, 1H, NH), 7.36–7.82 (m, 4H,
mClPh), 4.28 (m, 1H, H–C7a), 2.75 (m, 1H, H–C4a), 1.64–2.27 (m, 6H, 3×CH2). Analysis: calculated
for C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26; found: C, 62.39; H, 5.43; N, 11.41; mp: 120–122°C (lit.7:
117–118°C); [α]20 = −55 (c=1.0, n HCl, lit.7: −54); ee>98%.
D
Compound 6 (0.58 g, 54%): the 1H NMR spectrum of 6 was identical to that of 5. Analysis: calculated
for C13H13ClN2O: C, 62.78; H, 5.27; N, 11.26; found: C, 62.48; H, 5.52; N, 11.12; mp: 122–123°C (lit.7:
117–118°C); [α]20 = +54 (c=1.0, n HCl, lit.7: +54); ee>98%.
D
To determine the enantiomeric purity, direct separation of 5 and 6 was performed on a CHIRAL-AGP
column (2-propanol:NaH2PO4 (0.01 M, pH=5.0) 3:97 v/v; flow rate, 0.9 ml/min; detection at 246 nm).
2.5. (−)-(4aR,8aS)- and (+)-(4aS,8aS)-2-Phenyl-3,4,4a,5,6,7,8,8a-octahydroquinazolin-4(3H)-one (10
and 11), (+)-(4aS,8aR)- and (−)-(4aR,8aR)-2-phenyl-3,4,4a,5,6,7,8,8a-octahydroquinazolin-4(3H)-one
(12 and 13)
The reaction was performed on 8 or 9 (1.20 g, 4.9 mmol) and ethyl benzimidate (0.73 g, 4.9 mmol),
as described for 5 and 6. The diastereomeric mixtures obtained were separated on a silica gel column
by flash chromatography (hexane:EtOAc=6:4) and the separated diastereomers were recrystallized from
isopropyl ether.

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Z. Szakonyi et al. / Tetrahedron: Asymmetry 9 (1998) 993–999
1
Compound 10 (0.30 g, 27%): H NMR (400 MHz, CDCl3): δ 8.43 (bs, 1H, NH), 7.42–7.78 (m,
5H, Ph), 3.90 (m, 1H, H–C8a), 2.69 (m, 1H, H–C4a), 1.44–2.11 (m, 8H, 4×CH2). Analysis: calculated
for C14H16N2O: C, 73.66; H, 7.06; N, 12.27; found: C, 73.81; H, 7.15; N, 12.08; mp: 170–172°C;
[α]20 = −75 (c=0.1, MeOH); ee>98%.
D
1
Compound 11 (0.15 g, 13%): H NMR (400 MHz, CDCl3): δ 7.49 (bs, 1H, NH), 7.41–7.78 (m, 5H,
Ph), 3.24 (m, 1H, H–C8a), 2.40 (overlapping m, 1H, H–C4a), 1.27–2.40 (m, 8H, 4×CH2). Analysis:
calculated for C14H16N2O: C, 73.66; H, 7.06; N, 12.27; found: C, 73.54; H, 7.02; N, 12.43; mp:
200–202°C; [α]20 = +107 (c=0.1, MeOH); ee>98%.
D
1
Compound 12 (0.32 g, 29%): the H NMR spectrum of 12 was identical to that of 10. Analysis:
calculated for C14H16N2O: C, 73.66; H, 7.06; N, 12.27; found: C, 73.78; H, 7.13; N, 12.21; mp:
172–174°C; [α]20 = +76 (c=0.1, MeOH); ee>98%.
D
1
Compound 13 (0.19 g, 17%): the H NMR spectrum of 13 was identical with that of 11. Analysis:
calculated for C14H16N2O: C, 73.66; H, 7.06; N, 12.27; found: C, 73.75; H, 7.27; N, 12.45; mp:
200–203°C; [α]20 = −106 (c=0.1, MeOH); ee>98%.
D
To determine the enantiomeric purity, direct separation of 10 and 12 was performed by GC on a
CHIRASIL-DEX CB column (170°C, 80 kPa), and that of 11 and 13 by HPLC on a cellulose triacetate
column (ethanol:water=75:25 v/v; flow rate, 0.8 ml/min; temperature, 50°C; detection at 246 nm).
2.6. General method for the hydrolysis, derivatization and absolute configuration determination
A quantity (0.5 mg) of 5, 6 or 10–13 was dissolved in 100 µl methanol, and 200 µl aqueous NaOH
solution (5 M) was added to each solution. The compounds were hydrolysed at 40°C for 6 days. The
reaction was stopped by adding aqueous HCl solution (2 M) until pH≤7 was reached. 1 mg/ml solutions
of 1, cispentacin, (ꢀ)-cis- and (ꢀ)-trans-2-amino-1-cyclohexanecarboxylic acid (cis- and trans-ACHC),
the 1R,2S and 1S,2S enantiomers of ACHC and 100 µl of solutions of each hydrolysed compound were
used for derivatization with GITC by the method of Nimura et al.22
The absolute configurations of 5, 6 and 10–13 were determined by comparison of the spectra and chro-
matograms of the GITC derivatives of 5, 6 (Vydac, a 0.1% aqueous solution of TFA:methanol=57.5:42.5
v/v; flow rate, 0.8 ml/min; detection at 250 nm) and 10–13 (Vydac, a 0.1% aqueous solution of
TFA:methanol=50:50 v/v; flow rate, 0.8 ml/min; detection at 250 nm), with those of the GITC derivatives
of cispentacin, and the 1R,2S and 1S,2S enantiomers of ACHC.23
Acknowledgements
Financial support from OTKA (grant T 20454) and MKM (grant FKFP 0910/1997 and 0087/1997) is
gratefully acknowledged. A. P. expresses his thanks to Merck Kft., Budapest for the cellulose triacetate
column.
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