Proceeding from natural amino acid L-asparagine and commercially available aldehydes a stereoselective synthesis was developed of (2S,4S)-2-alkyl(aryl)-3-(3-sulfanylpropanoyl)-6-oxohexahy- dropyrimidine-4-carboxylic acids, potential antihypertensive drugs, inhibitors of the angiotensin converting enzyme.
Efficient antihypertensive drugs function as inhibitors of the angiotensin converting enzyme (ACE). This enzyme is involved in the regulator system rennin-angiotensin-aldosterone, and the distortion of its operation results in the majority of hypertensive human diseases [
It was found by the analysis of published data that sodium (potassium) salts of 2-substituted 6-oxohexahydropyrimidine-4-carboxylic acids formed in the reaction of the natural amino acid L-asparagine with carbonyl compounds in alkaline medium. This reaction was investigated mainly by an example of derivatives of isobutyric, trimethylacetic, and benzoic aldehydes [
The derivatives of 6-oxohexahydropyrimidine-4-carboxylic acids are used as key intermediates in the synthesis of β-amino acids [
The goal of this study is the search for new and synthetically accessible potential antihypertensive substances, ACE inhibitors, compounds where the cyclic amino acid fragment is a derivative of pyrimidine-4-carboxylic acid.
Compounds 2а-i were obtained in 70% - 90% yields after maintaining L-asparagine, an appropriate aliphatic or aromatic aldehyde, and equivalent quantity of sodium hydroxide in methanol solution for 10 - 12 h at 25˚С (see Scheme 1 and
The first objects of our investigation were the condensation products of L-asparagine with a series of aliphatic aldehydes, compounds 2а-f. The cyclic pyrimidine structure of these compounds is unquestionable, as shows the appearance in the 1Н NMR spectra of the typical АВХ system due to the diastereotopic character of Н-5 and Н-4 protons, of the signals of Н-2 atom in the region 4.2 - 4.5 ppm, and in the 13С NMR spectra, of the signal of sp3- hybridized С-2 atom in the region 65 - 70 ppm. In the spectra of all obtained compounds 2а-f two sets of resonance signals from (2R,4S)-and (2S,4S)-stereoisomeric forms of the pyrimidine ring are observed. The assign- ment of the stereoisomeric forms of compounds 2а-f is based on the formerly established criteria and rules ob-
Scheme 1. i: RCH=O, NaOH/MeOH, 25˚C, 10 - 12 h. R = Me (a), Et (b), Bu (c), i-Pr (d), i-Bu (e), CH2CH2Ph (f), R =XC6H4, X = H (g), 4-Cl (h), 4-MeO (i).
Compound | [α]D25 in MeOH | Tautomeric composition in D2O, (%) | ||
---|---|---|---|---|
Form A | Form (2R,4S) | Form (2S,4S) | ||
2a | ?89.1, с 1.31 | ? | 95 | 5 |
2b | ?91.2, с 1.50 | ? | 93 | 7 |
2c | ?70.1, с 1.50 | ? | 90 | 10 |
2d | ?97.7, с 1.40 | ? | 93 | 7 |
2e | ?77.2, с 1.53 | ? | 87 | 13 |
2f | ?69.5, с 1.50 | ? | 92 | 8 |
2g | ?60.2, с 2.01 | 13 | 68 | 19 |
2h | ?35.1, с 2.02 | 51 | 40 | 9 |
2i | ?37.2, с 1.70 | 18 | 66 | 16 |
tained at the use of 1Н and 13С NMR spectroscopy [
The position of the configurational equilibrium of compounds 2а-f is shifted to a large extent to (2R,4S)-ste- reoisomer, therefore it is impossible to obtain a clear correlation between the logarithms of the constant of the configurational equilibrium and the Taft steric constants of alkyl substituents. The largest fraction of the minor (2S,4S)-isomer (13%) was observed in the D2O solution of compound 2e, isovaleric aldehyde derivative.
In the 1Н and 13С NMR spectra in D2O of the L-asparagine condensation products with aromatic aldehydes (compounds 2g-i) alongside the signals of two configuration isomers of the pyrimidine form signals appear of a linear form А. Not entering into details of the previously found by us [
By an example of compound 2g, the condensation product of L-asparagine with benzaldehyde, we studied the dependence of the position of the tautomeric equilibrium on the nature of the applied solvent (see
Hence the products of L-asparagine condensation with acetic, propionic, valeric, isobutyric, isovaleric, and hydrocinnamic aldehydes in alkaline medium have the cyclic pyrimidine structure, and in D2O solutions they are present as two cyclic spatial stereoisomers with a significant prevalence of the (2R,4S)-form. In neither case the appearance in the solutions of the linear imine form А was observed. In this respect compounds 2а-f fundamentally differ from the condensation products of L-asparagine with a series of aromatic aldehydes 2g-i where the occurrence of the ring-chain tautomerism has been found and alongside two pyrimidine stereoisomers a linear form exists in solutions.
The acylation of 2-substituted 6-oxohexahydropyrimidine-4-carboxylic acids results in the formation of optically pure N-acyl derivatives with (2S,4S)-configuration of the substituents at the pyrimidine ring [
It was found that acylation of compounds 2а-i with 3-(acetylthio)propionyl chloride proceeded in acetone and completed in 10-12 h with the formation of 3-(3-acetylsulfanylpropanoyl)-2-alkyl(aryl)-6-oxohexahydropyrimidine-4-carboxylic acids 3а-i (see Scheme 2 and
The acylation products 3а-i possess the (2S,4S)-configuration of the substituents of the pyrimidine ring, in their solutions in DMSO-D6, in keeping with the data of 1Н and 13С NMR spectra, the presence of two cis, trans- conformers has been found in the ratio ~3:2. It was confirmed by the coalescence of doubled signals at the re-
Solvent | Form A | Form (2R,4S) | Form (2S,4S) |
---|---|---|---|
Solid phase | ? | 100 | ? |
D2O | 13 | 68 | 19 |
Pyridine-D5 | 40 | 48 | 12 |
DMSO-D6 | 45 | 44 | 11 |
DMF-D7 | 51 | 40 | 9 |
Scheme 2. ii: AcSCH2CH2COCl/Me2CO, C5H5N, 5˚C - 10˚C, 10 - 12 h. R = Me (a), Et (b), Bu (c), i-Pr (d), i-Bu (e), CH2CH2Ph (f), R =XC6H4, X = H (g), 4-Cl (h), 4-MeO (i).
Compound | [α]D25 in DMF | mp, ˚C | Yield, % |
---|---|---|---|
3a | ?52.1, c 1.00 | 73 - 75 | 45 |
3b | ?87.2, c 1.20 | 121 - 123 | 52 |
3c | ?115.8, c 1.10 | 92 - 94 | 56 |
3d | ?114.8, c 1.10 | 133 - 135 | 65 |
3e | ?109.4, c 1.15 | 119 - 121 | 65 |
3f | ?57.4, c 1.10 | 125 - 127 | 68 |
3g | +52.1, c 1.00 | 88 - 91 | 53 |
3h | +19.4, c 1.10 | 93 - 95 | 56 |
3i | +35.1, c 1.20 | 78 - 81 | 62 |
gistering 1Н NMR spectra in DMSO-D6 at higher temperature (~80˚С - 85˚С). Proceeding from the comparison of the 1Н and 13С NMR spectra of compounds 3а-i with the published [
The removal of S-acetyl protection in compounds 3а-i occurs in the ammonia solution within several hours at room temperature and leads to the formation of (2S,4S)-2-alkyl(aryl)-3-sulfanylpropanoyl-6-oxohexahydropyrimidine-4-carboxylic acids 4а-i in 50% - 65% yields (see Scheme 3 and
1Н and 13С NMR spectra were registered on a spectrometer Bruker AV-400 at operating frequencies 400 and 100 MHz respectively (internal reference HMDS). The stereoisomeric composition of obtained compounds was estimated by the integration of the appropriate signals in the 1Н NMR spectra. The specific optical rotation was measured on a polarimeter P-161M at the wavelength of the plane-polarized light 589 nm. Elemental analysis of newly obtained compounds was carried out on a CHN Analyzer Hewlett Packard 185B. The purity of prepared compounds was checked by TLC on Silufol UV-254 plates, eluent benzene-acetone, 1:1.
Compounds 2а-i are white or light yellow amorphous hygroscopic powders, mp >250˚С. Spectral characteristics of compounds 2a-i, 3a-i, and 4a-i were described previously [
Hence we developed a three-stage stereoselective synthesis from L-asparagine of previously unknown (2S,4S)-
Scheme 3. iii: NH3(aq.), 25˚C, 5 - 10 h. R = Me (a), Et (b), Bu (c), i-Pr (d), i-Bu (e), CH2CH2Ph (f), R = XC6H4, X = H (g), 4-Cl (h), 4-MeO (i).
Compound | [α]D25 in MeOH | mp., ˚C | Yield, % |
---|---|---|---|
4a | ?48.6, c 1.30 | 189 - 191 | 66 |
4b | ?76.5, c 1.37 | 165 - 168 | 58 |
4c | ?84.2, c 1.15 | 122 - 125 | 50 |
4d | ?95.7, c 1.10 | 184 - 186 | 65 |
4e | ?122.8, c 1.20 | 162 - 164 | 60 |
4f | ?80.1, c 1.00 | 132 - 134 | 54 |
4g | +13.7, c 1.00 | 120 - 123 | 55 |
4h | +22.4, c 1.00 | 202 - 204 | 58 |
4i | +28.7, c 1.10 | 148 - 151 | 65 |
3-(3-sulfanylpropanoyl)-2-alkyl(aryl)-6-oxohexahydropyrimidine-4-carboxylic acids 4а-i, potential antihypertensive drugs, ACE inhibitors [
This work received financial support from the Ministry of Education and Science of the Russian Federation (contract 14.547.21.0002, no. RFMEFI57414X0002).
Andrei Ershov,Dmitry Nasledov,Igor Lagoda,Valery Shamanin, (2015) Synthesis of (2S,4S)-2-Substituted-3- (3-Sulfanylpropanoyl)-6- Oxohexahydropyrimidine-4-Carboxylic Acids as Potential Antihypertensive Drugs. Journal of Materials Science and Chemical Engineering,03,7-12. doi: 10.4236/msce.2015.36002