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Article

Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs

by
Attila Márió Remete
1,2 and
Loránd Kiss
1,2,*
1
Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
2
Interdisciplinary Excellence Centre, Institute of Pharmaceutical Chemistry, University of Szeged, Eötvös u. 6, H-6720 Szeged, Hungary
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(1), 161; https://doi.org/10.3390/molecules24010161
Submission received: 10 December 2018 / Revised: 21 December 2018 / Accepted: 23 December 2018 / Published: 3 January 2019
(This article belongs to the Special Issue Small Molecule Drug Design)
Browse Figures
Review Reports Versions Notes

Abstract

:
Stereocontrolled synthesis of some amino acid-based carbocyclic nucleoside analogs containing ring C=C bond has been performed on β- and γ-lactam basis. Key steps were N-arylation of readily available β- or γ-lactam-derived amino ester isomers and amino alcohols with 5-amino-4,6-dichloropyrimidine; ring closure of the formed adduct with HC(OMe)3 and nucleophilic displacement of chlorine with various N-nucleophiles in the resulting 6-chloropurine moiety.

Graphical Abstract

1. Introduction and Aims

In carbocyclic nucleoside analogs, a methylene group replaces the oxygen atom in the carbohydrate ring, thereby increasing stability towards hydrolases and phosphorylases. The synthesis of these molecules is an area of considerable interest to medicinal chemistry, thanks to their bioactivity. Within natural products, neplanocin A is an antitumor antibiotic, while aristeromycin has antibacterial and antiviral activities. With respect to synthetic compounds, (-)-carbovir (1) and abacavir (2) show anti-HIV activity (Scheme 1) while entecavir inhibits the hepatitis B virus [1,2,3,4,5,6]. Carbocyclic nucleoside analogs with a 6-membered ring received less attention. In their case, antiviral activity usually requires the presence of a C=C bond in the ring [1,2,3,5,7,8] (see 3 and 4), enabling the base to occupy a pseudoaxial position [1,5], but some (2-aminocyclohexyl)methanol derivatives (for example, 5 [9]) also exhibit bioactivity (Scheme 1).
Cyclic β-amino acids have gained significant attention in the last few decades [10,11,12,13,14]. They can be found in natural products, such as peptidyl nucleoside antibiotics amipurimycin (6), chryscandin (7), blasticidin S (8) or gougerotin (9), and related analogous derivatives (Scheme 2) [15,16,17]. In the latter three nucleoside analogs, the sugar ring was replaced with a cyclic β-amino acid unit. Cyclic β-amino acids are also promising building blocks of new bioactive peptides [14,15,16,17,18,19,20,21] and many simple representatives show relevant biological activity (Scheme 3), such as the analgesic drug tilidine (10) or antifungal antibiotics cispentacin and icofungipen (11) [10,11,12,13].
Highly-functionalized cyclic γ-amino acid derivatives possessing multiple stereogenic centers are also of considerable importance in drug research. Neuraminidase inhibitors Peramivir (12, Scheme 3), Zanamivir and Oseltamivir and their modified analogs are used in the treatment of influenza [22], while Gabapentin [23] and CPP-115 [24] (13, Scheme 3) are anticonvulsant drugs.

2. Results and Discussion

Taking into account the importance of carbocyclic nucleoside analogs and the bioactivity of peptidyl nucleoside antibiotics containing β-amino acids, our aim was the synthesis of new carbocyclic nucleoside analogs with an amino acid moiety on a β- and γ-lactam basis. This pathway is similar to the first synthesis of carbovir from unsaturated γ-lactam (±)-14 (also known as Vince lactam) [25,26,27]. The synthesis of some 6-membered carbocyclic nucleoside analogs containing γ-amino alcohol was also planned.
Our synthetic work started with the opening of the heteroring of racemic Vince lactam (±)-14 [28]. Construction of the nucleobase part on the resulting amino ester (±)-15 was accomplished in three steps. First, compound (±)-15 was subjected to N-arylation with 5-amino-4,6-dichloropyrimidine to furnish (±)-16. This process was accompanied by C=C bond migration thanks to the basic conditions, enabling the formation of a more stable conjugated π-system. Then, reaction with trimethyl orthoformate generated the second heteroring. The remaining chlorine atom of the obtained nucleoside analog (±)-17 was then replaced with N-nucleophiles to obtain adenosine analogs (±)-18, (±)-19 and (±)-20 (Scheme 4). It is worth to note that compound (±)-19 contains a cyclopropylamino group similar to abacavir, while the azido group of compound (±)-20 enables many further transformations (e.g., triazole formation).
We continued our synthetic work with ethyl cis β-amino ester hydrochloride (±)-22 obtained from β-lactam (±)-21 [29,30]. Lactam ring opening, construction of the nucleobase moiety, and aromatic nucleophilic substitution resulted in nucleoside analogs (±)-25 and (±)-26. From ethyl trans β-amino ester hydrochloride (±)-28 [31,32], azidonucleoside (±)-31 was prepared in a similar way (Scheme 5 and Scheme 6).
Note that the synthetic protocol took place with stereocontrol in both cases. Since the configuration of the chiral centers are not affected during the syntheses, their integrity is conserved and therefore, the cis-amino acid starting material led to the corresponding carbanucleoside analog in which the relative configuration of the groups is cis, while the trans-amino acid provided the carbocyclic nucleobase analog with trans relative steric arrangement of the ester and the heterocycle.
Analogous treatment of ethyl cis-2-aminocyclohex-3-enecarboxylate hydrochloride (±)-33 (a regioisomer of (±)-22), obtained from β-lactam (±)-32 [33,34], resulted in nucleoside analog (±)-35, the C=C regioisomer of compound (±)-24 (Scheme 7).
In order to synthesize compounds with a five-membered carbocycle, the strategy was also extended to β-lactam (±)-36. Nucleoside analog (±)-39 was obtained successfully using the protocol described above for the six-membered analogs, although both nucleobase construction steps had lower yields (Scheme 8).
Taking into account the bioactivity of compounds 3, (±)-4 and (±)-5, the synthesis of similar molecules was attempted. Reduction of β-amino acids (±)-40 and (±)-44 with LiAlH4 [32] afforded γ-amino alcohols (±)-41 and (±)-45, which were further reacted with 5-amino-4,6-dichloropyrimidine. Ring closing with trimethyl orthoformate in the last step yielded, through stereocontrol, nucleoside analogs (±)-43 and (±)-47 (Scheme 9). These compounds show high structural similarity to bioactive compound (±)-5.

3. Conclusions and Outlook

A stereocontrolled synthetic pathway was developed to prepare new carbocyclic nucleoside analogs containing a ring olefin bond with a β-amino acid, γ-amino acid or γ-amino alcohol moiety from readily available β- and γ-lactams (across the amino acid isomers). The structure of the starting cycloalkene amino acids determined the configuration of the stereogenic centers of the products. 6- Nucleoside analogs containing the chloropurine moiety proved to be useful intermediates in various reactions with nucleophiles to access substituted nucleobases. Taking into consideration our widespread experiences in selective and controlled functionalization of versatile unsaturated cyclic amino acid derivatives [35,36,37,38], further studies in order to investigate the possible functionalization of the ring olefin bond of product nucleoside analogs are currently being investigated in our laboratory. Furthermore, based on our experiences in enzymatic resolution of various bicyclic β- and γ-lactams [39,40], as well as on enzymatic ester hydrolysis methodologies [41], synthesis of enantiomerically pure substances will be performed.

4. Materials and Methods

4.1. General Information

Chemicals were purchased from Sigma–Aldrich (Budapest, Hungary). Solvents were used as received from the suppliers. Amino ester hydrochlorides (±)-15 [28], (±)-22 [29,30], (±)-28 [31,32], (±)-33 [33,34], (±)-37 [42] and γ-amino alcohols (±)-41, (±)-45 [32] were synthesized according to literature. The 1H-NMR and 13C-NMR spectra of all new compounds are available in Supplementary Materials.

4.1.1. General Procedure for N-Arylation of Amino Ester Hydrochlorides with 5-Amino-2,6-Dichloropyrimidine

To a solution of the amino ester hydrochloride (10 mmoles) in EtOH (30 mL), 5-amino-2,6-dichloropyrimidine (10 mmoles) and Et3N (30 mmoles) were added, then the mixture was treated at reflux temperature for 20 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was taken up in EtOAc (100 mL). The organic layer was washed with water (3 × 50 mL), dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 2:1).

4.1.2. General Procedure for N-Arylation of γ-Amino Alcohols with 5-Amino-2,6-Dichloropyrimidine

To a solution of the γ-amino alcohol (8 mmoles) in EtOH (25 mL), 5-amino-2,6-dichloropyrimidine (8 mmoles) and Et3N (24 mmoles) were added, then the mixture was kept at boiling temperature for 20 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was taken up in EtOAc (100 mL). The organic layer was washed with water (3 × 40 mL), dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:2).

4.1.3. General Procedure for the Formation of the Purine Skeleton of Amino Ester Nucleoside Analogs

To a solution of amino ester (2 mmoles) in trimethyl orthoformate (5 mL), a catalytic amount of methanesulfonic acid or p-TsOH (30 mg) was added. After stirring at 20 °C for 6 h, the reaction mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaCl solution (3 × 15 mL). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:1).

4.1.4. General Procedure for the Formation of the Purine Skeleton of Amino Alcohol Nucleoside Analogs

To a solution of amino alcohol nucleoside analog (1 mmol) in trimethyl orthoformate (4 mL), a catalytic amount of p-TsOH (20 mg) was added. After stirring at 20 °C for 6 h, the reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaCl solution (3 × 15 mL). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:2).

4.1.5. General Procedure for the Introduction of the Azido Group

To a solution of 6-chloropurinyl nucleoside analog (150 mg) in THF/H2O (10 mL, 4:1), sodium azide (4 eq.), acetic acid (3 drops), and Et3N (4 drops) were added. After heating at reflux temperature for 20 h, the reaction mixture was diluted with EtOAc (20 mL) and washed with water (2 × 15 mL). The organic phase was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:2).

4.1.6. General Procedure for the Introduction of the Cyclopropylamino Group

To a solution of 6-chloropurinyl nucleoside analog (150 mg) in EtOH (10 mL), cyclopropylamine (4 eq.) was added. After the mixture was kept at boiling temperature for 12 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:1).

4.2. Synthesis of Methylamino Compound (±)-18

To a solution of 6-chloropurinyl nucleoside analogue (±)-17 (150 mg) in EtOH (10 mL), MeNH2 (4 eq.) was added. After heating under reflux for 20 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluent: n-hexane-EtOAc 1:1).
Molecules 24 00161 i001
Ethyl (S*)-4-((5-amino-6-chloropyrimidin-4-yl)amino)cyclopent-1-ene-1-carboxylate, (±)-16.
Brownish white solid, m.p. 121–123 °C, 40%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.30 (t, 3H, CH3, J = 7.14 Hz), 2.43–2.59 (m, 2H, CH2), 3.00–3.16 (m, 2H, CH2), 3.44 (brs, 2H, NH2), 4.17–4.25 (m, 2H, OCH2), 4.79–4.86 (m, 1H, H-4), 5.08 (d, 1H, N-H, J = 5.76 Hz), 6.76-6.78 (m, 1H, H-2), 8.08 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 15.0, 39.3, 41.2, 51.3, 60.7, 124.6, 135.1, 137.7, 142.6, 146.4, 152.0, 164.9; MS (ES, pos) m/z = 283 (M + 1).
Molecules 24 00161 i002
Ethyl (S*)-4-(6-chloro-9H-purin-9-yl)cyclopent-1-ene-1-carboxylate, (±)-17.
Yellowish white solid, m.p. 83–85 °C, 81%; 1H-NMR (DMSO, 400 MHz): δ = 1.20 (t, 3H, CH3, J = 7.08 Hz), 2.93–3.05 (m, 2H, CH2), 3.06–3.20 (m, 2H, CH2), 4.09–4.17 (m, 2H, OCH2), 5.38–5.47 (m, 1H, H-4), 6.70–6.81 (m, 1H, H-2), 8.69 (s, 1H, Ar-H), 8.74 (s, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.6, 39.2, 40.9, 54.2, 61.2, 132.2, 135.5, 140.1, 143.5, 151.6, 151.8, 152.3, 164.2; MS (ES, pos) m/z = 293 (M + 1).
Molecules 24 00161 i003
Ethyl (S*)-4-(6-(methylamino)-9H-purin-9-yl)cyclopent-1-ene-1-carboxylate, (±)-18.
Yellow oil, 68%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.32 (t, 3H, CH3, J = 7.12 Hz), 2.86–3.03 (m, 2H, CH2), 3.10–3.29 (m, 5H, NCH3 and CH2), 4.20–4.31 (m, 2H, OCH2), 5.41–5.50 (m, 1H, H-4), 6.16 (brs, 1H, N-H), 6.86–6.89 (m, 1H, H-2), 7.75 (s, 1H, Ar-H), 8.41 (s, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.6, 39.3, 41.1, 50.6, 58.9, 61.1, 120.4, 135.5, 136.1, 137.7, 140.5, 153.4, 155.9, 164.5; MS (ES, pos) m/z = 288 (M + 1).
Molecules 24 00161 i004
Ethyl (S*)-4-(6-(cyclopropylamino)-9H-purin-9-yl)cyclopent-1-ene-1-carboxylate, (±)-19.
Yellow oil, 53%; 1H-NMR (CDCl3, 500 MHz): δ (ppm) = 0.64–0.69 (m, 2H, CH2), 0.90–0.97 (m, 2H, CH2), 1.32 (t, 3H, CH3, J = 7.13 Hz), 2.86–3.08 (m, 3H, CH2), 3.18–3.32 (m, 2H, CH2, CH), 4.21–4.28 (m, 2H, OCH2), 5.35–5.43 (m, 1H, H-4), 6.03 (brs, 1H, N-H), 6.86-6.91 (m, 1H, H-2), 7.75 (s, 1H, Ar-H), 8.48 (s, 1H, Ar-H); 13C-NMR (CDCl3, 126 MHz): δ (ppm) = 7.4, 14.3, 23.7, 38.9, 40.8, 52.9, 60.7, 119.9, 135.1, 137.6, 140.2, 153.2, 155.8, 164.1; MS (ES, pos) m/z = 314 (M + 1).
Molecules 24 00161 i005
Ethyl (S*)-4-(6-azido-9H-purin-9-yl)cyclopent-1-ene-1-carboxylate, (±)-20.
White solid, m.p. 145–147 °C, 68%; 1H-NMR (DMSO, 400 MHz): δ (ppm) = 1.22 (t, 3H, CH3, J = 7.08 Hz), 2.97–3.09 (m, 2H, CH2), 3.22–3.28 (m, 2H, CH2), 4.12–4.23 (m, 2H, OCH2), 5.53–5.64 (m, 1H, H-4), 6.86–6.89 (m, 1H, H-2), 8.66 (s, 1H, Ar-H), 10.07 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 15.0, 34.9, 39.2, 55.1, 61.0, 121.2, 134.5, 136.3, 141.8, 142.8, 143.8, 146.3, 164.5; MS (ES, pos) m/z = 300 (M + 1).
Molecules 24 00161 i006
Ethyl (1R*,6S*)-6-((5-amino-6-chloropyrimidin-4-yl)amino)cyclohex-3-ene-1-carboxylate, (±)-23.
White solid, m.p. 120–121 °C, 42%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.28 (t, 3H, CH3, J = 7.12 Hz), 2.26–2.38 (m, 1H, CH2), 2.42–2.56 (m, 2H, CH2), 2.62–2.73 (m, 1H, CH2), 2.95–3.03 (m, 1H, H-1), 3.39 (brs, 2H, NH2), 4.11–4.24 (m, 2H, OCH2), 4.74–4.85 (m, 1H, H-6), 5.66–5.87 (m, 3H, H-3, H-4, N-H), 8.08 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 14.8, 25.5, 30.4, 41.4, 47.1, 60.6, 124.6, 125.4, 125.9, 138.0, 146.1, 152.2, 173.4; MS (ES, pos) m/z = 297 (M + 1), 299 (M + 3).
Molecules 24 00161 i007
Ethyl (1R*,6S*)-6-(6-chloro-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-24.
Yellow oil, 76%. 1H-NMR (DMSO, 400 MHz): δ (ppm) = 0.98 (t, 3H, CH3, J = 7.12 Hz), 2.31–2.52 (m, 2H, CH2), 2.74–2.84 (m, 2H, CH2), 3.28–3.33 (m, 1H, H-1), 3.83–3.90 (m, 2H, OCH2), 5.25–5.32 (m, 1H, H-6), 5.85–5.89 (m, 2H, H-3, H-4), 8.56 (s, 1H, Ar-H), 8.78 (s, 1H, Ar-H). 13C-NMR (DMSO, 100 MHz): δ (ppm) = 14.5, 25.4, 29.3, 42.0, 51.2, 61.2, 125.3, 126.4, 131.2, 146.6, 149.9, 152.2, 153.0, 172.4; MS (ES, pos) m/z = 307 (M + 1).
Molecules 24 00161 i008
Ethyl (1R*,6S*)-6-(6-azido-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-25.
White solid, m.p. 130–132 °C, 51%; 1H-NMR (DMSO, 400 MHz): δ (ppm) = 1.03 (t, 3H, CH3, J = 7.10 Hz), 2.34–2.65 (m, 2H, CH2), 2.78–3.00 (m, 2H, CH2), 3.31–3.43 (m, 1H, H-1), 3.82–4.00 (m, 2H, OCH2), 5.40-5.48 (m, 1H, H-6), 8.54 (s, 1H, Ar-H), 10.13 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 14.6, 25.4, 29.7, 42.3, 51.5, 61.3, 125.3, 126.4, 129.4, 130.4, 135.3, 142.8, 147.9, 170.5; MS (ES, pos) m/z = 314 (M + 1).
Molecules 24 00161 i009
Ethyl (1R*,6S*)-6-(6-(cyclopropylamino)-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-26.
White solid, m.p. 128–129 °C, 62%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 0.61–0.65 (m, 2H, CH2), 0.88–0.93 (m, 2H, CH2), 1.20 (t, 3H, CH3), 2.48–2.55 (m, 2H, CH2), 2.70–2.74 (m, 2H, CH2), 2.99–3.04 (m, 1H, H-1), 3.14–3.20 (m, 1H, CH), 3.97–4.08 (m, 2H, OCH2), 5.30–5.38 (m, 1H, H-6), 5.91–5.98 (m, 2H, H-3, H-4), 6.04 (brs, 1H, N-H), 7.98 (s, 1H, Ar-H), 8.44 (s, 1H, Ar-H); 13C-NMR (CDCl3, 126 MHz): δ (ppm) = 7.4, 13.9, 23.7, 25.2, 29.8, 42.0, 49.2, 61.0, 119.3, 124.8, 125.9, 139.0, 148.6, 153.0, 155.7, 172.1; MS (ES, pos) m/z = 328 (M + 1).
Molecules 24 00161 i010
Ethyl (1S*,6S*)-6-((5-amino-6-chloropyrimidin-4-yl)amino)cyclohex-3-ene-1-carboxylate, (±)-29.
White solid, m.p. 120–121 °C, 42%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.19 (t, 3H, CH3, J = 7.12 Hz), 2.03–2.12 (m, 1H, CH2), 2.34–2.43 (m, 1H, CH2), 2.56–2.75 (m, 2H, CH2), 2.83–2.92 (m, 1H, H-1), 3.47 (brs, 2H, NH2), 4.06–4.16 (m, 2H, OCH2), 4.62–4.69 (m, 1H, H-6), 5.13 (d, 1H, N-H, J = 8.12 Hz), 5.66–5.78 (m, 2H, H-3, H-4), 8.09 (s, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.5, 27.5, 31.9, 45.2, 48.5, 61.3, 122.1, 124.2, 125.1, 143.7, 150.1, 154.8, 174.1; MS (ES, pos) m/z = 297 (M + 1).
Molecules 24 00161 i011
Ethyl (1S*,6S*)-6-(6-chloro-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-30.
Colorless oil, 58%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 0.96 (t, 3H, CH3, J = 7.12 Hz), 2.53–2.68 (m, 3H, CH2), 3.01–3.07 (m, 1H, CH2), 3.56–3.66 (m, 1H, H-1), 3.86–3.96 (m, 2H, OCH2), 4.94–5.03 (m, 1H, H-6), 5.78−5.89 (m, 2H, H-3, H-4), 8.17 (s, 1H, Ar-H), 8.76 (s, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.2, 29.0, 30.7, 44.1, 54.5, 61.4, 124.4, 125.6, 132.2, 145.3, 151.5, 151.9, 152.1, 173.0; MS (ES, pos) m/z = 307 (M + 1).
Molecules 24 00161 i012
Ethyl (1S*,6S*)-6-(6-azido-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-31.
White solid, m.p. 140–141 °C, 68%; 1H-NMR (DMSO, 400 MHz): δ (ppm) = 0.74 (t, 3H, CH3, J = 7.08 Hz), 2.46–2.57 (m, 3H, CH2), 2.86–3.00 (m, 1H, CH2), 3.60–3.66 (m, 1H, H-1), 3.69–3.76 (m, 2H, OCH2), 5.08–5.15 (m, 1H, H-6), 5.80–5.92 (m, 2H, H-3, H-4), 8.79 (s, Ar-H), 10.13 (s, 1H, Ar-H). 13C-NMR (DMSO, 100 MHz): δ (ppm) = 14.3, 29.3, 31.9, 44.7, 54.3, 61.1, 125.1, 125.9, 136.5, 139.3, 142.9, 144.6, 146.3, 173.1. MS (ES, pos) m/z = 314 (M + 1).
Molecules 24 00161 i013
Ethyl (1R*,2S*)-2-((5-amino-6-chloropyrimidin-4-yl)amino)cyclohex-3-ene-1-carboxylate, (±)-34.
Brown oil, 55%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.20 (t, 3H, CH3, J = 7.14 Hz), 1.99–2.19 (m, 4H, CH2), 2.99–3.05 (m, 1H, H-1), 4.00–4.17 (m, 2H, OCH2), 5.23–5.26 (m, 1H, H-2), 5.59 (d, 1H, N-H, J = 9.04 Hz), 5.70–5.78 (m, 1H, H-4), 5.87–5.92 (m, 1H, H-3), 8.06 (s, 1H, Ar-H), 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.5, 22.7, 23.6, 43.4, 46.9, 61.1, 122.4, 127.5, 130.0, 143.4, 149.7, 154.6, 174.2; MS (ES, pos) m/z = 297 (M + 1).
Molecules 24 00161 i014
Ethyl (1R*,2S*)-2-(6-chloro-9H-purin-9-yl)cyclohex-3-ene-1-carboxylate, (±)-35.
Brown solid, m.p. 119–121 °C, 68%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.03 (t, 3H, CH3, J = 7.14 Hz), 2.00–2.08 (m, 2H, CH2), 2.27–2.33 (m, 1H, CH2), 2.41–2.46 (m, 1H, CH2), 3.12–3.20 (m, 1H, H-1), 3.72–3.87 (m, 2H, OCH2), 5.67–5.70 (m, 1H, H-2), 5.83–5.90 (m, 1H, H-4), 6.28–6.33 (m, 1H, H-3), 8.23 (s, 1H, Ar-H), 8.73 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 14.3, 20.3, 24.4, 44.1, 50.1, 61.0, 123.1, 134.8, 147.5, 147.8, 149.9, 152.3, 152.9, 172.4; MS (ES, pos) m/z = 307 (M + 1), 309 (M + 3).
Molecules 24 00161 i015
Ethyl (1R*,2S*)-2-((5-amino-6-chloropyrimidin-4-yl)amino)cyclopent-3-ene-1-carboxylate, (±)-38.
Brownish white solid, m.p. 104–106 °C, 34%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 1.04 (t, 3H, CH3, J = 7.12 Hz), 2.56–2.67 (m, 1H, CH2), 2.83–2.90 (m, 1H, CH2), 3.44–3.54 (m, 1H, H-1), 3.57 (brs, 2H, NH2), 3.85–4.02 (m, 2H, OCH2), 5.34 (d, 1H, N-H, J = 8.76 Hz), 5.69–5.76 (m, 2H, H-2, H-4), 5.98–6.01 (m, 1H, H-3), 8.06 (s, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 14.2, 35.4, 46.4, 58.2, 61.1, 122.6, 130.2, 134.0, 143.0, 149.3, 154.1, 174.0; MS (ES, pos) m/z = 283 (M + 1), 285 (M + 3).
Molecules 24 00161 i016
Ethyl (1R*,2S*)-2-(6-chloro-9H-purin-9-yl)cyclopent-3-ene-1-carboxylate, (±)-39.
Yellowish white solid, m.p. 118–119 °C, 39%; 1H-NMR (CDCl3, 400 MHz): δ (ppm) = 0.72 (t, 3H, CH3, J = 7.14 Hz), 2.76–2.85 (m, 1H, CH2), 3.14–3.23 (m, 1H, CH2), 3.49–3.56 (m, 1H, H-1), 3.65–3.77 (m, 2H, OCH2), 5.86–5.89 (m, 1H, H-2), 5.15–5.17 (m, 1H, H-4), 6.44–6.47 (m, 1H, H-3), 7.99–8.01 (m, 1H, Ar-H), 8.78–8.81 (m, 1H, Ar-H); 13C-NMR (CDCl3, 100 MHz): δ (ppm) = 13.8, 34.9, 47.2, 60.9, 61.4, 126.8, 134.7, 138.7, 150.0, 152.2, 152.3, 154.2, 170.9; MS (ES, pos) m/z = 293 (M + 1), 295 (M + 3).
Molecules 24 00161 i017
((1R*,6S*)-6-((5-Amino-6-chloropyrimidin-4-yl)amino)cyclohex-3-en-1-yl)methanol, (±)-42.
White solid, m.p. 186–188 °C, 60%; 1H-NMR (DMSO, 400 MHz): δ (ppm) = 1.96–2.12 (m, 4H, CH2), 2.21–2.30 (m, 1H, H-1), 3.24–3.32 (m, 1H, OCH2), 3.40-3.49 (m, 1H, OCH2), 4.43–4.48 (m, 2H, H-6 and O-H), 5.16 (brs, 2H, N-H), 5.59–5.70 (m, 2H, H-3, H-4), 6.24 (d, 1H, N-H, J = 7.56 Hz), 7.68 (s, 1H, Ar-H); 13C-NMR (DMSO, 100 MHz): δ (ppm) = 25.9, 30.1, 39.8, 47.2, 61.4, 124.5, 125.6, 126.6, 138.0, 146.4, 152.6; MS (ES, pos) m/z = 255 (M + 1), 257 (M + 3).
Molecules 24 00161 i018
((1R*,6S*)-6-(6-Chloro-9H-purin-9-yl)cyclohex-3-en-1-yl)methanol, (±)-43.
White solid, m.p. 109–111 °C, 76%, 1H-NMR (CDCl3, 500 MHz): δ (ppm) = 1.36–1.47 (m, 1H, CH2), 2.05–2.15 (m, 1H, CH2), 2.34–2.44 (m, 1H, H-1), 2.50–2.59 (m, 1H, CH2), 2.73–2.81 (m, 1H, OCH2), 2.93–3.03 (m, 1H, CH2), 3.44–3.53 (m, 1H, OCH2), 4.65 (brs, 1H, OH), 5.31–5.37 (m, 1H, H-6), 5.98–6.06 (m, 2H, H-3, H-4), 8.33 (s, 1H, Ar-H), 8.76 (s, 1H, Ar-H); 13C-NMR (CDCl3, 126 MHz): 22.6, 31.0, 39.7, 48.6, 62.1, 124.7, 127.8, 131.1, 144.6, 151.6, 151.7, 152.5, MS (ES, pos) m/z = 265 (M + 1), 267 (M + 3).
Molecules 24 00161 i019
((1S*,6S*)-6-((5-Amino-6-chloropyrimidin-4-yl)amino)cyclohex-3-en-1-yl)methanol, (±)-46.
White solid, m.p. 164–167 °C, 64%; 1H-NMR (DMSO, 400 MHz): δ (ppm) = 1.70–1.84 (m, 1H, CH2), 1.89–2.05 (m, 2H, CH2), 2.14–2.25 (m, 1H, CH2), 2.26–2.36 (m, 1H, H-1), 3.26–3.43 (m, 2H, OCH2), 4.05–4.15 (m, 1H, H-6), 4.36 (t, 1H, O-H, J = 5.32 Hz), 4.99 (brs, 2H, N-H), 5.51-5.67 (m, 2H, H-3, H-4), 6.50 (d, 1H, N-H, J = 7.96 Hz), 7.64 (s, 1H, Ar-H), 13C-NMR (DMSO, 100 MHz): δ (ppm) = 28.7, 32.3, 41.3, 48.3, 62.9, 124.2, 125.5, 127.3, 137.7, 146.4, 152.7, MS (ES, pos) m/z = 255 (M + 1), 257 (M + 3).
Molecules 24 00161 i020
((1S*,6S*)-6-(6-Chloro-9H-purin-9-yl)cyclohex-3-en-1-yl)methanol, (±)-47.
White solid, m.p. 160–162 °C, 70%; 1H-NMR (DMSO, 500 MHz): δ (ppm) = 2.13–2.29 (m, 2H, CH2), 2.42–2.49 (m, 1H, CH2), 2.53–2.62 (m, 1H, H-1), 2.83–2.95 (m, 1H, CH2), 2.98–3.05 (m, 1H, OCH2), 3.11–3.17 (m, 1H, OCH2), 4.69–4.78 (m, 1H, H-6), 5.68–5.85 (m, 2H, H-3, H-4), 8.73–8.78 (m, 2H, Ar-H), 13C-NMR (DMSO, 126 MHz): 28.5, 31.3, 39.0, 54.1, 61.7, 124.6, 127.2, 131.6, 147.6, 149.4, 151.7, 152.4; MS (ES, pos) m/z = 265 (M + 1), 267 (M + 3).

Supplementary Materials

The Supplementary Materials are available online.

Author Contributions

Both authors equally contributed to the manuscript. L.K. designed the experiments. A.R. performed the analyses and wrote the paper. L.K. reviesed the manuscript.

Funding

We are grateful to the Hungarian Research Foundation (NKFIH No. K 119282) for financial support. The financial support of the GINOP-2.3.2-15-2016-00034 project is also acknowledged. This research was supported by the EU-funded Hungarian grant EFOP-3.6.1-16-2016-00008. Ministry of Human Capacities, Hungary grant 20391-3/2018/FEKUSTRAT is also acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of all compounds are available in mg amounts from the authors.
Molecules 24 00161 sch001 550
Scheme 1. Some bioactive nucleoside analogs.
Scheme 1. Some bioactive nucleoside analogs.
Molecules 24 00161 sch001
Molecules 24 00161 sch002 550
Scheme 2. Some bioactive β-amino acid-based nucleoside analogs.
Scheme 2. Some bioactive β-amino acid-based nucleoside analogs.
Molecules 24 00161 sch002
Molecules 24 00161 sch003 550
Scheme 3. Examples of bioactive cyclic amino acid derivatives.
Scheme 3. Examples of bioactive cyclic amino acid derivatives.
Molecules 24 00161 sch003
Molecules 24 00161 sch004 550
Scheme 4. Synthesis of cyclic γ-amino acid-based nucleoside analogs.
Scheme 4. Synthesis of cyclic γ-amino acid-based nucleoside analogs.
Molecules 24 00161 sch004
Molecules 24 00161 sch005 550
Scheme 5. Synthesis of β-amino acid-based nucleoside analogs from ethyl cis-2-aminocyclohex-4-enecarboxylate hydrochloride (±)-22.
Scheme 5. Synthesis of β-amino acid-based nucleoside analogs from ethyl cis-2-aminocyclohex-4-enecarboxylate hydrochloride (±)-22.
Molecules 24 00161 sch005
Molecules 24 00161 sch006 550
Scheme 6. Synthesis of β-amino acid-based nucleoside analogs from ethyl trans-2-aminocyclohex-4-enecarboxylate hydrochloride (±)-28.
Scheme 6. Synthesis of β-amino acid-based nucleoside analogs from ethyl trans-2-aminocyclohex-4-enecarboxylate hydrochloride (±)-28.
Molecules 24 00161 sch006
Molecules 24 00161 sch007 550
Scheme 7. Synthesis of β-amino acid-based nucleoside analog (±)-35 from ethyl cis-2-aminocyclohex-3-enecarboxylate hydrochloride (±)-33.
Scheme 7. Synthesis of β-amino acid-based nucleoside analog (±)-35 from ethyl cis-2-aminocyclohex-3-enecarboxylate hydrochloride (±)-33.
Molecules 24 00161 sch007
Molecules 24 00161 sch008 550
Scheme 8. Synthesis of β-amino acid-based nucleoside analog (±)-39 with a 5-membered carbocycle.
Scheme 8. Synthesis of β-amino acid-based nucleoside analog (±)-39 with a 5-membered carbocycle.
Molecules 24 00161 sch008
Molecules 24 00161 sch009 550
Scheme 9. Synthesis of unsaturated carbanucleoside isomers (±)-43 and (±)-47 analogs of carbocyclic nucleoside (±)-5.
Scheme 9. Synthesis of unsaturated carbanucleoside isomers (±)-43 and (±)-47 analogs of carbocyclic nucleoside (±)-5.
Molecules 24 00161 sch009

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Remete, A.M.; Kiss, L. Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs. Molecules 2019, 24, 161. https://doi.org/10.3390/molecules24010161

AMA Style

Remete AM, Kiss L. Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs. Molecules. 2019; 24(1):161. https://doi.org/10.3390/molecules24010161

Chicago/Turabian Style

Remete, Attila Márió, and Loránd Kiss. 2019. "Alicyclic β- and γ-Amino Acids: Useful Scaffolds for the Stereocontrolled Access to Amino Acid-Based Carbocyclic Nucleoside Analogs" Molecules 24, no. 1: 161. https://doi.org/10.3390/molecules24010161

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