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Organic Chemistry International
Volume 2012 (2012), Article ID 293945, 5 pages
Research Article

Preparation and Structure of Novel Chiral 4,6-Disubstituted Tetrahydropyrimidinones

School of Chemistry, National University of Ireland, University Road, Galway, Ireland

Received 9 July 2012; Accepted 11 October 2012

Academic Editor: Ken Shimizu

Copyright © 2012 David Frain et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The synthesis of a number of novel 4,6-disubstituted tetrahydropyrimidinones is described. The synthetic route described is applied to the synthesis of two stereoisomers. The structure of one tetrahydropyrimidinone was determined by XRD and showed an interesting hydrogen-bonded ribbon in the direction of crystal growth. These pyrimidinones are members of a class of compounds with diverse bioactivity. An initial study of their activity versus HIV protease is included.

1. Introduction

Cyclic ureas including tetrahydropyrimidinones are common heterocyclic motifs in biologically active molecules (Figure 1). Molecules of this type have been reported as having antineoplastic 1 [1], anti-viral 2 [2, 3], 3 [4, 5] and anti-arrhythmic 4 [6] activity amongst many others. The antineoplastic activity is linked to inhibition of dihydroorotase, a key enzyme which is present in problematic organisms such as clostridium bacteria and as such may be treatment target [7]. In the case of anti-viral drugs such as DMP-450 2 the interaction of the heterocycle with HIV-protease is understood via the reported X-ray structures of their complexes and extensive modelling leading to structure activity relationships [810].

Figure 1: Cyclic ureas with biological activity.

Synthetic methods for the synthesis of these heterocycles (5–7 membered) have previously been reported. Syntheses usually involve the reaction of an appropriate diamine with phosgene or a synthetically equivalent safer reagent [1113].

We have recently developed the synthesis of diamines 58 for the preparation of novel asymmetric catalysts (Figure 2) [1416]. We compared these to the structures of existing bioactive cyclic ureas 3. These ureas had shown good antiviral activity but their oral bioavailability was poor. We thought our new functionalised diamines, which we synthesised with control of the relative and absolute stereochemistry from sugar based precursors, could be transformed to novel tetrahydropyrimidinones. The synthetic route we chose would allow access to a large number of novel functionalised tetrahydropyrimidinones. What we present in this paper is the synthesis of the first few such tetrahydropyrimidinones.

Figure 2

2. Results and Discussion

We initially synthesised the tetrahyropyrimidinone ring from the TBS protected diaminodialcohols 7 and 8 by reaction with bis(trichloromethyl)carbonate (BTC) in the presence of pyridine (Scheme 1). The heterocycles 9 and 10 were isolated in moderate yields. Compound 9 when crystallised from DCM/hexane gave a very small number of very fine needles with aspect ratios of more than 50 : 1 allowing us to determine its structure from X-ray analysis. The absolute and relative stereochemistries were as predicted and in the crystal structure of 9 the molecules form hydrogen bonded ribbons in the needle direction (Figure 3) [17]. It is often observed that systems which have a tendency to needle formation have hydrogen bonded ribbons which are also in the needle direction [18]. However the reverse of this argument is not always true as the parent compound, perhydropyrimidinone, which also has the same hydrogen bonded ribbon in its structure has been reported to form block like crystals from acetone [19]. The strong tendency of 9 to form needles is likely to be aided by the presence of ten methyl groups in each molecule which effectively shield the hydrogen bonded ribbons from each other.

Scheme 1
Figure 3: Two views of the X-ray crystal structure of 9. The molecular structure (left) and hydrogen bonded ribbons in the crystal structure, which grow in the a direction (right). Hydrogen atoms have been omitted for clarity in the ribbon structure.

We wished to explore the possibility of functionalising the oxygens protected by the TBS groups in 9 and 10. The TBS protecting groups could be removed using TBAF to release the alcohols but synthetically this proved less favourable than an alternative synthesis. The synthesis of the TBS protected diaminodialcohols 7 and 8 which we have reported previously involves the introduction of the amines via mesylate activation of alcohols at the same site followed by displacement with azide and reduction. We discovered that if the hydrogenation was not carefully monitored deprotection of the alcohols would take place. Hydrogenation for extended periods led to the isolation of >40% of the mono TBS protected diaminodialcohol products which we discovered were the ideal starting materials for this work. Compounds 11 and 12 were separately reacted with carbonyl diimidazole (Scheme 2) in the presence of base to form the tetrahydropyrimidinone and the crude product treated with acid to remove the TBS group leading to the isolation of the functionalised tetrahydropyrimidinones 13 and 14. We were then in a position where we could functionalise 14 by perbenzylating it using benzylbromide and sodium hydride giving 15 in modest yield.

Scheme 2

The meso compound 13 has the same stereochemistry as 1 which is known to have antineoplastic activity. Our synthetic route offers possibilities for the synthesis of similar compounds with variations in functionality on the ring. Compounds 14 and 15 have obvious similarity to that of 3 which has antiviral activity and again our synthesis would allow significant variation in the functionality and substitution to modulate these compounds activity or bioavailability profile.

Synthesis via compounds 9 and 10 would allow for functionalisation of the urea nitrogens before deprotection of the alcohols which could then be reacted with a different substituent than the nitrogens. Synthesis from compounds 11 and 12 would allow for the two alcohols to be differently functionalised.

Compounds 14 and 15 were tested for inhibition of HIV-protease using pepstatin A as the reference compound for the assay [20]. Compound 15 in particular was chosen because of the structural similarity 3 which is known for its inhibitory activity. The compounds were tested for inhibition at 10 μM concentration and at this concentration showed inhibition of just 4% and 10%, respectively. These inhibitions are obviously very modest but antiviral activity is just one of the potential bioactivities available via the compounds accessible from this chemistry. We are further exploring the behaviour of these and similar molecules for activity as ligands for biomolecules.

3. Conclusions

In summary we report herein the synthesis of a number of novel tetrahydropyrimidinones. The synthetic method offers stereocontrol and may be adapted to synthesise a wide variety of such compounds with different substitution which given such compounds proven bioactivity will be of wide interest.

4. Experimental

4.1. (4S,6S)-4,6-Bis({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydropyrimidin-2(1H)-one 9

To a stirring solution of 7 (220 mg, 0.6 mmoL) in CH2Cl2 (7 mL) pyridine was added (0.7 mL). The mixture was cooled to −78°C and a solution of bistrichloromethyl carbonate (66 mg, 0.11 mmol) in CH2Cl2 (3 mL) was then added dropwise over a period of 2 h. The resulting mixture was allowed to return to room temperature and was stirred overnight. The reaction was quenched by the addition of sat. NH4Cl (1 mL), extracted with CH2Cl2 (3 × 1 mL), and the combined extracts were concentrated in vacuo. Purification by column chromatography on SiO2 (Pet. ether : EtOAc; 70 : 30) followed by recrystallisation from hexane: CH2Cl2 yielded 9 (98 mg, 42%) as a white solid; [α]D −28 (c 0.7, MeCN, 21°C); IR 3305, 2936, 1653, 1095 cm−1; δH (400 MHz, CDCl3); 0.00 [12H, s, 2 × Si(CH3)2], 0.83 (18H, s, 2 × C(CH3)3), 1.62 (2H, t, J 7.2, CHCH2CH), 3.39–3.66 (6H, m, 2 × CHNH2, 2 × CH2OSi), 4.89 (2H, br s, 2 × NH) ppm; δC (100 MHz, CDCl3); −5.4 (CH3, 4 × SiCH3), 18.2 [C, 2 × C(CH3)3], 25.8 [CH3, 2 × C(CH3)3], 49.6 (CH, 2 × CHN), 66.4 (CH2, 2 × CH2O), 155.9 (C, CO) ppm.

4.2. (4S,6S)-4,6-Bis(hydroxymethyl)tetrahydropyrimidin-2(1H)-one 14

To a stirring solution of 12 (300 mg, 1.2 mmoL) in DMF (5 mL) Et3N was added (367 μL, 2.64 mmoL). A solution of carbonyldiimidazole (250 mg, 1.56 mmoL) in DMF (2.5 mL) was then added dropwise over a period of 2 h. The resulting mixture was stirred overnight, then quenched by the addition of H2O (1 mL) and concentrated in vacuo. The residue was dissolved in H2O (20 mL) and Dowex 50W-X8 (H) was added until the pH measured 2-3. The acidic solution was stirred for 90 min, filtered, and concentrated in vacuo. Purification by column chromatography on SiO2 (EtOAc : MeOH; 80 : 20) yielded 13 (92 mg, 48%) as a yellow oil; [α]D −42 (c 0.7, MeOH, 21°C); δH (400 MHz, D2O); 1.64 (2H, t, J 5.0, CHCH2CH), 3.33–3.51 (6H, m, 2 × CH, 2 × CH2OH); δC (100 MHz, D2O); 23.5 (CH2, CHCH2CH), 48.8 (CH, 2 × CH), 64.0 (CH2, 2 × CH2OH), 158.5 (C, CO); IR 3271, 2931, 2875, 1630, 1041 cm−1; HRMS (ES + TOF) calcd for C6H12N2O3: 161.0926 (M + H); found: 161.0918 (M + H).

4.3. (4S,6S)-1,3-Dibenzyl-4,6-Bis[(benzyloxy)methyl]tetrahydropyrimidin-2(1H)-one 15

To a solution of 14 (60 mg, 0.37 mmol) in THF (3 mL) at 0°C NaH was added (60% dispersion in mineral oil, 14.8 mg, 0.37 mmol). The mixture was stirred for 20 min at this temperature. BnBr (44.6 μL, 0.37 mmol) was then added and stirring was continued for 20 min at 0°C. The process was repeated until five portions of NaH and BnBr had been added. The mixture was concentrated in vacuo, taken up in EtOAc (3 mL), and washed with H2O (3 × 1 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by column chromatography on SiO2 (Pet. ether : EtOAc; 90 : 10–25 : 75) gave 15 (34 mg, 18%); [α]D −68 (c 0.7, MeCn, 21°C); δH (400 MHz, CDCl3); 2.0 (2H, t, J 6, CHCH2CH), 3.38–3.44 (6H, m, 2 × CH2O, 2 × CHN), 4.12 (2H, d, J 15, 2 × one of NCH2Ph), 4.39 (4H, s, 2 × OCH2Ph), 5.26 (2H, d, J 15.6, 2 × one of NCH2Ph), 7.18–7.34 (20H, m, 4 × ArH) ppm; δC (100 MHz, CDCl3); 28.0 (CH2, CHCH2CH), 49.1 (CH2, 2 × CH2N), 51.1 (CH, 2 × CHN), 70.3 (CH2, 2 × CHCH2O), 73.2 (CH2, 2 × PhCH2O), 126.9 (CH, 4 × para ArCH), 127.7 (CH, 8 × ortho ArCH), 128.4 (CH, 8 × meta ArCH), 136.1 (C, 2 × ArC), 138.7 (C, 2 × ArC), 156.7 (C, CO) ppm.

4.4. Pyrimidinone 10

To a stirred solution of tbsdiamine 8 (0.22 g, 0.59 mmol) in CH2Cl2 (10 mL) at 0°C pyridine was added (0.29 mL, 3.6 mmol). A solution of bis(trichloromethyl)carbonate (BTC) in CH2Cl2 (4 mL) was added over ca. 3 h via a syringe pump. The solution was stirred at room temperature overnight. The solution was concentrated in vacuo and purified by column chromatography on SiO2 (Pet. ether : EtOAc; 1 : 4) to yield 10 (0.11 g, 47%) as a white solid.

MP 153–158°C; 1H-NMR (400 MHz, CDCl3) δ = 4.95 (2H, s, 2 × NH), 3.59 (2H, dd, J = 9.6, 3.7 Hz, 2 × CHHO), 3.53–3.46 (2H, m, 2 × CHN), 3.33 (2H, t, J = 9.2 Hz, 2 × CHHO), 1.71–1.68 (1H, m, one of CHCH2CH), 1.19–0.98 (1H, m, one of CHCH2CH), 0.83 [18H, s, 2 × C(CH3)3], 0.00 [12H, s, 2 × Si(CH3)2]; 13C-NMR (100 MHz, CDCl3) δ = 156.5 (C, C=O), 66.8 (CH2, 2 × CH2O), 51.8 (CH, 2 × CHN), 27.0 (CH2, CHCH2CH), 25.9 [CH3, 2 × C(CH3)3], 18.3 (C, 2 × C), −5.3 [CH3, 2 × Si(CH3)2]; IR 3449, 3203, 3088, 2954, 2928, 2856, 1674, 1500, 1471, 1463 cm−1; ESI-HRMS calcd for C18H40N2O3Si2 387.2500, found m/z 387.2484 (M-H).

4.5. Pyrimidinone 13

To a solution of 11 (0.62 g, 2.5 mmol) in DMF triethylamine was added (0.77 mL, 5.5 mmol). A solution of carbonyldiimidazole (0.40 g, 3.4 mmol) in DMF (4 mL) was added over ca. 3 h via a syringe pump. The mixture was stirred at room temperature over night and quenched with 1 mL water. The bulk of DMF was removed in vacuo. The resulting solution was dissolved in water and Dowex-50X8-100 (H+) was added until the pH of the solution was 2-3. The solution was stirred at room temperature for 4 hours. The solution was filtered and the filtrate concentrated in vacuo to yield a 13 as a brown oil (0.10 g, 25%).

1H-NMR (400 MHz, D2O) δ = 3.48 (2H, dd, J = 11.0, 3.9 Hz, 2 × CHHO), 3.43–3.37 (2H, m, 2 × CHN), 3.33 (2H, t, J = 5.7 Hz, 2 × CHHO), 1.78–1.73 (1H, m, one of CHCH2CH), 1.22 (1H, q, J = 24.3, 11.2 Hz, one of CHCH2CH); 13C-NMR (100 MHz, D2O) δ = 158.0 (C, C=O), 63.5 (CH2, 2 × CH2O), 51.0 (CH, 2 × CHN), 25.5 (CH2, CHCH2CH); IR 3271, 2933, 1623 cm−1; ESI-HRMS calcd for C6H12N2O3 159.0770, found m/z 159.0772.


This paper has emanated from research conducted with the financial support of Science Foundation Ireland (RFP).


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