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

Frain, David; Kirby, Fiona; McArdle, Patrick; O'Leary, Patrick

doi:https://doi.org/10.1155/2012/293945

Organic Chemistry International

On this page

Abstract Introduction Results and Discussion Conclusions Experimental References Copyright Related Articles

Research Article | Open Access

Volume 2012 | Article ID 293945 | https://doi.org/10.1155/2012/293945

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

David Frain,¹Fiona Kirby,¹Patrick McArdle,¹and Patrick O'Leary¹

Academic Editor: Ken Shimizu

Received09 Jul 2012

Accepted11 Oct 2012

Published04 Nov 2012

Abstract

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 [8–10].

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 [11–13].

We have recently developed the synthesis of diamines 5–8 for the preparation of novel asymmetric catalysts (Figure 2) [14–16]. 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.

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.

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.

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; δ_H (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; δ_C (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); δ_H (400 MHz, D₂O); 1.64 (2H, t, J 5.0, CHCH₂CH), 3.33–3.51 (6H, m, 2 × CH, 2 × CH₂OH); δ_C (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); δ_H (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; δ_C (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.

Acknowledgment

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

References

J. L. Adams, T. D. Meek, S. M. Mong, R. K. Johnson, and B. W. Metcalf, “cis-4-carboxy-6-(mercaptomethyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one, a potent inhibitor of mammalian dihydroorotase,” Journal of Medicinal Chemistry, vol. 31, no. 7, pp. 1355–1359, 1988.
View at: Google Scholar
H. O. Andersson, K. Fridborg, S. Löwgren et al., “Optimization of P1–P3 groups in symmetric and asymmetric HIV-1 protease inhibitors,” European Journal of Biochemistry, vol. 270, no. 8, pp. 1746–1758, 2003.
View at: Publisher Site | Google Scholar
M. E. Pierce, G. D. Harris, Q. Islam et al., “Stereoselective synthesis of HIV-1 protease inhibitor, DMP 323,” The Journal of Organic Chemistry, vol. 61, no. 2, pp. 444–450, 1996.
View at: Publisher Site | Google Scholar
P. Gayathri, V. Pande, R. Sivakumar, and S. P. Gupta, “A quantitative structure-activity relationship study on some HIV-1 protease inhibitors using molecular connectivity index,” Bioorganic and Medicinal Chemistry, vol. 9, no. 11, pp. 3059–3063, 2001.
View at: Publisher Site | Google Scholar
A. R. Katritzky, A. Oliferenko, A. Lomaka, and M. Karelson, “Six-membered cyclic ureas as HIV-1 protease inhibitors: a QSAR study based on CODESSA PRO approach,” Bioorganic and Medicinal Chemistry Letters, vol. 12, no. 23, pp. 3453–3457, 2002.
View at: Publisher Site | Google Scholar
S. Pelosi and Salvatore Jr., “Novel cyclic ureas useful as antiarrythmic and antifibrillatory agents,” WO 93/04060, 1993.
View at: Google Scholar
D. W. Pettigrew, R. R. Bidigare, B. J. Mehta, M. I. Williams, and E. G. Sander, “Dihydro-orotase from Clostridium oroticum. Purification and reversible removal of essential zinc,” Biochemical Journal, vol. 230, no. 1, pp. 101–108, 1985.
View at: Google Scholar
R. Garg and B. Bhhatarai, “A mechanistic study of 3-aminoindazole cyclic urea HIV-1 protease inhibitors using comparative QSAR,” Bioorganic and Medicinal Chemistry, vol. 12, no. 22, pp. 5819–5831, 2004.
View at: Publisher Site | Google Scholar
C. N. Hodge, P. E. Aldrich, L. T. Bacheler et al., “Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450,” Chemistry and Biology, vol. 3, no. 4, pp. 301–314, 1996.
View at: Google Scholar
P. Y. S. Lam, Y. Ru, P. K. Jadhav et al., “Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas,” Journal of Medicinal Chemistry, vol. 39, no. 18, pp. 3514–3525, 1996.
View at: Publisher Site | Google Scholar
F. Qian, J. E. McCusker, Y. Zhang et al., “Catalytic oxidative carbonylation of primary and secondary diamines to cyclic ureas. Optimization and substituent studies,” The Journal of Organic Chemistry, vol. 67, no. 12, pp. 4086–4092, 2002.
View at: Publisher Site | Google Scholar
Y. J. Kim and R. S. Varma, “Microwave-assisted preparation of cyclic ureas from diamines in the presence of ZnO,” Tetrahedron Letters, vol. 45, no. 39, pp. 7205–7208, 2004.
View at: Publisher Site | Google Scholar
W. R. Boon, “Respiratory stimulants. Part I. Fully-substituted ureas derived from αω-alkylenediamines,” Journal of the Chemical Society, pp. 307–318, 1947.
View at: Google Scholar
D. Frain, F. Kirby, P. McArdle, and P. O'Leary, “The synthesis of AraBOX, a new 4, $4^{'}$ -bis(oxazoline), from novel pentitol-derived bis-β-amino alcohols,” Synlett, no. 8, pp. 1261–1264, 2009.
View at: Publisher Site | Google Scholar
D. Frain, F. Kirby, P. McArdle, and P. O'Leary, “Preparation, structure and catalytic activity of copper(II) complexes of novel 4,4′-BOX ligands,” Tetrahedron Letters, vol. 51, no. 31, pp. 4103–4106, 2010.
View at: Publisher Site | Google Scholar
F. Kirby, D. Frain, P. McArdle, and P. O'Leary, “4,4′BOX based catalysts: synthesis, structure and catalytic application,” Catalysis Communications, vol. 11, no. 12, pp. 1012–1016, 2010.
View at: Publisher Site | Google Scholar
“The CIF files for compound 9 has been deposited with the The Cambridge Crystallographic Data Centre (deposition number CCDC, 800917)”.
View at: Google Scholar
N. Blagden, R. Davey, G. Dent et al., “Woehler and Liebig revisited: a small molecule reveals its secrets—the crystal structure of the unstable polymorph of benzamide solved after 173 years,” Crystal Growth and Design, vol. 5, no. 6, pp. 2218–2224, 2005.
View at: Publisher Site | Google Scholar
S. Calogero, U. Russo, and A. Del Pra', “Characterization of some high-spin iron(III) complexes with urea derivaties. Crystal structure of diaquatetrakis(perhydropyrimidin-2-one)iron trichloride dihydrate and of perhydrophyrimidin-2-one,” Journal of the Chemical Society, Dalton Transactions, pp. 646–653, 1980.
View at: Publisher Site | Google Scholar
“Testing was carried out by CEREP inc France”.
View at: Google Scholar

Copyright

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.

PDF Download Citation

Download other formats

Order printed copies

Views

1080

Downloads

468

Citations