Antiviral Bioactivity of Chiral β-Amino Acid Ester Derivatives Synthesized through a One-Pot, Solvent-Free Asymmetric Mannich Reaction

Abstract

A series of both enantiomers of chiral β-amino acid ester derivatives containing a 4-(piperidin-1-yl)pyrimidine moiety was prepared in high yield and excellent enantioselectivity excess (up to >99% enantiomeric excess) using a chiral cinchona alkaloid thiourea catalyst under one-pot solvent-free conditions. Antiviral bioassay experimental results showed that some of the chiral products exhibited higher antiviral activities against tobacco mosaic virus (TMV) in vivo than the commercial antiviral agent ningnanmycin.

Amino acid ester derivatives are one of the most useful molecular frameworks in medicinal chemistry because they exhibit a broad spectrum of biological activities.[1] [2] The β-amino acid ester derivatives were reported to possess promising biological activities, such as antifungal,[2,3] antitumor, [4] antiviral,[5] and anti-HBV[6] properties. The biological activity of β-amino acid ester derivatives depends on their chiral structural peculiarities, which is why there has been considerable interest in the synthesis of enantiomerically pure β-amino acid ester derivatives.[7] [8]

Among the methods of synthesis, there has been enormous interest in the asymmetric Mannich reaction because the catalytic asymmetric Mannich reaction is one of the most effective methods for preparation of optically active β-amino acid ester derivatives and is therefore a very important C–C bond-forming reaction.[9] However, preformed asymmetric Mannich reagents have some disadvantages, such as producing only moderate yields and enantiomeric excess (ee) or not being suitable for three-component reactions, despite their important synthetic value. In addition, there are few studies describing the use of the Mannich reaction to synthesize highly enantiomerically pure β-amino acid ester derivatives containing pyrimidine heterocycles that exhibit high biological activities. Herein, in order to generate highly effective and environmentally safe antiviral chiral agents, we report the efficient asymmetric Mannich reaction for the synthesis of novel chiral β-amino acid ester derivatives containing a 4-(piperidin-1-yl)pyrimidine moiety via cinchona alkaloid organic catalysts under one-pot solvent-free conditions. Chiral products were evaluated by testing their antiviral activity against tobacco mosaic virus (TMV).

Through hydrogen-bonding interactions, cinchona alkaloid catalysts have been successfully applied in different types of Mannich reactions.[10] These findings prompted us to utilize bifunctional cinchona alkaloid derivatives of thiourea Q1–Q5 that are capable of dual activation through double hydrogen bonding (Figure [1]). We employed them in a one-pot asymmetric catalytic Mannich reaction of 4-methyl-6-(piperidin-1-yl)pyrimidin-2-amine, benzaldehyde, and dimethyl malonate (Table [1]). These cinchona alkaloid catalysts were then examined for their ability to enantioselectively catalyze the model Mannich reaction. Among them, quinine was unable to accelerate this transformation, which indicates that the thiourea moiety on the catalyst is crucial for the enantioselectivity of the reaction. However, Q1, Q2, and Q3 possessed weak catalytic actions, and catalysts Q4 and Q5 afforded promising results (Table [1], entries 5, 6). The change in trend in the catalytic activity with the introduction of the different substituents on the aromatic ring indicated that the electron-withdrawing properties contributed to higher reactivity for the model Mannich reaction.

Table 1 Optimization of Reaction Conditions^a

Entry	Cat. (mol%)	Solvent	Temp (°C)	Time (h)	Yield (%)b	ee (%)c
1	Quinine (20)	toluene	50	72	12	10
2	Q1 (20)	toluene	50	72	25	32
3	Q2 (20)	toluene	50	72	40	41
4	Q3 (20)	toluene	50	72	45	55
5	Q4 (20)	toluene	50	72	63	63
6	Q5 (20)	toluene	50	72	60	65
7	Q4 (20)	THF	50	72	47	55
8	Q4 (20)	EtOH	50	72	33	43
9	Q4 (20)	MeOH	50	72	29	39
10	Q4 (20)	acetonitrile	50	72	40	45
11	Q4 (20)	neat	50	72	82	73
12	Q4 (20)	neat	60	72	94	95
13	Q4 (20)	neat	70	72	92	82
14	Q4 (10)	neat	60	36	93	95
15	Q4 (5)	neat	60	36	73	80
16	Q5 (10)	neat	60	36	91	94
17	Q4 (10)	neat	60	18	58	82

^a Reactions were performed with 0.30 mmol of 1, 0.30 mmol of 2a, and 10 equiv of 3a (3 mmol) in capped vials.

^b Yield of isolated product.

^c Determined by HPLC analysis.

Next, the influence of solvents on the model Mannich reaction was studied using the most efficient catalyst Q4 (Table [1], entries 5 and 7–11). In toluene, the yield and enantioselectivity of product were better than those of alternative normal solvents. When the reaction was performed in THF, EtOH, MeOH, or acetonitrile, the product was obtained in lower enantioselectivity or yield (Table [1], entries 7–10). When the model reaction was performed in neat malonate, both yield and enantioselectivity were obviously increased (Table [1], entry 11). The reaction temperature was also an important factor in this asymmetric Mannich reaction. Most notably, when the model reaction was performed in neat malonate at 60 °C, an excellent conversion was achieved (Table [1], entry 12). We also changed the reaction temperature from 60 °C to 70 °C, which resulted in lower enantioselectivity (Table [1], entry 13). Almost no change in enantioselectivity and reactivity was observed when the loading of Q4 was reduced from 20 mol% to 10 mol% (Table [1], entry 14). Notably, under these reaction conditions, the chemical yield did not decrease when the reaction time was reduced from 72 h to 36 h (Table [1], entry 14). However, a slight decrease of yield and enantioselectivity was observed when the catalyst load was reduced from 10 mol% to 5 mol% (Table [1], entry 15). When the reaction was carried out only for 18 h, both yield and enantioselectivity were sharply decreased (Table [1], entry 17). It should be noted that the other enantiomer of the product could be obtained using Q5 as the catalyst (Table [1], entry 16). Based on the above results, the optimized reaction conditions (Table [1], entries 14 and 16) were used for the model reaction. In contrast to conventional processes (Table [1], entries 5–10), the solvent-free synthetic approach dramatically reduced the reaction time, increased the yield, and simplified the post-treatment.

Under these optimized reaction conditions (Table [1], entry 14), a series of various aldehydes and malonates were investigated in this asymmetric Mannich reaction. As illustrated in Table [2], consistently excellent enantioselectivity was observed for a broad range of various aldehydes and malonates. Novel chiral β-amino acid ester derivatives with various substituents afforded Mannich adducts with excellent enantioselectivities (Table [2], entries 1–16). Both aromatic aldehydes and aliphatic aldehydes were equally excellent substrates for the present transformation (Table [2], entries 1–12). Heteroaromatic aldehydes, such as furfuraldehyde, were also good substrates, and the desired products were obtained with excellent enantioselectivities and in high yields (93–95% ee and 88–92% yield, respectively; Table [2], entries 13–16). Notable, cyclohexanecarbaldehyde smoothly underwent this Mannich reaction to give the corresponding products in excellent enantioselectivities (up to >99% ee; Table [2], entry 9). By comparison, p-anisaldehyde showed slightly reduced reactivity (Table [2], entry 6). When the methoxy group was substituted with 4-Cl or 4-Me, the enantioselectivity clearly increased (98–99% ee; Table [2], entries 7, 8, 11, 12). ECD analysis was to assess the structures of chiral products. This process involved comparing the experimental and calculated ECD spectra.[11] And so in this way, the absolute configuration of product 4e obtained using the Q5 catalyst was determined to be S (Table [2], entry 10). The absolute configuration of all other products was assigned by analogy.

Table 2 Scope of the Enantioselective Mannich-Type Reaction^a

Entry	4	Cat.	R1	R2	Yield (%)b	ee (%)c
1	(R)-4a	Q4	Ph	Me	93	95
2	(S)-4a	Q5	Ph	Me	91	94
3	(R)-4b	Q4	Ph	Et	88	92
4	(S)-4b	Q5	Ph	Et	87	94
5	(R)-4c	Q4	4-OMeC6H4	Et	87	95
6	(S)-4c	Q5	4-OMeC6H4	Et	85	83
7	(R)-4d	Q4	4-ClC6H4	Et	92	98
8	(S)-4d	Q5	4-ClC6H4	Et	91	98
9	(R)-4e	Q4	cyclohexyl	Et	90	>99
10	(S)-4e	Q5	cyclohexyl	Et	94	98
11	(R)-4f	Q4	4-MeC6H4	Me	93	98
12	(S)-4f	Q5	4-MeC6H4	Me	95	>99
13	(R)-4g	Q4	2-furyl	Me	88	93
14	(S)-4g	Q5	2-furyl	Me	91	95
15	(R)-4h	Q4	2-furyl	Et	92	94
16	(S)-4h	Q5	2-furyl	Et	90	95

^a Reactions were performed with 0.30 mmol of 1, 0.30 mmol of 2, and 10 equiv of 3 (3 mmol) in capped vials.

^b Yield of isolated product.

^c Determined by HPLC analysis.

A mixture of 4-methyl-6-(piperidin-1-yl)pyrimidin-2-amine (1) and benzaldehyde (2a) was treated with dimethyl malonate (3a) in the presence of catalyst Q4 at 60 °C for 5 h. The aldimine was confirmed by mass spectrometry. Thus, we propose that at the first step of the reaction, thermodynamics controlled aldimine formation. The second step was the activation of aldimine by the thiourea moiety through double hydrogen bonding and the activation of dimethyl malonate by the basic nitrogen atom in the tertiary amine of catalyst Q4. Then, dimethyl malonate attacks the Re-face of the carbon in aldimine, as shown Scheme [1].

The antiviral activities of our chiral reaction products against tobacco mosaic virus (TMV) were tested. Ningnanmycin was used as the positive control.[12] The bioassay results in vivo are shown in Table [3]. Most of the chiral compounds exhibited good antiviral activity against TMV at 500 μg/mL, and some of them even exhibited higher antiviral activity than the commercial agricultural antiviral product ningnanmycin. The results indicated that chiral compounds (R)-4c, (R)-4e, (R)-4g, and (R)-4h exhibited higher curative activity than ningnanmycin, with values of 52.7%, 51.3%, 50.7%, and 51.0% at 500 μg/mL, respectively.

The other chiral compounds showed moderate curative activities at 500 μg/mL. Among these chiral compounds, (R)-4c, (R)-4e, (S)-4e, and (R)-4h exhibited significant inactivation effects against TMV and produced relatively good antiviral activities with values of 61.2%, 59.3%, 57.2%, and 59.4% at 500 μg/mL. These values are similar to the antiviral product ningnanmycin at 500 μg/mL. Chiral compounds (R)-4c, (R)-4e, and (R)-4h exhibited efficacies of 91.4%, 89.4%, and 87.5%, respectively. These chiral products exhibited slightly higher protective activity than the control ningnanmycin (86.4%) at 500 μg/mL. Compound (R)-4c exhibited the best anti-TMV activity at 500 μg/mL (curative activity, 52.7%; inactivation activity, 61.2%; protection activity, 91.4%), which is significantly higher than that of ningnanmycin (curative activity, 49.2%; inactivation activity, 57.3%; protection activity, 86.4%).

Furthermore, two enantiomers of compounds 4a, 4b, 4d, and 4f showed low antiviral activity. In short, the above results indicated that the phenyl-substitution pattern markedly affected the antiviral activity of the chiral products. Among them, the phenyl-substitution pattern greatly affected the in vivo anti-TMV activity of the chiral products. The methoxy group at the 4-position of the phenyl ring (compound (R)-4c) showed good anti-TMV activity in vivo. In contrast, compounds in which the phenyl ring was without a substituent group (4a and 4b) showed very low antiviral activities. In addition, the chiral products with moieties 4-CH₃ and 4-Cl at the 4-position of the phenyl ring showed poor antiviral activities. Among them, compound (R)-4c offered considerable potential for further development as a chiral antiviral agent, and these results suggest that these chiral products can be used as lead structures in discovering new chiral anti-TMV agents.

In summary, we have developed a highly efficient and enantioselective one-pot, solvent-free method for the synthesis of novel chiral β-amino acid ester derivatives containing a 4-(piperidin-1-yl)pyrimidine moiety.[13] The Mannich chiral products were prepared in high yield and with excellent enantioselectivities (up to >99% ee) and were evaluated for their antiviral activities against TMV. Some of the chiral products exhibited excellent antiviral activity in vivo that was superior to the commercial antiviral agent ningnanmycin. Therefore, based on the anti-TMV mechanism, field experiments, and acute toxicity testing of these chiral compounds, they can be considered for further development as new anti-TMV chiral agents. Further studies aimed at determining the antiviral spectra and antiviral mechanisms of the products are ongoing in our laboratory.

• References and Notes

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• 13 General Experimental Procedure for the Preparation of (R)-4a Briefly, 4-methyl-6-(piperidin-1-yl)pyrimidin-2-amine (1, 0.30 mmol), benzaldehyde (2a, 0.30 mmol), dimethyl malonate (3a, 10 equiv, 3 mmol), and chiral catalyst Q4 (10 mol%) were added to capped vials at 60 °C and stirred for 36 h. After completion of the reaction, as observed by TLC, the mixture was directly purified by column chromatography on silica gel (hexane/EtOAc = 8:1), affording the product (R)-4a. However, the product (S)-4a was obtained using the Q5 catalyst. Enantiomeric excess of the product was determined by HPLC analysis using a Chiralpak IA column.

• References and Notes

• 1a Villalba ML. Enrique AV. Higgs J. Castaño RA. Goicoechea S. Taborda FD. Gavernet L. Lick ID. Marder M. Bruno Blanch LE. Eur. J. Pharmacol. 2016; 774: 55
  CrossrefPubMedSearch in Google Scholar
• 1b Stachulski AV. Swift K. Cooper M. Reynolds S. Norton D. Slonecker SD. Rossignol JF. Eur. J. Med. Chem. 2016; 126: 154
  PubMedSearch in Google Scholar
• 1c Khattab SN. Haiba NS. Asal AM. Bekhit AA. Amer A. Abdel-Rahman HM. El-Faham A. Bioorg. Med. Chem. 2015; 23: 3574
  CrossrefPubMedSearch in Google Scholar
• 2 Pawlak D. Schielmann M. Wojciechowski M. Andruszkiewicz R. Bioorg. Med. Chem. Lett. 2016; 26: 3586
  CrossrefPubMedSearch in Google Scholar
• 3a Karuvalam RP. Haridas KR. Nayak SK. Row TN. Rajeesh P. Rishikesan R. Kumari NS. Eur. J. Med. Chem. 2012; 49: 172
  CrossrefPubMedSearch in Google Scholar
• 3b Sharma S. Pandey AK. Shukla PK. Saxena AK. Bioorg. Med. Chem. Lett. 2011; 21: 6476
  CrossrefPubMedSearch in Google Scholar
• 3c Gellerman G. Pariente N. Paz Z. Shnaiderman A. Yarden O. J. Agric. Food Chem. 2009; 57: 8303
  CrossrefPubMedSearch in Google Scholar
• 4a Ma C. Cao R. Shi B. Li S. Chen Z. Yi W. Peng W. Ren Z. Song H. Eur. J. Med. Chem. 2010; 45: 1515
  CrossrefPubMedSearch in Google Scholar
• 4b Zhao M. Bi L. Wang W. Wang C. Baudy-Floc'H M. Ju J. Peng S. Bioorg. Med. Chem. 2006; 14: 6998
  CrossrefPubMedSearch in Google Scholar
• 5a Krecmerová M. Holý A. Andrei G. Pomeisl K. Tichý T. Brehová P. Masojídková M. Dracínský M. Pohl R. Laflamme G. J. Med. Chem. 2010; 86: 6825
  Search in Google Scholar
• 5b Sekiya K. Takashima H. Ueda N. Kamiya N. Yuasa S. Fujimura Y. Ubasawa M. J. Med. Chem. 2002; 45: 3138
  CrossrefPubMedSearch in Google Scholar
• 6 Fu X. Jiang S. Li C. Xin J. Yang Y. Ji R. Bioorg. Med. Chem. Lett. 2007; 17: 465
  CrossrefPubMedSearch in Google Scholar
• 7a Reddy AA. Prasad KR. J. Org. Chem. 2017; 82: 13488
  CrossrefPubMedSearch in Google Scholar
• 7b Ozeki M. Egawa H. Takano T. Mizutani H. Yasuda N. Arimitsu K. Kajimoto T. Hosoi S. Iwasaki H. Kojima N. Tetrahedron 2017; 73: 2014
  CrossrefSearch in Google Scholar
• 7c Zeng JL. Chachignon H. Ma JA. Cahard D. Org. Lett. 2017; 19: 1974
  CrossrefPubMedSearch in Google Scholar
• 7d Han J. Ai T. Nguyen T. Li G. Chem. Biol. Drug Des. 2008; 72: 120
  CrossrefPubMedSearch in Google Scholar

For reviews on β-amino acids, see the following:
• 8a Cole DC. Tetrahedron 1994; 50: 9517
  CrossrefSearch in Google Scholar
• 8b Juaristi E. Quintana D. Escalante J. Aldrichimica Acta 1994; 27: 3
  Search in Google Scholar
• 8c Cardillo G. Tomasini C. Chem. Soc. Rev. 1996; 25: 117
  CrossrefSearch in Google Scholar
• 8d Enantioselective Synthesis of β-Amino Acids. Juaristi E. Wiley-VCH; Weinheim: 1997
  Search in Google Scholar
• 8e Abele S. Seebach D. Eur. J. Org. Chem. 2000; 1
• 8f Cheng RP. Gellman SH. DeGrado WF. Chem. Rev. 2001; 101: 3219
  CrossrefPubMedSearch in Google Scholar
• 8g Liu M. Sibi MP. Tetrahedron 2002; 58: 7991
  CrossrefSearch in Google Scholar
• 8h Ma J.-A. Angew. Chem. Int. Ed. 2003; 42: 4290
  CrossrefPubMedSearch in Google Scholar
• 8i Weiner B. Szymański W. Janssen DB. Minnaard AJ. Feringa BL. Chem. Soc. Rev. 2010; 39: 1656
  CrossrefPubMedSearch in Google Scholar
• 8j Kim SM. Yang JW. Org. Biomol. Chem. 2013; 11: 4737
  CrossrefPubMedSearch in Google Scholar
• 9a Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed. 2010; 37: 1044
  Search in Google Scholar
• 9b Sawa M. Morisaki K. Kondo Y. Morimoto H. Ohshima T. Chem. Eur. J. 2017; 23: 17022
  CrossrefPubMedSearch in Google Scholar
• 9c Wu H. An H. Mo SC. Kodadek T. Chem. Eur. J. 2017; 15: 3255
  Search in Google Scholar
• 9d You Y. Zhang L. Cui L. Mi X. Luo S. Angew. Chem. 2017; 56: 13814
  CrossrefPubMedSearch in Google Scholar
• 10a Lu N. Fang Y. Gao Y. Wei Z. Cao J. Liang D. Lin Y. Duan H. J. Org. Chem. 2017; 83: 1486
  Search in Google Scholar
• 10b Xin H. Miao L. Pham K. Zhang X. Yi W. Jasinski JP. Wei Z. J. Org. Chem. 2016; 81: 5362
  CrossrefPubMedSearch in Google Scholar
• 10c Li J. Du T. Zhang G. Peng Y. Chem. Commun. 2013; 49: 1330
  CrossrefPubMedSearch in Google Scholar
• 10d Bai S. Liang X. Song B. Bhadury PS. Hu D. Yang S. Tetrahedron: Asymmetry 2011; 42: 518
  Search in Google Scholar
• 10e Lou S. Dai P. Schaus SE. J. Org. Chem. 2008; 39: 9998
  Search in Google Scholar
• 11a Freedman TB. Cao X. Dukor RK. Nafie LA. Chirality 2003; 15: 743
  CrossrefPubMedSearch in Google Scholar
• 11b Nugroho AE. Morita H. J. Nat. Med. 2014; 68: 1
  CrossrefPubMedSearch in Google Scholar
• 12a Gooding GG. Jr. Hebert TT. Phytopathology 1967; 57: 1285
  Search in Google Scholar
• 12b Fan ZJ. Shi ZG. Zhang HK. Liu XF. Bao L. Ma L. Zuo XA. Zheng QX. Mi N. J. Agric. Food Chem. 2009; 57: 4279
  CrossrefPubMedSearch in Google Scholar
• 12c Song B. Zhang H. Wang H. Yang S. Jin L. Hu D. Lili Pang A. Xue W. J. Agric. Food Chem. 2005; 53: 7886
  CrossrefPubMedSearch in Google Scholar
• 13 General Experimental Procedure for the Preparation of (R)-4a Briefly, 4-methyl-6-(piperidin-1-yl)pyrimidin-2-amine (1, 0.30 mmol), benzaldehyde (2a, 0.30 mmol), dimethyl malonate (3a, 10 equiv, 3 mmol), and chiral catalyst Q4 (10 mol%) were added to capped vials at 60 °C and stirred for 36 h. After completion of the reaction, as observed by TLC, the mixture was directly purified by column chromatography on silica gel (hexane/EtOAc = 8:1), affording the product (R)-4a. However, the product (S)-4a was obtained using the Q5 catalyst. Enantiomeric excess of the product was determined by HPLC analysis using a Chiralpak IA column.

• Supplementary Material