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Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate

1
Department of Chemistry, Tamkang University, No. 151 Yingzhuan rd., Tamsui Dist., New Taipei City 25137, Taiwan
2
School of Pharmacy, College of Pharmacy, China Medical University, Taichung 404, Taiwan
3
Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung 404, Taiwan
4
Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
*
Author to whom correspondence should be addressed.
Molbank 2014, 2014(2), M827; https://doi.org/10.3390/M827
Submission received: 31 March 2014 / Accepted: 21 May 2014 / Published: 30 May 2014

Abstract

:
The reported compound 4 was synthesized and fully characterized by 1H NMR, 13C NMR, 11B NMR, 19F NMR, and high resolution mass spectrometry.

Graphical Abstract

Of the boron-containing compounds that are currently in pharmaceutical development programs, boronic acids [1,2], boronate esters [3,4], benzoxaboroles [5,6], and oxazaborolidines [7,8] are frequently used boron functional groups. Having an empty p-orbital on the trivalent boron atom, these analogs interact with their targets to form tetrahedral intermediates. Organotrifluoroborates, on the other hand, are seldom considered in biological applications due to their lack of an empty p-orbital. Srebnik and coworkers, the first group to investigate the biological activity of a series of aryl organotrifluoroborates in enzyme-inhibition assays, reported that aryl potassium trifluoroborates were much more potent than the corresponding boronic acids against α-chymotrypsin and trypsin [9,10]. The toxicological profile of organotrifluoroborates were also investigated by Oliveira and co-workers, who showed that thiophene-3-trifluoroborate exhibits minimal toxicity in a mouse model, and concluded that this class of compounds is suitable for further development as pharmacologically active agents [11]. Despite their promising biological studies, the reported studies of organotrifluoroborates have focused mainly on simple aryl/heteroaryl structures. Herein, we report the synthesis of the dipeptidyl organotrifluroborate, which should possess additional hydrophilic elements and hydrophobic moieties, which are vital factors for ligand/receptor binding.

Result and Discussion

The desired product was prepared as follows. H-L-valine-methyl ester (1) was first coupled with Boc-L-phenylalanine-OH (2) by general peptide coupling protocol [12] followed by removal of t-butyloxycarbonyl (Boc) protecting group to afford dipeptide 3 (Scheme 1). Then, compound 3 was condensed with potassium 4-formylphenyltrifluoroborate to give the corresponding imine intermediate. Finally, the resulting intermediate was directly reduced by 5-ethyl-2-methylpyridine borane complex (PEMB) [13] to give the final product 4 in 64% yield.

Experimental

To a vial containing potassium 4-formylphenyltrifluoroborate (118 mg, 0.55 mmol) in MeOH was added 3 (411 mg, 0.83 mmol) to generate a 0.5 M solution. The reaction mixture was stirred for 3 h at room temperature. PEMB (0.042 mL, 0.28 mmol) was then added, and stirring was continued for 5 h. The solvent was then removed in vacuo, and the resulting crude material was washed with hexane. The crude solid was purified by continuous Soxhlet extraction (3 h) with acetone. The collected solvent was concentrated and then precipitated with acetone/ hexane to afford the desired pure product 4 as a white solid (167 mg, 64% yield). 1H NMR (300 MHz, CD3OD) δ 7.58 (d, J = 7.8 Hz, 2H), 7.36–7.29 (m, 3H), 7.28–7.18 (m, 2H), 4.34 (d, J = 9.9 Hz, 1H), 4.11–3.97 (m, 3H), 3.68 (s, 3H), 3.14 (d, J = 7.2 Hz, 2H), 2.09 (oct, J = 6.6 Hz, 1H), 0.95 (dd, J = 6.6, 3.9 Hz, 6H). 13C NMR (75.5 MHz, CD3OD) δ 172.4, 168.8, 135.2, 133.6, 130.7, 130.1, 129.5, 128.9, 128.8, 61.4, 59.7, 52.7, 51.8, 37.9, 32.1, 19.5, 18.8. 11B NMR (192.5 MHz, acetone-d6) δ 4.0. 19F NMR (564.6 MHz, CD3OD) δ 144.8. M.p. 207 °C. HRMS (ESI, negative ion) m/z calcd for [M-K] = 435.2069, m/z found 435.2088.

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4

Acknowledgments

This research was supported by the National Science Council in Taiwan (NSC-99-2113-032-002-MY2). We thank Department of Chemistry of Tamkang University for the equipment and financial support. We thank Ms. Shen-Shen Chen (Department of Chemistry of Tamkang University) for conducting 11B NMR experiments. We thank Ms. Chiu-Hui He (Department of Chemistry of National Normal University) for conducting 19F NMR experiments.

Author Contributions

Chia-Hua Tsai, Chia-Hung Lin, and Ching-Tien Hsieh are responsible for developing an optimal peptide coupling condition. Chih-Cheng Cai, Ting-Ju Lin, and Pin-Yi Liu are responsible for developing an optimal Boc removal condition. Meng-Hsuan Lin, Meng-Ju Wu, and Chia-Chieh Fu are responsible for developing an optimal imine formation and reduction conditions. Yang-Chang Wu, Fang-Rong Chang and Po-Shen Pan are responsible for designing the synthetic strategy as well as collaborative manuscript preparation.

Conflicts of Interest

The author declares no conflict of interest.

References

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Scheme 1. (a) TBTU (1.3 equiv), DIPEA (4.0 equiv), CH2Cl2 (0.1 M); (b) TFA (20%), CH2Cl2 (0.1 M); (c) 4-formylphenyltrifluoroborate (1.0 equiv), PEMB (0.5 equiv), MeOH (0.5 M).
Scheme 1. (a) TBTU (1.3 equiv), DIPEA (4.0 equiv), CH2Cl2 (0.1 M); (b) TFA (20%), CH2Cl2 (0.1 M); (c) 4-formylphenyltrifluoroborate (1.0 equiv), PEMB (0.5 equiv), MeOH (0.5 M).
Molbank 2014 m827 sch001

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MDPI and ACS Style

Tsai, C.-H.; Lin, C.-H.; Hsieh, C.-T.; Cai, C.-C.; Lin, T.-J.; Liu, P.-Y.; Lin, M.-H.; Wu, M.-J.; Fu, C.-C.; Wu, Y.-C.; et al. Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate. Molbank 2014, 2014, M827. https://doi.org/10.3390/M827

AMA Style

Tsai C-H, Lin C-H, Hsieh C-T, Cai C-C, Lin T-J, Liu P-Y, Lin M-H, Wu M-J, Fu C-C, Wu Y-C, et al. Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate. Molbank. 2014; 2014(2):M827. https://doi.org/10.3390/M827

Chicago/Turabian Style

Tsai, Chia-Hua, Chia-Hung Lin, Ching-Tien Hsieh, Chih-Cheng Cai, Ting-Ju Lin, Pin-Yi Liu, Meng-Hsuan Lin, Meng-Ju Wu, Chia-Chieh Fu, Yang-Chang Wu, and et al. 2014. "Potassium {4-[(3S,6S,9S)-3,6-dibenzyl-9-isopropyl-4,7,10-trioxo-11–oxa-2,5,8-triazadodecyl]phenyl}trifluoroborate" Molbank 2014, no. 2: M827. https://doi.org/10.3390/M827

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