Synthesis of Boronocysteine

Abstract

Herein we report the first synthesis of protected boronocysteine. The target compound was prepared via copper-catalysed diastereoselective nucleophilic borylation of a sulfinimine. After deprotection to give the amine as the hydrochloride salt, four boronocysteine amide derivatives were prepared through reaction with a variety of different active acylating agents.

Key words

amino acids - boron - copper - imines - peptides

• References and Notes

• 1a Yang W. Gao X. Wang B. Med. Res. Rev. 2003; 23: 346
• 1b Dembitsky VM. Al Aziz Quntar A. Srebnik M. Mini-Rev. Med. Chem. 2004; 4: 1001
• 1c Dembitsky VM. Srebnik M. Tetrahedron 2003; 59: 579
• 1d Matteson DS. Med. Res. Rev. 2008; 28: 233
• 1e Andrés P. Ballano G. Calaza MI. Cativela C. Chem. Soc. Rev. 2016; 45: 2291
• 2 Matteson DS. Sadhu KM. Organometallics 1984; 3: 614
• 3 Matteson DS. Cheng T.-C. J. Organomet. Chem. 1966; 6: 100
• 4a Tsai DJ. S. Jesthi PK. Matteson DS. Organometallics 1983; 2: 1543
• 4b Matteson DS. J. Organomet. Chem. 1999; 581: 51
• 5a Beenen MA. An C. Ellman JA. J. Am. Chem. Soc. 2008; 130: 6910
• 5b Buesking W. Bacauanu V. Cai I. Ellman JA. J. Org. Chem. 2014; 79: 3671
• 5c Solé C. Gulyás H. Fernández E. Chem. Commun. 2012; 48: 3769
• 6 Jagannathan S. Forsyth TP. Kettner CA. J. Org. Chem. 2001; 66: 6375
• 7 He Z. Zajdlik A. St Denis JD. Assem N. Yudin AK. J. Am. Chem. Soc. 2012; 134: 9926
• 8 Batsanov AS. Grosjean C. Schütz T. Whiting A. J. Org. Chem. 2007; 72: 6276

For other approaches, see:
• 9a Zheng B. Deloux L. Pereira S. Skrzypczak-Jankun E. Cheesman BV. Sabat M. Morris S. Appl. Organomet. Chem. 1996; 10: 267
• 9b Touchet S. Carreaux F. Molander GA. Carboni B. Bouillon A. Adv. Synth. Catal. 2011; 353: 3391
• 9c Kawamorita S. Miyazaki T. Iwai T. Ohimiya H. Sawamura M. J. Am. Chem. Soc. 2012; 134: 12924
• 9d Hu N. Zhao G. Zhang Y. Liu X. Li G. Tang W. J. Am. Chem. Soc. 2015; 137: 6746
• 9e Li C. Wang J. Barton LM. Yu S. Tian M. Peters DS. Kumar M. Yu AW. Johnson KA. Chatterjee AK. Yan M. Baran PS. Science 2017; 357: in press; DOI: 10.1126/science.aam7355
• 10a Kettner C. Mersinger L. Knabb R. J. Biol. Chem. 1990; 265: 18289
• 10b Lebarbier C. Carreaux F. Carboni B. Boucher JL. Bioorg. Med. Chem. Lett. 1998; 8: 2573
• 10c Watanabe T. Momose I. Abe M. Abe H. Sawa R. Umezawa Y. Ikeda D. Takahashi Y. Akamatsu Y. Bioorg. Med. Chem. Lett. 2009; 19: 2343
• 10d Lebarbier C. Carreaux F. Carboni B. Synthesis 1996; 1371
• 10e Matteson DS. Michnick TJ. Willett RD. Patterson CD. Organometallics 1989; 8: 726
• 11a Cowper B. Shariff L. Chen W. Gibson SM. Di W.-L. Macmillan D. Org. Biomol. Chem. 2015; 13: 7469
• 11b Macmillan D. Synlett 2017; 28: 1517
• 12 Matteson DS. J. Organomet. Chem. 1999; 581: 51
• 13 Lantos I. Razgaitis C. Sutton BM. J. Heterocycl. Chem. 1982; 19: 1375
• 14 Yoneda K. Ota A. Kawashima Y. Chem. Pharm. Bull. 1993; 41: 876
• 15 Ghosh S. Tochtrop GP. Tetrahedron Lett. 2009; 50: 1723
• 16 (E)-N-{2-[(4-Methoxybenzyl)thio]ethylidene}-2-methylpropane-2-sulfinamide (5) Copper(II) sulfate (1.27 g, 7.94 mmol) and aldehyde 4 (779 mg, 3.97 mmol, 1.1 equiv) were added to a solution of (±)-tert-butyl sulfinamide (438 mg, 3.61 mmol) in anhydrous CH₂Cl₂ (7.2 mL). The reaction was stirred at r.t. for 18 h, before filtering through Celite. The solvents were removed in vacuo and the residue obtained was purified by column chromatography to give an orange oil (865 mg, 2.89 mmol, 80%). ¹H NMR (600 MHz, CDCl₃): δ = 7.98 (1 H, t, J = 5.6 Hz, NCH), 7.23 (2 H, d, J = 6.5 Hz, ArH), 6.85 (2 H, d, J = 6.5 Hz, ArH), 3.79 (3 H, s, OCH₃), 3.66 (2 H, s, ArCH₂), 3.35 (1 H, dd, J = 14.3, 6.0 Hz, 1 × SCH ₂CH), 3.31 (1 H, dd, J = 14.3, 5.3, 1 × SCH ₂CH), 1.22 (9 H, s, ^t Bu). ¹³C NMR (150 MHz, CDCl₃): δ = 164.2, 158.9, 130.3, 129.2, 114.1, 57.0, 55.4, 35.02, 34.3, 22.5. LRMS (CI): m/z (%) = 420 (100), 300 (37) [M + H⁺], 240 (30), 195 (32) [M – SO ^t Bu]⁺), 121 (88) [PMB⁺]. HRMS: m/z calcd for C₁₄H₂₂NO₂S₂: 300.10865; found: 300.10877. IR (film): ν_max = 2958 (C–H), 1609 (C=C), 1510 (C=N), 1458 (C=C), 1083 (S=O) cm^-1.
• 17 N-{2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl}-2-methylpropane-2-sulfinamide (6) Using flame-dried glassware under an argon atmosphere, CuCl (38.4 mg, 0.388 mmol), (±)-BINAP (111.1 mg, 0.1784 mmol), and B₂pin₂(1.331 g, 5.242 mmol) were dissolved in anhydrous THF (4 mL). KO ^t Bu (1 M in THF, 1.4 mL, 1.4 mmol) was added whilst stirring at r.t. After 10 min, the reaction was cooled to –20 °C, and aldehyde 5 (1.0338 g, 3.4522 mmol) was added followed by MeOH (300 μL, 7.41 mmol) and the reaction stirred overnight. The solvent was removed in vacuo and the resultant oil purified by flash column chromatography using EtOAc in CH₂Cl₂ (20 → 35%) to give 6 as an orange oil (878 mg, 2.056 mmol, 60%); R_f = 0.08 (EtOAc/CH₂Cl₂ = 1:4). ¹H NMR (600 MHz, CDCl₃): δ = 7.24 (2 H, d, J = 8.6 Hz, ArH), 6.82 (2 H, d, J = 8.6 Hz, ArH), 3.78 (3 H, s, OCH₃), 3.71 (1 H, d, J = 5.6 Hz, NH), 3.69 (s, 2 H, ArCH₂S), 3.22 (1 H, m, CHB), 2.77 (1 H, dd, J = 13.4, 6.3 Hz, 1 × SCH ₂CH), 2.72 (1 H, dd, J = 13.4, 7.9 Hz, 1 × SCH ₂CH), 1.25 (s, 6 H, 2 × pinacol-CH₃), 1.23 (s, 9 H, ^t Bu), 1.20 (s, 6 H, 2 × pinacol-CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 158.7, 130.1, 130.0, 114.0, 84.3, 56.2, 55.3, 41.3 (br), 35.2, 34.6, 25.0 (2 C), 22.6. LRMS (CI): m/z (%) = 428 (41), [M + H]⁺, 371 (18) [M⁺ – ^t Bu)], 322 (38) [M⁺ – SO ^t Bu), 121 (100) [PMB⁺]. IR: ν_max = 2977 (C–H), 2930 (C–H), 1609 (Ar), 1511 (Ar), 1544 (Ar), 1369 (B–O), 1246, 1140 (B–C), 1033 (S=O). HRMS: m/z calcd for C₂₀H₃₄BNO₄S₂: 428.2095; found: 428.2095.
• 18 2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethanamine hydrochloride (7) A solution of HCl in dioxane (4 M, 585 μL, 2.34 mmol) was added to 6 (99.7 mg, 0.233 mmol) dissolved in anhydrous MeOH (3 mL) to give a pale yellow solution. The reaction was stirred for 3 h. The solvent was removed in vacuo to give an orange residue (75.3 mg). The residue was washed with Et₂O, sonicated, and centrifuged to give 7 as a light brown solid (68 mg, 0.190 mmol, 82%). ¹H NMR (400 MHz, MeOD-d ₄): δ = 7.29 (2 H, d, J = 8.7 Hz, ArH), 6.89 (2 H, d, J = 8.7 Hz, ArH) 3.80 (3 H, s, OCH₃), 3.79 (2 H, s, ArCH₂), 3.01 (1 H, dd, J = 8.7, 4.7 Hz, CHB), 2.85 (1 H, dd, J = 14.3,4.8 Hz, 1 × CΗ ₂CH), 2.73 (1 H, dd, J = 14.3, 8.8 Hz, 1 × CH ₂CH), 1.33 (12 H, s, 4 × CH₃). ¹³C NMR (100 MHz, MeOD-d ₄): δ = 159.1, 129.9, 129.5, 113.7, 85.5, 74.4, 54.5, 35.1, 30.4, 23.8, 23.7. LRMS (CI): m/z (%) = 323 (100) [M + H]⁺, 198 (18) [M – Bpin]⁺. HRMS: m/z calcd for C₁₆H₂₇BNO₃S: 323.1836; found: 323.18359. IR (solid): ν_max = 2975 (C–H), 2958 (C–H), 2831 (C–H), 1607, 1583, 1411 cm^–1.
• 19 tert-Butyl [2-({2-[(4-Methoxybenzyl)thio]-1-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)ethyl}amino)-2-oxoethyl]carbamate (10a) Using flame-dried glassware under an argon atmosphere, Boc-Gly-OH (87.5 mg, 0.50 mmol) was dissolved in anhydrous CH₂Cl₂ (1.5 mL) and cooled to –20 °C. To this was added NMM (66 μL, 0.60 mmol) followed by IBCF (58 μL, 0.45 mmol), and the mixture stirred for 5 h at –20 °C. HCl salt 7 (23.4 mg, 65.1 μmol) was added, followed by NMM (7 μL, 65 μmol), and the reaction stirred overnight. The reaction mixture was concentrated in vacuo and the resultant oil purified by flash column chromatography using deactivated silica (35% water w/w) eluting with MeOH in EtOAc (0 → 10%) to give 10a as a pale yellow oil (28 mg, 58.0 μmol, 89%). ¹H NMR (600 MHz, CDCl₃): δ = 7.51 (1 H, br s, CHNH), 7.21 (2 H, d, J = 8.7 Hz, ArH), 6.82 (2 H, d, J = 8.7 Hz, ArH), 5.29 (1 H, br s, CH₂NH), 3.93 (2 H, d, J = 5.7, NHCH ₂), 3.78 (3 H, s, OCH₃), 3.65 (2 H, s, ArCH₂), 2.81 (1 H, br d, J = 11.5 Hz, CHB), 2.75 (1 H, dd, J = 14.1, 3.2 Hz, 1 × SCH ₂CH), 2.46 (1 H, dd, J = 14.1, 11.5 Hz, 1 × SCH ₂CH), 1.44 (9 H, s, Bu), 1.18 (6 H, s, 2 × pinacol-CH₃), 1.16 (6 H, s, 2 × pinacol-CH₃). ¹³C NMR (150 MHz, CDCl₃): δ = 174.9, 158.7, 130.3, 130.1, 114.1, 81.6, 55.4, 54.0, 41.4, 35.2, 33.6, 29.8, 28.4, 25.0, 24.9, 14.3. LRMS (CI): m/z (%) = 481 (100) [M + H]⁺. HRMS: m/z calcd for C₂₃H₃₇BN₂O₆S: 480.2574; found: 480.2575. IR (film): ν_max = 2970 (C–H), 2926 (C–H), 1697 (br, C=O), 1609 (C=O), 1511, 1456 cm^–1.