A Facile Synthesis of Thioacids from N-Acylbenzotriazoles

Abstract

Protected amino/peptide thioacids have been synthesized in pure form in excellent yields and with retention of chirality by using protected aminoacyl- and peptidoylbenzotriazoles as active intermediates.

Key words

amino acids - peptides - chirality - thioacids - benzotriazole methodology

• References and Notes

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• 29 General Procedure: H₂S was bubbled through a precooled (0 °C) solution of N-protected α-aminoacylbenzotriazole (1.0 mmol), NMM (1 mmol) in THF (10 mL) for 5 min. The reaction mixture was allowed to warm at r.t. and stirred for an additional 1 h, diluted with Et₂O (25 mL) and washed several times with 2 N HCl. The organic layer was dried (MgSO₄), the solvent was removed, and the residue was crystallized from pentane–Et₂O to give the desired thioacids. (S)-2-{[(Benzyloxy)carbonyl]amino}-5-(2-nitroguani-dino)pentanethioic S-Acid [Cbz-l-Agr(NO₂)-SH, 2d; Table 2, Entry 5]: white microcrystals (yield: 84%); mp 153–155 °C; [α]²⁰ _D –9.0 (c = 0.5 in MeOH). ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.47 (s, 1 H), 7.79–8.14 (m, 3 H), 7.30–7.42 (m, 5 H), 5.04–5.21 (m, 2 H), 4.28–4.41 (m, 1 H), 3.07–3.22 (m, 2 H), 1.51–1.82 (m, 4 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 196.3, 159.4, 156.3, 136.7, 128.5, 128.0, 127.8, 66.1, 63.6, 60.9, 32.5, 28.0. Anal. Calcd for C₁₄H₁₉N₅O₅S: C, 45.52; H, 5.18; N, 18.96. Found: C, 45.85; H, 5.15; N, 18.62. 2-{[(Benzyloxy)carbonyl]amino}propanethioic S-Acid (Cbz-dl-Ala-SH, 2a + 2a′; Table 2, Entry 2): white microcrystals (yield: 93%); mp 65–66 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.28–7.40 (m, 5 H), 5.15 (br s, 2 H), 5.30–5.44 (m, 1 H), 4.36–4.50 (m, 1 H), 1.42 (d, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 200.2, 155.7, 136.1, 128.7, 128.4, 128.3, 77.2, 67.4, 57.7, 18.2. Anal. Calcd for C₁₀H₁₃NO₃S: C, 55.21; H, 5.48; N, 5.85. Found: C, 55.58; H, 5.11; N, 5.62. 2-{[(Benzyloxy)carbonyl]amino}ethanethioic S-Acid (Cbz-Gly-SH, 2b; Table 2, Entry 3): colorless needles (yield: 91%); mp 97–98.5 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.29–7.40 (m, 5 H), 5.32–5.48 (m, 1 H), 5.15 (br s, 2 H), 4.12 (d, J = 5.9 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 196.5, 136.5, 129.2, 128.92, 128.7, 77.6, 68.1, 52.4. Anal. Calcd for C₁₀H₁₁NO₃S: C, 53.32; H, 4.92; N, 6.22. Found: C, 53.32; H, 4.98; N, 6.24. (S)-2-{[(Benzyloxy)carbonyl]amino}-3-(1H-indol-3-yl)propanethioic S-Acid (Cbz-l-Trp-SH, 2e; Table 2, Entry 6): white microcrystals (yield: 86%); mp 114–115 °C; [α]²⁰ _D –44.5 (c = 0.2 in MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 8.09 (br s, 1 H), 7.57 (d, J = 7.7 Hz, 1 H), 7.29–7.39 (m, 6 H), 7.19–7.25 (m, 1 H), 7.01–7.06 (m, 1 H), 5.21–5.31 (m, 1 H), 5.11 (br s, 2 H), 4.67–4.79 (m, 1 H), 3.31 (d, J = 5.6 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 200.5, 156.0, 136.3, 128.6, 128.4, 128.2, 123.4, 122.5, 120.0, 118.7, 114.6, 111.5, 109.1, 68.1, 67.4, 62.2, 27.7, 25.7. Anal. Calcd for C₁₉H₁₈N₂O₃S: C, 64.39; H, 5.12; N, 7.90. Found: C, 64.62; H, 5.23; N, 7.70. (S)-2-[{[(9H-Fluoren-9-yl)methoxy]carbonyl}amino]-3-phenylpropanethioic S-Acid (Fmoc-l-Phe-SH, 2h; Table 2, Entry 9): white microcrystals (yield: 85%); mp 88.5–90 °C; [α]²⁰ _D –40.9 (c = 1.0 in MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.73–7.78 (m, 2 H), 7.47–7.56 (m, 2 H), 7.35–7.43 (m, 2 H), 7.25–7.34 (m, 5 H), 7.12–7.19 (m, 2 H), 5.14–5.25 (m, 1 H), 4.59–4.72 (m, 1 H), 4.35–4.49 (m, 2 H), 4.18 (t, J = 6.8 Hz, 1 H), 2.96–3.21 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 199.4, 155.7, 143.7, 141.4, 135.2, 129.4, 129.0, 127.9, 127.6, 127.2, 125.1, 120.1, 77.2, 67.3, 62.5, 47.2, 37.7. Anal. Calcd for C₂₄H₂₁NO₃S: C, 71.44; H, 5.25; N, 3.47. Found: C, 71.73; H, 5.12; N, 3.90. (S)-2-[2-{[(Benzyloxy)carbonyl]amino}propanamido]-ethanethioic S-Acid (Cbz-l-Ala-Gly-SH, 4a; Table 3, Entry 1): white microcrystals (yield: 87%); mp 100–102 °C. ¹H NMR (300 MHz, CD₃OD): δ = 7.23–7.40 (s, 5 H), 5.01–5.16 (m, 2 H), 4.80 (m, 1 H), 4.14–4.25 (m, 1 H), 3.99–4.13 (m, 1 H), 1.37 (d, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CD₃OD): δ = 176.1, 171.6, 138.1, 129.4, 129.0, 128.9, 111.4, 67.7, 51.9, 41.8, 18.3. HRMS (DART): m/z [M + H]⁺ calcd for C₁₃H₁₇N₂O₄S: 297.0904; found: 297.0891. (S)-2-[2-{[(Benzyloxy)carbonyl]amino}-3-methylbutan-amido]ethanethioic S-Acid (Cbz-l-Val-Gly-SH, 4b; Table 3, Entry 2): white microcrystals (yield: 73%); mp 159–161 °C; [α]²⁰ _D –25.2 (c = 0.5 in MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.27–7.45 (m, 5 H), 6.80–6.90 (m, 1 H), 5.35–5.50 (m, 1 H), 5.05–5.16 (m, 2 H), 4.11–4.24 (m, 2 H), 4.04–4.10 (m, 1 H), 2.11–2.25 (m, 1 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 195.1, 172.0, 156.8, 136.2, 128.7, 128.4, 128.2, 67.4, 60.5, 50.4, 30.8, 19.5, 17.9. HRMS (ESI^–): m/z [M – H]^– calcd for C₁₅H₁₉N₂O₄S: 323.1086; found: 323.1071. (S)-2-[(S)-2-{[(Benzyloxy)carbonyl]amino}propan-amido]-3-phenylpropanethioic S-Acid (Cbz-l-Ala-l-Phe-SH, 4c; Table 3, Entry 3): white microcrystals (yield: 79%); mp 107–109 °C; [α]²⁰ _D –17.9 (c = 0.14 in MeOH). ¹H NMR (300 MHz, CDCl₃): δ = 7.20–7.41 (m, 10 H), 7.10–7.19 (m, 2 H), 6.42–6.61 (m, 1 H), 5.04–5.18 (m, 2 H), 4.81–4.93 (m, 1 H), 4.10–4.27 (m, 1 H), 3.12–3.24 (m, 1 H), 2.97–3.17 (m, 1 H), 1.31 (d, J = 7.1 Hz, 3 H). HRMS (ESI^–): m/z [M – H]^– calcd for C₂₀H₂₁N₂O₄S: 385.1228; found: 385.1247. (5S,8S)-8-Benzyl-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecane-12-thioic S-Acid (Cbz-l-Ala-l-Phe-Gly-SH, 4d; Table 3. Entry 4): white microcrystals (yield: 69%); mp 162–163 °C; [α]²⁰ _D –31.4 (c = 0.5 in MeOH). ¹H NMR (300 MHz, CD₃OD): δ = 7.13–7.42 (m, 10 H), 5.00–5.14 (m, 5 H), 4.61–4.70 (m, 1 H), 4.00–4.13 (m, 3 H), 3.17–3.29 (m, 1 H), 2.91–3.03 (m, 1 H), 1.21 (d, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CD₃OD): δ = 175.5, 173.7, 138.4, 138.0, 130.3, 129.5, 129.4, 129.0, 128.9, 127.7, 67.9, 55.8, 52.3, 51.4, 49.0, 38.3, 17.9. HRMS (ESI^–): m/z [M – H]^– calcd for C₂₂H₂₄N₃O₅S: 442.1442; found: 442.1455.