A Straightforward Protocol for the Synthesis of Functionalized Tryptophan Peptides via Stille Coupling, Azidation and Photoinduced Nitrene Insertion

Abstract

Substituted and functionalized tryptophans are interesting building blocks in peptidic natural products. Stereoselective allylic alkylations of small peptides using stannylated allylic substrates allow the synthesis of stannylated peptides, which can be subjected to Stille couplings using (substituted) o-iodoanilines. Subsequent azidation and photochemical nitrene insertion allows the direct incorporation of modified tryptophans into peptides.

Key words

allylations - azides - nitrenes - peptides - Stille couplings - tryptophans

• References and Notes

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• 34 Stille Couplings; General Procedure 1: An oven-dried Schlenk tube was charged with LiCl (2.0 equiv) and heated with a heat gun under vacuum (< 0.1 mbar). After cooling to room temperature, CuI (2.0 equiv), (substituted) o-iodoaniline (1.0 equiv) and Pd(PPh₃)₄ (5 mol%) were added and the flask was evacuated and refilled with Ar three times. DMF (10 mL/mmol), which was previously degassed by bubbling with Ar, and the organotin compound (1.2 equiv) were added and the mixture was heated to 80 °C for 18 h. Upon reaching full conversion (TLC analysis), the mixture was diluted with EtOAc and 1 M KF solution (5 mL/mmol) was added. Upon vigorous shaking (in the Schlenk tube) a colourless precipitate formed and the mixture was filtered through a pad of Celite with EtOAc. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by (automated) flash chromatography. tert-Butyl N-Trifluoroacetyl-2-amino-4-(2-amino-5-ethoxycarbonylphenyl)pent-4-enoate (3c): According to General Procedure 1, 3-iodobenzocaine (73 mg, 0.250 mmol) was reacted with 1 (176 mg, 0.300 mmol, 96% purity), LiCl (21 mg, 0.500 mmol), CuI (95 mg, 0.500 mmol) and Pd(PPh₃)₄ (14 mg, 12.5 µmol). Flash chromatography (PE–EtOAc, 80:20) afforded aniline 3c (71 mg, 0.164 mmol, 66%) as a brown solid; mp 151–152 °C; R_f = 0.34 (PE–EtOAc, 70:30). ¹H NMR (400 MHz, CDCl₃): δ = 1.36 (t, J = 7.1 Hz, 3 H), 1.43 (s, 9 H), 2.93 (dd, J = 14.3, 5.3 Hz, 1 H), 3.12 (ddd, J = 14.3, 5.4, 0.7 Hz, 1 H), 4.25 (br s, 2 H), 4.32 (q, J = 7.1 Hz, 2 H), 4.56 (m, 1 H), 5.27 (d, J = 1.5 Hz, 1 H), 5.40 (m, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 7.06 (d, J = 7.29 Hz, 1 H), 7.69 (d, J = 2.0 Hz, 1 H), 7.77 (dd, J = 8.4, 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 27.9, 39.0, 52.5, 60.4, 83.6, 115.1, 120.2, 120.4, 125.7, 130.5, 130.6, 141.1, 147.3, 166.4, 169.0 ppm. Signals of the TFA group could not be observed. HRMS (CI): m/z [M]⁺ calcd for C₂₀H₂₅F₃N₂O₅: 430.1710; found: 430.1674. tert-Butyl N-Trifluoroacetyl-(S)-phenylalanyl-(R)-2-amino-4-(2-aminophenyl)pent-4-enoate (6c): According to General Procedure 1, 2-iodoaniline (42 mg, 0.191 mmol) was reacted with 5b (156 mg, 0.222 mmol), LiCl (16 mg, 0.370 mmol), CuI (71 mg, 0.370 mmol) and Pd(PPh₃)₄ (11 mg, 9 µmol). Column chromatography (PE–EtOAc, 70:30) afforded aniline 6c (83 mg, 0.170 mmol, 86%) as a brown solid; mp 57–59 °C; R_f = 0.24 (PE–EtOAc, 70:30); [α]_D ²⁰ = –23.0 (c 1.3, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.42 (s, 9 H), 2.73–2.92 (m, 4 H, 4-H), 3.83 (br s, 2 H), 4.46–4.54 (m, 2 H), 5.15 (d, J = 1.8 Hz, 1 H), 5.26 (m, 1 H), 6.68 (d, J = 8.3 Hz, 1 H), 6.71 (dd, J = 8.0, 1.0 Hz, 1 H), 6.76 (ddd, J = 7.5, 7.5, 1.1 Hz, 1 H), 6.96 (dd, J = 7.6, 1.5 Hz, 1 H), 7.02–7.09 (m, 4 H), 7.23–7.29 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 28.0, 37.8, 39.4, 52.5, 54.3, 82.6, 116.3, 119.0, 119.4, 127.3, 127.9, 128.6, 128.7, 128.7, 129.3, 135.2, 142.3, 142.6, 156.5 (² J _F = 37.5 Hz), 168.4, 169.7. The signal of the CF₃ group could not be observed. HRMS (CI): m/z [M + H]⁺ calcd for C₂₆H₃₁F₃N₃O₄: 506.2261; found: 506.2263.
• 35 Diazotation/Azidation of Anilines; General Procedure 2: The aniline derivative was dissolved in a mixture of MeCN and 0.5 M HCl (1:1, 0.05 M). Subsequently, NaNO₂ (1.6 equiv) was added at 0 °C. After stirring for 5 min, NaN₃ (1.6 equiv) was added. After stirring for 5 min, sat. NaHCO₃ solution was added and the aqueous phase was extracted three times with CH₂Cl₂. The organic layer was dried over Na₂SO₄, concentrated, and the residue was purified by (automated) flash chromatography. tert-Butyl N-Trifluoroacetyl-2-amino-4-(2-azido-5-ethoxycarbonylphenyl)pent-4-enoate (2c): According to General Procedure 2, 3c (55 mg, 0.128 mmol) was reacted with NaNO₂ (14 mg, 0.204 mmol) and NaN₃ (13.3 mg, 0.204 mmol). Automated flash chromatography (PE–EtOAc, 100:0 to 90:10) afforded azide 2c (46 mg, 0.101 mmol, 79%) as a colourless resin; R_f = 0.19 (PE–EtOAc, 90:10). ¹H NMR (400 MHz, CDCl₃): δ = 1.39 (t, J = 7.1 Hz, 3 H), 1.40 (s, 9 H), 2.99 (dd, J = 14.6, 6.0 Hz, 1 H), 3.21 (dd, J = 14.6, 5.8 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 4.44 (m, 1 H), 5.19 (d, J = 0.9 Hz, 1 H), 5.31 (d, J = 0.9 Hz, 1 H), 6.84 (d, J = 7.1 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.83 (d, J = 2.0 Hz, 1 H), 8.01 (dd, J = 8.4, 2.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.3, 27.8, 38.1, 52.1, 61.2, 83.4, 118.2, 121.2, 127.1, 130.5, 131.8, 132.6, 141.0, 141.7, 165.5, 169.0. Signals of the TFA group could not be observed. HRMS (CI): m/z [M – N₂]⁺ calcd for C₂₀H₂₃F₃N₂O₅: 428.1554; found: 428.1544. tert-Butyl N-Trifluoroacetyl-(S)-phenylalanyl-(R)-2-amino-4-(2-azidophenyl)pent-4-enoate (7c): According to General Procedure 2, 6c (64 mg, 0.123 mmol) was reacted with NaNO₂ (14 mg, 0.196 mmol) and NaN₃ (13 mg, 0.196 mmol). Column chromatography (PE–EtOAc, 80:20) gave azide 7c (59 mg, 0.111 mmol, 90%) as a colourless resin; R_f = 0.31 (PE–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 1.36 (s, 9 H), 2.87 (m, 2 H), 2.99 (d, J = 6.8 Hz, 2 H), 4.36 (m, 1 H), 4.57 (m, 1 H), 5.06 (m, 1 H), 5.10 (m, 1 H), 6.01 (d, J = 7.2 Hz, 1 H), 7.06–7.17 (m, 6 H), 7.27–7.35 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 27.9, 38.3, 38.8, 52.0, 54.5, 82.6, 118.4, 119.9, 125.0, 127.5, 128.8, 129.2, 129.2, 130.6, 133.1, 135.1, 137.1, 142.3, 168.4, 169.9. Signals of the TFA group could not be observed. HRMS (CI): m/z [M – N₂]⁺ calcd for C₂₆H₂₈F₃N₃O₄: 503.2026; found: 503.2034.
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For photochemical indole syntheses using aryl azides, see:
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• 39 UV-LED Smart from Opsytec Dr. Gröbel GmbH (λ = 365 nm, max. irradiance >25 W·cm^–2, beam profile: standard).
• 40 Photocyclization of Azides; General Procedure 3: The azide was dissolved in MeCN (10 mL/mmol) in a round-bottom flask, which was then wrapped with aluminium foil and irradiated with an UV-LED lamp at 25% (6.25 W·cm^–2) of the maximum irradiance for the specified time at room temperature under laboratory atmosphere (Figure 1). The solvent was removed by evaporation and the residue was purified by (automated) flash chromatography. tert-Butyl N-Trifluoroacetyl-(5-ethoxycarbonyl)tryptophanate (4c): According to General Procedure 3, azide 2c (45 mg, 98.6 µmol) was irradiated for 13 h. Automated flash chromatography (PE–EtOAc, 100:0 to 80:20) afforded indole 4c (30 mg, 70.0 μmol, 71%) as a colourless solid; mp 119–120 °C; R_f = 0.14 (PE–EtOAc, 80:20). ¹H NMR (400 MHz, CDCl₃): δ = 1.40 (s, 9 H), 1.41 (t, J = 7.1 Hz, 3 H), 3.41 (m, 2 H), 4.40 (q, J = 7.1 Hz, 2 H), 4.82 (m, 1 H), 6.96 (d, J = 7.1 Hz, 1 H), 7.07 (d, J = 2.2 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 1 H), 7.93 (dd, J = 8.6, 1.4 Hz, 1 H), 8.34 (s, 1 H), 8.47 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.4, 26.7, 27.8, 53.7, 60.7, 83.7, 110.8, 111.0, 121.5, 122.2, 123.9, 124.1, 127.1, 138.5, 167.5, 169.2. Signals of the TFA group could not be observed. HRMS (CI): m/z [M]⁺ calcd for C₂₀H₂₃F₃N₂O₅: 428.1554; found: 428.1569. tert-Butyl N-Trifluoroacetyl-(S)-phenylanalyl-(R)-tryptophanate (8c): According to General Procedure 3, azide 7c (42 mg, 79.0 μmol) was irradiated for 11.5 h. Column chromatography (PE–EtOAc, 70:30) gave dipeptide 8c (33 mg, 65.5 μmol, 83%) as a colourless solid; mp 178–179 °C. Diastereomeric ratio: (S,R)-8c/(S,S)-8c = 96:4; R_f = 0.26 (PE–EtOAc, 70:30). [α]_D ²⁰ = +26.3 (c 1.0, DMF). ¹H NMR (400 MHz, CD₃OD): δ = 1.37 (s, 9 H), 2.78 (dd, J = 13.8, 8.8 Hz, 1 H), 2.95 (dd, J = 13.8, 5.9 Hz, 1 H), 3.04 (dd, J = 14.6, 8.5 Hz, 1 H), 3.22 (dd, J = 14.6, 5.9 Hz, 1 H), 4.60 (m, 1 H), 4.71 (m, 1 H), 7.00–7.05 (m, 3 H), 7.10 (m, 1 H), 7.14–7.16 (m, 3 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H). Signals of N-H protons could not be observed. ¹³C NMR (100 MHz, CD₃OD): δ = 28.1, 28.5, 38.6, 55.5, 56.0, 82.9, 110.8, 112.3, 119.3, 119.8, 122.5, 124.5, 127.9, 128.7, 129.4, 130.2, 137.5, 138.1, 171.7, 172.4. Signals of the TFA group could not be observed. HPLC (Repropsil 100 Chiral-NR 8 μm (250 × 4.6 mm), hexane–i-PrOH, 90:10 (5 min), 90:10 to 70:30 (10 min), 70:30 (15 min); 1 mL/min): t_R = 11.20 [(S,S)-8c], 12.76 [(S,R)-8c] min. HRMS (CI): m/z [M + H]⁺ calcd for C₂₆H₂₉F₃N₃O₄: 504.2105; found: 504.2096.
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