Total Synthesis of Moiramide B Using an Allylic Alkylation Approach

Abstract

An allylic side chain is introduced onto a chiral γ-amino-β-ketoamide by a Pd-catalyzed allylic alkylation. Subsequent ozonolysis and oxidation proceed only with Cbz-protected ketoamides. The total synthesis of moiramide B is finalized by peptide coupling.

Key words

allylic alkylation - natural products - palladium - ozonolysis - stereoselective synthesis

Publication History

Received: 24 February 2024

Accepted after revision: 18 March 2024

Article published online:
02 April 2024

• References and Notes

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• 17 Preparation of β-Ketonitril 1b To a solution of Cbz-Val-OH (3.00 g, 9.45 mmol) in CH₂Cl₂ (40 mL), carbonyldiimidazole (1.75 g, 10.8 mmol) was added in one portion and stirred for 1.5 h at rt. The reaction solution was washed successively with saturated aq. NaHCO₃, HCl solution (1 M) and brine, dried (MgSO₄), and the solvent was removed under reduced pressure. The residue was taken up in dry THF (15 mL). In a dried three-necked flask diisopropylamine (DIPA, 3.70 mL, 25.7 mmol) in dry THF (35 mL) was cooled to –78 °C, before n-BuLi (9.80 mL, 24.5 mmol, 2.5 M in hexane) was added over 0.5 h. The solution was stirred for further 20 min before MeCN (1.30 mL, 24.9 mmol) in dry THF (15 mL) was added slowly over 1.5 h to keep the temperature below –75 °C. The nucleophile solution was stirred at –78 °C for 30 min before the freshly prepared imidazolide solution was added slowly over 1 h and stirred for further for 30 min. The reaction was hydrolyzed by adding aq. citric acid (10 w% solution), warmed to rt, and stirred for 30 min. The aqueous layer was extracted three times with EtOAc, the combined organic phases were dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/EtOAc, 70:30, 60:40). By adding petroleum ether to the obtained resin under vigorous stirring, filtration of the formed solid and drying, β-ketonitrile 1b (1.90 g, 6.93 mmol, 83%) was obtained as a pale yellow solid; mp 66–68 °C. [α]_D ²⁰ +5.6 (c 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.32 (m, 5 H), 5.30 (d, J  = 7.70 Hz, 1 H), 5.12 (s, 2 H), 4.33 (dd, J = 7.70, 5.3 Hz, 1 H), 3.67–3.56 (m, 2 H), 2.28–2.17 (m, 1 H), 1.04 (d, J  = 6.6 Hz, 3 H), 0.89 (d, J  = 6.7 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.3, 156.5, 135.8, 128.6, 128.4, 128.2, 113.1, 67.5, 64.4, 30.7, 29.6, 19.6, 17.0. HRMS (CI): m/z [M + H]⁺ calcd for C₁₅H₁₉N₂O₃: 275.1390; found: 275.1381.
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• 20 Preparation of β-Ketoamide 2b
  Preparation of Catalyst F [Ru(p-cymene)Cl₂]₂ (8.0 mg, 13.1 μmol) was dissolved in dry THF (2.2 mL) and stirred for 1 h at rt after addition of Ph₂PCl (15.4 μL, 81.4 μmol). The solvent was removed under reduced pressure, the red residue was washed three times with hexanes and dried in vacuo. Catalytic Hydration of β-Ketonitrile A suspension of β-ketonitrile 1b (382 mg,1.93 mmol) and freshly prepared catalyst were heated to 70 °C in water (4.0 mL, deionized) under vigorous stirring in a crimp vial. Complete conversion was indicated after about 15 min by the change of the suspension to a clear solution followed by precipitation of the β-ketoamide. After cooling to rt, the suspension was cooled to 0 °C in order to suction off the solid. Further white solid was obtained by concentrating the filtrate under reduced pressure (caution: foaming!). After flash chromatographic (silica gel, CH₂Cl₂/MeOH, 95:5, 90:10), a brown solid was obtained, which was purified by reversed-phase chromatography [TELOS Flash-LL C18 Column (prepacked), 12 g, H₂O/MeCN, 90:10 (2 min) – in 4 min → 50:50 (3 min) – in 3 min → 5:95 (3 min)] to give β-ketoamide 2b (372 mg, 1.27 mmol, 91%) as a colorless solid; mp 135–137 °C. [α]_D ²⁰ +21.1 (c 1.00 in CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.49–7.29 (m, 5 H), 6.83 (br s, 1 H), 5.74 (br s, 1 H), 5.42 (d, J = 7.9 Hz, 1 H), 5.12 (s, 2 H), 4.34 (dd, J = 7.9, 4.4 Hz, 1 H), 3.57–3.47 (m, 2 H), 2.30–2.20 (m, 1 H), 1.04 (d, J = 6.6 Hz, 3 H), 0.83 (d, J = 6.6 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 205.0, 167.2, 156.6, 136.0, 128.6, 128.3, 128.2, 67.3, 65.7, 46.8, 29.4, 19.8, 16.9. Enol (selected signals): ¹H NMR (400 MHz, CDCl₃): δ = 13.77 (br s, 1 H), 5.20 (d, ³ J _NH,₁ = 8.9 Hz, 1 H), 5.02 (s, 2 H), 3.92 (dd, J = 8.9, 7.9 Hz, 1 H), 2.10–2.02 (m, 1 H), 0.96–0.94 (m, 6 H). HRMS (CI): m/z [M + H]⁺ calcd for C₁₅H₂₁N₂O₄: 293.1496; found: 293.1494.
• 21 Allylic Alkylation of β-Ketoamide 2b In an oven-dried Schlenk tube β-ketoamide 2b (87.6 mg, 300 μmol) was dissolved in dry THF (1 mL). At –78 °C LHMDS (285 μL, 285 μmol, 1 M in THF) was added and stirred for 0.5 h. In a second oven-dried Schlenk tube [Pd(allyl)Cl]₂ (1.5 mg, 4.01 μmol), PPh₃ (4.2 mg, 16.0 μmol), and (R,E)-ethyl-(4-phenylbut-3-ene-2-yl) carbonate (44.1 mg, 200 μmol) were solved in dry THF (1 mL), which was stirred for 10 min before being added dropwise to the enolate solution. The reaction mixture was warmed to rt overnight. The solution was diluted with EtOAc (1 mL) and hydrolyzed with aq. KHSO₄ (1 M). The aqueous layer was extracted three times with EtOAc, the combined organic layers were dried (MgSO₄) and evaporated in vacuo. Column chromatography (silica gel, CH₂Cl₂/MeOH, 95:5) of the crude residue gave rise to allylated β-aminoketone 3b (57.2 mg, 135 μmol, 68 %, dr 55:45) as pale yellow solid. The diastereomers could be separated by an additional column chromatography (silica gel, petroleum ether/EtOAc, 1:1) into minor diastereomer 3b¹ (24.5 mg, 57.9 μmol, 30%) and major diastereomer 3b² (29.9 mg, 70.8 μmol, 35 %) as pale yellow solids. 3b¹ : mp 132 °C (dec.); [α]_D ²⁰ +73.0 (c 1.00 in CHCl₃). 3b² : mp 179 °C (dec.); [α]_D ²⁰ +85.3 (c 1.00 in CHCl₃). HPLC (OD-H Chiralcel RP-18 5 μm, n-hexane/i-PrOH, 80:20, 1.0 mL/min, 25 °C, 254 nm): t _R (3b² ) = 7.04 min; t _R (3b¹ ) = 11.53 min. Analytical Data for 3b^{1 1}H NMR (400 MHz, CDCl₃): δ = 7.39–7.20 (m, 10 H), 6.46 (d, J = 15.8 Hz, 1 H), 6.11 (dd, J = 15.8, 8.1 Hz, 1 H), 6.01 (br s, 1 H), 5.43 (br s, 1 H), 5.35 (d, J = 8.9 Hz, 1 H), 5.14–5.08 (m, 2 H), 4.39 (dd, J = 8.9, 4.2 Hz, 1 H), 3.70 (d, J = 9.0 Hz, 1 H), 3.14–3.04 (m, 1 H), 2.35–2.24 (m, 1 H), 1.12 (d, J = 6.6 Hz, 3 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.81 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 206.0, 168.4, 156.5, 136.9, 136.1, 131.0, 130.6, 128.6, 128.5, 128.3, 128.2, 127.5, 126.3, 67.3, 65.5, 63.8, 38.4, 28.6, 20.1, 18.9, 16.5. Analytical Data for 3b^{2 1}H NMR (400 MHz, CDCl₃): δ = 7.39–7.20 (m, 10 H), 6.60 (br s, 1 H), 6.35 (d, J = 15.8 Hz, 1 H), 6.00 (dd, J = 15.8, 8.7 Hz, 1 H), 5.47 (br s, 1 H,), 5.27 (d, J = 8.8 Hz, 1 H), 4.90 (d, J ₁ = 12.1 Hz, 1 H), 4.66 (d, J = 12.1 Hz, 1 H), 4.41 (dd, J = 8.8, 3.6 Hz, 1 H), 3.64 (d, J = 9.8 Hz, 1 H), 2.99–2.89 (m, 1 H), 2.33–2.22 (m, 1 H), 1.25 (d, J = 6.7 Hz, 3 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.72 (d, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 208.6, 168.7, 155.9, 136.3, 136.1, 132.0, 129.7, 128.5, 128.4, 128.2, 128.1, 127.6, 126.5, 66.9, 66.6, 64.9, 42.8, 28.9, 19.9, 18.6, 16.5. HRMS (CI): m/z [M + H₂]⁺ calcd for C₂₅H₃₂N₂O₄: 424.2357; found: 424.2363.
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• 24 Synthesis of Succinimide 7b Ozone was bubbled through a cooled solution (–78 °C) of allylated β-ketoamide 3b (39.7 mg, 94.0 μmol) dissolved in CH₂Cl₂ (1.8 mL) until the solution turned blue. Excess ozone was removed by bubbling air through the solution (15 min). The solution was warmed to 0 °C and Jones reagent (2.7 M) was added dropwise until the solution turned orange. After 10 min, excess Jones reagent was reduced by i-PrOH and complete reduction was indicated by the green color of the solution. The mixture was stirred for further 20 min at 0 °C. The solution was diluted with CH₂Cl₂, filtered over Celite, and the residue was washed with CH₂Cl₂. Saturated aq. NaHCO₃ was added carefully to the organic layer followed by addition of solid NaHCO₃ until the aqueous layer reached a basic pH value. The aqueous layer was extracted twice with CH₂Cl₂, and the combined organic layers were dried (MgSO₄). After removing the solvent under reduced pressure, the crude residue was purified by reversed-phase chromatography [TELOS Flash-LL C18 Column (prepacked), 4 g, H₂O/MeCN, 90:10 (2 min) – in 4 min → 50:50 (3 min) – in 3 min → 5:95 (3 min)] to yield succinimide 7b (12.7 mg, 36.6 μmol, 68 %) as a trans/enol/cis – mixture (according to ¹H NMR = 79:19:2); mp 45–47°C. [α]_D ²⁰ –13.4 (c 1.0 in CHCl₃). Analytical Data for trans-7b ¹H NMR (400 MHz, CDCl₃): δ = 7.99 (br s, 1 H), 7.42–7.30 (m, 5 H), 5.91 (d, J = 9.1 Hz, 1 H), 5.19–5.08 (m, 2 H), 4.70 (dd, J = 8.9, 4.1 Hz, 1 H), 3.85 (d, J = 5.3 Hz, 1 H), 3.50–3.43 (m, 1 H), 2.48–2.41 (m, 1 H), 1.29 (d, J = 7.3 Hz, 3 H), 1.05 (d, J = 6.7 Hz, 3 H), 0.80 (d, ³ J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 201.4, 178.4, 171.5, 156.6, 136.1, 128.6, 128.3, 128.2, 67.3, 65.2, 59.1, 38.1, 29.8, 19.7, 16.8, 15.2. Analytical Data for Enol 7b Selected signals: ¹H NMR (400 MHz, CDCl₃): δ = 11.4 (s, 1 H), 7.93 (s, 1 H), 5.26 (d, J = 9.9 Hz, 1 H), 4.11 (dd, J = 9.4, 9.4 Hz, 1 H), 3.37–3.32 (m, 1 H), 2.06–1.94 (m, 1 H), 1.56 (d, J = 7.5 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H). Analytical Data for cis-7b Selected signals: ¹H NMR (400 MHz, CDCl₃): δ = 4.31 (d, J = 9.2 Hz, 1 H). LC–MS (Luna, 1.0 mL/min, 280 nm, MeCN/H₂O 10:90 to 100:0, 15 min): t _R (7b) = 7.71 min. HRMS (CI): m/z [M + H]⁺ calcd for C₁₈H₂₃N₂O₅: 347.1601; found: 347.1624.