Synthesis of the C15-C35 Segment of Chivosazole A

Abstract

The synthesis of the C15-C35 segment of chivosazole A is reported using a convergent approach that incorporates an E-selective Wittig olefination for joining both subunits of this fragment.

chivosazole - natural product - antibiotic - myxobacteria

References and Notes

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<A NAME="RG27407ST-14">14</A>

Synthesis of Alkene 15
Reagent 14 (14 mg, 44 µmol) was dissolved in THF (1 mL) and cooled to 0 °C. Then, NaH (2.5 mg, 62 µmol, 60% dispersion on mineral oil) was added, the solution stirred for 15 min at 0 °C, and then cooled to -78 °C. Aldehyde 13 (27 mg, 49 µmol) was added and the mixture was warmed over 2 h to 0 °C and then quenched with sat. NH₄Cl solution (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over MgSO₄. The solvent was removed under reduced pressure and the residue was purified via flash chromatography. The reaction yielded 21 mg of the Z-olefin (0.03 mmol, 69%). R _f = 0.29 (EtOAc-hexane, 1:30); [α]_D ²³ +6.5 (c 1.07, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.29 (d, J = 8.5 Hz, 2 H), 6.87 (d, J = 8.5 Hz, 2 H), 6.40 (dd, J = 11.6, 10.2 Hz, 1 H), 5.82 (d, J = 11.6 Hz, 1 H), 4.57 (d, J = 10.6 Hz, 1 H), 4.52 (d, J = 10.6 Hz, 1 H), 4.15 (q, J = 7.1 Hz, 2 H), 3.95-3.90 (m, 1 H), 3.88-3.83 (m, 1 H), 3.80 (s, 3 H), 3.23 (dd, J = 5.8, 3.8 Hz, 1 H), 1.77-1.73 (m, 2 H), 1.57 (ddd, J = 14.0, 8.0, 1.9 Hz, 1 H), 1.41 (ddd, J = 13.7, 9.1, 4.1 Hz, 1 H), 1.28 (t, J = 7.2 Hz, 3 H), 1.15 (d, J = 6.2 Hz, 3 H), 1.11 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.90 (s, 9 H), 0.87 (s, 9 H), 0.10 (s, 3 H), 0.09 (s, 3 H), 0.02 (s, 3 H), -0.01 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.6, 166.1, 159.1, 156.3, 152.4, 131.4, 129.4, 119.8, 113.8, 83.8, 74.3, 72.2, 66.9, 59.8, 55.4, 43.7, 37.1, 26.2, 26.1, 25.4, 18.2, 17.7, 14.4, 9.5, -3.6, -3.8, -4.3, -4.3. ESI-HRMS: m/z calcd for C₃₃H₆₂O₆NaSi₂: 645.3983 [M + Na⁺]; found: 645.3975.
Synthesis of Lactone 28
Acid 25 (10 mg, 22.1 µmol) was dissolved in THF (0.25 mL) and treated with pyridine (0.25 mL). A HF-pyridine complex (ca. 70% HF, ca. 30% pyridine, 0.4 mL, 15.3 mmol) was added. The reaction mixture was stirred for 16 h at r.t. and then poured into sat. NaHCO₃ solution (10 mL). The layers were separated and the aqueous layer was extracted with MTBE (5 × 5 mL). The combined organic layers were washed with sat. NH₄Cl solution (5 mL) and brine (5 mL) and dried over MgSO₄. The solvent was removed under reduced pressure and the residue purified via flash chromatography. The reaction yielded 4 mg of lactone 28 (12.5 µmol, 56%). R _f = (EtOAc-hexane, 1:4); [α]_D ²³
-14.2 (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.91 (dt, J = 15.5, 5.2 Hz, 1 H), 5.82 (dd, J = 15.7, 6.0 Hz, 1 H), 4.75 (ddd, J = 10.6, 5.3, 5.3 Hz, 1 H), 4.46 (s, 2 H), 4.02 (d, J = 5.0 Hz, 2 H), 3.81 (s, 3 H), 3.73 (ddd, J = 6.8, 4.6, 4.6 Hz, 1 H), 3.31 (s, 3 H), 2.75 (dq, J = 6.8, 4.6 Hz, 1 H), 2.25 (ddd, J = 14.5, 6.9, 4.4 Hz, 1 H), 1.87 (ddd, J = 14.6, 11.2, 4.6 Hz, 1 H), 1.28 (d, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5, 159.4, 130.2, 130.1, 129.6, 129.5, 114.0, 76.2, 75.9, 72.3, 69.4, 56.8, 55.4, 39.6, 34.0, 11.5. ESI-HRMS: m/z calcd for C₁₈H₂₄O₅Na: 343.1521 [M + Na⁺]; found: 343.1533.
Synthesis of the C15-C35 Segment (29) Wittig salt 16 (17 mg, 20 µmol) was dissolved in toluene (1 mL) and cooled to 0 °C. A solution of the aldehyde 27 (10 mg, 24 µmol) in toluene (0.2 mL) was added to the mixture. The reaction mixture was then treated with a KOt-Bu solution (18 µL, 28 µmol, 1 M solution in THF). After 30 min H₂O (2 mL) was added, the layers separated, and the aqueous layer was extracted with MTBE (2 × 5 mL). The combined organic layers were dried over MgSO₄. The solvent was removed under reduced pressure and the residue was purified via flash chromatography. The reaction yielded 11 mg of compound 29 (15 µmol, 57%). R _f = 0.32 (EtOAc-hexane, 1:10); [α]_D ²³ +3.9 (c 1.02, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.17 (s, 1 H), 7.29 (d, J = 8.5 Hz, 2 H), 6.85 (d, J = 8.9 Hz, 2 H), 6.42-6.36 (m, 1 H), 6.18-6.09 (m, 2 H), 6.04 (t, J = 11.1 Hz, 1 H), 5.62 (t, J = 10.4 Hz, 1 H), 5.59 (dd, J = 14.0, 8.2 Hz, 1 H), 5.32-5.54 (m, 2 H), 4.51 (s, 2 H), 4.32-4.27 (m, 1 H), 3.97-3.92 (m, 1 H), 3.91 (s, 3 H), 3.84-3.81 (m, 1 H), 3.79 (s, 3 H), 3.78-3.76 (m, 1 H), 3.42 (dq, J = 6.8, 5.0 Hz, 1 H), 3.37 (s, 3 H), 3.12 (dd, J = 6.5, 3.8 Hz, 1 H), 2.93-2.84 (m, 1 H), 1.86-1.79 (m, 1 H), 1.43-1.37 (m, 4 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.16 (d, J = 5.8 Hz), 1.06 (d, J = 6.8 Hz, 3 H), 0.95 (d, J = 6.8 Hz, 3 H), 0.92 (s, 9 H), 0.86 (s, 9 H), 0.85 (s, 9 H), 0.10 (s, 6 H), 0.04 (s, 3 H), -0.01 (s, 3 H), -0.02 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.9, 162.0, 159.1, 144.1, 137.2, 134.6, 133.2, 132.6, 131.3, 130.0, 129.5, 128.9, 128.4, 113.8, 84.7, 79.1, 74.6, 71.7, 70.3, 66.7, 57.6, 55.4, 52.3, 43.1, 40.3, 36.2, 32.1, 29.9, 26.2, 26.1, 26.0, 25.6, 22.9, 18.8, 18.2, 14.3, 11.5, 9.2, 7.5, 1.2, -3.3, -3.5, -3.8, -4.1, -4.3, -4.8. ESI-HRMS: m/z calcd for C₅₂H₉₁NO₉Si₃Na: 980.5899 [M + Na⁺]; found: 980.5900.