Synthesis of the C₁–C₂₃ Fragment of the Archazolids and Evidence for V-ATPase but not COX Inhibitory Activity

Abstract

A convergent synthesis of a C₁–C₂₃ fragment of the archa­zolids has been completed based on a high-yielding Stille coupling to construct the substituted Z,Z,E-conjugated triene. After removal of the protecting groups, the resulting tetrol exhibited evidence for inhibition of the vacuolar-type ATPase (V-ATPase) but not cyclooxygenase (COX) inhibitory activity.

Key words

archazolid - natural product - Stille reaction - V-ATPase - cyclooxygenase - total synthesis.

• References and Notes

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• 21 Compound 11 To a solution of 9 (36 mg, 0.058 mmol, 1.0 equiv) and 10 (45 mg, 0.058 mmol, 1.0 equiv) in degassed THF (1.2 mL) was added [Ph₂PO₂][NBu₄] (75 mg, 0.17 mmol, 3.0 equiv), CuTC (28 mg, 0.07 mmol, 2.5 equiv), and Pd(PPh₃)₄ (7 mg, 0.006 mmol, 0.1 equiv), and the mixture was stirred for 15 h. The reaction was quenched with aq NaHCO₃ (15 mL) and extracted with MTBE (2 × 15 mL). The combined organic extracts were dried over MgSO₄, filtered, and concentrated in vacuo. Purification by flash chromatography on silica (20:1 to 10:1 hexanes–EtOAc) gave 11 (46 mg, 82%) as an oil. [α]_D ²⁰ –5.2 (c 0.5, CH₂Cl₂). IR (ATR): 3062, 2983, 1736, 1614, 1415, 1274, 1267, 1129, 1078, 930 cm^–1. ¹H NMR (500 MHz, C₆D₆): δ = 6.80 (d, J = 16.0 Hz, 1 H), 6.44 (ddd, J = 15.3, 10.7, 0.9 Hz, 1 H), 6.17 (d, J = 10.4 Hz, 1 H), 6.02 (s, 1 H), 5.90 (dd, J = 16.0, 7.2 Hz, 1 H), 5.58 (dd, J = 15.4, 8.0 Hz, 1 H), 5.34 (dd, J = 8.4, 0.8 Hz, 1 H), 5.29 (ddd, J = 9.8, 2.0, 1.0 Hz, 1 H), 5.07 (d, J = 7.4 Hz, 1 H), 4.29 (dd, J = 9.0, 6.0 Hz, 1 H), 3.63 (d, J = 10.0 Hz, 1 H), 3.58–3.53 (m, 2 H), 3.47 (dd, J = 9.7, 6.2 Hz, 1 H), 3.38 (dd, J = 9.7, 6.8 Hz, 1 H), 3.18 (s, 3 H), 2.71 (m, 1 H), 2.42 (m, 1 H), 1.96 (m, 2 H), 1.91 (s, 3 H), 1.86 (m, 1 H), 1.89 (d, J = 1.0 Hz, 3 H), 1.71 (d, J = 1.0 Hz, 3 H), 1.59 (s, 3 H), 1.50 (m, 2 H), 1.39 (m, 2 H), 1.08 (s, 6 H), 1.03 (s, 6 H), 1.02 (s, 3 H), 1.01 (s, 6 H), 1.00 (s, 3 H), 0.99 (d, J = 7.0 Hz, 3 H), 0.98 (s, 3 H), 0.96 (d, J = 7.0 Hz, 3 H), 0.95 (s, 6 H), 0.94 (d, J = 7.0 Hz, 3 H), 0.93 (s, 3 H), 0.19 (s, 3 H), 0.17 (s, 3 H), 0.13 (s, 6 H), 0.08 (s, 6 H), 0.05 (s, 6 H). ¹³C NMR (125 MHz, C₆D₆): δ = 137.8, 136.0, 134.9, 134.7, 133.4, 133.3, 133.0, 132.5, 130.9, 130.3, 126.3, 125.4, 73.8, 72.9, 68.5, 63.4, 63.4, 56.0, 43.7, 41.5, 40.6, 40.1, 33.1, 31.4, 30.3, 28.5, 26.7, 26.6, 26.5 25.4, 24.8, 24.8, 24.0, 21.0, 19.1, 18.9, 18.8, 17.4, 17.2, 17.1, 16.2, 14.3, 11.2, 9.8, 8.7, –3.0, –3.6, –4.2, –4.3, –4.4, –4.7, –4.8, –4.9. HRMS (ESI⁺): m/z calcd for C₅₅H₁₀₈O₅Si₄Na⁺ [M + Na]⁺: 983.7172; found 983.7179. Compound 1 To a solution of 11 (25 mg, 0.026 mmol) in THF (1.2 mL) at 0 °C was added pyridine (0.3 mL) and HF·py (60% HF, 0.2 mL), and the mixture was allowed to slowly warm to r.t. for 42 h. The reaction was cooled to 0 °C, diluted with EtOAc (15 mL), and quenched with aq NaHCO₃ (15 mL). The layers were separated, and the aqueous phase was re-extracted with EtOAc (2 × 15 mL). The combined organic extracts were dried over MgSO₄, filtered, and concentrated in vacuo. Purification by flash chromatography on silica (1:1 to 1:2 to 0:1 hexanes– EtOAc) gave 1 (7 mg, 58%) as an oil. [α] _D ²⁰ –6.0 (c 0.5, CH₂Cl₂). IR (ATR): 3350, 3955, 2929, 2872, 1716, 1688, 1525, 1471, 1418, 1369, 1244, 1126, 1084, 1008, 963, 919, 828, 730 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 6.52 (dd, J = 16.0, 0.7 Hz, 1 H, H13), 6.29 (ddd, J = 15.0, 10.8, 0.7 Hz, 1 H, H₂0), 5.90 (d, J = 11.0 Hz, 1 H, H19), 5.74 (s, 1 H, H11), 5.70 (dd, J = 15.8, 5.9 Hz, 1 H, H14), 5.57 (dd, J = 15.2, 7.6 Hz, 1 H, H21), 5.09 (d, J = 9.0 Hz, 1 H, H9), 5.07 (d, J = 8.0, 1.0 Hz, 1 H, H6), 4.46 (dd, J = 6.0, 3.5 Hz, 1 H, H15), 4.05 (dd, J = 9.0, 6.1 Hz, 1 H, H7), 3.48 (t, J = 6.0 Hz, 2 H, H1a/b), 3.38 (d, J = 8.4 Hz, 1 H, H17), 3.37 (dd, J = 10.6, 5.5 Hz, 1 H, H23a), 3.33 (dd, J = 10.6, 6.5 Hz, 1 H, H23b), 3.09 (s, 3 H, OMe), 2.36–2.28 (m, 2 H, H8/22), 1.97 (t, J = 7.3 Hz, 2 H, H4a/b), 1.81 (d, J = 1.2 Hz, 3 H, Me10), 1.70 (s, 3 H, Me12), 1.64 (m, 1 H, H16) 1.58 (d, J = 1.0 Hz, 3 H, Me5), 1.56 (d, J = 1.0 Hz, 3 H, Me18), 1.48–1.40 (m, 4 H, H2/3), 0.96 (d, J = 7.0 Hz, 3 H, Me22), 0.81 (d, J = 7.0 Hz, 3 H, Me8), 0.59 (d, J = 7.0 Hz, 3 H, Me16). ¹³C NMR (125 MHz, CD₃OD): δ = 139.3, 138.7, 134.7, 134.4, 133.6, 132.7, 131.5, 130.5, 129.9, 127.3, 126.9, 90.4, 73.1, 73.0, 71.7, 68.2, 63.0, 56.3, 42.8, 41.3, 41.2, 40.7, 33.3, 25.3, 25.0, 20.5, 17.2, 17.0, 16.3, 11.1, 10.7. HRMS (ESI⁺): m/z calcd for C₃₁H₅₂O₅Na⁺ [M + Na]⁺: 527.3712; found 527.3729.
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Due to short supply, archazolids themselves were not assayed. However, reported V-ATPase inhibitory activity of concanamycin A and archazolid A are similar. The IC₅₀ values for concanamycin A and archazolid A of purified M. sexta holoenzyme were reported as 0.8 nmol/mg V-ATPase and 0.5 nmol/mg V-ATPase, respectively. Archazolid:
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Concanamycin:
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