Studies towards the Synthesis of Aculeatin C

Abstract

Efficient activation/deprotection reactions of functional groups by PIFA reagent allowed for the construction of the polyspirocyclic core of aculeatin C according to a new polyspiro annulation approach. Addition of TFA increased the yield and the selectivity to the benefit of the desired conformer.

tandem reaction - oxidation - phenols - Michael addition - natural product synthesis

References and Notes

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10

To a stirred mixture of (±)-10 (308 mg, 0.45 mmol) in acetone-H₂O (10:1; 15.4 mL) was injected TFA (37 µL) followed by the addition of solid PIFA (1.17 g, 6 equiv) in one portion in darkness. The mixture was stirred for 18 h at r.t. and was quenched with a sat. solution of NaHCO₃. After extraction with EtOAc, the organic layer was dried over MgSO₄ and concentrated. The residue was subjected to silica gel column chromatography (100% CH₂Cl₂ → 1% MeOH in CH₂Cl₂) to give (±)-14 (32 mg, 24%) and (±)-15 (55 mg, 41%).

11

Spectroscopic data of compound (±)-14: R _f = 0.46 (MeOH-CH₂Cl₂, 1:9). IR (film): 3418, 2937, 1713, 1665, 1624, 1388, 1250, 1167, 1094, 1045, 990, 858 cm^-1. UV (MeOH): 338, 227, 204 nm. ¹H NMR (500 MHz, CDCl₃): δ = 1.50 (ddd, J = 2.6, 12.6, 13.1 Hz, 1 H), 1.76-1.81 (m, 1 H), 1.92-2.05 (m, 4 H), 2.15-2.24 (m, 1 H), 2.22 (s, 3 H), 2.27-2.38 (m, 1 H), 2.47 (dd, J = 2.8, 16.4 Hz, 1 H), 2.75 (dd, J = 9.7, 16.4 Hz, 1 H), 4.13-4.18 (m, 1 H), 4.67-4.72 (m, 1 H), 6.11 (dd, J = 2.0, 10.0 Hz, 1 H), 6.24 (dd, J = 2.0, 10.0 Hz, 1 H), 6.77 (dd, J = 2.8, 10.0 Hz, 1 H), 7.27 (dd, J = 2.8, 10.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 31.5, 34.2, 37.7, 39.0, 39.1, 49.2, 62.0, 64.8, 80.3, 109.0, 127.3, 127.7, 148.6, 151.7, 185.7, 206.6. LRMS (ESI+): m/z (%) = 292 (10) [M]⁺, 280 (100), 276 (39), 258 (95), 218 (52). HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₀O₅Na: 315.1208; found: 315.1202.

12

Spectroscopic data of compound (±)-15: R _f = 0.33 (MeOH-CH₂Cl₂, 1:9). IR (film): 3425, 2930, 1712, 668, 1628, 1385, 1204, 1167, 1119, 1053, 994, 854 cm^-1. UV (MeOH): 229, 200 nm. ¹H NMR (500 MHz, CDCl₃): δ = 1.24 (ddd, J = 11.8, 11.8, 11.8 Hz, 1 H), 1.64 (dd, J = 11.8, 11.8 Hz, 1 H), 1.92-2.04 (m, 2 H), 2.05-2.12 (m, 1 H), 2.13-2.23 (m, 2 H), 2.21 (s, 3 H), 2.26-2.40 (m, 1 H), 2.48 (dd, J = 3.1, 16.4 Hz, 1 H), 2.76 (dd, J = 9.2, 16.4 Hz, 1 H), 4.13-4.18 (m, 1 H), 4.33-4.38 (m, 1 H), 6.10 (dd, J = 2.1, 10.3 Hz, 1 H), 6.19 (dd, J = 2.1, 10.3 Hz, 1 H), 6.77 (dd, J = 2.8, 10.3 Hz, 1 H), 7.15 (dd, J = 2.8, 10.3 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 31.5, 34.6, 38.8, 40.2, 42.8, 49.2, 64.8, 65.3, 79.4, 109.0, 127.0, 127.3, 149.4, 152.4, 185.9, 206.8. LRMS (ESI+): m/z (%) = 292 (3) [M]⁺, 280 (5), 276 (2), 258 (68), 218 (100). HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₀O₅Na: 315.1208; found: 315.1208.

For reviews on the stereocontrolled synthesis of spiroketals, see:

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