Synthesis of the C19-C26 Segment of Amphidinolide H2

Abstract

The synthesis of the C19-C26 methyl ketone of amphidinolide H2 is described employing a stereoselective catalytic vinylogous Mukaiyama aldol reaction. Selective dihydroxylation and deoxygenation completes the synthesis of the C19-C26 segment.

Key words

aldol reactions - vinylogous - natural products - deoxygenation - dihydroxylation

References

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14

Typical Procedure for the Synthesis of 11. Freshly distilled aldehyde 10 (3.13 g, 24.0 mmol) dissolved in Et₂O (75 mL) was cooled to -50 °C under argon atmosphere. Tris(pentafluorophenyl)borane monohydrate [13] (318 mg, 600 µmol) was added, and a mixture of ketene acetal 9 [11a] (6.59 g, 28.8 mmol) and i-PrOH (1.27 mL, 16.6 mmol) dissolved in Et₂O (30 mL) was added via syringe pump over 40 min. After 1 h, the reaction mixture was warmed to r.t. The solvent was evaporated and flash chromatography using n-hexane-EtOAc (3:1 to 1:1) as eluent afforded 3.51 g (14.4 mmol, 60%, dr 14:1:1:0) of product 11 as a colorless oil: R _f = 0.24 (n-hexane-EtOAc, 2:1); [α]_D ²³ -51.5 (c 0.94, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 6.92 (dd, J = 15.7, 8.2 Hz, 1 H), 5.85 (dd, J = 15.7, 1.0 Hz, 1 H), 4.02 (q-like, J = 5.7 Hz, 1 H), 3.96 (dd, J = 8.0, 6.3 Hz, 1 H), 3.89 (dd, J = 7.9, 6.5 Hz, 1 H), 3.72 (s, 3 H), 3.71-3.68 (m, 1 H), 2.51-2.43 (m, 1 H), 2.24 (br s, 1 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 166.8, 150.3, 121.4, 109.0, 76.4, 73.5, 64.9, 51.6, 39.2, 26.6, 25.2, 14.3. HRMS (ESI): m/z calcd for C₁₂H₂₁O₅ [M + H]⁺: 245.1389; found: 245.1396.

17

It was crucial to sublime 1,1′-thiocarbonyldiimidazole prior to use.

19

Methyl ketone 8: R _f = 0.33 (n-hexane-EtOAc, 4:1); [α]_D ²³ +19.3 (c 1.01, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 4.17 (dddd, J = 8.9, 7.0, 5.9, 4.1 Hz, 1 H), 4.07 (d, J = 7.3 Hz, 1 H), 4.04 (dd, J = 8.0, 6.1 Hz, 1 H), 4.01 (dd, J = 7.3, 4.4 Hz, 1 H), 3.49 (dd-like, J = 7.7, 7.3 Hz, 1 H), 2.27 (s, 3 H), 2.04-1.95 (m, 1 H), 1.72 (ddd, J = 13.7, 9.1, 4.4 Hz, 1 H), 1.44 (s, 3 H), 1.42-1.35 (m, 1 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.00 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 209.2, 110.2, 108.7, 83.0, 81.3, 73.8, 69.8, 37.6, 32.5, 27.0, 26.8, 26.5, 26.1, 25.8, 13.8. HRMS (ESI): m/z calcd for C₁₅H₂₇O₅ [M + H]⁺: 287.1858; found: 287.1857.