Synthesis of the C1-C11 Segment of Tedanolide via Vinylogous Mukaiyama Aldol Reaction

Abstract

The successful construction of complex natural products depends to a large extent on how efficiently key intermediates can be generated. Here we report our efforts towards the first total synthesis of tedanolide (1), employing Evans’ aldol methodology in combination with a vinylogous Mukaiyama aldol reaction (VMAR) and Sharpless’ asymmetric dihydroxylation. This protocol allows for rapid access to its numerous chiral centers.

aldol reactions - Mukaiyama - natural products - dihydroxylations - stereoselective synthesis

References

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8

Aldehyde 11 (92 mg, 0.218 mmol) dissolved in diethyl ether (2 mL) was cooled to -78 °C under an argon atmosphere. Tris(pentafluorophenyl)borane (110 mg, 0.217 mmol) was added and a mixture of ketene acetal 12 (100 mg, 0.438 mmol) and isopropyl alcohol (17 µL, 0.24 mmol) dissolved in diethyl ether (1 mL) was added via syringe pump over 6 h. An additional equivalent of ketene acetal 12 (100 mg, 0.438 mmol) was added in diethyl ether (1 mL) over 4 h. After complete addition, the reaction was quenched by sat. aq NaHCO₃ (2 mL), slowly warmed to r.t. and stirred overnight. Water (3 mL) was added and the mixture was extracted with ether (2 × 15 mL). The organic layer was separated, dried with MgSO₄ and evaporated in vacuo. Flash column chromatography using petroleum ether/ethyl acetate (4:1) as eluent afforded 13 (73 mg, 62%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 8.78 Hz, 2 H), 6.85 (d, J = 8.78 Hz, 2 H), 6.70 (dd, J = 15.69, 9.29 Hz,
1 H), 5.80 (dd, J = 15.69, 0.75 Hz, 1 H), 5.16 (d, J = 9.54 Hz, 1 H), 4.38 (s, 2 H), 3.87 (d, J = 7.44 Hz, 1 H), 3.77 (s,
3 H), 3.70 (s, 3 H), 3.28 (dd, J = 8.90, 5.90 Hz, 1 H), 3.28-3.24 (m, 1 H), 3.18 (dd, J = 8.90, 8.03 Hz, 1 H), 2.77-2.66 (m, 1 H), 2.44-2.36 (m, 2 H), 1.59-1.51 (m, 1 H), 1.53 (d, J = 1.25 Hz, 3 H), 0.97 (d, J = 6.52 Hz, 3 H), 0.90 (d, J = 6.77 Hz, 3 H), 0.85 (d, J = 6.90 Hz, 3 H), 0.85 (s, 9 H), 0.02 (s, 3 H), -0.05 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃):
δ = 166.9, 159.2, 151.0, 136.2, 130.8, 130.3, 129.2, 120.7, 113.8, 82.4, 75.1, 72.7, 55.2, 51.4, 40.8, 39.7, 32.5, 26.9, 25.9, 18.1, 17.1, 16.7, 11.9, 8.1, -4.4, -5.1; HRMS calcd for C₃₀H₅₀O₆Si: 534.3377. Found: 534.3371.