A Synthesis of the C(17)-C(27) Fragment of Bryostatin 1

Abstract

An approach to the C(17)-C(27) fragment of bryostatin 1, based on forming the C(19)-C(20) bond by reaction of an acyl carbanion equivalent at C(19) with an aldehyde, is described.

Key words

acetals - metathesis - natural products - stereoselective synthesis - total synthesis

References and Notes

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15

To a solution of dithiane 23 (341 mg, 0.34 mmol) in THF (5.5 mL) and MeOH (5.5 mL) at 0 ˚C was added 2,6-lutidine (0.27 mL, 2.3 mmol) and mercury(II) perchlorate trihydrate (273 mg, 0.68 mmol). After stirring at 0 ˚C for 10 min, the reaction mixture was allowed to warm to r.t. and was stirred for 8 h. The resulting white suspension was filtered through Celite and partitioned between ether and sat. aq NaHCO₃. After separation of the organic layer, the aqueous phase was extracted with Et₂O. The combined organic extracts were dried (MgSO₄), filtered, and concentrated under reduced pressure. Flash chromatography of the residue using Et₂O (2%) in light PE as eluent afforded the acetal 3 (277 mg, 88%) as a colourless oil, R _f  = 0.34 (light PE-Et₂O, 15:1); [α]_D ^²4 -32 (c 0.5, CH₂Cl₂). IR: ν_max = 2954, 2894, 2864, 1471, 1463, 1380, 1361, 1251, 1148, 1102, 1058, 939, 883, 859, 835, 775 cm^-¹. ^¹H NMR (500 MHz, C₆D₆): δ = 0.00 [9 H, s, Si(CH₃)₃], 0.15, 0.16, 0.17, 0.23 [each 3 H, s, Si(CH₃)], 0.96 [2 H, m, CH ₂Si(CH₃)₃], 1.01, 1.03 [each 9 H, s, SiC(CH₃)₃], 1.05-1.15 {21 H, m, Si[CH(CH₃)₂]₃}, 1.31 (3 H, d, J = 6.0 Hz, 4′′′-H₃), 1.52 (6 H, s, 2 × 1′-CH₃), 1.68 (1 H, t, J = 12.5 Hz, 1′′′-H), 2.13 (1 H, dd, J = 10.5, 13.0 Hz, 1′′′-H′), 2.26 (1 H, dd, J = 3.0, 13.5 Hz, 5-H), 2.33 (1 H, t,
J = 12.5 Hz, 5-H′), 3.38 (3 H, s, OCH₃), 3.47 (1 H, m, OCHHCH₂Si), 3.75 (1 H, br. s, 2′-H), 3.82 (1 H, m, OCHHCH₂Si), 4.03-4.21 (3 H, m, 6-H, 2′-H′ and 2′′′-H), 4.28 (1 H, dd, J = 5.5, 12.5 Hz, 2′′-H), 4.30-4.38 (3 H, m, 3-H, 2′′-H′ and 3′′′-H), 4.60, 4.63 (each 1 H, d, J = 12.5 Hz, CHHPh), 4.74 (1 H, d, J = 7.0 Hz, OCHHO), 4.91 (1 H, br d, J = 7.0 Hz, OCHHO), 5.75 (1 H, m, 1′′-H), 7.10 (1 H, t, J = 7.4 Hz, ArH), 7.21 (2 H, t, J = 7.5 Hz, ArH), 7.44 (2 H, d, J = 7.5 Hz, ArH). ^¹³C NMR (75 MHz, C₆D₆): δ = -4.4, -4.2, -4.0, -3.4, -0.9, 12.7, 17.6, 18.7, 18.7, 18.8, 19.0, 21.9, 22.5, 26.6, 26.7, 31.9, 36.3, 46.7, 52.3, 60.1, 65.9, 68.7, 69.8, 73.9, 76.3, 76.9, 80.1, 97.2, 104.2, 127.8, 127.9, 128.9, 137.2, 140.4. MS (ES⁺): m/z (%) = 962 (100) [M + 23], 963 (70), 964 (38), 965 (13).