Synthesis of C3-C12 Fragment of 24-Demethylbafilomycin C₁ via anti-Selective Aldol Condensation as the Key Stereocontrol Step

Abstract

An efficient synthesis of the C3-C12 aldehyde fragment of 24-demethylbafilomycin C₁ was accomplished for assembling the 16-membered plecomacrolide skeleton according to a 1,3-diene-ene ring-closing metathesis (RCM) strategy. A boron-mediated anti-selective aldol condensation of Abiko’s chiral propionate was used to secure the C6 and C7 stereogenic centers while the C8 chirality was introduced from a chiral building block. The dithiane alkylation and the methyl ketone Horner-Wittig olefination using allyldiphenylphosphine oxide were employed for construction of the requisite (E)-1,3-diene subunit.

Key words

anti-selective aldol - 1,3-diene - dithiane - Horner-Wittig olefination - α,β-unsaturated aldehyde

References and Notes

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23

Procedure for Oxidation of the Alcohol 9 with Stabilized IBX to Form Aldehyde 10
To a solution of the alcohol 9 (1.990 g, 9.66 mmol) in DMSO (40 mL; without drying) was added stabilized IBX in six portions (45 wt%, 1.002 × 6 g, 9.66 mmol). After each addition of stabilized IBX, the resultant mixture was stirred for 2 h at r.t. The reaction was quenched by aq Na₂S₂O₃ followed by addition of sat. aq NaHCO₃. The aqueous mixture was extracted with EtOAc (100 × 2 mL) and the combined organic layer was dried over anhyd Na₂SO₄, filtrated, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, 14% EtOAc in hexane) to provide the aldehyde 10 (1.399 g, 71% yield).
Compound 10: yellow oil; [α]_D ²⁰ -2.2 (c 1.35, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.71 (d, J = 1.8 Hz, 1 H), 2.94-2.60 (m, 6 H), 2.10-1.80 (m, 2 H), 1.70 (dd, J = 14.7, 3.0 Hz, 1 H), 1.56 (s, 3 H), 1.15 (d, J = 7.2 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 203.4, 48.3, 43.2, 42.5, 28.3, 26.5 (¥2), 24.6, 16.2. HRMS (ESI⁺): m/z calcd for C₉H₁₇OS₂ [M + H⁺]: 205.0721; found: 205.0729.

27

We checked the diastereomeric ratio of the isolated aldol products prepared in several runs by ¹H NMR spectroscopy and found that the ratio is about 95:5 in all cases. We did not obtain any separable minor diastereomers on the 3-gram-scale reaction, implying that the minor diastereomer is not separable from the major isomer.

28

Epimerization of the aldehyde 20 obtained from both the DMP (aq NaHCO₃, CH₂Cl₂, r.t.) and SIBX (DMSO, r.t.) oxidation was observed. The diastereomeric ratios are about 95:5. We are not sure whether the epimerization occurred during the oxidation or over silica gel during column chromatographic separation.

29

Physical and Spectroscopic Data of 3
Colorless oil; [α]_D ²⁰ 31.9 (c 0.73, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.40 (s, 1 H), 6.72 (dd, J = 9.9, 1.2 Hz, 1 H), 6.61-6.48 (m, 1 H), 5.81 (d, J = 11.4 Hz, 1 H), 5.09 (dd, J = 16.8, 1.8 Hz, 1 H), 4.99 (d, J = 10.2 Hz, 1 H), 3.54 (dd, J = 4.5, 3.0 Hz, 1 H), 2.95-2.85 (m, 1 H), 2.19 (d, J = 8.4 Hz, 1 H), 1.85-1.64 (m, 2 H), 1.76 (s, 3 H), 1.71 (s, 3 H), 1.04 (d, J = 7.5 Hz, 3 H), 0.92 (s, 9 H), 0.74 (d, J = 6.3 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 195.6, 157.6, 137.3, 137.2, 133.0, 127.4, 115.0, 79.4, 43.7, 36.9, 35.9, 26.0 (¥3), 18.6, 18.3, 16.3, 15.3, 9.3, -3.9, -4.0. HRMS (ESI⁺): m/z calcd for C₂₁H₃₉O₂Si [M + H⁺]: 351.2719; found: 351.2729.