Total Synthesis of PF1163B

Abstract

A total synthesis of PF1163B has been achieved. The vinylogous Mukaiyama aldol reaction of ketene silyl N,O-acetal 6 (ent-6) mediated by excess TiCl₄ proceeded with saturated aldehydes to give adduct 10 in moderate yield with moderate stereoselectivity. The major isomer is the diastereomer that was provided by using one equivalent of TiCl₄. The Birch reduction of α,β-unsaturated imide 4, possessing a less hindered side chain, gave 12 in good stereoselectivity by employing 2-isopropylbenzimidazole as a bulky proton source. After elongation of the carbon chain and connection with the amino acid part, we accomplished a total synthesis of PF1163B. These methods constitute a concise synthetic route to obtain polyketides as well as depsipeptides.

Key words

PF1163B - total synthesis - vinylogous Mukaiyama aldol reaction - bulky proton source - depsipeptide - stereoswitching

• References and Notes

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• 10 Synthesis of PF1163B (1) from Acyclic 17 To a solution of compound 17 (85.9 mg, 0.114 mmol) in CH₂Cl₂ (4.0 mL) at 0 °C was added TFA (1.0 mL, 98%). The reaction mixture was stirred for 35 min at rt and then concentrated. The residue was then taken up in CH₂Cl₂ (64.0 mL) and cooled to 0 °C. Et₃N (0.19 mL, 1.368 mmol) was added dropwise, followed by the addition of BOP-Cl (174.1 mg, 0.684 mmol). The reaction mixture was stirred at 0 °C for 48 h. Then, it was concentrated and NaHCO₃ aq. (2.0 mL) was added. The aqueous layer was extracted two times with CHCl₃ (4.0 mL × 2) and the combined organic layers were concentrated, dried with Na₂SO₄, and purified by silica gel chromatography (n-hexane/EtOAc = 5:1) to give PF1163B (1) (27.0 mg, 0.058 mmoles, 50% over 2 steps) as a colorless oil. R_f = 0.48 (n-hexane/EtOAc = 1:1). [α]_D ²³ = –109.6 (c 0.49, MeOH). ¹H NMR (400 MHz, CDCl₃): δ = 7.21–7.05 (2 H, m), 6.88–6.79 (2 H, m), 5.84–5.75 (0.6 H, m), 4.94–4.78 (1 H, m), 4.60–4.54 (0.27 H, m), 4.09–4.01 (2 H, m), 3.99–3.91 (2 H, m), 3.60–3.14 (4 H, m), 3.04–2.90 (3 H, m), 2.84–2.61 (2 H, m), 2.47–1.96 (4 H, m), 1.54–1.03 (16 H, m), 0.92–0.79 (6 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 173.4, 171.1, 170.2, 157.2, 130.2, 129.7, 129.1, 114.9, 114.4, 75.3, 69.1, 69.0, 61.5, 55.4, 35.1, 35.0, 34.0, 33.7, 33.6, 33.5, 31.7, 31.6, 29.4, 29.3, 28.7, 26.5, 25.0, 20.5, 14.0. HRMS-ESI: m/z [M + Na]⁺ calcd for C₂₇H₄₃O₅NNa: 484.3033; found: 484.3033. IR (KBr): 3400, 2950, 2929, 1731, 1632, 1512, 1248, 1220, 1078, 772 cm^–1.