A Concise Enantioselective Synthesis of (S)-Preclamol via Asymmetric Catalytic Negishi Cross-Coupling Reaction

^◊ These authors contributed equally to this work and should be considered as co-first authors

Abstract

A novel, concise, and efficient enantioselective synthesis of (S)-preclamol (87% ee, 51% total yield) has been developed. The key steps of this synthetic approach included cobalt-catalyzed asymmetric catalytic cross-coupling of α-bromo ester with arylzinc and the reduction of chiral ester to diol with a tertiary carbon atom. Moreover, it was demonstrated that our enantioselective Negishi cross-coupling was a powerful tool to construct stereogenic benzylmethyl center in chiral drugs on a gram scale.

Key words

(S)-preclamol - enantioselective Negishi cross-coupling - cobalt - asymmetric synthesis - chiral drug

• References and Notes

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• 22 The Experimental Procedures and Characterization Data for (S)-3 Magnesium turnings (1.46 g, 60 mmol) were placed in a two-neck 250 mL Schlenk flask equipped with funnel, and the flask was heated at 80 °C for 1 h under an argon atmosphere. After being cooled to room temperature, anhydrous THF (50 mL) and 1-bromo-3-methoxybenzene (1.87 g, 10 mmol) were added sequentially. The reaction was initiated by gently heating with a heat gun, and additional 1-bromo-3-methoxybenzene (7.48 g, 40 mmol) in THF (10 mL) was added dropwise. The resulting mixture was stirred and refluxed for 2 h. The concentration of prepared (3-methoxyphenyl)magnesium bromide was titrated with I₂. ZnBr₂ (10.12 g, 45 mmol) was placed in another 250 mL Schlenk flask and was heated at 100 °C for 1.5 h under an argon atmosphere. After being cooled to ambient temperature, anhydrous THF (68.8 mL) was added, and the resulting mixture was stirred for 10 min. The prepared (3-methoxyphenyl)magnesium bromide (30 mmol, 0.586 M in THF, 51.2 mL) was added via syringe over 25 min. The resulting mixture was stirred for 2 h at room temperature. Anhydrous cobalt(II) iodide (160 mg, 0.50 mmol) was placed in a separate 100 mL Schlenk tube and heated at 80 °C for 2 h in vacuo. After being cooled to room temperature under an argon atmosphere, anhydrous THF (10 mL) and L1 (330 mg, 0.60 mmol) in THF (5 mL) were added. The mixture was stirred for 2 h at room temperature, racemic dibenzyl 2-bromopentanedioate (1, 1.97 g, 5.0 mmol) was added via syringe. The resulting mixture was cooled to –25 °C, the suspension of (3-methoxyphenyl)zinc bromide (2, 25 mmol) was added dropwise over 30 min. After stirring at –25 °C for 24 h, the reaction was quenched with saturated NH₄Cl solution (10 mL). The layers were separated, and the aqueous phase was extracted with Et₂O (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/dichloromethane, 1:2) to provide (S)-dibenzyl-2-(3-methoxyphenyl)pentanedioate (3, 1.94 g, 93% yield, 87% ee) as a colorless oil. The ee was determined by HPLC with a Daicel Chiralcel OD-H column (2% isopropanol in n-hexane, 1 mL/min, 220 nm, minor t _R = 22.27 min (R), major t _R = 25.49 min (S)). [α]_D ²³ + 24.6 (c 1.3, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.34–7.18 (m, 11 H), 6.84–6.79 (m, 3 H), 5.15–5.04 (m, 4 H), 3.74 (s, 3 H), 3.64 (t, J = 7.4 Hz, 1 H), 2.45–2.33 (m, 1 H), 2.31 (t, J = 7.4 Hz, 2 H), 2.20–2.09 (m, 1 H).¹³C NMR (75 MHz, CDCl₃): δ = 173.0, 172.6, 159.8, 139.5, 135.87, 135.80, 129.7, 128.5, 128.4, 128.2, 128.1, 127.9, 120.4, 113.5, 113.1, 66.5, 66.3, 55.1, 50.5, 31.8, 28.2. HRMS (ESI): m/z calcd for C₂₆H₂₇O₅ [M + H]⁺419.1853; found: 419.1840.
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