Asymmetric Synthesis of γ-Hydroxy-α,β-acetylenic Esters Catalyzed by Oxazolidine-Titanium Complex

Abstract

An efficient catalytic system has been developed for the enantioselective reaction of alkynoates with aromatic aldehydes for the synthesis of optically active γ-hydroxy-α,β-acetylenic esters (with up to 81% isolated yield and up to 84% enantioselectivity).

Key words

asymmetric synthesis - oxazolidine - aldehyde - addition - asymmetric alkynylation

References and Notes

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15

General Procedure for the Addition of Methyl Propiolate to Benzaldehyde All manipulations were carried out under an argon atmosphere. The ligand 2 (0.1 mmol), base (0.5 mmol), and DIMPEG (0.05 mmol) were mixed in dry toluene (2.0 mL) at r.t. Then, a solution of Me₂Zn (1.2 M in toluene, 1.5 mmol) and methyl propiolate (1.5 mmol) were added in turn. After the mixture was stirred at r.t. for 7 h, Ti(Oi-Pr)₄ (0.2 mmol, 60 µL) was added and the stirring continued for another 0.5 h. The yellow solution was cooled to 0 ˚C and treated with benzaldehyde (0.5 mmol, 50 µL), then the resultant mixture was allowed to warm up to r.t. naturally and stirred for 20 h. After the reaction was completed, it was cooled to 0 ˚C again and quenched by 5% aq HCl (2 mL). The mixture was extracted with EtOAc (2 × 10 mL). The organic layer was dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography (silica gel H, 10% EtOAc in PE) to give the pure product.
Methyl 4-Hydroxy-4-phenylbut-2-ynoate Yield 78%; 84% ee determined by HPLC analysis (Chiralcel OD-H column, IPA-hexane = 20:80). t _R(minor) = 6.60 min, t _R(major) = 7.33 min. ^¹H NMR (400 MHz, CDCl₃): δ = 2.67 (d, J = 6.4 Hz, 1 H), 3.80 (s, 3 H), 5.58 (d, J = 6.4 Hz, 1 H), 7.35-7.43 (m, 3 H), 7.52 (d, J = 6.8 Hz, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 53.4, 64.4, 77.8, 87.4, 127.1, 29.22, 129.3, 138.9, 154.4.