Access to Chiral Tertiary α-Hydroxy-β-Ynyl Esters via One-Pot Addition and Kinetic Resolution

Abstract

Chiral amino alcohol promoted one-pot addition of zinc alkynylides to α-keto esters and kinetic resolution of the resulting tertiary propargylic alcohols was developed. The reaction provided us an alternative approach to access optically active tertiary α-hydroxy-β-ynyl esters with enantiomeric excesses up to 98%.

Key words

alkynylation - propargylic alcohols - tertiary α-hydroxyl esters - kinetic resolution - amino alcohol

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• 10 Typical Procedure for One-Pot Addition and Kinetic Resolution To a solution of 1b (53.4 mg, 0.2 mmol) in THF (3 mL) phenylacetylene (0.33 mL, 3.0 mmol) and ZnMe₂ (1 M in toulene, 2 mL, 2.0 mmol) were added. The mixture was stirred at r.t. for 24 h, and methyl phenylglyoxylate (164 mg, 1.0 mmol) in THF (2 mL) was added via syringe. The resulting solution was stirred at r.t. for additional 30 h, quenched with diluted HCl (1 N, 6 mL), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with PE–EtOAc (20:1, v/v), which afforded (+)-methyl 2-hydroxy-2,4-diphenylbut-3-ynoate as pale yellow oil (104 mg, 0.39 mmol, 39%). [α]_D ²⁰ +14.6 (c 1.0, CHCl₃). IR (film): 3483 (br), 3061, 2954, 2230, 1739, 1490, 1450, 1255, 1184, 1115, 1099, 1069, 757, 693 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.80–7.75 (m, 2 H), 7.58–7.54 (m, 2 H), 7.47–7.33 (m, 6 H), 4.31 (s, 1 H), 3.85 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.4, 139.3, 132.0, 129.0, 128.8, 128.4, 128.3, 126.3, 121.9, 87.0, 86.3, 73.2, 54.3. ESI-HRMS: m/z calcd for C₁₇H₁₄O₃ [M + Na]⁺: 289.0835; found: 289.0831. HPLC [Chiralpak AD-H, hexane–i-PrOH (60:40), 1.0 mL/min, 30 °C, 242 nm]: t _r (major) = 5.8 min; t _r (minor) = 6.8 min, 94% ee.