Copper(I) Iodide-Catalyzed Asymmetric Synthesis of Optically Active Tertiary α-Allenols

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A facile CuI-catalyzed asymmetric synthesis of chiral tertiary α-allenols with up to 95% ee starting from common tertiary propargylic alcohols and aldehydes has been developed. The amount of chiral ­ligand used in this transformation can be as low as 2.5 mol%.

Key words

copper catalysis - asymmetric synthesis - allenols - propargylic alcohols - aldehydes

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• 10 1-[(1S)-4-Methylpenta-1,2-dien-1-yl]cyclohexanol [(S)-3ab]; Typical ProcedureA flame-dried Schlenk tube with a poly(tetrafluoroethylene) plug was charged with CuI (19.1 mg, 0.1 mmol), (R,S _a)-N-PINAP (14.1 mg, 0.025 mmol), and 1,4-dioxane (5 mL) under argon, and the mixture was stirred at r.t. for 30 min. Propargylic alcohol 1a (123.7 mg, 1 mmol)/1,4-dioxane (1 mL), aldehyde 2b (115.8 mg, 1.6 mmol)/1,4-dioxane (1 mL), and azocane (161.9 mg, 1.4 mmol)/1,4-dioxane (1 mL) were then added sequentially under argon. The mixture was then stirred at r.t. until the reaction was complete (TLC, ~1 h). The Schlenk tube was then placed in a preheated oil bath at 130 °C with stirring. After 8 h, the crude mixture was diluted with Et₂O (10 mL) and washed with 3 M aq HCl (10 mL). The organic layer was separated, and the aqueous layer was extracted with Et₂O (2 x 10 mL). The combined organic layer was washed with brine, dried (Na₂SO₄), filtered, and concentrated to give a residue that was purified by chromatography [silica gel, PE–EtOAc (20:1)] to give a liquid; yield: 97.0 mg (54%, 92% ee); [α]_D ²⁸ +80.8 (c 1.005, CHCl₃).HPLC [Chiralcel AD-H column, hexane–i-PrOH (95:5), 0.5 mL/min, λ = 214 nm]: t _R(major) = 11.8 min; t _R(minor) = 10.9 min. IR (neat): 3343, 2958, 2927, 2859, 1961, 1598, 1494, 1463, 1446, 1410, 1380, 1360, 1345, 1318, 1297, 1246, 1192, 1176, 1163, 1146, 1112, 1088, 1058, 1038 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 5.38-5.30 (m, 2 H, CH=C=CH), 2.41-2.27 (m, 1 H, CH), 1.79-1.41 (m, 10 H, protons from 5 × CH₂ + OH), 1.40–1.25 (m, 1 H, proton from CH₂), 1.030 (d, J = 6.8 Hz, 3 H, CH₃), 1.026 (d, J = 6.4 Hz, 3 H, CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 199.6, 102.3, 101.6, 70.5, 38.4, 38.3, 27.9, 25.5, 22.51, 22.47, 22.4. MS (EI): m/z (%) = 180 (M⁺, 1.51), 99 (100). HRMS: m/z [M⁺] calcd for C₁₂H₂₀O: 180.1514; found: 180.1512.
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