Synthesis of Diastereoenriched Acetylenic α-N-tert-Butanesulfinamidoalkyl Methoxymethyl Ethers

Abstract

The reaction of racemic 3-alkoxy allenylzinc species (±)-1, derived from (methoxymethyl)[(3-trimethylsilyl)prop-2-ynyl]ether (2), with enantiopure (S _S)-N-tert-butanesulfinimines 3 leads to the corresponding diastereomerically enriched acetylenic (S _S,3S,4R)-α-N-tert-butanesulfinamidoalkyl methoxymethyl ethers 4 with an excellent stereoselectivity.

asymmetric synthesis - chiral resolution - diastereo­selectivity - transition states - zinc

References and Notes

1 Ferreira F. Bejjani J. Denichoux A. Chemla F. Synlett  2004,  2051 

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(Methoxymethyl)[(3-trimethylsilyl)prop-2-ynyl]ether (2) was prepared in a two-step procedure from propargyl alcohol by (i) silylation at the acetylenic position [20] followed by (ii) treatment of the resulting product with an excess of dimethoxymethane in CHCl₃ in the presence of an excess of P₂O₅.

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Typical Procedure for the Synthesis of α-Sulfinamido-alkyl Ethers 4: Under a nitrogen atmosphere, at -80 °C, to a stirred solution of propargylic ether 2 (760 µL, 4.0 mmol) and TMEDA (60 µL, 0.4 mmol) in anhyd Et₂O (40 mL) was added dropwise s-butyllithium (1.3 M in cyclohexane-hexane, 3.1 mL, 4.0 mmol). The resulting clear orange mixture was stirred for 1 h at -80 °C and then a 1.0 M etheral solution of ZnBr₂ (4.0 mL, 4.0 mmol) was added. The resulting white slurry of allenylzinc (±)-1 (4.0 mmol) was stirred at -80 °C for an additional 15 min before the appropriate enantiopure (S _S)-N-tert-butanesulfinimine 3 (>99% ee, 1.0 mmol) in anhyd Et₂O (2 mL) was cannulated slowly over a period of 45 min via a syringe pump (for imines 3a-c) or rapidly over a period of 2 min (for imines 3d-g,i). After 1 h of stirring at -80 °C, aq 1.0 M HCl (40 mL) was added and the mixture was warmed to r.t. The layers were separated and the aqueous one was extracted with Et₂O (3 × 20 mL). The combined organic layers were washed with a sat. aq solution of NaHCO₃ (10 mL), water (20 mL) and brine (20 mL), dried over anhyd MgSO₄ and concentrated in vacuo to give an orange oil. The crude product was purified by flash chromatography over silica gel (gradient of eluent: 0-50% Et₂O in pentane) to lead to the corresponding α-sulfinamidoalkyl ether 4.

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CCDC 611562 contains the supplementary crystallographic data for compound 4g. These data can be obtained free of charge via www.ccdc.ac.uk/conts/retrieving.html [or from Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK. Fax: [phone]. E-mail: [e-mail]].

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