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.

Key words

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

References and Notes

• 1 Ferreira F. Bejjani J. Denichoux A. Chemla F. Synlett  2004,  2051 
• 2 Chemla F. Ferreira F. Curr. Org. Chem.  2002,  6:  539 
• 3 Chemla F. Bernard N. Ferreira F. Normant JF. Eur. J. Org. Chem.  2001,  3295 
• 4 Chemla F. Ferreira F. Hebbe V. Stercklen E. Eur. J. Org. Chem.  2002,  1385 
• 5 Chemla F. Ferreira F. J. Org. Chem.  2004,  69:  8244 
• 6 Chemla F. Ferreira F. Synlett  2004,  983 
• 7 Ferreira F. Audouin M. Chemla F. Chem. Eur. J.  2005,  11:  5269 
• 8 Palais L. Chemla F. Ferreira F. Synlett  2006,  1039 
• 12 Bharatam PS. Amita . Kaur D. J. Phys. Org. Chem.  2002,  15:  197 
• 13 Bharatam PS. Amita . Uppal P. Kaur D. J. Chem. Soc., Perkin Trans. 2  2000,  43 
• 14 Cainelli G. Galleti P. Giacomini D. Orioli P. Angew. Chem. Int. Ed.  2000,  39:  523 
• 15 Ferreira F. Herse C. Riguet E. Normant J.-F. Tetrahedron Lett.  2000,  41:  1733 
• 16 Poisson J.-F. Normant J.-F. Org. Lett.  2001,  3:  1889 
• 17 Basu A. Thayumanavan S. Angew. Chem. Int. Ed.  2002,  41:  716 
• 18 Hoffmann RW. Julius M. Chemla F. Ruhland T. Frenzen D. Tetrahedron  1994,  50:  6049 
• 19 Hirsch R. Hoffmann RW. Chem. Ber.  1992,  125:  975 
• 20 Jones TK. Denmark SE. Org. Synth.  1985,  64:  182 

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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]].