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4
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84913999586
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Bhisetti, G.R.; Murcko, M.A.; Tung, R.D.; World Patent Appl. no. WO 94/05639, publ. March 17, 1994.
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5
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84913999585
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Gorys, V.; Soucy, F.; Yoakim, C.; Beaulieu, P.L.; Eur. Patent Appl. no. 560269, publ. September 15, 1993.
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6
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84913999584
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Anderson, P.C.; Soucy, E.; Yoakim, C.; Laballée, P.; Beaulieu, P.L.; Eur. Patent Appl. no. 560268, publ. September 15, 1993.
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12
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84913999583
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NG, J.S.; Przybyla, C.A.; Mueller, R.A.; Vazquez, M.L.; Getman, D.P.; World Patent Appl. no. WO 93/23388, publ. November 25, 1993.
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16
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49949128203
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Torsional strain involving partial bonds. The stereochemistry of the lithium aluminium hydride reduction of some simple open-chain ketones
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(1968)
Tetrahedron Letters
, pp. 2199-2204
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Chérest1
Felkin2
Prudent3
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17
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0001399730
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Regio- and stereo-selectivities in some nucleophilic reactions
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(1980)
Top. Curr. Chem.
, vol.88
, pp. 145-162
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Anh1
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19
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84913999582
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® Company.
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21
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0013624593
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Crude aldehyde 3 obtained by this procedure was used directly without purification.
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(1967)
J. Am. Chem. Soc.
, vol.89
, pp. 5505-5507
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Parikh1
Doering2
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22
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0001566115
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When performed on a small scale as described by Reetz, the epoxides were obtained free of epimeric contaminants. However, when scaled-up to larger quantities (〉 10 g), the reaction was found to be very sensitive to temperature control and became unreliable.
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(1989)
Tetrahedron Lett.
, vol.30
, pp. 5425-5428
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Reetz1
Binder2
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27
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84913999581
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While our work was in progress, the addition of chloromethyllithium (generated in situ from alkyllithiums and chloroiodomethane) to chiral N,N-dibenzylaminoaldehydes was reported (ref. 3c and 3d). In both cases, diastereomerically pure epoxides were obtained only after careful chromatography. In addition, the use of highly pyrophoric alkyllithiums in the metal-halogen exchange reaction, the cost of chloroiodomethane and the fact that iodoalkanes are generated as by-products made these procedures less attractive on a large scale.
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28
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84913999580
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All compounds gave analytical and spectroscopic data consistent with their structure. Enantiomeric and diastereomeric purities were determined by HPLC using a Chiralcel OD column.
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29
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84913999579
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No improvement in yield was obtained when the same reaction was performed under sonochemical conditions as reported by Luche (ref. 10d).
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30
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84913999578
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Experimental procedure for the preparation of 4: Aldehyde 3 (2233 g, 6.77 mole) in THF (22 L, reagent grade) was cooled to −76 °C under an argon atmosphere. Lithium shot (4–16 mesh, bruised with mortar / pestle; 4 × 180 g, 104 mole) and bromochloromethane (4 × 245 g, 7.57 mole) were added alternatingly in four equal portions while maintaining an internal temperature below −65 °C at all times (additions were done at 45 min intervals). After complete addition, stirring was continued for 50 min at −70 °C. The solution was separated from floating lithium residues (the excess metal can be recovered for future use) and transferred into 6N HCl (7 L). The mixture was concentrated in vacuo until a clear aqueous layer separated from a gummy, brown residue. The aqueous layer was removed and the residue crystallized from hot methanol (3 L). The crude product was collected, washed with 10% methanol in [[Truncated]]
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31
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84913999577
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The free base of 5 must be generated in presence of the acylating agent to prevent decomposition. Epoxide 1a is of acceptable purity for most purposes but can be purified further by recrystallization from EtOAc-hexane or precipitation of a methanolic solution in a large volume of water. The product was found to be identical in all respects to material produced by other methods (ref. 3a). HPLC analysis (Chiralcel-OD) and comparison to authentic samples of all four possible isomers gave an isomeric purity in excess of 99.5%.
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