Boc-L-isoleucine methyl ester → 1,1-Dimethylethyl N-((1S,2S)-1-formyl-2-methylbutyl)carbamate

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Reaction Conditions

Reaction Steps

A mixture of L-isoleucine methyl ester (24.3 g., 0.134 mmoles) and triethylamine (13.5 g., 0.134 mmoles) in methylene chloride (210 ml.) was prepared and a solution of ditertbutyldicarbonate (Aldrich, 29.1 g., 0.134 mmoles) in methylene chloride (25 ml.) was added dropwise to this mixture at 0° C. After completion of this addition, the mixture was allowed to warm to room temperature overnight and was then filtered. The filtrate was washed successively with H2O (3×75 ml.), aqueous 0.1N HCl solution, H2O (1×100 ml.) and saturated aqueous NaHCO3 solution (1×75 ml.), dried (MgSO4) and evaporated to yield N-(t-butyloxycarbonyl)-L -isoleucine methyl ester as an oil [30.7 g; 93% yield; lH-NMR (CDCl3): delta 0.92 (d, J=7, 6H), 1.43 (s, 9H), 3.70 (s, 3H), 4.17 (dd, J=5, 9, 1H), 5.03 (d, J=9, 1H)]. A solution of the N-(t-butyloxycarbonyl)-L-isoleucine methyl ester oil (15.0 g., 61.1 mmoles) in dry toluene (260 ml.) was cooled to -78° C., and a 1M solution of diisobutyl aluminum hydride in hexane (153 ml.) was added dropwise thereto at such a rate that the temperature of the exothermic reaction did not exceed -65° C. Followed by 15 minutes of additional stirring at -78° C. After completion of this addition, the mixture was carefully quenched with 15 ml. of methanol (the mixture temperature was not allowed to exceed -65° C.) followed by 200 ml. of Rochelle salt solution. After warming to room temperature, the organic layer was separated and extracted with ether (3×200 ml.); additional Rochelle salt solution was added when necessary to dissolve the aluminum salts. The combined organic extract was dried (Na2SO4 ) and evaporated to afford a crude product as an oil. The oil was stored at -78° C. to avoid possible racemization and was used without purification in the next step [132 g.; 98% yield; Rf =0.32 in 35% ether in hexane; 1H-NMR (CDCl3) delta 1.00 (d, J=7, 6 H), 1.46 (s, 9H), 9.65 (s, 1H)].

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