A short synthesis of L-acosamine based on nitroaldol addition (Henry reaction). Analysis of the key step concerning solvent and temperature effects

Of several routes explored for the synthesis of 3-amino-2,3,6-trideoxyhexos es such as L-acosamine (L-arabino), two versions of the nitroaldol strategy were completed. The silyl nitronate approach with use of "anhydrous" tetra butylammonium fluoride (Bu4NF) turned out to be rather complex, since the k ey step led to a moderately diastereoselective, though still efficient solu tion. In a simpler mode, with Bu4NF trihydrate as a catalyst, the two C-3 b uilding blocks (2-O-benzyl-L-lactaldehyde 1 and 3-nitropropanal dimethyl ac etal 2) are combined to give the respective 3-nitrohexoses 4-7 in ratios ra nging from 37:22:22:19 (i-PrOH, 22 degrees C) to 29:62:1:8 (t-BuOMe, -30 de grees C) for the four diastereomers L-ribo/L-ambino/L-xylo/L-lyxo. In this context efficient analyses (HPLC) and separations (MPLC) of nitroaldol ster eoisomer mixtures were sought and found. This permitted the systematic stud y of the effects of temperature and solvents on such Henry reactions and al lowed the conclusion that higher reaction temperatures (above -10 degrees C ) would alter the kinetic diastereomer ratio (d.r.), due to ensuing retro-n itroaldol reaction and, possibly, some epimerization at the nitromethine (C HNO2) stereocentre. - The L-arabino compound 5 was obtained according to op timized conditions and converted to the N,O-diacetyl derivative 10 of L-aco saminide by acid-catalyzed formation of the nitropyranosides alpha/beta-8, hydrogenation of the nitro group and N,O-diacetylation of the intermediate methyl alpha-L-acosaminide 9. Overall, methyl N,O-diacetyl-alpha-L-acosamin ide 10 is obtained from 2-O-methoxymethyl-L-lactaldehyde 3 and beta-nitropr opionaldehyde dimethyl acetal 2 in 4 steps with 36% yield.