L-Acosamine

Several approaches based on nitro-aldol for the synthesis of amino sugars have been reported Alumina-catalyzed reaction of methyl 3- nitropropanoate with O-benzyl-o-lactaldehyde gives the o-ribo-nitro-aldol fanti, and isomeri in 63% yield, which is converted into L-dannosamine fsee Secdon 3 3 Jager and coworkers have reported a short synthesis of L-acosamine based on the stereoselective nitro-aldol reaction of 2-O-benzyl-L-lactaldehyde with 3-nitropropanal dimethyl acetal as shovm in Scheme 3 10 The stereoselecdve nitro-aldol reacdon is carried ont by the silyl nitronate approach as discussed in Secdon 3 3... 

Examples for the use of acetals such as 3, of 3-nitropropanal (1), and of 3-nitropropanol (2) or its O-protected derivatives are given in the references.22-24 A recent, notable application from this group is a short, high-yield synthesis of l-acosamine,25 the arabino isomer of 3-amino-2,3,6-trideoxyhexoses that form part of many antitumor aminoglycoside antibiotics 26... 

An intramolecular [3 + 2] nitrone cycloaddition reaction has been employed in the chiral assembly of L-acosamine and L-daunosamine (81JA3956). Heating the masked aldehyde (503) with the oxalate salt of (-)-(S)-7V-hydroxy-a-methylbenzenemethanamine generated a nitrone which underwent intramolecular cycloaddition to give an 82 18 mixture of diastereomers (504) and (505). The N—O bond of the major isomer was cleaved with zinc... 

SCHEME 13.52 Fuganti s synthesis of A -trifluoroacetyl-L-acosamine. Copyright 2006 by Taylor Francis Group LLC... 

A simple, divergent, asymmetric synthesis of the four stereoisomers of the 3-amino-2,3,6-trideoxy-L-hexose family was proposed by Dai and coworkers [222], which is based on the Katsuki-Sharpless asymmetric epoxidation of allylic alcohols (Scheme 13.115). Recently, A-trifluoroacetyl-L-daunosamine, A-trifluoroacetyl-L-acosamine, A-benzoyl-D-acosamine and A-benzoyl-D-nistosamine were derived from methyl sorbate via the methyl 4,5-epoxy-( -hex-2-enoates obtained via a chemoenzymatic method [223]. 

Addition of acetone cyanohydrin to 606 in the presence of a catalytic amount of triethyl-amine affords cyanohydrin 607 as a mixture of isomers. Ketalization with cyclohexanone dimethyl acetal gives a near statistical mixture (45 55) of (2S, 3 S)-608 and (2R, 3 S)-609, which is separable by column chromatography (96% overall yield). Each isomer, with an optical purity greater than 95%, is a versatile intermediate, and they have been used in the synthesis of amino sugars A-benzoyl-L-acosamine (614) [189] (Scheme 85) and A-benzoyl-L-daunosamine (615) [190]. 

In the synthesis of L-acosamine, condensation of the predominant isomer 609 with the magnesium enolate of tert-hutyl acetate gives 610 in 54% yield. Acetylation to 611 (77% yield) and subsequent catalytic hydrogenation in an autoclave (70 Kg/cm ) furnishes 612 as a single isomer. Acid hydrolysis of the ketal, benzoylation under Schotten—Baumann conditions, and lactonization affords 613. Reduction of the lactone to a lactol with diisobutyl-aluminum hydride gives N- benzoyl-L-acosamine (614) as an anomeric mixture. 

The racemic and L forms of the epoxide 101 were next employed for the preparation of dl- and L-acosamines (114, 3-amino-2,3,6-trideoxy-DL- and l-arabino-he osss), stereoisomers of daunosamine. 

In the synthesis of N-acetyl-L-acosamine (115), the first step, consisting in formation of 108, could not be used because of the potential danger of racemiza-tion. Therefore, the methyl ester of the optically active epoxide 101 was re-giospecifically opened with t-butanol in the presence of boron trifluoride to methyl irons 4-0-t-butyl-2,3,6-trideoxy-L-eo r/iro-hex-2-enoate (117). The free OH group of 117 was protected with 2 -tetrahydropyranyl and the remaining steps of the synthesis were performed as in the case of the racemic compound 108. 

G. Fronza, C. Fuganti, P. Crasselli, L. Majori, G. Pedrocchi-Fantoni, and F. Spreaflco, Synthesis of enantiomerically pure forms of N-acyl derivatives of C-methyl analogues of the aminodeoxy sugar L-acosamine from non-carbohydrate precursor," J. Org. Chem., 47, 3289 (1982). 

Another method for synthesis of useful derivatives of L-acosamine and L-daunosamine from rhamnal 23 was based on addition of chlorosulfonyl isocyanate to 2,3-unsaturated pyranosides 73 [66,67]. Since the anomeric alkyl substituent in this reaction ends up as the carbamate ester, aUyl glycoside securing easy deprotection was chosen for elaborating this reaction into large laboratory scale technical process. Method development for acosam-inal derivative 74 involved multiparameter optimization of the isocyanate addition step by exploration of the reaction response surface. The final daunosaminyl glycosylation synthon 76 was obtained in overall 35% yield (Scheme 12) [68]. 

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