Synthesis of 1-N-[(2S,4S)- and (2S,4R)-5-amino-4-fluoro-2-hydroxypentanoyl]dibekacins (study on structure–toxicity relationships)

(2S,4S)- and (2S,4R)-5-azido-2-O-benzyl-4-fluoro-2-hydroxypentanoic acids (15 and 19) have been prepared from l-malic acid (1), and coupled to the H2N-1 group of 3,2′,6′-tris(N-benzyloxycarbonyl)-3″-N-(trifluoroacetyl)dibekacin (23), to give, after reduction and deblocking, 1-N-[(2S,4S)- and (2S,4R)-5-amino-4-fluoro-2-hydroxypentanoyl]dibekacins (26 and 27). The fluorinated arbekacin analogs showed almost the same antibacterial activities as that of arbekacin, but lower toxicity. Comparision of the toxicity between 26 (and 27) and the arbekacin analogs (28–30) with change of the 1N-side-chain indicates that the observed decrease in toxicity was a function of the chain length rather than the introduction of flourine.