Synthesis of 3'-Deoxykanamycin B (Tobramycin)

Abstract

3'-Deoxykanamycin B (tobramycin) [19] was synthesiz ed from kanamycin B by a sequence of reactions involving 6'-N-benzyloxycarbonylation, N-tosylation, 4", 6"-O-cyclohexylidena tion, 4'-O-carbonylation, 3'-O-sulfonylation, and 3'-halogenation. Selective sulfonyla tion of [5 ] gave T-O-sulfonyl derivatives ([6] [9], [12]) as major products and 2", 3'di-O-sulfonyl derivatives ([7], [10], [13]) as minor products (Table 1). Therefore, the reactivity order of hydroxyl groups of [ 5 ] was 3'→2"→5-. Halogenation of the 3'-O-sul fonyl derivatives was easily performed with sodium iodide or lithium chloride in N, N-dimethyl formamide in spite of a bulky axial group at 1'. The 2", 3'-di-O-benzylsulfonyl derivativ[7] gave 3_eq'-chloro-2''-O-benzylsulfonyl derivative [17] via 3_ax'-chloro-2''-O-benzylsulfony derivative [16]by double S_N, 2 mechanism. Treatment of the 3'-halogeno derivatives wits sodium in liquid ammonia gave the 3'-deoxy derivative, the N-tosyl groups being simultaneous ly removed. Subsequent removal of the other protecting groups gave [19] in =30% of overall yield from kanamycin B, via [1 ]→[ 2]→[3]→[5]→([6], [7])→([15], [17]).