Total Synthesis of Kanamycins

Abstract

Structurally modified aminoglycosides, such as kanamycin, have shown promise as antibiotics and premature termination codon read-through drugs to fight against drug-resistant bacteria and to treat genetic diseases, respectively. Therefore, research on developing and discovering aminoglycoside antibiotics has recently increased. However, synthetic strategies for controllably positioning the two 1,2-cis-glycoside moieties on the symmetrical structure of kanamycin have not yet been established. Herein, we report on a novel route for the total synthesis of kanamycins A and B via regio- and stereoselective introduction of 1,2-cis-glycosidic linkages as the key step. We successfully synthesized α(1,6)-linked glycoside using a 1,2-anhydro donor and 2-deoxy-myo-inositol 1,3,5-orthoformate acceptor in the presence of a boronic acid catalyst via desymmetric boron-mediated aglycon delivery. In addition, we also synthesized α(1,4)-linked glycoside using its corresponding trichloroacetimidate donor.

Keywords: boron‐mediated aglycon delivery; desymmetrization; glycosylation; kanamycin; total synthesis.

Figure 1

Chemical structures of aminoglycoside antibiotics.

Figure 2

(A) Nakajima's and (B) Umezawa's total synthesis of kanamycin A. (C) Synthesis of kanamycin analogs using neomycin B. (D) Desymmetric BMAD reaction of 1,2‐anhydro donor 14 and meso‐diol 15. LG = leaving group, Cbz = benzyloxycarbonyl, Bn = benzyl, Ac = acetyl, TBS = tert‐butyldimethylsilyl, Ar = aryl.

Scheme 1

Retrosynthetic analysis of kanamycin A.

Scheme 2

(A) Synthetic scheme of meso‐diol 24. (B) Synthetic scheme of 1,2‐anhydro donor 25. (C) Desymmetric BMAD reaction of 24 and 25. Et = ethyl, Ts = toluenesulfonyl, DMF = N,N‐dimethylformamide, Tf = trifluoromethanesulfonyl, AIBN = 2,2′‐azobis(isobutyronitrile), TBAI = tetra‐n‐butylammonium iodide, Me = methyl, MeCN = acetonitrile, DCM = dichloromethane, THF = tetrahydrofuran, DMDO = dimetyldioxyrane.

Scheme 3

(A) Total synthesis of kanamycin A (1) and (B) kanamycin B (2). DIPEA = N,N‐diisopropylethylamine, DMAP = N,N‐4‐dimethylaminopyridine, Bz = benzoyl, Ph = phenyl, TMSOTf = trimethylsilyl trifluoromethanesulfonate, MS = molecular sieves, TMSOK = potassium trimethylsilanolate.