Stereocontrolled Synthesis of (+)-Negamycin by 1, 3-Asymmetric Induction

Abstract

Negamycin, [2-[(3 R, 5R)-3, 6-diamino-5-hydroxyhexanoy1]-1-methylhydrazino]acetic acid, which possesses a strong inhibitory activity against Gram-negative bacteria, has been synthesized in a highly stereocontrolled manner. A combination of enzymatic and chemical procedures was taken as our synthetic strategy.
The 3 R-absolute configuration was created by the enzyme-mediated asymmetric hydrolysis of the prochiral dimethyl 3-(benzyloxycarbonylamino)glutarate. The remaining 5 R-absolute configuration was introduced by the newly developed iodocyclocarbamation with high 1, 3asymmetric induction. Thus, the enzymatically produced chiral half ester, methyl hydrogen (3 S)-3-(benzyloxycarbonylamino)glutarate, was chemically converted to t-buty1(3 R)-3-benzyloxycarbonylamino5-hexenoate in 4 steps, and treatment of the N-(t-butyldimethylsily1)derivative with iodine afforded preferentially trans-cyclic carbamate, effecting high 1, 3-asymmetric induction. Further transformation of the. functional groups efficiently afforded the desired key intermediate, (3 R, 5 R)-6-azido-3-benzyloxycarbonylamino-5-(tetrahydropyran -2yloxy)hexanoic acid, which was then converted to natural negamycin in good overall yields.