A concise, stereocontrolled synthesis of spectinomycin

A simple and concise synthesis of the antibiotic spectinomycin is described. The key step comprises a reaction cascade initiated by the β-selective 5-O-glycosylation of an N,N-blocked myo-1,3-inosadiamine 10 with a suitable actinospectosyl donor—the d-glucose-derived enol benzoate of 4,6-dideoxy-α-d-hex-3-enulosyl chloride 5—which is spontaneously followed by regio- and stereospecific cyclo-hemiketalization and a 3-O→2-O-benzoyl group migration to directly elaborate the cis–cisoid–trans-fused pyran–dioxane–cyclohexane framework of 1. The approach is flexible enough to be applied to other inosadiamines towards the generation of novel spectinomycin analogues.

Figure optionsDownload as PowerPoint slide

(2S,6R)-2,4-Bis(benzoyloxy)-6-methyl-2H-pyran-3(6H)-one (1,3-di-O-benzoyl-β-actinospectose)C20H16O6[α]D22=-89 (c 1, CHCl3)Source of chirality: d-glucose

(2S,6R)-2-Chloro-4-benzoyloxy-6-methyl-2H-pyran-3(6H)-one (3-O-benzoyl-α-d-actinospectosyl chloride)C13H11ClO4[α]D22=+151 (c 1, CHCl3)Source of chirality: d-glucose

Spectinomycin dihydrochloride pentahydrateC14H24N2O6·2HCl·5H2O[α]D20=+14.3 (c 1.1, H2O)Source of chirality: d-glucose

N,N-Bis(benzyloxycarbonyl)-spectinomycinC30H36N2O11[α]D = −4.3 (c 0.9, CHCl3)Source of chirality: d-glucose

2′-O-Benzoyl-N,N-bis(benzyloxycarbonyl)-spectinomycinC37H40N2O12[α]D20=-5.3 (c 0.9, CHCl3)Source of chirality: d-glucose