Macrolides by Biljana Arsic Predrag Novak Jill Barber Maria Grazia Rimoli Goran Kragol Federica Sodano

Author:Biljana Arsic, Predrag Novak, Jill Barber, Maria Grazia Rimoli, Goran Kragol, Federica Sodano
Language: eng
Format: epub
Publisher: Walter de Gruyter
Published: 2018-05-27T04:00:00+00:00

2.5.3Macrolactone ring reconstruction

The ring reconstruction methodology of the macrolactone skeleton is also a very interesting platform that could enable the synthesis of novel classes of hybride macrolide antibiotics. An illustrative example is the synthesis of 11a-azalides possessing a variety of substituents in the C12 and/or C13 position [48–50]. The 11,12-diol moiety of the suitable protected erythromycin skeleton 146 can be oxidatively cleaved by treatment with lead tetraacetate to afford aldehyde 147 (Scheme 2.27). As β-ketoaldehyde moiety is unstable under reductive amination conditions, a subsequent reductive amination step with appropriate amino alcohols was conducted on structures bearing 9-OH or 9-E-oxime moiety instead to afford 148. After successive hydrolysis of the remaining original C12–13 residue from 149, the resulting acyclic skeleton 150 was cyclized by a macrolactonization reaction to provide 11a-azalide 151. The structural diversity can be generated via insertion of appropriately functionalized amino alcohols or via N-alkylation of an inserted secondary amine. An interesting example is the preparation of 11a-azaketolide 155 bearing an aryl side chain attached to the C13.

Scheme 2.27: The synthesis of 11a-azalides. Reagents and conditions: a) NaBH4, ethanol (79%); b) TESCl, imidazole, DMF (96%); c) Pb(OAc)4, DCM; d) 148, NaBH(OAc)3; e) HCHO (aq), NaBH(OAc)3; f) LiOH, THF/ethanol/water; g) 2,4,6-Cl3C6H2COCl, triethylamine, THF; h) DMAP, CH3CN, reflux; i) H2, Pd(OH)2, THF (53%); j) 153, DEAD, PPh3, THF; k) HF–pyridine, THF (36% over two steps).

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