Macrocyclic lactones can be prepared from lactams and hydroxyacid derivatives via an efficient 3- or 4-atom iterative ring expansion protocol. The products can also be expanded using amino acid-based linear fragments, meaning that macrocycles with precise sequences of hydroxy- and amino acids can be assembled in high yields by "growing" them from smaller rings, using a simple procedure in which high dilution is not required. The method should significantly expedite the practical synthesis of diverse nitrogen containing macrolide frameworks.

Astrategy for the synthesis of medium-sized lactones and lactams from linear precursors is described in whicha n amine acts as an internal nucleophilic catalyst to facilitate an ovel cyclisation/ring expansion cascade sequence.T his method obviates the need for the high-dilution conditions usually associated with medium-ring cyclisation protocols,a s the reactions operate exclusively via kinetically favourable "normal"-sized cyclic transition states.T his same feature also enables biaryl-containing medium-sized rings to be prepared with complete atroposelectivity by point-to-axial chirality transfer.

Backbone-homologated amino acids have been synthesized, containing three vicinal fluorine atoms placed stereospecifically along the carbon chain. Different trifluoro stereoisomers are found to have contrasting conformations, consistent with known stereoelectronic effects associated with C-F bonds.

The outcomeo fr ing-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previousw ork on Successive Ring Expansion (SuRE) methods, detailse fforts to betterd efine the scope andl imitations of these reactions on lactam and b-ketoester ring systems with respecttoring size and additional functionality. The synthetic resultsp rovide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using ad ensity functional theory(DFT) approach. Calculating the relative Gibbs free energies of the three isomeric speciest hat are formed reversibly duringr ing expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational resultsa re expected to support the design of new lactam-a nd b-ketoester-based ring-expansion reactions. Scheme1.Side-chain insertion ring-expansion reactionsand Successive Ring Expansion (SuRE).

A revised total synthesis of aurachin D (1a), an isoprenoid quinolone alkaloid that targets Mycobacterium tuberculosis (Mtb) cytochrome bd (cyt-bd) oxidase, was accomplished using an oxazoline ring-opening reaction. The ring opening enabled access to a range of electron-poor analogues, while electron-rich analogues could be prepared using the Conrad–Limpach reaction. The aryl-substituted and side-chain-modified aurachin D analogues were screened for inhibition of Mtb cyt-bd oxidase and growth inhibition of Mtb. Nanomolar inhibition of Mtb cyt-bd oxidase was observed for the shorter-chain analogue 1d (citronellyl side chain) and the aryl-substituted analogues 1g/1k (fluoro substituent at C6/C7), 1t/1v (hydroxy substituent at C5/C6) and 1u/1w/1x (methoxy substituent at C5/C6/C7). Aurachin D and the analogues did not inhibit growth of nonpathogenic Mycobacterium smegmatis, but the citronellyl (1d) and 6-fluoro-substituted (1g) inhibitors from the Mtb cyt-bd oxidase assay displayed moderate growth inhibition against pathogenic Mtb (MIC = 4–8 μM).