First and second generation total synthesis of the teicoplanin aglycon.

Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.

Synthesis of glycophostones: cyclic phosphonate analogues of biologically relevant sugars

Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction.

Synthesis of a phostone glycomimetic of the endothelin converting enzyme inhibitor phosphoramidon.

The phostone analog of phosphoramidon, an inhibitor of endothelin converting enzyme, was synthesized from L-rhamnose. Coupling of the cyclic phosphonic acid with the dipeptide H-Leu-Trp-OMe gave, after deprotection and purification by reverse-phase HPLC, the desired phostone which exhibited an IC50 of 5.05+/-2.7 microM.