The binding affinity of 4, which incorporates a methylene (CH2) in place of the key linking amide of Ac2-l-Lys-d-Ala-d-Ala, for vancomycin was compared with that of Ac2-l-Lys-d-Ala-d-Ala (3) and Ac2-l-Lys-d-Ala-d-Lac (5). The vancomycin affinity for 4 was approximately 10-fold less than that of 3, but 100-fold greater than that of 5. This suggests that the reduced binding affinity of 5 (4.1 kcal/mol) may be attributed to both the loss of a key H-bond (1.5 kcal/mol) and a destabilizing lone pair/lone pair electrostatic interaction introduced with the ester oxygen of 5 (2.6 kcal/mol) with the latter, not the H-bond, being responsible for the largest share of the 1000-fold reduction.

An effective synthesis of [Ψ[CH 2 NH]Tpg 4 ]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac countering resistance endowed to bacteria that remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester O for amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CD ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity) completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K a = 5.2 × 10 3 M −1 ) and a 35-fold reduction in affinity for D-Ala-D-Ala (K a = 4.8 × 10 3 M −1 ) providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 μg/mL) against a VanA resistant organism that remodels its D-Ala-D-Ala cell wall precursor to D-Ala-D-Lac upon glycopeptide antibiotic challenge displaying a potency that reflects these binding characteristics.The most common strains of enterococci resistant to vancomycin (1), VanA and VanB, possess an inducible resistance pathway in which the terminal dipeptide of the cell wall peptidoglycan precursor is modified from D-Ala-D-Ala to D-Ala-D-Lac. 1 Binding of the antibiotic to this modified ligand is reduced 1000-fold leading to a 1000-fold drop in antimicrobial activity. 1d,k In a recent disclosure, 2 we provided the first experimental study on the origin of this loss in binding affinity, partitioning the effect into lost H-bond and repulsive lone pair contributions, Figure 1. Thus, the binding affinity of vancomycin for 3, which incorporates a methylene (CH 2 ) in place of the linking amide NH of Ac 2 -L-Lys-D-Ala-D-Ala, was compared with that of Ac 2 -L-Lys-D-Ala-D-Ala (2) and Ac 2 -L-Lys-D-Ala-D-Lac (4). The vancomycin affinity for 3 was approximately 10-fold less than that of 2, but 100-fold greater than that of 4. This indicated that the reduced binding affinity of 4 (4.1 kcal/mol) may be attributed to both the loss of a key H-bond and a destabilizing lone pair/lone pair interaction introduced with the ester oxygen of 4 (2.6 kcal/mol) with the latter, not the H-bond, being responsible for the greater share (100-fold) of the 1000-fold binding reduction. The...

The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.

An appropriately constructed 2-substituted derivative of L-tryptophane undergoes conversion, in a single step, to a prephalarine structure. The reaction occurs in a diastereoselective fashion, leading shortly thereafter to the naturally occurring version of the alkaloid, phalarine.