Thermal Atropisomerism of Teicoplanin Aglycon Derivatives:  Preparation of the P,P,P and M,P,P Atropisomers of the Teicoplanin Aglycon via Selective Equilibration of the DE Ring System

The degradation of teicoplanin to a series of key aglycon derivatives, including those containing a cleaved FG ring system, and a study of their thermal atropisomerism are detailed. In all cases, selective equilibration of the DE ring system was observed to provide a 1:1 mixture of P : M atropisomers under conditions in which the AB and CD atropisomer stereochemistry were unaffected. The DE atropisomer equilibration was found to occur with an E a of 29.3 and 24.8−25.2 kcal/mol for 6a (FG ring system intact) and 10/12 (cleaved FG ring system), respectively, which is comparable to that of a vancomycin aglycon DE ring system (E a = 23.6 kcal/mol) and more facile than the CD (E a = 30.4 kcal/mol) or O-methylated AB ring system (E a = 37.8 kcal/mol). Consistent with intuitive expectations, the intact teicoplanin FG ring system slowed the rate of isomerization, contributing ca. 4.0 kcal/mol to the E a (6a vs 10), and the bulky C2 3 substituent on teicoplanin acyclo FG derivatives had a much less significant effect, contributing only 1−1.5 kcal/mol to the E a relative to the vancomycin aglycon. Neither precludes selective equilibration of the DE ring system, and neither had an effect on the thermodynamic ratio of the resulting atropisomers (1:1). Resynthesis of the teicoplanin aglycon (P,P,P-2) from 8 as a prelude to the synthesis of the teicoplanin aglycon unnatural DE atropisomer (M,P,P-17) from 13 is described and provides the final stages of a teicoplanin aglycon total synthesis and a key structural analogue. The comparative evaluation of 2 and 17 revealed that the DE atropisomer stereochemistry substantially impacts the antimicrobial activity (2 > 17, 50-fold) and the binding affinity for N,N ‘-Ac2-L-Lys-D-Ala-D-Ala (2 > 17, K a = 2.4 × 106 vs 1.9 × 104 M-1, 125 times).