American Chemical Society
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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

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journal contribution
posted on 2000-10-03, 00:00 authored by Dale L. Boger, Jian-Hui Weng, Susumu Miyazaki, J. Jeffrey McAtee, Steven L. Castle, Seong Heon Kim, Yoshiki Mori, Olivier Rogel, Harald Strittmatter, Qing Jin
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 Ea 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 (Ea = 23.6 kcal/mol) and more facile than the CD (Ea = 30.4 kcal/mol) or O-methylated AB ring system (Ea = 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 Ea (6a vs 10), and the bulky C23 substituent on teicoplanin acyclo FG derivatives had a much less significant effect, contributing only 1−1.5 kcal/mol to the Ea 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, Ka = 2.4 × 106 vs 1.9 × 104 M-1, 125 times).