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
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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DOI：
10.1021/ja002376i
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发表时间：
2000-10-18
影响因子：
15
通讯作者：
Jin, Q
中科院分区：
文献类型：
--
作者：
Boger, DL;Weng, JH;Jin, Q
替考拉宁降解为一系列关键苷元衍生物，包括含有裂解FG环系统的苷元衍生物，并对其热阻转异构性进行了详细研究。在所有情况下，观察到DE环系统的选择性平衡，以在AB和CD阻转异构体立体化学不受影响的条件下提供P：M阻转异构体的1：1混合物。发现DE阻转异构体平衡发生，对于6a，E-a为29.3和24.8- 25.2kcal/mol（FG;环系统完好）和10/12（裂解的FG环系统），其与万古霉素糖苷配基DE环系统相当（E-a = 23.6kcal/mol），比CD（E-a = 30.4kcal/mol）或O-甲基化AB环体系（E-a = 37.8kcal/mol）更易形成。与直观预期一致，完整的替考拉宁FG环系统减慢了异构化速率，导致约10%的异构化。4.0替考拉宁无环FG衍生物上的大体积C-2（3）取代基对E-a的影响要小得多，相对于万古霉素糖苷配基，其对E-a的贡献仅为1-1.5 kcal/mol。两者都不排除DE环系统的选择性平衡，并且两者都对所得阻转异构体的热力学比率（1：1）没有影响。描述了从8合成替考拉宁苷元（P、P、P-2）作为从13合成替考拉宁苷元非天然DE阻转异构体（M、P、P-17）的前奏，并提供了替考拉宁苷元总合成酸（关键结构类似物）的最后阶段。2和17的比较评价显示DE阻转异构体立体化学显著影响抗微生物活性（2 > 17，50倍）和对N，N '-Ac-2-L-Lys-D-Ala-D-Ala的结合亲和力（2 > 17，K-a = 2.4 × 10（6）对1.9 × 10（4）M-1，125倍）。
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 C-2(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 acid 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'-Ac-2-L-Lys-D-Ala-D-Ala (2 > 17, K-a = 2.4 x 10(6) vs 1.9 x 10(4) M-1, 125 times).