Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

被引:81
|
作者
Khomutnyk, Yaroslav Ya. [1 ]
Argueelles, Alonso J. [1 ]
Winschel, Grace A. [1 ]
Sun, Zhankui [1 ]
Zimmerman, Paul M. [1 ]
Nagorny, Pavel [1 ]
机构
[1] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA
基金
美国国家科学基金会;
关键词
INTRAMOLECULAR MICHAEL ADDITION; ASYMMETRIC-SYNTHESIS; STEREOCONTROLLED SYNTHESIS; CHEMICAL GLYCOSYLATION; TRANSITION-STATE; DIASTEREOSELECTIVE SYNTHESIS; KINETIC SPIROCYCLIZATION; BETA-MANNOPYRANOSIDES; COOPERATIVE CATALYSTS; GLYCAL EPOXIDES;
D O I
10.1021/jacs.5b12528
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S(N)1-like, S(N)2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective synselective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (rho = -2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 +/- 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value.
引用
收藏
页码:444 / 456
页数:13
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