| Summary: | 博士 === 國立清華大學 === 化學系所 === 105 === The reaction mechanisms of Wittig rearrangement and Nicholas reaction for glucose derivatives are studied using density functional theory (DFT) and ab initio methods. In cooperation research with Prof. Isobe, [2,3]-Wittig rearrangement of sugar-derived dihydropyran (dhp) allyl propargyl ether was applied in the synthesis, but the unexpected [1,2]-Wittig rearrangement were observed in experiment. UM06-2X/6-31+G(d) calculations were done to explore the regiocontrol in the Wittig rearrangement. The computational results show that different rearrangement products formed through different mechanisms depending on the R1 and R3 substituents of the dhp reactant. With an R1=O-iPr and R3=TMS-ethynyl group, an inversed stepwise [2,3]-process (first C3−C2 bond formation, then C1−O bond cleavage) is preferred. Without the R3 substituent, the regular stepwise pathway (first C1−O bond cleavage, then C3−C2' bond formation) is favored and the major [1,2]-product is formed. Without any R1 and R3 substituents, a concerted [2,3]-process is favored.
A solvent effect on the Wittig rearrangement was observed in the experiments, which is believed to originate from the coordination between Li + ion and tetrahydrofuran (THF). An extended study of the solvent and chelation effects was done using the CASSCF and DFT methods. Both the homolytic and heterolytic stepwise mechanism were examined. For the rearrangement of diallyl ether, the singlet diradical character is found in the transition state of C1−O bond cleavage, but a stable ionic pair intermediate should be formed. For the rearrangement of allyl propargyl ether, the bond cleavage mechanisms are controlled by the coordination of Li+ ion. The homolytic mechanism is observed with the coordination to the propargyl C4' atom, while that of the heterolytic mechanism is to the allyl C3 atom. The reaction modes are controlled by the coordination of Li+ ion to the solvent and substituent heteroatoms. The [2,3]-Wittig rearrangement is favored when the Li+ ion is coordinated to solvents; the [1,2]- is favored while the Li+ ion chelated by the ether oxygen and substituent methoxy oxygen on C4. The Nicholas epimerization reaction for the aziridinyl (azi) glycoside with two reactive sides was applied in the synthesis of Zanamivir by Prof. Isobe. However, the expected β-epimer product was not obtained in experiment. DFT calculations are used to rationalize the difference in reactivity for the Nicholas epimerization and substitution with azi and dhp glycosides. Six possible pathways are explored, and the rate determining steps in each path control the stereochemistry of C1. The results indicate the substituents, which can increase the rigidity of the backbone, slow down the epimerization reactions, so that the Nicholas substitution dominates.
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