| Dr. Jinkai Zhao(1996-2000) |
Directed by Prof. Xinhe Bao and Prof. Xiuwen Han |
| Abstract | Present address: Switzerland |
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Chirality
is a universal phenomenon in nature, and it is also an important sign
for the difference of life and non-life substance. Chiral compounds play
a key role in medicinal, pesticide, materials, biological and life science.
Asymmetric synthesis is an effective method of obtaining optical compound
(chiral compound). Asymmetric catalysis, which employs catalytic amount
of chiral source to realize the chiral catalytic cycle of the asymmetric
catalysis, and synthesizes the chiral product with high optical yield,
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Asymmetric hydroboration is a kind of widely applied and valuable reaction, in which borane reduction of prochiral ketones reaction is an important method. This reaction can be used to prepare some key intermediates from some very simple starting materials, and can also be applied to create the first chiral center during the synthesis of some very complex natural product. Oxazaborolidine, which derive from the coordination of amino alcohol and borane, are good catalysts for the borane reduction reaction. A kind of fused cyclic oxazaborolidine invented by Corey and derived from proline has been successfully used in the production of MK-0417 as excellent chiral catalyst by Merck company. Although many amino alcohols have been developed, but excellent bis-amino alcohols are seldom found. Shanghai Institute of Organic Chemistry and DuPont company cooperated and found an C2 symmetric bis-amino alcohol derived from the natural-rich and cheap tartaric acid, and it showed excellent properties in the borane reduction reaction. But the mechanism of the reaction applying the novel bis-amino alcohol is not clear. Thus we cooperate to study the function and mechanism of this catalyst in the asymmetric borane reduction reaction, and the following results are obtained.
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Employing in situ NMR analytical method, the process of the coordination of the ligand and borane was detected. The slow formation of the catalyst from dynamic stable structure to the thermal stable structure was observed. The key intermediate which can induce high enantioselectivities in the asymmetric borane reduction reaction was proved to be a new type of C2 symmetric bis-centered oxazaboralidine. On the basis of the variations of the energy and the inner-molecular interaction from the modeling result by the molecular mechanics method, the transformation of the structure of the catalyst can be understood.
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The interaction of the catalyst and the substrate was studied by temperature variation NMR technique, and the information of combination of the catalyst and the substrate was detected at low temperature. This signal was proved to be the key intermediate for the catalytic process, thus the performance of the catalyst in the asymmetric catalytic reaction was certified. The mechanism for the novel C2 symmetric bis-centered catalyst applied in the borane reduction reaction was in accord with the mechanism for the single-centered catalyst proposed by Corey et al.
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An abnormal phenomenon was observed during the detection by the temperature variation NMR method: the amount of the monomer of the catalyst decreased with the decrease of the temperature and in the mean time other new species formed. The increase of the dimer of the catalyst with the decrease of the monomer, which had been reported by many literatures, was not observed. No obvious changes of the amount of the dimer or polymer were found in the course of the detection. The reason for the great decrease of the optical yield of the borane reduction reaction at low temperature was explained according to these variations. The decrease of the amount of the catalyst monomer at low temperature was thought to be the reason for the temperature effect. The low asymmetric induction ability of half part of the ligand, which was a single amino alcohol, and the derivative of the ligand with a substituted groups at the amino group were also proved to be related to the same reason: the amount of the effective component formed during coordination was too small.
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Synthesis of some of the derivatives of the ligand was tried in order to study the properties of this series catalyst. According to the synthetic route reported by the literature and on the basis of optimization of the conditions of every synthetic steps, several derivatives with alkyl groups at the chiral carbon were obtained. The asymmetric reaction was not carried out as these ligands can not be dissolved in normal organic solvent. The result of the borane reduction reaction catalyzed by the ethyl substituted precursor of these ligands showed that the asymmetric induction ability of the ligand decreased after a relatively small group was introduced to the chiral carbon comparing with the original benzyl group.