Green And Efficient Strategies For Regioselective Protection Of Hydroxyl Groups

Selective protection strategy has always been a research hot spot in organic chemistry, especially in carbohydrate chemistry. There are two most important research topics in carbohydrate chemistry:one is to develop selective protection strategies to the hydroxyl groups which can be applied on the synthesis of building blocks; the other is to develop stereoselective glycosylation strategies which can be applied on the synthesis of oligosaccharides. The often used protection groups are acyl group, benzyl group, alkyl group and silane group. The often used protection methods include the organotin based protections, organoboron catalyzed protections and metal salts based protections. Although the organotin based reaction is easy to operate, leads to high selectivities, and has been used for many years, its potential toxicity limits its uses. So it is imperative to develop green, efficient and widely used catalysts that can replace organotin. An in-depth study on this topic was done in this paper which led to a series of research results.This paper first reviewed the development and research progress of green and efficient selective protection in carbohydrate chemistry in recent years, introduced protection methods based on organotin reagents, organoboron reagents, organosilicon reagents and metal salts (Ag2O, complex of copper, etc.), and further analyzed their advantages and disadvantages. Our researches are presented in three aspects in this thesis.1. Our laboratory previously developed tetrabutyl ammonium acetate catalyzed selective acetylation of diols substrates. Based on this we performed deep research in the mechanism, explored the reactions and extended it to selective acetylation and diacetylation of polyols. Theoretical calculation study and NMR test of kinetic isotope effect supported the proposed mechanism that the double hydrogen bond plays key role in the reactions. The zemplen condition is often used in deacylation because it was thought that sodium hydroxide could not catalyze the deacylation, but only sodium methoxide could completely catalyze the deacylation. We have demonstrated that the sodium hydroxide can also catalyze the deacetylation reactions by a large number of control experiments and a series of reactions with different substrates. We proposed a H-bonding activation mechanism which was further supported by theoretical calculation and NMR kinetic isotope effect tests.2. We have hypothesized that any reagent that can form cyclic intermediates with two hydroxyl groups can introduce selective protection to the hydroxyl groups. Based on this principle, we developed selective alkylation methods using Fe(dibm)3 as a catalyst. Fe(dibm)3 is the first catalyst that can replace the equivalent of organotin reagents used in selective benzylation, and it can get similar or better selectivity results than any catalysts before. The method is more green, non-toxic and efficient.3. Ag2O based reactions have been developed for many years. The catalytic amount of halogen anions in the Ag2O based reactions has obvious catalysis effect. Through our studies on the mechanism in-depth, we proposed that silver oxide and soft anion can generate strong alkaline AgO- by coordination, which plays the key roles in the reaction. XRD test and theoretical calculation further supported the proposed mechanism. Our further study found that silver oxide in the reaction can be partially recycled, so we can reduce the amount of Ag2O to 0.5 eqiv. in theory and the reactions can still complete. Then we conducted a series of hydroxyl substrate selective sulfonylation, acylation and alkylation reactions, and supported our proposed mechanism. This research makes Ag2O based reactions of silver oxide consumption reduced, and makes them greener.In summary, this thesis has carried out a series of researches on the selective protection of the carbohydrate hydroxyl groups, and has made some research results with theoretical value and practical value.