Constructing β-D-Mannopyranosides With The Direction Of 4-O-Acyl Group

β-D-mannopyranoside linkage exists in many natural products that have important physiological and pharmacological functions.Due to the importance of this linkage,much attention has been paid to its synthesis.However,stereoselective βmannosylation has been recognized as one of the greatest challenges of carbohydrate chemistry1.The mechanism of glycosylation is highly dependent on the reaction conditions.In the SN1 or SN1-like glycosylation,the oxocarbenium ion intermediate could be formed after the glycosyl donor was activated by the promotor.In addition to the solvent effect,this intermediate can also form covalent connections,contact ion pairs(CIP)or solvent-separated ion pairs(SSIP)with anions2.The preferred conformation of intermediates is generally half-chair conformation such as 3H4 and 4H3,and sometimes it could also exist as boat conformation such as B2,5 and B1,4.Different conformations often lead to different stereoselectivity.A large number of evidences have showed that the protective group on the glycan ring can adjust the conformation of the intermediate,thus affecting the results of glycosylation3,4.The most promising methodology of carbohydrate chemistry is based on the neighboring group participation of C-2 acyl substituents to provide 1,2-trans-glycosides5-8.Remote acyl participation,such as C-3,C-4,C-6 acyl participation have also been widely reported9.In view of the above problems and phenomena,we tried to use the control of conformation and direction of remote acyl group to achieve stereoselective βmannosylation,this thesis mainly includes the following four parts:Chapter 1 briefly introduction of the β-D-mannopyranoside and the difficulties of its chemical synthesis.Moreover,the progress of stereoselective β-mannosylation are also reviewed.Finally,the effect of remote acyl group direction and the conformation of glycan ring on the stereoselectivity of glycosylation are also briefly introduced.Chapter 2 introducing the chemical synthesis of glycosyl donor and the optimization of glycosylation.2,2-dichloro-1,3-benzodioxole was applied to protect the C-2 and C-3 hydroxyl groups of the mannose.2,3,4,5.6-pentafluorobenzoyl group was also been used to protect the C-4 hydroxyl group.Then we optimized the promotor and reaction solvent system of the glycosylation.Large steric hindrance silver salt(AgBArF4)and p-TolSCl were used as promotor.And the ethyl ether was also removed from the reaction solvent system.With methods mentioned above,we can avoid the interaction between anions and the intermediates.Thus,the remote acyl direction of 2,3,4,5,6pentafluorobenzoyl group at C-4 position was facilitated.Chapter 3 introducing the glycosylation of the glycosyl donor.We used the mannosyl donor to react with different acceptors which included primary alcohol,secondary alcohol and tertiary alcohol.After the deprotection of disaccharides,we verified the anomeric configuration of the disaccharides and showed the effecti veness and applicability of our method.For the primary alcohol as acceptor,the selectivity of glycosylation can reach β-only;For the secondary alcohol,the β-selectivity is above 30:1;As to the tertiary alcohol,there is no desired product.Chapter 4 introducing the mechanism study on glycosylation.Firstly,we analyzed the crystal structure of rhamnosyl donor and tried to capture the intermediates of the remote acyl direction.Secondly,we tried to verify the influence of C-2,C-3,C-4 protective groups and promotors on the stereoselectivity of glycosylation.Finally,a reasonable hypothesis about the mechanism of glycosylation was put forward.