Synthesis Of 2,2-Disubstituted Perhydrofuro-Pyran Derivatives Containing Indole

Objective:To construct a series of 2,2-disubstituted Perhydrofuro-pyran derivatives containing indole with potential δ opioid receptor activity.Methods:(1)3,4,6-Trio-acetyl-1,2-cyclopropanose was synthesized from Dglucose by a nine-step chemical reaction.(2)Lewis acid for the reaction of 1,2-cyclopropaneglucose with indole was screened,and then the reaction temperature,reaction solvent and catalyst amount were optimized to select the optimal reaction conditions.(3)After the optimal conditions were selected,the universality of the reaction was investigated.Various indoles were selected to conduct the reaction with 1,2-cyclopropaneglucose.(4)1,2cyclopropanegalactose and 1,2-cyclopropane xylose were synthesized and reacted with indole under the previous reaction conditions to research whether the reaction system was suitable for the reaction of other cyclopropane sugars with indole.(5)The reaction of other nucleophiles with 1,2-cyclopropanose was investigated.1,3,5-trimethoxy benzene was selected to react with 1,2cyclopropanose under the same conditions.(6)After the universality of the reaction was investigated,the reaction mechanism was studied and verified by DFT calculation.(7)The product 3aa was successfully bonded to δ-opioid receptor(PDB ID:4RWD)by hydrophobic bond,and the binding energy was-9.8KJ/mol,which provided a basis for the study of the anti-opioid receptor activity of 2,2-disubstituted Perhydrofuro-pyran derivatives containing indole compounds.Results:(1)The optimized condition was 0.05 equiv.BF3·Et2O in DCM at 0℃ to room temperature with 4A molecular sieves under argon atmosphere,the molar ratio of sugargroup to indole was 1:1.1.(2)The reaction of 1,2cyclopropaneglucose with various indoles was investigated.Finally,49 2,2disubstituted Perhydrofuro-pyran derivatives containing indole compounds were synthesized.(3)The reaction of indoles with 1,2-cyclopropanegalactose and 1,2-cyclopropane xylose was monitored by high resolution mass spectrometry.Although the proposed compounds were successfully detected,the products of the reaction system were relatively complex,and the reaction conditions needed to be further optimized.(4)1,2-cyclopropaneglucose was successfully reacted with 1,3,5-trimethoxy benzene with high yield and high stereoselectivity.(5)The possible mechanism of the reaction was summarized:the ring opening of cyclopropane was catalyzed by Lewis acid,and then the intramolecular ring expansion formed the bicyclic compound.Finally,2,2disubstituted Perhydrofuro-pyran derivatives were obtained by nucleophilic attack by position 3 of indole.(6)The selected successfully docked with δopioid receptor(PDB ID:4RWD)through hydrophobic bond,and the binding energy was-9.8KJ/mol,which provided the basis for the subsequent study of the activity of 2,2-disubstituted Perhydrofuro-pyran derivatives against opioid receptor.Conclusion:Under the catalysis of BF3·Et2O,1,2-cyclopropane-glucose ringopening and intramolecular rings were formed and then nucleophilic attack by indole was carried out.Finally,49 2,2-disubstituted Perhydrofuro-pyran derivatives were synthesized.It has been proved that indole can react with other cyclopropane sugars(1b,1c)successfully.In addition,1,2cyclopropaneglucose and 1,3,5-trimethoxybenzene can also carry out intermolecular ring extension-addition reaction in this system.Finally,a preliminary DOCK study was carried out by computer aided drug design,and the docking binding energy of 2,2-disubstituted Perhydrofuro-pyran derivatives with δ-opioid receptor(PDB ID:4RWD)protein was-9.8KJ/mol.