The Construction Of Drug-like Chiral Piperidine Alkaloids And The Preparation Of 2,3-Dihydrobenzofurans

Objective:Chiral periperidine skeletons are widely found in natural products with biological activities and drugs.We plan to achieve the efficient construction of alkaloid skeleton chiral spirocyclic periperidine via asymmetric catalysis in a one-pot cascade reaction.Natural products of dihydrobenzofurans are widely distributed in nature,and usually have good physiological activities.Furthermore,the biological activities of compounds with dihydrobenzofurans as the structural parent nucleus will be significantly improved after structural modification.We also accomplished the preparation of 2,3-Dihydrobenzofuran leading compounds through thioether catalysis.Methods:1.The construction of alkaloids drugs-like skeleton chiral spirocyclic piperidine:we began with heat-assisted Wolff rearrangement-amidation of the cyclic2-diazo-1,3-diketone with primary amine.The resulting cyclic?-ketoamide would directly participate in the secondary amine-catalytic cycle by serving as donor in an asymmetric Michael reaction involving enal under iminium activation.Subsequent hydrolysis and hemiaminalization would provide the desired spiro-hemiaminal.The structure could be confimed by ¹H NMR,¹³C NMR,HPLC,HRMS and X-ray single crystal and we would get the dr value,ee value,melting point and rotation of the target compounds.2.The preparation of leading compound 2,3-Dihydrobenzofurans:using bromide and sulfide to form the sulfur bromide salts eliminating in situ with base to release thioether and form sulfur ylide at the same time.The target compounds could obtained through[4+1]cyclization reaction with ortho-Quinone Methides as a highly active Michael receptor.The structure could be confimed by ¹H NMR,¹³C NMR,HRMS and X-ray single crystal and we would be the dr value and melting point of the desired compounds.Results:1.The construction of alkaloids drugs-like skeleton chiral spirocyclic piperidine:we have synthesized 21 chiral spirocyclic piperidine derivatives in total.The structures of each compound were confirmed ¹H NMR,¹³C NMR,HRMS.The relative configuration of 1.5m was determined by X-ray diffraction analysis and the ee values of the target products were determined by HPLC.2.The preparation of leading compound 2,3-Dihydrobenzofurans:we have prepared 30 2,3-dihydrobenzofurans derivatives from ortho-Quinone Methides substrates catalyzed by sulfide.Futhermore,2-allyl-substituted phenol were oxidized by Ag₂O to generate ortho-Quinone Methides substrates in situ.Subsequent participate in the annulations catalyzed by sulfide to provid the aimed products with moderate yield too and the diastereomeric selectivity of the target compound was well controlled.On this basis,chiral sulfide was used to the asymmetric synthesis of these compounds.The structure of each compound was confirmed by ¹H NMR,¹³C NMR,HRMS.The relative configuration of 2.4a was determined by X-ray diffraction analysis.Conclusion:1.We have achieved the efficient construction of chiral piperidine alkaloid drug skeletons by the Wolff rearrangement amidization and Michael addition ring reaction mediated by secondary amine on cascade in one-pot.It supplemented the synthesis methods of constructing such drug skeletons.2.We have accomplished the preparation of 2,3-dihydrobenzofurans derivatives from ortho-Quinone Methides substrates and 2-allyl-substituted phenol respectively based on the thioether catalytic system.It enriched the ways of preparing these compounds.