Study And Application On Allylation Of MBH Adducts

We summarized the biological activities and preparation of 1,4-diazepine and?-amino acid derivatives and proposed efficient synthetic methods based on MBH adducts.These compounds are important subunits that exist widely in the field of medicinal chemistry.1,4-benzodiazepine is a prominent class of central nervous system agonists in the treatment of various mental diseases.As non-protein derived fragments,?-amino acids have often been applied in the construction of peptides and natural products.Some improvements have been achieved on the synthetic methods,but there are still some limitations,such as difficult access to starting materials,lack of diversity for products,harsh reaction conditions,complicated experimental procedures,low atomic economy and so on.For example,the construction of nitrogen-containing heterocycles,such as indole or pyrrole-fused 1,4-diazepanones is less investigated.The preparation of dipeptide is still limited to the amide bonds formation by traditional coupling reagents.The synthesis of N-acyl-?-amino acids depends on strong base,high temperature and toxic metals.Morita–Baylis–Hillman(MBH)adduct refers to a multifunctional synthon,which contains acetyloxy or tert-butoxycarbonyl leaving groups on the allylic carbon.It can react with a variety of nucleophiles under mild conditions to prepare allylated products.It is expected to solve the problems about the structural diversity and synthetic methods through the study of cyclization as well as nucleophilic substitution between MBH adducts and nitrogen-containing nucleophiles.This work mainly focuses on the following three aspects:1.We explored the application of sequential amide coupling/intramolecular aza-Michael addition for the synthesis of indole/pyrrole fused 1,4-diazepanone scaffolds from 1H-indole/pyrrole-2-carboxylic acids and MBH allylamines.First,we investigated the stepwise method to construct indole-fused 1,4-diazepanone 2-4a.The amide intermediate 2-3a was prepared by the conventional coupling conditions,which was then underwent intramolecular cyclization at room temperature to get the product.K₂CO₃was identified as the suitable base while DMSO was identified as the key solvent to promote this cyclization reaction.The configuration of 2-4a was further characterized by single crystal X-ray analysis.It was found that the phenyl and ester groups were in the trans position,which showed the high stereoselectivity for the intramolecular cyclization.Next,a one-pot procedure for the desired product 2-4a was carried out from the perspective of atom-and step-economy.The amide coupling was performed in DMSO at room temperature.Then 3.0 equiv.K₂CO₃ was added into the reaction mixture immediately without any other treatment.The temperature was increased to 80°C,and the product 2-4a was obtained in 83%yield after 3 hours.Next,we investigated the substrate scope in one pot reaction and found that the allylamines derived from aliphatic and aromatic aldehydes were suitable substrates for this one-pot reaction,and the steric hindrance of the substituents on allylamine played an obvious role in yields.For example,bulky substituents such as i-Pr or Bn groups gave lower yields compared with less hindered Me or Bu groups.The allylamines with a more hindered t-Bu or inert Ph group failed to give any products under the current conditions.It was found that the reaction had excellent trans stereoselectivity in most cases,while the strong electron-withdrawing groups on MBH allylamine might lead to a mixture of trans and cis isomers.The reactions were significantly affected by the electronic effect of the substituents in1H-indole-2-carboxylic acid.Electron-withdrawing group led to a decreased yield,while the electron-donating one had no significant difference.In addition,we further expanded the substrate scope by replacing the indole unit with pyrrole-2-carboxylic acid,and desired cyclized product could also be obtained.Finally,twenty-one novel products were prepared through the one-pot synthetic method.Simple operation,wide substrate range,high stereoselectivity and gram-scale synthesis made this method useful for the preparation of highly substituted fused 1,4-diazepanone derivatives.2.We investigated the condition-controlled regioselective strategies for the synthesis of?/?-dipeptide derivatives.First,MBH carbonate 3-1a and amino acids-derived O-alkyl hydroxamates 3-2a were selected as the model substrates to afford the?-or?-substituted product.Under the catalysis of Lewis base DABCO(10mol%)in less polar solvent such as DCM,the reaction proceeded in a S_N2'-S_N2'fashion to provide the?-allylic product 3-3a in 96%yield.By contrast,the?-allylic product 3-4a could be obtained through an addition-elimination process in 94%yield under the catalysis of Br(?)nsted base K₃PO₄(10 mol%)in polar aprotic solvent DMF.Next,we investigated the substrate scope and found that either aromatic or aliphatic groups on the MBH carbonates could participate in the reaction.The reactions were significantly affected by the electronic effect of the substituents in MBH carbonates.Electron-withdrawing group led to a decreased yield,while the electron-donating one had no significant difference.Furthermore,it could also be extended to the non-amino acids derived hydroxamates.Finally,twenty-nine novel?/?-dipeptide derivatives were prepared through the condition-controlled regioselective strategies.This reaction featured with broad scope,high regioselectivity as well as gram-scale synthesis.3.We studied the allylation of N-arylamides with MBH carbonates for the synthesis of N-acyl-?-amino acids.First,acetanilide 4-1a and MBH carbonate 4-2a were selected as the model substrates to optimize the N-allylic alkylation reaction.The solvents were screened with 20 mol%DABCO as the catalyst based on the construction for?/?-dipeptides.The results revealed that the N-allylation reaction worked well in both polar and nonpolar aprotic solvents,but failed with the protonic one.Among the solvents screened,CH₃CN was proved to be the best,affording the product 4-3aa in 87%yield.With the optimal conditions in hand,we turned our attention to examine the substrate scope of the reaction.The results indicated that aliphatic or aromatic MBH carbonates as well as a broad range of N-aryl substituted amides proceeded smoothly under the optimized conditions,providing the corresponding products in moderate to good yields,including the cyclic N-arylamide drugs.Besides the gram-scale experiment,we also conducted the transformations of the final products to 4,5-dihydroisoxazole and 1,2-dihydroquinoline,which should have great potential applications in medicinal chemistry.Finally,twenty-eight novel N-acyl-?-amino acid derivatives were prepared through the N-allylic alkylation reaction.This reaction featured with broad scope and gram-scale synthesis.In conclusion,considering the pharmaceutical applications and synthetic limitations of 1,4-diazepine and?-amino acid derivatives,the efficient synthetic methods have been developed for the synthesis of indole/pyrrole fused 1,4-diazepanones,?/?-dipeptides and N-acyl-?-amino acids derivatives based on the MBH adducts.As a practical strategy,we envision that these approaches will provide unique opportunities in medicinal chemistry.