Rational Design Of Chiral 4-aryl-pyridine-n-oxides As Efficient Acyl Transfer Catalysts: Dynamic Kinetic Resolution To Access Azole Hemiaminal Esters

The design and synthesis of chiral acyl transfer catalyst is one of the research hotspots in organic catalysis.With the development of chiral DMAP catalysts,chiral DMAP-N-oxides are also used in asymmetric acyl transfer reactions.However,from chiral DMAP to DMAP-N-oxide,the nucleophilic site has been changed from nitrogen to oxygen atom.Meanwhile,due to the influence of chiral DMAP catalysts,in the design of chiral DMAP-N-oxides,the C-4 position at pyridine ring is still limited to N,N'-dialkylamino group.In order to break this limitation,through structural analysis,we intends to introduce an aryl group at the C-4 position of pyridine ring to generate a chiral 4-arylpyridine-N-oxide and apply it to the challenging three-component dynamic kinetic resolution reaction of tetrazoles,aldehydes and acid anhydrides.A series of chiral 2,5-disubstituted tetrazoles hemiaminal esters are obtained,and the small molecule PCSK9 inhibitor PF-07556769 could also be generated by further derivation.With 5 mol % of 4-aryl-pyridine-N-oxide as an acyl transfer catalyst,a series of aliphatic aldehydes,anhydrides,and 5-substituted tetrazoles reacted well,affording the corresponding 2,3-disubstituted tetrazoles hemiaminal esters in a regioselective manner,good yields and enantioselectivities.Other N-heteroaromatics were also suitable partners,including substituted pyrazole,imidazole,purines,benzoimidazole,and benzotriazole.This work paves the way for the utilization of the C-4 position of pyridine ring to develop more kinds of chiral 4-substituted pyridine-N-oxides as efficient nucleophilic organocatalysts.To expand the use of DMAP-N-oxides,we applied chiral DMAP-N-oxides to the rearrangement of indole carbonate.Compared to the widespread use of chiral DMAP and isothiourea catalysts,in which the nitrogen atom serves as the nucleophilic site,we found that chiral DMAP-N-oxides,that utilize the oxygen atom as the nucleophilic site,were also efficient organocatalysts in this rearrangement.Using 2.5 mol% of chiral DMAP-N-oxide,diverse oxindoles containing an all-carbon quaternary stereocenter were obtained up to 98% yield and up to 96% enantioselectivities.