Exploring The Highly Strained 1,2-Oxazetidines As Novel Reagents For The C-C And C-O Bond-Forming Reactions

Nitrogen or oxygen-containing small strained ring compounds are prevalent in bioactive natural products and pharmaceuticals.Some four-membered heterocycles,such as azetidines and oxetanes,have drawn tremeendous attention from the researchers due to their small rigid structure,which can improve the physicochemical properties of candidate drug molecules.In addition,owing to the the unique ring strain of such small compounds,the chemical bonds on the ring can be activated,and the inherent polarity of some chemical bonds could be even changed.Therefore,a large spectrum of important transformations can be achieved.Compared to the well-studied chemistry of three-membered heterocycles,such as oxiranes and oxaziridines,the reaction profiles of1,2-oxazetidines have been rarely investigated,therefore,it will be of great value to carry out the research of this type of four-membered heterocycles.Herein,we mainly focuses on the unique reactivity of 1,2-oxazetidines,and the following three aspects are studied in this thesis.Part one: Tandem ?-hydroxymethylation and ?-aminomethylation reactions was explored,in which the in situ generated N-nosyl-1,2-oxazetidine from the readily accessible N-nosyl-O-bromoethyl hydroxylamine precursor was involved.The in situ generated N-nosyl-1,2-oxazetidine would undergo hydroxymethylation and aminomethylation reaction with ?-keto phosphonate under mild DBU base,and a series of ?-hydroxymethyl-?-aminomethyl ketones were produced in good yields.Mechanistic study revealed that the whole process involved a complicated C-P bond cleavage ?C-N bond formation ? C-C bond formation sequence.Initially,N-Ns-O-bromoethyl hydroxylamine was quickly cyclized to the 1,2-oxazetidine,followed by decomposition to the formaldehyde and formaldimine in the presence of DBU base.Subsequently,the highly reactive formaldehyde intermediate was captured by ?-keto phosphonates and triggered the sequential Horner-Wadsworth-Emmons,Michael addition,and Aldol addition reactions.Target products 1,3-aminoalcohols could be flexibly converted into important bioactive molecules spirocyclic azetidines and azetidine-1,3,4-oxadiazoline bispirocycles via Mitsunobu cyclization reaction.In particular,products containing a novel vicinal bispirocyclic framework have not been synthesized previously.Part two: The aldol and Mannich reactions of N-nosyl-1,2-oxazetidine that is a novel one-carbon unit of formaldehyde and formaldimine surrogates were studied.In the first part,we found that N-nosyl-1,2-oxazetidine can be rapidly decomposition to equal molarof formaldehyde and formaldimine in the presence of DBU.Therefore,we believe that N-nosyl-1,2-oxazetidine can function as a novel one-carbon unit reagent for the synthesis of hydroxymethyl and aminomethyl compounds,respectively.We found that formaldimine intermediates can be selectively captured by using ?-keto esters,and a broad range of useful ??quaternary aminomethyl compounds could be obtained in good yields.Otherwise,the formaldehyde species could be chemoselectively trapped by the carbonyl nucleophiles to produce the aldol addition products.Part three: The catalytic asymmetric umpolung C-O bond-forming reactions with N-nosyl-1,2-oxazetidines was developed.N-nosyl-1,2-oxazetidines with high strain energy could distinctively function as unique electrophilic oxygen reagent.Accordingly,a highly enantio-and diastereoselective catalytic ring-opening reaction of N-nosyl-1,2-oxazetidines with indanone carboxylates had been subsequently developed in the presence of a chiral phase-transfer catalyst.Therefore,a wide range of highly functionalized chiral ether compounds bearing quaternary and multiple stereogenic carbon centers could be effectively constructed with high yields and stereoselectivities(up to 97% ee and 20:1 dr)from this new catalytic asymmetric umpolung strategy.Finally,synthetic utility of these versatile products had been also demonstrated by the concise synthesis of structurally diverse chiral fused morpholines and spiro morpholin-3-ones in short steps.In summary,this thesis mainly pay attention to our recent progress on the study of1,2-oxazetidine chemistry.N-nosyl-1,2-oxazetidines could function as novel and robust formaldehyde and formaldimine surrogates.By merely using this simple reagent,a broad range of useful hydroxymethyl and aminomethyl compounds could be obtained.Enabled by the unusual electrophilic oxygen reactivity of these compounds,the unprecedented catalytic asymmetric umpolung C-O bond-forming reactions of1,2-oxazetidines with ?-keto esters are also achieved.Our findings on the strain-enabled reactivity of 1,2-oxazetidines disclose the great synthetic potentials of such four-membered heterocycles in chemical synthesis.