Preparation of 4 '-spirocyclobutyl nucleoside analogues as novel and versatile adenosine scaffolds

Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4 '-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4 '-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4 '-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3 '-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4 '-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4 '-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5

Ab initio evaluation of metalated 3-halo-1-azaallylic anions as synthetic building blocks

C

Straightforward synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone

An efficient and straightforward approach towards the synthesis of 1-alkyl-2-(trifluoromethyl)aziridines starting from 1,1,1-trifluoroacetone via imination, alpha-chlorination, hydride reduction and ring closure was developed. In addition, novel primary beta-iodo amines were obtained by regioselective ring opening of these 2-(trifluoromethyl)aziridines using alkyl iodides, and their synthetic potential was demonstrated by converting them into novel alpha-CF(3)-beta-phenylethylamines upon treatment with lithium diphenylcuprate

Gold- and silver-mediated cycloisomerizations of N-propargylamides

Substituted N-propargylamides have proven to be valuable substrates for alkyne-activated cycloisomerization reactions. N-Tosyl-N'-propargylurea underwent reaction with AuCl3 to give the corresponding dihydroimidazolone, while N-propargyl-3-oxobutanamides and esters were used to construct furanyl fused pyrrolldinones and dihydrofuranones via Ag(I)-mediated alkyne activation

Synthesis of 2(5H)-furanones via oxidative ring expansion of 4-hydroxy-2-cyclobutenones

A

New synthesis of fluorinated pyrazoles

A new synthesis of fluorinated pyrazoles, a class of compounds with potential in medicinal chemistry, is described. The treatment of benzoylfluoroacetonitrile with hydrazine yielded the expected new 3-amino-4-fluoropyrazole, while the analogous reaction of α-cyano-α,α-difluoroketones with hydrazine in refluxing isopropanol surprisingly gave rise to 3-unsubstituted 4-fluoropyrazoles via an unprecedented mechanism. The isolation of intermediate hydrazine adducts led to a mechanistic rationale for this transformation