Addition of difluorocarbene to 4',5'-unsaturated nucleosides: synthesis and deoxygenation reactions of difluorospirocyclopropane nucleosides.
Synthetic routes to 4'-(2,2-difluorospirocyclopropane) analogues of adenosine, cytidine, and uridine are described. Treatment of 2',3'-O-isopropylidene-4',5'-unsaturated compounds derived from adenosine and uridine with difluorocarbene (generated from PhHgCF3 and NaI) gave diastereomeric mixtures of the 2,2-difluorospirocyclopropane adducts. Stereoselectivity resulting from hindrance by the isopropylidene group favored addition at the beta face. Removal of base and sugar protecting groups gave new difluorospirocyclopropane nucleoside analogues. The protected uridine analogue was converted into its cytidine counterpart via a 4-(1,2,4-triazol-1-yl) intermediate. Stannyl radical-mediated deoxygenation of the 3'-O-TBS-2'-thionocarbamate derivatives gave the 2'-deoxy products of direct hydrogen transfer. In contrast, identical treatment of the 2'-O-TBS-3'-thionocarbamate isomers resulted in opening of the vicinal difluorocyclopropane ring upon generation of a C3' radical followed by homoallylic hydrogen transfer to give 4'-(1,1-difluoroethyl)-3',4'-unsaturated nucleoside derivatives. Structural aspects and biological effect considerations are discussed.
Nowak
Ireneusz
I
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Robins
Morris J
MJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D018360:Crystallography, X-Ray; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry*; D013141:Spiro Compounds / Q000138:chemical synthesis*; D013237:Stereoisomerism; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis
C522022:4'-(2,2-difluorospirocyclopropane) adenosine; C522020:4'-(2,2-difluorospirocyclopropane) cytidine; C522021:4'-(2,2-difluorospirocyclopropane) uridine; D006845:Hydrocarbons, Fluorinated; D009705:Nucleosides; D013141:Spiro Compounds; C121084:difluorocarbene; D003562:Cytidine; D000241:Adenosine; D010100:Oxygen; D014529:Uridine