Electrophilic fluorination-nucleophilic addition reaction mediated by Selectfluor: Mechanistic studies and new applications

The electrophilic fluorination-nucleophilic addition reaction with Selectfl uor-type reagents upon glycals has been studied and optimized. This reactio n leads to selective fluorination at the 2-position with concomitant nucleo philic addition to the anomeric center. To understand the stereochemical ou tcome of this process, a mechanistic study has led to the discovery that, i n the fucose series, Selectfluor adds specifically in a syn manner, yieldin g a 1-[TEDA-CH2Cl]-2-fluoro saccharide that anomerizes slowly to a more sta ble intermediate. The anomeric alpha/beta distribution was studied as a fun ction of reactants and conditions, and it was found that a judicious choice of protective group strategy can improve the stereoselectivity of both flu orination and nucleophilic addition. Furthermore, a hypersensitive radical probe was used to probe the reaction, and no product characteristic of a ra dical process was isolated, suggesting that no single electron transfer occ urs during the attack of the glycal on Selectfluor. The importance of solve nt effect, Selectfluor counterion, and stepwise procedure has also been dis cussed. This study has brought an important improvement of yields and a bro ader range of allowed nucleophiles such as secondary alcohols of carbohydra tes, amino acids, phosphates, or phosphonates. This optimized process was f urther applied to the modification of important bioactive molecules, includ ing the synthesis of fluorinated daunomycin and oleandrin analogues and the oxidation of thioglycosides to the corresponding sulfoxides.