Systematic Synthesis of Multifluorinated α,α-Difluoro-γ-lactones through Intramolecular Radical Cyclization

Abstract

Carbon radicals from allyl O-(trimethylsilyl)-alpha-bromo-alpha,alpha-difluoroacetal can cyclize onto the olefinic part regiospecifically to give gamma-lactols in good yield. The lactols are then converted to the corresponding alpha,alpha-difluoro-gamma-lactones. Systematic synthesis of multifluorinated-alpha,alpha-difluoro-gamma-lactones has thus been accomplished through intramolecular radical cyclization as a key reaction. Semiempirical MO calculation study suggested a unique nature of alpha,alpha-difluoroacetate in that complete delocalization of the electrons in the SOMO orbital of alpha,alpha-difluoroacetyl radical occurred; this caused unsuccessful cyclization. To apply the present radical reaction, the first synthesis of both enantiomers of difluoroeldanolide, analogues of the sex pheromone of the male African sugarcane borer, has been demonstrated. Electrophysiological tests revealed that the difluorinated analogues were as active as the natural eldanolide on the olfactory receptors.

Atom transfer radical cyclization (ATRC) applied to a chemoenzymatic synthesis of Quercus lactones

“…This is physically achieved when the two reacting extremities are connected by a single bond chain. 13 The situation is different when the open-chain starting material is an unsaturated amide or ester, as it is in the present case. In fact the estereal and peptidic bonds introduce an element of rigidity in the tethering chain, that is, a high rotational barrier, which restricts the interconversion of the syn-and anti-conformers (Scheme 3).…”

Synthesis of α,α-difluoro-γ-butyrolactones via ethyl iododifluoroacetate

“…Systematic synthesis of multifluorinated-a,adifluoro-g-lactones was accomplished through intramolecular radical cyclization as a key reaction of O-(trimethylsilyl)-a-bromo-a,a-difluoroacetate. The efforts failed to synthesize the lactones via radical cyclization directly of allyl-a,a-difluoro-a-iodoacetate [4]. The addition product of N,N-diethyl iododifluoroacetamide with alkenes could be converted into a,a-difluoro-g-lactones by column chromatography on silica gel, which was considered that the amide groups were hydrolyzed on the surface of silica gel and subsequently cyclized to form g-lactones [7].…”

“…We have reported some polyfluoroalkyl-g-butyrolactones synthesized by the reaction of 4-pentenoic acids and polyfluoroalkyl iodides [3]. In addition, since it is believed that difluoromethylene moiety acts similar to ether-oxygen in vivo and interesting biological activity is anticipated for analogues of a,a-difluorinated biomolecules [4], several works have been reported on the methods to introduce the CF 2 group into organic molecules [5][6][7]. In this paper, we wish to report the synthesis of a,a-difluoro-g-butyrolactones through the hydrolysis of the adduct 3 by the reaction of alkenes (1) with ethyl iododifluoroacetate (2) initiated by sodium dithionite.…”

Radical Cyclization of α‐Bromo Aluminum Acetals onto Alkenes and Alkynes (Radic[Al] Process): A Simple Access to γ‐Lactols and 4‐Methylene‐γ‐Lactols

“…[12,13] Since the 1980s, aluminum acetals have found some applications in organic synthesis. In particular, they have been trapped with electrophiles, such as silyl triflates and silyl imidazole or acetic anhydride and acid fluorides to give the corresponding monosilyl acetals [14][15][16] and a-acetoxy acetals, [17,18] respectively. The latter were found to be very efficient for the generation of oxacarbenium ions, which could engage further in Prins [19] and oxonia-Cope [20] rearrangements or could be trapped by various nucleophiles.…”