A Fries-Type Rearrangement Strategy for the Construction of Stereodefined Quaternary Pseudoanomeric Centers: An Entry into C-Naphthyl Ketosides

Abstract

The stereodefined construction of quaternary pseudoanomeric centers by way of a BF 3 •Et 2 O-catalyzed, Fries-type rearrangement of O-ketosides is described. This method provides new access to C-naphthyl ketosides related to biologically relevant products with good to complete stereocontrol in favor of the β product.

An Unexpected Lewis Acid-Catalyzed Cascade during the Synthesis of the DEF-Benzoxocin Ring System of Nogalamycin and Menogaril: Mechanistic Elucidation by Intermediate Trapping Experiments and Density Functional Theory Studies

“…The use of a highly polar solvent mixture (nitromethane/chloroform) almost totally abolished the formation of the cyclized products 7 (entry 12). As observed in our previous work (Scheme 1), 12 lower yields were observed when the phenol in 1a was unprotected (see the Supporting Information, Scheme SI-2). At this stage, control experiments from pure compounds 7a and 7b were conducted to assess if the observed stereoselectivity of the cyclization reaction was due to a thermodynamically driven equilibration (see the Supporting Information, Scheme SI-6).…”

“…Finally, we examined several 1,5-bis-glycopyranoside substrates bearing a substituted phenyl group instead of the 4-methoxy-naphthalenyl motif (Scheme b). In a previous related study (Scheme ), we indeed found that the nature of the aromatic aglycone moiety strongly influenced the outcome of the Fries-type rearrangement, the substrate scope being limited so far to O -naphthyl ketosides. This result could be attributed in part to the higher reactivity of naphthalenes compared to the corresponding benzene derivatives in electrophilic substitution reactions .…”

“…Previous work in our group has shown that such key intermediates bearing the characteristic angular methyl group of nogalamycin anthracyclines and related compounds could be obtained from exo -glycals and 1,4-quinones by way of metal hydride HAT . In our strategy, the C -glycosidic bond would be established first by way of a Lewis acid-catalyzed Fries-type rearrangement. , One advantage of this process is the concomitant release of the pivotal phenolic hydroxyl group involved in the second glycosylation step. Subsequent introduction of the O -glycosidic bond through cyclization of the sugar-hydroquinones thus generated would complete the DEF-benzoxocin ring system of nogalamycin.…”

“…In conjunction with our continuing studies on glycomimetics, 10 we have recently reported a convenient strategy for the synthesis of C-naphthyl ketosides by way of a reaction sequence involving hydrogen atom transfer (HAT)-mediated glycosylation of quinones with exo-glycals 11 and BF 3 •Et 2 O-catalyzed O → C glycoside rearrangement (Scheme 1). 12 Our next objective was to apply this O-arylglycoside to Carylglycoside conversion to more synthetically challenging 1,5bis-glycopyranoside substrates. In addition to exploring the synthetic potential of an underexploited class of compounds and reactive intermediates, we were attracted by the prospect of developing a fast, efficient route to the DEF-benzoxocin ring system of nogalamycin and congeners.…”

“…11 In our strategy, the C-glycosidic bond would be established first by way of a Lewis acid-catalyzed Fries-type rearrangement. 12,20 One advantage of this process is the concomitant release of the pivotal phenolic hydroxyl group involved in the second glycosylation step. Subsequent introduction of the O-glycosidic bond through cyclization of the sugar-hydroquinones thus generated would complete the DEF-benzoxocin ring system of nogalamycin.…”