De Novo Synthesis and Biological Evaluation of C6″-Substituted C4″-Amide Analogues of SL0101

Abstract

In an effort to improve upon the in vivo half-life of the known ribosomal s6 kinase (RSK) inhibitor SL0101, C4″-amide/C6″-alkyl substituted analogues of SL0101 were synthesized and evaluated in cell-based assays. The analogues were prepared using a de novo asymmetric synthetic approach, which featured Pd-π-allylic catalyzed glycosylation for the introduction of a C4″-azido group. Surprisingly replacement of the C4″-acetate with a C4″-amide resulted in analogues that were no longer specific for RSK in cell-based assays.

A Survey of Recent Synthetic Applications of 2,3-Dideoxy-Hex-2-enopyranosides

“…This methodology has been applied to the addition of phenols [86], heterocyclic nucleophiles including uracil derivatives [87], and/or azides [88,89]. Nucleophilic substitution carried out in alkyl α- d - erythro -hex-2- enopyranosides, e.g., 70 and 72 , took place with a very high regio- and stereoselectivity to provide C-4 substituted derivatives 71 and 73 , respectively (Scheme 18a,b).…”

C-Aryl Glycosylation: Palladium-Catalyzed Aryl–Allyl Coupling of Achmatowicz Rearrangement Products with Arylboronic Acids

“…This result excluded the possible Ferrier-type pathway for the arylation of 1a and other Achmatowicz rearrangement products with arylboronic acids. Additional evidence was provided by O’Doherty, who failed to achieve satisfactory yields of Pd-catalyzed O-glycosylation of unactivated alcohols as either gylcal or 3a analogue (Scheme c) . This finding would be of exceptional significance because reverse reactivity was observed by Toshima and co-workers in the Lewis-acid-promoted O-glycosylation of related 2,3-unsaturated glycosyl donors (Scheme d).…”

Chloroperoxidase‐Catalyzed Achmatowicz Rearrangements

“…While the peroxidase/oxidase system for the biocatalytic ring expansion of furanols proved to be effective for a wide range of substrates with little to no bias towards existing stereogenic elements, the structural limitation regarding chain length and furan core substitution prompted us to reconsider alternative systems that would be independent on a productive active site binding of the furans. Here, the original protocol by Lefebvre utilizing peracids as oxidant for the rearrangement reaction served as the template for an enzyme cascade design providing a pathway for the catalytic generation of peracetic acid as diffusible redox mediator. Replacement of the peroxidase biocatalyst by a lipase (from Candida antarctica type B) rendered a system where glucose oxidase provided hydrogen peroxide to be used by the lipase to catalyze the perhydrolysis of acetic acid (from an acidic acetate buffer, pH 4.5) .…”

“…Over the past decades, the Achmatowicz‐type ring expansion – the oxidative conversion of α‐heterosubstituted furfuryl derivatives to six‐membered O‐ or N‐heterocyclic building blocks – has become a valuable tool in modern synthetic organic chemistry . Both the easy access to suitable heteroaromatic Achmatowicz substrates as well as the broad range of follow‐up chemistry offered by the pyranone or piperidinone products make this transformation an attractive instrument in the synthesis of complex natural products and biologically active agents.…”