Design And Synthesis of Ring-Expanded Analogues of Amino Sugars And Discovery of A Phosphine Catalyzed Tandem Cycloisomerization And [4+2] Cycloaddition Reaction Sequence

Date of Completion

January 2012


Chemistry, Organic




The preparation of 2-amino septanosides has been accomplished in two different processes. One route utilized a p-toluenesulfonic acid mediated cyclization of 1,6-hydroxyaldehydes at room temperature. Excess alcohol was necessary in this process for the formation of septanosyl glycosides. The other route used septanosyl fluorides, themselves prepared from the same 1,6-hydroxyaldehydes, as glycosyl donors in the presence of a variety of acceptors. This method provided more general and efficient access to different 2-amino septanosides. Based on the unique reactivities observed during intramolecular reactions of the septanosyl fluorides, we postulated that the transformation to septanosides for each process followed a different mechanistic pathway. Activation of septanosyl fluorides likely formed a cyclic oxocarbenium ion intermediate that then reacted with the acceptor to produce the corresponding glycosides; this is akin to reactions observed for pyranoses. In the case of hydroxyaldehyde cyclization and glycosylation, an acyclic oxocarbenium pathway was likely dominant. Glycosylations involving the septanosyl fluorides gave good reaction yields and high selectivity for formation of α-septanoside linkages. Both of the methods developed could serve as a starting point for more elaborate investigations with septanose-based glycoconjugates. ^ In a separate project, a phosphine catalyzed tandem process has been developed. Over the course of the tandem reaction. hemiketals (masked ynones) isomerize to cyclic keto enol ethers in the presence of a phosphine. The cyclic keto enol ethers serve as important building blocks and are amenable for functionalization either at the enol ether moiety or the keto group. Depending upon the nature of the alkyne-moiety present in original hemiketal, differential reactivity was observed for the formation of cyclic keto enol ether products. Hemiketals with a terminal alkyne gave the corresponding enone product, which was not isolable. It underwent a rapid dimerization that led to dimeric spiroketal products. Data collected in this study suggested that the dimerization occurs via a concerted hetero Diels-Alder process. In cases where a phenyl group was on the β carbon the cyclic keto enol ether, the product was stable and isolable. The utility of the methodology was further demonstrated by an one pot transformation of phenyl-substituted hemiketals to functionalized dihydropyrazoles. Overall, the tandem method allows for the rapid introduction of complexity in the products from relatively simple starting materials. ^