Hydroxymethyl-Branched Polyhydroxylated Indolizidines: Novel Selective α-Glucosidase Inhibitors.

α,α-Disubstituted piperidines and conformationally constrained polyhydroxylated indolizidines bearing a hydroxymethyl substituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylation under two sets of complementary conditions allowed access to both configurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branched indolizidines in high yield. The newly prepared iminosugars demonstrated highly potent inhibition of α-glucosidases. Most interestingly, compound 9b exhibits very high selectivity toward this class of enzymes, with an unusual mode of binding.

Enantioselective Arylation of N-Tosylimines by Phenylboronic Acid Catalysed by a Rhodium/Diene Complex: Reaction Mechanism from Density Functional Theory.

A DFT study of the reaction mechanism of the rhodium-catalysed enantioselective arylation of (E)-N-propylidene-4-methyl-benzenesulfonamide by phenylboronic acid [Lin et al J. Am. Chem. Soc. 2011, 133, 12394] is reported. The catalyst ([{Rh(OH)(diene)}2]) includes a chiral diene ligand and the reaction is conducted in 1,4-dioxane in the presence of drying agents (4 Šmolecular sieves). Because phenylboronic acid is in equilibrium with phenylboroxin and water under the reaction conditions, three catalytic cycles are proposed that differ in the way the transmetallation and the release of the product are brought about, depending on the availability of phenylboronic acid, water and boroxin in the reaction medium. Based on computations, a new mechanism for the title reaction is proposed, in which phenylboronic acid plays the double role of "aryl source" and proton donor. This path does not require the presence of adventitious water molecules, in keeping with a reaction conducted in a dry medium. Comparisons with the generally accepted mechanism for arylation of enones proposed by Hayashi and co-workers (J. Am. Chem. Soc. 2002, 124, 5052) show that the latter mechanism is less favourable and is not expected to operate in the case of the N-tosylimine substrate considered herein. Finally, the possibility that phenylboroxin is the aryl source has also been investigated, but is not found to be competitive.