Total Synthesis of (±)- and (+)-Valienamine via a Strategy Derived from New Palladium-Catalyzed Reactions

Abstract

A new strategy toward glycosidase inhibitors, represented by valienamine, which is such an inhibitor itself as well as a critical unit of pseudooligosaccharides that function this way, evolved from two newly developed palladium-catalyzed reactions. The applicability of a palladium(0)-catalyzed net regioselective cis-hydroxyamination derives from the reaction of vinyl epoxides with isocyanates. The utilization of a cocatalyst in this reaction is required in this case and may prove generally useful. A bidentate phosphite proved to be the most effective ligand. The requisite substrate was available via a Diels−Alder protocol and allowed the obtention of (±)-valienamine in only seven steps. The inability to perform the Diels−Alder reaction asymmetrically led to a different asymmetric synthesis of the pivotal epoxide intermediate in enantiomerically pure form, which derived from asymmetric palladium-catalyzed reactions. Using the desymmetrization of meso enedicarboxylates, the net equivalence of an asymmetric cis-hydroxycarboxylation led to the enantiomerically pure desired epoxide. (+)-Valienamine was available in 14 steps by this route.

Pd Asymmetric Allylic Alkylation (AAA). A Powerful Synthetic Tool.

“…10). 39) The enantiomerically pure novel heterocycle 32 was isolated in 87% yield and Ͼ99% ee. This compound was utilized in an asymmetric synthesis of valienamine, a component of novel glycosidase inhibitors, one of which is useful in the treatment of diabetes.…”

Enantioselective Allylic Substitutions in Natural Product Synthesis

“…Though reported over a decade ago, the total synthesis of (+)-valienamine remains a classic and powerful example of the utility of palladium-catalyzed allylic substitution reactions with a carbon nucleophile [14]. The strategy involved the desymmetrization of the meso allylic dicarbonate 34 with phenylsulfonyl-substituted nitromethane nucleophile 35 in the presence of the standard Trost ligand ent-L2 (Scheme 15).…”

Neue Fortschritte bei der Umwandlung von Kohlenhydratfuranosiden und -pyranosiden zu Carbocyclen

“…Einige der oben beschriebenen Reaktionen ermöglichen eine direkte Umwandlung von Kohlenhydratfuranosiden und -pyranosiden zu carbocyclischen Polyolen. Strategien mit enantiomerenreinen Carbocyclen als Ausgangsverbindungen beinhalten Umwandlungen von Chinasäure, [25] Inosit-oder Conduritderivaten, [26] die Desymmetrisierung von meso-Cyclohexenderivaten durch asymmetrische palladiumkatalysierte Hydroxycarboxylierung, [27] enantioselektive Alkylierungen [28] sowie die Umwandlung von homochiralen Carbocyclen entweder durch mikrobielle [29,30] oder durch chemische Oxidation. [28,31] Es Entwicklung von Synthesestrategien, die gut mit denen der Natur konkurrieren können.…”