As a result, DAB-1 and nectrisine have been the targets of many synthetic efforts and remain useful targets to demonstrate stereoselective reaction methods in complex settings. (21) Selective inhibitors of this type are implicated in the treatment of diabetes as well as other sugar-related diseases.
(20) Structurally related nectrisine ( 3) is also a strong inhibitor of α-glucosidases. (18,19) DAB-1 is a potent inhibitor (IC 50 = 9.3 μM) against a specific glycosidase, rabbit muscle glycogen phosphorylase, while being mostly ineffective toward glycogen synthesis enzymes. (11−17) DAB-1 ( 2) and nectrisine ( 3) are polyhydroxylated pyrrolidine iminosugars isolated from terrestrial sources. (10) Furthermore, the de novo chemical synthesis of coniine remains a touchstone for the synthesis of substituted piperidines. Coniine has a storied past in toxicology circles as the active poison of spotted hemlock and is known most notably for its role in the death of Socrates. We targeted (−)-coniine ( 1), DAB-1 ( 2), and nectrisine ( 3) as platforms to demonstrate the general applicability of our synthetic strategy toward the larger classes of saturated nitrogen heterocycles ( Figure 1). Our group has focused on augmenting the high enantioselectivities of enzyme-catalyzed reactions with transition metal-catalyzed processes that are able to stereospecifically alter the position and substitution of enzymatically derived stereochemistry. (5,6) One significant drawback of enzymes, however, is their often-limited substrate compatibility toward small organic molecules. Enzymatic reactions are a prime source of enantioenriched material, and their use has been critical to the development of enantioselective reactions. Therefore, deeper understanding of the importance of piperidine and pyrrolidine alkaloids is reliant on the development of new strategies for their enantioselective synthesis. (1−4) Importantly, the biological activity of these molecules is often tied to a specific enantiomer. Nitrogen heterocycles are ubiquitous among natural products and are found in countless pharmaceutical compounds. Functionalized piperidine and pyrrolidine alkaloids are a broad and diverse class of molecules that typically exhibit high levels of biological activity.
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