ABSTRACT
The iboga alkaloids are promising antiaddictive and neuroregeneration candidates for medical treatment. There is a lack of studies for C20-epi iboga alkaloids due to the synthetic difficulties. Herein we report the shortest total synthesis of (+)-epiibogamine in seven steps from trimethyl orthobutyrate. The novel N-sulfinyl silylenamine reagent enabled the key step, with three-component domino Michael/Michael/Mannich annulation providing the 1-amino-2,4-diester scaffold with four new chiral centers, and access to the isoquinuclidine in high yield (84%) and diastereoselectivity (>95:5 dr).
ABSTRACT
Chemicals possessing reactive electrophiles can denature innate proteins leading to undesired toxicity, and the overdose-induced liver injury by drugs containing electrophiles has been one of the major causes of non-approval and withdraw by the US Food and Drug Administration (FDA). Elucidating the associated proteins could guide the future development of therapeutics to circumvent these drugs' toxicities, but was largely limited by the current probing tools due to the steric hindrance of chemical tags including the common "click chemistry" labels. Taking the widely used non-steroidal anti-inflammatory drug acetaminophen (APAP) as an example, we hereby designed and synthesized an APAP analogue using fluorine as a steric-free label. Cell toxicity studies indicated our analogue has similar activity to the parent drug. This analogue was applied to the mouse hepatocellular proteome together with the corresponding desthiobiotin-SH probe for subsequent fluorine-thiol displacement reactions (FTDRs). This set of probes has enabled the labeling and pull-down of hepatocellular target proteins of the APAP metabolite as validated by Western blotting. Our preliminary validation results supported the interaction of APAP with the thioredoxin protein, which is an important redox protein for normal liver function. These results demonstrated that our probes confer minimal steric perturbation and mimic the compounds of interest, allowing for global profiling of interacting proteins. The fluorine-thiol displacement probing system could emerge as a powerful tool to enable the investigation of drug-protein interactions in complex biological environments.
ABSTRACT
The diastereoselective α-hydroxylation of N-tert-butanesulfinyl metallodienenamine and metalloenamines with Davis oxaziridine affords α-hydroxy N-sulfinyl imines with 50-88% yield and up to 98:2 diastereomeric ratio. Dramatic changes in diastereoselectivity and stereoselectivity were observed by choice of metal bases. The mechanistic understanding for the switch in diastereoselectivity was assisted by DFT computational modeling, which suggests the facial approach is governed by aza-enolate geometry. A one-pot protocol for the asymmetric synthesis of 1,2-amino alcohols is described.
Subject(s)
Amino Alcohols , Imines , Hydroxylation , Molecular Structure , Stereoisomerism , Sulfonium CompoundsABSTRACT
A novel and practical route to synthesize imidazol[1,5-a]indoles and pyrrolo[1,2-c]imidazoles via N-H functionalization has been developed. Indole-2-carboxylic acid or pyrrole-2-carboxylic acid with diverse aniline groups and carbonyldiimidazole (CDI), in the presence of a base under microwave conditions, resulted in imidazol[1,5-a]indoles and pyrrolo[1,2-c]imidazoles, respectively. The present method is free of work-up and no need for column chromatography. Both title scaffolds can serve as useful heterocyclic scaffolds in medicinal chemistry as such, or they can be used as building blocks to construct different classes of useful compounds.
