Ferrier Carbocyclization-Mediated Synthesis of Enantiopure Azido Inositol Analogues

Abstract

Azide-modified inositol (InoAz) analogues are valuable as inhibitors and have shown promise as metabolic chemical reporters (MCRs) for labeling inositol-containing glycoconjugates in eukaryotic cells and potentially in mycobacteria, but the synthesis of enantiomerically pure InoAz analogues via traditional approaches is challenging. As a complementary route, here we investigated the application of the Ferrier carbocyclization reaction to the synthesis of enantiopure InoAz analogues starting from readily available azido glucosides. Using this approach combined with a para-methoxybenzyl protecting group strategy, 3-azido-3deoxy-and 4-azido-4-deoxy-D-myo-inositol were efficiently synthesized. 5-Azido-5-deoxy-D-myo-inositol was inaccessible due to an unusual β-elimination reaction, wherein the azide anion acted as the leaving group. The reported strategy is expected to facilitate continued development of synthetic InoAz analogues as inhibitors or MCRs of inositol-containing glycoconjugates in eukaryotic and mycobacterial systems.

Azido Inositol Probes Enable Metabolic Labeling of Inositol-Containing Glycans and Reveal an Inositol Importer in Mycobacteria

“…We envisioned that the InoAz probes would potentially be incorporated into the core of PIM, LM, and LAM, and/or the inositol phosphate cap appended to terminal arabinofuranosyl residues of LAM, a modification that occurs in Msmeg . To access the target compounds, we used our recently reported Ferrier carbocyclization-mediated synthesis of enantiopure InoAz analogues, which was used here to produce 3- and 4-InoAz. Because this method failed to produce 5-InoAz due to an unusual azido group-ejecting elimination side reaction, we used Sureshan’s reported regioselective double S N 2 method to generate 5-InoAz …”

“…Chemical Synthesis. 3-and 4-InoAz were synthesized as reported by Ausmus et al 31 5-InoAz was synthesized as reported by Ravi et al 32 1 H and 13 C NMR spectral data for intermediates and products were acquired on either Varian Mercury 300, Varian Inova 500, or Bruker Avance Neo 500 systems, and matched the literature.…”

“…1 To access the target compounds, we used our recently reported Ferrier carbocyclization-mediated synthesis of enantiopure InoAz analogues, 31 which was used here to produce 3-and 4-InoAz. Because this method failed to produce 5-InoAz due to an unusual azido group-ejecting elimination side reaction, 31 we used Sureshan's reported regioselective double S N 2 method to generate 5-InoAz. 32 InoAz Analogues Do Not Support the Growth of an Inositol Auxotroph.…”

Metabolic labeling of glycerophospholipids via clickable analogs derivatized at the lipid headgroup

“…This could be attributed to the ability of 2API to produce important PI lipids while perhaps not repressing phospholipid biosynthesis, which natural myo-inositol is known to do. In addition to these articles, other clickable inositol probes have been reported as putative substrates for metabolic labeling of inositol-containing lipids (Ausmus et al, 2020;Pasari et al, 2015).…”

Access to Enantiomeric Organic Compounds with Potential for Synthesis via Racemic Conglomerates: Inositol Derivatives as a Case in Point

“…Synthesis of enantiomerically pure organic compounds and resolution of racemates have gained unprecedented significance due to different properties of enantiomers and racemates, e.g ., the therapeutic efficacy of drugs. − Enantiomeric organic compounds can be extracted routinely from natural sources, although with wide variation in inputs in terms of cost, effort, and time. Due to the high enantiomeric purity of organic compounds isolable from natural sources, many of them form the starting materials for the synthesis of natural and unnatural chiral molecular entities. − Most laboratory methods of preparation of enantiomeric compounds involve the use of enantiomeric molecular entities such as catalysts (including enzymes) for asymmetric synthesis, chiral auxiliaries, resolving agents, or chiral stationary phases for the separation of enantiomers (in a racemate). ,− Almost all of these methods to obtain enantiomers depend on the solution-state chemistry. Enantiomers present in a racemate can also be separated by preferential enrichment of enantiomers and by preferential crystallization of conglomerates .…”