Stereoselective organocatalyzed glycosylations – thiouracil, thioureas and monothiophthalimide act as Brønsted acid catalysts at low loadings

Abstract

Thiouracil catalyzes stereoselective glycosylations with galactals in loadings as low as 0.1 mol%.

A robust and tunable halogen bond organocatalyzed 2-deoxyglycosylation involving quantum tunneling

“…72% [a, b] D:E 79:21 OMe 1c: R 1 = TBS 1d: R 1 = Bn 1e: 1i-1k, which are challenging in thiourea catalysis 47,56 . Gratifyingly, natural (1i, 1j) and nonnatural pentose-based donors (1k) work generally well in our XB catalysis protocol, to generate the target glycosides (4a-4m) with good to excellent yields and good anomeric selectivity.…”

“…Specifically, we aim to harness and unravel noncovalent mechanisms unique to XB organocatalysis, so that enabling methodologies, which facilitates the preferential construction of challenging bonds over thiourea catalysis in biologically relevant molecules can be developed. In line with this aim, we have identified the biologically relevant 2-deoxyglycosylation as an ideal reaction model for the discovery for unknown XB catalytic mechanisms [46][47][48][49][50][51][52][53][54][55][56][57][58][59] . The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations.…”

“…The unique poly-oxygenated nature of glycosyl substrates and products provides numerous XB acceptor moieties for the in situ catalytic establishment of dynamic noncovalent activations. Moreover, the synthetic importance of 2deoxyglycosides as a privileged and biologically useful compound class is well exemplified by the continual intense interest by many different research groups [46][47][48][49][50][51][52][53][54][55][56][57][58][59] , due to its prevalence in glycosidic natural products, such as digitoxin and saccharomicin B (ref. 46 ).…”

“…On the organocatalytic front [60][61][62][63][64] , seminal studies by Galan and McGarrigle et al demonstrated the utility of thiourea catalysis in accessing 2-deoxyglycosides via mild organocatalytic conditions 47,56 . However, significant limitations still exist in such protocols.…”

“…1e), featuring robustness, mildness, substrate broadness, and mechanistic complexity via a switchable intricate reaction network. Noncovalent catalytic benchmarking studies are conducted between our protocol and widely established thiourea-catalyzed protocols 47,56 , and our protocol furnishes overall superior donor and acceptor substrate generality, noteworthily in silylated galactals, glucals, rhamnals, and pentose-derived donors. We introduce a halogen swapping strategy for challenging D-ribal substrates, and this was found to be effective in tolerating challenging 2-deoxypyranoribosylations.…”