Synthesis, Reactivity, and Stereoselectivity of 4-Thiofuranosides

Abstract

Thiosugars, sugars that have their endocyclic oxygen substituted for a sulfur atom, have been used as stable bioisosteres of naturally occurring glycans because the thiosugar glycosydic linkage is supposed to be stabilized toward chemical and enzymatic hydrolysis. We have performed an in-depth investigation into the stability and reactivity of furanosyl thiacarbenium ions, by assessing all four diastereoisomeric thiofuranosides experimentally and computationally. We show that all furanosyl thiacarbenium ions react in a 1,2-cis-selective manner with triethylsilane, reminiscent of their oxo counterparts. The computed conformational space occupied by the thiacarbenium ions is strikingly similar to that of the corresponding furanosyl oxycarbenium ions, indicating that the stereoelectronic substituent effects governing the stability of furanosyl oxocarbenium ions and thiacarbenium ions are very similar. While the thio-ribo-furanose appears to be less reactive than its oxo counterpart, the thio-ara-, lyxo-, and xylo-furanosides appear to be more reactive than their oxygen equivalents. These differences are accounted for using the conformational preference of the donors and the carbocation intermediates. The lower reactivity of the thio-ribo furanosides in (Lewis) acid-mediated reactions and the similarity of the thia- and oxocarbenium ions make thio-ribo-furanosides excellent stabilized analogues of the naturally occurring ribo-furanose sugars.

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

“…[43] Allyl-TMS and [D]TES are poor nucleophiles and are ideal acceptors to study the S N 1r eaction pathways of the glycosylations at hand. [15,16,[44][45][46] The results of theseglycosylations together with results obtained previously for the tri-O-benzyl series (i.e., donors 57-60)a re listed in Table 2. As previously described, the reactions in the tri-O-benzyl series proceed with good to excellent 1,2-cis selectivityf or all four configurations.…”

“…Based on acomputational strategy of Rhoad and co-workers, [14] we have recently introduced am ethod to determine the conformational behaviour of furanosyl oxocarbenium ions. [15][16][17] By calculating the relative energy of al arge number of fixed furanosyl oxocarbenium ion conformers and mapping these in energy contourp lots we could determine, which conformations played an important role during furanosylation reactions and we were abletorelate the population of the different conformational states to the stereoselectivity of the reactions. The introduced conformational energyl andscape mapping method provided detailed insighti nto how the ring substituents-as stand-alone entities but also collectively-influenced the shape, stability and reactivity of the furanosyl oxocarbenium ions.…”

“…However, it is extremely challenging to understand—let alone predict—what the overall effect of multiple ring substituents is on the reactivity of a particular glycosyl donor and as a result the effect on the stereoselectivity in a glycosylation reaction. Based on a computational strategy of Rhoad and co‐workers, we have recently introduced a method to determine the conformational behaviour of furanosyl oxocarbenium ions . By calculating the relative energy of a large number of fixed furanosyl oxocarbenium ion conformers and mapping these in energy contour plots we could determine, which conformations played an important role during furanosylation reactions and we were able to relate the population of the different conformational states to the stereoselectivity of the reactions.…”

Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

“…To understand why some acetyl esters engage in LRP and lead to the formation of bicyclic dioxolenium ions from the parent oxocarbenium ions, while others do not, we computationally investigated their relative stability. We recently developed a DFT protocol to compute the relative energy of a large ensemble of oxocarbenium ion conformers, filling the complete conformational space these cations can occupy and plotted their relative energy to afford CEL maps 29,[39][40][41] . Employing this method, we are able to find low energy conformers and relevant (conformational) pathways a Glycosyl donors used for IRIS and in silico experiments b Glycosyl donors used for glycosylation reactions in solution which connect these on the CEL.…”

Synthesis of Stable NAD+ Mimics as Inhibitors for the Legionella pneumophila Phosphoribosyl Ubiquitylating Enzyme SdeC

“…[21] First, we synthesized protected thioribitol 13 from ribose, essentially as described by us and others. [21,22] In brief, the synthesis started with readily accessible and inexpensive D-ribose that was first converted into lactol 9, the aldehyde functionality of which was next reduced to give ribitol 10. Mesylation and double bromide substitution then provided dibromide 12, which was treated with sodium sulfide to give thioribitol 13.…”