Mechanism of Glycosylation of Anomeric Sulfonium Ions

Abstract

Anomeric sulfonium ions are attractive glycosyl donors for the stereoselective installation of 1,2-cis glycosides. Although these donors are receiving increasing attention, their mechanism of glycosylation remains controversial. We have investigated the reaction mechanism of glycosylation of a donor modified at C-2 with a (1S)-phenyl-2-(phenylsulfanyl)ethyl chiral auxiliary. Preactivation of this donor results in the formation of a bicyclic β-sulfonium ion that after addition of an alcohol undergoes 1,2-cis-glycosylation. To probe the importance of the thiophenyl moiety, analogs were prepared in which this moiety was replaced by an anisoyl or benzyl moiety. Furthermore, the auxiliaries were installed as S- and R-stereoisomers. It was found that the nature of the heteroatom and chirality of the auxiliary greatly influenced the anomeric outcome and only the one containing a thiophenyl moiety and having S-configuration gave consistently α-anomeric products. The sulfonium ions are sufficiently stable at a temperature at which glycosylations proceed indicating that they are viable glycosylation agents. Time-course NMR experiments with the latter donor showed that the initial rates of glycosylations increase with increases in acceptor concentration and the rate curves could be fitted to a second order rate equation. Collectively, these observations support a mechanism by which a sulfonium ion intermediate is formed as a trans-decalin ring system that can undergo glycosylation through a bimolecular mechanism. DFT calculations have provided further insight into the reaction path of glycosylation and indicate that initially a hydrogen-bonded complex is formed between sulfonium ion and acceptor that undergoes SN2-like glycosylation to give an α-anomeric product.

Advances in Stereoselective 1,2‐cisGlycosylation using C‐2 Auxiliaries

“…[23] For example, glycosylations of glucosyl donor (S)-24,p rotected with acetyl esters at C-3, and C-6, gave the corresponding glucosides as only the a-anomer.H owever,s imilar glycosylations with glucosyl donor 26,p rotected with benzyle thers gave no or very poor anomerics electivity (Table 2B,e ntries 1-3v s. 6, 7). [25] These calculations showed that the C-3 acyl group destabilizes the oxocarbenium ion in the S N 1p athway therebyp romoting the S N 2p athway,a sw as postulated in earlier reports. After activationo ft he imidate leaving group, low-temperature NMR clearlys howedt he b-sulfonium ion had formed on the basis of the H-1 chemical shift and coupling constant (Figure 2C)a nd the correlation of C-1a nd H-8 in the HMBC spectrum ( Figure 2D).…”

“…[25] Three auxiliary variants werep repared, containing either at hiophenyl,ether (29), phenyle ther (30)o rb enzyl (31)m oiety.T he Rand S-configured auxiliaries were prepared giving rise to six variants in total. [25] Changing the S-configuration to the Rconfiguration had the largest effect on the auxiliaries that are expected to perform neighboring group participation (thiophenyle ther (29)a nd phenyl ether (30)a uxiliaries) suggesting ar ole of the sulfonium/oxonium ion in the reaction pathway. The benzyl auxiliary cannots tabilize the oxocarbenium ion and hence glycosylation through this intermediate is expected in al ess selective manner.I ns ome cases however,b enzyl auxiliary containing donor 31 performed quite well, but the same is true for a donor protected with aC -2 benzyl( data not shown, a/b = 15:1 with acceptor A6).…”

Stereoselective β‐Mannosylation by Neighboring‐Group Participation

“…[7] Oxidation of 7a/b (60-80 %) proceeded with moderate yields to provide 1 C 4 mannolactones 8a/b.F inally,t he compounds 8a/b were deallylated to afford glycosyl donors 9b/c. [12] However, 9c,w hich because of the high reactivity was activated at lower temperature (À78 8 8C), produced exclusively b-mannosides with both the primary and secondary acceptor (entries 5and 6).These results indicate that reactive intermediates other than the a-sulfonium ion are also important for the observed b-selectivity. Thed onors 9a-c were preactivated at low temperature (À78 8 8C, À40 8 8C respectively) with 1.0 equivalents of Tf 2 Oi nt he presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) as ab ase.A ll donors were activated almost instantaneously and reactions with 9a and 9b were warmed to À20 8 8Cbefore addition of the acceptor.A se xpected, 9a produced mainly a-mannosides, presumably via a cis-decalin sulfonium ion intermediate (entries 1a nd 2).…”

“…[12] However,glycosylation with the mannosyl donor 9c [12] However,glycosylation with the mannosyl donor 9c …”

Synergistic Glycosylation as Key to the Chemical Synthesis of an Outer Core Octasaccharide of Helicobacter pylori

“…[13] Convergent strategies can focus either on a[ 4 + +4] or a[ 3 + +5] key coupling. [16,18] Accordingly,t he orientation of the anomeric leaving groups had only little effect on the diastereoselectivity of the glycosylation. The selective formation of five 1,2-cis-a-glucosidic bonds (a-D-Glu) is the most challenging aspect of the assembly of octasaccharide 2.M any oligo-and polysaccharides that contain 1,2-cis-O-glycosidic linkages are biologically important.…”