Exhaustive Conformational Search for Sialyl Cation Reveals Possibility of Remote Participation of Acyl Groups

Abstract

Finding convenient ways for the stereoselective α‐sialylation is important due to the high practical significance of α‐sialic acid‐containing glycans and neoglycoconjugates. It was proposed that sialylation stereoselectivity is determined by the structure of the sialyl cation (also known in biochemistry as “sialosyl cation”), a supposed intermediate in this reaction. Here we design a new approach for studying the conformational space of highly flexible sialyl cation and find 1625 unique conformers including those stabilized by covalent remote participation (also known as long‐range participation) of 4‐O‐acetyl (4‐OAc), 5‐N‐trifluoroacetyl (5‐NTFA), as well as 7,8,9‐OAc from both α and β sides. The most energetically stable sialyl cation conformers are featured by 4‐OAc participation, closely followed by 5‐NTFA‐ and 7‐OAc‐stabilized conformers; unstabilized sialyl cation conformers are ∼10 kcal mol−1 less stable than the 4‐OAc‐stabilized ones. Analysis of all the obtained conformers by means of substituents positions, side chain conformations and ring puckering led us to a new “eight‐conformer hypothesis” which describes interconversions among the most important sialyl cation conformers and predicts that stronger remote participation of acyl groups favors β‐anomers. Thus, selective synthesis of the desired α‐sialosides requires minimization of acyl groups participation.

Comparison of glycosyl donors: a supramer approach

“…Noteworthy is a slightly higher stereoselectivity achieved when sialyl donor 1 with a trifluoroacetyl group at O-9 was used (α:β = 16:1 for 1 versus α:β = 13:1 for 2 ). One could speculate that a more nucleophilic carbonyl oxygen of the chloroacetyl group at O-9 in sialyl donor 2 might participate in a stabilization of the intermediate glycosyl cation from the α-side (as we discussed earlier [ 52 – 53 ]) diminishing the α/β ratio.…”

“…All this suggests that in the particular case of sialyl donors 1 and 2 studied it is not possible to conclude unambiguously which one of them is more reactive and which one of them provides higher stereoselectivity in the sialylation of the same glycosyl acceptor 3 . Thus, it is not possible to reveal a possible influence of remote acyl protective groups at O-9 on the sialylation outcome, hence experimentally confirm or disprove their putative participation in stabilization [ 52 – 53 ] of the glycosyl cation. More importantly, in our opinion, this result indicates the existence of unexpected difficulties in the determination of relative reactivities of glycosyl donors (vide infra).…”

“…During a study of a possible influence of remote acyl protective groups [ 23 ] on the sialylation outcome (which could become possible through participation in stabilization of glycosyl cation [ 24 , 47 – 48 ] in a conformation with all-axial substituents in the pyranose ring [ 49 – 53 ]), we needed to compare two different sialyl donors 1 [ 36 ] and 2 with trifluoroacetyl (TFA) and chloroacetyl (ClAc) groups at O-9, respectively, all other substituents being the same. Here, we report the unexpected problems encountered when comparing these glycosyl donors in the sialylation of the primary hydroxy group of the same galactose derivative 3 [ 54 ] (see Scheme 1 ), which eventually led to unprecedented conclusions concerning the very possibility of comparison of chemical properties of different glycosyl donors.…”

“…As in other glycosylation reactions [22][23][24][25][26][27][28][29], the result of sialylation is affected by a variety of variables [30][31][32][33][34][35][36][37][38][39] including the nature of protective groups on either partner [26,38,[40][41][42][43][44][45] and concentration of reagents [31,33,34,37,39,43,44,46]. During a study of a possible influence of remote acyl protective groups [23] on the sialylation outcome (which could become possible through participation in stabilization of glycosyl cation [24,47,48] in a conformation with all-axial substituents in the pyranose ring [49][50][51][52][53]), we needed to compare two different sialyl donors 1 [36] and 2 with trifluoroacetyl (TFA) and chloroacetyl (ClAc) groups at O-9, respectively, all other substituents being the same. Here, we report the unexpected problems encountered when comparing these glycosyl donors in the sialylation of the primary hydroxy group of th...…”

Binomial Uncertainty in Molecular Dynamics-Based Reactions Analysis

“…The ratio of trajectories converging into each product is considered the predicted product ratio. Likewise, there are systems 8,15 where a PES has a shallow flat barrier containing several high-energy intermediates, where the system can dwell for some time before converging into one of the products. In such cases nonstatistical dynamic effects can play a pivotal role, so MD stimulations launched from highenergy intermediates 16 can be used to predict product ratios.…”