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, 138 (9), 3002-11

Mechanism of Glycosylation of Anomeric Sulfonium Ions


Mechanism of Glycosylation of Anomeric Sulfonium Ions

Tao Fang et al. J Am Chem Soc.


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.

Conflict of interest statement

The authors declare no competing financial interest.


Figure 1
Figure 1
NMR structure and thermostability studies of cis-decalin sulfonium ion 19. (a) Schematic presentation of NMR structural identification of 19. (b) gHMBC spectrum of 19 showing C1–H8ax three bond coupling. (c) Thermostability of 19 (chemical shifts were referenced to CD2Cl2).
Figure 2
Figure 2
Kinetics (conversion vs time) of glycosylations with donor 1S using different concentrations of acceptor 14 (a: 1 eq., b: 5 eq., and c: 10 eq. of 14). The glycosyl donor was preactivated at −78 °C and the temperature was raised to −40 °C before adding the acceptor. The acceptor in DCM was precooled in a dry ice/acetone bath and quickly transferred through a double hollow needle to avoid temperature changes. Nonlinear regression analysis was based on F-test (null hypothesis: 1st order reaction; alternative hypothesis: 2nd order reaction.). In every case, Prism 6.0 denied the null hypothesis (P > 0.05); therefore all curves were fitted based on the second-order reaction. The experimental data fall in the 95% confidence intervals (thin lines). Details of statistic analysis are available in SI.
Figure 3
Figure 3
Model sulfonium ions used in the DFT calculations.
Figure 4
Figure 4
(a) Energy (kcal/mol)–distance (Å) plot for forced extension of C1–S bonds of sulfonium ion M1 and sulfonium ion-methanol complex Cpx1; (b) dO–C1 (Å)–dC1–S (Å) plot for forced extension of C1–S bonds of sulfonium ion–methanol complex Cpx1.
Figure 5
Figure 5
Optimized structures of SN1 and SN2 transition states associated with sulfonium ion M2. (Unit: kcal/mol).
Scheme 1
Scheme 1. Bicyclic Sulfonium Ions Mediated Stereoselective cis-Glycosylationsa
a(a) In situ formation of bicyclic sulfonium ions by the preactivation of donors with C-2 (S)-auxiliary; (b) direct conversion of preformed bicyclic oxathiane ketals by arylation.
Scheme 2
Scheme 2. Preparation of C-2 Modified Donorsa
aReagents and conditions: (i) BF3-Et2O, DCM, 2 h (8R: 48%, 8S: 44%, 8R: 88%, 8S: 90%); (ii) NaH, DMF, 90 °C, 16 h (6: 90%, 7: 88%); (iii) TMSOTf, Ac2O, 0 °C, 10 min; (iv) H2NNH2–HOAc, DMF, 45 °C, 90 min; then CF3C = (NPh)Cl, DBU, DCM, r.t., 10 min (2 steps, 2S: 68%, 2R: 73%, 3R: 80%, 3S: 75%).
Scheme 3
Scheme 3. Optimized Structures of SN1 and SN2 Transition States Associated with Sulfonium Ion M1a
aUnit: kcal/mol. The binding energy of a donor–acceptor complex is defined as the energy difference between the complex and the sum of its two components, the corresponding sulfonium ion and methanol: ΔGbnd = ΔGcpx − ΔGsulfonium − ΔGMeOH. The binding energy of an SN2 transition state is defined likewise: ΔGbnd = ΔGTS − ΔGoxacarbenium − ΔGMeOH.

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