Does Neighboring Group Participation by Non-Vicinal Esters Play a Role in Glycosylation Reactions? Effective Probes for the Detection of Bridging Intermediates

Abstract

Neighboring group participation in glycopyranosylation reactions is probed for esters at the 3-Oaxial and equatorial, 4-O-axial and equatorial, and 6-O-sites of a range of donors through the use tert-butoxycarbonyl esters. The anticipated intermediate cyclic dioxanyl cation is interrupted for the axial 3-O-derivative leading to the formation of a 1,3-O-cyclic carbonate ester, with loss of a tertbutyl cation, providing convincing evidence of participation by esters at that position. However, no evidence was found for such a fragmentation of carbonate esters at the 3-O-equatorial, 4-O axial and equatorial and 6-O positions indicating that neighboring group participation from those sites does not occur under typical glycosylation conditions. Further probes employing a 4-O-(2-carboxy) benzoate ester and a 4-O-(4-methoxybenzoate) ester, the latter in conjunction with an 18 O quench designed to detect bridging intermediates, also failed to provide evidence for participation by 4-Oesters in galactopyranosylation.

3-Oxodapagliflozin as a potent and highly selective SGLT2 inhibitor for the treatment of type 2 diabetes

“…Reduction of compound 15 with NaBH 4 [12] in THF at 0 °C produced a separable mixture of compound 21 and its C3-epimer (4) in a molar ratio of 3:1. The preference for the formation of compound 21 over compound 4 resulted from the attack of the hydride from the less sterically hindered β face, which is consistent with those reported [13] and observed for the formation of compound 17. Alkylation of compound 21 as described above for compound 4 afforded compounds 22-24, which yielded compounds 25-27 on acidic hydrolysis described above, respectively.…”

“…1 H nuclear magnetic resonance( 1 H NMR) and 13 C NMR spectra were recorded on a Bruker AV400 NMR spectrometer with DMSO-d 6 as solvent and TMS as internal standard. Infrared(IR) spectra were taken on a Bruker Vector 22 FTIR spectrometer with KBr discs.…”

Interplay of Protecting Groups and Side Chain Conformation in Glycopyranosides. Modulation of the Influence of Remote Substituents on Glycosylation?

“…The small changes in side chain conformation in a series of 4- O -alkanoyl and aroyl esters in both the galacto- and glucopyranosyl series do not provide strong support for a protecting-group-induced change in side chain population as the basis for the changes in anomeric selectivity and previously seen in the series of 17 – 20 77 and related systems, 78 previously explained by the controversial 61−66 concept of stereodirecting participation by remote groups. Similarly, the consistent side chain conformation observed with numerous protecting groups at the 6-position in the 2,3,4-tri- O -benzyl glucopyranosides (Table 3) does not support a role of the side chain conformation in the changes in anomeric reactivity and glycosylation selectivity reported in such series of compounds.…”

“…NaHCO 3 solution, dried over Na 2 SO 4 , and concentrated under a high vacuum. Silica gel column chromatography (eluent: 20% ethyl acetate in hexane) afforded 19 (61) (0.050 g, 80%) as a colorless oil. 1 H NMR (600 MHz, CDCl 3 ) δ 7.97–7.95 (m, 2H), 7.66–7.62 (m, 2H), 7.40–7.39 (m, 2H), 7.36–7.20 (m, 16H), 6.94–6.92 (m, 2H), 5.87 (d, J = 3.0 Hz, 1H), 4.86 (d, J = 11.4 Hz, 1H), 4.74 (br s, 2H), 4.71 (d, J = 9.2 Hz, 1H), 4.53 (d, J = 11.0, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 3.89 (s, 3H), 3.89–3.87 (m, 1H), 3.75 (dd, J = 9.2, 2.9 Hz, 1H), 3.71 (t, J = 9.2 Hz, 1H), 3.69 (dd, J = 9.6, 6.1 Hz, 1H), 3.59 (dd, J = 9.6, 6.5 Hz, 1H).…”

Study of the Stereoselectivity of 2-Azido-2-deoxygalactosyl Donors: Remote Protecting Group Effects and Temperature Dependency

“…Some recent work from Crich's group showed lack of participation of 3-O-acetyl in a benzylidene-protected mannosyl donor. 42 A series of calculations were carried out to test our hypothesis. Three potential participating intermediates P3-2 (P3-2 represents participation of 3-acetyl group in oxocarbenium ion derived from donor 2, the same rules are used for other acetyl participation intermediates), P4-2, and P6-2 were optimized and their energy calculated using quantum mechanical methods ( Figure 2).…”