Achiral 2-Hydroxy Protecting Group for the Stereocontrolled Synthesis of 1,2-cis-α-Glycosides by Six-Ring Neighboring Group Participation

Abstract

Glycosylation of a fully armed donor bearing a 2-O-(trimethoxybenzenethiol) ethyl ether protecting group is completely α-selective with a range of carbohydrate alcohol acceptors. Low-temperature NMR studies confirm the intermediacy of cyclic sulfonium ion intermediates arising from six-membered β-sulfonium ring neighboring group participation. Selective protecting group removal is achieved in high yield in a single operation by S-methylation and base-induced β-elimination.

Absence of Stereodirecting Participation by 2-O-Alkoxycarbonylmethyl Ethers in 4,6-O-Benzylidene-Directed Mannosylation

“…After stirring at rt for a further 3 h, the mixture was concentrated. Chromatographic purification (14% ethyl acetate/hexanes) afforded the desired ketone product as a colorless oil (78 mg, 77%): [ α ] D 21 +72.7 ( c 1.245, CHCl 3 ). 1 H NMR (500 MHz, CDCl 3 ) δ 7.97 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.56 – 7.46 (m, 4H), 7.44 – 7.28 (m, 11H), 5.91 (d, J = 1.4 Hz, 1H), 5.64 (s, 1H), 5.10 – 5.00 (m, 2H), 4.94 (d, J = 11.7 Hz, 1H), 4.70 (d, J = 11.8 Hz, 1H), 4.36 (td, J = 9.6, 4.7 Hz, 1H), 4.30 (t, J = 9.5 Hz, 1H), 4.26 (dd, J = 10.3, 4.7 Hz, 1H), 4.10 (dd, J = 3.0, 1.5 Hz, 1H), 4.04 (dd, J = 9.5, 3.0 Hz, 1H), 3.89 (t, J = 10.1 Hz, 1H).…”

“…for C 35 H 31 F 3 O 6 SNa ([M + Na] + ): 659.1691; found: 659.1662. Further elution (20% ethyl acetate/hexanes) gave the sulfoxide as a colorless oil (19 mg, 18%): [ α ] D 21 −10.4 ( c 0.94, CHCl 3 ). 1 H NMR (600 MHz, CDCl 3 ) δ 7.85 – 7.81 (m, 2H), 7.63 (dd, J = 7.6, 1.8 Hz, 4H), 7.57 – 7.52 (m, 3H), 7.49 (dd, J = 7.7, 1.9 Hz, 2H), 7.41 – 7.33 (m, 5H), 7.32 – 7.26 (m, 3H), 5.62 (s, 1H), 5.03 (d, J = 16.9 Hz, 1H), 4.97 (s, 1H), 4.96 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 16.9 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.33 (m, 3H), 4.25 (dd, J = 10.4, 4.9 Hz, 1H), 4.15 (td, J = 9.5, 4.9 Hz, 1H), 3.77 (t, J = 10.2 Hz, 1H).…”

“…After that, the reaction mixture was stirred at rt for 6 h before it was diluted with ethyl acetate, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. Chromatographic purification (6% ethyl acetate/hexanes) afforded the title compound as a colorless oil (140 mg, 89%): [ α ] D 21 +80.5 ( c 1.225, CH 2 Cl 2 ). 1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (d, J = 1.7 Hz, 1H), 7.61 – 7.53 (m, 3H), 7.53 – 7.29 (m, 14H), 5.72 (d, J = 1.5 Hz, 1H), 5.68 (s, 1H), 5.51 (d, J = 1.3 Hz, 1H), 5.22 (s, 1H), 4.94 (d, J = 11.8 Hz, 1H), 4.73 (d, J = 11.9 Hz, 1H), 4.40 (m, 2H), 4.35 (td, J = 9.7, 5.1 Hz, 1H), 4.29 (t, J = 10.0 Hz, 1H), 4.28 (dd, J = 10.2, 5.0 Hz, 1H), 4.10 (dd, J = 3.1, 1.4 Hz, 1H), 4.05 (dd, J = 9.7, 3.1 Hz, 1H), 3.90 (t, J = 10.1 Hz, 1H).…”

“…13 With certain notable exceptions for which cyclic intermediates have been demonstrated spectroscopically or crystallographically, 14–21 the evidence for such effects typically is limited to often modest changes in anomeric selectivity and comparisons with selectivities observed in the presence of non-participating groups. 13,22–31 Alternative explanations are always available for such examples, most notably protecting group-induced changes in: i) conformation; 32–34 ii) through space stabilization of oxocarbenium ions; 35–41 iii) in the degree of association of the leaving group with the anomeric carbon; 42–43 iv) and the extent of pre-association of the donor and acceptor through hydrogen bonding.…”

Recent Advances in NMR Studies of Carbohydrates

“…Baek et al [134] studied directing effect by remote electron-withdrawing protecting groups at O-3 and O-4 position of donor in glycosylation and galactosylation. Recently, Cox et al [135] and Singh et al [136] investigated participation of different two-substituted ethyl ethers. Variable-temperature NMR experiments have been used to study on a sulfoxide [137] and sulfonium ions [138].…”