Conformationally Armed 3,6-Tethered Glycosyl Donors: Synthesis, Conformation, Reactivity, and Selectivity

The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several promoter systems. Thiophenyl 2,4-di-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside gave α/β mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using SnCl₂/AgB­(C₆F₅)₄ as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation. Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-<i>O</i>-benzyl-3,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-α-d-glucopyranoside was found to be α-selective . The reactivity of the donors was investigated using competition experiments, and some but not all were found to be highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism supporting the unusual observations has been suggested

Effect of 2‑<i>O</i>‑Benzoyl para-Substituents on Glycosylation Rates

From a series of competition experiments, we have explored the degree to which various para-substituents (CN, Br, H, OMe, pyrrolidino) of a 2-<i>O</i>-benzoyl functionalized glucosyl donor of the thioglycoside type affect the rate of glycosylation under <i>N</i>-iodosuccinimide/triflic acid activation. As expected, electron-withdrawing groups were found to decrease the rate of glycosylation, whereas electron-donating groups resulted in the opposite outcome, underscoring the influence on the reaction rate exerted by a participating group. On this basis, a Hammett linear free-energy relationship was established (<i>R</i>² = 0.979, ρ = 0.6), offering fundamental insight into the magnitude of anchimeric assistance in glycosylation chemistry

Rhamnosylation: Diastereoselectivity of Conformationally Armed Donors

The α/β-selectivity of super-armed rhamnosyl donors have been investigated in glycosylation reactions. The solvent was found to have a minor influence, whereas temperature was crucial for the diastereoselectivity. At very low temperature, a modest β-selectivity could be obtained, and increasing temperature gave excellent α-selectivity. The donors were highly reactive, and activation was observed at temperatures as low as −107 °C. Different promoter systems and leaving groups were investigated, and only activation with a heterogeneous catalyst increased the amount of the β-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in β-product was observed

Remote Electronic Effects by Ether Protecting Groups Fine-Tune Glycosyl Donor Reactivity

It was established that <i>para</i>-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the <i>N</i>-iodosuccinimide/triflic acid promoter system. Having electron donating <i>p</i>-methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing <i>p</i>-chloro (PClB) or <i>p</i>-cyanobenzyl ether (PCNB) protecting groups, which decreased the reactivity of the glycosyl donor relative to the parent benzyl ether (Bn) protected glycosyl donor. These findings were used to perform the first armed-disarmed coupling between two benzylated glucosyl donors by tuning their reactivity. In addition, the present work describes a highly efficient palladium catalyzed multiple cyanation and methoxylation of <i>p</i>-chlorobenzyl protected thioglycosides. The results of this paper regarding both the different electron withdrawing properties of various benzyl ethers and the efficient and multiple protecting group transformations are applicable in general organic chemistry and not restricted to carbohydrate chemistry

3‑(Dimethylamino)-1-propylamine: A Cheap and Versatile Reagent for Removal of Byproducts in Carbohydrate Chemistry

Inexpensive 3-(dimethylamino)-1-propylamine (DMAPA) was found to be effective in anomeric deacylation reactions giving 1-<i>O</i> deprotected sugars in high yield as precursors for the formation of imidate glycosyl donors. DMAPA was also found to be useful for removing excess reagents such as benzoyl chloride, tosyl chloride, and 2,2,2-trifluoro-<i>N</i>-phenylacetimidoyl chloride. The deacylation reaction could be conducted in moist THF and did not require chromatographic purification since an acidic wash was sufficient to remove excess reagent and the formed byproduct

<i>p</i>‑Chlorobenzyl Ether: A <i>p</i>‑Methoxybenzyl Ether in Disguise

In the chemistry of polyfunctionalized organic compounds, protecting groups that can undergo mild and selective cleavage while still being stable during the entire synthetic sequence are often required. In this work, we present a straightforward conversion of the robust <i>p</i>-chlorobenzyl ether into the more labile and well-described <i>p</i>-methoxybenzyl ether using palladium catalysis. This reaction was demonstrated to be high yielding and compatible with a wide range of functionalities, thereby providing a useful supplement to the conventional ether protecting groups

β‑Selective Mannosylation with a 4,6-Silylene-Tethered Thiomannosyl Donor

Mannosylations using the new conformationally restricted donor phenyl 2,3-di-<i>O</i>-benzyl-4,6-<i>O</i>-(di-<i>tert</i>-butylsilylene)-1-thio-α-d-mannopyranoside (<b>6</b>) have been found to be β-selective with a variety of activation conditions. The simplest activation conditions were NIS/TfOH, in which case it is proposed that the β-mannoside is formed from β-selective glycosylation of the oxocarbenium ion <b>25</b> in a <i>B</i>_2,5 conformation

Superarming of Glycosyl Donors by Combined Neighboring and Conformational Effects

A novel glycosyl donor that combines the concepts of both conformational and electronic superarming has been synthesized. The reactivity and selectivity of the donor have been tested in competition experiments