An Inexpensive and Scalable Synthesis of Shld

A synthesis of the important FKBP ligand <b>Shld</b> is reported. The synthesis avoids stoichiometric use of expensive and chiral reagents, maintains enantioselectivity and provides a high overall yield (39%). The main features in the method are enantioselective alkylation for preparation of the phenyl acetic acid moiety (building block A), catalytic enantioselective reduction for obtaining the chiral diaryl-1-propanol (building block C), and direct acylation of <i>S</i>-pipecolic tartrate rather than use of expensive Fmoc-pipecolic acid. The assembly of the building blocks A–C is reversed in comparison to previous synthesis, which also eliminates the need for protective groups

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

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

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

Influence of O6 in Mannosylations Using Benzylidene Protected Donors: Stereoelectronic or Conformational Effects?

The stereoselective synthesis of β-mannosides and the underlying reaction mechanism have been thoroughly studied, and especially the benzylidene-protected mannosides have gained a lot of attention since the corresponding mannosyl triflates often give excellent selectivity. The hypothesis for the enhanced stereoselectivity has been that the benzylidene locks the molecule in a less reactive conformation with the O6 trans to the ring oxygen (O5), which would stabilize the formed α-triflate and subsequent give β-selectivity. In this work, the hypothesis is challenged by using the carbon analogue (C7) of the benzylidene-protected mannosyl donor, which is investigated in terms of diastereoselectivity and reactivity and by low-temperature NMR. In terms of diastereoselectivity, the C-7-analogue behaves similarly to the benzylidene-protected donor, but its low-temperature NMR reveals the formation of several reactive intermediate. One of the intermediates was found to be the β-oxosulfonium ion. The reactivity of the donor was found to be in between that of the “torsional” disarmed and an armed donor