Palladium-Catalyzed C-S Bond Formation as a Tool for Latent-Active Glycosylation.

A high-yielding palladium-catalyzed C-S cross-coupling is presented for utilization in carbohydrate chemistry as a key transformation for attachment of a second chelating sulfur atom that allows the exploitation of a latent-active glycosylation strategy with Cu(OTf)2 as the promoter. The novel approach employs o-Br-benzyl thioglycosides as latent glycosyl donors and o-SMe-benzyl thioglycosides as the active counterparts.

Dissection of the effects that govern thioglucoside and thiomannoside reactivity.

Neighboring group effects were investigated in gluco- and manno-configured thioglycosides under NIS/TfOH activation. Donors possessing a 2-O-benzoyl group that are capable (1,2-trans) and incapable (1,2-cis) of exerting nucleophilic push were compared with donors possessing a participatory neutral 2-O-benzyl group. By using competition experiments between sets of glycosyl donors the direct effect of neighboring group participation and the electron withdrawing effect of the 2-O-benzoyl group could be separated. The study brings insight into how the stereochemistry of the 1 and 2 position and how the nature of the aglycon (Ph or Et) have a pronounced effect on glycosyl donor reactivity.

On the generality of the superarmament of glycosyl donors.

It was established that 2-O-benzoyl-3,4,6-tri-O-benzyl protected ß-SEt, ß-SPh and ß-SBox glucosyl donors are not superarmed when using the NIS/TfOH promoter system, but instead have a similar reactivity as their classically armed tetra-O-benzyl protected glucosyl counterparts. The ß-SBox 2-O-benzoyl-3,4,6-tri-O-benzyl glucosyl donor, however, was found to be superarmed under DMTST activation. Our studies have shown that the increased reactivity of the ß-SBox 2-O-benzoyl-3,4,6-tri-O-benzyl glucosyl donor with DMTST activation could be a unique case, and that the high reactivity of glucosyl donors with the 2-O-benzoyl-3,4,6-tri-O-benzyl protection pattern is not general as earlier suggested.

Effect of 2-O-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-O-benzoyl functionalized glucosyl donor of the thioglycoside type affect the rate of glycosylation under N-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 (R 2 = 0.979, ρ = 0.6), offering fundamental insight into the magnitude of anchimeric assistance in glycosylation chemistry.

DIDMH in combination with triflic acid - A new promoter system for thioglycoside glycosyl donors.

We have explored the possibility of using 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) as an alternative to N-iodosuccinimide (NIS) for activation of glycosyl donors of the thioglycoside type in various glycosylation reactions. DIDMH was found to match NIS when it comes to the capability to activate thioglycosides and provide glycosylation products in good yields. Notably, with the two equivalents of reactive iodonium ions per molecule of DIDMH less mass needs to be added making this activator a more atom economically alternative to NIS. Furthermore, DIDMH was found to be stable upon storage for weeks and comparably priced to NIS. With this knowledge in hand we therefore encourage the carbohydrate community to consider using DIDMH for activation of thioglycosides in glycosylation reactions.

Removal of some common glycosylation by-products during reaction work-up.

With the aim of improving the general glycosylation protocol to facilitate easy product isolation it was shown that amide by-products from glycosylation with trichloroacetimidate and N-phenyl trifluoroacetimidate donors could be removed during reaction work-up by washing with a basic aqueous solution. Excess glycosyl acceptor or lactol originating from glycosyl donor hydrolysis could equally be removed from the reaction mixture by derivatization with a basic tag and washing with an acidic solution during reaction work-up.

p-Chlorobenzyl Ether: A p-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 p-chlorobenzyl ether into the more labile and well-described p-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.

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

It was established that para-substituted benzyl ether protecting groups affect the reactivity of glycosyl donors of the thioglycoside type with the N-iodosuccinimide/triflic acid promoter system. Having electron donating p-methoxybenzyl ether (PMB) groups increased the reactivity of the donor in comparison to having electron withdrawing p-chloro (PClB) or p-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 p-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.

ß-Mannosylation with 4,6-benzylidene protected mannosyl donors without preactivation.

Mannosylations with benzylidene protected mannosyl donors were found to be ß-selective even when no preactivation was performed. It was also found that the kinetic ß-product in some cases anomerizes fast to the thermodynamically favored α-anomer under typical reaction conditions.

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-O 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-N-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.

ß-Selective mannosylation with a 4,6-silylene-tethered thiomannosyl donor.

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

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-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-glucopyranoside gave α/ß mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly ß-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 ß-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-O-benzyl-3,6-O-(di-tert-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 ß; 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/ß-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 ß-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 ß-anomer significantly. By introducing an electron-withdrawing nonparticipating group, benzyl sulfonyl, on 2-O, an increase in ß-product was observed.

The influence of neighboring group participation on the hydrolysis of 2-O-substituted methyl glucopyranosides.

Does neighboring group participation actually enhance the reactivity of the anomeric center when the participating group is inherently disarming? To investigate the influence of the neighboring group effect from a 2-O protective group on acidic glycoside hydrolysis, 10 methyl glucosides having different protective groups on O2 have been synthesized and a clear trend between anomeric configuration, participation of the protective group, and the rate of hydrolysis could be observed.

Quantifying electronic effects of common carbohydrate protecting groups in a piperidine model system.

A study of the substituent effects of protecting groups in hydroxypiperidines was carried out and compared with the electronic effects in glycosylation chemistry. 1-Deoxynojirimycin, the aza-sugar analogue of 1-deoxy-D-glucose, was used as a carbohydrate model, and protected with the most common carbohydrate protecting groups. The different stabilization of positive charge on the ring heteroatom was determined by pK(a) measurements. The protecting groups could be ranked in the following way after their destabilization of the piperidinium ion: benzoyl ≥ acetyl ≫ 4,6-O-benzylidine >benzyl ≈ methyl > H > 3,6-anhydro > tert-butyldimethylsilyl. The observed effects of having protecting groups with different electronic characteristics were found to be in agreement with the "armed-disarmed" concept. Comparison of the pK(a) of benzylated and benzoylated epimers of 3-hydroxy-6-hydroxymethyl piperidines showed increased stabilization of the piperidinium ion in the axial epimer. The difference between axial and equatorial epimers was larger in the benzylated than in the benzoylated piperidines.