Gerrit Lodder

The impact of oxacarbenium ion conformers on the stereochemical outcome of glycosylations

The search for stereoselective glycosylation reactions has occupied synthetic carbohydrate chemists for decades. Traditionally, most attention has been focused on controlling the S(N)2-like substitution of anomeric leaving groups as highlighted by Lemieuxs in situ anomerization protocol and by the discovery of anomeric triflates as reactive intermediates in the stereoselective formation of beta-mannosides. Recently, it has become clear that also S(N)1-like reaction pathways can lead to highly selective glycosylation reactions. This review describes some recent examples of stereoselective glycosylations in which oxacarbenium ions are believed to be at the basis of the selectivity. Special attention is paid to the stereodirecting effect of substituents on a pyranosyl ring with an emphasis on the role of the C-5 carboxylate ester in the condensations of mannuronate ester donors.

Stereodirecting effect of the pyranosyl C-5 substituent in glycosylation reactions.

The stereodirecting effect of the glycosyl C-5 substituent has been investigated in a series of d-pyranosyl thioglycoside donors and related to their preferred positions in the intermediate (3)H(4) and (4)H(3) half-chair oxacarbenium ions. Computational studies showed that an axially positioned C-5 carboxylate ester can stabilize the (3)H(4) half-chair oxacarbenium ion conformer by donating electron density from its carbonyl function into the electron-poor oxacarbenium ion functionality. A similar stabilization can be achieved by a C-5 benzyloxymethyl group, but the magnitude of this stabilization is significantly smaller than for the C-5 carboxylate ester. As a result, the preference of the C-5 benzyloxymethyl to occupy an axial position in the half-chair oxacarbenium ions is much reduced compared to the C-5 carboxylate ester. To minimize steric interactions, a C-5 methyl group prefers to adopt an equatorial position and therefore favors the (4)H(3) half-chair oxacarbenium ion. When all pyranosyl substituents occupy their favored position in one of the two intermediate half-chair oxacarbenium ions, highly stereoselective glycosylations can be achieved as revealed by the excellent beta-selectivity of mannuronate esters and alpha-selectivity of 6-deoxygulosides.

The Stereodirecting Effect of the Glycosyl C5-Carboxylate Ester: Stereoselective Synthesis of β-Mannuronic Acid Alginates

Glycosylations of mannuronate ester donors proceed highly selectively to produce the 1,2-cis-linked products. We here forward a mechanistic rationale for this counterintuitive selectivity, based on the remote stereodirecting effect of the C5-carboxylate ester, which has been demonstrated using pyranosyl uronate ester devoid of ring substituents other than the C5- carboxylate ester. It is postulated that the C5-carboxylate ester prefers to occupy an axial position in the oxacarbenium intermediate, thereby favoring the formation of the (3)H4 half-chair over the (4)H3 conformer. Nucleophilic attack on the (3)H4 half-chair intermediate occurs in a beta-fashion, providing the 1,2-cis-mannuronates with excellent stereoselectivity. The potential of the mannuronate ester donors in the formation of the beta-mannosidic linkage has been capitalized upon in the construction of a mannuronic acid alginate pentamer using a convergent orthogonal glycosylation strategy.

Equatorial Anomeric Triflates from Mannuronic Acid Esters

Activation of mannuronic acid esters leads to a conformational mixture of alpha-anomeric triflates, in which the equatorial triflate ((1)C(4) chair) is formed preferentially. This unexpected intermediate clearly opposes the anomeric effect and is mainly stabilized by the electron-withdrawing carboxylate function at C-5. Because the anomeric center carries a significant positive charge, the (1)C(4) mannopyranosyl chair approximates the favored (3)H(4) half-chair oxacarbenium ion conformation. The excellent beta-selectivity in glycosylations of mannuronates is postulated to originate from the cooperative action of the triflate counterion and the (stereo)electronic effects governing oxacarbenium ion stabilization in the transition state leading to the 1,2-cis product.

Mannosazide Methyl Uronate Donors. Glycosylating Properties and Use in the Construction of β-ManNAcA-Containing Oligosaccharides

Mannosazide methyl uronate donors equipped with a variety of anomeric leaving groups (β- and α-S-phenyl, β- and α-N-phenyltrifluoroacetimidates, hydroxyl, β-sulfoxide, and (R(s))- and (S(s))-α-sulfoxides) were subjected to activating conditions, and the results were monitored by (1)H NMR. While the S-phenyl and imidate donors all gave a conformational mixture of anomeric α-triflates, the hemiacetal and β- and α-sulfoxides produced an oxosulfonium triflate and β- and α-sulfonium bistriflates, respectively. The β-S-phenyl mannosazide methyl uronate performed best in both activation experiments and glycosylation studies and provided the 1,2-cis mannosidic linkage with excellent selectivity. Consequently, an α-Glc-(1→4)-β-ManN(3)A-SPh disaccharide, constructed by the stereoselective glycosylation of a 6-O-Fmoc-protected glucoside and β-S-phenyl mannosazide methyl uronate, was used as the repetitive donor building block in the synthesis of tri-, penta-, and heptasaccharide fragments corresponding to the Micrococcus luteus teichuronic acid.

Mannopyranosyl Uronic Acid Donor Reactivity

The reactivity of a variety of mannopyranosyl uronic acid donors was assessed in a set of competition experiments, in which two (S)-tolyl mannosyl donors were made to compete for a limited amount of promoter (NIS/TfOH). These experiments revealed that the reactivity of mannuronic acid donors is significantly higher than expected based on the electron-withdrawing capacity of the C-5 carboxylic acid ester function. A 4-O-acetyl-β-(S)-tolyl mannuronic acid donor was found to have similar reactivity as per-O-benzyl-α-(S)-tolyl mannose.

Stereoselective Synthesis of L-Guluronic Acid Alginates

The glycosylation properties of gulopyranosides have been mapped out, and it is shown that gulose has an intrinsic preference for the formation of 1,2-cis-glycosidic bonds. It is postulated that this glycosylation behaviour originates from nucleophilic attack at the oxacarbenium ion, which adopts the most favourable 3H4 conformation. Building on the stereoselectivity of gulose, a guluronic acid alginate trisaccharide was assembled for the first time by using gulopyranosyl building blocks.

Irreversible binding with biological macromolecules and effects in bacterial mutagenicity tests of the radical cation of promethazine and photoactivated promethazine. Comparison with chlorpromazine.

The irreversible binding of the radical cation of promethazine (PMZ+.) to DNA and protein in vitro and bacterial macromolecules in situ has been studied. Binding experiments were performed with synthesized [35S] promethazine. The results are compared to those with the chlorpromazine radical cation (CPZ+.). Secondary reaction products which result from fission of the alkylamino side chain are involved in the macromolecular binding of PMZ+. Compared to CPZ+. the covalent DNA binding of PMZ+. is significantly less. A larger amount of PMZ+. binds to single-stranded DNA than to double-stranded DNA. The extent of binding to proteins and RNA is of the same order as that of CPZ+. Bacterial mutagenicity tests show that the low genotoxicity of PMZ+. is related to the low DNA binding. The bacterial cytotoxicity is possibly related to the covalent protein binding. Similar results have been obtained with photoactivated promethazine (PMZ) and chlorpromazine (CPZ). The role of radical cations in the photosensitization and metabolic activation of phenothiazine drugs is discussed.

Furanosyl Oxocarbenium Ion Stability and Stereoselectivity

Lewis acid mediated substitution reactions using [D]triethylsilane as a nucleophile at the anomeric center of the four pentofuranoses, ribose, arabinose, xylose, and lyxose, all proceed with good to excellent stereoselectivity to provide the 1,2-cis adducts. To unravel the stereoelectronic effects underlying the striking stereoselectivity in these reactions we have mapped the energy landscapes of the complete conformational space of the oxocarbenium ions of the four pentofuranoses. The potential energy surface maps provide a detailed picture of the influence of the differently oriented substituents and their mutual interactions on the stability of the oxocarbenium ions and the maps can be used to account for the observed stereoselectivities of the addition reactions.

Stereoselective Synthesis of 2,3-Diamino-2,3-dideoxy-β-d-mannopyranosyl Uronates

With the aim to find an efficient synthetic procedure for the construction of 2,3-diamino-2,3-dideoxy-β-D-mannuronic acids, we evaluated three mannosyl donors: (S)-phenyl 4,6-di-O-acetyl-2,3-diazido mannopyranoside, (S)-phenyl 2,3-diazido-4,6-O-benzylidene mannopyranoside, and (S)-phenyl 2,3-diazido mannopyranosyl methyl uronate. The first two mannosylating agents are rather unselective or slightly α-selective in their condensation with three different acceptors. The mannuronic acid donor on the other hand reliably provides the desired β-mannosidic linkage. A mechanistic rationale is put forward to account for the different behavior of the three donor types. Suitably protected 2,3-diazido mannuronic acids were employed to construct the all-cis-linked tetrasaccharide repeating unit of the capsular polysaccharide of Bacillus stearothermophilus , featuring two 2,3-diacetamido-2,3-dideoxy-β-D-mannuronic acids.