Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

Abstract

Glycosylation is an immensely important biological process and one that is highly controlled and very efficient in nature. However, in a chemical laboratory the process is much more challenging and usually requires the extensive use of protecting groups to squelch reactivity at undesired reactive moieties. Nonetheless, by taking advantage of the differential reactivity of the anomeric center, a selective activation at this position is possible. As a result, protecting group-free strategies to effect glycosylations are available thanks to the tremendous efforts of many research groups. In this review, we showcase the methods available for the selective activation of the anomeric center on the glycosyl donor and the mechanisms by which the glycosylation reactions take place to illustrate the power these techniques.

Keywords: glycosides; glycosylation; oligosaccharides; protecting groups.

Scheme 1

Solution-state conformations of D-glucose.

Scheme 2

Enzymatic synthesis of oligosaccharides.

Scheme 3

Enzymatic synthesis of a phosphorylated glycoprotein containing a mannose-6-phosphate (M6P)-terminated N-glycan. DMC = 2-chloro-1,3-dimethylimidazolinium chloride.

Scheme 4

A) Selected GTs-mediated syntheses of oligosaccharides and other biologically active glycosides. B) Inverting and retaining GTs. NDP = nucleotide diphosphate.

Scheme 5

Enzymatic synthesis of nucleosides.

Scheme 6

Fischer glycosylation strategies.

Scheme 7

The basis of remote activation (adapted from [37]).

Scheme 8

Classic remote activation employing a MOP donor to access α-anomeric alcohols, carboxylates, and phosphates.

Figure 1

Synthesis of monoprotected glycosides from a (3-bromo-2-pyridyloxy) β-D-glycopyranosyl donor under Lewis acid-catalyzed conditions [42].

Scheme 9

Plausible mechanism for the synthesis of α-galactosides. TBDPS = tert-butyldiphenylsilyl.

Scheme 10

Synthesis of the 6-O-monoprotected galactopyranoside donor for remote activation.

Scheme 11

UDP-galactopyranose mutase-catalyzed isomerization of UDP-Galp to UDP-Galf.

Scheme 12

Synthesis of the 1-thioimidoyl galactofuranosyl donor.

Scheme 13

Glycosylation of MeOH using a self-activating donor in the absence of an external activator. a) Synthesis of the 4-bromobutanyl donor. b) Proposed mechanism.

Scheme 14

The classical Lewis acid-catalyzed glycosylation.

Figure 2

Unprotected glycosyl donors used for the Lewis acid-catalyzed protecting group-free glycosylation reaction to access 1,2-cis glycosides.

Scheme 15

Four-step synthesis of the phenyl β-galactothiopyranosyl donor.

Scheme 16

Protecting-group-free C3′-regioselective glycosylation of sucrose with α–F Glc.

Scheme 17

Synthesis of the α-fluoroglucosyl donor.

Figure 3

Protecting-group-free glycosyl donors and acceptors used in the Au(III)-catalyzed glycosylation.

Scheme 18

Synthesis of the mannosyl donor used in the study [62].

Scheme 19

The Pd-catalyzed stereoretentive glycosylation of arenes using anomeric stannane donors.

Scheme 20

Preparation of the protecting-group-free α and β-stannanes from advanced intermediates for stereochemical retentive C-glycosylations.

Figure 4

Selective anomeric activating agents providing donors for direct activation of the anomeric carbon.

Scheme 21

One-step access to sugar oxazolines or 1,6-anhydrosugars.

Scheme 22

Enzymatic synthesis of a chitoheptaose using a mutant chitinase.

Scheme 23

One-pot access to glycosyl azides [73], dithiocarbamates [74], and aryl thiols using DMC activation and subsequent nucleophilic displacement [–76].

Scheme 24

Plausible reaction mechanism.

Scheme 25

Protecting-group-free synthesis of anomeric thiols from unprotected 2-deoxy-2-N-acetyl sugars.

Scheme 26

Protein conjugation of TTL221-PentK with a hyaluronan hexasaccharide thiol.

Scheme 27

Proposed mechanism.

Scheme 28

Direct two-step one-pot access to glycoconjugates through the in situ formation of the glycosyl azide followed by the click reaction.

Scheme 29

DMC as a phosphate-activating moiety for the synthesis of diphosphates. ^aβ-1,4-galactose transferase.

Figure 5

Triazinylmorpholinium salts as selective anomeric activating agents.

Scheme 30

One-step synthesis of DBT glycosides from unprotected sugars in aqueous medium.

Scheme 31

Postulated mechanism for the stereoselective formation of α-glycosides.

Scheme 32

DMT-donor synthesis used for metal-catalyzed glycosylation of simple alcohols.

Figure 6

Protecting group-free synthesis of glycosyl sulfonohydrazides (GSH).

Figure 7

The use of GSHs to access 1-O-phosphoryl and alkyl glycosides. A) Glycosylation of aliphatic alcohols. B) GSHs to access α-glycosyl 1-phosphates.

Scheme 33

A) Proposed mechanism of glycosylation. B) Proposed mechanism for stereoselective azidation of the GSH donor.

Scheme 34

Mounting GlcNAc onto a sepharose solid support through a GSH donor.

Scheme 35

Lawesson’s reagent for the formation of 1,2-trans glycosides.

Scheme 36

Protecting-group-free protein conjugation via an in situ-formed thiol glycoside [98].

Scheme 37

pH-Specific glycosylation to functionalize SAMs on gold.

Figure 8

Protecting-group-free availability of phenolic glycosides under Mitsunobu conditions. DEAD = diethyl azodicarboxylate.

Scheme 38

Accessing hydroxyazobenzenes under Mitsunobu conditions for the study of photoswitchable labels. DEAD = diethyl azodicarboxylate.

Scheme 39

Stereoselective protecting-group-free glycosylation of D-glucose to provide the β-glucosyl benzoic acid en route to the protecting-group-free total synthesis of two ellagitannins. DIAD = diisopropyl azodicarboxylate.

Figure 9

Direct synthesis of pyranosyl nucleosides from unactivated and unprotected ribose using optimized Mitsunobu conditions. ^aAs determined by ¹H NMR. The products were inseparable from the furanoside using silica gel chromatography. DIAD = diisopropyl azodicarboxylate.

Figure 10

Direct synthesis of furanosyl nucleosides from 5-O-monoprotected ribose in a one-pot glycosylation–deprotection strategy. ^aYield in parentheses is after crystallization from MeOH due to trace impurities still present after chromatographical purification. DIAD = diisopropyl azodicarboxylate.

Figure 11

Synthesis of ribofuranosides using a monoprotected ribosyl donor via an anhydrose intermediate.

Figure 12

C5′-modified nucleosides available under our conditions.

Scheme 40

Plausible reaction mechanism for the formation of the anhydrose.

Figure 13

Direct glycosylation of several aliphatic alcohols using catalytic Ti(Ot-Bu)₄ in the presence of D-mandelic acid. The furanoside is the major or exclusive product. ^aOnly 4 mol % D-mandelic acid used. ^bAfter 12 days and 1.0 equiv LiBr added. ^c1.0 equiv LiBr added to enhance the yield.

Figure 14

Access to glycosides using catalytic PPh₃ and CBr₄.

Figure 15

Access to ribofuranosyl glycosides as the major product under catalytic conditions. ^aLiOCl₄ (2.0 equiv.) was used to bolster the yield.