Intramolecular aglycon delivery

Last updated April 09, 2019

Intramolecular aglycon delivery is a synthetic strategy for the construction of glycans. This approach is generally used for the formation of difficult glycosidic linkages.

The terms glycan and polysaccharide are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate portion of a glycoconjugate, such as a glycoprotein, glycolipid, or a proteoglycan, even if the carbohydrate is only an oligosaccharide. Glycans usually consist solely of O-glycosidic linkages of monosaccharides. For example, cellulose is a glycan composed of β-1,4-linked D-glucose, and chitin is a glycan composed of β-1,4-linked N-acetyl-D-glucosamine. Glycans can be homo- or heteropolymers of monosaccharide residues, and can be linear or branched.

In chemistry, a glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate.

Introduction

Glycosylation reactions are very important reactions in carbohydrate chemistry, leading to the synthesis of oligosaccharides, preferably in a stereoselective manner. The stereoselectivity of these reactions has been shown to be affected by both the nature and the configuration of the protecting group at C-2 on the glycosyl donor ring. While 1,2-trans-glycosides (e.g. α-mannosides and β-glucosides) can be synthesised easily in the presence of a participating group (such as OAc, or NHAc) at the C-2 position in the glycosyl donor ring, 1,2-cis-glycosides are more difficult to prepare. 1,2-cis-glycosides with the α configuration (e.g. glucosides or galactosides) can often be prepared using a non-participating protecting group (such as Bn, or All) on the C-2 hydroxy group. However, 1,2-cis-glycosides with the β configuration are the most difficult to achieve, and present the greatest challenge in glycosylation reactions.

Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule. In biology, glycosylation mainly refers in particular to the enzymatic process that attaches glycans to proteins, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells. Glycosylation is a form of co-translational and post-translational modification. Glycans serve a variety of structural and functional roles in membrane and secreted proteins. The majority of proteins synthesized in the rough endoplasmic reticulum undergo glycosylation. It is an enzyme-directed site-specific process, as opposed to the non-enzymatic chemical reaction of glycation. Glycosylation is also present in the cytoplasm and nucleus as the O-GlcNAc modification. Aglycosylation is a feature of engineered antibodies to bypass glycosylation. Five classes of glycans are produced:

Carbohydrate chemistry is a subdiscipline of chemistry primarily concerned with the synthesis, structure, and function of carbohydrates. Due to the general structure of carbohydrates, their synthesis is often preoccupied with the selective formation of glycosidic linkages and the selective reaction of hydroxyl groups; as a result, it relies heavily on the use of protecting groups.

A glycosyl donor is a carbohydrate mono- or oligosaccharide that will react with a suitable glycosyl acceptor to form a new glycosidic bond. By convention, the donor is the member of this pair that contains the resulting anomeric carbon of the new glycosidic bond. The resulting reaction is referred to as a glycosylation or chemical glycosylation.

One of the most recent approaches to prepare 1,2-cis-β-glycosides in a stereospecific manner is termed ‘Intramolecular Aglycon Delivery’, and various methods have been developed based on this approach. [1] In this approach, the glycosyl acceptor is tethered onto the C-2-O-protecting group (X) in the first step. Upon activation of the glycosyl donor group (Y) (usually SR, OAc, or Br group) in the next step, the tethered aglycon traps the developing oxocarbenium ion at C-1, and is transferred from the same face as OH-2, forming the glycosidic bond stereospecifically. The yield of this reaction drops as the bulkiness of the alcohol increases.

A glycosyl acceptor: is any suitable nucleophile-containing molecule that will react with a glycosyl donor to form a new glycosidic bond. By convention, the acceptor is the member of this pair which did not contain the resulting anomeric carbon of the new glycosidic bond. Since the nucleophilic atom of the acceptor is typically an oxygen atom, this can be remembered using the mnemonic of the acceptor is the alcohol. A glycosyl acceptor can be a mono- or oligosaccharide that contains an available nucleophile, such as an unprotected hydroxyl.

Intramolecular Aglycon Delivery (IAD) methods

Carbon tethering

Acid-catalysed tethering to enol ethers

In this method, the glycosyl donor is protected at the C-2 position by an OAc group. The C-2-OAc protecting group is transformed into an enol ether by the Tebbe reagent (Cp₂Ti=CH₂), and then the glycosyl acceptor is tethered to the enol ether under acid-catalysed conditions to generate a mixed acetal. In a subsequent step, the β-mannoside is formed upon activation of the anomeric leaving group (Y), followed by work up. [2]

An enol ether is an alkene with an alkoxy substituent. The general structure is R₂C=CR-OR with R an alkyl or an aryl group. Enol ethers and enamines are electron-rich alkenes because the heteroatom (O, N, respectively) donates electrons into the pi-bond. Enol ethers have oxonium ion character. Important enol ethers are methyl vinyl ether, ethyl vinyl ether, and 3,4-dihydropyran.

Iodonium tethering to enol ethers

This method is similar to the previous method in that the glycosyl donor is protected at C-2 by an OAc group, which is converted into an enol ether by the Tebbe reagent. However, in this approach, N-iodosuccinimide (NIS) is used to tether the glycosyl acceptor to the enol ether, and in a second step, activation of the anomeric leaving group leads to intramolecular delivery of the aglycon to C-1 and formation of the 1,2-cis-glycoside product. [3]

<i>N</i>-Iodosuccinimide chemical compound

N-Iodosuccinimide (NIS) is a reagent used in organic chemistry for the iodination of alkenes and as a mild oxidant.

Iodonium tethering to prop-1-enyl ethers

The glycosyl donor is protected at C-2 by OAll group. The allyl group is then isomerized to a prop-1-enyl ether using a rhodium hydride generated from Wilkinson's catalyst ((PPh₃)₃RhCl) and butyllithium (BuLi). The resulting enol ether is then treated with NIS and the glycosyl acceptor to generate a mixed acetal. The 1,2-cis (e.g. β-mannosyl) product is formed in a final step through activation of the anomeric leaving group, delivery of the aglycon from the mixed acetal and finally hydrolytic work-up to remove the remains of the propenyl ether from O-2. [4]

Wilkinson's catalyst, is the common name for chloridotris(triphenylphosphane)rhodium(I), a coordination complex of rhodium with the formula [RhCl(PPh₃)₃] (Ph = phenyl). It is a red-brown colored solid that is soluble in hydrocarbon solvents such as benzene, and more so in tetrahydrofuran or chlorinated solvents such as dichloromethane. The compound is widely used as a catalyst for hydrogenation of alkenes. It is named after chemist and Nobel Laureate, Sir Geoffrey Wilkinson, who first popularized its use.

Oxidative tethering to para-methoxybenzyl (PMB) ethers

In this method, the glycosyl donor is protected at C-2 by a para-methoxybenzyl (PMB) group. The glycosyl acceptor is then tethered at the benzylic position of the PMB protecting group in the presence of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The anomeric leaving group (Y) is then activated, and the developing oxocarbenium ion is captured by the tethered aglycon alcohol (OR) to give 1,2-cis β-glycoside product. [5]

Solid-supported oxidative tethering to para-alkoxybenzyl ethers

This is a modification of the method of oxidative tethering to a para-methoxybenzyl ether. The difference here is that the para-alkoxybenzyl group is attached to a solid support; the β-mannoside product is released into the solution phase in the last step, while the by-products remain attached to the solid phase. This makes the purification of the β-glycoside easier; it is formed as the almost exclusive product. [6]

Silicon tethering

The initial step in this method involves the formation of a silyl ether at the C-2 hydroxy group of the glycosyl donor upon addition of dimethyldichlorosilane in the presence of a strong base such as butyllithium (BuLi); then the glycosyl acceptor is added to form a mixed silaketal. Activation of the anomeric leaving group in the presence of a hindered base then leads to the β-glycoside. [7]

A modified silicon-tethering method involves mixing of the glycosyl donor with the glycosyl acceptor and dimethyldichlorosilane in the presence of imidazole to give the mixed silaketal in one pot. Activation of the tethered intermediate then leads to the β-glycoside product. [8]

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References

↑ Cumpstey, I. Carbohydr. Res.2008, 343, 1553–1573
↑ Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc.1991, 113, 9376–9377
↑ Ennis, S. C.; Fairbanks, A. J.; Slinn, C. A.; Tennant-Eyles, R. J.; Yeates, H. S. Tetrahedron2001, 57, 4221–4230
↑ Seward, C. M. P.; Cumpstey, I.; Aloui, M.; Ennis, S. C.; Redgrave, A. J.; Fairbanks, A. J. Chem. Commun.2000, 1409–1410
↑ Ito, Y.; Ogawa, T. Angew. Chem. Int. Ed. Engl.1994, 33, 1765–1767
↑ Ito, Y.; Ogawa, T. J. Am. Chem. Soc.1997, 119, 5562–5566
↑ Stork, G.; Kim, G. J. Am. Chem. Soc.1992, 114, 1087-1088
↑ Stork, G.; La Clair, J. J. J. Am. Chem. Soc.1996, 118, 247–248

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[1] Cumpstey, I. Carbohydr. Res.2008, 343, 1553–1573

[2] Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc.1991, 113, 9376–9377

[3] Ennis, S. C.; Fairbanks, A. J.; Slinn, C. A.; Tennant-Eyles, R. J.; Yeates, H. S. Tetrahedron2001, 57, 4221–4230

[4] Seward, C. M. P.; Cumpstey, I.; Aloui, M.; Ennis, S. C.; Redgrave, A. J.; Fairbanks, A. J. Chem. Commun.2000, 1409–1410

[5] Ito, Y.; Ogawa, T. Angew. Chem. Int. Ed. Engl.1994, 33, 1765–1767

[6] Ito, Y.; Ogawa, T. J. Am. Chem. Soc.1997, 119, 5562–5566

[7] Stork, G.; Kim, G. J. Am. Chem. Soc.1992, 114, 1087-1088

[8] Stork, G.; La Clair, J. J. J. Am. Chem. Soc.1996, 118, 247–248