Intramolecular aglycon delivery
Encyclopedia
Intramolecular aglycon delivery is a synthetic strategy for the construction of glycans. This methodology is generally applied to the formation of difficult glycosidic linkage
.
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. alpha-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 alpha configuration (e.g. glucosides or galactosides) can often be prepared using a non-participating protecting group (such as Bn, or All) at C-2 (OH). However, 1,2-cis-glycosides with the β configuration are the most difficult to achieve, and present the greatest challenge in glycosylation reactions.
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 under this approach.
In this methodology, the glycosyl acceptor
is tethered into 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.
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 (Y) group followed by work up.
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.
((PPh3)3RhCl) and butyl lithium. The resulting enol ether is then reacted with NIS and the glycosyl acceptor to generate a mixed acetal. The 1,2-cis (e.g. β-mannosyl) product is formed in the last step upon 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.
at C-2 (OH) of the glycosyl donor upon addition of dimethyl dichloro silyl in the presence of a strong base such as (BuLi), then the glycosyl acceptor is added to form mixed silaketal. Activation of the anomeric leaving group then in the presence of a hindered base leads to the β-glycoside.
A modified silicon tethering method involves mixing of the glycosyl donor with the glycosyl acceptor and dimethyl dichloro silane 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.
Glycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
.
Introduction
GlycosylationGlycosylation
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 refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
reactions are very important reactions in carbohydrate chemistry
Carbohydrate chemistry
Carbohydrate chemistry is a subdiscipline of chemistry primarily concerned with the synthesis, structure, and function of carbohydrate structures. Due to the general structure of carbohydrates, their synthesis is often preoccupied with the selective formation of glycosidic linkages and the...
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
Glycosyl donor
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...
ring. While 1,2-trans-glycosides (e.g. alpha-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 alpha configuration (e.g. glucosides or galactosides) can often be prepared using a non-participating protecting group (such as Bn, or All) at C-2 (OH). However, 1,2-cis-glycosides with the β configuration are the most difficult to achieve, and present the greatest challenge in glycosylation reactions.
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 under this approach.
In this methodology, the glycosyl acceptor
Glycosyl acceptor
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...
is tethered into the C-2-O-protecting group (X) in the first step. Upon activation of the glycosyl donor
Glycosyl donor
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...
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.
Acid catalysed tethering on 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 etherEnol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...
by the Tebbe reagent (Cp2Ti=CH2), and then the glycosyl acceptor is tethered to the enol ether
Enol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...
under acid catalysed conditions to generate a mixed acetal. In a subsequent step, the β-mannoside is formed upon activation of the (Y) group followed by work up.
Iodonium tethering on 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 etherEnol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...
by the Tebbe reagent. However, in this approach, N-Iodosuccinimide (NIS
N-Chlorosuccinimide
N-Chlorosuccinimide is used for chlorinations and as a mild oxidant.N-Iodosuccinimide , the iodine analog of N-chlorosuccinimide, and N-bromosuccinimide , the bromine analog, are used for similar applications.-External links:...
) 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.
Iodonium tethering on prop-1-enyl ethers
The glycosyl donor is protected at C-2 by OAll group. The allyl group is then isomerized to prop-1-enyl ether using a Rhodium hydride generated from Wilkinson's catalystWilkinson's catalyst
Wilkinson's catalyst is the common name for chlorotrisrhodium, a coordination compound with the formula RhCl3 . It is named after the late organometallic chemist and 1973 Nobel Laureate, Sir Geoffrey Wilkinson who popularized its use.-Structure and basic properties:The compound is a square planar,...
((PPh3)3RhCl) and butyl lithium. The resulting enol ether is then reacted with NIS and the glycosyl acceptor to generate a mixed acetal. The 1,2-cis (e.g. β-mannosyl) product is formed in the last step upon 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.
Oxidative tethering on para-methoxybenzyl (PMB) ethers
In this method, the glycosyl donor is protected at C-2 by para-methoxy benzyl (PMB) group. The glycosyl acceptor is then tethered at the benzylic position of the PMB protecting group in the presence of dichloro dicyano quinone (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.Solid-supported oxidative tethering on 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.Silicon tethering
The initial step in this method involves the formation of a silyl etherSilyl ether
Silyl ethers are a group of chemical compounds which contain a silicon atom covalently bonded to an alkoxy group. The general structure is R1R2R3Si−O−R4 where R4 is an alkyl group or an aryl group. Silyl ethers are usually used as protecting groups for alcohols in organic synthesis...
at C-2 (OH) of the glycosyl donor upon addition of dimethyl dichloro silyl in the presence of a strong base such as (BuLi), then the glycosyl acceptor is added to form mixed silaketal. Activation of the anomeric leaving group then in the presence of a hindered base leads to the β-glycoside.
A modified silicon tethering method involves mixing of the glycosyl donor with the glycosyl acceptor and dimethyl dichloro silane in the presence of imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
to give the mixed silaketal in one pot. Activation of the tethered intermediate then leads to the β-glycoside product.