Aglycon delivery, intramolecular

An acetal tethered compound can easily be prepared by treatment of equimolar amounts of a 2-propenyl ether derivative of a saccharide with a sugar hydroxyl in the presence of a catalytic amount of acid. Activation of the anomeric thio moiety of the tethered compound with N-iodosuccinimide (NIS) in dichloromethane results in the formation of the p-linked disaccharide. In this reaction, no a-linked disaccharide is usually detected. It is of interest to note that when this reaction was performed in the presence of methanol, no methyl glycosides are obtained. This experiment indicates that the glycosylation proceeds via a concerted reaction and not a free anomeric oxocarbenium ion. 

The introduction of a methylene acetal tether needs some further discussion. The 2-propenyl ether is prepared by reaction of a C(2) acetyl group with Tebbe reagent, (C5H5)2TiMe2. Treatment of the resulting enol ether with p-toluenesulfonic acid results in the formation of an oxocarbenium ion, which upon reaction with an alcohol provides an acetal. As can be seen in the reaction scheme, the acid is regenerated, thus only a catalytic amount is required. 

it appears that a rigid five-membered ring transition state is important for high anomeric selectivities. 

Although this methodology provides access to anomericaUy pure p-mannosides, the experimental procedure is complex and when applied to more unreactive acceptors undesirable side reactions can occur. 

Stork and co-workers investigated the use of sdyl acetals as tethers for the stereoselective formation of P-mannosides [56]. Initial studies were performed on primary acceptors of glucose 57 and mannose. Glucosyl acceptor 57 is first converted to its chlorodimethyl ether derivative by treatment with n-butyllithium 

Attention was then directed towards the development of a one pot procedure. The success of the tethering reaction with NIS indicated a reactivity differential between the enol ether and the anomeric thiophenyl group. Choice of solvent proved to be crucial, with 1,2-dichloroethane giving the best results. 

Enol ether 70 and 3 equiv. of diacetone galactose 71 were treated with NIS in dichloroethane at — 40 C. When tethering was complete, as indicated by thin layer chromatography, a further 2 equiv. of NIS and DTBMP were added to the reaction flask. After 2 days the reaction mixture was treated with acidic ion exchange resin to solely afford the 3-mannoside 73 in an excellent yield of 84% (Method 6) [59]. As with HindsgauTs methodology, competition experiments confirmed the intramolecular nature of the reaction. 

NIS-mediated intramolecular aglycon delivery for entry to a Man-(3-(l,6)-Gal residue [59]. 

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Scheme 4.4 Synthesis of P-mannosides by intramolecular aglycon delivery.

The sulfoxide method has been applied to the concept [319,374] of intramolecular aglycone delivery for the formation of [1-mannosidcs by means of a silylene linker. In the original work, the acceptor and a thioglycoside donor were joined by means of a silylene group before the oxidation to the sulfoxide [141]. However, it was later found that the preformed sulfoxide was tolerated by the chemistry for the introduction of the linker [286,375]. The intramolecular aglycone delivery step was shown to function effectively for the transfer of the donor to the 2-, 3- and 6-position of glucopyr-anosides, as exemplified in Scheme 4.64. 

Sulfoxide-mediated intramolecular aglycone delivery has been conducted with a temporary linker formed in situ by the reaction of lanthanide triflates with the donor and acceptor-based alcohols (Scheme 4.66) [336], However, as the selectivities recorded were modest, it has to be assumed that intermolecular glycosylation was an important side reaction in this chemistry. 

Scheme 4.64 Sulfoxide-mediated intramolecular aglycone delivery.

Additional aspects of intramolecular aglycone delivery are discussed in Section 5.4. 

Scheme 4.66 Intramolecular aglycone delivery via metal complexes.

Scheme 16 Intramolecular aglycon delivery approach using NAP ether protected glycosyl donors.

Scheme 7.18 p-Methoxybenzyl-assisted intramolecular aglycon delivery. 

INTRAMOLECULAR AGLYCON DELIVERY ON POLYMER SUPPORT GATEKEEPER-CONTROLLED GLYCOSYLATION... 

Scheme 7.23 Intramolecular aglycon delivery on polymer support.

Ito, Y. Ogawa, T., Intramolecular aglycon delivery on polymer support Gatekeeper monitored glycosylation. J. Am. Chem. Soc. 1997, 119, 5562-5566. 

Barresi, F. Hindsgaul, O., Synthesis of Beta-Marmopyranosides by Intramolecular Aglycon Delivery. J. Chem. Soc. 1991, 113, 9376-9377. 

Scheme 15. The polymer-bound alkoxybenzyl protecting group in 67 serves as a directing group and enabled the intramolecular aglycon delivery to afford a stereoselective formation of /1-mannosides 69. Byproducts such as 70 and 71 remained on the polymeric support.

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