Intramolecular glycosidation reactions

Carbohydrate derivatives found in nature are almost always linked to each other by glycosidic bonds. There has been increasing interest in the synthesis of biologically active ohgo- and polysaccharides and reliable methods for the formation of gjyco-sidic linkages have been the subject of intensive study. 

Two problems are usually encountered in the synthesis of a glycosidic bond— unreactive hydroxyl groups and lack of diastereoselectivity (i.e. formation of a and P epimers). To overcome these problems in the last decade chemists have explored a new approach—intramolecular glycosidation reactions. 

The tether can be either a temporary tether which is removed during the glycosidation reaction or it can be a stable tether which is cleaved after the glycosidation procedure. This chapter is divided into two main parts  

2) reactions in which the tether does not participate in the reaction. 

Non-tethered intramolecular glycosidations which produce spiroketals [1] or natural products [2, 3] have been reported these will not be discussed here. 

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In this review we will define the term intramolecular glycosidation reaction as a type of reaction in which the glycosyl donor (the glycone) is linked to the glycosyl acceptor (the aglycone) by means of a tether producing a 0-glycosidic bond (Scheme 1). 

Scheme 1. Outline of tethered intramolecular glycosidation reactions. (T1 = temporary tether, T2 = stable tether)...

Since the first report of an intramolecular glycosidation reaction in 1991 chemists have shown much creativity within this area. The new and interesting chemistry... 

An interesting problem in stereoisomerism is found in the aldol reactions of the achiral aldehydes which are obtained by ozonolysis of the homoallylic alcohols 174. After stereospecific conversion by the FruA [230], the products can be readily induced to form an intramolecular glycoside 175 by acidic (R=OH) or alkaline treatment (R=C1), under which conditions the two equatorial ring hydroxyl groups completely direct the stereogenic acetal formation [234]. The corresponding RhuA catalyzed reactions deliver the enantiomeric... 

The aromatic phenol was varied to explore the scope of the O-to-C conversion with mannosyl phosphates. Using phosphate 9, the a-C-mannosides of 2-naphthol and 3-benzyloxy phenol (23 and 25, Table 1) were synthesized in excellent yield. O-Mannosides were obtained exclusively with less nucleophilic aromatic systems, such as 3-acetoxy phenol. Several non-phenolic aromatic systems were unsuccessful in the formation of C-aryl or O-aryl glycosides. Reaction of 9 with furan, thiophene, trimethoxybenzene, and indole in the presence of TMSOTf did not result in any product formation. Interestingly, activation of 9 in the absence of any aromatic nucleophiles gave 26 as the major product via an intramolecular C-glycosylation (Figure 1) (79). 

Craig, D, Munasinghem, V R N, Stereoselective template-directed C-glycosidation. Synthesis of bicyclic keto oxetanes via intramolecular cyclization reactions of (2-pyridylthio)glycosidic silyl enol ethers, J. Chem. Soc., Chem. Commun., 901-903, 1993. 

Treatment of 5,6-unsaturated sugar 382 (Scheme 11.79) with mercury(ll) salts was shown to induce what is called the second Ferrier rearrangement. The reaction proceeds via mercuration of the double bond and, in the presence of water, the alkyl glycoside 383 is then hydrolyzed to the aldehyde 384, which undergoes intramolecular aldol reaction to produce a (3-hydroxy cyclohexanone 385. This reaction produces only six-membered rings. An excellent review by Ferrier and Middleton was pubhshed some years ago [300]. 

E. Suarez and co-workers prepared chiral 7-oxa-2-azabicyclo[3.2.1]octane and 8-oxa-6-azabicyclo[3.2.1]octane ring systems derived from carbohydrates via an intramolecular hydrogen abstraction reaction promoted by A/-centered radicals. The A/-centered radicals were obtained under mild conditions (Suarez modification) from phenyl and benzyl amidophosphates and alkyl and benzyl carbamate derivatives of aminoalditols by treatment with PIDA/I2 or PhlO/l2. The initial A/-radical undergoes a 1,5-hydrogen abstraction to form an alkyl radical, which is oxidized to the corresponding stabilized carbocation (oxocarbenium ion) under the reaction conditions. The overall transformation may be considered as an intramolecular N-glycosidation reaction. 

The reader will have perhaps wondered why, in the Fischer glycosidation reaction, there is no acetalation by two alcohol functions of the sugar molecule, leading to a completely internal and bicyclic mixed acetal. As a general rule, an intramolecular reaction is faster than the intermolecular analogue and this type... 

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