Acetal tethers

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. 

The use of the p-methoxybenzyhdene acetal tethered intramolecular aglycone delivery was extended to polymer-supported oligosaccharide synthesis [77]. The method also proved to be successful in the synthesis of other difficult linkages, such as (3-D-fructofuranosides [78], (3-D-arabinofuranosides [79-81] and a-D-fucofuranosides [82]. 

SCHEME 5.27 Intramolecular aglycone delivery using p-methoxybenzylidene acetal tethering. 

One of the best tests for any synthetic methodology is in its application to the preparation of biologically important compounds. Posner et al. recently reported the use of a silyl acetal tether in an IMDA reaction for the preparation of the 2-fIuoroalkyl analog 10 of 1,25-dihydroxy vitamin Dj 11 (Figure 10-5) [8]. 

Scheme 10-9 Acetal tethers facilitate Diels-Alder cyclization.

Boeckman et al. used an acetal tether in a racemic synthesis of the cyclohexene subunit of tetronolide 33 [16], Although it had previously been recognized that a Diels-Alder strategy could provide rapid entry into this highly functionalized six-mem-bered ring, some of the earlier reported intermolecular reactions suffered from relatively poor reactivity and regio- and stereocontrol [17]. It was anticipated that an intramolecular variant would overcome some of these problems (Scheme 10-10). 

Formation of the acetal-tethered triene 34 was achieved by selective nucleophilic displacement of the secondary alkyl bromide in 35 with hydroxydiene 36. Subsequent thermolysis at 145 °C for 70 h resulted in completely regiospecific cycloaddition with the formation of two out of the possible four diastereoisomers 37 and 38 in a 2.5-3 1 ratio (Scheme 10-11). The presence of a stereogenic center in the tether provides the source of stereocontrol - the products derive from exo and endo T. S.s in which the bromomethyl group in the tether occupies a pseudo-equatorial position (Scheme 10-11). Small differences in non-bonding interactions between the tether and pyruvate ester most probably account for the slight exo. selectivity. The separated major product was further elaborated, and finally the tether was cleaved under reductive conditions to provide the advanced cyclohexene intermediate 39. 

Scheme 10-38 An acetal tether allows the desired endo-re cyclization to occur.

In most cases the radical generated after cyclization is quenched by H-abstraction. However, another possibility is to utilize the cyclized radical in another C-C bond-forming event. Fraser-Reid and co-workers utilized a silyl-tethered radical cyclization of the (L)-rhamnal-derived silyl ether 142 to generate the anomerically. stabilized radical 143, which could be trapped in the presence of an excess of acrylonitrile to generate acetate 144 after tether cleavage and peracetylation (Scheme 10-48) [55a]. This reaction sequence occurred with complete regio- and stereoselectivity. The same group has also used an acetal tether (vide infra) to effect similar transformations [55 b, 56]. 

Scheme 10-68 Preparation of the key silyl acetal tether in one step, during the synthesis of tuni-camycin V.

Scheme 10-72 Synthesis of the C(l)-C(9) fragment of rhizoxin in which Rama Rao used an acetal tether to direct a radical cyclization.

Scheme 10-81 Formation of the P-1,4-linkage using a silyl acetal tether proved problematic.

Scheme 10-85 )3-Mannosides may be produced by intramolecular aglycon delivery using a PMB acetal tether.

Scheme 10-87 A PMB acetal tether can be used to prepare j8-fructofuranosides.

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