Tethers ketals

The type of atoms in the tether have little effect on the cycloaddition process. Both alkyl (98,125-127) and ether tethers (128-131) have been extensively investigated and provide similar levels of reactivity. In addition, thioethers (132), amines (133), silanes (134), and silyl ketals (135) are all compatible with the dipolar cycloaddition. 

BTIB oxidations of aromatic ethers in which sulfido groups are tethered to the ring provide access to heterocyclic sulfides [64], while related oxidations of azido-tethered analogs lead to quinone imines and/or their dimethyl ketals... 

Silicon tethers based on bis-alkoxysilanes (silyl ketals) are commonly prepared from the dichlorosilanes by reaction with an alcohol in the presence of base. These conditions are not compatible with some base labile compounds. To make unsymmetrical bis-alkoxysilanes requires a method for breaking the symmetry of the dichlorosilane. Without such a method, one must accept a statistically determined mixture of mono-alkoxy and bis-alkoxy products. This may be acceptable for inexpensive readily available alcohols, but it precludes the use of bis-alkoxysilane tethers for high-value synthetic intermediates. To overcome these limitations to... 

SCHEME 5.26 Intramolecular aglycone delivery using isopropylidene ketal tethering. 

Scheme 11.77 shows that the two subunits 372 and 373 were linked by a silyl ketal tether to give 374. An anomeric radical was then produced by treatment with tributyltin hydride. This radical reacted with the enol ether acceptor to give the cyclic derivative 375 as the major product in a yield of 43% together with two of the three possible isomers in yields of 6 and 13%. The combined yield shows that more than 56% of the radical attack occurred from the a face of the gluco residue. However, the intermediate radical, located at C4, is mainly trapped by the a face of the furanose moiety. Although this approach is attractive, further elaboration to the... 

Other temporary connections, such as ketal tethers were also tested. Tebbe olefination of acetate 266 and ketal formation with sugar alcohol 255 lead to tethered intermediate 267, which is cyclized to a C-analog derivative 268 of the a-D-Man(l— 4)-D-Glc disaccharide after ketal cleavage [118] (O Scheme 56). 

There is now general agreement that Vilsmeier reactions with acetals, ketals, and the corresponding thio derivatives proceed by loss of a molecule of alcohol or thiol to give the reactive unsaturated ether or thioether with cyclic ketals the alcohol remains tethered, and may be chlorinated. The acetals and ketals are often more readily available than the unsaturated ethers, and yields of products are similar. A wide range of aliphatic and alicyclic acetals and ketals has been formylated the reaction can tolerate bulky groups at either end of the double bond, as is shown for compound 64 (Eq. 51). Products are isolated as iminium sails... 

The same group used a ketal tether as an alternative connecting group in the synthesis of the 1,4-linked C-disaccharide 236 [85 b]. Tebbe methylenation of acetate 237 provided the corresponding enol ether 238, which upon treatment with alcohol 235 in the presence of CSA at -40°C in acetonitrile, furnished linked disaccharide 239 in 81% yield. Subsequent radical cyclization, acidic hydrolysis of the tether and peracetylation provided the D-mannose-containing C-disaccharide 236 as the major product in 35% yield from 239 (Scheme 10-75). Cyclization was not completely stereoselective and a small amount of the )8-C-manno isomer was also isolated (a/)3 10 1). This result is in contrast to similar studies on tether-directed /J-C-mannoside syntheses (vide infra) where a much shorter tether attached to the axial 2-hydroxyl group forces obtention of the desired P-configuration. 

Scheme 10-75 A ketal tether was used in a 9-endo-tt g radical cyclization to prepare C-disaccha-ride 236.

Undeterred by this first Wessely oxidation obstacle, we set out to modify our design and give the dearomatization step the best opportunity to succeed. We postulated that an intramolecular Wessely oxidatirai approach would have a better chance of directing the oxidant to the desired site for dearomatization. The results of our investigations are presented in Scheme 4. We used the aldol addition product from the previous route (10) and instead of forming a cyclic ketal we developed a mild method to gently form the requisite ori/io-quinone methide, which we trapped in situ with ethyl vinyl ether to provide 11. Deprotection of the acetal and oxidation then afforded lactone 12, which served as precursor to the acetic acid tether (13) we needed for the dearomatization... 

The ketal connectors which were exploited earlier in O-glycosylations proved equally efficient in the synthesis of C-linked disaccharides as shown in Scheme 32 [61]. With acetate 123 a two-step sequence via vinyl ether formation with Tehbe s reagent and acetalization with alcohol 117 produced the linked sugars 124. Upon tin hydride-promoted cyclization and removal of the acetal tether the a-D-Man(l 4)-d-G1c C-disaccharide 125 was obtained in 35% yield. 

Acetonide-tethered alkynes (236), in fact masked diols, have been converted into the corresponding ketals (237) using a similar strategy (n = l, 2 Y = 0, NBn, NC02Me R = H, D, alkyl, Ar, alkynyl).i53.iS4... 

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