Orthoester approaches

Scaringe SA. Advanced 5 -silyl-2 -orthoester approach to RNA oligonucleotide synthesis. Methods Enzymol. 2000 317 3-18. 

An interesting twist on the orthoester approach was uncovered by Fraser-Reid and coworkers in which it was revealed that a 4-pentenyl orthobenzoate 123, on activation with ytterbium triflate in dichloromethane, was able to selectively glycosylate the primary hydroxyl group in a mannopyranosyl 2,6-diol 122. Treatment with a 2-O-benzoyl mannosyl trichloroacetimidate 126 in diethyl ether with the same promoter then introduced a second y-mannosidic linkage to the remaining secondary hydroxyl group (Scheme 22).30 This selectivity pattern was central to the development of a very efficient synthesis of a branched pentadecamannan 129. 

Fraser-Reid and coworkers took a very similar tack using, however, the orthoester approach to prepare the /1-glucosidic bond. The Swem oxidation/L-selectride reduction approach to inversion subsequently applied was identical to that of the Sinay laboratory, but further iterations of the process were applied until a / -(l—>2)-mannooctaose 270 was obtained (Scheme 45).125 Yet another variation on the theme... 

The p-(l->6), p-(1 6) linked trimers (and tetramers) of Glc and Gal and the a-(1 6), a-(l- 6) analogues of Man have been made by use of the 1,2-orthoester approach. The 4-pentenyl P-glycoside of the p-(l- 6) linked glucotriose was prepared via the resin-bound 2 and cleaved from the resin by elimination of bromine and application of Grubbs catalyst as an alkene cleaving agent. By... 

SYNTHESIS OF THE BIS-DIENE BUILDING BLOCK 3.1 Orthoester Approaches... 

Another approach to the l-oxo-l,2-dihydro-j8-carboline system is that due to King and Stiller. When 2-ethoxy carbonyl-3-formyl-indole is condensed with hippuric acid the azlactone 162 is formed, which, with 10% methanolic potassium hydroxide, gives a mixture of the orthoester 163 and the potassium salt 164. 

Another interesting approach was developed by Ikegami and coworkers, who used an anomeric orthoester as the key intermediate (Scheme 7.14).59 Formation of orthoester 16 from lactone was effected by TMSOTf and TMSOMe. Subsequent Lewis acid mediated reduction afforded p-mannoside in high selectivity, presumably because of the stereoelectronically controlled hydride delivery from the a face. 

Mukhopadhyay, B. Field, R. A., A simple one-pot method for the synthesis of partially protected mono- and disaccharide bnilding blocks nsing an orthoesterification-benzylation-orthoester rearrangement approach. Carbohydr. Res. 2003,338,2149-2152. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

In order to circumvent such a drawback, there has been a recent focus on the design of cleavable lipids whose hydrolysis is catalyzed by the drop in pH.10 This approach exploits acid-labile chemical groups such as acetals, ketals, orthoesters, and vinyl ethers. Such functional groups... 

Using this approach, the authors found the optimal reaction conditions to be a reactant concentration of 0.2 M, dimethylformamide (DMF) as the reaction solvent, a reaction temperature of 22 °C, 10 mol% p-TsOH 12, and 5.0 eq. of the orthoester 13. Under the aforementioned conditions, the target material 11 was obtained in 43% yield, with a residence time of... 

An orthoesterification-benzylation-orthoester rearrangement approach to synthesize partially protected mono- and disaccharide building blocks was reported by Robert Field and coworkers (Scheme 2.32) [200], The reaction of L-rhamnopyranoside 120 with triethyl orthoacetate catalyzed by PTSA formed the 4-alcohol intermediate 121, which was further benzylated to furnish the fully protected intermediate 122. Without workup, 1N HC1 was added to the same vessel to rearrange the orthoester to afford the 3-alcohol 123 in a one-pot yield of 78%. Such protocol can also be applied to sugars containing a.v-diol, such as D-mannopyranoside, D-galactopyranoside, L-fucopyrano-side, and lactosyl derivatives. 

Extremely useful ramifications of the Claisen rearrangement emerged with Johnson s discovery of the orthoester variant of this transformation. His approach (Scheme 2.156) involved the following sequence of steps, which were carried out in one reaction vessel (i) transesterification of the orthoester with an allylic alcohol to give 490 (ii) elimination to form the intermediate ketene acetal 491 and (iii) [3,3] sigmatropic rearrangement to yield the y, -unsaturated ester 492. The Johnson-Claisen procedure is properly considered to be one of the most efficient methods available to prepare y,(5-unsaturated esters such as 492. ° ... 

An alternate approach to these useful 1,3-dicarbonyl substrates may be achieved through enolate orthoester acylation. Titanium enolates have been employed to effect this transformation (eq 19). Similarly, treatment of the titanium enolate of p-ketoimide with dioxolane orthoesters results in the formation of a masked tricarbonyl compound (eq 20). Trimethyl orthoacetate and Triethyl Orthoacetate are not appropriate partners in these coupling reactions. ... 

To obtain acceptors with a free 3-OH, an approach exploiting the regioselec-tive opening of cyclic orthoesters was used. Debenzylation of 2 afforded the 2,3,4-triol 3, from which the 2,3-cyclic orthoester was formed. This was followed by acetylation of the 4-hydroxyl group to give a fully protected compound. Acidic opening of the orthoester then gave exclusively the 3-OH acceptor 4 (Scheme 3). 

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