Programmable Onepot Synthesis

A recent approach that shows promise for automation is the use of one-pot reaction schemes that use the reactivity profile of different protected sugars [42, 43] to determine the outcome. The reactivity of a sugar is highly dependent on the protecting groups and the anomeric activating group used. By adding substrates in sequence from the most to least reactive, one can assure the predominance of a desired target compound (Fig. 24.10). Compared with the stepwise solid-phase method, the one-pot method involves no protecting group manipulation in the iterative process. The key to this approach is to have extensive quantitative data regarding the relative reactivities of differentially protected sugar building blocks. A large amount of reactivity data for more than 100 protected p-methylphenyl thio-glycosides (Fig. 24.11) were recently generated and used as the basis of a computer program, termed OptiMer, which selects the best reactants for the one-pot synthesis

(A) Stepwise Solid-Phase Synthesis op„

op, op8

2nd Condition Coupling

1s1 Condition

Differential deprotection 1 out of 4

Differential 3rd Conditionj deprotection 1 out of 7

4th Condition Coupling

5" Condition Differential deprotection 1 out of 10

6th Condition Coupling


(B) OptlMer's Programmed One-Pot Synthesis

Most reactive 2 nd most reactive 3 rd..

6th Condition Coupling

STol op

op op,o op6

Fig. 24.10. (A) Traditional step-wise solidphase synthesis requires on-resin protecting group manipulation, which can become very complicated as the number of glycosidic linkages increases. (B) OptiMer's one-pot approach. OptiMer is a program which predicts the optimal type and order of addition group manipulation and intermediate isolation of partially protected sugars, based on a are required during the one-pot synthesis.

database of relative reactivities. This approach requires preparation of a number of building blocks with their glycosidation reactivities quantitatively measured. A reactivity difference greater than 1000 between the building blocks will give a high-yield in coupling. No protecting of a target compound [32, 43]. p-Methylphenyl thioglycosides were chosen as they are applicable to most monosaccharides and are more reactive toward thiophilic activators such as N-iodosuccinimide (NIS) and dimethylthiosulfonium triflate (DMTST) than other thioglycosides [11, 20, 44, 45] which have been used in practical synthesis.

This approach has been used with success in the synthesis of a large number of oligosaccharides including the cancer antigen Globo-H hexasaccharide (Fig. 24.12) [46]. In practice, the sequence of Globo-H was entered into the computer program OptiMer, three building blocks and their corresponding relative reactivities were shown. One simply mixes the building blocks and NIS in sequence, and after a few minutes the desired product is generated in protected form. After deprotection and purification, the target is obtained. If necessary, the trisaccharide building blocks can be prepared separately by the one-pot approach using the same procedure. While the one-pot strategy is quite effective, further work is needed to design a complete set of building blocks (probably @ 500 or so are needed) for use in the synthesis of most bioactive saccharides. So far, branchpoints have been incorporated by using the thioglycosides of disaccharides as reactants in the linear

Fig. 24.11. Building blocks and their relative reactivities (in parentheses) used for OptiMer's one-pot approach.

720 | 24 Strategies for Creating the Diversity of Oligosaccharides Programmed One Pot Synthesis of Globo H






Fig. 24.12. Synthesis of the cancer antigen Globo-H using OptiMer technology. In brief, the sequence of Globo-H is entered into the computer, which predicts the best building blocks to be used. These building blocks are then mixed in sequence, starting with the most reactive one, in the presence of an activator. The product obtained is then purified and deprotected to give the target. Ac, acetyl; Bn, benzyl; Bz, benzoyl; Tol, tolyl; Troc, trichloroethoxycarbonyl.

scheme. These reactions are typically performed in solution, but, in order to facilitate removal of reactants at the end, the final acceptor may be attached to solid support or other aglycons.

Future development in this approach is to expand the building-block repertoire and to ensure its applicability in programmable one-pot synthesis. Compared with stepwise solid-phase synthesis, the one-pot approach requires protecting group manipulation only at the stage of building-block synthesis, and thus holds greater potential for automation and for a greater diversity of oligosaccharide structures.

Other solution-phase syntheses of oligosaccharide libraries have been reported, especially the method for the synthesis of mixtures [47], but the methods have not been demonstrated to create great diversity. In addition, characterization of the mixture represents a difficult problem.

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