Silicon-based protecting groups are commonplace in synthetic routes to complex organic molecules. Their ability to be introduced under mild conditions, as well as their stability toward harsh reaction conditions, has made them a widespread tool in organic synthesis. Small silyl protecting groups, such as the trimethylsilyl group, can be removed under basic or acidic conditions, but larger silyl protecting groups are generally removed under fluoride-mediated conditions. One especially useful reagent for the removal of silyl protecting groups is tetrabutylammonium fluoride (TBAF). The solubility of this reagent in organic solvents, as well as its chemoselectivity, has contributed to its frequent usage in the removal of silyl protecting groups. On simple systems, where the products are relatively nonpolar, TBAF is easily removed via an aqueous workup. For more polar products, however, an aqueous workup can result in loss of material to the aqueous layer or challenging separations. An attractive alternative protocol for the removal of residual TBAF was reported by Kishi and co-workers in 2007. In this study, removal of these byproducts was achieved without an aqueous extraction, and applied in the total synthesis of Halichondrin B. In particular, it was discovered that the addition of a 50WX8 ion-exchange resin in combination with a mild base, such as calcium carbonate, was effective in sequestering cationic byproducts, such as tetrabutylammonium, from reaction mixtures. The proposed mechanism for this methodology is delineated in following Figure .
First, the tetrabutylammonium cation exchanges with a proton on the ion-exchange resin. This equilibrium process is then driven forward by calcium carbonate, which reacts with HF to form calcium fluoride, water, and carbon dioxide. After addition of the ion-exchange resin and calcium carbonate, the reaction mixture can be filtered to provide the desired product. This convenient and effective procedure removes undesired TBAF-related byproducts and obviates the need for aqueous extraction.
The Kishi group explored the utility of this methodology in the syntheses of several alcohol products . It was observed that carbohydrates, such as 3, could be isolated from their respective tert-butyl silyl (TBS)- protected precursors. Furthermore, diols such as 4 and 5 could also be isolated from the corresponding silyl alcohols using this methodology。
This strategy was also employed in the total synthesis of complex, highly polar natural products . For example, penta-ol 6 was accessed in near quantitative yield and served as a key late-stage intermediate in Kishi’s total synthesis of halichondrin B.The natural product alloviroidin (7) was also isolated following the removal of five TBS groups in the final step of the total synthesis, and tri-ol intermediate 8 was accessed using this methodology en route to etnangien. Finally, tetra-ol 9 was isolated and further derivitized en route to zincophorin methyl ester. Overall, the ion exchange resin strategy for the removal of TBAF related byproducts has shown to be a convenient and effective workaround to challenges encountered in the desilylation of alcohols and purification of the resultant polar products.
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