Synthesis of Polymer-Bound 4-Acetoxy-3-phenylbenzaldehyde Derivatives:  Applications in Solid-Phase Organic Synthesis

Abstract

Aminomethyl polystyrene resin was reacted with 4-(5′-formyl-2′-hydroxyphenyl)benzoic acid and 4-(5′-formyl-2′-hydroxyphenyl)phenyl propionic acid, respectively, in the presence of 1-hydroxybenzotriazole and 1,3-diisopropylcarbodiimide to yield polymer-bound benzaldehydes. The phenolic group in resins was acetylated with acetic anhydride to afford two polymer-bound 4-acetoxybenzaldehydes. The reductive amination of polymer-bound linkers by amines and sodium triacetoxyborohydride, followed by sulfonylation with alkyl or arylsulfonyl chloride derivatives in the presence of pyridine and the cleavage with TFA/DCM, produced pure sulfonamides.Solid-phase organic synthesis has emerged as a powerful tool to generate large molecular libraries 1-3 of small-sized molecules and to accelerate lead discovery and optimization processes. The challenge now is to extend the ability of solid-phase chemistry to generate a large number of structurally diversified compounds by developing suitable polymer-bound reagents 4,5 that accommodate the synthesis of various compounds.The reagents have to be attached to the polymer through a linker. Linkers that can generate different compounds depending on the attached compounds and the cleavage conditions are needed. A number of polymer-bound linkers have been used for the synthesis of different compounds. 5-29 In some cases, the purification of final products is still needed, because of the instability of polymer-bound linkers in different reaction conditions and/or the leakage of different materials upon cleavage. Therefore, the polymer-bound linkers that have application in producing pure final products are preferred. Stable polymer-bound linkers are needed that provide the concomitant cleavage of pure and various products and removal of the linker group without any loss in overall synthetic efficiency. Furthermore, for the synthesis of diverse number of compounds, such as organosulfur and organophosphorus compounds, polymerbound linkers have not been developed extensively.To explore further the synthetic utility of the polymer-bound linkers as tools for the synthesis of diverse number of compounds without the need of purification in the final cleavage step, two new polymer-bound linkers of p-acetoxybenzaldehyde, 1a and 1b, were synthesized ( Figure 1). Because of the proximity of the amino group and p-acetoxy group in the previous reported polymer-bound linkers of p-acetoxybenzyl alcohol 20,23,24 , the intramolecular reactions caused uncontrolled partial release of some intermediates before further modifications on attached moieties (X) (Scheme 1). Therefore, the yield of final products was lower than expected.Polymer-bound p-acetoxybenzaldehydes 1a and 1b offered several advantages compared to other polymer-bound linkers reported by us and others. 20,23,24 First, a large separation between the nitrogen atom in amide and p-acetoxy group was introduced in new polymerbound linkers 1a and 1b. The presence of the nitrogen atom in amide form and the large distance between amide bond and...

Facile Construction of Nanofibers as a Functional Template for Surface Boron Coordination Reaction

“…It should be noted that the gel–sol transition is reversible. Through increasing the HCl concentration of the solution to 6 M , hydrogels could be re‐formed ( Figure ) since the boronate esters have been demonstrated to hydrolyze under these conditions 41, 42…”

Inhibition of multi-drug resistant HIV-1 reverse transcriptase by nucleoside β-triphosphates

“…28 Our research on the solid-phase synthesis of organophosphorus and organosulfur compounds revealed that the polymer-bound p -acetoxybenzyl alcohol containing amide linker ( 5 ) was more stable than polymer-bound N -Boc p -acetoxybenzyl alcohol even in basic conditions and was used to generate sulfonamides and other organophosphorus compounds in high yields and without the need for extensive purifications of final products. 29,30 Thus, polymer-bound linker 5 instead of polymer-bound N -Boc p -acetoxybenzyl alcohol was selected for the reaction with β-triphosphitylating reagent 6 to generate a new polymer-bound β-triphosphitylating reagent 7 that was used for preparation of nucleoside β-triphosphates including two novel compounds 3 and 4 (Scheme 1). …”

Synthesis of nucleoside 5′-O-α,β-methylene-β-triphosphates and evaluation of their potency towards inhibition of HIV-1 reverse transcriptase

“…24 Our earlier studies revealed the application of polymer-bound p -acetoxybenzyl alcohol linkers in the synthesis of a diverse number of compounds 25. Polymer-bound linker 7 was selected for immobilization of reagent 6 .…”