Activation Method to Prepare a Highly Reactive Acylsulfonamide 'Safety-Catch' Linker for Solid-Phase Synthesis

摘要

Solid-phase synthesis methods are commonly employed for the preparation of oligonucleotides and peptides and are becoming increasingly important for the preparation of small organic molecules, in particular for the preparation of compound libraries for drug development programs. In almost all solid-phase peptide synthesis efforts, and in a majority of small molecule solid-phase synthesis approaches, the compound is attached to the support through a caiboxylic acid functionality, Linkage to support ismost often accomplished with amide-based linkage elements that provide primary amide products upon cleavage, or with ester-based linkage elements that provide carboxylic acid products upon cleavage. However, for many synthesis efforts it is desirable tocleave the compound from the support by nucleophilic displacement with amines or alcohols to provide the corresponding amide or ester products. To achieve this goal, researchers have worked to develop linkers that are stable through a given synthesis sequence, yet can be activated for nucleophilic cleavage upon synthesis completion.6 Of these, only Kenner's acylsulfonamide safety-catch linker7 is completely stable to basic or strongly nucleophilic conditions. Activation is accomplished by treatment with diazomethane to provide the N-methyl acylsulfonamide, which can then be cleaved with hydroxide or with nucieophilic amines. Kenner initially developed this linker for peptide synthesis and demonstrated the preparation of xid, primary amide, and hydrazide products. We have used an adaptation of the linker for the solid-phase synthesis of the arylacetic acid class of cyclooxygenase inhibitors where basic reaction conditions were employed including acylsulfonamide enolate alkylation reactions. For both peptide and small molecule synthesis, however, the reactivity of the N-methyl acylsulfonamide is poor: Non-nucleophilic amines do not react with the N-methylated acylsulfonamide, and even for nucleophilic amines, excess reagent is usually employed which can complicate product isolation. Herein, we report on the potential applications of an activation method to prepare a highly reactive acylsulfonamide linkage.