Hydroxylamine → Dl-Phenylalanine

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To explore the effectiveness of cyanide in the assistance of hydroxylamine mediated cleavage for solid phase library synthesis, hydroxymethylbenzamide (HMBA-AM) resin was chosen for the well-established compatibility between the ester linkage and Fmoc- and Boc-chemistry, and its stability towards Mitsunobu and reductive amination conditions. A solid phase library of DL-phenylalanine and several constrained analogs (AAa–c, Scheme 3) was prepared on the HMBA resin by the esterification of the Fmoc protected DL-aminoacids using standard DCC coupling conditions at room temperature overnight. The resin-bound Fmoc aminoacids BBa–c were deprotected with piperidine-DMF (1:4) and sulfonated with 4-methoxybenzenesulfonyl chloride to give Compounds IIIa–c. In this instance, the optimal reaction conditions for cleavage from the resin of the sulfonamide esters to yield the free hydroxamic acids (IVa–c, Table 2) were 5:5:2 THF:MeOH:50% aqueous NH2OH and 5 mg (0.08 mmol, 40 to 80 mol %) of KCN for 100 to 200 mg of loaded resin.

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