We have achieved an efficient solution-phase parallel synthesis of a library of natural piper-amide-like compounds from the bifunctional β-phosphono-N-hydroxy-succinimidyl ester intermediate. The primary important feature in our study is the construction of natural-product-like molecules through the adaptation of sophisticated organic reactions that create water-soluble byproducts for a chromatography-free purification. This simple and efficient method rapidly provides a combinatorial library of high yield and purity. The library was evaluated against GPCR targets to demonstrate its potential use as a tool for drug discovery and in chemical biology.