The orthoester, a functional group that features three alkoxy groups attaching to a single carbon atom, was an important structural subunit discovered in plant resource. Diverse phragmalin-type limonoids with different orthoester moiety and connected locations have been isolated from the Meliaceae family. Under the guidance of plausible biosynthetic pathway, phragmalin-type 1/8/9-orthoesters were effectively synthesized from its phragmalin mother nuclear through a key intermediate with an esterfunction at C-1. These interesting findings indicated that natural phragmalin-type 1/8/9-orthoesters were derived from phragmalins with esterified substituent at C-1 and hydroxyl groups at C-8 and C-9.