Ipecac alkaloids are medicinal monoterpenoid-derived tetrahydroisoquinoline alkaloids found in two distantly related plants: Carapichea ipecacuanha (Gentianales) and Alangium salviifolium (Cornales). Here we provide evidence suggesting that both plants initiate ipecac alkaloid biosynthesis through a nonenzymatic Pictet-Spengler reaction and we elucidate the biosynthetic fate of both the 1R and 1S stereoisomers that are produced in this nonstereoselective reaction. Although the biosynthesis of the 1S-derived protoemetine proceeds according to the same chemical logic in both species, each plant uses a distinct monoterpene precursor. Phylogenetic analyses show examples of independent pathway evolution through parallel and convergently evolved enzymes. This work provides insight into how nature can capitalize on highly reactive starting substrates and the manner in which multistep pathways can arise and lays the foundation for metabolic engineering of these important medicinal compounds.