Tetrahydroisoquinoline (THIQ) alkaloids are an important group of compounds that exhibit a range of bioactivities. Here, a phosphate buffer-catalyzed Pictet-Spengler reaction (PSR) using unreactive ketone substrates is described. A variety of 1,1′-disubstituted and spiro-tetrahydroisoquinoline alkaloids were readily prepared in one-step and high yields, highlighting the general applicability of this approach. This study features the role of phosphate in the aqueous-based PSR and provides an atom-efficient, sustainable route to new THIQs. © 2019 American Chemical Society.