Precursor directed biosynthesis (PDB) presents a useful approach for modifying large scale drug and drug lead mole cules . Large molecular structures are synthetically modified as part of total synthesis approach, and often result in l ow yield and expensive r eagents. Of particular interest are plant alkaloid drugs, many of which come from tetrahydroisoquinoline (THI) precursor. We present an organic synthesis of novel dopamine and 4 - hydroxyphenacetaldehyde (4-HPAA) analogs as precursors for enzymatic conversion to tetrahydroisoquinoline analogs using norcoclaurine synthase (NCS) . Modifications for investigation include halogenation of the 2 and 5 positions of the aromatic ring and variation of atoms in the ethylamine chain of the dopamine molecule. Modifications for 4- HPAA include exploration of different amino acids as starting materials for THI conversion. Exploration of THI analogs a llows for investigation of complex molecules such as, berberine, sanguinarine, galanthamine, and other plant alkaloid drugs. Precursor directed biosynthesis presents an interesting way to incorporate structural modifications for large drug candidates without total synthetic approach
