Probing ergot alkaloid biosynthesis: Synthesis and feeding of a proposed intermediate along the biosynthetic pathway. A new amidomalonate for tryptophan elaboration

The total synthesis of the diastereomeric amino acids 2 and their N-trideuteriomethyl analogues has been carried out. These compounds represent possible intermediates along the biosynthetic pathway from 4-(γ,γ dimethylallyl) tryptophan (1) to the ergot alkaloids (e.g., 3a). The synthetic scheme features the preparation of an (indolylvinyl)metallic reagent from 4-ethynylindole via a hydrostannylation/metal-metal exchange sequence, as well as the preparation of dimethyl [N-methyl-N-[(2,2,2-trichloroethoxy)carbonyl]amino]malonate, a new amidomalonate reagent for tryptophan elaboration. Incorporation experiments with Claviceps sp. SD58 followed by GC-MS analysis of the major alkaloid, elymoclavine, showed that neither diastereomer of 2-d₃ is an ergot alkaloid precursor.