Asymmetric Synthesis of Tryptophan Driviatives and Its Application to Streamlined Synthesis of Tryprosatain A and B

Abstract

Tryprostatins have been shown to be potential antitumor antimitotic agents. Tryprostatins have been isolated from the fermentation broth of marine fungal strain Aspergillus fumigatus in trace amounts. Our lab has developed a phase-transfer-catalyzed asymmetric alkylation reaction to produce protected tryptophans (Trp) with high enantioselectivity (90-95% ee) as synthetic precursors to Tryprostatins. Studies of Tryprostatins indicate that manipulation of ring-A may cause enhanced activity. We propose a general synthetic route to several new tryprostatins that may be tolerant to ring-A analogues of gramine utilizing achiral reactants. The synthesis of Tryprostatin B has been completed with 20% overall yield in 7 steps. In the future our group will hopefully be able to utilize this chemistry to develop a large number of Tryprostatin analogs. We hope that one of these derivatives will be selective against cancer cells, with therapeutic concentrations in the nanomolar region.