Synthesis of tryptophan-containing 2,5-diketopiperazines <i>via</i> sequential C–H activation: total syntheses of tryprostatin A, maremycins A and B

Abstract

Indole 2,5-diketopiperazines (DKPs) are an important type of metabolic cyclic dipeptides containing a tryptophan (Trp) unit possessing a range of interesting biological activities. The intriguing structural features and divergent activities have stimulated tremendous efforts towards their efficient synthesis. Herein, we report the development of a unified strategy for the synthesis of three Trp-containing DKPs, namely tryprostatin A, and maremycins A and B, <i>via</i> a sequential C-H activation strategy. The key Trp skeletons were synthesized from the inexpensive, readily available alanine <i>via</i> a Pd(ii)-catalyzed β-methyl C(sp³)-H monoarylation. A subsequent C2-selective prenylation of the resulting 6-OMe-Trp by Pd/norbornene-promoted C-H activation led to the total synthesis of tryprostatin A in 12 linear steps from alanine with 25% overall yield. Meanwhile, total syntheses of maremycins A and B were successfully accomplished using a sequential Pd-catalyzed methylene C(sp³)-H methylation as the key step in 15 linear steps from alanine.