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

• Published in: Chemical science (Cambridge) 2021-10, Vol.12 (39), p.13137-13143
• Main Authors: Yin, Xue-Song, Qi, Wei-Yi, Shi, Bing-Feng
• Format: Article
• Language: English
• Subjects: Alanine; Chemistry; Synthesis; Tryptophan
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc02343h

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, via a sequential C–H activation strategy. The key Trp skeletons were synthesized from the inexpensive, readily available alanine via a Pd( ii )-catalyzed β-methyl C(sp 3 )–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(sp 3 )–H methylation as the key step in 15 linear steps from alanine.