The stereocontrolled total synthesis of (+)-pleiocarpamine and the total syntheses of (+)-voacalgine A and (+)-bipleiophylline have been achieved. The scalable and concise 10-step synthesis of (+)-pleiocarpamine features construction of stereochemistry at the C16 position by radical cyclization and that of the highly strained cage-like structure via Pd-catalyzed intramolecular aromatic C−H functionalization. By modifying the biomimetic aerobic oxidative coupling of tryptophane derivatives catalyzed by FePc(CO 2 H) 8 , the oxidative coupling of the synthesized (+)-pleiocarpamine with pyrocatechuic acid was established to produce (+)-voacalgine A. The total synthesis of (+)-bipleiophylline was completed by the second coupling of (+)-voacalgine A with (+)-pleiocarpamine or one-pot couplings of 2 equiv of (+)-pleiocarpamine with pyrocatechuic acid.

The bicyclic depsipeptide FR901375 was efficiently synthesized in a highly convergent manner. The synthesis involved the condensation of a d‐valine–d‐valine–d‐cysteine‐containing segment with a (3S,4E)‐3‐hydroxy‐7‐mercapto‐4‐heptenoic acid–l‐threonine‐containing segment to directly assemble the corresponding seco‐amino acid, followed by cyclization to construct the desired 16‐membered macrocyclic ring. The potency of the synthesized FR901375 was determined in assays for histone deacetylase (HDAC) inhibition and cell‐growth inhibition, and the results were compared to those obtained for the clinically approved depsipeptide FK228 (romidepsin). It was found that FR901375 shows extremely high selectivity (957‐fold) for a class I HDAC 1 (GI50 = 1.7 nm) over a class II HDAC 6 (GI50 = 1627 nm), and shows cell‐growth inhibition GI50 values in the low nanomolar region. Furthermore, new aspects of the structure–activity relationship of bicyclic depsipeptide HDAC inhibitors were revealed.

Synthetic studies on a dimeric indole alkaloid, cimiciduphytine, were conducted based on modifying our synthesis of (+)-haplophytine. The key feature of this synthesis is the development of chemoselective deallylation of an N,O-diallyl derivative of a hydroxy aniline derivative, and copper sulfate-mediated oxidative lactonization via oxidation of the amino moiety. A highly convergent strategy led us to synthesize the originally proposed cimiciduphytine. However, the compound was unstable under air and underwent cyclization to generate a bridged derivative.

A bioinspired convergent total synthesis of (+)‐haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described. This synthesis involves the direct coupling of the two segments in a AgNTf2‐mediated Friedel–Crafts reaction and construction of the diazabicyclo[3.3.1]nonane skeleton through late‐stage chemoselective aerobic oxidation of the 1,2‐diaminoethene moiety and a sequential semipinacol‐type rearrangement.