Our ability to access the more complex members of the cyclotryptamine family of alkaloids, and to exploit their disparate biological activities, is limited by the synthetic challenge posed by their oligomeric, polyindoline structures. A recurring structural theme within these molecules is the presence of multiple quaternary stereocenters in close proximity to one another. Over the last decade, we have developed a set of transformations that allow rapid access to polyindolines, a number of which exploit the ability of catalytic levels of palladium to orchestrate carbon-carbon bond formation with impressive levels of regio- and stereocontrol. This review tells the story behind the development of this toolbox of synthetic methods, and their validation through the total synthesis of a number of structurally complex cyclotryptamine alkaloids. It also highlights an aspect of asymmetric catalysis that has received little attention, the ability of catalytic asymmetric reactions to selectively elaborate complex, polyfunctional molecules.

Total synthesis of complex cyclotryptamine alkaloids: stereocontrolled construction of quaternary carbon stereocenters.

Concise total synthesis of (-)-calycanthine, (+)-chimonanthine, and (+)-folicanthine.

Hexahydropyrroloindoline alkaloids are a large class of natural products that are formally derived from two molecules of tryptophan.[1] A subset of this class, the C3–C3′ indole alkaloids, contain the 3a-(3-indolyl)-hexahydropyrrolo-[2,3-b]indole skeleton and include compounds such as gliocladin C,[2] gliocladine C,[3] leptosin D,[4] and the bionectins[5] (Figure 1). Aside from their interesting structural features, they exhibit a broad range of potent biological activities. For example, gliocladin C[2] and leptosin D[4] are cytotoxic against P-388 lymphocytic leukemia cell lines with ED50 values of 240 ng mL−1 and 86 ng mL−1, respectively, while bionectins A and B[5] exhibit antibacterial activity against MRSA (methicillin-resistant S. aureus) and QRSA (quinolone-resistant S. aureus) with MIC = 10–30 µm mL−1.

Total synthesis of (+)-gliocladin C enabled by visible-light photoredox catalysis.

The first total synthesis of (+)-chaetocin has been accomplished in nine steps starting from known N-Cbz-N-Me-serine using radical α-bromination reaction of diketopiperazine 10 and Co(I)-mediated reductive dimerization reaction of 12 as key reactions. The enantiomers show comparable inhibitory activity toward histone methyltransferase (HMT) G9a, but analogues without the sulfur functionality are inactive.

Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity

Direct Stereo- and Enantiocontrolled Synthesis of Vicinal Stereogenic Quaternary Carbon Centers. Total Syntheses of meso- and (−)-Chimonanthine and (+)-Calycanthine

Hiroyuki Sugumi

Papers

Oxidative dimerization of Nb-acyltryptophans total synthesis and absolute configuration of ditryptophenaline