Total synthesis, biosynthesis and biological profiles of clavine alkaloids

Abstract

This review highlights noteworthy synthetic and biological aspects of the clavine subfamily of ergot alkaloids. Recent biosynthetic insights have laid the groundwork for a better understanding of the diverse biological pathways leading to these indole derivatives. Ergot alkaloids were among the first fungal-derived natural products identified, inspiring pharmaceutical applications in CNS disorders, migraine, infective diseases, and cancer. Pergolide, for example, is a semi-synthetic clavine alkaloid that has been used to treat Parkinson’s disease. Synthetic activities have been particularly valuable to facilitate access to rare members of the Clavine family and empower medicinal chemistry research. Improved molecular target identification tools and a better understanding of signaling pathways can now be deployed to further extend the biological and medical utility of Clavine alkaloids.

Fischer indole synthesis applied to the total synthesis of natural products

“…It has become an striking target for whole synthesis campaigns because of the interesting synthetic challenge presented by the fused azepinoindole nucleus and its jub as a biosynthetic pioneer to the communesin alkaloids, that show cytotoxicity against leukemia cell rules. 127 In 2016, total synthesis of (À)-aurantioclavine has been accomplished by Cho and co-workers. 128 However, the signicant step of this total synthesis was the production of 3,4-fused tricyclic indole derivatives via intramolecular FIS of aryl hydrazides, that contain a carbonyl group including a side chain connected to the meta-position of the aromatic ring.…”

Eight‐Step Enantioselective Total Synthesis of (−)‐Cycloclavine

“…Key features include the first catalytic asymmetric cyclopropanation of allene, mediated by dirhodium catalyst Rh 2 (S-TBPTTL) 4 , and the enone 1,2-addition of a new TEMPOcarbamate methyl carbanion. An intramolecular strain-promoted Diels-Alder methylenecyclopropane (IMDAMC) reaction provided a pivotal tricyclic enone intermediate in >99% ee after crystallization.…”

“…Members of this family have long served as an inspiration for the design of therapeutic agents and agrochemicals due to their potent and diverse biological activities. [4] In recent years, major advances in elucidating the biogenetic origin of ergot alkaloids have been made. [4] A unique …”

“…[4] In recent years, major advances in elucidating the biogenetic origin of ergot alkaloids have been made. [4] A unique …”

“…The degree of enantioinduction depended on the nature of the ester, with the sterically hindered t-butyl diazopropanoate providing the best er at low temperatures (entries 2 and 3). However, MCPs bearing an activated ester facilitated direct aminolysis and were therefore strategically more appealing (entries [4][5][6]. While the succinimide and pentachlorophenyl diazopropanoates provided only moderate enantioinduction (entries 4 and 5), the pentafluorophenyl diazopropanoate provided the desired cyclopropane in high yield with a good er of 87:13 that could be further upgraded to an excellent er by crystallization (vide infra).…”