Epidithiodioxopiperazines. occurrence, synthesis and biogenesis

Abstract

Epidithiodioxopiperazine alkaloids possess an astonishing array of molecular architecture and generally exhibit potent biological activity. Nearly twenty distinct families have been isolated and characterized since the seminal discovery of gliotoxin in 1936. Numerous biosynthetic investigations offer a glimpse at the relative ease with which Nature is able to assemble this class of molecules, while providing synthetic chemists inspiration for the development of more efficient syntheses. Herein, we discuss the isolation and characterization, proposed fungal biogeneses, and total syntheses of epidithiodioxopiperazines.

Figure 1

Representative epidithiodioxopiperazines derived from tyrosine and/or phenylalanine.

Figure 2

Representative tryptophan-derived epidithiodioxopiperazines.

Figure 3

Gliotoxins.

Figure 4

Redox cycling of epidithiodioxopiperazines.

Figure 5

Mixed disulfide formation.

Figure 6

Simple biologically active epidithiodioxopiperazines.

Figure 7

Hyalodendrins and related compounds.

Figure 8

Silvatins.

Figure 9

Aranotins.

Figure 10

Emethallicins.

Figure 11

Emestrins and related metabolites.

Figure 12

Epicorazines.

Figure 13

Scabrosin esters.

Figure 14

Sirodesmins.

Figure 15

Sporidesmins.

Figure 16

Metabolites of the fungus Chaetomium cochliodes.

Figure 17

Chetoseminudins.

Figure 18

Chaetocins and related metabolites.

Figure 19

Fungal metabolites related to the chaetocins.

Figure 20

Verticillin A and related metabolites.

Figure 21

Verticillin-type epipolythiodioxopiperazines.

Figure 22

Leptosins.

Figure 23

Putative epidithiodioxopiperazine gene clusters for sirodemsin PL (A) and gliotoxin (B).

Scheme 1

Proposed biosynthesis of gliotoxin.

Scheme 2

Proposed oxepine ring formation.

Scheme 3

Proposed biosynthetic pathway of sirodesmin PL.

Scheme 4

Proposed biosynthetic pathway for acetylaranotin.

Scheme 5

Proposed biosynthetic pathway for bisdethiodi(methylthio)acetylaranotin.

Scheme 6

Total synthesis of (±)-sporidesmin A.

Scheme 7

Synthesis of (±)-sporidesmin B.

Scheme 8

Synthesis of (±)-dehydrogliotoxin.

Scheme 9

Synthesis of (+)-gliotoxin.

Scheme 10

Synthesis of (±)-hyalodendrin.

Scheme 11

Total synthesis of (±)-gliovictin and epi-gliovictin.

Scheme 12

Williams and Rastetter's total synthesis of (±)-hyalodendrin.

Scheme 13

Total synthesis of (±)-aspirochlorine.

Scheme 14

Biomimetic total synthesis of (+)-11,11′-dideoxyverticillin A.

Scheme 15

Sodeoka's total synthesis of (+)-chaetocin.

Scheme 16

Movassaghi's total synthesis of (+)-chaetocin.

Scheme 17

Total syntheses of chaetocin C and 12,12′-dideoxychetracin A.

Scheme 18

Synthesis of (+)-gliocladine C.

Scheme 19

Divergent syntheses of (+)-leptosin D, (+)-T988C, (+)-bionectin A and (+)-bionectin C.

Scheme 20

Total synthesis of (+)-gliocladin B.

Scheme 21

Synthesis of (+)-12-deoxybionectin A and (+)-gliocladin B.

Scheme 22

Total synthesis of (+)-bionectin A and (+)-bionectin C.

Scheme 23

Total synthesis of epicoccin G.

Scheme 24

Key pyrrolidine synthesis.

Scheme 25

Completion of the total synthesis of (–)-acetylaranotin.

Scheme 26

Tokuyama's formal synthesis of (–)-acetylaranotin.