Total Synthesis of Azinomycin A

Abstract

Eine der widerspenstigsten Synthesezielverbindungen ist das nun erstmals hergestellte antitumorwirksame Azinomycin A 1. Der Synthese lag ein modulares Konzept zugrunde, das es erlaubte, stereokontrolliert in mehreren konvergenten Routen Bausteine zur Verfügung zu stellen, die dann verknüpft wurden, um schließlich die Cyclisierung zum strukturell einzigartigen Aziridino[1,2‐a]pyrrolidin‐Ringsystem durchzuführen.

Application of Intramolecular 1,3-Dipolar Cyclic Addition of Azide and Olefin; Construction of (Pyrrolidine-2-ylidene)glycinate and Glycinamides

“…We already reported 5) an efficient synthetic method for (pyrrolidin-2-ylidene)glycinates 5a and 5b, which are the basic skeleton of unique unsaturated cyclic dehydro amino acid 3, by intramolecular-1,3-dipolar cyclic addition of azide and olefin as a key reaction using azide 4a and 4b. Recently, several synthetic studies 6,7) and investigation of biological properties of carzinophilin and its related synthetic products have been reported 8) and it is mentioned there that a five-membered unsaturated dehydro amino acid part like 3 has an important role in the biological activity of carzinophilin. Our work concerning the intramolecular 1,3-dipolar cyclic addition of azide and olefin would serve to construct (pyrrolidine-2-ylidene)glycinates, which are the key compounds for 3.…”

Chasing Molecules That Were Never There: Misassigned Natural Products and the Role of Chemical Synthesis in Modern Structure Elucidation

“…[160] However, a structural reassignment that involves a much smaller alteration to the molecular architecture can throw a synthetic approach into a similar degree of disarray. This discrepancy would not be reconciled for 20 years.…”

“…disparate, as no structural element apart from the terminal aromatic motif is shared by all. [160] However, a structural reassignment that involves a much smaller alteration to the molecular architecture can throw a synthetic approach into a similar degree of disarray. A good illustration resides in the elucidation of the structure of the liminoid insect antifeedant azadirachtin.…”

Essential role of an unknown geneaziU3in the production of antitumor antibiotic azinomycin B verified by utilizing optimized genetic manipulation systems forStreptomyces sahachiroi

“…These compounds can selectively electrophilic attack suitably disposed purine bases to form covalent interstrand crosslinks within the major groove of DNA that results in DNA alkylation and crosslinking (Hartley et al, 2000;Coleman et al, 2002;LePla et al, 2005). Despite efforts made by chemists to synthesize stable azinomycin analogues, their antitumor potency is much lower than azinomycin A and B in addition to a narrow antitumor spectrum (Coleman et al, 2001(Coleman et al, , 2007Casely-Hayford et al, 2005a, b;David-Cordonnier et al, 2006). However, progress in pharmaceutical applications is hampered by their chemical instability and low availability in natural sources (Alcaro & Coleman, 2000).…”

“…However, progress in pharmaceutical applications is hampered by their chemical instability and low availability in natural sources (Alcaro & Coleman, 2000). Despite efforts made by chemists to synthesize stable azinomycin analogues, their antitumor potency is much lower than azinomycin A and B in addition to a narrow antitumor spectrum (Coleman et al, 2001(Coleman et al, , 2007Casely-Hayford et al, 2005a, b;David-Cordonnier et al, 2006). 2008), although its biosynthetic pathway is still not completely understood.…”