Theoretical Study on the Mechanism of Spirocyclization in Spiroviolene Biosynthesis

Abstract

Spiroviolene is a spirocyclic triquinane diterpene produced by Streptomyces violens. Recently, a biosynthetic pathway that includes secondary carbocation intermediates and a complicated concerted skeletal rearrangement was proposed for spiroviolene, based upon careful labeling experiments. On the basis of density functional theory (DFT) calculations, we propose a revised pathway for spiroviolene biosynthesis, involving a multistep carbocation cascade that bypasses the formation of unstable secondary carbocations by breaking the adjacent C-C bond to form a more stable tertiary carbocation (IM3) and by Wagner-Meerwein 1,2-methyl rearrangement (IM7).

Concertedness and Activation Energy Control by Distal Methyl Group during Ring Contraction/Expansion in Scalarane‐Type Sesterterpenoid Biosynthesis

“…[11] However, TS_ 2-3 is approximately 15 kcal mol À 1 higher in energy than IM1, which is comparatively high. Although some systems, such as those involving secondary carbocations as transition state structures, require activation energies of approximately 15 kcal mol À 1 , [2,3,12] this scalarane-type skeletal rearrangement reaction does not involve a secondary carbocation. Consequently, we carefully investigated the reason for this high energy barrier; our investigation revealed that the distal 24-Me substituent affects both the concertedness and energy barrier of this reaction.…”

Subrutilan – Ein Hexacyclisches Sesterterpen aus Streptomyces subrutilus

“…Terpencyclisierungen erfolgen meist über tertiäre Kationen, wohingegen sekundäre Kationen normalerweise eine nichtklassische Stabilisierung erfahren [49] . In diesem Sinne wurden kürzlich die vorgeschlagenen sekundären Kationen für die Biosynthese von Variedien, [50] Spiroviolen, [20,51] Asperterpenol, [52] und Diterpenoiden vom Verrucosan‐ [53,54] und Mangicol‐Typ [55,56] basierend auf computerchemischen Daten in Frage gestellt [57–60] . Diese frühere Debatte über die Beteiligung sekundärer Kationen an Terpencyclisierungen zeigt auch, dass die Aufdeckung der wahren Mechanismen von Terpensynthasen ein kompliziertes Problem von hoher Komplexität ist.…”

Revision of the Peniroquesine Biosynthetic Pathway by Retro-Biosynthetic Theoretical Analysis: Ring Strain Controls the Unique Carbocation Rearrangement Cascade

“…Despite methodological advances in quantum-chemical calculations, theoretical studies of complicated biosynthetic processes that involve extensive bond rearrangements remain challenging, partly because of the existence of many possible associated pathways/conformations/mechanisms. Most previous theoretical studies of complex biosynthetic reactions have examined only a few selected pathways, chosen rather arbitrarily on the basis of experimentally proposed pathway(s)/mechanism(s). − We have recently established a powerful combination of quantum-chemical calculations with the global reaction route mapping (GRRM) method to unveil the complicated reaction pathways/mechanisms of biosynthetic reactions. − However, even with this method, it was extremely difficult to elucidate the biosynthesis of peniroquesine, with its characteristic pentacyclic C 25 skeleton and eight stereogenic centers, the formation of which requires complex rearrangements or fragmentation reactions. After extensive investigations, we performed a retro-biosynthetic theoretical analysis that proved effective for this highly complicated molecule, and on the basis of these results, we propose a different route/mechanism, which is in good agreement with previous isotope-labeling experimental findings.…”