“Cation-Stitching Cascade”: exquisite control of terpene cyclization in cyclooctatin biosynthesis

Abstract

Terpene cyclization is orchestrated by terpene cyclases, which are involved in the biosynthesis of various cyclic natural products, but understanding the origin and mechanism of the selectivity of terpene cyclization is challenging. In this work, we describe an in-depth mechanistic study on cyclooctatin biosynthesis by means of theoretical calculations combined with experimental methods. We show that the main framework of cyclooctatin is formed through domino-type carbocation transportation along the terpene chain, which we call a “cation-stitching cascade”, including multiple hydrogen-shifts and a ring rearrangement that elegantly determine the stereoselectivity.

Mechanistische Studien an zwei bakteriellen Diterpencyclasen: Spiroviolen‐Synthase und Tsukubadien‐Synthase

“…Diese Beobachtung verwies auf eine direkte 13 C‐ 2 H‐Bindung, die in Übereinstimmung mit zwei sequenziellen 1,2‐Hydridverschiebungen ist. Ähnliche Ergebnisse wurden für die Cyclisierungsmechanismen der Synthasen für Cyclooctat‐9‐en‐7‐ol und die Corvolether berichtet . Die vorläufig zugewiesene relative Orientierung des Cyclopropanringes in den Intermediaten 13 – 16 kann nicht mit Sicherheit aus der Struktur des finalen Produktes 9 abgeleitet werden, aber die Orientierung wie sie in Schema gezeigt ist verlangt Inversion der Konfiguration an C6 in dem Schritt von 14 nach 16 , was wahrscheinlicher als Retention der Konfiguration erscheint.…”

Interrogating chemical mechanisms in natural products biosynthesis using quantum chemical calculations

“…In addition, the conversion of carbocation H to I , supported by labelling experiments, is unusual . Using DFT calculations (mPW1PW91/6‐31+G(d,p)//B3LYP/6‐31G(d) and M06‐2X/6‐31G**), two groups arrived at the same conclusions: the lowest energy pathway involves conversion of carbocation A to carbocation B , two‐step hydride migration from carbocation C is preferred over direct hydride transfer to form carbocation E , carbocation F (with its delocalized 3‐center 2‐electron bonding array) is an intermediate between carbocations E and G and the H ‐to‐ I conversion has a low barrier (~6–11 kcal/mol). Additional labelling experiments confirmed the prediction concerning the C ➔ E reaction, showing that the inherent preference for stepwise migration was not overturned in the enzyme.…”

“…Using DFT calculations (mPW1PW91/6‐31+G(d,p)//B3LYP/6‐31G(d) and M06‐2X/6‐31G**), two groups arrived at the same conclusions: the lowest energy pathway involves conversion of carbocation A to carbocation B , two‐step hydride migration from carbocation C is preferred over direct hydride transfer to form carbocation E , carbocation F (with its delocalized 3‐center 2‐electron bonding array) is an intermediate between carbocations E and G and the H ‐to‐ I conversion has a low barrier (~6–11 kcal/mol). Additional labelling experiments confirmed the prediction concerning the C ➔ E reaction, showing that the inherent preference for stepwise migration was not overturned in the enzyme. This example shows that fairly large, structurally/stereochemically complex reactive intermediates can be modeled reliably and reproducibly and provides more examples that the inherent reactivity of carbocations is apparently expressed in terpene synthase active sites …”

Understanding the Role of Active Site Residues in CotB2 Catalysis Using a Cluster Model

“…The intracellular target of cyclooctatin is a, as yet uncharacterized lysophospholipase, which is involved in early steps of the inflammatory signaling cascade. [21][22][23] In the last decade numerous interdisciplinary studies have addressed the chemical mechanism of CotB2 catalysis utilizing different detection and analysis methods.…”