Abstract:The first total synthesis of sespenine, a rare indole sesquiterpenoid from a mangrove endophyte, has been accomplished. A bioinspired aza-Prins/Friedel-Crafts/retro Friedel-Crafts cascade reaction assembles the bridged tetrahydroquinoline core. Further investigations on the aza-Prins cyclization imply that the C3 configuration of the hydroxyindolenine intermediate is crucial to the biosynthesis of sespenine and its congener xiamycin A.
“…Recently, we accomplished the total syntheses of a series of naturally occurring indole terpenoids (Scheme A) . From a retrosynthetic point of view, indole terpenoid scaffolds can be disassembled into indole (highlighted in red, Scheme A) and terpenoid (highlighted in blue, Scheme A) motifs in general –,,. Thus, structurally diverse indole terpenoid mimics can be directly prepared from simple indole and terpenoid building blocks (Scheme B), if efficient cross‐coupling‐type reactions are available for forming the linkage bonds (highlighted in cyan, Scheme ).…”
We constructed a small library of indole terpenoid mimics using a hybridizing strategy to link various indole and α,β-unsaturated enone building blocks together. Prepared compounds were evaluated for the cytotoxicity against a panel of cancer cell lines. An indolyl ketone called JP18 was identified as a cell cycle regulator, and the underlying mechanism was investigated.
“…Recently, we accomplished the total syntheses of a series of naturally occurring indole terpenoids (Scheme A) . From a retrosynthetic point of view, indole terpenoid scaffolds can be disassembled into indole (highlighted in red, Scheme A) and terpenoid (highlighted in blue, Scheme A) motifs in general –,,. Thus, structurally diverse indole terpenoid mimics can be directly prepared from simple indole and terpenoid building blocks (Scheme B), if efficient cross‐coupling‐type reactions are available for forming the linkage bonds (highlighted in cyan, Scheme ).…”
We constructed a small library of indole terpenoid mimics using a hybridizing strategy to link various indole and α,β-unsaturated enone building blocks together. Prepared compounds were evaluated for the cytotoxicity against a panel of cancer cell lines. An indolyl ketone called JP18 was identified as a cell cycle regulator, and the underlying mechanism was investigated.
“…This was achieved by preparing the acetyl derivatives (acetyl-102 a/b) followed by HPLC purification. [84] synthetic organic chemistry can be an important tool to elucidate biosynthetic pathways, even up to intricate stereochemical details. Only the acetyl-102 a epimer was smoothly converted into the sespenine-like rearrangement product 104.…”
Section: Oxidative Cyclizations Of Indoloterpenoidsmentioning
confidence: 99%
“…This consideration was recently successfully employed for the first total synthesis of sespenine (Scheme 26 A). [84] Initial attempts with various oxidizing agents showed that strictly biomimetic conditions only gave low yields of sespenine (< 21 %), because the lack of a C2 substituent in indole promoting oxidative cleavage of the pyrrole ring. As a consequence of their convergent synthesis route, this problem could easily be solved by using methoxycarbonylsubstituted indole derivative 101, which was obtained in 12 steps.…”
Section: Oxidative Cyclizations Of Indoloterpenoidsmentioning
confidence: 99%
“…The intermediary cation can either be quenched by a pinacol-like rearrangement to afford 104 or by simple proton elimination to give 105. [84] synthetic organic chemistry can be an important tool to elucidate biosynthetic pathways, even up to intricate stereochemical details. In addition, this example again underlines that stereochemistry plays a pivotal role in the fate of carbocations and can lead to completely different scaffolds.…”
Section: Oxidative Cyclizations Of Indoloterpenoidsmentioning
Terpene and terpenoid cyclizations are counted among the most complex chemical reactions occurring in nature and contribute crucially to the tremendous structural diversity of this largest family of natural products. Many studies were conducted at the chemical, genetic, and biochemical levels to gain mechanistic insights into these intriguing reactions that are catalyzed by terpene and terpenoid cyclases. A myriad of these enzymes have been characterized. Classical textbook knowledge divides terpene/terpenoid cyclases into two major classes according to their structure and reaction mechanism. However, recent discoveries of novel types of terpenoid cyclases illustrate that nature's enzymatic repertoire is far more diverse than initially thought. This Review outlines novel terpenoid cyclases that are out of the ordinary.
“…Im Falle des Sespenins ( 50 ) handelt es sich beim Nukleophil für die oxidative Cyclisierung um die terminale Doppelbindung der Sesquiterpengruppe – formal eine Aza‐Prins‐Reaktion. Diese Überlegung wurde kürzlich für die erste Totalsynthese von Sespenin angewendet (Schema ) 84. Erste Versuche mit verschiedenen Oxidationsmitteln zeigten, dass strikt biomimetische Bedingungen nur zu niedrigen Ausbeuten an Sespenin (<21 %) führten, da das Fehlen eines Substituenten an C2 des Indols die oxidative Spaltung des Pyrrolringes begünstigte.…”
Section: Neue Biomimetische Syntheseansätzeunclassified
Cyclisierungsreaktionen von Terpenen und Terpenoiden zählen zu den komplexesten chemischen Reaktionen in der Natur und tragen maßgeblich zur enormen Strukturvielfalt dieser größten Naturstofffamilie bei. Zahlreiche Studien auf chemischer, genetischer und biochemischer Ebene wurden durchgeführt, um mechanistische Einblicke in diese faszinierenden Reaktionen zu erlangen, die von Terpen‐ und Terpenoid‐Cyclasen katalysiert werden. Eine Vielzahl dieser Enzyme konnte seither charakterisiert werden. Nach klassischer Lehrbuchmeinung werden Terpen‐/Terpenoid‐Cyclasen gemäß ihrer Struktur und ihrem Reaktionsmechanismus in zwei große Klassen eingeteilt. Jüngste Entdeckungen neuartiger Terpenoid‐Cyclasen zeigen jedoch, dass das natürliche enzymatische Repertoire deutlich vielseitiger ist, als zunächst gedacht. Dieser Aufsatz stellt eben diese Terpenoid‐Cyclasen in den Fokus, die aus dem Rahmen fallen.
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