Bioinspired Total Synthesis of Sespenine

Sun, Yu; Chen, Pengxi; Zhang, Deliang; Baunach, Martin; Hertweck, Christian; Li, Ang

doi:10.1002/ange.201404191

Cited by 39 publications

(14 citation statements)

References 59 publications

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“…In the current model for xiamycin biosynthesis, it was proposed that a hydroxylated intermediate would set the basis for terpenoid cyclization 20 21 22 . While bioinspired synthetic studies support this model 25 54 , experimental evidence for an enzymatic hydroxylation as trigger for the cyclization reaction has been missing. Using indole as substrate surrogate, we unveiled the ‘cryptic hydroxylation’ at C-3 of the indole ring, which is clearly indicated by the formation of indigoid pigments.…”

Section: Discussionmentioning

confidence: 99%

“…The first cyclization yields the decalin system of indosespene ( 2 ), which is further cyclized into the spiro compound sespenine ( 4 ) or the carbazole ring system of xiamycin ( Fig. 1 ) 13 21 22 25 26 .…”

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confidence: 99%

“…This non-canonical terpenoid cyclization is mechanistically intriguing and has been the subject of several biosynthetic 21 22 26 and synthetic studies 17 25 . Through bioinformatics and mutational analysis, we found that XiaF is a flavin-dependent monooxygenase that catalyses the conversion of 2 to the carbazole scaffold of 3 (ref.…”

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Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

et al. 2017

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Terpenoid natural products comprise a wide range of molecular architectures that typically result from C–C bond formations catalysed by classical type I/II terpene cyclases. However, the molecular diversity of biologically active terpenoids is substantially increased by fully unrelated, non-canonical terpenoid cyclases. Their evolutionary origin has remained enigmatic. Here we report the in vitro reconstitution of an unusual flavin-dependent bacterial indoloterpenoid cyclase, XiaF, together with a designated flavoenzyme-reductase (XiaP) that mediates a key step in xiamycin biosynthesis. The crystal structure of XiaF with bound FADH2 (at 2.4 Å resolution) and phylogenetic analyses reveal that XiaF is, surprisingly, most closely related to xenobiotic-degrading enzymes. Biotransformation assays show that XiaF is a designated indole hydroxylase that can be used for the production of indigo and indirubin. We unveil a cryptic hydroxylation step that sets the basis for terpenoid cyclization and suggest that the cyclase has evolved from xenobiotics detoxification enzymes.

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Cryptic indole hydroxylation by a non-canonical terpenoid cyclase parallels bacterial xenobiotic detoxification

et al. 2017

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“…Indolosesquiterpenoids have attracted increasing attention from chemical and biosynthetic perspectives 1 2 3 4 5 7 ; however, their biological activities are yet to be systematically explored through chemical synthesis 8 9 10 11 12 13 14 . Xiamycin A ( 1 , Fig.…”

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Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

Meng

et al. 2015

Nat Commun

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Indolosesquiterpenoids are a growing class of natural products that exhibit a wide range of biological activities. Here, we report the total syntheses of xiamycin A and oridamycins A and B, indolosesquiterpenoids isolated from Streptomyces. Two parallel strategies were exploited to forge the carbazole core: 6π-electrocyclization/aromatization and indole C2–H bond activation/Heck annulation. The construction of their trans-decalin motifs relied on two diastereochemically complementary radical cyclization reactions mediated by Ti(III) and Mn(III), respectively. The C23 hydroxyl of oridamycin B was introduced by an sp3 C–H bond oxidation at a late stage. On the basis of the chemistry developed, the dimeric congener dixiamycin C has been synthesized for the first time. Evaluation of the antiviral activity of these compounds revealed that xiamycin A is a potent agent against herpes simplex virus–1 (HSV-1) in vitro.

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“…During synthetic studies on indole terpenoids, [1] we noticed a common structural motif (1, Scheme 1) appearing in 10,23-dihydro-24,25-dehydroaflavinine [2] (2) and the hapalindoletype natural products (e.g. 3-7), [3][4][5][6][7] and were intrigued by its biogenesis.…”

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confidence: 99%