Total synthesis of the plant alkaloid racemic microthecaline A: first example of a natural product bearing a tricyclic quinoline-serrulatane scaffold

Penjarla, Thirupathi Reddy; Kundarapu, Maheshwar; Baquer, Syed M.; Bhattacharya, Anupam

doi:10.1039/c9ra04675e

Cited by 3 publications

(3 citation statements)

References 21 publications

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“…While relatively few have been identified in other genera, the Eremophila genus is especially rich in these anti-microbial compounds ( Ndi et al ., 2007b ; Anakok et al ., 2012 ; Barnes et al ., 2013 ; Mon et al ., 2015 ; Algreiby et al ., 2018 ; Hossain et al ., 2019 ) and at least three are found in the Myoporum genus ( Aminimoghadamfarouj and Nematollahi, 2017 ). Given their promise in therapeutic applications, there has been a substantial effort to devise total chemical syntheses ( Best and Wege, 1986 ; Lu et al ., 2013 ; Yu et al ., 2016 ; R. Kumar et al ., 2017 ; Tenneti et al ., 2018 ; Penjarla et al ., 2019 ) as an alternative to extraction and purification from natural sources ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

et al. 2020

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SUMMARY Serrulatane diterpenoids are natural products found in plants from a subset of genera within the figwort family (Scrophulariaceae). Many of these compounds have been characterized as having anti-microbial properties and share a common diterpene backbone. One example, leubethanol from Texas sage ( Leucophyllum frutescens ) has demonstrated activity against multi-drug-resistant tuberculosis. Leubethanol is the only serrulatane diterpenoid identified from this genus; however, a range of such compounds have been found throughout the closely related Eremophila genus. Despite their potential therapeutic relevance, the biosynthesis of serrulatane diterpenoids has not been previously reported. Here we leverage the simple product profile and high accumulation of leubethanol in the roots of L . frutescens and compare tissue-specific transcriptomes with existing data from Eremophila serrulata to decipher the biosynthesis of leubethanol. A short-chain cis -prenyl transferase ( Lf CPT1) first produces the rare diterpene precursor nerylneryl diphosphate, which is cyclized by an unusual plastidial terpene synthase ( Lf TPS1) into the characteristic serrulatane diterpene backbone. Final conversion to leubethanol is catalyzed by a cytochrome P450 (CYP71D616) of the CYP71 clan. This pathway documents the presence of a short-chain cis -prenyl diphosphate synthase, previously only found in Solanaceae, which is likely involved in the biosynthesis of other known diterpene backbones in Eremophila . Lf TPS1 represents neofunctionalization of a compartment-switching terpene synthase accepting a novel substrate in the plastid. Biosynthetic access to leubethanol will enable pathway discovery to more complex serrulatane diterpenoids which share this common starting structure and provide a platform for the production and diversification of this class of promising anti-microbial therapeutics in heterologous systems.

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Section: Introductionmentioning

confidence: 99%

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

et al. 2020

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“…Compared to a typical serrulatane diterpene, distinct features of 1 include a nitrogen substituent at C5 and a higher oxidation at C18, the terminal carbon center. To date, there is only one racemic synthesis of 1 reported, and it proceeds in 15 steps with a 5 % overall yield …”

Section: Resultsmentioning

confidence: 99%

“…To date,t here is only one racemic synthesis of 1 reported, and it proceeds in 15 steps with a5% overall yield. [14] One key question regarding the synthesis of 1 is how to efficiently introduce the C1 stereocenter and the C5 nitrogen moiety.W ee nvisioned that the pentasubstituted quinoline core in 1 could be constructed using aF riedländer condensation between the aldehyde 8 and amine-substituted atetralone 9 (Scheme 2). Thec ompound 9 could be possibly prepared by CÀHa mination of the intermediate 10 in as traightforward manner,a nd 10 is expected to be synthesized through the catalytic CÀCactivation of the 3-arylcyclopentanone 11,w hich can be conveniently accessed from 2cyclopentenone and commercially available 1-bromo-2-methoxy-4-methylbenzene.…”

Section: Resultsmentioning

confidence: 99%

Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

et al. 2020

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To show the synthetic utility of the catalytic C−C activation of less strained substrates, described here are the collective and concise syntheses of the natural products (−)‐microthecaline A, (−)‐leubehanol, (+)‐pseudopteroxazole, (+)‐seco‐pseudopteroxazole, pseudopterosin A–F and G—J aglycones, and (+)‐heritonin. The key step in these syntheses involve a Rh‐catalyzed C−C/C−H activation cascade of 3‐arylcyclopentanones, which provides a rapid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products. Other important features include 1) the direct C−H amination of the tetralone substrate in the synthesis of (−)‐microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C−C activation reactions, and 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.

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Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

et al. 2020

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To show the synthetic utility of the catalytic C À C activation of less strained substrates,d escribed here are the collective and concise syntheses of the natural products (À)microthecaline A, (À)-leubehanol, (+ +)-pseudopteroxazole, (+ +)-seco-pseudopteroxazole,p seudopterosin A-F and G-J aglycones,a nd (+ +)-heritonin. The key step in these syntheses involve aR h-catalyzed C À C/C À Ha ctivation cascade of 3arylcyclopentanones,w hichp rovides ar apid and enantioselective route to access the polysubstituted tetrahydronaphthalene cores presented in these natural products.Other important features include 1) the direct CÀHa mination of the tetralone substrate in the synthesis of (À)-microthecaline A, 2) the use of phosphoric acid to enhance efficiency and regioselectivity for problematic cyclopentanone substrates in the C À Ca ctivation reactions,a nd 3) the direct conversion of serrulatane into amphilectane diterpenes by an allylic cyclodehydrogenation coupling.

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Total synthesis of the plant alkaloid racemic microthecaline A: first example of a natural product bearing a tricyclic quinoline-serrulatane scaffold

Abstract: First total synthesis of quinoline-serrulatane alkaloid microthecaline A.

Cited by 3 publications

References 21 publications

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

The biosynthesis of the anti‐microbial diterpenoid leubethanol in Leucophyllum frutescens proceeds via an all‐cis prenyl intermediate

Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

Asymmetric Total Syntheses of Di‐ and Sesquiterpenoids by Catalytic C−C Activation of Cyclopentanones

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