Optimising Terpene Synthesis with Flow Biocatalysis

Tang, Xiaoping; Allemann, Rudolf Konrad; Wirth, Thomas

doi:10.1002/ejoc.201601388

Cited by 32 publications

(33 citation statements)

References 51 publications

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“…A colourless oil was isolated from the incubation of 60 mg of 8 (ESI) in 41 % yield, which is a typical value for natural terpenoids produced from FDP in batch processes . Unoptimised segmented‐flow procedures, which improve the extraction of the hydrophobic product from the aqueous phase, improved the yield to 75 % . Both substrates ( 7 and 8 ) were prepared and used in racemic form, and the products were analysed by GC on a chiral stationary‐phase and found to be a mixture of enantiomers with a ratio of 48:52 (Figures S6 and S7).…”

Section: Methodsmentioning

confidence: 75%

“…One of these products is a potent attractant of grain aphids and a potential crop protection agent . The efficiency of these transformations could be improved dramatically by using segmented‐flow methods . Using the understanding of terpene synthase chemistry gained from this and others’ previous work, we surmised that this could be done by introducing a nucleophile into a substrate analogue to intercept a known carbocationic configuration generated through the templating effect of the enzyme.…”

Section: Methodsmentioning

confidence: 95%

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Sesquiterpene Synthase‐Catalysed Formation of a New Medium‐Sized Cyclic Terpenoid Ether from Farnesyl Diphosphate Analogues

et al. 2018

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Terpene synthases catalyse the first step in the conversion of prenyl diphosphates to terpenoids. They act as templates for their substrates to generate a reactive conformation, from which a Mg -dependent reaction creates a carbocation-PP ion pair that undergoes a series of rearrangements and (de)protonations to give the final terpene product. This tight conformational control was exploited for the (R)-germacrene A synthase- and germacradien-4-ol synthase-catalysed formation of a medium-sized cyclic terpenoid ether from substrates containing nucleophilic functional groups. Farnesyl diphosphate analogues with a 10,11-epoxide or an allylic alcohol were efficiently converted to a 11-membered cyclic terpenoid ether that was characterised by HRMS and NMR spectroscopic analyses. Further experiments showed that other sesquiterpene synthases, including aristolochene synthase, δ-cadinene synthase and amorphadiene synthase, yielded this novel terpenoid from the same substrate analogues. This work illustrates the potential of terpene synthases for the efficient generation of structurally and functionally novel medium-sized terpene ethers.

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Section: Methodsmentioning

confidence: 75%

Section: Methodsmentioning

confidence: 95%

Sesquiterpene Synthase‐Catalysed Formation of a New Medium‐Sized Cyclic Terpenoid Ether from Farnesyl Diphosphate Analogues

et al. 2018

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“…Terpene synthases generate many high‐value products with applications, for instance, as drugs, agrochemicals or fragrances. Understanding the intricate details of their catalytic mechanism will lead to improved methods for the production of naturally occurring terpenes and help the development of designer products with new or improved properties …”

Section: Resultsmentioning

confidence: 99%

Nucleophilic Water Capture or Proton Loss: Single Amino Acid Switch Converts δ‐Cadinene Synthase into Germacradien‐4‐ol Synthase

et al. 2017

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Abstractδ‐Cadinene synthase is a sesquiterpene cyclase that utilises the universal achiral precursor farnesyl diphosphate (FDP) to generate predominantly the bicyclic sesquiterpene δ‐cadinene and about 2 % germacradien‐4‐ol, which is also generated from FDP by the cyclase germacradien‐4‐ol synthase. Herein, the mechanism by which sesquiterpene synthases discriminate between deprotonation and reaction with a nucleophilic water molecule was investigated by site‐directed mutagenesis of δ‐cadinene synthase. If W279 in δ‐cadinene synthase was replaced with various smaller amino acids, the ratio of alcohol versus hydrocarbon product was directly proportional to the van der Waals volume of the amino acid side chain. DCS‐W279A is a catalytically highly efficient germacradien‐4‐ol synthase (k cat/K M=1.4×10−3 μm s−1) that produces predominantly germacradien‐4‐ol in addition to 11 % δ‐cadinene. Water capture is not achieved through strategic positioning of a water molecule in the active site, but through a coordinated series of loop movements that allow bulk water access to the final carbocation in the active site prior to product release.

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“…Flow chemistry has been used to overcome the slow release of products in the synthesis of sesquiterpene 25 from farnesyldiphosphate using a terpene synthase as biocatalyst (Scheme ) . Continuous extraction of the product from the aqueous layer is necessary to make the biocatalytic process viable.…”

Section: Enabling Technologymentioning

confidence: 99%

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

Foley

Maguire

2019

Eur J Org Chem

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While biocatalytic transformations are very powerful in enantioselective synthesis, frequently occurring under mild conditions, and proceed with extraordinary selectivity, there are practical challenges associated with the use of biocatalysis, such as limited substrate scope, stability, and reusability. Recent technological developments, for example immobilization, continuous flow, and molecular biology, all contribute towards enhancing the use of enzymes in synthesis.

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Optimising Terpene Synthesis with Flow Biocatalysis

Cited by 32 publications

References 51 publications

Sesquiterpene Synthase‐Catalysed Formation of a New Medium‐Sized Cyclic Terpenoid Ether from Farnesyl Diphosphate Analogues

Sesquiterpene Synthase‐Catalysed Formation of a New Medium‐Sized Cyclic Terpenoid Ether from Farnesyl Diphosphate Analogues

Nucleophilic Water Capture or Proton Loss: Single Amino Acid Switch Converts δ‐Cadinene Synthase into Germacradien‐4‐ol Synthase

The Impact of Recent Developments in Technologies which Enable the Increased Use of Biocatalysts

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