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Organic Synthesis Biocatalysis Cascade Reactions Enabled by Synthetic Biology Nicholas J. Turner School of Chemistry & Manchester Institute of Biotechnology, University of Manchester, UK ELRIG Research & Innovation 2016 Nottingham, UK 23rd March 2016 Manchester Synthetic Biology Research Centre for Fine and Speciality Chemicals Nigel Scrutton (PI/Director) Eriko Takano (Director) Nick Turner (Director) Manchester Institute of Biotechnology Discovery through innovation CENTRES CoE for Biocatalysis, Biotransformations and Biocatalytic Manufacture (est. 2005). M C Manchester Centre for Biophysics B NEW CENTRES C and Catalysis (est. 2009). EPSRC National Biocatalysis and Manchester Centre for Integrative Biotransformations Hub Systems Biology (est. 2006). (coordinated by MIB/Harwell) (est. 2015). BBSRC IB NETWORKS (est. 2014) BBSRC/EPSRC SYNBIOCHEM Centre for Synthetic Biology of Network in Biocatalyst Discovery, Fine and Speciality Chemicals Development and Scale-up. (est. 2014). Glycoscience Tools for Biotech. and Bioenergy Network. Natural Products Discovery and Bioengineering Network. Manchester Institute of Biotechnology Discovery through innovation SYNBIOCHEM Approach Compilation and Fully integrated technology platforms assembly tools ICEJr Speedy Genome-editing Genes CAD tools Predictive modelling tools Gene Genie metabolism kinetic/flux Regulatory devices catalysis light activation machine learning riboswitches circuit design Pathway design Biocatalyst/Pathway Vector promoter Chassis engineering Selection RBS design design Gene cluster order modify modify homologues homologues TEST Eg. Carbon source, Pathway assembly minimal genome synthesis automated assembly Scale-up Fermentation optimisation Testing targeted analysis High Throughput untargeted metabolomics State of the Art Microfluidics Tools analytics facility Screening assays (Robotics, microscale growth/expression, analysis/assays) 3 Approaches to (un)natural product synthesis Organic Biosynthesis Biocatalysis Synthesis • Natural products • New reagents • Engineered biocatalysts • Biosynthetic pathways • New catalysts • Broad specificity • Enzyme mechanism • Retrosynthesis • Systems biocatalysis • Specialised enzymes • Synthetic strategy • Synthetic biology Biocatalytic retrosynthesis Telaprevir (Incivek) launched May 2011 for Hepatitis C H biocatalyst N O O H H H H N N N N N N N N H H . O O O O 99% e e Nature Chem. Biol., 2013, 9, 285-288. Challenges for biocatalysis • Design new & general synthetic routes to target classes (e.g. amino acids, alkaloids, terpenes etc.) based upon bio- and chemo-catalysis? • Develop guidelines for route design for synthetic chemists (biocatalytic retrosynthesis). • Where are the gaps in biocatalysis – which reactions are currently not available in the biocatalysis toolbox? • How many different biocatalyst classes do we need to be able to do real organic synthesis? 50 or 500 or 5000 … • Need biocatalysts with broad substrate scope that are active and stable under the conditions of a chemical process (fit biocatalyst to process rather than vice-versa). Design – Evolution - Diversity Protein Design NH N H Natural Biocatalysts Synthesis Diversity Design features: HN • Selectivity • Specificity • Stability Protein Evolution Alkaloids MeO MeO N N N HO HO H OH OH (R)-coniine (hemlock) OMe OMe (S)-reticuline (S)-scoulerine N MeO Me NH N N MeO N (S)-nicotine H H H Me A (R)-Eleagnine Crispine cocoa) (anti-tumour) (chocolate, N MeO N H NH H MeO (R)-harmicine (anti-leishmania) (R)-salsolidine Synthetic APIs H O N OH N N O O N O Cl Levocetirizine Solifenacin O NH N CO H H 2 N O O S O O O NH H NH O O N N H N N H O HN N H H2N NH Telaprevir Argatroban (Asymmetric) biocatalytic amine toolbox O transaminase NH2 ammonia lyase CO2H CO2H Ar Ar R1 R2 PLP R1 R2 NH2 amine O dehydrogenase NH2 imine reductase R R1 R2 NADH R1 R2 N R NADPH N H H Pictet-Spenglerase NH2 amine oxidase NH NH+ NH R1 R2 FAD R1 R2 X X R R O DH N + R Opine N R H NADPH Biocatalytic Cascade Reactions Regio- and stereoselective ω-transaminase/MAO-N cascades Regio- & stereoselective reductive-amination Accumulates (S) (R) RS RL NH3.BH3 N O (S)-selective non-selective H R omega-TA reduction R L (S) + S RS N RL O MAO-N oxidation (S) (S) non-symmetric diketone RS N RL One-pot H Regio- & stereoselective oxidation E. O’Reilly et al., Angew. Chem. Int. Ed., 2014, 53, 2447-2450. ω-TA - MAO-N tandem reaction MAO-N D9 BH3NH3 violaceum N N C. )- H (S transaminase ee: >99% (S) de: >99%(2R,5S) O O ( R )- transaminaseArthrobacter MAO-N D9 BH NH N 3 3 N H ee: >99% (R) de: 90%(2R,5R) E. O’Reilly et al., Angew. Chem. Int. Ed., 2014, 53, 2447. Cascade reactions with TAs/IREDs NH2 O O O ω IRED -H2O -TA R2 N R1 R2 N R1 2 1 2 1 H R R R R 1,5-diketone 2,6- disubstituted piperidine ω-TA - IRED tandem reactions O or ω (R)- (S)- -TA IRED N N O H ee: >99% (S) O O or ω (R)- (S)- -TA IRED N N H X X X ee: >99% (S) Shahed Hussain, Elaine O’Reilly. Cascade reactions with IREDs NH2 O O O ω IRED -H2O -TA R2 N R1 R2 N R1 2 1 2 1 H R R R R 1,5-diketone 2,6- disubstituted piperidine R2 R2 NH2 O O O O O ω R2 -TA R2 R2 IRED -H2O CAR N R1 N R1 R1 H R1 1 H HO R 1,5-ketoaldehyde 1,5-ketoacid CAR - ω-TA - IRED tandem reactions O HO n O carboxylic acid reductase, ATP, NADH O or ω n (R)- (S)-IRED n H -TA n N N O H ee: >99% (S) irreversible amine donor ω-TA NH2 O N NH NH2 NH2 H polyisoindole (coloured) O’Reilly et al., Angew. Chem. Int. Ed. 2014, 53, 10714 - 10717 (VIP). Elaine O’Reilly, Shahed Hussain, Scott France, Andy Hill. MAO-N/Berberine bridge enzyme MeO MeO N . - : : N HO 1 MAO N D11 NH3 BH3 HO OH . OH 2 Berberine Bridge Enzyme OMe OMe -re cu ne - (R/S) ti li (S) scoulerine yield = 97% . e e = 99% R1 N R1 . .' e e s > 98% R1 R1 J. Schrittwieser, D. Ghisleri, W. Kroutil, N.J. Turner et al., Angew. Chem. Int. Ed., 2014, 53, 3731-3734. Biocatalytic asymmetric hydrogen borrowing OH NH2 * R R' NAD+ R R' catalytic H2O ADH AmDH NADH O + NH3 / NH4 R R' F (R)-ADH F OH NH (R)-AmDH 2 NH3 (2.5M) conv. 95% NADH (1 mol%) ee: >99% (R) F (S)-ADH F OH NH (R)-AmDH 2 NH3 (2.5M) conv. 95% NADH (1 mol%) ee: >99% (R) F.G. Mutti. T. Knaus, N.S. Scrutton, M. Breuer and N.J. Turner, Science, 2015, 349, 1525-1529. Biocatalytic asymmetric hydrogen borrowing OH OH X Me Me R' X X OH X = H, F, Me, MeO; R' = Me, Et X = CH2 or O X = H, F, Me = 30-95% = yields yields = 84-96% yields 7-96% e.e.'s up to 99% e.e.'s to 99% e.e.'s up to 99% up OH R Alkyl Me OH - R = n-C H , n-C H , n-C H Alkyl = n-C6H13, n-C5H11. n 7 15 6 13 5 11 n-C H , iso-C H , n-C H , PhCH C4H9, n-C3H7, iso-C4H9 4 9 4 9 3 7 2 = 8-99% yields = 66-96% yields e.e.'s >99% F.G. Mutti. T. Knaus, N.S. Scrutton, M. Breuer and N.J. Turner, Science, 2015, 349, 1525-1529. Whole-cell biocatalysts for stereoselective C-H amination reactions P. Both et al, Angew. Chem. Int. Ed., 2015, 54, in press. Acknowledgements amine biocatalysis: Rachel Heath, Marta Pontini, Friedemann Leipold, Shahed Hussain, Godwin Aleku, James Galman, Anthony Green, Elaine O’Reilly, Beatrice Bechi, Scott France, Iustina Slabu, Andy Hill, Fabio Parmeggiani, Syed Ahmed, Nick Weise, Wojciech Zawodny, Agata Brzezniak, Francesco Mutti, Diego Ghislieri, Juan Mangas and everyone else in the group … Sam Staniland, Sasha Derrington, Chantel Jensen- Loughrey, Will Birmingham, Ian Rowles, Mark Corbett, Jane Kwok, Frank Xu, Mark Dunstan, Daniela Quaglia .
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