Publications by authors named "Stephen P Fletcher"

69 Publications

A molecular assembler that produces polymers.

Nat Commun 2020 08 19;11(1):4156. Epub 2020 Aug 19.

Department of Chemistry, Chemistry Research Laboratory University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Molecular nanotechnology is a rapidly developing field, and tremendous progress has been made in developing synthetic molecular machines. One long-sought after nanotechnology is systems able to achieve the assembly-line like production of molecules. Here we report the discovery of a rudimentary synthetic molecular assembler that produces polymers. The molecular assembler is a supramolecular aggregate of bifunctional surfactants produced by the reaction of two phase-separated reactants. Initially self-reproduction of the bifunctional surfactants is observed, but once it reaches a critical concentration the assembler starts to produce polymers instead of supramolecular aggregates. The polymer size can be controlled by adjusting temperature, reaction time, or introducing a capping agent. There has been considerable debate about molecular assemblers in the context of nanotechnology, our demonstration that primitive assemblers may arise from simple phase separated reactants may provide a new direction for the design of functional supramolecular systems.
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http://dx.doi.org/10.1038/s41467-020-17814-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438324PMC
August 2020

Emergence and Rearrangement of Dynamic Supramolecular Aggregates Visualized by Interferometric Scattering Microscopy.

ACS Nano 2020 09 18;14(9):11160-11168. Epub 2020 Aug 18.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom OX1 3TA.

Studying dynamic self-assembling systems in their native environment is essential for understanding the mechanisms of self-assembly and thereby exerting full control over these processes. Traditional ensemble-based analysis methods often struggle to reveal critical features of the self-assembly that occur at the single particle level. Here, we describe a label-free single-particle assay to visualize real-time self-assembly in aqueous solutions by interferometric scattering microscopy. We demonstrate how the assay can be applied to biphasic reactions yielding micellar or vesicular aggregates, detecting the onset of aggregate formation, quantifying the kinetics at the single particle level, and distinguishing sigmoidal and exponential growth of aggregate populations. Furthermore, we can follow the evolution in aggregate size in real time, visualizing the nucleation stages of the self-assembly processes and record phenomena such as incorporation of oily components into the micelle or vesicle lumen.
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http://dx.doi.org/10.1021/acsnano.0c02414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513470PMC
September 2020

Coupled Metabolic Cycles Allow Out-of-Equilibrium Autopoietic Vesicle Replication.

Angew Chem Int Ed Engl 2020 11 3;59(46):20361-20366. Epub 2020 Sep 3.

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, UK.

We report chemically fuelled out-of-equilibrium self-replicating vesicles based on surfactant formation. We studied the vesicles' autocatalytic formation using UPLC to determine monomer concentration and interferometric scattering microscopy at the nanoparticle level. Unlike related reports of chemically fuelled self-replicating micelles, our vesicular system was too stable to surfactant degradation to be maintained out of equilibrium. The introduction of a catalyst, which introduces a second catalytic cycle into the metabolic network, was used to close the first cycle. This shows how coupled catalytic cycles can create a metabolic network that allows the creation and perseverance of fuel-driven, out-of-equilibrium self-replicating vesicles.
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http://dx.doi.org/10.1002/anie.202007302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692917PMC
November 2020

Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile.

Org Lett 2020 06 12;22(11):4103-4106. Epub 2020 May 12.

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.

The Taxol core was prepared in five steps via a key copper-catalyzed asymmetric conjugate addition trapping sequence. The use of a bromodiene-derived alkylzirconium nucleophile followed by trapping with POCl/DMF gave a highly functionalized intermediate featuring a quaternary center in 69% yield with 92% ee. After 1,2-addition, Suzuki-Miyaura cross-coupling, allylic oxidation, and a type II intramolecular Diels-Alder reaction, the taxol core was obtained in 11% overall yield with 92% ee.
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http://dx.doi.org/10.1021/acs.orglett.0c01165DOI Listing
June 2020

An Asymmetric Suzuki-Miyaura Approach to Prostaglandins: Synthesis of Tafluprost.

Org Lett 2020 04 27;22(8):2991-2994. Epub 2020 Mar 27.

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford OX1 3TA, U.K.

We report the catalytic asymmetric synthesis of Tafluprost (), a prostaglandin analogue. This synthesis demonstrates a new approach to prostaglandins involving symmetrization and desymmetrization of a racemic precursor to control the absolute and relative stereochemistry of the cyclopentyl core. Key steps include a diastereo- and enantioselective Rh-catalyzed Suzuki-Miyaura reaction of a racemic bicyclic allyl chloride and an alkenyl boronic acid and a regio- and diastereoselective Pd-catalyzed Tsuji-Trost reaction with an enolate surrogate.
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http://dx.doi.org/10.1021/acs.orglett.0c00745DOI Listing
April 2020

Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach.

ACS Catal 2019 Aug 2;9(8):7179-7187. Epub 2019 Jul 2.

Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom.

The development of catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. Here, we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically demanding. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the synthesis of modified phosphoramidite ligands, designed using quantitative structure-selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across 20 examples.
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http://dx.doi.org/10.1021/acscatal.9b01814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011729PMC
August 2019

Highly Enantioselective Hiyama Cross-Coupling via Rh-Catalyzed Allylic Arylation of Racemic Allyl Chlorides.

Organometallics 2019 Oct 10;38(20):3991-3995. Epub 2019 May 10.

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.

Highly enantioselective Hiyama cross-coupling reactions have been achieved through rhodium(I)-catalyzed dynamic kinetic asymmetric transformations between aryl siloxanes and cyclic racemic allyl halides. This process affords valuable enantiomerically enriched aryl-substituted cyclic allyl products and is compatible with heterocyclic allyl chloride electrophiles.
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http://dx.doi.org/10.1021/acs.organomet.9b00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009026PMC
October 2019

Selection from a pool of self-assembling lipid replicators.

Nat Commun 2020 01 10;11(1):176. Epub 2020 Jan 10.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.

Replication and compartmentalization are fundamental to living systems and may have played important roles in life's origins. Selection in compartmentalized autocatalytic systems might provide a way for evolution to occur and for life to arise from non-living systems. Herein we report selection in a system of self-reproducing lipids where a predominant species can emerge from a pool of competitors. The lipid replicators are metastable and their out-of-equilibrium population can be sustained by feeding the system with starting materials. Phase separation is crucial for selective surfactant formation as well as autocatalytic kinetics; indeed, no selection is observed when all reacting species are dissolved in the same phase. Selectivity is attributed to a kinetically controlled process where the rate of monomer formation determines which replicator building blocks are the fittest. This work reveals how kinetics of a phase-separated autocatalytic reaction may be used to control the population of out-of-equilibrium replicators in time.
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http://dx.doi.org/10.1038/s41467-019-13903-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954257PMC
January 2020

Highly enantioselective rhodium-catalyzed cross-coupling of boronic acids and racemic allyl halides.

Nat Protoc 2019 10 20;14(10):2972-2985. Epub 2019 Sep 20.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, UK.

Although Csp-Csp Suzuki-Miyaura couplings (SMCs) are widely used in small-molecule synthesis, related methods that allow the incorporation of Csp-hybridized coupling partners, particularly in an asymmetric manner, are less developed. This protocol describes catalytic asymmetric SMC reactions that provide access to enantiomerically enriched cyclic allylic products. The method couples racemic allyl halide starting materials with sp-hybridized boronic acid derivatives and is compatible with heterocyclic coupling partners. These reactions are catalyzed by a rhodium-ligand complex and typically display very high levels of enantioselectivity (>95% enantiomeric excess (ee)). In this protocol, we detail a procedure using a dihydropyridine-derived allyl chloride for the synthesis of (-)-(S)-tert-butyl-3-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, an intermediate in the synthesis of the anticancer drug niraparib. This procedure affords 1.17 g (86% yield) of the coupling product with 96% ee. The initial experimental setup of the reaction takes 45-50 min, and the reaction is complete within 4-5 h.
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http://dx.doi.org/10.1038/s41596-019-0209-8DOI Listing
October 2019

Enantio- and Diastereoselective Suzuki-Miyaura Coupling with Racemic Bicycles.

Angew Chem Int Ed Engl 2019 08 25;58(35):12128-12132. Epub 2019 Jul 25.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Herein, we describe a rhodium-catalyzed enantio- and diastereoselective Suzuki-Miyaura cross-coupling between racemic fused bicyclic allylic chlorides and boronic acids. The highly stereoselective transformation allows for the coupling of aryl, heteroaryl, and alkenyl boronic acids and gives access to functionalized bicyclic cyclopentenes, which can be converted into other five-membered-ring scaffolds with up to five contiguous stereocenters. Preliminary mechanistic studies suggest that these reactions occur with overall retention of the relative stereochemistry and are enantioconvergent for pseudo-symmetric allylic chloride starting materials. In addition, a bicyclic allylic chloride starting material without pseudo-symmetry undergoes a highly enantioselective regiodivergent reaction.
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http://dx.doi.org/10.1002/anie.201906478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771587PMC
August 2019

A chemically fuelled self-replicator.

Nat Commun 2019 03 1;10(1):1011. Epub 2019 Mar 1.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.

The continuous consumption of chemical energy powers biological systems so that they can operate functional supramolecular structures. A goal of modern science is to understand how simple chemical mixtures may transition from non-living components to truly emergent systems and the production of new lifelike materials and machines. In this work a replicator can be maintained out-of-equilibrium by the continuous consumption of chemical energy. The system is driven by the autocatalytic formation of a metastable surfactant whose breakdown products are converted back into building blocks by a chemical fuel. The consumption of fuel allows the high-energy replicators to persist at a steady state, much like a simple metabolic cycle. Thermodynamically-driven reactions effect a unidirectional substrate flux as the system tries to regain equilibrium. The metastable replicator persists at a higher concentration than achieved even transiently in a closed system, and its concentration is responsive to the rate of fuel supply.
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http://dx.doi.org/10.1038/s41467-019-08885-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397266PMC
March 2019

Controlling the Kinetics of Self-Reproducing Micelles by Catalyst Compartmentalization in a Biphasic System.

J Org Chem 2019 03 12;84(5):2741-2755. Epub 2019 Feb 12.

Department of Chemistry, Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford , OX1 3TA , U.K.

Compartmentalization of reactions is ubiquitous in biochemistry. Self-reproducing lipids are widely studied as chemical models of compartmentalized biological systems. Here, we explore the effect of catalyst location on copper-catalyzed azide-alkyne cycloadditions which drive the self-reproduction of micelles from phase-separated components. Tuning the hydrophilicity of the copper-ligand complex, so that hydro-phobic or -philic catalysts are used in combination with hydro-philic and -phobic coupling partners, provides a wide range of reactivity patterns. Analysis of the kinetic data shows that reactions with a hydrophobic catalyst are faster than with a hydrophilic catalyst. Diffusion-ordered spectroscopy experiments suggest compartmentalization of the hydrophobic catalyst inside micelles while the hydrophilic catalyst remains in the bulk aqueous phase. The autocatalytic effects observed can be tuned by varying reactant structure and coupling a hydrophilic alkyne and hydrophobic azide results in a more pronounced autocatalytic effect. We propose and test a model that rationalizes the observations in terms of the phase behavior of the reaction components and catalysts.
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http://dx.doi.org/10.1021/acs.joc.8b03149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459585PMC
March 2019

Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles.

Nat Commun 2019 01 3;10(1):21. Epub 2019 Jan 3.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

The desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.
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http://dx.doi.org/10.1038/s41467-018-07871-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318275PMC
January 2019

β-Chloroaldehydes from Trapping Zirconium Enolates Produced in Asymmetric 1,4-Additions.

Org Lett 2019 01 31;21(2):378-381. Epub 2018 Dec 31.

Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford OX1 3TA , U.K.

Zirconium enolates, derived from copper-catalyzed asymmetric conjugate additions, are trapped with the Vilsmeier-Haack reagent. Asymmetric additions generate quaternary carbon centers with high enantioselectivity (generally ∼90% ee), and the enolates are converted to unsaturated β-chloroaldehydes (41-57% yields). The reaction tolerates changes to the nucleophile, can be used to form five-, six-, or seven-membered ring products, and is scalable to 5 mmol, and the products are readily elaborated by condensation, cross coupling, and addition reactions.
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http://dx.doi.org/10.1021/acs.orglett.8b03520DOI Listing
January 2019

Catalytic asymmetric synthesis of geminal-dicarboxylates.

Chem Sci 2018 Aug 28;9(29):6307-6312. Epub 2018 Jun 28.

Department of Chemistry , Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford OX1 3TA , UK . Email:

Stereogenic acetals, spiroacetals and ketals are well-studied stereochemical features that bear two heteroatoms at a common carbon atom. These stereocenters are normally found in cyclic structures while linear (or acyclic) analogues bearing two heteroatoms are rare. Chiral geminal-dicarboxylates are illustrative, there is no current way to access this class of compounds while controlling the stereochemistry at the carbon center bound to two oxygen atoms. Here we report a rhodium-catalysed asymmetric carboxylation of ester-containing allylic bromides to form stereogenic carbon centers bearing two different carboxylates with high yields and enantioselectivities. The products, which are surprisingly stable to a variety of acidic and basic conditions, can be manipulated with no loss of enantiomeric purity as demonstrated by ring closing metathesis reactions to form chiral lactones, which have been extensively used as building blocks in asymmetric synthesis.
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http://dx.doi.org/10.1039/c8sc01786gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063137PMC
August 2018

Self-reproducing micelles coupled to a secondary catalyst.

Chem Commun (Camb) 2018 Aug;54(63):8777-8780

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

We report a physical autocatalytic system where micelles self-reproduce via a copper-catalyzed azide-alkyne cycloaddition in a biphasic reaction mixture. The coupling of a secondary catalyst to an autocatalytic cycle opens up new opportunities to control and probe autocatalytic processes.
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http://dx.doi.org/10.1039/c8cc02136hDOI Listing
August 2018

A transient self-assembling self-replicator.

Nat Commun 2018 06 8;9(1):2239. Epub 2018 Jun 8.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Developing physical models of complex dynamic systems showing emergent behaviour is key to informing on persistence and replication in biology, how living matter emerges from chemistry, and how to design systems with new properties. Herein we report a fully synthetic small molecule system in which a surfactant replicator is formed from two phase-separated reactants using an alkene metathesis catalyst. The replicator self-assembles into aggregates, which catalyse their own formation, and is thermodynamically unstable. Rather than replicating until the reactants are fully consumed, the metastable replicator is depleted in a second metathesis reaction, and closed system equilibrium is eventually reached. Mechanistic experiments suggest phase separation is responsible for both replicator formation and destruction.
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http://dx.doi.org/10.1038/s41467-018-04670-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993787PMC
June 2018

Formation of quaternary centres by copper catalysed asymmetric conjugate addition to β-substituted cyclopentenones with the aid of a quantitative structure-selectivity relationship.

Chem Sci 2018 Mar 5;9(9):2628-2632. Epub 2018 Feb 5.

Department of Chemistry , Colorado State University , Fort Collins , Colorado 80523 , USA . Email:

A new asymmetric conjugate addition method was developed for β-substituted cyclopentenones to form quaternary centres using alkylzirconocene nucleophiles giving up to 97% yield and 92% ee. Key to the reaction's success was the design of suitable phosphoramidite ligands which was aided by a linear quantitative structure-selectivity relationship (QSSR). QSSR models were created from the ligand screening data (a total of 36 ligands) which revealed important electronic and steric requirements and led to the synthesis of more enantioselective ligands. DFT calculations of competing transition structures enable the interpretation of the electronic and steric terms present in the QSSR models.
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http://dx.doi.org/10.1039/c7sc05304eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892328PMC
March 2018

Construction of β to carbonyl stereogenic centres by asymmetric 1,4-addition of alkylzirconocenes to dienones and ynenones.

Chem Commun (Camb) 2018 Apr;54(29):3601-3604

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Copper-catalyzed asymmetric 1,4-addition of alkylzirconium species to linear α,β,γ,δ unsaturated dienones and ynenones is reported. A variety of alkyl nucleophiles are introduced with good yields and excellent regio- and enantio-selectivities to give tertiary carbon centres bearing multiple functional groups. The method is also applicable to an ynethioate with ee's over 96%.
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http://dx.doi.org/10.1039/C8CC01201FDOI Listing
April 2018

Asymmetric cross-coupling of alkyl, alkenyl and (hetero)aryl nucleophiles with racemic allyl halides.

Chem Commun (Camb) 2017 Nov;53(93):12499-12511

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Single enantiomer molecules are important for the pharmaceutical and agrochemical industries and increasingly so in materials science. Most strategies to obtain enantiomerically enriched molecules rely on either generating new stereogenic centres from prochiral substrates or resolving racemic mixtures of enantiomers. Dynamic asymmetric processes are powerful methods that use racemic mixtures of chiral substrates as starting material. This Feature Article focuses on asymmetric additions to racemic substrates using non-stabilized sp- and sp-hybridized nucleophiles. These reactions bear considerable resemblance to traditional sp-sp cross-coupling reactions in terms of the starting materials used and the products obtained, but the reaction mechanisms are necessarily different.
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http://dx.doi.org/10.1039/c7cc07151eDOI Listing
November 2017

Asymmetric conjugate addition of alkylzirconium reagents to α,β-unsaturated thioesters: access to fragrances and acyclic stereochemical arrays.

Chem Commun (Camb) 2017 Sep;53(73):10216-10219

Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Copper-catalyzed asymmetric conjugate addition of alkylzirconium species to α,β-unsaturated thioesters is reported. A variety of functionalized alkyl nucleophiles were introduced with yields around 70% and ee's over 92%. The method was applied to the straightforward syntheses of the commercially important fragrances phenoxanol (both enantiomers 97% ee), and hydroxycitronellal (98% ee). The 1,4-addition products can be converted to enantiomerically enriched linear building blocks bearing a terminal functional group. Formation of further α,β-unsaturated thioesters provides an iterative route for the stereocontrolled synthesis of functionalized acyclic arrays and we demonstrate almost complete catalyst control in the formation of additional stereocentres.
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http://dx.doi.org/10.1039/c7cc05433eDOI Listing
September 2017

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates.

Nat Commun 2017 06 13;8:15762. Epub 2017 Jun 13.

Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.

Using asymmetric catalysis to simultaneously form carbon-carbon bonds and generate single isomer products is strategically important. Suzuki-Miyaura cross-coupling is widely used in the academic and industrial sectors to synthesize drugs, agrochemicals and biologically active and advanced materials. However, widely applicable enantioselective Suzuki-Miyaura variations to provide 3D molecules remain elusive. Here we report a rhodium-catalysed asymmetric Suzuki-Miyaura reaction with important partners including aryls, vinyls, heteroaromatics and heterocycles. The method can be used to couple two heterocyclic species so the highly enantioenriched products have a wide array of cores. We show that pyridine boronic acids are unsuitable, but they can be halogen-modified at the 2-position to undergo reaction, and this halogen can then be removed or used to facilitate further reactions. The method is used to synthesize isoanabasine, preclamol, and niraparib-an anticancer agent in several clinical trials. We anticipate this method will be a useful tool in drug synthesis and discovery.
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http://dx.doi.org/10.1038/ncomms15762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474734PMC
June 2017

Transmission of chirality through space and across length scales.

Nat Nanotechnol 2017 05;12(5):410-419

Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.

Chirality is a fundamental property and vital to chemistry, biology, physics and materials science. The ability to use asymmetry to operate molecular-level machines or macroscopically functional devices, or to give novel properties to materials, may address key challenges at the heart of the physical sciences. However, how chirality at one length scale can be translated to asymmetry at a different scale is largely not well understood. In this Review, we discuss systems where chiral information is translated across length scales and through space. A variety of synthetic systems involve the transmission of chiral information between the molecular-, meso- and macroscales. We show how fundamental stereochemical principles may be used to design and understand nanoscale chiral phenomena and highlight important recent advances relevant to nanotechnology. The survey reveals that while the study of stereochemistry on the nanoscale is a rich and dynamic area, our understanding of how to control and harness it and dial-up specific properties is still in its infancy. The long-term goal of controlling nanoscale chirality promises to be an exciting journey, revealing insight into biological mechanisms and providing new technologies based on dynamic physical properties.
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http://dx.doi.org/10.1038/nnano.2017.62DOI Listing
May 2017

Acyclic quaternary centers from asymmetric conjugate addition of alkylzirconium reagents to linear trisubstituted enones.

Chem Sci 2017 Jan 2;8(1):641-646. Epub 2016 Sep 2.

Department of Chemistry , University of Oxford. Chemistry Research Laboratory , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email:

Synthetic methods for the selective formation of all carbon quaternary centres in non-cyclic systems are rare. Here we report highly enantioselective Cu-catalytic asymmetric conjugate addition of alkylzirconium species to twelve different acyclic trisubstituted enones. A variety of sp-hybridized nucleophiles generated by hydrozirconation of alkenes with the Schwartz reagent can be introduced, giving linear products bearing quaternary centres with up to 98% ee. The method is tolerant of several important functional groups and 27 total examples are reported. The method uses a new chiral nonracemic phosphoramidite ligand in a complex with copper triflate as the catalyst. This work allows the straightforward stereocontrolled formation of a valuable structural motif using only a catalytic amount of chiral reagent.
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http://dx.doi.org/10.1039/c6sc02811jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358539PMC
January 2017

Mechanistic Studies on a Cu-Catalyzed Asymmetric Allylic Alkylation with Cyclic Racemic Starting Materials.

J Am Chem Soc 2017 04 10;139(15):5614-5624. Epub 2017 Apr 10.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford , 12 Mansfield Road, Oxford, OX1 3TA, U.K.

Mechanistic studies on Cu-catalyzed asymmetric additions of alkylzirconocene nucleophiles to racemic allylic halide electrophiles were conducted using a combination of isotopic labeling, NMR spectroscopy, kinetic modeling, structure-activity relationships, and new reaction development. Kinetic and dynamic NMR spectroscopic studies provided insight into the oligomeric Cu-ligand complexes, which evolve during the course of the reaction to become faster and more highly enantioselective. The Cu-counterions play a role in both selecting different pathways and in racemizing the starting material via formation of an allyl iodide intermediate. We quantify the rate of Cu-catalyzed allyl iodide isomerization and identify a series of conditions under which the formation and racemization of the allyl iodide occurs. We developed reaction conditions where racemic allylic phosphates are suitable substrates using new phosphoramidite ligand D. D also allows highly enantioselective addition to racemic seven-membered-ring allyl chlorides for the first time. H and H NMR spectroscopy experiments on reactions using allylic phosphates showed the importance of allyl chloride intermediates, which form either by the action of TMSCl or from an adventitious chloride source. Overall these studies support a mechanism where complex oligomeric catalysts both racemize the starting material and select one enantiomer for a highly enantioselective reaction. It is anticipated that this work will enable extension of copper-catalyzed asymmetric reactions and provide understanding on how to develop dynamic kinetic asymmetric transformations more broadly.
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http://dx.doi.org/10.1021/jacs.7b02440DOI Listing
April 2017

High-Power Actuation from Molecular Photoswitches in Enantiomerically Paired Soft Springs.

Angew Chem Int Ed Engl 2017 03 9;56(12):3261-3265. Epub 2017 Feb 9.

Bio-inspired and Smart Materials, University of Twente, P.O. Box 207, 7500, AE, Enschede, The Netherlands.

Motion in plants often relies on dynamic helical systems as seen in coiling tendrils, spasmoneme springs, and the opening of chiral seedpods. Developing nanotechnology that would allow molecular-level phenomena to drive such movements in artificial systems remains a scientific challenge. Herein, we describe a soft device that uses nanoscale information to mimic seedpod opening. The system exploits a fundamental mechanism of stimuli-responsive deformation in plants, namely that inflexible elements with specific orientations are integrated into a stimuli-responsive matrix. The device is operated by isomerization of a light-responsive molecular switch that drives the twisting of strips of liquid-crystal elastomers. The strips twist in opposite directions and work against each other until the pod pops open from stress. This mechanism allows the photoisomerization of molecular switches to stimulate rapid shape changes at the macroscale and thus to maximize actuation power.
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http://dx.doi.org/10.1002/anie.201611325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363340PMC
March 2017

Visualization of the spontaneous emergence of a complex, dynamic, and autocatalytic system.

Proc Natl Acad Sci U S A 2016 10 16;113(40):11122-11126. Epub 2016 Sep 16.

Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, United Kingdom

Autocatalytic chemical reactions are widely studied as models of biological processes and to better understand the origins of life on Earth. Minimal self-reproducing amphiphiles have been developed in this context and as an approach to de novo "bottom-up" synthetic protocells. How chemicals come together to produce living systems, however, remains poorly understood, despite much experimentation and speculation. Here, we use ultrasensitive label-free optical microscopy to visualize the spontaneous emergence of an autocatalytic system from an aqueous mixture of two chemicals. Quantitative, in situ nanoscale imaging reveals heterogeneous self-reproducing aggregates and enables the real-time visualization of the synthesis of new aggregates at the reactive interface. The aggregates and reactivity patterns observed vary together with differences in the respective environment. This work demonstrates how imaging of chemistry at the nanoscale can provide direct insight into the dynamic evolution of nonequilibrium systems across molecular to microscopic length scales.
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http://dx.doi.org/10.1073/pnas.1602363113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056079PMC
October 2016

Preparation of biomimetic photoresponsive polymer springs.

Nat Protoc 2016 10 1;11(10):1788-97. Epub 2016 Sep 1.

Bio-inspired and Smart Materials, MESA+ Institute for Nanotechnology, University of Twente, Enschede, the Netherlands.

Polymer springs that twist under irradiation with light, in a manner that mimics how plant tendrils twist and turn under the effect of differential expansion in different sections of the plant, show potential for soft robotics and the development of artificial muscles. The soft springs prepared using this protocol are typically 1 mm wide, 50 μm thick and up to 10 cm long. They are made from liquid crystal polymer networks in which an azobenzene derivative is introduced covalently as a molecular photo-switch. The polymer network is prepared by irradiation of a twist cell filled with a mixture of shape-persistent liquid crystals, liquid crystals having reactive end groups, molecular photo-switches, some chiral dopant and a small amount of photoinitiator. After postcuring, the soft polymer film is removed and cut into springs, the geometry of which is determined by the angle of cut. The material composing the springs is characterized by optical microscopy, scanning electron microscopy and tensile strength measurements. The springs operate at ambient temperature, by mimicking the orthogonal contraction mechanism that is at the origin of plant coiling. They shape-shift under irradiation with UV light and can be pre-programmed to either wind or unwind, as encoded in their geometry. Once illumination is stopped, the springs return to their initial shape. Irradiation with visible light accelerates the shape reversion.
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http://dx.doi.org/10.1038/nprot.2016.087DOI Listing
October 2016

Cp2ZrMeCl: A Reagent for Asymmetric Methyl Addition.

Org Lett 2016 08 26;18(15):3814-7. Epub 2016 Jul 26.

Department of Chemistry, Chemistry Research Laboratory, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.

The use of Cp2ZrMeCl is described as a source of nucleophilic methyl in asymmetric catalysis. This easily prepared reagent is bench stable, weighable in air, and generally useful in highly enantioselective copper-catalyzed addition reactions at room temperature. Methyl is successfully (generally >90% ee) added in 1,4-additions to cyclic and acyclic α,β-unsaturated ketones to provide tertiary and quaternary centers. Examples of catalyst controlled diastereoselective 1,6-addition and dynamic kinetic asymmetric allylic alkylation reactions are also reported. The reagent is used in the catalytic asymmetric synthesis of naturally occurring fragrance (R)-(-)-muscone (82% yield, 91% ee).
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http://dx.doi.org/10.1021/acs.orglett.6b01829DOI Listing
August 2016