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Dynamic Chemistry for Asymmetric Synthesis, Molecular Motion and Constitutional Exchange
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Chemistry, Organic chemistry.ORCID iD: 0000-0001-5807-8343
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Living matter is built on complex dynamic systems consisting of numerus biotransformations. By exploiting the adaptive and evolutive behaviors ofmolecular matter, dynamic chemistry has developed as an important tool tounderstand the organization of nonliving matter into complex living systems.This thesis concerns three aspects of dynamic chemistry with a general focus onthe influence of different stimuli on the structures and functions of dynamicsystems.The first section focuses on dynamic kinetic resolution, where enzymes areutilized for asymmetric synthesis of an enantiopure (2R,5R)-1,3-oxathiolane. Byemploying surfactant-treated subtilisin Carlsberg and Candida antarcticalipase B, the absolute configuration of the resulting 1,3-oxathiolane ring couldbe efficiently controlled.The second section addresses the motional dynamics of configurational enamineswitch systems controlled by multiple stimuli. Complete forward and backwardrotation around the enamine C=C bond could be precisely regulated uponaddition of acid/base or metal ions. The enamine switches exhibited specificsensing ability for CuII ions in solution. Moreover, the enamines exhibitedswitchable aggregation-induced emission in the solid state, which could beapplied in the development of sensors as well as fluorescent organogel.Lastly, the enamine switches could readily undergo constitutional exchange withprimary amines under catalytic acidic conditions, resulting in dynamic enaminesystems. However, under basic conditions or in the presence of excessive acid,this process exhibited extremely slow kinetics, leading to an efficient regulationof the exchange process by controlling the switch status with regulation of pHin the system.

Abstract [sv]

Levande organismer är uppbyggda av komplexa dynamiska system avsammankopplade biokemiska transformationer. Dynamisk kemi har genom attutnyttja adaptiva och evolutionära effekter hos molekylära system utvecklats tillett viktigt verktyg för att förstå principerna som styr självorganisation av ickelevande materia. Denna avhandling behandlar tre aspekter av dynamisk kemi,med fokus på vilken påverkan olika stimuli kan ha på strukturer och funktionerhos dynamiska system.Den första sektionen fokuserar på dynamisk kinetisk resolvering, där enzymeranvänds för asymmetrisk syntes av enantiomeriskt rena (2R,5R)-1,3-oxatiolanstrukturer. Genom att utnyttja surfaktant-behandlad subtilisinCarlsberg och Candida antarctica lipas B kunde absolutkonfigurationen av denresulterande 1,3-oxatiolanringen effektivt kontrolleras.Det andra avsnittet behandlar utvecklingen av konfigurationella dynamiskaenamin-omkopplare vars rörelsedynamiska beteende kan påverkas genomstimuli. Rotation av enaminens C=C-binding kunde specifikt kontrolleras i bådefram- och bakåtriktning genom addition av syra/bas eller metalljoner.Enanminkopplingen visade även upp specifik molekylär igenkänningsförmågaför CuII-joner i lösning. Vidare uppvisade enaminen reversibeltaggregationsinducerad emission i det fasta tillståndet, vilket kunde tillämpasinom utveckling av sensorer samt inom materialvetenskap.Slutligen kunde enaminomkopplaren visas genomgå reversibelt utbyte medprimära aminer i närvaro av katalytiska mängder syra, vilket resulterade idynamiska enaminsystem. Under basiska förhållanden eller i närvaro av ettöverskott syra uppvisade denna process mycket långsam kinetik, vilket ledde tilleffektiv reglering av utbytesprocessen och full kontroll av riktning ochkonstitution hos omkopplaren genom systemets pH-värde.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2018. , p. 76
Series
TRITA-CBH-FOU ; 2018:55
Keywords [en]
dynamic chemistry, constitutional dynamic chemistry, motional dynamics, dynamic kinetic resolution, enzyme, subtilisin Carlsberg, Candida antarctica lipase B, anti-HIV, 1, 3-oxathiolane, dynamic exchange, enamines, E/Z-isomerization, molecular switches, aggregation, gelation, fluorescence.
Keywords [sv]
dynamisk kemi, konstitutionell dynamisk kemi, molekylär rörelsedynamik, dynamisk kinetisk resolvering, enzym, subtilisin Carlsberg, Candida antarctica lipase B, anti-HIV, 1, 3-oxatiolan, dynamisk utbyte, enaminer, E/Z-isomerisering, molekylära omkopplare, aggregering, gelbildning, fluorescens.
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-237420ISBN: 978-91-7873-000-1 (print)OAI: oai:DiVA.org:kth-237420DiVA, id: diva2:1259067
Public defence
2018-12-05, F3, Lindstedtsvägen 26, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20181030

Available from: 2018-10-30 Created: 2018-10-26 Last updated: 2018-10-31Bibliographically approved
List of papers
1. Chirality Control in Enzyme-Catalyzed Dynamic Kinetic Resolution of 1,3-Oxathiolanes
Open this publication in new window or tab >>Chirality Control in Enzyme-Catalyzed Dynamic Kinetic Resolution of 1,3-Oxathiolanes
2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 16, p. 8478-8481Article in journal (Refereed) Published
Abstract [en]

The origin of enantioenrichment in enzyme-catalyzed dynamic kinetic resolution of 1,3-oxathiolane derivatives, key intermediates for asymmetric lamivudine synthesis, was elucidated. The chirality control could be determined by chiral HPLC and NOE NMR spectroscopy using a modified 1,3-oxathiolane compound obtained through enzyme-catalyzed selective hydrolysis. Solvent-dependent stereoselectivity was observed under biphasic conditions using different organic solvents with phosphate buffer.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-173775 (URN)10.1021/acs.joc.5b01585 (DOI)000360103000072 ()26237578 (PubMedID)2-s2.0-84940069665 (Scopus ID)
Funder
Swedish Research Council
Note

QC 20150921

Available from: 2015-09-21 Created: 2015-09-18 Last updated: 2018-10-30Bibliographically approved
2. Multienzymatic Cascade Synthesis of an Enantiopure (2R,5R)-1,3-Oxathiolane Anti-HIV Agent Precursor
Open this publication in new window or tab >>Multienzymatic Cascade Synthesis of an Enantiopure (2R,5R)-1,3-Oxathiolane Anti-HIV Agent Precursor
(English)Manuscript (preprint) (Other academic)
Abstract [en]

An enantiopure (2R,5R)-1,3-oxathiolane derivative was obtained using amultienzymatic cascade protocol. By employing a combination of surfactant-treatedsubtilisin Carlsberg and Candida antarctica lipase B, the absolute configuration of theresulting 1,3-oxathiolane ring was efficiently controlled, resulting in an excellentenantiomeric excess (> 99%). This enantiopure 1,3-oxathiolane derivative is a keyprecursor to anti-HIV agents, such as lamivudine, through subsequent N-glycosylation.

Keywords
enzyme, subtilisin Carlsberg, Candida antarctica lipase B, HIV, 1, 3-oxathiolane
National Category
Organic Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-237416 (URN)
Note

QC 20181030

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2018-10-30Bibliographically approved
3. Multistimuli-Responsive Enaminitrile Molecular Switches DisplayingH+‑Induced Aggregate Emission, Metal Ion-Induced Turn-OnFluorescence, and Organogelation Properties
Open this publication in new window or tab >>Multistimuli-Responsive Enaminitrile Molecular Switches DisplayingH+‑Induced Aggregate Emission, Metal Ion-Induced Turn-OnFluorescence, and Organogelation Properties
Show others...
2018 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 42, p. 13640-13643Article in journal (Refereed) Published
Abstract [en]

Multistimuli-responsive enaminitrile-based configurational switches displaying aggregation-induced emission (AIE), fluorescence turn-on effects, and supergelation properties are presented. The E-isomers dominated (>97%) in neutral/basic solution, and the structures underwent precisely controlled switching around the enamine C═C bond upon addition of acid/base. Specific fluorescence output was observed in response to different external input in the solution and solid states. In response to H+, configurational switching resulted in complete formation of the nonemissive Z-H+-isomers in solution, however displaying deep-blue to blue fluorescence (ΦF up to 0.41) in the solid state. In response to CuII in the solution state, the E-isomers exhibited intense, turn-on, blue-green fluorescence, which could be turned off by addition of competitive coordination. The acid/base-activated switching, together with the induced AIE-effects, further enabled the accomplishment of a responsive superorganogelator. In nonpolar solvents, a blue-fluorescent supramolecular gel was formed upon addition of acid to the E-isomer suspension. The gelation could be reversed by addition of base, and the overall, reversible process could be repeated at least five cycles.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-237425 (URN)10.1021/jacs.8b09843 (DOI)000448755200025 (PubMedID)2-s2.0-85055124605 (Scopus ID)
Note

QC 20181030

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2019-10-17Bibliographically approved
4. Stimuli-responsive Enaminitrile Molecular Switches as Tunable AIEgens Covering theChromaticity Space and Acting as Vapor Sensors
Open this publication in new window or tab >>Stimuli-responsive Enaminitrile Molecular Switches as Tunable AIEgens Covering theChromaticity Space and Acting as Vapor Sensors
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

A family of responsive enaminitrile molecular switches showing tunable turn-onfluorescence upon switching and aggregation is reported. Activated by addition of acid/base,isomerization around the C=C bond could be effectuated, resulting in complete, reversible switchingto the E- or Z-isomers. Typical aggregation-induced emission could be recorded for one specificstate of the different switches. By subtle tailoring of the parent structure, a series of compounds withemission covering almost the full visible color range were obtained. The switchable AIE features ofthe enaminitrile structures enabled their demonstration as solid state chemosensors to detect acidicand basic vapors, where the emission displayed an “off-on-off” effect. X-ray crystal analysis andDFT calculations suggested a restriction of intramolecular rotation mechanism, and anintramolecular charge transfer effect in the AIE luminogens.

Keywords
enaminitrile, switch, responsive, aggregation, fluorescence
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-237418 (URN)
Note

QC 20181030

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2018-10-30Bibliographically approved
5. Configurational and Constitutional Dynamics in Enamine Molecular Switches
Open this publication in new window or tab >>Configurational and Constitutional Dynamics in Enamine Molecular Switches
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Dual configurational and constitutional dynamics in systems based on enamine molecularswitches has been systematically studied. pH-responsive moieties, such as 2-pyridyl and 2-quinolinyl units, were required on the “stator” part, also providing enamine stability throughintramolecular hydrogen-bonding (IMHB) effects. Upon protonation or deprotonation, forward andbackward switching could be rapidly achieved. Extension of the stator π-system in the 2-quinolinylderivative provided a higher E-isomeric equilibrium ratio under neutral conditions, pointing to ameans to achieve quantitative forward/backward isomerization processes. The ‘rotor’ part of theenamine switches exhibited constitutional exchange ability with primary amines. Interestingly,considerably higher exchange rates were observed with amines containing ester groups, indicatingpotential stabilization of the transition state trough IMHB. Acids, particularly BiIII, were found toefficiently catalyze the constitutional dynamic processes. In contrast, the enamine and the formeddynamic enamine system showed excellent stability under basic conditions. This coupledconfigurational and constitutional dynamics expand the scope of dynamic C-C and C-N bonds, andpotentiates further studies and applications in the fields of molecular machinery and systemschemistry.

Keywords
enamine, switch, responsive, dynamic, constitutional
National Category
Organic Chemistry
Identifiers
urn:nbn:se:kth:diva-237419 (URN)
Note

QC 20181030

Available from: 2018-10-26 Created: 2018-10-26 Last updated: 2018-10-30Bibliographically approved
6. A Multicontrolled Enamine Configurational Switch Undergoing Dynamic Constitutional Exchange
Open this publication in new window or tab >>A Multicontrolled Enamine Configurational Switch Undergoing Dynamic Constitutional Exchange
2018 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 57, no 21, p. 6256-6260Article in journal (Refereed) Published
Abstract [en]

A multiresponsive enamine-based molecular switch is presented, in which forward/backward configurational rotation around the C=C bond could be precisely controlled by the addition of an acid/base or metal ions. Fluorescence turn-on/off effects and large Stokes shifts were observed while regulating the switching process with Cu-II. The enamine functionality furthermore enabled double dynamic regimes, in which configurational switching could operate in conjunction with constitutional enamine exchange of the rotor part. This behavior was used to construct a prototypical dynamic covalent switch system through enamine exchange with primary amines. The dynamic exchange process could be readily turned on/off by regulating the switch status with pH.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2018
Keywords
dynamic exchange, enamines, fluorescence, E/Z isomerization, molecular switches
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-230434 (URN)10.1002/anie.201802994 (DOI)000432710100049 ()29601656 (PubMedID)2-s2.0-85046299449 (Scopus ID)
Note

QC 20180615

Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-10-30Bibliographically approved

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