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Chiral alcohols and amines are important structural units widely existing in pharmaceuticals, agrochemicals, and food additives. Dynamic kinetic resolution (DKR) is an efficient strategy to deliver optically active alcohols and amines from their racemates. For the development of DKR method, racemization catalyst plays as a crucial element with the requirement of compatibility with the kinetic resolution (KR) system. In this paper, recent advance in the catalytic racemization of secondary alcohols and amines is summarized based on different types of racemizing intermediates, which are redox racemization via ketone/imine intermediates, racemization via radical intermediates, and racemization via carbocation intermediates. Enzymatic racemization of secondary alcohols and amines is also enclosed. (c) 2024 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Lipase-catalyzed organic reactions have been widely practiced in the past three decades. Especially interesting are insoluble/immobilized forms due to providing a possibility of facile use and recyclability, thus reducing process costs, and making the procedure more environmentally friendly. Carbon-based supports have been extensively exploited for this purpose, because of neutral and biodegradable nature and thermal and chemical stability. Their high specific surface area, characteristic surface morphology and lower mass transfer resistances play a vital role in the performance of the attached enzyme. This review paper presents an overview of the main aspects of lipase immobilized on multi-walled carbon nanotubes (MWCNTs). Moreover, different immobilization strategies to achieve a biocatalyst with improved performances are discussed. Furthermore, as lipases are considered to have high commercial worth for synthesis of valuable organic molecules, the second part of the paper is dedicated to the overview of the most important industrial sectors in which these nanobiocatalysts have been used. In specific, applications in biodiesel production, flavour ester synthesis and racemization are summarized., Lipaze su poslednjih decenija široko rasprostanjeni katalizatoriu raznovrsnim organskim reakcijama. Posebno su interesantne u imobilisanom/nerastvornom obliku jer je na ovaj način olakšana njihova upotreba uz mogućnost recikliranja i ponovne upotrebe čime se smanjuju troškovi samog procesa i postupak je ekološki prihvatljiviji. Kao nosači za vezivanje nanomaterijali na bazi ugljenika, posebno ugljenične nanocevi, su našli primenu zbog svojih izuzetnih fizičkih, mehaničkih i hemijskih svojstava. Njihova velika specifična površina, karakteristična površinska morfologija i smanjen otpor prenosu mase igraju vitalnu ulogu u performansama vezanog enzima. Ovaj pregledni rad predstavlja prikaz glavnih aspekata lipaze imobilisane na višeslojne ugljenične nanocevi i različitih strategija imobilizacije za dobijanje biokatalizatora sa poboljšanim svojstvima. Takođe, kako su lipaze enzimi od velikog komercijalnog značaja za organsku sintezu i primenu u biotehnologiji, drugi deo rada posvećen je pregledu najvažnijih industrijskih sektora u kojima su ovi nanobiokatalizatori našli primenu. Shodno tome, dat je pregled proizvodnje biodizela, mirisnih estara i racemizacije

Lipase-catalyzed organic reactions have been widely practiced in the past three decades. Especially interesting are insoluble/immobilized forms due to providing a possibility of facile use and recyclability, thus reducing process costs, and making the procedure more environmentally friendly. Carbon-based supports have been extensively exploited for this purpose, because of neutral and biodegradable nature and thermal and chemical stability. Their high specific surface area, characteristic surface morphology and lower mass transfer resistances play a vital role in the performance of the attached enzyme. This review paper presents an overview of the main aspects of lipase immobilized on multi-walled carbon nanotubes (MWCNTs). Moreover, different immobilization strategies to achieve a biocatalyst with improved performances are discussed. Furthermore, as lipases are considered to have high commercial worth for synthesis of valuable organic molecules, the second part of the paper is dedicated to the overview of the most important industrial sectors in which these nanobiocatalysts have been used. In specific, applications in biodiesel production, flavour ester synthesis and racemization are summarized., Lipaze su poslednjih decenija široko rasprostanjeni katalizatoriu raznovrsnim organskim reakcijama. Posebno su interesantne u imobilisanom/nerastvornom obliku jer je na ovaj način olakšana njihova upotreba uz mogućnost recikliranja i ponovne upotrebe čime se smanjuju troškovi samog procesa i postupak je ekološki prihvatljiviji. Kao nosači za vezivanje nanomaterijali na bazi ugljenika, posebno ugljenične nanocevi, su našli primenu zbog svojih izuzetnih fizičkih, mehaničkih i hemijskih svojstava. Njihova velika specifična površina, karakteristična površinska morfologija i smanjen otpor prenosu mase igraju vitalnu ulogu u performansama vezanog enzima. Ovaj pregledni rad predstavlja prikaz glavnih aspekata lipaze imobilisane na višeslojne ugljenične nanocevi i različitih strategija imobilizacije za dobijanje biokatalizatora sa poboljšanim svojstvima. Takođe, kako su lipaze enzimi od velikog komercijalnog značaja za organsku sintezu i primenu u biotehnologiji, drugi deo rada posvećen je pregledu najvažnijih industrijskih sektora u kojima su ovi nanobiokatalizatori našli primenu. Shodno tome, dat je pregled proizvodnje biodizela, mirisnih estara i racemizacije

This journal is © the Owner Societies 2011. One of the authors (I. G.) acknowledges fruitful discussions with A. S. Sanz and F. Carreño. This work was supported by MICINN (Spain) through projects FIS2010-22082, FIS2010-21372, and through the Juan de la Cierva program (P. B.)., We study the tunnel dynamics of a chiral molecule between its left (L) and right (R) conformations, under the global effect of collisional decoherence together with the effect of a mean-field generated by the environment where an energetic difference, K, between homochiral and heterochiral interactions is assumed. We show that this decoherence leads unavoidably to equal populations of the L and R chiral conformations even for a high enough value of K which tends to keep localized an initial chiral state. However, we also show that K contributes to the stabilization of an initial L or R state for times that could be many orders of magnitude larger than the tunneling time, in the case the decoherence rate is much greater than the tunneling rate. In this case, an estimation of this stabilization time and a critical tunneling time is made. Even in the case in which the tunneling rate is greater than the decoherence rate, the effect of K is to keep localized the initial chiral state for times greater than the tunneling time. A possible slight chiral asymmetry is also considered., Ministerio de Ciencia e Innovación (MICINN), España, Ministerio de Economía y Competitividad (MINECO), España, Depto. de Óptica, Fac. de Ciencias Físicas, TRUE, pub

The undesired reaction between carbodiimides (peptide coupling reagent) and OxymaPure (peptide coupling additive), which takes place in very low extension during peptide bond formation, is dependent on the steric hindrance around the carbodiimide backbone. Carbodiimides containing tertiary substituents on N such as di-tert-butylcarbodiimide do not activate the carboxylic group properly; the presence of secondary substituents such as in the case of diisopropylcarbodiimide (DIC) leads to the formation of oxadiazole and HCN; finally, primary substituents render an adduct of oxadiazine and no formation of HCN. tert-Butylethylcarbodiimide (TBEC), which is a hybrid of primary and tertiary substituents, leads to the formation of oxadiazine with no concomitant formation of HCN. Furthermore, TBEC outperforms DIC in terms of yield and minimization of racemization as it is demonstrated herein.

Methodologies for the quantitative assessment of the spine tissues, in particular the intervertebral disc (IVD), have not been well established in terms of long-term reliability. This is required for designing prospective studies. 1H water T2 in the IVD (“T2”) has attained wider use in assessment of the lumbar intervertebral discs via magnetic resonance imaging. The reliability of IVD T2 measurements are yet to be established. IVD T2 was assessed nine times at regular intervals over 368 days on six anatomical slices centred at the lumbar spine using a spin-echo multi-echo sequence in 12 men. To assess repeatability, intra-class correlation co-efficients (ICCs), standard error of the measurement, minimal detectable difference and co-efficients of variation (CVs) were calculated along with their 95% confidence intervals. Bland-Altman analysis was also performed. ICCs were above 0.93, with the exception of nuclear T2 at L5/S1, where the ICC was 0.88. CVs of the central-slice nucleus sub-region ranged from 4.3% (average of all levels) to 10.1% for L5/S1 and between 2.2% to 3.2% for whole IVD T2 (1.8% for the average of all levels). Averaging between vertebral levels improved reliability. Reliability of measurements was least at L5/S1. ICCs of degenerated IVDs were lower. Test-retest reliability was excellent for whole IVD and good to excellent for IVD subregions. The findings help to establish the long-term repeatability of lumbar IVD T2 for the implementation of prospective studies and determination of significant changes within individuals.

The synthesis of purine conjugates with natural amino acids is one of the promising directions in search for novel therapeutic agents, including antimycobacterial agents. The purpose of this study was to synthesize N-(purin-6-yl)dipeptides containing the terminal fragment of (S)-glutamic acid. To obtain the target compounds, two synthetic routes were tested. The first of them is based on coupling of N-(purin-6-yl)-(S)-amino acids to dimethyl (S)-glutamate in the presence of carbodiimide coupling agent followed by the removal of ester groups. However, it turned out that this coupling process was accompanied by racemization of the chiral center of N-(purin-6-yl)-α-amino acids and in all cases led to mixtures of (S,S)- and (R,S)-diastereomers (6:4). Individual (S,S)-diastereomers were obtained using an alternative approach based on the nucleophilic substitution of chlorine in 6-chloropurine or 2-amino-6-chloropurine with corresponding dipeptides as nucleophiles. The enantiomeric purity of the target compounds was confirmed by chiral HPLC. To test the assumption that racemization of the chiral center of N-(purin-6-yl)-α-amino acids occurs with the participation of nitrogen atoms of the imidazole ring via the stage of formation of a chirally labile intermediate, we obtained such structural analogs of N-(purin-6-yl)-(S)-alanine as N-(9-benzylpurin-6-yl)-(S)-alanine and N-(7-deazapurin-6-yl)-(S)-alanine. It was found that coupling of these compounds to dimethyl (S)-glutamate was also accompanied by racemization. This indicates that the imidazole fragment does not play a crucial role in this process. When testing the antimycobacterial activity of some of the obtained compounds, conjugates with moderate activity against the laboratory Mycobacterium tuberculosis H37Rv strain (MIC 3.1–6.25 μg/mL) were identified. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, AT part of Springer Nature.

The activation process of a known Ru-catalyst, dicarbonyl(pentaphenylcyclopentadienyl)ruthenium chloride, has been studied in detail using time resolved in situ X-ray absorption spectroscopy. The data provide bond lengths of the species involved in the process as well as information about bond formation and bond breaking. On addition of potassium tert-butoxide, the catalyst is activated and an alkoxide complex is formed. The catalyst activation proceeds via a key acyl intermediate, which gives rise to a complete structural change in the coordination environment around the Ru atom. The rate of activation for the different catalysts was found to be highly dependent on the electronic properties of the cyclopentadienyl ligand. During catalytic racemization of 1-phenylethanol a fast-dynamic equilibrium was observed.

Byla provedena rozsahla literarni re.er.e zam..ena na metody syntezy a popsane biologicke aktivity salicylamid., na mo.nosti syntezy peptid. v.etn. pou.itych .inidel, aditiv a aspekt. racemizace substratu, a na molekuly schopne inhibice proteasomu. Bylo navr.eno a experimentaln. ov..eno n.kolik mo.nych p.istup. ke konstrukci salicylamid. s peptidovym .et.zcem, ktere navazuji a roz.i.uji sou.asne znalosti v teto oblasti. Byla vybrana nejvhodn.j.i synteticka metoda, ktera byla dale optimalizovana zejmena za u.elem omezeni racemizace. Byla provedena synteza serie slou.enin odvozenych od substituovane kyseliny salicylove a dipeptid., ktere byly vhodnym zp.sobem charakterizovany (1H a 13C NMR, I., HRMS v uspo.adani MALDI-TOF, CHN analyza). Dale bylo provedeno testovani jejich biologickych aktivit (antiproliferativni aktivita v..i kmen.m leukemie K562 a CEM a mnoho.etneho myelomu U266, proteasomalni inhibice U266 v.etn. selektivity v..i jednotlivym podjednotkam ?Ŕ kruhu proteasomu 20S U266 a .asovemuho pr.b.hu inhibice v r.znych koncentracich p.ipravenych salicylamid.)., Extensive literary review describing biological activities and methods of salicylamide synthesis, describing peptide synthesis including used reagents, aditives and aspects of substrate racemization, and describing molecules able of proteasomal inhibition was carried out and is presented. Several synthetical strategies for salicylamide containing a peptide chain was designed and experimentaly verified. Proposed samlicylamides are extending current state of knowledge about said topic. The most suitable synthetic method was chosen and further optimized with the aim of resolve the peptide racemisation issue which occured during the synthesis. Series of salicylamides with peptide sidechain was synthesized and characterized (1H a 13C NMR, IR, HRMS in the MALDI-TOF setting, CHN analysis). Furthermore, prepared compounds were tested for their biological activities (antiproliferative activity against leukemia cell lines K562 and CEM and multiple myeloma cell line U266, proteasomal inhibition of U266 including the selectivity towards proteolytic subunits of â ring of 20S proteasome U266, time progress of proteasomal inhibition at various salicylamide concentration levels)., Fakulta chemicko-technologická, Dokončená práce s úspěšnou obhajobou

Biocatalysis is the branch of science at the intersection between chemistry and biology and specifcally dedicated to the application of natural evolvable catalysts, i.e. enzymes, in human-designed chemical processes. Among the array of promising biocatalysts, transaminases (EC 2.6.1.x) are possibly one of the enzyme classes with the largest unrealized potential. Fast inactivation, poor acceptance towards unnatural substrates and limited tolerance to cosolvents are some of the main factors hampering their implementation in chemical synthesis. In the present thesis work advances in both transaminase application and molecular understanding are presented. Indeed, these two topics are deeply interconnected, as a better molecular understanding is expected to ease the generation of novel enzyme variants suitable for new desired applications. From the application perspective, the design of an effective one-pot transaminase-based racemization system offers new possibilities for the design of fully biocatalytic dynamic kinetic resolutions of valuable chiral amines. Similarly, the successful structure-guided redesign of the small substrate binding pocket of the Chromobacterium violaceum (S)-selective transaminase (Cv-TA) granted access to a new enzyme variant active on semi-preparative scale towards the unnatural substrate 1,2-diphenylethylamine. From the molecular understanding perspective, the combination of crystallographic and computational techniques led to the formulation of a dimer dissociation model valid for Cv-TA and possibly for other enzymes belonging to the same fold type. This model, which aided the improvement of the Cv-TA stability by structure-based engineering, will hopefully enable similar results in other structurally related enzymes., Biokatalys är den del av naturvetenskapen mellan kemi och biologi som är specifkt inriktad på tillämpningar av naturligt utvecklade biokatalysatorer, dvs enzymer, i av människan skapade kemiska processer. Av alla lovande biokatalysatorer som existerar, är transaminaser (EC 2.6.1.x) kanske den enzymkategori som har störst outnyttjad potential. Snabb inaktivering, låg acceptans mot icke- naturliga substrat och en begränsad tolerans mot organiska lösningsmedel är några av de huvudsakliga faktorerna som begränsar användningen i kemiska synteser. I denna avhandling presenteras både framsteg inom transaminas-tillämpningar och molekylär förståelse. Dessa är i grunden djupt sammanhängande, då en bättre molekylär förståelse kan förväntas underlätta skapandet av tidigare okända enzymer som kan användas i nya önskade tillämpningar. Från ett applikationsperspektiv, skapar designen av ett effektivt en- kärls transaminasbaserat racemiserings-system nya möjligheter att designa biokatalytiska kinetiska resolveringar av värdefulla kirala aminer. På ett likartat sätt skapar den nya strukturbaserade designen av en liten substratbindande fcka i det (S)-selektiva transaminaset från Chromobacterium violaceum (Cv-TA) en ny enzymvariant som är aktiv i semi-preparativ skala med det icke-naturliga substratet 1,2- difenyletylamin. Från perspektivet av molekylär förståelse, ledde kombinationen av kristallograf och beräkningsteknik till formuleringen av en modell för dimer dissociationen av Cv-TA och som möjligtvis också gäller andra enzymer av samma struktur-typ. Med stöd av denna modell, har stabiliteten hos Cv-TA förbättrats med strukturbaserad modellering. Liknande resultat för strukturellt besläktade enzymer kommer förhoppningsvis produceras., La biocatalisi è quel ramo delle discipline scientifche situato all’intersezione tra chimica a biologia e dedicato all’applicazione di enzimi in processi chimici messi a punto dall’uomo. La classe enzimatica delle transaminasi (EC 2.6.1.x) è forse tra quelle con il più grande potenziale irrealizzato in questo settore. La rapida inattivazione, scarsa attività verso substrati non naturali e limitata stabilità in presenza di cosolventi ne limitano infatti l’uso in applicazioni di sintesi organica. Il lavoro presentato in questa tesi è dedicato all’avanzamento delle possibilità applicative delle transaminasi e al raggiungimento di una loro migliore comprensione a livello molecolare. Questi due aspetti sono sostanzialmente interconnessi, dal momento che una più profonda comprensione teorica può contribuire al successo di strategie di ingegnerizzatione dirette all’ottenimento di varianti enzimatiche adatte per particolari applicazioni. Nell’ambito applicativo, l’ideazione di un sistema basato sull’uso di transaminasi per la racemizzazione in one-pot di ammine chirali offre nuove possibilità per la risoluzione cinetica dinamica di questa classe di molecole. Allo stesso tempo, l’ingegnerizzazione della tasca minore del sito attivo della transaminasi (S)-selettiva isolata da Chromobacterium violaceum (Cv-TA) ne ha ampliato l’utilizzo per la risoluzione su scala semi-preparativa del substrato non-naturale 1,2- difeniletilamine. Nell’ambito dell’avanzamento teorico, la combinazione di tecniche cristallografche e computazionali ha portato alla formulazione di un modello in grado di descrivere il processo di dissociazione dell’organizzazione dimerica valido per Cv-TA e, verosimilmente, per altri enzimi appartenenti alla medesima classe strutturale. Questo modello ha guidato con successo l’ingegnerizzazione di Cv- TA per migliorarne la stabilità ed è possibile che possa contribuire al raggiungimento di risultati simili in altri enzimi strutturalmente correlati., QC 2019-10-01

Chiral molecules exhibiting a quinone and/or hydroquinone moiety are ubiquitous in natural products and small molecule drugs. Herein, we describe a chiral quinone-hydroquinone molecule that racemizes through a reversible redox reaction. Using a combined computational and experimental approach, we show that this racemization proceeds via an intermolecular reaction mechanism. Starting from two achiral reactants, this molecule could be obtained in enantiopure form using Viedma ripening.

The main focus of this thesis lies in the development of new transition metal-catalyzed chemoenzymatic dynamic kinetic resolutions (DKR) of both alcohols and amines. The first part of the thesis deals with the development of new heterogeneous systems for the DKR of amines. The racemization catalysts in these different systems are all composed of palladium nanoparticles supported on either mesoporous silica or incorporated in a biocomposite that is composed of a bioactive cross-linked enzyme aggregate. The second part of the thesis deals with the development of a homogeneous iron catalyst in the racemization of sec-alcohols for the implementation in a chemoenzymatic DKR. Two protocols for the racemization of sec-alcohols are reported. The first one could not be combined with a chemoenzymatic kinetic resolution, although this was overcome in the second iron based protocol. Following the successful iron catalyzed chemoenzymatic DKR of sec-alcohols, the iron catalyst was used in the cyclization of α-allenic alcohols and N-protected amines to furnish 2,3-dihydrofurans and 2,3-dihydropyrroles, respectively. The cyclization is proceeding in a diastereoselective manner. The last part of the thesis deals with attempts to further elucidate the mechanism of activation of a known ruthenium racemization catalyst. X-ray absorption spectroscopy using synchrotron radiation was used for this purpose., At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 7: Manuscript. Paper 8: Manuscript.

Dynamic kinetic resolution (DKR) reactions in which a stereoselective enzyme and a racemization step are coupled in one‐pot would represent powerful tools for the production of enantiopure amines through enantioconvergence of racemates. The exploitation of DKR strategies is currently hampered by the lack of effective, enzyme‐compatible and scalable racemization strategies for amines. In the present work, the proof of concept of a fully biocatalytic method for amine racemization is presented. Both enantiomers of the model compound 1‐methyl‐3‐phenylpropylamine could be racemized in water and at room temperature using a couple of wild‐type, non‐proprietary, enantiocomplementary amine transaminases and a minimum amount of pyruvate/alanine as a co‐substrate couple. The biocatalytic simultaneous parallel cascade reaction presented here poses itself as a customizable amine racemization system with potential for the chemical industry in competition with traditional transition‐metal catalysis., QC 20181001

The first part of my thesis concerns the use of heterogeneous acidic resins for racemization of tert-alcohols without any side-product formation. The focus was to develop a system which can be further extended to a DKR protocol consisting of an enzymatic KR reaction. Based on our knowledge of the resins, an unexpected migratory DKR protocol turned out to be an efficient method for the synthesis of carbocyclic allylic carbinols. The development of enzyme and metal catalyst hybrids was already an ongoing theme in our group. A supporter-free biohybrid catalyst was developed which can be used in several different types of reactions. The Pd(0)-CalB CLEA catalyst was applied in a two-step-cascade transformation and in the DKR of benzylic primary amines. The catalyst was characterized by different analytical techniques, to understand its composition and structure. The enzymes have always been the main focus of the studies and therefore wild type enzymes were initially utilized. However, these natural biocatalysts are associated with certain limitations. In contrast, protein engineering allows for enzymes to be modified and optimized. We have used the technique to create a subtilisin Carlsberg mutant, which was studied both by modeling and in vitro. The mutant was found to catalyze the (S)-selective transesterification of sec-alcohols containing long aliphatic carbon chains, and it also exhibited higher performance in organic solvent. The last project concerned the protein engineering of CalA enzyme towards tert-alcohols. The kinetic resolution of tert-alcohols with this enzyme is very slow but it occurs with good enantioselectivity. The aim was therefore to improve the activity of CalA via protein engineering. Seven amino acids were mutated close to the active site and a library was created based on our prediction. Throughout the screening, a few variants showed higher activity, which were sequenced and further analyzed in the transesterification of tert-alcohols., At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 6: Manuscript.

Tertiary alcohols are important structural motifs in natural products and building blocks in organic synthesis but only few methods are known for their enantioselective preparation. Chiral resolution is one of these approaches that leaves one enantiomer (50% of the material) unaffected. An attractive method to increase the efficiency of those resolutions is to racemize the unaffected enantiomer. In the present work, we have developed a practical racemization protocol for tertiary alcohols. Five different acidic resin materials were tested. The Dowex 50WX8 was the resin of choice since it was capable of racemizing tertiary alcohols without any byproduct formation. Suitable solvents and a biphasic system were investigated, and the optimized system was capable of racemizing differently substituted tertiary alcohols.

type:Journal Article, Photolysis of poly(L-lactic acid) (PLLA) has many unclear points, such as the degradation mechanism, kinetics, products, and racemization mechanism. To clarify these features of PLLA photolysis, we examined the relationship between photolysis and racemization. The hexad stereosequential analysis of photodegraded PLLA was investigated to specify the racemized positions within a chain in comparison with hydrolysis and thermal degradation. Results from 13C NMR spectra of UV-irradiated PLLA samples indicated that the samples have racemized D-lactate units at chain ends. From the comparison of racemization behavior among photolysis, hydrolysis, and thermal degradation, it was confirmed that the preferential racemization behavior of each of these three degradation processes is characteristic and distinct, being identified as chain-end racemization, poor racemization, or internal-unit racemization, respectively. The characteristic chain-end racemization behavior of photolysis was first confirmed in this study., source:http://dx.doi.org/10.1021/bm200775r

type:Journal Article, To achieve the feed stock recycling of poly(L-lactide) (PLLA) to L,L-lactide, PLLA composites including alkali earth metal oxides, such as calcium oxide (CaO) and magnesium oxide (MgO), were prepared and the effect of such metal oxides on the thermal degradation was investigated from the viewpoint of selective L,L-lactide formation. Metal oxides both lowered the degradation temperature range of PLLA and completely suppressed the production of oligomers other than lactides. CaO markedly lowered the degradation temperature, but caused some racemization of lactide, especially in a temperature range lower than 250 °C. Interestingly, with MgO racemization was avoided even in the lower temperature range. It is considered that the effect of MgO on the racemization is due to the lower basicity of Mg compared to Ca. At temperatures lower than 270 °C, the pyrolysis of PLLA/MgO (5 wt%) composite occurred smoothly causing unzipping depolymerization, resulting in selective L,L-lactide production. A degradation mechanism was discussed based on the results of kinetic analysis. A practical approach for the selective production of L,L-lactide from PLLA is proposed by using the PLLA/MgO composite., source:https://doi.org/10.1016/j.polymer.2003.12.058

type:Journal Article, To control the depolymerization process of poly (L-lactic acid) into L,L-lactide for feedstock recycling, the racemization of L,L-lactide as a post-depolymerization reaction was investigated. In the absence of a catalyst, the conversion to meso-lactide increased with increase in the heating temperature and time at a higher rate than the conversion into oligomers. The resulting high composition of meso-lactide suggests that the direct racemization of L,L-lactide had occurred in addition to the known racemization mechanism that occurs on the oligomer chains. In the presence of MgO, the oligomerization rapidly proceeded to reach an equilibrium state between monomers and oligomers. The equilibrium among L,L-, meso-, and D,D-lactides was found to be a convergent composition ratio: L,L-:meso-:D,D-lactides = 1:1.22:0.99 (wt/wt/wt) after 120 min at 300 °C. This composition ratio also indicates that, in addition to the known racemization reaction on the oligomer chains, direct racemization among the lactides is also a frequent occurrence.

Herein, we report on a metalloenzymatic dynamic kinetic resolution of sec-alcohols employing an iron-based racemization catalyst together with a lipase. The iron catalyst was evaluated in racemization and then used in dynamic kinetic resolution of a number of sec-alcohols to give enantiomerically pure products in good to high yields. The iron catalyst is air and moisture stable and is readily accessible.

Fe and Ru pincer-type catalysts are used for the racemization of benzylic alcohols. Racemization with the Fe catalyst was achieved within 30 minutes under mild reaction conditions, with a catalyst loading as low as 2 mol %. This reaction constitutes the first example of an iron-catalyzed racemization of an alcohol. The efficiency for racemization of the Fe catalyst and its Ru analogue was evaluated for a wide range of sec-benzylic alcohols. The commercially available Ru complex proved to be highly robust and even tolerated the presence of water in the reaction mixture.

Racemization in proteins and peptides at sites of L-asparaginyl and L-aspartyl residues contributes to their spontaneous degradation, especially in the biological aging process. Amino acid racemization involves deprotonation of the alpha carbon and replacement of the proton in the opposite stereoconfiguration; this reaction is much faster for aspartate/asparagine than for other amino acids because these residues form a succinimide ring in which resonance stabilizes the carbanion resulting from proton loss. To determine if the replacement of the hydrogen atom on the alpha carbon with a deuterium atom might decrease the rate of racemization and thus stabilize polypeptides, we synthesized a hexapeptide, VYPNGA, in which the three carbon-bound protons in the asparaginyl residue were replaced with deuterium atoms. Upon incubation of this peptide in pH 7.4 buffer at 37 °C, we found that the rate of deamidation via the succinimide intermediate was unchanged by the presence of the deuterium atoms. However, the accumulation of the D-aspartyl and D-isoaspartyl-forms resulting from racemization and hydrolysis of the succinimide was decreased more than five-fold in the deuterated peptide over a 20 day incubation at physiological temperature and pH. Additionally, we found that the succinimide intermediate arising from the degradation of the deuterated asparaginyl peptide was slightly less likely to open to the isoaspartyl configuration than was the protonated succinimide. These findings suggest that the kinetic isotope effect resulting from the presence of deuteriums in asparagine residues can limit the accumulation of at least some of the degradation products that arise as peptides and proteins age.

(R)-1,1'-Bi(2-naphthol) ((R)-BINOL) in an acetonitrile solution lost optical activity upon irradiation with an Hg-Xe lamp. HPLC resolution of the product indicated that (R)-BINOL was racemized upon irradiation, and SEC analysis suggested that a polymeric product was formed in the course of racemization. It is proposed that polymerization of BINOL can occur before it is racemized and that a unit in a polymer derived from BINOL may lose its optical activity afterwards due to in-chain racemization and/or reduction. The polymeric products seem to consist not only of BINOL residues but also of residues derived from acetonitrile as well as those derived through reduction of BINOL.

Dating is basic for archaeological and paleontological investigations and results of different dating methods used in Azokh caves are described in this chapter. Fossils from Azokh were not dated by any method previously. Lithic technology and taxonomy suggested a middle Pleistocene age for Unit V (from where Acheulian industries and a human mandible fragment were recovered) while Units III and II yielded Mousterian industries indicating middle Paleolithic ages. Dates from Azokh by Electron Spin Resonance (ESR) previously published elsewhere were given before final calculations and they slightly differ from those given in this Appendix, which are the definitive dating results.

The Marismas Formation is the upper part of the sedimentary infill of the SW sector of the Guadalquivir basin. Previous chronological data of the Lebrija core sediments, indicated that the age at the top of this formation was 9.6 kyr BP and the bottom, 60 m, is near or beyond the range of radiocarbon, but post Matuyama - Brunhes reversal. In this work we present 17 new ages coming from the analysis of racemization of amino acid on valves of ostracods, in order to complete the chronology and the age-depth model of the Marismas Formation. The results indicates that the section located below the meter 56, throws ages ranging between 164685±14110 and 202830±30255, which correlates with the marine isotope stage MIS6-7 Middle Pleistocene, significantly lower in age than described in other parts of the lower Guadalquivir basin., Postprint (published version)

This thesis is divided into three parts, revolving around the developments of dynamic systems utilized in dynamic kinetic resolution (DKR) and constitutional dynamic chemistry (CDC). The first section gives an introduction to constitutional dynamics, the core concept of this thesis. Constitutional dynamics can be tuned through reversible interactions. Then, the basic principles of constitutional dynamics in DKR and CDC are discussed, along with their applications. The second section explores the asymmetric synthesis of oxazolidinone derivatives using lipase catalysis through kinetic resolution (KR) and dynamic kinetic resolution. In the first example, synthetic protocol to enantioenriched 5-phenyloxazolidin-2-ones is described, where a kinetically controlled carbamation is followed by lipase-catalyzed cyclization. In contrast to the 5-substituted species, the synthesis of 3-phenyloxazolidin-2-one derivatives could be achieved through lipase-catalyzed cascade O- and N- alkoxycarbonylations in one pot. Furthermore, this KR system could be coupled to a ruthenium-catalyzed racemization process of 1,2-aminoalcohols, thus providing an efficient DKR methodology for asymmetric transformations. The third section focuses on dynamic systems built through reversible covalent reactions. In the first example, a selective gelation process is described, and employed to resolve dynamic imine systems consisting of gelator candidates. In the second example, reversible reactions with aldehyde enamines are presented, including enamine formation and exchange reactions. In particular, Bi(III) and Sc(III) were discovered to accelerate the enamine exchange reactions by 50-400 times, in which the equilibria could be reached within hours. The last example describes reversible nitroaldol reactions in aqueous media, where rapid and efficient equilibration was identified for selected structures in neutral phosphate buffer., QC 20150911

In this article, racemization of various olefinic sec-alcohols by Ru(CO)(2)((5)-C5Ph5)Cl was investigated. The racemization of three aliphatic sec-alcohols with different chain lengths containing terminal double bonds was studied. A dramatic decrease of the racemization rate was found for these sec-alcohols compared to that of the corresponding saturated substrates. The slow racemization rate of the former alcohols is ascribed to coordination of the double bond to the ruthenium centre, which blocks the free site needed for -hydride elimination. This mechanism was supported by a recent study, in which 5-hexen-2-ol was found to form an alkoxycarbonyl complex having the double bond coordinated to the ruthenium atom. Aliphatic sec-alcohol substrates with a di- or trisubstituted double bond were found to give a lower degree of inhibition of the racemization rate than the substrates with a monosubstituted double bond., AuthorCount:2

The goal of this research was to develop a series of mixed-metal supramolecular complexes with specialized light absorbing units to probe perturbation of excited-state properties by ligand deuteration and long-term complex stability via racemization of initially enantiopure light absorbing subunits. Varying bidentate polypyridyl terminal ligands (TL), bridging ligands (BL), reactive metal center (RM), or number of Ru(II) light absorbers (LA) tunes the electrochemical, spectroscopic, photophysical, and photochemical properties within the supramolecular architecture. Ru(II) monometallics of the design [(bpy)2Ru(prolinate)](PF6) utilize prolinate as a chiral directing ligand to impart chirality to the Ru(II) LAs in the synthesis of more sophisticated supramolecular complexes. Ru(II) monometallics of the design [(TL)2Ru(BL)](PF6)2 (TL = bpy or d8-bpy; BL = dpp or d10-dpp; bpy = 2,2′-bipyridine; dpp = 2,3-bis(2-pyridyl)pyrazine) covalently couple two TLs and one BL to a central Ru(II) metal center forming a LA subunit. Larger bi- and trimetallic complexes are formed by coupling an additional Ru(II), Rh(III), or Pt(II) metal center to an existing Ru(II) LA through a BL. Ru(II),Ru(II), Ru(II),Rh(III), and Ru(II),Pt(II) bimetallics of the design [(TL)2Ru(BL)Ru(TL)2](PF6)4, [(TL)2Ru(BL)RhCl2(TL′)](PF6)3, and [(TL)2Ru(BL)PtCl2](PF6)2 (TL/TL′ = bpy or d8-bpy; BL = dpp or d10-dpp) couple only one Ru(II) LA to a Ru(II), Rh(III), or Pt(II) metal center through the BL. Ru(II),Rh(III),Ru(II) trimetallics of the design [{(TL)2Ru(BL)}2RhCl2](PF6)5 (TL = bpy or d8-bpy; BL = dpp or d10-dpp) covalently couple two Ru(II) LAs to a central Rh(III) RM through polyazine BLs. The complexes discussed herein are synthesized using a building block approach, permitting modification of the supramolecular architecture through multiple synthetic steps. Electrochemical analysis of the mono-, bi-, and trimetallic complexes displays several common features: a Ru-based HOMO and either a bridging ligand

Dual promiscuous racemization/amidation activities of lipases leading to efficient dynamic kinetic resolution protocols of racemic alpha-aminonitrile compounds are described. alpha-Amidonitrile products of high enantiomeric purity could be formed in high yields. Several lipases from different sources were shown to exhibit the dual catalytic activities, where opposite enantioselectivities could be recorded for certain substrates., QC 20141021

Proteomics may have enabled the root cause of a major human-blinding condition, age-related cataract, to be established. Cataract appears to result from the spontaneous decomposition of long-lived macromolecules in the human lens, and recent proteomic analysis has enabled both the particular crystallins, and the specific sites of amino acid modification within each polypeptide, to be identified. Analysis of proteins from cataract lenses has demonstrated that there are key sites on some structural proteins that show a consistently greater degree of deterioration than age-matched normal lenses. Proteomic analysis, using MS, revealed that the most abundant posttranslational modification of aged lens proteins is racemization. This is somewhat ironic, since structural isomers can be viewed as the "Achilles heel" of MS and there are typically few, if any, differences in the MS/MS spectra of tryptic peptides containing one d-amino acid. It is proposed that once a certain level of spontaneous PTM at key sites occurs, that protein-protein interactions are disrupted, and binding of complexes to cell membranes takes place that impairs cell-to-cell communication. These findings may apply more widely to age-related human diseases, in particular where the deterioration of long-lived proteins is a crucial component in the etiology.

Although almost 200-years-old, several unknown aspects remain to be explored of colchicine, the unique available drug for acute flares of gout. In this article, we report density-functional theory (DFT) studies of geometry, energy, and NMR; 1H-, 13C-, and 15N-NMR chemical shifts and some spin-spin coupling constants, including the complete analysis of the saturated part (ring B); the assignment of both enantiomers by NMR using a chiral solvating agent; solid-state NMR experiments of the different forms of natural and racemic colchicine, and IR and vibrational circular dichroism (VCD) studies of these same forms. Copyright © 2014 Verlag Helvetica Chimica Acta AG, Zürich.

Age-dependent deterioration of long-lived proteins in humans may have wide-ranging effects on health, fitness and diseases of the elderly. To a large extent, denaturation of old proteins appears to result from the intrinsic instability of certain amino acids; however, these reactions are incompletely understood. One method to investigate these reactions involves exposing peptides to elevated temperatures at physiological pH. Incubation of PFHSPSY, which corresponds to a region of human αB-crystallin that is susceptible to age-related modification, resulted in the appearance of a major product. NMR spectroscopy confirmed that this novel peptide formed via racemization of the N-terminal Pro. This phenomenon was not confined to Pro, because peptides with N-terminal Ser and Ala residues also underwent racemization. As N-terminal racemization occurred at 37 degrees celsius, a long-lived protein was examined. LC-MS/MS analysis revealed that approximately one third of aquaporin 0 polypeptides in the centre of aged human lenses were racemized at the N-terminal methionine.

The main focus of this thesis lies on transition metal-catalyzed hydrogen transfer reactions. In the first part of the thesis, the mechanism for racemization of sec-alcohols with a ruthenium complex, Ru(CO)2Cl(η5-C5Ph5) was studied. The reaction between 5-hexen-2-ol and Ru(CO)2(Ot-Bu)(η5-C5Ph5) was studied with the aim to elucidate the origin of the slow racemization observed for this sec-alcohol. Two diastereomers of an alkoxycarbonyl complex, which has the double bond coordinated to ruthenium, were characterized by NMR and in situ FT-IR spectroscopy. The observed inhibition of the rate of racemization for substrates with double bonds provided further confirmation of the importance of a free coordination site on ruthenium for β-hydride elimination. Furthermore, we observed that CO exchange, monitored by 13C NMR using 13CO, occurs with both the precatalyst, Ru(CO)2Cl(η5-C5Ph5), and the active catalytic intermediate, Ru(CO)2(Ot-Bu)(η5-C5Ph5). It was also found that added CO has an inhibitory effect on the rate of racemization of (S)-1-phenylethanol. Both these observations provide strong support for reversible CO dissociation as a key step in the racemization mechanism. In the second part of this thesis, Ru(CO)2Cl(η5-C5Ph5) was combined with an enzymatic resolution catalyzed by a lipase, leading to several efficient dynamic kinetic resolutions (DKR). DKR of exocyclic allylic alcohols afforded the corresponding acetates in high yields and with excellent enantiomeric excess (ee). The products were utilized as synthetic precursors for α-substituted ketones and lactones. DKR of a wide range of homoallylic alcohols afforded the products in good to high yields and with high ee. The homoallylic acetates were transformed into 5,6-dihydropyran-2-ones in a short reaction sequence. Furthermore, DKR of a wide range of aromatic β-chloroalcohols afforded the products in high yields and with excellent ee. The β-chloro acetates were further transformed into chiral epoxides., At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 5: Mansucript.

Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipaseB and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transformed into homoallylic acrylates after hydrolysis of the ester function and subsequent DMAP-catalyzed esterification with acryloyl chloride. After ring-closing metathesis 5,6-dihydropyran-2-ones were obtained in good yields. Selective hydrogenation of the carboncarbon double bond afforded the corresponding -lactones without loss of chiral information., AuthorCount:5

Racemization is one of the most abundant modifications in long-lived proteins. It has been proposed that the accumulation of such modifications over time could lead to changes in tissues and ultimately human age-related diseases. Serine is one of the main amino acids involved in racemization; however, the site of D-Ser in any aged protein has yet to be reported. In this study, racemization of two residues, Ser 59 and Ser 62, has been demonstrated in an unstructured region of the small heat shock protein, aA-crystallin. aA-crystallin is also the most abundant structural protein in the human lens. D-Ser increased linearly with age in normal lenses, until it accounted for approximately 35% of the Ser at both sites by the age of 75 years. In agreement with a possible role in human age-related disease, levels were significantly higher in cataract lenses. It is likely that such prevalent age-related changes contribute to the denaturation of a-crystallin, and therefore its ability to act as a chaperone. Racemization of amino acids, such as serine, in flexible regions of long-lived proteins, could be associated with the development of human age-related conditions such as cataract.

An enantioselective synthesis of almorexant, a potent antagonist of human orexin receptors, is presented. The chiral tetrahydroisoquinoline core structure was prepared via iridium-catalysed asymmetric intramolecular allylic amidation. Further key catalytic steps of the synthesis include an oxidative Heck reaction at room temperature and a hydrazine-mediated organocatalysed reduction.

Ibuprofen (isobutyl-propanoic-phenolic acid) is a chiral drug which essentially well-known for its analgesic, antipyretic and anti-inflammatory effects. In the present work, an enzymatic membrane reactor (EMR) has been developed for the production of optically pure (S)-ibuprofen acid. The EMR is equipped with a multi-tubular fixed bed racemization unit to enhance the enzymatic deracemization of (R,S)-ibuprofen ester. Several process parameters such as enzyme loading, racemization catalyst loading, reaction temperature, buffer pH as well as the flow rate were investigated. These experimental results were then compared with the proposed process model. It was found that the experimental data were in good agreement with the theoretical results. The optimum condition of the lipase-catalyzed dynamic kinetic resolution (DKR) using the EMR could give 96-98% conversion with 97-99% of product enantiomeric excess (eep).

In forensic medicine, the personal identification of cadavers is one of the most important tasks. One method of estimating age at death relies on the high correlation between racemization rates in teeth and actual age, and this method has been applied successfully in forensic odontology for several years. In this study, we attempt to facilitate the analysis of racemized amino acids and examine the determination of age at death on the basis of the extent of aspartic acid (Asp) racemization in skull bones. The specimens were obtained from 61 human skull bones (19 females and 42 males) that underwent judicial autopsy from October 2010 to May 2012. The amount of D-Asp and L-Asp, total protein, osteocalcin, and collagen I in the skull bones was measured. Logistic regression analysis was performed for age, sex, and each measured protein. The amount of D-Asp in the female skull bones was significantly different from that in the male skull bones (p = 0.021), whereas the amount of L-Asp was similar. Thus, our study indicates that the amount of D-Asp in skull bones is different between the sexes.

The preparation of optically pure alcohols, axially chiral allenes, and amine derivatives by using enzymes and transition-metal catalysts through dynamic kinetic resolution (DKR) is reviewed. After a general introduction into enzymatic kinetic resolutions and racemizations catalyzed by transition-metal complexes, selected examples of DKRs are presented, from early work to more recent outstanding contributions, and also applications of this approach., AuthorCount:2

PURPOSE. Long-lived proteins are widespread in man, yet little is known about the processes that affect their function over time, or their role in age-related diseases. METHODS. Racemization of two proteins from normal and cataract human lenses were compared with age using tryptic digestion and LC/mass spectrometry. Asp 151 in alpha A crystallin and Asn 76 in gamma S crystallin were studied. RESULTS. Age-dependent profiles for the two proteins from normal lenses were different. In neither protein did the modifications increase linearly with age. For alpha A crystallin, racemization occurred most rapidly during the first 15 years of life, with approximately half of L-Asp 151 converted to D-isoAsp, L-isoAsp, and D-Asp in a ratio of 3:1:0.5. Values then changed little. By contrast, racemization of Asn 76 in gamma S crystallin was slow until age 15, with isoAsp accounting for only 5%. Values remained relatively constant until age 40 when a linear increase (1%/year) took place. When cataract lenses were compared with age-matched normal lenses, there were marked differences in the time courses of the two crystallins. For alpha A crystallin, there was no significant difference in Asp 151 racemization between cataract and normal lenses. By contrast, in gamma S crystallin the degree of conversion of Asn 76 to isoAsp in cataract lenses was approximately double that of normals at every age. CONCLUSIONS. Modification of Asn and Asp over time may contribute to denaturation of proteins in the human lens. An accelerated rate of deamidation/racemization at selected sites in proteins, such as gamma S crystallin, may contribute to cataract formation. (Invest Ophthalmol Vis Sci. 2012;53:3554-3561) DOI:10.1167/iovs.11-9085

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution. The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol. In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield. A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry. In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation., At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Epub ahead of print.

In this paper, we have shown that the [RuCl2(p-cymene)] 2 complex associated with simple hemisalen ligands is able to racemize (S)-1-phenylethanol. The influence on the racemization process of the ligand's structure as well as the nature of a co-catalyst have been evaluated and optimized. This [RuCl2(p-cymene)]2/Ligand/TEMPO racemization system was then associated with the Candida Antarctica B lipase in order to carry out dynamic kinetic resolution experiments on rac-phenylethanol. This led us to identify the best conditions for effective DKR, which was then applied to various secondary benzylic and aliphatic alcohols. It was thus possible to obtain (R)-1-cyclohexylethyl acetate from rac-1-cyclohexylethanol in quantitative conversion and with high enantioselectivity (98%). © 2011 Elsevier Ltd. All rights reserved.

The restricted environment of the Black Sea is particularly sensitive to climatic and oceanographic fluctuations, owing to its connection with the Mediterranean Sea via the narrow Bosphorus Strait. The exact mechanism and timing of the most recent connection between these water bodies is controversial with debate on the post-glacial history of the Black Sea being dependent on radiocarbon dating for numerical ages. Here we present new 23 accelerator mass spectrometer (AMS) radiocarbon ages on peat and bivalve molluscs, supported by the first amino acid racemization (AAR) dating of bivalve molluscs (n ¼ 66) in the Black Sea. These data indicate infilling of the Black Sea during the early Holocene from an initial depth 107m below sea-level, and 72 m below that of the Bosphorus Sill. These data combined with a review of previous radiocarbon ages has enabled a unique perspective on the post-glacial Black Sea. A sea-level curve based on conventional and AMS radiocarbon ages on peat and AMS-based ages on Dreissena sp. shells indicate the water-level in the earlier lake phase continued, until the early Holocene, to be lower than the Bosphorus Sill after the Younger Dryas ended. However, the absence of AMS-dated mollusc ages from the shelves of this basin older than the Younger Dryas is suggestive of sub-aerial exposure of the shelves, and comparatively lower water-levels when the Younger Dryas began. Thus post-glacial outflow from the Black Sea occurred through a lowered or open Bosphorus seaway. Basinwide radiocarbon ages on peat indicate a prompt increase in water-level from that of the pre-existing and unconnected palaeo-lake during the earliest Holocene (9600e9200 cal a BP). Mass colonisation of the Black Sea by Mediterranean taxa did not occur until salinity had risen sufficiently, a process which took 1000 a or more from the initial transgressive event. This gradual change in salinity contrasts with the prompt transgression which would have taken w400 a to occur.

Dynamic kinetic resolution (DKR) has been applied to primary amines utilizing a ruthenium catalyst and an (R)-selective lipase to provide the corresponding amides in up to 95% isolated yield and up to >99% ee. Further investigations of the chemoenzymatic DKR of amines show that it is general and can be applied to a wide range of amines. The protocol was found to be applicable with both isopropyl acetate and dibenzyl carbonate as acyl donors. In the latter case, release of the free amine from the carbamate products was carried out under very mild conditions. A new route to prepare norsertraline, an antidepressant, utilizing DKR as one of the key steps has also been developed. Further investigations of the DKR of 1-phenylethylamine led to the development of a protocol that could be used on gram scale. Several parameters were studied including catalyst loading, acyl donor used, and concentration of the reaction. The Ru-catalyst loading was decreased from 4 mol% to 1.25 mol% and the enzyme catalyst loading was decreased from 40 mg/mmol substrate to 10 mg/mmol substrate. The racemization of pipecoloxylidide, an intermediate in the synthesis of commonly used anesthetics, was carried out. This racemization method was developed for its potential use in an integrated process that combines enantiomer separation techniques and racemization of the undesired enantiomer. The integration of racemization of the undesired enantiomer would increase the overall yield of the desired enantiomer and thus make the procedure highly efficient. DKR has also been applied to allylic alcohols utilizing a ruthenium catalyst and either an (R)-selective lipase or an (S)-selective protease to provide the corresponding allylic esters in high yield and high ee. A copper-catalyzed allylic substitution was then applied to provide the corresponding alkenes with inversion of stereochemistry. Subsequent C-C double bond cleavage afforded pharmaceutically important a-methyl substituted carboxylic acids i, At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript. Paper 7: Manuscript.

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-phenylethylamine (1). Several reaction parameters have been investigated to modify the method for application on multigram scale. A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst loadings could be used to obtain (R)-2-methoxy-N-(1-phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.

Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1-phenylethylamine ( 1 ). Several reaction parameters have been investigated to modify the method for application on multigram scale. A comparison of isopropyl acetate and alkyl methoxyacetates as acyl donors was carried out. It was found that lower catalyst loadings could be used to obtain ( R )-2-methoxy- N -(1-phenylethyl)acetamide ( 3 ) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl donor.

Dimethylacrylamide can be hydroformylated with very high chemo- and regioselectivity. Asymmetric hydroformylation of this substrate is possible, provided steps are taken to minimise racemisation of the aldehyde products, and this work demonstrates the effect of various conditions and variables on racemisation. Using the Landis diazaphospholane ligands up to 68% ee can be realised under very mild conditions. Other dialkylacrylamides were also hydroformylated under mild conditions giving similar or better enantioselectivities, including the Weinreb amide of acrylic acid (71% ee), and the asymmetric hydroformylation of diethylacrylamide producing the chiral aldehyde with up to 82% ee.

Mechanistic studies on three different ruthenium-based catalysts have been performed. The catalysts have in common that they have been employed in hydrogen transfer reactions involving alcohols and ketones, amines and imines or both. Bäckvall’s catalyst, η5-(Ph5C5)Ru(CO)2Cl, finds its application as racemization catalyst in dynamic kinetic resolution, where racemic alcohols are converted to enantiopure acetates in high yields. The mechanism of the racemization has been investigated and both alkoxide and alkoxyacyl intermediates have been characterized by NMR spectroscopy and in situ FT-IR measurements. The presence of acyl intermediates supports a mechanism via CO assistance. Substantial support for coordination of the substrate during the racemization cycle is provided, including exchange studies with both external and internal potential ketone traps. We also detected an unexpected alkoxycarbonyl complex from 5-hydroxy-1-hexene, which has the double bond coordinated to ruthenium. Shvo’s catalyst, [Ru2(CO)4(μ-H)(C4Ph4COHOCC4Ph4)] is a powerful catalyst for transfer hydrogenation as well as for dynamic kinetic resolution. The mechanism of this catalyst is still under debate, even though a great number of studies have been published during the past decade. In the present work, the mechanism of the reaction with imines has been investigated. Exchange studies with both an external and an internal amine as potential traps have been performed and the results can be explained by a stepwise inner-sphere mechanism. However, if there is e.g. a solvent cage effect, the results can also be explained by an outer-sphere mechanism. We have found that there is no cage effect in the reduction of a ketone containing a potential internal amine trap. If the mechanism is outer-sphere, an explanation as to why the solvent cage effect is much stronger in the case of imines than ketones is needed. Noyori’s catalyst, [p-(Me2CH)C6H4Me]RuH(NH2CHPhCHPhNSO2C6H4-p-CH3), has successfully been use

It has been found that the simple grinding of crystals in a solution causes the conversion of the chiral structure of crystals and, in the case of organic molecules, the resultant conversion of molecular chirality. In order to clarify the mechanism of the chirality conversion, we study the change in the size distribution of chiral clusters in a Becker-D¨oring type model, in which chiral dimer reaction and grinding are implemented. In the absence of grinding, Ostwald ripening may cause chirality conversion if the initial size distribution is appropriate. With grinding crystals, the crystallization of chiral clusters causes an exponential amplification of the initial chiral imbalance resulting in a homochiral state. During chirality conversion, the total size distribution does not change.