Synthesis of Cysteine Analogues in Enantiopure Form

La cisteína es un α-aminoácido proteinogénico, no esencial, presente en el organismo. La importancia de este aminoácido reside en sus propiedades antioxidantes y su presencia en la estructura de moléculas como el glutatión y lantionina, entre otros muchos péptidos de interés biológico e industrial. El glutatión es un tripéptido, cuya función principal es reducir los radicales peróxido que se generan en el organismo, por ello es considerado un potente antioxidante natural, mientras que la lantionina es un bis-aminoácido componente de los lantiobióticos, una familia de péptidos antimicrobianos.Una estrategia habitual para mejorar las propiedades de los péptidos es la introducción de aminoácidos modificados que confieran rigidez a su estructura secundaria. En este sentido, las modificaciones que se pueden realizar en la cadena lateral de la cisteína se pueden englobar en 7 grandes grupos. Esta tesis se ha centrado en la síntesis de derivados cíclicos de L-cisteína de forma enantioméricamente pura que incorporen ciclos de diferente tamaño y naturaleza química entre las posiciones α y β. Dichas cisteínas modificadas podrían ser introducidas en moléculas bioactivas, con el objetivo final de mejorar sus propiedades biológicas.Por ello, se llevó a cabo el diseño y optimización de una metodología sintética que permitiese acceder de una manera sencilla y en pocos pasos sintéticos a la obtención de dehidrocisteinas homoquirales y enantioméricamente puras que pudieran ser, a priori, sustratos versátiles sobre los que llevar a cabo reacciones de cicloadición. En este sentido, se consiguió optimizar una ruta sintética para la obtención de tiazolinas homoquirales, enantiopuras y en escala de multigramos, con diferentes estados de oxidación en su átomo de azufre, como equivalentes sintéticos de dehidrocisteína. Dichas tiazolinas fueron empleadas como sustratos de partida en reacciones de cicloadición 1,3-dipolar con diazoalcanos,4 nitronas e iluros de azometino y en reacciones de cicloadición Diels-Alder con dienos con el fin de obtener análogos de cisteínas que incorporasen distintos ciclos (ciclopropilos, isoxazolidinas, prolinas y ciclohexilos) entre las posiciones α y β. La elevada reactividad de los sustratos de partida con el átomo de azufre oxidado se debe al efecto electrón atractor del grupo sulfinilo y sulfonilo. Por otra parte, la excelente diastereoselectividad observada es promovida por el grupo terc-butilo que bloquea la cara Re,Si del doble enlace durante las reacciones de cicloadición. Por tanto, en esta ruta sintética cobra gran importancia el fenómeno de autoreproducción de la quiralidad de Seebach.Los cicloaductos obtenidos mediante reacción de cicloadición de la tiazolina que incorpora un grupo sulfinilo y distintos dienos, tras la secuencia sintética de hidrogenación del doble enlace, reducción del grupo sulfinilo a tioéter, desprotección de los grupos protectores de las funciones carboxilo y amino y apertura del anillo de tiazolina permitieron acceder a cisteínas modificadas en su forma oxídada, cistina (puente disulfuro), que incorporan anillos de 6 miembros entre las posiciones α y β.Por último, la cistína que incorpora un ciclohexano en su cadena lateral fue empleada para la preparación de una lantionina modificada enantioméricamente pura, y para la obtención un dipéptido precursor de glutationes modificados.Por lo tanto, en la presenta tesis se ha desarrollado una metodología competitiva para la obtención de derivados cíclicos homoquirales de L-cisteína empleando como sustratos de partida tiazolinas enantioméricamente puras y se ha desarrollado así mismo un procedimiento sintético para obtener péptidos y lantioninas a partir de las cisteínas modificadas obtenidas.<br /

Synthesis of cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives via thio-Michael addition

The reactivity of 2,3-dehydroproline and 2,3-dehydropipecolic acid methyl ester derivatives with S-nucleophiles in the thio-Michael addition reaction has been explored. The addition of triphenylmethanethiol and subsequent trityl cleavage led to the corresponding cis- and trans-(±)-3-mercaptoproline and pipecolic acid derivatives in good yields.The authors thank the Ministerio de Economía y Competitividad (project number CTQ2013-40855-R) and DGA-FSE (research group E40) for financial support.Peer reviewe

The Crucial Role of S

The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover. Enantiopure proline-cysteine analogs were obtained by 1,3-dipolar cycloaddition between homochiral thiazolines and azomethine ylides. The reactivity and regioselectivity are controlled by the oxidation state of the thiazoline sulfur atom. Sulfoxide and sulfone groups led to 2,3 addition whereas reactions starting from the thioether group resulted in 2,4 addition. Diastereofacial selectivity is controlled by the bulky tert-butyl group at the thiazoline ring.The authors thankfully acknowledge MINECO (Ministerio de Economía y Competitividad, grant CTQ2013-40855-R) and Gobierno de Aragon-FEDER (Grupo Aminoácidos y Péptidos E19_20R; FEDER 2014–2020‘Construyendo Europa desde Aragón’), for the financial support provided to this work. J. G.-V. thanks the Gobierno de Aragón–FSE for a pre-doctoral Grant.Peer reviewe

The crucial role of s-oxidation state on the selectivity and reaction rate of the 1,3-dipolar cycloaddition of azomethine ylides and homochiral thiazolines

The novel enantiopure synthesis of protected proline-cysteine analogs by means of 1,3-dipolar cycloaddition of homochiral thiazolines and azomethine ylides is described. The important role of the oxidation state of the sulfur atom of the dipolarophile in such reaction is demonstrated affecting strongly the regioselectivity and reactivity of the 1,3-dipolar cycloaddition. Mono-oxidized sulfur atom (sulfoxide group) and di-oxidized (sulfone group) led to 2,3 regio-addition whereas reactions starting from non-oxidized sulfur atom resulted in the 2,4 addition. Besides, sulfur oxidized thiazolines reacted smoothly upon heating in an organic solvent media but the non-oxidized sulfur thiazoline required metal catalysis. Diastereofacial selectivity was observed to be independent of the oxidation state of the sulfur atom but controlled by the bulky tert-butyl group at the thiazoline ring. The highly substituted and functionalized enantiopure pyrrolidine-thiazolidine bicyclic compounds are considered as novel (homo)cysteine-proline analogs with important properties to discover. Enantiopure proline-cysteine analogs were obtained by 1,3-dipolar cycloaddition between homochiral thiazolines and azomethine ylides. The reactivity and regioselectivity are controlled by the oxidation state of the thiazoline sulfur atom. Sulfoxide and sulfone groups led to 2,3 addition whereas reactions starting from the thioether group resulted in 2,4 addition. Diastereofacial selectivity is controlled by the bulky tert-butyl group at the thiazoline ring.The authors thankfully acknowledge MINECO (Ministerio de Economía y Competitividad, grant CTQ2013-40855-R) and Gobierno de Aragon-FEDER (Grupo Aminoácidos y Péptidos E19_20R; FEDER 2014–2020‘Construyendo Europa desde Aragón’), for the financial support provided to this work. J. G.-V. thanks the Gobierno de Aragón–FSE for a pre-doctoral Grant.Peer reviewe

Stereoselective synthesis of modified cysteines

This review provides an overview of the literature concerning the stereoselective synthesis of a large group of modified cysteines. The different synthetic approaches are classified according to the bonds formed to build the cysteine backbone skeleton.The authors thank the Ministerio de Economía y Competitividad (project number CTQ2013-40855-R) and DGA-FSE (research group E40) for financial support. Jaime Gracia-Vitoria thanks the Gobierno de Aragón for the concession of a predoctoral fellowship.Peer Reviewe

Correction to "Self-regeneration of chirality with L‑cysteine through 1,3-dipolar cycloadditions between diazoalkanes and enantiomerically pure thiazolines: Experimental and computational studies"

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Synthesis of enantiopure constrained α,β-cycloaliphatic cystines via Diels−Alder reaction with homochiral thiazolines

The behavior of homochiral 2,3-dihydrothiazoles, easily available from l-cysteine in Diels-Alder reaction with different dienes, "en route" to sterically constrained modified cystines, has been studied. The oxidation level of the sulfur atom of the heterocyclic ring was crucial for the course of the reaction. Whereas 2,3-dihydrothiazoles did not lead to Diels-Alder adducts, 1-oxide and 1,1-dioxide derivatives afforded the exo adduct enantiopurely in high yields and diastereoselectivities. Further elaboration of the resulting adducts provided conformationally restricted quaternary cystines. DFT calculations correctly predict both the reactivity and stereoselectivity observed experimentally.This work was supported by the Ministerio de Economía y Competitividad (grants CTQ2013-40855-R to C.C. and CTQ2016-76155-R to P.M.) and the Gobierno de Aragón − FSE (research groups E-10 and E40). J.G.-V. thanks the Gobierno de Aragoń −FSE for the predoctoral Grant.Peer reviewe

Self-regeneration of chirality with L‑cysteine through 1,3-dipolar cycloadditions between diazoalkanes and enantiomerically pure thiazolines: Experimental and computational studies

Addition/Correction: This article has been corrected.Enantiopure 2-thia-4-azabicyclo[3.1.0]hexanes, which can be considered constrained cysteines, have been obtained from l-cysteine by application of the “self-regeneration of chirality” concept. The key intermediates are homochiral thiazolines that can be prepared in multigram scale and react smoothly with a series of diazoalkanes providing Δ1-pyrazolines except for phenyldiazomethane that yield the isomeric Δ2-pyrazolines. Nitrogen extrusion in Δ1-pyrazolines and further reduction of the sulfinyl group yielded the target compounds in good overall yield. Computational studies of the cycloaddition reaction were used for determining the polarity of the process and explaining the observed stereoselectivity. Additional topological studies were employed for determining the influence of noncovalent interactions in the stereochemical course of the reaction, which showed to be a highly asynchronous concerted process.This work was supported by the Ministerio de Economia y Competitividad (grants CTQ2013-40855-R to C.C. and CTQ2016-76155-R to P.M.) and the Gobierno de Aragon-FSE (research groups E-10 and E40). J.G.-V. thanks the Gobierno de Aragon-FSE for the predoctoral grant.Peer reviewe

Half-sandwich complexes of rhodium containing cysteine-derived ligands

The modified cysteine ligand, S-benzyl-α-methyl-l-cysteine (HL2), was prepared from l-cysteine hydrochloride methyl ester. The reaction of commercial S-benzyl-l-cysteine (HL1) or HL2 with the dimer, [{(η-CMe)RhCl}(μ-Cl)], gives rise to the cationic complexes, [(η-CMe)RhCl(HL)]Cl (HL = HL1 (1), HL2 (2)), in which the cysteine ligand exhibits a κN,S coordination mode. In a basic medium, HL1 or HL2 reacts with [{(η-CMe)RhCl}(μ-Cl)] to afford mixtures of two epimers at the metal centre of the neutral complexes, [(η-CMe)RhCl(κN,O-L)] (HL = HL1 (3), HL2 (4)), in which amino carboxylate adopts a κN,O mode of coordination along with variable amounts of the cationic compounds, [(η-CMe)Rh(κN,O,S-L)]Cl (HL = HL1 (6Cl), HL2 (7Cl)), which contain κN,O,S coordinated cysteine-derived ligands. However, in a basic medium, the N-Boc substituted cysteine S-benzyl-N-Boc-l-cysteine (HL3) only yields the κO,S coordinated derivative, [(η-CMe)RhCl(κO,S-L3)] (5), as a mixture of two diastereomers depending on the configuration of the metal centre. The bidentate chelate complexes 3-5 react with AgSbF to give the hexafluoroantimonates [(η-CMe)Rh(κN,O,S-L)][SbF] (HL = HL1 (6Sb), HL2 (7Sb), HL3 (8Sb)) with tridentate coordination. Compound 8Sb reacts with NaHCO to give the neutral complex [(η-CMe)Rh(κN,O,S-L3)] (9), which can also be prepared by reacting the dimer [{(η-CMe)RhCl}(μ-Cl)] with HL3 in the presence of two equivalents of NaHCO. The new compounds contain up to four stereogenic centres, namely, Rh, S, N, and C. The absolute configuration of the complexes has been established by spectroscopic and diffractometric investigations, including the crystal structure determination of [(η-CMe)RhCl(κO,S-L3)] (5), [(η-CMe)Rh(κN,O,S-L1)][SbF] (6Sb), [(η-CMe)Rh(κN,O,S-L2)][SbF] (7Sb) and [(η-CMe)Rh(κN,O,S-L3)] (9). Variable temperature H NMR studies reveal the existence of epimerization processes and theoretical calculations were used to discriminate their nature.We thank the Ministerio de Economía y Competitividad of Spain (CTQ2012-32095, CTQ2014-53033-P, CTQ2015-67366-P and CTQ2013-408555R) and Gobierno de Aragón and European Social Fund (Grupos Consolidados: Catalizadores Organometálicos Enantioselectivos, Aminoácidos y Péptidos and Inorganic Molecular Architecture) for financial support. This work was supported by the CONSOLIDER INGENIO 2010 program under the project “Factoría de Cristalización” (CSD2006-0015). M. C. acknowledges Diputación General de Aragón, CSIC and European Social Fund for a grant. R. R. and P. G. O. acknowledge CSIC, European Social Fund and Ministerio de Economía y Competitividad of Spain for a JAE and a Ramón y Cajal (RYC-2013-13800) grants and for a PTA contract, respectively.Peer Reviewe