Organocatalytic α-functionalization of carbonyl compounds: chemo-, regio- and stereoselectivity.

606 p.The aim of this thesis has been the development of new synthetic procedures for the asymmetric formation of carbonyl componenets bearing a stereocenter at C¿. Covered topics include (i) the particular case of the use of ¿-unsaturated aldehydes as donors in the aldol reaction with propargylic aldehydes and the subsequent Pauson-Khand reaction of the resulting 1,¿-enynes (Scheme 1), (i) the behaviour of alkynyl ketones (ynones) as acceptors in such aldol reactions. Main results on these topics have been published in Chem. Eur. J. 2014, 20, 15543¿15554.Scheme 1A second chapter deals with the use of ¿¿-oxy enones as acrylate equivalents in Brønsted base-catalyzed enantioselective conjugate addition of oxazolones for the stereoselective generation of new tetrasubstituted carbon stereocenters (results published in JACS 2014, 136, 17869¿17881; Scheme 2). Three situations have been addressed: a) addition to the unsubstituted enone (acrylate equivalent), b) addition to ß-substituted enones, and c) addition to ¿-substituted enones (metacrylate equivalent). Scheme 2As a complement, the behaviour of the homologue ¿¿-hydroxy dienones have been studied with the aim to ascertain to which extent both the stereoselectivity, and the regioselectivity of the process (1,4- vs 1,6-addition) could be controlled. For this purpose, new chiral guanidine and phosphanimines were synthetized and tested(Scheme 3). Scheme 3Chapter 3 deals with the Brønsted base-catalyzed addition of ¿-substituted cycloalkanones to suitable acceptors to produce the corresponding ¿,¿-disubstituted (quaternary) ketones in good yield and overall high selectivity. The method was demonstrated to be robust, admitting cycloalkanones with different ring-sizes (n = 0, 1, 2, 3; Scheme 4a). In the same context, the completely regio- and stereoselective functionalization of ¿-substituted ß-tetralones through the bifunctional Brønsted base-catalyzed Michael reaction with nitroalkenes (ACIE 2017, 56, 2059¿2063) and addition to azodicarboxylates have been achieved (Scheme 4b). Scheme 4The last part of this Thesis was carried out in the laboratory of Prof. Jonathan Clayden in the School of Chemistry of the University of Bristol. Studies there were focused on routes to the synthesis of the aromatic amino acid precursor arogenate from the natural amino acid L-tyrosine (Scheme 5). Scheme

Organocatalytic α-functionalization of carbonyl compounds: chemo-, regio- and stereoselectivity.

606 p.The aim of this thesis has been the development of new synthetic procedures for the asymmetric formation of carbonyl componenets bearing a stereocenter at C¿. Covered topics include (i) the particular case of the use of ¿-unsaturated aldehydes as donors in the aldol reaction with propargylic aldehydes and the subsequent Pauson-Khand reaction of the resulting 1,¿-enynes (Scheme 1), (i) the behaviour of alkynyl ketones (ynones) as acceptors in such aldol reactions. Main results on these topics have been published in Chem. Eur. J. 2014, 20, 15543¿15554.Scheme 1A second chapter deals with the use of ¿¿-oxy enones as acrylate equivalents in Brønsted base-catalyzed enantioselective conjugate addition of oxazolones for the stereoselective generation of new tetrasubstituted carbon stereocenters (results published in JACS 2014, 136, 17869¿17881; Scheme 2). Three situations have been addressed: a) addition to the unsubstituted enone (acrylate equivalent), b) addition to ß-substituted enones, and c) addition to ¿-substituted enones (metacrylate equivalent). Scheme 2As a complement, the behaviour of the homologue ¿¿-hydroxy dienones have been studied with the aim to ascertain to which extent both the stereoselectivity, and the regioselectivity of the process (1,4- vs 1,6-addition) could be controlled. For this purpose, new chiral guanidine and phosphanimines were synthetized and tested(Scheme 3). Scheme 3Chapter 3 deals with the Brønsted base-catalyzed addition of ¿-substituted cycloalkanones to suitable acceptors to produce the corresponding ¿,¿-disubstituted (quaternary) ketones in good yield and overall high selectivity. The method was demonstrated to be robust, admitting cycloalkanones with different ring-sizes (n = 0, 1, 2, 3; Scheme 4a). In the same context, the completely regio- and stereoselective functionalization of ¿-substituted ß-tetralones through the bifunctional Brønsted base-catalyzed Michael reaction with nitroalkenes (ACIE 2017, 56, 2059¿2063) and addition to azodicarboxylates have been achieved (Scheme 4b). Scheme 4The last part of this Thesis was carried out in the laboratory of Prof. Jonathan Clayden in the School of Chemistry of the University of Bristol. Studies there were focused on routes to the synthesis of the aromatic amino acid precursor arogenate from the natural amino acid L-tyrosine (Scheme 5). Scheme

Palladium-Catalyzed Site-Selective C(sp2)−H Acetoxylation of Tyrosine-Containing Peptides

A Pd-catalyzed C(sp2)−H acetoxylation of Tyr-containing peptides is described. The method relies on the use of a removable 2-pyridyloxy group as directing group and is distinguished by its reliable scalability and easily tuned regioselectivity to perform mono- and diacetoxylation reactions. Remarkably, the assembly of L–DOPA peptidomimetics is beyond reach upon cleavage of the directing group.We are grateful to Ministerio de Ciencia e Innovación (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and Basque Government (IT-1741-22) for financial support. We thank for the technical and human support provided by Central Service of Analysis-SGIker of UPV/EHU and European funding (ERDF and ESF)

Late-Stage C-H Acylation of Tyrosine-Containing Oligopeptides with Alcohols

The selective tagging of amino acids within a peptide framework while using atom-economical C-H counterparts poses an unmet challenge within peptide chemistry. Herein, we report a novel Pd-catalyzed late-stage C-H acylation of a collection of Tyr-containing peptides with alcohols. This water-compatible labeling technique is distinguished by its reliable scalability and features the use of ethanol as a renewable feedstock for the assembly of a variety of peptidomimetics.The authors are grateful to the Ministerio de Ciencia e Innovacion (RTI2018-093721-B-I00, MCI/AEI/FEDER, UE) and the Basque Government (IT1033-16) for financial support. The authors thank the technical and human support provided by the Central Service of Analysis-SGIker of UPV/EHU and European funding (ERDF and ESF). In~aki Urruzuno thanks UPV/EHU for the postdoctoral research grant (EspDoc2020

Synthesis of β-Hydroxy α-Amino Acids Through Brønsted Base-Catalyzed syn-Selective Direct Aldol Reaction of Schiff Bases of Glycine o-Nitroanilide

Here we report the highly enantio- and syn-selective synthesis of β-hydroxy α-amino acids from glycine imine derivatives under Brønsted base (BB) catalysis. The key of this approach is the use of benzophenone-derived imine of glycine o-nitroanilide as a pronucleophile, where the o-nitroanilide framework provides an efficient hydrogen-bonding platform that accounts for nucleophile reactivity and diastereoselectivity.Support has been provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant IT1236-19), and Ministerio de Ciencia e Innovación (MICINN, CTQ2016-78487-C2), Spain. A.V. thanks Basque Government, and I.U. and S.d.P. thank UPV/EHU. We also thank SGIker (UPV/EHU) for providing NMR, HRMS, X-ray, and computational resources

Organocatalytic &-functionalization of carbonyl compounds: chemo-, regio- and stereoselectivity.

606 p.The aim of this thesis has been the development of new synthetic procedures for the asymmetric formation of carbonyl componenets bearing a stereocenter at C¿. Covered topics include (i) the particular case of the use of ¿-unsaturated aldehydes as donors in the aldol reaction with propargylic aldehydes and the subsequent Pauson-Khand reaction of the resulting 1,¿-enynes (Scheme 1), (i) the behaviour of alkynyl ketones (ynones) as acceptors in such aldol reactions. Main results on these topics have been published in Chem. Eur. J. 2014, 20, 15543¿15554.Scheme 1A second chapter deals with the use of ¿¿-oxy enones as acrylate equivalents in Brønsted base-catalyzed enantioselective conjugate addition of oxazolones for the stereoselective generation of new tetrasubstituted carbon stereocenters (results published in JACS 2014, 136, 17869¿17881; Scheme 2). Three situations have been addressed: a) addition to the unsubstituted enone (acrylate equivalent), b) addition to ß-substituted enones, and c) addition to ¿-substituted enones (metacrylate equivalent). Scheme 2As a complement, the behaviour of the homologue ¿¿-hydroxy dienones have been studied with the aim to ascertain to which extent both the stereoselectivity, and the regioselectivity of the process (1,4- vs 1,6-addition) could be controlled. For this purpose, new chiral guanidine and phosphanimines were synthetized and tested(Scheme 3). Scheme 3Chapter 3 deals with the Brønsted base-catalyzed addition of ¿-substituted cycloalkanones to suitable acceptors to produce the corresponding ¿,¿-disubstituted (quaternary) ketones in good yield and overall high selectivity. The method was demonstrated to be robust, admitting cycloalkanones with different ring-sizes (n = 0, 1, 2, 3; Scheme 4a). In the same context, the completely regio- and stereoselective functionalization of ¿-substituted ß-tetralones through the bifunctional Brønsted base-catalyzed Michael reaction with nitroalkenes (ACIE 2017, 56, 2059¿2063) and addition to azodicarboxylates have been achieved (Scheme 4b). Scheme 4The last part of this Thesis was carried out in the laboratory of Prof. Jonathan Clayden in the School of Chemistry of the University of Bristol. Studies there were focused on routes to the synthesis of the aromatic amino acid precursor arogenate from the natural amino acid L-tyrosine (Scheme 5). Scheme

alpha-Branched Ketone Dienolates: Base-Catalyzed Generation and Regio- and Enantioselective Addition Reactions

In this study, the unique capacity of bifunctional Brønsted bases to generate α-branched ketone dienolates and control both site- and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented. We demonstrate that by using selected chiral tertiary amine/squaramide catalysts, the reactions of β,γ-unsaturated cycloalkanones proceed through the dienolate Cα almost exclusively and provide all-carbon quaternary cyclic ketone adducts in good yields with very high enantioselectivities. A minor amount (<5 %) of γ-addition is observed when nitroolefins are used as electrophiles. The parent acyclic ketone dienolates proved to be less reactive under these conditions, and thus still constitute a challenging class of substrates. Quantum chemical calculations correctly predict these differences in reactivity and explain the observed site-specificity and enantioselectivity.Financial support was provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22, GIU18/159) and the Ministerio de Economía y Competitividad (MEC, Grant CTQ2016-78487-C2), Spain. O.M. thanks the MEC and I.U. thanks the Basque Government for fellowships. G.Z. and E.G.-B thank the European Funding Horizon 2020-MSCA (ITN-EJD CATMEC 14/06-721223)

Enantioselective Construction of Tetrasubstituted Stereogenic Carbons through Brønsted Base Catalyzed Michael Reactions: α´-Hydroxy Enones as Key Enoate Equivalent

Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C–C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Brønsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.Financial support was provided by the University of the Basque Country UPV/EHU (UFI 11/22), Basque Government (Grant No IT-628-13 and Saiotek 2014), and Ministerio de Economía y Competitividad (Grant CTQ2013-47925-C2), Spain. E.B. and I.O. thank Ministerio de Educación y Ciencia, and I.U. thanks Gobierno Vasco for Fellowships. B.F. thanks the European Commission (FP7-3163792012-ITN). We also thank SGIker (UPV/EHU) for providing NMR, HRMS, X-ray, and computational resources