N-Alkyl-α-amino acids in Nature and their biocatalytic preparation

PWS would like to acknowledge the European Union for his current funding: “This project has received funding from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement No 665919”.N-alkylated-α-amino acids are useful building blocks for the pharmaceutical and fine chemical industries. Enantioselective methods of N-alkylated-α-amino acid synthesis are therefore highly valuable and widely investigated. While there are a variety of chemical methods for their synthesis, they often employ stoichiometric quantities of hazardous reagents such as pyrophoric metal hydrides or genotoxic alkylating agents, whereas biocatalytic routes can provide a greener and cleaner alternative to existing methods. This review highlights the occurrence of the N-alkyl-α-amino acid motif and its role in nature, important applications towards human health and biocatalytic methods of preparation. Several enzyme classes that can be used to access chiral N-alkylated-α-amino acids and their substrate selectivities are detailed.PostprintPeer reviewe

Biocatalytic synthesis of chiral N-functionalized amino acids

N-functionalized amino acids are important building blocks for the preparation of diverse bioactive molecules including peptides. The development of sustainable manufacturing routes to chiral N-alkylated amino acids remains a significant challenge in the pharmaceutical and fine chemical industries. Herein we report the discovery of a structurally diverse panel of biocatalysts which catalyze the asymmetric synthesis of N-alkyl amino acids via the reductive coupling of ketones and amines. Reactions have been performed on a gram scale to yield optically pure N-alkyl functionalized products in high yields.PostprintPeer reviewe

Unsaturated 4,4′-bis-[5(4H)-oxazolones]: Synthesis and evaluation of their ortho-palladation through C–H bond activation

5 páginas, 2 figuras, 2 esquemas, 1 gráfico.Aromatic unsaturated 4,4′-bis-[5(4H)-oxazolones] have been prepared and their structural properties discussed. Metallation studies of these substrates towards palladium(II) acetate were also investigated.The financial support of this work by CNCSIS–UEFISCSU PNII– IDEI 570/2007, TD87/2007 (Romania), the Ministerio de Ciencia e Innovacion (Projects CTQ2008–01784, CTQ2010-17436 and CTQ2007–62245, Spain), and Gobierno de Aragon (PI071–09) is gratefully acknowledged.Peer reviewe

Reactivity of unsaturated 5(4H)-oxazolones with Hg(II) acetate: Synthesis of methyl N-benzoylamino-3-arylacrylates

An efficient and high-yield procedure to prepare methyl N-benzoylamino-3-arylacrylates from unsaturated (Z)-2-aryl-4-arylidene-5-(4H)- oxazolones and Hg(OAc)2 in methanol is described herein. The observed reactivity of mercury(II) acetate here is different than its usual metallating behavior and it cleaves the unsaturated oxazolone ring without change of stereochemistry.Funding from CNCSIS TD87=2007 (Romania), the Ministerio de Ciencia e Innovacion (Projects CTQ2008-01784 and CTQ2007-62245, Spain), and Gobierno de Aragon (PI071-09) is gratefully acknowledged. D. R. also thanks the World Federation of Scientists (WFS) for financial support.Peer Reviewe

Regioselective orthopalladation of (Z)-2-Aryl-4-arylidene-5(4H)-oxazolones: Scope, kinetico-mechanistic, and density functional theory studies of the C–H bond activation

Orthopalladated complexes derived from (Z)-2-aryl-4-arylidene-5(4H)-oxazolones have been prepared by reaction of the oxazolone with palladium acetate in acidic medium. The reaction is regioselective, only the ortho C–H bond of the arylidene ring being activated, producing a six-membered ring. The scope and reaction conditions of the orthopalladation are dependent on the acidity of the solvent. In CF3CO2H a large number of oxazolones can be metalated under mild conditions. As acidity decreases a lesser number of oxazolones can be efficiently palladated and harsher conditions must be used to achieve similar yields. The C–H bond activation in acidic medium agrees with an ambiphilic mechanism, as determined from kinetic measurements at variable temperature and pressure for different oxazolones substituted at the arylidene ring. The mechanism has been confirmed by density functional theory (DFT) calculations, where the formation of the six-membered ring is shown to be favored from both a kinetic and a thermodynamic perspective. In addition, the dependence of the reaction rate on the acidity of the medium has also been accounted for via a fine-tuning between the C–H agostic precoordination and the proton abstraction reaction in the overall process occurring on coordinatively saturated [Pd(κN-oxazolone)(RCO2H)3]2+.Funding by the Ministerio de Ciencia e Innovación (MICINN, Spain, Projects CTQ2008-01784, CTQ2009-14443-C02-02, CTQ2008-06670-C02-01 and CTQ2010-17436) and Gobierno de Aragón (Spain, Project PI071/09, and groups E97 and E40) is gratefully acknowledged.Peer Reviewe

Ortho-Palladation of (Z)-2-Aryl-4-Arylidene-5(4H)-Oxazolones. Structure and Functionalization

Ortho-palladated complexes of (Z)-2-aryl-4-arylidene-5(4H)-oxazolones have been prepared through oxidative addition. The reaction of (Z)-2-phenyl-4-(2-bromobenzylidene)-5(4H)-oxazolone (4) with Pd2(dba)3·CHCl3 gives the six-membered cyclopalladated dinuclear complex [Pd(μ-Br)(o-C6H4CH═CNC(O)OCPh)]2 (7). The reaction of 7 with PPh3 gives dinuclear 9, which incorporates one phosphine per Pd atom through cleavage of the Pd−N bond, and preserves the bromide bridging system. However, reaction with PPh2Me gives mononuclear 8, which incorporates two phosphines as a results of the cleavage of the μ-Br system and N displacement. In contrast, the reaction of 7 with pyridine gives complex 12 due to simple cleavage of the Br bridge, leaving the N-bonding intact. Therefore, three different reaction pathways have been characterized. The reactivity of the Pd−C bond in 7 has also been examined, and functionalized oxazolones can be obtained. The reaction of 7 with PhI(OAc)2 in acetic acid gives the starting oxazolone C6H4-2-Br-CH═CNC(O)OCPh (4), through the presumed oxidation of the Pd center and C−Br bond formation by reductive coupling. In contrast, the reaction of the acetate dimer 14 with PhI(OAc)2 in acetic acid gives C6H4-2-OAc-CH═CNC(O)OCPh (20) through C−O coupling. When treatment of 7 with PhI(OAc)2 is performed in MeOH or EtOH, the oxazolones C6H4-2-OR-CH═CNC(O)OCPh (R = Me (18), Et (19)) are obtained. The reaction of 7 with CO in alcohols ROH gives cleanly the oxazolones C6H4-2-CO2R-CH═CNC(O)OCPh (R = Me (21), iPr (22)) through CO migratory insertion into the Pd−C bond and further nucleophilic attack of the RO− fragment.Funding from CNCSIS 92/2004, PNII Idei 515, and Idei 570 (Romania), the Ministerio de Ciencia e Innovación (Projects CTQ2008-01784 and CTQ2007-62245, Spain), and Gobierno de Aragón (PI071-09) is gratefully acknowledged.Peer Reviewe

Induced Axial Chirality in Biocatalytic Asymmetric Ketone Reduction

Catalytic asymmetric reduction of prochiral ketones of type 4-alkylidene cyclohexanone with formation of the corresponding axially chiral <i>R</i>-configurated alcohols (up to 99% ee) was achieved using alcohol dehydrogenases, whereas chiral transition-metal catalysts fail. Reversal of enantioselectivity proved to be possible by directed evolution based on saturation mutagenesis (up to 98% ee (<i>S</i>)). Utilization of ketone with a vinyl bromide moiety allows respective <i>R</i>- and <i>S</i>-alcohols to be exploited as key compounds in Pd-catalyzed cascade reactions

Biocatalytic synthesis of chiral N-functionalized amino acids

N-functionalized amino acids are important building blocks for the preparation of diverse bioactive molecules including peptides. The development of sustainable manufacturing routes to chiral N-alkylated amino acids remains a significant challenge in the pharmaceutical and fine chemical industries. Herein we report the discovery of a structurally diverse panel of biocatalysts which catalyze the asymmetric synthesis of N-alkyl amino acids via the reductive coupling of ketones and amines. Reactions have been performed on a gram scale to yield optically pure N-alkyl functionalized products in high yields

Biocatalytic Route to Chiral Acyloins: P450-Catalyzed Regio- and Enantioselective α‑Hydroxylation of Ketones

P450-BM3 and mutants of this monooxygenase generated by directed evolution are excellent catalysts for the oxidative α-hydroxylation of ketones with formation of chiral acyloins with high regioselectivity (up to 99%) and enantioselectivity (up to 99% ee). This constitutes a new route to a class of chiral compounds that are useful intermediates in the synthesis of many kinds of biologically active compounds