Project description:We herein report a novel entry towards chiral α-SCF3-β2,2-amino acids by carrying out the ammonium salt-catalyzed α-trifluoromethylthiolation of isoxazolidin-5-ones. This approach allowed for high enantioselectivities and high yields and the obtained heterocycles proved to be versatile platforms to access other targets of potential interest.
Project description:Methods have recently been developed for the phosphine-catalyzed asymmetric γ-addition of nucleophiles to readily available allenoates and alkynoates to generate useful α,β-unsaturated carbonyl compounds that bear a stereogenic center in either the γ or the δ position (but not both) with high stereoselectivity. The utility of this approach would be enhanced considerably if the stereochemistry at both termini of the new bond could be controlled effectively. In this report, we describe the achievement of this objective, specifically, that a chiral phosphepine can catalyze the stereoconvergent γ-addition of a racemic nucleophile to a racemic electrophile; through the choice of an appropriate heterocycle as the nucleophilic partner, this new method enables the synthesis of protected α,α-disubstituted α-amino acid derivatives in good yield, diastereoselectivity, and enantioselectivity.
Project description:Allylating agents were explored for the asymmetric synthesis of α-allyl-α-aryl α-amino acids by tandem N-alkylation/π-allylation. Cross-metathesis of the tandem product was developed to provide allylic diversity not afforded in the parent reaction; the synthesis of homotyrosine and homoglutamate analogues was completed. Cyclic α-amino acid derivatives could be accessed by ring-closing metathesis presenting a viable strategy to higher ring homologue of enantioenriched α-substituted proline. The eight-membered proline analogue was successfully converted to the pyrrolizidine natural product backbone.
Project description:Selenium-containing amino acids are valuable targets but methods for the stereoselective α-selenation of simple amino acid precursors are rare. We herein report the enantioselective electrophilic α-selenation of azlactones (masked α-amino acid derivatives) and isoxazolidin-5-ones (masked β-amino acids) using Cinchona alkaloids as easily accessible organocatalysts. A variety of differently substituted derivatives was accessed with reasonable levels of enantioselectivities and further studies concerning the stability and suitability of these compounds for further manipulations have been carried out as well.
Project description:An enantioselective Pd-catalyzed 6-endo-trig reaction for the synthesis of 2-aryl-chromenes has been developed. A systematic optimization of a TADDOL-derived ligand set resulted in the identification of a novel monodentate phosphoramidite-palladium catalyst that accesses 2-aryl-2H-chromenes with high yield and enantioselectivity under mild conditions. The products obtained from this method can be transformed into biologically active compounds through functionalization of the chromene alkene.
Project description:Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel-Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel-Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel-Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.
Project description:The synthesis of α-aryl-β2 -amino esters through enantioselective aminomethylation of an arylacetic acid ester in high yields and enantioselectivity via cooperative isothiourea and Brønsted acid catalysis is demonstrated. The scope and limitations of this process are explored (25 examples, up to 94 % yield and 96:4 er), with applications to the synthesis of (S)-Venlafaxine⋅HCl and (S)-Nakinadine B. Mechanistic studies are consistent with a C(1)-ammonium enolate pathway being followed rather than an alternative dynamic kinetic resolution process. Control studies indicate that (i) a linear effect between catalyst and product er is observed; (ii) an acyl ammonium ion can be used as a precatalyst; (iii) reversible isothiourea addition to an in situ generated iminium ion leads to an off-cycle intermediate that can be used as a productive precatalyst.
Project description:A general, asymmetric synthesis of amino acid derivatives is reported. Masked acyl cyanide (MAC) reagents are shown to be effective umpolung synthons for enantioselective additions to N-Boc-aldimines. The reactions are catalyzed by a modified cinchona alkaloid, which can function as a bifunctional, hydrogen bonding catalyst, and afford adducts in excellent yields (90-98%) and high enantioselectivities (up to 97.5:2.5 er). Unmasking the addition products gives acyl cyanide intermediates that are intercepted by a variety of nucleophiles to afford α-amino acid derivatives. Notably, the methodology provides an alternative method for peptide bond formation.
Project description:We describe highly enantioselective synthesis of beta-amino acid derivatives (1a-c) using asymmetric hydrogenation of alpha-aminomethylacrylates (2a-c), which contain a free basic N H group, as the key step. The alpha-aminomethylacrylates (2a-c) were prepared using the Baylis-Hillman reaction of an appropriate aldehyde with methyl acrylate followed by acetylation of the resulting allylic alcohols (4a-b) and S(N)2'-type amination of the allylic acetates (3a-b).
Project description:An operationally simple Knoevenagel condensation/asymmetric epoxidation/domino ring-opening esterification (DROE) approach has been disclosed to successfully access a good variety of (R)- and (S)-α-arylglycine esters from commercially available aldehydes, phenylsulfonyl acetonitrile, cumyl hydroperoxide, anilines, and readily available Cinchona alkaloid-based catalysts using a single solvent and reaction vessel. DFT calculations performed on the key asymmetric epoxidation showed the importance of cooperative H-bonding interactions in affecting the stereocontrol.