Electrophilic Building Blocks Research Articles

DFT-Guided Discovery of Ethynyl-Triazolyl-Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling.

We report the density functional theory (DFT) guided discovery of ethynyl-triazolyl-phosphinates (ETPs) as a new class of electrophilic warheads for cysteine selective bioconjugation. By using CuI -catalysed azide alkyne cycloaddition (CuAAC) in aqueous buffer, we were able to access a variety of functional electrophilic building blocks, including proteins, from diethynyl-phosphinate. ETP-reagents were used to obtain fluorescent peptide-conjugates for receptor labelling on live cells and a stable and a biologically active antibody-drug-conjugate. Moreover, we were able to incorporate ETP-electrophiles into an azide-containing ubiquitin under native conditions and demonstrate their potential in protein-protein conjugation. Finally, we showcase the excellent cysteine-selectivity of this new class of electrophile in mass spectrometry based, proteome-wide cysteine profiling, underscoring the applicability in homogeneous bioconjugation strategies to connect two complex biomolecules.

Taming the Reactivity of Phosphiranium Salts: Site‐Selective C‐Centered Ring Opening for Direct Synthesis of Phosphinoethylamines

AbstractAdvances in the field of phosphorus chemistry are documented, by revealing the synthetic utility of previously underutilized quaternary phosphiranium salts (QPrS) as three‐chain‐atom electrophilic building blocks. Notably, control of their challenging C‐centered electrophilicity is disclosed with an expedient synthesis of tertiary β‐anilino phosphines as a proof‐of‐concept.

Taming the Reactivity of Phosphiranium Salts: Site-Selective C-Centered Ring Opening for Direct Synthesis of Phosphinoethylamines.

Advances in the field of phosphorus chemistry are documented, by revealing the synthetic utility of previously underutilized quaternary phosphiranium salts (QPrS) as three-chain-atom electrophilic building blocks. Notably, control of their challenging C-centered electrophilicity is disclosed with an expedient synthesis of tertiary β-anilino phosphines as a proof-of-concept.

Stereoselective Synthesis of Multi-substituted Fluoro-β-lactams and Their Conversion to Fluorinated β-Amino Acid Core

Multi-substituted β-lactam compounds have not only attracted considerable interest as core structures of pharmaceutical compounds such as antibiotics but also have been used as building blocks for the construction of β-amino acids. Electrophilic β-lactams can be used to enhance essential biological activities. Furthermore, the ring-opening reactions of electrophilic β-lactams can be used to provide facile access to β-amino acids. The introduction of an electronegative fluorine atom to a β-lactam ring to give the corresponding fluoro-β-lactam can be used as an effective strategy for the preparation of electrophilic β-lactams. In this review, we provide a summary of our recent research towards the direct functionalization of fluoro-β-lactams. This review has been divided into four topics, including: 1) the alkylation and hydroxyalkylation of α-bromo-α-fluoro-β-lactams (1); 2) the nickel-catalyzed cross coupling reaction of 1; 3) the asymmetric synthesis of fluoro-β-lactams using chiral ligands; and 4) the utilization of fluoro-β-lactams as highly electrophilic building blocks.

ChemInform Abstract: Synthesis of Fused Thiazolo[3,2‐a]pyrimidinones: N‐Aryl‐2‐chloroacetamides as Doubly Electrophilic Building Blocks.

AbstractTwo facile procedures for the cyclocondensation of substrate (I) with the building blocks (II) or (IV) to produce fused thiazolopyrimidinone derivatives are developed.

Synthesis of fused thiazolo[3,2-a]pyrimidinones: N-aryl-2-chloroacetamides as doubly electrophilic building blocks

2-Chloro-N-phenylacetamide and N-(benzo[d]thiazol-2-yl)-2-chloroacetamide are doubly electrophilic building blocks for the formation of ring annulated thiazolo[3,2-a]pyrimidinone products. This synthetic route involves formation of the title compound in acceptable product yields by the elimination of the by-product, aniline/2-aminobenzothiazole. Analytical and spectral studies, as well as single crystal X-ray data on the representative compound 6c confirmed the structure of all the reaction products.

ChemInform Abstract: 2‐Cyanoazetidines and Azetidinium Ions: Scaffolds for Molecular Diversity

AbstractReview: 80 refs.

2‐Cyanoazetidines and Azetidinium Ions: Scaffolds for Molecular Diversity

AbstractRing strain in azetidines and azetidinium ions can be efficiently used to promote ring‐expansion and ring‐opening reactions, and this renders these four‐membered heterocycles ideal scaffolds for diversity oriented synthesis. This microreview focuses on 2‐cyanoazetidines, which are easily prepared from β‐amino alcohols through a ring‐closing reaction involving C–C bond formation. The azetidines can be readily expanded to five‐ to eight‐membered nitrogen heterocycles after suitable functionalization and/or activation. Alternatively, N‐alkylated derivatives, namely, azetidinium ions, are easily prepared and displayed rich reactivity as new electrophilic building blocks and as sources of nitrogen ylides.

Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

AbstractThree types of synthesised compounds, the aziridine 1, the epoxide 2 and the acceptor‐substituted olefin 3, were chosen as model compounds for electrophilic building blocks, which can covalently block the nucleophilic amino acids of the active sites of proteases (Cys in cysteine proteases or Asp in aspartate proteases). In order to rationally design optimised inhibitors and to understand the differences in inhibition properties of the scrutinised building blocks their structural and electronic properties were studied by ultra‐high resolution X‐ray diffraction and ab initio calculations to yield the experimental electron‐density distribution. It could be shown that the carbon atom C1 of the three‐membered heterocycle is the preferred electrophilic centre for attack of the nucleophiles, which is consistent with the results of corresponding chemical experiments with sulfur and oxygen nucleophiles.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Cover Picture: Electron‐Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors (Eur. J. Org. Chem. 17/2007)

AbstractThe cover picture shows iso‐surfaces of a protease inhibitor model compound that provides information on its reactivity. The electrostatic potential mapped on the electron density of the complete molecule and on the biologically active aziridine region shows that a nucleophilic attack must take place at carbon atom C1 of the aziridine ring. The Zero Laplacian iso‐surface shows possible sites of the attack by means of holes in this surface. The results were obtained from ultra‐high resolution synchrotron X‐ray experiments at 9 K. Details are discussed in the article by T. Schirmeister et al. on pp. 2759 ff. C. B. Hübschle is acknowledged for preparing the artwork for the cover picture.

ｇｅｍ‐二亜鉛種を用いる反応 構造・反応性について

Reactions of gem-dimetallic reagents have attracted considerable attention as versatile reagents in organic synthesis. Consequently preparations of gem-dimetallic reagents have been extensively studied. Synthetic applications of the reagents have been focused on two reactions, regioselective olefination of carbonyl compounds and coupling with two different electrophilic building blocks.

An asymmetric approach to 2-deoxynucleosides via organosulfur building blocks as chemical chameleons

An asymmetric synthesis of 6- N-benzoyl-5′- O-benzyl-2′-deoxyadenosine and its a anomer from non-carbohydrate building blocks is achieved in 7 steps. The sequence builds the basic structures using bis(methylthio)methane and methylthiomethyl phenyl sulfone as both nucleophilic and electrophilic building blocks, a feature that suggests their behavior as chemical chameleons. The asymmetric induction is achieved utilizing a kinetic resolution based upon catalytic asymmetric epoxidation.

Doppelt und dreifach funktionalisierte, enantiomerenreine C4‐Synthesebausteine aus β‐Hydroxybuttersäure, Äpfelsäure und Weinsäure

Enantiomerically Pure Synthetic Building Blocks with Four C‐Atoms and Two or Three Functional Groups from β‐Hydroxy‐butanoic, Malic, and Tartaric AcidThe pool of chiral, non‐racemic electrophilic building blocks, which are available from simple natural products in both enantiomeric forms is enlarged by the epoxides 3, 5, and 10, by the tosylate 12a, and by the aldehydes 18 (cf. symbols A‐D, 14, and Scheme 1). Key steps of the conversions leading from hydroxyacids to the building blocks are: epoxide‐opening by triethylborohydride (1 → 2a) and tosylate reduction (12a → 12b); the Mitsunobu inversion (2a → 4a); the reduction of (R, R)‐tartaric ester to (R)‐malic ester by NBS (N‐bromosuccinimide) opening of the benzaldehyde acetal 8 and tin hydride reduction (6c → 7c); the enantiomer enrichment of optically active ethyl β‐hydroxy‐butanoate through the crystalline dinitrobenzoate 21b. Detailed procedures are given for large scale preparations of the key intermediates. The enantiomeric purities of the building blocks are secured by correlations.