Practical syntheses of 4-fluoroprolines

4-Fluoroprolines are among the most useful nonnatural amino acids in chemical biology. Here, practical routes are reported for the synthesis of the 2S,4R, 2S,4S, and 2R,4S diastereomers of 4-fluoroproline. Each route starts with (2S,4R)-4-hydroxyproline, which is a prevalent component of collagen and hence readily available, and uses a fluoride salt to install the fluoro group. Hence, the routes provide process-scale access to these useful nonnatural amino acids.     

Synthesis of 2-(4-carboxybutenyl)- and 2-(4-carboxybutynyl)-cyclopentene-1-carboxamides

Syntheses of 2-(4-carboxybut-1-enyl/4-carboxypent-1-ynyl)cyclopentene-1-carboxamides, compounds designed to mimic the phosphoSer-Pro dipeptide motif (the recognition sequence for the prolyl cis-trans isomerase Pin1), have been developed. Stille, Sonogashira and Suzuki couplings were envisaged to join the pentynoic and pentenoic acid side chains to the 2-position of cyclopentene-1-carboxylate esters. The ring- and side-chain carboxylic acids required orthogonal protection for later attachment of a Ph-NH(4-nitrophenyl) unit to the cyclopentene-1-carbonyl. The cyclopentenecarboxylates were unmasked and standard PyBOP peptide coupling afforded the target compounds. Comparisons of two routes using Bu^t and Me esters are reported.     

Crystal structure and luminescence properties of 4-(4-benzoyloxy-2-hydroxyphenyl)-2,2-difluoro-6-phenyl-1,3,2-dioxaborine

The crystal structure of 4-(4-benzoyloxy-2-hydroxyphenyl)-2,2-difluoro-6-phenyl-1,3,2-dioxaborine (1) was determined by X-ray diffraction analysis. π-π-Stacking interaction between the molecules results in joining the molecules into a three-dimensional layered framework. Luminescence of the aggregates is observed in concentrated solutions of compound 1. Two routes of excimer formation in crystal were revealed by steady-state and time-resolved luminescence spectroscopy: via excitation of single molecules and via excitation of aggregates.     

A study on thermal behaviors of mono ethyl ester azocalix[4]arene derivatives

In the present study, thermal stabilities of five new family of azocalix[4]arene mono ethyl ester derivatives, 4a–e, were investigated using thermogravimetry, differential thermogravimetry, and differential thermal analysis methods. It was found that all compounds showed thermal stability up to 236 °C averagely. After this temperature, decomposition of compounds starts gradually. The decomposition routes of 4a–c compounds are similar and occur with two stages. Ester alkyl groups decompose and remove from the structure in the first stage. Second stage corresponds to rest of structure decomposition. The decomposition routes of the 4d–e compounds are different from the decomposition routes of the 4a–c compounds. These compounds include halogen, and decomposition reactions realize with three and four stages respectively.     

Synthesis of (S)-3-amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and SNAr reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzo[b][1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S_NAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.     

Polyfluorine-containing chromen-4-ones: synthesis and transformations

Theoretical and experimental data related to the chemistry of polyfluorinated 4H-chromen-4-ones were summarized and analyzed. The synthesis of the substances under investigation was reviewed. The aspects of reactivity, the routes for the functionalization of polyfluorinated 4H-chromen-4-ones and the formation of the novel heterocyclic systems on their basis are considered.     

Ch-stretching gas phase overtone spectrum of symmetric neopentane-d4

The overtone spectrum of neopentane-d₄, C(CH₂D)₄, is examined and the local mode model is used to assign the prominent peaks. Proposed coupling routes for intramolecular vibrational relaxation of CH-stretching overtones are discussed. The dominant vibrational relaxation pathway is identified by comparisons of neopentane-d₄, neopentane and benzene overtone bandwidths.     

Development of two diastereoselective routes towards trans-4-aminomethyl-piperidin-3-ol building blocks

Two diastereoselective, scaleable routes towards trans-3,4-disubstituted piperidines with a 4-hydroxymethyl-3-hydroxy or 4-aminomethyl-3-hydroxy substitution pattern are being described. In the first route, the 3,4-trans configuration was introduced regio- and diastereoselectively via a hydroboration/oxidation sequence starting from 4-hydroxymethylpyridine. In the second route, regioselective epoxide ring opening of N-benzyl-3,4-epoxy-piperidine was achieved with LiCN, in situ generated from acetocyanohydrin and LiNH₂. The regioselectivity of both the hydroboration and the epoxide ring opening was positively influenced by the presence of the basic piperidine nitrogen. Both routes have been optimized to be performed at large scale.     

Thermolysis features of manganese(II) and zinc dihydrogenphosphate solid solution

The thermolysis of dihydrogenphosphates with the general formula MnMn_1?x Zn_x(H₂PO₄)₂ · 2H₂O (0 < x < 1.00) is studied. Two parallel thermolysis routes are found to yield cyclotetraphosphate solid solution of composition (Mn_1?x Zn_x)₂P₄O₁₂ (monoclinic space group C 2/c, Z = 4) as the final product. The sequence of physicochemical transformations and structural reorganizations is determined in both routes. Quantitatively, the involvement of the routes is largely determined by the composition of the starting dihydrogenphosphate solid solution. Two mechanisms are discussed for both removal of crystal water and liberation of free phosphoric acid. A scheme of the process is designed.     

Synthesis and reactivity of 3-amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones: development of a novel kinase-focussed library

3-Amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones represent a potentially attractive heteroaromatic scaffold for drug-discovery chemistry. In particular, the arrangement of hydrogen bond donor and acceptor groups in the bicyclic core can fulfil the requirements for ATP competitive binding to kinase enzymes. Efficient and regioselective routes from simple starting materials to novel functionalised 3-amino-1H-pyrazolo[4,3-c]pyridin-4(5H)-ones and related 3-amino-2H-pyrazolo[4,3-c]pyridines were explored and adapted for parallel synthesis, resulting in a library of compounds suitable for screening against kinases and other cancer drug targets. Methods for substituent variation at five distinct positions around the bicyclic core were devised to generate sets of compounds containing two- or three-point diversity.     

Isomerization of 4-arylamino-1,2-naphthoquinones to 2-arylamino-1,4-naphthoquinones

4-Arylamino-1,2-naphthoquinones isomerize into 2-arylamino-1,4-naphthoquinones upon refluxing in acetic acid. The isomerization follows two routes via intermediate 2-hydroxy-1,4-naphthoquinone and 2-arylamino-1,4-naphthoquinone 4-N-arylimines.     

Synthetic approaches to imino sugar (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol from naturally occurring sugar and amino acid

Imino sugar compound 3 was prepared by two alternative routes starting from ribose and d-serine. From d-serine (3R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-one was prepared in five steps in 50% overall yield, which was further converted into (2R,3R,4S)-2-(hydroxymethyl)-4-methylpyrrolidine-3,4-diol in three steps in 23% overall yield.     

Extension of β-chloroenals to ethyl 5-chloro-2,4-pentadienoates using Wadsworth-Emmons reactions: subsequent conversions to 5-aryl-5-chloro-2,4-pentadienoic acids and 5-aryl-2-penten-4-ynoic acids

Convenient routes from (Z)-3-aryl-3-chloroenals to (2E,4Z)-5-aryl-5-chloro-2,4-pentadienoates and (2E)-5-aryl-2-penten-4-ynoates are described. The stereochemical assignments are based on NMR spectral data.     

Route selection in the synthesis of C-4 and C-6 substituted thienopyrimidines

Three different routes have been investigated for the preparation of 6-aryl-N-(1-arylethyl)thienopyrimidin-4-amines. First the possibilities of selective Suzuki reactions on 6-bromo-4-chlorothienopyrimidine were investigated. The preference for mono arylation at C-6 could be increased, in the case of Pd(PPh₃)₄ catalysis, by reducing the water content of the reaction, or by using less electron rich Pd-ligands. The highest selectivity was obtained with Pd(OAc)₂ or Pd₂(dba)₃, while reactions with the more electron rich Pd(PPh₃)₄ and especially XPhos gave a lower mono- to dicoupled product ratio. Secondly, two alternative strategies avoiding this selectivity issue were tested. Suzuki reaction on C-6 of 6-bromothienopyrimidin-4(3H)-one (three examples) proceeded in 70-89% yield using Pd(PPh₃)₄ in dioxane/water. Similar conditions on 4-amino-6-bromo-thienopyrimidine (eight examples) gave 67-95% yield. The reaction could be performed with boronic acids containing nonprotected phenolic groups in the ortho, meta and para positions. By prolonging the reaction time, coupling with sterically crowded arylboronic acids was also efficient. Diarylation of 6-bromo-4-chlorothienopyrimidine gave the corresponding 4,6-diarylated derivatives in 71-80% yield depending on the nature of the arylboronic acid.     

Synthesis of (3S,3S′,4S,4S′)-1,1′-ethylenedipyrrolidine-3,3′,4,4′-tetraol and related diamino diols: donor–acceptor hydrogen-bonding motifs of the C2 symmetric 3,4-dihydroxypyrrolidine unit

Enantiopure 1,1′-ethylenedipyrrolidines possessing 3,4-disubstitution have been prepared from esters of l-(+)-tartaric acid. Although diacylation routes via the diacetoxypyrrolidin-2,5-diones were problematic, N,N-dialkylation protocols proved to be reliable and led to the synthesis of (3S,3S′,4S,4S′)-1,1′-ethylenedipyrrolidine-3,3′,4,4′-tetraol, (3R,3′S,4R,4′S)-3,4-diamino-1,1′-ethylenedipyrrolidine-3′,4′-diol and (3R,3′R,4S,4′S)-3,3′-diamino-1,1′-ethylenedipyrrolidine-4,4′-diol. The tetraol possesses a crystal structure that exhibits an unusual zig-zag intermolecular pattern comprising a network of hydrogen bonds involving the terminal hydroxyl groups and a nitrogen atom of one of the pyrrolidine rings.     

Synthesis of 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine, and its conversion to other 2,6-di(pyrazol-1-yl)pyridines substituted at the pyridine ring

Two routes to 2,6-di(pyrazol-1-yl)-4-hydroxymethylpyridine (1) from 2,6-dihydroxy-isonicotinic acid, in four and six steps, are reported. Reaction of 1 with 48% HBr yields 2,6-di(pyrazol-1-yl)-4-bromomethylpyridine (2), which is a powerful precursor to a range of new tridentate ligands for transition metals functionalised at the pyridine ring. As a proof of principle, we describe the further elaboration of 2 to give two 2,6-di(pyrazol-1-yl)pyridines bearing nucleobase substituents, and the back-to-back ligand 1,2-bis[2,6-di(pyrazol-1-yl)pyrid-4-yl]ethane. Crystal structures of two of these new derivatives are presented.     

The electronic structure of FeO 4 2− , RuO4, RuO 4 − , RuO 4 2− and OsO4 by the HFS-DVM method

The electronic structures of FeO ₄ ^2? , RuO₄, RuO ₄ ^? , RuO ₄ ^2? and OsO₄ have been investigated using the Hartree-Fock-Slater Discrete Variational Method. The calculated ordering of the valence orbitals is 2t ₂, 1e, 2a ₁, 3t ₂ andt ₁ with thet ₁ orbital as the highest occupied. The first five charge transfer bands are assigned as:t ₁→2e(v ₁), 3t ₂→2e(v ₂),t ₁→4t ₂(v ₃), 3t ₂→4t ₂(v ₄) and 2a ₁→4t ₂(v ₅). It is suggested that ad-d transition should be observed at 1.5 eV in RuO ₄ ^? and RuO ₄ ^2? .     

Azaindolines: derisking the indoline structural alert

4-Substitued azaindolines, which are isosteres of indolines, are useful synthetic building blocks that reduce the risk of bioactivation induced idiosyncratic toxicity have been prepared. Multigram routes to 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-4-triflate 16, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile 20 and 4-chloro-2,3-dihydro-1H-pyrrolo[2,3-d]pyridazine 30 are outlined.     

Homochiral 4-hydroxy-5-hexenoic acids and their derivatives and homologues from carbohydrates

Efficient routes to chiral 4-hydroxy-5-hexenoic acids and lactones from d-gluconic acid-δ-lactone and l-mannonic acid-γ-lactone are described. In this approach, the starting lactones are converted to 2,6-dibromo compounds that readily undergo zinc mediated elimination to generate the terminal alkene group in concert with 2-deoxygenation. The integrity of the remaining stereocenters is preserved during the reaction. The related important pharmaceutical intermediates (S)-3-hydroxy-4-pentenoic acid and (S)-1,3-dihydroxy-4-pentene were also prepared from 2-deoxyribose via the corresponding aldonolactone.     

Synthesis of 2-bromo-7-methyl-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 3-alkyl-2-bromo-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and their selective elaboration

Two synthetic routes to the versatile 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones 2 and 5 have been developed that allow the production of multigram quantities without the need of any chromatographic purification. Broad and selective elaboration of the heteroaromatic scaffolds has also been accomplished.