Gold catalyzed stereoselective tandem hydroamination–formal aza-Diels–Alder reaction of propargylic amino esters

A gold-catalyzed tandem intramolecular hydroamination-formal aza-Diels-Alder reaction of propargylic amino esters is described. The overall process leads to the formation of a tetracyclic framework as a single diastereoisomer, with the creation of four bonds and five stereocenters.

ChemInform Abstract: Unique Reactivity of Fluorinated Molecules with Transition Metals

Organofluorine and organometallic chemistry by themselves constitute two potent areas in organic synthesis. Thus, the combination of both offers many chemical possibilities and represents a powerful tool for the design and development of new synthetic methodologies leading to diverse molecular structures in an efficient manner. Given the importance of the selective introduction of fluorine atoms into organic molecules and the effectiveness of transition metals in C-C and C-heteroatom bond formation, this review represents an interesting read for this aim.

From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of Pyrazoles

Gold-Catalyzed Intramolecular Hydroamination of o-Alkynylbenzyl Carbamates: A Route to Chiral Fluorinated Isoindoline and Isoquinoline Derivatives

Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellman’s N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group.

Regio-specific synthesis of new 1-(tert-butyl)-1H-pyrazolecarboxamide derivatives

Regio-specific and non-regiospecific condensation reactions on 1,3-dicarbonyl compounds rendered 1,3,5-trisubstituted pyrazoles. Herein, the control of regio-specificity was a significant improvement in pyrazole research. A high yield acylation of poorly nucleophilic aryl amines, which resulted in mono- or diacylated products depending on the reaction conditions, is described. As a result, a library of potentially bioactive compounds was obtained. Fil: Ruatta Merke, Santiago Matías. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina Fil: Murguia, Marcelo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Co…

ChemInform Abstract: Gold Catalyzed Stereoselective Tandem Hydroamination-Formal Aza-Diels-Alder Reaction of Propargylic Amino Esters.

The overall sequence of the tandem reaction presented here leads to nitrogen-containing tetracycles under formation of 4 bonds and five stereocenters, in most cases as single diastereoisomers.

A Versatile Synthesis of Fluorinated Uracils in Solution and on Solid-Phase.

[reaction: see text] An efficient and convenient two-step synthesis of new fluorinated uracils is described. The first step involves the condensation of an ester enolate with a fluorinated nitrile to furnish fluorinated beta-enamino esters. In turn, these compounds react with organic isocyanates or isothiocyanates to give C-6 fluorinated uracils or thiouracils, respectively, in excellent yields. This synthesis has been successfully adapted to solid-phase conditions with high diversity, thereby facilitating the creation of small (thio)uracil libraries.

8-Iodonaphthalene-1-carbaldehyde: A Versatile Building Block for Diversity-Oriented Synthesis.

The scarcely studied 8-halonaphthalene-1-carbaldehyde structure has been converted into the corresponding Ellman’s imine and subjected to several transformations, thus achieving an assorted library of polycyclic carbo- and heterocycles. The potential of this scaffold for Diversity-Oriented Synthesis has been shown. Most of these skeletons are unprecedented and, therefore, cover unexplored regions of the chemical space.

Synthesis and 1H-NMR configurational study of δ3-thiazolines from 2-aza-1,3-dienes

Abstract A [4+1] heterocyclization process involving 2-aza-1,3-dienes and elemental sulphur leading to the synthesis of Δ3-thiazolines with excellent yields is described. A 1D TOCSY and 1D NOESY study of these systems was made in order to establish the configurations of the diastereoisomeric mixture.

First Fluorous Synthesis of Fluorinated Uracils

This paper describes a novel fluorous synthesis of fluorinated uracils 4. In this new protocol, fluorous alcohols 1, which are used as fluorous tags, are acetylated to yield acetates 2, which in turn are treated with a base to form their enolates. These are then reacted with fluorinated nitriles to furnish tagged β-enamino esters 3. Although this condensation step had been performed easily in previous solution and solid-phase syntheses, it proved to be very elusive in the fluorous version. Meticulous control of the reaction conditions was thus essential in order to achieve satisfactory yields of β-enamino esters 3. The final treatment of compounds 3 with isocyanates or isothiocyanates effic…

Solution-, solid-phase, and fluorous synthesis of beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives: a comparative study.

The diastereoselective synthesis of cyclic beta,beta-difluorinated alpha-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated alpha-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated alpha-amino acids was succe…

A Selective Synthesis of Fluorinated Cispentacin Derivatives

A facile selective method has been developed for the synthesis of new fluorine-containing cispentacin stereoisomers. Mono- and difluorinated cispentacin derivatives were synthetized from a bicyclic β-lactam in five or six steps involving a regio- and stereoselective hydroxylation through iodooxazoline formation, followed by deoxygenation by fluorination. Starting from an enantiomerically pure bicyclic β-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure allowed the preparation of both dextro- and levorotatory difluorinated cispentacins.

ChemInform Abstract: Asymmetric Synthesis of Fluorinated Amino Macrolactones Through Ring-Closing Metathesis.

The synthesis of new chiral fluorinated amino and azamacrolactones of types 1 and 2 is described. A ring-closing metathesis (RCM) reaction constitutes the key step in this methodology, which uses fluorinated amino alcohols 7 as starting materials. The influence of the CF2 group, which is located in the alpha-position relative to the carbon bearing the amino group, on the efficiency of the RCM reaction is noteworthy. This method allows for the preparation of the desired fluorinated macrolactones in excellent yields.

ChemInform Abstract: Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines Through Ring-Closing Metathesis.

Condensation of unsaturated esters (I) and (VII) with 1,2-diamines proceeds in the presence of trimethylaluminum providing imidazolines (III) and (VIII) which are further allylated giving suitable dienes (V) and (IX).

ChemInform Abstract: Gold-Catalyzed Povarov-Type Reaction of Fluorinated Imino Esters and Furans.

A gold-catalyzed Povarov-type reaction of fluorinated imino esters and furans is described. The process, which takes place in dichoromethane at room temperature, gives rise to novel fluorinated tetrahydrofuran-fused tetrahydroquinolines in good yields and moderate levels of diastereoselectivity in a very simple manner. The reported examples expand the versatility of the Povarov reaction to unprecedented fluorinated substrates, generating scaffolds that contain quaternary α-amino acid units.

Asymmetric synthesis of polycyclic 3-fluoroalkylproline derivatives by intramolecular azomethine ylide cycloaddition

The asymmetric synthesis of polycyclic fluorinated proline derivatives has been accomplished by means of an intramolecular azomethine ylide cycloaddition with fluorinated dipolarophiles. Thus, the reaction of benzaldehydes bearing a trifluoromethyl alkene in ortho position with an azomethine ylide precursor derived from chiral 2-amino indanol takes place with excellent levels of diastereoselectivity, with simultaneous generation of four stereocenters. In order to determine the influence of the fluorine moiety in the process, starting material bearing non-fluorinated alkenes were synthesised. In this case, a dramatic drop of selectivity occurred, which indicates that the role of the fluorine…

Diastereoselective synthesis of 2-phenyl-3-(trifluoromethyl)piperazines as building blocks for drug discovery.

The synthesis of enantiomerically pure cis- and trans-2-phenyl-3-(trifluoromethyl)piperazines is described. It involved, as the key step, a diastereoselective nucleophilic addition of the Ruppert-Prakash reagent (TMSCF3) to alpha-amino sulfinylimines bearing Ellman's auxiliary. This methodology allows an entry into hitherto unknown trifluoromethylated and stereochemically defined piperazines, key scaffold components in medicinal chemistry.

Dual Role of Vinyl Sulfonamides as N -Nucleophiles and Michael Acceptors in the Enantioselective Synthesis of Bicyclic δ-Sultams

Asymmetric Allylation/Pauson-Khand Reaction: A Simple Entry to Polycyclic Amines. Application to the Synthesis of Aminosteroid Analogues

Asymmetric allylation of o-iodoarylsulfinylimines has been achieved in high diastereoselectivities. The thus-obtained o-iodoarylhomoallylic sulfinamides participate in a subsequent Sonogashira coupling followed by a diastereoselective intramolecular Pauson-Khand reaction. In this way, tricyclic amines showing a unique benzo-fused indenyl backbone were obtained. The methodology has been applied to the synthesis of amino steroid analogues.

ChemInform Abstract: Novel Strategy for the Synthesis of Fluorinated β-Amino Acid Derivatives from Δ2-Oxazolines.

Abstract Racemic and chiral non-racemic β-fluoroalkyl-β-amino acid derivatives have been prepared in two steps starting from 2-alkyl-Δ2-oxazolines and fluorinated imidoyl chlorides. Subsequent chemoselective reduction of the C-masked β-enamino acid derivatives initially formed provided the target β-amino acids. The process takes place with total chemoselectivity, high yields and satisfactory diastereoselectivity.

Synthetic and Biological Applications of Fluorous Reagents as Phase Tags

The search for new and better techniques for the purification of organic compounds has made the recent emergence of fluorous chemistry in the field of organic synthesis possible. Using fluorous reagents as phase tags allows for the access of different synthetic routes, and this has been translated into a time reduction and higher simplicity compared to standard, nonfluorous procedures. The synthesis in fluorous phase of target molecules can be pursued in a parallel or combinatorial manner in order to access chemical libraries with structural and/or stereochemical diversity. The preparation of radiolabeled molecules also benefits from the advantages of fluorous synthesis. Finally, biochemica…

Enantioselective synthesis of fluorinated alpha-amino acids and derivatives in combination with ring-closing metathesis: intramolecular pi-stacking interactions as a source of stereocontrol.

[reaction: see text]. Hydride reduction of C=N bonds stereocontrolled by intramolecular pi-stacking interactions of 1-naphthylsulfinyl and N-aryl groups, nonoxidative Pummerer rearrangement, and ring-closing metathesis are efficiently combined in a highly stereoselective entry to enantiomerically pure cyclic and acyclic fluorinated beta-amino alcohols and alpha-amino acid derivatives, respectively.

ChemInform Abstract: From 2000 to Mid-2010: A Fruitful Decade for the Synthesis of Pyrazoles

1-Chloro-1,1-difluoro-N-(4-methoxyphenyl)-3-(pyrrolidin-2-ylidene)propan-2-imine

In the title compound, C(14)H(15)ClF(2)N(2)O, the Z configuration has been confirmed. The molecular structure shows an intramolecular N-H.N hydrogen bond [H.N 2.04 (6), N.N 2.709 (6) A and N-H.N 124 (5) degrees ]. This interaction could be responsible for the Z configuration.

A Stereocontrolled Protocol to Highly Functionalized Fluorinated Scaffolds through a Fluoride Opening of Oxiranes

A novel selective and substrate-dependent synthetic protocol has been developed towards the synthesis of various fluorine-containing, highly functionalized cycloalkane derivatives. The method involves the stereoselective epoxidation of some unsaturated cyclic beta-amino acid derivatives as model compounds, followed by a regioselective fluoride opening of oxiranes under various conditions with Deoxofluor and XtalFluor-E reagents, thereby offering an insight into this new epoxide opening methodology with fluoride.

Structure-Based Design of an RNA-Bindingp-Terphenylene Scaffold that Inhibits HIV-1 Rev Protein Function

ChemInform Abstract: Differential Reactivity of Fluorinated Homopropargylic Amino Esters vs Gold(I) Salts. The Role of the Nitrogen Protecting Group.

The gold(I)-catalyzed hydroarylation/isomerization reaction of N-protected homopropargyl amino esters (III) gives quinoline derivatives of type (IV).

Chemoselective, Substrate-directed Fluorination of Functionalized Cyclopentane β-Amino Acids

This work describes a substrate-directed fluorination of some highly functionalized cyclopentane derivatives. The cyclic products incorporating CH2 F or CHF2 moieties in their structure have been synthesized from diexo- or diendo-norbornene β-amino acids following a stereocontrolled strategy. The synthetic study was based on an oxidative transformation of the ring carbon-carbon double bond of the norbornene β-amino acids, followed by transformation of the resulted "all cis" and "trans" diformyl intermediates by fluorination with "chemodifferentiation".

Novel strategy for the synthesis of fluorinated β-amino acid derivatives from Δ2-oxazolines

Abstract Racemic and chiral non-racemic β-fluoroalkyl-β-amino acid derivatives have been prepared in two steps starting from 2-alkyl-Δ2-oxazolines and fluorinated imidoyl chlorides. Subsequent chemoselective reduction of the C-masked β-enamino acid derivatives initially formed provided the target β-amino acids. The process takes place with total chemoselectivity, high yields and satisfactory diastereoselectivity.

ChemInform Abstract: Solution-, Solid-Phase, and Fluorous Synthesis of β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives: A Comparative Study.

The diastereoselective synthesis of cyclic β,β-difluorinated α-amino acid derivatives bearing a quaternary stereocenter is described. The process relies on the chemo- and diastereoselective addition of allylic organometallic reagents to fluorinated α-imino esters and a subsequent ring-closing metathesis reaction (RCM). Complete selectivity in the nucleophilic addition was achieved with (R)-phenylglycinol methyl ether as a chiral auxiliary. The resulting amino acids were introduced into peptide chains, which could facilitate the preparation of potentially bioactive dipeptide derivatives. In addition, the solution synthesis of these cyclic fluorinated α-amino acids was successfully adapted to…

Frontispiece: Fluorine‐Containing Drugs Approved by the FDA in 2018

Tandem asymmetric Michael reaction-intramolecular Michael addition. An easy entry to chiral fluorinated 1,4-dihydropyridines.

A novel one-pot tandem asymmetric Hantzsch-type process has been employed to generate fluorinated 1,4-dihydropyridines (1,4-DHPs) as single diastereoisomers. It involves the condensation of (R)-(+)-allyl p-tolyl sulfoxide, fluorinated nitriles, and alkyl propiolates, giving access to a new family of enantiomerically pure fluorine-containing 1,4-DHPs.

Recent Developments in the Chiral Brønsted Acid-catalyzed Allylboration Reaction with Polyfunctionalized Substrates

Asymmetric allylboration has played a central role in organic synthesis ever since the pioneering work by Hoffman and Brown, having found applications in the total synthesis of many natural products. A new dawn for this 40 year-old reaction occurred with the beginning of the new century when the first catalytic asymmetric methods came into play. In less than one decade, several methodologies, able to achieve the desired homoallylic alcohols with ee ranges in the high 90s, were developed. Among them, in the present account, we will disclose our contribution to the development of the chiral binolphosphoric-derived BrOnsted acid-catalyzed allylboration of aldehydes originally reported by Antil…

Recent progress in the application of fluorinated chiral sulfinimine reagents

Abstract The development of synthetic methodology allowing for a strategic incorporation of fluorine into target compounds is in a high demand in many areas of the chemical and pharmaceutical industries. In this regard, application of fluorinated chiral sulfinimine reagents, in particularly, N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine, is one of the most general and practical approaches for preparation of compounds containing pharmacophoric fluoro-amino-keto/hydroxy moieties. This article provides a timely and comprehensive overview of the recent synthetic applications of fluorinated chiral sulfinimine reagents for asymmetric synthesis of fluoro-containing polyfunctional amino-compound…

An Efficient and Simple Entry to N-Substituted beta-Enamino Acid Derivatives from 2-Alkyl-2-oxazolines and 2-Alkyl-2-thiazolines.

Reaction of azaenolates of 2-alkyl-oxa(thia)zolines 6 with imidoyl chlorides 7 as electrophiles to furnish masked N-substituted beta-enamino acid derivatives 1-2 in 70-90% yield is described. Alternative routes are discussed. Compounds 1-2 generally appear in one tautomeric form, imino or enamino, depending on the nature of the imidoyl chloride. The configuration of the enamino moiety (Z) and the conformation (s-cis) of compounds 1-2 obtained were established by an NMR study and unequivocally set by nuclear Overhauser effect difference experiments. An X-ray structure of compound 1e is also reported, showing a strong intramolecular NH.N hydrogen bond. Ab initio calculations (HF/3-21G and HF/…

A new strategy for the synthesis of fluorinated 3,4-dihydropyrimidinones

A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-type process relies on the gamma-addition of the ester-derived enolate to fluorinated nitriles. A tandem nucleophilic addition aza-Michael reaction sequence completes the synthetic process. (C) 2009 Elsevier B.V. All rights reserved.

Stereoselective Mannich-Type Reaction of an Acyclic Ketimine with a Substituted Chlorotitanium Enolate:  Efficient Approach to d-erythro-α-Trifluoromethylβ-hydroxyaspartic Units

Efficient regio- and stereoselective access to novel fluorinated ?-aminocyclohexanecarboxylates

A regio- and stereoselective method has been developed for the synthesis of novel fluorinated 2-aminocyclohexanecarboxylic acid derivatives with the fluorine attached to position 4 of the ring. The synthesis starts from either cis- or trans-β-aminocyclohex-4-enecarboxylic acids and involves regio- and stereoselective transformation of the ring C–C double bond through iodooxazine formation and hydroxylation, followed by hydroxy–fluorine or oxo–fluorine exchange.

Synthesis of nonracemic α-trifluoromethyl α-amino acids from sulfinimines of trifluoropyruvate

We describe a novel and useful method for the synthesis of nonracemic α-trifluoromethyl α-amino acids (α-Tfm-AAs). Key building blocks are the sulfinimines (S)-1a and (S)-1b, prepared by Staudinger reaction from trifluoropyruvate esters and the chiral N-sulfinyl iminophosphorane (S)-8, which were treated with benzyl, allyl, and alkylmagnesium halides. The resulting diastereomeric N-sulfinyl α-Tfm α-amino esters, 12 and 13, were produced with moderate to good stereoselectivity and yields. When alkyl Grignard reagents were used, stereocontrol became progressively higher with increasing steric bulk, while reversed, though poor, stereocontrol was achieved with benzyl/allyl Grignard reagents. An…

ChemInform Abstract: Gold-Catalyzed Tandem Hydroamination/Formal Aza-Diels-Alder Reaction of Homopropargyl Amino Esters: A Combined Computational and Experimental Mechanistic Study.

Under optimized conditions, the title reaction leads to formation of a tetracyclic nitrogen-containing framework with generation of 4 bonds and 5 stereocenters.

ChemInform Abstract: Olefin Metathesis Reactions with Fluorinated Substrates, Catalysts, and Solvents

Synthesis of fluorinated allylic amines: Reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides with fluorinated imines

A new synthesis of fluorinated allylamines through the reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides (as vinyl anion equivalents) with imines and imino esters has been described. The process includes a TBAF-mediated fragmentation of 2-(trimethylsilyl)ethyl sulfones to afford the desired allylic amines. When the reaction is performed with the corresponding sulfoxides, the fragmentation takes place under the addition conditions, affording the final products in a single step. (C) 2007 Elsevier B.V. All rights reserved.

New Strategies for the Synthesis of Fluorinated Vinylogous Amidines and β-Enamino Ketones

Reaction of fluorinated imidoyl chlorides 3 with ketimines 1a provides fluorinated 1,3-diimines, which were exclusively isolated as vinylogous amidine tautomers 2beta, with good yields. Fluorinated beta-enamino ketones 4 are obtained by regioselective hydrolysis of 2. Complementary methods for the synthesis of regioisomeric beta-enamino ketones 4 and 5 are also reported. These methods include the reaction of azaenolates of ketimines with fluorinated esters 6 and reactions of ketone enolates with fluorinated imidoyl chlorides 3. The behavior of these systems in hydrolysis reactions was also tested.

ChemInform Abstract: Tandem Asymmetric Michael Reaction-Intramolecular Michael Addition. An Easy Entry to Chiral Fluorinated 1,4-Dihydropyridines.

The sequential treatment of optically active sulfoxide (I) with fluorinated nitriles and alkyl propiolates affords (sulfinylmethyl)dihydropyridines of type (IV) as single diastereomers in most cases.

Novel Approach for Asymmetric Synthesis of Fluorinated β-Amino Sulfones and Allylic Amines

[reaction: see text] Enantiomerically pure gamma-fluoroalkyl beta-amino sulfones are readily synthesized in three steps starting from fluorinated imidoyl chlorides and arylmethyl sulfones. A complementary two-step sequence starting from chiral fluorinated beta-amino sulfoxides has also been developed. To illustrate the application of this procedure, a new method for the synthesis of alpha-fluoroalkyl allylic amines in optically pure form involving a Julia methylenation-desulfonylation reaction is presented.

One-pot cross-enyne metathesis (CEYM)-Diels-Alder reaction of gem-difluoropropargylic alkynes.

Propargylic difluorides 1 were used as starting substrates in a combination of cross-enyne metathesis and Diels–Alder reactions. Thus, the reaction of 1 with ethylene in the presence of 2nd generation Hoveyda–Grubbs catalyst generates a diene moiety which in situ reacts with a wide variety of dienophiles giving rise to a small family of new fluorinated carbo- and heterocyclic derivatives in moderate to good yields. This is a complementary protocol to the one previously described by our research group, which involved the use of 1,7-octadiene as an internal source of ethylene.

ChemInform Abstract: Cross-Metathesis Reactions as an Efficient Tool in the Synthesis of Fluorinated Cyclic β-Amino Acids.

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions …

A new and expeditious strategy for the synthesis of β-amino acids from Δ2-oxazolines

Abstract A new, mild two-step synthesis of racemic β-amino acids starting from 2-alkyl-Δ2-oxazolines is described. The process implies the initial formation of masked N-substituted or N-unsubstituted β-enamino acid derivatives followed by chemoselective reduction of the enamino moiety. The process takes place with high yields, total chemoselectivity and moderate diastereoselectivity.

ChemInform Abstract: Microwave-Assisted Organocatalytic Enantioselective Intramolecular Aza-Michael Reaction with α,β-Unsaturated Ketones.

The combination of an epi-hydroquinine catalyst and pentafluoropropionic acid accelerates the process.

Chemistry of detrifluoroacetylativelyin situgenerated fluoro-enolates

This review article comprehensively profiles all literature reports (2015-2018) related to the detrifluoroacetylative in situ generation of fluorine-containing enolates and their reactions with electrophilic reagents. The innovative facets of this unconventional methodology and its synthetic generality for the preparation of fluorine-containing compounds of high medicinal value are highlighted.

Inside Back Cover: Structure-Based Design of an RNA-Bindingp-Terphenylene Scaffold that Inhibits HIV-1 Rev Protein Function (Angew. Chem. Int. Ed. 50/2013)

ChemInform Abstract: Microwave-Assisted Tandem Organocatalytic Peptide-Coupling Intramolecular aza-Michael Reaction: α,β-Unsaturated N-Acyl Pyrazoles as Michael Acceptors.

Conjugated N-acyl pyrazoles are successfully employed in the organocatalytic enantioselective intramolecular aza-Michael reaction as ester surrogates.

Functionalized Dialdehydes as Promising Scaffolds for Access to Heterocycles and β-Amino Acids: Synthesis of Fluorinated Piperidine and Azepane Derivatives

Functionalized dialdehydes are considered important substrates that can be transformed into various substituted heterocyclic, alicyclic, and polysubstituted compounds. Here, we report a robust stereocontrolled procedure for the synthesis of novel functionalized trifluoromethyl-containing piperidine and azepane derivatives, based on oxidative ring cleavage of the C=C bond of diversely substituted cycloalkenes, followed by reductive ring closure of the diformyl intermediates in the presence of fluorine-containing amines.

Intramolecular Nitrone Cycloaddition of α-(Trifluoromethyl)styrenes. Role of the CF3 Group in the Regioselectivity

The intramolecular 1,3-dipolar cycloaddition of ortho-substituted 1,1,1-trifluoromethylstyrene-derived nitrones is described. Tricyclic fused isoxazolidines were obtained as major or exclusive products, in contrast to the case for nonfluorinated substrates, which rendered the bridged derivatives. This change in the regioselectivity was attributed to the electronic and, particularly, steric requirements of the trifluoromethyl group in comparison to the methyl group. It is worth mentioning that trifluoromethylstyrenes have been employed for the first time as dipolarophiles in a 1,3-dipolar intramolecular cycloaddition reaction, leading to the corresponding isoxazolidines bearing a quaternary …

A novel heterocyclic sulfonamide: N-benzyl-5-[N-benzyl-N-(tert-butyloxycarbonyl)amino]-N-(tert-butyloxycarbonyl)-1,3,4-thiadiazole-2-sulfonamide

The title compound, C(26)H(32)N(4)O(6)S(2), is a heterocyclic sulfonamide which is a 1,3,4-thiadiazole derivative. Structural data for this compound are compared with those of related compounds.

Diastereoselectivity of the Addition of Propargylic Magnesium Reagents to Fluorinated Aromatic Sulfinyl Imines.

The addition of propargylmagnesium bromide to fluorinated aromatic sulfinyl imines gave homopropargyl amines with total regio- and diastereoselection. Complete reversal of diastereoselectivity can be achieved in some cases using coordinating (THF) or noncoordinating (DCM) solvents. Substituted propargylic magnesium reagents have been also tested toward fluorinated aryl sulfinyl imines affording chiral homoallenyl amines with good yields and selectivity control. DFT calculations helped to rationalize the origin of the experimental regio- and diastereoselectivities observed in each case.

Synthesis and application of β-substituted Pauson-Khand adducts: trifluoromethyl as a removable steering group.

The reaction between alkynes (I) and norbornadiene (II) affords the β-substituted Pauson—Khand adducts (III) as single regioisomers and the trifluoromethyl steering group can be easily removed in the presence of DBU and water.

The role of fluorine in the stereoselective tandem Aza-Michael addition to acrylamide acceptors: An experimental and theoretical mechanistic study

Aza-Michael additions of alpha-amino esters to fluorinated acceptors take place in a highly stereoselective manner, to give partially modified Psi-[NHCH2]retropeptides incorporating a hydrolytically stable trifluoroalanine mimic. The reaction mechanism has been investigated experimentally and theoretically, in order to explain the effect of the trifluoromethyl group on the reactivity and the origins of the experimentally observed stereocontrol. The reaction is a two-step process, involving a tandem aza-Michael addition followed by a stereoselective hydrogen transfer. Both steps are base-catalyzed. The high level of stereocontrol is the result of a combination of electrostatic interactions a…

Diversity-Oriented Synthesis of Highly Functionalized Alicycles across Dipolar Cycloaddition/Metathesis Reaction

AbstractThis Account gives an insight into the selective functionalization of some readily available commercial cyclodienes across simple chemical transformations into functionalized small-molecular scaffolds. The syntheses involved selective cycloadditions, followed by ring-opening metathesis (ROM) of the resulting azetidin-2-one derivatives or isoxazoline frameworks and selective cross metathesis (CM) by discrimination of the C=C bonds on the alkenylated heterocycles. The CM protocols have been described when investigated under various conditions with the purpose on exploring chemodifferentiation of the olefin bonds and a study on the access of the corresponding functionalized β-lactam or…

A metal-free and regioselective approach to (Z)-β-fluorovinyl sulfones and their chemoselective hydrogenation to β-fluoroalkyl sulfones

Abstract A highly regioselective, metal-free hydrofluorination reaction of alkynyl sulfones was developed using TBAF—one of the cheapest and most commonly available fluoride sources. In addition, the reactivity of the resulting β-fluorovinyl sulfones was studied, focusing on their selective hydrogenation reaction. Both β-fluorovinyl sulfones and their hydrogenation products β-fluoroalkyl sulfones may find applications in medicinal and agrochemical sciences.

Highly stereoselective tandem aza-Michael addition-enolate protonation to form partially modified retropeptide mimetics incorporating a trifluoroalanine surrogate.

Fluorine-containing functionalized cyclopentene scaffolds through ring contraction and deoxofluorination of various substituted cyclohexenes

The fluorination of some highly‐functionalized cyclopentene derivatives, obtained from various substituted cyclohexenes through a ring‐opening/ring‐contraction procedure, has been investigated. The transformations were found to be highly substrate dependent, and led to the formation of various functionalized alicyclic compounds or heterocycles containing allyl difluoride or vinyl fluoride moieties. peerReviewed

ChemInform Abstract: An Approach to 2,4-Substituted Pyrazolo[1,5-a]pyridines and Pyrazolo[1,5-a]azepines by Ring-Closing Metathesis.

Based on the title approach, the diastereoselective synthesis of potential peptidomimetics [(XI) and (XIV)] is described.

Differential reactivity of fluorinated homopropargylic amino esters vs gold(I) salts. The role of the nitrogen protecting group

The reaction of several homopropargyl amino esters 4, bearing aromatic substituents and a benzyl group as nitrogen substituents, with gold(I) salts gave rise to fluorinated quinolines 6 in a tandem hydroarylation-isomerization process. On the other hand, homopropargyl amino esters 7 containing a carbamate group underwent the carbonyl addition over the triple bond in the presence of gold(I) salts, rendering fluorinated oxazines 8. The use of chiral sulfoxides allowed us to develop the asymmetric version of this protocol. This two processes complete the differential reactivity showed by these types of susbtrates, depending on the nature of the nitrogen protecting group. (C) 2014 Elsevier B.V.…

Synthesis of a New Fluorinated Oxazolidinone and Its Reactivity as a Chiral Auxiliary in Aldol Reactions.

A new enantiomerically pure fluorinated oxazolidinone has been prepared from a fluorinated imidoyl chloride and an optically pure sulfoxide. The diastereoselective reduction of the β-iminosulfoxide thus formed followed by elimination of the sulfoxide and cyclization of the created aminoalcohol furnishes the desired product. The fluorinated oxazolidinone was subsequently used as a chiral auxiliary in Aldol reactions. We also found that the selective formation of the syn-Evans and syn-non-Evans diastereoisomer can be controlled by adjusting the Lewis acid/base ratio.

Cross-Metathesis Reactions as an Efficient Tool in the Synthesis of Fluorinated Cyclic β-Amino Acids

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions …

Chiral Monofluorobenzyl Carbanions: Synthesis of Enantiopure β‐Fluorinated β‐Phenylethylamines

The preparation of a stabilized monofluorobenzyl carbanion by means of a remote homochiral sulfinyl group and its completely stereoselective reactions with N-p-tolylsulfinylimines are described. The use of these reactions followed by the simultaneous removal of both chiral auxiliaries with tBuLi, which occurs without epimerization at the benzylic position, provides the quickest entry to enantiomerically pure β-fluorinated β-phenylethylamines.

ChemInform Abstract: Organocatalytic Approach to Benzofused Nitrogen-Containing Heterocycles: Enantioselective Total Synthesis of (+)-Angustureine.

An Insight into Substrate-Dependent Fluorination of some Highly Substituted Alicyclic Scaffolds

The substrate-dependent fluorination of some highly-functionalized cyclopentane derivatives with multiple chiral centers has been investigated. The key steps of the stereocontrolled syntheses are the oxidative cleavage of the ring carbon–carbon double bond of readily available diexo or diendo norbornene β-amino acid derivatives followed by transformation of the resulted dialdehyde stereoisomers by reduction. Finally, substrate-directable chemodifferentiation of different types of hydroxy groups under fluorination procedures gave various densely functionalized alicyclic derivatives or heterocycles.

Copper-catalyzed regioselective synthesis of (E)-β-fluorovinyl sulfones

Organofluorine compounds are finding increasing application in a variety of fields such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of fluorine-containing natural products, advancement in this area depends almost entirely on the development of new synthetic methodologies. In this article, we present the synthesis of a series of previously undescribed (E)-&beta

ChemInform Abstract: New Strategy for the Stereoselective Synthesis of Fluorinated β-Amino Acids.

Racemic and chiral nonracemic α-substituted and α-unsubstituted β-fluoroalkyl β-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained γ-fluorinated β-enamino esters 4 by using ZnI2/NaBH4 in a nonchelated aprotic medium (dry CH2Cl2) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction of chiral β-enamino esters 4…

ChemInform Abstract: Asymmetric Allylation/Ring Closing Metathesis: One-Pot Synthesis of Benzo-Fused Cyclic Homoallylic Amines. Application to the Formal Synthesis of Sertraline Derivatives.

A stepwise process consisting of asymmetric allylation of imines of type (I) and following ring-closing metathesis of the resulting dienes (III) is developed to synthesize cyclic homoallylic amines.

Tiratricol neutralizes bacterial endotoxins and reduces lipopolysaccharide-induced TNF-alpha production in the cell.

Contains fulltext : 70610.pdf (Publisher’s version ) (Closed access) The screening of a commercially available library of compounds has proved a successful strategy for the identification of a lead compound in a drug discovery programme. Here, we analysed 880 off-patent drugs, which initially comprised the Prestwick Chemical library, as sources of bacterial endotoxin neutralizers. We identified 3,3',5-triiodo-thyroacetic acid (tiratricol) as a non-antibacterial compound that neutralizes the toxic lipopolysaccharide.

N-(Diphenylmethylene)benzenesulfonamide andN-(Diphenylmethylene)-4-methylbenzenesulfonamide

[10398-99-9] C19H15NO2S (MW 332.42) InChI = 1S/C19H15NO2S/c21-23(22,18-14-8-3-9-15-18)20-19(16-10-4-1-5-11-16)17-12-6-2-7-13-17/h1-15H InChIKey = LECLPBHPQOFADH-UHFFFAOYSA-N (reagent used as an activated imine) Physical Data: mp 119–120 °C. Form Supplied in: colorless crystals. Not commercially available. Purification: recrystalization from CH3OH. [10399-00-5] C20H17NO2S (MW 346.45) InChI = 1S/C20H17NO2S/c1-16-12-14-19(15-13-16)24(22,23)21-20(17-8-4-2-5-9-17)18-10-6-3-7-11-18/h2-15H,1H3 InChIKey = ODLFJRFKAOOIKO-UHFFFAOYSA-N (reagent used as an activated imine) Physical Data: mp 103–104 °C1; 102–103 °C2; 101–102 °C5; 103 °C6; 102–104 °C.7 Solubility: soluble in pyridine, dimethylformamide, …

ChemInform Abstract: Asymmetric Tandem Reactions: New Synthetic Strategies

The use of domino and multicomponent reactions in asymmetric synthesis is con- stantly increasing nowadays. This allows for the synthesis of complex molecules in a single synthetic sequence, usually with high atom economy. Herein, we report three examples of new asymmetric tandem reactions recently developed in our laboratories, giving rise to new families of enantiomerically enriched fluorinated and nonfluorinated heterocycles. Thus, 1,4-dihydropyridines (1,4-DHPs) bearing fluorinated substituents at C6 were assembled by means of a Hantzsch-type reaction; cyclic β-amino carbonyl derivatives were prepared using a cross-metathesis (CM)-intramolecular aza-Michael sequence; while fluorinated i…

Pauson–Khand reaction of fluorinated compounds

The Pauson–Khand reaction (PKR) is one of the key methods for the construction of cyclopentenone derivatives, which can in turn undergo diverse chemical transformations to yield more complex biologically active molecules. Despite the increasing availability of fluorinated building blocks and methodologies to incorporate fluorine in compounds with biological interest, there have been few significant advances focused on the fluoro-Pauson–Khand reaction, both in the inter- and intramolecular versions. Furthermore, the use of vinyl fluorides as olefinic counterparts had been completely overlooked. In this review, we collect the advances both on the stoichiometric and catalytic intermolecular an…

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence.

A study exploring the chemical behavior of some dihydroxylated β-amino ester stereo- and regioisomers, derived from unsaturated cyclic β-amino acids is described. The nucleophilic fluorinations involving hydroxy–fluorine exchange of some highly functionalized alicyclic diol derivatives have been carried out in view of selective fluorination, investigating substrate dependence, neighboring group assistance and chemodifferentiation.

The Ruthenium‐Catalyzed Domino Cross Enyne Metathesis/Ring‐Closing Metathesis in the Synthesis of Enantioenriched Nitrogen‐Containing Heterocycles

Fluorinated Pyrazoles and Indazoles

The synthesis of fluorine containing pyrazoles has been boosted in the past decades due to the interesting properties that confer these building blocks in pharmaceutical and agricultural active ingredients. There are two main methods for the synthesis of fluorine-containing organic compounds, namely, the direct replacement of an atom or functional group such as diazo, hydroxyl, halogen or hydrogen by fluorine, and the modification of fluorine-containing building blocks. In the case of fluorinated pyrazoles the latter approach is the most commonly applied. This chapter deals primarily with the pivotal procedures that allow the preparation of fluoro- and fluoroalkyl- pyrazoles. Their benzocon…

1,7-Octadiene-Assisted Tandem Multicomponent Cross-Enyne Metathesis (CEYM)-Diels-Alder Reactions: A Useful Alternative to Mori’s Conditions

The use of 1,7-octadiene as an in situ source of ethylene led us to develop a novel multicomponent tandem cross-enyne metathesis (CEYM)-Diels-Alder reaction. The process can be considered a relay metathesis, in which the ethylene liberated in the ring-closing metathesis (RCM) of 1,7-octadiene initiates the tandem sequence. Aliphatic, aromatic, and fluorinated alkynes and several dienophiles are compatible with the process, which is particularly efficient with aromatic alkynes. This methodology constitutes a useful variant of Mori's conditions in CEYM-related reactions.

Regio- and diastereoselective fluorination of alicyclic β-amino acids.

A regio- and stereoselective approach to fluorinated β-aminocyclohexene or cyclohexane esters has been developed, starting from a bicyclic β-lactam (1). The procedure involves six or seven steps, based on regio- and stereoselective iodolactonization, lactone opening and hydroxy–fluorine exchange. The method has been extended to the synthesis of fluorinated amino ester enantiomers.

An efficient entry to optically active anti- and syn-beta-amino-alpha-trifluoromethyl alcohols.

The reaction of chiral 5,6-dihydro-2H-1,4-oxazin-2-ones with TMSCF3 in the presence of a suitable activator leads to trifluoromethyl lactols, which can be selectively reduced to anti-beta-amino-alpha-trifluoromethyl alcohols. The corresponding syn diastereoisomers are obtained when the starting imines are reduced and the nitrogen atom is conveniently protected. In addition, a novel rearrangement of the CF3 group in the lactol intermediates has been observed. This represents a formal CF3 addition to the imine function in the starting substrates.

ChemInform Abstract: Asymmetric Synthesis of Monofluorinated 1-Amino-1,2-dihydronaphthalene and 1,3-Amino Alcohol Derivatives.

Enantioenriched 1-amino-4-fluoro-1,2-dihydronaphthalene derivatives are accessed via two complementary synthetic strategies. The careful optimization of the reaction conditions required for the elimination step in one route has allowed both the identification of an anchimerically assisted reaction pathway and, more importantly, access to a divergent reaction pathway toward fluorinated 1,3-amino alcohols from a common intermediate just by adjusting the number of equivalents of base used.

ChemInform Abstract: A Versatile Approach to CF3-Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors.

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.

ChemInform Abstract: Intramolecular Michael Reaction of tert-Butylsulfinyl Ketimines: Asymmetric Synthesis of 3-Substituted Indanones.

The reaction proceeds in the presence of the Ruppert—Prakash reagent (Tms-CF3) with either TBAT or TBAF as a base.

ChemInform Abstract: Tandem Cross Enyne Metathesis (CEYM)-Intramolecular Diels-Alder Reaction (IMDAR). An Easy Entry to Linear Bicyclic Scaffolds.

A new tandem cross enyne metathesis (CEYM)–intramolecular Diels–Alder reaction (IMDAR) has been carried out. It involves conjugated ketones, esters or amides bearing a remote olefin and aromatic alkynes as the starting materials. The overall process enables the preparation of a small family of linear bicyclic scaffolds in a very simple manner with moderate to good levels of diastereoselectivity. This methodology constitutes one of the few examples that employ olefins differently than ethylene in tandem CEYM–IMDAR protocols.

ChemInform Abstract: A New Tandem Cross Metathesis-Intramolecular Aza-Michael Reaction for the Synthesis of α,α-Difluorinated Lactams.

Difluorinated amides are treated with methyl vinyl ketone or analogous esters to produce the desired γ- and δ-lactam units including optically active versions.

Selective Synthesis of New Fluorinated Alicyclic β-Amino Ester Stereoisomers (Eur. J. Org. Chem. 26/2011)

The cover picture shows a waterfall located in the Eastern Carpathians in Transylvania, near Bicaz Canyon. Although fluorinated organic compounds are nonexistent in nature, an increasing number of drugs (25 %) on the market contain at least one fluorine atom. Cyclic fluorinated β-amino acid derivatives have been synthesized by selective hydroxylation and hydroxy?fluorine exchange. Details are discussed in the article by F. Fulop et al. on p. 4993 ff.

Synthesis of Fluorinated and Nonfluorinated Tebufenpyrad Analogues for the Study of Anti-angiogenesis MOA

In this contribution we report the synthesis of fluorinated and nonfluorinated tebufenpyrad analogues to explore potential druglike properties through the phenotypic screening as part of the Lilly Open Innovation Drug Discovery (OIDD) program.

ChemInform Abstract: Organocatalytic anti-Selective Mannich Reactions with Fluorinated Aldimines: Synthesis of anti-γ-Fluoroalkyl-γ-amino Alcohols.

The asymmetric Mannich reaction between fluoroalkyl aldimines and aldehydes catalyzed by α,α-diphenylprolinol trimethylsilyl ether is reported. The corresponding Mannich adducts were reduced in situ to afford anti-β-alkyl-γ-fluoroalkyl-γ-amino alcohols in moderate yields and with very high diastereo- and enantioselectivities. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Back Cover: Chemoselective, Substrate-directed Fluorination of Functionalized Cyclopentane β-Amino Acids (Chem. Asian J. 23/2016)

Enantioselective Palladium-Catalyzed Oxidative β,β-Fluoroarylation of α,β-Unsaturated Carbonyl Derivatives

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim The site-selective palladium-catalyzed three-component coupling of deactivated alkenes, arylboronic acids, and N-fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step-economical approach to the stereoselective β-fluorination of α,β-unsaturated systems.

Microwave-Assisted Tandem Organocatalytic Peptide-Coupling Intramolecular aza-Michael Reaction: α,β-UnsaturatedN-Acyl Pyrazoles as Michael Acceptors

Conjugated N-acyl pyrazoles have been successfully employed in the organocatalytic enantioselective intramolecular aza-Michael reaction as ester surrogates. Bifunctional squaramides under microwave irradiation provided the best results in this transformation. Furthermore, this protocol has been combined with a peptide-coupling reaction in a tandem sequence. The final products were easily converted into the corresponding ethyl esters.

Synthesis of 3-substituted isoindolin-1-ones via a tandem desilylation, cross-coupling, hydroamidation sequence under aqueous phase-transfer conditions

A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2-iodobenzamides 1 and (silyl) alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently "unmasked" upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene …

Chemodiscrimination of Olefin Bonds Through Cross‐Metathesis Reactions – Synthesis of Functionalized β‐Lactam and β‐Amino Acid Derivatives

Addition of Nucleophiles to Fluorinated Michael Acceptors

A series of nucleophiles, including primary and secondary amines, primary alcohols, and thiols, as well as diethyl malonate and nitromethane, were added to different fluorinated Michael acceptors including 2-fluoroalk-1-en-3-ones and 2-fluoro-1-phenylprop-2-en-1-one. The resulting beta-substituted afluoro ketones were isolated in 34-92 % yield, depending on the substrate and the nucleophile. The best yields were obtained with secondary amines and with p-methylthiophenol.

Diastereoselective synthesis of fluorinated, seven-membered beta-amino acid derivatives via ring-closing metathesis.

[reaction: see text] Cis and trans seven-membered gamma,gamma-difluorinated beta-amino acid derivatives (III) have been prepared with a sequence that starts with imidoyl halides (I), which are condensed with suitable ester enolates to give intermediates (II). These, in turn, can be cyclized by means of a ring-closing olefin metathesis reaction and the product stereoselectively reduced to yield compounds (III) in good overall yields.

Tandem Organocatalytic Cycloaromatization/Intramolecular Friedel-Crafts Alkylation Sequence for the Synthesis of Indolizinones and Pyrrolo-azepinone Derivatives.

The organocatalytic synthesis of indolizinones and pyrrolo-azepinones has been accomplished in a tandem fashion through a sequence that comprises initial cycloaromatization followed by intramolecular Friedel-Crafts alkylation. The process takes place under Bronsted acid catalysis, giving rise to final products in moderate to good yields. Attempts to carry out the tandem protocol in an enantioselective fashion were performed with chiral (R)-BINOL-derived N-triflyl phosphoramides. After initial optimization, the tandem process took place with moderate levels of enantioselectivity.

An AM1 study on π-facial selectivity in Diels-Alder reactions of 2-aza-1, 3-dienes with azodienophiles

Abstract A theoretical study of the π-facial selectivity in Diels-Alder reactions of chloro derivatives of 2-aza-1,3-dienes with azodienophiles has been carried out using the semiempirical AM1 method. Three transition structures for the model reaction of the diene 3 with the dienophile 4 were located. The Diels-Alder reaction of the non-substituted 2-aza-1,3-diene 6 with the trans -diimide was studied. All transition structures located show an important asynchronicity and the calculations reveal the presence of stereoelectronic effects. The predicted stereoselectivity is in agreement with the experimental evidence.

Role of the gem-Difluoro Moiety in the Tandem Ring-Closing Metathesis−Olefin Isomerization:  Regioselective Preparation of Unsaturated Lactams

Careful selection of the metathesis catalyst, solvent, and reaction conditions allows for the efficient and regioselective synthesis of isomeric fluorinated and nonfluorinated lactam derivatives II and III from precursor amides I through a ring-closing metathesis (RCM) reaction or a tandem RCM-isomerization protocol, respectively. The presence of the gem-difluoro moiety in the starting materials exerts a pivotal effect by directing the isomerization step, making the overall tandem transformation a regioselective process. The scope, limitations, and synthetic usefulness of this protocol are also discussed.

Solution and fluorous phase synthesis of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives

An efficient protocol for the preparation of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives was developed. 2,2-Difluro-4-phenyl-3-butenoic acid 6 was used as substrate for the preparation of the starting vinyl difluoro imino esters 8. The key steps of this methodology rely on the chemo- and diastereoselective addition of allylzinc bromides over the iminic functionality of 8 and subsequent RCM reaction. This synthetic sequence was successfully applied to fluorous synthesis.

Fluorine-containing drugs approved by the FDA in 2019

Abstract Eleven new fluorine-containing FDA-approved drugs have been profiled and details of their discovery and preparation are discussed. Therapeutic areas include schizophrenia, migraine, multiple sclerosis, insomnia, rheumatoid arthritis, anti-tuberculosis, breast cancer, lymphoma kinase inhibitor, serotonin receptor antagonist. New pharmaceuticals feature four examples of aromatic fluorine, three aromatic CF3 group, three aliphatic CF3 and one compound with aromatic CF3O group. Furthermore, among the new compounds, six are chiral and seven are derived from tailor-made amino acids.

Selective Synthesis of New Fluorinated Alicyclic β-Amino Ester Stereoisomers

New fluorinated alicyclic β-amino ester stereoisomers with a cyclohexene or cyclohexane skeleton were prepared from cis- or trans-2-aminocyclohex-3-enecarboxylic acids in five or six steps through a regio- and stereoselective hydroxylation and hydroxy–fluorine exchange. Fluorinated aminoester enantiomers were synthesized from enantiopure cis- or trans-2-aminocyclohexenecarboxylic acid (prepared byenzymatic resolution of the racemic substances).

Asymmetric synthesis of fluorinated cyclic beta-amino acid derivatives through cross metathesis.

The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fluorinated imidoyl chlorides. Subsequent chemoselective hydrogenation of the olefin moiety, Dieckmann condensation, and stereoselective reduction of the iminic double bond afforded the corresponding beta-amino esters with several ring sizes. The asymmetric version of the process was achieved by using (-)-8-phenylmenthol as a chiral auxiliary.

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012−2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.

Base-Dependent Stereodivergent Intramolecular Aza-Michael Reaction: Asymmetric Synthesis of 1,3-Disubstituted Isoindolines

The nucleophilic addition (A(N)) / intramolecular aza-Michael reaction (IMAMR) process on Ellman's tert-butylsulfinyl imines, bearing a Michael acceptor in the ortho position, is studied. This reaction affords 1,3-disubstituted isoindolines with a wide range of substituents in good yields and diastereoselectivities. Interestingly, careful choice of the base for the aza-Michael step allows either the cis or the trans diastereoisomers to be exclusively obtained. This stereodivergent cyclization has enabled the synthesis of C2-symmetric bisacetate-substituted isoindolines. In addition, bisacetate isoindolines bearing two well-differentiated ester moieties are also noteworthy because they may a…

Asymmetric Michael Addition in Synthesis of β-Substituted GABA Derivatives

γ-Aminobutyric acid (GABA) represents one of the most prolific structural units widely used in the design of modern pharmaceuticals. For example, β-substituted GABA derivatives are found in numerous neurological drugs, such as baclofen, phenibut, tolibut, pregabalin, phenylpiracetam, brivaracetam, and rolipram, to mention just a few. In this review, we critically discuss the literature data reported on the preparation of substituted GABA derivatives using the Michael addition reaction as a key synthetic transformation. Special attention is paid to asymmetric methods featuring synthetically useful stereochemical outcomes and operational simplicity. This research was funded by the National Na…

Gold-Catalyzed Tandem Hydroamination/Formal Aza-Diels-Alder Reaction of Homopropargyl Amino Esters: A Combined Computational and Experimental Mechanistic Study

A tandem gold-catalyzed hydroamination/formal aza-Diels-Alder reaction is described. This process, which employs quaternary homopropargyl amino ester substrates, leads to the formation of an intrincate tetracyclic framework and involves the generation of four bonds and five stereocenters in a highly diastereoselective manner. Theoretical calculations have allowed us to propose a suitable mechanistic rationalization for the tandem protocol. Additionally, by studying the influence of the ligands on the rate of the gold-catalyzed reactions, it was possible to establish optimum conditions in which to perform the process with a variety of substituents on the amino ester substrates. Notably, the …

Antioxidant activity of 5-FU and new fluorinated uracil derivates

The intake of antioxidants has increased in the last years in order to treat some pathologies associated with oxidative stress such as cancer, diabetes mellitus, atherosclerosis, myocardial infarction, acute pancreatitis, Parkinson's and Alzheimer's disease among others. In colorectal cancer, a widely antineoplastic drug used is the fluorinated uracil molecule 5-Fluorouracile (5-FU). The aim of this study is to assess the antioxidant capacity observed by the inhibition of lipid peroxidation by 5-FU and other fluorinated uracil derivates: 6-[Difluoro(phenyl)methyl]-3-(2,4,6-trifluorophenyl)pyrimidine-2,4(1H,3H)-dione (S-81), 3-[2-Chloroethyl]-6-[difluoro(phenyl)methyl]pyrimidine-2,4(1H,3H)-d…

Innentitelbild: Synthesis and Application of β-Substituted Pauson-Khand Adducts: Trifluoromethyl as a Removable Steering Group (Angew. Chem. 20/2013)

Improved Regioselectivity in Pyrazole Formation through the Use of Fluorinated Alcohols as Solvents: Synthesis and Biological Activity of Fluorinated Tebufenpyrad Analogs

The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity. Fil: Fustero, Santos. Universidad de Valencia; España Fil…

Asymmetric Intramolecular Aza-Michael Reaction in Desymmetrization Processes. Total Synthesis of Hippodamine and epi-Hippodamine

The use of chiral sulfinyl amines both as nucleophilic nitrogen sources and chiral inducers has been described for the first time in a desymmetrization-type process involving an intramolecular aza-Michael reaction. The resulting product was employed as an advanced intermediate in the total synthesis of the natural product hippodamine and epi-hippodamine, taking advantage of the special symmetry of these molecules. In addition, this is the first asymmetric total synthesis of epi-hippodamine.

Fluorine-Containing Functionalized Cyclopentene Scaffolds Through Ring Contraction and Deoxofluorination of Various Substituted Cyclohexenes

Asymmetric Synthesis of Monofluorinated 1-Amino-1,2-dihydronaphthalene and 1,3-Amino Alcohol Derivatives.

Enantioenriched 1-amino-4-fluoro-1,2-dihydronaphthalene derivatives are accessed via two complementary synthetic strategies. The careful optimization of the reaction conditions required for the elimination step in one route has allowed both the identification of an anchimerically assisted reaction pathway and, more importantly, access to a divergent reaction pathway toward fluorinated 1,3-amino alcohols from a common intermediate just by adjusting the number of equivalents of base used.

Highly enantioselective synthesis of fluorinated gamma-amino alcohols through proline-catalyzed cross-Mannich reaction.

A new, simple route for the synthesis of fluorinated beta-alkyl gamma-amino alcohols in optically pure form in only two steps and featuring proline catalysis from inexpensive and readily available starting materials is described. The applied strategy allows for the introduction of diversity into both the beta-fluoroalkyl and alpha-alkyl groups of these compounds. [reaction: see text]

ChemInform Abstract: Tandem Nucleophilic Addition-Intramolecular Aza-Michael Reaction: Facile Synthesis of Chiral Fluorinated Isoindolines.

A highly stereoselective synthesis of fluorinated 1,3-disubstituted isoindolines is described. To this end, a tandem reaction consisting of a diastereoselective addition of fluorinated nucleophiles to Ellman’s N-(tert-butanesulfinyl)imines followed by an intramolecular aza-Michael reaction has been developed. This strategy allows for the construction of isoindolines bearing several degrees of fluorination (mono-, di-, or trifluoromethyl as well as heavier fluorinated groups). In the majority of all cases, the products are formed as single isomers.

Synthesis of new fluorinated Tebufenpyrad analogs with acaricidal activity through regioselective pyrazole formation.

In previous studies, our group has shown that the use of fluorinated alcohols such as trifluoroethanol (TFE) and hexafluoroisopropanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation from 1,3-diketone with methylhydrazine. We have now applied this synthetic method to the preparation of new fluorinated pyrazoles, which have then been used as synthetic intermediates in the preparation of fluorinated analogs of Tebufenpyrad, a commercial acaricide. These compounds display a strong acaricidal activity that is either comparable to or better than that of the commercial compound.

Vinyl Fluorides: Competent Olefinic Counterparts in the Intramolecular Pauson–Khand Reaction

Despite the great advances achieved in the Pauson-Khand reaction and the ever-increasing demand for fluorinated compounds, the use of vinyl fluorides as olefinic counterparts in the above-mentioned transformation had been completely overlooked. Herein, we describe, for the first time, the intramolecular Pauson-Khand reaction of enynes containing a vinyl fluoride moiety.

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Fluorinated Chaperone−β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease

Amphiphilic glycomimetics encompassing a rigid, undistortable nor-tropane skeleton based on 1,6-anhydro-L-idonojirimycin and a polyfluorinated antenna, when formulated as the corresponding inclusion complexes with β-cyclodextrin (βCD), have been shown to behave as pharmacological chaperones (PCs) that efficiently rescue lysosomal β- glucocerebrosidase mutants associated to the neuronopathic variants of Gaucher disease (GD), including the highly refractory L444P/L444P and L444P/P415R single nucleotide polymorphs, in patient fibroblasts. The body of work here presented includes the design criteria for the PC prototype, the synthesis of a series of candidates, the characterization of the PC:βC…

ChemInform Abstract: Synthesis and Reactivity of β-Amino α,β-Unsaturated Oxa- and Thiazolines.

Abstract A simple and efficient route to masked β-amino-α,β-unsaturated acids 3 by reaction of metalated oxa- and thiazolines with nitriles has been developed. The reactivity of 3 has also been explored.

γ-Silylboronates in the chiral Brønsted acid-catalysed allylboration of aldehydes.

The use of functionalised allylboronic esters in the catalytic enantioselective allylboration of aldehydes is described for the first time. γ-Silylallyl pinacolate derivatives give rise to α-silyl homoallylic alcohols in high yields, with complete diastereoselectivities and high enantioselectivities, in most of the cases. The usefulness of such intermediates is showcased by their transformation into fluorinated allylic alcohols.

Organocatalytic approach to benzofused nitrogen-containing heterocycles: enantioselective total synthesis of (+)-angustureine.

Enantioselective organocatalytic intramolecular aza-Michael reaction: a concise synthesis of (+)-sedamine., (+)-allosedamine, and (+)-coniine

The intramolecular aza-Michael reaction of carbamates bearing remote alpha,beta-unsaturated aldehydes under organocatalytic conditions took place with good yields and excellent ee's when Jorgensen catalyst IV was used in the process, giving rise to the enantioselective formation of several five- and six-membered heterocycles. The developed methodology was applied to the synthesis of three piperidine alkaloids.

Fluorine in Medicinal Chemistry and Chemical Biology. Edited by Iwao Ojima.

Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms

Background: There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms. Methods: Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GA…

Microwave-Assisted Organocatalytic Enantioselective Intramolecular aza-Michael Reaction with α,β-Unsaturated Ketones

An organocatalytic enantioselective intramolecular aza-Michael reaction of carbamates bearing conjugated ketones as Michael acceptors is described. By using 9-amino-9-deoxy-epi-hydroquinine as the catalyst and pentafluoropropionic acid as a co-catalyst, a series of piperidines, pyrrolidines, and the corresponding benzo-fused derivatives (indolines, isoindolines, tetrahydroquinolines, and tetrahydroisoquinolines) can be obtained in excellent yields and enantioselectivities. In addition, the use of microwave irradiation at 60 °C improves the efficiency of the process giving rise to the final products with comparable yields and enantiomeric excesses. Some mechanistic insights are also consider…

ChemInform Abstract: Fluorous TBAF: A Convenient and Selective Reagent for Fluoride-Mediated Deprotections.

A fluorous analogue of TBAF has been developed for its use in the clean removal of silicon-derived protecting groups. Purification of the crude mixtures by fluorous solid-phase extractions allowed alcohols, amines, and carboxylic acids to be obtained in high purity, with no need of chromatographic separations. The moderate reactivity of fluorous TBAF was exploited in selective deprotections of several bifunctional molecules.

Pentafluoroethylation of Carbonyl Compounds by HFC-125 via the Encapsulation of the K Cation with Glymes

A simple protocol to overcome the explosive pentafluoroethylation of carbonyl compounds by HFC-125 is described. The use of potassium (K) bases with triglyme or tetraglyme as a solvent safely yield...

New Cathepsin Inhibitors to Explore the Fluorophilic Properties of the S 2 Pocket of Cathepsin B: Design, Synthesis, and Biological Evaluation

5 páginas, 1 figura, 2 tablas -- PAGS nros. 5256-5260

Biochemical quantitation of the eIF5A hypusination in Arabidopsis thaliana uncovers ABA-dependent regulation.

The eukaryotic translation elongation factor eIF5A is the only protein known to contain the unusual amino acid hypusine which is essential for its biological activity. This post-translational modification is achieved by the sequential action of the enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase (DOHH). The crucial molecular function of eIF5A during translation has been recently elucidated in yeast and it is expected to be fully conserved in every eukaryotic cell, however the functional description of this pathway in plants is still sparse. The genetic approaches with transgenic plants for either eIF5A overexpression or antisense have revealed some activities related to t…

Design, Synthesis, and Biological Evaluation of Novel Fluorinated Ethanolamines

The preparation of novel fluorinated allylamines and their use as key fragments for the stereoselective synthesis of hydroxyethyl secondary amine (HEA)-type peptidomimetics is described. Our strategy employs chiral sulfinyl imines as synthesis intermediates, by treatment of hemiaminal precursors with two equivalents of vinylmagnesium bromide. The subsequent oxidation of the allylic amines to the corresponding epoxides was achieved by treatment with methyl(trifluoromethyl)dioxirane. Finally, epoxide ring opening with a range of nitrogen nucleophiles provided a library of HEA-derived peptidomimetics with a phenyldifluoromethylene moiety. The biological evaluation of these derivatives revealed…

Selective Transformation of Norbornadiene into Functionalized Azaheterocycles and β‐Amino Esters with Stereo‐ and Regiocontrol

Novel functionalized azaheterocycles with multiple chiral centers have been accessed from readily available norbornene β-amino acids or β-lactams across a stereocontrolled synthetic route, based on ring-opening metathesis (ROM) of the staring unsaturated bicyclic amino esters, followed by selective cyclization through ring-closing metathesis (RCM). The RCM transformations have been studied under various experimental conditions to assess the scope of conversion, catalyst, yield, and substrate influence. The structure of the starting norbornene β-amino acids predetermined the structure of the new azaheterocycles, and the developed synthetic route took place with the conservation of the config…

Fluorous (Trimethylsilyl)ethanol:  A New Reagent for Carboxylic Acid Tagging and Protection in Peptide Synthesis

Starting with a fluorous analogue of 2-(trimethylsilyl)ethanol, we have designed an easy method for preparing a new fluorous tag ((F)TMSE) for the protection of carboxylic acids. Because mild conditions are employed in the tag cleavage (TBAF in the presence of 4 A molecular sieves, which prevent racemization), this tag can be advantageously used in the synthesis of peptides and modified peptides, as we have demonstrated with several examples, including the fluorous synthesis of short alpha- and beta-peptides as well as of modified fluorinated retropeptides.

Tandem gold self-relay catalysis for the synthesis of 2,3-dihydropyridin-4(1 H)-ones: combination of σ and π Lewis acid properties of gold salts.

The dual ability of gold salts to act as π- and σ Lewis acids has been exploited in a tandem self-relay catalysis. Thus, triphenylphosphanegold(I) triflate mediated the intramolecular carbonyl addition of the amide functionality of homoprogargyl amides to a triple bond. The formation of a σ complex of the gold salt with the intermediate oxazine promoted a nucleophilic addition followed by a Petasis-Ferrier rearrangement. This tandem protocol, catalyzed by the same gold salt under the same reaction conditions, gave rise to the efficient synthesis of 2,3-dihydropyridin-4-(1 H)-ones, which contain a cyclic quaternary α-amino acid unit. The asymmetric version was performed by generating the sta…

Tandem cross enyne metathesis (CEYM)–intramolecular Diels–Alder reaction (IMDAR). An easy entry to linear bicyclic scaffolds

A new tandem cross enyne metathesis (CEYM)–intramolecular Diels–Alder reaction (IMDAR) has been carried out. It involves conjugated ketones, esters or amides bearing a remote olefin and aromatic alkynes as the starting materials. The overall process enables the preparation of a small family of linear bicyclic scaffolds in a very simple manner with moderate to good levels of diastereoselectivity. This methodology constitutes one of the few examples that employ olefins differently than ethylene in tandem CEYM–IMDAR protocols.

N-sulfinyl amines as a nitrogen source in the asymmetric intramolecular aza-Michael reaction: total synthesis of (-)-pinidinol.

N-Sulfinyl amines have been successfully employed as nitrogen nucleophiles for the asymmetric intramolecular aza-Michael reaction. The synthetic strategy involves a cross-metathesis reaction followed by the Michael-type cyclization, either in a base-catalyzed two-step procedure or in a tandem fashion. The developed methodology allows access to chiral substituted pyrrolidines and piperidines bearing one or two stereocenters and it has been applied to the synthesis of the piperidine alkaloid (-)-pinidinol.

An efficient synthesis of new fluorinated uracil derivatives.

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields. Fustero Lardies, Santos, Santos.Fustero@uv.es ; Sanz Cervera, Juan Francisco, Juan.F.Sanz@uv.es ; Asensio Martinez, Amparo, Amparo.Asensio@uv.es

ChemInform Abstract: Asymmetric Synthesis of Fluorinated Isoindolinones Through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates.

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding α-fluoroalkyl o-iodobenzylamines. A base-mediated anti β-hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pKa of the base.

Inside Cover: Synthesis and Application of β-Substituted Pauson-Khand Adducts: Trifluoromethyl as a Removable Steering Group (Angew. Chem. Int. Ed. 20/2013)

Benzodiazines: recent synthetic advances.

Benzodiazines (diazonaphthalenes with both nitrogens in the same ring) – cinnolines (1,2-benzodiazine), quinazolines (1,3-benzodiazine), phthalazines (2,3-benzodiazine) and quinoxalines (1,4-benzodiazine) – are important class of compounds with broad biological properties and wide application in pharmaceutical as well as agrochemical arenas. These diazaheterocycles are present in a wide variety of bioactive natural products as well as synthetic molecules that are good drug candidates constituting key structural units responsible for their pronounced therapeutic activities. Their rapidly growing uses and applications in medicinal and agrochemical arenas prompt the researchers for further stu…

Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Structural analysis of modern pharmaceutical practices allows for the identification of two rapidly growing trends: the introduction of tailor-made amino acids and the exploitation of fluorinated motifs. Curiously, the former represents one of the most ubiquitous classes of naturally occurring compounds, whereas the latter is the most xenobiotic and comprised virtually entirely of man-made derivatives. Herein, 39 selected compounds, featuring both of these traits in the same molecule, are profiled. The total synthesis, source of the corresponding amino acids and fluorinated residues, and medicinal chemistry aspects and biological properties of the molecules are discussed.

A practical entry to β-aryl-β-alkyl amino alcohols: application to the synthesis of a potent BACE1 inhibitor

The 1,2-addition of alkyl Grignard reagents to readily available N-tert-butanesulfinyl ketimines, bearing an α-silyloxy substituent, proceeds in high yields and excellent diastereocontrol. The utility of the present method was demonstrated by the synthesis, in enantiomerically pure form, of one recently disclosed β-secretase (BACE1) inhibitor.

Asymmetric Synthesis of Fluorinated Monoterpenic Alkaloid Derivatives from Chiral Fluoroalkyl Aldimines via the Pauson‐Khand Reaction

Asymmetric Allylation/RCM-Mediated Synthesis of Fluorinated Benzo-Fused Bicyclic Homoallylic Amines As Dihydronaphthalene Derivatives

Enantiomerically enriched fluorinated benzo-fused bicyclic homoallylic amities have been synthesized through an asymmetric allylation/ring closing metathesis (RCM) sequence. This sequence has been carried out using alpha-trifluoromethylstyrene derivatives as key intermediates, synthesized by microwave radiation. The great deactivating effect exerted by such substituents has been brought to light by a comparative study.

Synthesis and biological evaluation of new bicyclic fluorinated uracils through ring-closing metathesis.

Two families of bicyclic fluorinated uracils have been prepared starting from a gem-difluorinated unsaturated nitrile, by means of a ring-closing metathesis reaction to form the new ring, which is fused at the C-5/C-6 or N-1/C-6 positions of the uracil moiety. The selective formation of olefin regioisomers in the metathesis process can be controlled according to the reaction conditions (catalyst, solvent, and temperature). The acaricidal activities of the resulting compounds have also been investigated.

ChemInform Abstract: Selective Formal Transesterification of Fluorinated 2-(Trimethylsilyl)ethyl α-Imino Esters Mediated by TBAF.

The scope of the transesterification reaction between β-fluorinated α-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated α-imino esters.

An efficient synthesis of new fluorinated uracil derivativesElectronic supplementary information (ESI) available: general procedures for the preparation of compounds 3, 6 ,7, 8 and 9. See http://www.rsc.org/suppdata/cc/b3/b300796k/

A series of potentially biologically active fluorinated uracil derivatives has been prepared in three steps from oxazolines and fluorinated nitriles with good chemical yields.

Diels-Alder Reactions of 2-Azabutadienes with Aldehydes: Ab Initio and Density Functional Theoretical Study of the Reaction Mechanism, Regioselectivity, Acid Catalysis, and Stereoselectivity

The Diels−Alder reaction of 2-azabutadiene with aldehydes has been studied using high level ab initio molecular orbital and density functional methods. Multiconfigurational calculations were carried out on the concerted and stepwise mechanisms. At the CASPT2F/6-31G*//CASSCF/6-31G* level of theory, the [π4s + π2s]-cycloaddition of 2-azabutadiene with formaldehyde is predicted to be a concerted reaction, in good agreement with the experimental evidence. The regio- and stereoselectivity of the reaction was studied at the HF/6-31G*, MP2/6-31G*, and Becke3LYP/6-31G* levels of theory. The density functional calculations appears to give a good description of the basic features of the reaction. The…

Cover Picture: A Versatile Approach to CF3-Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors (Chem. Eur. J. 33/2015)

Synthesis and reactivity of β-amino-α,β-unsaturated oxa- and thiazolines

Abstract A simple and efficient route to masked β-amino-α,β-unsaturated acids 3 by reaction of metalated oxa- and thiazolines with nitriles has been developed. The reactivity of 3 has also been explored.

Gold-Catalyzed Povarov-Type Reaction of Fluorinated Imino Esters and Furans

A gold-catalyzed Povarov-type reaction of fluorinated imino esters and furans is described. The process, which takes place in dichoromethane at room temperature, gives rise to novel fluorinated tetrahydrofuran-fused tetrahydroquinolines in good yields and moderate levels of diastereo-selectivity in a very simple manner. The reported examples expand the versatility of the Povarov reaction to unprecedented fluorinated substrates, generating scaffolds that contain quaternary alpha-amino acid units.

Organocatalyticanti-Selective Mannich Reactions with Fluorinated Aldimines: Synthesis ofanti-γ-Fluoroalkyl-γ-amino Alcohols

The asymmetric Mannich reaction between fluoroalkyl aldimines and aldehydes catalyzed by α,α-diphenylprolinol trimethylsilyl ether is reported. The corresponding Mannich adducts were reduced in situ to afford anti-β-alkyl-γ-fluoroalkyl-γ-amino alcohols in moderate yields and with very high diastereo- and enantioselectivities. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Unique Reactivity of Fluorinated Molecules with Transition Metals

Organofluorine and organometallic chemistry by themselves constitute two potent areas in organic synthesis. Thus, the combination of both offers many chemical possibilities and represents a powerful tool for the design and development of new synthetic methodologies leading to diverse molecular structures in an efficient manner. Given the importance of the selective introduction of fluorine atoms into organic molecules and the effectiveness of transition metals in C–C and C–heteroatom bond formation, this review represents an interesting read for this aim.

Microwave-assisted tandem cross metathesis intramolecular Aza-Michael reaction: an easy entry to cyclic beta-amino carbonyl derivatives.

Hoveyda−Grubbs catalyst in combination with BF3·OEt2 efficiently promotes tandem cross metathesis intramolecular aza-Michael reaction between enones and unsaturated carbamates resulting in the creation of β-amino carbonyl units. The use of microwave irradiation dramatically accelerates the process, enhancing the synthetic utility of this methodology for the preparation of these types of derivatives. When enantiomerically enriched α-branched amines were used as starting materials, the process was also very efficient, although with modest selectivity in the newly created stereocenter. The use of microwave irradiation led to an interesting effect, inverting the selectivity in the addition proc…

Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding -fluoroalkyl o-iodobenzylamines. A base-mediated anti -hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pK(a) of the base.

ChemInform Abstract: Diastereodivergent Synthesis of Fluorinated Cyclic β3-Amino Acid Derivatives.

The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions.

Recent developments and applications of the chiral Brønsted acid catalyzed allylboration of carbonyl compounds

The 50-year-old allylboration reaction has seen dramatic developments since the dawn of the new century after the first catalytic asymmetric versions came into play. In the past decade alone, several methodologies capable of achieving the desired homoallylic alcohols in over 90% ee have been developed. This review focuses on the chiral Brønsted acid catalyzed allylboration reaction, covering everything from the very first examples and precedents to modern day variations and applications.1 Introduction2 Early Developments3 Synthetic Applications4 Variants5 Computational Contribution6 Conclusions

A New Tandem Cross Metathesis-Intramolecular Aza-Michael Reaction for the Synthesis of α,α-Difluorinated Lactams

A new tandem cross metathesis–intramolecular aza-Michael­ reaction in which an α,α-difluorinated amide serves as a source of nucleophilic nitrogen is described. This process gives rise to a new family of fluorinated γ- and δ-lactams. The tandem protocol is catalyzed by the Hoveyda–Grubbs second-generation ruthenium catalyst with titanium(IV) tetraisopropoxide as a co-catalyst and it is highly efficient when conjugated ketones are used as the Michael acceptors. With conjugated esters, however, it is necessary to perform a step-by-step procedure in which the cyclization event is activated by the addition of a base. An asymmetric version of the process is also evaluated.

Olefin-Bond Chemodifferentiation through Cross-Metathesis Reactions: A Stereocontrolled Approach to Functionalized β2,3 -Amino Acid Derivatives

Tandem Nucleophilic Addition−Intramolecular Aza-Michael Reaction: Facile Synthesis of Chiral Fluorinated Isoindolines

A highly stereoselective synthesis of fluorinated 1,3-disubstituted isoindolines is described. To this end, a tandem reaction consisting of a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by an intramolecular aza-Michael reaction has been developed. This strategy allows for the construction of isoindolines bearing several degrees of fluorination (mono-, di-, or trifluoromethyl as well as heavier fluorinated groups). In the majority of all cases, the products are formed as single isomers.

A new method for the regioselective synthesis of β-enamino acid derivatives

Abstract A mild, simple and efficient route to β-enamino imidazole carbonilic derivatives 3 by reaction of ketimines with N,N′ -carbonyl diimidazole in the presence of boron triflouride as catalyst has been developed. The conversion of 3 to esters has also been explored.

Asymmetric Vinylogous Mukaiyama‐Mannich Reactions of Heterocyclic Siloxy Dienes with Ellman's Fluorinated Aldimines

ChemInform Abstract: Addition of Nucleophiles to Fluorinated Michael Acceptors.

A series of nucleophiles, including primary and secondary amines, primary alcohols, and thiols, as well as diethyl malonate and nitromethane, were added to different fluorinated Michael acceptors including 2-fluoroalk-1-en-3-ones and 2-fluoro-1-phenylprop-2-en-1-one. The resulting β-substituted α-fluoro ketones were isolated in 34–92 % yield, depending on the substrate and the nucleophile. The best yields were obtained with secondary amines and with p-methylthiophenol.

Chiral Brønsted Acid-Catalyzed Asymmetric Allyl(propargyl)boration Reaction of ortho-Alkynyl Benzaldehydes: Synthetic Applications and Factors Governing the Enantioselectivity

Chiral Bronsted acid-catalyzed allyl(propargyl)boration of ortho-alkynyl benzaldehydes gives rise to ω-alkynyl homoallylic(homopropargylic)alcohols that can be further transformed to complex molecular scaffolds via subsequent hydroalkoxylation, ring-closing enyne metathesis (RCEYM), or intramolecular Pauson–Khand reaction (PKR). Optimizations of each two-step transformation is reported. A strong dependence between enantioselectivities and the nature of the substitution at the alkynyl moiety is observed, showcasing that the triple bond is not merely a spectator in this transformation. Density functional theory (DFT) calculations (M06-2X/6-311+G(d,p)–IEFPCM//B3LYP/6-31G(d)) show that this dep…

Selective Formal Transesterification of Fluorinated 2-(Trimethylsilyl)ethyl α-Imino Esters Mediated by TBAF

The scope of the transesterification reaction between beta-fluorinated alpha-imino esters and various electrophiles in the presence of TBAF as fluorine source is described. The reaction is highly selective for alkyl iodides, bromides, and mesylates, while alkyl chlorides react at a significantly slower rate and tosylates do not react under the reaction conditions. This methodology represents a simple and useful alternative for the preparation of a wide variety of fluorinated alpha-imino esters.

ChemInform Abstract: Gold-Catalyzed Intramolecular Hydroamination of o-Alkynylbenzyl Carbamates: A Route to Chiral Fluorinated Isoindoline and Isoquinoline Derivatives.

Title compounds are prepared in enantiomerically pure form by the diastereoselective addition of fluorinated nucleophiles to N-(tert-butanesulfinyl)imines (I) followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate.

Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins

A simple, user-friendly, metal-free protocol for the regioselective anti-Markovnikov hydrofluorination of olefins using readily available and inexpensive reagents has been developed. This new approach displays a broader scope than previously reported methodologies and has been applied to the late-stage fluorination of a complex molecule, giving rise to a fluorosteroid derivative. The stereochemistry of the process has also been studied in some detail.

Asymmetric Vinylogous Mannich-Type Addition of α,α-Dicyanoalkenes to α-Fluoroalkyl Sulfinyl Imines

Abstract. The asymmetric vinylogous Mannich reaction (AVMR) of alfa,alfa-dicyanoalkenes with alfa-fluoroalkyl sulfinyl imines has been successfully accomplished. This transformation is unprecedented with fluorinated imines at the same time as the use of dicyanoalkenes in AVMR has been scarcely reported. Several fluorinated sulfinyl imines are compatible with the process, which gaves access to a family of chiral fluorinated amines with excellent level of stereocontrol. Interestingly, the selectivity found in our protocol is reverse to that encountered in analogous AVMR previously reported. Additionally, the synthetic applicability of the addition products has been exemplified with several tr…

New Fluorinated 1,3-Vinylogous Amidines as Versatile Intermediates: Synthesis of Fluorinated Pyrimidin-2(1H)-ones.

The condensation of the azaenolates derived from readily available ketimines with fluorinated nitriles offers an efficient and straightforward entry to new fluorinated 1,3-vinylogous amidines. These versatile compounds, in turn, react with triphosgene to yield new fluorinated pyrimidin-2(1H)-ones in high yields.

Activation of Neurogenesis in Multipotent Stem Cells Cultured In Vitro and in the Spinal Cord Tissue After Severe Injury by Inhibition of Glycogen Synthase Kinase-3

AbstractThe inhibition of glycogen synthase kinase-3 (GSK-3) can induce neurogenesis, and the associated activation of Wnt/β-catenin signaling via GSK-3 inhibition may represent a means to promote motor function recovery following spinal cord injury (SCI) via increased astrocyte migration, reduced astrocyte apoptosis, and enhanced axonal growth. Herein, we assessed the effects of GSK-3 inhibition in vitro on the neurogenesis of ependymal stem/progenitor cells (epSPCs) resident in the mouse spinal cord and of human embryonic stem cell–derived neural progenitors (hESC-NPs) and human-induced pluripotent stem cell–derived neural progenitors (hiPSC-NPs) and in vivo on spinal cord tissue regenera…

Recent advances in the synthesis of functionalised monofluorinated compounds.

Over the past few years, we have tackled the synthesis of interesting monofluorinated organic molecules, such as: dihydronaphthalene derivatives, β-fluoro sulfones and related carbonyl compounds, fluorohydrins and allylic alcohols. Overall, a wide range of modern synthetic techniques are covered in this feature article including transition-metal, photo- and organocatalysis, nucleophilic and electrophilic fluorinations, chiral auxiliaries and enantioselective catalysis.

Relay Catalysis: Enantioselective Synthesis of Cyclic Benzo-Fused Homoallylic Alcohols by Chiral BrOnsted Acid-Catalyzed Allylboration/Ring Closing Metathesis

Six- and seven-membered benzo-fused cyclic homoallylic alcohols can be readily synthesized by a tandem chiral BrOnsted acid-catalyzed allyl (crotyl)boration/ring closing metathesis sequence performed under orthogonal relay catalysis conditions. Excellent enantio- and diastereoselectivities are obtained in most of the cases. In addition, the parent crotylboration/RCM process is also described. The required substrates, ortho-vinylbenzaldehydes, are readily available in one step from commercially available starting materials. Both catalysts and reactants are also available from commercial suppliers. The reaction shows broad functional group compatibility and is also suitable for heteroaromatic…

ChemInform Abstract: Synthesis and Reactivity of New β-Enamino Acid Derivatives: A Simple and General Approach to β-Enamino Esters and Thioesters.

A new strategy has been developed for the synthesis of several β-enamino acid derivatives. N,N‘-Carbonyldiimidazole has been used as C-acylating agent of methyl ketimines, providing a direct and simple route to new β-enamino carbonyl imidazole derivatives 2. These derivatives 2 were cleanly and efficiently transformed into β-enamino esters 4 (X = O) and thioesters 4 (X = S) by reaction with a great variety of alcohols and thiols, including tertiary ones. Alternative and complementary routes to compounds 4 were also investigated. In addition, β-keto esters 6 have been obtained by mild acid hydrolysis of β-enamino esters 4.

Asymmetric tandem reactions: New synthetic strategies

The use of domino and multicomponent reactions in asymmetric synthesis is constantly increasing nowadays. This allows for the synthesis of complex molecules in a single synthetic sequence, usually with high atom economy. Herein, we report three examples of new asymmetric tandem reactions recently developed in our laboratories, giving rise to new families of enantiomerically enriched fluorinated and nonfluorinated heterocycles. Thus, 1,4-dihydropyridines (1,4-DHPs) bearing fluorinated substituents at C6 were assembled by means of a Hantzsch-type reaction; cyclic β-amino carbonyl derivatives were prepared using a cross-metathesis (CM)–intramolecular aza-Michael sequence; while fluorinated ind…

ChemInform Abstract: A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

When the principle of vinylogy is applied to imines as electrophiles, the so-called vinylogous Mannich reaction (VMR), γ-aminocarbonyl (such as butenolides) and β-aminocarbonyl compounds are generated in a very efficient manner. The asymmetric version of this vinylogous Mannich reaction gives access to highly functionalized chiral synthons, which are suitable for further transformations. The versatility of this methodology is exemplified with the synthesis of several alkaloids and natural products. 1 Introduction 2 Asymmetric Vinylogous Mannich Reactions (VMR) with 2-Silyl­oxyfurans and 2-Silyloxypyrroles 3 Asymmetric VMR with Acyclic Silyl Dienolates and Silyl Dienol Ketene Acetals 4 Asymm…

Anionic-anionic asymmetric tandem reactions: one-pot synthesis of optically pure fluorinated indolines from 2-p-tolylsulfinyl alkylbenzenes.

Organocatalytic enantioselective synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide

The organocatalytic synthesis of quinolizidine alkaloids (+)-myrtine, (-)-lupinine, and (+)-epiepiquinamide is described. It involved, as the key step, an enantioselective intramolecular aza-Michael reaction (IMAMR) catalyzed by Jorgensen catalyst I, affording the common precursor with high enantioselectivity. This compound was subsequently transformed into the three alkaloids in a highly diastereoselective manner. (C) 2011 Elsevier Ltd. All rights reserved.

Solution versus Fluorous versus Solid-Phase Synthesis of 2,5-Disubstituted 1,3-Azoles. Preliminary Antibacterial Activity Studies

A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate α-amido-β-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson’s reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used as a starting material, the synthesis can be easily completed without column chromatography purification of intermediate compounds with good to excellent yields, thus affording a suitable entry to the prepara…

A Decade of Advance in the Asymmetric Vinylogous Mannich Reaction

When the principle of vinylogy is applied to imines as electrophiles, the so-called vinylogous Mannich reaction (VMR), γ-aminocarbonyl (such as butenolides) and β-aminocarbonyl compounds are generated in a very efficient manner. The asymmetric version of this vinylogous Mannich reaction gives access to highly functionalized chiral synthons, which are suitable for further transformations. The versatility of this methodology is exemplified with the synthesis of several alkaloids and natural products. 1 Introduction 2 Asymmetric Vinylogous Mannich Reactions (VMR) with 2-Silyl­oxyfurans and 2-Silyloxypyrroles 3 Asymmetric VMR with Acyclic Silyl Dienolates and Silyl Dienol Ketene Acetals 4 Asymm…

New approaches to the synthesis of organofluorine nitrogenated derivatives

Fluorinated carboxylic acids are valuable building blocks for several types of organofluorine nitrogenated derivatives. In this review paper, several strategies that use these compounds as starting materials are described. First, fluorinated seven-membered cyclic β-amino esters can be diastereoselectively synthesized from these compounds with a ring-closing metathesis (RCM) reaction as the key step. The use of the RCM reaction in a different approach enables the preparation of fluorinated cyclic α-amino acid derivatives. Fluorinated carboxylic acids also constitute the starting material for the asymmetric synthesis of fluorinated allylic amines. Finally, a solution and solid-phase synthesis…

Asymmetric Synthesis of New β,β-Difluorinated Cyclic Quaternary α-Amino Acid Derivatives

The synthesis of new beta,beta-difluorinated cyclic quaternary alpha-amino acid derivatives 1 in which a ring-closing metathesis reaction (RCM) constitutes the key step is described. The approach employs imidoyl chlorides 3 as fluorinated building blocks, and the overall process involves the stereoselective creation of a quaternary stereocenter. Complete selectivity was achieved when (R)-phenylglycinol methyl ether was used as chiral auxiliary, allowing for the preparation of new six-membered cyclic fluorinated alpha-amino acids as single enantiomers.

Synthesis and NMR configurational study of imidazo[2,1-b]thiazoles from 1H-1,4-diazepine-7(6H)-thiones

Abstract A thermal intramolecular cyclization of 1-vinyl2,3-dihydro-3 H -imidazole-2-thiones to imidazo[2,1-b]thiazoles is reported. A heteronuclear correlation study of these systems was made in order to establish the configuration of the products.

ChemInform Abstract: Synthesis of Fluorinated Allylic Amines: Reaction of 2-(Trimethylsilyl)ethyl Sulfones and Sulfoxides with Fluorinated Imines.

A new synthesis of fluorinated allylamines through the reaction of 2-(trimethylsilyl)ethyl sulfones and sulfoxides (as vinyl anion equivalents) with imines and imino esters has been described. The process includes a TBAF-mediated fragmentation of 2-(trimethylsilyl)ethyl sulfones to afford the desired allylic amines. When the reaction is performed with the corresponding sulfoxides, the fragmentation takes place under the addition conditions, affording the final products in a single step.

ChemInform Abstract: A New Strategy for the Synthesis of Fluorinated 3,4-Dihydropyrimidinones.

A new family of 3,4-dihydropyrimidinones (DHPMs) bearing fluorinated substituents at C6 have been prepared from gem-difluorinated nitriles, alkyl 3-butenoates and iso(thio)cyanates. This novel Biginelli-type process relies on the γ-addition of the ester-derived enolate to fluorinated nitriles. A tandem nucleophilic addition aza-Michael reaction sequence completes the synthetic process.

A Concise, Asymmetric Synthesis of Tetramic Acid Derivatives

[reaction: see text] A simple, asymmetric synthesis of tetramic acid derivatives is described in this paper. The key step is a carbonyl transfer from carbonyldiimidazole (CDI) to alpha-diimines (I) to form N-alkyl-4-alkylamino-5-methylenepyrrol-2-ones (II). In turn, these compounds can be easily transformed into tetramic acid derivatives (III) in two additional steps.

Recent Advances in the Synthesis of Pyrazoles. A Review

Pyrazole (Figure 1), a five-membered, two-nitrogen-containing heterocycle ring, is widely found as the core structure in a large variety of compounds that possess important agrochemical and pharmac...

AuX3-Mediated Selective Head-to-Head Dimerization of Difluoropropargyl Amides

A dimerization of difluoropropargyl amides by reaction with gold(III) halides is described. A reductive elimination of a divinylgold species can be invoked to rationalize its formation. Initial studies of the unusual reactivity of these 1,4-dihalo-1,3-dienes have been performed.

Asymmetric Allylation/Ring Closing Metathesis: One-Pot Synthesis of Benzo-fused Cyclic Homoallylic Amines. Application to the Formal Synthesis of Sertraline Derivatives

A one-pot asymmetric allylation/ring closing metathesis (RCM) sequence for the synthesis of cyclic homoallylic amines has been developed. A library of six- and seven-membered benzo-fused products has been synthesized in good yields and complete diastereoselectivity. The new methodology has been applied to the formal syntheses of the antidepressant Sertraline and the epimeric Norsertraline. The methodology is amenable for the synthesis of analogs.

ChemInform Abstract: C-C versus C-N Annulation Reactions of 2-Alkyl-2-oxazolines and 2-Alkyl-2-thiazolines: A Simple Synthesis of Novel 3-Aminoindene, Phthalimidine, Pyrrolidine, and Piperidine Derivatives.

The effect of various aromatic and aliphatic dielectrophiles on the lithium azaenolates of 2-alkyl-2-oxazolines and 2-alkyl-2-thiazolines has been examined. This effect varies greatly, depending on the nature of the dielectrophile used. 3-Aminoindene (3) and 3-alkylidenephthalimidine (4−5) derivatives were formed as a result of the reactions with dielectrophiles derived from ortho-substituted benzonitriles. Similarly, 2-alkylidenepyrrolidine (7) and 2-alkylidenepiperidine (8) derivatives were obtained in high yields from 2-alkyl-2-oxazolines or 2-alkyl-2-thiazolines and aliphatic dielectrophiles derived from ω-haloalkyldiphenylacetonitrile. C−C versus C−N annulation reactions are discussed.

An efficient synthesis of uracil derivatives from 2-alkyl-Δ2-oxazolines and nitriles

An efficient and convenient synthesis of new fluorinated and non-fluorinated uracils is described herein. The condensation of nitriles with enolates generated from 2-alkyl-Δ 2 -oxazolines (I) affords fluorinated β-enamino acid derivatives, which react with triphosgene to give an isomeric mixture of oxazolopyrimidinones. These can then be easily transformed into a single C-6 pyrimidindione derivative through reaction with a suitable nucleophile.

C−C versus C−N Annulation Reactions of 2-Alkyl-2-oxazolines and 2-Alkyl-2-thiazolines: A Simple Synthesis of Novel 3-Aminoindene, Phthalimidine, Pyrrolidine, and Piperidine Derivatives

The effect of various aromatic and aliphatic dielectrophiles on the lithium azaenolates of 2-alkyl-2-oxazolines and 2-alkyl-2-thiazolines has been examined. This effect varies greatly, depending on the nature of the dielectrophile used. 3-Aminoindene (3) and 3-alkylidenephthalimidine (4−5) derivatives were formed as a result of the reactions with dielectrophiles derived from ortho-substituted benzonitriles. Similarly, 2-alkylidenepyrrolidine (7) and 2-alkylidenepiperidine (8) derivatives were obtained in high yields from 2-alkyl-2-oxazolines or 2-alkyl-2-thiazolines and aliphatic dielectrophiles derived from ω-haloalkyldiphenylacetonitrile. C−C versus C−N annulation reactions are discussed.

New Strategy for the Stereoselective Synthesis of Fluorinated β-Amino Acids

Racemic and chiral nonracemic alpha-substituted and alpha-unsubstituted beta-fluoroalkyl beta-amino acid derivatives 6 and 9 have been synthesized in two steps starting from fluorinated imidoyl chlorides 1 and ester enolates. This approach is based on the chemical reduction of previously obtained gamma-fluorinated beta-enamino esters 4 by using ZnI(2)/NaBH(4) in a nonchelated aprotic medium (dry CH(2)Cl(2)) as the reducing agent. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction. The process takes place with high yields and with moderate to good diastereoselectivity. The best results related to diastereoselective reduction…

Olefin metathesis reactions with fluorinated substrates, catalysts, and solvents.

ChemInform Abstract: Solution and Fluorous Phase Synthesis of β,β-Difluorinated 1-Amino-1-cyclopentane Carboxylic Acid Derivatives.

An efficient protocol for the preparation of β,β-difluorinated 1-amino-1-cyclopentane carboxylic acid derivatives was developed. 2,2-Difluro-4-phenyl-3-butenoic acid 6 was used as substrate for the preparation of the starting vinyl difluoro imino esters 8. The key steps of this methodology rely on the chemo- and diastereoselective addition of allylzinc bromides over the iminic functionality of 8 and subsequent RCM reaction. This synthetic sequence was successfully applied to fluorous synthesis.

Asymmetric synthesis of fluorinated amino macrolactones through ring-closing metathesis

The synthesis of new chiral fluorinated amino and azamacrolactones of types 1 and 2 is described. A ring-closing metathesis (RCM) reaction constitutes the key step in this methodology, which uses fluorinated amino alcohols 7 as starting materials. The influence of the CF2 group, which is located in the alpha-position relative to the carbon bearing the amino group, on the efficiency of the RCM reaction is noteworthy. This method allows for the preparation of the desired fluorinated macrolactones in excellent yields.

Intramolecular Michael reaction of tert-butylsulfinyl ketimines: asymmetric synthesis of 3-substituted indanones.

Aromatic tert-butylsulfinyl ketimines bearing a suitable Michael acceptor at the ortho position readily undergo an intramolecular conjugate addition achieving indanone derivatives in good yields and complete diastereoselectivity.

ChemInform Abstract: A New Method for the Regioselective Synthesis of β-Enamino Acid Derivatives.

Abstract A mild, simple and efficient route to β-enamino imidazole carbonilic derivatives 3 by reaction of ketimines with N,N′ -carbonyl diimidazole in the presence of boron triflouride as catalyst has been developed. The conversion of 3 to esters has also been explored.

ChemInform Abstract: Asymmetric Allylation/Pauson-Khand Reaction: A Simple Entry to Polycyclic Amines. Application to the Synthesis of Aminosteroid Analogues.

Asymmetric allylation of o-iodoarylsulfinylimines has been achieved in high diastereoselectivities. The thus-obtained o-iodoarylhomoallylic sulfinamides participate in a subsequent Sonogashira coupling followed by a diastereoselective intramolecular Pauson–Khand reaction. In this way, tricyclic amines showing a unique benzo-fused indenyl backbone were obtained. The methodology has been applied to the synthesis of amino steroid analogues.

Asymmetric Tandem Reactions: New Strategies and Applications

Abstract The application of allylic sulphoxides and, particularly, the chiral amine reagent tert-butanesulphinamide has been extended to three different tandem processes. The condensation of (R)-(+)-allyl p-tolyl sulphoxide, fluorinated nitriles and alkyl propiolates led to a new family of enantiomerically pure fluorine-containing 1,4- dihydropyridines. A diastereoselective nucleophilic addition of fluorinated nucleophiles onto (R)-(tert-butanesulphinyl) imines, followed by an intramolecular aza-Michael reaction gave rise to either fluorinated isoindolines or 3-substituted indanones in a stereoselective manner.

ChemInform Abstract: Diastereoselective Intramolecular Additions of Allyl- and Propargylsilanes to Iminium Ions: Synthesis of Cyclic and Bicyclic Quaternary Amino Acids.

Cyclization of the chiral imino lactones with allylic or propargylic groups required acidic conditions to afford spirocyclic (II) or (XII).

Fluorous TBAF: A Convenient and Selective Reagent for Fluoride-Mediated Deprotections

A fluorous analogue of TBAF has been developed for its use in the clean removal of silicon-derived protecting groups. Purification of the crude mixtures by fluorous solid-phase extractions allowed alcohols, amines, and carboxylic acids to be obtained in high purity, with no need of chromatographic separations. The moderate reactivity of fluorous TBAF was exploited in selective deprotections of several bifunctional molecules.

ChemInform Abstract: Anionic-Anionic Asymmetric Tandem Reactions: One-Pot Synthesis of Optically Pure Fluorinated Indolines from 2-p-Tolylsulfinyl Alkylbenzenes.

Organocatalytic enantioselective synthesis of trifluoromethyl-containing tetralin derivatives by sequential (hetero)Michael reaction–intramolecular nitrone cycloaddition

The enantioselective synthesis of tetralin derivatives bearing a trifluoromethylated all‐carbon quaternary stereocenter has been accomplished through a synthetic sequence comprising an organocatalytic β‐functionalization of ortho‐1‐trifluoromethylvinyl‐(hetero)aromatic conjugated aldehydes followed by the intramolecular nitrone 1,3‐cycloaddition reaction (INCR). Both nitromethane and N‐Cbz‐hydroxylamine were employed as nucleophiles in the initial organocatalytic conjugate addition step, which provided the chiral information required for the subsequent diastereoselective INCR. Although diastereoselectivity was moderate, good yields and enantioselectivities were, in general, obtained. Intere…

ChemInform Abstract: Microwave-Assisted Tandem Cross Metathesis Intramolecular Aza-Michael Reaction: An Easy Entry to Cyclic β-Amino Carbonyl Derivatives.

Hoveyda−Grubbs catalyst in combination with BF3·OEt2 efficiently promotes tandem cross metathesis intramolecular aza-Michael reaction between enones and unsaturated carbamates resulting in the creation of β-amino carbonyl units. The use of microwave irradiation dramatically accelerates the process, enhancing the synthetic utility of this methodology for the preparation of these types of derivatives. When enantiomerically enriched α-branched amines were used as starting materials, the process was also very efficient, although with modest selectivity in the newly created stereocenter. The use of microwave irradiation led to an interesting effect, inverting the selectivity in the addition proc…

Straightforward Stereoselective Access to Cyclic Peptidomimetics

The preparation of cyclic dipeptide mimetics from chiral imino lactones derived from (R)-phenylglycinol is described. Key steps of the synthetic route included the fully stereoselective construction of a quaternary center, the formation of six-, seven-, or eight-membered lactams by means of an RCM cyclization, and the introduction of a new amino group within the lactam ring. The synthesis of a tripeptide mimetic is also reported.

ChemInform Abstract: Base-Dependent Stereodivergent Intramolecular Aza-Michael Reaction: Asymmetric Synthesis of 1,3-Disubstituted Isoindolines.

For the reaction of the compounds (I) the careful choice of the base allows the exclusive formation of either cis or trans diastereoisomer with the exception of the trihalogenates (Ie) and (If), which afford the cis-products regardless of the base used.

Stereoselective Access to Fluorinated and Non-fluorinated Quaternary Piperidines: Synthesis of Pipecolic Acid and Iminosugar Derivatives

The preparation of optically pure quaternary piperidines, both fluorinated and non-fluorinated, has been achieved from a chiral imino lactone derived from (R)-phenylglycinol. In the case of the fluorinated derivatives, the addition of (trifluoromethyl)trimethylsilane (TMSCF(3)) followed by iodoamination and migration of the CF(3) group allowed access to four derivatives of α-(trifluoromethyl)pipecolic acid. A theoretical study of the CF(3)-group rearrangement has been carried out to help establish the reaction mechanism of this uncommon transformation. Moreover, a route to trifluoromethyl-substituted iminosugars was also developed through the diastereoselective dihydroxylation of suitable s…

A novel and selective fluoride opening of aziridines by XtalFluor-E. synthesis of fluorinated diamino acid derivatives.

The selective introduction of fluorine onto the skeleton of an aminocyclopentane or cyclohexane carboxylate has been developed through a novel and efficient fluoride opening of an activated aziridine ring with XtalFluor-E. The reaction proceeded through a stereoselective aziridination of the olefinic bond of a bicyclic lactam and regioselective aziridine ring opening with difluorosulfiliminium tetrafluoroborate with the neighboring group assistance of the sulfonamide moiety to yield fluorinated diamino acid derivatives. The method based on the selective aziridine opening by fluoride has been generalized to afford access to mono- or bicyclic fluorinated substances.

Innenrücktitelbild: Structure-Based Design of an RNA-Bindingp-Terphenylene Scaffold that Inhibits HIV-1 Rev Protein Function (Angew. Chem. 50/2013)

Biorelevant fluorine-containing N-heterocycles

Abstract Over the course of many decades, life sciences have gained an insight into the structure–activity relationship of biologically active molecules, thereby allowing for a deeper understanding of how such molecules can be modified to produce the desired effect within a living organism. The introduction of either a nitrogen-containing heterocycle or a fluorine-containing unit are commonly used strategies in the pharmaceutical and agrochemical industries to fine-tune the activity, toxicity, and metabolic stability, among other properties, of their respective products. Herein, an overview of the latest fluorine containing N-heterocyclic molecules of significant biological importance, eith…

Diastereoselective Intramolecular Additions of Allyl- and Propargylsilanes to Iminium Ions: Synthesis of Cyclic and Bicyclic Quaternary Amino Acids

Chiral imino lactones derived from (R)-phenylglycinol containing an allyl- or propargyltrimethylsilyl group in the side chain readily cyclized in the presence of acidic reagents to afford spirocyclic compounds with high diastereoselectivity. Removal of the chiral auxiliary produced 2-substituted 1-aminocycloalkanecarboxylic acids, whereas further cyclizations by means of metathesis or hydroamination reactions led to bicyclic derivatives of pipecolic acid and proline.

ChemInform Abstract: Enantioselective Palladium-Catalyzed Oxidative β,β-Fluoroarylation of α,β-Unsaturated Carbonyl Derivatives.

The site-selective palladium-catalyzed three-component coupling of deactivated alkenes, arylboronic acids, and N-fluorobenzenesulfonimide is disclosed herein. The developed methodology establishes a general, modular, and step-economical approach to the stereoselective β-fluorination of α,β-unsaturated systems.

Synthesis of fluorinated amino acid derivatives through late-stage deoxyfluorinations

Abstract Fluorine chemistry has represented a hot topic in drug research over the last decade. Because of their pharmaceutical potential, fluorine-containing amino acids and related derivatives have acquired high importance among medicinal chemists. Therefore their synthesis and the development of various synthetic methods for these types of molecular scaffolds have gained increasing interest in synthetic organic chemistry. The current review focuses on synthetic protocols towards fluorine-containing amino acid derivatives through late-stage fluorination with various nucleophilic reagents, describing the access of various open-chain and cyclic α-, β-, γ-amino acid derivatives.

Diastereodivergent Synthesis of Fluorinated Cyclic β(3)-Amino Acid Derivatives.

The ability of 2-p-tolylbenzyl carbanions to behave as a source of chiral benzylic nucleophiles has been shown in its reaction with fluorinated imines. The process takes place with high levels of stereocontrol, rendering the corresponding amines as single diastereoisomers. Subsequent cross-metathesis followed by intramolecular aza-Michael reaction makes the synthesis of fluorinated homoproline derivatives bearing three stereogenic centers possible. Furthermore, the selectivity of the cyclization process can easily be tuned up in a diastereodivergent manner simply by changing the reaction conditions.

Substrate-dependent fluorinations of highly functionalized cycloalkanes

Abstract Substrate-dependent fluorinations of several highly functionalized cycloalkanes with multiple stereocentres were investigated. The synthetic transformations were based on selective functionalization of the ring C C bonds of the readily available bicyclic β-lactams by epoxidation and regioselective nucleophilic oxirane opening with azide or cyanide, followed by hydroxy–fluorine exchange with Deoxofluor. Depending on the substituents and their relative steric arrangement, the attempted fluorinations produced different types of substituted cycloalkanes. These selective, substrate-directed synthetic procedures and their presumed pathways towards interesting highly functionalized fluori…

Fluorine-Containing Drugs Approved by the FDA in 2018

Over the last two decades, fluorine substitution has become one of the essential structural traits in modern pharmaceuticals. Thus, about half of the most successful drugs (blockbuster drugs) contain fluorine atoms. In this review, we profile 17 fluorine-containing drugs approved by the food and drug administration (FDA) in 2018. The newly approved pharmaceuticals feature several types of aromatic F and CF3 , as well as aliphatic (CF2 ) substitution, offering advances in the treatment of various diseases, including cancer, HIV, malarial and smallpox infections.

An Approach to 2,4-Substituted Pyrazolo[1,5-a]pyridines and Pyrazolo[1,5-a]azepines by Ring-Closing Metathesis

The ring-closing metathesis (RCM) reactions of dienylpyrazoles have been employed in the synthesis of pyrazolo[1,5-a]pyridine and pyrazolo[1,5-a]azepine derivatives. Based on this approach, the diastereoselective synthesis of potential peptidomimetics containing four amino acid residues with the second (i+1) and third (i+2) fragments having been substituted by bicyclic frameworks is described.

Synthesis of Fluorinated and Non-Fluorinated Bicyclic Amidines through Ring-Closing Metathesis

[EN] An efficient method for the synthesis of fluorinated and non-fluorinated imidazoazepines by a ring-closing metathesis reaction as the key step is described. The influence of the fluorine atoms on the preparation of these bicyclic systems is also studied.

Chemical Aspects of Human and Environmental Overload with Fluorine

Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons an…

First Highly Diastereoselective Synthesis of syn α-Methyl β-Fluoroalkyl β-Amino Esters

A new two-step approach for the diastereoselective synthesis of the syn α-methyl β-fluoroalkyl β-amino esters 4 has been developed. This approach is based on the chemical reduction of the fluorinated β-enamino esters 3, which have been previously obtained from imidoyl chlorides 1 and lithium ester enolates, with ZnI2/NaBH4 as the reducing agent. The process takes place with high syn diastereoselectivity and good to excellent yields. A metal-chelated six-membered model has been suggested to explain the stereochemical outcome of the reduction reaction.

New Fluorinated Peptidomimetics through Tandem Aza-Michael Addition to α-Trifluoromethyl Acrylamide Acceptors: Synthesis and Conformational Study in Solid State and Solution

A range of partially modified retro (PMR) psi[NHCH(2)] peptide mimetics containing a hydrolytically stable CH(2)CH(CF(3))CO unit have been synthesized. The first kind of peptidomimetics is obtained from the highly efficient aza-Michael addition of different amines to alpha-trifluoromethyl acrylamide acceptors. Subsequent deprotection of the amino group furnishes the key common intermediate for the synthesis of other families of peptidomimetics: dipeptides, tripeptides, peptidomimetics containing a urea moiety, and structures containing two units of alpha-trifluoromethyl-beta(2)-alanine. Finally, a conformational study of several of the newly synthesized peptidomimetics, performed with the a…

Asymmetric Methods for Carbon‐Fluorine Bond Formation

ChemInform Abstract: Synthesis of 3-Substituted Isoindolin-1-ones via a Tandem Desilylation, Cross-Coupling, Hydroamidation Sequence under Aqueous Phase-Transfer Conditions.

A simple and expedient method for the synthesis of 3-methylene-isoindolin-1-ones 4 under aqueous phase-transfer conditions has been developed. Starting from 2-iodobenzamides 1 and (silyl)alkynes, the products are obtained in high yields and short reaction times (30 min) with the use of inexpensive CuCl/PPh3 catalyst system in the presence of n-Bu4NBr (TBAB) as a phase-transfer agent. Terminal alkynes are conveniently “unmasked” upon in situ desilylation under the reaction conditions. Alkynes possessing heterocyclic moieties were also found as amenable substrates. Furthermore, a one-pot process starting from 2-iodobenzamides 1, aryl halides (bromides or iodides) and trimethylsilylacetylene (…

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

Ring-opening metathesis (ROM) of various unsaturated, constrained bicyclic ring systems has been investigated with the use of commercial ruthenium-based catalysts. Starting from various cyclodienes, the corresponding derived bicyclic lactone, lactam, and isoxazoline derivatives were submitted to ROM under ethenolysis. These functionalized, strained bicyclic systems afforded novel highly-functionalized diolefinated heterocyclic scaffolds in ROM reactions with stereocontrol, through the conservation of the configuration of the stereogenic centers of the starting compounds.

Synthesis of polyfluoroalkyl sp2-iminosugar glycolipids and evaluation of their immunomodulatory properties towards anti-tumor, anti-leishmanial and anti-inflammatory therapies

Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and anti-inflammatory mediators that antagonize each other and negatively affect the immune response. The synthesis of analogues with narrower cytokine secretion-inducing capabilities is hampered by the intrinsic difficulty at controlling the stereochemical outcome in glycosidation reactions, particularly if targeting the α-anomer, which seriously hamper…

Stereoselective Synthesis of Fluorine-Containing β-Amino Acids

ChemInform Abstract: Solution versus Fluorous versus Solid-Phase Synthesis of 2,5-Disubstituted 1,3-Azoles. Preliminary Antibacterial Activity Studies.

A small library of compounds with an oxa(thia)zole scaffold and structural diversity in both positions 2 and 5 has been synthesized. Double acylation of a protected glycine affords intermediate alpha-amido-beta-ketoesters, which in turn can be dehydrated to afford 1,3-oxazoles or reacted with Lawesson's reagent to furnish 1,3-thiazoles. This procedure was designed with its adaptation to fluorous techniques in mind. Thus, when a protected glycine with a fluorous tag in the ester moiety is used as a starting material, the synthesis can be easily completed without column chromatography purification of intermediate compounds with good to excellent yields, thus affording a suitable entry to the …

Synthesis and Reactivity of New β-Enamino Acid Derivatives:  A Simple and General Approach to β-Enamino Esters and Thioesters

A new strategy has been developed for the synthesis of several β-enamino acid derivatives. N,N‘-Carbonyldiimidazole has been used as C-acylating agent of methyl ketimines, providing a direct and simple route to new β-enamino carbonyl imidazole derivatives 2. These derivatives 2 were cleanly and efficiently transformed into β-enamino esters 4 (X = O) and thioesters 4 (X = S) by reaction with a great variety of alcohols and thiols, including tertiary ones. Alternative and complementary routes to compounds 4 were also investigated. In addition, β-keto esters 6 have been obtained by mild acid hydrolysis of β-enamino esters 4.

ChemInform Abstract: 1,7-Octadiene-Assisted Tandem Multicomponent Cross-Enyne Metathesis (CEYM)-Diels-Alder Reactions: A Useful Alternative to Mori′s Conditions.

The protocol relies on a relay metathesis process, in which 1,7-octadiene acts as an in situ source of ethylene.

Frontispiece: Tailor‐Made Amino Acids and Fluorinated Motifs as Prominent Traits in Modern Pharmaceuticals

Stereocontrolled solid-phase synthesis of fluorinated partially-modified retropeptides via tandem aza-Michael/enolate-protonation

N-Acylation of Wang resin-bound l-α-amino acids with 2-trifluoromethyl-propenoyl chloride, followed by asymmetric tandem aza-Michael/enolate-protonation by a series of l-α-amino esters and final release from the resin, afforded a representative library of partially-modified retropeptides incorporating a stereodefined trifluoroalanine surrogate. The stereocontrol can be dramatically improved (up to 15:1) by using apolar solvents like carbon tetrachloride and DABCO as base.

A Versatile Approach to CF3-Containing 2-Pyrrolidones by Tandem Michael Addition-Cyclization: Exemplification in the Synthesis of Amidine Class BACE1 Inhibitors

The synthesis of new fluorinated pyrrolidones starting from unprotected amino esters and amino nitriles through a Michael addition-lactamization sequence is described. The resulting CF3 -containing building blocks, bearing a quaternary stereogenic center adjacent to the fluorinated group, have been converted into amino pyrrolidines that display potent β-secretase 1 (BACE1) inhibitory activity. This work constitutes an example of selective fluorination as a valid strategy for the modulation of physicochemical and biological properties of lead compounds in drug discovery.

Diastereoselective Synthesis of Enantioenriched Trifluoromethylated Ethylenediamines and Isoindolines Containing Two Stereogenic Carbon Centers by Nucleophilic Trifluoromethylation Using HFC-23.

Fluoroform, HFC-23, is an industrial byproduct from the synthesis of polytetrafluoroethylene and is a vastly underused resource; however, its physicochemical properties have hindered progress toward synthetic uses. Herein, we describe the use of HFC-23 as a cheap trifluoromethylating agent in two reactions for the highly diastereoselective synthesis of medicinally attractive chiral amines with two stereogenic carbon centers: a base-dependent, stereodivergent nucleophilic addition to synthesize enantioenriched vicinal diamines and a tandem nucleophilic addition/aza-Michael sequence toward enantioenriched isoindolines.

The Fluoro-Pauson-Khand Reaction in the Synthesis of Enantioenriched Nitrogenated Bicycles Bearing a Quaternary C-F Stereogenic Center

The authors are grateful to the Spanish MICINN and the AEI (CTQ2017-84249-P) for financial support, the SCSIE (Universitat de Valencia) for access to instrumental facilities, and M. ̀ R. Pedrosa (Universidad de Burgos) for providing us with MoO2Cl2. The technical and human support provided by SGIker (UPV/EHU, MINECO, GV/DJ, ERDF, and ESF) is also gratefully acknowledged. P.B. thanks the Spanish Ministry of Economy for a Ramon y Cajal contract (RyC-2016-20951). ́ The authors are also grateful to Jose Cabeza for assistance in the synthesis of certain starting materials.

CCDC 1495998: Experimental Crystal Structure Determination

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CCDC 914060: Experimental Crystal Structure Determination

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CCDC 1564495: Experimental Crystal Structure Determination

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CCDC 1578271: Experimental Crystal Structure Determination

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CCDC 1031785: Experimental Crystal Structure Determination

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CCDC 1562225: Experimental Crystal Structure Determination

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CCDC 1814087: Experimental Crystal Structure Determination

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CCDC 1057565: Experimental Crystal Structure Determination

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CCDC 1972570: Experimental Crystal Structure Determination

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CCDC 841484: Experimental Crystal Structure Determination

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CCDC 984448: Experimental Crystal Structure Determination

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CCDC 1908613: Experimental Crystal Structure Determination

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CCDC 1401005: Experimental Crystal Structure Determination

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CCDC 1937096: Experimental Crystal Structure Determination

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CCDC 989965: Experimental Crystal Structure Determination

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CCDC 1564490: Experimental Crystal Structure Determination

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CCDC 927146: Experimental Crystal Structure Determination

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CCDC 2067817: Experimental Crystal Structure Determination

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CCDC 1427402: Experimental Crystal Structure Determination

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CCDC 1536511: Experimental Crystal Structure Determination

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CCDC 941485: Experimental Crystal Structure Determination

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CCDC 1426924: Experimental Crystal Structure Determination

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CCDC 916244: Experimental Crystal Structure Determination

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CCDC 1899383: Experimental Crystal Structure Determination

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CCDC 1495999: Experimental Crystal Structure Determination

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CCDC 935857: Experimental Crystal Structure Determination

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CCDC 1578275: Experimental Crystal Structure Determination

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CCDC 1839885: Experimental Crystal Structure Determination

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CCDC 1954729: Experimental Crystal Structure Determination

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CCDC 914059: Experimental Crystal Structure Determination

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CCDC 1434367: Experimental Crystal Structure Determination

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CCDC 1908615: Experimental Crystal Structure Determination

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CCDC 982910: Experimental Crystal Structure Determination

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CCDC 1814088: Experimental Crystal Structure Determination

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CCDC 914062: Experimental Crystal Structure Determination

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CCDC 1908614: Experimental Crystal Structure Determination

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CCDC 1578276: Experimental Crystal Structure Determination

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CCDC 2067822: Experimental Crystal Structure Determination

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CCDC 982909: Experimental Crystal Structure Determination

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CCDC 914061: Experimental Crystal Structure Determination

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CCDC 1434366: Experimental Crystal Structure Determination

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CCDC 1057564: Experimental Crystal Structure Determination

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CCDC 916245: Experimental Crystal Structure Determination

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