Persistent guaiazulene arylmethylium ions as electrophilic traps for metal enolates.

Guaiazulene-stabilized cations reacted with metal enolates affording carbonyl compounds with an azulene moiety. Metal enolates generated by asymmetric conjugate addition of organometallic reagents led to enantioenriched products. Additionally, guaiazulene-substituted cations efficiently react with silyl enol ethers. DFT calculations allowed estimation of the electrophilicities of the carbocations. Reaction progress was monitored by a decrease in the reactant's Vis-light absorption and an increase in the product's anti-Kasha emission.

Mechanochemical Pd-Catalyzed Amino- and Oxycarbonylations using FeBr2(CO)4 as a CO Source.

Herein, we describe the development of mechanochemical amino- and oxycarbonylation employing FeBr2(CO)4 as a solid CO source. This Pd/XantPhos-catalyzed reaction affords a range of carboxamides and esters from aryl iodides and various amines or phenols. Both primary and secondary amines, including amino acids, can be employed as N-nucleophiles.

Asymmetric tandem conjugate addition and reaction with carbocations on acylimidazole Michael acceptors.

We present here a stereoselective tandem reaction based on the asymmetric conjugate addition of dialkylzinc reagents to unsaturated acylimidazoles followed by trapping of the intermediate zinc enolate with carbocations. The use of a chiral NHC ligand provides chiral zinc enolates in high enantiomeric purities. These enolates are reacted with highly electrophilic onium compounds to afford densely substituted acylimidazoles. DFT calculations helped to understand the reactivity of the zinc enolates derived from acylimidazoles and allowed their comparison with metal enolates obtained by other conjugate addition reactions.

Enolates ambushed - asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles.

Metal enolates are useful intermediates and building blocks indispensable in many organic synthetic transformations. Chiral metal enolates obtained by asymmetric conjugate additions of organometallic reagents are structurally complex intermediates that can be employed in many transformations. In this review, we describe this burgeoning field that is reaching maturity after more than 25 years of development. The effort of our group to broaden possibilities to engage metal enolates in reactions with new electrophiles is described. The material is divided according to the organometallic reagent employed in the conjugate addition step, and thus to the particular metal enolate formed. Short information on applications in total synthesis is also given.

Asymmetric Organocatalysis Under Mechanochemical Conditions.

Asymmetric organocatalysis is a robust methodology providing access to numerous valuable compounds while having green chemistry principles in mind. The realization of organocatalytic transformation under solvent-free mechanochemical conditions brings additional benefits in terms of yields, selectivities, and, last but not least overall improved sustainability. This overview describes developments in the use of mechanochemistry as a vehicle for asymmetric organocatalytic transformations. The material is organized according to main catalytic activation modes, starting with covalent activation and proceeding to non-covalent activation modes. The advantages of mechanochemical organocatalytic reactions are particularly highlighted, but in some cases also, limitations are mentioned. Possibilities for target compound synthesis are also discussed.

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates.

Herein, we present the synthesis and utilization of derivatives of 4H-benzo[b][1,4]thiazine-3-carboxylic acid. These benzothiazine compounds were assembled via the coupling of aminothiols and bromopyruvates. Oxidative dimerization of these starting materials was also observed and the corresponding benzothiazine dimers were isolated. Moreover, the coupling of benzothiazines with amino acids was realized. In doing so, an enantioselective synthesis of the nonproteinogenic amino acid 2-amino-3-propylhexanoic acid was accomplished.

Mechanochemical Pd-Catalyzed Cross-Coupling of Arylhalides and Organozinc Pivalates.

Cross-coupling reactions are essential tools in target molecule synthesis. However, the use of highly reactive organometallic reagents limits their applicability. Here, we present a mechanochemical Pd-catalyzed cross-coupling reaction between aryl halides and organozinc pivalates that can be carried out under ambient temperature and atmosphere. This operationally simple procedure affords a wide range of biaryl and aryl-heteroaryl derivatives in high yields and short times. The reaction tolerates various functional groups and can be realized on a synthetically useful scale. Its practical value was demonstrated in the short synthesis of the pharmaceutical diflunisal.

Organocatalytic Diastereodivergent Enantioselective Formal oxa-Diels-Alder Reaction of Unsaturated Ketones with Enoates Under Liquid-Assisted Grinding Conditions.

Chiral heterocycles occur in many compounds of interest, but their efficient synthesis is challenging. This study concerns the enantioselective and diastereoselective synthesis of densely substituted chiral pyran derivatives. Diastereodivergence of the oxa-Diels-Alder reaction is achieved by using either a bifunctional amino-thiourea or a monofunctional quinine organocatalyst under ball-milling conditions. Liquid-assisted grinding proves a highly efficient means of affording pyrans in high yield, with high enantiomeric purities and short reaction times.

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts.

The synthesis of bifunctional N-sulfinylureas and thioureas with an appended pyrrolidine unit is presented. These organocatalysts were evaluated in Michael additions of aldehydes to nitroalkenes both under solvent-free conditions and in solution. The N-sulfinylurea catalyst was more efficient than the corresponding thiourea. For some substrates, enantioselectivities reached 98% ee. The stereogenic center on the sulfur did not have a considerable influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of aldehydes and hydrogen-bond activation of nitroalkenes.

Diastereoselective Double C-H Functionalization of Chiral Ferrocenes with Heteroaromatics.

Diastereoselective double C-H heteroarylation of chiral ferrocenes provides valuable compounds with multiple functionalities using mild reaction conditions and simple reagents. Pd-Complexes with chiral mono-protected amino acids afforded corresponding heteroarylated ferrocenyl amines in good yields and high diastereomeric purities. In this way, a variety of indole, thiophene, pyrrole, or furan substituents were introduced to the ferrocene moiety. Furthermore, a range of relevant functional groups, for example ketone, ester, chloro, nitro, or silyl, are tolerated by this method. An alternative combination of amino acid and ferrocenyl amine configurations was leveraged to provide the complementary diastereomeric products. The products of C-H heteroarylation can be transformed into corresponding phosphines. Absolute configurations of CH-activation products were confirmed by the combination of X-ray crystallographic analysis and CD spectroscopy. 19 F NMR kinetic study and DFT calculations provided insights into the reaction mechanism and reasons governing stereoinduction.

Hybrid Peptide-Thiourea Catalyst for Asymmetric Michael Additions of Aldehydes to Heterocyclic Nitroalkenes.

Bifunctional organocatalysis combining covalent and noncovalent activation is presented. The hybrid peptide-thiourea catalyst features a N-terminal proline moiety for aldehyde activation and a thiourea unit for electrophile activation. This catalyst effectively promotes asymmetric Michael additions of aldehydes to challenging but biologically relevant heterocycle-containing nitroalkenes. The catalyst can be used under solvent-free conditions. Spectroscopic and density functional theory studies elucidate the catalyst structure and mode of action.

Asymmetric copper-catalyzed conjugate additions of organometallic reagents in the syntheses of natural compounds and pharmaceuticals.

Access to enantiopure complex molecular structures is crucial for the development of new drugs as well as agents used in crop-protection. In this regard, numerous asymmetric methods have been established. Copper-catalyzed 1,4-additions of organometallic reagents are robust C-C bond formation strategies applicable in a wide range of circumstances. This review analyses the syntheses of natural products and pharmaceutical agents, which rely on the application of asymmetric Cu-catalyzed conjugate additions of various organometallic reagents. A wide range of available organometallics, e.g. dialkylzinc, trialkylaluminum, Grignard, and organozirconium, can now be used in conjugate additions to address various synthetic challenges present in targeted natural compounds. Furthermore, efficient catalysts allow high levels of stereofidelity over a diverse array of starting Michael acceptors.

Green Asymmetric Organocatalysis.

Asymmetric organocatalysis is becoming one of the main tools for the synthesis of chiral compounds that are needed as medicines, crop protection agents, and other bioactive molecules. It can be effectively combined with various green chemistry methodologies. Intensification techniques, such as ball milling, flow, high pressure, or light, bring not only higher yields, faster reactions, and easier product isolation, but also new reactivities. More sustainable reaction media, such as ionic liquids, deep eutectic solvents, green solvent alternatives, and water, also considerably enhance the sustainability profile of many organocatalytic reactions.

Trapping of chiral enolates generated by Lewis acid promoted conjugate addition of Grignard reagents to unreactive Michael acceptors by various electrophiles.

Here we show trapping of chiral enolates with carbenium ions, Michael acceptors, and bromine. Silyl ketene aminals, disilyl acetals, and aza-enolates were obtained via Lewis acid mediated enantioselective conjugate addition of Grignard reagents to unsaturated amides, carboxylic acids and alkenyl heterocycles.

Diastereoselective Pd-Catalyzed C-H Arylation of Ferrocenylmethanamines with Arylboronic Acids or Pinacol Esters.

An efficient diastereoselective synthesis of planar chiral ferrocenes via Pd(II)-catalyzed direct C-H activation with arylboronic acids or pinacol esters is presented. The reaction was performed under mild conditions using commercially available achiral or chiral amino acids as ligands. The best results were obtained with ( R)-Boc-alanine, which yielded products in 27-83% yield with diastereoselectivities ranging from 5:1 to 20:1 (11 examples). Diastereoisomeric products can also be obtained using ( S)-Boc-alanine as a ligand. Stereoinduction of the reaction was explained by density functional theory calculations of possible transition states.

Why do thioureas and squaramides slow down the Ireland-Claisen rearrangement?

A range of chiral hydrogen-bond-donating organocatalysts was tested in the Ireland-Claisen rearrangement of silyl ketene acetals. None of these organocatalysts was able to impart any enantioselectivity on the rearrangements. Furthermore, these organocatalysts slowed down the Ireland-Claisen rearrangement in comparison to an uncatalyzed reaction. The catalyst-free reaction proceeded well in green solvents or without any solvent. DFT calculations showed that the activation barriers are higher for reactions involving hydrogen-donating organocatalysts and kinetic experiments suggest that the catalysts bind stronger to the starting silyl ketene acetals than to transition structures thus leading to inefficient rearrangement reactions.

Bifunctional Amine-Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of ß,γ-Unsaturated α-Ketoesters and α,ß-Unsaturated Ketones with 4-Hydroxycoumarins.

The catalytic efficiency of various amine-squaramides was tested in Michael/hemiketalization reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide organocatalysts afforded the best results regarding both activity and enantioselectivity when ß,γ-unsaturated α-ketoesters were used as the Michael acceptors (yields up to 98%, enantioselectivities up to 90% ee). On the other hand, the primary amine-squaramides are the best choice for related reactions of 4-hydroxycoumarins with enones. The corresponding pyrano[3,2- c]chromen-5-on products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-hydroxycoumarin to 4-phenylbut-3-en-2-on directly produced chiral anticoagulant drug ( S)-warfarin in 92% ee when green solvent 2-MeTHF and catalyst ( S, S)-C8 were used. Moreover, an enantiomeric catalyst ( R, R)-C8 gave ( R)-warfarin in >99% ee.

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure.

Chiral derivatives of γ-aminobutyric acid are widely used as medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide catalyst. Furthermore, specific organocatalysts can provide respective stereoisomers of the key Michael adduct in up to 99:1 er.

Stereoisomers of oseltamivir - synthesis, in silico prediction and biological evaluation.

Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.