Development of Mefloquine-Based Bifunctional Secondary Amine Organocatalysts for Enantioselective Michael and Friedel-Crafts Reactions.

The chiral framework based on 11-aminomefloquine has been utilized for the first time to construct bifunctional organocatalysts. These catalysts demonstrate high enantioselectivity in both Michael additions and Friedel-Crafts reactions across a variety of substrates, achieving up to >99% ee. The distinctive feature is the incorporation of a secondary amine group, offering unique tight hydrogen-bonding capabilities in the protonated state, as supported by DFT computation. The diversity of these organocatalysts suggests their broad applicability across multiple reaction classes.

Stereoselective Domino Rearrangement peri-Annulation of Cinchona Alkaloid Derivatives with 8-Bromo-1-naphthyl Grignard.

The unexpected domino coupling and rearrangement of the Cinchona alkaloid skeleton has been found to occur in the reaction of 9-chloro-9-deoxy-alkaloids with Grignards from peri-dihalogenonaphthalene. The cyclization and migration of the central quinuclidinylmethyl group (C9) from position C-4' to position C-3' of quinoline formed a novel chiral ring system of 5-aza-7H-benzo[no]tetraphene, yielding products of unlike configuration. The proposed reaction pathway involves radical intermediates.

A Review of Modifications of Quinoline Antimalarials: Mefloquine and (hydroxy)Chloroquine.

Late-stage modification of drug molecules is a fast method to introduce diversity into the already biologically active scaffold. A notable number of analogs of mefloquine, chloroquine, and hydroxychloroquine have been synthesized, starting from the readily available active pharmaceutical ingredient (API). In the current review, all the modifications sites and reactivity types are summarized and provide insight into the chemistry of these molecules. The approaches include the introduction of simple groups and functionalities. Coupling to other drugs, polymers, or carriers afforded hybrid compounds or conjugates with either easily hydrolyzable or more chemically inert bonds. The utility of some of the compounds was tested in antiprotozoal, antibacterial, and antiproliferative assays, as well as in enantiodifferentiation experiments.

Chiral Vicinal Diamines Derived from Mefloquine.

Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino-Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo-11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro-11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi-aminoquinine in terms of selectivity.

Regioselective and Stereodivergent Synthesis of Enantiomerically Pure Vic-Diamines from Chiral ß-Amino Alcohols with 2-Pyridyl and 6-(2,2'-Bipyridyl) Moieties.

In this report, we describe the synthetic elaboration of the easily available enantiomerically pure ß-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of ß-amino alcohols gave eight chiral aziridines in 45-82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc)2 under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN3 to form the corresponding azido amines as single regio- and diastereomers in 90-97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting ß-amino alcohols. To obtain a complete series of diastereomeric vic-diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in SN2 reaction (25-58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral vic-diamines of defined stereochemistries.

2-Unsubstituted Imidazole N-Oxides as Novel Precursors of Chiral 3-Alkoxyimidazol-2-ylidenes Derived from trans-1,2-Diaminocyclohexane and Other Chiral Amino Compounds.

'Desymmetrization' of trans-1,2-diaminocyclohexane by treatment with α,ω-dihalogenated alkylation reagents leads to mono-NH2 derivatives ('primary-tertiary diamines'). Upon reaction with formaldehyde, these products formed monomeric formaldimines. Subsequently, reactions of the formaldimines with α-hydroxyiminoketones led to the corresponding 2-unsubstituted imidazole N-oxide derivatives, which were used here as new substrates for the in situ generation of chiral imidazol-2-ylidenes. Upon O-selective benzylation, new chiral imidazolium salts were obtained, which were deprotonated by treatment with triethylamine in the presence of elemental sulfur. Under these conditions, the intermediate imidazol-2-ylidenes were trapped by elemental sulfur, yielding the corresponding chiral non-enolizable imidazole-2-thiones in good yields. Analogous reaction sequences, starting with imidazole N-oxides derived from enantiopure primary amines, amino alcohols, and amino acids, leading to the corresponding 3-alkoxyimidazole-2-thiones were also studied.

A permutation approach to the assignment of the configuration to diastereomeric tetrads by comparison of experimental and ab initio calculated differences in NMR data.

Scoring permutations of experimental chemical shift deviations and DFT/GIAO calculated deviations of isotropic shieldings for sets of four diastereomers can help to assign their relative configurations. This method was exercised on a set of diastereomeric Cinchona alkaloid derivatives, where 13C NMR data always identified the proper configuration. The presented approach is also an attempt to quantify the assignment by exclusion.

Click-Dimerized Cinchona Alkaloids.

A series of Cinchona alkaloid-derived dimers were obtained in high yields in copper-catalyzed 1,3-dipolar "click" cycloaddition using bis(TMS)butadiyne and other bivalent alkynes. The products with bitriazole linkers were effective ligands for asymmetric copper-catalyzed Michael addition. It was shown that the presence of such linker was responsible for effective chirality transfer.

Tricyclic Quaternary Ammonium Salts Derived from Cinchona Alkaloids.

Tricyclic systems with quaternary bridgehead nitrogen atoms are rare but an interesting class of compounds. Chiral quinuclidine derivative salts with fused five and six-membered rings (X-ray) were obtained via modification of Cinchona alkaloids. The ease of ring formation was dependent on its size, while even mild activation sufficed to close the five membered ring. On the other hand the systems with fused benzene and a six-membered ring formed atropisomers separated by a barrier of ca. 15 kcal/mol, whose interconversion was studied by DFT and NMR.

Room-temperature distance measurements of immobilized spin-labeled protein by DEER/PELDOR.

Nitroxide spin labels are used for double electron-electron resonance (DEER) measurements of distances between sites in biomolecules. Rotation of gem-dimethyls in commonly used nitroxides causes spin echo dephasing times (Tm) to be too short to perform DEER measurements at temperatures between ∼80 and 295 K, even in immobilized samples. A spirocyclohexyl spin label has been prepared that has longer Tm between 80 and 295 K in immobilized samples than conventional labels. Two of the spirocyclohexyl labels were attached to sites on T4 lysozyme introduced by site-directed spin labeling. Interspin distances up to ∼4 nm were measured by DEER at temperatures up to 160 K in water/glycerol glasses. In a glassy trehalose matrix the Tm for the doubly labeled T4 lysozyme was long enough to measure an interspin distance of 3.2 nm at 295 K, which could not be measured for the same protein labeled with the conventional 1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-(methyl)methanethio-sulfonate label.

Dimeric Cinchona alkaloids.

Nature is full of dimeric alkaloids of various types from many plant families, some of them with interesting biological properties. However, dimeric Cinchona alkaloids were not isolated from any species but were products of designed partial chemical synthesis. Although the Cinchona bark is amongst the sources of oldest efficient medicines, the synthetic dimers found most use in the field of asymmetric synthesis. Prominent examples include the Sharpless dihydroxylation and aminohydroxylation ligands, and dimeric phase transfer catalysts. In this article the syntheses of Cinchona alkaloid dimers and oligomers are reviewed, and their structure and applications are outlined. Various synthetic routes exploit reactivity of the alkaloids at the central 9-hydroxyl group, quinuclidine, and quinoline rings, as well as 3-vinyl group. This availability of reactive sites, in combination with a plethora of linker molecules, contributes to the diversity of the products obtained.

High-spin S = 2 ground state aminyl tetraradicals.

Aminyl tetraradicals with planar tetraazanonacene backbones have quintet (S = 2) ground states and do not show any detectable thermal population of the low-spin excited states up to the highest temperature investigated (100 K) in the 2-methyltetrahydrofuran (2-MeTHF) matrix. This indicates that the nearest electronic excited state (triplet) is at least ~0.3 kcal mol(-1) higher in energy, that is, the triplet-quintet energy gap, ΔE(TQ) > 0.3 kcal mol(-1), which is consistent with the broken-symmetry-DFT-computed ΔE(TQ) of about 5 kcal mol(-1). In concentrated (ca. 1-10 mM) solutions of tetraradical 4 in 2-MeTHF at 133 K, a fraction of tetraradicals form a dimer (association constant, K(assoc) ≈ 60 M(-1)), with a weak, antiferromagnetic exchange coupling, J/k ≈ -0.1 K ~ 0.2 cal mol(-1), between the S = 2 tetraradicals. This weak intradimer exchange coupling is expected for two tetraradicals at the distance of about 6 Å. The most sterically shielded tetraradical 5 in 2-MeTHF has a half-life of 1 h at room temperature; the product of its decay is the corresponding tetraamine, suggesting that the hydrogen atom abstraction from the solvent is primarily responsible for the decomposition of the tetraradical.

Diastereoselective Corey-Chaykovsky 9-epoxymethylation of Cinchona alkaloids: access to chiral scaffolds with diverse functionalities.

Reaction of dimethylsulfonium methylide with Cinchona alkaloid ketones proceeds with complete diastereoselectivity to give epoxides of 8,9-like configuration. The reaction of dimethylsulfoxonium methylide gives different isomers, albeit with lower (4:1) selectivity. α-Epimerization of the alkaloid ketones resulted in formation of two separable diasteromeric products. The configurations of the epoxides were elucidated on the basis of NMR data combined with DFT calculations. Models explaining observed selectivity are discussed. The epoxides were efficiently transformed to a number of derivatives through selective S(N)2-type ring-opening reactions with various nucleophiles, often without the need of additional purification steps.

Ladder oligo(m-aniline)s: derivatives of azaacenes with cross-conjugated π-systems.

We describe the synthesis and electronic properties of ladder oligomers of poly(m-aniline) that may be considered as derivatives of azaacenes with cross-conjugated π-systems. Syntheses of ladder oligo(m-aniline)s with 9 and 13 collinearly fused six-membered rings employed Pd-catalyzed aminations and Friedel-Crafts-based ring closures. Structures were confirmed by either X-ray crystallography or correlations between DFT-computed and experimental spectroscopic data such as (1)H, (13)C, and (15)N NMR chemical shifts and electronic absorption spectra. All compounds have planar "azaacene" moieties. The experimental band gaps E(g) ≈ 3.5-3.65 eV, determined by the UV-vis absorption onsets, were in agreement with the TD-DFT-computed vertical excitation energies to the S(1) state. Fluorescence quantum yields of up to 20% were found. Electrochemically estimated HOMO energies of -4.8 eV suggested propensity for a facile one-electron oxidation and just sufficient environmental stability toward oxygen (O(2)). For two oligomers with "tetraazanonacene" moieties, potentials of E(4+/3+) ≈ 1.6-1.7 V vs SCE were determined for four-electron oxidation to the corresponding tetraradical tetracations.

Oxidation of annelated diarylamines: analysis of reaction pathways to nitroxide diradical and spirocyclic products.

Oxidation of diaryldiamine 2, a tetrahydrodiazapentacene derivative, provides diarylnitroxide diradical 1 accompanied by an intermediate nitroxide monoradical and a multitude of isolable diamagnetic products. DFT-computed tensors for EPR spectra and paramagnetic (1)H NMR isotropic shifts for nitroxide diradical 1 show good agreement with the experimental EPR spectra in rigid matrices and paramagnetic (1)H NMR spectra in solution, respectively. Examination of the diamagnetic products elucidates their formation via distinct pathways involving C-O bond-forming reactions, including Baeyer-Villiger-type oxidations. An unusual diiminoketone structure and two spirocyclic structures of the predominant diamagnetic products are confirmed by either X-ray crystallography or correlations between DFT-computed and experimental spectroscopic data such as (1)H, (13)C, and (15)N NMR chemical shifts and electronic absorption spectra.

Intramolecular cyclization of thiophene-based [7]helicenes to quasi-[8]circulenes.

Intramolecular cyclization in a series of thiophene-based dibromo[7]helicenes (4-6) with different helix structures is investigated by vacuum pyrolysis, tin- and palladium-mediated C-C bond forming reactions. The product with the cyclic structure of the annelated aromatic rings, which resembles [8]circulene devoid of an atom linkage, is referred to as quasi-[8]circulene. Vacuum pyrolysis of 4 gives insoluble, unidentified products, while 5 and 6 yield the corresponding quasi-[8]circulenes under similar conditions. Thermogravimetry (TG) and differential scanning calorimetry (DSC) analyses for 4 indicate complex reaction pathways, while those for 5 and 6 show a single process corresponding to a loss of 1 equiv of Br(2) at about 330 degrees C. Pd-mediated reductive cyclization provides quasi-[8]circulenes for all three [7]helicenes, though only 4 gives a good isolated yield. Tributyltin hydride-mediated radical cyclization of 4-6 provides quasi-[8]circulenes in excellent yields, and it is practically insensitive to the helix structure. Experimental and calculated UV-vis absorption spectra for quasi-[8]circulenes and [8]circulenes are reported. The results suggest that the lack of atom linkage in quasi-[8]circulene does not significantly affect properties and conformation, compared to those for the corresponding [8]circulenes.

Cinchona Alkaloids-Derivatives and Applications.

Major Cinchona alkaloids quinine, quinidine, cinchonine, and cinchonidine are available chiral natural compounds (chiral pool). Unlike many other natural products, these alkaloids are available in multiple diastereomeric forms which are separated on an industrial scale. The introduction discusses in short conformational equilibria, traditional separation scheme, biosynthesis, and de novo chemical syntheses. The second section concerns useful chemical applications of the alkaloids as chiral recognition agents and effective chiral catalysts. Besides the Sharpless ethers and quaternary ammonium salts (chiral PTC), the most successful bifunctional organocatalysts are based on 9-amino derivatives: thioureas and squaramides. The third section reports the main transformations of Cinchona alkaloids. This covers reactions of the 9-hydroxyl group with the retention or inversion of configuration. Specific Cinchona rearrangements enlarging [2.2.2]bicycle of quinuclidine to [3.2.2] products are connected to the 9-OH substitution. The syntheses of numerous esterification and etherification products are described, including many examples of bi-Cinchona alkaloid ethers. Further derivatives comprise 9-N-substituted compounds. The amino group is introduced via an azido function with the inversion of configuration at the stereogenic center C9. The 9-epi-amino-alkaloids provide imines, amides, imides, thioureas, and squaramides. The syntheses of 9-carbon-, 9-sulfur-, and 9-selenium-substituted derivatives are discussed. Oxidation of the hydroxyl group of any alkaloid gives ketones, which can be selectively reduced, reacted with Grignard reagents, or subjected to the Corey-Chaykovsky reaction. The alkaloids were also partially degraded by splitting C4'-C9 or N1-C8 bonds. In order to immobilize Cinchona alkaloids the transformations of the 3-vinyl group were often exploited. Finally, miscellaneous functionalizations of quinuclidine, quinoline, and examples of various metal complexes of the alkaloids are considered.

Stereoselective C9 arylation and vinylation of Cinchona alkaloids.

A simple and efficient method for the highly stereoselective C-9 arylation and vinylation of Cinchona alkaloids was developed. Both 9S- and 9R-chloroquinine with PhMgBr yielded 9S-phenylquinine (X-ray structure). The reactions with various aryl and vinyl Grignard reagents resulted in the series of 9S-aryl and vinyl alkaloid derivatives. The stereochemical outcome was rationalized by coordination of the magnesium atom to the quinuclidine nitrogen, thus directing the nucleophilic attack at the C-9 stereogenic center.

Stereoselective C9 carbon-carbon couplings of quinine: synthesis and conformational analysis of new C2-symmetric dimers.

An unexpected stereoselective direct dimerization occurred when 9-quinine halide was treated with butyllithium. The reaction of either (9S)- or (9R)-chloroquinine gave the same C2-symmetric dimer with 9R configuration (X-ray structure). A tentative mechanism involving radical recombination is discussed. This highly congested dimer forms two atropisomers, and their reversible interconversion was studied by NMR. Another C2-symmetric (9S)-quinine dimer connected solely by carbon-carbon bonds was obtained by the stereoselective coupling of bis(arylbromomagnesium) derivative with (9S)-chloroquinine.

Threonine at position 6 is not essential for the immunosuppressive activity of HLA-DQ(beta164-172)-hexapeptide.

It has been previously found that the nonapeptide fragment of human leukocyte antigen (HLA)-DQ molecule, located in the beta chain 164-172 with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence, suppresses the immune response. The hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr was the shortest fragment of HLA-DQ showing both cellular and humoral immunosuppressive activity, while the analog deprived of the last amino acid (Arg-Gly-Asp-Val-Tyr) showed very weak stimulatory activity with respect to the humoral immune response. This suggested that the threonine residue in the hexapeptide plays an essential role in immunosuppression. In this study, the role of the side chain of threonine residue was scrutinized in a series of synthetic analogs in which the Thr residue was substituted by various amino acids, amides and methyl ester. The synthesized peptides were evaluated for their immunosuppressive activity. Our results indicate that the substitutions did not significantly affect the immunomodulatory properties, revealing that the threonine side chain is not critical for the immunosuppressive potency of the peptides. Interestingly, a simple analogue, pentapeptide amide H-Arg-Gly-Asp-Val-Tyr-NH2 possessed high immunosuppressive potency, comparable to that of cyclosporine.