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This article is a continuation of our previous research on the catalytic capability of a chiral copper complex based on commercially available ( S )-2-aminomethylpyrrolidine and 3,5-di- tert -butylsalicylaldehyde with various counter-anions in the asymmetric Henry reaction. Our findings indicate that depending on the type of base used, chiral nitroalcohols with yields up to 98% and ee values up to 77%, as well as β-nitrostyrenes with yields up to 88%, can be produced. Additionally, it has been found that the outcome of the reaction and the catalytic properties of copper (II) complexes ( S )- Cu1 and ( S )- Cu2 are influenced by the structure of the aldehyde used.

Asymmetric catalysis holds a prominent position among the important developments in chemistry during the 20th century. This was acknowledged by the 2001 Nobel Prize in chemistry awarded to Knowles, Noyori, and Sharpless for their development of chiral metal catalysts for organic transformations. The key feature of the catalysts was the crucial role of the chiral ligand and the nature of the metal ions, which promoted the catalytic conversions of the substrates via direct coordination. Subsequently the development of asymmetric organic catalysis opened new avenues to the synthesis of enantiopure compounds, avoiding any use of metal ions. Recently, an alternative approach to asymmetric catalysis emerged that relied on the catalytic functions of the ligands themselves boosted by coordination to metal ions. In other words, in these hybrid chiral catalysts the substrates are activated not by the metal ions but by the ligands. The activation and enantioselective control occurred via well-orchestrated and custom-tailored non-covalent interactions of the substrates with the ligand sphere of chiral metal complexes. In these metal-templated catalysts, the metal served either as a template (a purely structural role), or it constituted the exclusive source of chirality (metal-centred chirality due to the spatial arrangement of achiral or chiral bi-/tridentate ligands around an octahedral metal centre), and/or it increased the Brønsted acidity of the ligands. Although the field is still in its infancy, it represents an inspiring combination of both metal and organic catalysis and holds major unexplored potential to push the frontiers of asymmetric catalysis. Here we present an overview of this emerging field discussing the principles, applications and perspectives on the catalytic use of chiral metal complexes that operate as "organocatalysts in disguise". It has been demonstrated that these chiral metal complexes are efficient and provide high stereoselective control in asymmetric hydrogen bonding catalysis, phase-transfer catalysis, Brønsted acid/base catalysis, enamine catalysis, nucleophilic catalysis, and photocatalysis as well as bifunctional catalysis. Also, many of the catalysts have been identified as highly effective catalysts at remarkably low catalyst loadings. These hybrid systems offer many opportunities in the synthesis of chiral compounds and represent promising alternatives to metal-based and organocatalytic asymmetric transformations.

The acid-base neutralization reaction of commercially available disodium 2,6-naphthalenedisulfonate (NDS, 2 equivalents) and the tetrahydrochloride salt of tetrakis(4-aminophenyl)methane (TAPM, 1 equivalent) in water gave a novel three-dimensional charge-assisted hydrogen-bonded framework (CAHOF, F-1 ). The framework F-1 was characterized by X-ray diffraction, TGA, elemental analysis, and 1 H NMR spectroscopy. The framework was supported by hydrogen bonds between the sulfonate anions and the ammonium cations of NDS and protonated TAPM moieties, respectively. The CAHOF material functioned as a new type of catalytically active Brønsted acid in a series of reactions, including the ring opening of epoxides by water and alcohols. A Diels-Alder reaction between cyclopentadiene and methyl vinyl ketone was also catalyzed by F-1 in heptane. Depending on the polarity of the solvent mixture, the CAHOF F-1 could function as a purely heterogeneous catalyst or partly dissociate, providing some dissolved F-1 as the real catalyst. In all cases, the catalyst could easily be recovered and recycled., (Copyright © 2020, Kuznetsova et al.; licensee Beilstein-Institut.)

Chiral copper(II) and cobalt(III) complexes ( 1 - 5 and 6 , respectively) derived from Schiff bases of ( S )-2-(aminomethyl)pyrrolidine and salicylaldehyde derivatives were employed in a mechanistic study of the Henry reaction-type condensation of nitromethane and o -nitrobenzaldehyde in CH 2 Cl 2 (CD 2 Cl 2 ), containing different amounts of water. The reaction kinetics was monitored by 1 H and 13 C NMR. The addition of water had a different influence on the activity of the two types of complexes, ranging from a crucial positive effect in the case of the copper(II) complex 2 to insignificant in the case of the stereochemically inert cobalt(III) complex 6 . No experimental support was found by 1 H NMR studies for the classical Lewis acid complexation of the carbonyl group of the aldehyde by the central copper(II) ion, and, moreover, density functional theory (DFT) calculations support the absence of such coordination. On the other hand, a very significant complexation was found for water, and it was supported by DFT calculations. In fact, we suggest that it is the Brønsted acidity of the water molecule coordinated to the metal ion that triggers the aldehyde activation. The rate-limiting step of the reaction was the removal of an α-proton from the nitromethane molecule, as supported by the observed kinetic isotope effect equaling 6.3 in the case of the copper complex 2 . It was found by high-resolution mass spectrometry with electrospray ionization that the copper(II) complex 2 existed in CH 2 Cl 2 in a dimeric form. The reaction had a second-order dependence on the catalyst concentration, which implicated two dimeric forms of the copper(II) complex 2 in the rate-limiting step. Furthermore, DFT calculations help to generate a plausible structure of the stereodetermining transition step of the condensation.

Carbocation/polyol systems are shown to be highly efficient catalysts for the synthesis of cyclic carbonates from epoxides and carbon dioxide at 50 °C and 5 MPa CO 2 pressure. The best activity was shown by the combination of crystal violet and 1,1'-bi-2-naphthol (BINOL), which could be recycled five times with no loss of activity. The presence of specific interactions between the amino groups of the carbocation and the hydroxyl protons was confirmed by NMR experiments. The Job plots for the crystal violet iodide/BINOL and brilliant green iodide/BINOL systems showed that the catalytic systems consist of one molecule of the carbocation and one molecule of BINOL. Mechanistic studies using a deuterated epoxide indicate that there was some loss of epoxide stereochemistry during the reaction, but predominant retention of stereochemistry is observed. On this basis, a catalytic cycle is proposed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Stereochemically inert cationic cobalt(III) complexes were shown to be one-component catalysts for the synthesis of cyclic carbonates from epoxides and carbon dioxide at 50 °C and 5 MPa carbon dioxide pressure. The optimal catalyst possessed an iodide counter anion and could be recycled. A catalytic cycle is proposed in which the ligand of the cobalt complexes acts as a hydrogen-bond donor, activating the epoxide towards ring opening by the halide anion and activating the carbon dioxide for subsequent reaction with the halo-alkoxide. No kinetic resolution was observed when terminal epoxides were used as substrates, but chalcone oxide underwent kinetic resolution., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two new one-component aluminium-based catalysts for the reaction between epoxides and carbon dioxide have been prepared. The catalysts are composed of aluminium-salen chloride complexes with trialkylammonium groups directly attached to the aromatic rings of the salen ligand. With terminal epoxides, the catalysts induced the formation of cyclic carbonates under mild reaction conditions (25-35 °C; 1-10 bar carbon dioxide pressure). However, with cyclohexene oxide under the same reaction conditions, the same catalysts induced the formation of polycarbonate. The catalysts could be recovered from the reaction mixture and reused.

(S)- and (R)-BIMBOL were efficient PT catalysts of asymmetric Michael addition of prochiral Ni-PBP-Gly (1) to acrylic esters and malonic esters to Ni-PBP-Δ-Ala (2) correspondingly. The salient feature of the catalysis is opposite configurations of Glu prepared via the two paths with BIMBOL of the same configuration and a perspective novel catalytic procedure for the synthesis of Gla derivatives.

There is a high demand for tumor specific PET tracers in oncology imaging. Besides glucose, certain amino acids also serve as energy sources and anabolic precursors for tumors. Therefore, (18)F-labeled amino acids are interesting probes for tumor specific PET imaging. As glutamine and glutamate play a key role in the adapted intermediary metabolism of tumors, the radiosynthesis of 4-[(18)F]fluoro l-glutamic acid (BAY 85-8050) as a new specific PET tracer was established. Cell-uptake studies revealed specific tumor cell accumulation.

A novel simple synthetic protocol for the preparation of both (2S,4R)- and (2S,4S)-FGlu, applying Michael addition of methyl α-fluoroacrylate to a NiII complex of glycine Schiff base with BPB, was elaborated. In addition, same reaction of mentioned complex with ethyl α-bromoacrylate leads to the NiII complex of the Schiff base of BPB with (2S,4R)-4-bromo-glutamic acid monoester, that can be transformed into the corresponding complexes of 1-aminocyclopropane-1,2-dicarboxylic acid. The decomposition of the diastereoisomerically pure complexes leads to corresponding enantiomerically enriched (ee>98%) amino acids.

Catalyze this! Detailed study of the mechanism of asymmetric cyanohydrin synthesis catalyzed by VO(salen)X complexes (see figure) led to the development of VO(salen)NCS, as the most active vanadium-based catalyst yet developed for this reaction.The mechanism by which oxovanadium(V)(salen) complexes(1) VO(salen)X catalyze the asymmetric addition of trimethylsilyl cyanide to benzaldehyde has been studied. The reaction kinetics indicated that the structure of the counterion (X) had a significant influence on the rate, but not on the enantioselectivity of the reaction. The less coordinating the counterion, the lower the catalytic activity; a trend that was confirmed by a Hammett analysis. Variable temperature kinetics allowed the enthalpies and entropies of activation to be determined for some catalysts, and showed that, for others, the overall reaction order changes from second order to zero order as the temperature is reduced. The order with respect to the catalyst was determined for nine of the VO(salen)X complexes and showed that the less active catalysts were active predominantly as mononuclear species whilst the more active catalysts were active predominantly as dinuclear species. Mass spectrometry confirmed the formation of dinuclear species in situ from all of the VO(salen)X complexes and indicated that the dinuclear complexes contained one vanadium(V) and one vanadium(IV) ion. The latter conclusion was supported by cyclic voltammetry of the complexes, by fluorescence measurements and by the fact that catalyst deactivation occurs when reactions are carried out under an inert atmosphere. Based on this evidence, it has been deduced that the catalysis involves two catalytic cycles: one for catalysis by mononuclear VO(salen)X species and the other for catalysis by dinuclear species. The catalytic cycle involving dinuclear species involves activation of both the cyanide and aldehyde, whereas the catalytic cycle involving mononuclear species activates only the aldehyde, thus explaining the higher catalytic activity observed for catalysts which are predominantly active as dinuclear complexes. Based on these mechanistic results, two new VO(salen)X complexes (X=F and NCS) were predicted to form highly active catalysts for asymmetric cyanohydrin synthesis. VO(salen)NCS was indeed found to be the most active catalyst of this type and catalyzed the asymmetric addition of trimethylsilyl cyanide to thirteen aldehydes. In each case, high yields and enantioselectivities were obtained after a reaction time of two hours at room temperature using just 0.1 mol % of the catalyst.

A combination of high-resolution electrospray mass spectrometry and (1)H NMR spectroscopy has been used to prove that when a mixture of [(salen)TiO]2 complexes containing two different salen ligands (salen and salen') is formed, an equilibrium is established between the homodimers and the heterodimer [(salen)TiO2Ti(salen')]. Depending upon the structure and stereochemistry of the two salen ligands, the equilibrium may favor either the homodimers or the heterodimer. Extension of this process to mixtures of titanium(salen) complexes [(salen)TiO]2 and vanadium (V)(salen') complexes [(salen')VO] (+)Cl (-) allowed the in situ formation of the heterobimetallic complex [(salen)TiO2V(salen')] (+)X (-) to be confirmed for all combinations of salen ligands studied except when the salen ligand attached to titanium contained highly electron-withdrawing nitro-groups. The rate of equilibration between heterobimetallic complexes is faster than that between two titanium complexes as determined by line broadening in the (1)H NMR spectra. These structural results explain the strong rate-inhibiting effect of vanadium (V)(salen) complexes in asymmetric cyanohydrin synthesis catalyzed by [(salen)TiO]2 complexes. It has also been demonstrated for the first time that the titanium and vanadium complexes can undergo exchange of salen ligands and that this is catalyzed by protic solvents. However, the ligand exchange is relatively slow (occurring on a time scale of days at room temperature) and so does not complicate studies aimed at using heterobimetallic titanium and vanadium salen complexes as asymmetric catalysts. Attempts to obtain a crystal structure of a heterobimetallic salen complex led instead to the isolation of a trinuclear titanium(salen) complex, the formation of which is also consistent with the catalytic results obtained previously.

O-(2'-[(18)F]fluoroethyl)-l-tyrosine ([(18)F]FET) has gained much attention as a promising amino acid radiotracer for tumor imaging with positron emission tomography (PET) due to favorable imaging characteristics and relatively long half-life of (18)F (110min) allowing remote-site application. Here we present a novel type of chiral enantiomerically pure labeling precursor for [(18)F]FET, based on NiII complex of a Schiff's base of (S)-[N-2-(N'-benzylprolyl)amino]benzophenone (BPB) with alkylated (S)-tyrosine, Ni-(S)-BPB-(S)-Tyr-OCH2CH2X (X=OTs (3a), OMs (3b) and OTf (3c)). A series of compounds 3a-c was synthesized in three steps from commercially available reagents. Non-radioactive FET as a reference was prepared from 3a in a form of (S)-isomer and (R,S) racemic mixture. Radiosynthesis comprised two steps: (1) n.c.a. nucleophilic fluorination of 3a-c (4.5-5.0mg) in the presence of either Kryptofix 2.2.2.or tetrabutylammonium carbonate (TBAC) in MeCN at 80 degrees C for 5min, followed by (2) removal of protective groups by treating with 0.5M HCl (120 degrees C, 5min). The major advantages of this procedure are retention of enantiomeric purity during the (18)F-introduction step and easy simultaneous deprotection of amino and carboxy moieties in 3a-c. Radiochemically pure [(18)F]FET was isolated by semi-preparative HPLC (C18 mu-Bondapak, Waters) eluent aq 0.01M CH(3)COONH(4), pH 4/C(2)H(5)OH 90/10 (v/v). Overall synthesis time operated by Anatech RB 86 laboratory robot was 55min. In a series of compounds 3a-c, tosyl derivative 3a provided highest radiochemical yield (40-45%, corrected for radioactive decay). Enantiomeric purity was 94-95% and 96-97%, correspondingly, for Kryptofix and TBAC assisted fluorinations. The suggested procedure involved minimal number of synthesis steps and suits perfectly for automation in the modern synthesis modules for PET radiopharmaceuticals. Preliminary biodistribution study in experimental model of turpentine-induced aseptic abscess and Glioma35 rat's tumor (homografts) in Wistar rats has demonstrated the enhanced uptake of radiotracer in the tumor area with minimal accumulation in the inflamed tissues.

The nature of the anionic ligand X (X = EtOSO3, BF4, Cl, Br, OSO2CF3, F or CN) in vanadium(V)salen complexes [V+ O(salen) X-] was found to have a significant influence on the catalytic activity of the complexes, but not on their enantioselectivities; with the complexes in which X = Cl or F being most active and the complex with X = OSO2CF3 being totally inactive.

In the presence of potassium cyanide or the potassium cyanide/18-crown-6 complex as a cocatalyst, 1-2 mol% of titanium(salen) complex catalyses the asymmetric addition of achiral cyanoformates to aldehydes, giving cyanohydrin carbonates with high enantiomeric excesses; and catalyses the diastereoselective addition of chiral cyanoformates derived from alpha-methylbenzyl alcohol to aldehydes, a reaction which exhibits double asymmetric induction.

Hammett data indicate that the asymmetric alkylation of enolates catalysed by copper(II)salen complex 1, proceeds by an asynchronous S(N)2 reaction and that the role of the catalyst is to enhance the nucleophilicity of the enolate.

We describe a new method for the asymmetric synthesis of [(18)F]fluorinated aromatic alpha-amino acids (FAA) under phase transfer conditions using achiral glycine derivative NiPBPGly and (S)-NOBIN as a novel substrate/catalyst pair. The key alkylation step proceeds under mild conditions. Substituted [(18)F]fluorobenzylbromides were prepared using nucleophilic [(18)F]fluoride and were used as alkylation agents. Two important FAA, 2-[(18)F]fluoro-L-tyrosine (2-FTYR) and 6-[(18)F]fluoro-L-3,4-dihydroxyphenylalanine (6-FDOPA), were synthesized with an ee of 92 and 96%, respectively. The total synthesis time was 110-120 min and radiochemical yields (d.c.) were 25+/-6% for 2-FTYR and 16+/-5% for 6-FDOPA.

[reaction: see text] The bimetallic titanium complex [(salen)TiO](2), where salen is the ligand derived from (R,R)-cyclohexanediamine and 3,5-di-tert-butyl-salicylaldehyde, has been shown to catalyze the asymmetric addition of ethyl cyanoformate to aldehydes leading to cyanohydrin carbonates with high enantiomeric excesses.

Achiral, diamagnetic Ni(II) complexes 1 and 3 have been synthesized from Ni(II) salts and the Schiff bases, generated from glycine and PBP (7) and PBA (11), respectively, in MeONa/MeOH solutions. The requisite carbonyl-derivatizing agents pyridine-2-carboxylic acid(2-benzoyl-phenyl)-amide 7 (PBP) and pyridine-2-carboxylic acid(2-formyl-phenyl)-amide 11 (PBA) were readily prepared from picolinic acid and o-aminobenzophenone or picolinic acid and methyl o-anthranilate, respectively. The structure of 1 was established by X-ray crystallography. Complexes 1 and 3 were found to undergo C-alkylation with alkyl halides under PTC conditions in the presence of beta-naphthol or benzyltriethylammonium bromide as catalysts to give mono- and bis-alkylated products, respectively. Decomposition of the complexes with aqueous HCl under mild conditions gave the required amino acids, and PBP and PBA were recovered. Alkylation of 1 with highly reactive alkyl halides, carried out under the PTC conditions in the presence of 10% mol of (S)- or (R)-2-hydroxy-2'-amino-1,1'-binaphthyl 31a (NOBIN) and/or its N-acyl derivatives and by (S)- or (R)-2-hydroxy-8'-amino-1,1'-binaphthyl 32a (iso-NOBIN) and its N-acyl derivatives, respectively, gave rise to alpha-amino acids with high enantioselectivities (90-98.5% ee) in good-to-excellent chemical yields at room temperature within several minutes. An unusually large positive nonlinear effect was observed in these reactions. The Michael addition of acrylic derivatives 37 to 1 was conducted under similar conditions with up to 96% ee. The (1)H NMR and IR spectra of a mixture of the sodium salt of NOBIN and 1 indicated formation of a complex between the two components. Implications of the association and self-association of NOBIN for the observed sense of asymmetric induction and nonlinear effects are discussed.

The title binaphthyls 19 and 26, which are the positional isomers of 2-methoxy-2'-(diphenylphosphino)-1,1'-binaphthyl (MOP, 19) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN, 26), have been synthesized by Suzuki coupling as the key step (10 + 15-->18), followed by functional group transformations, involving C-P and C-N bond formation (18-->19 and 18-->23). Racemic intermediate 22 was resolved by co-crystallization with N-benzylcinchonidinium chloride and the absolute configuration determined by X-ray crystallography. These novel binaphthyls are configurationally stable and, as such, potentially usable as chiral ligands in asymmetric reactions. Michael addition of the glycine-derived enolate 40 to methyl acrylate, carried out in the presence of (R)-(-)-27 as the chiral phase-transfer catalyst, afforded L-glutamic acid (S)-(+)-43 of 92% ee (after hydrolysis of the primary product).

A (salen)titanium catalyst has been found to induce the asymmetric addition of potassium cyanide and acetic anhydride to aldehydes, giving enantiomerically enriched cyanohydrin esters with up to 92% enantiomeric excess using just 1 mol% of the catalyst. This is the first report of the asymmetric synthesis of cyanohydrin derivatives using a cyanide source which is non-volatile and inexpensive.

A new type of efficient chiral catalyst has been elaborated for asymmetric C-alkylation of CH acids under PTC conditions. Sodium alkoxides formed from chiral derivatives of tartaric acid and aminophenols (TADDOL's 2a-e and NOBIN's 3a-h) can be used as chiral catalysts in the enantioselective alkylation, as exemplified by the reaction of Schiff's bases 1a-e derived from alanine esters and benzaldehydes with active alkyl halides. Acid-catalyzed hydrolysis of the products formed in the reaction afforded (R)-alpha-methylphenylalanine, (R)-alpha-naphthylmethylalanine, and (R)-alpha-allylalanine in 61-93% yields and with ee 69-93%. The procedure could be successfully scaled up to 6 g of substrate 1b. When (S,S)-TADDOL or (R)-NOBIN are used, the (S)-amino acids are formed. A mechanism rationalizing the observed features of the reaction has been suggested.

Based on a mechanistic understanding of asymmetric cyanohydrin synthesis catalyzed by chiral titanium-salen complexes, a new catalyst based on vanadium(IV) has been developed. The chiral (salen)VO catalyst is more enantioselective than the titanium-based systems, 0.1 mol % of the catalyst being sufficient to convert aromatic and aliphatic aldehydes into the corresponding trimethylsilyl ethers of cyanohydrins with 68-95% enantiomeric excess at room temperature.

The first two examples of the successful application of chiral salen ligands for diastereoselective syntheses of dinuclear Ti(IV), (L1Ti)2O2 and (PdI2L2Ti)2O2 species with defined chirality and geometry at the metal centre are presented. The structure of the complexes was established by X-ray structural analysis. Both complexes have similar structural features: (1) chiral salen ligands have cis-beta configuration around Ti centres, (2) (R,R) chirality of ligands induces delta helicity of ligand, and (3) syn arrangement of ligand donor atoms in relation to the TiO2Ti plane. Stereoselective effects of the dimers are discussed engaging available literature data. A model has been proposed to rationalise high syn selectivity in the formation of dimers.