A synthetic route to artificial chiral α-amino acids featuring a 3,4-dihydroisoquinolone core through a Rh(III)-catalyzed functionalization of allyl groups in chiral Ni(II) complexes.

Currently, non-proteinogenic α-amino acids (α-AAs) have attracted increasing interest in bio- and medicinal chemistry. In this context, the first protocol for the asymmetric synthesis of artificial α-AAs featuring a 3,4-dihydroisoquinolone core with two stereogenic centers was successfully elaborated. A straightforward Rh(III)-catalysed C-H activation/annulation reaction of various aryl hydroxamates with a set of robust and readily available chiral Ni(II) complexes, which have allylic appendages derived from glycine (Gly), alanine (Ala) and phenylalanine (Phe), allowed incorporation of a 3,4-dihydroisoquinolone scaffold into the chiral amino acid residue. The reaction was performed in methanol and under mild conditions (at room temperature under air atmosphere), providing separable diastereomeric complexes with up to 94% total yield. The target α-AA with a 3,4-dihydroisoquinolone core in an enantiopure form was subsequently released from the obtained chiral Ni(II) complexes via an acidic decomposition in aqueous HCl, along with the recovery of the chiral auxiliary ligand.

Correction: An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes.

Correction for 'An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes' by Mikhail A. Arsenov et al., Org. Biomol. Chem., 2022, 20, 9385-9391, https://doi.org/10.1039/D2OB01970A.

Synthesis, Characterization, and Study of Catalytic Activity of Chiral Cu(II) and Ni(II) Salen Complexes in the α-Amino Acid C-α Alkylation Reaction.

A new family of Cu(II) and Ni(II) salen complexes was synthesized and fully characterized through various physicochemical methods. Their catalytic activity was evaluated in the phase transfer Cα-alkylation reaction of the Schiff bases of D,L-alanine ester and benzaldehyde derivatives. It was found that the introduction of a chlorine atom into the ortho- and para-positions of the phenyl ring of the substrate resulted in an increase in both the chemical yield and the asymmetric induction (ee 66-98%). The highest enantiomeric excess was achieved in the case of a Cu(II) salen complex based on (S,S)-cyclohexanediamine and salicylaldehyde at -20 °C. The occurrence of a bulky substituent in the ligand present in the complexes led to a drastic decrease in ee and chemical yield. For instance, the introduction of bulky substituents at positions 3 and 5 of the phenyl ring of the catalyst resulted in a complete loss of the stereoselectivity control in the alkylation reaction.

Family of Well-Defined Chiral-at-Cobalt(III) Complexes as Metal-Templated Hydrogen-Bond-Donor Catalysts: Effect of Chirality at the Metal Center on the Stereochemical Outcome of the Reaction.

A family of well-defined Λ- and Δ-diastereomeric octahedral cationic chiral-at-cobalt complexes were obtained by a simple two-step reaction of (R,R)-1,2-diaminocyclohexane, (R,R)-1,2-diphenylethylenediamine, or (S)-2-(aminomethyl)pyrrolidine and substituted salicylaldehydes with a cobalt(III) salt. It was observed for the first time that the use of an excess of cobalt(III) salt provides both the enantiopure Λ and Δ forms of the corresponding cobalt(III) complexes 1 and 2 in a ratio of diastereomers ranging from 1:1.6 to >20:1 (Λ/Δ) and in 31-95% combined yields. The obtained complexes were robust, air- and bench-stable, soluble in most of organic solvents, and insoluble in water. Through variation of the substituents in the phenyl ring of the salicylaldehyde moiety, it was shown that both steric and electronic effects of substituents have a significant impact on the formation of Λ and Δ isomers. Next, the efficacies of the enantiopure metal-templated complexes 1-3 were investigated in three benchmark asymmetric reactions in order to compare their catalytic activity. The chiral cobalt(III) complexes 1-3 were tested as enantioselective hydrogen-bond-donor catalysts in such important reactions as the Michael addition of the O'Donnell substrate to methyl acrylate, epoxidation of chalcone, and trimethylsilylcyanation of benzaldehyde. It was clearly demonstrated that the chirality at the cobalt center has an impact on the stereochemical outcome of the reactions. In particular, the Λ(R,R)-1 and Δ(R,R)-1 complexes acted as "pseudoenantiomeric" catalysts in the epoxidation and trimethylsilylcyanoation reactions, providing both enantiomers of the products with up to 57% enantiomeric excess.

An asymmetric metal-templated route to amino acids with an isoquinolone core via a Rh(III)-catalyzed coupling of aryl hydroxamates with chiral propargylglycine Ni(II) complexes.

A general protocol for the asymmetric synthesis of artificial amino acids (AAs) comprising an isoquinolone skeleton was successfully elaborated via a straightforward Rh(III)-catalyzed C-H activation/annulation of various aryl hydroxamates with a series of robust chiral propargylglycine Ni(II) complexes derived from glycine (Gly), alanine (Ala) and phenylalanine (Phe) in a green solvent (methanol) under mild conditions (at room temperature under air). Notably, in the case of phenylalanine-derived complexes, the formation of unfavorable 4-substituted isoquinolone regioisomers was achieved by a catalyst control for the first time. The subsequent acidic decomposition of the obtained Ni(II) complexes provides the target unnatural α- and α,α-disubstituted AAs with an isoquinolone core in an enantiopure form.

Synthesis and a Catalytic Study of Diastereomeric Cationic Chiral-at-Cobalt Complexes Based on (R,R)-1,2-Diphenylethylenediamine.

Here we report the first synthesis of two diastereomeric cationic octahedral Co(III) complexes based on commercially available (R,R)-1,2-diphenylethylenediamine and salicylaldehyde. Both diastereoisomers with opposite chiralities at the metal center (Λ and Δ configurations) were prepared. The new Co(III) complexes possessed both acidic hydrogen-bond donating (HBD) NH moieties and nucleophilic counteranions and operate as bifunctional chiral catalysts for the challenging kinetic resolution of terminal and disubstituted epoxides by the reaction with CO2 under mild conditions. The highest selectivity factor (s) of 2.8 for the trans-chalcone epoxide was achieved at low catalyst loading (2 mol %) in chlorobenzene, which is the best achieved result currently for this type of substrate.

A general asymmetric synthesis of artificial aliphatic and perfluoroalkylated α-amino acids by Luche's cross-electrophile coupling reaction.

Aliphatic artificial α-amino acids (α-AAs) have attracted great interest in biochemistry and pharmacy. In this context, we developed a promising practical protocol for the asymmetric synthesis of these α-AAs through the selective and efficient intermolecular cross-electrophile coupling of Belokon's chiral dehydroalanine Ni(ii) complex with different alkyl and perfluoroalkyl iodides mediated by a dual Zn/Cu system. The reaction afforded diastereomeric complexes with dr up to 21.3 : 1 in 24-95% yields (19 examples). Exemplarily, three enantiomerically pure aliphatic α-AAs were obtained through acidic decomposition of (S,S)-diastereomers of Ni(ii) complexes. Importantly, the chiral auxiliary ligand (S)-BPB ((S)-2-(N-benzylprolyl)aminobenzophenone) was easily recycled by simple filtration after acidic complex decomposition and reused for the synthesis of the initial dehydroalanine Ni(ii) complex.

Henry Reaction Revisited. Crucial Role of Water in an Asymmetric Henry Reaction Catalyzed by Chiral NNO-Type Copper(II) Complexes.

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 CH2Cl2 (CD2Cl2), containing different amounts of water. The reaction kinetics was monitored by 1H and 13C 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 1H 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 CH2Cl2 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.

Robust bifunctional aluminium-salen catalysts for the preparation of cyclic carbonates from carbon dioxide and epoxides.

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.

Using the same organocatalyst for asymmetric synthesis of both enantiomers of glutamic acid-derived Ni(II) complexes via 1,4-additions of achiral glycine and dehydroalanine Schiff base Ni(II) complexes.

(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.

Sequential Heck Cross-Coupling and Hydrothiolation Reactions Taking Place in the Ligand Sphere of a Chiral Dehydroalanine Ni(II) Complex: Asymmetric Route to ß-Aryl Substituted Cysteines.

A practically useful protocol for the asymmetric synthesis of artificial ß-aryl-substituted cysteine derivatives was developed through sequential Pd(II)-catalyzed Heck cross-coupling with aryl iodides and hydrothiolation reaction with various alkyl thiols in the presence of triethylamine taking place in the ligand sphere of a robust and bench-stable chiral dehydroalanine Ni(II) complex. The subsequent acidic decomposition of the single diastereomeric Ni(II) complexes led to the target enantiopure cysteine derivatives.

Asymmetric synthesis of enantiomerically and diastereoisomerically enriched 4-[F or Br]-substituted glutamic acids.

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.

Mechanism-guided development of VO(salen)X complexes as catalysts for the asymmetric synthesis of cyanohydrin trimethylsilyl ethers.

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.

Interaction of a trinuclear copper(i) pyrazolate with alkynes and carbon-carbon triple bond activation.

The trinuclear copper(i) pyrazolate {[3,5-(CF3)2Pz]Cu}3 forms η2-copper/alkyne triple bond coordinated structures in the presence of acetylenes. There is no coordination of copper atoms to the phenyl ring of phenylacetylene and copper(i) acetylide formation during the interaction. It was observed that the complexes formed are the active catalytic species in click reactions.

No carrier added synthesis of O-(2'-[18F]fluoroethyl)-L-tyrosine via a novel type of chiral enantiomerically pure precursor, NiII complex of a (S)-tyrosine Schiff base.

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.

Carbocation/Polyol Systems as Efficient Organic Catalysts for the Preparation of Cyclic Carbonates.

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 CO2 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.

VO(salen)(X) catalysed asymmetric cyanohydrin synthesis: an unexpected influence of the nature of anion X on the catalytic activity.

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.

Chiral Cobalt(III) Complexes as Bifunctional Brønsted Acid-Lewis Base Catalysts for the Preparation of Cyclic Organic Carbonates.

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.

Ruthenium-catalyzed reductive amination without an external hydrogen source.

A ruthenium-catalyzed reductive amination without an external hydrogen source has been developed using carbon monoxide as the reductant and ruthenium(III) chloride (0.008-2 mol %) as the catalyst. The method was applied to the synthesis of antianxiety agent ladasten.

Atom- and step-economical preparation of reduced Knoevenagel adducts using CO as a deoxygenative agent.

A highly efficient one-step Rh-catalyzed preparation of reduced Knoevenagel adducts of various aldehydes and ketones with active methylene compounds has been developed. The protocol does not require an external hydrogen source and employs carbon monoxide as a deoxygenative agent. The use of malonic acid or cyanoacetamide enabled efficient formal deoxygenative addition of methyl acetate or acetonitrile to aldehydes. The developed methodology was applied to the synthesis of the precursors of biomedically important compounds.