Recent Developments in the Synthesis of β-Diketones

Apart from being one of the most important intermediates in chemical synthesis, broadly used in the formation of C–C bonds among other processes, the β-dicarbonyl structure is present in a huge number of biologically and pharmaceutically active compounds. In fact, mainly derived from the well-known antioxidant capability associated with the corresponding enol tautomer, β-diketones are valuable compounds in the treatment of many pathological disorders, such as cardiovascular and liver diseases, hypertension, obesity, diabetes, neurological disorders, inflammation, skin diseases, fibrosis, or arthritis; therefore, the synthesis of these structures is an area of overwhelming interest for organic chemists. This paper is devoted to the advances achieved in the last ten years for the preparation of 1,3-diketones, using different chemical (Claisen, hydration of alkynones, decarboxylative coupling) or catalytic (biocatalysis, organocatalytic, metal-based catalysis) methodologies: Additionally, the preparation of branched β-dicarbonyl compounds by means of α-functionalization of non-substituted 1,3-diketones are also discussed.

Quantum-chemical study on the relative stability of sildenafil tautomers

The tautomeric equilibrium of sildenafil molecule was theoretically studied using B3LYP and M06-2X density functional theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by polarizable continuum model (PCM). Three tautomeric forms are possible. Two keto forms: A — where the tautomeric proton in more distant from carbonyl group and B — where it is closer, and one enol form denoted, C. Both DFT methods qualitatively give similar tautomer stability order: B > A > C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/aug-cc-pVDZ, the relative Gibbs-free energies for A and C relative to B are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ, the relative Gibbs-free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions, we expect that the B tautomer is dominant, and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences, we performed additional calculations for a series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of sildenafil and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

Quantum-Chemical Study on the Relative Stability of Sildenafil Tautomers

The tautomeric equilibrium of Sildenafil molecule was theoretically studied using B3LYP and M06-2X Density Functional Theory (DFT) methods in connection with aug-cc-pVDZ correlation consistent basis set. Calculations were performed for gas phase and water solution conditions modelled by Polarizable Continuum Model (PCM). Three tautomeric forms are possible. Two keto forms: A – where the tautomeric proton in more distant from carbonyl group, B – where it is closer, and one enol form denoted C. Both DFT methods qualitatively give similar tautomer stability order: B>A>C. The B tautomer is dominant in gas phase and water environment, whereas the C tautomer is too high in energy to be present in the tautomeric mixture. Regarding the A tautomer, it is not present in the gas phase but is present in small amounts in water solution. According to B3LYP/ aug-cc-pVDZ the relative Gibbs free energies for A and C relative to B, are 10.05 kcal/mol and 11.91 kcal/mol for gas phase and 5.49 kcal/mol and 12.49 kcal/mol for water solution. According to M06-2X/aug-cc-pVDZ the relative Gibbs free energies for A and C are 9.12 kcal/mol and 10.60 kcal/mol for gas phase and 4.27 kcal/mol and 10.23 kcal/mol for water solution. Therefore, for in vivo conditions we expect that the B tautomer is dominant and there may exist small amounts of the A tautomer. The C enol tautomer is not present at all. This picture is very different from the parent tautomeric system: 4-hydroxypyrimidine/4-pyrimidinone where the C enol tautomer is less stable than keto B only by about 1 kcal/mol in the gas phase and the A keto tautomer is the least stable and not present in the tautomeric mixture. In order to understand these differences we performed additional calculations for series of parent molecules starting from 4-hydroxypyrimidine/4-pyrimidinone, going through two in-between model molecules and ending at Sildenafil molecule. We found that the most important reasons of C form destabilization are: dearomatization of the 6-membered ring caused by the fusion with pyrazole ring, lack of strong intramolecular hydrogen bond in C form of Sildenafill and presence of destabilizing steric interaction of oxygen and nitrogen atoms of two 6-memberd rings in this tautomer.

Synthesis, isolation and characterization of a stable lithium stannenolate. A keto or an enol tautomer?

The synthesis and isolation of the first stable lithium stannenolate is reported. Structural and spectroscopic data, in combination with DFT quantum-mechanical calculations, indicate that the stannenolate adopts the keto tautomeric structure.

Structural insights into the bypass of the major deaminated purines by translesion synthesis DNA polymerase

The exocyclic amines of nucleobases can undergo deamination by various DNA damaging agents such as reactive oxygen species, nitric oxide, and water. The deamination of guanine and adenine generates the promutagenic xanthine and hypoxanthine, respectively. The exocyclic amines of bases in DNA are hydrogen bond donors, while the carbonyl moiety generated by the base deamination acts as hydrogen bond acceptors, which can alter base pairing properties of the purines. Xanthine is known to base pair with both cytosine and thymine, while hypoxanthine predominantly pairs with cytosine to promote A to G mutations. Despite the known promutagenicity of the major deaminated purines, structures of DNA polymerase bypassing these lesions have not been reported. To gain insights into the deaminated-induced mutagenesis, we solved crystal structures of human DNA polymerase η (polη) catalyzing across xanthine and hypoxanthine. In the catalytic site of polη, the deaminated guanine (i.e. xanthine) forms three Watson–Crick-like hydrogen bonds with an incoming dCTP, indicating the O2-enol tautomer of xanthine involves in the base pairing. The formation of the enol tautomer appears to be promoted by the minor groove contact by Gln38 of polη. When hypoxanthine is at the templating position, the deaminated adenine uses its O6-keto tautomer to form two Watson–Crick hydrogen bonds with an incoming dCTP, providing the structural basis for the high promutagenicity of hypoxanthine.

8-(Pyridin-2-yl)quinolin-7-ol as a Platform for Conjugated Proton Cranes: A DFT Structural Design

Theoretical design of conjugated proton cranes, based on 7-hydroxyquinoline as a tautomeric sub-unit, has been attempted by using ground and excited state density functional theory (DFT) calculations in various environments. The proton crane action request existence of a single enol tautomer in ground state, which under excitation goes to the excited keto tautomer through a series of consecutive excited-state intramolecular proton transfer (ESIPT) steps with the participation of the crane sub-unit. A series of substituted pyridines was used as crane sub-units and the corresponding donor-acceptor interactions were evaluated. The results suggest that the introduction of strong electron donor substituents in the pyridine ring creates optimal conditions for 8-(pyridin-2-yl)quinolin-7-ols to act as proton cranes.

Unexpected formation of a co-crystal containing the chalcone (E)-1-(5-chlorothiophen-2-yl)-3-(3-methylthiophen-2-yl)prop-2-en-1-one and the keto–enol tautomer (Z)-1-(5-chlorothiophen-2-yl)-3-(3-methylthiophen-2-yl)prop-1-en-1-ol

The title crystal structure is assembled from the superposition of two molecular structures, (E)-1-(5-chlorothiophen-2-yl)-3-(3-methylthiophen-2-yl)prop-2-en-1-one, C12H9ClOS2 (93%), and (Z)-1-(5-chlorothiophen-2-yl)-3-(3-methylthiophen-2-yl)prop-1-en-1-ol, C12H11ClOS2 (7%), 0.93C12H9ClOS2·0.07C12H11ClOS2. Both were obtained from the reaction of 3-methylthiophene-2-carbaldehyde and 1-(5-chlorothiophen-2-yl)ethanone. In the extended structure of the major chalcone component, molecules are linked by a combination of C—H...O/S, Cl...Cl, Cl...π and π–π interactions, leading to a compact three-dimensional supramolecular assembly.

Unravelling the Keto-Enol Tautomer Dependent Photochemistry and Degradation Pathways of the Protonated UVA Filter Avobenzone

Avobenzone (AB) is a widely used UVA filter known to undergo irreversible photodegradation. Here, we investigate the detailed pathways by which AB photodegrades by applying UV laser-interfaced mass spectrometry to protonated AB ions. Gas-phase infrared multiple-photon dissociation (IRMPD) spectra obtained with the free electron laser for infrared experiments, FELIX, (600-1800 cm-1) are also presented to confirm the geometric structures. The UV gas-phase absorption spectrum (2.5-5 eV) of protonated AB contains bands that correspond to selective excitation of either the enol or diketo forms, allowing us to probe the resulting, tautomer-dependent photochemistry. Numerous photofragments (i.e. photodegradants) are directly identified for the first time, with m/z 135 and 161 dominating, and m/z 146 and 177 also appearing prominently. Analysis of the production spectra of these photofragments reveals that that strong enol to keto photoisomerism is occurring, and that protonation significantly disrupts the stability of the enol (UVA active) tautomer. Close comparison of fragment ion yields with the TDDFT-calculated absorption spectra give detailed information on the location and identity of the dissociative excited state surfaces, and thus provide new insight into the photodegradation pathways of avobenzone, and photoisomerisation of the wider class of β-diketone containing molecules.<br>

Unravelling the Keto-Enol Tautomer Dependent Photochemistry and Degradation Pathways of the Protonated UVA Filter Avobenzone

Avobenzone (AB) is a widely used UVA filter known to undergo irreversible photodegradation. Here, we investigate the detailed pathways by which AB photodegrades by applying UV laser-interfaced mass spectrometry to protonated AB ions. Gas-phase infrared multiple-photon dissociation (IRMPD) spectra obtained with the free electron laser for infrared experiments, FELIX, (600-1800 cm-1) are also presented to confirm the geometric structures. The UV gas-phase absorption spectrum (2.5-5 eV) of protonated AB contains bands that correspond to selective excitation of either the enol or diketo forms, allowing us to probe the resulting, tautomer-dependent photochemistry. Numerous photofragments (i.e. photodegradants) are directly identified for the first time, with m/z 135 and 161 dominating, and m/z 146 and 177 also appearing prominently. Analysis of the production spectra of these photofragments reveals that that strong enol to keto photoisomerism is occurring, and that protonation significantly disrupts the stability of the enol (UVA active) tautomer. Close comparison of fragment ion yields with the TDDFT-calculated absorption spectra give detailed information on the location and identity of the dissociative excited state surfaces, and thus provide new insight into the photodegradation pathways of avobenzone, and photoisomerisation of the wider class of β-diketone containing molecules.<br>