Highly Diastereoselective Construction of Carbon– Heteroatom Quaternary Stereogenic Centers in the Synthesis of Analogs of Bioactive Compounds: From Monofluorinated Epoxyalkylphosphonates to α-Fluoro-, β-, or γ-Amino Alcohol Derivatives of Alkylphosphonates

The synthesis of the stable surrogates of an important amino acid (R)-4-amino-3-hydroxybutyric acid (GABOB) such as substituted hydroxy aminophosphonic acids bearing a quaternary stereogenic center is presented. Highly diastereoselective formations of fluorinated spiroepoxy alkylphosphonate or related tertiary carbon-containing oxiranes from β-keto phosphonates possessing methyl, phenyl, or cyclohexenyl substituents, are reported. Stereoselective acid-promoted epoxide opening by bromide or azide followed by reduction/protection afforded tertiary bromides or N-Boc derivatives of β-amino-γ-hydroxy alkylphosphonates in most cases, while the reactions of oxiranes with different amines yielded their β-hydroxy-γ-amino regioisomers. Surprisingly, during the synthesis of amino phosphonic acids, we observe that the acid-induced rearrangement proceeded in a high diastereospecific manner, leading finally to substituted β-hydroxy-γ-aminoalkylphosphonic acids.

α-(Imino)pyridyldifluoroethyl Phosphonates: Novel Promising Building Blocks in Synthesis of Biorelevant Aminophosphonic Acids Derivatives

A convenient synthetic approach to previously unknown NH-iminophosphonates bearing 2-, 3-, and 4-pyridyldifluoromethyl groups at the imine carbon atom was developed. The synthetic potential of these novel building blocks was demonstrated by their conversion into highly functionalized acyclic and heterocyclic aminophosphonates and phosphonic acids combining in their structure biorelevant aminophosphonic fragment, difluoromethyl group, and pyridyl, piperidyl, thiazolidin-4-one, or thiazidinan-4-one heterocyclic moieties in a single molecular platform.

Z,E-Isomerism in a Series of Substituted Iminophosphonates: Quantum Chemical Research

Esters of iminophosphonic acids (iminophosphonates, or IPs), including a fragment, >P(=O)-C=N, can be easily functionalized, for instance to aminophosphonic acids with a wide range of biological activity. Depending on the character of the substitution, the Z- or E-configuration is favorable for IPs, which in turn can influence the stereochemistry of the products of chemical transformations of IPs. While the Z,E-isomerism in IPs has been thoroughly studied by NMR spectroscopy, the factors stabilizing a definite isomer are still not clear. In the current work, density functional theory (DFT, using M06-2X functional) and ab initio spin-component–scaled second-order Møller–Plesset perturbation theory (SCS-MP2) calculations were carried out for a broad series of IPs. The calculations reproduce well a subtle balance between the preferred Z-configuration inherent for C-trifluoromethyl substituted IPs and the E-form, which is more stable for C-alkyl- or aryl-substituted IPs. The predicted trend of changing activation energy values agrees well with the recently determined experimental ΔG≠298 magnitudes. Depending on the substitution in the aromatic moiety, the Z/E-isomerization of N-aryl-substituted IPs proceeds via two types of close-in energy transition states. Not a single main factor but a combination of various contributions should be considered in order to explain the Z/E-isomerization equilibrium for different IPs.

Octahydroquinoxalin-2(1H)-One-Based Aminophosphonic Acids and Their Derivatives—Biological Activity towards Cancer Cells

In the search for new antitumor agents, aminophosphonic acids and their derivatives based on octahydroquinoxalin-2(1H)-one scaffold were obtained and their cytotoxic properties and a mechanism of action were evaluated. Phosphonic acid and phosphonate moieties increased the antiproliferative activity in comparison to phenolic Mannich bases previously reported. Most of the obtained compounds revealed a strong antiproliferative effect against leukemia cell line (MV-4-11) with simultaneous low cytotoxicity against normal cell line (mouse fibroblasts-BALB/3T3). The most active compound was diphenyl-[(1R,6R)-3-oxo-2,5-diazabicyclo[4.4.0]dec-4-yl]phosphonate. Preliminary evaluation of the mechanism of action showed the proapoptotic effect associated with caspase 3/7 induction.

The Synthesis of α-Aminophosphonates via Enantioselective Organocatalytic Reaction of 1-(N-Acylamino)alkylphosphonium Salts with Dimethyl Phosphite

α-Aminophosphonic acids are phosphorus analogues of α-amino acids. Compounds of this type find numerous applications in medicine and crop protection due to their unique biological activities. A crucial factor in these activities is the configuration of the stereoisomers. Only a few methods of stereoselective transformation of α-amino acids into their phosphorus analogues are known so far and all of them are based on asymmetric induction, thus involving the use of a chiral substrate. In contrast, we have focused our efforts on the development of an effective method for this type of transformation using a racemic mixture of starting N-protected α-amino acids and a chiral catalyst. Herein, a simple and efficient stereoselective organocatalytic α-amidoalkylation of dimethyl phosphite by 1-(N-acylamino)alkyltriphenylphosphonium salts to enantiomerically enriched α-aminophosphonates is reported. Using 5 mol% of chiral quinine- or hydroquinine-derived quaternary ammonium salts provides final products in very good yields up to 98% and with up to 92% ee. The starting phosphonium salts were easily obtained from α-amino acid derivatives by decarboxylative methoxylation and subsequent substitution with triphenylphosphonium tetrafluoroborate. The appropriate self-disproportionation of enantiomers (SDE) test for selected α-aminophosphonate derivatives via achiral flash chromatography was performed to confirm the reliability of the enantioselectivity results that were obtained.

Synthesis, Crystal Structure and Interaction with Bovine Serum Albumin (BSA) of Two α-Aminophosphonic Acids Derivatives

Two α-amino-phosphonate derivatives (1 & 2) were synthesized and their compositions and structures were characterized by Elemental Analysis (EA), FT-IR Spectrascopy (FT-IR), Electrospray Ionization Mass Spectrometry (ESI-MS), Nuclear Magnetic Resonance (NMR, 1H, 13C and 31P) and X-ray crystallography. Compound 1 & 2 were crystallized in monoclinic system with the space group P2(1)/n and P2(1)/c, respectively. The interaction effects of two α-aminophosphonate derivatives (1 & 2) with BSA were investigated and the binding constants were 1.07 × 104 M-1, 1.68 × 104 M-1, respectively. Besides, the values of n were indicated that 1:1 complex was formed between BSA and 1&2.

Protolysis and Complex Formation of Organophosphorus Compounds—Characterization by NMR-Controlled Titrations

Phosphonic acids, aminophosphonic acids, and phosphonocarboxylic acids are characterized by an advanced hyphenated technique, combining potentiometric titration with NMR spectroscopy. Automated measurements involving 13C, 19F and 31P nuclei lead to “pseudo 2D NMR” spectra, where chemical shifts or coupling constants are correlated with analytical parameters. Dissociation constants, stability constants, dynamic and specific chemical shifts are determined. Macroscopic and microscopic dissociation equilibria are discussed.