José Luis Viveros-Ceballos

Este artículo recorre la historia del ácido γ-aminobutírico (GABA), desde su primera síntesis en el siglo XIX hasta su re-conocimiento como el principal neurotransmisor inhibitorio del sistema nervioso central. Se describen, su papel en la sinapsis GABAérgica y la forma en que su estudio impulsó el desarrollo de agentes neuroactivos. Asimismo, se destaca cómo la química del GABA sigue inspirando nuevas estrategias de diseño de mo-léculas con potencial terapéutico.

An efficient and practical procedure for the synthesis of (E)-α,β-unsaturated amides incorporating α-aminophosphonates, derived from readily accessible phosphonoacetamides, via the Horner–Wadsworth–Emmons (HWE) reaction was developed. The influence of reaction parameters, including base, solvent, and temperature, as well as the scope of the method with different aldehydes, was examined, affording the target compounds in good yields and with high (E)-selectivity. The required phosphonoacetamides were conveniently prepared through a Kabachnik–Fields reaction of aldehydes, benzylamine and dimethyl phosphite followed by hydrogenolytic cleavage of the N-Bn bond, acylation with bromoacetyl bromide, and a subsequent Arbuzov reaction. This HWE protocol provides straightforward access to a broad range of (E)-α,β-unsaturated amides incorporating α-aminophosphonates under mild conditions, offering valuable scaffolds with potential pharmacological relevance as anticancer agents.

We present the first stereoselective synthesis of phosphonic and phosphinic analogues not only of (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylic acid, the pivotal intermediate in ramipril synthesis, but also of all its cis-fused stereoisomers. Key to this accomplishment is the highly diastereoselective synthesis of cis-fused bicyclic (3aS,6aS)- and (3aR,6aR)-hexahydrocyclopenta[b]pyrrol-2-one using Meyers’ tricyclic lactam methodology. The nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to chiral N-acyliminium ions affords the diastereoisomers, which are easily separated by column chromatography. The diastereoselectivity in the nucleophilic addition of the phosphorus reagents is completely consistent with our previous reports and all synthesized compounds were fully characterized.

Phosphonic analogs of octahydroisoindole-1-carboxylic acids are bicyclic proline derivatives of interest in drug design and enzymatic mechanism studies. Here we report the stereoselective synthesis of the cis- and trans-fused octahydroisoindole system using oxazoloisoindolone lactam and 1,2-cyclohexanedicarboxylic anhydride as advanced chiral precursors, respectively, yielding enantiopure octahydroisoindolone intermediates with the desired stereochemistry at the ring junction. Finally, using these intermediates, the target (1R,3aR,7aS)- and (1R,3aR,7aR)-octahydroisoindole-1-phosphonic acids and their enantiomers were obtained with complete stereocontrol via highly diastereoselective addition of trimethyl phosphite to chiral N-acyliminium ions as the key step.

Herein we report for the first time the diastereoselective synthesis of (2R,3aR,7aS)- and (2S,3aS,7aR)-octahydroindole-2-phosphonic acid (Oic^P trans-fused stereoisomers) from diethyl (R)- and (S)-phosphopyroglutamate derivative. The key steps of this procedure are the ruthenium tetroxide oxidation of enantiomerically pure diethyl (R)- and (S)-phosphoprolinate obtained through Katritzky’s benzotriazole-oxazolidine methodology, a highly diastereoselective successive double 4,5-diallylation of diethyl (R)- and (S)-phosphopyroglutamate with allyl bromide and allyltrimethylsilane with a trans-addition mode, and a ring-closing metathesis with Grubbs’ first-generation ruthenium catalyst.

An expedient synthetic entry to cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic analogs of cis-4-hydroxypipecolic acid is presented in this paper. The main feature of this methodology is the highly regioselective addition of silyl phosphites or phosphonites to cyclic 1-benzyloxycarbonyl enaminones. Interestingly, the hydride reduction of the resulting 2-phospho-4-oxopiperidine proceeds with high diastereofacial preference using NaBH₄. In the last step, the cleavage of N-Cbz group under hydrogenolysis followed by the hydrolysis of the phosphonate or phosphinate functionalities, led to the target cis-4-hydroxyphosphonic and cis-4-hydroxyphosphinic acids, respectively.

Chitinases represent an alternative therapeutic target for opportunistic invasive mycosis since they are necessary for fungal cell wall remodeling. This study presents the design of new chitinase inhibitors from a known hydrolysis intermediate. Firstly, a bioinformatic analysis of Aspergillus fumigatus chitinase B1 (AfChiB1) and chitotriosidase (CHIT1) by length and conservation was done to obtain consensus sequences, and molecular homology models of fungi and human chitinases were built to determine their structural differences. We explored the octahydroisoindolone scaffold as a potential new antifungal series by means of its structural and electronic features. Therefore, we evaluated several synthesis-safe octahydroisoindolone derivatives by molecular docking and evaluated their AfChiB1 interaction profile. Additionally, compounds with the best interaction profile (1–5) were docked within the CHIT1 catalytic site to evaluate their selectivity over AfChiB1. Furthermore, we considered the interaction energy (MolDock score) and a lipophilic parameter (aLogP) for the selection of the best candidates. Based on these descriptors, we constructed a mathematical model for the IC₅₀ prediction of our candidates (60–200 μM), using experimental known inhibitors of AfChiB1. As a final step, ADME characteristics were obtained for all the candidates, showing that 5 is our best designed hit, which possesses the best pharmacodynamic and pharmacokinetic character.

Kinetically controlled cyclocondensation of stereoisomeric and ring–chain tautomeric mixture of (±)-hydroxylactone 1 and 0.5 equiv of (R)-phenylglycinol provided tricyclic oxazoloisoindolone lactam (3R,5aS,9aR,9bS)-2a, a versatile intermediate for further stereocontrolled transformations to access enantiopure cis-fused octahydroisoindolones. An extension of this methodology was successfully applied to the synthesis of the 5,6-dihydroxy derivative (3aR,5R,6S,7aS)-17.

Two new strategies for the efficient synthesis of racemic 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (Tic^P) (±)-2 have been developed. The first strategy involves the electron-transfer reduction of the easily obtained α,β-dehydro phosphonophenylalanine followed by a Pictet–Spengler cyclization. The second strategy involves a radical decarboxylation–phosphorylation reaction on 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic). In both strategies, the highly electrophilic N-acyliminium ion is formed as a key intermediate, and the target compound is obtained in good yield using mild reaction conditions and readily available starting materials, complementing existing methodologies and contributing to the easy accessibility of (±)-2 for further research.

This paper describes the first diastereoselective synthesis of cyclic α‐aminophosphonic and α‐amino phosphonic acids from glycyl‐l‐proline 2,5‐diketopiperazine (S)‐6 prepared according to the usual peptide coupling procedures. The highlights of this contribution is the chemoselective reduction of the carbamate‐imide activated carbonyl group in the N‐Boc 2,5‐diketopiperazine (S)‐11 to generate the unstable hemiaminals (1R,8aS)‐12 and (1S,8aS)‐13, followed by the highly diastereoselective nucleophilic addition of trimethyl phosphite or dimethyl phenylphosphonite to the chiral carbenium ion (S)‐5. Acid hydrolysis of the phosphonate and phosphinate functionalities with simultaneous cleavage of the tert‐butyl carbamate protecting group led to the target compounds. The high diastereoselectivity in the nucleophilic addition of trivalent phosphorus to the chiral carbenium ion (S)‐5 is in agreement with our precedent reports.