Bernardo Herradón

Short syntheses of (S)-pipecolic acid, (R)-coniine, and (S)-δ-coniceine using biocatalytically-generated chiral building blocks

Abstract The kinetic resolutions of both (±)-N-(benzyloxycarbonyl-2-(hydroxymethyl)piperidine [(±)- 5 ] and (±)-N-( tert -butoxycarbonyl)-2-(hydroxymethyl)piperidine [(±)- 6 ] catalyzed by the enzyme acylase I from Aspergillus species (AA-I) afforded the chiral building blocks ( S )- 5 and ( S )- 6 , respectively; which were used for the syntheses of the title natural products and derivatives of ( S )-pipecolic acid. The syntheses were short (2–4 steps) and proceeded with satisfactory overall yield.

The reaction of carbohydrate-derived alkoxyaldehydes with methoxycarbonylmethylenetriphenylphosphorane: stereoselective synthesis of β-unsaturated esters

Abstract The reaction of several carbohydrate-derive alkoxyaldehydes with methoxycarbonylmethylenetriphenylphosphorane afford α, β-unsaturated esters with Z-stereoselectivity. The stereoselectivity depends on the substrate stucture and the nature of the solvent used.

A universal scale of aromaticity for π‐organic compounds

Aromaticity is an essential concept in chemistry, invented to account for the stability, reactivity, molecular structure, and properties of many organic and inorganic compounds. In recent years, numerous methods to quantify aromaticity based on the energetic, magnetic, structural, and electronic properties of molecules have been proposed but none of them is universal. The inability of establishing a universal scale of aromaticity based on a single parameter is due to the multidimensional character of this phenomenon. Consequently, aromaticity analyses should be carried out by employing a set of aromaticity descriptors on the basis of different physical manifestations of aromaticity. Here, we report a universal scale of aromaticity for π‐organic compounds based on the Euclidean distance between neurons in a self‐organizing map. The most widely used aromaticity indicators have been used as molecular descriptors, and so our approach provides the first scale of aromaticity which contains the energetic, magnetic, and structural aspects of this property. The method is applicable to a wide variety of unsaturated organic compounds and allows quantification of both aromaticity and antiaromaticity. Additionally, the position of a compound on the bidimensional map determinates immediately the following: (a) the group (aromatic, nonaromatic, or antiaromatic) to which the system belongs, (b) their degree of π‐electronic delocalization, and (c) the similarity in aromaticity/antiaromaticity between different compounds. This new scale of aromaticity is able to indicate the expected order of aromaticity of analogues of fulvene and heptafulvene, heteroaromatic species, substituted benzenes, and functionalized cyclopentadienyl compounds.

Stereoselective syntheses and reactions of chiral oxygenated α,β-unsaturated-γ- and δ-lactones

Abstract The syntheses of the chiral α,β-unsaturated lactones (+)-5, (−)-6, (+)-8, (+)-9, and (+)-10 have been efficiently achieved from readily available starting materials. The lactone (+)-5 has been synthesized in 7 steps from (R,R)-dimethyl tartrate (38–43% overall yield). The use of (+)-5 in formal syntheses of natural (+)-asperlin 4 and advanced intermediates for (+)-olguine 2 are also reported. The lactone (−)-6 has been prepared in 5 steps from (R)-malic acid (44–50% overall yield). It can be a useful precursor for the syntheses of branched chain and deoxy nucleoside analogues. The preparation of (−)-6 constitues formal syntheses of natural (+)-eldanolide 53 and the (+)-Geissman-Waiss lactone 54 (an intermediate for the syntheses of a variety of pyrrolizidine alkaloids). The lactones (+)-8, (+)-9 and (+)-10 have been synthesized from 3,4-di-O-acetyl-L-rhamnal 58. The highly diastereoselective transformations of (+)-9 and (+)-10, through sequential conjugate nucleophilic addition and enolate reaction, into densely functionalized chiral γ-lactones 12 are also reported.

The synthesis of (-)-anamarine

Abstract The enantiospecific total synthesis of (-)-anamarine, starting from D-glucose, has been carried out.

Efficient synthesis of (R)-5-(2-hydroxyethyl)-2(5H)-furanone from (R)-malic acid

Abstract The title compound has been synthesized in five steps, 48% overall yield, from (R)-malic acid.

The use of l-tartaric acid in the synthesis of enanthiomerically pure compounds: synthesis of 4-O-benzyl-2,3-dideoxi-L- threo-hex-2-eno no-1,5-lactone.

Abstract The title compound was obtained through a seven steps sequence and using - dimethyl L-tartrate as the starting material (30% overall yield). The system 2,3-dideoxy-L-threo-hex-2-enono-1,5-lactone is present in several natural compounds.

The synthesis of D-asperlin

The synthesis of the D-enantiomer of asperlin has been carried out. The stereochemistry of the epoxide ring has been assigned as 6R,7S for this D-enantiomer.

Efficient Synthesis of Chiral Isoquinoline and Pyrido[1,2-b]-isoquinoline Derivatives via Intramolecular Heck Reactions

The palladium(0)-catalyzed reaction of derivatives of γ-amino-α,β-unsaturated esters bearing an N-(2-iodobenzoyl) substituent results in an intramolecular Heck reaction, the outcome of which depends on the structure of the substrate as well as on the experimental conditions. The methodology developed has been applied to the efficient syntheses of chiral isoquinoline and pyrido[1,2-b]–isoquinoline derivatives.

Activation of the aryl hydrocarbon receptor by carbaryl: Computational evidence of the ability of carbaryl to assume a planar conformation

It has been accepted that aryl hydrocarbon receptor (AhR) ligands are compounds with two or more aromatic rings in a coplanar conformation. Although general agreement exists that carbaryl is able to activate the AhR, it has been proposed that such activation could occur through alternative pathways without ligand binding. This idea was supported by studies showing a planar conformation of carbaryl as unlikely. The objective of the present work was to clarify the process of AhR activation by carbaryl. In rat H4IIE cells permanently transfected with a luciferase gene under the indirect control of AhR, incubation with carbaryl led to an increase of luminescence. Ligand binding to the AhR was studied by means of a cell-free in vitro system in which the activation of AhR can occur only by ligand binding. In this system, exposure to carbaryl also led to activation of AhR. These results were similar to those obtained with the AhR model ligand beta-naphthoflavone, although this compound exhibited higher potency than carbaryl in both assays. By means of computational modeling (molecular mechanics and quantum chemical calculations), the structural characteristics and electrostatic properties of carbaryl were described in detail, and it was observed that the substituent at C-1 and the naphthyl ring were not coplanar. Assuming that carbaryl would interact with the AhR through a hydrogen bond, this interaction was studied computationally using hydrogen fluoride as a model H-bond donor. Under this situation, the stabilization energy of the carbaryl molecule would permit it to adopt a planar conformation. These results are in accordance with the mechanism traditionally accepted for AhR activation: Binding of ligands in a planar conformation.