Vesna Petrović Peroković

Mannosylated N-Aryl Substituted 3-Hydroxypyridine-4-Ones: Synthesis, Hemagglutination Inhibitory Properties, and Molecular Modeling

Structural alterations of the aglycon portions of α‐mannosides influence their inhibitory potency toward type 1‐fimbriated Escherichia coli. The aim of our work was to prepare and explore inhibitory properties of novel mannosylated N‐aryl‐substituted 3‐hydroxypyridine‐4‐ones because they possess needed structural characteristics as possible FimH antagonists. Hemagglutination inhibitory tests showed that the examined 3‐hydroxypyridine‐4‐one α‐mannosides exhibited better inhibitory activity than methyl α‐d‐mannopyranoside used as a reference compound. Molecular modeling studies revealed the specific interactions responsible for the observed binding activities toward the mannose‐specific FimH lectin. The activity depends on the substituent in p‐position on the aglycon aromatic ring.

Organic Chemistry from Retrosynthesis to Asymmetric Synthesis

Retrosynthetic analysis as an imaginative process is introduced. Disconnection and functional group interconversion are discussed. 1-(Pyridine-3-yl) propan-1-ol is selected as an exemplary target molecule for retrosynthetic analysis and its (S)-enantiomer for asymmetric synthesis. Interconversions of oxygen functionalities are overviewed. The acidity of the C–H bond as a key property for C–C disconnections is indicated. Some historical and environmental aspects of organic synthesis are concisely presented. 1.

Disconnection with Participation of Two Functional Groups

The concept of charge alteration in compounds with one functional group and the resulting match or mismatch of partial charges in compounds with two functional groups is introduced. The favorable relation of oxygen functionalities in a 1,3- and 1,5-dioxygenated pattern supporting logical disconnections is demonstrated. The Mannich reaction, Michael addition and Robinson annelation are presented as synthetic approaches to this target molecule based on illogical disconnections. Diastereo- and enantioselective (asymmetric) aldol reactions are presented and the mechanism for the preferred formation of syn/anti products discussed. Examples of non-catalytic and catalytic asymmetric aldol and Mannich reactions are given and their mechanistic aspects and experimental protocols presented. Asymmetric syntheses of optically pure compounds with a 1,3-CO pattern (α-alkyl-β-hydroxy carboxylic acids, β-hydroxy ketones, dihydropyranones) and asymmetric Mannich reactions on the route to the optically pure herbicide (S)-fenpropimorph, (S)-phenylglycine and (2S, 3R)-α-amino-γ-keto acids are discussed.

Stereoisomers and Stereoselective Reactions—“Departure into Third Dimension”

The basics of stereoselective reactions and reaction stereochemistry—the relation of stereoselectivity to the topology of tetrahedral and planar units in organic molecules—are discussed. The kinetic control of enantioselective reactions and characteristics of enantioselective and diastereoslective reactions is presented. Asymmetric syntheses are exemplified by the hydrogenation of C=O and C=NR bonds in prochiral substrates catalyzed by organometallic complexes with chiral phosphine ligands. The mechanism of asymmetric alkylation of stabilized carbanions in specifically designed chiral substrates and the practicability of this method in the preparation of optically pure α-alkyl carboxylic acids are discussed. The synthetic approach to chiral auxiliaries and importance of recycling are presented.

Specific Synthetic Methods

Some innovative synthetic methods in organic chemistry are concisely presented, multicomponent reactions, specifically the Ugi multicomponent reaction, parallel syntheses and combinatorial chemistry, mechanochemically promoted organic reactions, organic reactions promoted by microwave irradiation and syntheses in ionic liquids. Examples of chemoselective or asymmetric syntheses completed by one of the presented specific methods are presented for the antihypertensive drug nifedipine, the alkaloid tropinone, the local anesthetic xylocaine and the HIV inhibitor tipranavir.

Disconnection, Synthons, Introductory Example

Retrosynthetic analysis as an imaginative process is introduced. Disconnection and functional group interconversion are discussed. 1-(Pyridine-3-yl)propan-1-ol is selected as an exemplary target molecule for retrosynthetic analysis and its (S)-enantiomer for asymmetric synthesis. Interconversions of oxygen functionalities are overviewed. The acidity of the C–H bond as a key property for C–C disconnections is indicated. Some historical and environmental aspects of organic synthesis are concisely presented.

Retrosynthetic Considerations and Syntheses of Complex, Biologically Active Molecules

Retrosyntheses and related syntheses of four selected products and biologically active compounds are presented. Retrosynthesis of (±)-menthol and synthesis of (−)-menthol are presented in the first section. Synthesis of (±)-chloramphenicol and asymmetric synthesis of the antibiotic (−)-chloramphenicol are compared in the second section. The third section deals with (−)-sertraline, a compound with antidepressive and anxiolytic activity. The example of (−)-sertraline illustrates diverse approaches to biologically active compounds in the optically pure form, which is regularly investigated and used in a certain phase of the development of new drug entities (NDEs) in the pharmaceutical industry. In the last section, the retrosynthesis, stereoselective synthesis and asymmetric synthesis of diastereomeric α-, β- and γ-lycoranes, members of an important class of alkaloids and a goldmine for new drugs, are discussed.

Rearrangements—Synthetic Reactions “Not Liable” to Retrosynthetic Analysis

Molecular rearrangements are not amenable to retrosynthesis because of their complex mechanisms. Still, in some cases retro-rearrangements are a conceivable and useful approach to selected target molecules. In this chapter, arguments for the retrosynthetic approach to some well-known rearrangements, Beckmann, Hofmann, Arndt-Eistert, Favorskii, pinacol and Bayer-Villiger, are presented. The mechanism of these rearrangements is explained. Retrosynthesis and synthesis, which include a specific rearrangement in the key step, are proposed for selected target molecules, among them paracetamol, dinestrol and spasmolytic biphenyl carboxylic acid.

Illogical Disconnections with Participation of Two Groups

Compounds with a 1,2-, 1,4- and 1,6-dioxygen pattern and related bifunctional structures are presented. Disconnection of the internal bonds results in illogical synthons because of the mismatch of charges in the patterns with an even number of C atoms between the functional groups. Three-membered heterocyclic rings are presented as an important class of illogical nucleophiles in the retrosynthesis of the 1,2-difunctional pattern. Retrosynthesis of the 1,6-dicarbonyl pattern by reconnection and retro-Birch reduction of the aromatic building block is related to chemoselective Birch reduction and ozonolysis in the synthetic route. The retrosynthesis and synthesis of salbutamol and asymmetric synthesis of (−)-frontalin are presented.

Retrosynthetic Consideration of Heterocyclic Structures

An overview of two-heteroatom reagents and the retrosynthesis of five- to seven-membered heterocycles to building blocks with heteroatoms O, N and S in the 1,2-, 1,3- and 1,4-position is presented. Their use in the cyclization of medium-large rings is exemplified. Retrosyntheses and syntheses of biologically active heterocyclic compounds, lanycil, sulfisoxazole , sulfamethoxazole, primicarb, hydralazine and glutethimide, are presented. Cyclizations to three- to seven-membered heterocycles with one or more heteroatoms in the ring obey the Baldwin rules. The mechanistic origin of the favored route and heuristic value of the Baldwin rules are discussed.