Application of 2-Azabicyclo[2.2.1]Hept-5-En-3-One (Vince Lactam) in Synthetic Organic and Medicinal Chemistry.

2-Azabicyclo[2.2.1]hept-5-en-3-one (Vince lactam) is known to be a valuable building block in synthetic organic chemistry and drug research. It is an important precursor to access of some blockbuster antiviral drugs such as Carbovir or Abacavir as well as other carbocyclic neuraminidase inhibitors as antiviral agents. The ring C=C bond of the Vince lactam allows versatile chemical manipulations to create not only functionalized γ-lactams, but also γ-amino acid derivatives with a cyclopentane framework. The aim of the current account is to summarize the chemistry of Vince lactam, its synthetic utility and application in organic and medicinal chemistry over the last decade.

Application of Metathesis Protocols to the Stereocontrolled Synthesis of some Functionalized ß-Amino Esters and Azaheterocycles.

In this account our aim was to give an insight into the application of metathesis protocols (ROM, RCM, RCEYM, CM, RRM) for the synthesis of various azaheterocyclic frameworks. Due to the high biological potential and importance in peptide chemistry and drug design of ß-amino acids our intention is to give a highlight on the synthetic procedures and transformation of these class of compounds with the above-mentioned metathesis strategies with emphasis on selectivity, stereocontrol, substrate-directing effect or functional group tolerance.

Palladium-Catalyzed Arylfluorination of Alkenes: A Powerful New Approach to Organofluorine Compounds.

Fluorine incorporation into organic molecules is often beneficial to their absorption, distribution, metabolism, and excretion (ADME) properties or bioactivity. As a consequence, organofluorine compounds have become quite common amongst drugs and agrochemicals, and their preparation is a highly important topic in both synthetic organic chemistry and pharmaceutical chemistry. One of the newly developed methods for accessing organofluorine compounds is Pd-catalyzed arylfluorination of alkenes. It is an olefin difunctionalization process that simultaneously introduces an aryl group and a fluorine atom into an alkene framework. This review provides a concise overview of this powerful and versatile method.

Recent Progress in the Selective Fluorinations of Some Functionalized Cycloalkenes.

Organofluorine compounds have had an increasing impact in synthetic organic chemistry and pharmaceutical research over the past two decades. Their syntheses and the development of novel synthetic approaches towards versatile fluorinated small molecules have received great interest. Our research team has designed various selective and stereocontrolled methods for the construction of fluorine-containing small molecular entities, involving the transformation of various functionalized cycloalkenes across their ring olefin bond. The synthetic methodologies developed to access various pharmacologically interesting fluorinated derivatives with multiple chiral centers might be valuable protocols for the preparation of other classes of organic compounds as well.

Recent Progress in Aryltrifluoromethylation Reactions of Carbon-Carbon Multiple Bonds.

Due to the increasing relevance of fluorine-containing organic molecules in drug design, the synthesis of organofluorine compounds has gained high significance in synthetic organic chemistry. Trifluoromethylative difunctionalizations of carbon-carbon multiple bonds, with the simultaneous incorporation of a CF3 group and another functional element, have considerable potential. Because of the high importance of carbon-carbon bond-forming reactions in organic synthesis, carbotrifluoromethylations and, in particular, aryltrifluoromethylations or heteroaryltrifluoromethylations are considered to be increasing fields of synthetic organic chemistry. The aim of the current review is to summarize recent developments of aryltrifluoromethylation or heteroaryltrifluoromethylation reactions.

Synthesis of novel fluorinated building blocks via halofluorination and related reactions.

A study exploring halofluorination and fluoroselenation of some cyclic olefins, such as diesters, imides, and lactams with varied functionalization patterns and different structural architectures is described. The synthetic methodologies were based on electrophilic activation through halonium ions of the ring olefin bonds, followed by nucleophilic fluorination with Deoxo-Fluor®. The fluorine-containing products thus obtained were subjected to elimination reactions, yielding various fluorine-containing small-molecular entities.

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols.

Fluorine-containing organic scaffolds are of significant interest in medicinal chemistry. The incorporation of fluorine into biomolecules can lead to remarkable changes in their physical, chemical, and biological properties. There are already many drugs on the market, which contain at least one fluorine atom. Saturated functionalized azaheterocycles as bioactive substances have gained increasing attention in pharmaceutical chemistry. Due to the high biorelevance of organofluorine molecules and the importance of N-heterocyclic compounds, selective stereocontrolled procedures to the access of new fluorine-containing saturated N-heterocycles are considered to be a hot research topic. This account summarizes the synthesis of functionalized and fluorine-containing saturated azaheterocycles starting from functionalized cycloalkenes and based on oxidative ring cleavage of diol intermediates followed by ring expansion with reductive amination.

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers.

Ring-opening metathesis (ROM) of various unsaturated, constrained bicyclic ring systems has been investigated with the use of commercial ruthenium-based catalysts. Starting from various cyclodienes, the corresponding derived bicyclic lactone, lactam, and isoxazoline derivatives were submitted to ROM under ethenolysis. These functionalized, strained bicyclic systems afforded novel highly-functionalized diolefinated heterocyclic scaffolds in ROM reactions with stereocontrol, through the conservation of the configuration of the stereogenic centers of the starting compounds.

Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence.

A study exploring the chemical behavior of some dihydroxylated ß-amino ester stereo- and regioisomers, derived from unsaturated cyclic ß-amino acids is described. The nucleophilic fluorinations involving hydroxy-fluorine exchange of some highly functionalized alicyclic diol derivatives have been carried out in view of selective fluorination, investigating substrate dependence, neighboring group assistance and chemodifferentiation.

A Stereocontrolled Protocol to Highly Functionalized Fluorinated Scaffolds through a Fluoride Opening of Oxiranes.

A novel selective and substrate-dependent synthetic protocol has been developed towards the synthesis of various fluorine-containing, highly functionalized cycloalkane derivatives. The method involves the stereoselective epoxidation of some unsaturated cyclic ß-amino acid derivatives as model compounds, followed by a regioselective fluoride opening of oxiranes under various conditions with Deoxofluor and XtalFluor-E reagents, thereby offering an insight into this new epoxide opening methodology with fluoride.

Chemoselective, Substrate-directed Fluorination of Functionalized Cyclopentane ß-Amino Acids.

This work describes a substrate-directed fluorination of some highly functionalized cyclopentane derivatives. The cyclic products incorporating CH2 F or CHF2 moieties in their structure have been synthesized from diexo- or diendo-norbornene ß-amino acids following a stereocontrolled strategy. The synthetic study was based on an oxidative transformation of the ring carbon-carbon double bond of the norbornene ß-amino acids, followed by transformation of the resulted "all cis" and "trans" diformyl intermediates by fluorination with "chemodifferentiation".

Investigation of the structure-selectivity relationships and van't Hoff analysis of chromatographic stereoisomer separations of unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids on Cinchona alkaloid-based chiral stationary phases.

The enantiomers of four unusual, rather rigid isoxazoline-fused 2-aminocyclopentanecarboxylic acids were directly separated on a quinine- or a quinidine-based zwitterionic ion-exchanger as chiral selector. The effects of the mobile phase composition, the structures of the analytes and temperature on the separations were investigated. Experiments were performed at constant mobile phase composition in the temperature range 10-50°C to study the effects of temperature, and thermodynamic parameters were calculated from plots of ln α versus 1/T. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. It was found that the enantiomer separations were in most cases predominantly enthalpy-driven, but entropically-driven separations were also observed. The sequence of elution of the enantiomers was determined in all cases.

A novel and selective fluoride opening of aziridines by XtalFluor-E. synthesis of fluorinated diamino acid derivatives.

The selective introduction of fluorine onto the skeleton of an aminocyclopentane or cyclohexane carboxylate has been developed through a novel and efficient fluoride opening of an activated aziridine ring with XtalFluor-E. The reaction proceeded through a stereoselective aziridination of the olefinic bond of a bicyclic lactam and regioselective aziridine ring opening with difluorosulfiliminium tetrafluoroborate with the neighboring group assistance of the sulfonamide moiety to yield fluorinated diamino acid derivatives. The method based on the selective aziridine opening by fluoride has been generalized to afford access to mono- or bicyclic fluorinated substances.

Asymmetric synthesis of chloroisothreonine derivatives via syn-stereoselective Mannich-type additions across N-sulfinyl-α-chloroimines.

Mannich-type reactions of O-Boc glycolic esters across chiral N-sulfinyl-α-chloroaldimines resulted in the efficient and syn-stereoselective synthesis of new γ-chloro-α-hydroxy-ß-amino esters (dr > 99 : 1). The α-coordinating ability of the chlorine atom was of great importance for the diastereoselectivity of the Mannich-type reaction and overruled the chelation of the sulfinyl oxygen with the lithium ion of the incoming E-enolate in the transition state model. These novel chloroisothreonine derivatives proved to be excellent building blocks in asymmetric synthesis of novel syn-ß,γ-aziridino-α-hydroxy esters and biologically relevant trans-oxazolidinone carboxylic esters.

Efficient regio- and stereoselective access to novel fluorinated ß-aminocyclohexanecarboxylates.

A regio- and stereoselective method has been developed for the synthesis of novel fluorinated 2-aminocyclohexanecarboxylic acid derivatives with the fluorine attached to position 4 of the ring. The synthesis starts from either cis- or trans-ß-aminocyclohex-4-enecarboxylic acids and involves regio- and stereoselective transformation of the ring C-C double bond through iodooxazine formation and hydroxylation, followed by hydroxy-fluorine or oxo-fluorine exchange.

High-performance liquid chromatographic enantioseparation of isoxazoline-fused 2-aminocyclopentanecarboxylic acids on a chiral ligand-exchange stationary phase.

The application of a chiral ligand-exchange column for the direct high-performance liquid chromatographic enantioseparation of unusual ß-amino acids with a sodium N-((R)-2-hydroxy-1-phenylethyl)-N-undecylaminoacetate-Cu(II) complex as chiral selector is reported. The investigated amino acids were isoxazoline-fused 2-aminocyclopentanecarboxylic acid analogs. The chromatographic conditions were varied to achieve optimal separation. The effects of temperature were studied at constant mobile phase compositions in the temperature range 5-45°C, and thermodynamic parameters were calculated from plots of lnk or lnα versus 1/T. Δ(ΔH°) ranged from -2.3 to 2.2 kJ/mol, Δ(ΔS°) from -3.0 to 7.8 J mol(-1) K(-1) and -Δ(ΔG°) from 0.1 to 1.7 kJ/mol, and both enthalpy- and entropy-controlled enantioseparations were observed. The latter was advantageous with regard to the shorter retention and greater selectivity at high temperature. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. The sequence of elution of the enantiomers was determined in all cases.

Enantiomeric discrimination of isoxazoline fused ß-amino acid derivatives using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent.

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is a useful chiral NMR solvating agent for isoxazoline-fused ß-amino acid derivatives. Isoxazoline substrates are analyzed as their hydrochloride salts in methanol-d(4). The crown ether and substrate associate through the formation of three hydrogen bonds between the protonated amine and crown ether oxygen atoms. Enantiomeric discrimination is observed for two or more resonances of every substrate. At least one of these resonances is free of overlap with other resonances in the spectrum and has large enough enantiomeric discrimination to enable the determination of enantiomeric purity. 2D COSY methods can be used to identify additional resonances that exhibit enantiomeric discrimination in the NMR spectrum.

Synthesis of highly functionalized fluorinated cispentacin derivatives.

Fluorinated highly functionalized cispentacin derivatives were synthetised starting from an unsaturated bicyclic ß-lactam through C=C bond functionalization via the dipolar cycloaddition of a nitrile oxide, isoxazoline opening, and fluorination by OH/F exchange.

High-performance liquid chromatographic enantioseparation of unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid-based chiral stationary phases.

The enantiomers of four unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids were directly separated on chiral stationary phases containing (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid as chiral selector. The nature of the alcoholic modifier (MeOH, EtOH, IPA) exerted a great effect on the retention, whereas the selectivity and resolution did not change substantially. Two types of dependence of retention on alcohol content were detected: k(1) increased continuously with increasing alcohol content or a U-shaped retention curve was observed. A comparison of the chromatographic data obtained with HCOOH, AcOH, TFA, HClO(4), H(2)SO(4), or H(3)PO(4) as acidic modifier at a constant concentration demonstrated that in most cases, larger k values were obtained on the application of AcOH or HCOOH, and an increase of the acid content resulted in a decrease of retention. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes and selector. The sequence of elution of the enantiomers was determined in all cases.

Synthesis of highly functionalized ß-aminocyclopentanecarboxylate stereoisomers by reductive ring opening reaction of isoxazolines.

A rapid and simple procedure was devised for the synthesis of multifunctionalized cyclic ß-amino esters and γ-amino alcohols via the 1,3-dipolar cycloaddition of nitrile oxides to ß-aminocyclopentenecarboxylates. The opening of the isoxazoline reductive ring to the corresponding highly functionalized 2-aminocyclopentanecarboxylates occurred stereoselectively with good yields.