The Use of Chiro-Inositols in Asymmetric Synthesis

<p>D- and L- chiro-inositols are readily and inexpensively available as their O-methyl ethers pinitol and quebrachitol. To date the use of the choro-inositols in synthesis has not been exploited as fully as that of the more common isomer myo-inositol. The chiro-inositols were protected as either the di-isopropylidene or the di-cyclohexylidene systems to give them more steric bulk and were subsequently evaluated in the three areas of asymmetric synthesis: as chiral reagents, as chiral auxiliaries, as chiral ligands. Outside of these areas was the successful application of methodology for the mono esterification of C-2 symmetric diols to these inositol systems. This allowed a series of molecules to be generated that proved useful in the areas outlined above. For the use of chiro-inositols as chiral reagents, two reagents were investigated. The first was a hydroboration reagent similar to pinenyl borane. The second was the generation of a strained silacycle for use as a reagent in the enantioselective allylation of aldehydes. In the area of chiral auxiliaries, these inositols were successfully used to give selectivity in the Michael reaction. Unfortunately this success was not repeatable in the aldol reaction. Investigations into the development of chiral ligands were unsuccessful in that we were unable to synthesize either a diamine or an amino alcohol from this system. A diol and an amino ether were trialed in asymmetric reactions but failed to provide any catalytic effect. This section of the project did lead to some interesting chemistry and a better understanding of this system that can be applied to future work.</p>

The Use of Chiro-Inositols in Asymmetric Synthesis

<p>D- and L- chiro-inositols are readily and inexpensively available as their O-methyl ethers pinitol and quebrachitol. To date the use of the choro-inositols in synthesis has not been exploited as fully as that of the more common isomer myo-inositol. The chiro-inositols were protected as either the di-isopropylidene or the di-cyclohexylidene systems to give them more steric bulk and were subsequently evaluated in the three areas of asymmetric synthesis: as chiral reagents, as chiral auxiliaries, as chiral ligands. Outside of these areas was the successful application of methodology for the mono esterification of C-2 symmetric diols to these inositol systems. This allowed a series of molecules to be generated that proved useful in the areas outlined above. For the use of chiro-inositols as chiral reagents, two reagents were investigated. The first was a hydroboration reagent similar to pinenyl borane. The second was the generation of a strained silacycle for use as a reagent in the enantioselective allylation of aldehydes. In the area of chiral auxiliaries, these inositols were successfully used to give selectivity in the Michael reaction. Unfortunately this success was not repeatable in the aldol reaction. Investigations into the development of chiral ligands were unsuccessful in that we were unable to synthesize either a diamine or an amino alcohol from this system. A diol and an amino ether were trialed in asymmetric reactions but failed to provide any catalytic effect. This section of the project did lead to some interesting chemistry and a better understanding of this system that can be applied to future work.</p>

Enantioselective Synthesis of the Sex Pheromone of Lichen Moth, Miltochrista calamine, and Its Diastereomer

The synthesis of a Miltochrista calamine sex pheromone and its diastereomer has been developed. The key steps of the synthetic approach involved Evans’ chiral auxiliaries and the addition of alkyne to aldehyde, which were firstly applied to prepare this sex pheromone and its diastereomer. The synthetic sex pheromone could be used to trap insects and study physiological and ecological questions of the lichen moth.

Estimation of Enantiomeric Excess Based on Rapid Host–Guest Exchange

Chiral molecules possess enantiomers that have non-superimposable chemical structures but exhibit identical nuclear magnetic resonance (NMR) spectra. This feature prevents the use of NMR spectroscopic methods for the determination of enantiomeric excesses (ee) of chiral molecules, using simple mixtures of their enantiomers. Recently, however, it was reported that the addition of a symmetrical prochiral molecule (a reporter or host) into a solution of chiral analyte can lead to estimation of ee through interactions involving rapid exchange of the chiral analyte (guest) in the formed host–guest complex. This is due to the ee-dependent splitting of NMR resonances of the prochiral host molecule based on averaging the chemical shift non-equivalency caused by the presence of a chiral guest. The mechanism is not dependent on diastereomer formation, and 1:1 host–guest complexes can also show ee-dependent NMR peak splitting. Prochiral molecules capable of ee sensing using the NMR technique are now referred to as so-called prochiral solvating agents (pro-CSAs). pro-CSAs represent a family of reagents distinct from the commonly used NMR chiral derivatizing reagents (where chiral auxiliaries are used to derivatize enantiomers to diastereomers) or chiral solvating agents (where chiral auxiliaries interact in an asymmetric manner with analyte enantiomers). pro-CSA methods are unique since neither pro-CSA nor NMR contains chiral factors, making the technique neutral with respect to chirality. Here, we review our recent work on this matter involving several different nominally achiral receptor molecules whose unique guest binding properties and solution characteristics (especially with regard to NMR spectroscopy) allow for the estimation of ee in the corresponding chiral guests.

Chiral Auxiliaries and Chirogenesis II

Chirality is an inevitable property of our Universe, having an enormous impact in different fields, ranging from nuclear physics and astronomy to living organisms and human beings [...]

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

The synthesis of nitrogen-containing heterocycles, including natural alkaloids and other compounds presenting different types of biological activities have proved to be successful employing chiral sulfinyl imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high diastereoisomeric excess and the free amines obtained after an easy removal of the tert-butanesulfinyl group can be transformed into enantioenriched nitrogen-containing heterocycles. The goal of this review is to the highlight enantioselective syntheses of heterocycles involving the use of chiral N-tert-butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the heterocycles. The present work will comprehensively cover the most pertinent contributions to this research area from 2012 to 2020. We regret in advance that some contributions are excluded in order to maintain a concise format.

Catalytic asymmetric reductive hydroalkylation of enamides and enecarbamates to chiral aliphatic amines

To increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.