New Chiral Zwitterionic Phosphorus Heterocycles: Synthesis,Structure, Properties and Application as Chiral Solvating Agents

A family of new chiral zwitterionic phosphorus‐containing heterocycles (zPHC) have been derived from methylene‐bridged bis(imidazolines). These structures were unambiguously determined, including single‐crystal XRD analysis for two compounds. The stability, acid/base and electronic properties of these dipolar phosphorus heterocycles were subsequently investigated. zPHCs can be successfully employed as a new class of chiral solvating agents for the enantiodifferentiation of chiral carboxylic and sulfonic acids by NMR spectroscopy. The stoichiometry and binding constants for the donor–acceptor complexes formed were established by NMR titration methods.     

Reactions between Grignard reagents and heterocyclic N-oxides: stereoselective synthesis of substituted pyridines, piperidines, and piperazines

In this perspective we discuss the recent developments of stereoselective synthesis of substituted pyridines, piperidines, and piperazines from cheap and commercially readily available starting materials. Pyridine N-oxides and pyrazine N-oxides are reacted with alkyl, aryl, alkynyl and vinyl Grignard reagents to give a diverse set of heterocycles in high yields. Optically active substituted piperazines are obtained by an asymmetric reaction from pyrazine N-oxides using sparteine as chiral ligand. In addition, a stereoselective synthesis of dienal-oximes from the reaction between pyridine N-oxides and Grignard reagents is presented, which results in a useful intermediate for the synthesis of a diverse set of compounds.     

Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2-Amido Benzyl Alcohols: Asymmetric Synthesis of 4H-3,1-Benzoxazines

An efficient method for the asymmetric synthesis of 4H-3,1-benzoxazines was developed by kinetic resolution of 2-amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram-scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.     

Asymmetric Synthesis of Axially Chiral C−N Atropisomers

Molecules with restricted rotation around a single bond or atropisomers are found in a wide number of natural products and bioactive molecules as well as in chiral ligands for asymmetric catalysis and smart materials. Although most of these compounds are biaryls and heterobiaryls displaying a C−C stereogenic axis, there is a growing interest in less common and more challenging axially chiral C−N atropisomers. This review offers an overview of the various methodologies available for their asymmetric synthesis. A brief introduction is initially given to contextualize these axially chiral skeletons, including a historical background and examples of natural products containing axially chiral C−N axes. The preparation of different families of C−N based atropisomers is then presented from anilides to chiral five- and six-membered ring heterocycles. Special emphasis has been given to modern catalytic asymmetric strategies over the past decade for the synthesis of these chiral scaffolds. Applications of these methods to the preparation of natural products and biologically active molecules will be highlighted along the text.     

Michael addition of chloroalkyloxazolines to electron-poor alkenes: synthesis of heterosubstituted cyclopropanes

Lithiated 2-(1-chloroethyl)-4,4-dimethyl-2-oxazoline 7 adds to electron-poor alkenyl heterocycles to afford substituted cyclopropanes in excellent yields. A route to chiral nonracemic heterosubstituted cyclopropanes, starting from optically active 2-chloromethyl-2-oxazolines, is highlighted as well.     

Chiral N-acyloxazolidines: synthesis, structure, and mechanistic insights

A series of chiral imines derived from 1-amino-1-deoxyalditols such as d-glucamine, a rather unexplored raw material from the chiral pool, have been serendipitiously transformed into a novel family of N-acetyl-1,3-oxazolidines by means of an unexpected acetylation. The structure of these substances is supported by spectroscopic and crystallographic data. The acetylates also trigger a complex dynamic transformation, in which an initially configured trans oxazolidine converts into a more stable cis-configured derivative. Both isomers can also exist as rotational conformers (E,Z) as a consequence of the restricted rotation around the N-acetyl bond. The barriers to rotation have been determined by variable-temperature experiments. Overall, this transformation most likely involves the intermediacy of a chiral iminium ion, which has been documented in the synthesis of nitrogen heterocycles, thus explaining the experimental facts.     

Alkene isomerization/enamide-ene and diene metathesis for the construction of indoles, quinolines, benzofurans and chromenes with a chiral cyclopropane substituent

A synthetic method for bicyclic heterocycles, such as indole, benzofuran and chromene derivatives bearing a chiral cyclopropane at the 2-position, was established using isomerization of a terminal olefin and enamide-ene or diene metathesis. This route can also be applied to chiral 2-cyclopropylquinoline synthesis (both cis and trans).     

Versatile, diastereoselective additions of silyl ketene acetals, allyl tributylstannane, and Me(3)SiCN to N-acyl pyrazolines: asymmetric synthesis of densely functionalized pyrazolidines

We report the diastereoselective addition of a wide range of nucleophiles to chiral pyrazolines to provide facile access to a range of useful densely functionalized building blocks for asymmetric synthesis. Coupled with the asymmetric cycloaddition reaction of Me(3)SiCHN(2) to chiral acrylates, access to these chiral heterocycles is considerably expanded.     

Potential‐Driven Chirality Manifestations and Impressive Enantioselectivity by Inherently Chiral Electroactive Organic Films

The typical design of chiral electroactive materials involves attaching chiral pendants to an electroactive polyconjugated backbone and generally results in modest chirality manifestations. Discussed herein are electroactive chiral poly‐heterocycles, where chirality is not external to the electroactive backbone but inherent to it, and results from a torsion generated by the periodic presence of atropisomeric, conjugatively active biheteroaromatic scaffolds, (3,3′‐bithianaphthene). As the stereogenic element coincides with the electroactive one, films of impressive chiroptical activity and outstanding enantiodiscrimination properties are obtained. Moreover, chirality manifestations can be finely and reversibly tuned by the electric potential, as progressive injection of holes forces the two thianaphthene rings to co‐planarize to favor delocalization. Such deformations, revealed by CD spectroelectrochemistry, are elastic and reversible, thus suggesting a breathing system.     

Catalytic activities of modified hydrolytic enzymes in organic media : syntheses of optically active trifluoromethylated compounds

Modifications of hydrolytic enzymes by incorporation of fluorine-containing molecules have been found to improve the catalytic activity of the parent enzymes. Syntheses of optically active compounds possessing a trifluoromethyl group, via enzymatic chiral Michael addition reaction and synthesis of heterocycles, have been undertaken in organic solvents.     

Highly Enantioselective Nucleophilic Dearomatization of Pyridines by Anion‐Binding Catalysis

The asymmetric dearomatization of N‐heterocycles is an important synthetic method to gain bioactive and synthetically valuable chiral heterocycles. However, the catalytic enantio‐ and regioselective dearomatization of the simplest six‐membered‐ring N‐heteroarenes, the pyridines, is still very challenging. The first anion‐binding‐catalyzed, highly enantioselective nucleophilic dearomatization of pyridines with triazole‐based H‐bond donor catalysts is presented. Contrary to other more common NH‐based H‐bond donors, this type of organocatalyst shows a prominent higher C2‐regioselectivity and is able to promote high enantioinductions via formation of a close chiral anion‐pair complex with a preformed N‐acyl pyridinium ionic intermediate. This method offers a straightforward and useful synthetic approach to chiral N‐heterocycles from abundant and readily available pyridines.     

Bisoxazoline-Lewis acid-catalyzed direct-electron demand oxo-hetero-Diels-Alder reactions of N-oxy-pyridine aldehyde and ketone derivatives

A general catalytic oxo-hetero-Diels-Alder reaction for pro-chiral aldehyde and ketone N-oxy-pyridines is presented. The catalytic and asymmetric oxo-hetero-Diels-Alder reaction of electron-rich dienes with N-oxy-pyridine-2-carbaldehyde and ketone derivatives, catalyzed by chiral copper(II)-bisoxazoline complexes, gives optically active six-membered oxygen heterocycles in moderate to good yields and with excellent enantioselectivities.     

Chiral aminophosphines as catalysts for enantioselective double-Michael indoline syntheses

The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient acetylenes is an efficient process for the synthesis of many nitrogen-containing heterocycles. Because the resulting heterocycles contain at least one stereogenic center, this double-Michael reaction would be even more useful if an asymmetric variant of the reaction were to be developed. Aminophosphines can also facilitate the double-Michael reaction and chiral amines are more readily available in Nature and synthetically; therefore, in this study we prepared several new chiral aminophosphines. When employed in the asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and 3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with moderate asymmetric induction.     

Photoenzymatic Enantioselective Synthesis of Oxygen-Containing Benzo-Fused Heterocycles

New-to-nature biocatalysis in organic synthesis has recently emerged as a green and powerful strategy for the preparation of valuable chiral products, among which chiral oxygen-containing benzo-fused heterocycles are important structural motifs in pharmaceutical industry. However, the asymmetric synthesis of these compounds through radical-mediated methods is challenging. Herein, a novel asymmetric radical-mediated photoenzymatic synthesis strategy is developed to realize the efficient enantioselective synthesis of oxygen-containing benzo-fused heterocycles through structure-guided engineering of a flavin-dependent ‘ene’-reductase GluER. It shows that variant GluER-W100H could efficiently produce various benzoxepinones, chromanone and indanone with different benzo-fused rings in high yields with great stereoselectivities under visible light. Moreover, these results are well supported by mechanistic experiments, revealing that this photoenzymatic process involves electron donor-acceptor complex formation, single electron transfer and hydrogen atom transfer. Therefore, we provide an alternative green approach for efficient chemoenzymatic synthesis of important chiral skeletons of bioactive pharmaceuticals.     

Pd‐Catalyzed Enantioselective [6+4] Cycloaddition of Vinyl Oxetanes with Azadienes to Access Ten‐Membered Heterocycles

We report herein the first enantioselective cycloaddition of vinyl oxetanes, the reaction of which with azadienes provided unprecedented access to ten‐membered heterocycles through a [6+4] cycloaddition. By using a commercially available chiral Pd‐SIPHOX catalyst, a wide range of benzofuran‐ as well as indole‐fused heterocycles could be accessed in excellent yield and enantioselectivity. A unique Lewis acid induced fragmentation of these ten‐membered heterocycles was also discovered.     

Enantioselective Reactions of N‐Acyliminium Ions Using Chiral Organocatalysts

N‐acyliminium ions are reactive intermediates that can act as electron‐deficient electrophiles toward weak or soft nucleophiles, thereby providing useful methods for both intermolecular‐ and intramolecular carbon–carbon and carbon–heteroatom bond formation. Nucleophilic additions to N‐acyliminium ions constitute an important method for providing α‐functionalized amino compounds and many other biologically active nitrogen‐containing heterocycles. The development of efficient catalytic asymmetric reactions is a key objective in modern organic chemistry and is very important for the synthesis of natural products, pharmaceuticals, and agrochemicals. Various methods are available for this purpose and mostly rely on the use of chiral catalysts for enantioselective synthesis. This review deals with one aspect of such catalysis, which has emerged only in the past few years, and its applications in enantioselective reactions of N‐acyliminium ions to provide various nitrogen‐containing heterocycles.     

Diastereoselective control of intramolecular aza-Michael reactions using achiral catalysts

An intramolecular aza-Michael reaction with a Cbz carbamate and an enone is reported to result in 3,5-disubstituted nitrogen-containing heterocycles. Either cis or trans isomers were obtained selectively using chiral substrates and an achiral Pd(II) complex or strong Br?nsted acid catalysis. A range of substrates undergoes these selective transformations. Functionalization of the resulting products yielding bicyclic heterocycles is also demonstrated.     

Production of pyrans, pyridazines, pyrimidines, pyrazines and triazine compounds using benzoylacetonitriles as a precursor

Benzoylacetonitriles are easily available and have high chemical reactivity due to the presence of three active moieties; nitrile, carbonyl, and active methylene functions. This review article represents a survey covering the synthetic strategies leading to five six-membered heterocycles; pyrans, pyridazines, pyrimidines, pyrazines, and triazine compounds; utilizing benzoylacetonitriles as starting precursor since 1985. The reactions are subdivided into groups that cover the synthetic methods of these heterocycles.     

New Chiral Phosphocontaining Heterocycles on the Basis of Natural Oligohydroxyl Compounds

Principal possibilities of creation of chiral phosphocontaining heterocycles on the basis of natural derivatives of cyclodextrins and dianhydro-D-mannitol are discussed. The obtained compounds possess an internal chiral cavity of a definite size and represent an interest for the solution of modern tasks of biomimetic and supramolecular chemistry.