1,2,3-Benzotriazine Synthesis by Heterocyclization of p-Tosylmethyl Isocyanide Derivatives.

An efficient methodology to form 4-alkoxy- and 4-aryloxybenzo[d][1,2,3]triazines via an intramolecular heterocyclization of 1-azido-2-[isocyano(p-tosyl)methyl]benzenes under basic conditions has been developed. DFT calculations have been performed to further understand the mechanism of this heterocyclization, which occurs in good to excellent yields with a broad scope.

Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base.

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2' alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.

Sustainable Synthesis of Oximes, Hydrazones, and Thiosemicarbazones under Mild Organocatalyzed Reaction Conditions.

Pyrrolidine catalyzes very efficiently, presumably via iminium activation, the formation of acyloximes, acylhydrazones, and thiosemicarbazones derived from aromatic and aliphatic aldehydes using equimolar amounts of reagents and green solvents. Experimental simplicity and excellent yields after a simple filtration are the main advantages of the method, being an alternative to those currently available especially for the acyl derivatives, which do not work under uncatalyzed conditions. Its application to the synthesis of acyloximes by direct condensation between aldehydes and acylhydroxylamines is unprecedented.

Asymmetric Synthesis of (2S,3S)-α-(1-Oxoisoindolin-3-yl)glycines under Low-Basicity "Kinetic" Control.

The previously illusive (2S,3S)-configured α-(1-oxoisoindolin-3-yl)glycines can be prepared under mild DBU-catalyzed, low-basicity conditions. The overall process includes a cascade of aldol addition, cyclization, rearrangement, and conjugate addition reactions, leading to the target products with moderate to good chemical yields and diastereoselectivity.

A general overview of the organocatalytic intramolecular aza-Michael reaction.

The organocatalytic intramolecular aza-Michael reaction gives access to enantiomerically enriched nitrogen-containing heterocycles in a very simple manner. Enals, enones, conjugated esters and nitro olefins have been employed as Michael acceptors, while moderate nitrogen nucleophiles such as sulphonamides, carbamates and amides have been shown to be appropriate Michael donors in this type of reaction. Additionally, the process has been performed under both covalent and non-covalent catalysis, with diaryl prolinols, imidazolidinones, thioureas and chiral binol phosphoric acids being the most frequently used catalysts. The level of efficiency reached with this protocol is demonstrated by the implementation of numerous tandem processes, as well as the total synthesis of several natural products.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations.

The major goal of this review is a critical discussion of the literature data on asymmetric synthesis of α-amino acids via Michael addition reactions involving Ni(II)-complexes of amino acids. The material covered is divided into two conceptually different groups dealing with applications of: (a) Ni(II)-complexes of glycine as C-nucleophiles and (b) Ni(II)-complexes of dehydroalanine as Michael acceptors. The first group is significantly larger and consequently subdivided into four chapters based on the source of stereocontrolling element. Thus, a chiral auxiliary can be used as a part of nucleophilic glycine Ni(II) complex, Michael acceptor or both, leading to the conditions of matching vs. mismatching stereochemical preferences. The particular focus of the review is made on the practical aspects of the methodology under discussion and mechanistic considerations.

Inexpensive chemical method for preparation of enantiomerically pure phenylalanine.

Here, we report the most inexpensive procedure for chemical synthesis of enantiomerically pure phenylalanine. As a source of chirality, we use the ultimately inexpensive chiral auxiliary, 1-(phenyl)ethylamine, incorporated into the specially designed ligands which form the corresponding intermediate Ni(II) complexes with racemic phenylalanine. Diastereomerically pure Ni(II) complexes, containing either (S)- or (R)-phenylalanine, were disassembled to produce enantiomerically pure target amino acid, along with recycling the chiral ligand. All reactions were conducted under operationally convenient conditions, featuring high yields and thus underscoring attractive cost structure of this method.

The self-disproportionation of the enantiomers (SDE) of methyl n-pentyl sulfoxide via achiral, gravity-driven column chromatography: a case study.

This work explores the self-disproportionation of enantiomers (SDE) of chiral sulfoxides via achiral, gravity-driven column chromatography using methyl n-pentyl sulfoxide as a case study. A major finding of this work is the remarkable persistence and high magnitude of the SDE for the analyte. Thus, it is the first case where SDE is observed even in the presence of MeOH in the mobile phase. The study demonstrated the practical preparation, in line with theory, of enantiomerically pure (>99.9% ee) samples of methyl n-pentyl sulfoxide starting from a sample of only modest ee (<35%). Remarkably, it was found that the order of elution was inverted, i.e. enantiomerically depleted fractions preceded later eluting enantiomerically enriched ones, when the stationary phase was changed from silica gel to aluminum oxide. To the best of our knowledge, this is the first occurrence of inverted SDE behavior due solely to a change in the stationary phase. Aberrant SDE behavior was observed in that the ee did not always fall continuously during the progression of the chromatography, and this was attributed to the complexity of the system at hand which cannot be described in simple terms such as the formation only of homo- and heterochiral dimers based on a single interaction. The results nevertheless suggest that all compounds with a chiral sulfoxide moiety in their structure are likely to exhibit the SDE phenomenon and thus this work constitutes the first example of SDE predictability. Moreover, it could well be that optical purification based on the SDE phenomenon is a simple, convenient, and inexpensive method for the optical purification of this class of compounds with a high degree of proficiency.

Design and synthesis of (S)- and (R)-α-(phenyl)ethylamine-derived NH-type ligands and their application for the chemical resolution of α-amino acids.

This work presents the first chemical approach for the resolution of α-amino acids offering the following advantages: (1) The specially designed resolving reagent is derived from α-(phenyl)ethylamine, the most inexpensive chiral auxiliary, which can be recycled and reused, rendering the cost structure of the complete process very attractive; (2) the time-efficient two-step process can be conducted under operationally convenient conditions with virtually quantitative yields; and (3) the process can readily be adapted to large-scale use.

Asymmetric Mannich reaction between (S)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine and malonic acid derivatives. Stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids.

Inorganic as well as organic base catalysis was found to be effective for diastereoselective Mannich additions of malonic acid derivatives to (SS)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine. In the presence of catalytic amounts of inorganic bases, n-BuLi or DMAP, the reaction gives the corresponding (R,SS)-ß-aminomalonates in good yield and with diastereoselectivity up to 9/1 dr. In contrast, phosphazene bases favour the formation of the (S,SS)-diastereomer with selectivities as high as 99/1. Simple choosing of an appropriate base catalyst for the Mannich addition reaction allowed us to obtain enantiomerically pure (R)- or (S)-configured 3-amino-4,4,4-trifluorobutanoic acids after hydrolysis and decarboxylation of the corresponding ß-aminomalonates.

NH-type of chiral Ni(II) complexes of glycine Schiff base: design, structural evaluation, reactivity and synthetic applications.

The work being reported here deals with the design of a new type of "N-H" Ni(II) complexes of glycine Schiff bases and study general aspects of their reactivity. It was confirmed that the presence of NH function in these Ni(II) complexes does not interfere with the homologation of the glycine residue, rendering these derivatives of high synthetic value for the general synthesis of α-amino acids. In particular, the practical application of these NH-type complexes was demonstrated by asymmetric synthesis of various ß-substituted pyroglutamic acids via Michael addition reactions with chiral Michael acceptors.

Chemical kinetic resolution of unprotected ß-substituted ß-amino acids using recyclable chiral ligands.

The first chemical method for resolution of N,C-unprotected ß-amino acids was developed through enantioselective formation and disassembly of nickel(II) complexes under operationally convenient conditions. The specially designed chiral ligands are inexpensive and can be quantitatively recycled along with isolation of the target ß-substituted-ß-amino acids in good yields and excellent enantioselectivity. The method features a broad synthetic generality including ß-aryl, ß-heteroaryl, and ß-alkyl-derived ß-amino acids. The procedure is easily scaled up, and was used for the synthetically and economically advanced preparation of the anti-diabetic drug sitagliptin.

Chemical dynamic kinetic resolution and S/R†interconversion of unprotected α-amino acids.

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α-amino acids (α-AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α-AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen.

A family of chiral ligands derived from α-phenylethylamine and 2-aminobenzophenone were prepared by alkylation of the nitrogen atom. Upon reaction with glycine and a Ni(II) salt, these ligands were transformed into diastereomeric complexes, as a result of the configurational stability of the stereogenic nitrogen atom. Different diastereomeric ratios were observed depending on the substituent R introduced in the starting ligand, and stereochemical assignments were based on X-ray analysis, along with NMR studies and optical rotation measurements.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids.

This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-ß-hydroxy and α,ß-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations.

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.

Synthesis of polysubstituted ß-amino cyclohexane carboxylic acids via Diels-Alder reaction using Ni(II)-complex stabilized ß-alanine derived dienes.

This paper describes the design and synthesis of a new class of ß-alanine derived dienes stabilized by Ni(II)-complex. Preliminary study of their Diels-Alder cycloaddition reactions with several types of dienophiles demonstrates their significant synthetic potential for the preparation of various polyfunctional ß-aminocyclohexane carboxylic acids.

Chemical approach for interconversion of (S)- and (R)-α-amino acids.

Here we report a general method for the preparation of unnatural (R)-α-amino acids via complexation of α-(phenyl)ethylamine derived chiral reagent (S)- with various (S)-α-amino acids. The reactions proceed with synthetically useful chemical yields and thermodynamically controlled diastereoselectivity. Chiral reagent (S)- can be conveniently recovered and reused without any loss of enantiomeric purity and reactivity.

Synthesis of bis-α,α'-amino acids through diastereoselective bis-alkylations of chiral Ni(II)-complexes of glycine.

The Ni(II) complex derived from glycine Schiff base with (S)-N-(benzylprolyl)-2-aminobenzophenone can be effectively alkylated with α,ω-dibromide reagents to furnish the corresponding bis-alkylated products. This method presents a direct approach for the preparation of the corresponding bis-α,α'-amino acids with high biological importance. Heterogeneous (phase-transfer) as well as homogeneous conditions for the alkylation reactions have been investigated and the latter proved to be more efficient in terms of stereochemical outcome. In particular, alkylation of the glycine Schiff base Ni(II) complex with 1,3-dibromopropane followed by acid-catalysed hydrolysis of the resulting bis-alkylation product, allowed for the preparation of naturally occurring (2S,6S)-diaminopimelic acid in high overall yield.