Tailor-Made Amino Acids in Pharmaceutical Industry: Synthetic Approaches to Aza-Tryptophan Derivatives.

Over the recent years there has been a noticeable upsurge of interest in aza-analogs of tryptophan which are isosteric to the latter and found numerous applications in medicinal, bioorganic chemistry, and peptide research. In the present review article, five aza-tryptophan derivatives are profiled, including aza-substitution in the positions 2, on the five-membered ring, as well as in positions 4, 5, 6, and 7 on the six-membered ring. A detailed and comprehensive literature overview of the synthetic methods for the preparation of these aza-tryptophans is presented and general facets of the biological properties and most promising applications are discussed.

High temperature sublimation of α-amino acids: a realistic prebiotic process leading to large enantiomeric excess.

The reiterative high temperature co-sublimation of an enantiopure or an enantioenriched α-amino acid mixed with racemic α-amino acids leads to deracemization of the latter. A synergistic effect is observed for complex mixtures, and the sense of the handedness is, for all compounds, identical to that of the enantioenriched starting material.

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.

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.

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.

Partial sublimation of enantioenriched amino acids at low temperature. Is it coming from the formation of a euatmotic composition of the gaseous phase?

The partial sublimation of enantioenriched amino acids was performed slowly at low temperature with the aim to determine the rules of sublimation of these compounds. Although the formation of a euatmotic composition of the gaseous phase starting from DL + L mixtures of Leu, Pro, and Phe can be deduced from the enantiomeric excess of sublimates, the behavior of the kinetic conglomerate explains the results for D + L mixtures of Ala, Leu, Val, and Pro. Consequently, the enantiomeric excess of the partial sublimate is dependent not only on the studied compound but also on the composition of the starting mixture.

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.

Deracemization of amino acids by partial sublimation and via homochiral self-organization.

Deracemization of a 50/50 mixture of enantiomers of aliphatic amino acids (Ala, Leu, Pro, Val) can be achieved by a simple sublimation of a pre-solubilized solid mixture of the racemates with a huge amount of a less-volatile optically active amino acid (Asn, Asp, Glu, Ser, Thr). The choice of chirality correlates with the handedness of the enantiopure amino acids--Asn, Asp, Glu, Ser, and Thr. The deracemization, enantioenrichment and enantiodepletion observed in these experiments clearly demonstrate the preferential homochiral interactions and a tendency of natural amino acids to homochiral self-organization. These data may contribute toward an ultimate understanding of the pathways by which prebiological homochirality might have emerged.

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.

Optical purifications via self-disproportionation of enantiomers by achiral chromatography: case study of a series of α-CF3-containing secondary alcohols.

This work demonstrates that self-disproportionation of enantiomers via achiral chromatography can be recommended as inexpensive and general method for optical purification of enantiomerically enriched compounds. In particular, the advantage of this approach over conventional recrystallization is that it can be used for both crystalline as well as liquid compounds.

Self-disproportionation of Enantiomers of Enantiomerically Enriched Compounds.

This review describes self-disproportionation of enantiomers (SDE) of non-racemic mixtures, subjected to distillation, sublimation, or chromatography on achiral stationary phase using achiral eluent, which leads to the substantial enantiomeric enrichment and corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. This phenomenon is of a very general nature as SDE has been reported for different classes of chiral organic compounds bearing various functional groups and possessing diverse elements of chirality. The literature data discussed in this review clearly suggests that SDE is typical for enantiomerically enriched chiral organic compounds and special care should always be taken in evaluation of the stereochemical outcome of enantioselective reactions as well as determination of enantiomeric ratios of non-racemic mixtures of natural products after any purification process. The role of molecular association of enantiomers on the magnitude and preparative efficiency of SDE, as a new, nonconventional method for enantiomerc purifications, is emphasized and discussed.

Unconventional preparation of racemic crystals of isopropyl 3,3,3-trifluoro-2-hydroxypropanoate and their unusual crystallographic structure: the ultimate preference for homochiral intermolecular interactions.

This work reports the first example of the transformation of conglomerate (R)- and (S)-crystals into racemic crystals via sublimation. Crystallographic analysis of racemic isopropyl 3,3,3-trifluoro-2-hydroxypropanoate did not reveal the highly expected heterochiral dimer indicating that this compound is capable of forming exclusively homochiral oligomers via infinite multi-centred H-bonding networks.

Efficient asymmetric synthesis of trifluoromethylated ß-aminophosphonates and their incorporation into dipeptides.

Addition of anions derived from dialkyl methylphosphonates to (Ss)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded (Ss,R) addition adducts in moderate to good yield (53-75%) with excellent diastereoselectivity (94-95% de). After selective removal of the N-sulfinyl group, dipeptides containing enantiomerically pure diethyl 2-amino-3,3,3-trifluoropropylphosphonate were synthesized to investigate the influence of the trifluoromethyl substituent on N-terminal coupling.

Self-disproportionation of enantiomers via achiral chromatography: a warning and an extra dimension in optical purifications.

This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral-phase chromatography.

Organic base-catalyzed stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids.

Organic base-catalyzed reaction of (S)-N-tert-butanesulfinyl (3,3,3)-trifluoroacetaldimine with dialkyl malonates was found to be effective for synthesis of both (S,S(S)) and (R,S(S)) ß-aminomalonates in high yield with good to excellent diastereoselectivity (76-98% de). The products of this Mannich reaction provide direct access to ß-trifluoromethyl-ß-alanine of either (R) or (S) absolute configuration.

Practical synthesis of fluorine-containing α- and ß-amino acids: recipes from Kiev, Ukraine.

Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kiev's school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and ß-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the 'normal' reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

Novel Syntheses of N-Pivot Lariat Diaza-Crown Ethers from 4,13-Bis(benzotriazolylmethyl)-4,13-diaza-1,7,10,16-tetraoxacyclooctadecane.

4,13-Bis(benzotriazolylmethyl)-4,13-diaza-1,7,10,16-tetraoxacyclooctadecane (6) was synthesized as a versatile intermediate in the preparation of bis(lariats) of diaza-18-crown-6. N,N'-Bis(umbelliferon-8-ylmethyl) derivative 8, bis(lariats) with terminal unsaturated groups (11c,e), ester functionalities (11d), N,N'-di-beta-aralkyl derivatives (11a,b), and gamma-oxy-substituted (13, 14) and gamma-amino-substituted (17-19) propylene-side-armed derivatives were thus prepared in moderate to excellent yields. The X-ray structure of bis(lariat) 6 and stability constants for several of the complexes of bis(lariats), derivatives of 6, with metal cations are discussed.