Pyrrole‐Assisted and Easy Oxidation of Cyclic α‐Amino Acid‐ Derived Diketopiperazines under Mild Conditions

A new procedure for the aerobic oxidation of α‐amino acids acylated by pyrrole‐carboxylic acid with triplet dioxygen is introduced. The reaction is general for a variety of pyrrole‐amino acid derivatives and represents a very practical and controllable method for the selective preparation of α‐hydroperoxy‐ or α‐hydroxy‐α‐amino acid diketopiperazines with molecular dioxygen. Furthermore, the non‐catalyzed direct oxidation of amino acid derivatives at the α‐position with molecular dioxygen represents a fundamental question.     

Heterocycles as Nonclassical Bioisosteres of α‐Amino Acids

Bioisosterism of α‐amino acids is often accomplished by replacing the α‐carboxylate with one of the many known carboxylic acid bioisosteres. However, bioisosterism of the whole α‐amino acid moiety is accomplished with heterocyclic bioisosteres that often display an acidic function. In this Minireview, we summarized the reported heterocycles as nonclassical bioisosteres of α‐amino acids, which include quinoxaline‐2,4(1H)‐dione, quinoxaline‐2,3(1H)‐dione and quinolin‐2(1H)‐one, azagrevellin and azepine‐derived structures. The binding mode of the crystalized bioisosteres were compared with those of the crystalized α‐amino acids that bind in the same domain, and where no data on the crystal structure were available, the displacement studies of known orthosteric ligands were used. The reported bioisosteres share the following essential structural features for mimicking α‐amino acids: an aromatic ring system joined to a lactam ring system with an acidic feature next to the lactam carbonyl, where this acidic feature together with the lactam carbonyl can mimic the α‐carboxylate, and the lactam nitrogen together with the aromatic ring system can mimic the α‐ammonium. The majority of these heterocycles can be prepared from three common corresponding starting materials: the corresponding anilines, isatins or anthranilic esters. The data collected here show the potential of this class of bioisosteres in the design of glutamate receptor ligands and beyond.     

Chemo‐ and Enantioselective Brønsted Acid‐Catalyzed Reduction of α‐Imino Esters with Catecholborane

The chemo‐ and enantioselective reduction of α‐imino esters with catecholborane has been developed employing 10 mol% of an enantiopure BINOL‐based phosphoric acid as organocatalyst. Various differently substituted aromatic α‐amino acid derivatives can be achieved in almost quantitative yields and very good to excellent enantioselectivities of up to 96% ee under mild reaction conditions.     

Enzymatic Conversion of Unnatural Amino Acids by Yeast D‐Amino Acid Oxidase

Unnatural amino acids, particularly synthetic α‐amino acids, are becoming crucial tools for modern drug discovery research. In particular, this application requires enantiomerically pure isomers. In this work we report on the resolution of racemic mixtures of the amino acids d,l ‐naphthylalanine and d,l ‐naphthylglycine by using a natural enzyme, D ‐amino acid oxidase from the yeast Rhodotorula gracilis. A significant improvement of the bioconversion is obtained using a single‐point mutant enzyme designed by a rational approach. With this D ‐amino acid oxidase variant the complete resolution of all the unnatural amino acids tested was obtained: in this case, the bioconversion requires a shorter time and a lower amount of biocatalyst compared to the wild‐type enzyme. The simultaneous production of the corresponding α‐keto acid, a possible precursor of the amino acid in the L ‐form, improves the significance of the procedure.     

A General Approach to the Synthesis of β2‐Amino Acid Derivatives via Highly Efficient Catalytic Asymmetric Hydrogenation of α‐Aminomethylacrylates

A new strategy was developed for the synthesis of a valuable class of α‐aminomethylacrylates via the Baylis–Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′‐type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et‐Duphos) catalysts provided the corresponding β²‐amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)‐configurated substrates was studied for the synthesis of β²‐amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²‐amino acids and their derivatives under mild reaction conditions.     

Transition Metal‐Catalyzed Synthesis of Novel Biologically Relevant Tryptophan Analogues

A synthetic approach to the synthesis of novel tryptophan derivatives and benzofuran‐containing amino acids is detailed. The sequence starts from enzymatically resolved enantiopure acetylene‐containing amino acids, of which the acetylene function can be efficiently transformed into the targeted 2‐substited indole and benzofuran moieties via Sonogashira‐type coupling and metal‐catalyzed cyclization.     

Titanium‐Mediated Direct Carbon‐Carbon Double Bond Formation to α‐Trifluoromethyl Acids: A New Contribution to the Knoevenagel Reaction and a High‐Yielding and Stereoselective Synthesis of α‐Trifluoromethylacrylic Acids

An efficient strategy for a high‐yielding and stereoselective synthesis of α‐trifluoromethyl unsaturated carboxylic acids directly from the reactions of 3,3,3‐trifluoropropanoic acid (CF₃CH₂COOH) with various aryl aldehydes in the presence of titanium tetrachloride (TiCl₄) is reported here for the first time, which is a valuable expansion for the classical Knoevenagel reaction. Because these compounds may have potential applications in organic electronics and can be easily converted to the corresponding fluorinated alcohols and amino acids with excellent bioactivity, this route should be a good choice for the preparation of α‐trifluoromethyl‐containing derivatives.     

Synthesis and Use of Tetrahydrofuran‐ and Tetrahydropyran‐Amino Acids

Progress in the synthesis and the use of amino acids containing a THF or THP ring is reported. Different synthetic routes from carbohydrates or α‐amino acids as starting compounds are discussed. Examples for THF‐ and THP‐amino acids as peptidomimetics or building blocks for foldamers and combinatorial libraries are given. The role of THF‐amino acids in the synthesis of artificial ion channels, e.g. THF‐gramicidin hybrids, is highlighted.     

Samarium‐Promoted Asymmetric Aldol–Tishchenko Reaction: Synthesis of Amino Acid‐Derived 4‐Amino‐1,3‐diols

A samarium‐mediated novel synthesis of enantiopure 4‐amino‐1,3‐diols is carried out through a samarium‐promoted aldol–Tishchenko reaction starting from chiral α′‐amino‐α‐chloro ketones (derived from natural α‐amino acids) and aldehydes. The process takes place with moderate levels of stereoselectivity and in high yields. A mechanism is proposed to explain these results while the absolute configuration and structure of the aldol–Tishchenko adducts were established by X‐ray analysis. This method has also been utilized for the synthesis of enigmols, 1‐deoxysphingoid base analogues.     

Phosphine‐Catalyzed [3+2] and [4+3] Annulation Reactions of C,N‐Cyclic Azomethine Imines with Allenoates

Phosphine‐catalyzed [3+2] and [4+3] annulation reactions of C,N‐cyclic azomethine imines with allenoates have been developed to give a variety of pharmaceutically attractive tetrahydroisoquinoline derivatives in moderate to excellent yields. The two distinct reaction pathways, [3+2] and [4+3] cyclization, depend on the nature of the nucleophilic phosphine and the allenoate. Generally, for α‐alkylallenoates, the reactions always proceed with [3+2] cyclization as the major pathway no matter what phosphine was used; for α‐ArCH₂‐substituted allenoates, the reaction pathway was controlled by the phosphine catalyst used.     

α‐Amino acids as initiators of ε‐caprolactone and L,L‐lactide polymerization

Biodegradable polymers/oligomers were successfully synthesized through a ring‐opening polymerization of ε‐caprolactone and L ,L ‐lactide, initiated by L ‐arginine and L ‐citrulline. The α‐amino acid initiators are natural, operationally simple, inexpensive, environmentally friendly and safe for human health. The polymerizations were performed with no solvents and without introducing any metal impurities. The chemical structures of the polymers obtained were elucidated using ¹H NMR, ¹³C NMR and Fourier transform infrared spectroscopies. In addition, incorporation of α‐amino acid molecules into the polymer chain was confirmed using matrix‐assisted laser desorption ionization time‐of‐flight mass spectrometry. Due to the significant biological activity of L ‐arginine and L ‐citrulline, these α‐amino acid initiators may open a new route for the synthesis of functional polymers especially for pharmaceutical applications. Copyright © 2011 Society of Chemical Industry     

Catalytic Hydrogenation of Chiral α‐Amino and α‐Hydroxy Esters at Room Temperature with Nishimura Catalyst without Racemization

The hydrogenation of carboxylic acid derivatives at room temperature was investigated. With a mixed Rh/Pt oxide (Nishimura catalyst), low to medium activity was observed for various α‐amino and α‐hydroxy esters. At 100 bar hydrogen pressure and 10% catalysts loading, high yields of the desired amino alcohols and diols were obtained without racemization. The most suitable α‐substituents were NH₂, NHR, and OH, whereas β‐NH₂ were less effective. Usually, aromatic rings were also hydrogenated, but with the free bases of amino acids as substrates, some selectivity was observed. No reaction was found for α‐NR₂, α‐OR, and unfunctionalized esters; acids and amides were also not reduced under these conditions. A working hypothesis for the mode of action of the catalyst is presented.     

A Helix‐Stabilized Cell‐Penetrating Peptide as an Intracellular Delivery Tool

Two types of cationic cyclic α,α‐disubstituted α‐amino acids: Api (which possesses a lysine mimic side chain) and Api^C2Gu (which possesses an arginine mimic side chain), were developed. These amino acids were incorporated into an arginine‐based peptide sequence [(l ‐Arg‐l ‐Arg‐dAA)₃: dAA=Api or Api^C2Gu], and the relationship between the secondary structures of the resulting peptides and their ability to pass through cell membranes was investigated. The peptide containing Api^C2Gu formed a stable α‐helical structure and was more effective at penetrating cells than the nonhelical Arg nonapeptide (R₉). Furthermore, the peptide was able to deliver plasmid DNA into various types of cells in a highly efficient manner.     

Multiple Site‐Selective Insertions of Noncanonical Amino Acids into Sequence‐Repetitive Polypeptides

A simple and efficient method is described for the introduction of noncanonical amino acids at multiple, defined sites within recombinant polypeptide sequences. Escherichia coli MRA30, a bacterial host strain with attenuated activity of release factor 1 (RF1), was assessed for its ability to support incorporation of a diverse range of noncanonical amino acids in response to multiple encoded amber (TAG) codons within genes derived from superfolder GFP and an elastin‐mimetic protein polymer. Suppression efficiency and protein yield depended on the identity of the orthogonal aminoacyl‐tRNA synthetase/tRNA^CUA pair and the noncanonical amino acid. Elastin‐mimetic protein polymers were prepared in which noncanonical amino acid derivatives were incorporated at up to 22 specific sites within the polypeptide sequence with high substitution efficiency. The identities and positions of the variant residues were confirmed by mass spectrometric analysis of the full‐length polypeptides and proteolytic cleavage fragments from thermolysin digestion. The data suggest that this multisite suppression approach permits the preparation of protein‐based materials in which novel chemical functionalities can be introduced at precisely defined positions within the polypeptide sequence.     

Primary Amine‐Thioureas with Improved Catalytic Properties for “Difficult” Michael Reactions: Efficient Organocatalytic Syntheses of (S)‐Baclofen, (R)‐Baclofen and (S)‐Phenibut

Among the class of primary amine‐thioureas based on tert‐butyl esters of α‐amino acids, the most efficient organocatalyst for “difficult” Michael reactions was identified. The derivative based on (S)‐di‐tert‐butyl aspartate and (1R,2R)‐diphenylethylenediamine provided the products of the reaction between aryl methyl ketones and nitroolefins in excellent yields and enantioselectivities. In addition, this new catalyst can be used at low catalyst loading (5 mol%). The utility of this methodology was highlighted by the efficient synthesis of (S)‐baclofen, (R)‐baclofen and (S)‐phenibut.     

Organocatalytic Enantioselective Strecker Synthesis of α‐Quaternary α‐Trifluoromethyl Amino Acids

The first organocatalytic enantioselective Strecker synthesis of α‐quaternary α‐trifluoromethylated amino acids has been developed. Employing Takemoto’s thiourea catalyst the nucleophilic addition of trimethylsilyl cyanide to trifluoromethyl ketimines affords α‐amino nitriles in good to excellent yields (50–99%) and very good enantioselectivities (ee=83–95%). The enantiopure amino nitriles can be obtained by recrystallization. Deprotection and hydrolysis leads to the title amino acids.     

Enzymatic Synthesis of Enantiopure α‐ and β‐Amino Acids by Phenylalanine Aminomutase‐Catalysed Amination of Cinnamic Acid Derivatives

The phenylalanine aminomutase (PAM) from Taxus chinensis catalyses the conversion of α‐phenylalanine to β‐phenylalanine, an important step in the biosynthesis of the N‐benzoyl phenylisoserinoyl side‐chain of the anticancer drug taxol. Mechanistic studies on PAM have suggested that (E)‐cinnamic acid is an intermediate in the mutase reaction and that it can be released from the enzyme's active site. Here we describe a novel synthetic strategy that is based on the finding that ring‐substituted (E)‐cinnamic acids can serve as a substrate in PAM‐catalysed ammonia addition reactions for the biocatalytic production of several important β‐amino acids. The enzyme has a broad substrate range and a high enantioselectivity with cinnamic acid derivatives; this allows the synthesis of several non‐natural aromatic α‐ and β‐amino acids in excellent enantiomeric excess (ee >99 %). The internal 5‐methylene‐3,5‐dihydroimidazol‐4‐one (MIO) cofactor is essential for the PAM‐catalysed amination reactions. The regioselectivity of amination reactions was influenced by the nature of the ring substituent.     

Stereocontrolled synthesis of the taxol C‐13 side chain: Methyl (2R,3S)‐3‐benzoylamino‐2‐hydroxy‐3‐phenylpropanoate

Addition of lithiated methoxyallene 5 to literature‐known amino aldehyde 3 followed by ozonolysis provided syn‐configurated α‐hydroxy‐β‐amino ester 6 in moderate overall yield and with an ee of 90%. The predominant formation of syn‐compounds may be due to a chelate controlled addition step.     

Reverse Micellar Encapsulation of d‐ and l‐Enantiomers of Some Aromatic α‐Amino Acids and Nucleobases by Glucose‐Derived Non‐ionic Gemini Surfactants in Neat n‐Hexane

Novel carbohydrate‐based non‐ionic gemini surfactants consisting of two sugar head groups, two hydrophobic tails having chain lengths of C12, C14, and C16 and a flexible –(CH₂)₆– spacer were synthesized and investigated for their reverse micellar encapsulation properties. The head groups of the geminis comprise glucose entities (with reducing function blocked in a cyclic acetal group) connected through C‐6 to tertiary amines. These surfactants were explored for reverse micellar encapsulation of d ‐ and l ‐enantiomers of aromatic α‐amino acids viz. histidine (His), phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) in neat n‐hexane. Similar studies were carried out for encapsulation of nucleobases viz. adenine (Ade), guanine (Gua), thymine (Thy), cytosine (Cyt) and Uracil (Ura). Reverse micellar studies revealed that aromatic α‐amino acids were encapsulated in the sequence His>Tyr>Phe>Trp. In most cases, a difference in the degree of encapsulation of d ‐ and l ‐enantiomers of aromatic amino acids in reverse micellar phases of gemini amphiphiles in neat n‐hexane, was revealed. For Tyr, l ‐enantiomer was better encapsulated than its antipode, i.e., d ‐enantiomer but for Trp, d ‐enantiomer was better encapsulated then l ‐enantiomer. In the case of nucleobases, Ura was found selectively encapsulated by reverse micelles formed by these new amphiphiles.     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.