A beta-lactam-based stereoselective access to beta,gamma-dihydroxy alpha-amino acid-derived peptides with either alpha,beta-like or unlike configurations

A concise access to alpha,beta-dihydroxy alpha-amino acid-derived N-carboxy anhydrides (NCAs) with either like or unlike relative configuration is described. The key steps of the synthetic route are the preparation of the nonracemic 4-alkenyl beta-lactams, through either Horner-type olefination of a common 4-formyl beta-lactam or the Corey-Winter alkene synthesis applied to 4-dihydroxyalkyl beta-lactams, followed by the Sharpless AD reaction, and a subsequent ring expansion of the corresponding 4-substituted 3-hydroxy beta-lactams promoted by TEMPO. The opening of thus-prepared NCAs upon treatment with different O- and N-nucleophiles, including alpha-amino esters which lead to peptides, has also been studied under various reaction conditions.     

New synthetic routes to optically active alpha-quaternary alpha-aryl amino acid derivatives via the diastereoselective Stevens and Sommelet-Hauser rearrangements

The Stevens rearrangement of N-allylic alpha-aryl amino acid-derived ammonium salts and the Sommelet-Hauser rearrangement of N-benzylic alpha-alkyl amino acid-derived ammonium salts are shown to proceed with remarkably high levels of diastereoselectivity. The methods presented in this work provide new routes to optically active alpha-quaternary alpha-aryl amino acid derivatives.     

The synthesis of sterically demanding amino acid-derived cyclic phosphonamides

The preparation and utilization of C(2)-symmetric 1,4-diamines in the synthesis of amino acid-derived cyclic phosphonamides 1-3 are described. The 1,4-diamines are synthesized via three methods: (i) amino acid/fumaryl chloride coupling followed by amide reduction, (ii) amino acid/1,4-diamine coupling followed by amide reduction, and (iii) a template-supported ring-closing metathesis/hydrolysis sequence. The pseudo C(2)-symmetric cyclic phosphonamides 1-3 are prepared by condensation of the C(2)-symmetric 1,4-diamines to P(III) centers, followed by oxidation.     

A Comparative Synthetic Strategy Perspective on α-Amino Acid- and Non-Amino Acid-Derived Synthons towards Total Syntheses of Selected Natural Macrolides

Macrocyclic alkaloids (macrolides) and cyclopeptides have an immense range of applications in drug discovery research because of their natural abundance and potential biological and physicochemical properties. Presently, more than 100 approved drugs or clinical drug candidates contain macrocyclic scaffolds as the biologically active component. This review provides an interesting perspective about the use of amino acid-derived chiral pools versus other methods derived from miscellaneous synthons towards the total synthesis of non-peptidic macrolides. The synthetic routes and the key strategies involved in the total syntheses of ten natural macrolides have been discussed. Both the amino acid-derived and non-amino acid-derived synthetic routes have been illustrated to present a comparative study between the two approaches.     

Unprecedented formation of benzo[d][1,2,3,6]oxatriazocine derivatives via diazo-oxygen bond formation and synthesis of enantiomerically pure 1-alkyl benzotriazole derivatives

A series of amino acid-derived enantiomerically pure substituted benzo[d][1,2,3,6]oxatriazocine derivatives and 1-alkyl substituted benzotriazoles has been prepared by the diazotization of amino acid-derived benzo-fused alicycles. The first unprecedented diazo-oxygen bond formation in acidic medium led to an entirely new kind of substituted benzo[d][1,2,3,6]oxatriazocine heterocycles.     

Stereoselective gamma-lactam synthesis via palladium-catalysed intramolecular allylation

A novel route to the synthesis of 3-(tolylsulfonyl)-4,5-cis-disubstituted gamma-lactams using a diastereoselective palladium-catalysed intramolecular allylation of amino acid-derived allylic carbonates has been developed.     

Additive-Free Chemoselective Acylation of Amines

Aliphatic and aromatic amines are efficiently acylated by acetic, pivalic, benzoic, phthalic, or maleic anhydrides in ethyl acetate at room temperature. Under the same experimental conditions, amino alcohols are chemoselectively acylated at the amino group.     

Modified Coumarins. 5. Amino-Acid Derivatives of 3-Hydroxy-7,8,9,10-tetrahydrobenzo[c]Chromen-6-one

Peptide-chemistry methods (symmetric anhydrides and activated esters) and the Mannich reaction were used to prepare various conjugates of amino acids with 7,8,9,10-tetrahydrobenzo[c]chromen-6-one in which the amino acids are bound to the coumarin by the C- or N-terminus.     

Mixed Anhydride Intermediates in the Reaction of 5(4H)‐Oxazolones with Phosphate Esters and Nucleotides

5(4H)‐Oxazolones can be formed through the activation of acylated α‐amino acids or of peptide C termini. They constitute potentially activated intermediates in the abiotic chemistry of peptides that preceded the origin of life or early stages of biology and are capable of yielding mixed carboxylic‐phosphoric anhydrides upon reaction with phosphate esters and nucleotides. Here, we present the results of a study aimed at investigating the chemistry that can be built through this interaction. As a matter of fact, the formation of mixed anhydrides with mononucleotides and nucleic acid models is shown to take place at positions involving a mono‐substituted phosphate group at the 3’‐ or 5’‐terminus but not at the internal phosphodiester linkages. In addition to the formation of mixed anhydrides, the subsequent intramolecular acyl or phosphoryl transfers taking place at the 3’‐terminus are considered to be particularly relevant to the common prebiotic chemistry of α‐amino acids and nucleotides.     

Chain extension of amino acid skeletons: preparation of ketomethylene isosteres

Ketomethylene isosteric replacements for peptide bonds were generated through a zinc carbenoid-mediated chain extension reaction in which a variety of amino acid-derived β-keto esters are converted to γ-keto esters in a single step. The reaction tolerates a variety of protecting groups and amino acid side chains with no epimerization of the amino acid stereocenter.     

A simple, rapid and mild one pot synthesis of benzene ring acylated and demethylated analogues of harmine under solvent-free conditions

A simple, rapid, solvent-free, room temperature one pot synthesis of benzene ring acylated and demethylated analogues of harmine using acyl halides/acid anhydrides and AlCl(3) has been developed. Eight different acyl halides/acid anhydrides were used in the synthesis. The resulting mixture of products was separated by column chromatography to afford 10- and 12-monoacyl analogues, along with 10,12-diacyl-11-hydroxy products. In five cases the corresponding 10-acyl-11-hydroxy analogues were also obtained. Yields from the eight syntheses (29 products in total) were in the 6-34% range and all compounds were fully characterized.     

Diastereoselective aldol reaction of N,N-dibenzyl-alpha-amino aldehydes with ketones catalyzed by proline

[reaction: see text] L-proline-catalyzed direct aldol reaction of L-amino acid-derived N,N-dibenzyl amino aldehydes with acetone, cyclopentanone, or hydroxyacetone provides gamma-amino-beta-hydroxy- or gamma-amino-alpha,beta-dihydroxy-ketones with moderate to excellent yields and diastereoselectivities.     

Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient cascade reaction of amino acid-derived epoxides

Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaffolds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially available amino acid derivatives in ?6 steps, contain an orthogonally-protected β-hydroxy amine moiety, and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59-72%) from readily available epoxide derivatives.     

A facile synthesis of N-Z/Boc-protected 1,3,4-oxadiazole-based peptidomimetics employing peptidyl thiosemicarbazides

Synthesis of 1,3,4-oxadiazole containing peptidomimetics is described by a p-TsCl/pyridine-mediated cyclization of the corresponding dipeptidyl thiosemicarbazides, which are readily prepared by coupling N-protected amino acid hydrazides with amino acid-derived isothiocyanato esters. Further, the protocol has also been extended for the synthesis of orthogonally protected 1,3,4-oxadiazole tethered mimetics as well. The synthetic route is simple and mild conditions are used so that the chirality of the starting amino acids is retained.     

High-temperature continuous flow synthesis of 1,3,4-oxadiazoles via N-acylation of 5-substituted tetrazoles

Applying continuous flow processing in a high-temperature/high-pressure regime (200-220 °C, 11-14 bar) 2,5-disubstituted-1,3,4-oxadiazoles are prepared in high yields within 5-10 min residence time by treatment of 5-substituted-1H-tetrazoles with anhydrides or acid chlorides as electrophiles (Huisgen reaction).     

Caged O-phosphorothioyl amino acids as building blocks for Fmoc-based solid phase peptide synthesis

The synthesis of 1-(2-nitrophenylethyl) caged O-phosphorothioylserine, -threonine, and -tyrosine derivatives is reported. These amino acid building blocks can be directly incorporated into peptides by Fmoc-based solid phase synthesis as their pentafluorophenyl esters or as symmetric anhydrides. Upon irradiation with UV light, the thiophosphate group, representing a hydrolysis resistant phosphate analog, is revealed.     

Determination of Enantiomeric Purity and Absolute Configuration of β-Lactams by High-Performance Liquid Chromatography on Chiral Columns

Enantiomers of β-lactams bearing aryl, furyl or styryl substituents in the 4-position were chromatographically separated by means of high-performance liquid chromatography on chiral column packed with amino acid-derived chiral stationary phase. Separation factors are generally modest. To improve further the resolution of enantiomers, the rings of these β-lactams were opened with octanol in acidic conditions and converted into N-3,5- dinitrobenzoyl ester derivatives of the resulting β-amino acids. Enantiomers of these derivatives are efficiently separated on an amide-derived chiral stationary phase. The chromatographic separations enable accurate determination of optical purity of the chiral β- lactams, prepared from homochiral ester enolate-imine condensation. The absolute configuration of the major enantiomer of the β-amino acid derivatives was determined from elution order on a chiral column.     

Amino acid-derived iodobenzene dicarboxylates: reagents for oxidative conversion of alkenes to amino acid esters

[reaction: see text] New amino acid-derived iodobenzene dicarboxylates were prepared by the reaction of (diacetoxyiodo)benzene with N-protected natural amino acids. These compounds in the presence of iodide anion can be used as reagents for beta-iodocarboxylation of alkenes leading to the respective amino acid esters.     

Pyrrolinone-pyrrolidine oligomers as universal peptidomimetics

Peptidomimetics 1-3 were prepared from amino acid-derived tetramic acids 7 as the key starting materials. Calculations show that preferred conformations of 1 can align their side-chain vectors with amino acids in common secondary structures more effectively than conformations of 3. A good fit was found for a preferred conformation of 2 (an extended derivative of 1) with a sheet/β-turn/sheet motif.     

An enantioselective synthesis of the cyclopentene fragment of nucleoside Q

An enantioselective synthesis of (3S,4R,5S)-(+)-3-amino-4,5-dihydroxycyclopentene, a segment of nucleoside Q and Q base, is reported utilizing an amino acid-derived acylnitroso Diels-Alder cycloaddition.