The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine-2,5-diones

Alkoxycarbonylpiperazine-2,5-diones are versatile precursors for the α-functionalisation of piperazine-2,5-diones. The alkoxycarbonyl group activates the α-carbon position to alkylation reactions and this provides a mild and selective method for the extension of the carbon framework of piperazine-2,5-diones. In addition, the alkoxycarbonyl group can be converted to the carboxy group, which in turn can be ‘deleted’ or manipulated for the installation of carbon and/or heteroatom substituents where desired, the latter via N-acyliminium chemistry. We also demonstrate that hydroxymethylpiperazine-2,5-diones complement carboxypiperazinediones as precursors for the generation of N-acyliminium ions.     

Studies on pyrrolidinones. Oxidations and rearrangements in the hexahydrobenz[f]indolizine-3,10-dione series

Air oxidation of hexahydrobenz[f]indolizine-3,10-diones in MeOH/MeONa yields alcohols, which are easily and selectively transformed, in very good yields, to succinimides, isoquinoline propanoic acids or dehydrated to ene lactams.     

Directed 1,3-dipolar cycloadditions of ylidene piperazine-2,5-diones

The reactivities and selectivities of 1,3-dipolar cycloaddition reactions of ylidene piperazine-2,5-diones with mesitonitrile oxide are reported. The stereoselectivities of reactions with chiral ylidene piperazine-2,5-diones can be directed by judicious choice of substituents on the N- and/or C-substituents of the piperazinedione ring.     

A practical approach to the fused β-carboline system. Asymmetric synthesis of indolo[2,3-a]indolizidinones via a diastereoselective intramolecular α-amidoalkylation reaction

Fused β-carboline systems, as indolo[2,3-a]indolizidinones, indolo[2,3-a]quinolizidinones, their 2-oxa analogues, and benzo[a]indolo[2,3-a]indolizidinones are prepared efficiently via an RLi addition-N-acyliminium ion cyclisation sequence on readily available imides. In an enantioselective variant of these α-amidoalkylation reactions, the addition of MeLi to a chiral non-racemic imide derived from tryptophan yielded an oxo amide, which was cyclised diastereoselectively upon treatment with BF₃·OEt₂, to afford 5,11b-trans-indoloindolizidinone in moderate yield and high ee (99%).     

Chemo-, regio- and stereospecific addition of amino acids to acylacetylenes: a facile synthesis of new N-acylvinyl derivatives of amino acids

The one-pot reaction of natural amino acids (glycine, β-alanine, γ-aminobutyric and ?-aminocapronic acids, d,l-valine, d,l-leucine, anthranilic acid) with bielectrophilic acylacetylenes proceeds chemo-, regio- and stereospecifically in the presence of NaOH (45-50 °C, 4 h, EtOH-H₂O) to give (after treatment of the reaction mixture with aqueous HCl) Z-isomers of N-acylvinyl derivatives of amino acids in 87-94% yield.     

Spiro cyclisations of N-acyliminium ions involving an aromatic π-nucleophile

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.     

Facile and rapid regeneration of free amino acids from N-benzyloxycarbonyl-5-oxazolidinones and from N-benzyloxycarbonylamino derivatives by treatment with BCl3 in dichloromethane

Reaction of benzyloxycarbonyl-5-oxazolidinones and of N-benzyloxycarbonylamino acids with BCl₃ in dichloromethane at room temperature affords the corresponding free amino acids.     

Lanthanide triflate catalyzed generation of N-acyliminium ions from α-amido sulfones: the synthesis of (1-alkyl-1-aryl)methyl phenyl sulfones

The reaction of α-amido sulfones with various aromatic and heteroaromatic compounds in the presence of a catalytic amount of lanthanide triflate provides a facile route for the synthesis of (1-alkyl-1-aryl)methyl phenyl sulfones.     

An improved large scale procedure for the preparation of N-Cbz amino acids

A simple and scalable method for the preparation of N-Cbz protected amino acids is presented which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH during the addition of benzyl chloroformate. The method has been extended to other N-protections and is amenable to large scale preparation of an intermediate toward Zofenopril, an ACE inhibitor.     

On the non-classical course of Polonowski reactions of N-benzylmorpholine-N-oxide (NBnMO)

The Polonowski reaction of NBnMO (4) afforded tropone (10) and the novel isoindole 11 besides the expected products benzaldehyde and acetmorpholide, in a temperature-dependent ratio. The reaction proceeded via two primary carbenium-iminium ion intermediates, an exo-centered species 5 which underwent a benzylium-tropylium type rearrangement, and a ring-centered species 6, which reacted further to isoindole 11 by intramolecular electrophilic substitution. The experimental findings were in good agreement with DFT computational data.     

First total synthesis of fumaridine

The first total synthesis of the alkaloid fumaridine 1a is reported. The key step is the assemblage of the arylmethylene isoindolinone 2a (E) by Horner reaction between the phosphorylated isoindolinone 3a and the suitably substituted benzaldehyde 4. N-Lactam deprotection and concomitant E→Z isomerization complete the synthesis of the title compound.     

Highlighting the possible secondary interactions in the role of balhimycin and its analogues for enantiorecognition in capillary electrophoresis

It is believed that the enantiorecognition mechanism based on macrocyclic antibiotics involves multimodal interactions via hydrogen bonding, π–π interaction, steric hindrance, hydrophobic interaction and so on. A variety of enantiomeric N-benzoylated amino acids were separated using balhimycin (A) or its analogues bromobalhimycin (B) and dechlorobalhimycin (C) as chiral mobile phase additive using a CE method, which combined the partial filling technique with the dynamic coating technique and the co-EOF electrophoresis technique. The enantioresolution and the migration time were highly relevant to the structure of analytes, especially to the substitutions on the N-tagged benzoyl moiety of the amino acids. A steric effect and π–π interaction based mechanism is proposed in order to explain some observed enantioresolution differences between positional isomers. Notably dechlorobalhimycin exhibited the best enantioresolution for several N-benzoylated derivatives of leucine, which was rarely observed for N-dansylated amino acid derivatives. The hydrophobicity difference of the aglycone pocket among three chiral selectors was assumed to account for this behaviour.     

Short stereocontrolled synthesis of trans and cis-tetrahydro-pyrazinoisoquinolinediones

Addition of aldehyde dimethyl acetals (here acetaldehyde) to unisolated O-trimethylsilyl derivatives of 1-acetyl-3-arylmethylpiperazine-2,5-diones (here 2,5-dimethoxyphenyl), in the presence of TMSOTf as the catalyst, gave nearly quantitatively the corresponding N-methoxyalkyl derivatives which, under acidic treatment, gave in very good yield through a Pictet-Spengler-type reaction involving N-acyliminium cations (6S*,11aR*)-2-acetyl-6-alkyl-3,6,11,11a-tetrahydro-2H-pyrazino[1,2-b]isoquinoline-1,4-diones. Epimerization of the 11a-stereocentre was accomplished by radical bromination, spontaneous hydrobromide elimination and catalytic hydrogenation, to give the (6S*,11aS*)-isomers. We propose these compounds as precursors of tetrahydroisoquinoline antitumour antibiotics.     

endo-Mode cyclizations of vinylogous N-acyliminium ions as a route to the synthesis of condensed thiazolidines

endo-Mode cyclizations of vinylogous N-acyliminium ions incorporating heteroatom-based nucleophiles have been examined as a route to the synthesis of condensed thiazolidines. The scope of these reactions and stereochemical outcome are discussed and explained using quantum chemical calculations.     

On the efficiency of two-coordinate palladium(0) N-heterocyclic carbene complexes in amination and Suzuki-Miyaura reactions of aryl chlorides

The catalytic activity of novel two-coordinate palladium N-heterocyclic carbene complexes that differ in their steric and electronic properties is compared in catalytic amination and Suzuki-Miyaura cross-couplings.     

Environmentally benign process for the synthesis of N-formyl amino acid esters

Several amino acid ester hydrochlorides were reacted with ammonium formate to give N-formyl amino acid esters in good yields.     

Studies on the application of the Passerini reaction and enzymatic procedures to the synthesis of tripeptide mimetics

A new, efficient method for the multicomponent synthesis of tripeptide mimetics is presented. Simple, chemoenzymatic transformations of Passerini reaction products enable the introduction of varied amino acid moieties into the tripeptide scaffold, with control of the stereochemistry. Additionally, this method allows the convenient introduction of a methyl group to the amide nitrogen, leading to derivatives of N-methylated amino acids—compounds of interest for medicinal chemistry.     

A mild high yielding synthesis of oxazole-4-carboxylate derivatives

Several 2,5-disubstituted oxazole-4-carboxylates were prepared in high yields from the methyl esters of N-acyl-β-halodehydroaminobutyric acid derivatives by treatment with a 2% solution of DBU in acetonitrile. The scope of this reaction was investigated and it was found that dehydrodipeptides having a β-bromodehydroaminobutyric acid residue gave the corresponding oxazoles in good yields. The photophysical properties of some of the oxazoles prepared were studied in four solvents of different polarity. All compounds have reasonable high fluorescence quantum yields and a moderate solvent sensitivity, which makes them good candidates to be used as fluorescent probes. One of the fluorescent oxazoles prepared was inserted after cleavage of the methyl ester into two model peptides using a conventional solution phase strategy. The photophysical properties of the labelled peptides were studied in ethanol and water and compared with those of the oxazole. The results obtained showed that the oxazole maintains a good fluorescence level and the same solvent sensitivity when linked to a peptide chain.     

Asymmetric synthesis of fluorine-containing amines, amino alcohols, α- and β-amino acids mediated by chiral sulfinyl group

This review article provides a critical overview of several different synthetic approaches developed for asymmetric preparation of fluorine-containing amines, amino alcohols, α- and β-amino acids. The common feature of these methods is the application of sulfinyl group as a chiral auxiliary to control the stereochemical outcome of the reactions under study. In particular, the following general methods are critically discussed: diastereoselective methylene transfer from diazomethane to the carbonyl of β-keto-γ-fluoroalkyl sulfoxides as a general approach for preparation of various α-fluoroalkyl α-sulfinylalkyl oxiranes. The resulting compounds were used as true chiral synthons for their further elaboration via oxidative or reductive desulfurization, to numerous fluorine-containing and biologically relevant amino- and hydroxy-containing derivatives. Another general approaches discussed here are asymmetric additions to CN double bond. One of them is addition of chiral sulfoxide stabilized carbon nucleophiles to fluorine-containing imines, leading to convenient preparation of alpha-fluoroalkyl derivatives of alpha amino acids and amines. Another approach is asymmetric Reformatsky reaction between N-sulfinyl imines and ethyl bromodifluoroacetate allowing operationally convenient preparation of α,α-difluoro-β-amino acids in enantiomerically pure form. Finally, structurally similar but mechanistically different addition reactions of diethyl difluoromethylphosphonate to N-sulfinyl imines, as a general approach to asymmetric synthesis of α,α-difluoro-β-aminophosphonates and phosphonic acids, are discussed. Effect of fluorine on the mechanism and stereochemical outcome of these reactions is discussed in detail and compared, where it is possible, with that of the analogous reactions of fluorine-free substrates.     

Ion‐Induced Fragmentation of Amino Acids: Effect of the Environment

In general, radiation‐induced fragmentation of small amino acids is governed by the cleavage of the C? C_α bond. We present results obtained with 300 keV Xe²⁰⁺ ions that allow molecules (glycine and valine) to be ionised at large distances without appreciable energy transfer. Also in the present case, the C? C_α bond turns out to be the weakest link and hence its scission is the dominant fragmentation channel. Intact ionised molecules are observed with very low intensities. When the molecules are embedded in a cluster of amino acids, a protective effect of the environment is observed. The fragmentation pattern changes: the C? C_α bond becomes more protected and stable amino acid cations are observed as fragments of the molecular clusters. Evidently, the molecular cluster acts as a “buffer” for the excess energy, capable of rapidly redistributing excess energy and charge.