Intramolecular Aminolysis Research Articles

Stereoselective Synthetic Routes to Iminosugars: A Divergent Approach Utilizing a Common Multifunctional Chiral Scaffold

AbstractStarting from an l-serine-derived multifunctional aminobutenolide as a common chiral building block, stereoselective synthetic routes to representative examples of di-, tri-, and tetrahydroxylated iminosugars have been developed. Key steps in the synthetic routes involved an intramolecular aminolysis protocol to form the azaheterocyclic core, and functionalization of a resident alkene moiety towards installation of the desired substituents at the various positions of the piperidine ring. The strategy and the approach described are expected to provide flexible synthetic routes to various iminosugar scaffolds of structural and medicinal chemical significance.

Highly Regioselective 5-endo-tet Cyclization of 3,4-Epoxy Amines into 3-Hydroxypyrrolidines Catalyzed by La(OTf)3.

Highly regioselective intramolecular aminolysis of 3,4-epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti-Baldwin 5-endo-tet cyclization. This reaction affords 3-hydroxy-2-alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide.

Spontaneous Aminolytic Cyclization and Self‐Assembly of Dipeptide Methyl Esters in Water

AbstractDipeptides are known to spontaneously cyclize to diketopiperazines, and in some cases these cyclic dipeptides have been shown to self‐assemble to form supramolecular nanostructures. Herein, we demonstrate the in situ cyclization of dipeptide methyl esters in aqueous buffer by intramolecular aminolysis, leading to the formation of diverse supramolecular nanostructures. The chemical nature of the amino acid side chains dictates the supramolecular arrangement and resulting nanoscale architectures. For c[LF], supramolecular gels are formed, and the concentration of starting materials influences the mechanical properties of these hydrogels. Moreover, by adding metalloporphyrins to the starting dipeptide starting solution, these become incorporated through cooperative assembly, resulting in the formation of nanofibers able to catalyse the oxidation of organic phenol in water. The approach taken here, which combines chemically activated assembly with the versatility of short peptides, demonstrates a new and easy method to achieving spontaneous formation of a variety of functional supramolecular materials using simple building blocks.

Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest.

The assigned structure of the dinoflagellate-derived toxin belizentrin was prepared by total synthesis in form of the corresponding methyl ester for stability reasons. The successful route features an unusual solution for the preparation of a recalcitrant ylide on a C-glycosidic segment; moreover, it involves an asymmetric hetero-Diels-Alder reaction en route to the tertiary hemiacetal substructure, a Negishi cross-coupling of two elaborate building blocks, and a macrocyclization based on an intramolecular aminolysis of a spirolactone. A modified Kocienski olefination ultimately allowed the polyol side chain to be attached to the macrocycle although this transformation faced the exceptional base sensitivity of this polyunsaturated target compound.

Total Synthesis of Belizentrin Methyl Ester: Report on a Likely Conquest

AbstractThe assigned structure of the dinoflagellate‐derived toxin belizentrin was prepared by total synthesis in form of the corresponding methyl ester for stability reasons. The successful route features an unusual solution for the preparation of a recalcitrant ylide on a C‐glycosidic segment; moreover, it involves an asymmetric hetero‐Diels–Alder reaction en route to the tertiary hemiacetal substructure, a Negishi cross‐coupling of two elaborate building blocks, and a macrocyclization based on an intramolecular aminolysis of a spirolactone. A modified Kocienski olefination ultimately allowed the polyol side chain to be attached to the macrocycle although this transformation faced the exceptional base sensitivity of this polyunsaturated target compound.

Facile Synthesis of New Functionalized Triazacyclopenta[cd]indenones Through a Multicomponent Reaction Followed by an Intramolecular Aminolysis

An efficient tandem route to the synthesis of triazacyclopenta[cd]indenone derivatives of the cyclazine family has been developed. Target compounds were obtained in moderate to good yields by Groebke–Blackburn–Bienaymé reaction involving a potassium carbonate promoted intramolecular aminolysis. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocyclic skeletons containing the imidazo[1,2‐a]pyridine ring.

Enantiospecific Synthesis of Imidazoquinazolin-2-ones via Base-Catalyzed Tandem Cyclization

A facile protocol for the enantiospecific synthesis of novel (S)-3-substituted imidazo[2, l-b]quinazoline-2-ones via tandem reaction of substituted (S)-3-amino-4-aminomethylbenzoates and cyanogen bromide under basic conditions is explored. This tandem process involves addition reaction of substituted (S)-3-amino-4-aminomethylbenzoates to CNBr to yield 2-imino tetrahydroquinazoline carboxylate intermediates followed by in situ intramolecular aminolysis to afford the triheterocyclic imidazo[2, l-b]quinazoline-2-ones in good yields and high enantiomeric purity.

ChemInform Abstract: Intramolecular Aminolysis of 2′‐Aminochalcone Epoxides Using InBr3 or BiCl3 as Efficient Catalysts.

AbstractInBr3 as well as InCl3 prove to be mild and efficient catalysts for the regioselective ring opening and intramolecular aminolysis of 2′‐aminochalcone epoxides (I) furnishing azaflavanone derivatives (II) in excellent yields and diastereoselectivity.

Intramolecular Aminolysis of 2′-Aminochalcone Epoxides Using InBr3 or BiCl3 as Efficient Catalysts

In the synthesis of aza-flavanone derivatives, several metal halides were screened for their catalytic activity. Among them, BiCl3 and InBr3 catalyze the ring opening of 2′-aminochalcone epoxides followed by intramolecular aminolysis under mild conditions. The reactions proceed efficiently at room temperature to afford highly functionalized 2-aryl-3-hydroxy-2,3-dihydro-4-quinolones (aza-flavanones) in excellent yields (82–92%). Intermolecular aminolysis of 2′-aminochalcone epoxides with aniline derivatives failed under the same catalytic conditions.

Study of intramolecular aminolysis in peptides containing N-alkylamino acids at position 2

Many peptides and proteins, containing Nα-alkylamino acids (including proline) at the second position, are prone to intramolecular aminolysis (IA) with elimination of N-terminal dipeptide sequence as 2,5-diketopiperazines (DKP). We synthesized a series of short peptides, containing N-alkylamino acids at position 2, and studied their stability in the presence of acetic acid and amines. The presence of side chains in the second and the third amino acid residues and alkylation at Nα of the third amino acid residue slowed down IA. Nα-Alkyl residue in the first amino acid residue impeded IA only in peptides, containing three or more residues. Side chains of the first amino acids did not affect significantly the cleavage rates. Acetic acid promoted IA more strongly than aqueous ammonia, while tertiary amines were less effective. Peptides with methionine-S-oxide residues were more labile than the unoxidized analogs, suggesting intramolecular assistance of the S-oxide group in aminolysis. Surprisingly, intermediate compounds of the formula Boc–Met-MeXaa-Sar–NHR underwent rapid cleavage (endopeptolysis) upon attempted acidolytic deprotection.

Hydrophobic Vitamin B12 Derivatives: Unprecedented Formation of a 7‐Membered Lactam

AbstractThe synthesis of a new hydrophobic cobalamin derivative through intramolecular aminolysis is described. Under acidic conditions, (CN)2CobIII(10‐NH2)7C1‐ester formed a seven‐membered lactam between the ester and amino groups present at the C8 and C10 positions. Subsequent Boc protection of the NH group enabled ring opening with primary amines, leading to derivatives functionalized at the C8 and C10 positions.

A double prodrug system for colon targeting of benzenesulfonamide COX-2 inhibitors

The design, synthesis and delivery potential of a new type of benzenesulfonamide cyclo-oxygenase-2 (COX-2) inhibitor prodrug is investigated using celecoxib. The approach involves a double prodrug that is activated first by azoreductases and then by cyclization triggering drug release. We studied the intramolecular aminolysis of the acylsulfonamide. The cyclization was surprisingly rapid at physiological pH and very fast at pH 5. The prodrug is activated specifically under conditions found in the colon but highly stable in the presence of human and rodent intestinal extracts. Finally, the prototype with celecoxib was transported much more slowly in the Caco-2 transepithelial model than the parent. The design therefore shows significant promise for the site specific delivery of benzenesulfonamide COX-2 inhibitors to the colon.

Reaction of ampicillin with serum albumin to produce penicilloyl-protein conjugates and a piperazinedione.

Formation of penicilloyl-protein conjugates in the body by reaction of penicillins with nucleophilic groups of proteins is considered to be involved in penicillin allergy. In this study the kinetics and mechanism of reaction of ampicillin with human and bovine serum albumin in aqueous solution at 37 degrees C and pH 6.6-10.4 have been investigated and compared with the reaction of benzylpenicillin previously reported. In addition to forming penicilloyl-protein conjugates, ampicillin was found to react with the proteins to yield a free piperazine-2,5-dione derivative. This product is suggested to arise from intramolecular aminolysis of an N-(penicilloyl)imidazole intermediate at pH 6-8 and of a penicilloyl ester intermediate at higher pH values. The piperazinedione formation was found to compete effectively with formation of penicilloyl-protein conjugates at physiological pH and, along with studies of ampicillin with protein model compounds, the reaction allowed suggestions to be made abut the penicillin-reacting sites in the proteins.

ChemInform Abstract: Ligation—Desulfurization: A Powerful Combination in the Synthesis of Peptides and Glycopeptides

AbstractReview: 60 refs.

Synthesis of Dipeptide Esters of Metronidazole and Evaluation of Their Hydrolytic Stability

Amino acid and dipeptide esters of metronidazole were synthesized and evaluated on their hydrolytic stability in various buffers and culture media. The hydrolytic susceptibility of the different esters was minimal in the pH range 3 - 5. In the alkaline region, pH 6.5 - 8, the half-lifes were of the order of 1 - 6.6 hrs. At alkaline pH the dipeptide esters were more susceptible towards hydrolysis. At pH 8.8 the observed half-life for the gly-gly and the gly-phe esters was 0.2 h, whereas for the gly and the phe ester it was 1.1 h, respectively 2.7 h. It was demonstrated that the increased rate of hydrolysis for the dipeptide esters was due to an intramolecular aminolysis with the formation of a diketopiperazine accompanied by the release of free metronidazole.

Invited reviewligation—Desulfurization: A powerful combination in the synthesis of peptides and glycopeptides

The native chemical ligation enables the chemoselective coupling of two unprotected protein segments. In the initial format of this reaction, the side chain of N-terminal cysteine residues serves to capture a peptide thioester. The N-terminus of the cysteinyl peptide is involved in a subsequent intramolecular aminolysis reaction, upon which the "native" peptide bond is established. Considerable efforts have been invested to remove the restriction to cysteine-containing ligation sites. In this review, we focus on the combination of two chemoselective reactions, native chemical ligation, and desulfurization, which has extended the repertoire of accessible ligation junctions. Based on this two-step approach, native alanine-containing peptides are accessible through postligation desulfurization of cysteine-ligation products. Recently, significant progress has been achieved in the development of new thiolated building blocks that serve as precursors to other amino acids. Ligations at phenylalanine can be accomplished by means of a beta-mercaptophenylalanine building block and subsequent desulfurization. The building blocks beta-mercaptovaline (penicillamine) and gamma-mercaptovaline provide access to hydrophobic ligation sites (Xaa-Val). Lysine has been equipped with a delta- and gamma-mercapto groups, which enables ligations at both the alpha- and the epsilon-amino group. This review also describes the recent improvements of desulfurization chemistry, which have widened the scope of the ligation-desulfurization approach and offer a promising alternative for the synthesis of Cys-free peptides and glycopeptides.

Kinetic and Mechanistic Studies of NEt3-Catalyzed Intramolecular Aminolysis of Carbamate

The mechanism of the NEt 3-catalyzed intramolecular aminolysis of Z- 1 in acetonitrile or aqueous acetonitrile solutions is suggested to involve rate-determining collapse of T (+/-) through simultaneous H-abstraction and ethoxide expulsion of E2 process. The evidence for that includes the primary isotope effect of k H/ k D = 1.66 in acetonitrile, general-base catalysis in aqueous buffer solutions, salt effect, and the proposed water-stabilized rate-determining transition states (TS1 and TS2) in the water-titration experiments.

1,4-Diazepanes derived from ( S)-serine – Homopiperazines with improved σ 1 (sigma) receptor affinity and selectivity

Starting from the proteinogenic amino acid ( S)-serine chiral non-racemic 1,4-diazepanes 4 with a hydroxymethyl residue in position 2 are synthesized and pharmacologically evaluated. The key step in the synthesis is the formation of the bicyclic system 8 by consecutive nucleophilic substitution of the chloropropionamide 7 with primary amines and intramolecular aminolysis. Both reaction steps require catalysis with the Lewis acid Ti(O- iPr) 4. Homologation of the piperazine to the 1,4-diazepane ring results in a remarkable improvement of σ 1 receptor affinity and σ 1/σ 2 selectivity. The 1,4-dibenzyl derivative 4a interacts with a K i value of 7.4 nM with σ 1 receptors and shows a 53-fold selectivity for σ 1 receptors over σ 2 receptors.

One-Pot Synthesis of Quinoline-Based Tetracycles by a Tandem Three-Component Reaction

A practical one-pot synthetic strategy for the efficient synthesis of a range of structurally interesting and bioactive quinoline-based tetracycles has been developed. A key step in the synthesis is a tandem three-component reaction of heteroaromatic amine, methyl 2-formylbenzoate and (t)butyl isonitrile, followed by TFA-mediated lactamization via intramolecular aminolysis of an adjacent ester. Results related to a kinase-panel screening for several selected compounds are also discussed in this article.

Unambiguous Evidence for Efficient Chemical Catalysis of Adenosine Ester Aminolysis by Its 2‘/3‘-OH

Intramolecular aminolysis reactions, catalyzed by a vicinal OH group, were studied computationally as model reactions of ribosome-catalyzed intracomplex aminolysis. The results predicts 2−6-fold higher enthalpic than entropic contribution to the reduction of the activation free energy, caused by the combined proximity effect of the attacking syn-NH2 group and the catalytic syn-OH group. The acceleration predicted by the theory is supported by the observed instantaneous lactamization of ornithinyl adenosine as compared to the much slower lactamization of ornithinyl 2‘-deoxyadenosine. This observation is the first unambiguous experimental demonstration of chemical catalysis of the 1,2-diol monoester aminolysis by its vicinal 2-OH groupthe reaction naturally catalyzed by ribosome.