Β-amino Acid Moiety Research Articles

Synthesis of (R)-3-(tert-Butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic Acid, a Key Intermediate, and the Formal Synthesis of Sitagliptin Phosphate.

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.

Chiral β3-isocyanopropionates for multicomponent synthesis of peptides and depsipeptides containing a β-amino acid fragment.

An efficient three-step synthesis of a novel family of enantiomerically pure isocyanides derived from β3-isocyanopropionic acids was elaborated. Easily available N-formylated α-amino acids were used as starting materials towards this aim. The 3-step sequence (Arndt-Eistert reaction-Wolff rearrangement-dehydration) resulted in target isonitriles in good yields (up to 97%). As a result a new family of isocyanides bearing a fragment of β3-amino acids with different functional groups (amides, esters and short peptides) was obtained. It was demonstrated that these new isonitriles can be used in the Ugi and Passerini reactions to prepare short peptides and depsipeptides having a β-amino acid fragment incorporated.

Synthesis and structural investigation of 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing a peptide analogue of the amyloidogenic AS(6-7) sequence: inhibition of fibril formation.

The incorporation of a single β-amino acid moiety in a highly amyloidogenic peptide sequence resulted in the complete inhibition of amyloid fibril formation. The Boc-l-Phe-l-Leu-OMe sequence 1, which has sequence identity with the N-terminal AS(6-7) of the non-immunoglobulin amyloid fibril protein AS, which is responsible for rheumatoid arthritis, self-associates to produce fibrils. The d-Phe analogue peptide 2 shows an elongated ribbon-like morphology. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid containing analogue peptide 3 exhibits a polydisperse microsphere morphology. Moreover, fibrils from peptides 1 and 2 exhibit typical green-gold birefringence upon Congo red (CR) staining and show an amyloid-like morphological resemblance. However, the 2-aminomethyl-3-(4-methoxy-phenyl)-propionic acid modified peptide 3 does not respond to the Congo red assay. From X-ray crystallography, peptide 1 with the l-Phe residue adopts an extended structure, whereas the d-Phe analogue 2 adopts a kink-like structure. Both peptides 1 and 2 show twisted anti-parallel sheet-like structures at higher order assembly. However, peptide 3 adopts a nine-membered hydrogen bonded δ-turn-like structure in the solid state and self-associates to form a loop-like supramolecular structure through multiple intermolecular hydrogen bonds. The structural analysis presented herein may foster new studies for de novo design and therapeutics.

Cispentacin - Enzymatic Highlights of its 25-Year History

Because of its natural occurrence and novel biological activity, interest in the investigation of (1R,2S)-2-aminocyclopentanecarboxylic acid (cispentacin) has rapidly increased. Since its activity against Candida albicans, C. neoformans, and a systemic C. infection, a number of enzymatic strategies for its preparation in enantiomerically pure form have been developed. Structural optimization of cispentacin resulted in the synthesis of derivatives such as (1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid with even superior efficacy in view of antifungal activity. Not only cispentacin itself and some of its small-molecule derivatives have been described as molecules of interesting bioactivity but it was also found that the cyclopentane β-amino acid moiety may be a key element of larger molecules with important pharmacological properties, such as the antibiotic amipurimycin. The present review is intended to give a brief insight into the most relevant enzymatic strategies for the synthesis of 25-year-old cispentacin and its close analogues containing the cispentacin subunit. These methods are classified as indirect or direct strategies. Some practical details for the preparative-scale resolution of a selected racemate furnishing cispentacin with excellent ee and very good yield are highlighted at the end of this overview. © 2016 Bentham Science Publishers.

Stereoselective Synthesis of Chiral Pyrrolidine Derivatives of (+)-α-Pinene Containing a β-Amino Acid Moiety

We report the synthesis of several enantiopure pyrrolidine derivatives containing a β-amino acid moiety. These novel chiral compounds were prepared through stereospecific chlorosulfonyl isocyanate (CSI) addition to the readily available, natural terpene (+)-α-pinene. Coupling of N-Boc-protected β-amino acid derivatives with various bulky amines and amino acids using the mixed anhydride activation method, followed by N-deprotection, afforded the corresponding chiral amino amides in good yields. Despite the severe steric hindrance anticipated in α-pinene-based heterocycles, efficient coupling of the amino amides and an amino ester with the acyl chloride of N-Cbz-protected (S)-proline provided the corresponding pyrrolidinic pinene derivatives in good yields. Moreover, a convenient synthesis of N-Cbz- and N-Boc-monoprotected (S)-prolinamine is reported.

A free-standing condensation enzyme catalyzing ester bond formation in C-1027 biosynthesis

Nonribosomal peptide synthetases (NRPSs) catalyze the biosynthesis of many biologically active peptides and typically are modular, with each extension module minimally consisting of a condensation, an adenylation, and a peptidyl carrier protein domain responsible for incorporation of an amino acid into the growing peptide chain. C-1027 is a chromoprotein antitumor antibiotic whose enediyne chromophore consists of an enediyne core, a deoxy aminosugar, a benzoxazolinate, and a beta-amino acid moiety. Bioinformatics analysis suggested that the activation and incorporation of the beta-amino acid moiety into C-1027 follows an NRPS mechanism whereby biosynthetic intermediates are tethered to the peptidyl carrier protein SgcC2. Here, we report the biochemical characterization of SgcC5, an NRPS condensation enzyme that catalyzes ester bond formation between the SgcC2-tethered (S)-3-chloro-5-hydroxy-beta-tyrosine and (R)-1-phenyl-1,2-ethanediol, a mimic of the enediyne core. SgcC5 uses (S)-3-chloro-5-hydroxy-beta-tyrosyl-SgcC2 as the donor substrate and exhibits regiospecificity for the C-2 hydroxyl group of the enediyne core mimic as the acceptor substrate. Remarkably, SgcC5 is also capable of catalyzing amide bond formation, albeit with significantly reduced efficiency, between (S)-3-chloro-5-hydroxy-beta-tyrosyl-(S)-SgcC2 and (R)-2-amino-1-phenyl-1-ethanol, an alternative enediyne core mimic bearing an amine at its C-2 position. Thus, SgcC5 is capable of catalyzing both ester and amide bond formation, providing an evolutionary link between amide- and ester-forming condensation enzymes.

Characterization of the Two-Component, FAD-Dependent Monooxygenase SgcC That Requires Carrier Protein-Tethered Substrates for the Biosynthesis of the Enediyne Antitumor Antibiotic C-1027

C-1027 is a potent antitumor antibiotic composed of an apoprotein (CagA) and a reactive enediyne chromophore. The chromophore has four distinct chemical moieties, including an ( S)-3-chloro-5-hydroxy-beta-tyrosine moiety, the biosynthesis of which from l-alpha-tyrosine requires five proteins: SgcC, SgcC1, SgcC2, SgcC3, and SgcC4; a sixth protein, SgcC5, catalyzes the incorporation of this beta-amino acid moiety into C-1027. Biochemical characterization of SgcC has now revealed that (i) SgcC is a two-component, flavin adenine dinucleotide (FAD)-dependent monooxygenase, (ii) SgcC is only active with SgcC2 (peptidyl carrier protein)-tethered substrates, (iii) SgcC-catalyzed hydroxylation requires O 2 and FADH 2, the latter supplied by the C-1027 pathway-specific flavin reductase SgcE6 or Escherichia coli flavin reductase Fre, and (iv) SgcC efficiently catalyzes regioselective hydroxylation of 3-substituted beta-tyrosyl-S-SgcC2 analogues, including the chloro-, bromo-, iodo-, fluoro-, and methyl-substituted analogues, but does not accept 3-hydroxy-beta-tyrosyl-S-SgcC2 as a substrate. Together with the in vitro data for SgcC4, SgcC1, and SgcC3, the results establish that SgcC catalyzes the hydroxylation of ( S)-3-chloro-beta-tyrosyl-S-SgcC2 as the final step in the biosynthesis of the ( S)-3-chloro-5-hydroxy-beta-tyrosine moiety prior to incorporation into C-1027. SgcC now represents the first biochemically characterized two-component, FAD-dependent monooxygenase that acts on a carrier-protein-tethered aromatic substrate.

Nakinadines B–F: new pyridine alkaloids with a β-amino acid moiety from sponge Amphimedon sp.

Five new 3-alkylpyridine alkaloids with a β-amino acid moiety, nakinadines B–F ( 1– 5), have been isolated from an Okinawan marine sponge Amphimedon sp. (SS-1059), and the structures and stereochemistry were elucidated by spectroscopic data. Nakinadines B ( 1) and C ( 2) showed modest cytotoxicity.

Nakinadine A, a Novel Bis‐pyridine Alkaloid with a β‐Amino Acid Moiety from Sponge Amphimedon sp.

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Nakinadine A, a novel bis-pyridine alkaloid with a β-amino acid moiety from sponge Amphimedon sp.

A novel cytotoxic bis-3-alkylpyridine alkaloid with a β-amino acid moiety, nakinadine A ( 1), has been isolated from an Okinawan marine sponge Amphimedon sp., and the structure and stereochemistry were elucidated by spectroscopic data.

Synthesis of Chiral-β-Amino Esters via Titanium Ester Enolates

Τηε β-amino acid moiety is widely presented in nature and is an integral part of many bio­logically active compounds. New methods of stereoselective synthesis of β-amino acids are therefore quite important. Herein, the authors reported a simple and efficient protocol for the preparation of syn-substituted β-amino acids starting from simple carboxylic esters and aldimines derived from chiral α-methylbenzylamine. This method uses only inexpensive, readily available compounds and offers α-alkyl-β-amino acids, otherwise rather difficult to achieve, with high diastereo­selectivity and in good yields.

Nostophycin, a Novel Cyclic Peptide from the Toxic Cyanobacterium Nostoc sp. 152

For the elucidation of the biosynthetic relationship between nontoxic and hepatotoxic peptides produced by cyanobacteria, we investigated the secondary metabolites from the toxic cyanobacterium Nostoc sp. strain 152, which produces microcystins. A novel cyclic peptide, nostophycin, possessing weakly cytotoxic activity was isolated together with microcystins from this strain. Nostophycin is composed of six amino acids, d-glutamine, glycine, l-phenylalanine, d-allo-isoleucine, 2 mol of l-proline, and a novel β-amino acid moiety, (2S,3R,5R)-3-amino-2,5-dihydroxy-8-phenyloctanoic acid (Ahoa). The sequence of the constituent amino acids in nostophycin and its structure were determined by 2D-NMR techniques and MS/MS experiments, and the advanced Marfey's method has been used to simultaneously determine their absolute configurations including the β-amino acid moiety. The stereochemistries at the C-2 and C-5 positions of Ahoa were determined by the 1H NMR spectral analysis of its lactone derivative with the acety...

Synthesis of an eight carbon homologue of α-homomannojirimycin via a bicyclic aminolactone

A thermally induced intramolecular 1,3-dipolar cycloaddition of an azidoester and subsequent sodium cyanoborohydride reduction of the resulting bicyclic vinylogous urethane to give a bicyclic aminolactone allows access to an eight carbon homologue of α-homomannojirimycin which is a weak fucosidase inhibitor. Intermediates with both an α- and β-amino acid moiety are described and may be useful for incorporation of homopipecolic acids into novel peptide libraries.

The structure of a cyclic peptide toxin, cyanogenosin-rr from microcystis aeruginosa

The structure of a cyclic peptide toxin from Microcystis aeruginosa was established by chemical and enzymatic methods. The stereochemistry of two chiral centers in the unusual β-amino acid moiety was also deduced by chemical degradation.