Synthesis and Characterization of the Tetrazole Analogues of α-Amino Acids

Tetrazoles have found wide applications in coordination chemistry, medicinal chemistry and material science. Especially, when the tetrazole moiety is served as a surrogate for terminal carboxylic acid residues, the peptides have been presented some pharma…     

Synthesis and Heterocyclization of β-Aroyl-α-diphenylphosphorylpropionic Acids

It has been established that diphenylphosphine oxide reacts smoothly with -aroylacrylic acids with the formation of -aroyl--diphenylphosphorylpropionic acids, which were cyclized under the action of hydroxylamine, hydrazine hydrate, and phenylhydrazine hydrochloride into phospho derivatives of dihydrooxazinone and tetrahydropyridazinone respectively. It was shown that imidazole may serve as nucleophilic protection for the synthesis of dihydropyridazinone derivatives from -aroylacrylic acids.     

α-Amino Acids: An Emerging Versatile Synthon in Visible Light-Driven Decarboxylative Transformations

α-Amino acids have been widely recognized as environmental-benign and non-fossil carbon sources both in biological and synthetic chemistry. In recent years, with the remarkable development of visible-light photocatalysis in organic synthesis, α-amino acid and its derivatives have received tremendous attention as radical precursors via photocatalyzed decarboxylation, thus realizing diverse aminoalkylated transformations or constructions of novel N-bearing heterocyclic motifs by taking advantage of N-atoms from α-amino acid. This review aims to provide a comprehensive update on the recent exploitation of α-amino acids in visible light photocatalysis, with particular emphasis on the types of α-amino acids employed and their distinct mechanisms applied wherein.     

Versatile Biocatalytic C(sp3)−H Oxyfunctionalization for the Site- Selective and Stereodivergent Synthesis of α- and β-Hydroxy Acids

C(sp³)−H oxyfunctionalization, the insertion of an O-atom into C(sp³)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp³)−H oxyfunctionalization has the potential to overcome limitations inherent to small-molecule-mediated approaches by delivering catalyst-controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp³)−H bonds, providing concise synthetic routes towards four types of 92 α- and β-hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.     

Selection of Amino Acids and the Biomimetic Synthesis of Amido Bond in the Presence of β-CD

A new method was developed to construct a special amido bond in the presence of β-cyclodextrin. This process is similar to peptide synthesis in organisms. NMR experiments were performed to investigate the possible mechanism. This work has potential application in biomimetic peptide synthesis.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

Polyenolates of Unsaturated Carboxylic Acids in Synthesis. Synthesis of Unsaturated α-Amino Acids and β-Hydrazing Acids

Regioselective reaction of lithium diene-and triene-diolates 1 and 2 with O-diphenylphosphinyl hydroxylamine affords unsaturated α-amino acids 3 and 4. Addition to DEAD leads selectively to γ-hydrazino unsaturated acids 5 and 6.     

Convenient Syntheses of Aroylamino Acids and α-amino ketones

C-Acylamino acid, especially aroylamino acid is a key and still currently interest compound for the pharmaceutical intermediate in which β-arylserine prepared by the reduction in an example would be physiologically important.     

Hydrolysis Reaction of N-Phosphoryl-α-, β- and γ-amino Acids Studied by HPLC

The hydrolysis reactions of N-（O,O＇diisopropyl）phosphoryl-L-α-alanine （DIPP-L-α-Ala）, N-（O,O＇diisopropyl）- phosphoryl-D-α-alanine （DIPP-D-α-Ala）, N-（O,O＇-diisopropyl）phosphoryl-β-alanine （DIPP-β-Ala） and N-（O,O＇-diisopropyl）phosphoryl-γ-amino butyric acid （DIPP-γ-Aba）, were studied by HPLC and their hydrolysis reaction kinetic equations were obtained. Under acid conditions, the reaction rate of DIPP-L-α-Ala was close to that of DIPP-D-α-Ala and the same rule was true between DIPP-β-Ala and DIPP-γ-Aba. Meantime, the reaction rate of DIPP-L/D-α-Ala was as 10 times as that of DIPP-β-Ala or DIPP-γ-Aba. Under basic conditions, the hydrolysis reactions of DIPP-β-Ala and DIPP-γ-Aba almost did not take place and the reaction rate of DIPP-L/D-α-Ala was about 1/10 of that under acid conditions. Moreover, theoretical calculation further illuminated the differences of the hydrolysis rate from the view of energy. The results would provide some helpful clues to why nature chose a-amino acids but not other kinds of analogs as protein backbones.     

Termite Trail Attractants: New Syntheses of Racemic (E)-α-, (Z)-α- and β-Bisabolenes

Racemic (E)-α-bisabolene (E)(1) was synthetized starting from 4-methyl-3-cyclohexenecarboxylic acid (3) by a reaction sequence involving the Pd(0)-catalyzed cross-coupling reaction between the (E)-2-methyl-1-alkenyltrimethylstannane 8 and 3-methyl-2-buten-1-yl acetate (9). Three different procedures, in which a common precursor was used as key intermediate, were tested for the synthesis of racemic (Z)-α-bisabolene (Z)(1). The best one, which involved the reaction between bromide 18 and lithium dialkenylcuprate 19, afforded a mixture of (Z)- and (E)-1 in a 93 : 7 molar ratio, respectively. Finally, racemic β-bisabolene (2) was synthetized by a simple reaction sequence involving the Zr-promoted methylenation of ketone 22 prepared from 3.     

Single Step Syntheses of ω-9-Fluorenylmethyl Esters of Aspartic and Glutamic Acids

Base lability of the 9-fluorenylmethyl ester makes this group useful in solid phase peptide synthesis when used in combination with the tBoc methodology for preparing cyclic peptides. We describe a simple one step synthesis of the 9-fluorenylmethyl esters of aspartic and glutamic acids.     

Enzymatic Syntheses of N-Acetyllactosamine and N-Acetylallolactosamine by the Use of β-D-Galactosidases

Abstract

A β-D-galactosidase from Bacillus circulans induced β-D-galactopyranosyl transfer from lactose predominantly to a secondary (OH-4) rather than the primary hydroxyl group (OH-6) of 2-acetamido-2-deoxy-D-glucopyranose. 4-O-β-D-Galacto-pyranosyl-2-acetamido-2-deoxy-D-glucopyranose (N-acetyl-lactosamine) was thus readily synthesized on a gram scale and conveniently isolated by chromatography on a column of charcoal-Celite. On the other hand, the glycosyl transfer to the 6-position predominantly was efficiently induced to give 6-O-β-D-galactopyranosyl-2-acetamido-2-deoxy-D-glucopyranose (N-acetyl-allolactosamine) by consecutive use of β-D-galactosidases from Kluyveromyces lactis and B. circulans. These enzyme reactions were efficient enough to allow the one-pot preparation of the desired disaccharides.     

Character of Enolization of the β-Dicarbonyl Fragment in α , γ-Dioxocarboxylic Acids. Crystal and Molecular Structure of Benzoyl- and Cinnamoylpyruvic Acids

Benzoyl- and cinnamoylpyruvic acids have been investigated by X-ray diffraction. In crystals these acids exist as 2-hydroxy-4-oxo-4-phenyl-3(Z)-butenic and 4-hydroxy-2-oxo-6-phenyl-3(Z),5(E)-hexadienic acids, respectively, stabilized by intramolecular hydrogen bonding.     

Engineered Biocatalytic Synthesis of β-N-Substituted-α-Amino Acids

Non-canonical amino acids (ncAAs) are useful synthons for the development of new medicines, materials, and probes for bioactivity. Recently, enzyme engineering has been leveraged to produce a suite of highly active enzymes for the synthesis of β-substituted amino acids. However, there are few examples of biocatalytic N-substitution reactions to make α,β-diamino acids. In this study, we used directed evolution to engineer the β-subunit of tryptophan synthase, TrpB, for improved activity with diverse amine nucleophiles. Mechanistic analysis shows that high yields are hindered by product re-entry into the catalytic cycle and subsequent decomposition. Additional equivalents of l -serine can inhibit product reentry through kinetic competition, facilitating preparative scale synthesis. We show β-substitution with a dozen aryl amine nucleophiles, including demonstration on a gram scale. These transformations yield an underexplored class of amino acids that can serve as unique building blocks for chemical biology and medicinal chemistry.     

A Novel Synthesis of β-Hydroxy-α-amino Acids

β-hydroxy-α-amino acids constitute an important class of compounds as naturally occurring amino acids and as components of many complex natural products possessing a wide range of biological activities. [1] As a consequence of the essential role played by these amino acids in the biological systems and their utility as synthetic building blocks, a number of useful strategies have been devised for their preparation. [2]     

Syntheses of β- and γ-fluorophenyl cis- and trans-α-methylene-γ-butyrolactones

Preparation of a series of cis-γ-fluorophenyl-β-phenyl-α-methylene-γ-butyrolactones is reported via ‘allylboration’ of fluorobenzaldehydes with (E)-methyl 3-phenyl-2-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)acrylate. The corresponding trans-γ-fluorophenyl lactones were prepared either (i) via ‘allylboration’ using the (Z)-reagents or (ii) via an indium triflate-mediated isomerization of the cis-products. The difficulty in isomerizing difluorinated cis-products confirms the probable intermediacy of carbocations. Finally, the synthesis of cis-β-fluorophenyl-γ-phenyl-α-methylene-γ-butyrolactones was achieved via an indium-catalyzed allylation–lactonization of aldehydes with (Z)-2-(bromomethyl)-3-(fluorophenyl)acrylates.     

Mechanism of the Debromination in Heterocyclization Using α,α-Dibromocarbonyl Compounds as Synthons

α,α-dibromocarbonyl compounds on condensation with phenylacetic acid or thioamide give the furanone or thiazole instead of the expected corresponding 5-bromo products. The mechanistic study have been made to find the reaction path way.     

Preparation of 4′-Spirocyclobutyl Nucleoside Analogues as Novel and Versatile Adenosine Scaffolds

Despite the large variety of modified nucleosides that have been reported, the preparation of constrained 4′-spirocyclic adenosine analogues has received very little attention. We discovered that the [2+2]-cycloaddition of dichloroketene on readily available 4′-exo-methylene furanose sugars efficiently results in the diastereoselective formation of novel 4′-spirocyclobutanones. The reaction mechanism was investigated via density functional theory (DFT) and found to proceed either via a non-synchronous or stepwise reaction sequence, controlled by the stereochemistry at the 3′-position of the sugar substrate. The obtained dichlorocyclobutanones were converted into nucleoside analogues, providing access to a novel class of chiral 4′-spirocyclobutyl adenosine mimetics in eight steps from commercially available sugars. Assessment of the biological activity of designed 4′-spirocyclic adenosine analogues identified potent inhibitors for protein methyltransferase target PRMT5.     

Versatile Glycosyl Sulfonates in β-Selective C-Glycosylation

C-Glycosides are both a common motif in many bioactive natural products and important glycoside mimetics. We demonstrate that activating a hemiacetal with a sulfonyl chloride, followed by treating the resultant glycosyl sulfonate with an enolate results in the stereospecific construction of β-linked C-glycosides. This reaction tolerates a range of acceptors and donors, including disaccharides. The resulting products can be readily derivatized into C-glycoside analogues of β-glycoconjugates, including C-disaccharide mimetics.     

Syntheses of 4- and/or 4′-Phosphate Derivatives of Methyl 3-O-l-Glycero-α-d-manno-heptopyranosyl-l-glyceroα-d-manno-heptopyranoside and Their 2-(4-Trifluoro-acetamidophenyl)ethyl Glycoside Analogues.

Abstract

Syntheses are described of the three disaccharides: methyl 3-O-L-glycero-α-D-manno-heptopyranosyl-L-glycero-α-D-manno-heptopyranoside 4-phosphate, methyl 3-O-(L-glycero-α-D-manno-heptopyranosyl 4-phosphate)-L-glycero-α-D-manno-heptopyranoside, and methyl 3-O-(L-glycero-α-D-manno-heptopyranosyl 4-phosphate)-L-glycero-α-D-manno-heptopyranoside 4-phosphate together with their 2-(4-trifluoroacetamidophenyl)ethyl glycoside analogues. These correspond to phosphorylated structures found in the inner core region of lipopolysaccharides from Salmonella. The known derivative methyl 6,7-di-O-acetyl-2,3,4-tri-O-benzyl-L-glycero-α-D-manno-heptopyranoside was used as a common heptose precursor. Phosphorylation on suitably protected disaccharide derivatives was performed by treatment with phosphorus triimidazolate in dichloromethane followed by the addition of benzyl alcohol and in situ oxidation with m-chloroperbenzoic acid to give the dibenzyltriester phosphate derivatives, which after deprotection gave the target compounds.