Regioselective Azidolysis Research Articles

Asymmetric azidohydroxylation of styrene derivatives mediated by a biomimetic styrene monooxygenase enzymatic cascade.

Enantioenriched azido alcohols are precursors for valuable chiral aziridines and 1,2-amino alcohols, however their chiral substituted analogues are difficult to access. We established a cascade for the asymmetric azidohydroxylation of styrene derivatives leading to chiral substituted 1,2-azido alcohols via enzymatic asymmetric epoxidation, followed by regioselective azidolysis, affording the azido alcohols with up to two contiguous stereogenic centers. A newly isolated two-component flavoprotein styrene monooxygenase StyA proved to be highly selective for epoxidation with a nicotinamide coenzyme biomimetic as a practical reductant. Coupled with azide as a nucleophile for regioselective ring opening, this chemo-enzymatic cascade produced highly enantioenriched aromatic α-azido alcohols with up to >99% conversion. A bi-enzymatic counterpart with halohydrin dehalogenase-catalyzed azidolysis afforded the alternative β-azido alcohol isomers with up to 94% diastereomeric excess. We anticipate our biocatalytic cascade to be a starting point for more practical production of these chiral compounds with two-component flavoprotein monooxygenases.

Montmorillonite K10 catalyzed highly regioselective azidolysis of epoxides: A short and efficient synthesis of phenylglycine

A series of β‐hydroxyazides were effectively synthesized from the regioselective ring opening of epoxides by sodium azide using montmorillonite K10 as a novel heterogeneous catalyst in aqueous acetonitrile in good to excellent yields. The utility of this method has been demonstrated by achieving a short synthesis of phenylglycine in 33.5% overall yield.

ChemInform Abstract: 1‐(1‐Alkylsulfonic)‐3‐methylimidazolium Chloride as a Reusable Broensted Acid Catalyst for the Regioselective Azidolysis of Epoxides under Solvent‐Free Conditions.

Abstract1‐(1‐Propylsulfonic)‐3‐methylimidazolium chloride is used as a green and reusable catalyst for the regioselective ring‐opening reactions of various epoxides with sodium azide to afford the corresponding β‐azido alcohols in excellent yields within short reaction times under mild conditions.

Total synthesis and in vitro bioevaluation of clavaminols A, C, H & deacetyl clavaminol H as potential chemotherapeutic and antibiofilm agents

A highly concise and expedient total synthesis of bioactive clavaminols (1–4) has been executed using commercially available achiral compound decanol. The synthetic strategy relied on trans-Wittig olefination, Sharpless asymmetric epoxidation, regioselective azidolysis and in situ detosylation followed by reduction as key reactions with good overall yield. Based on biological evaluation studies of all the synthesized compounds, it was observed that the clavaminol A (1) exhibited good cytotoxicity against DU145 and SKOV3 cell lines with IC50 value of 10.8 and 12.5 μM, respectively. Clavaminol A (1) and deacetyl clavaminol H (3) displayed selective promising inhibition towards Gram-positive pathogenic bacterial strains and showed good antifungal activity against the tested Candida strains. In addition, compounds 1 and 3 have demonstrated significant bactericidal activity. Compound 3 was found to be equipotent to the standard drug Miconazole displaying MFC value of 15.6 μg/mL against Candida albicans MTCC 854, C. albicans MTCC 1637, C. albicans MTCC 3958 and Candida glabrata MTCC 3019. Compounds 1 and 3 were also able to inhibit the biofilm formation of Micrococcus luteus MTCC 2470 and Staphylococcus aureus MLS16 MTCC 2940. Clavaminol A (1) increased the levels of reactive oxygen species (ROS) accumulation in M. luteus MTCC 2470.

1-(1-Alkylsulfonic)-3-methylimidazolium chloride as a reusable Brønsted acid catalyst for the regioselective azidolysis of epoxides under solvent-free conditions

Abstract In this study, 1-(1-alkylsulfonic)-3-methylimidazolium chloride as a new, green, and reusable Bronsted acid catalyst was prepared. In this protocol, we used for the regioselective ring-opening reactions of various epoxiodes with sodium azide to afford the corresponding β -azido alcohols in excellent yields and short reaction time under mild and neutral reaction conditions. This method offers several advantages including excellent regioselectivity, clean reactions, simple work-up procedure, a recyclable catalyst, and use of an eco-friendly catalyst.

Synthesis of β-amino-α.-ketoamides

β-Amino-α-ketoamides 1 are a class of compounds exhibiting biological activity as reversible covalent enzyme inhibitors. The representative examples are clinically approved drugs for the treatment of hepatitis C virus Boceprevir 2 and Telaprevir 3. β-Amino-α- ketoamide substructure is also found in a number of natural products, many of which display a remarkable biological activity. The methods for the synthesis of β-amino-α-ketoamide can be classified based on the key steps of the synthetic routes: from unsaturated amide involving epoxydation followed by a regioselective azidolysis; from esters involving aminohydroxylation; from adehydes via Passerini reaction, cyanohydrin formation, addition of the masked acylcyanide (MAC) reagent or orthothioester; from imines via addition of dithiolane derived from oxoacetic acid, addition of isoxazolyl-4-triflates or via azetidinone formation; from acids via acylation of (cyanomethylene) triphenylphosphorane (the Wasserman procedure), via acylfurane formation or via Dakin-West reaction; from nitroalkanes via Henry reaction. In this review, the information from the scientific literature published within the period from 1990 till 2014 for the synthesis of β-amino-α-ketoamides is covered and systematized according to the above mentioned key steps. Keywords: Azetidinones, cyanohydrins, dakin-west reaction, epoxides, MAC reagent, orthothioesters, henry reaction, passerini reaction, protease inhibitors, wasserman procedure, β-Amino-α-ketoamides.

Synthesis of 1,2-trans-2-acetamido-2-deoxyhomoiminosugars.

The first synthesis of 1,2-trans-homoiminosugars devised as mimics of β-D-GlcNAc and α-D-ManNAc is described. Key steps include a regioselective azidolysis of a cyclic sulfite and a β-amino alcohol skeletal rearrangement applied to a polyhydroxylated azepane. The β-D-GlcNAc derivative has been coupled to serine to deliver an iminosugar C-amino acid. The two homoiminosugars demonstrate moderate glycosidase inhibition.

SO3H-Carbon derived from glycerol: An efficient and recyclable catalyst for smooth and regioselective azidolysis of oxiranes in water

A series of β -hydroxyazides were effectively synthesized from the regioselective ring opening of oxiranes by azide anion in presence of glycerol-based sulfonic acid functionalized carbon as a novel reusable heterogeneous catalyst in H 2 O achieving good yields (80-98%). The workup procedure was simple, and the catalyst could be reused over five times without losing its catalytic activity and selectivity.

Lewis acid-mediated azidolysis of 2,3-three membered heterocyclic amines

The Lewis acid-catalyzed regioselective azidolysis of 2,3-three membered heterocyclic amines has been investigated. The results obtained demonstrated that using TMSN3 as a source of azide, the appropriate choice of Lewis acid allowed to obtain different regio- and stereocontrolled precursors of aminoalcoholic and triaminic sequences. Considering the occurrence of these moieties in the structure of many biologically active compounds, the present methodologies could represent a powerful tool in organic synthesis for the preparation of interesting molecules.

Total synthesis and biological evaluation of clavaminol-G and its analogs

The first total synthesis of clavaminol-G (1) and 1-aminoundecan-2-ol (2) has been achieved from 10-undecenoic acid using epoxidation, regioselective azidolysis and in situ detosylation and reduction reactions as key steps. The methodology is extended for the synthesis of 1-aminoundecan-2-ol derivatives; namely, methyl 11-amino-10-hydroxyundecanoate (3), 11-amino-10-hydroxyundecanoic acid (4) and 11-aminoundecan-1,10-diol (5). Among these, 1-aminoundecan-2-ol (2) exhibited good antimicrobial activity and promising cytotoxicity towards HeLa, MDA-MB-231, MCF-7 and A549 cell lines with IC50 values of 4.36, 4.02, 3.88 and 6.78 μM, respectively. Compound 3 exhibited good activity against HeLa cells (IC50 = 3.59 μM), while compound 5 showed moderate activity towards HeLa and A549 cell lines. Clavaminol G (1) and compound 4 showed no activity towards all the cell lines.

Ni2+ supported on hydroxyapatite-core-shell γ-Fe2O3 nanoparticles: a novel, highly efficient and reusable lewis acid catalyst for the regioselective azidolysis of epoxides in water

In this research, Ni2+ supported on hydroxyapatite-core-shell magnetic γ-Fe2O3 nanoparticles (γ-Fe2O3@HAp-Ni2+) as a novel, efficient, reusable and heterogeneous catalyst was reported. In this protocol, we used this catalyst for the ring opening of epoxide with sodium azide in water. The catalyst can be readily isolated using an external magnet and no obvious loss of activity was observed when the catalyst was reused in seven consecutive runs. The mean size and the surface morphology of the nanoparticles were characterized by transmission electron microscopy, scanning electron microscope, vibrating sample magnetometry, X-ray powder diffraction and Fourier transform infrared techniques.

Bioglycerol-based Sulphonic Acid Functionalized Carbon: An Efficient and Recyclable, Solid Acid Catalyst for the Regioselective Azidolysis of Epoxides in Aqueous Acetonitrile

A convinent and efficient method was developed for the synthesis of 1,2-azidoalcohols by ring opening of terminal epoxides with sodium azide employing glycerol-based sulphonic acid functionalized carbon as heterogeneous catalyst in aqueous acetonitrile. The reaction is highly regioselective and affords the corresponding products in excellent yields (78-100%) under mild reaction conditions. The catalyst exhibited efficient reusability without loosing its activity even after 5 cycles of azidolysis of methyl 10,11-epoxy undecanoate under optimized conditions within 2 h.

3D-network porous polymer based on calix[4]resorcinarenes as an efficient phase transfer catalyst in regioselective conversion of epoxides to azidohydrins

Abstract The present study, for the first time, describes the application of 3D‐network polymer based on calix[4]resorcinarene, as an efficient heterogeneous and phase transfer catalyst for regioselective azidolysis of epoxides. The surface morphology and the structure of this polymer were investigated by atomic force microscopy (AFM). This method offers several advantages including clean reactions, ease of work-up and reusability of the catalyst.

BF3·OEt2/TMSN3 Mediated Regioselective Azidolysis of Vinylaziridines

An easy and general azidolysis of vinylepoxides mediated by BF3·OEt2 and TMSN3 recently reported by our group has been extended to vinylaziridines. The reaction affords unsaturated azido derivatives with complete stereoselectivity and regioselectivity, when in the presence of electron-poor olefins, regardless of the size of substituents on the heterocyclic ring.

A highly regioselective azidolysis of 2,3-epoxy amines: an unexpected [Ti(O-i-Pr)2(N3)2] mediated C-2 opening

The Lewis acid-catalysed regioselective azidolysis of 2,3-epoxy amines has been investigated. The results obtained demonstrated that using TMSN3 as a source of azide, the appropriate choice of Lewis acid allowed to direct the regiochemistry of the ring opening. The present methodologies provide a powerful tool in organic synthesis for the preparation of diaminoalcohol moieties.

Total synthesis and antifungal activity of (2S,3R)-2-aminododecan-3-ol

We report the total synthesis of (2S,3R)-2-aminododecan-3-ol has been achieved starting from commercially available 10-undecenoic acid. The key steps involved are Sharpless asymmetric epoxidation, Miyashita’s boron-directed C-2 regioselective azidolysis, generated the asymmetric centers and in situ detosylation and reduction of azido tosylate. The antifungal activity of the synthesized (2S,3R)-2-aminododecan-3-ol was evaluated on several Candida strains and was comparable to miconazole, a standard drug

Catalytic activity of halohydrin dehalogenases towards spiroepoxides

A novel activity of halohydrin dehalogenases towards spiroepoxides has been found. The enzyme from Arthrobacter sp. (HheA) catalysed highly regioselective azidolysis of spiroepoxides containing 5, 6 and 7-membered cycloalkane rings, while the enzyme from Agrobacterium radiobacter (HheC), besides high regioselectivity, also displayed moderate to high enantioselectivity (E up to >200) that can be applied for the kinetic resolution of chiral spiroepoxides. The orientations of spiroepoxides in the active site of halohydrin dehalogenases were studied by quantum-chemical calculations and docking simulations. Analyses of the complexes obtained revealed the origins of diastereoselectivity and enantioselectivity of the investigated biotransformations.

Asymmetric total syntheses of spisulosine, its diastereo- and regio-isomers

Starting from palmityl alcohol, divergent stereoselective syntheses of spisulosine and its diastereo- and regio-isomers have been achieved. In the Sharpless asymmetric dihydroxylation-based approach, the key step is the synthesis of monoprotected diol, whereas Miyashita’s boron-directed C-2 regioselective azidolysis of enantiomerically pure epoxy alcohol is the vital step in the Sharpless asymmetric epoxidation-based route. The latter approach involves the first protecting-group-free synthesis of spisulosine.

Chemical reactivity predictions: Use of data mining techniques for analyzing regioselective azidolysis of epoxides

Azidolysis of epoxides followed by reduction of the intermediate azido alcohols constitutes a valuable synthetic tool for the construction of beta-amino alcohols, an important chemical functionality occurring in many biologically active compounds of natural origin. However, depending on conditions under which the azidolysis is carried out, two regioisomeric products can be formed, as a consequence of the nucleophilic attack on both the oxirane carbon atoms. In this work, predictive models for quantitative structure-reactivity relationships were developed by means of multiple linear regression, k-nearest neighbor, locally weighted regression, and Gaussian Process regression algorithms. The specific nature of the problem at hand required the creation of appropriate new descriptors, able to properly reflect the most relevant features of molecular moieties directly involved in the opening process. The models so obtained are able to predict the regioselectivity of the azidolysis of epoxides promoted by sodium azide, in the presence of lithium perchlorate, on the basis of steric hindrance, and charge distribution of the substituents directly attached to the oxirane ring.

Green Regioselective Azidolysis of Epoxides Catalyzed by Multi‐Site Phase‐Transfer Catalyst

AbstractA facile synthesis of 1,2‐azidoalcohols from their epoxides using α,α',α”‐N‐hexakis(triethylammoniummethylene chloride)‐melamine as a multi‐site phase‐transfer catalyst in water was developed. By this eco‐friendly and highly atom‐economic method, a variety of 1,2‐azidoalcohols was obtained in high yields with excellent regioselectivity and in short reaction times. Application of this six‐site PTC in the ring opening of epoxides by cyanide, acetate and chloride anions was also studied. The catalyst can be recovered after completion of the reaction and can be recycled without affecting the catalytic property.