Β-amino Alcohols Research Articles

Direct α-Imination of N-Acyl Pyrazoles with Nitrosoarenes.

Unprecedented α-imino N-acyl pyrazoles were efficiently and selectively prepared through the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD)-catalyzed reaction of nitrosoarenes with N-acyl pyrazoles via an N-nitroso aldol reaction/dehydration sequence. The α-imino acyl pyrazoles were demonstrated to be new versatile intermediates for practical one-pot syntheses of α-imino amides, dipeptide precursors, esters, and β-amino alcohols. The synthetic method competes with known protocols in terms of ready availability of the reagents and catalyst, mild and catalytic reaction conditions, gram-scale applicability, and scope of the α-imino acid derivatives achievable.

Synthesis of (R)-2-benzylmorpholine employing catalytic stereospecific rearrangement of L-Phenylalaninol

An efficient synthesis of (R)-2-benzylmorpholine has been accomplished starting from L-phenylalaninol by employing stereospecific rearrangement of β-amino alcohol using catalytic amount of (CF3CO)2O as a key step.

α-Selective glycosidation of d-tagatofuranose with a 3,4-O-isopropylidene protection

An α-selective glycosidation reaction of d-tagatofuranose was successfully achieved using 3,4-O-isopropylidene-protected d-tagatofuranose as a glycosyl donor. A variety of glycosyl acceptors, including primary, secondary, and β-amino alcohols, and carbohydrates, can be used for this d-tagatofuranosidation reaction with complete α-selectivities and good yields (57–83%). The stereochemistries at the anomeric positions were determined by nuclear Overhauser effect spectroscopic correlations, as well as comparison of the chemical shifts in the 13C NMR spectra.

Enantioselective Markovnikov Addition of Carbamates to Allylic Alcohols for the Construction of α-Secondary and α-Tertiary Amines.

Herein we describe the development of a Pd-catalyzed enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of α-tertiary and α-secondary amines. The reaction affords a range of β-amino alcohols, after reduction of the aldehyde in situ, which contain a variety of functional groups in moderate yields and moderate to good enantioselectivities. These products can be readily oxidized to β-amino acids, valuable building blocks for the synthesis of biologically active compounds. Mechanistic studies indicate that the C-N bond formation occurs via a syn amino-palladation mechanism, an insight which may guide future reaction development given the limited number of enantioselective syntheses of α-tertiary amines.

The Hydrosilylation and Cyanosilylation of Ketones Catalyzed using Metal Borohydrides.

The hydrosilylation reaction of carbonyl compounds has emerged as a powerful method in organic synthesis. The catalytic hydrosilylation of ketones is a valuable transformation because it generates protected cyanosilylation reaction of carbonyl compounds is an efficient procedure for the synthesis of silylated cyanohydrins, which are readily converted into useful functionalized compounds, such as cyanohydrins, α-hydroxy acids, β-amino alcohols and other biologically active compounds. A facile, economic and efficient method has been developed for the hydrosilylation and cyanosilylation of ketones using metal borohydrides. A series of silylated ethers and silylated cyanohydrins can be isolated via direct distillation. The catalytic properties of a range of metal borohydrides in the hydrosilylation reaction of acetophenone with diphenylsilane were investigated. The relative catalytic activity of the borohydride catalyst studied was as follows: (CH3)4NBH4> (PhCH2)(CH3)3NBH4> (CH2CH3)4NBH4> (CH3CH2CH2CH3)4NBH4> NaBH4> KBH4> LiBH4. The cyanosilylation of acetophenone using trimethylsilyl cyanide (TMSCN) in the presence of NaBH4 occurred under similar reaction conditions. An excellent reaction rate and high conversion were obtained. The metal borohydride-catalyzed hydrosilylation alcohols in one step. The and cyanosilylation of ketones could be carried out smoothly under mild reaction conditions. Among the metal borohydrides studied, an excellent reaction rate and high conversion were obtained using NaBH4, NaBH (CH2CH3)3 or (alkyl)4 NBH4 as the reaction catalyst.

Formylation of Fluoroalkyl Imines through Visible-Light-Enabled H-Atom Transfer Catalysis: Access to Fluorinated α-Amino Aldehydes.

A visible-light-enabled catalytic formylation of fluoroalkyl imines is developed. With readily accessible starting materials and organocatalysts, this method provides a general approach to masked fluoroalkyl amino aldehydes. A synergistic catalytic effect between the photosensitizer and the H atom transfer agent was proven pivotal to this transformation. After removing the mask, free aldehydes can be obtained and further converted to various β-fluoroalkyl β-amino alcohols, which are attractive building blocks in the synthesis of bioactive and pharmaceutical compounds.

Preparation of 1,3-Thiazolidine-2-thiones by Using Potassium Ethylxanthate as a Carbon Disulfide Surrogate

A simple procedure is presented for preparing 1,3-thiazolidine-2-thiones by using potassium ethylxanthate and the corresponding β-amino alcohols as the starting materials in the presence of ethanol.

In situ hyper-cross-linking of glycidyl methacrylate–based polyHIPEs through the amine-enriched high internal phase emulsions

The synthesis of glycidyl methacrylate–based polyHIPEs by free-radical polymerization in the presence of 1,8-diaminoctane or tris(2-aminoethyl)amine-enriched high internal phase emulsions is presented. This innovative “one-pot” synthetic route was developed to produce the so-called in situ hyper-cross-linked polyHIPEs without the use of any additional catalyst, cross-linker, or solvent. In situ hyper-cross-linking was performed through the amine-epoxy reaction before the gel point had been reached, resulting in the formation of the β-amino alcohol derivatives that represent cross-linking knots between the neighboring epoxy repeating units within the poly (glycidyl methacrylate) backbone. In this way, the volume of the mesopores smaller than 3 nm significantly increased. Thus, by changing the amounts of ethylene glycol dimethacrylate and amines in the HIPE templates, the porous structure and the pore volume of the hyper-cross-linked polyHIPEs were systematically altered in order to amplify the polyHIPE’s specific surface area.

Asymmetric ring opening of racemic epoxides for enantioselective synthesis of (S)-β-amino alcohols by a cofactor self-sufficient cascade biocatalysis system

Asymmetric ring opening of racemic epoxides to enantiopure β-amino alcohols via a cascade biocatalysis system.

Direct hydroxyethylation of amines by carbohydrates via ruthenium catalysis

A halogen-free catalytic methodology for the synthesis of β-amino alcohols from aromatic amines and biomass-related carbohydrates is demonstrated for the first time.

Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof

A robust continuous flow procedure for the transformation of bio-based glycerol into high value-added β-amino alcohol active pharmaceutical ingredients.

Enantioselective synthesis of enantiopure β-amino alcohols via kinetic resolution and asymmetric reductive amination by a robust transaminase from Mycobacterium vanbaalenii

Chiral β-amino alcohols are very important chiral building block for preparing bioactive compounds for use in pharmaceutical and fine chemical industries. Synthesis of chiral β-amino alcohols by transaminase is big challenging due to the strict substrate specificities and very low activity of the enzyme. In this work, a (R)-selective ω-transaminase (MVTA) from Mycobacterium vanbaalenii was employed as a biocatalyst for the first time for the synthesis of chiral β-amino alcohol via kinetic resolution and asymmetric reductive amination. The enzyme was purified and characterized. Kinetic resolution of a set of racemic β-amino alcohols including two cyclic β-amino alcohols by MVTA was demonstrated, affording (R)-β-amino alcohols, (1S, 2S)-trans-2-aminocyclopentanol and (1R, 2S)-cis-1-amino-2-indanols in >99% ee and 50–62% conversion. Asymmetric reductive amination of three α-hydroxy ketones (10–300 mM) by MVTA was conducted, (S)-β-amino alcohols were obtained with >99% ee and 80–99% conversion. Preparation experiment for the reductive amination of 200 mM 2-hydroxyacetophenone by the resting cells of recombinant E. coli (MVTA) was proceeded smoothly and product (S)-2-amino-2-phenylethanol was obtained with 71% isolated yield, >99% ee and 68.6 g/L/d volumetric productivity. The current research proved that the MVTA is a robust enzyme for the preparation of chiral β-amino alcohol with high volumetric productivity.

The Heterogeneous Aminohydroxylation Reaction Using Hydrotalcite-Like Catalysts Containing Osmium

The aminohydroxylation reaction of olefins is a key organic transformation reaction, typically carried out homogeneously with toxic and expensive osmium (Os) catalysts. Therefore, heterogenisation of this reaction can unlock its industrial potential by allowing reusability of the catalyst. Os–Zn–Al hydrotalcite-like compounds (HTlcs), as potential heterogeneous aminohydroxylation catalysts, were synthesised by the co-precipitation method and characterised by several techniques. Reaction parameters (i.e., solvent system, reaction temperature, and catalyst structure) were optimized with cyclohexene, styrene, and hexene as substrates. The different classes of olefins (aliphatic, aromatic, and functionalised) that were tested gave >99% conversion and high selectivity (>97%) to the corresponding β-amino alcohol. The catalyst HTlc structure had a significant effect on the reaction time and yield of the β-amino alcohols. Under the same testing conditions, a heat treated catalyst (non-HTlc) showed a shorter reaction time, but drop in the yield of β-amino alcohols and rise in diol formation was observed. Leaching tests showed that 2.9% and 3.4% of Os (inactive) leached from the catalyst to the reaction solution when MeCN/water (1:1 v/v) and t-BuOH/water (1:1 v/v), respectively, were used as the solvent system. Recycling studies showed that the catalyst can be reused at least thrice, with no significant difference in the yield of the β-amino-alcohol.

Intramolecular Umpolung Synthesis of Exocyclic β-Amino Alcohols through Decarboxylative Amination.

An intramolecular aminative Umpolung cyclization strategy has been developed by using α,α-diphenylglycine (2) as the amination and Umpolung reagent. Aldehydes (1) bearing an additional carbonyl group underwent condensation with α,α-diphenylglycine to form an imine, decarboxylation to generate a delocalized 2-azaallylanion, and subsequent intramolecular Umpolung cyclization to produce a variety of exocyclic β-amino alcohols (6) in 60–93% yields with up to >20:1 trans/cis selectivity under mild conditions.

SELECTION OF PROTECTIVE GROUPS UPON OPTIMIZING THE SYNTHESIS OF γ-PNA BASED ON L-GLU

This work is devoted to optimization of the synthesis of γ-S-carboxyethyl monomers of PNA based on L-Glu. PNA are promising compounds that hybridize with DNA or RNA, and due to their properties they are used in molecular biology, personalized medicine, and can also be used to create nanomaterials. To increase the yield of the desired monomers, it has been proposed to replace the benzyl protecting group with the carboxy function of the side radical by cyclohexyl one. Two synthetic schemes were proposed. In the first of them, γ-benzyl-N-Boc-glutamic acid, which was reduced to β-amino alcohol, was the starting compound. The hydroxyl group was protected by a dimethyl-tert-butylsilyl group. The benzyl ester in the side radical was cleaved by reduction on a palladium catalyst using ammonium formate. However, the subsequent acylation of cyclohexyl alcohol failed. In the second of the proposed schemes, a known sequence of reactions was used, which led to the formation of a cyclic derivative of Cbz-protected glutamic acid. Then, the resulting compound was acylated with cyclohexyl alcohol to give the desired ester. The subsequent transformation of the protective groups of the ester resulted in the diprotected L-glutamic acid in three stages. Subsequent reduction gave the desired protected β-amino alcohol containing a cyclohexyl protecting group in the side radical. This compound was further used in the Mitsunobu reaction to obtain a completely protected core of the PNA monomer. Subsequent thiolysis reaction resulted in the formation of the target secondary amine, the stability of which substantially exceeded the stability of its analog with benzyl protection, obtained and investigated before. The structure of the new compounds obtained is confirmed by 1H-NMR spectroscopy.

Synthesis, structure, and catalytic performance of heterobimetallic coordination polymers with β-diketone containing imidazole group

Four heterobimetallic coordination polymers [Cd[Al(L)3]2(NO3)2 (1), Zn[Al(L)3]2(NO3)2 (2), Zn[Fe(L)3]2(NO3)2 (3), and [ZnFe(L)3Cl](NO3)·3(MeOH)·3(DMF) (4) have been synthesized. The structural analyses of coordination polymers 1–4 showed that they were trigonal space group, among which, coordination polymer 4 was P3 chiral space group. The circular dichroism spectra also confirmed that coordination polymer 4 had chirality. Zn(II) ion in coordination polymer 4 was tetracoordinated, unsaturated, can act as Lewis acid catalyst. Therefore, coordination polymer 4 can catalyze the ring opening of epoxides with aromatic amines to produce β-amino alcohols at room temperature. The catalytic reaction was regioselective, easy to operate, and had good catalyst recovery and repeatability.

Fe(II) complexes: reservoirs for Lewis acids and carbenes and their utility in the conversion of CO2 to oxazolidinones

Several Fe(II) complexes were prepared as catalysts for the synthesis of oxazolidinones from terminal epoxides, aryl amines, and carbon dioxide. DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) was identified as a highly active co-catalyst for the formation of oxazolidinones. Mechanistic studies reveal that Fe(II) complexes act as reservoirs of the two active species including Lewis acid and carbene. The epoxides were activated via a Fe-O σ-bond between the Fe atom of the Lewis acid and the oxygen atom of the epoxide. Simultaneously, a nucleophilic carbene activates CO2 to form a carbene−CO2 adduct. In addition, interactions between the Lewis acid and epoxides accelerate the reaction of epoxides with aryl amines. DBU plays a crucial role in the reaction between the β-amino alcohol and cyclic carbonate. Under mild reaction conditions, various epoxides and aryl amines were converted to the corresponding oxazolidinones with good yields in the presence of CO2.

Preparative enantioseparation of synephrine by conventional and pH-zone-refining counter-current chromatography

Synephrine, a chiral adrenergic agonist, exists as R- (more active) and S-enantiomers (less active) that are difficult to separate because of their alkalinity and high polarity. Herein, we show that although this enantioseparation can hardly be achieved by high-performance liquid chromatography, acceptable preparative separation can be realized using high-speed counter-current chromatography (HSCCC) and pH-zone-refining counter-current chromatography (CCC) under optimal conditions. Specifically, 23.0 mg of S-synephrine and 25.0 mg of R-synephrine were isolated from 60.0 mg of racemic synephrine by conventional HSCCC, while 70.0 mg of S-synephrine and 69.0 mg of R-synephrine were obtained from 200.0 mg of racemic synephrine by pH-zone-refining CCC. The pH-zone-refining CCC was identified as the most efficient enantioseparation technique for synephrine and can be applied for the preparative enantioseparation of other β-amino alcohols.

β-amino alcohols and their respective 2-phenyl-N-alkyl aziridines as potential DNA minor groove binders

It is known that aziridines and nitrogen mustards exert their biological activities, especially in chemotherapy, via DNA alkylation. The studied scaffold, 2-phenyl-1-aziridine, provides a distinct conformation compared to commonly used aziridines, and therefore, leads to a change in high-strained ring reactivity towards biological nucleophiles, such as DNA. The above series of compounds was tested in three breast cell lines: MCF-10, a healthy cell; MCF-7, a hormone responsive cancer cell; and MDA-MB-231, a triple negative breast cancer cell. Both aziridines and their precursors, β-amino alcohols, showed activity towards these cells, and some of the compounds showed higher selectivity index than cisplatin, the drug used as control. When the type of cell death was investigated, the synthesized compounds demonstrated higher apoptosis and lower necrosis rates than cisplatin, and when the mechanism of action was studied, the compounds were shown to interact with DNA via its minor groove instead of alkylation or intercalation.

Chiral sensor for enantiomeric purity of amines, amino alcohols and amino esters based on bis-cyclometalated Ir(III) complex using 1H NMR spectroscopy

A new chiral sensor assembly with enantiomeric Ir(III) complex Δ-[Ir(ppy)2(MeCN)2](PF6) (ppy is 2-phenylpyridine) and 3-hydroxypyridine-2-carboxaldehyde as anxiliaries for chiral amines and amino derivatives, including α-amines, α-amino alcohols, α-amino esters, β-amines and β-amino alcohols as well as amino ether, was developed on the basis of 1H NMR spectroscopy. The assembly reaction is rapid and quantitative in equivalent under mild conditions, generating the corresponding diastereomers that are applied to discriminate the absolute configuration and quantitatively determine the enantiomeric excess (ee) directly without physical separation. The chelating coordination to Ir(III) ion much enhances the stability of the formed Schiff base ligand. Furthermore, more than one pair of diastereotopic resonances in wide detection regions ensures a convenient and high degree of accuracy in quantifying the ee value of chiral amines and amino derivatives. The absolute errors of the ee determinations by 1H NMR spectroscopy in different detection windows are within 1.9%. The linear relationship between the experimentally measured ee values and the gravimetrically prepared samples is found to be excellent.