Β-amino Alcohols Research Articles

Mn-Catalyzed Highly Efficient Aerobic Oxidative Hydroxyazidation of Olefins: A Direct Approach to β-Azido Alcohols.

An efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for synthesis of β-azido alcohols has been developed. The aerobic oxidative generation of azido radical employing air as the terminal oxidant is disclosed as the key process for this transformation. The reaction is appreciated by its broad substrate scope, inexpensive Mn-catalyst, high efficiency, easy operation under air, and mild conditions at room temperature. This chemistry provides a novel approach to high value-added β-azido alcohols, which are useful precursors of aziridines, β-amino alcohols, and other important N- and O-containing heterocyclic compounds. This chemistry also provides an unexpected approach to azido substituted cyclic peroxy alcohol esters. A DFT calculation indicates that Mn catalyst plays key dual roles as an efficient catalyst for the generation of azido radical and a stabilizer for peroxyl radical intermediate. Further calculation reasonably explains the proposed mechanism for the control of C-C bond cleavage or for the formation of β-azido alcohols.

Efficient Synthesis of 3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric Acid

3-R-Boc-amino-4-(2,4,5-trifluorophenyl)butyric acid (9) was obtained from L-methionine in six steps with a total yield of 32%. The α-amino acid segment of L-methionine was transferred to chiral aziridine by amino protection, reduction, hydroxyl derivation, and cyclization. After ring opening of 2,4,5-trifluoro-phenyl magnesium bromide, the methylthiomethyl group was then hydrolyzed to β-amino alcohol and oxidized to the target β-amino acid.

One-Pot Synthesis of N-Substituted β-Amino Alcohols from Aldehydes and Isocyanides.

A practical two-stage one-pot synthesis of N-substituted β-amino alcohols using aldehydes and isocyanides as starting materials has been developed. This method features mild reaction conditions, broad scope, and general tolerance of functional groups. Based on a less common central carbon-carbon bond disconnection, this protocol complements traditional approaches that involve amines and various carbon electrophiles (epoxides, α-halo ketones, β-halohydrins). Medicinally relevant products can be prepared in a concise and efficient way from simple building blocks, as demonstrated in the synthesis of the antiasthma drug salbutamol. Upgrading the synthesis to an enantioselective variant is also feasible.

A Rapid, Robust and Ultra-Sensitive HPLC Enantioseparation of β-Amino Alcohols.

Enantioseparation of amino acid analogues racemic β-amino alcohols has hitherto been thought impossible without prior derivatization. Method developers of chromatographic enantioseparation often face detection challenge due to low ultraviolet (UV) absorbance of these molecules. A new chiral derivatizing reagent, benzimidazole-(S)-naproxen amide, was synthesized to provide UV detectable chiral moiety for detection of respective diastereomers of eight β-amino alcohols (dl-alaninol, dl-leucinol, dl-prolinol, dl-phenylalaninol, dl-phenylglycinol, dl-valinol, dl-homophenylalaninol and dl-methioninol). An HPLC method has been developed and validated and both the diastereomers were separated within 31 min runtime. Excellent resolution to a pmol detection limit level was achieved. The developed HPLC method for enantioseparation of β-amino alcohols is the first-ever report of its own kind having such a high detection sensitivity.

Highly enantioselective hydrogenation of ο-alkoxy tetrasubstituted enamides catalyzed by a Rh/(R,S)-JosiPhos catalyst.

Rh/(R,S)-JosiPhos complex-catalyzed asymmetric hydrogenation of o-alkoxy tetrasubstituted enamides has been achieved, and it furnished a set of β-amino alcohol analogues in high yields and excellent enantiomeric excesses (>99% conversion, up to 99% ee).This method provides valuable chiral building blocks in chiral pharmaceuticals and useful motifs for catalysts.

Asymmetric Cu-catalyzed Henry reaction promoted by chiral camphor-derived β-amino alcohols with a thiophene moiety

Four chiral amino alcohols with a sulfur substituent were synthesized from d-(+)-camphor and utilized as ligands in Cu(I)-catalyzed asymmetric Henry reactions between nitromethane and various aldehydes. The reactions were carried out under mild conditions with excellent enantioselectivities and good yields without the exclusion of air or moisture. The highest enantioselectivity was observed (up to 96% ee) with ligand 3c in CH3NO2 at 0°C.

ChemInform Abstract: Asymmetric Reduction of α‐Amino Ketones with a KBH4 Solution Catalyzed by Chiral Lewis Acids.

An efficient enantioselective reduction of α-amino ketones with potassium borohydride solution catalyzed by chiral N,N'-dioxide-metal complex catalysts was accomplished under mild reaction conditions for the first time. It provided a simple, convenient, and practical approaches for obtaining synthetically important chiral β-amino alcohols in good to excellent yields (up to 98%) and enantioselectivities (up to 97% ee).

Use of In Situ Generated Nitrosocarbonyl Compounds in Catalytic Asymmetric α-Hydroxylation and α-Amination Reactions

Abstract Nitroso compounds are highly fascinating electrophiles as they are able to selectively transfer both the heteroatoms in a variety of oxidation reactions. Bench stable aryl-nitroso compounds are most extensively utilized for this purpose. However, the prominent success of aryl-nitroso chemistry is still immature because of the difficulty in the cleavage of N-aryl bond. Nitrosocarbonyl compounds with easily removable protecting groups (e.g. Boc and Cbz) on the other hand are more attractive reagents. They are highly reactive, easily manipulable, and readily available via the oxidation of N-protected hydroxylamines. However, the transient nature and incompatibility of the catalytic processes with their generation has incarcerated their use mostly in hetero-Diels–Alder and ene reactions. In this account we will summarize our efforts to utilize the nitrosocarbonyl compounds as a source of electrophilic oxygen and nitrogen in a variety of asymmetric carbon–heteroatom bond-forming reactions. The O- vs. N-selectivity can be tuned by switching reaction conditions. Thus, highly functionalized tertiary α-hydroxy and α-amino carboxylic acids, tertiary α-hydroxy phosphonic acid derivatives and β-amino alcohols were synthesized in high yields and high enantioselectivities using nitrosocarbonyl compounds as a source of electrophilic oxygen and nitrogen.

Iridium-catalyzed direct synthesis of tryptamine derivatives from indoles: exploiting n-protected β-amino alcohols as alkylating agents.

The selective C3-alkylation of indoles with N-protected ethanolamines involving the "borrowing hydrogen" strategy is described. This method provides convenient and sustainable access to several tryptamine derivatives.

Synthesis of the β3-adrenergic receptor agonist solabegron and analogous N-(2-ethylamino)-β-amino alcohols from O-acylated cyanohydrins - expanding the scope of minor enantiomer recycling.

A novel methodology to produce highly enantioenriched N-(2-ethylamino)-β-amino alcohols was developed. These compounds were obtained from O-(α-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the β3-adrenergic receptor agonist Solabegron.

ChemInform Abstract: Synthesis of 1,2‐Amino Alcohols via Catalytic C—H Amidation of sp3 Methyl C—H Bonds.

Herein a new synthetic route to 1,2-amino alcohols is presented by using C–H amidation of sp3 methyl C–H bonds as a key step. Readily available alcohols were employed as starting materials after converting them to removable ketoxime chelating groups. Iridium catalysts were found to be effective for the C–H amidation, and LAH reduction was then used to furnish β-amino alcohol products.

Synthesis of oxazolines from amides via palladium-catalyzed functionalization of unactivated C(sp(3))-H bond.

A complementary method that enables the expeditious synthesis of oxazolines from amides via Pd-catalyzed C(sp(3))-H functionalization has been described. Preliminary studies indicate that the reaction might go through a chlorination/nucleophilic cyclization sequence, and the high efficiency of this sequence is enhanced by the in situ cyclative capture of the chlorinated intermediate. The resulting oxazolines can be further converted into the corresponding β-amino alcohols without chromatography.

Catalytic metallodendrimers grafted on mesoporous polymethacrylate beads for the regioselective synthesis of β-amino alcohols under solvent-free conditions

Metallodendrimer-grafted mesoporous polymethyacrylate beads for the regioselective, solvent-free, efficient and scalable catalytic synthesis of β-amino alcohols at ambient temperature.

Continuous and convergent access to vicinyl amino alcohols.

Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.

Novel efficient fluorophores synthesized from citric acid

Citric acid was reacted with α,β-diamines, β-amino thiols and β-amino alcohols to produce fluorescent derivatives of 2-pyridone (QY up to ∼79%). The chemical structures of these compounds were confirmed by analyses of 1D, 2D NMR and ESI-MS data.

Mesoporous Zr-Beta zeolites prepared by a post-synthetic strategy as a robust Lewis acid catalyst for the ring-opening aminolysis of epoxides

Mesoporous Zr-Beta exhibits a remarkable catalytic activity and regio-selectivity to β-amino alcohols in epoxide aminolysis. Intra-crystalline mesopores greatly promote the reaction through enhanced mass transfer and suppress the catalytic deactivation.

ChemInform Abstract: Trapping of Carboxylic Oxonium Ylides with N‐Boc Imines for the Facile Synthesis of β‐Amino Alcohol Derivatives.

A Rh2(OAc)4-catalyzed three-component reaction of carboxylic acids, α-diazoacetophenones, and N-Boc imines has been developed to efficiently produce β-amino alcohol derivatives. Oxonium ylides generated from carboxylic acids and metal carbenoids have been intercepted by electrophiles for the first time.

Enantioselective addition of dialkylzinc to aromatic aldimines mediated by camphor-derived chiral β-amino alcohols.

The enantioselective addition of diethylzinc or dimethylzinc to N-(diphenylphosphinoyl)imines mediated by 1 or 2 could be achieved in high yields (70-97 %) and enantioselectivities (85-98 % ee). The catalytic loading of 1 or 2 a could be reduced to 10 mol % for methylation or ethylation of imines in high yields and enantioselectivities (79-96 %) when the reaction was conducted in the presence of 1.8 equiv of methanol. N-Monosubstituted amino alcohols induced higher enantioselectivity than their N,N-disubstituted congener in our catalytic system.

ChemInform Abstract: Efficient Asymmetric Addition of Diethylzinc to Aldehydes Using C2‐Novel Chiral Pyridine β‐Amino Alcohols as Chiral Ligands.

A series of novel C2-symmetric chiral pyridine β-amino alcohol ligands have been synthesized from 2,6-pyridine dicarboxaldehyde, m-phthalaldehyde and chiral β-amino alcohols through a two-step reaction. All their structures were characterized by 1H NMR, 13C NMR and IR. Their enantioselective induction behaviors were examined under different conditions such as the structure of the ligands, reaction temperature, solvent, reaction time and catalytic amount. The results show that the corresponding chiral secondary alcohols can be obtained with high yields and moderate to good enantiomeric excess. The best result, up to 89% ee, was obtained when the ligand 3c (2S,2′R)-2,2′-((pyridine-2,6-diylbis(methylene))bisazanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was used in toluene at room temperature. The ligand 3g (2S,2′R)-2,2′-((1,3-phenylenebis(methylene))bis(azanediyl))bis(4-methyl-1,1-diphenylpentan-1-ol) was prepared in which the pyridine ring was replaced by the benzene ring compared to 3c in order to illustrate the unique role of the N atom in the pyridine ring in the inductive reaction. The results indicate that the coordination of the N atom of the pyridine ring is essential in the asymmetric induction reaction. Copyright © 2014 John Wiley & Sons, Ltd.

Asymmetric autocatalysis of pyrimidyl alkanol and its application to the study on the origin of homochirality.

CONSPECTUS: Amplification of enantiomeric excess (ee) is a key feature for the chemical evolution of biological homochirality from the origin of chirality. We describe the amplification of ee in the asymmetric autocatalysis of 5-pyrimidyl alkanols in the reaction between diisopropylzinc (i-Pr2Zn) and pyrimidine-5-carbaldehydes. During the reaction, an extremely low ee (ca. 0.00005% ee) can be amplified to >99.5% ee, and therefore, the initial slightly major enantiomer is automultiplied by a factor of ca. 630000, while the initial slightly minor enantiomer is automultiplied by a factor of less than 1000. In addition, pyrimidyl alkanols with various substituents at the 2-position of the pyrimidine ring, 3-quinolyl alkanol, 5-carbamoyl-3-pyridyl alkanol, and large multifunctionalized pyrimidyl alkanols also act as highly efficient asymmetric autocatalysts in the addition of i-Pr2Zn to the corresponding aldehydes. The asymmetric autocatalysis of pyrimidyl alkanol can discriminate the chirality of various compounds. Chiral substances such as alcohols, amino acids, hydrocarbons, metal complexes, and heterogeneous chiral materials can act as chiral triggers for asymmetric autocatalysis to afford pyrimidyl alkanols with the corresponding absolute configuration of the initiator. This recognition ability of chiral compounds is extremely high, and chiral discrimination of a cryptochiral quaternary saturated hydrocarbon was established by applying asymmetric autocatalysis. By using the large amplification effect of the asymmetric autocatalysis, we can link various proposed origins of chirality with highly enantioenriched organic compounds in conjunction with asymmetric autocatalysis. Thus, a statistical fluctuation in ee of racemic compounds can be amplified to high ee by using asymmetric autocatalysis. Enantiomeric imbalance induced by irradiation of circularly polarized light can affect the enantioselectivity of asymmetric autocatalysis. The asymmetric autocatalysis was also triggered by the morphology of inorganic chiral crystals such as quartz, sodium chlorate, and cinnabar. Chiral organic crystals of achiral compounds also act as chiral initiators, and during the study of a crystal of cytosine, enantioselective chiral crystal phase transformation of the cytosine crystal was achieved by removal of the water of crystallization in an achiral monohydrate crystal. Enantioselective C-C bond formation was realized on the surfaces of achiral single crystals based on the oriented prochirality of achiral aldehydes. Furthermore, asymmetric autocatalysis of pyrimidyl alkanols is a highly sensitive reaction that can recognize and amplify the significantly small effect of a chiral compound arising solely from isotope substitution of hydrogen, carbon, and oxygen (D/H, (13)C/(12)C, and (18)O/(16)O). These examples show that asymmetric autocatalysis with an amplification of chirality is a powerful tool for correlating the origin of chirality with highly enantioenriched organic compounds. Asymmetric autocatalysis using two β-amino alcohols reveals a reversal of enantioselectivity in the addition of i-Pr2Zn to aldehyde and is one approach toward understanding the mechanism of asymmetric dialkylzinc addition, where heteroaggregates act as the catalytic species.