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Organic & Biomolecular Chemistry Jan 2016Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building blocks. However, N,N-dialkyl aziridinium ions are relatively...
Aziridinium ions are useful reactive intermediates for the synthesis of enantiomerically enriched building blocks. However, N,N-dialkyl aziridinium ions are relatively underutilized in the synthesis of optically active molecules as compared to other three-membered ring cogeners, aziridines and epoxides. The characterization of both optically active aziridinium ions and secondary β-halo amines as the precursor molecules of aziridinium ions has been scarcely reported and is often unclear. In this paper, we report for the first time the preparation and experimental and theoretical characterization of optically active aziridinium ions and secondary β-halo amines. Optically active secondary N,N-substituted β-halo amines were efficiently synthesized from N,N-substituted alaninol via formation and ring opening at the more hindered carbon of aziridinium ions by halides. Optically active β-halo amines and aziridinium ions were characterized by NMR and computational analyses. The structure of an optically active β-chloro amine was confirmed via X-ray crystallographic analysis. The aziridinium ions derived from N,N-dibenzyl alaniol remained stable only for several hours, which was long enough for analyses of NMR and optical activity. The stereospecific ring opening of aziridinium ions by halides was computationally studied using DFT and highly-accurate DLPNO-CCSD(T) methods. The highly regioselective and stereoselective ring opening of aziridinium ions was applied for efficient one-pot conversion of β-alaninols to enantiomerically enriched β-amino alcohols, β-amino nitriles, and vicinal diamine derivatives.
Topics: Amino Alcohols; Aziridines; Crystallography, X-Ray; Diamines; Halogenation; Ions; Models, Molecular; Molecular Structure; Nitriles; Quantum Theory; Stereoisomerism
PubMed: 26608561
DOI: 10.1039/c5ob01692d -
Journal of the American Chemical Society Apr 2021A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable β-amino alcohols. This strategy enables chemoselective conversion...
A cross-selective aza-pinacol coupling of aldehydes and imines has been developed to afford valuable β-amino alcohols. This strategy enables chemoselective conversion of aliphatic aldehydes to ketyl radicals, in the presence of more easily reduced imines and other functional groups. Upon carbonyl-specific activation by AcI, a photoinitiated Mn catalyst selectively reduces the resulting α-oxy iodide by an atom transfer mechanism. The ensuing ketyl radical selectively couples to imines, precluding homodimerization by a classical reductive approach. In this first example of reductive, ketyl coupling by atom transfer catalysis, Zn serves as a terminal reductant to facilitate Mn catalyst turnover. This new strategy also enables ketyl radical couplings to alkenes, alkynes, aldehydes, propellanes, and chiral imines.
Topics: Aldehydes; Amino Alcohols; Aza Compounds; Catalysis; Free Radicals; Imines; Magnesium; Oligopeptides; Oxidation-Reduction; Stereoisomerism
PubMed: 33830738
DOI: 10.1021/jacs.1c00886 -
International Journal of Molecular... Oct 2021Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were stereoselectively synthesised. The acid-catalysed hydrolysis and rearrangement of...
Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were stereoselectively synthesised. The acid-catalysed hydrolysis and rearrangement of natural stevioside gave isosteviol, which was transformed to the key intermediate methyl ester. In the next step, Mannich condensation of diterpenoid ketone, paraformaldehyde, and secondary amines resulted in the formation of 1,3-aminoketones with different stereoselectivities. During the Mannich condensation with dibenzylamine, an interesting -benzyl → -methyl substituent exchange was observed. Reduction of 1,3-aminoketones produced diastereoisomeric 1,3-aminoalcohols. Alternatively, aminoalcohols were obtained via stereoselective hydroxy-formylation, followed by oxime preparation, reduction, and finally, reductive alkylation of the obtained primary aminoalcohols. An alternative 1,3-aminoalcohol library was prepared by reductive amination of the intermediate 3-hydroxyaldehyde obtained from isosteviol in two-step synthesis. Cytotoxic activity of compounds against human tumour cell lines (A2780, SiHa, HeLa, MCF-7 and MDA-MB-231) was investigated. In our preliminary study, the 1,3-aminoalcohol function and -benzyl substitution seemed to be essential for the reliable antiproliferative activity. To extend their application, a diterpenoid condensed with 2-phenylimino-1,3-thiazine and -1,3-oxazine was also attempted to prepare, but only formation of thioether intermediate was observed.
Topics: Amino Alcohols; Antineoplastic Agents; Apoptosis; Catalysis; Cell Proliferation; Diterpenes, Kaurane; Humans; Neoplasms; Stereoisomerism; Tumor Cells, Cultured
PubMed: 34681892
DOI: 10.3390/ijms222011232 -
Journal of Biochemistry Jul 1964
Topics: Adenine Nucleotides; Amino Alcohols; Aspergillus; Chloromercuribenzoates; Choline; Chromatography; Enzyme Inhibitors; Mercaptoethanol; Nucleotidyltransferases; Phosphotransferases; Research; Sulfates; Sulfotransferases; Sulfur Isotopes; Transferases
PubMed: 14202240
DOI: 10.1093/oxfordjournals.jbchem.a127963 -
Organic Letters Jun 2010An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by...
An efficient synthetic pathway to the possible stereoisomers of skeletally diverse heterocyclic small molecules is presented. The change in shape brought about by different intramolecular cyclizations of diastereoisomeric amino propargylic alcohols is quantified using principal moment-of-inertia (PMI) shape analysis.
Topics: Amino Alcohols; Cyclization; Heterocyclic Compounds, 4 or More Rings; Molecular Structure; Stereoisomerism
PubMed: 20481457
DOI: 10.1021/ol100914b -
Angewandte Chemie (International Ed. in... Nov 2022Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. However, high substrate specificity can hinder the scope of...
Biocatalytic cascades are uniquely powerful for the efficient, asymmetric synthesis of bioactive compounds. However, high substrate specificity can hinder the scope of biocatalytic cascades because the constituent enzymes may have non-complementary activity. In this study, we implemented a substrate multiplexed screening (SUMS) based directed evolution approach to improve the substrate scope overlap between a transaldolase (ObiH) and a decarboxylase for the production of chiral 1,2-amino alcohols. To generate a promiscuous cascade, we engineered a tryptophan decarboxylase to act efficiently on β-OH amino acids while avoiding activity on l-threonine, which is needed for ObiH activity. We leveraged this exquisite selectivity with matched substrate scope to produce a variety of enantiopure 1,2-amino alcohols in a one-pot cascade from aldehydes or styrene oxides. This demonstration shows how SUMS can be used to guide the development of promiscuous, C-C bond forming cascades.
Topics: Amino Alcohols; Aldehydes; Amines; Biocatalysis; Substrate Specificity
PubMed: 36136093
DOI: 10.1002/anie.202212637 -
Journal of the American Chemical Society Dec 2018The functionalization of unactivated C(sp)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present...
The functionalization of unactivated C(sp)-H bonds of aliphatic amines catalyzed by transition-metal complexes is important because amine-based functionality is present in a majority of biologically active molecules and commercial pharmaceuticals. However, such reactions are underdeveloped and challenging to achieve in general because the basicity and reducing properties of alkylamines tends to interfere with potential reagents and catalysts. The functionalization of C-H bonds β to the nitrogen of aliphatic amines to form prevalent 1,2-amino functionalized structures is particularly challenging because the C-H bond β to nitrogen is stronger than the C-H bond α to nitrogen, and the nitrogen in the amine or its derivatives usually directs a catalyst to react at more distal γ- and δ-C-H bonds to form 5- or 6-membered metallacyclic intermediate. The enantioselective functionalization of a C-H bond at any position in amines also has been vexing and is currently limited to reactions of specific, sterically hindered, cyclic structures. We report iridium-catalyzed, β-selective silylations of unactivated C(sp)-H bonds of aliphatic amines to form silapyrrolidines that are both silicon-containing analogs of common saturated nitrogen heterocycles and precursors to 1,2-amino alcohols by Tamao-Fleming oxidation. These silylations of amines are accomplished by introducing a simple methylene linker between the heteroatom and silicon that has not been used previously for the silylation of C-H bonds. The reactions occur with high enantioselectivity when catalyzed by complexes of new chiral, pyridyl imidazoline ligands, and the rates of reactions with catalysts of these highly basic ligands are particularly fast, occuring in some cases at or even below room temperature.
Topics: Amines; Amino Alcohols; Catalysis; Coordination Complexes; Iridium; Organosilicon Compounds; Oxidation-Reduction; Pyrrolidines; Stereoisomerism
PubMed: 30354144
DOI: 10.1021/jacs.8b10428 -
Nature Apr 2016The chirality, or 'handedness', of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and...
The chirality, or 'handedness', of a biologically active molecule can alter its physiological properties. Thus it is routine procedure in the drug discovery and development process to prepare and fully characterize all possible stereoisomers of a drug candidate for biological evaluation. Despite many advances in asymmetric synthesis, developing general and practical strategies for obtaining all possible stereoisomers of an organic compound that has multiple contiguous stereocentres remains a challenge. Here, we report a stereodivergent copper-based approach for the expeditious construction of amino alcohols with high levels of chemo-, regio-, diastereo- and enantioselectivity. Specifically, we synthesized these amino-alcohol products using sequential, copper-hydride-catalysed hydrosilylation and hydroamination of readily available enals and enones. This strategy provides a route to all possible stereoisomers of the amino-alcohol products, which contain up to three contiguous stereocentres. We leveraged catalyst control and stereospecificity simultaneously to attain exceptional control of the product stereochemistry. Beyond the immediate utility of this protocol, our strategy could inspire the development of methods that provide complete sets of stereoisomers for other valuable synthetic targets.
Topics: Amination; Amino Alcohols; Catalysis; Chemistry Techniques, Synthetic; Copper; Molecular Structure; Stereoisomerism
PubMed: 27018656
DOI: 10.1038/nature17191 -
Organic Letters Feb 2020Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with -cyanomethylbenzaldehydes. These amine α-C-H bond functionalization reactions are...
Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox-neutral annulations with -cyanomethylbenzaldehydes. These amine α-C-H bond functionalization reactions are promoted by acetic acid. The resulting β-aminonitriles can be converted to the corresponding β-aminoalcohols in diastereoselective fashion.
Topics: Acetic Acid; Amino Alcohols; Benzaldehydes; Molecular Structure; Oxidation-Reduction; Stereoisomerism; Tetrahydroisoquinolines
PubMed: 31984752
DOI: 10.1021/acs.orglett.9b04506 -
Molecules (Basel, Switzerland) May 2011In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)-catalyzed mixed double-Michael reactions of β-amino alcohols with...
In this study, we prepared oxizolidines through 1,3-bis(diphenylphosphino)-propane (DPPP)-catalyzed mixed double-Michael reactions of β-amino alcohols with electron-deficient acetylenes. These reactions are very suitable for the diversity-oriented parallel syntheses of oxizolidines because: (i) they are performed under mild metal-free conditions and (ii) the products are isolated without complicated work-up. To demonstrate the applicability of mixed double-Michael reactions for the preparation of five-membered-ring heterocycles, we prepared 60 distinct oxazolidines from five β-amino alcohols and 12 electron-deficient acetylenes. We synthesized 36 of these 60 oxazolidines in enantiomerically pure form from proteinogenic amino acid-derived β-amino alcohols.
Topics: Alkynes; Amino Alcohols; Catalysis; Molecular Structure; Oxazoles; Phosphines; Propane
PubMed: 21546881
DOI: 10.3390/molecules16053802