Vicinal Amino Research Articles

Enantioselective Intramolecular Oxidative Aminoacetoxylation from Aryl-Substituted Alkene via Chiral Triazole-oxazoline Palladium Complexes.

Here, we describe an enantioselective intramolecular oxidative aminoacetoxylation reaction using a palladium catalyst and an aryl-substituted internal alkene compound as the substrate under mild conditions in several hours. The triazole-oxazoline ligand was selected for the asymmetric catalyst. A range of enantioenriched pyrrolidine-derived vicinal amino acetate compounds were synthesized, showing yields from 47% to 84%, diastereomer ratios from 57:43 to 95:5, and enantiomer excesses from 67% to 92%.

Intramolecular Silanoxy-Michael Reactions with Pendant Nitroalkenes: Racemic and Enantioselective.

We present the first racemic and scalemic examples of di-tert-butyl silanoxy-Michael additions. Our operationally simple protocol is selective for nitro-olefins and simply involves stirring the substrate with an appropriate hydrogen-bond donor catalyst without any special precautions to exclude air or moisture. For each substrate examined, we have developed complementary protocols that optimize yield and enantioselectivity. Our reactions scale well, and the products are valuable intermediates for further transformations, including for the preparation of enantioenriched vicinal amino alcohols.

Correction to “Double Asymmetric Hydrogenation of α-Iminoketones: Facile Synthesis of Enantiopure Vicinal Amino Alcohols”

Correction to “Double Asymmetric Hydrogenation of α-Iminoketones: Facile Synthesis of Enantiopure Vicinal Amino Alcohols”

Copper-Catalyzed Three-Component Synthesis of Highly Substituted Morpholines.

Unprotected, highly substituted morpholines were obtained through a copper-catalyzed three-component reaction utilizing amino alcohols, aldehydes, and diazomalonates. The transformation was effective for diversely substituted aldehydes and for a broad range of readily available vicinal amino alcohols, including those derived from glycine, α-substituted, and α,α-disubstituted amino acids. Epimerization of morpholines using light-mediated stereochemical editing was demonstrated, and the unprotected morpholine products were readily elaborated through efficient transformations.

Synthesis of Vicinal anti-Amino Alcohols from N-tert-Butanesulfinyl Aldimines and Cyclopropanols.

The stereoselective synthesis of vicinal amino alcohols derivatives from 1-substituted cyclopropanols and chiral N-tert-butanesulfinyl imines is described. Cyclopropanols are easily prepared from carboxylic esters upon reaction with ethylmagnesium bromide in the presence of titanium tetraisopropoxide and undergo carbon-carbon bond cleavage by means of diethylzinc to produce, upon base deprotonation, enolized zinc homoenolates, which react with chiral sulfinyl imines in a highly regio- and stereoselective manner.

Synthesis of Chiral Vicinal Amino Alcohol Derivatives via Lewis Acid‐Catalyzed Asymmetric Ring Opening of Aziridines with Alcohols and Carboxylic Acids

AbstractUnder the catalysis of a Cu(I) or Ag(I) salt with a chiral diphosphine ligand, the enantioselective nucleophilic ring opening of racemic 2‐styrenylaziridines via kinetic resolution or dynamic kinetic asymmetric transformation (DyKAT) and of meso aziridines via desymmetrization with alcohols was realized. The reaction provided a range of chiral vicinal amino ether derivatives in 47%‐98% yields and with 50%–98% ee. The reaction could be extended to aliphatic carboxylic acids as nucleophiles. The synthetic utility was demonstrated in a four‐step formal synthesis of a diastereomer of the antirythmetic agent vernakalant.

New strategies for asymmetric photocatalysis: asymmetric organocatalytic/photoredox relay catalysis for efficient synthesis of polycyclic compounds containing vicinal amino alcohols

New strategies for asymmetric photocatalysis: asymmetric organocatalytic/photoredox relay catalysis for efficient synthesis of polycyclic compounds containing vicinal amino alcohols

Insight into the Stereoselective Synthesis of (1S)‐Nor(pseudo)ephedrine Analogues by a Two‐Steps Biocatalytic Process

AbstractNor(pseudo)ephedrines (N(P)Es), vicinal amino alcohols possessing sympathomimetic biological activity, constitute valuable intermediates and chiral building blocks for the organic synthesis of several active pharmaceutical ingredients (APIs). Due to the presence of two chiral centers, their conventional chemical asymmetric syntheses often involve long, multi‐step procedures, frequently with the aid of expensive and harmful metal catalysts, making it challenging to achieve high yields and optical purities overall. A two‐steps biocatalytic synthetic sequence for the preparation of (1S)‐N(P)E analogues was therefore designed and carried out, consisting of a benzoin‐type condensation catalysed by the (S)‐selective acetoin:dichlorophenolindophenol oxidoreductase (Ao:DCPIP OR) and a transamination mediated by either an (S)‐ or (R)‐selective amine transaminase (ATA). A multistep chemical synthesis of racemic N(P)Es was also optimised in order to obtain reference material for evaluating the performance of the biocatalysed reactions. The novel bi‐enzymatic synthesis provided the desired products with acceptable yields and good diastereo‐ and enantiomeric excesses, thereby paving the way for greener production of these important building blocks.

Cobalt-Catalyzed Efficient Asymmetric Hydrogenation of α-Primary Amino Ketones.

Based on an amino-group-assisted coordination strategy and a proton-shuttle-activated outer-sphere mode, the cobalt-catalyzed asymmetric hydrogenation of α-primary amino ketones has been developed, resulting in the efficient synthesis of chiral vicinal amino alcohols bearing functionalized aryl rings in high yields and enantioselectivities (up to 99% enantiomeric excess (ee)) within 0.5 h.

Room Temperature Construction of Vicinal Amino Alcohols via Electroreductive Cross-Coupling of N-Heteroarenes and Carbonyls

Despite the widespread applications of α-hydroxyalkyl cyclic amines, direct and diverse access to such a class of unique vicinal amino alcohols still remains, to date, a challenge. Here, through a strategy of electroreductive α-hydroxyalkylation of inactive N-heteroarenes with ketones or electron-rich arylaldehydes, we describe a room temperature approach for the direct construction of α-hydroxyalkyl cyclic amines, which features a broad substrate scope, operational simplicity, high chemoselectivity, and no need for pressurized H2 gas and transition metal catalysts. The zinc ion generated from anode oxidation plays a crucial role in the activation of both reactants by decreasing their reduction potentials. The strategy of electroreduction in combination with substrate activation by Lewis acids in this work is anticipated to develop more useful transformations.

Expeditious preparation of β-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis.

An economical route providing quick access to chiral β-amino alcohols bearing one β-sec-alkyl group was developed. This protocol starts with commercially available and cheap chiral sources such as derivatives of L-serine and L-threonine. A series of vicinal amino alcohols with high optical purity were prepared in good yields through 4 or 6 operationally simple steps. Two different strategies (three routes) were designed for the synthesis of amino alcohols bearing β-sec-alkyl groups with various steric hindrance.

Ring Opening of Aziridines by Pendant Silanols Allows for Preparations of (±)-Clavaminol H, (±)-Des-Acetyl-Clavaminol H, (±)-Dihydrosphingosine, and (±)-N-Hexanoyldihydrosphingosine.

We present a unique strategy for the synthesis of vicinal amino alcohols. Ring opening of aziridines with pendant silanols is compatible with a range of substrates. To engage productively in ring opening, the aziridine must be at least mildly activated, and a variety of such N-substituents are tolerated. The utility of this methodology is highlighted in facile preparations of the natural products (±)-Clavaminol H, (±)-dihydrosphingosine, and (±)-N-hexanoyldihydrosphingosine as well as a natural product analogue (±)-des-acetyl-Clavaminol H.

Synthesis, resolution, and absolute configuration determination of a vicinal amino alcohol with axial chirality. Application to the synthesis of new box and pybox ligands.

New racemic vicinal amino alcohol derivatives with 4‐benzylidenecyclohexane skeleton and axial chirality have been prepared. A preparatively easy and efficient protocol for resolution of the N‐benzoylamino alcohol is described. Using a 250 × 20 mm (L × ID) Chiralpak® IA column, and the appropriate mixture of n‐hexane/ethanol/chloroform as eluent, both enantiomers of N‐benzoylamino alcohol 3 are obtained with >99% enantiomeric excess (ee) by successive injections of a solution of the racemic sample in chloroform. The obtained axially chiral vicinal amino alcohol is used to synthesize structurally novel bisoxazoline ligands in high yields.

Regio‐, Diastereo‐, and Enantioselective Decarboxylative Hydroaminoalkylation of Dienol Ethers Enabled by Dual Palladium/Photoredox Catalysis

Intermolecular photocatalytic hydroaminoalkylation (HAA) of alkenes have emerged as a powerful method for the construction of alkyl amines. Although there are some studies aiming at stereoselective photocatalytic HAA reactions, the alkenes are limited to electrophilic alkenes. Herein, we report a highly regio-, diastereo-, and enantioselective HAA of electron-rich dienol ethers and α-amino radicals derived from α-amino acids using a unified photoredox and palladium catalytic system. This decarboxylative 1,2-Markovnikov addition enables the construction of vicinal amino tertiary ethers with high levels of regio- (up to >19 : 1 rr), diastereo- (up to >19 : 1 dr), and enantioselectivity control (up to >99 % ee). Mechanistic studies support a reversible hydropalladation as a key step.

Regio-, Diastereo-, and Enantioselective Decarboxylative Hydroaminoalkylation of Dienol Ethers Enabled by Dual Palladium/Photoredox Catalysis.

Intermolecular photocatalytic hydroaminoalkylation (HAA) of alkenes have emerged as a powerful method for the construction of alkyl amines. Although there are some studies aiming at stereoselective photocatalytic HAA reactions, the alkenes are limited to electrophilic alkenes. Herein, we report a highly regio‐, diastereo‐, and enantioselective HAA of electron‐rich dienol ethers and α‐amino radicals derived from α‐amino acids using a unified photoredox and palladium catalytic system. This decarboxylative 1,2‐Markovnikov addition enables the construction of vicinal amino tertiary ethers with high levels of regio‐ (up to >19 : 1 rr), diastereo‐ (up to >19 : 1 dr), and enantioselectivity control (up to >99 % ee). Mechanistic studies support a reversible hydropalladation as a key step.

Synthesis of carbo- and heterofused 5-amino-2H-1,2-thiazine 1,1-dioxides via the CSIC reaction strategy

Herein, we present a full account of our studies with respect to the synthesis of carbo- and heterofused β-enamino-δ-sultams annelated on face c (3,4-bond). This class of compounds was designed as isomeric counterpart of known pharmacological templates – fused δ-sultams annelated through a face e (5,6-bond) following the principles of bioisosteric replacement. The starting material for this synthesis is cyclic vicinal amino nitriles. In particular, several methods were developed for methanesulfonylation of 5- and 6-membered carbo- and heteroaromatic as well as sp3-enriched β-enamino nitriles depending on their chemical nature and reactivity. The obtained N-mono- or/and N,N-dimesylates were converted into the corresponding N-methylmethanesulfonamides, which were subjected to the CSIC (Carbanion-mediated Sulfonate (Sulfonamide) Intramolecular Cyclization) reaction protocols thus affording target carbo- and heterofused β-enamino-δ-sultams. Their synthetic utility was demonstrated by the reactions with carbo- and hetero electrophiles.

Liquid chromatography enantiomeric separation of chiral ethanolamine substituted compounds.

Eleven racemic ethanolamine derivatives were prepared, and their enantiomers were separated using liquid chromatography with various chiral columns. These derivatives included chiral vicinal amino alcohols, β-hydroxy ureas, β-hydroxy thioureas, and β-hydroxy guanidines, all of which are present in many active pharmaceutical ingredients. The screening study was performed with six chiral stationary phase containing columns, including four recently introduced superficially porous particles bonded with two macrocyclic glycopeptides, a cyclodextrin derivative and a cyclofructan derivative. The two remaining columns contained chiral stationary phases, based on either a cellulose derivative or derivatized amylose, both bonded to fully porous particles. The cyclodextrin and cellulose-based chiral stationary phases proved to be the most broadly effective selectors and were able to separate 8 and 7 of the 11 tested compounds, respectively. With respect to analyte structural features, marked differences in enantiorecognition were observed between compounds containing phenyl and cyclohexyl groups adjacent to the stereogenic center. Additionally, replacing a small electronegative oxygen atom by a larger and less electronegative sulfur atom induced a significant difference in chiral recognition by the cellulose derivative as well as by the vancomycin-based chiral selectors.

PREPARATION OF HYDROXYAMINO DERIVATIVES OF POLYCYCLIC BRIDGING HYDROCARBONS AND THEIR ANTIMICROBIAL PROPERTIES

The paper present results of studies of the two-stage preparation of C10-C12 tricyclic vicinal amino alcohols from partially hydrogenated condensation products of cyclopentadiene and cyclohexa-1,3-diene, by epoxidizing them with hydrogen peroxide in the presence of cobalt-containing polyoxomolybdate, followed by aminolysis of the oxidate with diethylamine, morpholine, or piperidine. The structure of the synthesized compounds was confirmed by IK and 1H NMR and spectroscopy. The research into the antimicrobial properties of N-substituted amino alcohols showed their effectiveness as antimicrobial additives to M-8 engine oil.

Iron-Catalyzed Enantioselective Radical Carboazidation and Diazidation of α,β-Unsaturated Carbonyl Compounds.

Azidation of alkenes is an efficient protocol to synthesize organic azides which are important structural motifs in organic synthesis. Enantioselective radical azidation, as a useful strategy to install a C-N3 bond, remains challenging due to the inherently instability and unique structure of radicals. Here, we disclose an efficient enantioselective radical carboazidation and diazidation of α,β-unsaturated ketones and amides catalyzed by chiral N,N'-dioxide/Fe(OTf)2 complexes. An array of substituted alkenes was transformed to the corresponding α-azido carbonyl derivatives in good to excellent enantioselectivities, benefiting the preparation of chiral α-amino ketones, vicinal amino alcohols, and vicinal diamines. Control experiments and mechanistic studies proved the radical pathway in the reaction process. The DFT calculations showed that the azido transferred to the radical intermediate via an intramolecular five-membered transition state with the internal nitrogen of the Fe-N3 species.

Switchable Mono‐ and Dipropargylation of Amino Alcohols: A Unique Property of the Iodide Anion in Controlling Ring‐Opening Alkynylation

AbstractThe application of multicomponent reactions has been recognized as the most versatile strategy to achieve molecular diversity in organic synthesis. The reaction pathway and selectivity control of multicomponent reactions are associated with the effectiveness, the economy, and cleanliness of the process. Herein, a copper‐catalyzed switchable process for the selective synthesis of N‐propargyl oxazolidines and N,N‐dipropargyl vicinal amino alcohols, by propargylation of amino alcohols, is disclosed. Mechanistic studies support a sequential process involving a copper‐catalyzed annulation/A3‐coupling of amino alcohol, and copper‐catalyzed ring‐opening alkynylation of the oxazolidine intermediate. Notably, the iodide anion would not affect the generation of oxazolidines, but it could shut down the cascade procedure of the alkynylation of these oxazolidines.