Chiral Amide Research Articles

Chiral Primary Amino Amide Alcohol Organocatalyst for the Asymmetric Michael Addition of 4-Hydroxycoumarin with α,β-Unsaturated Ketones

Chiral Primary Amino Amide Alcohol Organocatalyst for the Asymmetric Michael Addition of 4-Hydroxycoumarin with α,β-Unsaturated Ketones

Catalytic asymmetric endo-selective [3+2] cycloaddition reactions of Schiff bases of α-aminophosphonates with olefins using chiral metal amides.

Catalytic asymmetric endo-selective [3+2] cycloaddition reactions of Schiff bases of α-aminophosphonates with olefins are described. While the efficient asymmetric synthesis of several phosphonate analogues of proline derivatives is important in bioorganic chemistry, a direct catalytic method to prepare optically active endo [3+2] cycloadducts of α-aminophosphonates with olefins has never been developed. We found for the first time that catalyst systems prepared from Group 11 metal amides with the (R)-FeSulphos ligand were effective for the asymmetric endo-selective [3+2] cycloaddition to afford the desired proline phosphonate analogues in high yields with high endo- and high enantioselectivities.

A comprehensive examination of the self-disproportionation of enantiomers (SDE) of chiral amides via achiral, laboratory-routine, gravity-driven column chromatography

The behavior of a series of chiral amides during column chromatography using an achiral stationary phase revealed that a self-disproportionation of enantiomers (SDE) was always observed regardless of amide structure or chromatographic conditions.

Highly efficient stabilisation of meta-ethynylpyridine polymers with amide side chains in water by coordination of rare-earth metals.

An amphiphilic meta-ethynylpyridine polymer with chiral amide side chains was developed. The polymer was prepared by sequential Sonogashira reactions, and the product was soluble in polar and apolar solvents. The additive effects of metal salts on the polymer were examined in water and aqueous EtOH on the basis of UV-vis and CD spectra. The enhancement of the positive Cotton effect and hypochromism around 360 nm occurred by the addition of various metal salts, indicating the coordination of the cations to the amide side chains of the polymer to stabilise the helical structure. Among them, rare-earth metal salts, especially Sc(OTf)3 showed more efficient additive effects probably because of its strong coordination ability even in water. Positive cooperativity was observed for the coordination of Sc(OTf)3 to the polymer in aqueous EtOH.

Asymmetric Carbamoyl Anion Additions to Chiral N-Phosphonyl Imines via the GAP Chemistry Process and Stereoselectivity Enrichments.

Carbamoyl anions were found to smoothly react with chiral N-phosphonyl imines in toluene at −78 °C to r.t. using LiHMDS as the base. Group-assisted purification (GAP) has been utilized to give the pure amides without using column chromatography or recrystallization. The asymmetric reaction resulted in chiral N-phosphonyl amino amides with good to excellent yields (71–99%) and good crude diastereoselectivities (dr 84:16–95:5). In this GAP procedure, the crude solids are washed with diethyl ether to afford the pure products, as revealed by 1H NMR analysis; GAP washing consistently increases the diastereopurity of the products, resulting in excellent diastereoselectivities, often with final dr > 99:1. Interestingly, the diastereoenriched products can be obtained either in the ether solution or as the suspended solid, depending on the substrate.

Synthesis and Chiroptical Properties of Helical Polyallenes Bearing Chiral Amide Pendants

Two allene derivatives, l- and d-N-(1-(octylamino)-1-oxopropan-2-yl)-4-(propa-1,2-dien-1-yloxy)benzamide (l-1 and d-1), bearing chiral amide pendants were designed and synthesized. Living polymerizations of l-1 and d-1 with allylnickel complex as a catalyst afforded poly-l-1m and poly-d-1m with controlled molecular weights and narrow molecular weight distributions. These polymers were found to possess a stable helical conformation with a preferred handedness in aprotic solvents on the basis of their circular dichroism (CD) spectra and specific rotation as well as computer simulation. The helical conformation of the polymers was revealed to be stabilized by elongation of the repeating unit until the degree of the polymerization reaches 80. The slightly influence of temperature on the CD spectra of poly-l-1100 in CHCl3 indicated the helical conformation was quite stable at least in the range of 0–55 °C. Although poly-l-1100 showed similar CD spectra in different aprotic solvents, remarkable decrease was observed upon the addition of protic solvents such as methanol due to the weakened hydrogen bonding interactions between the adjacent repeating units. The poly-l-1100 behaves as a pH-responsive property; the helical structure of the main chain can be transformed to random coil by addition of trifluoroacetic acid to the THF solution which again switches back to helical conformation by neutralization with triethylamine. It was confirmed that the copolymerization of l-1 and d-1 obeyed the majority rule as supported by the nonlinear correlation between the enantiomeric excess of monomer 1 with the CD intensities of the generated copolymers. Atomic force microscope (AFM) and scanning electron microscope (SEM) studies revealed poly-l-1100 self-assembled into well-defined helical fibrils with distinct handedness.

Synthesis of enantiopure β-amino amides via a practical reductive amination of the corresponding β-keto amides

A convenient and efficient reductive amination for the preparation of chiral β-amino amides is developed utilizing microwave heating. A variety of chiral β-keto amides react with ammonium acetate and sodium cyanoborohydride to afford the desired functionalized amines in good yields. This improved procedure takes advantage of microwave heating to significantly accelerate the reaction and offers a convenient and effective method to access some interesting molecules containing primary amine functionalities.

Synthesis of chiral porous coordination polymer that shows structural transformation induced by guest molecules

We report the synthesis of a new chiral porous coordination polymer [Zn2{(R)-5,5′-BDA}2(dabco)]n·DMF (5,5′-BDA=2,2′-dihydroxy-1,1′-binaphthalene-5,5′-dicarboxylic acid, dabco=1,4-diazabicyclo[2.2.2]octane). This compound had one-dimensional (1D) channels which were occupied by DMF molecules. The hydroxyl groups on the surface of the channels acted as DMF interactive sites. Removal of DMF from the pores resulted in an amorphous solid. However, the apohost underwent a structural (amorphous-to-crystalline) transformation in response to the addition of guest molecules with amide groups. Interestingly, the observed degree of crystallinity was different for chiral amides, depending on the stereoisomer used.

ChemInform Abstract: Sulfinylimidates as Chiral Amide Equivalents for Irreversible, Asymmetric Aldol Reactions.

A highly selective N-sulfinylimidate aldolization has been developed under mildly basic conditions leading to diastereopure products of high synthetic potential. The innate reversibility of this aldolization was suppressed by the use of titanium as the Lewis acid. An application of this methodology via the synthesis of a potential neurotransmitter reuptake inhibitor is illustrated.

Mono- & ditrityl ethers, amines & amides – a family of multifaceted materials

In the course of our recent study on the possible transfer of chirality from the stereogenic center(s) to the inherently helical triphenylmethyl (Tr) substituent we have structurally characterized mono- and ditrityl derivatives of chiral alcohols, amines and amides. During the course of our investigations we have experienced various kinds of packing peculiarities caused by the presence of sterically demanding chiral molecules, e.g. quasi-isomorphism between a pair of enantiomerically pure and racemic crystals, microporosity, lattice inclusion, multiplication of asymmetric units and pseudosymmetry. The total absence of classical amide...amide hydrogen bonding and rare involvement of amine hydrogen in intermolecular hydrogen bonding opens the door to intra- and intermolecular interactions involving π-electron systems and points to the dispersion energy as the crystal structure determining factor, despite a common believe that the intermolecular hydrogen bonds are the crucial determinants of crystal packing.

Structures and Properties of Diastereomeric Multi-component Crystals

Multi-component crystals composed of two different chiral molecules have the potential to form diastereomers. In the present study a selection of chiral amides and acids was employed to form multi-component crystals. Since growing these multi-component crystals from solution failed, solvent assisted grinding was used. The resulting diastereomeric pairs, which are present as polycrystalline powders showed distinctly different powder diffraction patterns. In order to elucidate the crystal structures direct space global optimization structure solution methods were successfully used in several cases. A potential application of these diastereomeric multi-component crystals is the determination of the absolute configuration of one of the two components based on the known absolute configuration of the other.[1] In addition, Raman spectroscopy and DSC were employed to determine thermodynamic properties. In subsequent grinding experiments racemic conglomerates and racemates formed the starting material. These experiments demonstrated in several cases a relationship between melting point differences and preferential formation of only one diastereomer.

ChemInform Abstract: Chiral Amide Directed Assembly of a Diastereo‐ and Enantiopure Supramolecular Host and Its Application to Enantioselective Catalysis of Neutral Substrates.

The synthesis of a novel supramolecular tetrahedral assembly of K12Ga4L6 stoichiometry is reported. The newly designed chiral ligand exhibits high diastereoselective control during cluster formation, leading exclusively to a single diastereomer of the desired host. This new assembly also exhibits high stability toward oxidation or a low pH environment and is a more robust and efficient catalyst for asymmetric organic transformations of neutral substrates.

Development of chiral heteroleptic magnesium amides; asymmetric deprotonations mediated by six-membered metallocyclic amidomagnesium naphtholates

A series of enantioenriched six-membered metallocyclic amidomagnesium naphtholates were prepared and used to probe the structure–reactivity/selectivity relationships of heteroleptic magnesium base complexes within asymmetric deprotonation reactions. An effective complex was identified and applied within enantioselective enolisation processes, delivering good levels of enantioselectivity and also revealing key structural requirements for achieving such selectivity.

ChemInform Abstract: Chiral Amides via Copper‐Catalyzed Enantioselective Conjugate Addition.

AbstractA highly enantioselective one pot procedure for the synthesis of β‐substituted amides (IV) is developed starting from the corresponding α,β‐unsaturated esters (I).

Exploring the Reactivity of Chiral Glycidic Amides for Their Applications in Synthesis of Bioactive Compounds

AbstractA new class of chiral sulfonium salts, derived from L‐ and D‐methionine, has been designed and successfully employed in our laboratories for the diastereoselective synthesis of glycidic amides. The epoxy amides obtained were converted cleanly into 1,2‐difunctionalized products through oxirane ring‐opening reactions with different types of nucleophiles. The resulting ring‐opened products represent valuable and useful building blocks for the synthesis of different bioactive products. Thus, the expedient synthesis of clavaminol H as well as the synthesis of key precursors for other bioactive compounds, for example, polyketide‐derived natural products, have been achieved, demonstrating the synthetic efficiency and utility of this chemistry.

Organocatalyzed enantioselective Mannich reaction of pyrazoleamides with isatin-derived ketimines.

The first organocatalytic enantioselective Mannich reaction of pyrazoleamides with isatin-derived N-Boc ketimines has been developed to afford 2-oxindole-based chiral β-amino amides in good yields (84-97%) with excellent diastereo- and enantioselectivities (up to 99:1 dr and >99% ee).

Stereoselective total synthesis of almorexant

A highly stereoselective synthesis of almorexant has been achieved using (R)-tert-butanesulfinamide as a chiral source. The chiral tetrahydroisoquinoline core was constructed through allylation of chiral N-sulfinyl imine followed by ring closure of the secondary amide with a tethered halide. The chiral α-phenyl amide was introduced by means of SN2 substitution of (S)-methyl 2-phenyl-2-(tosyloxy)acetate with chiral tetrahydroisoquinoline.

Sulfinylimidates as Chiral Amide Equivalents for Irreversible, Asymmetric Aldol Reactions

A highly selective N-sulfinylimidate aldolization has been developed under mildly basic conditions leading to diastereopure products of high synthetic potential. The innate reversibility of this aldolization was suppressed by the use of titanium as the Lewis acid. An application of this methodology via the synthesis of a potential neurotransmitter reuptake inhibitor is illustrated.

Discovery of a Novel Class of Potent HCV NS4B Inhibitors: SAR Studies on Piperazinone Derivatives

HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C-3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p-fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development.

Magnetic CuFe2O4 nanoparticles: a retrievable catalyst for oxidative amidation of aldehydes with amine hydrochloride salts

The application of magnetic CuFe2O4 nanoparticles for the oxidative amidation of aldehydes with amine hydrochloride salts is described. A wide range of amides have been synthesized in good to excellent yields under mild conditions. Chiral amide also synthesized from its corresponding chiral amine salt with retention of the stereochemistry. In particular, the performance of the magnetic separation of the catalyst was very efficient and an alternative to time, solvent and energy-consuming separation procedures. The catalytic activity of the catalyst remains unaltered after five consecutive cycles, making it environmentally benign and widely applicable due to its efficiency, ease of handling and cost effectiveness.