Chiral Amide Research Articles

Purification and characterization of R-stereospecific amidase from Brevibacterium epidermidis ZJB-07021

A R-stereospecific amidase was purified from Brevibacterium epidermidis ZJB-07021 and characterized in detail. The amidase was purified to homogeneity by three chromatographic steps for up to 328.9-fold with specific activity of 31.9Umg⿿1. The enzyme was a homodimer with a molecular mass of 94kDa. It exhibited maximum activity at 40°C and pH 7.5. The enzyme was strongly inactivated by serine protease inhibitor PMSF. The values of Km and Vmax for racemic 2,2-dimethylcyclopropane carboxamide (DMCPCA) were 4.58mM and 35.03μmolmin⿿1mg⿿1 protein, respectively. The amidase showed a broad substrate spectrum toward aliphatic, aromatic and heterocyclic amides, but could hardly hydrolyze the bulky side-chain-containing amides. Furthermore, kinetic resolution of racemic DMCPCA by the amidase afforded S-DMCPCA in 46.3% yield and 99% ee with an average E-value of 67. These unique properties of the amidase imply that it is a promising biocatalyst for the production of chiral amides and carboxylic acids.

Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

Diastereoselective reaction of 1,3-dihydroxy calixarene with acylisocyanates: new and easy approach for preparing inherently chiral calyx[4]arenes

The facile method of generating internal chirality into the calixarene with two hydroxy groups at the lower rim via an attached chiral substituent has been proposed. The reaction with acylisocyanates, catalyzed by a small amount of triethylamine, proceeds forming predominantly one of the two possible calixarene carbamates. The best diastereomeric excess (60 %) has been achieved in the reaction of trichloroacyl isocyanates with 1,3-hydroxycalixarene substituted with the chiral phenylethyl amide moiety. The individual diastereomers of trichloroacetyl-carbamoylcalix[4]arenas were isolated by crystallization, and their absolute configuration was determined by X-ray diffraction study. The most favored conformations predicted for 1,3-dihydroxy calixarene structures by quantum chemical calculations possess very similar stability. However, the triethylamine molecule preferably connects to the one hydroxyl group of the two available ones, providing the most favorable adduct, which predominantly participates in the reaction with acylisocyanates. This gives rise to the observed diastereomeric excess. The subsequent treatment of the formed carbamoyl with n-propyl bromide in presence of NaH and hydrolysis of the product of alkylation easily provide a persistent internally chiral calixarene.

Highly stereoselective cyclopropanation of diazo Weinreb amides catalyzed by chiral Ru(ii)-Amm-Pheox complexes.

The first highly stereoselective cyclopropanation of diazo Weinreb amides with olefins was accomplished using chiral Ru(ii)-Amm-Pheox complex to give the corresponding chiral cyclopropyl Weinreb amides in high yields (up to 99%) with excellent diastereoselectivities (up to 99 : 1 dr) and enantioselectivities (up to 96% ee).

Bottom-Up Hierarchical Self-Assembly of Chiral Porphyrins through Coordination and Hydrogen Bonds.

A series of chiral synthetic compounds is reported that shows intricate but specific hierarchical assembly because of varying positions of coordination and hydrogen bonds. The evolution of the aggregates (followed by absorption spectroscopy and temperature-dependent circular dichroism studies in solution) reveal the influence of the proportion of stereogenic centers in the side groups connected to the chromophore ring in their optical activity and the important role of pyridyl groups in the self-assembly of these chiral macrocycles. The optical activity spans 2 orders of magnitude depending on composition and constitution. Two of the aggregates show very high optical activity even though the isolated chromophores barely give a circular dichroism signal. Molecular modeling of the aggregates, starting from the pyridine-zinc(II) porphyrin interaction and working up, and calculation of the circular dichroism signal confirm the origin of this optical activity as the chiral supramolecular organization of the molecules. The aggregates show a broad absorption range, between approximately 390 and 475 nm for the transitions associated with the Soret region alone, that spans wavelengths far more than the isolated chromophore. The supramolecular assemblies of the metalloporphyrins in solution were deposited onto highly oriented pyrolitic graphite in order to study their hierarchy in assembly by atomic force microscopy. Zero and one-dimensional aggregates were observed, and a clear dependence on deposition temperature was shown, indicating that the hierarchical assembly took place largely in solution. Moreover, scanning electron microscopy images of porphyrins and metalloporphyrins precipitated under out-of-equilibrium conditions showed the dependence of the number and position of chiral amide groups in the formation of a fibrillar nanomaterial. The combination of coordination and hydrogen bonding in the complicated assembly of these molecules-where there is a clear hierarchy for zinc(II)-pyridyl interaction followed by hydrogen-bonding between amide groups, and then van der Waals interactions-paves the way for the preparation of molecular materials with multiple chromophore environments.

ChemInform Abstract: A Single Lipase‐Catalyzed One‐Pot Protocol Combining Aminolysis Resolution and Aza‐Michael Addition: An Easy and Efficient Way to Synthesise β‐Amino Acid Esters.

AbstractEnantiopure β‐amino acid esters and chiral amides are simultaneously prepared by the title protocol.

A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters.

Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.

A Catalyst Designed for the Enantioselective Construction of Methyl‐ and Alkyl‐Substituted Tertiary Stereocenters

AbstractTertiary methyl‐substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama–Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three‐parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α‐methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4–C13 segment of (−)‐bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.

ChemInform Abstract: Pd(II)‐Catalyzed Intermolecular Enantioselective Hydroamination of Styrenes.

A Pd-catalyzed intermolecular asymmetric hydroamination of styrenes was developed to give various chiral benzyl amides exclusively, in which the oxidation-stable pyridine-oxazoline was used as the chiral ligand to provide moderate to good enantioselectivities.

Efficient and practical synthesis of modular chiral β-organochalcogeno amines, ArYCH2CH(R)NH2, and single crystal structures of [formula omitted] and [formula omitted

Modular chiral β-organochalcogeno amines, ArYCH2CH(R)NH2 (4a-4g) where R = Me, Bz, Ph; and ArY = PhS, BzSe and 4-MeOC6H4Te respectively have been synthesized and characterized. Compounds 4a-4g were synthesized (Method II) from chiral aminoalkyl β-methanesulfonate hydrochlorides, MsOCH2CH(R)NH3+·Cl− (2a-2c) through nucleophilic displacement of MsO− with organochalcogenolate (ArY−). In another attempt (Method I) chiral β-organotelluro amines (4a-4c) were prepared by deprotection of chiral N-boc β-organotelluro amides, 4-MeOC6H4TeCH2CH(R)NH-Boc (3a-3c), which in turn were made from chiral N-boc β-methanesulfonate amides (1a-1c) and ArTeNa. 1H, 13C{1H} NMR and FT-IR spectra of all the compounds (3a-3c and 4a–4g) were characteristic. The composition of 3a-3c was determined by elemental analysis. The [α]DT values of 3b-3c and 4a-4g were determined. The single crystal structures of (S)-2b and (R)-2c were determined by X-Ray diffraction studies. Both (S)-2b and (R)-2c were crystallized in orthorhombic system and the Flack parameter x was found −0.08(12) and 0.00(2) respectively. The crystal of (S)-2b contain two asymmetric units with gauche (A) and staggered (B) conformations. There are NH⋯Cl−, NH⋯O and CH⋯O intra and intermolecular secondary interactions in (S)-2b and (R)-2c resulting in supramolecular structures.

Palladium-Catalyzed Synthesis of Planar Chiral Amides

Key words palladium - bisphosphine ligands - planar chiral compounds - cyclic amides

A Single Lipase‐Catalysed One‐Pot Protocol Combining Aminolysis Resolution and Aza‐Michael Addition: An Easy and Efficient Way to Synthesise β‐Amino Acid Esters

AbstractA novel one‐pot protocol combining aza‐Michael addition and aminolysis resolution was developed to obtain chiral β‐amino acid esters with lipase B from Candida antarctica (CAL‐B) as the only catalyst. This method is conducted under mild reaction conditions and is very easy to handle. After a series of detailed optimization studies, ten racemic aromatic or aliphatic amines were subjected to this one‐pot procedure, and twelve chiral β‐amino acid esters and ten chiral amides were successfully synthesised with excellent ee values in theoretical yields. Scaled‐up procedures also worked without apparent reduction in reaction rate or enantioselectivity, which makes this method suitable for large‐scale production of chiral β‐amino acid esters.

Chirality- and sequence-selective successive self-sorting via specific homo- and complementary-duplex formations.

Self-recognition and self-discrimination within complex mixtures are of fundamental importance in biological systems, which entirely rely on the preprogrammed monomer sequences and homochirality of biological macromolecules. Here we report artificial chirality- and sequence-selective successive self-sorting of chiral dimeric strands bearing carboxylic acid or amidine groups joined by chiral amide linkers with different sequences through homo- and complementary-duplex formations. A mixture of carboxylic acid dimers linked by racemic-1,2-cyclohexane bis-amides with different amide sequences (NHCO or CONH) self-associate to form homoduplexes in a completely sequence-selective way, the structures of which are different from each other depending on the linker amide sequences. The further addition of an enantiopure amide-linked amidine dimer to a mixture of the racemic carboxylic acid dimers resulted in the formation of a single optically pure complementary duplex with a 100% diastereoselectivity and complete sequence specificity stabilized by the amidinium–carboxylate salt bridges, leading to the perfect chirality- and sequence-selective duplex formation.

Palladium-Catalyzed Asymmetric Arylation of C(sp(3))-H Bonds of Aliphatic Amides: Controlling Enantioselectivity Using Chiral Phosphoric Amides/Acids.

Enantioselective arylation of secondary β-C(sp(3))-H bonds of 8-aminoquinoline amides was realized with a palladium catalyst. Chiral phosphoric amides and acids were used for the first time to control the stereoselectivity at the C-H bond cleavage step in the C-H activation reactions.

ChemInform Abstract: Development of Chiral Heteroleptic Magnesium Amides; Asymmetric Deprotonations Mediated by Six‐Membered Metallocyclic Amidomagnesium Naphtholates.

AbstractA series of chiral six‐membered metallocyclic amidomagnesium naphthalates is prepared and used in the asymmetric deprotonation of prochiral ketones.

ChemInform Abstract: Exploring the Reactivity of Chiral Glycidic Amides for Their Applications in Synthesis of Bioactive Compounds.

AbstractThe opening of the oxirane ring in chiral glycidyl amides with a variety of nucleophiles is studied.

Enantiospecific synthesis of (S)-(−)-8-oxoxylopinine

The enantiospecific synthesis of (S)-(−)-8-oxoxylopinine 1 was performed using a lateral metallation strategy, in which (S)-alaninol or (S)-phenylalaninol was applied as chiral auxiliary and building block. (4S)-3-(4,5-Dimethoxy-2-methylbenzoyl)-2,2,4-trimethyl-1,3-oxazolidine 12 was synthesized starting from veratraldehyde 13. The addition reaction of benzylic anion generated in situ from chiral amide 12 into 6,7,-dimethoxy-3,4-dihydroisoquinoline 7a proceeded with simultaneous cyclization leading to the protoberberine alkaloid with high enantioselectivity.

Direct enantioselective conjugate addition of carboxylic acids with chiral lithium amides as traceless auxiliaries.

Michael addition is a premier synthetic method for carbon–carbon and carbon–heteroatom bond formation. Using chiral dilithium amides as traceless auxiliaries, we report the direct enantioselective Michael addition of carboxylic acids. A free carboxyl group in the product provides versatility for further functionalization, and the chiral reagent can be readily recovered by extraction with aqueous acid. The method has been applied in the enantioselective total synthesis of the purported structure of pulveraven B.

Chiral alkaline earth metal complexes with M–Se direct bond (M = Mg, Ca, Sr, Ba): syntheses, structures and ε-caprolactone polymerisation

Synthesis and structural details of enantiomerically pure alkaline earth metal complexes (Mg, Ca, Sr, Ba) supported by chiral phosphinoselenoic amides are reported.

Multi-stimuli-responsive chiral organogels based on peptide derivatives.

A series of chiral aryl amide compounds bearing peptide pendants have been investigated as low molecular weight gelators. A mechanistic study reveals that complementary hydrogen bonding from peptide pendants is the main driving force for the formation of organogels. This new class of organogels can exhibit multi-stimuli-responsive behavior upon applying (1) thermal, (2) pH, (3) enantiomeric purity, and (4) fluoride anion stimuli. Enantiomeric purity as a new external stimulus displays sensitive stimuli-responsiveness; only 0.02 equiv. of the enantiomer can completely disassemble the gel aggregate. They will serve as excellent smart materials with potential applications in chiral sensors, recognition, and separation.