Zn-Catalyzed Enantioselective Allylation and Allenylation of Isatins by virtue of Proline-derived Chiral Ligand

An asymmetric allylation and allenylation of isatins with facile organoboron reagents was developed under the catalysis of Lewis acid. A series of optically pure 3-allyl-3-hydroxyoxindoles and 3-allenyl-3-hydroxyoxindoles can be obtained...

Access to Enantioenriched Molecules with Diverse Fluorinated Tetrasubstituted Stereocenters Using Hydroxy as Kinetic Resolution Auxiliary Group

Developing a general method affording optically pure fully-substituted carbon molecules bearing various fluorinated groups is highly important but very challenging. Here we show that using secondary OH as the kinetic...

Identification, Characterization, and In Silico Analysis of New Imine Reductases From Native Streptomyces Genomes

The development of biocatalytic tools for the synthesis of optically pure amines has been the focus of abundant research in recent years. Among other enzymes, imine reductases have attracted much attention associated with the possibility of attaining chiral secondary amines. Furthermore, the reductive aminase activity associated with some of these enzymes has facilitated the production of optically pure amines from a prochiral ketone, a transformation that opens doors to an incredible array of products. In this work, the genomes from native Streptomyces strains isolated in our lab have been explored on the search for novel imine reductases. Application of different structural criteria and sequence motif filters allowed the identification of two novel enzymes, Ss-IRED_S and Ss-IRED_R. While the former presented outstanding activity towards bulky cyclic imine substrates, the latter presented reductive aminase activity with the assayed ketones. A bioinformatic analysis based on modeling and docking studies was performed in order to explain the differences in enzyme activity, searching for additional criteria that could be used to analyze enzyme candidates in silico, providing additional tools for enzyme selection for a particular application. Our findings suggest that imine reductase activity could be predicted by this analysis, overall accounting for the number of docking positions that meet the catalytic requirements.

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

<p>(-)-Zampanolide (1), a natural product isolated from a marine sponge, is a microtubule-stabilizing agent that exhibits activity in the nanomolar range against various cancer cells, including in P-gp pump overexpressing cells. This attribute makes (-)-zampanolide an interesting target for further investigation. In this work, a new method for a modular and convergent total synthesis of optically pure zampanolide was investigated, which would also allow the generation of “zampanalogs” following the same basic strategy. Their biological activity may then be assessed to allow the elucidation of structure-activity relationships of (-)-zampanolide and its analogs in tubulin binding. The synthetic plan consisted of the modular combination of four major fragments, which would be connected in the late stages of the synthesis and could therefore be easily exchanged to allow the generation of analogs. The C15-C16 bond would be connected via an alkynylation reaction, and a subsequent reductive methylation would install the trisubstituted alkene. The connections at C1 and C3 could be achieved through a Bestmann ylid linchpin reaction, while the macrolactonization would be completed using a ring-closing metathesis to form the C8-C9 alkene. The side chain could be attached at C20 using one of the established aza-aldol methods. The fragments necessary for the formation of the macrocycle were synthesized successfully. The purification strategy throughout the synthetic route was rationalized and provides an improvement with respect to yield and time compared to work previously done in this research group. Alongside these fragments, modified fragments that were originally intended to serve as model systems were synthesized, which could also be used as building blocks in the synthesis of “zampanalogs”. Several methods for a stereoselective alkynylation at C15 were tested. These led to only meager successes, so an approach using a non-stereoselective alkynylation, followed by oxidation and a stereoselective CBS-reduction, was chosen. For the installation of the trisubstituted alkene a reductive methylation with vitride was tested, but this only led to the reduction of the alkyne without methylation. This product may be employed for the synthesis of C17-desmethyl analogs. The reductive methylation at C16-C17 was ultimately achieved using the Gilman reagent in a similar manner to the installation of the C5 methyl group in the C3-C8 fragment. A linchpin strategy with the Bestmann ylid simultaneously formed the connectivity at C1 and C3. This process was successfully performed on multiple substrates arising from the model systems used in the alkynylation and reductive methylation reactions, yielding precursors to the ring-closing metathesis and potentially enabling the synthesis of various analogs. The ring-closing metathesis proved to be difficult in analogs lacking the C17 methyl group and cis-tetrahydropyran ring, and due to this tendency further investigations are necessary. Once the macrocycle has been closed, a global deprotection and oxidation of hydroxy groups is necessary to allow for the installation of the sidechain.</p>

Chasing "Zampanalogs": Advancing the Synthesis of the Zampanolide Macrocycle

<p>(-)-Zampanolide (1), a natural product isolated from a marine sponge, is a microtubule-stabilizing agent that exhibits activity in the nanomolar range against various cancer cells, including in P-gp pump overexpressing cells. This attribute makes (-)-zampanolide an interesting target for further investigation. In this work, a new method for a modular and convergent total synthesis of optically pure zampanolide was investigated, which would also allow the generation of “zampanalogs” following the same basic strategy. Their biological activity may then be assessed to allow the elucidation of structure-activity relationships of (-)-zampanolide and its analogs in tubulin binding. The synthetic plan consisted of the modular combination of four major fragments, which would be connected in the late stages of the synthesis and could therefore be easily exchanged to allow the generation of analogs. The C15-C16 bond would be connected via an alkynylation reaction, and a subsequent reductive methylation would install the trisubstituted alkene. The connections at C1 and C3 could be achieved through a Bestmann ylid linchpin reaction, while the macrolactonization would be completed using a ring-closing metathesis to form the C8-C9 alkene. The side chain could be attached at C20 using one of the established aza-aldol methods. The fragments necessary for the formation of the macrocycle were synthesized successfully. The purification strategy throughout the synthetic route was rationalized and provides an improvement with respect to yield and time compared to work previously done in this research group. Alongside these fragments, modified fragments that were originally intended to serve as model systems were synthesized, which could also be used as building blocks in the synthesis of “zampanalogs”. Several methods for a stereoselective alkynylation at C15 were tested. These led to only meager successes, so an approach using a non-stereoselective alkynylation, followed by oxidation and a stereoselective CBS-reduction, was chosen. For the installation of the trisubstituted alkene a reductive methylation with vitride was tested, but this only led to the reduction of the alkyne without methylation. This product may be employed for the synthesis of C17-desmethyl analogs. The reductive methylation at C16-C17 was ultimately achieved using the Gilman reagent in a similar manner to the installation of the C5 methyl group in the C3-C8 fragment. A linchpin strategy with the Bestmann ylid simultaneously formed the connectivity at C1 and C3. This process was successfully performed on multiple substrates arising from the model systems used in the alkynylation and reductive methylation reactions, yielding precursors to the ring-closing metathesis and potentially enabling the synthesis of various analogs. The ring-closing metathesis proved to be difficult in analogs lacking the C17 methyl group and cis-tetrahydropyran ring, and due to this tendency further investigations are necessary. Once the macrocycle has been closed, a global deprotection and oxidation of hydroxy groups is necessary to allow for the installation of the sidechain.</p>

Water-Soluble Ruthenium (II) Complex Derived From Optically Pure Limonene and Its Microencapsulation Are Efficient Tools Against Bacterial Food Pathogen Biofilms: Escherichia coli, Staphylococcus aureus, Enteroccocus faecalis, and Listeria monocytogenes

Bioactive aminooxime ligands based on optically pure (R)-limonene have been synthesized in two steps. Their ruthenium (II) cationic water-soluble complex was prepared by a reaction between dichloro (para-cymene) ruthenium (II) dimers and aminooxime ligands in a 1:2 molar ratio. Antibacterial and antibiofilm activities of the synthetized complex were assessed against Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Enterococcus faecalis. The results revealed that the ruthenium (II) complex has higher antibacterial and antibiofilm activities in comparison with free ligands or the enantiopure (R)-limonene. Moreover, microencapsulation of this complex reduced its cytotoxicity and improved their minimum inhibitory concentration and antibiofilm activity toward the considered bacteria. The ruthenium (II) complex targets the bacterial cell membrane, which leads to rapid leakage of intracellular potassium. Our study suggests that the developed ruthenium (II) complexes could be useful as an alternative to conventional disinfectants.

Biomimetic enantioselective synthesis of β,β-difluoro-α-amino acid derivatives

Although utilization of fluorine compounds has a long history, synthesis of chiral fluorinated amino acid derivatives with structural diversity and high stereoselectivity is still very appealing and challenging. Here, we report a biomimetic study of enantioselective [1,3]-proton shift of β,β-difluoro-α-imine amides catalyzed by chiral quinine derivatives. A wide range of corresponding β,β-difluoro-α-amino amides were achieved in good yields with high enantioselectivities. The optically pure β,β-difluoro-α-amino acid derivatives were further obtained, which have high application values in the synthesis of fluoro peptides, fluoro amino alcohols and other valuable fluorine-containing molecules.

Mini Review: Advances in 2-Haloacid Dehalogenases

The 2-haloacid dehalogenases (EC 3.8.1.X) are industrially important enzymes that catalyze the cleavage of carbon–halogen bonds in 2-haloalkanoic acids, releasing halogen ions and producing corresponding 2-hydroxyl acids. These enzymes are of particular interest in environmental remediation and environmentally friendly synthesis of optically pure chiral compounds due to their ability to degrade a wide range of halogenated compounds with astonishing efficiency for enantiomer resolution. The 2-haloacid dehalogenases have been extensively studied with regard to their biochemical characterization, protein crystal structures, and catalytic mechanisms. This paper comprehensively reviews the source of isolation, classification, protein structures, reaction mechanisms, biochemical properties, and application of 2-haloacid dehalogenases; current trends and avenues for further development have also been included.

Arylmalonate Decarboxylase—A Versatile Biocatalyst for the Synthesis of Optically Pure Carboxylic Acids

Bacterial arylmalonate decarboxylase (AMDase) is an intriguing cofactor-independent enzyme with a broad substrate spectrum. Particularly, the highly stereoselective transformation of diverse arylmalonic acids into the corresponding chiral α-arylpropionates has contributed to the broad recognition of this biocatalyst. While, more than 30 years after its discovery, the native substrate and function of AMDase still remain undiscovered, contributions from multiple fields have ever since brought forth a powerful collection of AMDase variants to access a wide variety of optically pure α-substituted propionates. This review aims at providing a comprehensive overview of the development of AMDase from an enzyme with unknown function up to a powerful tailored biocatalyst for the synthesis of industrially relevant optically pure α-arylpropionates. Historical perspectives as well as recent achievements in the field will be covered within this work.