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Relevant academic research and scientific papers

Synthesis method of gamma-or delta-substituted alkyl chiral lactone

The invention discloses a synthesis method of gamma-or delta-substituted alkyl chiral lactone, the synthesis method comprises the following steps: mixing nickel salt, a chiral bidentate organic phosphorus ligand, aliphatic gamma-or delta-ketonic acid and a solvent, and carrying out asymmetric reduction reaction under the action of a reducing agent to obtain the gamma-or delta-substituted alkyl chiral lactone. According to the invention, asymmetric hydrogenation of aliphatic gamma-and delta-ketonic acids is realized through a cheap, green and efficient homogeneous chiral nickel-phosphorus complex catalytic system, and gamma-or delta-substituted alkyl chiral lactone is obtained with excellent yield and high enantioselectivity.

First chemo-enzymatic synthesis of the (R)-Taniguchi lactone and substrate profiles of CAMO and OTEMO, two new Baeyer–Villiger monooxygenases

Abstract: This study investigates the substrate profile of cycloalkanone monooxygenase and 2-oxo-Δ3-4,5,5-trimethylcyclopentenylacetyl-coenzyme A monooxygenase, two recently discovered enzymes of the Baeyer–Villiger monooxygenase family, used as whole-cell biocatalysts. Biooxidations of a diverse set of ketones were performed on analytical scale: desymmetrization of substituted prochiral cyclobutanones and cyclohexanones, regiodivergent oxidation of terpenones and bicyclic ketones, as well as kinetic resolution of racemic cycloketones. We demonstrated the applicability of the title enzymes in the enantioselective synthesis of (R)-(?)-Taniguchi lactone, a building block for the preparation of various natural product analogs such as ent-quinine. Graphical abstract: [Figure not available: see fulltext.]

Lipase-catalyzed doubly enantioselective ring-opening resolution between alcohols and lactones: Synthesis of chiral hydroxyl esters with two stereogenic centers

A novel lipase B from Candida antarctica-catalyzed doubly enantioselective ring-opening resolution between racemic alcohols and lactones was developed. By using this strategy, three optically pure compounds including hydroxyl esters with two stereogenic centers and recovered alcohols and lactones were obtained simultaneously in high yields and ee. This process was used for the resolution of various racemic alcohols with different substituent groups and lactones with different ring sizes (four- and seven- membered lactones). The scale-up experiments were also successful. Moreover, molecular docking was performed to explain the molecular basis of this doubly enantioselective ring-opening resolution. As an attractive and efficient strategy, lipase-catalyzed doubly enantioselective ring-opening resolution will be widely used in the synthesis of optically pure hydroxyl esters with two stereogenic centers. Opening new doors: A novel lipase B from Candida antarctica-catalyzed doubly enantioselective ring-opening resolution between racemic alcohols and lactones is developed.

Induced allostery in the directed evolution of an enantioselective Baeyer-Villiger monooxygenase

The molecular basis of allosteric effects, known to be caused by an effector docking to an enzyme at a site distal from the binding pocket, has been studied recently by applying directed evolution. Here, we utilize laboratory evolution in a different way, namely to induce allostery by introducing appropriate distal mutations that cause domain movements with concomitant reshaping of the binding pocket in the absence of an effector. To test this concept, the thermostable Baeyer-Villiger monooxygenase, phenylacetone monooxygenase (PAMO), was chosen as the enzyme to be employed in asymmetric Baeyer-Villiger reactions of substrates that are not accepted by the wild type. By using the known X-ray structure of PAMO, a decision was made regarding an appropriate site at which saturation mutagenesis is most likely to generate mutants capable of inducing allostery without any effector compound being present. After screening only 400 transformants, a double mutant was discovered that catalyzes the asymmetric oxidative kinetic resolution of a set of structurally different 2-substituted cyclohexanone derivatives as well as the desymmetrization of three different 4-substituted cyclohexanones, all with high enantioselectivity. Molecular dynamics (MD) simulations and covariance maps unveiled the origin of increased substrate scope as being due to allostery. Large domain movements occur that expose and reshape the binding pocket. This type of focused library production, aimed at inducing significant allosteric effects, is a viable alternative to traditional approaches to designed directed evolution that address the binding site directly.

Laboratory evolution of robust and enantioselective Baeyer-Villiger monooxygenases for asymmetric catalysis

The Baeyer-Villiger Monooxygenase, Phenylacetone Monooxygenase (PAMO), recently discovered by Fraaije, Janssen, and co-workers, is unusually thermostable, which makes it a promising candidate for catalyzing enantioselective Baeyer-Villiger reactions in organic chemistry. Unfortunately, however, its substrate scope is very limited, reasonable reaction rates being observed essentially only with phenylacetone and similar linear phenyl-substituted analogs. Previous protein engineering attempts to broaden the range of substrate acceptance and to control enantioselectivity have been met with limited success, including rational design and directed evolution based on saturation mutagenesis with formation of focused mutant libraries, which may have to do with complex domain movements. In the present study, a new approach to laboratory evolution is described which has led to mutants showing unusually high activity and enantioselectivity in the oxidative kinetic resolution of a variety of 2-aryl and 2-alkylcyclohexanones which are not accepted by the wild-type (WT) PAMO and of a structurally very different bicyclic ketone. The new strategy exploits bioinformatics data derived from sequence alignment of eight different Baeyer-Villiger Monooxygenases, which in conjunction with the known X-ray structure of PAMO and induced fit docking suggests potential randomization sites, different from all previous approaches to focused library generation. Sites harboring highly conserved proline in a loop of the WT are targeted. The most active and enantioselective mutants retain the high thermostability of the parent WT PAMO. The success of the "proline" hypothesis in the present system calls for further testing in future laboratory evolution studies.

Convenient double-enzymatic synthesis of both enantiomers of 6-methyl-ε-caprolactone

Both enantiomers of 6-methyl-ε-caprolactone (6-MeCL) are obtained in high enantiomeric excess by the combination of an enzymatic ring opening of racemic 6-methyl-ε-caprolactone and subsequent enzymatic ring closure. Immobilized Candida antarctica lipase B (Novozym 435) was selected as the biocatalyst for both the ring-opening and the ring-closing reaction. This route provides ready access to enantiopure (S)-6-MeCL (ee = 99.6%) and (R)-6-MeCL (ee = 98.8%).

Assessing the Substrate Selectivities and Enantioselectivities of Eight Novel Baeyer-Villiger Monooxygenases toward Alkyl-Substituted Cyclohexanones

Genes encoding eight Baeyer-Villiger monooxygenases have recently been cloned from bacteria inhabiting a wastewater treatment plant. We have carried out a systematic investigation in which each newly cloned enzyme, as well as the cyclohexanone monooxygenase from Acinetobacter sp. NCIB 9871, was used to oxidize 15 different alkyl-substituted cyclohexanones. The panel of substrates included equal numbers of 2-, 3-, and 4-alkyl-substituted compounds to probe each enzyme's stereoselectivity toward a homologous series of synthetically important compounds. For all 4-alkyl-substituted cyclohexanones tested, enzymes were discovered that afforded each of the corresponding (S)-lactones in ≥98% ee. This was also true for the 2-alkyl-substituted cyclohexanones examined. The situation was more complex for 3-akyl-substituted cyclohexanones. In a few cases, single Baeyer-Villiger monooxygenases possessed both high regio- and enantioselectivities toward these compounds. More commonly, however, they showed only one type of selectivity. Nonetheless, enzymes with such properties might be useful as parts of a two-step bioprocess where an initial kinetic resolution is followed by a regioselective oxidation on the isolated, optically pure ketone.

Enzymatic Resolution of Medium-Ring Lactones. Synthesis of (S)-(+)-Phoracantholide I

The horse liver and pig liver esterase hydrolysis of racemic medium ring lactones gives with excellent enantiomeric excess the S- (or R) lactones and the corresponding R- (or S) hydroxy acids.This is the first general method to obtain optically pure medium ring lactones.Application to the preparation of (S)-(+)-Phoracantholide I is reported.