High Enantiomeric Excess Research Articles

Chemoenzymatic Synthesis of trans-β-Aryl-δ-hydroxy-γ-lactones and Enzymatic Kinetic Resolution of Their Racemic Mixtures.

Two novel and convenient routes to obtain enantiomerically enriched trans-β-aryl-δ-hydroxy-γ-lactones 5a–d with potential antifeedant and anticancer activity were developed. In the first method starting from corresponding enantiomers of γ,δ-unsaturated esters 4a–d derived from enzymatically resolved allyl alcohols 1a–d, both enantiomers of hydroxylactones 5a–d were synthesized with high enantiomeric excesses (73%–97%). Configurations of the stereogenic centers of the synthesized compounds were assigned based on the mechanism of acidic lactonization of esters 4a–d in the presence of m-chloroperbenzoic acid (m-CPBA). An alternative method for the production of optically active trans-β-aryl-δ-hydroxy-γ-lactones 5a–d was lipase-catalyzed kinetic resolution of their racemic mixtures by transesterification with vinyl propionate as the acyl donor. The most efficient enzyme in the screening procedure was lipase B from Candida antarctica. Its application on a preparative scale after 6 h afforded unreacted (+)-(4S,5R,6S)-hydroxylactones 5a–d and (+)-(4R,5S,6R)-propionates 6a–d, most of them with high enantiomeric excesses (92%–98%). Resolution of lactone 5d with bulky 1,3-benzodioxol ring provided products with significantly lower optical purity (ee = 89% and 84% for hydroxylactone 5d and propionate 6d, respectively). The elaborated methods give access to both enantiomers of trans-β-aryl-δ-hydroxy-γ-lactones 5a–d with the defined absolute configurations of stereogenic centers, which is crucial requirement for the investigations of relationship: spatial structure–biological activity.

Practical Synthesis of MDM2 Antagonist RG7388. Part 1: A Cu(II)-Catalyzed Asymmetric [3 + 2] Cycloaddition

An efficient asymmetric synthesis of MDM2 antagonist RG7388 is reported. The highly functionalized chiral pyrrolidine carboxamide was assembled via a Cu(OAc)2/(R)-BINAP catalyzed asymmetric [3 + 2] cycloaddition, which gave the exo and endo adducts in a ratio of 10:1, with high enantiomeric excess for the exo isomer. A one-pot hydrolysis and retro-Mannich/Mannich isomerization of the cycloaddition adducts in the presence of aqueous sodium hydroxide afforded RG7388 in high chemical and enantiomeric purities and 69% overall yield.

Bioreduction of α‐Acetoxymethyl Enones: Proposal for an SN2′ Mechanism Catalyzed by Enereductase

Abstract(Z)‐3‐Acetoxymethyl‐4‐R‐3‐buten‐2‐ones (R=aryl, alkyl) and (Z)‐3‐methyl‐4‐R‐3‐buten‐2‐ones (R=aryl) were synthesized and submitted to reduction by the yeast Saccharomyces cerevisiae producing the (R)‐ and (S)‐4‐R‐3‐methybutan‐2‐ones, respectively. This stereochemistry control strategy was applied in the syntheses of (R)‐ and (S)‐Tropional® with moderate to high enantiomeric excesses. Other (Z)‐3‐acyloxymethyl‐4‐phenyl‐3‐buten‐2‐ones showed similar behavior to the (Z)‐3‐acetoxymethyl counterpart, and the acylated Morita–Baylis–Hillman adduct 1‐acetoxy‐2‐methylene‐1‐phenylbutan‐3‐one produced a mixture of products, with and without the acetoxy group, via three different reaction pathways. In addition to experiments employing whole cells, those in which isolated enereductases were used suggested that the main pathway through which the loss of the acetoxy group occurs during the biocatalytic cascade is an SN2′‐type reaction, rather than formal hydrogen addition followed by acetic acid elimination. Finally, related ethyl enones were reduced enantioselectively by the yeast Candida albicans, producing both (R)‐ and (S)‐reduction products, depending on the presence of the acetoxy group in the starting material.magnified image

ChemInform Abstract: Rhodium‐Catalyzed Enantioselective Silylation of Cyclopropyl C—H Bonds.

AbstractHydrosilyl ethers, generated in situ by dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C—H bonds in high yields.The reaction proceeds with high enantiomeric excesses in the presence of a rhodium catalyst derived from a rhodium precursor and the bisphosphine (S)‐DTBM‐SEGPHOS.

ChemInform Abstract: Chiral N‐Heterocyclic Carbene Ligand Enabled Nickel(0)‐Catalyzed Enantioselective Three‐Component Couplings as Direct Access to Silylated Indanols.

AbstractThe title reaction between norbornene derivatives, aromatic aldehydes, and silanes provides silyl protected indanol scaffolds as single diastereomers with high enantiomeric excess.

A Modular Strategy for the Direct Catalytic Asymmetric α-Amination of Carbonyl Compounds

Summary Direct catalytic methods for the stereoselective introduction of various non-protected amines at the carbon atom adjacent to a carbonyl group remain elusive in synthetic chemistry, even though they offer the most straightforward entry to chiral α-aminocarbonyl compounds. Here, we demonstrate that the in situ activation of hydroxylamines with trichloroacetonitrile enables direct transfer of their amine moieties to the C-3 position of oxindoles with rigorous enantiocontrol under the catalysis of chiral 1,2,3-triazolium salts. This protocol provides a powerful and practical means of accessing optically active 3-aminooxindoles with a wide array of alkyl and aryl substituents on nitrogen. Other carbonyl compounds, such as β-ketoesters and α-cyanoesters, can also be directly transformed into the corresponding α-aminocarbonyls with high enantioselectivity.

Evaluation of two nucleophilic syntheses routes for the automated synthesis of 6-[18F]fluoro-l-DOPA

Two different strategies for the nucleophilic radiosynthesis of [18F]F-DOPA were evaluated regarding their applicability for an automated routine production on an Ecker&Ziegler Modular-Lab Standard module.Initially, we evaluated a promising 5-step synthesis based on a chiral, cinchonidine-derived phase-transfer catalyst (cPTC) being described to give the product in high radiochemical yields (RCY), high specific activities (AS) and high enantiomeric excesses (ee). However, the radiosynthesis of [18F]F-DOPA based on this strategy showed to be highly complex, giving the intermediate products as well as the final product in insufficient yields for automatization. Furthermore, the automatization proved to be problematic due to incomplete radiochemical conversions and the formation of precipitates during the enantioselective reaction step. Furthermore, the required use of HI at 180°C during the last reaction step led to partial decomposition of lines and seals of the module which further counteracts an automatization.Further on, we evaluated a 3-step synthesis using the commercially available, enantiomerically pure precursor AB1336 for automatization. This synthesis approach gave much better results and [18F]F-DOPA could be produced fully automated within 114min in RCYs of 20±1%, ee of >96%, a radiochemical purity (RCP) of >98% and specific activities of up to 2.2GBq/μmol.

Organic Synthesis via Oxidative Cascade Biocatalysis

Oxidative cascade biocatalysis enabling multistep enzyme-catalyzed reactions in one pot and utilizing molecular oxygen as a green and cheap oxidant is an emerging tool for selective and sustainable chemical synthesis. In this Account, we summarize several new types of oxidative cascade biocatalysis for the regioselective and mostly enantio­selective transformations recently developed in our laboratory. These cascades offer a green and efficient synthesis of many high-value chiral chemicals in high enantiomeric excesses, such as diols, amino alcohols, hydroxy acids, amino acids, hydroxy ketones, ketones, and lactones. 1 Introduction 2 Asymmetric trans-Dihydroxylation of Alkenes to Vicinal Diols 3 Asymmetric Aminohydroxylation of Alkenes to 1,2-Amino Alcohols 4 Asymmetric Transformation of Alkenes into α-Hydroxy Acids 5 Asymmetric Transformation of Alkenes into α-Amino Acids 6 Oxidative Kinetic Resolution of Vicinal Diols 7 Enantioselective Conversion of Epoxides into α-Hydroxy Ketones 8 Regioselective Oxidation of Alkanes to Ketones 9 Enantioselective Conversion of α,β-Unsaturated Ketones into δ-Lactones and Ketones 10 Conclusion

Green preparation and selective permeation of d-Tryptophan imprinted composite membrane for racemic tryptophan

Enantioseparation of racemic tryptophan is very important for pharmaceutical production. Conventional separation methods are high costly, energy intensive and environmentally unfriendly. Permeation separation based on membrane separation technique is a promising technology with advantages of energy efficient, clean and no additives. However, lots of organic compounds are commonly used for the traditional preparation of various membranes for enantioseparation of racemic tryptophan. Thus, we developed a totally green and clean preparation method using nature polymer sodium alginate as functional polymer, water as solvent and CaCl2 as crosslinking agent. Besides, polyvinylidene fluoride membrane was selected as supported membrane. Molecularly imprinted technology with d-Tryptophan as template molecule was introduced to enlarge mass transfer flux. Various methods were used in characterization of molecularly imprinted composite membrane (MICM) and non-imprinted composite membrane (NICM). Effects of preparing conditions, permeation conditions and concentration polarization on permeation performance of MICM by pressure-driven were investigated. High enantiomeric excess (ee%>98%) of the permeation solution could be obtained under mild conditions. Reducing the presence of concentration polarization was beneficial to maintaining high ee% (>98%). Moreover, the thermo and chemical stability of MICM were studied too. Comparison with previous studies indicated that the proposed totally green and clean method was not only low costly and environment friendly but also beneficial to significantly increasing ee.

ChemInform Abstract: Enantioselective Intermolecular C—H Functionalization of Allylic and Benzylic sp3 C—H Bonds Using N‐Sulfonyl‐1,2,3‐triazoles.

AbstractThe products are often formed with high enantiomeric excess.

ChemInform Abstract: Sulfinamide Phosphinates as Chiral Catalysts for the Enantioselective Organocatalytic Reduction of Imines.

AbstractThe reaction tolerates diverse arylmethyl imines while delivering the corresponding arylmethyl amines in high yields and with high enantiomeric excesses.

ChemInform Abstract: N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Diels—Alder Reaction of Cyclopentadiene with 2,3‐Dioxopyrrolidines and 2‐Alkenoyl Pyridines.

AbstractThe scalable procedure provides chiral bridged compounds in high yields and with very high diastereomeric and enantiomeric excesses.

ChemInform Abstract: Asymmetric Synthesis of Multisubstituted Dihydrobenzofurans by Intramolecular Conjugate Addition of Short‐Lived C—O Axially Chiral Enolates.

AbstractThe products are formed with high diastereomeric and enantiomeric excesses.

Enantioselective Cu-Catalyzed Arylation of Secondary Phosphine Oxides with Diaryliodonium Salts toward the Synthesis of P-Chiral Phosphines.

Catalytic synthesis of nonracemic P-chiral phosphine derivatives remains a significant challenge. Here we report Cu-catalyzed enantioselective arylation of secondary phosphine oxides with diaryliodonium salts for the synthesis of tertiary phosphine oxides with high enantiomeric excess. The new process is demonstrated on a wide range of substrates and leads to products that are well-established P-chiral catalysts and ligands.

Asymmetric Synthesis of 2,3,4-Trisubstituted Piperidines

Two different organocatalytic approaches for the asymmetric synthesis of 2,3,4-trisubstituted piperidines were developed. Both approaches were based on an aza-Michael addition followed by cyclization and gave products in high enantiomeric excess.

Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes.

A number of cyclic olefins were prepared and evaluated for the asymmetric hydrogenation reaction using novel N,P-ligated iridium imidazole-based catalysts (Crabtree type). The diversity of these cyclic olefins spanned those having little functionality to others bearing strongly coordinating substituents and heterocycles. Excellent enantioselectivities were observed both for substrates having little functionality (up to >99% ee) and for substrates possessing functional groups several carbons away from the olefin. Substrates having functionalities such as carboxyl groups, alcohols, or heterocycles in the vicinity of the C═C bond were hydrogenated in high enantiomeric excess (up to >99% ee). The hydrogenation was also found to be regioselective, and by controlling the reaction conditions, selective hydrogenation of one of two trisubstituted olefins can be achieved. Furthermore, trisubstituted olefins can be selectively hydrogenated in the presence of tetrasubstituted olefins.

ChemInform Abstract: Catalytic Enantioselective Conversion of Epoxides to Thiiranes.

AbstractThe Broensted acid‐catalyzed kinetic resolution of variously functionalized aryl epoxides delivers the thiiranes as well as the epoxides in very high yields and with very high enantiomeric excesses.

ChemInform Abstract: Synthesis and Application of Chiral Spiro Cp Ligands in Rhodium‐Catalyzed Asymmetric Oxidative Coupling of Biaryl Compounds with Alkenes.

AbstractThe coupling between 1‐(naphthalen‐1‐yl)benzo[h]isoquinoline and various styrene derivatives as well as unsaturated esters, amides and phosphonates proceeds under mild conditions and delivers the products in high yields and with often very high enantiomeric excesses.

ChemInform Abstract: Asymmetric [3 + 2] Cycloaddition of Donor—Acceptor Aziridines with Aldehydes via Carbon—Carbon Bond Cleavage.

AbstractThe protocol allows for the preparation of a broad range of cis‐1,3‐oxazolidines in high yields and with high enantiomeric excesses.

ChemInform Abstract: Enantioselective Synthesis of Ring‐Fused Spiroannulated 1,2,3‐Thiadiazole Derivatives.

AbstractThe domino reaction between thioamides and azodicarboxylates provides the products in high yields and with high enantiomeric excesses.