Chemoenzymatic Asymmetric Synthesis of Pyridine-Based α-Fluorinated Secondary Alcohols

Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64–95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95–>99 % and up to 98 % yield.     

Recent Advances in Lipase-Mediated Preparation of Pharmaceuticals and Their Intermediates

Biocatalysis offers an alternative approach to conventional chemical processes for the production of single-isomer chiral drugs. Lipases are one of the most used enzymes in the synthesis of enantiomerically pure intermediates. The use of this type of enzyme is mainly due to the characteristics of their regio-, chemo- and enantioselectivity in the resolution process of racemates, without the use of cofactors. Moreover, this class of enzymes has generally excellent stability in the presence of organic solvents, facilitating the solubility of the organic substrate to be modified. Further improvements and new applications have been achieved in the syntheses of biologically active compounds catalyzed by lipases. This review critically reports and discusses examples from recent literature (2007 to mid-2015), concerning the synthesis of enantiomerically pure active pharmaceutical ingredients (APIs) and their intermediates in which the key step involves the action of a lipase.     

Advanced Monte Carlo simulations of the adsorption of chiral alcohols in a homochiral metal‐organic framework

Grand canonical Monte Carlo (GCMC) simulations with configurational biasing were used to study the enantioselective adsorption of four alkanols in a homochiral metal‐organic framework, known as hybrid organic‐inorganic zeolite analogue HOIZA‐1. Conventional GCMC simulations are not able to converge satisfactorily for this system due to the tight fit of the chiral alcohols in the narrow pores. However, parallel tempering and parallel mole‐fraction GCMC simulations overcome this problem. The simulations show that the enantioselective adsorption of the different (R,S)‐alkanols is due to the specific geometry of the chiral molecules relative to the pore size and shape. © 2014 American Institute of Chemical Engineers AIChE J, 60: 2324–2334, 2014     

Enantioselective Copper(II)‐Catalyzed Conjugate Addition of Indoles to β‐Substituted Unsaturated Acyl Phosphonates

The first copper‐catalyzed enantioselective conjugate addition of indoles to β‐substituted unsaturated acyl phosphonates was successfully realized by using a heteroarylidene‐tethered bis(oxazoline) ligand. The reaction features high efficiency, cheap catalyst and broad generality. In the case of either β‐alkyl‐ or β‐aryl‐substituted unsaturated acyl phosphonates, the 3‐indolyl adducts were achieved in high yields with good to excellent enantioselectivities (up to 97% ee). The 3‐indolyl adducts can serve as important intermediates in the synthesis of indole alkaloids.

     

Synthesis of Chiral Cyclopropyl Carbocyclic Purine Nucleosides via Asymmetric Intramolecular Cyclopropanations Catalyzed by a Chiral Ruthenium(II) Complex

The synthesis of chiral cyclopropyl carbocyclic purine nucleoside analogues via the highly enantioselective intramolecular cyclopropanation reactions has been reported. With a chiral ruthenium(II)‐phenyloxazoline complex as the catalyst, cyclopropyl carbocyclic purine nucleoside analogues containing three contiguous stereocenters were obtained with up to 99% yield and 99% ee. Furthermore, a chiral cyclopropyl carbocyclic adenosine nucleoside having anti‐BLV activity could be synthesized in a concise manner using this strategy.

     

Enantioselective Construction of Cyclic Enaminone‐Based 3‐Substituted 3‐Amino‐2‐oxindole Scaffolds via Catalytic Asymmetric Additions of Isatin‐Derived Imines

The first catalytic asymmetric construction of the cyclic enaminone‐based 3‐substituted 3‐amino‐2‐oxindole scaffold with potential bioactivity has been developed via chiral phosphoric acid‐catalyzed enantioselective addition reactions of cyclic enaminones to isatin‐derived imines, which afforded a series of cyclic enaminone‐based 3‐substituted 3‐amino‐2‐oxindoles in high yields and excellent enantioselectivities (up to 99% yield, 97% ee). The investigation of the reaction mechanism suggested that it was facilitated by a dual hydrogen‐bonding activation mode between the two substrates and the chiral phosphoric acid. Besides, this method could be utilized for a large‐scale synthesis with maintained enantioselectivity. This approach will not only offer a useful method for enantioselective construction of the cyclic enaminone‐based 3‐substituted 3‐amino‐2‐oxindole scaffold, but also enrich the research on catalytic asymmetric addition reactions of isatin‐derived imines by using electron‐rich olefins as nucleophiles. More importantly, a preliminary evaluation on the cytotoxicity of some selected products revealed that two of the enantio‐pure compounds exhibited moderate to strong cytotoxicity to A549, 786‐0, ECA109 and BT474 cancer cell lines.

     

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

(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 S_N2′‐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.

     

Enantioseparations in Achiral Environments and Chromatographic Systems

Since the very first resolution of racemic tartaric acid by Pasteur, the importance of resolution and methodology has been on a path of continuous understanding and expansion. The science and chemistry of achieving such targets has changed a lot. The advent of chromatography changed the direction by involving synthetic, semisynthetic, or naturally occurring chiral materials for a direct approach to resolution, where rapid and reversible association occurs to form diastereomers with different stabilities and partition coefficients responsible for overall enantioseparation. It has now reached a stage where the separation of excess enantiomers from nonracemic mixtures has been achieved in a totally achiral environment, which does not appear to be in line with the prevalent concepts of basic stereochemistry. Caution should be exercised when enantiomerically enriched mixtures – obtained by enantioselective synthesis – are chromatographed for purification in preparative organic synthesis.     

Gas Chromatographic Enantiomer Separation of Polychlorinated Biphenyls (PCBs): Methods,Metabolisms, Enantiomeric Composition in Environmental Samples and their Interpretation

The year 2016 not only marks the 50^th anniversary of the first successful discovery of gas chromatographic (GC) enantiomer separations in 1966 by Gil-Av, but also the less appraised 50^th anniversary of the discovery of polychlorinated biphenyls (PCBs) in the environment. This article reports on GC enantiomer separations of axially stable, chiral PCBs (PCB atropisomers) with modified cyclodextrins. Nineteen atropisomeric PCBs exist, but most data exists for four PCB atropisomers (PCB 95, PCB 132, PCB 149, and PCB 136), which can be resolved without significant coelutions on three columns coated with modified cyclodextrins. Nonracemic compositions of PCB atropisomers and their hydroxylated metabolites have been documented in various studies. However, the measured enantiomer fractions are currently difficult to interpret und understand. The most plausible reasons for these difficulties are discussed and interpreted with the help of selected examples from the literature.     

Diastereo‐ and Enantioselective Synthesis of Chiral Pyrrolidine‐Fused Spirooxindoles via Organocatalytic [3+2] 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Maleimides

In the presence of a Cinchona alkaloid‐based squaramide organocatalyst, the [3+2] cycloaddition of isatin‐derived azomethine ylides with maleimides proceeded readily, thus delivering the desired pyrrolidine‐fused spirooxindoles in 61–89% yields with >20:1 dr and 12 to >99 % ee. The absolute configuration of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione was unambiguously determined by means of X‐ray single crystal structure analysis. The reaction mechanism was hypothesized to account for the enantioselective formation of 5‐chloro‐1,5′‐dimethyl‐3′‐phenyl‐3′,3a′‐dihydro‐2′H‐spiro[indoline‐3,1′‐pyrrolo[3,4‐c]pyrrole]‐2,4′,6′(5′H,6a′H)‐trione.