Stereoselective Process Research Articles

Azlactone Reaction Developments.

Azlactones (also known as oxazolones) are heterocycles usually employed in the stereoselective synthesis of α,α-amino acids, heterocycles and natural products. The versatility of the azlactone scaffold arises from the numerous reactive sites, allowing its application in a diversity of transformations. This review aims to cover classical and recent applications of oxazolones, especially those involving stereoselective processes. After a short introduction on their structures and intrinsic reactivities, dynamic kinetic resolution (DKR) processes as well as reactions involving stereoselective formation of a new σ C-C bond, such as alkylation/allylation/arylation, aldol, ene, Michael and Mannich reactions will be exposed. Additionally, cycloadditions, Steglich rearrangement and sulfenylation reactions will also be discussed. Recent developments of the well-known Erlenmeyer azlactones will be described. For the most examples, the proposed mechanism, activation modes and/or key reaction intermediates will be exposed to rationalize both the final product and the observed stereochemistry. Finally, this review gives an overview of the synthetic utility of oxazolones.

Synthesis of the 16S,17S-Epoxyprotectin Intermediate in the Biosynthesis of Protectins by Human Macrophages.

The n-3 polyunsaturated fatty acids act as substrates during the resolution phase of acute inflammation for the biosynthesis of specialized pro-resolving lipid mediators. One premier example is the C22-dihydroxy-polyunsaturated fatty acid protectin D1 (1). The human 15-lipoxygenase type I, via stereoselective processes and with docosahexaenoic acid as the substrate, enables the formation of this specialized pro-resolving lipid mediator. Herein, based on results from LC/MS-MS metabololipidomics, support is presented for the apprehended biosynthesis of 1 in human macrophages occurring via the intermediate 16S,17S-epoxyprotectin (5). Stereochemically pure 5 was obtained using the Katsuki-Sharpless epoxidation protocol, establishing the chirality at the C16 and C17 atoms, one Z-selective reduction, and E- and Z-stereoselective Wittig reactions. In addition, information on the nonenzymatic aqueous hydrolysis products and the half-life of 16S,17S-epoxyprotectin (5) is presented.

Hammond Postulate Mirroring Enables Enantiomeric Enrichment of Phosphorus Compounds via Two Thermodynamically Interconnected Sequential Stereoselective Processes.

The dynamic resolution of tertiary phosphines and phosphine oxides was monitored by NMR spectroscopy. It was found that the stereoselectivity is set during the formation of the diastereomeric alkoxyphosphonium salts (DAPS), such that their initial diastereomeric excess (de) limits the final enantiomeric excess (ee) of any phosphorus products derived from them. However, (31)P NMR monitoring of the spontaneous thermal decomposition of the DAPS shows consistent diastereomeric self-enrichment, indicating a higher rate constant for decomposition of the minor diastereomer. This crucial observation was confirmed by reductive trapping of the unreacted enriched DAPS with lithium tri-sec-butylborohydride (commercially distributed as L-Selectride reagent) at different time intervals after the start of reaction, which gives progressively higher ee of the phosphine product with time. It is proposed that the Hammond postulate operates for both formation and decomposition of DAPS intermediate so that the lower rate of formation and faster subsequent collapse of the minor isomer are thermodynamically linked. This kinetic enhancement of kinetic resolution furnishes up to 97% ee product.

ChemInform Abstract: Stereoselective Organocatalytic Addition of Nucleophiles to Isoquinolinium and 3,4‐Dihydroisoquinolinium Ions: A Simple Approach for the Synthesis of Isoquinoline Alkaloids

AbstractReview: 118 refs.

Stereoselective Organocatalytic Addition of Nucleophiles to Isoquinolinium and 3,4-dihydroisoquinolinium Ions: A Simple Approach for the Synthesis of Isoquinoline Alkaloids

The frequent occurrence of chiral 1-substituted-1,2,3,4-tetrahydroisoquinoline ring systems in a large number of alkaloids, possessing a broad spectrum of biological and pharmaceutical properties, has prompted out a considerable interest in their synthesis. Economical and valuable stereoselective processes based on organocatalytic transformations represent a new avenue for approaching isoquinoline alkaloids with efficiency and creativity.

Protecting-group-free one-pot synthesis of glycoconjugates directly from reducing sugars.

The conversion of sugars into glycomimetics typically involves multiple protecting-group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high-yielding and stereoselective process is highly desirable. The combined use of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate and the Cu-catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one-step reaction directly from reducing sugars under aqueous conditions. The reaction, which is completely stereoselective, may be applied to the convergent synthesis of triazole-linked glycosides, oligosaccharides, and glycopeptides. The procedure provides a method for the one-pot aqueous ligation of oligosaccharides and peptides bearing alkyne side chains.

Protecting‐Group‐Free One‐Pot Synthesis of Glycoconjugates Directly from Reducing Sugars

AbstractThe conversion of sugars into glycomimetics typically involves multiple protecting‐group manipulations. The development of methodology allowing the direct aqueous conversion of free sugars into glycosides, and mimics of oligosaccharides and glycoconjugates in a high‐yielding and stereoselective process is highly desirable. The combined use of 2‐azido‐1,3‐dimethylimidazolinium hexafluorophosphate and the Cu‐catalyzed Huisgen cycloaddition allowed the synthesis of a range of glycoconjugates in a one‐step reaction directly from reducing sugars under aqueous conditions. The reaction, which is completely stereoselective, may be applied to the convergent synthesis of triazole‐linked glycosides, oligosaccharides, and glycopeptides. The procedure provides a method for the one‐pot aqueous ligation of oligosaccharides and peptides bearing alkyne side chains.

Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence.

Stereoselective synthesis of a cyclopentane nucleus by convergent annulations constitutes a significant challenge for synthetic chemists. Though a number of biologically relevant cyclopentane natural products are known, more often than not, the cyclopentane core is assembled in a stepwise fashion due to lack of efficient annulation strategies. Herein, we report the rhodium-catalyzed reactions of vinyldiazoacetates with (E)-1,3-disubstituted 2-butenols generate cyclopentanes, containing four new stereogenic centers with very high levels of stereoselectivity (99% ee, >97 : 3 dr). The reaction proceeds by a carbene–initiated domino sequence consisting of five distinct steps: rhodium–bound oxonium ylide formation, [2,3]-sigmatropic rearrangement, oxy-Cope rearrangement, enol–keto tautomerization, and finally an intramolecular carbonyl ene reaction. A systematic study is presented detailing how to control chirality transfer in each of the four stereo-defining steps of the cascade, consummating in the development of a highly stereoselective process.

Deracemization of Racemic Amino Acids Using (R)- and (S)-Alanine Racemase Chiral Analogues as Chiral Converters

Department of Chemistr/Division of Nano Sciences, Ewha Womans University, Seoul 120-750, Korea Received March 10, 2014, Accepted March 19, 2014Key Words : Amino acid, Alanine racemase chiral analogue, Chiral converter, Chiral HPLCDeracemization is the stereoselective process of convert-ing a racemate into either a pure enantiomer or a mixture inwhich one enantiomer is present in excess.

Sorption of single enantiomers and racemic mixture of (+/−)-α-pinene into Nafion membranes

The aim of this work was to elucidate the sorption of α-pinene in the membranes of solution-cast and melt-extruded Nafion. The extruded membrane was Nafion® 115 in H+ form (DuPont). The cast Nafion membrane was prepared by casting from a 20 wt.% solution of Nafion® (H+ form) in lower aliphatic alcohols and water. (+)-α-pinene, (−)-α-pinene and racemic mixture sorption isotherms were determined by a gravimetric method using the sorption balance. It was found that the sorption of α-pinene in the Nafion membrane is a stereoselective process. The sorption of α-pinene in cast Nafion is much higher than in extruded Nafion. The sorption of (+)-α-pinene in the extruded Nafion membrane is quite low while the sorption of (−)-α-pinene approaches zero. The sorption of (−)-α-pinene in the cast Nafion membrane is high while the sorption of (+)-α-pinene is low.

ChemInform Abstract: Biomolecules at Interfaces. Chiral, Naturally

AbstractReview: 242 refs.

Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir

A stereoselective process for the manufacture of bicyclopyrrolidine 7 to 2 has been developed. The process utilizes a stereoselective lithiation/carboxylation sequence. The achiral diamine ligand DPBP induces excellent diastereocontrol, and resolution with (S)-THNA provides the corresponding salt of 8 in high er and dr. Subsequent processing of 8 gives 2 as the oxalate salt in an overall yield of 27% from 7 (based on total molar charge of 7). Compound 2 was obtained with high chemical and chiral purities. The process was successfully demonstrated on >100 kg scale.

Dechlorane Plus in surface soil of North China: levels, isomer profiles, and spatial distribution

Eighty-seven soil samples collected from North China were analyzed for Dechlorane Plus (DP). The concentrations of DP ranged from not detectable (ND) to 12.21 ng/g with a mean of 0.55 ng/g. The mean concentrations of total DP and syn-DP in four regions of North China were in the following order: Jingjin (Beijing and Tianjin) > Shandong > Shanxi > Hebei, while the mean concentrations of anti-DP in the four regions were in a different order: Shandong > Jingjin > Shanxi > Hebei. The mean f syn values for Jingjin (0.27), Hebei (0.24), and Shanxi (0.24) were close to 0.25, while the mean f syn value for Shandong (0.31) was closer to 0.35. In addition, the f syn value for Shandong was significantly higher (P < 0.01) than those of the other regions (Jingjin, Heibei, and Shanxi), indicating specific sources of DP. Syn-DP displayed a strong linear relationship with anti-DP (R(2) = 0.74), indicating that no obvious stereoselective process occurred in the soil of North China. Ordinary kriging was undertaken to map the spatial patterns of DP. High concentrations of DP in soils were present in south of Shanxi, central Hebei, south of Tianjin, and the south and northeast of Shandong, which were suggested to be connected with human activities such as e-waste dismantling.

Synergy, Compatibility, and Innovation: Merging Lewis Acids with Stereoselective Enamine Catalysis

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a "golden rush" in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a "happy marriage" between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.

ChemInform Abstract: Bimolecular Coupling Reactions Through Oxidatively Generated Aromatic Cations: Scope and Stereocontrol.

Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Bronsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon–hydrogen bond cleavage.

A Stereoselective Process for the Manufacture of a 2′-Deoxy-β-d-Ribonucleoside Using the Vorbrüggen Glycosylation

A practical and scalable process for the manufacture of cladribine (1) is described. Vorbruggen glycosylation of doubly silylated 2-chloroadenine 2 with protected 1-O-acetyl-2-deoxy-α,β-d-ribofuranose 3 under reversible conditions in the presence of 20 mol % triflic acid in a solvent that selectively precipitated the desired β-anomer β-4a whilst leaving the unwanted α-anomer α-4a in solution to isomerise allowed good overall stereoselectivity with exclusive regioselectivity. An aging step allowed anomerisation of α-4a to β-4a, thereby improving the isolable yield of the β-anomer. Direct filtration of the product mixture without a catalyst quench or aqueous workup furnished the crude β-anomer β-4a in good yield (up to 68%) and purity (>95% by HPLC) with no regioisomers detected and only ∼1–3% (by HPLC) of the undesired α-anomer. Deprotection of the crude, unpurified intermediate β-4a followed by recrystallisation provided drug-grade cladribine (1). The process includes three isolation steps and was demonst...

First chemoenzymatic synthesis of (R)- and (S)-1-(9H-fluoren-9-yl)ethanol

A simple chemoenzymatic synthesis of 1-(9H-fluoren-9-yl)ethanol stereoisomers is described. The enantiomers were resolved by a kinetically controlled transesterification with vinyl acetate in the presence of commercially available lipases. High-throughput screening and subsequent exhaustive investigation of the utility of the lipases in a stereoselective process of introducing chirality have been carried out. Lipase A from Candida antarctica as a cross-linked aggregate (CAL-A-CLEA) was the most efficient enzyme for the resolution of the title compound providing (S)-1-(9H-fluoren-9-yl)ethanol and its (R)-acetate in enantiopure form (>99% ee). Under mild reaction conditions, excellent enantioselectivity (E=407), and good isolated yields of the products were obtained.

Organic Stereochemistry. Part 7

AbstractThis review continues a general presentation of the principles of stereochemistry with special emphasis on the biomedicinal sciences. Here, we discuss and illustrate the phenomenon of substrate stereoselectivity in biochemistry (endogenous metabolism) and principally in xenobiochemistry or drug metabolism. The review begins with an overview of the stereoselective processes occurring in the biomedicinal sciences. The general rule is for distinct stereoisomers, be they enantiomers or diastereoisomers, to elicit different pharmacological responses (Part 5), to a lesser extent be transported with different efficacies (Part 5), and to be metabolized at different rates (this Part). In other words, biological environments discriminate between stereoisomers both when acting on them and when being acted upon by them. The concept of substrate stereoselectivity describes this phenomenon in endogenous biochemistry and xenobiotic metabolism, as discussed and illustrated in the present Part. The sister concept of product stereoselectivity will be presented in Part 8.

Bimolecular coupling reactions through oxidatively generated aromatic cations: scope and stereocontrol

Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Brønsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon–hydrogen bond cleavage.

Fe-catalyzed synthesis of (4E)-tridec-4-en-1-yl acetate, sex pheromone of tomato pinworm (Keiferia lycopersicella)

Starting with industrially available 1,3-dichloropropene a stereoselective process was developed for the preparation of (4E)-tridec-4-en-1-yl acetate, sex pheromone of tomato pinworm (Keiferia lycopersicella) using in the key stage the Fe-catalyzed cross-coupling of ethyl (4E)-5-chloropent-4-enoate with octylmagnesium bromide.