Nonracemic Form Research Articles

Streamlined Stereoselective Entry to (-)-Quinagolide and to 3-Substituted Octahydrobenzo[g]-Quinolines.

A very short stereoselective synthesis of enantiomerically pure (3S, 4aS, 10aR)-quinagolide has been developed. The key steps involved are a copper-catalyzed regioselective arylation of (S)-epichlorohydrin with 1,6-dimethoxynaphthalene and a diastereoselective trans-reduction of a cyclic enamine intermediate. The possibility to use both enantiomers of epichlorohydrin and the diastereodivergency found in the reduction process paves the way for a general preparation also in the nonracemic form of chiral trans-fused 3-substituted octahydrobenzo[g]quinolines that are privileged structures in medicinal chemistry.

Recent Progresses in the Catalytic Stereoselective Dearomatization of Pyridines.

1,2- and 1,4-dihydropyridines and N-substituted 2-pyridones are very important structural motifs due to their synthetic versatility and vast presence in a variety of alkaloids and bioactive molecules. In this article, we gather and summarize the catalytic and stereoselective synthesis of partially hydrogenated pyridines and pyridones via the dearomative reactions of pyridine derivatives up to mid-2023. The material is fundamentally organized according to the type of reactivity (electrophilic/nucleophilic) of the pyridine nucleus. The material is further sub-divided taking into account the nucleophilic species when dealing with electrophilic pyridines and considering the reactivity manifold of pyridine derivatives behaving as nucleophiles at the nitrogen site. The latter more recent approach allows for an unconventional entry to chiral N-substituted 2- and 4-pyridones in non-racemic form.

Scope and limitations of absolute configuration determination of allenic natural products using the CCC stretching VCD signal.

The allene functional group in natural products isolated so far exists in a non-racemic form, but its axial chirality is difficult to elucidate. Allenes exhibit a characteristic antisymmetric CCC stretching mode at around 1950 cm-1, and their VCD properties have not been studied in detail. This work, for the first time, applied VCD spectroscopy to allenic natural products and allenic molecules with other asymmetric centers focusing on the antisymmetric CCC stretching mode. This vibrational mode yielded a negligibly weak VCD signal for several molecules, but in the presence of electron-withdrawing and/or conjugating substituents, it generated a stronger one. Its sign was found to be influenced by the nature of substituents. These findings should deepen the understanding of the VCD properties of the allene functional group and should be useful for future studies of chiral allenes.

Stereoselective profiling of methamphetamine in a full-scale wastewater treatment plant and its biotransformation in the activated sludge batch experiments

The stereoselective biotransformation of methamphetamine (METH), as a chiral compound, during biological treatment in wastewater treatment plants (WWTPs) is often ignored. In this study, a non-racemic form of METH was detected in the raw influent of a full-scale WWTP, with S-(+)-METH as the predominant enantiomer. Stereoselective biotransformation of METH in favor of S-(+)-METH occurred in anaerobic/anoxic and aerobic processes, resulting in the detection of R-(-)-METH as the only enantiomer in the secondary sedimentation tank. To evaluate the stereoselective biotransformation of METH in an activated sludge system, controlled laboratory experiments were conducted under aerobic and anaerobic conditions. Different stereoselective enrichment was observed in a racemic METH batch experiment at various initial concentrations. Batch experiment results with different initial concentrations of nutrient substances demonstrated that the biotransformation of S-(+)-METH occurred simultaneously with the biodegradation of COD and NH4+-N, proving its cometabolism nature. Enzymes released under microbial starvation stress likely stimulated R-(-)-METH biotransformation. Compared with the biotransformation rate of METH under the anaerobic condition, the presence of dissolved oxygen led to a higher biotransformation rate of METH under the aerobic condition.

Multi-residue enantioselective analysis of chiral drugs in freshwater sediments

Pharmaceutical and illicit drugs are emerging contaminants found in the environment globally. Many are chiral and stereochemistry plays an important role on their environmental fate and effects. However, investigations at the enantiomeric level are limited, particularly for complex particulate matrices such as sediments. This is due to further sample processing requirements and a lack of suitable analytical methods. Therefore, here a new enantioselective methodology is proposed for 15 drugs in sediment. Sample treatment by accelerated solvent extraction and solid phase extraction was critical for subsequent enantioselective separations. Using liquid chromatography–tandem mass spectrometry, a Chiral-V enantioselective column enabled multi-residue separations of anti-depressants, beta-blockers, beta-agonist, anti-histamine and stimulants. Method trueness for all enantiomers was 86–121% and method quantitation limits were below 3 ng g−1 dry weight. Application of the method revealed the enantiomeric composition of fluoxetine, amphetamine, propranolol, venlafaxine and citalopram in sediment for the first time. All drugs except venlafaxine were present in non-racemic form, i.e. unequal enantiomer concentrations. This is significant considering drug toxicity towards benthic organisms could be enantiospecific.

Quaternized α,α'-Amino Acids via Curtius Rearrangement of Substituted Malonate-Imidazolidinones.

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate-imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89-99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets 5a-i supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate-imidazolidinone enolate in its Z-configuration, with the auxiliary in an s-transC-N conformation.

Chiral (2-cyanophenoxy)methyl-15-crown-5 in diastereomeric discrimination of amino acid esters according to the data of electrospray ionization mass spectrometry

The ability of [(2-cyanophenoxy)methyl]-15-crown-5 lariat ether enantiomers to diastereomeric discrimination with respect to hydrochlorides of 1-phenylethylamine and methyl esters of alanine, phenylalanine, and phenylglycine was studied by electrospray ionization mass spectrometry. The mentioned crown ether is available in non-racemic form owing to the procedure of preferential crystallization of enantiomers of its precursor. The quantitative estimation of the differences in the formation of diastereomeric complexes between the crown ether and the guests was performed by two independent methods: application of the guests with isotopic markers and using an additive of achiral amine-displacer. Both approaches indicate the existence of a moderate chiral discrimination: The (S)-enantiomer of the crown ether binds prevailingly the (S)-enantiomer of the guest, and vice versa.

One hundred years of helicene chemistry. Part 3: applications and properties of carbohelicenes

Carbohelicenes are a class of fascinating chiral helical molecules which have a rich history in chemistry. Over a period of almost 100 years, chemists have developed many methods to prepare them in a racemic or in a non-racemic form. They also possess a series of interesting chiral, physical, electronic and optical properties. However, their utilization in chemistry or chemistry-related fields has rarely appeared in a detailed and comprehensive review. It is the purpose of this review to collect fundamental applications and functions involving carbohelicenes in various disciplines such as in materials science, in nanoscience, in biological chemistry and in supramolecular chemistry. From the numerous synthetic methodologies reported up to now, carbohelicenes and their derivatives can be tailor-made for a better involvement in several subfields. Among those domains are: nanosciences, chemosensing, liquid crystals, molecular switches, polymers, foldamers, supramolecular materials, molecular recognition, conductive and opto-electronic materials, nonlinear optics, chirality studies and asymmetric synthesis. Helicene chemistry is now at a developmental stage, where sufficient application data are now collected and are extremely useful. They provide many more ideas for setting up the basis for future innovative applications.

ChemInform Abstract: Enantioselective [2 + 2 + 2] Cycloisomerization of Alkynes in the Synthesis of Helicenes: The Search for Effective Chiral Ligands.

AbstractIn order to construct helicene backbones in nonracemic form under Ni(0) catalysis, a large collection of phosphorus ligands is tested to achieve an enantioselective cycloisomerization of aromatic triynes.

First total synthesis of (+)-vedelianin, a potent antiproliferative agent

The total synthesis of (+)-vedelianin has been accomplished in 18 steps from vanillin. Preparation of a key intermediate in nonracemic form through a Shi epoxidation has allowed determination of the absolute stereochemistry of the natural product as the (2S,3R,4aR,9aR)-isomer.

Asymmetric Synthesis of O‐Protected Acyloins Using Enoate Reductases: Stereochemical Control through Protecting Group Modification

AbstractO‐Protected cyclic acyloins were obtained in nonracemic form through asymmetric bioreduction of α,β‐unsaturated alkoxy ketones by using 11 different enoate reductases from the “Old Yellow Enzyme” family. The stereochemical outcome of the biotransformation could be switched by variation of the O‐protecting group or by the ring size of the substrate, which allows access to both stereoisomers in up to >97 % ee Whereas α‐alkoxy enones were readily accepted as substrates, β‐analogs were not converted. Overall, α‐alkoxy enones represent a novel type of substrate for flavin‐dependent ene‐reductases.

Stereospecificity of the Au(I)-catalyzed reaction of 1-alkynyl-bicyclo[4.1.0]-heptan-2-ones with nucleophiles

The stereospecificity of the Au(I)-catalyzed reaction of 1-alkynyl-bicyclo[4.1.0]-heptan-2-ones with nucleophiles was investigated. The substrates were prepared in non-racemic form (up to 88% ee) through parallel kinetic resolution (CBS reduction) and reoxidation of the separated diastereomeric alcohols. The key Au-catalyzed reaction was then found to proceed without significant loss of absolute stereochemical information; this way, an achiral carbocationic intermediate could be excluded. Thus, a bicyclobutonium-type intermediate seems to be attacked in a S N2-type fashion by the nucleophile in accordance with computational predictions.

Synergistic effect of binary component ligands in chiral catalyst library engineering for enantioselective reactions

This article highlights our recent efforts in the development of highly efficient and cost-effective chiral catalysts for asymmetric reactions through a combinatorial approach by assembling the component ligands (at least one of which is in non-racemic form, while the other might be optically pure, racemic or achiral) with metal ions to generate modular chiral catalyst libraries. The synergistic effect of the binary ligands in terms of both enantioselectivity and activity of the catalysis has been observed in a variety of catalyst systems, including catalysts containing Ti(IV), Zn(II), Rh(I) or Ru(II) ions, for asymmetric hetero-Diels-Alder, carbonyl-ene, alkylation, and hydrogenation reactions, respectively.

Synthesis of 5‐Alkylidene‐1,3‐dioxane‐4,6‐diones, an Easily Accessible Family of Axially Chiral Alkenes: Preparation in Nonracemic Form and Platinum Binding Studies.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Synthesis of 5-alkylidene-1,3-dioxane-4,6-diones, an easily accessible family of axially chiral alkenes: preparation in non-racemic form and platinum binding studies

A general synthetic route to 5-alkylidene-1,3-dioxane-4,6-diones, which are a family of axially chiral alkenes, is described. Conformational issues are explored and the platinum-binding properties of these species are discussed. That these alkenes exist as stable enantiomers is established by their partial kinetic resolution upon reaction with cysteine.

Helicity control in the synthesis of helicenes and related compounds

Abstract Asymmetric synthesis of helicenes and their congeners has been demonstrated to rely either on enantioselective Ni0/PR3 *-catalyzed [2+2+2] cycloisomerization of triynes or on diastereoselective CoI-catalyzed [2+2+2] cycloisomerization of chiral triynes. The former approach providing tetrahydrohelicenes in a nonracemic form requires further development as moderate enantioselectivities (up to 54 % ee) have so far been achieved under kinetic control. The latter approach affording helicene-like structures in a diastereomerically enriched form allows for reaching good to excellent diastereoselectivities (up to 100:0) under thermodynamic control.

α‐Phosphono Lactone Analogues of Farnesyl Pyrophosphate: An Asymmetric Synthesis via Ring‐Closing Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Alpha-phosphono lactone analogues of farnesyl pyrophosphate: an asymmetric synthesis via ring-closing metathesis.

An alpha-phosphono lactone derivative of farnesol has been prepared, in both racemic and nonracemic forms, to provide a new type of farnesyl pyrophosphate analogue. Attempted preparation of the racemic alpha-phosphono lactone through rearrangement of a vinyl phosphate derived from the parent lactone resulted in both rearrangement and lactone ring opening, revealing that the farnesyl lactone was not stable to the excess of strong base required for the rearrangement. A procedure for C-P bond formation based on generation of the lactone enolate, reaction with a P(III) reagent, and oxidation was successful in providing the racemic alpha-phosphono lactone, in part, because only 1 equiv of strong base was required. The same strategy for phosphonate synthesis then was applied to the nonracemic farnesyl lactone, prepared through a sequence including allylation of farnesal with a nonracemic borane reagent, reaction of the product alcohol with acryloyl chloride, and formation of an unsaturated lactone through ring-closing metathesis. A similar strategy gave the corresponding racemic alpha-phosphono lactam through a six-step sequence from farnesal.

A short route to new cyclobutene nucleoside analogues

Nucleoside analogues (+)- 4a and (+)- 4b were obtained in non-racemic form by a short and efficient way. The key step was a Mitsunobu reaction of alcohol (−)- 8 with adenine or protected thymine. The title products were obtained after deprotection steps.

Synthesis, characterization and resolution of racemic (2-methylsulfinyl)phenylphosphonic acid methyl ester via its cinchoninium salts

The synthesis of new (2-methylsulfinyl)phenylphosphonic acid methyl and dimethyl esters in both racemic and non-racemic forms is reported. Resolution of the racemic phosphonic acid mono-ester 1 was accomplished via diastereomeric salt formation with cinchonine. The absolute stereochemistry of the phosphonic ester products was deduced from asymmetric sulfoxidation experiments and confirmed by chemical correlation with ( S)-(−)-2-methylsulfinylaniline.