Stereochemical Information Research Articles

Theoretical VCD response in the C-H stretching region of methyl α and β L-Fucopyranoside: a different behavior from monosaccharides

Vibrational circular dichroism (VCD) band near 2840 cm−1 in the C-H stretching region is likely to play an important role as an alternative approach to extract stereochemical information namely, glycosidic O-linkages α or β for monosaccharides. Indeed, the experimental results attribute a positive sign for the S absolute configuration (α-anomers for D-sugars and β-anomers for L-sugars) and a negative sign for the R absolute configuration (β-anomers for D-sugar and α-anomers for L-sugar) at C-1 anomeric carbon site. This band was assigned as a symmetric stretching motion of glycosidic methyl group. The idea was to reproduce and explain these experimental results by using theoretical powerful methods and go farther, by studying how to extract stereochemical information from polysaccharides. The obtained theoretical VCD spectra for six monosaccharides were in good agreement with the experiment, except for methyl L-Fucopyranoside. Truly, for this particular sugar, two VCD bands with different signs were obtained for the S-configuration (β form) and assigned both to the symmetric stretching of the methyl glycosidic group. It becomes more interesting to explore this VCD response, to allow us, possibly to examine another way to differentiate between the alpha and the beta forms for this molecule.

Carbon-Carbon Bond Cleavage at Allylic Positions: Retro-allylation and Deallylation.

The development of C-C bond-cleaving transformations is an issue in modern organic chemistry that is as challenging as it is important. Among these transformations, the retro-allylation and deallylation of allylic compounds are uniquely intriguing methods for the cleavage of C-C σ bonds at the allylic position. Retro-allylation is regarded as a prospective method for the generation of highly valuable regio- and stereodefined allylic metal compounds. Because the C-C cleavage proceeds via a favorable six-membered chairlike transition state, the regio- and stereochemical information on the starting homoallylic alcohols can be transferred onto the products. Moreover, retro-allylation can also be achieved using enantioselective C-C cleavage powered by chiral catalysts for the synthesis of enantiomerically enriched compounds. As a result of these attractive features, retro-allylation has wide utility in regio-, stereo-, and enantioselective synthesis. Deallylation is C-C σ-bond cleavage involving the departure of an allylic fragment and the formation of a relatively stable carbanion or radical, and it proceeds via either oxidative addition to a low-valent metal or an addition/β-elimination cascade. The removal of the versatile allylic group might seem to be unproductive; however, this unique transformation offers the opportunity of using the allylic group as a protective group for acidic C-H bonds. This Review aims to exhibit the synthetic utility as well as the uniqueness of these two C-C σ-bond cleavage methods by presenting a wide range of transformations of allylic compounds with the aid of main group metals, transition-metal catalysts, and radical species.

An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly.

An economical synthesis of lamivudine was developed by employing a new method to establish the stereochemistry about the heterocyclic oxathiolane ring. Toward this end, an inexpensive and readily accessible lactic acid derivative served the dual purpose of activating the carbohydrate’s anomeric center for N-glycosylation and transferring stereochemical information to the substrate simultaneously. Both enantiomers of the lactic acid derivative are available, and either β-enantiomer in this challenging class of 2′-deoxynucleoside active pharmaceutical ingredients can be formed.

Copper(I)-Catalyzed Ketenimine Formation/Aza-Claisen Rearrangement Cascade for Stereoselective Synthesis of α-Allylic Amidines.

A copper-catalyzed three-component reaction of terminal alkynes, TsN3, and tertiary allylic amines is developed toward the one-pot synthesis of α-allylic amidines. The product was synthesized on gram scale under 1 mol % of catalyst loading. Transformations of products into alkenyl amine and other nitrogen-containing compounds are demonstrated without any loss of stereochemical information.

Proposal for a New Stereochemically Informative Nonproprietary Drug Naming System.

The stereochemical aspects of drugs are generally recognized as fundamentally important influencers of drug action and disposition. Nevertheless, the nonproprietary names of the vast majority of stereochemically relevant therapeutic agents in the USP Dictionary of United States Adopted Names(USAN) and International Drug Names and in the WHO Drug Information listings provide no information on the stereochemical aspects. In view of the importance of stereochemistry in drug action and disposition, it is desirable to have a nonproprietary drug nomenclature system that provides basic information on the stereochemical identity and composition of drugs. The USP Dictionary of USAN and International Drug Names, the WHO Drug Information listings, and the chemical literature were examined for stereochemical information on drugs as a basis for proposing a new stereochemically informative nonproprietary drug name system. A new system of stereochemically informative nonproprietary nomenclature system was designed that provides a "flag" alerting to the presence of stereochemical elements in the drug structure and includes basic information on the stereoisomerism of the drug. One of five prefixes would be added to the name: [dex]- (dextrorotatory single chiral stereoisomer); [lev]- (levorotatory single chiral stereoisomer); [rac]- (racemic mixture); [uni]-, (single achiral stereoisomer); and [mix]-, (mixture of stereoisomers other than racemic). The proposed system would be useful in the various domains of drug information, therapy, and research.

Inverting External Asymmetric Induction via Selective Energy Transfer Catalysis: A Strategy to β-Chiral Phosphonate Antipodes.

Enantiodivergent, catalytic reduction of activated alkenes relays stereochemical information encoded in the antipodal chiral catalysts to the pro‐chiral substrate. Although powerful, the strategy remains vulnerable to costs and availability of sourcing both catalyst enantiomers. Herein, a stereodivergent hydrogenation of α,β‐unsaturated phosphonates is disclosed using a single enantiomer of the catalyst. This enables generation of the R‐ or S‐configured β‐chiral phosphonate with equal and opposite selectivity. Enantiodivergence is regulated at the substrate level through the development of a facile E → Z isomerisation. This has been enabled for the first time by selective energy transfer catalysis using anthracene as an inexpensive organic photosensitiser. Synthetically valuable in its own right, this process enables subsequent RhI‐mediated stereospecific hydrogenation to generate both enantiomers of the product using only the S‐catalyst (up to 99:1 and 3:97 e.r.). This strategy out‐competes the selectivities observed with the E‐substrate and the R‐catalyst.

A Hydroperoxide-Mediated Decarboxylation of α-Ketoacids Enables the Chemoselective Acylation of Amines.

Strategies for the formation of amide bonds, that is, one of the most basic and important transformations in organic synthesis, have so far focused predominantly on dehydration reactions. Herein, we report and demonstrate the practical utility of a novel decarboxylative amidation of α-ketoacids by using inexpensive tert-butyl hydroperoxide (TBHP), which is characterized by high yields, a broad substrate scope, mild reaction conditions, and a unique chemoselectivity. These features enable the synthesis of peptides from amino acid derived α-ketoacids under preservation of the stereochemical information.

Steroid identification via deep learning retention time predictions and two-dimensional gas chromatography-high resolution mass spectrometry

Untargeted steroid identification represents a great analytical challenge even when using sophisticated technology such as two-dimensional gas chromatography coupled to high resolution mass spectrometry (GC × GCHRMS) due to the chemical similarity of the analytes. Moreover, when analytical standards, mass spectral and retention index databases are not available, compound annotation is cumbersome. Hence, there is a need for the development of retention time prediction models in order to explore new annotation approaches. In this work, we evaluated the use of several in silico methods for retention time prediction in multidimensional gas chromatography. We use three classical machine learning (CML) algorithms (Partial Least Squares (PLS), Support Vector Regression (SVR) and Random Forest Regression (RFR)) and two deep learning approaches (dense neural network (DNN) and three-dimensional convolutional neural network (CNN)). Whereas molecular descriptors were utilized for the CLM and DNN algorithms, three-dimensional molecular representation based on the electrostatic potential (ESP) was studied as input data as is for the CNN. All the developed models showed similar performances with Q2 values over 0.9. However, among all CNN showed the best performance, resulting in average retention time prediction errors of 2% and 6% for the first and second separation dimension, respectively. Additionally, only the three-dimensional ESP representation coupled with CNN was able to extract the stereochemical information crucial for the separation of diastereomers. The combination of retention time prediction and high-resolution mass spectral data applied to clinical samples enabled the untargeted annotation of 12 steroid metabolites in the urine of new-borns.

Bidirectional Hiyama–Denmark Cross‐Coupling Reactions of Bissilyldeca‐1,3,5,7,9‐pentaenes for the Synthesis of Symmetrical and Non‐Symmetrical Carotenoids

The construction of the carotenoid skeleton by Pd-catalyzed Csp2 -Csp2 cross-coupling reactions of symmetrical and non-symmetrical 1,10-bissilyldeca-1,3,5,7,9-pentaenes and the corresponding complementary alkenyl iodides has been developed. Reaction conditions for these bidirectional and orthogonal Hiyama-Denmark cross-coupling reactions of bisfunctionalized pentaenes are mild and the carotenoid products preserve the stereochemical information of the corresponding oligoene partners. The carotenoids synthesized in this manner include β,β-carotene and (3R,3'R)-zeaxanthin (symmetrical) as well as 9-cis-β,β-carotene, 7,8-dihydro-β,β-carotene and β-cryptoxanthin (non-symmetrical).

Enantioselectivity Induced by Stereoselective Interlocking: A Novel Core Motif for Tropos Ligands.

Well‐defined supramolecular interactions are a powerful tool to control the stereochemistry of a catalytic reaction. In this paper, we report a novel core motif for fluxional 2,2′‐biphenyl ligands carrying (S)‐amino acid‐derived interaction sites in 5,5′‐position that cause spontaneous enrichment of the Rax rotamer. The process is based on strong non‐covalent interlocking between interaction sites, which causes diastereoselective formation of a supramolecular ligand dimer, in which the axial chirality of the two subunits is dictated by the stereochemical information in the amino acid residues. The detailed structure of the dimer was elucidated by NMR spectroscopy and single‐crystal X‐ray analysis. Three different phosphorus‐based ligand types, namely a bisphosphine, a bisphosphinite and a phosphoramidite were synthesized and characterized. Whereas the first one was found to exist in a strongly weighted equilibrium, the two others each exhibited stereoconvergent behavior transforming into the diastereopure Rax rotamer. Enriched ligands were used in rhodium‐mediated asymmetric hydrogenation reactions of prochiral olefins in which very high enantioselectivities of up to 96:4 were achieved.

A Diastereodynamic Probe Transducing Molecular Length into Chiroptical Readout.

Nature takes advantage of molecular conformational changes to express functions such as signaling across cellular membranes or allosteric protein activation. At the synthetic level, molecular recognition events have been used to induce conformational changes able to trigger functions such as catalysis or sensing. In this context, transduction of stereochemical information has been the leading strategy. In particular, stereodynamic elements have been extensively employed to amplify and/or transduce chiral information. In this article, we report a chiral supramolecular cage with two stereodynamic units, which invert their helicities according to the length of the molecular guest confined within the system. Interestingly, achiral information is transduced by the supramolecular system to different diastereomeric states that have opposite chiroptical absorptions. This is the first example in which it is possible to produce a continuous modulation of the chiroptical output of a system by varying a physical achiral molecular property (viz. molecular dimension). This phenomenon can be exploited for the establishment of novel methods to program conformational control, for the development of innovative sensors and/or for transduction of molecular properties into chiroptical information.

RDChiral: An RDKit Wrapper for Handling Stereochemistry in Retrosynthetic Template Extraction and Application.

There is a renewed interest in computer-aided synthesis planning, where the vast majority of approaches require the application of retrosynthetic reaction templates. Here we introduce RDChiral, an open-source Python wrapper for RDKit designed to provide consistent handling of stereochemical information in applying retrosynthetic transformations encoded as SMARTS strings. RDChiral is designed to enforce the introduction, destruction, retention, and inversion of chiral tetrahedral centers as well as the cis/trans configuration of double bonds. We also introduce an open-source implementation of a retrosynthetic template extraction algorithm to generate SMARTS patterns from atom-mapped reaction SMILES strings. In this application note, we describe the implementation of these two pieces of code and illustrate their use through many examples.

Weinreb Amides as Privileged Acylating Agents for Accessing α-Substituted Ketones

The acylation of α-substituted carbanion-type reagents (MCR1R2X; X = halogen, OR, SR, NR3R4, SeR, etc.) with Weinreb amides constitutes a highly versatile and flexible approach for accessing α-functionalized ketones. In this short review we will present a series of transformations—from our own and the work of others—documenting the general applicability of the methodology. Chemoselectivity is uniformly manifested including for critical substrates featuring additional electrophilic functionalities or sterically demanding elements. Importantly, the stereochemical information contained in the Weinreb amides can be fully transferred to the targeted ketones without affecting the optical purity. The protocol is also applicable to chiral carbanions generated through sparteine-mediated asymmetric deprotonation: the careful design of the experimental procedure allows recycling of the sparteine and the Weinreb ‘amine’ (N,O-dimethylhydroxylamine), thus improving the sustainability perspective of the processes.1 Introduction1.1 The Problem of the Synthesis of α-Substituted Ketones1.2 Weinreb Amides: General Features and Preparation2 Synthesis of α-Substituted Ketones2.1 α-Haloketones2.2 Synthesis of α-Cyanoketones2.3 Synthesis of α-Oxyketones2.4 Synthesis of β-Oxo Thioethers (α-Thioketones)2.5 Synthesis of Chiral α-Oxy and α-Nitrogen Ketones via the Sparteine-Mediated Generation of Optically Active Organolithiums2.6 Synthesis of α-Selenomethyl Ketones2.7 Reactivity of α-Phosphorus Carbanions with Weinreb Amides2.8 Modification of the Weinreb Amide Core: The CLAmP Reagent3 Competing Attack of Nucleophiles at More Reactive Electrophilic Sites than Weinreb Amides4 Conclusions

Utilization of Cyclic Amides as Masked Aldehyde Equivalents in Reductive Amination Reactions.

An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp2ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.

Enantiopure [Cs+/Xe⊂Cryptophane]⊂FeII4L4 Hierarchical Superstructures.

Hierarchically nested hosts offer new opportunities to control the guest binding of the inner host, functionalize the cavity of the outer host, and investigate communication between different layers. Here we report a self-assembled triazatruxene-based FeII4L4 capsule, which was able to encapsulate a covalent cage, cryptophane-111 (CRY). The resulting cage-in-cage complex was capable of accommodating a cesium cation or xenon atom with altered guest binding behavior compared to the CRY alone. A crystal structure of the Russian doll complex [Cs+⊂CRY]⊂FeII4L4 unambiguously demonstrated the unusual encapsulation of a cation within a capsule bearing a 8+ charge. Moreover, the binding of enantiopure CRY occurred with high enantioselectivity (530-fold) between the two enantiomers of the tetrahedron. This discrimination resulted in stereochemical information transfer from the inner covalent cage to the outer self-assembled capsule, leading to the formation of enantiopure [guest⊂cage]⊂cage complexes. The stereochemistry of the tetrahedron persisted even after displacement of CRY with an achiral guest.

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes

AbstractThe chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4‐oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α‐silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels–Alder cycloaddition through a point‐chirality, axial‐chirality, point‐chirality transfer process.

Cycloadditions of Oxacyclic Allenes and a Catalytic Asymmetric Entryway to Enantioenriched Cyclic Allenes.

The chemistry of strained cyclic alkynes has undergone a renaissance over the past two decades. However, a related species, strained cyclic allenes, especially heterocyclic derivatives, have only recently resurfaced and represent another class of valuable intermediates. We report a mild and facile means to generate the parent 3,4-oxacyclic allene from a readily accessible silyl triflate precursor, and then trap it in (4+2), (3+2), and (2+2) reactions to provide a variety of cycloadducts. In addition, we describe a catalytic, decarboxylative asymmetric allylic alkylation performed on an α-silylated substrate, to ultimately permit access to an enantioenriched allene. Generation and trapping of the enantioenriched cyclic allene occurs with complete transfer of stereochemical information in a Diels-Alder cycloaddition through a point-chirality, axial-chirality, point-chirality transfer process.

Graphing Ecotoxicology: The MAGIC Graph for Linking Environmental Data on Chemicals

Assessing the impact of chemicals on the environment and addressing subsequent issues are two central challenges to their safe use. Environmental data are continuously expanding, requiring flexible, scalable, and extendable data management solutions that can harmonize multiple data sources with potentially differing nomenclatures or levels of specificity. Here, we present the methodological steps taken to construct a rule-based labeled property graph database, the “Meta-analysis of the Global Impact of Chemicals” (MAGIC) graph, for potential environmental impact chemicals (PEIC) and its subsequent application harmonizing multiple large-scale databases. The resulting data encompass 16,739 unique PEICs attributed to their corresponding chemical class, stereo-chemical information, valid synonyms, use types, unique identifiers (e.g., Chemical Abstract Service registry number CAS RN), and others. These data provide researchers with additional chemical information for a large amount of PEICs and can also be publicly accessed using a web interface. Our analysis has shown that data harmonization can increase up to 98% when using the MAGIC graph approach compared to relational data systems for datasets with different nomenclatures. The graph database system and its data appear more suitable for large-scale analysis where traditional (i.e., relational) data systems are reaching conceptional limitations.

Hydrophobic chirality amplification in confined water cages

The manipulation of the transition states of a chemical process is essential to achieve the desired selectivity. In particular, transition states of chemical reactions can be significantly modified in a confined environment. We report a catalytic reaction with remarkable amplification of stereochemical information in a confined water cage. Surprisingly, this amplification is significantly dependent on droplet size. This water-induced chirality amplification stems from the hydrophobic hydration effects, which ensures high proximity of the catalyst and substrates presumably at the transition state, leading to higher enantioselectivity. Flow and batch reactors were evaluated to confirm the generality of this water-induced chirality amplification. Our observation on efficient chiral induction in confined water cages might lead to an understanding of the chirality amplification in the prebiotic era, which is a key feature for the chemical evolution of homochirality.

Allenes and Derivatives in Gold(I)- and Platinum(II)-Catalyzed Formal Cycloadditions.

ConspectusCycloaddition reactions, by involving the formation of at least two bonds and one cycle in a single operation, represent one of the more practical ways to assemble carbo- and heterocyclic structures from simple acyclic precursors. Especially appealing are formal cycloadditions promoted by transition metals, owing to the ability of these reagents to open mechanisms that are not accessible using classical chemistry. Therefore, along the years, a great variety of annulations based on first-, and particularly second-row transition metals have been discovered. Most of these reactions involve inner sphere mechanisms, with the metal participating via standard oxidative addition or reductive elimination processes. Curiously, metals of the third row like platinum and, especially, gold remained largely unexplored, likely because of the belief that they were inert and expensive. However, from the beginning of this century, many groups realized that these metals can open very interesting mechanistic scenarios and promote novel types of transformations. In particular, the π-acidic, carbophilic behavior of gold(I) complexes, together with the possibility of tuning their reactivity using designed ligands, has triggered important activity in the field. Many gold-catalyzed transformations involved addition or cycloisomerization processes, but during recent years, there have been also important advances in the development of formal cycloaddition reactions. While many of these reactions rely on the activation of alkynes, there has been an increasing number of reports that exploit the peculiar reactivities of allenes and derivatives.In this Account, we present recent efforts on the development of platinum- and gold-catalyzed formal cycloadditions of allenes. For the sake of simplicity, we only include annulations initiated by a direct metal-promoted activation of the allene moiety. Thus, alternative Pt- or Au-catalyzed reactions wherein the allene does not interact with the metal catalyst are not covered. Upon activation by the metals, allenes generate allyl-cation alkenylmetal species that can behave as 1,2- or 1,3-carbon dipoles in cycloaddition processes. Especially relevant is the reactivity of allenamides. The presence of the amide substituent provides for the generation of gold intermediates with a good balance of reactivity and stability, which can therefore react with the corresponding partners in a controlled manner. Moreover, despite the difficulties associated with the transfer of stereochemical information from chiral linear gold(I) complexes, a variety of enantioselective gold-catalyzed annulations have been discovered.This Account is organized considering the number of atoms engaged in the annulation process, and when possible, we present the results in a chronological order.