Single Stereoisomer Research Articles

Synthesis of Spirocyclic Amines by 1,3-Dipolar Cycloaddition of Azomethine Ylides and Azomethine Imines

Simple ketone starting materials with a halide leaving group and an alkene were prepared in one step and heated with glycine or glycine esters to promote a tandem imine formation, cyclization, and dipolar cycloaddition cascade. The chemistry was also feasible with acetylhydrazide. In each case a single stereoisomer of the tricyclic amine or pyrazolidine product was formed and the stereochemistry was verified by single crystal X-ray diffraction. When the reaction with glycine, which occurs with loss of CO2, was unsuccessful, the cascade process could be promoted by cross metathesis to give the vinyl sulfone starting material that provides a more reactive dipolarophile. Reductive cleavage of the pyrazolidine gave a spirocyclic diamine product.

A silver-catalyzed radical ring-opening reaction of cyclopropanols with sulfonyl oxime ethers.

A silver-catalyzed ring-opening reaction of cyclopropanols with sulfonyl oxime ethers has been developed. The protocol was conducted under mild reaction conditions to provide a series of γ-keto oxime ethers with moderate to good yields. The reaction proceeded in a stereoselective manner for CF3-containing oxime ethers to provide a single stereoisomer, while an inseparable E and Z mixture was obtained for CN-containing oxime ethers. Mechanistic studies indicate that the reaction proceeded via a radical mechanism.

Stereodivergent synthesis of 2-alkynyl buta-1,3-dienes using Sonogashira coupling with controllable retention or inversion of olefin geometry

A stereodivergent approach to 2-alkynyl buta-1,3-dienes from a single stereoisomer of starting α-bromoenal has been developed. By simply switching the sequence of Sonogashira and Horner-Wadsworth-Emmons reactions, it is possible to obtain these branched dienynes with retention or almost complete inversion of the double bond configuration.

Stereospecific Synthesis of (Z,Z)‐Isobenzofurans via Radical‐Enabled Cleavage of C(sp3)−C(sp3) and C(sp2)‐Halogen Bonds

AbstractA novel radical‐induced annulation/1,8‐halosulfonylation of β‐alkynyl ketones with haloaryl diazonium tetrafluoroborates and DABCO.bis(sulfur dioxide) was first achieved via the cleavage/recombination of C(sp3)−C(sp3) and C(sp2)‐halogen bonds, from which 47 examples of sulfone‐containing 1,3‐dimethylene‐substituted (Z,Z)‐isobenzofurans as single stereoisomers were synthesized in generally good yields. This multicomponent pathway is proposed to proceed through the in‐situ generation of arylsulfonyl radicals, followed by selective radical addition‐cyclization and ring‐opening of the cyclopropyl unit as well as C(sp2)‐halogen bond cleavage, resulting in the consecutive construction of three new chemical bonds, including C−S, C−O and C‐halogen bonds.magnified image

Efficient reductive desymmetrization of bulky 1,3-cyclodiketones enabled by structure-guided directed evolution of a carbonyl reductase

Reductive desymmetrization of 2,2-disubstituted prochiral 1,3-cyclodiketones to 2,2-disubstituted-3-hydroxycycloketones is a highly desired transformation for the construction of complex molecules with multiple chiral centres, but the generation of a single stereoisomer is difficult and an extremely challenging task in organic chemistry. In this study, by using ethyl secodione as the model substrate and an engineered carbonyl reductase from Ralstonia sp. as the biocatalyst, we realized the efficient reductive desymmetrization of 2,2-disubstituted cyclodiketones to give essentially one single stereoisomer. The mutant enzyme F12 (I91V/I187S/I188L/Q191N/F205A) showed an 183-fold enhancement of enzyme activity and outstanding stereoselectivity towards most of the tested prochiral 1,3-cyclodiketones. Crystal structural analysis and molecular dynamics studies reveal the molecular basis for activity improvement and the stereoselectivity control mechanism. Our results show that by altering the active site conformation populations (particularly the position of an α-helix) to properly accommodate the larger substrate and co-factor for catalysis, this challenging synthetic problem can ultimately be addressed. Reductive desymmetrization of 2,2-disubstituted cyclodiketones can provide valuable complex molecules with multiple chiral centres, but the generation of a single stereoisomer is difficult. This work addresses this synthetic challenge by engineering the activity and stereoselectivity of a carbonyl reductase.

Synthesis and Glycan-Protein Interaction Studies of Se-Sialosides by 77Se NMR.

To expand the potential of Se-carbohydrates for multifunctional mimicry of sugars, herein we addressed the synthesis of the highly challenging and biologically significant Se-glycosides of sialic acid (Se-sialosides). An α-sialyl selenolate anion generated in situ smoothly reacted with electrophiles to give α-Se-sialosides as single stereoisomers. A Se-sialoside was sequentially incorporated with selenium, producing a triseleno-sialoside. This molecule was used as a 77Se NMR-active handle for studying glycan-protein interaction, revealing different binding profiles of sialic acid binding proteins.

Synthesis and Bioactivity of the Alanyl Phosphonamidate Stereoisomers Derived from a Butyrophilin Ligand.

Aryloxy phosphonamidate derivatives of a butyrophilin 3A1 ligand are stimulants of Vγ9 Vδ2 T cells. However, when bonded to an aryl ester and an amine, the phosphorus is stereogenic, and past compounds were studied as racemates. To determine the impact of stereochemistry on the activity, we now have prepared phosphonate derivatives of l- and d-alanine ethyl ester, separated the diastereomers, and evaluated their biological activity as single stereoisomers. The results demonstrate that phosphonamidates substituted with l-alanine stimulate Vγ9 Vδ2 T cells at lower concentrations than the racemic glycine counterpart, while those derived from d-alanine require higher concentrations. All four diastereomers are more active than charged phosphoantigens such as HMBPP. Surprisingly, only a 2-fold difference was observed between the l-alanine phosphorus isomers, with the R P isomer more potent. This suggests that the small phosphoantigen scaffold reduces but does not eliminate dependence upon phosphorus stereochemistry for cellular activity.

Synthesis of a [6]rotaxane with singly threaded γ-cyclodextrins as a single stereoisomer.

A series of hetero [4]-, [5]- and [6]rotaxanes containing both cucurbit[6]uril (CB[6]) and γ-cyclodextrin (γ-CD) as the macrocyclic components have been synthesized via a threading-followed-by-stoppering approach. Due to the orthogonal binding of CB[6] to ammonium and γ-CD to biphenylene/tetra(ethylene glycol), the [n]rotaxanes display a specific sequence of the interlocked macrocycles. In addition, despite of the asymmetry of γ-CD with respect to the orthogonal plane of the axle, only one stereoisomer of the [6]rotaxane was obtained.

Comparison between Conventional and Nonconventional Methods for the Synthesis of Some 2-Oxazolidinone Derivatives and Preliminary Investigation of Their Inhibitory Activity Against Certain Protein Kinases

A series of propargyl and allyl carbamates were prepared directly from propargyl and allyl alcohols and phenyl or cyclohexyl isocyanate or indirectly by generating the isocyanates in situ from the corresponding Cbz-protected amines. The obtained carbamates underwent intramolecular nucleophilic cyclization in presence of cesium hydroxide monohydrate as a base catalyst under conventional and ultrasonic irradiation conditions to give the corresponding substituted 4-(benzylidene)methylidene-2-oxazolidinones in good to excellent yields. The use of ultrasonic irradiation provided remarkably improved yield of the cyclization products and significant shortening of the reaction time. In some cases the reaction was highly stereoselective, and (Z)-4-benzylideneoxazolidinones were formed as a single stereoisomer. A series of biological tests were performed to evaluate the inhibitory potential of all synthesized compounds against some protein kinases.

Strategies for the Synthesis of Chiral Carbon-Bridged Group IV ansa-Metallocenes.

This minireview provides a survey of the various synthetic approaches to chiral ansa-metallocenes of Ti, Zr, and Hf containing a carbon-based bridge. The individual strategies to install substitution patterns at either the cyclopentadienyl framework or the bridging unit are highlighted with focus on the progress made towards a direct preparation of single complex stereoisomers. The review further includes the discussion of potential problems such as the formation of undesired diastereomers, the threat of racemization of enantiopure material, and synthetic challenges originating from the synthesis, purification, and isolation of the target complexes. The review has been written with the goal in mind to facilitate the design and synthesis of new chiral ansa-metallocene derivatives for emerging research areas in asymmetric catalysis and organometallic chemistry.

Palladium-Catalyzed Regioselective C-H Iodination of Unactivated Alkenes.

A palladium-catalyzed C-H iodination of unactivated alkenes is reported. A picolinamide directing group enables the regioselective functionalization of a wide array of olefins to furnish iodination products as single stereoisomers. Mechanistic investigations suggest the reversible formation of a six-membered alkenyl palladacycle intermediate through a turnover-limiting C-H activation.

Stereoselective Convergent Synthesis of Tetrahydro-5 H-benzo[ c]fluorene via Nine-Membered Ring-Closing Metathesis and Transannular Acid-Mediated Cyclization/Nucleophilic Addition.

The diene methyl ethers or acetates, constructed from the Li-Br exchange/addition reactions of 2-vinylbenzaldehydes and 2-(but-3-en-1-yl)bromoarenes followed by etherification or acetylation of the corresponding alcohols, smoothly underwent the ring-closing metathesis (RCM) by using Hoveyda-Grubbs II as a catalyst to provide the corresponding benzannulated ( Z)-cyclononenes as single products in good yields (up to 75%). The ensuing one-pot acid-mediated transannular cyclization/nucleophilic addition at C7 furnished the corresponding tetrahydro-5 H-benzo[ c]fluorenes as single stereoisomers with the exclusive cis stereochemistry at the ring junction (C5-C6) and trans at the site of nucleophilic attack (C6-C7) on the three contiguous stereogenic centers in good to excellent yield (up to 94%). The developed strategy was general; the reaction conditions were compatible with hydride, azide, and electron-rich aromatics as nucleophiles. In addition, various methoxylated benzannulated cyclononene acetates could be employed as substrates. Thus, tetrahydro-5 H-benzo[ c]fluorenes could be prepared in four steps from appropriately substituted bromoarenes and benzaldehydes in good yields (up to 56%) with excellent stereo- and regio-control.

Synthesis of Enantiomerically Pure 5-Substituted Piperazine-2-Acetic Acid Esters as Intermediates for Library Production.

The piperazine heterocycle is housed within a large number of FDA-approved drugs and biological probe compounds. Structurally, however, these compounds are mostly confined to substitutions on the two ring nitrogen atoms, rationalizing the expansion of piperazine chemical diversity through carbon substitutions. On the basis of the concept of systematic chemical diversity, a divergent six-step synthesis was developed in which chiral amino acids were transformed, with high diastereoselectivity, into either cis or trans 5-substituted piperazine-2-acetic acid esters that could be chromatographically rendered diastereomerically homogeneous. Starting from six commercially available amino acids or their respective amino alcohols (both antipodes), we obtained a complete set of 24 protected chiral 2,5-disubstituted piperazines, as single stereoisomers in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as starting materials for parallel library synthesis and as intermediates for the targeted production of more complex C-substituted piperazine compounds.

Synthesis, structure of 7-oxa-1-azabicyclo[2.2.1]heptane derivative obtained from sugar nitrone and analysis of its conformational variety

Dispiro derivative of 7-oxa-1-azabicyclo [2.2.1]heptane 5 was synthesized as a single stereoisomer from N-(5-allyl-spiro [1,3-dioxan-2,1′-cyclohexane]-5-yl)hydroxylamine 2 and protected d-mannose 3, through intramolecular 1,3-dipolar cycloaddition of in situ formed N-(but-3-en-1-yl)nitrone 4. Structure of product 5 was attributed on the basis of NMR and X-ray analyses. In the solid state, three crystallographically independent molecules of 5 were detected, every exhibiting a different orientation of spiro connected rings. Conformational analysis performed by DFT calculations in the gas phase was performed and revealed that the conformations observed in the crystal correspond to the most stable molecular geometries. Two of them were also found to be dominant in solution.

Domino Synthesis of Benzo-Fused β,γ-Unsaturated Ketones from Alkenylboronic Acids and N-Tosylhydrazone-Tethered Benzonitriles

The transition-metal-free domino reaction between alkenylboronic acids and N-tosylhydrazones from o-(2-oxoalkyl)- and o-(3-oxoalkyl)benzonitriles leads to β,γ-unsaturated indanones and tetralones featuring an α-"all-carbon" quaternary center. The employment of derivatives of α-substituted cyclopentanones and cyclohexanones led to the stereoselective preparation of β,γ-unsaturated tetrahydrocyclopenta[ a]inden-8(1 H)-ones, hexahydrofluorenones, and hexahydroanthracenones as cis-fused single stereoisomers. A domino sequence involving diazo compound formation/reductive alkenylation/1,3-borotropic rearrangement/intramolecular bora-aza-ene reaction is proposed to justify the formation of the products as well as the stereoselectivity.

Covalent bonding photosensitizer–catalyst dyads of ruthenium-based complexes designed for enhanced visible-light-driven water oxidation performance

We have successfully prepared two ruthenium-based covalent bonding photosensitizer–catalyst dyads through a simple procedure. 1H NMR spectra of both dyads show that only a single stereoisomer was formed for each dyad. The spectroscopic and electrochemical properties and photocatalytic water oxidation activities of both dyads were investigated in detail. The results indicate that there is negligible electron communication between the photosensitizer and catalyst centers, and each component maintains the desired photophysical and electrochemical properties, which would diminish excited-state electron recombination by facilitating the intramolecular electron transfer. In the presence of excess sacrificial electron acceptor, the dyad with iodide ligand shows a 5.5-fold increase in catalytic performance as compared to its chloro analogue, indicating that the iodide ligand plays an important role during the catalytic cycle. Moreover, compared with the multi-component system, the dyad with iodide ligand exhibits a fourfold increase in catalytic turnover number.

An elusive thermal [2 + 2] cycloaddition driven by visible light photocatalysis: tapping into strain to access C2-symmetric tricyclic rings.

A mild and operationally simple methodology is reported for the synthesis of cyclobutane rings imbedded within a C2-symmetric tricyclic framework. The method uses visible light and an iridium-based photocatalyst to drive the oft-stated "forbidden" thermal [2 + 2] cycloaddition of cycloheptenes and analogs. Importantly, it generates cyclobutane with four new stereocenters with excellent stereoselectivity, and perfect regioselectivity. The reaction is propelled forward when the photocatalyst absorbs a visible light photon, which transfers this energy to the cycloheptene. Key to success is, upon excitation to the triplet via sensitization from the photocatalyst, the double bond isomerizes to give the transient, highly strained, trans-cycloheptene. The trans-cycloheptene undergoes a strain relieving thermal, intermolecular [π2s + π2a] cycloaddition with another cis-cycloheptene. X-ray analysis reveals that the major product is the head-to-head, C2-symmetric all trans-cyclobutane. Additionally, a dramatic display structural complexity enhancement is observed with the use of chiral cycloheptenols possessing one stereocenter, which results in the formation of cyclobutanes with six contiguous stereocenters with good to excellent diastereocontrol, and can be used to isolate single stereoisomers of stereochemically complex cyclobutanes in good yield.

Synthesis of the Campylobacter jejuni 81-176 Strain Capsular Polysaccharide Repeating Unit Reveals the Absolute Configuration of its O-Methyl Phosphoramidate Motif.

The O-methyl phosphoramidate (MeOPN) motif is a non-stoichiometric modification of capsular polysaccharides (CPS) in ≈70 % of all Campylobacter jejuni strains. Infections by C. jejuni lead to food-borne illnesses and the CPS they produce are key virulence factors. The MeOPN phosphorus atom in these CPS is stereogenic and is found as a single stereoisomer. However, to date, the absolute stereochemistry at this atom has been undefined. We report the synthesis of the three repeating units found in C. jejuni 81-176 CPS; one of these possesses a MeOPN group. In the course of these studies we established that the stereochemistry of the phosphorus atom in this MeOPN group is R. These studies represent the first unequivocal proof of stereochemistry of this group in any C. jejuni CPS. The compounds produced are anticipated to be useful tools in investigations targeting the function and biosynthesis of this structurally-interesting modification, which so far has only been identified in campylobacter.

Synthesis of the Campylobacter jejuni 81‐176 Strain Capsular Polysaccharide Repeating Unit Reveals the Absolute Configuration of its O‐Methyl Phosphoramidate Motif

AbstractThe O‐methyl phosphoramidate (MeOPN) motif is a non‐stoichiometric modification of capsular polysaccharides (CPS) in ≈70 % of all Campylobacter jejuni strains. Infections by C. jejuni lead to food‐borne illnesses and the CPS they produce are key virulence factors. The MeOPN phosphorus atom in these CPS is stereogenic and is found as a single stereoisomer. However, to date, the absolute stereochemistry at this atom has been undefined. We report the synthesis of the three repeating units found in C. jejuni 81‐176 CPS; one of these possesses a MeOPN group. In the course of these studies we established that the stereochemistry of the phosphorus atom in this MeOPN group is R. These studies represent the first unequivocal proof of stereochemistry of this group in any C. jejuni CPS. The compounds produced are anticipated to be useful tools in investigations targeting the function and biosynthesis of this structurally‐interesting modification, which so far has only been identified in campylobacter.

Synthesis of Enantiomerically Pure 3-Substituted Piperazine-2-acetic Acid Esters as Intermediates for Library Production.

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient six-step synthesis, chiral amino acids were transformed into 3-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products (dr 0.56 → 2.2:1, respectively) could be chromatographically separated. From five amino acids (both antipodes) was obtained a complete matrix of 20 monoprotected chiral 2,3-disubstituted piperazines, each as a single absolute stereoisomer, all but one in multigram quantities. In keeping with our overall purpose of constructing more Csp3-enriched compound libraries for drug discovery, these diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis and as intermediates for the production of novel piperazine compounds.