Stereochemical Control Research Articles

Iron Trichloride-Mediated Cascade Reaction of Aminosugar Derivatives for the Synthesis of Fused Tetrahydroisoquinoline-Tetrahydrofuran Systems.

A method to obtain tetrahydroisoquinolines (THIQs) fused to tetrahydrofuran rings from aminosugar derivatives has been developed. The procedure relies on a key deprotection of benzyl ethers followed by a double-cyclization sequence, using FeCl3 as the sole reagent. This tandem reaction affords the construction of novel fused polycyclic heterocycles with total stereochemical control.

Reaching High Stereoselectivity and Activity in Organocatalyzed Ring-Opening Polymerization of Racemic Lactide by the Combined Use of a Chiral (Thio)Urea and a N-Heterocyclic Carbene.

Stereochemical control during polymerization is a key strategy of polymer chemistry to achieve semicrystalline engineered plastics. The stereoselective ring-opening polymerization (ROP) of racemic lactide (rac-LA), which can lead to highly isotactic polylactide (PLA), is one of the emblematic examples in this area. Surprisingly, stereoselective ROP of rac-LA employing chiral organocatalysts has been under-leveraged. Here we show that a commercially available chiral thiourea (TU1), or its urea homologue (U1), can be used in conjunction with an appropriately selected N-heterocyclic carbene (NHC) to trigger the stereoselective ROP of rac-LA at room temperature in toluene. Both a high organic catalysis activity (>90% monomer conversion in 5-9 h) and a high stereoselectivity (probability of formation of meso dyads, Pm, in the range 0.82-0.93) can be achieved by thus pairing a NHC and a chiral amino(thio)urea. The less sterically hindered and the more basic NHC, that is, a NHC bearing tert-butyl substituents (NHCtBu), provides the highest stereoselectivity when employed in conjunction with the chiral TU1 or U1. This asymmetric organic catalysis strategy, as applied here in polymerization chemistry, further expands the field of possibilities to achieve bioplastics with adapted thermomechanical properties.

Iridium-Catalyzed Stereoselective Transfer Hydrogenation of 1,5-Benzodiazepines.

An iridium-catalyzed highly stereoselective transfer hydrogenation of N-protected 2,4-disubstituted-1,5-benzodiazepines as well as dibenzo[1,5]oxa/thiazepines is realized in an aqueous solvent under acidic conditions, with formic acid as the hydride donor. Only trans-products are obtained in all the cases where diastereoselective issues are associated. The catalyst efficiency is highly dependent on the electronic and steric properties of the substrates. Topologically analyzing the angle of attack for hydride delivering revealed, stereoelectronically, that the steric interaction between the N-protecting group and the sterically large iridium hydride intermediate constitutes the main contributor to the excellent stereochemical control. Highly deuterated products can also be accessible with DCO2D as the deuteride donor. The observed primary kinetic isotope effect (kH/kD = 4.24) suggests that the formation of iridium hydride through β-hydride elimination should be the rate-determining step (with C-H bond cleavage). The potential use of the chirally modified iridium catalysts in a chemical resolution of racemic 1,5-benzodiazepines is also conceptually demonstrated.

Structural Basis of Stereospecific Vanadium-Dependent Haloperoxidase Family Enzymes in Napyradiomycin Biosynthesis.

Vanadium-dependent haloperoxidases (VHPOs) from Streptomyces bacteria differ from their counterparts in fungi, macroalgae, and other bacteria by catalyzing organohalogenating reactions with strict regiochemical and stereochemical control. While this group of enzymes collectively uses hydrogen peroxide to oxidize halides for incorporation into electron-rich organic molecules, the mechanism for the controlled transfer of highly reactive chloronium ions in the biosynthesis of napyradiomycin and merochlorin antibiotics sets the Streptomyces vanadium-dependent chloroperoxidases apart. Here we report high-resolution crystal structures of two homologous VHPO family members associated with napyradiomycin biosynthesis, NapH1 and NapH3, that catalyze distinctive chemical reactions in the construction of meroterpenoid natural products. The structures, combined with site-directed mutagenesis and intact protein mass spectrometry studies, afforded a mechanistic model for the asymmetric alkene and arene chlorination reactions catalyzed by NapH1 and the isomerase activity catalyzed by NapH3. A key lysine residue in NapH1 situated between the coordinated vanadate and the putative substrate binding pocket was shown to be essential for catalysis. This observation suggested the involvement of the ε-NH2, possibly through formation of a transient chloramine, as the chlorinating species much as proposed in structurally distinct flavin-dependent halogenases. Unexpectedly, NapH3 is modified post-translationally by phosphorylation of an active site His (τ-pHis) consistent with its repurposed halogenation-independent, α-hydroxyketone isomerase activity. These structural studies deepen our understanding of the mechanistic underpinnings of VHPO enzymes and their evolution as enantioselective biocatalysts.

Recent Advances in Transition-Metal-Catalyzed Asymmetric Functionalization of Enamides

AbstractEnamides, as prefunctionalized electron-rich heteroatom-substituted alkenes represent a powerful platform to synthesize useful nitrogen-containing natural products and bioactive molecules. This review discloses recent progress in the transition-metal-catalyzed enantioselective functionalization of enamides, including the Heck reaction, hydrofunctionalization, and difunctionalization, with a focus on the general scope, current limitations, stereochemical reaction control, and mechanistic aspects.1 Introduction2 Asymmetric Heck Reaction of Enamides3 Asymmetric Hydrofunctionalization of Enamides3.1 Nickel Catalysis3.2 Copper Catalysis3.3 Rhodium Catalysis3.4 Iridium Catalysis4 Asymmetric Difunctionalization of Enamides4.1 Palladium Catalysis4.2 Nickel Catalysis4.3 Copper Catalysis5 Summary and Outlook

Visible Light-Induced Regio- and Enantiodifferentiating [2 + 2] Photocycloaddition of 1,4-Naphthoquinones Mediated by Oppositely Coordinating 1,3,2-Oxazaborolidine Chiral Lewis Acid.

A range of asymmetric photochemical transformations using visible light have recently become considerably attractive. Among the various approaches, chiral Lewis acid association to enones for [2 + 2] and ortho photocycloadditions and oxadi-π-methane rearrangements have shown to be very promising. Naturally, chiral Lewis acid coordination protects one of the prochiral faces of the C═C double bond, which enables an effective enantiodifferentiation in the following bond-forming process(es). Here, we studied regio- and enantiodifferentiating [2 + 2] photocycloaddition reactions of naphthoquinone derivatives mediated by chiral oxazaborolidines. A stereochemical control was quite challenging for the 2-ene-1,4-dione substrate, as a double coordination of Lewis acid essentially cancels out the face selectivity, and a mono-coordination to each carbonyl group leads to an opposite stereochemical outcome. Furthermore, a stepwise coordination in the ground state of Lewis acid in a 1:1 fashion was practically inaccessible. We found that the excited-state decomplexation is a key to accomplish high regio- and enantioselectivities in the photocycloaddition of an ene-dione.

Strategies for the Synthesis of Fluorinated Nucleosides, Nucleotides and Oligonucleotides.

Fluorinated nucleosides and oligonucleotides are of specific interest as probes for studying nucleic acids interaction, structures, biological transformations, and its biomedical applications. Among various modifications of oligonucleotides, fluorination of preformed nucleoside and/or nucleotides have recently gained attention owing to the unique properties of fluorine atoms imparting medicinal properties with respect to the small size, electronegativity, lipophilicity, and ability for stereochemical control. This review deals with synthetic protocols for selective fluorination either at sugar or base moiety in a preformed nucleosides, nucleotides and nucleic acids using specific fluorinating reagents.

Concise and Stereodivergent Approach to Chromanone Lactones through Copper-Catalyzed Asymmetric Vinylogous Addition of Siloxyfurans to 2-Ester-Substituted Chromones.

Vicinal oxygen-containing tetra- and tri-substituted stereocenters exist widely in chromanone lactone and tetrahydroxanthone natural products. Their enantioselective construction in a single step remains elusive and poses a formidable challenge for chemical synthesis. Here, we report the first copper(I)-catalyzed asymmetric vinylogous additions of siloxyfurans to 2-ester-substituted chromones, which enable concise and enantioselective assembly of chromanone lactones. Both syn and anti adducts can be accessed with excellent diastereo- and enantioselectivity by judicious choice of the chiral ligands. Our approach allowed for the efficient synthesis of (-)-blennolide B with precise stereochemical control, which provides a formal synthesis of secalonic acid A.

Concise and Stereodivergent Approach to Chromanone Lactones through Copper‐Catalyzed Asymmetric Vinylogous Addition of Siloxyfurans to 2‐Ester‐Substituted Chromones

AbstractVicinal oxygen‐containing tetra‐ and tri‐substituted stereocenters exist widely in chromanone lactone and tetrahydroxanthone natural products. Their enantioselective construction in a single step remains elusive and poses a formidable challenge for chemical synthesis. Here, we report the first copper(I)‐catalyzed asymmetric vinylogous additions of siloxyfurans to 2‐ester‐substituted chromones, which enable concise and enantioselective assembly of chromanone lactones. Both syn and anti adducts can be accessed with excellent diastereo‐ and enantioselectivity by judicious choice of the chiral ligands. Our approach allowed for the efficient synthesis of (−)‐blennolide B with precise stereochemical control, which provides a formal synthesis of secalonic acid A.

Ligand‐Promoted, Enantioconvergent Synthesis of Aliphatic Alkanes Bearing Trifluoromethylated Stereocenters via Hydrotrifluoroalkylation of Unactivated Alkenes

Comprehensive SummaryWhile drug chirality remains one of the most important themes in medicinal chemistry and fluorine‐containing drugs have comprised large portion of global pharmaceutical market, the synthesis of fluorine‐containing compounds featuring a trifluoromethylated stereogenic carbon center is still underdeveloped. Recent strategy of enantioconvergent cross‐coupling of trifluoromethylated alkyl halide has significantly updated previous toolbox that is dependent on additional functional group to achieve desired bond formation and highly enantioselective control. However, evident limitations were present in specific coupling candidate (sp2 carbon) and/or prerequisite heteroatom in trifluoroalkyl source for inducing effective stereoconvergent differentiation. Leveraging novel design of sterically hindered bisoxazoline ligand and drastic increase of molecular complexity of in situ generated sp3 coupling partner via metal‐hydride atom transfer, herein, we report a nickel‐catalyzed, highly enantioselective hydrotrifluoroalkylation of unactivated alkenes for diverse synthesis of enantioenriched aliphatic alkanes featuring trifluoromehylated stereogenic carbon. Excellent stereochemical control (mostly >95: 5 er), high catalytic reactivity, mild conditions, and broad substrate scope (40+ examples), enable convenient late‐stage asymmetric trifluoroalkylation of various biologically active complex molecules.

Improvements to Hybridization-Ligation ELISA Methods to Overcome Bioanalytical Challenges Posed by Novel Oligonucleotide Therapeutics.

As oligonucleotides (ONs) and similar nucleic acid therapeutic modalities enter development pipelines, there is continual need to develop bioanalytical methodologies addressing unique challenges they pose. Novel ONs back bone chemistries, especially those enabling stereochemical control, and base modifications are being exploited to improve pharmacological properties, potency, and increase half-lives. These changes have strained established methods, oftentimes precluding development of assays sensitive and specific enough to meet the needs of preclinical programs. For stereopure ONs representing a single molecular species, nontrivial presence of chain-shortened metabolites in biological samples necessitate assays with high specificity. To meet these needs, this report presents a toolbox of novel techniques, easy to implement for existing hybridization-ligation enzyme-linked immunosorbent assay formats, which address this challenge and yield significant sensitivity and specificity enhancements. Ligation efficiency was improved up to 61-fold through addition of polyethylene glycol, betaine, or dimethylsulfoxide, mitigating major differences among sequence-matched ONs of varying stereopurity, enabling sensitivities below 0.100 ng/mL for quantitation. These improvements enabled further refinement of capture probe designs engendering sufficient specificity to discriminate N-1 chain-shortened metabolites at both the 5′ and 3′ end of the ONs. These generalizable methods advance the performance of mainstay bioanalytical assays, facilitating research and development of innovative ONs therapeutics.

Three-Component Friedel-Crafts Transformations: Synthesis of Alkyl and Alkenyl Trifluoromethyl Sulfides and Alkenyl Iodides.

Straightforward and mild hexafluoroisopropanol (HFIP)-mediated, metal-free, three-component Friedel-Crafts approaches are reported for the synthesis of alkenyl and alkyl trifluoromethyl sulfides from arenes, (PhSO2)2NSCF3, and alkynes or alkenes, respectively. The transformations proceed with high regio- and stereochemical control via the initial formation of cationic thiirenium and thiiranium intermediates, respectively, followed by Friedel-Crafts reactions with the arene. A mechanistically related three-component synthesis of alkenyl iodides from arenes, alkenes, and N-iodosuccinimide is also reported.

Stereochemical control of the diphosphine and alkyne ligands in triruthenium clusters: The effect of reversible CO loss/addition on the ligand distribution in [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7,8

Thermolysis of [Ru3{µ-Ph2PCH(Me)PPh2}(CO)10] (1) in the presence of diphenylacetylene affords the corresponding alkyne-substituted cluster [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)8] (2) and its unsaturated counterpart [Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7] (3), along with the alkyne-coupled complexes [Ru3{κ2-Ph2PCH(Me)PPh2}{µ3,η4-(CPh)4}(CO)4(µ-CO)2] (4) and [Ru2{µ-Ph2PCH(Me)PPh2}{µ,η4-(CPh)4}(CO)4] (5). The backbone-modified diphosphine in 2 has facilitated the growth of single crystals of the same and whose molecular structure was established by X-ray crystallography. The Ph2PCH(Me)PPh2 ligand bridges two ruthenium centers and occupies adjacent axial sites at one of the metallic faces. The diphosphine is situated trans to the alkyne ligand that caps the opposite metallic face. X-ray structural analysis of 3 reveals a perpendicular conformation of the alkyne relative to the metal triangle and a bridging diphosphine that coordinates the adjacent equatorial sites of the alkyne-bisected Ru–Ru bond. The kinetics for the conversion of 2 → 3 + CO under argon have been investigated over the temperature range 298–343 K in toluene. The calculated activation parameters [ΔHǂ = 13.3(3) kcal/mol; ΔSǂ = − 31(1) eu] are inconsistent with a rate-limiting step involving a dissociative loss of CO. Consistent with earlier reports on the related analog [Ru3(µ3,η2-PhCCPh)(µ-Ph2PCH2PPh2)(CO)7] by Lavigne and coworkers, the addition of CO to 3 (1 atm CO) at 258 K is rapid and affords 2 with a rate constant of 1.12(2) e−1s−1. Cluster 3 exhibits high reactivity toward 2e donors. Control experiments confirm that 3 reacts with additional PhCCPh (66 °C, 1 h) to give the diruthenium derivative 5 and that 4 also gives 5 in refluxing THF. The reaction of 3 with hydrogen gas (1 atm, 25 °C, 20 min) yields the dihydride [H2Ru3(µ3,η2-PhCCPh){µ-Ph2PCH(Me)PPh2}(CO)7] (6) in 85% yield. Clusters 2−6 were characterized by IR, 1H, and 31P NMR spectroscopies, and the solid-state structures of 2−5 were established by single-crystal X-ray crystallography. The bonding in clusters 2 and 3 and the thermodynamics for the equilibrium involving 2 ⇆ 3 + CO have been evaluated by electronic structure calculations.

Total Synthesis and Stereochemical Assignment of (-)-Psychotridine.

We report the first enantioselective total synthesis and stereochemical assignment of (-)-psychotridine. The application of our diazene-directed assembly of enantiomerically enriched cyclotryptamines afforded a highly convergent synthesis of the pentameric alkaloid, allowing its detailed structural assignment. Highlights of the synthesis include the introduction of four quaternary stereocenters with complete stereochemical control in a single step via the photoextrusion of three molecules of dinitrogen from an advanced intermediate and metal-catalyzed C-H amination reactions in challenging settings.

Highly sensitive LC-MS method for stereochemical quality control of a pharmaceutical drug substance intermediate.

Stereochemical quality control for pharmaceutical drug substance intermediates is a daunting task, especially considering the need to separate multiple stereoisomers simultaneously with low ppm level sensitivity. To address these challenges, we have successfully implemented chiral column screening, and developed an ultrasensitive liquid chromatography-mass spectrometry (LC-MS) method to separate four stereoisomers including the API intermediate, its enantiomer, and two other diastereomers. Parameters such as mobile phase additives, MS fragmentor, and column temperature were optimized to achieve the desired selectivity and sensitivity. The method enabled stereoisomer detection with high sensitivity (2ppm LOD and 5ppm LOQ), good linearity, and desired spike recovery, and it has been successfully applied for stereoisomer quantitation in multiple large-scale batches and demonstrated chiral quality control of the drug substance intermediate.

Diastereoselective Addition of Prochiral Nucleophilic Alkenes to α-Chiral N-Sulfonyl Imines.

The Lewis-acid-promoted addition of prochiral E- and Z-allyl nucleophiles to chiral α-alkoxy N-tosyl imines is described. Alkene geometry is selectively transferred to the newly formed carbon-carbon bond, resulting in stereochemical control of C1, C2, and C3 of the resulting 2-alkoxy-3-N-tosyl-4-alkyl-5-hexene products. A computational analysis to elucidate the high selectivity is also presented. This methodology was employed in the synthesis of two naturally occurring isomers of clausenamide.

Closing the “One Monomer–Two Polymers–One Monomer” Loop via Orthogonal (De)polymerization of a Lactone/Olefin Hybrid

Two well-known low-ceiling-temperature (LCT) monomers, γ-butyrolactone (γ-BL) toward ring-opening polymerization (ROP) to polyester and cyclohexene toward ring-opening metathesis polymerization (ROMP) to poly(cyclic olefin), are notoriously "nonpolymerizable". Here we present a strategy to render not only polymerizability of both the γ-BL and cyclohexene sites, orthogonally, but also complete and orthogonal depolymerization, through creating an LCT/LCT hybrid, bicyclic lactone/olefin (BiL=). This hybrid monomer undergoes orthogonal polymerization between ROP and ROMP, depending on the catalyst employed, affording two totally different classes of polymeric materials from this single monomer: polyester P(BiL=)ROP via ROP and functionalized poly(cyclic olefin) P(BiL=)ROMP via ROMP. Intriguingly, both P(BiL=)ROP and P(BiL=)ROMP are thermally robust but chemically recyclable under mild conditions (25-40 °C), in the presence of a catalyst, to recover cleanly the same monomer via chain unzipping and scission, respectively. In the ROP, topological and stereochemical controls have been achieved and the structures characterized. Furthermore, the intact functional group during the orthogonal polymerization (i.e., the double bond in ROP and the lactone in ROMP) is utilized for postfunctionalization for tuning materials' thermal and mechanical performances. The impressive depolymerization orthogonality further endows selective depolymerization of both the ROP/ROMP copolymer and the physical blend composites into the same starting monomer.

Stereoselective hydrogen atom transfer to acyclic radicals: a switch enabling diastereodivergent borylative radical cascades

Radical cascade reactions are powerful tools to construct structurally complex molecules. However, the stereochemical control of acyclic radical intermediates remains a persistent challenge, due to the low differentiation between the two faces of these species. This hurdle further makes stereodivergent synthesis rather more difficult to be accomplished, in particular for intermediates resulted from complex cascades. Here we report an efficient strategy for stereoselective hydrogen atom transfer (HAT) to acyclic carbon radicals, which are generated via N-heterocyclic carbene (NHC)-boryl radicals triggered addition-translocation-cyclization cascades. A synergistic control by the NHC subunit and a thiol catalyst has proved effective for one facial HAT, while a ZnI2-chelation protocol allows for the preferential reaction to the opposite face. Such a stereoselectivity switch enables diastereodivergent construction of heterocycles tethering a boron-substituted stereocenter. Mechanistic studies suggest two complementary ways to tune HAT diastereoselectivity. The stereospecific conversions of the resulting boron-handled products to diverse functionalized molecules are demonstrated.

Photoredox-Catalyzed Giese Reactions: Decarboxylative Additions to Cyclic Vinylogous Amides and Esters.

An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields.

C-H bond activation and sequential addition to two different coupling partners: a versatile approach to molecular complexity.

Sequential multicomponent C-H bond addition is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C-H bonds are typically added across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two σ-bonds in a single reaction sequence. Many sequential C-H bond addition reactions have been developed to date, including additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C-H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Given the large number of possible combinations of coupling partners, there are enormous opportunities for the discovery of new sequential C-H bond addition reactions.