Single Stereoisomer Research Articles

Nickel-Catalyzed Stereoconvergent C(sp2)-F Alkenylation of Monofluoroalkenes.

The stereoconvergent synthesis of a single stereoisomer from E/Z-olefin mixtures remains one of the foremost challenges in organic synthesis. Herein, we describe a nickel-catalyzed stereoconvergent cross-coupling between E- and Z-mixed monofluoroalkenes and alkenyl electrophiles, which allows the construction of C(sp2)-C(sp2) bonds. This defluorinative transformation offers facile access to various 1,3-dienes with E-selectivity and good functional group tolerance. Preliminary mechanistic studies indicate that the reaction most likely proceeds through a migratory insertion/β-F elimination/isomerization process.

Structural Modification and Characteristics of Lappaconitine Alkaloid for the Discovery of Bioactive Components by Hypervalent Iodine Reagent.

Lappaconitine, a diterpene alkaloid isolated from Aconitum sinomontanum Nakai, exhibits a wide range of biological activities, making it a promising candidate for the development of novel derivatives with therapeutic potential. In our research, we executed a two-step transformation via oxidative cleavage of lappaconitine's vicinal diol using the hypervalent iodine reagent PhI(OAc)2, followed by strong alkaline hydrolysis. This approach yielded four new unanticipated compounds, whose structures were identified by spectroscopic methods and/or X-ray crystallography. Thus, we proposed plausible reaction mechanisms for their formations and particularly investigated the remarkable diastereoselectivity for the formation of single stereoisomer 8 observed during the alkaline hydrolysis step. Among them, compound 8 (code name: QG3030) demonstrated both enhanced osteogenic differentiation of human mesenchymal stem cells and significant osteogenic effect in an ovariectomized rat model with no acute oral toxicity.

Skin- and airway-deliverable TRPA1 inhibitor

This study explored the potential of perfumery compounds as sources of transient receptor potential ankyrin 1 (TRPA1) inhibitors that could be formulated for effective delivery to the skin and airways. A highly potent, small, and selective TRPA1 inhibitor, 2-methyl-4-phenyl-1-pentanol (1), was discovered in perfumery compounds. Compound 1 demonstrated promising inhibitory activity against a broad range of TRPA1 agonists. A single stereoisomer of 1 was identified as the most effective TRPA1 inhibitor, indicating the potential for stereoselective synthesis to enhance its potency. Additionally, the structure–activity relationship of 1 was evaluated to elucidate the structural features of TRPA1 inhibitors within the fragrance-like compounds. Notably, the topical application of 1 alleviated sensory irritation in individuals with sensitive skin, while the inhalation of 1 resulted in a significant reduction in ammonia irritation, underscoring its efficacy in both skin and airway applications.

Room Temperature Diels-Alder Reactions of 4-Vinylimidazoles.

In the course of studying Diels-Alder reactions of 4-vinylimidazoles with N-phenylmaleimide, it was discovered that they engage in cycloaddition at room temperature to give high yields of the initial cycloadduct as a single stereoisomer. In certain cases, the product precipitated out of the reaction mixture and could be isolated by simple filtration, thereby avoiding issues with aromatization observed during chromatographic purification. Given these results, intramolecular variants using doubly activated dienophiles were also investigated at room temperature. Amides underwent cycloaddition at room temperature in modest yields, but the initial adducts were not isolable with Nimid-benzyl-protected systems. Attempts to extend these results to the corresponding esters and hydroxamate were less successful with these substrates only undergoing cycloaddition at elevated temperatures in lower yields. Density functional theory calculations were performed to evaluate the putative transition states for both the inter- and intramolecular variants to rationalize experimental observations.

Enantio‐ and Diastereoselective NiH‐Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α‐Bromoamides**

AbstractCatalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio‐, enantio‐, and diastereoselective NiH‐catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α‐bromoamides or Katritzky salts). This reaction produces high‐value β‐aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn‐hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.

Enantio- and Diastereoselective NiH-Catalyzed Hydroalkylation of Enamides or Enecarbamates with Racemic α-Bromoamides.

Catalytic methods which control multiple stereogenic centers simultaneously are highly desirable in modern organic synthesis and chemical manufacturing. Herein, we report a regio-, enantio-, and diastereoselective NiH-catalyzed hydroalkylation process which proceeds with simultaneous control of vicinal stereocenters originating from two readily accessible partners, prochiral internal alkenes (enamides or enecarbamates) and racemic alkyl electrophiles (α-bromoamides or Katritzky salts). This reaction produces high-value β-aminoamides and their derivatives under mild conditions and with precise selectivity. Preliminary studies of the mechanism indicate that the reaction involves an enantioselective syn-hydronickelation to generate an enantiomerically enriched alkylnickel(II) species. Subsequent enantioconvergent alkylation with a racemic alkyl electrophile generates the desired product as a single stereoisomer.

Impact of conformation and intramolecular interactions on vibrational circular dichroism spectra identified with machine learning

Vibrational Circular Dichroism (VCD) spectra often differ strongly from one conformer to another, even within the same absolute configuration of a molecule. Simulated molecular VCD spectra typically require expensive quantum chemical calculations for all conformers to generate a Boltzmann averaged total spectrum. This paper reports whether machine learning (ML) can partly replace these quantum chemical calculations by capturing the intricate connection between a conformer geometry and its VCD spectrum. Three hypotheses concerning the added value of ML are tested. First, it is shown that for a single stereoisomer, ML can predict the VCD spectrum of a conformer from solely the conformer geometry. Second, it is found that the ML approach results in important time savings. Third, the ML model produced is unfortunately hardly transferable from one stereoisomer to another.

Attraction of Male Pine Sawflies, Diprion jingyuanensis, to Synthetic Pheromone Candidates: Synergism between Two Stereoisomers

The pine sawfly Diprion jingyuanensis Xiao and Zhang (Hymenoptera: Diprionidae) is a serious pest of Pinus tabulaeformis Carr. in the Shanxi, Gansu, and Inner Mongolia provinces in P. R. China. The sex pheromone of D. jingyuanensis was shown to be the propionate ester of 3,7-dimethyl-2-tridecanol. Virgin females contained an approximate 1:3 blend of the pheromone precursors erythro-(2S,3S,7R/S and 2R,3R,7R/S)-3,7-dimethyl-2-tridecanol and threo-(2S,3R,7R/S and 2R,3S,7R/S)-3,7-dimethyl-2-tridecanol, but the exact stereoisomers were not determined. Males responded the strongest to the propionate ester of the two threo-isomers, (2S,3R,7R) and (2S,3R,7S), in electroantennogram (EAG) recordings, followed by a significant EAG response to the (2S,3R,7R) propionate of diprionol (pheromone component of D. similis), whereas the remaining two isomers (2S,3S,7S and 2S,3S,7R) of the propionate ester of 3,7-dimethyl-2-tridecanol and the acetate of the (2S,3R,7R) isomer (one of the two pheromone components of D. pini) did not elicit any significant increase in antennal response. In the field, the strongly EAG-active (2S,3R,7R)-isomer alone was only weakly (but significantly) attractive to D. jingyuanensis males at 100 µg, while the equally EAG- active (2S,3R,7S)-isomer alone at the same loading was 8–14 times more attractive than was the (2S,3R,7R)-isomer alone. Traps baited with the same amounts of the two threo-isomers ((2S,3R,7R) and (2S,3R,7S), 100 µg + 100 µg) caught significantly more males than did traps baited with other isomers, either of the two isomers alone or other proportions of the two isomers. Thus, the (2S,3R,7S)-isomer is considered as a strong and essential sex-attractant component for D. jingyuanensis males, whereas the (2S,3R,7R)-isomer is a weak but synergistic sex-attractant. This is one of the few examples of a pine sawfly responding significantly stronger to a binary blend of stereoisomers in a synergistic fashion than to a single stereoisomer alone.

A Straightforward Synthesis of Emericellamide A Using Matteson’s Homologation Approach

AbstractThe Matteson homologation is the perfect approach for the synthesis of polyketide–peptide natural products such as the emericellamides. In only four steps, the polyketide fragment with three stereogenic centers can be obtained as a single stereoisomer. The peptide fragment is easily available via solid-phase peptide synthesis.

A combined experimental and computational chiroptical approach to establish the biosynthesis and absolute configuration of licochalcone L

Often, chiral natural products exist as single stereoisomers; however, simultaneous occurrences of both enantiomers can exist in nature, resulting in scalemic or racemic mixtures. Ascertaining theabsolute configuration (AC) of natural products is pivotal for attributing their specific biological signature. Specific rotation data commonly characterize chiral non-racemic natural products; however, measurement conditions, viz., solvent and concentration, can influence the sign of specific rotation values, especially when characterizing natural products possessing small values. For example, licochalcone L, a minor constituent of Glycyrrhiza inflata, was reported with a specific rotation of [α]D22= +13 (c 0.1, CHCl3); however, not establishing the AC and the reported zero specific rotation for an identical compound, licochalcone AF1, resulted in debatable chirality and its biogenesis. In this study, a combined experimental and computational chiroptical approach involving specific rotation and electronic circular dichroism (ECD) data, supported by time-dependent density functional theory (TDDFT), were effectively utilized to establish the AC of licochalcone L as the (E, 2″S)-isomer. Establishing the 2″S absolute configuration permitted the conception of a reasonable biosynthetic pathway involving intramolecular ‘5-exo-tet’ ring opening of a chiral oxirane to form chiral licochalcone L in G. inflata.

Desymmetric Reductive Amination of 1,3-Cyclopentadiones to Single Stereoisomer of β-Amino Ketones with an All-Carbon Quaternary Stereocenter by Engineered Amine Dehydrogenases

Regio- and stereoselective reductive amination of diketones offers an attractive method to access chiral β-amino ketones with multiple stereocenters which are unique scaffolds and building blocks for bioactive molecules, but it is still a great challenge in organic chemistry. In this study, mutant amine dehydrogenases (LsAmDHs) were created by directed evolution of a l-phenylalanine dehydrogenase from Lysinibacillus sphaericus to catalyze the desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones. Using these beneficial LsAmDHs, the corresponding (2R, 3R)-β-amino ketones with an all-carbon quaternary stereocenter were prepared with up to 99% de and ee and up to 84% isolated yields. A cyclopenta[b]hydroquinoline derivative was obtained from 2-methyl-2-(2′-bromobenzyl)-1,3-cyclopentadione or 2-methyl-2-(2′-chlorobenzyl)-1,3-cyclopentadione via sequential enzymatic desymmetric reductive amination and an intramolecular Buchwald–Hartwig cross coupling reaction. Molecular docking and dynamics simulations provided some insights into the roles of key mutations on the improved activity and excellent stereoselectivity toward these un-native substrates. This study not only developed biocatalysts to realize the unprecedented desymmetric reductive amination of 2,2-disubstituted-1,3-cyclopentadiones to the single stereoisomer of the corresponding β-amino ketones but also suggested that engineering of amine dehydrogenase provides a useful tool to address the challenges in asymmetric reductive amination of diketones.

Catalytic Homologation-Allylboration Sequence for Diastereo- and Enantioselective Synthesis of Densely Functionalized β-Fluorohydrins with Tertiary Fluoride Stereocenters.

Homologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of β-fluorohydrin and amine products. In the presence of (R)-iodo-BINOL catalyst enantioselectivities up to 99% can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C-F center.

Catalytic Homologation‐Allylboration Sequence for Diastereo‐ and Enantioselective Synthesis of Densely Functionalized β‐Fluorohydrins with Tertiary Fluoride Stereocenters

AbstractHomologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of β‐fluorohydrin and amine products. In the presence of (R)‐iodo‐BINOL catalyst enantioselectivities up to 99 % can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C−F center.

Catalytic Asymmetric Imine Cross-Coupling Reaction

Catalytic asymmetric cross-coupling of imines constitutes a particularly desirable method for the synthesis of chiral vicinal diamines directly from readily available achiral precursors. The potential of this method lies in the possibility of utilizing a variety of imines as reacting partners. However, the realization of highly stereoselective cross-coupling of two different imines proved to be a formidable challenge. Herein we report an unprecedented catalytic asymmetric cross-coupling reaction that tolerates a variety of ketimines and aldimines as nucleophiles and electrophiles, respectively. The realization of this reaction resulted from the development of a new chiral ammonium catalyst, which was guided by insights from studies of catalyst-substrate interactions. With a 0.5 mol % loading of an organocatalyst, this reaction proceeded in a highly diastereo- and enantioselective manner to afford a diverse range of chiral vicinal diamines as nearly single stereoisomers. This catalytic reaction establishes a new approach for the asymmetric synthesis of chiral vicinal diamines.

Synthesis of Chiral Hypervalent Trifluoromethyl Organobismuth Complexes and Enantioselective Olefin Difluorocarbenation Screenings.

Two hypervalent trifluoromethyl organobismuth complexes were prepared from commercially available chiral amines, (R)-1-cyclohexylethylamine and (1R, 2R, 3R, 5S)-(-)-isopinocampheylamine; however, only the complex from the latter amine was prepared as a single stereoisomer. Both organobismuth complexes were fully characterized by NMR spectroscopy and single-crystal X-ray crystallography, revealing that the structures were similar to previously reported complexes with a hypervalent Bi-N bond. The complexes were catalytically active in olefin difluorocarbenation with Ruppert-Prakash reagent (TMS-CF3 ) used as a terminal source of CF2 . The catalyst derived from isopinocampheylamine was screened with three prochiral olefins of various reactivity in DCM and toluene. All reactions afforded the 1,1-difluorocyclopropanes in good yields, but no enantiomeric excess was observed.

Chiral Silver Complex-Catalyzed Asymmetric Conjugate Addition of 1-Pyrroline-5-Carbonitrile to α-Enones.

The conjugated addition reaction of 1-pyrroline-5-carbonitrile to α-enones was effectively catalyzed by AgF/ThioClickFerrophos (TCF) in diethyl ether in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and nearly single diastereomers of adducts with good enantiomeric excesses (up to 97% ee) were obtained in high yields. The reduction of the nitrile group with H2/Raney Ni in ethanol successfully transformed the conjugate adduct to the corresponding spirocyclic piperidine (60% yield) as a single stereoisomer.

Terpyridine Diphosphine Ruthenium Complexes as Efficient Photocatalysts for the Transfer Hydrogenation of Carbonyl Compounds.

The cationic achiral and chiral terpyridine diphosphine ruthenium complexes [RuCl(PP)(tpy)]Cl (PP=dppp (1), (R,R)-Skewphos (2) and (S,S)-Skewphos (3)) are easily obtained in 85-88 % yield through a one-pot synthesis from [RuCl2 (PPh3 )3 ], the diphosphine and 2,2':6',2''-terpyridine (tpy) in 1-butanol. Treatment of 1-3 with NaPF6 in methanol at RT affords quantitatively the corresponding derivatives [RuCl(PP)(tpy)]PF6 (PP=dppp (1 a), (R,R)-Skewphos (2 a) and (S,S)-Skewphos (3 a)). Reaction of [RuCl2 (PPh3 )3 ] with (S,R)-Josiphos or (R)-BINAP in toluene, followed by treatment with tpy in 1-butanol and finally with NaPF6 in MeOH gives [RuCl(PP)(tpy)]PF6 (PP=(S,R)-Josiphos (4 a), (R)-BINAP (5 a)) isolated in 78 % and 86 % yield, respectively. The chiral derivatives have been isolated as single stereoisomers and 3 a, 4 a have been characterized by single crystal X-ray diffraction studies. The tpy complexes with NaOiPr display high photocatalytic activity in the transfer hydrogenation (TH) of carbonyl compounds using 2-propanol as the only hydrogen donor and visible light at 30 °C, at remarkably high S/C (up to 5000) and TOF values up to 264 h-1 . The chiral enantiomers 2, 2 a and 3, 3 a induce the asymmetric photocatalytic TH of acetophenone, affording (S)- and (R)-1-phenylethanol with 51 and 52 % ee, respectively, in a MeOH/2-propanol mixture.

Cobalt-Catalyzed Enantioconvergent Hydrogenation of Minimally Functionalized Isomeric Olefins.

Investigation on asymmetric hydrogenation of olefins is of great importance in both pharmaceutical molecule synthesis and chemical industry due to the high demand for enantiopure compounds. The established methods often require geometrically pure olefins. The enantioconvergent reaction provided the possibility to access a single stereoisomer via hydrogenation of E/Z-olefin mixtures; however, a polar functional group next to the carbon-carbon double bond was usually necessary. Here, we reported a cobalt-catalyzed enantioconvergent hydrogenation of readily available minimally functionalized E/Z-olefin mixtures. This strategy shows good functional group tolerance and provides an alternative means to enantioconvergent transformation. The preliminary mechanistic studies indicated that cobalt-catalyzed isomerization was the key to achieve the convergent transformation.

Syntheses and Aromaticity Parameters of Hexahydroxypyrrocorphin, Porphotrilactones, and Their Oxidation State Intermediates.

Triple OsO4-mediated dihydroxylation of meso-tetrakis(pentafluorophenyl)porphyrin formed a non-aromatic hexahydroxypyrrocorphin as a single stereo-isomer. A one-step oxidative conversion of all three diol functionalities to lactone moieties generated three out of the four possible porphotrilactone regioisomers that were spectroscopically and structurally characterized. This conversion recovered most of the porphyrinic macrocycle aromatic ring current, as seen in their 1H NMR spectra and modeled using DFT computations. Stepwise OsO4-mediated dihydroxylations of porpho-mono- and -di-lactones generated intermediate oxidation state compounds between the pyrrole-three pyrroline macrocycle of the pyrrocorphin and the pyrrole-three oxazolone chromophore of the trilactones. The aromaticity of these chromophores was reduced with increasing number of oxazolone to pyrroline replacements, showing the importance for the presence of three lactone moieties for the retention of the macrocycle aromaticity in the tris-β,β'-modified macrocycles. This work first describes hexahydoxypyrrocorphins, porphotrislactones, and the oxidation state intermediates between them; furthers the understanding of the roles of β-lactone moieties in the expression of porphyrinic macrocycle aromaticity; and generally broadens access to chemically stable pyrrocorphins and pyrrocorphin analogues.

Synthesis of Functionalized Five-Membered Heterocycles from Epoxides: A Hydrogen-Bond Donor Catalytic Approach.

The synthesis of highly functionalized five-membered oxa- and aza-heterocycles has been reported utilizing hydrogen-bond donor (HBD) catalysis. In this method, an epoxide was taken as a substrate and reacted with functionalized arylidene/alkylidene malononitrile derivatives in the presence of a newly designed HBD catalyst. In all the cases, the products 2,5-disubstituted tetrahydrofurans (2,5-THFs) were obtained in good to excellent yields (up to 86%) with high diastereoselectivity (dr up to 99:1) as a single regioisomer. The stereochemistry at the 2- and 5-positions of the five-membered ring has been confirmed by single-crystal X-ray analysis, and cis is found to be the major product. The same strategy has been further utilized to obtain substituted oxazolidines whenever the epoxide has been reacted with isocyanate as an electrophile. In order to induce enantioselectivity, a chiral epoxide has been reacted with both the electrophiles in the presence of the same catalyst system to afford the single stereoisomer of the final products. This synthetic methodology involves a low catalyst loading and ambient reaction condition and has been generalized with various substituents present in the starting electrophiles to produce the resultant products in acceptable yields and stereoselectivity.