Stereogenic Carbon Research Articles

Nickel‐Catalyzed Reductive Cross‐Coupling of α–Trifluoromethylated Alkyl Electrophiles and Allylic Sulfones

AbstractFluorinated motifs are commonly found in drugs and agrochemicals. The inclusion of fluorine‐containing motifs in drug candidates during lead optimization has become a valuable strategy in pharmaceutical research and development. Significant research efforts have been dedicated to synthesizing molecules with a trifluoromethyl (CF3−) group on a stereogenic carbon. Herein, we disclose a mild and efficient nickel‐catalyzed reductive cross‐coupling between α–trifluoromethyl alkyl bromides and allylic sulfones, enabling the efficient synthesis of α–trifluoromethyl homoallylic alkanes. This reaction featuring base‐free, mild conditions, a broad substrate scope, and high functional group tolerance. The synthetic versatility of this approach is further underscored by its successful application in the late‐stage functionalization of a range of drug molecules. Our preliminary mechanistic study suggests that this allylation process operates through a radical intermediate.

Monoterpene Hydroxy Lactones Isolated from Thalassiosira sp. Microalga and Their Antibacterial and Antioxidant Activities.

Two monoterpenoid lactones, loliolide (1) and epi-loliolide (2), were isolated from the crude dichloromethane extract of a microalga, Thalassiosira sp.). The structures of loliolide (1) and epi-loliolide (2) were elucidated by 1D and 2D NMR analysis, as well as a comparison of their 1H or/and 13C NMR data with those reported in the literature. In the case of loliolide (1), the absolute configurations of its stereogenic carbons were confirmed by X-ray analysis, whereas those of epi-loliolide (2) were determined by NOESY correlations. Loliolide (1) and epi-loliolide (2) were tested for their growth inhibitory activity against two Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and two Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) bacteria, as well as one clinical isolate (E. coli SA/2, an extended-spectrum β-lactamase producer-ESBL) and two environmental isolates, S. aureus 74/24, a methicillin-resistant (MRSA), and E. faecalis B3/101, a vancomycin-resistant (VRE) isolates. The results showed that none of the tested compounds exhibited antibacterial activity at the highest concentrations tested (325 μM), and both revealed low antioxidant activity, with ORAC values of 2.786 ± 0.070 and 2.520 ± 0.319 µmol TE/100 mg for loliolide (1) and epi-loliolide (2), respectively.

Twist along Central C-C Bonds in a Series of Fully π-Fused Propellanes.

Without stereogenic carbon centers, organic molecules can be chiral when they have large energy barriers for conformational inversion. In this work, conformational behaviors are investigated for a series of tricyclic propellane skeletons with increasing 6-membered-ring peripheral moieties fused with aromatic rings. According to theoretical calculations, trinaphtho[3.3.3]propellane has three vertical naphthalene rings like triptycene shape without torsion along the central C-C single bond. On the other hand, hexabenzo[4.4.4]propellane shows hexaphenylethane-like ca. 60° twist along the bond with large activation energy of 64 kcal mol-1 for twist inversion because of the high congestion caused by three 6-membered-ring loops. Indeed, the [4.4.4]propellane gives a stable pair of chiroptical enantiomers toward heating at 146 °C. By contrast, a hybrid [4.3.3]propellane exhibits fast interconversion between two twisted conformations even at -80 °C.

Synthesis of Axially Chiral Monofluoroalkenes via Nickel-Catalyzed Reductive Cross-Coupling of gem-Difluoroalkenes.

Enantioenriched monofluoroalkenes are important structural motifs in life science and functional materials. To date, only limited strategies were reported for the synthesis of monofluoroalkenes with stereogenic carbon centers; the axially chiral counterpart is still highly desirable. Herein, we report Ni-catalyzed defluorinative cross-electrophile coupling of gem-difluoroalkenes with biaryl electrophiles for the synthesis of axially chiral monofluoroalkenes. The resulting axially chiral monofluoroalkenes are formed with excellent regio- and stereoselectivities. Synthetic transformation of these axially enantioenriched monofluoroalkenes was also demonstrated.

Novel Metabolites from the Marine-Derived Fungus Peniophora sp. SCSIO41203 Show Promising In Vitro Antitumor Activity as Methuosis Inducers in PC-3 Cells.

Two new cytochalasin derivatives, peniotrinins A (1) and B (2), three new citrinin derivatives, peniotrinins C-E (4, 5, 7), and one new tetramic acid derivative, peniotrinin F (12), along with nine structurally related known compounds, were isolated from the solid culture of Peniophora sp. SCSIO41203. Their structures, including the absolute configurations of their stereogenic carbons, were fully elucidated based on spectroscopic analysis, quantum chemical calculations, and the calculated ECD. Interestingly, 1 is the first example of a rare 6/5/5/5/6/13 hexacyclic cytochalasin. We screened the above compounds for their anti-prostate cancer activity and found that compound 3 had a significant anti-prostate cancer cell proliferation effect, while compounds 1 and 2 showed weak activity at 10 μM. We then confirmed that compound 3 exerts its anti-prostate cancer effect by inducing methuosis through transmission electron microscopy and cellular immunostaining, which suggested that compound 3 might be first reported as a potential anti-prostate methuosis inducer.

Biocatalytic, Enantioenriched Primary Amination of Tertiary C-H Bonds.

Intermolecular functionalization of tertiary C-H bonds to construct fully substituted stereogenic carbon centers represents a formidable challenge: without the assistance of directing groups, state-of-the-art catalysts struggle to introduce chirality to racemic tertiary sp 3 -carbon centers. Direct asymmetric functionalization of such centers is a worthy reactivity and selectivity goal for modern biocatalysis. Here we present an engineered nitrene transferase (P411-TEA-5274), derived from a bacterial cytochrome P450, that is capable of aminating tertiary C-H bonds to provide chiral α-tertiary primary amines with high efficiency (up to 2300 total turnovers) and selectivity (up to >99% enantiomeric excess (e.e.)). The construction of fully substituted stereocenters with methyl and ethyl groups underscores the enzyme's remarkable selectivity. A comprehensive substrate scope study demonstrates the biocatalyst's compatibility with diverse functional groups and tertiary C-H bonds. Mechanistic studies elucidate how active-site residues distinguish between the enantiomers and enable the enzyme to perform this transformation with excellent enantioselectivity.

One-Carbon Homologation of Knoevenagel Adducts: Enantioselective Access to Benzhydryl Derivatives.

A one-carbon homologation of Knoevenagel adducts enabling the insertion of a CHAr fragment is reported. The strategy involves a sulfur ylide mediated cyclopropanation followed by the rearrangement of cyclopropanes and enables the synthesis of a series of benzhydryl derivatives. Mechanistic studies reveal that the cyclopropane rearrangement involves a Lewis acid catalyzed ring-opening followed by the 1,2-migration of an aryl group. The possibility of controlling the absolute stereochemistry of the generated stereogenic allylic carbon center using a chiral sulfonium ylide is demonstrated.

Lemneolemnanes A-D, Four Uncommon Sesquiterpenoids from the Soft Coral Lemnalia sp.

Four undescribed sesquiterpenoids, lemneolemnanes A-D (1-4), have been isolated from the marine soft coral Lemnalia sp. The absolute configurations of the stereogenic carbons of 1-4 were determined by single-crystal X-ray crystallographic analysis. Compounds 1 and 2 are epimers at C-3 and have an unusual skeleton with a formyl group on C-6. Compound 3 possesses an uncommonly rearranged carbon skeleton, while 4 has a 6/5/5 tricyclic system. Compound 1 showed significant anti-Alzheimer's disease (AD) activity in a humanized Caenorhabditis elegans AD pathological model.

Hydroxytakakiamide and Other Constituents from a Marine Sponge-Associated Fungus Aspergillus fischeri MMERU23, and Antinociceptive Activity of Ergosterol Acetate, Acetylaszonalenin and Helvolic Acid.

An unreported prenylated indole derivative hydroxytakakiamide (4) was isolated, together with the previously described ergosterol (1), ergosterol acetate (2), and (3R)-3-(1H-indol-3-ylmethyl)-3, 4-dihydro-1H-1,4-benzodiazepine-2,5-dione (3), from the column fractions of the crude ethyl acetate extract of the culture of a marine sponge-associated fungus, Aspergillus fischeri MMERU 23. The structure of 4 was elucidated by the interpretation of 1D and 2D NMR spectral data and high-resolution mass spectrum. The absolute configuration of the stereogenic carbon in 3 was proposed to be the same as those of the co-occurring congeners on the basis of their biogenetic consideration and was supported by the comparison of its sign of optical rotation with those of its steroisomers. The crude ethyl acetate extract and 2 were evaluated, together with acetylaszonalenin (5) and helvolic acid (6), which were previously isolated from the same extract, for the in vivo antinociceptive activity in the mice model. The crude ethyl acetate extract exhibited antinociceptive activity in the acetic acid-induced writhing and formalin tests, while 2, 5, and 6 displayed the effects in the late phase of the formalin test. On the other hand, neither the crude ethyl acetate extract nor 2, 5, and 6 affected the motor performance of mice in both open-field and rotarod tests. Additionally, docking studies of 2, 5, and 6 were performed with 5-lipoxygenase (5-LOX) and phosphodiesterase (PDE) enzymes, PDE4 and PDE7, which are directly related to pain and inflammatory processes. Molecular docking showed that 6 has low affinity energy to PDE4 and PDE7 targets while retaining high affinity to 5-LOX. On the other hand, while 2 did not display any hydrogen bond interactions in any of its complexes, it achieved overall better energy values than 6 on the three antinociceptive targets. On the other hand, 5 has the best energy profile of all the docked compounds and was able to reproduce the crystallographic interactions of the 5-LOX complex.

Rapid Access to cis-1,3-Dialkylindanes: Asymmetric Formal Syntheses of epi-Mutisianthol and epi-Jungianol

AbstractConcise and strategically unique asymmetric formal syntheses of epi-mutisianthol and epi-jungianol are presented. A novel disconnection approach is introduced to complement previous intramolecular cyclopentannulation strategies. Noteworthy features include: (a) control of the stereogenic benzylic carbon center through 1,3-chirality transfer from chiral indenols via the Johnson–Claisen rearrangement, which yields advanced indene-containing γ,δ-unsaturated esters, and (b) the diastereoselective construction of the cis-1,3-dialkylindane backbone via catalytic hydrogenation of the resulting indene. This approach presents a remarkable method for synthesizing structurally intriguing indane motifs.

Enantioselective Ir-Catalyzed Allyl Alkylation/Semipinacol Rearrangement.

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

Stereoselective Construction of Vicinal Quaternary Stereocenters via the 1,6-Conjugate Addition of β,β-Disubstituted N-Sulfinyl Metalloenamines to Isatin-Derived para-Quinone Methides

AbstractA 1,6-conjugate addition reaction of β,β-disubstituted N-tert-butanesulfinyl metalloenamines, generated via stereospecific α-deprotonation of enantioenriched α,α-disubstituted ketimines or deprotonation of the NH in geometry-defined enesulfinamides, with isatin-derived para-quinone methides is developed to build vicinal quaternary stereocenters with high stereocontrol. The resulting 3,3-disubstituted oxindoles contain a less-accessible acyclic quaternary stereogenic carbon substituted with two sterically and electronically similar groups at the α-position of the imino group. This protocol constitutes a rare example of the stereoselective construction of vicinal quaternary stereocenters via the conjugate addition of acyclic enolates/aza-enolates bearing two similar β-substituents.

Enantioselective synthesis of molecules with multiple stereogenic elements.

This review explores the fascinating world of molecules featuring multiple stereogenic elements, unraveling the different strategies designed over the years for their enantioselective synthesis. Specifically, (dynamic) kinetic resolutions, desymmetrisations and simultaneous installation of stereogenic elements exploiting either metal- or organo-catalysis are the principal approaches to efficiently create and control the three-dimensional shapes of these attractive molecules. Although most molecules presented in this review possess a stereogenic carbon atom in combination with a stereogenic axis, other combinations with helices or planes of chirality have started to emerge, as well as molecules displaying more than two different stereogenic elements.

Modular α-tertiary amino ester synthesis through cobalt-catalysed asymmetric aza-Barbier reaction.

Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

Kueishanamides A and B from the Hydrothermal Vent Sediment Derived Streptomyces sp. WU20.

Marine actinomycetes are known for their production of remarkable organic molecules, particularly those featuring polyoxygenated long-chain backbones. Determining the absolute configurations of these compounds remains a challenging task even today. In this study, we successfully established the planar structures and absolute configurations of two highly flexible amide alkaloids from Streptomyces sp. WU20: kueishanamides A (1) and B (2). These compounds possess a C13 linear backbone and each contains five stereogenic carbon centers. Our approach involved a combination of spectroscopic and computational methods, including J-based configurational analysis and VCD calculations, ensuring the unambiguous determination of their configurations. Kueishanamide A (1) and kueishanamide B (2) showed moderate antifungal activity against pathogenic fungus Crytococcus neoformans, with MIC values of 25 μg/mL each.

Enantio- and Diastereoselective Copper-Catalyzed Synthesis of Chiral Aziridines with Vicinal Tetrasubstituted Stereocenters.

A Cu-catalyzed coupling of cyclic imino esters with 2H-azirines has been developed to synthesize novel optically active aziridines in high yields with excellent levels of diastereo- and enantioselectivities under mild conditions. This novel protocol features a broad substrate scope and good functional group compatibility, and it enriches the existing reaction type of rapid synthesis of optically active aziridines bearing vicinal tetrasubstituted stereogenic carbon centers.

Ni‐Catalyzed Regio‐ and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5‐Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis

AbstractAsymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio‐ and enantioselective synthesis of chiral 1,5‐dienes featuring quaternary stereocenters is reported via nickel‐promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo‐ and E‐selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)‐allyl intermediates empowering a unique formal bimetallic cross‐electrophile manifold in two separate kinetic regimes.

Ni-Catalyzed Regio- and Enantioselective Homoallylic Coupling: Synthesis of Chiral Branched 1,5-Dienes Featuring a Quaternary Stereogenic Center and Mechanistic Analysis.

Asymmetric synthesis of small molecules comprising quaternary stereogenic carbon centers represents a challenging objective. Here regio- and enantioselective synthesis of chiral 1,5-dienes featuring quaternary stereocenters is reported via nickel-promoted by reductive homoallylic coupling. The developed methodology features an atypical preference for the formation of unusual branched regioisomers (rr >20 : 1) in a sterically challenging allylic substitution event and furnishes the products with enantiomeric ratios of up to 98 : 2 and with high chemo- and E-selectivity. A range of experimental evidences suggest that zinc plays a dual role to generate electrophilic and nucleophilic Ni(II)-allyl intermediates empowering a unique formal bimetallic cross-electrophile manifold in two separate kinetic regimes.

Chiral-Boron-Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of β-Trifluoromethyl α,β-Unsaturated Ketones with N,N'-Cyclic Azomethine Imines.

The (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-boron-complex-catalyzed asymmetric 1,3-dipolar cycloaddition of β-trifluoromethyl α,β-unsaturated ketone with N,N'-cyclic azomethine imines was developed to afford N,N'-bicyclic pyrazolidine derivatives bearing a stereogenic carbon center containing CF3 motifs in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This catalytic system features mild reaction conditions, high efficiency, and a broad substrate scope.

Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization

Abstract2,5‐Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by a photochemical deracemization (53 examples, 74 % to quantitative yield, 71–99 % ee). A chiral benzophenone catalyst in concert with irradiation at λ=366 nm enables to establish the configuration at the stereogenic carbon atom C6 at will. If other stereogenic centers are present in the diketopiperazines they remain unaffected and a stereochemical editing is possible at a single position. Consecutive reactions, including the conversion into N‐aryl or N‐alkyl amino acids or the reduction to piperazines, occur without compromising the newly created stereogenic center. Transient absorption spectroscopy revealed that the benzophenone catalyst processes one enantiomer of the 2,5‐diketopiperazines preferentially and enables a reversible hydrogen atom transfer that is responsible for the deracemization process. The remarkably long lifetime of the protonated ketyl radical implies a yet unprecedented mode of action.