Relative Stereochemistry Research Articles

Total Synthesis of Spiro[cyclohexane‐2‐indoline] Alkaloids: A Regio‐ and Diastereoselective Spirocyclization Approach

AbstractA direct spirocyclization approach for the chemical synthesis of spiro[cyclohexane‐2‐indoline] alkaloids is reported. The absolute stereochemistry was introduced by a desymmetrizing Dieckmann condensation, and the relative stereochemistry was controlled by the manipulation of the kinetic and thermodynamic pathways of the spirocyclization. By contrast to the biogenetic proposal involving the diester‐type alkaloid as the precursor, we demonstrate that chemically a common lactone‐type intermediate could bridge the chemical synthesis of this class of natural products.

Total Synthesis of Spiro[cyclohexane-2-indoline] Alkaloids: A Regio- and Diastereoselective Spirocyclization Approach.

A direct spirocyclization approach for the chemical synthesis of spiro[cyclohexane-2-indoline] alkaloids is reported. The absolute stereochemistry was introduced by a desymmetrizing Dieckmann condensation, and the relative stereochemistry was controlled by the manipulation of the kinetic and thermodynamic pathways of the spirocyclization. By contrast to the biogenetic proposal involving the diester-type alkaloid as the precursor, we demonstrate that chemically a common lactone-type intermediate could bridge the chemical synthesis of this class of natural products.

Diastereomerically pure (S)‐verbenone‐isoxazoline hybrids: Synthesis, molecular structure, Hirshfeld surface analysis, density functional theory, cytotoxic effect, and apoptosis induction

AbstractIn this paper, a new diastereomerically pure isoxazolines were efficiently prepared from (S)‐verbenone, the procedure involves a regioselective and a diastereoselective 1,3‐dipolar cycloaddition of nitrile oxides on the monoterpene's enone. The structures of the newly obtained cycloadducts were confirmed by analytical and spectral studies (HRMS, 1H NMR, and 13C NMR). The relative stereochemistry of isoxazoline compounds 3a, 3c, and 3d were confirmed by x‐ray single crystal analysis. Hirshfeld surface analysis and two‐dimensional fingerprint plots were performed to analyze the different intermolecular contacts in crystal packing. Further, density functional theory calculations have been used to analyze the electronic and geometric frontier molecular orbital and molecular electrostatic map analyses of the compounds to predict the reactive site. All compounds were evaluated in vitro for their cytotoxic activity against four human cancer cell lines including fibrosarcoma HT‐1080, lung carcinoma A‐549 and breast adenocarcinoma (MCF‐7 and MDA‐MB‐231). Compound 3d was the most potent compound especially against HT‐1080 and A‐549 cancer cells with IC50 values of 21.35 ± 1.51 and 14.92 ± 1.74 μM, respectively. Mechanistically, the compound 3d induced apoptosis by significant caspase activation in HT‐1080 and A‐549 cancer cell lines utilizing flow cytometric analysis and caspase 3/7 activation assay. The examined compound 3d caused S cell cycle arrest in both HT‐1080 and A‐549 cells.

Amitorin, a Cytotoxic Diterpenoid from a Sponge Halichondria sp.

A new diterpenoid endoperoxide showing cytotoxicity named amitorin (1) was isolated from an extract of a sponge Halichondria sp. Its structure along with relative stereochemistry was elucidated with spectral analysis and calculation studies. The structure and cytotoxicity (IC50 2.3 µM against NBT-II cells) of the molecule are described herein.

Briavioids A–C, discovery of new polyacetoxybriaranes from octocoral Briareum violaceum (Quoy & Gaimard, 1833)

Three new polyacetoxybriarane diterpenoids, briavioids A–C (1–3), as well as two known analogues, briaexcavatin M (4) and excavatolide F (5), were isolated from a cultured soft coral Briareum violaceum. The structures and relative stereochemistry of new metabolites 1–3 were assigned on the basis of NMR studies. Single-crystal X-ray diffraction analysis was performed to identify the structure of 1. Briaranes 1–5 were assessed in terms of their inflammation activity by screening their inhibition abilities against iNOS protein in LPS-stimulated RAW264.7 macrophage cells.

Inositol Derivatives with Anti-Inflammatory Activity from Leaves of Solanum capsicoides Allioni

Eight new inositol derivatives, solsurinositols A–H (1–8), were isolated from the 70% EtOH extract of the leaves of Solanum capsicoides Allioni. Careful isolation by silica gel column chromatography followed by preparative high-performance liquid chromatography (HPLC) allowed us to obtain analytically pure compounds 1–8. They shared the same relative stereochemistry on the ring but have different acyl groups attached to various hydroxyl groups. This was the first time that inositol derivatives have been isolated from this plant. The chemical structures of compounds 1–8 were characterized by extensive 1D nuclear magnetic resonance (NMR) and 2D NMR and mass analyses. Meanwhile, the in vitro anti-inflammatory activity of all compounds was determined using lipopolysaccharide (LPS)-induced BV2 microglia, and among the isolates, compounds 5 (IC50 = 11.21 ± 0.14 µM) and 7 (IC50 = 14.5 ± 1.22 µM) were shown to have potential anti-inflammatory activity.

Mechanistic Basis for the Iridium-Catalyzed Enantioselective Allylation of Alkenyl Boronates.

Iridium(phosphoramidite) complexes catalyze an enantio- and diastereoselective three-component coupling reaction of alkenyl boronic esters, organolithium reagents, and secondary allylic carbonates. The reaction proceeds through an allylation-induced 1,2-metalate shift of the alkenyl boronate to form non-adjacent stereocenters. Mechanistic investigations outline the overall catalytic cycle and reveal trends in reactivity and selectivity. Analysis of relative stereochemistry in products derived from a variety of 1,1-disubtituted alkenyl boronates provides insight into the transition state of the addition and indicates a concerted pathway. Kinetic analysis of the reaction revealed the kinetic order dependence in boronate, the catalyst, and both the slow- and fast-reacting enantiomer of allylic carbonate as well as the turnover-limiting step of the reaction. Determination of nucleophile-specific parameters N and sN for alkenyl boronate complexes enabled comparison to other classes of nucleophiles. DFT calculations indicate the addition of the alkenyl boronate to the cationic Ir(π-allyl) intermediate and the 1,2-metalate shift occur in a concerted mechanism. The stereoselectivity is determined by ligand-substrate steric repulsions and dispersion interactions in the syn addition transition state. Hammett studies supported the computational results with regard to electronic trends observed with both aryl-derived alkenyl boronates and aryl carbonates.

Ir and NHC Dual Chiral Synergetic Catalysis: Mechanism and Stereoselectivity in γ-Butyrolactone Formation.

Cooperative dual catalysis is a powerful strategy for achieving unique reactivity by combining catalysts with orthogonal modes of action. This approach allows for independent control of the absolute and relative stereochemistry of the product. Despite its potential utility, the combination of N-heterocyclic carbene (NHC) organocatalysis and transition metal catalysis has remained a formidable challenge as NHCs readily coordinate metal centers. This characteristic also makes it difficult to rationalize or predict the stereochemical outcomes of these reactions. Herein, we use quantum mechanical calculations to investigate formation of γ-butyrolactones from aldehydes and allyl cyclic carbonates by means of an NHC organocatalyst and an iridium catalyst. Stereoconvergent activation of the racemic allyl cyclic carbonate forms an Ir-π-allyl intermediate and activation of an unsaturated aldehyde forms an NHC enolate, the latter of which is rate-limiting. Union of the two fragments leads to stereodetermining C-C bond formation and ultimately ring closure to generate the product lactone. Notably, CO2 loss occurs after formation of the C-C bond and Et3NH+ plays a key role in stabilizing carboxylate intermediates and in facilitating proton transfer to form the NHC enolate. The computed pathways agree with the experimental findings in terms of the absolute configuration, the enantiomer excess, and the different diastereomers seen with the (R)- and (S)-spiro-phosphoramidite combined with the NHC catalyst. Calculations reveal the lowest energy pathway includes both an NHC ligand and a phosphoramidite ligand on the iridium center. However, the stereochemical features of this Ir-bound NHC were found to not contribute to the selectivity of the process.

A new capnellene skeleton from the octocoral Capnella imbricata (Quoy & Gaimard, 1833)

Chemical investigations on the ethyl acetate extract of the octocoral Capnella imbricata collected from the waters of Taiwan, which led to the isolation of three capnellenes (1–3), including one new metabolite, △9(12)-capnellene-8β,10α,15-triol (1), along with two known metabolites, △9(12)-capnellene-5α,8β,10α-triol (2), and △9(12)-capnellene-8β,10α-diol (3). The structures of the isolated metabolites were elucidated through extensive spectroscopic analyses, while the relative stereochemistry of 3 was confirmed by a single-crystal X-ray diffraction analysis for the first time in this study. Compounds 1–3 were evaluated in terms of their anti-inflammatory activity by examining their inhibitory effects on the generation of superoxide anions and the release of elastase by human neutrophils.

Cycloiridated Helicenes as Chiral Catalysts in the Asymmetric Transfer Hydrogenation of Imines

The asymmetric synthesis of optically pure and conformationally locked oxabenzo[5]helicenes bearing pyridin-2-yl or isoquinolin-3-yl substituents and their transformation into the corresponding cycloiridated organometallics are described. These helically chiral Cp*IrIII(X)C,N-complexes (X = Cl, I) also contain a configurationally unstable pseudotetrahedral iridium center. This center undergoes epimerization at room temperature, and its relative stereochemistry, especially in the solid state, depends on the nature of the coordinated ligands. Cycloiridated helicenes were used in the asymmetric transfer hydrogenation of prochiral aromatic imines with formic acid/triethylamine to reach up to 96:4 er. It is assumed that the chirality transfer is controlled by the auxiliary helix rather than the IrIII stereogenic center of the chiral iridacycles.

A Concise Synthesis of Pleurotin Enabled by a Nontraditional C-H Epimerization.

An 8-step synthesis of a known pentacyclic intermediate toward the natural product pleurotin (1) is described. Pleurotin and related benzoquinone natural products are of great interest for their powerful anticancer and antibiotic activities. The route features a regio- and diastereoselective intermolecular photoenolization/Diels-Alder cycloaddition and an alkoxy-radical-induced hydrogen atom transfer-mediated C-H epimerization to construct pleurotin's carbon framework with appropriate relative stereochemical relationships. The synthesis concludes with a ring-forming benzylic C-H oxidation to deliver oxepane 19.

An Intramolecular Hydroaminomethylation-Based Approach to Pyrrolizidine Alkaloids under Microwave-Assisted Heating

A general method for the synthesis of pyrrolizidine derivatives using an intramolecular hydroaminomethylation protocol (HAM) under microwave (MW) dielectric heating is reported. Starting from a 3,4-bis(benzyloxy)-2-[(benzyloxy)methyl]-5-vinylpyrrolidine, MW-assisted intramolecular HAM in the presence of gaseous H2 and CO gave the natural alkaloid hyacinthacine A2 protected as benzyl ether. The same approach gave a lentiginosine analogue starting from the corresponding vinyl N-hydroxypyrrolidine. The nature of the reaction products and the yields were strongly influenced by the relative stereochemistry of the starting pyrrolidines, as well as by the catalyst/ligand employed. The use of ethanol as a solvent provides environmentally friendly conditions, while the ligand/catalyst system can be recovered by separating the alkaloid product with an SCX column and recycling the ethanolic solution. HAM worked up to three times with the recycled catalyst solution without any significant impact on yield.

A Simple and Efficient Two-step Synthesis of Hexahydro-diazecane-dione Derivatives

Various substituted Dispiro [pyrrolo-piperazino-oxindole] have been synthesized by utilizing a simple and efficient two-step synthetic protocol by Grubbs metathesis in dichloromethane at 40°C. The structures and relative stereochemistry of the cycloadduct were confirmed by single-crystal X-ray diffraction, 1H and 13C NMR spectroscopy, and mass spectrometry.
 
 Keywords: Hexahydro-diazecane-dione, Metathesis, Cycloaddition, Grubbs Catalyst.

New halogenated C15 acetogenins from Okinawan sea hare Aplysia dactylomela

Two new C15 acetogenins 1 and 2, along with four known sesquiterpenes isolaurenisol (3), laurokamurene D (4), itomanol (5), and acetylelatol (6), were isolated from sea hare Aplysia dactylomela. The structures, including the relative stereochemistries, of 1 and 2 were determined based on spectroscopic evidence. Finally, the in vitro cytotoxicities of the six compounds against S1T cells, an adult T-cell leukemia cell line, were evaluated.

Unified total synthesis of eburnamine-vincamine indole alkaloids based on catalytic asymmetric hydrogenation/lactamization cascade

The enantioselective total synthesis of representative members of the eburnamine-vincamine alkaloids (+)-vincamine, (−)-eburnamonine, and (−)-criocerine has been accomplished. The synthesis took advantage of a highly stereoselective Ir-catalyzed hydrogenation/lactamization cascade reaction, which allows for the stereoselective construction of the C/D rings as well as the installation of the critical cis-C20/C21 relative stereochemistry of the eburnamine-vincamine alkaloid skeleton in one pot.

Retusone A, a Guaiane-Type Sesquiterpene Dimer from Wikstroemia retusa and Its Inhibitory Effects on Histone Acetyltransferase HBO1 Expression.

Retusone A (1), a new sesquiterpene dimer consisting of two guaiane-type sesquiterpenoids, and oleodaphnal (2) were isolated from heartwood of Wikstroemia retusa (Thymelaeaceae). The planar structure of 1 was elucidated on the basis of HRESIMS and NMR spectroscopic data, and the relative stereochemistry was established by X-ray diffraction analysis. The absolute configuration of 1 was determined by electronic circular dichroism. Compound 1 suppressed luciferase reporter gene expression driven by the HBO1 (histone acetyltransferase binding to ORC1) gene promoter in human breast cancer MCF7 cells. Compound 1 also decreased the expression of endogenous HBO1 mRNA and protein, and inhibited proliferation of the cells. These results suggest that retusone A (1), which has a unique dimeric sesquiterpenoid structure with inhibitory activity against HBO1 expression, may contribute to the development of a novel therapeutic candidate for the treatment of breast cancer.

Stereodivergent total synthesis of rocaglaol initiated by synergistic dual-metal-catalyzed asymmetric allylation of benzofuran-3(2H)-one

<h2>Summary</h2> The stereodivergent total synthesis of all stereoisomers of bioactive natural compounds to enable complete evaluation of stereochemical structure-activity relationships is highly challenging and valuable. Naturally occurring flavaglines, containing a compact functionalized cyclopenta[<i>b</i>]benzofuran scaffold, display a wide range of biological activities. Herein, we disclose a novel stereodivergent allylic alkylation of benzofuran-3(2<i>H</i>)-one that relies on the synergistic catalysis of a chiral <i>N</i>,<i>N</i>′-dioxide-Co(or Ni) complex and a phosphoramidite-Ir catalyst. All four possible stereoisomers of the α-allylated product are provided with excellent diastereo- and enantioselectivities by appropriate permutations of the two chiral catalysts. The concise synthesis of the targeted molecule rocaglaol is furnished in a stereodivergent manner, following a uniform synthetic route and using the same set of starting materials. Subsequently, a preliminary study on the anticancer activity for eight stereoisomers of rocaglaol reveals the pronounced influence of stereochemistry variations on biological activity.

Chiral Analysis of Linalool, an Important Natural Fragrance and Flavor Compound, by Molecular Rotational Resonance Spectroscopy

The chiral analysis of terpenes in complex mixtures of essential oils, necessary for authentication, has been further developed using chiral tagging molecular rotational resonance (MRR) spectroscopy. One analyte that is of particular interest is linalool (3,7-dimethyl-1,6-octadien-3-ol), a common natural chiral terpene found in botanicals with its enantiomers having unique flavor, fragrance, and aromatherapy characteristics. In this MRR demonstration, resolution of the enantiomers is achieved through the addition of a chiral tag, which creates non-covalent diastereomeric complexes with distinct spectral signatures. The relative stereochemistry of the complexes is identified by the comparison of calculated spectroscopic parameters with experimentally determined parameters of the chiral complexes with high accuracy. The diastereomeric complex intensities are analyzed to determine the absolute configuration (AC) and enantiomeric excess (EE) in each sample. Here, we demonstrate the use of chiral tagging MRR spectroscopy to perform a quantitative routine enantiomer analysis of linalool in complex essential oil mixtures, without the need for reference samples or chromatographic separation.

Structural Analysis of the Michael-Michael Ring Closure (MIMIRC) Reaction Products.

A representative number of decalin and hydrindane derivatives 2a–l were prepared in 11–91% yield by means of a cascade reaction of cyclohexanone/cyclopentanone enolates and methyl acrylate through a Michael–Michael ring closure (MIMIRC) process. The relative stereochemistry of the four stereogenic centers formed in all products was determined by analyzing the vicinal coupling constants from the 1H NMR and X-ray crystallography. Such a stereochemical outcome was corroborated by conformational analysis supported by DFT calculations and simulating the 1H NMR spectra of representative products. All products showed the same relative stereochemistry at C-1 and C-8a, while at C-3 and bridgehead carbon C-4a, configurational changes were observed. The present results provide some insights about the scope and limitations of the triple cascade reaction between cycloalkanone enolates with methyl acrylate. This synthetic protocol is still a simple and very practical alternative to generate decalin and hydrindane derivatives with great structural diversity.

Sesquiterpenoids from the rhizomes of Homalomena pendula and their anti-inflammatory activities

Sixteen sesquiterpenoids including two new ones, homalolides A − B (1‒2), were firstly isolated from the methanolic extract of the rhizomes of Homalomena pendula collected in Vietnam. The structures and relative stereochemistry of new compounds were elucidated by 1D-/2D-NMR, IR, UV and HRESIMS analyses. The GCMS experiment demonstrated that homalolide A (1) is an artifact due to the methylation during methanolic extraction process. All isolates (1‒16) were tested for their inhibitory activities against lipopolysaccharide-induced nitric oxide production in the RAW 264.7 macrophage cell line. Compounds 1, 3, 6‒8, 10‒12 displayed moderate inhibitory effect on NO production with IC50 values ranging from 35.41 to 64.06 μM.