Major Diastereoisomer Research Articles

Diastereomeric N,S-Dialkyl Dithiocarbamates Derived from (E)-Chalcones and ʟ-Tryptophan: Microwave-Assisted Synthesis and In Vitro Studies Against Fusarium oxysporum

The synthesis of indole phytoalexin-like analogs related to alkyl (((1-(4-substitutedphenyl)-3-oxo-3-phenylpropyl)thio)carbonothioyl)-ʟ-tryptophanate 1a–d and the evaluation of their antifungal activity against the phytopathogen Fusarium oxysporum is reported. The target compounds were synthesized in the following two stages: (1) the initial esterification of ʟ-tryptophan, which reacted with trimethyl silane chloride and simple aliphatic alcohols (R = Me, Et) under microwave irradiation (MWI) at 100 °C to obtain the respective alkyl ester 2a–b; (2) the resulting mixture of ʟ-tryptophanates 2a–b with carbon disulfide and (E)-chalcone 3a–b under MWI at 50 °C during 60 min, followed by purification through classical column chromatography (55–76% yields). The products were obtained as mixtures of (S,R) and (S,S) diastereoisomers. An LC-DAD-MS analysis allowed us to establish the ratio of these diastereoisomers, and subsequent DFT/B3LYP-based computational calculations of the NMR 1H chemical shifts suggested that the major diastereoisomer involved an (S,R) absolute configuration, comprising more than 60% of the mixture. The compounds 1a–d were subjected to an antifungal activity test against the phytopathogen F. oxysporum using an amended medium-based assay. Compound series 1 showed inhibition percentages of 80% at the first concentration and IC50 values between 0.33 and 5.71 mM, demonstrating greater potential as antifungal agents compared to other ʟ-tryptophan derivatives like alkyl (2S)-3-(1H-indol-3-yl)-2-{[(1Z)-3-oxobut-1-en-1-yl]amino}propanoate, which presented lower inhibition percentages. In summary, phytoalexin analogs derived from ʟ-tryptophan and (E)-chalcones significantly inhibited the mycelial growth of Fusarium oxysporum, indicating their potential as effective antifungal agents.

Enantioselective Preparation of Cyclopentene-Based Amino Acids with a Quaternary Carbon Center.

Azlactone is an important starting material for synthesizing amino acids containing a quaternary α-carbon. In this study, we have developed a sequential "one-pot" procedure involving an enantioselective spirocyclization reaction followed by acidic azlactone opening, which led to amino acid derivatives. The key step of this procedure is a spirocyclization between propargylated azlactones and enals by using a cooperative catalytic approach that combines chiral secondary amine and achiral Pd(0) complexes. The final acid opening of the azlactone motif allows isolation of the corresponding amino acid derivatives as major diastereoisomers in yields ranging from 37% to 70% with enantioselectivities of 85-97% ee. These synthesized amino acid derivatives hold great potential in the pharmaceutical and bioactive compound industries. Moreover, the final amino acid products with a cyclopentene moiety can be further derivatized, opening up even more possibilities for their application.

Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Enantioselective (3+2) Annulation of Donor‐Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted‐base catalyzed enantioselective (3+2) annulation of donor‐acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5‐substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic β‐cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis‐2,5‐substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans‐cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Total Synthesis of (+)-Prezizaan-15-ol, (+)-Jinkohol II, and (+)-Jinkoholic Acid.

A recently developed photochemical cascade reaction provides access to diastereomeric pentacyclic products, which display the carbon skeleton of prezizane natural products. The minor diastereoisomer with a 2β-Me configuration was converted in 12 reaction steps into (+)-prezizaan-15-ol. The major diastereoisomer with a 2α-Me configuration gave in an analogous route (+)-jinkohol II, which was oxidized at C13 to (+)-jinkoholic acid. A previous ambiguity regarding the configuration of the natural products could be clarified by total synthesis.

Influence of Achiral Phosphine Ligands on a Synergistic Organo- and Palladium-Catalyzed Asymmetric Allylic Alkylation.

An unusual diastereodivergent stereoselective allylation reaction is presented. It consists of a palladium-catalyzed allylation reaction of an organocatalytically generated amino isobenzofulvene, where the diastereoselectivity is controlled by the electronic properties of a monodentate, achiral ligand on palladium. One major diastereoisomer is formed using triarylphosphines substituted with neutral or electron-donating substituents of the aryl group, while those with electron-withdrawing substituents favor the other diastereoisomer. The diastereoselectivity correlates with the Taft inductive parameter of substituents on the triarylphosphine ligand on palladium. The synergistic reaction involves both a catalytic secondary amine catalyst for the indene-aldehyde activation and the monodentate phosphine ligands on palladium, affording a highly enantioselective reaction with up to 98 % enantiomeric excess. Based on computational investigations, the role of the monodentate phosphine ligand on the diastereoselectivity is discussed.

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Asymmetric synthesis of (1R,5S)-2-methyl-6,7-benzomorphan via Aza-Prins reaction.

(1R,5S)-2-Methyl-6,7-benzomorphan has been synthesised from (R)-(benzyloxy)(phenyl)acetaldehyde. On a 2-mmol scale Bi (OTf)3 promoted Aza-Prins reaction with N-tosylhomoallylamine afforded an 88/12 mixture of 6-oxa-2-azabicyclo[3.2.1]octanes. Major diastereoisomer was converted to enantiomerically pure (2S,4S)-2-benzyl-1- methylpiperidin-4-ol via a high-yielding sequence hydrogenolysis/N-detosylation/N-methylation. Acid-catalysed intramolecular Friedel-Crafts cyclisation of the piperidinol afforded (1R,5S)-2-methyl-6,7-benzomorphan in five steps with a yield of 25%.

Diastereoselective synthesis of chiral 3-substituted isoindolinones via rhodium(III)-catalyzed oxidative C-H olefination/annulation.

A new method for the direct and stereoselective synthesis of 3-substituted isoindolinones via Rh(iii)-catalyzed chiral N-sulfinyl amide directed asymmetric [4 + 1] annulation of benzamides with acrylic esters has been developed. The reaction proceeded through an oxidative C-H olefination and a subsequent cyclization by intramolecular aza-Michael addition, producing a series of diastereoisomeric chiral isoindolinones (20 examples) in generally good yields with a dr value up to 5.5 : 1. The absolute configurations of the newly formed C-stereocenters in the major and minor diastereomers of the catalysis product have been determined by X-ray crystal diffraction analysis to be S and R, respectively. The separation of the major diastereoisomers from the catalysis products and subsequent removal of the N-sulfinyl chiral auxiliary afforded enantiomerically pure (S)-isoindolinones. The application of the obtained (S)-isoindolinones in the synthesis of several biologically active isoindolinones such as (S)-PD172938, (S)-pazinaclone and (S)-pagoclone is presented.

Catalytic Asymmetric Mannich‐Type Reaction Enabled by Efficient Dienolization of α,β‐Unsaturated Pyrazoleamides†

Main observation and conclusion(E)‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1Z,3Z)‐dienolates as the major in the presence of a copper(I)‐(R)‐DTBM‐SEGPHOS catalyst and Et3N, which react with aldimines to afford syn‐vinylogous products as the major diastereoisomers in high regio‐ and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)‐(1Z,3Z)‐dienolates to copper(I)‐(1Z,3E)‐dienolates. (Z)‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1Z,3Z)‐dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)‐β,γ‐unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)‐catalyzed asymmetric vinylogous Mannich‐Type reaction and anti‐vinylogous products were obtained. In the previous reaction, copper(I)‐ (1Z,3E)‐dienolates were generated through α‐deprotonation, which might form an equilibrium with (E)‐allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)‐α,β‐unsaturated pyrazoleamides lead to syn‐products and (E)‐β,γ‐unsaturated pyrazoleamides lead to anti‐products. Finally, by use of (E)‐β,γ‐unsaturated pyrazoleamide, (E)‐α,β‐unsaturated pyrazoleamide, (R)‐DTBM‐SEGPHOS, and (S)‐DTBM‐SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three‐step reaction sequence, all four stereoisomers of N‐Boc‐2‐Ph‐3‐Me‐piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.

Diastereoselective Rhodium-Catalyzed Hydrogenation of 2-Oxindoles and 3,4-Dihydroquinolones.

The benzene ring of indolin-2-ones (2-oxindoles) and 3,4-dihydroquinol-2-ones was converted to a saturated cyclohexane ring by hydrogenation in the presence of the rhodium complex Cy(CAAC)Rh(cod)Cl. The stereoselectivity of the process was found to be high with respect to both external substituent R1 within the saturated part of the heterocyclic ring and substituent X on the benzene ring. Twenty-one hexahydroindolin-2(3H)-ones (70-99% yield, dr = 83/17 to >99/1) and twelve octahydro-2(1H)-quinolinones (87-96% yield, dr = 64/36 to >99/1) were obtained with the major diastereoisomer exhibiting the hydrogen atoms in an all-cis arrangement. The high tolerance toward functional groups and the compatibility with existing stereogenic centers are key features of the hydrogenation protocol presented here.

Chiral Cobalt(II) Complex Catalyzed Asymmetric [2,3]-Sigmatropic Rearrangement of Allylic Selenides with α-Diazo Pyrazoleamides

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...

Tetrabromobisphenol A and hexabromocyclododecanes in sediments and biota from two typical mangrove wetlands of South China: Distribution, bioaccumulation and biomagnification

Tetrabromobisphenol A (TBBPA) and hexabromocyclododecanes (HBCDs) were examined in sediments and biota species from two mangrove wetlands of the Pearl River Estuary (PRE) and the Jiulong River Estuary (JRE), South China, to investigate their distribution, bioaccumulation and biomagnification in mangrove food webs. Levels of TBBPA and ΣHBCD (sum of α-, β- and γ-HBCDs) ranged from 0.003 to 0.31 and not detected (nd) to 1.11 ng/g dry weight in the sediments, and from 0.56 to 22.1 and nd to 56.3 ng/g lipid weight in the biota species, respectively. γ-HBCD was the major diastereoisomer in the PRE sediments, while α- and γ-HBCDs predominated in the JRE sediments. In contrast, α-HBCD was dominant in the biota. Mean enantiomeric fractions (EFs) of α-, β- and γ-HBCDs in the sediments all followed the trend of JRE > racemic standard > PRE. A significant enrichment of (−)-α-HBCD was found in the biota (p = 0.04), with EFs in the range of 0.297–0.485. Bioaccumulations were seen for TBBPA and α-HBCD as their biota-sediment accumulation factors (BSAFs) were greater than 1. (−)-α-HBCD had significantly greater BSAFs than (+)-α-HBCD (p = 0.04), indicating the preferential bioaccumulation of (−)-α-HBCD. Biomagnification factors (BMFs) of TBBPA ranged from 0.83 to 1.51, which varied among feeding relationships and mangroves. Positive relationships were found between TBBPA concentrations and trophic levels of the biota species with trophic magnification factors of 2.17 for the PRE and 1.22 for the JRE, suggesting that TBBPA biomagnifies in the mangrove food webs. No biomagnifications were observed for ΣHBCD, α-HBCD and its enantiomers.

Asymmetric Borylative Coupling of Vinylazaarenes and Ketones Catalyzed by a Copper(I) Complex

Azaarenes are attractive structural units widely found in chiral pharmaceuticals, agrochemicals, and biologically active natural products. An ongoing strategy has been the construction of new chira...

Coetaneous catalytic kinetic resolution of alkynes and azides through asymmetric triazole formation

A non-enzymatic simultaneous (coined coetaneous) kinetic resolution of a racemic alkyne and racemic azide, utilising an asymmetric CuAAC reaction is reported. The use of a CuCl (R,R)-Ph-Pybox catalyst system effects a simultaneous kinetic resolution of two racemic starting materials to give one major triazolic diastereoisomer in the ratio 74:12:4:10 (dr 84:16, 90% ee maj). The corresponding control reaction using an achiral copper catalyst gives the four possible diastereoisomers in a 23:27:23:27 ratio, demonstrating minimal inherent substrate control.

Synthesis of Tetrahydroisoquinolines by Visible-Light-Mediated 6-exo-trig Cyclization of α-Aminoalkyl Radicals

Starting from the respective tertiary α-silylmethyl amines, the intramolecular cyclization of α-aminoalkyl radicals to Michael acceptors produced tetrahydroisoquinolines. The reaction conditions included the use of 5 mol% of an iridium photoredox catalyst, dimethylformamide as the solvent, and equimolar amounts of water and cesium carbonate as the additives. 13 substrates were synthesized from ortho-alkylbenzaldehydes in a three-step procedure involving a carbonyl condensation, a radical bromination, and a substitution by a secondary α-silylmethyl amine. After optimization of the photocyclization, the reaction delivered tetrahydroisoquinolines in moderate to high yields (41–83%). A facial diastereoselectivity (dr ≅ 80:20) was observed with chiral substrates and a crystal structure provided evidence for the relative configuration of the major diastereoisomer. A catalytic cycle with direct electron transfer to the photoexcited metal catalyst is proposed.

Bioaccumulation and translocation of tetrabromobisphenol A and hexabromocyclododecanes in mangrove plants from a national nature reserve of Shenzhen City, South China

Brominated flame retardants (BFRs) such as tetrabromobisphenol A (TBBPA) and hexabromocyclododecanes (HBCDs) are of ecological concern due to their ubiquitous presence and adverse effects. There is a paucity of data on environmental fate of such compounds in mangrove wetlands, which are unique ecosystems in coastal intertidal areas and act as natural sinks for many pollutants. In this study, mangrove plants and sediments were collected from an urban nature reserve in South China to investigate bioaccumulation and translocation of TBBPA and HBCDs. The mean (range) concentrations of TBBPA and ΣHBCD in roots, stems and leaves were 67 (<MDL-999), 174 (0.73–1105) and 20 (0.59–250) pg/g dry weight (dw), and 329 (15.6–2234), 766 (32.9–3255) and 298 (19.9–1520) pg/g dw, respectively. Tissue-specific accumulations were observed, varying with plant species and compounds. HBCD diastereoisomer patterns were similar for all plant species. γ-HBCD was the major diastereoisomer in roots, while α-HBCD dominated in stems and leaves. The predominance of α-HBCD in aboveground tissues may be ascribed to diastereoisomer-specific translocation, isomerization and/or metabolization in mangrove plants. Preferential enrichment of (−)-α-, (−)-β- and (+)-γ-HBCDs was found in all mangrove plant tissues, suggesting the enantioselectivity for HBCDs in mangrove plants. Translocation factors (log TF, root to stem) of HBCD diastereoisomers and log Kow were negatively correlated (p = 0.03), indicating passive translocation of HBCDs, driven by water movement during transpiration. Sediment-root bioaccumulation factors and log TFs (stem to leaf) both showed no obvious correlation with log Kow of HBCD diastereoisomers. These results reflected the complex behavior of HBCDs in mangrove plants, which have not been sufficiently captured in laboratory-based studies of plant contaminant accumulation.

Structure Determination of Diastereoisomeric Thia-Michael Bis-adducts of Methyl (5-Methylidene-4-oxocyclopent-2-en-1-yl)acetate with Ethanethiol

Three of the four possible diastereoisomeric thia-Michael addition products of the reaction of methyl (5-methylidene-4-oxo-cyclopent-2-en-1-yl)acetate with ethanethiol have been isolated and characterized. The major diastereoisomer is all-trans, while the overall fraction of the minor cis,trans and trans,cis isomers does not exceed 30%. The diastereoisomer structure has been determined on the basis of characteristic coupling constants of CH protons of the cyclopentane ring in the 1H NMR spectra.

1,3-Dipolar cycloadditions with azomethine ylide species generated from aminocyclopropanes

Two types of bicyclic N-cyclopropyl glycine ester derivatives have been prepared and put under scrutiny as possible precursors of azomethine ylides. The results demonstrate that they can indeed participate in 1,3-dipolar cycloaddition reactions with dipolarophiles, as illustrated in the cases of phenyl vinyl sulfone, N-phenylmaleimide, diethyl fumarate and diethyl maleate. The relative configurations of the major diastereoisomers produced are consistent with the predicted generation of azomethine ylide species, reacting in concerted cycloaddition processes. This unprecedented way of generating such 1,3-dipoles provides access to functionalised pyrrolizidine and pyrrolidine derivatives, that would be difficult to make directly by more classic methods. It was also found that using phenyl vinyl sulfone or N-phenylmaleimide as the dipolarophile reactant, a domino nucleophilic conjugate addition/1,3-dipolar cycloaddition process may operate competitively.

Cyclodimerization of 3-phenacylideneoxindolines with amino esters for the synthesis of dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines

Abstract Triethylamine-promoted domino cyclodimerization reaction of 3-phenacylideneoxindolines with amino ester hydrochlorides in acetonitrile afforded substituted dispiro[indoline-3,1′-cyclopentane-3′,3″-indolines] in good yields. The relative configuration of the major diastereoisomers was determined by the X-ray diffraction analysis of three single crystal structures.