Stereospecific Synthesis Research Articles

Studies towards iodine-catalyzed dehydrative-cycloisomerization of pent-4-yne-1,2-diols to di- and tri-substituted furans

An efficient and single-step iodine catalyzed and metal-free synthesis of di and tri-substituted 2-methylfuran derivatives were achieved from 1-popargyl-1,2-diols. Stereospecific synthesis of starting 1,2-diols was achieved by indium mediated Barbier type propargylation on corresponding keto-alcohols or by sodium borohydride mediated reduction of 2-hydroxy-2-propargyl ketones. The furan synthesis proceeded through iodine mediated 5-exo-trig cyclization, dehydration and reductive deiodination. The method was applied to the synthesis of 2-methylfuran fused to phenanthrene, pyrene and acenaphthylene rings.

Borinic Acid/Halide Co-catalyzed Semipinacol Rearrangements of 2,3-Epoxy Alcohols.

A new mode of catalysis of the semipinacol rearrangement of 2,3-epoxy alcohols is described. In combination with a halide salt additive, diarylborinic acids promote a Type II rearrangement that occurs with net retention of configuration. This unusual stereochemical outcome is consistent with a mechanism involving regioselective ring opening of the epoxy alcohol by halide, followed by rearrangement of the resulting halohydrin-derived borinic ester. The protocol is applicable to a range of substrates, enabling ring contractions and expansions as well as stereospecific syntheses of acyclic β-hydroxycarbonyl compounds.

Stereospecific Synthesis of Fluorinated Pyrazolidinones and Isoxazolidines via a Catalyst‐Free 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones

AbstractA highly atom‐economic, regio‐ and stereospecific synthesis of fluorinated pyrazolidinones and isoxazolidines is disclosed under catalyst‐ and additive‐free mild conditions. The diastereoselectivity with different type of 1,3‐dipoles is elucidated by using DFT calculations in CH3CN. Furthermore, a reaction using a chiral azomethine imine, a gram‐scale synthesis, and a reductive desulfonylation are also presented.

A Combination of Furfuryl Cation Induced Three-Component Reactions and Photocatalyst-Free Photoisomerization To Construct Complex Triazoles.

A novel stereospecific synthesis of ( Z)- and ( E)-β-triazole-acrylates by the combined use of a multicomponent reaction and photocatalyst-free photoisomerization is presented. The former can be regarded as a furfuryl cation induced formal [3 + 2]-cycloaddition/ring-opening/esterification domino sequence, which provides fast access to a variety of structurally diverse ( Z)-β-triazole-acrylates. The products were further photoisomerized to ( E)-configuration by UV irradiation. This efficient strategy was utilized in the concise synthesis of histone deacetylase inhibtor NSC746457 in high yield.

Self-Assembly Stereo-Specific Synthesis of Silver Phosphate Microparticles on Bacterial Cellulose Membrane Surface For Antimicrobial Applications

In situ self-assembly stereo-specific synthesis of silver phosphate (AgP) microparticles (MPs) in one side bacterial cellulose (BC) membrane surface and loading of ciprofloxacin provides BC scaffolds with a broad-spectrum antimicrobial activity against Escherichia coli and Staphylococcus aureus. The BC membranes containing AgP-MPs can be loaded >5 times with ciprofloxacin compared to naked BC. The reuse of ciprofloxacin-loaded AgP-BC scaffolds in fresh cultures of both tested microbes showed high inhibition haloes without any signal of microbial resistance or scaffold activity decay after 30 days of assays. Additionally, microbial biofilms of E. coli and S. aureus were mostly killed by AgP-BC scaffolds loaded with ciprofloxacin in 1 h. The biophysical characterization of the hybrid AgP-BC scaffolds was performed by scanning electron microscopy (SEM), vibrational spectroscopy (FTIR), calorimetric techniques and X-ray diffraction (XRD). SEM images display AgP-MP spheroid structures with a high homogenous distribution on BC scaffold surfaces. The properties of the novel AgP-BC matrices are very promissory for biomedical applications, like a therapeutic dressing patches for the prevention and treatment of microbial infections in skin wounds and burns.

Regio- and stereospecific synthesis of rac-carbasugar-based cyclohexane pentols; Investigations of their α- and β-glucosidase inhibitions

In the present study, (3aR,7aS)-1,3,3a,4,7,7a-hexahydroisobenzofuran was submitted to photooxygenation and two isomeric hydroperoxides were successfully obtained. Without any further purification, reduction of the hydroperoxides with titanium tetraisopropoxide catalyzed by dimethyl sulfide gave two alcohol isomers in high yields. After acetylation of alcohol with Ac2O in pyridine, epoxidation reaction of formed monoacetates with m-CPBA, then chromatographed and followed by hydrolysis of the acetate groups with NH3 in CH3OH resulted in the formation of epoxy alcohol isomers respectively. These epoxy alcohol isomers were subjected to trans-dihydroxylation reaction with acid (H2SO4) in the presence of water to afford triols. Acetylation of the free hydroxyl groups produced benzofuran triacetates in high yields. Ring-opening reaction of furan triacetates with sulfamic acid catalyzed in the presence of acetic acid/acetic anhydrate and subsequently hydrolysis of the acetate groups with ammonia gave the targeted cyclohexane carbasugar-based pentols. All products were separated and purified by chromatographic and crystallographic methods. Structural analyses of all compounds were conducted by spectral techniques including NMR and X-ray analyses. The biological inhibition activity of the target compounds was tested against glycosidase enzymes, α- and β-glucosidase.

Comprehensive study towards the desulfonylation/desulfinylation of cis-3-functionalized 3-phenylsulfonyl/sulfinyl-β-lactams to access novel cis-3-monosubstituted-β-lactams

An inclusive study towards the stereospecific synthesis of novel cis-3-monosubstituted-β-lactams from cis-3-functionalized 3-phenylsulfonyl/sulfinyl-β-lactams is described. 3-Sulfinyl-β-lactams 5/5ʹ successfully furnished stereospecific cis-3-monosubstituted-β-lactams 6, however 3-sulfonyl-β-lactams 2 failed to give the desulfurized product 6ʹ. The final stereochemical and structural conformations of novel β-lactams were established by single crystal X-ray crystallographic study (5c). The cis configuration of the β-lactams 5/5ʹ and 6 was assigned in relevance to E and C4-H and C3-H and C4-H respectively.

Abstract 2668: Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads

Abstract The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2668.

Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization of Activated Aziridines with α-Acidic Isocyanides.

An expeditious synthetic route to access structurally diverse 1,4,5,6-tetrahydropyrimidines via domino ring-opening cyclization of activated aziridines with α-acidic isocyanides has been established. The transformation proceeds via Lewis acid mediated SN2-type ring opening of activated aziridines with α-carbanion of the isocyanides followed by a concomitant 6- endo- dig cyclization in a domino fashion to furnish the 1,4,5,6-tetrahydropyrimidine derivatives in excellent yields (up to 84%) and also in diastereo- and enantiomerically pure form (dr >99:1, ee >99%).

Synthesis of Enantiomerically Pure 1′,2′-cis-dideoxy, -dideoxydi­dehydro, -ribo and -deoxy Carbocyclic Nucleoside Analogues

We describe a short and stereospecific synthesis of different series of 1′,2′-cis-disubstituted carbocyclic nucleoside analogues. All-natural nucleobases or their precursors are coupled in a microwave-assisted Mitsunobu-type reaction with enantiomerically pure (1R,2S)-2-(benzyloxymethyl)cyclopent-3-enol. By modifying the cyclopentene scaffold, our synthetic strategy gives access to a series of 1′,2′-cis-disubstituted carbocyclic nucleoside analogues of the dideoxy (dd), di­deoxydidehydro (d4) or the ribo series. The ribo series is synthesized in a more convenient way compared to a previous route. The deoxy series of 1′,2′-cis-disubstituted carbocyclic nucleoside analogues is prepared following an earlier reported approach. This synthesis involves the microwave-assisted coupling of (1R,2S,3S)-3-(benzyloxy)-2-[(benzyl­oxy)methyl]cyclopentan-1-ol with the appropriate nucleobases.

Enzyme Engineering Based on X-ray Structures and Kinetic Profiling of Substrate Libraries: Alcohol Dehydrogenases for Stereospecific Synthesis of a Broad Range of Chiral Alcohols

The narrow substrate scope of naturally occurring alcohol dehydrogenases (ADHs) greatly limits the enzymatic synthesis of important chiral alcohols. On the basis of X-ray crystal structures and kinetic profiling of a substrate library, we engineered variants of the stereospecific alcohol dehydrogenase from Candida parapsilopsis. This resulted in a set of four mutant enzymes which enable the asymmetric reduction of a broad range of prochiral ketones, including valuable pharmaceuticals and fine chemicals. The engineering strategy of this study paves the way for creating additional ADHs tailored for production of complex chiral alcohols.

Regio- and Stereospecific Synthesis of Oridonin D-Ring Aziridinated Analogues for the Treatment of Triple-Negative Breast Cancer via Mediated Irreversible Covalent Warheads.

Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure-activity relationship (SAR) and the structure-reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in vivo while displaying lower toxicity to normal human mammary epithelial cells in comparison to oridonin.

Regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol

The regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol is reported. Bromination of p-benzoquinone followed by reduction of the carbonyl groups with NaBH4 gave the corresponding trans-dibromodiol compound, which was reacted with sodium methoxide to produce dimethoxy conduritol-B. Regiospecific bromination of the alkene moiety furnished the desired chiro-inositol derivative.

Stereospecific Syntheses of Enaminonitriles and β-Enaminoesters via Domino Ring-Opening Cyclization (DROC) of Activated Cyclopropanes with Pronucleophilic Malononitriles.

Two novel synthetic protocols for the syntheses of highly functionalized five-membered carbocyclic enaminonitriles and β-enaminoesters have been developed via domino ring-opening cyclization (DROC) and DROC/decarboxylative tautomerization of activated cyclopropanes with malononitrile pronucleophiles, respectively. Both of the efficient strategies (yield up to 93%) have been generalized with various donor-acceptor and acceptor cyclopropanes as well as with malononitrile derivatives. The stereospecific variants of the two SN2-type DROC strategies have also been developed by employing enantiopure donor-acceptor (DA) cyclopropanes to synthesize the corresponding nonracemic products with excellent stereoselectivities (dr up to >99:1, ee up to >99%).

Copper-Catalyzed Stereospecific Synthesis of α-Silylated Nitriles and Esters

Copper-Catalyzed Stereospecific Synthesis of α-Silylated Nitriles and Esters

Alkene functionalization for the stereospecific synthesis of substituted aziridines by visible-light photoredox catalysis.

A novel strategy involving visible-light-induced functionalization of alkenes for the synthesis of substituted aziridines was developed. The readily prepared N-protected 1-aminopyridinium salts were used for the generation of N-centered radicals. This approach allowed the synthesis of aziridines bearing various functional groups with excellent diastereoselectivity under mild conditions. Moreover, this protocol was successfully applied to prepare structurally diverse nitrogen-containing frameworks.

Copper-catalysed cross-coupling of alkyl Grignard reagents and propargylic ammonium salts: stereospecific synthesis of allenes.

Herein we describe a robust and practical method to prepare enantiomerically enriched trisubstituted allenes using alkyl Grignard reagents and bench stable propargylic ammonium salts. Excellent yields as well as regio- and stereoselectivities are observed. Our conditions provide a solution to the allene racemization, which has been a long-standing problem when using Grignard reagents.

Synthesis of methyl 4-dihydrotrisporate B and methyl trisporate B, morphogenetic factors of Zygomycetes fungi.

(9Z)-Methyl 4-dihydrotrisporate B and (9Z)-methyl trisporate B, pheromones of Zygomycetes fungi, have been synthesized using Stille cross-coupling from previously described cyclohexenone precursors. Conducting the coupling without protection groups allowed for a short and stereospecific synthesis route of the late trisporoids. Stability studies for both the compounds revealed (9Z)-methyl trisporate B to be very unstable against UV irradiation.

Pheromone Research and Development in Israel 1975–2015

The review describes the history of pheromone research in Israel in 1975–2015. The research focused on sex pheromones of moths that were important agricultural pests. Identification, synthesis and field application of sex pheromones was performed. Synthetic procedures of several known sex pheromones were developed. Monitoring and control of key pest moths was evaluated. The interactions of pheromone components of closely related species were studied in field and laboratory experiments. The sex pheromones of three scale insects, two mealybug species and Matsucoccus josephi were studied. New syntheses were developed and the pheromones were implemented in pest management. Structure activity relationship of the pheromonal and kairomonal of the M. josephi pheromone was investigated. Different pherotypes of P. ficus were identified and evaluated. The aggregation pheromone of sap beetles in combination with food baits was evaluated. The aggregation pheromone of the almond bark beetle was identified and a stereospecific synthesis of its enantiomers was developed. Monitoring the pest in stone fruit orchards was implemented. The activity of the pheromone biosynthesis activating neuropeptide (PBAN) was studied in Helicoverpa armigera and Heliothis peltigera. The ligation technique was used to assess the effect of PBAN on the production of female and male pheromones. A structure-activity relationship study of PBAN indicated that shorter peptides display activity as the full length PBAN. A series of linear and cyclic peptide analogs was prepared, resulting in the discovery of a lead antagonist. The research and development activity facilitated the intensive integration of pheromones in the pest management regimes in Israeli agriculture.

Facile and Stereospecific Synthesis of Various Dienones Using Task‐specific Ionic Liquid/Borohydride as Stable and Promoted Hydrogen Release Reagent

In this work, for the first time, task‐specific ionic liquid, 1‐n‐butyl‐3‐methylimidazolium borohydride ([bmim]BH4), was used as the medium as well as reagent for the regiospecific reduction of triarylpyrylium perchlorates to provide aromatic dienones as only product. The [bmim]BH4 having a reactive anion also could promote the desired reaction thereby reducing the reaction times and improving the yields substantially. The products could be easily isolated from the reaction mixture by simple extraction.