Enol Ether Moiety Research Articles

Reagent-controlled chemo/stereoselective glycosylation of ʟ-fucal to access rare deoxysugars

2,6-Dideoxy sugars constitute an important class of anticancer antibiotics natural products and serve as essential medicinal tools for carbohydrate-based drug discovery and vaccine development. In particular, 2-deoxy ʟ-fucose or ʟ-oliose is a rare sugar and vital structural motif of several potent antifungal and immunosuppressive bioactive molecules. Herein, we devised a reagent-controlled stereo and chemoselective activation of ʟ-fucal, enabling the distinctive glycosylation pathways to access the rare ʟ-oliose and 2,3-unsaturated ʟ-fucoside. The milder oxo-philic Bi(OTf)3 catalyst induced the direct 1,2-addition predominantly, whereas B(C6F5)3 promoted the allylic Ferrier-rearrangement of the enol-ether moiety in ʟ-fucal glycal donor, distinguishing the competitive mechanisms. The reagent-tunable modular approach is highly advantageous, employing greener catalysts and atom-economical transformations, expensive ligand/additive-free, and probed for a diverse range of substrates comprising monosaccharides, amino-acids, bioactive natural products, and drug scaffolds embedded with susceptible or labile functionalities.

Ring Transformation of Annulated Benzofuran Derivatives to Medium-Sized Lactones

AbstractBenzannulated eight- and nine-membered-ring lactones were prepared by ring transformation of annulated benzofuran derivatives. The reaction sequence starts with a Brønsted acid catalyzed hydration of the enol ether moiety of the starting materials furnishing hemiacetals as intermediate products which underwent retro-Claisen-type C–C bond cleavage under the reaction conditions. The use of 15 mol% TfOH and two equivalents of water in CHCl3 at 85 °C turned out to be optimal. Products with exocyclic carboxylate function could be further derivatized by amide formation. In total, eleven medium-sized lactones were prepared. Furthermore, three benzannulated spirolactones were obtained from starting materials with exocyclic carboxamide moiety.

Three previously undescribed metabolites from Cordyceps cicadae JXCH-1, an entomopathogenic fungus

Three previously undescribed compounds, cordycicadione (1), cordycicadin F (2), and 7-hydroxybassiatin (3), were isolated from the cultures of Cordyceps cicadae JXCH1, an entomopathogenic fungus. Their structures and relative configurations were elucidated primarily by NMR spectroscopic analysis. The absolute configurations of 1 and 2 were determined by ECD calculations. Single-crystal X-ray diffraction method was adopted to determine the absolute configuration of 3. Compound 2 is a polycyclic polyketide with an unusual enol ether moiety and a spiro ring. The compounds obtained in this study were subjected to screening their inhibition against the proliferation of the human lung cancer cell line A549 and the production of nitric oxide in murine macrophages RAW264.7.Graphical

Re-evaluation and a Structure-Activity Relationship Study for the Selective Anti-anaerobic Bacterial Activity of Luminamicin toward Target Identification.

Luminamicin (1) isolated in 1985, is a macrodiolide compound exhibiting selective antibacterial activity against anaerobes. However, the antibacterial activity of 1 was not fully examined. In this research, re-evaluation of the antibacterial activity of 1 revealed that 1 is a narrow spectrum and potent antibiotic againstClostridioides difficile(C. difficile) and effective against fidaxomicin resistantC. difficilestrain. This prompted us to obtain luminamicin resistantC. difficilestrains for the determination of the molecular target of 1 inC. difficile. Sequence analysis of 1-resistantC. difficileindicated that the mode of action of 1 differs from that of fidaxomicin. This is because no mutation was observed in RNA polymerase and mutations were observed in a hypothetical protein and cell wall protein. Furthermore, we synthesized derivatives from 1 to study the structure-activity relationship. This research indicated that the maleic anhydride and the enol ether moieties seem to be pivotal functional groups to maintain the antibacterial activity againstC. difficileand the 14-membered lactone may contribute to taking an appropriate molecular conformation.

Features of the intramolecular Hosomi–Sakurai reaction of allylic cyclopentenylsilane containing an enol ether moiety

A new intramolecular variant of the Hosomi–Sakurai reaction of 5-(2-methoxyvinyl)-4-((phenylthio)methyl)cyclopent-2-en-1-yl)trimethylsilane is presented, which is a by-process between hydrolysis to aldehyde and acetalization to dimethylacetal. The key steps are the generation of methoxy methylene carbocation from enol ether during acid catalysis and its subsequent attack on the allylsilane moiety with formation of norbornene derivative. In turn, the corresponding aldehyde undergoes Hosomi–Sakurai cyclization by interaction with BF3·Et2O in acetonitrile, as well as by reaction with TBAF in THF through various transition states, leading to epimeric alcohols of the same norbornene structure. At the same time, the starting enol ether by treatment with TBAF undergoes exclusively protodesilylation and hydrolysis, while with BF3·Et2O it gives mixtures of epimeric products of topology both bicyclo[2.2.1]heptane and bicyclo[3.2.0]heptane.

Sequence-Controlled Polymer Synthesis Derived from Alcohols, Cyclic Enol Ethers, and Vinyl Ethers: Selective Generation of 2-Alkoxy Cyclic Ethers Followed by Living Cationic Alternating Copolymerization by the One-Pot Process

Syntheses of sequence-controlled copolymers with controllable molecular weights and chain ends composed of alcohols, cyclic enol ethers, and vinyl ethers (VEs) were demonstrated using an approach consisting of selective monomer generation and subsequent alternating copolymerization. Acid-catalyzed additions of alcohols to 2,3-dihydrofuran or 3,4-dihydro-2H-pyran proceeded quantitatively to yield 2-alkoxy cyclic ethers (2-ACEs). Subsequent cationic alternating copolymerization of the 2-ACE and a VE proceeded successfully via concurrent ring-opening and vinyl-addition mechanisms, yielding copolymers with periodically arranged alcohol-derived side chain-containing cyclic enol ether and VE moieties in the repeating units. Complete degradation of the obtained copolymers into a single compound by alcoholysis confirmed the alternating sequences. The use of 2-propanol, (−)-menthol, and (1R)-endo-(+)-fenchyl alcohol was effective for the syntheses of well-defined polymers, whereas the use of methanol resulted in oligomers. The bulkiness of the alkoxy groups of the 2-ACEs likely contributed to the preference for propagation rather than chain transfer.

The Fluorocarbene Exploit: Enforcing Alternation in Ring-Opening Metathesis Polymerization.

Fluoroalkenes are known to be notoriously reluctant substrates for olefin metathesis due to the generation of thermodynamically stable Fischer-type fluorocarbene intermediates, which invariably fail to undergo further reaction. In the present disclosure, we find that fluorine substitution on the sp2 carbon also strictly suppresses homopolymerization of norbornene derivatives (NBEs), and this can be harnessed to achieve alternating ring-opening metathesis polymerization (ROMP) with an appropriately electron-rich comonomer. Dihydrofuran (DHF) is thereby shown to undergo alternating ROMP with fluorinated norbornenes, the perfectly alternating structure of the resulting copolymer having been unambiguously elucidated by 1H, 19F, and 13C NMR analyses. Furthermore, we find that the degradability of the resultant copolymers in acidic media via hydrolysis of enol ether moieties in the backbone can be predictably modulated by the number of fluorine atoms present in the NBE comonomer, affording an opportunity to engage with the desirable physical properties of fluorinated polymers while limiting their attendant environmental degradability issues.

Synthesis of a Diacetonide-Protected, Mannose-Based Oxepine: Configurational Control of Anomeric Acetate Activation.

Carbohydrate-based oxepines are seven-membered-ring oxacycles containing an enol ether moiety. These compounds have been used as intermediates in the preparation of septanose carbohydrates by functionalization through their double bond. Reported here is a new synthesis of a carbohydrate based oxepine that uses 2,3;4,6-di-O-acetonide mannose as a key starting material. The oxepine is an important precursor used in the synthesis of septanose glycomimetics of mannopyranosides. The central feature of the synthesis is a two-step sequence that converts a septanose 1,2-di-O-acetate to the septanosyl bromide and onward to the oxepine via a reductive elimination.

Oxygenated Cyclopentenones via the Pauson-Khand Reaction of Silyl Enol Ether Substrates.

We report here the application of silyl enol ether moieties as efficient alkene coupling partners within cobalt-mediated intramolecular Pauson–Khand reactions. This cyclization strategy delivers synthetically valuable oxygenated cyclopentenone products in yields of ≤93% from both ketone- and aldehyde-derived silyl enol ethers, incorporates both terminal and internal alkyne partners, and delivers a variety of decorated systems, including more complex tricyclic structures. Facile removal of the silyl protecting group reveals oxygenated sites for potential further elaboration.

Stereoselective Synthesis of δ- and ε-Amino Ketone Derivatives from N-tert-Butanesulfinyl Aldimines and Functionalized Organolithium Compounds.

The addition of functionalized organolithium compounds derived from 5-chloro-2-methoxy-1-pentene and 6-chloro-2-methoxy-1-hexene to N-tert-butanesulfinyl aldimines imines, and a subsequent hydrolysis of the enol ether moiety, yielded different δ- and ε-amino ketone derivatives, respectively, in moderate yields and diastereoselectivities. The application of these compounds in organic synthesis was demonstrated by the preparation of 2-substituted 6-methylpiperidines in a stereoselective manner, among them natural alkaloids (+)- and (−)-isosolenopsin A.

A new “Mitsunobu homocoupling” reaction using aldol adducts of kojic acid

In this study, we attempted to carry out the Mitsunobu 1,4-elimination using the kojic acid analog 3, which carries a hydroxymethyl group on C-6 introduced by aldol condensation, to obtain an effective Michael acceptor 4. To the ethyl acetate solution of 3 and Ph3P, diisopropyl azodicarboxylate was added quickly at 0 °C, resulting in the immediate generation of a yellow precipitate. NMR, mass spectrometry, and X-ray crystal structure analyses allowed to identify the precipitate as a diastereomeric/racemic mixture of dimeric compounds of 4. The dimerization reaction was hypothesized to occur through two major steps: (i) intramolecular dehydration of 3 by Mitsunobu reagents and (ii) homocoupling of the dehydration product 4 to form a new trans-carbon–carbon double bond. Presumably, the enol ether moiety of 4 acts as an electron donor and immediately attacks the α,β-unsaturated carbonyl group of another molecule via a reaction that can be dubbed “Mitsunobu homocoupling.”

7-Siloxy-Substituted Hexahydronaphthalene Derivatives: Samarium Diiodide Promoted Synthesis and Typical Reactions

The samarium diiodide promoted reductive cyclization of a series of γ-aryl ketones with acetoxy, alkoxy, and siloxy groups in ortho-, meta-, and para-positions was investigated. Only precursors with p-acetoxy, p-tert-butoxy, or p-siloxy substituents furnished decent yields of the desired 7-oxy-1,2,3,4,6,8a-hexahydronaphthalene derivatives. The products were formed without contamination with the regio­isomeric bicyclic products containing conjugated double bonds. Typical reactions exploiting the silyl enol ether moiety of the 7-(tert-butyl­dimethylsiloxy)-1,2,3,4,6,8a-hexahydronaphthalene derivative were performed, allowing stereoselective access to highly substituted hexahydro­-, octahydro-, or decahydronaphthalene derivatives.

Alkoxyallene-based syntheses of preussin and its analogs and their cytotoxicity.

Short syntheses of oxa-preussin, racemic preussin and (-)-preussin are reported. Starting from a racemic 3-nonyl-substituted methoxyallene derivative, its lithiation and addition to phenylethanal provided the corresponding allenyl alcohol that was converted into two diastereomeric dihydrofuran derivatives by silver nitrate-catalyzed 5-endo-trig cyclization. The acid hydrolysis of the enol ether moiety gave heterocyclic ketones and subsequent highly stereoselective reductions with l-selectride furnished 2-benzyl-5-nonylfuran-3-ol derivatives in good overall yield. The major all-cis-diastereomer has the skeleton and relative configuration of preussin and is hence called oxa-preussin. An analogous sequence with the same allene, but an N-sulfonyl imine as the electrophile, finally led to racemic preussin. The stereoselectivities of the individual steps are discussed in detail. With an enantiopure 2-benzyl-5-nonylpyrrolidin-3-one intermediate the preparation of (-)-preussin with an enantiomeric ratio of >95 : 5 could be accomplished in a few steps. The sign of the optical rotation of this product finally proved the absolute configurations of its precursors and demonstrated that our chiral auxiliary-based route led to the antipode of the natural product. The cytotoxicity of several of the prepared heterocycles against MCF-7 tumor cells was investigated and five compounds, including racemic and enantiopure (-)-preussin, were identified as highly cytotoxic with IC50 values in the range of 3-6 μM.

Addition of Metalated 3‐Alkyl‐Substituted Alkoxyallenes to Imines: Preparation of Tetrasubstituted 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Pyrroles

Metalated 3‐alkyl‐substituted methoxyallenes were either generated by lithiation of the corresponding methoxyallenes or, according to a procedure of Brandsma, from 3‐alkyl‐substituted propargyl methyl ethers. Additions of these axially chiral intermediates to various imines afforded the expected allenylamines in good yields, but low diastereoselectivity. The products were cyclized either under basic conditions or with silver nitrate as catalyst to furnish the desired 1,2,3,5‐tetrasubstituted 2,5‐dihydropyrrole derivatives. Under basic conditions the cyclization is stereospecific whereas the presence of silver nitrate can induce partial crossover. The mechanisms of the two cyclization modes are discussed. Two of the N‐tosyl‐substituted dihydropyrroles were subjected to an excess of potassium tert‐butoxide giving the expected aromatized 3‐methoxypyrrole derivatives by elimination of p‐tolyl sulfinate. Acid‐promoted hydrolysis of the enol ether moiety of 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones in good yields. The sodium borohydride reduction of these intermediates gave the corresponding 3‐hydroxypyrrolidine derivatives with high diastereoselectivity that strongly depends on the substitution pattern of the precursor. This study reveals that 3‐alkyl‐substituted methoxyallenes and their propargylic ether equivalents allow an efficient and flexible approach to 1,2,3,5‐substituted pyrrole derivatives that are useful intermediates for subsequent stereoselective elaboration and promising candidates for natural product syntheses.

Different hybridized oxygen atoms controlled chemoselective formation of oxocarbenium ions: synthesis of chiral heterocyclic compounds.

Based on the electronic properties of different hybridized oxygen atoms (sp3versus sp2) in the structure of O,O-acetals containing an enol ether moiety, the chemoselective formation of oxocarbenium ions was realized to furnish diversified chiral heterocyclic compounds with excellent stereoselectivities by reacting with different types of nucleophiles. Additionally, an unexpected intramolecular oxocarbenium ion transfer was also reported to form polycyclic products containing the O,O-acetal functional group.

A Chirality‐Returning Sequence for the Synthesis of an Unnatural Isomer of Hirsutellone B

AbstractHerein, we have achieved the synthesis of an unnatural isomer of hirsutellone B. Previously, we reported the total synthesis of the antituberculosis agent hirsutellone B. The key step in that synthetic strategy involved the direct construction of a highly strained 13‐membered macrocycle by utilizing an intramolecular Ullmann reaction. In this work, we studied the effect of the configuration at the C19 position on the macrocyclization of the 13‐membered ring. The central chirality at the C19 position of the cyclization precursor was specifically transferred to give the planar chirality of the enol ether moiety of the 13‐membered macrocycle, and the planar chirality was then transferred back to the central chirality at the C19 position of the final product. This chirality‐returning sequence enabled the stereoselective construction of the γ‐hydroxylactam of the 13‐membered macrocycle of the unnatural isomer of hirsutellone B.

Efficient Syntheses of 2,5‐Dihydropyrroles, Pyrrolidin‐3‐ones, and Electron‐Rich Pyrroles from N‐Tosylimines and Lithiated Alkoxyallenes

N‐Tosylimines and lithiated alkoxyallenes afforded the corresponding allenyl N‐tosylamines in good to excellent yields. The 5‐endo‐trig cyclizations of these intermediates to 2,5‐dihydropyrrole derivatives were achieved under strongly basic conditions with potassium tert‐butoxide or under milder conditions with either silver(I) or gold(I) catalysis. In general, gold chloride catalyzed reactions occurred with the lowest catalyst loadings and delivered the best yields. With phenyl‐substituted 2,5‐dihydropyrrole, we investigated typical reactions such as oxidative and reductive transformations. The acid‐promoted hydrolysis of the enol ether moieties of three 2,5‐dihydropyrroles furnished the corresponding pyrrolidin‐3‐ones, which were reduced to give 3‐hydroxypyrrolidine derivatives in good yields. The aromatization of 2,5‐dihydropyrroles to 3‐methoxypyrrole derivatives was accomplished by base treatment, which caused the elimination of p‐tolyl sulfinate. Electron‐rich pyrrole derivatives were synthesized in good yields even on a large scale. All of the experiments illustrate the efficacy and flexibility of the alkoxyallene approach to pyrrole derivatives.

ChemInform Abstract: Regioselective Direct Difunctionalization of Glycals: Convenient Access to 2‐Deoxyglycoconjugates Mediated by Tetra‐n‐butylammonium Iodide/Sodium Periodate.

A combination of nBu4NI and NaIO4 promoted the intermolecular stereo and regioselective bisfunctionalization of glycals in a metal-free, one-pot process. The oxidative iodocaboxylation, iodoamination, and iodoazidation of enol ether moieties by employing carboxylic or aromatic acids, and N-nucleophiles such as 1-H-benzotriazole or NaN3 led to glycosyl carboxylates, glycosyl amines, and glycosyl azides, respectively. The protocol is operationally simple, employs readily available and environmental benign reagents, and was applicable for a diverse range of substrates to obtain stereodivergent glycoconjugates in yields up to 99 % with diastereomeric ratios up to 100 %.

Alkoxyallene-ynes: Selective Preparation of Bicyclo[5.3.0] Ring Systems Including a δ-Alkoxy Cyclopentadienone.

The development of an intramolecular rhodium(I)-catalyzed Pauson-Khand reaction of alkoxyallene-ynes with a proximal alkoxy group is reported. This reaction, in the presence of a [Rh(cycloocta-1,5-diene)Cl]2/propane-1,3-diylbis(diphenylphosphane) system under a CO atmosphere, constitutes a powerful tool for selectively accessing carbo- and heterobicyclo[5.3.0] frameworks featuring an enol ether moiety. Through this procedure, a straightforward access to guaiane skeletons with a tertiary hydroxy group at the C10 position was achieved.

Regioselective Direct Difunctionalization of Glycals: Convenient Access to 2‐Deoxyglycoconjugates Mediated by Tetra‐n‐butylammonium Iodide/Sodium Periodate

AbstractA combination of nBu4NI and NaIO4 promoted the intermolecular stereo and regioselective bisfunctionalization of glycals in a metal‐free, one‐pot process. The oxidative iodocaboxylation, iodoamination, and iodoazidation of enol ether moieties by employing carboxylic or aromatic acids, and N‐nucleophiles such as 1‐H‐benzotriazole or NaN3 led to glycosyl carboxylates, glycosyl amines, and glycosyl azides, respectively. The protocol is operationally simple, employs readily available and environmental benign reagents, and was applicable for a diverse range of substrates to obtain stereodivergent glycoconjugates in yields up to 99 % with diastereomeric ratios up to 100 %.