New convergent one pot synthesis of amino benzyl ethers bearing a nitrogen-containing bicycle

We report herein a new convergent one pot method for the synthesis of amino benzyl ethers containing a bicyclic amine, derived from different substituted benzyl alcohols and bicyclic amino alcohols such as tropine, pseudotropine, and 3-quinuclidinol, using chlorotrimethylsilane and sodium iodide. In order to avoid the competitive reaction with the nitrogen atom, a solution of the separately prepared alkoxide of tropine, pseudotropine, and 3-quinuclidinol was added to the preformed substituted benzyl iodides and allowed to reflux at 90?°C for 15?h under nitrogen atmosphere. This method provides an efficient alternative of the preparation of amino benzyl ethers in organic synthesis with good yields in comparison with existed methods.     

Eleuthesides and their analogs: V. Medium- and large-ring lactones based on levoglucosenone

Ozonolysis of the bridging double bond in bicyclic enol ethers obtained by the Michael reaction and subsequent intramolecular etherification afforded chiral decanolides fused to a tetrahydropyran ring. Three-step procedures were developed for the synthesis of chiral lactones with medium and large rings via oxidative cleavage with pyridinium chlorochromate of mixed bicyclic ketals which were prepared by treatment with methanolic HCl of Michael adducts derived from levoglucosenone and cyclopenta-, cyclohexa-, cyclohepta-, and cyclododecanone.     

C-C bond formation on reduction of organomercurial and its application to biomimetic synthesis of strobane carbon skeleton

The bicyclic ethers obtained by the oxymercuration-demercuration reaction of linalool was found to be formed in the demercuration step. The facile C-C bond formation is due to the proximity of Hg and the vinyl group in the organomercurial intermediate. Applying this process to epimanool a biomimetic synthesis of strobane carbon skeleton was achieved.     

Gold(I)-catalyzed synthesis of dihydropyrans

A trinuclear gold(I)-oxo complex, [(Ph3PAu)3O]BF4, serves as the catalyst for the stereocontrolled synthesis of 2-hydroxy-3,6-dihydropyrans from propargyl vinyl ethers. Importantly, the rearrangement proceeds with excellent diastereoselectivity, and the rearrangement of chiral nonracemic propargyl vinyl ethers proceeds with excellent chirality transfer to furnish enantioenriched pyrans. Additionally, the reaction is amenable to the synthesis of spiroketals from appropriately functionalized precursors. In this case, from a linear precursor, in a single step, the bicyclic spiroketal framework is established with complete stereocontrol over three centers and an alkene functional group in the product.     

Stereocontrolled synthesis of substituted bicyclic ethers through oxy-Favorskii rearrangement: total synthesis of (±)-communiol E

The potential of the oxy-Favorskii rearrangement to form branched cis-fused bicyclic ethers was explored. Both tertiary and quaternary centers were constructed in highly stereospecific manners. Methanol and primary amines were effective nucleophiles for the rearrangement. The total synthesis of (±)-communiol E was achieved based on this method.     

Synthesis and conformational analysis of fructose-derived scaffolds: molecular diversity from a single molecule

Bi- and tricyclic compounds were synthesized starting from fructose. The different hydroxyl groups present in fructose were exploited in the formation of a number of conformationally constrained sugar-based scaffolds, including azido acids. Introduction of an azido group and carboxy terminus into different bicyclic iodo ethers, allowed the synthesis of different conformationally constrained azido acids. Conformational analysis of compounds 10, 11, 17, and 20 by NMR experiments assisted by molecular mechanics, allowed the determination of the distances between the relevant functional groups, that is the azido and carboxy functionalities.     

C2-Symmetric hemiaminal ethers and diamines: new ligands for copper-catalyzed desymmetrization of meso-1,2-diols and asymmetric Henry reactions

The synthesis of novel, enantiomerically pure C₂-symmetrical hemiaminal ethers and diamines containing piperazine core is presented. The key steps of the synthesis involve the dimerization of an in situ generated α-amino aldehyde into the corresponding cyclic bis-hemiaminal, followed by dehydration in the presence of a base to give a 7-oxa-2,5-diaza-bicyclo[2.2.1]heptane derivative, which can be regarded as a bicyclic bis-hemiaminal inner ether. These compounds represent a new class of molecule, with a structure unambiguously established for the first time. Finally, sodium triacetoxy-borohydride reduction gave the corresponding diamines. Both classes of compounds, new diamines and hemiaminal ethers, were shown to be good ligands for the copper(II)-catalyzed desymmetrization of meso-diols (up to 87% ee) and Henry reactions (up to 84% ee).     

Acetal-vinyl sulfide cyclization on sugar substrates: effect of structure and substituent

A range of 2-deoxyfuranoside and -pyranoside derivatives were fashioned into derivatives that carry a vinyl or propenyl side chain. Extension of the alkene by a Suzuki cross-coupling reaction with 1-bromo-1-(phenylthio)ethene gave thioenol ethers as the cyclization substrates. The treatment of these substrates with BF(3).Et(2)O in tert-butylmethyl ether below 0 degrees C induced cyclization to optically active bicyclic ethers. If the cyclizations are carried out in toluene as the solvent, the isomerization of the terminal thioenol ether to the inner thioenol ether can take place prior to the cyclization. The cyclization reactions can be impeded by steric and electronic factors. The opening of the bicyclic ethers could be illustrated with the base-induced conversion of the ketone 53 to the cyclooctenone 54.     

Synthesis of novel bicyclic 2-amino-4(1h)-pyridones. Reaction of lactim ethers with α-cyanoacetone dianion.

Reactions of lactim ethers with α-cyanoacetone dianion gave bicyclic 2-amino-4(1H)-pyridones.     

Photoactivated tungsten hexacarbonyl-catalyzed conversion of alkynols to glycals

The photoactivated W(CO)(6)/DABCO/THF system has been used for the formal endo-cyclization of alkynes to pyran rings. We found that the regioselectivity of ring closure depends on the relative configuration of the 3,5-dihydroxy-1-alkynes, as well as, more decisively, on the type of O-protective group. Oxygen substitution at the propargylic carbon slows the rate of alkyne insertion and allows for dihydrofuran formation through exo-cyclization. In contrast, the use of bulky silyl ethers or carbon substituents leads to dihydropyrans through endo-cyclization. Substrates bearing leaving groups such as esters, phenols, or thiophenols at the propargylic site eliminate and thus represent a limitation to the cycloisomerization methodology. Propargyl vinyl ethers will rearrange to give dienals instead of glycals. 1,2-Wittig rearrangement products of dihydropyrans are readily prepared and converted to complex bicyclic building blocks for organic synthesis.     

New Sesquiterpenoids from Cabreuva Oil

Six sesquiterpenoids 1 – 6 , formally derived from (+)-(S)-nerolidol by oxidative cyclization, have been isolated for the first time from commercial cabreuva oil. Whereas the two tetrahydrofurans 5 and 6 have already been described, the four bicyclic ethers (cabreuva oxides A–D) 1 – 4 are new. The structures of 1 – 4 are confirmed by synthesis and their absolute configurations are shown to be 3S. The organoleptic properties of the synthetic cabreuva oxides are discussed.     

Formation of bicyclic ethers from Lewis acid promoted cyclizations of cyclic oxonium ions

Oxacycles carrying a vinyl group and an acetal were extended with a cyclization terminator (vinyl silane or vinyl sulfide) by Suzuki coupling. Treatment with Lewis acid induced cyclization to provide bicyclic ethers in reasonable yields. In the case of the vinyl silane, an ene-like mechanism is preferred, whereas the thioenol ether enters into a Prins-type reaction channel. In one instance, the bicyclic compound was opened to give the ten-membered functionalized enone 24. [reaction: see text]     

Allylsilyl Propargyl Ethers as Substrates for Intramolecular Pauson–Khand Reactions

Silyl ethers that are synthesized by coupling a propargylic alcohol with an allylsilyl chloride are shown to undergo sulfide‐promoted Pauson–Khand reactions, affording bicyclic enones.     

Radical cyclization of sugar-derived beta-(alkynyloxy)acrylates: synthesis of novel fused ethers

[formula: see text] Tributyltin radical mediated cyclization of carbohydrate-derived beta-(alkynyloxy)acrylates leading to highly functionalized cis- and trans-fused bicyclic ethers of various ring sizes is described. The efficacy of the radical cyclization is nicely illustrated in the iterative construction of a trans-fused tricyclic tetrahydropyran.     

A new method for synthesis of n-(3-acyloxypropyl)-substituted six- to thirteen-membered alkan-n-olides

A new method for the synthesis of n-(3-acyloxypropyl)-substituted six- to thirteen-membered alkan-n-olides was developed. The method is based on the H₂SO₄-catalyzed reactions of oxabicycloalkenes, obtained from 2-(3-acetoxypropyl)cycloalkanes, with H₂O₂ and formic or acetic acid. The method includes the subsequent transformations of oxabicycloalkenes into bicyclic hydroperoxides, peroxy ethers, and, at the final stage, into target lactones formed in 56—71% yields. These transformations are carried as a one-pot reaction.     

Decomposition d'hypobromites prepares par action de l'oxyde de mercure et du brome sur des alcools bicycliques pontes

Hydrobromites of bridged bicyclic alcohols have been decomposed to yield tetrahydrofuran-type ethers as well as fragmentation products. The latter results from the cleavage of the carbon-carbon bond α, β to the hydroxyl group. In the case of 3-hydroxy-3-methyl bicyclo[3.2.1]octane, conjugated ketones and brominated olefins are formed, whereas tetrahydrofuran-type ethers are formed only under different experimental conditions different from those applicable to general cases. The reaction mechanisms have been established. The influence of the various reaction parameters has been studied in order to obtain selectively either tetrahydrofuran-type ethers or a mixture of conjugated ketones and brominated olefins.     

Mannich Reaction as a Key Strategy for the Synthesis of Benzoazacrown Ethers and Benzocryptands

A convenient method for the synthesis of mono- and polycyclic azacrown macrocycles containing aromatic fragments using the Mannich condensation of phenols and secondary diamines has been studied. This new approach allowed the synthesis of bisphenols connected by oligoazaoxaalkane units in good yields without the need to protect the phenolic OH groups. These bisphenols (13-16) were alkylated with ditosylates of polyethylene glycols to give benzoazacrown ethers 25-30. Intermediate bisphenols 13-15 were also treated with three bis(methoxymethyl)-substituted diamines to form benzoazacrowns 10-12 containing internal phenolic functions. Phenol-containing mono- (11) and bicyclic (3, n = 1) compounds, which were synthesized via the Mannich aminomethylation process, were used as building blocks for construction of bi- (32) and tricyclic (33) ligands.     

Oxydation ausgewählter δ,ϵ- und ϵ,ξ-ungesättigter Alkohole mit Blei(IV)-acetat

The lead tetraacetate (LTA) oxidation of dihydro-γ-jonol ( 2 ) gives the new bicyclic ether 4 in high yield. On the other hand, LTA oxidation of the alcohols 8, 14, 20 , results in the formation of complex mixtures of oxidation products, from which the spiro compounds 10, 16, 22 , the bicyclic ethers 11, 12, 17, 18, 23 , and the carbonyl compounds 13, 19 have been isolated.     

Diels-Alder reactions of masked o-benzoquinones: new experimental findings and a theoretical study of the inverse electron demand case

Diels-Alder reactions of the masked o-benzoquinone (MOB) 2 with vinylene carbonate (3), the bicyclic derivatives 4, 5, and 6, and the intramolecular version of the 2-hydroxymethylfuran-MOB Diels-Alder reaction are described. In addition, a theoretical study of the Diels-Alder reactions of MOBs with enol and thioenol ethers is presented.     

Current development of bicyclic peptides

Bicyclic peptides, a class of polypeptides with two loops within their structure, have emerged as powerful tools in the development of new peptide drugs. They have the potential to bind to challenged drug targets, with antibody-like affinity and selectivity. Meanwhile, bicyclic peptides possess small molecule-like access to chemical synthesis, which is conducive to large-scale synthesis and screening. In the last five years, bicyclic peptide technology has been increasingly developed, and researchers have carried out a variety of studies to elucidate the potential functions of bicyclic peptides. With the continuous development of synthetic methods and the advances of new technology to build bicyclic peptide libraries, bicyclic peptides are now becoming widely used in the development of new drugs for various diseases. This perspective provides an overview of the structure types, synthesis and applications of bicyclic peptides in current drug development, and our own views on future challenges of bicyclic peptides.