Regioselectivity in the formation of small- and medium-sized cyclic ethers by diene-ene ring-closing metathesis

In the formation of medium-sized ethers by diene-ene ring-closing metathesis, the formation of cyclic allyl ethers with a smaller ring size and of pentadienyl ethers with a larger ring size compete with each other. In the competition between six- and eight-membered and seven- and nine-membered ring formation, the smaller rings are formed exclusively, whereas in the competition between the five- and seven-membered rings, both products are formed in comparable amounts.     

Gold‐Catalyzed 1,2‐Acyloxy Migration/Intramolecular [3+2] 1,3‐Dipolar Cycloaddtion Cascade Reaction: An Efficient Strategy for Syntheses of Medium‐Sized‐Ring Ethers and Amines

A highly efficient strategy for the formation of medium‐sized‐ring ethers and amines based on a gold‐catalyzed cascade reaction, involving enynyl ester isomerization and intramolecular [3+2] cyclization, has been developed. Various multisubstituted medium‐sized‐ring unsaturated ethers and amines were obtained through this transformation. This method represents one of the relatively few transition metal catalyzed intramolecular cycloaddition reactions for medium‐sized ring synthesis.     

Stereoselective synthesis of cyclic ethers by intramolecular trapping of dicobalt hexacarbonyl-stabilized propargylic cations

The intramolecular attack of a hydroxy group on an exo-biscobalthexacarbonyl propargylic cation provides cyclic ethers with six- to nine-membered rings. The scope and limitations of the methodology are described. The reaction is stereoselective when additional stereocenters are present, providing iterative methodology to access ladder-like cyclic ethers.     

Studies on transannulation reactions across a nine-membered ring: the synthesis of natural product-like structures

A series of diverse natural product-like structures have been synthesised by the use of a number of novel transannulation reactions across a cyclononene ring. Transannular cyclisations through oxygen functionality have generated a number of bicyclo[5.3.1]systems containing bridged cyclic ethers and bicyclo[5.2.2]lactones, as well as a tetrahydrofuran-containing bridged analogue of hexacyclinic acid. An unprecedented Br?nsted acid mediated transannular cyclisation between proximal carbons generated bicyclo[4.3.0]nonanes which form the core of the pinguisane and austrodorane families of sesquiterpenoids. In all cases the key factor that determined the mode of reactivity was the conformation of the nine-membered ring and the distance between the reacting centres.     

Ring expansion of lactones and lactams via propiolate 1-carbon intercalation

Readily available five- and six-membered lactones and N-sulfonyllactams undergo efficient addition of t-butyl propiolate, and the resulting adducts undergo cycloisomerization to six- and seven-membered cyclic ethers or amines in the presence of pyridinium acetate. The ring expansion process occurs in generally good yields and is proposed to involve a nucleophilic catalysis mechanism.     

Stereospecific synthesis of eight- and nine-membered cyclic ethers by Eu(fod)3-mediated cyclization of hydroxy epoxides

An efficient and versatile method for the stereospecific construction of α,ω-cis- and α,ω-trans-disubstituted eight- and nine-membered cyclic ethers was developed. Cyclization of the hydroxy epoxides promoted by Eu(fod)₃ proceeded via an S_N2 process and exo mode to provide the corresponding cyclic ethers in excellent yields.     

Visible-light-driven palladium-catalyzed Dowd–Beckwith ring expansion/C–C bond formation cascade

A visible-light-induced palladium-catalyzed Dowd–Beckwith ring expansion/C–C bond formation cascade is described. A range of six to nine-membered β-alkenylated cyclic ketones possessing a quaternary carbon center were accessed under mild conditions. Besides styrenes, the electron-rich alkenes such as silyl enol ethers and enamides were also compatible, providing the desired β-alkylated cyclic ketones in moderate to good yields.

An intermolecular Dowd–Beckwith ring expansion/C–C bond formation is achieved through light-induced palladium catalysis. Not only styrenes but also the electron-rich alkenes such as silyl enol ethers and enamides were also compatible in this reaction.     

A Migratory Ether Formation Route to Medium‐Sized Sugar Mimetics

Polyol‐substituted cyclic ethers are fundamental building blocks of biomolecules. The position and stereochemistry of multiple hydroxy substituents of cyclic ethers play a central role in their biological function. Current methods for the synthesis of such structures are limited to “naked” ring products with no or few substituents. Here we describe a general route to medium‐sized polyol cyclic ethers using a migratory ether formation strategy. In contrast to the common pathway of direct opening of epoxides, Me₃Al was found to promote an unprecedented ether addition reaction, opening a neighboring epoxide. The resulting oxonium intermediate triggers a 1,3‐methyl shift to yield 2‐deoxyribital products. When the hemiacetal auxiliary is a monosaccharide, the sugar ring is expanded by four atoms to give the corresponding 9‐ to 11‐membered analogues. This method provides an entry into the untapped chemical space of medium‐sized sugar mimetics.     

Synthesis of benzo-fused medium ring cyclic ethers via a Michael addition-ring closing metathesis strategy involving nitroaliphatic compounds

Nitroalkenes derived from O-protected salicylaldehyde undergo facile Michael-type addition of nucleophiles possessing unsaturated tether. Ring closing metathesis of the Michael adducts provides benzo-fused medium ring cyclic ethers possessing a nitroalkyl functionality.     

Tetrahydropyran formation by rearrangement of an epoxy ester: a model for the biosynthesis of marine polyether toxins

Acid-catalyzed rearrangement of the (S)-epoxide derived from 2alpha-allyl cholestanyl acetate resulted in a 1:1 mixture of a steroidal tetrahydrofuran and a steroidal tetrahydropyran. Formation of a six-membered ring supports the hypothesis that epoxy ester-orthester-cyclic ether rearrangement may be involved in the biosynthesis of ladder-type marine polyether toxins. This reaction represents a new biomimetic preparation of medium ring cyclic ethers.     

A general approach to medium-sized ring ethers via hydrolytic and oxidative kinetic resolutions: stereoselective syntheses of (−)-cis-lauthisan and (+)-isolaurepan

A short and enantioselective approach to medium ring ethers and its application to the syntheses of (−)-cis-lauthisan and (+)-isolaurepan are described. The synthetic strategy features Jacobson's Hydrolytic Kinetic Resolution (HKR), oxidative resolution of secondary alcohol, and highly diastereoselective Et₃SiH/TMSOTf-promoted reductive cyclization of a hydroxy ketone to give exclusively the different medium-sized cis-disubstituted cyclic ethers.     

Synthesis of symmetrical disulfides by reaction of fluorine-containing thiiranes with cyclic amines

Regioselective opening of the thiirane ring in fluorine-containing thioglycidyl ethers and [(perfluorobutyl) methyl]thiirane by the action of cyclic amines afforded 1,2-aminothiols which were oxidized in situ to symmetrical disulfides. The rate of formation of the latter depended on the amine basicity. According to the NMR data, the resulting disulfides were mixtures of erythro and threo diastereoisomers.     

Researches on alkoxysilanes

Reaction of 1,2-, 1,3-, 1,4-, 1,5-, and 1,6-glycols, and of catechol, pentaerythritol, and glycerol with dialkyldichlorosilanes (in the presence of tertiary amines) dialkyldialkoxysilanes, or polydialkylsiloxanes gives 30 ethers of dialkylsilanediols containing 5, 6, 7, 8, 9, and 10-membered rings (16 being new). Among them are 8-membered ring ethers containing along with Si, O, and C, N or S, and 6-membered ring ethers containing NH₂, NO₂, and OH groups. 2-Sila -1,3-dioxolanes are obtained only when formation of the 1,3,6,8-tetraoxa-2, 7-disilacyclodecane ring is hindered or prevented by the presence of one or two substituents on each carbon atom with two substituents on the silicon. 2, 2-Dialkyl-1, 3-dioxa-2-silacyclanes, which contain 8 and 9-membered rings, can be obtained only by thermal depolymerization of originally formed polymeric ethers of the type [-O(CH₂)_nOSiR₂-]_m. Many of the monomeric cyclic ethers prepared dimerize or polymerize on keeping.For Part XVI see [1].     

Oxidations of N-(3-indoleethyl) cyclic aliphatic amines by horseradish peroxidase: the indole ring binds to the enzyme and mediates electron-transfer amine oxidation

Although oxidations of aromatic amines by horseradish peroxidase (HRP) are well-known, typical aliphatic amines are not substrates of HRP. In this study, the reactions of N-benzyl and N-methyl cyclic amines with HRP were found to be slow, but reactions of N-(3-indoleethyl) cyclic amines were 2-3 orders of magnitude faster. Analyses of pH-rate profiles revealed a dominant contribution to reaction by the amine-free base forms, the only species found to bind to the enzyme. A metabolic study on a family of congeneric N-(3-indoleethyl) cyclic amines indicated competition between amine and indole oxidation pathways. Amine oxidation dominated for the seven- and eight-membered azacycles, where ring size supports the change in hybridization from sp3 to sp2 that occurs upon one-electron amine nitrogen oxidation, whereas only indole oxidation was observed for the six-membered ring congener. Optical difference spectroscopic binding data and computational docking simulations suggest that all the arylalkylamine substrates bind to the enzyme through their aromatic termini with similar binding modes and binding affinities. Kinetic saturation was observed for a particularly soluble substrate, consistent with an obligatory role of an enzyme-substrate complexation preceding electron transfer. The significant rate enhancements seen for the indoleethylamine substrates suggest the ability of the bound indole ring to mediate what amounts to medium long-range electron-transfer oxidation of the tertiary amine center by the HRP oxidants. This is the first systematic investigation to document aliphatic amine oxidation by HRP at rates consistent with normal metabolic turnover, and the demonstration that this is facilitated by an auxiliary electron-rich aromatic ring.     

Facile synthesis of medium-sized cyclic amines based on Friedel-Crafts reaction via iminium cation by use of acetylene dicobalt complex

An intramolecular Friedel-Crafts reaction of N-methoxymethyl sulfoneamides 3e-j containing an acetylene dicobalt moiety was found to proceed smoothly to afford eight- and nine-membered cyclic amines 4e-j in high yields.     

Synthesis of Polycyclic Ethers by Two-Directional Double Ring-Closing Metathesis

trans-Fused tricyclic ethers containing combinations of six-, seven-, eight-, and nine-membered rings are constructed using two-directional double ring-closing metathesis reactions (see scheme). Such double cyclizations of precursors bearing alkenes, allylic ethers, enol ethers, or alkynyl ethers offer a new strategy for the synthesis of brevetoxins and ciguatoxins. PMB=(p-MeOC(6)H(4)CH(2)).     

Introduction of Alkyl- or Phenylseleno Group by the Ring Opening of Cyclic Ethers Using Dialkyl- or Alkylphenylselenium Dibromide and Sodium Borohydride

The reaction of dialkyl- or alkylphenylselenium dibromide with cyclic ethers in the presence of sodium borohydride gave ω-hydroxyalkyl alkyl or phenyl selenides as the ring opening products of the cyclic ethers.     

Ring fission of chiral cyclic acetals plus intramolecular [4 + 2] cycloaddition: a sequential access to medium-size lactones. Application to the synthesis of carbasugars

A set of alpha,beta-unsaturated cyclic acetals were reacted with t-butyllithium in THF. A conjugate elimination took place, triggering a ketal ring cleavage when two eq. of TMEDA were added to the medium. The lithium alcoholate thus obtained could be trapped in situ by 2,2,2-trifluoroethyl acrylate. The resulting acryloyl (1Z,3E)-dienyl ether was then submitted to an intramolecular Diels-Alder cycloaddition under high pressure (12 kbar, 50 degrees C). Depending on the structure of the linkage between the diene and the acrylate, the expected ("fused") lactones were obtained with total endo- or exo-selectivities and high to complete diastereoselectivities. A remarkable inversion of selectivity, from endo to exo, with respect to the stereochemical elements of the tether could be observed in these cases. A five step diastereoselective transformation of two of the resulting nine-membered ring lactones into modified carbasugars was finally achieved in 23% overall yield.     

Nickel‐Catalyzed Amination of Silyloxyarenes through C–O Bond Activation

Silyloxyarenes were utilized as electrophilic coupling partners with amines in the synthesis of aniline derivatives. A diverse range of amine substrates were used, including cyclic or acyclic secondary amines, secondary anilines, and sterically hindered primary anilines. Additionally, a range of sterically hindered and unhindered primary aliphatic amines were employed, which have previously been challenging with other classes of aryl ether electrophiles. Orthogonal couplings of silyloxyarenes with aryl methyl ethers are illustrated, where selectivity between the two C?O electrophiles is determined by ligand control, thereby allowing complementary and selective late‐stage diversification of either electrophile. Finally, a sequential coupling displays the utility of this amination method along with the reversal in intrinsic reactivity between aryl methyl ethers and silyloxyarenes.     

Mechanism of the photochemical reactions of substituted benzoquinones

Photoreactions of 2,6-dimethyl-, 2,6-di-tert-butyl-, and 2,6-diphenyl-1,4-benzoquinones with alcohols, organic acids, thioalcohols, amines (primary, secondary, and tertiary), cyclic ethers, tri- and tetraethoxysilanes are accompanied by the effect of chemical polarization of nuclei (CINDP) and lead, along with the formation of hydroquinones, to bicyclic and tricyclic structures and the products of radical substitution in the aromatic ring. The mechanisms of elementary photoreactions were elucidated. The intermediate excited states and radical structures were considered. For the first time permanent generation of radio waves in the course of the reversible photochemical reaction of substituted 1,4-benzoquinones with alcohols was detected.