Medium-sized Cyclic Ethers Research Articles

Palladium-catalyzed annulative allylic alkylation for regioselective construction of indole-fused medium-sized cyclic ethers

A new palladium-catalyzed annulative allylic alkylation (AAA) reaction of 2-(indol-2-yl)phenols with dual allylic electrophiles such as isobutylene dicarbonate and butene dicarbonate is described, leading to the regioselective synthesis of tetracyclic medium-sized cyclic ethers possessing a bridged aryl-indole scaffold, namely, benzo[2,3]oxocino[4,5-b]indoles and benzo[2,3]oxepino[4,5-b]indoles, in good to excellent yields. This protocol demonstrates a broad substrate scope, good compatibility with substituents and high regioselectivity, providing a catalytic and flexible method for creating bridged aryl-indole skeletons.

Silver(I)-Catalyzed Reductive Cross-Coupling of Aldehydes to Structurally Diverse Cyclic and Acyclic Ethers.

A range of medium-sized cyclic ethers (5 to 11 membered) have been effectively synthesized through intramolecular reductive coupling of dialdehydes initiated by 50 ppm to 0.5% of AgNTf2 with hydrosilane at 25 °C. The catalytic system is also suitable for the coupling of two different monoaldehydes to provide unsymmetrical ethers. This protocol features broad functional group compatibility, high product diversity, high efficiency, and utility in the late-stage modification of complex biorelevant molecules.

Site- and Enantiodifferentiating C(sp3)-H Oxidation Enables Asymmetric Access to Structurally and Stereochemically Diverse Saturated Cyclic Ethers.

A manganese-catalyzed site- and enantiodifferentiating oxidation of C(sp3)-H bonds in saturated cyclic ethers has been described. The mild and practical method is applicable to a range of tetrahydrofurans, tetrahydropyrans, and medium-sized cyclic ethers with multiple stereocenters and diverse substituent patterns in high efficiency with extremely efficient site- and enantiodiscrimination. Late-stage application in complex biological active molecules was further demonstrated. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity. The ability to employ ether substrates as the limiting reagent, together with a broad substrate scope, and a high level of chiral recognition, represent a valuable demonstration of the utility of asymmetric C(sp3)-H oxidation in complex molecule synthesis.

Stereoselective Synthesis of Medium-Sized Cyclic Ethers by Sequential Ring-Closing Metathesis and Tsuji-Trost Allylation.

Fully functionalized medium-sized cyclic ethers, of the type found in fused polyether natural products, have been prepared by sequential ring-closing diene metathesis, conversion of the resulting cyclic enone into an allylic enol carbonate, and Tsuji-Trost allylation using a chiral palladium complex. Very high levels of diastereocontrol, favoring the diastereomer in which there is a cis relationship between the allyl group at C-2 of the medium-ring ether and the substituent at C-7/C-8, are obtained in cases where catalyst control and substrate control are matched.

Lewis Acid Mediated Cyclizations: Diastereoselective Synthesis of Six- to Eight-Membered Substituted Cyclic Ethers.

Cyclic ethers are widely abundant in natural products. Cyclic ether templates are also utilized in drug design and medicinal chemistry. Although the synthetic processes for this class of compounds have been studied extensively with respect to five- and six-membered rings, medium-sized cyclic ethers are synthetically more challenging due to a variety of factors. Herein, we report our results on the Lewis acid catalyzed synthesis of medium-sized cyclic ethers in a diastereoselective manner.

Medium-Sized Cyclic Ethers via Stevens [1,2]-Shift of Mixed Monothioacetal-Derived Sulfonium Ylides: Application to Formal Synthesis of (+)-Laurencin.

A novel approach to medium-sized cyclic ethers was devised using a Stevens [1,2]-shift of a sulfonium ylide derived from a readily accessible six-membered mixed-monothioacetal precursor. The concise and efficient transformation offers a surprising degree of chirality transfer with observed retention of stereochemical configuration on the anomeric migrating carbon and has been applied as the key step in an enantioselective formal synthesis of (+)-laurencin.

Templated Assembly of Chiral Medium-Sized Cyclic Ethers via 8-endo-trig Nucleophilic Cyclization of Cyclopropenes.

An efficient approach toward enantioenriched eight-membered heterocycles via the intramolecular formal substitution of bromocyclopropanes with oxygen-based nucleophiles has been developed. The reaction proceeds via a reactive cyclopropene intermediate, which undergoes a rapid 8-endo-trig cyclization affording cis-fused [6.1.0] bicyclic products exclusively. The quaternary chiral center in the cyclopropene governs the configuration of the other two stereocenters in the final product.

Diastereoselective Ring-Closing Metathesis as a Means to Construct Medium-Sized Cyclic Ethers: Application to the Synthesis of a Photoactivatable Gambierol Derivative.

This paper describes a concise synthesis of six- to eight-membered α,α'-substituted cyclic ethers by exploiting diastereoselective ring-closing metathesis (RCM) of 1,4-pentadien-3-yl ether derivatives. The RCM precursors could be efficiently prepared via a vinylation of the corresponding α-acetoxy ether derivatives using divinylzinc. Diastereoselective RCM of 1,4-pentadien-3-yl ether derivatives afforded a series of six- to eight-membered α,α'-substituted cyclic ethers with moderate to good diastereoselectivity. The stereochemical consequence of the diastereoselective RCM appeared to be dependent on the structure of the ring being forged. The diastereoselectivity of six- and seven-membered cyclic ethers appeared to be largely under kinetic control irrespective of the catalyst reactivity, whereas that of an eight-membered cyclic ether could be controlled by the catalyst reactivity. Finally, the diastereoselective RCM chemistry was applied to the synthesis of a biotin-tagged photoactivatable derivative of gambierol.

Access to Diverse Oxygen Heterocycles via Oxidative Rearrangement of Benzylic Tertiary Alcohols.

A facile method for the synthesis of challenging medium-sized cyclic ethers has been developed via a novel oxidative rearrangement of benzylic tertiary alcohols. The reaction provides access to cyclic acetals with diverse substitution at both C2 and the aromatic ring. The unique reactivity is enabled by poly(cationic) hypervalent iodine reagents and represents the first synthetic application of this underexplored class of compounds.

Stereoselective Synthesis of Medium-Sized Cyclic Ethers: Application of C-Glycosylation Chemistry to Seven- to Nine-Membered Lactone-Derived Thioacetals and Their Sulfone Counterparts

Stereoselective synthesis of α,α'-substituted medium-sized cyclic ethers has been achieved by means of nucleophilic substitution of the corresponding lactone-derived thioacetals and their sulfone counterparts. Nucleophilic substitution of medium-sized lactone-derived thioacetals could be achieved efficiently either by (i) activation with NIS/TMSOTf in the presence of allyltrimethylsilane or TMSCN or by (ii) oxidation to the corresponding sulfones followed by treatment with an appropriate organometallic species such as divinylzinc or dimethyl(2-phenylethynyl)aluminum. Interestingly, the stereochemical consequence was found to be largely dependent on the local structure of substrates. In some cases, the gauche steric interaction developed in the transition state was considered to be responsible for the observed diastereoselectivity. The present method enables an efficient synthesis of a variety of α,α'-substituted seven- to nine-membered cyclic ethers from readily accessible lactone precursors.

Convergent Method via ^|^alpha;-Cyano Ethers: A Powerful Strategy for Synthesizing Ladder-Shaped Polyethers

Ladder-shaped polyether (LSP) toxins attract considerable attention among synthetic organic chemists due to their potent biological activities coupled with their unique molecular structures. Although a number of methods for synthesizing LSPs have been reported, developments of convergent and practical methods are necessary for efficient synthesis of LSPs in order to reveal their biological function at the molecular level and because of their limited availability from natural sources. During the course of our synthetic studies of LSPs, we developed a convergent method via α-cyano ethers (α-cyano ether method). An additional two rings can be constructed through the coupling of fragments, which is an advantage of this strategy for the construction of polycyclic systems. Medium-sized cyclic ethers are formed by ring-closing metathesis, and tetrahydropyran rings are stereoselectively constructed by reductive etherification or thioacetal formation followed by alkylation. The α-cyano ether method was successfully applied to the synthesis of the partial structure corresponding to the ABCDEFGHIJ ring system of yessotoxin, where utilization of a microflow reactor was found to be effective for reductive etherification. The α-cyano ether method was also applicable for synthesizing the WXYZA'B'C' ring system of maitotoxin, and designed artificial tetra-, hepta-, and decacyclic LSPs.

Thiol mediated 8- endo-trig radical cyclization: an easy access to medium-sized cyclic ethers

An efficient new method for the synthesis of eight-membered heterocycles has been developed via a thiophenol mediated intramolecular 8- endo radical cyclization reaction. Alkenyl radicals are generated from easily available terminal alkynes and thiophenol.

Titanocene(III) mediated radical cyclizations of epoxides for the synthesis of medium-sized cyclic ethers

Titanocene(III) chloride (Cp 2TiCl) mediated 7- exo and 8- endo radical cyclizations of epoxides towards the synthesis of 7- and 8-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride (Cp 2TiCl 2) and activated zinc dust in THF.

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.

Efficient Metathesis Route to the B‐Ring of Eleutherobin and Other Medium‐Sized Cyclic Ethers.

A short and efficient RCM route is reported for the synthesis of the B-ring of eleutherobin and other medium-sized cyclic ethers from readily available 1,2,5,6-diisopropylidene-D-glucose. This strategy is successfully extended to the synthesis of a few bicyclic ethers, which may find applications in the synthesis of novel bicyclic nucleosides.

Synthesis of the EF-ring segment of ciguatoxin CTX1B based on novel regioselective reduction of unsaturated cyanohydrins and ring-closing olefin metathesis

Aiming at a convergent total synthesis of ciguatoxin CTX1B, its EF-ring segment has been synthesized. During the synthesis, a novel method for the construction of branched ethers, based on regioselective reduction of γ-alkoxy β,γ-unsaturated α-silyloxy nitriles with borontrifluoride etherate and trialkyl silane or tributyltin hydride, has been developed. Combination use of the method and ring-closing olefin metathesis successfully provided medium-sized cyclic ethers. Efficient site-selective reduction of vinyl epoxides into homoallyl alcohols has also been developed.

Efficient metathesis route to the B-ring of eleutherobin and other medium-sized cyclic ethers

A short and efficient RCM route is reported for the synthesis of the B-ring of eleutherobin and other medium-sized cyclic ethers from readily available 1,2,5,6-diisopropylidene- d-glucose. This strategy is successfully extended to the synthesis of a few bicyclic ethers, which may find applications in the synthesis of novel bicyclic nucleosides.

Stereoselective synthesis of cis- and trans-2,3-disubstituted eight-membered medium-ring ethers based on Ireland–Claisen rearrangement of 3-alkoxy-2-propenyl glycolate esters and ring-closing olefin metathesis

A simple stereoselective synthesis of cis- and trans-2,3-disubstituted medium-sized cyclic ethers has been developed based on geometry-selective synthesis of 3-alkoxy-2-propenyl glycolate esters, Ireland–Claisen rearrangement of the glycolate esters, and ring-closing olefin metathesis.

New Strategies for the Efficient Synthesis of Medium-Sized Bicyclic γ-Alkylidenebutenolides Based on Regioselective Cyclizations of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with Oxalyl Chloride

Medium-sized bicyclic γ-alkylidenebutenolides were efficiently prepared by Me3SiOTf-catalyzed cyclization of cyclic bis(silyl enol ethers) with oxalyl chloride. In addition, a new strategy for the synthesis of medium-sized bicyclic hybrids of butenolides and medium-sized cyclic ethers − based on sequential [3+2] cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes, Mitsunobu reaction, and ring-closing metathesis − is reported.

ポリエーテル系天然物の化学合成 新しい中員環エーテル構築法とエーテル環連結法の開発

ポリエーテル系天然物の化学合成 新しい中員環エーテル構築法とエーテル環連結法の開発