Oxacycle formation

It has been demonstrated that group 6 Fischer-type metal carbene complexes can in principle undergo carbene transfer reactions in the presence of suitable transition metals [122]. It was therefore interesting to test the compatibility of ruthenium-based metathesis catalysts and electrophilic metal carbene functionalities. A series of examples of the formation of oxacyclic carbene complexes by metathesis (e.g., 128, 129, Scheme 26) was published by Dotz et al. [123]. These include substrates where double bonds conjugated to the pentacarbonyl metal moiety participate in the metathesis reaction. Evidence is... 

Another possible termination step that has been utilized for the cycloetherification of alkynols involves CO insertion and esterification of the resulting acyl metal with an exogenous alcohol. This process has typically employed MeOH as solvent and a stoichiometric oxidant since the catalyst is turned over in a reduced form. Following this mechanistic motif, a variety of alkynols have been cyclized under Pd(n) catalysis to five- and six-membered oxacycles with incorporation of methyl esters into the products.294,327-329 For the formation of five-membered ring products, this reaction has been carried out in both exo- and endo-mode to provide 1- and 2-substituted... 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

J. O. Hoberg, Formation of seven-membered oxacycles through ring expansion of cyclopropanated carbohydrates, J. Org. Chem., 62 (1997) 6615-6618. 

A solid-phase synthesis of furo[3,2-3]pyran derivatives utilizing highly functionalized sugar templates has been reported <2003JOC9406>. After incorporation of alkenes within the sugar template, such as compound 95, the solid support is introduced via formation of the acid amide. This immobilized system then allows a ruthenium-catalyzed ring-closing metathesis that leads to the formation of the fused oxacycles. 

Muthusamy et al. (82) prepared a number of oxacyclic ether compounds from the tandem ylide formation-dipolar cycloaddition methodology. Their approach provides a synthetic tactic to compounds such as ambrosic acid, smitopsin, and linearol. Starting with either cyclopentane or cyclohexane templates, they prepared ylide sizes of five or six, which are trapped in an intermolecular cycloaddition reaction by the addition of DMAD. The products are isolated in good overall yield. In a second system, 2,5-disubstituted cyclohexenyl derivatives are utilized to generate the pendent ylide, then, A-phenylmaleimide is added in an intermolecular reaction, accessing highly substituted oxatricyclic derivatives such as 182 (Scheme 4.43). 

A number of reports have appeared on the use of carbonyl-alkene additions to construct oxacyclic ring systems efficiently with high diastereoselectivity. Nakata showed that even the formation of seven-membered cyclic ethers using the transformation can be remarkably efficient and utilised the strategy to form the E ring of the polycyclic ether marine natural product yessotoxin (Scheme 5.34).64... 

Formation of oxacycles via intramolecular radical addition reactions of oxygen-centered radicals under oxidative and reductive conditions is known [116] (see also Chapter 5.2, Volume 2). However, cyclic ether formation via intramolecular displacement reaction of iodohydrins obtained by hydrogen abstraction of oxy radicals has been more widely used, as exemplified in the reports by Suarez [117]. The usefulness of this reaction was amply demonstrated by Paquette in the synthesis of (-t-)-epoxydiclymene (179) [118] (Scheme 61), in which the strained trans-... 

Stereoselective hydrogen transfer reactions on oxacyclic radical intermediates are useful as shown in the synthesis of lauthisan (32) [126]. A key step in the total synthesis of brevetoxin B by Nicolaou [127] (Scheme 65) features conversion of the hydroxy dithioketal 189 into the oxoeene system 190 via cyclic hemithioketal formation and stereoselective radical-mediated desulfurization. More recently, Tachi-bana employed the same reaction sequence in the partial synthesis of ciguatoxin ]128]. 

Heterocyclizations. An n-donor atom at a proper distance to an a-diazomethyl ketone participates in metal-catalyzed decomposition of the functional group, giving rise to a heterocyclic ketone. For medium azacycle formation the soluble Cu(acac)2 complex is much superior to Rh2(OAc)4- Oxacycles are similarly accessible using the hexafluoroacetylacetonate. ... 

By this cyclization tetrahydroftiran derivatives have also been prepared. Compare the Lewis-acid induced tandem oxacyclization with oxepane formation in ref [9]. 

Based on a transformation described by Catellani and coworkers [80], Lautens s group [81] developed a series of syntheses of carbocycles and heterocycles from aryl iodide, alkyl halides and Mizoroki-Heck acceptors. In an early example, the authors described a three-component domino reaction catalysed by palladium for the synthesis of benzo-annulated oxacycles 144 (Scheme 8.37). To do so, they used an m-iodoaryl iodoalkyl ether 143, an alkene substimted with an electron-withdrawing group, such as t-butyl acrylate and an iodoalkane such as -BuI in the presence of norbomene. It is proposed that, after the oxidative addition of the aryliodide, a Mizoroki-Heck-type reaction with nor-bornene and a C—H activation first takes place to form a palladacycle PdCl, which is then alkylated with the iodoalkane (Scheme 8.37). A second C—H activation occurs and then, via the formation of the oxacycle OCl, norbomene is eliminated. Finally, the aryl-palladium species obtained reacts with the acrylate. The alkylation step of palladacycles of the type PdCl and PdCl was studied in more detail by Echavarren and coworkers [82] using computational methods. They concluded that, after a C—H activation, the formation of a C(sp )—C(sp ) bond between the palladacycle PdCl and an iodoalkane presumably proceeds by oxidative addition to form a palladium(IV) species to give PdC2. This stays, in contrast with the reaction between a C(sp )—X electrophile (vinyl or aromatic halide) and PdCl, to form a new C(sp )—C(sp ) bond which takes place through a transmetallation. 

Eight-membered-ring oxacycles were available from an analogous route. Formation of the sodium enolate from oxacyloheptenone 85 and reaction with acyl silane 82 provided 86 in good yield and with high diastereoselectivity. The proper choice of enolate coimterion and solvent were crucial in these systems. ... 

Scheme 3.1 General pathways for the synthesis of oxacycles. (a) C-H activation/C-O formation and (b) C-H activation/C-C formation.

Palladium-Catalyzed C-H Activation/C-C Formation to Construct Oxacycles... 

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