Ethers cyclic, activation

The reaction processes shown in Scheme 8 not only accomplish the construction of an oxepane system but also furnish a valuable keto function. The realization that this function could, in an appropriate setting, be used to achieve the annulation of the second oxepane ring led to the development of a new strategy for the synthesis of cyclic ethers the reductive cyclization of hydroxy ketones (see Schemes 9 and 10).23 The development of this strategy was inspired by the elegant work of Olah 24 the scenario depicted in Scheme 9 captures its key features. It was anticipated that activation of the Lewis-basic keto function in 43 with a Lewis acid, perhaps trimethylsilyl triflate, would induce nucleophilic attack by the proximal hydroxyl group to give an intermediate of the type 44. 

As a strategy for the construction of cyclic ethers, the radical cyclization of jS-alkoxyacrylates was used for the preparation of czs-2,5-disubstituted tetrahy-drofurans and cis-2,6-disubstituted tetrahydropyrans. An example is given with S-alkoxymethacrylate 38 as precursor of the optically active benzyl ether of (+)-methyl nonactate, exclusively formed as the threo product (Reaction 44). ° ... 

The deoxygenation of cyclic ethers means the cleavage of both C-O bonds and leads to alkenes or alkanes depending on the hydrogenating activity of the catalyst (Scheme 4.2). 

Alkyl groups of compounds other than alkanes can be regioselectively functionalized using C-H activation chemistry. For example, acyclic and cyclic ethers can be activated by Ir(m) complexes to yield carbene complexes (Equation (25)).35... 

The oxidation of both linear and cyclic ethers to the corresponding acids and lactones by aqueous H202 as catalyzed by TS-1 and TS-2 was reported by Sasidharan et al. (241) (Scheme 17 and Table XXXV). The titanosilicates exhibited significantly better activity (about 55% conversion) and selectivity (98%) than chromium silicates, although vanadium silicates totally failed to catalyze the reaction. Such conversions are usually accomplished using either stoichiometric amounts of chromium trioxide, lead tetraacetate, or ruthenium tetroxide as oxidants (242) or catalytic amounts of Ru04 in the presence of... 

Cyclization of mixed acetals (13,300).4 This reaction is a particularly useful route to eight-membered cyclic ethers (oxocanes) and provides the first practical route to a natural oxocene, (- )-laurenyne (3), from an optically active mixed acetal 1. Thus cyclization of 1 followed by O-desilylation affords 2 as the only cyclic product. Remaining steps to 3 involved C-desilylation, for which only HF/pyridine is useful, introduction of unsaturation into the C2-side chain, and extension of the C8-side chain. Exploratory studies showed that unsaturation at the p- or y-positions to the cite of cyclization of 1 prevent or retard cyclization with a wide variety of Lewis acids. The cyclization is apparently more tolerant of substitution in the terminator position, C3-Q, of the oxocene. 

As far as the polymerisation of heterocyclic monomers is concerned, the situation is qualitatively similar, but quantitatively different. As a model for the active species in oxonium polymerisations, Jones and Plesch [10] took Et30+PF6 and found its K in methylene dichloride at 0 °C to be 8.3 x 10"6 M however, in the presence of an excess of diethyl ether it was approximately doubled, to about 1.7 x 10 5 M. This effect was shown to be due to solvation of the cation by the ether. Therefore, in a polymerising solution of a cyclic ether or formal in methylene dichloride or similar solvents, in which the oxonium ion is solvated by monomer, the ion-pair dissociation equilibrium takes the form... 

Considerable effort has been carried out by different groups in the preparation of amphiphihc block copolymers based on polyfethylene oxide) PEO and an ahphatic polyester. A common approach relies upon the use of preformed co- hydroxy PEO as macroinitiator precursors [51, 70]. Actually, the anionic ROP of ethylene oxide is readily initiated by alcohol molecules activated by potassium hydroxide in catalytic amounts. The equimolar reaction of the PEO hydroxy end group (s) with triethyl aluminum yields a macroinitiator that, according to the coordination-insertion mechanism previously discussed (see Sect. 2.1), is highly active in the eCL and LA polymerization. This strategy allows one to prepare di- or triblock copolymers depending on the functionality of the PEO macroinitiator (Scheme 13a,b). Diblock copolymers have also been successfully prepared by sequential addition of the cyclic ether (EO) and lactone monomers using tetraphenylporphynato aluminum alkoxides or chloride as the initiator [69]. 

Cationic ROP of lactones in the presence of an alcohol proceeds by an activated monomer mechanism similar to that for cyclic ethers (Sec. 7-2b-3-b) [Endo et al., 2002 Lou et al., 2002]. Propagation proceeds by nucleophilic attack of the hydroxyl end group of a propagating chain on protonated (activated) monomer ... 

For copolymerizations proceeding by the activated monomer mechanism (e.g., cyclic ethers, lactams, /V-carboxy-a-amino acid anhydrides), the actual monomers are the activated monomers. The concentrations of the two activated monomers (e.g., the lactam anions in anionic lactam copolymerization) may be different from the comonomer feed. Calculations of monomer reactivity ratios using the feed composition will then be incorrect. 

Chiral l,3-dioxin-4-ones photochemically react intermolecular with (cyclic) ethers, acetals, and secondary alcohols to give the addition products in reasonable yields. The radical addition was completely stereoselective at C-6 of the heterocycle <1999EJO1057>. The exocyclic diastereoselectivity, where relevant, was about 2 1 (Equation 30). In analogy, an intramolecular cascade reaction of a 1,3-dioxin -one derived from menthone was used to get a terpenoid or a steroid framework in optically active form <1997JA1129, 1999JA4894>. 

Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group of sildenafil derivatives 60 might enhance coplanarity of the molecule. The torsional angles were calculated to be 2-3° for sildenafil analogues with a five-membered ether ring and 12-16° for the derivatives of 60 with a six-membered ether ring. The least planar molecules are the most active enzyme inhibitors <2001BMC1609>. 

Using a/n-dihaloalkanes the alkylation can be stopped at the monoalkylation stage. Oxidation of the intermediate gives halo alcohols which can be cyclized under basic conditions to the optically active cyclic ethers. 

The ability of cyclic ethers to complex biologically important alkylammonium cations makes the choice of crown ethers as enzyme binding site models a natural one. In recent years a number of molecules containing both a crown ether-based substrate binding site and a potentially reactive group have been prepared as models for enzyme active sites (79PAC979, B-82MI52100). 

Laurepinnacin (23) and isolaurepinnacin (24) are acetylenic cyclic ethers from the red alga Laurencia pinnata Yamada that demonstrate insecticidal activity.47 Z-laureatin (25), Z-isolau-reatin (26), and deoxyprepacifenol (27) are other related compounds from the red alga... 

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