Intramolecular etherification

Intermediate 8, the projected electrophile in a coupling reaction with intermediate 7, could conceivably be derived from iodolactone 16. In the synthetic direction, cleavage of the acetonide protecting group in 16 with concomitant intramolecular etherification could result in the formation of the functionalized tetrahydrofuran ring of... 

The hydroxylation reaction, whose stereochemical course is controlled by the strong inherent preference for the formation of a cis-fused 5,5 ring system, creates a molecule which would appear to be well suited for an intramolecular etherification reaction to give ring E of ginkgolide B (1). Indeed, when a solution of 11 in methylene chloride is exposed to camphorsulfonic acid (CSA), a smooth cycli-zation reaction takes place to give intermediate 10 in an overall yield of 75% from 12. The action of CSA on 11 produces a transient oxonium ion at C-12 which is intercepted intramolecularly by the proximal hydroxyl group at C 4. 

A trifold anionic/pericyclic domino reaction was used for the synthesis of the dioxapyrrolizidine 2-655 combining a nitro aldol condensation, SN-type cyclization, SN-type etherification, and an intramolecular 1,3-dipolar cyclization as described by Rosini and coworkers (Scheme 2.148) [339]. 

Scheme 21 shows the synthesis of a dihydrofuran derivative 86. Synthesis of this compound was described by Nam et al. [68] utilizing a furanone compound 87 synthesized by Kim et al. [61] via a similar synthetic approach as described in Scheme 17. The lactone was reduced using lithium aluminum hydride to give the diol 88 and intramolecular etherification using the Mitsunobu reaction afforded the dihydrofuran 86 in moderate yield (47%).

This intramolecular etherification approach has successfully been applied to the syntheses136 of siccanin137 and clusifoliol,136 and a formal synthesis of morphine.138 Examples of tandem inter- and intramolecular etherification reactions have also been reported which convert catechol and o-aminophenol derivatives into benzodioxins (Equation (24)),139-141 benzodioxepines,142 and morpholines.139,140... 

Pd-catalyzed intramolecular etherification reactions of aliphatic alcohols have also been practiced in tandem with other bond-forming processes, such as a Pd-catalyzed allyltin addition to an aldehyde (Equation (32)).160 Similarly, a tandem C-N and G-O bond formation sequence occurs (Equation (33)) during the reactions of /3-amino alcohols with biscarbonates in the presence of the N,O-acetal-derived ligand 43.161-163... 

In rare cases, the Pd-catalyzed intramolecular allylic etherification has been extended to the construction of medium-sized rings. Both an 11-membered bis-ether ring (Equation (34))164 and an eight-membered ether ring (Equations (35) and (36))155 have been prepared in this fashion. In the latter case, the choice of ligand dictated the regiochemical outcome. 

The literature is replete with synthetic methods to prepare 5-bromofurans. One of the more practical syntheses [10, 11] commenced with etherification of 4-bromophenol with bromoacetaldehyde diethyl acetal using either NaH in DMF or KOH in DMSO. Treatment of the resulting aryloxyacetaldehyde acetal with polyphosphoric acid (PPA) afforded 5-bromofuran in good yield via intramolecular cyclocondensation. However, cyclization of m-aryloxyacetaldehyde acetal 1 resulted in a mixture of two regioisomers, 6-bromofuran (2) and 4-bromofiiran (3). Finally, 7-bromofuran 5 can be prepared similarly using the intramolecular cyclocondensation of aryloxyacetaldehyde acetal 4 generated from etherification of 2-bromophenol with bromoacetaldehyde diethyl acetal. 

Synthesis of a sugar derived allene and its intramolecular silver mediated etherification followed by ring closing metathesis has been explored for building the tricyclic framework of eunicin (Fig. 52).68... 

Sucrose Ethers. Being next to the anomeric center and intramolecularly hydrogen-bonded, the 2 -OH of sucrose is the most acidic, which means it is deprotonated first under alkaline conditions, and thus preferentially yields to etherification. Benzylation with NaH/benzylbromide in DMF, for example, results in an 11 2 1 mixture of 2 -(9-benzyl-sucrose (Figure 2.8) and its 1-0- and 3 -0-isomers. Because the former is readily accessible, it proved to be a versatile intermediate for the generation of 2 -modified sucroses, for example, the 2 -keto and 2 -deoxy derivatives as well as sucrosamine (2 -amino-2 -deoxy-sucrose), whose application profiles remain to be investigated. 

The reaction of acceptor-substituted carbene complexes with alcohols to yield ethers is a valuable alternative to other etherification reactions [1152,1209-1211], This reaction generally proceeds faster than cyclopropanation [1176], As in other transformations with electrophilic carbene complexes, the reaction conditions are mild and well-suited to base- or acid-sensitive substrates [1212], As an illustrative example, Experimental Procedure 4.2.4 describes the carbene-mediated etherification of a serine derivative. This type of substrate is very difficult to etherify under basic conditions (e.g. NaH, alkyl halide [1213]), because of an intramolecular hydrogen-bond between the nitrogen-bound hydrogen and the hydroxy group. Further, upon treatment with bases serine ethers readily eliminate alkoxide to give acrylates. With the aid of electrophilic carbene complexes, however, acceptable yields of 0-alkylated serine derivatives can be obtained. 

Alkoxy(trisdimethylamino)phosphonium salts (PF6, C104 or BF4 as anions)765 are also used for the same purpose with good yields of course, alkoxy groups can be chosen as optically active451,766,767. Moreover, when the alkoxy chain is functionalized in the appropriate position by oxyanions, intramolecular etherification is made possible 3,6-anhydrohexosides were prepared in this way537 (reaction 232). 

Etherification. Carbohydrates are involved in ether formation, both intramolecularly and intermolecularly (1,13)- The cyclic ether, 1,4-sorbitan, an 1,4-anhydroalditol, has already been mentioned. 3,6-Anhydro-CC-D-galactopyranosyl units are principal monomer units of the carrageenans. Methyl, ethyl, carboxymethyl, hydroxyethyl, and hydroxypropyl ethers of cellulose (qv) are all commercial materials. The principal starch ethers are the hydroxyethyl and hydroxypropylethers (see Cellulose ethers Starch). 

Intramolecular platinum-catalyzed etherification of 1,6-diphenylhexane-l,6-diol to give corresponding oxepane (Equation 8) smoothly proceeds in the presence of platinum hexafluoroantimonate in situ prepared from PtCl2 and AgSbF6 <2005SL152>. 

C-M bond addition, for C-C bond formation, 10, 403-491 iridium additions, 10, 456 nickel additions, 10, 463 niobium additions, 10, 427 osmium additions, 10, 445 palladium additions, 10, 468 rhodium additions, 10, 455 ruthenium additions, 10, 444 Sc and Y additions, 10, 405 tantalum additions, 10, 429 titanium additions, 10, 421 vanadium additions, 10, 426 zirconium additions, 10, 424 Carbon-oxygen bond formation via alkyne hydration, 10, 678 for aryl and alkenyl ethers, 10, 650 via cobalt-mediated propargylic etherification, 10, 665 Cu-mediated, with borons, 9, 219 cycloetherification, 10, 673 etherification, 10, 669, 10, 685 via hydro- and alkylative alkoxylation, 10, 683 via inter- andd intramolecular hydroalkoxylation, 10, 672 via metal vinylidenes, 10, 676 via SnI and S Z processes, 10, 684 via transition metal rc-arene complexes, 10, 685 via transition metal-mediated etherification, overview,... 

Intramolecular geometries, database studies, 1, 597 Intramolecular hydroalkoxylation, and etherification, 10, 672 Intramolecular pinacol coupling to cyclic 1,2-diols, 11, 51 with samarium reagents, 11, 60 Intramolecular silylformylation, alkynes and alkenes, 11, 489 Intramolecular solvomercuration alkenes, 2, 436 alkynes, 2, 439... 

A high-yielding stereoselective intramolecular reductive etherification of the 5-silyloxy substituted ketone 310 provides the final step in a total synthesis of the antibiotic (—)-centrolobine 311 (Equation 134) <2003OL3883>. 

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