Ether tethers

Importantly, the tethers in these bisadduds can be readily removed, making them true templating units. This point is illustrated by the cleavage of the crown ether tether in conjugate 24 to give untethered trans-1 fundionalized fullerenes that are of interest for use as further molecular scaffoldings (Scheme 5).156 60 611... 

A free radical cyclization of oxime ethers tethered to an aldehyde has been used in the synthesis of azepine derivatives . For example, oxime ether 389 is cyclized to azepine 390 by reaction with Sml2 in HMPA and f-BuOH at —78°C (equation 170) . Similar free radical cyclization of oxime ethers can be carried out also in the presence of Bu3SnH/AIBN in benzene . Oxime 0-methyl ether 391 underwent thermal cyclization in refluxing o-dichlorobenzene (ODCB) leading to the mixture of two products 392 and 393 in ratio 69 31 in overall yield of 91% (equation 171) °. Rearrangement of oxime 0-tosylates in the presence of piperidine also leads to azepine ring formation . ... 

The type of atoms in the tether have little effect on the cycloaddition process. Both alkyl (98,125-127) and ether tethers (128-131) have been extensively investigated and provide similar levels of reactivity. In addition, thioethers (132), amines (133), silanes (134), and silyl ketals (135) are all compatible with the dipolar cycloaddition. 

The same research group has demonstrated a similar intramolecular process in the construction of bicychc adducts 326 (92). The CsF desilyation of precursors 327, after subsequent reaction of the internal dipolarophile, dehvered the expected cycloadducts with complete stereocontrol when either thioether and ether tethers or activated and unactivated dipolarophiles were used. In contrast with intermolecular protocols, the reaction was successful with both activated and unactivated alkenes. In addition, unlike the previous example, formation of both six (n = 2)- and five (n= l)-membered rings occurs (Scheme 3.109). 

The ether-tethered allenyne 248 undergoes a rhodium(l)-catalyzed intramolecular allenic Alder ene reaction to afford the ( )-3,6-dihydropyran 249 as the major product (Equation 111) <2002JA15186>. Likewise, ether tethered enynes can undergo rhodium(i)-catalyzed cycloisomerizations to afford 3,6-dihydropyrans <2005JA10180>. 

Substrates containing an electron-rich double bond, such as enol ethers and enol acetates, are easily oxidized by means of PET to electron-deficient aromatic compounds, such as dicyanoanthracene (DCA) or dicyanonaphthalene (DCN), which act as photosensitizers. Cyclization reactions of the initially formed silyloxy radical cation in cyclic silyl enol ethers tethered to an olefinic or an electron-rich aromatic ring, can produce bicyclic and tricyclic ketones with definite stereochemistry (Scheme 9.14) [20, 21]. 

The use of a functionalized silica-supported salen-nickel complex has allowed Kumada cross-couplings to be performed in flow the corresponding polystyrene supported complex was shown to be inferior for a number of reasons. Catalyst 33 (Figure 4.7) with the longer tether was found to be more active than the benzyl ether tether used for catalyst 34. This was postulated to be due to the fact that catalyst 33 resided further away from the silica surface and hence was more available for reaction. Under the conditions used a maximum conversion of 65% was found for the 1 1 reaction of 4-bromoanisole and phenylmagnesium chloride, which was found to be comparable to that obtained in batch mode. However, during the reaction catalyst degradation was observed and the conversion reduced from 60% in the first hour to 30% in the fifth hour of the reaction [155,156]. 

The next three chapters by Fleming, Armesto, and Rao deal with different aspects of alkene photochemistry alkene [2+2]-photocycloaddi-tions to other alkenes, di-7i-methane (DPM) rearrangements of 1,4-dienes and oxa-di-7i-methane (ODPM) rearrangements of 3,y-unsaturated carbonyl compounds. Photocycloaddition of an ether-tethered 1,6-diene by Cu(I)-catalysis leads to the exo-selective formation of the bicyclic tetrahydrofuran derivative 4 [4]. By direct electronic excitation of a... 

Copper catalyzed 2+2 of ether tethered alkenes has also shown regio-and stereoselectivity [18a]. Irradiation of the substituted diallyl ether shown in Sch. 15 yields predominantly the exo product via a coordinated... 

The ether-tethered allenyne 4 is converted into a cross-conjugated triene, the 5,6-dihydro-2tf-pyran 5, in a Rh-catalysed allenic Alder ene reaction <02JA15186> and allylic halides undergo a Pd-catalysed coupling reaction with 3,4-allen-l-ols to give 5,6-dihydro-2//-pyrans (Scheme 2) <02JOC6104>. 

The anodic cyclization reaction of furans was applied as a key step to construct the [5-6-7]-fused tricyclic core of cyathins <19990L1535>, and the [5-6-5]-fused tricyclic core of alliacol A using the acyclic silyl enol ether tethered furan 34 during its total synthesis (Scheme 21) <2004JA9106, 2003JA36>. 

Templates based on ether tethers also have been examined. Improvements in product yield may be anticipated from the reduced steric congestion in the cyclization step due to the substitution of an -O linkage for a -CH2 linkage [43]. In addition, such oxygenated tethers might serve as crown-ether type substrates, sequestering ions that in turn serve to promote macrocyclization. The beneficial effect on macrocyclization rates by complex-ation of this type has precedent in the work of Mandolini and Illuminati [44]. 

Cyclization studies were carried out in sealed tubes in toluene solutions at 165 °C and provided excellent yields of the corresponding bicyclic cycloadducts in 5-9 h. Reactions of tertiary alkyl ethers showed moderate to complete trans selectivity. This selectivity was observed even for inherently cw-directing systems and may be attributed to the gem-dimethyl group in the ether tether comparison of the reacting conformations leading to cis- and rrans-fused decalins reveals, in the cis case, an unfavorable non-bonding interaction between the axial methyl group and H-C(3) of the diene (Scheme 10-15). 

Scheme 10-16 Triene 44 linked through a benzylic ether tether also undergoes a stereoselective IMDA reaction.

Scheme 10-18 Cleavage of the ether tethers after cycloaddition.

A similar tethering strategy was more recently used by Inouye et al. in their formal, racemic synthesis of precapnelladiene 94 [37]. The reacting enone and cyclopentene were linked through an ether tether. Irradiation of 95 in hexane effected cyclization. 

Temporary tethering of radical precursors has found other applications in natural product synthesis. Crimmins and O Mahony utilized a silyl ether temporary eonnection to direct a hydro-hydroxymethylation of enol ether 139 in their synthesis of talaromycin A, 140 [54]. Since talaromycin A is susceptible to acid-catalyzed isomerization to the thermodynamically more stable talaromycin B in which the hydroxymethyl substituent is equatorial, the use of the essentially neutral conditions of a radical cyclization to install the requisite axial hydroxymethyl group would avoid any potential isomerization problems. Formation of enol ether 139 was achieved in five steps from (4R)-4-ethylvalerolac-tone 141. Exposure of 139 to Bu3SnH in benzene at reflux in the presence of AIBN as initiator effected radical cyclization with delivery of the radical to the same face to whieh the ether tether was attached. Tamao oxidation proceeded uneventfully, furnishing the desired natural product (Scheme 10-47). 

Scheme 10-57 Two radical cyclizations are possible with a (dichloromethyl)silyl ether tether.

Previous examples of silyl-tethered radical cyclizations have involved the incorporation of the radical precursor during the formation of the silyl ether tether. An alternative would be to incorporate the radical acceptor. A number of suitable silyl chlorides are commercially available which facilitate the preparation of such cyclization precursors. 

The same group have also investigated the incorporation of the radical acceptor moiety via a silyl ether tether [76b]. A phenylseleno substituent was stereospecifically incorporated into either the 2 - or 3 -position of four thymidine nucleosides, followed by incorporation of an olefinic radical acceptor into the vicinal hydroxyl group by reaction with (allyl)dimethy]silyl chloride. In all cases, only produets resulting from a 1-endo cyclization mode were isolated after treatment with Bu3SnH/AIBN. 

Scheme 10-92 A bis-ether tether was used in a stereoselective synthesis of cellobioside 285.

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