Radical cyclization, with ethers

Eq. 3.6 shows the direct preparation of furan derivative (19) by the successive treatment of vinyl ethers with propargyl alcohol/NBS, radical cyclization with Bu3SnH/AIBN, and lastly, aromatization with p-TsOH. 

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). 

By using various trapping reagents, it has been deduced that the transannular fragmentation is rapidly reversible. The cyclization of the fragmented radical C is less favorable, and it is trapped at rates which exceed that for recyclization under most circumstances. " Radicals derived from ethers and acetals by hydrogen abstraction are subject to fragmentation, with formation of a ketone or ester, respectively. 

An efficient two-step annelation of functionalized orthoesters with trimethyl-silyloxyfuran derivatives has been reported that produces bicyclo[3. .0]lactones. ° The reaction in Scheme 7 shows an example in which the initial condensation between silyl enol ether and orthoester is followed by the radical cyclization reaction under standard conditions. It is worth underlining the complete diastereocontrol in which three contiguous stereocenters are generated in one step with >95% stereoselectivity. 

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 (TMS)3Si radical addition to terminal alkenes or alkynes, followed by radical cyclization to oxime ethers, were also studied (Reaction 50). The radical reactions proceeded effectively by the use of triethylborane as a radical initiator to provide the functionalized pyrrolidines via a carbon-carbon bond-forming process. Yields of 79 and 63% are obtained for oxime ethers connected with an olefin or propargyl group, respectively. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

Radical cascades that feature a 7-exo acyl radical cyclization followed by a 6-exo or 5-exo alkyl radical cyclization proceed with very good yields and diastereoselectivities. Two examples are shown in Reaction (80), where treatment of 100 with E3B, air, and (TMS)3SiH provided the tricycle 101 in excellent yields as a single diastereomer. Interestingly, the bulky silyl ether moiety is not required to achieve stereoselectivity in this process. 

The reverse reaction (that is, the oxidation of a vinyl radical by Fe to the corresponding vinyl cation) may be involved in the reaction of the dimethyl ester of acetylenedicarboxyUc acid 261 with Fenton s reagent [Fe —H2O2, (217)] (216). When 261 was treated with Fe —H2O2 and the reaction mixture was extracted with ether, a small amount of furan 262 was isolated. A possible mechanism (216) for its formation may be addition of hydroxyl radical to the triple bond of 261, followed by addition of the intermediate vinyl radical to a second molecule of 261 and oxidation of the resulting radical with Fe to the corresponding vinyl cation, followed by cyclization to 262, as shown in Scheme XX. 

Ketoaldehydes and 1,4-diketones are reduced to cA-cyclopentanediols 258 1,5-Diketo compounds can be cyclized to cyclopentanediols, again with a preference for cis-diols.259 These reactions are believed to occur through successive one-electron transfer, radical cyclization, and a second electron transfer with Sm2+ ether serving as a tether and Lewis acid, as well as being the reductant. 

Radical cyclization of cx,a)-dinitroalkanes is reported, as shown in Eq. 5.45. Oxidation of the dinitronate derived from 2,6-dinitroheptane with K3Fe(CN)6 in a two-phase system (water-ether) yields the cyclized vicinal dinitrocyclopentane in 71-85% yield in a cis-to-trans ratio of 60 4c).64... 

Allenyl ethers are useful key building blocks for the synthesis of a-methylene-y-butyrolactones [129, 130], The synthesis of the antileukemic botryodiplodin was accomplished with the crucial steps briefly presented in Scheme 8.56. Bromoallenyl ethers 225 were easily prepared by base-induced isomerization from the corresponding /3-bromoalkyl alkynyl ether compounds and then subjected to electrophilic bro-mination with NBS. The resulting acetals 226 were converted into 2-alkoxy-3-methy-lenetetrahydrofurans 227 by dehydrohalogenation of the alkenyl bromide unit to an alkyne and subsequent radical cyclization employing tributyltin hydride [130],... 

This radical cyclization strategy was utilized for the synthesis of the smaller fragment silyl ether 54 as well (Scheme 8). Evans aldol reaction of the boron eno-late derived from ent-32 with aldehyde 33, samarium(III)-mediated imide methyl ester conversion, and protecting group exchange led to tosylate 51. Elaboration of 51 to ketone 53 was achieved under the conditions used for construction of the second tetrahydrofuran moiety of 49 from 46. A highly diastereoselective reduc-... 

It is worth mentioning that in a few cases the (3-elimination of the silyl radical from the a-silyl alkoxyl radical (47) with the formation of corresponding carbonyl derivative was observed [63,64]. Evidently the fate of a-silyl alkoxyl radical depends on the method of radical generation and/or the nature of the substrate. Two examples that delineate the potentialities of this rearrangements are reported in Reactions (5.33) and (5.34). In the former, the 5-exo cyclization of secondary alkyl radical on the carbonyl moiety followed by the radical Brook rearrangement afforded the cyclopentyl silyl ether [65], whereas Reaction (5.34) shows the treatment of an a-silyl alcohol with lead tetracetate to afford the mixed acetyl silyl acetal under mild conditions [63]. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Bromoallyloxy)phenyl oxime O-ethers 290 have been cyclized with BusSnH and azoisobutyronitrile (AIBN) to alkoxyamino-3-methylidenechromanes 291 (equation 125). The cyclization of oxime 290 proceeds through formation of vinyl radicals . 

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 . ... 

Radical cyclizations are often used in ring formations and are an effective methodology in the synthesis of piperidines. The intramolecular cyclization of an oxime ether, such as 63 onto an aldehyde or ketone gives a new entry into cyclic amino alcohols <99JOC2003, 99H(51)2711>. Similarly, reaction of a terminal acetylene with BujSnH generates a vinyl radical, which will cyclize with an imine moiety to give 3-methylenepiperidine <99TL1515>. The indolizidine alkaloid ipalbidine was prepared by a sulfur-controlled 6-exo-selective radical cyclization of an a/p/ia-phenylthio amide <99H(50)31>. 

The keto group of the trisubstituted dioxanone 133 generated by ozonolysis was removed by radical deoxygenation according to the Barton-McCombie protocol [80] via the alcohols 134 and the corresponding xanthate, leading after deben-zylation to the dioxane 135 in excellent yield. After conversion to the tosylate, cleavage of the acetonide and protection of the secondary alcohol function as a TBS ether provided access to oxirane 128 by cyclization with NaH in 99% yield and in virtually diastereo- and enantiomerically pure form (de, ee > 96%). 

The phenylthionocarbonate procedure was also used for the cyclization of a 5-oxime-ether radical (Scheme 6) [17]. The stereochemical outcome of this reaction is almost identical with that observed for a closely related 6-methoxyhex-5-enyl radical cyclization [12,14]. A related glucosamine-derived radical cyclization has been employed for the synthesis of allosamizoline 13 [18]. Other examples in this area include the cyclization of... 

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