Ketones radical cyclizations

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nucleophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular S-exo radical cyclization reaction with the alkene moiety. The resultant... 

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-... 

Pandey and co-workers developed two photosystems useful for initiating one-electron reductive chemistry and applied them to activate a, 3-unsaturated ketones. The resulting carbon-centered radicals cyclize stereoselectively with proximate olefins. Their concept involved a secondary and dark electron transfer from... 

On addition of S04 to the triple bond in the lO-member cycloalkyne 24 and cyclo-aUcynone 27, a nonchain, and anionic, self-terminating radical cyclization cascade is induced. In the former reaction (equation 22) the bicyclic ketones 25 and 26 are formed, and in the latter reaction (equation 23) the a,/3-epoxy ketones 28 and 29 are formed in good yields. Because of the difficulty of oxidizing isolated triple bonds, 804 does not react as an electron-transfer reagent in these reactions but acts as a donor of atomic oxygen. 

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>. 

Sam Zard of the Ecole Polytechnique in Paliseau has developed elegant and affordable free-radical methods for C-C bond construction. In the context of the total synthesis of pleuromutilin, he recently reported (Organic Lett. 5 325, 2003) that the free radical cyclization of 12 proceeded smoothly to give the eight-membered ring product 13. The ketone 12 is easily prepared from m-toluic acid. It is a tribute to the efficacy of the cyclization procedure that the conformation drawn, the conformation required for cyclization, is the less stable chair available to 12. 

Phenylhydrazones of /i-stannyl ketones undergo oxidative radical cyclization to afford azocyclopropanes upon treatment with an oxidizing agent such as DDQ, Pb(OAc)4 and NBS (equation 27)43. 

Radical cyclizations to carbon-nitrogen multiple bonds resemble additions to carbon-carbon multiple bonds in that they usually give products of irreversible exo cyclization. To date, the most useful acceptors have been oximes189 and nitriles,190 and one example of each type of cyclization is given in Scheme 45.191 Nitriles are useful because the intermediate imines are readily hydrolyzed by mild acid to ketones. Although this route to ketones is shorter than the two-step sequence of alkyne cyclization/ozo-nolysis, nitriles are slightly poorer acceptors than terminal alkynes, and much poorer acceptors than activated alkynes. Thus, when slow cyclizations are involved, the two-step protocol is preferable. 

Intermolecular coupling of ketones and alkenes, promoted by SmH, occurs with excellent stereochemical control. In one such reaction, samarium(II) iodide has been used to prepare cyclobutanones and cyclobutanols from chiral, 6-oxohex-2-enoates (equation 137)520. The reaction is performed in THF in the presence of HMPT and occurs in good yield with excellent stereocontrol. If appropriately located carbonyl and alkene moieties are present in a molecule, then Sml2-HMPT can be used to form cyclooctanols by a radical cyclization process in some cases there is a reasonable degree of diastereoselectivity (equation 138)521,522. 

Hepteny radical cyclizations proceed about 40 times slower than the 5-hexenyl counterpart. Therefore, in most cases, a rate-enhancing factor is required to achieve a synthetically useful reaction. The most common rate-enhancing factors are a,f)-unsaturated esters, nitriles, and ketones, or other electron withdrawing groups. a,p-Unsaturated esters are the most widely employed precursors. 

Aryl radical cyclization.10 Sml2 in HMPA/THF at 25° can effect cyclization of l-allyloxy-2-iodobenzene to a Sm(III) intermediate (a) that can be trapped by electrophiles, including aldehydes or ketones. The report suggests that a similar mechanism operates in the Barbier-type coupling generation of an alkyl radical followed by formation of RSml2, which adds to a carbonyl compound to form an adduct that is hydrolyzed to an alcohol. 

The reaction of /3-dicarbonyl compounds and simple ketones with Mn(OAc)3 or ceric ammonium nitrate is a general and effective method for C-H activation that has been extensively reviewed [1-6]. The oxidative free-radical cyclizations of la... 

Once a chiral silane is synthesized, intramolecular reaction such as the Heck reaction and the radical cyclization reaction with transfer of chirality from the silicon center can be pursued. Other reactions of interest include the stereoselective hydrosilylation of aldehydes and ketones. Our method could be used to tether chiral silanes to solid support for uses in solid support... 

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