Ketyl radical cyclization

Aldehydes can be converted directly into 0,Se-acetals and used for radical cyclizations. This procedure is equivalent to a ketyl radical cyclization process, a typical example is shown in Eq. (13) [31]. Acetals such as 54 can also easily be converted into 0,Se-acetals by treatment with (z-Bu)2AlSePh. The selenide 55 is used for an efficient radical carbon-carbon bond formation [Eq. (14)1 [32]. A very reliable route to 0,Se-acetals from alcohols through the corresponding (tributylstannyl)methyl ethers has been used for the preparation of tetrahydro-furan derivatives [33]. 

Our first specific Wessely oxidation approach is outlined in Scheme 2. Following an aldol-type reaction between an appropriately protected resorcinol fragment and an aldehyde, we expected the Wessely oxidation to selectively dearomatize at the ortho position of both phenols. The intramolecular Diels-Alder cycloaddition reaction was then expected to form the tricyclic core, which could then be converted to the critical tetracyclic cage via a samarium diiodide(II)-type 6-exo-trig ketyl radical cyclization reaction. 

A total synthesis of pseudolaric acid A was reported, featuring a Sml2-mediated intramolecular alkene-ketyl radical cyclization to generate the highly functionalized cyclopentane 141 (Scheme 25.67). ° When 140 was subjected to the annulation reaction in the presence of HMPA without... 

Sml2 has also been used to form cyclooctanols by cyclization of 7,8-enones.262 These alkene addition reactions presumably proceed by addition of the ketyl radical to the double bond, followed by a second electron transfer. 

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... 

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

Scheme 11.16 Diastereocontrol via chelate effect stereoselective 5-exo-trig cyclization on to a cumulated Jt-bond of a chelated ester-substituted ketyl radical anion 50 [74]. a 94 6 mixture of diastereomers.

Electrolysis of b-al Ionic ketone 61 at a controlled cathode potential of-2.43 V (versus Ag/AgI) in anhydrous DMF using tetraethylammonium p-toluenesulfonate as co-electrolyte provides the derived ketyl radical that undergoes a 5-exo-trig selective ring closure, presumably via transition structure 62 (Scheme 11.19). The cyclization product is further reduced and subsequently protonated to afford traus-configurcd cyclopentanol 63 as single diastereomer in a total yield of 55% [80]. 

The major product of the keto olefin cyclizations often corresponds to what one would predict, assuming the intermediate ketyl behaves like the corresponding monoradical (Eq. 34). For example, given an option between a 5-exo and a 6-endo-trig cyclization, the former predominates in radical cyclizations [51], and constitutes the exclusive cyclization path in the electrochemical counterpart, 110 - 112 [47]. In addition, the stereochemical outcome parallels that of the radical... 

The previous chapter covered radical cation cyclization reactions that were a consequence of single-electron oxidation. In the following section, radical anion cyclization reactions arising from single-electron reduction will be discussed. In contrast to the well documented cyclization reactions via carbon-centered free radicals [3, 4], the use of radical anions has received limited attention. There are only a few examples in the literature of intramolecular reductive cyclization reactions via radical anions other than ketyl. Photochemi-cally, electrochemically or chemically generated ketyl radical anions tethered to a multiple bond at a suitable distance, have been recognized as a promising entry for the formation of carbon-carbon bonds. 

The electroreductive cyclization reaction of 6-heptene-2-one 166, producing CIS-1,2-dimethylcyclopentanol 169, was discovered more than twenty years ago [166]. In agreement with Baldwin s rules, the 5-exo product is obtained in a good yield. Since that time, the mechanism of this remarkable regio- and stereoselective reaction has been elucidated by Kariv-Miller et al. [167-169]. Reversible cyclization of the initially formed ketyl radical anion 167 provides either the cis or the trans distonic radical anion. Subsequent electron transfer and protonation from the kinetically preferred 168 leads to the major cis product 169. The thermodynamically preferred 170 is considered as a source of the trace amounts of the trans by-product 171 (Scheme 32). 

Apart from PET-reductive cyclization, chemical reduction has also been applied to the total synthesis of natural products such as capnellenediol 186 [184]. Naphthalene sodium is shown to be a suitable oxidant for generating ketyl radical anions which cyclize efficiently in a 5-exo-dig mode. In contrast, electroreductive cyclization of 184 does not lead to 185, but exclusively to the thermodynamically preferred 5-exo isomer with a remaining double bond in the endocyclic position [185] (Scheme 35). The steroid precursor 4.5-secocholes-tan-5-one 187, in which the lOa-side chain is varied, has been cyclized under the same conditions [186-188] (Scheme 36). Reduction with naphthalene sodium or sodium in ether exclusively produces the A B-cis steroid 188 with an exo double... 

Samarium diiodide has been used by Enholm and co-workers for the generation and cyclization of ketyl radicals from aldehydic substrates [Eq. (9) and (10) 33], As noted, the... 

Samarium(H) diiodide mediated ketyl radical addition to alkyne results in the formation of an alkene after radical cyclization [95SL277]. Compound 65, a product from one such reaction, has been converted to the carbohydrate portion of miharamycin A, a nucleoside antibiotic. 

Marcus treatment does not exclude a radical pathway in lithium dialkyl-amide reduction of benzophenone. It does, however, seem to be excluded (Newcomb and Burchill 1984a,b) by observations on the reductions of benzophenone by N-lithio-N-butyl-5-methyl-l-hex-4-enamine in THF containing HMPA. Benzophenone is reduced to diphenylmethanol in good yield, and the amine yields a mixture of the acyclic imines no cyclic amines, expected from radical cyclization of a putative aminyl radical, were detected. An alternative scheme (17) shown for the lithium diethylamide reduction, accounts for rapid formation of diphenylmethoxide, and for formation of benzophenone ketyl under these conditions. Its key features are retention of the fast hydride transfer, presumably via the six-centre cyclic array, for the formation of diphenylmethoxide (Kowaski et al., 1978) and the slow deprotonation of lithium benzhydrolate to a dianion which disproportion-ates rapidly with benzophenone yielding the ketyl. The mechanism demands that rates for ketyl formation are twice that for deprotonation of the lithium diphenylmethoxide, and, within experimental uncertainty, this is the case. 

A particularly stable ketyl radical is derived from benzophenone (cf. Figure 17.52). This is why additions of the Grignard reagents R2Mg2Hal2 to this substrate proceed more frequently via radicals as intermediates than others. An example in which the occurrence of such a radical intermediate is documented by the typical radical cyclization 5-hexenyl —> cyclopentyl-carbinyl (cf. Section 1.10.2) is the following ... 

In parallel the cocatalysis of cobalt compounds with A7-hydroxyphthalimide 398 was developed extensively for oxidative radical reactions [434]. Ishii and colleagues showed that these conditions can be used in radical additions (Fig. 92). Ketyl radicals generated by hydrogen abstraction from secondary alcohols 396 add to a.p-unsaturated esters 397 affording 2,4-dihydroxy esters, which cyclized to lactones 399 under the reactions conditions [435]. Using 0.1 mol% of Co(OAc)2, 1 mol% of Co(acac)3, and 10 mol% of 398 under 1 atm of oxygen, the cyclic products 399 were isolated in 14—90% yield. As observed for similar reactions, Co(III) alone needs an induction period (see below). 

Regioselective photocyclization of ethylthiopropyl phenylglyoxalate 793, by an electron-transfer process, produced the 1,5-oxathiocin 773 in 96% yield. The mechanism proposed for such a photocyclization involved excitation of the keto ester 793 to its triplet state (T) upon irradiation (350 nm), and electron transfer between the donor and acceptor occurred in T producing the ketyl radical anion (A). This was deactivated to ground state 793 by back electron transfer or was converted to biradical (B) by proton transfer process. Cyclization occurred between the excited carbonyl group and the carbon a to the sulfur on the remote side (Scheme 156) <1997T7165>. 

Attempts to extend this work to the keto-oxime substrate 54 derived from D-glucosamine with an JV-phthalimido group resulted in the formation of a completely different product (Scheme 40). In this case, cyclization was initiated by reduction of the phthalimido carbonyl group to its corresponding ketyl radical anion followed by cyclization onto the ketone, providing an a-hydroxylactam 55 which was proposed to be a potentially useful scaffold for diversity-oriented synthesis. 

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