Diastereoselective ketyl radicals

Pestalotiopsin A and 6-epitaedolidol are structurally related caryophyllene-type sesquiterpenes. In 2003, Procter reported the use of a Sml2-mediated 4-exo-trig carbonyl-alkene cyclisation to construct the core of pestalotiopsin A.57 Treatment of cyclisation substrate 33 with Sml2 in THF, MeOH and 2,2,2-trifluoroethanol gave cyclobutanol products 34 and 35 in good yield and with moderate diastereoselectivity. The major diastereoisomer is believed to arise from a cyclisation in which coordination to the silyl ether group directs addition of the ketyl radical anion to the alkene (Scheme 7.17).57... 

An extension of this methodology has been developed for epoxides containing an adjacent enol acetate and reaetion sequenees similar to the one described in Scheme 11 are reported [21]. An attractive feature of the overall transformation is the retention of the enol acetate moiety in the product that allows for further synthetic elaboration. It has been demonstrated that epoxide opening ean also be initiated by the intramolecular addition of ketyl radicals formed by electron transfer from Sml2. For an example proeeeding with excellent diastereoselectivity see Seheme 14 [25]. 

Ketone-Alkene Coupling Reactions. Ketyl radicals derived fromreduction of ketones or aldehydes with Sml2 may be coupled both inter- and intramolecularly to a variety of alkenic species. Excellent diastereoselectivities are achieved with intramolecular coupling of the ketyl radical with Q ,/3-unsaturated esters. In the following example, ketone-alkene cyclization took place in a stereocontrolled manner established by chelation of the resulting Sm(III) species with the hydroxyl group incorporated in the substrate (eq 22). ... 

Aqueous TiCU also promotes a chemoselective reduction of a,p-dicar-bonyl compounds to give ketyl radicals that add to the carbonyl carbon of aldehydes affording a,p-dihydroxyketones. The reaction yields are excellent and the diastereoselection depends on the steric hindrance of the groups bonded to the reagents [80e]. When the ketyl radical is generated from methyl phenylglyoxalate and added to p-ketoesters and p-keto acids, the intermediate pinacols rapidly afford lactones by intramolecular cyclization [80d]. 

Early proposals suggested that addition of HMPA produces a sterically encumbered reduc-tant that not only dictates the diastereoselectivity of the reactions, but also stabilizes reactive intermediates (ketyls, radicals) in close proximity to the Sm-HMPA complex, thereby... 

In studies toward the synthesis of the antibacterial natural product pleuromutilin (Scheme 25.66), Procter et al. reported a cascade double annulation process using Sml2 to generate an initial ketyl radical from 137. After a subsequent cyclization, the resulting new ketyl radical was reduced to form the organosamarium (III) intermediate 138, which in turn promoted a diastereoselective intramolecular aldol reaction to give 139. ° ... 

Irradiation of 1,3-dioxolanes in the presence of a sensitizer such as benzophenone (PhjCO), leads to the abstraction of an acetal hydrogen atom (by the triplet state ketone) to generate 1,3-dioxolanyl radicals, together with the resonance-stabilized diphenyl ketyl radical (Scheme 16). These nucleophilic 1,3-diox-olanyl radicals have been shown to add to a variety of alkenes to form adduct radicals, which can then accept a hydrogen atom from the diphenyl ketyl radical to give the desired alkylated product. The diastereoselective addition of 1,3-dioxolanyl radicals to alkenes bearing chiral auxiliaries has also recently been reported, while the photochemical alkylation of diketene with 2-undecyl-l,3-dioxolane has been utilized as a key step in the synthesis of (-)-tetrahydrolipstatin (Scheme 17). ... 

A much more highly diastereoselective process results when alkenic 3-keto ester and 3-ketoamide substrates can be utilized in the ketone-alkene reductive coupling process. Both electron deficient and unactivated alkenes can be utilized in the reaction (equations 65 and 66). In such examples, one can take advantage of chelation to control the relative stereochemistry about the developing hydroxy and car-boxylate stereocenters. Favorable secondary orbital interactions between the developing methylene radical center and the alkyl group of the ketyl,and/or electrostatic interactions in the transition state account for stereochemical control at the third stereocenter. 

Studies of similar reactions under a variety of conditions had been previously reported. Thus, electroreductive, photoreductive, as well as metal-induced ketyl-olefm cyclizations had all been explored prior to our investigations. Many of these cyclization reactions using simple unsaturated ketones took place with reasonably high diastereoselectivity at two stereocenters (Eq. 3). This feature of the transformation was ascribed to favorable secondary orbital interactions between (he developing methylene radical center and the alkyl group of the ketyl, and/or to electrostatic interactions in the transition state leading to product. ... 

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