Ketyl-alkene couplings

Intermolecular ketyl alkene coupling reactions have been incorporated into a cascade that ultimately affords medium sized rings [58]. Specifically, chloroalkyl ketones react with acrylates, whereupon chloroalkyl lactones are formed in situ. Photolysis of these intermediates in the presence of excess Sml2 initiates an intramolecular nucleophilic acyl substitution reaction between the halide and the lactone, creating the medium-sized ring (Eq. 50). 

Not surprisingly, intramolecular ketyl alkene coupling reactions are much more common than the preceding bimolecular examples. The diversity of structures that can be obtained utilizing these procedures is impressive, and, as will be described, the method has been employed for the construction of a wide array of natural products. 

A similar strategy utilizing 8-keto esters provided very high diastereoselectivities in the ketyl-alkene coupling process. In these examples, chelation control about the developing hydroxyl and carboxylate stereocenters was the source of the high diastere-oselectivity achieved (eq 23) ... 

The ketyl radical anion intermediates can be exploited in carbon-carbon bond-forming reactions. Intermolecular and intramolecular pinacol couplings between the carbonyl groups of ketones and aldehydes are well known (Chapter 5, Section 5.1), as are intermolecular and intramolecular carbonyl-alkene couplings (Chapter 5, Section 5.2). 

In addition to alkenes, arenes can sometimes be used as radical acceptors in Sml2-mediated carbonyl-alkene couplings. For example, Schmalz reported extensive studies on ketyl additions to arenechromium tricarbonyl complexes 66,67 tetralin-Cr(CO)3 complex 49 underwent reductive carbonyl addition to the aromatic ring upon treatment with Sml2 to furnish the skeleton of the naturally occurring aryl glycoside pseudopterosin G (Scheme 5.37).66,67 Here, the bulky metal tricarbonyl group not only serves to control the... 

There is an inherent competition between simple reduction of the ketone and the reductive cyclization process with unsaturated carbonyl substrates. Cyclization processes that are slower than that of the ketyl-alkene cyclization forming a five-membered ring, suffer frtxn lower yields owing to this competition. For example, ketyl-alkyne coupling can also be achieved when mediated by Smb, but yields are lower than those achieved with analogous keto-alkenes (equation 68). This might have been expected on the basis that radical additions to alkynes are slower than corresponding additions to alkenes. Similarly, the rate... 

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). ... 

Samarium(ir) iodide in the presence of HMPA effectively promotes the intramolecular coupling of unactivated alkenic ketones by a reductive ketyl-alkene radical cyclization process (eq 25). This protocol provides a means to generate rather elaborate carbocycles through a sequencing process in which the resulting organosamarium species is trapped with various electrophiles to afford the cyclized product in high yield. ... 

In the presence electron-rich alkenes such as 2,3-dimethylbut-2-ene, irradiation of CA gives the allylethers 59 and 60, whereas with BQ, a substantial amount of the spiro-oxetane is also formed.The product distribution of the allyl ethers is rationalized by steric effects on the H+ abstraction and on the recombination of radicals as well as spin densities. The crucial role of solvent polarity in CA photochemistry is well illustrated by the results of a study into the reaction between the quinone and cyclohexanone enol trimethylsilyl ether 61 using time-resolved (ps) spectroscopy. The influence of the solvent occurs following the formation of the radical ion pair (CA - 61+-). The CA- species is short lived in nonpolar solvents and cyclohex-2-en-l-one and 62 are the reaction products, whereas in acetonitrile, the lifetime is much longer, which allows diffuse separation of the radical ion pair and transference of the TMS to the solvent. The resulting ketyl radical couples to CA - yielding 63. 

The initial step of the coupling reaction is the binding of the carbonyl substrate to the titanium surface, and the transfer of an electron to the carbonyl group. The carbonyl group is reduced to a radical species 3, and the titanium is oxidized. Two such ketyl radicals can dimerize to form a pinacolate-like intermediate 4, that is coordinated to titanium. Cleavage of the C—O bonds leads to formation of an alkene 2 and a titanium oxide 5 ... 

The Cp2TiCl/H20 combination can also be used for the chemoselective reduction of aromatic ketones. The reaction discriminates between ketones and alkenes, between ketones and esters and, remarkably, between conjugated and non-conjugated ketones [80]. There is strong evidence that this reduction proceeds via ketyl-type radicals, which are finally reduced by H-atom transfer from 42 [81]. Under dry conditions, titanium-promoted ketyl radicals from aromatic ketones can be used for intermolecular and intramolecular cross-coupling of ketones [82], Thus, depending on whether water is added or not, complementary and versatile synthetic procedure protocols are available. 

The ability of Sml2 to generate ketyls prompted its use for the reductive cross-coupling of ketones with alkenes. Both intermolecular and intramolecular processes of this type have been described. 

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. 

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