Keck radical allylation

The mechanism of this transformation was examined by M. Kosugi. He found that the reaction was promoted by benzoyl peroxide, a radical initiator and was retarded by p-quinone, a radical scavenger. These results are in accordance with a free radical chain mechanism. The initiation of the reaction may take place via a variety of possible pathways, one possibility is depicted below. 

Danishefsky and co-workers reported the total synthesis of pentacyclic sesquiterpene dilactone, merrilactone A. ° In their approach, they utilized Keck s radical allylation method to achieve the required chain extension. This sidechain was later used to construct one of the cyclopentane rings of the natural product. 

The total synthesis of Stemona alkaloid (-)-tuberostemonine was accomplished by P. Wipf. Late in the synthesis, the introduction of an ethyl sidechain was required. This could be achieved in a novel four-step sequence. First, the allyl sidechain was introduced by the Keck radical allylation. To this end, the secondary alkyl phenylselenide substrate was treated with allyltriphenyltin in the presence of catalytic amounts of AIBN. This was followed by the introduction of a methyl group onto the lactone moiety. The allyl group then was transformed into the desired ethyl group as follows the terminal double bond was isomerized to the internal double bond by the method of R. Roy. This was followed by ethylene cross metathesis and catalytic hydrogenation to provide the desired ethyl sidechain. 

Manzamine A is an alkaloid that was shown to inhibit the growth of P-388 mouse leukemia cells. The synthesis of the tetracyclic substructure of this natural product was reported by D.J. Hart. For the construction of the perhydroisoquinoline moiety, he utilized the Keck radical allylation. This transformation was carried out under standard conditions, reacting a secondary alkyl iodide with allyltributyltin. 

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The Keck radical allylation is a representative example of a radical fragmentation reaction employing the reagent allyltributyltin in the allylation process. " The first synthesis of the Stemona alkaloid stenine by Hart in 1990 established an iodolactonization/Keck allylation (93 —> 94) sequence (Scheme 25.44) as a solution to the problem of stereoselective ethyl group installation. ... 

D. Mootoo, P. Wilson, and V. Jammalamadaka, Application of the Keck radical coupling reaction to the preparation of allylated C-5 furanosides and C-6 pyranosides, J. Carbohydr. Chem. 73 841 (1994). 

Allyltributyltin (5) is the most commonly used reagent for carrying out allylation reactions via a free radical fragmentation process [5]. Keck reported the first practical use of allyltributyltin for free radical allylation reactions in 1982 in the context of a synthesis of perhydrohistrionicotoxin [6]. Heating bromide 4 with allyltributyltin in the presence of AIBN as a radical initiator gave the allylated derivative 6 (Scheme 3) in high yield with complete control of stereochemistry. Similar transformations had proven to be very difficult by standard ionic reactions. 

C-6-Allylated pyranoses and C-S-allylated fliranoses were prepared from the corresponding iodides by Keck radical coupling with allyltributyltin (e.g. 44->4S). The selective formation of product 47 in the chain-extension of the acetal-protected uronic acid derivative 46 by radical addition of methyl acrylate using Barton s method was ascribed to addition from the less hindered side to a conformationally stable radical intermediate the peracetate 48 furnished a 1 1 mixture of 49 and 50. ... 

Another interesting procedure is the free radical addition-fragmentation developed by Keck [117]. A radical is generated from a suitable carbohydrate precursor 86 and reacts with allyltributyltin to provide the allyl branched sugar 87 in good yield (Scheme 31) [118]. 

A useful solution to the latter problem, introduced by Keck and Byers,141 makes possible crotylation and isoprenylation. Irradiation of an allyl sulfide (28 3 equiv.), a reactive radical precursor (29 1 equiv.) and hexabutylditin (1.5 equiv.) produces substitution products (30) in good yields (Scheme 41). The... 

Further investigation by Keck of the scope of allylation reactions with allyltributyltin revealed that the reaction could be carried out with numerous different types of radicals, for example simple alkyl radicals, aryl radicals and radicals a to the oxygen atoms of ethers and esters [7]. These radicals were generated from several types of free radical precursors, such as bromides, iodides, phenylselenides,... 

C-Glycopyranosides may be obtained from glycopyranosyl halides via intermolecular addition of glycopyranosyl radicals [129]. In a more useful example, the a-aminoacrylate 192 was used as the radical acceptor for preparation of C-glycosyl amino acids 193 and 194 [130] (Scheme 66). In a concise synthesis of showdomycin (197), Barton utilized the trigger reaction of the 7V-hydroxy-2-thiopyridone derivative and the exceptional radicophilicity of tellurides in concocting the conditions for the conversion from the anisyl telluride 195 to the intermediate 196 after oxidative elimination [131] (Scheme 67). In Keck s synthesis of (-t-)-pseudomonic acid C (201), the intermediate 200 was prepared via stereocontrolled intermolecular addition of the radical generated from the iodide 198 to the allylic sulfone 199 [132] (Scheme 68). 

Demonstrated here is the mechanism of the Keck allylation proceeding via a radical pathway. 

Keck and Byers introduced a protocol in which the allyl sulfide was used together with (Bu Sn), when thiyl radical is unable to propagate the chain [87]. Two examples are reported below (equations (41) and (42)), in which an alkyl iodide and phenylselenide were treated with two equivalents of an appropriate sulfide and one equivalent of hexabutylditin under sunlamp irradiation [87, 88]. 

The first reports of radical addition-fragmentation processes appeared in the synthetic organic chemistry literature in the early 1970s. Well-known examples of processes that involve a reaction step with an Sh2 mechanism include allyl transfer reactions with allyl sulfides and stannanes (the Keck... 

For the synthesis of (-)-magellanine and related Lycopodium alkaloids, Mukai et al. used a Ueno-Stork cycliza-tion coupled with a Keck allylation to generate an advanced intermediate. Thus, bromoacetal derivative 97 was exposed to conventional radical conditions in the presence of allyltributyltin to give the tricyclic compound 98 (after an oxidation step) with the quaternary carbon center formed and an allyl group installed stereoselectively (Scheme 25.46). 

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