Acyl Radical Cyclization Approaches

It has long been known that autoxidation of aldehydes leads to carboxylic acids via a radical mechanism which involves the formation and oxidation of acyl radicals, leading to acyl cations via one-electron oxidation processes [68]. However, the recent topic in this field relates to the fact that many new synthetic methods for the synthesis of carboxylic acids derivatives have been developed which rely on the power of one-carbon homologative radical reactions. 

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D. Batty and D. Crich, Acyl radical cyclizations in synthesis. Part 4. Tandem processes The l-endo/5-exo serial cyclizations approach to enantiomerically pure bicyclo[5.3.0]decan-2-ones, J. Chem. Soc. Perkin Trans 7 3193 (1992). 

A variety of indirect and direct methods are now available for ketone synthesis by radical reactions. Due to space limitations, this section will focus on selected topics, and only a few examples are shown for cases of frequently investigated approaches by acyl radical cyclizations. A recent review article on acyl radical chemistry provides a comprehensive survey of acyl radical cyclizations [la]. 

The synthesis of cyclic ketones via acyl radical cyclizations represent by far the most frequently investigated approaches in the past two decades and such cyclizations are well discussed in a recent review [la]. Two recent examples of the application to natural product synthesis are given here. A seven-membered ring, a key compound in the overall synthesis of (-i-)-confertin, was prepared by Shishido and co-workers, utilizing 1-endo-trig acyl radical cyclization which occurred in a highly efficient manner (Scheme 4-39) [66]. 

The importance of radical processes in the chemistry of pyrroles and indoles remain vital in expanding the repertoire of reaction processes available to these heterocycles. For example, Allin and Mclnally have devised a novel approach lo (l,2-a -fused pyrroles 76 via intramolecular acyl radical cyclization of Al-(oi-acyl)-radicals 75 generated from acyl-selenide precursors 74 <01TL7887>. This reaction can be conducted even in the absence of CO and has also been shown feasible on electron rich pyrrole rings. 

The second example in Table 5 shows the cyclization-carbonylation-allylation sequence, in which 5-hexenyl radical cyclization precedes CO trapping. Because of the nucleophilic nature of acyl radicals, in a mixed alkene system comprised of an electron deficient alkene and allyltin, they favor the electron deficient alkene first and the resulting product radical, which have an electrophilic character, and then smoothly add to allyltributyltin. This four-component coupling reaction provides a powerful radical cascade approach leading to y -functionalized, -unsaturated ketones, which are not readily accessible by other methods [52]. 

Smith MW, Hunter R, Patten DJ, Hinz W. A new approach to indolo[2,3-a] quino-lizidines through radical cyclization of 2-acyl-1-phenyIthiotetrahydro-beta-carbolines bearing pendent alpha, beta-unsaturated esters. Tetrahedron Lett 2009 50(46) 6342-6. 

Two unselective approaches to the two alkaloids are illustrated in Scheme 50. A straightforward synthesis by King relied on acid-induced intramolecular Mannich reaction of ammoketone 396, prepared from 5-aminopentanal diethyl acetal and pent-3-en-2-one, to give a mixture of ( )-394 (55%) and ( )-395 (20%) (367). The synthesis by Pilli et at. involved a one-pot trimethylsilyl triflate-catalyzed condensation between pent-3-en-2-one and the acyliminium ion derived fium JV-Boc-2-ethoxypiperidine (397) (368,369). Under the reaction conditions, the intermediate 398 underwent spontaneous V-deprotection and cyclization to give a 5.5 1 mixture of ( )-394 and ( )-395 (67%). In the same Scheme is also shown the much shorter stereoselective synthesis of ( )-394 by Beckwith et al, who used a radical-mediated cyclization on the V-acylated 2,3-dihydropyridin-4-one 399 to give the bicyclic product 400 as the sole diastereomer (91%) (370). Compound 400 was readily converted into the target alkaloid by reduction of both carbonyl groups with lithium aluminum hydride followed by reoxidation of the secondary alcohol at C-2. 

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