9-endo-trig radical cyclization

Scheme 1. Disfavored 5-endo-trig radical cyclization and application to erythrinane framework...

Demethoxyerythratidinone (10), one of the simplest of the erythrina alkaloids, was isolated in 1973 by Barton et al. from Erythrina lithosperma [14]. A concise approach to such Erythrina alkaloids using a disfavored 5-endo-trig radical cyclization mediated by nickel powder was described by Zard and coworkers [15]. A-Alkenyl trichloroacetamide 7 was... 

Scheme 2. Nickel powder promoted 5-endo-trig radical cyclization in erythrina alkaloid synthesis...

As described in section 3.1, when a radical cyclization reaction involves the 5-hexenyl radical intermediate, the 6-endo-trig radical cyclization will prevail when the usually favoTed 5-exo-trig regioselectivity is suppressed by substitution at the 5-position. Such a tactic was... 

Imines have been employed as radical acceptors in the preparation of nitrogen heterocycles [95AJC291]. A highly selective 6-endo-trig radical cyclization onto a chiral aldehyde imine has been developed by Werstiuk et al. Reductive cyclization of 218 provides a 3.8 1 diastereomeric mixture of the tetrahydroisoquinoline 219. A minor amount of 220, a product arising from a 5-exo cyclization is also produced. 

Preparation of highly functionalized medium-sized carbocycles (210) and (212), derived from carbohydrates, can also be carried out with the same procedure via 8-endo-trig and 1-exo-trig manners, as shown below (eqs. 3.81, 3.82). Moreover, preparation of (3-C-disaccharide (214) proceeds selectively via 8-endo-trig radical cyclization of two temporarily tethered monosaccharide (213), by means of the addition of a carbohydrate-... 

H. Ishibashi, T. Sato, M. Ikeda, 5-Endo-Trig Radical Cyclizations, Synthesis 2002, 695-713. 

We have also achieved imusual 7-endo-dig and 7-endo-trig radical cyclizations employing the MesSiCl/col combination as titanocene-regenerating agent [69]. Moreover, we have provided theoretical and experimental evi-... 

SCHEME 8.24 Synthesis of a carba-pyranose using a 6-endo-trig radical cyclization. 

Gomez, A M, Danelon, G O, Valverde, S, Lopez, J C, Regio- and StereocontroUed 6-endo-trig radical cyclization of vinyl radicals a novel entry to carbasugars from carbohydrates, J. Org. Chem., 63, 9626-9627, 1998. 

Chatgilialoglu, C., Ferrari, C., Guerra, M., Timokhin, V., Froudakis, G., Gimisis, T. 5-Endo-trig Radical Cyclizations Disfavored or Favored Processes J. Am. Chem. Soc. 2002, 124, 10765-10772. 

Formation of five-membered A, A-heterocycles by 5-endo-trig radical cyclizations 02S695. 

Crich and coworkers [37] investigated the influence of oxygen substituents at various carbons on the 1-endo trig cyclization of 6-heptenoyl radicals. Presence of one or two oxygen substituents at C-5 favored the 1-endo trig radical cyclizations along with simple reduction (130 131 -I-132), and the competitive 6-exo cycliza-... 

Shishido and coworkers [42] have employed a highly stereoselective 1-endo trig radical cyclization reaction for the construction of a key intermediate 174 in their synthesis of a pseudoguanolide (-l-)-confertin starting from the selenoester 173. 

Chattopadhyay and coworkers [51] extended this strategy for the construction of glucose-derived benzoxocine ring ethers. Thus, reaction of the bromoethers 215, obtained from glucose, with BubSoH and AIBN furnished the tetracyclic compounds 216 via i-endo trig radical cyclization in 50-60% yield. 

Aryl radical cyclizations using enamides as radical receptors have been reported for the construction of a variety of polyhydroazepins. Rigby and Qaber [66] reported the 1-endo trig radical cyclization of the aryl bromide 262 to generate the tetracyclic compound 263. 

Castedo, Dominguez and coworkers [67] carried out the cyclization of the N-formyl enamines 264. The 1-endo trig radical cyclization of the enamines 264 with Bu3SnH and AIBN using slow addition technique proceeded with excellent stereoselectivity to generate only the trans isomer of the tetracyclic system 265. 

Atom transfer radical methodology was also explored in the 1-endo cyclizations. Curran and Chang [71] have investigated the cyclization of a-iodoesters. Photolysis of the a-iodo ester and a-iodo malonates 280 in the presence of hexabutyldistannane generated a mixture of the 6-exo and 1-endo trig radical cyclized iodides 281 and 282. Quite expectedly, the presence of a methyl group on the internal carbon of the olefin (283) shifted the reaction to 1-endo mode exclusively. The product underwent spontaneous cyclization to furnish the lactone 284. 

Hoepping, A., Johnson, K.M., George, C., Flippen-Anderson, J. and Kozikowski, A.P. (2000) Novel conformationally constrained tropane analogues by 6-endo-trig radical cyclization and Stille coupling-switch of activity toward the serotonin and/or norepinephrine transporter. J. Med. Chem. 43 2064-2071. 

Interestingly, another example of a [1,5]-radical translocation coupled with an unusual 5-endo-trig radical cyclization was reported in a structurally different system (Scheme 10). In this case, the a-bromovinyl radical abstracted a hydrogen either from (TMSjsSiH to give vinyl bromide in 25% yield or from the anomeric position to generate the C-1 radical which underwent an unusual 5-endo-trig cyclization onto the proximal double bond to generate an anomeric mixture of spironucleosides after bromine atom ejection. 

Chiral amine catalysts have also been used in cascade reactions mediated by SOMO catalysis [143] and Lewis base catalysis [144]. MacMillan s group developed a powerful cascade reaction moderated by SOMO catalysis. The radical cation, generated from an enamine in condensation of imidazolidinone catalyst 208 with aldehyde 207 and subsequent oxidation by Cu oxidant, was expected to engage in a series of 6-endo-trig radical cyclizations terminated by a suitable arene to give a cyclohexadi-enyl radical. After a second oxidation, rearomatization, and liberation of the catalyst, the requisite 209 would be generated (Scheme 1.90). 

The diastereospecific synthesis of novel [3.6.6.4.7]-fused pentacyclic /3-lactams via a novel 6-exo-trig,7-endo- %-tandem radical cyclization has been reported. The use of this method for the construction of a polycyclic system fused to an azetidin-2-one template has been very little exploited. The mixture of /3-lactams 509 and 510 (R = -f 4 I—Cl C. -Cl I—Cl ICH3) in their racemic forms on treatment with tributyltin hydride gave diastereomeric mixtures of tetracyclic 511 and 512 in the same ratio as in the starting materials (Equation 84) <2003TL1827>. 

Marco-Contelles and de Opazo utilised 8-ewd< -trig and 1-exo-Aig cyclizations, mediated by B113S11H, in their construction of chiral, polyfunctionalised medium-sized carbo-cycles670. For example, treatment of iodide (104) with BujSnll under standard radical conditions afforded 7-membered carbocycles (105) in moderate yield (equation 79). Prado and coworkers reported the synthesis of benzolactams by 11 -endo aryl radical cyclization, an example of which is highlighted in equation 80675. 

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