Lactams intramolecular radical cyclization

Intramolecular radical cyclization of haloarenes 464 (Rz = CH=CHPh, CH=NCH2Ph, CH=CHC02Me, CMe=CHPh) in the presence of tributyltin hydride gave the fused tricyclic /3-lactams 465 in reasonable yields (Equation 75) <1997M1149, 2005T2767>. 

Moreover, using the same starting materials, they have reported the regio- and stereoselective synthesis of enantiopure or racemic benzofused tricyclic (3-lactams such as benzocarbapenems and benzocarbacephems (III and IV, Fig. 17) via intramolecular aryl radical cyclization [287]. 

The Wittig-Horner olefination of the aldehyde 28 provided alkenes 29 which were subjected to radical cyclization leading to benzofused tricyclic j6-lactams 30, obtained as single diastereomers (Scheme 8) [36]. A convenient, direct regio- and stereoselective route to optically pure unusually fused or bridged tricyclic /3-lactams has been developed by the use of intramolecular nitrone-alkene cycloaddition reactions. For example, the aldehyde 21 can be transformed into nitrone 31 which subsequently was used for a variety... 

The extension of the above radical intramolecular cyclization of /V-haloaryl-p-lactams to 2-azetidinones bearing the proradical center at C3 was also explored. The treatment of haloarenes 109a-c under similar conditions for the preparation of benzocarbapenems and benzocarbacephems 104—108 gave the fused tricyclic (1-lactams llOa-c (Scheme 37, Table 2). Compounds 110a and 110b were obtained as mixtures of diastereomers, which are epimers at the newly formed C5 stereocenter, while the amino derivative 110c could be prepared as a single isomer. 

Radical methods have found limited use in the preparation of four-membered heterocycles. Intramolecular cyclization of a-bromoeneamide (5) has been examined for the synthesis of p-lactams. The reaction proceeds cleanly through a 4-exo-trig pathway to furnish 6. As had been previously established, this regioselectivity is dependent on the nature of the substituent on the olefin. This methodology has been applied in the synthesis of p-lactam antibiotics ( )-PS-5 (7) and (+)-thienamycin [95JOC1276] [95SL912],... 

The Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes gave homoallylic alcohols, which have been used for the diastereoselective preparation of fused bicyclic, tricyclic and tetracyclic p-lactams of non-conventional structure 49 and 50, using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences <03JOC3106>. 

CV studies indicate that Ph3SnY, where Y = Cl, OTf, OCHO, SnPh3, do not serve as a source of the triphenyltin radical because in these instances the radical is generated at potentials where it is either oxidized or reduced [19]. Reaction of the triphenyltin radical with an alkyl halide or a disulfide produces a carbon- or a sulfur-centered radical, respectively. Use of the latter transformation in conjunction with a subsequent intramolecular cyclization onto an alkene is nicely illustrated by the conversion of /6-lactam 62 to the cephalosporin analog 63. 

Bennasar extended his research on 2- and 3-indolylacyl radicals to intramolecular cyclizations to yield 2,3-fused indoles [112], Under nomeductive conditions (n-Bu6Sn2, hv), radical 201 underwent a cascade addition-oxidative cyclization sequence with a number of alkene acceptors including dimethyl fumarate (45%), methyl 1-cyclohexenecarboxylate (53%), methyl crotonate (71%), vinyl sulfone (22%), and the a,p-unsaturated lactam ester, 2-oxo-5,6-dihydro-2H-pyridine-l,3-dicarboxylic acid dibenzyl ester (41%) to form cyclopenta[h]indol-3-ones 202. Reaction of 201 with acrylonitrile and methyl acrylate, however, generated cyclo-hepta[h]indoles, the products of bis-addition-cyclization sequences. 

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