Free radical cyclization stereochemistry

T. V. RajanBabu, Stereochemistry of intramolecular free-radical cyclization reactions, Acc. Chem. Res. 24 139 (1991). 

The free radical cyclizations of hex-5-enes (7 in Fig. 7.1) were accomplished some time ago, and although the origin of selectivity was not initially understood, the stereochemistry at the newly created centers was predictable in some of the cases. 

The projected free radical cyclization proceeded as planned to give 172. Ozonolysis of the vinyl group, oxidation of the resulting aldehyde to an acid, and alkylation with diazomethane provided projected intermediate 162. Reduction of the lactone provided 173. Treatment of 173 with 6-methoxytryptamine and pivalic acid then provided a nearly equal mixture of lactams 174 (isoreserpine stereochemistry at Cg) and 175 (reserpine stereochemistry at C3). The correct C3 stereoisomer was moved forward to 176 (protection of the tertiary alcohol followed by reduction of the lactam). The silyl ethers were removed, the secondary ether was re-protected, and reaction with samarium iodide accomplished reduction of the a-hydroxy ester to provide 177. Removal of the TBS group and esterification of the alcohol completed the synthesis of reserpine. 

Wawzonek et al. first investigated the mechanism of the cyclization of A-haloamines and correctly proposed the free radical chain reaction pathway that was substantiated by experimental data. "" Subsequently, Corey and Hertler examined the stereochemistry, hydrogen isotope effect, initiation, catalysis, intermediates, and selectivity of hydrogen transfer. Their results pointed conclusively to a free radical chain mechanism involving intramolecular hydrogen transfer as one of the propagation steps. Accordingly, the... 

Photoinduced electron transfer promoted cyclization reactions of a-silyl-methyl amines have been described by two groups. The group of Pandey cyclized amines of type 135 obtaining pyrrolidines and piperidines 139 in high yields [148]. The cyclization of the a-silylated amine 140 leads to a 1 1 mixture of the isomers 141 and 142 [149]. The absence of diastereoselectivity in comparison to analogous 3-substituted-5-hexenyl radical carbocyclization stereochemistry [9] supports the notion that a reaction pathway via a free radical is unlikely in this photocyclization. The proposed mechanism involves delocalized a-silylmethyl amine radical cations as reactive intermediates. For stereochemical purposes, Pandey has investigated the cyclization reaction of 143, yielding... 

In germanium chemistry the importance of free radical pathways in substitution reactions of secondary bromides with R3GeLi (R = CH3, CgHs) reagents is strongly indicated by product stereochemistry in cyclohexyl systems and by cyclization of the cA-heptene-2-yl moiety to yield [(2-methylcyclopentenyl)methyl]germanes, with the appropriate cis/trans ratio, as shown in equation 180, Table 9 and equations 181 and 182189. 

Although most attention has focussed on a cationic mechanism in the oxidative cyclization of squalene [20]. Breslow was concerned with the possibility that nature utilizes a free-radical pathway [21]. and studied the addition of benzoyloxy radical to trans, trani-famesyl acetate [22]. The benzoyloxy radicals generated by CuCl-catalyzed thermal decomposition and copper(II) benzoate was added to provide a termination mechanism. Excluding any intervention of a carbocationic process, Breslow obtained a tran -decalin compound (20 30% yield) bearing an exomethylene moiety. As pointed out by Breslow, despite a limited biochemical interest , this work evidenced a new synthetic reaction of considerable potential . An application shortly followed with the first example of a triple cyclization by Julia [23]. Triene isomers 40 were treated by benzoylperoxide in benzene and alforded after saponification alcohol 41 in 12% yield as a single diastereomer (relative stereochemistry confirmed by an X-ray analysis) with a similar tra 5-decalin system (A and B rings. Scheme 14). 

In most of the studies of the Cy6/Cy7 cyclization with the next higher homolog of 356 (Scheme 136) the stereochemistry of the (Cy6) compounds obtained has not been reported. " Nevertheless, during free radical addition of isobutyric acid to 1,7-octadiene (368) (Scheme 139) Forbes obtained the three products 369 (9%), 370 (17%), and 371 (6%), after methanol... 

---