Cyclizations 7- exo- trig

It should also be noted that the 5-exo-trig cyclization of achiral olefinic organolithiums has been found to proceed enantioselectively when conducted in the presence of a chiral ligand that serves to render the lithium atom stereogenic. Thus, for example, R) 1 -allyl-3-methylindolinc has been prepared in 86 % ee by cyclization of an achiral aryllithium in the presence of an equivalent of (-)-sparteine.15... 

Zard and coworkers [32] reported a simple approach to create another group of natural products, namely the lycopodium alkaloids [15]. These authors first investigated the reaction of O-benzoyl-N-allylhydroxylamide 3-60 with tributyltin hydride and ACCN in refluxing toluene, which led (after formation of the N-radical 3-61 in a 5-exo-trig/5-exo-trig cyclization) to the undesired pyrrolidine 3-62 in 48% yield. Nevertheless, a small structural modification, namely the placement of a chlorine atom at the allyl moiety as in 3-63, induced a 5-exo-/G-endo- instead of the 5-exo-/5-... 

An efficient methodology for the construction of pyrrolizidines and other polycyclic nitrogen heterocycles using a radical domino sequence has been revealed by Bowman and coworkers [46]. These authors employed sulfenamides as substrates, which easily form aminyl radicals by treatment with tributyltin hydride and AIBN. For instance, 3-101 smoothly underwent a twofold 5-exo-trig cyclization to give the tetracyclic pyrrolizidine product 3-105 in 90% yield (Scheme 3.26). As intermediates, the radicals 3-102 to 3-104 can be assumed. 

Another Lewis acid-catalyzed atom-transfer domino radical cyclization, to produce various bicyclic and tricyclic ring skeletons, has been developed by Yang and coworkers [54]. Reactions of the a-bromo-(3-keto ester 3-125 with Yb(OTf)3 and Et3B/02 led to the bicycle 3-126 in 85 % yield (Scheme 3.33). The reaction proceeds via a (>-endo-Irig and 5-exo-trig cyclization after initial abstraction of the bromine... 

The reaction sequence is assumed to be launched by the fragmentation of initially formed aziridinylmethyl radicals to give a N-allylaminyl radical, which undergoes a twofold 5-exo-trig cyclization. 

Figure 11.5 Ball-and-stick transition state models for (i) the 5-dig-cyclization of the hexa-4,5-dien-l-yl radical (left) and the 5-exo-trig-cyclization of the hepta-5,6-dien-l-yl radical (right).

Scheme 11.16 Diastereocontrol via chelate effect stereoselective 5-exo-trig cyclization on to a cumulated Jt-bond of a chelated ester-substituted ketyl radical anion 50 [74]. a 94 6 mixture of diastereomers.

Scheme 11.18 Auxiliary control in an Ueno-Stork-type 5-exo-trig cyclization in the synthesis of an enantiomerically pure lactone 60 [77]. a)90 10 mixture of diastereomers. b)>99% ee.

Fig. 47 Stereoselective 5-exo-trig-cyclization and heterocoupling to a prostaglandine precursor [246].

The principle side reaction corresponds to reduction of the carbonyl without cyclization. For example, reduction of 6-methylhept-6-en-2-one (113) leads to a 12% yield of alcohol 114 no cyclized adduct 115 is produced. Were the intermediate to behave precisely like the monoradical, one would have anticipated that the presence of the methyl group on the alkene would have slowed the rate of 5-exo-trig cyclization to a point where closure to form 115, the product of a 6-endo-trig cyclization, would have dominated it did not. 

Unfortunately, the scope of the process appears to be limited by the need to form a five-membered ring in the second ring closure event [64]. For example, reduction of 220 affords 221 and 222, each the result of a 5-exo-trig cyclization (Table 10). Apparently, the rate of 6-exo-trig cyclization of the putative... 

An example of the influence of structure and geometry on radical cyclization is shown by the stereoselectivity of the 5-enJo-tng cyclization in compound 52 and 5-exo-trig cyclization in 53 using (TMS)3SiH as radical mediators [66]. In system52 a mixture of cA-fused and trans-imtd rings are obtained, whereas in system 53 the reaction proceeds in a stereoselective manner to give only the cw-fused product. 

For the synthesis of tricyclic isoindolinones, the 5-exo-trig cyclization of aryl radicals has been applied [69]. Reaction (7.59) shows the example of a tricyclic system obtained in a 71 % yield. 

In model studies directed towards the synthesis of ( )-gelsemine, 5-exo-trig cyclization of an aryl radical, derived from the vinylogous uretane 58, onto a methoxymethyl enolether resulted in partial fragmentation of the intermediate... 

The following examples demonstrate, however, the applicability of the above procedures to 5-exo-trig cyclization giving a five-membered ring. 

In addition to intermolecular reactions, C-glycosides can also be synthesized by intramolecular sequences. A radical cyclization is a very fast reaction, in particular 5-exo-trig cyclizations. Thus, intermediate anomeric radicals have only a short time window of reactivity before undergoing the desired cyclization. 

Considering the racemization in the cross-coupling process of enantiomerically pure alkyl halides (Table 5.8, entry 18), Fiirstner et al. partially support a theory delineating a metal-bound radical. However, they also call attention to several compounds set up for analogous 5-exo-trig cyclizations but that do not cyclize under identical conditions of the cross-coupling reaction [Scheme 5.18, reaction (3)]. Consequently, care has to be taken in generalizing this mechanistic proposal. 

Scheme 6. Total synthesis of ( )-cw-trikentrin A via a 5-exo-trig cyclization...

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