Cyclization 6 ®-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... 

With 6-alkenoic acids the intermediate radical partially cyclizes to a cyclopentyl-methyl radical in a 5-exo-trig cycHzation [139] (Eq. 6) [138 a, 140] (see also chap. 6). To prevent double bond migration with enoic acids the electrolyte has to be hindered to become alkaline by using a mercury cathode. Z-4-Enoic acids partially isomerize to -configurated products. Results from methyl and deuterium labelled carboxylic acids support an isomerization by way of a reversible ring closure to cyclopropyl-carbinyl radicals. The double bonds of Z-N-enoic acids with N > 5 fully retain their configuration [140]. 

When free radicals are added to 1,5- or 1,6-dienes, the initially formed radical (9) can add intramolecularly to the other bond, leading to a cyclic product (10). When the radical is generated from an precursor that gives vinyl radical 11, however, cyclization leads to 12, which is in equilibrium with cyclopropylcarbinyl radical 13 via a 5-exo-trig reaction. A 6-endo-trig reaction leads to 14, but unless there are perturbing substituent effects, however, cyclopropanation should be the major process. 

An analogous catalytic system has been applied to the IH of y- and 5-allenic amines which cyclize smoothly in the 5-Exo-Trig or 6-Exo-Trig mode, giving vinylpyrrolidines and vinylpiperidines, respectively (Eq. 4.92) [313]. 

The first type of process is characterized by cyclization reactions, which are found in a plethora of examples and hence can be considered as the flagship of the different classes being discussed in this section. In spite of the fact that this reaction type distinguishes a broad scope of subsections, the 5-exo-trig ring closure can be regarded as the most frequent and productive one. Furthermore, 6-endo and 6-... 

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... 

A dramatic improvement in this new round trip radical domino processes developed by Curran s group was presented by Takasu, Ihara and coworkers. The new method relies on the introduction of a conjugated ester moiety at the terminal olefm, thereby effecting an acceleration of the domino reaction accompanied with an enhancement of the regio- and stereoselectivity [81]. Thus, reaction of 3-196 with Bu3SnH led to a 4 3 mixture of the two diastereomeric tricycles 3-197 and 3-198 in 83% yield. In this process, the vinyl radical 3-199 is initially formed, but this smoothly cyclizes in 5-exo-trig manner to give radical 3-200 (Scheme 3.52). Due to... 

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. 

Iodoetherification (vide supra) of ( )-aIlyl alcohols 99 followed by transannular radical cyclization in a 5-exo-trig mode was reported to provide ci s-fused bicyclic acetals with high diastereoselectivities. To illustrate, an example is given below <00SL1193>. 

Hegedus proposed the probable course of the cyclization reaction, which follows a Wacker-type reaction mechanism. Coordination of the olefin to Pd(II) results in precipitate 110, which upon treatment with Et3N undergoes intramolecular amination to afford intermediate 111. As expected, the nitrogen atom attack occurs in a 5-exo-trig fashion to afford 112. Hydride... 

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.

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