Exo-trig cyclization reaction

The first vinyllithium carbolithiation reaction was reported by Chamberlin and Bloom15, who showed that Shapiro-derived organolithium 10 cyclized onto a terminal alkene giving stereoselectively (>50 1) bicyclic compounds 11, after treatment with electrophiles (Scheme 4). The intermediate alkyllithiums 12 are generated via a 5-exo-trig cyclization reaction from 10, which undergo the carbolithiation reaction at approximately the same rate as reported by Bailey for the simple parent compound 5-hexenylIithium, i.e. with a half-life of a few minutes at 0 °C. 

Araki and coworkers [20] during their approaches to higher sugars discovered an efficient 1-exo trig cyclization. Reaction of the allofuranose derivatives bromoacry-lates 175 with Bu3SnH and AIBN furnished the bicyclic product 176 via 1-endo radical cyclization in a stereoselective manner. 

Appropriately substituted alkenic a-alkoxylithiums, derived from the corresponding tri-w-butyltin compounds on treatment with w-BuLi, have also been used to initiate 5-exo-trig cyclization reactions to give tetrahydrofuran derivatives (eq 23). 20 other related ring-forming reactions have been... 

RCM was used as a key step in the total synthesis of (+)-puraquinonic acid (86), a fungal metaboHte that induces differentiation in HL-60 cells [16]. Starting from aromatic aldehyde 87, the RCM precursor 88 was prepared in a few steps. Following RCM leading to 89 (88%), the newly formed trisubstituted alkene was involved in a radical cyclization. Bromo acetal 90 was treated with BusSnH and AIBN thus triggering a stereoselective 5-exo trig cyclization reaction. Further steps led to the natural product 86 (Scheme 1.13). 

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-... 

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. 

Another illustration of the utility of this chemistry is provided by its use as the key step in a synthesis of prostaglandin PGF2Q [24]. In this case, the radical formed from bromoacetal (35) undergoes an intramolecular S-exo-trig cyclization onto the olefin of the cyclopentene ring, thereby generating a new radical capable of undergoing another reaction. When it was intercepted intermolecularly by ynone (36), enone (37) was produced in a 55% yield (Scheme 10). 

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. 

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. 

The intramolecular Heck reaction of an iodobenzyl piperidone exo-trig cyclization) affords a mixture of regioisomers 89a and b, inseparable by flash chromatography (02S87). An analogous reaction gives lactam ester 89c (96H(42)155). 

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. 

The reactions of oj-hydrosilylalkynes (328) catalyzed by Rh4(CO)i2/NEt3 or Rh+(COD) (/)6-C6H5BPh3r give 2-(l-formyl-l-alkylene)-l-silacycloalkanes (329) through 5- or 6-exo-trig cyclization in moderate to high yields (equation 134)333. 

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. 

An analogous strategy was applied for annelation of ring D in Kuehne s syntheses of 20-epi- ((/-vincadifformine (96) and yz-vincadifformine (97). Upon slow addition of n-BujSnH and AIBN via syringe pump to the phenylselenyl ether 94,20-epi- vincadifformine (96) and vincadifformine (97) were formed in a 1 2 ratio. The separated products did not epimerize under the reaction conditions, indicating a facial preference in the hydrogen transfer to the pentacyclic radical intermediate 95. The ethyl substituent blocked 5-exo-trig cyclization. 

The addition of sulfur radicals to isocyanides produces imidoyl radicals as intermediates. The stereocontrolled 5-exo-trig cyclization of imidoyl radicals in the synthesis of substituted (alkylthio)pyrrolines, pyroglutamates, and thiopyroglutamates has been reported [95JOC6242], The intermediate 137 is not isolated but undergoes further thermal reaction to furnish a pyroglutamate derivative. 

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