S-exo cyclizations

Substituent effects on cyclizations of simple nucleophilic hexenyl radicals have been well studied, and much quantitative rate data is available.12 The trends that emerge from this data can often be translated to qualitative predictions in more complex settings. Once the large preference for S-exo cyclization is understood, other substituent effects can often be interpreted in the same terms as for addition reactions. For example, electronegative substituents activate the alkene towards attack, and alkyl substituents retard attack at the carbon that bears them. The simple hexenyl radical provides a useful dividing point = 2 x 10s s-1. More rapid cyclizations are easily conducted by many methods, but slower cyclizations may cause difficulties. Like the hexenyl radical, most substituted analogs undergo irreversible S-exo closure as the predominate path. However, important examples of kinetic 6-endo closure and reversible cyclization will be presented. 

All of these decelerating effects are easily overridden by appropriate alkene substitution. Indeed, any terminal alkene substituent will decelerate 6-endo cyclization. To accelerate S-exo cyclization, one requires only an electronegative alkene substituent at C-6. 

The appropriate placement of activating groups can also be used to accelerate 6-endo cyclizations, as illustrated by the examples in Scheme 5.14-16 However this prescription is not a guaranteed cure to overcome S-exo cyclizations when 6-endo products are desired. As illustrated by the last example in Figure 6,17 the preference for S-exo cyclization can often be so high that it cannot be overridden by an activating group. 

In contrast to aminyl radicals, alkoxyl (and acyloxy) radicals are highly reactive. As illustrated in equation (7), their cyclization reactions are extremely rapid and irreversible. However, the rapidity of such cyclizations does not guarantee success because alkoxyl radicals are also reactive in inter- and intramolecular hydrogen abstractions, and -fragmentations (see Section 4.2.S.2). This lack of selectivity may limit the use of alkoxyl radicals in cyclizations, but S-exo cyclizations are so rapid that they should succeed in many cases, and other types of cyclizations may also be possible. 

Diphenylphosphanyl radicals, Ph2P , generated from diphenylphosphane in the presence of a radical initiator were used to cyclize the alkynyl-substituted carbohydrate derivative 195 in a radical addition/S-exo cyclization sequence to give the bicyclic deoxysugar derivative 196 (Scheme 2.36). Ph2p have also been used as promoters for the cyclization of alkynyl p-lactam 181 for a highly efficient, diaster-eoselective synthesis of bicyclic p-lactams (see Scheme 2.33). ... 

Both S-endo and 8-exo Heck cyclizations have been described. In an early example, Sundberg and Cherney reported an S-endo cyclization of 88 to the homoibogamine analog 89 (Scheme 6-15) [30]. Among the most striking examples of the application of intramolecular Heck cyclizations to assemble complex polycyclic products, Danishefsky, Masters, and co-workers have reported several S-exo cyclizations during investigations that culminated in a total synthesis of baccatin III (96) [32]. In an early example, exposure of... 

Scheme 8. Two types of selective S-exo cyclization onto N-C double bonds...

Scheme 11. Kinetic data of the S-exo cyclization of 31 and the reverse reaction...

In 2007, Larhed and co-workers reported a palladium-catalyzed cyclization of o-halobenzyl cyclohexenyl ethers. " A number of new spiro[cyclohexane-l,l -isobenzofuran]-based compounds were synthesized by palladium(O)-catalyzed S-exo cyclization of a series of cyclohexenyl o-halobenzyl ethers. Controlled microwave heating was found to promote both product yield and reaction rate without compromising the selectivity. Heck cyclization of... 

Phenolic oxygen participates in facile oxypalladation. The intramolecular reaction of 2-hydroxychalcone (105) produces the flavone 106[127]. The ben-zofuran 107 is formed from 2-allyIphenol by exo cyclization with Pd(OAc)2, but benzopyran 108 is obtained by endo cyclization with PdChf S], Normal cyclization takes place to form the furan 109 from 2-(l-phenylethenyl)phe-nol[129]. Benzofuran formation by this method has been utilized in the synthesis of aklavinione (110)[130]. 

Vinyl radicals can also participate in 6-exo cyclizations. In pioneering work, Stork and his group at Columbia University showed that stereoisomeric vinyl bromides 20 and 21 (see Scheme 3) can be converted to cyclohexene 22.7 The significance of this finding is twofold first, the stereochemistry of the vinyl bromide is inconsequential since both stereoisomers converge upon the same product and second, the radical cyclization process tolerates electrophilic methoxycarbonyl groups. The observation that the stereochemistry of the vinyl bromide is inconsequential is not surprising because the barrier for inversion of most vinyl radicals is very low.8 This important feature of vinyl radical cyclization chemistry is also exemplified in the conversion of vinyl bromide 23 to tricycle 24, the key step in Stork s synthesis of norseychellanone (25) (see Scheme 4).9 As in... 

The transformation of2-734 involves an initial generation of an organosamarium species 2-735 with subsequent nucleophilic addition to the lactone carbonyl. Presumably, a tetrahedral intermediate 2-736 is formed that collapses to yield the ketone 2-737. This reacts with Sml2 to give a ketyl radical 2-738, which undergoes an intramolecular S-exo radical cyclization reaction with the alkene moiety. The resultant... 

The preparation of 2,3,5-trisubstituted 4,5-dihydrofurans 81 with complete regio-control can be realized by an one-pot transformation involving epoxidation of 2-alkenyl-1,3-dicarbonyls by in situ generated dimethyldioxirane, and is followed by a S-exo-ieX intramolecular nucleophilic cyclization under the same basic condition <00TL10127>. 

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). 

A S-exo-trig cyclization of the metalated aminyl radical provided pyrrolidine (123) as a single isomer in a 53% yield. A routine series of transformations converted it to the target structure (124). 

Unsaturated carboxylic acids can be de-carboxylated to alkyl radicals that undergo an intramolecular addition. The S-exo-trig-cyclization of fi-allyloxy radicals, generated from an appropriate carboxylic acid, combined with a final heterocoupling has been applied to synthesize a precursor of prostaglandine PGF2q (Fig. 47) [246] and a branched carbohydrate (ratio of diastereo-mers 1.8 1) (Fig. 48) [247]. A radical tandem cyclization of a doubly unsaturated monocyclic carbocyclic acid provides a... 

Rhode and Hoffmann have investigated sequential radical-mediated cyclizations of enynes as a method for the stereocontrolled synthesis of heteroannular acetals. The sequence generally followed a S-exo-trigfi-endo-dig-patlmay and gave the products in a stereocontrolled manner <2000T6479>. 

Yttrocene complexes catalyze the cascade cyclization/hydrosilylation of trienes to form saturated silylated bicyclic compounds.For example, reaction of the 4-silyloxy-4-vinyl-l,6-hexadiene 69 and phenylsilane catalyzed by Gp 2YMe(THF) at room temperature for 1 h followed by oxidation of crude 70a gave [3.3.0]bicyclic diol 70b in 73% yield over two steps as a single diastereomer (Scheme 18). Selective conversion of 69 to 70a presumably requires initial 1,2-hydrometallation of one of the less-hindered G=G bonds to form alkylyttrium alkene complex II (Scheme 18). Selective S-exo carbometallation of II in preference to -exo carbometallation would form cyclopentyl-methylyttrium complex III (Scheme 18). Gyclization of III via a chairlike transition state would form the strained /r< /75 -fused alkylyttrium complex IIIl, which could undergo silylation to form 70a. 

Yttrium-catalyzed cascade cyclization/hydrosilylation of 3-(3-butynyl)-l,5-hexadienes was stereospecific, and syn-19 (R =Gy, R = OGPh3) underwent cascade cyclization/hydrosilylation to form 80b (R = Gy, R = OGPh3) in 97% yield as a single diastereomer (Scheme 20). The regio- and stereoselective conversion of syn-19 to 80b was proposed to occur through an initial 5- x -intramolecular carbometallation via a chairlike transition state that resembles alkenyl olefin eomplex syn- m. followed by S-exo intramolecular carbometallation via a boatlike transition state that resembles alkyl olefin complex boat-llm. The second intramolecular carbometallation presumably occurs via a boatlike transition state to avoid the unfavorable 1,3-interaction present in the corresponding chairlike transition state (Scheme 20). 

Few applications of cyclizations to form fused ring 8-lactones or tetrahydropyrans are found. Two consecutive bromolactonizations were used to effect stereoselective dihydroxylation of a cyclohexadi-enone system in a total synthesis of erythronolide B (Scheme S).64 Iodolactonization of an NJV-di-ethylbenzamide derivative to form a ds-fused benzolactone was a key step in a recent synthesis of pancratistatin.641 A di-fused tetrahydropyran was produced in good yield by intramolecular oxymercura-tion as shown in equation (17),59 although attempts to cyclize a more highly functionalized system have been reported to fail.65 Formation of a fused ring tetrahydropyran via an anti-Markovnikov 6-endo sel-enoetherification has been reported in cases where steric and stereoelectronic factors disfavor a 5-exo cyclization to a spirocyclic structure.38... 

Regiochemistry of the electrophilic cyclization of 166 has been studied. Interestingly, 6(S)-endo-Trig cyclization seems to be more favoured than the expected 5(S)-exo-Trig... 

Fraser-Reid s stereocontrolled synthesis of the Woodward reserpine precursor 195 relied upon a tandem 5-exol6-exo radical cyclization of pyranose-derived dienes [76-77]. As outlined in Scheme 36, a,P-unsaturated ester 188 was prepared by free radical coupling of iodide 187 with a tin acrylate. After hydrolysis of 188 (MeONa, MeOH, 100%) to give primary alcohol 189, the silicon tethered diene 190 was installed by silylation. Treatment of 190 with n-BujSnH led to the desired cage molecule 192 in high yield via a 5-exo-trig cyclization to intermediate 191 followed by a 6-exo cyclization. Tamao oxidation of tricycle 192 led to diol... 

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