Cyclizations 4- exo

Similar 5-exo cyclization procedures have been widely utilized by Evans in his total syntheses of complex natural compounds, such as the synthesis of ionomycin [12a] and polyether antibiotic X-206 [12b]. A 5-exo cyclization of a y-epoxy alcohol has also been observed under basic conditions [12c]. 

The procedure described above may be used for the generation and 5-exo cyclization of a variety of substituted 5-hexenyllithiums and, with appropriate modification, provides a general route to a variety of other olefinic7 and acetylenic8 organolithiums that cyclize upon warming.9... 

Scheme 1 5-exo Cyclization initiated by phosphinyl radical addition onto an alkyne... 

Part B of Scheme 4.5 gives some examples of cyclizations induced by selenium electrophiles. Entries 9 to 13 are various selenyletherifications. All exhibit anti stereochemistry. Entries 14 and 15 are selenyllactonizations. Entries 17 and 18 involve amido groups as the internal nucleophile. Entry 17 is an 5-exo cyclization in which the amido oxygen is the more reactive nucleophilic site, leading to an iminolactone. Geometric factors favor N-cyclization in the latter case. 

The reaction in Entry 5 was used in the syntheses of linetin, which is an aggregation pheromone of the ambrosia beetle. In Entry 6, a transannular 5-exo cyclization occurs. Entry 7 is an example of formation of a lactone by carboxylate capture. In this case, the product was isolated as the mercurochloride. 

Entry 10 shows the occurrence of 5-exo cyclization. The radical in this case is generated from an amino sulfide. This reaction requires a specific, somewhat disfavored conformation of the reactant in order for cyclization to occur. When the unsubstituted vinyl substituent was used, no cyclization occurred. However, increasing the reactivity of the double bond by adding the ester substituent led to successful cyclization. 

The reaction of the unsaturated aldehyde 32 with cat. Cp2 VCl2/Me3SiCl/ Zn is conducted in THF to afford the cyclic alcohol 33 with excellent dia-stereoselectivity (Scheme 19) [21]. The transformation may be explained by 5-exo-cyclization of the corresponding radical anion, followed by chlorination. 

Intramolecular radical cyclization of methylenecyclopropanes accompanies ring rearrangement [115]. In the case of (methylenecyclopropyl)propyl radicals, 5-exo-cyclization is observed as illustrated in Scheme 83, but 6-exo- and 1-endo-cyclizations occur with (methyleneeyelopropyl)butyl radicals, depending on the substituent. (Scheme 83)... 

The (3-metaloxy radical was first exploited for synthetic purposes in C—H and C—C bond-forming reactions by Nugent and RajanBabu through the use of titanocene(III) chloride as an electron-transfer reagent [5]. They established that the (3-titaniumoxy radicals formed after electron transfer can be reduced by hydrogen atom donors, e. g. 1,4-cy-clohexadiene or tert-butyl thiol, that they add to a,(3-unsaturated carbonyl compounds, and that they can react intramolecularly with olefins in 5-exo cyclizations. 

The formation of C—C bonds is generally considered to be more important than the formation of C—H bonds. It is therefore not surprising that these reactions have attracted more attention. Of special importance in organic synthesis are 5 -exo cyclizations [17], and the titanocene-mediated reactions are a valuable tool for carrying out these transformations. Three examples are shown in Scheme 12.9. 

As a first step towards this goal, we managed to develop a titanocene-catalyzed 5 -exo cyclization of radicals derived from suitably unsaturated epoxides. The mechanism of the cyclization is depicted in Scheme 12.18 [31],... 

In an extensive investigation of the stereochemical memory effect, a series of six diastereomeric pairs of substrates was prepared to probe the effect of single, then multiple substituents on the 5-exo cyclization of amines onto alkene radical cations [144,145]. Overall, these cyclizations were highly dia-stereoselective and were accounted for by a transition-state model employing a chairlike transition state with attack of the nucleophilic amine on the opposite face of the alkene radical to the one shielded by the phosphate anion in the initial contact ion pair (Scheme 34), as exemplified in Schemes 35 and 36. 

In order to clarify these points and to verify the practicability of our concept, we investigated the course of the overall transformation by density functional theory (DFT) as depicted in Scheme 16. As expected, both the ring opening of 40 to 41 and the 5-exo cyclizations to 42 are exothermic. The calculated Ti - 0 bond lengths (1.86 A) are in excellent agreement with values obtained from crystallographic structures (1.85-1.89 A) [67-69]. 

The calculations suggest that the well-documented kinetically controlled course of 5-exo cyclizations that has been manifested in the Beckwith-Houk... 

The formation of THF derivatives through SH2 reaction with mono- and disubstituted olefins was also investigated to define the overall scope of the transformation. Some of our results are summarized in Table 8. Not surprisingly, the monosubstituted alkene 53 gave essentially none of the desired 54 (5%). It is well known that the primary radicals produced during the 5-exo cyclization are rapidly trapped by Cp2TiCl to yield the products of a reductive cyclization [17-20,65,66,73,74]. Epoxides containing disubstituted... 

The by-products originate from the initial 5-exo cyclization and constitute the product of the usual reductive cyclization and protonation of the Ti - O and Ti - C bonds 61 (dr = 71 29) and the product 62 (single isomer) of /J-hydridc elimination from an organotitanium intermediate in a ratio of 63 37 and in a combined yield of 35%. The major isomer of 61 was assigned as all-czs, in analogy to related systems that reacted with essentially the same selectivity. The mixture of these compounds can be converted into 61 quantitatively by hydrogenation over Pd/C. It turned out that 62 was converted into... 

In synthetic work, amidyl radicals, prepared by BusSnH/AIBN-mediated homolysis of O-benzoylhydroxamic acid derivatives, have been shown to cyclize in a A-exo fashion to give -lactams (Scheme 10). In addition, radicals generated in this way have also been reported to undergo 5-exo cyclization to give mixtures of cis- and Iranx-pyrrolidinones with the steric nature of the Al-substituent having little effect on the stereochemical outcome (Scheme 11). The major products detected were those predicted by application of the Beckwith rule. ... 

The cyclization of a range of fluorinated radicals has attracted interest. - The rate constants for the 5-exo cyclization of a range of fluorinated 5-hexenyl radicals have been studied as a function of the position and number of fluorine substiments. For fluorine substituents at or close to the alkene there is little effect on the rate, whereas... 

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