5-exo radical cyclizations

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

Osmium tetroxide used in combination with sodium periodate can also effect alkene cleavage.191 Successful oxidative cleavage of double bonds using ruthenium tetroxide and sodium periodate has also been reported.192 In these procedures the osmium or ruthenium can be used in substoichiometric amounts because the periodate reoxidizes the metal to the tetroxide state. Entries 1 to 4 in Scheme 12.18 are examples of these procedures. Entries 5 and 6 show reactions carried out in the course of multistep syntheses. The reaction in Entry 5 followed a 5-exo radical cyclization and served to excise an extraneous carbon. The reaction in Entry 6 followed introduction of the allyl group by enolate alkylation. The aldehyde group in the product was used to introduce an amino group by reductive alkylation (see Section 5.3.1.2). 

The benzannulated analogs were also found to behave in a similar fashion. Attachment of a pendent olefin to the benzannulated enyne-allene system as depicted in 89 allowed the aryl radical in 90 to be captured in a 5-exo radical cyclization reaction leading to 91 and then the dihydrobenz[e]indene 92 (Scheme 20.20) [55, 56]. 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

Scheme 16 An example of a one pot DIB/l2-mediated decarboxylation and iodination sequence followed by a 5-exo radical cyclization step...

Samarium diiodide-promoted 5-exo radical cyclization and further transformation lead only to the C-analog derivative 21 of methyl isomaltoside. 

Exo radical cyclizations of bromoacetals that contain allylic chiral centers are often referred to as Ueno-Stork reactions [50]. It was recently discovered that stereochemistry in these cyclizations could also be controlled by the acetal center, as shown in Eq. (13.39) [51]. A chair-like transition state (125) is envisaged where the alkene occupies a pseudoequatorial position leading to predominantly cis product 126. Yields of approximately 70% and cis trans ratios of up to 98 2 are obtained. 

Stereoselectivity in the cyclization of substituted 5-hexenyl radicals often follows the guidelines proposed by Beckwith1. According to this model, the early transition state of a 5-exo radical cyclization resembles a cyclohexane ring, preferring the chair over the boat conformation, with the substituents being pseudoequatorial rather than pseudoaxiai1 3 31. 

Use in Free Radical Chemistry. Chloride 4 has been used in free radical cyclizations. Treatment of chloride 4 with tri-n-butyltin hydride (TBTH)/AIBN in benzene at reflux gave a high yield of reduced material 13 together with some of the 6-endo cyclization product 14, a minor product (eq 7). The radical cy-clization was shown to be irreversible. This example represents a deviation from the usual preference for 5-exo radical cyclizations. 

A study has been reported on the stereoselectivity of the 5-exo radical cyclization reaction of some allylic 2-deoxy-2-iodoglucopyranosides (Scheme 19). ... 

Bertrand and coworkers have reported that quaternization of the nitrogen center upon coordination with BH3, provides a significant increase in the selectivity of the 5-exo radical cyclization of 3-aza-5-hexenyl radicals derived from substrates equipped with a terminal double bond (Equation 28) [30]. Coordination of BH3 to the nitrogen of the parent amine creates strong steric interactions, which disfavor the trans product. 

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