6- exo radical cyclization

A report on a regiospecific 6-exo radical cyclization for the generation of lactams 173 highlights a remarkable halogen-substitution effect on the direct reactions of unsaturated N-H amides on vinylic halogen substituents <06OL2647>. 

Scheme 36. A tandem 5-exo/6-exo radical cyclization of a pyronose-derived diene...

Intramolecular 6-exo-radical cyclization of 7-bromo-3-methoxy-l-methylthio-1 -(p-tolylsulfonyl)-1 -heptene (66) exhibited a highly efficient 1,2-asymmetric induction to yield the trans ring-closure product 67 (Scheme 17).45 Also reported are radical cyclizations ofy-oxygenated-a,P-unsaturated sulfones, often with very high observed stereoselectivity.45,46... 

A report on a regiospecific 6-exo radical cyclization for the generation of lactams 173... 

Keck, G E, McHardy, S F, Murry, J A, Diastereoselective 6-exo radical cyclizations of oxime ethers total s3mthesis of 7-deox3fpancratistatin, J. Org. Chem., 64, 4465-4476, 1999. 

The stereoselective introduction of an ethynyl group in various flve- and six-membered iodohydrins has also been developed by the same group (O Scheme 37) [60]. Treatment of 3 -ethynyldimethylsilyl 2-deoxy-2-iodo-D-mannopyranoside 142 with Et3B and TBAF in toluene furnished the methyl 2-deoxy-2-C-ethynyl-4,6-0-benzylidene-a-D-mannopyranoside 144 in 85% yield. However, a similar reaction of 3-iodo-D-ribosyl substrate 143 having the [2-(trimethylsilyl) ethynyl]dimethylsilyl at C-5 gave the desired product 5-0-acetyl-3-deoxy-3-C-ethynyl-l,2-0-(l-methyl ethylidene)-a -D-xylofuranose, in which the ethynyl group was introduced at the y-cis position to the 5 -hydroxyl, in only 31% yield. This may be explained by an unfavored 6-exo radical cyclization. 

Kaoudi T, Miranda LD, Zard SZ (2001) An easy entry into berbane and alloyohimbane alkaloids via a 6-exo radical cyclization. Org Lett 3 3125-3127... 

In the year 2013, Parker and coworkers reported the first total synthesis of ( )-bisabosqual (94) employing a tandem 5-exo, 6-exo radical cyclization as the key step to construct the fiilly functionalized tetracyclic core of bisabosqual A (Scheme 13.13) [15],... 

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). 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

Scheme 31. A 6-exo-trig cyclization from a 3-aza-6-heptenyl radical in the total synthesis of ( )-melinonine-E...

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... 

A 6-exo-trig cyclization of a pyran derived radical onto an oxime has been employed as the key step in the synthesis of Amaryllidace alkaloid (+)-7-deoxypancratistatin [95JA7289], Treatment of 202 under reductive cyclization conditions gave 203 as a single stereoisomer in good yield. The compatibility of the radical reaction conditions with the dense functionality present in 202 is noteworthy. 

The fragmentation of nitrate esters to carbon radicals under thermal or photochemical conditions has been exploited by Batsanov and co-workers in the stereoselective construction of 8-lactones [95JCS(P1)1281]. Treatment of 205 with tin hydride in refluxing benzene gave the 6-exo-trig cyclization product 206 in good yield and high stereoselectivity. 

The occurrence of the indole subunit is well established within the class of natural products and pharmaceutically active compounds. Recently, the Reissig group developed an impressive procedure for the assembly of highly functionalized in-dolizidine derivatives, highlighting again the versatility of domino reactions [8]. The approach is based on a samarium(II) iodide-mediated radical cyclization terminated by a subsequent alkylation which can be carried out in an intermolecular - as well as in an intramolecular - fashion. Reaction of ketone 3-11 with samarium(II) iodide induced a 6-exo-trig cyclization, furnishing a samarium enolate intermediate... 

An attempted enantioselective synthesis of ipalbidine from the protected (S)-prolinol 860 was based on the regioselective 6-exo-trig cyclization of the radical intermediate derived from the reaction of the phenylthio compound 861 with tributyltin hydride (Scheme 111) (577). The reaction gave a 1 1 mixture of two indolizidin-5-one diastereomers 862 in 65% yield. At the end of the synthesis, the target 842 was found to possess virtually no optical activity. The most likely candidate for racemization is the aldehyde 863, which might scramble under the basic conditions required for the subsequent Wittig reaction. 

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