Ashley Robison My Preferences Site Tools Popular pages MindTouch User Guide FAQ Sign Out If you like us, please share us on social media. The latest UCD Hyperlibrary newsletter is now complete, check it out. ChemWiki BioWiki GeoWiki StatWiki PhysWiki MathWiki SolarWiki Periodic Table of the Elements Reference Tables Physical Constants Units & Conversions Lab Techniques ChemWiki: The Dynamic Chemistry E-textbook > Organic Chemistry > Carbohydrates > Radical Reactions of Carbohydrates > II: Radical Reactions of Carbohydrates > 19: Compounds With Carbon Carbon Multiple Bonds II: Cyclization Reactions > IV. Unsaturated Carbohydrates That Undergo Radical Cyclization IV. Unsaturated Carbohydrates That Undergo Radical Cyclization The unsaturated carbohydrates that undergo radical cyclization are an eclectic mixture of compounds in which the reactive multiple bond in each typically is electron-deficient. Reduced electron density in the multiple bond can be caused either by conjugation of this bond with a carbonyl group or by having an electronegative substituent attached to it. Ring forma tion still can occur when a double or triple bond is not electron-deficient, but as described earlier in this Chapter (Section II), in such a situation cyclization is slower and less able to compete with other radical reactions. A. α,β-unsaturated Carbonyl Compounds The electron-deficient double bond in an α,β-unsaturated ester is an attractive target for in ternal addition of a carbon-centered radical. 44,60 94 The majority of reactions of this type produce five- membered rings; 62 85,93 fewer, but still a significant number, form six-membered rings. 60,81,82,86 91 Forma tion of smaller 27 and larger 27,94 rings also takes place, but such reactions are far less common. (Exam ples of internal radical addition in α,βunsat urated esters are found in the reactions shown in Schemes 8, 16, and 17.) The radicals that participate in this type of reac tion usually are generated from halo genated carbohydrates but also can be formed from reaction of carbo hy drates containing O-thiono car bonyl, 79 cyclic O-thio nocar - bonyl, 65 O-thiono car bam oyl, 72-74 phenyl seleno, 50 aryl telluro, 77 O-acyl-N-hydroxy-2-thio pyridonyl, 88 and vinyl 75,76 groups. Other α,β-unsaturated carbonyl compounds that undergo radical cycli zation include nuc leo sides that have a carbon-centered radical in the sugar portion of the molecule. In these reactions cyclization occurs by internal radical addition to a carbon carbon double bond in the nitrogenous base. 95 101 Since the substrate in most of these reactions is a derivative of uridine, cyclization is, in effect, an internal addition to an α,β-unsaturated lactam (eq 20). 96 http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 1/7
Other cyclization reactions of carbonyl compounds include internal addition to α,β-un saturated aldehydes, 109 ketones, 110,111 and lactones, 112 and to lactams that are α,β- and γ,δ-un saturated. 102 108 Reaction of the unsat urated lactam pictured in Scheme 20 begins with halogen-atom abstraction that is followed by 1,5-transfer of a hydrogen atom to give the interconverting radicals 39α and 39β. New rings form when these radicals react to give the cyclic, stereoisomeric radicals 40α and 40β, respec tively. 102 The stereo selec tivity of this reaction depends upon the stereo chem istry of the C-2' substituent and changes when the config uration at C-2' is inverted. 102 B. Silyl Ethers and Silaketals One method for connecting a radical forming group and a multiple bond is with a silicon oxygen tether. In some compounds of this type (e.g., the substrate in the reaction pictured in eq 6 11 ) the multiple bond is located in a substituent group, 11 13,113 123 while in others 23,124 133 (eq 21), 124 it is part of a ring system. As mentioned earlier in the chapter (Section III.B.4), connecting the reacting segments of a mole cule through a silicon oxygen bond is particularly useful in producing larger (seven-, 24,29 eight-, 31 36 and nine- membered 38 42 ) rings. An example of a reaction that forms a larger ring is shown in Scheme 18, where an allyl group is tethered to the 2-position in the phenyl selenide 34. 24,29b A similar tether connects the two saccharide units in the radical 41, an intermediate des tined to form an eight-membered ring that then is converted into a partially protected C- di sac - charide (Scheme 21). 32 The carbon-centered radicals in these reactions usually are generated by treating phenyl selenides with tri-n-butyltin hydride. Having a vinyl group tethered to a radical-forming substituent through a silyl ether linkage can provide the structure needed to form either a fivemembered or a six-membered ring. 11-13,113-120 It is worth recalling (Section III.B) that in compounds of this type the size of a ring formed can depend on the concen tration of the hydrogen-atom transfer; thus, in the reaction shown in eq 6, higher Bu 3 SnH concen tration causes formation of a five-membered ring, but lower concentration favors a six-membered one. 11 Scheme 3 contains a rational i zation for this concen tration depend ence. In the radical reactions of the unsaturated silyl ethers pictured in Schemes 18, 19, and 21 and eq 21, the final step is hydrogen-atom abstraction from Bu 3 SnH. When the substrate is an unsaturated iodide and no Bu 3 SnH is present in the reaction mixture, the cyclic product is a silyl ether that http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 2/7
contains an iodine atom (Scheme 22). 119b Reaction of this product with fluoride ion eliminates both the silicon-containing group and an iodide ion and intro duces additional unsaturation into the final product. A process similar to that shown in Scheme 22 takes place in the reac tion pictured in Scheme 23, where homolytic cleavage of the C Se bond is fol - lowed by ring formation to generate the cyclic radical 44. If diphenyl diselenide (C 6 H 5 SeSeC 6 H 5 ) is added to the reaction mixture, the yield of the unsaturated nucleoside 45 increases from 47% to 77%. Diphenyl diselenide reduces competing radical reactions (e.g., hydrogen-atom abstraction) by rapidly reacting with 44 to form an intermediate selenide from which the product 45 is produced by an elim in ation reaction. 115b C. Alkenyl and Alkynyl Ethers, Esters, Acetals, and Alcohols http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 3/7
A molecule with an O-allyl 5,9,45,58,134 146 or an O-propargyl 21,147 157 group and a properly positioned, radical-forming substituent will react to form a new ring system. Equations 22 136 and 23 152 describe reactions of compounds of this type. These reac tions take place even though ring forma - tion produces highly reactive radicals, a primary radical from an allyl ether (eq 24) and a vinylic one from a propargyl ether (eq 25). Not surprisingly, ring formation takes place readily in compounds where cyclization does not need to produce such reactive radicals; in fact; as long as reactive centers can come within bonding distance, radical cyclization occurs in a wide variety of unsaturated radicals. 158 186 Some specific examples are shown in equations 26 and 27, where ring formation takes place in molecules in which the multiple bond is located in an existing ring system (eq 26) 159 or is part of an acyclic structure (eq 27). 185 Cyclization takes a different course in its final stage when a radical is formed by electron transfer from samarium(ii) iodide. 187 In such a reaction the cyclic radical reacts with additional SmI 2 to form an organosamarium inter mediate that undergoes elimination to produce a carbon carbon double bond (Scheme 24). 164 In the reaction shown in Scheme 24 an O-acetyl group is eliminated, but even a hydroxyl group (presumably complexed with SmI 2 ) can depart in forming the double bond (eq 28). 164 http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 4/7
The course of radical cyclization in allyl ethers and related compounds sometimes is altered by internal hydrogen-atom abstraction. 58,88,134,138,171,172,185 Hydrogen-atom abstraction by a carbon-centered radical from a C H bond does not take place readily. The best possibility for this type of reaction occurs when a radical is partic ularly reactive [e.g., the primary radical produced from an allyl ether (eq 24) or the vinyl radical from a propargyl ether (eq 25)] and the abstraction is internal. Such reaction happens following cycli zation of the pyranos-1-yl radical 46 (Scheme 25). 58,134,138 Although the radicals 47 and 48, produced in this reaction, are both pri mary, only 48 has the proper stereo chemistry for internal hydrogen-atom abstraction. In a similar reaction the vinyl radical 49, produced during ring formation, abstracts a hydrogen atom from the neighboring O-benzyl group in route to formation of a mixture of cyclic compounds (Scheme 26). 172 D. Compounds with Terminal Triple Bonds A triple bond in a molecule can have more than one role in a radical cyclization reaction. In addition to being the multiple bond that combines with a radical centered on a carbon atom else where in the molecule, as occurs in the reaction shown in eq 27, a triple bond also can be the source for a http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 5/7
carbon-centered radical that adds to another multiple bond. 188 When a radical (usually the tri-n-butyltin radical) reacts with the triple bond in a compound such as the propargyl ether 50 to form a vinylic radical, rapid internal reaction of this radical takes place if there is a second multiple bond within bonding distance (Scheme 27 190 ). 189 200 Although the tri-n-butyltin radical also can add to a double bond, 75 triple bond addition is a far more likely beginning step in a cyclization reac - tion. 193,201 The difference in reactivity between a double and a triple bond is apparent in the reaction shown in eq 29, 193 where a triple bond reacts in pref er ence to a similarly positioned double bond. These differences in reactivity between double and triple bonds are determined by the rate of radical cyclization rather than stannyl radical addi tion. The stannyl radical actually adds more rapidly to a double bond than to triple bond, but the adduct radical from addition to a double bond reverts more rapidly and cyclizes more slowly than that from addition to a triple bond. 201 E. Compounds in Which the Multiple Bond is not Electron-Deficient If a carbon-centered radical and a multiple bond are in separate mole cules, radical addition only competes effectively with other radical reactions (e.g., hydrogen-atom abstraction) when the mul tiple bond is electron-deficient. If this bond is not electron-deficient, successful addition is rare and requires condi tions that minimize competing reactions. When the two reactive centers are in the same molecule and can come into close proximity, cycli zation can be competitive when the mul tiple bond is not electron-deficient (eq 3 5 ). 5,183,202 210 In fact, even if this bond is electron-rich, ring formation can take place (eq 30 211 ). 211 221 http://chemwiki.ucdavis.edu/organic_chemistry/carbohydrates/radical_reactions_of_carbohydrates/ii%3a_radical_reactions_of_carbohydrates/19%3a_compo 6/7
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