Asymmetric radical cyclization reaction

To obtain a chiral intermediate, we tried several methods, including synthesis through an asymmetric radical cyclization reaction and synthesis from a chiral starting material, as described below. 

Synthesis Through Asymmetric Radical Cyclization Reaction... 

Abstract This review covers recent advances in the field of radical chemistry on solid phase. Intermolecular processes using both immobilized radicals with solution-phase acceptors and immobilized acceptors with radicals in solution are discussed, as are radical cyclization reactions on polymer supports. Progress in the development of solid-phase asymmetric radical processes and the design of linkers cleaved by radical processes are also discussed. 

Radical cyclization reaction often proceeds with high diastereoselectivity and high asymmetric induction when chiral precursors are used. Internal alkynes... 

Scheme 3.37. Domino radical addition/cyclization-reaction for the asymmetric synthesis of (3-aminobutyrolactones.

Radical cyclization of polyfunctional 5-hexenyl halides mediated by Et2Zn and catalyzed by nickel or palladium salts has been demonstrated to produce stereoselectively polyfunctional 5-membered carbo- and heterocycles [56, 57]. Based on this strategy a formal synthesis of methylenolactocin (11) was achieved (Scheme 20). The acetal 130, readily being built up by asymmetric alkylation of aldehyde 127 followed by reaction with butyl vinyl ether and NBS, served as the key intermediate for the construction of the lactone ring. Nickel(II)-catalyzed carbometallation was initiated with diethylzinc to yield exclusively the frans-disubstituted lactol 132, which could be oxidized directly by air to 134. Final oxidation under more forcing conditions then yielded the lactone (-)-75 as a known intermediate in the synthesis of (-)-methylenolactocin (11) [47aj. 

Asymmetric radical reactions. Several groups have reported asymmetric radical reactions observed with (S,S)- or (R,R)-1 as the chiral auxiliary. Thus the iodide 2 in the presence of BuySnH and AIBN cyclizes mainly to two diastereomeric endo-cyclic products 3 in the ratio 14 1.2... 

Radical reactions provide a powerful means for manipulating the structure of organic compounds. A vast range of radical transformations is available to the synthetic organic chemist, ranging from functional group interconversions to asymmetric reactions and complex, sequential cyclization reactions where molecular complexity can be increased spectacularly in a single step. Many of these processes are complementary to more traditional polar processes and are characterized by attractive features such as the mild, neutral reaction con-... 

In addition to cationic cyclizations, other conditions for the cyclization of polyenes and of ene-ynes to steroids have been investigated. Oxidative free-radical cyclizations of polyenes produce steroid nuclei with exquisite stereocontrol. For example, treatment of (259) and (260) with Mn(III) and Cu(II) afford the D-homo-5a-androstane-3-ones (261) and (262), respectively, in approximately 30% yield. In this cyclization, seven asymmetric centers are established in one chemical step (226,227). Another intramolecular cyclization reaction of iodo-ene poly-ynes was reported using a carbopaUadation cascade terminated by carbonylation. This carbometalation—carbonylation cascade using CO at 111 kPa (1.1 atm) at 70°C converted an acycHc iodo—tetra-yne (263) to a D-homo-steroid nucleus (264) [162878-44-6] in approximately 80% yield in one chemical step (228). Intramolecular aimulations between two alkynes and a chromium or tungsten carbene complex have been examined for the formation of a variety of different fiised-ring systems. A tandem Diels-Alder—two-alkyne annulation of a triynylcarbene complex demonstrated the feasibiHty of this strategy for the synthesis of steroid nuclei. Complex (265) was prepared in two steps from commercially available materials. Treatment of (265) with Danishefsky s diene in CH CN at room temperature under an atmosphere of carbon monoxide (101.3 kPa = 1 atm), followed by heating the reaction mixture to 110°C, provided (266) in 62% yield (TBS = tert — butyldimethylsilyl). In a second experiment, a sequential Diels-Alder—two-alkyne annulation of triynylcarbene complex (267) afforded a nonaromatic steroid nucleus (269) in approximately 50% overall yield from the acycHc precursors (229). 

Both intermolecular and intramolecular additions of carbon radicals to alkenes and alkynes continue to be a widely investigated method for carbon-carbon bond formation and has been the subject of a number of review articles. In particular, the inter- and intra-molecular additions of vinyl, heteroatomic and metal-centred radicals to alkynes have been reported and also the factors which influence the addition reactions of carbon radicals to unsaturated carbon-carbon bonds. The stereochemical outcome of such additions continues to attract interest. The generation and use of alkoxy radicals in both asymmetric cyclizations and skeletal rearrangements has been reviewed and the use of fi ee radical reactions in the stereoselective synthesis of a-amino acid derivatives has appeared in two reports." The stereochemical features and synthetic potential of the [1,2]-Wittig rearrangement has also been reviewed. In addition, a review of some recent applications of free radical chain reactions in organic and polymer synthesis has appeared. The effect of solvent upon the reactions of neutral fi ee radicals has also recently been reviewed. ... 

Recently, Curran and coworkers had demonstrated that chiral radicals derived from camphor sultam give high levels of asymmetric addition in cyclization reactions with... 

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