Alkynes free radical cyclization

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). 

Free radical cyclizations have been used extensively to convert carbohydrates into carbocycles [39,40]. The general strategy consists of opening the sugar, transforming the carbonyl into a radical acceptor (alkene or alkyne) and converting one of the hydroxyls into a nucleophilic radical suitable to achieve cychzation. 

In 1989 Curran and co-workers reported on a photocatalytically induced free-radical cyclization leading to various cyclic, bi-, or polycyclic carbocycles (fused and spiro) via isomerization of unsaturated iodides (alkenes, alkynes) [63]. This corresponds to the nonreductive variant of the tin hydride method. Under sunlight irradiation and in the presence of 10 mol% hexabutylditin, a-iodo esters, ketones, and malonates are efficiently transformed via an iodide atom transfer chain mechanism (eq. (4)). 

Free radical cyclization of the azetidinone (223 R = —CH=CHPh) gives a mixture of the debrominated starting material together with the carbapenem (224) and the benz[6]azepin-2(3//) one (225) <87CJC104>. The carbapenem is unstable and is converted into (225) on standing. A similar result is obtained with the alkyne analogue (223 R = —C=CPh). 

The first example of a cyclization of fluorine-containing 5-hexenyl radicals was the study of the radical-iniOated cyclodimenzation reaction of 3,3,4,4-tetra-fluoro-4-iodo-1-butene. In this reaction, the intermediate free radical adds either to more of the butene or to an added unsaturated species [54, 55] (equation 56). Electron-deficient alkenes are not as effective trapping agents as electron-nch alkenes and alkynes [55]. 

For the reduction of sulfides and selenides to free radicals and subsequent cyclization onto alkynes, see page 413, Section 2.3. 

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. ... 

As mentioned in an earlier section in this Report, free-radical carbon-carbon bond-forming processes are becoming increasingly important in synthesis, and this year they have proved themselves particularly useful for the synthesis of pyrrolizidine alkaloids. Thus, Hart and his group have now applied their intramolecular tin hydride generated ot-acylamino radical to alkyne cyclization [viz. (97) - (98)] and to the synthesis of (-)-dehydrohastanecine (99), (+)-heliotridene (100), and (+)-hastanecine (101). In addition, free radical in mechanism is the photochemical cyclization of the -acylpyrrolidine (102) to the pyrrolizidene (103), a key intermediate in a synthesis of ( )-isoretronecanol (104). 

The reaction could be quenched by radical quenchers like 2,4,6-tii-rerr-butyl-phenol, which indicates that a radical pathway is involved. Initially, the homolysis of fert-butyl nitrite leads to the addition of ferf-butyl oxy radical and nitroso radical to alkyne. Species 119 then cyclizes and gives a reactive four-membered ring 120 [153]. Then 120 undergoes proton abstraction, and isobutylene extmsion. Ring-opening of 121 by the elimination of formic acid finally gives the nitrile product. This reaction is the first example of metal-free condition and the use of fert-butyl nitrite in nitrogenation of alkynes (Scheme 4.48). 

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