1 - -, radical cyclisation

In other cyclisations to functionalised oxepanes, Rychnovsky and Dahanukar have shown that the epoxide 36 cyclises with BF3 etherate and TMSCN to form the oxepane 37 as single product <96TL339>, and Evans and Roseman have prepared a series of cyclic ethers by radical cyclisation of the acylselenides 38 (Scheme 8) <96JOC2252>. The major product was always the cw-isomer and the best yields were obtained with (TMSjaSiH. 

The cyclic sulfinates 87 and 88 have been prepared by radical cyclisation of the corresponding haloalkyl ferf-butylsulfinates as shown <06AG(E)633. 

The base-catalysed ring contraction of 1,3-dioxepanes offers an attractive route to 4-formyl tetrahydropyrans (Scheme 14) , whilst fused exo-cyclic dienes 27 result from the radical cyclisation of alkenyl iodides 26 (Scheme 15) <00OL2011>. Intramolecular radical addition to vinylogous sulfonates is highly stereoselective, leading to the ci s-2,6-disubstituted tetrahydropyran (Scheme 16) . 

In fact, the formation of five-membered rings during the radical cyclisation has been used extensively in the past few years for the synthesis of several polyquinanes. 

High stereoselectivity is achieved in radical cyclisations leading to pentagonal rings. 

For the route A, acyl radicals donors like iS are readily generated from acyl selenides (ISa) or acyl cobalt derivatives (iSb) and radicals acceptors 2S are usually multiple bonds as in methyl vinyl ketone (2Sa) -although some homolytic substitutions are possible. On the other hand, nitriles GSal are useful acceptors (3S) in radical cyclisations and 4Sa is an obvious synthon equivalent of radical donor 4S (See Table 7.2). 

From an exhaustive retrosynthetic analysis and from the experimental work performed by Curran [29] [32], it was clear that the synthesis of modhephene required an elaborate strategy. In the first place, the tandem radical cyclisation should be conducted individually rather than just in one step since it allows more flexibility. In the second place, Curran s observation that the precursor of modhephene (54) could be the olefmic exocyclic derivative 55 allows the application of a series of heuristic principles already familiar to us, which greatly simplifies the retrosynthetic analysis and leads to diquinane and, finally, through a second radical retroannulation to the very simple cyclopentanone derivative (Scheme 7.24). 

The synthesis of modhephene (54), which proceeds according to plan in an overall yield of >16%, with complete control of relative stereochemistry, demonstrates the ability of radical cyclisations to form propellane systems and generate highly crowded neopentyl quaternary centres. The accepted pathway for the cyclisation of the vinyl trimethylstannane is shown in Scheme 7.25. The chair-like transition state in which the methyl substituent on the radical is pseudoequatorial, accounts for the observed endo stereoselectivity. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

Radical cyclisation of the trimethylsilylalkyne 12 affords the macrocycles 13 and 14 (Scheme 2). These in turn can also be induced to cyclise by treatment with borane-... 

A conceptually different C-C bond forming reaction involving intramolecular radical cyclisation of allylic esters of bromodifluoroacetic acid was described by Itoh et al. [200]. Reduction to the acetal sets the stage for a tin hydride-mediated cyclisation (Eq. 65). 

The precursor was prepared via a lengthy sequence involving the elaboration of a Reformatsky adduct. The cyclic product was obtained as a 1.2 1 mixture of cis and trans isomers.The presence of the fluorine atoms had no effect on the efficiency of the cyclisation reaction. A subsequent study [384] extended the range of cyclisations to include trifluoromethyl alkyl and alkenyl radicals (Eq. 157). Free radical cyclisation reactions therefore show considerable promise for the rational synthesis of fluorinated carbocycles. 

The first sesquiterpene thiocyanate to be isolated from a marine sponge was (15, 45, 65, 7/ )-4-thiocyanato-9-cadinene (253) from Trachyopsis aplysinoides. The structures of this compound and of an isothiocyanate with a new carbon skeleton (254), were determined by X-ray analysis and two additional isothiocyanates (255-256) were identified [258]. Isothiocyanate 254 was synthesised using an oxidative radical cyclisation reaction as a key step [259]. 

Y. Chapleur and N. Moufid, Radical cyclisation of some unsaturated carbohydrate derived acetals, J. Chem. Soc. Chem. Common, p. 39 (1989). 

R. Nouguier, C. Lesueur, E. De Riggi, M. P. Bertrand, and A. Virgili, Stereoselective free-radical cyclisation on a sugar template. Hie sulphonyl radical as a synthetic tool for functionalized glycosides. Tetrahedron Lett. 37 3541 (1990). 

G. Stork and M. Kahn, Control of ring junction stereochemistry via radical cyclisation, J. Am. Chem. Soc. 107 500 (1985). 

J. K. Dickson, R. Tsang, J. M. Lleia, and B. Fraser-Reid, Serial radical cyclisation of branched carbohydrates 1. Simple pyranosides diquinanes, J. Org. Chem. 54 5350 (1989). 

Following their syntheses of ( )-pancracine and related alkaloids (vide supra), Hoshino et al [106] had described a different approach involving radical cyclisation of an isoquinoline derivative which permitted a rapid assembly of keto-5,11-methanomorphanthridine skeleton. The syntheses of 413, 414 and 415 commenced with the known 4-hydroxy-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoIine (439) (Scheme 62). Subsequent to protection of the amino group as the trifluoroacetyl derivative, the amide alcohol 440 was converted into the amide thioether 441, by reaction with phenylthiol in the presence of zinc iodide. Alkaline hydrolysis of 441,... 

Termination steps can be caused by radical-radical combinations which remove radicals from the chain reaction. An example of a chain reaction using the commonly encountered tributyltin hydride (BusSnH) to carry out a radical cyclisation is shown in Scheme 10.3 to illustrate SH2 and addition reactions. The radicals act as the chain carriers, each reacting with a neutral molecule, and when a radical is removed from the chain by termination, the chain breaks down. 

Scheme 10.11 shows a PRE-mediated 5-exo-trig radical cyclisation in which the controlled thermal formation of active radicals from the dormant alkoxyamine 2 is facilitated by steric compression of the alkoxyamine C—O bond by the bulky N-alkyl and O-alkyl groups [8]. Intramolecular H-bonding between a —CH2—OH and the nitroxyl oxygen of the incipient nitroxide in a six-membered cyclic transition structure further facilitated the dissociation of 2. After cyclisation, the resultant primary cyclopentylmethyl radical was trapped by the free nitroxide to form the new dormant isomerised alkoxyamine 3, which is more stable than 2 since the O-alkyl is now primary. The same reaction using TEMPO as the nitroxide component did not work presumably because the C—O bond in the alkoxyamine precursor is much stronger. 

Alkoxyamines have been promoted as alternative initiators to metal hydrides in radical cyclisations since metal hydride reactions often lack regioselectivity and produce mixtures of reduced uncyclised and cyclised products. Further, the nitroxide portion of the alkoxyamine... 

Scheme 10.11 Alkoxyamine-initiated 5-exo trig radical cyclisation...

The elucidation of mechanisms of reactions of Sml2 have involved polarography, kinetics, radical clocks and trapping techniques (radical cyclisation) [19, 20]. The reagent is able to reduce alkyl halides and ketones/aldehydes, as shown in Scheme 10.25, in non-chain radical reactions. 

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