Fused rings radical cyclizations

Fused Five-membered Rings.- Radical cyclizations continue to give ready access to fused cyclopentanoids. For example the stereo-controlled formation of (37) allows a radical-induced ring closure to the cyclopentanol (38) in a process which has been described as... 

It is important to note here that both of the 5-exo radical cyclizations (133—>132—>131, Scheme 27) must proceed in a cis fashion the transition state leading to a strained mms-fused bicy-clo[3.3.0]octane does not permit efficient overlap between the singly occupied molecular orbital (SOMO) of the radical and the lowest unoccupied molecular orbital (LUMO) of the alkene. The relative orientation of the two side chains in the monocyclic radical precursor 134 is thus very significant because it dictates the relationship between the two outer rings (i. e. syn or anti) in the tricyclic product. The cis-anti-cis ring fusion stereochemistry of hirsutene would arise naturally from a cyclization precursor with trans-disposed side chain appendages (see 134). 

The N,0- and N,S-heterocyclic fused ring products 47 were also synthesized under radical chain conditions (Reaction 53). Ketene acetals 46 readily underwent stereocontrolled aryl radical cyclizations on treatment with (TMSlsSiH under standard conditions to afford the central six-membered rings.The tertiary N,0- and N,S-radicals formed on aryl radical reaction at the ketene-N,X(X = O, S)-acetal double bond appear to have reasonable stability. The stereoselectivity in hydrogen abstractions by these intermediate radicals from (TMSlsSiH was investigated and found to provide higher selectivities than BusSnH. 

In addition to the radical ipso-substitution of indolyl sulfones producing stannanes described earlier <96T11329>, Caddick has also reported an approach to fused [l,2-a]indoles based on the intramolecular cyclization of alkyl radicals. Thus, treatment of 112 with BuaSnH leads to the fused ring derivatives 113 (n = 1-4) <96JCS(P1)675>. 

The following syntheses of five-membered carbocyclic systems involve radical-induced epoxide fragmentation with radical translocation and cyclization. The resulting bicyclic alcohols are formed as a mixture of two epimeric esters with cw-fused rings.[71]... 

PET reactions [2] can be considered as versatile methods for generating radical cations from electron-rich olefins and aromatic compounds [3], which then can undergo an intramolecular cationic cyclization. Niwa and coworkers [4] reported on a photochemical reaction of l,l-diphenyl-l, -alkadienes in the presence of phenanthrene (Phen) and 1,4-dicyanobenzene (DCNB) as sensitizer and electron acceptor to construct 5/6/6- and 6/6/6-fused ring systems with high stereoselectivity. 

The construction of the central ring can also be accomplished by a radical cyclization of a non-fused heterobiaryl system composed of two six-membered heterocycles and linked by a two-atom bridge. An example is the synthesis of 106 from the bromo derivative 105 in the presence of AIBN and Bu3SnH (Equation 8) <1999TL4073>. 

In an alternate mode of radical cyclization, indolyl-2-radicals generated from the corresponding 2-bromo derivatives 152 (n=l-3) undergo intramolecular reactions with appended aromatic rings to afford fused [ 1,2-a]indoles 153 <00TL4209>. 

A new entry to exocyclic dienes was reported by Sha who uncovered that a radical cyclization of the vinyl iodide 100 can lead to the formation of an exocyclic dienes fused with a tetrahydrofuran ring. The cyclization is proposed to proceed in a 5-(n-exo)-exo-dig fashion <00OL2011>. 3,4-Disubstituted tetrahydrofurans can also be constructed via the cyclization of O-stannyl ketyls and allylic 0-stannyI ketyls onto electron-rich or electron-poor alkenes <00TL8941>. 

In the gluco case (Scheme 13) the radical cyclization, with its requirement for the formation of a czs-fused ring junction [129,130], takes place uneventfully on the opposite face of the alkene radical cation to the one shielded by the phosphate anion, whereas in the manno series cyclization is severely retarded by the presence of the phosphate group above the face of the radical cation on which cyclization must occur. This steric retardation of the cyclization step results in a breakdown of chain propagation and results in the longer reaction times observed. Furthermore, the retardation of the radical cyclization step in the manno case enables the alkene radical cation to take... 

The Kolbe electrolysis has also been used to initiate tandem radical cyclization reactions [21]. Recently, Matzeit and Schafer reported that these reactions could be used to construct angularly fused tricyclic ring skeletons (Scheme 8) [22]. The reaction led to the formation of three new C-C bonds. In addition to the desired tricyclic product, the reaction formed a pair of products having the... 

An example of the influence of structure and geometry on radical cyclization is shown by the stereoselectivity of the 5-enJo-tng cyclization in compound 52 and 5-exo-trig cyclization in 53 using (TMS)3SiH as radical mediators [66]. In system52 a mixture of cA-fused and trans-imtd rings are obtained, whereas in system 53 the reaction proceeds in a stereoselective manner to give only the cw-fused product. 

The presence of a 4-methoxy substituent on the 2-phenylethyloxyl or 3-phenylpropyl-oxyl side chains radically altered the course of these cyclizations (Scheme 4). 31a and 31b afforded the spiro-fused ring systems 32 and 33 in 26 and 69% yields, respectively, as the only cyclization products. With this substituent, cyclization onto the activated ipso positions was favoured over direct attack, even where the strained transition state for Atj -5 cyclization of 31a to 32 was involved. Demethylation of the intermediate spirocyclohexa-dienyl cation is favoured over rearrangement in these cases. Kikugawa and coworkers effected the formation of 32 (82%) and 33 (39%) with reverse efficiencies using AgaCOs in TFA . 

C. Audin, J. M. Lancelin, and J. M. Beau, Radical cyclization on carbohydrate pyranosides A controlled formation of functionalized ring-fused bicyclic acetals. Tetrahedron Lett. 29 3691 (1988). 

In 2001, tetracyclic 3.6.6.4 ring systems fused to a (3-lactam (IV, Fig. 6) have been reported to form via 6-exo-trig radical cyclization [252],... 

Fig. 1. Synthesis of ring-fused and C-2 branched 1,5-anhydroalditols.125 Conditions A, addition of n-BujSnH during 12 h B, n-Bu3SnCl (0.1 eq) and NaBH3CN (2 eq) C, radical cyclization followed by treatment with KF, oxidation, and acetylation.

Fused tetracyclic biaryl-2-azetidinones have been prepared by the radical cyclization of aryl /3-lactam-tethered haloarenes. Azetidin-2-one 504, having an extra radical acceptor on C-3, underwent radical cyclization with tributyltin hydride to give the biaryl-2-azetidinone 505 in a low yield, with debrominated 3-phcnoxyA-phcnyl-l -(/ -methoxy-phenyl)-2-azetidinone as the main product (60% yield) (Equation 82). But when the azetidinones 506 (Rz = R6 = H) bearing an extra link (O) on the radical precursor at C-3 or N-l of the /3-lactam ring were treated with tributyltin hydride, the expected cyclization products 507 were obtained. If azetidinones 506 (Rz = OMe, or Me R6 = H, OMe, or Me) were treated in the same way then the tetracyclic azetidinones 508 were produced (Equation 83) <2005T7894>. 

Alcaide s group has reported further work on the radical cyclization of alkenyl or alkynyl substituted 4-allenynol-/)-lactams (see Section 2.04.9.6) <2007JOC1604>. Titanocene monochloride mediated reductive radical cyclization of l-cyanoalkyl-4-(epoxy-2-phenylethyl)-2-azetidinones yielded bi- or tri-cyclic /3-lactams, the latter having an aryl group fused to a seven membered ring <2007T3017>. 

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