Cyclic radical cyclization stereoselectivities

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic... 

Fused cyclic ethers can be derived from appropriately substituted sugars. An example is given with the stereoselective 5-exo radical cyclization of allylic 2-bromo-2-deoxysugars, in the presence of 1,1,2,2-tetraphenyldisilane as the radical mediator and AIBN in refluxing ethyl acetate. The corresponding cis-fused bicyclic sugars have been prepared in moderate to good yields (Reaction 7.28) [39]. 

Free-radical cyclizations using ethyl radicals generated by EtsB/air system or stannyl radicals systems provide a range of carbocyclic and heterocyclic hydroxylamines (equation 77). Stereoselectivity in these reactions is variable but can be semiquaUtatively predicted by Beckwith-Houk models . Depending on the substitution pattern of the emerging cyclic system, stereoselectivity can be very high, especially in fused polycyclic systems (equation... 

Free-radical cyclization of phenyl selenide 15 to indolizidinone 16 represented a key step in the total synthesis of (—)-slaframine (equation 52). The two pairs of diastereomers were first separated and then hydrolyzed to the corresponding alcohols in 76% overall yield77. (TMS)3SiH-mediated acyl radical reactions from phenylseleno esters 17 have recently been utilized for the stereoselective synthesis of cyclic ethers78. In fact, the experimental conditions reported in equation 53 are particularly good for both improving cis diastereoselectivity and suppressing decarbonylation. 

When there is no programmed radical cyclization reaction as discussed in the preceding section, the anomeric radical generated under reductive metallation conditions will obviously be reduced to an organometallic. This is no longer radical chemistry but the radical initiation will impose the stereoselectivity of the anionic process that follows if kinetic conditions are maintained. This situation is observed in the reductive lithiation with lithium naphthalenide (LN) of derivatives 10 where X can be Cl, SPh, or SOjPh (Fig. 13), a process first reported on cyclic a-alkoxyphenyl sulfides. ... 

Free-radical reactions have begun to find increasingly wide application in synthetic chemistry. Because of their high stereoselectivity, some of them are very appealing. At the same time, many such processes have serious limitations since they use iodine-containing systems as substrates. Nevertheless, radical cyclization has become a known technique of both cyclic and heterocyclic system design. 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

Vinylogous sulfonates are valuable radical acceptors for the stereoselective synthesis of cyclic ethers [48]. Evans used the Z-vinylogous sulfonate 73 for preparation of the intermediate 74, which will be used in the synthesis of mucocin [49] (Scheme 26). More recently, an intermediate in the synthesis of garsubellin A was prepared via E -vinylogous sulfonate radical cyclization by Nicolaou [50]. 

The extention of radical cyclization of (bromomethyl)dimethylsilyl allyl ethers to propargyl analogs 17 has been studied by Malacria and coworkers. The intermediate exocyclic vinyl radical 18 can be either trapped by the hydrogen atom to give, after simple chemical transformations, the trisubstituted alkene 19 (equation 25) or can be added intramolecularly to give cyclic products when suitably located double bonds are present (equations 26 and 27). An attempt to apply this methodology to the stereoselective synthesis of angular and linear triquinane has also been performed. When = t rt-butyl,... 

In sharp contrast to the acyclic radicals, cyclic radicals exhibited much better stereoselectivities. Cyclization of radical 24a or24b prepared from 4,6-0-benzylidene-2,3-di-0-benzyl-D-glucopyranose 23 gave a single trans product (25a or 25b) in each case (Fig. 7.7) [11]. Likewise, a radical with the 3-benzyloxy substituent removed (26) also cychzes to give almost exclusively the, 5-trans product 27. 

From a synthetic point of view, the regioselectivity and stereoselectivity of the cyclization are of paramount importance. As discussed in Section 11.2.3.3 of Part A, the order of preference for cyclization of alkyl radicals is 5-exo > 6-endo 6-exo > 7-endo S-endo > 1-exo because of stereoelectronic preferences. For relatively rigid cyclic structures, proximity and alignment factors determined by the specific geometry of the ring system are of major importance. Theoretical analysis of radical addition indicates that the major interaction of the attacking radical is with the alkene LUMO.321 The preferred direction of attack is not perpendicular to the it system, but rather at an angle of about 110°. 

The reaction of the unsaturated aldehyde 32 with cat. Cp2 VCl2/Me3SiCl/ Zn is conducted in THF to afford the cyclic alcohol 33 with excellent dia-stereoselectivity (Scheme 19) [21]. The transformation may be explained by 5-exo-cyclization of the corresponding radical anion, followed by chlorination. 

Hirano et al. reported on the stereoselective cyclization to give tetralin derivatives using the phenanthrene-p-dicyanobenzene sensitizer system. Pandey independently reported the intramolecular photocyclization of methoxybenzene derivatives bearing silyl enol ether chromophore via their heterodimer radical cations in the presence of 1,4-dicyanonaphthalene gave benzo-annulated cyclic ketones in 70% yields [490] (Scheme 133). 

One of the main advantages of the anionic cyclizations is their regioespecificity and stereoselectivity when compared with radical or other types of reactions leading to cyclic systems. This is usually due to the formation of complexes involving the lithiated alkyl, vinyl or aryl substrate and an unsaturated, double or triple, C—C bond. In some cases, a heteroatom is involved in stabilizing the transition state for the reaction. In other cases, the stereoselectivity of the cyclization is determined by the presence of several functional groups in the substrate. 

Korshin et al. reported an outstanding double stereoselective alkenyla-tion through a 1,5 sulfur-to-carbon translocation on a proline-derived scaffold [169]. 5-Exo-trig cyclization of the radical derived from 181 led to bi-cyclic adduct 182, which collapsed to the open thiyl radical (Scheme 59). The sole stereocontrol exerted by the cyclization step allows for the resulting vinyl translocation to occur entirely stereoselectively. Since the reaction was carried out in the presence of a styryltin derivative, consecutive intermolecular vinylation occurred, leading to bisvinyl compoimd 183 in very high yield (86%). The styrylsulfonyl moiety could be converted to a formyl group. 

Ueda et al. reported a tandem radical addition-cycUzation reaction in aqueous media [184]. This reaction was initiated by single-electron transfer from indium to an alkyl iodide. Fragmentation of the iso-propyl iodide radical anion generated the iso-propyl radical, which triggered the addition/cyclization tandem. Final SET and in situ hydrolysis delivered cyclic sulfonamides in good yield but low stereoselectivity. 

Sibi and coworkers examined some of the factors that control the radical addition/cyclization reactions for the formation of cyclic ethers in terms of the stereoselectivity of the reaction as well as the size of the cyclic ether that is formed. 

---