Cyclization stereoelectronic effects

Another route involves a palladium-copper-catalyzed tandem carbon-carbon formation/cycloaddition sequence (Equation 12) <2005TL8531>. Notably, cycloadditions of azide to the internal alkynes failed under click chemistry reaction conditions <2003DDT1128>. Cyclization under oxidative conditions has been reported from dithioacetal 163 (Equation 13) <1996TL3925>. The formation of 164 as a single diastereoisomer has been explained by stereoelectronic effects. 

The first results which indicate that stereoelectronic effects play an important role in the aldol condensation were reported by Hajos and Parrish (6) who found that (a) triketone J8 cyclizes to the bicyclo[3.2.1]octane ketol on treatment with piperidinium acetate in water and (b) ketol 19 undergoes an epimerization at C-4 yielding the more stable isomeric ketol 20 on treatment with piperidine. The authors concluded that the formation of ketol 19 from 18 under kinetically controlled conditions is the result of... 

In the biogenesis of steroids, the enzyme-catalyzed polycyclization of squalene (225) produces the tetracyclic substance lanosterol (225) which is eventually converted into cholesterol (227) Eschenmoser, Stork, and their co-workers (80-82) have proposed that the squalene-1anosterol conversion can be rationalized on the basis of stereoelectronic effects. The stereochemical course of this biological cyclization (83, 84) can be illustrated by considering the transformation of squalene oxide (228) (an intermediate in the biosynthesis of cholesterol (83, 84)) into dammaradienol 229. This transfor-... 

Treatment of polyolefinic ketal 230 with stannic chloride in pentane gave a mixture (30% yield) of about equal amounts of the two racemic D-homoster-oidal tetracyclic isomers 231 (88). In this cyclization, the first cationic intermediate is not chiral and the two faces of the 5,6-double-bond can react with equal facility with the carbonium ion as a consequence, the product obtained (231) is necessarily racemic. The conversion of the open-chain tetraenic acetal 230 having no chiral centers into a tetracyclic system having seven such centers and producing only two (231) out of a possible 64 racemates is a striking tribute to the power of stereoelectronic effects. 

In this publication the author describes the phenomenon that most times the thermodynamically less stable product (see 29) of the two possible rings (e.g. 5-exo and 6-endo) is formed. Today looking at the 5-exo cyclization it is known that, although the generated primary radical is less stable than a secondary one, stereoelectronic effects favor reaction to the kinetically controlled product. According to MO-calculations, for a successful cyclization, an angle of 70° of the incoming radical to the plane of the alkene-/alkyne-bond is necessary.11... 

The formation of bi- and tricyclic compounds by transannular photochemical cyclization of monocyclic reactants mostly follows special rules that are caused by the molecular rigidity, equilibria of ring conformers and distinct stereoelectronic effects and, therefore, will be discussed in a separate section. Naturally, it is no longer possible to strictly structure the reactions according to the size and the type of the ring and, furthermore, vastly different examples are known. Therefore, only some representative examples will be discussed in this section and the selection does not claim to be complete. 

Figure 7.25. Stereoelectronic effects on the Norrish type II reaction. Presumed optimal orbital alignments a) for cyclization and b) for elimination.

Draw a mechanism for the following multistep reaction. Do the cyclization steps follov. Baldwin s rules What other stereoelectronic effects are involved ... 

Stereoelectronic effects are also important for intramolecular cyclizations, which are discussed in Secs. II.B, III.B, and IV.B. In these cases, Baldwin s rules usually apply [26,27]. 

Free-radical cyclization reactions (i.e., the intramolecular addition of an alkyl radical to a C=C ir bond) have emerged as one of the most interesting and widespread applications of free-radical chemistry to organic synthesis. Free-radical cyclizations are useful because they are so fast. The cyclization of the 5-hexenyl radical to the cyclopentylmethyl radical is very fast, occurring at a rate of about 1.0 X 105 s-1. In fact, the rate of formation of the cyclopentylmethyl radical is much faster than the rate of cyclization to the lower energy cyclohexyl radical. This stereoelectronic effect is derived from the fact that the overlap between the p orbital of the radical and the rr MO of the double bond is much better when Cl attacks C5 than when it attacks C6. The relative rates of 5-exo and 6-endo ring closures are strongly dependent on the nature of the substrate and especially on the amount of substitution on the ir bond. Cyclization of the 6-heptenyl radical in the 6-exo mode is also very favorable. 

The reaction of endocyclic enamines with a,p-unsaturated ketones to afford cu-fused hydroindolones or hydroquinolones constitutes a complementary and highly useful annulation sequence developed extensively by Stevens and coworicers, see the reaction of (5) to give (6) in Scheme 7. ° The importance of stereoelectronic effects is highlighted in the reaction of (7) with methyl vinyl ketone, which provided only the alkylated product (8) and none of the expected ci5-hydroindolone (9)." The failure of intermediate (8) to cyclize in this case was attributed to nonbonded interactions between the aryl group and the side chain. This destabilizing allylic interaction s disfavors formation of conformer (10), the intermediate required for antiperiplanar addition of the enol nucleophile (Scheme 8). Cyclization via the alternate conformation would require a double boat-like transition state. 

Two of the factors that determine the reactivity of tethered ir-nucleophiles in Mannich-type cycliza-tions have been emphasized stereoelectronic effects and reaction medium effects. The stereoelectronics of orbital overlaps between the ir-nucleophile and the iminium electrophile are best evaluated by considerations such as antiperiplanar addition trajectories and Baldwin s rules for ring formation. The critical importance of the reaction medium has received serious attention only recently. However, it already appears clear that Tr-nucleophiles that would lead, upon cyclization, to relatively unstable carbocations can have their reactivity markedly increased by carrying out the cyclization in the presence of a nucleophilic solvent or additive which, by nucleophilic participation, can obviate the formation of high energy cyclic carbenium ion intermediates. 

The cyclization of the 5-hexenyl radical to cyclopentylmethyl (Entry 33) is a commonly observed reaction. The is 6 kcal/mol. The cyclization shows a preference for exo cyclization to a five-membered ring over endo cyclization to a six-membered ring/ even though it results in formation of a less stable primary radical. The cause for this preference has been traced to stereoelectronic effects. In order for a bonding interaction to occur, the radical center must interact with the it orbital of the alkene. According to MO calculations, the preferred direction of attack is from an angle of about 70° with respect to the plane of the double bond. ° ... 

The observed results agree with the calculated trend. Relative rates of cyclization are in the order 5-exo > 6-endo 6-exo > 1-endo. The relationship holds only for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity by a steric effect. The underlying conformational and stereoelectronic effects can be modified by both steric and electronic effects of substituents. For example, a 5-methoxycarbonyl substituent promotes the 6-endo mode of cylization by an electronic effect. The reactivity of the (3-carbon is enhanced by the substituent. 

In summary, the anti diol should cyclize faster than the syn when steric effects are the only controlling factor in the reaction. If both aUylic 1,3-strain and stereoelectronic effects are involved, then the syn diol should react more rapidly. 

The good yields obtained in the cyclization of appropriate radical precursors show that this is a convenient method for the synthesis of branched-chain cyclitols from carbohydrates. In addition, an interesting stereoelectronic effect in the cyclization of these acychc sugar derivatives is demonstrated the stabilizing effect of electron-attracting groups vicinal to carbon-centered radicals determines the preferred conformation in the transition state and the stereochemical outcome of the reaction. 

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