Cross-selective cyclization

As mentioned earlier, a random and statistical cyclization with two different and regio-defined Ti-compounds would produce a synthetically unattractive mixture of ten different zirconacycles. In reality, however, there are a few factors that can be exploited to produce a single desired zirconacycle. A systematic investigation has revealed that there are several discrete types offive-membered zirconacycle formation, as shown in Scheme 1.53 [88,89] (Generalization 20). In the Type I reaction, the cross-selective cyclization is kinetically favored. Presumably, little ethylene is displaced during the reaction. Type I reactions cannot be readily observed with ZrCp2 complexes with 1-butene. In contrast, Type II cyclization must be thermodynamically controlled, as 1-butene is readily displaced by a number of better Ti-ligands. It is predicted, however, that the cross-combination of the two Ti-com-... 

Type I Kinetically favored cross-selective cyclization... 

Type IV Cross-selective cyclization (the original alkene is released)... 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

In this analysis, the activation barrier for both C1-C6 and C1-C5 cyclizations of enediyne radical-anions can be described as the avoided crossing between the out-of-plane and in-plane MOs (configurations). One-electron reduction populates the out-of-plane LUMO of the enediyne moiety. At the TS (the crossing), the electron is transferred between the orthogonal re-systems to the new (in-plane) LUMO. This effect leads to the accelerated cyclization of radical-anions of benzannelated enediynes, a large sensitivity of this reaction to re-conjugative effects of remote substituents and the fact that this selectivity is inverse compared to that of the Bergman cyclization. Similar electronic effects should apply to the other reductive cyclization reactions that were mentioned in the introduction. 

The 1 1 mixture of 24 and 20 (or 25 and 20) in aqueous media (0.5 mM each) was subjected to the same conditions used for forming 19-20. MALDl results showed that neither 24 nor 25 selectively cross-linked with 20. In sharp contrast to the exclusive formation of 19-20 or 21-22, multiple products were detected from the 1 1 mixture of 24 and 20, among which 24, formed from the self-cyclization of 24, and 20-20 from the homodimerization of 20, represented the major products (Fig. 9.16b). Product 24-20, from the cross-linking of 24 and 20, only appeared as a minor peak. Similarly, when mixed together, 25 and 20 could not be cross-linked exclusively into 25-20 (Fig. 9.16c). The observed distribution of products, that is, the self-cyclized 25, heterodimer 25-20, and homodimer 20-20, can be regarded as being a statistical one. 

As one partial solution, the selective cross-cyclization is possible by stepwise reaction of Cp2Zr (113), generated from zirconocene dichloride and BuLi, with three different symmetric internal alkynes in one pot. The method is based on the conversion of zirconacyclopentadiene 114 to the benzene derivative 115 by the treatment with dimethyl acetylenedicarboxylate and CuCl [52],... 

Cleavage via alkene metathesis is particularly useful because clean and selective scissoring of molecules is possible. Cleavage by metathesis can be performed either by cyclization during cleavage [95-101] (ring closing metathesis, RCM), inter-molecular metathesis [101] (cross metathesis), or intramolecular metathesis [95] (Scheme 6.1.23). 

Grigg et al. also introduced another Heck-type reaction. 2,6-Dibromo-hepta-1,6-dienes 80 cyclize to the same products 83 (n = 5) as do 2-bromo-1,6-dienes 78 (n = 5) when treated with the usual precatalyst mixture, yet containing a stoichiometric amount of triphenylphosphine [63,64], In this case, palladium dibromide rather than hydridopalladium bromide is eliminated in the final step of the cross-coupling reaction, and the palladium(II) salt is reduced by the phosphine to regenerate the reactive palladium(O) species. Completely selective exo-trig cyclizations occur in these examples, however, the respective cyclohexane derivatives with n = 6 are formed in poor yields. Additionally, it is sometimes difficult to separate the product from the phosphine oxide after aqueous work-up. This latter difficulty was circum-... 

Recently, studies were carried out to explain the exo/endo selectivity the Patemo-Buchi reaction [30]. These studies were carried out mostly achiral or racemic substrates. Excited monocyclic aromatic aldehydes 33 re in their 3n,/rr state with cyclic enol ether derivatives like 2,3-dihydrofuran (Scheme 8) [31]. In these cases, the sterically disfavored endo isomer 35a obtained as major product. This result was explained by the fate of the trip biradical intermediate G. In order to favor cyclization to the oxetanes 35a,b, radical p-orbitals have to approach in a perpendicular fashion to increase spin-orbit coupling needed for the triplet to singlet intersystem crossing [32]. sterically most favored arrangement of this intermediate is depicted as G. encumbering Ar substituent is orientated upside and anti to the trihydrofur moiety. Cyclization from this conformation yields the major isomer 35a. 

The formal total synthesis of the selective muscarinic receptor antagonist (+)-himbacine was accomplished by M.S. Sherburn and co-workers using an intramoiecuiar Dieis-Aider reaction, a Stiiie cross-coupling, and a 6-exo-trig acyi radical cyclization as the key steps.In order to prepare the selenoate ester precursor for the radical cyclization step, the aldehyde-enyne substrate was converted to the carboxylic acid via the Pinnick oxidation without affecting the delicate enyne moiety. 

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