Cyclization thermodynamic considerations

Thermodynamic considerations during the formation of the six-membered rings indicate that only one of the rings is initially formed, resulting in a new Si-CHBr-Si bridging group. Depending on whether the Br atom is equatorial or axial, the second cyclization step will lead to a trans- or cis-1,1,3,3,5,7,7,9,9-nonamethyl-1,3,5,7,9-penta-sila-decaline. 

Spiroketalization. The synthesis of talaron ycin B (3) with four chiral centers by cyclization of an acyclic precursor presents stcrcot hcmical problems. A solution involves cyclization of a protected (3-hydroxy ketone witii only one chiral center. Because of thermodynamic considerations (i.e.. all substituents being equatorial and the anomcric effect), cyclization of 1 with HgCl, in CH,CN lollowcd by acetonation results in the desired product (2, 65% yield) with a stereoselectivity of —10 1. Final steps involve conversion of the hydroxymethyl group to ethyl by tosylation and displacement with lithium dimethylcupratc (80% yield) and hydrolysis of the acetonidc group. 

Two elements of the cyclization have yet to be addressed the isomerization of geranyl pyrophosphate to linalyl pyrophosphate (or the equivalent ion-pair) and the construction of bicyclic skeleta. Studies on the biosynthesis of linalool (61), and on the analogous nerolidyl system in the sesquiterpene series (52), have shown this allylic transposition to occur by a net suprafacial process, as expected. On the other hand, the chemical conversion of acyclic or monocyclic precursors to bicyclic monoterpenes, under relevant cationic cyclization conditions, has been rarely observed (47,62-65) and, thermodynamic considerations notwithstanding (66), bicyclizations remain poorly modeled. 

The point at which stereodifferentiation occurs in these reactions is not obvious (vide infra). If the asymmetric induction is the result of thermodynamic considerations or kinetically preferred cyclization, then an additional organizational consideration such as the exo-anomeric effect in 21.5 may be important. 

Three new centers of dissymmetry are formed on cyclization of a dialdehyde with nitroethane, hence — depending on the type of substitution of the dialdehyde — three, six or eight diastereomeric methyl-nitro-diols (2, R = CHs) can be expected a priori. In view of the analogy of this reaction to the dialdehyde-nitromethane-cyclization, which is endowed with a marked stereoselectivity, the thermodynamically more stable isomers should arise in considerable preponderance. The steric effects determining the orientation of the hydroxyl groups can reasonably be assumed to be the same, thus an e,c-arrangement (4) or (5) is to be expected for the major products. 

When the cyclization substrate (A Scheme 3) contains stereogenic centers, and the formation of the C—Z bond generates a new stereogenic center, two diastereomers of the cyclization product (H) can be formed (stereospecific anti addition assumed). The factors which lead to high stereoselectivity in this process are of considerable importance and have been the subject of numerous studies in recent years. This reaction mechanism shows that all pathways leading to cyclic products are potentially reversible thus, the ratios of products in these reactions may be the result of thermodynamic rather than kinetic control. Unfortunately, many studies have not determined which type of control was operating under the reaction conditions used. 

Generation of a radical in a molecule that contains a site of unsaturation presents an opportunity for (yclization. These types of radical cyclizations have been developed into very useful synthetic reactions. The synthetic utility of these cyclizations is enhanced by the abhity to predict the regiochemistry of cyclization by applying the Baldwin rules. The Baldwin rules cover the formation of three- to seven-membered rings by various reactions and are based on consideration of both kinetic and thermodynamic factors. (See Beckwith, A. L. J. Easton, D. J. Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482-483, and Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734-736.)... 

Also formed in considerable quantities are C9-C12 polycyclic hydrocarbons, particularly Tetralins and indanes. The formation of these bi-cyclic species is surprising. Under the high hydrogen pressures employed in the hydrocracking reaction, dehydrocyclization is not favored thermodynamically. For example, in Table V, equilibrium calculations indicate that the cyclization of n-butylbenzene to form Tetralin and hydrogen is unfavorable. 

Although the mechanism of the base-induced formation of calixarenes has been studied in some detail, the reaction pathways remain uncertain. The most intuitively reasonable proposal is that the immediate precursor of any particular calixarene, regardless of size, is the linear oligomer carrying the requisite number of aryl residues. Another proposal, however, postulates that calix[8]arenes, for example, arise from intermolecularly hydrogen-bonded dimers (hemicalixarenes) formed from a pair of crescent-shaped, intramolecularly hydrogen-bonded linear tetramers. Calix[4]arenes, formed under considerably more strenuous conditions, have been postulated to be the result not of direct cyclization of the linear tetramer but of reversion of the calix[8]arene. The cyclic octamer is viewed as the product of kinetic control, and the cyclic tetramer is viewed as the product of thermodynamic control. The particular efficacy of KOH and RbOH for the formation of calix[6]arenes suggests that the hexamer is the product of template control. 

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