Highly substituted cyclohexane ring

B.M. Trost and co-workers conducted studies toward the total synthesis of saponaceolide B, an antitumor agent active against 60 human cancer cell lines. " One of the challenging structural features of this compound was the cis 2,4-disubstituted 1-methylene-3,3-dimethylcyclohexane ring. The key steps to construct this highly substituted cyclohexane ring were a diastereoselective Barbier reaction to install a vinyl bromide moiety followed by an intramolecular Heck cyclization reaction. 

Some natural products outside the carbohydrate field - particularly those with highly hydroxylated cyclohexane ring components - have been subject to synthetic studies which are dependent on the mercury-based rearrangement reaction the alkaloid (+)-lycoricidine (30) [12] and the cycloheptane-based (+)-calystegine 62(31) which stimulates growth of nitrogen-fixing Rhizobia [29] are examples, and compound 32 which offers novel access to the anthracyclinone components of anthracyclin anti-cancer compounds, has been produced by cycloaddition of a naphthalene-based o-xylylene to a 2,3-unsaturated hex-4-uloside followed by carbocyclization of the product by use of the mercuration procedure [30]. Studies on HMG-CoA reductase inhibitors like compactin have afforded the tetra-carbon-substituted 33 made from a hex-5-enopyranoside with deoxy-branch chains at C-2, C-3 and C-4 [31]. 

A barrier of about 12.8 kcal/mol at —15 °C has been determined for a symmetrical 1,2,3,4,5,6-hexachlorocyclohexane 2) while the highest barrier yet found is) for a substituted cyclohexane which retains a skeleton with six carbon atoms is that of the cis form of 1,2,3,4,5,6-hexamethylcyclohexane 10b. The barrier in this instance is 17.0 kcal/mol at 60 C It appears i 8) that the barrier to ring inversion in as-l,2-di- -butylcyclohexane is 16.3 kcal/mol, a high value that can be explained in terms of the f-butyl groups being eclipsed or nearly eclipsed in the transition state. The conformational processes taking place in this molecule are not thoroughly understood. )... 

A more detailed analysis of the chair-form (3C-ring yields some interesting results. The method followed is that used by Barton in assessing the relative stability of substituents at various positions in highly substituted derivatives of cyclohexane. 

In more highly substituted or strained systems the double bond in a vinylic position with respect to the cyclopropane ring can indeed hinder formation of the cycloproparene, Thus, tricyclo[5.2.0.0 " ]nona-l,4,6-triene (8) could not be prepared from dichlorotricyclononene 9 which contains the double bond endo to the cyclobutane ring, while the less strained isomer 7, with the double bond endo only to the cyclohexane ring, gave the product in low yield. ... 

One much-studied subject is the ring inversion of cyclohexane and polymethylcyclo-hexanes, as shown in Table 8. The subject has been reviewed " but, very generally, compounds with flattened chair conformations due to methyl-methyl 1,3-diaxial interactionshave lowered barriers. Simply substituted compounds where rotation about substituted bonds can take place in the boat-twist manifold of conformations have barriers similar to that of cyclohexane, while more highly substituted compounds, where rotation about substituted bonds must take place on the way to the transition state have markedly higher barriers than in cyclohexane. 

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