Six-membered carbocyclic systems

Five-Membered Heterocycles Fused with Six-Membered Carbocyclic Systems... 

Generally, oxepins have a tendency to contract to a six-membered carbocycle when treated with acid. The driving force is the aromaticity of the phenol formed. However, when the less stable cyclohexa-2,5-diene-1,4-diol with an appropriate substitution pattern is treated with acid, the oxepin system is obtained. The treatment of cyclohexadienediols that are substituted with tert-butyl groups in the 2- and 6-positions and aryl at Cl and C4 with trifluoroacetic acid produces oxepins 1 with elimination of water.186 187 This reaction, however, is restricted to certain aryl substituents with at least some electron-donating effect. Generally, cyclohexa-2,4-dienone derivatives 2 are formed.187,188... 

Intramolecular arylation of G-H bonds gives cyclic aromatic compounds. In this intramolecular arylation, the carbon-palladium cr-bond is first formed by the oxidative addition of Pd(0) species and then the resulting electrophilic Pd(n) species undergoes the intramolecular G-H bond activation leading to the formation of the palladacycle, which finally affords the cyclic aromatic compounds via reductive elimination.87 For example, the fluoroanthene derivative is formed by the palladium-catalyzed reaction of the binaphthyl triflate, as shown in Scheme 8.88 This type of intramolecular arylation is applied to the construction of five- and six-membered carbocyclic and heterocyclic systems.89 89 89 ... 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Transition metal catalyzed intermolecular carbocyclization has been used in the construction of six-membered ring systems (10, 352) and provides a powerful approach to the construction of complex polycyclic systems. The rhodium-catalyzed intermolecular [2 - - 2 - - 2] carbocychzation of heteroatom-tethered 1,6-enynes with symmetrical and unsymmetrical alkynes affords the corresponding bicyclohexadienes in a highly efficient and regioselective... 

Table 4.1. Representative torsional sequences generated by CSD Software System for six-membered carbocycles...

One impediment to straightforward comparison is the lack of solid-phase enthalpies of formation for most low molecular weight molecules. Examination of the few examples for which there are both solid- and liquid-phase values shows, however, that the liquid- and solid-phase enthalpies of reaction do not vary too much, at least within the uncertainties of the steroid combustion measurements. We are additionally hampered by not having available enthalpies of formation for those small molecules which most resemble the steroid substructure. The prototype small molecules required for the analysis are primarily those of substituted five- or six-membered carbocyclic rings. Although the functional groups on the available prototypes and the steroids are identical, stereochemical aspects (such as axial vs. equatorial substituent positions) and their consequent interactions are different due to the differences in conformational flexibility of the monocyclic and polycyclic systems. The prototype molecules and their liquid-phase enthalpies of formation are listed in Table 3. 

Six-membered carbocycles often play the role of starting materials in the construction of the oxepin ring system however, for many syntheses rather stable intermediates of a different nature are known, for example those with fused six-membered carbocycles and three-membered oxygen heterocycles. The use of such systems is described in the next section. Here, several other transformations are mentioned. Some of them also may have heterocycles as intermediates but the latter are unstable under normal conditions or their structures were not studied in detail. 

Torand 1 consists of alternating, angularly fused pyridine and six-membered carbocyclic rings. When this molecular architecture is applied to open-ended systems, the ends overlap when a total of 12 rings is reached, or when a benzylidene group is introduced as a steric barrier in an... 

In view of screening the structural and functional properties of deox-yoligonucleotides incorporating 3, 5 -bicyclic 2-deoxy nucleosidic building blocks, Leumann developed a synthetic sequence to prepare the thymine-based phosphoramidite (11) in which the bicyclic system incorporates a 5-membered ring ribose adjacent to a six-membered carbocyclic ring. In this isomer, the cyclohexyl ring adopted a chair conformation with the 5 -substituent in an axial position while the furanoside moiety adopted a... 

When investigating the first syntheses of five-membered carbocycles (Section 5.2), Grigg et al. [8, 9] at the same time also revealed Mizoroki-Heck cyclizations forming the structurally related six-membered ring systems. Cyclization of 2-bromo-l,7-octadiene 79 gave 80 with a 4 1 ratio of exocyclic to endocyclic double-bond isomers in 86% yield, and without any 7-endo-ttig product (79 80, Scheme 5.17). Reaction of 81 was less successful, only providing 66% yield and a 2.5 1 ratio of double-bond isomers (81 82). Both products 80 and 82 were later successfully employed in Diels-Alder... 

Dipolar cycloaddUions. Interest in 1,3-dipolar cycloadditions increased dramatically during the past 20 years, largely because of the pioneering studies of Huisgen [7, 2] The versatility of this class of pericychc reactions in the synthesis of five-membered-ring heterocyclic compounds is comparable with that of the Diels-Alder reaction in the synthesis of six-membered-ring carbocyclic systems (equation 1)... 

A variety of functionalities, tether lengths, and alkene substitution patterns were tolerated (Equation (35)).52,53 Of particular significance is the synthesis of a-methylene-y-butyrolactone 55, as only Zhang had reported successfully using Alder-ene chemistry to gain access to this novel system (see Section 10.12.4.3). The reaction was sensitive to the length of the tether, since there was a marked decrease in yield for the formation of the six- and seven-membered carbocycles (53 and 54, respectively) compared to the five-membered case 52. 

Tricyclic Systems Central Carbocyclic Ring with Fused Five- and Six-membered Rings... 

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