Cyclohexane derivatives intramolecular cyclization

The intramolecular Michael addition of acyclic systems is often hampered by competing reactions, i.e., aldol condensations. With the proper choice of Michael donor and acceptor, the intramolecular addition provides a route to tram-substituted cyclopentanones, and cyclopentane and cyclohexane derivatives. Representative examples are the cyclizations of /3-oxo ester substituted enones and a,/J-unsaturated esters. 

Furthermore, intramolecular cyclization of acyclic chiral imines, in which the imine and the enone groups are separated by alkyl chains, yield optically active cyclohexane and cyclopentane derivatives. /ra .v-l,2-Disubstitutcd carbocyclic compounds are exclusively or predominantly formed with diastereomeric ratios in the range 80 20 100 0, strongly dependent on the conditions used to induce cyclization, i.e. heat, pressure or Lewis acid (MgBr2) catalysis227. 

Allenylsilanes undergo intramolecular additions to appropriately positioned aldehydes, imines, conjugated esters and alkenes to afford various alkynylcyclopentane and cyclohexane derivatives (Eqs. 9.66-9.70) [66]. The reactions are promoted by SnCl4 or by thermolysis. The stereochemistry of these cyclization reactions is consistent with a concerted sigmatropic process as illustrated in Scheme 9.17. 

Lanthanide-catalyzed enyne cyclization/hydrosilylation was also applied to the synthesis of silylated alkylidene cyclohexane derivatives. For example, reaction of the 3-silyloxy-l,7-enyne 17 with methylphenylsilane catalyzed by Gp 2YMe(THF) at 50°G for 8h gave 18 in quantitative yield as a 4 1 mixture of trans cis isomers (Equation (11)). Employment of methylphenylsilane in place of phenylsilane was required to inhibit silylation of the initially formed yttrium alkenyl complex, prior to intramolecular carbometallation (see Scheme 8). 

Further reactions that are highly suited to the synthesis of cyclohexane derivatives, such as cycloaddition processes, 1,3-dipolar additions, and Diels-Alder cyclizations, have been used extensively. In the latter set, carbohydrate-based dienes or dienophiles have been employed and, in addition, intramolecular processes have provided highly suitable means of synthesizing complex polycyclic systems. 

Carbocyclic compounds can be formed by the nucleophilic intramolecular capture of a seleniranium intermediate of an olefinic bond. The carbonium ion which is formed as intermediate can react with another nucleophile or with the solvent. The first examples of these carbocyclization reactions were observed with dienes. Clive [105] reported that the reaction of the diene 203 with phenyl-selenyl chloride in acetic acid afforded the intermediate 204 which reacted with the solvent to give the bicyclic compound 205 (Scheme 31). Carbocyclization reactions were efficiently promoted by phenylselenyl iodide produced by diphenyl diselenide and iodine. As indicated in Scheme 31,Toshimitsu reported that the reaction of 1,5-hexadiene 206, in acetonitrile and water, afforded the acetamido cyclohexane derivative 209, derived from the cyclization of the seleniranium intermediate 207 followed by the reaction of the carbocation 208 with acetonitrile [106]. In several cases, carbocyclization reactions can be more conveniently effected by independently generating the seleniranium intermediates. A simple procedure consists of the reaction of trifluoromethane-sulfonic acid with j9-hydroxyselenides, which can be easily obtained from the... 

Intramolecular cross-coupling of allyl acetate and allylstaimane in 361 via bis-rr-allylpalladium was carried out using Pd2(dba)3 and PPI13 to give the cyclohexane derivative 362 as a single regio- and stereoisomer. The presence of LiCl and H2O is essential. The cyclized product 362 was converted to epi-elemol [137]. 

Intramolecular Heck reactions have frequently been used for the synthesis of cyclopen-tanoid structures. In nearly all cases reported so far, the ring closure occurs as a 5-exo process (for an exception, see Table 4, entry 6), for which 2-halo-l,6-heptadienes and related compounds are the appropriate starting materials. In some cases, however, these substrates cyclize by a 6-endo mode to give cyclohexane derivatives (see Sect. IV.2.2.1.B.V). 

Haseltine has described an enantioselective formal synthesis of pancratistatin in which the stereocontrol is driven by the aeetonide of conduritol A. The enantioselective hydrolysis (desymmetrization) of this compound was achieved with a lipase, and the aryl-cyclohexane ring bond was formed through an intramolecular cyclization of the activated benzene ring with an allylic triflate (278). Plumet reported a total synthesis of (-l-)-7-deoxypaneratistatin based on the conjugate addition of an aryl-lithium species to a bicyclic conjugated sulfone derived from furan, which enabled the efficient installation of the six stereogenic centers of the cyclohexane ring (279) (Scheme 13). 

A newer possibility for the intramolecular cyclization of the phosphorane/ylide was demonstrated by the final outcome of the reaction of TPP, DAAD and cyclohexane-l,3-diones after microwave irradiation of the intermediate. Electron-poor 2H-chromenes were the products of the reactions (Scheme 111). Interestingly, hydroquinone acted as a C-nucleophile in reaction with the TPP-DAAD adduct to result in the formation of a 3-aryl phosphorane that provided another 2H-chromene derivative on K2HPO4 catalyzed intramolecular ring closure (Scheme 112). ... 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

Fleet s group have examined the utility of carbohydrate-derived 2-azido- and 2-iodo-lactones for synthesis of novel, highly functionalized cyclopentanes and cyclohexanes. The azido lactone 11 undergoes KF-catalysed intramolecular aldol reaction to give 12 (major) and 13 (minor). The minor isomer arises through epimerization at C5 prior to the aldol cyclization. Lactone hydrolysis of the major isomer leads to 15. Similar hydrolysis of the minor isomer yields 16, and thus epimerization via retro-aldol must precede lactone ring opening via the intermediacy of 14. 

The substitution pattern in the enolate is crucial for the ring size of the cyclization product. Upon reaction with carbene complex 58 /3-substituted lithium enolates 59a H) lead to densely substituted cyclopentanols 60 suggesting a [2-i-2-i-l]cycloaddition pathway. /3-Unsubstituted lithium enolates 59b (R =H), however, form 1,3,3,5-tetrasubstituted cyclohexane-l,4-diols 61 that indicates a [2-I-2-I-1-I-1] sequence [41]. The branching point in the mechanism seems to be intermediate B formed upon addition of the allyl magnesium bromide to penta-carbonylchromate intermediate A. Intermediate B formed from /3-substituted enolates 59a is supposed to undergo an intramolecular carbometallation reaction to give cyclopentanol derivative 60. In contrast, intermediate B originating from... 

---