Cyclohexane derivatives, synthesis

Several substituted cyclohexane derivatives may also be obtained by the reduction of a benzenoid precursor. Partial reduction of resorcinol, for example, and subsequent methyla-tion yields 2-methylcyclohexane-I,3-dione, which is frequently used in steroid synthesis (M.S. Newman, 1960 see also p. 71f.), From lithium-ammonia reduction of alkoxybenzenes l-alkoxy-l,4-cyclohexadienes are obtained (E.J. Corey, 1968 D). 

The fusion of a benzene ring to pyrazine results in a considerable increase in the resistance to reduction and it is usually difficult to reduce quinoxalines beyond the tetrahydroquinoxa-line state (91). Two possible dihydroquinoxalines, viz. the 1,2- (92) and the 1,4- (93), are known, and 1,4-dihydroquinoxaline appears to be appreciably more stable than 1,4-dihydropyrazine (63JOC2488). Electrochemical reduction appears to follow a course anzdogous to the reduction of pyrazine, giving the 1,4-dihydro derivative which isomerizes to the 1,2- or 3,4-dihydroquinoxaline before subsequent reduction to 1,2,3,4-tetra-hydroquinoxaline (91). Quinoxaline itself is reduced directly to (91) with LiAlH4 and direct synthesis of (91) is also possible. Tetrahydroquinoxalines in which the benzenoid ring is reduced are well known but these are usually prepared from cyclohexane derivatives (Scheme 30). 

In considering the retrosynthetic analysis of juvabione, two factors draw special attention to the bond between C(4) and C(7). First, this bond establishes the stereochemistry of the molecule. The C(4) and C(7) carbons are stereogenic centers and their relative configuration determines the diastereomeric structure. In a stereocontrolled synthesis, it is necessary to establish the desired stereochemistry at C(4) and C(7). The C(4)-C(7) bond also connects the side chain to the cyclohexene ring. As a cyclohexane derivative is a logical candidate for one key intermediate, the C(4)-C(7) bond is a potential bond disconnection. 

Two types of synthesis of this skeleton are reported depending on the positions of the sulfur introduced either at the bridge or at the bridgehead the former has been studied by Stetter s research group189-191 and the latter by Klages and Schmidt192 starting from bicyclo[3.3.1]nonane derivatives and cyclohexane derivatives, respectively. 

Recently, a synthesis of tetrodotoxin from D-glucose was described (Scheme 36). After a Michael addition of the lithium salt of bis(phenylthio)-methane to the nitroolefin 116, the major component (117b) of the resulting epimeric mixture 117a + 117b was subjected to a reaction sequence that involved an intramolecular nitroaldol reaction, to give the complex nitro cyclohexane derivative 118. 

A more subtle example of identical functional groups with different steric enviroment is found in the intermediate H which Corey [8] uses in the synthesis of fumagillin (13). The two identical secondary hydroxyl groups in the cyclohexane derivative H can be differentiated by using a bulky reagent since the axially disposed hydroxyl group is less accesible than the one which is equatorially disposed and can be chemoselectively methylated (12) in the presence of sodium rert-amylate (Scheme 12.2). 

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). 

Review coverage of the chemistry involved in the synthesis of enantiomerically pure natural products from carbohydrates is now extensive [2]. It is relevant to note that whereas, in 1983, the numbers of carbocyclic target compounds were relatively limited, as outlined in an authoritative monograph written by Hanessian [3], a comprehensive review of the methods available for making cyclopentane and cyclohexane derivatives from carbohydrates published 10 years later [4] cited 338 references, more than 80% of which were dated 1980 or later. The attention afforded the synthesis of carbocyclic products also features prominently iu a 1993 review of the use of sugars in the preparation of enantiomerically pure natural products [2],... 

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. 

NEN1TZESCIJ INDOLE SYNTHESIS. Hydrogenanve acylation of cycloolefins with acid chlorides in the presence of aluminum chloride with five- and six-membered rings, no change in ring size occurs, but with seven-membered rings, rearrangement takes place with formation of a cyclohexane derivative. 

Two other examples of the synthesis of bicyclic compounds whose skeleton consists only of carbon atoms are shown in Sch. 24, each of them is instructive in its own way. Upon irradiation of the cyclohexane derivative 65, not the expected product from a hydrogen abstraction from the allylic position, but the bicyclo[3.3.1]heptane 67 was obtained by cyclization of the less stable biradical 66-B [57]. The reason for this is the exclusive hydrogen back-transfer of the more stable biradical and it underlines the importance of this process in regioselectivity phenomena of the Norrish-Yang reaction. 

Another class of substrates investigated in this reaction are the cyclohexane derivatives 162. The stereoselective oxidation of the selenide followed by an elimination provided a novel useful method for the synthesis of chiral cyclohexylidenemethyl ketones 163 (Scheme 46).289... 

Further investigations on the synthesis of ring system 8 started from the 1,3,5-trisila-cyclohexane derivatives. A reaction sequence is proposed in Eq. (25). 

Desmaele and co-workers have developed a sequence involving attack onto a jr-allylPd complex followed by an intramolecular Michael addition leading to functionalized cyclohexane derivatives [95]. This useful transformation was used as a key step in the total synthesis of racemic dihydroery-thramine 110, a biologically active compound of the Erythrina alkaloids family [96] (Scheme 42). 

Considerable work was done to induce chirality via chiral auxiliaries. Reac tions with aromatic a-ketoesters like phenylglyoxylates 21 and electron-rich al kenes like dioxoles 22 and furan 23 were particularly efficient (Scheme 6). Yield up to 99% and diastereoselectivities higher than 96% have been observed whet 8-phenylmenthol 21a or 2-r-butylcyclohexanol 21b were used as chiral auxiliarie [14-18]. It should be noted that only the exoisomers 24 and 25 were obtained from the reaction of dioxoles 22. Furthermore, the reaction with furan 23 wa regioselective. 24 were suitable intermediates in the synthesis of rare carbohydrate derivatives like branched chain sugars [16], Other heterocyclic compounds liki oxazole 28 [19] and imidazole 29 [20] derivatives as well as acyclic alkenes 3fl 31, and 32 [14,15,21,22] were used as olefinic partners. Numerous cyclohexane derived alcohols [18,21-24] and carbohydrate derivatives [25] were used as chiri... 

Cesium fluoride promoted oxirane preparation starting from bis(sulfonyl fluorides) has been reported. In general, epoxide formation predominates over furan synthesis. Investigations of cyclohexane derivatives 1 show trans elimination to form 2 this still holds true when the syn chlorine is substituted by a bromine.Epoxide 4 is a versatile, general, enan-liomerically pure building block that is best synthesized by substitution of the mesylate 3. ... 

Ring closure to cyclobutanes and cyclopentane-s The synthesis of cyclo-propanones by elimination of lithium thiophenoxicMe with this base has been extended to similar syntheses of functionalized cyclob tanes and cyclopentanes, as shown in equations (I) and (II), When extended to synthesis of a cyclohexane derivative, this method resulted in a very low yield. One possible mechanism is formation of a dianion followed by loss of thiophenoxid e ion to give a carbene-anion, which cyclizes with loss of the second thiophenoxide ion. 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

Steric control of the mechanism has been clearly demonstrated by the reduction of 3-tosyl-1 -cyclohexane derivatives (Scheme 5). This control has been deployed in the synthesis of coenzyme Qio. The wider use of these reductions has been studied and very high stereoselectivity is observed for hydrogenolysis of famesyl derivatives, —Cl, —OPh, —OSiMe2Bu , —SPh, —SOMe, —S02Me and N(=[Pg.961]

This reaction has been utilized in the context of natural product synthesis. A recent example is the synthesis of colletodiol by Keck, shown in equation (45). In this example, no problems were encountoed with epimerization or ester cleavage. The desireid ( )-ester (182) was synttesized in 80% yield. Two examples are outlined (in equations 46 and 47) in which epimerization was a substantial problem with sodium or potassium salts, while the LiCl/amine method effectively suppressed this side reaction. When the phosphonate was allowed to react with the cyclohexanal derivative (183), the sodium salt gave epi-merized material. Use of LiCl and diisopropylethylamine gave an 88% yield of alkene (184), free of epimer (equation 46). In the synthesis of norsecurinine, Heathcock found that the phosphonate anion... 

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