Cyclohexanes trisubstituted

A A trisubstituted cyclohexane with three substituents—red, yellow, and blue—undergoes a ring-flip to its alternative chair conformation. Identify each substituent as axial or equatorial, and show the positions occupied bv the three substituents in the ring-flipped form. 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

It was an interesting idea to create the giant tube-like structures 46 capped with a Lewis acid center by the homologation reaction of 42 with dimethylsulfoxonium methylide and their deboronation to the three-armed star polymethylene polymers 47 incorporating a m, r-l,3,5-trisubstituted cyclohexane core (Scheme 12) <2003JA12179, 20010L3063>. 

When an a-chloroaldehyde or an a-chloroketone is condensed with a /3-ketoester, in the presence of aqueous base, a furan is produced bearing an ester substituent at the /3-position. It is thought that the reaction is of the aldol type intermediate dihydrofurans (256) have been isolated in certain cases (Scheme 70) (74BSF519). The condensation of ethyl bromopyru-vate and sodium oxaloacetate follows a similar mechanism (54JOC1671). The one-pot synthesis of 2,4,5-trisubstituted furans (257) from ketones and ethyl 3,4-dibromo-2-butenoate is a useful addition to a well known route (80S52). The analogous reaction of cyclic /3-diketones, i.e. cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-l,3-dione, results in the formation of the condensed furans (258) and (259). These reactions are preformed either in ethanol with sodium ethoxide or in DMF with potassium carbonate. 

Several cycloaddition reactions of 2,5-dihydrothiophene derivatives have been reported. Compounds possessing an enamine system undergo [2 + 2] cycloaddition with acetylene-dicarboxylic ester (Scheme 215) (77AHC(2l)253). Diels-Alder addition of the 2,5-di-hydrothiophene-3-carboxylic ester (557) with butadiene, followed by desulfurization, leads to the trisubstituted cyclohexane (558) (B-74MI31404). 

Using the CH multiplicities as obtained from two DEPT experiments (Fig. 2.59(d, e)), the CH skeleton can be derived in the next step, so that the compound turns out to be a 1,2,4-trisubstituted cyclohexane of the menthane type ... 

Citronellal, an aldehyde with a trisubstituted double bond, was hydrogenated to citronellol over a ruthenium catalyst poisoned with lead acetate in 90-100% yields (eq. 5.22)46 or over chromium-promoted Raney Ni in 94% yield in methanol at 75°C and about 0.31 MPa H2.47 Court et al. studied the selective hydrogenation of citral (1, eq. 5.24) to citronellol over unsupported Nij. o catalysts, prepared by reduction of mixtures of metal iodides with naphthalene-sodium as reducing agent, in cyclohexane and in 2-propanol at 80°C and 1.0 MPa H2.48 Higher yields of citronellol were obtained in 2-propanol than in cyclohexane, primarily via citronellal as the predominant intermediate. The yields of citronellol for the overall hydrogenation in 2-propanol over Mo-promoted catalysts were Mo0 03 96%, Mo0 06 98%, and Mo012 96%. 

Actually, repeating the tandem addition of Scheme 38 with the (R) enantiomer of Davies amide affords total control on the three created asymmetric centers, and provides the trisubstituted cyclohexane in 72% yield and as a single (1R, 2R, 6R) enantiomer (i.e. absolute configurations reported in Scheme 38)173,174. 

The polyhomologation of 1-boraadamantane THF by dimethylsulfoxonium methylide formed a series of new macrocyclic trialkylboranes 24, oxidation generated a three-armed star polymethylenic polymer, based on a c/s,m-l,3,5-trisubstituted cyclohexane core <03JA12179>. 

Figure 1.16 Rigid tripodai Ligands based on 1,3,5-trisubstituted cyclohexane (Left) and 1,3,9-triazacycLononane (right)...

The H NMR spectra of quinoxaline and its monosubstituted derivatives have been reported <67JCS(B)l24l>, and those of di- and trisubstituted quinoxalines have also been measured <68JCS(C)1274>. The spectra of a number of phenazine derivatives have been reported <66CPB419>. The H NMR solvent shifts in acetone, carbon tetrachloride and cyclohexane have been measured for the parent pyrazine, quinoxaline and phenazine <86BCJ1650>. For the last two compounds the NMR spectra of both for the neutral and the acidic species are reported <91BCJ2668>. 

Rapamycin (sirolimus 2), isolated from Streptomyces hygroscopicus, is a highly functionalized 31-membered macrolide that exhibits potent antibiotic, cytotoxic, and immunosuppressive activity. FK506 (1) and rapamycin (2) are the structurally related macrolides (Fig. 1) thus, rapamycin possesses an a,p-diketoamide hemi-ketal system, a pipecolic acid moiety, 1,2,4-trisubstituted cyclohexane, and trisub-stituted tetrahydropyran rings, which are similar to those of FK506. In addition to these units, rapamycin (2) includes an ( , , )-triene moiety, two stereochemically complex aldol units, and 15 chiral centers beyond those found in FK506. 

One of the analogues of FK506, rapamycin (sirolimus) produced by Strepto-myces hygroscopicus, is a 31-membered macrocyclic lactone that contains a masked a- and P-diketo amide L-pipecolic acid residue similar to that found in FK506, and a unique triene segment including a distinctive shikimic acid-derived trisubstituted cyclohexane moiety (Fig. 1) [19]. It was originally isolated as an... 

To maintain the spatial orientation of the pharmacophore elements while not extending beyond the geometric boundaries of THR itself, researchers" at Hoffmann-La Roche selected the 1,3,5-ds-trisubstituted cyclohexane framework to replace the peptide backbone. This structure was then substituted with the appropriate recognition features to yield Ro 24-9975 (87). Superposition of... 

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