Bicyclo octan 2- methyl

Cobalt (4-Ethyl-2,6,7-trioxa-l-phospha-bicyclo[2.2.2]octan)-methyl-tricarbonyl- XIII/9b, 18... 

Cyclopropan-octan Methyl -8,8-dimethy 1-4-metho xycarbo ny 1-... 

The squalestatins, e.g. 6.28, also known as the zaragozic adds, have attracted considerable interest as inhibitors of squalene synthase and hence of cholesterol biosynthesis and lipid deposition in the circulatory system. They are also inhibitors of farnesyl protein transferase and thus they may have other potentially useful biological applications. They are formed by Phoma spedes and also by Setosphaeria khartoumensis. The squalestatins are characterized by a dioxabicyclo-octane core bearing three carboxyl groups and two polyketide chains, one of which is attached as an ester. The biosynthetic incorporation of succinic acid into part of the bicyclo-octane, together with its oxygenation pattern, indicate that it may be derived via oxaloacetic acid. Both the polyketide chains have several pendant methyl groups attached to them, which arise from methionine, whilst benzoic add ads as a starter unit for one of the chains. These complex structures are thus the summation of several biosynthetic pathways. 

Hajos, Z. Parrish, D. R. (1974) Synthesis and conversion of 2-methyl-2-(3-oxobutyl)-l,3-cyclopentanedione to the isomeric racemic ketols of the [3.2.1] bicyclo octane and of the perhydroindan series, / Org. Chem., 39,1612-15. 

When formation of either the five- or six-membered ring was possible for N-chloroamine 37, only the five-membered ring was conducive under the Hofmann-Ldffler-Freytag reaction conditions, forming exclusively 6-ethyl-6-aza-bicyclo[3.2.1]-octane (38). No 2-ethyl-2-aza-bicyclo[2.2.2]-octane (39) was observed. On the other hand, 2-methyl-2-aza-bicyclo[2,2.2]octan-6-one (41) was installed by UV irradiation of a solution of A -chloroamine 40 in TFA. Ironically, when the ketone functionality on 40 was protected as its ethylene ketal group, the resultant steric interactions completely prohibited the classic Hofmann-Loffler-Freytag reaction. 

N H3c —COO H3C-COO It 0 K[BH4] 3-Hydroxy-8-methyl-trans-6,7-diacetoxy-8-aza-bicyclo[3.2.1]octan 84 3... 

Zu einer Losung von 0,6 g (16 mMol) Natriumboranat in 30 ml Methanol und 6 ml Wasser tropft man eine Losung von 0,7 g (2,3 mMol)4-Tosyloxy-2-oxo-l-methyl-bicyclo[2.2.2]octan in 90ml Methanol, riihrt 24 Stdn. bei 20°, gibt 300 ml ges. Calciumchlorid-Losung hinzu, schiittelt mit Petrolather aus, trocknet iiber Natriumsulfat und destilliert Ausbeute 0,3 g (95% d.Th.) Kpi, 108°. 

Mehta et al. also studied the facial selectivities of 5,6-exo,eji o-disubstituted bicyclo[2.2.2]octan-2-ones 18 [75, 78]. These systems are related to the 2,3-exo,ex( -disubstituted 7-norbomanones 14, but differ in the direction of the carbonyl n face. Hydride reduction of 5,6-exo,ex( -disubstituted bicyclo[2.2.2] octan-2-ones (18) with NaBH and DIBAL-H and methylation with MeLi were smdied [75, 78],... 

Scheme 13.17 depicts a synthesis based on enantioselective reduction of bicyclo[2.2.2]octane-2,6-dione by Baker s yeast.21 This is an example of desym-metrization (see Part A, Topic 2.2). The unreduced carbonyl group was converted to an alkene by the Shapiro reaction. The alcohol was then reoxidized to a ketone. The enantiomerically pure intermediate was converted to the lactone by Baeyer-Villiger oxidation and an allylic rearrangement. The methyl group was introduced stereoselec-tively from the exo face of the bicyclic lactone by an enolate alkylation in Step C-l. 

Twofold Michael additions have been utilized by the groups of Spitzner [2] and Hagiwara [3] to construct substituted bicyclo[2.2.2]octane frameworks. In Hagiwara s approach towards valeriananoid A (2-6) [4], treatment of trimethylsily-enol ether 2-2, prepared from the corresponding oxophorone 2-1, and methyl acrylate (2-3) with diethylaluminum chloride at room temperature (r.t.) afforded the bicyclic compound 2-4 (Scheme 2.2). Its subsequent acetalization allowed the selective protection of the less-hindered ketone moiety to provide 2-5, which could be further transformed into valeriananoid A (2-6). 

Figure 21. Absorption spectra of (a) S-D dyads (3a 3b = 1 1), (b) 1-methyl-4-(2-naphthyl)bicyclo[2.2.2]octane (2-S), and (c) butylferrocene (Bu-Fc) in cyclohexane.

The results obtained in combination with the data on the transformations of cations 9-11, led to the conclusion that 1,2-shifts of methyl groups occur readily in carbocations having a pentalene fragment. On the basis of the data obtained for rearrangements of such carbocations, an alternative mechanism has been proposed (52) for the rearrangement of structurally related carbocation 16 having a bicyclo[3.3.0]octane skeleton described in (33) (Scheme 12). 

The pKR+ value for the parent tri(l-azulenyl)methyl cation (2a+) is 11.3. Hydrocarbon-based carbocations, which comprise only of carbon and hydrogen, are generally very reactive species. Some extremely stable hydrocarbon carbocations, which exist even under basic conditions, were reported in the literature (5). However, most of these examples are cyclic cations, such as cyclopropenylium or tropylium ions (Figure 8). The tropylium ion 8+ annelated to three bicyclo[2.2.2]octane units is one of the most stable hydrocarbon-based carbocation ever reported (9). 

Unfortunately, the situation is even more complicated In bi- and tricyclic compounds the a-SCS may experience further alterations apparently produced by intramolecular strain. The usually large a-SCS(CH3) in 1-methyl-bicyclo[2.2.1]heptane (9) (93) has already been mentioned. The a-effects of other substituents (OH, OCH3, Cl, I, and COOH) in the same molecular system do not correlate with those in bridgehead-substituted bicyclo[2.2.2]octanes or adamantanes again this was attributed to internal strain (125). The a-SCS(F)... 

Nucleophilic addition of ester-derived enolate to the bicyclo[3.3.0]octan-2-one system of diacetone glucos-3-ulose usually occurs at the convex jS-face of the carbonyl (as for other nucleophiles), except for senecioate-derived enolate (from 3-methyl cro-tonate) for which a-attack in diethylether solvent is in contrast to the jS-face attack in THF the reason for this anomalous behaviour is not clear. 

It has been shown" that isomerization of the exocyclic allylic system of the five-membered ring D of kaurenols depends on the orientation of the C(15) hydroxyl group. The total synthesis of methyl atis-16-en-19-oate, a tetracyclic diterpenoid possessing a bicyclo[2.2.2]octane skeleton, has been accomplished" using a homoallyl-homoallyl radical rearrangement process of methyl 12-hydroxykaur-16-en-19-oate monothioimid-azolide (280) as the pivotal step. Two plausible mechanisms have been presented" ... 

The Michael addition followed by Intramolecular Ring Closure (MIRC) reactions have been recognized as a general synthetic approach to carbocyclic three-membered ring derivatives [1]. The enhanced Michael reactivity of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) towards thiolates, alkoxides, lithiated amides and cyclohexadienolates (see below) allows one to perform highly efficient assemblies of spiropentane, tricyclo [3.2.1.0 ]octane, bicyclo [2.2.2] octane... 

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4-methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of p-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been transformed into gymnomitrol. 

The validity of Eq. (6.1) has been carefully established for linear and branched paraffins, cyclohexane and methylated cyclohexanes, including molecules consisting of several cyclohexane rings in the chair conformation (e.g., cis- and frani-decalin, bicyclo[3.3.1]nonane, adamantane, and methylated adamantanes) as well as in boat conformation (e.g., iceane and bicyclo[2.2.2]octane) [44]. No special effect seems to contribute to the chemical shift because of the presence of cyclic stmctures. 

But there are many cases known where the (4+2) cycloaddition fails even with siloxy-activated dienes, e.g., methyl (E)-crotonate does not react with diene 1 at normal pressure and elevated temperature llO C), whereas the aprotic double Michael addition does give the desired bicyclo[2.2.2]octane in high yield. This reaction gives mainly (92%) bicyclic esters with the endo configuration. 

Asymmetric elimination in the -hydroxy sulfoximine of bicyclo[3.3.0]octane-2,5-dione monoethylene ketal 3, which is obtained in high yield and diastereoselectivity by addition of (S)-.S -lithiomethyl-A -methyl-S-phenylsulfoximine7, 72 to the latter, by sequential treatment with chlorotrimethylsilane and butyllithium, gives the diastereomeric alkenylsulfoximines (S1)-( )- and (Sy(Z)-4 in a ratio 98 273. 

Amino-5-[l-(2-furyl)-2-(5-nitro-2-furyl)-ethenyl]-1,3,4-o.xadiazols0 (Furamizol ) wirktbak-terizid, 2-[3-(5-Methyl-1,3,4-oxadiazol-2-yl)-3,3-diphenyl-propyl]-2-aza-bicyclo[2.2.2]octan (SC-27166 )81 ist ein Antidiarrhoicum. 

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