Bicyclic enones

The next step is an intramolecular aldol reaction leading to closure of a six-membered ring. Subsequent dehydration yields the bicyclic enone 4 ... 

The reaction of the enantiomerically pure sulfoxide anion (0.5 equiv) with a racemic bicyclic enone allows for the kinetic resolution of the enone15b. 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

The synthesis in Scheme 13.13 leads diastereospecifically to the erythro stereoisomer. An intramolecular enolate alkylation in Step B gave a bicyclic intermediate. The relative configuration of C(4) and C(7) was established by the hydrogenation in Step C. The hydrogen is added from the less hindered exo face of the bicyclic enone. This reaction is an example of the use of geometric constraints of a ring system to control relative stereochemistry. 

The photolysis of bicyclic enones is frequently a high-yield route to new tricyclic compounds ... 

Finally, a rather early (but from a mechanistic viewpoint a very interesting) sequence of radical reactions has been described by Pattenden and coworkers, in which an acetylenic oxime ether 3-312 was converted into the bicyclic oxime 3-319 in 70% yield (Scheme 3.78) [126]. Hydrolysis of 3-319 led to the bicyclic enone 3-320, which in fact can also more easily be synthesized by a Robinson annulation. 

Resolution of bicyclic enones. This optically active diol selectively forms a hydrogen-bonded insoluble complex with one enantiomer of the bicyclic enone 2, which when heated liberates ( — )-2 of 100% ee. This resolution is useful for a few... 

Cyclopentenone annelation. The reaction of the dilithio derivative (2) of dimethyl 4-cyclohexene-1,2-dicarboxylate (LDA, THF/HMPT) with 1 at -45 -> 0° results in the bicyclic enone 3 in 72% yield. The reaction may involve conjugate addition of 2 to 1 to give a ketene (a) with loss of lithium phenoxide. Several other... 

Cyclic alkynyl carbonates undergo carbonylation in the presence of a palladium catalyst and carbon monoxide (5 MPa) in MeOH to give allenic carboxylates (Eq. 9.118) [92], Bu3P proved superior to Ph3P as the catalyst ligand. An enynyl cyclic carbonate underwent double vicinal carbonylation at 80 °C to produce a five-membered lactone product in 52% yield (Eq. 9.119). When the reaction was performed at 50 °C, the bicyclic enone lactone was produced in 75% yield along with 10% of the y-lactone. 

Both enantiomers of the bicyclic enone 78 and their derivatives have been proved to be useful chiral building blocks for the synthesis of natural products [29], among them y-butyrolactones. 78 is readily available in either enantiomeric form by a Diels-Alder reaction of furan with a-acetoxyacry-lonitrile and subsequent hydrolysis, followed by a resolution of the racemate... 

The earliest pioneering work, due to Georgian and Saltzman began with Robinson annulation of 436 and intramolecular [2+2] photocyclization of the bicyclic enone. 

The bicyclic enone 665 (see Scheme IX) has been utilized as a precursor to hirsu-tene The mold metabolite has also been attained in clever fashion from 666 using meta-photocycloaddition methodology... 

The first naturally occurring tricyclo[6.3.0.0 ]undecane to be synthesized was isocomene (757), a colorless oily sesquiterpene hydrocarbon isolated from several plant sources. In 1979, Paquette and Han reported an efficient, stereospecific approach starting with a preformed bicyclic enone, to which the third five-membered ring was appended with proper attention to stereochemistry and position of unsaturation (Scheme LXXX) The pivotal steps are seen to be the stannic chloride-induced cyclization of aldehyde 732 and the conjugate addition of lithium dimethylcuprate to 733 which sets the stereochemistry of the last methyl group. 

The approach chosen by Schostarez and Paquette (Scheme XCII) was fully regio-controUed and designed to generate modhephene and epimodhephene independently Bicyclic enone 787 was transformed by conju te addition into 788 or 789. When the first sutetrate was thermolyzed, ene chemistry locked the condary methyl sub-... 

Noteworthily. the sign of the 220-200 CD band of enones is not sensitive to conformational changes. Examples of the Colton effects of two configurational types of bicyclic enones are shown below51. 

The initial success with early transition metals, such as zirconium and titanium, reported by the Buchwald group, included an indirect cycloaddition between an enyne and isocyanides. The first protocol that used [Gp2Ti(PMc3)2] or Ni(GOD) together with triphenylphosphine failed to cyclize the enynes under the pressure of GO, but provided the cyclic imines with trialkylsilyl isocyanides, and bicyclic enones were obtained by hydrolysis of the resultant imine products (Equation (9)). ... 

Propargylic mesylates such as fluorine-substituted derivative 265 react with PhZnCl in the presence of Pd(PPh3)4 (5 mol%) in THF at 0°C within 2 h to provide the anti-Si 2 product in excellent yield and complete transfer of the stereochemistry leading to the allene 266 (Scheme 78). Copper(I) catalyzed allylic substitutions with functionalized diorganozincs proceed with high 8 2 selectivity. Thus, the reaction of the chiral allylic phosphate 267 with 3-carbethoxypropylzinc iodide in the presence of CuCN 2LiCl (2 equivalents) furnishes the awf/-Sjv2 substitution product 268 in 68% yield. By the addition of w-BuLi (1.2 equivalents) and TMSCl (1.5 equivalents), the bicyclic enone 269 is obtained in 75% yield and 93% ee (Scheme 79) . 

These approaches led to ternary stereogenic centers. Brian Stoltz has found J. Am. Chem. Soc. 2004,126, 15044) that the Pd-mediated conversion of 7 to 8 can be induced to proceed in high enantiomeric excess. This appears to be a general method for the preparation of quaternary stereogenic centers. Wacker oxidation followed by aldol condensation converted 8 into the bicyclic enone 9. 

The absolute course of the intramolecular Michael reaction can also be mediated by organo catalysts. Benjamin List of the Max-Planck-Institut, Miilheim, has shown (Angew. Chem. Int. Ed. 2004, 43, 3958) that 9 is particularly effective. Michael addition followed by intramolecular aldol condensation gives the Irons bicyclic enone 11 in high . 

Bicyclic or polycyclic enones may give slow or inefficient reaction with organocuprates. In particular, it is those enones which contain substituents arranged so as to create a steric hindrance on the carbon 3 to the carbonyl that see the greatest effect. The yields are often low to moderate, unless additional activation is provided. For example, when the bicyclic enone (23) was treated with R2C11U (R = 3-pentynyl), the -substituted product was formed in only 46% yield,69 while exposure of the same enone to RQ1BF3 (R = 3-pentynyl) gave the same (3-alkylated product in 76% yield (Scheme 9).70... 

In many cases a Lewis acid has been added to a cuprate to enhance its reactivity with an enone, but there are also examples for which the Lewis acid-organocopper reagents do not work well, (Scheme 10). Reaction of the bicyclic enonate (24) with Me2CuLi led to smooth conjugate addition,71 but the use of either Me2CuLiBF3 or MeCuBFj resulted in formation of a dark resinous material. It is often difficult to predict when the reaction will go astray, but it should be recognized that a Lewis acid-cuprate complex is not always an effective solution to a reactivity problem. 

The absolute configuration of Wieland-Miescher ketone analogues bearing an angular protected hydroxymethyl group was unambiguously determined after regio- and stereoselective reduction of the saturated ketone function to cis -alcohols and application of the exciton chirality method to bicyclic enone-benzoate chromophoric systems 155-158352. 

It has been demonstrated by Olah et al.420 that a,/3-unsaturated ketones are O-protonated in HF-SbF5 to form hydroxyallylic cations, which were directly observed by NMR spectroscopy. Jacquesy and Coustard have found indirect evidence for diprotonation of a,/3-unsaturated ketones (enones) by trapping the dication with CO.421 The resulting acylium ion centers are then quenched with methanol or benzene. An interesting synthetic method was therefore developed for carboxylation of bicyclic enones in superacid media at atmospheric pressure [Eqs. (5.158) and (5.159)]. 

Piers and co-workers (44) have reported that the cuprous chloride catalyzed 1,4-addition of isopropenylmagnesium bromide to the bicyclic enones 127 (R=H or CH3) gave exclusively the bicyclic ketones 128 (R=H or CH3) with the isopropenyl group axially oriented. Interestingly, with their trans ft/B ring junction, these enones are essentially conformationally rigid and their reactivity is in accord with the predictions made on the basis of stereo-electronic effects. 

The bicyclic enone 84 in which ring A can adopt the two conformations 85 and 86 can now be examined. A stereoelectronically controlled attack of cyanide ion on the o face of conformation 85 gives the chair-like intermediate 87 while that on the B face of conformation 86 yields the chair-like intermediate 88. An approach from the top face of 85 or the bottom face of 86 is not considered because it leads to intermediates having a boatlike conformation. Intermediate 87 with its trans junction is more stable on the basis of steric effects than intermediate 88 which has a cis ring junction consequently, the formation of the a-cyano adduct 89 should prevail over the B-cyano adduct 90. 

---