Cyclohexenones, photocycloaddition

Control over the absolute configuration in cyclohexenone photocycloadditions has been achieved by auxiliary-induced diastereoselectivity. In particular, esters related to compound 26, which are derived from a chiral alcohol but not from methanol, lend themselves as potential precursors, from which the chiral auxiliary can be effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to increase the diastereomeric excess in these reactions [44], An intriguing auxiliary-induced approach was presented by Piva et al., who employed chiral 13-hydroxy-carboxylic adds as tethers to control both the regioselectivity and the diastereoselectivity of intramolecular [2 + 2]-photocycloaddition reactions [45]. In Scheme 6.14 the reaction of the (S)-mandelic acid derived substrate 38 is depicted, which led with very good stereocontrol almost exclusively to product 39a, with the other diastereoisomer 39b being formed only in minor quantities (39a/39b = 96/4). Other acids, such as (S)-lactic acid, performed equally well. The chiral tether could be cleaved under basic conditions to afford enantiomerically pure cydobutane lactones in good yields. 

Xu, W. and Mariano, P.S., Substituent effects on amine cation radical acidity in regiocontrol of P-(aminoethyl)cyclohexenones photocycloaddition,/. Am. Chem. Soc., 113,1431,1991. 

In recent years the application of photocycloaddition reactions to organic synthesis has been growing in importance. - The procedure described is illustrative of a general method based on a photocycloaddition reaction for the introduction of an activated alkyl group specifically to the a-carhon atom of an a,/3-unsaturated cyclohexenone. Especially significant is the fact that the method is also applicable to... 

Most investigations of the photocycloaddition of simple a,0-unsaturated carbonyls have involved the reactions of the ring compounds cyclopentenone and cyclohexenone. The photoaddition of 2-cyelohexenone to a number of different olefins has been reported by Corey and co-workers(94) ... 

Absorption studies of 2-cyclohexenone-ethoxylethylene solutions failed to reveal evidence of donor-acceptor complex formation. It should be noted, however, that photocycloaddition from ground state 7r-complexes (such as would be observed from absorption studies) does not correctly predict the observed orientational effects. 

Photocycloaddition of allene to cyclohexenone (341) gave the (3,y-enone (342), which reacted with vinyl magnesium bromide to produce the tertiary alcohol (343) in 79% yield. When the compound (343) was treated with KH and 18-crown-6 in THF at room temperature for two hours and quenched with aq. NH4C1, the cyclobutene (344) was obtained. The thermal ring opening of the cyclobutene (344) proceeded in toluene in a sealed-tube at 180 °C for twelve hours to give a readily separable 5 1 mixture of the civ-olefin (345), and the trans-olefin (346) respectively in 95 % yield. Moreover, (345) could be converted to a mixture of (346) and (345) in the ratio of 10 1 by irradiation. The compounds (345) and (346) possess the skeleton of the germacranes (347), (348) and (349) 122). 

Ring enlargement.1 A new route to seven-membered ring systems from a cyclohexenone (1) involves a photocycloaddition of ethylene to provide the bicy-clooctanone 2. Addition of lithio-1,3-dithiane to 2 provides the adduct 3, which on reaction with HgO and HBF4 forms an unstable rearranged hydroxy aldehyde... 

Cis,anti,cis products are favored in the intermolecular photocycloaddition of cyclopentenones with cyclic alkenes87 (Scheme 34). However, intermolecular photoaddition of some cyclohexenones provided preferred /raw. -fused product as the major product with cyclic alkenes60. From the large number of examples presented in Schemes 37, 42, 43, 45, 46, 48 and other examples, it could be concluded that cis -fused products are usually preferred. 

Further studies, on the same principle, were carried out by Lange and coworkers on the intermolecular photocycloadditions of cyclohexenones 167 to alkene 168, possessing different chiral auxiliaries at the enone91 or alkene92. Diastereomeric mixtures of cis,anti,cis 169 and cis,syn,cis isomers were obtained in low to moderate diastereomeric excess (Scheme 37). 

The effect of substituents on the stereoselectivity of the intramolecular photocycloadditions of alkenes to cyclohexenones was systematically examined by Becker and coworkers84 who obtained high stereofacial selectivity in compounds 283a-c. However, small changes in the position, geometry or steric effect of the substituents have dramatically affected the selectivity, indicating the complexity in predicting the stereoselectivity in such system (Scheme 61). 

Cyclohexenones require essentially identical irradiation conditions as cyclopente-nones (vide supra). The outcome of the intermolecular [2 + 2]-photocycloaddition to alkenes is somewhat more complex as compared to cyclopentenones, because the... 

The formation of trans-products is observed to a lesser extent in the reaction of 3-alkoxycarbonyl-substituted cyclohexenones, in the reaction with electron-deficient alkenes and in the reaction with olefinic reaction partners, such as alkynes and allenes, in which the four-membered ring is highly strained (Scheme 6.11). The ester 26 reacted with cyclopentene upon irradiation in toluene to only two diastereomeric products 27 [36]. The exo-product 27a (cis-anti-cis) prevailed over the endo-product 27b (cis-syn-cis) the formation of trans-products was not observed. The well-known [2 + 2]-photocycloaddition of cyclohexenone (24) to acrylonitrile was recently reinvestigated in connection with a comprehensive study [37]. The product distribution, with the two major products 28a and 28b being isolated in 90% purity, nicely illustrates the preferential formation of HH (head-to-head) cyclobutanes with electron-acceptor substituted olefins. The low simple diastereoselectivity can be interpreted by the fact that the cyano group is relatively small and does not exhibit a significant preference for being positioned in an exo-fashion. 

Intramolecular reactions of cyclohexenones follow pathways similar to those of cyclopentenones, both with regard to regio- and stereocontrol. The initially mentioned intramolecular [2 + 2]-photocycloaddition of carvone (1) is a typical example for five-membered ring formation with high diastereofacial control (Scheme 6.1). In this case, the rule of five requires the terminal carbon atom of the intermolecular... 

Substrates A3 (Q = O) have been employed not only as starting materials for fragmentation reactions but also to probe novel stereoselectivity concepts. The photochemical transformation of axial chirality into central chirality was achieved by Carreira et al., who employed chiral, enantiomerically pure allenes in intramolecular [2 + 2]-photocycloaddition reactions (Scheme 6.27) [79]. The reaction of enantiomerically pure (99% ee) cyclohexenone 71, for example, yielded the two diastereomeric products 72a and 72b, which differed only in the double bond configuration. Apparently, the chiral control element directs the attack at the allene to its re face. The double bond isomerization is due to the known configurational liability of the vinyl radical formed as intermediate after the first C—Cbond formation step (see Scheme 6.2, intermediate C). 

The photocycloaddition chemistry of oc,P-unsaturated 8-lactones is similar to the chemistry of y-lactones. Complications arise as with cyclohexenones because anti-addition to the a,P-unsaturated double bond can occur, particularly in the intermolecular addition mode. Even if one product prevails, intermolecular [2 + 2]-photocycloaddition reactions are often sluggish. Despite the fact that alkene 92, for example, was employed in a twofold excess relative to dihydropyranone 91, the reaction delivered only 32% of the desired product 93 (43% based on recovered starting material Scheme 6.33). The relative product configuration, which was established by X-ray crystallography, came as a surprise because the lactone apparently... 

Tsutsumi, K., Nakano, H., Furutani, A., Endou, K., Merpuge, A., Shintani, T., Morimoto, T., and Kakiuchi, K. (2004) Novel enhancement of diastereoselectivity of [2 + 2] photocycloaddition of chiral cyclohexenones to ethylene by adding naphthalenes. Journal of Organic Chemistry, 69, 785-789. 

Properly alkylated bicyclo[4.2.0]-octan-2-ones formed by 2+2 photocycloaddition of alkenes to cyclohexenones cleave to 5, -unsaturated ketones, one example leading to a sesquiterpene synthesis [73]. 

The first such reaction published in 1908 by Ciamician and Silber was the light induced carvone —> carvonecamphor isomerization, corresponding to type b [1]. Between 1930 and 1960 some examples of photodimerizations (type c) of steroidal cyclohexenones and 3-alkylcyclohexenones were reported [2-5]. In 1964, Eaton and Cole accomplished the synthesis of cubane, wherein the key step is again a type b) photocycloisomerization [6]. The first examples of type a) reactions were the cyclopent-2-enone + cyclopentene photocycloaddition (Eaton, 1962) and then the photoaddition of cyclohex-2-enone to a variety of alkenes (Corey, 1964) [7,8]. Very soon thereafter the first reviews on photocycloaddition of a,(3-unsaturated ketones to alkenes appeared [9,10]. Finally, one early example of a type d) isomerization was communicated in 1981 [11]. This chapter will focus mainly on intermolecular enone + alkene cycloadditions, i.e., type a), reactions and also comprise some recent developments in the intramolecular, i.e., type b) cycloisomerizations. 

The photocycloaddition of 1-alkenylboranes in cyclohexane provided m-fused head-to-head adducts for 2-cyclopen-tenone and a mixture of cis- and trans-isomer for 2-cyclohexenone (Equation (71)).397... 

All these results indicate that enantioselective photocycloadditions of s thetic interest should be possible with the help of a removable chiral auxilii as soon as the right chiral auxiliaries could be defined. In order to test the limit of this strategy, functionalized cyclohexenones and cyclopentenones were si lected to look for new chiral inductors. When co-alkenyl substituents were attach to the cyclic enone through an enamide, a carboxamide, or an ester group (Schei... 

The importance of the ethylene ketal described above with respect to stereocontrol of the de-Mayo reaction is emphasized by later published works of two other teams. Fetizon and co-workers obviously followed a similar concept and carried out photocycloaddition reactions with 96a in model studies (Scheme 23) (Si). As can be seen from retroaldol product 98, exclusive a attack of the cyclohexene has taken place. Thus, the relative stereochemistry of the BC ring connection is opposite to that of taxane. Totally comparable results were obtained by Berkowitz et al. in the course of cycloaddition reactions of cyclopentene, cyclohexene, or those of a cyclohexenone ketal to the camphor derivative 96b (.84). 

Steric interactions can dramatically affect regioselectivity as well. This is demonstrated by the result that cyclohexenone reacts with vinyl acetate to give exclusively the head-to-tail regioisomer (9) while 3-methylcyclohexenone produces a 1 4 mixture of the head-to-head head-to-tail isomers (10) (11) (equation 8). Additionally, 3-n-butylcyclopentenone undergoes photocycloaddition with vinyl acetate to give a 3 1 mixture of head-to-tail head-to-head photoadducts while 1-acetoxy-l-hexene gives rise to exclu-... 

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