Enones photocycloaddition

Both target compounds discussed in this review, kelsoene (1) and preussin (2), provide a fascinating playground for synthetic organic chemists. The construction of the cyclobutane in kelsoene limits the number of methods and invites the application of photochemical reactions as key steps. Indeed, three out of five completed syntheses are based on an intermolecular enone [2+2]-photocycloaddition and one—our own—is based on an intramolecular Cu-catalyzed [2+2]-photocycloaddition. A unique approach is based on a homo-Favorskii rearrangement as the key step. Contrary to that, the pyrrolidine core of preussin offers a plentitude of synthetic alternatives which is reflected by the large number of syntheses completed to date. The photochemical pathway to preussin has remained unique as it is the only route which does not retrosynthetically disconnect the five-membered heterocycle. The photochemical key step is employed for a stereo- and regioselective carbo-hydroxylation of a dihydropyrrole precursor. 

Brimioulle R, Bach T (2013) Enantioselective Lewis acid catalysis of intramolecular enone [2 +2] photocycloaddition reactions. Science 342 840-843... 

Bauslaugh s Biradical Proposal Trapping and Detection of Biradical Intermediates in Enone [2+2]-Photocycloadditions... 

The Gorey-de Mayo exciplex mechanism " for photocycloaddition of enones to alkenes has provided a stimulus for workers in this field and undoubtedly has had heuristic value in accounting for experimental observations in a vast number of reactions. Nonetheless, the experimental findings discussed above make it clear that this mechanism for enone [2 2]-photocycloadditions has been discredited and should be abandoned. 

Akritopoulou-Zanze I, Whitehead A, Waters JE, Henry RE, Djuric SW (2007) Synthesis of novel and uniquely shaped 3-azabicyclo[4.2.0]octan-4-one derivatives by sequential Ugi/[2 -I- 2] ene-enone photocycloadditions. Org Lett 9 1299-1302... 

Surface adsorption can also influence observed stereochemistry in a profound way. In enone photocycloadditions on silica gel and on alumina, the reaction which normally occurs from the less hindered alpha face is shifted toward the more hindered beta face, Eq. (9) Adsorption thus apparently disfavors conformational inversion in the intermediate biradical, as is required for formation of trans-fused products. The magnitude of the effect is sufficient to be synthetically useful the above reaction represents a complete reversal of stereochemistry from that observed in methanolic solution... 

The role of the dioxinone chromophore on the selectivity in the first bond formation, was examined by comparison to the enone analogs 149 and 151, lacking the /1-oxygen found in the dioxinone chromophore. Irradiation of 149 and 151 afforded only the fraws-fused photoproducts 150 and 152 respectively, which indicates that in contrast to dioxinones, the first bond formation in the enone photocycloadditions can take place from either the a- or /1-carbon of the enone via six-membered ring of the corresponding diradical intermediate (Scheme 32). 

In another approach to control the absolute configuration of enone photocycloaddition products, an intermediate iminium ion with a chiral secondary amine was employed by Mariano et al. (Scheme 6.28) [80]. Irradiation of substrate 73 at relatively short wavelength (direct nn excitation) led, via intermediate 74, to the chiral... 

An interesting intramolecular [2+2] ene-enone photocycloaddition generating the lactam moiety of 3-azabicyclo[4.2.0]octan-4-one derivatives 155 and 156, creating up to five stereocenters with only two diastereomers observed, was disclosed this year <07OL1299>. 

Stereochemistry is also affected in a significant way by surface adsorption. When enone photocycloadditions are allowed to occur as adsorbates on silica gel or alumina, larger fractions of reaction product derived from attack on the more hindered P face are observed. Thus, surface adsorption apparently influences conformational inversion, enhancing the formation of /ra s-fused products. This effect is synthetically useful, for sometimes a complete reversal of stereochemistry is observed compared with that seen in methanolic solution. 

An intramolecular variation of the ene/enone photocycloaddition is described by J. D. Winkler. As already described for the intermolecular transformation (see Demuth s enone cycloaddition reaction), a dioxenone is formed via cyclization of a 3-ketoester and subsequently irradiated. Intramolecular cycloaddition then leads to a strained tetracyclic photoproduct which can be ring-opened and decarboxylated to give the trans-fused bicyclo[5.3.1 ]undecan-11 -one. 

Stereochemistry of enone photocycloaddition is more complicated than regiochemistry. Considering the stereochemistry at the four carbons of the newly formed cyclobutane ring, eight stereomers can result from each regiomer. However, not all of the possible products are usually obtained. Structure I represents a typical photoadduct from a cyclic enone and an acyclic alkene5. 

Irradiation of 3-(alk-l-ynyl)cyclohept-2-en-l-ones (32) leads to selective formation of tricyclic head-to-head dimers. However, in the presence of 2,3-dimethylbuta-1,3-diene, [2 + 2], [4 + 2] or [4 + 4] cycloadducts can be obtained, depending on the enone structure. In the case of cyclohex-2-enones, photocycloaddition to the diene leads to cyclobutane adducts. A special case are 3-(alk-l-ynyl)-cyclohex-2-enones, which undergo [2 + 2] cycloaddition exclusively at the C=C bond to afford 3-cyclobutenylcyclo-hex-2-enones (33). ... 

Stereochemistry of Ring Fusion of Cycloadducts Stereochemistry of the Alkene Component in Enone Photocycloadditions Regiochemistry in Enone-Alkene [2+2]-Photocycloadditions Reactivity of Alkenes Toward Photoexcited Enones... 

Biradical reversion appears to be a much more important process in enone additions to electron-deficient alkenes. Thus, Schuster and co-workers found that, in the reaction of 3-methylcyclohexenone (3-MCH) with Z- and E-l,2-dicyanoethene (maleo- and fumaronitrile), isomerization of the alkenes accompanies formation of cycloadducts. Based upon quantum yields for aU processes and the rate constants for quenching of the enone triplet by these alkenes, Schuster et al. concluded that alkene isomerization occurred by reversion of 1,4-biradical intermediates (i.e., a Schenck-type mechanism) rather than by triplet-triplet energy transfer from the enone to the alkenes, although the latter was a distinct possibility due to the relatively low triplet energies of these particular alkenes.The full significance of biradical reversion as a critical factor in affecting the course of enone photocycloadditions is discussed below. 

These data were accepted for a long time as proper measures of alkene reactivity in photocycloadditions and were critical elements in the formulation of Corey s famous exciplex mechanism to explain enone photocycloadditions.However, as is now well known, product ratios in photochemical processes reflect relative quantum efficiencies for disappearance of starting materials and/or formation of products and rarely reflect relative rates of reaction of the photoexcited state, particularly when it is a triplet state. ° ... 

The lack of a relationship between product quantum yields and the rate constants of a single reaction step in a multistep reaction pathway was demonstrated dramatically many years ago by Wagner for Norrish type II reactions of aromatic ketones. In this reaction, quantum efficiencies are determined by the competition between reversion of 1,4-biradical intermediates to starting material and product formation and do not correlate at all with the rate constants for formation of the biradicals from ketone triplet states. Because 1,4-biradicals clearly play a crucial role in enone photocycloaddition to alkenes, it would be surprising if relative yields of enone-alkene photoadducts directly reflect the rates of the initial interaction of alkenes with enone triplet excited states.In fact, such a correlation does not exist. 

Conclusions and Future Directions in Research on Enone Photocycloadditions... 

A which is not observed in individual solutions of the two enones at the same concentrations and may thus be indicative of a complex formation. However, the ratio of isomeric cyclobutane products resulting from such photocycloadditions is generally seen to be a quite sensitive function of steric effects and of the properties of the reaction solvent, of the excited state(s) involved (in some cases two different excited triplet states of the same enone have been found to lead to different adducts) and of the substituents of the excited enone and substrate. No fully satisfactory theory has yet been put forth to draw together all the observations reported thus far. 

In this synthesis, we have witnessed the dramatic productivity of the intramolecular enone-olefin [2+2] photocycloaddition reaction. This single reaction creates three contiguous and fully substituted stereocenters and a strained four-membered ring that eventually provides the driving force for a skeletal rearrangement to give isocomene. 

Scheme 6.10. Photocycloadditions of Enones with Alkenes and Alkynes... 

The final type of reaction that will be discussed is the highly interesting cross photocycloaddition of cyclic a, (3- unsaturated ketones with olefins. Examples were given in Eqs. 28—31. A general mechanism 94), to which there may be exceptions to be discussed later, would involve a triplet state of the enone and the reactions steps given in Eqs. 32, 33, and 35, complex formation, biradical formation, and product formation. An earlier idea that two different excited triplet states were reacting has been discounted. 100,141,142) The inefficiency of the reaction is attributed to an alternate decay of complex 77,78,ioo,i42)( an(j the excited state has a n-n configuration. 100,142)... 

This chapter deals with [2 + 2]cycloadditions of various chromophors to an olefinic double bond with formation of a four-membered ring, with reactions proceeding as well in an intermolecular as in an intramolecular pattern. Due to the variety of the starting materials available (ketones, enones, olefins, imines, thioketones, etc.. . .), due to the diversity of products obtained, and last but not least, due to the fact that cyclobutanes and oxetanes are not accessible by such a simple one-step transformation in a non-photo-chemical reaction, the [2+2]photocycloaddition has become equivalent to the (thermal) Diels-Alder reaction in importance as for ring construction in organic synthesis. 

Mechanistic evidence indicates 450,451> that the triplet enone first approaches the olefinic partner to form an exciplex. The next step consists in the formation of one of the new C—C bonds to give a 1,4-diradical, which is now the immediate precursor of the cyclobutane. Both exciplex and 1,4-diradical can decay resp. disproportionate to afford ground state enone and alkene. Eventually oxetane formation, i.e. addition of the carbonyl group of the enone to an olefin is also observed452. Although at first view the photocycloaddition of an enone to an alkene would be expected to afford a variety of structurally related products, the knowledge of the influence of substituents on the stereochemical outcome of the reaction allows the selective synthesis of the desired annelation product in inter-molecular reactions 453,454a b). As for intramolecular reactions, the substituent effects are made up by structural limitations 449). 

Allenes behave as somehow special olefins in such photocycloadditions 476a,b,477) Additions of enones to allene have been used as key step in the synthesis of the alkaloids annotinine 478a) (4.65) and chasmanine (4.66) 478b). 

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). 

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