Intramolecular photocycloaddition, regioselectivity

Intermolecular and intramolecular photocycloaddition and photoaddition to aromatic rings in the electron-donor and electron-acceptor systems were discussed in this chapter. The highly stereoselective and regioselective photocycloaddition is a synthetically useful method for the construction of polycyclic carbon-skeleton compounds, including natural products. New aspects for the stereoselective intermolecular and intramolecular photocycloaddition reactions via exciplexes in less... 

Strained cage compounds can be made by intramolecular photocycloaddition of properly designed ene/enone substrates. In an interesting example from J. R. Scheffer, a ben-zoquinone derived Diels-Alder product is regioselectively transformed into a (halO cage compound. This is a more complicated version of the classical intramolecular photochemical cyclization reactions of benzoquinone derivatives (for example see B. Pandey s cage synthesis from a naphthoquinone-cyclopentadiene in Chapter 3). 

If five-membered ring Formation is not possible (n > 3) a six-membered ring is the next most favored. The major product is typically the straight adduct. An example of intramolecular photocycloaddition in dioxinone proceedng with high regioselectivity is shown in Table 5, entry 15127. 

The unstable cycloadducts (24) and (25) are obtained from the photolysis of the enone ethers (26).A similar approach has been reported by Barker and Pattenden in their study of the photocyclization of enol acetates. Thus the intramolecular photocycloaddition affords the adducts (27) from the mixture of enol acetates derived from (28). An analogous regioselective cycloaddition is encountered in the irradiation of the enol acetates derived from (29) to afford the adduct (30). 

An add-bond strategy via an overbred skeleton offers the possibilities (a) and (b) shown in Scheme 13.31. Choice (a) suggests an intramolecular photocycloaddition between a cyclobutene and a cyclohexene—not really attractive. Choice (b) indicates a well precedented cyclopropanation reaction, that was indeed used [29] to realize a quick synthesis of twistane. However, this faced the problem of the regioselective cleavage of a distinct cyclopropane bond. 

The intramolecular photocycloadditions of butenolides with a 2,3-butadienyl substituent at the 5-position (16) produced tricyclic cycloadducts (17) with a methylenecyclobutane moiety as the core unit. The key reaction is the regioselective crossed 2- -2-cycloaddition of the internal allene double bond (Scheme 5). The ruthenium-catalysed 2- -2-intramolecular cycloaddition of allenes and alkynes (18) yielded bicyclo[3.2.0]heptane cycloadducts (19) under mild conditions and with a high diastereo-selectivity (Scheme 6). ... 

The course of the intramolecular photocycloadditions of the isoelectronic ketene and allene of structure (372 X = O or CH2) is quite different the ketene cyclizes to (373), whereas the allene gives (374). Similar behaviour is found for other cyclo-hexenones, and opposite charge distribution in the ground states of the allenes and ketenes is thought to be responsible for the differences in regioselectivity. Deuteriumlabelling studies show that the isomerization of the benzobarrelene (375) into the benzocyclo-octatetraene (376) occurs by way of initial [2 + 2] photo-addition between the aliphatic C=C bonds. This is not the pathway favoured by previous investigators or by the Epiotis polar pericyclic theory. The photochemical addition... 

The mechanisms of regioselective and stereoselective 2 -E 2-photocycloadditions have been extensively reviewed. The intramolecular 2 -E 2-photocycloaddition of 2-allyl-2-(l//)-naphthalenone (13) on the surface of silica produces all four cycloadducts (14)-(17) (Scheme 4). ° Molecular mechanics have been used to study the regio- and stereo-selectivity of the 2 -E 2-photocycloadditions in complexes containing crown ether styryl dyes and alkaline earth metal cations."... 

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. 

Photocycloaddition reactions have been used as key transformations in many organic syntheses to construct organic compounds having unique structures that are hardly accessible by other methods. However, their stereoselectivity is not necessarily high, and many efforts have been done to attain the highly regioselective and stereoselective photocycloadditions. They are discussed in terms of the electronic nature of substrates, the steric repulsions between substituents, and the conformational restrictions of intramolecular reactions. 

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. 

Mizuno et al. demonstrated an intramolecular version of [2 + 2] photocycloaddition using a microreactor made of PDMS [poly(dimethoxysilane)] (channel dimensions 300 pm wide, 50 pm deep and 45 or 202 mm long) [40], Because one of the products photochemically reverts to the starting material, while the other does not, a much shorter residence time, that is, 3.4 min (batch reaction time = 3 h), inside the microchannel reduces the possibility of the reverse reaction. The difference in residence times explains the slight difference in regioselectivity between the microflow and batch systems (Scheme 4.27). 

In contrast to these intermolecular enone + alkene photocycloadditions, the regioselectivity in the corresponding intramolecular cycloisomerizations of alkenylcycloalkenones is controlled primarily by... 

Synthetic applications of [2 + 2] photocycloadditions of unactivated alkenes have been limited due to the low regioselectivity and stereoselectivity observed in this process. However, Wender recently reported an intramolecular example of a diene- iene photochemical [2 + 2] which provides rapid access to cif-fused 5-8 ring systems and subsequently linearly fused triquinanes. ° Sensitized irradiation of (65)... 

The regioselectivity of analogous cycloadditions in 4-(alkenyloxy)-quinolin-2-(1H)-ones is determined by the chain length irradiation of quinolone (92 n=1), for example, gave the adduct (93), whereas the related quinolone (92 n=3) was converted photochemically into the adduct (94). Intramolecular [ 2 + 2] photocycloaddition has also been employed in the preparation of photoresponsive cyclobutane-1,2-dicarbonyl-capped[2.n]diazacrown ethers. 

The course of intramolecular enone alkene photocycloaddition is dependent on the number of atoms between the two reactive C=C bonds. For example, E- and Z-isomers of 1-acylhepta-1,6-diene (147) form a 1 1 mixture of stereoisomeric cycloadducts 148 and 149 upon irradiation, while no E Z isomerization occurs (Scheme 6.67a).764 The initial bonding takes place between the C2 (Cp) and C6 atoms, in agreement with the empirical rule of five,165 the regioselective, kinetically preferred formation of five-membered ring biradical intermediates over larger rings due to the entropies of cyclization. As a result, the biradical 150 is not observed. For comparison, the acylhexadiene 151 photolysis also proceeds via a 1,4-biradical (152) formed by an initial 1,5-cyclization (Scheme 6.67b).766... 

This reaction pathway is usually favoured when an aromatic moiety and an alkene bear electron-withdrawing and electron-donating substituents, respectively (or vice versa). This addition involves a charge transfer and the course of the reaction is sensitive to the solvent polarity. Such a mechanism may resemble that of [2 + 2] photocycloaddition of alkenes to aji-unsaturated carbonyl compounds (Section 6.3.2). Scheme 6.81 shows examples of two intermolecular processes and one intramolecular [2 + 2] photocycloaddition reaction (a) crotononitrile (196) is added to anisole (197) to yield several stereoisomers of 198 in 38% chemical yield and with high regioselectivity, which is linked to bond polarization in the exciplex 818 (b) hexafluorobenzene (199) reacts with 1-ethynylbenzene (200) to form the bicyclo[4.2.0]octa-2,4,7-triene 201 in 86% yield 819 and (c) irradiation of 202 in methanol leads to the single photoproduct 203. 820... 

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