Photocycloaddition reactions enantioselectivity

In enantioselective photocycloaddition reactions, 4-alkoxyquinolones perform in superior fashion to l,5-dihydropyrrol-2-ones and 5,6-dihydro-lff-pyridin-2-ones. Both, intermolecular and intramolecular reactions were performed with excellent enantioselectivity in the presence of the chiral template 115, or of its enantiomer ent-115 [147, 148], The well-established photocycloaddition reactions [149, 150] enabled access to a variety of chiral dihydroquinolones. 4-Methoxyquinolone (157) produced, upon direct irradiation in the presence of allyl acetate, the formal HT product 158 in 80% yield and with 92% ee (Scheme 6.56) [151]. 

Despite the fact that the [2 + 2] -photocycloaddition reaction of enones has a history of more than 100 years, it has remained a vital and attractive reaction. The continuing interest and many applications to increasingly more complex targets not only bear testimony to its utility but also contradict the myth that photochemical reactions are nonselective and unpredictable. It would be desirable if this most useful chemistry could also be appreciated in the life sciences industry. The first blockbuster drug to be synthesized via a [2 + 2]-photocycloaddition is yet to be developed. Apart from the conventional evolution of the reaction, which involves an increase in scope and an improvement in its practical execution [154], it is expected that sensitization - as a means of catalyzing photochemical reactions in general [155-157] - will become a dominant factor in the development of catalytic enantioselective [2 + 2]-photo-cycloaddition variants. 

Bach, T., Bergmann, H., and Harms, K. (2000) Enantioselective intramolecular [2 + 2]-photocycloaddition reactions in solution. Angewandte Chemie, International Edition, 39, 2302-2304. 

The intermolecular [2 + 2] photocycloaddition reactions of 2-quinolones such as 59 mediated by a chiral lactam host 60 or ent-60 were reported with enantioselectivities of 93%. The intermolecular version of this reaction was also shown to be highly enantioselective. One example shown in Scheme 9 afforded cycloadduct 63 in 92% ee with a diastereoselectivity of >95 5 <02JA7982>. 

Chiral transition metal complexes have been employed in the enantioselective [2 4- 2]-photocycloaddition reaction, in asymmetric electron transfer reactions and photooxidations/reductions. In the enantiodifferentiating step of the latter reaction type the chiral transition metal complex is involved in an electron transfer, i.e., the metal is converted from an excited oxidative state to a more stable one. This... 

Mattay et al. employed asymmetric copper(I)-catalyzed intramolecular [2 + 2]-photocycloaddition reactions in a synthetic approach to (+)- and (— )-grandisol [56]. Racemic dienol 33 was irradiated in the presence of CuOTf and a chiral ligand to yield mainly cyclobutanes 34 and ent-34 as a mixture of enantiomers. Other 1,6-dienes were also employed. A number of chiral nitrogen-containing bidentate ligands were tested, the most effective of which, (4S,4 S)-4,4 -diisopropyl-2,2 -bisoxazoline (35) and (4R,47 )-4,4 -diethyl-2,2 -bisoxazoline (36), ensured a minor enantiomeric excess of <5% ee (Scheme 12). The coordination of the diene to the chiral Cu(I) complex under formation of a complex of type 37 was proved by CD analysis. The authors suggest a lower reactivity of the chiral complex compared to the copper ion coordinated to solvent molecules as the reason for the low enantioselectivities observed. 

The efficiency of these chiral host compounds has been shown in highly enantioselective photocyclization and photocycloaddition reactions of prochiral lactams. These substrates, for example 2-quinolone derivatives, are expected to coordinate to lactam 44 with its NH-group as the hydrogen donor and the carbonyl group as the hydrogen acceptor, as depicted in Scheme 15. In this complex, any... 

The scope of this approach was widened by the observation of excellent enantioselectivities in intermolecular [2+ 2]-photocycloaddition reactions with various alkenes [62,71]. In the presence of an excess amount of alkene, 4-me thoxy-2-quinolone (57) was converted with high chemo- and regioselectivity to the exo and endo cyclobutanes 59 and 60. With 4-penten-1-ol (58a), allyl acetate (58b), methyl acrylate (58c), and vinyl acetate (58d), the exo diastereomers 59a-d were formed with high simple diastereoselectivity and in high yields (80-89%), Under optimized irradiation conditions (2.4 eq. of host 44 or ent-44, — 60°C), high enantiomeric excesses were achieved in all instances, as depicted in Scheme 22. These enantiomeric excesses are unprecedented for an intermolecular photochemical reaction. 

While the chiral complexing agents (+)-12 and (-)-12 proved to be generally suitable for a wide range of enantioselective [2+2]-photocycloaddition reactions on the c-bond of 2(l//)-quinolones, their applicabil-... 

Selig P, Bach T (2006) Photochemistry of 4-(aminoethyl)quinolones Enantioselective synthesis of tetracyclic tctrahydro-1 af/-pyrido[4, 3 2,3]cyclo-buta[l,2-c]quinoline-2,11(377,877)-diones by intra- and intermolecular [2+2]-photocycloaddition reactions in solution. J Org Chem 71 5662-5673... 

Kakiuchi has reviewed some recent advances in enantioselective (2 + 2)- and (2 + 4)-photocycloaddition reactions in solution. Particular attention is given to the use of chiral host molecules and chiral auxiliary groups. 

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

Alonso R, Bach T (2014) A chiral thioxanthone as an organocatalyst for enantioselective [2+2] photocycloaddition reactions induced by visible light. Angew Chem Int Ed 53 4368-4371... 

Toda, F., Miyamoto, H. and Kikuchi, S., Enantioselective intramolecular [2+2] photocycloaddition reaction of n-allyl-3-oxo-l-cyclohexenecarboxamides in inclusion crystals with chiral host compounds, /. Chem. Soc., Chem. Commun., 1995, 621—622. 

In photocycloaddition reactions, the degree of enantioselectivity depends on the effectiveness with which the enantiotopic faces of a prochiral olefin can be distinguished (enantioface-differentiation). The conventional way to achieve this goal is to covalently attach a chiral auxiliary (see Section 61.2) to the prochiral substrate. The consecutive reaction is diastereoselective, and the auxiliary has to be removed afterwards. The degree of diastereoselectivity in the selectivity-determining step is measured by the diastereomeric excess (DE), which is defined by analogy to the enantiomeric excess, and the ee corresponds to the DE after removal of the auxiliary. The auxiliary-based process consequently consists of three steps, two of which are, in principle, superfluous as they are not concerned with the reaction under scrutiny. 

In contrast, until very recently only a few studies of asymmetric photocycloadditions by chiral sensitizers have been reported. Kim and Schuster achieved enantiomeric excesses of up to 23% ee in the sensitized [4+2]-cycloaddition of trcms-P-methylstyrene 34 with cyclohexa-1,3-diene (35), which represents the first reported enantioselective photocycloaddition reaction. This reaction is called the triplex Diels-Alder reaction, as it was shown to occur by formation of a ternary complex of the singlet excited sensitizer, (-)-l,l -fcis(2,4-dicyanonaphthalene) 36, with the diene and the dienophile. The Diels-Alder product 38 is formed in up to 11% chemical yield (Scheme 13) other products are the dimers of cyclohexa-1,3-diene (83%) and [2+2]-cycloadducts of 34 and 35 (5%). ... 

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