Photocycloaddition enantioselective

It will be interesting to follow the developments on the highly efficient and more stereoselective photocycloaddition and photoaddition to aromatic rings from the viewpoints for the synthesis of more complex compounds, including natural products. In addition, the chiral induction in the excited states should be more attractive projects in the near future. Although some excellent reviews about the asymmetric photochemical reactions have been reported in recent years [490-492], the highly enantioselective or diastereoselective photocycloaddition and photoaddition have been reported in only limited cases. 

The intramolecular [2 + 2] photocycloaddition of cyclohexadienone derivative 51, which is substituted with chiral piperidine ring in the solid state, proceeds enantioselectively and optically active products 52 and 53 were obtained [28], Two crystal modifications of 51, the a-form (mp 102-104°C) and (3-form (mp 127-128°C), gave optically active 52 and 53, respectively, upon irradiation in the solid state. 

The sesquiterpene (+)-asteriscanolide 1 was first isolated from Asteriscus aquaticus L and characterized by San Feliciano in 1985.1 It has captured the attention of organic chemists mainly because of its uncommon bicyclo[6.3.0]undecane ring system bridged by a butyrolactone fragment. The only prior enantioselective synthesis of 1 has been described by Wender in 1988 featuring an Ni(0)-promoted [4 + 4]-cycloaddition.2 Booker-Milburn and co-workers described the sequential application of intramolecular [2 + 2]-photocycloaddition, Curtius rearrangement, and oxidative fragmentation to produce the 7-desmethyl derivative in 1997.3... 

A very useful extension of the de Mayo reaction has been recently introduced by Blechert et al. (Scheme 6.26) [78]. The retro-aldol fragmentation was combined with an intramolecular enantioselective allylation (asymmetric ring-expanding allylation) catalyzed by a chiral Pd complex. Bicycloheptane 68, for example, was accessible by intermolecular [2 + 2]-photocycloaddition of cyclopentenone 67 with allene. Further transformation in the presence of Pd2(dba)3 (dba = dibenzylideneacetone) and the chiral oxazoline ligand 69 (tBu-phox) resulted in the enantioselective formation of cycloheptadione 70. 

Recent interest in the use of N-unsubstituted 2-quinolones stems from the fact, that they coordinate effectively to chiral lactam-based templates via two hydrogen bonds. The prototypical template to be used in photochemical reactions is compound 115, which can be readily prepared from Kemp s triacid [108]. The template is transparent at a wavelength X > 290 nm, and can be nicely used in stoichiometric amounts for enantioselective photochemical and radical reactions [109]. Conditions which favor hydrogen bonding (nonpolar solvent, low temperature) are required to achieve an efficient association of a given substrate. The intramolecular [2 + 2]-photocycloaddition of 4-alkylquinolone 114 proceeded in the presence of 115 with excellent enantioselectivity, and delivered product 116 as the exclusive stereoisomer (Scheme 6.41) [110]. Application of the enantiomer ent-115 ofcomplexing agent 115 to the reaction 111 —> 112 depicted in Scheme 6.40 enabled enantioselective access to (+ )-meloscine [111]. 

The intramolecular photodimerization and [2 + 2]-photocycloaddition in DNA involves thymine or cytosine as the chromophore. This chemistry has been intensively investigated with regards to DNA damage and repair [131]. Despite the fact that the area is of continuous interest [132], the synthetic applications are limited and are not covered here in detail. However, some preparative aspects of 4-pyrimidinone photocycloaddition chemistry will be addressed. Aitken et al. have prepared a plethora of constrained cyclobutane P-amino acids by intra- or intermolecular [2 + 2]-photocycloaddition to uracil and its derivatives [133, 134]. In a chiral adaptation of this method, the uracil-derived enone 140 was employed to prepare the diastereomeric cyclobutanes 141 in very good yield (Scheme 6.49). The compounds are easily separated and were - despite the relatively low auxiliary-induced diastereoselectivity - well suited to prepare the as-2-aminocyclobutanecarboxylic acids 142 in enantiomerically pure form. Enantioselective access to the corresponding trans-products was feasible by epimerization in a-position to the carboxyl group [135],... 

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. 

Enantioselectivity in intermolecular enone+ alkene photocycloadditions is quite difficult to accomplish, due to the fact that stereochemical information inherent in the starting materials can easily be lost on the stage of the triplet 1,4-biradical intermediate. Nevertheless highly enantioselective photocycloadditions of quinolones to alkenes mediated by a chiral lactam... 

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>. 

In solution, the great conformational mobility of molecules does not favor tight transition states. For a good asymmetric induction, there is a need to decrease this mobility and to introduce the chiral information as close as possible from the prochiral centers. An efficient way to introduce the chiral environment in asymmetric [2 4- 2]-photocycloadditions is to connect chiral auxiliaries to the reactants. When removable chiral auxiliaries are attached to the starting molecules before the photochemical step, photocycloadditions proceed diastereoselectively. After removal of the chiral auxiliary, the overall process can be considered as a byroad for an enantioselective reaction. 

The first report of an enantioselective photocycloaddition of prochiral conjugated esters involved the introduction of (+ )-2,3-di-0-methyl-erythritol as chiral auxiliary in a diastereoselective and intramolecular photocycloaddition of the bis cinnamate 78 (Scheme 18). Among the isolated isomers, the chiral 8-truxinate (+ )-79 could be obtained as the major product with a de up to 86% [59] (Scheme 18). 

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... 

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... 

Even higher enantioselectivities were accomplished in the case of intra-and intermolecular [2 + 2]-photocycloadditions of 2-quinolone derivatives. Upon... 

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. 

In the host-guest complex of template 60 with substrate 61, the two enantio-faces of quinolone 61 are distinctly discriminated. As one of the enantiofaces of 61 is blocked by the benzotriazole moiety of 60, photochemical attack to the substrate is expected to occur from the open face. Indeed, in the presence of 60 and its enantiomer (ent-60), highly enantioselective intramolecular [2 + 2] photocycloaddition of allyl quinolonyl ether 62 [134] and intermolecular [2 + 2] photocycloaddition of quinolone 61 to alkenes 63 [135] were reported to occur in solution (Scheme 23). The intermolecular photocyeloaddition of 63 to 61, as well as the intramolecular photocyeloaddition of 62 proceeded with excellent enantioselectivities (81-98% ee) and in high yields (61-89%). 

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... 

Control of absolute asymmetry is a relatively untouched area for [2 + 2] photochemical cycloaddition reactions despite the recent advances in the field of asymmetric synthesis. The first example of the use of a removable chiral auxiliary was reported by Tolbert, who obtained impressive enantioselectivity in the photocycloaddition of bomyl fumarate to stilbenes (equation 37). More recently, Lange has shown that menthyl cyclohexenonecarboxylates are useful in control of absolute stereochemistry (equation 38). Baldwin and Meyers have also obtained excellent facial selectivity in systems where the stereogenic center which controls the diastereoselectivity can be excised to afford products of high enantiomeric purity (equations 39,40). 

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