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Heterocyclic Compounds in Enantioselective Photochemical Reactions

Norbert Hoffmann

Université de Reims Champagne-Ardenne, CNRS, ICMR, Equipe de Photochimie, UFR Sciences, B.P. 1039, Reims, 51687, France

1.1 Introduction

The present chapter deals with different key topics. Heterocyclic compounds play a central role in many domains of chemistry such as the search of new biologically active compounds in pharmaceutical and agricultural chemistry [1]. Also, many new materials such as semiconducting compounds contain heterocyclic moieties [2]. In these domains, a large structural diversity and molecular complexity is highly needed. Here, traditional methods of organic synthesis find their limits. Photochemical reactions extend such limits. As electronic excitation completely changes the chemical reactivity of compounds or whole family of compounds [3], products, which cannot be synthesized by more conventional methods become accessible and are of high interest for application in the field of bioactive compounds [4, 5]. Furthermore, the outcome of known reactions, especially catalytic reactions, can be improved when they are carried out under photochemical conditions. Based on the enormous quantity of recent and past results in the field of photochemical reactions, it makes sense to subdivide chemical reactions into two classes: reactions that occur in the electronic ground state and reactions in which electronic excitation is involved. From the economic and ecological point of view, photochemical reactions are particularly interesting, since many of them can be carried out without an additional chemical reagent. The photon is considered as a traceless reagent [6, 7]. For these reasons, these reactions are now highly appreciated in chemical and pharmaceutical industry [8-10].

Stereoselectivity also plays a central role in organic synthesis. Biological activity and material properties strongly depend on the stereochemistry of chemical compounds. Sooner or later, almost all synthesis methods will face this problem. In the past, photochemical reactions have been considered as being inherently stereo-unselective. It was thought that the high energy uptake by light absorption induces uncontrolled relaxation processes that lead to unselective reactions with large amounts of degradation either of the substrates or the photoproducts [11]. In this regard, it must however be pointed out that stereoselective and stereospecific photochemical reactions have been known from the very beginning of this research area [12, 13]. The controlled dissipation of the high electronic excitation energy in photochemical reactions is the reason for the high stereoselectivity in such reactions [11]. In particular, photochemical reactions can be conducted enantioselectively in chiral supramolecular structures [14, 15]. Enantiopure compounds are obtained in different ways: they can be prepared directly from other chiral precursors such as natural products ("chiral pool") or by optical resolution using different types of chromatography or crystallization techniques. Asymmetric syntheses using chiral auxiliaries, which are removed after the stereoselective reaction, also provide enantiopure compounds. Asymmetric catalysis and enzymatic catalysis directly yield enantioenriched compounds. A chiral enantiopure environment in a supramolecular structure or in a crystal may be the inductor of chirality in asymmetric reactions. In the present chapter, methods will be discussed leading directly to enantiopure heterocyclic compounds via photochemical reactions.

1.2 Asymmetric Catalysis with Chiral Templates

Photochemical substrates may be complexed with chiral structures that induce chirality [16]. A typical example is described in Scheme 1.1 [17]. The quinolone derivative 1 carrying a pyrrolidine moiety undergoes an intramolecular cyclization leading to the spirocyclic indolizidine compound 6. The substrate is complexed with the enantiopure Kemp acid derivative (2) via hydrogen bonds between two lactam moieties. In this arrangement, the pyrrolidine approaches the reaction center mainly by one diastereotopic half-space. In this complex, the shielding group acts also as an aromatic ketone sensitizer (sens). After photochemical excitation of the latter, electron transfer from the tertiary amine moiety to the ketone leads first to a radical ion pair 3 and after proton transfer to intermediate 4 [18]. The nucleophilic a-aminoalkyl radical attacks with 70% of stereoselectivity the electrophilic double bond of the quinolone moiety. Thus, an electrophilic oxoallyl radical is generated affording the diradical intermediate 5. The final product 6 results from a hydrogen transfer from the ketyl radical to the oxoallyl radical. It must be pointed out that in the present case this step is favored because it is an intramolecular process. In these radical steps, polar effects play an important role [19-21]. In the corresponding intermolecular stereoselective reactions, these effects contribute essentially to the efficiency of these processes [18]. The intermolecular addition of tertiary amines to indolone derivatives with an exocyclic electron-deficient olefinic double bond has been carried out with similar Kemp acid derivatives [22]. In this case, however, ruthenium or iridium complexes have been used as external photoredox catalysts that were excited by visible light absorption.

Scheme 1.1 Enantioselective synthesis of a spirocyclic indolizidine compound induced by a photochemical electron transfer.

Using a similar chiral sensitizer, an intramolecular [2+2] photocycloaddition has been carried out with high enantioselectivity (Scheme 1.2) [23]. The quinolone derivative 7 is transformed, under visible light irradiation, into a complex polycyclic compound 8 containing a pyrrolidine moiety. It must be pointed out that the same [2+2] photocycloaddition is also induced by UV irradiation via direct light absorption but no chiral induction takes place. It is therefore necessary to choose a sensitizer that absorbs in the visible domain of the light spectrum to ensure enantioselectivity. The thioxanthone derivative 9 absorbs in the visible light region and transfer its triplet energy to the complexed substrate (10). Again, this complexation occurs via hydrogen bonds between the two lactams of the substrate and the Kemp acid moiety of the sensitizer. In this structure the olefinic double bond in the side chain approaches the reactive center of the quinolone almost only by one diastereotopic half-space. Similar asymmetric reactions have been performed with 3-alkylquinolones carrying a 4-O alkene side chain. In this case, tetrahydrofuran moieties are formed [24].

Scheme 1.2 Construction of a pyrrolidine moiety using an enantioselective [2+2] photocycloaddition.

Source: Alonso and Bach [23] / John Wiley & Sons.

The substrate can also be complexed to a metal or a strong coordinating atom. In such a case, chirality is induced by a chiral ligand sphere [25]. In this context, chiral Lewis acid 11 was used to catalyze the asymmetric intramolecular [2+2] photocycloaddition of the dihydropyridinone derivative 12 (Scheme 1.3) [26]. In this reaction, a d-valerolactam moiety (13) is formed. By complexation with a Lewis acid, the absorption maximum of compound 12 is shifted from 290 to 350?nm. Using fluorescent lamps with an emission ?max = 366?nm, complex 14 was excited almost exclusively since the noncomplexed substrate 12 does not absorb light in this spectral range. Thus, the formation of racemic product as background reaction is suppressed. In the complex 14, the approach of the olefin to the reaction center again occurs by one diastereotopic half-space.

Scheme 1.3 Enantioselective Lewis acid catalysis of an intramolecular [2+2] photocycloaddition reaction.

Source: Brimioulle and Bach [26] / American Association for the Advancement of Science.

a,a,a´,a´-Tetraaryl-2,2-disubstituted 1,3-dioxolane-4,5-dimethanols (TADDOLs, e.g. 23) are capable of complexing numerous substrates via hydrogen bonds [27]. When a photochemical substrate is complexed with such compounds, chirality can be induced. Under these conditions, when the flavone derivative 15 was irradiated with the diphenyl butadiene 16, a [2+3] cycloaddition took place, leading to compounds 17 and 18 (Scheme 1.4) [28]. After reduction with NaBH4, compounds 19 and 20 were isolated in good yields. Furthermore, the major diastereoisomer 19 was obtained in high enantioselectivity, and recrystallization led to almost enantiopure samples. The high enantioselectivity of the photochemical reaction was explained by the structure of complex 21, which strongly favors the attack of the olefin by only one diastereotopic half-space. Interestingly, when the sterically much less encumbered chiral alcohol 22 was added instead of the TADDOL compound 23, an efficient chiral induction was still observed. The high enantioselectivity observed with...