HETEROCYCLES

Review | Regular issue | Vol. 89, No. 3, 2014, pp. 579-625
Received, 12th November, 2013, Accepted, 28th November, 2013, Published online, 17th December, 2013.
DOI: 10.3987/REV-13-787

■ Photoinduced Electron Transfer-Initiated Cyclization Reactions and Asymmetric Transformations of (Z)-α-Dehydroamino Acid Derivatives

Tetsutaro Igarashi and Tadamitsu Sakurai*

Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa University, 3-27-1 Rokkakubashi, Kanagawa-ku, Yokohama 221-8686, Japan

Abstract

We systematically investigated the cyclization reactions of N-acyl-α-dehydroamino acid derivatives, initiated by electron transfer (ET) from aliphatic amines to these derivatives in the excited state. On the basis of the percent conversion of the starting α-dehydroamino acid and the composition of the cyclization products, we demonstrated that the photoinduced ET reactions of N-acyl-α-dehydroarylalaninamides, 1,2,4-triazole-substituted α-dehydroarylalaninamides, and N-acyl-α-dehydroarylalanine alkyl esters efficiently proceeded to afford various 3,4-dihydroquinolinone; quinolinone; and 4,5-dihydrooxazole derivatives, respectively, with high selectivities. In addition, the introduction of chiral auxiliary groups into N-acyl-α-dehydroamino acid amide and ester derivatives and the presence of chiral aliphatic amines induced efficient diastereoselective and enantioselective photocyclization reactions of these amide and ester derivatives, respectively, to enable the construction of the chiral dihydroquinolinone and dihydrooxazole rings.

CONTENTS
1. Introduction
2. Photoinduced electron transfer-initiated cyclization reactions
2-1. (Z)-N-Acyl-α-dehydro(1-naphthyl)alanine N´-dialkylaminopropylamides
2-2. (Z)-N-Acyl-α-dehydronaphthylalanine N´-alkylamides
2-3. 1,2,4-Triazole-substituted (Z)-α-dehydroarylalaninamides
2-4. (Z)-N-Acyl-α-dehydroarylalanine alkyl esters
3. Achiral amine- and chiral amine-catalyzed asymmetric photocyclization reactions
3-1. Chiral auxiliary-substituted (Z)-N-acyl-α-dehydroarylalaninamides
3-2. (Z)-N-Acetyl-α-dehydro(1-naphthyl)alaninamides
3-3. Chiral auxiliary-substituted (Z)-N-benzoyl-α-dehydronaphthylalanine alkyl esters and related
derivatives
3-4. (Z)-N-Benzoyl-α-dehydronaphthylalanine tert-butyl esters
4. Conclusion

1. INTRODUCTION
Organic photochemical reactions contribute to unique methods for the synthesis of organic compounds with complicated structures, which could not be synthesized by conventional methods.1,2 Particularly, photocycloaddition and photocyclization reactions have enabled the construction of various types of carbocyclic and heterocyclic ring systems, even at low temperatures. Recently, photoinduced electron transfer (PET)-initiated cyclization reactions have received considerable attention owing to their wide range of synthetic applications.1a,2 In addition, a systematic study of these PET reactions proceeding through exciplexes or radical ions has provided new and interesting mechanistic information on organic photochemistry. Whether one should employ one-electron reductants or one-electron oxidants in these PET reactions depends on the redox potentials of the reactants that undergo PET-initiated cycloaddition and cyclization.
It has long been known that the irradiation of various types of aromatic olefins, including heteroaromatic-substituted olefins, induces interesting cycloaddition and cyclization reactions in the presence of oxidizing agents to produce valuable carbocyclic and heterocyclic compounds.1b,c However, there has been no systematic study on the photochemical reactivity of naturally occurring α,β-unsaturated aromatic amino acid derivatives (aromatic α-dehydroamino acid derivatives) that have potential pharmacological activity. Because these dehydroamino acids possess photochemically reactive olefins, they are expected to undergo either photocycloaddition or photocyclization under various irradiation conditions to construct pharmacologically active heterocyclic rings. Unfortunately, the high thermal reactivity of unsubstituted α-dehydroamino acids renders the use of these amino acids as reactants very difficult for the photochemical study.3 To overcome this difficulty, the amino functional group of α-dehydroamino acids was N-acylated to enable the design of N-acyl-α-dehydroarylalaninamides and N-acyl-α-dehydroarylalanine alkyl esters. We expected that the presence of the acylamino- and aryl-substituted vinyl groups in these α-dehydroamino acid derivatives would enhance the ability to remove an electron from typical one-electron reductants. In this review, we describe intramolecular and intermolecular PET-initiated cyclization reactions of various substituted α-dehydroamino acid derivatives and PET-initiated diastereoselective and enantioselective cyclization reactions of these derivatives.

2. PHOTOINDUCED ELECTRON TRANSFER-INITIATED CYCLIZATION REACTIONS

2-1. (Z)-N-Acyl-α-dehydro(1-naphthyl)alanine N´-dialkylaminopropylamides4–7
In previous studies, we have shown that the selective excitation of the 1-naphthyl chromophore in N-acetyl-1-naphthylalanine N´-diethylaminopropylamide 1 causes efficient fluorescence quenching of this chromophore.8 The effects of solvent polarity, solvent viscosity, and the distance between the naphthalene ring and diethylamino nitrogen on the rate constant of the fluorescence quenching presented kinetic evidence for the participation of a singlet exciplex mechanism in both polar and nonpolar solvents. In addition, the observation of a correlation between the free energy change in electron transfer (ET) and the solvent viscosity supported the existence of an exciplex-derived solvent-separated radical ion pair intermediate in polar solvents (Scheme 1).

Thus, it is expected that intramolecular PET in (Z)-N-acyl-α-dehydro(1-naphthyl)alanine N´-dialkylaminopropylamides (Z)-2 generates the corresponding radical ion pair intermediates in polar solvents (Figure 1).
Substituted α-dehydro(1-naphthyl)alaninamides (Z)-2 were synthesized by the ring-opening reactions of thermodynamically more stable (Z)-4-(1-naphthylmethylene)-5(4H)-oxazolones, prepared from the improved Perkin reaction between aromatic aldehydes and N-acyl glycines, with N,N-dialkylaminopropylamines in good yields (Scheme 2).9 To test the photocyclization reaction,

a nitrogen-saturated methanol solution containing (Z)-2a was irradiated at room temperature. When the crystalline product mixture was washed with ether and hexane, analytical grade 3,4-dihydrobenzo[f]quinolinone 3a was isolated in 60% yield. 1H NMR spectral analysis of the remaining products indicated the formation of benzo[f]isoquinoline 4a, cis-4,5-dihydrooxazole cis-5a, and (E)-2a (Scheme 3).
The photoproducts isolated were very stable during irradiation, which allowed us to monitor the reaction by 1H NMR spectroscopy, as shown in Table 1. Time-course analysis of the product composition demonstrated the rapid production of (E)-2a and the subsequent increase in the percent compositions of 3a–5a with a decrease in the percent compositions of (Z)- and (E)-2a; these results are consistent with a mechanism in which these excited-state isomers serve as precursors of the photoproducts 3a–5a.
In addition to the observation of intramolecular fluorescence quenching by ET from the dimethylamino nitrogen to the excited-state naphthylmethylene moiety in 2a, energy-minimized conformations for (Z)-2a and (E)-2a suggest that the (E)-2a-derived radical ion pair is the precursor of the dihydrobenzoquinolinone 3a and the dihydrooxazole 5a while the benzoisoquinoline 4a is formed via

cyclization of the (Z)-2a-derived radical ion pair, as shown in Scheme 4.
To extend the synthetic utility of the highly selective cyclization reaction constructing the 3,4-dihydroquinolinone ring, the effects of the substituents R1 and R2 on the photoreactivity of 2a–c and 2d–f, respectively, and the selectivity of 3 were explored under the same irradiation conditions, as those for (Z)-2a (Table 2). Although R1 in 2b and 2c exerts only a small effect on the photoreactivity (conversion) of 2a, the electron-withdrawing Cl, CF3, and CN groups in 2g–i lower the photoreactivity of 2f.
It is likely that the charge-transfer interaction between the dimethylamino and aromatic acyl groups

contributes to the deactivation of the excited-state (Z)- and (E)-isomers. In contrast, the selectivity of the photochemically stable dihydrobenzoquinolinone derivatives 3a–i (39–92%) is not significantly affected by the substituents R1 and R2. Thus, the intramolecular PET-initiated cyclization reactions described above constitute a novel photochemical method for constructing the 3,4-dihydrobenzoquinolinone ring.
In the course of a study regarding the inhibitory effect of oxygen on the aforementioned photocyclization reactions, we found the quantitative conversion of (Z)-N-acetyl-α-dehydroarylalanine N´-dialkylaminoethylamides (Z)-6a–d to the corresponding (Z)-2-imidazolin-5-one derivatives (Z)-7 and hydrogen peroxide in oxygen-saturated methanol (Scheme 5). The X-ray single-crystal structural analysis of the imidazolinone (Z)-7c provided definitive evidence for its structure and configuration (Scheme 5).

The facts that the protic polar solvent methanol greatly accelerates the cyclization reaction and the exclusion of a dimethylamino group in reactant (Z)-6a completely inhibits this reaction substantiate the participation of ET from the tertiary amino nitrogen to oxygen in the initiation step of the reaction, as shown in Scheme 6.
Although many routes to 2-imidazolin-5-one derivatives have been developed,10 there is no synthetic method that utilizes the cyclization reaction of N-acetyl-α-dehydroarylalaninamides activated by ET to oxygen in methanol. Therefore, the oxidative cyclization reaction of (Z)-6 provides a novel synthetic route to the imidazolinone (Z)-7.

2-2. (Z)-N-Acyl-α-dehydronaphthylalanine N´-alkylamides11–13

To explore the PET-initiated cyclization reaction (enabling the construction of the dihydroquinolinone ring) in more detail, (Z)-N-acyl-α-dehydronaphthylalaninamides 8a–g, 9a–f, and 10a–c were designed and synthesized in good yields according to the same procedures as described in the preceding section (Figure 2). Irradiation of a nitrogen-saturated methanol solution containing 8f (R1 = Bu) and triethylamine (TEA) (electron donor) at room temperature resulted in the formation of 3,4-dihydrobenzo[f]quinolinone 11f (isolated yield, 45%), benzo[f]isoquinoline 12f (14%), and (E)-8f (5%) (Scheme 7). 1H NMR spectral analysis of the irradiated mixture suggested the existence of minor amounts of cis-4,5-dihydrooxazole 13f.

The finding that the fluorescence of 8f in methanol is quenched by TEA, according to the Stern–Volmer equation, is consistent with the involvement of ET from TEA to the excited-state 8f in the primary step of the photocyclization reaction observed, as already suggested. Furthermore, 1H NMR spectral analysis of the reaction showed no change in the TEA concentration during irradiation, and the N´-butylamide deuteron of the starting (Z)-8f was transferred to the 3-position on the dihydroquinolinone ring formed by its photocyclizaton. Thus, the intermolecular PET-initiated cyclization processes shown in Scheme 8 provide a reasonable explanation for these observations.
Comparison of the dependence of the product compositions, derived from (Z)-8f and (E)-8f, on irradiation time confirms that photoisomerization between these two isomers is not as fast as the subsequent ET and cyclization processes (Table 3). Additionally, analysis of the compositions for 11f–13f led us to conclude that the excited-state (Z)- and (E)-isomers serve as precursors to benzoisoquinoline 12f and dihydrobenzoquinolinone 11f/dihydrooxazole 13f, respectively, as depicted in Scheme 8. ET from TEA to the two excited-state isomers supports a mechanism in which the isoquinoline skeleton is constructed by the cyclization of the (Z)-isomer-derived radical anion.

To inspect the synthetic utility of the intermolecular PET-initiated cyclization reaction, effects of the substituent R1 on the photoreactivity (conversion) of 8 and selectivity of 11–13 were analyzed (Table 4). Clearly, dihydrobenzoquinolinone 11 gives the highest selectivity among these three cyclization products, and its selectivity decreases with an increase in the steric bulk of R1. This decrease in selectivity is reflected in enhanced selectivity for 12 and 13, providing additional evidence for a mechanism in which ET to the excited-state (E)-8 and the subsequent cyclization to 11 occurs in competition with the isomerization to (Z)-8 and cyclization eventually affording 13. It is also noteworthy that the introduction of bulky tert-butyl and phenyl groups as R1 completely inhibits the formation of the corresponding dihydrobenzoquinolinones.

Meanwhile, when nitrogen-saturated methanol solutions containing (Z)-9 or (Z)-10 were irradiated in the presence of TEA (for 9) or DBU (for 10) under the same conditions as those for (Z)-8, the corresponding 3,4-dihydrobenzoquinolinones 14 (Scheme 9) or 16 (Scheme 10) were produced with high selectivity (>82% and >63%, respectively), along with minor amounts of 4,5-dihydrooxazoles 15 or 17. Replacement of the N-acetyl group in 8 by bulky aroyl and pivaloyl groups greatly lowers the photoreactivity of this α-dehydro(1-naphthyl)alaninamide. As already suggested in the preceding section, this may be owing to the decreased efficiency of ET from TEA to the 1-naphthylmethylene moiety of 9 in the excited state. Moreover, substituting the 1-naphthylmethylene chromophore with 2-naphthylmethylene drastically lowered the reactivity of (Z)-9.

We found that the free energy change for ET from TEA to (E)-9e [R2 = 2,4-(OMe)2C6H3] in the singlet excited state is –85 kJ mol–1, and this excited-state (E)-isomer quantitatively yields dihydrobenzoquinolinone 14e. These results enabled us to estimate relative rates for ET and related processes through the analysis of the TEA concentration dependence of quantum yield for the appearance of this cyclization product (Φ14e, Scheme 11). The relative rates summarized in Table 5 demonstrate that the rate of ET (ket) is faster than that of the deactivation and isomerization (kd + ki) of (E)-9e in the excited state by a factor of around 2, and that the rate of back ET (k–et) is 14 times as fast as that of cyclization eventually affording 14e (k14e). Therefore, analysis of these relative rates led to the conclusion that the relative rate k–et/k14e is a major factor that controls the overall efficiency of the PET-initiated cyclization reaction of (E)-9e.

To further expand the study of the PET-initiated cyclization reactions forming substituted dihydroquinolinones, (Z)-N-acyl-α-dehydro(methoxy-substituted phenyl)alanine N´-methylamides (Z)-18a–g were designed and synthesized in good yields (Figure 3). Irradiation of nitrogen-saturated methanol solutions containing these α-dehydroarylalaninamide derivatives and DBU gave nearly the same product distribution as that for (Z)-9 (Scheme 12).

When TEA was used instead of DBU as an electron donor, the conversion of 18a decreased and the selectivity of 19a also decreased with the increased selectivity of 20a. The former finding confirms that α-dehydrophenylalaninamide derivative 18 is considerably less reactive than the corresponding 1-naphthylalaninamide derivative 9. The latter finding is consistent with the involvement of two different modes of cyclization competitively forming 19 (selectivity: 82–94%) and 20. The minor products 20 and 21 were readily removed by recrystallization from ethanol.
As described in sections 2-1 and 2-2, intramolecular and intermolecular PET-initiated cyclization reactions of various (Z)-N-acyl-α-dehydroarylalaninamides in methanol proceed cleanly and efficiently to produce the corresponding substituted 3,4-dihydrobenzoquinolinones in good to high yields, although these photochemical transformations experience significant steric hindrance. There are many synthetic routes to medium-sized lactams fused to an aromatic ring,14 whereas convenient photochemical routes to these lactams are scarce.15 Thus, our PET-initiated cyclization reactions present a novel method for constructing the 3,4-dihydroquinolinone ring.

2-3. 1,2,4-Triazole-substituted (Z)-α-dehydroarylalaninamides16–18
Hydrazides have frequently been utilized as convenient building blocks for creating various heterocyclic ring systems.19 If we could introduce a hydrazide chromophore into an α-dehydroamino acid derivative, it would be possible to pave the way for a new mode of a PET-initiated cyclization reaction. When (Z)-2-methyl-4-(1-naphthylmethylene)-5-(4H)-oxazolone was allowed to react with an equimolar amount of acetohydrazide in acetonitrile, 1,2,4-triazole-substituted (Z)-2-propenoic acid derivative (Z)-22a was quantitatively obtained (Scheme 13). The X-ray crystal structure depicted in Scheme 13 provided definitive evidence for the structure of 22a [hereafter, referred to as 1,2,4-triazole-substituted (Z)-α-dehydro(1-naphthyl)alanine].

The reactions of (Z)-2-methyl-4-arylmethylene-5-(4H)-oxazolones with several hydrazide nucleophiles led to the formation of the corresponding 1,2,4-triazole-substituted (Z)-α-dehydroarylalanines (Z)-22a–m in high yields (Table 6). Meanwhile, the observation that a small amount of the expected ring-opening product 23 was detected along with (Z)-22 and (E)-22 in the mixture of products obtained from the

reaction of the oxazolone with acetohydrazide suggests that this oxazolone has three sites for the nucleophilic addition of hydrazides, as shown in Scheme 14. The first site is the C=O double bond in the oxazolone ring, the second site is the C=N double bond in this ring, and the third site is the arylmethylene C=C double bond. A comparison of the heats of formation (ΔHf) for the energy-minimized adducts I (ΔHf for Ar = Ph, R = Me = –290.1 kJ mol–1), II (–257.0 kJ mol–1), and III (–272.8 kJ mol–1) proves that the adduct I is the most stable intermediate; hence, its formation becomes a major process in the reaction. The ring-opening reaction with hydrazides is considered to be a thermodynamically controlled process.
Because little is known about the photochemical behavior of triazole derivatives,20 we synthesized 1,2,4-triazole-substituted (Z)-α-dehydro(1-naphthyl)alaninamides (Z)-24a–h (Figure 4) and explored their PET-initiated cyclization reactions. When a nitrogen-saturated methanol solution containing (Z)-24a and TEA was irradiated at room temperature (internal irradiation), 1-methylbenzo[f]quinolinone (25a), 3,4-dihydrobenzo[f]quinolinone 26a, and 3,5-dimethyl-1,2,4-triazole (27a) were isolated in 65%, 15%, and 40% yields, respectively (Scheme 15).

Analysis of solvent and substituent effects on the composition ratio of 25 to 26, summarized in Table 7,
led us to propose that the relative composition of these cyclization products is controlled by an equilibrium between the initially formed 1-naphthylmethylene radical ion pair intermediates (E)-IVA and (E)-IVB, as depicted in Scheme 16.

On the other hand, the replacement of the 1-naphthyl group in (Z)-24 by the methoxy-substituted phenyl ring [(Z)-28a–c, Figure 5] lowered the photoreactivity of the alaninamide derivative without exerting a great effect on the quinolinone selectivity.

Although there are several synthetic studies aimed at constructing the quinolinone ring,21 only limited photochemical routes are available for this nitrogen-containing aromatic heterocycle.22 Thus, the PET-initiated cyclization reactions of triazole-substituted (Z)-α-dehydroarylalaninamides provide a convenient method for synthesizing several quinolinone derivatives.

2-4. (Z)-N-Acyl-α-dehydroarylalanine alkyl esters23–25
We already showed that in the PET-initiated cyclization reactions of (Z)-N-acyl-α-dehydro(1-naphthyl)alaninamides that produce the corresponding 3,4-dihydrobenzoquinolinone, benzoisoquinoline, and 4,5-dihydrooxazole derivatives, the replacement of the N-acetyl group by the N-benzoyl group greatly lowered the benzoisoquinoline selectivity owing to the steric hindrance by the latter acyl group. Additionally, the N´-alkylamide nitrogen was shown to be involved in the dihydrobenzoquinolinone-forming cyclization process. Thus, it was predicted that (Z)-N-aroyl-α-dehydro(1-naphthyl)alanine alkyl esters (Z)-29a–l would undergo PET-initiated cyclization reactions to selectively afford the corresponding 4,5-dihydrooxazoles (Figure 6).

After a nitrogen-saturated methanol solution containing (Z)-29a and TEA was irradiated for a set period of time at room temperature, standard workup of the reaction mixture allowed us to almost quantitatively isolate cis- and trans-4-methoxycarbonyl-5-(1-naphthyl)-2-phenyl-4,5-dihydrooxazoles (cis-30a and trans-30a, Scheme 17). This result is consistent with our prediction and the unambiguous structure of these two photoproducts was provided by X-ray single-crystal structural analysis, as depicted in Figure 7. We unexpectedly found that the compositon ratio of cis-30a to trans-30a decreases with irradiation time, suggesting the occurrence of the TEA-catalyzed isomerization of the cis-isomer to the thermodynamically more stable trans-isomer (see Scheme 18). This isomerization was substantiated by a control study showing that cis-30a slowly isomerized in the presence of TEA to furnish a 9:1 equilibrium mixture of the trans- and cis-isomers, respectively. The observed isomerization also confirms the involvement of a carbanion intermediate in this process.

The use of the reduction potential of 29a (Ered = –2.26 eV vs. Ag/AgCl in MeCN), the oxidation potential of TEA (Eox = 0.76 V), and the first singlet excitation energy of 29a (ES = 368 kJ mol–1) enabled the estimation of the free energy change (ΔGet) for ET from TEA to this singlet excited-state α-dehydronaphthylalanine methyl ester as –77 kJ mol–1, on the basis of the simplified Weller equation: ΔGet = 96.5(Eox – Ered) – ES. The additional finding that the fluorescence intensity of (Z)-29a–e is considerably reduced with increasing electron-withdrawing ability of the substituent R2 attached to the N-benzoyl benzene ring confirms the formation of the acyl radical anion intermediate in a stepwise manner, as shown in Scheme 18.
As already discussed, 4,5-dihydrooxazole derivatives 30 are likely produced through the (E)-29-derived radical ion pair intermediate (E)-VB. In this scheme, significant steric hindrance by the bulky naphthyl group bonded at the 5-position of the oxazole ring causes a hydrogen shift in the biradical intermediate VI to proceed from the opposite side of this group, preferentially forming cis-30. Thus, the hydrogen shift can be regarded as a kinetically controlled process. Additionally, because the introduction of the bulky tert-butyl group into the alkoxy carbonyl moiety produces the corresponding cis-isomers with high selectivity without undergoing any TEA-catalyzed cis → trans isomerization (Table 8), the use of N-acyl-α-dehydroarylalanine tert-butyl esters (Z)-29f–l enables a discussion about the substituent effects on the cis-30 selectivity and photoreactivity of the starting 29.
As shown in Table 9, the cis-isomer selectivity has a clear tendency to increase with an increase in the steric bulk of the aryl substituents. Moreover, the photoreactivity (conversion) of 29 decreases in the

following order: 29c (Ar = 1-naphthyl) > 29h (Ar = phenyl) > 29l (Ar = 2,6-Me2C6H3), and this reactivity tends to be enhanced with increased electron-withdrawing ability of the aromatic acyl group. These results suggest that the reactivity is mainly determined by intermolecular electron transfer efficiency from TEA to 29 in the excited state, intramolecular ET efficiency from the 1-naphthylmethylene radical anion to the aromatic acyl group in (E)-VA, and steric hindrance to the cyclization process of the radical ion pair intermediate (E)-VB (Scheme 18).
There are several synthetic routes to 4,5-dihydrooxazole derivatives, but a convenient photochemical route to these derivatives has not yet been developed.26 The PET reactions described above efficiently proceed to quantitatively afford cis- and trans-4,5-dihydrooxazoles, and the composition ratio of these two cyclization products can be controlled by utilizing the steric and electronic effects of the alkyl and aryl substituents introduced into (Z)-29. Therefore, the PET-initiated cyclization reactions of (Z)-N-acyl-α-dehydronaphthylalanine alkyl esters constitute a novel photochemical method for constructing a pharmaceutically useful 4,5-dihydrooxazole ring.
On the basis of the photocyclization mode, according to which α-dehydro(1-naphthyl)alanine alkyl esters (Z)-29 are converted into substituted 4,5-dihydrooxazoles 30, we predict that the replacement of the N´-amide hydrogen in (Z)-N-benzoyl-α-dehydro(1-naphthyl)alanine N´-alkylamides by an alkyl group would funnel the corresponding N´,N´-dialkylamide derivatives (Z)-31a,b toward the 4,5-dihydrooxazole heterocycles by eliminating the pathway to the 3,4-dihydroquinolinones (Figure 8).

The PET reactions of (Z)-31 in nitrogen-saturated methanol containing TEA less efficiently proceeded than those of the corresponding 1-naphthylalanine tert-butyl esters to produce cis-4,5-dihydrooxazole derivatives cis-32 in preference to trans-32 as predicted (Scheme 19). Additionally, the use of 1,2-dichloroethane as a solvent greatly enhanced the cis-isomer selectivity and photoreactivity of the starting α-dehydronaphthylalaninamides under the same irradiation conditions.

3. A CHIRAL AMINE- AND CHIRAL AMINE-CATALYZED ASYMMETRIC PHOTOCYCLIZATION REACTIONS

3-1. Chiral auxiliary-substituted (Z)-N-acyl-α-dehydroarylalaninamides27–29
As described in the preceding chapter, the PET-initiated cyclization reactions of (Z)-N-acyl-α-dehydroarylalaninamides cleanly proceeded to construct the dihydroquinolinone ring in high selectivity. Because this heterocyclic ring possesses an asymmetric carbon at the 3-position, it is possible to develop our PET-initiated reactions into diastereoselective cyclizations by introducing various chiral auxiliary groups into the starting α-dehydroarylalaninamides. To find a new type of asymmetric photocyclization and shed more light on the dihydroquinolinone ring formation mechanism, we synthesized (Z)-N-acyl-α-dehydro(1-naphthyl)alaninamides bearing the (S)-alanine methyl ester auxiliary group, (Z)-33a,b (Figure 9) and calculated the diastereomeric excess (de) of each of the corresponding 3,4-dihydrobenzo[f]quinolinone derivatives formed under several cyclization conditions.

Irradiation of a nitrogen-saturated methanol solution containing (Z)-33 and TEA led to the formation of the 3,4-dihydrobenzoquinolinone diastereomers (S,S)-34 and (R,S)-34, along with benzoisoquinoline derivative 35 (Scheme 20). On the basis of the absolute configuration of one of these two diastereomers (R,S)-34b, shown in Figure 10, and the chemical shifts of their methine proton NMR signals, we could determine the compositions and de of (S,S)-34 and (R,S)-34, which were collected in Table 10.

Inspection of the data in this Table reveals that the increased steric bulk of the tertiary amine significantly lowers the de for the (S,S)-diastereomer formed in excess; the decreased hydrogen-bonding solvation ability of methanol has a clear tendency to substantially enhance the de for this diastereomer. As

discussed in the preceding chapter, the asymmetric carbon at the 3-position of the dihydroquinolinone ring is likely generated through the tautomerization of the corresponding enol intermediate (Scheme 8). In addition, energy-minimized conformations of this intermediate containing the N-benzoyl group are very similar to the X-ray crystal structure of (R,S)-34b (Figure 11), confirming that the methoxycarbonyl group in the (S)-alanyl chiral auxiliary is preferentially directed to the re face; hence, there is a difference in the extent of hydrogen bonding and electrostatic interactions of the tertiary amine with the enol intermediate between the two diastereofaces. It is likely that more favorable hydrogen bonding and electrostatic interactions in the re-face side of this intermediate force the enol hydroxy proton to add to the olefinic carbon preferentially from the re face, affording the (S,S)-diastereomer in excess, as depicted in Scheme 21.

Because the conformation of the chiral auxiliary in the enol intermediate clearly plays an essential role in controlling the configuration and de of the diastereomer formed in excess, the use of the (S)-alaninamide-type chiral auxiliaries shown in Figure 12 was expected to exert a great effect on the stereochemistry of enol → keto tautomerization. Irradiation of a nitrogen-saturated methanol solution containing (Z)-36a and TEA at room temperature led to the formation of 3,4-dihydrobenzoquinolinones (S,S)-37a and (R,S)-37a with higher selectivity (71%) than that (49%) for the 33a-derived dihydroquinolinone, along with benzoisoquinoline 38a and 4,5-dihydrooxazole 39a (Scheme 22).

On the basis of the sign of the 255-nm circular dichroism (CD) bands for (S,S)-37 and (R,S)-37 and the 1H NMR spectral data of these diastereomers, the de value of the major diastereomer was determined. The effects of the substituent, solvent, tertiary amine, and reaction temperature on the selectivity and de of 37 were summarized in Table 11. In contrast to the asymmetric photocyclization behavior of (S)-alanine methyl ester auxiliary-substituted derivatives (Z)-33, the temperature exerted a great effect on the de, whereas this de was only slightly affected by the steric bulk of the amine and the solvent. These findings suggest that the aforementioned hydrogen bonding and electrostatic interactions between the amine and the enol intermediate make a negligible contribution to asymmetric induction observed in the cyclization process of (S)-alaninamide auxiliary-substituted derivatives (Z)-36.

A marked temperature dependence of de and a large difference in thermodynamic stability between the cyclized enol intermediates VIIIA (ΔHf for R = Me = –300.8 kJ mol–1) and VIIIB (–294.4 kJ mol–1), shown in Scheme 23, led us to suggest two conclusions: a pre-equilibrium exists between the enol biradical intermediates VIIA and VIIB, and steric repulsion between the methyl hydrogen in the chiral auxiliary and/or the naphthalene ring hydrogen at its 2-position and the enol hydroxy hydrogen is a predominant factor determining both the major diastereomer formed and the position of this pre-equilibrium. Higher thermodynamic stability of VIIIA (that shifts the pre-quilibrium to the VIIA side) and enol → keto tautomerization (that preferentially proceeds from the re face in VIIIA) are consistent with the preferential formation of the (S,S)-diastereomer (Table 11). Additionally, the alkyl and aryl substituents incorporated into the chiral auxiliaries are considered to affect the relative stability of VIIIA and VIIIB. The use of an (S)-alanine N´-(4-cyanophenyl)amide auxiliary enhanced de for (S,S)-37 up to 92%.

3-2. (Z)-N-Acetyl-α-dehydro(1-naphthyl)alaninamides30
In the preceding section, we demonstrated that in addition to the relative stability of the diastereomeric

enol intermediate, hydrogen bonding and electrostatic interactions between the tertiary amine and this intermediate are factors controlling the magnitude of de for the observed diastereoselective photocyclization. The latter finding makes it possible to design an enantioselective photocyclization of N-acyl-α-dehydro(1-naphthyl)alaninamides in the presence of a chiral amine. To develop a new type of asymmetric photocyclization, nitrogen-saturated 2-propanol or dichloromethane solutions containing α-dehydroamino acid amides (Z)-40a–d and (S)-1-methyl-2-pyrrolidinemethanol (S-MPM) or (S)-nicotine (S-NT) were irradiated at room temperature and –78 °C (Figure 13).

The absolute configuration of 3,4-dihydrobenzo[f]quinolinone products (S)-41 and (R)-41 obtained by irradiation at room temperature or –78 °C was determined by separating the 40-derived enantiomeric product mixture into the (S)- and (R)-enantiomers using a chiral HPLC column, followed by measuring their CD spectra (Scheme 24). The effects of chiral amine, solvent, temperature, and substituent on the enantiomeric excess (ee), summarized in Table 12, reveal that the use of S-MPM induces an asymmetric photocyclization reaction of (Z)-40a to produce (R)-41a in 7% ee (i-PrOH) and 30% ee (CH2Cl2), whereas the change of chiral amine to S-NT reverses the configuration of the major enantiomer with an accompanying remarkable enhancement in ee in 2-propanol at room temperature (7% → 23%).
Furthermore, the lowering of temperature enhanced selectivity and ee for (S)-41a in all solvents, although ee for the (R)-enantiomer formed in excess was only slightly increased by this temperature depression, substantiating the participation of a different mode of hydrogen-bonding interaction by S-NT and S-MPM. The data in Table 12 also show that an increase in the steric bulk of the substituent R has a clear tendency to diminish ee for (S)-41; hence, the amide N–H hydrogen is involved in the hydrogen bonding between S-NT and the enol intermediates IX and X (Scheme 25).

In addition, in the PET-initiated enantioselective cyclization reactions of (Z)-40, it is reasonable to assume a pre-equilibrium between the biradical enol intermediates IXA and IXB, depicted in Scheme 25, to explain the observed chiral amine, temperature, and substituent effects. Thus, the foregoing hydrogen-bonding interaction is considered to control the pre-equilibrium and assist the tautomerization of the cyclized enol intermediates XA and XB. The fact that the (S)- and (R)-enantiomers are produced in excess in the presence of S-NT and S-MPM, respectively, confirms that the former chiral amine is preferentially hydrogen bonded to the biradical enol IX (R = Me) in the si face and the latter amine to the re face (Figure 14).

3-3. Chiral auxiliary-substituted (Z)-N-benzoyl-α-dehydronaphthylalanine alkyl esters and related derivatives31–33
In the preceding chapter, we described the selective formation of substituted 4,5-dihydrooxazoles by the PET-initiated cyclization reactions of (Z)-N-benzoyl-α-dehydroarylalanine alkyl esters. As the 4,5-dihydrooxazole ring possesses two asymmetric carbon atoms in its ring, it was possible to develop a novel PET-initiated asymmetric cyclization reaction of these α-dehydroarylalanine alkyl esters by introducing a chiral auxiliary into the ester moiety.

To explore the effects of chiral auxiliary, solvent, and temperature on the de for cis- and trans-4,5-dihydrooxazoles formed in the presence of TEA or 2-(diethylamino)ethanol (DEAE), three types of bulky chiral auxiliary-substituted (Z)-N-benzoyl-α-dehydro(1-naphthyl)alanine alkyl ester derivatives (Z)-42a–c were designed and synthesized in good yields (Figure 15).
As shown in Scheme 26, irradiation of a nitrogen-saturated methanol solution containing (Z)-42a and TEA or DEAE at room temperature mainly yielded trans-dihydrooxazole-derived diastereomeric mixture [(4S,5R)-43a + (4R,5S)-43a], along with minor amounts of a cis-43a-derived mixture [(4R,5R)-43a + (4S,5S)-43a]. These four diastereomers were readily isolated, and the successful growth of single crystals of the diastereomer (4S,5S)-43d (Ar = 1-naphthyl, R = t-Bu), the structure of which is very similar to that of (4S,5S)-43a, enabled the determination of absolute configurations of the four diastereomers isolated, on the basis of the sign of their CD bands at 220 nm and their 1H NMR spectral and HPLC data (Figure 16).

The diastereomer compositions and de values, summarized in Table 13, reveal that the change in solvents from methanol to 1,2-dichloroethane reverses the configuration of the major diastereomer for cis-43a,b without affecting it for trans-43a,b. Additionally, the introduction of a bulky phenylmenthyl auxiliary results in a great increase in de, especially for trans-43c, without affecting it for the cis- and trans-diastereomers formed in these two solvents. These findings suggest that steric and hydrogen-bonding interactions in the π-face selective cyclization process of the (E)-42-derived radical ion pair intermediate XI and a hydrogen shift within the biradical intermediate XIII play predominant roles in inducing asymmetry at the 5- and 4-positions of the dihydrooxazole ring, respectively, as depicted in Scheme 27.

Evidence supporting the hydrogen-bonding interactions of DEAE with the (E)-42-derived reaction intermediates and/or methanol results from the observations that the de’s for cis-43 and trans-43 formed in 1,2-dichloroethane are increased (9% → 30% for the former and 22% → 47% for the latter) with decreasing temperature (50 °C → –78 °C), whereas their de values in methanol are abruptly decreased at –78 °C (32% at 50 °C → 0% at –78 °C for the former and 33% → 11% for the latter). Because configurational interconversions between the intermediates XIIA and XIIB and between the intermediates XIIIA and XIIIB are unlikely to occur during irradiation, we could estimate the compositions of these intermediates and the rate ratios of Paths A, B, and C on the basis of the four diastereomer compositions (Table 14).
Comparison of the composition of XIIA with that of XIIB confirms that asymmetric induction for (Z)-42a and (Z)-42b in 1,2-dichloroethane is achieved at the stage of hydrogen shift in the biradical intermediate XIII while the difference in the radical ion pair XII-forming cyclization rates is responsible for asymmetric induction in methanol. Additionally, the finding that the presence of the phenylmenthyl auxiliary in (Z)-42c greatly enhances the relative composition of XIIA in both solvents implies that steric

repulsion between this bulky chiral auxiliary and the N-benzoyl carbonyl oxygen in the radical ion pair (E)-XI is a dominant factor controlling the relative rate of Path A (Scheme 27). The bulky phenylmenthyl group is considered to exist preferentially in the re face of (E)-XI, leading to a cycloaddition reaction in the si face of this intermediate.
As already demonstrated, the replacement of the alkoxycarbonyl group in N-benzoyl-α-dehydro(1-naphthyl)alanine alkyl esters by the N´,N´-disubstituted aminocarbonyl completely suppressed the TEA-catalyzed isomerization of cis-4,5-dihydrooxazole derivatives formed, although the amidation of the ester moiety lowered the photoreactivity. Furthermore, the increased steric bulk of the alkoxy carbonyl group enhanced selectivity for the cis-dihydrooxazole isomer. Thus, it is predicted that the introduction of a sterically congested chiral auxiliary into the naphthylalaninamide nitrogen enables the selective formation of this cis-isomer; hence, a more detailed analysis of the diastereoselective PET-initiated cyclization reactions of (Z)-44a–g is required (Figure 17).

Irradiation of a nitrogen-saturated methanol solution containing (Z)-44a and TEA selectively gave the corresponding cis-dihydrooxazole-derived diastereomers (4S,5S)-45a and (4R,5R)-45a, as predicted (Scheme 28).

The absolute configurations and compositions of these two diastereomers and the de’s were determined on the basis of their CD and 1H NMR spectral data and summarized in Table 15.
When the solvent was changed from 1,2-dichloroethane to methanol, the configuration of the major diastereomer formed was reversed to afford (4R,5R)-45 in excess in all systems. Intermolecular hydrogen-bonding interactions between this protic solvent molecule and a key intermediate, probably a radical ion pair intermediate, and/or intramolecular hydrogen-bonding interactions within this intermediate are considered to exert a significant effect on the intermediate configuration. As can be

inferred from Scheme 29, no formation of trans-45 suggests that the hydrogen shift in the biradical XVI occurs stereoselectively; hence, de for the cis-isomer is determined in the cyclization of the radical ion pair (E)-XIV to XV. It is likely that hydrogen-bonding and steric interactions in (E)-XIV play decisive roles in controlling stereochemistry of the π-face selective attack of the N-benzoyl carbonyl oxygen.
Analysis of the effects of the aprotic and protic solvents on the magnitude of de for cis-45g, summarized in Table 16, shows that de for (4R,5R)-45g is enhanced with decreasing polarity of protic solvents (de in: MeOH < i-PrOH < t-BuOH), and this de value has a marked tendency to increase as the polarity of aprotic solvents is lowered (de in: CH2ClCH2Cl < CH2Cl2 < CHCl3), although the configuration of the major diastereomer formed in 1,2-dichloroethane is different from that obtained in dichloromethane and chloroform. Because the (4R,5R)-diastereomer is formed as a major photoproduct in methanol, these findings suggest that in addition to the electrostatic interaction in the initially formed radical ion pair intermediate (E)-XIV, a charge-transfer interaction operates between the radical anion in this intermediate and dichloromethane or chloroform. Additional stabilization of (E)-XIV through these electrostatic and hydrogen-bonding interactions is also reflected in a large increase in the photoreactivity of the starting (Z)-44g.

3-4. (Z)-N-Benzoyl-α-dehydronaphthylalanine tert-butyl esters33–35
In the preceding section, we showed that asymmetric induction in the PET-initiated cyclizations of chiral auxiliary-substituted α-dehydroamino acid derivatives was achieved at the stages of intramolecular cycloaddition in the radical ion pair intermediate and hydrogen shift in the biradical intermediate. At the former stage, the steric bulk of chiral auxiliaries is a significant factor controlling the magnitude of de, while at the latter stage, the hydrogen-bonding interaction between the biradical intermediate and aliphatic amine is a major factor governing this magnitude. Thus, the use of chiral amines such as S-PM and S-MPM (Figure 13) was predicted to bring about an asymmetric photocyclization of (Z)-N-benzoyl-α-dehydronaphthylalanine tert-butyl esters (Z)-46a,b (Figure 18).

The PET-initiated cyclization reactions of (Z)-46 quantitatively proceeded in the presence of S-MPM to produce four types of the 4,5-dihydrooxazole enantiomers (Scheme 30). The absolute configuration of these enantiomers and the ee were determined according to the procedure described in the preceding section (Table 17). Additionally, the relative compositions of the biradical intermediates XIIIA and XIIIB (R = t-Bu in Scheme 27) and the rate ratios of Paths A, B, and C were estimated from the relative compositions of (4S,5S)-47, (4R,5S)-47, (4R,5R)-47, and (4S,5R)-47 and collected in Table 18.

Clearly, the rate ratio Rr (A1/A2) for the cyclization process of the radical ion pair (E)-XI is unity, irrespective of the starting α-dehydronaphthylalanine tert-butyl ester and chiral amine (Table 18). Thus, the finding that the replacement of the 1-naphthyl group by the 2-naphthyl enhances ee for cis-47, with a decrease in ee for trans-47 may be explained by the different steric effects of these naphthyl groups on the hydrogen shift in the re and si faces of the intermediate XIII (Table 17). Further inspection of the data in Table 17 shows that when S-PM is used instead of S-MPM, the configuration of major enantiomers for cis-47 and trans-47 is reversed. Participation of the hydrogen-bonded biradical XIII in the key step of asymmetric induction suggests that S-MPM assists the hydrogen shift on the si face through hydrogen bonds formed between the N–Me nitrogen in this chiral amine and N–H hydrogen in XIII and between the O–H hydrogen and ester carbonyl oxygen in this intermediate, as depicted in Figure 19. In contrast, S-PM partially blocks the si face through similar hydrogen-bonding interactions to promote a hydrogen shift in the re face (Figure 19).
On the other hand, irradiation of a nitrogen-saturated 1,2-dichloroethane solution containing (Z)-N-benzoyl-α-dehydro(1-naphthyl)alanine N´-arylamides (Z)-48a,b and S-MPM almost quantitatively afforded the corresponding four 4,5-dihydrooxazole enantiomers (4R,5R)-49, (4S,5S)-49, (4S,5R)-49, and (4R,5S)-49 (Scheme 31).

Analysis of the compositions of these enantiomers, collected in Table 19, establishes that the introduction of a phenolic hydroxy group into (Z)-48a dramatically lowers ee’s for (4S,5S)-49a and (4R,5S)-49a. This finding indicates the negligible participation of a hydrogen-bonding interaction between the aforementioned biradical intermediate and S-MPM in the hydrogen shift within this intermediate. It is likely that intramolecular hydrogen bonding between the N–H nitrogen and phenolic O–H hydrogen in the 48b-derived biradical intermediate, depicted in Figure 20, inhibits the formation of intermolecular hydrogen bonding between S-MPM and this intermediate and increases the relative rate of the hydrogen shift forming the trans-dihydrooxazole isomer. Therefore, the findings described above provide additional evidence for the intervention of a hydrogen-bonded biradical intermediate in the enantioselective photocyclization process of N-benzoyl-α-dehydro(1-naphthyl)alanine tert-butyl esters.

4. CONCLUSION
In this review we highlighted not only PET-initiated cyclization reactions of various (Z)-N-acyl-α-dehydroarylalanine N´-alkylamides, (Z)-N-acyl-α-dehydroarylalanine alkyl esters, and 1,2,4-triazole-substituted (Z)-α-dehydroarylalaninamides but also asymmetric transformations of these α-dehydroarylalanine derivatives.
The intramolecular and intermolecular PET reactions of α-dehydroarylalanine N´-alkylamides in methanol cleanly and efficiently proceeded to mainly produce variously substituted 3,4-dihydroquinolinones, along with minor amounts of isoquinolines and 4,5-dihydrooxazoles, the compositions of which varied depending on the steric bulk of the N-acyl and N´-alkyl groups. The replacement of the N´-amide bond in N-aroyl-α-dehydroarylalaninamides by the ester bond exerted a dramatic effect on the product distribution to cause a selective formation of 4,5-dihydrooxazole derivatives. Inspection of this structural effect on the product distribution and composition revealed that (Z)- and (E)-α-dehydroarylalanine isomers in the excited state serve as the precursors of substituted isoquinolines and dihydroquinolinones/dihydrooxazoles, respectively. When the 1,2,4-triazol-4-yl group was introduced instead of the acylamino group, the PET reactions of the triazole-substituted derivatives afforded substituted quinolinones and dihydroquinolinones without forming any other products, and the composition ratio of these two heterocyclic compounds greatly varied depending on the properties of solvents and substituents examined. Mechanistic analysis of the aforementioned three types of PET-initiated cyclization reactions revealed that the stability of the α-dehydroarylalanine radical anion/aliphatic amine radical cation pair intermediate plays a key role in controlling the distribution and composition of the photocyclization reaction products.
In addition, through the detailed analysis of the effects of chiral auxiliary, chiral amine, aryl and alkyl substituents, protic and aprotic solvents, and temperature on the PET-initiated asymmetric photocyclization reactions enabling the construction of chiral 3,4-dihydroquinolinone and 4,5-dihydrooxazole rings, we were led to propose the following asymmetry-inducing processes: (1) the tautomerization process of the (E)-N-acyl-α-dehydroarylalaninamide-derived hydrogen-bonded enol intermediates and (2) the cyclization process of the (E)-N-acyl-α-dehydroarylalanine alkyl ester-derived radical anion intermediates and the hydrogen shift process of the hydrogen-bonded biradical intermediates, which served as the precursors of the corresponding 4,5-dihydrooxazole derivatives. Furthermore, we could show that the magnitude of de or ee for these asymmetric photocyclization reactions was mainly controlled by the steric and electronic effects of the chiral auxiliary or chiral amine on the asymmetry-inducing processes described above.

ACKNOWLEDGEMENTS
Our study described in this review was partially supported by a 'High-Tech Research Project' and a 'Scientific Frontier Research Project' from the Ministry of Education, Culture, Sports, Science and Technology in Japan.

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