HETEROCYCLES

Communication | Regular issue | Vol. 83, No. 10, 2011, pp. 2255-2263
Received, 21st May, 2011, Accepted, 19th July, 2011, Published online, 22nd July, 2011.
DOI: 10.3987/COM-11-12265

■ Asymmetric Photocyclization Reactions of N-Acetyl-α-dehydro(1-naphthyl)alaninamides in the Presence of Chiral Amine

Kei Maekawa, Toshiyuki Tanami, Tetsutaro Igarashi, and Tadamitsu Sakurai*

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

Abstract

Irradiation of the title compound having an N’-methyl group in 2-propanol and dichloromethane containing (S)-1-methyl-2-pyrrolidinemethanol at room temperature afforded (R)-3,4-dihydrobenzo[f]quinolinone derivative in enantiomeric excesses (ee’s) of 7 and 30%, respectively. On the other hand, the corresponding (S)-enantiomer was obtained in 21–23% ee’s on room temperature irradiation in the above solvents containing (S)-nicotine which enhanced these ee values up to 34–59% at –78 °C.

Excited-state chemistry for organic molecules has continued to contribute to the development of novel synthetic methods that enable the construction of pharmaceutically useful hetero atom-containing rings.1 While sophisticated organic photochemistry has also contributed to the enhancement of enantio- and diastereoselectivities in many asymmetric reactions,2–5 there have been only a few enantio- and diastereodifferentiating photochemical reactions of synthetic utilities, particularly in liquid phase. Taking into account the potential that in many cases photoinduced electron transfer reactions are able to construct heterocyclic rings with high efficiencies,6 we attempted to develop a new type of diastereodifferentiating cyclization of N-acyl-α-dehydronaphthylalaninamides carrying some chiral auxiliaries via photoinduced electron transfer in the polar solvents, methanol and acetonitrile, and found the highly diastereoselective photocyclization that proceeds catalytically through electron transfer from triethylamine to the excited-state naphthylalaninamide derivatives.7 A detailed analysis of the effects of tertiary amine, solvent, chiral auxiliary, and temperature on the diastereomeric excess (de) demonstrated that hydrogen bonding interactions between diastereomeric enol-type intermediates and a given tertiary amine as well as relative stabilities of these intermediates play essential roles in controlling the magnitude of de. The former finding allowed us to predict the progress of catalytic and enantioselecive photocyclization of N-acyl-α-dehydronaphthylalaninamides in the presence of chiral amine. In recent years much attention is being directed to the photoinduced electron transfer-catalyzed asymmetric cyclization reaction proceeding through an exciplex or an ion radical pair intermediate.7,8 Enantiomeric excesses (ee’s) obtained for highly enantioselective and catalytic sensitization reactions reported so far are in the range of 58–77% in the presence of 15–30 mol% catalysts,8 and hence an attempt to develop such photoinduced electron transfer-initiated asymmetric sensitization reactions of high ee values is attractive and also of great significance from mechanistic and synthetic points of view. For this attempt we selected (S)-proline-based chiral amines, namely, prolinamide (PA), 1-methyl-2-pyrrolidinemethanol (MPM), and nicotine (NT) as electron donor catalysts and investigated the effects of chiral amine, temperature, and substituent on the asymmetric sensitization reaction of N-acetyl-α-dehydro(1-naphthyl)alaninamide derivatives (1a–d) in the less polar solvents, 2-propanol and dichloromethane, which are considered to greatly suppress the dissociation of ion radical pairs formed, hoping to shed much more light on the role of key intermediates proposed previously (Chart 1).

The (Z)-isomers of 1a–d were prepared in high yields (72–93%) by the ring-opening reactions of (Z)-4-(1-naphthylmethylene)-2-methyl-5(4H)-oxazolone with the corresponding primary amines in the presence of triethylamine (TEA).6c,9 After a nitrogen-saturated 2-propanol solution of (Z)-1a (3.75´10–3 mol dm–3, 200 mL) containing TEA (0.10 mol dm–3) was irradiated with Pyrex-filtered light (>280 nm) from a 400 W high-pressure Hg lamp for 1 h at room temperature (rt; conversion, 70%), the reaction mixture obtained was subjected to preparative thin layer chromatography over silica gel (eluent: EtOAc-hexane or EtOAc-CHCl3). Usual workup allowed us to isolate 3-acetylamino-3,4-dihydro-1-methyl-2(1H)-benzo[f]quinolinone (2a; isolated yield, 22%) as its enantiomeric mixture, 3-(methylaminocarbonyl)-1-methylbenzo[f]isoquinoline (3a; 14%), and 3-acetylamino-1-methyl-2(1H)-benzo[f]quinolinone (4a; 18%), in addition to (E)-1a (Scheme 1).10 Although 1H NMR signals for cis-4-(methylaminocarbonyl)-5-(1-naphthyl)-2-methyl-4,5-dihydrooxazole (cis-5a; NMR yield, <1%) having the vicinal coupling constant (J4,5) of 10.7 Hz were detected at 5.03 and 6.51 ppm in DMSO-d6, its isolation was not attempted. In the previous studies we have already shown that the moderate fluorescence quenching of the (Z)-α-dehydronaphthylalaninamide derivative by TEA as well as the large negative value of free energy change for electron transfer provides evidence in support of an electron transfer mechanism for formation of the corresponding 3,4-dihydro-2(1H)-benzo[f]quinolinone.6c,6d In addition to this evidence, the finding that without TEA the dihydroquinolinone 2a is not formed at all substantiates the above mechanism. Similar product distribution was observed also in dichloromethane.

The dihydrobenzoquinolinone rings having (S)- and (R)-configurations in the product 2 were previously proved to exhibit relatively intense circular dichroism (CD) bands of negative and positive signs at 255 nm, respectively.7b Based on this finding, it was possible to determine the absolute configuration of the enantiomer formed in excess and the magnitude of ee for this enantiomer by separating the 2-derived racemate into (S)- (retention time = 13–15 min) and (R)-enantiomers (20–31 min) using a chiral HPLC column [mobile phase, i-PrOH:hexane = 1:2 (2a) or 1:3 (2b–d) v/v] and then by measuring their CD spectra in methanol. A nitrogen-saturated 2-propanol or dichloromethane solution of (Z)-1 (3.75´10–3 mol dm–3, 50 mL) containing a given chiral amine (0.10 mol dm–3) was irradiated under similar conditions at rt or –78 °C. After the reaction mixture irradiated for 1.5 h (rt) or 0.5 h (–78 °C) had been concentrated to dryness in vacuo, the resulting residue was dissolved in chloroform, washed with 0.20 mol dm–3 hydrochloric acid and dried for HPLC and 1H NMR spectral analyses. In Table 1 are summarized conversion of (Z)-1, selectivity of 2, and ee and configuration for major enantiomer obtained in a given solvent containing PA, MPM or NT at each temperature. While the use of PA induced asymmetry at 3-position on the dihydroquinolinone ring in 4–6% ee in any solvents at rt, a much larger ee (30%) was obtained with the configurational change of major enantiomer upon performing the asymmetric photocyclization in dichloromethane containing (S)-MPM. These alterations in configuration and ee for major enantiomer suggests that the mode in which chiral amine interacts with key intermediates depends on the structure of this amine as well as on the property of solvent. Interestingly, the change in chiral amine from MPM to NT reversed the configuration of major enantiomer with accompanying a remarkable enhancement in ee in 2-propanol at rt. If we take into account that there are two hydrogen-bonding sites in both of these amines, the above finding is consistent with the involvement of different types of hydrogen-bonding interactions in the ee-determining step of the dihydrobenzoquinolinone derivative 2.

Temperature effects on the magnitude of asymmetric induction (de) in our previous studies showed that temperature exerts a great effect not only on the relative stability of diastereomeric enol-type biradical intermediates but also on the ability of TEA to form hydrogen bonds to protic solvents as well as to these intermediates. As demonstrated in Table 1, a lowering of temperature in the NT-catalyzed asymmetric photocyclization of (Z)-1a in any solvents greatly enhanced ee for the corresponding (S)-2a with a considerable increase in the selectivity of this product, whereas ee for (R)-2a obtained in excess by the MPM-catalyzed asymmetric reaction was only slightly increased. This observation substantiates the participation of a different mode of hydrogen-bonding interaction between the given chiral amine and the biradical intermediate and also is consistent with the existence of the interaction of this amine with the solvent. Interestingly, an increase in the bulkiness of the substituent R attached to the amide nitrogen in (Z)-1 showed a clear tendency to diminish the magnitude of ee for (S)-2, suggesting that the amide N–H hydrogen is involved in the hydrogen bonding formed between NT and the intermediate described above.

Our attention is now directed to the mechanism of photoinduced electron transfer-initiated asymmetric cyclization for (Z)-1. We proposed in a previous study that the radical ion pair I, the enol-type biradical II, and the cyclized enol-type intermediate III are involved as key reaction intermediates (Scheme 2).7b It is well known that the amide N–H hydrogen and carbonyl oxygen act as hydrogen-bond donor and hydrogen-bond acceptor, respectively.11a Thus, a given chiral amine is considered to form a hydrogen bond to the amide N–H hydrogen and to exist in the neighborhood of the α-dehydronaphthylalaninamide derivative 1.11b On the other hand, the previous result (that at the early stage of the photocyclization reaction the composition ratio of (Z)-1 and (E)-1 exhibits a negligible dependence on the TEA concentration) is consistent with the hypothesis that the (Z)-1 radical anion is isomerized to its (E)-isomer to a negligible extent and, hence, the radical ion pair (Z)-I undergoes exclusive back electron transfer to regenerate (Z)-1 and chiral amine (Scheme 2).6d Additionally, interconversion between IIIA and IIIB is very unlikely to occur during the asymmetric reaction, so that we were led to propose that the extent to which a given dynamic equilibrium is shifted to either IIA or IIB is a major factor governing the magnitude of ee for 2. MM2 and PM5 calculations of the conformation of III derived from chiral auxiliary-substituted N-acetyl-α-dehydronaphthylalaninamide confirmed that steric repulsion between hydrogen at the 2-position in the hydronaphthalene ring and the auxiliary group determines the relative stabilities of III and its precursor II, and also controls the magnitude of asymmetric induction in the tautomerization of the former cyclized enol-type intermediate.7b In the absence of the chiral auxiliary group the chiral amines PA, MPM, and NT play the role of this group through hydrogen-bonding interactions with the enol hydroxy hydrogen, the acetylamino hydrogen, and the methylamino nitrogen in II and III. These interactions should assist the tautomerization in either the re or the si face of the latter intermediate to induce asymmetry at the 3-position in the dihydroquinolinone ring of 2.

The fact that in the presence of NT and MPM (S)-2 and (R)-2 are produced in excess, respectively, reveals that at two different sites the former amine is preferentially hydrogen bonded to IIA in the si face and the latter to IIB in the re face, as depicted in Figure 1 (R = Me). These two-site hydrogen-bonding interactions of IIA with NT in the si face and of IIB with MPM in the re face are considered to greatly shift a given equilibrium to IIA and IIB to produce (S)-2 and (R)-2 in excess, respectively. The above considerations allow us to interpret a much less enantioselectivity for the 1a/PA system in terms of less favorable two-site hydrogen-bonding interactions in this system (Table 1). As already described, there exist interactions of the chiral amines not only with the enol-type intermediates II and III but also with the solvent, depending on temperature. Thus, the observation of the higher ee value in 2-propanol than in dichloromethane, especially in the presence of NT at –78 °C, suggests that the protic solvent molecules are involved in additional hydrogen-bonding interactions with IIA and IIB so as to enhance the relative stability of the former enol-type biradical intermediate.

ACKNOWLEDGMENTS
This research was partially supported by a “Scientific Frontier Research Project” from the Ministry of Education, Sports, Culture, Science and Technology, Japan.

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9. K. Noda, Y. Shimohigashi, and N. Izumiya, ‘The Peptides–Analysis, Synthesis, Biology,’ Vol. 5 (Part B), ed. by E. Gross and J. Meienhofer, Academic Press, New York, 1983, pp. 305–308; Data for (Z)-1a: mp 190.0–190.5 °C (EtOH-hexane); IR (KBr) ν/cm–1 = 3340, 3236, 3180, 1644, 1628; 1H NMR (500 MHz, DMSO-d6) δ = 1.84 (3H, s), 2.72 (3H, d, J = 4.6 Hz), 7.51–7.58 (5H, m), 7.90 (1H, d, J = 8.3 Hz), 7.94–7.98 (2H, m), 8.04 (1H, q, J = 4.6 Hz), 9.24 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ = 22.7, 26.2, 124.2, 124.2, 125.5, 126.0, 126.2, 126.3, 128.3, 128.4, 131.1, 131.3, 133.2, 132.5, 165.2, 169.5. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.49; H, 5.73; N, 10.31..
10. Data for (E)-1a: mp 167.5–168.5 °C (EtOAc-hexane); IR (KBr) ν/cm–1 = 3268, 1626, 1615; 1H NMR (500 MHz, DMSO-d6) δ = 2.02 (3H, s), 2.43 (3H, d, J = 4.9 Hz), 7.36 (1H, d, J = 6.7 Hz), 7.42 (1H, dd, J = 6.7, 7.3 Hz), 7.44 (1H, s), 7.53 (1H, dd, J = 6.7, 7.3 Hz), 7.56 (1H, dd, J = 6.7, 7.3 Hz), 7.78 (1H, q, J = 4.9 Hz), 7.79 (1H, d, J = 7.3 Hz), 7.91 (1H, d, J = 7.3 Hz), 8.00 (1H, d, J = 7.3 Hz), 9.75 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ = 23.5, 25.7, 112.9, 124.4, 125.2, 125.4, 125.8, 126.0, 127.1, 128.3, 131.2, 132.5, 133.1, 134.7, 165.1, 168.6. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.50; H, 6.01; N, 10.32.
Data for 2a: mp 231.5–232.5 °C (EtOH-hexane); IR (KBr) ν/cm–1 = 3320, 1672, 1634; [α]D25 = +105.4 [(S)-2a], –106.0 [(R)-2a] (c 0.5, MeOH); CD (4.0×10–5 mol dm–3, MeOH) [θ]250 = –984 [(S)-2a], +1019 [(R)-2a]; 1H NMR (500 MHz, DMSO-d6) δ = 1.95 (3H, s), 3.01 (1H, dd, J = 14.7, 15.7 Hz), 3.41 (3H, s), 3.65 (1H, dd, J = 6.1, 15.7 Hz), 4.57 (1H, ddd, J = 6.1, 7.9, 14.7 Hz), 7.45 (1H, dd, J = 7.0, 7.9 Hz), 7.49 (1H, d, J = 8.9 Hz), 7.56 (1H, dd, J = 7.0, 7.9 Hz), 7.91 (1H, d, J = 7.9 Hz), 7.93 (1H, d, J = 8.9 Hz), 8.01 (1H, d, J = 7.9 Hz), 8.34 (1H, d, J = 7.9 Hz); 13C NMR (125 MHz, DMSO-d6) δ = 22.6, 26.8, 30.3, 48.0, 116.1, 117.6, 123.0, 124.5, 127.0, 128.0, 128.3, 129.6, 130.5, 137.1, 168.2, 169.3. Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.52; H, 5.86; N, 10.41.
Data for 3a: mp 135.0–136.0 °C (EtOAc-hexane); IR (KBr) ν/cm–1 = 3406, 1659; 1H NMR (500 MHz, DMSO-d6) δ = 2.94 (3H, d, J = 4.9 Hz), 3.03 (3H, s), 7.81–7.85 (2H, m), 8.11 (1H, d, J = 9.2 Hz), 8.12–8.14 (1H, m), 8.16 (1H, d, J = 9.2 Hz), 8.84 (1H, q, J = 4.9 Hz), 8.91–8.93 (1H, m), 9.11 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ = 22.5, 26.0, 112.8, 122.7, 123.8, 126.1, 127.9, 128.6, 128.7, 129.0, 129.5, 132.8, 134.5, 144.3, 157.0, 164.7. Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64; N, 11.19. Found: C, 76.69; H, 5.71; N, 11.37.
Data for 4a: mp 208.0–208.5 °C (EtOAc-hexane); IR (KBr) ν/cm–1 = 3316, 1680, 1605; 1H NMR (500 MHz, DMSO-d6) δ = 2.25 (3H, s), 3.88 (3H, s), 7.58 (1H, dd, J = 6.7, 7.3 Hz), 7.73 (1H, dd, J = 6.7, 8.5 Hz), 7.81 (1H, d, J = 9.2 Hz), 8.02 (1H, d, J = 7.3 Hz), 8.07 (1H, d, J = 9.2 Hz), 8.30 (1H, d, J = 8.5 Hz), 9.58 (1H, s), 9.61 (1H, s); 13C NMR (125 MHz, DMSO-d6) δ = 24.3, 30.7, 113.8, 115.3, 115.4, 121.5, 125.4, 127.8, 128.2, 128.7, 128.9, 129.1, 129.5, 134.0, 156.7, 170.1. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.47; H, 5.02; N, 10.63..
11. a) A. Fersht, ‘Enzyme Structure and Mechanism,’ 2nd ed, W. H. Freeman, New York, 1985, pp. 1–46; b) K. Miyoshi, K. Kubo, T. Sakurai, and H. Inoue, Nippon Kagaku Kaishi, 1999, 37.