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Cite this: Org. Biomol. Chem., 2014, 12, 2049 Received 3rd January 2014, Accepted 29th January 2014 DOI: 10.1039/c4ob00018h www.rsc.org/obc
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Carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins: highly enantioselective and chemoselective access to a chiral benzylmethyl center† Shuang Yang,a,b Shou-Fei Zhu,a,b Na Guo,a,b Song Songa,b and Qi-Lin Zhou*a,b
A carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins was developed by using a chiral spiro iridium catalyst, providing a highly efficient approach to the compounds with a chiral benzylmethyl center. The carboxy-directed hydrogenation prohibited the isomerization of the terminal olefins, and realized the chemoselective hydrogenation of various dienes. The concise enantioselective syntheses of (S)-curcudiol and (S)-curcumene were achieved by using this catalytic asymmetric hydrogenation as a key step.
The chiral benzylmethyl center is a ubiquitous subunit in natural products and bioactive compounds (Scheme 1).1 Transition-metal-catalyzed asymmetric hydrogenation of α-alkylα-aryl terminal olefins provides an ideal method for the enantioselective construction of chiral benzylmethyl centers. However, the asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins remains a challenge,2 although iridium-catalyzed asymmetric hydrogenation of trisubstituted olefins, which could also generate a chiral benzylmethyl center, has been well established.3 The easily accessible α-alkyl-α-aryl terminal olefins avoid the tedious separation of Z/E isomers in the synthesis of trisubstituted olefins. Quite recently, several groups, including us, developed highly enantioselective hydrogenation reactions of α,α-diarylethenes by using –OH,4 –COOH,5 –OMe,6 and –NH2 7 as directing groups. In this communication, we report a highly enantioselective (up to 99.8% ee) and highly chemoselective carboxy-directed hydrogenation of α-alkylα-aryl terminal olefins catalyzed by iridium complexes of chiral spiro phosphine-oxazolines ligands (1), providing an efficient method for the construction of chiral benzylmethyl centers. In the initial study, the asymmetric hydrogenation of 2-(hex-1-en-2-yl)benzoic acid (2a) was performed at 6 atm
a State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures, characterization data, HPLC and SFC spectra for the products. See DOI: 10.1039/c4ob00018h
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Scheme 1 center.
Selected natural products containing a chiral benzylmethyl
hydrogen pressure in methanol using 0.25 mol% chiral spiro iridium catalysts 18 (Table 1). With catalyst (Sa,S)-1a, 24% conversion and 89% ee were obtained in 24 h (entry 1). The catalyst (Sa,R)-1a exhibited lower enantioselectivity compared to its diastereoisomer (Sa,S)-1a (entry 2). The catalyst (Sa)-1b having no substituent on the oxazoline ring accomplished the hydrogenation in 3.5 h with 99.1% ee (entry 3). The chiral spiro iridium catalyst 1 bearing less bulky P-Ar, such as 3,5dimethylphenyl (1c) and phenyl (1d), showed slightly lower enantioselectivity (entries 4 and 5). The basic additive is critical for obtaining a high reaction rate and full conversion. The inorganic bases, including Cs2CO3 and Na2CO3, gave essentially the same results as those obtained with NEt3; however, the reaction became sluggish without the basic additive (entries 6–8). The carboxy group is necessary for the hydrogenation reaction, and the ester is fully inert under the identical conditions (entry 9). The reaction could also be performed at room temperature albeit a longer reaction time (24 h) was required for full conversion (entry 10). The catalysts are less active to the internal double bond. As an example, no hydrogenation took place with 2-(but-2-en-2-yl)benzoic acid (E/Z = 4 : 1) under the standard reaction conditions for 24 h. Under the optimal reaction conditions, various α-alkylα-aryl terminal olefins (2a–2m)9 were hydrogenated in the presence of the catalyst (Sa)-1b at 6 atm hydrogen pressure
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Table 1 Iridium-catalyzed asymmetric hydrogenation of 2-(hex-1-en2-yl)benzoic acida
Entry
Catalyst
Base
Time (h)
Conv.b (%)
eec (%)
1 2 3 4 5 6d 7d 8 9e 10 f
(Sa,S)-1a (Sa,R)-1a (Sa)-1b (Sa)-1c (Sa)-1d (Sa)-1b (Sa)-1b (Sa)-1b (Sa)-1b (Sa)-1b
NEt3 NEt3 NEt3 NEt3 NEt3 Cs2CO3 Na2CO3 None NEt3 NEt3
24 24 3.5 5 5 3.5 3.5 24 24 24
24 28 100 100 100 100 100 32 0 100
89 79 99.1 97 98 97 97 95 — 99.2
a Reaction conditions: 1/2a/base = 0.00125 : 0.5 : 0.5 (mmol), in 2 mL methanol at 45 °C. b Determined by 1H NMR. c Determined by SFC using a Chiralpak AD-H column. d 0.5 Equiv. base was used. e Hydrogenation of methyl 2-(hex-1-en-2-yl)benzoate, the ester form of 2a. f Performed at 25 °C.
Table 2 Iridium-catalyzed asymmetric hydrogenation of 2-alkylvinyl benzoic acidsa
Entry
R1; R2
Product
Time (h)
Yieldb (%)
ee (%)
1 2 3 4 5
H; nBu (2a) H; Et (2b) H; nPent (2c) H; iPr (2d) H; Cy (2e)
3a 3b 3c 3d 3e
3.5 3 5 12 48
98 99 98 98 98
99.1 98 99.1 99.5 99.6
3f
2.5
98
99.1
3g
2.5
98
99.2
98 98 98 98 98 99
99.4 98 99 99.8 99.3 99.1
6 7 8 9 10 11 12 13
n
2-Naphthyl; Bu (2h) 5-Br; nBu (2i) 4-Br; nBu (2j) 4,5-Cl2; nBu (2k) 5-OMe; Et (2l) 5-Me; Et (2m)
3h 3i 3j 3k 3l 3m
10 9 10 10 13 11
side chain has a negligible influence on the reaction rate and enantioselectivity (entries 1–3). The substrates 2d and 2e having a bulkier R2 group required longer reaction time for full conversion (entries 4 and 5). The functional groups such as –OMe (2g and 2l), –Br (2i and 2j), and –Cl (2k) on the phenyl rings or at side chains of substrates could be tolerated in this hydrogenation reaction, which facilitates further transformations of the hydrogenation products. We then investigated the challenging substrates (2n–2q) having an additional carbon–carbon double bond at the side chain (Scheme 2). It is delightful that the internal double bonds in the diene substrates (2n–2p) remain unreacted in the hydrogenation reaction. When the substrate contains an additional terminal carbon–carbon double bond (2q), the reaction still showed a chemoselectivity in the hydrogenation of α-alkyl-α-aryl disubstituted double bond, producing 3q in 83% yield. Iridium-catalyzed asymmetric hydrogenation of 8-methylene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (2r) with an exo-terminal olefin was also investigated (Scheme 3). With catalyst (Sa)-1b, hydrogenation of 2r was accomplished within 18 h with 91% ee, showing that the carboxy-directed asymmetric hydrogenation is an efficient strategy for constructing a chiral cyclic benzylmethyl center.10 A deuterium-labeling study was performed to investigate whether there was olefin migration in the hydrogenation (Scheme 4). The absence of deuterium at the 3-position of the side chain of the hydrogenation product d-3a clearly demonstrated that olefin migration did not occur in the reaction. The presence of deuterium at the 6′-position on the phenyl ring
Scheme 2 Carboxy-directed hydrogenation of dienes.
enantioselective
and
chemoselective
a Reaction conditions and analyses of products were the same as those of Table 1, entry 3. Full conversions were obtained for all reactions. b Isolated yield.
(Table 2). All the tested substrates could be hydrogenated to the corresponding chiral 2-alkyl benzoic acids with excellent yields and enantioselectivities (98–99.8% ee). The length of the
2050 | Org. Biomol. Chem., 2014, 12, 2049–2052
Scheme 3 Iridium-catalyzed asymmetric hydrogenation of 8-methylene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid.
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hydrogenation of α-alkyl-α-aryl terminal olefins in organic synthesis (Scheme 5).
Conclusions
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Scheme 4
Deuterium-labeling study.
could be attributed to the carboxy-directed C–H activation by the iridium catalyst.11 To demonstrate the synthetic potential of the carboxydirected asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins further, we conducted the total synthesis of (S)-curcudiol,12 an inhibitor of gastric H, K-ATPase isolated from the marine sponge Epipolasis sp.13 First, 2-bromo-6-methylhepta1,5-diene (6) was prepared by copper-catalyzed coupling of 2,3dibromoprop-1-ene 4 and Grignard reagent 5.14 The Suzuki coupling of the bromide 6 and boronic acid 7, followed by a hydrolysis, gave compound 9. The hydrogenation of 9 was performed in the presence of 0.02 mol% catalyst (Ra)-1b (S/C = 5000) to produce the acid (S)-10 in 98% yield with 96% ee. The reduction of the carboxy group of (S)-10, followed by a Dess– Martin oxidation, produced the aldehyde 11 in 86% yield. The aldehyde 11 was converted to (S)-curcudiol by Baeyer–Villiger oxidation and a reduction in 81% yield. Thus, the synthesis of (S)-curcudiol was accomplished in 51% overall yield. Moreover, another natural product, (S)-curcumene, was also prepared in 89% yield by means of decarboxylation of the hydrogenation product (S)-10 with copper powder.15 The easily available starting materials, economical steps, and high yields of (S)-curcudiol and (S)-curcumene showed the high potential for wide applications of Ir-catalyzed asymmetric carboxy-directed
Scheme 5
Total syntheses of (S)-curcudiol and (S)-curcumene.
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In summary, we have developed a highly efficient iridium-catalyzed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins, which provides an efficient approach to the chiral benzylmethyl centers. The use of a carboxy group as the directing group prohibited the isomerization of the terminal olefins in the reaction, and realized the chemoselective hydrogenation of various dienes. Concise enantioselective syntheses of (S)-curcudiol and (S)-curcumene were achieved by using this highly efficient catalytic asymmetric hydrogenation as a key step.
Acknowledgements We thank the National Natural Science Foundation of China, the National Basic Research Program of China (973 Program) (2012CB821600), and the “111” project (B06005) of the Ministry of Education of China for financial support.
Notes and references 1 (a) N. P. Damodaran and S. Dev, Tetrahedron, 1968, 24, 4113; (b) A. E. Wright, S. A. Pomponi, O. J. McConnell, S. Kohmoto and P. J. McCarthy, J. Nat. Prod., 1987, 50, 976; (c) W. D. Inman, J. Luo, S. D. Jolad, S. R. King and R. Cooper, J. Nat. Prod., 1999, 62, 1088; (d) G. G. Bianco, H. M. C. Ferraz, A. M. Costa, L. V. Costa-Lotufo, C. Pessoa, M. O. de Moraes, M. G. Schrems, A. Pfaltz and L. F. Silva, Jr., J. Org. Chem., 2009, 74, 2561; (e) P. Joseph-Nathan, M. R. Hernandez-Medel, E. Martinez, M. Rojas-Gardida and C. M. Cerda, J. Nat. Prod., 1988, 51, 675; (f ) A. D. Rodriguez and I. I. Rodriguez, Tetrahedron Lett., 2002, 43, 5601. 2 For reviews, see: (a) J. J. Verendel, O. Pamies, M. Dieguez and P. G. Andersson, Chem. Rev., 2013, DOI: 10.1021/ cr400037u; For selected examples, see: (b) V. P. Conticello, L. Brard, M. A. Giardello, Y. Tsuji, M. Sabat, C. L. Stern and T. J. Marks, J. Am. Chem. Soc., 1992, 114, 2761; (c) G. S. Forman, T. Ohkuma, W. P. Hems and R. Noyori, Tetrahedron Lett., 2000, 41, 9471; (d) K. Kallstrom, C. Hedberg, P. Brandt, A. Bayer and P. G. Andersson, J. Am. Chem. Soc., 2004, 126, 14308; (e) S. McIntyre, E. Hörmann, F. Menges, S. P. Smidt and A. Pfaltz, Adv. Synth. Catal., 2005, 347, 282; (f ) M. Coll, O. Pamies and M. Dieguez, Chem. Commun., 2011, 47, 9215; (g) J. Mazuela, P.-O. Norrby, P. G. Andersson, O. Pamies and M. Dieguez, J. Am. Chem. Soc., 2011, 133, 13634; (h) S. Monfette, Z. R. Turner, S. P. Semproni and P. J. Chirik, J. Am. Chem. Soc., 2012, 134, 4561.
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3 For reviews, see: (a) A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hormann, S. McIntyre, F. Menges, M. Schonleber, S. P. Smidt, B. Wustenberg and N. Zimmermann, Adv. Synth. Catal., 2003, 345, 33; (b) X. Cui and K. Burgess, Chem. Rev., 2005, 105, 3272; (c) K. Kallstrom, I. Munslow and P. G. Andersson, Chem.–Eur. J., 2006, 12, 3194; (d) D. H. Woodmansee and A. Pfaltz, Chem. Commun., 2011, 47, 7912; (e) A. Cadu and P. G. Andersson, Dalton Trans., 2013, 42, 14345. 4 (a) X. Wang, A. Guram, S. Caille, J. Hu, J. P. Preston, M. Ronk and S. Walker, Org. Lett., 2011, 13, 1881; For an early ruthenium-catalyzed asymmetric hydrogenation of allylic alcohols, see: (b) H. Takaya, T. Ohta, N. Sayo, H. Kumobayashi, S. Akutagawa, S.-i. Inoue, I. Kasahara and R. Noyori, J. Am. Chem. Soc., 1987, 109, 1596. 5 (a) S. Song, S.-F. Zhu, Y.-B. Yu and Q.-L. Zhou, Angew. Chem., Int. Ed., 2013, 52, 1556; (b) T. Besset, R. GramageDoria and J. N. H. Reek, Angew. Chem., Int. Ed., 2013, 52, 8795; For the early catalytic asymmetric hydrogenation of unsaturated carboxylic acids, see: (c) T. Ohta, H. Takaya, M. Kitamura, K. Nagai and R. Noyori, J. Org. Chem., 1987, 52, 3176. 6 E. N. Bess and M. S. Sigman, Org. Lett., 2013, 15, 646. 7 E. Spahn, A. Albright, M. Shevlin, L. Pauli, A. Pfaltz and R. E. Gawley, J. Org. Chem., 2013, 78, 2731. 8 For the preparation of 1, see: S.-F. Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li and Q.-L. Zhou, J. Am. Chem. Soc., 2006, 128, 12886. 9 For the synthesis of α-alkyl-α-aryl terminal olefins, see ESI.† 10 (a) J. Bayardon, J. Holz, B. Schaffner, V. Andrushko, S. Verevkin, A. Preetz and A. Borner, Angew. Chem., Int. Ed.,
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11
12
13 14 15
2007, 46, 5971; (b) S. K. Chakka, B. K. Peters, P. G. Andersson, G. E. M. Maguire, H. G. Kruger and T. Govender, Tetrahedron: Asymmetry, 2010, 21, 2295; (c) S. P. Verevkin, V. N. Emel’yanenko, J. Bayardon, B. Schaffner, W. Baumann and A. Borner, Ind. Eng. Chem. Res., 2012, 51, 126. See also ref. 2h. (a) J. M. Kisenyi, G. J. Sunley, J. A. Cabeza, A. J. Smith, H. Adams, N. J. Salt and P. M. Maitlis, J. Chem. Soc., Dalton Trans., 1987, 2459; (b) K. Ueura, T. Satoh and M. Miura, J. Org. Chem., 2007, 72, 5362; (c) K. L. Engelman, Y. Feng and E. A. Ison, Organometallics, 2011, 30, 4572. For the synthesis of (S)-curcudiol based on enzymatic resolutions, see: (a) M. Ono, Y. Ogura, K. Hatogai and H. Akita, Tetrahedron: Asymmetry, 1995, 6, 1829; (b) M. Ono, Y. Ogura, K. Hatogai and H. Akita, Chem. Pharm. Bull., 2001, 49, 1581; For a diastereoselective synthesis, see: (c) J. C. Green, S. Jimenez-Alonso, E. R. Brown and T. R. R. Pettus, Org. Lett., 2011, 13, 5500. T. Ehara, H. Yokoyama, M. Ono and H. Akita, Heterocycles, 2007, 71, 627. C. S. Mushti, J.-H. Kim and E. J. Corey, J. Am. Chem. Soc., 2006, 128, 14050. For selected enantioselective syntheses of (S)-curcumene, see: (a) A. Zhang and T. V. Rajanbabu, Org. Lett., 2004, 6, 3159; (b) T. Nishimura, Y. Yasuhara, T. Sawano and T. Hayashi, J. Am. Chem. Soc., 2010, 132, 7872; (c) S. Afewerki, P. Breistein, K. Pirttila, L. Deiana, P. Dziedzic, I. Ibrahem and A. Cordova, Chem.–Eur. J., 2011, 17, 8784; (d) V. K. Aggarwal, L. T. Ball, S. Carobene, R. L. Connelly, M. J. Hesse, B. M. Partridge, P. Roth, S. P. Thomas and M. P. Webster, Chem. Commun., 2012, 48, 9230.
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Cite this: Org. Biomol. Chem., 2014, 12, 2049 Received 3rd January 2014, Accepted 29th January 2014 DOI: 10.1039/c4ob00018h www.rsc.org/obc
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Carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins: highly enantioselective and chemoselective access to a chiral benzylmethyl center† Shuang Yang,a,b Shou-Fei Zhu,a,b Na Guo,a,b Song Songa,b and Qi-Lin Zhou*a,b
A carboxy-directed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins was developed by using a chiral spiro iridium catalyst, providing a highly efficient approach to the compounds with a chiral benzylmethyl center. The carboxy-directed hydrogenation prohibited the isomerization of the terminal olefins, and realized the chemoselective hydrogenation of various dienes. The concise enantioselective syntheses of (S)-curcudiol and (S)-curcumene were achieved by using this catalytic asymmetric hydrogenation as a key step.
The chiral benzylmethyl center is a ubiquitous subunit in natural products and bioactive compounds (Scheme 1).1 Transition-metal-catalyzed asymmetric hydrogenation of α-alkylα-aryl terminal olefins provides an ideal method for the enantioselective construction of chiral benzylmethyl centers. However, the asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins remains a challenge,2 although iridium-catalyzed asymmetric hydrogenation of trisubstituted olefins, which could also generate a chiral benzylmethyl center, has been well established.3 The easily accessible α-alkyl-α-aryl terminal olefins avoid the tedious separation of Z/E isomers in the synthesis of trisubstituted olefins. Quite recently, several groups, including us, developed highly enantioselective hydrogenation reactions of α,α-diarylethenes by using –OH,4 –COOH,5 –OMe,6 and –NH2 7 as directing groups. In this communication, we report a highly enantioselective (up to 99.8% ee) and highly chemoselective carboxy-directed hydrogenation of α-alkylα-aryl terminal olefins catalyzed by iridium complexes of chiral spiro phosphine-oxazolines ligands (1), providing an efficient method for the construction of chiral benzylmethyl centers. In the initial study, the asymmetric hydrogenation of 2-(hex-1-en-2-yl)benzoic acid (2a) was performed at 6 atm
a State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental procedures, characterization data, HPLC and SFC spectra for the products. See DOI: 10.1039/c4ob00018h
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Scheme 1 center.
Selected natural products containing a chiral benzylmethyl
hydrogen pressure in methanol using 0.25 mol% chiral spiro iridium catalysts 18 (Table 1). With catalyst (Sa,S)-1a, 24% conversion and 89% ee were obtained in 24 h (entry 1). The catalyst (Sa,R)-1a exhibited lower enantioselectivity compared to its diastereoisomer (Sa,S)-1a (entry 2). The catalyst (Sa)-1b having no substituent on the oxazoline ring accomplished the hydrogenation in 3.5 h with 99.1% ee (entry 3). The chiral spiro iridium catalyst 1 bearing less bulky P-Ar, such as 3,5dimethylphenyl (1c) and phenyl (1d), showed slightly lower enantioselectivity (entries 4 and 5). The basic additive is critical for obtaining a high reaction rate and full conversion. The inorganic bases, including Cs2CO3 and Na2CO3, gave essentially the same results as those obtained with NEt3; however, the reaction became sluggish without the basic additive (entries 6–8). The carboxy group is necessary for the hydrogenation reaction, and the ester is fully inert under the identical conditions (entry 9). The reaction could also be performed at room temperature albeit a longer reaction time (24 h) was required for full conversion (entry 10). The catalysts are less active to the internal double bond. As an example, no hydrogenation took place with 2-(but-2-en-2-yl)benzoic acid (E/Z = 4 : 1) under the standard reaction conditions for 24 h. Under the optimal reaction conditions, various α-alkylα-aryl terminal olefins (2a–2m)9 were hydrogenated in the presence of the catalyst (Sa)-1b at 6 atm hydrogen pressure
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Table 1 Iridium-catalyzed asymmetric hydrogenation of 2-(hex-1-en2-yl)benzoic acida
Entry
Catalyst
Base
Time (h)
Conv.b (%)
eec (%)
1 2 3 4 5 6d 7d 8 9e 10 f
(Sa,S)-1a (Sa,R)-1a (Sa)-1b (Sa)-1c (Sa)-1d (Sa)-1b (Sa)-1b (Sa)-1b (Sa)-1b (Sa)-1b
NEt3 NEt3 NEt3 NEt3 NEt3 Cs2CO3 Na2CO3 None NEt3 NEt3
24 24 3.5 5 5 3.5 3.5 24 24 24
24 28 100 100 100 100 100 32 0 100
89 79 99.1 97 98 97 97 95 — 99.2
a Reaction conditions: 1/2a/base = 0.00125 : 0.5 : 0.5 (mmol), in 2 mL methanol at 45 °C. b Determined by 1H NMR. c Determined by SFC using a Chiralpak AD-H column. d 0.5 Equiv. base was used. e Hydrogenation of methyl 2-(hex-1-en-2-yl)benzoate, the ester form of 2a. f Performed at 25 °C.
Table 2 Iridium-catalyzed asymmetric hydrogenation of 2-alkylvinyl benzoic acidsa
Entry
R1; R2
Product
Time (h)
Yieldb (%)
ee (%)
1 2 3 4 5
H; nBu (2a) H; Et (2b) H; nPent (2c) H; iPr (2d) H; Cy (2e)
3a 3b 3c 3d 3e
3.5 3 5 12 48
98 99 98 98 98
99.1 98 99.1 99.5 99.6
3f
2.5
98
99.1
3g
2.5
98
99.2
98 98 98 98 98 99
99.4 98 99 99.8 99.3 99.1
6 7 8 9 10 11 12 13
n
2-Naphthyl; Bu (2h) 5-Br; nBu (2i) 4-Br; nBu (2j) 4,5-Cl2; nBu (2k) 5-OMe; Et (2l) 5-Me; Et (2m)
3h 3i 3j 3k 3l 3m
10 9 10 10 13 11
side chain has a negligible influence on the reaction rate and enantioselectivity (entries 1–3). The substrates 2d and 2e having a bulkier R2 group required longer reaction time for full conversion (entries 4 and 5). The functional groups such as –OMe (2g and 2l), –Br (2i and 2j), and –Cl (2k) on the phenyl rings or at side chains of substrates could be tolerated in this hydrogenation reaction, which facilitates further transformations of the hydrogenation products. We then investigated the challenging substrates (2n–2q) having an additional carbon–carbon double bond at the side chain (Scheme 2). It is delightful that the internal double bonds in the diene substrates (2n–2p) remain unreacted in the hydrogenation reaction. When the substrate contains an additional terminal carbon–carbon double bond (2q), the reaction still showed a chemoselectivity in the hydrogenation of α-alkyl-α-aryl disubstituted double bond, producing 3q in 83% yield. Iridium-catalyzed asymmetric hydrogenation of 8-methylene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (2r) with an exo-terminal olefin was also investigated (Scheme 3). With catalyst (Sa)-1b, hydrogenation of 2r was accomplished within 18 h with 91% ee, showing that the carboxy-directed asymmetric hydrogenation is an efficient strategy for constructing a chiral cyclic benzylmethyl center.10 A deuterium-labeling study was performed to investigate whether there was olefin migration in the hydrogenation (Scheme 4). The absence of deuterium at the 3-position of the side chain of the hydrogenation product d-3a clearly demonstrated that olefin migration did not occur in the reaction. The presence of deuterium at the 6′-position on the phenyl ring
Scheme 2 Carboxy-directed hydrogenation of dienes.
enantioselective
and
chemoselective
a Reaction conditions and analyses of products were the same as those of Table 1, entry 3. Full conversions were obtained for all reactions. b Isolated yield.
(Table 2). All the tested substrates could be hydrogenated to the corresponding chiral 2-alkyl benzoic acids with excellent yields and enantioselectivities (98–99.8% ee). The length of the
2050 | Org. Biomol. Chem., 2014, 12, 2049–2052
Scheme 3 Iridium-catalyzed asymmetric hydrogenation of 8-methylene-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid.
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hydrogenation of α-alkyl-α-aryl terminal olefins in organic synthesis (Scheme 5).
Conclusions
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Scheme 4
Deuterium-labeling study.
could be attributed to the carboxy-directed C–H activation by the iridium catalyst.11 To demonstrate the synthetic potential of the carboxydirected asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins further, we conducted the total synthesis of (S)-curcudiol,12 an inhibitor of gastric H, K-ATPase isolated from the marine sponge Epipolasis sp.13 First, 2-bromo-6-methylhepta1,5-diene (6) was prepared by copper-catalyzed coupling of 2,3dibromoprop-1-ene 4 and Grignard reagent 5.14 The Suzuki coupling of the bromide 6 and boronic acid 7, followed by a hydrolysis, gave compound 9. The hydrogenation of 9 was performed in the presence of 0.02 mol% catalyst (Ra)-1b (S/C = 5000) to produce the acid (S)-10 in 98% yield with 96% ee. The reduction of the carboxy group of (S)-10, followed by a Dess– Martin oxidation, produced the aldehyde 11 in 86% yield. The aldehyde 11 was converted to (S)-curcudiol by Baeyer–Villiger oxidation and a reduction in 81% yield. Thus, the synthesis of (S)-curcudiol was accomplished in 51% overall yield. Moreover, another natural product, (S)-curcumene, was also prepared in 89% yield by means of decarboxylation of the hydrogenation product (S)-10 with copper powder.15 The easily available starting materials, economical steps, and high yields of (S)-curcudiol and (S)-curcumene showed the high potential for wide applications of Ir-catalyzed asymmetric carboxy-directed
Scheme 5
Total syntheses of (S)-curcudiol and (S)-curcumene.
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In summary, we have developed a highly efficient iridium-catalyzed asymmetric hydrogenation of α-alkyl-α-aryl terminal olefins, which provides an efficient approach to the chiral benzylmethyl centers. The use of a carboxy group as the directing group prohibited the isomerization of the terminal olefins in the reaction, and realized the chemoselective hydrogenation of various dienes. Concise enantioselective syntheses of (S)-curcudiol and (S)-curcumene were achieved by using this highly efficient catalytic asymmetric hydrogenation as a key step.
Acknowledgements We thank the National Natural Science Foundation of China, the National Basic Research Program of China (973 Program) (2012CB821600), and the “111” project (B06005) of the Ministry of Education of China for financial support.
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