Organic Letters
Letter
H.; Zhao, F. W.; Wang, H.; Xu, J. J.; Kennelly, E. J.; Long, C. L.; Yin, G. F.
Planta Med. 2012, 78, 65. (d) Saito, S. Y.; Tanaka, M.; Matsunaga, K.; Li,
Y.; Ohizumi, Y. Biol. Pharm. Bull. 2004, 27, 1270.
(4) (a) Cushman, M.; Dekow, F. W. J. Org. Chem. 1979, 44, 407.
(b) Hanaoka, M.; Hirasawa, T.; Cho, W. J.; Yasuda, S. Chem. Pharm.
Bull. 2000, 48, 399. (c) Ma, L.; Seidel, D. Chem. - Eur. J. 2015, 21, 12908.
(d) Zhang, L.; Li, J.; Ma, F.; Yao, S.; Li, N.; Wang, J.; Wang, Y.; Wang, X.;
Yao, Q. Molecules 2012, 17, 11294.
(5) Mengozzi, L.; Gualandi, A.; Cozzi, P. G. Chem. Sci. 2014, 5, 3915.
(6) For racemic Cu-catalyzed reaction of alkynes, aldehydes, and
tetrahydroisoquinolines, see: (a) Seidel, D. Org. Chem. Front. 2014, 1,
426. (b) Das, D.; Sun, A. X.; Seidel, D. Angew. Chem. 2013, 125, 3853.
(c) Zheng, Q. H.; Meng, W.; Jiang, G. J.; Yu, Z. X. Org. Lett. 2013, 15,
5928.
The limitation of this domino Heck−Suzuki reaction was also
recognized: alkylboronic acid (e.g., 1-butaneboronic acid) was
not applicable in this system (9d, 0%).18 Finally, we were very
delighted to find that the Heck−Sonogashira19 and Heck−
Heck20 domino reactions21 occurred under similar conditions to
provide 9e−g and 9h−j in good yields (75−85%), respectively. It
should be noted that these products may not be prepared by the
redox-A3 reaction followed by the reductive Heck cyclization
because the corresponding alkynes (enynes and diynes) have
unknown reactivity or are not readily available for the redox-A3
reactions and/or reductive Heck cyclization. Therefore, these
domino reactions greatly expand the structural diversity of 13-
substituted THPBs for the biological evaluation.
(7) Zhou, S.; Tong, R. Chem. - Eur. J. 2016, 22, 7084.
In summary, we have identified the (S,R)-N-PINAP ligand for
the highly enantioselective CuI-catalyzed redox-A3 reaction of
tetrahydroisoquinolines, 2-bromobenzaldehyde derivatives, and
alkynes, which enables us to accomplish the first asymmetric total
synthesis of 12 natural 13-methyltetrahydroprotoberberines (13-
MeTHPBs) in three catalytic steps with 47−64% overall yields.
In addition, three Pd-catalyzed domino reactions (Heck−Suzuki,
Heck−Sonogashira, and Heck−Heck) have been developed to
provide the tetracyclic tetrahydroprotoberberine core bearing
otherwise poorly accessible substituted alkene at C13, which
substantially expands the structural diversity for medicinal
chemistry.
(8) (a) Lin, W.; Cao, T.; Fan, W.; Han, Y.; Kuang, J.; Luo, H.; Miao, B.;
Tang, X.; Yu, Q.; Yuan, W.; Zhang, J.; Zhu, C.; Ma, S. Angew. Chem., Int.
Ed. 2014, 53, 277. For application of this asymmetric redox-A3 reaction
in total synthesis of isoquinoline natural products, see: (b) Lin, W.; Ma,
S. Org. Chem. Front. 2014, 1, 338. During the peer-review process and
revision of this manuscript, Ma reported the employment of both (R,S)-
N-PINAP and (R,R)-N-PINAP for the highly enantioselective redox-A3
reaction of THIQ 1a, benzaldehyde (2a′), and 2-methyl-3-butyn-2-ol;
(9) (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(b) For a review, see: Desimoni, G.; Faita, G.; Quadrelli, P. Chem. Rev.
2003, 103, 3119.
(10) (a) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2002, 124, 5638. (b) Li, Z.;
Li, C. J. J. Am. Chem. Soc. 2004, 126, 11810. (c) Hashimoto, T.; Omote,
M.; Maruoka, K. Angew. Chem., Int. Ed. 2011, 50, 8952. (d) Sun, S.; Li,
C.; Floreancig, P. E.; Lou, H.; Liu, L. Org. Lett. 2015, 17, 1684.
(e) Dasgupta, S.; Liu, J.; Shoffler, C. A.; Yap, G. P.; Watson, M. P. Org.
Lett. 2016, 18, 6006.
(11) (a) Iwasa, K.; Gupta, Y. P.; Cushman, M. J. Org. Chem. 1981, 46,
4744. (b) Yu, C. K.; Maclean, D. B.; Rodrigo, R. G. A.; Manske, R. H. F.
Can. J. Chem. 1970, 48, 3673.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Experimental details, procedures, and characterization of
X-ray data for compound 4a (CIF)
(12) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
̈
Carreira, E. M. Angew. Chem. 2004, 116, 6097.
AUTHOR INFORMATION
■
(13) (a) Takao, N.; Iwasa, K.; Kamigauchi, M.; Sugiura, M. Chem.
Pharm. Bull. 1977, 25, 1426. (b) Hanaoka, M.; Yoshida, S.; Mukai, C.
Chem. Pharm. Bull. 1989, 37, 3264. (c) Hanaoka, M.; Hirasawa, T.; Cho,
W. J.; Yasuda, S. Chem. Pharm. Bull. 2000, 48, 399.
Corresponding Author
ORCID
(14) Albaladejo, M. J.; Gonzal
2016, 81, 9707.
́
ez-Soria, M. J.; Alonso, F. J. Org. Chem.
Notes
(15) (a) Iwasa, K.; Nanba, H.; Lee, D.-U.; Kang, S.-I. Planta Med. 1998,
64, 748. (b) Lee, G. E.; Lee, H. S.; Lee, S. D.; Kim, J. H.; Kim, W. K.; Kim,
Y. C. Bioorg. Med. Chem. Lett. 2009, 19, 954. (c) Iwasa, K.; Moriyasu, M.;
Yamori, T.; Turuo, T.; Lee, D.-U.; Wiegrebe, W. J. Nat. Prod. 2001, 64,
896. (d) Shi, J.; Zhang, X.; Ma, Z.; Zhang, M.; Sun, F. Molecules 2010, 15,
3556.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by Research Grant
Council of Hong Kong (ECS 605912, GRF 605113, and GRF
16305314).
(16) For selected reviews on palladium-catalyzed domino reactions,
see: (a) de Meijere, A.; von Zezschwitz, P.; Brase, S. Acc. Chem. Res.
̈
2005, 38, 413. (b) Pellissier, H. Chem. Rev. 2013, 113, 442. (c) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442. For
a recent representative example, see: (d) Pinto, A.; Neuville, L.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 3291.
REFERENCES
■
(1) Maiti, M.; Kumar, G. S. Top. Heterocycl. Chem. 2007, 10, 155.
(2) (a) Zhang, Z. H.; Zhang, H. J.; Deng, A. J.; Wang, B.; Li, Z. H.; Liu,
Y.; Wu, L. Q.; Wang, W. J.; Qin, H. L. J. Med. Chem. 2015, 58, 7557.
(b) Bhadra, K.; Kumar, G. S. Med. Res. Rev. 2011, 31, 821. (c) Li, Y. H.;
Yang, P.; Kong, W. J.; Wang, Y. X.; Hu, C. Q.; Zuo, Z. Y.; Wang, Y. M.;
Gao, H.; Gao, L. M.; Feng, Y. C.; Du, N. N.; Liu, Y.; Song, D. Q.; Jiang, J.
D. J. Med. Chem. 2009, 52, 492. (d) Zhang, Y.; Wang, C.; Wang, L.;
Parks, G. S.; Zhang, X.; Guo, Z.; Ke, Y.; Li, K.; Kim, M. K.; Vo, B.;
Borrelli, E.; Ge, G.; Yang, L.; Wang, Z.; Garcia-Fuster, M. J.; Luo, Z. D.;
Liang, X.; Civelli, O. Curr. Biol. 2014, 24, 117.
(3) (a) Ji, H. Y.; Liu, K. H.; Lee, H.; Im, S. R.; Shim, H. J.; Son, M.; Lee,
H. S. Molecules 2011, 16, 6591. (b) Li, W.; Zhang, H.; Niu, X.; Wang, X.;
Wang, Y.; He, Z.; Yao, H. Toxicol. Appl. Pharmacol. 2016, 305, 46.
(c) Huang, Q. Q.; Bi, J. L.; Sun, Q. Y.; Yang, F. M.; Wang, Y. H.; Tang, G.
(17) For a related recent example, see: Seashore-Ludlow, B.; Somfai, P.
Org. Lett. 2012, 14, 3858.
(18) Only a small amount of proto-debromination product was
obtained.
(19) Wang, D. C.; Wang, H. X.; Hao, E. J.; Jiang, X. H.; Xie, M. S.; Qu,
G. R.; Guo, H. M. Adv. Synth. Catal. 2016, 358, 494.
(20) Pawliczek, M.; Milde, B.; Jones, P. G.; Werz, D. B. Chem. - Eur. J.
2015, 21, 12303.
(21) Guo, L. N.; Duan, X. H.; Hu, J.; Bi, H. P.; Liu, X. Y.; Liang, Y. M.
Eur. J. Org. Chem. 2008, 2008, 1418.
D
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