This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Letter pubs.acs.org/OrgLett
Three-Step Catalytic Asymmetric Total Syntheses of 13Methyltetrahydroprotoberberine Alkaloids Shiqiang Zhou and Rongbiao Tong* Department of Chemistry, The Hong Kong University of Science and Technology, Clearwater Bay, Kowloon, Hong Kong, China S Supporting Information *
ABSTRACT: (S,R)-N-PINAP was identified to be the chiral ligand for highly enantioselective CuI-catalyzed reaction of tetrahydroisoquinolines (THIQs), alkynes, and 2-bromobenzaldehyde derivatives. This enables us to accomplish the first asymmetric total synthesis of 12 natural 13-methyltetrahydroprotoberberine (13-MeTHPB) alkaloids in only three catalytic steps with 47−64% overall yields. In addition, the Pd-catalyzed reductive Heck cyclization was successfully extended to three Pd-catalyzed domino reactions (Heck/Suzuki, Heck/Sonogashira, and Heck/Heck), which greatly expands the synthetic utility of this catalytic strategy and allows expeditious access to 13-substituted tetrahydroprotoberberines for further bioactivity evaluation.
T
Scheme 1. Previous Asymmetric Synthesis and Our Catalytic Asymmetric Strategy for 13Methyltetrahydroprotoberberines
he protoberberine alkaloids are an important class of isoquinoline natural products because they display various biological activities1 and are ubiquitous in plants such as Annoneceae, Papaveraceae, Berberidaceae, etc. These plants have been used in traditional Chinese medicine for treatment of inflammation and cancers.2 Among the known >150 members, the 13-methyltetrahydroprotoberberines (13-MeTHPB, Figure 1) represent an unusual group due to the presence of two chiral
Figure 1. Representative members of 13-methyltetrahydroprotoberberines (13-MeTHPBs).
carbon centers and beneficial medicinal effects with C13 substitution.3 Therefore, 13-MeTHPBs have aroused great interest in synthetic studies, leading to the development of both concise semisynthetic routes and totally synthetic strategies.4 However, all these syntheses delivered only racemic products. In 2014, Cozzi5 and co-workers reported an asymmetric synthesis of one analogue of natural 13-MeTHPBs in nine steps with 18% overall yield (Scheme 1a), and the extension of this chemistry to asymmetric total synthesis of 13MeTHPBs has not been demonstrated yet. Apparently, the asymmetric synthesis of 13-MeTHPBs is rather underdeveloped. Herein, we describe the identification of (S,R)-N-PINAP for the highly enantioselective, catalytic CuI-catalyzed reaction of alkynes, 2-bromobenzaldehyde derivatives, and tetrahydroisoquinolines, which enables us to achieve the first catalytic asymmetric three-step total syntheses of 12 natural 13© XXXX American Chemical Society
MeTHPBs with 47−64% overall yields and 91−96% ee optical purity (Scheme 1b). In early 2016, our group reported a concise and general strategy for the synthesis of protoberberines by exploiting the CuI-catalyzed redox-A3 reaction (redox-neutral three-component reaction of alkyne, amine, and aldehyde)6 as one of the key steps.7 We reasoned that if the asymmetric redox-A3 reaction first developed by Ma8a et al. in 2014 (Scheme 2b) could be applied to our substrates, the asymmetric synthesis of the natural 13MeTHPBs could be achieved concisely and efficiently. Surprisingly, we observed only 50% ee value (er, 75/25) when the reactions of electron-rich tetrahydroisoquinoline (THIQ) Received: February 10, 2017
A
DOI: 10.1021/acs.orglett.7b00414 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Control Experiments of Asymmetric CuICatalyzed Redox-A3 Reaction under Ma’s Conditions
Table 1. Screening of Chiral Ligands for CuI-Catalyzed Redox-A3 Reaction
1a, 2-bromobenzaldehyde derivative 2a, and alkyne 3a were carried out under otherwise identical conditions (Scheme 2a). To find out the cause for such low enantioselectivity, we first repeated the reaction with the substrates (1a′, 2a′, and 3a′) used by Ma and obtained the product 4a1 with 95% ee, consistent with the reported 95% ee (Scheme 2b). This result verified the excellent quality of the homemade (R,R)-N-PINAP ligand and our appropriate execution of the reaction. Next, we performed a series of parallel controlled reactions with one of the three substrates being replaced by the corresponding 1a, 2a, and 3a each time (Scheme 2b−e). The aldehyde 2a was rapidly identified to significantly lower the enantioselectivity (95% ee → 73% ee, Scheme 2d). THIQ 1a had a slight influence (95% ee → 86% ee, Scheme 2c; it was noted that Ma et al.8a,b reported a few examples of the redox-A3 reaction employing this electronrich THIQ 1a with 98% ee), but replacement of phenylacetylene with TMS acetylene (1a) did not erode the enantioselectivity (Scheme 2e). Taking all these results together, we could well explain our initial observation that the combination of 1a and 2a resulted in very low enantioselectivity (50% ee). To improve the enantioselectivity of this key redox-A3 reaction with the electronrich THIQ 1a and 2-bromobenzaldehyde derivative 2a, we set out to examine other chiral ligands9 for the asymmetric alkynylation of imine (Table 1). In light of the fact that the chiral PyBOX9b (a pyridine flanked by two oxazoline rings) is the most successful ligand tested for the copper-catalyzed enantioselective addition of terminal alkynes to the imines or iminium ions10 and that this asymmetric alkyne−imine addition is mechanistically similar to the copper-catalyzed redox-A3 reaction, we examined a small set of PyBOX ligands for the copper catalysis of the redox-A3 reaction (Table 1). To our disappointment, the PyBOX ligands (L4−L7) consistently gave no or poor enantioselectivity (0−40% ee) with incomplete consumption of starting materials (0−65% conversion) (Table 1, entries 2−6). Therefore, we closely re-examined the chiral PINAP ligands since they extraordinarily accelerate the reaction with the full conversion of THIQ 1a. Interestingly, (R,S)-NPINAP (L2, a diastereomer of (R,R)-N-PINAP (L1) used by Ma) was found to effect an excellent enantioselectivity (94% ee), providing the major product ent-4a0 with opposite absolute configuration compared to 4a0 (entry 7). This result was in sharp contrast to the previous observation by Ma8 that (R, S)-N-
a
entry
catalyst
ligand
conv
yield (%)
era
1 2 3 4 5 6 7 8
CuI CuI Cu(OTf)2 CuI CuI CuI CuI CuI
L1 L4 L4 L5 L6 L7 L2 L3
100 58 0 55 64 64 100 100
88 42 0 39 50 50 94 90
25:75 55:45 41:59 30:70 47:53 97:3 2.5:97.5
Enantiomeric ratio was determined by chiral HPLC.
PINAP (L2) resulted in lower enantioselectivity (83% ee) for the redox-A3 reaction of 1a′, 2a′, and 1-decyne (Scheme 2f). In order to make the natural 13-MeTHPBs with correct absolute configuration,11 we prepared the (S, R)-N-PINAP (L3), the enantiomer of L2, according to Carreira’s protocol12 and verified its efficiency for the same redox-A3 reaction (entry 8). These unexpected findings allowed us to conclude that (S, R)-N-PINAP [or (S,R)-N-PINAP] is an excellent chiral ligand for the CuIcatalyzed asymmetric redox-A3 reaction of sterically hindered aromatic aldehydes and THIQs and that (R, R)-N-PINAP is only applicable to benzaldehyde without neighboring substituents. After the identification of (S,R)-N-PINAP for the asymmetric redox-A3 reaction, we then expanded the substrates (1a−d and 2a−d) and successfully accomplished the asymmetric total synthesis of 12 natural 13-MeTHPBs (6a−l)13 through Pdcatalyzed reductive carbocyclization and hydrogenation under PtO2 (or Pd/C) catalysis14 (Scheme 3) using our previously reported protocols.7 For the hydrogenation step, we compared the stereochemistry integrity of the PtO2 and Pd/C catalysis and found that both catalysts reliably delivered the hydrogenation product (6a) with comparable optical purity (PtO2, 94% ee; Pd/ C, 92% ee) but with consistently higher yield by PtO2 catalysis. Therefore, we chose the PtO2-catalyzed hydrogenation for other substrates (5b−h) except for 5i−l. It was found that the Pd/Ccatalyzed hydrogenation of 5i−l could saturate the exomethylene and concomitantly remove the benzyl protection group, which could not be achieved by PtO2 catalysis. It was notable that no epimerization was observed in the last two catalytic reactions and that all natural products were obtained in excellent overall yield (47−64%) and high optical purity (91− 96% ee). To the best of our knowledge, it is the first time that the asymmetric total synthesis of these natural 13-MeTHPBs was B
DOI: 10.1021/acs.orglett.7b00414 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Catalytic Asymmetric Total Syntheses of 12 Natural 13-Methyltetrahydroprotoberberinesa
a
Note: ee (%) was determined by normal-phase chiral HPLC; isolated yield either of redox-A3 reaction or over three steps for natural products.
achieved, which confirmed their absolute configuration assignments.11 It is well recognized that 13-substitution of protoberberines significantly enhances the bioactivity (e.g., antibacterial and cytotoxicity).15 In principle, this three-component strategy would allow us to flexibly install different groups at C13 in the first step (Cu-catalyzed redox-A3 reaction) by employing different alkynes. However, we were more interested in expanding such substrate flexibility and product diversity at the second step (Pd-catalyzed reductive Heck cyclization) by exploring the possible Pd-catalyzed domino reactions16 (Scheme 4). If the alkenylpalladium intermediate derived from carbopalladation of alkynyl bromide (cf. 4a) could be captured by a nucleophile (or electrophile), not by the hydride (from HCO2Na), the one-pot, Pd-catalyzed cascade reaction would form two carbon−carbon bonds and provide the tetracyclic THPB core bearing a substituted alkene group at C13 (Scheme 4a). To verify our hypothesis, we carried out the Pd-catalyzed reaction with 4a as the substrate and aryl boronic acids as the trapping nucleophiles17 (Scheme 4b). To our delight, after slight modifications of the original reductive Heck conditions, this Heck−Suzuki domino reaction proceeded smoothly to provide 9a in 40% yield. Further experimentation revealed that the addition of water (DMF/ H2O = 3/1) dramatically improved the yields (9a−c, 92−95%), partially due to the increased solubility of K2CO3 in these mixed solvents. Notably, the optically active (+)-10,2a a potential antiulcerative colitis agent that was semisynthesized as a racemic form in five steps from the natural tetracyclic coptisine, was prepared in 55% overall yield by this domino Heck−Suzuki reaction of (−)-4e followed by PtO2-catalyzed hydrogenation.
Scheme 4. Pd-Catalyzed Domino Reactions for Synthesis of 13-Substituted Tetrahydroprotoberbines
C
DOI: 10.1021/acs.orglett.7b00414 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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. (7) Zhou, S.; Tong, R. Chem. - Eur. J. 2016, 22, 7084. (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; see: (c) Lin, W.; Ma, S. Org. Chem. Front. 2017, DOI: 10.1039/ C7QO00062F. (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. (12) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem. 2004, 116, 6097. (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. (14) Albaladejo, M. J.; González-Soria, M. J.; Alonso, F. J. Org. Chem. 2016, 81, 9707. (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. (16) For selected reviews on palladium-catalyzed domino reactions, see: (a) de Meijere, A.; von Zezschwitz, P.; Bräse, 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. (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.
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 13substituted THPBs for the biological evaluation. 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 (13MeTHPBs) 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.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00414. Experimental details, procedures, and characterization of all compounds (PDF) X-ray data for compound 4a (CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Rongbiao Tong: 0000-0002-2740-5222 Notes
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).
■
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. D
DOI: 10.1021/acs.orglett.7b00414 Org. Lett. XXXX, XXX, XXX−XXX
