Rapid Construction of the ABCE Tetracyclic Tertiary Amine Skeleton in

4 days ago - ... sequence to build up the aromatic ring;(5a) In 2014, She's group demonstrated .... to neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) i...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Rapid Construction of the ABCE Tetracyclic Tertiary Amine Skeleton in Daphenylline Enabled by an Amine−Borane Complexation Strategy Meng Deng, Yanmin Yao, Xiaohu Li, Nan Li, Xiao Zhang, and Guangxin Liang* State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China

Org. Lett. Downloaded from pubs.acs.org by UNIV OF MELBOURNE on 04/22/19. For personal use only.

S Supporting Information *

ABSTRACT: A synthetically challenging tetracyclic tertiary amine framework in the Daphniphyllum alkaloid daphenylline was established in a six-step sequence featuring an intermolecular Diels−Alder cycloaddition/oxidative aromatization sequence. The utilization of an amine−borane complexation strategy is the key to successful transformations on our tertiary amine substrates.

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up the aromatic ring;5a In 2014, She’s group demonstrated an intramolecular Diels−Alder/aromatization approach to install the DEF tricyclic core of 1.13c In 2017, Zhai and co-workers performed a biomimetic cationic rearrangement to establish the benzene ring.8 Shortly after, Li’s group disclosed their second synthesis using a base-promoted ring-expansion/ aromatization/aldol cascade to construct the benzene moiety of daphenylline.5c Herein, we report our rapid construction of the ABCE tetracyclic skeleton in daphenylline featuring an intermolecular Diels−Alder reaction and oxidative aromatization strategy, which highlights the use of amine complexation with borane to achieve the otherwise unmanageable transformations on tertiary amine substrates. The chirality of drugs as well as bioactive natural products has been a research hotspot considering that the enantiomers of a chiral molecule may display different pharmacological or biological behaviors in living organisms.14 In view of this, (+)-daphenylline (2, Figure 1), the enantiomer of naturally occurring 1, was chosen as our synthetic target. A brief retrosynthetic analysis is illustrated in Scheme 1. We envisioned a Norrish type II photoreaction15 to build the seven-membered D ring of 2, the C6, C10, and C18 stereogenic centers of which could be established through late-stage stereoselective hydrogenations. The aromatic E ring in the advanced intermediate 11 could be assembled through an inverse-electron-demand Diels−Alder reaction between 12 and a tunable dienophile followed by aromatization. Further deconstruction of 12 using transition-metal-catalyzed crosscoupling reaction could give tricyclic core 13 as a key

he Daphniphyllum alkaloids, isolated from plants of the genus Daphniphyllum, comprise more than 320 members with intricate architectures and diverse biological activities.1 Since Heathcock’s landmark syntheses of methyl homosecodaphniphyllate and other structurally related members in the late 1980s,2 this family of alkaloids has attracted enormous attention from synthetic chemists.3 Until now, the groups of Carreira,4 Li,5 Smith,6 Fukuyama−Yokoshima,7 Zhai,8 Dixon,9 Qiu,10 and Xu11 have disclosed their elegant syntheses of 11 members of the Daphniphyllum alkaloid family. (−)-Daphenylline (1, Figure 1), isolated in 2009 by Hao and co-workers,12 is a unique hexacyclic Daphniphyllum

Figure 1. Illustrations of (−)- and (+)-daphenylline (1 and 2).

alkaloid that contains an arene motif in the core structure. So far, five total syntheses5a,c,7,8,10 and several model syntheses13 of 1 have been admirably achieved. Structurally speaking, the most challenging problem of daphenylline synthesis resides in the assembly of the tetrasubstituted arene moiety in a sterically congested hexacyclic ring system. Figure 2 summarized relevant endeavors in this regard. In 2013, Li and co-workers developed a photoinduced olefin isomerization/6π-electrocyclization/aromatization sequence to build © XXXX American Chemical Society

Received: March 22, 2019

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DOI: 10.1021/acs.orglett.9b01021 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 2. Construction of Tricyclic Tertiary Amine Core 13

aza-Michael addition product 14a in 90% yield in a ratio of 7:1 (see the Supporting Information for details), which was used in the next step without further purification. The following palladium-catalyzed enolate α-vinylation process performed as well, producing the bowl-shaped tricyclic tertiary amine core 13 with a newly formed quaternary stereocenter in 82% yield. The stereochemistry of 13 was unambiguously confirmed through X-ray crystallographic analysis of its N-oxide derivative 17. This productive two-step approach ensured a sufficient supply of 13 for our further studies. With aza-tricyclic ketone 13 in hand, we moved on to prepare the diene segment for investigation of the Diels−Alder reaction (Scheme 3). Treatment of 13 with NaHMDS and Figure 2. Previous efforts for construction of the tetrasubstituted arene ring in daphenylline.

Scheme 3. Preparation of Diene 21 and Studies of the Intermolecular Diels−Alder Cycloaddition

Scheme 1. Synthetic Blueprint for (+)-Daphenylline (2)

Comins’ reagent (18)18 furnished triflate 19 in 49% yield, which further underwent Suzuki coupling with vinyl borate 20 to generate the templated diene 21 in 56% yield. The poor efficiency of this two-step procedure may be attributable to the strong basicity of tertiary amine nitrogen atom, which interfered with the reactivity and caused difficulties in purification. Nevertheless, we directed our attention to the intermolecular Diels−Alder reaction. A series of classical dienophiles such as maleic anhydride, bromomaleic anhydride, and dimethyl acetylenedicarboxylate (22) were examined with diene 21.19 Unfortunately, all trials led to the rapid decomposition of diene 21, while no cycloadduct was observed. It is not difficult to understand that these electrondeficient dienophiles were also excellent Michael acceptors, which could be subjected to Michael addition by the exposed tertiary amine moiety in 21.

intermediate. On the basis of our previous work,16 a simplified two-step procedure for 13 was devised, featuring a palladiumcatalyzed enolate α-vinylation strategy from 14 and a tandem N-alkylation/aza-Michael addition sequence using readily available starting materials 15 and 16.17 Our synthetic adventure began with the anticipated Nalkylation/aza-Michael addition cascade to create the bridged aza[3.3.1]bicycle 14 (Scheme 2). To our delight, this cascade ran smoothly between chloride 15 and amine 16 in the presence of K2CO3, generating a mixture of 14 and the retroB

DOI: 10.1021/acs.orglett.9b01021 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Inspired by Stotter’s seminal work on quinuclidine−borane derivatives,20 we intended to introduce a nitrogen−borane coordination to our tertiary amine intermediates so as to mask their basicity and nucleophilicity (Scheme 4). Addition of BH3·

Scheme 5. Diels−Alder Reaction/Elimination Cascade

Scheme 4. Amine−Borane Complex Facilitated Transformations in Substrates Bearing Tertiary Amines

(Scheme 6). Delightfully, this Diels−Alder reaction proceeded successfully, generating the desired cyclohexadiene intermediScheme 6. Completion of the ABCE Tetracyclic Skeleton of 2

THF to 13 formed the borane−complexed aza-tricyclicketone 23, which further underwent triflation with NaHMDS and Nphenylbis(trifluoromethanesulfonimide) (PhNTf2) to give 24 in nearly quantitative yield. The following Suzuki coupling of 24 with vinyl borate 20 proceeded smoothly, affording an amine−borane diene 25 in 94% yield. Gratifyingly, the Diels− Alder reaction between 25 and maleic anhydride proven successful, giving the endo cycloadduct 26 in 82% yield. All structures of the amine−borane complexes depicted in Scheme 4 were accurately elucidated by single-crystal X-ray crystallographic analyses. The effective Diels−Alder reaction with maleic anhydride encouraged us to investigate other dienophiles to further introduce unsaturation in the product. A Diels−Alder cycloaddition/E1cb elimination cascade was investigated by heating diene 25 with bromomaleic anhydride in the presence of 2,6-bis(tert-butyl)pyridine (Scheme 5). To our delight, the anticipated cyclohexadiene adduct 27 coordinated with monobromoborane was isolated in 79% yield as a moisturesensitive solid, whose structure was carefully characterized through X-ray crystallographic analysis. Unfortunately, subsequent attempts toward oxidative aromatization of the cyclohexadiene motif in 27 were fruitless, as the fragile boron−bromine bond and the reactive anhydride moiety fused on the E ring hampered the applications of many common oxidative conditions. In order to obtain a stable cyclohexadiene precursor for further aromatization study, dimethyl acetylenedicarboxylate (22) was employed as a dienophile to react with diene 25

ate 28 in excellent yield. However, the following aromatization step turned out to be more difficult than we have expected. Various oxidants or dehydrogenation reagents, such as Ce(NH4)2(NO3)6, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), pyridinium chlorochromate (PCC), MnO 2, 2iodoxybenzoic acid (IBX), SeO2, Pd/C, Rh/C, and Ir/C, failed in the aromatization attempt. Enlightened by Ikeda21 and Li’s5a elegant work, a base-prompted air oxidation at the C15 or C1 position of the cyclohexadiene E ring followed by E1cb elimination approach was tested. Gratifyingly, when 28 was exposed to neat 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in open air at room temperature, an aromatic tertiary amine 29 was isolated in 69% yield. To facilitate the purification, BH3· Me2S could be added in situ to generate an amine−borane complex 30 in 73% yield as a crystalline solid. The X-ray crystallographic structure of 30 displays an apparent correspondence with the ABCE tetracyclic skeleton in (+)-daphenylline (2). In summary, we have demonstrated an efficient synthetic approach for rapid construction of the tetracyclic tertiary amine skeleton (ABCE rings) in the Daphniphyllum alkaloid daphenylline with an overall yield of 42% over six steps. Our chemistry features an intermolecular Diels−Alder reaction/ oxidative aromatization sequence to assemble the highly fused aromatic E ring in daphenylline. A tandem N-alkylation/ Michael addition followed by palladium-catalyzed enolate αvinylation reaction ensured a sufficient supply of tricyclic core 13, the ring system of which was also commonly found in C

DOI: 10.1021/acs.orglett.9b01021 Org. Lett. XXXX, XXX, XXX−XXX

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(3) For synthetic studies published after ref 1d, see: (a) Coussanes, G.; Bonjoch, J. Org. Lett. 2017, 19, 878. (b) Shao, H.; Bao, W.; Jing, Z.-R.; Wang, Y.-P.; Zhang, F.-M.; Wang, S.-H.; Tu, Y.-Q. Org. Lett. 2017, 19, 4648. (c) Liu, Y. M.; Li, F.; Wang, Q.; Yang, J. Tetrahedron 2017, 73, 6381. (d) Kitabayashi, Y.; Fukuyama, T.; Yokoshima, S. Org. Biomol. Chem. 2018, 16, 3556. (e) Sasano, Y.; Koyama, J.; Yoshikawa, K.; Kanoh, N.; Kwon, E.; Iwabuchi, Y. Org. Lett. 2018, 20, 3053. (f) Yamada, R.; Fukuyama, T.; Yokoshima, S. Org. Lett. 2018, 20, 4504. (g) Li, Y.; Dong, Q.; Xie, Q.; Tang, P.; Zhang, M.; Qin, Y. Org. Lett. 2018, 20, 5053. (h) Mo, X.-F.; Li, Y.-F.; Sun, M.-H.; Dong, Q.-Y.; Xie, Q.-X.; Tang, P.; Xue, F.; Qin, Y. Tetrahedron Lett. 2018, 59, 1999. (i) Qiu, Y.; Zhong, J.; Du, S.; Gao, S. Chem. Commun. 2018, 54, 5554. (4) For the total synthesis of daphmanidin E, see: Weiss, M. E.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 11501. (5) For the total synthesis of daphenylline, see: (a) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nat. Chem. 2013, 5, 679. For the total synthesis of daphniyunnine C (longeracinphyllin A), see: (b) Li, J.; Zhang, W.; Zhang, F.; Chen, Y.; Li, A. J. Am. Chem. Soc. 2017, 139, 14893. For the total syntheses of daphenylline, daphnipaxianine A, and himalenine D, see: (c) Chen, Y.; Zhang, W.; Ren, L.; Li, J.; Li, A. Angew. Chem., Int. Ed. 2018, 57, 952. For the total syntheses of hybridaphniphylline B, daphnilongeranin B, daphniyunnine E, and dehydrodaphnilongeranin B, see: (d) Zhang, W.; Ding, M.; Li, J.; Guo, Z.; Lu, M.; Chen, Y.; Liu, L.; Shen, Y.-H.; Li, A. J. Am. Chem. Soc. 2018, 140, 4227. (6) For the total synthesis of calyciphylline N, see: (a) Shvartsbart, A.; Smith, A. B., III. J. Am. Chem. Soc. 2014, 136, 870. (b) Shvartsbart, A.; Smith, A. B., III. J. Am. Chem. Soc. 2015, 137, 3510. (7) For the total synthesis of daphenylline, see: Yamada, R.; Adachi, Y.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2016, 55, 6067. (8) For the total syntheses of daphnilongeranin B and daphenylline, see: Chen, X.; Zhang, H.-J.; Yang, X.; Lv, H.; Shao, X.; Tao, C.; Wang, H.; Cheng, B.; Li, Y.; Guo, J.; Zhang, J.; Zhai, H. Angew. Chem., Int. Ed. 2018, 57, 947. (9) For the total synthesis of himalensine A, see: Shi, H.; Michaelides, I. N.; Darses, B.; Jakubec, P.; Nguyen, Q. N. N.; Paton, R. S. P.; Dixon, D. J. J. Am. Chem. Soc. 2017, 139, 17755. (10) For the total synthesis of daphenylline, see: Xu, B.; Wang, B.; Xun, W.; Qiu, F. G. Angew. Chem., Int. Ed. 2019, 58, 5754. (11) For the total synthesis of himalensine A, see: Chen, Y.; Hu, J.; Guo, L.-D.; Zhong, W.; Ning, C.; Xu, J. Angew. Chem., Int. Ed. 2019, DOI: 10.1002/anie.201902908. (12) Zhang, Q.; Di, Y.-T.; Li, C.-S.; Fang, X.; Tan, C.-J.; Zhang, Z.; Zhang, Y.; He, H.-P.; Li, S.-L.; Hao, X.-J. Org. Lett. 2009, 11, 2357. (13) (a) Fang, B.; Zheng, H.; Zhao, C.; Jing, P.; Li, H.; Xie, X.; She, X. J. Org. Chem. 2012, 77, 8367. (b) Li, H.; Zheng, J.; Xu, S.; Ma, D.; Zhao, C.; Fang, B.; Xie, X.; She, X. Chem. - Asian J. 2012, 7, 2519. (c) Li, H.; Qiu, Y.; Zhao, C.; Yuan, Z.; Xie, X.; She, X. Chem. - Asian J. 2014, 9, 1274. (d) Wang, W.; Li, G.-P.; Wang, S.-F.; Shi, Z.-F.; Cao, X.-P. Chem. - Asian J. 2015, 10, 377. (14) (a) Chiral Drugs: Chemistry and Biological Action, 1st ed.; Lin, G.-Q., You, Q.-D., Cheng, J.-F., Eds.; John Wiley & Sons, 2011; ISBN: 9781118075647. (b) Logan, M. M.; Toma, T.; Thomas-Tran, R.; Du Bois, J. Science 2016, 354, 865. (15) (a) Norrish, R. G. W.; Bamford, C. H. Nature 1937, 140, 195. (b) Yang, N. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 2913. (c) Kärkäs, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev. 2016, 116, 9683. See also the references cited therein. (16) Yao, Y.; Liang, G. Org. Lett. 2012, 14, 5499. (17) Both 15 (CAS No. 86847-23-6) and 16 (CAS No. 459144-504) are commercially available. For the preparation and characterization of 15, see: (a) Chen, D.; Evans, P. A. J. Am. Chem. Soc. 2017, 139, 6046. For 16, see: (b) Liu, P.; Wang, J.; Zhang, J.; Qiu, F. G. Org. Lett. 2011, 13, 6426. (18) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299. (19) Maleic anhydride and dimethyl acetylenedicarboxylate have been used to test the reactivity of a diene system in an investigation

calyciphylline A type alkaloids. The utilization of an amine− borane complexation strategy dramatically boosted the tertiary amine substrate transformations and facilitated subsequent purification and characterization as well. We strongly believe that the application of amine−borane complexation will significantly benefit alkaloid synthesis in general. Continued efforts toward total syntheses of daphenylline and other types of Daphniphyllum alkaloids are currently underway in our laboratory.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01021. Experimental procedures and characterization data; copies of NMR spectra for new compounds; ORTEP drawings and crystallographic data (PDF) Accession Codes

CCDC 1893589−1893593 and 1899997−1899998 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Meng Deng: 0000-0003-0194-9296 Nan Li: 0000-0001-5490-322X Guangxin Liang: 0000-0003-3122-0332 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Key Research and Development Program of China (2017YFD0201404) and the National Natural Science Foundation of China (21772097, 21572104) for financial support. We also thank Prof. Haibin Song of the Institute of Elemento-organic Chemistry, Nankai University, for X-ray crystallographic analysis.

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REFERENCES

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DOI: 10.1021/acs.orglett.9b01021 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters for an intramolecular Diels−Alder cycloaddition strategy in daphenylline synthesis; see: Lu, Z. Ph.D. dissertation, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, 2013. (20) (a) Stotter, P. L.; Friedman, M. D.; Dorsey, G. O.; Shiely, R. W.; Williams, R. F.; Minter, D. E. Heterocycles 1987, 25, 251. For some accidentally captured amine−borane complexes in alkaloid syntheses, see: (b) Liu, X.; Cook, J. M. Org. Lett. 2001, 3, 4023. (c) Liu, X.; Deschamp, J. R.; Cook, J. M. Org. Lett. 2002, 4, 3339. (d) Liao, X.; Zhou, H.; Wearing, X. Z.; Ma, J.; Cook, J. M. Org. Lett. 2005, 7, 3501. (e) Solé, D.; Urbaneja, X.; Bonjoch, J. Org. Lett. 2005, 7, 5461. (f) Picazo, E.; Morrill, L. A.; Susick, R. B.; Moreno, J.; Smith, J. M.; Garg, N. K. J. Am. Chem. Soc. 2018, 140, 6483. (21) Ikeda, S.; Mori, N.; Sato, Y. J. Am. Chem. Soc. 1997, 119, 4779.

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DOI: 10.1021/acs.orglett.9b01021 Org. Lett. XXXX, XXX, XXX−XXX