Communication pubs.acs.org/JACS
Cite This: J. Am. Chem. Soc. 2017, 139, 14893-14896
Total Synthesis of Longeracinphyllin A Jian Li,† Wenhao Zhang,† Fei Zhang, Yu Chen, and Ang Li* State Key Laboratory of Bioorganic and Natural Products Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China S Supporting Information *
ABSTRACT: The first and asymmetric total synthesis of longeracinphyllin A, a hexacyclic Daphniphyllum alkaloid, has been accomplished. A tetracyclic intermediate was prepared through silver-catalyzed alkyne cyclization and Luche radical cyclization. A phosphine-promoted [3 + 2] cycloaddition reaction was exploited to construct the sterically congested E ring bearing vicinal tertiary and quaternary centers. The cyclopentenone motif was assembled by using intramolecular Horner−Wadsworth−Emmons olefination. Raney Ni reduction delivered the tertiary amine from a thioamide precursor at a late stage.
Daphniphyllum alkaloids are a large family of polycyclic natural products (>300 members) isolated from the evergreen plants of the genus Daphniphyllum.1 They exhibit a wide range of biological activities, including antitumor, antiviral, and nerve growth factor-regulating properties,1b and attract considerable attention from the synthesis community.1a−c The groups of Heathcock, Carreira, Smith, Fukuyama, and ours have accomplished the syntheses of nine Daphniphyllum alkaloids (1−9, Figure 1).2−13 The calyciphylline A subfamily comprises more than 50 members, most of which share a characteristic 6−6−5− 7−5−5-hexacyclic core.1c Despite the intense efforts toward the synthesis of this subclass,1b,c,14 the only member that has been synthesized to date is daphenylline (8, Figure 1) possessing a nonrepresentative arene-containing skeleton.10,12 Longeracinphyllin A (10, Figure 1) is a structural representative of the subfamily, which was isolated by Hao and co-workers from the leaves of Daphniphyllum longeracemosum.15 Its six consecutive stereocenters including the vicinal quaternary centers pose a challenge for chemical synthesis. Herein, we report the first and asymmetric total synthesis of this alkaloid. We first undertook a retrosynthetic analysis of 10 (Figure 2). A key issue for the synthesis of calyciphylline A-type alkaloids was considered to be the construction of the sterically congested E ring bearing quaternary C8. Among five-membered ring forming reactions, the phosphine-mediated [3 + 2] cycloaddition between an allenoate and an electron-deficient alkene, which was pioneered by Lu and co-workers,16 may allow an expedient access to the E ring, and meanwhile provide a flexible carboxylate handle to build the cyclopentenone motif. Based on this strategy, an initial disconnection at the C10C17 bond of 10 was envisioned, leading to compound 11 as a precursor for intramolecular Horner−Wadsworth−Emmons (HWE) olefination. Further simplification of 11 gave pentacyclic ester 12, which could be disassembled into enedione 1317 and allenoate 14 as potential substrates of the [3 + 2] cycloaddition. 13 may © 2017 American Chemical Society
Figure 1. Selected Daphniphyllum alkaloids.
arise from tetracycle 15 in a lower oxidation state. Disconnection of the C9−C10 bond of 15 provided iodide 16 as a precursor for 7-endo-trig radical cyclization. 16 was traced back to readily available materials 17−19 and formaldehyde. Although tetracyclic compounds similar to 15 had been synthesized by us18 and Bonjoch et al.,19 respectively, a rapid and scalable approach to 15 was still desired for the synthesis Received: August 29, 2017 Published: September 28, 2017 14893
DOI: 10.1021/jacs.7b09186 J. Am. Chem. Soc. 2017, 139, 14893−14896
Communication
Journal of the American Chemical Society
Scheme 1. Preparation of a Tetracyclic Intermediate on Decagram Scale
Figure 2. Retrosynthetic analysis of longeracinphyllin A.
of 10 as well as other congeners from the calyciphylline A subfamily. The synthesis commenced with a large-scale preparation of tetracycle 15 (Scheme 1). Enantioenriched alcohol 17 (99% ee) was obtained through enzymatic resolution of its racemic form (see Supporting Information (SI)),20 which then underwent a known two-step sequence10 to arrive at alkynyl silyl enol ether 20 as a substrate of Toste-type cyclization.21 Under modified Toste conditions [Au(PPh3)NTf2 (6 mol %), MeOH/toluene],18 the 6-exo-dig cyclization product 21 was obtained in 66% yield. A further decrease of the catalyst loading resulted in unsatisfactory efficiency, and the byproduct from direct desilylation of 20 interfered with the chromatographic purification of 21. Inspired by the silver-catalyzed spirocyclization of alkynyl silyl enol ethers reported by Miesch et al.,22 we developed a scalable and cost-effective protocol to prepare 21. In the presence of AgNTf2 and CyJohnPhos, 20 underwent cyclization to give 21 in an 84% yield on a 100 g scale, along with the 7-endo-dig cyclization product 22 in 5% yield; 2,4,6-tri-tert-butylpyrimidine23 (TTBP) and 4 Å molecular sieves were crucial to suppress acidpromoted desilylation of the substrate. The use of CyJohnPhos led to excellent regioselectivity of the cyclization. The optimization of the reaction conditions was detailed in the SI. We then constructed the 5- and 7-membered rings fused to the bridged bicyclic system (Scheme 1). Deprotection of the nosyl group of 21 followed by condensation with carboxylic acid 19 afforded a substrate for intramolecular Michael addition.10,25 Treatment with DBU at 95 °C afforded the cyclization product, which underwent aldol condensation with paraformaldehyde in one pot, to provide tricyclic enone 23 (69% overall yield from 21) as a single detectable diastereomer.
Sequential desilylation and iodination furnished compound 16 with good efficiency. In our synthesis of epoxyeujindole A,26 the Luche conditions (CuI, Zn, pyridine/water, sonication) were superior to conventional radical ones for an intramolecular conjugate addition. We used such conditions to effect the ring closure of 16. The resultant tetracycle was subjected to hydrogenation to establish the C18 stereochemistry. Inspired by our previous experience with asymmetric hydrogenation of unfunctionalized olefins,27 we exploited a rhodium-based catalytic system {[Rh(cod)Cl]2/PPh3/AgBF4 (1:2:3)} to achieve an excellent level of facial selectivity. Thus, the key intermediate 15 was obtained in 98% yield as a single detectable diastereomer. In this case, the hydrogenation with Crabtree’s catalyst exhibited unsatisfactory reproducibility, and that with Pd/C gave the undesired configuration of C18. The structures of 15 and its precursor were verified by X-ray crystallographic analysis (Scheme 1). The preparation of 15 was carried out on decagram scale. With a large quantity of 15 in hand, we completed the synthesis of 10 (Scheme 2). α-Selenation of this ketone followed by oxidative elimination afforded α,β-unsaturated enone 24 with good overall efficiency, the γ-proton of which was remarkably acidic. Exposure of the enone to DABCO and air furnished enedione 25 in 91% yield, presumably through enolate peroxidation and hydroxyl elimination. Et3N was ineffective because of weaker basicity, and DBU/air caused skeletal decomposition. Doyle allylic C−H oxidation28 [Rh2(cap)4, t-BuOOH] gave a 14894
DOI: 10.1021/jacs.7b09186 J. Am. Chem. Soc. 2017, 139, 14893−14896
Communication
Journal of the American Chemical Society Scheme 2. Completion of the Synthesis of Longeracinphyllin A
was slightly cleaner using (4-FC6H4)3P; however, overall efficiency was similar (entry 2). Bu3P preferentially accelerated the [4 + 2] reaction, leading to 27 in 67% yield (entry 3). Inspired by Wallace’s work,30 we directed our attention to diphosphines. BINAP showed low reactivity (entry 4), and the use of 1,4-bis(diphenylphosphino)butane (DPPB) gave 27 as the major product (entry 5). 1,1′-Bis(diphenylphosphino)ferrocene (DPPF) turned out to be an optimal promoter for the [3 + 2] pathway, providing 26 in 45% yield on a gram scale (entry 6). Notably, the electron deficiency of the olefin was crucial for the cycloaddition; enone 24 was essentially unreactive under similar conditions. Treatment of 26 with an excess of LiCH2PO(OMe)2 afforded β-ketophosphonate 28.31 The chemoselectivity of the addition may be attributable to the rapid formation of a ketone enolate that prevented the nucleophilic attack. Sequential hydrogenation and intramolecular HWE olefination furnished hexacycle 29 in 91% overall yield. The order of these two reactions was important: the HWE reaction of 28 was inefficient, and the CC bond of the E ring was found to migrate to the nonconjugated position, presumably due to the strain of the unsaturated [3.3.0]-bicyclic system. The preparation of 29 was performed on a gram scale. For the following Krapcho demethoxycarbonylation, commonly used DMSO10,18 was not a suitable solvent. MeCN turned out to be optimal in this case, and compound 30 was obtained in 95% yield. Both enone and lactam carbonyls of 30 were thiolated with Lawesson’s reagent, and more labile thioenone was oxygenated with air, leading to thioamide 31 with good efficiency. Reduction with Raney Ni rendered longeracinphyllin A (10). The spectra and physical properties of the synthetic sample were identical to those reported for the natural product.15 The structures of 10, 29, 30, and 31 were verified by X-ray crystallographic analysis (Scheme 2). We subsequently exploited the efficiency and flexibility of the current route in the synthetic approaches to structurally relevant Daphniphyllum alkaloids daphnipaxianine A32 and himalenine D,33 as described in the SI. Two analogues corresponding to these two alkaloids, respectively, were prepared from the advanced
Table 1. Studies of Phosphine Promoters for the [3 + 2] Cycloaddition of 14 and 25a
entry
promoters
26 (%)
27 (%)
1 2 3 4 5 6
Ph3P (4-FC6H4)3P Bu3P (±)-BINAP DPPB DPPF
31 35 5 15 21 45
40 38 67 23 57 22
a 30 mol % phosphine or diphosphine, 14 (1.2 equiv), CHCl3, 22 °C, 24 h.
moderate yield of 25. We examined a variety of phosphine promoters for the [3 + 2] cycloaddition of 25 and 14 (Table 1). In the presence of 30 mol % Ph3P (entry 1), the [3 + 2] and [4 + 2]29 cycloadducts 26 and 27 were obtained in 31% and 40% yields, respectively. Their structures were confirmed by X-ray crystallographic analysis (Table 1). The reaction profile 14895
DOI: 10.1021/jacs.7b09186 J. Am. Chem. Soc. 2017, 139, 14893−14896
Communication
Journal of the American Chemical Society
(8) For a beautiful synthesis of proto-daphniphylline, the imputed biogenetic ancestor of Daphniphyllum alkaloids, see: Piettre, S.; Heathcock, C. H. Science 1990, 248, 1532. (9) Weiss, M. E.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 11501. (10) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nat. Chem. 2013, 5, 679. (11) Shvartsbart, A.; Smith, A. B., III J. Am. Chem. Soc. 2014, 136, 870. (12) Yamada, R.; Adachi, Y.; Yokoshima, S.; Fukuyama, T. Angew. Chem., Int. Ed. 2016, 55, 6067. (13) For an elegant synthesis of isodaphlongamine H, a presumed Daphniphyllum alkaloid yet to be isolated from nature, see: Chattopadhyay, A. K.; Ly, V. L.; Jakkepally, S.; Berger, G.; Hanessian, S. Angew. Chem., Int. Ed. 2016, 55, 2577. (14) For a recent synthesis of a tetracyclic core of the calyciphylline A-type alkaloids published after ref 1b, see: Shao, H.; Bao, W.; Jing, Z.R.; Wang, Y.-P.; Zhang, F.-M.; Wang, S.-H.; Tu, Y.-Q. Org. Lett. 2017, 19, 4648. (15) Di, Y.-T.; He, H.-P.; Lu, Y.; Yi, P.; Li, L.; Wu, L.; Hao, X.-J. J. Nat. Prod. 2006, 69, 1074. (16) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Xu, Z.; Lu, X. Tetrahedron Lett. 1999, 40, 549. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (d) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (e) Wei, Y.; Shi, M. Org. Chem. Front. 2017, 4, 1876. (17) In a paper describing a concise synthesis of a tricyclic motif of calyciphylline A-type alkaloids, Stockdill et al. proposed an intermediate similar to 13 in the retrosynthetic analysis section. See: Stockdill, J. L.; Lopez, A. M.; Ibrahim, A. A. Tetrahedron Lett. 2015, 56, 3503. (18) Xiong, X.; Li, Y.; Lu, Z.; Wan, M.; Deng, J.; Wu, S.; Shao, H.; Li, A. Chem. Commun. 2014, 50, 5294. (19) Coussanes, G.; Bonjoch, J. Org. Lett. 2017, 19, 878. (20) O′Byrne, A.; Murray, C.; Keegan, D.; Palacio, C.; Evans, P.; Morgan, B. S. Org. Biomol. Chem. 2010, 8, 539. (21) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (22) Schäfer, C.; Miesch, M.; Miesch, L. Chem. - Eur. J. 2012, 18, 8028. (23) Li, Y.; Zhu, S.; Li, J.; Li, A. J. Am. Chem. Soc. 2016, 138, 3982. (24) For a silver and amine cocatalyzed enantioselective desymmetrizing alkyne cyclization reported recently, see: Manzano, R.; Datta, S.; Paton, R. S.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 5834. (25) Sladojevich, F.; Michaelides, I. N.; Darses, B.; Ward, J. W.; Dixon, D. J. Org. Lett. 2011, 13, 5132. (26) Lu, Z.; Li, H.; Bian, M.; Li, A. J. Am. Chem. Soc. 2015, 137, 13764. (27) Zhang, Z.; Wang, J.; Li, J.; Yang, F.; Liu, G.; Tang, W.; He, W.; Fu, J. J.; Shen, Y. H.; Li, A.; Zhang, W. D. J. Am. Chem. Soc. 2017, 139, 5558. (28) Catino, A. J.; Forslund, R. E.; Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622. (29) Yao, W.; Dou, X.; Lu, Y. J. Am. Chem. Soc. 2015, 137, 54. (30) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007, 72, 1051. (31) Halterman, R. L.; Vollhardt, K. P. C. Organometallics 1988, 7, 883. (32) Mu, S.-Z.; Li, C.-S.; He, H.-P.; Di, Y.-T.; Wang, Y.; Wang, Y.-H.; Zhang, Z.; Lü, Y.; Zhang, L.; Hao, X.-J. J. Nat. Prod. 2007, 70, 1628. (33) Zhang, H.; Shyaula, S. L.; Li, J.-Y.; Li, J.; Yue, J.-M. J. Nat. Prod. 2015, 78, 2761.
intermediate 30. Further studies are underway in our laboratories. In summary, we have accomplished the first total synthesis of longeracinphyllin A (10). The decagram preparation of tetracycle 15, featuring silver-catalyzed alkyne cyclization and Luche radical cyclization, formed a basis of the synthesis. The sterically congested E ring containing vicinal tertiary and quaternary carbons was constructed through a Lu [3 + 2] cycloaddition reaction promoted by DPPF. The late intermediate 29 was prepared on a gram scale. These endeavors may facilitate the biological studies of this alkaloid and analogues thereof.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b09186. Experimental procedures and spectroscopic data; HPLC traces; NMR spectra (PDF) Crystallographic data (CIF, CIF, CIF, CIF, CIF, CIF, CIF, CIF)
■
AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Ang Li: 0000-0002-8808-0636 Author Contributions †
J.L. and W.Z. contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This paper is dedicated to Prof. Xiyan Lu. We thank Dr. David Edmonds for discussion, and Xiaoli Bao and Lingling Li from the Instrumental Analysis Center of Shanghai Jiao Tong University for X-ray crystallographic analysis. Financial support was provided by Ministry of Science & Technology (2013CB836900), National Natural Science Foundation of China (21525209, 21290180, 21621002, 21761142003, and 21772225), Chinese Academy of Sciences (Strategic Priority Research Program XDB20000000 and Key Research Program of Frontier Sciences QYZDB-SSWSLH040), Shanghai Science and Technology Commission (15JC1400400 and 17XD1404600), and K. C. Wong Education Foundation.
■
REFERENCES
(1) (a) Kobayashi, J.; Kubota, T. Nat. Prod. Rep. 2009, 26, 936. (b) Chattopadhyay, A. K.; Hanessian, S. Chem. Rev. 2017, 117, 4104. (c) Kang, B.; Jakubec, P.; Dixon, D. J. Nat. Prod. Rep. 2014, 31, 550. (d) Yang, S.-P.; Yue, J.-M. Acta Pharmacol. Sin. 2012, 33, 1147. (2) Ruggeri, R. B.; Hansen, M. M.; Heathcock, C. H. J. Am. Chem. Soc. 1988, 110, 8734. (3) (a) Heathcock, C. H.; Davidsen, S. K.; Mills, S.; Sanner, M. A. J. Am. Chem. Soc. 1986, 108, 5650. (b) Ruggeri, R. B.; Heathcock, C. H. J. Org. Chem. 1990, 55, 3714. (4) Stafford, J. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 5433. (5) Heathcock, C. H.; Kath, J. C.; Ruggeri, R. B. J. Org. Chem. 1995, 60, 1120. (6) Heathcock, C. H.; Stafford, J. A.; Clark, D. L. J. Org. Chem. 1992, 57, 2575. (7) Ruggeri, R. B.; McClure, K. F.; Heathcock, C. H. J. Am. Chem. Soc. 1989, 111, 1530. 14896
DOI: 10.1021/jacs.7b09186 J. Am. Chem. Soc. 2017, 139, 14893−14896
