Catalytic Enantioselective Total Synthesis of the Picrotoxane Alkaloids

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Catalytic Enantioselective Total Synthesis of the Picrotoxane Alkaloids (−)-Dendrobine, (−)-Mubironine B, and (−)-Dendroxine Lei Guo, Wolfgang Frey, and Bernd Plietker* Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart, Germany

Downloaded via KAOHSIUNG MEDICAL UNIV on July 5, 2018 at 13:56:34 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A concise enantioselective total synthesis of three sesquiterpenoid alkaloids(−)-dendrobine, (−)-mubironine B, and (−)-dendroxineis presented, which highlights the state-of-art catalytic methods, including enantioselective Diels− Alder cycloaddition, iron-catalyzed aerobic lactonization, copper-catalyzed cycloisomerization, and free-radical-initiated hydroazidation.

T

achiral substrates have been published. In 2004, Corey reported a formal total synthesis by accessing Kende’s intermediate via a catalytic, enantioselective Diels−Alder reaction.7c,8e While the present work was in progress, Chen published a catalytic enantioselective formal synthesis of dendrobine by accessing the same intermediate via an asymmetric allylation reaction.8f Herein, we report a 10-/11step total synthesis of (−)-dendrobine 4, (−)-mubironine B 5, and (−)-dendroxine 6 featuring an asymmetric catalytic Diels− Alder reaction as an enantioselective key step (Figure 2). In our retrosynthetic analysis (Figure 2), we envisioned dehydropyrrolidine 7 to be a key intermediate for the final elaboration into the three alkaloids under either reductive or redox-neutral conditions. Disconnection of the imine in 7 would lead to amine 8, which could be realized by the challenging direct anti-Markovnikov hydroazidation reaction from olefin 9.9 The cyclopentane in 9 possessing a quaternary stereocenter could be derived from lactone 11 via a conjugate addition and catalytic cycloisomerization reaction.10 Before lactonization of 12 to lactone 11 under catalytic aerobic conditions,11 the introduction of chirality could be realized via an enantioselective catalytic [4 + 2]-cycloaddition using Danishefskýs diene 13.12−14 The synthesis started with a screening of enantiopure Lewisacid catalyst for the asymmetric Diels−Alder reaction between diene 13 and oxazolidinone 14 (see Table 1). However, cationic Cu2+-box complexes did not provide any product (Table 1, entry 1),13 with cationic Fe3+ and (R,R)-Ph-pybox L1 yielded the desired product in moderate yield with high diastereoselectivity but low enantioselectivity (Table 1, entries

he picrotoxane family of natural products can be divided into two main subfamilies, i.e., the picrotoxane sesquiterpenes and the dendrobine sesquiterpenoid alkaloids. Their complex molecular framework is the result of a complex polycyclization of farnesyl pyrophosphate and subsequent ring rearrangement to give the bicyclo[4.3.0]nonane core that is common in all picrotoxane natural products. Site-selective oxidation of the C-5/C-9 methyl groups and the adjacent C-2/ C-3-methylene groups delivers the tricyclic skeleton found in the aforementioned subfamilies.1 Further site-selective latestage aminations lead to dendrobine sesquiterpenoid alkaloids, such as dendrobine 4,2 mubironine 5,3 or dendroxine 64 (see Figure 1).

Figure 1. Biosynthesis of dendroine sesquiterpenoid alkaloids.

Dendrobine 4 as the most prominent representative of the reported sesquiterpenoid alkaloids was isolated in the 1930s from Dendrobium nobile Lindl.2 It shows hypertensive, antipyretic, analgesic, and anti-influenza A virus activities.5 Fifteen formal and total syntheses of this natural product have been reported,6−8 three of which are enantioselective chiralpool total syntheses.6 To date, only two reports in which chirality was introduced via enantioselective catalysis using © XXXX American Chemical Society

Received: June 7, 2018

A

DOI: 10.1021/acs.orglett.8b01782 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Scheme 1. Synthesis of Key Intermediate 9

Figure 2. Retrosynthesis of dendrobine sesquiterpene alkaloids.

Table 1. Asymmetric Catalytic [4 + 2] Cycloaddition

entry b

1 2b 3b 4b 5c

catalyst

ligand

additive

t (°C)

yield (%)/ee (%)a

Cu(OTf)2 FeBr3 FeBr3 FeBr3 Yb(OTf)3

L1 L1 L1 L2 L3

AgBF4 AgBF4 AgBF4 AgBF4 DBU

−40 −40 −50 −40 0

−/− 47/0 25/17 33/−25 78/91

With diol 12 in hand, we envisioned Ma’s most recently reported aerobic Fe-catalyzed oxidation of alcohols to carboxylic acids to offer the chance for an aerobic Fe-catalyzed oxidative lactonization.11 Indeed, upon subjecting diol 12 to Ma’s reaction condition, a chemoselective oxidation of the primary alcohol to the corresponding aldehyde and direct formation of the desired lactone 11 through condensation with the secondary alcohol at C-6, followed by hemiacetal oxidation in 89% yield was observed (see Scheme 1). Notably, the use of alternative oxidation conditions (TPAP/NMO, Swern-oxidation, etc.) led to aromatization. With lactone 11 in hand, we set out to install the central cyclopentane motif. Diastereoselective conjugate addition of 4-bromo-1-trimethylsilylbut-1-yne-derived cuprate, followed by methylation of the resulting copper enolate 18 and desilylating workup led to the isolation of stereoisomerically pure ketone 10 in 64% overall yield (see Scheme 1). Transformation of 10 into the corresponding TBS-enolether 19 under thermal conditions and subsequent treatment with Ph3PAuCl/AgBF4 resulted in a clean cyclization and a clean installation of the quaternary center in 9.10a Traditionally, the weak nucleophilicity of ketone requires the synthesis of TBSenolether as a well-precedented nucleophilic species to attack the Au+-complexed alkyne. Through application of Dixon’s

a

Isolated yield, the enantio excess was determined by compound 17. The reaction was stirred at indicated temperature for 7 h. cThe reaction was stirred at 0 °C for 3 h. b

2 and 3).14 To our delight, Nishida’s condition with Yb-(R)BINUREA complex Yb-L3 delivered the product with high diastereo- and enantioselectivity in 78% yield (Table 1, entry 5).12 With the scalable [4 + 2] cycloaddition in hand, we attempted to use the oxazolidinone motif for a direct lactone formation through a one-pot oxazolidinone hydrolysis with H2O2/LiOH, and subsequent substrate-directed Rubottomoxidation−epoxide opening−lactonization. However, we were not able to isolate any of the desired or intermediate products.15 At this point, we decided to treat oxazolidinone 16 directly with LiBH4 and subsequent acidic workup to give cyclohexenone 17 with 71% yield and an enantiomeric excess of 91% (see Scheme 1). Cyclohexenone 17 was converted to α-hydroxyketone 12 in a diastereoselective Rubottom oxidation in 82% yield and with correct relative configuration of the hydroxy group. B

DOI: 10.1021/acs.orglett.8b01782 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

accomplished in 11 or 10 steps with 6.7%, 7.8%, and 7.4% yields, respectively. The spectroscopic data of our synthesized alkaloids are identical to the data reported in the literature (see Scheme 2). In conclusion, we report here a concise catalytic enantioselective total synthesis of (−)-dendrobine, (−)-mubironine B, (−)-dendroxine overall yields of 6.7%, 7.8%, and 7.4%, respectively. The key to the efficiency of the total syntheses is the use of an Yb-catalyzed enantioselective Diels− Alder reaction to generate the central six-membered ring, a Fecatalyzed oxidative intramolecular lactonization, a Au- (or Cu)catalyzed cycloisomerization for the construction of the central cyclopentane motif featuring a exocyclic methylene group, and finally, a hydroboration-radical azidation to furnish the C−N-bond necessary to accomplish the formation of the pyrrolidine moiety.

most recently published method on Cu-enamine co-catalyzed cycloisomerization, a direct conversion of 10 to 9 without the need for the formation of an labile silylenolether was possible, albeit at lower overall yield, compared to the two-step Aucatalyzed sequence.10b Notably, attempts to combine the two Cu-mediated steps in a sequential manner (1,4-addition and subsequent cycloisomerization) were not successful. However, at this stage, we were able to improve the enantiomeric excess of 9 upon recrystallization to 99% with 86% yield. With olefin 9 in hand, we set out to finish the synthesis of the three alkaloids (see Scheme 2). Unexpectedly, the Scheme 2. Total Synthesis of (−)-Dendrobine 4, (−)-Mubironine B 5, and (−)-Dendroxine 6

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01782. Experimental procedures for preparation of starting materials and products, full characterization of all reported compounds, 1H NMR, 13C NMR, IR, HRMS spectra (PDF) Accession Codes

CCDC 1831627 contains 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], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lei Guo: 0000-0001-7038-8053 Bernd Plietker: 0000-0001-8423-6173

envisioned direct hydroamination of the 1,1-disubstituted double bond proved to be troublesome, which is an observation that might be explained by the steric hindrance imposed by the adjacent all-carbon quaternary center.15 Consequently, a hydrozirconition/amination sequence16 or copper-catalyzed direct hydroamination17 failed to give any products. After several unsuccessful attempts, we decided to make use of Renaud’s most recently published antiMarkovnikov-type hydroazidation through hydroboration of 9 to 20 and subsequent free-radical-initiated azidation of the C−B-bond in 20.9 This approach was successful and delivered the desired C−N-bond with exclusive diastereoselectivity and regioselectivity (see Scheme 2). Azide 8 was isolated in 47% yield over two steps. Gratifyingly, the intramolecular Staudinger-aza-Wittig reaction of 8 led to a clean formation of dehydropyrrolidine 7,6a from which (−)-dendrobine 4 and (−)-mubironine B 5 were obtained under reductive conditions and N-methylation. Upon treatment of imine 7 with 2-iodoethanol under thermal conditions, (−)-dendroxine 6 was obtained. In summary, the enantioselective total synthesis of 4, 5, and 6 were

Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS Financial support by the Deutsche Forschungsgemeinschaft and the Chinese Scholarship Council (through a Ph.D. grant for L.G.) is gratefully acknowledged. We are grateful to Dr. Wolfgang Frey (Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, DE-70569 Stuttgart, Germany) for X-ray structure analysis.

■

REFERENCES

(1) (a) Cordell, A. G. Chem. Rev. 1976, 76, 425−460. (b) Zhao, C.; Liu, Q.; Halaweish, F.; Shao, B.; Ye, Y.; Zhao, W. J. Nat. Prod. 2003, 66, 1140−1143. (c) Brocksom, T. J.; de Oliveira, K. T.; Desidera, A. L. J. Braz. Chem. Soc. 2017, 28, 933−942. (2) (a) Suzuki, H.; Keimatsu, I.; Ito, K. Yakugaku Zasshi 1932, 52, 1049−1060. (b) Suzuki, H.; Keimatsu, I.; Ito, K. J. Pharm. Soc. Jpn. 1934, 54, 802−812. (c) Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Yasui, B.; Konita, T.; Matsumoto, J.; Katarao, E.; Nakano, J. Tetrahedron 1964,

C

DOI: 10.1021/acs.orglett.8b01782 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters 20, 2007−2023. (d) Inubushi, Y.; Sasaki, Y.; Tsuda, Y.; Nakano, J. Tetrahedron Lett. 1965, 6, 1519−1523. (3) Morita, H.; Fujiwara, M.; Yoshida, N.; Kobayashi, J. Tetrahedron 2000, 56, 5801−5806. (4) Okamoto, T.; Natsume, M.; Onaka, T.; Uchimaru, F.; Shimizu, M. Chem. Pharm. Bull. 1966, 14, 672−675. (5) (a) Chen, K. K.; Chen, A. L. J. Biol. Chem. 1935, 111, 653−658. (b) Chen, K. K.; Chen, A. L. J. Pharmacol. 1935, 55, 319−325. (c) Li, R.; Liu, T.; Liu, M.; Chen, F.; Liu, S.; Yang, J. J. Agric. Food Chem. 2017, 65, 3665−3674. (6) For enantioselective total synthesis of dendrobine, see: (a) Sha, C.-K.; Chiu, R.-T.; Yang, C.−F.; Yao, N.-T.; Tseng, W.−H.; Liao, F.− L.; Wang, S.−L. J. Am. Chem. Soc. 1997, 119, 4130−4135. (b) Cassayre, J.; Zard, S. Z. J. Am. Chem. Soc. 1999, 121, 6072− 6073. (c) Kreis, L. M.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3436−3439. (7) For racemic total synthesis of dendrobine, see: (a) Yamada, K.; Suzuki, M.; Hayakawa, Y.; Aoki, K.; Nakamura, H.; Nagase, H.; Hirata, Y. J. Am. Chem. Soc. 1972, 94, 8278−8280. (b) Inubushi, Y.; Kikuchi, T.; Ibuka, T.; Tanaka, T.; Saji, I.; Tokane, K. J. Chem. Soc., Chem. Commun. 1972, 1252−1253. (c) Kende, A. S.; Bentley, T. J.; Mader, R. A.; Ridge, D. J. Am. Chem. Soc. 1974, 96, 4332−4334. (d) Roush, W. R. J. Am. Chem. Soc. 1978, 100, 3599−3601. (e) Lee, C. H.; Westling, M.; Livinghouse, T.; Williams, A. C. J. Am. Chem. Soc. 1992, 114, 4089−4095. (8) For formal synthesis of dendrobine, see: (a) Martin, S. F.; Li, W. J. Org. Chem. 1991, 56, 642−650. (b) Trost, B. M.; Tasker, A. S.; Rüther, G.; Brandes, A. J. Am. Chem. Soc. 1991, 113, 670−672. (c) Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date, T. J. Org. Chem. 1994, 59, 5633−5642. (d) Padwa, A.; Dimitroff, M.; Liu, B. Org. Lett. 2000, 2, 3233−3235. (e) Hu, Q.-Y.; Zhou, G.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 13708−13713. (f) Lee, Y.; Rochette, E. M.; Kim, J.; Chen, D. Y.-K. Angew. Chem., Int. Ed. 2017, 56, 12250−12254. (g) Williams, B. M.; Trauner, D. J. Org. Chem. 2018, 83, 3061−3068. (9) (a) Kapat, A.; König, A.; Montermini, F.; Renaud, P. J. Am. Chem. Soc. 2011, 133, 13890−13893. (b) Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. Pure Appl. Chem. 2012, 84, 1633−1641. (c) Meyer, D.; Renaud, P. Angew. Chem., Int. Ed. 2017, 56, 10858− 10861. (10) (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991−5994. (b) Manzano, R.; Datta, S.; Paton, R. S.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 5834−5838. (11) (a) Ma, S.; Liu, J.; Li, S.; Chen, B.; Cheng, J.; Kuang, J.; Liu, Y.; Wan, B.; Wang, Y.; Ye, J.; Yu, Q.; Yuan, W.; Yu, S. Adv. Synth. Catal. 2011, 353, 1005−1007. (b) Jiang, X.; Zhang, J.; Ma, S. J. Am. Chem. Soc. 2016, 138, 8344−8347. (12) (a) Sudo, Y.; Shirasaki, D.; Harada, S.; Nishida, A. J. Am. Chem. Soc. 2008, 130, 12588−12589. (b) Harada, S.; Toudou, N.; Hiraoka, S.; Nishida, A. Tetrahedron Lett. 2009, 50, 5652−5655. (c) Harada, S.; Ishii, H.; Shirasaki, D.; Nishida, A. Heterocycles 2015, 90, 967−977. (13) (a) Evans, D. A.; Miller, J.; Lectka, T. J. Am. Chem. Soc. 1993, 115, 6460−6461. (b) Evans, D. A.; Murry, J. A.; von Matt, P. R.; Norcross, D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 798− 800. (c) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem. Soc. 1999, 121, 7559−7573. (d) Evans, D. A.; Barnes, D. M.; Johnson, J. S.; Lectka, T.; von Matt, P.; Miller, S. J.; Murry, J. A.; Norcross, R. D.; Shaughnessy, E. A.; Campos, K. R. J. Am. Chem. Soc. 1999, 121, 7582−7594. (14) Usuda, H.; Kuramochi, A.; Kanai, M.; Shibasaki, M. Org. Lett. 2004, 6, 4387−4390. (15) For details, see the Supporting Information. (16) Strom, A. E.; Hartwig, J. F. J. Org. Chem. 2013, 78, 8909−8914. (17) Zhu, S.; Buchwald, S. L. J. Am. Chem. Soc. 2014, 136, 15913− 15916.

D

DOI: 10.1021/acs.orglett.8b01782 Org. Lett. XXXX, XXX, XXX−XXX