Communication pubs.acs.org/JACS
An Accelerated Intermolecular Rauhut−Currier Reaction Enables the Total Synthesis of (−)-Flueggenine C Sangbin Jeon†,‡ and Sunkyu Han*,†,‡ †
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea
‡
S Supporting Information *
ABSTRACT: The first total synthesis of dimeric securinega alkaloid (−)-flueggenine C is completed via an accelerated intermolecular Rauhut−Currier (RC) reaction. Despite the numerous reports on the total synthesis of monomeric securinegas, the synthesis of dimeric securinegas whose monomeric units are connected by a putative enzymatic RC reaction has not been reported to date. We have found that installation of a nucleophilic functional group at the γ-position of an enone greatly accelerates the rate of the diastereoselective intermolecular RC reaction. This discovery enabled an efficient and selective formation of the dimeric intermediate which was further transformed to (−)-flueggenine C. ince the first isolation of securinine in 1956, the securinega alkaloids, consisting of more than 70 natural products, have served as inspiration for the development of various new chemistries.1 Recent isolation campaigns aimed to unveil novel bioactive natural products from Flueggea virosa enabled the identification of various dimeric and oligomeric securinega alkaloids expanding its structural repertoire. In 2006, Yue and co-workers isolated the dimeric securinegas flueggenines A (4) and B (5), the first examples of C,C-linked dimers of norsecurinine (1) envisioned to be biosynthesized by a selfcatalyzed Baylis−Hillman reaction (Figure 1).2 Subsequently, other dimeric securinegas, presumably resulting from an RC reaction (vinylogous Morita−Baylis−Hillman reaction)3 of two monomeric securinega such as flueggine B,4 flueggenines C (6), D,5 G, H, and I,6,7 have been isolated. Trimeric securinegas fluevirosines A−H,5,6,8 tetrameric fluevirosinines A−F,5,9 and pentameric fluevirosinines G−J9 have also been reported. Notably, flueggenine A (4) showed modest cytotoxicity against the P-388 tumor cell line.2 Flueggenine D and fluevirosinine B exhibited promising anti-HIV activities.6,9 We hypothesize that all of these dimeric and oligomeric securinegas are biosynthesized by an enzymatic RC reaction. While a plethora of total syntheses of monomeric securinega alkaloids have been reported, synthetic access to dimeric and oligomeric securinega natural products remains as a daunting task exemplified by a dearth of syntheses reported.1,10 Ye and co-workers showed that virosecurinine undergoes a [2 + 2]photodimerization to yield flueggedine (2) in 5% yield in 2013.11 Li and co-workers reported an elegant total synthesis of flueggine A (3) via a biosynthetically inspired 1,3-dipolar cycloaddition reaction in the same year.12 However, no total
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© 2017 American Chemical Society
Figure 1. Representative monomeric, dimeric, and oligomeric securinega alkaloids.
synthesis of dimeric or oligomeric securinega whose monomer units are connected by an RC reaction has been reported to date. Herein, we report the first asymmetric total synthesis of flueggenine C (6), a C,C-linked dimeric securinega alkaloid presumably biosynthesized via an enzymatic intermolecular RC reaction between two norsecurinines (1). The RC reaction was first reported in 1963 by Rauhut and Currier;13 it forms a C−C bond between two Michael acceptors in the presence of a nucleophilic catalyst (Scheme 1A).14 Despite its conceptual simplicity, the low reactivity and the difficulty in controlling the selectivity for intermolecular reactions have limited the broad utility of this otherwise highly valuable reaction. The first step of the RC reaction is the conjugate addition of the nucleophilic catalyst to enone derivative 9 to yield enolate 10. Enolate 10 can either undergo a β-elimination of the nucleophilic catalyst or a Michael addition to another enone 9 to afford enolate 11, which after an internal proton transfer gives product 12. The reversible nature of the conjugate addition of nucleophilic catalyst to 9 renders the molar concentration of intermediate 10 low and the subsequent intermolecular conjugate addition to 9 challenging. Received: March 20, 2017 Published: April 24, 2017 6302
DOI: 10.1021/jacs.7b02751 J. Am. Chem. Soc. 2017, 139, 6302−6305
Communication
Journal of the American Chemical Society Scheme 1. Possible Modes of Reactivity in Rauhut−Currier Reactions
Scheme 2. Retrosynthetic Analysis of Flueggenine C (6)
acetic acid and a subsequent intramolecular Horner−Wadsworth−Emmons (HWE) reaction. We planned to synthesize 24 by a γ-hydroxylation of known enone 25. We commenced our investigation of the redesigned RC reaction by testing the reaction of γ-hydroxy enone 2418 with various bases (Table 1). We found that treatment of a THF It is mainly due to the aforementioned limitations that applications of the RC reaction in total synthesis are confined to the intramolecular RC reactions, in which two Michael acceptors are connected within a molecule (Scheme 1B).15,16 We envisioned that the inherent low reactivity of the intermolecular RC reaction may be addressed by using Michael acceptor 17 which incorporates a nucleophilic functionality within the molecule (Scheme 1C). Such substrate design may enable the nucleophilic moiety to undergo a facile intramolecular conjugate addition and set the stage for the next intermolecular conjugate addition (Path A). An alternative scenario may be that the nucleophilic component engages in an intermolecular conjugate addition to yield intermediate 19 and enables the subsequent intramolecular Michael addition (Path B). In either case, significant rate acceleration of the RC reaction is anticipated. Based on our proposed redesigned intermolecular RC reaction (Scheme 1C), we devised a synthetic scheme for flueggenine C (6). Our synthetic strategy includes three different monomeric Michael acceptors (1, 22, and 24) which are viable RC substrates containing a nucleophilic moiety within the molecule (Scheme 2). First, we planned to test whether the tertiary amine present in norsecurinine (1) can accelerate the vinylogous RC reaction.17 If successful, the dimerized product would be flueggenine C (6). Alternatively, we envisioned α,β,γ,δ-unsaturated ester 22 with a hydroxyl group at C13 as a potential substrate for the improved vinylogous RC dimerization. Successful vinylogous RC dimerization at this stage would afford dimer 21 which we sought to transform to flueggenine C (6) via an intramolecular N-alkylation. Third, we designed γ-hydroxy enone 24 as a plausible precursor for the accelerated RC reaction. Effective dimerization of 24 would grant access to dimer 23 which can be derivatized to 21 via an esterification with diethylphosphono-
Table 1. Rauhut−Currier Reactions of Michael Acceptors with a Nucleophilic Moiety
entry
substrate
reagenta
time (h)
product
yield (%)b
1 2 3 4 5
24c 24c 24c 22 1
KOHd TBAOHe TBAFg TBAFg TBAFg
12 1 3 24 24
23 23 23 no reaction no reaction
9 3f 60 − −
a 1 equiv of reagent was used. bIsolated yield. c>99% ee. d2.0 M aqueous solution. eTBAOH: tetrabutylammonium hydroxide, 40 wt % in water. fMultiple products are formed. g1.0 M THF solution.
solution of 24 with an aqueous potassium hydroxide solution provided the desired dimer 23 as a single diastereomer in 9% yield after 12 h (Table 1, entry 1). Encouraged by this initial finding, we continued to test various bases and noticed a significant reactivity enhancement with tetrabutylammonium hydroxide as a base. However, only trace amounts of 23 were formed along with multiple byproducts (Table 1, entry 2). To our pleasure, a nice balance between the reactivity and the product selectivity was achieved when TBAF was applied as a base and we could obtain dimer 23 in 60% yield as a single diastereomer (Table 1, entry 3).19 It is important to note that this successful intermolecular RC reaction was run at ambient temperature with complete diastereoselectivity. The TBAFmediated RC reaction was also attempted with lactone 22 and norsecurinine (1). However, neither 2218 nor 110 showed any noticeable reactivity (Table 1, entries 4 and 5).20 We attribute 6303
DOI: 10.1021/jacs.7b02751 J. Am. Chem. Soc. 2017, 139, 6302−6305
Communication
Journal of the American Chemical Society the lack of reactivity to the lower electrophilicity of the α,β,γ,δunsaturated ester derivative than that of the α,β-unsaturated ketone derivative. The complete diastereoselectivity observed in our accelerated RC reaction hints at the formation of a structurally rigid intermediate outlined by path B in Scheme 1C. We propose that the allylic alcohol moiety of monomer 24 undergoes a hydroxyl-directed intermolecular conjugate addition to another enone 24 to afford enolate intermediate 26 with high diastereoselectivity. (Scheme 3).21 Enolate 26 then may
Scheme 4. Total Synthesis of (−)-Flueggenine C (6)
Scheme 3. Proposed Reaction Mechanism of the TBAFMediated Accelerated RC Reaction of Enone 24
33 in 51% yield. This is rather impressive considering the transformation of diol 32 to diphosphonate 33 required the esterification of two tertiary alcohols. Treatment of phosphonate 33 with sodium hydride in THF solution followed by a subsequent addition of methanol to the reaction mixture afforded butenolide derivative 21 in 52% yield. Treatment of alcohol 21 with methanesulfonyl chloride and triethylamine followed by addition of TFA afforded the Boc-deprotected pyrrolidine derivative. Final base treatment to the resulting amine salt intermediate yielded the first synthetic sample of (−)-flueggenine C (6) in 62% yield over two steps. NMR and specific rotation data obtained from our synthetic sample matched those of the isolation report ([α]D of the natural flueggenine C: −84° (MeOH, c 0.13), [α]20D of our synthetic flueggenine C: −83° (MeOH, c 0.13)).5 In conclusion, the total synthesis of (−)-flueggenine C (6) has been achieved in 12 steps from commercially available Boc protected D-proline in an overall 1.7% yield.25 This is the first synthetic access to a dimeric securinega in which the two monomeric securinegas are connected by a presumed enzymatic RC reaction. Key to our success was the disclosure of an efficient and diastereoselective intermolecular RC reaction of γ-hydroxy enone 24 in the presence of TBAF. Efforts aimed at deciphering the detailed mechanism of the key RC reaction is currently underway. Our observations regarding the RC reaction are providing insights into the synthesis of other C,C-linked dimeric and oligomeric securinega natural products. Those will be the subjects of our future reports.
undergo a rapid intramolecular Michael addition to give tetrahydrofuran derivative 27 with a cis-fused B−C ring system in accordance with literature precedents.21,22 The enolate moiety in 27 will then trigger a proton transfer to yield enolate 28. Subsequent β-alkoxy elimination of intermediate 28 would give intermediate 29. We speculate that the tertiary alcohol at C6 in intermediate 27 plays a key role in lowering the pKa of the proton at C8 and promoting the proton transfer leading to the β-alkoxy elimination. With the key RC dimerization of γ-hydroxy enone 24 established, we could devise a streamlined synthesis of flueggenine C (6). Our optimized synthetic route commenced with the reported enone 25 which could be accessed in five steps from commercially available Boc protected D-proline (Scheme 4).10,23 While the direct γ-hydroxylation of enone 25 remained elusive, DMDO oxidation of silyl enol ether 30 afforded γ-hydroxylated enone derivative 31 as a single diastereomer.24 When silyl ether 31 was treated with a TBAF solution at 23 °C, diketone 23 was formed in 60% yield as a single diastereomer consistent with our previous observations (Table 1, entry 3). After further optimization of the synthetic process, we found that simple addition of acetic anhydride, triethylamine, and DMAP to the reaction mixture after full conversion of the monomeric unit in the presence of TBAF afforded acetylated dimer 32 in 74% yield. Slow addition of a diethyl phosphonoacetic acid solution to 32 in the presence of N,N′-dicyclohexylcarbodiimide (DCC) allowed the parallel ester bond formation to yield phosphonate
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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/jacs.7b02751. Comprehensive list of dimeric and oligomeric securinega alkaloids, experimental procedures, spectroscopic data, spectrometric data, and copies of 1H, 13C NMR spectra and HPLC traces of all new compounds (PDF) 6304
DOI: 10.1021/jacs.7b02751 J. Am. Chem. Soc. 2017, 139, 6302−6305
Communication
Journal of the American Chemical Society
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(19) Ohnemüller, U. K.; Nising, C. F.; Encinas, A.; Bräse, S. Synthesis 2007, 2007, 2175. (20) For previous total syntheses utilizing synthetic precursors to monomers as superior dimerization partners: (a) Snyder, S. A.; ElSohly, A. M.; Kontes, F. Angew. Chem., Int. Ed. 2010, 49, 9693. (b) Sherwood, T. C.; Trotta, A. H.; Snyder, S. A. J. Am. Chem. Soc. 2014, 136, 9743. (21) Zhao, K.; Cheng, G.-J.; Yang, H.; Shang, H.; Zhang, X.; Wu, Y.D.; Tang, Y. Org. Lett. 2012, 14, 4878. (22) (a) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink, E. R. T. J. Org. Chem. 2003, 68, 4239. (b) Carreňo, M. C.; Ribagorda, M. Org. Lett. 2003, 5, 2425. (c) Paddock, V. L.; Phipps, R. J.; CondeAngulo, A.; Blanco-Martin, A.; Giró-Maňas, C.; Martin, L. J.; White, A. J. P.; Spivey, A. C. J. Org. Chem. 2011, 76, 1483. (d) Christou, S.; Edwards, A. C.; Pritchard, R. G.; Quayle, P.; Stratford, I. J.; Whitehead, R. C. Synlett 2014, 25, 1263. (23) Reddy, A. S.; Srihari, P. Tetrahedron Lett. 2012, 53, 5926. (24) Piguel, S.; Ulibarri, G.; Grierson, D. S. Tetrahedron Lett. 1999, 40, 295. (25) An overall yield for the preparation of compound 25 was 28%.
AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Sunkyu Han: 0000-0002-9264-6794 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work is dedicated to Professor Hee-Yoon Lee in honor of his 60th birthday. We thank Prof. Mu-Hyun Baik and Prof. Sukbok Chang for helpful discussions. We thank Geon Kim, Jaekoan Yoon, and Joonoh Park for experimental assistance. We thank Thomas Taehyung Kim for helping us revise the manuscript. The authors are grateful for the financial support provided by the National Research Foundation of Korea (2015R1C1A1A020363) and the Institute for Basic Science (IBS-R010-D1).
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REFERENCES
(1) For reviews on securinega alkaloids, see: (a) Weinreb, S. M. Nat. Prod. Rep. 2009, 26, 758. (b) Chirkin, E.; Atkatlian, W.; Porée, F.-H. In The Alkaloids; Knölker, H.-J., Ed.; Academic Press; London, 2015; Chapter 1, pp 1−120. (2) Gan, L.-S.; Fan, C.-Q.; Yang, S.-P.; Wu, Y.; Lin, L.-P.; Ding, J.; Yue, J.-M. Org. Lett. 2006, 8, 2285. (3) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404. (4) Zhao, B.-X.; Wang, Y.; Zhang, D.-M.; Jiang, R.-W.; Wang, G.-C.; Shi, J.-M.; Huang, X.-J.; Chen, W.-M.; Che, C.-T.; Ye, W.-C. Org. Lett. 2011, 13, 3888. (5) Zhang, H.; Wei, W.; Yue, J.-M. Tetrahedron 2013, 69, 3942. (6) Zhang, H.; Zhang, C.-R.; Han, Y.-S.; Wainberg, M. A.; Yue, J.-M. RSC Adv. 2015, 5, 107045. (7) For a comprehensive list of dimeric/oligomeric securinega alkaloids isolated to date, see the Supporting Information. (8) Zhang, H.; Zhang, C.-R.; Zhu, K.-K.; Gao, A.-H.; Luo, C.; Li, J.; Yue, J.-M. Org. Lett. 2013, 15, 120. (9) Zhang, H.; Han, Y.-S.; Wainberg, M. A.; Yue, J.-M. Tetrahedron 2015, 71, 3671. (10) For a recent total synthesis of norsecurinine, see: Ma, N.; Yao, Y.; Zhao, B.-X.; Wang, Y.; Ye, W.-C.; Jiang, S. Chem. Commun. 2014, 50, 9284 and references therein. (11) Zhao, B.-X.; Wang, Y.; Li, C.; Wang, G.-C.; Huang, X.-J.; Fan, C.-L.; Li, Q.-M.; Zhu, H.-J.; Chen, W.-M.; Ye, W.-C. Tetrahedron Lett. 2013, 54, 4708. (12) Wei, H.; Liu, G.; Yang, Z.; Li, C.-C. Angew. Chem., Int. Ed. 2013, 52, 620. (13) Rauhut, M. M.; Currier, H. US. Patent 307,499,919,630,122, 1963; Chem. Abstr. 1963, 58, 11224a. (14) For reviews on RC reaction, see: (a) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Tetrahedron 2009, 65, 4069. (b) Xie, P.; Huang, Y. Eur. J. Org. Chem. 2013, 2013, 6213. (15) Representative applications of intramolecular RC reaction in total synthesis: (a) Agapiou, K.; Krische, M. J. Org. Lett. 2003, 5, 1737. (b) Mergott, D. J.; Frank, S. A.; Roush, W. R. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11955. (c) Stark, L. M.; Pekari, K.; Sorensen, E. J. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 12064. (d) Dermenci, A.; Selig, P. S.; Domaoal, R. A.; Spasov, K. A.; Anderson, K. S.; Miller, S. J. Chem. Sci. 2011, 2, 1568. (16) For a review on intramolecular RC reaction, see: Bharadwaj, K. C. RSC Adv. 2015, 5, 75923. (17) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. ACS Catal. 2017, 7, 2805. (18) See the Supporting Information for the experimental procedure. 6305
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