Letter Cite This: Org. Lett. 2018, 20, 6886−6890
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(+)-Dimericbiscognienyne A: Total Synthesis and Mechanistic Investigations of the Key Heterodimerization Geon Kim,†,‡ Myungjo J. Kim,† Garam Chung,†,‡ Hee-Yoon Lee,*,† 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
‡
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S Supporting Information *
ABSTRACT: The first total synthesis of (+)-dimericbiscognienyne A is described. Key to the successful access to (+)-dimericbiscognienyne A was a biosynthetically inspired Diels−Alder reaction between two differential epoxyquinoid monomers and the subsequent intramolecular hemiacetal formation. The selective formation of the natural product among other possible diastereomers during the late-stage [4+2] cycloaddition reaction was investigated by DFT calculations and experimental control studies.
N
proposed that dimericbiscognienyne A (7) biosynthetically originates from two biscognienyne B (6) units. They invoked an intermolecular redox reaction between two biscognienyne B (6) monomers to yield enone derivative 8 and triene 9 (Scheme 1). The isolation team proposed that a Diels−Alder reaction between dienophile 8 and diene 9 would assemble tricyclic intermediate 10. Finally, an intramolecular hemiacetal formation of intermediate 10 would produce dimericbiscognienyne A (7). Our group’s interest in biosynthetically inspired total synthesis of complex natural products13 led us to design a concise synthetic strategy for dimericbiscognienyne A (7, Scheme 2). We adopted the biogenetically relevant late-stage [4+2] cycloaddition reaction between 8 and 9 (Scheme 3) for the assembly of the target natural product. We envisioned to access both dienophile 8 and diene 9 from iodide 11 and its derivative via palladium-catalyzed cross-coupling reactions. We planned to access iodide 11 by an α-iodination of enone derivative 12. Enone 12 would be derived from epoxide 13 via a ketone reduction and a retro-Diels−Alder reaction. Cyclopentadiene cycloaddition adduct 13 was a key precursor that the Mehta group utilized in their total synthesis of (±)-jesterone.14 Our synthesis commenced with a reported ketone derivative 13 prepared in three steps from p-methoxyphenol. 14 A reduction of ketone 13 with DIBAL-H produced alcohol 14 in 91% yield. It is important to note that the reduction occurred regioselectively to the more accessible ketone moiety from the convex face to yield desired product 14 with high diastereoselectivity (20:1).15 The retro-Diels−Alder reaction of 14 was carried out at 240 °C under microwave irradiation to generate enone 12 in 94% yield. Treatment of enone 12 with iodine, DMAP, and BHT in dichloromethane/pyridine co-solvent afforded α-iodo enone 11 in 81% yield. The addition of BHT
atural epoxyquinoids comprise a large family of secondary metabolites biosynthesized from polyketide−terpenoid hybrid and shikimate−terpenoid hybrid pathways.1 Structurally unique cyclohexane/cyclohexene epoxide-based molecular structures in conjunction with their interesting biological activities such as antibiotic, antifungal, and antitumoral effects have attracted the interest of the synthetic community. As a result of the development of innovative synthetic strategies, various total syntheses of these natural products have been reported.2 In addition to diverse monomeric epoxyquinoids, several dimeric epoxyquinone-derived natural products have been isolated.3 From an evolutionary perspective, dimerization of natural products most likely aims at producing diverse secondary metabolites in short order in response to specific environmental stress.4 Organisms have consequently evolved various dimerization modes of their biosynthetic monomers.5 Structural examinations of dimeric epoxyquinoids reveal a biosynthetically relevant cycloaddition dimerization mode prevalent in this natural product family. These dimeric secondary metabolites have served as inspirations to expand the current understandings of intermolecular Diels−Alder reactions between highly complex coupling partners.6 Porco and co-workers reported an elegant biosynthetically inspired total synthesis of torreyanic acid (1, Figure 1A) using a late-stage tandem electrocyclization/ Diels−Alder reaction.7,8 Continued interests toward the synthesis of dimeric natural products from epoxycyclohexenone derivatives via a cycloaddition reaction have yielded total syntheses of natural products such as epoxyquinols A (2) and B,9 panepophenanthrin (3),10 and hexacyclinol (4).11 Gao, Yao, and co-workers recently isolated a structurally intriguing meroterpenoid dimer dimericbiscognienyne A (7, Figure 1B) along with its putative biosynthetic precursors, biscognienynes A (5) and B (6).12 The Gao research team found that dimericbiscognienyne A (7) showed short-term memory enhancement activities in fly models of Alzheimer’s disease. The Gao group © 2018 American Chemical Society
Received: September 21, 2018 Published: October 16, 2018 6886
DOI: 10.1021/acs.orglett.8b03025 Org. Lett. 2018, 20, 6886−6890
Letter
Organic Letters
Scheme 2. Retrosynthetic Analysis of Dimericbiscognienyne A (7)
Scheme 3. Syntheses of Dienophile (±)-8 and Diene (±)-9
Figure 1. Representative epoxyquinoid natural products.
Scheme 1. Biosynthetic Hypothesis of (+)-Dimericbiscognienyne A (7)
89% yield. For the synthesis of triene 9, ketone 11 was first transformed to trans-diol 17 in 68% yield under Luche reduction conditions. Subsequent Stille cross-coupling reaction of iodide 17 and vinyl stannane 16 produced triene 9 in 63% yield. On the other hand, a Stille reaction between iodide 17 and enyne stannane 15 produced the first synthetic sample of (±)-biscognienyne B (6) in 71% yield. Despite the possible formation of multiple diastereomers during the intermolecular Diels−Alder reaction, we made a strategic decision to synthesize 8 and 9 as racemic mixtures to expedite the evaluation of the key late-stage [4+2] cycloaddition reaction. To our pleasure, simple mixing of dienophile (±)-8 and diene (±)-9 in chloroform at ambient temperature yielded (±)-dimericbiscognienyne A (7) in 75% yield along with minor diastereomers resulting from the combination of opposite enantiomers (Scheme 4). The structure of synthetic dimericbiscognienyne A (7) was corroborated by HRMS, proton and carbon NMR spectroscopy, and X-ray crystallography (Scheme 4). Notably, attempted biomimetic dimerization of (±)-biscognienyne B (6) did not yield (±)-dimericbiscognienyne A (7) under various transition metal catalyzed intermolecular transfer hydrogenation reaction conditions tested.
was essential as its absence from the reaction mixture afforded 11 in only 21% yield.16 With a robust synthetic access to α-iodo enone 11, we envisioned obtaining both dienophile 8 and diene 9 from this common precursor. When iodide 11 and enyne stannane 15 were allowed to react in the presence of Pd(OAc)2, CuI, and AsPh3 ligand, the Stille coupling product 8 was obtained in 6887
DOI: 10.1021/acs.orglett.8b03025 Org. Lett. 2018, 20, 6886−6890
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Organic Letters
We subsequently investigated pathways that lead to four possible diastereomers (four diastereomers resulting from the combination of opposite enantiomers were not considered, vide inf ra) resulting from different facial and exo/endo selectivities between dienophile 8 and diene 9 (Figure 2). Among these pathways, the one passing through transition state TS-10 (Scheme 4) showed the lowest energy barrier of 20.93 kcal/mol in accordance with the experimental observation. Frontier molecular orbital analysis showed that the additional stabilization stems from the π−π interactions between the C5′C6′ π orbital of diene 9 and the π* orbitals of the C7C8 bond and the C1O bond of dienophile 8 (Figure 3). Furthermore, transition state TS-10
Scheme 4. Total Synthesis of (±)-Dimericbiscognienyne A (7)
Figure 3. Frontier molecular orbital analysis of 8 (LUMO) and 9 (HOMO). Primary HOMO−LUMO interaction is presented in blue dotted lines. Secondary π−π interactions are presented in green dotted lines. Hydrogen bonding is presented in orange dotted line.
In order to gain further mechanistic insights into reaction between (±)-8 and (±)-9, a density functional theory (DFT)17 calculation was carried out by utilizing B3LYP-D3/ cc-pVTZ(-f)//B3LYP-D3/LACVP**18 and self-consistent reaction field (SCRF) approximations19 (chloroform, ε = 4.806). We first examined the reaction sequence between the Diels−Alder reaction and the hemiacetal formation. Our calculation data revealed that the energy barrier of the intramolecular Diels−Alder reaction of the reversibly formed hemiacetal between 8 and 9 is significantly higher than that of the intermolecular cycloaddition reaction between 8 and 9.10,20 These results indicated that a plausible reaction mechanism for this remarkable transformation would comprise an initial intermolecular Diels−Alder reaction between 8 and 9, followed by an intramolecular hemiacetal formation consistent with Gao’s biosynthetic hypothesis of this natural product (Scheme 1).
showed that the C1′ hydroxyl group of diene 9 is involved in the hydrogen bonding with the C1 carbonyl moiety of dienophile 8. To gain further experimental insights about the importance of the aforementioned hydrogen bonding during the key cycloaddition reaction, dienes with partially or fully protected hydroxyl groups were synthesized and allowed to react with dienophile 8 (Table 1). The diene that is monosilylated at C1′ underwent a Diels−Alder reaction with the dienophile to produce cycloadduct 21 in 51% yield (entry 2).21 On the other hand, dienes with both C1′ and C4′ hydroxyl groups protected did not show any reactivity when they were allowed to react with 8 (entries 3 and 4). We reasoned that the formation of 21 would involve a hydrogen bonding between the C4′ hydroxyl moiety of the diene and the ketone moiety of dienophile 8.
Figure 2. Energy profiles for the dimerization between 8 and 9 which yielded 7. 6888
DOI: 10.1021/acs.orglett.8b03025 Org. Lett. 2018, 20, 6886−6890
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Organic Letters Table 1. Investigations of the Hydrogen Bonding Factor during the Diels−Alder Reaction for the Synthesis of Dimericbiscognienyne A (7)
Scheme 5. Enantioselective Total Synthesis of (+)-Dimericbiscognienyne A (7)
a Reactants were allowed to react for 7 days. bReactants were allowed to react for 3 days.
These experimental observations are consistent with the theoretically predicted importance of the hydrogen bonding during the key [4+2] cycloaddition reaction of 8 and 9. Furthermore, the mild reaction conditions during the key cycloaddition reaction (ambient temperature, absence of catalyst, and 0.17 M concentration) can be rationalized based on the aforementioned secondary π−π interactions and the hydrogen bonding. This is strikingly different from previous cycloaddition reactions for dimeric epoxiquinoid synthesis which required more forcing conditions such as acid catalysis7,8 or neat concentration.10a,11 We next sought to access an enantiomerically enriched sample of (+)-dimericbiscognienyne A (7) via an oxazaborolidinecatalyzed enantioselective Diels−Alder reaction reported by the Ryu group.22 Enone 22 and cyclopentadiene underwent an enantioselective [4+2] cycloaddition reaction in the presence of oxazaborolidine catalyst23 23 to produce cycloadduct (+)-24 in 97% yield and 92% ee. (+)-24 could be recrystallized to yield materials with 99% ee in 62% yield. A three-step reaction sequence involving a Stille cross coupling, an acetal deprotection, and an epoxidation afforded the Ryu intermediate (+)-25.22 Regio- and diastereoselective reduction of the ketone group in (+)-25 provided alcohol (+)-26 in 82% yield (Scheme 5). Finally, a retro-Diels−Alder reaction of (+)-26 (86% yield), followed by a cross-metathesis with isobutylene in the presence of Hoveyda−Grubbs secondgeneration catalyst afforded enone (−)-12 (45% yield). HPLC analysis of (−)-12 showed a 97% enantiomeric excess. Optically active (−)-12 could be further derivatized to (+)-dimericbiscognienyne A (7, [α]27 D of the synthetic sample = +42.8 (c 0.30, MeOH), [α]27.1 from the isolation report = D +42.5 (c 0.5, MeOH)). It is important to note that the reaction between optically enriched (−)-diene 9 and (−)-dienophile 8 (97% ee) did not yield any notable byproducts that were previously observed during our synthetic campaign using racemates and produced (+)-dimericbiscognienyne A (7) in an improved 85% yield.20
In conclusion, we have completed the first total synthesis of (±)- and (+)-dimericbiscognienyne A (7) in 9 and 12 longest linear steps from commercially available materials, respectively. Key to the successful total synthesis of this natural product was the biosynthetically inspired late-stage heterodimerization involving the Diels−Alder reaction and the hemiacetalization. We showed that secondary π−π interactions as well as hydrogen bonding were critical for the selective formation of the desired natural product among other possible diastereomers. Efforts to expand the utility of the intermolecular cycloaddition reaction to diverse types of epoxyquinoid natural products are currently ongoing and will be the subject of forthcoming reports.
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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.8b03025. Experimental procedures, spectroscopic data, spectrometric data, and copies of 1H and 13C NMR spectra of all new compounds, HPLC trace of 12, and X-ray crystal structure data of 7 (PDF) Accession Codes
CCDC 1844156 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, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. 6889
DOI: 10.1021/acs.orglett.8b03025 Org. Lett. 2018, 20, 6886−6890
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Organic Letters ORCID
(16) (a) Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron Lett. 1998, 39, 6849−6852. (b) Shoji, M.; Kishida, S.; Takeda, M.; Kakeya, H.; Osada, H.; Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155−9158. (17) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989. (18) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B. 1988, 37, 785− 789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 1372−1377. (c) Becke, A. D. Phys. Rev. A 1988, 38, 3098−3100. (d) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104-1−154104-19. (e) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270−283. (f) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284−298. (g) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299−310. (h) Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007−1023. (19) (a) Marten, B.; Kim, K.; Cortis, C.; Friesner, R. A.; Murphy, R. B.; Ringnalda, M. N.; Sitkoff, D.; Honig, B. J. Phys. Chem. 1996, 100, 11775−11788. (b) Edinger, S. R.; Cortis, C.; Shenkin, P. S.; Friesner, R. A. J. Phys. Chem. B 1997, 101, 1190−1197. (c) Friedrichs, M.; Zhou, R.; Edinger, S. R.; Friesner, R. A. J. Phys. Chem. B 1999, 103, 3057−3061. (20) See the Supporting Information for details. (21) Desilylation of cycloadduct 21 resulted in the sole formation of dimericbiscognienyne A (7). (22) Jung, S. H.; Hwang, G.-S.; Lee, S. I.; Ryu, D. H. J. Org. Chem. 2012, 77, 2513−2518. (23) Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100−2117.
Geon Kim: 0000-0002-1152-274X Myungjo J. Kim: 0000-0002-7031-7332 Garam Chung: 0000-0002-6968-8662 Hee-Yoon Lee: 0000-0002-3558-2894 Sunkyu Han: 0000-0002-9264-6794 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This paper is dedicated to Professor Han-Young Kang (Chungbuk National University) in memory of his honorable retirement. We thank Professor Mu-Hyun Baik (IBS/KAIST) for providing us with computational resources and Dr. Dongwook Kim (IBS) for solving the X-ray crystal structure of 7. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018R1A2B6004479).
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DOI: 10.1021/acs.orglett.8b03025 Org. Lett. 2018, 20, 6886−6890
