Article pubs.acs.org/JACS
Synthesis of (−)-11‑O‑Debenzoyltashironin: Neurotrophic Sesquiterpenes Cause Hyperexcitation Masaki Ohtawa,† Michael J. Krambis,§ Rok Cerne,§ Jeffrey M. Schkeryantz,§ Jeffrey M. Witkin,§ and Ryan A. Shenvi*,† †
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States
§
S Supporting Information *
ABSTRACT: 11-O-Debenzoyltashironin (1) is a member of the neurotrophic sesquiterpenes, trace plant metabolites that enhance neurite outgrowth in cultured neurons. We report its synthesis in six steps from a butenolide heterodimer via its likely biosynthetic precursor, 3,6-dideoxy-10-hydroxypseudoanisatin, here identified as the chain tautomer of 1. Access to the tashironin chemotype fills a gap in a comparison set of convulsive and neurotrophic sesquiterpenes, which we hypothesized to share a common target. Here we show that both classes mutually hyperexcite rat cortical neurons, consistent with antagonism of inhibitory channels and a mechanism of depolarization-induced neurite outgrowth.
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INTRODUCTION Beginning in 1993,1a Fukuyama began the isolation of polyoxygenated sesquiterpenes from Illicium sp. guided by neurite outgrowth enhancement of rat cortical neurons as a target property.1a−f Termed the ‘neurotrophic sesquiterpenes’ for this phenotype,1a,2 compounds exemplified by 1 and 3 (Figure 1) have seen limited biological study owing to their meager supply by nature. Although isolation and re-isolation have afforded single-digit milligram quantities, many of these molecules are trace metabolites that occur at ppm levels in plant material and therefore are difficult to procure on a large scale. For example, 3.7 kg Illicium merrilianum dry pericarps affords 3 mg of 1 after extraction and iterative chromatography.1e Chemical synthesis has not sufficiently solved this problem: 35 syntheses have been undertaken with an average of only 7.5 mg produced per completed synthesis.3 Notable exceptions include a 92 mg racemic synthesis of merrilactone A,3a an 8-step asymmetric synthesis of 1 g of 34 by our lab, and a 15-step asymmetric synthesis of 300 mg of 3.3x Nevertheless, relative scarcity within the biomedical community has prevented assignment of biological targets of any member of the neurotrophic sesquiterpenes. Chemical syntheses by Danishefsky and Theodorakis have at least allowed replication of the neurite outgrowth phenotype using the PC12 rat brain tumor-derived cell line and established a preliminary “SAR map” of what functional groups are necessary for activity.3t,5 Synthesis of the neurotrophic terpene merrilactone A (5) and its enantiomer (ent-5) by Inoue3g led to the observation of similar levels of neurite outgrowth enhancement by both isomers, which may be due to the © 2017 American Chemical Society
symmetry of its propellane-like skeleton: models of 5 and ent-5 overlap substantially, especially at oxygens. More recently, Tiefenbacher has found that simplified analogs of 5 enhance serum deprivation-induced neurite outgrowth in mouse N2a cells, albeit at 1000 nM, which contrasts the 10 nM maximal effective concentration of 3 observed in cultured cortical neurons.6 Fukuyama and co-workers have replicated the phenotype of 3 using human induced pluripotent stem cells (hiPSCs) and speculated that an endogenous neurotrophin receptor like TrkB is involved in jiadifenolide’s phenotype.7 However, the neurite outgrowth phenotype is notorious for its multifactorial origins,8 not indicative of a particular biological target in the absence of other data. Terpenoids of similar size and oxygenation pattern as 1 and 3 (e.g., 2 and 4) have been shown to induce convulsions in mammals9 by blockade of chloride influx through GABAA receptors (GABAARs, Figure 2): ligand gated ion channels (LGICs) agonized by γ-aminobutyric acid (GABA).10,11 GABAARs belong to the CysLoop superfamily of ionotropic receptors, which mediate inhibitory fast synaptic transmission between neurons in the mature central nervous system (CNS). Antagonism of GABAARs by 2 and 4 leads to hyperexcitation of neurons, that is, increased frequency of action potential spikes. At the organism level, this leads to ataxia, convulsion, and, at the extreme end, death. However, GABAARs are not involved in inhibitory signaling only. In the developing brain, agonism of GABAARs by GABA results in depolarizing excitation via Received: April 29, 2017 Published: June 23, 2017 9637
DOI: 10.1021/jacs.7b04206 J. Am. Chem. Soc. 2017, 139, 9637−9644
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Figure 1. Structural comparison of neuroactive terpenes, some of which (2, 4, 6, 7) are known to target CysLoop receptors.
Figure 2. (a) Structure, types, ion selectivity, and combinatorial assembly of CysLoop receptors.10,11,23 (b) Antagonism of anionselective (GABAAR, GlyR) and agonism of cation-selective (5-HT3R, nAChR) receptors usually lead to hyperexcitation under native conditions, i.e., increased frequency of action potentials.
chloride efflux due to elevated intracellular chloride in immature neurons.12 Subsequent calcium influx and intracellular signaling forms the basis of overall GABA-mediated trophic effects, including neurite outgrowth.13 Taken together, the structural overlap between 1/3 and 2/4, their mutual activation of neurons, and the role of CysLoop receptors in neurite outgrowth led us to propose this superfamily as probable targets for 1, 3, and their congeners.14 Such a correlation of structure to target is not unprecedented: The sesquiterpenes bilobalide (6) and ginkgolide B (7) reveal structural overlap with 4 and also antagonize GABAARs.15,16 However, these correlations can also be imprecise due to the close homology of receptors within the CysLoop superfamily: 7 also strongly inhibits the related glycine receptors (GlyRs).17,18 Assignment of the highest affinity target is further complicated by the combinatorial nature of receptors in the CysLoop superfamily: There are not just four types of receptors, but many subtypes. For example, GABAARs are assembled from 19 different subunit isoforms. An upper limit19 of 800 GABAAR subtypes has been estimated, but only 26 endogenous subtypes20 have been characterized with confidence.21,22 Point-mutation knock-in mice have illustrated the potential for subtype-selective ligands to maximize targeted effects (e.g., anxiolysis) and minimize undesired side effects (e.g., sedation, ataxia).23 Therefore, subtype-selective agonists and antagonists (e.g., benzodiazepine NAMs and PAMs) form an important subset of neurological drugs and tools24 with potential applications across multiple indications.25,21 Improved cognition via α5 subunit-selective inverse agonism has stimulated extensive interest for both Down syndrome26,27 and Alzheimer’s disease.28 Glycine receptors are homologous to GABAARs but are assembled from only 5 subtypes (α1−4 and β)
with a 3:2 or 4:1 likely stoichiometry. Both GABAARs and GlyRs respond to agonist binding by opening an anion-selective channel. Anion influx leads to hyperpolarization of the membrane and decreased likelihood of reaching the threshold potential needed to open voltage-gated ion channels and initiate an action potential. Agonism of 5-HT3 and nACh receptors leads to cation influx and excitation (depolarization) toward the threshold potential. Similarly, antagonism of GABAARs and GlyRs leads to hyperexcitation, as seen with the channel binders 2 and 4. Given the potential for new chemotypes of CysLoop receptors ligands to find widespread use, we have begun to interrogate the hypothesis that antagonism of these ion channels underlies the activity of the neurotrophic Illicium sesquiterpenes. Jiadifenolide (3) bears gross resemblance to the known GABAAR antagonist, picrotoxinin (4, Figure 1), closely sharing the peripheral rim of oxygen atoms embedded as γlactones. Another convulsant GABAAR antagonist, anisatin (2), overlaps poorly with 3, but contains the trans-hydrindane scaffold found in other neurotrophic congeners. Indeed, 2 overlaps well with 11-O-debenzoyltashironin (1), a challenging caged molecule that has been difficult to synthesize efficiently. We recently reported a concise synthesis of jiadefenolide (3) through the heterodimerization of two butenolides.4 Here we show that this approach is applicable to (1) by overcoming challenging problems of stereochemistry and chemoselectivity. We then use this comparison set of neurotrophic and convulsive terpenes (1 vs 2; 3 vs 4) to probe similarities or differences in the effect on neurons. 9638
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Figure 4, conversion of 11 (or 12) to 1 would require net inversion of the C4 C−O bond and resection of one skeletal
Two prior syntheses of 1 have been reported: A 25-step asymmetric synthesis by Danishefsky29a and an18-step formal effort by Mehta (Figure 3).29b Both approaches rely on an
Figure 4. Possible routes from 11/12 to (−)-1.
carbon. To invert C4, we planned elimination of the lactone to an alkene, followed by Drago−Mukaiyama hydration,31 but the stereochemistry of this HAT radical hydrofunctionalization32 was uncertain. Prior work from our lab has demonstrated preference for the thermodynamically preferred stereoisomer due to the intermediacy of pyramidalized C-radicals,33 but this preference is still kinetically determined and the tashironin skeleton did not show clear preference for one stereoisomeric transition state. Removal of a skeletal carbon was decided more quickly. Analysis of bond connectivity revealed that C12 could be resected to deliver aldehyde 13, which might engage in a McMurry-type coupling to link C10 and C11. Alternatively, C11 could be resected to deliver lactone 14, which might engage in trans-annular cyclization to link C6 to C12. Lactone 14 is itself a naturally occurring Illicium metabolite designated 3,6-dideoxy-10-hydroxypseudoanisatin.30 It is the chain tautomer of 1, and as a seco-prezizaene skeleton, it is the likely biosynthetic precursor of 1 (i.e., C6−C12 is not derived from farnesylpyrophosphate, FPP, cyclization). While the bottom pathway was appealing for these reasons, the reactivity of compound 12 determined the carbon we would excise: The C12 carbonyl proved extremely resistant to addition by nucleophiles. Alkoxides instead caused retro-Dieckmann reaction (12 → 15, Figure 5), which we thought might reflect a thermodynamic sink that could be avoided by kinetically controlled, irreversible addition by hydroxide. However, treatment with tetrabutylammonium hydroxide, solvent evaporation, and methylation with dimethylsulfate delivered the same retro-Dieckmann product 15 with no evidence of C12 lactone cleavage. Fortunately, we found that sodium hydroxide spared the ketone, and while the C12 lactone remained intact, the C11 lactone underwent clean ring opening, followed by decarboxylation. Spontaneous hemiketal formation occurred to yield compound 17. As noted above, the second lactone proved resistant to irreversible addition under basic conditions: Strong Brønsted acid (Figure 6, top) preferentially degraded the ketone to ketals 18 and 19, or cyclopropane 20, without affecting the lactone. Finally, we found that 17 could be cleanly converted to N,N-
Figure 3. Approaches to the synthesis of 1.
intramolecular Diels−Alder cycloaddition to establish the cyclohexane core, and both present challenges to material throughput in different ways. The first synthesis (racemic and asymmetric) requires multiple steps to prepare a bridging allene, which lowers the overall yield to 0.5%. The second synthesis (formal, racemic) avoids lengthy diene/dienophile preparation by sacrificing stereocontrol, which results in loss of material by separation of stereoisomers. Here we report a more concise synthesis of (−)-1 by leveraging our recently reported butenolide heterodimerization approach to the Illicium terpenes.4 Advance of the heterodimer to 11 intercepts the pseudoanisatin framework via 3,6-dideoxy-10-hydroxypseudoanisatin,30 which had not previously been identified as the chain tautomer of 1. As a result of its brevity, we were able to synthesize 27 mg of 1, whereas the only other asymmetric route was a formal effort that did not produce any target material. The significance of this general approach is shown by the ability to probe the effect of different neurotrophic sesquiterpenes on the polarization of neuron membrane potential, which offers one potential explanation of their neurite outgrowth phenotype and opens a new avenue for the selective modulation of synaptic signaling.
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RESULTS AND DISCUSSION Two features of 1 confounded direct application of our butenolide heterodimerization. As shown by the analysis in 9639
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shown in a 10 step synthesis of (−)-1 in Scheme 1. The synthesis began with our butenolide heterodimerization. Deprotonation of butenolide 9, followed by addition of butenolide 10 led to heterodimer 25. Without isolation, addition of titanium tetraisopropoxide and lithium diisopropylamide delivered tetracycle 11 according to our published procedure.4 C-selective α-methylation of the β-ketoester function with methyl iodide, followed by sodium hydroxide addition, led to carboxylate 26 via chemoselective attack at C11 versus C12. Decarboxylation to ketal 17 occurred upon acidification with HCl. This initial sequence could be conducted in two individual steps, but compression to one step did not affect the yield (see Supporting Information). The lactone was then opened by Me2N-AlMe2 to yield 21a/b, and to effect efficient elimination, the diol was first monosilated and then treated in situ with thionyl chloride, which afforded unsaturated ketone 28, circumventing chelates and cyclic sulfite 23. Since subsequent steps required selective α-functionalization of the less-acidic ketone and the ketone was subject to facile internal ketalization (Figure 6, 17 → 18), we chose not to isolate 28 but to add trimethylorthoformate prior to acidic workup. This resulted in clean conversion to a ketal (29), which served the dual roles of protecting the acidic ketone against deprotonation and directing the stereochemistry of amide oxidation (see below). Installation of the C10 hydroxyl proved challenging. The extreme steric shielding of the amide α-position in 29 prevented deprotonation with several strong bases, and prediction of α-oxidation stereochemistry was not straightforward. Eventually, we discovered that lithium dimethylamide35 in THF/HMPA was a sufficiently small and strong base to deprotonate 29 at 22 °C and that oxidation with triplet oxygen36 in the presence of triethylphosphite37 occurred with high stereoselectivity (>20:1 dr). X-ray crystallographic analysis assigned this α-hydroxyamide as the targeted stereoisomer (Scheme 1, bottom). The high selectivity for stereoisomer 31 appeared to be derived from preferred rotation of the amide enolate (30) to minimize steric clash and steric shielding of one enolate face by the bridging ketal. Now that the ketal had served its purposes of stereoinduction and ketone protection, it was removed under aqueous acidic conditions. Along with ketal cleavage, lactonization occurred at 80 °C38 to provide seven-membered lactone 32. This unusually facile amide esterification is promoted by the close proximity of the alcohol and amide substituents.39 With the pseudoanisatin skelton in hand, we pursued elaboration to 1. We had delayed installation of the C4-OH to a late stage in the synthesis due to problems with alkene hydration in earlier intermediates. It was hard to justify why a thermodynamically disfavored trans-hydrindane would predominate over the cisring junction, and attempts to effect hydration of earlier intermediates produced either complex mixtures or returned the propellane lactone 17 (Figure 7). Therefore, we were relieved to find that hydration of lactone 32 under standard Mukaiyama conditions31c generated a single diastereomer of alcohol. More compelling was the detection of traces of 1, simultaneously giving us confidence that the transring juncture was formed and that intramolecular cyclization would be facile. Indeed, addition of p-toluenesulfonic acid to the crude reaction mixture delivered 1 in 72% yield. We suspect that the stereochemistry of hydration40 is determined by steric shielding by the C10 alcohol. It should be noted that the initial product of hydration, 14, was difficult to purify completely due
Figure 5. Reactivity of bis-lactone 12.
Figure 6. Attempts to open the bridging lactone of 17.
dimethylamide ring−chain tautomers 21a/b by treatment with Me2N-AlMe2 at 100 °C in toluene (Figure 6, left). This reagent was prepared from dimethylamine solution in THF rather than the more commonly employed hydrochloride salt (Me2NH· HCl), which reacted with trimethylaluminum to yield the aluminum chloride complex, Me2N−AlClMe.34 This latter complex was found to preferentially deliver cyclopropane 22. Nevertheless, elimination of the C4 tertiary alcohol of 21 was frustrated by an extremely rapid relactonization (to 17) induced by Brønsted acid and the preferential reaction of the primary alcohol of 21b with electrophiles. For instance, use of thionyl chloride and triethylamine did not cause dehydration, but instead formed cyclic sulfite 23, which could not be eliminated to 24. A solution to this problem and implementation of the reactivity of Figures 5 and 6 are 9640
DOI: 10.1021/jacs.7b04206 J. Am. Chem. Soc. 2017, 139, 9637−9644
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Journal of the American Chemical Society Scheme 1. Synthesis of (−)-11-O-Debenzoyltashironin [(−)-1] in Seven Steps from 9 and 10
inin (4) can antagonize inhibitory (GABAAR, GlyR) or excitatory (5-HT3R, nAChR) channels with different affinities, leading to excitation or inhibition, respectively.42 The overall effects of 1 and 3 on neurons would identify the types of channels antagonized and allow us to probe efficacy. Comparison of the effects of 1−4 on primary cultures of rat cortical neurons showed the hyperexcitation expected from antagonism of inhibitory channels (Figure 8). In this case, neurotrophins 1 and 3 caused greater hyperexcitation than convulsants 2 and 4. However, the inherent variability in microelectrode array analysis prevented overinterpretation of these trends. We concluded that 1−4 similarly hyperexcite cortical neurons, consistent with overlap of structure and target class. Application of 10 and 30 μM (−)-1 reduces nearly in half the current evoked by exogenously applied GABA, similar to anisatin (2) (Figure 9a,b). The antagonistic effects of 1 are weaker than those of known GABAAR antagonist 2, a convulsant, but consistent with the same mechanism. Comparison of jiadifenolide (−)-(3) and picrotoxinin (4) shows a qualitatively similar relationship, but with lower potency for both, especially 3. Similarly, promotion of current block at recombinant GABAA receptors in HEK293 cells was measured across the comparison set (Figures 9c, SI-3, and SI4). Again, convulsants 2 and 4 significantly blocked current at 3 μM, whereas 1 and 3 required 10-fold higher concentration to approach that level of inhibition. Although no compounds
Figure 7. Attempted hydration of nonbridging intermediates.
to its facile conversion to 1 on silica. Interestingly, 14 is itself a secondary metabolite of I. merrillianum (the same plant that produces 1), and therefore 1 and 14 represent an unusual example of stable ring−chain tautomeric natural products. Treatment of 1 with methanolic hydrochloric acid regenerates 14 from 1, albeit as a mixture.41 Access to 11-O-debenzoyltashironin (−)-1 completed a comparison set of chemotypes that represent “neurotrophic” and “convulsive” sesquiterpenes: 1 overlaps with potent convulsant anisatin (2), whereas jiadifenolide (3) overlaps with picrotoxinin (4). We recently hypothesized that the neurite outgrowth enhancement caused by 1, 3 and their congeners might be accounted for by binding to CysLoop receptors, due to structural similarity to GABAAR antagonists 2 and 4. Missing from this hypothesis is any data whatsoever on the effects of 1 or 3 on the membrane potential of neurons or on neurotransmitter gated ion channels. Significantly, picrotox9641
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Figure 8. Effects of 1−4 on neuronal activity. (a) Effects of neurotrophic (1 and 3) and convulsive (2 and 4) terpenes on frequency of spikes of cultured rat cortical neurons (DIV 19−25) (n = 5−8). DIV = days in vitro. (b) Effects on spike frequency normalized. All error bars represent the standard error of the mean (SEM).
distinguished between the α-subunits, the effect of the other dozen subunits (β2, ρ2, etc.) on sensitivity to 1 and 3 is an open question.43 This question highlights the difficulty of distinguishing binding to a high affinity GABAA receptor at low abundance versus a low affinity receptor at high abundance. One interpretation of these data is that the “neurotrophic sesquiterpenes” cause a weak but persistent hyperexcitation of neuronal cells upon chronic treatment at very low concentration (10 nM to 1 μM). This model would be in line with the “calcium set point hypothesis,” where maximum trophic effects are observed at a “sweet spot” of intracellular calcium concentrations,44 below or above which decreased neurite outgrowth occurs. Intracellular calcium levels are modulated by voltage-gated calcium channels, which open in response to depolarization (excitation).45 Thus, our working model is that the “neurotrophic sesquiterpenes” cause depolarization-induced neurite outgrowth. These effects are also observed in PC12 cells, which have been common model cells to test 1, 3, and their congeners.46 Their relatively weak antagonism would promote growth but prevent excitotoxicity at the very low concentrations used in outgrowth assays.45 The neuriteoutgrowth activity of simplified merrilactone anlogs6 can be explained by this model combined with prior observations that simple γ-lactones antagonize GABAARs, albeit at low potency.47 Full interrogation of this hypothesis will only be possible through chemical synthesis, as the neurotrophic sesquiterpenes are not otherwise available. A definitive link has not been
Figure 9. Effects of 1−4 on GABAAreceptor function. (a) Effects of neurotrophic (1 and 3) and convulsive (2 and 4) terpenes on GABAevoked inhibitory currents of cultured rat cortical neurons (DIV 18− 25). (b) Effects on GABA-evoked current normalized (n = 3−6). (c) Inhibition of current through recombinant GABAA receptors: αxβ3γ2 expressed in HEK293 cells (n = 4−8). All error bars represent the SEM.
established between the short-term hyperexcitation we observe, and the long-term neurite outgrowth observed by others. Furthermore, the subunit requirements for binding of 1 and 3 to CysLoop family members have not been determined,43 knowledge of which may lead to the design of subtype-selective antagonists. The possibility also exists for the creation of a series of compounds whose potencies can be differentiated to promote neurite outgrowth without excitotoxicity or seizure.
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CONCLUSIONS We have reported a concise synthesis of 11-O-debenzoyltashironin (1) and its chain tautomer 3,6-dideoxy-10-hydroxypseudoanisatin (14). The synthesis relies on (1) the challenging 9642
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(2) (a) Xu, J.; Lacoske, M. H.; Theodorakis, E. A. Angew. Chem., Int. Ed. 2014, 53, 956. (b) Urabe, D.; Inoue, M. Tetrahedron 2009, 65, 6271. (3) For syntheses of Illicium neurotrophic sesquiterpenes, see [merrilactone A]: (a) Birman, V.; Danishefsky, S. J. J. Am. Chem. Soc. 2002, 124, 2080. (b) Inoue, M.; Sato, T.; Hirama, M. J. Am. Chem. Soc. 2003, 125, 10772. (c) Harada, K.; Kato, H.; Fukuyama, Y. Tetrahedron Lett. 2005, 46, 7407. (d) Meng, Z.; Danishefsky, S. J. Angew. Chem. 2005, 117, 1535. (e) Inoue, M.; Sato, T.; Hirama, M. Angew. Chem. 2006, 118, 4961. (f) Mehta, G.; Singh, S. R. Angew. Chem. 2006, 118, 967. (g) Inoue, M.; Lee, N.; Kasuya, S.; Sato, T.; Hirama, M.; Moriyama, M.; Fukuyama, Y. J. Org. Chem. 2007, 72, 3065. (h) He, W.; Huang, J.; Sun, X.; Frontier, S. J. J. Am. Chem. Soc. 2007, 129, 498. (i) He, W.; Huang, J.; Sun, X.; Frontier, S. J. J. Am. Chem. Soc. 2008, 130, 300. (j) Nazef, N.; Davies, R. D. M.; Greaney, M. F. Org. Lett. 2012, 14, 3720. (k) Shi, L.; Meyer, K.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 9250. (l) Chen, J.; Gao, P.; Yu, F.; Yang, Y.; Zhu, S.; Zhai, H. Angew. Chem. 2012, 124, 5999. [jiadifenin]: (m) Cho, Y. S.; Carache, D. A.; Tian, Y.; Li, Y. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 14358. (n) Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A. Org. Lett. 2011, 13, 4554. (o) Yang, Y.; Fu, X.; Chen, J.; Zhai, H. Angew. Chem., Int. Ed. 2012, 51, 9825. (p) Mehta, G.; Shinde, H. M.; Kumaran, R. S. Tetrahedron Lett. 2012, 53, 4320. (q) Trzoss, L.; Xu, K.; Lacoske, M. H.; Theodorakis, E. A. Beilstein J. Org. Chem. 2013, 9, 1135. (r) Cheng, X.; Micalizio, G. C. J. Am. Chem. Soc. 2016, 138, 1150. [jiadifenolide] (s) Xu, J.; Trzoss, L.; Chang, W. K.; Theododrakis, E. A. Angew. Chem., Int. Ed. 2011, 50, 3672. (t) Trzoss, L.; Xu, J.; Lacoske, M. H.; Mobley, W. C.; Theodorakis, E. A. Chem. - Eur. J. 2013, 19, 6398. (u) Siler, D. A.; Mighion, J. D.; Sorensen, E. J. Angew. Chem., Int. Ed. 2014, 53, 5332. (v) Paterson, I.; Xuan, M.; Dalby, S. M. Angew. Chem., Int. Ed. 2014, 53, 7286. (w) See ref 4. (x) Shen, Y.; Li, L. B.; Pan, Z. S.; Wang, Y. L.; Li, J. D.; Wang, K. Y.; Wang, X. C.; Zhang, Y. Y.; Hu, T. H.; Zhang, Y. D. Org. Lett. 2015, 17, 5480. See also: (y) Hung, K.; Condakes, M. L.; Morikawa, T.; Maimone, T. J. J. Am. Chem. Soc. 2016, 138, 16616. (4) Lu, H.-H.; Martinez, M. D.; Shenvi, R. A. Nat. Chem. 2015, 7, 604. (5) Carcache, D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 1016. (6) Richers, J.; Pöthig, A.; Herdtweck, E.; Sippel, C.; Hausch, F.; Tiefenbacher, K. Chem. - Eur. J. 2017, 23, 3178. (7) Shoji, M.; Nishioka, M.; Minato, H.; Harada, K.; Kubo, M.; Fukuyama, Y.; Kuzuhara, T. Biochem. Biophys. Res. Commun. 2016, 470, 798−803. (8) Calabrese, E. J. Crit. Rev. Toxicol. 2008, 38, 391. (9) Schmidt, T. J. Curr. Org. Chem. 1999, 3, 577. (10) Hibbs, R. E.; Gouaux, E. Nature 2011, 474, 54. (11) Nutt, D. J. Clin. Sleep Med. 2006, 2, S7. (12) Ben-Ari, Y.; Cherubini, E.; Corradetti, R.; Gaiarsa, J. J. Physiol. 1989, 416, 303. (13) vanKesteren, R. E.; Spencer, G. E. Rev. Neurosci. 2003, 14, 217. (14) Shenvi, R. A. Nat. Prod. Rep. 2016, 33, 535. (15) Huang, S. H.; Duke, R. K.; Chebib, M.; Sasaki, K.; Wada, K.; Johnston, G. A. R. Eur. J. Pharmacol. 2003, 464, 1. (16) Huang, S. H.; Duke, R. K.; Chebib, M.; Sasaki, K.; Wada, K.; Johnston, G. A. R. Eur. J. Pharmacol. 2004, 494, 131. (17) Ivic, L.; Sands, T. T. J.; Fishkin, N.; Nakanishi, K.; Kriegstein, A. R.; Strømgaard, K. J. Biol. Chem. 2003, 278, 49279. (18) Kondratskaya, E. L.; Fisyunov, A. I.; Chatterjee, S. S.; Krishtal, O. A. Brain Res. Bull. 2004, 63, 309. (19) Barnard, E. A.; Skolnick, P.; Olsen, R. W.; Mohler, H.; Sieghart, W.; Biggio, G.; Braestrup, C.; Bateson, A. N.; Langer, S. Z. Pharmacol Rev. 1998, 50, 291. (20) Olsen, R. W.; Sieghart, W. Pharm. Rev. 2008, 60, 243. (21) Whiting, P. J. Drug Discovery Today 2003, 8, 445. (22) Chebib, M.; Hanrahan, J. R.; Mewett, K. N.; Duke, R. K.; Johnston, G. A. R. Annu. Rep. Med. Chem. 2004, 39, 13. (23) Sigel, E.; Steinman, M. E. J. Biol. Chem. 2012, 287, 40224. (24) Johnston, G. A. R. Br. J. Pharmacol. 2013, 169, 328.
ring-opening of a kinetically trapped propellane lactone; (2) the stereoselective α-oxidation of a congested amide; (3) a radical hydration reaction that preferentially forms the transhydrindane skeleton; and (4) an unusually facile trans-annular Dieckmann-type reaction to complete the synthesis of (−)-1 in only six steps from butenolide heterodimer 11. Access to 1 and 3 via synthesis has allowed us to probe the functional relevance of structural overlap with convulsants anisatin (2) and picrotoxinin (4). All four compounds cause hyperexcitation of cortical neurons and inhibit GABA-evoked current, which is consistent with antagonism of inhibitory ion channels. We propose a model of chronic depolarization → elevated [Ca2+]i → increased neurotrophic factor expression, which leads to the observed neurite outgrowth phenotype of the “neurotrophic sesquiterpenes.” The full meaning and potential of these structural/functional relationships are now under interrogation.
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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.7b04206. Detailed experimental procedures, spectral data, chromatograms, and X-ray crystallography (PDF) Crystallographic data (CIF) Crystallographic data (CIF) Crystallographic data (CIF) Crystallographic data (CIF) Crystallographic data (CIF) Crystallographic data (CIF) Crystallographic data (CIF)
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AUTHOR INFORMATION
Corresponding Author
*
[email protected] ORCID
Ryan A. Shenvi: 0000-0001-8353-6449 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We would like to acknowledge the Lilly Open Innovation Drug Discovery Program (OIDD) for its role in the initiation of this collaboration. We also thank Dr. Milan Gembicky, Dr. Curtis Moore, and Professor Arnold L. Rheingold for X-ray crystallographic analysis. Financial support for this work was provided by the NIH (GM104180, GM105766) and the Uehara Memorial Foundation. Additional support was provided by Eli Lilly, Novartis, Bristol-Myers Squibb, Amgen, BoehringerIngelheim, the Sloan Foundation, and the Baxter Foundation.
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REFERENCES
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DOI: 10.1021/jacs.7b04206 J. Am. Chem. Soc. 2017, 139, 9637−9644
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DOI: 10.1021/jacs.7b04206 J. Am. Chem. Soc. 2017, 139, 9637−9644
