Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2018, 83, 2018−2026
Synthesis and Computational Studies Demonstrate the Utility of an Intramolecular Styryl Diels−Alder Reaction and Di‑t‑butylhydroxytoluene Assisted [1,3]-Shift to Construct Anticancer dl-Deoxypodophyllotoxin Diana I. Saavedra, Benjamin D. Rencher, Doo-Hyun Kwon, Stacey J. Smith, Daniel H. Ess,* and Merritt B. Andrus* Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, Utah 84604, United States S Supporting Information *
ABSTRACT: Deoxypodophyllotoxin is a secondary metabolite lignan possessing potent anticancer activity with potential as a precursor for known anticancer drugs, but its use is limited by scarcity from natural sources. We here report the total synthesis of racemic deoxypodophyllotoxin in seven steps using an intramolecular styryl Diels−Alder reaction strategy uniquely suited to assemble the deoxypodophyllotoxin core. Density functional theory was used to analyze concerted, polar, and singlet-open-shell diradical reaction pathways, which identified a low-energy concerted [4 + 2] Diels−Alder pathway followed by a faster di-t-butylhydroxytoluene assisted [1,3]-formal hydrogen shift.
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INTRODUCTION The intramolecular styryl Diels−Alder (ISDA) reaction is a [4 + 2] cycloaddition that utilizes styryl functionality acting as the diene to react with electron deficient alkyne dienophiles.1 While this cycloaddition holds significant promise for the construction of complex structures, there are only limited examples of successful use. Simple biaryl compounds have been reported, including N-alkyl amides with favorable conformational effects2 and unsubstituted phenylallyl esters.3 Variations on these reactions include AgF/K2CO3 (DCE, 100 °C),3 phosphazene base P4-t-Bu (100 °C),4 and microwave irradiation at 180 °C (Scheme 1).5 Detailed mechanistic studies with substituted esters and applications to complex synthetic targets are lacking. This is in part due to major drawbacks to this reaction, which include slow reactivity due to loss of aromaticity in the [4 + 2] reaction step and electronic mismatch with two electron-rich aryl functional groups when applied to lignan-type targets (Scheme 2). There is also the need for a potentially problematic thermal [1,3]-hydrogen shift for rearomatization. Despite these major potential drawbacks, here we report the successful use of the ISDA reaction strategy in a 7-step racemic synthesis of deoxypodophyllotoxin (DPT). To our knowledge, this is the first application of the ISDA reaction in the synthesis of a complex target. Density functional theory (DFT) calculations reveal that the key ISDA occurs in one step, and then the formal [1,3]-hydrogen shift is mediated by BHT in a two-step radical reaction. © 2018 American Chemical Society
Scheme 1. Examples of ISDA Reactions
Synthetic Target. DPT (Figure 1) isolated from the plant Anthriscus sylvestris in very small quantities,6 has recently received increasing interest due to its demonstrated potential as a less toxic antitumor and antiviral agent when compared to major isolate podophyllotoxin.7 DPT is a nonalkaloid lignan, closely related to podophyllotoxin that is a precursor of the FDA approved topoisomerase II drugs Etoposide and TenipoReceived: November 21, 2017 Published: January 17, 2018 2018
DOI: 10.1021/acs.joc.7b02957 J. Org. Chem. 2018, 83, 2018−2026
Article
The Journal of Organic Chemistry Scheme 2. ISDA Reaction Strategy in Route to DPT
tubule assembly and halting cell division (G2/M).9 Cell cycle arrest at this point leads to protein expression (cyclin A, B1, caspase 3,7), promoting apoptosis.11 DPT also shows promising anti-inflammatory (COX-1,2: IC50 10 nM, 12 μM),12 antiviral (HSV-1,2:ED50 4.0, 11 ng/mL vs acyclovir 50 ng/mL),13 antiallergy,14 antibacterial,15 and platelet aggregation inhibition activity.16 DPT development remains hampered by its scarcity of isolation from the mayapple plant A. silvestris and related species (232 mg/kg).6 These plants have recently been listed as endangered in India and China.7 Endophytic fungi (Aspergillus f umigatus) have also been shown to produce DPT but only in very small amounts.17 Previous DPT Synthesis and Comparison to ISDA Synthesis. The total synthesis of DPT has been previously reported ranging from 10 to 20 steps (Scheme 3).18 Rodrigo reported in 198018a a stereo- and regio-controlled synthesis using a series of reductions and isomerizations. The core of DPT was made in moderate yield using a classic normal demand Diels−Alder reaction of isobenzofuran with dimethyl acetylenedicarboxylate. Jones18c made the core in a similar fashion by performing a Diels−Alder reaction between a pyrone and dimethyl maleate followed by decarboxylation and a series of reductions. Other methodologies involving classic normal demand Diels−Alder reactions have been used. Takano18b and Charlton18d utilized in situ formed o-quinodimethane dienes reacted with maleic acid type dienophiles. Takano employed a Peterson-like reaction to make the diene, while Charlton used the decomposition of a cyclobutene for its formation and reaction. These approaches presented difficulties
Figure 1. Podophyllotoxin-based anticancer agents.
side used commonly for lung and testicular cancer treatment (Figure 1).8 DPT inhibits microtubule formation during mitosis with enhanced binding and inhibition activity compared with podophyllotoxin (ID 50 0.5 nM tubulin-β vs 0.6 nM podophyllotoxin).9 DPT is also less cytotoxic to normal, untransformed cells (WI-38, lung, 79 μM).10 The molecular targets of DPT include tubulin (0.5 nM), preventing microScheme 3. Comparison of Synthesis Strategies of DPT
2019
DOI: 10.1021/acs.joc.7b02957 J. Org. Chem. 2018, 83, 2018−2026
Article
The Journal of Organic Chemistry Scheme 4. Key Retrosynthetic Steps
concerning converting the dicarbonyl products to the needed lactone moiety. Alternatively, a promising enantioselective 14 step route by Achiwa employed asymmetric reduction to install the stereochemistry early in the synthesis followed by Friedel− Crafts cyclization.19 Unfortunately, catalytic hydrogenation and lactonization at the end of the synthesis gave a mixture of lactones decreasing the yield. Peng more recently reported a racemic 10-step radical cascade-based route to an analogue of DPT using mild conditions and air stable materials (Scheme 3).20 Our new approach now reports a short seven-step synthesis that involves simultaneous formation of the cyclohexyl core and lactone functionality together with a stereocenter in a single step using the ISDA strategy, a reaction uniquely suited to assemble lignans of this type (Scheme 4). Our synthesis began with inexpensive 3,4-methylenedioxy cinnamic acid 1 and 3,4,5-trimethoxybenzaldehyde 2 (Scheme 5). These two compounds contain the aryl substituents needed to directly assemble DPT. Transformation of cinnamic acid 1 via Fisher esterification 3 and subsequent DIBAL reduction gave the corresponding alcohol 4 in 73% yield. 3,4,5Trimethoxybenzaldehyde 2 was converted into the corresponding dibromoalkene 5. Treatment under Corey−Fuchs con-
ditions and trapping with carbon dioxide gave the corresponding alkyne acid 6 in 88% yield (Scheme 5). Compounds 4 and 6 are precursors for the key ester intermediate needed for the ISDA reaction. For the coupling of precursors 4 and 6, esterification with DCC and DMAP was explored, giving the electron-rich ester 7 in modest yield, 61%. Purification of this ester was made difficult due to product coelution with dicyclohexyl urea byproduct upon purification. Use of water-soluble EDCI for this step gave product in lower yield. Mitsunobu coupling conditions with alcohol 4 and alkyne acid 6 proved superior in this case, giving a 63% yield with improved product purification (Scheme 5). With the successful coupling of pieces 4 and 6, the original Klemm thermal conditions1 (DMF, reflux 190 °C) were initially examined for the key ISDA reaction of the electron-rich diaryl allyl propiolate ester 7 (Table 1). Unfortunately, these Table 1. ISDA Reaction Conditions
Scheme 5. Synthesis of Precursors Compounds 4 and 6 solvent 0.01 M DMF 0.02 M PhCN 0.1 M MeCN 0.1 M toluene 0.1 M PhCN 0.02 M PhCN
conditions (°C, h)
yield of 8 and 9 (%)
160, 6
14
BHT 20 mol %
160, 2
39
BHT 1.5 equiv
90, 8
11
AgSbF6 (l equiv)/K2CO3 (2 equiv) BHT 1.5 equiv
100, 18 160, 2
56
BHT 1.5 equiv
160, 2
20
additive
conditions resulted in low yields (15 kcal/mol exergonic and likely irreversible. The diastereoselectivity is due to a small intrinsic diene− dienophile interaction preference and steric interactions between the methoxy-subsituted arene group and the catechol group in the concerted transition states.26 This was examined by removing the 3,4,5-methoxy substitution of the arene followed by recalculation of the concerted transition states, which decreases the ΔΔG⧧ to 1.2 kcal/mol and ΔΔH⧧ to 1.4 kcal/mol between TS6 and TS7 (see insert in Scheme 8). We also verified that the concerted and stepwise transition states for pathway D are higher in energy than the concerted transition states TS4 and TS5. In this pathway, the diene and dieneophile are reversed. The concerted transition state, TS8, has a ΔG⧧ of 38.6 kcal/mol due to the highly strained allenyl type structure (Scheme 9). Therefore, the stepwise transition
The mixture of diastereomers 8 and 9 could result from pathway A with competitive cyclization and bond rotation. Therefore, we first examined stepwise polar and diradical pathways. The lowest-energy stepwise transition state, TS1, was first located with a zwitterionic electronic configuration. However, reoptimization of the wave function showed a lower energy open-shell singlet unrestricted solution with an ⟨S2⟩ value of ∼0.35. To provide an accurate estimate of the electronic energy, spin-projection was used to remove the triplet spin contamination. The spin-projected activation free energy ΔG⧧ for TS1 is 34.2 kcal/mol relative to the lowest energy conformation of 7. The IRC shows smooth connection of TS1 to diradical intermediate 10 with complete singlet open-shell character (⟨S2⟩ ∼ 1.0). From diradical 10, open-shell transition states TS2 and TS3 form the second C−C bond and lead to cycloadducts 11 and 12. We initially assumed that these transition states control cycloadduct selectivity because the ΔG⧧ values are 24.4 and 25.4 kcal/mol, respectively, which roughly matches the experimentally observed 1.6:1 selectivity. However, we also located concerted transitions TS4 and TS5 that lead in one step to 11 and 12. These concerted transition states are very asynchronous with a difference of ∼0.8 Å in the partial C−C bond forming distances. More importantly, the stabilizing effect of the second C−C partial bond in these concerted transition states is large enough to overcome the greater entropic penalty and decrease in aryl group radical 2022
DOI: 10.1021/acs.joc.7b02957 J. Org. Chem. 2018, 83, 2018−2026
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The Journal of Organic Chemistry Scheme 9. (a) Alkyne Diene Pathway and (b) Carbonyl Role in Defining Diene of ISDA Reaction (kcal/mol)
Scheme 10. [1,3]-Hydrogen Shift Pathways Leading to Isolated Product 8
state, TS1, is lower in energy with ΔG⧧ of 34.1 kcal/mol. While this free energy barrier is the same to the other stepwise transition state, it is higher than TS4 and TS5. More importantly, the strain in the allenyl-type group results in a cycloadduct 14 that is 16.4 kcal/mol endergonic. The carbonyl position plays a significant role in defining the reactivity of the diene and the dienophile. To explore this relationship, we calculated concerted and stepwise singlet pathways (see Supporting Information, Scheme S3) with substrate 15 in which the carbonyl has been moved into conjugation with the styryl group withdrawing electrons from
the diene (Scheme 9b). In this case, the concerted TS9 has a ΔG⧧ of 35.6 k/mol. The withdrawing effect of the carbonyl closer to the diene raises the energy barrier 6.8 kcal/mol when compared to the concerted mechanism pathway B. This suggested that the position of the carbonyl close to the dienophile plays a more important role than the electron donation of the substituents and that the electronic mismatch caused by the electron-rich aryl substituents can be overcome. Because a unimolecular thermal concerted [1,3]-shift is unlikely,27,28 we explored several pathways for BHT-assisted 2023
DOI: 10.1021/acs.joc.7b02957 J. Org. Chem. 2018, 83, 2018−2026
The Journal of Organic Chemistry
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hydrogen migration. These pathways included concerted and stepwise BHT assisted and stepwise BHT radical pathways. We examined BHT-mediated formal [1,3]-shift pathways for both intermediates 11 and 12. Scheme 10 shows several possible pathways for intermediate 11 (see Supporting Information for intermediate 12). While there is the potential that the hydroxyl version of BHT mediates either a one-step or two-step 1,3-tautomerization pathway, based on the barriers, this seems unlikely. For example, the transition state for a onestep concerted proton shuttling mechanism has a barrier of ΔG⧧ 50.7 kcal/mol relative to intermediate 11 and free BHT. The large size of BHT probably precludes a highly organized transition state with multiple BHTs shuttling the proton in one step. Also, as suspected, BHT is a poor mediator of stepwise proton transfer. Proton transfer from 11 to BHT requires approximately 50 kcal/mol. Addition of explicit benzonitrile solvent to the calculation to stabilize the resulting anion of 11 did not significantly stabilize this intermediate. BHT was added into the reaction to prevent radical side reactions, likely radical polymerization of the alkyne ester. Therefore, it is reasonable that at least small quantities of BHT hydroxyl radicals are formed under reaction conditions and potentially provide a route for the hydrogen [1,3]-shift. It is known that BHT reacts with trace oxygen to generate radicals.29 The reactivity of BHT hydroxyl radical as well as the parameters of its formation and stability have been previously examined.30 The lowest energy pathway we identified for the [1,3]-shift involves hydrogen atom transfer via TS10 to the BHT hydroxy radical to generate a transient, but relatively stabilized, delocalized carbon radical (Scheme 10). TS12 has a barrier of 26.9 kcal/mol relative to 11. The barrier for hydrogen atom transfer back to the radical intermediate to complete the [1,3]shift via TS13 is 20.3 kcal/mol. Both of these hydrogen-atom transfer barriers are lower in energy than the Diels−Alder pathways. Other stepwise radical-based paths may also be operative in this case for the formal [1,3]-hydrogen shift involving more complex species that were not addressed at this time. While there remains less certainty on this final process, it is clear that the Diels−Alder step is higher in energy, being rate and selectivity determining.
Article
EXPERIMENTAL SECTION
General Experimental Methods. All reactions were performed in flame or oven-dried glassware under argon. Air and moisture-sensitive reagents were introduced via dry syringe. Solvents used in the reactions (THF, DCM, and toluene) were drawn from a pressurized dry solvent system. In this system, HPLC or similar grade solvent is flushed through activated alumina casks and stored under argon, thus keeping the solvent dry. Purification through flash chromatography was performed using 230 × 400 mesh silica gel. All 1H and 13C NMR were obtained with 500 and 125 MHz using deuterium chloroform (7.27 ppm 1H NMR, 77.4 ppm 13C NMR) as reference. Multimode source mass spectrometer (ESI) was used for all the mass spectral data. Methyl (E)-3-(Benzo[d][1,3]dioxol-5-yl) Acrylate 3. To a solution of 3,4- (methylenedioxy)cinnamic acid (5.0 g, 25.9 mmol) in methanol (0.4 M, 65 mL) was added carefully and slowly concentrated H2SO4 (3.1 mL). The mixture was heated at reflux (65 °C) overnight. The reaction mixture was cooled to room temperature, and the white precipitate was filtrated (product). Solid NaHCO3 (6.1 g) was slowly added to the solution. The solution was added to a funnel extraction containing methylene chloride and washed with water (3 × 50 mL) and brine. The organic layer was dried (MgSO4) and concentrated. The resulting solid was crystallized with ethyl acetate and hexane (5.27 g, 99%), generating 3 as a white solid. Characterization data: TLC Rf 0.6 (35% EtOAc/hexanes); mp = 132−136 °C; 1H NMR (CDCl3, 500 MHz) 3.78 (s, 3H), 5.99 (s, 2H), 6.26 (d, J = 15.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 7.59 (d, J = 15.8, 1H); 13C NMR (CDCl3, 125 MHz) 51.6, 101.6, 106.5, 108.5, 115.7, 124.5, 128.8, 144.6, 148.3, 149.6, 167.6; IR 1703, 1625 cm−1; HRMS (ESI-TOF) m/z: [M]+• Calcd for C11H10O4 206.0579; Found 206.0566. (E)-3-(Benzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol 4. To a stirred solution of methyl (E)-3-(benzo[d][1,3]dioxol-5-yl) acrylate 3 (1.3 g, 6.31 mmol) in dry methylene chloride (0.1 M, 63 mL) cooled to 0 °C (ice water bath) under argon gas was slowly added DIBAL (diisobutylaluminum hydride, 16 mL, 1.0 M in heptanes, 2.5 equiv) via syringe. The mixture was allowed to warm to room temperature for 2 h. To the mixture was slowly added methanol (7 mL) followed by aqueous HCl (1 M, 61 mL). The mixture was added to a separatory funnel containing water (10 mL). The aqueous layer was extracted with methylene chloride (2 × 30 mL), and the combined organic layers were dried (MgSO4). The dry organic layers were submitted to silica gel chromatography (50% EtOAc/hexanes) to obtain the desired alcohol 4 (73%, 800 mg) as a white solid. Characterization data: TLC Rf 0.4 (35% EtOAc/hexanes); mp = 75.8−78.1 °C; 1H NMR (CDCl3, 500 MHz) 4.29 (d, J = 4.1 Hz, 2H), 5.96 (s, 2H), 6.17−6.23 (obs m, 1H), 6.53 (d, J = 15.9, 1H), 6.76 (d, J = 7.9, 1H), 6.81 (d, J = 7.9, 1H), 6.93 (s, 1H); 13C NMR (CDCl3, 125 MHz) 63.8, 101.1, 105.7, 108.3, 121.2, 126.7, 131.0, 131.1, 147.3, 148.0; IR 3264, 2888, 1445 cm−1; HRMS (ESI-TOF) m/z: [M]+• Calcd for C10H10O3 178.0630; Found 178.0629. 5-(2,2-Dibromovinyl)-1,2,3-trimethoxybenzene 5. To a solution of triphenylphosphine (3 equiv, 45.8 mmol, 12.03 g) in dry methylene chloride (0.3 M, 153 mL) cooled to 0 °C under argon gas was added carbon tetrabromide (1.5 equiv, 22.94 mmol, 7.60 g) and stir at 0 °C for 15 min. To the solution was added 3,4,5-trimethoxybenzaldehyde (3.0 g, 15.29 mmol) in dry methylene chloride (2 M, 8 mL). The resulting mixture was stir at rt overnight. The mixture was triturated with cold hexanes (45 mL) and filter (paper cone) to remove excess triphenylphosphine. The filtrate was concentrated and subjected to silica gel chromatography (10% EtOAc/hexanes) to obtain dibromoolefin product 5 (82%, 4.39 g) as a yellow solid. Characterization data: TLC Rf 0.6 (35% EtOAc/hexanes); mp = 57−60 °C; 1H NMR (CDCl3, 500 MHz) 3.85 (s, 6H), 3.86 (s, 3H), 6.78 (s, 2H), 7.39 (s, 1H); 13C NMR (CDCl3, 125 MHz) 56.1, 56.2, 60.8, 60.9, 88.8, 105.7, 130.5, 136.6, 138.3, 153.0; IR 3004, 2835, 1577 cm−1; HRMS (ESITOF) m/z: [M]+• Calcd for C11H12Br2O3 349.9153; Found 349.9147. 3-(3,4,5-Trimethoxyphenyl)propiolic Acid 6. To a solution of 5(2,2-dibromovinyl)-1,2,3-trimethoxybenzene (3.30 g, 9.43 mmol) in dry THF (0.6 M, 16.00 mL) under argon gas cooled to −78 °C (dry
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CONCLUSIONS The total synthesis of dl-deoxypodophyllotoxin was achieved in a seven-step synthesis using a key intramolecular styryl Diels− Alder reaction. DFT calculations were used to analyze this unique reaction, finding two major reaction steps to the process.31 The first one is the intramolecular Diels−Alder reaction of an electron-rich ester with arene dearomatization. The concerted, asynchronous pathway is favored over the singlet diradical mechanism. The small energy difference between TS4 and TS5 is due to steric interactions and correlates with the mixture of isomers obtained experimentally. The second component of the process is a BHT assisted [1,3]formal hydrogen transfer that leads to rearomatization. With this work, we demonstrate a short, practical route to a versatile lignan natural product with potential to generate new approaches to anticancer lead development. This work also showcases the development of new synthetic and theoretical tools, providing a sound platform for future development of the key ISDA reaction and applications to related lignan targets. 2024
DOI: 10.1021/acs.joc.7b02957 J. Org. Chem. 2018, 83, 2018−2026
Article
The Journal of Organic Chemistry ice/acetone bath) was added a solution of n-butyllithium (2.5 M, 1.9 equiv, 17.92 mmol, 7.16 mL); the dark brown solution was stirred for 20 min at −78 °C, and solid carbon dioxide (crushed, 10 equiv, 120 mmol, 5.00 g excess) was added at once. The mixture was gradually allowed to warm to rt, stirring continuously. The mixture was poured into water in a separatory funnel and a 1:1 mixture of EtOAc/hexanes (50 mL) was added. The aqueous part was acidified (pH 2 approximately) with HCl (6.0 N) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried (MgSO4), and concentrated to access the desired propiolic acid 6 (88%, 1.95 g) as an orange solid. Characterization data: TLC Rf 0.10 (35% EtOAc/ hexanes); mp= 137−142 °C, 1H NMR (CDCl3, 500 MHz) 3.86 (s, 6H), 3.89 (s, 3H), 6.85 (s, 2H); 13C NMR (CDCl3, 125 MHz) 56.3, 56.3, 61.1, 61.1, 79.4, 89.4, 110.6, 113.7, 113.7, 153.2, 158.4; IR 3472, 2951, 2213, 1704 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H13O5 237.0762; Found 237.0741. (E)-3-(Benzo[d][1,3]dioxol-5-yl)allyl 3-(3,4,5-trimethoxyphenyl)propiolate 7. To a THF solution (0.2 M, 7 mL) of (E)-3(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-ol 4 (1 equiv 1.4 mmol, 0.25 g) and 3-(3,4,5-trimethoxyphenyl)propiolic acid 6 (1.2 equiv, 1.68 mmol, 0.4 g) was added diisopropyl azodicarboxylate (1.2 equiv, 1.68 mmol, 0.35 mL) at once. The solution was cooled to 0 °C, and solid triphenylphosphine (1.2 equiv, 1.68 mmol, 0.44 g) was added along with additional 2 mL of THF. The solution was then warmed to rt and stirred for 48 h. The solution was concentrated and subjected to silica gel chromatography (30% ethyl acetate/hexanes) to yield the desired ester as a white solid 7 (63%, 357 mg). Characterization data: TLC Rf 0.46 (35% EtOAc/hexanes); mp = 128.0−129.6 °C; 1H NMR (CDCl3, 500 MHz) 3.86 (s, 6H), 3.89 (s, 3H) 4.86 (d, J = 6.4 Hz, 2H), 6.14−6.20 (obs m, 1H), 6.64 (d, J = 15.9, 1H), 6.77 (d, J = 9.0, 1H), 6.85 (s, 2H), 6.86 (d, J = 1.1, 1H), 6.95 (s, 1H); 13C NMR (CDCl3, 125 MHz) 56.2, 61.0, 66.7, 87.0, 101.2, 105.9, 108.3, 110.4, 114.1, 120.1, 121.8, 130.4, 135.4, 143.1, 153.9; IR 2853, 2217, 1708, 1700 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H21O7 397.1287; Found ([M + H]) 397.1278. (dl)-5-(3,4,5-Trimethoxyphenyl)-8a,9-dihydrofuro[3′,4’:6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one (Major) 8. To a solution of (E)-3-(benzo[d][1,3]dioxol-5-yl)allyl 3-(3,4,5-trimethoxyphenyl)propiolate 7 (1 equiv, 0.1 g, 0.25 mmol) in benzonitrile (0.1 M, 2.5 mL) was added 2,6 di-t-butylhydroxytoluene (BHT, 1.5 equiv, 0,37 mmol, 0.08 g). The mixture was heated at reflux (160 °C) for 2 h. The mixture was cooled to rt, diluted with hexane (5 mL) and subjected to radial chromatography (25% EtOAc/hexanes) to yield two Diels− Alder products (overall 56%, 55.1 mg) the major product 8 as white solid (34.4% yield, 34.1 mg) and the minor product 9 as a green solid (21.2% yield, 21 mg). Characterization data for major Diels−Alder product 8: TLC Rf 0.12 (35% EtOAc/hexanes); mp = 240−242 °C; 1 H NMR (CDCl3, 500 MHz) 2.81 (obs t, J = 15.8 Hz, 1H), 2.95 (dd, J = 6.6, 8.3 Hz, 1H), 3.44−3.36 (m, 1H), 3.85 (s, 6H), 3.93 (s, 3H), 4.02 (obs t, J = 8.8 Hz, 1H), 4.71 (obs t, J = 8.8, 1H), 5.98 (s, 2H), 6.10 (s, 1H), 6.52 (s, 1H), 6.56 (s, 1H), 6.78 (s, 1H) 13C NMR (CDCl3, 125 MHz) 33.3, 35.8, 56.2, 61.0, 68.0, 70.9, 101.8, 103.6, 107.2, 108.6, 109.5, 119.1, 119.9, 129.6, 130.7, 146.8, 147.3, 148.7, 153.0; IR cm−1 2917, 1744; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H21O7 397.1287; Found 397.1288. Minor Diels−Alder product 9: TLC Rf 0.14 (35% EtOAc/hexanes); mp = 194−197 °C; 1H NMR (CDCl3, 500 MHz) 2.75 (obs t J = 15.0 Hz, 1H), 2.97 (dd, J = 6.0, 8.6, 1H) 3.34−3.41 (m, 1H), 3.84 (s, 6H), 3.92 (s, 3H), 4.02 (obs t, J = 8.7, 1H), 4.69 (obs t, J = 8.9, 1H), 5.63 (s, 1H), 5.72 (s,1H), 6.62 (s, 2H), 6.75 (s, 1H), 6.76 (s, 1H); 13C NMR (CDCl3, 125 MHz) 33.5, 36.6, 56.2, 61.0, 70.6, 101.1, 109.1, 118.5, 120.4, 123.0, 129.0, 129.6, 144.4, 146.9, 147.8, 152.4, 167.9; IR cm−1 1747; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H21O7 397.1287; Found 397.1199. Deoxypodophyllotoxin (DPT) (5S,5aS,8aR)-5-(3,4,5-Trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3′,4’:6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one. To a solution of (R)-5-(3,4,5-trimethoxyphenyl)8a,9-dihydrofuro[3′,4’:6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one 8 (1 equiv, 0.02g, 0.038 mmol) in 1:1 MeOH (0.1M, 0.42 mL) and THF (0.1 M, 0.42 mL) at −15 °C (ethylene glycol-dry ice bath) was added freshly crushed Mg (30 equiv, 1.13 mmol, 0.03 g) and ammonium
chloride (2 equiv, 0.07 mmol, 0.004 g). The mixture was gradually allowed to warm to rt, stirring vigorously for 3 h. Saturated solution of NH4Cl (7 mL) was added at −15 °C and allowed to warm to rt. The mixture was placed in a funnel extraction and washed with dichloromethane and water (3 × 20 mL). The combined organic phases were dried in MgSO4, concentrated, and crystallized in hot methanol, obtaining white small precipitate of final product DPT (51.2% yield 7.7 mg). Characterization data: TLC Rf 0.10 (35% EtOAc/hexanes); mp = 199.0−200.5 °C; 1H NMR (CDCl3, 500 MHz) 2.52 (dd, J = 9.9, 5.4 Hz, 1H), 2.88 (dd, J= 9.1, 6.2 Hz, 1H), 3.0−3.09 (obs m, 1H), 3.35 (dd, J = 2.4, 7.1 Hz, 1H), 3.79 (s, 6H), 3.84 (s, 3H), 3.99 (dd, J = 2.6, 6.6 Hz 1H), 4.38 (d, J = 2.1 Hz, 1H), 4.46 (obs t, J = 8.3, 1H), 5.93 (s, 1H), 5.96 (s, 1H), 6.34 (s, 2H), 6.59 (s, 1H), 6.68 (s, 1H); 13C NMR (CDCl3, 125 MHz) 32.0, 33.0, 45.3, 46.4, 56.2, 60.4, 60.9, 72.7, 101.0, 104.9, 108.8, 109.9, 128.3, 130.4, 138.2, 146.8, 146.9, 153.4, 178.4; IR 1757 cm−1; HRMS (ESI-TOF) m/z: [M + NH4]+ Calcd for C22H26NO7 416.1709; Found 416.1705. To further prove the stereochemistry of hydrogens 4 and 5, 1D NOESY experiments were performed. When H2 was irradiated, increments on H3, H4, and H1 were enhanced. On the other hand when H4 was also irradiated, increments on H5, H2, and H3 were enhanced. The fact that enhancement on H5 occurs only when H4 is irradiated demonstrates the cis-configuration of the final product.31
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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.joc.7b02957. NMR, X-ray characterization, and computational assessments of all the pathways presented (PDF) (CIF) (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Daniel H. Ess: 0000-0001-5689-9762 Merritt B. Andrus: 0000-0002-7307-4313 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support was provided by the Simmons Cancer Center at Brigham Young University as a fellowship to D.I.S. REFERENCES
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