Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Flow Photochemistry as a Tool for the Total Synthesis of (+)-Epigalcatin Kamil Lisiecki and Zbigniew Czarnocki* Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland S Supporting Information *
ABSTRACT: The first total synthesis of (+)-epigalcatin was completed in a highly stereoselective manner starting from piperonal, 3,4-dimethylbenzaldehyde, and diethyl succinate. L-Prolinol was used as a chiral auxiliary. The crucial step in this procedure involves the construction of the cyclolignan framework by continuous-flow photocyclization of a chiral atropisomeric 1,2-bisbenzylidenesuccinate amide ester.
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Flow chemistry has many applications in organic synthesis, material science, and water treatment.15 It is successfully used in the synthesis of natural and pharmaceutical products mainly due to the fact that it is readily scalable and can be also easily combined to other enabling technologies.16,17 The synthesis starts from the construction of the carbon skeleton by means of Stobbe condensation. The known diester 5,13 easily available from piperonal and diethyl succinate, was condensed with 3,4-dimethoxybenzaldehyde to afford E,Ebisbenzylidenesuccinic acid monomethyl ester 6 in 79% yield. Introduction of the chiral auxiliary was the next step of the synthesis. The one-pot protocol starting with acid chloride preparation and its transformation into amide led to the amide−ester 7 with 91% yield. The subsequent hydrolysis of methyl ester using K2CO3 in methanol/water gave the corresponding acid 8 in nearly quantitative yield. Construction of the 8-membered ring was achieved via macrolactonization with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), which afforded product 9 with 65% yield (Scheme 1). Having product 9 in hand, we started to test the conditions for photocyclization. The batch experiments were carried out in a quartz cuvette. Methanolic solution of 9, with additive of TFA (0.01 mM),18 was irradiated for 1 h using a medium-pressure mercury lamp (λmax ≈ 365 nm, Figure S1) and followed by opening of 8-membered ring by methanolysis as previously reported.13 Under those conditions, however, the desired product 11 was obtained in only 21% yield, even after prolonged irradiation, which also caused the decomposition of the product. We therefore decided to use a simple homemade apparatus for continuous flow irradiation (Figure S2).13 A
ryltetralin cyclolignans are a family of important products that exhibit various biological properties, e.g., antiviral, antibacterial, and antineoplastic.1 Etoposide and teniposide (semisynthetic derivatives of podophyllotoxin (PPT)) are currently in clinical use.2 However, their therapeutic potential is limited because of low water solubility, low selectivity,3 and drug resistance.4 Thus, research on the isolation, synthesis, and structure−activity relationships (SARs) of cyclolignan analogues has received considerable attention, including derivatives of PPT,5−7 as well as other lignans, e.g., otobain.8 (−)-Galcatin (1) was isolated for the first time from Hirnantandra baccata in 1954,9 and its enantiomer (2) was synthesized in 1981 by Liu.10 It is worth noting that both of them have the trans configuration at C-1 and C-2 (1R,2S) and (1S,2R), respectively. Although the cis configuration (1S,2S) would have been more desirable, as it occurs in the most active cyclolignans,11 only one diastereomer (3) is known.12 We report the total synthesis of (+)-epigalcatin (4) (Figure 1) by taking advantage of the methodology developed by us in 2016.13 It involves the use of L-prolinol as a chiral auxiliary and photocyclization of a chiral atropisomeric 1,2-bisbenzylidenesuccinate amide ester. In order to ensure high yield and productivity14 the photocyclization process was carried out in continuous-flow conditions.
Figure 1. Chemical structures of galcatin and its enantiomer and diastereomers. © XXXX American Chemical Society
Received: December 21, 2017
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DOI: 10.1021/acs.orglett.7b03974 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Synthesis of Cyclic Amide Ester 9
interaction between those protons was observed, indicating that the relative configuration at C-2 and C-3 must be cis so the absolute configuration at C-3 must be S. Induction of asymmetry during the hydrogenation of 1aryldihydronaphthalene lignans was reported by Datta et al.,18 Reddel et al.,20 and Assoumatine et al.21 According to the results from previous work and this study, it can be concluded that the phenyl group at C-1 influences the configuration at C-3 in a way that product is formed as a 1,3-cis compound. Conversion of the ester group to methyl group was the last task for the completion of the total synthesis. According to Charlton’s protocol,18 13 was reduced with LiAlH4 to furnish the corresponding alcohol 14 in 97% yield. The transformation of the hydroxymethyl moiety into methyl group was accomplished in a one-pot procedure as follows. The hydroxyl group was converted to the triflate with triflic anhydride and then reduced with LiAlH4 to give (+)-epigalcatin (4) in 54% yield and in >98% ee (based on chiral HPLC) (Scheme 3).
solution of 9 in MeOH containing 0.01 mM of TFA was pumped through the reactor with flow rate 0.7 mL/min, irradiated with UV light, and transesterified during direct acidic workup. These conditions allowed us to obtain compound 11 with an isolated yield of 65% (Scheme 2).
Scheme 3. Completion of Total Synthesis of (+)-Epigalcatin (4)
Scheme 2. Synthesis of 11 in Direct Acidic Work-up Procedure
In conclusion, we have completed the highly stereoselective short total synthesis of (+)-epigalcatin (4) from piperonal in 11 steps with 5% overall yield using L-prolinol as the source of chirality. The crucial step of the synthesis, a photocyclization, was performed in continuous flow, which showed clear advantages over batch photochemical synthesis. Our results, along with previous studies, proved that the phenyl group at C1 influenced the configuration at C-3 during hydrogenation of the double bond in 1-aryldihydronaphthalene lignans. The main advantage of this approach, in comparison to the synthesis of (+)-galcatin,10 is that our synthesis starts from commercially available, cheap starting materials, while (+)-galcatin synthesis starts from the rather expensive natural compound chicanine. Since (+)-epigalcatin has not yet been synthesized or found in natural sources, it can be assumed that our synthetic strategy will allow access to cyclolignan analogues that are inaccessible from natural plant sources.
Removal of the chiral auxiliary was achieved by using the Schwartz reagent (Cp2Zr(H)Cl)19 with 65% yield. To determine the configuration of 12 at C-1 and C-2, we performed 2D NMR experiments (HSQC, HMBC, and ROESY). From the HSQC and HMBC spectra it was concluded that the proton at C-1 appeared as a doublet at 4.43 ppm, whereas the proton at C-2 appeared as a doublet at 3.97 ppm. The low value of the coupling constant (3JH,H = 8.5 Hz) and an interaction between those protons in the ROESY spectrum indicates that the relative configuration at C-1 and C2 must be cis, which is consistent with previous reports.13 Moreover, the absolute configuration (1R,2R) was confirmed by the same sign and almost the same value of optical rotation as in podophyllic aldehyde (+156.0 and +156.5, respectively).13 Hydrogenation of the double bond with simultaneous reduction of formyl group was performed in the presence of 10% Pd/C in ethanol to provide derivative 13 with 76% yield. Interestingly, the formyl group was reduced directly to the methyl group, and the reduction of double bond was highly stereoselectiveonly one diastereoisomer was isolated. The configuration of 13 at C-3 was also determined on the basis of 2D NMR experiments. From the HSQC and HMBC spectra it can be concluded that the proton at C-2 appeared as a doublet of doublets at 3.04 ppm, whereas the proton at C-3 appeared as a multiplet at ∼2.28 ppm. In the ROESY spectrum an
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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.7b03974. Descriptions of experimental procedures for compounds and analytical characterization (PDF) B
DOI: 10.1021/acs.orglett.7b03974 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zbigniew Czarnocki: 0000-0002-6581-9282 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Science Centre in the form of Grant No. NCN-2012/07/B/ST5/02476 is acknowledged. The work was also supported by Grant No. 501-D112-860115100.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03974 Org. Lett. XXXX, XXX, XXX−XXX
