A concise one-step synthesis of primin and iso-primin

A concise one-step synthesis of primin and iso-primin
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  Accepted Manuscript A concise one-step synthesis of primin and iso-priminHamid R. Nasiri, Jan Ferner, Caner Tükek, Robin Krishnathas, Harald SchwalbePII:S0040-4039(15)00519-5DOI: 46076To appear in: Tetrahedron Letters Received Date:15 January 2015Revised Date:6 March 2015Accepted Date:17 March 2015Please cite this article as: Nasiri, H.R., Ferner, J., Tükek, C., Krishnathas, R., Schwalbe, H., A concise one-stepsynthesis of primin and iso-primin, Tetrahedron Letters  (2015), doi: is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customerswe are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, andreview of the resulting proof before it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.    Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. A concise one-step synthesis of primin and iso-primin Nasiri, H.R.; Ferner, J.; Tükek, C.; Krishnathas, R. and Schwalbe, H. Leave this area blank for abstract info.    1   Tetrahedron Letters    journal homepage:   A concise one-step synthesis of primin and iso-primin Hamid R. Nasiri a ∗ , Jan Ferner a , Caner Tükek  a , Robin Krishnathas a  and Harald Schwalbe a ∗   a  Institute of Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance, Johann Wolfgang Goethe-University Frankfurt, Max-von- Laue-Straße 7, D-60438 Frankfurt am Main, Germany ——— ∗  Corresponding author. e-mail: ∗  Corresponding author. e-mail: Primin is a natural product found in several plants including Primula obconica 1 ,  Miconia spp . 2  and  Miconia lepidota 3  collected from northern South America. It was first isolated in 1927 4  and 40 years later its constitution was determined as 2-methoxy-6-pentyl-1,4-benzoquinone ( Figure 1 ). 5  Primin ( 1 ) is the substance that causes allergenic reaction after contact with Primula obconica . As a sensitizer it causes allergic contact dermatitis, also known as primrose dermatitis. 4, 5  Primin reveals significant antibacterial and antitumor activity with low toxicity to mammalian cells. The cytotoxic activity of primin has been evaluated by testing against cancer cells (murine lung cancer M109 with an IC 50  of 10 µg/mL and A2780 human ovarian cancer cell line with an IC 50  of 2.9 µg/mL). 3  Additionally, it displays antibacterial activity against Staphylococcus aureu s and more importantly against methicillin-resistant Staphylococcus aureus (MRSA) with an IC 50  of 8 µg/mL. 6  In Brazil, after a successful clinical trial, it was even launched onto the market for the treatment of basal cell carcinoma with promising results. In light of the interesting biological properties of primin and potential therapeutical applications, an easy access to primin and primin derivatives by synthetic chemistry is needed. In several publications, multi-step syntheses of primin ( 1 ) have been reported. 7-10  Watanabe et al. synthesized primin in six steps, including an alkyl Suzuki-Miyaura cross-coupling reaction and a final oxidation step. 10  A three step synthesis was reported by Gunatilaka. Their synthesis, however, suffered from long reaction times (2-5 days). 3, 9  Jacobs et al. utilized a combined Mitsunobu reaction with Claisen rearrangement and final oxidation in four reaction steps to obtain primin. 8  (placeholder Figure 1 ) The synthesis of primin by Bhattacharya et al. comprises nine synthetic steps, including a Grignard reaction and Johnson-Claisen rearrangement as the key steps. 11  Interestingly, they have also synthesized primin acid, a water-soluble analogue of the natural product. Herein, we report the efficient single-step synthesis of primin and its regioisomer based on a free-radical alkylation under silver catalysis. In comparison to previous reports, our approach does not require multistep procedures, long reaction times or harsh reaction conditions. The synthesis starts with the single step radical alkylation of the commercially available starting material 2-methoxy-benzoquinone 2  ( Scheme 1 ). The alkylation is promoted by silver nitrate as a catalyst in the presence of persulfate in an acetonitrile/water mixture. (placeholder Scheme 1 ) ARTICLE   INFO ABSTRACT  Article history: Received Received in revised form Accepted Available online   A short, efficient one-step synthesis of primin and its isomer is devised. The synthesis is basedon the introduction of an alkyl side chain via radical alkylation of 2-methoxy-benzoquinone. The required alkyl radical was either generated from the corresponding alkyl acid or alkyl boronic acid in the presence of persulfate under silver catalysis. The alkylation of 2-methoxy-benzoquinone occurs at the C-6 and C-5 position, generating the desired primin and iso-primin. The formation of the natural product primin was confirmed by NMR spectroscopy determining carbon-carbon constitution at 13 C natural abundance in an 1,1-ADEQUATE experiment. 2009 Elsevier Ltd. All rights reserved .   Keywords: Primin Quinones 1,1-ADEQUATE Radical allylation C-H functionalization of quinones    Tetrahedron 2 We (and others) have successfully applied this strategy for the synthesis of a wide range of different quinones of biological importance. 12-15  In this report, we evaluate the scope of these reactions by changing the precursor, co-oxidant and temperature to identify optimal reaction conditions for the synthesis of primin. When quinone 2  was treated with 1.5 equiv. of hexanoic acid under standard conditions 12 , no product was formed (see Table 1, entry 1). Upon increasing the amount of acid to 2 equiv., primin and its C5-isomer, were formed in 8% and 12% yield, respectively (entry 2). As shown in Table 1, the best yield was obtained by utilizing potassium persulfate as co-oxidant (entry 3). Next, we applied the C-H direct functionalization of 2-methoxy-benzoquinone 2  with n-pentylboronic acid catalyzed by silver-(I) nitrate in the presence of potassium persulfate as co-oxidant (entry 4). This method was first described by P. Baran as a scalable reaction, which proceeds at ambient temperature, in an open flask. 12  Using this procedure both isomers were obtained in a yield of 50%. The common mechanism of both reactions is 1) generation of the radical, 2) nucleophilic radical Michael addition to the quinone with an in situ  re-oxidation step. To determine the exact constitution of the products and to distinguish between primin 1  and iso-primin 3 , 2D NMR experiments were conducted. Since the n J(CH)-couplings in conjugated systems are hard to predict, a 2D 1 H, 13 C-HMBC did not permit an unambiguous assignment of the two regioisomers. Therefore, a 2D 1,1-ADEQUATE experiment, the proton-detected and therefore more sensitive analog of an INADEQUATE experiment, at carbon natural abundance was performed with the putative primin sample to correlate the quinone protons H3 and H5 with the carbonylic C4. 13  The experiment provided correlations between the proton frequencies of H3/H5 and frequencies of the sum of chemical shifts from C3/C5 and C4 (Figure 2) and yielded the unambiguous assignment of the reaction products to primin and iso-primin, respectively. (placeholder Figure 2 ) In summary, we have applied radical alkylation reactions to the synthesis of primin and its isomer. Both molecules were prepared in good yield in a single reaction step. Experimental section CAUTION: Primin ( 1 ) and its analogues are strong sensitizers. The contact with skin should be avoided. 1D and 2D NMR experiments of a 0.05 mM primin ( 1 ) sample in CDCl 3  were performed on a Bruker 600 MHz spectrometer equipped with a cryogenic probehead at 293 K. The 1,1-ADEQUATE experiment was setup with delays derived from coupling constants of 1 J(CH) = 168 Hz and 1 J(CC) = 80 Hz and with 128 complex points and 512 transients. Decarboxylation reaction: to a solution of quinone 2  (0.5 g, 3.6 mmol), 1.5 equiv. of hexanoic acid (5.4 mmol) and substoichiometric amounts of silver-(I) nitrate (0.06 g, 0.36 mmol) in 9 mL of an acetonitrile/water mixture (ratio 1 : 2) 2 mL of an aqueous solution of the corresponding persulfate (0.83 g, 3.6 mmol) were slowly added. After 1 h of heating the acid amount in the reaction mixture was increased by 0.5 equiv. and a second portion of persulfate (0.83 g, 3.62 mmol) in 2 mL of water was slowly added. After further 1 h of heating at 80°C, the reaction mixture was diluted with dichloromethane and washed with 5% sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated in vacuo. Both products ( 1  and 3 ) were separated by column chromatography (n-hexane : ethylacetate 4:1). Radical alkylation via boronic acid: to a mixture of quinone 2  (0.5 g, 3.6 mmol), 1.5 equiv. of the corresponding boronic acid (5.4 mmol), and substoichiometric amounts of silver-(I) nitrate (0.12 g, 0.72 mmol) in 18 mL of dichlormethane and 11 mL of water a solution of potassium persulfate (3 g, 10.8 mmol) in 58 mL of water was added. The solution was stirred vigorously at room temperature. After 3 h the reaction was diluted with dichloromethane and washed with 5% sodium bicarbonate. The layers were separated, and the aqueous layer was extracted with dichloromethane (3 x 10 mL), dried over sodium sulfate and evaporated in vacuo. The yield and the ratio of the isomeric mixture are listed in Table 1. Primin ( 1 ) and iso-primin ( 3 ) were subsequently seperated by column chromatography (n-hexane : ethylacetate 4:1). Table 1 . Reaction conditions, optimization and product distribution of the radical alkylation of 2-Methoxy-benzoquinone 2. Entry Alkyl precursor Co-oxidant (2 equiv.) *  Solvent Temperature/Time (°C / hr) AgNO 3  (equiv.) Yield (%) Ratio of isomers 1:3 1 Hexanoic acid (1.5 equiv.) (NH 4 ) 2 S 2 O 8  MeCN/H 2 O 80° / 3 0.1 - - 2 Hexanoic acid (2 equiv.) (NH4) 2 S 2 O 8  MeCN/H 2 O 80° / 3 0.1 20 1 : 1.6 3 Hexanoic acid (2 equiv.) K 2 S 2 O 8  MeCN/H 2 O 80° / 3 0.1 31 1 : 1.8 4 n-Pentylboronic acid (1 equiv.) K 2 S 2 O 8  DCM/H 2 O rt / 4 0.2 50 1 : 3 * added in two portions. MeCN = acetonitrile. DCM= dichloromethane. rt = room temperature Data for primin ( 1 ), yellow oil; IR (ATR):    [cm -1 ] = 3074, 2920, 2852, 1676, 1649, 1599, 1444, 1425, 1320, 1236, 1176, 1061, 899; 1 H-NMR: (600 MHz, CDCl 3 ): δ  [ppm] = 6.41 (dt, J = 2.3 Hz, 1.3 Hz, 1 H, H5), 5.80 (d, J = 2.3 Hz, 1 H, H3), 3.74 (s, 3    3 H, MeO), 2.36 (dt, J = 7,5 Hz, 1.3 Hz, 2 H, H1´), 1.43 (qn., J = 7,3 Hz, 2 H, H2´), 1.24-1.27 (m, 4 H, H3´and H4´), 0.82 (t, J = 6,7 Hz, 3 H, H5’). 13 C-NMR: (150 MHz, CDCl3): δ  [ppm] = 187.7 (C4), 182.1 (C1), 158.8 (C2), 147.5 (C6), 132.8 (C5), 107.0 (C3), 56.2 (MeO), 31.3 (C3’), 28.6 (C1’), 27.3 (C2’), 22.3 (C4’), 13.9 (C5’). Analytical data are in agreement with published data. 3  1D NMR experiments of a 0.05 mM iso-primin ( 3 ) sample in CDCl 3  were performed on a Bruker 500 MHz spectrometer equipped with a prodigy probehead at 293 K. Data for iso-primin ( 3 ), yellow crystals; IR (ATR):    [cm -1 ] = 3057, 2953, 1666, 1647, 1606, 1469, 1421, 1230, 1182, 912; Anal. calcd. for C 12 H 16 O 3 : C 69.21, H 7.74; found C 69.11, H 7.87; Melting point = 118°C; 1 H-NMR: (500 MHz,CDCl3): δ  [ppm] = 6.43 (t, J = 1.4 Hz, 1 H, H6), 5.85 (s, 1 H, H3), 3.74 (s, 3 H, MeO), 2.36 (dt, J = 7,7 Hz, 1.4 Hz, 2 H, H1´), 1.44 (quint, J = 7,7 Hz, 2 H, H2´), 1.24-1.27 (m, 4 H, H3´and H4´), 0.83 (t, J = 7,0 Hz, 3 H, H5’). 13 C-NMR: (125 MHz, CDCl3): δ  [ppm] = 187.5 (C4), 182.4 (C1), 158.5 (C2), 150.7 (C5), 130.4 (C6), 107.7 (C3), 56.2 (MeO), 31.5 (C3’), 28.9 (C1’), 27.6 (C2’), 22.4 (C4’), 13.9 (C5’). References 1. Nestler, A.,  Hautreizende Primeln Untersuchungen ueber  Entstehung, Eigenschaften und Wirkungen des Primelhautgiftes . Borntraeger: Berlin, 1904; p 1-46. 2. Marini-Bettolo, G. B.; Delle Monache, F.; Goncalvez da Lima, O.; De Barro Coelho, S., Miconidin, a new hydroquinone from thé wood of Miconia sp. (Melastomataceae). Gazz. Chim. Ital. 1971,   101 , 41-46. 3. Gunatilaka, A. A. L.; Berger, J. M.; Evans, R.; Miller, J. S.; Wisse, J. H.; Neddermann, K. M.; Bursuker, I.; Kingston, D. G. I., Isolation, synthesis, and structure-activity relationships of bioactive benzoquinones from Miconia lepidota from the Suriname rainforest.  J. Nat. Prod. 2001,   64 , 2-5. 4. Bloch, B.; Karrer, P., Vierteljahresschr. Naturforsch. Ges.  Zuerich 1927,   72 , 1-10. 5. Schildknecht, H.; Bayer, I.; Schmidt, H., Ueber Pflanzenabwehrstoffe .4. Struktur Des Primelgiftstoffes.  Z  Naturforsch B 1967,   22 , 36-41. 6. Tasdemir, D.; Brun, R.; Yardley, V.; Franzblau, S. G.; Ruedi, P., Antituberculotic and antiprotozoal activities of primin, a natural benzoquinone: In vitro and in vivo studies. Chem Biodivers 2006,   3 , 1230-1237. 7. Bieber, L. W.; Chiappeta, A. D.; Souza, M. A. D. E.; Generino, R. M.; Neto, P. R., Simple Synthesis of Primin and Its Analogs Via Lithiation of Protected Guaiacol.  J. Nat. Prod. 1990,   53 , 706-709. 8. Jacob, A. M.; Moody, C. J., Microwave-assisted combined Mitsunobu reaction - Claisen rearrangement and microwave-assisted phenol oxidation: rapid synthesis of 2,6-disubstituted-1,4-benzoquinone natural products. Tetrahedron Lett. 2005,   46  , 8823-8825. 9. Konig, W. A.; Faasch, H.; Heitsch, H.; Colberg, C.; Hausen, B. M., Synthesis of Side-Chain-Modified Analogs of the Allergen Primin.  Z Naturforsch B 1993,   48  , 387-393. 10. Watanabe, K.; Sugizaki, T.; Tozawa, Y.; Katoh, T., A New Entry to the Synthesis of Primin Via a B-Alkyl Suzuki-Miyaura Cross-Coupling Reaction.  Heterocycles 2012,   86  , 985-989. 11. Bhattacharya, A. K.; Kaur, T.; Ganesh, K. N., Synthesis of the Antibacterial Benzoquinone Primin and its Water-Soluble Analogue, Primin Acid. Synthesis-Stuttgart 2010 , 1141-1144. 12. Fujiwara, Y.; Domingo, V.; Seiple, I. B.; Gianatassio, R.; Del Bel, M.; Baran, P. S., Practical C-H Functionalization of Quinones with Boronic Acids.  J. Am. Chem. Soc. 2011,   133 , 3292-3295. 13. Reif, B.; Kock, M.; Kerssebaum, R.; Kang, H.; Fenical, W.; Griesinger, C., ADEQUATE, a new set of experiments to determine the constitution of small molecules at natural abundance.  J. Magn. Reson., Ser. A 1996,   118  , 282-285.
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