Note pubs.acs.org/jnp
Photochemical Synthesis of Nepetanudone Swapna Jayan and Paul B. Jones* Department of Chemistry, Wake Forest University, Winston-Salem, North Carolina 27109, United States S Supporting Information *
ABSTRACT: Nepetanudone and nepetaparnone have been suspected of being the products of a photochemical dimerization of nepetapyrone. Both are natural products found in a variety of Nepeta species. The synthesis of (±)-nepetapyrone and subsequent photochemical experiments are described. (±)-Nepetanudone was produced upon irradiation of (±)-nepetapyrone, while (±)-nepetaparnone, a diastereomer of nepetanudone, was not observed.
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RESULTS AND DISCUSSION (±)-Nepetalactone (4) was prepared from (±)-citronellol by the methods of Schreiber and Hofferberth.7 We expected to prepare (±)-nepetapyrone (3) by oxidation of 4. However, a variety of methods (Table 1) for dehydrogenation of 4,
epetanudone (1) and nepetaparnone (2) are isomeric cyclooctanes isolated from extracts of the aerial parts of Nepeta parnassica Heldr. and Sart., a perennial herb found in Greece and southern Albania, and from Nepeta tuberosa L. (catmint).1−3 Both compounds have been suspected of being derived from a photochemical dimerization of another natural product found in Nepeta, namely, nepetapyrone (3).1,3 Nepetapyrone is thought to form via oxidation of nepetalactone (4),4 one of the principal components in catnip. Oils derived from Nepeta species exhibit a number of biological properties including anti-inflammatory and antimicrobial effects.2,4,5 The diastereomers nepetanudone and nepetaparnone both exhibit insecticidal activity, suggesting a possible role in chemical defense of the plants in which they are biosynthesized.3
Scheme 1. Dehydrogenation of (±)-4
Table 1. Dehydrogenation of 4 method
results
DDQa IBX/(DMSO)b NBS/(BzO)2/Et3Nc NBS/sunlamp/DIPEAc 1. Br2/CCl4 2. DIPEAd 1. Br2/CCl4 2. THF/H2O 3. P2O5/MeSO3He
starting material, trace of 3 inseparable mixture/polymer low yields of 3, many byproducts multiple products, including 3 product 3 isolated in 20% yield, major product was aldehyde 10
a
Ref 9. bRef 8. cRef 10. dRef 11. eRef 13.
including 2-iodoxybenzoic acid (IBX),8 2,3-dichloro-5,6-dicyano1,4-benzoquinone (DDQ),9 and N-bromosuccinimde (NBS),10 either failed or were very low yielding and gave multiple products. The most successful dehydrogenation method attempted was treatment of 4 with bromine, followed by exposure to N,Ndiisopropylethylamine (DIPEA).11 Using this method, 3 was obtained in approximately 20% yield with the major product being aldehyde 10.12 A preliminary experiment suggested that aldehyde 10 could be converted to 3 by exposure to acid. Thus, we chose to pursue nepetapyrone 3 via aldehyde 10.
The cyclooctane core in 1 and 2 is suggestive of a [4π + 4π] photochemical dimerization of a pyrone.6 Such a biosynthetic step has been proposed,1 and the necessary pyrone (3) is known and can be plausibly derived by oxidation of nepetalactone (4). Nepetalactone is also a known metabolite of several Nepeta plants.1,3,4 Thus, either 1 or 2 might arise from [4π + 4π] cycloaddition of two nepetapyrones (3). We undertook this project to test the hypothesis that 1 and 2 can be obtained by photodimerization of 3. As part of the project, a synthesis for 3 was developed as well. © XXXX American Chemical Society and American Society of Pharmacognosy
nepetapyrone 3 obtained in 60% yield (over 3 steps)
Received: October 22, 2014
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DOI: 10.1021/np500832h J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products
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Scheme 2. Synthesis of Aldehydes (±)-10 and (±)-12
Scheme 4. Photochemical Conversion of (±)-Nepetapyrone (3) to (±)-Nepetanudone (1)
Table 2. Irradiation of (±)-3 to Give (±)-Nepetanudone 1 solvent
11
Exposure of (±)-4 to bromine and subsequent treatment of the crude adduct with a slightly alkaline mixture of THF and water gave aldehyde (±)-10 in 85% yield (Scheme 2). Pyrone 3 was not observed under these conditions. Alternatively, treatment of (±)-4 with m-CPBA, followed by exposure of the resulting epoxide (11) to NaOMe, gave the diastereomeric aldehyde 12 in 34% (overall, two steps) yield.13 As an added benefit, both aldehydes (±)-10 and (±)-12 were stable for weeks if kept dry at −20 °C. Thus, we could accumulate grams of (±)-10 and (±)-12 prior to conversion to pyrone (±)-3. Both diastereomeric aldehydes (±)-10 and (±)-12 could be converted in good yield to pyrone (3) by exposure to P2O5 in methanesulfonic acid (Eaton’s reagent).14 Thus, conversion of lactone ((±)-4) to either aldehyde (±)-10 or (±)-12 proved a convenient route to significant quantities of (±)-3. Given the observed instability of (±)-3, it was always prepared fresh for each photochemical experiment.
nonea benzene (10 M) nonea benzene (10 M) hexanes (10 M) Et2O (10 M)
T λ (°C) (nm) t (h) 35 35 35 20 20 20
result
Yield 1 (%)
360 40 no reaction 360 40 no reaction 300 96 significant decomposition 12 300 96 significant decomposition 8 300 192 51% conversion, 3 recovered 36 (71)b 300 96 40% conversion, 3 recovered 20 (50)b
A thin film of solid 3 was irradiated. bParenthetical yield based on recovered 3.
a
Thus, (±)-nepetapyrone (3) and (±)-nepetanudone (1) were synthesized for the first time. Irradiation of 3 gave nepetanudone (1), a natural product found in several species of Nepeta.1−3 Photochemical experiments confirmed that 1 is a plausible photochemically derived natural product. However, a known diastereomer of 1, nepetaparnone (2), found in Nepeta parnassica alongside 1, was not observed when 3 was irradiated. The failure of nepetapyrone (3) to produce nepetaparnone (2) under irradiation suggests that 2 either requires an alternate biosynthetic pathway or is derived from additional chemistry involving 1.
Scheme 3. Conversion of Aldehydes (±)-10 and (±)-12 to (±)-Nepetapyrone 3
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EXPERIMENTAL SECTION
General Experimental Procedures. All reagents and solvents were purchased from commercial sources or prepared as described. IR spectra were obtained using a Mattson Genesis II FTIR spectrometer. 1 H and 13C NMR spectra were recorded on a Bruker Avance 300 MHz spectrometer. HRMS analysis was performed at Old Dominion University, Norfolk, VA. The samples were dissolved in 1:1:1 THF/ MeOH/MeCN with NaCl and were analyzed by positive ion electrospray on a Bruker 12T Apex-Qe FTICR-MS with an Apollo II ion source. Thin-layer chromatography (TLC) was performed on silica gel doped with fluorescein. Photochemical reactions were conducted in a Rayonet reactor. Synthesis. (±)-Aldehyde (10). A solution of bromine (4.40 g, 25 mmol) in CCl4 (7 mL) was added to a solution of 4 (0.42 g, 2.5 mmol) in CCl4 (1.3 mL) cooled to 0 °C by immersion in an ice−water bath over a period of 30 min. After stirring at ambient temperature for 1 h, the resulting mixture was washed with 10% aqueous sodium thiosulfate solution and the organic layer dried over anhydrous MgSO4 and concentrated in vacuo. The residue was dissolved in 1:1 THF/H2O (10 mL) and stirred overnight at ambient temperature. The reaction mixture was diluted with brine and extracted with ether (3 × 50 mL). The organic layer was dried over anhydrous MgSO4, and the solvent evaporated to yield aldehyde 10 as a light yellow oil. The aldehyde was purified by chromatography over SiO2 using 10:1 EtOAc/hexanes as eluent. 1H NMR (CDCl3, 300 MHz, ppm) 9.36 (1H, s), 2.92 (2H, m) 2.34 (1H, m) 1.96 (2H, m), 1.78 (3H, s), 1.54 (2H, m), 1.05 (3H, d, J = 6.5 Hz); 13C NMR (CDCl3, 75 MHz, ppm) 192.2, 181.0, 74.5, 51.4, 48.5, 38.3, 33.8, 28.9, 23.0, 16.0; HRMS [C10H14O3+Na]+ calcd 205.0841, found 205.0837. (±)-Nepetapyrone (3). Aldehyde 10 (0.25 g, 1.4 mmol) was added to a mixture of CH3SO3H (1.0 g, 10.4 mmol) and P2O5 (0.04 g,
(±)-Nepetapyrone (3) was then irradiated under a variety of conditions. Table 2 summarizes the results. Irradiation at wavelengths longer than 350 nm failed to produce product under any condition, with the only result being decomposition at prolonged (>days) irradiation times. When 300 nm lamps were used, significant conversion was obtained and the formation of (±)-nepetanudone (1) was observed. However, the reaction was slow and increasing irradiation time also increased decomposition. The best result was obtained when a 10 M solution of (±)-3 in hexanes was irradiated at 300 nm for 4 days with continuous cooling in a water bath. Under these conditions, conversion was 51% and the yield of (±)-1 was 36% (71% yield based on recovered starting material). In contrast to (±)-nepetanudone (1), which was observed when (±)-3 was irradiated at 300 nm, (±)-nepetanudone (2) was never observed in any of the photochemical experiments. Therefore, we concluded that 1 is a plausible photochemically derived product of 3, but that 2 is either produced by another biosynthetic reaction, is derived by epimerization after formation of 1, or decomposed under our reaction conditions. Attempts to achieve an epimerization of 1 using either base (DBU) or acid (aqueous H2SO4) failed. B
DOI: 10.1021/np500832h J. Nat. Prod. XXXX, XXX, XXX−XXX
Journal of Natural Products
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0.14 mmol).14 The resulting solution was heated to 60 °C and stirred for 2 h. The reaction mixture was cooled to ambient temperature, diluted with Et2O (50 mL), and washed with saturated aqueous NaHCO3 (2 × 100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by chromatography over neutral alumina with 1:5 Et2O/ petroleum ether as eluent. 1H NMR (CDCl3, 300 MHz, ppm) 7.19 (1H, s), 3.26 (1, br q, J = 7.1 Hz), 2.69 (2H, m), 2.32 (2H, m), 1.93 (3H, d, J = 1.2 Hz), 1.27 (3H, d, J = 7.1 Hz); 13CNMR (CDCl3, 75 MHz, ppm) 162.3, 159.4, 146.7, 130.3, 114.2, 38.2, 31.2, 18.9, 12.9; IR (neat) 1715, 1690, 1555, 1115, and 940 cm−1; HRMS [C10H12O2+Na]+ calcd 187.0735, found 187.0730. Photochemical Experiments. General Procedure. All reactions were performed under argon. Reactions were conducted in Pyrex glassware, and the conditions are shown in Table 2. (±)-Nepetanudone (1). In a 1 dram vial, nepetapyrone 3 (174 mg, 1.06 mmol) was dissolved in freshly distilled hexanes (0.11 mL), and the vial was purged with Ar. The solution was then immersed in a water bath to maintain ambient temperature and irradiated in a Rayonet reactor equipped with 16 300 nm lamps for 4 days. The solution was concentrated in vacuo, and a crude 1H NMR spectrum obtained. The residue was chromatographed over SiO2 (16:1 Et2O/ pet. ether). (±)-Nepetapyrone 3 (85 mg, 0.52 mmol, 49%) was recovered along with nepetanudone 1 (61 mg, 0.19 mmol, 36%). Mp decomposed/charred >100 °C; 1H NMR (CDCl3, 300 MHz, ppm) 4.43 (1H, s), 4.09 (1H, s), 2.36 (1H, m), 2.34 (1H, m), 2.30 (2H, m), 2.29 (1H, m), 2.12 (1H, m), 1.88 (1H, m), 1.86 (1H, m), 1.78 (6H, s), 1.57 (1H, m), 1.39 (1H, m), 1.30 (3H, d, J = 6.7 Hz), 1.04 (3H, d, J = 6.9 Hz); 13C NMR (CDCl3, 75 MHz, ppm) 174.2 171.9, 142.5, 140.8, 132.2, 87.7), 79.1, 67.3, 65.0, 43.5, 41.3, 31.4, 30.6, 26.7, 25.6, 16.8, 16.6, 16.0, 14.0; HRMS [C20H24O4+Na]+ calcd 351.1572, found 351.1567. These data matched the literature.3
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Phytochemistry 1998, 47, 251−254. (d) Ahmad, V. U.; Mohammad, F. V. J. Nat. Prod. 1986, 49, 524−527. (e) Liblikas, I.; Santangelo, E. M.; Sandell, J.; Baeckstrom, P.; Svensson, M.; Jacobsson, U.; Unelius, C. R. J. Nat. Prod. 2005, 68, 886−890. (f) Wang, M.; Cheng, K.-W.; Wu, Q.; Simon, J. E. Phytochem. Anal. 2007, 18, 157−160. (6) Kaupp, G. Angew. Chem., Int. Ed. Engl. 1992, 31, 422−426. (7) (a) Schreiber, S. L.; Meyers, H. V.; Wiberg, K. B. J. Am. Chem. Soc. 1986, 108, 8274−8277. (b) Beckett, J. S.; Beckett, J. D.; Hofferberth, J. E. Org. Lett. 2010, 12, 1408−1411. (8) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem., Int. Ed. 2003, 42, 4077−4082. (9) Hilt, G.; Danz, M. Synthesis 2008, 2257−2263. (10) El-Kholy, I. E-S.; Mishrikey, M. M.; Abdoul-Ela, S. L. J. Heterocycl. Chem. 1982, 19, 1329−1334. (11) Mandal, A. K.; Jawalker, D. G. J. Org. Chem. 1989, 54, 2364− 2369. (12) The assignment of 10 and 12 was made by comparison with the literature 1H NMR spectrum of 12 (ref 13) and by the NOESY of 10 (see Supporting Information). (13) Willot, M.; Radtke, L.; Koenning, D.; Froehlich, R.; Gessner, V. H.; Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed. 2009, 48, 9105−9108. (14) Eaton, P. E.; Carlson, G. R.; Lee, J. T. J. Org. Chem. 1973, 38, 4071−4073.
ASSOCIATED CONTENT
S Supporting Information *
1
H and 13C NMR spectra for 1, 3, and 10, COSY and NOESY spectra for 10, and preparative procedures for 1, 3, and 10−12. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/np500832h.
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AUTHOR INFORMATION
Corresponding Author
*Tel: 1-336-758-3708. Fax: 1-336-758-4656. E-mail: jonespb@ wfu.edu. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the Wake Forest University Science Research Fund and is part of the M.S. thesis of S.J.
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REFERENCES
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DOI: 10.1021/np500832h J. Nat. Prod. XXXX, XXX, XXX−XXX
