From the treatment of 5-hydroxy-1,4-naphthoquinone (juglone) with acetic anhydride and H2SO4 followed subsequently by treatment with methanolic HCl, 5-hydroxy-3-methoxy-1,4-naphthoquinone (3-methoxy juglone) and 8-hydroxy-4-methoxy-1,2-naphthoquinone were obtained as products rather than the anticipated product 2,5-dihydroxy-1,4-naphthoquinone (2-hydroxy juglone). The reaction and the identification of the products are discussed in terms of NMR and DFT calculations. 1. Introduction As part of our ongoing investigation [1] into the C-ribosylation of (R)-prealnumycin (1) by AlnA, an enzyme produced by Streptomyces albus (Scheme 1), it was decided to test various 1,4-naphthoquinone substrates against AlnA in order to identify the structural motifs necessary for, or inhibitory to, reaction. Scheme 1: The C-ribosylation of ( R)-prealnumycin ( 1) by Streptomyces albus. Thus, we considered 2,5-dihydroxy-1,4-naphthoquinone (2, 2-hydroxy juglone, Figure 1) as a test substrate since it could potentially reveal aspects of the charge required to be present on C-3 for the reaction to proceed. Additionally, the facile preparation of 2,5-dihydroxy-7-methyl-1,4-naphthoquinone (2-hydroxy-7-methyl juglone, 3) from 5-hydroxy-7-methyl-1,4-naphthoquinone (7-methyl juglone, 4) had been reported [2] by treatment first with acetic anhydride and H2SO4 and then subsequently with methanolic HCl. After treating 5-hydroxy-1,4-naphthoquinone (5, juglone) as prescribed, we obtained not 2-hydroxy juglone (2) as anticipated, but rather 5-hydroxy-3-methoxy-1,4-naphthoquinone (6, 3-methoxy juglone) and 8-hydroxy-4-methoxy-1,2-naphthoquinone (7). Mahapatra et al. [2], in turn, seem to have taken their preparation from Lillie and Musgrave [3] who performed precisely the same reaction. Interestingly, whilst the former workers only reported the one product, namely, 2-hydroxy-7-methyl juglone (3), the latter pair reported the formation of both 3 (as the major product) and its regioisomer 3,5-dihydroxy-7-methyl-1,4-naphthoquinone (3-hydroxy-7-methyl juglone, 8). Mahapatra et al. [2] only reported 1H NMR chemical shifts ( ) for their compound, and indeed only one OH signal—which they assigned as HO-5—with no carbon or correlation spectra reported. As best we can ascertain, it appears that Mahapatra et al. [2] based their structural assignment on the work of Lillie and Musgrave [3] and the of HO-5 (vide infra). This structural assignment therefore carries with it some concern, not because it is a labile proton per se, but rather because of its value in relation to the reported value [3]. The
References
[1]
T. Oja, K. D. Klika, L. Appassamy et al., “Biosynthetic pathway toward carbohydrate-like moieties of alnumycins contains unusual steps for C-C bond formation and cleavage,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 16, pp. 6024–6029, 2012.
[2]
A. Mahapatra, S. P. N. Mativandlela, B. Binneman et al., “Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase,” Bioorganic and Medicinal Chemistry, vol. 15, no. 24, pp. 7638–7646, 2007.
[3]
T. J. Lillie and O. C. Musgrave, “Ebenaceae extractives. Part 7. Use of hydroxy-proton shifts of juglone derivatives in structure elucidation,” Journal of the Chemical Society, Perkin Transactions 1, no. 4, pp. 355–359, 1977.
[4]
H. Laatsch, “Methylation of 3, -dihydroxylated 2, -binaphtho-1,4; , -quinones,” Zeitschrift für Naturforschung B, vol. 45, no. 3, pp. 393–400, 1990.
[5]
G. Wurm and U. Geres, “1,4-Naphthoquinones, XVII: studies on the synthesis of 3-hydroxy-juglone derivatives,” Archiv der Pharmazie, vol. 322, no. 3, pp. 155–157, 1989.
[6]
H.-Y. Yu, X. Li, F.-Y. Meng, H.-F. Pi, P. Zhang, and H.-L. Ruan, “Naphthoquinones from the root barks of Juglans cathayensis Dode,” Journal of Asian Natural Products Research, vol. 13, no. 7, pp. 581–587, 2011.
[7]
H. Ruan and H. Yu, “Application of two naphthoquinone compounds in preparing the medical preparations for treating neoplasm,” Chinese Patent, CN 102552226 A 20120711, 2012.
[8]
W. Tang and F. Chen, “Preparation of antitumor agent from Juglans regia,” Chinese Patent, CN 101185671 A 20080528, 2008.
[9]
M.-l. Sun, Z.-q. Song, and G.-z. Fang, “Antifungal activities and active components of alcoholic extracts from leaves of Juglans mandshurica Maxim,” Linchan Huaxue Yu Gongye, vol. 27, pp. 81–84, 2007.
[10]
K. Ditrich, G. Hamprecht, E. Ammermann, G. Lorenz, and H. Laatsch, “Preparation of 1,2-naphthoquinones as fungicides,” German Patent, DE 3926747 A1 19910214, 1991.
[11]
G. Wurm and U. Geres, “1,4-Naphthoquinones, X: reactions of the methyl ethers of 1,5-dihydroxynaphthalene with singlet oxygen,” Archiv der Pharmazie, vol. 318, no. 10, pp. 931–937, 1985.
[12]
Peak Research NMR Software, Perch Solutions, Kuopio, Finland, 2003, http://www.perchsolutions.com.
[13]
R. Laatikainen, M. Niemitz, U. Weber, J. Sundeun, T. Hassinen, and J. Veps？l？inen, “General strategies for total-lineshape-type spectral analysis of NMR spectra using integral-transform iterator,” Journal of Magnetic Resonance, Series A, vol. 120, no. 1, pp. 1–10, 1996.
[14]
S. B？hm, J. Toma？？iková, J. Imrich et al., “Computational study to assign structure, tautomerism, E/Z and s-cis/s-trans isomerism, π-delocalization, partial aromaticity, and the ring size of 1,3-thiazolidin-4-ones and 1,3-thiazin-4-ones formed from thiosemicarbazides,” Journal of Molecular Structure, vol. 916, no. 1–3, pp. 105–118, 2009.
[15]
P. T？htinen, A. Bagno, K. D. Klika, and K. Pihlaja, “Modeling NMR parameters by DFT methods as an aid to the conformational analysis of cis-fused 7a(8a)-methyl octa(hexa)hydrocyclopenta[d][1,3]oxazines and [3,1]benzoxazines,” Journal of the American Chemical Society, vol. 125, no. 15, pp. 4609–4618, 2003.
[16]
K. Pihlaja, P. T？htinen, K. D. Klika, T. Jokela, A. Salakka, and K. W？h？l？, “Experimental and DFT 1H NMR study of conformational equilibria in trans-4′,7-dihydroxyisoflavan- -ol and trans-isoflavan-4-ol,” Journal of Organic Chemistry, vol. 68, no. 18, pp. 6864–6869, 2003.
[17]
J. M？ki, P. T？htinen, L. Kronberg, and K. D. Klika, “Restricted rotation/tautomeric equilibrium and determination of the site and extent of protonation in bi-imidazole nucleosides by multinuclear NMR and GIAO-DFT calculations,” Journal of Physical Organic Chemistry, vol. 18, no. 3, pp. 240–249, 2005.
[18]
P. Virta, A. Koch, M. U. Roslund et al., “Synthesis, characterisation and theoretical calculations of 2,6-diaminopurine etheno derivatives,” Organic and Biomolecular Chemistry, vol. 3, no. 16, pp. 2924–2929, 2005.
[19]
K. D. Klika, J. Bernát, J. Imrich, I. Chom？a, R. Silanp？？, and K. Pihlaja, “Unexpected formation of a spiro acridine and fused ring system from the reaction between an N-acridinylmethyl-substituted thiourea and bromoacetonitrile under basic conditions,” Journal of Organic Chemistry, vol. 66, no. 12, pp. 4416–4418, 2001.
[20]
E. Balentová, J. Imrich, J. Bernát et al., “Stereochemistry, tautomerism, and reactions of acridinyl thiosemicarbazides in the synthesis of 1,3-thiazolidines,” Journal of Heterocyclic Chemistry, vol. 43, no. 3, pp. 645–656, 2006.
[21]
J. Stonehouse, P. Adell, J. Keeler, and A. J. Shaka, “Ultrahigh-quality NOE spectra,” Journal of the American Chemical Society, vol. 116, no. 13, pp. 6037–6038, 1994.
[22]
K. Stott, J. Stonehouse, J. Keeler, T.-L. Hwang, and A. J. Shaka, “Excitation sculpting in high-resolution nuclear magnetic resonance spectroscopy: application to selective NOE experiments,” Journal of the American Chemical Society, vol. 117, no. 14, pp. 4199–4200, 1995.
[23]
T.-L. Hwang and A.-J. Shaka, “Water suppression that works. Excitation sculpting using arbitrary waveforms and pulsed field gradients,” Journal of Magnetic Resonance, Series A, vol. 112, no. 2, pp. 275–279, 1995.
[24]
M. J. Frisch, G. W. Trucks, H. B. Schlegel et al., Gaussian09, Revision A.01, Gaussian, Wallingford, Con, USA, 2009.
[25]
Y. Zhao and D. G. Truhlar, “The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals,” Theoretical Chemistry Accounts, vol. 120, no. 1–3, pp. 215–241, 2008.
[26]
Y. Zhao and D. G. Truhlar, “Density functionals with broad applicability in chemistry,” Accounts of Chemical Research, vol. 41, no. 2, pp. 157–167, 2008.
[27]
K. Wolinski, J. F. Hinton, and P. Pulay, “Efficient implementation of the gauge-independent atomic orbital method for NMR chemical shift calculations,” Journal of the American Chemical Society, vol. 112, no. 23, pp. 8251–8260, 1990.
[28]
A. D. Becke, “Density-functional thermochemistry. III. The role of exact exchange,” Journal of Chemical Physics, vol. 98, no. 7, pp. 5648–5652, 1993.
[29]
C. Lee, W. Yang, and R. G. Parr, “Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density,” Physical Review B, vol. 37, no. 2, pp. 785–789, 1988.
