HETEROCYCLES

Communication | Special issue | Vol. 86, No. 2, 2012, pp. 985-989
Received, 28th July, 2012, Accepted, 17th August, 2012, Published online, 28th August, 2012.
DOI: 10.3987/COM-12-S(N)104

■ A NEW ENTRY TO THE SYNTHESIS OF PRIMIN VIA A B-ALKYL SUZUKI–MIYAURA CROSS-COUPLING REACTION

Kazuhiro Watanabe, Tomohiro Sugizaki, Yumi Tozawa, and Tadashi Katoh*

Laboratory of Synthetic and Medicinal Chemistry, Department of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan

Abstract

Primin, a biologically active benzoquinone natural product, was efficiently synthesized in 57% overall yield in six steps starting from commercially available 5-iodovanillin. The synthetic method involves crucial steps, including a B-alkyl Suzuki–Miyaura cross-coupling reaction to directly install an alkyl side chain in an aromatic ring and elaboration of quinone functionality by degradative oxidation using Fremy’s salt to yield the target primin.

Primin, 2-methoxy-6-pentyl-1,4-benzoquinone (1) (Figure 1), was first isolated as the allergenic principle of the plant Primula obconia.1 Subsequently, this natural product was also isolated from the plant Miconia sp.2 and the fungus Botryosphaeria sp.3 In 2001, Kingston et al. reported the isolation of 1 from the plant Miconia lepidota collected from the Suriname rainforest.4 This substance was found to exhibit antiproliferative activity against M109 murine lung cancer cells (IC50 = 10 μg/mL) and A2780 human ovarian cancer cells (IC50 = 2.9 μg/mL).4 It has also been reported that primin displays antibacterial activity against Staphylococcus aureus (ATTC 25923) and methicillin-resistant Staphylococcus aureus (MRSA) with equal MIC values of 8 μg/mL.5

In the course of our continuing research on the synthesis of biologically active quinoid natural products,6 we became interested in the synthesis of primin and its analogues with the aim of searching for potential anticancer agents. Several reports on the synthesis of primin have been published to date,4,7 which involved strategic methods for the introduction of the alkyl side chain at the aromatic nucleus and the formation of the 1,4-benzoquinone moiety via oxidation of hydroquinone or phenol derivatives. However, some of these syntheses required severe and/or difficult reaction conditions, the yields were often unsatisfactory, and several of these methods are limited by the nature of the substituent in the aromatic rings. Therefore, we investigated an alternative, more flexible, and reliable method for the synthesis of primin, as well as its analogues. In this paper, we describe our results on the synthesis of primin using a B-alkyl Suzuki–Miyaura cross-coupling reaction8 and degradative phenol oxidation9 as the key steps.
Our synthetic plan for primin (1) is outlined in Scheme 1. We envisioned that the target molecule 1 could be derived from phenolic compound 2 by its oxidative degradation to the corresponding quinone.9 Intermediate 2 with the requisite alkyl side chain and appropriate functional groups was to be prepared via the B-alkyl Suzuki–Miyaura cross-coupling reaction8 between aryl iodide 3, which is accessible from 5-iodovanillin (5), and organoborane 4. To the best of our knowledge, the utilization of the direct alkylation method (cf. 3 + 4 → 2) for synthesizing 1 is unknown to date, and thus, this approach posed a challenge from the viewpoint of synthesis.

As shown in Scheme 2, the synthesis commenced with protection of the phenolic hydroxy group in commercially available 5-iodovanillin (5) to give the corresponding benzyl (Bn) ether 6 in 86% yield. Initial attempts to realize the B-alkyl Suzuki–Miyaura cross-coupling reaction of 6 and organoborane 4 [prepared in situ by hydroboration of 1-pentene with 9-borabicyclo[3.3.1]nonane (9-BBN)] resulted in an unsatisfactory yield of the coupling product (ca. ~50%). Therefore, we decided to conduct this cross-coupling reaction after protecting the sensitive formyl group in 6 as the ethylene acetal 7 (88%). As a result, the critical cross-coupling reaction of 7 with 4 proceeded smoothly and cleanly under the optimized conditions [PdCl2(dppf) (5 mol%), Cs2CO3, THF, reflux, 30 min]; the desired coupling product 810 was obtained in high yield (92%). Subsequent acidic hydrolysis of the ethylene acetal moiety in 8 followed by hydrogenation of the resulting aldehyde 9 (H2, 10% Pd/C, EtOH, rt, 3 h), provided p-hydroxybenzyl alcohol 10 in 94% yield after the two steps. Finally, the critical quinone formation reaction was successfully achieved by oxidative degradation of 10 using Fremy’s salt [(KSO3)2NO] in pH 6.0 phosphate buffer/CHCl3 (4:1) at room temperature, resulting in the formation of target 111 in high yield (86%).

Thus, we have accomplished the synthesis of primin (1) in 56% overall yield in six steps from the commercially available starting material 5. The key steps of the synthesis involve the B-alkyl Suzuki–Miyaura cross-coupling reaction of aryl iodide 7 and organoborane 4 to introduce the requisite alkyl side chain in the aromatic ring (7 → 8, Scheme 2) and elaboration of the quinone functionality by oxidative degradation of phenolic compound 10 to complete the projected synthesis (10 → 1, Scheme 2). The main advantages of the present methods are the higher yield, milder reaction conditions, and greater flexibility in producing primin analogues that with various alkyl side chains when compared to other reported methods.4,7 On the basis of the results of this study, we are currently synthesizing additional analogues of 1 with the aim of exploring their structure–activity relationships. In addition, further investigations to identify the action mechanism of 1 by using synthetic samples are in progress.

ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for the Strategic Research Foundation Program at Private Universities (2010–2014) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT). K. Watanabe would like to acknowledge the contribution of a Grant-in-Aid for Young Scientists (B) (No. 23790018) from MEXT, and T. Katoh is grateful to MEXT for the provision of a Grant-in-Aid for Scientific Research (C) (No. 24590017).

References

1. (a) H. Schildknecht, H. Bayer, and H. Schmidt, Z. Naturforsch, 1967, 22b, 36; (b) B. Bloch and P. Karrer, Vjschr. Naturforsch. Ges., 1927, 72, 1 (Chem. Abstr., 1928, 22, 2784).
2. (a) E. Bernays, A. Lupi, R. M. Bettolo, C. Mastrofrancesco, and P. Tagliatesta, Experientia, 1984, 40, 1010; CrossRef (b) G. B. Marini-Bettolo, F. D. Monache, O. G. da Lima, and S. B. Coelho, Gazz. Chim. Ital., 1971, 101, 41.
3. W. Pongcharoen, V. Rukachaisirikul, S. Phongpaichit, and J. Sakayaroj, Chem. Pharm. Bull., 2007, 55, 1404. CrossRef
4. A. A. L. Gunatilaka, J. M. Berger, R. Evans, J. S. Miller, J. H. Wisse, K. M. Neddermann, I. Bursuker, and D. G. I. Kingston, J. Nat. Prod., 2001, 64, 2. CrossRef
5. D. Tasdemir, R. Brun, V. Yardley, S. G. Franzblau, and P. Rüedi, Chem. Biodivers., 2006, 3, 1230. CrossRef
6. (a) K. Narita, K. Nakamura, Y. Abe, and T. Katoh, Eur. J. Org. Chem., 2011, 4985; CrossRef (b) J. Sakurai, T. Oguchi, K. Watanabe, H. Abe, S. Kanno, M. Ishikawa, and T. Katoh, Chem. Eur. J., 2008, 14, 829; CrossRef (c) A. Suzuki, M. Nakatani, M. Nakamura, K. Kawaguchi, M. Inoue, and T. Katoh, Synlett, 2003, 329; CrossRef (d) M. Nakamura, A. Suzuki, M. Nakatani, T. Fuchikami, M. Inoue, and T. Katoh, Tetrahedron Lett., 2002, 43, 6929; CrossRef (e) T. Katoh, M. Nakatani, S. Shikita, R. Sampe, A. Ishiwata, O. Ohmori, M. Nakatani, and S. Terashima, Org. Lett., 2001, 3, 2701. CrossRef
7. (a) A. K. Bhattacharya, T. Kaur, and K. N. Ganesh, Synthesis, 2010, 1141; CrossRef (b) L.-Q. Wu, C.-G. Yang, L.-M. Yang, and L.-J. Yang, J. Chin. Chem. Soc., 2009, 56, 47; (c) C. J. Davis, T. E. Hurst, A. M. Jacob, and C. J. Moody, J. Org. Chem., 2005, 70, 4414; CrossRef (d) A. M. Jacob and C. J. Moody, Tetrahedron Lett., 2005, 46, 8823; CrossRef (e) C. J. Davis and C. J. Moody, Synlett, 2002, 1874; CrossRef (f) S. Mabic, L. Vaysse, C. Benezra, and J.-P. Lepoittevin, Synthesis, 1999, 1127; CrossRef (g) S. S. Arogba, Org. Prep. Proced. Int., 1991, 23, 639; CrossRef (h) L. W. Bieber, A. de Andrade Chiappeta, M. A. de Moraes e Souza, R. M. Generino, and P. R. Neto, J. Nat. Prod., 1990, 53, 706; CrossRef (i) O. G. de Lima, G. B. Marini-Bettolo, F. Delle Monache, J. S. Coelho, L. I. d’Albuquerque, G. M. Maciel, A. Lacerda, and D. G. Martins, Rev. Inst. Antibiot., 1970, 10, 29 (Chem. Abstr., 1970, 77, 29622).
8. For a review on B-alkyl Suzuki–Miyaura cross-coupling reaction, see: S. R. Chemler, D. Trauner, and S. J. Danishefsky, Angew. Chem. Int. Ed., 2001, 40, 4544. CrossRef
9. For some examples of degradative phenol oxidation, see: (a) J. M. Saá, A. Llobera, A. G. Raso, A. Costa, and P. M. Deyá, J. Org. Chem., 1988, 53, 4263; CrossRef (b) P. M. Deyá, M. Dopico, A. G. Raso, J. Morey, and J. M. Saá, Tetrahedron, 1987, 43, 3523; CrossRef (c) J. M. Saá, J. Morey, and C. Rubido, J. Org. Chem., 1986, 51, 4471; CrossRef (d) J. M. Saá, J. Morey, and A. Costa, Tetrahedron Lett., 1986, 27, 5125. CrossRef
10. Data for 8. Colorless oil; IR (neat) 1091, 1158, 1216, 1507 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.84 (3H, t, J = 6.8 Hz), 1.25–1.29 (4H, m), 1.48–1.57 (2H, m), 2.54 (2H, dt, J = 1.9, 7.8 Hz), 3.89 (3H, s), 4.02–4.07 (2H, m), 4.14–4.17 (2H, m), 4.97 (2H, s), 5.73 (1H, s), 6.89 (1H, d, J = 1.9 Hz), 6.92 (1H, d, J = 1.9 Hz), 7.82–7.39 (3H, m), 7.45 (2H, dd, J = 1.4, 6.8 Hz); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.4, 30.1, 30.2, 31.8, 55.7, 65.2 (2C), 74.6, 103.7, 107.7, 120.1, 127.7, 127.9, 128.1, 128.2, 128.3, 132.9, 136.9, 137.9, 146.6, 152.7; HRMS (EI) calcd for C22H28O4 (M+), 356.1988, found 356.1994.
11. Data for primin (1). Yellow crystals: mp 62–63 °C (from MeOH) {lit.,2b mp 64–65 °C; lit.,7a mp 62–63 °C; lit.,7c mp 64.5–65.5 °C; lit.,7h mp 61–62 °C}; IR (KBr) 1655, 1681 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J = 6.8 Hz), 1.31–1.34 (4H, m), 1.47–1.55 (2H, m), 2.41 (2H, t, J = 7.3 Hz), 3.82 (3H, s), 5.87 (1H, s), 6.48 (1H, s); 13C NMR (100 MHz, CDCl3) δ 13.9, 22.3, 27.4, 28.6, 31.3, 56.2, 107.1, 132.9, 147.6, 158.8, 182.1, 187.6; HRMS (EI) calcd for C12H16O3 (M+), 208.1099, found 208.1099.