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First synthesis of (±)-cedarmycin B
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Chinese Chemical Letters 20 (2009) 1023–1024 www.elsevier.com/locate/cclet
First synthesis of ()-cedarmycin B Hai Shen Yang, Xiao Xiao Qiao, Qing Cui, Xiao Hua Xu * State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Received 13 February 2009
Abstract The synthesis of racemic cedarmycin B, an antibiotic from Streptomyces sp. TP-A0456 was achieved firstly from gbutyrolactone. The key step was a Barbier-type addition of 3-bromomethyl-5H-furan-2-one to formaldehyde mediated by zinc, which afforded the sole g-addition product 4-hydroxymethyl-3-methylene-dihydrofuran-2-one. The final compound was confirmed by 1H NMR, 13C NMR and HRMS. # 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Cedarmycin B; Antibiotic; Streptomyces sp.; Barbier reaction; 3-Bromomethyl-5H-furan-2-one
Natural products with the structural motif of g-butyrolactone are abundant in nature. They display a broad biological profile including strong antibiotic, antihelmitic, antifungal, antitumor, antiviral, antiinflammatory and cytostatic properties, which makes them interesting lead structures for new drugs [1]. In many cases, the a-methylene groups in the lactone ring, being potentially able to bind the nucleophilic sites of biomolecules by conjugate addition, manifest their biological activities [1]. Many methodologies have been developed towards natural a-methylene–gbutyrolactones and their analogs [1,2]. In continuation of our on-going program on the studies of this kind of natural products [3], we report here the development of a concise approach to a-methylene–g-butyrolactone and its application to the first synthesis of ()cedarmycin B 1, which was isolated from the cultured broth of the actinomycete Streptomyces sp. TP-A0456 as antibiotic (MIC 1.6 mg/mL) along with cedarmycin A (MIC 0.4 mg/mL) (Fig. 1) [4]. As shown in Scheme 1, the key intermediate 7 was synthesized following the sequence adopted by Calderon [5]. Bromination of g-butyrolactone 3 with Br2 catalyzed by red phosphorus gave 3-bromodihydrofuran-2-one 4 in 43% yield [6]. 3-Phenylsulfanyldihydrofuran-2-one 5 was obtained in 70% yield from 4 by reaction with sodium thiophenolate at room temperature. The hydroxymethyl group of thioether 6 was introduced in 95% yield by condensation of the anion of 5 with formaldehyde. The butenolide 7 was acquired in 70% yield from 6 via the pyrolytic elimination of its sulfoxide, which was obtained readily by oxidation with NaIO4 in ethanol at room temperature. Bromination of butenolide 7 with PBr3 in ether afforded 3-bromomethyl-5H-furan2-one 8 in 95% yield. Bromide 8 has been obtained previously in 12% yield from 7 by reaction with Br2 in CH2Cl2 [5].
* Corresponding author. E-mail address: [email protected] (X.H. Xu). 1001-8417/$ – see front matter # 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2009.04.029
1024
H.S. Yang et al. / Chinese Chemical Letters 20 (2009) 1023–1024
Fig. 1. Cedarmycin A and B.
Scheme 1. Conditions and reagents: (a) Br2, P, 43%; (b) PhSNa, CH3OH, rt, 70%; (c) LDA, THF, CH2O (g), 78 to 30 8C, 95%; (d) (1) NaIO4, EtOH, 0 8C to rt; (2) toluene, reflux, 70%; (e) PBr3, Et2O, 0 8C, 95%; (f) Zn, NH4Cl (s), THF, 40% formaldehyde solution, rt, 69%; (g) DCC, CH2Cl2, hexanoic acid, rt, 62%.
To the best of our knowledge, the addition of functionalized, nonsymmetric allylic organometallic reagents such as 9 to aldehydes has been scarcely studied [7]. To our delight, we found that bromide 8, precursor to 9 could react readily with formaldehyde mediated by zinc to give 10 as the sole addition product in 69% yield [8]. Cedarmycin B 1 was produced readily in 62% yield by acylation of 10 with hexanoic acid at the catalysis of DCC in CH2Cl2 [9]. The synthetic target compound was characterized on the basis of 1H NMR, 13C NMR and HRMS spectra data, which were identical to those reported in the literature [4]. In conclusion, a new approach has been developed to synthesize g-butyrolactone with a-methylene group, and this led to the first synthesis of cedarmycin B 1 in seven steps with 8% total yield from commercial available gbutyrolactone. Studies on the biological activities of 1 and its analogs are currently underway. This novel synthetic approach could serve as an alternative method to the synthesis of the natural products with the motif of a-methylene– g-butyrolactone. Acknowledgment We thank the National Science Foundation of China (Nos. 20421202, 20572055) for financial support. References [1] [2] [3] [4] [5] [6] [7] [8]
M. Seitz, O. Reiser, Curr. Opin. Chem. Biol. 9 (2005) 285. H.M.R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. Eng. 24 (1985) 94. H. Yang, X. Qiao, F. Li, et al. Tetrahedron Lett. 50 (2009) 1110. T. Sasaki, Y. Igarashi, N. Saito, et al. J. Antibiot. 55 (2001) 567. A. Calderon, P. March, M. Arrad, et al. Tetrahedron 54 (1994) 4201. C.C. Price, J.M. Judge, Org. Synth. Coll. 5 (1973) 255. R. Manchanayakage, S.T. Handy, Tetrahedron Lett. 48 (2007) 3819. New compound, 10: 1H NMR (CDCl3, 400 MHz, d ppm): 2.61 (s, 1H), 3.70–3.78 (m, 2H), 4.27 (dd, 1H, J = 4.4, 9.3 Hz), 4.45 (t, 1H, J = 8.8 Hz), 5.74 (d, 1H, J = 2.1 Hz), 6.31 (d, 1H, J = 2.4 Hz); 13C NMR (CDCl3, 75 MHz, d ppm): 40.9, 63.9, 68.5, 123.6, 135.2, 170.8; HRMS (ESI) m/z 151.0370 [M+Na]+ (calcd. for C6H8O3Na, 151.0366). [9] Cedarmycin B 1: 1H NMR (CDCl3, 400 MHz, d ppm): 0.87 (t, 3H, J = 6.7 Hz), 1.24–1.31 (m, 4H), 1.56–1.63 (m, 2H), 2.30 (t, 2H, J = 7.5 Hz), 3.42 (s, 1H), 4.11–4.24 (m, 3H), 4.46 (t, 1H, J = 8.9 Hz), 5.75 (s, 1H), 6.36 (d, 1H, J = 1.5 Hz); 13C NMR (CDCl3, 75 MHz, d ppm): 13.8, 22.2, 24.5, 31.2, 33.9, 38.0, 64.6, 68.0, 124.0, 134.5, 169.8, 173.4; HRMS (ESI) m/z 249.1097 [M+Na]+ (calcd. for C12H18O4Na, 249.1097).
Chinese Chemical Letters 20 (2009) 1023–1024 www.elsevier.com/locate/cclet
First synthesis of ()-cedarmycin B Hai Shen Yang, Xiao Xiao Qiao, Qing Cui, Xiao Hua Xu * State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China Received 13 February 2009
Abstract The synthesis of racemic cedarmycin B, an antibiotic from Streptomyces sp. TP-A0456 was achieved firstly from gbutyrolactone. The key step was a Barbier-type addition of 3-bromomethyl-5H-furan-2-one to formaldehyde mediated by zinc, which afforded the sole g-addition product 4-hydroxymethyl-3-methylene-dihydrofuran-2-one. The final compound was confirmed by 1H NMR, 13C NMR and HRMS. # 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Cedarmycin B; Antibiotic; Streptomyces sp.; Barbier reaction; 3-Bromomethyl-5H-furan-2-one
Natural products with the structural motif of g-butyrolactone are abundant in nature. They display a broad biological profile including strong antibiotic, antihelmitic, antifungal, antitumor, antiviral, antiinflammatory and cytostatic properties, which makes them interesting lead structures for new drugs [1]. In many cases, the a-methylene groups in the lactone ring, being potentially able to bind the nucleophilic sites of biomolecules by conjugate addition, manifest their biological activities [1]. Many methodologies have been developed towards natural a-methylene–gbutyrolactones and their analogs [1,2]. In continuation of our on-going program on the studies of this kind of natural products [3], we report here the development of a concise approach to a-methylene–g-butyrolactone and its application to the first synthesis of ()cedarmycin B 1, which was isolated from the cultured broth of the actinomycete Streptomyces sp. TP-A0456 as antibiotic (MIC 1.6 mg/mL) along with cedarmycin A (MIC 0.4 mg/mL) (Fig. 1) [4]. As shown in Scheme 1, the key intermediate 7 was synthesized following the sequence adopted by Calderon [5]. Bromination of g-butyrolactone 3 with Br2 catalyzed by red phosphorus gave 3-bromodihydrofuran-2-one 4 in 43% yield [6]. 3-Phenylsulfanyldihydrofuran-2-one 5 was obtained in 70% yield from 4 by reaction with sodium thiophenolate at room temperature. The hydroxymethyl group of thioether 6 was introduced in 95% yield by condensation of the anion of 5 with formaldehyde. The butenolide 7 was acquired in 70% yield from 6 via the pyrolytic elimination of its sulfoxide, which was obtained readily by oxidation with NaIO4 in ethanol at room temperature. Bromination of butenolide 7 with PBr3 in ether afforded 3-bromomethyl-5H-furan2-one 8 in 95% yield. Bromide 8 has been obtained previously in 12% yield from 7 by reaction with Br2 in CH2Cl2 [5].
* Corresponding author. E-mail address: [email protected] (X.H. Xu). 1001-8417/$ – see front matter # 2009 Xiao Hua Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2009.04.029
1024
H.S. Yang et al. / Chinese Chemical Letters 20 (2009) 1023–1024
Fig. 1. Cedarmycin A and B.
Scheme 1. Conditions and reagents: (a) Br2, P, 43%; (b) PhSNa, CH3OH, rt, 70%; (c) LDA, THF, CH2O (g), 78 to 30 8C, 95%; (d) (1) NaIO4, EtOH, 0 8C to rt; (2) toluene, reflux, 70%; (e) PBr3, Et2O, 0 8C, 95%; (f) Zn, NH4Cl (s), THF, 40% formaldehyde solution, rt, 69%; (g) DCC, CH2Cl2, hexanoic acid, rt, 62%.
To the best of our knowledge, the addition of functionalized, nonsymmetric allylic organometallic reagents such as 9 to aldehydes has been scarcely studied [7]. To our delight, we found that bromide 8, precursor to 9 could react readily with formaldehyde mediated by zinc to give 10 as the sole addition product in 69% yield [8]. Cedarmycin B 1 was produced readily in 62% yield by acylation of 10 with hexanoic acid at the catalysis of DCC in CH2Cl2 [9]. The synthetic target compound was characterized on the basis of 1H NMR, 13C NMR and HRMS spectra data, which were identical to those reported in the literature [4]. In conclusion, a new approach has been developed to synthesize g-butyrolactone with a-methylene group, and this led to the first synthesis of cedarmycin B 1 in seven steps with 8% total yield from commercial available gbutyrolactone. Studies on the biological activities of 1 and its analogs are currently underway. This novel synthetic approach could serve as an alternative method to the synthesis of the natural products with the motif of a-methylene– g-butyrolactone. Acknowledgment We thank the National Science Foundation of China (Nos. 20421202, 20572055) for financial support. References [1] [2] [3] [4] [5] [6] [7] [8]
M. Seitz, O. Reiser, Curr. Opin. Chem. Biol. 9 (2005) 285. H.M.R. Hoffmann, J. Rabe, Angew. Chem. Int. Ed. Eng. 24 (1985) 94. H. Yang, X. Qiao, F. Li, et al. Tetrahedron Lett. 50 (2009) 1110. T. Sasaki, Y. Igarashi, N. Saito, et al. J. Antibiot. 55 (2001) 567. A. Calderon, P. March, M. Arrad, et al. Tetrahedron 54 (1994) 4201. C.C. Price, J.M. Judge, Org. Synth. Coll. 5 (1973) 255. R. Manchanayakage, S.T. Handy, Tetrahedron Lett. 48 (2007) 3819. New compound, 10: 1H NMR (CDCl3, 400 MHz, d ppm): 2.61 (s, 1H), 3.70–3.78 (m, 2H), 4.27 (dd, 1H, J = 4.4, 9.3 Hz), 4.45 (t, 1H, J = 8.8 Hz), 5.74 (d, 1H, J = 2.1 Hz), 6.31 (d, 1H, J = 2.4 Hz); 13C NMR (CDCl3, 75 MHz, d ppm): 40.9, 63.9, 68.5, 123.6, 135.2, 170.8; HRMS (ESI) m/z 151.0370 [M+Na]+ (calcd. for C6H8O3Na, 151.0366). [9] Cedarmycin B 1: 1H NMR (CDCl3, 400 MHz, d ppm): 0.87 (t, 3H, J = 6.7 Hz), 1.24–1.31 (m, 4H), 1.56–1.63 (m, 2H), 2.30 (t, 2H, J = 7.5 Hz), 3.42 (s, 1H), 4.11–4.24 (m, 3H), 4.46 (t, 1H, J = 8.9 Hz), 5.75 (s, 1H), 6.36 (d, 1H, J = 1.5 Hz); 13C NMR (CDCl3, 75 MHz, d ppm): 13.8, 22.2, 24.5, 31.2, 33.9, 38.0, 64.6, 68.0, 124.0, 134.5, 169.8, 173.4; HRMS (ESI) m/z 249.1097 [M+Na]+ (calcd. for C12H18O4Na, 249.1097).