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First total synthesis of paecilodepsipeptide A
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Chinese Chemical Letters 20 (2009) 527–530 www.elsevier.com/locate/cclet
First total synthesis of paecilodepsipeptide A Ming Jun Yang a,b, Jing Wu b, Zhong Duo Yang b,*, Ying Mei Zhang a,1 b
a School of Life Sciences, Lanzhou University, Lanzhou 730000, China School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050,China
Received 7 October 2008
Abstract The first total synthesis of paecilodepsipeptide A is reported. A convergent, flexible strategy employing peptide chemistry and culminating in macrolactamisation is described. The previously reported structure of compound is confirmed. # 2009 Zhong Duo Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Paecilodepsipeptide A; Macrolactamisation; Total synthesis
Fungi belonging to the genus Paecilomyces have been the source of a wide range of bioactive compounds [1]. Fungi from the marine environment are well-known producers of novel and pharmacologically active secondary metabolites [2]. Representative secondary metabolites are paecilotoxins (highly toxic linear peptides; also designated as leucinostatins) from P. lilacinus [3], paeciloquinones (anthraquinones, protein tyrosine kinase inhibitors) from P. carneus P-177 [4], paecilosetin (a tetramic acid derivative, antibiotic) from P. farinosus [5], and a series of trichothecanes from P. tenuipes [6]. Paecilodepsipeptide A 1 was isolated from the insect pathogenic fungus P. cinnamomeus BCC 9616 in 2007 by Isaka et al. [7], as the extract of this strain had shown moderate cytotoxic activity, along with its linear derivatives paecilodepsipeptides B and C. Paecilodepsipeptide A 1 showed activity against the malarial parasite Plasmodium falciparum K1 with an IC50 value of 4.9 mmol/L. Also showed cytotoxicity to two cancer cell lines, KB (IC50 5.9 mmol/L) and BC (IC50 6.6 mmol/L). Before, as its analogues, Gliotide had been isolated from marine alga-derived fungus, Gliocladium sp. in 2006 by Munro, M.H.G. Group [8]. The only stereochemical detail remaining unclear was which alanine was of L- and which was of D-configuration. We have been interested for some time in cyclopeptides and cyclodepsipeptides. Here we report on our studies toward the synthesis of paecilodepsipeptide A. A unique structural feature of paecilodepsipeptide A 1, as a new cyclodepsipeptide, is that it possesses three D-amino acid residues, including an unusual O-prenyl-D-Tyr, whereas it contains only one L-amino acid (L-Ala).
* Corresponding author. E-mail address: [email protected] (Z.D. Yang). 1 Co-corresponding author. E-mail address: [email protected] (Y.M. Zhang). 1001-8417/$ – see front matter # 2009 Zhong Duo Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2009.01.032
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M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530
Scheme 1. Retrosynthetic analysis of paecilodepsipeptide A.
Retrosynthetic analysis (Scheme 1) suggested that paecilodepsipeptide A 1 might be synthesized from hexapeptide 2 through the macrolactamization. Because the unusual O-prenyl-D-tryptophan fragment 6 is not stable in the presence of acid, it is introduced latter. The precursor 3 might be obtained from dipeptide 5 and tripeptide 4, which can be assembled through fragments 7–11 (Scheme 2). Intermediate 3 was prepared efficiently according to literature procedures from dipeptide 5 and tripeptide 4, which were obtained by the standard peptide chemistry method [9] from amino acid fragments 7–11. Macrolactamization precursor hexpeptide 2 was gained by the esterfication 3 and 6 in the presence of EDCI and DMAP in 75% yield [10]. Finally, treatment of precursor hexpeptide 2 with TBAF to remove both 2(trimethylsilyl) ethyl ester and Teoc protecting groups, the amine-acid precursor was exposed, under high dilution conditions, to a variety of coupling reagents including bis-(2-oxo-3-oxazolidinyl)-phosphinyl chloride (BOP-Cl), 3-(diethoxy-phosphorylloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT); diethyl cyanophosphonate (DEPC); diphenyl phosphoryl azide (DPPA); Mukaiyama reagent, O-(7-azabenzotriazol-1-yl)-N,N,N0 ,N0 - tetramethyluronium and hexafluorophosphate /1-hydroxybenzotriazole (HATU/HOBt), EDCI/HOBt, in different solvents (DCM, DMF, MeCN). The results from these studies revealed that the acyclic precursor provided the best yield for the desired natural product paecilodepsipeptide A 1 in 72% yield when it was treated with HATU [11] as coupling reagent and DIPEA as base and under high dilution, 103 mol/L, in DMF at room temperature. Spectral and analytical data of synthetic paecilodepsipeptide A were in good agreement with those of the literature data [12]. In conclusion, we have achieved the first total synthesis of paecilodepsipeptide A in a convergent fashion using HATU mediated macrolactamization as a key step. The synthesis and the absolute configuration of Gliotide and the preparation of analogues and their biological study are under progress and will be reported in due course.
M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530
529
Scheme 2. Total symthesis of paecilodepsipeptide A.
Acknowledgments We are grateful to the National Natural Science Foundation of China (No. 20802031) and Dr. Shuo Li for NMR spectrum and mass spectrometric analyses. References [1] J.W. Blunt, B.R. Copp, M.H.G. Munro, Nat. Prod. Rep. 22 (2005) 15. [2] M. Isaka, P. Kittakoop, Y. Thebtaranonth, in: J.F. White, C.W. Bacon, Jr., N.L. Hywel-Jones, J.W. Spatafora (Eds.), Clavicipitalean Fungi: Evolutionary Biology, Chemistry, Biocontrol, and Cultural Impacts, Marcel Dekker, Inc., New York, 2003, p. 355. [3] (a) K. Fukushima, T. Arai, Y. Mori, J. Antibiot. 36 (1983) 1606; (b) K. Fukushima, T. Arai, Y. Mori, J. Antibiot. 36 (1983) 1613; (c) Y. Mikami, K. Yazawa, K. Fukushima, Mycopathologia 108 (1989) 195. [4] A. Frendenhagen, P. Hug, H. Sauter, J. Antibiot. 48 (1995) 199. [5] G. Lang, J.W. Blunt, N.J. Cummings, J. Nat. Prod. 68 (2005) 810. [6] (a) H. Kikuchi, Y. Miyagawa, Y. Sahashi, S. Inatomi, A. Haganuma, N. Nakahata, Y. Oshima, Tetrahedron Lett. 45 (33) (2004) 6225; (b) H. Kikuchi, Y. Miyagawa, K. Nakamura, Org. Lett. 6 (2004) 4531; (c) H. Kikuchi, Y. Miyagawa, Y. Sahashi, J. Org. Chem. 69 (2004) 352. [7] M. Isaka, S. Palasam, S. Lapanun, J. Nat. Prod. 70 (2007) 675. [8] G. Lang, M.I. Mitova, G. Ellis, J. Nat. Prod. 69 (2006) 621. [9] R. Van Heerbeek, P.C.J. Kamer, P.N.M.W. Van Leeuwen, Org. Biol. Chem. 4 (2006) 211. [10] Pentapeptide 3 (628 mg, 1 mmol) and O-prenyl-D-tryptophan fragment 6 (393 mg, 1.0 mmol) were dissolved in dichloromethane (10 mL) at 0 8C, after EDCI (320 g, 2.0 mmol) and DMAP (488 mg, 4 mmol) were added, the reaction was stirred at room temperature for 16 h. The reaction mixture successively washed with saturated NH4Cl solution (20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, using 5% ethyl acetate–hexane as eluent, to afford the desired ester (2) (750 mg, 75%) as clear oil. 1H NMR (500 MHz, CDCl3, d ppm): 7.36–7.17 (m, 11H), 7.12 (d, 2H, J = 7.5 Hz), 6.91 (d, 2H, J = 6.9 Hz), 6.86 (d, 2H, J = 7.8 Hz), 5.48 (br s, 1H), 5.25 (br s, 1H), 4.76 (br s, 1H), 4.48 (d, 2H, J = 5.5 Hz), 4.40 (q, 2H, J = 7.1 Hz), 4.26–4.14 (m, 6H), 3.91 (d, 1H, J = 12.1 Hz), 3.70 (d, 1H, J = 12.3 Hz), 3.17–3.08 (m, 4H), 2.98 (dd, 1H, J = 13.9, 7.6 Hz), 2.90 (dd, 1H, J = 13.9, 7.2 Hz), 2.02 (br s, 1H), 1.79 (s, 3H), 1.73 (s, 3H), 1.34 (d, 3H, J = 6.7 Hz), 1.21 (d, 3H, J = 6.9 Hz), 1.01–0.95 (m, 4H), 0.04 (s, 9H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3, d ppm): 174.4, 172.7, 172.5, 170.6, 168.9, 158.2, 149.3, 137.9, 137.0, 134.6, 130.4, 130.3, 129.6, 128.3, 127.4, 126.7, 121.2, 119.7, 115.0, 72.7, 64.8, 63.8, 54.2, 48.7, 48.5, 43.0, 40.3, 37.6, 25.7, 18.1, 17.7, 17.3, 17.2, 1.6. HRESIMS m/z Calcd. for C51H73N5O12Si2Na: [M+Na]+ 1026.4684. Found: [M+Na]+ 1026.4692. [11] L.A. Carpino, A. El-Faham, C.A. Minor, J. Chem. Soc. Chem. Commun. (1994) 201. [12] Precursor 2 (100 mg, 0.1 mmol) was treated with a solution of 0.1 mol/L TBAF in THF (5 mL) at 0 8C for 1 h. The reaction was allowed to warm to room temperature and stirred further for 4 h. The solvents were evaporated under reduced pressure to give the crude product, which was then dissolved in DMF (100 mL) and treated with HATU (142 mg, 0.4 mmol) at 25 8C for 30 min, and then DIPEA (0.11 mL, 0.6 mmol) was added to the reaction mixture. The reaction mixture was allowed to stir at this temperature for 48 h and DMF was then removed by
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M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530 distillation under vacuum at the temperature below 50 8C. The resulting crude product was purified by flash column chromatography on silica gel, using 2% MeOH in dichloromethane as eluent to afford the paecilodepsipeptide A (1) (54 mg, 72% over two steps) as a white solid. mp 1 25 138–140 8C; ½a25 D þ 21:5 (c, 0.5, MeOH), lit. ½aD þ 22 (c, 0.15, MeOH); H NMR (500 MHz, DMSO-d6, d ppm): 9.22 (br s, 1H, 7-OH, DTyr), 8.78 (d, 1H, J = 4.0, NH, O-prenyl-D-Tyr), 8.55 (d, 1H, J = 8.2 Hz, NH, D-Tyr), 8.01 (d, 1H, J = 8.3 Hz, NH, Gly), 7.84 (d, 1H, J = 7.3 Hz, NH, Ala-1), 7.56 (d, 1H, J = 8.4 Hz, NH, Ala-2), 7.20–7.175 (m, 3H, H-6, 7, 8, L-3-Ph-Lac), 7.01 (d, 2H, J = 8.5 Hz, H-5, 9, O-prenyl-D-Tyr), 6.97 (d, 2H, J = 8.5 Hz, H-5, 9, D-Tyr), 6.88 (m, 2H, H-6, 8, O-prenyl-D-Tyr), 6.79–6.76 (m, 2H, H-5, 9, L-3-Ph-Lac), 6.63 (d, 2H, J = 8.5 Hz, H6, 8, D-Tyr), 5.34 (t, 1H, J = 6.6 Hz, H-20 , O-prenyl-D-Tyr), 5.14 (t, 1H, J = 5.2 Hz, H-2, L-3-Ph-Lac), 4.44 (d, 2H, J = 6.6 Hz, H-10 , O-prenyl-DTyr), 4.28–4.15 (m, 4H, H-2 of Ala-1, H-2 of Ala-2, H-2 of O-prenyl-D-Tyr, H-2 of D-Tyr), 3.57 (dd, 1H, J = 15.8, 6.6 Hz, H-2a, Gly), 3.34 (m, 1H, H-2b, Gly), 2.98 (dd, 1H, J = 14.2, 5.8 Hz, H-3a, L-3-Ph-Lac), 2.95 (dd, 1H, J = 14.2, 4.3 Hz, H-3a, D-Tyr), 2.91 (dd, 1H, J = 13.2, 5.4 Hz, H-3a, O-prenyl-D-Tyr), 2.80 (dd, 1H, J = 13.2, 9.2 Hz, H-3b, O-prenyl-D-Tyr), 2.72 (dd, 1H, J = 13.9, 10.8 Hz, H-3b, D-Tyr), 2.58 (dd, 1H, J = 14.0, 4.3 Hz, H-3b, L-3-Ph-Lac), 1.63 (s, 3H, H-50 , O-prenyl-D-Tyr), 1.65 (s, 3H, H-40 , O-prenyl-D-Tyr), 1.26 (d, 3H, J = 7.1 Hz, H-2, Ala2), 1.04 (d, 3H, J = 6.9 Hz, H-2, Ala-1); 13C NMR (125 MHz, DMSO-d6, d ppm): 172.6 (s, C-1, Ala-2), 172.3 (s, C-1, Ala-1), 171.7 (s, C-1, Oprenyl-D-Tyr), 170.6 (s, C-1, D-Tyr), 169.6 (s, C-1, Gly), 168.2 (s, C-1, L-3-Ph-Lac), 158.0 (s, C-7, O-prenyl-D-Tyr), 156.2 (s, C-7, D-Tyr), 137.4 (s, C-3, O-prenyl-D-Tyr), 135.9 (s, C-4, L-3-Ph-Lac), 130.8 (d, C-5 and C-9, O-prenyl-D-Tyr), 130.2 (d, C-5 and C-9, D-Tyr), 130.2 (d, C-5 and C-9, L-3-Ph-Lac), 128.7 (s, C-4, D-Tyr), 128.3 (d, C-6 and C-8, L-3-Ph-Lac), 128.3 (s, C-4, O-prenyl-D-Tyr), 127.1 (d, C-7, L-3-Ph-Lac), 120.4 (d, C-2, O-prenyl-D-Tyr), 115.5 (d, C-6 and C-8, D-Tyr), 115.0 (d, C-6 and C-8, O-prenyl-D-Tyr), 73.6 (d, C-2, L-3-Ph-Lac), 64.6 (t, C-1, Oprenyl-D-Tyr), 56.5 (d, C-2, O-prenyl-D-Tyr), 56.1 (d, C-2, D-Tyr), 49.0 (d, C-2, Ala-1), 48.0 (d, C-2, Ala-2), 43.5 (t, C-2, Gly), 37.4 (t, C-3, L-3Ph-Lac), 36.0 (t, C-3, D-Tyr), 35.4 (t, C-3, O-prenyl-D-Tyr), 25.9 (q, C-4, O-prenyl-D-Tyr), 19.1 (q, C-3, Ala-2), 18.8 (q, C-3, Ala-1), 18.4 (q, C5, O-prenyl-D-Tyr). HR-ESIMS m/z Calcd. for C40H47N5O9Na: 764.3264 [M+Na]+ (Calcd. for C40H47N5O9Na, 764.3271).
Chinese Chemical Letters 20 (2009) 527–530 www.elsevier.com/locate/cclet
First total synthesis of paecilodepsipeptide A Ming Jun Yang a,b, Jing Wu b, Zhong Duo Yang b,*, Ying Mei Zhang a,1 b
a School of Life Sciences, Lanzhou University, Lanzhou 730000, China School of Life Science and Engineering, Lanzhou University of Technology, Lanzhou 730050,China
Received 7 October 2008
Abstract The first total synthesis of paecilodepsipeptide A is reported. A convergent, flexible strategy employing peptide chemistry and culminating in macrolactamisation is described. The previously reported structure of compound is confirmed. # 2009 Zhong Duo Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. Keywords: Paecilodepsipeptide A; Macrolactamisation; Total synthesis
Fungi belonging to the genus Paecilomyces have been the source of a wide range of bioactive compounds [1]. Fungi from the marine environment are well-known producers of novel and pharmacologically active secondary metabolites [2]. Representative secondary metabolites are paecilotoxins (highly toxic linear peptides; also designated as leucinostatins) from P. lilacinus [3], paeciloquinones (anthraquinones, protein tyrosine kinase inhibitors) from P. carneus P-177 [4], paecilosetin (a tetramic acid derivative, antibiotic) from P. farinosus [5], and a series of trichothecanes from P. tenuipes [6]. Paecilodepsipeptide A 1 was isolated from the insect pathogenic fungus P. cinnamomeus BCC 9616 in 2007 by Isaka et al. [7], as the extract of this strain had shown moderate cytotoxic activity, along with its linear derivatives paecilodepsipeptides B and C. Paecilodepsipeptide A 1 showed activity against the malarial parasite Plasmodium falciparum K1 with an IC50 value of 4.9 mmol/L. Also showed cytotoxicity to two cancer cell lines, KB (IC50 5.9 mmol/L) and BC (IC50 6.6 mmol/L). Before, as its analogues, Gliotide had been isolated from marine alga-derived fungus, Gliocladium sp. in 2006 by Munro, M.H.G. Group [8]. The only stereochemical detail remaining unclear was which alanine was of L- and which was of D-configuration. We have been interested for some time in cyclopeptides and cyclodepsipeptides. Here we report on our studies toward the synthesis of paecilodepsipeptide A. A unique structural feature of paecilodepsipeptide A 1, as a new cyclodepsipeptide, is that it possesses three D-amino acid residues, including an unusual O-prenyl-D-Tyr, whereas it contains only one L-amino acid (L-Ala).
* Corresponding author. E-mail address: [email protected] (Z.D. Yang). 1 Co-corresponding author. E-mail address: [email protected] (Y.M. Zhang). 1001-8417/$ – see front matter # 2009 Zhong Duo Yang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved. doi:10.1016/j.cclet.2009.01.032
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M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530
Scheme 1. Retrosynthetic analysis of paecilodepsipeptide A.
Retrosynthetic analysis (Scheme 1) suggested that paecilodepsipeptide A 1 might be synthesized from hexapeptide 2 through the macrolactamization. Because the unusual O-prenyl-D-tryptophan fragment 6 is not stable in the presence of acid, it is introduced latter. The precursor 3 might be obtained from dipeptide 5 and tripeptide 4, which can be assembled through fragments 7–11 (Scheme 2). Intermediate 3 was prepared efficiently according to literature procedures from dipeptide 5 and tripeptide 4, which were obtained by the standard peptide chemistry method [9] from amino acid fragments 7–11. Macrolactamization precursor hexpeptide 2 was gained by the esterfication 3 and 6 in the presence of EDCI and DMAP in 75% yield [10]. Finally, treatment of precursor hexpeptide 2 with TBAF to remove both 2(trimethylsilyl) ethyl ester and Teoc protecting groups, the amine-acid precursor was exposed, under high dilution conditions, to a variety of coupling reagents including bis-(2-oxo-3-oxazolidinyl)-phosphinyl chloride (BOP-Cl), 3-(diethoxy-phosphorylloxy)-1,2,3-benzotriazin-4-(3H)-one (DEPBT); diethyl cyanophosphonate (DEPC); diphenyl phosphoryl azide (DPPA); Mukaiyama reagent, O-(7-azabenzotriazol-1-yl)-N,N,N0 ,N0 - tetramethyluronium and hexafluorophosphate /1-hydroxybenzotriazole (HATU/HOBt), EDCI/HOBt, in different solvents (DCM, DMF, MeCN). The results from these studies revealed that the acyclic precursor provided the best yield for the desired natural product paecilodepsipeptide A 1 in 72% yield when it was treated with HATU [11] as coupling reagent and DIPEA as base and under high dilution, 103 mol/L, in DMF at room temperature. Spectral and analytical data of synthetic paecilodepsipeptide A were in good agreement with those of the literature data [12]. In conclusion, we have achieved the first total synthesis of paecilodepsipeptide A in a convergent fashion using HATU mediated macrolactamization as a key step. The synthesis and the absolute configuration of Gliotide and the preparation of analogues and their biological study are under progress and will be reported in due course.
M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530
529
Scheme 2. Total symthesis of paecilodepsipeptide A.
Acknowledgments We are grateful to the National Natural Science Foundation of China (No. 20802031) and Dr. Shuo Li for NMR spectrum and mass spectrometric analyses. References [1] J.W. Blunt, B.R. Copp, M.H.G. Munro, Nat. Prod. Rep. 22 (2005) 15. [2] M. Isaka, P. Kittakoop, Y. Thebtaranonth, in: J.F. White, C.W. Bacon, Jr., N.L. Hywel-Jones, J.W. Spatafora (Eds.), Clavicipitalean Fungi: Evolutionary Biology, Chemistry, Biocontrol, and Cultural Impacts, Marcel Dekker, Inc., New York, 2003, p. 355. [3] (a) K. Fukushima, T. Arai, Y. Mori, J. Antibiot. 36 (1983) 1606; (b) K. Fukushima, T. Arai, Y. Mori, J. Antibiot. 36 (1983) 1613; (c) Y. Mikami, K. Yazawa, K. Fukushima, Mycopathologia 108 (1989) 195. [4] A. Frendenhagen, P. Hug, H. Sauter, J. Antibiot. 48 (1995) 199. [5] G. Lang, J.W. Blunt, N.J. Cummings, J. Nat. Prod. 68 (2005) 810. [6] (a) H. Kikuchi, Y. Miyagawa, Y. Sahashi, S. Inatomi, A. Haganuma, N. Nakahata, Y. Oshima, Tetrahedron Lett. 45 (33) (2004) 6225; (b) H. Kikuchi, Y. Miyagawa, K. Nakamura, Org. Lett. 6 (2004) 4531; (c) H. Kikuchi, Y. Miyagawa, Y. Sahashi, J. Org. Chem. 69 (2004) 352. [7] M. Isaka, S. Palasam, S. Lapanun, J. Nat. Prod. 70 (2007) 675. [8] G. Lang, M.I. Mitova, G. Ellis, J. Nat. Prod. 69 (2006) 621. [9] R. Van Heerbeek, P.C.J. Kamer, P.N.M.W. Van Leeuwen, Org. Biol. Chem. 4 (2006) 211. [10] Pentapeptide 3 (628 mg, 1 mmol) and O-prenyl-D-tryptophan fragment 6 (393 mg, 1.0 mmol) were dissolved in dichloromethane (10 mL) at 0 8C, after EDCI (320 g, 2.0 mmol) and DMAP (488 mg, 4 mmol) were added, the reaction was stirred at room temperature for 16 h. The reaction mixture successively washed with saturated NH4Cl solution (20 mL), saturated NaHCO3 solution (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The crude product was purified by silica gel chromatography, using 5% ethyl acetate–hexane as eluent, to afford the desired ester (2) (750 mg, 75%) as clear oil. 1H NMR (500 MHz, CDCl3, d ppm): 7.36–7.17 (m, 11H), 7.12 (d, 2H, J = 7.5 Hz), 6.91 (d, 2H, J = 6.9 Hz), 6.86 (d, 2H, J = 7.8 Hz), 5.48 (br s, 1H), 5.25 (br s, 1H), 4.76 (br s, 1H), 4.48 (d, 2H, J = 5.5 Hz), 4.40 (q, 2H, J = 7.1 Hz), 4.26–4.14 (m, 6H), 3.91 (d, 1H, J = 12.1 Hz), 3.70 (d, 1H, J = 12.3 Hz), 3.17–3.08 (m, 4H), 2.98 (dd, 1H, J = 13.9, 7.6 Hz), 2.90 (dd, 1H, J = 13.9, 7.2 Hz), 2.02 (br s, 1H), 1.79 (s, 3H), 1.73 (s, 3H), 1.34 (d, 3H, J = 6.7 Hz), 1.21 (d, 3H, J = 6.9 Hz), 1.01–0.95 (m, 4H), 0.04 (s, 9H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3, d ppm): 174.4, 172.7, 172.5, 170.6, 168.9, 158.2, 149.3, 137.9, 137.0, 134.6, 130.4, 130.3, 129.6, 128.3, 127.4, 126.7, 121.2, 119.7, 115.0, 72.7, 64.8, 63.8, 54.2, 48.7, 48.5, 43.0, 40.3, 37.6, 25.7, 18.1, 17.7, 17.3, 17.2, 1.6. HRESIMS m/z Calcd. for C51H73N5O12Si2Na: [M+Na]+ 1026.4684. Found: [M+Na]+ 1026.4692. [11] L.A. Carpino, A. El-Faham, C.A. Minor, J. Chem. Soc. Chem. Commun. (1994) 201. [12] Precursor 2 (100 mg, 0.1 mmol) was treated with a solution of 0.1 mol/L TBAF in THF (5 mL) at 0 8C for 1 h. The reaction was allowed to warm to room temperature and stirred further for 4 h. The solvents were evaporated under reduced pressure to give the crude product, which was then dissolved in DMF (100 mL) and treated with HATU (142 mg, 0.4 mmol) at 25 8C for 30 min, and then DIPEA (0.11 mL, 0.6 mmol) was added to the reaction mixture. The reaction mixture was allowed to stir at this temperature for 48 h and DMF was then removed by
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M.J. Yang et al. / Chinese Chemical Letters 20 (2009) 527–530 distillation under vacuum at the temperature below 50 8C. The resulting crude product was purified by flash column chromatography on silica gel, using 2% MeOH in dichloromethane as eluent to afford the paecilodepsipeptide A (1) (54 mg, 72% over two steps) as a white solid. mp 1 25 138–140 8C; ½a25 D þ 21:5 (c, 0.5, MeOH), lit. ½aD þ 22 (c, 0.15, MeOH); H NMR (500 MHz, DMSO-d6, d ppm): 9.22 (br s, 1H, 7-OH, DTyr), 8.78 (d, 1H, J = 4.0, NH, O-prenyl-D-Tyr), 8.55 (d, 1H, J = 8.2 Hz, NH, D-Tyr), 8.01 (d, 1H, J = 8.3 Hz, NH, Gly), 7.84 (d, 1H, J = 7.3 Hz, NH, Ala-1), 7.56 (d, 1H, J = 8.4 Hz, NH, Ala-2), 7.20–7.175 (m, 3H, H-6, 7, 8, L-3-Ph-Lac), 7.01 (d, 2H, J = 8.5 Hz, H-5, 9, O-prenyl-D-Tyr), 6.97 (d, 2H, J = 8.5 Hz, H-5, 9, D-Tyr), 6.88 (m, 2H, H-6, 8, O-prenyl-D-Tyr), 6.79–6.76 (m, 2H, H-5, 9, L-3-Ph-Lac), 6.63 (d, 2H, J = 8.5 Hz, H6, 8, D-Tyr), 5.34 (t, 1H, J = 6.6 Hz, H-20 , O-prenyl-D-Tyr), 5.14 (t, 1H, J = 5.2 Hz, H-2, L-3-Ph-Lac), 4.44 (d, 2H, J = 6.6 Hz, H-10 , O-prenyl-DTyr), 4.28–4.15 (m, 4H, H-2 of Ala-1, H-2 of Ala-2, H-2 of O-prenyl-D-Tyr, H-2 of D-Tyr), 3.57 (dd, 1H, J = 15.8, 6.6 Hz, H-2a, Gly), 3.34 (m, 1H, H-2b, Gly), 2.98 (dd, 1H, J = 14.2, 5.8 Hz, H-3a, L-3-Ph-Lac), 2.95 (dd, 1H, J = 14.2, 4.3 Hz, H-3a, D-Tyr), 2.91 (dd, 1H, J = 13.2, 5.4 Hz, H-3a, O-prenyl-D-Tyr), 2.80 (dd, 1H, J = 13.2, 9.2 Hz, H-3b, O-prenyl-D-Tyr), 2.72 (dd, 1H, J = 13.9, 10.8 Hz, H-3b, D-Tyr), 2.58 (dd, 1H, J = 14.0, 4.3 Hz, H-3b, L-3-Ph-Lac), 1.63 (s, 3H, H-50 , O-prenyl-D-Tyr), 1.65 (s, 3H, H-40 , O-prenyl-D-Tyr), 1.26 (d, 3H, J = 7.1 Hz, H-2, Ala2), 1.04 (d, 3H, J = 6.9 Hz, H-2, Ala-1); 13C NMR (125 MHz, DMSO-d6, d ppm): 172.6 (s, C-1, Ala-2), 172.3 (s, C-1, Ala-1), 171.7 (s, C-1, Oprenyl-D-Tyr), 170.6 (s, C-1, D-Tyr), 169.6 (s, C-1, Gly), 168.2 (s, C-1, L-3-Ph-Lac), 158.0 (s, C-7, O-prenyl-D-Tyr), 156.2 (s, C-7, D-Tyr), 137.4 (s, C-3, O-prenyl-D-Tyr), 135.9 (s, C-4, L-3-Ph-Lac), 130.8 (d, C-5 and C-9, O-prenyl-D-Tyr), 130.2 (d, C-5 and C-9, D-Tyr), 130.2 (d, C-5 and C-9, L-3-Ph-Lac), 128.7 (s, C-4, D-Tyr), 128.3 (d, C-6 and C-8, L-3-Ph-Lac), 128.3 (s, C-4, O-prenyl-D-Tyr), 127.1 (d, C-7, L-3-Ph-Lac), 120.4 (d, C-2, O-prenyl-D-Tyr), 115.5 (d, C-6 and C-8, D-Tyr), 115.0 (d, C-6 and C-8, O-prenyl-D-Tyr), 73.6 (d, C-2, L-3-Ph-Lac), 64.6 (t, C-1, Oprenyl-D-Tyr), 56.5 (d, C-2, O-prenyl-D-Tyr), 56.1 (d, C-2, D-Tyr), 49.0 (d, C-2, Ala-1), 48.0 (d, C-2, Ala-2), 43.5 (t, C-2, Gly), 37.4 (t, C-3, L-3Ph-Lac), 36.0 (t, C-3, D-Tyr), 35.4 (t, C-3, O-prenyl-D-Tyr), 25.9 (q, C-4, O-prenyl-D-Tyr), 19.1 (q, C-3, Ala-2), 18.8 (q, C-3, Ala-1), 18.4 (q, C5, O-prenyl-D-Tyr). HR-ESIMS m/z Calcd. for C40H47N5O9Na: 764.3264 [M+Na]+ (Calcd. for C40H47N5O9Na, 764.3271).