A Pd-Mediated Approach to the Synthesis of an Unusual β-Hydroxy­tryptophan Amino Acid Constituent of Cyclomarin A

Abstract

A synthetic approach based on a palladium-mediated ­vinylation of indole derivatives was established for the preparation of 5, a key intermediate in the synthesis of N-(tert-butoxycarbonyl)-l-1H-[(R)-1,1-dimethyl-2,3-epoxypropyl]-β-hydroxytryptophan ethyl ester (6). Unsatisfying yields were obtained using N-alkyl-3-haloderivatives. The best method proved to be the oxidative coupling on 3-unsubstituted indole derivative.

Key words

indoles - palladium - Heck reaction - marine natural product - Stille reaction

References and Notes

• 1a Renner MK. Shen Y.-C. Cheng X.-C. Jensen PR. Frankmoelle W. Kauffmann CA. Fenical W. Lobkovsky E. Clardy J. J. Am. Chem. Soc.  1999,  121:  11273 
• 1b Fenical WH, Jacobs RS, and Jensen PR. inventors; U.S. Patent  5,444,043. 
• 1c Fenical WH, Jacobs RS, and Jensen PR. inventors; U.S. Patent  5,593,960. 
• 2 Pazoles CJ, and Siegel SA. inventors; U.S. Patent  5,759,995. 
• 3 Waters B. Saxena G. Wanggui Y. Kau D. Wrigley S. Stokes R. Davies J. J. Antibiot.  2002,  55:  407 
• 4 Sugiyama H. Shioiri T. Yokokawa F. Tetrahedron Lett.  2002,  43:  3489 
• 5 Tarver JE. Joullié MM. J. Org. Chem.  2004,  69:  815 
• 6 Tarver JE. Terranova KM. Joullié MM. Tetrahedron  2004,  60:  10277 
• 7 Hajra S. Karmakar A. Tetrahedron Lett.  2004,  45:  3185 
• 8 Hansen DB. Lewis AS. Gavalas SJ. Joullié MM. Tetrahedron: Asymmetry  2006,  17:  15 
• 9 Della Sala G. Capozzo D. Izzo I. Giordano A. Iommazzo A. Spinella A. Tetrahedron Lett.  2002,  43:  8839 
• 10 Pirrung MC. Li Z. Park K. Zhu J. J. Org. Chem.  2002,  67:  7919 
• 11 Franck WC. Kim YC. Heck RF. J. Org. Chem.  1978,  43:  2947 
• 12 Harrington PJ. Hegedus LS. J. Org. Chem.  1984,  49:  2657 
• 13a Ahaidar A. Fernández D. Danelón G. Cuevas C. Manzanares I. Albericio F. Joule JA. Álvarez M. J. Org. Chem.  2003,  68:  10020 
• 13b Ahaidar A. Fernández D. Pérez O. Danelón G. Cuevas C. Manzanares I. Albericio F. Joule JA. Álvarez M. Tetrahedron Lett.  2003,  44:  6191 
• 13c Álvarez M. Fernández D. Joule JA. Tetrahedron Lett.  2001,  42:  315 
• 14 Sakamoto T. Kondo Y. Yasuhara A. Yamanaka H. Tetrahedron  1991,  47:  1877 
• 15 Moritani I. Fujiwara Y. Tetrahedron Lett.  1967,  12:  1119 
• 16 Jia C. Piao D. Oyamada J. Lu W. Kitamura T. Fujiwara Y. Science  1992,  287:  1992 
• 17 Jia C. Lu W. Kitamura T. Fujiwara Y. Org. Lett.  1999,  1:  2097 
• 18 Grimster NP. Gauntlett C. Godfrey CRA. Gaunt MJ. Angew. Chem. Int. Ed.  2005,  44:  3125 
• 19 Capito E. Brown JM. Ricci A. Chem. Commun.  2005,  1854 

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Procedure for Pd(OAc) ₂ -Catalyzed Oxidative Heck Coupling (Table 2, Entry 4). A mixture of indole 13 (90 mg, 0.35 mmol), Pd(OAc)₂ (36 mg, 0.16 mmol), Cu(OAc)₂ (0.318 g, 1.75 mmol) and ethyl acrylate (0.11 mL, 1.0 mmol) in dry DMF-DMSO 9:1 (10 mL) was deoxygenated and heated at 80 °C in a capped Schlenk tube. After 24 h, the reaction vessel was cooled to r.t. and CH₂Cl₂ (20 mL) was added. The organic phase was washed with H₂O (3 × 30 mL) and the resulting aqueous phases were again extracted with CH₂Cl₂ (20 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution with PE-Et₂O mixtures from 100:0 to 1:1) afforded product 12 (87 mg, 70% yield) as a yellow oil and an additional product 19 (21 mg, 23% yield).

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Compound 12: [α]_D ²² +12.3 (c 1.8, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (1 H, m, indole H-4 or H-7), 7.90 (1 H, d, J = 16.0 Hz, β-acrylic CH), 7.70 (1 H, m, indole H-4 or H-7), 7.62 (1 H, s, indole H-2), 7.20-7.24 (2 H overlapped, m, indole H-5, H-6), 6.41 (1 H, d, J = 16.0 Hz, α-acrylic CH), 4.84 (1 H, dd, J = 7.0, 6.1 Hz, acetonide CH), 4.27 (2 H, q, J = 7.1 Hz, acrylate CH ₂), 3.86 (1 H, dd, J = 8.9, 7.0 Hz, acetonide CH ₂), 3.60 (1 H, dd, J = 8.9, 6.1 Hz, acetonide CH ₂), 1.79 (3 H, s, CH ₃), 1.72 (3 H, s, CH ₃), 1.41 (3 H, m, acetonide CH ₃), 1.35 (3 H, t, J = 7.1 Hz, acrylate CH ₃), 1.34 (3 H, m, acetonide CH ₃). ¹³C NMR (100 MHz, CDCl₃): δ = 168.3, 138.0, 136.6, 130.8, 127.7, 122.3, 121.1, 120.7, 114.2, 112.7, 111.6, 110.3, 79.1, 65.3, 61.0, 60.0, 25.9, 24.7, 24.2, 23.5, 14.4. MS (EI, 70 eV, 250 °C): m/z = 357 [M⁺], 256. Anal. Calcd for C₂₁H₂₇NO₄ (%): C, 70.56; H, 7.61; N, 3.92. Found: C, 70.27; H, 7.43; N, 3.92.

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Compound 19: ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (1 H, m, indole H-4 or H-7), 7.76 (1 H, m, indole H-4 or H-7), 7.53 (1 H, s, indole H-2), 7.21 (1 H, m, indole H-5 or H-6), 7.13 (1 H, m, indole H-5 or H-6), 4.95 (1 H, dd, J = 7.0, 6.0 Hz, acetonide CH), 3.83 (1 H, dd, J = 8.9, 7.0 Hz, acetonide CH ₂), 3.69 (1 H, dd, J = 8.9, 6.0 Hz, acetonide CH ₂), 1.87 (3 H, s, CH ₃), 1.79 (3 H, s, CH ₃), 1.45 (3 H, m, acetonide CH ₃), 1.37 (3 H, m, acetonide CH ₃). ¹³C NMR (100 MHz, CDCl₃) δ = 135.7, 129.1, 123.6, 121.3, 120.5, 119.2, 113.6, 110.1, 109.0, 79.5, 65.4, 60.3, 26.0, 25.1, 24.8, 23.2. MS (ES): m/z = 517 [M + H]⁺. Anal. Calcd for C₃₂H₄₀N₂O₄ (%): C, 74.39; H, 7.80; N, 5.42. Found: C, 74.37; H, 7.77; N, 5.39.

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Procedure for PdCl ₂ -Catalyzed Oxidative Heck Coupling (Table 2, Entry 5). A mixture of indole 13 (78 mg, 0.30 mmol), PdCl₂ (15 mg, 0.085 mmol), Cu(OAc)₂ (0.168 g, 0.92 mmol) and ethyl acrylate (0.10 mL, 0.92 mmol) in dry MeCN (3.5 mL) was deoxygenated and heated at 40 °C in a capped Schlenk tube. After 24 h, the reaction vessel was cooled to r.t. Brine was added (25 mL) and the mixture was extracted with EtOAc (3 × 25 mL). The combined organic phases were dried over MgSO₄, filtered and concentrated in vacuo. Purification by flash chromatography (gradient elution with PE-Et₂O mixtures from 8:2 to 4:6) afforded product 12 (92 mg, 86% yield).