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Synlett 2008(4): 569-574  
DOI: 10.1055/s-2008-1042759
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of the Proposed Structure of LL15G256γ

Shuo Lia, Shuo Lianga, Zhengshuang Xu*a,b, Tao Ye*a,b
a Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen, Xili, Nanshan District, Shenzhen 518055, P. R. of China
b Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax: +85222641912; e-Mail: bctaoye@inet.polyu.edu.hk;
Further Information

Publication History

Received 8 November 2007
Publication Date:
12 February 2008 (online)

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Abstract

The first total synthesis of a molecule possessing the stereochemistry proposed for LL15G256γ is described. The structure synthesized appears to be different from that of the marine natural product.

Key words

antifungal agents - cyclodepsipeptide - LL15G256γ - total synthesis - benzylic oxidation - macrolactamization

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Cyclodepsipeptide 2: [a]D 25 -3.6 (c 1.0, MeOH). 1H NMR (500 MHz, CD3OD): d = 7.56 (1 H, d, J = 7.9 Hz), 7.32 (1 H, d, J = 8.2 Hz), 7.18 (1 H, s), 7.09 (1 H, dd, J = 7.8, 7.8 Hz,), 7.01 (1 H, dd, J = 7.8, 7.1 Hz), 4.96 (1 H, dd, J = 9.2, 7.2 Hz), 4.62 (1 H, dd, J = 8.8, 5.0 Hz), 4.45 (1 H, dd, J = 7.8, 5.7 Hz), 3.98 (1 H, t, J = 7.4 Hz,), 3.54-3.46 (2 H, m), 3.26 (1 H, dd, J = 15.1, 5.3 Hz,), 3.26 (1 H, dd, J = 15.1, 8.9 Hz), 2.82 (1 H, dd, J = 9.7, 7.3 Hz), 2.20-2.17 (2 H, m), 2.04-1.95 (2 H, m), 1.85-1.80 (1 H, m), 1.43 (9 H, s), 1.31 (14 H, br s), 1.17 (3 H, d, J = 7.2 Hz), 0.90 (3 H, d, J = 6.9 Hz), 0.88 (3 H, t, J = 7.2 Hz) ppm. 13C NMR (125 MHz, CD3OD): δ = 176.6, 174.2, 173.9, 172.8, 169.2, 138.1, 128.7, 124.3, 122.6, 119.9, 119.2, 112.4, 110.7, 81.8, 80.4, 62.6, 57.3, 56.9, 54.2, 44.7, 36.1, 35.1, 33.0, 32.5, 30.8, 30.6, 30.4, 28.4 (3 C), 28.3, 27.8, 25.3, 23.7, 15.5, 14.4, 14.1 ppm. ESI-HRMS: m/z calcd for C37H56N4O8Na [M + Na]+: 707.3996; found: 707.3998.

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Procedure for the Synthesis of LL15G256γ (1)
To a stirred solution of cyclodepsipeptide 2 (30 mg, 0.044 mmol) in 90% THF (5 mL), DDQ (25 mg, 0.11 mmol) was added at 0 °C. The reaction was allowed to warm to r.t. and stirred for 6 h. Then, EtOAc (30 mL) was added and the mixture was washed with sat. aq NaHCO3 (3 × 15 mL) and brine (15 mL). The organic layer was dried over Na2SO4 and concentrated. The residue, after being purified by flash chromatography on silica gel, using MeOH-CH2Cl2 (5:95) as eluent, provided the desired β-keto product (21.1 mg, 69%). [a]D 25 -8.0 (c 0.8, CH2Cl2). IR (KBr): 3421.5, 3282.6, 2927.7, 2854.5, 1697.2, 1651.0, 1508.2, 1419.5, 1280.6, 1157.2, 1068.5, 748.3 cm-1. 1H NMR (500 MHz, DMSO-d 6): δ = 12.14 (1 H, s), 8.58 (1 H, d, J = 7.7 Hz), 8.40 (1 H, s), 8.31 (1 H, d, J = 6.9 Hz), 8.14 (1 H, dd, J = 8.4, 1.6 Hz), 7.50 (1 H, dd, J = 8.2, 1.3 Hz), 7.25-7.18 (3 H, m), 5.77 (1 H, d, J = 8.6 Hz), 5.02 (1 H, dd, J = 6.6, 4.6 Hz), 4.90 (1 H, d, J = 5.7 Hz), 4.28 (1 H, dd, J = 9.0, 6.3 Hz), 3.73 (1 H, d, J = 8.4 Hz), 3.40-3.34 (2 H, m), 2.74 (1 H, dd, J = 10.6, 7.1 Hz), 2.18-2.15 (1 H, m), 2.02-1.97 (1 H, m), 1.96-1.93 (1 H, m), 1.70-1.67 (1 H, m), 1.37 (9 H, s), 1.22 (14 H, br s), 1.35-1.30 (1 H, m), 1.05 (3 H, d, J = 6.7 Hz), 0.84 (3 H, t, J = 6.8 Hz), 0.83 (3 H, d, J = 6.9 Hz) ppm. 13C NMR (125 MHz, DMSO-d 6): δ = 186.2, 174.1, 172.4, 170.2, 167.9, 167.5, 137.1, 136.9, 126.1, 123.8, 122.8, 121.6, 113.9, 113.0, 80.1, 77.4, 62.1, 61.6, 56.1, 53.1, 42.9, 34.0, 33.9, 31.9, 31.7, 29.6, 29.4, 29.1, 28.3 (3 C), 27.3, 24.0, 22.5, 15.6, 14.4, 13.7 ppm. ESI-HRMS: m/z calcd for C37H54N4O9Na [M + Na]+: 721.3788; found: 721.3790. To a solution of the above β-keto macrocyclic peptide (21 mg, 0.03 mmol) in anhyd CH2Cl2 (2 mL) was added TFA (1 mL) at 0 °C. The reaction mixture was allowed to warm to r.t. and stirred for 6 h. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography on silica gel, using MeOH-CH2Cl2 (5:95 to 10:90) as eluent, to provide the desired target molecule (19 mg, 98%). [a]D 25 -11.6 (c 1.0, CD3OH). 1H NMR (500 MHz, DMSO-d 6): δ = 12.16 (1 H, s), 12.06 (1 H, s), 8.60 (1 H, d, J = 8.0 Hz), 8.38 (1 H, d, J = 3.0 Hz), 8.32 (1 H, br s), 8.15 (1 H, d, J = 6.8 Hz), 7.94 (1 H, s), 7.49 (1 H, d, J = 7.3 Hz), 7.49-7.19 (3 H, m), 5.77 (1 H, d, J = 8.7 Hz), 5.01 (1 H, t, J = 5.5 Hz), 4.95 (1 H, d, J = 10.6 Hz), 4.29 (1 H, dd, J = 8.9 Hz), 3.72 (1 H, br s), 3.38-3.34 (2 H, m), 2.76-2.71 (1 H, m), 2.08-2.03 (2 H, m), 1.99-1.94 (2 H, m), 1.70-1.65 (1 H, m), 1.34-1.30 (2 H, m), 1.28 (11 H, br s), 1.09-1.04 (1 H, m), 1.05 (3 H, d, J = 6.9 Hz), 0.83 (3 H, t, J = 7.0 Hz), 0.82 (3 H, d, J = 6.8 Hz) ppm. 13C NMR (125 MHz, CDCl3): δ = 185.7, 174.0, 173.5, 173.4, 167.3, 166.9, 136.5, 136.2, 125.5, 123.1, 122.3, 113.3, 112.3, 121.0, 76.7, 61.5, 61.0, 55.5, 52.5, 42.1, 33.4, 33.2, 31.1, 30.0, 29.1, 28.9, 28.7, 26.7, 23.1, 21.9, 15.1, 13.8, 13.1 ppm. ESI-HRMS: m/z calcd for C33H47N4O9 [M + H]+: 643.3343; found: 643.3334; m/z calcd for C33H46N4O9Na [M + Na]+: 665.3162; found: 665.3150.

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The HPLC comparison between the synthetic sample and the naturally occurring LL15G256γ were conducted by Dr. Gerhard Schlingmann (Wyeth Research, New York).