A Study Towards Total Synthesis of Antibiotic Agrocin 84

Abstract

A versatile synthetic route to compound 2 - an analog of the naturally occurring bacteriocin Agrocin 84 is described.

Notes

Abbreviations used: CNE, 2-cyanoethyl; DMAP, 4-dimethylaminopyridine; DIPEA, N,N-diiso-propylethylamine; DMT, 4.4′-dimethoxytrityl; TBS, tert-butyldimethylsilyl; DCA, trichloroacetic acid; TEA, triethylamine; TEAA, triethylammonium acetate; 5-MMT, 5-mercapto-1-methyltetrazole

³¹P NMR δ -1.6, -2.4 ppm, m/z (electrospray) 1445.4 (M+H)⁺, 1167 (M+Na)⁺

Analytical HPLC was performed at 40° C on LiChrospher^4,22 100 RP-18 column (Merck, 5 μm, 4.6 × 250 mm) using linear gradient from 0 to 50% of buffer B (0.05 M TEAA in 1:l MeCNlwater) in buffer A (0.05 M TEAA in 5% aq. MeCN); R₁ 9.8 min (compound 2), 13.8 min (compound 15). Preparative HPLC was done at 20° C on Econospher^4,22 C-18 column (All Tech, 10 μm, 250 × 22.5 mm) using linear gradient from 0 to 30% of B (0.02 M TEAA in 1:l MeCN/water) in buffer A (0.05 M TEAA in 5% aq. MeCN)

It is noteworthy that sodium salt of compound 2 could be prepared by passing a solution of 2 in water through a pad of Dowex-Na⁺ resin but found to be unstable and decomposed slowly releasing N-phosphorylated adenosine 15. Compound 2: (TEA⁺-salt): ¹H-COSY NMR (600 MHz, /D₂O) δ 8.51 (1H, s H-arom), 8.41 (1H, s, H-arom), 6.14 (IH, d, H-1′ J_1,2 5.8), 4.44 (1H, dd, H-3′, J, 3.7, J₂ 5.1), 4.34 (IH, m, H-4′). 4.14 (3H, m, H-5′, H-2′). 3.74 (2H, m, AA'X, H-3′), 3.17 (6, q, CH₂, TEA⁺ J 7.3) 1.64 (6H, m, cyclopentyl), 1.46 (2H, m, cyclopentyl), 1.24 (9, t, CH₃, TEA⁺ J 7.3). MS (electrospray, negative mode) m/z 581 (M-H), 603 (M-2H+Na). Compound 15 (Na⁺-salt): ¹H-COSY NMR (300 MHz, D₂O) 8.44 (1H, s H- arom), 8.40 (1H, s, H-arom), 6.11 (1H, d, H-l⁺, J_1′2′, 6.1), 4.45 (1H, dd, H-3′, J₁ 3.5, J₂ 5.2), 4.31 (1H, m, H-4′), 3.89 (2H, m, AA'X, H-5′), 1.57 (8H, m, cyclopentyl). MS (electrospray) m/z 438 (M+Na)⁺, 460 (M-H+2Na)⁺, 482 (M-2H+3Na)⁺