4
A.R. Rodriguez, B.W. Spur / Tetrahedron Letters xxx (xxxx) xxx
4.2, 1.8 Hz, 1H), 2.5 (dd, J = 16.5, 6.3 Hz, 1H ABsystem), 2.4 (dd, J = 16.5, 7.5 Hz,
1H ABsystem), 0.89 (s, 9H), 0.13 (s, 9H), 0.09 (s, 3H), 0.05 (s, 3H); 13C NMR
(CDCl3, 75.5 MHz): d 193.45, 157.82, 131.23, 102.05, 87.77, 70.49, 28.93, 25.70
(3C), 18.13, –0.06 (3C), –4.80, –4.87. Compound 21: 1H NMR (CDCl3, 300
MHz): d 6.5 (dd, J = 15.3, 11.1 Hz, 1H), 6.0–5.9 (t, J = 11.1 Hz, 1H), 5.7 (dd,
J = 15.3, 6.0 Hz, 1H), 5.5–5.2 (m, 3H), 4.4–4.2 (m, 1H), 3.0–2.8 (m, 2H), 2.5–2.4
(dd, J = 16.8, 6.9 Hz, 1H ABsystem), 2.4–2.3 (dd, J = 16.8, 6.3 Hz, 1H ABsystem),
2.1–2.0 (m, 2H), 1.0–0.9 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H), 0.12 (s, 9H), 0.09 (s, 3H),
0.05 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 135.34, 132.37, 130.32, 127.70,
126.60, 124.86, 104.17, 86.20, 71.92, 30.04, 25.96, 25.83 (3C), 20.55, 18.25,
14.22, 0.05 (3C), –4.52, –4.71. Compound 3: 1H NMR (CDCl3, 300 MHz): d 6.6–
6.5 (ddt, J = 15.3, 11.1, 1.2 Hz, 1H), 6.0 (t, J = 11.1 Hz, 1H), 5.8–5.7 (dd, J = 15.3,
5.7 Hz, 1H), 5.5–5.2 (m, 3H), 4.4–4.3 (m, 1H), 3.0–2.8 (m, 2H), 2.4 (ddd, J = 16.5,
6.0, 2.7 Hz, 1H ABsystem), 2.3 (ddd, J = 16.5, 6.9, 2.7 Hz, 1H ABsystem), 2.1–2.0
(m, 2H), 2.0–1.9 (t, J = 2.7 Hz, 1H), 1.0–0.9 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H), 0.08
(s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 134.97, 132.37, 130.46,
127.64, 126.56, 125.10, 81.29, 71.63, 69.97, 28.59, 25.98, 25.80 (3C), 20.55,
18.23, 14.22, –4.56, –4.80. Compound 22: 1H NMR (CDCl3, 300 MHz): d 6.6–
6.5 (br dd, J = 15.0, 11.1 Hz, 1H), 6.1–5.9 (m, 2H), 5.8–5.7 (dd, J = 15.0, 5.7 Hz,
1H), 5.6–5.5 (m, 1H), 5.5–5.2 (m, 3H), 4.4–4.3 (m, 1H), 4.2–4.0 (m, 1H), 3.6 (s,
3H), 3.0–2.8 (m, 2H), 2.5 (ddd, J = 16.5, 6.9, 2.1 Hz, 1H ABsystem), 2.4 (ddd,
J = 16.5, 6.3, 2.1 Hz, 1H ABsystem), 2.3–2.2 (t, J = 7.5 Hz, 2H), 2.1–2.0 (m, 2H),
1.7–1.2 (m, 8H), 1.0–0.9 (t, J = 7.5 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.08 (s, 3H),
0.05 (s, 3H), 0.01 (s, 3H), 0.00 (s, 3H). Compound 23: 1H NMR (CDCl3, 300
MHz): d 6.6 (ddt, J = 15.3, 11.1, 1.2 Hz, 1H), 6.1–6.0 (dd, J = 15.9, 6.3 Hz, 1H), 6.0
(t, J = 11.1 Hz, 1H), 5.8–5.7 (dd, J = 15.3, 6.6 Hz, 1H), 5.7–5.6 (m, 1H), 5.5–5.2
(m, 3H), 4.4–4.3 (m, 1H), 4.2–4.0 (m, 1H), 3.6 (s, 3H), 3.0–2.8 (m, 2H), 2.6 (ddd,
J = 16.8, 5.4, 2.1 Hz, 1H ABsystem), 2.5 (ddd, J = 16.8, 6.3, 2.1 Hz, 1H ABsystem),
2.3 (t, J = 7.5 Hz, 2H), 2.2–2.0 (m, 2H), 1.7–1.2 (m, 8H), 1.0–0.9 (t, J = 7.5 Hz,
3H); 13C NMR (CDCl3, 75.5 MHz): d 174.19, 145.16, 133.79, 132.48, 131.41,
127.53, 126.42, 126.37, 109.94, 86.39, 80.94, 72.17, 70.72, 51.48, 36.65, 33.94,
28.92, 28.70, 25.99, 24.86, 24.77, 20.56, 14.22. 7(S),13(R)-RvT4 methyl ester
(24): 1H NMR (CD3OD, 300 MHz): d 6.6–6.4 (2 dd, J = 15.3, 11.1Hz, 2H), 6.2–
6.0 (t, J = 11.1 Hz, 1H), 6.0–5.9 (t, J = 11.1 Hz, 1H), 5.7–5.6 (m, 2H), 5.5–5.2 (m,
4H), 4.2–4.1 (m, 1H), 4.1–4.0 (m, 1H), 3.6 (s, 3H), 3.0–2.9 (m, 2H), 2.5–2.4 (m,
2H), 2.3 (t, J = 7.5 Hz, 2H), 2.2–2.0 (m, 2H), 1.7–1.3 (m, 8H), 1.0–0.9 (t, J = 7.5
Hz, 3H); 13C NMR (CD3OD, 75.5 MHz): d 175.97, 138.02, 136.97, 133.13,
131.11, 131.08, 129.12, 128.13, 127.79, 126.55, 126.48, 73.22, 73.04, 51.97,
38.19, 36.80, 34.74, 30.11, 26.83, 26.22, 25.98, 21.47, 14.63. 7(S),13(R)-RvT4
(2): 1H NMR (CD3OD, 300 MHz): d 6.6–6.4 (2 dd, J = 15.3, 11.1 Hz, 2H), 6.2–6.0
(t, J = 11.1 Hz, 1H), 6.0–5.9 (t, J = 11.1 Hz, 1H), 5.7–5.6 (2 dd, J = 15.3, 6.3 Hz and
J = 15.3, 7.2 Hz, 2H), 5.5–5.2 (m, 4H), 4.2–4.1 (m, 1H), 4.1–4.0 (m, 1H), 3.0–2.9
(m, 2H), 2.5–2.3 (m, 2H), 2.3–2.2 (t, J = 7.5 Hz, 2H), 2.2–2.0 (m, 2H), 1.7–1.3 (m,
8H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR (CD3OD, 75.5 MHz): d 178.81, 138.07,
136.97, 133.12, 131.11 (2C), 129.13, 128.08, 127.79, 126.50 (2C), 73.24, 73.05,
38.29, 36.80, 35.86, 30.30, 26.83, 26.43, 26.32, 21.47, 14.63; UV (CH3OH) kmax
239 nm. HPLC/UV: Zorbax SB-C18, 1.8 mm, 50 x 2.1 mm, 237 nm, CH3OH/H2O
(0.1% formic acid) 50:50–70:30, 0.2 mL/min, tR = 17.3 min; HPLC/MS (m/z):
361.2 [M-H] –. 7(S),13(R),20(S)-RvT1 (1): 1H NMR (CD3OD, 300 MHz): d 6.8–
6.6 (m, 2H), 6.5 (dd, J = 15.3, 11.1 Hz, 1H), 6.2–6.0 (t, J = 11.1 Hz, 1H), 6.0–5.9
(m, 2H), 5.8–5.6 (3 dd, J = 15.3, 6.3 Hz, J = 15.3, 6.6 Hz and J = 15.3, 6.9 Hz, 3H),
5.5–5.4 (dt, J = 10.8, 7.5 Hz, 1H), 4.3–4.1 (m, 1H), 4.1–4.0 (m, 2H), 2.5–2.4 (m,
2H), 2.2 (t, J = 7.5 Hz, 2H), 1.7–1.3 (m, 10H), 1.0–0.9 (t, J = 7.5 Hz, 3H); 13C NMR
(CD3OD, 75.5 MHz): d C1 not observed, 138.42, 138.00, 137.74, 131.19, 130.11,
129.81, 127.95, 126.60, 126.53 (2C), 74.63, 73.27, 72.96, 38.19, 36.87, 36.70,
31.08, 30.32, 26.75, 26.27, 10.15. UV (EtOH) kmax 238, 260, 270, 280 nm.
HPLC/UV: Zorbax SB-C18, 1.8 mm, 50 x 2.1 mm, 269 nm, CH3OH/H2O (0.1%
formic acid) 50:50–70:30, 0.2 mL/min, tR = 12.4 min; HPLC/MS (m/z): 377.2
[M-H] –.
[28] Satisfactory spectroscopic data were obtained for all compounds. Selected
physical data: Compound 10: 1H NMR (CDCl3, 300 MHz): d 3.6 (s, 3H), 2.4–2.3
(t, J = 7.5 Hz, 2H), 2.3–2.2 (t, J = 7.5 Hz, 2H), 1.7–1.5 (m, 4H), 1.4–1.3 (m, 2H);
13C NMR (CDCl3, 75.5 MHz): d 179.43, 174.12, 51.53, 33.77, 33.74, 28.44,
24.48, 24.23. Compound 11: 1H NMR (CDCl3, 300 MHz): d 3.6 (s, 3H), 2.9–2.8
(t, J = 7.2 Hz, 2H), 2.3 (t, J = 7.5 Hz, 2H), 1.8–1.5 (m, 4H), 1.4–1.3 (m, 2H); 13C
NMR (CDCl3, 75.5 MHz): d 173.73, 173.62, 51.50, 46.77, 33.57, 27.78, 24.63,
24.27. Compound 12: 1H NMR (CDCl3, 300 MHz): d 3.6 (s, 3H), 2.6–2.5 (t,
J = 7.3 Hz, 2H), 2.3 (t, J = 7.3 Hz, 2H), 1.7–1.5 (m, 4H), 1.4–1.2 (m, 2H), 0.2 (s,
9H); 13C NMR (CDCl3, 75.5 MHz): d 187.60, 173.96, 101.93, 97.73, 51.47,
44.96, 33.77, 28.33, 24.56, 23.45, –0.79 (3C). Compound 13: 1H NMR (CDCl3,
300 MHz): d 4.4–4.3 (t, J = 6.6 Hz, 1H), 3.6 (s, 3H), 2.3 (t, J = 7.5 Hz, 2H), 1.9 (s,
1H), 1.7–1.6 (m, 4H), 1.5–1.3 (m, 4H), 0.14 (s, 9H); 13C NMR (CDCl3, 75.5
MHz): d 174.18, 106.72, 89.37, 62.71, 51.46, 37.38, 33.91, 28.67, 24.75, 24.70, –
0.15 (3C); [a]D20 = –0.5 (c 0.63, CHCl3). Compound 14: 1H NMR (CDCl3, 300
MHz): d 4.3 (t, J = 6.6 Hz, 1H), 3.6 (s, 3H), 2.3 (t, J = 7.5 Hz, 2H), 1.7–1.6 (m, 4H),
1.5–1.3 (m, 4H), 0.87 (s, 9H), 0.12 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H); 13C NMR
(CDCl3, 75.5 MHz): d 174.21, 107.78, 88.41, 63.24, 51.44, 38.21, 33.99, 28.72,
25.80 (3C), 24.87, 24.84, 18.27, –0.18 (3C), –4.48, –4.95; [a]D20 = –37 (c 0.58,
CHCl3). Compound 15: 1H NMR (CDCl3, 300 MHz): d 4.3 (td, J = 6.6, 2.1 Hz,
1H), 3.6 (s, 3H), 2.4–2.3 (d, J = 2.1 Hz, 1H), 2.3 (t, J = 7.5 Hz, 2H), 1.7–1.5 (m,
4H), 1.5–1.2 (m, 4H), 0.87 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3,
75.5 MHz): d 174.18, 85.58, 71.96, 62.61, 51.45, 38.30, 33.98, 28.75, 25.75 (3C),
24.85, 24.72, 18.20, –4.59, –5.09; [a]D20 = –36 (c 0.52, CHCl3). Compound 4:
1H NMR (CDCl3, 300 MHz): d 6.5 (dd, J = 14.4, 6.0 Hz, 1H), 6.2–6.1 (dd, J = 14.4,
1.2 Hz, 1H), 4.2–4.0 (m, 1H), 3.6 (s, 3H), 2.3 (t, J = 7.5 Hz, 2H), 1.7–1.2 (m, 8H),
0.86 (s, 9H), 0.02 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 174.17,
149.22, 75.58, 75.02, 51.47, 37.28, 33.99, 29.04, 25.80 (3C), 24.85, 24.48, 18.19,
[37] To compound 2 (2.8 mg, 7.7Â10À3 mmol) in 0.01 M solution of borate buffer
pH 10.7 (10 ml) was added lipoxidase Type I-B from soybean (Sigma cat. #
L7395-15MU, EC No. 232-853-1, 158000 U/mg) (9 mg) at rt and stirred for 1 h
45 min. The reaction was monitored by UV showing kmax at 271 nm. The
solution was purged with argon and TCEP-HCl (4.6 mg, 0.016 mmol) was
added. After stirring for 1 min the reaction mixture was passed through a
reversed phase C–18 cartridge, washed with H2O and compound 1 eluted with
CH3OH/H2O (8/2). Purification by HPLC [Zorbax SB-C18 250 Â 21.2 mm,
CH3OH/H2O (0.1% NH4OAc, pH 5.6, 0.05% EDTA disodium) 60/40] and
desalting gave pure 7(S),13(R),20(S)-RvT1 (1) (0.64 mg, 22%).
–4.53, –4.90; [a]D20 = –18.5 (c 0.35, CHCl3). Compound 18:1H NMR (CDCl3,
300 MHz): d 3.9–3.7 (m, 1H), 3.6–3.4 (2 dd, J = 10.2, 5.4 Hz and J = 10.2, 6.3 Hz ,
2H ABsystem), 2.5 (dd, J = 16.8, 5.4 Hz, 1H ABsystem), 2.3–2.2 (dd, J = 16.8, 6.6
Hz, 1H ABsystem), 0.88 (s, 18H), 0.12 (s, 9H), 0.09 (s, 3H), 0.06 (s, 3H), 0.03 (s,
3H), 0.03 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 104.71, 85.78, 72.08, 66.67,
25.96 (3C), 25.84 (3C), 25.76, 18.37, 18.13, 0.07 (3C), – 4.46, – 4.61, – 5.34, –
5.40; [a]D20 = +9.7 (c 0.23, CHCl3). Compound 19: 1H NMR (CDCl3, 300 MHz):
d 3.9–3.8 (m, 1H), 3.7–3.6 (dd, J = 11.1, 3.9 Hz, 1H ABsystem), 3.6–3.5 (dd,
J = 11.1, 4.8 Hz, 1H ABsystem), 2.5–2.4 (dd, J = 16.8, 6.9 Hz, 1H ABsystem), 2.4–
2.3 (dd, J = 16.8, 6.3 Hz, 1H ABsystem), 0.88 (s, 9H), 0.11 (s, 9H), 0.10 (s, 3H),
0.09 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d 103.31, 86.73, 71.47, 65.87, 25.76
(3C), 25.35, 18.03, –0.02 (3C), –4.52, –4.77. Compound 20: 1H NMR (CDCl3,
300 MHz): d 9.6 (d, J = 1.2 Hz 1H), 4.1 (ddd, J = 7.8, 5.1, 1.2 Hz, 1H), 2.7–2.6 (dd,
J = 16.8, 5.1 Hz, 1H ABsystem), 2.6–2.4 (dd, J = 16.8, 7.8 Hz, 1H ABsystem), 0.94
(s, 9H), 0.15 (s, 9H), 0.13 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 75.5 MHz): d
202.10, 101.85, 87.36, 76.08, 25.70 (3C), 24.47, 18.21, 1.01, –0.09 (3C), –4.75.
Compound 6: 1H NMR (CDCl3, 300 MHz): d 9.6 (d, J = 7.8 Hz, 1H), 6.9 (dd,
J = 15.6, 4.2 Hz, 1H), 6.3 (ddd, J = 15.6, 7.8, 1.8 Hz, 1H), 4.5 (dddd, J = 7.5, 6.3,
Please cite this article as: A. R. Rodriguez and B. W. Spur, First total syntheses of the pro-resolving lipid mediators 7(S),13(R),20(S)-Resolvin T1 and 7(S),13