M. Isaka et al. / Tetrahedron 65 (2009) 8808–8815
8813
(500 MHz, CDCl3)
d
5.29 (1H, br s, H-12), 5.18 (1H, br d, J¼9.8 Hz, H-
Ha-12), 4.17 (1H, m, H-8), 4.11 (1H, d, J¼12.7 Hz, Hb-12), 3.60 (1H,
br s, H-1), 2.66 (1H, dt, J¼13.2, 2.8 Hz, H-7), 2.36 (1H, dd, J¼14.8,
3.4 Hz, Hb-9), 2.16 (1H, ddt, J¼5.3, 3.5, 14.0 Hz, Ha-2), 2.02 (1H, m,
H-4), 1.91 (1H, t, J¼13.2 Hz, Ha-6), 1.73 (1H, dd, J¼14.8, 2.6 Hz,
Ha-9), 1.56 (1H, m, Hb-3), 1.51 (1H, m, Hb-2), 1.30 (1H, m, Ha-3),
1.24 (1H, dd, J¼13.2, 3.7 Hz, Hb-6), 1.06 (3H, s, H3-14), 0.78 (3H, d,
50), 4.38 (1H, m, H-1), 4.13 (1H, d, J¼9.0 Hz, H-30), 3.59 (1H, dd,
J¼10.5, 5.1 Hz, Ha-150), 3.51 (3H, s, 12-OCH3), 3.50 (1H, s, H-9), 3.39
(1H, dd, J¼10.5, 8.4 Hz, Hb-150), 3.38 (3H, s, 8-OCH3), 2.62 (1H, dq,
J¼9.0, 7.2 Hz, H-20), 2.56 (1H, m, H-60), 2.07 (1H, d, J¼12.5 Hz, Hb-6),
1.95 (1H, m, Ha-2), 1.94 (1H, br d, J¼12.5 Hz, Ha-6), 1.88 (1H, m,
H-4), 1.80 (1H, m, Hb-2), 1.70 (3H, s, H3-13), 1.66 (3H, d, J¼1.2 Hz,
H3-140), 1.63 (1H, m, Ha-3), 1.49 (1H, m, Hb-3), 1.40 (1H, m, Ha-70),
1.30–1.20 (8H, m, H2-80, H2-90, H2-100, and H2-110), 1.16 (1H, m, Hb-
70), 1.05 (3H, d, J¼7.2 Hz, H3-130), 0.96 (3H, s, H3-14), 0.92 (3H, d,
J¼6.8 Hz, H3-15), 0.88 (3H, t, J¼7.0 Hz, H3-120); 13C NMR (125 MHz,
J¼7.0 Hz, H3-15); 13C NMR (125 MHz, CDCl3)
d 149.7 (C, C-11),
115.0 (CH2, C-13), 75.2 (CH, C-1), 74.6 (C, C-10), 69.7 (CH, C-8),
65.1 (CH2, C-12), 41.8 (CH, C-7), 40.0 (C, C-5), 35.5 (CH2, C-9), 34.4
(CH, C-4), 32.6 (CH2, C-6), 28.7 (CH2, C-2), 25.3 (CH2, C-3), 15.7
(CH3, C-14), 15.0 (CH3, C-15); HRMS (ESI-TOF) m/z 293.1728
[MþNa]þ (calcd for C15H26O4Na, 293.1723).
CDCl3) d
174.7 (C, C-10), 137.1 (C, C-40), 133.1 (C, C-7), 131.8 (C, C-11),
131.5 (CH, C-50), 109.6 (C, C-12), 105.3 (C, C-8), 80.0 (CH, C-30), 75.1
(CH, C-1), 66.6 (CH2, C-150), 64.2 (C, C-10), 63.7 (CH, C-9), 55.8 (CH3,
12-OCH3), 50.4 (CH3, 8-OCH3), 43.6 (CH, C-20), 41.0 (C, C-5), 40.9
(CH, C-60), 38.7 (CH, C-4), 31.8 (CH2, C-100), 31.5 (CH2, C-70), 31.0
(CH2, C-6), 29.4 (CH2, C-90), 28.4 (CH2, C-2), 27.3 (CH2, C-80), 26.1
(CH2, C-3), 22.6 (CH2, C-110), 15.3 (CH3, C-14), 14.9 (CH3, C-15), 14.4
(CH3, C-130), 14.1 (CH3, C-120), 11.5 (CH3, C-140), 10.0 (CH3, C-13);
HRMS (ESI-TOF) m/z 587.3558 [MþNa]þ (calcd for C32H52O8Na,
587.3560).
3.4.4. Compound 9. Colorless gum; 1H NMR (500 MHz, CDCl3)
d
5.08 (1H, br d, J¼9.9 Hz, H-50), 3.88 (1H, d, J¼9.3 Hz, H-30), 3.72
(1H, dd, J¼10.8, 3.6 Hz, Ha-10), 3.65 (1H, dd, J¼10.8, 8.0 Hz, Hb-10),
3.60 (1H, dd, J¼10.6, 4.4 Hz, Ha-150), 3.32 (1H, dd, J¼10.6, 9.5 Hz,
Hb-150), 2.53 (1H, m, H-60), 1.93 (1H, m, H-20), 1.66 (3H, d, J¼1.0 Hz,
H-140), 1.31 (1H, m, Ha-70), 1.30–1.20 (8H, m, H-80, H-90, H-100, and
H-110), 1.11 (1H, m, Hb-70), 0.88 (3H, t, J¼7.0 Hz, H-120), 0.71 (3H, d,
J¼7.0 Hz, H-130); 13C NMR (125 MHz, CDCl3)
d
138.8 (C, C-40), 131.3
(CH, C-50), 84.8 (CH, C-30), 68.1 (CH2, C-10), 66.7 (CH2, C-150), 40.7
(CH, C-60), 37.0 (CH, C-20), 31.8 (CH2, C-100), 31.4 (CH2, C-70), 29.3
(CH2, C-90), 27.2 (CH2, C-80), 22.6 (CH2, C-110), 14.1 (CH3, C-120), 13.6
(CH3, C-130), 11.3 (CH3, C-140); HRMS (ESI-TOF) m/z 281.2091
[MþNa]þ (calcd for C15H30O3Na, 281.2093).
3.4. LiBH4 reduction of 1
To a solution of 1 (100 mg) in THF (1.5 mL) at 0 ꢁC was added
LiBH4 (30 mg). The cooling bath was removed and the mixture was
stirred at room temperature for 7 days. The reaction was termi-
nated by addition of H2O, and the mixture was extracted with
EtOAc. The organic layer was concentrated under reduced pressure
to leave a colorless gum (91 mg), which was separated by CC on Si
gel (MeOH/CH2Cl2) to obtain 9 (39 mg) and a mixture (23.3 mg) of
6, 7, and 8. The mixture was subjected to preparative HPLC
3.5. Synthesis of a p-bromobenzoate derivatives 10 and 11
and application of the modified Mosher method
A mixture of compound 6 (4.9 mg) and p-bromobenzoyl
chloride (10.8 mg, 2.2 equiv) in pyridine (0.2 mL) was stirred for
17 h. The mixture was diluted with EtOAc and washed with H2O
and 1 M NaHCO3, and the organic layer was concentrated in
vacuo. The residue was separated by CC on Si gel (MeOH/CH2Cl2)
to furnish mono- and bis-p-bromobenzoate derivatives 10
(1.1 mg) and 11 (1.1 mg), respectively. Compound 10 (0.4 mg) was
treated with (ꢀ)-(R)-MTPACl (5 mg) in pyridine (0.2 mL) at room
temperature for 16 h. The mixture was diluted with EtOAc and
washed with H2O and 1 M NaHCO3, and the organic layer was
concentrated in vacuo to afford a bis-(S)-MTPA ester derivative
12a. Similarly, bis-(R)-MTPA ester derivative 12b was prepared
from 10 and (þ)-(S)-MTPACl. Assignments of protons of the
Mosher ester derivatives 12a and 12b were established on the
basis of COSY and NOESY data.
(LiChroCARTÒ 250-10, 10
flow rate 4 mL/min) to furnish pure compounds; 6 (5.9 mg, tR
32 min), 7 (2.5 mg, tR 18 min), and 8 (5.6 mg, tR 27 min).
mm, 1.0ꢂ25.0 cm; MeOH/H2O¼30:70;
3.4.1. Compound 6. Colorless solid; 1H NMR (500 MHz, CDCl3)
d
5.14 (1H, br s, Ha-13), 5.02 (1H, s, Hb-13), 4.18 (1H, d, J¼12.1 Hz,
Ha-12), 4.11 (1H, d, J¼12.1 Hz, Hb-12), 3.83 (1H, d, J¼8.7 Hz, H-8),
3.31 (1H, br s, H-1), 3.08 (1H, s, H-9), 2.22 (1H, ddd, J¼13.2, 8.7,
3.3 Hz, H-7), 1.86 (1H, m, Ha-2), 1.78 (1H, m, Hb-2), 1.77 (1H, m,
Hb-3), 1.62 (1H, m, H-4), 1.47 (1H, t, J¼13.2 Hz, Ha-6), 1.39 (1H, m,
Ha-3), 1.25 (3H, s, H3-14), 1.23 (1H, dd, J¼13.2, 3.3 Hz, Hb-6), 0.83
(3H, d, J¼6.8 Hz, H3-15); 13C NMR (125 MHz, CDCl3)
d 151.3 (C,
C-11), 113.2 (CH2, C-13), 73.6 (CH, C-1), 70.8 (CH, C-8), 67.1 (CH2,
C-12), 65.3 (C, C-10), 63.4 (CH, C-9), 41.7 (CH, C-7), 39.0 (CH, C-4),
36.0 (CH2, C-6), 35.9 (C, C-5), 30.8 (CH2, C-2), 25.5 (CH2, C-3), 16.7
(CH3, C-14), 14.9 (CH3, C-15); HRMS (ESI-TOF) m/z 291.1565
[MþNa]þ (calcd for C15H24O4Na, 291.1567).
3.5.1. Compound 10. Colorless solid; 1H NMR (500 MHz, CDCl3)
d
7.92 (2H, d, J¼8.5 Hz, p-bromobenzoyl), 7.60 (2H, d, J¼8.5 Hz,
p-bromobenzoyl), 5.24 (1H, s, Ha-13), 5.12 (1H, s, Hb-13), 4.81 (2H,
s, H2-12), 4.00 (1H, br d, J¼8.9 Hz, H-8), 3.30 (1H, br s, H-1), 3.09
(1H, s, H-9), 2.28 (1H, ddd, J¼13.3, 8.9, 3.3 Hz, H-7), 1.84 (1H, m, Ha-
2), 1.77 (1H, m, Hb-2), 1.76 (1H, m, Hb-3), 1.62 (1H, m, H-4), 1.43 (1H,
t, J¼13.3 Hz, Ha-6), 1.39 (1H, m, Ha-3), 1.28 (1H, dd, J¼13.3, 3.3 Hz,
Hb-6), 1.25 (3H, s, H3-14), 0.82 (3H, d, J¼6.8 Hz, H3-15); HRMS
(ESI-TOF) m/z 473.0938 and 475.0959 [MþNa]þ (calcd for
C22H27O579BrNa and C22H27O581BrNa, 473.0934 and 475.0917,
respectively).
3.4.2. Compound 7. Colorless solid; 1H NMR (500 MHz, CDCl3)
d
5.21 (1H, s, Ha-13), 4.95 (1H, s, Hb-13), 4.17 (1H, d, J¼12.6 Hz, Ha-
12), 4.11 (1H, d, J¼12.6 Hz, Hb-12), 4.25 (1H, br s, H-8), 3.37 (1H, d,
J¼4.4 Hz, H-9), 3.31 (1H, m, H-1), 2.55 (1H, ddd, J¼13.0, 8.74.7,
2.8 Hz, H-7), 2.28 (1H, br s, 8-OH), 1.91 (1H, m, Ha-2), 1.77 (1H, m,
Hb-2), 1.76 (1H, m, Hb-3), 1.66 (1H, m, H-4), 1.55 (1H, t, J¼13.0 Hz,
Ha-6), 1.53 (1H, br s, 1-OH), 1.42 (1H, m, Ha-3), 1.24 (1H, dd, J¼13.0,
2.8 Hz, Hb-6), 1.18 (3H, s, H3-14), 0.87 (3H, d, J¼6.7 Hz, H3-15); 13C
NMR (125 MHz, CDCl3)
d
148.5 (C, C-11), 113.7 (CH2, C-13), 73.9 (CH,
3.5.2. Compound 11. Colorless solid; 1H NMR (500 MHz, CDCl3)
C-1), 68.1 (C, C-10), 66.0 (CH2, C-12), 64.7 (CH, C-8), 62.8 (CH, C-9),
39.5 (CH, C-4), 38.9 (CH, C-7), 36.2 (C, C-5), 33.1 (CH2, C-6), 31.4
(CH2, C-2), 25.3 (CH2, C-3), 16.3 (CH3, C-14), 14.8 (CH3, C-15); HRMS
(ESI-TOF) m/z 291.1568 [MþNa]þ (calcd for C15H24O4Na, 291.1567).
d
7.85 (4H, d, J¼8.5 Hz, p-bromobenzoyl), 7.55 (4H, d, J¼8.5 Hz,
p-bromobenzoyl), 5.32 (1H, d, J¼9.6 Hz, H-8), 5.23 (1H, s, Ha-13),
5.15 (1H, s, Hb-13), 4.78 (2H, s, H2-12), 3.29 (1H, br s, H-1), 3.13 (1H,
s, H-9), 2.71 (1H, ddd, J¼13.2, 9.6, 3.4 Hz, H-7), 1.90 (1H, m, Ha-2),
1.80–1.75 (2H, m, Hb-2 and Hb-3), 1.64 (1H, m, H-4), 1.54 (1H, t,
J¼13.2 Hz, Ha-6), 1.43 (1H, m, Ha-3), 1.42 (1H, dd, J¼13.2, 3.4 Hz,
Hb-6), 1.32 (3H, s, H3-14), 0.86 (3H, d, J¼6.7 Hz, H3-15); HRMS
3.4.3. Compound 8. Colorless solid; 1H NMR (500 MHz, CDCl3)
d
5.27 (1H, s, Ha-13), 5.12 (1H, s, Hb-13), 4.18 (1H, d, J¼12.7 Hz,