5764
K. A. Hollister et al. / Bioorg. Med. Chem. 21 (2013) 5754–5769
CDCl3) d 165.94, 165.85, 138.8, 133.5, 133.4, 130.08, 130.05, 129.8,
128.6, 114.9, 96.6, 70.8, 67.9, 67.0, 33.7, 30.0, 29.2, 25.7, 18.1.
(250 MHz, Chloroform-d) d 8.10 (d, J = 7.0, 1.4 Hz, 2H), 8.04 (d,
J = 7.1, 1.4 Hz, 2H), 7.65–7.51 (m, 2H), 7.51–7.38 (m, 4H), 5.27–
5.09 (m, 2H), 4.82 (s, 1H), 4.14–3.97 (m, 1H), 3.82 (dt, J = 9.8,
6.2 Hz, 1H), 3.70 (s, 3H), 3.54 (dt, J = 9.7, 6.1 Hz, 1H), 2.55–2.34
(m, 3H), 2.19 (ddd, J = 13.8, 11.3, 3.2 Hz, 1H), 1.99 (h, J = 6.5 Hz,
2H), 1.29 (d, J = 6.2 Hz, 3H). 13C NMR (62.5 MHz, CDCl3) d 173.8,
165.6, 165.5, 133.14, 133.07, 129.8, 129.73, 129.68, 129.5, 128.3,
96.3, 70.4, 67.2, 66.7, 51.4, 33.6, 29.6, 28.8, 21.7, 17.8.
4.1.35. Synthesis of (2R,3R,5R,6S)-2-(((E)-4-methoxy-4-oxobut-
2-en-1-yl)oxy)-6-methyltetrahydro-2H-pyran-3,5-diyl
dibenzoate (35)
See Ref. 2d for representative procedure. Started with 262.8 mg
(0.663 mmol) 32, 0.30 mL (3.3 mmol) methyl acrylate, and 56.3 mg
(66.3 lmol) Grubbs second generation catalyst in 22.2 mL CH2Cl2.
Purified to obtain 112.4 mg (37%) of a colorless oil. ½a D25
ꢁ
4.5, c
4.1.39. Synthesis of (2R,3R,5R,6S)-2-((5-methoxy-5-
oxopentyl)oxy)-6-methyltetrahydro-2H-pyran-3,5-diyl
dibenzoate (39)
The title compound was prepared in a manner similar to that of
23. Started with 131.1 mg (0.280 mmol) 36, 13.5 mg palladium on
activated carbon 10% palladium in 13.44 mL ethyl acetate. Purified
0.5; HRMS (m/z): [M+Na] calcd For C25H26O8Na 477.1531, found
477.1520; 1H NMR (250 MHz, Chloroform-d) d 8.10 (d, J = 7.3 Hz,
2H), 8.03 (d, J = 7.3 Hz, 2H), 7.64–7.51 (m, 2H), 7.51–7.37 (m,
4H), 7.02 (dt, J = 15.7, 4.3 Hz, 1H), 6.16 (dt, J = 15.7, 2.0 Hz, 1H),
5.32–5.11 (m, 2H), 4.89 (s, 1H), 4.45 (ddd, J = 16.0, 4.3, 2.1 Hz,
1H), 4.24 (ddd, J = 16.1, 4.6, 2.1 Hz, 1H), 4.13–3.98 (m, 1H), 3.76
(s, 3H), 2.46 (dt, J = 13.6, 4.0 Hz, 1H), 2.23 (ddd, J = 14.0, 11.3,
3.2 Hz, 1H), 1.29 (d, J = 6.2 Hz, 3H). 13C NMR (62.5 MHz, CDCl3) d
166.4, 165.50, 165.46, 143.3, 133.2, 133.1, 129.8, 129.6, 129.5,
128.4, 121.0, 96.0, 70.2, 70.1, 67.0, 65.7, 51.6, 29.6, 17.7.
to obtain 120.1 mg (91%) colorless oil. ½a D25
ꢁ
12.4, c 0.3; HRMS (m/z):
[M+Na] calcd For C26H30O8Na 493.1833, found 493.1826 1H NMR
(250 MHz, Chloroform-d) d 8.10 (d, 2H), 8.03 (d, J = 7.0, 1.6 Hz,
2H), 7.64–7.51 (m, 2H), 7.44 (ddd, J = 8.8, 6.9, 3.6 Hz, 4H), 5.27–
5.09 (m, 2H), 4.82 (s, 1H), 4.14–3.99 (m, 1H), 3.78 (dt, J = 9.4,
6.0 Hz, 1H), 3.67 (s, 3H), 3.51 (dt, J = 9.7, 5.7 Hz, 1H), 2.50–2.31
(m, 3H), 2.20 (ddd, J = 13.9, 11.3, 3.1 Hz, 1H), 1.75 (ddt, J = 12.3,
7.9, 4.7 Hz, 4H), 1.29 (d, J = 6.2 Hz, 3H). 13C NMR (62.5 MHz, CDCl3)
d 173.8, 165.6, 165.5, 133.14, 133.07, 129.8, 129.73, 129.68, 129.5,
128.3, 96.3, 70.4, 67.2, 66.7, 51.4, 33.6, 29.6, 28.8, 21.7, 17.8.
4.1.36. Synthesis of (2R,3R,5R,6S)-2-(((E)-5-methoxy-5-oxopent-
3-en-1-yl)oxy)-6-methyltetrahydro-2H-pyran-3,5-diyl
dibenzoate (36)
See Ref. 2d for representative procedure. Started with 429.8 mg
(1.047 mmol) 33, 0.47 mL (5.2 mmol) methyl acrylate, and 88.9 mg
(104
l
mol) Grubbs second generation catalyst in 36.6 mL CH2Cl2.
4.1.40. Synthesis of (2R,3R,5R,6S)-2-((7-methoxy-7-
oxoheptyl)oxy)-6-methyltetrahydro-2H-pyran-3,5-diyl
dibenzoate of (40)
The title compound was prepared in a manner similar to that of
23. Started with 103.4 mg (0.208 mmol) 37, 10.6 mg 10% palla-
dium on activated carbon in 10.6 mL ethyl acetate. Purified to ob-
Purified to obtain 258.8 mg (53%) of a colorless oil. ½a D25
ꢁ
11.2, c
0.2; HRMS (m/z): [M+Na] calcd For C26H28O8Na 491.1676, found
491.1672; 1H NMR (250 MHz, Chloroform-d) d 8.09 (d, J = 7.3 Hz,
2H), 8.02 (d, J = 7.3 Hz, 2H), 7.62–7.49 (m, 2H), 7.49–7.35 (m,
4H), 7.00 (dt, J = 15.7, 7.0 Hz, 1H), 5.94 (m, 1H), 5.28–5.08 (m,
2H), 4.84 (s, 1H), 4.04 (m, 1H), 3.86 (dt, J = 9.8, 6.5 Hz, 1H), 3.71
(s, 3H), 3.63 (dt, J = 9.8, 6.2 Hz, 1H), 2.62–2.47 (m, 2H), 2.41 (dt,
J = 13.5, 4.0 Hz, 1H), 2.17 (ddd, J = 13.9, 11.4, 3.2 Hz, 1H), 1.28 (d,
J = 6.2 Hz, 3H). 13C NMR (62.5 MHz, CDCl3) d 166.5, 165.5, 165.4,
145.2, 133.1, 133.0, 129.73, 129.67, 129.6, 129.4, 128.3, 122.8,
96.2, 70.2, 66.8, 65.6, 51.3, 32.2, 29.5, 17.7.
tain 84.4 mg (81%) colorless oil. ½a D25
ꢁ
2.8, c 0.3; HRMS (m/z):
[M+Na] calcd For C28H34O8Na 521.2146, found 521.2163; 1H
NMR (400 MHz, Chloroform-d) d 8.11 (d, J = 7.2 Hz, 2H), 8.04 (d,
J = 7.2 Hz, 2H), 7.64–7.54 (m, 2H), 7.52–7.42 (m, 4H), 5.24–5.12
(m, 2H), 4.82 (s, 1H), 4.06 (dq, J = 9.8, 6.3 Hz, 1H), 3.76 (dt, J = 9.7,
6.7 Hz, 1H), 3.67 (s, 3H), 3.50 (dt, J = 9.7, 6.5 Hz, 1H), 2.41 (dt,
J = 13.7, 4.0 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), 2.21 (ddd, J = 13.8,
11.4, 3.2 Hz, 1H), 1.67 (m, 4H), 1.41 (tdd, J = 10.6, 7.3, 4.2 Hz, 4H),
1.30 (d, J = 6.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) d 167.5, 166.0,
165.9, 133.5, 133.4, 130.2, 130.09, 130.06, 129.8, 128.7, 96.6 70.8,
68.0, 67.0, 51.7, 34.2, 30.0, 29.5, 29.2, 26.1, 25.1, 18.1.
4.1.37. Synthesis of (2R,3R,5R,6S)-2-(((E)-7-methoxy-7-oxohept-
5-en-1-yl)oxy)-6-methyltetrahydro-2H-pyran-3,5-diyl
dibenzoate (37)
See Ref. 2d for representative procedure. Started with 100 mg
(0.228 mmol) 34. Evaporation of the volatiles afforded 165.2 mg
of ruby oil. Silica gel column chromatography (12 g silica gel, gra-
dient run from 50% hexanes in CH2Cl2 to 100% CH2Cl2) afforded
4.1.41. Synthesis of (E)-4-(((2R,3R,5R,6S)-3,5-dihydroxy-6-
methyltetrahydro-2H-pyran-2-yl)oxy)but-2-enoic acid (asc-
60.6 mg (53%) of colorless oil. ½a D25
ꢁ
4.1, c 0.48; HRMS (m/z):
x
D
C4)
[M+Na] calcd For C27H32O6Na 519.1989, found 519.1996. 1H NMR
(400 MHz, Chloroform-d) d 8.11 (d, J = 8.4, 1.6 Hz, 2H), 8.05 (d,
2H), 7.64–7.54 (m, 2H), 7.47 (ddd, J = 8.8, 7.1, 5.2 Hz, 4H), 7.01
(dt, J = 15.7, 7.0 Hz, 1H), 5.88 (dt, J = 15.6, 1.6 Hz, 1H), 5.25–5.13
(m, 2H), 4.83 (s, 1H), 4.06 (dq, J = 9.9, 6.2 Hz, 1H), 3.78 (dt, J = 9.8,
6.3 Hz, 1H), 3.73 (s, 3H), 3.52 (dt, J = 9.8, 6.1 Hz, 1H), 2.48–2.37
(m, 1H), 2.29 (qd, J = 7.1, 1.6 Hz, 2H), 2.21 (ddd, J = 13.5, 11.3,
3.1 Hz, 1H), 1.74–1.56 (m, 4H), 1.30 (d, J = 6.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3) d 167.0 165.7, 165.6, 149.0, 133.24, 133.16,
130.0, 129.84, 129.79, 129.6, 128.4, 121.3, 96.4, 70.5, 67.4, 66.8,
51.4, 31.9, 29.7, 28.9, 24.7, 17.9.
See Ref. 4b for representative procedure. Started with 44.3 mg
(0.097 mmol) 35 and 7.8 mL (1 N) LiOH in 7.8 mL of tert-Butanol.
Purified to obtain 7.0 mg (31%) colorless oil. ½a D25
ꢃ100.2, c 0.1;
ꢁ
HRMS (m/z): [M+Na] calcd For
C10H16O6Na 255.0839, found
255.0841; 1H NMR (400 MHz, Methanol-d4) d 6.89 (dt, J = 15.6,
4.5 Hz, 1H), 6.04 (d, J = 15.6, 2.1 Hz, 1H), 4.57 (s, 1H), 4.34 (ddd,
J = 16.0, 4.3, 2.1 Hz, 1H), 4.16 (ddd, J = 16.0, 4.7, 2.0 Hz, 1H), 3.83
(q, J = 2.6 Hz, 1H), 3.54 (dq, J = 9.9, 5.0, 4.2 Hz, 2H), 3.34 (s, 1H),
1.98 (dt, J = 13.0, 3.6 Hz, 1H), 1.80 (ddd, J = 13.4, 10.6, 3.1 Hz, 1H),
1.23 (d, J = 5.6 Hz, 3H). 13C NMR (100 MHz, MeOD) d 170.8, 144.6,
123.9, 100.2, 71.4, 69.4, 68.4, 66.7, 36.2, 18.2.
4.1.38. Synthesis of (2R,3R,5R,6S)-2-(4-methoxy-4-oxobutoxy)-
6-methyltetrahydro-2H-pyran-3,5-diyl dibenzoate (38)
4.1.42. Synthesis of (E)-5-(((2R,3R,5R,6S)-3,5-dihydroxy-6-
methyltetrahydro-2H-pyran-2-yl)oxy)pent-2-enoic acid (asc-
The title compound was prepared in a manner similar to that of
23. Started with 89.7 mg (0.197 mmol) 35, 9.3 mg 10% palladium
on activated carbon in 9 mL ethyl acetate. Purified to obtain
x
D
C5)
See Ref. 4b for representative procedure. Started with 102.1 mg
(0.218 mmol) 36 and 17.9 mL (1 N) LiOH in 17.9 mL of tert-Butanol.
85.7 mg (95%) colorless oil. ½a D25
ꢁ
5.8, c 0.2; HRMS (m/z): [M+Na]
Purified to obtain 23 mg (43%) colorless oil. ½a D25
ꢃ53.8, c 0.3; HRMS
ꢁ
calcd For
C
25H28O8Na 479.1676, found 479.1700; 1H NMR
(m/z): [M+Na] calcd For C11H18O6Na 269.0996, found 269.1003; 1H