Total Synthesis of Asimicin and Bullatacin
J . Org. Chem., Vol. 65, No. 19, 2000 6047
10.0, 6.0, 3.2 Hz, 1H), 2.98 (s, 3H), 2.56 (ddd, J ) 17.6, 10.8,
7.6 Hz, 1H), 2.41 (ddd, J ) 17.2, 10.4, 6.8 Hz, 1H), 2.28 (m,
1H), 2.20-1.83 (m, 7H), 1.47 (m, 6H), 1.35 (s, 3H), 1.26 (s, 3H),
1.23-1.15 (m and br s, 14H), 0.81 (t, J ) 6.8 Hz, 3H); 13C NMR
δ 177.3, 107.5, 83.8, 81.1, 81.0, 81.8, 80.6, 77.9, 77.7, 31.8, 29.6,
29.51, 29.3, 28.6, 28.1, 27.7, 26.3, 26.1, 26.0, 25.8, 24.6, 22.6,
14.0 ppm; HRMS (C27H48O8SCs ) 665.2124) found 665.2144
(MCs+).
177.1, 131.1, 130.7, 129.3, 128.5, 83.0, 73.1, 32.7, 32.6, 31.9,
29.6, 29.5, 29.2, 28.6, 27.4, 24.1, 23.2, 22.7, 14.1 ppm; MS 387
(MNa+).
(tr a n s,4R,5R,8R,9S)-9-Hyd r oxy-5,8-oxid otr icos-12-en -
1,4-olid e, 48a . Compound 13 (1.4 g, 3.85 mmol) was added to
a mixture of trifluoroacetylrhenium(VII) oxide (prepared from
Re2O7 (5 g, 10.3 mmol) and TFAA (2.0 mL, 13.4 mmol) in dry
THF (50 mL) at 0 °C) and 2,6-lutidine (3.6 mL, 31 mmol) in
CH2Cl2 (40 mL). The mixture was stirred at 0 °C to rt for 8 h
and then worked up with a saturated solution of NaHCO3 (10
mL), H2O2 (2.0 mL), and EtOAc. The organic layer was washed
with brine, dried over MgSO4, and purified by column chro-
matography (silica gel, hexanes-EtOAc, 1:1) to afford 48a (1.1
(4R,5R,8R,9S,12R,13S)-12,13-Dih yd r oxy-9-m esyloxy-
5,8-oxid otr icosa -1,4-olid e, 46. Compound 45b (0.35 g, 0.65
mmol) was stirred with TsOH (50 mg) in MeOH-water (4:1,
2 mL) for 16 h as above for the conversion of 26b to 27. Workup
(saturated solution of NaHCO3-EtOAc) afforded the crude diol
1
1
(292 mg, 82%): [R]D -4.2 (c ) 0.79, CHCl3); H NMR δ 4.82
g, 75%): [R]D -7.0 (c ) 1.0, CHCl3); H NMR δ 5.41 (m, 2H),
(dt, J ) 7.9, 4.0 Hz, 1H), 4.44 (ddd, J ) 8.1, 5.6, 2.8 Hz, 1H),
4.12-4.02 (m, 2H), 3.59-3.52 (m, 2H), 3.03 (s, 3H), 2.64 (ddd,
J ) 17.6, 10.1, 6.6 Hz, 1H), 2.46 (ddd, J ) 16.9, 10.1, 6.7 Hz,
1H), 2.32-2.22 (m, 1H), 2.05 (m, 5H), 1.98-1.84 (m, 3H), 1.72-
1.61 (m, 2H), 1.53-1.40 (m, 4H), 1.24 (br s, 15H), 0.87-0.84
(t, J ) 6.8 Hz, 3H); 13C NMR δ 177.5, 84.0, 81.2, 81.0, 80.7,
74.7, 74.1, 38.6, 31.9, 31.6, 29.6, 29.3, 28.4, 28.1, 27.8, 26.7,
26.3, 26.0, 24.6, 22.7, 14.1 ppm; MS (C24H44O8S ) 625.1811)
found 625.1839 (MCs+).
(4R,5R,8R,9R,12R,13S)-13-Hyd r oxy-5,8:9,12-d ioxid otr i-
cosa -1,4-olid e, 7. Compound 46 (292 mg) was refluxed in
pyridine (20 mL) for 3 h as above for the conversion of
compound 27 to 6 to afford compound 7 (0.17 g, 81%, 65% from
46b) after purification by column chromatography (silica gel,
hexanes-EtOAc, 1:1). All physical data were identical to those
obtained for compound 32.
P en ta d ec-4-en -1-yl tr ip h en ylp h osp h on iu m Iod id e, 47.
Compound 47 was prepared from trans-1-iodopentadec-4-en-
1-ol11g via the corresponding iodide (for process, see preparation
of 23). The iodide was prepared using trans-pentadec-4-en-1-
ol (1 g, 4.4 mmol), iodine (1.34 g, 5.28 mmol), PPh3 (1.78 g, 6.8
mmol), and imidazole (0.42 g, 6.2 mmol) in CH2Cl2 (10 mL) to
afford the former (1.28 g, 86%) after column chromatography
(silica gel, hexanes-EtOAc, 19:1): 1H NMR δ 5.47 (m, 1H),
5.30 (m, 1H), 3.16 (t, J ) 7.2 Hz, 2H), 2.70 (q, J ) 6.8 Hz,
2H), 1.95 (q, J ) 6.4 Hz, 2H), 1.85 (m, 2H), 1.24 (m, 17H),
0.86 (t, J ) 6.4 Hz, 3H); 13C NMR δ 132.3, 127.6, 33.1, 32.6,
31.9, 29.6, 29.55, 29.5, 29.3, 29.2, 22.7, 14.1, 6.7 ppm.
Compound 47 (2.1 g, 92%) was obtained by refluxing iodide
(1.28 g, 3.8 mmol) and PPh3 (1.99 g, 7.6 mmol) in CH3CN (12
mL): 1H NMR δ 7.61 (m, 10H), 5.42 (dt, J ) 15.4, 6.7 Hz, 1H),
5.21 (dt, J ) 15.4, 6.7 Hz, 1H), 3.53 (m, 2H), 2.28 (q, J ) 6.8
Hz, 2H), 1.88 (q, J ) 6.8 Hz, 2H), 1.66 (m, 2H), 1.15 (m, 17H),
0.81 (t, J ) 6.4 Hz, 3H).
4.43 (m, 1H), 4.05 (m, 1H), 3.85 (m, 1H), 3.76 (m, 1H), 2.62
(m, 1H), 2.46 (m, 1H), 2.23 (m, 1H), 2.15 (m, 2H), 2.05-1.83
(m, 8H), 1.38 (q, J ) 7.4 Hz, 2H), 1.23 (m and br s, 16H), 0.85
(t, J ) 7.0 Hz, 3H); 13C NMR δ 177.5, 131.4, 129.2, 83.3, 81.4,
81.0, 71.0, 32.5, 32.4, 31.9, 29.6, 29.5, 29.3, 29.1, 28.9, 28.2,
28.0, 24.9, 24.6, 22.6, 14.1 ppm; MS 403 (MNa+).
(tr a n s,4R,5R,8R,9S)-9-Mesyloxy-5,8-oxid otr icos-12-en -
1,4-olid e, 48b. Mesylate 48b (1.22 g, 90%) was obtained by
reacting compound 48a (1.1 g, 2.9 mmol) with MsCl (0.45 mL,
5.8 mmol) and Et3N (2 mL) in CH2Cl2 (10 mL) as above in the
synthesis of 26b, followed by purification (silica gel, hexanes-
EtOAc, 7:3) in the form of a colorless oil: 1H NMR δ 5.46 (dt,
J ) 15.4, 6.6 Hz, 1H), 5.34 (dt, J ) 15.4, 6.2 Hz, 1H), 4.77
(quintet, J ) 4.5 Hz, 1H), 4.44 (ddd, J ) 8.1, 5.5, 2.6 Hz, 1H),
4.05 (m, 2H), 3.01 (s, 3H), 2.65 (ddd, J ) 17.6, 10.2, 7.0 Hz,
1H), 2.45 (ddd, J ) 17.6, 10.3, 6.6 Hz, 1H), 2.26 (m, 1H), 2.16
(m, 2H), 2.06 (m, 3H), 1.95 (m, 4H), 1.71 (m, 1H), 1.58 (m,
1H), 1.35-1.20 (m and br s, 16H), 0.87 (t, J ) 7.5 Hz, 3H); 13
C
NMR 177.5, 131.4, 129.3, 83.9, 81.1, 80.6, 74.3, 74.0, 60.3, 43.2,
38.5, 33.4, 31.8, 31.5, 29.5, 29.2, 28.1, 27.7, 26.1, 25.6, 24.6,
22.6, 21.0, 14.1 ppm; MS 481 (MNa+).
(4R,5R,8R,9S,12R,13R)-12,13-Dih yd r oxy-9-m esyloxy-
5,8-oxid otr icosa n -1,4-olid e, 27. Compound 48b (1.21 g, 2.64
mmol) was dihydroxylated using AD-mix-â (3.70 g) and MeSO2-
NH2 (251 mg, 2.64 mmol) in t-BuOH-water (1:1, mL) at 0 °C
(for process, see first stage of three-step process in the
conversion of 8 to 24) to afford compound 27 (1.1 g, 92%): 1H
NMR δ 5.18 (br s, 1H), 4.80 (m, 1H), 4.44 (m, 1H), 4.04 (m,
2H), 3.36 (m, 2H), 3.02 (s, 3H), 2.62 (m, 1H), 2.45 (m, 1H),
2.26 (m, 1H), 2.16-2.02 (m, 4H), 1.95-1.80 (m, 2H), 1.72-
1.62 (m, 2H), 1.54-1.37 (m, 3H), 1.33-1.15 (m and br s, 17H),
0.84 (t, J ) 7.0 Hz, 3H); 13C NMR δ 177.6, 83.9, 81.2, 80.6,
74.4, 74.1, 60.4, 43.3, 38.5, 33.5, 31.8, 31.6, 29.6, 29.3, 28.2,
27.7, 26.2, 25.6, 24.6, 22.1, 21.0, 14.1 ppm; MS 515 (MNa+).
(4R,5R,8R,9R)-9-Im id a zolylt h ioca r b on yloxy-5,8-oxi-
d on on a d eca n -1,4-olid e, 53. A solution of compound 528a (163
mg, 0.5 mmol), thiocarbonyldiimidazole (268 mg, 1.5 mmol),
and DMAP (10 mg) in CH2Cl2 (8 mL) was stirred at rt for 16
h. The crude product was chromatographed over silica gel
(hexanes-EtOAc, 3:2) to afford 53 (200 mg, 92%) as a colorless
oil: 1H NMR (300 MHz) δ 8.33 (s, 1H), 7.60 (s, 1H), 7.01 (s,
1H), 5.59 (dt, J ) 7.4, 6.1 Hz, 1H), 4.45 (ddd, J ) 7.9, 4.4, 1.8
Hz, 1H), 4.15 (dt, J ) 7.9, 5.7 Hz, 1H), 4.01 (td, J ) 7.0, 1.8
Hz, 1H), 2.58-1.95 (m, 6H), 1.82-1.18 (m and brs, 20H), 0.83
(t, J ) 6.6 Hz); MS 459 (MNa+).
(4R,5R,8R)-5,8-Oxid on on a d eca n -1,4-olid e, 54. Tribu-
tyltinhydride (0.25 mL, 0.91 mmol) was added dropwise to a
solution of compound 53 (200 mg, 0.46 mmol) and AIBN (10
mg) in dry toluene at 90 °C, and the mixture was stirred at
that temperature for 3 h. The crude product was chromato-
graphed over silica gel (hexanes-EtOAc, 7:3) to afford 54 (130
mg, 91%) as a colorless oil: 1H NMR (500 MHz) δ 4.44 (ddd,
J ) 7.7, 5.1, 2.6 Hz, 1H), 4.02 (td, J ) 7.3, 2.6 Hz, 1H), 3.88
(m, 1H), 2.67 (ddd, J ) 16.1, 10.0, 7.3 Hz, 1H), 2.43 (ddd, J )
16.1, 10.0, 5.8 Hz, 1H), 2.24 (m, 2H), 2.05-1.92 (m, 3H), 1.58-
1.20 (m and brs, 21H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR
(125.75 MHz): δ 177.7, 81.5, 80.8, 80.1, 35.7, 32.1, 31.1, 29.7,
29.5, 29.3, 28.2, 27.9, 26.2, 24.8, 22.7, 14.1 ppm; MS 311 (MH+).
(cis,tr a n s,4R,5R)-5-ter t-Bu tyld ip h en ylsilyloxytr icosa -
8,12-d ien -1,4-olid e, 13a . Compound 13a was prepared from
Wittig salt 47 (9.4 g, 15.7 mmol), KHMDS (0.5 M in toluene,
31.6 mL, 15.7 mmol), HMPA (5.6 mL, 31 mmol), and aldehyde
44 (5.68 g, 13.6 mmol) as above for compound 10. Purification
by flash chromatography (silica gel, hexanes-EtOAc, 4:1)
afforded compound 13a (6.48 g, 79%) in the form of an oil: 1H
NMR δ 7.68 (m, 4H), 7.39 (m, 6H), 5.33 (m, 2H), 5.22 (m, 1H),
4.97 (m, 1H), 4.51 (td, J ) 6.7, 3.5 Hz, 1H), 3.73 (m, 1H), 2.58
(m, 1H), 2.46 (m, 1H), 2.14 (q, J ) 7.3 Hz, 2H), 1.96-1.78 (m,
8H), 1.75-1.18 (m and br s, 18H), 1.04 (s, 9H), 0.87 (t, J ) 6.8
Hz, 3H); 13C NMR δ 177.3, 135.9, 135.8, 133.7, 133.0, 130.9,
129.9, 129.7, 129.3, 128.4, 127.7, 127.6, 80.7, 74.5, 32.6, 32.3,
31.9, 31.5, 29.6, 29.5, 29.3, 27.2, 27.0, 23.2, 23.0, 22.6, 19.5,
14.1; MS 625 (MNa+).
(cis,tr a n s,4R,5R)-5- Hyd r oxytr icosa -8,12-d ien -1,4-olid e,
13. Compound 13a (6.4 g, 10.6 mmol) was deprotected with
TBAF (1 M in THF, 12 mL, 12 mmol) in dry THF (20 mL) at
0 °C to rt (2 h) as above for the conversion of 11a to 11 to
afford 13 (3.44 g, 90%) after purification (silica gel, hexanes-
EtOAc, 1:1): [R]D +17.8 (c ) 1.12, CHCl3); 1H NMR (500
MHz): δ 5.38 (m, 4H), 4.40 (td, J ) 7.4, 4.8 Hz, 1H), 3.57 (dt,
J ) 8.8, 4.4 Hz, 1H), 2.59 (m, 1H), 2.50 (dd, J ) 18.0, 9.2 Hz,
1H), 2.22 (m, 3H), 2.08 (m, 3H), 2.08-1.82 (br, 1H), 2.02 (q, J
) 6.6 Hz, 2H), 1.94 (q, J ) 6.6 Hz, 2H), 1.58 (m, 2H), 1.35-
1.18 (m and br s, 16H), 0.86 (t, J ) 7.0 Hz, 3H); 13C NMR δ
(4R ,5R ,8S ,9S)-9-H y d r o xy -5,8-o xid on on a d e c a n -1,4-
olid e, 56. Dry TBHP (5-6 M solution in nonane, 0.5 mL, 2.5-