Synthesis of garsubellin A
M Uwamori and M Nakada
144
0.0788 mmol) at 0 1C. After the reaction was completed, saturated aqueous washed with brine (20 mlꢁ 1), dried (Na2SO4), filtered and concentrated under
NaHCO3 (10 ml) and saturated aqueous Na2S2O3 (10 ml) were added
reduced pressure. The residue was purified by flash chromatography (hexanes/
successively to the reaction mixture, and the aqueous layer was extracted with ethyl acetate ¼ 20/1) to afford 17 (9.6 mg, quant) as an oil.
Et2O (15 mlꢁ 2). The combined organic layers were washed with brine
(20 mlꢁ 1), dried (Na2SO4), filtered and concentrated under reduced pressure.
The residue was used for the next step without further purification.
(2-Th)Cu(CN)Li was prepared according to the literature method.17
RF ¼ 0.20 (hexanes/ethyl acetate ¼ 15/1); 1H NMR (400MHz, CDCl3) d
5.88-5.72 (1H, m), 5.68-5.51 (1H, m), 5.04-4.93 (3H, m), 4.91-4.84 (1H, m),
4.37, (1H, dd, J ¼ 10.4, 5.6 Hz), 4.25 (1H, d, J ¼ 8.0 Hz), 4.20 (1H, d, J ¼ 8.0
Hz), 3.11 (1H, dd, J ¼ 14.8, 6.4 Hz), 3.04 (1H, dd, J ¼ 14.8, 6.4Hz), 2.64 (1H,
dd, J ¼ 13.2, 10.4Hz), 2.33-2.21 (1H, brs), 2.09 (1H, dd, J ¼ 13.6, 4.4 Hz),
1.76-1.52 (3H, brs), 1.42 (1H, t, J ¼ 12.4Hz), 1.26 (3H, s), 1.21 (3H, s), 1.06
(3H), 1.02-0.93 (21H, brs), 0.72 (3H, s), 0.07 (9H, s); 13C NMR (100 MHz,
CDCl3) d 204.8, 194.2, 172.6, 136.9, 135.7, 116.7, 114.5, 90.0, 73.7, 70.9, 59.3,
58.4, 44.1, 40.5, 39.2, 33.0, 30.4, 27.6, 26.5, 25.5, 22.7, 17.9, 16.8, 12.0, 2.3; IR
(neat) nmax 2942, 2865, 1736, 1638, 1364 841cmꢀ1; HRMS (ESI) [Mþ Na]þ
calculated for C35H60NaO5Si2 639.3877, found 639.3879.
(4S*,6R*,8S*,18S*)-8-allyl-18-(1-hydroxy-1-methylethyl)-9,9-
dimethyl-6-((triisopropylsilyloxy)methyl)-31-
oxatricyclo[6.3.1.03,4]dodec-2-ene-1,5-dione (16)
To a crude solution of 15 in CH2Cl2 (1ml) was added TMSCl (67.1ml,
0.525 mmol, 10equiv) at 0 1C. After the reaction was completed, saturated
aqueous NaHCO3 (10 ml) was added to the reaction mixture, and the aqueous
layer was extracted with Et2O (10 mlꢁ 2). The combined organic layers were
washed with brine (10 mlꢁ 1), dried (Na2SO4), filtered and concentrated
under reduced pressure. The residue was purified by flash chromatography
(hexanes/ethyl acetate ¼ 10/1) to afford 16 (9.3mg, 35%) as a white powder.
(4S*,6R*,8S*,18S*)-2,8-diallyl-18-(1-hydroxy-1-methylethyl)-6-
hydroxymethyl-9,9-dimethyl-31-oxatricyclo[6.3.1.03,4]dodec-2-ene-
1
RF ¼ 0.50 (hexanes/ethyl acetate ¼ 1/1); H NMR (400MHz, CDCl3) d 5.81
(1H, s), 5.68-5.52 (1H, m), 5.05-4.85 (1H, brs), 4.49 (1H, dd, J ¼ 10.8, 6.0 Hz), 1,5-dione (17-1)
4.23 (1H, d, J ¼ 8.0 Hz), 4.19 (1H, d, J ¼ 8.0 Hz), 2.69 (1H, dd, J ¼ 13.2,
To a stirred solution of 17 (10.1 mg, 0.0164 mmol) in THF (1ml) was added
10.8Hz), 2.33-2.20 (1H, brs), 2.10 (1H, dd, J ¼ 13.6, 4.4Hz), 1.92-1.79 (1H,
brs), 1.75 (1H, dd, J ¼ 13.2, 6.0 Hz), 1.69-1.52 (1H, m), 1.44 (1H, t, J ¼ 13.6
Hz), 1.29 (3H, s), 1.16 (3H, s), 1.06 (3H, s), 1.05-0.81 (23H, brs), 0.71 (3H, s);
13C NMR (100MHz, CDCl3) d 204.6, 195.5, 176.3, 136.7, 116.9, 104.9, 90.0,
71.2, 71.0, 59.1, 58.7, 44.1, 40.3, 38.9, 33.0, 30.2, 26.3, 23.7, 22.7, 17.9, 16.8,
TBAF (0.082 ml, 1.0M in THF, 0.0820 mmol, 5.0 equiv) at room temperature.
After the reaction was completed, saturated aqueous NH4Cl (5ml) was added
to the reaction mixture, and the aqueous layer was extracted with Et2O
(10 mlꢁ 2). The combined organic layers were washed with brine (20 mlꢁ 1),
dried (Na2SO4), filtered and concentrated under reduced pressure. The crude
17-1 was used for the next step without further purification.
12.0; IR (neat) nmax 3408, 2941, 2865, 1736, 1637, 1463, 1366, 1161 cmꢀ1
;
HRMS (ESI) [Mþ Na]þ calculated for C29H48NaO5Si 527.3169, found
527.3148; mp 162–164 1C.
(4S*,6R*,8S*,18S*)-2,8-diallyl-18-(1-hydroxy-1-methylethyl)-9,9-
dimethyl-31-oxatricyclo[6.3.1.03,4]dodec-2-ene-1,5-dione-6-
carbaldehyde (18)
(4S*,6R*,8S*,18S*)-8-allyl-18-(1-methyl-1-trimethylsilyloxyethyl)-
9,9-dimethyl-6-((triisopropylsilyloxy)methyl)-31-
oxatricyclo[6.3.1.03,4]dodec-2-ene-1,5-dione (16-1)
To a stirred solution of crude 17-1 in CH2Cl2 (0.16 ml) was added Dess–
Martin periodinane (13.8 mg, 0.0328mmol, 2.0 equiv) and NaHCO3 (9.6mg,
0.115mmol, 7.0 equiv) at room temperature. After the reaction was completed,
Et2O (10 ml) and a mixture of saturated aqueous NaHCO3 solution (10 ml)
and saturated aqueous Na2S2O3 solution (10 ml) were added to the reaction
mixture. The aqueous layer was extracted with Et2O (10 mlꢁ 2). The
combined organic layers were washed with brine (20 mlꢁ 1), dried (Na2SO4),
filtered and concentrated under reduced pressure. The residue was purified by
flash chromatography (hexanes/ethyl acetate¼ 10/1) to afford 18 (5.1mg,
81%) as an oil.
RF ¼ 0.60 (hexanes/ethyl acetate¼ 2/3); 1H NMR (400MHz, CDCl3) d 9.46
(1H, s), 5.87-5.71 (1H, m), 5.69-5.54 (1H, m), 5.10-4.91 (4H, m), 4.58 (1H,
dd, J ¼ 11.0, 6.0Hz), 3.15 (1H, dd, J ¼ 14.4, 6.0 Hz), 3.06 (1H, dd, J ¼ 14.4,
6.8Hz), 2.69 (1H, dd, J ¼ 13.6, 11.2Hz), 2.35 (1H, brs), 2.09 (1H, dd, J ¼ 13.6,
4.0 Hz), 1.78 (1H, dd, J ¼ 13.6, 6.0Hz), 1.78-1.61 (3H, m), 1.54 (1H, dd,
J ¼ 13.6, 12.4Hz), 1.34 (3H, s), 1.23 (3H, s), 1.18 (3H, s), 1.06 (3H, s); 13C
NMR (100 MHz, CDCl3) d 202.8, 194.3, 191.7, 175.1, 136.3, 135.0, 117.3,
115.2, 115.0, 90.7, 79.3, 70.8, 59.6, 45.6, 40.9, 37.3, 32.5, 29.6, 27.1, 26.7, 24.1,
23.0, 16.4; IR (neat) nmax 3478, 2976, 2922, 2853, 1744, 1725, 1618, 1366,
1232 cmꢀ1; HRMS (ESI) [Mþ Na]þ calculated for C23H30NaO5 409.1991,
found 409.1975.
To a solution of 16 (8.8mg, 0.0175mmol) in DMF (1.0ml) was added
imidazole (11.9 mg, 0.175mmol, 10equiv), DMAP (0.21 mg, 1.75mmol) and
TMSCl (11.3 ml, 0.0875mmol, 5 equiv) at 0 1C. After the reaction was
completed, saturated aqueous NaHCO3 (5ml) was added to the reaction
mixture, and the aqueous layer was extracted with Et2O (10 mlꢁ 2). The
combined organic layers were washed with brine (20 mlꢁ 1), dried (Na2SO4),
filtered and concentrated under reduced pressure. The residue was purified by
flash chromatography (hexanes/ethyl acetate ¼ 20/1) to afford 16-1 (8.9mg,
88%) as an oil.
1
RF ¼ 0.25 (hexanes/ethyl acetate ¼ 2/1); H NMR (400MHz, CDCl3) d 5.76
(1H, s), 5.70-5.52 (1H, m), 5.00 (1H, s), 4.97 (1H, d, J ¼ 8.8 Hz), 4.36 (1H, d,
J ¼ 10.4, 6.0 Hz), 4.23 (1H, d, J ¼ 8.0 Hz), 4.19 (1H, d, J ¼ 8.0 Hz), 2.64 (1H,
dd, J ¼ 13.2, 10.4 Hz, 1H), 2.29 (1H, brs), 1.82-1.71 (1H, brs), 1.69 (1H, dd,
J ¼ 13.2, 6.0 Hz), 1.69-1.52 (1H, m), 1.43 (1H, t, J ¼ 14.3Hz), 1.28 (3H, s),
1.18 (3H, s), 1.06 (3H, s), 1.03-0.90 (23H, brs), 0.71 (3H, s), 0.05 (9H, s); 13
C
NMR (100MHz, CDCl3) d 204.8, 195.4, 176.9, 136.8, 116.8, 104.6, 90.5, 73.4,
71.1, 59.0, 58.6, 44.1, 40.3, 39.0, 33.1, 29.9, 26.8, 25.8, 22.7, 17.9, 16.7, 12.0, 2.3;
IR (neat) nmax 2941, 2865, 1735, 1639 cmꢀ1; HRMS (ESI) [Mþ Na]þ
calculated for C32H56NaO5Si2 599.3564, found 599.3544.
(4S*,6R*,8S*,18S*)-2,8-diallyl-18-(1-methyl-1-
trimethylsilyloxyethyl)-9,9-dimethyl-6-
((triisopropylsilyloxy)methyl)-31-oxatricyclo[6.3.1.03,4]dodec-2-
ene-1,5-dione (17)
To a stirred solution of 16-1 (8.9 mg, 0.0155 mmol) in THF (1.0 ml) was added
(4S*,6R*,8S*,18S*)-2,8-diallyl-18-(1-hydroxy-1-methylethyl)-6-(1-
hydroxy-2-methylpropyl)-9,9-dimethyl-31-
oxatricyclo[6.3.1.03,4]dodec-2-ene-1,5-dione (18-1)
To a stirred solution of 18 (3.2mg, 8.29mmol) was added CeCl3 ꢂ2LiCl in THF
(0.33 ml, 0.25M, 82.9mmol, 10equiv) at room temperature. After the resulting
LiTMP (0.16ml, 0.5M, 0.0775 mmol, 5.0 equiv) at ꢀ78 1C. After the resulting reaction mixture was stirred at the same temperature for additional 1 h, the
reaction mixture was stirred at the same temperature for additional 30 min,
(2-Th)Cu(CN)Li (0.78 ml, 0.1 M, 0.0775 mmol, 5.0 equiv) was added to the
mixture was cooled to ꢀ781C, and iPrMgCl (0.51 ml, 0.5M, 0.249 mmol,
30 equiv) was added to the reaction mixture. After the resulting mixture was
reaction mixture. After the resulting mixture was stirred at the same stirred at the same temperature for additional 30min, temperature of the
temperature for additional 30min, to the mixture was added allyl bromide reaction mixture was gradually warmed up to ꢀ201C. After the reaction was
(6.7 ml, 0.0775mmol, 5.0 equiv). After the reaction was completed, 30% aqueous completed, saturated aqueous NH4Cl solution (10 ml) was added to the
NH4OH solution (5 ml) was added to the reaction mixture and the aqueous
layer was extracted with Et2O (10 mlꢁ 3). The combined organic layers were
reaction mixture and the aqueous layer was extracted with Et2O (10 mlꢁ 3).
The combined organic layers were washed with brine (20 mlꢁ 1), dried
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