The Journal of Organic Chemistry
Article
organic layers were dried over MgSO4, filtered, and concentrated in
vacuo. The crude mixture was purified via flash chromatography on
SiO2 (50% EtOAc/hexanes) to afford a 1/2 mixture of the desired bis-
phenol and 3,4-dimethoxybenzalehyde, respectively. The mixture was
treated with a stock solution of MgBr2/n-BuSH/MeNO2 in Et2O
(0.140 mL; 25 equiv of MgBr2 and 25 equiv of n-BuSH; stock solution
89.9 mg of MgBr2, 36 μL of n-BuSH, 100 μL of MeNO2, and 0.98 mL
of Et2O). After 9.5 h, the reaction mixture was diluted with EtOAc and
quenched with a saturated aqueous solution of NaHCO3 and extracted
with EtOAc (5 × 0.5 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The crude mixture
was purified via flash chromatography on SiO2 (40% to 50% EtOAc/
hexanes) to afford (+)-C(11)-OBz-irciniastatin A (−)-9 (1.0 mg, 1.4
umol, 50% over two steps) as a white amorphous solid: [α]2D0 = −13.7
(c 0.08, CHCl3); IR (neat) 3372, 2943, 1726, 1663, 1599, 1446, 1377,
organic layers were dried over MgSO4, filtered, and concentrated in
vacuo. The crude mixture was purified via flash chromatography (50%
EtOAc/hexanes) to afford a 1/2 mixture of the desired bis-phenol and
3,4-dimethoxybenzalehyde, respectively. The mixture was treated with
a stock solution of MgBr2/n-BuSH/MeNO2 in Et2O (0.20 mL; 25
equiv of MgBr2, 25 equiv of n-BuSH; stock solution: 42.3 mg of
MgBr2, 18 μL of n-BuSH, 46 μL of MeNO2, and 0.46 mL of Et2O).
After 10 h, the reaction mixture was diluted with EtOAc and quenched
with a saturated aqueous solution of NaHCO3 and extracted with
EtOAc (5 × 0.5 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude mixture was
purified via flash chromatography on SiO2, (40% to 80% EtOAc/
hexanes with 5% v/v triethylamine) to afford (+)-C(11)-exo-
methyleneirciniastatin A (+)-10 (2.0 mg, 3.3 μmol, 77% over two
steps) as a white amorphous solid: [α]2D0 = +12.7 (c 0.17, CHCl3); IR
(neat) 3379, 2921, 1732, 1659, 1623, 1514, 1454, 1379, 1254, 1109
cm−1; 1H NMR (500 MHz, CDCl3) δ 11.15 (s, 1 H), 7.28 (d, J = 10.3,
6.7 Hz, 1H), 6.68 (bs, 1H), 6.30 (s, 1 H), 5.28 (dd, J = 10.3, 6.7 Hz,
1H), 4.87 (s, 2H), 4.81 (s, 1H), 4.79 (s, 1H), 4.52 (ddd, J = 4.0, 16.4,
8.0 Hz, 1H), 4.45 (d, J = 3.0 Hz, 1H), 4.01 (d, J = 10.1 Hz, 1H), 3.92−
3.88 (m, 2H), 3.77−3.74 (ddd, J = 12.7, 9.4, 3.8 Hz, 1H), 3.63 (d, J =
10.7 Hz, 1H), 3.40 (s, 3H), 3.35 (s, 3H), 3.34−3.31 (m, 1H), 2.93−
2.80 (m, 2H), 2.52 (dd, J = 14.2, 5.4 Hz, 1H), 2.42−2.35 (m, 2 H),
2.16 (dd, J = 3.9, 14.8 Hz, 1 H), 2.02 (s, 3 H), 1.88 (m, 1 H), 1.79 (dd,
J = 10.6, 2.8 Hz, 1H), 1.75 (s, 3H), 1.55 (d, J = 14.5 Hz, 1H), 1.14 (s,
3H), 1.10 (d, J = 7.0 Hz, 3H), 1.06 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 173.3, 170.7, 162.5, 161.2, 148.2, 142.2, 140.0, 113.4, 113.2,
110.0, 101.7, 101.5, 83.4, 80.6, 80.2, 79.1, 73.9, 73.2, 72.7, 58.0, 56.5,
43.0, 39.9, 37.5, 33.0, 32.1, 28.5, 25.0, 22.9, 21.7, 10.7, 9.5; HRMS
(ES−) m/z 606.3280 [(M − H)−; calcd for C32H48NO10 606.3278].
O-Methyloxime (+)-S9. To a solution of (−)-31 (6.0 mg, 5.1
μmol) in pyridine (0.3 mL) was added methoxyamine hydrochloride
(8.8 mg, 0.105 mmol, 20.6 equiv), and the reaction mixture was
warmed to 50 °C. After 2 h, the reaction mixture was quenched with a
saturated aqueous solution of NaHCO3 and extracted with EtOAc (3
× 0.5 mL). The combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude mixture was purified via
flash chromatography on SiO2 (35% to 40% EtOAc/hexanes) to
furnish O-methyloxime (+)-S9 (4.9 mg, 4.1 μmol, 80%) as an odorless
oil: [α]2D0 = +11.3 (c 0.4, CH2Cl2); IR (neat) 3421, 2930, 1715, 1680,
1593, 1516, 1462, 1378, 1247, 1157, 1029 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.36 (d, J = 10.1 Hz, 1H), 7.31 (d, J = 1.9 Hz, 1H), 6.98−
6.93 (m, 3H), 6.87 (d, J = 8.7 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.54
(s, 1H), 5.17 (dA,B, J = 12.1 Hz, 1H), 5.10 (dA,B, J = 11.8 Hz, 1H), 5.05
(dd, J = 10.1, 1.2 Hz, 1H), 4.98 (s, 2H), 4.84 (dA,B, J = 6.5 Hz, 1H),
4.79 (s, 1H), 4.77 (s, 1H), 4.69 (dA,B, J = 6.4 Hz, 1H), 4.65 (dA,B, J =
6.4 Hz, 1H), 4.60 (dA,B, J = 7.3 Hz, 1H), 4.40 (d, J = 2.3 Hz, 1H), 4.22
(ddd, J = 11.5, 8.5, 2.2 Hz, 1H), 4.02 (dd, J = 3.5, 12.1 Hz, 1H), 3.97−
3.93 (m, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H),
3.81 (s, 3H), 3.78−3.73 (m, 2H), 3.60−3.54 (m, 2H), 3.53−3.48
(ddd, J = 11.7, 9.6, 5.6 Hz, 1H), 3.44−3.43 (ddd, J = 11.6, 9.9, 5.8 Hz,
1H), 3.40 (s, 3H), 3.30 (s, 3H), 3.20 (dd, J = 16.6, 5.4 Hz, 1H), 3.07
(dd, J = 15.3, 4.0 Hz, 1H), 2.67 (dd, J = 16.6, 12.3 Hz, 1H), 2.38 (dd, J
= 14.7, 8.8 Hz, 1H), 2.23 (dd, J = 14.3, 4.5 Hz, 1H), 2.16−2.07 (m,
1H), 2.12 (s, 3H), 1.98−1.92 (m, 1H), 1.88 (dd, J = 15.0, 12.3 Hz,
1H), 1.75 (ddd, J = 14.5, 10.3, 3.8 Hz, 1H), 1.72 (s, 3H), 1.24 (s, 3H),
1.16 (d, J = 6.7 Hz, 3H), 1.03 (s, 3H), 0.96−0.85 (m, 2H), 0.82−0.76
(ddd, J = 13.7, 11.4, 5.4 Hz, 1H), 0.74−0.68 (ddd, J = 13.4, 11.7, 5.7
Hz, 1H), 0.00 (s, 9H), −0.10 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
171.5, 163.8, 161.3, 160.3, 158.2, 149.4, 149.3, 149.2, 148.7, 142.3,
141.9, 129.5, 128.8, 120.2, 119.1, 115.9, 113.1, 111.1, 110.9, 110.8,
110.6, 107.9, 97.6, 95.0, 94.7, 81.4, 81.3, 79.7, 79.5, 74.6, 71.0, 70.4,
70.4, 66.1, 65.6, 61.5, 58.0, 56.3, 56.2, 56.04, 56.00, 55.99, 40.6, 39.5,
38.3, 29.9, 29.8, 29.2, 27.2, 23.4, 22.9, 21.5, 18.1, 18.0, 11.4, 9.6, −1.2,
−1.4; HRMS (ES+) m/z 1219.6161 [(M + Na)+; calcd for
C62H96N2O17Si2Na 1219.6145].
1
1253, 1114 cm−1; H NMR (500 MHz, C6D6) δ 11.93 (bs, 1H), 8.17
(d, J = 7.5 Hz, 3H), 7.10 (t, J = 7.5 Hz, 2H), 6.31 (s, 1H), 5.67 (t, J =
8.3 Hz, 1H), 5.27 (dd, J = 9.9, 4.4 Hz, 1H), 5.04 (s, 1H), 4.92 (s, 1H),
4.61 (bs, 1H), 4.33 (m, 3H), 4.17 (d, J = 9.7 Hz, 1H), 3.91 (ddd, J =
4.0, 3.5, 3.5 Hz, 1H), 3.73 (d, J = 10.4 Hz, 1H), 3.59 (bs, 1H), 3.32 (s,
3H), 3.25 (s, 3H), 2.63 (d, J = 16.3 Hz, 1H), 2.65−2.51 (ddd, J = 12.4,
12.4, 8.7 Hz, 1H), 2.46 (dd, J = 14.0, 4.6 Hz, 2H), 2.26 (m, 1H), 2.02
(s, 3H), 1.93 (m, 1H), 1.79 (s, 3H), 1.58 (bs, 1H), 1.46 (d, J = 13.9
Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H), 0.96 (s, 3H), 0.79 (s, 3H); 13C
NMR (125 MHz, C6D6) δ 173.7, 170.9, 165.7, 163.2, 161.8, 142.6,
140.1, 133.2, 130.9, 129.9, 128.8, 127.5, 113.6, 113.5, 102.0, 101.6,
82.2, 81.5, 80.1, 78.9, 74.3, 73.8, 73.5, 57.8, 56.3, 43.1, 38.1, 37.8, 33.0,
32.4, 30.2, 30.1, 28.4, 27.2, 23.1, 14.4, 10.6, 9.2; HRMS (ES+) m/z
736.3286 [(M + Na)+; calcd for C38H51NO12Na 736.3309].
Olefin (−)-S8. To a solution of PPh3MeBr (75.4 mg, 0.211 mmol)
in THF (0.46 mL) was added KO-t-Bu (0.20 mL, 0.20 mmol) to
provide a yellow solution, which was stirred for 5 min. The solution
(40 μL, 0.32 M in THF, 2.5 equiv) was added to a separate vial
containing a solution of ketone (−)-31 (6.0 mg, 5.1 umol) in THF
(0.26 mL), and the yellow reaction mixture was stirred for 1 h at room
temperature. The reaction mixture was quenched with water and
extracted with EtOAc (4 × 0.5 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The crude
mixture was purified via flash chromatography on SiO2 (40% EtOAc/
hexanes) to furnish olefin (−)-S8 (5.0 mg, 4.3 μmol, 84%) as a white
amorphous oil: [α]2D0 = −3.4 (c 0.4, CHCl3); IR (neat) 3422, 2951,
1715, 1686, 1592, 1515, 1463, 1417, 1378, 1246, 1157, 1083, 1027
1
cm−1; H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 9.7 Hz, 1 H), 7.31
(app s, 1 H), 6.97−6.93 (m, 3 H), 6.87 (d, J = 8.5 Hz, 1 H), 6.88 (d, J
= 8.3 Hz, 1 H), 6.54 (s, 1 H), 5.17 (dA,B, J = 11.7 Hz, 1 H), 5.10 (dA,B
,
J = 11.7 Hz, 1 H), 5.03 (d, J = 19.9 Hz, 1 H), 4.98 (s, 2 H), 4.87 (d, J =
5.5 Hz, 1 H), 4.86 (s, 1 H), 4.78 (app s, 2 H), 4.70 (d, J = 13.6 Hz, 1
H), 4.64 (dA,B, J = 7.0 Hz, 1 H), 4.60 (dA,B, J = 6.8 Hz, 1 H), 4.42 (app
s, 1 H), 4.22 (ap t, J = 10.8 Hz, 1 H), 3.96 (m, 2 H), 3.92 (s, 3 H), 3.90
(s, 3 H), 3.88 (s, 3 H), 3.87 (s, 3 H), 3.80−3.74 (m, 2 H), 3.58 (ddd, J
= 9.7, 9.7, 6.4 Hz, 1 H), 3.53−3.48 (m, 2 H), 3.42 (dd, J = 11.0, 5.3
Hz, 1 H), 3.40 (s, 3 H), 3.30 (s, 3 H), 3.23 (d, J = 16.1 Hz, 1 H), 2.64
(dd, J = 16.2, 12.3 Hz, 1 H), 2.38 (dd, J = 14.9, 9.0 Hz, 1 H), 2.30−
2.22 (m, 2 H), 2.13 (s, 3 H), 2.06−1.97 (m, 2 H), 1.72 (s, 3 H), 1.66−
1.63 (m, 1 H), 1.19 (s, 3 H), 1.16 (d, J = 6.7 Hz, 3 H), 0.99 (s, 3 H),
0.95−0.86 (m, 2 H), 0.84−0.78 (ddd, J = 14.0, 12.0, 5.6 Hz, 1 H),
0.75−0.67 (ddd, J = 13.8, 12.2, 6.1 Hz, 1 H), 0.01 (s, 9 H), −0.10 (s, 9
H); 13C NMR (125 MHz, CDCl3) δ 171.5, 163.8, 161.3, 160.4, 149.6,
149.4, 149.3, 148.8, 148.3, 142.4, 142.1, 129.6, 128.9, 120.2, 119.2,
116.1, 113.0, 111.3, 111.1, 111.0, 110.8, 109.7, 108.2, 97.9, 94.9, 94.7,
81.6, 81.5, 79.7, 79.4, 74.6, 72.2, 71.2, 70.5, 66.1, 65.5, 58.1, 56.3, 56.2,
40.2, 39.5, 38.4, 33.8, 29.9, 28.7, 27.5, 23.2, 23.0, 18.2, 11.4, 9.6, −1.2,
−1.4; HRMS (ES+) m/z 1188.6088 [(M + Na)+; calcd for
C62H95NO16Si2Na 1188.6087].
C(11)-exo-Methyleneirciniastatin B (+)-10. To a solution of
olefin (−)-S8 (5.0 mg, 4.3 umol) in CH2Cl2 (0.05 mL) and H2O (15
μL) was added a suspension of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (0.1 mL, 0.34 M in CH2Cl2, 8.0 equiv). After 11.5 h,
the reaction mixture was quenched with a saturated aqueous solution
of NaHCO3 and extracted with EtOAc (5 × 0.5 mL). The combined
C(11)-O-Methyloximeirciniastatin B (+)-11. To a solution of O-
methyloxime (+)-S9 (4.9 mg, 4.1 μmol) in CH2Cl2 (0.160 mL) and
H2O (26 μL) was added a suspension of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (0.1 mL, 0.33 M in CH2Cl2, 8 equiv). After 11 h, the
L
J. Org. Chem. XXXX, XXX, XXX−XXX