The Journal of Organic Chemistry
Article
and DMAP (0.3 mg, 2.72 μmol, 10 mol %) were added. The reaction
was stirred for 30 min at 0 °C. Then, the reaction was quenched with
a half-saturated NH4Cl solution (3 mL). After separation of the
organic phase, the aqueous phase was extracted with DCM (3 × 3
mL). The combined organic layers were washed with brine (5 mL),
dried over MgSO4, and concentrated in vacuo. Purification by column
chromatography (SiO2, CyHex/EtOAc 20:1−5:1) gave butenoate
104 as a yellow oil (24.5 mg, 23.1 μmol, 85%). Rf = 0.40 (CyHex/
(ESI-TOF) m/z: [M + Na]+ calcd for C61H97NO8SSi2Na+ 1082.6366,
found 1082.6361.
Synthesis of (1S,2S,3E,5E,7S,8R,9R,10E,12Z,14Z,16S,17S,18E)-
9,17-Bis((tert-butyldimethylsilyl)oxy)-1-(2-((S)-1-((3,4-
dimethoxybenzyl)oxy)-3-methylbutyl)thiazol-4-yl)-7-methoxy-
2,6,8,12,14,16,19-heptamethylhenicosa-3,5,10,12,14,18,20-hep-
taen-1-yl But-3-enoate (76). To a solution of alcohol 105 (40.0 mg,
37.7 μmol, 1.00 equiv) in DCM (5 mL) and 3 Å molecular sieve were
added at 0 °C proton sponge (72.7 mg, 0.34 mmol, 9.00 equiv) and
Me3OBF4 (44.6 mg, 0.30 mmol, 8.00 equiv). The reaction was stirred
for 1 h 30 min at 0 °C. Afterward, the reaction was quenched at 0 °C
with a saturated NaHCO3 solution (2 mL). After separation of the
organic phase, the aqueous phase was extracted with DCM (3 × 3
mL). The combined organic layers were washed with brine (5 mL),
dried over MgSO4, and concentrated in vacuo. Purification by column
chromatography (SiO2, CyHex/EtOAc 10:1) gave methyl ether 76 as
a colorless oil (27.0 mg, 25.1 μmol, 67%). Rf = 0.40 (CyHex/EtOAc
5:1); [α]2D0 = −30.5° (c = 0.60, DCM); 1H NMR (700 MHz,
CD2Cl2): δ (ppm) = 7.20 (s, 1H), 6.89 (d, J = 1.7 Hz, 1H), 6.85 (dd,
J = 1.8, 8.1 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 6.42 (d, J = 15.9 Hz,
1H), 6.36 (ddd, J = 0.6, 10.7, 17.5 Hz, 1H), 6.33 (ddd, J = 0.7, 10.9,
15.1 Hz, 1H), 5.90 (ddt, J = 6.9, 10.5, 17.4 Hz, 1H), 5.89 (d, J = 10.8
Hz, 1H), 5.84 (s, 1H), 5.77 (d, J = 7.7 Hz, 1H), 5.71 (dd, J = 6.9, 15.9
Hz, 1H), 5.58 (dd, J = 8.5, 15.1 Hz, 1H), 5.40 (d, J = 8.9 Hz, 1H),
5.14 (d, J = 1.6, 17.1 Hz, 1H), 5.13 (ddd, J = 1.5, 1.6, 17.1 Hz, 1H),
5.12 (ddd, J = 1.4, 1.4, 10.2 Hz, 1H), 5.07 (dt, J = 1.4, 9.7 Hz, 1H),
4.99 (d, J = 10.8 Hz, 1H), 4.75 (dd, J = 5.1, 8.6 Hz, 1H), 4.69 (d, J =
6.9 Hz, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H),
4.25 (dd, J = 5.6, 9.0 Hz, 1H), 3.83 (s, 3H), 3.82 (s, 3H), 3.34 (d, J =
9.9 Hz, 1H), 3.10 (dddd, J = 1.5, 1.5, 1.5, 6.9 Hz, 2H), 3.08 (s, 3H),
3.02 (ddq, J = 7.0, 7.0, 7.1 Hz, 1H), 2.43 (ddq, J = 5.6, 7.0, 9.7 Hz,
1H), 1.85 (m, 1H), 1.84 (d, J = 1.3 Hz, 3H), 1.81 (m, 1H), 1.79 (s,
3H), 1.71 (d, J = 1.2 Hz, 3H), 1.61 (ddd, J = 5.0, 7.7, 13.2 Hz, 1H),
1.57 (m, 1H), 1.55 (d, J = 1.0 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H), 0.94
(d, J = 6.6 Hz, 3H), 0.92 (s, 9H), 0.88 (d, J = 6.5 Hz, 3H), 0.88 (d, J =
6.9 Hz, 3H), 0.85 (s, 9H), 0.63 (d, J = 7.0 Hz, 3H), 0.05 (s, 3H), 0.00
(s, 3H), −0.01 (s, 3H), −0.05 (s, 3H); 13C{1H} NMR (126 MHz,
CD2Cl2): δ (ppm) = 175.4, 171.0, 154.1, 149.7, 149.6, 142.1, 135.6,
135.2, 135.1, 134.6, 133.9, 133.33, 133.30, 132.4, 131.02, 130.96,
129.9, 129.6, 128.3, 127.8, 121.2, 118.7, 117.6, 112.4, 112.2, 111.7,
88.7, 77.8, 75.8, 73.2, 72.3, 72.1, 56.4, 56.3, 55.9, 47.1, 43.2, 42.1,
41.0, 39.8, 26.3 (3×), 26.1 (3×), 25.2, 25.1, 23.4, 22.4, 20.7, 18.65,
18.59, 17.2, 15.6, 12.8, 10.9, 9.3, −3.5, −4.2, −4.7, −4.8; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C62H99NO8SSi2Na+ 1096.6522,
found 1096.6492; [M + H]+ calcd for C62H99NO8SSi2H+ 1074.6703,
found 1074.6669.
Synthesis of (4E,6E,8S,9S,10Z,12Z,14E,16R,17R,18S,19E,21-
E,23S,24S)-8,16-Bis((tert-butyldimethylsilyl)oxy)-24-(2-((S)-1-((3,4-
dimethoxybenzyl)oxy)-3-methylbutyl)thiazol-4-yl)-18-methoxy-
6, 9, 11, 13, 17, 19, 23-heptamethyloxacyclotetracosa-
4,6,10,12,14,19,21-heptaen-2-one (77). A solution of ester 76 (20.0
mg, 18.9 μmol, 1.00 equiv) in toluene (25.1 mL resulting in a 0.75
mM solution) was refluxed for 30 min. Then, metathese catalyst 74d
(1.5 mg, 1.89 μmol, 10 mol %) was added in toluene (0.5 mL). The
solution was refluxed for 2 h, and afterward, another portion of
metatheses catalyst 74d (1.5 mg, 1.89 μmol, 10 mol %) was added in
toluene (0.5 mL). The solution was refluxed for an additional 2 h.
Then, the reaction was concentrated in vacuo. Purification by column
chromatography (SiO2, CyHex/EtOAc 8:1) gave the product 77
(10.0 mg, 9.55 μmol, 51%) and an undefined mixture of the starting
material 76 and product 77 (4.4 mg, about 4.15 μmol). This mixture
was subjected to another cycle of RCM by solving it in toluene (5.53
mL resulting in a 0.75 mM solution) and refluxing it for 30 min.
Then, the metathese catalyst 74d (0.3 mg, 0.41 μmol, 10 mol %) was
added in toluene (0.5 mL). The solution was refluxed for 2 h, and
afterward, another portion of metathese catalyst 74d (0.3 mg, 0.41
μmol, 10 mol %) was added in toluene (0.5 mL). The solution was
refluxed for an additional 2 h. Then, the reaction was concentrated in
vacuo. Purification by column chromatography (SiO2, CyHex/EtOAc
8:1) gave the product 77 (1.8 mg). In total, the product could be
isolated as a colorless oil (11.8 mg, 11.3 μmol, 60%). Rf = 0.42
EtOAc 5:1); [α]2D0 = −43.8 (c = 0.33, DCM); H NMR (500 MHz,
1
CD2Cl2): δ (ppm) = 7.20 (s, 1H), 6.97 (d, J = 10.8 Hz, 1H), 6.88 (s,
1H), 6.83 (m, 2H), 6.46 (ddd, J = 0.6, 10.6, 15.8 Hz, 1H), 6.36 (dd, J
= 11.0, 17.1 Hz, 1H), 6.33 (d, J = 15.7 Hz, 1H), 6.03 (dd, J = 8.7, 15.0
Hz, 1H), 5.89 (ddt, J = 6.8, 10.0, 17.2 Hz, 1H), 5.87 (s, 1H), 5.83 (d,
J = 7.3 Hz, 1H), 5.54 (dd, J = 7.5, 15.7 Hz, 1H), 5.39 (d, J = 9.0 Hz,
1H), 5.12 (m, 4H), 4.99 (d, J = 10.8 Hz, 1H), 4.75 (dd, J = 5.0, 8.5
Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.25
(dd, J = 5.6, 9.0 Hz, 1H), 4.21 (dd, J = 7.3, 7.3 Hz, 1H), 3.83 (s, 3H),
3.82 (s, 3H), 3.43 (dq, J = 6.9, 6.9 Hz, 1H), 3.14 (m, 1H), 3.11 (dt, J
= 1.4, 6.9 Hz, 2H), 2.39 (ddq, J = 5.6, 6.7, 9.5 Hz, 1H), 1.81 (m, 2H),
1.76 (m, 6H), 1.75 (d, J = 0.9 Hz, 3H), 1.71 (d, J = 1.2 Hz, 3H), 1.61
(ddd, J = 5.1, 7.6, 13.0 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 1.00 (d, J =
6.9 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.7 Hz, 6H), 0.87
(s, 9H), 0.85 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H), −0.02 (s, 3H),
−0.05 (s, 3H); 13C{1H} NMR (126 MHz, CD2Cl2): δ (ppm) =
204.2, 175.6, 171.0, 153.8, 149.8, 149.6, 143.5, 142.1, 138.4, 136.4,
135.4, 133.9, 133.2, 133.0, 132.5, 132.0, 130.9, 130.9, 130.5, 129.8,
128.4, 121.2, 118.9, 117.6, 112.4, 112.2, 111.7, 77.8, 77.4, 75.5, 73.3,
72.1, 56.4, 56.3, 47.1, 46.8, 42.5, 41.1, 39.7, 26.20 (3×), 26.15 (3×),
25.17, 25.16, 23.4, 22.4, 20.6, 18.60, 18.59, 17.1, 16.1, 14.9, 12.8, 12.1,
−3.7, −4.2, −4.5, −4.6; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C61H95NO8SSi2Na+ 1080.6209, found 1080.6177.
Synthesis of (1S,2S,3E,5E,7S,8R,9R,10E,12Z,14Z,16S,17S,18E)-
9,17-Bis((tert-butyldimethylsilyl)oxy)-1-(2-((S)-1-((3,4-
dimethoxybenzyl)oxy)-3-methylbutyl)thiazol-4-yl)-7-hydroxy-
2,6,8,12,14,16,19-heptamethylhenicosa-3,5,10,12,14,18,20-hep-
taen-1-yl But-3-enoate (105). A solution of ketone 104 (38.5 mg,
36.4 μmol, 1.00 equiv) in MeOH (1.5 mL) was prepared. Then, at 0
°C was added NaBH4 (5.5 mg, 0.15 mmol, 4.00 equiv). The reaction
was stirred for 1 h 50 min at this temperature. Then, the reaction was
diluted with EtOAc (3 mL) and quenched with a half-saturated
NH4Cl solution (2 mL). After separation of the organic phase, the
aqueous phase was extracted with EtOAc (3 × 3 mL). The combined
organic layers were washed with brine (5 mL), dried over MgSO4, and
concentrated in vacuo. Purification by column chromatography (SiO2,
CyHex/EtOAc 8:1) gave the alcohol 105 as a colorless oil (31.5 mg,
29.7 μmol, 82%, dr > 10:1). Rf = 0.36 (CyHex/EtOAc 5:1); [α]D20
=
1
−0.5° (c = 0.21, DCM); H NMR (500 MHz, CD2Cl2): δ (ppm) =
7.17 (s, 1H), 6.89 (s, 1H), 6.83 (m, 2H), 6.45 (d, J = 15.8 Hz, 1H),
6.36 (ddd, J = 0.6, 10.7, 17.4 Hz, 1H), 6.27 (ddd, J = 0.8, 10.8, 15.8
Hz, 1H), 5.91 (m, 3H), 5.78 (d, J = 7.2 Hz, 1H), 5.77 (dd, J = 7.6,
15.7 Hz, 1H), 5.56 (dd, J = 8.5, 15.1 Hz, 1H), 5.39 (d, J = 8.6 Hz,
1H), 5.14 (dd, J = 1.6, 17.1 Hz, 1H), 5.14 (d, J = 17.3 Hz, 1H), 5.13
(dt, J = 1.6, 10.8 Hz, 1H), 5.08 (dq, J = 1.4, 9.7 Hz, 1H), 4.99 (d, J =
10.8 Hz, 1H), 4.74 (dd, J = 5.0, 8.6 Hz, 1H), 4.50 (d, J = 11.2 Hz,
1H), 4.42 (dd, J = 2.4, 7.3 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.26
(dd, J = 5.6, 9.0 Hz, 1H), 3.88 (dd, J = 2.0, 9.4 Hz, 1H), 3.83 (s, 3H),
3.82 (s, 3H), 3.77 (d, J = 2.1 Hz, 1H), 3.11 (ddt, J = 1.5, 2.8, 7.0 Hz,
2H), 3.01 (ddq, J = 6.9, 6.9, 7.0 Hz, 1H), 2.43 (ddq, J = 5.8, 6.9, 9.9
Hz, 1H), 1.84 (m, 3H), 1.88 (d, J = 1.3 Hz, 3H), 1.78 (s, 3H), 1.71
(d, J = 1.1 Hz, 3H), 1.66 (d, J = 1.3 Hz, 3H), 1.60 (m, 1H), 0.95 (d, J
= 6.9 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.88 (d, J = 6.7
Hz, 3H), 0.86 (d, J = 6.7 Hz, 3H), 0.85 (s, 9H), 0.63 (d, J = 7.1 Hz,
3H), 0.09 (s, 3H), 0.04 (s, 3H), 0.00 (s, 3H), −0.04 (s, 3H); 13C{1H}
NMR (126 MHz, CD2Cl2): δ (ppm) = 175.3, 171.0, 154.2, 149.7,
149.6, 142.0, 138.3, 135.2, 135.0, 133.9, 133.2, 132.9, 132.4, 131.01,
130.97, 130.75, 130.72, 130.1, 127.9, 127.4, 121.2, 118.8, 117.3, 112.4,
112.2, 111.7, 81.0, 78.3, 77.7, 76.0, 73.2, 72.1, 56.4, 56.3, 47.1, 42.4,
42.0, 41.0, 39.7, 26.15 (3×), 26.14 (3×), 25.2, 25.0, 23.4, 22.4, 20.7,
18.6, 18.5, 17.3, 15.8, 12.9, 12.8, 11.6, −3.8, −4.2, −4.7, −4.8; HRMS
10218
J. Org. Chem. 2021, 86, 10190−10223