The Journal of Organic Chemistry
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anhydrous Na2SO4, and filtered, and the ether was removed under
reduced pressure. The yellow residue was purified by flash column
chromatography (gradient 0−5% ethyl acetate/hexane) to give TMS
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography (gradient 2−5% ethyl acetate/hexane) to obtain
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ether 17 (0.15 g, 96%) exclusively as a yellow oil. H NMR (CDCl3,
methyl ether 19 (0.048 g, 85%) as a colorless oil. H NMR (CDCl3,
500 MHz): δ 7.37−7.31 (m, 4H, Ph), 7.28−7.25 (m, 1H, Ph), 5.87−
5.79 (m, 1H), 5.27−5.20 (m, 2H), 4.56 (d, J = 11.4 Hz, 1H), 4.39 (d,
J = 11.4 Hz, 1H), 4.13−4.08 (m, 1H), 2.44 (s, 1H), 2.13 (dd, J = 14.5,
6.3 Hz, 1H), 1.95 (dd, J = 14.5, 5.05 Hz, 1H), 1.54 (s, 3H), 0.19 (s,
9H); 13C{1H} NMR (CDCl3, 125 MHz): δ 139.2, 138.7, 128.2,
127.3, 116.3, 88.4, 77.2, 72.3, 70.0, 67.7, 50.1, 31.2, 1.8; HRMS (ESI)
(m/z): [(M + Na)]+ calcd for C15H18NaO2, 253.1204; found,
253.1196.
500 MHz): δ 7.33−7.24 (m, 5H), 5.82−5.74 (m, 3H), 5.49 (d, J = 8.9
Hz, 1H), 5.24−5.19 (m, 2H), 5.02 (dd, J = 17.1, 1.9 Hz, 1H), 4.96 (d,
J = 10.1 Hz, 1H), 4.62−4.60 (m, 1H), 4.55−4.49 (m, 2H), 4.37−4.34
(m, 2H), 4.08 (q, J = 6.4 Hz, 1H), 3.30 (s, 3H, OMe), 2.27−2.21 (m,
1H), 2.10 (dd, J = 14.5, 6.3 Hz, 1H), 2.06−2.02 (m, 1H), 1.93 (dd, J
= 14.2, 4.4 Hz, 1H), 1.76 (s, 3H, Me), 1.73−1.65 (m, 2H), 1.54 (s,
3H, Me), 1.52 (s, 3H, Me), 1.34−1.32 (m, 1H), 1.33 (s, 3H, Me),
0.15 (s, 9H, TMS); 13C{1H} NMR (CDCl3, 125 MHz): δ 139.1,
138.7, 138.2, 137.74, 128.2, 127.7, 127.2, 126.3, 116.3, 114.9, 111.3,
105.0, 91.5, 80.6, 77.4, 75.8, 69.9, 67.9, 55.5, 50.3, 49.8, 31.7, 31.3,
26.7, 26.3, 23.4, 13.5, 1.8. Note that six carbon peaks were submerged
with other peaks; HRMS (ESI) (m/z): [M + Na]+ calcd for
C34H50NaO6Si, 605.3274; found, 605.3271.
(3R,6S,8S,E)-8-(Benzyloxy)-1-((3aR,5R,6R,6aR)-6-(but-3-enyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2,6-dimethyl-6-
(trimethylsilyloxy)deca-1,9-dien-4-yn-3-ol (18a). To a stirring
solution of alkyne 17 (0.234 g, 0.56 mmol, 1.0 equiv) in dry THF
at −20 °C was added EtMgBr (250 μL, 3 M in THF, 0.76 mmol, 1.35
equiv), and the reaction was warmed to room temperature and then
refluxed (using oil bath)at 50 °C for 1 h. The contents were cooled
again to −20 °C, and aldehyde 10 (0.150 g, 0.56 mmol, 1.0 equiv) in
dry THF was slowly added to the reaction mixture. The reaction was
gradually warmed to room temperature over 2 h, quenched by the
slow addition of saturated NH4Cl, and extracted with ether (3×). The
combined organic fractions were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was purified by flash column
chromatography (gradient 20−35% ethyl acetate/hexane) to yield
separable diastereomeric allylic alcohols 18a (0.157 g) and 18b
(0.110 g) as colorless syrups (267 mg, 83% overall yield; dr = 1.4:1)
with the recovery of starting materials. 1H NMR (CDCl3, 500 MHz):
δ 7.34−7.24 (m, 5H), 5.83−5.74 (m, 3H), 5.52 (d, J = 8.9 Hz, 1H),
5.25−5.19 (m, 2H), 5.03 (dd, J = 17.1, 1.9 Hz, 1H), 4.96 (dd, J =
10.1, 1.3 Hz, 1H), 4.72 (s, br, 1H, OH), 4.62−4.60 (t, J = 4.4 Hz,
1H), 4.54 (d, J = 11.4 Hz, 1H) 4.50 (t, J = 9.5 Hz, 1H), 4.35 (d, J =
11.4 Hz, 1H), 4.07 (q, J = 6.3 Hz, 1H), 2.27−2.21 (m, 1H), 2.10 (dd,
J = 14.2, 6.3 Hz, 1H), 2.06−2.02 (m, 1H), 1.93−1.90 (m, 1H), 1.80
(m, 1H), 1.80 (s, 3H, Me), 1.74−1.62 (m, 3H), 1.54 (s, 3H, Me),
1.50 (s, 3H, Me), 1.33 (s, 3H, Me), 0.15 (s, 9H, TMS); 13C{1H}
NMR (CDCl3, 125 MHz): δ 139.8, 139.2, 138.6, 138.2, 128.2, 127.7,
127.3, 124.7, 116.4, 114.9, 111.3, 105.0, 90.7, 82.5, 80.6, 77.4, 77.2,
69.9, 67.8, 67.1, 50.2, 49.7, 31.7, 31.2, 26.6, 26.2, 23.4, 13.6, 1.9. Note
that four carbon peaks were submerged with other peaks; HRMS
(ESI) (m/z): [M + Na]+ calcd for C33H48NaO6Si, 591.3118; found,
591.3118.
(4S,7R)-4-((S)-2-(Benzyloxy)but-3-enyl)-7-((E)-1-((3aR,5R,6-
R,6aR)-6-(but-3-enyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]-
dioxol-5-yl)prop-1-en-2-yl)-9,9-diethyl-2,2,4-trimethyl-3,8-dioxa-
2,9-disilaundec-5-yne (20a). To a stirring solution of 18a or 18b
(0.025 g, 0.044 mmol, 1.0 equiv) and triethyl amine (15 μL, 0.11
mmol, 2.5 equiv) in dry CH2Cl2 (3 mL) at 0 °C was added TESOTf
(33 μL, 0.11 mmol, 2.5 equiv). The reaction mixture was warmed to
room temperature and stirred for 2 h under the inert atmosphere.
Upon completion, the reaction was diluted with ether (15 mL) and
quenched with H2O. The aqueous layer was extracted with ether
(2×), and the combined organic fractions were washed with brine (25
mL), dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The crude residue was purified by flash column
chromatography (gradient 2−5% ethyl acetate/hexane) to obtain
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methyl ether 20a (82%) or 20b (87%) as a colorless oil. H NMR
(CDCl3, 500 MHz): δ 7.34−7.23 (m, 5H), 5.87−5.73 (m, 3H), 5.41
(d, J = 9.5 Hz, 1H), 5.22 (m, 1H), 5.18 (dd, J = 10.1, 1.3 Hz, 1H),
5.02 (dd, J = 17.0, 1.85 Hz, 1H), 4.96 (d, J = 10.1 Hz, 1H), 4.73 (s,
1H), 4.61 (t, J = 3.8 Hz, 1H), 4.53−4.47 (m, 2H), 4.35 (d, J = 11.35
Hz, 1H), 4.08 (dd, J = 12.0, 6.3, Hz, 1H), 2.27−2.21 (m, 1H), 2.06
(dd, J = 14.5, 6.3 Hz, 1H), 2.05−2.01 (m, 1H), 1.93−1.89 (m, 1H),
1.77 (d, J = 1.25 Hz, 3H, Me), 1.69−1.64 (m, 2H), 1.55−1.53 (m,
1H), 1.53 (s, 3H, Me), 1.50 (s, 3H, Me), 1.33 (s, 3H, Me), 0.95 (t, J =
8.15 Hz, 9H, TES), 0.65−0.59 (m, 6H, TES), 0.15 (s, 9H, TMS).
HRMS (ESI): m/z [M + Na]+ calcd for C39H62NaO6Si2, 705.3983;
found, 705.4005.
(4S,7S)-4-((S)-2-(Benzyloxy)but-3-enyl)-7-((E)-1-((3aR,5R,6R,6aR)-
6-(but-3-enyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-
prop-1-en-2-yl)-9,9-diethyl-2,2,4-trimethyl-3,8-dioxa-2,9-disilaun-
(3S,6S,8S,E)-8-(Benzyloxy)-1-((3aR,5R,6R,6aR)-6-(but-3-enyl)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-2,6-dimethyl-6-
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dec-5-yne (20b). H NMR (CDCl3, 500 MHz): δ 7.34−7.25 (m,
(trimethylsilyloxy)deca-1,9-dien-4-yn-3-ol (18b). H NMR (CDCl3,
5H), 5.84−5.73 (m, 3H), 5.40 (d, J = 8.9 Hz, 1H), 5.23 (m, 1H), 5.18
(dd, J = 10.1, 1.25 Hz, 1H), 5.02 (dd, J = 17.0, 1.9 Hz, 1H), 4.95 (d, J
= 9.5 Hz, 1H), 4.74 (s, 1H), 4.60 (t, J = 3.8 Hz, 1H), 4.53 (d, J = 11.9
Hz, 1H), 4.49 (t, J = 9.5 Hz, 1H), 4.36 (d, J = 11.4 Hz, 1H), 4.10 (dd
J = 12.0, 6.3 Hz, 1H), 2.25−2.18 (m, 1H), 2.07 (dd J = 13.9, 6.3 Hz,
1H), 2.05−2.01 (m, 1H), 1.92 (dd, J = 14.5, 5.0 Hz, 1H), 1.78 (s,
3H), 1.70−1.65 (m, 2H), 1.54 (s, 3H, Me), 1.49 (s, 3H, Me), 1.35−
1.31 (m, 1H), 1.33 (s, 3H, Me), 0.95 (t, J = 8.2 Hz, 9H), 0.67−0.58
(m, 6H, TES), 0.14 (s, 9H, TMS); 13C{1H} NMR (CDCl3,125
MHz): δ 140.8, 139.2, 138.7, 138.2, 128.2, 127.7, 127.2, 123.9, 116.0,
114.9, 111.2, 105.0, 88.9, 83.6, 80.6, 77.6, 77.3, 70.0, 67.9, 67.6, 50.2,
49.9, 31.8, 31.2, 26.6, 26.3, 23.4, 12.9, 6.7, 4.7, 1.8; HRMS (ESI): m/z
[M + Na]+ calcd for C39H62NaO6Si2, 705.3983; found, 705.4003.
Macrocyclization by RCM (22). Grubbs II catalyst 24 or 25 (0.015
mmol, 20 mol %) in degassed toluene (10 mL) was added to a
refluxing (using oil bath) solution of diene 19 (0.045 g, 0.077 mmol,
1.0 equiv) in degassed toluene (0.1 mM) over 2 h via the syringe
pump. Upon complete addition, the reaction was refluxed (using oil
bath) for a further 30 min followed by distillation of the solvent under
reduced pressure. The residue was purified by flash column
chromatography to isolate macrocycle 2219 (0.002 g, 5%) along
with other trace unidentified products and unreacted starting
materials (15−25%). 1H NMR (CDCl3, 500 MHz): δ 7.34−7.30
500 MHz): δ 7.34−7.24 (m, 5H), 5.84−5.74 (m, 3H), 5.48 (d, J = 8.9
Hz, 1H), 5.25−5.19 (m, 2H), 5.03 (dq, J = 17.0, 1.9 Hz, 1H), 4.98−
4.95 (m, 1H), 4.76 (d, J = 5.05 Hz, 1H), 4.62−4.60 (m, 1H), 4.54 (d,
J = 11.4 Hz, 1H), 4.52−4.48 (m, 1H), 4.36 (d, J = 12.0 Hz, 1H), 4.07
(q, J = 6.3 Hz, 1H), 2.27−2.20 (m, 1H), 2.10 (dd, J = 14.5, 6.3 Hz,
1H), 2.08−2.03 (m, 1H), 1.94−1.90 (m, 1H), 1.81 (s, 3H, Me),
1.72−1.63 (m, 3H), 1.54 (s, 3H, Me), 1.50 (s, 3H, Me), 1.34−1.32
(m, 4H), 0.15 (m, 9H, TMS); 13C{1H} NMR (CDCl3, 125 MHz): δ
140.0, 139.2, 138.7, 138.2, 128.2, 127.7, 127.3, 125.5, 125.0, 116.4,
114.9, 111.3, 105.0, 90.7, 82.5, 80.6, 77.5, 77.2, 69.9, 67.8, 67.4, 50.2,
49.7, 31.7, 31.2, 30.3, 29.6, 26.7, 26.3, 23.4, 13.2, 1.9. Note that a
carbon peak was submerged with other peaks; HRMS (ESI) (m/z):
[M + Na]+ calcd for C33H48NaO6Si, 591.3118; found, 591.3124.
((3S,5S,8R,E)-3-(Benzyloxy)-10-(3aR,5R,6R,6aR)-6-(but-3-enyl)-
2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)-8-methoxy-5,9-
dimethyldeca-1,9-dien-6-yn-5-yloxy)trimthylsila-ne (19). NaH
(60% in mineral oil, 10 mg, 0.25 mmol, 2.6 equiv) was added to
the stirring solution of 18a (0.055 g, 0.097 mmol, 1.0 equiv) and MeI
(15 μL, 0.24 mmol, 2.5 equiv) in dry THF (3 mL) at 0 °C. The
reaction mixture was warmed to room temperature and stirred for 3 h.
Upon completion, the reaction was diluted with ether (15 mL) and
quenched with H2O. The aqueous layer was extracted with ether
(2×), and the combined organic fractions were washed with brine (25
6165
J. Org. Chem. 2021, 86, 6160−6168