Organic Process Research & Development
Article
129.7, 129.5, 127.9, 127.8, 118.8, 113.8, 81.0, 80.5, 70.4, 68.8,
60.9, 55.4, 51.2, 45.5, 33.2, 27.0, 26.7, 19.4.
CDCl3) δ 7.67−7.64 (4H, m), 7.45−7.35 (6H, m), 5.99−5.88
(1H, m), 5.35 (1H, dt, J = 17.2, 1.7 Hz), 5.18 (1H, dt, J = 10.5,
1.5 Hz), 4.80 (1H, t, J = 3.1 Hz), 4.31−4.22 (3H, m), 3.93−
3.79 (3H, m), 3.75−3.64 (3H, m), 3.54−3.47 (1H, m), 3.33
(1H, dd, J = 5.7, 3.9 Hz), 2.66 (1H, d, J = 6.3 Hz), 2.58−2.43
(2H, m), 1.87−1.65 (4H, m), 1.61−1.50 (4H, m), 1.04 (9H,
s), 0.90 (9H, s), 0.11 (3H, s), 0.09 (3H, s); 13C NMR (75
MHz, CDCl3) δ 138.7, 135.7, 134.0, 129.7, 127.8, 116.2, 98.7,
83.8, 83.4, 83.3, 78.2, 71.3, 70.9, 69.6, 62.2, 62.1, 60.9, 60.5,
54.6, 33.3, 30.5, 27.0, 25.9, 25.5, 24.1, 21.2, 19.3, 18.2, 14.3,
−4.4, −4.6.
(5R,6R)-6-((1R)-1-((tert-Butyldimethylsilyl)oxy)-5-((tetra-
hydro-2H-pyran-2-yl)oxy)pent-3-yn-1-yl)-2,2,3,3,13,13-hex-
amethyl-12,12-diphenyl-5-vinyl-4,7,11-trioxa-3,12-disilate-
tradecane (14). To a solution of compound 13 (1.64 kg, 2.41
mol) in DMF (16.5 L) were added imidazole (0.263 kg, 3.86
mol) and TBSCl (0.546 kg, 3.62 mol) subsequently at rt. The
reaction mixture was stirred at 60 °C for 6 h, cooled to rt, and
quenched with water (1.6 L) and aqueous 5% NH4Cl solution
(13 L). The organic layer was separated with AcOEt (16.5 L),
washed with water (16.5 L), dried over Na2SO4, and
concentrated in vacuo. Purification by silica gel chromatog-
raphy (hexanes/AcOEt = 10: 1) gave product 14 (1.65 kg,
2.17 mol, 90%) as colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.68−7.64 (4H, m), 7.44−7.34 (6H, m), 5.93−5.81 (1H, m),
5.24 (1H, dt, J = 17.4, 1.5 Hz), 5.14−5.10 (1H, m), 4.79−4.78
(1H, m), 4.30−4.25 (1H, m), 4.20−4.13 (2H, m), 3.98−3.94
(1H, m), 3.86−3.67 (5H, m), 3.54−3.47 (1H, m), 3.26 (1H,
dd, J = 6.6, 1.5 Hz), 2.51−2.33 (2H, m), 1.86−1.47 (8H, m),
1.04 (9H, s), 0.89 (9H, s), 0.87 (9H, s), 0.08 (3H, s), 0.06
(3H, s), 0.04 (3H, s), 0.02 (3H, s); 13C NMR (75 MHz,
CDCl3) δ 138.5, 135.7, 134.2, 129.6, 127.7, 116.0, 98.9, 96.8,
74.4, 72.2, 69.6, 62.1, 61.3, 60.5, 54.9, 54.8, 33.5, 30.4, 27.0,
26.1, 26.0, 25.5, 23.6, 21.2, 19.3, 18.4, 18.2, 14.4, −4.3, −4.4,
−4.5.
(3R,4R,5R)-4-(3-((tert-Butyldiphenylsilyl)oxy)propoxy)-3-
((4-methoxybenzyl)oxy)-9-((tetrahydro-2H-pyran-2-yl)oxy)-
non-1-en-7-yn-5-ol (11). To a solution of THP-protected
propargyl alcohol 10 (1.81 kg, 12.9 mol) in THF (16.5 L) was
added 2.5 M n-BuLi in n-hexane (4.83 L, 12.1 mol) dropwise
at −65 °C. The reaction mixture was stirred at −65 °C for 1 h.
To the reaction mixture were added dropwise a solution of
compound 9 (2.36 kg, 4.32 mol) in THF (7 L) and BF3·OEt2
(0.59 L, 4.75 mol) subsequently. The reaction mixture was
warmed to rt, stirred at rt for 1 h, and quenched with aqueous
8.9% NH4Cl solution (11.5 L). The organic layer was extracted
with AcOEt (23 L), dried over Na2SO4, and concentrated in
vacuo. The crude oil of 11 (2.96 kg, 4.31 mol) was used in the
1
next step without further purification. H NMR (300 MHz,
CDCl3) δ 7.66−7.63 (4H, m), 7.45−7.34 (6H, m), 7.25−7.21
(2H, m), 6.86 (2H, dt, J = 9.2, 2.5 Hz), 5.98−5.86 (1H, m),
5.35−5.29 (2H, m), 4.79 (1H, t, J = 3.3 Hz), 4.59 (1H, d, J =
11.7 Hz), 4.30 (1H, d, J = 11.7 Hz), 4.27−4.23 (2H, m),
4.11−4.07 (1H, m), 3.87−3.82 (2H, m), 3.79 (3H, s), 3.75−
3.65 (4H, m), 3.55−3.46 (1H, m), 3.37−3.34 (1H, m), 2.99
(1H, d, J = 4.8 Hz), 2.56−2.40 (2H, m), 1.82−1.49 (8H, m),
1.04 (9H, s); 13C NMR (75 MHz, CDCl3) δ 159.5, 135.7,
135.0, 134.0, 129.9, 129.8, 129.7, 127.8, 119.1, 114.0, 96.9,
83.2, 82.1, 79.5, 78.2, 70.4, 69.6, 68.9, 62.2, 60.8, 55.4, 54.8,
33.2, 30.5, 27.0, 25.5, 24.0, 19.3, 14.3.
(5R,6S)-6-((R)-1-((4-Methoxybenzyl)oxy)allyl)-
2,2,3,3,13,13-hexamethyl-12,12-diphenyl-5-(4-((tetrahydro-
2H-pyran-2-yl)oxy)but-2-yn-1-yl)-4,7,11-trioxa-3,12-disilate-
tradecane (12). To a solution of crude compound 11 (2.96 kg,
4.31 mol) in DMF (30 L) were added imidazole (0.73 kg,
10.72 mol) and TBSCl (1.49 kg, 9.89 mol) subsequently at rt.
The reaction mixture was stirred at 60 °C for 15 h, cooled to
rt, and quenched with water (3 L) and aqueous 5% NH4Cl
solution (23 L). The organic layer was separated with AcOEt
(30 L), washed with water (30 L), dried over Na2SO4, and
concentrated in vacuo. The crude oil of 12 (3.45 kg, 4.31 mol)
was used in the next step without further purification. 1H NMR
(300 MHz, CDCl3) δ 7.68−7.64 (4H, m), 7.43−7.33 (6H, m),
7.23−7.20 (2H, m), 6.82 (2H, dt, J = 9.2, 2.5 Hz), 5.93−5.81
(1H, m), 5.31−5.28 (1H, m), 5.25 (1H, s), 4.84−4.76 (1H,
m), 4.49 (1H, d, J = 11.4 Hz), 4.30−4.21 (3H, m), 3.97−3.74
(10H, m), 3.53−3.47 (1H, m), 3.38−3.34 (1H, m), 2.51−2.49
(2H, m), 1.89−1.48 (8H, m), 1.04 (9H, s), 0.86 (9H, s), 0.07
(3H, s), 0.01 (3H, s); 13C NMR (75 MHz, CDCl3) δ 159.1,
136.5, 135.7, 134.2, 130.9, 129.6, 129.5, 127.7, 118.5, 113.8,
96.8, 96.7, 85.6, 84.7, 84.6, 80.8, 71.6, 70.4, 70.2, 62.1, 61.2,
60.5, 55.4, 54.8, 54.7, 33.5, 30.5, 27.0, 26.0, 25.8, 25.6, 23.6,
21.2, 19.3, 18.2, 14.3, −4.3, −4.5.
(5R,6R,7R)-5,7-Bis((tert-butyldimethylsilyl)oxy)-6-(3-((tert-
butyldiphenylsilyl)oxy)propoxy)non-8-en-2-yn-1-ol (15). To
a solution of compound 14 (1.65 kg, 2.17 mol) in CH2Cl2
(16.5 L) was added 0.9 M Me2AlCl in heptane (4.83 L, 4.34
mol) dropwise at 10 °C. The reaction mixture was stirred at rt
for 5 h, cooled to 0 °C, and quenched with MeOH (132 mL,
3.25 mol). To the resulting solution was added aqueous 3.6%
NaOH solution (16.5 L) and stirred for 10 min. The organic
layer was separated, dried over Na2SO4, and concentrated in
vacuo. Purification by silica gel column chromatography
(hexanes/AcOEt = 9:1) gave product 15 (1.42 kg, 1.84 mol,
1
85%) as colorless oil. H NMR (300 MHz, CDCl3) δ 7.68−
7.64 (4H, m), 7.44−7.34 (6H, m), 5.93−5.81 (1H, m), 5.24
(1H, dt, J = 17.3, 1.6 Hz), 5.13 (1H, dt, J = 10.5, 1.5 Hz),
4.29−4.21 (2H, m), 4.18−4.13 (1H, m), 3.98−3.93 (1H, m),
3.87−3.67 (4H, m), 3.27 (1H, dd, J = 6.6, 1.8 Hz), 2.49−2.34
(2H, m), 1.87−1.78 (2H, m), 1.37 (1H, t, J = 6.0 Hz), 1.04
(9H, s), 0.89 (9H, s), 0.88 (9H, s), 0.09 (3H, s), 0.06 (3H, s),
0.05 (3H, s), 0.02 (3H, s); 13C NMR (75 MHz, CDCl3) δ
138.5, 135.7, 134.2, 129.7, 127.8, 116.0, 87.0, 85.4, 79.5, 74.4,
72.1, 69.7, 61.0, 51.7, 33.5, 27.0, 26.1, 26.0, 23.5, 19.4, 18.4,
18.2, −4.3, −4.4, −4.5.
(3R,4S,5R)-5-((tert-Butyldimethylsilyl)oxy)-4-(3-((tert-
butyldiphenylsilyl)oxy)propoxy)-9-((tetrahydro-2H-pyran-2-
yl)oxy)non-1-en-7-yn-3-ol (13). To a solution of crude
compound 12 (3.45 kg, 4.31 mol) in CH2Cl2 (35 L) were
added water (25 L) and DDQ (1.17 kg, 5.15 mol) at rt. The
reaction mixture was stirred at rt for 2 h, quenched with
aqueous 0.75% NaOH solution (35 L), and stirred at rt for 10
min. The organic layer was separated, and aqueous 10%
NaHSO3 solution (38 L) was added and stirred at rt for 10
min. The organic layer was separated, dried over Na2SO4, and
concentrated in vacuo. Purification by silica gel chromatog-
raphy (hexanes/AcOEt = 9:1) gave product 13 (1.64 kg, 2.41
mol, 56% for three steps) as colorless oil. 1H NMR (300 MHz,
(5R,6R,7R, Z)-5,7-Bis((tert-butyldimethylsilyl)oxy)-6-(3-
((tert-butyldiphenylsilyl)oxy)propoxy)-3-iodonona-2,8-dien-
1-ol (16). To a solution of compound 15 (1.42 kg, 1.84 mol)
in Et2O (18.5 L) was added 60% Red-Al solution in toluene
(7.39 L, 2.65 mol) dropwise at 0 °C. The reaction mixture was
stirred at rt for 4 h and cooled to 0 °C, and AcOEt (0.2 L) was
F
Org. Process Res. Dev. XXXX, XXX, XXX−XXX