Organic & Biomolecular Chemistry
Paper
6
2
.71 (d, J = 8.2 Hz, 1H, Ar), 5.56 (s, 1H, CHOTBDMS), 4.57 (s, 2.20–2.03 (m, 2H, CH
2
), 1.87 (dd, J
1
= 18.8 Hz, J
2
= 12.1 Hz, 1H,
H, CH O), 3.97 (d, J = 4.0 Hz, 1H, CHCHCH ), 3.75 (p, J = 5.6 CHH), 1.81–1.72 (m, 1H, CH), 1.50 (s, 9H, (H C) CO),
2
3
3
3
Hz, 1H, CHOSi), 2.43 (m, 2H, CHCH
3
and CHHCv), 2.32–2.24 1.50–1.44 (m, 3H, CHH and CH
2
), 1.30–1.18 (m, 8H, 4CH
2
),
C
1
3
(m, 1H, CHHCv), 1.67–1.60 (m, 2H, CH
2
), 1.55 (d, J = 7.2 Hz, 1.07 (s, 9H, (H
3
C)
3
CSi), 0.84 (t, J = 7.2 Hz, 3H, CH
3
) ppm.
3
H, CH CH), 1.48 (s, 9H, (H C) CO), 1.44–1.35 (m, 2H, CH ), NMR (101 MHz, CDCl ) δ 219.2 (CO), 168.1 (CO), 155.9 (C),
3
3
3
2
3
1
.18–0.99 (m, 6H, 3CH
2
), 1.07 (s, 9H, (H
3
C)
CH
CH Si), 0.10 (s, 3H, CH Si) ppm. C NMR (101 MHz, CDCl ) δ 122.0 (CH), 108.1 (CH), 82.2 (C), 73.3 (CH), 65.6 (CH ), 57.0
3
CSi), 0.83 (s, 9H, 136.2 (C) 135.9 (4CH), 135.9 (C), 134.6 (C), 134.5 (C) 129.5
(H
3
C)
3
CSi), 0.78 (t, J = 7.2 Hz, 3H, CH
3
2
), 0.12 (s, 3H, (CH), 129.4 (CH), 127.45 (2CH), 127.39 (2CH), 125.9 (CH),
1
3
3
3
3
2
2
(
1
1
11.9 (CO), 172.7 (CO), 167.6 (C), 154.4 (C), 147.1 (C), 137.2 (CH), 41.4 (CH
C), 135.91 (2CH), 135.89 (2CH), 134.7 (C), 134.2 (C), 131.8 (C), (CH ), 31.4 (CH), 28.0 (3CH
29.5 (CH), 129.4 (CH), 128.8 (CH), 127.5 (2CH), 127.3 (2CH), (CH ), 24.3 (CH ), 22.6 (CH ), 20.1(CH ), 19.4 (C), 14.0 (CH )
2
), 36.3 (CH
2
), 34.9 (CH
2
), 34.7 (CH
2
), 31.8
2
3
), 27.1 (3CH
3
), 26.4 (CH
2
), 24.5
2
2
2
2
3
−
1
18.4 (CH), 111.4 (CH), 82.4 (C), 73.2 (CH), 69.7 (CH), 65.7 ppm. IR (NaCl) ν = 2952, 2927, 2858, 1740 and 1588 cm
.
(CH
2
), 51.9 (CH), 48.9 (CH), 36.2 (CH ), 34.3 (CH ), 31.7 (CH ), Elemental analysis calcd for C43 Si: C, 75.62; H, 8.56; Si,
2
2
2
58 5
H O
2
2
8.0 (3CH ), 27.1 (3CH ), 25.6 (3CH ), 24.4 (CH ), 22.5 (CH ), 7.17; found: C, 75.00; H, 8.41.
3
3
3
2
2
0.0 (CH
2
), 19.4 (C), 18.0 (C), 14.1 (CH
3
), 14.0 (CH
3
), −4.1
2
-(((1R,2R,3aS,9aS)-1-((S)-3-((tert-Butyldiphenylsilyl)oxy)octyl)-
(CH
3
), −4.2 (CH ) ppm. IR (NaCl) ν = 2956, 2932, 2860, 1749,
3
1
725, 1590 cm− . Elemental analysis calcd for C H O Si : C,
2-hydroxy-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]
naphthalen-5-yl)oxy)acetic acid (24)
1
7
4
9
70
6
2
2.55; H, 8.70; Si, 6.92; found: C, 72.72; H, 8.84.
To a cooled (−10 °C) and stirred solution of 23 (3.5 g,
tert-Butyl 2-(((3aS,9aS)-1-((S)-3-((tert-butyldiphenylsilyl)oxy)
octyl)-2-oxo-2,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]
naphthalen-5-yl)oxy)acetate (23)
5
.12 mmol) in ethanol (20 mL) was added a 5 M aqueous
sodium hydroxide solution (10.2 mL, 51.2 mmol). The reaction
mixture was stirred for 30 min and then NaBH (203 mg,
4
To a solution of 22 (5.6 g, 7.02 mmol) in absolute ethanol 5.38 mmol, 1.05 equiv.) was added and stirring was continued
60 mL) were added anhydrous K CO (280 mg, 5% w/w) and at −10 °C for 1 h. An additional equiv. of NaBH (203 mg) was
0% Pd/C (1.4 g, 50% wet, 25% w/w) and the mixture was added and stirring was continued for another 12 h at 0 °C.
(
2
3
4
1
hydrogenated at 3 bar of pressure. After 15 h stirring at room Upon completion (TLC), the reaction mixture was quenched
temperature, the pressure was carefully released, and the reac- with glacial acetic acid until pH 2–3 was achieved and the
tion mixture was filtered through Celite and washed with DCM solvent was removed in vacuo. The crude reaction mixture was
(100 mL). Silica gel column chromatography in hexane : ethyl dissolved in ethyl acetate (25 mL), washed with 1N HCl
acetate (15 : 1) gave 23 as mixture of 2 stereoisomers in a 3 : 1 (20 mL), water (20 mL), and brine (20 mL), dried with Na SO
2
4
1
ratio measured by H NMR. 3.60 g (75% yield). A small sample and concentrated in vacuo to obtain 3.1 g of crude tricyclic
of each isomer was isolated for characterization. Major isomer: alcohol 24 as a white solid. This was used for the next step
1
1
R
f
: 0.51 (hexane/AcOEt 6 : 1). H NMR (400 MHz CDCl
3
)
3
without further purification. H NMR (400 MHz, CDCl )
δ 7.67–7.64 (m, 4H, Ar), 7.40–7.31 (m, 6H, Ar), 7.08 (t, J = δ 7.70–7.67 (m, 4H, Ar), 7.41–7.34 (m, 6H, Ar), 7.08 (t, J =
7
1
.8 Hz, 1H, Ar), 6.71 (d, J = 7.6 Hz, 1H, Ar), 6.57 (d, J = 8.1 Hz, 7.8 Hz, 1H, Ar), 6.75 (d, J = 7.5 Hz, 1H, Ar), 6.67 (d, J = 8.3 Hz,
H, Ar), 4.51 (s, 2H, CH O), 3.73 (p, J = 5.1 Hz, 1H), 3.07 (dd, 1H, Ar), 4.66 (s, 2H, CH O), 3.76–3.70 (m, 1H, CHOH),
= 16.9 Hz, J = 6.7 Hz, 1H, CHH), 2.87 (dd, J = 16.4 Hz, J 3.61–3.55 (d, J = 7.4 Hz, 1H, CHOSi), 2.79 (dd, J = 14.8 Hz, J
.6 Hz, 1H, CHH), 2.54–2.44 (m, 2H, CH and CHH), 2.40–2.33 6.0 Hz, 1H, CHH), 2.62 (dd, J = 14.3 Hz, J = 6.1, 1H, CHH),
2
2
J
1
2
1
2
=
1
2
=
6
1
2
(
1
1
m, 2H, CH
2
), 2.18–2.08 (m, 2H, CHH and CH), 1.77–1.73 (m, 2.52 (dd, J
H, CH), 1.48 (s, 9H, (H C) CO), 1.51–1.40 (m, 6H, 3CH ), 14.2 Hz, J
.26–1.08 (m, 6H, 3CH ), 1.05 (s, 9H, (H C) CSi), 0.82 (t, J = 7.1 CH), 1.78–1.70 (m, 1H, CH), 1.54–1.42 (m, 6H, 3CH2),
1
= 14.7 Hz, J
2 1
= 6.4 Hz, 1H, CHH), 2.33 (dd, J =
3
3
2
2
= 6.4 Hz, 1H, CHH), 2.23–2.01 (m, 2H, CHH, and
2
3
3
13
Hz, 3H, CH
1
(
(
5
3
) ppm. C NMR (101 MHz CDCl
3
) δ 220.4 (CO), 1.29–1.01 (m, 8H, 3CH
2
, CH and CHH), 1.06 (s, 9H, (H
3
C)
) ppm. C NMR (101 MHz, CDCl
C) 129.4 (2CH), 127.41 (2CH), 127.38 (2CH), 126.2 (CH), 125.1 δ 172.6 (CO), 153.6 (C), 140.0 (C), 134.9 (4CH), 133.8 (C), 133.6
C), 121.8 (CH), 108.4 (CH), 82.2 (C), 73.2 (CH), 65.8 (CH ), (C), 128.4 (2CH), 126.6 (C), 126.4 (4CH), 125.1 (CH), 120.9
1.8 (CH), 45.1 (CH ), 38.6 (CH), 36.0 (CH ), 33.3 (CH ), 31.82 (CH), 108.7 (CH), 76.1 (CH), 72.6 (CH), 64.5 (CH ), 51.2 (CH),
3
CSi),
1
3
68.1 (CO), 155.1 (C) 137.2 (C), 135.9 (4CH), 134.7 (C), 134.5 0.83 (t, J = 7.2 Hz, 3H, CH
3
3
)
2
2
2
2
2
(
(
CH ), 31.79 (CH ), 30.5 (CH), 28.0 (3CH ), 27.1 (3CH ), 25.5 40.0 (CH ), 39.8 (CH), 35.1 (CH ), 33.0 (CH ), 32.7 (CH ), 31.7
2
2
3
3
2
2
2
2
CH
2
), 24.6 (CH
2
), 23.8 (CH
2
), 22.5 (CH
2
), 19.4 (C), 14.0 (CH
3
)
.
(CH), 30.9 (CH
(CH ), 21.6 (CH ), 18.4 (C), 13.0 (CH ) ppm. IR (NaCl) ν = 3417,
2 2 3
2
), 26.5 (CH
2
), 26.1 (3CH
3
2
), 24.8 (CH ), 23.7
−
1
ppm. IR (NaCl) ν = 2955, 2930, 2856, 1737 and 1590 cm
Elemental analysis calcd for C H O Si: C, 75.62; H, 8.56; Si, 2952, 2934, 2857, 1734 and 1585 cm
−1
.
4
3
58 5
7
.17; found: C, 74.90; H, 8.39. Minor isomer: R
f
: 0.48 (hexane/
1
2-(((1R,2R,3aS,9aS)-2-Hydroxy-1-((S)-3-hydroxyoctyl)-
,3,3a,4,9,9a-hexahydro-1H-cyclopenta[b]naphthalen-5-yl)oxy)
acetic acid, treprostinil (1)
AcOEt 6 : 1). H NMR (400 MHz, CDCl
Ar), 7.41–7.33 (m, 6H, Ar), 7.07 (t, J = 7.9 Hz, 1H, Ar), 6.68 (d,
J = 7.7 Hz, 1H, Ar), 6.55 (d, J = 8.1 Hz, 1H, Ar), 4.53 (s, 2H,
3
) δ 7.73–7.64 (m, 4H,
2
2
CH O), 3.75 (p, J = 5.8 Hz, 1H, CHOSi), 3.04–2.84 (m, 2H, To a stirred and cooled solution of the 3.1 g of the crude acid
CH ), 2.63–2.53 (m, 1H, CH), 2.51–2.29 (m, 3H, CH and CH ), in THF (31 mL) and pyridine (1.8 mL, 3.5 equiv.) in a falcon
2
2
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem., 2019, 17, 9489–9501 | 9499