6
T. Kim et al. / Tetrahedron xxx (xxxx) xxx
44.6, 25.9, 18.2, 15.7, 7.0, 5.0, ꢀ4.42, ꢀ4.5; LRMS (ESI): Calcd. for
equiv) in tetrahydrofuran (0.3 mL, 1 M) at 0 ꢁC. After 40 min, com-
pound 17 (15.2 mg, 0.025 mmol, 1.0 equiv) in tetrahydrofuran
(0.5 mL) was added to the reaction mixture at 0 ꢁC. After 30 min, the
reaction mixture was quenched with water (1 mL) and acidified by
1 N HCl to pH 1 at room temperature. The aqueous layer was
extracted with CH2Cl2 (3 ꢂ 2 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (Ethyl acetate:n-
Hexane ¼ 1:30) on silica gel to obtain the product 19 (15.0 mg, 87%
C
21H41NNaO2Si2 ([MþNa]þ): 418.26, found: m/z ¼ 418.25.
4.9. 2-((1R,2R,3R,5S)-3-(tert-Butyldimethylsilyloxy)-5-
(triethylsilyloxy)-2-vinylcyclopentyl)acetaldehyde (4)
To a stirred solution of 14 (536 mg, 1.35 mmol, 1.0 equiv) in
CH2Cl2 (20 mL) at ꢀ78 ꢁC was added dropwise diisobutylalumi-
nium hydride (1.76 mL, 1.76 mmol, 1.3 equiv, 1 M in cyclohexane).
After 15 min, the reaction mixture was quenched with saturated
Rochelle salt solution (5 mL). The aqueous layer was extracted with
CH2Cl2 (3 ꢂ 5 mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (Ethyl acetate:n-Hex-
ane ¼ 1:30) on silica gel to obtain the product 4 (536 mg, 99% yield)
yield, Only Z-form was observed.) as colorless oil: TLC Rf ¼ 0.22
25
(silica gel, Ethyl acetate:n-Hexane ¼ 1:3); [
a
]
D
¼ þ11.5 (c ¼ 1.0,
CHCl3); IR(neat) ymax 2955, 2929, 2856,1711, 1463, 1250, 1129, 1006,
970, 893, 836, 774, 673 cmꢀ1 1H NMR (500 MHz, CDCl3)
5.54e5.43 (m, 2H), 5.39 (dd, J ¼ 15.4, 8.4 Hz, 1H), 5.30 (dt, J ¼ 10.8,
;
d
7.3 Hz, 1H), 4.12 (dd, J ¼ 7.8, 5.3 Hz, 1H), 4.08 (dd, J ¼ 11.9, 5.9 Hz,
1H), 3.82 (dt, J ¼ 13.5, 6.9 Hz, 1H), 2.35 (dt, J ¼ 15.1, 7.8 Hz, 3H), 2.21
(ddd, J ¼ 14.1, 8.4, 5.9 Hz, 1H), 2.17e2.11 (m, 1H), 2.11e2.00 (m, 3H),
1.68 (dt, J ¼ 14.2, 7.2 Hz, 2H), 1.58 (ddd, J ¼ 14.0, 5.4, 2.8 Hz, 1H),
1.52e1.42 (m, 2H), 1.40e1.22 (m, 10H), 0.96 (t, J ¼ 7.9 Hz, 9H), 0.89
(s, J ¼ 5.1 Hz, 9H), 0.86 (s, 9H), 0.58 (ddd, J ¼ 9.9, 7.8,1.6 Hz, 6H), 0.06
as yellow oil: TLC Rf ¼ 0.61 (silica gel, Ethyl acetate:n-Hex-
25
ane ¼ 1:9); [
a
]
¼ þ40.4 (c ¼ 1.0, CHCl3); IR ymax 2955, 2934, 2878,
D
2857, 2712, 1726, 1462, 1415, 1366, 1250, 1142, 1109, 1075,1006, 939,
892, 836, 776, 742, 654 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d
9.80 (s,
1H), 5.50e5.56 (m, 1H), 5.08e5.10 (m, 1H), 5.07 (br s, 1H), 4.21 (td,
JAB ¼ 6.0 Hz, JAC ¼ 3.0 Hz, 1H), 3.80e3.84 (m, 1H), 2.74 (ddd,
JAB ¼ 18.0 Hz, JAC ¼ 9.0 Hz, JAD ¼ 1.2 Hz, 1H), 2.31e2.38 (m, 3H),
2.03e2.08 (m, 1H), 1.57 (ddd, JAB ¼ 13.8 Hz, JAC ¼ 6.6 Hz,
JAD ¼ 3.0 Hz, 1H), 0.93 (t, J ¼ 8.4 Hz, 9H), 0.86 (s,9H), 0.50e0.59 (m,
6H), 0.003 (s, 3H), ꢀ0.003 (s, 3H); 13C NMR (125 MHz, CDCl3)
(s, J ¼ 4.7 Hz, 3H), 0.04 (s, J ¼ 5.1 Hz, 3H), 0.00 (d, J ¼ 1.8 Hz, 6H); 13
C
NMR (125 MHz, CDCl3)
d 178.0, 134.9, 131.0, 130.2, 128.4, 77.4, 73.2,
71.5, 54.2, 49.4, 44.8, 38.4, 33.2, 31.9, 26.6, 25.9, 25.9, 25.2, 24.9,
24.6, 22.6, 18.3, 18.0, 14.0, 6.9, 5.0, ꢀ4.3, ꢀ4.5, ꢀ4.5, ꢀ4.7; HRMS
(ESI): Calcd. for C38H76NaO5Si3 ([MþNa]þ): m/z 719.4893, found: m/
z ¼ 719.4892.
d
202.7, 139.4, 117.6, 76.7, 71.1, 55.9, 45.1, 42.6, 42.2, 36.0, 18.2, 7.0,
5.0, ꢀ4.4, ꢀ4.4; LRMS (ESI): Calcd. for C21H42NaO3Si2 ([MþNa]þ):
421.26, found: m/z ¼ 421.25; HRMS (ESI): Calcd. for C21H42NaO3Si2
([MþNa]þ): m/z 421.2565, found: m/z ¼ 421.2563.
4.12. (Z)-7-((1R,2R,3R,5S)-3,5-Dihydroxy-2-((S,E)-3-hydroxyoct-1-
enyl)cyclopentyl)hept-5-enoic acid (PGF2a, 1)
4.10. 2-((1R,2R,3R,5S)-3-(tert-Butyldimethylsilyloxy)-2-((S,E)-3-
(tert-butyldimethylsilyloxy)oct-1-enyl)-5-(triethylsilyloxy)
cyclopentyl)acetaldehyde (17)
To a stirred solution of 19 (13.8 mg, 0.02 mmol, 1.0 equiv) in
acetone (1 mL) was added 1 N HCl (0.26 mL, 0.26 mmol, 13.0 equiv)
at room temperature. After 20 min, water (1 mL) and brine (1 mL)
were added to the reaction mixture. The aqueous layer was
extracted with CH2Cl2 (3 ꢂ 2 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (Acetic acid:Ethyl
acetate ¼ 1:30) on silica gel to obtain the product 1 (6.9 mg, 99%
yield) as colorless oil: TLC Rf ¼ 0.21 (silica gel, Acetic acid:Ethyl
To a stirred solution of 4 (15.7 mg, 0.039 mmol, 1.0 equiv) and 15
(58.6 ml, 0.197 mmol, 5.0 equiv) in dichloroethane (1 mL) at room
temperature was added second-generation Hoveyda-Grubbs cata-
lyst (2.4 mg, 0.0039 mmol, 0.1 equiv). The reaction mixture was
refluxed for 12 h. After 12 h, the reaction mixture was cooled to
room temperature and concentrated in vacuo. The residue was
purified by column chromatography (Diethyl ether:n-Hex-
ane ¼ 1:99) on silica gel to obtain the product 17 (15.2 mg, 64%
isolated yield, 92% brsm, Only E-form was observed.) as colorless
25
20
acetate ¼ 1:30); [
(c ¼ 0.5, THF) [20]; IR(neat) ymax 3406, 2959, 2929, 2879, 2858,
1729, 1560, 1458, 1410, 1254, 1188, 1116, 1068, 1035 cmꢀ1 1H NMR
(500 MHz, MeOD)
a
]
¼ þ24.7 (c ¼ 0.5, THF), Lit.: [
a
]
¼ þ23.7
D
D
;
d
5.52e5.41 (m, 3H), 5.33 (dt, J ¼ 10.4, 7.3 Hz,1H),
oil: TLC Rf ¼ 0.51 (silica gel, Ethyl acetate:n-Hexane ¼ 1:10);
4.07 (td, J ¼ 5.6, 2.1 Hz, 1H), 3.98 (q, J ¼ 6.4 Hz, 1H), 3.80 (dt, J ¼ 7.9,
5.7 Hz, 1H), 2.32 (ddd, J ¼ 14.4, 8.4, 6.0 Hz, 1H), 2.29e2.15 (m, 4H),
2.13e2.01 (m, 3H), 1.63 (dd, J ¼ 14.6, 7.3 Hz, 2H), 1.59e1.52 (m, 2H),
1.44 (td, J ¼ 9.7, 5.7 Hz, 2H), 1.36e1.28 (m, 6H), 0.88 (t, J ¼ 6.7 Hz,
25
[
a]
¼ þ13.0 (c ¼ 1.0, CHCl3); IR(neat) ymax 2956, 2929, 2857, 1727,
D
1472, 1361, 1256, 1086, 1005, 972, 894, 836, 774, 746, 684 cmꢀ1; 1H
NMR (500 MHz, CDCl3)
9.78 (s, 1H), 5.52 (dd, J ¼ 15.4, 5.4 Hz, 1H),
d
5.34 (dd, J ¼ 15.3, 8.8 Hz, 1H), 4.21 (dd, J ¼ 8.8, 5.8 Hz, 1H), 4.06 (dd,
J ¼ 11.4, 5.7 Hz, 1H), 3.83 (dd, J ¼ 14.6, 7.8 Hz, 1H), 2.74 (dd, J ¼ 18.0,
9.6 Hz, 1H), 2.39e2.28 (m, 3H), 2.04e1.97 (m, 1H), 1.56 (ddd,
J ¼ 13.8, 6.3, 3.2 Hz, 1H), 1.51e1.34 (m, 3H), 1.33e1.19 (m, 8H), 0.93
(t, J ¼ 7.9 Hz, 9H), 0.88 (s, 9H), 0.86 (s, 9H), 0.59e0.49 (m, 6H), 0.03
(s, J ¼ 5.2 Hz, 3H), 0.02 to ꢀ0.01 (m, 9H); 13C NMR (125 MHz, CDCl3)
3H); 13C NMR (125 MHz, MeOD)
d 136.6, 134.3, 130.7, 130.3, 78.0,
74.1, 72.3, 56.2, 51.0, 44.4, 38.5, 35.3, 33.1, 28.1, 27.0, 26.5, 26.3, 23.8,
14.5; HRMS (ESI): Calcd. for C20H34NaO5 ([MþNa]þ): m/z 377.2298,
found: m/z ¼ 377.2299.
4.13. (E)-Triisopropylsilyl 7-((1R,2R,3R,5S)-3-(tert-
butyldimethylsilyloxy)-5-(triethylsilyloxy)-2-vinylcyclopentyl)-6-
hydroxyhept-4-enoate (21)
d
202.4, 136.5, 129.6, 76.9, 72.7, 71.0, 53.8, 45.0, 42.9, 42.0, 38.6, 31.8,
25.9, 25.8, 25.1, 22.6, 18.2, 18.0, 14.0, 6.8, 4.8, ꢀ4.3, ꢀ4.5, ꢀ4.6, ꢀ4.8;
HRMS (ESI): Calcd. for C33H68NaO4Si3 ([MþNa]þ): m/z 635.4318,
found: m/z ¼ 635.4318.
To chromium(II) chloride (44.7 mg, 0.36 mmol, 4.1 equiv) and
nickel(II) chloride (4.6 mg, 0.036 mmol, 0.4 equiv) was added
DMSO (3 mL) and THF (1 mL) at room temperature. The reaction
mixture was stirred for 5 min and 4 (35.4 mg, 0.089 mmol, 1.0
equiv) and vinyl iodide 20 (0.68 mL, 0.22 mmol, 2.5 equiv) were
added to the reaction mixture and the reaction mixture was stirred
for 9 h at room temperature. The reaction mixture was quenched
with saturated NH4Cl solution (2 mL) at 0 ꢁC. The aqueous layer was
extracted with diethyl ether (3 ꢂ 5 mL). The combined organic
4.11. (Z)-7-((1R,2R,3R,5S)-3-(tert-Butyldimethylsilyloxy)-2-((S,E)-
3-(tert-butyldimethylsilyloxy)oct-1-enyl)-5-(triethylsilyloxy)
cyclopentyl)hept-5-enoic acid (19)
To a stirred solution of (4-carboxybutyl)triphenylphosphonium
bromide (18, 67.3 mg, 0.15 mmol, 6.0 equiv) in tetrahydrofuran
(0.5 mL) was added potassium tert-butoxide (34 mg, 0.3 mmol, 12.0
Please cite this article as: T. Kim et al., Total synthesis of PGF2a and 6,15-diketo-PGF1a and formal synthesis of 6-keto-PGF1a via three-component