solution of diol 20 (0.165 g, 1.1 mmol) in 7 mL of CH3CN was added camphor sulfonic acid. (0.0005 g, 0.0022 mmol), followed by 2,2-dimethoxy propane (206 ...
Enantio and Stereospecific Syntheses of 15(R)-Me-PGD2, a Potent and Selective DP2-Receptor Agonist Pranav Patel,a Gue-Jae Lee ,a Seongjin Kim,a Gail E Grant,b William S. Powell,b and Joshua Rokacha* a
Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 W. University Blvd., Melbourne, FL 32901, USA; bMeakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St-Urbain St., Montreal, QC, Canada H2X 2P2
Supporting Information Table of Contents GENERAL METHODS …………………………………………………….
S4
EXPERIMENTAL PROCEDURE………………………………………….
S5–S13
1
S14–S53
H NMR, and
13
C NMR SPECTRA ……………………………………….
1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-hexan-1-one 11 (1H NMR , CDCl3) …………………………………………………….
S14
1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-hexan-1-one 11 (13C NMR , CDCl3) ………………………………….………………...
S15
2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-heptan-2-ol 12 (1H NMR , CDCl3) …………………………………………………….
S16
2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-heptan-2-ol 12 (13C NMR , CDCl3) ………………………………….………………...
S17
2-Hydroxy-2-methyl-succinic acid dimethyl ester 19 (1H NMR , CDCl3) ……………………………………………………... S18 2-Hydroxy-2-methyl-succinic acid dimethyl ester 19 (13C NMR , CDCl3 ) ………………………………………………….. S19 3,4-Dihydroxy-3-methyl-butyric acid methyl ester
S1
20 (1H NMR , CDCl3 ) ………………………….…………………………. S20 3,4-Dihydroxy-3-methyl-butyric acid methyl ester 20 (13C NMR , CDCl3) ….………………………………………….
S21
(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester 21(1H NMR , CDCl3)
........................……………………
S22
(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester 21 (13C NMR , CDCl3)
…………………………………..
S23
2-(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-ethanol 22 (1H NMR , CDCl3)
..........……….……………………..
S24
2-(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-ethanol 22 (13C NMR , CDCl3)
……………………………….
S25
(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetaldehyde 23 (1H NMR , CDCl3)
………………….............................
S26
(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetaldehyde 23 (13C NMR , CDCl3)
…………………………………………
S27
2,2,4-Trimethyl-4-pent-2-enyl-[1,3]dioxolane 24 (1H NMR , CDCl3)
…………..…………………………….
S28
2,2,4-Trimethyl-4-pent-2-enyl-[1,3]dioxolane 24 (13C NMR , CDCl3)
……………………………………..
S29
2,2,4-Trimethyl-4-pentyl-[1,3]dioxolane 25(1H NMR , CDCl3) …….……....
S30
2,2,4-Trimethyl-4-pentyl-[1,3]dioxolane 25 (13C NMR , CDCl3) ..……..…
S31
2-Methyl-heptane-1,2-diol 26a (1H NMR , CDCl3) …………………….…
S32
2-Methyl-heptane-1,2-diol 26a (13C NMR , CDCl3) ……………..……….
S33
2-Hydroxy-2-methyl-heptanal 27 (1H NMR , CDCl3) ……………….………
S34
2-Hydroxy-2-methyl-heptanal 27 (13C NMR , CDCl3) ………………………
S35
3-Methyl-oct-1-en-3-ol 17(1H NMR , CDCl3) …..……………..…………….
S36
3-Methyl-oct-1-en-3-ol 17 (13C NMR , CDCl3) ……………………………...
S37
Benzoic acid 2-oxo-4-vinyl-hexahydro-cyclopenta[b] furan-5-yl ester 29 (1H NMR , CDCl3) …..……………..…………….
S38
Benzoic acid 2-oxo-4-vinyl-hexahydro-cyclopenta[b] furan-5-yl ester 29 (13C NMR , CDCl3) ……………………………...
S39
Benzoic acid 4-(3-hydroxy-3-methyl-oct-1-enyl)-2-oxo-hexahydrocyclopenta[b]furan-5-yl ester 30 (1H NMR , CDCl3) ...………………... S40 S2
Benzoic acid 4-(3-hydroxy-3-methyl-oct-1-enyl)-2-oxo-hexahydrocyclopenta[b]furan-5-yl ester 30 (13C NMR , CDCl3) .............……….. S41 Benzoic acid 4-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-2-oxohexahydro-cyclopenta[b]furan-5-yl ester 31 (1H NMR , CDCl3) ………... S42 Benzoic acid 4-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-2-oxohexahydro-cyclopenta[b]furan-5-yl ester 31 (13C NMR , CDCl3)………… S43 Benzoic acid 3-(6-carboxy-hex-2-enyl)-4-hydroxy-2-(3-methyl-3triethylsilanyloxy-oct-1-enyl)-cyclopentyl Ester 34 (1H NMR CDCl3)…... S44 Benzoic acid 3-(6-carboxy-hex-2-enyl)-4-hydroxy-2-(3-methyl-3triethylsilanyloxy-oct-1-enyl)-cyclopentyl Ester 34 (13C NMR , CDCl3) … S45 Benzoic acid 3-(6-carboxy-hex-2-enyl)-2-(3-methyl-3-triethyl silanyloxy-oct-1-enyl)-4-triethylsilanyloxy-cyclopentyl ester 35 (1H NMR , CDCl3) ..……...............................................…......... S46 Benzoic acid 3-(6-carboxy-hex-2-enyl)-2-(3-methyl-3-triethyl silanyloxy-oct-1-enyl)-4-triethylsilanyloxy-cyclopentyl ester 35 (13C NMR , CDCl3) ………………………………………......
S47
7-[3-Hydroxy-2-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-5-triethylsilanyloxycyclopentyl]-hept-5-enoic acid 36 (1H NMR , CDCl3) …..………….... S48 7-[3-Hydroxy-2-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-5-triethylsilanyloxycyclopentyl]-hept-5-enoic acid 36 (13C NMR , CDCl3)……………….…... S49 7-[2-(3-Methyl-3-triethylsilanyloxy-oct-1-enyl)-3-oxo-5-triethylsilanyloxy-cyclopentyl] -hept-5-enoic acid 37 (1H NMR , CDCl3) ................................................... S50 7-[2-(3-Methyl-3-triethylsilanyloxy-oct-1-enyl)-3-oxo-5-triethylsilanyloxy-cyclopentyl] -hept-5-enoic acid 37 (13C NMR , CDCl3) ..................................................
S51
15(R)-Me-PGD2 3 (1H NMR , CDCl3)
........................................................ S52
15(R)-Me-PGD2 3 (13C NMR , CDCl3)
.......................................................
S53
High Resolution Mass Spectral (HRMS) Analysis of Compound 17 and 15-(R)-Me-PGD2 3
….…………………………………………..
S54
HPLC Tracing 15-(R,S)-Me-PGD2 and Stereospecific 15-(R)-Me-PGD2 3
………………………….……….……………...
S55
S3
Reagents and Methods. Unless stated otherwise, all reagents and chemicals were obtained from commercial sources and used without further purification. All reactions were carried out under inert (nitrogen or argon) atmosphere with dry, freshly distilled solvents under anhydrous conditions unless otherwise noted. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous materials. Phosphomolybdic acid, KMnO4 or I2 vapor were used as the staining reagents for thin layer chromatography (TLC). The chemical shifts for the 1H and 13C NMR spectra are reported in parts per million (ppm) with the solvent as the internal standard; CDCl3: 7.26 ppm (1H NMR), 77.23 ppm (central peak, 13C NMR), and data are reported as follows: , chemical shift; multiplicity (recorded as br, broad; s, singlet; d, doublet; t, triplet; q, quadruplet; qt, quintet and m, multiplet, coupling constants (J in Hertz, Hz), and integration.
S4
Experiment Procedures 1-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-hexan-1-one (11). To a stirred solution of 10 (0.2 g, 0.99 mmol) in dry CH2Cl2 (20 mL) was added Dess-Martin periodinane (0.839 g, 1.98 mmol) at room temperature under argon. The reaction mixture was allowed to stir for 1 h. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 15% ethyl acetate–hexane solvent as eluent to afford 11 as colorless oil (0.195 g, 98.6%). TLC Rf 0.50 (15% EtOAc/hexanes); 1H NMR (CDCl3) 4.37-4.46 (1H, t, J = 5.8 Hz), 4.15-4.24 (1H, t, J = 8.2 Hz), 3.92-4.02 (1H, m), 2.57-2.63 (2H, t, J = 7.2 Hz), 1.51-1.62 (4H, m), 1.47 (3H, s), 1.39 (3H, s), 1.22-1.37 (2H, m), 0.83-0.92 (3H, t, J = 6.8 Hz); 13C NMR (CDCl3) 210.5, 109.1, 81.8, 65.2, 37.8, 32.4, 26.4, 25.2, 24.2, 23.1, 14.1; HRMS m/z calcd for C11H21O3+ 201.1491, found 201.1478. 2-Hydroxy-2-methyl-succinic acid dimethyl ester (19). To a stirred solution of R(-)-citramalic acid 18 (5.0 g, 33.75 mmol) in 400 mL of anhydrous MeOH at 0 oC was added dropwise SOCl2 (84.4 mL, 2 M in CH2Cl2, 168.8 mmol) under argon. The reaction mixture was allowed to stir overnight (12 h) at room temperature. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 70% ethyl acetate-hexane as eluent to afford 19 as colorless oil (5.78 g, 97.3%). TLC Rf 0.80 (only EtOAc); 1H NMR (CDCl3) 3.74 (3H, s), 3.62 (3H, s), 2.89-2.93 (1H, d, J = 16.4 Hz), 2.59-2.63 (1H, d, J = 16.4 Hz), 1.37 (3H, s); 13C NMR (CDCl3)
175.9, 171.4, 72.5, 52.9,
51.8, 43.9, 26.2; HRMS m/z calcd for C7H13O5+ 177.0763, found 177.0750; IR (cm-1) 1731.5. 3,4-Dihydroxy-3-methyl-butyric acid methyl ester (20). Borane-methyl sulfide complex (400 µL 2 M solution in THF, 0.8 mmol) was added dropwise to a stirred solution of ester 19 (0.140 g, 0.8 mmol) in 1 mL anhydrous THF at room temperature under argon.
S5
The reaction mixture was stirred for 20 min and then NaBH4 (0.003 g, 0.08 mmol) was added. Stirring continued for an additional 20 min, 500 µL of MeOH was added, and the mixture was stirred for another 30 min. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 70% ethyl acetatehexane as eluent to afford the diol 20 as colorless oil (0.053 g, 44%). TLC Rf 0.50 (50% EtOAc/hexanes); 1H NMR (CDCl3)
3.75 (3H, s), 3.45-3.54 (2H, m), 2.72-2.76 (1H, d, J =
15.7 Hz), 2.44-2.48 (1H, d, J = 15.7 Hz), 1.26 (3H, s); 13C NMR (CDCl3) 173.5, 71.6, 69.5, 51.9, 41.7, 24.0; HRMS m/z calcd for C6H11O3+ (M-H2O)+ 131.0708, found 131.0710. (2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetic acid methyl ester (21). To a stirred solution of diol 20 (0.165 g, 1.1 mmol) in 7 mL of CH3CN was added camphor sulfonic acid (0.0005 g, 0.0022 mmol), followed by 2,2-dimethoxy propane (206 µL, 1.67 mmol) at room temperature under argon. The reaction mixture was stirred for 1 h, quenched with 10 mL of 5% KHCO3, and extracted with ethyl acetate (three times).
The organic layers were
combined, washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 50% ethyl acetate-hexane solvent as eluent to afford 21 as colorless oil (0.155 g, 74%). TLC Rf 0.85 (70% EtOAc/hexanes); 1H NMR (CDCl3)
4.01-4.03 (1H, d, J = 8.8 Hz), 3.73-
3.76 (1H, d, J = 8.8 Hz), 3.61 (3H, s), 2.57 (2H, s), 1.33 (6H, s), 1.32 (3H, s); (CDCl3)
13
C NMR
171.0, 109.3, 79.0, 73.6, 51.6, 44.4, 26.9, 24.8; HRMS m/z calcd for C9H17O4+
189.1127, found 189.1105. 2-(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-ethanol (22).
To a stirred solution of
acetonide 21 (3.31 g, 17.59 mmol) in 5 mL dry THF at -78 oC was added LiAlH4 (35.2 mL, 1 M solution in ether, 35.2 mmol) under argon. The reaction mixture was stirred for 30 min at
S6
-78 oC and gradually warmed to room temperature over a period of 2 h. The reaction mixture was quenched with aqueous NH4Cl solution and then extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 70% ethyl acetate-hexane as eluent to afford 22 as colorless oil (2.79 g, 99%). TLC Rf 0.20 (30% EtOAc/hexanes); 1H NMR (CDCl3)
3.86-3.94 (2H, m),
3.75-3.81 (2H, m), 1.91-1.97 (1H, m), 1.73-1.79 (1H, m), 1.44 (3H, s), 1.43 (3H, s), 1.36 (3H, s); 13C NMR (CDCl3)
109.6, 81.4, 74.7, 59.6, 41.0, 27.1, 26.9, 25.0; HRMS m/z calcd
for C8H17O3+ 161.1178, found 161.1169. (2,2,4-Trimethyl-[1,3]dioxolan-4-yl)-acetaldehyde (23). To a stirred suspension of PCC (6.71 g, 31.1 mmol) and Al2O3 (7.052 g, 69.2 mmol) in 80 mL of dry CH2Cl2 was added the alcohol 22 (2.77 g, 17.3 mmol) in 10 mL of CH2Cl2 at 0 oC under argon. The reaction mixture was warmed to room temperature, stirred for 3 h, diluted with ether, and filtered through celite and florisil layers. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 50% ethyl acetate-hexane solvent as eluent to afford 23 as colorless oil (2.43 g, 90%).
TLC Rf 0.80 (30%
EtOAc/hexanes); 1H NMR (CDCl3)
9.66 (1H, s), 3.88-3.90 (1H, d), 3.66-3.68 (1H, d),
2.50-2.53 (2H, m), 1.25-1.28 (9H, m);
13
C NMR (CDCl3)
175.5, 109.8, 78.8, 73.6, 44.4,
27.0, 25.4, 24.5; HRMS m/z calcd for C8H15O3+ 159.1021, found 159.1013. 2,2,4-Trimethyl-4-pent-2-enyl-[1,3]dioxolane (24).
To a stirred suspension of
phosphonium salt 7 (40.2 g, 104.3 mmol) in 90 mL dry THF was added LiHMDS (90 mL, 1 M, 90 mmol) at room temperature under argon. The reaction mixture was stirred for 20 min, cooled to -78 oC, and then 9 mL of HMPA was added. After reaction was stirred for 3 min,
S7
the aldehyde 23 (3.3 g, 20.9 mmol) in 20 mL of dry THF was added slowly. The reaction was allowed to continue at -78 oC for 20 min and then slowly warmed to room temperature, quenched with aqueous saturated NH4Cl solution, and extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 5% ethyl acetate-hexane as eluent to afford 24 as colorless oil (1.82 g, 57%). TLC Rf 0.55 (5% EtOAc/hexanes); 1H NMR (CDCl3)
5.55 (1H, m), 5.4
(1H, m), 3.83-3.84 (1H, d, J = 8.3 Hz), 3.70-3.72 (1H, d, J = 8.3 Hz), 2.33-2.35 (2H, d, J = 7.5 Hz ), 2.07 (2H, m), 1.41 (6H, s), 1.28 (3H, s), 0.98 (3H, t, J = 7.5 Hz); 13C NMR (CDCl3) 134.5, 123.7, 109.2, 81.2, 73.5, 37.5, 27.13, 27.16, 24.8, 20.7, 14.2; HRMS m/z calcd for C11H21O2+ 185.1536, found 185.1512. 2,2,4-Trimethyl-4-pentyl-[1,3]dioxolane (25). To a stirred solution of acetonide 24 (1.77 g, 9.61 mmol) in 70 mL of anhydrous EtOH was added Pd/C (0.885 g, 50 wt%) under H2 gas for 3 h and the mixture was filtered through celite and florisil layers to remove the catalyst. The solvent was evaporated under reduced pressure to obtain 25 as pale yellow oil (1.76 g, 99%).
The material was used as such for the next step.
TLC Rf 0.60 (5%
EtOAc/hexanes); 1H NMR (CDCl3) 3.79-3.81 (1H, d, J = 8.2 Hz), 3.70-3.72 (1H, d, J = 8.2 Hz), 1.48-1.61 (2H, m), 1.42 (3H, s), 1.40 (3H, s), 1.31-1.37 (6H, m), 1.28 (3H, s), 0.89-0.93 (3H, t, J = 7.5 Hz); 13C NMR (CDCl3) 108.9, 81.3, 74.0, 40.1, 32.3, 27.3, 27.1, 24.8, 24.2, 22.6, 14.0; HRMS m/z calcd for C11H23O2+ 187.1698, found 187.1667. 2-Methyl-heptane-1,2-diol (26a). To a stirred solution of 25 (1.46 g, 7.83 mmol) in 80 mL THF:H2O (4:1) was added TFA (4.2 mL, 54.9 mmol) at 0 oC under argon. The ice bath was removed and the reaction mixture was stirred for 40 h at room temperature,
S8
quenched with aqueous NaHCO3 solution, and extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 75% ethyl acetate-hexane as eluent to afford 26a as colorless oil (1.13 g, 99%). TLC Rf 0.40 (70% EtOAc/hexanes); 1H NMR (CDCl3)
3.42-3.50 (2H, m), 1.46-
1.48 (2H, m), 1.39-1.41 (6H, m), 1.17 (3H, s), 0.88-0.91 (3H, t, J = 7.1 Hz); (CDCl3)
13
C NMR
73.0, 69.8, 38.7, 32.4, 23.4, 23.2, 22.6, 14.0; HRMS m/z calcd for C8H17O (M+ -
H2O) 129.1279, found 129.1249. 2-Hydroxy-2-methyl-heptanal (27). To a solution of 26a (0.05 g, 0.3 mmol) in dry 1.5 mL DMSO:CH2Cl2 (1:5) and Et3N (238 µL, 1.71 mmol) was added sulfur-trioxide pyridine complex (0.22 g, 1.36 mmol) at 0 oC in small portions over a period of 1 min. The reaction was continued for 2 h at 0 oC and then gradually warmed to room temperature. The reaction mixture was diluted with ether, washed with water, brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 30% ethyl acetate-hexane solvent as eluent to afford 27 (0.027 g, 55%) and was used in next step immediately. EtOAc/hexanes);1H NMR (CDCl3)
TLC Rf 0.65 (30%
9.52 (1H,s), 1.63-1.71 (2H, t, J = 8.1 Hz), 1.36-1.46
(1H, m), 1.29-1.32 (7H, m), 1.12-1.20 (1H, m), 0.87-0.92 (3H, t, J = 7.5 Hz);
13
C NMR
(CDCl3) 203.9, 78.0, 37.2, 32.0, 22.63, 22.59, 22.45, 14.0. Benzoic
acid
4-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-2-oxo-hexahydro-
cyclopenta[b]furan-5-yl ester (31). To a stirred solution of 30 (0.24 g, 0.62 mmol) in 16 mL THF was added DMAP (0.035 g, 0.31 mmol) and imidazole (0.845 g, 12.4 mmol) at room temperature and then TESCl (2.08 mL, 12.4 mmol) was added to the reaction mixture
S9
under argon. The reaction mixture was heated at 60 oC for 4 h and gradually cooled to room temperature, quenched with water, and extracted with ethyl acetate (three times).
The
organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 30% ethyl acetate-hexane as eluent to afford 31 as colorless oil (0.278 g, 90%). TLC Rf 0.70 (30% EtOAc/hexanes); 1H NMR (CDCl3)
7.91-7.93 (2H, d, J = 8.2
Hz), 7.45-7.51 (1H, m), 7.35-7.39 (2H, t, J = 7.6 Hz), 5.54-5.58 (1H, d, J = 15.6 Hz), 5.335.39 (1H, dd, J = 15.5, 7.6 Hz), 5.12-5.16 (1H, q, J = 6.1 Hz), 4.94-5.03 (1H, m), 2.76-2.83 (1H, dd, J = 17.8, 9.6 Hz), 2.63-2.74 (2H, m), 2.53-2.60 (1H, m), 2.43-2.47 (1H, m), 2.102.16 (1H, m), 1.27-1.38 (2H, m), 1.17 (3H, s), 1.08-1.15 (6H, m), 0.82-0.88 (9H, m), 0.730.84 (3H, t, J = 7.1 Hz), 0.42-0.50 (6H, m); 13C NMR (CDCl3)
176.6, 160.0, 141.4, 129.7,
129.62, 129.56, 128.5, 124.9, 83.2, 79.1, 75.0, 53.9, 44.1, 42.7, 37.6, 34.8, 32.2, 27.6, 23.8, 22.6, 14.4, 7.1, 6.8; HRMS m/z calcd for C16H23O2 (M+- OBz - OTES) 247.1698, found 247.1713. Benzoic acid 2-hydroxy-4-(3-methyl-3-triethylsilanyloxy-oct-1-enyl)-hexahydro cyclopenta [b]furan-5-yl ester (32). To a stirred solution of 31 (0.257 g, 0.51 mmol) was added 1.1 mL DIBAL-H (1 M in THF, 1.1 mmol) at -100 oC under argon. After 30 min the reaction mixture was gradually warmed to room temperature, stirred for 90 min at room temperature, quenched with saturated NH4Cl, extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 50% ethyl acetate-hexane as eluent to afford 32 (0.197 g, 76%) and was used immediately for the next step.
S10
Benzoic
acid
3-(6-carboxy-hex-2-enyl)-4-hydroxy-2-(3-methyl-3-triethyl
silanyloxy-oct-1-enyl)-cyclopentyl Ester (34). To a stirred solution of phosphonium salt 33, dried using anhydrous benzene (1.482 g, 3.34 mmol) in 60 mL dry THF, was added tBuOK (5.7 mL, 5.7 mmol) at room temperature under argon. The reaction mixture was stirred for 30 min, cooled to -78 oC, and the lactol 32 in 10 mL of dry THF was added. The reaction was continued at -78 oC for 45 min and then gradually warmed to room temperature, quenched with aqueous saturated NH4Cl solution, and then extracted with ethyl acetate (three times). The organic layers were combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 50% ethyl acetate-hexane solvent as eluent to afford 34 as pale yellow oil (0.245 g, 88%). TLC Rf 0.35 (50% EtOAc/hexanes); 1H NMR (CDCl3)
7.94-
7.98 (2H, d, J = 8.2 Hz), 7.45-7.56 (1H, t), 7.32-7.36 (2H, t, J = 7.4 Hz), 5.54-5.58 (1H, d, J = 15.5 Hz), 5.25-5.49 (3H, m), 4.97-5.05 (1H, m), 4.16-4.23 (1H, t), 2.64-2.71 (1H, m), 2.452.54 (1H, m), 2.21-2.33 (2H, m), 1.97-2.19 (3H, m) 1.51-1.76 (4H, m) 1.31-1.35 (2H, m), 1.04-1.17 (10H, m) 0.80-0.83 (9H, m), 0.68-0.73 (3H, t, J = 7.0 Hz), 0.39-0.48 (6H, m); 13C NMR (CDCl3)
178.8, 166.4, 141.0, 132.9, 130.3, 129.8, 129.6, 129.0, 128.3, 126.8, 79.3,
75.1, 71.8, 51.2, 49.2, 44.1, 40.9, 32.2, 27.5, 26.5, 25.1, 24.5, 23.8, 22.6, 14.0, 7.1, 6.9; HRMS m/z calcd for C21H54O6Si (M+- OBz - OTES) 333.2430, found 333.2428. Benzoic
acid
3-(6-carboxy-hex-2-enyl)-2-(3-methyl-3-triethylsilanyloxy-oct-1-
enyl)-4-triethylsilanyloxy- cyclopentyl ester (35). To a stirred solution of 34 (0.138 g, 0.24 mmol) in 18 mL of pyridine was added TESCl (0.355 g, 2.35 mmol) under argon. The reaction mixture was heated to 60 oC, stirred for 3 h, gradually cooled to room temperature, quenched with water, and extracted with ethyl acetate (three times). The organic layers were
S11
combined, washed with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography using 30% ethyl acetate-hexane as eluent to afford 35 as pale yellow oil (0.14 g, 85%). TLC Rf 0.60 (30% EtOAc/hexanes); 1H NMR (CDCl3)
7.94 (2H, d), 7.46 (1H, t), 7.34 (2H, t), 5.51-5.55
(1H, d, J = 15.5 Hz), 5.41-5.47 (1H, m), 5.25-5.37 (2H, m) 4.90-5.0 (1H, m), 4.16-4.19 (1H, m), 2.66-2.73 (1H, m), 2.40-2.47 (1H, m), 2.26-2.29 (2H, t, J = 7.6 Hz), 2.08-2.15 (2H, m), 1.96-2.06 (2H, m), 1.60-1.71 (3H, m), 1.42-1.49 (1H, m), 1.32-1.36 (2H, m), 1.05-1.18 (9H, m), 0.80-0.92 (18H, m), 0.69-0.75 (3H, t, J = 7.0 Hz), 0.43-0.57 (12H, m); (CDCl3)
13
C NMR
178.8, 166.6, 140.4, 132.7, 130.5, 129.7, 129.6, 128.9, 128.2, 127.5, 79.1, 75.3,
71.8, 51.3, 50.2, 44.1, 41.9, 32.3, 27.5, 26.6, 24.8, 24.6, 23.9, 22.6, 14.0, 7.1, 6.9, 6.8, 5.0; HRMS m/z calcd for C27H47O3Si (M+- OBz - 2(OTES)) 447.3294, found 447.3259. 7-[2-(3-Methyl-3-triethylsilanyloxy-oct-1-enyl)-3-oxo-5-triethylsilanyloxycyclopentyl]-hept-5-enoic acid (37). To a stirred solution of 36 (0.052 g, 0.087 mmol) in 15 mL of dry CH2Cl2 was added Dess-Martin periodinane (0.074 g, 0.174 mmol) at room temperature under argon. The reaction mixture was stirred for 30 min and purified by silica gel chromatography using 30% ethyl acetate-hexane as eluent to afford 37 as pale yellow oil (0.037 g, 71%). TLC Rf 0.75 (30% EtOAc/hexanes, developed two times); 1H NMR (CDCl3) 5.50-5.54 (1H, d, J = 15.6 Hz), 5.44-5.48 (1H, m), 5.33-5.37 (1H, m), 5.24-5.28 (1H, dd, J = 15.6, 7.9 Hz), 4.39-4.40 (1H, m), 2.66-2.71 (1H, m), 2.26-2.33 (4H, m), 2.19-2.23 (2H, t), 1.97-2.10 (2H, m), 1.81-1.88 (1H, m), 1.60-1.72 (2H, m) 1.38-1.42 (2H, m), 1.13-1.32 (9H, m), 0.84-0.90 (18H, m), 0.79-0.82 (3H, t), 0.47-0.55 (12H, m) ; 13C NMR (CDCl3)
216.4,
178.0, 142.1, 129.8, 128.5, 122.8, 75.5, 69.0, 54.3, 49.7, 48.5, 44.2, 33.1, 32.3, 27.6, 26.6,
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25.8, 24.5, 23.9, 22.7, 14.1, 7.1, 6.82, 6.76, 4.9; IR (cm-1) 1704.1, 1742.5; HRMS m/z calcd for C27H47O4Si (M+- OTES) 463.3239, found 463.3229.
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HRMS of Compound 17 and 15(R)-Me-PGD2 3 Mass spectrometry was performed on a DART (Direct Analysis in Real Time) mass spectrometer.
C9H17+ Exact Mass: 125.1325 Mol. Wt.: 125.2307 m/e: 125.1330 (100.0%), 126.1364 (10.0%) C, 86.32; H, 13.68
HO COOH
O
C21H33O4+ Exact Mass: 349.2373 Mol. Wt.: 349.4838 m/e: 349.2379 (100.0%), 350.2412 (23.4%), 351.2446 (2.6%) C, 72.17; H, 9.52; O, 18.31
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15-(R,S)-Methyl-PGD2
15-(R)-Methyl-PGD2 3 0.09
0.12
Absorbance units
Absorbance units
0.14
0.1 0.08 0.06 0.04 0.02 0 35
40
45
50
Tim e (m in)
55
60
0.07 0.05 0.03 0.01 -0.01 -0.03 35
40
45
50
55
60
T im e ( m in)
Supplementary Figure 42. HPLC Tracing of 15-(R,S)-Me-PGD2 and stereospecific 15(R)-MePGD2 3 (Scheme 4)
HPLC Conditions: The reversed phase HPLC column was (250 x 4.6mm) of Spherisorb ODS-2 (5 um particle size; Phenomenex) maintained at a temperature of 35oC, whereas the mobile phase was 49% MeOH in water containing 0.02% AcOH at a flow rate of 1.3ml/min. The products were detected on the basis of UV absorbance at 200nm.
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