Enantio- and Stereospecific Syntheses of 15(R)-Me-PGD2
a
SCHEME 5. Synthesis of 15(R,S)-Me-PGD2
a Reagents and conditions: (a) (38) NaHMDS, THF, -78 °C to rt, 96%; (b) CH3MgBr, THF, 96%; (c) DIBAL-H, CH2Cl2, 73%; (d) (33) t-BuOK, HMPA,
THF, 0 °C to rt; (2) CH2N2, 61% in 2 steps; (e) (1) TBDMSCl, py, 60 °C, 97%; (2) K2CO3, MeOH, rt, 90%; (f) Dess-Martin periodinane, CH2Cl2, rt, 94%;
(g) (1) formic acid; (2) HPLC.
δ (R isomer) 3.81-3.95 (3H, m), 1.47 (3H, s), 1.37 (3H, s),
1.23-1.36 (8H, m), 1.22 (3H, s), 0.83-0.95 (3H, t, J ) 7 Hz); 13
NMR (CDCl3) δ 109.2, 81.9, 71.9, 65.0, 37.9, 32.7, 26.6, 25.6,
24.3, 23.2, 22.8, 14.2; HRMS m/z calcd for C12H23O2+ (M+ - H2O)
199.1693, found 199.1679.
synthesis described in Schemes 1-3 has advantages over that
shown in Scheme 5. The final compound (Scheme 5) is a
mixture of diastereoisomers that needs HPLC for separation and
still requires assignment of the stereochemistry at C-15. We
were also disappointed at the lack of separation of the two
isomers in 40-44 by flash chromatography. At the final stage,
we separated 3 and 4 by HPLC. Also, the approach in Scheme
5 provides less flexibility in the synthesis of other PGD2
derivatives.
The importance and relevance of 15(R)-Me-PGD2 3 goes
beyond its enhanced agonist properties. It is highly selec-
tive for the DP2 receptor,3 and as such, it can be used to define
the DP2 receptor-mediated effects of PGD2, which is not possible
with PGD2 itself. For example, we have used 15(R)-Me-PGD2
along with a selective DP1 receptor agonist (BW245C) to
demonstrate that PGD2-induced pulmonary eosinophilia in rats
is mediated by the DP2 receptor.23 The high potency of 15(R)-
Me-PGD2, which has the unnatural R configuration at C-15, is
interesting and suggests that the addition of a methyl group in
this position may orient the C-15 OH and pentyl group in such
a way as to maximize the interaction of this compound with
the DP2 receptor. Studies on the conformation of these
compounds may be very useful in future molecular modeling
of DP2 agonists and in the design of selective antagonists of
this receptor.
C
3-Methyl-oct-1-en-3-ol (17). To a stirred suspension of phos-
phonium salt 15 (3.53 g, 9.9 mmol) in 60 mL of dry THF was
added dropwise NaHMDS (1 M solution in THF, 7.9 mL, 7.9
mmol) at -20 °C under argon. The mixture was stirred for 20 min
and cooled to -78 °C, and a solution of aldehyde 27 (0.57 g, 4
mmol) in 5 mL of dry THF was added. The reaction mixture was
warmed to room temperature, stirred for 8 h, quenched with
saturated NH4Cl solution, and extracted with ethyl acetate. 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 17 as colorless oil
1
(0.281 g, 56%): TLC Rf 0.55 (30% EtOAc/hexanes); H NMR
(CDCl3) δ 5.81-5.88 (1H, dd, J ) 17.4, 10.7 Hz), 5.10-5.15 (1H,
d, J ) 17.4 Hz), 4.96-4.99 (1H, d, J ) 10.7 Hz), 1.49 (3H, s),
1.43-1.47 (2H, m), 1.18-1.28 (6H, m), 0.80-0.83 (3H, t, J )
6.9 Hz); 13C NMR (CDCl3) δ 145.3, 111.5, 73.3, 42.4, 32.3, 27.7,
23.6, 22.6, 14.0; HRMS m/z calcd for C9H17 (M+ - H2O) 125.1330,
found 125.1305.
Benzoic Acid 2-Oxo-4-vinylhexahydrocyclopenta[b]furan-5-yl
ester (29). To a stirred suspension of phosphonium salt 15 (8.23 g,
23.05 mmol) in 80 mL of dry THF was added 19.2 mL of NaHMDS
(1 M solution in THF) at -30 °C under argon. The reaction mixture
was stirred for 30 min and cooled to -78 °C, and a solution of 28
(2.0 g, 7.68 mmol) in 20 mL of dry THF was added. The reaction
was continued at -78 °C for 30 min, warmed to room temperature,
quenched with saturated NH4Cl, 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 chroma-
tography using 35% ethyl acetate/hexane as eluent to afford 29 as
a white solid (1.055 g, 51%): TLC Rf 0.30 (30% EtOAc/hexanes);
1H NMR (CDCl3) δ 8.00-8.05 (2H, d, J ) 7.5 Hz), 7.55-7.60
(1H, t, J ) 7.4 Hz), 7.44-7.48 (2H, t, J ) 7.6 Hz), 5.71-5.82
(1H, ddd, J ) 17.5, 10.1, 7.1 Hz), 5.25-5.31 (1H, m), 5.13-5.24
(2H, m), 5.03-5.11 (1H, td, J ) 5.1, 1.8 Hz), 2.75-2.90 (2H, m),
2.72-2.75 (1H, m), 2.60 (1H, m), 2.49-2.56 (1H, m), 2.20-2.25
(1H, ddd, J ) 15.6, 4.7, 1.7 Hz); 13C NMR (CDCl3) δ 172.3, 161.8,
132.0, 129.1, 125.4, 124.3, 113.3, 113.0, 79.1, 74.7, 50.9, 38.0,
Experimental Section
2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-heptan-2-ol (12). To a
stirred solution of 11 (0.197 g, 2.45 mmol) in dry THF as solvent
was added methyl magnesium bromide at -100 °C under argon.
The reaction mixture was slowly warmed to room temperature. The
solvent was evaporated under reduced pressure, and the crude
residue was purified by silica gel chromatography using 15% ether/
hexane solvent as eluent to afford 12 as colorless oil (0.180 g,
84.9%) separated from the S-isomer approx (0.016 g, 7%): TLC Rf
0.38 (15% EtOAc/hexanes, developed two times); 1H NMR (CDCl3)
(21) After this work was completed, an interesting related application in the
synthesis of pladienolides B and D was brought to our attention by one of the
reviewers: Kanada, R. M.; Itoh, D.; Nagai, M.; Niijima, J.; Asai, N.; Mizui, Y.;
Abe, S.; Kotake, Y. Angew. Chem., Int. Ed. 2007, 46, 4350.
(22) Bundy, G. L.; Morton, D. R.; Peterson, D. C.; Nishizawa, E. E.; Miller,
W. L. J. Med. Chem. 1983, 26, 790.
+
33.3, 30.7; mp 65-66 °C; HRMS m/z calcd for C16H17O4
273.1127, found 273.1109; IR (cm-1) 1709.6 (CdO benzoate),
1764.8 (CdO lactone).
(23) Almishri, W.; Cossette, C.; Rokach, J.; Martin, J. G.; Hamid, Q.; Powell,
W. S. J. Pharmacol. Exp. Ther. 2005, 313, 64.
J. Org. Chem. Vol. 73, No. 18, 2008 7217