Enantioselective synthesis of 12-epi-PGF(2α) and 12,15-diepi-PGF(2α)

Article abstract of DOI:10.1021/jo990906r

An enantioselective synthesis of 12-epi-PGF(2α) (3) and 12,15-diepi- PGF(2α) (4), PG-like compounds that are probably generated in vivo by nonenzymatic, free-radical-induced peroxidation of arachidonic acid, has been achieved starting from the commercially available Corey lactone (9). The key strategy involves SmI₂ reduction of the γ,δ-epoxy-α,β-unsaturated ester 7, followed by in situ trapping with hexanal; subsequent hydrogenation and decarboxylation affords the stereoselective construction of the lower side chain. This new method is expected to provide a convenient access to various PG-like isoprostanes derived from oxidation of arachidonic acid and cis- 4,7,10,13,16,19-docosahexaenoic acid.

Full text of DOI:10.1021/jo990906r

J . Org. Chem. 1999, 64, 7213-7217
7213
En a n tioselective Syn th esis of 12-epi-P GF 2r a n d 12,15-d iepi-P GF 2r
Sheng Lai, Dongreyoul Lee, J ong Sun U, and J in Kun Cha*
Department of Chemistry, University of Alabama, Tuscaloosa, Alabama 35487
Received J une 3, 1999
An enantioselective synthesis of 12-epi-PGF2R (3) and 12,15-diepi-PGF2R (4), PG-like compounds
that are probably generated in vivo by nonenzymatic, free-radical-induced peroxidation of
arachidonic acid, has been achieved starting from the commercially available Corey lactone (9).
The key strategy involves SmI2 reduction of the , -epoxy-R, -unsaturated ester 7, followed by in
situ trapping with hexanal; subsequent hydrogenation and decarboxylation affords the stereose-
lective construction of the lower side chain. This new method is expected to provide a convenient
access to various PG-like isoprostanes derived from oxidation of arachidonic acid and cis-
4,7,10,13,16,19-docosahexaenoic acid.
Sch em e 1
In tr od u ction
Prostaglandins (PGs) exhibit a wide range of potent
pharmacological properties that have spurred the devel-
opment of many elegant synthetic methods.1 Roberts,
Morrow, and colleagues recently discovered a new class
of epimeric PGs, named isoprostanes, that are character-
ized by cis-dialkyl stereochemistry at the five-membered
ring junction.2 These PG-like compounds are produced
in vivo by nonenzymatic, free-radical induced peroxida-
tion of arachidonic acid (AA) (Scheme 1), independent of
cyclooxygenase activity that produces the more familiar
“primary” trans-dialkyl PGs. One of the compounds
whose formation was anticipated by the proposed 5-exo
radical cyclization, 8-epi-PGF2R (1), was isolated and
subsequently found to exert potent biological activity as
a renal vasoconstrictor. More recently, the same group
reported the formation of isoprostane-like compounds
(i.e., 5) from cis-4,7,10,13,16,19-docosahexaenoic acid
(DHA), which is highly enriched in the brain, by a similar
free-radical mechanism.2d These findings suggest that
warranted and timely for their identification and inves-
tigation of biological activities. Herein we report an
enantioselective synthesis of 12-epi-PGF2R (3) and 12,15-
diepi-PGF2R (4), which would also provide a general
method for preparation of other possible stereoisomers
and related compounds.
Resu lts a n d Discu ssion
In the cyclization of radical C, preponderance of cis-
dialkyl stereochemistry in the newly formed cyclopentane
ring is consistent with the Beckwith-Houk model of hex-
5-enyl cyclizations and typical for C1-substituted radicals
(2) (a) Morrow, J . D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr,
K. F.; Roberts, L. J ., II. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383.
(b) Morrow, J . D.; Awad, J . A.; Boss, H. J .; Blair, I. A.; Roberts, L. J .,
II. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 10721. (c) Morrow, J . D.;
Harris, T. M.; Roberts, L. J ., II. Anal. Biochem. 1990, 184, 1. (d)
Roberts, L. J ., II; Montine, T. J .; Markesbery, W. R.; Tapper, A. R.;
Hardy, P.; Chemtob, S.; Dettbarn, W. D.; Morrow, J . D. J . Biol. Chem.
1998, 273, 13605 and references therein. See also: (e) Pratico`, D.;
Barry, O. P.; Lawson, J . A.; Adiyaman, M.; Hwang, S.-W.; Khanapure,
S. P.; Iuliano, L.; Rokach, J .; FitzGerald, G. A. Proc. Natl. Acad. Sci.
U.S.A. 1998, 95, 3449.
isoprostanes may provide a useful marker of oxidative
injury such as kidney failure and Alzheimer’s disease.
Preparation of these structurally unique isoprostanes is
(1) For a recent review, see: Collins, P. W.; Djuric, S. W. Chem.
Rev. 1993, 93, 1533.
10.1021/jo990906r CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/25/1999

7214 J . Org. Chem., Vol. 64, No. 19, 1999
Lai et al.
Sch em e 2
Sch em e 3
(Scheme 2).3 A priori, it is difficult to predict the exo/
endo selectivity between the two cis isomers: “boat-axial”
transition structure C-I provides isoprostanes 1 and 2,
whereas all syn isomers 3 and 4 are expected from “chair-
equatorial” transition structure C-II. Closely related
model studies suggest that these two pathways are
indeed competitive in the absence of overriding steric
effects.4,5 So far, 1 is the only isoprostane isolated from
plasma and fully characterized. Independent syntheses
of 3 and 4 will be useful for ascertaining their presence
in biological fluids. Toward this end, 12-epi-PGF2R (3) and
12,15-diepi-PGF2R (4) were chosen as the target com-
pounds to develop general synthetic methods for isopros-
tanes.6,7
Sch em e 4
We chose the Corey lactone (9) as starting material in
light of its commercial availability in enantiomerically
pure form,8 as well as several, well-optimized synthetic
procedures for either antipode. Moreover, 9 is well-suited
for the installation of various types of two cis side chains
that could be formed in vivo from free-radical oxidation
of AA and DHA. As outlined in the retrosynthetic
analysis, our key strategy centers around SmI2 reduction
of , -epoxy-R, -unsaturated ester 7 and in situ treat-
ment with an appropriate aldehyde for the construction
of the lower side chain (Scheme 3). The requisite cis
stereochemistry can be conveniently established by ste-
reoselective hydrogenation of 6 from the less-hindered
convex face of the bicyclic lactone. Finally, the upper side
chain should be readily prepared by standard Wittig
olefination.
Treatment of 9 with DBU afforded the R, -unsaturated
aldehyde 10 in nearly quantitative yield (Scheme 4). The
allylic alcohol 11 was then prepared by Luche reduction
in 90-100% yield.9 Subsequent epoxidation with t-
BuOOH in the presence of VO(acac)2, surprisingly, gave
(3) For excellent reviews, see: (a) Curran, D. P.; Porter, N. A.; Giese,
B. Stereochemistry of Radical Reactions. Concepts, Guidelines, and
Synthetic Applications; VCH: New York, 1996. (b) Beckwith, A. L. J .
Tetrahedron 1981, 37, 3073.
(4) (a) Porter, N. A.; Funk, M. O. J . Org. Chem. 1975, 40, 3614. (b)
O’Connor, D. E.; Mihelich, E. D.; Coleman, M. C. J . Am. Chem. Soc.
1981, 103, 223; 1984, 106, 3577. (c) Corey, E. J .; Shih, C.; Shih, N.-Y.;
Shimoji, K. Tetrahedron Lett. 1984, 25, 5013. (d) Weinges, K.; Sipos,
W. Chem. Ber. 1988, 121, 363. See also: (e) RajanBabu, T. V.;
Fukunaga, T.; Reddy, G. S. J . Am. Chem. Soc. 1989, 111, 1759.
(5) See also: (a) Hwang, S.-W.; Adiyaman, M.; Khanapure, S.; Schio,
L.; Rokach, J . J . Am. Chem. Soc. 1994, 116, 10829. (b) Hwang, S.-W.;
Adiyaman, M.; Khanapure, S. P.; Rokach, J . Tetrahedron Lett. 1996,
37, 779.
(6) Total syntheses of 3 have been reported: (a) Larock, R. C.; Lee,
N. H. J . Am. Chem. Soc. 1991, 113, 7815. (b) Vionnet, J .-P.; Renaud,
P. Helv. Chim. Acta 1994, 77, 1781. (c) Reference 5b. (d) Roland, A.;
Durand, T.; Rondot, B.; Vidal, J .-P.; Rossi, J .-C. Bull. Soc. Chim. Fr.
1996, 133, 1149. (e) A synthesis of (()-4 was also reported: ref 6b.
(7) Total syntheses of 1 have been reported: (a) Reference 5a. (b)
Taber, D. F.; Herr, R. J .; Gleave, D. M. J . Org. Chem. 1997, 62, 194.
(8) Available in large quantities from Cayman Chemical, Ann Arbor,
MI 48108.
a g10:1 mixture of the requisite R-epoxide 8 and the
corresponding -isomer. The stereoselective preparation
of 8 was also achieved (75%) by means of the Sharpless
(9) Luche, J .-L. J . Am. Chem. Soc. 1978, 100, 2226.

Synthesis of 12-epi-PGF2R and 12,15-diepi-PGF2R
J . Org. Chem., Vol. 64, No. 19, 1999 7215
asymmetric epoxidation using diethyl D-tartrate.10 Sim-
iliarly, use of diethyl L-tartrate afforded exclusively the
-epoxide in 80% yield. Swern oxidation of 8 and subse-
quent Wittig olefination (Ph3PdCHCO2Bn) afforded the
, -epoxy-R, -unsaturated ester 7 in 88% yield.
a convenient access to other possible stereo- and struc-
tural isomers derived from oxidation of AA and DHA.
Exp er im en ta l Section
(1S,5R)-6-Hyd r oxym eth yl-2-oxa bicyclo[3.3.0]oct-6-en -
3-on e (11). A solution of commercially available Corey lactone
9 (1.154 g, 4.0 mmol) in CH2Cl2 (10 mL) was treated at -78
°C with DBU (0.65 mL, 4.26 mmol). The reaction mixture was
stirred at -78 °C for 1 h and concentrated in vacuo. Direct
purification of the residue by flash silica gel column chroma-
tography (using as eluant 1:2 and 1:3 hexanes-EtOAc) af-
forded 10 (608 mg, 100%) as pale yellow solids.
Now the stage was set for the introduction of the lower
side-chain by reductive epoxide opening,11 followed by in
situ trapping of the resulting dienolate with hexanal.12
Treatment of 7 with SmI2 in THF at -78 °C and
subsequent addition of excess hexanal afforded the
condensation product 6 (P1 ) P2 ) H; P3 ) Bn) in 95%
yield: upon protection of both hydroxyl groups, several
isomers were generated, but ∼90% of the products
consisted of two easily separable (by column chromatog-
raphy) fractions of a nearly equal amount, each of which
appeared to be a single diastereomer but epimeric at
C-15.13 In passing, we note that the stereoselective
introduction of the C-15 (PG numbering) alcohol function
would be achieved by use of a suitable chiral auxiliary
in place of the benzyl ester. In the present study,
however, stereorandom preparation of both epimers was
pursued to secure both 3 and 4. Subsequent hydrogena-
tion (PtO2, 60 psi) produced the free carboxylic acids 13R
and 13 ; cis-dialkyl stereochemistry at the cyclopentane
ring was assigned on the basis of the expected hydroge-
nation from the less hindered, convex face. Oxidative
decarboxyaltion by the procedure of Kochi then afforded
E-olefins 5-R and 5- , free from the Z-olefins, in overall
(from 6) 40% and 64% yields, respectively.14 The stereo-
chemistry at C-15, as well as that at C-12, was deter-
mined by ultimate conversion to 3 and 4 (vide infra).
With pure 5-R and 5- in hand, the remaining task
involved the construction of the other side chain, which
was readily accomplished by standard PG chemistry.
Each compound was subjected separately to DIBAL-H
reduction, followed by olefination with (4-carboxybutyl)-
triphenylphosphonium bromide and potassium tert-bu-
toxide to furnish 14 and 15, protected forms of 3 and 4,
respectively, in 81-89% yield. Finally, desilylation with
3:1:1 HOAc-THF-H2O at room temperature yielded 12-
epi-PGF2R (3) and 12,15-diepi-PGF2R (4) in 85% yield. The
1H and 13C NMR spectra of 3 and 4 were in excellent
agreement with literature values.6
The R, -unsaturated aldehyde was dissolved in 9 mL of 1:2
CH2Cl2-MeOH, and cerium(III) chloride heptahydrate (918
mg, 2.4 mmol) was then added. After the solution was cooled
to -78 °C, sodium borohydride (93 mg, 2.4 mmol) was added.
The resulting mixture was stirred at -78 °C for 90 min and
acidified to pH 3 with an aqueous 1 N HCl solution. Most of
the organic solvents were removed by evaporation. The residue
was then dissolved in H2O and extracted with EtOAc. The
combined extracts were washed with brine, dried (MgSO4), and
concentrated in vacuo. Purification by column chromatography
(SiO2, using EtOAc as eluant) provided alcohol 11 (592 mg,
96%) as white solids: mp 49-50 °C; [R]D +12° (c 1.02, CHCl3);
IR (film) 3418, 1770, 1651, 1178 cm-1 1H NMR (360 MHz,
;
CDCl3) 5.65 (br s, 1 H), 5.15 (t, J ) 6.0 Hz, 1 H), 4.22 (br d,
J ) 13.7 Hz, 1 H), 4.14 (br d, J ) 13.7 Hz, 1 H), 3.52 (m, 1 H),
2.75 (ddd, J ) 18.4, 6.0, 2.0 Hz, 1 H), 2.72 (dd, J ) 18.2, 9.5
Hz, 1 H), 2.64 (br d, J ) 18.4 Hz, 1 H), 2.59 (dd, J ) 18.2, 2.2
Hz, 1 H), 2.22 (br s, -OH, 1 H); 13C NMR (90 MHz, CDCl3)
176.9, 142.3, 125.0, 83.7, 59.7, 45.4, 38.7, 31.6; HRMS (M+)
calcd for C8H10O3 154.0630, found 154.0632.
(1S,5S,6R,7R)-6,7-Epoxy-6-h ydr oxym eth yl-2-oxabicyclo-
[3.3.0]octa n -3-on e (8). A mixture of titanium tetraisopro-
poxide (0.24 mL, 0.78 mmol), (-)-D-diethyl tartrate (0.15 mL,
0.87 mmol), and molecular sieves 4Å (289 mg) in CH2Cl2 (2
mL) was stirred at -23 °C for 15 min. A solution of allylic
alcohol 11 (100 mg, 0.65 mmol) in CH2Cl2 (2 mL), followed by
a 2.0 M solution of tert-butylhydroperoxide in CH2Cl2 (0.68 mL,
1.36 mmol), was added. After the reaction mixture was stirred
at -23 °C for 2.5 h, a 10% aqueous (-)-D-tartaric acid solution
(2.5 mL) was added. The mixture was then stirred at -23 °C
for 30 min and extracted with CH2Cl2. The combined extracts
were washed with brine, dried (MgSO4) and concentrated in
vacuo. Purification by column chromatography (SiO2, using as
eluant 1:1 hexanes-EtOAc, followed by EtOAc) gave, along
with a small amount of -epoxide (2.8 mg, 2.5%), the desired
R-epoxide 8 (82.5 mg, 75%) as white solids: mp 97-98 °C; [R]D
-27° (c 0.24, CHCl3); IR (film) 3450, 1745, 1188 cm-1; 1H NMR
(360 MHz, CDCl3) 5.03 (t, J ) 7.1 Hz, 1 H), 3.94 (dd, J )
12.6, 5.0 Hz, 1 H), 3.84 (dd, J ) 12.6, 7.1 Hz, 1 H), 3.67 (br s,
1 H), 3.04 (ddd, J ) 7.8, 7.1, 3.2 Hz, 1 H), 2.75 (dd, J ) 18.1,
3.2 Hz, 1 H), 2.69 (dd, J ) 18.1, 7.8 Hz, 1 H), 2.47 (d, J ) 16.2
Hz, 1 H), 2.17 (ddd, J ) 16.2, 7.1, 1.3 Hz, 1 H), 2.10 (dd, J )
7.1, 5.0 Hz, -OH, 1 H); 13C NMR (90 MHz, CDCl3) 176.4,
84.1, 70.9, 64.1, 60.6, 40.3, 34.1, 30.0; HRMS (M+ + H) calcd
for C8H11O4 171.0657, found 171.0653.
(1S,5S,6S,7R)-6,7-E p oxy-6-[(E)-2′-ca r b ob en zyloxy-1′-
vin yl]-2-oxa bicyclo[3.3.0]octa n -3-on e (7). To a solution of
oxalyl chloride (0.12 mL, 1.4 mmol) in CH2Cl2 (1 mL) at -78
°C was added slowly a solution of DMSO (0.16 mL, 2.2 mmol)
in CH2Cl2 (1 mL). After 10 min, a solution of alcohol 8 (71 mg,
0.42 mmol) in CH2Cl2 (1 mL) was added, and the resulting
mixture was then stirred at -78 °C for an additional 1 h.
Triethylamine (0.45 mL, 3.2 mmol) was added, and the
mixture was stirred at -78 °C for 10 min and at 0 °C for 40
min. The mixture was then extracted with ether several times.
The organic extracts were washed with brine and water, dried
(MgSO4) and concentrated in vacuo. Purification by flash
column chromatography (SiO2, using EtOAc as eluant) fur-
nished the desired aldehyde in quantitative yield.
Con clu sion
In summary, we have developed a convenient route to
isoprostanes containing cis-dialkyl stereochemistry at the
cyclopentane ring. The cornerstone of our approach
involves SmI2-induced reductive ring opening of a , -
epoxy-R, -unsaturated ester and in situ trapping of the
resulting dienolate with an aldehyde, where the requisite
cis-dialkyl stereochemistry is established by stereocon-
trolled hydrogenation from the less hindered, convex face
of the bicyclic lactone. This new method would also offer
(10) Cf. Finn, M. G.; Sharpless, K. B. In Asymmetric Synthesiss
Chiral Catalysis; Morrison, J . D., Ed.; Academic Press: Orlando, FL,
1985; Vol. 5, Chapter 8.
(11) Molander, G. A.; La Belle, B. E.; Hahn, G. J . Org. Chem. 1986,
51, 5259. For a review on synthetic applications of SmI2, see: Molander,
G. A. Chem. Rev. 1992, 92, 29.
(12) Samarium enolates are known to react readily with aldehydes.
For example, see: Enholm, E. J .; J iang, S. Tetrahedron Lett. 1992,
33, 313.
(13) We thank Mr. Haizhong Tang for technical assistance with the
initial preparation of 7.
The aldehyde was dissolved in CH2Cl2 (3 mL) and treated
with (carbobenzyloxymethylene)triphenylphosphorane (119
(14) (a) Sheldon, R. A.; Kochi, J . K. Org. React. 1972, 19, 279. (b)
Ogibin, Y. N.; Katzin, M. I.; Nikishin, G. I. Synthesis 1974, 889.

7216 J . Org. Chem., Vol. 64, No. 19, 1999
Lai et al.
mg, 0.3 mmol) at room temperature for 2 h. After the solvent
was removed by evaporation, the residue was purified by
column chromatography (using 2:1, 1:1 hexanes-EtOAc as
eluant) to give 7 (112 mg, 89%) as white solids: mp 125-126
°C; [R]D +50.8° (c 1.0, CHCl3); IR (film) 3064, 1771, 1717, 1657,
1498, 1173 cm-1; 1H NMR (360 MHz, CDCl3) 7.41-7.25 (m,
5 H), 6.88 (d, J ) 15.8 Hz, 1 H), 6.14 (d, J ) 15.8 Hz, 1 H),
5.20 (s, 2 H), 5.02 (t, J ) 7.0 Hz, 1 H), 3.68 (br s, 1 H), 3.19
(ddd, J ) 9.5, 7.0, 1.6 Hz, 1 H), 2.69 (dd, J ) 18.0, 9.5 Hz, 1
H), 2.54 (dd, J ) 18.0, 1.6 Hz, 1 H), 2.51 (d, J ) 16.2 Hz, 1 H),
2.23 (ddd, J ) 16.2, 7.0, 1.5 Hz, 1 H); 13C NMR (90 MHz,
CDCl3) 175.4, 165.0, 141.3, 135.5, 128.6, 128.4, 128.3, 124.1,
83.2, 69.1, 68.7, 66.7, 40.9, 34.4, 29.6; HRMS (M+ + H) calcd
for C17H17O5 301.1076, found 301.1091.
(1S,5R,7R,2′R,S,3′R,S)-7-Hyd r oxy-6-[(E,Z)-3′-h yd r oxy-
oct-2′-car boben zyloxy-1′-yliden e]-2-oxabicyclo[3.3.0]octan -
3-on e (6). To a solution of samarium(II) iodide (26 mL of 0.1
M in THF) in THF at -78 °C was added dropwise a solution
of 7 (219 mg, 0.73 mmol) and n-hexanal (0.4 mL, 3.3 mmol) in
THF (10 mL). The reaction mixture was stirred at -78 °C for
50 min, quenched by addition of a pH 7.4 buffer solution, and
extracted with CH2Cl2. The combined extracts were washed
with brine, dried (Na2SO4), and concentrated in vacuo. Puri-
fication by column chromatography (SiO2, using as eluant 10:
1, 5:1, 2:1, 1:1 hexanes-EtOAc, followed by EtOAc) afforded
6 (294 mg, 100%) as a pale yellow oil: IR (film) 3417, 1770,
1732, 1183 cm-1; MS m/z 277, 276 (M+ - OBn - H2O), 266,
234, 193. The 1H NMR spectrum indicated the presence of 6
diastereomers, which can be most easily separated after
silylation.
(1S,5R,7R,2′R,S,3′R,S)-7-[(ter t-Bu tyl)d im eth ylsiloxy]-6-
[(E,Z)-3′-(ter t-bu tyl)dim eth ylsiloxyoct-2′-car boben zyloxy-
1′-ylid en e]-2-oxa bicyclo[3.3.0]octa n -3-on e (12). A solution
of alcohol 6 (255 mg, 0.63 mmol) in CH2Cl2 (5 mL) was treated
at 0 °C with 2,6-lutidine (0.8 mL, 6.8 mmol) and tert-
butyldimethylsilyl trifluromethanesulfonate (0.8 mL, 3.4 mmol).
After the resulting solution was stirred at room temperature
for 45 min, 1 N HCl (20 mL) was added. The mixture was then
extracted with CH2Cl2. The combined extracts were washed
with H2O and brine, dried (Na2SO4), and concentrated in vacuo
to give 12 (391 mg, 98%) as a slightly yellow oil, whose 1H
NMR spectrum indicated the presence of 6 diastereomers [a ,
5.78 (dd, J ) 10.1, 1.0 Hz); b, 5.63 (dd, J ) 10.1, 1.4 Hz);
c, 5.56 (br d, J ) 10.7 Hz); d , 5.47 (br d, J ) 10.8 Hz); e,
5.46 (dd, J ) 10.5, 1.2 Hz); f, 5.39 (dd, J ) 10.1, 1.0 Hz)]
in a ratio of 4:4:0.8:0.6:1.5:1. IR (film) 1774, 1736 cm-1; HRMS
(M+ - tert-butyl) calcd for C31H49O6Si2 573.3068, found 573.3078.
in vacuo to give 118 mg of the crude product, which was used
for the next step without further purification.
The crude acid was treated with Cu(OAc)2 (66 mg, 0.36
mmol) and pyridine (64 mg, 0.8 mmol) in chlorobenzene (3 mL).
After the mixture was stirred for 35 min, a solution of Pb-
(OAc)4 (288 mg, 0.62 mmol) in 3 mL of chlorobenzene was
added. The resulting mixture was stirred in the dark at room
temperature for 1 h and then was heated at 125 °C for 4 h.
The reaction mixture was diluted with EtOAc, washed with
H2O and brine, dried over MgSO4, and concentrated in vacuo.
Purification of the crude product by flash column chromatog-
raphy (SiO2, using as eluant 20:1, 15:1, and 10:1 hexanes-
EtOAc) gave 5-R (44.5 mg, 44%) as a slightly yellow oil: [R]D
-2.4° (c 1.24, CHCl3); IR (film) 1780, 1255, 1092 cm-1; 1H NMR
(360 MHz, CDCl3) 5.79 (ddd, J ) 15.5, 8.5, 1.0 Hz, 1 H),
5.54 (dd, J ) 15.5, 5.8 Hz, 1 H), 5.07 (t, J ) 7.0 Hz, 1 H), 4.17
(dd, J ) 3.7, 3.4 Hz, 1 H), 4.10 (dq, J ) 1.0, 5.8 Hz, 1 H), 3.03
(dddd, J ) 11.7, 8.5, 7.0, 5.0 Hz, 1 H), 2.82 (dd, J ) 18.5, 5.0
Hz, 1 H), 2.50 (dt, J ) 3.4, 8.5 Hz, 1 H), 2.44 (dd, J ) 18.5,
11.7 Hz, 1 H), 2.16 (d, J ) 15.1 Hz, 1 H), 1.88 (ddd, J ) 15.1,
7.0, 3.7 Hz, 1 H), 1.55-1.35 (m, 2 H), 1.35-1.20 (m, 6 H), 0.89
(s, 9 H), 0.88 (s, 9 H), 0.87 (t, J ) 7.3 Hz, 3 H), 0.059 (s, 3 H),
0.045 (s, 3 H), 0.040 (s, 3 H), 0.014 (s, 3 H); 13C NMR (90 MHz,
CDCl3) 177.7, 137.4, 125.0, 84.7, 76.7, 73.0, 50.8, 42.3, 42.1,
38.2, 31.8, 31.1, 25.9, 25.7, 24.8, 22.6, 18.2, 18.0, 14.0, -4.3,
-4.7, -4.8, -5.2; HRMS (M+ - tert-butyl) calcd for C23H43O4-
Si2 439.2700, found 439.2718.
(1S,5R,6S,7R,3′R)-7-[(ter t-Bu tyl)d im eth ylsiloxy]-6-[(E)-
3′-(ter t-bu tyl)d im eth ylsiloxyoct-1′-en -1′-yl]-2-oxa bicyclo-
[3.3.0]octa n -3-on e (5- ). According to the experimental pro-
cedure described for the conversion of 12-II to 5-R, the epimer
5- (56 mg, 64%) was obtained as a slightly yellow oil from
12-III (112 mg, 0.18 mmol). Similarly, 12-I was also converted
to 5- (66% overall): [R]D -2.8° (c 0.75, CHCl3); IR (film) 1772,
1
1092 cm-1; H NMR (360 MHz, CDCl3) 5.69 (dd, J ) 15.6,
8.2 Hz, 1 H), 5.51 (dd, J ) 15.6, 7.0 Hz, 1 H), 5.07 (t, J ) 7.2
Hz, 1H), 4.17 (dd, J ) 3.7, 3.4 Hz, 1 H), 4.04 (q, J ) 7.0 Hz, 1
H), 3.06 (dddd, J ) 11.8, 8.2, 7.2, 5.0 Hz, 1 H), 2.81 (dd, J )
18.5, 5.0 Hz, 1 H), 2.49 (dt, J ) 3.4, 8.2 Hz, 1 H), 2.46 (dd, J
) 18.5, 11.8 Hz, 1 H), 2.15 (d, J ) 15.1 Hz, 1 H), 1.88 (ddd, J
) 15.1, 7.2, 3.7 Hz, 1 H), 1.45 (m, 1 H), 1.40 (m, 1 H), 1.35-
1.16 (m, 6 H), 0.87 (s, 9 H), 0.86 (s, 9 H), 0.85 (t, J ) 6.6 Hz,
3 H), 0.044 (s, 3 H), 0.036 (s, 3 H), 0.024 (s, 3 H), 0.006 (s, 3
H); 13C NMR (90 MHz, CDCl3) 177.6, 137.7, 126.0, 84.7, 76.7,
74.0, 50.5, 42.3, 41.8, 38.2, 31.7, 31.1, 25.9, 25.7, 25.0, 22.6,
18.2, 18.0, 14.0, -4.2, -4.66, -4.74, -5.2; HRMS (M+ - tert-
butyl) calcd for C23H43O4Si2 439.2700, found 439.2690.
11,15-Bis(ter t-bu tyld im eth ylsilyl)-12-ep i-P GF 2r (14). To
a solution of 5-R (50 mg, 0.1 mmol) in THF (5 mL) was added
dropwise DIBAL-H (0.7 mL of 1 M in hexanes) at -78 °C. The
reaction mixture was stirred at -78 °C for 5 h and then
quenched by slow addition of MeOH, followed by EtOAc and
H2O. The resulting mixture was stirred at room temperature
for 30 min, filtered through a pad of Celite-Na2SO4, and
washed thoroughly with EtOAc. The combined filtrates were
concentrated in vacuo. Purification by SiO2 column chroma-
tography (using as eluant 15:1, 10:1, and 5:1 hexanes-EtOAc)
afforded 48.7 mg (97%) of the hemiacetal as a colorless oil,
which was used immediately for the next step.
Most conveniently, these diastereomeric products were
separated by column chromatography (SiO2, using as eluant
15:1, 10:1, 8:1, and 4:1 hexanes-EtOAc) into three fractions
12-I (pure e, 44 mg, 11%), 12-II (a mixture of b, c, and f, 159
mg, 40%), and 12-III (a miture of a and d , 158 mg, 40%).
The spectral data of the pure isomer e (12-I) were listed
below: 1H NMR (360 MHz, CDCl3) 7.40-7.30 (m, 5 H), 5.46
(dd, J ) 10.5, 1.2 Hz, 1 H), 5.07 (s, 2 H), 5.06 (t, J ) 6.8 Hz,
1 H), 4.42 (br d, J ) 4.4 Hz, 1 H), 4.16 (m, 1 H), 3.49 (m, 1 H),
3.28 (dd, J ) 10.5, 8.5 Hz, 1 H), 2.81 (dd, J ) 18.4, 11.8 Hz, 1
H), 2.38 (dd, J ) 18.4, 3.9 Hz, 1 H), 2.17 (d, J ) 15.0 Hz, 1 H),
1.80 (ddd, J ) 15.0, 6.8, 4.4 Hz, 1 H), 1.48-1.35 (m, 3 H), 1.35-
1.10 (m, 5 H), 0.85 (s, 9 H), 0.84 (t, J ) 7.8 Hz, 3 H), 0.83 (s,
9 H), 0.05 (s, 3 H), 0.04 (s, 3 H), 0.02 (s, 3 H), -0.03 (s, 3 H);
13C NMR (90 MHz, CDCl3) 176.5, 171.7, 150.2, 135.3, 128.7,
128.5, 120.8, 84.0, 76.6, 73.0, 66.9, 52.7, 41.5, 38.6, 36.7, 34.1,
31.9, 25.7, 25.6, 23.1, 22.4, 18.0, 17.9, 13.9, -4.3, -4.6, -4.9,
-5.0; HRMS (M+ - tert-butyl) calcd for C31H49O6Si2 573.3068,
found 573.3083.
(1S,5R,6S,7R,3′S)-7-[(ter t-Bu tyl)d im eth ylsiloxy]-6-[(E)-
3′-(ter t-bu tyl)d im eth ylsiloxyoct-1′-en -1′-yl]-2-oxa bicyclo-
[3.3.0]octa n -3-on e (5-r). A solution of 12-II (128.5 mg, 0.2
mmol) in EtOAc (6 mL) was hydrogenated under pressure (60
psi) overnight in the presence of PtO2 (35 mg) and Li2CO3 (84.6
mg, 1.1 mmol). The solution was filtered through Celite, and
the filter cake was rinsed thoroughly with EtOAc, followed by
5:1 CH2Cl2-MeOH. The combined filtrates were concentrated
A solution of (4-carboxybutyl)triphenylphosphonium bro-
mide (508 mg, 1.1 mmol) in THF (2 mL) was treated at 0 °C
with a solution of potassium tert-butoxide (2.2 mL of 1 M in
THF) in THF. After the mixture was stirred for 30 min, a
solution of the hemiacetal in THF (2 mL) was added. The
resulting mixture was then stirred at 0 °C for 1 h, quenched
with addition of saturated aqueous NH4Cl solution, diluted
with water, adjusted to pH 3 with 1 N HCl, and then extracted
with EtOAc. The combined organic extracts were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography (SiO2, using as eluant
4:1, 2:1, 1:1, and 1:2 hexanes-EtOAc) yielded 14 (45 mg, 80%)
as a colorless oil: [R]D +8° (c 0.15, CHCl3); IR (film) 3518, 3457,
1
1710 cm-1; H NMR (360 MHz, CDCl3) 5.72 (ddd, J ) 15.4,
10.2, 1.0 Hz, 1 H), 5.51 (m, 1 H), 5.45 (dd, J ) 15.4, 5.2 Hz, 1
H), 5.32 (m, 1 H), 4.24 (m, 1 H), 4.20-4.10 (m, 2 H), 2.64 (ddd,

Synthesis of 12-epi-PGF2R and 12,15-diepi-PGF2R
J . Org. Chem., Vol. 64, No. 19, 1999 7217
J ) 10.2, 10.0, 5.2 Hz, 1 H), 2.33 (t, J ) 7.5 Hz, 2 H), 2.23 (m,
1 H), 2.14-2.07 (m, 2 H), 2.02 (m, 1 H), 1.96 (m, 1 H), 1.94-
1.84 (m, 2 H), 1.74-1.64 (m, 2 H), 1.55-1.40 (m, 2 H), 1.40-
1.20 (m, 6 H), 0.89 (s, 18 H), 0.88 (t, J ) 6.9 Hz, 3 H), 0.068 (s,
3 H), 0.050 (s, 3 H), 0.048 (s, 3H), 0.041 (s, 3 H);13C NMR (90
MHz, CDCl3) 178.7, 136.4, 130.6, 128.6, 126.9, 77.5, 74.3,
72.9, 50.5, 47.9, 43.0, 38.6, 33.4, 31.9, 26.6, 25.9, 25.0, 24.9,
24.6, 22.6, 18.2, 18.1, 14.0, -4.3, -4.7, -4.80, -4.82; HRMS
(M+ - tert-butyl - H2O) calcd for C28H51O4Si2 507.3326, found
507.3309.
11,15-Bis(ter t-b u t yld im et h ylsilyl)-12,15-d i-ep i-P GF 2r
(15). Prepared from 5- in 88% yield as a colorless oil according
to the procedure as described for 14: [R]D -5° (c 0.10, CHCl3);
IR (film) 3523, 3456, 1711 cm-1; 1H NMR (360 MHz, CDCl3)
5.65 (dd, J ) 15.4, 10.2 Hz, 1 H), 5.52 (m, 1 H), 5.42 (dd, J )
15.4, 7.2 Hz, 1 H), 5.34 (m, 1 H), 4.20 (m, 1 H), 4.18 (m, 1 H),
4.07 (q, J ) 7.2 Hz, 1 H), 2.61 (ddd, J ) 10.2, 9.7, 5.5 Hz, 1
H), 2.33 (t, J ) 7.5 Hz, 2 H), 2.26 (m, 1 H), 2.17-2.05 (m, 2
H), 2.08 (m, 1 H), 1.99 (m, 1 H), 1.97 (m, 1 H), 1.86 (m, 1 H),
1.76-1.63 (m, 2 H), 1.55-1.36 (m, 2 H), 1.36-1.18 (m, 6 H),
0.88 (s, 18 H), 0.87 (t, J ) 6.6 Hz, 3 H), 0.063 (s, 3 H), 0.049
(s, 6 H), 0.016 (s, 3 H); 13C NMR (90 MHz, CDCl3) 179.1,
136.9, 130.3, 128.8, 128.2, 77.1, 74.0, 73.8, 50.5, 47.6, 43.0, 38.6,
33.5, 31.8, 26.6, 25.9, 25.8, 25.0, 24.6, 22.6, 18.2, 18.1, 14.1,
-4.0, -4.7, -4.8, -4.9; HRMS (M+ - tert-butyl - H2O) calcd
for C28H51O4Si2 507.3326, found 507.3339.
2.20-2.08 (m, 3 H), 2.05 (m, 1 H), 2.00 (m, 1 H), 1.90 (m, 1
H), 1.73-1.62 (m, 2 H), 1.60-1.45 (m, 2 H), 1.45-1.22 (m, 6
H), 0.88 (t, J ) 6.6 Hz, 3 H);13C NMR (90 MHz, CDCl3) 178.6,
136.7, 130.0, 129.6, 127.8, 75.6, 73.7, 72.4, 50.2, 47.2, 42.3, 37.3,
33.3, 31.8, 26.3, 25.2, 24.6, 24.3, 22.6, 14.0; MS m/z 355 (M+
+
H), 336 (M+ - H2O), 300, 290, 277, 265, 245, 229, 207, 191.
These spectral data were found to be in excellent agreement
with literature values.6b
12-epi-P GF 2r Meth yl Ester . For additional characteriza-
tion of 12-epi-PGF2R (3), the methyl ester was prepared: To a
solution of 3 (7.0 mg, 0.02 mmol) in 1 mL of benzene-MeOH
(4:1) was added dropwise a 2.0 M (trimethylsilyl)diazomethane
solution in hexanes (0.1 mL, 0.2 mmol) at room temperature.
The reaction mixture was stirred for 6 h and then concentrated
in vacuo. The concentrate was purified by column chromatog-
raphy on silica gel (using as eluant 1:1 hexanes-EtOAc, 10:1
CH2Cl2-MeOH, and 3:1, 2:1, 1:1 CH2Cl2-acetone) to give 6.3
mg (87%) of the methyl ester as a white solid: [R]D +10.2° (c
1
0.29, CHCl3); IR (film) 3383, 3004, 1742 cm-1; H NMR (360
MHz, CDCl3) 5.82 (dd, J ) 15.3, 10.5 Hz, 1 H), 5.52 (dd, J )
15.3, 7.2 Hz, 1 H), 5.43 (m, 1 H), 5.35 (m, 1 H), 4.26-4.17 (m,
2 H), 4.10 (q, J ) 7.2 Hz, 1 H), 3.66 (s, 3 H), 3.10-2.84 (br s,
-OH, 2 H), 2.75 (ddd, J ) 10.5, 10.0, 6.5 Hz, 1 H), 2.50 (br s,
1 H, OH), 2.31 (t, J ) 7.4 Hz, 2 H), 2.27 (m, 1 H), 2.18-1.96
(m, 4 H), 1.93 (m, 1 H), 1.86 (m, 1 H), 1.73-1.63 (m, 2 H),
1.57 (m, 1 H), 1.47 (m, 1 H), 1.40-1.22 (m, 6 H), 0.88 (t, J )
6.6 Hz, 3 H); 13C NMR (90 MHz, CDCl3) 174.3, 137.5, 129.5,
129.4, 129.1, 75.6, 73.7, 73.0, 51.6, 50.0, 47.2, 42.7, 37.0, 33.4,
31.8, 26.7, 25.2, 24.8, 24.3, 22.6, 14.0; HRMS (M+ - H2O) calcd
for C21H34O4 350.2457, found 350.2461.
12-epi-P GF 2r (3). The TBS-protected 12-epi-PGF2R (14) (21
mg, 0.036 mmol) was stirred in HOAc-H2O-THF (3:1:1) (5
mL) for 2 d at ambient temperature. After being diluted with
H2O, the reaction mixture was extracted with Et2O. The
organic extracts were washed with brine, dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography using as
eluant 1:4 hexanes-EtOAc, followed by EtOAc and 2% HOAc-
EtOAc. Additional purification by preparative TLC (developed
with 1:4 hexane-2% HOAc in EtOAc) afforded 10.8 mg (84%)
of 3 as a colorless semisolid: [R]D -4.2° (c 0.48, THF); [R]D
+7.5° (c 0.43, CHCl3); IR (film) 3377, 3006, 1709 cm-1; 1H NMR
(360 MHz, CDCl3) 5.83 (dd, J ) 15.2, 10.3 Hz, 1 H), 5.51
(dd, J ) 15.2, 6.1 Hz, 1 H), 5.45-5.30 (m, 2 H), 4.50-4.05 (br
s, -OH, 3 H), 4.30-4.17 (m, 2 H), 4.12 (m, 1 H), 2.75 (m, 1 H),
2.31 (t, J ) 5.6 Hz, 2 H), 2.28 (m, 1 H), 2.25-2.02 (m, 4 H),
1.98 (m, 1 H), 1.90 (m, 1 H), 1.72-1.58 (m, 2 H), 1.58-1.42
(m, 2 H), 1.40-1.24 (m, 6 H), 0.88 (t, J ) 6.6 Hz, 3 H); 13C
NMR (90 MHz, CDCl3) 177.7, 137.0, 129.9, 129.4, 128.5, 75.6,
73.8, 72.6, 50.0, 47.1, 42.5, 37.0, 33.1, 31.8, 26.4, 25.2, 24.5,
24.3, 22.6, 14.0; MS m/z 355 (M+ + H), 336 (M+ - H2O), 300,
290, 277, 265, 245, 229, 207, 191. These spectral data were
found to be in excellent agreement with literature values.6b
12,15-Di-epi-P GF 2r (4). By following the procedure for the
preparation of 3, desilylation of 15 (22 mg, 0.038 mmol)
provided 11.4 mg (85%) of 4 as a colorless oil: [R]D +3.2° (c
0.56, THF); [R]D +27.6° (c 0.55, CHCl3); IR (film) 3376, 3006,
12,15-Di-epi-P GF 2r Meth yl Ester . For additional charac-
terization of 12,15-di-epi-PGF2R (4), its methyl ester was also
prepared in 86% yield as a colorless oil, as described for the
preparation of 12-epi-PGF2R methyl ester: [R]D +20° (c 0.27,
1
CHCl3); IR (film) 3382, 3005, 1738 cm-1; H NMR (360 MHz,
CDCl3) 5.86 (dd, J ) 15.4, 10.4 Hz, 1 H), 5.61 (dd, J ) 15.4,
6.3 Hz, 1 H), 5.45 (m, 1 H), 5.37 (m, 1 H), 4.23 (t, J ) 6.3 Hz,
1 H), 4.20-4.12 (m, 2 H), 3.67 (s, 3 H), 2.75 (ddd, J ) 10.4,
9.0, 6.3 Hz, 1 H), 2.34 (br s, -OH, 2 H), 2.32 (t, J ) 7.1 Hz, 2
H), 2.28 (m, 1 H), 2.16 (m, 1 H), 2.16-2.02 (m, 3 H), 1.96 (m,
1 H), 1.85 (m, 1 H), 1.74 (br s, -OH, 1 H), 1.73-1.63 (m, 2 H),
1.60-1.45 (m, 2 H), 1.45-1.24 (m, 6 H), 0.88 (t, J ) 6.6 Hz, 3
H);13C NMR (90 MHz, CDCl3) 174.4, 138.0, 129.7, 129.5,
127.6, 75.5, 73.6, 72.5, 51.6, 50.2, 47.1, 42.8, 37.3, 33.3, 31.8,
26.7, 25.2, 24.7, 24.3, 22.6, 14.0; HRMS (M+ - H2O) calcd for
C
21H34O4 350.2457, found 350.2447.
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM35956) for financial support. We are
indebted to Professor P. Renaud for providing spectra
of 3 and 4.
Su p p or tin g In for m a tion Ava ila ble: Photocopies of the
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
1710 cm-1; H NMR (360 MHz, CDCl3) 5.89 (dd, J ) 15.2,
10.7 Hz, 1 H), 5.56 (dd, J ) 15.2, 6.0 Hz, 1 H), 5.47 (m, 1 H),
5.39 (m, 1 H), 4.30-4.12 (m, 3 H), 3.80-3.20 (br s, -OH, 3
H), 2.75 (m, 1 H), 2.32 (m, 1 H), 2.31 (t, J ) 6.7 Hz, 2 H),
J O990906R