Regio- and stereoselective reactions of 17-phenyl-18,19,20-trinorprostaglandin F2α isopropyl ester

Article abstract of DOI:10.1021/jo960098t

Novel prostaglandin F_2α derivatives, functionalized at C13 and C14, have been prepared. 17-Phenyl-18,19,20-trinorprostaglandin F_2α isopropyl ester [(15S)-1] and its epimer [(15A)-1] were stereoselectively epoxidized, using Sharpless conditions, to produce each of the four diastereomeric epoxides (15S)-2, (15S)-3, (15R)-2, and (15R)-3. Treatment of the four epoxides with LiOH stereospecifically-produced the pentahydroxy substituted analogues 12 and 13. Alternatively, epoxides 2 and 3 were allowed to react with thiophenolate ion. The attack of the sulfur nucleophile on the epoxide occurred at either C13 or C14 depending on the stereochemistry of the epoxide and of C15.

Full text of DOI:10.1021/jo960098t

4028
J . Org. Chem. 1996, 61, 4028-4034
Regio- a n d Ster eoselective Rea ction s of
17-P h en yl-18,19,20-tr in or p r osta gla n d in F 2r Isop r op yl Ester
Charlotta Liljebris,†,‡ Bjo¨rn M. Nilsson,‡ Bahram Resul,‡ and Uli Hacksell*,†
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, Box 574, Uppsala
University, S-751 23 Uppsala, Sweden and Pharmacia AB, S-751 82 Uppsala, Sweden
Received J anuary 17, 1996X
Novel prostaglandin F2R derivatives, functionalized at C13 and C14, have been prepared. 17-Phenyl-
18,19,20-trinorprostaglandin F2R isopropyl ester [(15S)-1] and its epimer [(15R)-1] were stereose-
lectively epoxidized, using Sharpless conditions, to produce each of the four diastereomeric epoxides
(15S)-2, (15S)-3, (15R)-2, and (15R)-3. Treatment of the four epoxides with LiOH stereospecifically-
produced the pentahydroxy substituted analogues 12 and 13. Alternatively, epoxides 2 and 3 were
allowed to react with thiophenolate ion. The attack of the sulfur nucleophile on the epoxide occurred
at either C13 or C14 depending on the stereochemistry of the epoxide and of C15.
In tr od u ction
Ongoing studies in our laboratories focus on exploring
the relation between antiglaucoma activity and the
structure of the ω-chain of prostaglandin F2R (PGF2R
)
isopropyl ester analogues.1,2 Previously, we have re-
ported the synthesis of phenyl-substituted analogues of
the 15S and 15R epimers of 17-phenyl-18,19,20-trinor-
PGF2R isopropyl ester [(15S)-1 and (15R)-1, respec-
tively].3,4 In the present study, we have focused our
attention to the allylic function of the ω-chain since
functionalization of the allylic alcohol moiety would allow
for expansion of the structural diversity of this class of
molecules using a single and minimally protected key-
intermediate.
The asymmetric Sharpless epoxidation reaction5 pro-
vided a convenient method for stereoselectively convert-
ing (15S)-1 and (15R)-1 to the diastereomeric epoxy
alcohols (15S)-2, (15R)-2, (15S)-3, and (15R)-3. We have
also studied regioselective ring-opening reactions of the
epoxy alcohols using sulfur and oxygen nucleophiles, such
as thiophenolate and hydroxide anions. Most of these
reactions provide isomerically pure compounds in accept-
able yields.
Resu lts a n d Discu ssion
also represents a modified version of Corey’s general
method (Scheme 1);6 treatment of the Corey lactone 4
with tert-butyldimethylchlorosilane afforded a mixture
of mono- and disilylated products (5a and 5b) that were
separated by column chromatography. Reduction of the
lactone function of 5a using DIBAL-H7 afforded the lactol
6. Wittig reaction with (4-carboxybutyl)triphenylphos-
phonium bromide8 afforded the acid 7 as a 95:5 mixture
of cis and trans isomers. Compound 7 was esterified with
2-iodopropane and K2CO3 to give 8 in 66% overall yield
from 6. Compound 8 was deprotected using NaHSO4‚H2O,
affording triol 9 in 96% yield. The triol 9 was C9 and
C11 hydroxyl diprotected in situ using phenylboronic
acid9 and was then oxidized with pyridinium chlorochro-
mate (PCC)/Al2O310 to aldehyde 10 which was not isolated
Syn th esis of (15S)-1 a n d (15R)-1. These compounds
were prepared by a slightly different strategy than that
described by us previously,1-4 and the present method
† Uppsala University.
‡ Pharmacia AB.
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) Resul, B.; Stjernschantz, J .; No, K.; Liljebris, C.; Sele´n, G.; Astin,
M.; Karlsson, M.; Bito, L. Z. J . Med. Chem. 1993, 36, 243-248; 1993,
36, 2242.
(2) Stjernschantz, J .; Resul, B. Drugs Future 1992, 17, 691-704.
(3) Liljebris, C.; Resul, B.; Hacksell, U. Bioorg. Med. Chem. Lett.
1993, 3, 241-244.
(4) Liljebris, C.; Sele´n, G.; Resul, B.; Stjernschantz, J .; Hacksell, U.
J . Med. Chem. 1995, 38, 289-304.
(5) (a) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102,
5974-5976. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765-
5780. (c) J ohnson, R. A.; Sharpless, K. B. In Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Vol. 7,
Chapter 3.2. (d) Smith, J . G. Synthesis 1984, 629-656. (e) Rossiter,
B. E. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press:
New York, 1985; Vol. 5, Chapter 7, pp 193-245. (f) Pfenniger, A.
Synthesis 1986, 89-116. (g) Finn, M. G.; Sharpless, K. B. In Asym-
metric Synthesis; Morrison, J . D., Ed.; Academic Press: New York,
1985; Vol. 5, Chapter 8, p 247.
(6) (a) Corey, E. J .; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J . Am. Chem. Soc. 1969, 91, 5675-5677. (b) Corey, E. J .; Schaaf, T.
K.; Huber, W.; Koelliker, U.; Weinshenker, N. M. J . Am. Chem. Soc.
1970, 92, 397-398.
(7) Wilson, K. E.; Seidner, R. T.; Masamune, S. J . Chem. Soc., Chem.
Commun. 1970, 213-214.
(8) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927.
S0022-3263(96)00098-9 CCC: $12.00 © 1996 American Chemical Society

17-Phenyl-18,19,20-trinorprostaglandin F2R Isopropyl Ester
Sch em e 1a
J . Org. Chem., Vol. 61, No. 12, 1996 4029
but condensed with dimethyl (2-oxo-4-phenylbutyl)phos-
phonate2 under Horner-Wadsworth-Emmons condi-
tions.11 Deprotection with H2O2 furnished ketone 11 in
76% overall yield from 9. Nonstereoselective reduction
of 11 using sodium borohydride in the presence of cerium
chloride heptahydrate12 provided an epimeric mixture of
(15S)-1 and (15R)-1. The isomers were readily separated
by column chromatography to provide isomerically pure
(15S)-1 and (15R)-1 in 38% and 46% yield, respectively.
Alternatively, the reduction of 11 could be performed in
a stereoselective manner using lithium B-isopinocam-
pheyl-9-borabicyclo[3.3.1]nonyl hydride (S-Alpine hy-
dride)13 to provide predominantly the 15S-epimer (44%
de).
E p oxid a t ion R ea ct ion s of (15S)-1 a n d (15R)-1.
Asymmetric epoxidation of the borate ester of (15S)-1 by
the Sharpless method5 using (+)-L-diisopropyl tartrate
[(+)-DIPT] gave 93% de14 of the â-epoxide (15S)-2 in 66%
yield (Scheme 2). Attempts to epoxidize unprotected 1
were unsuccessful. Purification by preparative HPLC
afforded isomerically pure (15S)-2. The reaction was
complete after 10 min at 0 °C and 2 h at ambient
temperature. Attempts to increase the % de by running
the reaction at lower temperatures were not successful.
Epoxidation of the slow-reacting isomer (15R)-1, using
(+)-DIPT, gave a diastereomeric mixture of (15R)-2 and
(15R)-3 (â- and R-epoxide, respectively) in a total yield
of 60%; the epoxidation gave 22% de of the â-epoxide
(15R)-2 (Scheme 2). The reaction was complete after 12
h at 0 °C and 4 h at ambient temperature, which gave
an optimal % de. Separation of the mixture by prepara-
tive HPLC afforded isomerically pure (15R)-2 (21%) and
isomerically pure (15R)-3 (19%).
Sharpless epoxidation using (-)-DIPT gave the op-
posite results. The fast-reacting isomer (15R)-1 gave 92%
de of the R-epoxide (15R)-3 in 76% yield (Scheme 2).
Purification by preparative HPLC afforded isomerically
pure (15R)-3. Epoxidation of the slow-reacting isomer
(15S)-1 using (-)-DIPT produced a diastereomeric mix-
ture of (15S)-2 and (15S)-3 with 62% de of the R-epoxide
(15S)-3 (Scheme 2). Purification by preparative HPLC
afforded isomerically pure (15S)-3 (44%).
Rin g-Op en in g Rea ction s. Nucleophilic ring-opening
of the borate protected isomeric epoxides with LiOH
proceeded smoothly. Reaction of (15S)-2 with LiOH
afforded isomerically pure (15S)-12 (Scheme 2). The
proposed stereochemistry is based on nucleophilic attack
at C13. In neutral and basic conditions nucleophilic ring-
opening of epoxides occur by a SN2 mechanism at the
least sterically hindered carbon, but also electronic
factors play an important role. Electronically, a sub-
stituent may exert its effect through resonance or induc-
tion or both. An electron-withdrawing substituent dis-
(9) (a) Nishizawa, E. E.; Miller, W. L.; Gorman, R. R.; Bundy, G. L.
Prostaglandins 1975, 9, 109-120. (b) Ferrier, R. J .; Prasad, D.;
Rudowski, A.; Sangster, I. J . Chem. Soc. 1964, 3330-3334.
(10) Cheng, Y.-S.; Liu, W.-L.; Chen, S. Synthesis 1980, 223-224.
(11) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183-2186.
(12) Gemal, A. L.; Luche, J .-L. J . Am. Chem. Soc. 1981, 103, 5454-
5459.
(13) (a) Krishnamurthy, S.; Vogel, F.; Brown, H. C. J . Org. Chem.
1977, 42, 2534-2536. (b) Ramachandran, P. V.; Brown, H. C.;
Swaminathan, S. Tetrahedron: Asymmetry 1990, 1, 433-436.
(14) This is in agreement with the predicted stereoselectivity of
secondary allylic alcohols, see ref 5.

4030 J . Org. Chem., Vol. 61, No. 12, 1996
Liljebris et al.
Sch em e 2a
Ta ble 1. Vicin a l Cou p lin g Con sta n ts Used for
Ster eoch em ica l Assign m en ta
J
14,15 couplings in (15S)-13 and (15R)-12, where the C14-
OH and C15-OH have cis relationship, are of the same
magnitude. In (15S)-12 and (15R)-13, where the C14-
OH and C15-OH have trans relationship, the J 14,15
couplings are smaller (Table 1). The assignment of the
configuration at C15 is based on the assumption that the
stereochemistry of the starting materials is retained in
the products.
compound
J 12,13
J 13,14
J 14,15
(15S)-12
(15S)-13
(15R)-12
(15R)-13
3.6
2.0
3.3
2.1
8.6
7.0
8.5
7.9
1.6
6.7
5.5
2.5
a
Values are given in Hz.
When sodium thiophenolate was used as a nucleophile,
the ring-openings of the four borate protected epoxide
isomers proceeded with different regioselectivities (Scheme
3). Reaction of (15S)-2 with thiophenolate produced
sulfide (15S)-14, the thiolate ion attacking at C13. In
contrast, epoxides (15R)-2 and (15S)-3 were ring-opened
by attack at C14 producing sulfides (15R)-15 and (15S)-
16, respectively. Epoxide (15R)-3, on the other hand,
produced a 69:31 mixture of C13 and C14 ring-opened
products, (15R)-17 and (15R)-16, respectively, in 35%
overall yield. Column chromatographic separation gave
isomerically pure (15R)-17 (14%) and (15R)-16(11%).
couraged ring-opening at the proximal carbon atom.15
Based on the assumption that electronic factors domi-
nate, the electron withdrawing inductive effect of the
C15-OH should direct nucleophilic ring-opening to the
distal carbon atom. Nucleophilic ring-opening of (15S)-
3, (15R)-2, and (15R)-3 with LiOH gave (15S)-13, (15R)-
12, and (15R)-13, respectively, with similar regioselec-
tivities and yields (Scheme 2). The reactions were
monitored by analytical HPLC, and although some
negligible additional peaks could be detected, no other
products could be isolated.
The stereochemical assignments of the pentols are
supported by the NMR spectroscopic data. However, the
structural assignments for 12 and 13 are yet to be
determined with absolute certainty. In (15S)-12 and
(15R)-12, where the C13-OH is R-positioned, the vicinal
coupling constants between C12-H and C13-H have the
same magnitude (Table 1). In addition, the J 12,13 cou-
plings in (15S)-13 and (15R)-13, where the C13-OH is
â-positioned, are comparable. On the other hand, the
The stereochemical assignments of the sulfides where
based on NMR spectroscopic data and the mechanistic
assumption that ring opening occurred by
a SN2
mechanism. The 13C NMR chemical shifts of C13 and
C14 bearing a phenylthio group occur upfield (51-59
ppm) of carbons bearing a hydroxyl group (73-77 ppm)
(Table 2).
In conclusion, epoxides 2 and 3 may serve as readily
accessible key intermediates in the synthesis of novel
PGF2R derivatives substituted with various groups at C13
and C14.
(15) (a) Behrens, C. H.; Sharpless, K. B. Aldrichimica Acta 1983,
16, 67-79. (b) Behrens, C. H.; Sharpless, K. B. J . Org. Chem. 1985,
50, 5696-5704.

17-Phenyl-18,19,20-trinorprostaglandin F2R Isopropyl Ester
J . Org. Chem., Vol. 61, No. 12, 1996 4031
Sch em e 3a
ice bath was removed after 1.5 h, and the reaction mixture
was stirred for 16 h at room temperature. The reaction
mixture was then concentrated in vacuo. Ether was added,
and the triethylammonium hydrochloride salt was filtered off.
Concentration of the filtrate in vacuo afforded the crude
product as an oil, which was purified by column chromatog-
raphy using EtOAc/n-hexane (1:1) as eluent. First eluted was
the disilylated lactone 5b. Further elution gave 9.15 g (76%)
of pure monosilylated lactone 5a as a white solid. The
obtained disilylated 5b was contaminated with tBuMe2SiCl.
However, a second column on impure 5b using n-hexane/ether
(3:2) as eluent gave 577 mg (4%) of pure 5b as a white solid.
5a : TLC Rf ) 0.40 [n-hexane/EtOAc (1:1)]; mp 60.5-62 °C,
lit.16 61-62.5 °C; [R]D -22.7 (c 1.21, CH3CN), -15.3 (c 1.05,
1
CHCl3), lit.16 -14.1 (CHCl3); H NMR (CDCl3) δ 0.06 [6H, s,
Si(CH3)2], 0.89 [9H, s, C(CH3)3], 1.94-2.04 (2H, m, H6 and H8′),
2.42 (1H, ddd, H8′′, J ) 6.7, 6.7, 15.0), 2.50-2.54 (2H, m, H4â
and C7-OH), 2.62 (1H, m, H5), 2.78 (1H, dd, H4R, J ) 10.1,
18.0), 3.60 (1H, dd, CH2OSi, J ) 6.4, 10.1), 3.69 (1H, dd, CH2-
OSi, J ) 5.2, 10.1), 4.12 (1H, m, H7), 4.91 (m, 1H, H1). Anal.
Calcd for C14H26O4Si: C, 58.70; H, 9.15. Found: C, 58.8; H,
9.15.
5b: TLC Rf ) 0.53 [n-hexane/ether (1:1)]; mp 104.5-105.5
1
°C; [R]D -26.3 (c 1.03, CH3CN); H NMR (CDCl3) δ 0.04 (6H,
two peaks, Si(CH3)2′), 0.05 (6H, two peaks, Si(CH3)2′′), 0.87 (9H,
s, C(CH3)3′), 0.89 (9H, s, C(CH3)3′′), 1.94-2.01 (2H, m, H6 and
H8′), 2.23 (1H, ddd, H8′′, J ) 5.8, 6.9, 14.7), 2.53 (2H, dd, H4â,
J ) 3, 18), 2.67 (1H, m, H5), 2.77 (1H, dd, H4R, J ) 10.7, 17.8),
3.48 (1H, dd, CH2OSi, J ) 5.8, 10.2), 3.55 (1H, dd, CH2OSi, J
) 5.2, 10.4), 4.12 (1H, m, H7), 4.92 (m, 1H, H1). Anal. Calcd
for C20H40O4Si2: C, 59.95; H, 10.06. Found: C, 59.9; H, 10.2.
(1S,5R,6R,7R)-6-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
7-h yd r oxy-2-oxa bicyclo[3.3.0]octa n e-3-ol (6). Diisobuty-
laluminum hydride (DIBAL-H, 20 wt % in toluene, 65 mL, 79.1
mmol) was added dropwise during 30 min to a stirred solution
of lactone 5a (8.96 g, 31.3 mmol) in a 1:1 mixture of toluene
and THF (100 mL) kept at -78 °C. Additional DIBAL-H (5.0
mL, 6.1 mmol) was added after 1.5 h, and the stirring was
continued for 1 h. Crushed ice (∼80 g) was added, and a heavy
gelatinous substance formed when the mixture had reached
ambient temperature. EtOAc (∼400 mL) was added, and the
mixture was filtered when the precipitate had become flaky
(∼5 h). The filtrate was dried (MgSO4), filtered, and concen-
trated. The resulting oil was purified by column chromatog-
raphy using EtOAc/n-hexane (3:2) as eluent. This gave 7.0 g
(78%) of 6 as a 1:1 mixture of diastereomers: TLC Rf ) 0.28
[EtOAc/n-hexane (3:2)]; 1H NMR (CDCl3) δ 0.05 and 0.06 (6H,
s’s, Si(CH3)2), 0.89 [9H, two peaks, C(CH3)3], 1.80-1.90, 2.00-
2.06, 2.10-2.21, 2.25-2.34, 2.38-2.46 (1H, 1H, 1.5H, 1.5H,
and 1H, respectively), 2.71 and 3.21 (0.5H each, app d and br
s, respectively, OH), 3.52, 3.64, 3.71 (1H, 0.5H, 0.5H, respec-
tively, m, dd, dd, respectively, CH2OSi), 4.01-4.07 and 4.07-
4.12 (0.5H each, each m, H7), 4.62 and 4.66 (0.5H each, each
m, H1), 5.54 and 5.67 (0.5H each, each app d, H3). Anal. Calcd
for C14H28O4Si: C, 58.29; H, 9.78. Found: C, 58.3; H, 9.95.
13-[(ter t-Bu tyld im eth ylsilyl)oxy]-14,15,16, 17,18,19,20-
h ep ta n or p r osta gla n d in F 2r (7). Potassium tert-butoxide
(50.9 g, 453 mmol) was added to a stirred suspension of (4-
carboxybutyl)triphenylphosphonium bromide (105.4 g, 238
mmol) in THF (250 mL) at -10 °C (dry ice bath). A solution
of lactol 6 (28.6 g, 95 mmol) in THF (110 mL) was added to
the deep orange colored ylide at -30 °C. The cooling bath was
removed after 45 min, and water (∼250 mL) was added to the
reaction mixture. Most of the formed Ph3PO was removed
(TLC; EtOAc) by extractions with ether (6 × 300 mL). The
aqueous layer was made slightly acidic (pH ∼4.5) by addition
of NaH2PO4 monohydrate and was extracted with EtOAc (4
× 500 mL). The combined organic layers were dried (MgSO4)
and concentrated. The crude product was filtered through a
silica gel column by elution with ether. The main part (34.6
g) of the partially purified acid 7 was used directly in the next
step. However, a small fraction (0.35 g) was purified on a
second column using the same eluent. Analytical HPLC
Ta ble 2. 13C NMR Ch em ica l Sh ift Va lu es Used for
Regioch em ica l Assign m en ta
compound
C11
C12
C13
C14
C15
(15S)-14
(15R)-15
(15S)-16
(15R)-17
(15R)-16
73.2
77.4
73.9
79.4
74.0
51.2
56.1
56.0
52.1
55.9
52.8
76.0
72.9
55.3
72.4
77.1
59.4
59.5
76.2
59.0
71.9
71.5
72.7
71.7
71.7
a
Values are given as ppm referenced to internal TMS.
Exp er im en ta l Section 4
Preparative HPLC was performed using a silica gel column
(21.4 × 250 mm); mobile phase: 3-7% of ethanol in isohexane;
flow rate: 13 mL/min, unless otherwise noted; detection: 220
nm. Elemental analyses were performed by Mikro Kemi AB,
Uppsala, Sweden, or by Analytische Laboratorien, Gummers-
bach, Germany, and were within 0.4% of the calculated values.
(1S,5R,6R,7R)-6-[[(ter t-Bu tyldim eth ylsilyl)oxy]m eth yl]-
7-h yd r oxy-2-oxa b icyclo[3.3.0]oct a n e-3-on e (5a ) a n d
(1S,5R,6R,7R)-6-[[(ter t-Bu tyld im eth ylsilyl)oxy]m eth yl]-
7-[(ter t-bu tyldim eth ylsilyl)oxy]-2-oxabicyclo[3.3.0]octan e-
3-on e (5b). Triethylamine (4.28 g, 42.3 mmol) and 4-(dime-
thylamino)pyridine (533 mg, 4.36 mmol) were added to a
stirred suspension of the Corey lactone6 (1S,5R,6R,7R)-6-
(hydroxymethyl)-7-hydroxy-2-oxabicyclo[3.3.0]octane-3-one (4;
7.51 g, 43.6 mmol) in CH2Cl2 (60 mL). The reaction mixture
was temporarily cooled to -20 °C on a dry ice bath and tBuMe2-
SiCl (6.44 g, 42.7 mmol) in CH2Cl2 (60 mL) was added. The
(16) Andersen, N. H.; Imamoto, S.; Picker, D. H. Prostaglandins
1977, 14, 61-101.

4032 J . Org. Chem., Vol. 61, No. 12, 1996
Liljebris et al.
(straight phase; mobile phase 8% ethanol in n-hexane, flow:
2 mL/min) and 13C NMR spectroscopy showed that the product
contained ∼5% of the trans isomer. An analytical sample (49
mg) of isomerically pure 7 was obtained from 255 mg after 3
preparative HPLC (mobile phase 7.5% ethanol in n-hexane,
flow: 11 mL/min) runs. TLC Rf ) 0.20 (ether/methanol (95:
the solvent was evaporated in vacuo at 38 °C. The protected
triol was added to the PCC-Al2O3 mixture, and more CH2Cl2
(50 mL) and molecular sieves were added. The reaction
mixture was stirred for 3 h under N2 and was then filtered
through a short pad of SiO2 (prewashed with ether). The
product was eluted with ether, and the crude aldehyde 10 was
obtained as a brown oil after concentration of the eluents.
1
5)]; [R]D +41.1 (c 1.11, CH3CN); H NMR (CDCl3) δ 0.04 and
0.05 [6H, s’s, Si(CH3)2], 0.88 [9H, s, C(CH3)3], 1.60-1.75 (3H,
m, H3’s and H8), 1.82-1.95 (3H, m, H10’s and H12), 2.07-2.2.24
(3H, m, H4′ and H7’s), 2.31-2.38 (3H, m, H2’s and H4′′), 3.50
(1H, dd, H13′, J ) 5.8, 10.1), 3.78 (1H, dd, H13′′, J ) 4.0, 9.9),
4.05-4.32 (2H, br m, H9 and H11), 5.35-5.42 (1H, m, H6), 5.42-
5.49 (1H, m, H5). Anal. Calcd for C19H36O5Si: C, 61.25; H,
9.74. Found: C, 61.5; H, 9.65.
A solution of diisopropylethylamine (DIPEA; 1.13 g, 8.71
mmol) in CH3CN (10 mL) was added to a cold (-15 °C) stirred
suspension of LiCl (0.91 g, 21.6 mmol) and dimethyl (2-oxo-
4-phenylbutyl)phosphonate2 (1.17 g, 4.57 mmol) and molecular
sieves in CH3CN (20 mL) under N2. The mixture was stirred
for 45 min, and a solution of the crude aldehyde 10 in CH3CN
(30 mL) was added. The reaction mixture was stirred for 30
min at -15 °C and then at room temperature overnight. Ether
and MgSO4 was added, and the mixture was filtered and
concentrated. The residue was dissolved in THF (30 mL) and
30% aqueous H2O2 (8 mL) was carefully added. The reaction
mixture was stirred for 15 min and was then extracted with
EtOAc. The organic layer should be washed with a saturated
aqueous solution of Na2SO3. The organic layer was washed
with aqueous NaHCO3 (2 × 30 mL), dried (MgSO4), and
concentrated by careful evaporation in vacuo at room temper-
ature. Column chromatography (gradient system: CH2Cl2 to
EtOAc) afforded 1.36 g (76%) of 11 as an oil: TLC Rf ) 0.33
(EtOAc); [R]D +46.7 (c 0.83, CH3CN); 1H NMR (CDCl3) δ 1.22
(6H, d, CH(CH3)2, J ) 6.3), 1.62 (1H, m, H8), 1.67 (2H, app
quint, H3), 1.86 (1H, m, H10â), 2.0-2.30 (7H, m, H4, H7, H10R
and H2), 2.53 (1H, m, H12), 2.86-2.96 (4H, m, H16 and H17),
4.04 (1H, br m, H11), 4.22 (1H, app br t, H9), 5.00 (1H, sept,
CH(CH3)2, J ) 6.3), 5.34-5.40 (2H, m, H5 and H6), 6.18 (1H,
d, H14, J ) 15.7), 6.67 (1H, dd, H13, J ) 9.2, 15.7), 7.18-7.31
(5H, m, aromatic protons). Anal. Calcd for C26H36O5‚1/4H2O:
C, 72.11; H, 8.38. Found: C, 72.2; H, 8.2.
13-[(ter t-Bu tyld im eth ylsilyl)oxy]-14,15,16,17,18,19,20-
h ep ta n or p r osta gla n d in F 2r Isop r op yl Ester (8). 2-Io-
dopropane (27.58 g, 162.3 mmol) was added to a stirred
mixture of K2CO3 (11.03 g, 79.8 mmol) and partially purified
acid 7 (10.7 g, ∼26.6 mmol) in CH3CN (60 mL) kept at 85 °C.
More 2-iodopropane (3.0 g, 17.6 mmol) was added after 4 h,
and the stirring was continued for 5 h. The reaction mixture
was cooled to room temperature and ether (∼200 mL) was
added. Solids were removed by filtration, and concentration
of the filtrate gave the crude ester 8 as an oil. Repetitive
column chromatography using n-hexane/EtOAc (2:1) as eluent
gave 7.26 g (66% from lactol 6) of the title product. Analytical
HPLC was performed on 8 (straight phase; mobile phase 2.2%
ethanol in n-hexane, flow: 2 mL/min), and 13C NMR spectros-
copy indicated the presence of ∼5% of the trans isomer. An
analytical sample of isomerically pure 8 (140 mg) was obtained
190 mg after 4 preparative HPLC (mobile phase 3% ethanol
in n-hexane, flow: 12 mL/min) runs. TLC Rf ) 0.30 [n-hexane/
1
EtOAc (3:2)]; [R]D +38.2 (c 1.07, CH3CN); H NMR (CDCl3) δ
0.04 and 0.05 [6H, s’s, Si(CH3)2], 0.88 [9H, s, C(CH3)3], 1.23
(6H, d, CH(CH3)2, J ) 6.1), 1.59-1.64 (1H, m, H8), 1.69 (2H,
quint, H3’s), 1.80-1.93 (3H, m, H10’s and H12), 2.07-2.16 (1H,
m, H7’s), 2.16-2.24 (1H, m, H4′), 2.28 (2H, t, H2’s, J ) 7.4), 2.32-
2.38 (1H, m, H4′′), 2.61 (1H, br, OH), 2.92 (1H, br, OH), 3.50
(1H, dd, H13′, J ) 6.1, 10.0), 3.78 (1H, dd, H13′′, J ) 4.6, 9.9),
4.12 and 4.19 (each 1H, each m, H9 and H11), 5.00 (1H, sept,
CH(CH3)2, J ) 6.1), 5.36-5.42 (1H, m, H6), 5.43-5.49 (1H, m,
H5). Anal. Calcd for C22H42O5Si: C, 63.72; H, 10.21. Found:
C, 63.65; H, 10.25.
14,15,16,17,18,19,20-Hep t a n or p r ost a gla n d in F 2r Iso-
p r op yl Ester (9). To a solution of partially purified ester 8
(7.18 g, 17.3 mmol) in THF (100 mL) was added NaHSO4‚H2O
(9.56 g, 69.2 mmol) in water (50 mL). The mixture was stirred
at room temperature for 13 h. Water (80 mL) and CH2Cl2 (300
mL) were added, and the resulting mixture was extracted. The
aqueous layer was extracted with more CH2Cl2 (2 × 150 mL).
The combined organic layers were washed with saturated
aqueous NaHCO3 (80 mL), dried (MgSO4), filtered, and
concentrated. Column chromatography afforded 4.98 g (96%)
of 9 as an oil. Analytical HPLC (straight phase; mobile phase
6% ethanol in n-hexane, flow: 2 mL/min) and 13C NMR
spectroscopy indicated the precence of ∼5% of the trans isomer.
An analytical sample of isomerically pure 9 was obtained from
150 mg after 3 preparative HPLC (mobile phase 5.8% ethanol
in n-hexane, flow: 15 mL/min) runs: TLC Rf ) 0.32 [ether/
methanol (95:5)]; [R]D +43.0 (c 1.03, CH3CN); 1H NMR (CDCl3)
δ 1.23 (6H, d, CH(CH3)2, J ) 6.3), 1.45-1.51 (1H, m, H8), 1.68
(2H, quint, H3’s), 1.85 (1H, m, H10â), 1.90-1.98 (2H, m, H10R
and H12), 2.12 (2H, app q, H7’s), 2.20-2.26 (1H, m, H4′), 2.28
(2H, t, H2’s, J ) 7.3), 2.31-2.38 (1H, m, H4′′), 2.89 (1H, d, OH,
J ) 5.9), 3.01 (1H, br s, OH), 3.45 (1H, app t, H13′), 3.55 (1H,
m, OH), 3.78 (1H, dd, H13′′, J ) 4.1, 10.6), 4.17 (2H, m, H9 and
15r-Hyd r oxy-17-p h en yl-18,19,20-tr in or p r osta gla n d in
F
2r Isop r op yl Ester [(15S)-1] a n d 15â-Hyd r oxy-17-p h en yl-
18,19,20-tr in or P GF 2r Isop r op yl Ester [(15R)-1]. A solu-
tion of 11 (1.36 g, 3.17 mmol) and cerium chloride heptahy-
drate (0.35 g, 0.95 mmol) in MeOH/CH2Cl2 (2:1, 50 mL) was
stirred at -78 °C for 30 min under N2. NaBH4 (72.0 mg, 1.90
mmol) was added in small portions to the stirred reaction
mixture during a period of 1 h. After being stirred at -78 °C
for 1 h, the reaction mixture was acidified with 1 M aqueous
HCl to pH 4 and concentrated. The crude product was
extracted with EtOAc (50 mL), washed with brine (2 × 20 mL)
and 3% aqueous citric acid (2 × 20 mL), dried (MgSO4), and
concentrated. The residue consisted of a diastereomeric
mixture of (15S)-1 and (15R)-1 (R and â isomers). The epimers
were separated by column chromatography (gradient system;
CH2Cl2/EtOAc 3:1 to EtOAc) which furnished 0.63 g (46%) of
isomerically pure (15R)-1 and 0.52 g (38%) of isomerically pure
(15S)-1.
(15R)-1: HPLC (8.5% ethanol in isohexane), 1.0 mL/min,
tR ) 16.0 min; TLC Rf ) 0.23 (EtOAc); [R]D +21.1 (c 0.98, CH3-
CN); 1H NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2), 1.51 (1H, m,
H8), 1.66 (2H, app quint, H3), 1.75-1,90 (3H, m, H10â and H16),
2.10-2.35 (6H, m, H10R, H4, H7 and H12), 2.26 (2H, app t, H2),
2.72 (2H, m, H17), 3.95 (1H, br m, H11), 4.11 (1H, br m, H15),
4.18 (1H, br m, H9), 4.99 (1H, sept, CH(CH3)2), 5.36 (1H, m,
H5), 5.44 (1H, m, H6), 5.51 (1H, m, H13), 5.63 (1H, m, H14),
7.15-7.31 (5H, m, aromatic protons). Anal. Calcd for C26H38O5‚
1/4H2O: C, 71.77; H, 8.80. Found: C, 71.7; H, 8.4.
(15S)-1: HPLC (8.5% ethanol in isohexane), 1.0 mL/min,
tR ) 17.9 min; TLC Rf ) 0.13 (EtOAc); [R]D +27.4 (c 1.2, CH3-
CN); 1H NMR (CDCl3) δ 1.20 (6H, d, CH(CH3)2), 1.46 (1H, m,
H8), 1.64 (2H, app quint, H3), 1.70 (1H, m, H10â), 1.79 (1H, m,
H16′), 1.91 (1H, m, H16′′), 2.08 (3H, m, H4 and H7′), 2.23 (2H,
app t, H2), 2.24 (2H, m, H7′′ and H10R), 2.33 (1H, m, H12), 2.67
(2H, m, H17), 3.88 (1H, m, H11), 4.07 (1H, m, H15), 4.13 (1H,
m, H9), 4.97 (1H, sept, CH(CH3)2), 5.35 (1H, m, H5), 5.43 (1H,
m, H6), 5.45 (1H, m, H13), 5.59 (1H, m, H14), 7.10-7.25 (5H,
m, aromatic protons). Anal. Calcd for C26H38O5: C, 72.52; H,
8.89. Found: C, 72.5; H, 8.8.
H
11), 5.00 (1H, sept, CH(CH3)2, J ) 6.3), 5.37-5.42 (1H, m,
H6), 5.42-5.49 (1H, m, H5). Anal. Calcd for C16H28O5: C,
63.98; H, 9.39. Found: C, 63.6; H, 9.35.
15-Keto-17-ph en yl-18,19,20-tr in or pr ostaglan din F 2r Iso-
p r op yl Ester (11). Phenylboronic acid (1.14 g, 9.39 mmol)
was added to a mixture of 9 (1.27 g, 4.23 mmol), CH2Cl2 (30
mL) and molecular sieves (3 Å). The solution was stirred for
20 min at room temperature. Pyridinium chlorochromate
(PCC; 3.0 g, 14.0 mmol) and Al2O3 (9.0 g) was mixed in a 250
mL roundbottom flask. Acetone (∼100 mL) was added, and
Ep oxid a tion of (15S)-1 Usin g (+)-L-Diisop r op yl Ta r -
tr a te. P r ep a r a tion of 13â,14â-Ep oxy-15r-h yd r oxy-17-
p h en yl-18,19,20-tr in or p r osta gla n d in F2r Isop r op yl Ester
[(15S)-2]. Titanium tetraisopropoxide (117 mg, 0.41 mmol)

17-Phenyl-18,19,20-trinorprostaglandin F2R Isopropyl Ester
J . Org. Chem., Vol. 61, No. 12, 1996 4033
and (+)-L-diisopropyl tartrate (116 mg, 0.49 mmol) were
dissolved in CH2Cl2 (3 mL, dried over MgSO4). The solution
was stirred with molecular sieves (3 Å) at 0 °C for 20 min
under N2. Phenylboronic acid (136 mg, 1.12 mmol) was added
to a stirred solution of (15S)-1 (219 mg, 0.51 mmol) in CH2Cl2
(2 mL). The mixture was stirred for 10 min and was then
added to the above cold solution under N2. After 20 min, tert-
butyl hydroperoxide (0.63 mL, 2.54 mmol, 4 M in toluene) was
added and the mixture was stirred for 10 min at 0 °C and then
at room temperature for 2 h. The mixture was diluted with
THF (5 mL) and treated with 30% aqueous H2O2 (0.5 mL).
After 10 min, cold 10% aqueous citric acid (5 mL) was added
and stirring was continued until the aqueous layer became
clear (∼20 min). The organic layer should be washed with a
saturated aqueous solution of Na2SO3. The organic layer was
washed with brine and aqueous NaHCO3, dried (MgSO4), and
concentrated by careful evaporation in vacuo at room temper-
ature. Column chromatography (EtOAc) gave 150 mg (66%)
of an oily product which is a diastereomeric mixture of (15S)-2
and (15S)-3. Analytical HPLC showed a 93% de of (15S)-2.
Separation by preparative HPLC (5% ethanol in isohexane)
gave 114 mg (50%) of isomerically pure (15S)-2 as an oil:
HPLC (9% ethanol in isohexane), 1.8 mL/min, tR ) 9.7 min;
TLC Rf ) 0.22 (EtOAc); [R]D +1.4 (c 1.2, CH3CN); 1H NMR
(CDCl3) δ 1.22 (6H, d, CH(CH3)2, J ) 6.4), 1.63 (1H, m, H8),
1.67 (2H, m, H3), 1.80 and 1.91 (2H, m, H16), 1.84 and 1.95
(2H, m, H10), 1.84 (1H, m, H12), 2.12 (2H, m, H4), 2.28 (2H,
app t, H2), 2.30 and 2.38 (2H, m, H7), 2.74 and 2.86 (2H, m,
H17), 2.86 (1H, dd, H14, J ) 2.2, 3.9), 3.03 (1H, dd, H13, J )
2.2, 6.4), 3.74 (1H, m, H15), 4.08 (1H, br m, H11), 4.21 (1H, br
m, H9), 4.99 (1H, sept, CH(CH3)2, J ) 6.4), 5.41 (1H, m, H5),
5.45 (1H, m, H6), 7.20 (3H, m, aromatic protons), 7.28 (2H, m,
aromatic protons). Anal. Calcd for C26H38O6: C, 69.9; H, 8.6.
Found: C, 69.6; H, 8.4.
Ep oxid a tion of (15S)-1 Usin g (-)-D-Diisop r op yl Ta r -
tr a te. P r ep a r a tion of (15S)-2 a n d 13r,14r-Ep oxy-15r-
h yd r oxy-17-p h en yl-18,19,20-tr in or p r osta gla n d in F 2r Iso-
p r op yl Ester [(15S)-3]. Compounds (15S)-2 and (15S)-3 were
prepared from (15S)-1 (214 mg, 0.50 mmol) using (-)-D-
diisopropyl tartrate by the above method. The reaction
mixture was stirred at 0 °C for 12 h and then at room
temperature for 4 h. The workup was done as above, and the
product was purified by column chromatography (EtOAc)
which furnished 136 mg (61%) of the product as a diastereo-
meric mixture of (15S)-3 and (15S)-2. Analytical HPLC
showed a 62% de of (15S)-3. Separation by preparative HPLC
(6% ethanol in isohexane) gave 98 mg (44%) of isomerically
pure (15S)-3 as an oil and 19 mg (8%) of isomerically pure
(15S)-2 as an oil.
1.65 (3H, m, H8 and H3), 1.77 (1H, m, H12), 1.80 and 1.91 (2H,
m, H16), 1.85 and 1.96 (2H, m, H10), 2.10 (2H, m, H4), 2.25 (2H,
app t, H2), 2.25 and 2.35 (2H, m, H7), 2.73 and 2.87 (2H, m,
H17), 2.91 (2H, m, H14 and H13), 3.74 (1H, m, H15), 4.18 (1H,
m, H11), 4.19 (1H, m, H9), 4.99 (1H, sept, CH(CH3)2, J ) 6.4),
5.40 (1H, m, H5), 5.45 (1H, m, H6), 7.20 (3H, m, aromatic
protons), 7.28 (2H, m, aromatic protons). Anal. Calcd for
C26H38O6: C, 69.9; H, 8.6. Found: C, 69.7; H, 8.7.
Ep oxid a tion of (15R)-1 Usin g (+)-L-Diisop r op yl Ta r -
tr a te. P r ep a r a tion of 13â,14â-Ep oxy-15â-h yd r oxy-17-
p h en yl-18,19,20-tr in or p r osta gla n d in F2r Isop r op yl Ester
[(15R)-2] a n d (15R)-3. Compound (15R)-2 and (15R)-3 were
prepared from (15R)-1 (241 mg, 0.56 mmol) using (+)-L-
diisopropyl tartrate by the above method. The reaction
mixture was stirred at 0 °C for 12 h and then at room
temperature for 4 h. The workup was done as above and the
product was purified by column chromatography (EtOAc)
which furnished 153 mg (61%) of the product as a diastereo-
meric mixture of (15R)-2 and (15R)-3. Analytical HPLC
showed a 22% de of (15R)-2. Separation by preparative HPLC
(4% ethanol in isohexane) gave 47 mg (19%) of isomerically
pure (15R)-3 as an oil and 52 mg (21%) of isomerically pure
(15R)-2 as an oil.
(15R)-2: HPLC (9% ethanol in isohexane), 1.8 mL/min, tR
) 10.7 min; TLC Rf ) 0.22 (EtOAc); [R]D +15.6 (c 1.1, CH3-
CN); 1H NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2, J ) 6.5), 1.61
(1H, m, H8), 1.68 (2H, m, H3), 1.86 and 1.92 (2H, m, H16), 1.88
(3H, m, H12 and H10), 2.12 (2H, m, H4), 2.27 (3H, m, H7′ and
H2), 2.38 (1H, m, H7′′), 2.72 and 2.82 (2H, m, H17), 2.86 (1H,
dd, H14, J ) 2.2, 4.7), 2.96 (1H, dd, H13, J ) 2.2, 6.4), 3.52
(1H, m, H15), 4.08 (1H, br m, H11), 4.22 (1H, br m, H9), 5.00
(1H, sept, CH(CH3)2, J ) 6.5), 5.40 (1H, m, H5), 5.45 (1H, m,
H6), 7.20 (3H, m, aromatic protons), 7.28 (2H, m, aromatic
protons). Anal. Calcd for C26H38O6: C, 69.9; H, 8.6. Found:
C, 69.8; H, 8.5.
13r,14â,15r-Tr ih yd r oxy-17-p h en yl-18,19,20-tr in or p r os-
ta gla n d in F 2r Isop r op yl Ester [(15S)-12]. Phenylboronic
acid (17.2 mg, 0.14 mmol) was added to a solution of (15S)-2
(28.6 mg, 0.064 mmol) in THF (0.3 mL) and molecular sieves
(3 Å) in a thin-necked Pyrex tube, sealed with a screw cap
fitted with a Teflon gasket. After 10 min, LiOH (3.1 mg, 0.13
mmol) was added, and the mixture was flushed with N2,
sealed, and stirred at 80 °C for 24 h. The reaction mixture
was diluted with THF (∼0.5 mL) and was then treated with
30% aqueous H2O2 (0.3 mL). After being stirred for 10 min,
the mixture was extracted with EtOAc (2 mL). The organic
layer should be washed with a saturated solution of Na2SO3.
The organic layer was washed with brine (2 mL), dried
(MgSO4), and concentrated by careful evaporation in vacuo at
room temperature. Column chromatography (gradient sys-
tem: EtOAc to EtOAc/acetone 2:1) afforded 17.8 mg (59%) of
isomerically pure (15S)-12 as an oil: HPLC (9% ethanol in
(15S)-3: HPLC (9% ethanol in isohexane), 1.8 mL/min, tR
) 12.2 min; TLC Rf ) 0.22 (EtOAc); [R]D +42.0 (c 1.0, CH3-
CN); 1H NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2, J ) 6.1), 1.64
(1H, m, H8), 1.66 (2H, m, H3), 1.79 (1H, m, H12), 1.84 and 1.90
(2H, m, H16), 1.84 and 1.96 (2H, m, H10), 2.09 (2H, m, H4), 2.20
(1H, m, H7′), 2.24 (2H, app t, H2), 2.36 (1H, m, H7′′), 2.72 and
2.81 (2H, m, H17), 2.86 (1H, dd, H13, J ) 2.2, 6.7), 2.93 (1H,
dd, H14, J ) 2.2, 4.6), 3.54 (1H, m, H15), 4.15 (1H, br m, H11),
4.19 (1H, br m, H9), 4.99 (1H, sept, CH(CH3)2, J ) 6.1), 5.39
(1H, m, H5), 5.43 (1H, m, H6), 7.20 (3H, m, aromatic protons),
7.28 (2H, m, aromatic protons). Anal. Calcd for C26H38O6: C,
69.9; H, 8.6. Found: C, 69.6; H, 8.4.
isohexane), 1.8 mL/min, tR
) 18.3 min; TLC Rf ) 0.12 (EtOAc);
[R]D +16.2 (c 0.80, CH3CN); 1H NMR (CD3OD) δ 1.20 (6H, dd,
CH(CH3)2, J ) 1.5, 6.4), 1.65 (2H, app quint, H3), 1.76 (1H, m,
H
10â), 1.82 (1H, m, H16′), 1.92 (2H, m, H16′′ and H8), 1.97 (1H,
m, H10R), 2.13 (3H, m, H4 and H12), 2.27 (2H, app t, H2), 2.31
and 2.38 (2H, m, H7′ and H7′′), 2.65 (1H, m, H17′), 2.79 (1H, m,
H17′′), 3.37 (1H, dd, H14, J ) 1.6, 8.6), 3.82 (1H, dd, H13, J )
3.6, 8.6), 3.91 (1H, ddd, H15, J ) 1.6, 4.6, 8.8), 4.06 (1H, m,
H11), 4.13 (1H, app quart, H9), 4.94 (1H, sept, CH(CH3)2, J )
6.4), 5.35 (1H, m, H5), 5.59 (1H, m, H6), 7.13 (1H, m, aromatic
proton), 7.23 (4H, m, aromatic protons). Anal. Calcd for
C26H40O7: C, 67.21; H, 8.68. Found: C, 67.17; H, 8.66.
13â,14r,15r-Tr ih yd r oxy-17-p h en yl-18,19,20-tr in or p r os-
ta gla n d in F 2r Isop r op yl Ester [(15S)-13]. Isomerically pure
(15S)-13 was prepared from (15S)-3 by the above method in
56% yield as an oil: HPLC (9% ethanol in isohexane), 1.8 mL/
min, tR ) 12.6 min; TLC Rf ) 0.19 (EtOAc); [R]D +18.9 (c 0.53,
CH3CN); 1H NMR (CD3OD) δ 1.21 (6H, d, CH(CH3)2, J ) 6.1),
1.65 (2H, app quint, H3), 1.67 (1H, m, H10â), 1.74 (1H, m, H16′),
1.76 (1H, m, H8), 2.03 (1H, m, H16′′), 2.08 (1H, m, H10R), 2.12
(3H, m, H4 and H12), 2.16 (1H, m, H7′), 2.26 (3H, m, H2 and
Ep oxid a tion of (15R)-1 Usin g (-)-D-Diisop r op yl Ta r -
tr a te. P r ep a r a tion of 13r,14r-Ep oxy-15â-h yd r oxy-17-
p h en yl-18,19,20-tr in or p r osta gla n d in F2r Isop r op yl Ester
[(15R)-3]. Compound (15R)-3 was prepared from (15R)-1 (163
mg, 0.38 mmol) using (-)-D-diisopropyl tartrate by the above
method. The reaction mixture was stirred at 0 °C for 10 min
and then at room temperature for 2 h. The workup was done
as above and the product was purified by column chromatog-
raphy (EtOAc) which furnished 130 mg (76%) of the product
as a diastereomeric mixture of (15R)-2 and (15R)-3. Analytical
HPLC showed a 92% de of (15R)-3. Separation by preparative
HPLC (5% ethanol in isohexane) gave 90 mg (53%) of isomeri-
cally pure (15R)-3: HPLC (9% ethanol in isohexane), 1.8 mL/
min, tR ) 10.4 min; TLC Rf ) 0.22 (EtOAc); [R]D +55.8 (c 0.98,
H7′′), 2.64 (1H, m, H17′), 2.86 (1H, m, H17′′), 3.60 (1H, dd, H14
,
J ) 6.7, 7.0), 3.71 (1H, ddd, H15, J ) 2.4, 6.7, 9.4), 3.82 (1H,
dd, H13, J ) 2.0, 7.0), 4.10 (1H, m, H9), 4.30 (1H, ddd, H11, J
1
CH3CN); H NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2, J ) 6.4),

4034 J . Org. Chem., Vol. 61, No. 12, 1996
Liljebris et al.
) 3.7, 6.1, 8.0), 4.95 (1H, sept, CH(CH3)2), 5.36 (1H, m, H5),
5.54 (1H, m, H6), 7.13 (1H, m, aromatic proton), 7.23 (4H, m,
aromatic protons). Anal. Calcd for C26H40O7: C, 67.21; H,
8.68. Found: C, 66.95; H, 8.62.
10.2 min; TLC Rf ) 0.54 (EtOAc); [R]D +34.2 (c 0.87, CH3CN);
1H NMR (CDCl3) δ 1.22 (6H, d, CH(CH3)2, J ) 6.3), 1.66 (2H,
app quint, H3), 1.73-1.85 (3H, m, H8 and H10), 1.94 (1H, m,
H16′), 2.08 (2H, app q, H4), 2.2-2.3 (5H, m, H7′, H2, H16′′ and
H12), 2.33 (1H, m, H7′′), 2.72 (1H, m, H17′), 2.89 (1H, m, H17′′),
3.38 (1H, dd, H14, J ) 4.9, 5.9), 3.76 (1H, dd, H13, J ) 4.9,
8.2), 3.87 (1H, br m, H11), 4.05 (1H, m, H15), 4.17 (1H, br m,
H9), 5.00 (1H, sept, CH(CH3)2, J ) 6.3), 5.37 (1H, m, H5), 5.45
(1H, m, H6), 7.18-7.43 (10H, m, aromatic protons). Anal.
Calcd for C32H44O6S‚3/4H20: C, 67.40; H, 8.21. Found: C,
67.32; H, 7.73.
13r,14â,15â-Tr ih yd r oxy-17-p h en yl-18,19,20-tr in or p r os-
ta gla n d in F 2r Isop r op yl Ester [(15R)-12]. Isomerically
pure (15R)-12 was prepared from (15R)-2 by the above method
in 52% yield as an oil: HPLC (9% ethanol in isohexane), 1.8
mL/min, tR ) 13.9 min; TLC Rf ) 0.22 (EtOAc); [R]D +32.7 (c
0.85, CH3CN); 1H NMR (CD3OD) δ 1.20 (6H, dd, CH(CH3)2, J
) 6.1, 6.1), 1.65 (2H, app quint, H3), 1.75 (2H, m, H10â and
H16′), 1.98 (3H, m, H10R, H16′′ and H8), 2.13 (3H, m, H4 and H12),
2.29 (2H, app t, H2), 2.35 (2H, m, H7), 2.65 (1H, m, H17′), 2.89
(1H, m, H17′′), 3.45 (1H, dd, H14, J ) 5.5, 8.5), 3.74 (1H, dd,
H13, J ) 3.3, 8.5), 3.77 (1H, ddd, H15, J ) 2.4, 5.5, 8.2), 4.06
(1H, ddd, H11, J ) 4.3, 6.1, 8.5), 4.13 (1H, m, H9), 4.95 (1H,
sept, CH(CH3)2), 5.36 (1H, m, H5), 5.59 (1H, m, H6), 7.13 (1H,
m, aromatic proton), 7.23 (4H, m, aromatic protons). Anal.
Calcd for C26H40O7‚1/4H2O: C, 66.57; H, 8.70. Found: C, 66.57;
H, 8.62.
13â,14r,15â-Tr ih yd r oxy-17-p h en yl-18,19,20-tr in or p r os-
ta gla n d in F 2r Isop r op yl Ester [(15R)-13]. Isomerically
pure (15R)-13 was prepared from (15R)-3 by the above method
in 60% yield as an oil: HPLC (9% ethanol in isohexane), 1.8
mL/min, tR ) 11.2 min; TLC Rf ) 0.17 (EtOAc); [R]D +46.6 (c
0.90, CH3CN); 1H NMR (CD3OD) δ 1.21 (6H, d, CH(CH3)2),
1.65 (2H, app quint, H3), 1.70 (1H, m, H10â), 1.79 (1H, m, H8),
1.81 (1H, m, H16′), 1.91 (1H, m, H16′′), 2.04 (1H, m, H10R), 2.12
(3H, m, H4 and H12), 2.17 (1H, m, H7′), 2.27 (3H, m, H2 and
13r,15r-Dih yd r oxy-14â-(p h en ylth io)-17-p h en yl-18,19,-
20-tr in or p r osta gla n d in F 2r Isop r op yl Ester [(15S)-16].
Isomerically pure (15S)-16 was prepared from (15S)-3 by the
above method in 66% yield as an oil: HPLC (8.5% ethanol in
isohexane), 1.0 mL/min, tR ) 10.8 min; TLC Rf ) 0.45 (EtOAc);
1
[R]D +13.8 (c 0.89, CH3CN); H NMR (CDCl3) δ 1.20 (6H, dd,
CH(CH3)2, J ) 2.3, 6.2), 1.66 (2H, m, H3), 1.75 (1H, m, H8),
1.8-1.9 (2H, m, H10), 1.95 (1H, m, H16′), 2.05 (2H, m, H4), 2.21
(3H, m, H16′′ and H7), 2.27 (2H, app t, H2), 2.39 (1H, m, H12),
2.70 (1H, m, H17′), 2.85 (1H, m, H17′′), 3.40 (1H, dd, H14, J )
6.0, 8.9), 3.83 (1H, br m, H13), 4.05 (1H, br m, H15), 4.18 (1H,
br m, H9), 4.30 (1H, br m, H11), 4.94 (1H, sept, CH(CH3)2, J )
6.2), 5.38 (1H, m, H5), 5.53 (1H, m, H6), 7.15-7.48 (10H, m,
aromatic protons). Anal. Calcd for C32H44O6S: C, 69.04; H,
7.97. Found: C, 68.82; H, 7.84.
14r,15â-Dih yd r oxy-13â-(p h en ylth io)-17-p h en yl-18,19,-
20-tr in or p r osta gla n d in F 2r Isop r op yl Ester [(15R)-17]
a n d 13r,15â-Dih yd r oxy-14â-(p h en ylth io)-17-p h en yl-18,-
19,20-tr in or p r osta gla n d in F 2r Isop r op yl Ester [(15R)-16].
Compounds (15R)-17 and (15R)-16 were prepared from (15R)-3
by the above method, but with a reaction time of 3 days. This
gave a total yield of 35%. Analytical HPLC on the crude
product showed that the diastereomeric relationship was 69:
31 (15R)-17:(15R)-16. Separation by column chromatography
(gradient system: CH2Cl2 to CH2Cl2:EtOAc 5:1) furnished 11%
of isomerically pure (15R)-16 as an oil and 14% of isomerically
pure (15R)-17 as an oil.
(15R)-17: HPLC (8.5% ethanol in isohexane), 1.0 mL/min,
tR ) 12.1 min; TLC Rf ) 0.47 (EtOAc); [R]D +33.7 (c 0.89, CH3-
CN); 1H NMR (CDCl3) δ 1.23 (6H, d, CH(CH3)2, J ) 6.3), 1.68
(4H, m, H3 and H16), 1.88 (2H, m, H10â and H8), 2.13 (3H, m,
H10R and H4), 2.30 (4H, m, H2, H7′ and H17′), 2.52 (2H, m, H7′′
and H12), 2.73 (1H, m, H17′′), 3.62 (1H, dd, H13, J ) 3.3, 7.3),
3.74 (1H, m, H14), 3.97 (1H, br m, H15), 4.24 (2H, br m, H9 and
H11), 5.00 (1H, sept, CH(CH3)2, J ) 6.3), 5.41 (1H, m, H5), 5.49
(1H, m, H6), 6.99-7.43 (10H, m, aromatic protons). Anal.
Calcd for C32H44O6S: C, 69.04; H, 7.97. Found: C, 68.97; H,
7.93.
(15R)-16: HPLC (8.5% ethanol in isohexane), 1.0 mL/min,
tR ) 11.0 min; TLC Rf ) 0.51 (EtOAc); [R]D +44.6 (c 0.63, CH3-
CN); 1H NMR (CDCl3) δ 1.20 (6H, d, CH(CH3)2, J ) 6.2), 1.66
(2H, m, H3), 1.76 (1H, m, H8), 1.87 (2H, m, H10), 2.05 (2H, m,
H16), 2.10 (3H, m, H4 and H7′), 2.27 (3H, m, H2 and H7′′), 2.36
(1H, m, H12), 2.64 (1H, m, H17′), 2.82 (1H, m, H17′′), 3.45 (1H,
dd, H14, J ) 2.0, 8.5), 3.86 (1H, m, H13), 4.18 (1H, br m, H15),
4.20 (1H, br m, H9), 4.38 (1H, br m, H11), 4.96 (1H, sept,
CH(CH3)2, J ) 6.2), 5.38 (1H, m, H5), 5.49 (1H, m, H6), 7.12-
7.48 (10H, m, aromatic protons). Anal. Calcd for C32H44O6S:
C, 69.04; H, 7.97. Found: C, 68.80; H, 7.87.
H7′′), 2.68 (1H, m, H17′), 2.82 (1H, m, H17′′), 3.52 (1H, dd, H14
,
J ) 2.5, 7.9), 3.80 (1H, dd, H13, J ) 2.1, 7.9), 3.84 (1H, m,
H15), 4.10 (1H, m, H9), 4.28 (1H, m, H11), 4.96 (1H, sept,
CH(CH3)2), 5.36 (1H, m, H5), 5.53 (1H, m, H6), 7.13 (1H, m,
aromatic proton), 7.23 (4H, m, aromatic protons). Anal. Calcd
for C26H40O7‚1/4H2O: C, 66.57; H, 8.70. Found: C, 66.65; H,
8.59.
14â,15r-Dih yd r oxy-13r-(p h en ylth io)-17-p h en yl-18,19,-
20-tr in or p r osta gla n d in F 2r Isop r op yl Ester [(15S)-14]. A
solution of thiophenol (38.8 µL, 0.38 mmol) and sodium
methoxide (20.4 mg, 0.38 mmol) in ethanol (99.6%, 0.8 mL)
was stirred at 45 °C for 30 min. A solution of phenylboronic
acid (33.7 mg, 0.28 mmol) and (15S)-2 (56.2 mg, 0.13 mmol)
in THF (0.8 mL) was stirred for 10 min. The protected epoxide
was added to the above thiophenolate solution, and the
mixture was stirred at 45 °C overnight. The reaction mixture
was allowed to reach room temperature and was then treated
with 30% aqueous H2O2 (0.75 mL). After stirring for 10 min,
a saturated aqueous solution of Na2SO3 (1 mL) was added,
and the mixture was stirred vigorously until all H2O2 was
reduced (∼30 min). The product was extracted with EtOAc,
washed with brine, dried (MgSO4), and concentrated. Column
chromatography (gradient system: CH2Cl2/EtOAc 3:1 to EtOAc)
afforded 36.3 mg (52%) of isomerically pure (15S)-16 as an
oil: HPLC (8.5% ethanol in isohexane), 1.0 mL/min, tR ) 10.2
1
min; TLC Rf ) 0.31 (EtOAc); [R]D +47.7 (c 1.01, CH3CN); H
NMR (CDCl3) δ 1.21 (6H, d, CH(CH3)2, J ) 6.3), 1.63 (2H, m,
H3), 1.68 (1H, m, H16′), 1.77 (1H, m, H10â), 1.83 (1H, m, H16′′),
2.0-2.1 (4H, m, H7′, H8, and H4), 2.15 (1H, m, H10R), 2.22 (2H,
app t, H2), 2.28 (1H, m, H7′′), 2.50 (1H, m, H17′), 2.55 (1H, m,
H12), 2.81 (1H, m, H17′′), 3.60 (1H, m, H13), 3.87 (1H, m, H14),
3.98 (1H, m, H15), 4.16 (1H, m, H9), 4.25 (1H, m, H11), 4.98
(1H, sept, CH(CH3)2, J ) 6.3), 5.35 (2H, m, H5 and H6), 7.1-
7.55 (10H, m, aromatic protons). Anal. Calcd for C32H44O6S:
C, 69.04; H, 7.97. Found: C, 68.86; H, 7.98
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectro-
scopic data and peak assignment of all compounds (7 pages).
This material is contained in libraries on microfiche, im-
mediately follows this article in the microfilm version of the
journal, and can be ordered from ACS; see any current
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13â,15â-Dih yd r oxy-14r-(p h en ylth io)-17-p h en yl-18,19,-
20-t r in or p r ost a gla n d in F 2r Isop r op yl E st er [(15R)-15].
Compound (15R)-15 was prepared from (15R)-2 with the above
method, but with a reaction time of 3 days, and in a total yield
of 33%: HPLC (8.5% ethanol in isohexane), 1.2 mL/min, tR
)
J O960098T