Synthesis of prostaglandin E2 methyl ester on a soluble-polymer support for the construction of prostanoid libraries

Full text of DOI:10.1021/ja971634h

8724
J. Am. Chem. Soc. 1997, 119, 8724-8725
Synthesis of Prostaglandin E2 Methyl Ester on a
Soluble-Polymer Support for the Construction of
Prostanoid Libraries
Shaoqing Chen and Kim D. Janda*
Department of Chemistry, The Scripps Research Institute
and Skaggs Institute for Chemical Biology
10550 North Torrey Pines Road, La Jolla, California 92037
ReceiVed May 20, 1997
Figure 1.
The prostaglandin family of natural products constitute
perhaps the most physiologically potent nonprotein molecules
found in mammals. They play a vital role in the processes of
inflammation, tissue repair, and immune response.1 Given their
enormous potential therapeutic benefits, extensive efforts have
been directed at the design and synthesis of pharmacologically
useful analogues.2 The screening of large numbers of com-
pounds would greatly improve the probability of finding
appropriate biological activity.
Combinatorial chemistry has developed into an important tool
for drug discovery.3 However, to fully empower this technol-
ogy, it remains necessary to adapt the construction of more
complicated reactions and molecules to the solid-phase,4 liquid-
phase,5 or fluorous system6 methods. Prostaglandins represent
a challenging target and have served as a proving ground for
new synthetic strategies for over 3 decades. The preeminent
approaches that have been applied to the assembly of the
prostaglandin framework are the linear/multistep Corey-type
plan,7 the two-component process,8 and the three-component
coupling methodology.9 The convergent nature and synthetic
flexibility of the three-component synthesis pioneered by Noyori,
and then modified by others,10 is often the most desirable.
Herein, we report the application of a three-component coupling
strategy10a in the efficient liquid-phase synthesis of PGE2.
Two principal formats for a polymer-supported prostaglandin
synthesis can be conceptualized. The three components A, B,
and C represent, respectively, the cyclopentanoid ring, the
R-chain, and the ω-chain of a prostaglandin derivative. We
have chosen to exploit strategy I in our current research. To
Figure 2. Chemical building blocks used in the construction of PGE2
methyl ester.
this end, a set of chemical building blocks were selected for
the construction of PGE2 methyl ester.11 The choice of a
suitable support was the key step in the design in that it required
compatibility with some extreme reaction and workup condi-
tions.12 Poly(ethylene glycol) (PEG) has been shown to be an
excellent polymer for liquid-phase synthesis.5 However, PEG
was not applicable here due to its low solubility in tetrahydro-
furan (THF) at the low temperatures (-78 °C) necessary in the
synthesis. PEG also poses a problem during the removal of
excess organometallic reagents and inorganic materials due to
its water solubility. Hence, a soluble non-cross-linked chlo-
romethylated polystyrene (NCPS) previously used for peptide
synthesis13 was investigated as a support in the prostaglandin
synthesis. This copolymer is readily prepared and the functional
group content easily controlled, and then quantified via NMR,
by using varying ratios of starting monomers. Non-cross-linked
polystyrene has remarkable solubility properties that are ame-
nable to organic chemistry. It is soluble in THF, dichlo-
romethane, chloroform, and ethyl acetate even at low temper-
atures (-78 °C) and is insoluble in water and methanol. These
features allow implementation of solvent extraction techniques
used in traditional organic synthesis in conjunction with the
polymer crystallization techniques currently used in the PEG
liquid-phase approach.5 Consequently, after the homogeneous
reaction of supported intermediates, the polymer-bound products
can be diluted with dichloromethane or ethyl acetate and the
organic layer subjected to the usual aqueous extractions.
Methanol is then used to precipitate the polymer and its uniquely
bound product as a solid to remove excess reactants and
* To whom correspondence should be addressed.
(1) Samuelsson, B.; Paoletti, R. AdVances in Prostaglandin, Thrombox-
ane, and Leukotriene Research; Raven: New York, 1983-1989; Vols. 11-
19.
(2) Collins, P. W.; Djuric, S. W. Chem. ReV. 1993, 93, 1533.
(3) Reviews: (a) Chaiken, I. M.; Janda, K. D. Molecular DiVersity and
Combinatorial Chemistry: Libraries and Drug DiscoVery; Chaiken, I. M.,
Janda, K. D., Eds.; American Chemistry Society: Washington, DC, 1996.
(b) Balkenhohl, F.; von dem Bussche-Hunnefeld, C.; Lansky, A.; Zechel,
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288. (c) Terrett, N. K.; Gardner,
M.; Gordon, D. W.; Kobylecki, R. J.; Steel, J. Tetrahedron 1995, 51, 8135.
(d) Liskamp, R. M. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 633. (e)
Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E.
M. J. Med. Chem. 1994, 37, 1233. (f) Gordon, E. M.; Barrett, R. W.; Dower,
W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
(4) (a) Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996, 96, 555. (b)
Ellman, J. A. Acc. Chem. Res. 1996, 29, 132. (c) Armstrong, R. W.; Combs,
A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996,
29, 123.
(5) (a) Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc. Natl.
Acad. Sci. U.S.A. 1995, 92, 6419. (b) Han, H.; Janda, K. D. J. Am. Chem.
Soc. 1996, 118, 2539. (c) Han, H.; Janda, K. D. J. Am. Chem. Soc. 1996,
118, 7632. (d) Gravert, D. J.; Janda, K. D. Chem. ReV. 1997, 97, 489. (e)
Zhao, X.-Y.; Jung, K. W.; Janda, K. D. Tetrahedron Lett. 1997, 38, 977.
(f) Han, H.; Janda, K. D. Tetrahedron Lett. 1997, 38, 1527.
(6) (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531. (b)
Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran,
D. P. Science 1997, 275, 823.
(11) PGE2 itself contains a free carboxylic acid on the R-chain. A variety
of acid and ester analogues will be desirable for preparation of libraries.
Here we chose to construct the methyl ester derivative since the R-chain
precursor was known in the literature. Synthesis of natural PGE2 would
entail utilization of an R-chain building block protected as an ester (i.e.,
trimethylsilyl ethyl) that could be cleanly removed under our subsequent
deprotection conditions. Alternatively, methyl ester derivatives could be
hydrolyzed by lipases (See ref 8a and Tanaka, T.; Toru, T.; Okamura, N.;
Hazato, A.; Sugiura, S.; Manabe, K.; Kurozumi, S.; Suzuki, M.; Kawagishi,
T.; Noyori, R. Tetrahedron Lett. 1983, 24, 4103).
(12) A review article (ref 3b) describes Ellman and co-workers approach
using insoluble matrices for the synthesis of prostaglandin analogues. See
also: Thompson, L. A.; Ellman, J. A. 209th ACS National Meeting
Anaheim, CA, 1995; Poster ORGN 262.
(7) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am.
Chem. Soc. 1969, 91, 5675.
(8) (a) Sih, C. J.; Price, P.; Sood, R.; Salomon, R. G.; Peruzzotti, G.;
Casey, M. J. Am. Chem. Soc. 1972, 94, 3643. (b) Sato, F.; Tsujiyama, H.;
Ono, N.; Yoshino, T.; Okamuko, S. Tetrahedron Lett. 1990, 4481.
(9) (a) Noyori, R.; Suzuki, M. Chemtracts: Org. Chem. 1990, 173. (b)
Suzuki, M.; Morita, Y.; Koyano, H.; Koga, M.; Noyori, R. Tetrahedron
1990, 46, 4809.
(13) (a) Narita, M.; Hirata, M.; Kusano, K.; Itsuno, S.-I.; Ue, M.;
Okawara, M. Peptide Chemistry; Yonehara, H., Ed.; Protein Research
Foundation: Osaka, 1979; pp 107-112. (b) Narita, M. Bull, Chem. Soc.
Jpn. 1978, 51, 1477.
(10) (a) Gooding, O. W. J. Org. Chem. 1990, 55, 4209. (b) Johnson, C.
R.; Braun, M. P. J. Am. Chem. Soc. 1993, 115, 11014. (c) Lipshutz, B. H.;
Wood, M. R. J. Am. Chem. Soc. 1994, 116, 11689.
S0002-7863(97)01634-X CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 37, 1997 8725
byproducts. This is especially important for modern syntheses
that utilize a host of organic and organometallic reagents.
Finally, because NCPS is a soluble polymer, NMR analysis of
all intermediates may be accomplished in a nondestructive
manner without the need for any specialized NMR techniques
or equipment currently used in solid-phase synthesis.14
Scheme 1a
The NCPS was prepared by the copolymerization of styrene
with 4-(chloromethyl)styrene (3 mol %) in the presence of 2,2′-
azobis(isobutyronitrile) (AIBN) in benzene at 70 °C for 40 h.
The loading value obtained and used for yield calculations in
the prostaglandin synthesis was 0.3 mmol/g. The synthesis of
PGE2 methyl ester on this support is outlined in Scheme 1. The
polymer 4 was dissolved in dimethylacetamide and treated with
the sodium salt of 6-(hydroxymethyl)-3,4-dihydro-2H-pyran at
room temperature.15 The DHP-modified polymer was extracted
with dichloromethane and washed with brine. After concentra-
tion of the organic layer, the polymer 5 was precipitated with
methanol and approximately 100% of the polymer was recov-
ered. Significantly, the polymer mass balance for each subse-
quent step in the synthesis was g97%. Furthermore, only a
single polymer-bound species was detected by NMR in all cases.
(R)-(+)-4-Hydroxy-2-cyclopenten-1-one (1)16 was then at-
tached to 5 through the hydroxyl group in the presence of PPTS
in dichloromethane at 40 °C. The product was obtained using
extraction and precipitation techniques (Vide supra). The NMR
spectrum indicated that the reaction was complete after 16 h.
The vinylstannane ω-chain building block 2 was synthesized
from the corresponding alkyne,17 and the triflate R-chain
fragment 310a was prepared from the alcohol.18 With the three
components of the prostaglandin in hand, 2, was added to the
polymer-bound cyclopentenone 6 and Li2CuCNMe2 in THF at
-78 °C. The resulting enolate was converted to a stable and
isolable enol silyl ether intermediate upon treatment with
chlorotrimethylsilane and triethylamine. Following our de-
scribed combination workup (Vide supra), the stable, pure
polymer-bound product 7 was obtained. After addition of MeLi
to 7 in THF at -23 °C, the enolate intermediate was trapped
with the highly reactive triflate 3. The standard workup afforded
the complete 20-carbon prostaglandin framework 8 linked to
NCPS. This acetylenic intermediate has been a valuable
compound for the general synthesis of a wide spectrum of
prostanoids.19
a Reagents and conditions: (a) 3 equiv of 6-(hydroxymethyl)-3,4-
dihydro-2H-pyran, 3.3 equiv of NaH, dimethylacetamide, rt, 24 h; (b)
3 equiv of 1, 0.5 equiv of PPTS, CH2Cl2, 40 °C, 16 h; (c) 4.2 equiv of
2, 3.9 equiv of Li2CuCNMe2, THF, -78 °C, 15 min; (d) 15 equiv of
chlorotrimethylsilane, -78 °C, 30 min; 30 equiv of triethylamine, 0
°C, 15 min; (e) 3 equiv of MeLi, THF, -23 °C, 20 min; (f) 6 equiv of
3, -78 °C, 10 min; -23 °C, 30 min; (g) H2, 5% Pd-BaSO4, quinoline,
benzene/cyclohexane (1:1), 48 h; (h) 48% aqueous HF/THF (3:20, v/v),
45 °C, 6 h.
of the C4 and C7 protons were clearly observed.
The cleavage of PGE2 methyl ester from the support must
be compatible with the sensitive â-ketol configuration. While
several methods have been employed for THF-modified resins,3b,15
here they resulted in partial or complete elimination of the C11
hydroxyl group. Several other THP deprotection conditions
such as AcOH/THF/H2O or Amberite20 gave incomplete and
unclean reactions. Finally, it was discovered that 48% aqueous
HF-THF (3:20 v/v) at 45 °C for 6 h, used for removal of the
TBS protecting group,21 also afforded efficient liberation of the
product. A saturated NaHCO3 wash removed HF. After
removal of polymeric material by precipitation, the crude
product showed only one major spot on TLC and contained
<2% of the dehydration byproduct as measured by NMR. Flash
chromatography afforded pure PGE2 methyl ester 10, identical
to an authentic sample.22,23The overall yield was 37% for the
eight chemical steps starting from 4.24
We have shown that it is possible to prepare a complex natural
product through liquid-phase synthesis. In addition, the NCPS
method will complement the previous PEG-based approach for
the construction of combinatorial libraries. The “convergent
generation of diversity” from a “toolbox” of prostanoid com-
ponents (enones, R-chains, and ω-chains), augmented with
additional polymer-bound transformations, will enable the
assembly of large arrays of potentially valuable compounds.
Partial hydrogenation of the acetylenic bond at the C5-C6
position (prostaglandin numbering) was accomplished over 5%
Pd/BaSO4 and gave the Z alkene 9. Since NCPS is soluble in
the benzene/cyclohexane reaction solvent, NMR could be used
to follow the progress of the reduction. Both the appearance
of the olefinic C5-C6 protons and the chemical shift change
(14) (a) Fitch, W. L.; Detre, G.; Holmes, C. P.; Shoolery, J. N.; Keifer,
P. A. J. Org. Chem. 1994, 59, 7955. (b) Keifer, P. A. J. Org. Chem. 1996,
61, 1558. (c) Wehler, T.; Westman, J. Tetrahedron Lett. 1996, 37, 4771.
(d) Pop, I. E.; Dhalluin, C. F.; Deprez, B. P.; Melnyk, P. C.; Lippens, G.
M.; Tartar, A. L. Tetrahedron 1996, 52, 12209.
(15) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333.
(16) Paquette, L. A.; Earle, M. J.; Smith, G. F. Org. Synth. 1995, 73,
36.
(17) Corey, E. J.; Niimura, K.; Konishi, Y.; Hashimoto, S.; Hamada, Y.
Tetrahedron Lett. 1986, 27, 2199.
(18) Casy, G.; Patterson, J. W.; Taylor, R. J. K. Org. Synth. 1993, Collect.
Vol. VIII, 415.
(19) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984, 23, 847.
(20) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis; John Wiley & Sons, Inc.: New York, 1991; pp 31-34.
(21) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981.
(22) Authentic PGE2 methyl ester was obtained from Sigma Chemical.
(23) Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1988, 110, 4726.
(24) The yield was calculated according to the method used for solid-
phase peptide synthesis: Hence, starting with 1 g of polymer 4 (0.3 mmol/g
of loading) should result in theoretical return of 1.2 g of polymer 9 by
accounting for the increase in the molecular weight and assuming 100%
recovery. After cleavage of product, this would afford a maximum yield of
110 mg of PGE2 methyl ester. We recovered 95% of the polymer mass
through 9 at which stage 0.2 g was used for cleavage. This resulted in 7
mg of final purified PGE2 methyl ester (18 mg theoretical) for a calculated
yield of 37% (7 mg/18 mg × 0.95).
Acknowledgment. We thank Dr. Peter Wirsching for insightful
discussions and Professor Dale Boger for critical reading of the
manuscript. This work was supported in part by the Scripps Research
Institute, the R. W. Johnson Pharmaceutical Research Institute, and
the Skaggs Institute for Chemical Biology.
Supporting Information Available: Synthetic details and spectral
data for compounds 4-10 (13 pages). See any current masthead page
for ordering and Internet access instructions.
JA971634H