Formal synthesis of antiplatelet drug, beraprost

Article abstract of DOI:10.1021/ol203060v

The first stereocontrolled and enantiospecific formal synthesis of antiplatelet drug beraprost has been achieved from readily available 1-tetralone.

Full text of DOI:10.1021/ol203060v

ORGANIC
LETTERS
2012
Vol. 14, No. 1
299–301
Formal Synthesis of Antiplatelet Drug,
Beraprost
Naredla Kesava Reddy, Bodduri Venkata Durga Vijaykumar, and
Srivari Chandrasekhar*
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical
Technology, Hyderabad, India 500 007
*srivaric@iict.res.in
Received November 14, 2011
ABSTRACT
The first stereocontrolled and enantiospecific formal synthesis of antiplatelet drug beraprost has been achieved from readily available 1-tetralone.
Prostacyclin (PGI2, Figure 1) has been a prime synthetic
target for researchers, ever since its discovery, due to its
excellent ability to inhibit platelet aggregation and
vasodilation.1 The biggest problem associated with hand-
ling these classes of compounds is their very labile nature,
even in neutral media, due to the ‘enol’ functionality, let
alone the acidic medium of the gastrointestinal tract.2
Thus, the design, synthesis, and evaluation of stable
analogs of PGI2 has been a primary objective of scientists
engaged in this field. Toray industries have come up with
a very stable form of PGI2 and named it beraprost (1).
The researchers from Toray have developed beraprost
as a drug for the treatment of platelet aggregation.3 It is
less toxic and more stable than other PGI2 analogs and
sold in the market as Careload (sodium salt of beraprost).4
The commercial route used to manufacture this drug
involves brominationꢀdebromination steps and resolu-
tion for obtaining the chiral tricyclic cyclopenta[b]
benzofuran core.5 Other approaches have also been re-
ported in literature for the construction of this core for
beraprost synthesis.6
The profound clinical use, the difficulty associated with
construction of the tricyclic core with full enantiocontrol,
and the synthetic challenges posed by the beraprost
structure encouraged us to take up its total synthesis.
(1) (a) Moncada, S.; Grygleski, S.; Bunting, S.; Vane, J. R. Nature
1976, 263, 663. (b) Johnson, R. A.; Morton, D. R.; Kinner, J. H.;
Gorman, R. R.; McGuire, J. C.; Sun, F. F.; Whittaker, N.; Bunting, S.;
Salmon, J.; Moncada, S.; Vane, J. R. Prostaglandins 1976, 12, 915. (c)
Johnson, R. A.; Lincoln, F. H.; Nidy, E. G.; Schneider, W. P.; Thompson,
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Nickolson, R. C.; Town, M. H.; Vorbruggen, H. J. Med. Res. Rev. 1985,
5, 1. (c) Ansoff, P. A. Adv. Prostaglandin Thromboxane Leukotriene Res.
1985, 14, 309.
Figure 1. Structure of prostacyclin (PGI2).
Our retrosynthesis of beraprost (Scheme 1) used an
oxa-Michael reaction to dissect the AB ring system.7
This was allied with a stereoselective IrelandꢀClaisen
rearrangement8 and a Grubbs metathesis based enone
(4) Nagase, H.; Matsumo, K.; Nishiya, H. J. Synth. Org. Chem. 1996,
54, 1055.
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R.; Nishiyama, H.; Nagase, H. Tetrahedron 1999, 55, 2449.
r
10.1021/ol203060v
2011 American Chemical Society
Published on Web 12/14/2011

construction to build the C ring. Lipase catalyzed asym-
metric induction was also conceived as a key step toward
the target.9,10
The forward strategy started from commercially avail-
able 1-tetralone (7), which was converted to the di-MOM
derivative 8 in decent yields, in a process amenable to
scaleup.11 Classical formylation of 8 using DMF and t-
BuLi smoothly afforded the di-MOM protected aldehyde
9. Aldehyde 9 was subjected to aldol reaction with
acetone in the presence of 10% aqueous NaOH, furnish-
ing the enone which was reduced with NaBH4 into
racemic allyl alcohol 6 in 88% yield over two steps
(Scheme 2). Attention was then directed to introduction
of the chiral hydroxyl group via Burkholderia cepacia
lipase-mediated (Amano Lipase PS, Sigma-Aldrich)
resolution.10
Scheme 1. Retrosynthetic Analysis of Beraprost
After successful enzymatic resolution, using lipase and
vinyl acetate in tert-butylmethyl ether at room temperature,
(R)-acetate 10 was obtained in 45% yield and ∼97% ee as
confirmed by HPLC analysis.12 The hydrolysis of the acetyl
group in 10 resulted in chiral alcohol (þ)-6 in 85% yield.
4-Methyl 3-pentenoic acid 11 was coupled with (þ)-6 in the
presence of DCC/DMAP to furnish ester 5. The other
enantiomer (ꢀ)-6 was also converted to the desired 5 via
esterification with 11 under Mitsunobu conditions13 (total
51% yield of 5 from rac-10).
Scheme 2. Preparation of Intermediate 5
(6) (a) Review: Saibal, D.; Chandrasekhar, S.; Yadav, J. S.; Gree, R.
Chem. Rev. 2007, 107, 3286. (b) Review: Collins, P. W.; Djuric, S. W.
Chem. Rev. 1993, 93, 1533. (c) Jahn, U.; Galano, J. M.; Durand, T.
Angew. Chem., Int. Ed. 2008, 47, 5894. (d) Nagase, H.; Matsumoto, K.;
Nishiyama, H. Yuki Gousei Kagaku Kyoukaishi 1999, 57, 1116. (e)
Nishino, S.; Nagase, H.; Kanou, K.; Aoki, S.; Kanabayashi, Y. Yaku-
gaku Zasshi 1997, 117, 509. Synthesis of (()-Beraprost:(f) Ohno, K.;
Nagase, H.; Matsumoto, K. European Patent EP84,-856, 1983; Eur-
opean patent specification EP 1 519 930 B1; Chem. Abstr. 1984, 100,
51356m. (g) Ohno, K.; Nishiyama, H.; Nagase, H.; Matsumoto, K.;
Ishikawa, M. Tetrahedron Lett. 1990, 31, 4489. Synthesis of optically
active Beraprost:(h) Nagase, H.; Yoshiwara, H.; Tajima, A.; Ohno, K.
Tetrahedron Lett. 1990, 31, 4493. (i) Wakita, H.; Yoshiwara, H.; Tajima,
A.; Kitano, Y.; Nagase, H. Tetrahedron: Asymmetry 1999, 10, 4099. (i)
Wakita, H.; Yoshiwara, H.; Nishiyama, H.; Nagase, H. Heterocycles
2000, 53, 1085. (j) Wakita, H.; Yoshiwara, H.; Kitano, Y.; Nishiyama,
H.; Nagase, H. Tetrahedron: Asymmetry 2000, 11, 2981. (k) Yukio, Y.;
Yoshitaka, S.; Sentaro, O.; Fumie, S. J. Chem. Soc., Chem. Commun.
1995, 811. (l) Richard, C. L.; Nam, H. L. J. Org. Chem. 1991, 56, 6253.
(m) Kazuhiro, H.; Kazuyuki, S.; Hisanori, N.; Takeshi, S.; Yasuyuki, K.
Org. Lett. 2003, 5, 3703.
The desired IrelandꢀClaisen rearrangement was per-
formed on 5 with LDA/TBSCl and HMPA; this resulted
in selective formation of the (Z)-silyl ketene acetal prior
to rearrangement at ꢀ78 °C and furnished the required
stereoisomer 12 (Scheme 3). This can be explained by
invoking the chairlike transition state TS-1. A steady
increase in temperature to 25 °C followed by an acidic
workup, gave the desired rearrangement product 12
which was further derivatized as the methyl ester 4
(7) (a) Tatjana, G. K.; Martina, P.; Svjetlana, K.; Damjan, M.; Janez,
P.; Tobias, L. R.; Simon, M. A.; Silvana, R. M. Molecules 2011, 16, 5113.
(b) Carl, F. N.; Stefan, B. Chem. Soc. Rev. 2008, 37, 1218.
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Sanghee, K. J. Org. Chem. 2004, 69, 112. (b) Yanling, S.; Soonho, H.;
Ping, G.; Deukjoon, K.; Sanghee, K. Org. Lett. 2008, 10, 269.
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Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c) Schuster, M.;
Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037. (d) Ulman, M.;
Grubbs, R. H. Organometallics 1998, 17, 2484. (c) Thomas, N.; Michael,
B.; Kai, D.; Paul, K. Org. Process Res. Dev. 2005, 9, 513. (d) Nathan,
K. Y.; Vittorio, F.; Ioannis, N. H.; Nizar, H.; Rogelio, P. F.; Fabrice, G.;
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(12) See the Supporting Information for details.
(13) The enantiomeric purity of (S)-isomer (ꢀ)-6 was improved by
repeated resolution (twice), which was subjected to esterification with 11
under Mitsunobu inversion reaction conditions to realize compound 5 in
65% yield.
(10) Brenna, E.; Fuganti, C.; Galli, F. G.; Passoni, M.; Serra, S.
Tetrahedron: Asymmetry 2003, 14, 2401.
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300
Org. Lett., Vol. 14, No. 1, 2012

Scheme 3. Preparation of Intermediate 3
Scheme 4. Synthesis of 2
acid formed was isolated as methyl ester 18 by diazo-
methane treatment. The keto functionality in 18 was
reduced with NaBH4 to produce alcohol 19 as a single
diastereomer, as anticipated. The osmylative cleavage of
olefin 19 to unstable aldehyde 20 was followed by reduc-
tion with NaBH4. It resulted in a late-stage fully func-
tional core 2 of beraprost in enantiopure form.14
(78% yield over two steps) with >15:1 diastereoselec-
tivity.12 The relative stereochemistry was tentatively as-
signed for the two newly generated stereocenters of 4 on
the basis of literature precedent and was solvent depen-
dent, with 20% HMPA being critical to obtaining high
levels of diastereoselectivity.8
In summary, the present stereospecific formal synthesis
of beraprost was successfully achieved using enzymatic
resolution, IrelandꢀClaisen rearrangement, Grubbs’ me-
tathesis, and oxa-Michael reaction as key transforma-
tions starting from commercially available 1-tetralone.
DIBAL-H reduction of 4 yielded aldehyde 13 which
was reacted with vinyl magnesium bromide in THF at
0 °C to furnish a diastereomeric mixture (1:1) of allylic
alcohol 14 in 75% yield. Ring-closing metathesis9 was
facile with the first generation Grubbs catalysis and gave
16. Oxidation of 16 with Dess-Martin reagent produced
enone 3. This enone required exposure to BCl3 not only
for deprotection of two MOM protecting groups but also
to induce an in situ oxa-Michael cyclization to provide the
cyclopenta[b]benzofuran 17 having all the required func-
tionalities to arrive at the target (Scheme 4). Thus,
oxidation of 17 was achieved with BAIB, TEMPO. The
Acknowledgment. N.K.R. and B.V.D.V. thank UGC
and CSIR-New Delhi respectively for the award of a
research fellowship.
Supporting Information Available. Experimental pro-
cedures, characterization data, and NMR spectra for all
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) Wakita, H.; Yoshiwara, H.; Nishiyama, H.; Nagase, H. Hetero-
cycles 2000, 53, 1085.
Org. Lett., Vol. 14, No. 1, 2012
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