Diastereoselective total synthesis of isocarbacyclin from L-ascorbic acid

Article abstract of DOI:10.1021/jo048738c

Diastereoselective total synthesis of isocarbacyclin, which features a fused bicyclic key intermediate available from L-ascorbic acid, is described. The key intermediate was prepared in multigram quantities by the Pauson-Khand reaction of L-ascorbic acid-based (R)-4,4-diallyl-2,2-dimethyl-5- (trimethylsilyl)ethynyl-1,3-dioxolane (3), discriminating diastereotopic groups and faces of the geminal allyl substituents.

Full text of DOI:10.1021/jo048738c

SCHEME 1. Retro Synthetic Analysis of
Isocarbacyclin 1 from L-Ascorbic Acid 5
Diastereoselective Total Synthesis of
Isocarbacyclin from L-Ascorbic Acid
Teruhiko Ishikawa,† Hirokazu Ishii,‡ Kazuo Shimizu,‡
Hiroe Nakao,‡ Jin Urano,‡ Takayuki Kudo,‡ and
Seiki Saito*,‡
School of Education, and Department of Bioscience and
Biotechnology, School of Engineering, Okayama University,
Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received July 23, 2004
Abstract: Diastereoselective total synthesis of isocarba-
cyclin, which features a fused bicyclic key intermediate
available from L-ascorbic acid, is described. The key inter-
mediate was prepared in multigram quantities by the
Pauson-Khand reaction of L-ascorbic acid-based (R)-4,4-
diallyl-2,2-dimethyl-5-(trimethylsilyl)ethynyl-1,3-di-
oxolane (3), discriminating diastereotopic groups and faces
of the geminal allyl substituents.
Prostacyclin (PGI2)1 is a potent vasodilator and inhibi-
tor of blood platelet aggregation and plays an important
role in the central nervous system.2 Clinical applications
of PGI2 in its natural form suffer from severe limitations
because of its lability (its half-life is ∼10 min at pH 7.6,
25 °C). Therefore, extensive efforts have been made to
develop or synthesize metabolically stable analogues
bearing physiological activities similar to those of PGI2.
Isocarbacyclin (1),4 one of these analogues, is a thera-
peutically useful agent3 for the treatment of various
vascular diseases. In addition, some derivatives of 1,
carrying modified side chains, have been utilized as
agents for studying the role of PGI2 in the brain.5 In any
event, due to its chemical stability and potent physiologi-
cal activities, including an antiaggregatory profile, a
number of methods for the synthesis of 1 have been
reported.6 In our continuing interest in the synthesis of
1,6i we had a promising clue to a novel method for the
synthesis of 1. This features a key intermediate, such as
2, prepared by the diastereoselective Pauson-Khand
reaction of 3, available from L-ascorbic acid (5), via
(2R,3S)-3,4-O-isopropylidene-2,3,4-trihydroxybutanoic acid
ester (4), as shown in Scheme 1. It can readily be
recognized that enone 2 has a functional group assembly
suitable for introducing the R- and ω-side chains and the
endocyclic olefinic moiety of 1.
Scheme 2 outlines the previous synthesis of the Pau-
son-Khand substrate 37 starting from an expensive
three-carbon chiral source, such as I, which required
eight steps with an acceptable overall yield (∼40%).
However, to prepare for a large-scale production of 3, we
felt that we should replace I with a less-expensive
alternative. Thus, we examined chiral carbon sources
other than I and found that 4, available from L-ascorbic
acid 5,8 provided a solution to this problem. In light of
both the availability and the inexpensive cost of 5, 2
would be obtained in multigram quantities if so desired,
(6) For the enantioselective synthesis of 1, see: (a) Shibasaki, M.;
Fukasawa, H.; Ikegami, S. Tetrahedron Lett. 1983, 24, 3497-3500.
(b) Torisawa, Y.; Okabe, H.; Shibasaki, M.; Ikegami, S. Chem. Lett.
1984, 1069-1072. (c) Sodeoka, M.; Shibasaki, M. Chem. Lett. 1984,
579-582. (d) Mase, T.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett.
1984, 25, 5087-5090. (e) Torisawa, Y.; Okabe, H.; Ikegami, S. J. Chem.
Soc., Chem. Commun. 1984, 1602-1603. (f) Ogawa, Y.; Shibasaki, M.
Tetrahedron Lett. 1984, 25, 1067-1070. (g) Bannai, K.; Tanaka, T.;
Okamura, N.; Hazato, A.; Sugiura, S.; Manabe, K.; Tomimori, T.;
Kurozumi, S. Tetrahedron Lett. 1986, 27, 6353-6356. (h) Suzuki, M.;
Koyano, H.; Noyori, R. J. Org. Chem. 1987, 52, 5583-5588. (i) Mandai,
T.; Matsumoto, S.; Kohama, M.; Kawata, M.; Tsuji, J.; Saito, S.;
Moriwake, T. J. Org. Chem. 1990, 55, 5671-5673. (j) Suzuki, M.;
Kayano, H.; Noyori, R.; Hashimoto, H.; Negishi, M.; Ichikawa, A.; Ito,
S. Tetrahedron 1992, 48, 2635-2658. (k) Park, H.; Lee, Y. S.; Jung, S.
H.; Shim, S. C. Synth. Commun. 1992, 22, 1445-1452. (l) Park, H.;
Lee, Y. S.; Shim, S. C. Bull. Korean Chem. Soc. 1993, 14, 86-91. (m)
Mikami, K.; Toshida, A. Synlett 1995, 29-31. (n) Mikami, K.; Yoshida,
A.; Matsumoto, Y. Tetrahedron Lett. 1996, 37, 8515-8518. (o) Bund,
J.; Gais, H.-J.; Schmitz, E.; Erdelmeier, I.; Raabe, G. Eur. J. Org. Chem.
1998, 1319-1335.
* To whom correspondence should be addressed. Tel.(Fax) +81 86-
251-8209.
† School of Education.
‡ School of Engineering.
(1) Moncada, S.; Gryglewski, R.; Bunting, S.; Vane, J. R. Nature
1976, 263, 663-665.
(2) For example, see: Takechi, H.; Matsumura, K.; Watanabe, Y.;
Kato, K.; Noyori, R.; Suzuki, M.; Watanabe, Y. J. Biol. Chem. 1996,
271, 5901-5906.
(3) (a) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533-1564.
For more recent example, see: (b) Moriarty, R. M.; Rani, N.; Enache,
L. A.; Rao, M. S.; Batra, H.; Guo, L.; Penmasta, R. A.; Staszewski, J.
P.; Tuladhar, S. M.; Prakash, O.; Crich, D.; Hirtopeanu, A.; Gilardi,
R. J. Org. Chem. 2004, 69, 1890-1902 and references therein.
(4) Shibasaki, M.; Torisawa, Y.; Ikegami, S. Tetrahedron Lett. 1983,
24, 3493-3496.
(7) Ishikawa, T.; Shimizu, K.; Ishii, H.; Ikeda, S.; Saito, S. J. Org.
Chem. 2001, 66, 3834-3847.
(8) Wei, C. C.; Bernard, S. D.; Tengi, J. P.; Borgese, J.; Weigele, M.
J. Org. Chem. 1985, 50, 3462-3467.
(5) Suzuki, M.; Kato, K.; Noyori, R.; Watanabe, Y.; Takechi, H.;
Matsumura, K.; Långstro¨m, B.; Watanabe, Y. Angew. Chem., Int. Ed.
Engl. 1996, 35, 334-336.
10.1021/jo048738c CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/13/2004
J. Org. Chem. 2004, 69, 8133-8135
8133

SCHEME 2. Previous Synthesis of the
Pauson-Khand Substrate 3
SCHEME 4. Transformation of 2 to 1a
SCHEME 3. Synthesis of the Key Intermediate 2
from L-Ascorbic Acid Featuring the
Diastereoselective Pauson-Khand Reactiona
a Reagents and conditions: (a) 1. LDA, THF, 1 h; 2. (2E)-octenal,
THF, -78 °C, 50 min, 88%; (b) separation of diastereomers; (c)
NaTeH, EtOH, rt, 3.5 h, 91%; (d) Ac2O, pyridine, DMAP, THF, rt,
2 h, 87%; (e) Pd(MeCN)2Cl2, THF, rt, 4 h, and then NaBH4, 0 °C,
30 min, 50%; (d 11 to 12) rt, 4 h, 93%; (f) 9-BBN, THF, rt, 4 h,
and then H2O2, NaHCO3, rt, 1 h, 93%; (g) SO3‚Py, Et3N, DMSO,
rt, 30 min, 86%; (h) (i-PrO)2P(O)CH(Na)COOMe, THF, -78 °C, 1
h, 99%; (i) NaTeH, EtOH, rt, 12 h, 88%; (j) 80% AcOH/H2O, 70
°C, 15 h, 69%; (k) HC(OEt)3, 130 °C, 15 h, and then Ac2O, 150 °C,
4 h, 66%; (l) NaOH, EtOH/H2O, rt, 24 h, 95%.
the deprotection of the terminal acetonide group of 6 and
the subsequent oxidative diol cleavage to give the desired
aldehyde V. Application of Corey’s protocol9 to V afforded
dienyne 3 in high yield (48% overall yield from 4), and
the Pauson-Khand reaction of 3 (3.64 g) with 100 mol
% cobalt complex nicely proceeded to afford 9 (3.30 g, 78%
yield) as a single diastereomer.10 Furthermore, we found
that desilylation of 9 readily took place by using potas-
sium carbonate in methanol at room temperature to give
the desired enone 2 in good yield (80%), which is ready
for elaborating the whole carbon framework of 1.
Careful NOE experiments for 9 led to the relative
configurations, as indicated in Scheme 3.11 This finding
clearly indicated that the reaction proceeded with the
simultaneous discrimination of both diastereotopic allyl
groups, and the π-faces of the allyl group reacted. Thus,
the protected diol unit can play an important role as a
stereocontrol element in this diastereo differentiation
reaction. We presumed that the expected transition state
a Reagents and conditions: (a) TMSCl, imidazole, CH2Cl2, 0 °C,
30 min; (b) CH2dCHCH2MgBr, THF, -78 °C, 1 h; (c) p-TsOH‚H2O,
THF, and then 2-methoxypropene, 60 °C, 6 h, 87% from 4; (d) 2 N
HCl, THF, rt, 12 h, 82%; (e) HIO4‚2H2O, THF, 0 °C, 45 min, 92%;
(f) PPh3, CBr4, CH2Cl2, rt, 16 h; (g) n-BuLi, -30 °C, 30 min, and
then TMSCl, THF, -78 °C, 1 h, 73% from 7; (h) Co2(CO)8, CH2Cl2,
0 °C to rt, 3 h, and then MeCN, 65 °C, 3 h, 78%; (i) CO, 5 mol %
7, 10 mol % Et3SiH, 10 mol % CyNH2, DME, 70 °C, 76% (67%
conversion); (j) K2CO3, MeOH, rt, 3.5 h, 80%.
which would make the present synthesis highly practical
and attractive.
Scheme 3 outlines the L-ascorbic acid route to 3 and
the key intermediate 2, as well. Chiral hydroxyester 4
was converted to 6 via a four-step sequence involving
silylation (TMSCl, imidazole) of the hydroxy group,
conversion of the ester group to an R,R-diallyl alcohol unit
with allylmagnesium bromide, deprotection of the TMS
group, and acetonide protection of the generated internal
1,2-diol functionality. Treatment of 6 with 2 N HCl in
THF, and followed with periodic acid treatment, effected
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769-3772.
(10) Tricyclic enone 9 was previously synthesized in a small-scale
experiment in which 3 (0.100 g) led to 9 (0.075 g, 74%) in the presence
of Co2(CO)8 (0.367 g) in CH3CN (65 °C, 11 h). The present larger-scale
case resulted in a better yield (78%) during a shortened reaction time
(3 h). Elucidation for the exact nature of this significant scale effect
must await future systematic studies.
(11) For the determination of relative configurations, see ref 7.
8134 J. Org. Chem., Vol. 69, No. 23, 2004

(8, Scheme 3)7 could explain such a remarkable stereo-
chemical consequence in this case.
and acetylation of the generated hydroxy group gave 12
as an exclusive stereoisomer.
A requisite two-carbon unit for the complete R-chain
was incorporated into 12 as follows. Hydroboration-
oxidation of the allyl group in 12, using 9-BBN-H, and
oxidation of the produced primary alcohol followed by
H-W-E olefination and selective reduction of the conju-
gated double bond (NaTeH)14 gave 13 in good yield. After
deprotection of the acetonide group of 13, the formed syn-
1,2-diol unit was converted into the desired double bond
via thermal cleavage of the intermediary ortho-ester16
upon treatment with triethylorthoformate in the presence
of acetic anhydride. Final saponification of 14 afforded
isocarbacyclin 1, of which spectral data and optical
rotation were identical in all respects with those reported
previously.6
In conclusion, we have demonstrated the enantio-
selective total synthesis of isocarbacyclin from the key
intermediate 2, available from L-ascorbic acid in multi-
gram quantities in optically pure form (26% overall yield
from 4). Not only the functional group assembly in 2 but
also the conventional synthetic reactions required for
converting 2 to 1 might make the present approach
attractive and deserving of consideration for flexible
access to the side-chain analogues of 1.
Besides the L-ascorbic acid route to 3 (Scheme 3), the
Pauson-Khand reaction of 3 should be switched from the
present stoichiometric system to the desired catalytic
system in order to prepare for a large-scale production
of 9. According to Livinghouse’s protocol,12 we employed
the cobalt complex 7, shown in Scheme 3, for this purpose
and found that a catalytic amount of 7 (5 mol %), indeed,
led to the formation of 9. However, at the present stage,
the catalytic process was so slow that it was difficult to
quantitatively convert 3 to 9 under the given catalytic
conditions; 9 was obtained in 76% yield based on 67%
conversion of 3.
The synthetic route to 1 from 2 is summarized in
Scheme 4. The introduction of the ω-chain was the first
task in this synthesis. Aldol reaction of 2 with (2E)-
octenal led to 10 in good yield (88%). However, the level
of enantioface differentiation for the formyl group was
unacceptable (1.2:1 in preference to the desired 10R)13
under the given conditions (LDA, THF, 1 h; (2E)-octenal,
THF, -78 °C, 50 min), whereas diastereoface differentia-
tion of an enolate generated from 2 was almost perfect.
Fortunately, separation of the resulting mixture of di-
astereomers (10R and 10â) by column chromatography
on silica gel was successful. Thus, a series of routine
reactions from 10R involving 1,4-reduction of the enone
unit, using NaTeH,14 and acetylation afforded 11. Pd-
(II)-catalyzed stereospecific allylic rearrangement15 fol-
lowed by reduction of the cyclopentanone moiety (NaBH4)
Acknowledgment. We thank the NMR Laboratory
of Okayama University for 500 MHz NMR experiments.
Supporting Information Available: Complete experi-
mental procedures and copies of the 1H and 13C NMR spectra
for compounds 1-3, 6, V, and 9-14. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Belanger, D. B.; Livinghouse, T. Tetrahedron Lett. 1998, 39,
7641-7644.
(13) No effort has been made to improve this ratio. Aldol reaction
between 9 and (2E)-octenal led to a diastereomeric ratio of 1:2 in
preference of the undesired â-isomer (10â) (LDA, THF, -78 °C, 1 h,
and then the aldehyde, -78 °C, 50 min).
(14) (a) Yamashita, M.; Tanaka, Y.; Arita, A.; Nishida, M. J. Org.
Chem. 1994, 59, 3500-3502. (b) Bargues, V.; Blay, G.; Cardona, L.;
Garcia, B.; Pedro, J. R. Tetrahedron 1998, 54, 1845-1852.
JO048738C
(15) For example, see: Saito, S.; Kuroda, A.; Matsunaga, H.; Ikeda,
S. Tetrahedron 1996, 52, 13919-13932 and references therein.
(16) For a review regarding the cleavage of cyclic ortho-esters, see:
Block, E. Org. React. 1984, 30, 457-566.
J. Org. Chem, Vol. 69, No. 23, 2004 8135