A new synthetic approach for 4(S)-hydroxycyclopent-2-enone: A precursor to prostanoid synthesis

Article abstract of DOI:10.1016/j.tetlet.2005.07.035

A new and efficient approach to 4(S)-hydroxycyclopent-2-enone is presented. This methodology allows the preparation of 4(S)-hydroxycyclopent-2-enone in large scale and with high optical purity.

Full text of DOI:10.1016/j.tetlet.2005.07.035

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6325–6328
A new synthetic approach for 4(S)-hydroxycyclopent-2-enone:
a precursor to prostanoid synthesis
Chih-Tsung Chang,a Sheila H. Jacobo,a William S. Powell,b John A. Lawson,c
a,
Garret A. FitzGerald,c Domenico Praticoc andJoshua Rokach
*
aClaude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 W. University Blvd., Melbourne,
FL 32901, USA
bMeakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada H2X 2P2
cInstitute for Translational Medicine and Therapeutics, The University of Pennsylvania, Philadelphia, PA 19104, USA
Received2 June 2005; revised7 July 2005; accepted8 July 2005
Available online 26 July 2005
Abstract—A new andefficient approach to 4( S)-hydroxycyclopent-2-enone is presented. This methodology allows the preparation of
4(S)-hydroxycyclopent-2-enone in large scale and with high optical purity.
Ó 2005 Elsevier Ltd. All rights reserved.
4(S)-Hydroxy and 4(R)-hydroxycyclopent-2-enone, syn-
thons 1 and 2, have been the key building blocks in the
syntheses of several natural products.1–5 For example,
4(R)-hydroxycyclopent-2-enone 2 was widely used in
the syntheses of prostaglandins through the 3-compo-
nent coupling route (Scheme 1a).6–10 Our group had
recently used4( S)-hydroxycyclopent-2-enone 1 as start-
ing point in the thermal-Diels–Alder approach to iso-
prostanes (Scheme 1b).11 The importance of these
synthons is clearly revealedby the numerous syntheses
reportedin the literature. These syntheses can be cate-
procedure relying on making the Mosher ester derivative
is time consuming andhas to be performedon every
batch of the material.
We are reporting here on a straightforwardprocedure
for the synthesis of 1. This synthetic approach is based
on olefin metathesis. Over the few past years, olefin
metathesis has emergedas an excellent methodfor
carbon–carbon bondformation. It has been usedto
prepare several natural products.27,28 Preparation of
compounds with complex ring systems from acyclic
synthons was made possible with the development of
Grubbsꢀ catalysts.29–31 One advantage of using Grubbsꢀ
catalyst in the synthesis of organic compounds is its
goodtolerance to thef functional groups.
12–18
gorizedinto two groups: enzymatic/semisynthetic
19–25
andsynthetic.
Recently, we have reporteda synthesis of 4( S)-hydroxy-
cyclopent-2-enone.26 This synthetic procedure afforded
1 in high quality andenantiomeric purity. A brief out-
line of the synthesis is shown in Scheme 2. As can be
seen, all the steps from the dithio intermediate 9 to the
final compound 1 are acid-catalyzed steps. As a result,
contamination of 10, 11 and 1 in steps 1 and2 ( Scheme
2) makes purification, even with goodyieldreactions,
tedious and time consuming. In addition, determination
of the stereochemical purity of the –OH group by our
We have designed the synthesis of 1 in such a way that it
is amenable to large scale preparation andat the same
time affords an optically pure compound. We have
decided to synthesize the dithio intermediate 13 from
D-arabinose 12, as described by us previously.32 Using
this procedure, 200 g of 13 can be preparedin one batch.
13 can also be synthesizedfollowing a new two-step pro-
cedure from 2-deoxy-D-ribose 14 (Scheme 3).
Scheme 4 shows the detailed synthesis of 1 from dithio
intermediate 13. First, the –OH group in 13 was pro-
tectedwith TBDMSCl affording 15 in 99% yield. Treat-
ment of 15 with periodic acid in THF/ether gave the
aldehyde, which was immediately reacted with 5 equiv
Keywords: 4(S)-Hydroxycyclopent-2-enone; Olefin metathesis; Syn-
thesis.
*
Corresponding author. Tel.: +1 3216 747329; fax: +1 3216 747743;
e-mail: jrokach@fit.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.035

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C.-T. Chang et al. / Tetrahedron Letters 46 (2005) 6325–6328
HO
HO
O
O
2
1
O
O
Rα
Rω
COOH
(a)
(b)
OH
OH
PGE2
OR
OR
4
3
OH
RO
OCH3
OCH3
COOH
+
OH
OCH3
OH
O
iPF2α-V
O
OCH3
5
8
7
6
Scheme 1.
HO
O
O
S
O
S
CH3
CH3
Amberlyst
HO
HO
O
O
Amberlyst
CSA
HO
HO
O
resin
(acid form)
resin
(acid form)
SCH3
SCH3
step3
9
11
10
1
step2
step1
Scheme 2.
O
HO
O
O
O H
O
HO
OH
OH
H O
OH
D-arabinose
SEt
SEt
4 steps
2 steps
14
2-deoxy-D-ribose
OH
12
1
3
Scheme 3.
O
O
O
BrPh3PCH3
O
O
RO
CHO
OBz
O
RO
HO
RO
19
f
d
e
b, c
SEt
SEt
18
16
OBz
17
OH
13, R=H
a
15, R=TBDMS
OR
OTBDMS
OH
h
i
j
g
OH
21
OR
OH
22
OR OBz
20
O
O
23
1
Scheme 4. Reagents andconditions: (a) TBDMSCl, Im, DMF, 100 °C, 2 h, 99%; (b) H5IO6, THF/Et2O, 0 °C, 15 min; (c) CH2CHMg+BrÀ (5 equiv),
rt, 1.5–2 min, 74% (two steps); (d) BzCl, Et3N, DMAP, CH2Cl2, rt, 12 h, 93%; (e) H5IO6, THF/Et2O, rt, 12 h, 98%; (f) NaHMDS, THF, À30 °C to rt,
1.5 h, 76%; (g) K2CO3, MeOH, 10 h, rt, >99%; (h) Grubbsꢀ catalyst (1st Gen), 6 mol % catalyst, CH2Cl2, 4 h, rt, 89%; (i) Dess–Martin periodinane,
CH2Cl2, 2.5 h, rt, 99%; (j) HFÆpy, pyridine, 30 min, rt, 97%.
of vinyl magnesium bromide at rt, affording 16 in 74%
yield(two steps). After protecting 16 with benzoyl group
using benzoyl chloride in CH2Cl2, the resulting interme-
diate (17) was treatedwith periodic acidin THF/ether
and was stirred overnight to afford aldehyde 18 in 98%
yield. 18 was coupledwith the phosphorane derived
from the commercially available phosphonium salt 19
to give diene 20 in 76% yield. Treatment of 20 with
K2CO3 afforded hydroxy-diene 21 in quantitative yield.
Ring closing metathesis of 21 catalyzedby Grubbs ꢀ first

C.-T. Chang et al. / Tetrahedron Letters 46 (2005) 6325–6328
6327
TBDMSO
HO
O
OH
O
OH
O
O
TBDMSO
TBDMSO
TBDMSO
a
b
c
+
OH
TBDMSO
16
24
25
22
21
OH
Scheme 5. Reagents andconditions: (a) H 5IO6, THF/Et2O, 15 h, rt, 58%; (b) BrÀPh3P+CH3, NaHMDS, THF, À30 °C to rt, 7 h, 20%; (c) Grubbsꢀ
catalyst (1st Gen), 6 mol % catalyst, CH2Cl2, 4 h, rt, 89%.
3. Nagaoka, H.; Miyakoshi, T.; Yamada, Y. Tetrahedron
generation catalyst [PhCH@RuCl2(PCy3)2] afforded 22
Lett. 1984, 25, 3621–3624.
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1990, 31, 1573–1576.
5. Forsyth, C. J.; Clardy, J. J. Am. Chem. Soc. 1990, 112,
in 89% yield. Oxidation of 22 with Dess–Martin period-
inane gave 23 in quantitative yield. Finally, hydrolysis of
23 with HFÆpy gave the desired compound 1 in 97%
yield. The NMR33 and other analytical data are identi-
3497–3505.
26
cal to the one reportedby us previously.
6. Tanaka, T.; Toru, T.; Okamura, N.; Hazato, A.; Sugiura,
S.; Manabe, K.; Kurozumi, S. Tetrahedron Lett. 1983, 24,
4103–4104.
7. Suzuki, M.; Yanagisawa, A.; Noyori, R. Tetrahedron Lett.
1984, 25, 1383–1396.
8. Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem.
Soc. 1988, 110, 4718–4726.
It is interesting to note that cyclization of 21 using
Grubbsꢀ secondgeneration catalyst also afforded 22 in
excellent yield. However, we opted to use Grubbsꢀ first
generation catalyst since it is more economical.34–36
9. Kolb, M.; VanHijfte, L.; Ireland, R. E. Tetrahedron Lett.
1988, 29, 6769–6772.
10. Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984,
23, 847–876.
11. Pudukulathan, Z.; Manna, S.; Hwang, S. W.; Khanapure,
S. P.; Lawson, J. A.; FitzGerald, G. A.; Rokach, J. J. Am.
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To make sure that the optical purity of hydroxy group
in 1 was preservedafter a series of steps from D-arabi-
nose or 2-deoxy-D-ribose, a Mosher ester derivative
was preparedby acylation of 1 with (R)-(À)-a-meth-
oxy-a-(trifluoromethyl)phenylacetyl chloride in pyridine
as described by us previously.26 By NMR analysis, a
high ee of >96% was observed.
We initially performedthe synthesis in a slightly simpler
way as shown in Scheme 5. The hydroxy group in 16 was
not protectedwith benzoyl group andthus upon treat-
ment with periodic acid resulted to the formation of lac-
tols 24 and 25. However, the one-carbon Wittig reaction
of 24 and 25 with 19 gave a low yieldof the desired
product 21 (ꢀ20%). We think that the synthesis shown
in Scheme 5 is, in spite of the low yieldWittig reaction,
a goodalternative to the one shown in Scheme 4.
18. Ghorpade, S. R.; Bastawade, K. B.; Gokhale, D. V.;
Shinde, P. D.; Mahajan, V. A.; Kalkote, U. R.; Ravin-
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4122.
19. Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J.
Am. Chem. Soc. 1984, 106, 6717–6725.
In summary, we have developed an efficient synthesis of
4(S)-hydroxycyclopent-2-enone 1 andits edrivatives.
This approach not only allows us to prepare 1 in large
quantities but also with high optical purity.
20. Ogura, K.; Yamashita, M.; Tsuchihashi, G. Tetrahedron
Lett. 1976, 10, 759–762.
21. Gill, M.; Rickards, R. W. Tetrahedron Lett. 1979, 20,
1539–1542.
Acknowledgements
The present study was supported by grants from the Na-
tional Institutes of Health (DK-44730 (J.R.), HL-69835
(J.R.), HL-70128 (G.A.F.), AG-11542 (D.P.)); the NSF
for an AMX-360 NMR instrument (CHE-90-13145); the
Canadian Institutes of Health Research (MOP-6254)
22. Nara, M.; Terashima, S.; Yamada, S. Tetrahedron 1980,
36, 3161–3170.
23. Kitamura, M.; Manabe, K.; Noyori, R.; Takaya, H.
Tetrahedron Lett. 1987, 28, 4719–4720.
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´
(W.S.P.); the Heart andStroke Foundation of Que bec
(W.S.P.).
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