University of Groningen
Catalytic enantioselective synthesis of (-)-prostaglandin E-1 methyl ester based on a tandem
1,4-addition-aldol reaction
Arnold, L.A.; Naasz, R.; Minnaard, A.J.; Feringa, B.L.
Published in:
Journal of Organic Chemistry
DOI:
10.1021/jo025987x
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Arnold, L. A., Naasz, R., Minnaard, A. J., & Feringa, B. L. (2002). Catalytic enantioselective synthesis of (-)-
prostaglandin E-1 methyl ester based on a tandem 1,4-addition-aldol reaction.
Journal of Organic
Chemistry
,
67
(21), 7244-7254. https://doi.org/10.1021/jo025987x
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Catalytic Enantioselective Synthesis of (-)-Prostaglandin E
1
Methyl Ester Based on a Tandem 1,4-Addition-Aldol Reaction
Leggy A. Arnold, Robert Naasz, Adriaan J. Minnaard, and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
feringa@chem.rug.nl
Received May 29, 2002
Catalytic enantioselective 1,4-additions and tandem 1,4-addition-aldol reactions of dialkylzinc
reagents to cyclopentene-3,5-dione monoacetals in the presence of an in situ generated Cu(OTf)
2
/
chiral phosphoramidite catalyst result in highly functionalized cyclopentane building blocks with
ee’s up to 97%. A new synthesis of cyclopentene-3,5-dione monoacetals is presented as well as its
use in a tandem 1,4-addition-aldol protocol for the catalytic asymmetric total synthesis of (-)-
PGE
1
methyl ester. This synthesis represents a new approach to this class of natural products. By
using only 3 mol % of an enantiomerically pure catalyst in the key step, the absolute configurations
at three stereocenters of the basic structure of the PGE
1
are established at once.
Introduction
Prostaglandins (PGs) belong to the family of polyoxy-
genated fatty acids that are produced by a cyclooxygenase
enzyme system widely distributed in mammalian tissue.
1
Their biological functions are restricted locally because
of the rapid metabolism, but nevertheless, their phar-
macological effects are so diverse that they have become
the subjects of intensive research for the past decades.
2
Several synthetic prostaglandin derivatives are currently
used as drugs, but their synthesis is often still the subject
of considerable improvement and innovation.
3
Synthetic
routes are largely based on three strategies, the Corey
synthesis,
4
the two-component coupling,
5
and the three-
component coupling,
6
although a number of other ap-
proaches have been reported.
7
The latter method, devel-
oped by Noyori,
8
is particular attractive because of the
limited number of steps in this convergent synthetic
approach. The key step of this route is the tandem 1,4-
addition-enolate-trapping reaction (Scheme 1). The opti-
cally active enone 1 is treated with a functionalized
cuprate prepared from chiral vinyl iodide 2 and the in
situ generated enolate is trapped with aldehyde 3 as
electrophile.
9
This sequence provides a convenient way
to introduce simultaneously the R and ω side chains
necessary for the elaborations into (-)-PGE
1
5.
The versatility of organocopper reagents
10
and the
possibility of enolate trapping resulting in R-functional-
ization
11
(exemplified in Scheme 1), makes the 1,4-
addition one of the most versatile carbon-carbon bond
formation reactions in organic synthesis.
12
In the past
decade, considerable progress has been achieved in the
development of a catalytic enantioselective 1,4-addition
to enones.
13
In the copper-catalyzed 1,4-addition of di-
alkylzinc reagents to enones, full stereocontrol has been
observed using phosphoramidites as simple chiral ligands
for copper.
14
The reaction of 6-, 7-, and 8-membered
2-cycloalkenones and (functionalized) dialkylzinc (R
2
Zn)
reagents gave, in the presence of 1 mol % of an in situ
prepared catalyst based on Cu(OTf)
2
and phosphoramid-
(1) (a) Needleman, P.; Isakson, P. C. J. Rheumatol. 1997, 24,6.(b)
Masferrer, J. L.; Seibert, K.; Zweifel, B.; Needleman, P. Proc. Natl.
Acad. Sci. U.S.A. 1992, 89, 3917.
(2) Marks, F.; Fu¨rstenberger, G. Prostaglandins, Leukotrienes and
other Eicosanoids. From Biogenesis to Clinical Applications; Wiley-
VCH: Weinheim, 1999.
(3) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533.
(4) (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W.
J. Am. Chem. Soc. 1969, 91, 5675. (b) Corey, E. J.; Ensley, H. E. J.
Am. Chem. Soc. 1975, 97, 6908.
(5) (a) Alvarez, F. S.; Wren, D.; Prince, A. J. Am. Chem. Soc. 1972,
94, 7823. (b) Kluge, A. F.; Untch, K. G.; Fried, J. H. J. Am. Chem. Soc.
1972, 97, 7827. (c) Babiak, K. A.; Ng, J. S.; Dygos, J. H.; Weyker, C. L.
J. Org. Chem. 1990, 55, 3377.
(6) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John
Wiley & Sons: New York, 1994.
(7) (a) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis;
John Wiley & Sons: New York, 1989. (b) ApSimon, J. The Total
Synthesis of Natural Products; John Wiley & Sons: New York, 1981;
Vol. 4.
(8) Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988,
110, 4718.
(9) Suzuki, M.;Yanagishi, T.; Suziki, T.; Noyori, R. Tetrahedron Lett.
1982, 23, 4057.
(10) (a) Posner, G. H. Organic Reactions; John Wiley & Sons, Inc.:
New York, 1972; Vol. 19, Chapter 1. (b) Lipshutz, B. H.; Sengupta, S.
Organic Reactions; John Wiley & Sons, Inc.: New York, 1992; Vol.
41, Chapter 2.
(11) Chapdelaine, M. J.; Hulce, M. Organic Reactions; John Wiley
& Sons, Inc.: New York, 1990; Vol. 38, Chapter 2.
(12) Perlmutter, P. Conjugate Addition Reactions in Organic Syn-
thesis; Tetrahedron Organic Chemistry Series, No. 9; Pergamon:
Oxford, 1992.
(13) For the latest reviews, see: (a) De Vries, A. H. M.; Feringa, B.
L. Advances in Catalytic Processes; Doyle, M. P., Ed.; JAI: Greenwich,
CT, 1995; Vol. 1, pp 151-192. (b) Sibi, M. P.; Manyem, S. Tetrahedron
2000, 56, 8033. (c) Tomioka, K.; Nagaoka, Y. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer-Verlag: Berlin/Heidelberg, 1999; Vol. 3, Chapter 31.1. (d)
Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171. (e) Feringa, B.
L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern Organocopper
Chemistry; Krause, N., Ed.; Wiley VCH: Weinheim, 2002; Chapter 7.
(14) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
7244 J. Org. Chem. 2002, 67, 7244-7254
10.1021/jo025987x CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/24/2002
ite L1, the corresponding 1,4-addition products in high
yields and with ee’s up to >98% (Scheme 2).
15
On the basis of this methodology, catalytic routes are
now available to enantiomerically pure products embed-
ding cyclohexane and larger rings in their structure.
16
In addition to the enantioselective copper-catalyzed 1,4-
addition of organozinc reagents, a highly enantioselective
rhodium-catalyzed conjugate addition of aryl- and alk-
enylboronic acids to enones has been developed by
Hayashi.
17
For cyclic and acyclic enones, ee’s between 92
and 99% have been found in the presence of 1.5 mol % of
a [Rh(OH)((S)-binap)]
2
catalyst. For example, 3-phenyl-
cyclopentanone was obtained in 95% yield and 98% ee.
In contrast, the enantioselective copper-catalyzed 1,4-
addition of dialkylzinc reagents to 2-cyclopentenone
remained a major challenge, particularly because chiral
cyclopentane structures are ubiquitous in natural prod-
ucts such as prostaglandins. Surprisingly, the use of
phosphoramidite L1 as ligand for Cu(OTf)
2
in the 1,4-
addition of diethylzinc to 2-cyclopentenone resulted in
hardly any selectivity at all (10% ee).
16a
Employing
TADDOL
18
-based phosphoramidite ligand L2,upto62%
ee was obtained for the corresponding 1,4-addition prod-
uct when the reaction was run in the presence of
molecular sieves (Figure 1).
19
Under the same conditions,
chiral bidentate phosphoramidite ligand L3 gave an
enantioselectivity of 83%.
20
Chan
21
reached 89% ee using
the diphosphite ligand L4 in the 1,4-addition of dieth-
ylzinc to 2-cyclopentenone, whereas Pfaltz
22
enhanced the
enantioselectivity to 94% using phosphite L5 containing
a chiral oxazoline group. Recently, Hoveyda
23
reported
ee values up to 97% using a chiral peptide-based phos-
phine ligand L6 in this conjugate addition reaction.
Although these ligands give excellent enantioselectivi-
ties in the copper-catalyzed 1,4-addition to 2-cyclopen-
tenone, the isolated yields for the corresponding 1,4-
addition products are often moderate compared to those
with other enones.
24
When the reaction was performed
in the presence of an aldehyde, representing a three-
component coupling procedure, the yield increased con-
siderably.
19,20,24
Despite the fact that 2-cyclopentenone is
frequently used as a model substrate, it is as such less
suitable as a starting material for natural products
including the prostaglandins. In the search for a suitable
prochiral enone as starting material for the total syn-
thesis of this class of natural products, we focused on
cyclopentene-3,5-dione monoacetals because of the fol-
lowing reasons:
(1) These compounds represent easy accessible highly
functionalized prochiral 2-cyclopentenones.
(2) The acetal functionality can be readily converted
into a ketone or alcohol.
(3) These enones are more sterically demanding than
2-cyclopentenone, which increases the steric interaction
with the catalyst.
(4) The two oxygen atoms of the acetal might induce
an electronic interaction with the catalyst during the
tandem 1,4-addition-aldol reaction, giving rise to a
higher selectivity.
We report here a new synthesis of cyclopentene-3,5-
dione monoacetals and their application as substrate for
highly enantioselective catalytic tandem 1,4-addition-
aldol reaction. Furthermore, we illustrate the practicality
of this new methodology in a short total synthesis of (-)-
PGE
1
methyl ester including full experimental details.
25
The new features of this strategy are the application of
a catalytic three-component coupling, the use of only
achiral starting materials, and the observation that the
enantioselective introduction of the three stereocenters
with absolute stereocontrol is possible in a single key
step.
Results and Discussion
The preparation of monoacetals of cyclopentene-3,5-
dione has been described only in few cases in the
literature.
26
The reported syntheses are not generally
applicable, which encouraged us to develop a new pro-
cedure for their preparation. Treatment of commercial
(15) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries,
A. H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620.
(16) (a) Naasz, R.; Arnold, L. A.; Pineschi, M.; Keller, E.; Feringa,
B. L. J. Am. Chem. Soc. 1999, 121, 1104. (b) Naasz, R.; Arnold, L. A.;
Minnaard, A. J.; Feringa, B. L. Chem. Commun. 2001, 735.
(17) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052 and references cited herein.
(18) Seebach, D.; Beck, A.; Heckel, A. Angew. Chem., Int. Ed. 2001,
40, 92.
(19) Keller, E.; Maurer, J.; Naasz, R.; Schrader, T.; Meetsma, A.;
Feringa, B. L. Tetrahedron: Asymmetry 1998, 9, 2409.
(20) Mandoli, A.; Arnold, L. A.; Salvadori, P.; Feringa, B. L.
Tetrahedron: Asymmetry 2001, 12, 1929.
(21) Yan, M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645.
(22) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(23) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc.
2001, 123, 755.
(24) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron
Lett. 1996, 37, 5141.
(25) For a preliminary communication: Arnold, L. A.; Naasz, R.;
Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2001, 123, 5841.
SCHEME 1
SCHEME 2
Synthesis of (-) Prostaglandin E
1
Methyl Ester
J. Org. Chem, Vol. 67, No. 21, 2002 7245
available cyclopentene-3,5-dione 6 with different alcohols
in the presence of boron trifluoride gave the correspond-
ing cyclopentene-3,5-dione monoacetals 7a-e summa-
rized in Table 1.
The reactions were stopped after a certain conversion
to avoid the formation of side products. The reaction of
6 with methanol was stopped after 50% conversion, and
the acetal 7a could be isolated in 26% yield (Table 1,
entry 1). An interesting observation was made, namely
the formation of 4-ethoxy-4-methoxy-2-cyclopenten-1-one
in 7% yield. The EtO fragment of this compound origi-
nates from BF
3
‚Et
2
O. The acetals 7b and 7c were
obtained in 29% and 25% yield at conversions of 58% and
45%, respectively (Table 1, entries 2 and 3). The acetal-
ization of 6 with 2,2-diphenyl-1,3-propanediol gave 71%
conversion after3hat0°Cand50%yield of 7d (Table
1, entry 4). Employing a different purification method
27
instead of column chromatography improved the isolated
yield to 64%. The reaction of 6 and pinacol inthe presence
of BF
3
‚Et
2
O afforded 7e in 29% yield (76% conversion)
after 3 days at room temperature (Table 1, entry 5). In
addition, 6% yield of the diacetal was obtained. In the
case of 2-propanol and benzyl alcohol, no acetal formation
was observed even after 2 days at room temperature
(Table 1, entries 6 and 7).
Catalytic Asymmetric 1,4-Addition. The monoac-
etals 7b and 7d were employed in the 1,4-addition with
dialkylzinc reagents catalyzed by different chiral copper
complexes. The copper catalyst was prepared in situ
using 2 mol % Cu(OTf)
2
and 4 mol % phosphoramidite
L1 or L7 (for structures of ligands, see Scheme 2 and
Figure 3). The reactions were carried out in toluene at
-45 °C, and the results are summarized in Table 2.
Full conversions were reached in all reactions after 16
h affording the corresponding substituted ketones in
moderate yields (31-40%). The 1,4-addition of diethylzinc
to 7b in the presence of 2 mol % Cu(OTf)
2
/L1 catalyst
afforded 8 in 31% isolated yield (Table 2, entry 1).
Unfortunately, no separation of the enantiomers was
achieved by chiral HPLC. Derivatization with optically
pure (1S,2S)-diphenylethylenediamine
28
was also unsuc-
cessful. Apart from the formation of 8, 8a and 8b were
(26) (a) Yoshida, Z.-I.; Kimura, M.; Yoneda, S. Tetrahedron Lett.
1975, 12, 1001. (b) Sugihara, Y.; Wakabayashi, S.; Murata, I. J. Am.
Chem. Soc 1983, 22, 6718. (c) Bauermeister, H.; Riechers, H.; Schom-
burg, D.; Washausen, P.; Winterfeldt, E. Angew. Chem., Int. Ed. Engl.
1991, 30, 191.
(27) See the Experimental Section.
FIGURE 1. Different ligands used for the catalytic asymmetric 1,4-addition of diethylzinc to 2-cyclopentenone.
TABLE 1. Monoacetalization of 6 in the Presence of BF
3
‚Et
2
O
entry alcohol time (h) T (°C) convn
a
(%) acetal yield
b
(%)
1 methanol 1.5 0 50 7a 26 (+7)
c
2 2,2-dimethyl-1,3-propanediol 1.5 0 58 7b 29
3 ethylene glycol 1.5 0 45 7c 25
4 2,2-diphenyl-1,3-propanediol 3 0 71 7d 50 (64)
d
5 pinacol 72 25 76
f
7e 29 (6)
e
6 isopropyl alcohol 48 25 0
f
7 benzyl alcohol 48 25 0
f
a
Determined by
1
H NMR after 3 h.
b
Isolated yield.
c
4-Ethoxy-4-methoxy-2-cyclopenten-1-one.
d
Purification by different purification
procedure.
27 e
Diacetal.
f
After3datroom temperature.
Arnold et al.
7246 J. Org. Chem., Vol. 67, No. 21, 2002
isolated in 42% combined yield (Figure 2). Similar
products, formed by an aldol reaction between a zinc
enolate prepared by a 1,4-addition and an enone, have
been reported.
29
NMR analysis identified these diaster-
eomers, which differ in the configuration of the tertiary
alcohol. The presence of these products shows the dif-
ferent reactivity between the five-membered-ring zinc
enolate and the six-membered-ring zinc enolate.
20,30
In
the case of the copper-catalyzed 1,4-addition of diethyl-
zinc to 2-cyclohexenone, the formation of this type of
products was not detected even at elevated temperature.
Much to our delight, the use of 2-cyclopentenone with
an additional acetal functionality increases the enant-
ioselectivity of the Cu(OTf)
2
/L1-catalyzed 1,4-addition
dramatically. The reaction of 7d and diethylzinc afforded
9 in 40% yield and 90% ee (Table 1, entry 2). Using L7
(Figure 3) instead of L1 as ligand for copper, no asym-
metric induction was observed and 9 was isolated in 37%
yield (Table 2, entry 3). The 1,4-addition of dibutylzinc
to 7d in the presence of Cu(OTf)
2
/L7 afforded 10 in 32%
yield and 5% ee (Table 2, entry 4). In contrast, catalyst
Cu(OTf)
2
/L1 gave in the same reaction 10 in 37% yield
with an ee of 94% (Table 2, entry 5). In all cases, the
1,4-addition suffers from considerable side product for-
mation (vide supra) resulting in modest isolated yields.
Catalytic Tandem 1,4-Addition-Aldol Reaction.
To circumvent the formation of 8a and 8b (Figure 2), an
aldehyde (more reactive than a ketone in an aldol
reaction) was added to the reaction mixture from the
start. This tandem 1,4-addition-aldol reaction procedure,
trapping the intermediate zinc enolate, was first reported
by Noyori.
24
The reaction was carried out using enone
7d, p-bromobenzaldehyde, and dibutylzinc at -45 °C. We
were very pleased to find that only 2 mol % of the
catalyst, prepared in situ from Cu(OTf)
2
and ligand L1,
was sufficient to obtain the β-hydroxy ketones 11a and
11b with three consecutive stereocenters in 64% yield
(Scheme 3 and Table 3, entry 14).
Under these reaction conditions, virtually one stere-
oisomer out of the possible four diastereomers was
formed. A ratio of 97:3 between 11a trans-threo and 11b
trans-erythro was detected by
1
H NMR based on different
absorptions of H
1
(4.77 ppm 11a and 5.11 ppm 11b).
COSY-NMR and
1
H NMR was used to assign the relative
configurations of the two compounds. The coupling
constant for 11a and 11b was J
2,3
) 7.2 Hz. This value
is typical for a trans configuration of H
2
and H
3
(Scheme
4).
31
In addition, 11a and 11b have different coupling
constants for their H
1
and H
2
. The large difference is
probably due to strong hydrogen bonding between the
hydroxy and carbonyl group, thus preventing free rota-
(28) Alexakis, A.; Frutos, J. C.; Mangeney, P. Tetrahedron: Asym-
metry 1993, 4, 2431.
(29) Imamoto, T.; Takiyama, N.; Nakamura, K. Tetrahedron Lett.
1985, 26, 4763.
(30) De Vries, A. H. M.; Meetsma, A.; Feringa, B. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2374.
TABLE 2. Catalytic Enantioselective 1,4-Addition with
Cyclopentene-3,5-dione Monoacetals
entry enone R′
2
Zn ligand product
yield
a
(%)
ee
b
(%)
1 7b Et
2
Zn L1 8 31 (42)
c
d
2 7d Et
2
Zn L1 9 40 90
3 7d Et
2
Zn L7 9 37 0
4 7d Bu
2
Zn L7 10 32 5
5 7d Bu
2
Zn L1 10 37 94
a
Isolated yield.
b
Determined by chiral HPLC.
c
Side product,
see: Figure 2.
d
No separation by chiral HPLC.
FIGURE 2. Side products formed in the catalytic enantiose-
lective 1,4-addition of diethylzinc to 7b.
FIGURE 3. Different phosphoramidite ligands.
SCHEME 3
Synthesis of (-) Prostaglandin E
1
Methyl Ester
J. Org. Chem, Vol. 67, No. 21, 2002 7247
