Catalytic enantioselective synthesis of prostaglandin E1 methyl ester using a tandem 1,4-addition-aldol reaction to a cyclopenten-3,5-dione monoacetal [2]

Full text of DOI:10.1021/ja015900+

J. Am. Chem. Soc. 2001, 123, 5841-5842
5841
Scheme 1
Catalytic Enantioselective Synthesis of Prostaglandin
E1 Methyl Ester Using a Tandem 1,4-Addition-Aldol
Reaction to a Cyclopenten-3,5-dione Monoacetal
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
ReceiVed March 28, 2001
ReVised Manuscript ReceiVed May 4, 2001
Conjugate addition reactions are among the most important
carbon-carbon bond formation reactions in organic synthesis,1
and considerable progress has been made in the development of
asymmetric Michael additions and 1,4-additions of organometallic
reagents.2 Recently, highly enantioselective copper-catalyzed
conjugate addition reactions of diorganozinc reagents to enones
have been reported.3 Among the various chiral ligands introduced
for this purpose phosphoramidite 4, developed in our laboratories,
shows nearly complete stereocontrol in the reaction of (function-
alized) dialkylzinc (R2Zn) reagents with six-, seven- and eight-
membered cycloalkenones.4 On the basis of this methodology,
catalytic routes are now available to enantiomerically pure
products, embedding cyclohexane and larger rings in their
structure.5 In contrast, the catalytic enantioselective 1,4-addition
to 2-cyclopentenone is a major challenge, particularly because
chiral cyclopentane structures are ubiquitous in natural products.
Employing TADDOL-based phosphoramidite ligands we obtained
up to 62% ee when the Et2Zn addition to 2-cyclopentenone was
run in the presence of molecular sieves.6 Furthermore, with using
chiral bidentate phosphoramidite ligands, the enantioselectivity
improved to 83%.7 Chan8 reached 89% ee using a diphosphite
ligand, whereas Pfaltz9 enhanced the enantioselectivity in this
addition to 94%. Recently Hoveyda10 reported ee values up to
97% using a chiral peptide-based phosphine ligand in the 1,4-
addition of diethylzinc to 2-cyclopentenone. Although these
catalysts give excellent enantioselectivities, the isolated yields for
the 3-substituted cyclopentanones are often moderate. Possible
reasons are the lower reactivity of 2-cyclopentenone in comparison
with other cyclic enones, the side-reactions of the resulting zinc
enolate with the starting material and the high volatility of the
1,4-addition product. Performing the reaction in the presence of
an aldehyde increases the yield considerably.4,6,11
Table 1. Results of Tandem 1,4-Addition-Aldol Reactions
According to Scheme 1
yield ee (3a-f)
entry enone
R′2Zn
R′′CHO
prod. [%]a
[%]b
1
2
3
4
5
6
1a
1a
1b
1b
1b
1b
Et
n-Bu
Et
n-Bu
Et
n-Bu
Ph
Ph
Ph
Ph
p-Br-Ph
p-Br-Ph
2a
2b
2c
2d
2e
2f
67
64
76
69
69
64
87
87
94
94
96
97
a Isolated Yields. b Determined with HPLC (Daicel CHIRAL PAK-
AD).
We report here the highly enantioselective catalytic tandem
1,4-addition-aldol reaction of dialkylzinc reagents to cyclopenten-
3,5-dione monoacetals in the presence of aldehydes. These
compounds show a higher reactivity, and the heavily function-
alized products are less volatile. The usefulness of this new
method is illustrated by the total synthesis of (-)-PGE1 methyl
ester in seven steps using achiral starting materials and only a
catalytic amount of a chiral copper complex.
Monoacetals 1a and 1b were employed in the tandem 1,4-
addition-aldol reaction with various aldehydes and dialkylzinc
reagents (Scheme 1).12 The catalyst was prepared in situ from 2
mol % Cu(OTf)2 and 4 mol % (S,R,R)-phosphoramidite 4.
Full conversion was reached after 16 h to provide exclusively
trans substituted cyclopentanones 2a-f in isolated yields up to
76% (Table 1). Excellent stereocontrol is also observed in the
subsequent aldol step, as for the hydroxy ketones 2a-2f diaster-
eomeric ratios higher than 95:5 were measured. The configuration
of the main product was determined by NOESY-NMR. The
adducts 2a-f were converted into the corresponding diketones
3a-f in good yields to give single diastereomers suitable for ee
determination by chiral HPLC. The enantioselectivity strongly
depends on the acetal moiety present in the starting material as
87% ee for enone 3a (entry 1) and 94% ee for enone 3c (entry
3) was obtained. The use of different dialkylzinc reagents,
however, has no influence on the selectivity of this reaction
(entries 3 and 4). The structure of the aldehyde has a minor
influence: the use of benzaldehyde and p-bromo benzaldehyde
shows ee values of 94% and 97%, respectively (entries 4 and 6).
We have demonstrated therefore, that in the presence of 2 mol
% of [(S,R,R)-4]Cu(OTf)2 nearly complete stereocontrol over the
formation of three consecutive stereocenters in this tandem 1,4-
addition-aldol reaction is achieved, providing multifunctional
cyclopentanones. These results inspired us to demonstrate the
(1) (a) Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis;
Tetrahedron Organic Chemistry Series, No. 9; Pergamon: Oxford, 1992. (b)
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.
(2) For a review, see: Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56,
8033.
(3) For reviews, see: (a) Krause, N. Angew. Chem., Int. Ed. 1998, 37, 283.
(b) Krause, N. Hoffmann-Ro¨der, A. Synthesis 2001, 171.
(4) (a) Feringa, B. L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; de Vries, A.
H. M. Angew. Chem., Int. Ed. Engl. 1997, 36, 2620. (b) Feringa, B. L. Acc.
Chem. Res. 2000, 33, 346.
(5) (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, in press.
(6) Keller, E.; Maurer, J.; Naasz, R.; Schrader, T.; Meetsma, A.; Feringa,
B. L. Tetrahedron: Asymmetry 1998, 9, 2409.
(7) Mandoli, A.; Arnold, L. A.; Salvadori, P.; Feringa, B. L.; Tetrahe-
dron: Asymmetry 2001, in press.
(8) Yan M.; Chan, A. S. C. Tetrahedron Lett. 1999, 40, 6645.
(9) Escher, I. H.; Pfaltz, A. Tetrahedron 2000, 56, 2879.
(10) Degrado, S. J.; Mizutani, H.; Hoveyda, A. H. J. Am. Chem. Soc. 2001,
123, 755.
(11) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Tetrahedron Lett.
1996, 37, 5141.
(12) (a) Yoshida, Z.; Kimura, M.; Yoneda, S. Tetrahedron Lett. 1975, 16,
1001. (b) All compounds exhibited spectroscopic data (1H NMR, 13C NMR,
HRMS) in accordance with the structures. Details of the synthesis of 1a, 1b,
and 5 will be published in due course.
10.1021/ja015900+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/26/2001

5842 J. Am. Chem. Soc., Vol. 123, No. 24, 2001
Communications to the Editor
Scheme 2
Scheme 3a
of 7 proceeds with 95% stereoselectivity using Zn(BH4)2 in ether
at -30 °C. Compound 8 was isolated after chromatography as a
single isomer in 63% yield with an ee of 94%. In the next step
the silyl substituent was removed using Bu4NF in THF/DMSO
to give compound 9 (Scheme 3). This concept comprises a novel
protection and deprotection sequence for enones suitable for the
catalytic 1,4-addition with dialkylzincs. The cleavage of vinyl
carbon-silicon bonds with Bu4NF was developed by Nozaki.18
However, under the normal reaction conditions hydrolysis of
compound 9 was observed to be caused by water in the
commercial THF solution of Bu4NF. Adding first sacrificial
methylpropionate to remove the water by hydrolysis and only
afterwards 8, the desilylated compound 9 was obtained as the
only product and used without further purification. Acetylation
of 9 afforded 10 in 71% yield over two steps.
The 1,3-allylic transposition of 10 with a catalytic amount of
Pd(CH3CN)2Cl2 in THF proceeded with reasonable yield and full
retention of configuration19 to give allylic acetate 11 with the
required stereochemistry. After deacetylation in the presence of
K2CO3 in MeOH, compound 12 was obtained in excellent yield.
The last step is the deprotection of the ketone functionality to
provide the labile â-hydroxy ketone moiety of the prostaglandin.
This conversion was realized using a catalytic amount of (NH4)2-
Ce(NO3)6 under nearly neutral conditions.20 In this way PGE1
methyl ester21 is obtained in 7% overall yield with 94% optical
purity in seven steps from 1b.
a Key: (a) (1) 3 equiv Bu4NF (1 M in THF), methylpropionate, DMSO,
80 °C, 20 min; (2) Ac2O, DMAP, pyridine, 20 min; (b) 5 mol %
Pd(CH3CN)2Cl2, THF, 3 h; (c) K2CO3, MeOH, 18 h; (d) (NH4)2Ce(NO3)6,
MeCN, borate-HCl buffer (pH ) 8), 60 °C, 2 h.
usefulness of this catalytic method by applying it to the synthesis
of (-)-PGE1 methyl ester.13
The initial approach we followed for this catalytic asymmetric
total synthesis is reminiscent of the three component coupling
reaction introduced by Noyori et al.,14 a methodology which gives
access to a variety of prostaglandins.15 However, the use of the
required dialkenylzinc reagents instead of the previously used
dialkylzincs did not lead to product formation. For this reason
we developed a new strategy involving the introduction of the
saturated R-chain with a functionalized zinc reagent and the
ω-chain via an unsaturated aldehyde. The synthesis starts with
enone 1b, aldehyde 5,12b,16 and the functionalized zinc reagent
617 (Scheme 2). In the presence of 3 mol % of the catalyst we
obtained compound 7 in 60% yield as the only product as a
mixture of diastereomers (ratio 83:17) which differ in the
configuration at the exocyclic stereocenter bearing the hydroxy
functionality. This one-pot procedure is carried out with an enone
and an enal. To differentiate between these, the unsaturated
aldehyde is equipped with a removable silyl substituent, exploiting
the fact that â-disubstituted enones are not reactive in the 1,4-
addition under these conditions. Reduction of the ketone moiety
In conclusion we have demonstrated that cyclopenten-3,5-dione
monoacetals give highly enantioselective tandem 1,4-addition-
aldol reactions in the presence of dialkylzinc reagents and
aldehydes using a catalytic amount of Cu(OTf)2 and phosphora-
midite ligand 4. Furthermore this reaction is the key step in a
short total synthesis of PGE1 methyl ester, comprising a new route
to this natural product.
Acknowledgment. Financial support by the ministry of economic
affairs (EET grant) is gratefully acknowledged.
Supporting Information Available: Experimental details (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
JA015900+
(18) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron
1985, 41, 3257.
(13) Corey, E. J.; Cheng, X.-M. The Logic of Chemical Synthesis; Wiley:
New York, 1989, Chapter 11.
(19) For the Pd(II)-mediated allylic acetate transposition in a modified
prostaglandin intermediate, see: Grieco, P. A.; Takigawa, T.; Bongers, S. L.;
Tanaka, H. J. Am. Chem. Soc. 1980, 102, 7588.
(14) Suzuki, M.; Kawagishi, T.; Suzuki, T.; Noyori, R. Tetrahedron Lett.
1982, 23, 4057.
(20) Marko´, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J, -M.;
Quesnel, Y.; Vanherck, J.-C. Angew. Chem., Int. Ed. 1999, 38, 3207.
(15) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley &
Sons: New York, 1994, Chapter 4.
1
(21) The analytical and spectral data (TLC, HPLC, H NMR, 13C NMR,
(16) Magriotis, P. A.; Kim, K. D. Tetrahedron Lett. 1990, 31, 6137.
(17) Langer, F.; Waas, J.; Knochel, P. Tetrahedron Lett. 1993, 34, 5261.
CD, MS) [R]23 -51° (c 1.0, CH3OH) of 13 were identical with those of
authentic materDial (Sigma) [R]23 -54° (c 1.0, CH3OH).
D