Catalytic enantioselective conia-ene reaction

Article abstract of DOI:10.1021/ja055059q

An enantioselective intramolecular Conia-ene reaction of β-dicarbonyl compounds and alkynes to afford methylene cyclopentanes is described. The reaction employs a DTBMSegphos-Pd(II)/Yb(III) dual catalyst system that allows for the asymmetric synthesis of

Full text of DOI:10.1021/ja055059q

Published on Web 11/17/2005
Catalytic Enantioselective Conia-Ene Reaction
Britton K. Corkey and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received July 26, 2005; E-mail: fdtoste@berkeley.edu
The Michael addition of compounds containing active methylenes
to a π-acceptor provides an attractive method for the stereoselective
construction of all carbon quaternary centers.1 Recently, significant
progress has been made in the development of enantioselective
intermolecular addition of prochiral nucleophiles to olefinic π-ac-
ceptors.2 On the other hand, enantioselective intramolecular Michael
addition of pronucleophiles is rare.3 The related addition to the
π-bond of an unactivated alkyne offers the advantage that the
product contains an alkene that can be further functionalized and
that the noncatalyzed reaction proceeds only at elevated tempera-
tures; however, enantioselective R-vinylation4 by addition to alkynes
is extremely rare.5
We recently reported a gold(I)-catalyzed intramolecular addition
of â-ketoesters to alkynes.6 This catalyst system provided the basis
for our initial studies on the development of a transition metal-
catalyzed enantioselective Conia-ene reaction. To this end, treatment
of â-ketoester 1 with 5% of cationic chiral gold complexes 2 or 3
resulted in the expected product 4 in good yield. Unfortunately, no
enantioselectivity was observed in the product of either reaction
(Table 1, entries 1-2).
Figure 1. ORTEP of (DTBM-SEGPHOS)Pd(OTf)2. Viewed down the C2
axis of the molecule. Thermal ellipsoids shown at 50% probability.
Hydrogens and triflate ligands (except Pd-O) omitted for clarity.
Table 1. Enantioselective Conia-Ene Reaction
entry
cat.
additive
solvent
time (h)
yield (%)
ee (%)
We rationalized that lack of enantioselectivity derived from the
poor transmission of the ligand chirality as a consequence of the
linear geometry of the gold(I) complexes. We therefore examined
electrophilic late metal catalysts containing bidentate chiral ligands.
While chiral Cu(II), Ni(II), and Pt(II) complexes gave poor
selectivity,7-9 treatment of â-ketoester 1 with a catalytic amount
of cationic BINAP-Pd(II)2a complex generated the Conia-ene
adduct 4 in low yield and with moderate enantiomeric excess (68%
ee). Examination of various cationic chiral bisphosphine-palla-
dium(II) complexes revealed that the bis(triflate)-Pd(II) complex
derived from DTBM-SEGPHOS10 (5; Figure 1) produced Conia-
ene product 4 in 81% ee albeit in only 18% yield (entry 3).11
In contrast to previous reports of palladium-catalyzed addition
of â-ketoester to alkynes under basic conditions,12 addition of an
amine base completely inhibited our enantioselective Conia-ene re-
action (entry 4). On the other hand, a stoichiometric amount of
acid increased the yield of 4 dramatically, with no deterioration of
ee (entries 5,6); however, the reaction required 72 h to reach com-
pletion. While the use of Yb(OTf)3 as a cocatalyst dramatically in-
creased the rate of consumption of 1 at the expense of yield of 4
(entry 7), the combination of a protic and Lewis acid produced the
desired rate enhancement without deterioration in the yield or en-
antioselectivity of the palladium-catalyzed reaction (entries 8,9).9,13
Finally, switching the solvent from methylene chloride to diethyl
ether and lowering the reaction concentration to 0.02 M allowed
for the preparation of 4 in 84% yield and 89% ee (entry 10).
A wide range of â-dicarbonyl compounds undergo the Pd(II)/
Yb(III)-catalyzed enantioselective Conia-ene reaction (Table 2).14
For example, replacing isopropyl ester of 1 with ethyl (6) or allyl
esters (8) produced methylenecyclopentenes 7 and 9 with 89% ee
and 90% ee, respectively (entries 2,3). Surprisingly, tert-butyl ester
analogue 10 cyclized to give 11 with significantly lower enanti-
1
2
3
5
5
5
5
5
5
-
-
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
8
85
80
18
0
60
81
15
81
0
0
81
-
81
81
80
80
2
3
4
5
6
7
8
72
72
72
72
3
Et3N (100%)
PPTS (100%)
AcOH (100%)
Yb(OTf)3 (20%) CH2Cl2
AcOH (500%),
Yb(OTf)3 (20%)
AcOH (500%),
Yb(OTf)3 (20%)
AcOH (1000%),
CH2Cl2
3
9
5
5
Et2O
2
83
84
82
89
10
Et2O
12
Yb(OTf)3 (20%) (0.02 M)
oselectivity (entry 4). Substitution of the aromatic ring with an ortho
methyl group produced an enhancement in the enantiomeric excess
to 93% and 94% (entries 5 and 7); however, Pd(II)/Yb(III)-catalyzed
reaction of o-iodoaryl ketone 14 furnished 15 with 85% ee (entry
6). While introduction of an electron donating substituent at the
para position only moderately influenced the enantioselectivity of
the reaction (entry 8), the presence of an electron-withdrawing para
nitro group produced a notable decrease in the selectivity of the
cyclization (entry 9). Larger aryl ketones, such as 1-naphthyl (22)
and 2-naphthyl (24) ketones participate equally well in the
enantioselective Conia-ene (entries 10, 11). On the other hand, the
use of aliphatic ketone 26 afforded 27 with only 44% ee (entry
12). â-Diketone substrates 28 and 30 underwent cyclization with
diminished enantioselectivity to give 29 and 31, respectively (entries
12 and 13).
9
17168
J. AM. CHEM. SOC. 2005, 127, 17168-17169
10.1021/ja055059q CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd(II)-Catalyzed Enantioselective Conia-ene Reactiona
Research Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont,
GlaxoSmithKline, and Eli Lilly & Co. for financial support. We
thank Takasago for their generous donation of the SEGPHOS
ligands.
Supporting Information Available: Experimental procedures,
compound characterization data; X-ray structure data in CIF format.
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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(2) For recent examples of enantioselective intermolecular Michael of prochiral
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Chem. Soc. 2002, 124, 11240. (b) Harada, S.; Kumagai, N.; Kinoshita,
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Org. Chem. 1991, 56, 5750. (d) Stork, G.; Saccomano, N. A. NouV. J.
Chim. 1986, 28, 677. For a review of the intramolecular Michael addition,
see: (e) Little, R. D.; Masjedizadeh, M. R.; Wallquist, O.; McLoughlin,
J. I. Org. React. 1995, 47, 315.
(4) Enantioselective R-vinylaton of ketones with vinyl halides, see: Chieffi,
A.; Kamikawa, K.: Åhman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett.
2001, 3, 1897. For Pd-catalyzed R-allylation of ketoesters using alkynes,
see: (b) Yamamoto, Y.; Patil, N. T. J. Org. Chem. 2004, 69, 6478.
(5) Enantioselective addition to alkynones: (a) Bella. M. Jørgensen, K. A. J.
Am. Chem. Soc. 2004, 126, 5672. (b) Papillon, J. P. N.; Taylor, R. J. K.
Org. Lett. 2002, 4, 119. For an enantioselective cycloaddition of an alkyne
see: (c) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10788.
(6) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith J. J.; Toste, F. D.
Angew. Chem., Int. Ed. 2004, 43, 5350.
(7) (PyBOX)Copper(II) triflate failed to catalyze the reaction even in the
presence of a cationic gold(I) cocatalyst.8 Both cationic BINAP-nickel-
(II)8 (<5% ee) and BINAP-platinum(II) (18% ee) complexes promoted
the reaction; however, the enantioselectivity was poor.
(8) Cu-catalyzed Conia-ene reaction: Bouyssi, D.; Monteiro, N.; Balme, G.
Tetrahedron Lett. 1999, 40, 1297-1300.
(9) Ni-catalyzed Conia-ene reaction: Gao, Q.; Zheng, B.-F.; Li, J.-H.; Yang.
D. Org. Lett. 2005, 7, 2185.
a Reaction conditions: 10 mol % 5, 20% Yb(OTf)3, 10 equiv of AcOH,
0.02 M in diethyl ether, rt. b Run in 0.5 M CH2Cl2
The reaction also proceeds well with cyclic ketones allowing
for the enantioselective synthesis of polycycles through a kinetic
resolution. For example, ketone 32 underwent palladium-catalyzed
cyclization to afford 33 in 82% ee at 41% conversion (s ) 18) (eq
1). Notably, in this case the reaction proceeded well in the absence
(10) For enantioselective reactions catalyzed by [(DTBM-SEGPHOS) Pd(II)-
(H2O)2](OTf)2, see: (a) Hamashima, Y.; Yagi, K.; Takano, H.; Tama´s.;
Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 14530. (b) Hamashima, Y.;
Suzuki, T.; Shimura, T.; Umebayashi, N.; Tamura, T.; Sasamoto, N.;
Sodeoka, M. Tetrahedron: Asymmetry 2005, 46, 1447.
(11) The low yield is a result of competitive alkyne dimerization, which is
presumably suppressed by the acid. Trost, B. M.; Sorum, M. T.; Chan,
C.; Harms, A. E.; Ru¨hter, G. J. Am. Chem. Soc. 1997, 119, 698.
(12) (a) Moneitro, N.; Balme, G.; Gore, J. Tetrahedron 1992, 48, 10103. (b)
Balme, G.; Bouyssi, D.; Faure, R.; Gore, J.; Van Hemelryck, B.
Tetrahedron 1992, 48, 3891.
of Yb(OTf)3. A mechanistic hypothesis involving generation of a
palladium enolate2a of the â-dicarbonyl nucleophile that undergoes
Lewis acid (or Brønsted acid in the case of eq 1)-promoted addition
to the alkyne is envisioned.15,16
In conclusion, we have developed the first enantioselective
intramolecular Conia-ene reaction of â-dicarbonyl compounds and
alkynes. The Pd(II)/Yb(III) dual catalyst system allows for the
asymmetric synthesis of all-carbon quaternary centers and generates
a product containing an alkene that can be further manipulated.
For example, Conia-ene adduct 15 was employed in an intramo-
lecular reductive-Heck cyclization to produce tricyclic ketone 3417
(eq 2). Further applications of this Pd(II)/Yb(III) dual catalyst
system for enantioselective synthesis will be reported in due course.
(13) Addition of â-dicarbonyl compounds to olefins catalyzed by Pt(II), Eu-
(III) and stoichiometric HCl, see: Liu, C.; Widenhoefer, R. A. Tetrahedron
Lett. 2005, 46, 285.
(14) The corresponding 5-endo-dig carbocyclization6b required prolonged
reaction times (7 days) and gave racemic products.
(15) In accord with a mechanism involving trans addition to the alkyne,
cyclization of a deutero-acetylene resulted in isolation of the adduct in
which deuterium was only incorporated cis to the ketoester; however, this
experiment was complicated by deuterium exchange of acetylenic proton.
(16) A mechanism involving alkyne activation by Pd(II) was excluded in
isomerization of 1,6-enynes catalyzed by related cationic bis(phosphine)-
palladium(II) complexes: Mikami, K.; Hatano, M. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5767.
(17) The absolute stereochemistry of 34 was assigned using the mandelate
method on alcohol 35 (see Supporting Information). The stereochemistry
of remaining ketoesters was assigned by analogy and is consistent with
the stereochemistry predicted by the Sodeoka model.2a
Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, NIHGMS (R01 GM073932-01) Merck
JA055059Q
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