Chemical Communications
Q1
b907151b
Palladium-catalysed enantioselective a-hydroxylation of
b-ketoesters
Alexander M. R. Smith, Denis Billen and King Kuok
(Mimi) Hii
Highly enantioselective a-hydroxylation of cyclic and acyclic
1,3-ketoesters can be achieved with up to 98% ee using a
dicationic palladium(II) catalyst and dimethyldioxirane as
oxidant.
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COMMUNICATION
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www.rsc.org/chemcomm | ChemComm
Palladium-catalysed enantioselective a-hydroxylation of b-ketoestersw
1
Alexander M. R. Smith,a Denis Billenb and King Kuok (Mimi) Hii*a
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5
Received (in Cambridge, UK) 8th April 2009, Accepted 1st May 2009
First published as an Advance Article on the web
DOI: 10.1039/b907151b
10 Highly enantioselective a-hydroxylation of cyclic and acyclic
1,3-ketoesters can be achieved with up to 98% ee using a
dicationic palladium(II) catalyst and dimethyldioxirane as oxidant.
15 Direct a-hydroxylation of b-ketoesters produces valuable
synthetic intermediates containing three contiguous carbons
in different oxidation states.1 Achieved by the addition of an
electrophilic oxygen to a stabilised enol(ate), good enantioselectivity can be obtained using stoichiometric amounts of
20 base and an optically pure oxidant, such as camphorylsulfonyl-oxaziridine (also known as Davis’ reagent).2
Asymmetric catalytic reactions were first accomplished by
Mezzetti et al., who set an important benchmark of 94% ee by
using a TADDOL-Ti(IV) catalyst and N-arylsulfonyloxaziri25 dine as oxidant.3 To date, this was matched only by Shibata
et al., who attained up to 97% ee in the reactions of cyclic
substrates, by employing a catalyst generated from
DPFOX/Ni(ClO4)2 and a saccharin-derived oxaziridine
(Fig. 1).4,5
30
Previously, we reported the use of dicationic (diphosphine)
palladium(II) catalysts for highly enantioselective addition of
aromatic amines to Michael acceptors containing 1,3-dicarbonyl chelating substrates.6 Herein, we will demonstrate that
these catalysts can also be used to effect enantioselective
35 hydroxylation of several cyclic and acyclic b-ketoesters
(Fig. 2).7
Using [(R-BINAP)Pd(OH2)2]21[TfO] 2 (1)8 as the catalyst,
dimethyldioxirane (DMD) was chosen as the source of electrophilic oxygen in this work:9 the volatility of this oxidant
40 and its side product (acetone) eliminates the need for column
chromatography, expediting reaction workup and analysis.
Two cyclic b-ketoesters 2-alkylcarboxylate indanone (I) and
2-alkyl caboxylate cyclopentanone (II) were initially selected as
substrates. At 5 mol% catalyst loading, reactions were com45 pleted uniformly in 0.5 h at 20 1C, affording hydroxylated
products with encouragingly high levels of selectivity (Table 1,
entries 1–7).z As noted in earlier studies, the size of the ester
substituent proved critical for the attainment of high ee
values—for the hydroxylation of 2-alkylcarboxylate indanone
50 (I), a steady rise from 26 to 85% ee was observed with
increasing steric bulk (2a–2d, entries 1–4). In comparison, a
greater level of stereoselectivity was obtained in the absence of
the fused aromatic ring: for the hydroxylation of 2-alkyl
carboxylate cyclopentanones (II), 87% ee was obtained for
the ethyl ester 3a, increasing to 98% for the tert-butyl ester 3c
(entries 5–7)—the highest stereoselectivity reported for this
substrate.
Given that hydroxylated pyrrolidines and pyrrolidinones
are prevalent core structures in biologically active molecules
and natural products,10 the effect of incorporating nitrogen
heteroatom into the cyclic ring was examined. Retaining the
tert-butyl ester for maximum stereodifferentiation, three pyrrolidin-4-one-3-carboxylates (III), containing different N-protecting groups, were prepared and subjected to the
hydroxylation reaction (entries 8–10). The results showed that
a nitrogen heteroatom can be accommodated at this position
without any detrimental effect, and ee’s in excess of 90% can
be obtained. However, the choice of the N-substituent is
important for the product stability—the Moc-protected product 4a decomposes within an hour at room temperature.
Next, two tert-butyl pyrrolidin-2-one carboxylates (IV) were
prepared and subjected to the hydroxylation reaction. Compared to other substrates, the acidity of the enolisable proton
is significantly lower in these systems. This resulted in a
notable attenuation in reactivity, which was overcome by
raising the temperature to 0 1C. Under these conditions, the
reaction provided 77% ee for the substrate 5a (entry 11).
Furthermore, by substituting the benzyl protecting group with
a carbamate (Boc), the formation of 5b can be accelerated, to
afford an excellent yield and 96% ee (entry 12).
Acyclic b-ketoesters are challenging substrates for electrophilic hydroxylation reactions. Due to their inherent low
reactivity, processes such as the Baeyer–Villiger rearrangement
often become competitive during the oxidation process.2,11
With this in mind, preliminary experiments were conducted
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a
Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington, London, UK SW7 2AZ.
55 E-mail: [email protected]; Fax: þ44-(0)20-7594-5804
b
Pfizer Animal Health, 333 Portage Street, Kalamazoo, MI 49001,
USA
w Electronic supplementary information (ESI) available: Detailed
experimental procedure, characterisation data and selected NMR
spectra. See DOI: 10.1039/b907151b
This journal is
c
The Royal Society of Chemistry 2009
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Fig. 1 Reported catalysts for enantioselective a-hydroxylation of bketoesters.
Chem. Commun., 2009, 1–3 | 1
Table 1 a-Hydroxylation of cyclic b-ketoestersa
1
1
5
5
Fig. 2 b-Ketoester substrates examined in this work.
using 2-benzyl substituted acetoacetic acid esters V (entries
10 13–15). As anticipated, the reactions were sluggish, requiring
increased amount of catalyst, oxidant, and reaction time.
Nevertheless, the products can be obtained in moderate yields,
with a modest 65% ee for the methyl ester 6a, raising to a
notable 88% ee with the tert-butyl ester 6c. As far as we are
15 aware, this is the highest enantioselectivity reported for the
hydroxylation of acyclic substrates.12 Significantly, the formation of competitive side products was not evident, as only
unreacted starting material was recovered from the reaction
mixtures, which we attribute to a combination of soft Lewis
20 acidity of the catalyst and mild reaction conditions.
Preliminary mechanistic investigations revealed interesting
aspects of catalyst behaviour. The palladium–enolate complex
8 can be generated by mixing the cyclic ketoester Ia (methyl 1indanone-2-carboxylate)
with
[(R-BINAP)Pd(m25 OH)]212[TfO] 2 713 (10 mol%, Scheme 1, eqn 1), indicated
in the 31P NMR spectrum (Fig. 3) by the transformation of the
precursor’s singlet resonance (dP þ29.0) to an AB pattern (dP
þ34.8 and þ29.8 ppm, J 27 Hz). The addition of DMD to
complex 8 did not lead to any product formation at 78 1C. In
30 contrast, the addition of Ia to the bis–aqua complex 1 showed
no visible change to its broad singlet 31P resonance (dP þ33.0
ppm), but the addition of oxidant to the mixture ( 78 1C) led
to the formation of the hydroxylated product (67% conversion
in 5 h).14
These observations suggest that the chelation of the ketoe35
ster to Pd(II) is not the only means of activation. We postulate
that the concomitant release of trifluoromethanesulfonic acid
upon the (reversible) coordination of the substrate to complex
1 is necessary to protonate the DMD reagent, to enhance the
40 catalytic reaction (Scheme 1, eqn 2), i.e. the reaction proceeds
via cooperate Lewis and Brønsted acid catalysis.
In the postulated transition state (Fig. 4), steric interaction
between the bound substrate’s ester moiety with one of the
ligand’s equatorial Ph groups causes the alkyl substituent to
45 occupy the least sterically congested quadrant of the coordination sphere. This directs the DMD oxidant to approach the
enolate via a least-hindered face. According to this model, the
pro-(S) face of the enolate should be kinetically more accessible using the R-BINAP-ligated catalyst. Indeed, this corre50 sponds to the stereochemistry of predominant enantiomers
obtained for 3a15 and 3c.4
Dicationic BINAP–palladium complex 1 catalyses highly
enantioselective a-hydroxylation of cyclic and acyclic b-ketoesters, using DMD as a ‘clean’ oxidant. Unprecedented enan55 tioselectivities of up to 98% can be obtained with cyclic
substrates and 88% for acyclic substrates. Compared to previously described catalytic systems, the Pd catalyst is particularly air- and moisture-stable; reactions can be performed in
air with reagent-grade solvents without any noticeable degra2 | Chem. Commun., 2009, 1–3
Temp/1C Time/h Yield%b eec (%)
Entry Product
10
1
2
3
4
2a (R ¼ Me)
2b (R ¼ Et)
2c (R ¼ i-Pr)
2d (R ¼ t-Bu)
20
20
20
20
0.5
0.5
0.5
0.5
95
88
86
95
26
48
48
85
15
20
5
6
7
3a (R ¼ Et)
3b (R ¼ Bn)
3c (R ¼ t-Bu)
20
20
20
0.5
0.5
0.5
89
78
88
87
66
98d
25
8
9
10
4a (Z ¼ CO2Me)
4b (Z ¼ CO2Bn)
4c (Z ¼ CO2t-Bu)
20
20
20
0.5
0.5
0.5
38e
97
93
95
90
93
30
35
11f
12
5a (Z ¼ Bn)
5b (Z ¼ Boc)
0
0
48
18
91
99
77
96
40
13f
14f
15f
6a (R ¼ Me)
6b (R ¼ Et)
6c (R ¼ t-Bu)
0
0
0
48
48
48
62
65
55
65
62
88
45
a
Unless otherwise stated, general reaction conditions: ketoester substrate (0.123 mmol), catalyst 1 (0.0123 mmol, 5 mol%), DMD
(0.05–0.09 M in acetone, 1.2 equiv.), CH2Cl2 (0.5 mL). b Isolated yield
of the purified product, replicated to 5%. c Determined by chiral
HPLC. d Determined by chiral GC. e Low yield due to product
decomposition at room temperature. f Reactions performed with 20
mol% catalyst and 2 equivalents of oxidant.
dation in yield or selectivity.16 Furthermore, formation of side
product is not an issue, even when reactions are slow. Preliminary mechanistic studies revealed that reaction is likely to
occur via cooperative Brønsted and Lewis acid catalysis.
Further studies are underway, including the reaction
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sions during this period. The authors thank EPSRC (DTA)
and Pfizer for financial support, and Johnson Matthey Plc for
the loan of Pd salts.
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Notes and references
Scheme 1 Coordination behaviour of a 1,3-ketoester to dicationic
palladium catalysts 1 and 7.
Fig. 3 31P–{1H} spectra recorded with solutions in CD2Cl2: complex
7 (top), and with Ia added (bottom).
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Fig. 4 Predicted stereochemical pathways in the transition state.
45 optimisation of acyclic ketoester substrates, and their application to asymmetric synthesis.
Part of this work was performed by AMRS at Pfizer’s
Sandwich laboratories (January–March 2008). We are grateful
to Dr Richard Webster for his assistance and useful discus50
1
z Typical reaction procedure: a mixture of ketoester (0.123 mmol) and
catalyst 1 (6.15 mmol) in CH2Cl2 (0.5 mL) was cooled to 20 1C,
whereupon a solution of DMD (0.05–0.09 M in acetone, 0.148 mmol)
was added slowly. Upon completion of the reaction (monitored by
TLC), the mixture was filtered through a short plug of silica and
concentrated. If necessary, the crude product was further purified by
column chromatography.
1 J. Christoffers, A. Baro and T. Werner, Adv. Synth. Catal., 2004,
346, 143.
2 F. A. Davis, H. Liu, B.-C. Chen and P. Zhou, Tetrahedron, 1998,
54, 10481.
3 P. Y. Toullec, C. Bonaccorsi, A. Mezzetti and A. Togni, Proc.
Natl. Acad. Sci. U. S. A., 2004, 101, 5810.
4 T. Ishimaru, N. Shibata, J. Nagai, S. Nakamura, T. Toru and
S. Kanemasa, J. Am. Chem. Soc., 2006, 128, 16488.
5 During the preparation of this manuscript, enantioselective ahydroxylation reactions were reported using a chiral Brønsted acid
and PhNO as oxidant (effective for cyclic b-dicarbonyl substrates
only): M. Lu, D. Zhu, Y. Lu, X. Zeng, B. Tan, Z. Xu and
G. Zhong, J. Am. Chem. Soc., 2009, 131, 4562.
6 P. H. Phua, S. P. Mathew, A. J. P. White, J. G. de Vries,
D. G. Blackmond and K. K. Hii, Chem.–Eur. J., 2007, 13, 4602,
and references therein.
7 Palladium-catalysed a-hydroxylation of 1,3-dicarbonyl compounds was reported once before in racemic reactions (using
10% Pd/C and oxygen, in the presence of NEt3): Y. Monguchi,
T. Takahashi, Y. Iida, Y. Fujiwara, Y. Inagaki, T. Maegawa and
H. Sajiki, Synlett, 2008, 2291.
8 Catalyst 1 was prepared by using Pd(OTf)2 and BINAP, see:
P. H. Phua, J. G. de Vries and K. K. Hii, Adv. Synth. Catal.,
2006, 348, 587.
9 Uncatalysed reaction was reported to be very slow: W. Adam and
F. Prechtl, Chem. Ber., 1991, 124, 2369.
10 H. Yoda, Curr. Org. Chem., 2002, 6, 223.
11 For example, see ref. 2, also: J. Christoffers, T. Werner, S. Unger
and W. Frey, Eur. J. Org. Chem., 2003, 425; D. Li, K. Schröder,
B. Bitterlich, M. K. Tse and M. Beller, Tetrahedron Lett., 2008, 49,
5976.
12 Previously, ee values of 56%, 9% and 40% were attained for 6b
using stoichiometric chiral oxaziridine (ref. 2), Ti catalyst (ref. 4),
and achiral Brønsted acid catalyst (ref. 5), respectively.
13 Y. Hamashima, D. Hotta, N. Umebayashi, Y. Tsuchiya, T. Suzuki
and M. Sodeoka, Adv. Synth. Catal., 2005, 347, 1576.
14 At 20 1C, reaction was completion within 30 min in the presence
of 10 mol% complex 1, but only 41% conversion was observed
with complex 7 after 2 h. The product ee is identical in both cases
(35%). Similar protonolysis (of a Michael acceptor) has been
proposed previously, see ref. 13.
15 By comparison to optical value reported for (R)-(þ)-3a:
D. Buisson, X. Baucherel, E. Levoirier and S. Juge, Tetrahedron
Lett., 2000, 41, 1389.
16 Trace of moisture present in DMD caused decomposition of the
Ti-TADDOL catalyst (ref. 3), while the presence of molecular
sieves is necessary for nickel catalysis (ref. 4).
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Chem. Commun., 2009, 1–3 | 3