COMMUNICATION
Palladium-catalysed enantioselective a-hydroxylation of b-ketoestersw
Alexander M. R. Smith,a Denis Billenb and King Kuok (Mimi) Hii*a
Received (in Cambridge, UK) 8th April 2009, Accepted 1st May 2009
First published as an Advance Article on the web 22nd May 2009
DOI: 10.1039/b907151b
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.
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).
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 enantio-
selectivity can be obtained using stoichiometric amounts of
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-arylsulfonyloxaziridine
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
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 hydroxylation
of several cyclic and acyclic b-ketoesters (Fig. 2).7
Using [(R-BINAP)Pd(OH2)2]2+[TfO]ꢀ (1)8 as the catalyst,
2
dimethyldioxirane (DMD) was chosen as the source of electro-
philic oxygen in this work:9 the volatility of this oxidant 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
completed 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
(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
Acyclic b-ketoesters are challenging substrates for electro-
philic 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
using 2-benzyl substituted acetoacetic acid esters V (entries
13–15). As anticipated, the reactions were sluggish, requiring
a Department of Chemistry, Imperial College London, Exhibition
Road, South Kensington, London, UK SW7 2AZ.
E-mail: mimi.hii@imperial.ac.uk; Fax: +44-(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
Fig. 1 Reported catalysts for enantioselective a-hydroxylation of
b-ketoesters.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 3925–3927 | 3925