Palladium-catalyzed chemo- and enantioselective oxidation of allylic esters and carbonates

Full text of DOI:10.1021/ja057163d

Published on Web 02/07/2006
Palladium-Catalyzed Chemo- and Enantioselective Oxidation of Allylic Esters
and Carbonates
Barry M. Trost,* Jeffery Richardson, and Kelvin Yong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
Received October 20, 2005; E-mail: bmtrost@stanford.edu
Scheme 1. Mechanism of Allylic Oxidation
The palladium-catalyzed asymmetric allylic alkylation of nu-
cleophiles with allyl halides, esters, carbonates, and phosphonates
provides an efficient and atom-economical access to a variety of
useful chiral and achiral compounds.1 The use of nitronates as
nucleophiles in allylic alkylation typically results in C-alkylation
to afford synthetically useful nitroalkanes.2 However, by tuning the
steric and electronic properties of the nitronate, we have discovered
that O-alkylation can be favored and, thus, by the fragmentation
mechanism shown in Scheme 1, provide a novel access to R,â-
unsaturated carbonyl compounds. The use of nitronates as nucleo-
philic oxidants for benzyl halides has been known for a long time,3
although it is seldom utilized in synthesis.
Table 1. Oxidation of Allylic Esters and Carbonates
Nitronate 1 was chosen to disfavor C-alkylation by placing
sterically encumbering groups in the adjacent positions as well as
to favor O-alkylation electronically by minimizing disruption of
conjugation in the transition state. It was generated in situ by
deprotonation of the corresponding nitro compound using KHMDS,4
which itself was generated by mixing KH and freshly distilled
HMDS in the reaction vessel prior to addition of the nitro
compound.
Our studies began with the attempted oxidation of methyl-5-
(benzoyloxy)-3-cyclohexene-1-carboxylate, where only moderate
conversion to the enone could be obtained in 8 h using PPh3 as
ligand. Upon screening a small number of other leaving groups,
we discovered that the 3,5-dinitrobenzoate derivative was a
significantly better substrate, affording the enone in essentially
quantitative yield in less than 1 h (Table 1, entry 1). A small screen
of other phosphines showed that PPh3 was the best ligand for this
process, and that bidentate ligands resulted in prolonged reaction
times.
A variety of substrates bearing this activated leaving group were
prepared and tested (Table 1), and the inherent chemoselectivity
of this process toward allylic leaving groups was demonstrated.
For example, a good leaving group that does not occupy an allylic
position is undisturbed (Table 1, entry 7), and a variety of functional
groups that might otherwise be affected by other commonly utilized
oxidants also remain unchanged by this oxidation protocol. Tertiary
amines (Table 1, entry 2), thioethers (Table 1, entry 3), and
unprotected primary alcohols (Table 1, entry 9) are all comfortably
tolerated with no occurrence of undesired oxidation. Acyclic
substrates (e.g., Table 1, entries 11 and 12) can also be oxidized to
the corresponding enones, although racemic ligand 2 appears to be
more effective than PPh3 in the case studied.
The ability of chiral ligands to mediate allylic alkylation reactions
and impart high levels of enantioselectivity in the products is one
of the most appealing aspects of these processes. The desymme-
trization of meso substrates as well as the dynamic kinetic
asymmetric transformations (DYKATs) of racemic substrates with
alcohols, amines, phthalimide, and acetoacetates using ligands, such
as 2, has been shown to be both highly efficient and enantioselective
for a broad range of substrates.1 Applying our chiral ligands to the
a 95% brsm. b Volatile material. Actual yield may be higher.
desymmetrization of meso compounds to generate chiral enones
was first studied (Table 2, entries 1-3). The five- and six-membered
rings performed well, affording the desired products in good yields
and excellent enantioselectivity. The seven-membered ring was
9
2540
J. AM. CHEM. SOC. 2006, 128, 2540-2541
10.1021/ja057163d CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Oxidation of Allylic Esters and Carbonates
Scheme 2. Synthesis of Ba¨ckvall’s Paenilactone A Intermediate
For chiral substrates that lead to chiral products (entries 4-8)
via a symmetrical π-allylpalladium intermediate in a DYKAT
process, the yields and enantioselectivities were uniformly high,
although with some substrates, the reactions became more sluggish
than with PPh3 and did not reach completion.
Kinetic resolution is also possible using this protocol (Table 2,
entry 10), and the conversion of the carbonate can be stopped at
around 50% to afford the starting material in a highly enantio-
enriched state.
To demonstrate the further synthetic utility of this method, the
synthesis of γ-substituted enone 4 was undertaken. This material
is an intermediate in Ba¨ckvall’s synthesis of paenilactone A and
was previously prepared in three steps from the bis-acetate.8
Palladium-catalyzed malonate addition led to 3 in 68% yield and
excellent enantioselectivity (Scheme 2). Oxidation using the newly
developed conditions and PPh3 as ligand afforded 4 in good yield
while retaining the high levels of enantioenrichment.
In conclusion, we have demonstrated a new and highly chemo-
selective method for the oxidation of allylic esters and carbonates.
We have also shown that the reaction can be highly enantioselective
for the oxidation of meso compounds and chiral substrates that
proceed via symmetrical π-allyl Pd complexes. For chiral materials
that do not proceed through such symmetrical Pd complexes, kinetic
resolution is also possible. It should be noted that the nitroalkane
6 readily derives from the oxidation of the corresponding oxime
(5) by oxidation with sodium perborate.4 Thus, recycling of the
oxime byproduct can enhance the efficiency of this method.
Acknowledgment. We thank the National Science Foundation
and National Institutes of Health, GM33049, for their generous
support of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Californias
San Francisco, supported by the NIH Division of Research
Resources.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
a Absolute stereochemistry confirmed by comparison of optical rotation
with known compound. b Absolute stereochemistry assigned by analogy.
c Determined by chiral HPLC or GC analysis. d Determined by hydrolysis
to alcohol. e Nitronate (1 equiv) was used. f Based on 50% theoretical yield.
(1) Trost, B. M. J. Org. Chem. 2004, 69, 5813-5837.
(2) Trost, B. M.; Surivet, J.-P. Angew. Chem., Int. Ed. 2000, 3122-3124.
(3) (a) Hass, H. B.; Bender, M. L. J. Am. Chem. Soc. 1949, 71, 1767-1769.
(b) Hass, H. B.; Bender, M. L. Org. Synth. 1950, 30, 99-101.
(4) Generation of potassium nitronate 1. It was necessary to generate KHMDS
significantly more sluggish and lower yielding, although the
enantioselectivity of the process remained excellent.
Cyclopentenones differing only in the oxygen protecting group
to that prepared in Table 2, entry 1 are common intermediates in
the synthesis of prostaglandins and their analogues.5 A similarly
close analogue of 4-oxo-2-cyclohexenyl benzoate (Table 2, entry
2) was recently employed in a partial synthesis of superstolide A.6
In both cases, these enones were prepared by enzymatic desym-
metrization of a meso ester followed by a number of subsequent
transformations.7 Our new oxidation method affords closely related
products, which are readily available in either enantiomeric form
in just one step from almost identical starting materials.
in situ to avoid reproducibility issues encountered using stock and
commercially available solutions.
(5) (a) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl. 1984, 23, 847-
876. (b) Jung, M. E.; Kers, A.; Subbanagounder, G.; Berliner, J. A. Chem.
Commun. 2003, 2, 196-197.
(6) Hua, Z.; Yu, W.; Su, M.; Jin, Z. Org. Lett. 2005, 7, 1939-1942.
(7) Paquette, L. A.; Heidelbaugh, T. A. Org. Synth. 1996, 73, 44-48.
(8) Jonasson, C.; Roenn, M.; Ba¨ckvall, J.-E. J. Org. Chem. 2000, 65,
2122-2126.
JA057163D
9
J. AM. CHEM. SOC. VOL. 128, NO. 8, 2006 2541