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Efficient 1 5-Chirality Transfer in Palladium-Catalyzed Allylic Alkylations of Chelated Amino Acid Ester Enolates.

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Stereoselective Reactions
Efficient 1,5-Chirality Transfer in PalladiumCatalyzed Allylic Alkylations of Chelated Amino
Acid Ester Enolates**
Uli Kazmaier* and Thomas Lindner
Dedicated to Professor Franz Effenberger
on the occasion of his 75th birthday
Of the palladium-catalyzed reactions, allylic alkylations are
especially popular, not least because of a number of stereoselective variants.[1] In general, heteronucleophiles are used as
well as symmetric stabilized carbanions such as malonates as
C nucleophiles. The advantage of the latter is that in the CC
coupling step only one stereogenic center is created, that is,
that in the allyl fragment. In contrast, the use of unsymmetrical nucleophiles (Nu) such as b-ketoesters[2] and imines
of amino acid esters[3] in general results in mixtures of
diastereomers. Therefore, most examples in the literature
dealing with the stereochemical outcome of the allylic
alkylation focus on 1,3-disubstituted allylic systems
(Scheme 1). In reactions of substrates A, which form a
symmetric achiral p-allyl palladium complex B, the stereochemical outcome can be controlled by chiral ligands (L*). In
contrast, unsymmetric substrates C give rise to the chiral allyl
complex D, and stereogenic information is transferred from
the starting material C to the product E.[1] The only snag is the
Scheme 1. Asymmetric palladium-catalyzed allylic alkylations.
[*] Prof. Dr. U. Kazmaier, Dipl.-Chem. T. Lindner
Institut fr organische Chemie
Universitt des Saarlandes
Im Stadtwald, Geb. 23.2, 66123 Saarbrcken (Germany)
Fax: (+ 49) 681-302-2409
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(SFB 247 and Ka 880/5) and the Fonds der Chemischen Industrie.
Angew. Chem. Int. Ed. 2005, 44, 3303 –3306
DOI: 10.1002/anie.200500095
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
problem of regioselectivity. Especially the reaction of substrates bearing very similar substituents R and R’ results in
the formation of product mixtures (E + E’).[4]
This problem is less significant with substrates F and G,
which form the terminal p-allylpalladium complexes H, since
these allyl complexes are usually attacked at the sterically
least hindered position (!I). Therefore, for stereoselective
synthesis these substrates are uninteresting, because in
reactions of symmetrical nucleophiles only achiral products
are obtained, while the application of unsymmetrical nucleophiles gives rise to racemic mixtures. Even the use of
enantiomerically pure substrates G is not a solution to this
problem, because the chiral information is lost nearly
immediately through p-s-p isomerization.[5] To the best of
our knowledge a suitable protocol for transferring chiral
information from the allyl substrate to the stereogenic center
in the attacking nucleophile has not yet been reported.
Terminal complexes such as H can be converted into
optically active products J only if the nucleophilic attack can
be directed towards the sterically more hindered position.
According to Pfaltz et al. this goal can be reached by
switching the reaction mechanism from an SN2-type towards
a more SN1-type mechanism.[6] For example, with phosphite
ligands[7] instead of phosphanes, the branched products J are
formed preferentially. These can be obtained in an enantiomerically enriched form when chiral ligands such as phosphite
oxazolines[6] and sterically demanding monophosphanes are
used.[8] Other metals such as molybdenum,[9] tungsten,[10] and
iridium[11] also have a higher tendency for the formation of
branched product J. It is known that rhodium complexes in
general do not undergo p-s-p isomerization, and therefore
they facilitate chirality transfer from an optically active
substrate to the product J.[12]
Our group is investigating reactions of chelated amino
acid ester enolates K and also their application as nucleophiles in palladium-catalyzed allylic alkylations.[13] These
nucleophiles react under much milder conditions than the
“standard nucleophiles”. In addition, they also allow the
generation of a second stereogenic center, and this generally
in a highly stereoselective fashion. Because these chelated
enolates already react at 78 8C, p-s-p isomerization can be
suppressed nearly completely.[14] Therefore, Z-configurated
allyl substrates L can be converted into the corresponding
syn/anti allyl complex M (without isomerization), which then
is attacked by K regioselectively at the “anti position”
(Scheme 2). This allows a chirality transfer from L to N. The
diastereoselectivity of the formation of the allylation product
N depends on the substituent R and increases with the
decreasing bulk of R.
Scheme 2. Palladium-catalyzed allylic alkylations of chelated enolates.
Tfa = trifluoroacetyl.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
One might therefore expect the best selectivity for R = H.
In this case only one stereogenic center is formed, and we
hoped that the high selectivity of the nucleophilic attack on
the allyl complex could be used for chirality transfer directly
to the a-position of the amino acid formed. But with R = H
the problems discussed above take effect, and the very fast ps-p isomerization of terminal p-allyl palladium complexes
prevents chirality transfer from L to N. Therefore we focused
our attention on reactions of substrates such as 1 which are
easily obtained from lactic acid. We investigated the influence
of the O-protecting group (PG) on the stereochemical
outcome of the reaction (Scheme 3, Table 1). We chose
Scheme 3. Diastereoselective allylation of chelated enolates; see also
Table 1.
Table 1: Diastereoselective allylation of chelated enolates; see also
Scheme 3.
Yield [%]
ds [%][a]
[a] MOM = methoxymethyl,
THP = tetrahydropyranyl,
Bn = benzyl,
TBDMS = tert-butyldimethylsilyl, TBDPS = tert-butyldiphenylsilyl, Trt =
trityl, Piv = pivaloyl, ds = diastereoselectivity. [b] Determined by
C NMR spectroscopy. [c] Determined by HPLC.
methyl carbonate as the leaving group and trifluoroacetylprotected tert-butyl glycinate as the nucleophile. The yields
were excellent and nearly independent of the O-protecting
group used; only with the tritylated substrate (Table 1,
entry 6) was no reaction observed. It seems in this case that
the coordination of the palladium to the alkene is hindered
for steric reasons. Apparently the coordination occurs from
the face opposite to the oxygen atom, giving rise to allyl
complex 1’, which then is attacked by the chelated enolate K
from the backside. The diastereoselectivities obtained nicely
correlate with the size of the O-protecting group, which is
especially significant in the switch from the TBDMS to the
sterically more demanding TBDPS protecting group. The
latter protecting group gave 96 % ds, an excellent result
especially when one considers that this is an example of 1,5induction.
Angew. Chem. Int. Ed. 2005, 44, 3303 –3306
An equally good result was obtained with the pivaloyl
derivative 1 g. This substrate is quite interesting because it has
two leaving groups, which should both be replaceable. The
primary carbonate leaving group is the significantly more
reactive one. With one equivalent of nucleophile the monosubstitution product 2 f was formed exclusively, while with
2.6 equivalents of K a mixture of 2 f (55 %) and the
disubstituted product 3 f (44 %, 75 % ds) in almost quantita-
tive overall yield was obtained. In principle it should be
possible to use the pivaloate group in the first step to control
the configuration at the a-position of the amino acid before it
is replaced in the second step by various other nucleophiles.
To get an impression of how fast the p-s-p isomerization
of these terminal allyl substrates occurs, we also subjected the
Z substrate rac-4 e to the same reaction conditions
(Scheme 4). As mentioned earlier, with 1,3-disubstituted
because these substrates are easily accessible. Therefore we
investigated the reaction of the two silyl-protected derivatives
5 d and 5 e, and indeed, the selectivities obtained were exactly
the same as with the linear substrates 1 d and 1 e.
In all examples investigated so far, the syn-configurated
product was obtained preferentially. To provide the corresponding anti isomer, the palladium must be coordinated to
the opposite face of the alkene, in other words, the face of the
O-substituent. Breit et al. reported for hydroformylation
reactions that coordinating protecting groups such as the
diphenylphosphanylbenzoate (o-dppb) are especially suitable
for this purpose.[15] As illustrated with the o-dppb-protected
substrate 1 h, such a directing effect can also be used for
stereoselective allylations. By this synthetic protocol both
stereoisomeric products can be obtained from one substrate
(allylic alcohol) in a highly stereoselective fashion.
To test the generality of this concept we also subjected
substrate 6 a (with the sterically demanding isopropyl group)
and the 6 b (with a ketal protecting group) to our reaction
conditions (Scheme 5). Indeed, the results were comparable
to those obtained with the corresponding methyl-substituted
derivatives 1.
Scheme 5. Reactions of substituted allylic substrates.
Scheme 4. Diastereoselective allylation of chelated enolates.
substrates of type L (Scheme 2) the isomerization was
suppressed completely.[14] If this is also true with terminal
allyl complexes one might expect (Z)-2 e as the substitution
product. In contrast, rac-2 e was formed with exactly the same
selectivity as obtained from 1 e. This clearly indicates that in
terminal p-allyl complexes the p-s-p isomerization is even
faster than the substitution with these highly reactive
With this in mind one should expect that analogous
substrates 5 with a secondary leaving group should provide
the same substitution products, independent of the configuration of the leaving group. This is a very interesting option,
Angew. Chem. Int. Ed. 2005, 44, 3303 –3306
In conclusion we could show that chelated enolates are
good nucleophiles for stereoselective allylations of both 1,3disubstituted and also terminal allylic substrates. Neither the
position and configuration of the leaving group nor the olefin
geometry influences on the stereochemical outcome of the
reaction. This is exclusively controlled by the O-protecting
group used. Further investigations are in progress.
Experimental Section
General procedure for palladium-catalyzed allylic alkylations: Hexamethyldisilazane (226 mg, 1.40 mmol) was dissolved in THF
(1.5 mL) in a Schlenk flask under argon. After the solution had
been cooled to 78 8C, nBuLi (1.6 m, 0.80 mL, 1.25 mmol) was added
slowly. The reaction mixture was stirred for 20 min at this temperature, and then the cooling bath was removed and stirring was
continued for further 15 min. In a second Schlenk flask N-trifluoroacetyl tert-butyl glycinate (114 mg, 0.50 mmol) was dissolved in THF
(3 mL). The solution was cooled to 78 8C, before the fresh prepared
lithium hexamethyldisilazanide solution was added. After 15 min a
solution of dried ZnCl2 (75 mg, 0.55 mmol) in THF (0.5 mL) was
added, and stirring was continued for 30 min.
2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
A solution was prepared from [{PdCl(allyl)}2] (10 mg,
0.025 mmol) and PPh3 (30 mg, 0.113 mmol) in THF (5 mL). After
this solutionwas stirred for 15 min at room temperature, it was added
to the chelated enolate at 78 8C. At the same temperature the allyl
substrate (0.3 mmol) was added in THF (0.5 mL) before the mixture
was allowed to warm to room temperature overnight. The solution
was diluted with ether before 1m KHSO4 was added (NH4Cl for ketalprotected substrates). After separation of the layers, the aqueous
layer was extracted three times with ether, and the combined organic
layers were dried over Na2SO4. The solvent was evaporated in vacuo,
and the crude product was purified by flash chromatography.
Received: January 11, 2005
Published online: April 25, 2005
Keywords: allylation · amino acids · chelates · enolates ·
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acid, efficiency, enolate, palladium, alkylation, esters, transfer, amin, chirality, allylic, chelate, catalyzed
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