Substrate-controlled palladium-catalyzed allylic alkylations of chelated enolates - Scope and limitations

Article abstract of DOI:10.1002/adsc.200505140

Chelated enolates of amino acid derivatives were found to be excellent nucleophiles for stereoselective palladium-catalyzed allylic alkylations via terminal π-allyl complexes. Neither the olefin geometry (linear substrates) nor the configuration of second

Full text of DOI:10.1002/adsc.200505140

FULL PAPERS
DOI: 10.1002/adsc.200505140
Substrate-Controlled Palladium-Catalyzed Allylic Alkylations of
Chelated Enolates -- Scope and Limitations
Thomas Lindner, Uli Kazmaier*
Institut für organische Chemie, Universität des Saarlandes, Im Stadtwald, Geb. 23.2, 66123 Saarbrücken, Germany
Fax: (þ49)-681-302-2409, e-mail: u.kazmaier@mx.uni-saarland.de
Received: April 5, 2005; Accepted: July 22, 2005
Dedicated to Prof. Helmchen on the occasion of his 65th birthday.
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: Chelated enolates of amino acid derivatives the chiral centre. Therefore, depending on the pro-
were found to be excellent nucleophiles for stereose- tecting group used, both diastereomeric amino acids
lective palladium-catalyzed allylic alkylations via ter- can be obtained in a highly stereoselective fashion
minal p-allyl complexes. Neither the olefin geometry (up to 96% ds for 1,5 induction) from one allylic alco-
(linear substrates) nor the configuration of secondary hol.
allylic substrates has an influence on the newly
formed stereogenic centre of the amino acid. This is Keywords: allylic alkylation; amino acids; chelates;
exclusively controlled by the protecting group on enolates; palladium; stereoselective synthesis
Introduction
p-Allyl metal complexes play an important role in mod-
ern organic synthesis. Among the different metals used,
palladium plays a dominant role, but other metals, espe-
cially later transition metals enlarge the synthetic poten-
tial of these important intermediates.[1] Their most pop-
ular applications are palladium-catalyzed allylic alkyla-
tions, not least because of the different possibilities to
control the stereochemical outcome of the reaction.[2]
In general, heteronucleophiles as well as symmetrical
stabilized carbanions such as malonates are used as C-
nucleophiles. The advantage of the symmetrical C-nu-
cleophiles results from the fact that in their reactions
only one stereogenic centre is created in the allyl frag-
ment. In contrast, the use of unsymmetrical nucleophiles
(Nu) such as b-keto esters[3] or imines of amino acid es-
ters[4] in general results in the formation of diastereo-
meric mixtures. This can be explained by the configura-
tional lability of the allylated nucleophiles. Thus, consid-
erably better results are obtained with alkylated deriva-
tives.[5]
So far, most examples in the literature dealing with the
stereochemical outcome of the allylic alkylation focus
on 1,3-disubstituted allylic systems (Scheme 1). In appli-
cations of substrates of type A, which form a symmetri-
cal p-allyl-palladium complex B, the stereochemical
outcome of the reactions can be controlled by chiral li- tions.
Scheme 1. Asymmetric palladium-catalyzed allylic alkyla-
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gands (ligand*). In contrast, unsymmetrical substrates C Results and Discussion
under inversion give rise to a chiral allyl complex D, al-
lowing an overall chirality transfer from the starting ma- Our group is investigating reactions of chelated amino
terial C towards the product E.[2] The only snag is the acid ester enolates (K), which were found to be excellent
problem of regioselectivity. Especially, the reaction of nucleophiles in a wide range of reactions,[16] including
substrates bearing very similar substituents R and R’ re- palladium-catalyzed allylic alkylations.[17] These nucleo-
sults in the formation of product mixtures (E and E’).[6] philes react under much milder conditions in compari-
This problem is less significant with substrates F and G, son to malonates or the other “standard nucleophiles”.
forming terminal p-allyl-palladium complexes H, which In addition, they also allow the generation of a second
in general are attacked at the sterically least hindered stereogenic centre at the a-position of the amino acid,
position (I). But with respect to stereoselective syn- and this generally in a highly stereoselective fashion. Be-
thesis, these substrates are relatively uninteresting, be- cause these chelated enolates react at temperatures as
À À
cause in reactions of symmetrical nucleophiles only low as À788C, in their reaction the p s p-isomeriza-
achiral products are obtained, while the application of tion can be suppressed nearly completely.[18] Therefore,
unsymmetrical nucleophiles gives rise to racemic mix- for example, (Z)-configured allyl substrates L can be
tures. To the best of our knowledge up to date there is converted into the corresponding syn/anti-allyl complex
no suitable protocol to transfer the chiral information M (without isomerization), which then is attacked by K
from the allyl substrate to the stereogenic centre in the regioselectively at the “anti-position” (Scheme 2). This
attacking nucleophile.
Even the use of enantiomerically pure substrates G is
not a solution to this problem, because the chiral infor-
À À
mation is lost nearly immediately via p s p-isomeriza-
tion.[7] The p s p isomerization is an important mech-
À À
anistic feature in the p-allyl-palladium chemistry and re-
sults in a fast interconversion of p-allyl complexes into
s-complexes and reverse. At the stage of the s-allyl com-
plex rotations around s-bonds are possible and there-
fore either the thermodynamically most stable com-
plexes are formed, or like in this case the p-complexes
undergo epimerization.
Scheme 2. Regioselective allylic alkylations.
allows a chirality transfer from L to N, and also regiose-
In principle, because this isomerization is fast, the ap- lective reactions of allyl substrates bearing similar sub-
plication of chiral ligands can provide optically active stituents R and R’.[19] Under “standard conditions”
products J, if the nucleophilic attack can be directed to- such substrates are critical, normally giving mixtures
wards the sterically more hindered position. This goal of regioisomers. The diastereoselectivity with which
can be reached, for example, if the allylic alkylation is the allylation product N is formed depends on the sub-
performed not in an inter- but in an intramolecular fash- stituent R, and increases with decreasing steric size of R.
ion. In this case, the formation of the “preferred ring
Therefore, one might expect the best selectivity for
size” can direct the nucleophilic attack to the sterically R¼H, and we focused our attention on reactions of sub-
more hindered position.[8] Pfaltz et al. observed the strates such as 1 and 2 (Scheme 3), which should provide
same tendency in intermolecular reactions by switching
the reaction mechanism from an SN2-type more towards
an SN1-type mechanism.[9] If the nucleophile attacks in
an SN2-type fashion, attack should occur at the sterically
least hindered position, while if the reaction proceeds
via an SN1-type mechanism, with a cationic transition
state, the opposite regioselectivity can be expected.
And indeed, with phosphite ligands[10] instead of phos-
phanes, the branched products J are formed preferen-
tially. These can be obtained in an enantiomerically en-
riched form if chiral phosphite oxazolines[9] or sterically
demanding monophosphanes are used.[11] Other metals
Scheme 3. Allylic alkylations using substrates 1 and 2.
such as molybdenum,[12] tungsten[13] or iridium[14] also
have a higher tendency for the formation of branched
product J. It is also known that rhodium complexes in the same diastereomeric p-allyl-palladium complexes
À À
À À
general do not undergo p s p-isomerization, and which can interconvert via a very rapid p s p-isomeri-
therefore they allow a chirality transfer from an optical- zation. In this case, attack of the nucleophile on the ter-
ly active substrate into product J.[15]
minal position of the p-allyl complex generates only one
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chosen to prove the option to direct the palladium via
precoordination.[21]
We began our investigations with the TBDMS-protect-
ed derivative 1a, using allylpalladium chloride dimer as
catalyst in the presence of PPh3. In substrates of type 1
the leaving group is located on a primary, achiral position
and the coordination of the palladium, resulting in the p-
allylcomplexformation, shouldbedirectedbytheO-pro-
tecting group. Based onour experience thatallylic alkyla-
tions of chelated enolates in general proceed in the same
À À
temperature range as the p s p-isomerization, we first
investigated the influence of the reaction temperature
in reactions of substrate 1a (Table 1). Warming up the re-
action mixture from À908C to room temperature over-
night (entry 1) provided substitution product 3a in excel-
lent yield and high diastereoselectivity.
Figure 1. Allylic substrates obtained from lactic acid.
The selectivity could slightly be increased by keeping
the temperature lower (entries 2 to 4), although this ef-
stereogenic centre, and we hoped that the high selectiv- fect was not dramatic. Quenching the reaction mixture
ity of the nucleophilic attack could be used for chirality at À688C after 1.5 h gave 87% ds, but the reaction
transfer from the O-functionality directly to the a-posi- was incomplete and 52% of starting material 1a was re-
tion of the amino acid formed.[20]
covered. Prolonging the reaction time solved this prob-
Both substrate types could easily be obtained from lem without significant influence on the selectivity (en-
lactic acid using standard operations, and we synthe- try 5). Nearly independent of the reaction conditions,
sized several protected derivatives to investigate the in- the yields and selectivities obtained were both reprodu-
fluence of the O-protecting group (PG) on the stereo- cible in the range of 85%. In contrast to reactions of 1,3-
chemical outcome of the reaction (Figure 1). We decid- disubstituted allylic substrates, the temperature obvi-
ed to use the carbonate leaving group (E¼COOMe), ously has no significant influence on the stereochemical
because in previous investigations this group proved su- outcome of the reaction. This might be an indication that
À À
perior to the acetate group, and with diacylated sub- for terminal p-allyl-palladium complexes p s p-iso-
strates such as 1e selective reactions should be possible. merization takes place, even at these very low tempera-
The diphenylphosphinobenzoyl group (dppb) (1e) was tures. But it was not obvious if the selectivity results
Table 1. Influence of the temperature on the diastereoselectivity.
Entry
Substrate
Reaction Conditions[a]
Yield of 3a [%]
ds[b] [%]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
2a
2a
À908C to rt, 12 h
À788C to À688C, 1.5 h
À788C to À608C, 3 h
À788C to À428C, 4 h
À708C, 24 h
88
32
93
84
85
94
66
48
61
84
87
86
88
82
81
83
88
82
À908C to rt, 12 h
À788C to rt, 12 h
À408C, 12 h
2a
2a*[c]
À908C to rt, 12 h
[a]
1) 0.05 M enolate solution in THF, 5 mol % [allylPdCl]2, 20 mol % PPh3, temperature program, 2) 1 M KHSO4.
Selectivity determined by HPLC.
The corresponding acetate was used.
[b]
[c]
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Table 2. Allylic alkylations using different substrates
and 2.[a]
1
selectivities obtained so far, while with the “smaller”
benzyl- (entry 3) and THP protecting groups (entry 4)
the diastereoselectivity was comparable to the TBDMS
derivative. Under standard conditions the reaction mix-
tures were allowed to warm up from À788C to room
temperature overnight. Again, the selectivities obtained
with the diastereomeric mixture of 2b (entry 8) were
identical to those obtained with the linear substrate 1b.
Replacing the carbonate leaving group by acetate (entry
9) gave a lower selectivity (as observed previously) al-
beit in nearly quantitative yield.
The diastereomeric ratio for the silylated derivative
3b could be determined by HPLC using the chiral col-
umn Daicel OD-H, while for the less selectively formed
derivatives 3c/d the second set of signals in the 13C NMR
spectra could be utilized. Based on the specification of
the chiral column, the HPLC analysis could also be
used to determine the absolute configuration of the ami-
no acids obtained. With the column used, a-(R)-amino
acids are eluted prior to a-(S)-amino acids. To make
sure that all stereoisomers can be separated and tofigure
out which major isomer is formed, we also synthesized
rac-1b and subjected it to our allylation conditions.
The HPLC chromatogram of rac-3b is shown in Figure
2a, while Figure 2bcorresponds to 3b obtained from
[a]
E¼COOMe.
Determined by 13C NMR.
The product with the opposite configuration at C-2 (2R)
was obtained (see Scheme 5).
The corresponding acetate was used.
[b]
Determined by HPLC.
[c]
[d]
[e]
from a diastereotopic differentiation in the p-allyl com-
plex formation and/or equilibration of the p-allyl com-
plexes. To get further insight into the mechanism we sub-
jected also substrate 2a as a diastereomeric mixture to
the same reaction conditions. Interestingly, the selectiv-
ities observed were nearly the same as obtained with 1a,
and the yields dropped if the reactions were run at high-
er temperature, while the selectivity increased. The best
selectivity (88% ds) was obtained by running the reac-
tion at À408C overnight. To prove the influence of the
chelating metal we carried out this reaction without
ZnCl2, but no reaction was observed under these condi-
tions, and only starting material was recovered. We also
replaced the carbonate leaving group by an acetate (2a*,
entry 9), but the selectivities were comparable, although
the yield was lower. Increasing the amount of base used
had also no influence on the yield or the selectivity.
If the stereochemical outcome of the reaction is solely
controlled by the steric demand of the O-protecting
group, one might expect a more or less direct correlation
of these parameters. And indeed, increasing the “bulki-
ness” by using the sterically more demanding TBDPS
Figure 2. Determination of stereoselectivity via HPLC (col-
protecting group (Table 2, entry 1) resulted in the best umn: Daiced OD-H). a) rac-3b; b) 3b obtained from 1b/2b.
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Figure 3. Common cleavage products.
1b. The small peak designated as (R,R)-3b results from a
partial epimerization during the synthesis of the starting
materials.
This clearly indicates that the (2S,6S)-isomer is the
major product which was formed in all reactions investi-
gated. From all products 3 obtained, cleavage of the pro-
tecting groups provided the same e-hydroxyamino acid
derivatives 4a and 4b (Figure 3), respectively.
Scheme 5. Allylic alkylation via precoordination.
moderate yield obtained with 1e might be caused by the
The formation of the (S,S)-product can be explained fact that the Pd-directing group is also an allylic leaving
by the following rationale (Scheme 4). Obviously the group and probably 3a undergoes a second ionization.
The Pd complex formed then can react with other nucle-
ophilesinsolution. Unfortunately, wewerenotabletoget
a significant amount of a definite side product.
So far, only substrates with an (E)-olefin geometry
were used. Our investigations with 1,3-disubstituted all-
yl complexes clearly indicated that (Z)-allylic substrates
are more reactive and selective in comparison to the cor-
responding (E)-analogues. With (Z)-substrates a syn/
anti-p-allyl complex is formed in first instance which is
attacked preferentially at the anti position, as far as
À À
p s p-isomerization can be suppressed. With the sub-
strates investigated herein, the isomerization seems to
be much faster than nucleophilic attack of the enolate.
Therefore 1f should give more or less the same result
Scheme 4. Substrate directed allylic alkylation.
as 1b. Compound 1f was obtained from TBDPS-protect-
ed lactic aldehyde by the Ando version[23] of the Horner–
O-functionality directs the attacking palladium to the Emmons reaction and subsequent Dibal reduction/es-
opposite face of the double bond, giving rise to complex terification. And indeed, 3b was formed exclusively
A, with the Pd in front of the allyl fragment. Nucleophil- [no (Z)-double bond of other regioisomers was detect-
ic attack occurs from the back face in such a way that ed] with the same selectivity as obtained from 1b, albeit
steric interactions are minimized.[17a] This is in good the yield was lower (Table 2, entry 6). This clearly indi-
´
agreement with calculations carried out by Szabo cates that also the olefin geometry has no influence on
et al.[22] These indicate that electron-withdrawing sub- the selectivity.
stituents adjacent to the p-allyl-palladium complex are
To prove the generality of this approach we also inves-
oriented more or less antiperiplanar to the palladium, tigated the influence of the substitution pattern on the
and that the nucleophilic attack occurs at the allylic po- outcome of the reaction. The substrates used are shown
sition away from the heteroatom.
in Table 3. The phenyl derivative 5a was obtained from
In this situation for us it was interesting to see if the methyl mandelate, 5b from valine[24] via standard proto-
(2R)-stereoisomer can also be obtained by directing cols. The polyoxygenated derivatives 5c and 5d were
the palladium to the opposite face, e.g., by using a coor- synthesized starting from mannitol, 5e from tartaric
dinating protecting group such as the diphenylphosphi- acid.[25] All substrates gave the expected amino acids 6
nobenzoyl (dppb) group (Scheme 5). This directing in high to nearly quantitative yields. With the isopropyl
group was introduced by Breit et al. preferentially for derivative 5b the selectivity was the same as observed
rhodium-catalyzed hydroformylations.[21] And indeed, with 1b, interestingly the phenyl derivative 5a reacted
subjecting allylic substrate 1e to our reaction conditions less selectively. The ketal-protected derivatives 5c to
provided (2R,6S)-3e with high selectivity but moderate 5e gave selectivities in the same range and comparable
yield.
to the benzyl- and THP-protected substrates 1c and
Therefore, from one chiral allylic alcohol both stereo- 1d. The high yields obtained clearly indicate that this
isomeric amino acid derivativescan be obtained, depend- protocol can be used for the introduction of highly func-
ing on the O-protecting group used. The comparatively tionalized side chains.
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Table 3. Allylic alkylations using substrates 5.[a]
lated glycine enolate, this base is not strong enough to
deprotonate the corresponding alanine derivative. But
with LDA deprotonation was not a problem. Both sub-
strates investigated gave nearly the same results as ob-
tained with the glycine enolates, and the yields were still
very high.
Conclusion
In conclusion, we have shown that chelated enolates are
good nucleophiles for stereoselective allylations of not
only 1,3-disubstituted but also terminal allylic sub-
strates. The position and configuration of the leaving
group as well as the olefin geometry have no influence
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 Remarks
All reactions were carried out in oven-dried glassware (1008C)
under argon. All solvents were dried before use. THF was dis-
tilled from LiAlH4 and stored over molecular sieves. The prod-
ucts were purified by flash chromatography on silica gel (32–
63 mm). Mixtures of EtOAc and hexanes were generally used
as eluents. TLC: commercially precoated Polygramꢁ SIL-G/
UV 254 plates (Machery-Nagel). Visualization was accom-
plished with UV light and KMnO4 solution. Melting points
were determined on a Büchi melting point apparatus and are
[a]
E¼COOMe.
1
uncorrected. H and 13C NMR: Bruker DRX-500 spectrome-
ter. Selected signals for the minor diastereomers were extract-
ed from the spectra of the diastereomeric mixture. Enantio-
meric and diastereomeric excesses were determined either by
GC and/or by HPLC and NMR. For GC analyses a Varian
3400 and a Varian CP-3380 gaschromatograph with a Chira-
Si-L-Val and a permethyl-b-cyclodextrin capillary column
(Chrompack) was used, in combination with the software
Star GC Workstation Ver. 5.3 (Varian). For HPLC analyses a
Shimazu SPD-M10AT VP Liquid Chromatograph was used
with an LC-10AT VP diode array detector, in combination
with the Shimazu software Class-VP and a chiral Daicel “Chir-
alcel OD-H” column. Optical rotations were measured on a
Perkin-Elmer polarimeter PE 241. High resolution mass spec-
tra were recorded on a Joel JMS-700 (FAB) and a Finnigan
MAT 90 (CI) mass spectrometer. Elemental analyses were car-
ried out at the Department of Chemistry, University of Saar-
brücken.
Last but not least we also varied the nucleophile. From
a pharmaceutical point of view, a-methylated amino
acids are especially interesting, because their incorpora-
tion into potential drug candidates increases their stabil-
ity versus proteolytic cleavage. Therefore, we also inves-
tigated the allylic alkylation of TFA-protected tert-butyl
alaninate with two different substrates (Scheme 6).
While LHMDS is suitable for the generation of the che-
General Procedure Afor the Preparation of Allyl
Carbonates 1 and 5
A solution of the corresponding allylic alcohol (10 mmol) in
CH2Cl2 (20 mL) was cooled to 08C. Pyridine (25 mmol) and
DMAP (2 mmol) were added, followed by methyl chlorofor-
mate (20 mmol). The mixture was allowed to warm to room
Scheme 6. Synthesis of a-alkylated amino acids.
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Palladium-Catalyzed Allylic Alkylations of Chelated Enolates
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temperature overnight, before it was hydrolyzed with 1N
KHSO4. The hydrolysis of the ketal substrates 5c to 5e was per-
formed using saturated NH4Cl. The layers were separated and
the aqueous layer was extracted twice with CH2Cl2. The com-
bined organic layers were dried (Na2SO4) and after filtration
evaporated under vacuum. The crude product was purified
by flash chromatography or by distillation.
(4S)-tert-Butyldimethylsilyloxy-2-pentenyl Methyl Car-
bonate (1a): According to the general procedure A, 1a was ob-
tained from (4S)-tert-butyldimethylsilyloxy-2-penten-1-ol[26]
(0.87 g, 4.02 mmol) after flash chromatography (hexanes/
EtOAc 9:1) as a pale yellow liquid; yield: 1.08 g (3.94 mmol,
98%); [a]2D0: þ4.88 (c 1.1, CHCl3); 1H NMR (CDCl3,
500 MHz): d¼0.02, 0.03 (2 s, 6H, 8-H), 0.87 (s, 9H, 7-H), 1.18
(d, J5,4 ¼6.6 Hz, 3H, 5-H), 3.76 (s, 3H, 10-H), 4.30 (m, 1H, 4-
H), 4.59 (d, J1,2 ¼6.0 Hz, 2H, 1-H), 5.70 (ddt, J2,3 ¼15.5 Hz,
J2,1 ¼6.0 Hz, J2,4 ¼1.3 Hz, 1H, 2-H), 5.79 (dd, J3,2 ¼15.5 Hz,
J3,4 ¼4.7 Hz, 1H, 3-H); 13C NMR (CDCl3, 125 MHz): d¼
À4.8, À4.7 (2q, C-8), 18.2 (s, C-6), 24.1 (q, C-5), 25.8 (3q, C-
7), 54.7 (q, C-10), 67.9 (t, C-1), 68.2 (d, C-4), 121.5 (d, C-2),
140.1 (d, C-3), 155.6 (s, C-9); HRMS (ESI): calcd. for
C13H26O4SiNa [MþNa]þ: 297.1498; found: 297.1483;
C13H26O4Si (274.44): calcd. C 56.90, H 9.55; found: C 56.77,
H 9.92.
4.31 min; HR-MS (EI): calcd. for C13H25O4Si [MþH]þ:
273.1509; found: 273.1522.
General Procedure C for Palladium-Catalyzed Allylic
Alkylations
In a Schlenk flask hexamethyldisilazane (226 mg, 1.40 mmol)
or diisopropylamine (142 mg, 1.40 mmol) was dissolved in
THF (1.5 mL) under argon. After cooling the solution to
À788C n-BuLi (1.6 M, 0.80 mL, 1.25 mmol) was added slowly.
After stirring for 20 min at this temperature the cooling bath
was removed and stirring was continued for further 15 min.
In a second Schlenk flask tert-butyl N-trifluoroacetylglycinate
(114 mg, 0.50 mmol) or tert-butyl N-trifluoroacetylalaninate
(121 mg, 0.50 mmol) was dissolved in THF (3 ml). The solution
was cooled to À788C, before the freshly prepared LHMDS
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.
A solution was prepared from allylpalladium chloride dimer
(10 mg, 0.025 mmol) and PPh3 (30 mg, 0.113 mmol) in THF
(5 mL). After stirring for 15 min at room temperature, this sol-
ution was added to the chelated enolate at À788C. 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 tem-
perature overnight. The solution was diluted with ether before
1 M KHSO4 was added (NH4Cl for ketal-protected 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 under vacuum
and the crude product was purified by flash chromatography.
tert-Butyl (2S,6S)-2-Trifluoroacetylamino-6-tert-butyldi-
methylsilyloxy-4-heptenoate (3a): According to general pro-
cedure C 3a was obtained from (S)-1a (87 mg, 0.317 mmol) –
and for analytical purposes from rac-1a – as a colorless oil;
yield: 135 mg (0.317 mmol, 99%); ds¼84%. The reactions
with the secondary allylic carbonate 2a were performed under
General Procedure B for the Preparation of Allyl
Carbonates 2
A
solution of vinylmagnesium bromide (1 M, 5.5 mL,
5.5 mmol) was added dropwise under Ar to a solution of the
O-silylated lactic aldehyde (5 mmol) in THF (10 mL) at 08C.
After complete addition the cooling bath was removed, the re-
action mixture was warmed to room temperature, and the reac-
tion was monitored by TLC. After complete consumption of
the aldehyde the mixture was again cooled to 08C before meth-
yl chloroformate (12.5 mmol) was added. After warming up to
room temperature overnight, work-up was carried out accord-
ing to general procedure A.
the
conditions
described
in
Table 1.
[a]2D0:
(2S,3R/S)-2-tert-Butyldimethylsilyloxy-4-penten-3-yl
Methyl Carbonate (2a): According to general procedure B 2a
was obtained from TBDMS-protected (S)-methyl lactate in 3
steps as a diastereomeric mixture (syn/anti¼12:88); yield:
3.49 g (15.0 mmol, 68%). anti-2a: 1H NMR (CDCl3,
500 MHz): d¼0.03 (s, 6H, 8-H), 0.86 (s, 9H, 7-H), 1.10 (d,
J5,4 ¼6.2 Hz, 3H, 5-H), 3.75 (s, 3H, 10-H), 3.94 (dq, J4,5 ¼6.2,
J4,3 ¼4.0 Hz, 1H, 4-H), 4.87 (dd, J3,2 ¼7.1, J3,4 ¼4.0 Hz, 1H, 3-
þ31.88 (c 1.2, CHCl3, 84% ds).
(2S,6S)-3a: 1H NMR (CDCl3, 500 MHz): d¼0.01, 0.02 (2 s,
6H, 10-H), 0.86 (s, 9H, 9-H), 1.15 (d, J7,6 ¼6.3 Hz, 3H, 7-H),
1.47 (s, 9H, 12-H), 2.53 (m, 1H, 3-Ha), 2.64 (m, 1H, 3-Hb),
4.24 (m, 1H, 6-H), 4.48 (m, 1H, 2-H), 5.39 (dt, J4,5 ¼15.1,
J4,3a ¼J4,3b ¼6.9, J4,6 ¼1.3 Hz, 1H, 4-H), 5.57 (dd, J5,4 ¼15.1,
J5,6 ¼4.7 Hz, 1H, 5-H), 6.82 (d, JNH,2 ¼6.6 Hz, 1H, NH); 13C
NMR (CDCl3, 125 MHz): d¼ À5.0, À4.8 (2q, C-10), 18.2 (s,
C-8), 24.3 (q, C-7), 25.8 (3q, C-9), 28.0 (3q, C-12), 34.0 (t, C-
H), 5.17 (d, J1trans,2 ¼10.2 Hz, 1H, 1-H), 5.27 (d, J1cis,2
¼
17.0 Hz, 1H, 1-H), 5.85 (ddd, J2,1cis ¼17.0 Hz, J2,1trans ¼10.2 Hz,
J2,3 ¼7.1 Hz, 1H, 2-H); 13C NMR (CDCl3, 125 MHz): d¼
À4.9, À4.7 (2q, C-8), 18.0 (s, C-6), 19.5 (q, C-5), 25.7 (3q, C-
7), 54.6 (q, C-10), 69.4 (d, C-4), 82.8 (d, C-3), 119.3 (t, C-1),
3), 52.6 (d, C-2), 68.3 (d, C-6), 83.4 (s, C-11), 115.7 (q, J14,F
287.9 Hz, C-14), 120.2 (t, C-4), 140.6 (d, C-5), 156.4 (q, J13,F
37.4 Hz, C-13), 169.3 (s, C-1).
¼
¼
(2R,6S)-3a (selected signals): 13C NMR (CDCl3, 125 MHz):
d¼ À4.9 (2q, C-10), 18.2 (s, C-8), 24.4 (q, C-7), 28.0 (3q, C-12),
34.2 (t, C-3), 52.6 (d, C-2), 68.5 (d, C-6), 83.4 (s, C-11), 120.4 (t,
C-4), 169.2 (s, C-1); GC (Chirasil-Val, 1408C, isothermic):
tR(2R,6S) ¼52.43 min, tR(2S,6S) ¼53.83 min; HPLC (OD-H, Hex/i-
PrOH¼99.85:0.15, flow: 1.1 mL/min): tR(2R,6R) ¼5.73 min,
tR(2R,6S) ¼7.65 min, tR(2S,6S) ¼8.52 min, tR(2S,6R) ¼10.40 min; HR-
MS (CI): calcd. for C19H34F3NO4Si [M]þ: 425.2209; found:
425.2204; C19H34F3NO4Si (425.56): calcd. C 53.63, H 8.05, N
3.29; found C 53.65, H 8.29, N 3.23.
1
132.6 (d, C-2), 155.3 (s, C-9); syn-2a (selected signals): H
NMR (CDCl3, 500 MHz): d¼0.05 (s, 6H, 8-H), 3.86 (m, 1H,
4-H), 4.94 (dd, J3,2 ¼J3,4 ¼6.6 Hz, 1H, 3-H), 5.79 (ddd, J2,1cis
¼
17.2, J2,1trans ¼10.6, J2,3 ¼6.6 Hz, 1H, 2-H); 13C NMR (CDCl3,
125 MHz): d¼ À5.0 (2q, C-8), 19.2 (q, C-5), 25.7 (3q, C-7),
54.6 (q, C-10), 69.1 (d, C-4), 82.3 (d, C-3), 118.7 (t, C-1), 155.2
(s, C-9); GC (Chirasil-Val, 1408C, isothermic): tR(2S,3R)
36.85 min, tR(2S,3S) ¼37.43 min; HPLC (OD-H, Hex/i-PrOH¼
99.75:0.25, flow: 1.0 mL/min): tR(2S,3S) ¼4.13 min, tR(2S,3R)
¼
¼
Adv. Synth. Catal. 2005, 347, 1687 – 1695
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asc.wiley-vch.de
1693

Thomas Lindner, Uli Kazmaier
FULL PAPERS
tert-Butyl (2S,6S)-2-Trifluoroacetylamino-6-tert-butyldi-
phenylsilyloxy-4-heptenoate (3b): According to general pro-
cedure C 3b was obtained from (S)-1b (120 mg, 0.301 mmol)
– and for analytical purposes from rac-1a – as a colorless oil;
yield: 153 mg (0.279 mmol, 93%); ds¼96%; [a]2D0: þ15.28 (c
Wiley-VCH, Weinheim, 2004, pp 531–584, and referen-
ces cited therein.
[2] Reviews: a) S. A. Godleski, in: Comprehensive Organic
Synthesis, Vol. 4, (Eds.: B. M. Trost, I. Fleming), Perga-
mon, Oxford, 1991, pp 585–661; b) T. Lübbers, P. Metz,
in: Houben-Weyl – Stereoselective Synthesis, (Eds.: G.
Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann),
Thieme, Stuttgart, New York, 1996, pp 2371–2473;
c) B. M. Trost, D. L. Van Vranken, Chem. Rev. 1996,
96, 395–422; d) J. M. J. Williams Synlett 1996, 705–710,
and references cited therein.
[3] a) I. Shimizu, M. Toyoda, T. Terashima, M. Oshima, H.
Hasegawa, Synlett 1992, 301–302; b) N. Greeves, J. S.
Torode, Synthesis 1993, 1109–1112; c) T. Hayashi, A.
Ohno, S. Lu, Y. Matsumoto, E. Fukuyo, K. Yanagi, J.
Am. Chem. Soc. 1994, 116, 4221–4226; d) K. Hiroi, A.
Hidaka, R. Sezaki, Y. Imamura, Chem. Pharm. Bull.
1997, 45, 769–777.
[4] a) D. Ferroud, J. P. Genet, R. Kiolle, Tetrahedron Lett.
1986, 27, 23–26; b) J. C. Baldwin, J. M. J. Williams, R. P.
Beckett, Tetrahedron: Asymmetry 1995, 6, 1515–1518.
[5] M. Sawamura, H. Nagata, H. Sakamoto, Y. Ito, J. Am.
Chem. Soc. 1992, 114, 2586–2592.
[6] a) B. M. Trost, T. R. Verhoeven, in: Comprehensive Or-
ganometallic Chemistry, (Eds.: G. Wilkinson, F. G. A.
Stone, E. W. Abel), Pergamon, Oxford, 1982, Vol. 8, pp
799–938; b) L. S. Hegedus, in: Organometallics in Syn-
thesis, (Ed.: M. Schlosser), Wiley, Chichester, 1994, pp
427–444; c) J. Tsuji, Palladium Reagents and Catalysts –
Innovations in Organic Synthesis, Wiley, Chichester,
1995.
1
1.1, CHCl3, 96% ds, 96% ee); H NMR (CDCl3, 500 MHz):
d¼1.03 (s, 9H, 9-H), 1.06 (d, J7,6 ¼6.3 Hz, 3H, 7-H), 1.44 (s,
9H, 15-H), 2.47 (m, 1H, 3-Ha), 2.57 (m, 1H, 3-Hb), 4.25 (m,
1H, 6-H), 4.46 (m, 1H, 2-H), 5.30 (dt, J4,5 ¼15.1, J4,3 ¼7.8 Hz,
1H, 4-H), 5.56 (dd, J5,4 ¼15.1, J5,6 ¼5.1 Hz, 1H, 5-H), 6.78 (d,
JNH,2 ¼6.9 Hz, 1H, NH), 7.33–7.40 (m, 6H, 12-H/13-H), 7.60,
7.65 (4d, J11,12 ¼6.9 Hz, 4H, 11-H); 13C NMR (CDCl3,
125 MHz): d¼19.2 (s, C-8), 24.1 (q, C-7), 26.9 (3q, C-9), 28.0
(3q, C-15), 34.0 (t, C-3), 52.5 (d, C-2), 69.3 (d, C-6), 83.3 (s, C-
14), 115.6 (q, J17,F ¼287.9 Hz, C-17), 120.6 (d, C-4), 127.47,
127.48 (4d, C-12), 129.58, 129.59 (2d, C-13), 134.0, 134.4 (2 s,
C-10), 135.82, 135.84 (4d, C-11), 140.2 (d, C-5), 156.4 (q,
J16,F ¼37.4 Hz, C-16), 169.20 (s, C-1); HPLC (OD-H, Hex/i-
PrOH¼99.75:0.25, flow: 1.0 mL/min): tR(2R,6R) ¼6.58 min,
tR(2R,6S) ¼7.12 min, tR(2S,6S) ¼10.03 min, tR(2S,6R) ¼12.01 min;
HR-MS (CI): calcd. for C29H38F3NO4Si [M]þ: 549.2522; found:
549.2517; C29H38F3NO4Si (549.71): calcd. C 63.36, H 6.97, N
2.55; found C 63.09, H 7.04, N 2.70
tert-Butyl (2S,6S)-2-Trifluoroacetylamino-6-hydroxy-4-
heptenoate (4a): The deprotected alcohol 4a was obtained un-
der standard cleaving conditions of the protecting groups used.
In the case of the TBDMS derivative 3a it was directly obtained
after the acidic work-up and storage of the crude product at
room temperature for 24 h; [a]2D0: þ52.98 (c 1.0, CHCl3, 84%
ds).
1
(2S,6S)-4a: H NMR (CDCl3, 500 MHz): d¼1.22 (d, J7,6
¼
6.6 Hz, 3H, 7-H), 1.47 (s, 9H, 9-H), 1.65 (bs, 1H, OH), 2.48
(ddd, J3a,3b ¼13.6, J3a,4 ¼7.3, J3a,2 ¼6.3 Hz, 1H, 3-Ha), 2.66
(ddd, J3b,3a ¼13.6, J3b,4 ¼7.3, J3b,2 ¼6.3 Hz, 1H, 3-Hb), 4.25 (m,
1H, 6-H), 4.51 (m, 1H, 2-H), 5.48 (dt, J4,5 ¼15.5, J4,3 ¼7.3 Hz,
1H, 4-H), 5.62 (dd, J5,4 ¼15.5, J5,6 ¼6.0 Hz, 1H, 5-H), 6.91 (bs,
1H, NH); 13C NMR (CDCl3, 125 MHz): d¼23.2 (q, C-7), 28.0
(3q, C-9), 34.5 (t, C-3), 52.6 (d, C-2), 68.1 (d, C-6), 83.6 (s, C-
8), 115.6 (q, J11,F ¼287.9 Hz, C-11), 122.4 (d, C-4), 139.7 (d,
C-5), 156.5 (q, J10,F ¼37.4 Hz, C-10), 169.2 (s, C-1).
[7] a) P. Corradini, G. Maglio, A. Musco, G. Paiaro, J. Chem.
Soc., Chem. Commun. 1966, 618–619; b) T. Cavigny, M.
Julia, C. Rolando, J. Organomet. Chem. 1985, 285, 395.
[8] a) K. Yamamoto, J. Tsuji, Tetrahedron Lett. 1982, 23,
3089–3092; b) G. Koch, A. Pfaltz, Tetrahedron: Asymme-
try 1996, 7, 2213–2216.
´ ˆ
[9] a) R. Pretot, A. Pfaltz, Angew. Chem. 1998, 110, 337–
(2R,6S)-4a (selected signals): 13C NMR (CDCl3, 125 MHz):
d¼23.3 (q, C-7), 34.6 (t, C-3), 68.2 (d, C-6), 83.6 (s, C-8), 122.4
(d, C-4), 139.7 (d, C-5); HPLC (OD-H, Hex/i-PrOH¼
339; Angew. Chem. Int. Ed. 1998, 37, 323–325; b) R. Hil-
graf, A. Pfaltz, Synlett 1999, 1814–1816; c) S.-L. You, X.-
Z. Zhu, Y.-M. Luo, X.-L. Hou, L.-X. Dai, J. Am. Chem.
Soc. 2001, 123, 7471–7472.
99.75:0.25, flow: 1.0 mL/min): tR(2R,6S) ¼17.15 min, tR(2S,6S)
¼
20.73 min; HRMS (CI): calcd. for C13H20F3NO4 [M]þ:
311.1344; found: 311.1336.
[10] J. Ansell, M. Wills, Chem. Soc. Rev. 2002, 31, 259–268.
[11] a) T. Hayashi, M. Kawatsura, Y. Uozumi, Chem. Com-
mun. 1997, 561–562; b) T. Hayashi, J. Organomet.
Chem. 1999, 576, 195–202.
[12] a) B. M. Trost, M. Lautens, Tetrahedron 1987, 43, 4817–
4840; b) B. M. Trost, I. Hachiya, J. Am. Chem. Soc.
1998, 120, 1104–1105; c) B. M. Trost, S. Hildbrand, K.
Dogra, J. Am. Chem. Soc. 1999, 121, 10416–10417;
d) F. Glorius, A. Pfaltz, Org. Lett, 1999, 1, 141–144;
e) A. v. Malkov, I. R. Baxendale, D. J. Mansfield, P. Ko-
covsky, Perkin Trans 1 2001, 1234–1240; f) F. Glorius,
M. Neuburger, A. Pfaltz, Helv. Chim. Acta 2001, 84,
3178–3196.
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft
(SFB 247 and Ka 880/5) and the Fonds der Chemischen Indus-
trie is gratefully acknowledged. We also thank Degussa AG for
generous gifts of palladium salts.
References and Notes
[1] Reviews: a) L.S. Hegedus, Organische Synthese mit
Übergangsmetallen, VCH, Weinheim, 1995; b ) U. Kaz-
[13] a) B. M. Trost, M. H. Hung, J. Am. Chem. Soc. 1983, 105,
7757–7759; b) J. Lehmann, G. C. Lloyd-Jones, Tetrahe-
dron 1995, 51, 8863–8874; c) G. C. Lloyd-Jones, A.
À
À
maier, M. Pohlman, in: Metal Catalyzed C C and C N
Coupling Reactions, (Eds.: A. de Meijere, F. Diederich),
1694
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Adv. Synth. Catal. 2005, 347, 1687 – 1695

Palladium-Catalyzed Allylic Alkylations of Chelated Enolates
FULL PAPERS
Pfaltz, Angew. Chem. 1995, 107, 534–536; Angew. Chem.
Int. Ed. 1995, 34, 462–464.
[18] a) U. Kazmaier, F. L. Zumpe, Angew. Chem. 2000, 112,
805–807; Angew. Chem. Int. Ed. Engl. 2000, 39, 802–
804; b) U. Kazmaier, F. L. Zumpe, Eur. J. Org. Chem.
2001, 4067–4076; c) U. Kazmaier, M. Pohlman, Synlett
2004, 623–626.
[19] T. Hayashi, A. Yamamoto, T. Hagihara, J. Org. Chem.
1986, 51, 723–727.
[20] U. Kazmaier, T. Lindner, Angew. Chem. 2005, 117,
3368–3371, Angew. Chem. Int. Ed. 2005, 44, 3303–3306.
[21] B. Breit, P. Demel, C. Studte, Angew. Chem. 2004, 116,
3874–3877; Angew. Chem. Int. Ed. 2004, 43, 3786–3789.
[14] a) R. Takeuchi, M. Kashio, Angew. Chem. 1997, 109,
268–270; Angew. Chem. Int. Ed. 1997, 36, 263–265;
b) R. Takeuchi, M. Kashio, J. Am. Chem. Soc. 1998,
120, 8647–8655; c) B. Bartels, G. Helmchen, Chem.
Commun. 1999, 741–742; d) K. Fuji, N. Kinoshita, K. Ta-
naka, T. Kawabata, Chem. Commun. 1999, 2289–2290.
[15] a) P. A. Evans, J. D. Nelson, J. Am. Chem. Soc. 1998, 120,
5581–5582; b) P. A. Evans, L. J. Kennedy, Org. Lett.
2000, 2, 2213–2215; c) P. A. Evans, L. J. Kennedy, J.
Am. Chem. Soc. 2001, 123, 1234–1235.
´
[22] Review: K. J. Szabo, Chem. Soc. Rev. 2001, 30, 136–143,
[16] Reviews: a) U. Kazmaier, Liebigs Ann./Recl. 1997, 285–
295; b) U. Kazmaier, in: The Claisen Rearrangement,
(Eds.: M. Hiersemann, U. Nubbemayer), Wiley-VCH,
Weinheim, 2005, in press.
and references cited therein.
[23] a) K. Ando, J. Org. Chem. 1999, 64, 8406–8408; b) P. M.
Pihko, T. M. Salo, Tetrahedron Lett. 2003, 44, 4361–4364.
´
[24] W. R. Li, W. R. Ewing, B. D. Harris, M. M. Jouille, J. Am.
[17] a) U. Kazmaier, F. L. Zumpe, Angew. Chem. 1999, 111,
1572–1574; Angew. Chem. Int. Ed. 1999, 38, 1468–
1470; b) U. Kazmaier, D. Schauß, M. Pohlman, Org.
Lett. 1999, 1, 1017–1019; c) U. Kazmaier, M. Pohlman,
D. Schauß, Eur. J. Org. Chem. 2000, 2761–2766;
d) T. D. Weiss, G. Helmchen, U. Kazmaier, Chem. Com-
mun. 2002, 1270–1271; e) U. Kazmaier, Current Org.
Chem. 2003, 317–328.
Chem. Soc. 1990, 112, 7659–7672.
[25] a) T. Katsuki, A. W. M. Lee, P. Ma, V. S. Martin, S. Masa-
mune, K. B. Sharpless, D. Tuddenham, F. J. Walker, J.
Org. Chem. 1982, 47, 1373–1378; b) U. Kazmaier, C.
Schneider, Synthesis 1998, 1321–1326.
[26] U. Nubbemeyer, R. ꢂhrlein, J. Gonda, B. Ernst, D. Bel-
´
lus, Angew. Chem. 1991, 103, 1533–1534; Angew. Chem.
Int. Ed. 1991, 30, 1465–1467.
Adv. Synth. Catal. 2005, 347, 1687 – 1695
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