Halogenated Allyl Alcohol Derivatives - Versatile Electrophiles for Palladium-Catalyzed Allylic Alkylations

Article abstract of DOI:10.1002/ejoc.201900310

Brominated and iodinated allylic substrates can be subjected to palladium-catalyzed allylic alkylation of amino acid and peptide ester enolates. The incorporation of a vinylic halide functionality into the allylic substrate allows a direct modification of the allylated peptide via cross coupling chemistry. Therefore, the direct introduction of a vinylhalide side chain into a peptide is an interesting alternative to the stannylallylation/halogenation approach. However, the haloallylation is not as trivial as normal allylic alkylations, because the incorporation of a second, competitive electrophilic center into the allyl moiety requires careful optimization of the reaction conditions.

Full text of DOI:10.1002/ejoc.201900310

A Journal of
Accepted Article
Title: Halogenated allyl alcohol derivatives - versatile electrophiles for
palladium-catalyzed allylic alkylations
Authors: Michael Kohr and Uli Kazmaier
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900310
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900310
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10.1002/ejoc.201900310
European Journal of Organic Chemistry
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Halogenated allyl alcohol derivatives - versatile electrophiles for palladium-
catalyzed allylic alkylations
Michael Kohr and Uli Kazmaier*[a]
Keywords: Allylic alkylation / Amino acids / Cross coupling / Peptides / Vinyl halides
Brominated and iodinated allylic substrates can be subjected to
palladium-catalyzed allylic alkylation of amino acid and peptide
ester enolates. The incorporation of a vinylic halide functionality
into the allylic substrate allows a direct modification of the allyla-
ted peptide via cross coupling chemistry. Therefore, the direct
introduction of a vinylhalide side chain into a peptide is an interes-
ting alternative to the stannylallylation/halogenation approach.
But the haloallylation is not as trivial as normal allylic
alkylations, because the incorporation of a second, competitive
electrophilic center into the allyl moiety asks for careful
optimization of the reaction conditions.
(© WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2019)
Introduction
Transition metal catalyzed allylic alkylations and cross
coupling reactions have developed into some of the most powerful
tools in organic synthesis.1 Their often mild conditions even allow
the modification of complex molecules including late stage
modifications of natural products and drugs, an important
advantage in medicinal chemistry.2 Based on our interest in the
synthesis and modifications of peptidic natural products,3 we
developed a protocol for the stereoselective allylic alkylation of
peptide enolates.4 If stannylated allylic substrates are used as
electrophiles, the vinyl stannane side chain incorporated into an
amino acid or peptide5 allows subsequent modifications via Stille
couplings and related processes.6 Metal-halogen exchange induces
an umpolung of the side chain and hence the coupling with a wide
range of organometallic reagents (Scheme 1).
The great advantage of this protocol is the easy access to the
required stannylated allylic substrates via regioselective molyb-
denum-catalyzed hydrostannation7 and the mildness of the Stille
coupling.8 Under neutral conditions no epimerization of the
stereogenic centres in the peptide chain is observed. The only
disadvantage is the toxicity of tin compounds, which makes the
method critical for medicinal chemistry applications. Therefore, we
were interested to figure out if it is also possible to introduce
halogenated allyl side chains directly, without a stannylated
intermediate. In this case, 2-halogenated allylic substrates have to
be used, which is not a trivial issue, because two reactive
functionalities might compete for the palladium. While the vinyl
halide can undergo oxidative addition, the allylic leaving group can
form a -allyl complex. The respective reaction rates probably
depend on both the halide and the leaving group used.
Scheme 1. Stereoselective modifications of dipeptides via stannylated
intermediates
If the oxidative addition occured first, the vinyl-Pd-
intermediate should undergo elimination forming an allene. This
competition reaction increases the difficulty of developing a
method with balanced reactivities: the vinyl halide should be
reactive enough to undergo cross coupling in the subsequent
modification step, but it should be less reactive than the allyl
leaving group. Probably, that is the reason why only a very few
examples of Pd-catalyzed reactions of halogenated allyl substrates
are reported in the literature.9-12
Anderson et al. described Stille couplings of functionalized
vinyl stannanes with brominated substrates 1. While carbonate 1a
underwent Stille coupling at the vinyl bromide subunit, the corres-
ponding allyl bromide 1b provided the allylation product (Scheme
2).9

[a] M. Kohr, Prof. Dr. Uli Kazmaier
Organic Chemistry, Saarland University
P.O. Box 151150, 66041 Saarbrücken (Germany)
Fax: +49-681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
Homepage: http://www.uni-saarland.de/lehrstuhl/kazmaier.html

Supporting information for this article is available on the WWW
under http://dx.doi.org/
Scheme 2. Regioselective Stille couplings with brominated allyl substrates
1
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10.1002/ejoc.201900310
European Journal of Organic Chemistry
Table 1. Allylic alkylation of glycine ester enolates with halogenated allyl
substrates 1 and 2
A similar behaviour was reported by Organ et al. using iodi-
nated allylic substrates.10 Iodoallyl acetates and carbonates were
selectively subjected to Suzuki couplings via preferred activation
of the vinylic iodide. The arylated allyl acetate was subsequently
reacted in an allylic alkylation with malonates. Interestingly, no
reaction was observed if the iodo allyl acetates and -carbonates
were subjected to allylic alkylation first, while the corresponding
iodovinyl chloride gave the desired product in high yield.
Pleixats et al. reported the Pd-catalyzed allylic alkylation of
nitroalkanes using brominated allyl carbonate 1a, while the corres-
ponding allyl bromide 1b was used for the direct (Pd-free) allyla-
tion of imino glycinates.11 Furthermore Trost et al. reported the
asymmetric bromo- and iodo-allylation of a cyclic aminomalonate
derivative as a key step of the synthesis of Ranirestat.12 These
examples clearly show, that both reaction pathways are competitive,
and that the outcome of the reactions depends not only on the
allylic substrate but also on the nucleophile used.
Entry
1,2
1a
1b
2a
X
Br
Br
I
LG
OCOOEt
Br
Yield [%]
Product
3a
3a
1
2
3
73
52
0
OCOOEt
3b
4
5
6
2b
2c
2d
I
I
I
Br
OTs
OMs
45
<10
65
3b
3b
3b
With these results in hand, we also tried to transfer the proce-
dure to peptide enolates with the goal to use the chiral information
of the peptide chain in order to control the stereochemical outcome
of the allylation step. The phenylalanine dipeptide 4a was used to
figure out the optimal reaction conditions (Table 2). First of all, we
used our standard protocol for peptide allylations (entry 1). The
dipeptide was used in slight excess and the reaction mixture was
warmed from −78 °C to room temperature overnight. Under these
conditions, the desired product was obtained in good yield but as a
2:1 diastereomeric mixture. For comparison, other allylic substrates,
e.g. the stannylated ones give diastereomeric ratios > 90:10. It
should be mentioned that in previous studies we never observed
significant epimerization (> 5%) of stereogenic centers, neither by
HPLC, GC or NMR. Therefore, the low stereoselectivity was
surprising, and we varied the reaction conditions to figure out the
reasons for that. If the reaction was quenched at −35°C the
selectivitiy could be increased to 4:1 without a drop in the yield
(entry 2). Next, we carried out the reaction at a constant
temperature of −40 °C. The reaction was finished after 80 min, and
both the yield and selectivity were comparable to the first warm up
experiment (entry 1). At −30 °C the reaction required only 30 min
for completion, but the selectivity kept dropping to 58:42 (entry 4).
This strong temperature dependence of the selectivity was
surprising for us, since we had never observed such a strong effect
with other allylic substrates before. Probably the bromine atom at
the double bond is responsible for that. The electron withdrawing
effect might cause epimerization of the allylated dipeptide at higher
temperatures.
To prove this option we also allylated the corresponding
dipeptide 6, with an alanine instead of glycine at the C-terminus
(Scheme 3). Here, an epimerization is not possible and we should
see the diastereoselectvity of the allylation step. And indeed, the
selectivity was here in the “usual” range of 9:1 as with other allylic
substrates. The yield of 7 was significantly lower, probably for
steric reasons. But in our case the yield was not relevant, only the
diastereoselectivity. Probably with the glycine peptides the reaction
starts at low temperature with high diastereoselectivity, but during
warm up and long reaction times the product undergoes
epimerization.
Results and Discussion
Based on our good results obtained in allylic alkylation with
chelated amino acid ester enolates13 we also tried to use halogena-
ted allyl substrates for the introduction of halogenated side chains.
In general, the highly reactive chelated enolates already react with
-allyl complexes at temperatures as low as −78 °C, even allowing
the suppression of -isomerizations.14 Therefore, we were
optimistic to also prefer allylic alkylation over oxidative addition,
which in general requires higher reaction temperatures. The desired
halogenated allyl substrates 1 and 2 could easily be obtained
according to literature via bromination/HBr-elimination from the
corresponding alkene15 or by esterification of 2-iodo-2-propenol.16
We began our investigations with the brominated allyl substrates 1
using TFA-protected t-butyl glycinate as nucleophile under the
previously optimized standard conditions (Table 1). Both allyl
substrates delivered the desired product (entries 1 and 2) while the
carbonate 1a was clearly better suited than the bromide 1b,
especially because the reaction provided a cleaner product. One
should keep in mind that the bromide 1b might react directly with
the chelated ester enolate without participation of the Pd-catalyst.
This is not a serious issue in the glycine allylation, but would
become one in allylations of peptides. Here, allylations with allyl
halides are generally unselective, giving almost 1:1 diastereomeric
mixtures of the allylated product, while the Pd-catalyzed version
proceeds with high diastereoselectivity.4 Since the brominated allyl
carbonate gave the desired product in good yield, we investigated
the iodinated carbonate 2a under the same conditions (entry 3).
Unfortunately, no allylation product could be obtained in this case.
As a side product, we could isolate an aminomalonate derivative,
resulting from a direct attack of the chelated enolate on the
carbonyl group of the allyl carbonate.17 This is a typical side
reaction of allylic substrates which do not or only slowly undergo
-allyl complex formation. This side reaction could be suppressed
by using the t-butyl carbonate12 but in that case no allylation
product was formed either. This observation is in accordance with
the results described by Organ et al.10
Therefore, we investigated the iodinated allyl bromide 2b16 and
the sulfonates 2c18 and 2d19 next. And indeed, with bromide 2b the
desired product was obtained in acceptable yield (entry 4). With
the corresponding tosylate only tiny amounts of product were
formed (entry 5) and by far the best results were obtained with
mesylate 2d (entry 6). The yield was comparable to the two step
process of stannyl allylation/tin-iodine exchange and is therefore
an interesting alternative to this protocol.
Scheme 3. Stereoselective bromoallylation of dipeptide 6
2
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10.1002/ejoc.201900310
European Journal of Organic Chemistry
It should be mentioned that in cross coupling reactions of vinyl
iodides like 8 we never observed epimerizations of the peptide
backbone, independent on the coupling reaction performed.
Obviously vinyl iodides such as 8 are configurationally more stable
than the corresponding bromides 5. But to illustrate that also these
bromides can undergo cross coupling reactions, we performed a
Sonogashira reaction and an aminocarbonylation with diastereo-
merically pure peptide 5f (Scheme 5).20 Both reactions proceeded
epimerization-free, delivering the desired coupling products as
single stereoisomers.
Table 2. Allylic alkylation of dipeptide ester enolates with brominated allyl
substrate 1a
Yield Ratio[a]
Entry
4
R
Reaction conditions
5
[%]
82
79
84
85
56
78
75
65
86
(S,R):(S/S)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4b
4c
4d
4e
4f
Bn
Bn
Bn
Bn
Me
iBu
sBu
iPr
−78 °C to rt, 16 h
5a
66:34
80:20
69:31
58:42
58:42
67:33
70:30
78:22
92: 8
−78 °C to −35 °C, 4 h 5a
−40 °C, 80 min
−30 °C, 30 min
5a
5a
−78 °C to −35 °C, 4 h 5b
−78 °C to −35 °C, 4 h 5c
−78 °C to −35 °C, 4 h 5d
−78 °C to −35 °C, 4 h 5e
CH2OR[b] −78 °C to −35 °C, 4 h 5f
[a] Determined by NMR. [b] R = TBDPS
The reaction conditions used in entry 2 seemed to be a good
compromise and we investigated the allylation of a set of other
dipeptides 4. The fact that the alanine dipeptide 4b did not give
good diastereoselectivities was not surprising, but the rather low
yield was astonishing (entry 5). All other dipeptides 4c–4e gave
comparable yields to 4a, although the diastereoselectivity was a
little lower (entries 6 to 8). By far the best results were obtained
with the protected serine derivative 4f, which not only gave the
best yield but also a very high selectivity in the range of “normal”
allylic alkylations (entry 9).
The varying selectivities might be caused by the
stereochemical lability of the individual dipeptides, which seems to
be a limitation of this approach because it requires individual
optimization for each peptide. Obviously, the serine peptide does
not undergo epimerizations, while the others do.
If the electron withdrawing effect of the bromine is responsible
for the epimerization, one might expect better selectivities in iodo
allylations. And indeed, allylation with the iodo allylmesylate 2d
gave the expected product 8 in good yield and acceptable selecti-
vity, even though here an uncatalyzed direct allylation of the
enolate might compete with the Pd-catalyzed process, and the
reaction mixture was warmed up to room temperature (Scheme 4).
In order to suppress the direct allylation, and with respect to the
circumstance that iodinated allyl acetates and carbonates do not
undergo allylic alkylation, we investigated a set of other leaving
groups. In fact, with the corresponding allyl phosphate 2e an
excellent diastereoselectivity was obtained, but the reaction
became very sluggish and provided only a very modest yield. But
this example clearly shows that high selectivities can be obtained if
competitive allylations and epimerizations are suppressed, although
this brings us to the limitations of this protocol.
Scheme 5. Cross coupling reactions of brominated dipeptide 5f
Conclusions
In conclusion, we could show that brominated and iodinated
allylic substrates can be subjected to palladium-catalyzed allylic
alkylation or amino acid and peptide ester enolates. The
incorporation of a vinylic halide functionality into the allylic
substrate allows a direct modification of the allylated peptide via
cross coupling chemistry, but causes also selectivity issues. While
brominated allyl acetates and carbonates undergo the desired
allylation reaction, iodinated allyl carbonates do not react. Here the
corresponding mesylates or phosphates have to be used. In case of
the highly reactive mesylates a direct nucleophilic substitution
competes with the catalytic process, resulting in moderate dia-
stereoselectivities. In contrast, the less reactive phosphates react
only in the catalyzed fashion with high diastereoselectivity but
moderate yield. While the iodinated dipeptides are configuration-
nally stable under the reaction conditions of the allylation, the
brominated analogues obviously can undergo epimerization at the
newly formed stereogenic center.
Experimental Section
General remarks: All air- or moisture-sensitive reactions were
carried out in dried glassware (>100 °C) under an atmosphere of
nitrogen. Zinc chloride was dried in vacuo with a heat gun. Dried
solvents were distilled before use: DMF was purchased from Acros
Organics. The products were purified by flash chromatography on
silica gel (0.063−0.2 mm or 0.04–0.063). Mixtures of EtOAc and
petroleum ether were generally used as eluents. Analytical TLC
was performed on pre-coated silica gel plates (Macherey-Nagel,
Polygram® SIL G/UV254). Visualization was accomplished with
UV-light or KMnO4 solution. Melting points were determined with
a MEL-TEMP II (Laboratory Devices) melting point apparatus and
1
are uncorrected. H and 13C NMR spectra were recorded with a
Bruker AC-400 [400 MHz (1H) and 100 MHz (13C)]. Chemical
shifts are reported in ppm relative to internal solvent. Mass spectra
were recorded with a Finnigan MAT 95 spectrometer (quadrupole)
using the CI technique.
Scheme 4. Iodoallylation of dipeptide 4a
3
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10.1002/ejoc.201900310
European Journal of Organic Chemistry
phosphine (5.6 mg, 21.4 µmol). Aqueous work-up and flash
chromatography (silica, n-pentane/ethyl acetate 90:10) provided 5a
(89.1 mg, 181 µmol, 79%, NMR: dr 80:20) as a yellowish solid. Rf
= 0.24 (petroleum ether/ethyl acetate 80:20). Mp = 111–112 °C.
Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 9 H),
2.73 (dd, J = 14.9, 6.7 Hz, 1 H), 2.79 (dd, J = 14.9, 6.0 Hz, 1 H),
3.07 (dd, J = 13.8 , 8.0 Hz, 1 H), 3.15 (dd, J = 13.8, 5.8 Hz, 1 H),
4.62 (ddd, J = 7.6, 6.7, 6.0 Hz, 1 H), 4.68 (ddd, J = 8.0, 6.7, 5.8 Hz,
1 H), 5.47 (d, J = 1.7 Hz, 1 H), 5.53 (m, 1 H), 6.05 (d, J = 7.6 Hz, 1
H), 7.17 (d, J = 6.7 Hz, 1 H), 7.22 (m, 2 H), 7.28 (m, 1 H), 7.32 (m,
2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.9, 38.6, 43.2, 51.6,
54.6, 83.3, 120.6, 127.6, 127.6, 129.0, 129.3, 135.1, 168.7, 169.1
ppm. The TFA-signals could not be detected. Minor diastereomer:
1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 9 H), 2.91 (dd, J = 14.6,
5.8 Hz, 1 H), 3.18 (dd, J = 13.9, 5.3 Hz, 1 H), 4.56 (ddd, J = 7.5,
6.4, 5.8 Hz, 1 H), 5.46 (d, J = 1.7 Hz, 1 H), 5.51 (m, 1 H), 6.02 (d,
J = 7.5 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0, 43.1,
51.7, 54.6, 83.2, 127.6, 128.9, 129.4 ppm. HRMS (CI): m/z calcd.
C20H25BrF3N2O4 [M+H]+:493.0944; found 493.0968.
General procedure A: Allylic alkylation of tert-butylglycinate:
tert-Butylglycinate (1.5 equiv.) and zinc chloride (1.6 equiv.) were
dissolved in THF (0.25 M according to the dipeptide). The
resulting solution was added slowly to an LHMDS solution (1 M in
THF, 3.6 equiv.) at –78 °C and stirring was continued for 30 min.
[(allyl)PdCl]2 (0.02 equiv.) and triphenylphosphine (0.08 equiv.)
were dissolved in THF (0.5 M according to the electrophile) and
stirred at room temperature for 5 min before the corresponding
halogenated electrophile (1.0 equiv.) was added. This solution was
added dropwise to the cold zinc enolate solution. The excess dry
ice was removed from the cooling bath and the reaction mixture
was allowed to warm to room temperature overnight. After dilution
with aqueous HCl (1 M) the resulting mixture was extracted three
times with ethyl acetate. After the combined organic layers had
been dried (Na2SO4) and the solvents removed by evaporation in
vacuo, the crude product was purified by flash chromatography.
General procedure B: Allylic alkylation of dipeptides: The
corresponding dipeptide (1.5 equiv.) and zinc chloride (1.7 equiv.)
were dissolved in THF (0.25 M according to the dipeptide). The
solution was added slowly to an LHMDS solution (1 M in THF,
5.3 equiv.) at –78 °C and stirring was continued for 30 min.
[(allyl)PdCl]2 (0.02 equiv.) and triphenylphosphine (0.08 equiv.)
were dissolved in THF (0.5 M according to the electrophile) and
stirred at room temperature for 5 min before the corresponding
halogenated electrophile (1.0 equiv.) was added. This solution was
added dropwise to the cold zinc enolate solution. The excess dry
ice was removed from the cooling bath and the reaction mixture
was allowed to warm to – 35 °C within 4 hours. After dilution with
aqueous HCl (1 M) the resulting mixture was extracted three times
with ethyl acetate. After the combined organic layers had been
dried (Na2SO4) and the solvents removed by evaporation in vacuo,
the crude product was purified by flash chromatography.
tert-Butyl [N-trifluoroacetyl-(S)-alanyl]-(R)-2-amino-4-bromo-
pent-4-enoate (5b): According to general procedure B 1a (51.4
mg, 246 µmol) was reacted with 4b (113 mg, 377 µmol), zinc
chloride (60.0 mg, 440 µmol), LHMDS (1 M in THF, 1.31 mL,
1.31 mmol), [(allyl)PdCl]2 (2.1 mg, 5.74 µmol) and
triphenylphosphine (6.9 mg, 26.3 µmol). Aqueous work-up and
flash chromatography (silica, n-pentane/ethyl acetate 90:10)
provided 5b (57.7 mg, 138 µmol, 56%, NMR: dr 58:42) as a
yellowish resin. Rf = 0.14 (petroleum ether/ethyl acetate 80:20).
1
Major diastereomer: H NMR (400 MHz, CDCl3): δ = 1.47–1.48
(m, 12 H), 2.89 (dd, J = 14.7, 6.7 Hz, 1 H), 3.04 (dd, J = 14.7, 5.5
Hz, 1 H), 4.55 (dq, J = 6.9, 5.3 Hz, 1 H), 4.69 (ddd, J = 7.5, 6.7,
5.5 Hz, 1 H), 5.54 (d, J = 1.6 Hz, 1 H), 5.64 (m, 1 H), 6.47 (d, J =
7.5 Hz, 1 H), 7.31 (d, J = 5.3 Hz, 1 H) ppm. 13C NMR (100 MHz,
tert-Butyl 4-bromo-2-(2,2,2-trifluoroacetamido)pent-4-enoate
(3a):[18] According to general procedure A 1a (105 mg, 502 µmol)
was reacted with tert-butyl-(2,2,2-trifluoroacetyl)glycinate (179
mg, 788 µmol), zinc chloride (112 mg, 822 µmol), LHMDS (1 M
in THF, 1.88 mL, 1.88 mmol), [(allyl)PdCl]2 (3.5 mg, 9.57 µmol)
and triphenylphosphine (11.1 mg, 42.3 µmol). Aqueous work-up
and flash chromatography (silica, n-pentane/diethyl ether 95:5)
provided 3a (127 mg, 367 µmol, 73%) as a colourless resin. Rf =
0.20 (petroleum ether/ethyl acetate 90:10). 1H NMR (400 MHz,
CDCl3): δ = 1.50 (s, 9 H), 2.97 (dd, J = 14.8, 6.0 Hz, 1 H), 3.11 (dd,
CDCl3): δ = 18.9, 28.0, 43.1, 49.2, 51.5, 83.4, 115.6 (q, JC-F
=
286.8 Hz), 120.9, 127.7, 156.6 (q, JC-F = 37.4 Hz), 169.3, 170.1
1
ppm. Minor diastereomer (selected signals): H NMR (400 MHz,
CDCl3): δ = 3.01 (dd, J = 14.1, 5.8 Hz, 1 H), 5.54 (d, J = 1.7 Hz, 1
H), 6.35 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 18.4, 28.0, 43.0, 49.1, 51.7, 83.4, 121.0, 127.5, 169.3, 170.0 ppm.
HRMS (CI): m/z calcd. C10H13BrF3N2O4 [M–C4H8+H]+: 361.0005;
found 361.0013.
tert-Butyl [N-trifluoroacetyl-(S)-leucyl]-(R)-2-amino-4-bromo-
J = 14.8, 5.8 Hz, 1 H), 4.67 (ddd, J = 6.0, 6.0, 5.8 Hz, 1 H), 5.58 (d, pent-4-enoate (5c): According to general procedure B 1a (52.9
J = 1.8 Hz, 1 H), 5.66 (m, 1 H), 6.97 (bs, 1 H) ppm. 13C NMR (100
mg, 253 µmol) was reacted with 4c (126 mg, 371 µmol), zinc
MHz, CDCl3): δ = 27.9, 42.4, 51.8, 84.1, 115.5 (q, JC-F = 288.3 Hz), chloride (75.0 mg, 550 µmol), LHMDS (1 M in THF, 1.31 mL,
121.5, 126.6, 156.6 (q, JC-F = 38.2 Hz), 168.3 ppm. HRMS (CI): m/z
1.31 mmol), [(allyl)PdCl]2 (1.7 mg, 4.65 µmol) and
triphenylphosphine (7.7 mg, 29.4 µmol). Aqueous work-up and
flash chromatography (silica, petroleum ether/ethyl acetate 95:5)
provided 5c (90.6 mg, 197 µmol, 78%, NMR: dr 67:33) as a white
solid. Mp = 73–74 °C. Rf = 0.29 (petroleum ether/ethyl acetate
80:20). Major diastereomer: 1H NMR (400 MHz, CDCl3): δ = 0.95
(d, J = 6.0 Hz, 3 H), 0.96 (d, J = 5.8 Hz, 3 H), 1.47 (s, 9 H), 1.59–
1.74 (m, 3 H), 2.89 (m, 1 H), 3.00 (m, 1 H), 4.53 (m, 1 H), 4.68 (m,
1 H), 5.53 (d, J = 1.7 Hz, 1 H), 5.65 (m, 1 H), 6.45 (d, J = 7.2 Hz, 1
H), 7.06 (d, J = 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 22.1, 22.7, 24.8, 27.9, 41.9, 43.1, 51.6, 52.0, 83.4, 115.7 (q, JC-F
= 288.0 Hz), 120.8, 127.9, 156.9 (q, JC-F = 37.9 Hz), 169.3, 170.0
calcd. C11H16BrF3NO3 [M+H]+:346.0260; found 346.0274.
tert-Butyl
4-iodo-2-(2,2,2-trifluoroacetamido)pent-4-enoate
(3b):[18] According to general procedure A 2d (68.7 mg, 262 µmol)
was reacted with tert-butyl-(2,2,2-trifluoroacetyl)glycinate (87.1
mg, 383 µmol), zinc chloride (58.5 mg, 429 µmol), LHMDS (1 M
in THF, 0.94 mL, 940 µmol), [(allyl)PdCl]2 (3.0 mg, 8.20 µmol)
and triphenylphosphine (6.7 mg, 25.5 µmol). Aqueous work-up
and flash chromatography (silica, n-pentane/ethyl acetate 95:5)
provided 3b (66.8 mg, 170 µmol, 65%) as a yellowish resin. Rf =
0.27 (petroleum ether/ethyl acetate 90:10). 1H NMR (400 MHz,
CDCl3): δ = 1.50 (s, 9 H), 2.93 (ddd, J = 14.8, 6.7, 0.6 Hz, 1 H),
3.05 (ddd, J = 14.8, 5.9, 0.7 Hz, 1 H), 4.66 (ddd, J = 6.7, 6.7, 5.9
Hz, 1 H), 5.88 (d, J = 1.8 Hz, 1 H), 6.13 (m, 1 H), 6.88 (bs, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0, 46.3, 52.5, 84.1,
101.6, 130.3, 168.3 ppm. The TFA-signals could not be detected.
HRMS (CI): m/z calcd. C11H16IF3NO3 [M+H]+: 394.0121; found
394.0115.
1
ppm. Minor diastereomer (selected signals): H NMR (400 MHz,
CDCl3): δ = 1.48 (s, 9 H), 5.52 (d, J = 1.8 Hz, 1 H), 5.63 (m, 1 H),
6.42 (d, J = 8.0 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 22.7, 24.7, 28.0, 41.4, 43.1, 83.2, 120.9,
127.5, 169.3, 169.9 ppm. HRMS (CI): m/z calcd. C17H27BrF3N2O4
[M+H]+:459.1101; found 459.1084.
tert-Butyl [N-trifluoroacetyl-(2S,3S)-isoleucyl]-(R)-2-amino-4-
bromopent-4-enoate (5d): According to general procedure B 1a
(52.9 mg, 253 µmol) was reacted with 4d (128 mg, 377 µmol),
zinc chloride (63.5 mg, 466 µmol), LHMDS (1 M in THF, 1.31
mL, 1.31 mmol), [(allyl)PdCl]2 (1.9 mg, 5.19 µmol) and triphenyl-
tert-Butyl [N-trifluoroacetyl-(S)-phenylalanyl]-(R)-2-amino-4-
bromopent-4-enoate (5a): According to general procedure B 1a
(47.8 mg, 229 µmol) was reacted with 4a (143 mg, 381 µmol), zinc
chloride (65.8 mg, 483 µmol), LHMDS (1 M in THF, 1.31 mL,
1.31 mmol), [(allyl)PdCl]2 (2.6 mg, 7.11 µmol) and triphenyl-
4
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900310
European Journal of Organic Chemistry
phosphine (7.4 mg, 28.2 µmol). Aqueous work-up and flash
chromatography (silica, n-pentane/ethyl acetate 90:10) provided 5d
(87.1 mg, 190 µmol, 75%, NMR: dr 70:30) as a yellowish resin. Rf
= 0.32 (petroleum ether/ethyl acetate 80:20). Major diastereomer:
1H NMR (400 MHz, CDCl3): δ = 0.91–0.97 (m, 6 H), 1.24 (m, 1
H), 1.48 (s, 9 H), 1.53 (m, 1 H), 1.92 (m, 1 H), 2.89 (dd, J = 14.8,
6.6 Hz, 1 H), 3.00 (dd, J = 14.8, 5.6 Hz, 1 H), 4.35 (dd, J = 8.3, 6.6
Hz, 1 H), 4.70 (m, 1 H), 5.53 (m, 1 H), 5.63 (m, 1 H), 6.27 (d, J =
7.7 Hz, 1 H), 7.07 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.3, 15.0, 25.0, 28.0, 37.7, 43.1, 51.6, 57.8, 83.3,
115.7 (q, JC-F = 288.2 Hz), 121.0, 127.5, 156.9 (q, JC-F = 38.0 Hz,
168.8, 169.2 ppm. Minor diastereomer (selected signals): 1H NMR
(400 MHz, CDCl3): δ = 4.42 (dd, J = 8.3, 5.6 Hz, 1 H), 5.66 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.4, 15.1, 24.7, 27.9,
38.0, 43.3, 51.7, 60.4, 83.4, 120.7, 128.1 ppm. HRMS (CI): m/z
calcd. C17H27BrF3N2O4 [M+H]+:459.1101; found 459.1095.
mg, 440 µmol) were dissolved in THF (1.5 mL). The resulting
solution was added dropwise to the prepared LDA solution at –
78°C and stirring was continued for 30 min. [(allyl)PdCl]2 (1.9 mg,
5.19 µmol) and triphenylphosphine (7.5 mg, 28.6 µmol) were
dissolved in THF (0.5 mL) and stirred at room temperature for 5
min before 1a (53.7 mg, 257 µmol) was added. This solution was
added dropwise to the cold zinc enolate solution. The excess dry
ice was removed from the cooling bath and the reaction mixture
was allowed to warm up to room temperature overnight. After
dilution with aqueous HCl (1 M) the resulting mixture was
extracted three times with ethyl acetate. After the combined
organic layers had been dried (Na2SO4) and the solvents removed
by evaporation in vacuo, the crude product was purified by flash
chromatography (silica, petroleum ether/ethyl acetate 90:10) to
afford 7 (29.5 mg, 58.1 µmol, 23%, NMR: dr 90:10) as a yellowish
resin. Rf = 0.14 (petroleum ether/ethyl acetate 90:10). Major
1
diastereomer: H NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.47
tert-Butyl [N-trifluoroacetyl-(S)-valyl]-(R)-2-amino-4-bromo-
pent-4-enoate (5e): According to general procedure B 1a (54.4
mg, 260 µmol) was reacted with 4e (124 mg, 380 µmol), zinc
chloride (63.7 mg, 467 µmol), LHMDS (1 M in THF, 1.31 mL,
1.31 mmol), [(allyl)PdCl]2 (2.3 mg, 6.29 µmol) and
triphenylphosphine (7.4 mg, 28.2 µmol). Aqueous work-up and
flash chromatography (silica, n-pentane/ethyl acetate 90:10)
provided 5e (74.8 mg, 168 µmol, 65%, NMR: dr 78:22) as a
yellowish solid. Mp = 71–72 °C. Rf = 0.25 (petroleum ether/ethyl
acetate 80:20). Major diastereomer: 1H NMR (400 MHz, CDCl3): δ
= 1.00 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.48 (s, 9 H),
2.16 (dqq, J = 6.8, 6.8, 6.2 Hz, 1 H), 2.89 (dd, J = 14.9, 5.8 Hz, 1
H), 3.00 (dd, J = 14.9, 6.5 Hz, 1 H), 4.32 (dd, J = 8.4, 6.2 Hz, 1 H),
4.70 (ddd, J = 7.1, 6.5, 5.8 Hz, 1 H), 5.54 (m, 1 H), 5.64 (m, 1 H),
6.27 (d, J = 7.1 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 17.9, 18.8, 28.0, 31.6, 43.1, 51.6, 58.6,
83.3, 115.8 (q, JC-F = 279.8 Hz ), 121.0, 127.5, 157.0 (q, JC-F = 38.1
(s, 3 H), 2.91 (d, J = 14.8 Hz, 1 H), 3.05 (dd, J = 13.7, 8.3 Hz, 1 H),
3.15 (dd, J = 13.7, 5.8 Hz, 1 H), 3.49 (d, J = 14.8 Hz, 1 H), 4.61
(ddd, J = 8.3, 7.3, 5.8 Hz, 1 H), 5.45 (d, J = 1.3 Hz, 1 H), 5.50 (m,
1 H), 6.59 (bs, 1 H), 7.17 (d, J = 7.3 Hz, 1 H), 7.19–7.34 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 23.4, 27.8, 38.5, 45.9, 55.9,
60.1, 83.5, 115.6 (q, JC-F = 287.6 Hz), 121.4, 127.1, 127.4, 128.8,
129.4, 135.2, 156.5 (q, JC-F = 37.4 Hz), 167.8, 171.6 ppm. Minor
1
diastereomer (selected signals): H NMR (400 MHz, CDCl3): δ =
3.39 (d, J = 15.0 Hz, 1 H), 5.57 (m, 1 H), 6.57 (bs, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 27.8, 46.0, 54.8, 59.9, 83.3, 121.7,
127.4, 128.9, 129.4 ppm. HRMS (CI): m/z calcd. C21H27BrF3N2O4
[M+H]+:507.1102; found 507.1107.
tert-Butyl [N-trifluoroacetyl-(S)-phenylalanyl]-(R)-2-amino-4-
iodopent-4-enoate (8): According to general procedure B 2d (63.7
mg, 243 µmol) was reacted with 4a (144 mg, 384 µmol), zinc
chloride (80.8 mg, 593 µmol), LHMDS (1 M in THF, 1.31 mL,
1.31 mmol), [(allyl)PdCl]2 (2.1 mg, 5.33 µmol) and triphenyl-
phosphine (7.5 mg, 28.6 µmol). Aqueous work-up and flash
chromatography (silica, petroleum ether/ethyl acetate 95:5)
provided 8 (97.1 mg, 180 µmol, 74%, NMR: dr 80:20) as a brown
resin. Rf = 0.22 (petroleum ether/ethyl acetate 80:20). Major
1
Hz), 168.9, 169.3 ppm. Minor diastereomer (selected signals): H
NMR (400 MHz, CDCl3): δ = 1.48 (s, 9 H), 4.38 (dd, J = 8.3, 5.6
Hz, 1 H), 5.53 (m, 1 H), 5.66 (m, 1 H), 6.32 (d, J = 7.8 Hz, 1 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 17.7, 18.9, 27.9, 29.7,
168.9 ppm. HRMS (CI): m/z calcd. C16H25BrF3N2O4 [M+H]+:
445.0944; found 445.0957.
1
diastereomer: H NMR (400 MHz, CDCl3): δ = 1.48 (s, 9 H), 2.69
(dd, J = 14.8, 7.3 Hz, 1 H), 2.78 (dd, J = 14.8, 5.9 Hz, 1 H), 3.14
(dd, J = 13.7, 9.4 Hz, 1 H), 3.19 (dd, J = 13.7, 5.9 Hz, 1 H), 4.64
(ddd, J = 7.6, 7.3, 5.9 Hz, 1 H), 4.76 (ddd, J = 9.4, 7.5, 5.9 Hz, 1
H), 5.80 (m, 1 H), 6.04 (m, 1 H), 6.26 (d, J = 7.6 Hz, 1 H), 7.24–
7.41 (m, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 27.9, 38.5,
47.1, 52.4, 54.6, 83.3, 103.4, 115.6 (q, JC-F = 287.6 Hz), 127.5,
128.9, 129.3, 129.3, 135.2, 156.7 (q, JC-F = 37.4 Hz), 168.9, 169.2
tert-Butyl
[O-(tert-butyldiphenylsilyl)-N-trifluoroacetyl-(S)-
seryl]-(R)-2-amino-4-bromopent-4-enoate (5f): According to
general procedure B 1a (52.9 mg, 253 µmol) was reacted with 4f
(207 mg, 375 µmol), zinc chloride (80.0 mg, 587 µmol), LHMDS
(1 M in THF, 1.31 mL, 1.31 mmol), [(allyl)PdCl]2 (1.7 mg, 4.65
µmol) and triphenylphosphine (7.7 mg, 29.4 µmol). Aqueous
work-up and flash chromatography (silica, petroleum ether/ethyl
acetate 90:10) provided 5f (146 mg, 217 µmol, 86%, NMR: dr
92:8) as a yellowish solid. Mp = 64–65 °C. Rf = 0.30 (petroleum
ether/ethyl acetate 80:20). Major diastereomer: 1H NMR (400 MHz,
CDCl3): δ = 1.10, (s, 9 H), 1.48 (s, 9 H), 2.82 (dd, J = 14.8, 7.0 Hz,
1 H), 3.77 (dd, J = 10.2, 7.1 Hz, 1 H), 4.05 (dd, J = 10.2, 4.2 Hz, 1
H), 4.55 (ddd, J = 7.1, 6.3, 4.2 Hz, 1 H), 4.73 (ddd, J = 7.8, 7.0, 5.8
Hz, 1 H), 5.41 (d, J = 1.7 Hz, 1 H), 5.50 (m, 1 H), 6.91 (d, J = 7.8
Hz, 1 H), 7.30 (d, J = 6.3 Hz, 1 H), 7.37–7.48 (m, 6 H), 7.64 (m, 4
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.2, 26.8, 28.0, 43.4,
51.8, 54.4, 63.1, 83.2, 115.6 (q, JC-F = 288.3 Hz), 120.6, 127.7,
128.0, 128.0, 130.2, 130.2, 131.8, 132.3, 135.4, 135.5, 156.9 (q, JC-
1
ppm. Minor diastereomer (selected signals): H NMR (400 MHz,
CDCl3): δ = 1.51 (s, 9 H), 2.90 (dd, J = 14.8, 5.9 Hz, 1 H), 4.59
(ddd, J = 7.3, 6.2, 5.9 Hz, 1 H), 6.01 (m, 1 H), 6.17 (d, J = 7.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0, 38.2, 46.9, 52.5,
83.2, 102.8, 128.8, 168.7, 169.0 ppm. HRMS (CI): m/z calcd.
C20H25F3IN2O4 [M+H]+:540.0727; found 540.0722.
tert-Butyl
[O-(tert-butyldiphenylsilyl)-N-trifluoroacetyl-(S)-
seryl]-(R)-2-amino-4-methylene-6-(trimethylsilyl)hex-5-ynoate
(9): Trimethylsilylacetylene (29.5 mg, 300 µmol), triethylamine
(30.4 mg, 300 µmol), copper iodide (1.9 mg, 10.0 µmol) and
Pd(PPh3)4 (4.0 mg, 3.50 µmol) were added to a solution of 5f (67.2
mg, 100 µmol) in THF (590 µL). The reaction mixture was heated
to 50 °C and stirred at this temperature for 18 hours. The solvent
was evaporated in vacuo and the crude product was purified by
flash chromatography (silica, n-pentane/ethyl acetate 95:5) to
afford 9 (55.0 mg, 77.0 µmol, 77%) as a yellowish resin. Rf = 0.57
(petroleum ether/ethyl acetate 70:30). [α]2D0 = +12.7 (c = 1.0,
= 38.2 Hz), 167.8, 169.1 ppm. Minor diastereomer (selected
F
signals): 1H NMR (400 MHz, CDCl3): δ = 5.58 (m, 1 H), 6.99 (d, J
= 7.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 28.0, 130.1,
135.5 ppm. HRMS (CI): m/z calcd. C30H39BrF3N2O5Si [M+H]+:
671.1758; found 671.1747.
tert-Butyl [N-trifluoroacetyl-(S)-phenylalanyl]-(R)-2-amino-2-
methyl-4-bromopent-4-enoate (7): Diisopropylamine (144 mg,
1.42 mmol) was dissolved in THF (2 mL) and cooled to –78 °C. A
solution of n-butyllithium (1.6 M in hexanes, 0.82 mL, 1.31 mmol)
was added dropwise and stirred at room temperature for 10
minutes. Dipeptide 6 (147 mg, 377 µmol) and zinc chloride (60.0
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.18 (s, 9 H), 1.08 (s, 9
H), 1.47 (s, 9 H), 2.54 (dd, J = 14.3, 7.3 Hz, 1 H), 2.62 (dd, J =
14.3, 6.0 Hz, 1 H), 3.79 (dd, J = 10.3, 6.7 Hz, 1 H), 4.02 (dd, J =
10.3, 4.2 Hz, 1 H), 4.54 (ddd, J = 6.6, 4.4, 4.2 Hz, 1 H), 4.70 (ddd,
J = 7.5, 6.6, 6.3 Hz, 1 H), 5.19 (m, 1 H), 5.40 (m, 1 H), 6.86 (d, J =
7.5 Hz, 1 H), 7.33–7.50 (m, 7 H), 7.64 (m, 4 H) ppm. 13C NMR
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900310
European Journal of Organic Chemistry
(100 MHz, CDCl3): δ = 0.2, 19.2, 26.8, 28.0, 39.1, 52.0, 54.4, 63.1,
82.7, 95.7, 104.3, 125.3, 126.3, 128.0, 130.2, 131.9, 132.3, 135.4,
135.5, 156.8 (q, JC-F = 37.4 Hz), 167.7, 169.8 ppm. One TFA
signal could not be determined. HRMS (CI): m/z calcd.
C35H47O5N2F3Si2 [M]+: 688.2970; found 688.2994.
57, 11432−11435; h) P. Servatius, U. Kazmaier, J. Org.
Chem. 2018, 83, 11341−11349; i) J. Gorges, L. Kjaerulff, F.
Panter, T. Hoffmann, U. Kazmaier, R. Müller, Angew. Chem.
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57,14270–14275.
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118, 4973–4976; Angew. Chem. Int. Ed. 2006, 45, 4855–
4858; b) J. Deska, U. Kazmaier, Chem. Eur. J. 2007, 13,
6204–6211; c) S. Datta, A. Bayer, U. Kazmaier, Org. Biomol.
Chem. 2012, 10, 8268–8275; d) A. Bayer, U. Kazmaier, J.
Org. Chem. 2014, 79, 8491–8497.
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4649–4652; b) G. T. Crisp, P. T. Glink, Tetrahedron 1994,
50, 3213–3234; c) U. Kazmaier, D. Schauß, M. Pohlman, S.
Raddatz, Synthesis 2000, 914–916; d) U. Kazmaier, D.
Schauß, S. Raddatz, M. Pohlman, Chem. Eur. J. 2001, 7,
456–464.
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4657; Angew. Chem. Int. Ed. 2007, 46, 4570–4573; b) J.
Deska, U. Kazmaier, Curr. Org. Chem. 2008, 12, 355–385.
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1017–1019; b) U. Kazmaier, M. Pohlman, D. Schauß, Eur. J.
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Methyl
{[O-(tert-butyldiphenylsilyl)-N-trifluoroacetyl-(S)-
seryl]-α-tert-butyl-[(R)-4-methylene-γ-glutamatyl]}-(S)-leuci-
nate (10): Methyl-(S)-leucinate hydrochloride (21.8 mg, 120
µmol), triethylamine (40.5 mg, 400 µmol) and Pd(PPh3)4 (5.8 mg,
5.00 µmol) were added to a solution of 5f (67.2 mg, 100 µmol) in
DMF (1.3 mL). The reaction mixture was put under CO pressure (1
atm) and stirred at 80 °C for 18 h. The mixture was hydrolyzed
with aqueous HCl (1 M) and extracted three times with ethyl
acetate. The combined organic phases were dried over Na2SO4 and
evaporated in vacuo. The crude product was purified by flash
chromatography (a: silica, petroleum ether/ethyl acetate 80:20–
70:30 b: C18, water/ acetonitrile 100:0–0:100) to afford 10 (41.2
mg, 54.0 µmol, 54%) as a colourless resin. Rf = 0.29 (petroleum
ether/ethyl acetate 70:30). [α]2D0 = +2.4 (c = 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 0.93 (d, J = 5.6 Hz, 3 H), 0.94 (d, J = 5.8
Hz, 3 H), 1.05 (s, 9 H), 1.44 (s, 9 H), 1.59–1.70 (m, 3 H), 2.69 (dd,
J = 14.2, 7.1 Hz, 1 H), 2.78 (dd, J = 14.2, 5.1 Hz, 1 H), 3.73 (s, 3
H), 3.88 (dd, J = 10.5, 5.3 Hz, 1 H), 4.03 (dd, J = 10.5, 4.4 Hz, 1
H), 4.49 (ddd, J = 6.7 Hz, 5.7 Hz, 5.6 Hz, 1 H), 4.56–4.63 (m, 2 H),
5.38 (m, 1 H), 5.67 (m, 1 H), 6.63 (d, J = 8.2 Hz, 1 H), 7.35–7.45
(m, 7 H), 7.62 (m, 4 H), 8.03 (d, J = 6.7 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 19.2, 21.8, 22.7, 25.0, 26.7, 28.0, 35.0,
40.9, 51.1, 52.5, 53.0, 54.6, 63.2, 82.4, 115.7 (q, JC-F = 287.6 Hz),
122.2, 127.8, 127.9, 130.0, 130.0, 132.3, 132.5, 135.4, 135.5, 140.4,
156.8 (q, JC-F = 37.4 Hz), 167.9, 168.9, 169.4, 173.7 ppm. HRMS
(CI): m/z calcd. C38H53O8N3F3Si [M+H]+: 764.3549; found
764.3564.
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Supporting Information: Copies of NMR spectra of all new
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Acknowledgement
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J. 2008, 14, 1322–1329.
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[20] The minor diastereomer could be removed by flash
chromatography.
Financial support from Saarland University is gratefully
acknowledged.
___________
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10.1002/ejoc.201900310
European Journal of Organic Chemistry
Entry for the Table of Contents
Allylic alkylation
Michael Kohr and Uli Kazmaier
Page No. – Page No.
Halogenated allyl alcohol derivatives -
versatile dielectrophiles for palladium-
catalyzed allylic alkylations
Brominated and iodinated allylic substra-
tes can be subjected to palladium-cataly-
zed allylic alkylation of amino acid and
peptide ester enolates. The incorporation
of a vinylic halide functionality into the
allylic substrate allows a direct modifica-
tion of the allylated peptide via cross
coupling chemistry.
Keywords: Allylic alkylation / Amino
acids / Cross coupling / Peptides / Vinyl
halides
This article is protected by copyright. All rights reserved.