Highly stereoselective modifications of peptides via Pd-catalyzed allylic alkylation of internal peptide amide enolates

Article abstract of DOI:10.1039/c2ob26351c

Pd-catalyzed allylations are excellent tools for stereoselective peptide modifications, showing several advantages compared to normal alkylations. Reactions of internal peptide amide enolates with Pd-allyl complexes proceed not only with high yields of up to 86%, they show also high regio- and diastereoselectivities (88-99%), giving rise to the trans-configured products. Therefore, this protocol is a powerful synthetic tool for the synthesis of natural product and drug molecules.

Full text of DOI:10.1039/c2ob26351c

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 8268
www.rsc.org/obc
PAPER
Highly stereoselective modifications of peptides via Pd-catalyzed allylic
alkylation of internal peptide amide enolates†‡
Swarup Datta, Anton Bayer and Uli Kazmaier*
Received 13th July 2012, Accepted 20th August 2012
DOI: 10.1039/c2ob26351c
Pd-catalyzed allylations are excellent tools for stereoselective peptide modifications, showing several
advantages compared to normal alkylations. Reactions of internal peptide amide enolates with
Pd–allyl complexes proceed not only with high yields of up to 86%, they show also high regio- and
diastereoselectivities (88–99%), giving rise to the trans-configured products. Therefore, this
protocol is a powerful synthetic tool for the synthesis of natural product and drug molecules.
ring, and therefore the attack of the electrophile occurs preferen-
tially from the face opposite to the peptide ring. It should be
Introduction
Bacteria or marine organisms are an excellent source of peptide-
and cyclopeptide-based natural products, containing a wide
range of unusual amino acids.1 Many of these contain also
N-alkylated and (R)-amino acids as building blocks. In most
cases, these secondary metabolites show interesting biological
properties, and therefore some of them found application as
drugs2 or at least as lead structures for drug development. For
the optimization of such lead structures highly flexible and
modular concepts are desired. For example, the direct introduc-
tion of a side chain onto a given peptide, or the manipulation of
a suitable functionalized side chain, represents a powerful
alternative to classical peptide synthesis, since a multitude of
modified analogues can be prepared from only one parent
peptide precursor.3
While the modification of a functionalized side chain in
general is not a big problem,4 the direct introduction of a side
chain onto a given peptide is not a trivial issue. Especially the
stereoselective introduction of side chains was an unsolved
problem in most cases so far. In principle, peptide-incorporated
glycine cations,5 radicals6 as well as anions can be generated as
reactive intermediates for further modifications. Especially the
last approach was investigated intensively by Seebach et al.7
Probably the most spectacular success was the regio- as well as
stereoselective alkylation of the sarcosine (sar) subunit in cyclo-
sporine (Scheme 1).8 At this position, the secondary amide
allowed the formation of an amide enolate, which could be
reacted with electrophiles such as alkyl halides. Here, one face
of the enolate is probably shielded by the deprotonated peptide
mentioned that even with a large excess of base, no epimeriza-
tion of the peptide occurs, because the N-methylated amino
acids are not deprotonated for steric reasons, and the unmethyla-
ted amino acids are protected by deprotonation of the acidic NH-
bonds.7 In contrast to such cyclic peptides, modifications of
linear peptides generally proceed unselectively, because of the
high flexibility of the peptide chain.9
Our group has been also investigating stereoselective peptide
modifications for some time, with the aim to apply these modifi-
cations to natural product and drug synthesis. Our major goal is
to transfer the chiral information of a given peptide chain via
metal peptide complexes to the newly formed stereogenic center.
We recognized that besides the chelate–enolate Claisen
rearrangements10 also palladium-catalyzed allylations of peptides
give high yields and selectivities (Scheme 2).11 In all examples
investigated so far, an (S)-amino acid generated an (R)-amino
acid and vice versa.12 At the beginning, these reactions were
limited to peptide esters, but recently we could show that such
stereoselective allylic alkylations are also possible with
Institute for Organic Chemistry, Saarland University, D-66123
Saarbruecken, Germany. E-mail: u.kazmaier@mx.uni-saarland.de;
Fax: +49 681 302 2409; Tel: +49 681 302 3409
†Dedicated to Prof. Th. Eicher on the occasion of his 80th birthday.
‡Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26351c
Scheme 1 Stereoselective cyclopeptide modifications according to
Seebach et al.
8268 | Org. Biomol. Chem., 2012, 10, 8268–8275
This journal is © The Royal Society of Chemistry 2012

View Online
Scheme 3 Modifications of proline dipeptides.
Scheme 2 Stereoselective peptide modifications via allylic alkylations.
formed, while the other monosubstituted linear substrates gave
mixtures of linear (7l) and branched products (7b), while also
here the linear product was the predominant one (entries 5–7).
It should be mentioned that only the formation of the trans-
configured product was observed by NMR, also with cis-confi-
gured substrates (entry 7). This clearly indicates that the
π–σ–π-isomerization of the π-allyl intermediate is faster than the
nucleophilic attack of the peptide enolate, which is in contrast to
reactions of chelated amino acid ester enolates.18 But with
respect to the steric demand of the peptide enolates, this is not
surprising. They react at slightly higher temperatures (−55 °C)
than the amino acid ester enolates (−78 °C), allowing the iso-
merization to occur.
Disubstituted allylic substrates behave differently when com-
pared to the monosubstituted ones. Isoprenyl acetate, for
example, surprisingly gave rise to a significant amount of the
branched product with a quaternary center at the β-position of
the newly formed amino acid (entry 8). Obviously, a nucleophi-
lic attack in an SN1-type fashion is favored over the generally
observed SN2-type process.19 Both regioisomers were formed
with the same high diastereoselectivity and we assume that this
is also true for the other examples, where we could determine
only one stereoisomer for the minor branched products (entries
5–7). To prove the generality of our process we subjected also
some other tripeptides (4–6) to allylations using methallyl car-
bonate (entries 9–11). The yields obtained were comparable in
the range of 80% ( 5%). While the Ile-peptide 6 was slightly
less selective, with the tert-leucine (7) and the tyrosine derivative
(8) the diastereomeric ratio (dr) exceeded 20 : 1, and it was
difficult to identify the second diastereomer.
Therefore, for analytical purposes, we subjected peptides 3–6
also to “normal” allylations using methallyl bromide
(Scheme 4). The yields obtained were comparable to the Pd-cata-
lyzed process, but the allylations proceeded completely unselec-
tive. This clearly demonstrates the power and the advantages of
the Pd-catalyzed version. Catalytic hydrogenations of these pep-
tides gave rise to the leucine-peptides, which could be used to
determine the configuration of the peptide formed. Also here, the
N-terminal (S)-amino acid induces an (R)-configured amino acid
and therefore an (S,R,S)-configuration can be assumed for the
peptides 7–10.
Although the C-terminal proline of the dipeptides 1 had no
significant effect on the stereochemical outcome of the allylation
reaction, in principle one might expect some influence of the
C-terminal chiral amino acids as well. Therefore, we replaced
the proline by N-alkylated leucine (R and S) and investigated the
allylation of substrates 11 and 12 using methallyl carbonate
(Table 2, entries 1 and 2). Two (S)-amino acids flanking the
secondary amide enolates.13 Originally, we began our investi-
gations with alkylations of different protected (Cbz, Boc, Ts,
Tfa) secondary dipeptide amides to figure out the best conditions
for the required amide enolate modifications. Although good
yields (70–90%) were obtained with all protecting groups used,
no selectivity was observed in any case, independent of the alky-
lating agent used. Therefore, we switched to the Pd-catalyzed
allylic alkylation which proved to be much better suited for
stereoselective modifications than simple alkylations.12 Based on
our previous observations made with amino acid14 and peptide
ester enolates,15 we chose the trifluoroacetyl (Tfa-) protected
peptides as substrates. And indeed, with a wide range of allyl
carbonates the allylation products were obtained in high yields
and good diastereoselectivities, providing the (S,R)-configured
peptides preferentially (Scheme 2).
Results and discussion
With these results in hand, we next tried to transfer these reaction
conditions also to proline-containing tripeptides. As long as the
stereogenic center of the proline has no influence on the stereo-
chemical outcome of the allylation, one might have a chance to
get similar results also with these larger peptides. Therefore, as a
control experiment, we subjected dipeptides 116 to both, a
methylation and an allylic alkylation (Scheme 3). Both reactions
proceeded very well, and, as we hoped, without significant
selectivity.
This was an excellent precondition to switch to the corre-
sponding tripeptides such as 3 (Table 1). And indeed, the results
were comparable to those obtained with the dipeptides. Although
both, LHMDS as well as LDA, can be used as a base, in the
case of the tripeptides the stronger base LDA gave slightly better
yields.
The stannylated allyl carbonate (entry 3) is an especially inter-
esting substrate, not only because it provided only one stereo-
isomer, but also because the stannylated peptide 7c is an ideal
substrate for subsequent peptide modification via Stille
couplings.12
In all other examples investigated so far the diastereoselecti-
vity was in the range of 90% or better, relatively independent of
the substitution pattern in the allylic substrate. The only excep-
tion was a functionalized substrate having an additional stereo-
genic center adjacent to the π-allyl complex formed (entry 4).
Probably this has an influence on the stereoselectivity,17 and we
assume that we observe a mismatched situation here. Interest-
ingly, in this case only the linear substitution product (7dl) was
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8268–8275 | 8269

View Online
Table 1 Modifications of tripeptide amides 3–6
Entry
Substrate
R
R1
R2
R3
Yield (%)
Product
Ratioal : b
dr
1
2
3
4
3
3
3
3
Bn
Bn
Bn
Bn
Me
Ph
SnBu3
H
H
H
H
H
H
H
H
82
73
75
67
7a
7b
7c
7d
—
—
—
100 : 0
92 : 8
88 : 12
>99 : 1
81 : 19
5
6
7
8
9
10
11
3
3
3
3
4
5
6
Bn
Bn
Bn
Bn
iBu
tBu
p-MeOBn
H
H
H
H
Me
Me
Me
nPr
Ph
H
Me
H
H
H
H
H
75
86
70
54
80
84
85
7e
7f
7g
7h
8a
9a
10a
87 : 13
96 : 4
93 : 7
46 : 54
—
90 : 10
92 : 8
97 : 3
92 : 8b
88 : 12
96 : 4
96 : 4
CH2OTBDMS
Me
H
H
H
—
—
a l: Linear product; b: branched product. b Diastereoselectivity of both products (l and b).
diastereoselectivity (entries 5 and 6), giving rise to the (S,R,S)-
products with ds values of 91–99%, being slightly lower for the
alanine-containing peptide.
Furthermore Boc- and Cbz-protected analogues of tripeptides
11, 14 and 15 were tested as substrates in the Pd-catalyzed tri-
peptide allylation with methallyl carbonate. The reactions
proceeded with similar diastereoselectivities as with the Tfa-pro-
tected peptides but gave significantly lower yields (38–41%)
along with several by-products (data not shown).
The absolute configuration of the allylation products 16–20
was confirmed by total hydrolysis, followed by derivatization
of the fragments, GC-analysis on a chiral stationary phase
(L-Chirasil-Val) and comparison with racemic references.
Conclusion
Scheme 4 Allylation of tripeptide amide enolates.
In conclusion, we have shown that the Pd-catalyzed allylation is
an excellent tool for stereoselective peptide modifications, being
clearly superior to normal alkylations. The reactions proceed not
only in high yields, but also high regio- and diastereoselec-
tivities, and trans-products are formed exclusively. Therefore,
this is a powerful synthetic tool for natural product and drug syn-
thesis. Further investigations using even larger peptides are cur-
rently in progress.
glycine led to the expected (S,R,S)-configured product 16a with
excellent diastereoselectivity (matched case), whereas a combi-
nation of an (S)- and an (R)-amino acid was completely unselec-
tive, resulting in the formation of product 17 as a nearly
1 : 1 mixture of both diastereomers (mismatched case). To show
the generality of the observed stereoselectivity, the (S,S)-N-ben-
zylated substrate 13 was also subjected to allylic alkylation.
Despite the sterically crowded environment around the glycine
unit the allylated product was obtained in quite acceptable yield
with very high diastereoselectivity (entry 3). Next the employ-
ment of a sterically more hindered TMBDMSO-substituted
allylic substrate was attempted with tripeptide 11 and provided
the expected product 16b with excellent diastereoselectivities
in a slightly lower yield (entry 4). The variation of the
N-terminal amino acid in the tripeptides containing a C-terminal
N-methylleucine (14, 15) had a relatively little influence on the
Experimental
General remarks
Optical rotations were measured with a Perkin-Elmer polarimeter
(Model 341) at 20 °C using a sodium vapor lamp (λ = 589 nm).
1H and 13C NMR spectra were recorded with a Bruker AC-400
[400 MHz (1H) and 100 MHz (13C)] spectrometer in CDCl3.
Compounds which showed a mixture of rotamers at room
8270 | Org. Biomol. Chem., 2012, 10, 8268–8275
This journal is © The Royal Society of Chemistry 2012

View Online
Table 2 Modifications of tripeptide amides 11–15
Entry
Substrate
R1
R2
R3
Leu
Yield (%)
Product
dr
1
2
3
4
5
6
11
12
13
11
14
15
Bn
Bn
Bn
Bn
Me
iPr
Me
Me
Bn
Me
Me
Me
Me
Me
Me
S
R
S
S
S
S
80
78
66
56
70
71
16a
17
18
16b
19
20
97 : 3
49 : 51
94 : 6
97 : 3
89 : 11
>99 : 1
CH2OTBDMS
Me
Me
temperature, their spectra were recorded with a Bruker DRX-500
[500 MHz (1H) and 125 MHz (13C)] spectrometer at 80 °C
(353 K) in DMSO-d6. HRMS were recorded with a Finnigan
MAT 95 spectrometer using a CI technique. Peptide substrates
3–6 and 11–15 were obtained by standard peptide coupling reac-
tions. Diastereomeric ratios were measured using HPLC (Merck
Hitachi) using a silica gel or Reprosil column. Total hydrolyses
of tripeptides were carried out with 6 M HCl at 130 °C for 24 h,
followed by esterification with n-propanol/cat. 4 M HCl at
110 °C and subsequent perfluoroacylation with trifluoroacetic
anhydride/methyl trifluoroacetate (1 : 1) at 130 °C for 10 min.
The fragments were separated on a chiral GC (L-Chirasil-Val, 80 °C,
4 min, 80–110 °C, 4 °C min−1, 110–180 °C, 5 °C min−1), detected
with FID and identified by comparison with racemic references.
Elemental analyses were performed at the Saarland University.
0.262 mmol) in 92% yield (101.5 mg, 0.241 mmol). Major dia-
stereomer (60%): H NMR (400 MHz, CDCl3): δ 9.14 (bs, 1 H,
1
NH), 7.37 (d, J = 8.0 Hz, 2 H, ArH), 7.26–7.18 (m, 5 H, ArH),
7.21 (t, J = 8.0 Hz, 2 H, ArH), 6.96 (t, J = 8.0 Hz, 1 H, ArH),
5.73 (d, J = 8.4 Hz, 1 H, NH), 5.64 (m, 1 H, CHvCH2),
5.01–4.93 (m, 4 H, PhCH2, CHvCH2), 4.67 (dd, J = 8.0,
2.0 Hz, 1 H, NCH), 4.54 (q, J = 8.0 Hz, 1 H, NHCH), 3.65 (m,
1 H, NCH2), 3.55 (m, 1 H, NCH2), 2.50–2.31 (m, 3 H,
CH2CHvCH2, CH2), 2.10 (m, 1 H, CH2), 1.94 (m, 1 H, CH2),
1.80 (m, 1 H, CH2). 13C NMR (100 MHz, CDCl3): δ 172.0
(CvO), 168.5 (CvO), 155.8 (OCvO), 138.0 (ArC), 136.1
(ArC), 131.6 (CHvCH2), 128.7 (ArC), 128.4 (ArC), 128.1
(ArC), 128.0 (ArC), 123.8 (ArC), 119.6 (ArC), 119.4
(CHvCH2), 66.9 (PhCH2), 60.6 (NCHCO), 51.9 (NHCHCO),
47.5 (NCH2), 37.0 (CH2CHvCH2), 26.6 (CH2), 25.0 (CH2).
HRMS (CI) m/z calcd for C24H28N3O4 [M + H]+ 422.2080;
found 422.2089. Minor diastereomer (40%, mixture with major
1
General procedure for palladium-catalyzed allylic alkylations of
dipeptides
diastereomer): H NMR (400 MHz, CDCl3): δ 9.01 (bs, 1 H,
NH), 7.59 (d, J = 8.0 Hz, 2 H, ArH), 7.37–7.25 (m, 7 H, ArH),
7.06 (d, J = 7.6 Hz, 1 H, ArH), 5.78 (m, 1 H, CHvCH2), 5.38
(d, J = 6.0 Hz, 1 H, NH), 5.22 (d, J = 15.6 Hz, 1 H, CHvCH2),
5.20 (d, J = 9.6 Hz, 1 H, CHvCH2), 5.14 (d, J = 12.0 Hz, 1 H,
PhCH2), 5.03 (d, J = 12.0 Hz, 1 H, PhCH2), 4.78 (dd, J = 6.8,
1.2 Hz, 1 H, NCH), 4.52 (q, J = 6.8 Hz, 1 H, NHCH), 3.94 (t,
J = 7.6 Hz, 1 H, NCH2), 3.58 (q, J = 7.6 Hz, 1 H, NCH2),
2.59–2.53 (m, 2 H, CH2CHvCH2), 2.46 (m, 1 H, CH2),
2.19–1.92 (m, 3 H, CH2). 13C NMR (100 MHz, CDCl3):
δ 171.7 (CvO), 168.9 (CvO), 156.3 (OCvO), 138.1 (ArC),
135.9 (ArC), 132.0 (CHvCH2), 128.6 (ArC), 128.4 (ArC),
128.1 (ArC), 127.9 (ArC), 123.9 (ArC), 120.0 (ArC), 119.4
(CHvCH2), 67.0 (PhCH2), 61.1 (NCHCO), 52.4 (NHCHCO),
47.3 (NCH2), 35.8 (CH2CHvCH2), 28.3 (CH2), 24.4 (CH2).
HRMS (CI) m/z calcd for C24H28N3O4 [M + H]+ 422.2080;
found 422.2078. HPLC (silica, hexane–EtOAc = 60 : 40, 1 mL
min−1, 254 nm): tR (60%) = 15.23 min, tR (40%) = 20.72 min.
n-BuLi (1.6 M, 0.50 mL, 0.81 mmol) was added to a solution of
HMDS (0.18 mL, 0.87 mmol) in THF (0.4 mL) in a Schlenk
flask at −20 °C and stirred for 20 min. The cooling bath was
removed and stirring was continued for a further 10 min before
cooling again to −78 °C. In a second Schlenk flask a mixture of
N-protected dipeptide (0.23 mmol) and ZnCl2 (37.7 mg,
0.28 mmol) was dissolved in THF (1 mL). The solution was
added to the LHMDS solution at −78 °C and stirring was contin-
ued for 30 min at −78 °C. A solution was prepared from the pal-
ladium catalyst (1.7 mg, 4.6 μmol) and triphenylphosphine
(20.7 μmol) in THF (0.2 mL) and stirred at room temperature for
10 min before the allyl carbonate (0.16 mmol) was added. The
resulting solution was added slowly to the chelated enolate at
−78 °C. The mixture was allowed to warm up to room temp-
erature overnight. The solution was diluted with ethyl acetate
before 1 M KHSO4 was added. After extraction with ethyl acetate
the organic layers were dried over Na2SO4, concentrated in vacuo
and the crude product was purified by column chromatography.
General procedure for palladium-catalyzed allylic alkylations of
tripeptides
N-Benzyloxycarbonyl-(R/S)-allylglycyl-(S)-prolinanilide (2b).
According to the procedure for palladium-catalyzed allylic alky-
lations of dipeptides 2b was obtained from 1b (100 mg,
n-BuLi (1.6 M, 0.51 mL, 0.81 mmol) was added to a solution of
DIPA (0.11 mL, 0.84 mmol) in THF (0.4 mL) in a Schlenk flask
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8268–8275 | 8271

View Online
at −20 °C. The cooling bath was removed and stirring was con-
tinued for a further 10 min before the mixture was cooled again
to −78 °C. In a second Schlenk flask a mixture of N-protected
tripeptide (0.20 mmol) and ZnCl2 (41.7 mg, 0.31 mmol) was
dissolved in THF (3 mL). This solution was added to the LDA
solution at −78 °C and the mixture was warmed up to −40 °C
within 30 min, before the solution was cooled again to −78 °C
and stirred for a further 15 min. The palladium catalyst
(1.46 mg, 4.0 μmol) and triphenylphosphine (4.8 mg,
18.3 μmol) were dissolved in THF (0.2 mL). After stirring for
10 min at room temperature the allyl substrate (0.20 mmol) was
added to the yellow solution formed, and the resulting mixture
was added slowly to the chelated enolate at −78 °C. The solution
was allowed to warm up to room temperature overnight, before it
was diluted with ethyl acetate and 1 M KHSO4 was added. After
extraction with ethyl acetate, the organic layers were dried over
Na2SO4, concentrated in vacuo and the crude product was
purified by flash chromatography.
(NCH2), 41.2 (CH2CvCH2), 39.7 (PhCH2), 28.8 (CH2), 24.9
(CH2), 21.9 (CH3). HRMS (CI) m/z calcd for C28H32F3N4O4
[M + H]+ 545.2376; found 545.2368. C28H31F3N4O4 (544.57)
calcd C 61.76, H 5.74, N 10.29; found C 61.14, H 5.72, N 9.78.
HPLC (silica, hexane–EtOAc = 50 : 50, 1 mL min−1, 254 nm):
tR (8%) = 9.47 min, tR (92%) = 13.51 min.
N-Trifluoroacetyl-(S)-phenylalanyl-(R)-[(2-tributylstannyl)allyl]-
glycyl-(S)-prolinanilide (7c). According to the general procedure
for palladium-catalyzed allylic alkylations of tripeptides 7c was
obtained from 3 (100 mg, 0.204 mmol) in 75% yield (125.5 mg,
0.153 mmol). [α]D20 = −65.6° (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ 8.76 (s, 1 H, NH), 7.59 (d, J = 7.6 Hz,
2 H, ArH), 7.28–7.18 (m, 6 H, ArH, NH), 7.11 (dd, J = 8.0,
2.0 Hz, 2 H, ArH), 7.04 (t, J = 7.6 Hz, 1 H, ArH), 6.52 (d, J =
5.2 Hz, 1 H, NH), 5.70 (dd, J = 231.6, 1.6 Hz, 1 H, CvCH2),
5.28 (dd, J = 58.0, 1.6 Hz, 1 H, CvCH2), 4.76 (q, J = 7.2 Hz,
2 H, NCH), 4.70 (dd, J = 7.8, 2.0 Hz, 1 H, NCH), 4.48 (dt, J =
8.5, 5.7 Hz, 1 H, NCH), 3.94 (m, 1 H, NCH2), 3.51 (m, 1 H,
NCH2), 3.08 (dd, J = 14.0, 6.8 Hz, 1 H, PhCH2), 3.01 (dd, J =
14.0, 6.8 Hz, 1 H, PhCH2), 2.63 (dd, J = 13.6, 5.7 Hz, 1 H,
CH2CvCH2), 2.42 (m, 2 H, CH2CvCH2, CH2), 2.06 (m, 3 H,
CH2), 1.50 (m, 6 H, SnCH2CH2), 1.35 (m, 6 H, CH2CH3), 0.94
N-Trifluoroacetyl-(S)-phenylalanyl-(R)-(2-methylallyl)-glycyl-(S)-
prolinanilide (7a). According to the general procedure for palla-
dium-catalyzed allylic alkylations of tripeptides 7a was obtained
from 3 (100 mg, 0.204 mmol) in 82% yield (91.2 mg,
0.167 mmol). Major diastereomer (92%): [α]2D0 = −102.5° (c =
(m, 15 H, SnCH2, CH2CH3). 13C NMR (100 MHz, CDCl3):
1
2
0.5, CHCl3). M.p. 150–152 °C. H NMR (400 MHz, CDCl3):
δ 171.0 (CvO), 169.6 (CvO), 168.9 (CvO), 156.8 (q, JC,F
=
δ 8.79 (s, 1 H, NH), 7.57 (d, J = 7.2 Hz, 2 H, ArH), 7.28–7.25
(m, 6 H, ArH, NH), 7.12 (d, J = 7.6 Hz, 2 H, ArH), 7.06 (t, J =
7.2 Hz, 1 H, ArH), 6.83 (d, J = 6.0 Hz, 1 H, NH), 4.83 (s, 1 H,
CvCH2), 4.80 (q, J = 7.2 Hz, 1 H, NHCH), 4.78 (s, 1 H,
CvCH2), 4.69 (dd, J = 6.0, 2.4 Hz, 1 H, NCH), 4.60 (m, 1 H,
NHCH), 3.95 (m, 1 H, NCH2), 3.53 (m, 1 H, NCH2), 3.11–2.99
(m, 2 H, PhCH2), 2.44 (m, 1 H, CH2), 2.37 (dd, J = 14.0,
5.2 Hz, 1 H, CH2CvCH2), 2.26 (dd, J = 14.0, 9.2 Hz, 1 H,
CH2CvCH2), 2.15 (m, 1 H, CH2), 2.05 (m, 2 H, CH2), 1.75 (s,
3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 171.3 (CvO),
37.4 Hz, CF3CO), 148.9 (CH2vCSn), 137.9 (ArC), 135.2
(ArC), 129.9 (ArC), 129.1 (ArC), 128.8 (ArC), 128.7
(CH2vCSn), 127.4 (ArC), 124.2 (ArC), 120.1 (ArC), 115.5 (q,
1JC,F = 289.7 Hz, CF3), 61.4 (NCHCO), 54.2 (NHCHCO), 50.1
(NHCHCO), 47.5 (NCH2), 41.9 (CH2CvCH2), 38.1 (PhCH2),
29.0 (JC,Sn = 19.8 Hz, SnCH2CH2), 28.8 (CH2), 27.4 (JC,Sn
56.5 Hz, CH2CH3), 24.3 (CH2), 13.6 (CH2CH3), 9.7 (JC,Sn
=
=
328.6 Hz, SnCH2). HRMS (CI) m/z calcd for C39H57F3N4O4Sn
[M + H]+ 821.3276; found 821.3259. HPLC (silica, hexane–
EtOAc = 70 : 30, 1 mL min−1, 254 nm): tR = 10.24 min.
2
169.7 (CvO), 168.9 (CvO), 156.7 (q, JC,F = 36.5 Hz,
CF3CO), 139.5 (CvCH2), 137.8 (ArC), 135.2 (ArC), 129.1
(ArC), 128.8 (ArC), 127.4 (ArC), 124.3 (ArC), 120.0 (ArC),
115.5 (q, JC,F = 286.0 Hz, CF3), 115.4 (CvCH2), 61.3
N-Trifluoroacetyl-(S)-phenylalanyl-(R)-[3-(2,2-dimethyl-1,3-
dioxolan-4-yl)allyl]-glycyl-(S)-prolinanilide (7d). According to
the general procedure for palladium-catalyzed allylic alkylations
of tripeptides 7d was obtained from 3 (200 mg, 0.409 mmol) in
67% yield (173.2 mg, 0.274 mmol). Major diastereomer (81%):
1
(NCHCO), 54.4 (NHCHCO), 50.0 (NHCHCO), 47.4 (NCH2),
39.6 (CH2CvCH2), 38.5 (PhCH2), 28.8 (CH2), 24.4 (CH2),
21.9 (CH3). HRMS (CI) m/z calcd for C28H32F3N4O4 [M + H]+
1
[α]2D0 = −29.0° (c = 1.0, CH3OH). M.p. 70–72 °C. H NMR
545.2376; found: 545.2355. Minor diastereomer (8%): [α]D20
=
(400 MHz, CDCl3): δ 8.74 (s, 1 H, NH), 7.57–7.48 (m, 4 H,
ArH, NH), 7.31–7.22 (m, 5 H, ArH), 7.13 (d, J = 6.4 Hz, 2 H,
ArH), 7.07 (t, J = 6.4 Hz, 1 H, ArH), 5.63 (dt, J = 15.5, 6.5 Hz,
1 H, CH2CHvCH), 5.56 (dd, J = 15.5, 6.4 Hz, 1 H,
CH2CHvCH), 4.85 (q, J = 6.8 Hz, 1 H, NHCH), 4.68 (dd, J =
7.6, 2.0 Hz, 1 H, NCH), 4.62 (q, J = 6.8 Hz, 1 H, NHCH), 4.43
(m, 1 H, CHvCHCHO), 4.06 (dd, J = 8.0, 6.0 Hz, 1 H, CH2O),
3.84 (m, 1 H, CH2O), 3.54 (m, 2 H, NCH2), 3.11 (dd, J = 14.0,
6.8 Hz, 1 H, PhCH2), 3.05 (dd, J = 14.0, 7.2 Hz, 1 H, PhCH2),
2.44–2.32 (m, 3 H, CH2, CH2CHvCH), 2.18–1.97 (m, 3 H,
CH2), 1.40 (s, 3 H, CH3), 1.37 (s, 3 H, CH3). 13C NMR
(100 MHz, CDCl3): δ 170.5 (CvO), 169.7 (CvO), 168.9
−116.8° (c = 0.5, CHCl3). M.p. 239–240 °C. 1H NMR
(400 MHz, CDCl3): δ 8.68 (s, 1 H, NH), 8.49 (bs, 1 H, NH),
7.61 (d, J = 8.8 Hz, 1 H, ArH), 7.43 (d, J = 7.6 Hz, 2 H, ArH),
7.26–7.17 (m, 5 H, ArH), 7.06–7.01 (m, 3 H, ArH, NH), 5.26
(m, 1 H, NCH), 5.05 (m, 1 H, NCH), 4.65 (dd, J = 8.0, 3.6 Hz,
1 H, NCH), 4.44 (s, 1 H, CvCH2), 4.32 (s, 1 H, CvCH2),
3.89–3.77 (m, 2 H), 3.03 (dd, J = 13.6, 4.8 Hz, 1 H, PhCH2),
2.87 (dd, J = 13.6, 8.8 Hz, 1 H, PhCH2), 2.49 (dd, J = 13.6,
3.2 Hz, 1 H, CH2CvCH2), 2.31 (m, 1 H, CH2CvCH2),
2.26–2.20 (m, 2 H, CH2), 2.15–2.06 (m, 2 H, CH2), 1.61 (s,
3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 171.2 (CvO),
2
2
169.3 (CvO), 169.2 (CvO), 155.0 (q, JC,F = 37.4 Hz,
(CvO), 156.6 (q, JC,F = 37.4 Hz, CF3CO), 137.8 (ArC), 135.3
CF3CO), 138.9 (CvCH2), 138.1 (ArC) , 135.4 (ArC), 129.1
(ArC), 128.7 (ArC), 128.4 (ArC), 127.4 (ArC), 123.9 (ArC),
119.3 (ArC), 115.6 (q, 1JC,F = 285.1 Hz, CF3), 115.5 (CvCH2),
60.9 (NCHCO), 53.9 (NHCHCO), 49.3 (NHCHCO), 47.6
(ArC), 132.6 (CH2CHvCH), 129.1 (ArC), 128.7 (ArC), 128.6
(ArC), 128.5 (CH2CHvCH), 127.5 (ArC), 124.2 (ArC), 119.9
(ArC), 115.5 (q, JC,F = 286.1 Hz, CF3), 109.3 (OCO), 76.2
1
(CHvCHCHO), 69.1 (CH2O), 61.2 (NCHCO), 54.3
8272 | Org. Biomol. Chem., 2012, 10, 8268–8275
This journal is © The Royal Society of Chemistry 2012

View Online
(NHCHCO), 51.3 (NHCHCO), 47.4 (NCH2), 38.4 (PhCH2),
34.3 (CH2CHvCH), 28.7 (CH2), 26.5 (CH3), 25.6 (CH3), 24.3
(CH2). HRMS (CI) m/z calcd for C29H32F3N4O5 [M − C3H6O +
H]+ 573.2325; found 573.2300. Minor diastereomer (19%):
[α]2D0 = −30.6° (c = 0.5, CHCl3). M.p. 88–90 °C. 1H NMR
(400 MHz, CDCl3): δ 8.90 (s, 1 H, NH), 7.48 (d, J = 8.8 Hz,
2 H, ArH), 7.34–7.28 (m, 5 H, ArH), 7.19–7.07 (m, 5 H, ArH,
NH), 5.57 (dt, J = 15.5, 7.2 Hz, 1 H, CH2CHvCH), 5.43 (dd,
J = 15.5, 6.7 Hz, 1 H, CH2CHvCH), 4.82 (q, J = 7.2 Hz, 1 H,
NHCH), 4.76–4.70 (m, 2 H, NHCH), 4.21 (q, J = 6.8 Hz, 1 H,
CHvCHCHO), 3.80 (dd, J = 8.0, 8.0 Hz, 1 H, CH2O),
3.86–3.61 (m, 2 H, NCH2), 3.35 (dd, J = 8.0, 8.0 Hz, 1 H,
CH2O), 3.09 (dd, J = 13.8, 6.5 Hz, 1 H, PhCH2), 3.03 (dd, J =
13.8, 7.0 Hz, 1 H, PhCH2), 2.58–2.44 (m, 2 H, CH2CHvCH),
2.35 (m, 1 H, CH2), 2.22 (m, 1 H, CH2), 2.10–1.93 (m, 2 H,
CH2), 1.37 (s, 3 H, CH3), 1.34 (s, 3 H, CH3). 13C NMR
(100 MHz, CDCl3): δ 170.9 (CvO), 168.6 (CvO), 168.3
(CvO), 137.9 (ArC), 135.1 (ArC), 132.7 (CH2CHvCH), 129.2
(ArC), 129.0 (ArC), 128.7 (CH2CHvCH), 127.5 (ArC), 126.8
(ArC), 124.2 (ArC), 119.5 (ArC), 109.2 (OCO), 76.1
(CHvCHCHO), 69.0 (CH2O), 60.4 (NCHCO), 54.4
(NHCHCO), 50.6 (NHCHCO), 47.7 (NCH2), 38.6 (PhCH2),
35.2 (CH2CHvCH), 29.7 (CH2), 26.6 (CH3), 25.7 (CH3), 25.1
(CH2). HRMS (CI) m/z calcd for C29H32F3N4O5 [M − C3H6O +
H]+ 573.2325; found 573.2300. HPLC (silica, hexane–EtOAc =
50 : 50, 1 mL min−1, 254 nm): tR (19%) = 26.85 min, tR (81%)
= 46.20 min.
(m, 1 H, NCH2), 2.49 (dd, J = 13.6 Hz, J = 4.0 Hz, 1 H,
CH2CvCH2), 2.30–2.25 (m, 2 H, CH2), 2.19 (dd, J = 13.6,
9.6 Hz, 1 H, CH2CvCH2), 2.12–2.06 (m, 2 H, CH2), 1.65 (s,
3 H, CvCCH3), 0.94 (s, 9 H, C(CH3)3). 13C NMR (100 MHz,
CDCl3): δ 171.0 (CvO), 169.5 (CvO), 169.0 (CvO), 156.9
2
(q, JC,F = 37.2 Hz, CF3CO), 139.8 (CvCH2), 138.0 (ArC),
1
128.7 (ArC), 123.9 (ArC), 119.5 (ArC), 115.9 (q, JC,F
=
285.9 Hz, CF3), 115.0 (CvCH2), 60.8 (NCHCO), 60.3
(NHCHCO), 49.3 (NHCHCO), 47.3 (NCH2), 41.9
(CH2CvCH2), 35.2 (C(CH3)3), 28.6 (CH2), 26.5 (C(CH3)3),
24.5 (CH2), 21.7 (CH3). HRMS (CI) m/z calcd for
C25H34F3N4O4 [M
+
H]+ 511.2532; found 511.2528.
C25H33F3N4O4 (510.56) calcd C 58.81, H 6.51, N 10.97; found
C 58.91, H 6.54, N 10.45. HPLC (silica, hexane–EtOAc =
70 : 30, 1 mL min−1, 254 nm): tR (4%) = 7.77 min, tR (96%) =
8.61 min.
N-Trifluoroacetyl-(S)-phenylalanyl-(R)-(2-methylallyl)-glycyl-
(S)-N-methylleucineanilide (16a). According to the general pro-
cedure for palladium-catalyzed allylic alkylations of tripeptides
16a was obtained from 11 (208 mg, 0.400 mmol) in 80% yield
(183 mg, 0.310 mmol). Major diastereomer (97%): [α]D20
=
−128.0° (c = 1.0, CHCl3). M.p. 112–113 °C. 1H NMR
(400 MHz, CDCl3): δ 8.29 (s, 1 H, ArNH), 7.59 (d, J = 7.6 Hz,
2 H, ArH), 7.35–7.25 (m, 6 H, ArH, NH), 7.17 (m, 2 H, ArH),
7.08 (t, J = 7.4 Hz, 1 H, ArH), 6.46 (d, J = 5.6 Hz, 1 H, NH),
5.30 (dd, J = 10.0, 5.4 Hz, 1 H, NCHCO), 4.86 (m, 1 H,
CvCH2), 4.82–4.70 (m, 3 H, CvCH2, NHCHCO), 3.13–3.09
(m, 2 H, ArCH2), 3.07 (s, 3 H, NCH3), 2.33 (dd, J = 14.0, 5.7
Hz, 1 H, CH2CvCH2), 2.23 (dd, J = 13.9, 9.1 Hz, 1 H,
CH2CvCH2), 1.98–1.88 (m, 2 H, NCHCH2), 1.73 (s, 3 H,
CH3CvCH2), 1.67 (m, 1 H, CHCH3), 0.96 (d, J = 6.6 Hz, 3 H,
CHCH3), 0.90 (d, J = 6.6 Hz, 3 H, CHCH3). 13C NMR
(100 MHz, CDCl3): δ 172.9 (CvO), 169.6 (CvO), 168.3
N-Trifluoroacetyl-(S)-tert-leucyl-(R)-(2-methylallyl)-glycyl-(S)-
prolinanilide (9a). According to the general procedure for palla-
dium-catalyzed allylic alkylations of tripeptides 9a was obtained
from 5 (100 mg, 0.219 mmol) in 84% yield (93.8 mg,
0.184 mmol). Major diastereomer (96%): [α]2D0 = −54.6° (c =
0.5, CHCl3). M.p. 82–83 °C. 1H NMR (400 MHz, CDCl3):
δ 8.88 (s, 1 H, NH), 7.52 (d, J = 7.6 Hz, 2 H, ArH), 7.27 (t, J =
7.6 Hz, 2 H, ArH), 7.07 (t, J = 7.6 Hz, 1 H, ArH), 6.96 (d, J =
8.9 Hz, 1 H, NH), 6.75 (d, J = 6.4 Hz, 1 H, NH), 4.92 (s, 1 H,
CvCH2), 4.86 (s, 1 H, CvCH2), 4.77 (m, 1 H, NCH), 4.72 (dd,
J = 8.0, 1.2 Hz, 1 H, NHCH), 4.35 (d, J = 8.9 Hz, 1 H, NHCH),
3.92 (m, 1 H, NCH2), 3.52 (m, 1 H, NCH2), 2.49 (m, 1 H, CH2),
2.45–2.39 (m, 2 H, CH2CvCH2), 2.15 (m, 1 H, CH2), 2.10 (m,
1 H, CH2), 1.96 (m, 1 H, CH2), 1.80 (s, 3 H, CvCCH3), 0.98
(s, 9 H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ 171.2
(CvO), 168.9 (CvO), 168.7 (CvO), 156.8 (q, 2JC,F = 37.2 Hz,
CF3CO), 139.7 (CvCH2), 137.8 (ArC), 128.8 (ArC), 124.2
2
(CvO), 156.7 (q, JC,F = 37.6 Hz, CF3CvO), 139.2 (CvCH2),
137.9 (ArC), 135.2 (ArC), 129.1 (ArC), 128.9 (ArC), 128.8
(ArC), 127.5 (ArC), 124.3 (ArC), 120.0 (ArC), 115.7 (CvCH2),
1
115.5 (q, JC,F = 287.4 Hz, CF3), 56.1 (NCHCO), 54.3
(NHCHCO), 48.3 (NHCHCO), 39.8 (CH2CvCH2), 38.3
(ArCH2), 36.1 (NCHCH2), 31.0 (NCH3), 24.9 (CHCH3), 23.2
(CHCH3), 21.9 (CHCH3), 21.7 (CH3CvCH2). HRMS (CI) m/z
calcd for C30H37F3N4O4 [M + H]+ 575.2840; found: 575.2798.
C30H37F3N4O4 (574.63) calcd C 62.70, H 6.49, N 9.75; found C
62.78, H 6.79, N 9.33. HPLC (Reprosil, hexane–iPrOH = 9 : 1
to 7 : 3, 40 min, 1 mL min−1, 252 nm): tR (3%) = 16.16 min,
tR (97%) = 20.48 min.
1
(ArC), 120.0 (ArC), 115.6 (q, JC,F = 286.2 Hz, CF3), 115.4
(CvCH2), 61.2 (NCHCO), 60.5 (NHCHCO), 50.0 (NHCHCO),
47.3 (NCH2), 39.9 (CH2CvCH2), 35.4 (C(CH3)3), 28.3 (CH2),
26.4 (C(CH3)3), 24.4 (CH2), 21.8 (CH3). HRMS (CI) m/z calcd
for C25H34F3N4O4 [M + H]+ 511.2532; found 511.2483.
C25H33F3N4O4 (510.56) calcd C 58.81, H 6.51, N 10.97; found:
N-Trifluoroacetyl-(S)-phenylalanyl-(R/S)-(2-methylallyl)-glycyl-
(R)-N-methylleucineanilide (17). According to the general pro-
cedure for palladium-catalyzed allylic alkylations of tripeptides
17 was obtained from 12 (208 mg, 0.400 mmol) in 78% yield
(180 mg, 0.310 mmol) as a mixture of diastereomers (dr =
C 58.41, H 6.48, N 10.68. Minor diastereomer (4%); [α]D20
=
1
1
−52.5° (c = 0.5, CHCl3). M.p. 89–91 °C. H NMR (400 MHz,
CDCl3): δ 9.06 (s, 1 H, NH), 8.03 (d, J = 8.8 Hz, 1 H, NH),
7.68 (d, J = 7.6 Hz, 2 H, ArH), 7.26 (t, J = 7.6 Hz, 2 H, ArH),
7.19 (d, J = 9.4 Hz, 1 H, NH), 7.04 (t, J = 7.6 Hz, 1 H, ArH),
5.03 (ddd, J = 9.6, 8.8, 4.0 Hz, 1 H, NHCH), 4.94 (dd, J = 8.4,
2.4 Hz, 1 H, NCH), 4.64 (d, J = 9.4 Hz, 1 H, NHCH), 4.45 (s, 1
H, CvCH2), 4.42 (s, 1 H, CvCH2), 3.85 (m, 1 H, NCH2), 3.76
51 : 49): H NMR (500 MHz, d6-DMSO, 373 K): δ 9.34/9.17
(bs, 1 H, NH), 9.02/8.96 (d, J = 7.3 Hz, 1 H, NH), 8.07 (bs, 1 H,
NH), 7.57 (m, 2 H, ArH), 7.31–7.10 (m, 7 H, ArH), 7.05 (m,
1 H, ArH), 5.14 (m, 1 H, NCHCO), 4.97 (m, 1 H, NHCHCO),
4.78 (m, 2 H, CvCH2), 4.67 (m, 1 H, NHCHCO), 3.20–2.95
(m, 2 H, ArCH2), 3.05 (s, 3 H, NCH3), 2.44 (m, 1 H,
CH2CvCH2), 2.32 (m, 1 H, CH2CvCH2), 1.82–1.60 (m, 2 H,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8268–8275 | 8273

View Online
NCHCH2), 1.76/1.73 (s, 3 H, CH3CvCH2), 1.56 (m, 1 H,
CHCH3), 1.00–0.89 (m, 6 H, CHCH3). 13C NMR (125 MHz,
d6-DMSO, 373 K): δ 171.3 (CvO), 168.7 (CvO), 168.6
(CvO), 155.4/155.3 (q, JC,F = 36.6 Hz, CF3CvO), 140.3/
140.1 (CvCH2), 138.0 (ArC), 136.4/136.3 (ArC), 128.3/128.2
NHCHCH), 1.91 (ddd, J = 14.7, 9.2, 5.8 Hz, 1 H, NCHCH2),
1.80 (s, 3 H, CH3CvCH2), 1.69 (ddd, J = 14.1, 9.7, 5.0 Hz,
1 H, NCHCH2), 1.47 (m, 1 H, CHCH3), 0.98 (d, J = 3.2 Hz, 3
H, CHCH3), 0.96 (d, J = 3.3 Hz, 3 H, CHCH3), 0.94 (d, J =
6.9 Hz, 3 H, CHCH3), 0.91 (d, J = 6.6 Hz, 3 H, CHCH3). 13C
NMR (100 MHz, CDCl3): δ 173.1 (CvO), 169.5 (CvO), 168.2
2
(ArC), 127.7/127.6 (ArC), 127.3 (ArC), 125.7/125.6 (ArC),
1
2
122.9/122.8 (ArC), 119.6/119.5 (ArC), 115.1 (q, JC,F
=
(CvO), 157.0 (q, JC,F = 37.5 Hz, CF3CvO), 139.5 (CvCH2),
288.4 Hz, CF3), 112.5/112.4 (CvCH2), 54.1 (NCHCO), 53.8
(NHCHCO), 47.9 (NHCHCO), 47.2 (CH2CvCH2), 36.6
(ArCH2), 36.0 (NCHCH2), 24.0(NCH3), 23.9 (CHCH3), 22.2/
22.0 (CHCH3), 21.5/21.4 (CHCH3), 20.9 (CH3CvCH2).
HRMS (CI) m/z calcd for C30H37F3N4O4 [M + H]+ 575.2840;
found: 575.2881. HPLC (Reprosil, hexane–iPrOH = 9 : 1 to
7 : 3, 40 min, 1 mL min−1, 252 nm): tR (51%) = 15.67 min,
tR (49%) = 20.33 min.
137.8 (ArC), 128.8 (ArC), 124.3 (ArC), 119.9 (ArC), 115.7 (q,
1JC,F = 287.8 Hz, CF3), 115.6 (CvCH2), 58.2 (NCHCO), 56.0
(NHCHCO), 48.3 (NHCHCO), 40.4 (CH2CvCH2), 36.1
(NCHCH2), 31.7 (NCH3), 30.9 (CHCH3), 24.9 (CHCH3), 23.2
(CHCH3), 21.8 (CH3CvCH2, CHCH3), 18.8 (CHCH3), 17.6
(CHCH3). HRMS (CI) m/z calcd for C26H37F3N4O4 [M + H]+
527.2767; found: 527.2861. C26H37F3N4O4 (526.59) calcd C
59.30, H 7.08, N 10.64; found C 58.92, H 7.00, N 10.48. HPLC
(Reprosil, hexane–iPrOH = 9 : 1 → 7 : 3, 40 min, 1 mL min−1
252 nm): tR (>99%) = 23.93 min.
,
N-Trifluoroacetyl-(S)-phenylalanyl-(R)-(2-methylallyl)-glycyl-
(S)-N-benzylleucineanilide (18). According to the general pro-
cedure for palladium-catalyzed allylic alkylations of tripeptides
18 was obtained from 13 (239 mg, 0.400 mmol) in 66% yield
Acknowledgements
(172 mg, 0.260 mmol). Major diastereomer (94%): [α]D20
=
Financial support by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged. S. Datta thanks the Alexander von
Humboldt Foundation for a postdoctoral fellowship.
1
−121.7° (c = 1.0, CHCl3). M.p. 74–75 °C. H NMR (400 MHz,
CDCl3): δ 8.56 (s, 1 H, ArNH), 7.55 (d, J = 7.6 Hz, 2 H, ArH),
7.36–7.21 (m, 10 H, ArH), 7.18 (d, J = 7.6 Hz, 1 H, NH),
7.12–7.06 (m, 3 H, ArH), 6.16 (d, J = 4.8 Hz, 1 H, NH), 5.35
(t, J = 6.9 Hz, 1 H, NCHCO), 4.94 (d, J = 17.4 Hz, 1 H, ArCH2N),
4.72–4.60 (m, 3 H, CvCH2, NHCHCO), 4.57 (d, J = 17.4 Hz,
1 H, ArCH2N), 4.35 (dt, J = 10.6, 4.2 Hz, 1 H, NHCHCO),
References
1 Reviews: (a) N. Fusetani and S. Matsunaga, Chem. Rev., 1993, 93,
1793–1806; (b) D. J. Faulkner, Nat. Prod. Rep., 1998, 15, 113–158;
(c) A. Schaller, in Bioactive Peptides as Signal Molecules in Plant Defense,
Growth and Development, ed. A. U. Rahman, Elsevier Science Bv, Amster-
dam, Nederlands, 2001 vol. 25, pp. 367–411; (d) D. R. W. Hogson and
J. M. Sanderson, Chem. Soc. Rev., 2004, 33, 422–430.
2 (a) D. Kahne, C. Leimkuhler, W. Lu and C. Walsh, Chem. Rev., 2005,
105, 425–448; (b) F. v. Nussbaum, M. Brands, B. Hinzen, S. Weigand
and D. Häbich, Angew. Chem., 2006, 118, 5194–5254, (Angew. Chem.,
Int. Ed., 2006, 45, 5072–5129).
3 Recent review: J. Deska and U. Kazmaier, Curr. Org. Chem., 2008, 12,
7355–7385.
4 Some recent examples: (a) S. Kotha and K. Lahiri, Biopolymers, 2003,
69, 517–528; (b) M. Vilaró, G. Arsequell, G. Valencia, A. Ballesteros and
J. Barluenga, Org. Lett., 2008, 10, 3243–3245.
3.08–3.04 (m,
2 H, ArCH2CH), 2.25–2.10 (m, 2 H,
CH2CvCH2), 1.95 (dd, J = 13.9, 3.5 Hz, 1 H, NCHCH2), 1.71
(m, 1 H, NCHCH2), 1.57 (m, 1 H, CHCH3), 1.13 (s, 3 H,
CH3CvCH2), 0.99 (d, J = 3.9 Hz, 3 H, CHCH3), 0.98 (d, J =
4.1 Hz, 3 H, CHCH3). 13C NMR (100 MHz, CDCl3): δ 174.5
(CvO), 169.4 (CvO), 168.3 (CvO), 156.6 (q, 2JC,F = 37.9 Hz,
CF3CvO), 139.6 (CvCH2), 138.0 (ArC), 137.0 (ArC), 135.0
(ArC), 129.1 (ArC), 129.0 (ArC), 128.9 (ArC), 128.8 (ArC),
128.0 (ArC), 127.5 (ArC), 126.5 (ArC), 124.3 (ArC), 120.1
1
(ArC), 115.5 (q, JC,F = 287.7 Hz, CF3), 115.6 (CvCH2), 57.7
(NCHCO), 54.2 (NHCHCO), 49.7 (NHCHCO), 48.5 (ArCH2N),
39.9 (CH2CvCH2), 38.2 (ArCH2CH), 37.0 (NCHCH2), 25.4
(CHCH3), 22.7 (CHCH3), 22.3 (CHCH3), 20.7 (CH3CvCH2).
HRMS (CI) m/z calcd for C36H41F3N4O4 [M + H]+ 651.3153;
found: 651.3149. C36H41F3N4O4 (650.73) calcd C 66.45, H
6.35, N 8.61; found C 66.55, H 6.68, N 8.27. HPLC (Reprosil,
hexane–iPrOH = 9 : 1 to 7 : 3, 40 min, 1 mL min−1, 252 nm):
tR (6%) = 15.13 min, tR (94%) = 18.87 min.
5 (a) C. J. Easton, I. M. Scharfbillig and E. W. Tan, Tetrahedron Lett.,
1988, 29, 1565–1568; (b) G. Apitz and W. Steglich, Tetrahedron Lett.,
1991, 32, 3163–3166; (c) W. Steglich, M. Jäger, S. Jaroch and P. Zistler,
Pure Appl. Chem., 1994, 66, 2167–2170.
6 (a) C. Wyss, R. Batra, C. Lehmann, S. Sauer and B. Giese, Angew.
Chem., 1996, 108, 2660–2662, (Angew. Chem., Int. Ed. Engl., 1996, 35,
2529–2531); (b) C. J. Easton, Chem. Rev., 1997, 97, 53–82; (c) M. Ricci,
L. Madariaga and T. Skrydstrup, Angew. Chem., 2000, 112, 248–252,
(Angew. Chem., Int. Ed., 2000, 39, 242–246); (d) M. Ricci, P. Blakskjaer
and T. Skrydstrup, J. Am. Chem. Soc., 2000, 122, 12413–12421;
(e) J.-P. Ebran, C. M. Jensen, S. A. Johannesen, J. Karaffa, K. B. Lindsay,
R. Taaning and T. Skrydstrup, Org. Biomol. Chem., 2006, 4, 3553–3564.
7 Reviews: (a) D. Seebach, Angew. Chem., 1988, 100, 1685–1715, (Angew.
Chem., Int. Ed. Engl., 1988, 27, 1624); (b) D. Seebach, Aldrichimica
Acta, 1992, 25, 59–66; (c) D. Seebach, A. K. Beck and A. Studer, in
Modern Synthetic Methods, ed. B. Ernst and C. Leumann, Helvetica
Chimica Acta/VCH, Basel/Weinheim, 1995, vol. 7, pp. 1–178.
8 (a) S. A. Miller, S. L. Griffiths and D. Seebach, Helv. Chim. Acta, 1993,
76, 563–595; (b) D. Seebach, A. K. Beck, H. G. Bossler, C. Gerber,
S. Y. Ko, C. W. Murtiashaw, R. Naef, S.-I. Shoda, A. Thaler, M. Krieger
and R. Wenger, Helv. Chim. Acta, 1993, 76, 1564–1590.
N-Trifluoroacetyl-(S)-valyl-(R)-(2-methylallyl)-glycyl-(S)-N-
methylleucineanilide (20). According to the general procedure
for palladium-catalyzed allylic alkylations of tripeptides 20 was
obtained from 15 (189 mg, 0.400 mmol) in 71% yield (150 mg,
0.285 mmol). Major diastereomer (>98%): [α]2D0 = −162.6° (c =
1
1.0, CHCl3). M.p. 141–143 °C. H NMR (400 MHz, CDCl3):
δ 8.22 (s, 1 H, ArNH), 7.56 (d, J = 7.6 Hz, 2 H, ArH),
7.32–7.26 (m, 2 H, ArH, NH), 7.15–7.05 (m, 2 H, ArH), 6.67
(d, J = 6.4 Hz, 1 H, NH), 5.27 (dd, J = 9.8, 5.8 Hz, 1 H,
NCHCO), 4.98–4.90 (m, 2 H, NHCHCO, CvCH2), 4.85 (s,
1 H, CvCH2), 4.44 (dd, J = 8.3, 5.3 Hz, 1 H, NHCHCO), 3.09
(s, 3 H, NCH3), 2.48–2.32 (m, 2 H, CH2CvCH2), 2.19 (m, 1 H,
9 (a) D. Seebach, H. Bossler, H. Gründler, S.-I. Shoda and R. Wenger,
Helv. Chim. Acta, 1991, 74, 197–224; (b) S. A. Miller, S. L. Griffiths and
D. Seebach, Helv. Chim. Acta, 1993, 76, 563–595; (c) D. Seebach,
O. Bezençon, B. Jaun, T. Pietzonka, J. L. Matthews, F. N. M. Kühnle and
W. B. Schweizer, Helv. Chim. Acta, 1996, 79, 588–608.
8274 | Org. Biomol. Chem., 2012, 10, 8268–8275
This journal is © The Royal Society of Chemistry 2012

View Online
10 (a) U. Kazmaier, J. Org. Chem., 1994, 59, 6667–6670; (b) U. Kazmaier
and S. Maier, Chem. Commun., 1998, 2535–2536; (c) U. Kazmaier and
S. Maier, Org. Lett., 1999, 1, 1763–1766; (d) S. Maier and U. Kazmaier,
Eur. J. Org. Chem., 2000, 1241–1251.
11 U. Kazmaier, S. Maier and F. L. Zumpe, Synlett, 2000, 1523–1535.
12 (a) U. Kazmaier, D. Schauß, M. Pohlman and S. Raddatz, Synthesis,
2000, 914–916; (b) J. Deska and U. Kazmaier, Angew. Chem., 2007, 119,
4654–4657, (Angew. Chem., Int. Ed., 2007, 46, 4570–4573); (c) J. Deska
and U. Kazmaier, Chem.–Eur. J., 2007, 13, 6204–6211.
13 S. Datta and U. Kazmaier, Org. Biomol. Chem., 2011, 9, 872–880.
14 (a) U. Kazmaier, Curr. Org. Chem., 2003, 7, 317–328; (b) U. Kazmaier
and M. Pohlman, Synlett, 2004, 623–626.
15 (a) U. Kazmaier, J. Deska and A. Watzke, Angew. Chem., 2006, 118,
4973–4976, (Angew. Chem., Int. Ed., 2006, 45, 4855–4858);
(b) K. Krämer, J. Deska, C. Hebach and U. Kazmaier, Org. Biomol.
Chem., 2009, 7, 103–110.
16 To avoid an epimerization of the proline, the anilide was used at the
C-terminus. Deprotonation of the amide under the basic reaction con-
ditions protects the α-position of the proline towards deprotonation. In
addition, the aromatic system facilitates the determination of the diastereo-
meric ratio via HPLC.
17 (a) U. Kazmaier and T. Lindner, Angew. Chem., 2005, 117, 3368–3371,
(Angew. Chem., Int. Ed., 2005, 44, 3303–3306); (b) T. Lindner and
U. Kazmaier, Adv. Synth. Catal., 2005, 347, 1687–1695.
18 (a) U. Kazmaier and F. L. Zumpe, Eur. J. Org. Chem., 2001, 4067–4076;
(b) U. Kazmaier and K. Krämer, J. Org. Chem., 2006, 71, 8950–8953.
19 T. Cuvigny, M. Julia and C. Rolando, J. Organomet. Chem., 1985, 285,
395–413.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 8268–8275 | 8275