Palladium-catalyzed allylic alkylations as versatile tool for amino acid and peptide modifications

Article abstract of DOI:10.1055/s-0033-1338477

Palladium-catalyzed allylic alkylations are especially suitable for the introduction of γ,δ-unsaturated side chains into amino acids and even peptides. Glycine ester enolates are generally used as nucleophiles in these reactions, they react at a very low

Full text of DOI:10.1055/s-0033-1338477

1462▌
PRACTICAL SYNTHETIC PROCEDURES
practical synthetic procedures
Palladium-Catalyzed Allylic Alkylations as Versatile Tool for Amino Acid and
Peptide Modifications
Palladium-Catalyzed Allylic Alkylations
Uli Kazmaier,* Anton Bayer, Jan Deska
PSP
Institut für Organische Chemie, Universitaet des Saarlandes, 66123 Saarbruecken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received: 06.04.2013; Accepted: 16.04.2013
No249
Abstract: Palladium-catalyzed allylic alkylations are especially suitable for the introduction of γ,δ-unsaturated side chains into amino acids
and even peptides. Glycine ester enolates are generally used as nucleophiles in these reactions, they react at a very low temperature (–78 °C)
to give the products of isomerization-free allylation. In reactions of cis-configured allylic substrates, the olefin geometry can be transferred
to the product. Because the syn position of the corresponding syn/anti π-allyl complex formed in this case is more reactive, this isomeriza-
tion-free protocol also allows regioselective and stereoselective allylations. Using stannylated allylic substrates gives metalated amino acid
derivatives that are ideal substrates for subsequent Stille couplings or tin–iodine exchange reactions. If peptides are deprotonated with
excess strong base, the corresponding ester or amide enolates formed can also be subjected to allylation; in this case the stereochemical
outcome can be controlled by the peptide chain.
Key words: allylic alkylations, amino acids, enolates, peptides, peptide modifications, palladium
OCO2Et
procedure 1
TfaHN
CO2t-Bu
2
Ot-Bu
LHMDS (2.5 equiv)
ZnCl2 (1.2 equiv)
81%, 96% ds, 96% ee
TfaHN
CO2t-Bu
THF, –78 °C
[AllylPdCl]2 (1 mol%)
Ph3P (4.5 mol%)
THF, –78 °C
O
N
Ph
OCO2Et
Tfa
Zn
1
Ph
TfaHN
CO2t-Bu
5
69%, 98% ds, 97% ee
O
procedure 2
O
Ph
OCO2Et
(0.5 equiv)
[AllylPdCl]2 (2 mol%), Ph3P (8 mol%)
BnO
H
N
Ph
OBn
R
CO2t-Bu
LHMDS (3.5 equiv)
ZnCl2 (1.2 equiv)
S
TfaHN
H
N
CO2t-Bu
O
THF, –78 °C
TfaHN
THF, –78 °C, to r.t., 16 h
O
O
9
O
89%, 98% ds
SnBu3
Ph
O
H
Ph
OCO2Et
LHMDS (3.5 equiv)
ZnCl2 (1.2 equiv)
O
N
N
R
H
N
(1.1 equiv)
S
TfaHN
N
TfaHN
THF, –78 °C
[AllylPdCl]2 (2 mol%)
Ph3P (8 mol%)
THF, –78 °C, to r.t., 16 h
O
O
Bu3Sn
11
92%, 94% ds
procedure 3
OCO2Et
Ph
LDA (5.0 equiv)
ZnCl2 (1.5 equiv)
Ph
O
O
(1.0 equiv)
H
N
H
N
R
NHPh
NHPh
THF, –78 °C
[AllylPdCl]2 (2 mol%)
Ph3P (9 mol%)
THF, –78 °C, to r.t., 16 h
S
S
TfaHN
N
TfaHN
N
O
Me
O
O
Me
O
12
80%, 97% ds
Scheme 1 Stereoselective palladium-catalyzed allylic alkylations for the modification of amino acids and peptides
SYNTHESIS 2013, 45, 1462–1468
Advanced online publication: 08.05.2013
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DOI: 10.1055/s-0033-1338477; Art ID: SS-2013-Z0267-PSP
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Introduction
Palladium-Catalyzed Allylic Alkylations
1463
SnBu3
SnBu3
OCO2Me
π-Allyl–palladium complexes play an important role in
modern organic synthesis;1 with respect to their various
synthetic applications, allylic substitution is probably one
of the most popular. Herein, a π-allyl complex is attacked
by a nucleophile such as an amine or a stabilized carban-
ion (in most cases malonate). In contrast to symmetrical
malonates, unsymmetric nucleophiles, such as β-keto es-
ters, are more critical, generally giving diastereomeric
mixtures. Chelated enolates 1 (see Scheme 1 and Scheme
2), obtained by deprotonation of protected amino acid es-
ters, are an exception; due to their fixed enolate geometry,
their conversion often proceeds with a high degree of ste-
reoselectivity. In addition, chelation causes a marked en-
hancement of thermal stability without decreasing the
reactivity of these enolates. Excellent results are obtained
in typical enolate reactions, such as aldol2 or Michael ad-
ditions,3 as well as in palladium-catalyzed allylic alkyl-
ations.4
TfaHN
Ph
CO2t-Bu
( )-3
88%
OAc
Ph
TfaHN
CO2t-Bu
4
73%, 92% ds, 96% ee
Ot-Bu
Ph
OCO2Et
O
N
Tfa
Zn
Ph
TfaHN
1
CO2t-Bu
[AllylPdCl]2 (1 mol%)
Ph3P (4.5 mol%)
–78 °C to r.t., 16 h
5
69%, 98% ds, 97% ee
OCO2Et
Pr
Pr
TfaHN
( )-6
83%, 92% ds, 98% rs
CO2t-Bu
Besides allyl carbonates, the corresponding carboxylates
can also be used, but with the more reactive carbonates the
yields and selectivities are usually better. The trifluoro-
acetyl (Tfa) group is the best N-protecting group with re-
spect to yield and selectivity. As a result of the high
reactivity of the chelated enolates, allylations take place
under very mild conditions at –78 °C or even below, this
has an extremely positive effect on the selectivity of the
reaction. In general, the anti products are formed with ex-
cellent stereoselectivity (Scheme 2).5
OCO2Et
TfaHN
CO2t-Bu
2
81%, 96% ds, 96% ee
Scheme 3 Isomerization-free regio- and stereoselective palladium-
catalyzed allylic alkylation of chelated glycine ester enolate 1
TfaHN
–78 °C
CO2t-Bu
If allyl derivatives with different substituents are used, un-
symmetrical π-allyl–palladium complexes are formed,
which can be attacked by the nucleophile at both allylic
positions. Although this can be problematic, these sub-
strates also have the advantage that if optically active allyl
substrates are used, the π-allyl–palladium complexes
formed are chiral, and nucleophilic attack on these com-
plexes provides optically active substitution products
such as 4. With the chelated enolate 1 an almost perfect
transfer of chirality is observed.5
LHMDS (2.5 equiv)
ZnCl2 (1.2 equiv)
OCO2Et
Ot-Bu
[AllylPdCl]2 (1 mol%)
Ph3P (4.5 mol%)
–78 °C to r.t., 16 h
O
N
TfaHN
( )-2
88%, 96% ds
CO2t-Bu
Tfa
Zn
1
Scheme 2 Stereoselective palladium-catalyzed allylic alkylation of
chelated glycine ester enolate 1
In general, the diastereoselectivities obtained with allylic
acetates are worse in comparison to those obtained with
carbonates. This can be explained by the higher reactivity
of the carbonates, which react at –78 °C (or even lower).
Therefore, the high reactivity of these enolates can also be
used to suppress isomerization processes of the π-allyl
complexes formed as intermediates.8 The reaction with Z-
carbonates almost exclusively yields the desired Z-substi-
tution product 5, with selectivities even higher than those
obtained with the E-carbonates. In contrast, the corre-
sponding acetates furnish E/Z-mixtures in lower yields.
The selectivities are markedly worse than those obtained
with the carbonates, clearly indicating that with acetates
both processes, direct allylic substitution and isomeriza-
tion, compete, while the carbonates react isomerization-
free.9
Scope and Limitations
This protocol allows the straightforward introduction of a
wide range of side chains into the glycine unit, but an even
more flexible concept would be the introduction of a side
chain that can be further modified at a later stage. This can
easily be accomplished by using stannylated allylic sub-
strates (Scheme 3), giving amino acids with a vinylstan-
nane in the side chain, such as 3,6 which can be subjected
to Stille couplings or tin–halogen exchange.7
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1462–1468

1464
U. Kazmaier et al.
PRACTICAL SYNTHETIC PROCEDURES
In these cases the regioselectivity in the allylation step can
be explained by the preferred formation of the conjugated
double bond in, for example, 4 and 5. Without such a con-
jugation effect (no aryl substituent) the formation of re-
gioisomeric mixtures might be expected, but the anti
position is more reactive allowing regioselective (rs) sub-
stitutions to give 6.10 This advantage can also be used to
stereoselectively introduce allyl fragments bearing two
identical substituents at the allylic positions in 2,9 which
is only possible with Z-substrates, while E-substrates re-
sult in the formation of achiral π-allyl complexes.
OTHP
OTHP
OCO2Et
TfaHN
CO2t-Bu
7
87% (98% Z)
OCO2Et
TBDPSO
75%
OTBDPS
Ot-Bu
OTBDPS
Terminal π-allyl complexes show an even higher tenden-
cy towards isomerization than 1,3-disubstituted deriva-
tives. But also with tetrahydropyranyl-protected (Z)-but-
2-ene-1,4-diol carbonates the required amino acids 7 are
obtained with near perfect transfer of the olefin geometry
(Scheme 4).11 Comparable results are obtained with chiral
substrates, which also showed significant chiral induction
from the allyl substrate to the α-position of the newly
formed amino acid. The chiral induction depends on the
steric demands of the protecting group, and the best re-
sults are obtained with the very demanding tert-butyldi-
phenylsilyl (TBDPS) group, but with such substrates
isomerization occurs, giving trans-configured products 8
O
N
Tfa
Zn
OCO2Et
1
98%
[AllylPdCl]2 (1 mol%)
Ph3P (4.5 mol%)
–78 °C to r.t., 16 h
TfaHN
CO2t-Bu
8
OTBDPS
96% ds
OCO2Et
93%
Scheme 4 Allylic alkylation via terminal π-allyl–palladium com-
plexes
O
O
Ph
H
N
OCO2Et
(0.5 equiv)
BnO
R
CO2t-Bu
OBn
O
S
TfaHN
THF, –78 °C, to r.t., 16 h
O
Ph
LHMDS (3.5 equiv)
ZnCl2 (1.2 equiv)
[AllylPdCl]2 (2 mol%)
Ph3P (8 mol%)
9
O
H
N
89%, 98% ds
CO2t-Bu
SnBu3
S
THF, –78 °C
THF, –78 °C
TfaHN
Ph
OCO2Et
O
H
N
(1.2 equiv)
R
CO2t-Bu
SnBu3
S
TfaHN
THF, –78 °C, to r.t., 16 h
O
10
73%, > 98% ds
SnBu3
Ph
O
N
Ph
OCO2Et
H
N
LHMDS (3.5 equiv)
ZnCl2 (1.2 equiv)
O
N
R
H
N
(1.1 equiv)
S
TfaHN
S
TfaHN
THF, –78 °C
[AllylPdCl]2 (2 mol%)
Ph3P (8 mol%)
THF, –78 °C, to r.t., 16 h
O
O
Bu3Sn
11
92%, 94% ds
OCO2Et
LDA (5.0 equiv)
ZnCl2 (1.5 equiv)
Ph
Ph
O
H
O
(1.0 equiv)
H
N
N
R
NHPh
NHPh
THF, –78 °C
[AllylPdCl]2 (2 mol%)
Ph3P (9 mol%)
THF, –78 °C, to r.t., 16 h
S
S
S
S
TfaHN
N
TfaHN
N
O
Me
O
O
Me
O
12
80%, 97% ds
Scheme 5 Stereoselective palladium-catalyzed allylic alkylation of peptide enolates
Synthesis 2013, 45, 1462–1468
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Allylic Alkylations
1465
μmol, 4.5 mol%), and the corresponding allylic ester (0.5 mmol) in
THF (3 mL) was added. The soln was stirred and warmed up to r.t.
in the cooling bath overnight. Subsequently, the soln was diluted
with Et2O and hydrolyzed with 1 M KHSO4 soln. The aqueous
phase was extracted with Et2O (2 ×), and the combined organic
phases were dried (anhyd Na2SO4). After evaporation of the sol-
vent, the crude product was purified by column chromatography
(silica gel).
with excellent diastereoselectivity. In this case, the stereo-
chemical outcome is independent of the allylic substrate
used (E or Z, linear or branched allylic carbonates) as the
reaction proceeds via the same π-allyl intermediate.12
The high isomerization tendency of terminal π-allyl com-
plexes makes them good candidates for nucleophile con-
trolled allylic alkylations. Therefore, this approach is
especially suitable for the diastereoselective allylation of
peptides, where the stereochemical outcome can be con-
trolled by the peptide chain (Scheme 5). An S-amino acid
in the peptide chain results in the generation of an R-ste-
reogenic center in the allylation step giving 9. The best re-
tert-Butyl (2S,3S,E)-3-Methyl-2-[(trifluoroacetyl)amino]hex-4-
enoate (2)5b
According to general procedure 1 using Tfa-Gly-Ot-Bu (57 mg,
0.25 mmol) and ethyl (S,Z)-pent-3-en-2-yl carbonate (79 mg, 0.5
mmol) with purification by flash chromatography (hexanes–
EtOAc, 9:1) to give ester 2 as a colorless oil; yield: 65 mg (0.22
20
sults are obtained with peptide esters containing aromatic mmol, 88%); ratio anti/syn 96:4; [α]D +21.7 (c 1.0, CHCl3, 96%
and sterically demanding amino acids.13 With stannylated
ds, 96% ee).
allyl carbonates the stannylated peptides 10 are obtained
GC (Chirasil-L-Val, 80 °C, isothermic): tR = 17.39 (2R,3R), 17.95
(2R,3S), 23.21 (2S,3S), 24.60 min (2S,3R).
as a single stereoisomer.14
1H NMR (300 MHz, CDCl3): δ = 1.03 (d, J = 6.9 Hz, 3 H), 1.45 (s,
9 H), 1.65 (d, J = 6.3 Hz, 3 H), 2.75 (m, 1 H), 4.42 (dd, J = 8.7, 4.7
Hz, 1 H), 5.24 (dd, J = 15.3, 7.7 Hz, 1 H), 5.52 (dqd, J = 15.3, 6.3,
1.0 Hz, 1 H), 6.65 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 16.4, 17.6, 27.7 (3 C), 39.4, 57.0,
82.8, 115.6 (JFC = 286 Hz), 128.0, 129.3, 156.7 (JFC = 37 Hz),
168.8.
This protocol is not limited to peptide esters, generating a
C-terminal ester enolate, but can also be applied to sec-
ondary peptide amides 11. The results obtained with ter-
minal amides are comparable to those obtained with
esters.15 This also allows stereoselective allylations in the
middle of a peptide chain, as long as the glycine subunit is
connected to a proline or an N-alkylated amino acid such
as in the formation of 12. Excellent enantioselectivities
are obtained with all-S-configured peptides (double ste-
reoinduction).16
Anal. Calcd for C13H20F3NO3 (295.30): C, 52.88; H, 6.83; N, 4.74.
Found C, 52.85; H, 6.60; N, 4.71.
tert-Butyl 4-(Tributylstannyl)-2-[(trifluoroacetyl)amino]pent-
4-enoate (3)7d
According to general procedure 1 using Tfa-Gly-Ot-Bu (57 mg,
0.25 mmol) and methyl 2-(tributylstannyl)allyl carbonate (83 mg,
0.205 mmol) with purification by flash chromatography (hexanes–
EtOAc–Et3N, 95:4:1) to give ester 3 as a colorless oil; yield: 100 mg
(0.180 mmol, 88%).
1H NMR (300 MHz, CDCl3): δ = 0.81–0.96 (m, 15 H), 1.23–1.36
(m, 6 H), 1.49 (s, 9 H), 1.42–1.55 (m, 6 H), 2.49 (dd, J = 14.1, 9.4
Hz, 1 H), 2.85 (dd, J = 14.2, 9.1 Hz, 1 H), 4.36 (m, 1 H), 5.25 (s,
Herein we describe three different procedures for the ste-
reoselective allylic alkylation of glycine and peptide eno-
lates. Procedure 1 is the standard procedure used for the
allylation of glycine ester enolates. This protocol can be
used for a very wide range of substrates and is generally
applicable. Procedures 2 and 3 should be used for the
modifications of peptide enolates, independently if ester
or amide enolates are generated. These procedures mainly
differ in the amount of base used, depending on the length
of the peptide chain.
J
SnH = 57 Hz, 1 H), 5.70 (s, JSnH = 127 Hz, 1 H), 6.52 (d, J = 6.0 Hz,
1 H).
13C NMR (75 MHz, CDCl3): δ = 9.9 (JSnC = 327 Hz), 13.4, 27.1
(JSnC = 57 Hz), 28.7 (JSnC = 20 Hz), 27.7, 43.5 (JSnC = 40 Hz), 52.4,
82.8, 115.5 (JFC = 285 Hz), 129.0, 149.0, 156.1 (JFC = 37 Hz),
169.4.
All reactions were carried out in oven-dried glassware (100 °C) un-
der argon. All solvents were dried before use. THF was distilled
from LiAlH4 or Na. The products were purified by flash chromatog-
raphy on silica gel. TLC: commercially precoated Polygram® SIL-
G/UV 254 plates. Visualization was accomplished with UV-light,
I2, and KMnO4 soln. Melting points are uncorrected. Selected sig-
nals in the NMR spectra for the minor isomers are extracted from
the spectra of the isomeric mixture. Enantiomeric and diastereomer-
ic excesses were determined by GC using a Chirasil-L-Val capillary
column. Helium was used as carrier gas. Diastereomeric ratios were
also determined by analytical HPLC using a Trentec Reprosil-100
Chiral-NR 8-mm column. Optical rotations were measured on a
Perkin–Elmer polarimeter PE 341. Chemical ionization (CI) mass
spectra were performed on a Finnigan MAT 95.
Anal. Calcd for C23H42F3NO3Sn (555.9): C, 49.66; H, 7.61; N, 2.52.
Found: C, 49.94; H, 7.72; N, 2.62.
tert-Butyl (2R,3R,E)-3-Methyl-5-phenyl-2-[(trifluoroace-
tyl)amino]pent-4-enoate (4)5b
According to general procedure 1 using Tfa-Gly-Ot-Bu (57 mg,
0.25 mmol) and (R,E)-4-phenylbut-3-en-2-yl acetate (55 mg, 0.25
mmol) with purification by flash chromatography (hexanes–
EtOAc, 9:1) to give ester 4 as a colorless solid; yield: 64 mg (0.18
mmol, 71%); ratio anti/syn 92:8. Recrystallization (Et2O–hexanes)
provided a diastereomerically pure white powder; mp 93–95 °C;
[α]D25 –12.5 (c 1.2, CHCl3, 92% ds, 96% ee).
GC (Chirasil-L-Val, 145 °C, isothermic): tR = 17.92 (2R,3R), 18.30
(2R,3S), 19.96 (2S,3S), 20.67 min (2S,3R).
Palladium-Catalyzed Allylic Alkylations of Chelated Glycine
Ester Enolate; General Procedure 1
Anal. Calcd for C18H22F3NO3 (357.37): C, 60.50; H, 6.20; N, 3.92.
Found: C, 60.50; H, 6.39; N, 3.82.
A soln of LHMDS was prepared from HMDS (111 mg, 0.69 mmol)
and 1.6 M BuLi (0.39 mL, 0.625 mmol) in THF (1 mL) at –20 °C.
This soln was cooled to –78 °C, and then it was added to a soln of
the protected amino acid ester (0.25 mmol) in THF (1 mL). After 20
min at –78 °C a soln of ZnCl2 (38 mg, 0.275 mmol) in THF (1 mL)
was added under vigorous stirring, and after an additional 30 min a
soln of [allylPdCl]2 (1 mg, 2.5 μmol, 1 mol%), Ph3P (3 mg, 11.3
(2R,3R)-4
1H NMR (300 MHz, CDCl3): δ = 1.17 (d, J = 6.9 Hz, 3 H), 1.47 (s,
9 H), 3.00 (m, 1 H), 4.59 (dd, J = 8.4, 4.7 Hz, 1 H), 6.04 (dd,
J = 15.9, 7.8 Hz, 1 H), 6.46 (dd, J = 15.9, 1.0 Hz, 1 H), 6.90 (d,
J = 8.0 Hz, 1 H), 7.20–7.33 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York
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1466
U. Kazmaier et al.
PRACTICAL SYNTHETIC PROCEDURES
13C NMR (75 MHz, CDCl3): δ = 16.2, 28.0, 40.0, 57.3, 83.4, 115.7
(JFC = 287 Hz), 126.2, 128.5, 128.6, 127.7, 132.2, 136.7, 157.0
(JFC = 37 Hz), 169.5.
1 H), 4.11 (m, 2 H), 4.44 (m, 1 H), 4.67 (m, 1 H), 5.48 (m, 1 H), 5.76
(m, 1 H), 7.52 (d, J = 6.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 18.9, 25.3, 27.9, 29.4, 30.2, 52.6,
61.9, 62.6, 83.0, 98.7, 115.6 (JFC = 286 Hz), 127.7, 129.7, 156.4
(JFC = 38 Hz), 169.4.
(2S,3R)-4
1H NMR (300 MHz, CDCl3): δ (selected signals) = 1.20 (d, J = 6.9
Hz, 3 H), 1.46 (s, 9 H), 2.87 (m, 1 H), 4.56 (m, 1 H), 6.02 (dd,
J = 15.9, 7.8 Hz, 1 H), 6.41 (d, J = 15.9 Hz, 1 H).
Minor diastereomer
1H NMR (300 MHz, CDCl3): δ (selected signals) = 1.46 (s, 9 H),
3.50 (m, 1 H), 3.96 (dd, J = 12.4, 7.1 Hz, 1 H), 4.27 (dd, J = 6.1, 2.4
Hz, 1 H), 4.59 (m, 1 H), 7.27 (d, J = 5.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 16.3, 28.0, 40.5, 57.1, 83.5, 127.6,
131.9, 168.9.
13C NMR (75 MHz, CDCl3): δ = 19.6, 28.3, 29.5, 30.4, 52.5, 61.5,
62.6, 83.2, 96.4, 126.4, 130.3, 169.2.
tert-Butyl (2S,3S,Z)-3-Methyl-5-phenyl-2-[(trifluoroacetyl)ami-
no]pent-4-enoate (5)5b
According to general procedure 1 using Tfa-Gly-Ot-Bu (57 mg,
0.25 mmol) and ethyl (S,Z)-4-phenylbut-3-en-2-yl carbonate (41
mg, 0.2 mmol) with purification by flash chromatography (hex-
anes–EtOAc, 95:5) to give ester 5 as a colorless solid; yield: 49 mg
(0.138 mmol, 69%); ratio anti/syn 98:2. Recrystallization (Et2O–
hexanes) provided an enantiomerically pure, white solid; mp 78–
79 °C; [α]D23 +3.5 (c 2.6, CHCl3, 99% ds, 99% ee).
(E)-7
Major diastereomer
1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.47–1.57 (m, 4 H),
1.68 (m, 1 H), 1.78 (m, 1 H), 2.55 (m, 1 H), 2.65 (m, 1 H), 3.48 (m,
1 H), 3.82 (m, 1 H), 3.91 (dd, J = 12.8, 6.2 Hz, 1 H), 4.15 (dd,
J = 12.8, 5.4 Hz, 1 H), 4.52 (m, 1 H), 4.58 (m, 1 H), 5.54 (m, 1 H),
5.63 (ddd, J = 15.4, 6.2, 5.4 Hz, 1 H), 6.88 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 19.4, 25.4, 28.0, 30.6, 34.6, 52.6,
62.2, 67.0, 83.5, 97.9, 115.6 (JFC = 286 Hz), 125.3, 132.1, 156.4
(JFC = 38 Hz), 169.2.
GC (Chirasil-L-Val, 140 °C, isothermic): tR = 11.03 (2R,3S), 11.84
(2S,3R), 12.96 (2R,3R), 15.09 min (2S,3S).
1H NMR (300 MHz, CDCl3): δ = 1.21 (s, 9 H), 1.66 (d, J = 4.7 Hz,
3 H), 3.59 (m, 1 H), 4.74 (t, J = 8.6 Hz, 1 H), 5.60–5.69 (m, 2 H),
6.88 (d, J = 8.6 Hz, 1 H), 7.19–7.34 (m, 5 H).
Minor diastereomer
13C NMR (75 MHz, CDCl3): δ = 17.54, 27.36 (3 C), 52.86, 56.75,
82.84, 115.52 (JFC = 286 Hz), 126.05, 127.18 (2 C), 127.49, 128.20
(2 C), 129.49, 138.83, 156.37 (JFC = 37 Hz), 168.80.
13C NMR (75 MHz, CDCl3): δ (selected signals) = 19.4, 62.2, 66.9,
83.5, 97.9, 132.1.
tert-Butyl (2S,6S,E)-6-(tert-Butyldiphenylsiloxy)-2-[(trifluoro-
acetyl)amino]hept-4-enoate (8)12b
Anal. Calcd for C18H22F3NO3 (357.37): C, 60.50; H, 6.20; N, 3.92.
Found: C, 60.42; H, 6.44; N, 3.99.
According to general procedure 1 using Tfa-Gly-Ot-Bu (114 mg,
0.50 mmol) and (S,E)-4-(tert-butyldiphenylsiloxy)pent-2-enyl ethyl
carbonate (120 mg, 0.301 mmol) with purification by flash chroma-
tography (hexanes–EtOAc, 93:7) to give ester 8 as a colorless oil;
yield: 153 mg (0.28 mmol, 93%); [α]D20 +15.2 (c 1.1, CHCl3, 96%
ds, 96% ee).
tert-Butyl (E)-3-Methyl-2-[(trifluoroacetyl)amino]oct-4-enoate
(6)10
According to general procedure 1 using Tfa-Gly-Ot-Bu (114 mg,
0.50 mmol) and ethyl (Z)-hept-2-en-4-yl carbonate(68 mg, 0.40
mmol) with purification by flash chromatography (hexanes–
EtOAc, 92:8) to give ester 6 as a colorless oil; yield: 106 mg (0.33
mmol, 83%); ratio anti/syn 92:8.
HPLC (OD-H, hexane–i-PrOH, 99.75:0.25, flow: 1.0 mL/min):
tR = 6.58 (2R,6R), 7.12 (2R,6S), 10.03 (2S,6S), 12.01 min (2S,6R).
1H NMR (300 MHz, CDCl3): δ = 1.03 (s, 9 H), 1.06 (d, J = 6.3 Hz,
3 H), 1.44 (s, 9 H), 2.47 (m, 1 H), 2.57 (m, 1 H), 4.25 (m, 1 H), 4.46
(m, 1 H), 5.30 (dt, J = 15.1, 7.8 Hz, 1 H), 5.56 (dd, J = 15.1, 5.1 Hz,
1 H), 6.78 (d, J = 6.9 Hz, 1 H), 7.33–7.40 (m, 6 H), 7.606 (d, J = 6.9
Hz, 1 H), 7.609 (d, J = 6.9 Hz, 1 H), 7.650 (d, J = 6.9 Hz, 1 H),
7.653 (d, J = 6.9 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 19.2, 24.1, 26.9, 28.0, 34.0, 52.5,
69.3, 83.3, 115.6 (JFC = 288 Hz), 120.6, 127.47, 127.48, 129.58,
129.59, 134.0, 134.4, 135.82, 135.84, 140.2, 156.4 (JFC = 37 Hz),
169.20.
GC (Chira-Si-L-Val, 140 °C, T0 [3 min] = 100 °C, 2 °C/min to
T = 180 °C): tR = 19.82 (2R,3S), 20.56 (2S,3R), 22.50 (2R,3R),
23.01 min (2S,3S).
1H NMR (300 MHz, CDCl3): δ = 0.86 (t, J = 7.4 Hz, 3 H), 1.04 (d,
J = 7.0 Hz, 3 H), 1.34 (qt, J = 7.4 Hz, 2 H), 1.45 (s, 9 H), 1.96 (td,
J = 6.9 Hz, 2 H), 2.76 (m, 1 H), 4.41 (dd, J = 8.6, 4.4 Hz, 1 H), 5.22
(dd, J = 15.4, 7.7 Hz, 1 H), 5.52 (dt, J = 15.4, 6.6 Hz, 1 H), 6.64 (d,
J = 7.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): δ = 13.5, 16.8, 22.4, 27.8, 34.6, 39.5,
57.2, 83.0, 115.8 (JFC = 288 Hz), 128.4, 133.7, 157.0 (JFC = 37 Hz),
169.1.
Anal. Calcd for C29H38F3NO4Si (549.71): C, 63.36; H, 6.97; N,
2.55. Found: C, 63.09; H, 7.04; N, 2.70.
Anal. Calcd for C15H24F3NO3 (323.36): C, 55.72; H, 7.48; N, 4.33;
found: C, 55.96; H, 7.46; N, 4.37.
Palladium-Catalyzed Allylic Alkylations of Dipeptides; General
Procedure 2
tert-Butyl (Z)-6-(Tetrahydro-2H-pyran-2-yloxy)-2-[(trifluoro-
acetyl)amino]hex-4-enoate (7)11
To a soln of HMDS (233 mg, 1.44 mmol) in anhyd THF (2 mL) was
added dropwise 1.6 M BuLi in hexanes (0.82 mL, 1.31 mmol) at
–78 °C. The cooling bath was removed and the soln was allowed to
warm up to r.t. In a second flask ZnCl2 (57 mg, 0.42 mmol) was
carefully dried in vacuo with a heatgun. After cooling to r.t. the cor-
responding dipeptide (0.375 mmol) was added dissolved in anhyd
THF (2 mL). The freshly prepared LHMDS soln was cooled to
–78 °C and the ZnCl2/peptide soln was slowly added via syringe. In
a third flask [allylPdCl]2 (1.8 mg, 5.0 μmol) and Ph3P (5.9 mg, 22.5
μmol) were dissolved in anhyd THF (0.5 mL), allylic carbonate
(0.20–0.45 mmol) was added and the catalyst/carbonate soln was
transferred to the cold zinc enolate via syringe. The excess dry ice
was removed from the cooling bath and the mixture was allowed to
warm to r.t. After diluting with Et2O, the mixture was quenched by
According to general procedure 1 using Tfa-Gly-Ot-Bu (114 mg,
0.50 mmol) and ethyl (Z)-4-(tetrahydro-2H-pyran-2-yloxy)but-2-
enyl carbonate (60 mg, 0.26 mmol) with purification by flash chro-
matography (hexanes–EtOAc, 85:15) to give ester 7 as a colorless
oil; yield: 83 mg (0.22 mmol, 87%); ratio Z/E 98:2; dr 55:45.
Anal. Calcd for C17H26F3NO5 (381.39): C, 53.54; H, 6.87; N, 3.67.
Found: C, 53.18; H, 6.74; N, 3.58.
(Z)-7
Major diastereomer
1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 1.47–1.57 (m, 4 H),
1.68 (m, 1 H), 1.78 (m, 1 H), 2.67 (m, 2 H), 3.55 (m, 1 H), 3.81 (m,
Synthesis 2013, 45, 1462–1468
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Palladium-Catalyzed Allylic Alkylations
1467
the addition of 1 M HCl (sat. NH4Cl if substrates with acid labile
groups were used). The aqueous layer was extracted with Et2O (2 ×)
and the combined organic layers were dried (Na2SO4). The solvent
was evaporated and the residue was purified by column chromatog-
raphy.
HRMS (CI): m/z [M – C4H9]+ calcd for C33H43F3N3O3Sn: 706.2279;
found: 706.2268.
(S,R)-11
1H NMR (500 MHz, DMSO-d6): δ = 0.75–0.87 (m, 15 H), 1.22–
1.29 (m, 6 H), 1.39–1.45 (m, 6 H), 1.77–1.84 (m, 1 H), 1.94–2.02
(m, 1 H), 2.38 (dd, J = 13.7, 7.6 Hz, 1 H), 2.56–2.64 (m, 2 H), 2.76
(dt, J = 16.0, 6.5 Hz, 1 H), 2.96 (dd, J = 14.0, 10.0 Hz, 1 H), 3.09
(dd, J = 14.0, 5.0 Hz, 1 H), 3.30–3.34 (m, 1 H), 4.03–4.10 (m, 1 H),
4.71–4.73 (m, 1 H), 5.02–5.06 (m, 1 H), 5.17 (d, J = 2.4 Hz,
tert-Butyl N-(Trifluoroacetyl)-(S)-phenylalanyl-(2R,4E)-2-ami-
no-5-[(4S,5S)-5-(benzyloxymethyl)-2,2-dimethyldioxolan-4-
yl]pent-4-enoate (9)12c
According to general procedure 2 using Tfa-Phe-Gly-Ot-Bu (140
mg, 0.375 mmol) and 1-[(4S,5S)-5-(benzyloxymethyl)-2,2-dimeth-
yl-1,3-dioxolan-4-yl]allyl ethyl carbonate (70.0 mg, 0.20 mmol)
and purification by flash chromatography (hexanes–EtOAc, 93:7)
to give dipeptide ester 9 as a colorless oil; yield: 113 mg (0.18
mmol, 89%); dr 98:2.
J
SnH = 63.9, 1 H), 5.66 (d, J = 2.4 Hz, JSnH = 134.9, 1 H), 7.13 (dt,
J = 7.0, 1.5 Hz, 1 H), 7.17–7.20 (m, 2 H), 7.23–7.28 (m, 5 H), 7.52
(dd, J = 8.0, 1.5 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 9.19 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 8.6 (JSnC = 324 Hz), 12.6,
23.0, 25.4, 25.9 (JSnC = 53 Hz), 27.8 (JSnC = 19 Hz), 36.7, 42.2, 42.7
(JSnC = 40 Hz), 48.8, 54.1, 115.2 (JFC = Hz), 123.8, 124.6, 125.4,
125.8, 127.3, 127.4, 127.8, 128.5, 132.2, 136.6, 138.1, 149.1, 155.5
(JFC = 36 Hz), 168.6, 170.3.
HPLC (Reprosil 100 Chiral-NR 8 mm, hexane–i-PrOH, 98:2, 1.0
mL/min): tR = 12.17 (S,S,S,S), 15.09 min (S,R,S,S).
1H NMR (300 MHz, CDCl3): δ = 1.36 (s, 9 H), 2.24 (ddd, J = 14.4,
5.8, 5.8 Hz, 1 H), 2.35 (ddd, J = 14.4, 5.5, 5.5 Hz, 1 H), 2.95 (dd,
J = 13.6, 8.4 Hz, 1 H), 3.04 (dd, J = 13.6, 5.9 Hz, 1 H), 1.33 (s, 3 H),
1.32 (s, 3 H), 3.46 (dd, J = 10.3, 4.3 Hz, 1 H), 3.50 (dd, J = 10.3, 5.3
Hz, 1 H), 3.73 (ddd, J = 8.4, 5.0, 4.3 Hz, 1 H), 4.04 (dd, J = 8.4, 6.3
Hz, 1 H), 4.41 (ddd, J = 7.8, 5.5, 5.5 Hz, 1 H), 4.50–4.55 (m, 3 H),
5.32–5.34 (m, 2 H), 6.00 (br s, 1 H), 7.10–7.30 (m, 11 H).
13C NMR (75 MHz, CDCl3): δ = 26.9, 27.0, 27.9, 35.0, 38.7, 52.1,
54.8, 69.6, 73.6, 79.0, 79.7, 82.8, 109.3, 115.6 (JFC = 287 Hz),
127.5, 127.7, 127.8, 128.1, 128.4, 128.9, 129.2, 132.1, 135.3, 137.7,
156.5 (JFC = 38 Hz), 168.5, 169.5.
(S,S)-11
1H NMR (500 MHz, DMSO-d6): δ (selected signals) = 3.99–4.03
(m, 1 H), 7.46 (dd, J = 8.0, 1.0 Hz, 1 H), 8.13 (d, J = 8.0 Hz, 1 H),
9.05 (br s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ (selected signals) = 12.7, 23.1,
49.2, 53.8, 123.6, 128.4, 149.2, 168.7.
Palladium-Catalyzed Allylic Alkylations of Tripeptides; Gener-
al Procedure 3
A 1.6 M BuLi soln (0.63 mL, 1.0 mmol) was added to a soln of
i-Pr2NH (0.145 mL, 1.1 mmol) in THF (0.5 mL) in a Schlenk flask
at –20 °C. The cooling bath was removed and stirring was contin-
ued for further 10 min before the mixture was cooled again to
–78 °C. In a second Schlenk flask a mixture of N-protected tripep-
tide (0.20 mmol) and ZnCl2 (41.7 mg, 0.31 mmol) was dissolved in
THF (3 mL). This soln was added to the LDA soln at –78 °C and the
mixture was warmed up to –40 °C over 30 min, and then the soln
was cooled again to –78 °C and stirred for a further 15 min. The pal-
ladium catalyst (1.46 mg, 4.0 μmol) and Ph3P (4.8 mg, 18.3 μmol)
were dissolved in THF (0.2 mL). After stirring for 10 min at r.t. the
allyl substrate (0.20 mmol) was added to the yellow soln thus
formed, and the resulting mixture was added slowly to the chelated
enolate at –78 °C. The soln was allowed to warm up to r.t. over-
night, before it was diluted with EtOAc and 1 M KHSO4 was added.
After extraction with EtOAc, the organic layers were dried
(Na2SO4), concentrated in vacuo and the crude product was purified
by flash chromatography.
HRMS (CI): m/z [M – C4H9]+ calcd for C29H32F3N2O4: 577.2162;
found: 577.2191.
tert-Butyl N-(Trifluoroacetyl)-(S)-phenylalanyl-(R)-[2-(tribu-
tylstannyl)allyl]glycinate (10)14a
According to general procedure 2 using Tfa-Phe-Gly-Ot-Bu (562
mg, 1.5 mmol) and ethyl 2-(tributylstannyl)allyl carbonate (755 mg,
1.8 mmol) with purification by flash chromatography (hexanes–
EtOAc–Et3N, 95:4:1) to give dipeptide ester 10 as a colorless solid;
20
yield: 765 mg (1.09 mmol, 73%); dr >98:2; mp 55–56 °C; [α]D
–6.3 (c 1.0, CHCl3, >98% ds).
1H NMR (400 MHz, CDCl3): δ = 0.84 (t, J = 7.3 Hz, 9 H), 0.89 (t,
J = 8.1 Hz, JSnH = 50.8, 6 H), 1.27 (tq, J = 7.3, 7.3 Hz, 6 H), 1.35 (s,
9 H), 1.40–1.54 (m, 6 H), 2.27 (dd, J = 14.1, 8.1 Hz, 1 H), 2.49 (dd,
J = 14.1, 6.2 Hz, 1 H), ), 2.97 (dd, J = 13.8, 7.9 Hz, 1 H), 3.06 (dd,
J = 13.8, 5.8 Hz, 1 H), 4.49 (ddd, J = 7.7, 7.7, 5.5 Hz, 1 H), 4.58
(ddd, J = 7.5, 7.5, 6.2 Hz, 1 H), 5.12 (d, J = 1.3 Hz, JSnH = 59.5, 1
H), 5.53 (d, J = 1.1 Hz, JSnH = 128.0, 1 H), 5.77 (d, J = 7.6 Hz, 1 H),
7.11–7.25 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 9.6 (JSnC = 328 Hz), 13.7, 27.4
(JSnC = 57 Hz), 27.9, 29.0 (JSnC = 19.7 Hz), 38.5, 44.1 (JSnC = 40.3
Hz), 52.6 (JSnC = 12.4 Hz), 54.5, 82.5, 115.6 (JFC = 288 Hz), 127.5,
128.3 (d, JSnC = 23.6 Hz), 128.9, 129.2, 135.3, 149.6, 156.6
(JFC = 37.6 Hz), 168.4, 170.5.
N-(Trifluoroacetyl)-(S)-phenylalanyl-(R)-4,5-dehydroleucyl-
(S)-N-methylleucine Anilide (12)16
According to general procedure 3 using Tfa-Phe-Gly-MeLeu-
NHPh (208 mg, 0.40 mmol) and ethyl methallyl carbonate (58 mg,
0.40 mmol) with purification by flash chromatography (hexanes–
EtOAc, 8:2) to give tripeptide amide 12 as a colorless solid; yield:
183 mg (0.32 mmol, 80%); mp 112–113 °C; dr 97:3; [α]D20 –128.0
(c 1.0, CHCl3).
119Sn NMR (149 MHz, CDCl3): δ = –43.7.
HPLC (Reprosil, hexane–i-PrOH, 9:1 to 7:3, 40 min, 1 mL/min, 252
nm): tR = 16.16 (S,S), 20.48 min (S,R).
Anal. Calcd for C32H51F3N2O4Sn (703.46): C, 54.64; H, 7.31; N,
3.98. Found: C, 54.41; H, 6.97; N, 3.95.
1H NMR (400 MHz, CDCl3): δ = 0.90 (d, J = 6.6 Hz, 3 H), 0.96 (d,
J = 6.6 Hz, 3 H), 1.67 (m, 1 H), 1.73 (s, 3 H), 1.88–1.98 (m, 2 H),
2.23 (dd, J = 13.9, 9.1 Hz, 1 H), 2.33 (dd, J = 14.0, 5.7 Hz, 1 H),
3.07 (s, 3 H), 3.09–3.13 (m, 2 H), 4.70–4.82 (m, 3 H), 4.86 (m, 1 H),
5.30 (dd, J = 10.0, 5.4 Hz, 1 H), 6.46 (d, J = 5.6 Hz, 1 H), 7.08 (t,
J = 7.4 Hz, 1 H), 7.17 (m, 2 H), 7.25–7.35 (m, 6 H), 7.59 (d, J = 7.6
Hz, 2 H), 8.29 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 21.7, 21.9, 23.2, 24.9, 31.0, 36.1,
38.3, 39.8, 48.3, 54.3, 56.1, 115.5 (JFC = 287.4 Hz), 115.7, 120.0,
124.3, 127.5, 128.8, 128.9, 129.1, 135.2, 137.9, 139.2, 156.7
(JFC = 37 Hz), 168.3, 169.6, 172.9.
N-(Trifluoroacetyl)-(S)-phenylalanyl-(R)-[2-(tributylstan-
nyl)allyl]glycine 3,4-Dihydroquinolinide (11)15
According to general procedure 2 using Tfa-Phe-Gly-(3,4-di-
hydro)quinolinide (100 mg, 0.23 mmol) and ethyl 2-(tributylstan-
nyl)allylcarbonate (104 mg, 0.25 mmol) with purification by flash
chromatography (hexanes–EtOAc, 8:2) to give dipeptide amide 11
as a colorless oil; yield: 102 mg (0.21 mmol, 92%); dr 94:6.
HPLC (Reprosil, hexanes–i-PrOH 95:5, 1 mL/min): tR = 6.88 (S,S),
8.07 min (S,R).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1462–1468

1468
U. Kazmaier et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS (CI): m/z [M + H]+ calcd for C30H37F3N4O4: 575.2840;
found: 575.2798.
(5) (a) Kazmaier, U.; Zumpe, F. L. Angew. Chem. 1999, 111,
1572; Angew. Chem. Int. Ed. 1999, 38, 1468. (b) Kazmaier,
U.; Zumpe, F. L. Eur. J. Org. Chem. 2001, 4067.
(6) (a) Kazmaier, U.; Schauß, D.; Pohlman, M. Org. Lett. 1999,
1, 1017. (b) Kazmaier, U.; Pohlman, M.; Schauß, D. Eur. J.
Org. Chem. 2000, 2761.
Anal. Calcd for C30H37F3N4O4 (574.63): C, 62.70; H, 6.49; N, 9.75.
Found: C, 62.78; H, 6.79; N, 9.33.
(7) (a) Crisp, G. T.; Glink, P. T. Tetrahedron Lett. 1992, 33,
4649. (b) Crisp, G. T.; Glink, P. T. Tetrahedron 1994, 50,
3213. (c) Kazmaier, U.; Schauß, D.; Pohlman, M.; Raddatz,
S. Synthesis 2000, 914. (d) Kazmaier, U.; Schauß, D.;
Raddatz, S.; Pohlman, M. Chem. Eur. J. 2001, 7, 456.
(8) Consiglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 257.
(9) Kazmaier, U.; Zumpe, F. L. Angew. Chem. 2000, 112, 805;
Angew. Chem. Int. Ed. 2000, 39, 802.
(10) Kazmaier, U.; Pohlman, M. Synlett 2004, 623.
(11) Kazmaier, U.; Krämer, K. J. Org. Chem. 2006, 71, 8950.
(12) (a) Kazmaier, U.; Lindner, T. Angew. Chem. 2005, 117,
3368; Angew. Chem. Int. Ed. 2005, 44, 3303. (b) Lindner, T.;
Kazmaier, U. Adv. Synth. Catal. 2005, 1687. (c) Krämer, K.;
Deska, J.; Hebach, C.; Kazmaier, U. Org. Biomol. Chem.
2009, 7, 103. (d) Gawas, D.; Kazmaier, U. Org. Biomol.
Chem. 2010, 8, 457.
(13) Kazmaier, U.; Deska, J.; Watzke, A. Angew. Chem. 2006,
118, 4973; Angew. Chem. Int. Ed. 2006, 45, 4855.
(14) (a) Deska, J.; Kazmaier, U. Angew. Chem. 2007, 119, 4654;
Angew. Chem. Int. Ed. 2007, 46, 4570 . (b) Deska, J.;
Kazmaier, U. Chem. Eur. J. 2007, 13, 6204.
(15) Datta, S.; Kazmaier, U. Org. Biomol. Chem. 2011, 9, 872.
(16) Datta, S.; Bayer, A.; Kazmaier, U. Org. Biomol. Chem.
2012, 10, 8268.
Acknowledgment
Financial support from the Deutsche Forschungsgemeinschaft (Ka
880/8-1,2) was gratefully acknowledged.
References
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Synthesis 2013, 45, 1462–1468
© Georg Thieme Verlag Stuttgart · New York