Selective peptide modifications via ruthenium-catalyzed allylic alkylations

Article abstract of DOI:10.1021/jo501731y

Ruthenium-catalyzed allylic alkylations are an interesting alternative to palladium-catalyzed processes, since they can provide products which are not accessible under Pd-catalysis. Chiral terminal allylic substrates can be reacted with perfect stereo- and regioretention, and also (Z)-configured allylic substrates can be converted isomerization-free. This allows highly stereoselective modifications of peptides at glycine subunits. The configuration at the α-position of the new generated α-amino acid can be controlled by the chiral peptide chain, and at the β-position by using chiral allylic substrates.

Full text of DOI:10.1021/jo501731y

Note
pubs.acs.org/joc
Selective Peptide Modifications via Ruthenium-Catalyzed Allylic
Alkylations
Anton Bayer and Uli Kazmaier*
Universitat des Saarlandes, Institut fur Organische Chemie, Campus, Geb. C4.2, D-66123 Saarbrucken, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Ruthenium-catalyzed allylic alkylations are an interesting alternative to palladium-catalyzed processes, since they
can provide products which are not accessible under Pd-catalysis. Chiral terminal allylic substrates can be reacted with perfect
stereo- and regioretention, and also (Z)-configured allylic substrates can be converted isomerization-free. This allows highly
stereoselective modifications of peptides at glycine subunits. The configuration at the α-position of the new generated α-amino
acid can be controlled by the chiral peptide chain, and at the β-position by using chiral allylic substrates.
icroorganisms are highly productive producers of natural
Mproducts, and a wide range of their secondary
metabolites became lead structures for the development of
drugs.1 Peptides and cyclo(depsi)peptides formed by non-
ribosomal peptide synthetases (NRPS) are especially interest-
ing from a pharmaceutical point of view.2 Many of these
peptides contain not only (S)- and (R)-configured or N-
methylated amino acids but also rather unusual side chains. In
classical peptide syntheses, these unusual amino acids are
synthesized separately, and are subsequently coupled using
suitable coupling reagents. No question, this protocol is suitable
for the synthesis of a single target molecule (natural product or
drug) but is by far less suited for the synthesis of libraries of
related peptidic structures, as required for SAR studies or lead
structure optimizations. In these cases, a concept allowing
modifications in a very late stage of the synthesis would be
much more attractive. Selective peptide modifications are a
suitable tool to address this issue, while one can differentiate
between two diverse protocols.3 The advantage of the rather
simple side chain modifications results from the fact, that the
stereogenic α-center can be transmitted from the parent amino
acid,4 but on the other hand one is limited to the possible
modifications of a given functionalized side chain. A
significantly higher structural variety can be generated via
peptide-backbone modifications, where complete side chains
can be introduced at glycine subunits.3 According to this
protocol reactive glycine intermediates are generated in a
peptide chain and reacted selectively. These intermediates can
be either cations,5 anions,6 or even radicals,7 but the other
amino acids in the peptide chain should not be affected under
the reaction conditions used.
flexibility of a linear peptide chain, in general diastereomeric
mixtures of substitution products are formed.5−8 The situation
is better in the case of cyclic peptides, where one face of the
glycine intermediate is shielded by the peptide ring. In this case
stereoselective modifications become possible.9 Probably, the
most spectacular natural product modification based on this
concept was the stereo- and regioselective alkylation of
cyclosporine, reported by Seebach et al.10
Since a couple of years our group is also involved in
stereoselective peptide modifications, focusing on linear
peptides. For example, peptide allylesters can be subjected to
a stereoselective chelate enolate Claisen rearrangement, where
the stereochemical outcome is controlled by the stereogenic
centers in the peptide chain.11 An (S)-amino acid generates an
adjacent new (R)-amino acid and vice versa. In case of trans-
substituted allylic esters the new β-branched amino acid is
formed with syn-configuration. Alternatively, similar unsatu-
rated side chains can also be introduced via Pd-catalyzed allylic
alkylation, generating also the (S)/(R)-peptides.12 This
approach nicely complements the Claisen rearrangement,
since the anti-configured amino acids can be obtained by this
protocol. But in contrast to the chelate Claisen rerarrangement,
the Pd-catalyzed version is not limited to C-terminal glycine
units, but can also be applied in the middle of a peptide chain,
as long as an amide enolate can be formed.13 Excellent
diastereoselectivities are obtained with sterically demanding
allylic substrates (>95% ds) (Scheme 1).12 Although this
sounds pretty good, the Pd-catalyzed version has nevertheless
some drawbacks.
The control of the stereochemical outcome of this side chain
Received: July 29, 2014
introduction is found to be not a trivial issue. Due to the
Published: August 13, 2014
© 2014 American Chemical Society
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The Journal of Organic Chemistry
Note
showing a significantly lower regioretention (75% rs).23 The
isomerization-free and highly regioselective allylations with
[(cymene)RuCl2]2 prompted us to investigate this catalyst also
for peptide allylations, since this protocol should allow the
stereoselective incorporation of β-branched amino acids into
peptides. The configuration at the β-position should be
transferred from a chiral allylic substrate (stereoretention),
while the configuration at the α-position should be controlled
by the peptide chain, in analogy to the Pd protocol.12
Scheme 1. Stereoselective Pd-Catalyzed Allylation of
Peptides
To prove the appropriations of peptide enolates in Ru-
catalyzed allylic alkylations, we exemplarily investigated two
peptides 1, using the reaction conditions optimized in the Pd-
catalyzed reactions. We used N-trifluoroacetylated tert-butyl
esters, which in general give the best yields and selectivities.
The nucleophile (deprotonated dipeptide) was used in a slight
excess. In principle, six different products can be formed, which
should be separable by chromatography (Table 1). Besides the
four β-branched products 3−6, the linear products 7 and 8 also
might be formed, and the product ratio should depend on the
configuration of the chiral allylic substrate used (matched/
mismatched situation). To prove this option we used rac-
butenyl acetate 2a in our initial experiments (entry 1). In good
yield a mixture of the four expected β-branched products (3−
6) was obtained, while the linear products were not observed.
This clearly indicates that peptide enolates also react with
terminal allylic substrates with perfect regioretention. In
addition, the adjacent chiral amino acid caused a high induced
diastereoselectivity of 90% (3 + 5/4 + 6). The (S)-configured
acetate reacts faster than the (R)-form, since 70% of the peptide
shows a (3S)-configuration (3 + 4/5 + 6). To verify this
observation and to assign the stereoisomers we also subjected
rac-pentenyl acetate 2b to the same reaction conditions (entry
2). In this case catalytic hydrogenation removes the stereogenic
β-center, and the remaining stereoisomers are clearly the result
of the induced distereoselectivity. In this case the yield was
slightly lower as in the first example, but the selectivities
observed were comparable. Also here the (3S)-isomer was
The reactions proceed via π-allyl complexes, generating
regioisomeric mixtures if 1,3-disubstituted allylic substrates are
used. If terminal π-allyl complexes are formed, the nucleophilic
attack of the peptide enolate occurs preferentially at the
sterically least hindered position, generating only linear side
chains. In addition, terminal π-allyl Pd-complexes are highly
sensitive to isomerization,14 resulting in a racemization of chiral
allylic substrates. With highly reactive chelated glycine ester
enolates such isomerizations can be suppressed almost
completely15 but not with the less reactive peptide enolates.16
A (Z/E)-isomerization is also observed if (Z)-configured allyl
substrates are used. In these cases the thermodynamically more
stable (E)-configured side chains are incorporated almost
exclusively into the peptides.
This forced us to search for an alternative protocol. Although
Pd is the by far most often used transition metal for allylic
alkylations, several other metals such as Ir17 or Ru18 moved
mainstream during the last years.19 Recently, we reported Ru-
catalyzed allylic alkylations of chelated glycine ester enolates,
proceeding with excellent regioretention (>95% rs).20 In
addition, no isomerizations were observed if [(cymene)RuCl2]2
was used as catalyst.21 We assume that with this catalyst the
allylations probably proceed via a (σ+π)-allyl complex
(regioretention via double SN′-reaction), as discussed also for
Rh-catalyzed processes,22 and not via a π-allyl complex as with
the Pd catalysts. Other Ru complexes such as [Cp*Ru-
(MeCN)3]PF6 seem to react via such π-allyl complexes,
Table 1. Ru-Catalyzed Allylic Alkylations of Dipeptide Esters 1
product ratio [%]
entry
1
R
equiv 1
2
R′
OX
conf.
ee
x
yield [%]
3
4
5
6
7
8
1
1a
1a
1a
1a
1a
1b
1a
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Ph
1.5
1.3
1.3
1.3
1.3
1.3
1.3
2.0
2.0
2.0
2.0
2a
2b
2b
2c
2c
2c
2c
2c
2c
2d
2b
Me
Et
OAc
OBz
OBz
OAc
OAc
OAc
OAc
OAc
OAc
OBz
OBz
(R/S)
(R/S)
(S)
−
−
97
2
2
2
2
2
2
5
5
5
5
5
74
54
54
34
43
67
63
78
80
99
95
63
64
83
49
67
72
66
62
4
7
27
23
3
3
3
0
3
1
0
1
0
6
0
0
0
0
0
0
2
2
1
2
4
3
0
1
2
10
14
6
0
0
3
Et
4
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
(R/S)
(R)
−
26
7
14
14
9
5
99
99
99
99
97
97
97
9
6
OTBDPS
(R)
15
10
9
3
7
Ph
Ph
Ph
Ph
Ph
(R)
7
14
19
13
3
8
(R)
6
9
(S)
1
73
3
10
11
(S)
74
73
20
19
(S)
3
4
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Note
formed in excess (74%). Afterward, the same experiment was
carried out with the almost enantiomerically pure (S)-2b,
verifying the yields and selectivities. Reisolated allylic substrate
and peptide had an unchanged ee of 97%, clearly indicating that
under our reaction conditions neither the allylic substrate nor
the peptides undergo epimerization.
Scheme 2. Ru-Catalyzed Allylic Alkylations of Tripeptide 9
Aryl-substituted allyl substrates often behave differently from
the corresponding alkyl analogues.24 Therefore, we also
investigated the reaction of phenyl-substituted allyl acetate 2c
in racemic as well as enantiopure form (entries 4 and 5).
Indeed, significant differences could be observed. Not only was
the yield lower, in these cases also the linear product was
formed as a side product (∼15%). The induced diastereose-
lectivity (88−89% ds) was comparable to the results obtained
with the Pd catalysts, although in this case only the linear
product was formed.12 Also here, one of the enantiomers of 2c
reacted preferentially (entry 4). Due to altered Cahn−Ingold−
Prelog preferences,25 the (3R)-isomer is incorporated prefer-
entially (3R:3S = 65:35). The slower reacting (S)-2c was
enriched in the recovered starting material (20% ee).
Interestingly, even if enantiopure 2c was used, a certain
amount (8%) of the (3S)-isomers 5 and 6 were formed (entry
5), clearly indicating that either the allyl substrate 2c or the
allyl-ruthenium complex formed underwent isomerization
during the reaction. To prove this option we isolated unreacted
2c and recognized a drop of the ee value from 99% to 90%.
Comparable isomerizations were observed by Kawatsura et al.
in allylations of malonates with this catalyst.26 To figure out if
this is a general problem in Ru-catalyzed peptide allylations, we
investigated several other peptides such as the O-protected
serine derivative 1b. In this case almost no isomerization was
observed and the yield was also higher (entry 6). The moderate
yields obtained with 2c forced us to optimize the reaction
conditions. An increase of the catalyst concentration to 5 mol %
caused an increased yield, without significant influence on the
product ratio (entry 7). A further improvement was observed
by using the peptide enolate in excess (2 equiv) (entry 8).
Interestingly, under competitive conditions the slower reacting
(S)-2c gave the allylation product in almost the same yield and
even slightly better selectivity, without significant isomerization
(entry 9). By far the best results were obtained with the
corresponding benzoates 2b and 2d. In an almost perfect yield
and regioretention the reaction proceeded isomerization free
with an induced diastereoselectivity of ∼4:1 (entries 10 and
11).
To determine the configuration of the new products we
synthesized reference samples via chelate Claisen rearrange-
ment. In this case also the (S/R)-peptides are formed
preferentially, while the new amino acid is obtained as the
syn-isomer (90−95% syn).11 This allows an easy assignment of
the isomers via HPLC. To differentiate between the induced
and the simple diastereoselectivity, we subjected the allylation
products obtained from 2b to catalytic hydrogenation providing
only two isomers in the ratio of 6:1 (entry 3) or 4:1 (entry 11).
To illustrate that this protocol is not limited to terminal
dipeptide esters but can also be applied to larger peptides and
also in the middle of a peptide chain, we investigated allylations
of tripeptide 9 (Scheme 2). In this case the valuable peptide
and the allylic substrate were reacted in a stoichiometric 1:1
ratio. Under the reaction conditions used, the acidic NH bonds
were deprotonated, protecting the adjacent stereogenic centers
from epimerization.6 Only the central glycine unit was able to
form an amide enolate. Reaction with the almost enantiopure
benzoate (S)-2b gave access to the allylation product 10 with
excellent regio- and diastereoselectivity and with perfect
chirality transfer. Only traces of the other stereoisomers
could be detected by HPLC.
Another great advantage of Ru-catalyzed allylations is the
isomerization-free allylation using (Z)-allyl substrates, while in
this case best results are obtained with allyl phosphates.20 To
depict that the good results obtained with glycine ester enolates
can also be transferred to peptides, 9 was also reacted with two
(Z)-allyl phosphates 11a and 11b. With perfect retention of the
olefin geometry the desired products 12 were formed almost
diastereomerically pure. The yields in both reactions were in
the range of 50%, and unreacted dipeptide could be recovered
almost completely (33−50%).
In conclusion, it was shown that the Ru-catalyzed allylic
alkylation is an excellent tool to modify peptides not only at the
C-terminus (via ester enolate) but also in the middle of a
peptide chain (via amide enolate). The reactions proceed
isomerization-free and in the case of alkyl-substituted allylic
substrates with perfect regioretention. Therefore, the Ru-
catalyzed reactions show a completely different reaction
behavior compared to the Pd-catalyzed processes. The
stereochemical outcome at the α-position of the newly formed
amino acid is controlled by the peptide chain, while the
configuration at the β-position can be transferred from the
allylic substrate (stereoretention).
EXPERIMENTAL SECTION
■
General Remarks. All air- or moisture-sensitive reactions were
carried out in dried glassware (>100 °C) under an atmosphere of
nitrogen. THF was distilled from Na/benzophenone. The products
were purified by flash chromatography on silica gel columns (0.063−
0.2 mm). Mixtures of ethyl acetate and hexanes were generally used as
eluents. Analytical TLC was performed on precoated silica gel plates.
Visualization was accomplished with UV-light and KMnO4 solution.
Melting points are uncorrected. 1H and 13C NMR spectra were
recorded with a 400 MHz (1H) and 100 MHz (13C) spectrometer in
CDCl3. Chemical shifts are reported in ppm relative to TMS, and
CHCl3 was used as the internal standard. The correct assignment of
signals was verified by H,H-COSY and C,H-COSY spectral data.
Selected signals for the minor regio- and diastereomers are extracted
from the spectra of the isomeric mixture. Regioisomeric and
diastereomeric ratios were determined by HPLC equipped with a
chiral ReproSil 100 Chiral-NR column (250 mm × 4.6 mm, 100 Å, 8
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The Journal of Organic Chemistry
Note
μm). n-Hexane/isopropanol was used as eluent. In cases where
separation on HPLC was not sufficient, integration of characteristic 1H
NMR signals was additionally used. Chirality transfer was determined
by comparison of product mixtures received starting from racemic with
those of enantiopure substrates. Absolute stereochemistry of the
products 3a and 5c was assigned by comparison with products
obtained by peptide ester enolate Claisen rearrangement of the
corresponding crotyl or cinnnamyl esters.27 Mass spectra were
recorded with a high resolution quadrupole spectrometer (CI) and
with an ion trap spectrometer (ESI).
Synthesis of Starting Materials. Allylic alcohols as precursors for
2a, 2b, 11a, and 11b were purchased from commercial suppliers. The
racemic precursor for 2c was prepared by addition of vinylmagnesium
bromide to benzaldehyde. Enzymatic resolution of the resulting allylic
alcohol with Novozyme 435 led to (R)-2c and after the acetylation of
the remaining enantiomer with acetanhydride to (S)-2c.28 11a and
11b were prepared as described previously.15b (S)-2a and (S)-2b were
obtained by the method described by Feringa et al.29 The allylic
alcohols were converted to benzoates, acetates, and phosphates by
standard literature methods.30
The dipeptides 1a and 1b were obtained by standard peptide
coupling respectively of N-Boc-protected phenylalanine and O-
TBDPS-serine with tert-butyl glycinate using iso-butyrochloroformate
(IBCF) and N-methyl morpholine (NMM) as base, followed by Boc-
deprotection and Tfa-protection of the N-terminus.12b N,N-Boc-
methyl leucine was obtained by N-methylation of Boc-leucine with
methyl iodide and sodium hydride in THF.31
(S)-N,N-(tert-Butoxycarbonyl)methyl-leucine Anilide. To a
stirred solution of N,N-Boc-methyl leucine (6.13 g, 25.0 mmol) and
N-methyl morpholine (2.53 g, 25.0 mmol) in THF (75 mL) iso-
butyrochloroformate (3.25 g, 23.8 mmol) was slowly added at −10 °C.
After 15 min at this temperature a solution of aniline (2.33 g, 25.0
mmol) in THF (25 mL) was added, and the reaction mixture was
stirred at rt for 16 h. The resulting solution was diluted with diethyl
ether, washed with 1 M HCl, sat. NaHCO3 solution, water, and brine.
The organic layer was dried over Na2SO4, and the solvent was
removed in vacuo. The residue was suspended twice in n-pentane and
CH2Cl2 (20 mL) propylphosphonic anhydride (T3P) (1.91 g 50% in
ethyl acetate, 3.00 mmol). The reaction mixture was stirred for 16 h at
rt. Water was added, and the aqueous solution was extracted with ethyl
acetate. The combined organic phases were washed with sat. NaHCO3
solution, water, and brine and were dried over Na2SO4. The solvent
was removed in vacuo, and the residue was purified by column
chromatography (SiO2, hexanes/ethyl acetate = 6:4), providing
tripeptide 9 as a colorless foam (930 mg, 1.79 mmol, 89% yield).
[α]20D = −110.3° (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
0.91 (d, J = 6.5 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.57−1.42 (m, 1
H), 1.70 (ddd, J = 14.2, 8.9, 5.6 Hz, 1 H), 1.82 (ddd, J = 14.6, 8.3, 6.6
Hz, 1 H), 2.96 (s, 3 H), 3.12 (m, 2 H), 4.06 (d, J = 4.1 Hz, 2 H), 4.94
(ddd, J = 8.0, 8.0, 8.0 Hz, 1 H), 5.18 (dd, J = 8.8, 6.6 Hz, 1 H), 7.06
(m, 1 H), 7.30−7.12 (m, 8 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.46 (m, 2
H), 8.11 (s, 1 H); 13C NMR (100 MHz, CDCl3): δ = 22.0, 22.9, 25.0,
29.9, 36.6, 38.6, 41.7, 54.4, 55.9, 115.6 (q, JF = 288 Hz), 119.8, 124.5,
127.4, 128.7, 129.0, 129.1, 135.2, 137.6, 155.9 (q, JF = 38.1 Hz), 168.2,
169.1, 169.4; Analysis calcd for C26H31F3N4O4: C, 59.99, H, 6.00, N,
10.76; found: C, 59.94, H, 6.02, N, 10.50.
General Procedure. Ru-catalyzed allylic alkylations of dipeptide
ester enolates were performed with 1 mmol of the allylic substrate in
oven-dried glassware (>100 °C) under a nitrogen atmosphere.
Preparation of the des-Zn-Chelated Enolate. In a Schlenk tube
was dissolved HMDS (1.14 g, 7.08 mmol, 3.5 equiv/peptide) in
absolute THF (2 mL). After cooling to −20 °C a 1.6 M n-butyl lithium
solution (3.9 mL, 6.23 mmol, 3.1 equiv/peptide) was slowly added.
The cooling bath was removed, and the colorless solution was stirred
for 15 min at rt. The LHMDS solution was cooled again to −78 °C,
before the N-trifluoroacetyl-protected dipeptide tert-butyl ester 1 (2.00
mmol, 2 equiv) and dry zinc chloride (327 mg, 2.40 mmol, 1.2 equiv/
peptide) (dried at 0.01 mbar, > 100 °C) in absolute THF (4 mL) were
slowly added. For complete transmetalation the solution was stirred
for 45 min at −78 °C.
Preparation of the Catalyst/Allylic Substrate Solution. In a second
Schlenk tube di-μ-chlorobis-(p-cymene)chlororuthenium (30.6 mg, 50
μmol, 5 mol %) and triphenylphosphine (26.2 mg, 100 μmol, 10 mol
%) were dissolved in absolute THF (2.0 mL). The deep-red solution
was stirred for 5 min at rt, before the allylic substrate (1.00 mmol) was
added.
filtered, giving rise to the title compound (23.8 mmol, quant.) as a
1
colorless solid, mp 87−88 °C; [α]20 = −65.7° (c = 1.0, CHCl3); H
D
NMR (400 MHz, CDCl3): δ = 0.95 (d, J = 6.6 Hz, 3 H), 0.98 (d, J =
6.7 Hz, 3 H), 1.50 (s, 9 H), 1.52−1.63 (m, 1 H), 1.64−1.74 (m, 1 H),
1.75−1.95 (m, 1 H), 2.80 (s, 3 H), 4.76 (m, 1 H), 7.08 (m, 1 H), 7.30
(m, 2 H), 7.46−7.52 (m, 2 H), 7.62 and 8.33 (bs, 1 H, 2 rotamers);
13C NMR (100 MHz, CDCl3): δ = 22.1, 23.1, 24.8, 28.4, 30.1, 36.1,
57.0, 80.9, 119.5, 119.6, 124.1, 129.0, 138.1, 157.4, 169.5; HRMS (CI)
m/z calcd for C18H29N2O3 [M + H]+: 321.2173, found: 321.2173;
Analysis calcd for C18H28N2O3: C, 67.47, H, 8.81, N 8.74; found: C
67.84, H 8.98, N 8.72.
The catalyst/allylic substrate solution was slowly added to the zinc
enolate solution at −78 °C, and the mixture was warmed up to rt
overnight. The reaction mixture was diluted with wet diethyl ether and
hydrolyzed with 1 M KHSO4 solution. The aqueous phase was three
times extracted with ethyl acetate, and the combined organic phases
were dried over sodium sulfate. After filtration the solution was
concentrated in vacuo. An analytical sample was taken to determine
the selectivities, before the crude product was purified by flash
chromatography (hexanes/ethyl acetate).
General Procedure. Ru-catalyzed allylic alkylations of internal
tripeptide amide enolates were performed with 0.4 mmol of the allylic
substrate in oven-dried glassware (>100 °C) under a nitrogen
atmosphere.
Preparation of the Zn-Chelated Enolate. 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 (4 mL) in a Schlenk flask at −20 °C. The cooling bath was
removed, and stirring was continued for further 10 min before the
mixture was cooled again to −78 °C. In a second Schlenk flask a
mixture of N-protected tripeptide 8 (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 further 15 min.
Preparation of the Catalyst/Allylic Substrate Solution. The
ruthenium catalyst di-μ-chlorobis-(p-cymene)chlororuthenium (12.2
mg, 5 mol %) and triphenylphosphine (10.5 mg, 10 mol %) were
dissolved in THF (2 mL). After stirring for 10 min at room
temperature the allyl substrate (0.40 mmol) was added to the red
solution formed.
(S)-N-Methyl-leucine Anilide. To a stirred solution of (S)-N,N-
Boc-methyl-leucine anilide (3.20 g, 10.0 mmol) in CH2Cl2 (6 mL) was
slowly added trifluoroacetic acid (6 mL) at 0 °C. The reaction mixture
was stirred at rt for 16 h. The solvent was removed in vacuo, the
residue was dissolved in sat. NaHCO3 solution (20 mL) and extracted
twice with ethyl acetate (30 mL each). The combined organic layers
were washed with water and brine and dried over Na2SO4, and the
solvent was removed in vacuo. The title compound was obtained as
colorless oil (2.20 g, quant.) which crystallized on standing. [α]20
=
D
36.1° (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 0.96 (d, J =
6.4 Hz, 3 H), 0.98 (d, J = 6.4 Hz, 3 H), 1.45 (ddd, J = 13.6, 9.2, 5.4 Hz,
1 H), 1.50 (bs, 1 H), 1.63−1.79 (m, 2 H), 2.45 (s, 3 H), 3.09 (dd, J =
9.2, 4.5 Hz, 1 H), 7.09 (m, 1 H), 7.28−7.36 (m, 2 H), 7.60 (m, 2 H),
9.30 (bs, 1 H); 13C NMR (100 MHz, CDCl3): δ = 22.0, 25.1, 34.9,
42.2, 63.8, 119.5, 124.1 (d, C-9), 128.9, 137.8, 171.9; HRMS (CI) m/z
calcd for C13H21N2O [M + H]+: 221.1648; found: 221.1652. Analysis
calcd for C13H20N2O: C, 70.87, H, 9.15, N, 12.72; found: C, 71.03, H,
9.15, N, 12.59.
(S)-N-Trifluoroacetyl-phenylalanyl-glycyl-(S)-N-methyl-leu-
cine Anilide (9). To a solution of (S)-N-TFA-phenylalanyl-glycine
(637 mg, 2.00 mmol) was added (S)-N-methyl-leucine anilide (441
mg, 2.00 mmol) and N-methyl-morpholine (242 mg 2.40 mmol) in
The resulting mixture was added slowly to the chelated enolate at
−78 °C. The solution was allowed to warm up to room temperature
8494
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The Journal of Organic Chemistry
Note
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 and concentrated in vacuo, and the crude product was
purified by flash chromatography (hexanes/ethyl acetate).
CDCl3): δ = 27.8, 38.4, 52.0, 54.8, 56.4, 82.9, 115.5 (q, JF = 288 Hz),
118.1, 127.4, 127.5, 128.2, 128.7, 128.8, 129.3, 135.1, 136.0, 138.6,
156.6 (d, JF = 38.0 Hz), 168.9, 169.2. Minor diastereomer (S,2S,2R)-4c
1
(9%): H NMR (400 MHz, CDCl3, selected signals): δ = 1.22 (s, 9
tert-Butyl (S)-N-Trifluoroacetyl-phenylalanyl-(2R,3S)-(1-
methylallyl)glycinate (3a). By following the general procedure for
Ru-catalyzed allylic alkylation of dipeptide ester enolates, 3a (405 mg,
0.95 mmol, 95% yield) was obtained from allyl benzoate (S)-2d (176
mg, 1.00 mmol, 97% ee) and 1a (749 mg, 2.00 mmol) as a colorless
solid consisting of a mixture of mainly branched (97% rs),
diastereomeric allylation products with a diastereomeric ratio of
H), 3.50 (dd, J = 8.7, 8.7 Hz, 1H). Minor diastereomer (S,2R,3S)-5c
(6%): H NMR (400 MHz, CDCl3, selected signals): δ = 1.22 (s, 9
1
H), 3.56 (dd, J = 8.3, 8.3 Hz, 1H). The 1H and 13C NMR spectral data
of the minor linear regioisomers 7c and 8c were in good agreement
with the literature data.13b HPLC (Reprosil, n-hexane/iPrOH = 99:1,
1.0 mL/min, 210 nm): tR [(S,2S,3R)-4c] = 8.85′ (9%), tR [(S,2S,3S)-
6c] = 10.04′ (0%), tR [(S,2R,3S)- 5c] = 13.44′ (6%), tR [(S,2R,3R)-3c]
= 15.49′ (62%), tR [(S,S)-8c] = 18.76′ (4%), tR [(S,R)-7c] = 23.68′
(19%); HRMS (CI) m/z calcd for C26H30F3N2O4 [M + H]+:
491.2152; found: 491.2148.
74:20:3:0 in favor of the (S,2R,3S)-isomer. Mp 97−98 °C; [α]20
=
D
−11.4° (c = 1.0, CHCl3). Major diastereomer (S,2R,3S)-3a (74%): 1H
NMR (400 MHz, CDCl3): δ = 0.93 (d, J = 7.0 Hz, 3 H), 1.43 (s, 9 H),
2.49 (m, 1 H), 3.10 (m, 2 H), 4.43 (dd, J = 8.3, 4.6 Hz, 1 H), 4.73 (dt,
J = 7.9, 6.0 Hz, 1 H), 4.92 (ddd, J = 17.1, 1.3, 1.3 Hz, 1 H), 5.01 (ddd,
J = 10.3, 1.3, 1.3 Hz, 1 H), 5.55 (m, 1 H), 6.17 (d, J = 8.3 Hz, 1H),
7.29 (m, 5 H), 7.48 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ = 15.2,
28.0, 38.7, 40.4, 54.8, 56.6, 82.8, 115.6 (q, JF = 288 Hz), 116.2, 127.5,
128.9, 129.2, 135.5, 138.2, 156.6 (d, JF = 37 Hz), 169.0, 169.5. Minor
diastereomer (S,2S,3R)-4a (20%): 1H NMR (400 MHz, CDCl3,
selected signals): δ = 0.99 (d, J = 7.4 Hz, 1 H), 1.48 (s, 9 H), 2.69 (m,
1 H), 4.43 (dd, J = 8.3, 5.0 Hz, 1 H), 6.09 (d, J = 8.2 Hz, 1 H); 13C
NMR (100 MHz, CDCl3, selected signals): δ = 15.8, 39.1, 40.2, 54.7,
56.9, 82.6, 115.6 (q, JF = 288 Hz), 116.9, 128.8, 129.4, 135.2, 137.4,
169.0, 169.5; HPLC (Reprosil, n-hexane/iPrOH = 99:1, 1.0 mL/min,
210 nm): tR [(S,2S,3S)-4a] = 14.64′ (21%), tR [(S,2R,3S)-3a] = 21.61′
(79%); HRMS (CI) m/z calcd for C21H28F3N2O4 [M + H]+:
429.1996, found: 429.2007; Analysis calcd for C21H27F3N2O4: C,
58.87, H, 6.35, N, 6.54; found: C, 59.25, H, 6.56, N, 6.33.
tert-Butyl (S)-N-trifluoroacetyl-phenylalanyl-(2R,3S)-(1-
phenylallyl)glycinate (5c). Following the general procedure for
Ru-catalyzed allylic alkylation of dipeptide ester enolates 5c (390 mg,
0.80 mmol, 80% yield) was obtained from allyl acetate (S)-2c (176 mg,
1.00 mmol, 97% ee) and 1a (749 mg, 2.00 mmol) as a colorless solid
consisting of a mixture of mainly branched (84% rs), diastereomeric
allylation products with a diastereomeric ratio of 4:1:73:6 in favor of
the (S,2R,3S)-isomer. [α]20 = −32.3° (c = 1.0, CHCl3).
D
Major diastereomer (S,2R,3S)-5c (87%): 1H NMR (400 MHz,
CDCl3): δ = 1.22 (s, 9 H, 11-H), 3.06 (d, J = 6.9 Hz, 2 H), 3.57 (dd, J
= 8.4, 8.4 Hz, 1H), 4.73 (dt, J = 7.4, 7.4 Hz, 1 H), 4.75 (dd, J = 8.1, 8.1
Hz, 1 H), 5.11 (ddd, J = 16.8, 1.1, 1.1 Hz, 1 H), 5.12 (ddd, J = 9.5, 1.1,
1.1 Hz, 1 H), 5.84 (ddd, J = 16.8, 10.3, 8.8 Hz, 1 H), 6.25 (d, J = 7.1
Hz, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 7.28 (m, 10 H). 13C NMR (100
MHz, CDCl3): δ = 27.6, 38.4, 53.0, 54.6, 56.7, 82.5, 115.6 (q, JF = 288
Hz), 118.3, 127.4, 127.4, 128.3, 128.5, 128.8, 129.2, 135.2, 136.2,
138.7, 156.6 (d, JF = 38.2 Hz), 169.1, 169.5. Minor diastereomer
(S,2S,3S)-6c (6%): 1H NMR (400 MHz, CDCl3, selected signals): δ =
1.39 (s, 9 H), 3.69 (dd, J = 7.7, 7.7 Hz, 1H), 6.22 (d, J = 7.1 Hz, 1 H).
Minor diastereomer (S,2R,3R)-3c (4%): 1H NMR (400 MHz, CDCl3,
selected signals): δ = 1.36 (s, 9 H), 3.72 (dd, J = 7.8, 7.8 Hz, 1 H). The
1H and 13C NMR spectral data of the minor linear regioisomer 7c and
tert-Butyl (S)-N-Trifluoroacetyl-phenylalanyl-(2R,3S)-(1-
ethylallyl)glycinate (3b). By following the general procedure for
Ru-catalyzed allylic alkylation of dipeptide ester enolates, 3b (413 mg,
0.97 mmol, 97% yield) was obtained from allyl benzoate (S)-2b (190
mg, 1.00 mmol, 97% ee) and 1a (749 mg of 2.00 mmol) as a colorless
solid consisting of a mixture of mainly branched (95% rs),
diastereomeric allylation products with a diastereomeric ratio of
8c were in good agreement with the literature data.13b HPLC
(Reprosil, n-hexane/iPrOH = 99:1, 1.0 mL/min, 210 nm): tR
[(S,2S,3R)-4c] = 8.85′ (1%), tR [(S,2S,3S)-6c] = 10.04′ (6%), tR
[(S,2R,3S)-5c] = 13.44′ (73%), tR [(S,2R,3R)-3c] = 15.49′ (4%), tR
[(S,S)-8c] = 18.76′ (3%), tR [(S,R)-7c] = 23.68′ (13%); HRMS (CI)
m/z calcd for C26H30F3N2O4 [M + H]+: 491.2152; found: 491.2153;
Analysis calcd for C26H29F3N2O4): C, 63.66, H, 5.96, N, 5.71; found:
C, 63.79, H, 5.84, N, 5.76.
73:19:3:0 in favor of the (S,2R,3S)-isomer. Mp 77−81 °C; [α]20
=
D
−1.4° (c = 1.0, CHCl3). Major diastereomer (S,2R,3S)-3b) (73%): 1H
NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.4 Hz, 3 H), 1.24 (m, 2
H), 1.44 (s, 9 H), 2.02 (tdd, J = 9.8, 5.8, 5.8, Hz, 1 H), 3.12 (m, 2 H),
4.42 (dd, J = 8.4, 5.2 Hz, 1 H), 4.74 (m, 1 H), 4.85 (ddd, J = 17.0, 1.1,
1.1 Hz, 1 H), 5.05 (ddd, J = 10.2, 1.7, 1.7 Hz, 1 H), 5.39 (m, 1 H),
6.28 (d, J = 8.7 Hz, 1 H), 7.27 (m, 5 H), 7.65 (m, 1 H); 13C NMR
(100 MHz, CDCl3): δ = 11.7, 23.6, 28.0, 38.7, 49.0, 54.9, 55.8, 82.9,
115.6 (q, JF = 288 Hz), 118.4, 127.4, 128.9, 129.3, 135.4, 136.3, 156.7
(d, JF = 38 Hz), 169.0, 169.6. Minor diastereomer (S,2S,3S)-4b (19%):
1H NMR (400 MHz, CDCl3, selected signals): δ = 0.99 (t, J = 7.4 Hz,
tert-Butyl (S)-N-trifluoroacetyl-O-(tert-butyldiphenylsilyl)-
seryl-(2R,3R)-(1-phenylallyl)-glycinate (3d). Following the general
procedure for Ru-catalyzed allylic alkylation of dipeptide ester enolates
3d (447 mg, 0.67 mmol, 67% yield) was obtained from allyl acetate
(R)-2c (176 mg, 1.00 mmol, 98% ee) and 1b (718 mg, 1.30 mmol) as
a colorless solid consisting of a mixture of mainly branched (90% rs),
diastereomeric allylation products with a diastereomeric ratio of
1 H), 1.48 (s, 9 H), 2.69 (m, 1 H), 4.43 (dd, J = 8.3, 5.0 Hz, 1 H), 6.09
(d, J = 8.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3, selected signals): δ
= 11.6, 23.5, 28.0, 38.1, 49.0, 54.9, 55.8, 82.6, 118.6, 127.4, 128.7,
129.3, 135.2, 135.8, 169.4, 170.0; HPLC (Reprosil, n-hexane/iPrOH =
99:1, 1.0 mL/min, 210 nm): tR [(S,2S,3S)-4b] = 13.15′ (20%), ttR
[(S,2R,3S)-3b] = 20.48′ (74%), tR [(S,2R,3R)-5b] = 22.61′ (3%);
HRMS (CI) m/z calcd for C22H30F3N2O4 [M + H]+: 443.2152; found:
443.2150.
tert-Butyl (S)-N-Trifluoroacetyl-phenylalanyl-(2R,3R)-(1-
phenylallyl)glycinate (3c). By following the general procedure for
Ru-catalyzed allylic alkylation of dipeptide ester enolates, 3c (383 mg,
0.78 mmol, 78% yield) was obtained from allyl acetate (R)-2c (176
mg, 1.00 mmol, 99% ee) and 1a (749 mg 2.00 mmol) as a colorless
solid consisting of a mixture of mainly branched (77% rs),
diastereomeric allylation products with a diastereomeric ratio of
72:15:3:0 in favor of the (S,2R,3R)-isomer. Mp 48−50 °C; [α]20
−6.3° (c = 1.0, CHCl3).
=
D
Major diastereomer (S,2R,3R)-3d (72%): 1H NMR (400 MHz,
CDCl3): δ = 1.09 (s, 9 H), 1.39 (s, 9 H), 3.56 (dd, J = 10.4, 6.0 Hz, 1
H), 3.76 (dd, J = 8.8, 6.2 Hz, 1 H), 3.89 (dd, J = 10.4, 4.3 Hz, 1 H),
4.45 (ddd, J = 6.3, 6.3, 4.3 Hz, 1 H), 4.92 (dd, J = 8.9, 6.8 Hz, 1 H),
5.08−5.15 (m, 2 H), 6.04 (ddd, J = 16.8, 10.4, 8.5 Hz, 1 H), 6.55 (d, J
= 8.9 Hz, 1 H), 7.08−7.71 (m, 16 H); 13C NMR (100 MHz, CDCl3):
δ = 19.2, 26.8, 27.9, 52.6, 54.6, 56.4, 63.3, 82.8, 118.1, 127.3, 127.9,
128.1, 128.5, 130.2, 132.0, 132.4, 135.4, 135.5, 135.6, 136.0, 138.7,
167.5, 169.2. The signals of C-12 and C-13 were not found. LC-MS
(Luna C18(2) 5 cm, 3 μm, H2O/ACN = 40:60 to 20:80, 1.0 mL/min,
254 nm, ESI−): tR = 9.00′ (19%, m/z 667); tR = 9.97′ (81%, m/z 667);
HRMS (CI) m/z calcd for C36H44F3N2O5Si [M + H]+: 669.2966;
found: 669.2967; Analysis calcd for C36H43F3N2O5Si: C, 64.65, H,
6.48, N, 4.19; found C, 64.31, H, 6.23, N, 4.37.
62:9:6:0 in favor of the (S,2R,3R)-isomer. Mp 122−130 °C; [α]20
=
D
+10.1° (c = 1.0, CHCl3). Major diastereomer (S,2R,3R)-3c (62%): 1H
NMR (400 MHz, CDCl3): δ = 1.36 (s, 9 H), 2.93 (d, J = 6.8 Hz, 2 H),
3.71 (dd, J = 7.5, 7.5 Hz, 1H), 4.63 (dt, J = 7.4, 7.1 Hz, 1 H), 4.84 (dd,
J = 8.7, 6.5 Hz, 1 H), 5.07 (ddd, J = 17.0, 1.1, 1.1 Hz, 1 H), 5.17 (ddd,
J = 10.3, 1.1, 1.1 Hz, 1 H), 5.93 (ddd, J = 17.0, 10.3, 8.3 Hz, 1 H), 6.06
(d, J = 8.6 Hz, 1 H), 7.05−7.33 (m, 11 H). 13C NMR (100 MHz,
(S)-N-Trifluoroacetyl-phenylalanyl-(2R,3S)-(1-ethylallyl)-
glycyl-(S)-N-methyl-leucine Anilide (10). Following the general
procedure for Ru-catalyzed allylic alkylation of tripeptide ester enolates
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The Journal of Organic Chemistry
Note
10 (150 mg, 0.26 mmol, 64% yield) was obtained from allyl benzoate
(S)-2b (58, 0.40 mmol, 97% ee) and tripeptide 9 (208 mg, 0.40
mmol) as a colorless solid consisting of a mixture of diastereomeric
allylation products with a diastereomeric ratio of 97:3 in favor of the
(S,2R,3S,S)-isomer. Mp 65−69 °C; [α]20D = −96.0° (c = 1.0, CHCl3).
Major diastereomer (S,2R,3S,S)-10 (97%): 1H NMR (400 MHz,
CDCl3): δ = 0.79 (t, J = 7.4 Hz, 3 H), 0.89 (d, J = 6.5 Hz, 3 H), 0.96
(d, J = 6.7 Hz, 3 H), 1.22−1.52 (m, 3 H), 1.66 (ddd, J = 14.5, 10.1, 4.5
Hz, 1 H), 1.90 (ddd, J = 14.8, 9.8, 5.5 Hz, 1 H), 2.12 (dddd, J = 10.7,
8.3, 8.3, 3.0 Hz, 1 H), 3.08 (s, 3 H), 3.10−3.20 (m, 2 H), 4.63 (dd, J =
7.4, 7.4 Hz, 1 H), 4.77 (ddd, J = 7.8 Hz, 7.8, 6.0 Hz, 1 H), 5.01 (dd, J =
17.0, 1.2 Hz, 1 H), 5.11 (dd, J = 10.2, 1.5 Hz, 1 H), 5.27 (dd, J = 10.0,
5.4 Hz, 1 H), 5.47 (ddd, J = 17.0, 9.9, 9.9 Hz, 1 H), 6.71 (d, J = 6.9 Hz,
1 H), 7.08 (m, 1 H), 7.18 (m, 2 H), 7.25−7.33 (m, 5 H), 7.36 (d, J =
6.9 Hz, 1 H), 7.55 (m, 2 H), 8.28 (s, 1 H);13C NMR (100 MHz,
CDCl3): δ = 11.4, 21.5, 22.8, 23.3, 24.6, 31.4, 36.3, 38.4, 48.3, 53.2,
54.5, 56.2, 115.5 (q, JF = 288 Hz), 119.3, 120.0, 124.3, 127.5, 128.8,
128.9, 129.1, 135.3, 135.7, 137.8, 156.7 (q, JF = 38.1 Hz), 168.3, 170.0,
172.8;HPLC (Reprosil, n-hexane/iPrOH = 9:1 to 7:3, 40 min, 1 mL/
min, 252 nm): tR [(S,2S,3S,S)-10] = 13.03′ (3%), tR [(S,2R,3S,S)-10]
= 18.67′ (97%); HRMS (CI) m/z calcd for C25H33F3N3O4 [M −
PhNH2]+: 496.2423; found: 496.2412.
154.5, 156.6 (q, JF = 37.6 Hz), 168.2, 169.4, 172.3; HPLC (Reprosil, n-
hexane/iPrOH = 9:1 to 7:3, 40 min, 1 mL/min, 254 nm): tR [(S,S,S)-
12b] = 35.68′ (2%), tR [(S,R,S)-12b] = 40.11′ (98%); HRMS (CI) m/
z calcd for C31H37F3N3O6 [M − PhNH2]+: 604.2629; found:
604.2627.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Analytical data and copies of H and 13C NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: u.kazmaier@mx.uni-saarland.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Deutsche Forschungsgemein-
schaft (Ka 880/8-2).
■
(S)-N-Trifluoroacetyl-phenylalanyl-(R)-(2-(Z)-hexenyl)-glycyl-
(S)-N-methyl-leucine Anilide (12a). Following the general
procedure for Ru-catalyzed allylic alkylation of tripeptide ester enolates
12a (114 mg, 0.19 mmol, 47% yield) was obtained from allyl
phosphate (Z)-11a (95 mg, 0.40 mmol) and tripeptide 9 (208 mg,
0.40 mmol) as a colorless solid consisting of a mixture of linear,
diastereomeric allylation products with a diastereomeric ratio of 98:2
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signals): δ = 3.08 (s, 3 H), 4.86 (ddd, J = 7.6, 6.2, 6.2 Hz, 1 H), 6.57
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[(S,R,S)-12a] = 21.40′ (98%); HRMS (CI) m/z calcd for
C26H35F3N3O4 [M − PhNH2]+: 510.2574; found: 510.2563.
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noxy)-2-(Z)-butenyl)-glycyl-(S)-N-methyl-leucine Anilide (12b).
Following the general procedure for Ru-catalyzed allylic alkylation of
tripeptide ester enolates 12b (139 mg, 0.20 mmol, 50% yield) was
obtained from allyl phosphate (Z)-11b (132 mg, 0.40 mmol) and
tripeptide 9 (208 mg, 0.40 mmol) as a colorless solid consisting of a
mixture of linear, diastereomeric allylation products with a
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diastereomeric ratio of 98:2 in favor of the (S,R,S)-isomer. [α]20
=
D
1
−90.4° (c = 1.0, CHCl3). Major diastereomer (S,R,S)-12b (98%): H
NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 6.6 Hz, 3 H), 0.95 (d, J =
6.7 Hz, 3 H), 1.43 (m, 1 H), 1.66 (ddd, J = 14.6, 10.0, 4.8 Hz, 1 H),
1.90 (ddd, J = 14.6, 9.4, 5.5 Hz, 1 H), 2.37−2.54 (m, 2 H), 3.04 (s, 3
H), 3.06−3.12 (m, 2 H), 3.77 (s, 3 H), 4.41 (ddd, J = 12.0, 6.3, 0.8 Hz,
1 H), 4.49 (ddd, J = 11.8, 6.5, 1.1 Hz, 1 H), 4.68 (ddd, J = 7.6, 7.6, 6.2
Hz, 1 H), 4.74 (ddd, J = 7.7, 7.1, 7.0 Hz, 1 H), 5.28 (dd, J = 10.0, 5.5
Hz, 1 H), 5.46 (dt, J = 10.7, 8.3 Hz, 1 H), 5.89 (dt, J = 11.4, 6.3 Hz, 1
H), 6.80−6.95 (m, 4 H), 7.01 (d, J = 5.8 Hz, 1 H), 7.04−7.14 (m, 3
H), 7.20−7.35 (m, 6 H), 7.54−7.56 (m, 2 H), 8.29 (s, 1 H); 13C NMR
(100 MHz, CDCl3): δ = 21.7, 23.2, 24.9, 29.8, 31.1, 36.0, 38.4, 49.6,
54.4, 55.7, 56.1, 64.4, 114.9, 115.5 (q, JF = 288 Hz), 116.0, 119.9,
124.3, 127.5, 127.7, 128.8, 128.9, 129.2, 129.4, 135.1, 137.9, 152.2,
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