Synthesis of small tripeptide molecules through a catalysis sequence comprising metathesis and aminohydroxylation

Article abstract of DOI:10.1002/chem.200501123

Tripeptidic structures were synthesized by using a combination of two independent consecutive catalytic procedures. Cross-metathesis of N-acroyl amino acid esters yields fumaric amide compounds with exclusive E double-bond geometry. This represents an unp

Full text of DOI:10.1002/chem.200501123

DOI: 10.1002/chem.200501123
Synthesis of Small Tripeptide Molecules through a Catalysis Sequence
ComprisingMetathesis and Aminohydroxylation
Jan Streuff,[a, b] Martin Nieger,[c] and Kilian MuÇiz*[a, b]
Abstract: Tripeptidic structures were
synthesized by using a combination of
two independent consecutive catalytic
procedures. Cross-metathesis of N-
acroyl amino acid esters yields fumaric
amide compounds with exclusive E
double-bond geometry. This represents
an unprecedented example of complete
double-bond selectivity in this kind of
reaction transforms the central fumaric
amide unit into a hydroxy aspartic acid
moiety and relies on the inherent ster-
eochemistry of the starting fumaric dia-
mides. An additional feature of our se-
quence is the ease of generating stereo-
chemical diversification within the ami-
nohydroxylation reaction. As a conse-
quence, rapid conformational and
configurational diversification can be
achieved from the overall two-step cat-
alytic sequence. The versatility of this
approach is demonstrated by starting
from two different N-acroyl amino
esters, which led to the synthesis of
eight structurally and stereochemically
different tripeptides that could all be
identified individually. As such, the
present two-step catalytic approach
should serve to efficiently synthesize
large families of tripeptidic molecular
probes.
reaction.
A subsequent asymmetric
Keywords: amino acids
· amino-
aminohydroxylation of the chiral fuma-
ric amides was carried out without the
need of any further ligand and gave
high yields and no side products. This
AHCTREUNG
ysis · metathesis · organocatalysis ·
peptides
Introduction
entated synthesis.[3] The basic principle in this approach con-
sists of accessing complex and structurally diverse com-
pounds through defined organic synthesis procedures.
From this point of view, a sequence of different catalytic
transformations would definitely be a strategic asset toward
the realization of this goal. On the other hand, to target bio-
molecules or related chiral substances requires matching of
the stereochemistry between the target molecule itself and
the probe. Hence, there is a demand for stereochemical di-
versity within a given set of conformationally designed enti-
ties. Herein, we present a two-step sequence of catalytic
transformations that readily generates stereochemically di-
verse tripeptides through a sequence of two defined catalytic
processes.
Recent impressive advances in the area of chemical biology
rely on small organic molecules employed as probes for the
systematic exploration of biological functions.[1,2] To effi-
ciently address a given biological question, there is a
demand for the synthesis of configurationally and conforma-
tionally defined molecular entities. To this end, Schreiber
and co-workers have introduced the concept of diversity-ori-
[a] Dipl.-Chem. J. Streuff, Dr. K. MuÇiz
KekulØ-Institut für Organische Chemie und Biochemie
Rheinische Friedrich-Wilhelms-Universität
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[b] Dipl.-Chem. J. Streuff, Dr. K. MuÇiz
New address:
Such an approach is of importance since the synthesis of
natural peptides and novel peptide derivatives as well as the
study of their structural properties and their biological and
pharmaceutical evaluation[4] is of paramount importance for
modern society. In particular, evaluation of small peptidic
structures has recently emerged as a powerful tool for eluci-
dation of biological response.[5,6] Generally, these com-
pounds are obtained from iterative coupling of individual
amino acid entities upon the application of activating agents
and protecting groups.[4c,d] For the synthesis of peptides in-
corporating non-natural amino acids, the same sequential
Institut de Chimie
UniversitØ Louis Pasteur
4, rue Blaise Pascal, 67070 Strasbourg Cedex (France)
Fax : (+33)390-241-526
E-mail: muniz@chimie.u-strasbg.fr
[c] Dr. M. Nieger
Institut für Anorganische Chemie
Rheinische Friedrich-Wilhelms-Universität
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Chem. Eur. J. 2006, 12, 4362 – 4371

FULL PAPER
approach starting from the particular monomer is usually
employed.[7]
Recent impressive advances in the area of olefin metathe-
sis have led to the development of ruthenium- and molybde-
num-based catalysts that enable the construction of a broad
variety of alkenes within cross-metathesis.[10] To realize the
concept outlined in Figure 1, fumaroyl was chosen as spacer.
Fumaroyl should be accessible through catalytic homo-
cross-metathesis of acrylamides incorporating amino acids.
For this purpose a number of amino acids were condensed
with acryl chloride under stand-
To construct tripeptide derivatives, a sequence of two cat-
alytic processes[8] was envisioned consisting first of a cou-
pling of two amino acid units upon introduction of a prochi-
ral spacer. Asymmetric transformation of this spacer should
then create a new amino acid entity and thereby generate a
tripeptide molecule (Figure 1, left). This approach will be
ard conditions (CH2Cl2, NEt3,
room temperature), which fur-
nished the respective N-acroyl
amino acid esters 1a–f of ala-
nine, phenylalanine, valine, leu-
cine, tert-leucine, and b-alanine
(Scheme 1).
Acryl amides have not been
among the more popular sub-
strates for metathesis processes.
In fact, they were regarded as
rather problematic alkenes, and
to date there is only a single
report on their general use in
cross-metathesis with other al-
kenes.[11] First experiments re-
vealed that the desired homo-
cross-coupling of the acryloyl
alanine ester did not go to com-
pletion with the standard
Figure 1. Concept for tripeptide synthesis employing catalytic transformations: fundamental two-step sequence
(left), diversity-generating processes (right).
particularly valuable in generating structures that contain
non-natural amino acids and that are not readily accessible
through conventional coupling. As another important fea-
ture, the final catalytic transformation may generate more
than a single stereoisomer leading to several enantiopure tri-
peptides due to the initial amino acid residues (Figure 1,
right). Such a modular approach should therefore meet the
criteria for stereochemical diversity[5] if we intentionally
choose substrates or catalysts that bring about the formation
of more than a single stereoisomeric product. As such, com-
plete configurational diversity should be feasible for those
Scheme 1. Synthesis of N-acroyl amino esters.
processes that produce all stereochemically possible amino
acid entities at once. Thus, a potential application in biologi-
cal screening processes will be able to evaluate all absolute
configurations.
Grubbs catalyst [(PCy3)2RuCl2=CHPh]. However, the corre-
sponding second-generation catalyst 2 containing an N-het-
erocyclic carbene substituent proved to be highly efficient
and, at 2.5 mol% loading, induced the formation of the de-
sired fumaric amides (Scheme 2, Table 1).
Results and Discussion
In general, the homo-cross-metathesis reaction with cata-
lyst 2 proceeded smoothly in refluxing dichloromethane and
yielded the respective fumaroyl-linked amino acid products
3a–f in good to excellent yields (Scheme 2). In particular,
the respective products from alanine and phenylalanine
gave quantitative conversion under these conditions and 94–
97% isolated yield (Table 1, entries 1,2). Other examples
led to incomplete yields after a reaction time of 10 h with
To achieve our goal olefin metathesis was chosen for the
first transformation. Over the years, olefin metathesis has
developed into one of the most broadly applicable tools in
synthesis. For their outstanding contributions to the initia-
tion and the development of olefin metathesis, Chauvin,
Grubbs, and Schrock were awarded the Nobel Prize in
Chemistry in 2005.[9]
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4363

K. MuÇiz et al.
conversion.[13] Transformation
of products 3a–f into peptidic
structures requires nitrogen in-
corporation. Recent advances
in the aminohydroxylation[14] of
unsaturated esters have led to
the synthesis of various serine
and isoserine derivatives, of
which the side chain of Pacli-
taxel represents the most prom-
inent example.[15] Still, this reac-
tion generates amino acid mon-
omers that require elaboration
within the usual coupling proc-
esses. On the other hand, unsa-
Scheme 2. Synthesis of amino-acid-incorporated fumaric amides through catalytic homo-cross-coupling.
turated amides represent
a
unique class of starting compounds for Sharpless aminohy-
droxylation within the so-called second catalytic cycle. This
reaction forms serine and isoserine amides in racemic form
only and due to the specific oxidation conditions of second
cycle catalysis cannot be carried out enantioselectively.[16,17]
However, the realization of an aminohydroxylation reac-
tion course toward chiral non-racemic molecules should in
principle be feasible by the use of an enantiopure a,b-unsa-
turated starting material as is the case for 3a–e. A catalytic
cycle will begin with an aminohydroxylation to give an os-
ma(vi)azaglycolate A, which subsequently functions as a cat-
alyst (Scheme 3). Reoxidation to compound B with a central
Table 1. Cross-metathesis of N-acroyl amino esters.
Entry Substrate/amino
acid
R
R’
Product Yield[%]
1[a,b]
2[a,b]
3[a]
1a/alanine
1b/phenylalanine CH2
1c/leucine
1d/valine
CH3
CH3
CH2CH3 3b
CH3
3a
94
A
97
CH
A
3c
3d
3e
79 (92)[c]
80 (89)[c]
74 (84)[c]
4[a]
ACHTREUNG
5[a]
1e/tert-leucine
C
ACHTREUNG
[a] Reactions were carried out on a 1 mmol scale with 2.5 mol% of cata-
lyst 2 in dichloromethane (2m solution), at 408C and for 10 h. [b] Re-
action time of 4 h. [c] Estimated conversion according to the 1H NMR
spectrum of the crude reaction mixture.
the remaining starting material in the range of 8–15% as es-
timated from the 1H NMR spectra of the crude material
(Table 1, entries 4,5 and 35% in the formation of product
3 f from b-alanine incorpora-
osmium(viii) atom occurs with the nitrenoid chloramine-T.
Then, subsequent aminohydroxylation of another fumaric
amide occurs resulting in the formation of a bisazaglycolate
A
tion). In these cases, analytical-
ly pure products 3d–f were ob-
tained directly through crystalli-
zation from the reaction mix-
ture or after column chroma-
tography.[12] Importantly, all
products were obtained as pure
fumaric amides, that is, with
complete
E
selectivity with
regard to the newly established
C=C double bond. Given the
usual reversibility of transition-
metal-catalyzed metathesis, this
rarely observed complete selec-
tivity may be attributed to the
high insolubility of the product
in the reaction solvent. Alterna-
tively, a decisive influence of
the amide group on the final E/
Z selectivity through additional
interaction with the metal
Scheme 3. Catalytic cycle for expected oxidative transformation of fumaric amides 3 into tripeptides 4,5.
center cannot be ruled out at the present stage.
C. One tripeptidic product is released by hydrolysis and aza-
glycolate A is regenerated.
Any stereoselection in conventional second-cycle catalysis
relies solely on the remote chiral information of glycolate
The catalytic metathesis step with its well-defined product
formation poses the interesting question on subsequent use
of the products as starting materials for oxidative alkene
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Stereochemically Diverse Tripeptides
FULL PAPER
and azaglycolate ligands, respectively. In view of the gener-
ally observed low induction in the step to produce C from
B, the formation of diastereomeric mixtures at stage C
arises. We previously discussed the impossibility for high
stereoselectivity in self-replication processes of related
second-cycle catalysis and therefore expected the formation
of both stereoisomers for the present aminohydroxylation
reaction of 3a–e.[18,19] Such a result is well-suited for the
present purpose of a stereodiversified peptide synthesis. The
synthesis has been achieved for enantiopure fumaric amides
3a–e incorporating amino acid residues, which upon amino-
hydroxylation directly and exclusively yield two diastereo-
meric tripeptides with hydroxy aspartic acid incorporated as
bridging entity (Scheme 4).
acid, b-amino acid, a-hydroxy, and b-hydroxy acid, respec-
tively. To our surprise, no X-ray data on a small organic
molecule incorporating the structural connection present
here was available from the CCDC.[21] Therefore, the major
isomer from aminohydroxylation of fumaric amide 3c was
crystallized and its absolute S,S,S,S configuration was unam-
biguously established by X-ray analysis (Figure 2).
The asymmetric unit contains four independent molecules
that differ in the respective orientation of their leucine
units. As a common motif there is a single intramolecular
hydrogen bond present, which is located between the OH
group of the central b-hydroxyl aspartic acid moiety and the
ester group of a valine terminus producing a nine-membered
helical arrangement. While for three of the molecules this
connects to the carbonyl group
(Figure 2, top), the remaining
structure shows
a
hydrogen
bridge to the methoxy group
(Figure 2, bottom). This intra-
molecular hydrogen bridge be-
tween the OH group of the
newly generated amino acid
and the ester of one valine unit
determines the overall structure
of the molecule. All remaining
Scheme 4. Asymmetric aminohydroxylation of chiral fumaric amides.
In all cases, quantitative conversion was achieved and no
products other than the expected b-hydroxy aspartic acid
derivatives were observed. Depending on the original amino
acid residues, different diastereomeric ratios (d.r.) were ob-
served that ranged from 55:45–85:15 (Table 2). As expected
Table 2. Aminohydroxylation of amino acid based fumaric amides.
Entry
Substrate
Products
Conversion[%][a]
d.r.[b]
1
2
3
4
5
3a
3b
3c
3d
3e
4a, 5a
4b, 5b
4c, 5c
4d, 5d
4e, 5e
>99
>99
>99
>99
>99
67:33
62:38
85:15
55:45
58:42
[a] Determined by 1H NMR spectroscopy and TLC. [b] Determined by
1H NMR spectroscopy of the crude reaction mixture.
from the literature,[16] the usually employed chiral cinchona
alkaloid ligands[14] did not influence the diastereomeric
ratios. The incomplete stereoselectivity was expected for the
present project, since product diversification demands the
formation of diastereomeric mixtures.[20] For the purpose of
full characterization, all product mixtures 4/5 could be readi-
ly separated, either by conventional silica-gel column chro-
matography or by semi-preparative HPLC on a silica-gel
phase.
b-Hydroxy aspartic acid with its particular functional
groups represents a structural chimera classified as a-amino
Figure 2. Solid-state structure of (S,S,S,S)-4c. Two of four independent
molecules from the asymmetric unit.
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K. MuÇiz et al.
hydrogen bonds are intermolecular bridging bonds resulting
in a typical b-sheet arrangement. Figure 3 displays the cen-
tral entity of the four independent molecules. Two molecules
the reaction of fumaric amides with differentiation with
regard to the absolute amino acid configuration or the
amino acid residues themselves.
To demonstrate the high potential of this approach, we
conducted a cross-metathesis of N-acryl alanine and N-acryl
leucine, which furnished all three different fumaric amides
in the expected statistical ratio of 1:1:2. Subsequent amino-
hydroxylation of the three unseparated compounds then led
to formation of a mixture of all eight possible different tri-
peptides within a single aminohydroxylation step, which
could be identified unambiguously by HLPC analysis
(Scheme 5).[24]
Again, the individual components could be characterized
by starting from the isolation of the mixed fumaric amide 6.
Subsequent aminohydroxylation of the asymmetric fumaric
amide 6 led to complete conversion with no detection of
side products. As expected, all four possible isomers 7a–d
were obtained in a 38:12:38:12 ratio and could be conven-
iently separated (Scheme 6).
After having obtained the respective tripeptide from the
oxidations of 3a and 3c (Table 2, entries 1 and 3), all eight
Figure 3. Intermolecular-hydrogen-bonding
pattern
for
[(S,S,S,S)-
4c]4·acetone.
are connected to form an anti-
parallel sheet structure through
six intermolecular hydrogen
À
bonds. These involve five N H
À
and one O H moieties.
A
common observation is that the
involvement of the latter ren-
ders the intermolecular hydro-
gen bonds to be of bifocal char-
acter.[22] The resulting two sheet
structures are again orientated
in an antiparallel fashion to-
wards each other through two
À
additional NH OC bonds.
These examples of generating
enantiomerically pure com-
pounds 4a–d and 5a–d prove
that structural diversification of
small molecules based on tri-
peptides is quite possible within
two consecutive catalytic trans-
formations. In addition, the
asymmetric aminohydroxylation
relies on the inherent stereo-
chemical information provided
by the amino acid residues
from the fumaric amide sub-
strates. Thus, no further source
of chirality is required, which
renders the present conversion
highly economical.[23] In princi-
ple, an even higher diversifica-
Scheme 5. Generation of eight different tripeptides from sequential catalytic transformation of two N-acroyl
tion should be possible from amino esters.
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Stereochemically Diverse Tripeptides
FULL PAPER
was set under argon atmosphere. The
second-generation Grubbs catalyst
(0.05 equiv) was dissolved in absolute
dichloromethane and the N-substitut-
ed acrylic amide was added to the
dark violet solution (2.00 equiv,
[amide]ꢀ0.5 mmolmLÀ1). The mixture
was refluxed for about 6 h and the
metathesis reaction initiated after
a
couple of minutes. When the reaction
was finished (TLC control), the sol-
vent was removed under reduced pres-
sure and the conversion was estimated
by NMR measurements performed on
the crude material. The crude precipi-
tate was purified by recrystallization
from dichloromethane/hexanes unless
otherwise stated. The products were
usually obtained as a white solid.
Representative procedure B for ami-
nohydroxylation: The fumaric acid di-
amide (1.00 equiv) was suspended in a
mixture of tBuOH/H2O (1:1) and
Chloramine-T hydrate (1.10 equiv)
Scheme 6. Synthesis of tripeptides from mixed fumaric amide 6.
tripeptides from aminohydroxylation of the unseparated re-
action mixture from metathesis could thus be isolated and
characterized.
was added. After a few minutes of stirring, K2[OsO2(OH)4] (0.03 equiv)
N
was added and stirring was continued until the reaction was complete
(controlled by TLC). A small amount of saturated Na2S2O3 solution was
added to quench the reaction and stirring was continued for 20 min. The
mixture was extracted several times with CH2Cl2 and the combined or-
ganic layers were dried over MgSO4. The solvent was removed under re-
duced pressure and an NMR spectrum of the crude yellow-white product
was taken to calculate the diastereomeric excess. The stereoisomers were
separated by flash chromatography and/or semi-preparative HPLC chro-
matography as specified in the procedures.
Conclusions
We have described a two-step catalytic process leading to
the preparation of chiral, optically active tripeptides within
two consecutive catalytic reactions and in high overall
yields. The formation of the additional stereogenic centers
relies solely on the inherent stereochemistry of the incorpo-
rated amino acids and represents the proof of principle for
this new conceptual approach in peptide synthesis. More-
over, it can be used as a powerful synthesis tool to promote
stereochemical diversity in the generation of novel peptides,
both as individual compounds in an analytically pure form
and as diversified mixtures for potential biological screen-
ing.
Representative procedure C for the synthesis of N-monosubstituted acryl
amides: A flame-dried Schlenk flask was equipped with a magnetic stir-
rer bar and set under argon atmosphere, then freshly distilled dichloro-
methane (100 mL) and triethylamine (6.23 mL, 45 mmol, 4.5 equiv) were
added. The primary amine (1.0 equiv, 10 mmol) was dissolved in this mix-
ture and the solution was cooled down to À108C. Then acroyl chloride
(1.22 mL, 15 mmol, 1.5 equiv) was added dropwise. The solution was al-
lowed to warm to room temperature and was stirred for 4 h. The color of
the solution changed from a light green-yellow to orange-red. The reac-
tion was quenched by the addition of HCl solution and additional wash-
ing with HCl (3.5%), and the separated organic layer was washed several
times with saturated Na2CO3 solution. The organic phase was dried over
MgSO4 and the solvent was removed under reduced pressure. The crude
product was purified by flash chromatography when necessary.
Experimental Section
(S)-N-1-Methoxycarbonylethylacrylamide (N-acryloyl-l-alanine methyl
ester) (1a):[25]
1H and 13C NMR spectra were measured on a Bruker DPX 300 MHz or a
Bruker DPX 400 MHz spectrometer. The 1H and 13C NMR chemical
shifts were referenced to the solvent signals (1H NMR: CDCl3 =7.26,
[D6]DMSO=2.49, [D4]methanol=3.30 ppm. 13C NMR: CDCl3 =77.00,
[D6]DMSO=39.50, [D4]methanol=49.00 ppm). The mass spectra and the
high-resolution mass spectra were measured on a Kratos MS50 mass
spectrometer. The polarization angle was obtained by using a Perkin–
Elmer PE-241 polarimeter. All measurements were obtained at room
temperature by using a Na-lamp with a wavelength at 589 nm. The
Compound 1a was synthesized according to general procedure C.
1H NMR (400 MHz, CDCl3): d=1.43 (d, J=7.1 Hz, 3H), 3.75 (s, 3H),
4.68 (m, 1H), 5.66 (ddd, J1 =10.4 Hz, J2 =1.5 Hz, J3 =0.8 Hz, 1H), 6.12
(dd, J1 =16.9 Hz, J2 =10.4 Hz, 1H), 6.29 ppm (dd, J1 =16.9 Hz, J2 =
1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=18.49, 48.03, 52.48, 127.00,
130.39, 164.82, 173.51 ppm.
(S)-N-1-Ethoxycarbonyl-2-phenylethylacrylamide (N-acryloyl-l-phenyla-
lanine ethyl ester) (1b):[26] Compound 1b was synthesized according to
general procedure C.
sample length was d=10 cm and the concentration is given in g mLÀ1
.
1H NMR (400 MHz, CDCl3): d=1.18 (t, J=7.1 Hz, 3H), 3.10 (dd, J1 =
5.6 Hz, J2 =2.3 Hz, 2H), 4.11 (dq, J1 =7.1 Hz, J2 =1.0 Hz, 2H), 4.87 (td,
J1 =5.6 Hz, J2 =7.8 Hz, 1H), 5.59 (dd, J1 =10.4 Hz, J2 =1.3 Hz, 1H), 6.02
(dd, J1 =16.9 Hz, J2 =10.4 Hz, 1H), 6.21 (dd, J1 =16.9 Hz, J2 =1.3 Hz,
1H), 7.03 (m, 2H), 7.19 ppm (m, 3H); 13C NMR (75 MHz, CDCl3): d=
14.09, 37.91, 53.18, 61.58, 127.06, 127.09, 128.49, 129.35, 130.39, 135.81,
164.84, 171.47 ppm.
HPLC determinations and separations were carried out on a Knauer
Wellchrome instrument (injection valve A0258, pump K-100, solvent or-
ganiser K-1500, UV-detector K-2600) by using Eurosphere columns as
standard columns for semi-preparative separations.
General procedures
Representative procedure A for cross-metathesis: A flame-dried Schlenk
flask was equipped with a magnetic stirrer bar, a reflux condenser, and
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K. MuÇiz et al.
(S)-N-1-Methoxycarbonyl-2-isopropylethylacrylamide (N-acryloyl-l-leu-
cine methyl ester) (1c): Compound 1c was synthesized according to gen-
eral procedure C.
[a]2D3 =À29 (c=0.14, DMSO); 1H NMR (300 MHz, [D6]DMSO): d=1.10
(t, J=7.0 Hz, 6H), 2.90 (dd, J1 =14,0 Hz, J2 =9.1 Hz, 2H), 3.05 (dd, J1 =
14.0 Hz, J2 =5.8 Hz, 2H), 3.14 (quin, J=1.6 Hz, 2H), 4.03 (q, J=7.2 Hz,
4H), 4.55 (dd, J1 =9.1 Hz, J2 =5.8 Hz, 2H), 6.80 (s, 2H) 7.14–7.24 ppm
(m, 10H); 13C NMR (75 MHz, [D6]DMSO): d=14.10, 54.60, 61.35,
127.16, 128.80, 129.57, 133.14, 137.60, 164.53, 171.74 ppm; IR (KBr): n˜ =
3311, 3064, 3030, 2978, 1736, 1630, 1539, 1377, 1354, 1201, 1119, 1024,
698 cmÀ1; MS(EI): m/z (%): 466.2 [M]+, 421.1 (35), 393.1 (65), 375.1
(15), 350.2 (20), 304.2 (1), 291.1 (3), 290.1 (10), 274.1 (25), 246.1 (2),
228.0 (2), 217.1 (4), 200.0 (30), 182.0 (5), 177.1 (15), 176.1 (100), 148.0
(8), 131.0 (12), 120.1 (30), 103.0 (8), 91.0 (15), 82.0 (6); HRMS: m/z calcd
for C26H30N2O6: 466.2104; found: 466.2111.
[a]2D5 =À34.9 (c=1.00, acetone); 1H NMR (300 MHz, CDCl3): d=0.93
(dd, J1 =6.4 Hz, J2 =4.2 Hz, 6H), 1.50–1.71 (m, 3H), 3.73 (s, 3H), 4.72
(td, J1 =8.5 Hz, J2 =5.1 Hz, 1H), 5.65 (dd, J1 =10.2 Hz, J2 =1.7 Hz, 1H),
6.12 (dd, J1 =17.0 Hz, J2 =10.2 Hz, 1H), 6.29 ppm (dd, J1 =17.0 Hz, J2 =
1.7 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=21.95, 22.72, 24.85, 41.77,
50.69, 52.27, 127.04, 130.34, 165.12, 173.58 ppm; IR (KBr): n˜ =3272, 3067,
2958, 2914, 2873, 1749, 1659, 1630, 1547, 1255, 1209, 1153, 985 cmÀ1; MS
(EI): m/z (%): 199.2 [M]+, 184.1 (2), 168.1 (2), 156.1 (3), 143.1 (16),
140.1 (100), 124.1 (4), 111.1 (10), 98.1 (4), 86.1 (75), 84.1 (6), 72.1 (4),
59.1 (2), 55.1 (62); HRMS: calcd: 199.1208; found: 199.1212.
N,N’-Bis[(S)-1-methoxycarbonyl-1-isobutylmethyl]fumaric diamide (3c):
Compound 3c was synthesized according to general procedure A with
0.025 equivalents of catalyst. The crude product was purified by flash
chromatography (CH2Cl2/EtOAc 1:1, 79% yield).
(S)-N-1-Methoxycarbonyl-2,2-dimethylethylacrylamide
(N-acryloyl-l-
valine methyl ester) (1d):[25b] Compound 1d was synthesized according to
general procedure C.
[a]2D3 =À62 (c=0.23, MeOH); 1H NMR (300 MHz, CDCl3): d=0.94 (dd,
J1 =6.2 Hz, J2 =1.9 Hz, 12H), 1.50–1.74 (m, 6H), 3.75 (s, 6H), 4.73 (dt,
J1 =8.7, J2 =4.7 Hz, 2H), 6.61 (d, J=8.7 Hz, 2H), 6.90 ppm (s, 2H);
13C NMR (75 MHz, CDCl3): d=21.87, 22.80, 24.92, 41.48, 51.04, 52.46,
133.11, 163.77, 173.49 ppm; IR (KBr): n˜ =3548, 3467, 3417, 3319, 3062,
2960, 2889, 1753, 1738, 1635, 1535, 1439, 1280, 1255, 1185, 997 cmÀ1; MS
(EI): m/z (%): 370.2 [M]+, 355.2 (5), 339.2 (5), 311.2 (100), 226.1 (40),
183.1 (5), 166.1 (25), 146.1 (8), 124.0 (10), 110.0 (10), 98.0 (8), 86.1 (56),
69.1 (10); HRMS: m/z calcd for C18H30N2O6: 370.2104; found: 370.2111.
1H NMR (300 MHz, CDCl3): d=0.91 (dd, J1 =8.1 Hz, J2 =6.8 Hz, 6H),
2.15 (m, 1H), 3.71 (s, 3H), 4.62 (dd, J1 =8.9 Hz, J2 =5.1 Hz, 1H), 5.63
(dd, J1 =10.0 Hz, J2 =1.9 Hz, 1H), 6.15 (dd, J1 =17.0 Hz, J2 =10.0 Hz,
1H), 6.30 ppm (dd, J1 =17.0 Hz, J2 =1.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=17.81, 18.82, 31.33, 52.05, 57.02, 126.93, 130.42, 165.27,
172.48 ppm.
(S)-N-1-Methoxycarbonyl-1-tert-butylmethyl-acrylamide
(N-acryloyl-l-
tert-leucine methyl ester) (1e): Compound 1e was synthesized according
to general procedure C. The crude product was purified by flash chroma-
tography (EtOAc/hexanes 1:1, 80% isolated yield). [a]2D3 =À37.5 (c=
N,N’-Bis[(S)-1-methoxycarbonyl-1-iso-propyl-methyl]fumaric
diamide
(3d): Compound 3d was synthesized according to general procedure A
with 0.05 equivalents of catalyst. The crude product was dissolved in
CH2Cl2 and hexanes were added to cause precipitation. The white solid
was filtered off and purified by flash chromatography (ethyl acetate) to
separate it from the remaining ruthenium salts (80% yield).
[a]2D3 =À50.7 (c=0.44, methanol); 1H NMR (300 MHz, [D4]methanol):
d=0.96 (dd, J1 =6.8 Hz, J2 =1.3 Hz, 12H), 2.17 (heptet, J=6.8 Hz, 2H),
3.72 (s, 6H), 4.41 (d, J1 =6.0 Hz, 2H), 7.04 ppm (s, 2H); 13C NMR
(75 MHz, [D4]methanol): d=18.52, 19.43, 31.85, 52.53, 59.66, 133.97,
166.80, 173.21 ppm; IR (KBr): n˜ =3298, 3070, 2968, 1741, 1639, 1547,
1437, 1356, 261, 1207, 1196, 991 cmÀ1; MS(EI): m/z (%): 342.2 [M]+,
283.1 (100), 229.1 (12), 212.1 (38), 169.1 (17), 152.0 (40), 132.1 (6), 98.0
(10), 82.0 (10), 72.1 (50); HRMS: m/z calcd for C16H26N2O6: 342.1791;
found: 342.1794.
1
0.49, MeOH); H NMR (300 MHz, CDCl3): d=0.99 (s, 9H), 3.73 (s, 3H),
4.57 (d, J=9.4 Hz, 1H), 5.68 (dd, J1 =10.1 Hz, J2 =1.5 Hz, 1H), 6.07 (brs,
1H; NH), 6.15 (dd, J1 =17.0 Hz, J2 =10.1 Hz, 1H), 6.30 ppm (dd, J1 =
17.0 Hz, J2 =1.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=26.54, 35.00,
51.83, 59.86, 127.12, 130.52, 165.09, 172.12 ppm; IR (KBr): n˜ =3301, 3062,
3034, 2968, 2910, 2875, 1743, 1654, 1619, 1544, 1413, 1261, 1238, 1219,
1162, 1115, 991 cmÀ1; MS(EI): m/z (%): 199.1 [M]+, 184.1 (2), 168.1 (2),
156.1 (0), 152.0 (6), 143.0 (100), 140.1 (20), 124.1 (4), 111.0 (84), 97.0 (2),
86.1 (30), 83.0 (16), 73.1 (2), 70.1 (4), 57.1 (18), 55.0 (36); HRMS: m/z
calcd: 143.0582 [M+ÀC
ACHTREUNG
N-2-Methoxycarbonylethylacrylamide
methyl
ester) (1 f): Compound 1 f was synthesized according to general proce-
dure C.
1H NMR (300 MHz, CDCl3): d=2.53 (t, J=6.0 Hz, 2H), 3.53 (psq, J=
6.0 Hz, 2H), 3.63 (s, 3H), 5.55 (dd, J1 =10.0 Hz, J2 =1.9 Hz, 1H), 6.06
(dd, J1 =17.0 Hz, J2 =10.0 Hz, 1H), 6.20 (dd, J1 =17.0 Hz, J2 =1.9 Hz,
1H), 6.56 ppm (br, 1H); 13C NMR (75 MHz, CDCl3): d=33.61, 34.83,
51.61, 126.18, 130.73, 165.50, 172.77 ppm; IR (KBr): n˜ =3284, 3074, 2954,
1738, 1660, 1628, 1549, 1439, 1244, 1200, 1178, 1084, 987 cmÀ1; MS(EI):
m/z (%): 157.1 [M]+, 126.1 (16), 102.1 (56), 98.1 (16), 88.1 (4), 86.0 (8),
84.1 (35), 72.1 (5), 70.1 (10), 59.1 (4), 55.1 (100); HRMS: m/z calcd:
157.0739; found: 157.0740.
N,N’-Bis[(S)-1-methoxycarbonyl-2,2-dimethylpropyl]fumaric
diamide
(3e): Compound 3e was synthesized according to general procedure A
with 0.025 equivalents of catalyst. The crude product was purified by re-
crystallization from CH2Cl2/hexanes (73.5% isolated yield).
[a]2D3 =À34 (c=0.65, MeOH); 1H NMR (300 MHz, CDCl3): d=1.00 (s,
18H), 3.74 (s, 6H), 4.59 (d, J=9.4 Hz, 2H), 6.36 (d, J=9.4 Hz, 2H),
6.95 ppm (s, 2H); 13C NMR (75 MHz, CDCl3): d=26.54, 35.15, 51.96,
60.25, 133.30, 163.61, 171.60 ppm; IR (KBr): n˜ =3550, 3475, 3413, 2966,
2916, 2875, 1741, 1639, 1533, 1369, 1230, 1188, 1169 cmÀ1; MS(EI): m/z
(%): 355.1 [M+ÀCH3], 339.1 (4), 314.1 (10), 311.1 (12), 227.0 (100), 195.0
(4), 167.0 (8), 146.0 (5), 98.0 (5), 86.0 (8), 69.0 (4), 57.1 (4); HRMS: m/z
calcd for C17H27N2O6: 355.1869; found: 355.1875.
N,N’-Bis[(S)-1-methoxycarbonylethyl]fumaric diamide (3a): Compound
3a was synthesized according to general procedure A with 0.05 equiv-
alents of catalyst. The crude product was purified by recrystallization
from CH2Cl2/hexanes (94% yield).
N,N’-Bis(2-methoxycarbonylethyl)fumaric diamide (3 f): Compound 3 f
was synthesized according to general procedure A with 0.05 equivalents
of catalyst. The crude product was purified by recrystallization from
CH2Cl2/hexanes (62% yield).
1H NMR (300 MHz, [D6]DMSO): d=2.56 (t, J1 =6.8 Hz, 6H), 3.36 (dt,
J1 =6.8 Hz, J2 =5.7 Hz, 4H), 3.59 (s, 6H), 6.77 (s, 2H), 8.47 ppm (t, J=
5.7 Hz, 2H); 13C NMR (75 MHz, [D6]DMSO): d=33.34, 34.90, 51.32,
132.40, 163.70, 171.52 ppm; IR (KBr): n˜ =3259, 3080, 2958, 1726, 1626,
1562, 1441, 1346, 1194, 1174, 1088, 976, 887 cmÀ1; MS(EI): m/z (%):
286.1 [M]+, 257.1 (2), 255.1 (56), 227.1 (10), 213.0 (10), 195.0 (2), 185.0
(100), 171.0 (2), 157.0 (3), 156.0 (8), 152.0 (46), 127.0 (4), 125.0 (10),
110.0 (62), 102.0 (54), 98.0 (10), 81.9 (14), 70.0 (8), 55.0 (15); HRMS: m/z
calcd for C12H18N2O6: 286.1165; found: 286.1164.
[a]2D3 =À44 (c=0.1, DMSO); 1H NMR (300 MHz, [D6]DMSO/
[D4]methanol): d=1.30 (d, J=7.2 Hz, 6H) 3.62 (s, 6H) 4.35 (qd, J1 =
7.2 Hz, J2 =7.2 Hz, 2H), 6.87 (s, 2H) 8.81 ppm (d, J=7.2 Hz, 2H);
13C NMR (75 MHz, [D6]DMSO/[D4]methanol): d=16.80, 47.75, 51.87,
132.49, 163.36, 172.65 ppm; IR (KBr): n˜ =3304, 3080, 3066, 3049, 2999,
2954, 2935, 2885, 2852, 1734, 1630, 1554, 1539, 1456, 1358, 1338, 1279,
1227, 1198, 1119, 1057, 991, 688, 667 cmÀ1; MS(EI): m/z (%): 286.1 [M]+,
255.1 (4), 227.1 (100), 184.0 (30), 125.0 (8), 124.0 (60), 96.0 (3), 82.0 (4),
70.0 (4), 59.0 (3); HRMS: m/z calcd for C12H18N2O6: 286.1165; found:
286.1169.
N,N’-Bis[(S)-1-(ethoxycarbonyl)-2-phenylethyl]fumaric diamide (3b):
Compound 3b was synthesized according to general procedure A with
0.05 equivalents of catalyst. The crude product was purified by recrystalli-
zation from CH2Cl2/hexanes (97% yield).
N,N’-Bis[(S)-1-methoxycarbonylethyl]-(2S,3S)-3-hydroxy-2-(tosylamino)-
succinic diamide (5a) and N,N’-bis[(S)-1-methoxycarbonylethyl]-
4368
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 4362 – 4371

Stereochemically Diverse Tripeptides
FULL PAPER
(2R,3R)-3-hydroxy-2-(tosylamino)succinic diamide (4a): Compound 4a
was synthesized according to general procedure B. Stereoisomer 1 was
isolated by recrystallization from methanol. The NMR data for stereo-
isomer 2 were deduced from the NMR data of the remaining mixture
that was enriched in stereoisomer 2.
tion of the isomers was achieved by flash chromatography (CH2Cl2/
EtOAc 2:1).
N,N’-Bis[(S)-1-methoxycarbonylisobutylmethyl]-(2R,3R)-3-hydroxy-2-
(tosylamino)succinic diamide (4c): [a]2D3 =+7 (c=0.5, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d=0.91 (m, 12H), 1.58 (m, 6H), 2.42 (s, 3H), 3.72 (s,
3H), 3.73 (s, 3H), 4.05 (dd, J1 =6.4 Hz, J2 =4.0 Hz, 1H), 4.13 (br, 1H),
4.40 (dd, J1 =13.9 Hz, J2 =8.7 Hz, 1H), 4.51 (dd, J1 =13.9 Hz, J2 =8.3 Hz,
1H), 5.11 (d, J=6.8 Hz, 1H), 6.55 (br, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.21
(d, J=8.3 Hz, 1H), 7.30 (d, J=7.9 Hz, 2H), 7.75 ppm (d, J=8.2 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=21.57, 21.67, 21.83, 22.67, 22.78, 24.74,
24.82, 40.66, 41.20, 50.59, 51.24, 52.34, 52.46, 57.07, 70.44, 127.30, 129.87,
136.24, 144.16, 170.54, 170.88, 172.48, 172.70 ppm; IR (KBr): n˜ =3358,
3298, 2958, 2872, 1745, 1655, 1533, 1439, 1346, 1165, 1092, 816, 667,
555 cmÀ1; MS(EI): m/z (%): 556.2 [M]+, 542.2 (30), 526.2 (15), 498.2
(10), 480.2 (1), 438.2 (0), 413.1 (5), 395.1 (3), 385.1 (55), 353.1 (5), 325.1
(20), 297.1 (5), 231.1 (15), 214.1 (60), 203.1 (85), 201.1 (100), 169.1 (5),
157.0 (25), 155.0 (40), 146.1 (25), 139.0 (20), 91.1 (30), 86.1 (35), 69.1 (5),
60.1 (10); HRMS: m/z calcd for C24H36N3O7S: 542.2172 [M+ÀCH3];
found: 542.2173.
Stereoisomer 1: [a]2D3 =À34 (c=0.14, MeOH); 1H NMR (300 MHz,
[D4]methanol): d=1.26 (d, J=7.2 Hz, 3H), 1.31 (d, J=7.4 Hz, 3H), 2.41
(s, 3H), 3.69 (s, 3H), 3.70 (s, 3H), 4.19 (d, J=7.4 Hz, 1H), 4.25 (d, J=
7.2 Hz, 1H), 4.30 (d, J=1.9 Hz, 1H), 4.40 (d, J=1.9 Hz, 1H), 7.32 (d, J=
8.6 Hz, 2H), 7.69 ppm (d, J=8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=17.65, 17.72, 21.43, 52.83, 60.15, 73.27, 128.32, 130.58, 139.26, 144.85,
171.07, 172.81, 174.09, 174.36 ppm; IR (KBr): n˜ =3419, 3392, 3327, 2970,
2935, 2524, 2476, 1736, 1749, 1653, 1522, 1450, 1335, 1236, 1159, 1097,
816, 675, 544 cmÀ1; MS(EI): m/z (%): 473.2 [M]+, 442.1 (2), 424.1 (2),
414.1 (8), 396.1 (10), 378.1 (2), 371.1 (5), 353.1 (15), 343.1 (60), 314.1 (5),
293.0 (10), 283.1 (12), 253.1 (5), 235.1 (2), 214.1 (70), 200.0 (3), 189.1
(15), 171.0 (5), 161.1 (90), 159.1 (100), 155.0 (75), 139.0 (25), 114.0 (5),
104.0 (35), 91.0 (65), 70.0 (16), 60.1 (15); HRMS: m/z calcd for
C19H27N3O7S: 473.146; found: 473. 1463.
Stereoisomer 2: 1H NMR (300 MHz, [D4]methanol): d=1.24 (d, J=
7.2 Hz, 3H), 1.32 (d, J=7.2 Hz, 3H), 2.39 (s, 3H), 3.70 (s, 3H), 3.76 (s,
3H), 4.17 (d, J=7.2 Hz, 1H), 4.27 (d, J=7.2 Hz, 1H), 4.32 (d, J=1.7 Hz,
1H), 4.42 (d, J=2.3 Hz, 1H), 7.28 (d, J=8.66 Hz, 2H), 7.70 ppm (d, J=
8.3 Hz, 2H); 13C NMR (75 MHz, [D4]methanol): d=17.60, 18.09, 23.71,
53.02, 60.07, 73.00, 128.26, 130.56, 139.18, 144.80, 171.32, 172.47, 174.15,
174.25 ppm; HRMS: m/z calcd for C19H27N3O7S: 473.146; found:
473.1456.
N,N’-Bis[(S)-1-methoxycarbonylisobutylmethyl]-(2S,3S)-3-hydroxy-2-(to-
sylamino)succinic diamide (5c): [a]2D3 =À7 (c=0.5, CH2Cl2); 1H NMR
(300 MHz, CDCl3): d=0.86 (m, 12H), 1.58 (m, 6H), 2.39 (s, 3H), 3.69 (s,
3H), 3.69 (s, 3H), 4.02 (dd, J1 =8.3 Hz, J2 =3.8 Hz, 1H), 4.31 (dd, J1 =
9.4 Hz, J2 =3.8 Hz, 1H), 4.38 (m, 1H), 4.47 (dd, J1 =14.1 Hz, J2 =8.7 Hz,
1H), 4.83 (d, J=8.3 Hz, 1H), 6.51 (d, J=9.4 Hz, 1H), 7.14 (d, J=8.7 Hz,
1H), 7.28 (d, J=7.9 Hz, 2H), 7.35 (d, J=8.2 Hz, 1H), 7.77 ppm (d, J=
8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=21.49, 21.59, 21.81, 22.68,
22.70, 24.62, 24.63, 40.47, 41.13, 50.46, 51.07, 52.26, 52.37, 56.70, 71.20,
127.12, 129.93, 136.72, 143.93, 170.49, 171.66, 172.32, 172.49 ppm; IR
(KBr): n˜ =3373, 3317, 2958, 2872, 1743, 1662, 1533, 1439, 1340, 1163,
1091, 810, 671, 559 cmÀ1; MS(EI): m/z (%): 556.2 [M]+, 542.2 (20), 526.2
(15), 498.2 (5), 480.2 (1), 466.2 (0), 438.2 (0), 413.1 (3), 395.1 (2), 385.1
(30), 353.1 (5), 335.1 (1), 325.1 (15), 295.1 (3), 231.1 (15), 214.1 (40),
203.1 (80), 201.1 (100), 169.1 (5), 157.0 (20), 155.0 (30), 146.1 (20), 139.0
(15), 112.1 (2), 102.0 (2), 91.1 (20), 86.1 (25), 60.1 (10); HRMS: m/z calcd
for C24H36N3O7S: 542.2173 [M+ÀCH3]; found: 542.2172.
N,N’-Bis[(S)-1-(ethoxycarbonyl)-2-phenylethyl]-(2S,3S)-3-hydroxy-2-(to-
sylamino)succinic diamide (5b) and N,N’-bis[(S)-1-(ethoxycarbonyl)-2-
phenylethyl]-(2R,3R)-3-hydroxy-2-(tosylamino)succinic diamide (4b):
Compounds 5b and 4b were synthesized according to general procedure
B. Separation of the isomers was carried out by using flash chromatogra-
phy (hexanes/EtOAc 5:2).
Stereoisomer 1: [a]2D3 =À37.5 (c=0.50, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=1.20 (td, J1 =7.1 Hz, J2 =1.0 Hz, 6H), 2.41 (s, 3H), 3.01 (m,
2H), 3.08 (m, 2H), 3.92 (dd, J1 =5.6 Hz, J2 =3.5 Hz, 1H), 4.09–4.15 (m,
4H), 4.49–4.54 (m, 1H), 4.67–4.73 (m, 1H), 4.80 (d, J=7.1 Hz, 1H), 6.38
(d, J=8.1 Hz, 1H), 7.02–7.04 (m, 2H), 7.13–7.32 (m, 10H), 7.37 (d, J=
8.1 Hz, 1H), 7.69 ppm (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=13.98, 14.02, 21.54, 37.63, 37.80, 53.03, 53.60, 56.86, 61.53, 61.68, 70.55,
127.08, 127.18, 127.24, 128.48, 128.69, 129.13, 129.28, 129.81, 135.35,
135.60, 136.52, 144.00, 170.31, 170.57, 170.60, 170.64 ppm; IR (KBr): n˜ =
3547, 3394, 3313, 3064, 3030, 2981, 2935, 1740, 1660, 1529, 1444, 1342,
1213, 1163, 1090, 1030, 702, 667, 555 cmÀ1; MS(EI): m/z (%): 653.1 [M]+,
580.1 (10), 562.1 (6), 461.0 (5), 433.0 (60), 403.0 (8), 387.0 (6), 359.0 (25),
341.0 (10), 279.0 (15), 257.0 (20), 251.0 (100), 249.0 (50), 220.0 (10), 214.0
(40), 194.0 (30), 176.0 (70), 154.9 (50), 138.9 (15), 120.0 (70), 102.0 (20),
91.0 (65), 60.0 (5); HRMS: m/z calcd for C33H39N3O9S: 653.2407; found:
653.2426.
Stereoisomer 2: [a]2D3 =+50.5 (c=0.50, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=(q, J=7.1 Hz, 6H), 2.38 (s, 3H), 2.90 (dd, J1 =13.9 Hz, J2 =
6.06 Hz, 1H), 3.01–3.06 (m, 3H), 3.84 (dd, J1 =8.8 Hz, J2 =4.0 Hz, 1H),
4.08–4.16 (m, 4H), 4.66–4.71 (m, 2H), 4.83 (d, J=9.1 Hz, 1H), 6.60 (d,
J=9.1 Hz, 1H), 7.07–7.32 (m, 15H), 7.40 (d, J=8.0 Hz, 1H), 7.71 ppm
(d, J=8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=14.01, 21.53, 37.77,
38.03, 52.90, 53.67, 56.37, 61.56, 61.68, 70.58, 127.11, 127.20, 127.25,
128.59, 128.65, 129.31, 129.84, 130.02, 135.29, 136.61, 144.19, 170.08,
170.48, 170.64, 171.85 ppm; IR (KBr): n˜ =3398, 3331, 3277, 3064, 3030,
2981, 2933, 1740, 1662, 1527, 1456, 1340, 1203, 1165, 1092, 1030, 702, 667,
555 cmÀ1; MS(EI): m/z (%): 653.2 [M]+, 608.2 (5), 580.1 (20), 562.1 (10),
488.1 (10), 461.1 (12), 433.1 (10), 361.1 (15), 258.0 (15), 251.1 (75), 214.1
(50), 194.1 (30), 176.1 (95), 155.0 (60), 131.0 (20), 120.1 (70), 102.0 (35),
91.0 (100), 60.1 (10); HRMS: m/z calcd for C33H39N3O9S: 653.2407;
found: 653.2416.
N,N’-Bis[(S)-1-methoxycarbonylisopropylmethyl]-(2S,3S)-3-hydroxy-2-
(tosylamino)succinic diamide (5d) and N,N’-bis[(S)-1-methoxycarbonyli-
sopropylmethyl]-(2R,3R)-3-hydroxy-2-(tosylamino)succinic diamide (4d):
Compound 4d was synthesized according to general procedure B. The
isomers were separated by using flash chromatography and preparative
HPLC.
Stereoisomer 1: [a]D23 =+8 (c=0.50, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=0.88 (m, 12H), 2.15 (m, 2H), 2.40 (s, 3H), 3.71 (s, 3H), 3.72
(s, 3H), 4.20 (m, 2H), 4.25 (dd, J1 =9.1 Hz, J2 =4.9 Hz, 1H), 4.40 (dd,
J1 =8.7 Hz, J2 =4.9 Hz, 1H), 5.10 (d, J=6.6 Hz, 1H), 6.53 (d, J=7.4 Hz,
1H), 7.26 (m, 3H), 7.36 (d, J=8.7 Hz, 1H), 7.72 ppm (dt, J1 =8.3 Hz, J2 =
1.7 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=17.51, 17.67, 18.74, 18.83,
21.48, 26.90, 30.77, 31.06, 52.11, 52.25, 56.95, 57.11, 57.65, 70.66, 127.21,
129.76, 136.31, 144.03, 170.43, 170.86, 171.42, 171.55 ppm; IR (KBr): n˜ =
3411, 3355, 3293, 2966, 2879, 1742, 1675, 1527, 1450, 1337, 1276, 1214,
1158, 1096, 671, 554 cmÀ1; MS(EI): m/z (%): 529.3 [M]+, 498.3 (15),
480.2 (15), 470.3 (10), 399.2 (5), 371.1 (80), 339.1 (5), 311.1 (35), 281.1
(3), 217.2 (20), 214.1 (80), 201.1 (5), 189.1 (100), 187.1 (100), 157.1 (30),
155.0 (40), 139.0 (20), 132.1 (25), 130.1 (20), 127.1 (15), 115.1 (3), 98.1
(8), 91.1 (45), 72.1 (40), 60.1 (15), 55.1 (8); HRMS: m/z calcd for
C23H35N3O9S: 529.2094; found: 529.2106.
Stereoisomer 2: [a]D23 =À9 (c=0.50, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d=0.84 (d, J=7.0 Hz, 6H), 0.85 (d, J=7.0 Hz, 6H), 2.10 (m,
2H), 2.40 (s, 3H), 3.70 (s, 3H), 3.71 (s, 3H), 3.88 (dd, J1 =9.3 Hz, J2 =
4.0 Hz, 1H), 4.22 (dd, J1 =9.3 Hz, J2 =4.0 Hz, 1H), 4.32 (dd, J1 =8.9 Hz,
J2 =5.1 Hz, 1H), 4.35 (dd, J1 =9.2 Hz, J2 =5.1 Hz, 1H), 5.05 (d, J=
9.2 Hz, 1H), 6.72 (d, J=9.2 Hz, 1H), 7.22 (d, J=9.2 Hz, 1H), 7.29 (d, J=
8.2 Hz, 2H), 7.40 (d, J=8.9 Hz, 1H), 7.77 ppm (d, J=8.2 Hz, 2H);
13C NMR (75 MHz, CDCl3): d=17.62, 18.75, 18.79, 21.49, 30.85, 31.08,
52.14, 52.22, 56.51, 56.85, 57.54, 70.89, 127.10, 130.01, 136.65, 144.15,
170.98, 171.01, 171.43, 172.22 ppm; IR (KBr): n˜ =3406, 3305, 2964, 2877,
1741, 1660, 1531, 1437, 1344, 1269, 1211, 1165, 1092, 667, 555 cmÀ1; MS
N,N’-Bis[(S)-1-methoxycarbonylisobutylmethyl]-(2S,3S)-3-hydroxy-2-(to-
sylamino)succinic diamide (5c) and N,N’-bis[(S)-1-methoxycarbonyliso-
butylmethyl]-(2R,3R)-3-hydroxy-2-(tosylamino)succinic diamide (4c):
Compound 4c was synthesized according to general procedure B. Separa-
Chem. Eur. J. 2006, 12, 4362 – 4371
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4369

K. MuÇiz et al.
(EI): m/z (%): 530.2 [M]+, 498.2 (20), 480.2 (20), 470.2 (5), 399.1 (5),
371.1 (40), 342.1 (3), 311.1 (20), 217.1 (10), 214.1 (50), 201.1 (2), 189.1
(100), 187.1 (100), 157.0 (25), 155.0 (30), 132.1 (20), 130.1 (10), 115.1 (2),
98.0 (5), 91.0 (25), 72.1 (25), 60.1 (10); HRMS: m/z calcd for
C21H32N3O7S: 470.1961; found: 470.1960.
Aminohydroxylation of the asymmetrical fumaric diamide 6 was carried
out following the general procedure B. Analytical data for the four ster-
eoisomers 7a–d are as follows:
1
Stereoisomer 1: H NMR (300 MHz, CDCl3): d=0.83 (d, J=6.2 Hz, 3H),
0.85 (d, J=6.2 Hz, 3H), 1.33 (d, J=7.2 Hz, 3H), 1.50–1.56 (m, 3H), 2.35
(s, 3H), 3.64 (s, 3H), 3.66 (s, 3H), 3.97 (dd, J=6.9, 9.2 Hz, 1H), 4.36–4.43
(m, 2H), 4.97 (d, J=8.4 Hz, 1H), 6.56 (d, J=9.2 Hz, 1H), 7.26 (d, J=
8.3 Hz, 2H), 7.72 ppm (d, J=8.3 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=17.97, 21.46, 21.65, 22.77, 24.57, 41.27, 48.36, 50.38, 52.44, 52.59, 56.74,
70.97, 127.14, 130.00, 136.73, 144.13, 170.44, 171.93, 172.13, 172.54 ppm;
HRMS: m/z calcd for C22H33N2O9S: 515.1938; found: 515.1940.
N,N’-Bis[(S)-1-methoxycarbonyl-2,2-dimethylpropyl]-(2S,3S)-3-hydroxy-
2-(tosylamino)succinic diamide (5e) and N,N’-bis[(S)-1-methoxycarbon-
yl-2,2-dimethylpropyl]-(2R,3R)-3-hydroxy-2-(tosylamino)succinic diamide
(4e): Compound 4e was synthesized according to general procedure B.
Separation of the isomers was done by flash chromatography and prepa-
rative HPLC.
1
Stereoisomer 1: [a]D23 =À6 (c=1.00, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=0.93 (s, 9H), 0.96 (s, 9H), 2.43 (s, 3H), 3.72 (s, 3H), 3.72 (s,
3H), 4.01 (dd, J1 =8.1 Hz, J2 =4.3 Hz, 1H), 4.13 (dd, J1 =7.8 Hz, J2 =
4.3 Hz, 1H), 4.22 (d, J=9.4 Hz, 1H), 4.29 (d, J=9.1 Hz, 1H), 5.05 (d, J=
8.1 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 7.44 (d, J=
9.4 Hz, 1H), 7.77 ppm (d, J=8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=21.57, 26.49, 26.52, 34.66, 34.75, 51.87, 51.95, 56.29, 60.10, 60.75, 70.32,
127.20, 130.04, 136.29, 144.34, 170.38, 170.63, 170.70, 171.33 ppm; IR
(KBr): n˜ =3412, 2966, 2910, 2875, 1741, 1666, 1525, 1437, 1344, 1221,
1163, 1092, 816, 667, 550 cmÀ1; MS(EI): m/z (%): 558.3 [M]+, 542.3 (75),
524.3 (35), 501.3 (30), 498.3 (10), 451.2 (3), 441.2 (10), 395.2 (2), 385.2
(85), 356.2 (5), 325.2 (50), 298.1 (5), 239.1 (5), 231.2 (20), 214.1 (65),
203.2 (100), 201 (95), 171.1 (10), 155.0 (40), 112.1 (10), 98.0 (2), 91.1 (40),
86.1 (60), 69.1 (10), 60.1 (15), 57.1 (10); HRMS: m/z calcd for
C25H39N3O7S: 557.2407; found: 557.2427.
Stereoisomer 2: [a]D23 =À16 (c=0.5, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=0.91 (s, 9H), 0.93 (s, 9H), 2.44 (s, 3H), 3.71 (s, 3H), 3.73 (s,
3H), 3.76 (dd, J1 =9.9 Hz, J2 =4.3 Hz, 1H), 4.14 (dd, J1 =9.5 Hz, J2 =
4.3 Hz, 1H), 4.25 (d, J=9.9 Hz, 1H), 4.26 (d, J=9.5 Hz, 1H), 5.14 (d, J=
9.9 Hz, 1H), 6.87 (d, J=9.5 Hz, 1H), 7.26 (d, J=9.9 Hz, 1H), 7.33 (d, J=
8.1 Hz, 2H), 7.48 (d, J=9.4 Hz, 1H), 7.78 ppm (d, J=8.6 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=21.57, 26.43, 26.46, 34.59, 51.87, 51.95,
56.30, 59.79, 60.48, 127.14, 130.18, 136.57, 144.38, 170.33, 171.01, 171.17,
172.56 ppm; IR (KBr): n˜ =3412, 3358, 3309, 2964, 2873, 1741, 1662, 1529,
1437, 1348, 1221, 1165, 1093, 820, 671, 559 cmÀ1; MS(EI): m/z (%): 558.3
[M]+, 542.3 (35), 524.3 (25), 501.2 (15), 498.3 (5), 441.2 (5), 413.2 (5),
385.2 (40), 356.1 (5), 325.2 (30), 298.1 (2), 231.2 (10), 214.1 (40), 203.1
(80), 201.2 (100), 171.1 (10), 155.0 (25), 146.1 (15), 139.0 (10), 127.0 (2),
112.1 (5), 98.0 (1), 91.1 (25), 86.1 (40), 60.1 (10); HRMS: m/z calcd for
C25H39N3O7S: 557.2407; found: 557.2416.
Stereoisomer 2: H NMR (300 MHz, CDCl3): d=0.82 (d, J=6.2 Hz, 3H),
0.84 (d, J=6.2 Hz, 3H), 1.34 (d, J=7.1 Hz, 3H), 1.49–1.55 (m, 3H), 2.35
(s, 3H), 3.65 (s, 3H), 3.66 (s, 3H), 3.87 (dd, J=6.7, 9.2 Hz, 1H), 4.29–4.44
(m, 2H), 4.83 (d, J=7.1 Hz, 1H), 6.46 (d, J=9.2 Hz, 1H), 7.22 (d, J=
8.2 Hz, 2H), 7.70 ppm (d, J=8.2 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=17.29, 21.49, 21.52, 22.77, 24.61, 40.37, 47.84, 51.03, 52.35, 52.51, 56.42,
71.08, 127.17, 129.94, 136.67, 144.03, 170.54, 171.50, 172.36, 172.56 ppm;
HRMS: m/z calcd for C22H33N2O9S: 515.1938; found: 515.1951.
1
Stereoisomer 3: H NMR (300 MHz, CDCl3): d=0.80 (d, J=6.2 Hz, 3H),
0.86 (d, J=6.2 Hz, 3H), 1.32 (d, J=7.1 Hz, 3H), 1.52–1.57 (m, 3H), 2.35
(s, 3H), 3.66 (s, 3H), 3.66 (s, 3H), 4.13–4.40 (m, 3H), 5.05 (d, J=6.4 Hz,
1H), 6.52 (d, J=9.2 Hz, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.71 ppm (d, J=
8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=17.52, 21.53, 21.72, 22.59,
24.75, 41.11, 47.89, 51.29, 52.43, 52.60, 57.40, 71.07, 127.10, 129.80, 136.44,
143.71, 170.35, 171.46, 172.81, 173.04 ppm; HRMS: m/z calcd for
C22H33N2O9S: 515.1938; found: 515.1942.
1
Stereoisomer 4: H NMR (300 MHz, CDCl3): d=0.77 (d, J=6.1 Hz, 3H),
0.86 (d, J=6.1 Hz, 3H), 1.33 (d, J=7.1 Hz, 3H), 2.87 (dd, J=6.7, 9.2 Hz,
3H), 4.15–4.48 (m, 3H), 5.10 (d, J=6.6 Hz, 1H), 6.47 (d, J=9.2 Hz, 1H),
7.24 (d, J=8.2 Hz, 2H), 7.70 ppm (d, J=8.2 Hz, 2H); 13C NMR
(75 MHz, CDCl3): d=17.27, 21.55, 21.69, 22.63, 24.26, 40.46, 48.53, 50.53,
52.44, 52.61, 57.45, 70.78, 127.29, 129.77, 136.97, 143.68, 170.61, 171.32,
172.91, 173.16 ppm; HRMS: m/z calcd for C22H33N2O9S: 515.1938; found:
515.1939.
X-ray structure analysis
Compound 4c: C25H39N3O9S·0.25acetone: colorless crystals, crystal di-
mensions 0.10”0.30”0.50 mm3, Mr =572.17, monoclinic, space group P21
(no. 4), a=15.0198(3), b=27.4936(7), c=15.0819(4) Š, b=102.355(2)8,
V=6083.8(3) Š3, Z=8,
m
G
,
T=123(2) K,
F(000)=
U
2448. A total of 44665 reflections were measured up to 2qmax =508 on a
Nonius Kappa CCD diffractometer with MoKa radiation, 20236 of which
were independent and used for all calculations. The structure was solved
by direct methods and refined to F2 anisotropically, the hydrogen atoms
were refined with a riding model. The final quality coefficient wR2(F2)
for all data was 0.2235, with a conventional R(F)=0.0866 for 1393 pa-
rameters and 21 restraints. The absolute configuration was determined by
refinement of Flackꢁs x-parameter (X=0.10(9)).
N4-[1-Methoxycarbonyl-3-methylbutyl]-N1-[1-methoxycarbonylethyl]fu-
maric diamide (6): Compound 6 was synthesized according to general
procedure A from N-acroyl leucine and N-acroyl alanine (1.00 and
1.00 equiv) and was obtained as the as the second fraction and major
product from a 2:1:1 mixture by using flash chromatography (EtOAc).
The minor products corresponded to the homo-cross-metathesis products
and gave identical data as detailed above. The solvent was removed
under reduced pressure and the product was isolated by column chroma-
tography (EtOAc).
CCDC-276677 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
1
[a]2D3 =À44 (c=0.3, MeOH); H NMR (300 MHz, CDCl3): d=0.83 (d, J=
6.2 Hz, 3H), 0.87 (d, J=6.2 Hz, 3H), 1.32 (d, J=7.6 Hz, 3H), 1.50–1.58
(m, 3H), 3.62 (s, 3H), 3.63 (s, 3H), 4.36–4.47 (m, 2H), 5.60 (brd, J=
9.0 Hz, 1H), 6.18 (brd, J=10.0 Hz, 1H), 6.83 (s, 1H), 6.84 ppm (s, 1H);
1H NMR (300 MHz, [D4]methanol): d=0.94 (dd, J1 =10.6 Hz, J2 =6.4 Hz,
6H), 1.40 (d, J=7.4 Hz, 3H), 1.65 (m, 3H), 3.71 (s, 3H), 3.72 (m, 3H),
4.51 (m, 2H), 6.95 ppm (s, 2H); 13C NMR (75 MHz, [D6]DMSO): d=
17.62, 22.09, 23.48, 26.34, 41.70, 50.04, 52.81, 53.02, 53.09, 134.06, 134.15,
166.52, 166.82, 174.48, 174.55 ppm; 13C NMR (75 MHz, CDCl3): d=15.91,
20.38, 21.77, 24.63, 39.99, 48.33, 51.10, 51.31, 132.36, 132.45, 164.82,
165.13, 172.79, 172.85 ppm; HRMS: m/z calcd for C15H24N2O6: 328.1634;
found: 328.1637.
Acknowledgements
This work was generously supported by the Fonds der Chemischen Indus-
trie and the Deutsche Forschungsgemeinschaft. J.S. is grateful to Bonn
University for a Theodor-Laymann stipend.
HPLC characterization of all eight isomers from aminohydroxylation of
the three fumaric diamides from metathesis: Chiralcel-OD, n-hexane/tert-
butyl methyl ether, 20:80 (v/v), 1.0 mLminÀ1; retention times: 14.3 (4d),
15.1 (5d), 16.3, 16.5, 17.2, 17.9, 18.6 (4a), and 19.4 min (5a). The peaks
between 16.3 and 17.9 min refer to the known products from aminohy-
droxylation of the asymmetrical substrate.
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4370
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Chem. Eur. J. 2006, 12, 4362 – 4371

Stereochemically Diverse Tripeptides
FULL PAPER
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Received: September 10, 2005
Revised: January 16, 2006
Published online: March 23, 2006
Chem. Eur. J. 2006, 12, 4362 – 4371
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4371