Linear and cyclic hybrids of alternating thiophene-amino acid units: Synthesis and effects of chirality on conformation and molecular packing

Article abstract of DOI:10.1002/chem.201302143

The dipeptide isostere 5-aminothiophene carboxylic acid has been combined with L-phenylalanine moieties to provide linear and cyclic hybrid oligopeptides. A suitable protecting group strategy and appropriate coupling methods have been developed to guarantee a high degree of enantiopurity of the resulting amides. Cyclic tetraamides have been efficiently obtained by macrocyclization of the linear derivatives. In the case of racemized cyclization precursors, two diastereomeric macrocycles (S,S/R,R and meso) have been isolated. Their crystal structures show clear effects of the stereogenic centers on the ring conformations and molecular packing. Chirality matters! Different synthetic routes toward linear and cyclic hybrid oligoamides with backbones containing alternating thiophene and phenylalanine units have been explored. Methods to retain the enantiopurity of the α-amino acid units have been developed. Depending on the stereogenic centers of the cyclic tetraamide derivatives, different crystal structures with crown or boat conformations of the rings and different molecular packings have been observed (see scheme; Cbz=carbenzyloxy; Bn=benzyl).

Full text of DOI:10.1002/chem.201302143

FULL PAPER
DOI: 10.1002/chem.201302143
Linear and Cyclic Hybrids of Alternating Thiophene–Amino Acid Units:
Synthesis and Effects of Chirality on Conformation and Molecular Packing
Thien H. Ngo, Hꢀlya Berndt, Michael Wilsdorf, Dieter Lentz, and
Hans-Ulrich Reissig*[a]
Dedicated to Professor Hisashi Yamamoto on the occassion of his 70th birthday
Abstract: The dipeptide isostere 5-aminothiophene carboxylic acid has been com-
bined with l-phenylalanine moieties to provide linear and cyclic hybrid oligopep-
ACHTUNGTRENNUNGtides. A suitable protecting group strategy and appropriate coupling methods have
Keywords: amino acids
· crystal
been developed to guarantee a high degree of enantiopurity of the resulting
amides. Cyclic tetraamides have been efficiently obtained by macrocyclization of
the linear derivatives. In the case of racemized cyclization precursors, two
packing · dipeptide isosteres · mac-
rocycles · peptidomimetics · ring
conformation · thiophene
diastereoACHTUNGTRENNUNGmeric macrocycles (S,S/R,R and meso) have been isolated. Their crystal
structures show clear effects of the stereogenic centers on the ring conformations
and molecular packing.
Introduction
Our research interest in this
area was provoked by the dis-
covery of biological activities of
some natural cyclic compounds
built up by amide bonds, for ex-
ample, those extracted from
marine plants.[1] Due to their
multifaceted
environment,
marine plants have developed a
variety of complex mechanisms
that allow them to survive and
resist infections. Studies have
shown that 3.5% of marine
plant extracts exhibit cytotoxic
or antitumor effects.[1] For ex-
ample, the calyxamides A/B[2]
from the marine sponge Disco-
dermia calyx proved to be cyto-
toxic, while solomonamide A[3]
Figure 1. Bioactive natural cyclic peptides extracted from marine organisms.
from
Theonella
swinhoei
showed in vivo anti-inflamma-
tory activity (Figure 1). Another class of bioactive cyclopep-
tides containing five-membered heterocycles, such as the an-
titumor trunkamide A[4] and the cytotoxic ascidiacycl-
[a] Dr. T. H. Ngo, Dr. H. Berndt, Dr. M. Wilsdorf, Prof. Dr. D. Lentz,+
Prof. Dr. H.-U. Reissig
AHCTUNGTRENNUNG
amide[1,5] and ulicyclamide[1c,6] (all three from the Lissocli-
Institut fꢀr Chemie und Biochemie, Freie Universitꢁt Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax : (+49)30-838-55367
E-mail: hreissig@chemie.fu-berlin.de
Homepage: http://www.bcp.fu-berlin.de/chemie/oc/reissig
num[7] class of cyclic peptides), play important roles in
Nature, as they are found in many marine organisms. Most
of these cyclic compounds contain at least one aromatic ring
within the macrocycle. The rigidity introduced by heterocy-
cles in the cyclopeptides could lead to a better fit in host–
guest interactions. This feature is particularly shown by the
[+] Responsible for X-ray crystal structure determination
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302143.
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Lissoclinum class, in which five-membered heterocycles are
linked by amide bonds to segments containing stereogenic
centers. This alternating sequence of heterocyclic rings and
amino acids containing stereogenic units led to speculation
that both the heterocyclic structure and the configuration of
the backbone are essential prerequisites for biological activi-
ty. These metabolites may have a role to play in vivo as host
agents for metal transport,[8] and/or metals may act as tem-
plates in their biological assembly from constituent amino
acids/heterocyclic rings.[9] Despite intense investigation by
the scientific community, there is still a need for new syn-
thetic methods for novel peptides or simplified and more
stable peptidomimetics.[10] In particular, cyclic amides incor-
porating heterocyclic units other than oxazole or thiazole
moieties, which are biosynthetically derived from the func-
tionalized amino acids serine, threonine, or cysteine, should
afford interesting compounds with new properties. To the
best of our knowledge, no cyclic amides containing thio-
phene units are found in Nature, which is the key feature of
the current study.
trend of decreasing yields with higher homologues was ob-
served.[11b] The same reaction conditions were applied to
achieve macrocyclization under high dilution affording low
to moderate yields. In our last report, we revealed an opti-
mized procedure for our systems employing propylphos-
phonic anhydride (T3P)[18] as a coupling reagent combined
with ultrasound activation.[17] These proved to be excellent
reaction conditions for fast and high-yielding (up to quanti-
tative) amide couplings, including those of higher homo-
logues that gave fairly low yields under conventional condi-
tions. This optimized procedure was applied to prepare
cyclic amides in high yields; the selectivity in terms of the
size of the macrocycles could be controlled by the choice of
dilution level.
These promising results encouraged us to expand the
scope of our developed methods toward linear and cyclic
oligoamides with alternating 5-aminothiophene carboxylic
acids and natural amino acids, introducing stereogenic cen-
ters into the backbone. In this report, we disclose different
reaction conditions and synthetic pathways for the construc-
tion of these new peptidomimetics. The high tendency of in-
termediates and products to undergo racemization is dis-
cussed, as well as the conformations of macrocyclic products
in the solid state, including their crystal packing.
In recent years, our group has explored the synthesis and
reactivity of 5-aminothiophenecarboxylic acids[11] obtained
by a three-component Gewald reaction[12–15] using methyl
2-siloxycyclopropanecarboxylates A as equivalents of func-
tionalized aldehydes B (Scheme 1).[15,16] This process gives
Results and Discussion
For the construction of such hybrid oligoamides with alter-
nating 5-aminothiophene carboxylic acids and natural amino
acids, l-phenylalanine was chosen as an enantiopure compo-
nent to introduce a stereogenic center. In the initial period
of our investigation, we focused on yield optimization of the
chain elongation and cyclization reactions of oligoamides.
The peptide coupling between 5-aminothiophene carboxylic
acid 1 and carboxybenzyl-protected (Cbz) l-phenylalanine 2
was carried out under conditions of conventional stirring.
PyBOP-mediated amide coupling in the presence of DMAP
(see footnote to Table 1 for abbreviations) proved to be a
good synthetic method for obtaining the desired monoamide
3 (90%, Scheme 2). Deprotection of 3 according to the liter-
ature procedures afforded the desired carboxylic acid 4 and
amine 5 in excellent yields of 91 and 90%, respectively. By
combining these two components under the same coupling
conditions, we obtained a high yield (84%) of triamide 6a.
After deprotections of the reactive termini, precursor 6a
was ready for the cyclization step. Remarkably, the above
described synthetic sequence occurred with high to quantita-
tive yields in each step. At the stage of the acyclic inter-
mediates, there was no evidence that (partial) racemization
had occurred, which would have led to diastereomers for
compounds 6a–c. The cyclization step was carried out with
different coupling reagent systems, for example, BOP with
DMAP or PyBroP with DIPEA (Scheme 2, Table 1). Under
high-dilution reaction conditions (c=0.004 molLꢀ1) with
BOP/DMAP, 61% of the desired cyclic tetraamide 7 was
obtained after 2 days (Table 1, entry 1). By changing the sol-
Scheme 1. Synthesis of 5-aminothiophenecarboxylic acids
Gewald reaction with siloxycyclopropanes A.
C by the
direct access to compounds C, which can be considered as
unnatural amino acids with a thiophene backbone and as
isosteres of dipeptides D. The ready accessibility of the
unique amino acids C opens new prospects for the prepara-
tion of a variety of novel linear and cyclic peptidomimetics
containing thiophene moieties.
During the past few years, we have focused on the devel-
opment of methods for constructing unnatural oligoamides
by peptide coupling reactions between the carboxylic acid
derived from C and the notoriously unreactive 5-amino
group at the thiophene ring. Hence, different synthetic pro-
cedures have been tested involving both traditional method-
ology (conventional stirring) and ultrasound activation, in
conjunction with various coupling reagents, to achieve the
optimal reaction conditions for linear and cyclic oligoamides
with a thiophene backbone.[11b,17] Initial studies clearly indi-
cated that under conventional stirring the coupling reagent
N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide
chloride (EDCI·HCl) gave the best results, though a clear
hydro-
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Thiophene–Amino Acid Hybrid Structures
FULL PAPER
and that two diastereomers
were probably present in the
mixture. Two sets of signals in a
ratio of 1:3 were likewise ob-
served in the 1H NMR spec-
trum of the product derived
from the cyclization with
PyBroP/DIPEA, indicating that
mixtures of diastereomers were
generated in the reaction
sequence.
After careful purification by
HPLC, two fractions were iso-
lated and characterized. Their
1H NMR spectra in [D6]DMSO
clearly showed single sets of
signals (Figure 3). The com-
pounds in these fractions were
characterized as two diaster-
eomers
(S,S)/ACTHNGUTERN(UNG R,R)-7=rac-7
and (S,R)-7=meso-7. Evidently,
racemization at the stereogenic
centers had occurred during our
synthetic sequence. After crys-
tallization of the separated
macrocycles, the solid-state
structures revealed the expect-
ed C2-symmetry for each of the
enantiomers of rac-7 and
Ci-symmetry for meso-7. The
solid-state structures are dis-
cussed in detail below.
The spectroscopic data and
solid-state structures clearly
proved that during our synthe-
sis of tetraamide 7 extensive
racemization occurred, ulti-
Scheme 2. Synthesis of macrocyclic tetraamide 7, affording a mixture of the (S,S)/
(Bn=benzyl, Pd/b=palladium/black)
ACHTUNGERTN(NUNG R,R), and (R,S) isomers
Table 1. Synthesis of macrocyclic tetraamide 7 from precursor 6c.
mately resulting in the production of diastereomers. In the
second part of this work, we therefore investigated pathways
toward enantiomerically pure macrocyles and resumed our
synthesis with the same precursors once more.
Entry
Coupling reagent[a]
Solvent
Yield
[%]
1
2
3
4
BOP/DMAP
BOP/DMAP
BOP/DMAP
PyBroP/DIPEA
CH2Cl2
DMF
DMF/CH2Cl2
CH2Cl2
61
49
59
37
We first sought the optimal reaction conditions for the ini-
tial coupling of amine 1 with l-phenylalanine derivative 2 to
afford amide (S)-3 with regard to yield and enantiopurity
(Scheme 3, Table 2). The choice of base not only affected
the yield, but also influenced the extent of racemization.
When the amount of DMAP was reduced from three
(Table 2, entry 1) to two equivalents with PyBOP as the
coupling reagent, a decreased yield of 60% and a low ee
(22%) were observed (Table 2, entry 2). By changing the
base to DIPEA or 2,4,6-collidine,[18] the degree of racemiza-
tion was reduced, but the yield decreased to 36 and 6%, re-
spectively (Table 2, entries 3 and 4). In the case of the cou-
pling reagent TFFH[20] (see footnote to Table 2), better ee
values (85–97%) were achieved, but the yields were only
moderate to low (47–73%), depending on the base (Table 2,
entries 5 and 6). A similar influence of the base was also ob-
[a] PyBOP=benzotriazol-1-yloxy(tripyrrolidino)phosphonium
hexafluorophosphate, BOP=benzotriazol-1-yloxytris(dimethylamino)-
phosphonium hexafluorophosphate, DMAP=4-(dimethylamino)pyridine,
PyBroP=bromo(tripyrrolidino)phosphonium
DIPEA=N,N-diisopropylethylamine.
ACHTUNGTRENNUNG
hexafluorophosphate,
vent system from CH2Cl2 to DMF or a mixture of DMF and
CH2Cl2, the yields dropped to 49 and 59%, respectively.
When PyBroP and DIPEA were employed in CH2Cl2, only
a 37% yield of the macrocyclic product 7 was isolated.
NMR data for macrocycle 7 obtained by the BOP/DMAP
method are displayed in Figure 2. The observation of a
double set of signals in a ratio of 1:1 indicates that the 18-
membered macrocycle did not show the expected symmetry
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H.-U. Reissig et al.
Figure 2. 1H NMR (500 MHz, CD3OD, CDCl3) and 13C NMR (126 MHz, CD3OD, CDCl3) spectra of tetraamide 7 obtained by cyclization according to
the BOP/DMAP method (Table 1, entry 1).
Figure 3. 1H NMR (500 MHz, [D6]DMSO) spectra of purified cyclic oligoamides rac-7 [in red, (S,S)-enantiomer shown only)] and meso-7 (in blue).
served with PyBOP as the coupling reagent. DIPEA ap-
peared to induce less racemization, but gave lower yields
than DMAP. When EDCI·HCl[21] was employed without a
base, a high ee value (96%) was obtained with moderate
yield (47%, Table 2, entry 7). This coupling reagent gave no
racemization in the presence of HOBt,[22] but the observed
yields decreased significantly to 8–10% (Table 2, entries 8
and 9). In all cases, the enantiomeric excesses were deter-
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Thiophene–Amino Acid Hybrid Structures
FULL PAPER
of 88% was obtained, but only
a moderate ee was observed
(Table 3, entry 1). By decreas-
ing the amount of base to
1.1 equivalents,
a
higher ee
value was obtained with a slight
loss of yield (84%, Table 3,
Scheme 3. Peptide coupling of 1 and 2 in order to prepare enantiopure amide (S)-3.
entry 2). Lowering the tempera-
ture to 08C favored the ee (91%), but the yield de-
creased further to 75% (Table 3, entry 3). A good
yield was achieved with H2O2 as an additive,[23] but
again a higher degree of racemization was observed
(Table 3, entry 4). When the reaction temperature
was reduced to ꢀ788C and then slowly increased to
08C in the presence of 1.3 equivalents of LiOH,
both the yield and ee decreased (Table 3, entry 5).
All of these experiments indicated the significant
effects of temperature and amount of base. Other
reaction conditions reported in the literature were
also examined, but they gave no satisfactory results.
Table 2. Synthesis of monoamide (S)-3 by coupling of 1 with 2 under different condi-
tions.
Entry Coupling
reagent[a]
Base
([equiv])
Conditions
Yield ee
G
[%]
[%]
1
2
3
4
5
6
7
8
9
PyBOP
PyBOP
PyBOP
PyBOP
TFFH
TFFH
EDCI·HCl
EDCI·HCl/HOBt
EDCI·HCl/HOBt
DMAP (3)
DMAP (2)
DIPEA (2)
2,4,6-collidine (2) RT, 1 d
DIPEA (2)
RT, 1 d
RT, 1 d
RT, 1 d
90
60
36
6
46
22
76
97
97
85
96
>99
>99
08C, 30 min!RT, 8 h 47
DMAP (2)
08C, 30 min!RT, 8 h 73
–
–
–
08C, 30 min!RT, 8 h 47
08C, 30 min!RT, 8 h
8
10
RT, 1 d
[a] TFFH=N,N,N’,N’-tetramethylfluoroformamidinium hexafluorophosphate, HOBt= Saponifications mediated by PhSH/KF[24] and
1-hydroxybenzotriazole.
bis(tributyltin) oxide (BBTO)[25] gave poor yields
mined by HPLC using an enantiopure stationary phase
(Chiralpak IA column).
Table 3. Saponification of amide (S)-3 to form carboxylic acid (S)-4.
Entry
Conditions ([equiv])
Yield
[%]
ee
The above mentioned experimental data reveal that
either the yield of (S)-3 is good but there is considerable
racemization, or else the enantiopurity is fair to excellent
but the yields are low. In spite of this conundrum, moderate
yields in the first step would be tolerable if the subsequent
steps of our synthesis could be achieved without problems.
Therefore, the TFFH/DIPEA- and EDCI·HCl-promoted
amide couplings (Table 2, entries 5 and 7) might have been
acceptable for further elongation and cyclization steps em-
ploying (S)-3. However, we encountered a severe setback in
the next step, namely the deprotection of the carboxylic acid
moiety of amide (S)-3 (Scheme 4, Table 3). While deprotec-
tion of the amino group by removal of the Cbz group of (S)-
3 to furnish (S)-5 could be smoothly achieved in high yield
and without racemization by reduction with palladium in cy-
clohexene, saponification of the ester moiety of (S)-3
proved more challenging. Due to the acidic protons in the
a-position with respect to the amide moiety, the saponifica-
tion occurred with remarkably facile racemization at the
stereogenic center. By using 3 equivalents of LiOH, a yield
[%][a]
1
2
3
4
5
6
7
8
9
LiOH (3), RT, 1 h
LiOH (1.1), RT, 2.5 h
LiOH (1.1), 08C, 2.5 h
LiOH (3), H2O2 (9 eq), RT, 80 min
LiOH (1.3), ꢀ78!08C, 6 h
PhSH (1), KF (0.1), NMP, 4 h
NaI (2), DMSO, 808C, overnight
LiCl, DMF, microwave, 2 h
BBTO (2), toluene, 808C, overnight
88
84
75
91
69
30
–
74
89
91
63
64
58
–
–
54
–
83
[a] Determined by HPLC.
and low ee values (Table 3, entries 6 and 9), and no reaction
was observed when NaI and LiCl[26] were employed
(Table 3, entries 7 and 8).
The results collected above indicate that a considerable
degree of racemization in each of the steps will lower the ee
of the final cyclic oligoamide 7. Therefore, an alternative
strategy for the synthesis of enantiomerically pure 7 was ex-
plored (Scheme 5). To avoid the racemization during libera-
tion of the carboxylic acid, a
benzyl group was chosen for
protection of this moiety,
whereas a tert-butoxycarbonyl
(Boc) group was introduced at
the amino unit as an orthogo-
nal protecting unit, allowing
for selective deprotections at
later stages. The required
5-aminothiophene 8 was pre-
Scheme 4. Selective deprotections of the amino and carboxylic acid groups of amide (S)-3.
pared by routine operations
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H.-U. Reissig et al.
Scheme 5. Synthesis of enantiopure monoamides 10a–c
Scheme 6. Synthesis of enantiopure cyclic tetraamide (S,S)-7.
(see the Supporting Information). Boc-protection of 5-ami-
nothiophene 1 was followed by saponification and subse-
quent esterification of the carboxylic acid moiety with
benzyl alcohol. The amino group was finally deprotected af-
reagent in the presence of triethylamine.[17] These findings
prompted us to investigate the above described steps toward
cyclic tetraamide (S,S)-7 employing these reaction condi-
tions.
fording aminothiophene
8
in reasonable quantities
(Scheme 5). Although the yield of the coupling generating
amide 10a from thiophene derivative 8 and commercially
available l-phenylalanine-derived active ester 9 was only
moderate, racemization could essentially be avoided. The
protective groups were easily and selectively removed by
palladium-mediated hydrogenation with cyclohexene and
treatment with trimethylsilyl triflate in the presence of 2,6-
lutidine, respectively, to afford the deprotected products in
high to quantitative yields, again without racemization.[27]
To couple the obtained monoamides 10b and 10c, the
PyBroP/DIPEA and PyBOP/DMAP methods were tested
(Scheme 6). The first approach provided an acceptable yield
of 48%, whereas the yield of the second method was much
higher (86%). Both procedures were essentially free of rac-
emization (HPLC control). The obtained triamide 11a was
easily deprotected by the same procedures as described
above, providing the precursor for the cyclization, (S,S)-6c,
in high to near-quantitative yield. Under high-dilution con-
ditions (c=0.004m), cyclic tetraamide (S,S)-7 was obtained
by the PyBroP/DIPEA method in only 2% yield and with a
diastereomeric ratio (d.r.) of 95:5. Better results were ach-
ieved when the PyBOP/DMAP method was applied; the
yield increased to a more impressive 51% and the d.r. was
98:2, demonstrating that essentially no racemization had oc-
curred in any of the relevant steps.
First, the reaction of 5-aminothiophene 1 and l-phenylala-
nine derivative 2 was carried out under conventional stirring
and the conversion was monitored by TLC (Scheme 3).
With T3P and 1.3 equivalents of triethylamine, the reaction
proceeded slowly at room temperature. After five days,
94% of the desired monoamide (S)-3 had been obtained
with an ee of 98%. We then reduced the amount of base to
one equivalent and applied ultrasound activation to speed
up the reaction. Slow addition of triethylamine to the reac-
tion mixture ensured a low concentration of base and mini-
mized the racemization process. After six hours, the conver-
sion was complete and (S)-3 was isolated in 92% yield.
Much to our delight, no racemization was observed under
these conditions. The two termini were deprotected as de-
scribed above, with slight modification of the saponification
(Scheme 4, Table 3). Since the extent of racemization de-
creases with lower amounts of base, we used only 1.0 equiv-
alent of LiOH, performing the reaction at 08C. LiOH solu-
tion was added dropwise to the solution of the ester to
ensure a high excess of the precursor. This small, but impor-
tant modification raised the ee value to 94% with an accept-
able yield of 67%. The deprotected monoamides (S)-4 and
(S)-5 were subjected to further peptide coupling (Scheme 7).
After two hours of sonication in the presence of T3P and
triethylamine, 93% of the desired product (S,S)-6a was iso-
lated. HPLC showed a high ee of 99%. Applying the same
deprotection procedures as previously, the cyclization pre-
In a recent publication, we reported a high-yielding syn-
thesis of linear and cyclic oligoamides with a thiophene
backbone under ultrasound activation, employing T3P
(1-propanephosphonic acid cyclic anhydride) as a coupling
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Thiophene–Amino Acid Hybrid Structures
FULL PAPER
pling reagents. By changing the protecting groups of the ter-
mini of the precursors (from Me to Bn for the carboxylic
acid group and from Cbz to Boc for the amine group), race-
mization during the synthetic sequence was avoided. The
combination of T3P as a coupling agent under ultrasound
activation and a lower amount of LiOH during the saponifi-
cation also contributed to affording the desired cyclic tetra-
AHCTUNGTREGaNNNU mide (S,S)-7 in acceptable yield and with high ee value.
Solid-state structures: Slow diffusion of hexanes into solu-
tions of the macrocycles rac-7 and meso-7 in dichlorome-
thane afforded crystals suitable for X-ray analyses. From the
crystal structure data, both diastereomers rac-7 (S,S+R,R)
and meso-7 (S,R=R,S) could be unequivocally assigned.
The racemic macrocycle crystallized in the centrosymmetric
orthorhombic space group Pbcn with eight molecules in the
unit cell. Figure 4a shows one of the four RR units with all
of its substituents.
When all external substituents are removed, the side view
of (R,R)-7 with the stereogenic centers marked in violet
gives a clearer picture (Figure 4c,d). One can recognize the
C2-symmetry of the 18-membered ring and the angle of
71.28 defined by the two thiophene planes. These features
combined with the fixing of the sulfur in the same direction
give the unit molecule a crown-like overall conformation
(Figure 4c). The two enantiomeric molecules (S,S and R,R)
are significantly offset against each other, creating a void be-
tween the two (Figure 4d).
The second diastereomer meso-7 crystallized in the cen-
trosymmetric monoclinic space group P21/n. Half of the
molecule forms the asymmetric unit, which is complemented
by the crystallographic center of symmetry to the complete
molecule. The entire molecule with all of its substituents is
depicted in Figure 4b, whereas the side view without exter-
Scheme 7. Ultrasound-mediated synthesis of enantiopure cyclic oligo-
ACHTUNGTRENNUNGamide (S,S)-7 by starting from (S)-4 and (S)-5 with T3P as the coupling
reagent.
cursor (S,S)-6c was obtained in reasonable yield and with
high ee. Under high-dilution conditions, precursor (S,S)-6c
provided cyclic tetraamide (S,S)-7 in good yield and with
high diastereomeric and enantiomeric purity.
The above described synthetic work shows three pathways
toward the desired cyclic amides 7 with different stereogenic
centers. In the first stage, a mixture of rac-7 and meso-7 was
obtained in high yields by using BOP and PyBroP as cou-
Figure 4. a) Crystal structure of (R,R)-7 of the racemic mixture rac-7 (ORTEP-3; ellipsoids drawn at the 50% probability level); b) crystal structure of
meso-7 (ORTEP-3; ellipsoids drawn at the 50% probability level); c) side view of (R,R)-7 (being part of rac-7) without external substituents
(XSHELL); d) intermolecular stacking of (R,R)-7 and (S,S)-7 (XSHELL); and e) side view of meso-7 without external substituents with Xi as the inver-
sion center (XSHELL).
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H.-U. Reissig et al.
nal substituents given in Figure 4e displays the 18-mem-
bered macrocycle with antiparallel bonds. The same can be
said for the two thiophene planes, which are oriented in an
antiparallel manner. The full molecule shows a double-boat
conformation. This conformation leads to parallel intermo-
lecular stacking of the macrocycles.
Not only do the individual molecules of rac-7 and meso-7
have different conformations, but this dissimilarity also af-
fects their intermolecular packing within the unit cells. In
the case of rac-7 enantiomers, four (R,R)- and four (S,S)-
macrocycles fill the unit cell. The two enantiomers are ar-
ranged in pairs, one above the other (Figure 5a).
The unit cell of meso-7 shows the packing as rows of iden-
tically arranged cycles with a linear sequence of inversion
centers in between rows with a different orientation of the
ring (Figure 5b).
Unfortunately, no suitable crystals of enantiopure macro-
cycle (S,S)-7 could be obtained. Different crystallization
methods were applied, but none proved to be successful.
The crystal packing of (S,S)-7 most likely differs from that
of the racemic compound.
Conclusion
Our first synthetic approach to linear and cyclic peptides af-
forded the alternating peptides as mixtures of diastereomers
due to extensive racemization of the l-amino acid derived
units during the synthetic sequence. Different synthetic
strategies were investigated and after analysis and optimiza-
tion of each reaction step an improved synthetic sequence
was established for which racemization at the stereogenic
centers was essentially avoided. Encouraged by our earlier
discovery, ultrasound-activated amide coupling of thiophene
and l-phenylalanine with T3P as a coupling reagent was ap-
plied, which afforded the enantiopure tetraamide in high
yield and with excellent enantiomeric excess.
The solid-state structures of two diastereomeric cyclic tet-
rapeptides (SS/RR and meso) were elucidated by X-ray crys-
tallographic analysis. The solid-state conformations show a
crown-like (SS/RR) or a double-boat (meso) shape. Depend-
ing on the stereogenic centers, the packing of the two dia-
stereomers within the unit cells defines box-like subunits
constructed from two enantiomers of rac-7 or perfectly ar-
ranged rows of parallel-stacked meso-7 macrocycles.
Experimental Section
General information: 1H and 13C NMR spectra were recorded on com-
mercial 250, 400, 500, and 700 MHz instruments from samples in CDCl3;
chemical shifts (d) are reported in parts per million (ppm) referenced to
tetramethylsilane or the internal (NMR) solvent signals. Detailed NMR
peak assignments were obtained by analysis of DEPT, HMQC, HMBC,
and COSY NMR spectra. NMR signals indicating the presence of dia-
stereomers are given by “/”. NMR signals indicating the presence of ro-
tamers are indicated by “*”. High-resolution mass spectra were obtained
on an ESI-TOF spectrometer. Silica gel (0.040–0.063 mm) was used for
column chromatography. HPLC separations were carried out with 5 mm
Nucleosil 50 as the stationary phase. Chiral HPLC analyses were per-
formed on a Chiralpak IA column. Melting points are uncorrected.
X-ray crystallography: Single crystals for X-ray diffraction experiments
were selected by using a microscope and mounted on the top of a glass
fiber. Crystallographic data were collected on a diffractometer by using
MoKa radiation (l=0.71073 ꢃ, graphite monochromator) at low tempera-
ture. CCDC-942503 (meso-7) and 942504 (rac-7) contain the supplemen-
tary 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. IR spectra were recorded on an
FTIR spectrometer with a DTGS detector and a Nicolet Smart Dura-
Samp1IR ATR device. An ultrasound bath set at 35 kHz, 100% power,
was used for syntheses.
Synthesis of cyclic tetraamides meso-7 and rac-7: BOP (0.059 g,
0.134 mmol) and DMAP (0.033 g, 0.267 mmol) were added to a solution
of precursor 6c (0.070 g, 0.089 mmol) in CH2Cl2 (23 mL). The reaction
mixture was stirred for 3 d at room temperature, then diluted with
CH2Cl2, and the organic phase was washed with 1m HCl, saturated
NaHCO3, and saturated NaCl solutions, and dried with Na2SO4. The sol-
vent was evaporated under reduced pressure. Chromatographic purifica-
tion (silica gel; hexanes/EtOAc, 2:1) yielded 7 (42 mg, 61%, d.r.ꢁ4:6) as
a mixture of rac-7 (R,R and S,S) and meso-7 as a colorless solid. The d.r.
was determined by HPLC (5% isopropanol in hexanes, 2.0 mLminꢀ1).
After preparative HPLC purification, meso-7 (22 mg, 31%) and rac-7
(16 mg, 24%) were isolated.
Figure 5. a) Molecular packing of rac-7 in the unit cell (XSHELL, picture
without external substituents); b) molecular packing of meso-7 in the unit
cell (XSHELL, picture without external substituents).
ꢀ
Data for the mixture of diastereomers: IR (ATR): v˜ =3325–3265 (N H),
ꢀ1
ꢀ
ꢀ
3085–2855 (=C H, C H), 1670 (C=O), 1560–1525 cm (C=C); HRMS
15162
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 15155 – 15165

Thiophene–Amino Acid Hybrid Structures
FULL PAPER
(ESI-TOF): m/z calcd for C40H44N4O8S2+Na+: 795.2493 [M+Na]+;
found: 795.2493; rac-7: 1H NMR (500 MHz, CDCl3, CD3OD): d=1.26 (s,
18H; tBu), 2.81, 3.02 (2dd, J=7.8, 14.2 Hz and 7.8, 14.2 Hz, 2H each;
CH2Ph), AB system (dA =3.15, dB =3.24, JAB =13.0 Hz, 4H; CH2), 4.80
(t, J=7.8 Hz, 2H; COCHN), 6.62 (s, 2H; Hthioph), 6.92–7.03 ppm (m,
10H; Ph); 13C NMR (126 MHz, CDCl3, CD3OD): d=27.4 (q; tBu), 34.7
(t; CH2Ph), 37.2 (t; CH2), 54.1 (d; COCHN), 81.3 (s; tBu), 114.9 (s;
CCO2-tBu), 123.3 (d; CHthioph), 126.4 (s; SCCH2), 127.12, 128.1, 128.6,
136.1 (3d, s; Ph), 144.7 (s; SCN), 162.9 (s; CO2tBu), 167.0 (s; NCOCH),
171.3 ppm (s; NHCOCH2); meso-7: 1H NMR (500 MHz, CDCl3,
CD3OD): d=1.32 (s, 18H; tBu), 2.72, 2.84 (2dd, J=7.8, 14.2 Hz for both,
2H each; CH2Ph), AB system (dA =3.108/3.110, dB =3.45, JAB =13.8 Hz,
4H; CH2), 4.70 (t, J=7.8 Hz, 2H; COCHN), 6.71 (s, 2H; Hthioph), 6.92–
7.03 ppm (m, 10H; Ph); 13C NMR (126 MHz, CDCl3, CD3OD): d=27.5
(q; tBu), 35.5 (t; CH2Ph), 37.8 (t; CH2), 55.2 (d, COCHN), 81.5 (s; tBu),
114.6 (s; CCO2tBu), 123.5 (d; CHthioph), 126.5 (s; SCCH2), 127.08, 128.08,
128.5, 135.7 (3d, s; Ph), 145.2 (s; SCN), 163.4 (s; CO2tBu), 167.5 (s;
NCOCH), 172.0 ppm (s; NHCOCH2).
Amide (S)-3: A solution of aminothiophene 1 (1.00 g, 3.69 mmol), l-phe-
nylalanine derivative 2 (1.30 g, 4.34 mmol), and T3P (2.00 g, 6.46 mmol)
in CH2Cl2 (25 mL) was ultrasonicated and Et3N (0.359 g, 3.66 mmol) was
slowly added. Following the addition, the mixture was further sonicated
for 6 h. EtOAc was then added and the mixture was washed with water.
The organic phase was dried with Na2SO4 and the solvent was removed
under reduced pressure. Purification of the residue by column chroma-
tography (silica gel; hexanes/EtOAc, 4:1) gave amide (S)-3 (1.79 g, 92%,
>99% ee) as a colorless solid. The enantiomeric excess was determined
by HPLC analysis (20% isopropanol in hexanes, 0.7 mLminꢀ1). M.p. 41–
448C; [a]2D2 =ꢀ31.5 (c=0.75 in CHCl3); the NMR data were consistent
with those of racemic 3; HRMS (ESI): m/z calcd for C29H32N2O7S+Na+:
575.1828 [M+Na]+; found: 575.1852.
Amide (S)-4: LiOH (36.4 mg, 1.52 mmol) was added in small portions to
a solution of enantiopure (S)-3 (0.840 g, 1.52 mmol) in THF (10 mL) and
H2O (4 mL) at 08C and the mixture was stirred for 6 h at 08C. It was
then acidified to pH 2–3 with HCl (1m) and extracted with EtOAc. The
organic phase was washed with water until the washings were neutral and
dried with Na2SO4. The solvent was removed under reduced pressure and
the residue was purified by column chromatography (silica gel; CH2Cl2/
MeOH, 9:1) to afford amide (S)-4 (0.550 g, 67%, 94% ee) as a colorless
solid. The enantiomeric excess was determined by HPLC analysis (30%
isopropanol in hexanes, 0.7 mLminꢀ1). M.p. 68–718C; [a]D22 =ꢀ35.4 (c=
0.98 in CHCl3); the NMR data were consistent with those of racemic 4;
HRMS (ESI): m/z calcd for C28H30N2O7S+Na+: 561.1666 [M+Na]+;
found: 561.1687.
Data for the individual diastereomers:
Compound rac-7: Melting range 76–818C; [a]2D2 = +4.7 (c=0.11 in
CHCl3); 1H NMR (500 MHz, [D6]DMSO): d=1.51 (s, 18H; tBu), 2.99,
3.17 (2dd, J=8.1, 13.8 Hz for both, 2H each; CH2Ph), AB system (dA =
3.30, dB =3.43, JAB =12.7 Hz, 4H; CH2), 4.68–4.72 (m, 2H; COCHN),
6.75 (s, 2H; Hthioph), 7.20–7.23, 7.29–7.32, 7.36–7.38 (3m, 2H, 4H, 4H;
Ph), 8.97 (d, J=7.2 Hz, 2H; NH), 10.30 ppm (s, 2H; NH); 13C NMR
(101 MHz, [D6]DMSO): d=27.9 (q; tBu), 34.4 (t; CH2Ph), 37.0 (t; CH2),
54.3 (d; COCHN), 81.2 (s; tBu), 114.0 (s; CCO2tBu), 123.0 (d; CHthioph),
126.5 (s; SCCH2), 128.2, 128.3, 129.3, 137.6 (3d, s; Ph), 145.1 (s; SCN),
162.6 (s; CO2tBu), 167.8 (s; NCOCH), 170.4 ppm (s; NHCOCH2).
Compound meso-7: M.p. 173–1768C; [a]2D2 = +5.4 (c=0.37 in CHCl3/
CH3OH, 1:1); 1H NMR (500 MHz, [D6]DMSO): d=1.56 (s, 18H; tBu),
2.91, 3.06 (2dd, J=9.3, 13.7 Hz and 6.2, 13.7 Hz, 2H each; CH2Ph), AB
system (dA =3.17, dB =3.65, JAB =13.2 Hz, 4H; CH2), 4.62–4.66 (m, 2H;
COCHN), 6.90 (s, 2H; Hthioph), 7.19–7.22, 7.27–7.30, 7.33–7.35 (3m, 2H,
4H, 4H; Ph), 8.58 (d, J=8.4 Hz, 2H; NH), 10.50 ppm (s, 2H; NH);
13C NMR (101 MHz, [D6]DMSO): d=28.0 (q; tBu), 34.9 (t; CH2Ph), 37.8
(t; CH2), 55.4 (d; COCHN), 81.3 (s; tBu), 113.8 (s; CCO2tBu), 123.2 (d;
CHthioph), 126.6 (s; SCCH2), 127.9, 128.3, 129.3, 137.3 (3d, s; Ph), 145.5 (s;
SCN), 163.1 (s; CO2tBu), 168.3 (s; NCOCH), 171.2 ppm (s; NHCOCH2).
Amide (S)-5: Cyclohexene (3.5 mL) and Pd/b (98%, 0.200 g) were added
to
a solution of enantiopure (S)-3 (0.940 g, 1.70 mmol) in MeOH
(3.5 mL) and the mixture was heated at reflux for 24 h. After cooling, it
was filtered through Celite and the solvent was removed under reduced
pressure. Chromatographic purification of the residue (silica gel; CH2Cl2/
EtOAc, 9:1) afforded (S)-5 (0.614 g, 86%, 99% ee) as a yellow solid. The
enantiomeric excess was determined by HPLC analysis (20% isopropa-
nol in hexanes, 0.7 mLminꢀ1). [a]D22 =ꢀ39.6 (c=1.0 in CHCl3); the NMR
data were consistent with those of racemic 5.
Triamide (S,S)-6a: T3P (0.501 g, 1.62 mmol) was added to a solution of
enantiopure (S)-4 (0.500 g, 0.928 mmol) and enantiopure (S)-5 (0.466 g,
1.11 mmol) in CH2Cl2 (25 mL). The solution was activated by ultrasound
and Et3N (0.094 g, 0.928 mmol) was added dropwise. The mixture was so-
nicated for 2 h. EtOAc was then added and the mixture was washed with
water. The organic phase was dried with Na2SO4 and the solvent was re-
moved under reduced pressure. Purification of the residue by column
chromatography (silica gel; CH2Cl2/EtOAc, 9:1) gave enantiopure (S,S)-
6a (0.808 g, 93%, 99% ee) as a colorless solid. The enantiomeric excess
was determined by HPLC analysis (30% isopropanol in hexanes,
0.7 mLminꢀ1). M.p. 83–868C; [a]D22 =ꢀ13.9 (c=0.38 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=1.53, 1.54 (2s, 9H each; tBu), 3.07–3.11, 3.19–3.26
Synthesis of enantiomerically pure (S,S)-7: PyBOP (0.157 g, 0.302 mmol)
and DMAP (0.062 g, 0.504 mmol) were added to a solution of triamide
(S,S)-6c (0.199 g, 0.252 mmol) in CH2Cl2 (63 mL) at 08C. The mixture
was stirred for 2 d at room temperature. It was then diluted with CH2Cl2,
and the organic phase was washed with 1m HCl, saturated NaHCO3, and
saturated NaCl solutions, and then dried with Na2SO4. The solvent was
then evaporated under reduced pressure. Purification by column chroma-
tography (silica gel; hexanes/EtOAc, 2:1!1:1) afforded (S,S)-7 (0.094 g,
51%, d.r.ꢁ98:2) as a colorless solid. The ratio of diastereomers was de-
termined by HPLC (5% isopropanol in hexanes, 1.5 mLminꢀ1). Traces of
the meso-7 diastereomer (4 mg, 2%) could be separated by an additional
HPLC purification together with 0.087 g of the desired (S,S)-7 (45%)
with a d.r.>99:1. M.p. 162–1668C; [a]2D2 = +162.8 (c=1.03 in CHCl3);
1H NMR (700 MHz, [D6]DMSO): d=1.52 (s, 18H; tBu), 2.30, 3.17 (2dd,
J=9.8, 13.7 Hz and 5.4, 13.7 Hz, 2H each; CH2Ph), AB system (dA =
3.30, dB =3.44, JAB =12.8 Hz, 4H; CH2), 4.68–4.72 (m, 2H; COCHN),
6.75 (s, 2H; Hthioph), 7.20–7.23, 7.29–7.32, 7.36–7.37 (3m, 2H, 4H, 4H;
Ph), 8.95 (d, J=9.2 Hz, 2H; NH), 10.28 ppm (s, 2H; NH); 13C NMR
(126 MHz, [D6]DMSO): d=27.8 (q; tBu), 34.4 (t; CH2Ph), 37.0 (t; CH2),
54.2 (d; COCHN), 81.1 (s; tBu), 113.9 (s; CCO2tBu), 122.9 (d; CHthioph),
126.4 (s; SCCH2), 128.1, 128.2, 129.2, 137.5 (3d, s; Ph), 145.0 (s; SCN),
162.5 (s; CO2tBu), 167.7 (s; NCOCH), 170.3 ppm (s; NCOCH2); IR
(2m, 1H, 3H; CH2Ph), AB system (dA =3.64, dB =3.64/3.78, JAB
17.2 Hz, 2H; CH2), 3.70 (s, 2H; CH2), 3.72 (s, 3H; OMe), 4.73–4.77,
4.88–4.92 (m, 1H each; COCHN), AB system (dA =5.10, dB =5.14, JAB
=
=
12.3 Hz, 2H; CH2Ph), 5.42–5.45, 6.19–6.22 (2m, 1H each; NH), 6.93, 6.96
(2s, 1H each; Hthioph), 6.98–7.00, 7.13–7.14, 7.18–7.22, 7.25–7.26, 7.28–7.34
(5m, 2H, 3H, 3H, 2H, 5H; Ph), 11.37, 11.39 ppm (brs, s, 2H; NH);
13C NMR (126 MHz, CDCl3): d=28.3, 28.4 (2q; tBu), 35.0, 36.8 (2t;
CH2-thioph), 37.5, 38.3 (2t; CH2Ph), 52.5 (q; OMe), 54.3, 56.4 (2d;
COCHNH), 67.5 (t; OCH2Ph), 81.95, 82.0 (2s; tBu), 114.9, 115.2 (2s; C-
CO2tBu), 123.8, 124.8 (2d; CHthioph), 125.0, 125.3 (2s; SCCH2), 127.3,
127.4, 128.2, 128.3, 128.6, 128.9, 129.0, 129.2, 129.3, 135.3, 135.7, 136.1
(9d, 3s; Ph), 146.8, 147.0 (2s; SCNH), 156.0 (s; Cbz), 164.5, 164.8 (2s;
CO2tBu), 167.8, 168.4, 169.5 (3s; CHCONH), 170.7 ppm (s, CO2Me);
HRMS (ESI): m/z calcd for C49H54N4O11S2+Na+: 961.3123 [M+Na]+;
found: 961.3129.
ꢀ
ꢀ
ꢀ
(ATR): n˜ =3280 (N H), 3110–2930 (=C H, C H), 1670 (C=O), 1560–
1525 cmꢀ1 (C=C); HRMS (ESI-TOF): m/z calcd for C40H44N4O8S2+Na+:
795.2493 [M+Na]+; found: 795.2509.
Triamide (S,S)-6b: Hydrogen gas was flushed through a suspension of
10% Pd/C (0.500 g) in MeOH (15 mL) for 15 min. A solution of carba-
mate (S,S)-6a (0.890 g, 0.948 mmol) in CH2Cl2 (5 mL) was then added
and hydrogen gas was flushed through the mixture for 16 h (TLC con-
trol). The mixture was then filtered through Celite and the solvent was
removed under reduced pressure. Chromatographic purification (silica
Synthesis of enantiopure oligoamides (S)-3, (S)-4, (S)-5, (S,S)-6a, (S,S)-
6b, (S,S)-6c, and (S,S)-7 by employing the ultrasound and T3P-promoted
protocol:
Chem. Eur. J. 2013, 19, 15155 – 15165
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
15163

H.-U. Reissig et al.
gel; CH2Cl2/EtOAc, 9:1) afforded (S,S)-6b (0.656 g, 86%, 98% ee) as a
colorless solid. The enantiomeric excess was determined by HPLC analy-
sis (20% isopropanol in hexanes, 0.7 mLminꢀ1). M.p. 81–848C; [a]D22 = +
7.2 (c=1.05 in CHCl3); 1H NMR (500 MHz, CDCl3): d=1.55, 1.57 (2s,
9H each; tBu), 2.86/2.88, 3.36/3.39 (2dd, J=9.4, 13.8 Hz and J=3.9,
13.8 Hz, 1H each; CH2Ph), 3.09/3.12, 3.23/3.26 (2dd, J=6.3, 13.9 Hz for
both, 1H each; CH2Ph), AB system (dA =3.67, dB =3.81, JAB =17.2 Hz,
2H; CH2), 3.71 (s, 2H; CH2), 3.72 (s, 3H; OMe), 3.86–3.89 (m, 1H;
COCHN), 4.89–4.93 (m, 1H; COCHN), 6.30 (d, J=7.8 Hz, 1H; NH),
6.96, 6.99 (2s, 1H each; Hthioph), 7.00–7.02, 7.14–7.16, 7.23–7.27, 7.31–7.34
(4m, 2H, 3H, 3H, 2H; Ph), 11.40, 12.16 ppm (2s, 1H each; NH);
13C NMR (126 MHz, CDCl3): d=28.4, 28.5 (2q; tBu), 35.0, 36.9 (2t;
CH2-thioph), 37.5 (t; CH2Ph), 40.8 (t; CH2Ph), 52.5 (q; OMe), 54.3, 56.5
(2d; COCHN), 81.7, 81.9 (2s; tBu), 114.8, 115.3 (2s; C-CO2tBu), 123.7,
124.9 (2d; CHthioph), 125.0, 125.1 (2s; SCCH2), 127.1, 127.2, 128.8, 128.9,
129.2, 129.4, 135.5, 137.4 (6d, 2s; Ph), 146.8, 147.2 (2s, SCN), 164.1, 164.8
(2s, CO2tBu), 167.8, 169.7, 170.7 (3s; CHCONH), 172.3 ppm (s;
CO2Me); HRMS (ESI): m/z calcd for C41H48N4O9S2+H+: 805.2940
[M+H]+; found: 805.2941.
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Triamide (S,S)-6c: LiOH (0.013 g, 0.542 mmol) was added in small por-
tions to a solution of triamide (S,S)-6b (0.426 g, 0.545 mmol) in THF
(10 mL) and H2O (4 mL) at 08C and the mixture was stirred at this tem-
perature for 6 h. It was then acidified to pH 2–3 with HCl (1m) and ex-
tracted with EtOAc. The organic phase was washed with water until the
washings were neutral and dried with Na2SO4. The solvent was removed
under reduced pressure and purification of the residue by column chro-
matography (silica gel; CH2Cl2/MeOH, 9:1) afforded (S,S)-6c (0.335 g,
78%, 98% ee) as a colorless solid. The enantiomeric excess was deter-
mined by chiral HPLC analysis (30% isopropanol in hexanes,
0.7 mLminꢀ1). The spectroscopic and physical properties were in agree-
ment with those recorded above.
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Hakimi, Y.-S. Wong, J. Org. Chem. 2013, 78, 3655–3675.
ACHTUNGTRENNUNG(S,S)-7: Et3N (16.6 mg, 0.928 mmol) was added dropwise to a solution of
enantiopure (S,S)-6c (0.130 g, 0.164 mmol) and T3P (0.200 g,
0.656 mmol) in CH2Cl2 (50 mL) activated by ultrasound. The mixture was
sonicated for 6 h. EtOAc was then added and the mixture was washed
with water. The organic phase was dried with Na2SO4 and the solvent
was removed under reduced pressure. Purification by column chromatog-
raphy (silica gel; CH2Cl2/EtOAc, 9:1) afforded enantiopure (S,S)-7
(0.040 g, 31%, >99% ee) as a colorless solid. The enantiomeric excess
was determined by HPLC analysis (30% isopropanol in hexanes,
0.7 mLminꢀ1). The spectroscopic data were in agreement with those re-
corded above. M.p. 160–1648C; [a]2D2 = +159.8 (c=0.95 in CHCl3).
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Received: June 5, 2013
Published online: September 17, 2013
Chem. Eur. J. 2013, 19, 15155 – 15165
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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