Efficient synthesis and astonishing supramolecular architectures of several symmetric macrolactams

Article abstract of DOI:10.1002/chem.200700522

The synthesis of four C_n symmetric macrocyclic lactams cyclo-[NH-CH₂-CH=CH-CH₂-CO], (1, n = 2; 2, n = 3; 3, n = 4) and cyclo-[NH-CH₂-CH₂-CH=CH-CO]₃ (4) has been achieved by two approaches. A linear route leads to precursors that are subsequently macrocyclized in a separate step. The second, convergent approach relies on the symmetry of the targets: it includes suitably activated subunits, which are subjected to macrocyclization conditions. The subunits first oligomerize, then cyclize to form either pure macrolactams or mixtures. The macrolactam units 1, 2 and 4 stack on top each other through weak interactions (hydrogen bond and van der Waals), to form endless square, rectangular and triangular prisms, respectively. These stacks are further packed side by side in crystals grown from isotropic media. The overall dipoles in the crystals from lactams 1 and 4, which result mostly from the alignment of amide groups, are zero and large, respectively. Macrolactam 2 displays an astonishing isomorphism when allowed to cool down in anisotropic liquid crystal solutions. Large hollow hexagonal tubes are then obtained through a fractal process. Contrary to the three previous rings, 3 yields crystals where prisms of any shape are absent.

Full text of DOI:10.1002/chem.200700522

FULL PAPER
DOI: 10.1002/chem.200700522
Efficient Synthesis and Astonishing Supramolecular Architectures of Several
Symmetric Macrolactams
Pierre Baillargeon,[a] Sylvain Bernard,[a] David Gauthier,[b] Rachid Skouta,[c] and
Yves L. Dory*[a]
Abstract: The synthesis of four Cn sym-
metric macrocyclic lactams cyclo-[NH-
CH2-CH=CH-CH2-CO]n (1, n=2; 2,
n=3; 3, n=4) and cyclo-[NH-CH2-
CH2-CH=CH-CO]3 (4) has been ach-
ieved by two approaches. A linear
route leads to precursors that are sub-
sequently macrocyclized in a separate
step. The second, convergent approach
relies on the symmetry of the targets:
it includes suitably activated subunits,
which are subjected to macrocycliza-
tion conditions. The subunits first oli-
gomerize, then cyclize to form either
pure macrolactams or mixtures. The
macrolactam units 1, 2 and 4 stack on
top each other through weak interac-
tions (hydrogen bond and van der
Waals), to form endless square, rectan-
gular and triangular prisms, respective-
ly. These stacks are further packed side
by side in crystals grown from isotropic
media. The overall dipoles in the crys-
tals from lactams 1 and 4, which result
mostly from the alignment of amide
groups, are zero and large, respectively.
Macrolactam 2 displays an astonishing
isomorphism when allowed to cool
down in anisotropic liquid crystal solu-
tions. Large hollow hexagonal tubes
are then obtained through a fractal
process. Contrary to the three previous
rings, 3 yields crystals where prisms of
any shape are absent.
Keywords: crystal engineering
·
·
·
lactams
·
oligomerization
chemistry
supramolecular
synthetic methods
Introduction
sions occupy a privileged position.[12–23] One such natural
molecule, gramicidin A, is a channel acting as an efficient
ion transporter across cell membranes.[24] Other much larger
proteins similarly shaped as tubes yield pores in lipid bilay-
ers for the same purpose of transport.[25] Synthetic supra-
molecular tubes[26–31] could find many uses in medicine as
drugs[22] or drug delivery systems.[32] However, the applica-
tions of such aggregates are not at all limited to the biology
realm. A plethora of domains such as catalysis, photonics,
material science, can also be targeted.[33–36]
Non-covalent synthesis[1,2] is a rapidly growing field of re-
search, because the resulting supramolecular objects may
find numerous applications as new materials endowed with
very diverse properties.[3–11] Among the different shapes that
can be sculptured, tubular supramolecules of various dimen-
[a] P. Baillargeon, S. Bernard, Prof. Y. L. Dory
Laboratoire de synth›se supramolØculaire
DØpartement de chimie, Institut de Pharmacologie
UniversitØ de Sherbooke, 3001, 12e avenue nord
Sherbrooke, QuØbec J1H 5N4 (Canada)
Fax : (+1)819-820-6823
We have been particularly interested in synthesizing tubes
through controlled stacking of sufficiently rigid ring units 1–
4; each unit consisted of a macrolactam[37–44] of Cn symmetry
(n=2, 3, 4, Figure 1).[45,46]
Owing to the vast potential of such compounds we looked
for expedient and efficient syntheses. We also tried to scruti-
nize the relationships between structure of macrocycles and
how they assemble to supramolecular objects. Such under-
standing is obviously of much value for any work dealing
with closely related or even more remote supramolecular
tubes.
E-mail: Yves.Dory@USherbrooke.ca
[b] D. Gauthier
OmegaChem, 8800, Boulevard de la Rive-Sud.
LØvis, QuØbec G6V9H1 (Canada)
[c] R. Skouta
Department of Chemistry, McGill University
801, Sherbrooke Street West
MontrØal, QuØbec H3A2K6 (Canada)
Supporting information for this article is available on the WWW
1
under http://www.chemeurj.org/ or from the author: Selected H
NMR spectra.
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sponding Boc-protected amine 7 (97%).[50] n-Butanethiol
was coupled with 7 by means of EDCI, DMAP and HOBt
at ꢀ178C to yield the thioester 8 (86%). Many other condi-
tions involving DCC and higher temperatures led to various
amounts of conjugated thioester 17 (Scheme 3). TFA treat-
ment of 8 gave the corresponding ammonium salt, that was
coupled with acid 7 by means of DCC to afford the dimeric
thioester 9 (89%). Boc cleavage of 9, followed by coupling
(DCC) of the resulting ammonium salt with 7, gave the tri-
meric thioester 10 (100%).
Acid 7 was DCC-coupled with the ammonium salt corre-
sponding to 10 to give 12 (48%). Alternatively, the same
tetrameric thioester 12 was better prepared by DCC cou-
pling of two dimers: the ammonium salt obtained from thio-
ester 9 and acid 11 (71%), the latter resulting from KOH
hydrolysis of thioester 9 (100%).
Figure 1. Cn symmetric macrolactams 1–4 (ring size in italics) and their
repeating motifs.
Since preliminary cyclooligomerization attempts from
thioester 8 proved unsuccessful (Table 1), we then selected
pentafluorophenyl (Pfp) esters as cyclooligomerization and/
Results and Discussion
Synthesis: We tackled the synthesis of targets 1–4 in two
ways: macrocyclization,[47] or cyclooligomerization[48,49] of re-
peating subunits A and B (Figure 1) to take advantage of
their symmetry. The thioesters 9, 10 and 12, based on the
same d-amino acid 6 (corresponding to subunit A), were se-
lected as linear precursors to macrocycles 1–3 (Scheme 1).
Thus, trans-b-hydromuconic acid 5 was transformed into the
unsaturated d-amino-acid 6 (49%) and then into its corre-
Table 1. Results of macrocyclization and cyclooligomerization.
Starting ester[a,b]
Ring product
Yield [%]
monomeric thioester 8
monomeric Pfp ester 13
–
dimer 1
trimer 2
tetramer 3
–
dimer 1
tetramer 3
trimer 2
trimer 2
tetramer 3
trimer 4
21
37
12
dimeric thioester 9
dimeric Pfp ester 14
22
49
55
88
67
41
7
trimeric thioester 10
trimeric Pfp ester 16
tetrameric thioester 12
monomeric Pfp ester 21
AHCTREUNG
trimeric thioester 20
50
[a] Conditions for thioesters: i) TFA, ii) AgTFA (3 equiv), DIPEA, DMF,
458C. [b] Conditions for Pfp esters: i) TFA, ii) NMM, dioxane, 808C.
or macrocyclization precursors.[51,52] The first Pfp ester 13,
equivalent to the thioester 8 (Scheme 2), was prepared from
acid 7 with DCC and an equal molar amount of pentafluor-
ophenol (96%). The previously prepared dimeric acid 11
(Scheme 1) was obtained by a new very efficient method by
simply stirring a mixture of Pfp ester 13, amino acid 6 and
K2CO3 in acetone and water (79%). The dimeric Pfp ester
14 was prepared from 11 (83%) as before (DCC, PfpOH).
Amino acid 6 was coupled with dimeric Pfp ester to produce
trimeric acid 15 (85% from 11). Alternatively, Boc cleavage
of carbamate 11 afforded its corresponding dimeric zwitter-
ionic amino acid, that was allowed to react with monomeric
Pfp ester 13 to produce the same acid 15 (82% from 11).
Although both routes are in effect two-step sequences, the
latter proved more effective since it involves a quantitative
cleavage of the Boc group with TFA. All attempts to pre-
pare Pfp ester 16 in the usual way (DCC and equal amount
of PfpOH) from the corresponding acid 15 yielded various
amounts of an undesired and practically inseparable isomer
of 16, in which the alkene at the C-terminal side of the tri-
Scheme 1. Preparation of thioester precursors 8–10 and 12. i) H2SO4,
NaN3, CHCl3, 458C; ii) Boc2O, NaOH, tBuOH, H2O, RT; iii) nBuSH,
EDCI, DMAP, HOBt, CH2Cl2, ꢀ178C; iv) TFA, CH2Cl2, RT; v) DCC,
DMAP, NMM, CH2Cl2, 08C; vi) KOH, H2O, MeOH, RT; vii) DCC,
DMAP, NMM, EtOAc, 08C.
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Symmetric Macrolactams
FULL PAPER
Scheme 3. Preparation of ester precursors 20 and 21. i) DBU, CH2Cl2,
RT; ii) 2,6-lutidine, THF, H2O, AgNO3, reflux; iii) TFA, CH2Cl2, RT; iv)
DCC, DMAP, NMM, CH2Cl2, 08C; v) DIC·3PfpOH (complex), dioxane,
MeCN, 08C.
We then studied the formation of macrolactams 1–4. The
macrocyclizations and cyclooligomerizations were carried
out in similar way. All Boc groups from carbamates 8–10,
12–13, 16, 20 and 21 were cleaved with TFA. The resulting
ammonium salts were added to solutions of DIPEA and
AgTFA in DMF at 458C (thioesters)[56,57] or to solutions of
NMM in dioxane at 808C (Pfp esters). All rings 1–4 were
obtained with various yields (Table 1).
Scheme 2. Preparation of Pfp ester precursors 13, 14 and 16. i) DCC,
PfpOH, EtOAc, RT; ii) K2CO3, MeAc, H2O, RT; iii) DCC, PfpOH,
EtOAc, DMF, RT; iv) TFA, CH2Cl2, RT; v) EDCI·3PfpOH (complex),
CH2Cl2, RT.
peptide had shifted to become conjugated. It is worth noting
that this side reaction had not been observed during the
preparation of its smaller congeners 13 and 14. This synthet-
ic drawback was solved by using the DCC·3PfpOH com-
plex,[53] since no conjugated isomer had been observed with
this reagent. Nevertheless, it was very tedious to get rid of
dicyclohexyl urea (DCU) formed as a side product. The
same purification problem was present with DIC·3PfpOH
complex. Finally, adaptation of the complex methodology to
EDCI afforded the much sought for Pfp ester 16 (69%).
The last macrocyclic target 4 was based on motif B
(Figure 1) that differs from motif A only by the position of
the alkene. Thus, in order to make its corresponding macro-
cyclization thioester precursor 20 (Scheme 3), the alkene of
8 was first conjugated with DBU (100%).[54] The resulting
thioester 17 was hydrolyzed (74%) with 2,6-lutidine and
AgNO3 to trap released nBuSH and prevent it from adding
to unreacted thioester.[55] Acid 18 thus obtained was coupled
with DCC to the TFA salt issued from 17 to give the dimeric
conjugated thioester 19 (43%). TFA treatment of 19, then
DCC coupling of the resulting TFA salt with acid 18, gave
the macrocyclization precursor thioester 20 with a very dis-
appointing yield (14%). On the other hand, the Pfp ester
cyclooligomerization precursor 21 was prepared from acid
18 using DIC·3PfpOH complex (99%).
It immediately appears that the thioester methodology is
much less efficient than the Pfp ester methodology since
thioester 8 did not produce any of the expected lactam
products 1–3. Contrarily, its equivalent Pfp activated esters
13 afforded mixture of three macrolactams 1–3 with good
yields (total yield of 70%). Thus, cyclooligomerization ap-
pears to be favored in the case of Pfp esters but disfavored
in the case of thioesters. The limitation of the thioester
methodology is also clearly visible at the direct macrocycli-
zation level, since dimeric Pfp ester 14 yielded both cyclic
dimer 1 (22% of macrocyclization) and cyclic tetramer 3
(49% of cyclodimerization); dimeric thioester 9 produced
nothing. This latter experiment confirms that thioesters do
not cyclooligomerize, but it also demonstrates that cycliza-
tion to strained rings such as 12-membered lactam 1 is not
possible either. Even for macrocyclizations to stain-free lac-
tams, the Pfp approach remains more efficient, as shown in
the results from trimeric esters 10 and 16 to 18-membered
lactam 2 (yields of 55% from thioester 10 and 88% from
Pfp ester 16). The thioester 12 led also to the larger 24-
membered macrolactam 3 with a similar yield (67%).
Another 18-membered ring, the conjugated macrolactam
4, was obtained by the same route from trimeric thioester 20
and with a comparable yield as that obtained in the case of
isomeric unconjugated lactam 2 from trimeric thioester 10
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Y. L. Dory et al.
Table 2. Structural information for rings 1–4.
(50% for 4 and 55% for 2). We also attempted the cyclooli-
gomerization of monomeric Pfp activated ester 21 to pre-
pare the same target 4. TFA treatment of 21 gave its corre-
sponding salt which was immediately injected to a hot solu-
tion of base in dioxane (Scheme 4).
Ring
Crystal
growth
Unit
symmetry
Tubular
shape
Crystal
polarity
1[a]
2[b]
2[a]
2[c]
3[b]
3[a]
4[b]
MeOH
EtOH/Et2O
EtOAc
liquid crystal
iPrOH/Et2O
nBuOH/tBuOMe
EtOH/Et2O
Ci
C1
C1
C3
Ci
Ci
C3
square
zero
small
small
zero
zero
zero
large
rectangle
rectangle
hexagone
no tubes
no tubes
triangle
[a] Crystal data in ref. [59]. [b] Crystal data in ref. [45]. [c] Structure de-
scribed in ref. [46].
The large 24-membered ring 3 did not produce tubes, but
an interlaced network of rings (Figure 2). Two related con-
formations 3a and 3b are observed in the crystal; their only
difference being the orientation of two opposing alkene
groups. Although the shape of individual macrocycles with
Ci symmetry is roughly circular, they are linked through hy-
drogen bonds to four neighboring macrocycles instead of
only two as would be expected for nanotubes. All possibili-
ties for hydrogen bonding amounting to eight are totally ful-
filled. The doughnut molecules (inner cavity of about 5 Š)
manage to fill all available room by adopting an edge to
centre geometry relationship in the crystal. Obviously, no
tubes could ever form from such large rings, unless other ob-
jects could be inserted into the resulting hollow cylinder.
For that reason, we tried to crystallize 3 with another set of
solvents (tert-butyl methyl ether and n-butanol) to obtain
porous materials with inclusion of solvent molecules. How-
ever, 3 crystallized in a very similar way as before with ex-
clusion of solvent.[59]
Scheme 4. Cyclooligomerization of monomeric Pfp ester 21.
Under these conditions, released free amine [22] pro-
duced small amounts of six-membered lactam 24, possibly
through four-membered ring intermediate [23] resulting
from a favored amine 4-exo-trig cyclization.[58] But [22]
mostly gave linear dimer [25] which cannot cyclize to
medium 12-membered ring 26 (isomeric to 1), as it would be
very strained, suffer transannular interactions and would
likely have more energetic s-cis amides or distorted s-trans
amides. Consequently, [25] had no other choice but to add
statistically another monomer [22] (obviously in higher con-
centration than itself) to yield Pfp activated trimer [27] that
readily cyclized to finally afford 4 (41%).
A similar attempt to provoke polymorphism by using dif-
ferent solvent systems for crystal growth was tried with the
18-membered macrocycle 2.[59] However, both systems
Structures of supramolecular assemblies: We managed to
crystallize all four rings 1–4 from common solvents, al-
though smaller macrocycle 1 crystallization proved much
more difficult (Table 2). The macrocycles 2, 3 and 4 had al-
ready been crystallized by diffusion of diethyl ether in etha-
nol, isopropanol and ethanol, respectively.[45] The unconju-
gated trimer 3 yielded long hexagonal hollow nanotubes
when it was dissolved into some liquid crystals at high tem-
perature, then allowed to slowly cool down.[46] New crystalli-
zation conditions were applied to rings 2 and 3 in order to
study possible polymorphism and to improve the structural
precision for 3. Indeed the length of the double bounds pre-
viously found for 3 were rather short at 1.28 Š and even
1.22 Š. In the new crystal, obtained by diffusion of tert-butyl
methyl ether into a solution of 3 in n-butanol, the refined
alkene bond lengths are 1.30 and 1.31 Š as expected.
Figure 2. a) and b) Two crystal Ci symmetric conformations 3a and 3b of
3 (nBuOH/tBuOMe) (arrows show rotating alkenes); c) Parallel stereo-
views. CH are omitted.
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Symmetric Macrolactams
FULL PAPER
(EtOH/Et2O and EtOAc) produced crystals with similar 3D
arrangements of C1 symmetric molecules (Figure 3). Two
conformers, 2a and 2b, are present in the crystals grown in
Figure 3. a) and b) Two crystal conformations 2a and 2b of 2 (EtOAc);
c) Parallel stereoviews of tubes formed by stacking of conformers 2a and
2b.
ethyl acetate. Noteworthy, these conformations differ only
from each other by rotation of an alkene moiety. These con-
formations share also a common important feature: a b-turn
that is responsible for the flat rectangular shape of the ring.
Polymorphism for such compounds is not too surprising
since a crystal of cyclohexaglycine isosteric[60] to 2 (the three
alkenes of the latter being replaced by amides in the
former) is also polymorphous (Figure 4).[61] In this case,
however, there are as many as four different conformations
present in the same crystal. These conformers belong to two
groups in terms of distinctive features. Thus, conformer a is
held rectangular by means of two b-turns, whereas, conform-
ers b, c and d which have no such intramolecular bonds tend
to adopt more hexagonal shapes. It is worth noting that con-
formers b and c differ from each other by the orientation of
two opposite amides; conformer d represents an intermedi-
ate geometry between b and c where only one of the floppy
amides has rotated. Consequently, a, b and c are all Ci sym-
metric molecules whereas conformer d has no symmetry. In-
terestingly, conformer a has very much the same backbone
geometry as that of b. Simply the intramolecular hydrogen
bonds present in a are disrupted in b and the two floppy
amides adopt a slightly different orientation. Conformer a
of cyclo-(Gly)6 corresponds to conformer 2b of cyclo-(d-
aminoacyl)3 2 (Figure 3). A cooperative effect is obviously
at work in cyclo-(Gly)6 (conformer a): its two b-turn CO–
HN distances are very short at 2.07 and 2.12 Š. Only one
such b-turn exists in the corresponding conformer 2b of 2
with a much longer CO–HN bond length of 2.40 Š.
Figure 4. a), b), c) and d) Four crystal conformations a, b, c and d of cy-
clohexaglycine; e) Parallel stereoviews of tubes formed by stacking of
conformers a (top) and b, c and d (bottom).
together by intra-stacked hydrogen bonds. These stacks can
be compared to endless tubes. Only one kind of flat tube is
observed in 2, and there are no interstacked hydrogen
bonds that could bring more strength to the whole architec-
ture. In the case of cyclo-(Gly)6 the same shape of rectangu-
lar tube is also present. This rectangular tube arises from
conformation a only. The three other more hexagonal con-
formers b–c lead to another more hollow tube in which
some molecules of water are trapped. Contrarily to 2, all
cyclo-(Gly)6 tubes have developed inter-stack hydrogen
bonds (Figure 4e).
When a hot solution of macrolactam 2 in a lipophilic
liquid crystal (BL006) was left to cool down to room tem-
perature, very long and thick fibres crystallized out.[46] These
fibres later proved to be hexagonal hollow tubes when ob-
served by scanning electron microscopy (SEM) after the
liquid crystal matrix had been removed with hexane (Fig-
ure 5a). Obviously this type of hexagonal object could not
be obtained from the same rectangular conformers of 2 as
those obtained from crystal grown from isotropic media
(Table 2 and Figure 3). A quick study of polymorphism for
the macrolactam 2 successfully proved that several forms
can coexist. Thus, crystals of 2 could be grown on an ITO
substrate by diffusion of diethyl ether into a solution of 2 in
methanol (ITO coated glass plate in MeOH solution). Scan-
ning electron microscopy showed tiny crystals shaped-like
Both crystals of cyclo-(d-aminoacyl)3 2 and cyclo-(Gly)6
are constituted of parallel stacks of cyclopeptide rings held
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Y. L. Dory et al.
Figure 5. SEM images of a) a hollow hexagonal tube resulting from cool-
ing down of a hot solution of ring 2 in a liquid crystal; and b), c) and d)
crystals of the same macrocycle 2 grown on the ITO substrate from a
methanol solution.
rectangular prisms (Figure 5b) similar to those also obtained
from isotropic media.[45,59] Aside from this first type of crys-
tal, many smaller hexagonal crystalline objects were also
present (Figure 5c and d).
Conformation analysis calculations (HF/6-31Gd and
MM2) to fit micro-Raman data from tubes extracted from
the liquid crystal matrix showed that such hexagonal hollow
tubes could result from two conformers 2c and 2d of 2 (Fig-
ure 6a and b).[41] These two conformers, which present many
similarities with cyclohexaglycine conformers b–d (Fig-
ure 4b–d), stack on top of each other in an alternate way
(···2c–2d···) to fulfil their hydrogen-bonding capabilities.
The resulting so-called first-generation tubes pack side by
side in an antiparallel fashion by means of interstack hydro-
gen bonds (Figure 6c); the surrounding aggregates of liquid
crystals act as templates for the lipophilic faces of the first
generation tubes (Figure 6d). A second-generation tube of
six first-generation tubes is then constructed. The same frac-
tal self-assembly process is carried on until mesoscopic hex-
agonal tubes appear (Figures 5a and 7).
Thus, the macrocycle 2 proved very flexible, since it could
adopt numerous different conformations. Although poly-
morphism can be sometimes an asset, it can also be trouble-
some as in the case of marketed drugs.[62] We wanted to ad-
dress this matter in the next generation by conceiving a ring
monomer for which stacking and packing processes are com-
pletely controlled and limited to only one possibility.
In order to gain control over the shape of the macrocyclic
monomers and consequently also over the shape of their ag-
gregates, we designed the conformationally restricted mac-
rocyclic 4. Although ring 4 has the same ring size as 2 (18
atoms), its conformation is entirely locked in a triangular
crown (Figure 8a). All intramolecular hydrogen bond as b-
turns found in 2 and cyclohexaglycine (Figures 3 and 4) are
prevented. Conjugation of the alkenes with the amide car-
bonyls imposes all three amides plans to be parallel to the
C3 axis of the cyclotripeptide. The s-trans conformation of
the enamides brings also control over the conformation of
Figure 6. a) and b) calculated conformers 2c and 2d found in hollow hex-
agonal microscopic tubes formed from solution of 2 in a lipophilic liquid
crystal; c) Parallel stereoviews of two antiparallel tubes constituted of al-
ternating conformers 2c and 2d; d) 3D arrangement via interstack hydro-
gen bonds of six antiparallel tubes around bundles of oriented liquid
crystal chains (shown as a yellow object).
the three ethane tethers. As a whole all the regions of the
entire molecule are conformationally coupled, resulting in a
very rigid macrocycle. A direct consequence of the confor-
mational coupling is that the three amides are oriented in
the same direction. Therefore, all amide dipoles add up and
the molecule displays a very strong electric dipole moment
of 9.08 D from B3LYP/6-31G(d) calculations.[63] By compari-
son the calculated dipole moments of conformers 2a and 2b
of the isomeric ring 2 (Figure 3) are 7.22 and 7.40 D, respec-
tively. Such a high dipole is rather surprising for a neutral
molecule; it is in fact equivalent to the extremely polar
NaCl molecule having a experimental dipole of 9.00 D.[64]
The extreme polarity of the molecule is also clearly visible
from its 3D molecular electrostatic potential map (MEP
map).[65] The MEP map indicates that all three carbonyl
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Symmetric Macrolactams
FULL PAPER
the same C3 symmetry of the ring constituents is retained in
the resulting stack and the dipole is amplified. Intuitively,
we were expecting that all the highly polar stacks would
pack in such a way that the gross crystal dipole would be
minimized. On the contrary, all dipoles moments aligned
perfectly in the crystal (Figure 8c). Monocrystals of that
type are very anisotropic;[21,23] they belong to the very rare
trigonal R3 space group.[66]
Cyclo-(d-aminoacyl)2 1 and cyclo-(Gly)4 are isosteric, in
the same way as cyclo-(d-aminoacyl)3 2 and cyclo-(Gly)6.[60]
However, no crystallography reports exist for such a simple
molecule as cyclotetraglycine. In fact cyclotetrapeptides in
general are rather scarce in the literature. This is not too
surprising since these 12-membered rings are very strained
as can be inferred from the fact that most of them crystallize
with either 25%[67] or even 50%[68–76] of their amide bonds
in a more energetic cis conformation. It is therefore amazing
that macrolactam 1 crystallizes from MeOH solution in a C2
conformation corresponding to a cyclotetrapeptide with four
trans amides (Figure 9a). Nevertheless, it appears that there
is much tension in the C2 conformation of 1, since amides
are distorted by as much as 218 from planarity. This tension
even shows up in the alkenes also twisted by a quite large
value of 188. There exists only one known crystallized cyclo-
tetrapeptide whose backbone is conformationally isosteric
to that of 1, the natural product dihydrochlamydocin mono-
hydrate.[77] However, one of the residues being a proline,
stacking of the rings is completely hindered. This is not the
Figure 7. Fractal self-assembly of ring 2 in a lipophilic liquid crystal
matrix. Stacking of 2 leads to a first generation tube Gen-1. A second
generation tube Gen-2 is built through side by side packing of six Gen-1
tubes. Repetition of the same self-assembly process eventually produces
larger objects Gen-X.
Figure 8. a) Crystal conformation of C3 symmetric ring 4. b) Parallel ster-
eoviews of the 3D molecular electrostatic potential map of 4. c) Its crys-
tal stacking and packing.
work cooperatively and impart large charge separation to
the triangular lactam (Figure 8b). The preformed polar mon-
omeric units stack perfectly on top of each other like coins
could do (e.g. all faces up and all tails down). Consequently,
Figure 9. Parallel stereoviews of a) stacked C2 symmetric rings 1 and, b)
and c) its crystal unit cell with two possible orientations of the macrocy-
cles.
Chem. Eur. J. 2007, 13, 9223 –9235
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9229

Y. L. Dory et al.
case for macrolactam 1, for which no such steric interactions
exist. Thus, stacking of units 1 along the C2 axis is favored
(Figure 9a). However, this process occurs in the same way
as for antiparallel b-sheets. This is opposite to the case of 4,
for which stacking is the same as in parallel b-sheets. The
calculated electric dipole moment of 1 is 5.94 D, correspond-
ing roughly to 2/3 of the value calculated for ring 4 (9.08 D).
This comes as no surprise since only two amides participate
to the dipole of 1; three are involved in the case of 4. The
highly polar stacks further pack side by side like 4. Howev-
er, the order in the crystal is far from being perfect. Contra-
rily to 4, there are two possible orientations for each ring
with an average occupancy of 50% (Figure 9b and c). The
two possible orientations at each ring position result from
908 rotation around the C2 axis (z axis) followed by xy plan
inversion. This is obviously a major difference with 4, where
the order can be considered to be perfect. But, the most
striking difference resides in the relative orientation of the
stacks dipoles. All these dipoles are parallel in the case of 4,
resulting in a strong monocrystal gross dipole. Whereas,
they contrary each other in the crystal of 1. There are at
present no clear reasons for this.
ExperimentalSection
Generalmethods : 1,4-Dioxane was distilled over pellets of KOH. Italic
integral figures for 1H NMR signals indicate that they vary with time be-
1
cause of D/H exchange; selected H NMR spectra are shown in the Sup-
porting Information.
Amino acid 6: Commercially available trans-b-hydromuconic acid
5
(30 g, 207.9 mmol) was dissolved in CHCl3 (900 mL) at 458C under stir-
ring. Concentrated H2SO4 (90 mL) was then added, followed by small
portions of NaN3 (13.5 g, 207.9 mmol) over a period of 35 min. The vis-
cous solution was stirred for 5 h at 458C and further overnight at RT.
The resulting solution was extracted with H2O (3”250 mL) and the com-
bined aqueous layers were diluted with H2O (400 mL) to dissolve small
floating particles. Meanwhile, Dowex resin 50WX8-100 (about 650 mL)
was washed with de-ionized H2O (1.5 L) and HCl (0.1n, 1.0 L). The re-
sulting resin was then loaded with the aqueous extract, rinsed with de-
ionized H2O until pH 7 (about 1.0 L). The product was finally eluted
with pyridine (0.1n, 2.0 L). All washings and elutions were performed
under atmospheric pressure. The fractions with the desired product 6
were concentrated. The resulting white precipitate was filtered, rinsed
with iPrOH and dried under vacuum (11.7 g, 49%). M.p. 166–1678C;
1H NMR (300 MHz, D2O, TMS): d=5.86 (m, 1H), 5.50 (m, 1H), 3.45 (d,
J=6.5 Hz, 2H), 2.87 ppm (d, 2H, 7 Hz); 13C NMR (75 MHz, D2O, TMS):
d=180.0, 132.8, 123.0, 40.8 ppm; IR (KBr): n˜ =2800 br, 1630, 1560, 1490,
1370, 980 cmꢀ1; MS (70 eV): m/z: 114 [MꢀH+], 116 [M+H+]; HRMS
(70 eV): m/z: calcd for C5H8NO2: 114.0555; found: 114.0553 [MꢀH+],
116.0709 [M+H+].
Carbamate 7: Di-tert-butyl dicarbonate (2.89 g, 13.2 mmol) in tBuOH
(5 mL) was added to a solution of amine 6 (1.69 g, 14.7 mmol) and 2.1n
aqueous NaOH (7 mL, 14.7 mmol) in tBuOH (5 mL). The solution was
stirred for 5 min, then 2.1n aqueous NaOH (7 mL, 14.7 mmol) was
added. The mixture was subsequently stirred for an additional 17 h at
RT. The solution was concentrated under reduced pressure, and the resi-
due was acidified with 6n aqueous HCl until pH 3 was reached. The
aqueous phase was extracted with Et2O (3”20 mL). The combined or-
ganics extracts were dried over Na2SO4, filtrated and concentrated to
give the title compound as a white solid (2.75 g, 97%). Rf =0.30 (EtOAc/
hexane/AcOH 60:39:1); m.p. 59–618C; 1H NMR (300 MHz, CDCl3,
TMS): d=9.39 (br, 1H), 5.75–5.55 (m, 2H), 4.69 (br, 1H), 3.70 (br, 2H),
3.09 (d, J=6.5 Hz, 2H), 1.43 ppm (s, 9H); 13C NMR (75 MHz, CDCl3,
TMS): d=176.8, 154.5, 130.8, 122.8, 81.0, 41.3, 37.0, 27.6 ppm; 13C NMR
(75 MHz, CD3OD, TMS): d=174.1, 156.9, 130.2, 123.6, 78.6, 41.4, 36.9,
27.3 ppm; IR (NaCl): n˜ =3335, 3000 br, 1715, 1520, 1170, 970 cmꢀ1; MS
(70 eV): m/z: 159 [M+ꢀC4H8]; HRMS (70 eV): m/z: calcd for C6H9NO4:
159.0532; found: 159.0536 [M+ꢀC4H8].
Conclusion
Cyclooligomerization is a rapid method to prepare conjugat-
ed trimers like 4; it is also efficient to synthesize unconjugat-
ed dimeric, trimeric and even tetrameric lactams like 1–3, al-
though mixtures of these products cannot be avoided. De-
spite this apparent drawback, this technique remains attrac-
tive because the three products 1–3 can be very easily puri-
fied. Introduction of side chains and groups to these Cn
symmetric frameworks to obtain specific properties is the
current goal from now on.
The polymorphism of crystals constituted of cyclic pep-
tides can be controlled by reducing the mobility of the ring.
It is possible to achieve that goal when the conformational
shapes of all regions of the macrocycle are interdependent.
Such total rigidity was reached in the conjugated ring 4. In
that particular case, the molecular charge distribution was
also completely controlled. Our data (for 1 and 4) suggest
that ring rigidity coupled with well separated charges might
be the major contributors to monomorphism. However,
these simple rules apply only to stacking, since it seems im-
possible for now to explain why some stacks prefers to pack
in parallel fashion (4), while other prefer an antiparallel ar-
rangement (1). For more floppy systems (2 and 3), confor-
mational flexibility is present so that polymorphs are likely.
Nevertheless, the medium of crystallization has a great influ-
ence on the final outcome as shown in the case of 2 where
rectangular or hexagonal conformers are selectively sorted
in isotropic and anisotropic media, respectively.
Thioester 8: Acid
7 (600 mg, 2.79 mmol) was dissolved in CH2Cl2
(20 mL) and cooled with an ice bath. The reagents were added in the fol-
lowing order: HOBt (452 mg, 3.35 mmol), DMAP (851 mg, 6.97 mmol),
nBuSH (313 mL, 2.93 mmol) and EDCI (639 mg, 3.35 mmol). The flask
was sealed with a rubber septum and purged with N2. The resulting mix-
ture was stirred until a clear homogenous solution was obtained and im-
mediately placed in the freezer at ꢀ178C for 18 h without stirring. Some
starting material 7 was still present, and more nBuSH (60 mL, 0.56 mmol)
and EDCI (106 mg, 0.56 mmol) were quickly added to the reaction mix-
ture placed in an ice bath. The flask was sealed and purged with nitrogen
and set at ꢀ178C for another 18 h, after that time the reaction was com-
plete. The reaction mixture was poured directly from the freezer into sa-
turated aqueous NH4Cl (30 mL). The CH2Cl2 layer was isolated and the
remaining aqueous solution was extracted with CH2Cl2 (3”20 mL). The
combined organics layers were dried on Na2SO4, filtrated and concentrat-
ed. The rude residue was purified by flash chromatography on silica gel
eluting with Et2O/hexane 7:3 to yield a colorless oil (688 mg, 86%). Rf =
0.80 (Et2O/hexane 7:3); 1H NMR (300 MHz, CDCl3, TMS): d=5.75–5.5
(m, 2H), 4.64 (br, 1H), 3.72 (br, 2H), 3.24 (d, J=5.5 Hz, 2H), 2.84 (t, J=
7.5 Hz, 2H), 1.52 (m, 2H), 1.42 (s, 9H), 1.38 (m, 2H), 0.89 ppm (t, J=
7 Hz, 3H); 13C NMR (75 MHz, CDCl3, TMS): d=197.5, 155.7, 131.9,
123.4, 79.4, 47.0, 42.1, 31.5, 28.7, 28.3, 21.9, 13.5 ppm; IR (NaCl): n˜ =
3355, 2965, 2930, 2870, 1695, 1515, 1250, 1170, 970 cmꢀ1; MS (70 eV):
9230
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9223 –9235

Symmetric Macrolactams
FULL PAPER
m/z: 214 [M+ꢀC4H9O]; HRMS (70 eV): m/z: calcd for C10H16NO2S:
214.0902; found: 214.0909 [M+ꢀC4H9O].
(br, 1H), 5.8–5.5 (m, 4H), 3.76 (m, 2H), 3.62 (d, J=5 Hz, 2H), 3.04 (d,
J=7 Hz, 2H), 2.94 (d, 4H, 6 Hz), 1.43 ppm (s, 9H); IR (KBr): n˜ =3340,
3310, 2900 br, 1685, 1635, 1530, 1170, 970 cmꢀ1
.
Dipeptide 9: Carbamate 8 (0.98 g, 3.41 mmol) was dissolved in a mixture
of TFA (5 mL) and CH2Cl2 (5 mL) and stirred for 45 min at RT. Toluene
(5 mL) was added to the solution and concentrated in order to remove
the excess of TFA. This operation was repeated four more times to give
the corresponding ammonium salt. 1H NMR (300 MHz, CDCl3, TMS):
d=7.68 (br, 3H), 5.96 (m, 1H), 5.70 (m, 1H), 3.64 (br, 2H), 3.31 (d, J=
6.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 1.54 (m, 2H), 1.38 (m, 2H),
0.90 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3, TMS): d=198.2,
130.1, 125.3, 46.5, 41.5, 31.2, 28.9, 21.8, 13.4 ppm; IR (NaCl): n˜ =3000 br,
1675, 1530, 1200, 1140, 975 cmꢀ1; MS (70 eV): m/z: 188 [M+H+]; HRMS
(70 eV): m/z: calcd for C9H18NOS: 188.1109; found: 188.1115 [M+H+].
Tetrapeptide 12: Method 1: A solution of carbamate 9 (20 mg, 53 mmol)
in TFA (2 mL) and CH2Cl2 (2 mL) was stirred for 45 min at RT. Toluene
(2 mL) was added to the solution and concentrated. This operation was
repeated four more times to give the corresponding ammonium salt, that
was dissolved in a mixture of CH2Cl2 (2 mL), EtOAc (1 mL) and DMF
(100 mL). NMM (17 mL, 0.16 mmol) was added and the mixture was
stirred for 30 min. DMAP (1 mg, 8 mmol) and acid 11 (18 mg, 58 mmol)
were added and the resulting solution was cooled to 08C. DIC (9 mL,
58 mmol) was added to the mixture, that was stirred for 30 min at 08C
and for 7 d at RT. The reaction was filtered on Celite and concentrated
before being purified by flash chromatography on silica gel eluting with
MeOH/EtOAc 1:9. 12 was obtained as a white solid (22 mg, 71%).
The salt was dissolved in CH2Cl2 (10 mL) and NMM (1.5 mL, 13.6 mmol)
was added. The resulting solution was stirred for 10 min before addition
of DMAP (42 mg, 0.34 mmol) and the acid 7 (807 mg, 3.75 mmol). The
mixture was cooled to 08C and a 1m solution of DCC in cyclohexane
(3.75 mL, 3.75 mmol) was added. It was stirred for 5 min at 08C and for
17 h at RT. The reaction mixture was filtered on Celite and concentrated
before being purified by flash chromatography on silica gel eluting with
hexane/EtOAc 2:3 to afford the title compound as a white solid (1.17 g,
89%). Rf =0.27 (EtOAc/hexane 7:3); m.p. 75–768C; 1H NMR (300 MHz,
CDCl3, TMS): d=6.03 (br, 1H), 5.75–5.55 (m, 4H), 4.78 (br, 1H), 3.85 (t,
J=5.5 Hz, 2H), 3.71 (t, J=5.5 Hz, 2H), 3.25 (d, J=6 Hz, 2H), 2.97 (d,
J=6.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 1.52 (m, 2H), 1.42 (s, 9H), 1.38
(m, 2H), 0.90 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3, TMS):
d=197.5, 170.6, 155.9, 132.1, 131.0, 124.6, 124.0, 79.5, 47.0, 42.3, 41.1,
39.9, 31.5, 28.7, 28.4, 21.9, 13.6 ppm; IR (NaCl): n˜ =3350, 3295, 2930,
1685, 1640, 1525, 1245, 1170, 970 cmꢀ1; MS (70 eV): m/z: 328 [M+
ꢀC4H8]; HRMS (70 eV): m/z: calcd for C15H24N2O4S: 328.1457; found:
328.1451 [M+ꢀC4H8].
Method 2: Carbamate 10 (38 mg, 79 mmol) in TFA (2 mL) and CH2Cl2
(2 mL) was stirred for 45 min at RT. Toluene (2 mL) was added to the so-
lution and concentrated (same operation repeated 4”) to yield the corre-
sponding salt. M.p. 134–1378C; 1H NMR (300 MHz, CDCl3/TFA 1:1,
TMS): d=6.89 (br, 3H), 6.04 (m, 1H), 5.95–5.55 (m, 5H), 4.05–3.85 (m,
4H), 3.80 (t, J=6 Hz, 2H), 3.41 (d, J=7 Hz, 2H), 3.35–3.2 (m, 4H), 2.96
(t, J=7.5 Hz, 2H), 1.60 (m, 2H), 1.41 (m, 2H), 0.93 ppm (t, J=7 Hz,
3H); IR (KBr): n˜ =3290, 3100 br, 1690, 1640, 1545, 1140, 970 cmꢀ1
.
The compound was dissolved in EtOAc (3 mL) and DMF (1 mL). NMM
(26 mL, 0.24 mmol) was added and the resulting solution was stirred for
10 min. DMAP (5 mg, 40 mmol) and acid 7 (19 mg, 87 mmol) were added.
The solution was cooled to 08C before addition of a 1m solution of DCC
in CH2Cl2 (87 mL, 87 mmol). The resulting mixture was stirred for 5 min
at 08C and for 3 h at RT. The mixture was filtered on Celite and concen-
trated before being purified by flash chromatography on silica gel eluting
with MeOH/EtOAc 1:9. The peptide 12 was obtained as a white solid
(22 mg, 48%). 1H NMR (300 MHz, CDCl3, TMS): d=6.45 (br, 1H), 6.28
(br, 1H), 6.19 (br, 1H), 5.8–5.5 (m, 8H), 4.88 (br, 1H), 3.9–3.75 (m, 6H),
3.70 (m, 2H), 3.27 (d, J=6 Hz, 2H), 2.98 (d, J=6 Hz, 6H), 2.86 (t, J=
7.5 Hz, 2H), 1.65–1.2 (m, 4H), 1.43 (s, 9H), 0.91 ppm (m, 3H); IR
Tripeptide 10: Carbamate 9 (131 mg, 0.34 mmol) was dissolved in TFA
(5 mL) and CH2Cl2 (5 mL) and stirred for 45 min at RT. Toluene (5 mL)
was added to the solution and concentrated. This operation was repeated
four more times to give the corresponding ammonium salt. M.p. 107–
1108C; 1H NMR (300 MHz, CD3OD, TMS): d=8.10 (br, 1H), 5.99 (dt,
J=15.5 Hz, 7 Hz, 1H), 5.8–5.55 (m, 3H), 3.78 (m, 2H), 3.53 (d, J=
6.5 Hz, 2H), 3.30 (m, 2H), 3.05 (d, J=7 Hz, 2H), 2.87 (t, J=7 Hz, 2H),
1.54 (m, 2H), 1.39 (m, 2H), 0.92 ppm (t, J=7 Hz, 3H); IR (KBr): n˜ =
(NaCl): n˜ =3300, 2960, 1685, 1635, 1530, 970 cmꢀ1
.
Pentafluorophenyl ester 13: Acid 7 (1.00 g, 4.65 mmol) was dissolved at
RT in EtOAc (30 mL) and PfpOH (898 mg, 4.88 mmol) was added. A so-
lution of DCC (1.01 g, 4.88 mmol) in EtOAc (30 mL) was added to the
reaction by means of an addition funnel. The solution became cloudy
after a few minutes and a white precipitate appeared. The solution was
allowed to stir overnight. Hexane (20 mL) was added and the precipitate
of DCU was filtered off. The clear solution was concentrated and the res-
idue purified by flash chromatography on silica gel eluting with EtOAc/
hexane 3:7 to afford the title compound as a white solid (1.64 g, 96%).
Rf =0.67 (EtOAc/hexane 3:7); 1H NMR (300 MHz, CDCl3, TMS): d=
5.85–5.65 (m, 2H), 4.64 (br, 1H), 3.79 (br, 2H), 3.43 (m, 2H), 1.45 ppm
(s, 9H); 13C NMR (75 MHz, CDCl3, TMS): d=167.4, 155.7 (5 very weak
signals around 140 from Pfp ring), 132.7, 121.3, 79.5, 41.9, 36.3, 28.3 ppm;
19F NMR (282 MHz, CDCl3, TMS): d=ꢀ76.55 (d, J=18.5 Hz, 2F),
ꢀ82.60 (t, J=21.5 Hz, 1F), ꢀ86.40 ppm (t, J=19.5 Hz, 2F); IR (NaCl):
n˜ =3350, 2980, 2935, 1795, 1700, 1525, 1175, 1095, 1005 cmꢀ1; MS (70 eV):
m/z: 325 [M+ꢀC4H8]; HRMS (70 eV): m/z: calcd for C12H8F5NO4:
325.0373; found 325.0367 [M+ꢀC4H8].
Acid 11: The activated ester 13 (589 mg, 1.61 mmol) was dissolved in a
mixture of MeAc (30 mL) and H2O (2 mL) along with the zwitterionic
amino acid 6 (204 mg, 1.77 mmol) and K2CO3 (222 mg, 1.77 mmol). The
reaction was complete after 2 h. The solution was concentrated under re-
duced pressure and the residue was taken in CH2Cl2 (50 mL) and 1n
aqueous HCl (50 mL). The organic phase was isolated and the remaining
aqueous layer was extracted with CH2Cl2 (3”30 mL). The combined or-
ganics layers were dried on Na2SO4, filtrated and hexane (50 mL) was
added before the solution was concentrated. The white solid that formed
during the concentration was filtrated before complete evaporation of
the solvent and rinsed with hexane to afford pure product. More product
precipitated in the mother liquor; it was filtered and rinsed in the same
way. The combined powder gave pure white product 11 (382 mg, 79%).
3290, 3100 br, 1685, 1640, 1545, 1140, 975 cmꢀ1
.
The compound was dissolved in CH2Cl2 (10 mL) followed by NMM
(112 mL, 1.0 mmol). The resulting solution was stirred for 30 min. DMAP
(4 mg, 0.03 mmol) and acid 7 (81 mg, 0.37 mmol) were added. The result-
ing solution was cooled to 08C. A 1 m solution of DCC in cyclohexane
(370 mL, 0.37 mmol) was added to the reaction mixture, that was stirred
for 5 min at 08C and then for 19 h at RT. The mixture was filtered on
Celite and concentrated before being purified by flash chromatography
on silica gel eluting with MeOH/EtOAc 1:9. The desired product was ob-
tained as a white solid (164 mg, 100%). Rf =0.31 (MeOH/EtOAc 1:9);
m.p. 140–1438C; 1H NMR (300 MHz, CDCl3, TMS): d=6.53 (br, 1H),
6.32 (br, 1H), 5.75–5.5 (m, 6H), 4.98 (br, 1H), 3.85–3.75 (m, 4H), 3.67
(br, 2H), 3.24 (d, J=6 Hz, 2H), 2.97 (d, J=6.5 Hz, 4H), 2.83 (t, J=
7.5 Hz, 2H), 1.6–1.2 (m, 4H), 1.40 (s, 9H), 0.88 ppm (t, J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3, TMS): d=197.7, 171.3, 170.9, 156.1, 132.2,
131.0, 130.9, 125.0, 124.4, 123.9, 79.6, 47.0, 42.3, 41.2, 41.1, 39.7, 31.4, 29.7,
28.7, 28.3, 21.9, 13.6 ppm; IR (KBr): n˜ =3335, 3300, 2960, 1685, 1635,
1530, 1170, 970 cmꢀ1
;
MS (70 eV): m/z: 408 [M+ꢀOtBu], 425 [M+
ꢀC4H8]; HRMS (70 eV): m/z: calcd for C24H39N3O5S: 481.2610; found:
481.2616 [M+].
Acid 11: Thioester
9 (100 mg, 0.26 mmol) was dissolved in MeOH
(4 mL). 2% w/v aqueous KOH (900 mL, 0.31 mmol) was added and the
resulting mixture was stirred at RT for 23 h. The solvent was removed
under reduced pressure and H2O (10 mL) was added to the residue. The
aqueous solution was washed with EtOAc (5 mL), acidified with 1n
aqueous HCl until pH 2 was reached, then extracted with EtOAc (3”
10 mL). The combined organics layers were dried on Na2SO4, filtrated
and concentrated. The product was recovered as a white solid (81 mg,
100%). M.p. 109–1188C; 1H NMR (300 MHz, CD3OD, TMS): d=8.03
Chem. Eur. J. 2007, 13, 9223 –9235
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9231

Y. L. Dory et al.
Pentafluorophenyl ester 14: Acid 11 (120 mg, 0.38 mmol) and PpfOH
(70 mg, 0.38 mmol) were added to a mixture of EtOAc (25 mL) and
DMF (2 mL) at RT. DCC (78 mg, 0.38 mmol) in EtOAc (10 mL) was
added to the reaction dropwise with an addition funnel. The solution was
allowed to stir overnight. Hexane (20 mL) was added and the solution
was then filtrated to remove the white precipitate. The clear solution was
concentrated and the residue purified by flash chromatography on silica
gel eluting with CH2Cl2/EtOAc 1:1. The title product was obtained as a
white solid (152 mg, 83%). Rf =0.45 (CH2Cl2/EtOAc 1:1); 1H NMR
(300 MHz, CD3OD, TMS): d=8.10 (br, 1H), 6.70 (br, 1H), 5.85–5.55 (m,
4H), 3.81 (m, 2H), 3.63 (m, 2H), 3.51 (d, J=4.5 Hz, 2H), 2.96 (d, J=
6.5 Hz, 2H), 1.42 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, TMS): d=
170.8, 167.4, 166.0, 156.0, 132.2, 131.9, 124.5, 121.9, 79.5, 42.4, 41.0, 39.8,
37.7, 28.3 ppm; 19F NMR (282 MHz, CDCl3, TMS): d=ꢀ76.55 (d, J=
18.5 Hz, 2F), ꢀ82.60 (t, J=21.5 Hz, 1F), ꢀ86.40 ppm (t, J=19.5 Hz, 2F);
IR (NaCl): n˜ =3355, 2990, 1790, 1705, 1655, 1520, 1000 cmꢀ1; MS (70 eV):
m/z: 422 [M+ꢀC4H8]; HRMS (70 eV): m/z: calcd for C17H15F5N2O5:
422.0901; found 422.0911 [M+ꢀC4H8].
Acid 15: Method 1: Acid 11 (376 mg, 1.20 mmol) was dissolved in a mix-
ture of TFA (1 mL) and CH2Cl2 (3 mL) and stirred for 35 min. Toluene
(5 mL) was added to the solution and concentrated in order to remove
TFA. This operation was repeated four more times to ensure complete
azeotropic removal of TFA. To the resulting residue was added a solution
of activated ester 13 (505 mg, 1.32 mmol) in MeAc (20 mL). Aqueous
K2CO3 (530 mg in 1.5 mL H2O, 384 mmol) was slowly added and the re-
action mixture was stirred for 5 h. The reaction was found to be complete
after that time and the solution was concentrated under reduced pressure
to remove the MeAc. The residue was diluted with H2O (5 mL) and
washed three times with CH2Cl2. The aqueous phase was acidified with
1n aqueous HCl until pH 4 was reached and the acid 15 was simply fil-
trated and rinsed with H2O then dried to afford a white powder (405 mg,
82%).
washed with aqueous 1n HCl (2”60 mL) and with brine. The organic
layer was dried on Na2SO4, filtrated and concentrated to afford the title
product as an orange oil (7.81 g, 100%). Rf = 0.75 (Et2O/hexane/AcOH
70:29:1); 1H NMR (300 MHz, CDCl3, TMS): d=6.81 (td, J=7 Hz,
15.5 Hz, 1H), 6.15 (td, J=1.5 Hz, 15.5 Hz, 1H), 4.56 (br, 1H), 3.27 (m,
2H), 2.94 (t, J=7 Hz, 2H), 2.39 (m, 2H), 1.58 (m, 2H), 1.44 (s, 9H), 1.39
(m, 2H), 0.92 ppm (t, J=7 Hz, 3H); 13C NMR (75 MHz, [D6]DMSO,
TMS): d=189.1, 156.0, 143.3, 129.8, 77.9, 38.7, 32.6, 31.7, 28.6, 28.0, 21.8,
13.8 ppm; IR (NaCl): n˜ =3340, 3000 br, 1700, 1170 cmꢀ1; MS (70 eV):
m/z: 231 [M+ꢀC4H8]; HRMS (70 eV): m/z: calcd for C10H17NO3S:
231.0929; found: 231.0924 [M+ꢀC4H8].
Acid 18: AgNO3 (19.8 g, 117 mmol) was added to a solution of thioester
17 (2.23 g, 7.8 mmol) in THF (72 mL), H2O (18 mL) and 2,6-lutidine
(6.8 mL, 58.2 mmol). The mixture was heated under reflux for 24 h. Gla-
cial acetic acid (20 mL) and Et2O (400 mL) were added. The solution
was filtrated on Celite and washed successively with saturated aqueous
CuSO4 (100 mL) and brine (100 mL). Organic layer was dried (MgSO4),
filtrated and concentrated under reduced pressure. The crude product
(1.31 g) was dissolved in EtOAc (50 mL) and extracted with 3m aqueous
K2CO3 (50 mL). 1n aqueous HCl was added to the aqueous layer until
pH 3 was reached. It was then extracted with EtOAc (3”50 mL). Com-
bined organic extract was dried (Na2SO4), filtrated and concentrated to
give 18 as a yellow solid (1.26 g, 74%). 1H NMR (300 MHz, CD3OD,
TMS): d=6.96 (td, J=7 Hz, 15.5 Hz, 1H), 5.84 (td, J=1.5 Hz, 15.5 Hz,
1H), 4.95 (br, 1H), 3.17 (t, J=7 Hz, 2H), 2.37 (qd, J=7 Hz, 1.5 Hz, 2H),
1.42 ppm (s, 9H); 13C NMR (75 MHz, CD3OD, TMS): d=168.3, 157.0,
146.3, 122.8, 78.6, 38.5, 32.3, 27.3 ppm; IR (KBr): n˜ =3365, 3000 br, 1685,
1520, 1280, 1165 cmꢀ1; MS (70 eV): m/z: 159 [M+ꢀC4H8], 200 [M+
ꢀCH3]; HRMS (70 eV): m/z: calcd for C6H9NO4: 159.0532; found:
159.0528 [M+ꢀC4H8], 200.0916 [M+ꢀCH3].
Dipeptide 19: TFA (10 mL) was added to a solution of the carbamate 17
(2.0 g, 6.96 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 45 min.
Toluene (5 mL) was added to the solution and concentrated. This opera-
tion was repeated four more times to ensure complete azeotropic remov-
al of TFA and to yield the corresponding ammonium salt. 1H NMR
(300 MHz, CDCl3, TMS): d=8.15 (br, 3H), 6.74 (m, 1H), 6.20 (d, J=
5.5 Hz, 1H), 3.10 (m, 2H), 2.92 (t, J=7.5 Hz, 2H), 2.59 (brq, J=7 Hz,
2H), 1.55 (m, 2H), 1.39 (m, 2H), 0.91 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3, TMS): d=190.4, 162.4, 148.1, 143.7, 137.7, 131.5, 38.2,
31.4, 29.7, 28.6, 21.9, 13.6 ppm; IR (NaCl): n˜ =3000 br, 1680, 1205, 1140,
1020 cmꢀ1; MS (70 eV): m/z: 188 [M+H+]; HRMS (70 eV): m/z: calcd
for C9H18NOS: 188.1109; found: 188.1113 [M+H+].
Method 2: A mixture of activated ester 14 (200 mg, 418 mmol), zwitter-
ionic amino acid 6 (50 mg, 439 mmol) and K2CO3 (63 mg, 459 mmol) in
MeAc (20 mL) and H2O (1 mL) was stirred for 18 h. The solution was
concentrated to remove MeAc and the residue was diluted with H2O
(5 mL) and washed three times with CH2Cl2. The aqueous phase was
acidified with 1n aqueous HCl until pH 4 was reached and the precipi-
tate was filtrated, rinsed with H2O then dried to afford the title com-
pound as a white powder (145 mg, 85%). 1H NMR (300 MHz, CD3OD,
TMS): d=8.1–7.95 (br, 2H), 5.8–5.5 (m, 6H), 3.8–3.75 (m, 4H), 3.62 (d,
J=5 Hz, 2H), 3.05 (d, J=7 Hz, 2H), 2.94 (d, J=6 Hz, 4H), 1.43 ppm (s,
9H); IR (NaCl): n˜ =3335, 3290, 2900 br, 1685, 1630, 1530, 965 cmꢀ1; MS
(70 eV): m/z: 409; HRMS (70 eV): m/z: calcd for C20H31N3O6: 409.2213;
found: 409.2206 [M+].
The compound was dissolved in CH2Cl2 (60 mL) and NMM (2.3 mL,
20.9 mmol) was added. DMAP (85 mg, 0.7 mmol) and the acid 18 (1.65 g,
7.66 mmol) were added 10 min later. The resulting solution was cooled to
08C and 1m DCC in CH2Cl2 (7.7 mL, 7.7 mmol) was added and stirred
for 1 h. The reaction mixture was allowed to warm up to RT and was
stirred for 15 h. It was filtered on Celite and the solvent was removed
under reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel eluting with hexane/EtOAc 30:70 to yield the title prod-
Pentafluorophenyl ester 16: PfpOH (797 mg, 4.32 mmol) and EDCI
(276 mg, 1.44 mmol) were added to dioxane (15 mL). The mixture was
heated by means of a heat gun to ensure complete dissolution of the sus-
pension. The resulting clear solution was stirred for 6 h at RT. Dioxane
was removed and a thick yellowish oil was obtained. Some of this result-
ing EDCI·3PFP complex (653 mg, 0.88 mmol) was dissolved in dioxane
(2 mL) and added to solution of the acid 15 (120 mg, 0.29 mmol) in
CH2Cl2 (10 mL). The reaction mixture was stirred for 24 h and concen-
trated under reduced pressure to afford a white paste. The crude product
was purified by flash chromatography on silica gel starting with CH2Cl2
only to elute first the PfpOH, then with MeOH/CH2Cl2 1:9 to yield the
title product as a white powder (115 mg, 69%). Rf =0.70 (MeOH/CH2Cl2
uct as
a
white solid (1.15 g, 43%). Rf =0.48 (EtOAc); 1H NMR
(300 MHz, CDCl3, TMS): d=6.8–6.6 (m, 3H), 6.07 (d, J=15.5 Hz, 1H),
5.81 (d, J=15.5 Hz, 1H), 4.96 (br, 1H), 3.35 (q, J=6.5 Hz, 2H), 3.13
(brq, J=6.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.35 (q, J=6.5 Hz, 2H),
2.27 (q, J=6.5 Hz, 2H), 1.48 (m, 2H), 1.33 (s, 9H), 1.31 (m, 2H),
0.82 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3, TMS): d=189.8,
165.7, 155.9, 141.0, 140.9, 130.4, 125.3, 79.2, 39.2, 37.9, 32.5, 35.1, 28.4,
28.3, 29.1, 13.5 ppm; IR (KBr): n˜ =3360, 3300, 2960, 1685, 1625, 1535,
1280, 1175, 975 cmꢀ1; MS (70 eV): m/z: 328 [M+ꢀC4H8]; HRMS (70 eV):
m/z: calcd for C15H24N2O4S: 328.1457; found 328.1451 [M+ꢀC4H8].
Tripeptide 20: TFA (10 mL) was added to a solution of the carbamate 19
(1.15 g, 2.99 mmol) in CH2Cl2 (20 mL). The mixture was stirred for
45 min. Toluene (5 mL) was added to the solution and concentrated. This
operation was repeated four more times to ensure complete azeotropic
removal of TFA and to yield the corresponding ammonium salt.
1H NMR (300 MHz, CD3OD, TMS): d=8.23 (br, 3H), 6.84 (td, J=7 Hz,
15.5 Hz, 1H), 6.68 (td, J=7 Hz, 15.5 Hz, 1H), 6.20 (d, J=15.5 Hz, 1H),
6.07 (d, J=15.5 Hz, 1H), 3.39 (m, 2H), 3.07 (t, J=7 Hz, 2H), 2.92 (t, J=
1
1:9); H NMR (300 MHz, CDCl3, TMS): d=6.24 (br, 1H), 6.12 (br, 1H),
5.8–5.5 (m, 6H), 4.84 (br, 1H), 3.90 (m, 2H), 3.84 (t, J=5 Hz, 2H), 3.70
(t, J=5 Hz, 2H), 3.44 (m, 2H), 2.99 (d, J=8 Hz, 2H), 2.97 (d, J=8 Hz,
2H), 1.44 ppm (s, 9H); 13C NMR (75 MHz, CDCl3, TMS): d=170.9,
170.6, 167.5, 156.1, 132.4, 131.9, 131.4, 124.9, 124.4, 121.9, 79.6, 41.3, 41.0,
39.9, 39.8, 36.3, 28.3 ppm; IR (NaCl): n˜ =3440, 3355, 3000, 1785, 1705,
1655, 1515, 995 cmꢀ1; MS (70 eV): m/z: 476 [M+ꢀBoc]; HRMS (70 eV):
m/z: calcd for C21H23F5N3O4: 476.1609; found: 476.1615 [M+ꢀBoc].
Conjugated alkene 17: DBU (2 mL, 13.1 mmol) was added to a solution
of conjugated thioester 8 (7.81 g, 27.2 mmol) in CH2Cl2 (140 mL) and the
resulting solution was allowed to stir at RT for 3 d. The solution was
9232
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9223 –9235

Symmetric Macrolactams
FULL PAPER
7 Hz, 2H), 2.55 (q, J=7 Hz, 2H), 2.44 (q, J=6.5 Hz, 2H), 1.56 (m, 2H),
1.40 (m, 2H), 0.92 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CD3OD,
TMS): d=190.0, 166.4, 141.5, 137.9, 129.8, 126.5, 38.0, 37.5, 31.5, 29.4,
27.7, 21.5, 12.5 ppm; IR (NaCl): n˜ =2900 br, 2930, 1670, 1625, 1460, 1210,
1140, 980 cmꢀ1; MS (70 eV): m/z: 285 [M+H+]; HRMS (70 eV): m/z:
calcd for C14H25N2O2S: 285.1637; found: 285.1643 [M+H+].
975 cmꢀ1; MS (70 eV): m/z: 291 [M+]; HRMS (70 eV): m/z: calcd for
C15H21N3O3: 291.1583; found 291.1585 [M+].
Lactam 3: Rf =0.45 (MeOH/CH2Cl2 1:4); m.p. degradation at 2508C;
1H NMR (300 MHz, CD3OD, TMS): d=8.10 (m, 4H), 5.75–5.55 (m, 8H),
3.76 (d, J=4 Hz, 8H), 2.94 ppm (d, J=6 Hz, 8H); 13C NMR (75 MHz,
CD3OD, TMS): d=172.4, 129.9, 124.2, 40.2, 39.2 ppm; IR (NaCl): n˜ =
2950, 1685, 1650, 1545, 1440, 1205, 1135, 970 cmꢀ1; MS (70 eV): m/z: 388
[M+]; HRMS (70 eV): m/z: calcd for C20H28N4O4: 388.2110; found
388.2104 [M+].
The salt was dissolved in CH2Cl2 (35 mL) and NMM (0.99 mL,
8.97 mmol) was added. DMAP (37 mg, 0.1 mmol) and the acid 18
(708 mg, 3.29 mmol) were added 10 min later. The solution was cooled to
08C and 1m DCC in CH2Cl2 (3.29 mL, 3.29 mmol) was added. It was
stirred for 1 h, left to warm up to RT and stirred for 15 h. The reaction
mixture was filtered on Celite and concentrated under reduced pressure
to give a residue that was purified by flash chromatography on silica gel
eluting with MeOH/EtOAc 1:9. The desired product 20 was obtained as
a white solid (365 mg, 14%). Rf =0.42 (MeOH/hexane 1:9); 1H NMR
(300 MHz, CD3OD, TMS): d=6.9–6.6 (m, 3H), 6.20 (d, J=15.5 Hz, 1H),
5.95 (d, J=15.5 Hz, 1H), 5.93 (d, J=15.5 Hz, 1H), 3.45–3.25 (m, 4H),
3.15 (q, J=6.5 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 2.5–2.3 (m, 6H), 1.56 (m,
2H), 1.42 (s, 9H), 1.38 (m, 2H), 0.92 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CD3OD, TMS): d=190.0, 167.0, 166.9, 157.0, 141.5, 141.0,
140.8, 129.8, 124.9, 124.9, 78.6, 39.0, 37.8, 37.5, 32.2, 31.6, 31.5, 31.4, 27.7,
27.4, 21.5, 12.6 ppm; IR (KBr): n˜ =3300, 2935, 1675, 1620, 1455, 1170,
Macrocyclization and cyclooligomerisation of pentafluorophenyl ester 14
to lactams 1 and 3: Carbamate 14 (102 mg, 0.21 mmol) was dissolved in a
mixture of CH2Cl2 (5 mL) and TFA (1 mL) and stirred for 45 min at RT
until complete removal of the tert-butyl carbamate protecting group. The
resulting mixture was concentrated under reduced pressure and the resid-
ual TFA was co-evaporated with toluene under reduced pressure. The
same procedure was repeated four more times. The crude ammonium
salt was dissolved in dioxane (100 mL) and a solution of NMM (230 mL,
2.1 mmol) in dioxane (1 mL) was added. The solution was then stirred
for 18 h at 808C and then concentrated under reduced pressure. The
crude residue was purified by flash chromatography on silica gel eluting
with MeOH/CH2Cl2 1:9 to 1:4 to afford the pure lactams 1 (9 mg, 22%)
and 3 (20 mg, 49%) as solids.
970 cmꢀ1 MS (70 eV): m/z: 482 [M+H+], 499 [M+NH4+]; HRMS
;
Macrocyclization of thioester 10 to lactam 2: Carbamate 10 (197 mg,
0.41 mmol) was dissolved in a mixture of CH2Cl2 (3 mL) and TFA
(1 mL) and stirred for 45 min at RT. The resulting mixture was concen-
trated under reduced pressure and the residual TFA was co-evaporated
with toluene under reduced pressure. The same procedure was repeated
4 more times. The corresponding ammonium salt was dissolved in DMF
(60 mL). DIPEA (78 mL, 0.45 mmol) was then added followed by
AgTFA (272 mg, 1.23 mmol). The solution was heated to 458C during
45 min and concentrated under reduced pressure. The crude residue was
purified by flash chromatography on silica gel eluting with MeOH/
EtOAc 15:85 to give lactam 2 (66 mg, 55%) as a white solid.
(70 eV): m/z: calcd for C24H40N3O5S: 482.2688; found: 482.2693 [M+H+],
499.2960 [M+NH4+].
Pentafluorophenyl ester 21: DIC (1.6 mL, 10.21 mmol) was added to a
solution of PfpOH (5.62 g, 30.53 mmol) in EtOAc (10 mL) at 08C. The
resulting solution was stirred for 15 min, then added to a solution of the
acid 18 (1.99 g, 9.25 mmol) in MeCN (20 mL) and dioxane (20 mL) at
08C. The reaction was stirred for 17 h at RT, then filtered on Celite. The
solution was concentrated and the residue was purified by flash chroma-
tography on silica gel eluting with EtOAc/hexane 3:7 to yield the title
product as a colorless oil (3.52 g, 99%). Rf =0.4 (EtOAc/hexane 1:4);
1H NMR (300 MHz, CDCl3, TMS): d=7.22 (dt, J=15.5 Hz, 7 Hz, 1H),
6.10 (d, J=15.5 Hz, 1H), 4.84 (br, 1H), 3.31 (brq, J=6 Hz, 2H), 2.51
(brq, J=6.5 Hz, 2H), 1.41 ppm (s, 9H); 13C NMR (75 MHz, CDCl3,
TMS): d=161.6, 155.8, 151.5, 119.7, 79.5, 38.7, 33.4, 28.1 ppm; 19F NMR
(282 MHz, CDCl3, TMS): d=ꢀ76.55 (d, J=18.5 Hz, 2F), ꢀ82.60 (t, J=
21.5 Hz, 1F), ꢀ86.40 ppm (t, J=19.5 Hz, 2F); IR (NaCl): n˜ =3355, 2980,
2935, 1765, 1695, 1655, 1520, 1370, 1255, 1170, 1005 cmꢀ1; MS (70 eV):
m/z: 399 [M+NH4+]; HRMS (70 eV): m/z: calcd for C16H20F5N2O4:
399.1343; found: 399.1352 [M+NH4+].
Macrocyclization of pentafluorophenyl ester 16 to lactam 2: The activat-
ed ester 16 (45 mg, 0.078 mmol), dissolved in a mixture of CH2Cl2 (1 mL)
and TFA (0.2 mL), was stirred for 45 min at RT until complete removal
of the tert-butyl carbamate group. The resulting mixture was concentrat-
ed under reduced pressure and the residual TFA was co-evaporated with
toluene under reduced pressure. The same procedure was repeated four
more times. The resulting ammonium salt was dissolved in dioxane
(30 mL) and NMM (86 mL, 0.780 mmol) was added in the reaction. The
solution was then stirred for 18 h at 808C and then concentrated. The
crude residue was purified by flash chromatography on silica gel eluting
MeOH/CH2Cl2 1:9 to 1:4 to give pure lactam 2 (20 mg, 88%).
Cyclo-oligomerisation of pentafluophenyl ester 13 to lactams 1–3: Carba-
mate 13 (106 mg, 0.29 mmol) was dissolved in a mixture of CH2Cl2
(3 mL) and TFA (1 mL) and stirred for 45 min at RT. The resulting mix-
ture was concentrated under reduced pressure and the residual TFA was
co-evaporated with toluene under reduced pressure. The same procedure
was repeated four more times. The corresponding ammonium salt was
Macrocyclisation of thioester 12 to lactam 3: Carbamate 12 (14 mg,
24 mmol) was dissolved in a mixture of CH2Cl2 (3 mL) and TFA (1 mL)
and stirred for 45 min at RT. The resulting mixture was concentrated
under reduced pressure and the residual TFA was co-evaporated with tol-
uene under reduced pressure. The same procedure was repeated four
more times. The corresponding ammonium salt was dissolved in DMF
(5 mL). DIPEA (17 mL, 96 mmol) was then added followed by AgTFA
(16 mg, 72 mmol). The solution was kept at 458C and stirred during
80 min, then concentrated. The crude residue was purified by flash chro-
matography on silica gel eluting with MeOH/EtOAc 3:7 to give lactam 3
(7 mg, 67%) as a white solid.
dissolved in dioxane (112 mL) and
a solution of NMM (320 mL,
2.9 mmol) in dioxane (1 mL) was added to the reaction mixture. The so-
lution was then stirred for 18 h at 808C and then concentrated. The
crude residue was purified by flash chromatography on silica gel eluting
with MeOH/CH2Cl2 1:9 to 3:7. Pure macrolactams 1 (6 mg, 21%), 2
(10 mg, 37%) and 3 (3 mg, 12%) were obtained as solids.
Lactam 1: Rf =0.70 (MeOH/CH2Cl2 1:4), 0.36 (MeOH/EtOAc 1:4); m.p.
degradation at 2758C; 1H NMR (300 MHz, CD3OD, TMS): d=6.15–5.85
(m, 4H), 3.51 (d, J=7 Hz, 4H), 2.68 ppm (d, J=7 Hz, 4H); 13C NMR
(75 MHz, CD3OD, TMS): d=176.56, 133.44, 130.29, 39.19, 39.09 ppm; IR
(KBr): n˜ =3300, 2930, 1680, 1640, 1530, 1440, 1230, 1170, 970 cmꢀ1; MS
(70 eV): m/z: 194 [M+]; HRMS (70 eV): m/z: calcd for C10H14N2O2:
194.1055; found: 194.1058 [M+].
Cyclooligomerization of pentafluorophenyl ester 21 to lactams 4 and 24:
Carbamate 21 (294 mg, 0.77 mmol) was dissolved in a mixture of CH2Cl2
(2 mL) and TFA (1 mL) and stirred for 45 min at RT until complete re-
moval of the protecting group. The resulting mixture was concentrated
under reduced pressure and the residual TFA was co-evaporated with tol-
uene under reduced pressure. The same procedure was repeated 4 more
times. The resulting ammonium salt was dissolved in dioxane (10 mL)
and added over a 1 h period to a solution of NMM (980 mL, 8.91 mmol)
in dioxane (440 mL). The solution was then stirred for 18 h at 808C, then
concentrated. The crude residue was purified by flash chromatography
on silica gel eluting with MeOH/EtOAc 3:7 to 1:3. The pure lactams 4
(36 mg, 41%) and six-membered lactam 24 (6 mg, 7%) were obtained as
a white solid and as a colorless oil, respectively.
Lactam 2: Rf =0.55 (MeOH/CH2Cl2 1:4), 0.72 (MeOH/CH2Cl2 3:7); m.p.
degradation at 2508C; 1H NMR (300 MHz, [D6]DMSO, TMS): d=7.75
(brt, J=5.5 Hz, 3H), 5.60–5.45 (m, 6H), 3.63 (brd, J=4.5 Hz, 6H),
2.81 ppm (brd, J=2.5 Hz, 6H); 1H NMR (300 MHz, CD3OD, TMS): d=
7.92 (br, 3H), 5.75–5.55 (m, 6H), 3.79 (m, 6H), 2.95 ppm (m, 6H);
13C NMR (75 MHz, CD3OD, TMS): d=172.6, 130.2, 124.2, 40.0,
39.3 ppm; IR (KBr): n˜ =3360, 3300, 3070, 2905, 1645, 1545, 1420, 1285,
Chem. Eur. J. 2007, 13, 9223 –9235
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9233

Y. L. Dory et al.
Lactam 4: Rf =0.55 (MeOH/EtOAc 1:1); m.p. degradation at 2508C;
1H NMR (300 MHz, [D6]DMSO, TMS): d=7.56 (brt, J=6 Hz, 3H), 6.33
(dt, J=15.5 Hz, J=7 Hz, 6H), 5.68 (d, J=15.5 Hz, 3H), 3.24 (brq, J=
15.5 Hz, 1H), 5.95 (d, J=15.5 Hz, 1H), 3.4–3.3 (m, 4H), 3.06 (t, J=
6.5 Hz, 2H), 2.93 (t, J=7 Hz, 2H), 2.55 (q, J=6.5 Hz, 2H), 2.5–2.35 (m,
4H), 1.56 (m, 2H), 1.40 (m, 2H), 0.93 ppm (t, J=7.5 Hz, 3H); IR (KBr):
n˜ =2930, 1670, 1625, 1460, 1210, 1140, 980 cmꢀ1. The ammonium salt was
dissolved in DMF (70 mL). DIPEA (146 mL, 0.84 mmol) was then added
followed by AgTFA (503 mg, 2.28 mmol). The solution was stirred at
458C during 45 min and concentrated under reduced pressure. The crude
residue was purified by flash chromatography on silica gel eluting with
MeOH/EtOAc 1:9 to 3:7 to give lactam 4 as a white solid (111 mg,
50%).
1
6 Hz, 6H), 2.25 ppm (brm, 6H); H NMR (300 MHz, CD3OD, TMS): d=
7.82 (3H, m), 6.56 (dt, J=15.5 Hz, J=7 Hz, 6H), 5.79 (dt, J=15.5 Hz,
J=1.5 Hz, 3H), 3.42 (m, 6H), 2.41 ppm (m, 6H); 13C NMR (75 MHz,
CD3OD, TMS): d=166.5, 140.4, 125.8, 36.6, 31.4 ppm; IR (KBr): n˜ =
3300, 3095, 2915, 1675, 1635, 1560, 980 cmꢀ1; MS (70 eV): m/z: calcd for
C15H21N3O3: 291.1583; found 291.1571 [M+].
Lactam 24: Rf =0.68 (MeOH/EtOAc 1:1); 1H NMR (300 MHz, CD3OD,
TMS): d=6.78 (dt, J=10 Hz, J=4 Hz, 1H), 5.83 (dt, J=10 Hz, J=
0.5 Hz, 1H), 3.38 (t, J=7.5 Hz, 2H), 2.36 ppm (m, 2H); 13C NMR
(75 MHz, CD3OD, TMS): d=167.1, 142.8, 123.2, 38.6, 23.5 ppm; IR
Crystallography (Table 3)[59]
Ring 1: The data were collected on a Nonius CAD4 diffractometer;
CuKa; w and q scan; the structure was solved by the application of direct
methods and refined using SHELX97;[78] the refinements were against
jF2 j, the data were reduced using XCAD4 (K. Harms, S. Wocadlo, Uni-
versity of Marburg, Germany), all programs included in the WinGX
package;[79] the H atoms were geometrically placed.
(KBr): n˜ =3350, 1670, 1603, 1490, 1430, 1380, 1345, 1210, 1140, 810 cmꢀ1
;
MS (70 eV): m/z: 98 [M+H+]; HRMS (70 eV): m/z: calcd for C5H8NO:
98.1095; found 98.1092 [M+H+].
Macrocyclization of thioester 20 to lactam 4: Carbamate 20 (365 mg,
0.76 mmol) was dissolved in a mixture of CH2Cl2 (20 mL) and TFA
(10 mL) and stirred for 45 min at RT. The resulting mixture was concen-
trated under reduced pressure and the residual TFA was co-evaporated
with toluene (5 mL) under reduced pressure (same procedure repeated
four times) to afford the corresponding ammonium salt. 1H NMR
(300 MHz, CD3OD, TMS): d=8.15 (br, 3H), 6.84 (dt, 1H, J=15.5 Hz,
J=7 Hz, 1H), 6.75–6.6 (m, 2H), 6.20 (d, J=15.5 Hz, 1H), 6.06 (d, J=
Rings 2 and 3: A hemisphere of data was collected on a Bruker AXS P4/
SMART 1000 diffractometer; CCD area detector; MoKa; w and f scans
with a scan width of 0.38 and 40 s (2) or 30 s (3) exposure times; The de-
tector distance was 6 cm (2) or 5 cm (3). The data were reduced (SAINT
6.02, 1997–1999, Bruker AXS, Inc., Madison, Wisconsin, USA.) and cor-
rected for absorption (SADABS, George Sheldrick, 1999, Bruker AXS,
Inc., Madison, Wisconsin, USA). The structures were solved by direct
methods and refined by full-matrix least squares on F2 (SHELXTL 5.1,
George Sheldrick, 1997, Bruker AXS, Inc., Madison, Wisconsin, USA).
Table 3. Crystallographic data for rings 1–3.
1
2
3
formula
Fw
T [K]
l [Š]
crystal system
space group
a [Š]
b [Š]
c [Š]
a [8]
b [8]
C10H14N2O2
194.23
293(2)
1.54176
orthorhombic triclinic
Pbnb
7.557(3)
9.662(5)
14.100(6)
90
C15H21N3O3
291.35
198(1)
C20H28N4O4
388.46
198(1)
0.71073
monoclinic
P2(1)/c
11.295(3)
10.301(3)
9.437(2)
90
113.020(4)
90
1010.6(4)
2
1.277
0.090
Acknowledgements
0.71073
We thank NSERC Canada and FQRNT QuØbec for financial support. I
wish to thank Professor John M. Mellor for introducing me to the beauty
of symmetry within molecules.
P1
4.6797(18)
7.606(3)
10.983(5)
72.878(6)
78.027(4)
88.016(4)
365.3(3)
1
[1] G. M. Whitesides, J. P. Mathias, C. T. Seto, Science 1991, 254, 1312–
1319.
[2] K. Müller-Dethlefs, P. Hobza, Chem. Rev. 2000, 100, 143–167.
[3] D. N. Reinhoudt, J. F. Stoddart, R. Ungaro, Chem. Eur. J. 1998, 4,
1349–1351.
[4] D. N. Reinhoudt, M. Crego-Calama, Science 2002, 295, 2403–2407.
[5] M. Seo, G. Seo, S. Y. Kim, Angew. Chem. 2006, 118, 6451–6454;
Angew. Chem. Int. Ed. 2006, 45, 6306–6310.
[6] H.-T. Zhang, Y.-Z. Li, T.-W. Wang, E. N. Nfor, H.-Q. Wang, X.-Z.
You, Eur. J. Inorg. Chem. 2006, 3532–3536.
[7] M. Crisma, C. Toniolo, S. Royo, A. I. JimØnez, C. Cativiela, Org.
Lett. 2006, 8, 6091–6094.
[8] S. Ray, M. G. B. Drew, A. Kumar Das, A. Banerjee, Tetrahedron
2006, 62, 7274–7283.
[9] S.-G. Youm, K. Paeng, Y.-W. Choi, S. Park, D. Sohn, Y.-S. Seo, S. K.
Satija, B. G. Kim, S. Kim, S. Y. Park, Langmuir 2005, 21, 5647–5650.
[10] Z.-Q. Hu, C.-F. Chen, Chem. Commun. 2005, 2445–2447.
[11] E. Demers, T. Maris, J. D. Wuest, Cryst. Growth Des. 2005, 5, 1227–
1235.
[12] P. DeSantis, S. Morosetti, P. Rizzo, Macromolecules 1974, 7, 52–58.
[13] J. D. Hartgerink, T. D. Clark, M. R. Ghadiri, Chem. Eur. J. 1998, 4,
1367–1372.
90
90
g [8]
V [Š3]
Z
1029.5(8)
4
1.253
0.723
416
1calcd [mgmꢀ3
]
1.324
0.094
156
m [mmꢀ1
(000)
]
F
A
416
crystal size [mm]
q range [8]
completeness [%]
index ranges
0.4”0.25”0.15 0.6”0.35”0.05 0.3”0.2”0.025
6.65–69.76
95.9
0<h<9
0<k<11
0<l<17
935
935
0.0000
empirical
0.9753/0.6734
1.98–25.69
90.4
ꢀ5<h<5
ꢀ8<k<8
ꢀ12<l<13
1717
1170
0.0109
SADABS
0.9953/0.9460
1170/3/209
1.103
1.96–27.49
97.4
ꢀ13<h<14
ꢀ12<k<13
ꢀ12<l<12
6816
2255
0.0317
SADABS
Ratio 0.688
2255/5/227
1.022
reflns collected
independent reflns
R
A
absorb correction
max/min transmission
data/restraints/params 935/38/129
GOF on F2
0.984
final R indices
[I>2s(I)]
R1
wR2
R indices (all data)
R1
wR2
[14] D. Ranganathan, C. Lakshmi, I. L. Karle, J. Am. Chem. Soc. 1999,
121, 6103–6107.
0.0751
0.1829
0.040
0.1051
0.0399
0.0892
[15] D. T. Bong, T. D. Clark, J. R. Granja, M. R. Ghadiri, Angew. Chem.
2001, 113, 1016–1041; Angew. Chem. Int. Ed. 2001, 40, 988–1011.
[16] V. Semetey, C. Didierjean, J.-P. Briand, A. Aubry, G. Guichard,
Angew. Chem. 2002, 114, 1975–1978; Angew. Chem. Int. Ed. 2002,
41, 1895–1898.
0.1286
0.2156
0.248/ꢀ0.187
0.0438
0.1108
0.291/ꢀ0.199
0.0761
0.0972
0.179/ꢀ0.156
largest diff. peak/hole
[17] M. Amorin, L. Castedo, J. R. Granja, J. Am. Chem. Soc. 2003, 125,
2844–2845.
ꢀ3
[eŠ
]
9234
www.chemeurj.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 9223 –9235

Symmetric Macrolactams
FULL PAPER
[18] L. S. Shimizu, A. D. Hughes, M. D. Smith, M. J. Davis, B. P. Zhang,
H.-C. zur Loye, K. D. Shimizu, J. Am. Chem. Soc. 2003, 125, 14972–
14973.
[19] M. R. Ghadiri, J. R. Granja, R. A. Milligan, D. E. McRee, N. Khaza-
novich, Nature 1993, 366, 324–327.
[20] M. R. Ghadiri, J. R. Granja, L. K. Buehler, Nature 1994, 369, 301–
304.
[21] T. D. Clark, L. K. Buehler, M. R. Ghadiri, J. Am. Chem. Soc. 1998,
120, 651–656.
[22] S. Fernandez-Lopez, H.-S. Kim, E. C. Choi, M. Delgado, J. R.
Granja, A. Khasanov, K. Kraehenbuehl, G. Long, D. A. Weinberger,
K. M. Wilcoxen, M. R. Ghadiri, Nature 2001, 412, 452–455.
[23] D. Seebach, J. L. Matthews, A. Meden, T. Wessels, C. Baerlocher,
L. B. McCusher, Helv. Chim. Acta 1997, 80, 173–182.
[24] R. R. Ketchem, W. Hu, T. A. Cross, Science 1993, 261, 1457–1460.
[25] D. A. Doyle, J. M. Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis,
S. L. Cohen, B. T. Chait, R. Mackinnon, Science 1998, 280, 69–77.
[26] M. A. Balbo Block, C. Keiser, A. Khan, S. Hecht, Top. Curr. Chem.
2005, 245, 89–150.
[27] F. Fujimura, M. Fukuda, J. Sugiyama, T. Morita, S. Kimura, Org.
Biomol. Chem. 2006, 4, 1896–1901.
[28] M. Amorín, L. Castedo, J. R. Granja, Chem. Eur. J. 2005, 11, 6543–
6551.
[29] W. S. Horne, N. Ashkenasy, M. R. Ghadiri, Chem. Eur. J. 2005, 11,
1137–1144.
[30] H. Mansikkamäki, M. Nissinen, K. Rissanen, Angew. Chem. 2004,
116, 1263–1266; Angew. Chem. Int. Ed. 2004, 43, 1243–1246.
[31] M. Katoh, S. Kohmoto, K. Kishikawa, Cryst. Res. Technol. 2006, 41,
1242–1245.
[50] R. D. Allan, H. W. Dickenson, G. A. R. Johnston, R. Kazlauskas,
H. W. Tran, Aust. J. Chem. 1985, 38, 1651–1656.
[51] U. Schmidt, A. Lieberknecht, H. Griesser, J. J. Talbiersky, Org.
Chem. 1982, 47, 3261–3264.
[52] Y. L. Dory, J. M. Mellor, J. F. McAleer, Tetrahedron 1996, 52, 1343–
1360.
[53] J. Kovacs, L. Kisfaludy, M. Q. Ceprini, J. Am. Chem. Soc. 1967, 89,
183–184.
[54] J. Hine, S.-M. Linden, J. Org. Chem. 1983, 48, 584–587.
[55] G. E. Keck, E. P. Boden, M. R. Wiley, J. Org. Chem. 1989, 54, 896–
906.
[56] R. Schwyzer, C. Hürlimann, Helv. Chim. Acta 1954, 37, 155–166.
[57] L. Zhang, J. P. Tam, J. Am. Chem. Soc. 1999, 121, 3311–3320.
[58] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734–736.
[59] CCDC-639425 (1), -639426 (2) and -639427 (3) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif
[60] R. B. Gardner, G.-B. Liang, S. H. Gellman, J. Am. Chem. Soc. 1999,
121, 1806–1816.
[61] I. L. Karle, J. Karle, Acta Crystallogr. 1963, 16, 969–975.
[62] S. R. Chemburkar, J. Bauer, K. Deming, H. Spiwek, K. Patel, J.
Morris, R. Henry, S. Spanton, W. Dziki, W. Porter, J. Quick, P.
Bauer, J. Donaubauer, B. A. Narayanan, M. Soldani, D. Riley, K.
McFarland, Org. Process Res. Dev. 2000, 4, 413–417.
[63] M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S.
Gordon, J. H. Jensen, S. Koseki, N. Matsunaga, K. A. Nguyen, S. J.
Su, T. L. Windus, M. Dupuis, J. A. Montgomery, J. Comput. Chem.
1993, 14, 1347–1363.
[32] G. W. Gokel, O. Murillo, Acc. Chem. Res. 1996, 29, 425–432.
[33] P. M. Ajayan, O. Z. Zhou, Top. Appl. Phys. 2001, 80, 391–425.
[34] G. R. Patzke, F. Krumeich, R. Nesper, Angew. Chem. 2002, 114,
2554–2571; Angew. Chem. Int. Ed. 2002, 41, 2446–2461.
[35] X. Gao, H. Matsui, Adv. Mater. 2005, 17, 2037–2050.
[36] M. Amorin, V. Villaverde, L. Castedo, J. R. Granja, J. Drug Delivery
Sci. Technol. 2005, 15, 87–92.
[64] W. J. Hehre, L. Radom, P. v. R. Schleyer, J. A. Pople, in Ab Initio
Molecular Theory, Wiley-Interscience, New York, 1986, pp. 324–
341.
[65] B. M. Bode, M. S. Gordon, J. Mol. Graphics Modell. 1998, 16, 133–
138.
[66] N. Padmaja, S. Ramakumar, M. A. Viswamitra, Acta Crystallogr.
Sect. A 1990, 46, 725–730.
[37] C. H. Gçrbitz, Curr. Opin. Solid State Mater. Sci. 2002, 6, 109–116.
[38] D. Pasini, M. Ricci, Current Org. Synth. 2007, 4, 59–80.
[39] T. O. Yeates, J. E. Padilla, Curr. Opin. Struct. Biol. 2002, 12, 464–
470.
[40] T. K. Chakraborty, S. Tapadar, T. V. Raju, R. Annapurna, H. Singh,
Synlett 2004, 2484–2488.
[41] B. Jagannadh, M. S. Reddy, C. L. Rao, A. Prabhakar, B. Jagadeesh,
S. Chandrasekhar, Chem. Commun. 2006, 4847–4849.
[42] F. Büttner, M. ErdØlyi, P. I. Arvidsson, Helv. Chim. Acta 2004, 87,
2735–2741.
[67] H. Nakai, K. Nagashima, H. Itazaki, Acta Crystallogr. Sect. C: Cryst.
Struct. Commun. 1991, 47, 1496–1499.
[68] J. P. Declercq, G. Germain, M. van Meerssche, T. Debaerdemaeker,
J. Dale, K. Titlestad, Bull. Soc. Chim. Belg. 1975, 84, 275–287.
[69] C. C. Chiang, I. L. Karle, Int. J. Pept. Protein Res. 1982, 20, 133–138.
[70] I. Ueda, T. Ueda, I. Sada, T. Kato, M. Mikuriya, S. Kida, N. Izumiya,
Acta Crystallogr. Sect. C 1984, 40, 111–113.
[71] P. Groth, Acta Chem. Scand. 1970, 24, 780–790.
[72] P. N. Swepston, A. W. Cordes, L. F. Kuyper, W. L. Meyer, Acta Crys-
tallogr. Sect. B 1981, 37, 1139–1141.
[43] T. K. Chakraborty, S. Roy, D. Koley, S. K. Dutta, A. C. Kunwar, J.
Org. Chem. 2006, 71, 6240–6243.
[44] J. H. van Maarseveen, W. Seth Horne, M. R. Ghadiri, Org. Lett.
2005, 7, 4503–4506.
[45] D. Gauthier, P. Baillargeon, M. Drouin, Y. L. Dory, Angew. Chem.
2001, 113, 4771–4774; Angew. Chem. Int. Ed. 2001, 40, 4635–4638.
[46] S. Leclair, P. Baillargeon, R. Skouta, D. Gauthier, Y. Zhao, Y. L.
Dory, Angew. Chem. 2004, 116, 353–357; Angew. Chem. Int. Ed.
2004, 43, 349–353.
[73] D. Seebach, O. Bezencon, B. Jaun, T. Pietzonka, J. L. Matthews,
F. N. M. Kuhnle, W. B. Schweizer, Helv. Chim. Acta 1996, 79, 588–
608.
[74] D. S. Seetharama Jois, S. S. M. Vijayan, K. R. K. Easwaran, Int. J.
Pept. Protein Res. 1996, 48, 12–20.
[75] G. Shoham, S. K. Burley, W. N. Lipscomb, Acta Crystallogr. Sect. C
1989, 45, 1944–1948.
[76] S. A. Miller, S. L. Griffiths, D. Seebach, Helv. Chim. Acta 1993, 76,
563–595.
[47] J. S. Davies, J. Pept. Sci. 2003, 9, 471–501.
[77] J. L. Flippen, I. L. Karle, Biopolymers 1976, 15, 1081–1092.
[78] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467–473.
[79] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
[48] Y. Singh, N. Sokolenko, M. J. Kelso, L. R. Gahan, G. Abbenante,
D. P. Fairlie, J. Am. Chem. Soc. 2001, 123, 333–334.
[49] A. Bertram, A. J. Blake, F. Gonzalez-Lopez de Turiso, J. S. Hannam,
K. A. Jolliffe, G. Pattenden, M. Skae, Tetrahedron 2003, 59, 6979–
6990.
Received: April 3, 2007
Published online: September 21, 2007
Chem. Eur. J. 2007, 13, 9223 –9235
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9235