Synthesis of enniatin-like cyclic depsipeptides via 'direct amide cyclization'

Article abstract of DOI:10.1002/hlca.200690069

The synthesis of several 18-membered cyclodepsipeptides with an alternating sequence of α,α-disubstituted α-amino acids and α-hydroxy acids (compounds 14a-14e) is described. The ring closure via macrolactonization was accomplished by treatment of a dilute

Full text of DOI:10.1002/hlca.200690069

Helvetica Chimica Acta – Vol. 89 (2006)
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Synthesis of Enniatin-like Cyclic Depsipeptides via ꢀDirect Amide
Cyclizationꢁ
by Peter Kçttgen1), Anthony Linden, and Heinz Heimgartner*
Organisch-chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
The synthesis of several 18-membered cyclodepsipeptides with an alternating sequence of a,a-disub-
stituted a-amino acids and a-hydroxy acids (compounds 14a–14e) is described. The ring closure via mac-
rolactonization was accomplished by treatment of a diluted suspension of the corresponding linear pre-
cursors 12a–12e in toluene with HCl gas, i.e., the so-called ꢀdirect amide cyclizationꢁ. The incorporation
of the a,a-disubstituted a-amino acids was achieved via the ꢀazirine/oxazolone methodꢁ with 2H-azirin-3-
amines of type 6 and 9 as building blocks. The structure of the cyclic depsipeptide 14a was established by
X-ray crystallography.
1. Introduction. – Cyclic depsipeptides are peptide analogues in which one or sev-
eral lactam bonds of the cyclic skeleton are displaced by lactone bonds. The cyclization
of these compounds is usually the most demanding step in their synthesis. Several suc-
cessful cyclizations via ester bond formation (lactonization) have been reported [1–3],
but ring closure via formation of an amide bond (lactamization) [4–6] is usually easier
and, therefore, preferred [7].
Cyclization of a peptide or depsipeptide reduces its conformational freedom. This
constraint can be increased further if a,a-disubstituted a-amino acids are incorporated
into the peptide chain [8], and limiting the flexibility often results in higher receptor-
binding affinities [7]. Effective methods for the introduction of a,a-disubstituted a-
amino acids and subsequent ring closure to give a cyclic depsipeptide are, therefore,
of interest. A useful cyclization method for depsipeptides containing a C-terminal
a,a-disubstituted a-amino acid, the so-called ꢀdirect amide cyclizationꢁ, has been devel-
oped in our laboratory [9–20]. The basic concept is depicted in Scheme 1: if an amide of
type 1 is treated with dry HCl gas, the corresponding 1,3-oxazol-5(4H)-one derivative 2
is formed via ring closure and elimination of Me2ACHTRENUGN H·HCl. In the absence of other
nucleophiles, a ring enlargement to yield the cyclic product 3 occurs by an intramolec-
ular attack of the w-OHgroup of the intermediate oxazolone at the lactone group.
Several cyclic depsipeptides containing one hydroxy acid and several a,a-disubsti-
tuted a-amino acids have been prepared by this cyclization method [9–17]. A subgroup
among the depsipeptides consists of the so-called regular cyclodepsipeptides [21][22],
whose cyclic core shows an alternating pattern of a-amino acids and a-hydroxy acids.
Some of these regular cyclodepsipeptides show high biological activity, such as the anti-
1
)
Part of the Ph.D. thesis of P. K., Universität Zürich, 2006.
ꢂ 2006 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 1
biotics valinomycin [23–25] and the enniatins [26], which act as ionophores [27]. Some
twelve-membered regular cyclodepsipeptides, which also contain a,a-disubstituted a-
amino acids, have been synthesized in our group via ꢀdirect amide cyclizationꢁ [11].
It was, therefore, of interest to investigate whether 18-membered regular cyclodepsi-
peptides of the ꢀenniatin typeꢁ, composed of a-amino acids and a-hydroxy acids,
could also be synthesized by this method. Some preliminary experiments have already
been carried out [28]. The incorporation of the a,a-disubstituted a-amino acid units
can be achieved via the elegant and efficient ꢀazirine/oxazolone methodꢁ that has
been developed in our group [29] and successfully applied to the synthesis of peptaibols
[30–35], endothiopeptides [36–39], and conformationally restricted cyclic peptides
[40–44].
2. Results and Discussion. – 2.1. Synthesis of the Linear Precursors. The desired lin-
ear precursors 12 were synthesized according to a strategy similar to that reported for
the twelve-membered depsipeptides [11] (see also [28]). The same approach has been
used in the synthesis of a 24-membered cyclic depsipeptide [45][46].
Three different a-hydroxy acids, 4a–4c, and six different 2H-azirin-3-amines 6a–6c
and 9a–9c, which are the building blocks for the a,a-disubstituted a-amino acids, were
used to prepare the precursors for the ꢀdirect amide cyclizationꢁ. An overview of the
syntheses is shown in Scheme 2.
As the 2-benzyl-2-methyl-2H-azirin-3-amines 6c and 9c were employed as race-
mates, the synthesis yielded the precursor 12c for the macrolactonization as a racemic
mixture of four diastereoisomers.
2.2. Macrolactonizations. With the linear precursors 12a–12e in hand, we studied
their cyclizations via the ꢀdirect amide cyclizationꢁ method (Scheme 3). Initial optimiza-
tion of the reaction conditions was undertaken by using compound 12a. The solvent and
the reaction temperature were adopted from the protocols of the cyclizations that led to
similar twelve-membered cyclodepsipeptides [11].
A 10–15 mM solution of 12a in toluene was treated with a stream of dry HCl gas at
1008. The reaction mixture was then allowed to cool to room temperature, while bub-
bling N2 through it. Evaporation of the solvent gave a mixture of the crude product and
Me CHTRENUNG H·HCl, which was separated by column chromatography.
2A
It turned out that longer reaction times reduce the yield of the desired product,
probably due to decomposition of the product as well as of the starting material, caused
by the limited stability of the ester bonds (see below). On the other hand, short reaction
times result in a lower conversion of the starting material, so a compromise for the reac-
tion time had to be found. The treatment with HCl gas over a period of 4.5 min proved

Helvetica Chimica Acta – Vol. 89 (2006)
733
Scheme 2
to be the optimum, yielding 27% of the macrocycle 14a. The 1H- and 13C-NMR spectra
of 14a clearly show that a single isomer is present, and epimerization had occurred at
one of the three stereogenic centers. Epimerization of one of the a-hydroxy acids leads
to three topologically different a-hydroxy acid units, as well as three different a,a-
dimethyl a-amino acid units in 14a. Indeed, the NMR spectra showed three different
sets of signals instead of one, as would be expected without epimerization. On the
other hand, it is worth mentioning that 14a is optically active. The structure and the rel-

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Helvetica Chimica Acta – Vol. 89 (2006)
Scheme 3
ative configuration of the recrystallized 14a were established by X-ray crystallography,
and the molecular structure confirms the inverted configuration at one stereogenic cen-
ter (Fig.).
The crystals of 14a are enantiomerically pure, and there are two molecules of the
same enantiomer in the asymmetric unit; however, the absolute configuration of the
molecule has not been determined. The enantiomer used in the refinement was chosen
arbitrarily. This enantiomer has the (3R,9S,15S)-configuration2), but due to the absence
of a strong anomalous scatterer in the structure, this enantiomer cannot be distin-
guished crystallographically from the (3S,9R,15R)-enantiomer. Although all sites
were expected to have the (S)-configuration, it is not possible to determine if one
site has inverted, or two. The two symmetry-independent molecules have almost iden-
tical conformations, with the only difference being a small rotation in the orientation of
the Ph ring of the Bn substituent at C(15). Each of the two symmetry-independent mol-
ecules has the same pattern of H-bonds. Two of the amide groups in each molecule form
a total of three intramolecular H-bonds. One of these is an interaction with the amide
O-atom of the next amide unit around the macrocyclic ring, thereby giving rise to a ten-
membered loop with a graph set motif [48] of S(10). The other two intramolecular inter-
actions emanate from the same N-atom as weak bifurcated interactions with the ether
O-atoms of the ester groups on either side of this N-atom, thereby creating small loops
with graph set motifs of S(5). The third amide group forms an intermolecular H-bond
2
)
Arbitrary C-atom numbering was used in the Figure.

Helvetica Chimica Acta – Vol. 89 (2006)
735
Figure. ORTEP Plot [47] of the molecular structure of one of the symmetry-independent molecules of
14a (30% probability ellipsoids; arbitrary numbering of atoms, most H-atoms omitted for clarity)
with an amide O-atom of an adjacent symmetry-unrelated molecule, thereby linking
molecules A and B alternately into extended chains which run parallel to the z-axis
with an ···A···B···A···B··· sequence that yields a binary graph set motif of C22(20).
We used the optimized conditions mentioned above for the cyclization of the other
linear precursors 12b–12e. In the case of 12b, which differs from 12a only in the sub-
stituent on the a-amino acid units being a cyclopentane ring instead of the two Me
groups, the desired depsipeptide 14b was obtained in a yield of 25%, which is compa-
rable with the cyclization yield of 12a. Again, 1H- and 13C-NMR spectra show that com-
plete epimerization at one of the stereogenic centers had occurred.
Compared with 12b, the third hydroxy acid of the cyclization precursor 12e
(counting from the amide terminus) bears a Me group instead of the Bn residue
(R=Me, R1 =Bn). This should allow the (otherwise undistinguishable) stereogenic
centres in the cyclized product to be identified, provided that this variation still leads
to the same phenomenon of complete inversion at one stereogenic center. The ring-
closing reaction was accomplished successfully by applying the same conditions as men-
tioned before, and the corresponding depsipeptide 14e was isolated in 33% yield. The
1H- and 13C-NMR spectra of 14e showed that this compound was again formed as a sin-
gle diastereoisomer. As the configuration of 14e cannot be determined by means of
NMR spectroscopy, we tried to establish the structure by X-ray crystallography.
Unfortunately, we were unable to grow crystals suitable for a structure determination,
so the relative configurations of the stereogenic centers in 14e could not be determined.
Therefore, this experiment could not clarify the proposal that the configuration at the

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Helvetica Chimica Acta – Vol. 89 (2006)
stereogenic center adjacent to the oxazolone ring of the intermediate 13 was inverted
during the cyclization.
The linear precursor 12d used for the next ring closure differs from 12a in that there
is no substituent next to the w-OHgroup. The cyclization experiment, therefore, shows
the difference between a primary and a secondary OHgroup attacking the oxazolone
intermediate. When the cyclization was carried out under the same conditions as for
12a and 12b, the depsipeptide 14d could be isolated with a significantly higher yield
of 43%, and less by-products were formed. In contrast to 14a and 14b, the macrolactone
14d was formed as a mixture of two diastereoisomers, most likely due to the configura-
tional instability of the first stereogenic center (counting from the former amide termi-
nus (see below)).
The linear depsipeptide 12c also bears a primary w-OHgroup and is substituted
with Bn groups at the a-amino acid units to ensure the UVactivity of the corresponding
macrocycle. Ring closure under the usual conditions gave the desired cyclodepsipeptide
14c in 46% yield, which is comparable with that of ring 14d. Since the linear precursor
12c was synthesized as a racemic mixture of different diastereoisomers, the reaction
yielded 14c as a mixture of the two possible diastereoisomers in racemic form.
Due to the lower steric hindrance, linear precursors with a primary w-OHgroup
seem to be more appropriate for the ꢀdirect amide cyclizationꢁ method than those bear-
ing a secondary OHgroup. The yields, ranging from 25 to 46%, are comparable with
those of other cyclization methods for macrolactones of similar ring sizes. A possible
explanation for the moderate yields in the present study could be the instability of
the ester bonds of the cyclization precursors under the conditions of the ꢀdirect
amide cylizationꢁ. This could indeed be shown by a control experiment, in which the
HCl treatment was carried out in the presence of MeOH as an external nucleophile.
Under these conditions, amide 10a, which does not contain ester bonds, was converted
into the corresponding methyl ester quantitatively. On the other hand, the analogous
treatment of 12a resulted in a lower yield of products, and a mixture of the homologous
esters was obtained (cf. also [46]; Scheme 4).
Scheme 4

Helvetica Chimica Acta – Vol. 89 (2006)
737
Most likely, the depsipeptide bonds are cleaved via the intramolecular formation of
1,3-oxazol-5(4H)-ones as intermediates under the conditions of the ꢀdirect amide cyc-
lizationꢁ. Alternatively, an intermolecular attack of the free OHgroup of the corre-
sponding linear precursor could cleave one of the ester bonds, thereby further reducing
the yields of the cyclodepsipeptides.
As already mentioned, cyclodepsipeptides 14a and 14b were formed as single dia-
stereoisomers with inverted configuration at one of the stereogenic centers. It is already
known from the synthesis of six-membered cyclic depsipeptides that the ꢀdirect amide
cylizationꢁ can lead to a partial epimerization at the center in the a-position to the pro-
tonated oxazolone [10]. However, complete isomerization to give only the other dia-
stereoisomer was surprising, as one would expect a mixture of diastereoisomers to be
obtained. Therefore, we decided to examine at which position the inversion of config-
uration occurs. For this purpose, we subjected the optically active amide segments 10b
and 15 to the ꢀdirect amide cylizationꢁ conditions that were used for the syntheses of the
18-membered macrocycles (Scheme 5).
Scheme 5
In the case of amide 10b, which is able to form a 1,3-oxazol-5(4H)-one, the expected
piperazine dione 16 was formed as a racemate. On the other hand, amide 15, which can-
not form an oxazolone, proved to be configurationally stable under these conditions.
Even after a prolonged HCl treatment (30 min) at 1008, the other enantiomer could
not be detected3). These results indicate that the only stereogenic center in the linear
precursors 12, where the observed epimerization occurs, is the first one, counting
from the former amide terminus, i.e., the stereogenic center in the a-position of the
intermediate oxazolone.
3
)
Amide 15 and piperazine dione 16 were analyzed by means of HPLC on a chiral column with the
racemic compounds as standards.

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Helvetica Chimica Acta – Vol. 89 (2006)
Although the position of the inversion of the configuration was clarified, the reason
for the formation of a single diastereoisomer of the depsipeptide was not clear. To
determine if this phenomenon is an attribute of the ꢀdirect amide cyclizationꢁ, or if
other macrolactonization methods would show a similar effect, a test reaction accord-
ing the Corey–Nicolaou method [49] was carried out. In a control experiment to synthe-
size piperazine dione 16, almost no racemization occurred. Therefore, amide 12b was
hydrolyzed to give the corresponding carboxylic acid 17b by treatment with 3N HCl
in THF/H2O (Scheme 6). Subsequent reaction with Ph3ACHTERPUNG and 2,2’-dipyridyl disulfide
(DPS) in CH2Cl2 did not yield the desired cyclodepsipeptide 14b, and only decomposi-
tition products were found. If the same reaction sequence was performed with the epi-
mer 12b’ (prepared analogously to 12b according to Scheme 2) under identical condi-
tions, the macrocycle 14b could be isolated in 16% yield (Scheme 6)4).
Scheme 6
This result indicates that the precursor with one inverted configuration is more
favorable for the cyclization step than the homochiral analogue. Probably, the epimer-
ized precursor promotes a conformation that is more suitable for the ring closure.
3. Conclusions. – Five different 18-membered regular cyclodepsipeptides of the
enniatin type, which contain a,a-disubstituted a-amino acid moieties, have been syn-
thesized. The efficient ꢀazirine/oxazolone methodꢁ was used to incorporate the steri-
cally demanding amino acid units into the linear precursors. The cyclizations via macro-
lactonization were achieved by the ꢀdirect amide cyclizationꢁ method and gave the
desired products with yields ranging from 25 to 46%. The ring closure of precursors
with a primary w-OHgroup gave the products in higher yields than those with the cor-
responding compounds bearing a secondary OHgroup. Cyclizations of the two similar
4
)
NMR Spectra of 17b and 17b’ showed that no epimerization occurred during the acid-catalyzed
amide hydrolysis.

Helvetica Chimica Acta – Vol. 89 (2006)
739
compounds 12a and 12b, which possess three a-substituted a-hydroxy acid moieties,
lead to cyclic depsipeptides with one epimerized stereogenic center. The results of
some control experiments indicate that the epimerization occurs at the adjacent stereo-
genic center of the intermediate 1,3-oxazol-5(4H)-one. The structure of the cyclic dep-
sipeptide 14a has been established by X-ray crystallography.
We thank the analytical sections of our institue for spectra and analyses, the Swiss National Science
Foundation, the Betty Sassella-Keller Legat, and F. Hoffmann-La Roche AG, Basel for financial support.
Experimental Part
1. General. See [18]. Solvents were purified by standard procedures. TLC: Merck TLC aluminium
sheets, silica gel 60 F254. Flash column chromatography (CC): Uetikon-Chemie ꢀChromatographiegelꢁ
C-560. M.p.: Büchi 540 apparatus, uncorrected. IR Spectra: Perkin-Elmer Spectrum One spectrometer;
in CHCl3, unless otherwise stated, absorption bands in cmꢀ1 1H- (300 and 600 MHz) and 13C-NMR
.
(75.5 and 151 MHz) spectra: Bruker ARX-300 and DRX-600 instruments, in CDCl3 at 300 K, TMS as
internal standard, d in ppm, coupling constants J in Hz; 13C-signal multiplicity from DEPT spectra.
MS: Finnigan MAT 90 for electron-impact ionization (EI), Finnigan SSQ-700 for chemical ionization
(CI, with NH3) and electrospray ionization (ESI, in MeOH+NaI).
The 2H-azirin-3-amines 6a–6c and 9a–9c were prepared according to standard procedures (cf. [29]
and refs. cit. therein). 2-(Benzyloxy)acetic acid (5b) was prepared according to [50], and 2-(benzyloxy)-
propanoic acid (5c) was prepared according to [51]. All other products used were commercially available.
The syntheses and spectroscopic data of 5a, 7a, 8a, 10a, 11a, and 12a are described in [45] (see also [46]).
General Procedure 1 (GP 1). Reaction of Azirines 6 and 9 with Acids 4 and 5. To a soln. of the acid in
MeCN was added a soln. of the azirine in MeCN. The mixture was stirred at r.t. for 16 h, evaporated, and
the residue was purified by column chromatography (CC).
General Procedure 2 (GP 2). Hydrolysis of Amides 7 to Acids 8. A soln. of 7 (3.0 mmol) in THF (15
ml) was treated with aq. 6N HCl (15 ml) and stirred for 6 h at r.t. Subsequent addition of aq. 2N HCl (15
ml), extraction with Et2ACHTREOUNG , drying (MgSO4), and evaporation gave 8 in pure form.
General Procedure 3 (GP 3). Esterification of Acids 8 with Alcohols 10, 11, and Subsequent Hydro-
genolysis of the Benzyl Ether. A soln. of 8 and 1.0 equiv. of 1,1’-carbonyldiimidazole (CDI) in dry THF
was stirred for 2 h under N2. The corresponding alcohol was then added, followed by 10 drops of a Na-
imidazolide suspension (freshly prepared by the reaction of 45 mg of a 60% suspension of NaHin min-
eral oil with 73 mg of 1H-imidazole in 3 ml of dry THF). After the completion of the reaction (TLC, 2–16
h), the solvent was evaporated, and the mixture was purified by CC. The coupling product was then dis-
solved in THF/i-PrOH1:1, a catalytic amount of Pd on charcoal was added, and the suspension was stir-
red under H2 until completion of the reaction (TLC). The mixture was then filtered over Celite, evapo-
rated, and purified by CC.
General Procedure 4 (GP 4). Cyclization of the Linear Precursors 12a–12e and 10b. A soln. of
12a–12e or 10b in toluene was treated with a strong stream of dry HCl gas for 4.5 min at 1008. The mix-
ture was then allowed to cool to r.t., while bubbling N2 through it. Evaporation of the solvent and puri-
fication by CC gave the corresponding cyclodepsipeptide.
2. Synthesis of Linear Precursors. 2.1. 1-{[(S)-2-(Benzyloxy)-3-phenylpropanoyl]amino}-N-methyl-
N-phenylcyclopentane-1-carboxamide (7b). According to GP 1, 5a (1.0 g, 3.9 mmol) in MeCN (20 ml),
6b (780 mg, 3.9 mmol) in MeCN (5 ml), 14 h, CC (SiO2; hexane/Et2CAHTREOUNG 1:1): 1.62 g (91%) of 7b. White
1
powder. M.p. 106–1078. [a]2D5 =ꢀ61.4 (c=1.1, CHCl3). H-NMR: 1.30–1.70, 2.20–2.30, 2.40–2.50 (3m,
6 H+1 H+1 H, (CH2)4); 2.92 (dd, J=7.6, 14.1, 1 Hof PhC H2ACHTRECUNG ); 3.15 (dd, J=3.8, 14.1, 1 Hof PhC H2-
ACHTREUNGC); 3.22 (s, MeN); 3.83 (dd, J=3.8, 7.6, CH2ACHERTNUCG HO); 4.10, 4.29 (2d, J=11.8, PhCH2ACHTREOGNU ); 7.00–7.40 (m,
10 arom. H, NH). EI-MS: 456, (3, M+C), 350 (21, [MꢀPh(Me)N]+), 322 (43, [MꢀCON(Me)Ph]+), 107
O+), 91 (100, C Hþ7 ).
(67, C7ACHTREUGNH7ACHERTGNU 7ACHTRENUG
2.2. 2-{[2-(Benzyloxy)acetyl]amino}-2,N-dimethyl-3,N-diphenylpropanamide (7c). According to GP
1, 5b (1.31 g, 7.9 mmol) in MeCN (30 ml), 6c (2.2 g, 7.9 mmol) in MeCN (5 ml), 14 h, CC (SiO2; hexane/

740
Helvetica Chimica Acta – Vol. 89 (2006)
tBuOMe 1:1): 2.67 g (81%) of 7c. Yellowish oil. IR: 3405m, 3010s, 1770w, 1680s, 1635s, 1595m, 1520s,
1495m, 1380s, 1110s, 700m. 1H-NMR: 1.49 (s, Me); 3.26 (s, MeN); 3.23, 3.43 (2d, J=13.7, PhCH
2AC);
3.60 (s, PhCH2A
O); 4.21, 4.29 (2d, J=11.7, CH2CO); 6.60 (s, NH); 7.00–7.40 (m, 15 arom. H). 13C-
NMR: 24.2 (q, Me); 41.5 (q, MeN); 43.1 (t, PhCH2C); 60.7 (s, PhCH2A(Me)C); 69.7, 73.0 (2t, PhCH2-
CHTREUNG
CTHREUNG
CTHREUNG
ACHTREUNGOCH2); 126.8, 127.4, 127.5, 127.6, 127.9, 128.1, 128.3, 129.1, 130.4 (9d, 15 arom. CH); 136.2, 136.8 (2s,
2 arom. C); 144.6 (s, arom. CN); 168.3, 172.0 (2s, 2 C=O). CI-MS: 417 (60, [M+1]+), 310 (100,
[MꢀPh(Me)N]+).
2.3. 2-{[2-(Benzyloxy)acetyl]amino}-2,N-dimethyl-N-phenylpropanamide (7d). According to GP 1,
5b (2.86 g, 17.2 mmol) in MeCN (60 ml), 6a (3.0 g, 17.2 mmol) in MeCN (15 ml), 14 h, CC (SiO2; hex-
1
ane/Et
2A
3.67, 4.39 (2s, 2 CH2); 6.63 (br. s, NH); 7.20–7.38 (m, 5 arom. H). 13C-NMR: 26.7 (q, Me
MeN); 57.5 (s, Me2C); 69.7, 73.3 (2t, PhCH2AOCH2); 127.5, 127.7, 127.8, 128.0, 128.4, 129.2 (6d, 10
arom. CH); 136.7 (s, arom. C); 144.6 (s, arom. CN); 168.1, 172.8 (2s, 2 C=O).
2.4. 1-{[(S)-2-(Benzyloxy)propanoyl]amino}-N-methyl-N-phenylcyclopentane-1-carboxamide (7e).
According to GP 1, 5c (1.80 g, 10.0 mmol) in MeCN (50 ml), 6b (2.0 g, 10.0 mmol) in MeCN (10 ml),
14 h, CC (SiO2; CH2Cl2/MeOH1:6): 3.27 g (86%) of 7d. White powder. M.p. 107–1088. [a] 2D5 =ꢀ48.4
(c=1.0, CHCl3). IR (KBr): 3314s, 2975m, 2929m, 2874m, 1686s, 1627s, 1536m, 1494s, 1388m, 1153m,
1114m, 1066w, 1023w, 770w, 745m, 699m. 1H-NMR: 1.31 (d, J=6.7, Me); 1.48–1.63, 1.64–1.88,
2.30–2.47, 2.50–2.62 (4m, 2 Heach, (CH 2)4); 3.25 (s, MeN); 3.67 (q, J=6.7, MeCH); 4.21, 4.41 (2d,
O); 6.16 (br. s, NH); 7.13–7.37 (m, 10 arom. H). 13C-NMR: 17.0 (q, Me); 24.1, 24.2,
J=11.5, PhCH2ACHTREUNG
38.7, 39.3 (4t, (CH2)4); 40.7 (q, MeN); 66.7 (s, NCCO); 71.3 (t, PhCH2O); 75.8 (d, MeCH); 127.1,
127.2, 127.3, 127.8, 128.3, 129.1 (6d, 10 arom. CH); 137.3 (s, arom. C); 144.9 (s, arom. CN); 171.3,
172.3 (2s, 2 C=O). ESI-MS: 403 (100, [M+Na]+).
2.5. 1-{[(S)-2-(Benzyloxy)-3-phenylpropanoyl]amino}cyclopentane-1-carboxylic Acid (8b). Accord-
ing to GP 2, 7b (1.37 g, 3.0 mmol) in THF (15 ml), aq. 6N HCl (15 ml): 1.06 g (96%) of 8b. White powder.
M.p. 136–1388. [a]D25 =ꢀ56.8 (c=1.0, CHCl3). IR: 3414m, 3066m, 3021s, 1713s, 1675s, 1513s, 1454m,
1239m, 1090s. 1H-NMR: 1.55–1.92, 2.20–2.39 (2m, 6 H+2 H, (CH2)4); 2.96 (dd, J=7.6, 14.1, 1 Hof
PhCH CHRTNUECG ); 3.16 (dd, J=3.6, 14.1, 1 Hof PhC H2ACHTRECUGN ); 4.16 (dd, J=3.6, 7.6, CHO); 4.10, 4.29 (2d, J=11.8,
2A
PhCH CHTREUNG
2A
38.8 (4t, (CH2)4); 41.3 (t, PhCH2C); 56.7 (s, NCCO); 73.1 (t, PhCH2O); 80.7 (d, CHO); 126.5, 127.9,
128.0, 128.1, 128.5, 129.7 (6d, 10 arom. CH); 136.8, 136.9 (2s, 2 arom. C); 172.9, 177.6 (2s, 2 C=O). CI-
MS: 368 (100, [M+1]+), 274 (9), 108 (6).
2.6. 2-{[2-(Benzyloxy)acetyl]amino}-2-methyl-3-phenylpropanoic Acid (8c). According to GP 2, 7c
(1.25 g, 3.0 mmol) in THF (15 ml), aq. 6N HCl (15 ml): 883 mg (90%) of 8c. White powder. M.p.
117–1188. IR (KBr): 3363s, 3030m, 2887s, 1715s, 1670s, 1542s, 1454m, 1211s, 1133s, 995m, 741m, 696m.
1H-NMR: 1.70 (s, Me); 3.35, 3.50 (2d, J=13.6, PhCH
CHRTUNEGC); 3.94, 4.02 (2d, J=15.6, PhCH2ACHTREOUGN ); 4.39, 4.43
2A
(2d, J=11.8, CH2CO); 7.10–7.40 (m, 10 arom. H); 10.60 (br. s, CO2H). 13C-NMR: 23.1 (q, Me); 41.3
(t, PhCH2C); 60.6 (s, PhCH2A(Me)C); 69.3, 73.4 (2t, PhCH2AOCH2); 127.0, 127.8, 128.0, 128.3, 128.4,
C
CHTREUNG
129.8 (6d, 10 arom. CH); 135.7, 136.6 (2s, 2 arom. C); 170.3, 176.9 (2s, 2 C=O). CI-MS: 328 (100,
[M+1]+).
2.7. 2-{[2-(Benzyloxy)acetyl]amino}-2-methylpropanoic Acid (8d). According to GP 2, 7d (1.02 g, 3.0
mmol) in THF (15 ml), aq. 6N HCl (15 ml): 730 mg (97%) of 8d. White powder. M.p. 89–908.
[a]2D5 =ꢀ39.8 (c=0.7, CHCl3). 1H-NMR: 1.60 (s, Me); 4.02 (s, PhCH
O); 4.62 (s, CH2CO); 7.05 (s,
2AC); 56.3 (s, Me2C); 69.4,
NH); 7.30–7.40 (m, 5 arom. H); 9.85 (br. s, CO2H). 13C-NMR: 24.6 (q, Me
CHTREUNG
73.7 (2t, PhCH
2ACHTREOUNG CH2); 127.9, 128.2, 128.5 (3d, 5 arom. CH); 136.6 (s, arom. C); 170.2, 177.5 (2s, 2
C=O). CI-MS: 259 (5, [M+NH4]+), 252 (100, [M+1]+).
2.8. 1-{[(S)-2-(Benzyloxy)propanoyl]amino}cyclopentane-1-carboxylic Acid (8e). According to GP
2, 7e (2.20 g, 5.8 mmol) in THF (30 ml), aq. 6N HCl (30 ml): 1.60 g (95%) of 8e. White powder. M.p.
968. [a]2D5 =ꢀ39.8 (c=1.0, CHCl3). IR (KBr): 3360s, 2939s, 1706s, 1628s, 1531s, 1418m, 1337m, 1242s,
1191s, 1109s, 1062m, 934m, 773m, 736s, 695m. 1H-NMR: 1.41 (d, J=6.8, Me); 1.69–2.04, 2.20–2.38
(2m, 6 H+2 H, (CH2)4); 3.99 (q, J=6.8, MeCH); 7.06 (br. s, NH); 7.25–7.38 (m, 5 arom. H); 11.22

Helvetica Chimica Acta – Vol. 89 (2006)
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(br. s, CO2H). 13C-NMR: 18.4 (q, Me); 24.4, 24.5, 37.1, 37.3 (4t, (CH2)4); 65.6 (s, NCCO); 72.2 (t,
PhCH2O); 76.2 (d, CHO); 127.8, 128.1, 128.6 (3d, 5 arom. CH); 137.1 (s, arom. C); 177.4 (s, C=O).
ESI-MS: 314 (100, [M+Na]+).
2.9. 1-{[(S)-2-Hydroxy-3-phenylpropanoyl]amino}-N,N-dimethylcyclopentane-1-carboxamide (10b).
According to GP 1, 4a (2.0 g, 12.1 mmol) in MeCN (50 ml), 9b (1.66 g, 12.1 mmol) in MeCN (15 ml),
14 h, CC (SiO2; CH2Cl2/MeOH30 :1): 3.46 g (94%) of 10b. White powder. M.p. 179–1808.
[a]2D5 =ꢀ40.7 (c=1.1, CHCl3). IR: 3407m, 3020m, 3011m, 2964m, 2877m, 1673s, 1632s, 1511s, 1454m,
1393m, 1242m, 1152m, 1086m, 1057m, 1031m, 1005w, 905w, 842m. 1H-NMR: 1.50–1.90, 2.30–2.50
(2m, 6 H+2 H, (CH2)4); 2.94 (s, Me
Hof PhC H2); 4.32 (dd, J=4.0, 7.6, CHO); 6.72 (s, NH); 7.25–7.40 (m, 5 arom. H). 13C-NMR: 24.1,
24.2, 37.0, 37.2 (4t, (CH2)4); 37.5 (q, Me2AN); 40.3 (t, PhCH2); 66.0 (s, NCCO); 72.4 (d, CHO); 126.7,
2ACHTRENUNG ); 2.95 (dd, J=7.6, 14.0, 1 Hof PhC H2); 3.21 (dd, J=4.0, 14.0, 1
CTHREUNG
128.4, 129.7 (3d, 3 arom. CH); 136.9 (s, arom. C); 171.5, 172.1 (2s, 2 C=O). CI-MS: 322 (13,
[M+NH4]+), 305 (100, [M+1]+).
2.10. 2-[(2-Hydroxyacetyl)amino]-2,N,N-trimethyl-3-phenylpropanamide (10c). According to GP 1,
4b (2.17 g, 28.6 mmol) in MeCN/THF 5 :1 (100 ml), 9c (5.40 g, 28.6 mmol) in MeCN (15 ml), 14 h, CC
(SiO2; CH2Cl2/MeOH40 :1): 6.05 g (80%) of 10c. White powder. M.p. 149–1508. IR (KBr): 3293s,
3064m, 1680s, 1615s, 1550m, 1393m, 1223m, 1096s, 701m. 1H-NMR: 1.51 (s, Me); 3.00 (br. s, Me
CHTRENUNG );
2A
3.30 (s, PhCH2); 3.98 (s, CH2O); 4.30 (br. s, OH); 7.00–7.30 (m, 5 arom. H); 7.36 (br. s, NH). 13C-
NMR: 22.8 (q, Me); 38.1 (q, Me2AN); 41.5 (t, PhCH2); 59.5 (s, PhCH2A(Me)C); 61.9 (t, CH2O); 126.8,
C
CHTREUNG
128.2, 130.2 (3d, 5 arom. CH); 136.1 (s, arom. C); 171.1, 172.0 (2s, 2 C=O). CI-MS: 265 (100, [M+1]+).
2.11. (S)-1-{[1-(Dimethylcarbamoyl)cyclopentyl]carbamoyl}-2-phenylethyl 1-{[(S)-2-Hydroxy-3-phe-
nylpropanoyl]amino}cyclopentane-1-carboxylate (11b). According to GP 3, 8b (1.32 g, 3.60 mmol), CDI
(583 mg, 3.60 mmol), 10b (1.09 g, 3.60 mmol), THF (40 ml), 2 h, CC (SiO2; CH2Cl2/MeOH50 :1): 2.07 g
(88%) of 11b, direct conversion into 13b without further characterization.
2.12. {[1-(Dimethylcarbamoyl)-1-methyl-2-phenylethyl]carbamoyl}methyl 2-[(2-Hydroxyacetyl)-
amino]-2-methyl-3-phenylpropanoate (11c). According to GP 3, 8c (1.18 g, 3.60 mmol), CDI (583 mg,
3.60 mmol), 10c (950 mg, 3.60 mmol), THF (40 ml), 2 h, CC (SiO2; CH2Cl2/MeOH60 :1): 1.02 g (59%)
of 11c (mixture of 2 diastereoisomers). White powder. M.p. 84–868. IR (KBr): 3394w, 3283s, 3029m,
2942m, 1748s, 1672s, 1540s, 1454m, 1108s, 740m, 702m. 1H-NMR: 1.31, 1.46, 1.58, 1.58 (4s, 2 Me);
2.8–3.6 (m, Me
4.43, 4.59, 4.71 (4d, J=15.6, CH2CO2); 6.90–7.40 (m, 10 arom. H, NH); 7.71, 7.88 (2s, NH). 13C-NMR:
20.6, 22.0, 22.4, 22.6 (4q, 2 Me); 38.2 (q, Me2AN); 40.5, 40.7, 41.1, 43.1 (4t, 2 PhCH2); 58.4, 58.9, 60.0,
60.2 (4s, 2 PhCH2A(Me)C); 61.7, 61.8, 63.1, 63.2 (4t, 2 CH2O); 126.6, 127.1, 127.3, 128.0, 128.2, 128.4,
2ACHTRENUGN +2 PhCH2 +1 Hof HOC H2 +OH); 3.73, 3.76 (2d, J=16.5, 1 Hof HOC H2); 4.41,
CTHREUNG
CTHREUNG
130.1, 130.3, 130.4 (9d, 10 arom. CH); 134.6, 135.0, 136.5, 136.6 (4s, 2 arom. C); 166.0, 166.2, 171.8,
172.3, 172.4, 172.7, 172.8, 174.7 (8s, 4 C=O). ESI-MS: 989 (30, [2 M+Na]+), 506 (100, [M+Na]+).
2.13. (S)-1-{[1-(Dimethylcarbamoyl)cyclopentyl]carbamoyl}-2-phenylethyl 1-({(S)-2-[1-({[(S)-2-Hy-
droxy-3-phenylpropanoyl]amino}cyclopentyl)carbonyloxy]-3-phenylpropanoyl}amino)cyclopentane-1-
carboxylate (12b). According to GP 3, 8b (1.32 g, 3.60 mmol), CDI (583 mg, 3.61 mmol), 11b (2.03 g, 3.60
mmol), THF (40 ml), 16 h, CC (SiO2; CH2Cl2/MeOH50 :1): 2.52 g (85%) of 11. White powder. M.p.
117–1188. [a]2D5 =ꢀ69.3 (c=1.0, CHCl3). IR: 3414m, 3292s, 3065m, 3021m, 2963m, 2876m, 1740s,
1651s, 1541s, 1497m, 1454m, 1395m, 1298m, 1238s, 1168s, 1083s, 1031m, 969w, 913w, 861w. 1H-NMR:
1.50–1.92, 1.96–2.58 (2m, 18 H+6 H, 3 (CH2)4); 2.95–3.35 (m, Me2ACHTRENUNG +3 PhCH2); 4.30–4.35 (m,
CHOH); 5.20–5.30 (m, 2 CHOCO); 7.20–7.40 (m, 15 arom. H, NH); 7.77, 8.03 (2s, 2 NH). 13C-NMR:
23.9, 24.1, 24.1, 24.2, 24.4, 24.5, 35.7, 36.7, 36.8, 37.0, 37.3, 38.0, 38.1, 38.4, 40.2 (15t, 3 (CH2)4 +3
PhCH2); 65.2, 65.9, 66.4 (3s, 3 NCCO); 72.3, 74.7, 75.3 (3d, 3 CHO); 126.5, 126.8, 126.9, 128.1, 128.2,
128.3, 129.5, 129.7, 129.8 (9d, 15 arom. CH); 135.8, 136.6, 137.0 (3s, 3 arom. C); 168.5, 170.7, 172.8,
172.8, 173.3, 174.1 (6s, 6 C=O). ESI-MS: 845 (100, [M+Na]+). Anal. calc. for C47H58N4O9 (823.01): C
68.59, H7.10, N 6.81; found: C 68.51, H7.19, N 6.59.
2.14. (S)-1-{[1-(Dimethylcarbamoyl)cyclopentyl]carbamoyl}-2-phenylethyl 1-({(S)-2-[1-({[(R)-2-Hy-
droxy-3-phenylpropanoyl]amino}cyclopentyl)carbonyloxy]-3-phenylpropanoyl}amino)cyclopentane-1-
carboxylate (12b’). Synthesis as described for 12b, with (R)-10b instead of (S)-10b. Intermediate com-
pounds have not been characterized. White powder. M.p. 121–1238. [a]2D5 =ꢀ17.8 (c=1.0, CHCl3). IR
(KBr): 3398m, 3283s, 3030w, 2957s, 2874w, 1743s, 1649s, 1540s, 1454m, 1264m, 1165s, 1072s, 745m,

742
Helvetica Chimica Acta – Vol. 89 (2006)
700m. 1H-NMR: 1.31–1.95, 1.92–2.40 (2m, 18 H+6 H, 3 (CH2)4); 2.56–3.23 (m, Me
2ACHTRENUNG +3 PhCH2);
4.35–4.40 (m, CHOH); 5.28–5.38 (m, 2 CHOCO); 7.10–7.35 (m, 15 arom. H, NH); 7.70, 8.25 (2s, 2
NH). 13C-NMR: 23.9, 24.1, 24.4, 24.5, 24.7, 35.8, 37.4, 37.6, 37.7, 38.2, 40.4 (11t, 3 (CH2)4); 37.0 (q, Me
2AN);
CTHREUNG
65.3, 66.1, 66.5 (3s, 3 NCCO); 72.5, 74.7 (2d, 3 CHO); 126.8, 126.9, 126.9, 128.3, 128.5, 129.1, 129.8 (7d, 15
arom. CH); 136.4, 136.5 (2s, 3 arom. C); 168.3, 170.7, 172.8, 172.8, 173.4, 174.1 (6s, 6 C=O). ESI-MS: 845
(100, [M+Na]+). Anal. calc. for C47H58N4O9 (823.01): C 68.59, H7.10, N 6.81; found: C 68.13 H7.11 N
6.69.
2.15. {[1-({[1-(Dimethylcarbamoyl)-1-methyl-2-phenylethyl]carbamoyl}methoxycarbonyl)-1-methyl-
2-phenylethyl]carbamoyl}methyl
2-[(2-Hydroxyacetyl)amino]-2-methyl-3-phenylpropanoate
(12c).
According to GP 3, 8c (1.18 g, 3.60 mmol), CDI (583 mg, 3.60 mmol), 11c (1.74 g, 3.60 mmol), THF
(40 ml), 16 h, CC (SiO2; CH2Cl2/MeOH40 :1): 1.19 g (47%) of 12c (mixture of 4 diastereoisomers).
White powder. M.p. 112–1158. IR (KBr): 3275s, 2943w, 1750s, 1655s, 1548s, 1256m, 1110s, 910m, 733m,
703m. 1H-NMR: 1.20–1.50 (m, 2.5 Me); 1.61, 1.62 (2s, 0.5 Me) 2.80–4.10 (m, Me
CHTRENNUG , 3 PhCH2,
2A
HOCH2, OH); 4.20–4.95 (m, 2 CH2O); 6.95–7.40 (m, 15 arom. H); 7.60–8.00 (m, 3 NH). 13C-NMR:
21.7, 22.0, 22.1, 22.4, 22.6, 22.8 (6q, 3 Me); 38.0, 38.3 (2q, Me2AN); 40.6, 40.7, 41.2, 42.2, 42.5, 42.9, 43.1
CTHREUNG
(7t, 3 PhCH2); 58.4, 58.7, 59.1, 59.2, 59.5, 59.7, 59.8, 60.0, 60.1 (9s, 3 Ph(Me)C); 61.9, 62.0, 62.6, 63.1,
63.2, (5t, 3 CH2O); 126.4, 126.7, 127.3, 127.8, 128.0, 128.3, 128.4, 130.0, 130.1, 130.2, 130.3, 130.4, 130.7,
130.8, 130.9, 131.0 (16d, 15 arom. CH); 134.6, 134.8, 135.0, 135.1, 135.2, 136.5, 136.6, 136.7, 136.9 (9s, 3
arom. C); 165.9, 166.1, 166.7, 166.8, 167.9, 168.1, 158.3, 168.4, 168.5, 171.9, 172.0, 172.1, 172.3, 172.4,
172.6, 172.7, 172.8, 172.9 (18s, 6 C=O). ESI-MS: 725 (85, [M+Na]+), 506 (100). Anal. calc. for
C38H46N4O9 (702.81): C 64.94, H6.60, N 7.97; found: C 65.32, H6.22, N 7.85.
2.16.
(S)-1-({1-[((S)-1-{[1-(Dimethylcarbamoyl)-1-methylethyl]carbamoyl}-2-phenylethoxy)car-
bonyl]-1-methylethyl}carbamoyl)-2-phenylethyl 2-[(2-Hydroxyacetyl)amino]-2-methylpropanoate (12d).
According to GP 3, 8d (904 mg, 3.60 mmol), CDI (583 mg, 3.61 mmol), 11a (1.84 g, 3.60 mmol), THF
(40 ml), 8 h, CC (SiO2; CH2Cl2/MeOH50 :1): 2.14 g (91%) 12d. White powder. M.p. 112–1148.
[a]2D5 =ꢀ33.2 (c=1.0, CHCl3). IR: 3402m, 3281s, 3066w, 3021m, 3009m, 2941m, 1745s, 1652s, 1545s,
1497m, 1471m, 1455m, 1440m, 1388m, 1367m, 1342w, 1291m, 1268m, 1146s, 1082m, 1064m, 1031m,
1
1001w, 940w, 888w, 842w. H-NMR: 1.15, 1.29, 1.31, 1.52, 1.54, 1.57 (6s, 6 Me); 2.90–3.15 (m, Me
2A
Hof PhC H2); 3.20–3.39 (m, 1 Hof PhC H2); 3.96, 4.14 (2d, J=16.3, CH2O); 5.20–5.30 (m, 2 CHO);
7.10–7.40 (m, 10 arom. H); 7.51, 7.79, 8.03 (3s, 3 NH). 13C-NMR: 24.1, 24.4, 24.9, 25.2, 25.9, 26.2 (6q,
6 Me); 37.6, 37.9 (2t, 2 PhCH2); 37.4 (q, MeN); 55.6, 56.1, 56.6 (3s, 3 Me2C); 62.1 (t, CH2O); 74.6, 74.9
(2d, 2 CHO); 126.8, 127.1, 128.3, 128.4, 129.5, 129.7 (6d, 10 arom. CH); 135.9, 136.7 (2s, 2 arom. C);
168.8, 179.1, 173.2, 173.2, 173.3, 173.5 (6s, 6 C=O). ESI-MS: 677 (100, [M+Na]+). Anal. calc. for
C34H46N4O9 (645.75): C 62.37, H7.08, N 8.56; found: C 61.58, H7.08, N 8.34.
2.17. (S)-1-{1-[(Dimethylcarbamoyl)cyclopentyl]carbamoyl}-2-phenylethyl 1-({(S)-2-[1-({[(S)-2-
Hydroxypropanoyl]amino}cyclopentyl)carbonyloxy]-3-phenylpropanoyl}amino)cyclopentane-1-carbox-
ylate (12e). According to GP 3, 8e (1.05 g, 3.60 mmol), CDI (583 mg, 3.61 mmol), 11b (2.03 g, 3.60
mmol), THF (40 ml), 16 h, CC (SiO2; CH2Cl2/MeOH45 :1): 2.36 g (88%) of 12e. White powder. M.p.
137–1388. [a]2D5 =ꢀ36.3 (c=1.2, CHCl3). IR (KBr): 3464m, 3304s, 3062w, 3033w, 2958s, 2874w, 1740s,
1645s, 1547s, 1454m, 1265m, 1164m, 1127w, 1072s, 741m, 699m. 1H-NMR: 1.46 (d, J=6.8, Me);
1.51–2.42 (m, 3 (CH2)4); 2.55–2.78, 3.02–3.21 (2m, 2 PhCH2); 2.92 (s, Me2CATHRENUNG ); 4.26 (q, J=6.8,
MeCH); 5.30 (m, 2 CHO); 7.11–7.32 (m, 10 arom. H); 7.49, 7.72, 8.18 (3s, 3 NH). 13C-NMR: 20.8 (q,
Me); 24.1, 24.2, 24.3, 24.4, 24.6, 35.7, 37.0, 37.2, 37.3, 37.5, 37.8, 38.0 (12t, 3 (CH2)4 +2 PhCH2); 37.6 (q,
Me2ACHTREUNNG ); 65.3, 66.0, 66.4 (3s, 3 NCCO); 68.3, 74.5, 74.6 (3d, 3 CHO); 126.9, 127.0, 128.4, 128.5, 129.1,
129.8 (6d, 10 arom. CH); 136.5, 136.5 (2s, 2 arom. C); 168.4, 170.7, 172.8, 173.0, 173.4, 176.1 (6s, 6 C=
O). ESI-MS: 769 (100, [M+Na]+).
3. Cyclization Reactions. 3.1. (6R,12S,18S)-6,12,18-Tribenzyl-3,3,9,9,15,15-hexamethyl-1,7,13-trioxa-
4,10,16-triazacyclooctadecane-2,5,8,11,14,17-hexaone (14a). According to GP 4, 12a (280 mg, 0.4
mmol), toluene (30 ml), CC (SiO2; CH2Cl2/MeOH60 :1): 70 mg (27%) of 14a. White powder. M.p.
112–1138. [a]2D5 =ꢀ25.8 (c=1.8, CHCl3). IR: 3414w, 3276s, 3031w, 3011w, 2928m, 2856w, 1746s, 1648s,
1
1552s, 1455m, 1388m, 1269m, 1144s, 1064m. H-NMR: 1.19, 1.37, 1.44, 1.44, 1.46, 1.56 (6s, 6 Me); 2.82
(dd, J=4.2, 6.9, 1 Hof PhC H2); 3.16 (dd, J=2.7, 7.2, 1 Hof PhC H2); 3.33 (dd, J=2.4, 6.9, 1 Hof
PhCH2); 3.41 (dd, J=2.7, 7.2, 1 Hof PhC H2); 3.02–3.05 (m, PhCH2); 5.17 (t, J=3.3, 1 CHO); 5.22 (t,

Helvetica Chimica Acta – Vol. 89 (2006)
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J=3.0, 1 CHO); 5.37 (dd, J=2.1, 4.2, 1 CHO); 6.71, 6.96, 6.98 (3s, 3 NH); 7.15–7.30 (m, 15 arom. H). 13C-
NMR: 23.0, 23.6, 24.2, 24.9, 24.9, 25.3 (6q, 6 Me); 36.8, 37.0, 37.5 (3t, 3 PhCH2); 56.7, 56.8, 57.6 (3s, 3
Me2C); 74.8, 74.9, 75.2, (3d, 3 CHO); 126.9, 127.0, 127.1, 128.3, 128.4, 128.5, 129.4, 129.7, 129.8 (9d, 15
arom. CH); 135.1, 135.3, 135.7 (3s, 3 arom. C); 167.9, 168.1, 168.3, 172.0, 172.5, 173.0 (6s, 6 C=O).
ESI-MS: 722 (100, [M+Na]+). Anal. calc. for C39H45N3O9 (702.81): C 66.94, H6.48, N 6.00; found: C
66.23, H6.54, N 5.82.
3.2. (6R,12S,18S)-6,12,18-Tribenzyl-3,3,9,9,15,15-tris(tetramethylene)-1,7,13-trioxa-4,10,16-triazacy-
clooctadecane-2,5,8,11,14,17-hexaone (14b). According to GP 4, 12b (330 mg, 0.4 mmol), toluene (30
ml), CC (SiO2; CH2Cl2/Et
2A
(c=1.4, CHCl3). IR: 3427w, 3318m, 3021m, 2964m, 2878w, 1744s, 1680s, 1529s, 1497w, 1454w, 1236m,
1165s, 1071m. 1H-NMR: 1.52–2.12, 2.18–2.26, 2.43–2.49 (3m, 20 H+3 H+1 H, 3 (CH2)4); 2.73 (dd,
J=4.8, 7.2, 1 Hof PhC H2); 3.00 (dd, J=3.3, 6.9, 1 Hof PhC H2); 3.06 (dd, J=2.7, 7.2, 1 Hof PhC H2);
3.15 (dd, J=3.0, 7.2, 1 Hof PhC H2); 3.33 (dd, J=2.4, 7.2, PhCH2); 3.39 (dd, J=2.7, 6.9, 1 Hof
PhCH2); 5.20–5.25 (m, 2 CHO); 5.30 (dd, J=2.4, 4.8, 1 CHO); 6.72 (s, 1 NH); 7.10–7.30 (m, 15 arom.
H, 2 NH). 13C-NMR: 23.9, 24.0, 24.6, 24.7, 25.1, 25.2, 31.6, 34.9, 36.1, 36.5 37.0, 37.0, 37.1, 37.4, 37.9
(15t, 3 (CH2)4 +3 PhCH2); 66.3, 66.9 (2s, 3 NCCO); 74.9, 75.0, 75.1 (3d, 3 CHO); 126.9, 127.0, 127.1,
128.3, 128.5, 128.5, 129.4, 129.7, 129.8 (9d, 15 arom. CH); 135.1, 135.5, 136.1 (3s, 3 arom. C); 168.2,
168.3, 168.5, 171.7, 172.7, 173.3 (6s, 6 C=O). ESI-MS: 800 (100, [M+Na]+). Anal. calc. for C45H51N3O9
(777.92): C 69.47, H6.61, N 5.40; found: C 69.12, H6.70, N 5.27.
3.3.
3,9,15-Tribenzyl-3,9,15-trimethyl-1,7,13-trioxa-4,10,16-triazacyclooctadecane-2,5,8,11,14,17-
hexaone (14c). According to GP 4, 12c (280 mg, 0.4 mmol), toluene (30 ml), CC (SiO2; CH2Cl2/MeOH
60 :1): 121 mg (46%) of 14c as a mixture of 2 diastereoisomers. White powder. M.p. 88–898. IR:
1
3279s, 3030m, 2977m, 1751s, 1654s, 1523s, 1422s, 1333m, 1112m, 1046m, 849w. H-NMR5): 1.24–1.50
(br. m, 3 Me); 3.00–3.50 (br. m, 3 PhCH2); 4.10–4.75 (br. m, 3 CH2O); 7.00–7.35 (m, 15 arom. H);
7.60–8.00 (br. m, 3 NH). 13C-NMR (br. signals): 22.4 (q, Me); 41.5 (t, PhCH2); 59.4 (s, Ph(Me)C); 62.7
(t, CH2O); 126.9, 128.1, 130.5 (3d, 15 arom. CH); 135.1 (s, 3 arom. C); 168.3, 172.3 (2s, 6 C=O). ESI-
MS: 680 (100, [M+Na]+). Anal. calc. for C36H39N3O9 ·0.5 H2O (657.27·0.5 H2O): C 64.85, H6.05, N
6.30; found: C 64.77, H6.12, N 6.22.
3.4. 6,12-Dibenzyl-3,3,9,9,15,15-hexamethyl-1,7,13-trioxa-4,10,16-triazacyclooctadecane-2,5,8,11,14,
17-hexaone (14d). According to GP 4, 12d (260 mg, 0.4 mmol), toluene (30 ml), CC (SiO2; CH2Cl2/
MeOH55 :1): 105 mg (43%) of 14d as a mixture of 2 diastereoisomers. White powder. M.p. 159–1628.
[a]2D5 =ꢀ31.9 (c=1.2, CHCl3). IR: 3279s, 3067w, 3033w, 2993m, 2946m, 2857w, 1748s, 1650s, 1554s,
1471m, 1455m, 1388m, 1368w, 1308m, 1266m, 1140s, 1065m, 909m. 1H-NMR5): 1.08–1.70 (br. m, 6
Me); 2.80–3.45 (br. m, 2 PhCH2); 4.00–4.80 (br. m, CH2O); 5.10–5.50 (br. m, 2 CHO); 7.00–7.35 (m,
10 arom. H); 7.50–8.30 (br. m, 3 NH). 13C-NMR (br. signals): 23.7 (q, 6 Me); 37.5 (t, 2 PhCH2); 56.1
(s, NCCO); 63.3 (t, CH2O); 74.9 (d, 2 CHO); 126.9, 128.3, 129.4 (3d, 10 arom. CH); 136.2 (s, 2 arom.
C); 170.5, 173.4 (2s, 6 C=O). ESI-MS: 632 (100, [M+Na]+). Anal. calc. for C32H39N3O9 (609.67): C
63.04, H6.45, N 6.89; found: C 62.88, H6.77, N 6.93.
3.5. 6,12-Dibenzyl-18-methyl-3,3,9,9,15,15-tris(tetramethylene)-1,7,13-trioxa-4,10,16-triazacycloocta-
decane-2,5,8,11,14,17-hexaone (14e). According to GP 4, 12e (250 mg, 0.34 mmol), toluene (30 ml), CC
(SiO2; CH2Cl2/MeOH45 :1): 79 mg (33%) of 14e. White powder. M.p. 134–1358. [a]2D5 =ꢀ16.8
(c=1.0, CHCl3). IR (KBr): 3426w, 3298m, 2959m, 2875w, 1745s, 1659s, 1545s, 1453m, 1301m, 1239s,
1
1166s, 1073m, 746m, 700m. H-NMR: 1.48 (d, J=6.7, Me); 1.49–2.57 (m, 3 (CH2)4); 2.74 (dd, J=9.7,
14.1, 1 Hof PhC H2); 3.13–3.39 (m, 3 Hof PhC H2); 6.54 (br. s, NH); 7.11–7.38 (m, 10 arom. H+2
NH). 13C-NMR: 17.6 (q, Me); 23.9, 24.0, 24.4, 24.5, 25.3, 25.5, 34.8, 36.3, 36.4, 36.5, 36.9, 37.3, 37.5,
37.9 (14t, 3 (CH2)4 +2 PhCH2); 66.2, 66.3, 66.8 (3s, 3 NCCO); 71.4, 74.9, 75.0 (3d, 3 CHO); 126.8,
127.1, 128.4, 128.5, 129.2, 129.6 (6d, 10 arom. CH); 134.9, 136.1 (2s, 2 arom. C); 168.2, 168.5, 169.6,
171.5, 172.4, 173.5 (6s, 6 C=O). ESI-MS: 724 (100, [M+Na]+).
1H- and 13C-NMR spectra of 14c and 14d show broad signals, probably due to the co-existence of dif-
ferent conformers that convert to one another. The same phenomenon has been observed with sim-
ilar depsipeptides with 18-membered [28] and 24-membered [45][46] rings.
5
)

744
Helvetica Chimica Acta – Vol. 89 (2006)
4. Control Experiments. 4.1. 8-Benzyl-9-oxa-6-azaspiro[4.5]decane-7,10-dione (16). According to GP
4, 10b (152 mg, 0.5 mmol), toluene (30 ml), CC (SiO2; CH2Cl2/Et2CAHTREOUNG 10 :1): 66 mg (51%) of racemic 16.
White powder. M.p. 106–1078. IR (KBr): 3189m, 3086m, 2964m, 2926m, 2880w, 1741s, 1679s, 1454m,
1436m, 1346m, 1261m, 1185m, 1093m, 1021w, 828m, 740w, 694m. 1H-NMR ((D6)DMSO): 1.44–2.15
(m, (CH2)4); 3.07 (dd, J=7.5, 14.7, 1 Hof PhC H2); 3.31 (dd, J=4.0, 14.7, 1 Hof PhC H2); 5.31 (dd,
J=4.0, 7.5, CHO); 7.25–7.41 (m, 5 arom. H); 8.76 (br. s, NH). 13C-NMR: 23.9, 24.3, 36.4, 38.0, 39.8
(5t, (CH2)4 +PhCH2); 63.6 (s, NCCO); 77.8 (d, CHO); 126.5, 128.1, 129.6 (3d, 5 arom. CH); 136.1 (s,
arom. C); 166.2, 171.0 (2s, 2 CO). ESI-MS: 282 (100, [M+Na]+). Anal. calc. for C15H17NO3 (259.31):
C 69.47, H6.61, N 5.40; found: C 69.50, H6.78, N 5.38.
4.2. (S)-N-Butyl-2-hydroxy-3-phenylpropanamide (15). To a soln. of (S)-phenyllactic acid (300 mg,
1.81 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU;
2 mmol, 760 mg) in CH2Cl2 (10 ml) was added BuNH2 (396 mg, 0.54 ml, 5.5 mmol). After 4 h stirring
at r.t., H2O (10 ml) was added. The org. layer was washed with 0.5M HCl (3”5 ml) and sat. aq.
NaHCO3 soln. (3”5 ml), and dried (MgSO4). Evaporation of the solvent and CC yielded 15 (288 mg,
72%). White powder. M.p. 83–848. [a]2D5 =ꢀ43.3 (c=1.1, CHCl3). IR (KBr): 3335s, 2962m, 2934m,
1
2875w, 1627s, 1556s, 1411m, 1292m, 1084s, 729m, 699m. H-NMR: 0.89 (t, J=7.2, Me); 1.21–1.47 (m,
MeCH2ACHTERUCGN H2); 2.81–2.94 (m, 1 Hof PhC H2); 3.14–3.30 (m, CH2N+1 Hof PhC H2 +OH); 4.26 (m,
CHO); 6.46 (br. s, NH); 7.20–7.33 (m, 5 arom. H). 13C-NMR: 13.6 (q, Me); 19.9, 31.4, 38.7, 40.8 (4t, 4
CH2); 72.7 (d, CHO); 126.9, 128.6, 129.6 (3d, 3 arom. CH); 137.1 (s, arom. C); 172.8 (s, C=O). ESI-
MS: 244 (100, [M+Na]+).
5. X-Ray Crystal-Structure Determination of 14a (Table and Fig.)6). All measurements were per-
formed on a Nonius KappaCCD area-detector diffractometer [52] using graphite-monochromated
MoKa radiation (l 0.71073 Š) and an Oxford Cryosystems Cryostream 700 cooler. The data collection
and refinement parameters are given in the Table, and a view of the molecule is shown in the Figure.
Data reduction was performed with HKL Denzo and Scalepack [53]. The intensities were corrected
for Lorentz and polarization effects, but not for absorption. Equivalent reflections were merged. The
Table. Crystallographic Data for Compound 14a
Crystallized from
hexane/CH
39A 45A 3AO9
699.80
colorless, needle 2q(max) [8]
0.07”0.10”0.30 Total reflections measured
G
]
m(MoKa) [mmꢀ1
Scan type
1.223
0.0870
w
Empirical formula
Formula weight [g molꢀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C
U
N
N
]
]
50
34567
160(1)
Crystal system
Space group
Z
Reflections for cell determination 6575
2q Range for cell determination [8] 4–50
Monoclinic
P21
4
Reflections with I>2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) [I>2s(I) reflections]
wR(F2) (all data)
4833
6877
956; 1
0.0416
0.1007
Weights: w=[s2(F2o)+(0.0514P)2]ꢀ1
Unit cell parameters a [Š]
11.3280(1)
where P=(F2o +2 Fc2)/3
b [Š]
c [Š]
24.3225(3)
13.7975(2)
90.0072(6)
3801.56(8)
1488
Goodness-of-fit
Secondary extinction coefficient
Final Dmax/s
D1 (max; min) [e Š
1.000
0.0079(7)
0.001
0.32; ꢀ0.19
b [8]
V [Š3]
]
ꢀ3
F(000)
6
)
CCDC-297488 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre, via www.ccdc.cam.ac.uk/
data_request/cif.

Helvetica Chimica Acta – Vol. 89 (2006)
745
structure was solved by direct methods using SIR92 [54], which revealed the positions of all non-H-
atoms. There are two symmetry-independent molecules in the asymmetric unit. The atomic coordinates
of the two molecules were tested carefully for a relationship from a higher symmetry space group using
the program PLATON [55], but none could be found. The non-H-atoms were refined anisotropically.
The amide H-atoms were placed in the positions indicated by a difference electron density map, and
their positions were allowed to refine together with individual isotropic displacement parameters. All
remaining H-atoms were placed in geometrically calculated positions and refined using a riding model
where each H-atom was assigned a fixed isotropic displacement parameter with a value equal to
1.2Ueq of its parent C-atom (1.5Ueq for the Me groups). The refinement of the structure was carried
out on F2 using full-matrix least-squares procedures, which minimized the function Sw(Fo2 ꢀF2c )2. A cor-
rection for secondary extinction was applied. Nine reflections, whose intensities were considered to be
extreme outliers, were omitted from the final refinement. Neutral-atom-scattering factors for non-H-
atoms were taken from [56a], and the scattering factors for H-atoms were taken from [57]. Anomalous
dispersion effects were included in Fc [58]; the values for f’ and f’’ were those of [56b]. The values of the
mass attenuation coefficients are those of [56c]. All calculations were performed using the SHELXL97
[59] program.
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Received February 9, 2006