Synthesis of a regular 24-membered cyclodepsipeptide by direct amide cyclization

Article abstract of DOI:10.1515/znb-2009-0615

Aminoisobutyric Acid, Crystal Structure The synthesis of a 24-membered cyclic depsipeptide with an alternating sequence of phenyllactic acid and α-aminoisobutyric acid (Aib) is described. The linear precursor was prepared via the 'azirine/oxazolone method

Full text of DOI:10.1515/znb-2009-0615

Synthesis of a Regular 24-membered Cyclodepsipeptide
by Direct Amide Cyclization
Peter Ko¨ttgen∗, Anthony Linden, and Heinz Heimgartner
Organisch-chemisches Institut der Universita¨t Zu¨rich, Winterthurerstrasse 190, 8057 Zu¨rich,
Switzerland
Reprint requests to Prof. H. Heimgartner. E-mail: heimgart@oci.uzh.ch
Z. Naturforsch. 2009, 64b, 689 – 698; received March 30, 2009
Dedicated to Professor Gerhard Maas on the occasion of his 60th birthday
The synthesis of a 24-membered cyclic depsipeptide with an alternating sequence of phenyl-
lactic acid and α-aminoisobutyric acid (Aib) is described. The linear precursor was prepared via
the ‘azirine/oxazolone method’ using 2,2-dimethyl-3-amino-2H-azirines as building blocks for the
α,α-disubstituted α-amino acid Aib. The macrolactonization leading to the cyclodepsipeptide was
achieved by the ‘direct amide cyclization’, i. e., by treatment of a solution of the linear precursor in
toluene with HCl gas.
Key words: Cyclodepsipeptides, Direct Amide Cyclization, Azirine/Oxazolone Method,
Aminoisobutyric Acid, Crystal Structure
Introduction
the formation of either the amide bond (lactamization)
[7] or the ester bond (lactonization) [8].
Cyclic depsipeptides are macrocycles composed of
both amino acids and hydroxy acids, i. e., containing
lactam as well as lactone groups. As a result of the
well known biological activity of some representatives,
they are the subject of continous and current investiga-
tions. The majority of naturally occuring cyclic dep-
sipeptides have been isolated from marine or surface
cultures of the corresponding microorganisms [1]. The
current efforts to find new biologically active natural
examples are reflected in a large number of recent pa-
pers [2]. Two of the most well known cyclodepsipep-
tides are the antibiotics valinomycin [3] and enniatins
[4], which act as ionophores [5]. The special feature
of these 36- and 18-membered cyclodepsipeptides, re-
spectively, is their alternating sequence of α-amino
and α-hydroxy acids leading to macrocycles with al-
ternating lactam and lactone bonds. The pharmaceuti-
cal importance of, e. g., natural enniatins and synthetic
analogs stimulates the search for new natural exam-
ples and the attempts at synthesizing modified com-
pounds [6]. In practically all syntheses of cyclodep-
sipeptides, the cyclization is the crucial step. The ma-
jority of these ring closures have been carried out by
A useful cyclization method for depsipeptides con-
taining α,α-disubstituted α-amino acids, the so-called
‘direct amide cyclization’, has been developed in
our group [9 – 13]. The basic concept is shown in
Scheme 1: a solution or suspension of an amide of
type 1 in toluene is treated with dry HCl gas, whereby
the corresponding 1,3-oxazol-5(4H)-one derivative 2
is formed by ring closure and elimination of dimeth-
ylamine hydrochloride. In the absence of other nucle-
ophiles, the oxazolone 2 undergoes a ring enlargement
to yield the cyclic product 3 via an intramolecular at-
tack of the ω-hydroxy group onto the lactone func-
tionality.
Several cyclic depsipeptides which contain one hy-
droxy acid and several α,α-disubstituted α-amino
acids have been prepared in our group by using this
cyclization method [9 – 12], e. g., the 12-membered 4
[9b] and the 16-membered 5 [12a]. In addition, syn-
theses of a 12-membered [9c] as well as some 18-
membered cyclodepsipeptides of type 6 [14, 15] with
an alternating sequence of α-hydroxy acids and α-
amino acids have been accomplished. Sterically de-
manding disubstituted amino acids have been incor-
porated into the linear precursors by the so-called
‘azirine/oxazolone method’ [16]. This particularly use-
∗
Part of the Ph. D. thesis of P. K., Universita¨t Zu¨rich, 2006.
c
0932–0776 / 09 / 0600–0689 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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690
P. Ko¨ttgen et al. · A Regular 24-membered Cyclodepsipeptide
Scheme 1.
ful approach has also been applied successfully in the phenyllactic acid (9) could not be synthesized by stan-
syntheses of peptaibols [17], endothiopeptides [18], dard procedures, as it turned out that the configuration
and conformationally restricted cyclic peptides [19].
On the basis of these results it was of interest to as-
certain whether cyclodepsipeptides with a larger ring
size, and an alternating pattern of α-hydroxy acids and
α,α-disubstituted α-amino acids can be synthesized
using the ‘direct amide cyclization’ for the macrolac-
tonization step. Our aim was to prepare a 24-membered
cyclic depsipeptide containing four phenyllactic acid
and four Aib units. The incorporation of the amino acid
units into the linear precursor was again to be achieved
by using the ‘azirine/oxazolone method’.
at the α-carbon atom is labile under the basic condi-
tions of the benzylation of the OH group as well as the
basic ester hydrolysis. However, the enantiomerically
pure building block 9 was obtained by the use of benzyl
trichloroacetimidate as the benzylating agent [20] and
subsequent acid-catalyzed hydrolysis of the methyl es-
ter. The enantiomeric purity of 9 has been proved after
coupling with 8b by means of HPLC chromatography
on a chiral stationary phase and comparison with the
racemic compound.
The diamide 10 was obtained in excellent yield by
coupling of 9 with azirine 8b. Then, the terminal amide
bond was hydrolyzed by following the standard pro-
cedure of the ‘azirine/oxazolone method’ (3N HCl in
THF/H2O at r. t.) leading to the enantiomerically pure
building block 11 needed for the subsequent esterifi-
cation reaction. The required alcohol 12 was prepared
by coupling (S)-phenyllactic acid (7) with the azirine
8a. The N,N-dimethylazirine 8a, which affords the ter-
minal Me2N-amide 12, was chosen instead of the N-
methyl-N-phenyl azirine 8b, which leads to the N-
methyl-N-phenyl amide. Whereas the hydrolysis of the
Ph(Me)N amides is easier and usually occurs at r. t., it
had turned out in earlier experiments that the terminal
Me2N group is more suitable for the lactonization via
‘direct amide cylization’ [9 – 15].
Results and Discussion
Synthesis of the linear precursor
For our model compound, we selected an α-
hydroxy acid, which contained a chromophore to en-
sure that the final product can be detected by UV light.
Furthermore, the linear precursor was to bear a steri-
cally less congested alcohol function to facilitate the
ring closure. Therefore, (–)-(S)-phenyllactic acid (7)
was chosen. It was applied in its enantiopure form with
the aim of generating only a single diastereoisomer of
the linear precursor for the cyclization, and, hopefully,
of the cyclodepsipeptide. As synthons for the introduc-
tion of the α,α-dimethyl glycine (Aib) units, 3-(N,N-
dimethylamino)-2H-azirine (8a) and 3-(N-methyl-N-
phenylamino)-2H-azirine (8b) were used in the cou-
pling steps to give the corresponding amides.
The esterification of 11 and 12 was performed
in high yield using 1,1ꢀ-carbonyldiimidazole (CDI)
as the coupling reagent and sodium imidazolide as
The synthesis of the linear depsipeptide 15 is shown the catalyst [9c]. Deprotection of the alcohol group
in Scheme 2. The required O-benzyl-protected (S)- of the product 13 was achieved by hydrogenolysis
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P. Ko¨ ttgen et al. · A Regular 24-membered Cyclodepsipeptide
691
Scheme 2.
◦
(Pd catalysis). Subsequent twofold repetition of the 100 C with a stream of dry HCl gas for 4.5 min
esterification and deprotection steps yielded the de- led to a new product (TLC control). During work-up
sired precursor for the macrolactonization, viz. the and column chromatography, the latter decomposed,
‘tetramer’ 15.
so we assumed that only the oxazolone 16 was formed
In order to obtain a ‘dimeric’ building block that al- during this relatively short reaction time, and that the
ready contains four alternating units and a carboxylic ring enlargement via nucleophilic addition of the ω-
acid function at the C terminus, attempts were made to hydroxy group onto the oxazolone to give the desired
hydrolyze the terminal amide bond of 13 selectively. 24-membered ring did not take place.
Unfortunately, under the conditions applied, the es-
ter bond was also partially broken and, therefore, this
shorter approach to 15 was not successful.
Therefore, in a second experiment, the reaction mix-
ture was first treated with HCl gas as above and then
stirred under reflux for another 20 min to enable the
ring enlargement. Again, the same unstable intermedi-
ate was detected but could not be isolated. In the sub-
Macrolactonization
The first cyclization attempt was carried out by ap- sequent lactonization attempt, the mixture was again
plying the optimized conditions for the ring closure treated with HCl gas and then heated for 20 min under
to give 18-membered cyclodepsipeptides [15]. Treat- reflux while the bubbling of a gentle HCl gas stream
ment of a solution of the precursor 15 in toluene at through the solution was continued. In fact, a new
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692
P. Ko¨ttgen et al. · A Regular 24-membered Cyclodepsipeptide
Scheme 3.
product was formed (TLC), and the desired macrocy-
cle 17 could be isolated in 34 % yield as a colorless
solid (Scheme 3).
These observations indicate a rapid formation of the
oxazolone intermediate 16 during the first HCl treat-
ment, but, in contrast to the synthesis of the corre-
sponding 18-membered cyclodepsipeptides [15], the
ring enlargement of the oxazolone via nucleophilic at-
tack of the ω-hydroxy group at the oxazolone C=O
group does not take place. Entropic reasons may be re-
sponsible for this difference in reactivity, as the chance
for the two reaction centers to come together is smaller
with increasing length of the chain. Even prolonged
heating under reflux does not lead to the 24-membered
ring. The ring closure/ring expansion only proceeds if
HCl gas is bubbled through the reaction mixture dur-
ing heating. Apparently, the intermediate oxazolone 16
has to be activated by protonation, which can be en-
sured by maintaining a high HCl concentration in the
reaction mixture.
The yield of 34 % for the cyclodepsipeptide 17 is
comparable with that of other cyclization methods for
macrolactones of this ring size. Unfortunately, the es-
ter bonds of the cyclization precursor 15 are not com-
pletely stable under the conditions of the ‘direct amide
cylization’, as has been shown by control experiments
in methanolic solution [15]. It is most likely that cleav-
age of ester groups in the linear depsipeptide under
these acidic conditions also occurs via the formation of
1,3-oxazol-5(4H)-ones as intermediates, which, with
traces of water or during workup, are transformed into
the corresponding acids.
Fig. 1. ORTEP plot [21] of the molecular structure of 17
(50 % probability ellipsoids, arbitrary numbering of atoms).
Crystallization of a sample of 17 from a mixture
of xylene, CCl4 and acetone by slow evaporation of
the solvent gave crystals suitable for an X-ray crystal
structure determination. The molecular structure of 17
is shown in Fig. 1. It shows the cyclic depsipeptide
with an epimerized configuration of one of the four
stereogenic centers, i. e., the molecule has the 3R,9S,
15S,21S configuration.
The available crystal was not of optimal quality and
weakly diffracting, thus the refinement results are of
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P. Ko¨ ttgen et al. · A Regular 24-membered Cyclodepsipeptide
693
only moderate precision. However, the overall struc- might be anticipated. But in the case of a similar 18-
ture is unambiguous. The space group suggests that membered depsipeptide, a different lactonization using
the compound in the crystal is enantiomerically pure, the Corey-Nicolaou method [24] showed that the R,S,S
but the absolute configuration of the molecule has not epimer undergoes the cyclization much easier than the
been determined. The compound has either the R,S, S,S,S isomer [15]. The inverted configuration may pro-
S,S or the S,R,R,R configuration. Based on the expec- mote a different conformation that is more suitable for
tation from the chemical synthesis that the compound the attack of the ω-hydroxy group onto the oxazolone
should have the R,S,S,S configuration, this assumption moiety. A comparable observation was reported re-
was used to define the model used in the refinement as cently [25]: The base-catalyzed cyclooligomerization
3R,9S,15S,21S. Despite the obvious asymmetry aris- of (3S,6S)-3-isopropyl-6-methylmorpholine-2,5-dione
ing from the chiral centers, the molecule is pseudo- led to cyclic di-, tri-, and tetramers, i. e., cyclic dep-
centrosymmetric with 97 % of the atoms closely fitting sipeptides with alternating lactic acid and valine units,
the centrosymmetric relationship. The asymmetric unit with extensive epimerization. For example, one of the
also includes two molecules of p-xylene. The macro- isomeric 24-membered rings was obtained in crys-
cyclic molecule contains two intramolecular hydro- talline form, and the X-ray crystal structure determi-
gen bonds [N(11)–H···O(4) and N(23)–H···O(16)], nation established the (R,R,R,S,R,R,R,S)-configuration
which link two diametrically opposite amide N–H with only two valine residues showing the original (S)-
groups to the next amide O atom around the ring, af- configuration.
ter an intervening ester group. These interactions form
loops with a graph set motif [22] of S(10), i. e., β-
turns. The other amide N–H groups form intermolec-
ular hydrogen bonds to diametrically opposed ester
carbonyl O atoms in adjacent molecules, one inter-
action being with the next molecule in the [100] di-
rection [N(5)–H···O(13ꢀ)], and the other interaction
Conclusions
The 24-membered cylic depsipeptide 17 with an al-
ternating sequence of an α-hydroxy acid and an α,α-
disubstituted α-amino acid, i. e., phenyllactic acid and
aminoisobutyric acid (Aib), has been synthesized. The
preparation of the linear depsipeptide 15 as the precur-
sor of the cyclization has been accomplished by the use
of the efficient ‘azirine/oxazolone method’ to incorpo-
rate the Aib units, followed by ester formation of the
segments. The macrolactonization step was achieved
via the ‘direct amide cyclization’ and yielded the de-
sired product 17 in a yield of 34%. The structure of
the cyclic depsipeptide has been determined by X-ray
analysis, which has proved that the cyclization occurs
with inversion of the configuration of the α-hydroxy
acid next to the amide terminus of 15. It has thus been
demonstrated that this methodology is also useful for
the preparation of cyclodepsipeptides with larger rings,
i. e., higher homologs of the enniatins. However, the
cyclization step has to be improved to avoid epimeriza-
tion.
¯
with the next molecule in the [100] direction [N(17)–
H···O(1ꢀꢀ)]. Each of the intermolecular interactions
links the molecules into extended chains which run
parallel to the crystallographic x axis and have a graph
set motif of C(11). As these interactions run antiparal-
lel to one another and link the same pairs of molecules,
the two independent intermolecular interactions com-
bined give rise to the formation of a ring between
the molecules which has a binary graph set motif of
R22(14).
In accord with the observations for the correspond-
ing 18-membered cyclodepsipeptides [15], epimeriza-
tion also occurred in the present case at one of the
stereogenic centers, and only one diastereoisomer was
obtained. The stereogenic center in α-position to the
oxazolone 16 (Scheme 3), i. e., the first stereogenic
center counting from the former amide terminus, is
configurationally unstable under the applied conditions
of the ‘direct amide cyclization’, as could be shown
by control experiments in the case of the lower ho-
mologs of type 14 [15] (see also ref. [23]). Therefore,
it is reasonable to assume that the epimerization also
took place at this center in the case of 15. It has not
been clarified why only the product with one inverted
Experimental Section
General remarks
The azirines 8a and 8b, i. e., 2,2,N,N-tetramethyl-2H-
azirin-3-amine and 2,2,N-trimethyl-N-phenyl-2H-azirin-3-
amine, were prepared according to standard procedures (see
ref. [16] and refs. cited therein). All other products used
were commercially available. Solvents were purified by stan-
center was obtained, as a mixture of diastereoisomers dard procedures. Thin-layer chromatography (TLC): Merck
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694
P. Ko¨ttgen et al. · A Regular 24-membered Cyclodepsipeptide
TLC aluminium sheets, silica gel 60 F254. Flash chromatog- maining starting material by FCC (SiO2, hexane/Et2O 1 : 1),
raphy (FCC): Uetikon-Chemie ‘Chromatographiegel’ C-560. and dissolved in dioxane (70 mL). Aqueous 2M HCl (70 mL)
◦
Melting points: Bu¨chi 540 apparatus, uncorrected. IR Spec- was added, and the mixture was stirred at 70 C for 6 h.
tra: Perkin-Elmer Spectrum one spectrometer; in CHCl3, ab- Then, brine (100 mL) was added, most of the organic sol-
1
sorption bands in cm−1. H NMR (300 and 600 MHz) and vent evaporated, and the residue extracted with ethyl acetate
13C NMR (75.5 and 151 MHz) spectra: Bruker ARX-300 (3×80 mL). The combined organic fractions were extracted
and Bruker DRX-600 instrument, respectively, in CDCl3 at with saturated aqueous NaHCO3 solution (6 × 50 mL), the
300 K, TMS as internal standard, δ in ppm, coupling con- combined aqueous fractions were adjusted to pH = 1 by ad-
stants J in Hz, 13C signal multiplicities from DEPT spec- dition of HCl and extracted with ethyl acetate (3 × 80 mL).
tra. Mass spectrometry (MS): Finnigan MAT 90 for electron- Evaporation of the solvent after drying with MgSO4 gave
impact ionization (EI), Finnigan SSQ-700 for chemical ion- 9 (1.45 g, 5.66 mmol, 51 %) in pure form. Analytical data
ization (CI, with NH3) and electrospray ionization (ESI, in including the [α]D value were in accord with the data in
MeOH + NaI).
ref. [26].
(–)-(S)-2-Benzyloxy-N-[1-methyl-1-(N-methyl-N-
phenylcarbamoyl)ethyl]-3-phenylpropanamide (10)
General procedure 1 (GP 1). Reaction of azirines 8a and 8b
with acids 7 and 9
According to GP 1, 9 (1.0 g, 3.9 mmol) in MeCN (20 mL),
8b (680 mg, 3.9 mmol) in MeCN (5 mL), 14 h, FCC (SiO2,
hexane/Et2O 1 : 1): 1.49 g (89 %) of 10. White powder, m. p.
92 ◦C. – IR: ν = 3407m, 3353w, 3031m, 3020s, 3013m,
2930w, 2876w, 2460w, 1952w, 1674s, 1636s, 1594m, 1496s,
1455m, 1388m, 1365m, 1245m, 1205m, 1117m, 1092s,
1030w, 912w. – 1H NMR: δ = 1.36 (s, 6H, 2 Me), 2.89 (dd,
J = 7.7, 14.1, 1H of PhCH2), 3.14 (dd, J = 3.6, 14.1, 1H
of PhCH2), 3.25 (s, 3H, MeN), 3.86 (dd, J = 3.6, 7.7, 1H,
CHO), 4.29 (s, 2H, PhCH2O), 7.10 – 7.40 (m, 11H, NH + 2
Ph). – 13C NMR: δ = 25.7, 26.3 (2q, 2 Me), 38.4 (t, PhC
H2), 41.4 (q, MeN), 57.8 (s, Me2C), 72.8 (t, PhCH2O), 81.1
(d, CHO), 126.3, 127.8, 128.1, 128.3, 129.2, 129.7 (6d, 10
arom. CH), 137.1, 137.4 (2s, 2 arom. C), 170.3, 173.0 (2s, 2
C=O). – MS (EI): m/z (%) = 324 (21) [M–Ph(Me)N]+, 296
(36) [M–Ph(Me)NCO]+, 107 (54) [C7H7O]+, 91 (100) [C7
H7]+. – [α]25 = −51.4 (c = 1.1, CHCl3). The enantiomeric
purity was pDroved by analytical HPLC on a Chiralcel OD-H
column (hexane/iPrOH 13 : 1).
To a stirred solution of the corresponding acid in dry
MeCN was added a solution of the azirine in dry MeCN. The
mixture was stirred at r. t. for 16 h, the solvent was evapo-
rated, and the residue was purified by FCC.
General procedure 2 (GP 2). Esterification of acid 11 with
the corresponding alcohols and subsequent hydrogenolysis
of the benzyl ether
A solution of 11 and 1.0 equiv. of 1,1ꢀ-carbonyldiimid-
azole (CDI) in dry THF was stirred for 2 h under N2. The
corresponding alcohol was then added, followed by 10 drops
of a sodium imidazolide suspension (freshly prepared by the
reaction of 45 mg of a 60 % dispersion (w/w) of NaH in min-
eral oil and 73 mg of imidazole in 3 mL of dry THF). After
completion of the reaction (monitored by TLC, 2 – 16 h), the
solvent was evaporated and the mixture purified by FCC. The
product was then dissolved in THF/iPrOH 1 : 1, a catalytic
amount of Pd on charcoal was added, and the suspension
was stirred under a hydrogen atmosphere until completion of
the reaction (TLC monitoring). The mixture was then filtered
over Celite, the solvent evaporated, and the residue purified
by FCC.
(–)-(S)-2-(2-Benzyloxy-3-phenylpropanoylamino)-2-
methylpropanoic acid (11)
To a solution of amide 10 (1.29 g, 3.0 mmol) in THF
(15 mL) was added 6N HCl (15 mL), and the mixture was
stirred for 6 h at r. t. Subsequent addition of 2N HCl (15 mL),
extraction with Et2O (3×20 mL), drying of the combined or-
(–)-(2S)-2-Benzyloxy-3-phenylpropanoic acid (9)
To a solution of (–)-(S)-phenyllactic acid (7, 11.1 mmol, ganic fractions with MgSO4, and evaporation of the solvent
1.84 g) in MeOH (20 mL) were added 5 drops of conc. gave 11 (1.00 g, 98 %). White powder, m. p. 126 – 127 ◦C. –
H2SO4, and the mixture was heated for 1 h under reflux. IR: ν = 3413m, 3066m, 3031s, 3021s, 2929m, 2876m,
Then, ethyl acetate (30 mL) was added, the mixture extracted 1951w, 1718s, 1675s, 1517s, 1497m, 1456s, 1300m, 1228m,
once with 20 mL of a saturated aqueous NaHCO3 solution, 1171m, 1090s, 911w. – 1H NMR: δ = 1.45, 1.47 (2s, 2×3H,
dried with MgSO4, and evaporated. Within 2 h, benzyl 2,2,2- 2 Me), 2.94 (dd, J = 7.6, 14.1, 1H of PhCH2), 3.18 (dd, J =
trichloroacetimidate (2.80 g, 11.1 mmol, 2.07 mL) was added 3.6, 14.1, 1H of PhCH2), 4.10 (dd, J = 3.6, 7.6, 1H, CHO),
to a solution of the obtained methyl ester followed by 5 drops 4.47 (s, 2H, PhCH2O), 6.96 (s, 1H, NH), 7.18 – 7.34 (m,
of CF3SO3H in CH2Cl2/hexane 1 : 1 (100 mL) in analogy to 10H, 2 Ph), 8.20 (br. s, 1H, CO2H). – 13C NMR: δ = 24.2,
ref. [20], and the mixture was stirred for 10 h. After evap- 24.8 (2q, 2 Me), 38.8 (t, PhCH2), 56.3 (s, Me2C), 73.2 (t,
oration of the solvent, the product was separated from re- PhCH2O), 80.7 (d, CHO), 126.6, 127.9, 128.1, 128.1, 128.5,
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P. Ko¨ ttgen et al. · A Regular 24-membered Cyclodepsipeptide
695
129.7 (6d, 10 arom. CH), 136.8 (s, 2 arom. C), 172.7, 177.0 White powder, m. p. 101 – 103 ◦C. – IR: ν = 3671w, 3601w,
(2s, 2 C=O). – MS (CI): m/z (%) = 359 (7) [M + NH4]+, 342 3410m, 3283s, 3066m, 3010m, 2939m, 2463w, 2338w,
(100) [M + H]+. – [α]D25 = −58.7 (c = 1.3, CHCl3).
1950w, 1878w, 1744s, 1650s, 1543s, 1497m, 1471m, 1455,
1440, 1388, 1366, 1269s, 1198m, 1146s, 1089m, 1063m,
1031m, 1001w, 960w, 941w, 912w, 888w, 864w, 844w. –
1H NMR: δ = 1.24, 1.26, 1.38, 1.44, 1.56, 1.60 (6s, 6 ×3H,
6 Me), 2.98 – 3.45 (m, 12H, Me2N + 3 × PhCH2), 3.50 (br.
s, 1H, OH), 4.28 – 4.35 (m, 1H, CHOH), 5.30 – 5.40 (m, 2H,
2 CHOCO), 7.19 – 7.41 (m, 16H, 3 Ph + 1 NH), 7.82, 8.10
(2s, 2×1H, 2 NH). – 13C NMR: δ = 24.2, 24.3, 24.9, 25.3,
25.8, 26.2 (6q, 6 Me), 37.5, 38.0, 40.2 (3t, 3 PhCH2), 37.8
(q, Me2N), 55.5, 56.1, 56.4 (3s, 3 Me2C), 72.3, 74.6, 74.9
(3d, 3 CHO), 126.6, 126.8, 126.9, 128.2, 128.2, 128.4, 129.4,
129.6, 129.7 (9d, 15 arom. CH), 136.0, 136.5, 136.7 (3s,
3 arom. C), 168.4, 169.9, 172.8, 172.86, 173.3, 173.6 (6s,
6 C=O). – MS (ESI): m/z (%) = 767 (100) [M + Na]+. –
Anal. for C41H52N4O9 (744.89): calcd. C 66.11, H 7.04,
N 7.52; found C 65.53, H 7.09, N 7.37. – [α]2D5 = −60.4
(c = 1.4, CHCl3).
(–)-(S)-N-(1-Dimethylcarbamoyl-1-methylethyl)-2-hydroxy-
3-phenyl-propanamide (12)
According to GP 1, 7 (2.0 g, 12.1 mmol) in MeCN
(50 mL), 8a (1.49 g, 13.3 mmol) in MeCN (15 mL), 14 h,
FCC (SiO2, CH2Cl2/MeOH 30 : 1): 3.06 g (91 %) of 12.
White powder, m. p. 156 – 158 ◦C. – IR: ν = 3603w, 3406m,
3346m, 3021s, 3012m, 2942w, 2460w, 1671s, 1629s, 1508s,
1454w, 1395m, 1242m, 1120m, 1086m. – 1H NMR: δ =
1.55, 1.56 (2s, 2 × 3H, 2 Me), 2.89 (dd, J = 8.0, 13.9, 1H
of PhCH2), 2.98 (s, 6H, Me2N), 3.18 (dd, J = 4.0, 13.9, 1H
of PhCH2), 4.27 (dd, J = 4.0, 8.0, 1H, CHO), 7.20 – 7.32 (m,
5H, Ph), 7.41 (s, 1H, NH). – 13C NMR: δ = 24.8, 24.9 (2q,
2 Me), 38.0 (q, Me2N), 40.6 (t, PhCH2), 56.5 (s, Me2C), 72.6
(d, CHO), 126.8, 128.5, 129.6 (3d, 5 arom. CH), 136.9 (s,
arom. C), 171.1, 172.6 (2s, 2 C=O). – MS (CI): m/z (%) =
279 (100) [M + H]+, 234 (23) [M–Me2N]+. – [α]2D5 = −58.4
(c = 1.0, CHCl3).
(–)-(S)-1-[(1-{1-[(1-Dimethylcarbamoyl-1-methylethyl)
carbamoyl]-(S)-2-phenylethoxycarbonyl}-1-methylethyl)
carbamoyl]-2-phenylethyl 2-{(S)-2-[2-((S)-2-hydroxy-
3-phenylpropanoylamino)-2-methylpropanoyloxy]-3-
phenylpropanoylamino}-2-methylpropanoate (15)
(–)-(S)-1-[(1-Dimethylcarbamoyl-1-methylethyl)carb-
amoyl]-2-phenylethyl 2-((S)-2-hydroxy-3-phenylpropanoyl-
amino)-2-methylpropanoate (13)
According to GP 2, 11 (1.23 g, 3.60 mmol), CDI (583 mg,
3.61 mmol), 14 (2.68 g, 3.60 mmol), THF (40 mL), 16 h,
FCC (SiO2, CH2Cl2/MeOH ◦50 : 1): 2.81 g (80 %) of 15.
White powder, m. p. 88 – 90 C. – IR: ν = 3601w, 3413m,
3282s, 3066m, 3021m, 3009m, 2930m, 1951w, 1744s,
1651s, 1547s, 1497m, 1471m, 1455m, 1388m, 1366m,
1269m, 1147s, 1083m, 1063m, 1031m, 1002w, 939w, 889w,
864w. – 1H NMR: δ = 1.23, 1.41, 1.45, 1.52, 1.59 (5s,
8 × 3H, 8 Me), 2.90 – 3.35 (m, 14H, Me2N + 4 PhCH2),
4.21 – 4.29 (m, 1H, CHOH), 5.02 – 5.09, 5.21 – 5.31 (2m,
1H + 2H, 3 CHOCO), 7.16 – 7.39 (m, 21H, 4 Ph + 1 NH),
7.80, 8.04, 8.11 (3s, 3 × 1H, 3 NH). – 13C NMR: δ =
24.3, 25.2, 25.4, 25.9, 26.3 (5q, 8 Me), 37.6, 37.8, 38.0,
40.2 (4t, 4 PhCH2), 37.9 (q, Me2N), 55.6, 56.1, 56.6 (3s,
4 Me2C), 72.4, 74.6, 75.1, 75.6 (4d, 4 CHO), 126.7, 126.86,
126.91, 127.0, 128.3, 128.3, 128.5, 129.6, 129.8, 129.9 (10d,
20 arom. CH), 136.1, 136.6, 136.7, 137.0 (4s, 4 arom. C),
168.6, 170.1, 170.5, 172.9, 173.1, 173.4, 173.5, 173.8 (8s, 8
C=O). – MS (ESI): m/z (%) = 1000 (100) [M + Na]+. – Anal.
for C54H67N5O12 (978.14): calcd. C 66.31, H 6.90, N 7.16;
found C 65.55, H 6.88, N 7.00. – [α]2D5 = −58.7 (c = 1.0,
CHCl3).
According to GP 2, 11 (1.23 g, 3.60 mmol), CDI
(583 mg, 3.60 mmol), 12 (1.0 g, 3.60 mmol), THF (40 mL),
2 h, FCC (SiO2, CH2Cl2/MeOH 50 : 1): 1.56 g (85 %) of
13. White powder, m. p. 96 – 97 ◦C. – IR: ν = 3672w,
3601w, 3413m, 3303m, 3021m, 3010m, 2462w, 1950w,
1745s, 1662s, 1624s, 1532s, 1498m, 1455m, 1396m, 1366m,
1286m, 1247m, 1147s, 1089m, 1061m, 1031w, 998w, 889w,
862w. – 1H NMR: δ = 1.26, 1.33, 1.48, 1.53 (4s, 4 × 3H,
4 Me), 2.70 – 3.60 (m, 10H, Me2N + 2 PhCH2), 4.10 – 4.26
(m, 2H, CHOH + OH), 5.29 – 5.41 (m, 1H, CHOCO), 7.10 –
7.36 (m, 12H, 2 Ph + 2 NH). – 13C NMR: δ = 24.4, 24.9,
25.4, 26.1 (4q, 4 Me), 37.6, 40.1 (2t, 2 PhCH2), 37.9 (q,
Me2N), 55.4, 56.5 (2s, 2 Me2C), 72.3, 74.4 (2d, 2 CHO),
126.6, 126.7, 128.2, 128.2, 129.5, 129.6 (6d, 10 arom. CH),
136.2, 137.0 (2s, 2 arom. C), 168.1, 172.9, 173.0, 173.9 (4s, 4
C=O). – MS (ESI): m/z ( %) = 556 (14) [M + MeOH + Na]+,
534 (100) [M + Na]+. – Anal. for C28H37N3O6 (511.61):
calcd. C 65.73, H 7.29, N 8.21; found C 65.24, H 7.65,
N 7.96. – [α]2D5 = −60.3 (c = 1.0, CHCl3).
(–)-(S)-1-[(1-Dimethylcarbamoyl-1-methylethyl)carb-
amoyl]-2-phenylethyl 2-{(S)-2-[2-((S)-2-hydroxy-3-phen-yl
propanoylamino)-2-methylpropanoyloxy]-3-phenyl-
propanoylamino}-2-methylpropanoate (14)
(–)-(6R,12S,18S,24S)-6,12,18,24-Tetrabenzyl-3,3,9,9,
15,15,21,21-octamethyl-1,7,13,19-tetraoxa-4,10,16,22-
tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone (17)
According to GP 2, 11 (1.23 g, 3.60 mmol), CDI (583 mg,
3.61 mmol), 13 (1.84 g, 3.60 mmol), THF (40 mL), 8 h,
Dry HCl gas was bubbled through a solution of 15
FCC (SiO2, CH2Cl2/MeOH 50 : 1): 2.22 g (83 %) of 14. (300 mg, 0.31 mmol) in toluene (30 mL) at 100 ◦C for
Unauthenticated
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696
P. Ko¨ttgen et al. · A Regular 24-membered Cyclodepsipeptide
4.5 min. The mixture was then heated under reflux for by using a riding model where each H atom was assigned a
20 min while a gentle stream of dry HCl gas was bub- fixed isotropic displacement parameter with a value equal to
bled through the solution. The mixture was allowed to cool 1.2 Ueq of its parent C atom (1.5 Ueq for the methyl groups).
to r. t. while bubbling N2 through it. Evaporation of the The refinement of the structure was carried out on F2 using
solvent and column chromatography (SiO2, CH2Cl2/MeOH full-matrix least-squares procedures, which minimized the
2
50 : 1) gave 17 (96 mg, 34 %). White powder, m. p. 133 – function Σw(Fo −Fc2)2. A correction for secondary extinc-
◦
134 C. – IR: ν = 3272m, 3066w, 3031w, 3009w, 2930w, tion was applied. Neutral atom scattering factors for non-H
1745s, 1645s, 1553m, 1455w, 1388m, 1309w, 1269m, 1145s, atoms were taken from ref. [31], and the scattering factors for
1
1064m, 909w. – H NMR: δ = 1.18 – 1.68 (m, 24H, 8 Me), H atoms were taken from ref. [32]. Anomalous dispersion ef-
2.86 – 3.43 (m, 8H, 4 PhCH2), 4.95 – 5.49 (m, 4H, 4 CHO), fects were included in Fc [33]; the values for f ꢀ and f ” were
6.90 – 7.47 (m, 20H, 4 Ph), 7.89 – 8.40 (m, 4H, 4 NH). – those of ref. [34]. The values of the mass attenuation coeffi-
13C NMR (broad signals): δ = 24.8 (q, 8 Me), 37.6 (t, cients are those of ref. [35]. All calculations were performed
4 CH2), 56.0 (s, 4 Me2C), 75.4 (d, 4 CHO), 126.8, 128.2, using the SHELXL-97 [36] program.
129.7 (3d, 20 arom. CH), 136.8 (s, 4 arom. C), 170.0, 173.6
Crystal data for 17: C52H60N4O12·2C8H10, M = 1145.39,
(2s, 8 C=O). – MS (ESI): m/z (%) = 955 (100) [M + Na]+. – crystallized from xylene/CCl4/acetone, colorless, prism,
Anal. for C52H60N4O12·H2O (933.04·H2O): calcd. C 65.67, crystal dimensions: 0.10×0.20×0.22 mm3, triclinic, space
H 6.57, N 5.89; found C 65.75, H 6.89, N 5.73. – [α]D25
−41.0 ( c = 0.8, CHCl3).
=
group P1, Z = 1, reflections for cell determination: 5495,
2θ range for cell determination: 4 – 50◦, a = 10.0596(4),
◦
˚
b = 11.1402(5), c = 14.◦9075(7) A, α = 76.869(2) , β =
◦
3
˚
87.668(2) , γ = 76.776(2) , V = 1583.7(1) A , T = 160(1) K,
Dx = 1.201 g cm−3, µ(MoKα ) = 0.0820 mm−1, scan type
ω, 2θmax = 50◦, total reflections measured: 23521, sym-
metry independent reflections: 5539, reflections with I ≥
2σ(I): 3042, reflections used in refinement: 5539, param-
eters refined: 770, restraints: 3, R(F) [I ≥ 2σ(I) reflec-
tions] = 0.0638, wR(F2) (all data) = 0.1714 (w = [σ2(Fo2) +
X-Ray crystal-structure determination of 17
The measurement was performed on a Nonius Kap-
paCCD area detector diffractometer [27] using graphite-
˚
monochromatized MoKα radiation (λ = 0.71073 A) and an
Oxford Cryosystems Cryostream 700 cooler. The data col-
lection and refinement parameters are given below [28], and
a view of the molecule is shown in Fig. 1. Data reduction
was performed with HKL DENZO and SCALEPACK [29].
The intensities were corrected for Lorentz and polarization
effects, but not for absorption. Equivalent reflections were
merged. The structure was solved by Direct Methods using
SIR92 [30], which revealed the positions of all non-H atoms.
The non-H atoms were refined anisotropically. All H atoms
were placed in geometrically calculated positions and refined
(0.0568P)2]−1, where P = (Fo +2Fc2)/3), goodness of
2
fit: 1.037, final ∆max/σ = 0.001, ∆ρ (max; min) = 0.26;
−0.30 e A−3, secondary extinction coefficient = 0.015(3).
˚
Acknowledgements
The authors thank the analytical sections of our institute
for spectra and analyses, and the University of Zurich and F.
Hoffmann-La Roche AG, Basel, for financial support.
[1] a) H. Vervoort, W. Fenical, R. de Epifanio, J. Org.
Chem. 2000, 65, 782 – 792; b) N. Sitachitta, R. T.
Williamson, W. H. Gerwick, J. Nat. Prod. 2000,
63, 197 – 200; c) F. D. Horgan, D. B. de los San-
tos, G. Goetz, B. Sakamoto, Y. Kan, H. Nagai, P. J.
Scheuer, J. Nat. Prod. 2000, 63, 152 – 154; d) K. Fu-
jii, K. Sivinen, E. Naganawa, K. Harada, Tetrahedron
2000, 56, 725 – 733; e) A. K. Gosh, A. Bischoff, Org.
Lett. 2000, 2, 1573 – 1575; f) H. Luesch, R. Pangili-
nan, W. Y. Yoshida, R. E. Moore, V. J. Paul, J. Nat.
Prod. 2001, 64, 304 – 307; g) F. Sarabia, S. Chammaa,
F. J. Lopez-Herrera, Tetrahedron Lett. 2002, 43, 2961 –
2965; h) J. Hong, L. Zhang, Frontiers of Biotechnology
& Pharmaceuticals 2002, 3, 193 – 199; i) H. Luesch,
P. G. Williams, W. Y. Yoshida, R. E. Moore, V. J. Paul,
J. Nat. Prod. 2002, 65, 996 – 1000; k) Y. J. Feng,
J. W. Blunt, A. L. J. Cole, J. F. Cannon, W. T. Robinson,
M. H. G. Munro, J. Org. Chem. 2003, 68, 2002 – 2005;
l) G. Bringmann, G. Lang, S. Steffens, K. Schaumann,
J. Nat. Prod. 2004, 67, 311– 315; m) C.-H. Chen,
G. Lang, M. Mitova, A. C. Murphy, A. L. J. Cole, L. B.
Din, J. W. Blunt, M. H. G. Munro, J. Org. Chem. 2006,
71, 7947 – 7951.
[2] a) H. Huang, Z. She, Y. Liu, L. L. P. Vrijmoed,
W. Lin, J. Nat. Prod. 2007, 70, 1696 – 1699; b)
C. M. Boot, T. Amagata, K. Tenney, J. E. Compton,
H. Pietraszkiewicz, F. A. Valerrote, P. Crews, Tetra-
hedron 2007, 63, 9903 – 9914; c) S. P. Gunasekera,
R. Ritson-Williams, V. J. Paul, J. Nat. Prod. 2008, 71,
2060 – 2063; d) K. Taori, V. J. Paul, H. Luesch, J. Nat.
Prod. 2008, 71, 1625 – 1629; e) Z. Yu, G. Lang, I. Ka-
jahn, R. Schmaljohann, J. F. Imhoff, J. Nat. Prod. 2008,
71, 1052 – 1054; f) D. Dwivedi, R. Jansen, G. Molinari,
M. Nimtz, B. N. Johri, V. Wray, J. Nat. Prod. 2008, 71,
Unauthenticated
Download Date | 2/23/17 4:30 PM

P. Ko¨ ttgen et al. · A Regular 24-membered Cyclodepsipeptide
697
637 – 641; g) K. Taori, V. J. Paul, H. Luesch, J. Am.
Chem. Soc. 2008, 130, 1806 – 1807.
A. Lefranc, Y.-N. P. Chen, A. W. Wood, P. Crowe, P. Er-
win, M. El-Tamani, Org. Lett. 2009, 11, 737 – 740.
[8] a) S. Cerrini, E. Gavuzzo, G. Luisi, F. Pinnen, Int. J.
Pept. Protein Res. 1993, 41, 282 – 290; b) Y. Hirai,
K. Yokota, T. Momose, Heterocycles 1994, 39, 603 –
612; c) K. W. Li, J. Wu, W. Xing, J. A. Simpson, J.
Am. Chem. Soc. 1996, 118, 7237 – 7238; d) G. R. Pettit,
S. Hu, J. C. Knight, J.-C. Chapuis, J. Nat. Prod. 2009,
Doi: 10.1021/np800607x.
[9] a) D. Obrecht, H. Heimgartner, Helv. Chim. Acta
1984, 67, 526 – 533; b) D. Obrecht, H. Heimgartner,
Helv. Chim. Acta 1987, 70, 329 – 338; c) D. Obrecht,
H. Heimgartner, Helv. Chim. Acta 1990, 73, 221 – 228.
[10] J. M. Villagordo, H. Heimgartner, Helv. Chim. Acta
1997, 80, 748 – 766.
[11] H. Heimgartner, F. S. Arnhold, S. Fritschi, K. N. Koch,
A. Linden, J. E. F. Magirius, Lectures Heterocycl.
Chem. 1999, 36, 1539 – 1547.
[12] a) K. N. Koch, A. Linden, H. Heimgartner, Helv. Chim.
Acta 2000, 83, 233 – 257; b) K. N. Koch, H. Heimgart-
ner, Helv. Chim. Acta 2000, 83, 1881 – 1900; c) K. N.
Koch, A. Linden, H. Heimgartner, Tetrahedron 2001,
57, 2311 – 2326; d) K. N. Koch, G. Hopp, A. Linden,
K. Moehle, H. Heimgartner, Helv. Chim. Acta 2001,
84, 502 – 512.
[3] a) K. Brockmann, G. Schmidt-Kastner, Chem. Ber.
1955, 88, 57 – 61; b) M. M. Shemyakin, N. A. Al-
danova, R. I. Vinogradova, V. Y. Feigina, Tetrahedron
Lett. 1963, 28, 1921 – 1925; c) B. C. Pressman, E. J.
Harris, W. S. Jagger, J. N. Johnson, Procl. Nat. Acad.
Sci. U.S.A. 1967, 58, 1949 – 1956.
[4] a) Y. A. Ovchinnikov, V. T. Ivanov, A. V. Evstratov, I. I.
Mikhaleva, V. F. Bystrov, S. L. Portnova, T. A. Bal-
ashova, E. N. Meshcheryakova, V. M. Tul’chinskii, Int.
J. Pept. Protein Res. 1974, 6, 465 – 498; b) P. Jeschke,
W. Etzel, A. Harder, M. Schindler, A. Gohrt,
U. Pleiss, H. Kleinkauf, R. Zocher, G. Thielking,
W. Gau, G. Bonse, Bioorg. Chem. 1999, 207 – 214;
c) S. Fira´kova´, B. Proksa, M. Sturdikova, Pharmazie
2007, 62, 563 – 568; d) M. Jestoi, Crit. Rev. Food Sci.
Nutr. 2008, 48, 21 – 49.
[5] B. C. Pressman, Ann. Rev. Biochem. 1976, 45, 501 –
530.
[6] a) M. Krause, A. Lindemann, M. Glinski, T. Horn-
bogen, G. Bonse, P. Jeschke, G. Thielking, W. Gau,
R. Zocher, J. Antibiot. 2001, 54, 797 – 804; b) A. Lo-
grieco, A. Rizzo, R. Ferracane, A. Ritieni, Appl. En-
viron. Microbiol. 2002, 82 – 85; c) Y. Lin, J. Wang,
X. Wu, S. Zhou, L. L. P. Vrijmoed, E. B. G. Jones,
Austral. J. Chem. 2002, 55, 225 – 227; d) C. Ni-
lanonta, M. Isaka, R. Chanphen, N. Thong-orn,
M. Tanticharoen, Y. Thebtaranonth, Tetrahedron 2003,
59, 1015 – 1020; e) P. Vongvilai, M. Isaka, P. Kit-
takoop, P. Srikitikulchai, P. Kongsaeree, S. Prab-
pai, Y. Thebtaramonth, Helv. Chim. Acta 2004, 87,
2066 – 2073; f) A. Pohanka, K. Capieau, A. Broberg,
J. Stenlid, E. Stenstro¨m, L. Kenne, J. Nat. Prod.
2004, 67, 851 – 857; g) K. Hiraga, S. Yamamoto,
H. Fukuda, N. Hamanaka, K. Oda, Biochem. Biophys.
Res. Commun. 2005, 328, 1119 – 1125; h) L. Ivanova,
E. Skjerve, G. S. Eriksen, S. Uhlig, Toxicon 2006, 47,
868 – 857; i) S. C. Feifel, T. Schmiederer, T. Horn-
bogen, H. Berg, R. D. Su¨ssmuth, R. Zocher, Chem-
BioChem 2007, 8, 1767 – 1770; k) H.-H. Song, H.-S.
Lee, J.-H. Jeong, H.-S. Park, C. Lee, Int. J. Food. Mi-
crobiol. 2008, 122, 296 – 301; l) J. Mu¨ller, S. C. Feifel,
T. Schmiederer, R. Zocher, R. D. Su¨ssmuth, Chem-
BioChem 2009, 10, 323 – 328.
[13] a) B. Iliev, A. Linden, H. Heimgartner, Helv. Chim.
Acta 2003, 86, 3215 – 3234; b) B. Iliev, A. Linden,
R. W. Kunz, H. Heimgartner, Tetrahedron 2006, 62,
1079 – 1094.
[14] J. E. F. Magirius, PhD Thesis, Universita¨t Zu¨rich, 1995.
[15] P. Ko¨ttgen, A. Linden, H. Heimgartner, Helv. Chim.
Acta 2006, 89, 731 – 746.
[16] H. Heimgartner, Angew. Chem. 1991, 103, 271 – 297.
Angew. Chem., Int. Ed. Engl. 1991, 30, 238 – 264.
[17] a) P. Wipf, H. Heimgartner, Helv. Chim. Acta 1990,
73, 13 – 24; b) R. Luykx, C. B. Bucher, A. Linden,
H. Heimgartner, Helv. Chim. Acta 1996, 79, 527 – 540;
c) R. T. N. Luykx, A. Linden, H. Heimgartner, Helv.
Chim. Acta 2003, 86, 4093 – 4111; d) N. Pradeille,
H. Heimgartner, J. Pept. Sci. 2003, 9, 827 – 837;
e) N. Pradeille, O. Zerbe, K. Mo¨hle, A. Linden,
H. Heimgartner, Chem. Biodivers. 2005, 2, 1127 –
1152; f) W. Altherr, A. Linden, H. Heimgartner, Chem.
Biodivers. 2007, 4, 1144 – 1169.
[18] a) J. Lehmann, A. Linden, H. Heimgartner, Tetrahe-
dron 1998, 54, 8721 – 8736; b) J. Lehmann, A. Linden,
H. Heimgartner, Tetrahedron 1999, 55, 5359 – 5376;
c) J. Lehmann, A. Linden, H. Heimgartner, Helv. Chim.
Acta 1999, 82, 888 – 908; d) J. Lehmann, A. Linden,
H. Heimgartner, Helv. Chim. Acta 1999, 82, 1899 –
1915; e) A. Budzowski, A. Linden, H. Heimgartner,
Helv. Chim. Acta 2008, 91, 1471 – 1488; A. Ba¨rtsch,
B. Bischof, H. Heimgartner, Pol. J. Chem. 2009, 83,
195 – 206.
[7] a) A. M. Sefler, M. C. Kozlowski, T. Guo, P. A. Bartlett,
J. Org. Chem. 1977, 62, 93 – 102; b) Y. L. Dory,
J. M. Mellor, J. F. McAleer, Tetrahedron Lett. 1996,
52, 1343 – 1360; c) T. Imaeda, Y. Hamada, T. Shioiri,
Tetrahedron Lett. 1994, 35, 591 – 594; d) N. Bisek,
S. Wetzel, H.-D. Arndt, H. Waldmann, Chem. Eur.
J. 2008, 14, 8847 – 8860; e) K. J. Hale, S. Manavi-
azar, L. Lazarides, J. George, M. A. Walters, J. Cai,
V. M. Delisser, G. S. Bhatia, S. A. Peak, S. M. Dalbey,
Unauthenticated
Download Date | 2/23/17 4:30 PM

698
P. Ko¨ttgen et al. · A Regular 24-membered Cyclodepsipeptide
[19] a) F. S. Arnhold, PhD Thesis, Universita¨t Zu¨rich,
1997; b) T. Jeremic, A. Linden, H. Heimgartner, Helv.
Chim. Acta 2004, 87, 3056 – 3079; c) T. Jeremic,
A. Linden, H. Heimgartner, Chem. Biodiv. 2004, 1,
1730 – 1761; d) T. Jeremic, A. Linden, K. Moehle,
H. Heimgartner, Tetrahedron 2005, 61, 1871 – 1883;
e) T. Jeremic, A. Linden, H. Heimgartner, J. Pept. Sci.
2008, 14, 1051 – 1061; f) I. Dannecker-Do¨rig, A. Lin-
den, H. Heimgartner, Collect. Czech. Chem. Commun.
2009, in press.
[20] P. Eckenberg, U. Groth, T. Huhn, N. Richter,
C. Schmeck, Tetrahedron 1993, 49, 1619 – 1624.
[21] C. K. Johnson, ORTEP II, Report ORNL-5138, Oak
Ridge National Laboratory, Oak Ridge, TN (USA)
1976.
lographic Data Centre, via www.ccdc.cam.ac.uk/data
request/cif.
[29] HKL DENZO, SCALEPACK, Z. Otwinowski, W. Mi-
nor, in Methods in Enzymology, Vol. 276, Macromolec-
ular Crystallography, Part A (Eds.: C. W. Carter, Jr.,
R. M. Sweet), Academic Press, New York, 1997, pp.
307 – 326.
[30] A. Altomare, G. Cascarano, C. Giacovazzo,
A. Guagliardi, M. C. Burla, G. Polidori, M. Ca-
malli, SIR92, A Program for the Automatic Solution
of Crystal Structures by Direct Methods; see: J. Appl.
Crystallogr. 1994, 27, 435.
[31] E. N. Maslen, A. G. Fox, M. A. O’Keefe, in Inter-
national Tables for Crystallography, Vol. C (Ed.:
A. J. C. Wilson), Kluwer Academic, Dordrecht, 1992;
pp. 477 – 486; Table 6.1.1.1.
[22] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang,
Angew. Chem. 1995, 107, 1689 – 1708; Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1555 – 1573.
[32] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem.
Phys. 1965, 42, 3175 – 3187.
[23] P. Wipf, H. Heimgartner, Helv. Chim. Acta 1986, 69,
[33] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17,
1153 – 1162.
781 – 782.
[24] K. C. Nicolaou, Tetrahedron 1977, 33, 683 – 710.
[25] M. H. Chisholm, J. C. Gallucci, H. Yin, PNAS 2006,
103, 15315 – 15320.
[26] V. Srirajan, A. R. A. S. Deshmukh, V. G. Puranik, B. M.
Bhawal, Tetrahedron: Asymmetry 1996, 7, 2733 –
2738.
[34] D. C. Creagh, W. J. McAuley, in International Tables
for Crystallography, Vol. C (Ed.: A. J. C. Wilson),
Kluwer Academic, Dordrecht, 1992; pp. 219 – 222; Ta-
ble 4.2.6.8.
[35] D. C. Creagh, J. H. Hubbell, in International Tables
for Crystallography, Vol. C (Ed.: A. J. C. Wilson),
Kluwer Academic, Dordrecht, 1992; pp. 200 – 206; Ta-
ble 4.2.4.3.
[27] R. Hooft, COLLECT, Nonius KappaCCD Software,
Nonius BV, Delft (The Netherlands) 1999.
[28] CCDC 725269 contains the supplementary crystallo-
graphic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystal-
[36] G. M. Sheldrick, SHELXL-97, Program for the Refine-
ment of Crystal Structures, University of Go¨ttingen,
Go¨ttingen (Germany) 1997.
Unauthenticated
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