The 'azirine/oxazolone approac' to the synthesis of Aib-Pro endothiopeptides

Article abstract of DOI:10.1002/hlca.200890160

The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-L-prolinate (2a) with thiobenzoic acid at room temperature gave the endothiopeptide Bz-Aibψ[CS]-Pro-OMe (7) in high yield. In an analogous manner, (benzyloxy)carbonyl (Z)-protected proline was transformed into the thioacid, which was reacted with 2a to give the endothiotripeptide Z-Pro-Aibψ[CS]-Pro- OMe (12). The corresponding thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with H ₂S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro² was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe-OMe and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy- 1H-benzotriazole (TBTU/HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the pure diastereoisomer Bzψ[CS]-Aib-Pro- Aibψ[CS]-N(Me)Ph (21) was achieved via isomerization of 7 to Bzψ[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-trimethyl-N-phenyl-2H-azirin-3-amine (1a). The structures of 12 and 21 were established by X-ray crystallography.

Full text of DOI:10.1002/hlca.200890160

Helvetica Chimica Acta – Vol. 91 (2008)
1471
The ꢀAzirine/Oxazolone Approachꢁ to the Synthesis of Aib-Pro
Endothiopeptides
by Artur Budzowski1), Anthony Linden, and Heinz Heimgartner*
Organisch-Chemisches Institut der Universität Zürich, Winterthurerstrasse 190, CH-8057 Zürich
(phone: þ 41446354282; fax: þ 41446356812; e-mail: heimgart@oci.uzh.ch)
The reaction of methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a) with thiobenzoic acid at
room temperature gave the endothiopeptide Bz-AibY[CS]-Pro-OMe (7) in high yield. In an analogous
manner, (benzyloxy)carbonyl (Z)-protected proline was transformed into the thioacid, which was
reacted with 2a to give the endothiotripeptide Z-Pro-AibY[CS]-Pro-OMe (12). The corresponding
thioacid of 7 was prepared in situ via saponification, formation of a mixed anhydride, and treatment with
H2S. A second reaction with 2a led to the endodithiotetrapeptide 9, but extensive epimerization at Pro2
was observed. Similarly, saponification of 12 and coupling with either 2a or H-Phe-OMe and 2-(1H-
benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1-hydroxy-1H-benzotriazole (TBTU/
HOBt) gave the corresponding endothiopeptides as mixtures of two epimers. The synthesis of the
pure diastereoisomer BzY[CS]-Aib-Pro-AibY[CS]-N(Me)Ph (21) was achieved via isomerization of 7
to BzY[CS]-Aib-Pro-OMe (16), transformation into the corresponding thioacid, and reaction with N,2,2-
trimethyl-N-phenyl-2H-azirin-3-amine (1a). The structures of 12 and 21 were established by X-ray
crystallography.
Introduction. – Peptides with modified backbones are of considerable pharma-
ceutical interest [1]. The concept of peptidomimetics, i.e., compounds with different
chemical structure but maintained ability to interact with specific peptide receptors,
proved to be a successful approach in the design of novel inhibitors of enzymes. For
example, the stabilization of b-turns and helical peptide conformations can be achieved
by the replacement of protein amino acids by a,a-disubstituted a-amino acids [2], while
N-methylated a-amino acids can disrupt helices, and direct secondary and tertiary
structures [3], thereby enhancing the hydrophobicity [4] and improving the stability
towards proteolytic enzymes [5]. The substitution of proteolyzable amide bonds by
thioamides also leads to increased proteolytic stability, while other biological effects
remain unaltered [6].
The ꢀazirine/oxazolone methodꢁ, which was developed in our laboratory [7], has
proven to be a powerful tool for the synthesis of such modified peptides. Thus, 2H-
azirin-3-amines 1 are useful synthons for sterically demanding a,a-disubstituted a-
amino acids in peptides. The reaction of the most widely applied reagent 1a with
peptide acids leads to elongated peptides containing an a-aminoisobutyric acid (Aib)
and a terminal amide bond [8][9]. Moreover, a family of dipeptide synthons 2a – 2g has
been prepared for the same purpose. The synthon 2a has been successfully applied for
1
)
Postdoctoral stay at the University of Zürich (02.2003 – 08.2004). Present address: Department of
Organic Chemistry, Jagiellonian University, ul. Ingardena 3, PL-30-060 Krakow, Poland.
ꢂ 2008Verlag Helvetica Chimica Acta AG, Zürich

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the elongation at the C-terminus of various peptides with the Aib-Pro fragment [10 –
12]. Thus, the ꢀazirine/oxazolone methodꢁ has proven to be successful in the solution-
phase synthesis of naturally occurring antibiotic peptaibols [10][12 – 14]. Recently, the
method has been applied for the synthesis of Aib-containing peptides on solid phase
[15].
Peptides containig a,a-disubstituted a-amino acids (2,2-disubstituted glycines)
show restricted conformational flexibility, and secondary structures such as helices or b-
turns are stabilized [2][16]. For most of the peptaibols, which adopt helical structures,
the presence of Aib-Pro fragments is characteristic [5][17]. The first total synthesis of
alamethicin I, one of the most well-known peptaibols, which contains the starting
sequence Ac-Aib-Pro-Aib, was accomplished by the traditional coupling (with N,N’-
dicyclohexylcarbodiimide (DCC)) of the amino acids in solution [18], as well as on solid
phase [19]. Other approaches involved the use of Fmoc-Aib chloride and the potassium
salt of 1-hydroxy-1H-benzotriazole (HOBt) [20] or 2-chloro-1,3-dimethylimidazolium
hexafluorophosphate (CIP) as coupling reagents [21]. The structural studies on the
peptaibols suggested that the alternating Pro and Aib residues might be responsible for
adopting a 310-helix by the peptide chain. Thus, a series of model compounds with
terminally blocked -(Pro-Aib)n- units have been synthesized [22]. The conformational
analysis has shown that the formation of the ꢀb-bend ribbon spiralꢁ starts to form
already at the -Aib-Pro-Aib- tripeptide level. In that paper, some problems with the
instability of the Aib-Pro linkage under acidic condition were also reported.
The methods for the incorporation of the C¼S group into the peptide chain so far
involved direct thionation, e.g., with Lawesson reagent (LR) [6a][23], thioacylation
with activated amino thioacid derivatives, e.g., thio- or dithioesters [24], or combined
protocols involving thionation of an amide intermediate with P4S10 or LR with
subsequent transacylation [25]. However, most of these methods have certain
limitations, e.g., they are accompanied by epimerization or side reactions. Very
recently, it has been shown that endothiopeptides can be obtained via the Ugi reaction
with thioacids as acid components [26]. A different approach developed in our
laboratory is based on the ꢀazirine/oxazolone methodꢁ [27][28]. The reactions of the
building blocks 1 or 2 with a-amino thioacids 3, which are prepared from protected a-
amino acids via mixed anhydrides, leads to products 4 containing an AibY[CS]
fragment. On treatment with ZnCl2 and HCl in AcOH, the peptides 4, with a C-
terminal thioamide group, isomerize to give the endothiodipeptides 5 without
epimerization (Scheme 1). The reaction mechanism for the azirine coupling has been

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1473
Scheme 1
discussed earlier [7], that of the isomerization involves the formation of an 1,3-oxazole-
5(4H)-thione, which is transformed to the isomeric 1,3-thiazol-5(4H)-one via
spirocyclic intermediates or dipolar nitrilium ions [27b][28a].
Only a few examples concerning the preparation of endothiopeptides with more
than one C¼S group are known. Attempts at synthesizing a dithio analogue of
zervamicin IIA, e.g., by coupling of the two monothiopeptides Boc-Trp-Ile-AlaY[CS]-
Aib-Ile-OH and H-ValY[CS]-Aib-Leu-OMe using 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU)/HOBt led to an endothiooctapeptide
with a 1,3-thiazol-5(4H)-imine residue as the main product (60%) instead of the
endodithiooctapeptide with the AlaY[CS]-Aib fragment [27d]. An additional problem
was the extensive epimerization, the obtained ratio of the epimers being 66 :34. A
similar coupling of Z-ValY[CS]-Aib-Ile-OH with H-ValY[CS]-Aib-N(Me)Ph afford-
ed an analogous cyclized product, but without detectable epimerization [28b]. Some
model 1,3-thiazol-5(4H)-imine derivatives reacted with H2S in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) to give peptides containing two thioamide
bonds, e.g., Z-AlaY[CS]-AibY[CS]-Ile-Aib-N(Me)Ph; however, epimerization occur-
red at the Ala residue.
In the present work, we report new results of the application of the ꢀazirine/
oxazolone methodꢁ in endothiopeptide synthesis.
Results and Discussion. – The aim of this work was to develop synthetic procedures
for the preparation of endothiopeptides, containing Aib-Pro units and more than one
thioamide group, which can serve as model compounds for structural and conforma-
tional studies.
The first endothiopeptide Bz-AibY[CS]-Pro-OMe (7; Bz ¼ benzoyl) was prepared
according to the ꢀazirine/oxazolone methodꢁ from thiobenzoic acid (PhCOSH; 6) and
N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a). The reaction was carried out analo-
gously to reactions of 2b and 2c with 6 [15c], and proceeded smoothly, to give 7 in
almost quantitative yield (Scheme 2). The solid product 7 was fully characterized; most
indicative were the signals in the 13C-NMR spectrum at 205.8(thioamide), 170.8

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Scheme 2
(ester), and 164.7 ppm (amide), and the corresponding IR absorptions (KBr) at 1425,
1740, and 1657 cmÀ1.
The attempted direct conversion of the methyl ester 7 to the corresponding thioacid
according to [29] failed, as 7 was resistant to the treatment with NaSH in THF solution
even at reflux temperature. An alternative pathway was the saponification of 7 with
subsequent conversion of the carboxylic acid into the thioacid via a mixed anhydride
[30]. Thus, the reaction of 7 with LiOH afforded Bz-AibY[CS]-Pro-OH (8) in high
yield (94%). The acid 8 was transformed to the thioacid by the reaction of the in situ
prepared mixed anhydride with H2S at À 208, and the crude mixture was instantly
treated with an excess (2.5 equiv.) of the Aib-Pro synthon 2a (Scheme 3). Surprisingly,
two epimers of the expected product Bz-AibY[CS]-Pro-AibY[CS]-Pro-OH (9), i.e., 9a
and 9b were formed. Separation by means of prep. TLC gave the two epimers in poor
yield (7% each). However, 2D-NMR techniques did not allow assignment of the
configurations of Pro2 for the samples 9a and 9b. The main product obtained from the
reaction described above was (S)-perhydro-3,3-dimethyl-4-thioxopyrrolo[1,2-a]pyra-
zin-1-one (10), which also arose from the reaction of 2a with H2S. Our extensive studies
on the reactions of 2a, 2d, and 2e with H2S have already been published [31].
Scheme 3

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1475
Measurements of the optical rotation of samples of the acid 8 recovered from the
reaction mixture unequivocally indicated complete racemization, although the above-
mentioned protocol had been shown to give, e.g., Boc-Val-AibY[CS]N(Me)Ph and
Boc-Leu-AibY[CS]-Pro-OMe without epimerization [27]. Obviously, Pro-OH is more
susceptible to enolization under the chosen conditions (see also [18]). Another
explanation is the presence of the thioamide group in the precursor 7. All attempts to
optimize the reaction conditions, e.g., by using pyridine as the base instead of N-
methylmorpholine (NMM), or by replacing isobutyl chloroformate by 1,1’-carbon-
yldiimidazole (CDI) [32] in order to avoid the anhydride formation were unsuccessful,
and the epimerization still occurred, and the yield of 9a/9b was even lower.
With the intention of preparing an endothiopeptide with a Pro residue as the N-
terminus, we converted (benzyloxy)carbonyl (Z)-protected proline (11) into the
corresponding thioacid via the mixed anhydride under the conditions described above.
Subsequent reaction with the Aib-Pro synthon 2a afforded the desired product Z-Pro-
AibY[CS]-Pro-OMe (12) in very good yield (89%, Scheme 4). The NMR spectrum of
1
12 in CDCl3 was not conclusive, because all signals were very broad. In the H-NMR
spectrum in (D6)DMSO, only some of the signals were broadened, but others appeared
1
doubled. In a series of H-NMR measurements at increased temperatures, most of
these signals coalesced at 360 K, suggesting the presence of a single epimer of 12, which
exists as two rotamers at lower temperatures. However, it was not possible to observe
the coalescence of all the broadened signals, since the sample decomposed at 380 K.
Finally, crystallization from AcOEt gave suitable crystals, and the structure of 12 was
unequivocally established by X-ray crystallography (Fig. 1).
Scheme 4
The compound in the crystal is enantiomerically pure, and the absolute config-
uration of the molecule (4S,10S) has been determined by the diffraction experiment.
The asymmetric unit contains two symmetry-independent molecules of 12, plus two
molecules of AcOEt. The two peptide molecules have quite different conformations.
First, the molecules differ by a small twist of ca. 148 about the C(8)ÀN(9) bond, then
the central five-membered rings have an inverted puckering, and finally, the benzyloxy
group is rotated by ca. 1008 about the O(1)ÀC(14) bond in molecule A, compared with
its orientation in molecule B. The amide NH group of molecule A forms an
intermolecular H-bond with the amide O-atom of molecule B. In turn, molecule B has
an identical interaction with a different molecule A. These interactions link the peptide
molecules in an ··· A ··· B ··· A ··· B ··· sequence into extended chains which run

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Fig. 1. ORTEP Plot [33] of the molecular structure of one of the crystallographically independent
molecules of 12 (50% probability ellipsoids, arbitrary numbering of the atoms)
parallel to the [0 1 0] direction and have a graph set motif [34] of C22(8). In both
molecules, the five-membered ring containing N(3) and N(33) has an envelope
conformation with C(22) and C(52), respectively, as the envelope flap, while that
containing N(9) and N(39) has a half-chair conformation twisted on C(27)ÀC(28) and
C(57)ÀC(58), respectively. The Et group of one of the AcOEt molecules is disordered
over two orientations with the major conformation existing in ca. 66% of the molecules.
The methyl ester 12 was hydrolyzed by treatment with LiOH according to the
standard procedure. The yield of the acid 13 was good (80%), but the NMR spectra of
the product showed two sets of signals, indicating extensive epimerization. However,
the ratio of the epimers could not be determined due to the overlap of the broad signals.
To characterize 13 appropriately, it was submitted directly to further reactions. We
chose the standard reactions with the dipeptide synthon 2a without previous thionation
and the traditional coupling (TBTU/HOBt) with phenylalanine methyl ester (H-Phe-
OMe). In both cases, diastereoisomeric mixtures of products were obtained

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(Scheme 5). The reaction of 13 with 2a at room temperature afforded a mixture of the
epimers 14a and 14b in a ratio of 13 :10, and in a total yield of 69%. After separation by
column chromatography, 30% of 14a and 12% of 14b were isolated. The coupling of 13
with H-Phe-OMe gave a mixture of 15a and 15b in the same ratio of 13 :10, and in a
total yield of 51%. Again, the products were separated by column chromatography
affording 26% of 15a and 8% of 15b.
Scheme 5
Control experiments showed that the partial epimerization occurred during the
base-promoted hydrolysis of 12. The small excess of one epimer of 13 let us hope for
successful optimization of the reaction conditions. But, unfortunately, preliminary
experiments revealed that the conversion of 13 to the corresponding thioacid, and
subsequent treatment with 2a did not provide the expected endothiopeptide analogue
of 14 with an additional C¼S function.
Our study on the synthesis of proline-containing endothiopeptides described above
has shown that the peptides with the C¼S group adjacent to the Pro residue, i.e., with
the ÀCS-ProÀ unit, are particularly susceptible to epimerization. To circumvent this
problem, we decided to prepare analogous endothiopeptides with the C¼S group not
adjacent to Pro. Therefore, we used the optimized protocol for the isomerization of
Aib-containing thiopeptides, which was elaborated in our laboratory [27][28]
(Scheme 1). The acid-catalyzed shift of the S-atom from the terminal position to the
penultimate one has been shown to occur via the formation of an intermediate 1,3-
oxazole-5(4H)-thione and its rearrangement into the isomeric 1,3-thiazol-5(4H)-one.
So, a sample of 7, which had been additionally purified by crystallization from t-

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BuOMe, was treated with ZnCl2 in AcOH solution and then with a saturated solution
of HCl in AcOH. The isomerization proceeded smoothly at room temperature to afford
product 16, with the C¼S group shifted to the benzamide linkage, in 78% yield
(Scheme 6). The endothiopeptide 16 was then submitted to saponification with LiOH
under standard conditions, but the product was destroyed during acidic workup with 1m
HCl. The acid-promoted cleavage of the Aib-Pro unit in aqueous solution afforded Ph-
CS-Aib-OH (17) almost quantitatively (99%); the proline methyl ester was identified
in the filtrates. We assumed that the formation of a 1,3-thiazol-5(4H)-one was
responsible for the cleavage. Therefore, in a control experiment, HCl gas was bubbled
through a solution of 16 in THF affording 4,4-dimethyl-2-phenyl-1,3-thiazol-5(4H)-one
(18) in 73% yield (Scheme 6). The spectroscopic data of 18 were in full agreement with
those in [35].
Scheme 6
Since the product of the hydrolysis of 16 was sensitive to traces of acid, the
procedure had to be modified. After the saponification with a smaller excess of LiOH
(2 equiv.), the mixture was gradually saturated with solid NH4Cl (see Exper. Part).
Extraction with CH2Cl2 and evaporation of the solvent without heating afforded ca.
60% of the crude compound 19 (Scheme 7). The samples were also unstable, and slow
decomposition occurred even at 08. With the aim of characterizing the deprotected acid
19, the crude material was reacted with the Aib synthon 1a. The coupling at room
temperature proceeded slowly, and the resulting product, Ph-CS-Aib-Pro-Aib-
N(Me)Ph (20), was obtained only in moderate yield (48%). This positive result
encouraged us to perform the transformation of the unstable intermediate 19 to the
mixed anhydride and subsequently to the corresponding thioacid, which was
immediately treated with 1a. The Aib synthon 1a has been chosen again, in order to
avoid the formation of side products, such as 10, in the presence of H2S. The desired
endothiopeptide 21 with two thioamide groups was isolated in 37% yield (Scheme 7).
The final product 21 was a single stereoisomer, i.e., no detectable epimerization had

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Scheme 7
occurred, and the obtained sample was analytically pure. After crystallization from
CH2Cl2/t-BuOMe by slow evaporation of the solvent, its structure was additionally
confirmed by an X-ray crystal-structure determination (Fig. 2).
Fig. 2. ORTEP Plot [33] of the molecular structure of 21 (50% probability ellipsoids, arbitrary
numbering of the atoms)
The compound 21 in the crystal is enantiomerically pure, and the absolute
configuration has been determined independently by the diffraction experiment. The
molecule has the expected (5S)-configuration. The asymmetric unit contains one

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Helvetica Chimica Acta – Vol. 91 (2008)
peptide molecule 21 and one H2O molecule. The peptide molecule has one
intramolecular NÀH ··· S H-bond between N(7)ÀH and S(17). This interaction
serves to maintain the helical conformation of the molecule and has a graph set motif
[34] of S(10). N(1)ÀH forms an intermolecular H-bond with O(3) of an adjacent
peptide molecule and links the molecules 21 into extended chains which run parallel
to the [0 1 0] direction and have a graph set motif of C(5). The H2O molecule donates
one H-bond to S(9) in one peptide molecule and to O(6) in another peptide molecule,
and thereby links the peptide and H2O molecules into extended chains which run
parallel to the [1 0 0] direction and have a graph set motif of C22(9). The
intermolecular interactions combine to link the moieties in the structure into a
three-dimensional framework.
In summary, new applications and limitations of the ꢀazirine/oxazolone methodꢁ in
the synthesis of proline-containing endothiopeptides are described. Whereas the
introduction of AibY[CS]-Pro units was possible, the results demonstrate the
extraordinary lability of these thiopeptides towards epimerization of the Pro unit.
The use of the acid-catalyzed isomerization protocol for thiopeptides and the
optimization of some reaction conditions allowed the synthesis of an optically pure
peptide fragment with two thioamide groups. However, this attractive site-selective
incorporation of more thioamide groups into endothiopeptides by using the ꢀazirine/
oxazolone methodꢁ still needs improvement, especially for avoiding epimerization.
We thank the analytical units of our institute for spectra and elemental analyses. Financial support of
this work by the Dr. Helmut Legerlotz-Foundation and F. Hoffmann-La Roche AG, Basel, is gratefully
acknowledged.
Experimental Part
1. General. See [12b][36]. Abbreviations. Aib, 2-aminoisobutyric acid (2-methylalanine); DCC,
N,N’-dicyclohexylcarbodiimide; HOBt, 1-hydroxy-1H-benzotriazole; i-BuOCOCl, isobutyl carbono-
chloridate; NMM, N-methylmorpholine; TBTU, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate. M.p.: Mettler FP-5 or Büchi B-450 apparatus; uncorrected. IR Spectra: Perkin-Elmer
781 or Perkin-Elmer 1600-FT-IR spectrophotometer. 1H- and 13C-NMR Spectra: Bruker AC-300 or
Bruker ARX-300 instrument (300 and 75.5 MHz, resp.), and Bruker DRX-600 instrument (600 and
150.9 MHz, resp.), in CDCl3; multiplicity of C-atoms from DEPT spectra. MS: Finnigan MAT-90 or
Finnigan SSQ-700 instrument (EI, 70 eV, or CI (NH3)). Elemental analyses were performed by the
Mikroanalytisches Laboratorium des Organisch-chemischen Instituts der Universität Zürich.
2. GeneralProcedures . GeneralProcedure A (GP A). To a soln. of 1 equiv. of a N-protected peptide
or a thiocarboxylic acid in dry CH2Cl2, a soln. of 1.02 – 1.3 equiv. of methyl N-(2,2-dimethyl-2H-azirin-3-
yl)-l-prolinate (Aib-Pro synthon; 2a) in dry CH2Cl2 was added slowly at 08. The mixture was stirred at 08
for 0.5 h, then at r.t. until the starting material was consumed (TLC). The soln. was diluted with CH2Cl2,
washed with 5% aq. KHSO4, the org. layer was dried (MgSO4), and evaporated. The crude product was
purified by column chromatography (CC) or prep. TLC (SiO2).
GeneralProcedure B (GP B). To a soln. of 1 equiv. of a N-terminal-protected peptide ester in THF/
MeOH/H2O 3 :1:1, 4 equiv. of LiOH · H2O were added, and the mixture was stirred at r.t. until the
starting material was consumed (TLC). Then, the mixture was slowly acidified with 1m HCl until pH 3
was reached, and the org. solvent was evaporated. The precipitated solid was collected by filtration,
washed with H2O, and dried in vacuo.
GeneralProcedure C (GP C). To a soln. of 1 equiv. of a N-terminal-protected amino acid or peptide
in dry THF or THF/DMF, 2.4 equiv. of NMM, and, after 15 min, 1.2 equiv. of i-BuOCOCl were added
slowly at À 208, and a white solid precipitated. After stirring for 1 h, a slow stream of H2S was bubbled

Helvetica Chimica Acta – Vol. 91 (2008)
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through the mixture for 2 h, and then N2 for 1 h, while the temp. was kept below À 208. A soln. of 2 – 2.5
equiv. of 2a or 1a in THF was added dropwise, the mixture was stirred at À 108 for 2 h, and at r.t.
overnight. Then, the mixture was diluted with Et2O, washed with 5% aq. KHSO4, dried (MgSO4), and
evaporated. The crude products were purified by chromatography (CC or prep. TLC; SiO2).
GeneralProcedure D (GP D). To a soln. of 1 equiv. of a N-terminal-protected amino acid or peptide,
2 equiv. (3 equiv. when the hydrochloride of the protected amino acid was used) of EtN(i-Pr)2, 1 equiv. of
TBTU, and 1 equiv. of HOBt in MeCN, 1.1 equiv. of an amino acid ester were added. The mixture was
stirred at r.t. until the starting material was consumed (TLC). Then, the soln. was diluted with CH2Cl2,
and extracted 3 Â with 5% aq. NaHCO3 and KHSO4 soln. The combined aq. phase was washed with
Et2O, and the combined org. phase dried (MgSO4), filtered, and concentrated in vacuo. The crude
product was purified by CC or prep. TLC (SiO2) or recrystallization.
GeneralProcedure E (GP E). A soln. of a thiopeptide in AcOH was treated with ZnCl2 and stirred
vigorously at r.t. for 20 min; ZnCl2 only partially dissolved. Then, AcOH saturated with HCl (2.1m) was
added to the mixture. After 30 min of stirring, the mixture was carefully added to 5% aq. NaHCO3 soln.
and extracted with CH2Cl2. The combined org. phase was dried (MgSO4), evaporated, and the residue
was purified by CC or prep. TLC (SiO2).
3. Starting Materials. Methyl N-(2,2-dimethyl-2H-azirin-3-yl)-l-prolinate (2a)2) [10a] and N,2,2-
trimethyl-N-phenyl-2H-azirin-3-amine (1a) [37] were synthesized according to the procedures described
in the literature.
4. Synthesis of Endothiopeptides. 4.1. Methyl(2 S)-1-[2-(Benzoylamino)-2-methyl-1-thioxopropyl]-
pyrrolidine-2-carboxylate (Bz-AibY[CS]-Pro-OMe; 7). According to GP A, PhCOSH (6; 276 mg,
2.0 mmol) in CH2Cl2 (20 ml), 2a2) (435 mg, 2.04 mmol) in CH2Cl2 (9 ml); reaction time 30 h. CC
(AcOEt) yielded 650 mg (97%) of 7. Colorless solid. M.p. 149 – 1528. [a]2D3 ¼ À150.4 (c ¼ 1.00, MeOH).
IR (KBr): 3396m, 2985m, 2952w, 2880w, 1740vs, 1657vs, 1580w, 1515s, 1484s, 1425vs, 1389m, 1362m,
1
1352w, 1284m, 1263w, 1244w, 1198s, 1161s, 1149m, 1041m, 1000w, 970m. H-NMR (CDCl3): 8.58 (br. s,
NH ) ; 7.87 – 7.82 ( m, 2 arom. H); 7.49 – 7.37 (m, 3 arom. H); 5.16 (dd, J ¼ 8.8, 4.2, HÀC(a)(Pro)); 4.03 –
3.89 (m, CH2(d)(Pro)); 3.72 (s, MeO); 2.29 – 2.11 (m, CH2(b)(Pro)); 2.07 – 1.98( m, CH2(g)(Pro)); 1.93,
1.86 (2s, 2 Me(Aib)). 13C-NMR (CDCl3): 205.8(C ¼S); 170.8, 164.7 (2 C¼O); 135.0 (arom. C); 131.2,
128.4, 126.8 (5 arom. CH); 68.8 (CH(a)(Pro)); 61.0 (C(a)(Aib)); 53.3 (CH2(d)(Pro)); 52.2 (MeO); 27.8,
25.8(CH (b)(Pro), CH2(g)(Pro)); 25.6, 24.8(2 Me(Aib)). CI-MS: 335 (13, [ M þ 1]þ), 303 (84), 300
2
(100), 286 (7), 234 (24), 200 (75), 198 (14), 172 (14), 165 (24), 139 (23), 130 (52). Anal. calc. for
C17H22N2O3S (334.43): C 61.05, H 6.63, N 8.38, S 9.59; found: C 61.15, H 6.84, N 8.35, S 9.38.
4.2. (2S)-1-[2-(Benzoylamino)-2-methyl-1-thioxopropyl]pyrrolidine-2-carboxylic Acid (Bz-Aib-
Y[CS]-Pro-OH; 8). According to GP B, 7 (1.67 g, 5.0 mmol), LiOH · H2O (0.84 g, 20.0 mmol), THF/
MeOH/H2O 3 :1:1 (500 ml); reaction time 2 d: 1.51 g (94%) of 8. Colorless crystals. M.p. 230 – 2318.
[a]2D3 ¼ À51.6 (c ¼ 1.00, MeOH). IR (KBr): 3343w, 3283m, 2977m, 2939w, 2877w, 2672m, 1741s, 1610s,
1572m, 1544s, 1494w, 1449w, 1425vs, 1390s, 1361m, 1339w, 1321m, 1265m, 1247w, 1223m, 1166m, 1148w,
1047w, 972w. 1H-NMR ((D6)DMSO): 12.31 (br. s, OH); 8.64 (br. s, NH); 7.8 8 – 7.8 4m( , 2 arom. H); 7.57 –
7.44 (m, 3 arom. H); 4.86 (dd, J ¼ 8.2, 2.6, HÀC(a)(Pro)); 4.03 – 3.97, 3.60 – 3.43 (2m, CH2(d)(Pro));
2.08– 1.82 ( m, CH2(b)(Pro), CH2(g)(Pro)); 1.75, 1.56 (2s, 2 Me(Aib)). 13C-NMR ((D6)DMSO): 203.9
(C¼S); 171.2, 164.9 (2 C¼O); 133.9 (arom. C); 131.6, 128.1, 127.4 (5 arom. CH); 67.8 (CH(a)(Pro)); 60.7
(C(a)(Aib)); 52.2 (CH2(d)(Pro)); 29.8, 26.9 (2 Me(Aib)); 27.3, 25.3 (CH2(b)(Pro), CH2(g)(Pro)). CI-
MS: 321 (8, [M þ 1]þ), 305 (13), 303 (10), 287 (100), 190 (21), 116 (14). Anal. calc. for C16H20N2O3S
(320.40): C 59.98, H 6.29, N 8.74, S 10.01; found: C 59.91, H 6.46, N 8.75, S 10.18.
4.3. Methyl(2 S)-1-[2-({(2S/2R)-1-[2-(Benzoylamino)-2-methyl-1-thioxopropyl]pyrrolidine-2-car-
bonyl}amino)-2-methyl-1-thioxopropyl}pyrrolidine-2-carboxylate (Bz-AibY[CS]-Pro-AibY[CS]-Pro-
OMe; 9a) and Methyl(2 S)-1-[2-({(2R/S)-1-[2-(Benzoylamino)-2-methyl-1-thioxopropyl]pyrrolidine-2-
carbonyl}amino)-2-methyl-1-thioxopropyl]pyrrolidine-2-carboxylate (9b). According to GP C, 8
(320 mg, 1.0 mmol) in THF/DMF 5 :2 (28ml), NMM (242 mg, 2.4 mmol), i-BuOCOCl (164 mg,
1.2 mmol), 2a2) (533 mg, 2.5 mmol) in THF (8ml). CC (AcOEt/hexane 2 :1 ! 4 :1) and separation of the
2
)
Azirine 2a was contaminated with 8% of methyl N-(2-methylpropanoyl)-l-prolinate, the starting
material of its preparation [10a].

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Helvetica Chimica Acta – Vol. 91 (2008)
diastereoisomers by prep. TLC (SiO2; AcOEt/hexane 1.8:1) gave 36 mg (7%) of 9a, 36 mg (7%) of 9b,
and 173 mg of (S)-perhydro-3,3-dimethyl-4-thioxopyrrolo[1,2-a]pyrazin-1-one (10) [31].
Data for 9a. Colorless solid. M.p. 260 – 2638 (dec.). IR (KBr): 3355m, 3299m, 3000w, 2979w, 2946w,
1722s, 1669s, 1643vs, 1578w, 1525s, 1487w, 1428s, 1409m, 1388m, 1362m, 1304w, 1207m, 1164m, 1147w,
1047w, 1001w, 968w. 1H-NMR (CDCl3): 7.84 – 7.81 (m, 2 arom. H); 7.77 (br. s, NH); 7.59 – 7.47 (m, 3 arom.
H); 7.11 (br. s, NH); 5.51 (dd, J ¼ 8.2, 5.8, HÀC(a)(Pro)); 5.10 – 5.06 (m, HÀC(a)(Pro)); 4.32 – 4.24,
4.21 – 4.12, 3.96 – 3.88, 3.51 – 3.43 (4m, 2 CH2(d)(Pro)); 3.70 (s, MeO); 2.25 – 1.99 (m, 5 H of Pro); 1.97 (s,
Me(Aib)); 1.97 – 1.88 (m, 3 H of Pro); 1.75, 1.73, 1.69 (3s, 3 Me(Aib)). 13C-NMR (CDCl3): 205.6, 204.1
(2 C¼S); 171.7, 169.1, 166.4 (3 C¼O); 133.0 (arom. C); 132.4, 129.1, 127.1 (5 arom. CH); 69.5, 68.1
(2 CH(a)(Pro)); 62.3, 61.1 (2 C(a)(Aib)); 53.3, 53.0 (2 CH2(d)(Pro)); 51.9 (MeO); 32.1, 30.8
(2 Me(Aib)); 28.3, 27.8, 25.8, 25.4 (2 CH2(b)(Pro), 2 CH2(g)(Pro)); 26.9, 26.0 (2 Me(Aib)). ESI-MS:
555 (100, [M þ Na]þ).
Data for 9b. Colorless solid. IR (KBr): 3278s, 2984m, 2946m, 2876w, 1741s, 1642vs, 1578w, 1534s,
1488m, 1462m, 1419vs, 1387m, 1362m, 1302m, 1244w, 1200m, 1150s, 1088w, 1046m, 1002w, 967w.
1H-NMR (CDCl3): 7.87 – 7.83 ( m, 2 arom. H); 7.68(br. s, NH); 7.58– 7.45 ( m, 3 arom. H); 7.39 (br. s, NH);
5.36 (dd, J ¼ 8 .4, 6.1, HÀC(a)(Pro)); 5.06 (dd, J ¼ 8 .6, 4.6, HÀC(a)(Pro)); 4.22 – 4.12 (m,
HÀC(d)(Pro)); 4.03 – 3.93 (m, 2 HÀC(d)(Pro)); 3.70 (s, MeO); 3.55 – 3.47 (m, HÀC(d)(Pro)); 2.32 –
1.84 (m, 2 CH2(b)(Pro), 2 CH2(g)(Pro)); 1.96, 1.82, 1.77, 1.72 (4s, 4 Me(Aib)). 13C-NMR (CDCl3):
205.6, 204.8(2 C ¼S); 171.4, 168.9, 166.1 (3 C¼O); 133.3 (arom. C); 132.2, 128.9, 127.2 (5 arom. CH);
70.0, 68.3 (2 CH(a)(Pro)); 62.1, 61.6 (2 C(a)(Aib)); 53.3, 52.9 (2 CH2(d)(Pro)); 52.2 (MeO); 31.0, 28.41
(2 Me(Aib)); 28.37, 27.8 (2 CH2(b)(Pro)); 27.1, 26.7 (2 Me(Aib)); 25.8, 25.6 (2 CH2(g)(Pro)). ESI-MS:
555 (100, [M þ Na]þ).
4.4. Methyl(2 S)-1-[2-({(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carbonyl}amino)-2-methyl-1-thi-
oxopropyl]pyrrolidine-2-carboxylate (Z-Pro-AibY[CS]-Pro-OMe; 12). According to GP C, Z-Pro-OH
(1.0 g, 4.0 mmol) in THF (100 ml), NMM (969 mg, 9.6 mmol), i-BuOCOCl (656 mg, 4.8mmol), 2a2)
(1.87 mg, 8.8 mmol) in THF (20 ml). After CC (AcOEt), a yellow oil was isolated and triturated with t-
BuOMe. Filtration and recrystallization from t-BuOMe gave 1.64 g (89%) of 12. Colorless crystals. M.p.
138– 140 8. [a]2D3 ¼ À114.4 (c ¼ 1.00, CDCl3). IR (KBr): 3443w, 3303w, 2976m, 2950w, 2883w, 1745s,
1697vs, 1660s, 1543w, 1422vs, 1386w, 1360s, 1270w, 1241w, 1203s, 1163s, 1118m, 1086m, 1047w, 1004w,
967w. 1H-NMR ((D6)DMSO, 300 K): 8.41, 8.36 (2 br. s, NH); 7.37 – 7.29 (m, 5 arom. H); 5.16 – 4.98( m,
PhCH2); 4.83 – 4.80, 4.73 – 4.68, 4.38 – 4.32, 4.26 – 4.21 (4m, 2 HÀC(a)(Pro)); 4.16 – 4.07, 3.88 – 3.77 (2m,
CH2(d)(Pro)); 3.57, 3.53 (2s, MeO); 3.49 – 3.36 (m, CH2(d)(Pro)); 2.28– 2.04, 1.96 – 1.72, 1.57 – 1.48(3 m,
1
CH2(b)(Pro), CH2(g)(Pro)); 1.61, 1.59, 1.40, 1.38(4 s, 2 Me(Aib)). H-NMR ((D6)DMSO, 360 K): 8.01
(br. s, NH); 7.36 – 7.27 (m, 5 arom. H); 5.12, 5.03 (AB, J ¼ 13.0, PhCH2); 4.96 – 4.89 (m, HÀC(a)(Pro));
4.28( dd, J ¼ 8.5, 3.0, HÀC(a)(Pro)); 4.04 – 3.95, 3.84 – 3.76 (2m, CH2(d)(Pro)); 3.59 (s, MeO); 3.48–
3.42 (m, CH2(d)(Pro)); 2.21 – 2.09, 2.01 – 1.78(2 m, 2 CH2(b)(Pro), 2 CH2(g)(Pro)); 1.64 (s, 2 Me(Aib));
1.49 (s, 2 Me(Aib)). 13C-NMR ((D6)DMSO, 360 K): 203.8, 203.6 (C¼S); 170.6, 170.4, 170.3 (2 C¼O);
154.0, 153.5 (PhCH2OCO); 137.2, 137.0 (arom. C); 128.2, 128.1, 127.6, 127.3, 126.2 (5 arom. CH); 67.8, 67.6
(CH(a)(Pro)); 65.8, 65.4 (PhCH2); 60.0, 59.8(C( a)(Aib)); 59.1, 58.7 (CH(a)(Pro)); 52.0, 51.9
(CH2(d)(Pro)); 51.5 (MeO); 47.0, 46.4 (CH2(d)(Pro)); 30.0, 29.5, 26.5, 26.1 (2 Me(Aib)); 31.2, 29.8,
27.2, 26.9 (2 CH2(b)(Pro)); 25.4, 25.1, 23.7, 22.6 (2 CH2(g)(Pro)). ESI-MS: 484 (100, [M þ Na]þ). Anal.
calc. for C23H31N3O5S · C5H12O (13 · t-BuOMe; 549.72): C 61.18, H 7.88, N 7.64; found: C 61.11, H 8.08, N
7.60.
Suitable crystals for an X-ray crystal-structure determination were obtained from AcOEt by slow
evaporation of the solvent.
4.5. (2S)-1-[2-({(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carbonyl}amino)-2-methyl-1-thioxopro-
pyl]pyrrolidine-2-carboxylic Acid (Z-Pro-AibY[CS]-Pro-OH; 13). According to GP B, 12 (1.38g,
3.0 mmol), LiOH · H2O (0.504 g, 12.0 mmol), THF/MeOH/H2O 3 :1:1 (400 ml); reaction time 26 h.
After collection of the precipitated solid, additional portions of the product were recovered by extraction
of the filtrate with CH2Cl2, and crystallization from t-BuOMe. Total yield of 13: 1.07 g (80%). Colorless
solid. M.p. 161 – 1648. IR (KBr): 3254m, 3034w, 2979m, 2881w, 2861w, 1704vs, 1540m, 1424vs, 1360s,
1
1265m, 1245m, 1209s, 1167s, 1150m, 1121m, 1090w, 1046w, 972w. H-NMR ((D6)DMSO): 12.27 (br. s,
OH); 8.39, 8.34, 8.32 (3 br. s, NH); 7.36 – 7.30 (m, 5 arom. H); 5.15 – 4.91 (m, PhCH2); 4.82 – 4.79, 4.72 –

Helvetica Chimica Acta – Vol. 91 (2008)
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4.69, 4.38– 4.33, 4.28– 4.23 (4 m, 2 HÀC(a)(Pro)); 4.20 – 4.07, 3.84 – 3.69, 3.47 – 3.38 (3m,
2 CH2(d)(Pro)); 2.24 – 2.03, 1.94 – 1.73 (2m, 2 CH2(b)(Pro), 2 CH2(g)(Pro)); 1.62, 1.60, 1.40, 1.38(4 s,
2 Me(Aib)). 13C-NMR ((D6)DMSO, 360 K): 203.8, 203.6 (C¼S); 170.3, 169.8, 169.6 (2 C¼O); 153.7,
153.6 (PhCH2OCO); 136.5, 136.4 (arom. C); 127.5, 126.8, 126.5 (5 arom. CH); 67.2 (CH(a)(Pro)); 65.4
(PhCH2); 60.2, 60.0 (C(a)(Aib)); 59.5, 59.3 (CH(a)(Pro)); 51.9, 46.4, 46.2 (2 CH2(d)(Pro)); 29.4, 27.2
(2 Me(Aib)); 28.7, 28.6 (2 CH2(b)(Pro)); 24.1, 22.7 (2 CH2(g)(Pro)). ESI-MS: 486 (14, [M þ K]þ), 470
(100, [M þ Na]þ), 454 (8). Anal. calc. for C22H29N3O5S (447.54): C 59.04, H 6.53, N 9.39; found: C 58.75,
H 6.40, N 7.14.
4.6. Methyl(2 S)-1-[2-({(2S/2R)-1-[2-({(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carbonyl}ami-
no)-2-methyl-1-thioxopropyl]pyrrolidine-2-carbonyl}amino)-2-methylpropanoyl]pyrrolidine-2-carboxy-
late (Z-Pro-AibY[CS]-Pro-Aib-Pro-OMe; 14a) and Methyl(2 S)-1-[2-({(2R/2S)-1-[2-({(2S)-1-[(Benzy-
loxy)carbonyl]pyrrolidine-2-carbonyl}amino)-2-methyl-1-thioxopropyl]pyrrolidine-2-carbonyl}amino)-
2-methylpropanoyl]pyrrolidine-2-carboxylate (14b). According to GP A, 13 (233 mg, 0.5 mmol) in
CH2Cl2 (30 ml), 2a2) (138mg, 0.65 mmol) in CH 2Cl2 (8ml); reaction time 36 h. Two diastereoisomers
14a and 14b were formed in a ratio 1.3 :1 (1H-NMR). CC (AcOEt/MeOH 20 :1) yielded 95 mg (30%) of
14a, 39 mg (12%) of 14b, and 88 mg (27%) of a mixture of both.
Data for 14a. 1H-NMR (CDCl3): 7.98, 7.59 (2 br. s, NH); 7.36 – 7.28( m, 5 arom. H); 7.03 (br. s, NH);
5.45 – 5.39 (m, HÀC(a)(Pro)); 5.16 – 5.07 (m, PhCH2); 4.52 (dd, J ¼ 8.8, 4.3, HÀC(a)(Pro)); 4.40 – 4.36
(m, HÀC(a)(Pro)); 4.08– 4.01, 3.92 – 3.83 (2 m, 2 CH2(d)(Pro)); 3.68( s, MeO); 3.71 – 3.43 (m,
CH2(d)(Pro)); 2.44 – 2.35, 2.23 – 1.72 (2m, 3 CH2(b)(Pro), 3 CH2(g)(Pro)); 1.49, 1.47 (2s, 4 Me(Aib)).
13C-NMR (CDCl3): 205.3 (C¼S); 173.5, 171.9, 171.6, 169.7, 169.4, 168.6 (4 C¼O); 154.0, 153.5
(PhCH2OCO); 136.1 (arom. C); 128.4, 128.1, 127.8 (5 arom. CH); 69.2 (CH(a)(Pro)); 67.1 (PhCH2);
61.3 (C(a)(Aib)); 60.3, 59.7, 58.8 (2 CH(a)(Pro)); 57.3, 56.2 (C(a)(Aib)); 51.7 (MeO); 52.6, 48.1, 46.9,
45.5 (3 CH2(d)(Pro)); 32.1, 27.2, 26.1, 25.8, 25.3, 23.6 (4 Me(Aib)); 29.3, 28.9, 28.7 (3 CH2(b)(Pro)); 25.9,
25.3, 24.3, 22.2 (3 CH2(g)(Pro)). ESI-MS: 666 (100, [M þ Na]þ).
1
Data for 14b. H-NMR (CDCl3): 7.47 (br. s, NH); 7.39 – 7.31 (m, 5 arom. H, NH); 5.28– 5.11 ( m,
HÀC(a)(Pro), PhCH2); 4.53 – 4.49, 4.37 – 4.33 (2m, 2 HÀC(a)(Pro)); 4.03 – 3.94, 3.75 – 3.47 (2m,
3 CH2(d)(Pro)); 3.70 (s, MeO); 2.32 – 1.90 (m, 3 CH2(b)(Pro), 3 CH2(g)(Pro)); 1.70, 1.52, 1.51, 1.45 (4s,
4 Me(Aib)). 13C-NMR (CDCl3): 204.6 (C¼S); 173.3, 172.0, 169.4 (4 C¼O); 153.8(PhCH 2OCO); 136.1
(arom. C); 128.5, 128.3, 127.8 (5 arom. CH); 69.4 (CH(a)(Pro)); 67.5 (PhCH2); 61.5 (C(a)(Aib)); 60.3
(2 CH(a)(Pro)); 56.8(C( a)(Aib)); 51.8(MeO); 53.0, 47.6, 47.1 (3 CH 2(d)(Pro)); 32.5, 26.8, 24.5,
24.4 (4 Me(Aib)); 28.5, 27.8 (3 CH2(b)(Pro)); 25.8, 25.6 (3 CH2(g)(Pro)). ESI-MS: 666 (100,
[M þ Na]þ).
4.7. Methyl(2 S)-2-({(2S/2R)-1-[2-({(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carbonyl}amino)-2-
methyl-1-thioxopropyl]pyrrolidine-2-carbonyl}amino)-3-phenylpropionate (Z-Pro-AibY[CS]-Pro-Phe-
OMe; 15a) and Methyl(2 S)-2-({(2R/2S)-1-[2-({(2S)-1-[(Benzyloxy)carbonyl]pyrrolidine-2-carbonyl}-
amino)-2-methyl-1-thioxopropyl]pyrrolidine-2-carbonyl}amino)-3-phenylpropionate (15b). According
to GP D, 14 (233 mg, 0.5 mmol) in MeCN (20 ml), EtN(i-Pr)2 (194 mg, 1.5 mmol), TBTU (177 mg,
0.55 mmol), HOBt · H2O (78mg, 0.5 mmol), Phe-OMe · HCl (119 mg, 0.55 mmol); reaction time 48h.
Two diastereoisomers, 15a and 15b, were formed in a ratio 1.3 :1 (1H-NMR). CC (AcOEt/MeOH 20 :1)
yielded 80 mg (26%) of 15a, 24 mg (8%) of 15b, and 50 mg (17%) of a mixture of both.
Data for 15a. 1H-NMR (CDCl3): 7.84 (br. s, NH); 7.66 (d, J ¼ 6.0, NH); 7.48– 7.12 ( m, 10 arom. H);
5.31 – 5.08( m, HÀC(a)(Pro), PhCH2); 4.69 – 4.58( m, HÀC(a)(Phe)); 4.41 – 4.37 (m, HÀC(a)(Pro));
4.15 – 4.04 (m, HÀC(d)(Pro)); 3.80 – 3.42 (m, 3 HÀC(d)(Pro), MeO); 3.23 – 2.92 (m, CH2(b)(Phe));
2.31 – 1.37 (m, 2 CH2(b)(Pro), 2 CH2(g)(Pro)); 1.80, 1.44 (s, 2 Me(Aib)). 13C-NMR (CDCl3): 205.0, 204.4
(C¼S); 172.6, 171.0, 170.3 (3 C¼O); 156.2, 155.3 (PhCH2OCO); 137.1, 136.3 (2 arom. C); 129.2, 129.1,
128.5, 128.2, 128.1, 127.5, 126.9, 126.4 (10 arom. CH); 69.4 (CH(a)(Pro)); 67.5, 67.3 (PhCH2); 63.4, 61.4
(C(a)(Aib)); 60.1, 60.0 (CH(a)(Pro)); 52.4, 47.0 (2 CH2(d)(Pro)); 54.2, 53.7 (CH(a)(Phe)); 51.7 (MeO);
36.8, 36.7 (CH2(b)(Phe)); 34.0, 30.0, 28.7, 27.3, 25.5, 24.4, 24.0, 21.3 (2 CH2(b)(Pro), 2 CH2(g)(Pro)); 31.7,
31.2, 26.6 (2 Me(Aib)).
1
Data for 15b. H-NMR (CDCl3): 7.38– 7.15 ( m, 10 arom. H, 2 NH); 5.26 – 5.10 (m, HÀC(a)(Pro),
PhCH2); 4.80 (ddd, J ¼ 9.3, 8.5, 5.3, HÀC(a)(Phe)); 4.37 – 4.33 (m, HÀC(a)(Pro)); 3.87 – 3.76 (m,
HÀC(d)(Pro)); 3.70 (s, MeO); 3.57 – 3.38( m, 3 HÀC(d)(Pro)); 3.24 (dd, J ¼ 14.0, 5.3, HÀC(b)(Phe));

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Helvetica Chimica Acta – Vol. 91 (2008)
3.05 (dd, J ¼ 14.0, 9.3, HÀC(b)(Phe)); 2.38 – 2.29, 2.19 – 2.08, 1.99 – 1.85, 1.77 – 1.72, 1.63 – 1.53 (5m,
2 CH2(b)(Pro), 2 CH2(g)(Pro)); 1.70, 1.48( s, 2 Me(Aib)). 13C-NMR (CDCl3): 204.3 (C¼S); 171.7, 170.4,
170.2 (3 C¼O); 154.2 (PhCH2OCO); 137.2, 135.2 (2 arom. C); 129.1, 128.5, 128.3, 128.1, 127.8, 126.6 (10
arom. CH); 69.4 (CH(a)(Pro)); 67.5 (PhCH2); 61.4 (C(a)(Aib)); 60.5 (CH(a)(Pro)); 53.0, 47.2
(2 CH2(d)(Pro)); 52.8(CH( a)(Phe)); 51.9 (MeO); 37.1 (CH2(b)(Phe)); 28.4, 28.0, 25.5, 24.4
(2 CH2(b)(Pro), 2 CH2(g)(Pro)); 27.3, 20.9 (2 Me(Aib)).
4.8. Methyl(2 S)-1-{2-Methyl-2-[(thiobenzoyl)amino]propanoyl}pyrrolidine-2-carboxylate (BzY[CS]-
Aib-Pro-OMe; 16). According to GP E, 7 (167 mg, 0.5 mmol), ZnCl2 (2.73 g, 20 mmol), 2.1m HCl in
AcOH (0.65 ml). CC (AcOEt) and evaporation of the solvent gave 131 mg (78%) of 16. Yellow crystals.
M.p. 193 – 1948. [a]D23 ¼ À78.2 (c ¼ 1.00, CDCl3). IR (KBr): 3442w, 3288s, 2986w, 2951w, 2875w, 1743s,
1726s, 1634vs, 1527s, 1446s, 1414s, 1357m, 1293w, 1247w, 1213m, 1181m, 1149w, 1092w, 1053w, 1007w,
927w. 1H-NMR (CDCl3): 8.41 (br. s, NH); 7.79 – 7.73 (m, 2 arom. H); 7.49 – 7.34 (m, 3 arom. H); 4.59 (dd,
J ¼ 8.2, 3.2, HÀC(a)(Pro)); 3.82 – 3.74, 3.57 – 3.48 (2m, CH2(d)(Pro)); 3.73 (s, MeO); 2.16 – 2.01, 1.99 –
1.94 (2m, CH2(b)(Pro), CH2(g)(Pro)); 1.93, 1.85 (2s, 2 Me(Aib)). 13C-NMR (CDCl3): 196.6 (C¼S);
172.7, 171.0 (2 C¼O); 142.3 (arom. C); 130.9, 128.4, 126.4 (5 arom. CH); 60.9 (C(a)(Aib)); 60.8
(CH(a)(Pro)); 52.0 (MeO); 47.6 (CH2(d)(Pro)); 27.7, 25.8(CH 2(b)(Pro)), CH2(g)(Pro)); 23.5, 22.2
(2 Me(Aib)). ESI-MS: 357 (100, [M þ Na]þ). Anal. calc. for C17H22N2O3S (334.43): C 61.05, H 6.63, N
8.38; found: C 60.82, H 6.62, N 8.31.
4.9. (2S)-1-{2-Methyl-2-[(thiobenzoyl)amino]propanoyl}pyrrolidine-2-carboxylic Acid (BzY[CS]-
Aib-Pro-OH; 19). To a soln. of 16 (334 mg, 1.0 mmol) in THF/H2O 3 :1 (80 ml), 2 equiv. of LiOH · H2O
(84 mg, 2.0 mmol) were added, and the mixture was stirred vigorously at r.t. for 24 h. Then, NH4Cl
(107 mg, 2.0 mmol) was added slowly, and N2 was bubbled through the mixture until most of the NH3 had
evolved. The org. solvent was evaporated at r.t. under reduced pressure. The H2O phase was treated
again with small portions of NH4Cl, and each time extracted with plenty of CH2Cl2. The combined yellow
org. layers were dried (MgSO4), and the solvent was removed under reduced pressure at r.t. to afford
211 mg (66%) of 19. Yellow gum. The unstable crude product was deep frozen (below À 708) or used
directly for the next steps. 1H-NMR (CDCl3): 8.12 (br. s, NH); 7.77 – 7.73 (m, 2 arom. H); 7.50 – 7.36 (m, 3
arom. H); 4.63 – 4.61 (m, HÀC(a)(Pro)); 3.72 – 3.64, 3.47 – 3.37 (2m, CH2(d)(Pro)); 2.25 – 2.15, 2.07 –
1.83 (2m, CH2(b)(Pro), CH2(g)(Pro)); 1.82, 1.74 (2s, 2 Me(Aib)). 13C-NMR (CDCl3): 197.4 (C¼S);
173.7, 172.8(2 C ¼O); 141.4 (arom. C); 131.3, 128.5, 126.4 (5 arom. CH); 61.7 (CH(a)(Pro)); 61.1
(C(a)(Aib)); 47.8(CH 2(d)(Pro)); 26.7, 25.9 (CH2(b)(Pro), CH2(g)(Pro)); 24.6, 23.2 (2 Me(Aib)). ESI-
MS (neg.): 639 (100, [2M À H]À), 542 (7), 319 (37, [M À H]À).
4.10. N,2-Dimethyl-2-[((2S)-1-{2-methyl-2-[(thiobenzoyl)amino]propanoyl}pyrrolidine-2-carbonyl)-
amino]-N-phenylpropanamide (BzY[CS]-Aib-Pro-Aib-N(Me)Ph; 20). To a soln. of crude 19 (39 mg,
0.122 mmol) in dry CH2Cl2 (10 ml), a soln. of 1.5 equiv. 1a (32 mg, 0.183 mmol) in dry CH2Cl2 (4 ml) was
added slowly at 08. The mixture was stirred at 08 for 30 min, then at r.t. for 24 h, and evaporated. CC
(SiO2; AcOEt) and recrystallization from t-BuOMe yielded 29 mg (48%) of 20. Pale yellow crystals. M.p.
205 – 2068. IR (KBr): 3443m, 3289m, 2986w, 2938w, 1641vs, 1593m, 1530m, 1493m, 1469w, 1450m, 1399s,
1360s, 1288w, 1251w, 1199w, 1176w, 1092w, 1011w, 924w. 1H-NMR (CDCl3): 8.37 (br. s, NH); 7.73 (d, J ¼
7.4, 2 arom. H); 7.52 – 7.46 (m, 1 arom. H); 7.43 – 7.18( m, 7 arom. H, NH); 4.39 – 4.34 (m, HÀC(a)(Pro));
3.60 – 3.52, 3.47 – 3.39 (2m, CH2(d)(Pro)); 3.29 (s, MeN); 2.18– 2.10, 2.00 – 1.78 (2 m, CH2(b)(Pro),
CH2(g)(Pro)); 1.78, 1.66, 1.46, 1.45 (4s, 4 Me(Aib)). 13C-NMR (CDCl3): 197.4 (C¼S); 173.0, 171.2, 170.1
(3 C¼O); 145.2, 141.6 (2 arom. C); 131.2, 129.0, 128.4, 127.4, 127.1, 126.6 (10 arom. CH); 62.5
(CH(a)(Pro)); 61.5, 57.5 (2 C(a)(Aib)); 47.2 (CH2(d)(Pro)); 40.6 (MeN); 27.0, 25.6 (CH2(b)(Pro),
CH2(g)(Pro)); 26.4 (2 Me(Aib)); 24.7, 23.9 (2 Me(Aib)). ESI-MS: 533 (4, [M þ K]þ), 517 (100, [M þ
Na]þ). Anal. calc. for C27H34N4O3S (494.65): C 65.56, H 6.93, N 11.33; found: C 65.32, H 6.66, N 11.28.
4.11. N,2-Dimethyl-2-[((2S)-1-{2-methyl-2-[(thiobenzoyl)amino]propanoyl}pyrrolidine-2-carbonyl)-
amino]-N-phenylpropanethioamide (BzY[CS]-Aib-Pro-AibY[CS]-N(Me)Ph; 21). According to GP C,
a soln. of crude 19 (211 mg, 0.66 mmol) in dry THF/DMF 10 :1 (44 ml), NMM (160 mg, 1.58mmol), i-
BuOCOCl (1 equiv., 90.3 mg, 0.66 mmol), 1a (229 mg, 1.32 mmol) in THF (10 ml). After stirring at À
108 for 2 h and at r.t. overnight, the solvent was removed at r.t. under reduced pressure, the residue
was treated with AcOEt, filtered, and the deep yellow filtrate purified by CC (SiO2; AcOEt). The
resulting oil was triturated with t-BuOMe, and 21 was collected by filtration: 125 mg (37%). Yellow

Helvetica Chimica Acta – Vol. 91 (2008)
1485
crystals. M.p. 190 – 1928. [a]2D3 ¼ À35.1 (c ¼ 1.00, MeOH). IR (KBr): 3443m, 3301m, 2992w, 2937w,
1658vs, 1626s, 1530s, 1492s, 1450s, 1399s, 1368s, 1283w, 1246m, 1208w, 1181w, 1099m, 1005w, 923w.
1H-NMR (CDCl3): 8.10 (br. s, NH); 7.76 – 7.72 (m, 2 arom. H); 7.58(br. s, NH); 7.51 – 7.45 (m, 1 arom. H);
7.42 – 7.13 (m, 5 arom. H); 7.22 – 7.17 (m, 2 arom. H); 4.32 – 4.28( m, HÀC(a)(Pro)); 3.70 (s, MeN); 3.55 –
3.50 (m, CH2(d)(Pro)); 2.22 – 2.14, 2.10 – 1.96, 1.91 – 1.78(3 m, CH2(b)(Pro), CH2(g)(Pro)); 1.79, 1.75,
1.70, 1.59 (4s, 4 Me(Aib)). 13C-NMR (CDCl3): 208.6, 197.2 (2 C¼S); 171.2, 169.4 (2 C¼O); 141.7 (2 arom.
C); 131.3, 129.3, 128.5, 127.9, 126.4, 126.0 (10 arom. CH); 62.6 (CH(a)(Pro)); 62.3, 61.4 (2 C(a)(Aib));
47.4 (CH2(d)(Pro)); 30.6, 29.4 (2 Me(Aib)); 26.6, 25.7 (CH2(b)(Pro), CH2(g)(Pro)); 24.2, 24.3
(2 Me(Aib)). ESI-MS: 549 (5, [M þ K]þ), 533 (100, [M þ Na]þ). Anal. calc. for C27H34N4O2S2
(510.71): C 63.50, H 6.71, N 10.97; found: C 63.35, H 6.43, N 10.87.
5. X-Ray Crystal-Structure Determination of 12 and 21 (Table, and Figs. 1 and 2)3). All
measurements were performed on a Nonius KappaCCD diffractometer [38] using graphite-monochro-
mated 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 views of the molecules are shown in
Figs. 1 and 2. Data reduction was performed with HKL Denzo and Scalepack [39]. The intensities were
corrected for Lorentz and polarization effects, and absorption corrections based on the multi-scan
method [40] were applied. Each structure was solved by direct methods using SIR92 [41], which revealed
the positions of all non-H-atoms. In the case of 12, the asymmetric unit contains two symmetry-
independent molecules of the peptide, plus two molecules of AcOEt. Substantial differences in the
conformations of the two peptide molecules preclude the possibility of additional overlooked
crystallographic symmetry. The Et group of one of the AcOEt molecules is disordered. Two positions
were defined for each of the Et atoms, and refinement of the site occupation factors yielded a value of
0.66(2) for the major conformation. Bond-length and similarity restraints were applied to all chemically
equivalent bond lengths and angles involving the disordered atoms. Furthermore, neighboring atoms
within and between each disordered conformation were restrained to have similar and pseudo-isotropic
atomic displacement parameters. A bond-length restraint was also applied to the CÀC bond of the Et
group in the ordered AcOEt molecule. In the case of 21, the asymmetric unit contains one peptide and
one H2O molecule. In each structure, the non-H-atoms were refined anisotropically. The amide and H2O
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, while restraining the
H2O OÀH and H ··· H distances to suitable values. All remaining H-atoms in each structure 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 1.2 Ueq of its parent C-atom (1.5 Ueq for the
Me groups). The refinement of each structure was carried out on F2 using full-matrix least-squares
procedures, which minimized the function Sw(F2o À Fc2 )2. A correction for secondary extinction was
applied in the case of 12. In the case of 21, one reflection, whose intensity was considered to be an
extreme outlier, was omitted from the final refinement. Refinement of the absolute structure parameter
[42] yielded values of À 0.02(7) for 12 and 0.12(7) for 21, which confirms that the refined coordinates
represent the true enantiomorph. Neutral atom scattering factors for non-H-atoms were taken from
[43a], and the scattering factors for H-atoms were taken from [44]. Anomalous dispersion effects were
included in Fc [45]; the values for f’ and f’’ were those of [43b]. The values of the mass attenua-
tion coefficients are those of [43c]. All calculations were performed using the SHELXL97 [46] pro-
gram.
3
)
CCDC-683046 – 683047 contain the supplementary crystallographic data for this article. These data
can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://
www.ccdc.cam.ac.uk/data_request/cif.

1486
Helvetica Chimica Acta – Vol. 91 (2008)
Table 1. Crystallographic Data for Compounds 12 and 21
12
21
Crystallized from
Empirical formula
Formula weight
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
AcOEt
C23H31N3O5S · C4H8O2
549.68528
colorless, prism
0.22 Â 0.25 Â 0.27
160(1)
CH2Cl2/t-BuOMe
C27H34N4O2S2 · H2O
.73
colorless, needle
0.08 Â 0.10 Â 0.25
160(1)
Crystal system
Space group
orthorhombic
P212121
orthorhombic
P212121
Z
8
4
Reflections for cell determination
69201
56524
2q Range for cell determination [8]
4 – 50
4 – 55
Unit cell parameters a [Š]
14.4030(2)
18.5950(2)
21.8300(3)
5846.6(1)
1.249
0.1580.228
f and w
50
8.3334(2)
10.1403(3)
32.6404(9)
2758.2(1)
1.273
b [Š]
c [Š]
V [Š3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
f and w
55
2q(max) [8]
Transmission factors [min; max]
Total reflections measured
Symmetry independent reflections
Reflections with I > 2s(I)
Reflections used in refinement
Parameters refined; restraints
Final R(F) [I > 2s(I) reflections]
wR(F2) (all data)
0.809; 0.970
62916
10302
7870
10302
724; 66
0.0465
0.1204
0.0660; 0.8380
1.035
0.820; 0.990
33484
6286
4542
6285
345; 3
0.0482
0.1059
0.0409; 0.7345
1.037
Weighting parameters [a; b]a)
Goodness-of-fit
Secondary extinction coefficient
0.0032(4)
0.001
0.69; À 0.22
–
Final Dmax/s
D1 (max; min) [e Š
0.002
0.24; À 0.29
À3
]
a) wÀ1 ¼ s2(F2o ) þ (aP)2 þ bP where P ¼ (Fo2 þ 2F2c )/3
REFERENCES
[1] ꢀPeptides: Chemistry and Biologyꢁ, Eds. N. Sewald, H.-D. Jakubke, Wiley-VCH, Weinheim, 2002,
pp. 339 – 378; A. F. Spatola, in ꢀChemistry and Biochemistry of Amino Acids, Peptides and Proteinsꢁ,
Ed. B. Weinstein, Marcel Dekker, New York, 1983, Vol. 7, pp. 267 – 375.
[2] S. Vijayalakshmi, R. Balaji Rao, I. L. Karle, P. Balaram, Biopolymers 2000, 53, 84; U. Slomczynska,
D. D. Bensen, J. Zabrocki, K. Kociolek, A. Redlinski, F. Reusser, W. C. Hutton, M. T. Leplawy, G. R.
Marshall, J. Am. Chem. Soc. 1992, 114, 4095.
[3] C.-F. Chang, M. H. Zehfus, Biopolymers 1996, 40, 609; J. Samanen, T. Cash, D. Narindray, E.
Brandeis, W. Adams, H. Weideman, T. Yellin, J. Med. Chem. 1991, 34, 3036.
[4] B. Vitoux, A. Aubry, M. T. Cung, M. Marraud, Int. J. Pept. Protein Res. 1986, 27, 617; W. F. Degrado,
Adv. Protein Chem. 1988, 39, 51.
[5] J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97, 2243.

Helvetica Chimica Acta – Vol. 91 (2008)
1487
[6] a) M. Schutkowski, M. Jakob, G. Landgraf, I. Born, K. Neubert, G. Fischer, Eur. J. Biochem. 1997,
245, 381; b) D. Krumme, H. Tschesche, Tetrahedron 1999, 55, 3007; c) B. Zacharie, M. Lagraoui, M.
Dimarco, C. Penney, L. Gagnon, J. Med. Chem. 1999, 42, 2046.
[7] H. Heimgartner, Angew. Chem., Int. Ed. 1991, 30, 238.
[8] D. Obrecht, H. Heimgartner, Helv. Chim. Acta 1981, 64, 482; D. Obrecht, H. Heimgartner, Helv.
Chim. Acta 1987, 70, 102.
[9] P. Wipf, H. Heimgartner, Helv. Chim. Acta 1986, 69, 1153; P. Wipf, H. Heimgartner, Helv. Chim. Acta
1987, 70, 354; P. Wipf, H. Heimgartner, Helv. Chim. Acta 1988, 71, 140.
[10] a) R. Luykx, C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1996, 79, 527; b) R. T. N.
Luykx, A. Linden, H. Heimgartner, Helv. Chim. Acta 2003, 86, 4093.
[11] R. A. Breitenmoser, T. R. Hirt, R. T. N. Luykx, H. Heimgartner, Helv. Chim. Acta 2001, 84, 972.
[12] a) N. Pradeille, H. Heimgartner, J. Pept. Sci. 2003, 9, 827; b) N. Pradeille, O. Zerbe, K. Mçhle, A.
Linden, H. Heimgartner, Chem. Biodivers. 2005, 2, 1127.
[13] P. Wipf, H. Heimgartner, Helv. Chim. Acta 1990, 73, 13.
[14] W. Altherr, A. Linden, H. Heimgartner, Chem. Biodivers. 2007, 4, 1144.
[15] a) S. Stamm, H. Heimgartner, Eur. J. Org. Chem. 2004, 3820; b) S. Stamm, A. Linden, H.
Heimgartner, Helv. Chim. Acta 2006, 89, 1; c) S. Stamm, H. Heimgartner, Helv. Chim. Acta 2006, 89,
1841; d) S. Stamm, H. Heimgartner, Tetrahedron 2006, 62, 9671.
[16] J. Rizo, L. M. Gierasch, Annu. Rev. Biochem. 1992, 61, 38 7.
[17] ꢀTopical Issue Peptaibioticsꢁ, Eds. C. Toniolo, H. Brückner, Chem. Biodivers. 2007, 4, pp. 1021 – 1412.
[18] R. Nagaraj, P. Balaram, Tetrahedron 1981, 37, 1263.
[19] B. F. Gisin, D. G. Davis, Z. K. Borowska, J. E. Hall, S. Kobayashi, J. Am. Chem. Soc. 1981, 103, 6373.
[20] V. V. Suresh Babu, H. N. Gopi, Tetrahedron Lett. 1998, 39, 1049.
[21] K. Akaji, Y. Tamai, Y. Kiso Tetrahedron Lett. 1995, 36, 9341.
[22] M. Crisma, M. Anzolin, G. M. Bonora, C. Toniolo, E. Benedetti, B. Di Blasio, V. Pavone, M. Saviano,
A. Lombardi, F. Nastri, C. Pedone, Gazz. Chim. Ital. 1992, 122, 239.
[23] K. Clausen, M. Thorsen, S.-O. Lawesson, Tetrahedron 1981, 37, 3635; M. Thorsen, B. Yde, U.
Pedersen, K. Clausen, S.-O. Lawesson, Tetrahedron 1983, 39, 3429; D. W. Brown, M. M. Campbell,
C. V. Walker, Tetrahedron 1983, 39, 1075; H. Ripperger, J. Prakt. Chem. 1987, 329, 1039; S. F. Guziek
Jr., L. M. Wasmund, J. Chem. Res., Synop. 1989, 155; S. F. Guziek Jr., M. Wasmund, Tetrahedron
Lett. 1990, 31, 23; J. Jurayj, M. Cushman, Tetrahedron 1992, 48, 8601; K. C. Nicolaou, B. S. Safina, M.
Zak, S. H. Lee, M. Nevalainen, M. Bella, A. A. Estrada, C. Funke, F. J. Zecri, S. Bulat, J. Am. Chem.
Soc. 2005, 127, 11159; C. Giordano, G. Lucente, A. Masi, M. Paglialunga Paradisi, A. Sansone, S.
Spisani, Amino Acids 2007, 33, 477.
[24] K. Clausen, M. Thorsen, S.-O. Lawesson, A. F. Spatola, J. Chem. Soc., Perkin Trans. 1 1984, 78 5; T.
Hoeg-Jensen, C. E. Olsen, A. Holm, J. Org. Chem. 1994, 59, 1257; T. Hoeg-Jensen, A. F. Spatola, A.
Holm, Int. J. Pept. Protein Res. 1996, 47, 190; K. Hartke, A. Barrmeyer, J. Prakt. Chem. 1996, 338,
251.
[25] B. Zacharie, G. Sauve, C. Penney, Tetrahedron 1993, 49, 10489; M. A. Shalaby, C. W. Grote, H.
Rapoport, J. Org. Chem. 1996, 61, 9045; C. T. Brain, A. Hallett, S. Y. Ko, J. Org. Chem. 1997, 62, 3808.
[26] U. Kazmaier, S. Ackermann, Org. Biomol. Chem. 2005, 3, 3184.
[27] a) J. Lehmann, A. Linden, H. Heimgartner, Tetrahedron 1998, 54, 8721; b) J. Lehmann, A. Linden,
H. Heimgartner, Helv. Chim. Acta 1999, 82, 888; c) J. Lehmann, A. Linden, H. Heimgartner,
Tetrahedron 1999, 55, 5359; d) J. Lehmann, H. Heimgartner, Helv. Chim. Acta 1999, 82, 1899.
[28] a) R. A. Breitenmoser, H. Heimgartner, Helv. Chim. Acta 2001, 84, 786; b) R. A. Breitenmoser, A.
Linden, H. Heimgartner, Helv. Chim. Acta 2002, 85, 990.
[29] S. V. Pansare, J. Vederas, J. Org. Chem. 1989, 54, 2311.
[30] F. M. Arcamone, M. Altamura, E. Perrotta, A. Crea, S. Manzini, D. Poma, A. Salimbeni, A. Triolo,
C. A. Maggi, J. Antibiot. 2000, 53, 1086.
[31] A. Budzowski, A. Linden, H. Heimgartner, Heterocycles 2004, 64, 417.
[32] M. A. McKervey, M. B. OꢁSullivan, P. L. Myers, R. H. Green, J. Chem. Soc., Chem. Commun. 1993,
94.

1488
Helvetica Chimica Acta – Vol. 91 (2008)
[33] C. K. Johnson, ꢀORTEP IIꢁ, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
[34] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem., Int. Ed. 1995, 34, 1555.
[35] M. Blagoev, A. Linden, H. Heimgartner, Helv. Chim. Acta 1999, 82, 1458.
[36] T. Jeremic, A. Linden, H. Heimgartner, Chem. Biodivers. 2004, 1, 1730.
[37] J. M. Villalgordo, H. Heimgartner, Helv. Chim. Acta 1993, 76, 2830.
[38] R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
[39] Z. Otwinowski, W. Minor, in ꢀMethods in Enzymologyꢁ, Vol. 276, ꢀMacromolecular Crystallographyꢁ,
Part A, Eds. C. W. Carter Jr., R. M. Sweet, Academic Press, New York, 1997, p. 307.
[40] R. H. Blessing, Acta Crystallogr., Sect. A 1995, 51, 33.
[41] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli,
SIR92, J. Appl. Crystallogr. 1994, 27, 435.
[42] H. D. Flack, G. Bernardinelli, Acta Crystallogr., Sect. A 1999, 55, 908; H. D. Flack, G. Bernardinelli,
J. Appl. Crystallogr. 2000, 33, 1143.
[43] a) E. N. Maslen, A. G. Fox, M. A. OꢁKeefe, in ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992 Vol. C, Table 6.1.1.1, p. 477; b) D. C. Creagh,
W. J. McAuley, in ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C. Wilson, Kluwer Academic
Publishers, Dordrecht, 1992 Vol. C, Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, in
ꢀInternational Tables for Crystallographyꢁ, Ed. A. J. C. Wilson, Kluwer Academic Publishers,
Dordrecht, 1992 Vol. C, Table 4.2.4.3, p. 200.
[44] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[45] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 78 1.
[46] G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
Received April1, 2008