N-methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine - Synthesis and reactions of a synthon for AN UNKNOWN α-AMINO ACID

Article abstract of DOI:10.3987/COM-10-S(E)73

The synthesis of the heterospirocyclic amino azirine N-methyl-N-phenyl-5- oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a) was achieved from 3,4-dihydro-2H-pyrane (7) via N-methyl-N-phenyltetrahydropyran-3-thiocarboxamide (11). The reactions of 6a with thiobenzoic acid and Z-Phe-OH, respectively, leading to the corresponding 3-benzoylaminotetrahydropyran-3-thiocarboxamide (13) and the diastereoisomeric dipeptide amides (14), respectively, demonstrate that 6a is a valuable synthon for the hitherto unknown 3-aminotetrahydropyrane-3-carboxylic acid. The structure of 13 was established by X-Ray crystallography. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)73

HETEROCYCLES, Vol. 82, No. 2, 2011
1267
HETEROCYCLES, Vol. 82, No. 2, 2011, pp. 1267 - 1282. © The Japan Institute of Heterocyclic Chemistry
Received, 25th June, 2010, Accepted, 10th August, 2010, Published online, 12th August, 2010
DOI: 10.3987/COM-10-S(E)73
N-METHYL-N-PHENYL-5-OXA-1-AZASPIRO[2.5]OCT-1-EN-2-AMINE –
SYNTHESIS AND REACTIONS OF A SYNTHON FOR AN UNKNOWN
α-AMINO ACID
Michael Löpfe,1 Anthony Linden, and Heinz Heimgartner
University of Zürich, Institute of Organic Chemistry, Winterthurerstrasse 190,
CH-8057 Zürich, Switzerland; E-mail: heimgart@oci.uzh.ch
Dedicated to Professor Albert Eschenmoser on the occasion of his 85th birthday
Abstract
–
The synthesis of the heterospirocyclic amino azirine
N-methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a) was achieved
from 3,4-dihydro-2H-pyrane (7) via N-methyl-N-phenyltetrahydropyran-
3-thiocarboxamide (11). The reactions of 6a with thiobenzoic acid and Z-Phe-OH,
respectively, leading to the corresponding 3-benzoylaminotetrahydropyran-
3-thiocarboxamide (13) and the diastereoisomeric dipeptide amides (14),
respectively, demonstrate that 6a is a valuable synthon for the hitherto unknown
3-aminotetrahydropyrane-3-carboxylic acid. The structure of 13 was established
by X-Ray crystallography.
INTRODUCTION
Knowledge of the conformation of peptides and proteins is of central importance for the understanding of
their biological functions. Therefore, there is continuing interest in the factors which determine the local
or global conformation as the basis for peptide design. Among a series of structural modifications of
natural α-amino acids, the α-alkylation is known to restrict the conformational freedom significantly.2-5
The most well-known α,α-disubstituted α-amino acid is 2-aminoisobutyric acid (Aib), which is
widespread in nature, e.g., in linear, amphiphilic polypeptides called ‘peptaibols’.6,7 Aib and many other
α,α-disubstituted α-amino acids enhance the tendency of peptides to adopt defined secondary structures
like β-turns or helices. This structural quality is a prerequisite for these peptides to form ion channels

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HETEROCYCLES, Vol. 82, No. 2, 2011
through membranes8 and to act as antibiotics.9 Recently, their activity as cytotoxic substances has also
been studied.10
A special group of α,α-disubstituted α-amino acids are 1-aminocycloalkane-1-carboxylic acids. It was
demonstrated that they also show biological activites,11,12 and their influence on peptide conformations is
similar to that of Aib.13,14 Furthermore, heterocyclic α-amino acids of type 1,15–17 2,16b,18–20 and 318c,19a,21 (X
= NR, O, S) were studied with the same goal. Whereas in the cases of 1 and 2 the N, O, and S-analogues
were used, only the N and S derivatives of type 3 were included. Surprisingly, the analogous
3-aminotetrahydropyran-3-carboxylic acid (3, X = O) is hitherto unknown.
H2N
COOH
NH2
COOH
NH2
COOH
X
X
X
1
2
3
X
N(Me)Ph
N(Me)Ph
X
N(Me)Ph
X
N
N
N
4
(X = O, S)27
5
(X = NR, O, S)28
6
(X = NR)29
In the past, we have shown that 2,2-disubstituted 2H-azirine-3-amines are useful building blocks for
α,α-disubstituted α-amino acids.22,23 The so-called ‘azirine/oxazolone method’ was successfully used to
synthesize linear and cyclic peptides and depsipeptides, which contain α,α-disubstituted α-amino acids in
their backbone.24–26 For this reason, we have prepared a series of 2,2-disubstituted 2H-azirin-3-amines,
including heterospirocyclic ones. For example, the azirines (4 – 6) were used as synthons for the
corresponding amino acids (1 – 3). The chiral building blocks 4 and 6 were synthesized as racemates.
Because the heterocyclic amino acid (3, X = O) was not known, we decided to prepare the related synthon
6a (= 6, X = O) and to evaluate if it can be used in peptide synthesis.
RESULTS AND DISCUSSION
We planned the synthesis of 6a in analogy to earlier described approaches, i.e., the transformation of
N-methyl-N-phenyltetrahydrofuran-3-carboxamide into the azirine under the conditions described in ref.29
Therefore, the corresponding tetrahydrofuran-3-carboxylic acid (10) had to be prepared first. Although
the synthesis of this acid via acid-catalyzed dimerization of acrolein, followed by oxidation of the
aldehyde group and hydrogenation of the C=C bond was described repeatedly (e.g. ref.30), we decided to
carry out the synthesis as depicted in Scheme 1.

HETEROCYCLES, Vol. 82, No. 2, 2011
1269
O
CN
c)
a),b)
O
O
O
7
8
9
d)
X
COOH
e)
g)
N(Me)Ph
N(Me)Ph
O
X = S
O
O
N
6a
11 (X = O)
10
f)
12 (X = S)
Scheme 1
Reagents and conditions: a) 1. BH3⋅THF, THF, 0 °C; 2. NaOH, H2O2, 25 °C; b) PCC, molecular sieves
(3Å), CH2Cl2, rt; c) Tosmic, t-BuOK, t-BuOH/DME, 0 °C → rt; d) NaOH, EtOH/H2O, reflux; e) 1. SOCl2,
reflux; 2. Ph(Me)NH, Et3N, CH2Cl2, 0 °C → rt; f) Lawesson reagent, toluene, 110 °C; g) 1. COCl2 in
toluene, CH2Cl2, DMF, 0 °C; 2. DABCO, THF, rt; 3. NaN3, DMF/THF, rt
The hydroboration of 3,4-dihydro-2H-pyran (7) with the BH3⋅THF complex was performed according to
the protocol of Brown et al.,31 which gave 3-hydroxytetrahydropyran in the modest yield of 47%.
Subsequent oxidation was performed under various conditions, and the best result (90% yield of 8) was
obtained by using pyridinium chlorochromate (PCC) in the presence of molecular sieves (3Å) at room
temperature.32 As in a previously described example,28 the transformation of 8 into the nitrile (9) was
achieved according to the method of Oldenziel and van Leusen,33 that is by treatment with tosylmethyl
isocyanate (Tosmic) and potassium tert-butanolate at room temperature (48% yield). Finally,
saponification with NaOH in ethanol/water (1:2) under reflux led to the desired acid (10) in 95% yield.
A solution of the acid (10) in thionyl chloride was heated to reflux to give the acid chloride in quantitative
yield, which was reacted with N-methylaniline under standard conditions. After chromatographic
purification, N-methyl-N-phenyltetrahydropyran-3-carboxamide (11) was obtained in 90% yield.
Surprisingly, all attempts to convert 11 into the desired azirine (6a) according to the method described in
ref.29 and successfully applied for the synthesis of azirines of type (5)28 failed, and, in addition to starting
amide (11), a mixture of unidentified products was detected (NMR). A similar result was obtained in the
attempted synthesis of 4 (X = O).27a A possible explanation is the ring opening A → B under strong basic
conditions, leading to acrylamide derivatives, which undergo further reactions.

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HETEROCYCLES, Vol. 82, No. 2, 2011
X
X
N(Me)Ph
N(Me)Ph
(CH2)n
O
(CH2)n
O
A
B
Finally, we succeeded in the preparation of azirine (6a) via a modification34 of the classical method of
Rens and Ghosez.35 The amide (11) was transformed into the corresponding thioamide (12) by treatment
with Lawesson reagent in boiling toluene (ref.27), which was then reacted sequentially with phosgene in
dichloromethane and catalytic amounts of dimethylformamide (DMF), 1,4-diazabicyclo[2.2.2]octane
(DABCO) in THF, and sodium azide in DMF/THF (Scheme 1). After chromatographic purification, 6a
was obtained in 82% yield, contaminated with small amounts of the amide (11).36 The IR spectrum of 6a
showed the characteristic C=N absorption at 1756 cm–1 and the base-peak in the CI-MS appeared at m/z
217 ([M+1]+). All other spectroscopic data were in accordance with the structure.
A chemical proof for the ‘aminoazirine structure’ is the reaction with thiobenzoic acid.27–29 For this reason,
1.15 mol-equivalents of thiobenzoic acid were added to a solution of 6a in dichloromethane at 0 °C. After
only 10 min, the reaction was almost complete. Chromatographic workup gave the expected thioamide
(13) in 93% yield (Scheme 2). The structure of the product was elucidated on the basis of the
spectroscopic data and elemental analysis. Indicative were the ESI-MS with m/z 377 for [M+Na]+ and the
13C-NMR spectrum with a signal at 203.5 ppm for the thioamide C-atom. Finally, single crystals were
obtained from ethyl acetate/hexane, and the crystal-structure was established by X-Ray crystallography
(Figure 1).
O
O
O
CH2Cl2
0 °C
N(Me)Ph
N(Me)Ph
O
+
Ph
N
H
Ph
SH
N
S
6a
13
Scheme 2
Since the space group of 13 is centrosymmetric, the crystals are racemic. The torsion angles
φ(C(1)–N(2)–C(3)–C(4)) and ψ(N(2)–C(3)–C(4)–N(5)) of the tetrahydropyran-3-yl residue are 59.8(2)
and 37.5(2)°, respectively. These values are very close to those expected for an amino acid involved in a
β-turn of type I or III.38 Very similar torsion angles have been observed for heterocyclic amino acids 1 (X
= O) and 2 in short peptides and thiopeptides.27a,28,39 The six-membered heterocycle adopts a chair
conformation. Surprisingly, the amide group does not partake in any hydrogen bonding interactions.

HETEROCYCLES, Vol. 82, No. 2, 2011
1271
Figure 1. ORTEP plot37 of the molecular structure of 13 (arbitrary numbering of the atoms; 50%
probability ellipsoids)
With the aim of testing the potential of 6a as an amino acid synthon in the synthesis of peptides, the
reaction with Z-Phe-OH was performed in acetonitrile. After addition of 1.1 mol-equivalents of
Z-Phe-OH at 0 °C and stirring the mixture for 60 h at room temperature, the protected dipeptide amide
(14) was obtained in quantitative yield as a mixture of two diastereoisomers (Scheme 3). The 1:1 ratio of
1
the diastereoisomers was determined by means of H- and 13C-NMR spectroscopy as well as by
chromatography (HPLC, Nucleosil 100-7). Again, the structure of 14, as a mixture of diastereoisomers,
was determined on the basis of the spectroscopic data, the ESI-MS with m/z 538 ([M+Na]+, 100%), and
elemental analysis. In a small-scale HPLC experiment, the separation of the diastereoisomers of 14 was
achieved.
An additional prerequisite for the use of 6a in peptide synthesis is the selective deprotection of the N- and
C-termini of the coupling products. For the model dipeptide (14), this means that the transformation to the
free amino component (15) as well as that to the peptide acid (16) should be possible selectively. The
deprotection of the amino group of 14 via hydrogenolysis was carried out under standard conditions with
Pd on charcoal in methanol at room temperature to give 15 as a 1:1 mixture of diastereoisomers (HPLC).
The separation of the isomers was accomplished by column chromatography on silica gel; the two
isomers were obtained in 27 and 28% yield, respectively. The selective hydrolysis of the terminal amide
group of 14 was achieved under mild conditions by treatment with 3N HCl in H2O/THF at room

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HETEROCYCLES, Vol. 82, No. 2, 2011
temperature. After 4 h, chromatographic workup gave 58% of 16 as a 1:1 mixture of diastereoisomers and
ca. 25% of the starting material 14. All attempts to separate the diastereoisomeric dipeptide acids of type
(16) by column chromatography were unsuccessful.
O
O
H
Z-Phe-OH
N(Me)Ph
N
N(Me)Ph
O
Z
N
H
MeCN, 0°C to rt
N
O
Ph
6a
14
3N HCl
THF/H2O
0°C to rt
H2, Pd/C
MeOH, rt
O
O
O
O
O
H
N
H2N
Ph
N(Me)Ph
OH
N
H
Z
N
H
O
Ph
16
15
Scheme 3
CONCLUSIONS
A practical synthesis of the heterospirocyclic 2H-azirin-3-amine (6a) was elaborated. The coupling
reactions of 6a with thiobenzoic acid and Z-protected phenylalanine, respectively, together with the
subsequent selective deprotection of the amino and carboxyl group of the coupling product, i.e., the
protected dipeptide (14), demonstrated that 6a is a useful synthon for the hitherto unknown
3-aminotetrahydropyrane-3-carboxylic acid (3, X = O).
EXPERIMENTAL
General remarks. TLC: silica gel 60 F254 plates (0.25 mm, Merck). Column chromatography (CC): silica
gel 60 (0.043–0.063 mm, Merck). High performance liquid chromatography (HPLC): Nucleosil 100-7
(Machery-Nagel); UV-detection (λ = 240 nm; Varian 2550 or Jasco UV-975). Melting points: Büchi
B-540 apparatus, uncorrected. IR spectra: Perkin-Elmer-Spektrum ONE FT-IR, in KBr or as film; in cm–1.
1H-NMR (300 MHz) and C-NMR (75 MHz) spectra: Bruker AC-300 and ARX-300 instrument, in
13
CDCl3; chemical shifts in ppm, coupling constants J in Hz. The multiplicities of 13C signals were
determined with DEPT 135 and DEPT 90 measurements, and the assignments of 1H signals were made on
the basis of COSY experiments. EI-MS (70 eV) and CI-MS (NH3 as carrier gas): Finnigan MAT-95 or
Finnigan SSQ-700 instrument. ESI-MS: Finnigan TSQ-700. Elemental analyses were carried out on a
Vario-EL (Elementar) instrument.

HETEROCYCLES, Vol. 82, No. 2, 2011
1273
Synthesis of N-methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a). Tetrahydropyran-3-ol.31
To a solution of 3,4-dihydro-2H-pyran (7) (17.5 mL, 16.24 g, 193 mmol) in THF (82 mL) at 0 °C was
added drop-wise BH3⋅THF (95 mL of a 1M solution in THF, 8.29 g, 95 mmol) and the mixture stirred for
3 h at 0 °C. Then, 3N NaOH (64 mL) and a 30% H2O2-solution (31 mL) were added drop-wise at 0 °C,
and the mixture was stirred for 5 h at rt. After addition of K2CO3 (100 g), the organic phase was separated,
the aqueous phase extracted with Et2O (3 × 150 mL), and the combined organic phase was dried with
MgSO4. The solvent was evaporated, and the residue distilled at 65 °C (3 mbar) yielding 9.30 g (47%) of
tetrahydropyran-3-ol as colorless oil. IR (film): 3406vs, 2942vs, 2854vs, 2753w, 1469s, 1441vs, 1381s,
1366s, 1297s, 1254s, 1208s, 1174s, 1144s, 1084vs, 1029vs, 995vs, 979s, 963vs, 913vs, 871vs, 845m,
1
803m, 712m. H-NMR: 3.79–3.51 (m, CH2(2), CH2(6)); 3.42–3.36 (m, CH(3)); 2.44 (br. s, OH);
1.96–1.77, 1.65–1.48 (2m, CH2(4), CH2(5)). 13C-NMR: 72.9 (t, C(2)); 68.0 (t, C(6)); 65.8 (d, C(3)); 31.4,
23.1 (2t, C(4), C(5)). EI-MS: 102 (49, M+·), 84 (17, [M–H2O]+), 74 (10, [C4H6O]+), 72 (24), 71 (45,
[M–CH2OH]+), 70 (36, [M–CH3OH]+), 59 (6), 58 (21), 57 (34, [C3H5O]+), 56 (15), 55 (14), 45 (43), 44
(100, [C2H4O]+).
Tetrahydropyran-3-one (8).40 According to the protocol in ref.32, pyridinium chlorochromate (PCC)
(94.98 g, 440 mmol) and ground molecular sieves 3Å (88.12 g) were suspended in CH2Cl2 (300 mL), and
a solution of tetrahydropyran-3-ol (18.00 g, 176 mmol) in CH2Cl2 (140 mL) was added. After stirring for
2.5 h at rt, Et2O (400 ml) was added and the suspension filtered through silica gel (containing 7% MgSO4).
Purification by CC (pentane/Et2O 1:4) gave 15.82 g (90%) 8 as colorless oil. IR (film): 2961s, 2859m,
1724vs, 1446w, 1417m, 1337w, 1317m, 1289w, 1247s, 1194s, 1166m, 1102vs, 1036w, 985w, 940w, 915s,
1
857m, 734w, 647w. H-NMR: 4.01 (s, CH2(2)); 3.95–3.75 (m, CH2(6)); 2.53 (t, J = 6.9, CH2(4));
13
2.19–2.00 (m, CH2(5)). C-NMR: 207.4 (s, CO); 74.8 (t, C(2)); 65.8 (t, C(6)); 37.3 (t, C(4)); 24.7 (t,
C(5)). EI-MS: 100 (57, M+·), 71 (24), 70 (14), 55 (9, [C3H3O]+), 45 (10), 44 (6), 43 (12), 42 (100,
[C2H2O]+).
Tetrahydropyran-3-carbonitrile (9).41 According to ref.,33 a solution of t-BuOK (11.26 g, 100 mmol) in
t-BuOH/dimethoxyethane (DME) 1:1 (200 mL) was added to a solution of 8 (5.00 g, 49.94 mmol) and
tosylmethyl isocyanide (Tosmic) (10.73 g, 54.98 mmol) in DME (200 mL) at 0 °C. After stirring the
mixture for 1.5 h at 0 °C and 2 h at rt, Et2O (100 mL) was added. The mixture was washed with an
aqueous 5%-solution of NaHCO3 (2×), dried over NaSO4, and the solvent evaporated. Distillation at
70 °C, 0.15mbar (Kugelrohr) yielded 2.672 g (48%) of 9 as colorless oil. IR (film): 2954vs, 2857vs,
2241s, 1470s, 1453s, 1438s, 1386w, 1363w, 1326w, 1301w, 1276m, 1249w, 1217m, 1197vs, 1177s,
1148w, 1098vs, 1083s, 1068vs, 1034s, 1015s, 967m, 947w, 910s, 878vs, 863s, 832m, 786w, 687w.

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HETEROCYCLES, Vol. 82, No. 2, 2011
1H-NMR: 3.87 (dd, J = 11.4, 3.3, 1 H of CH2(2)); 3.74–3.61 (m, 1 H of CH2(2), 2 H of CH2(6)); 2.80–2.72
(m, CH(3)); 2.10–2.00 (m, 1 H of CH2(4)); 1.96–1.76 (m, 1 H of CH2(4), 1 H of CH2(5)); 1.67–1.54 (m, 1
13
H of CH2(5)). C-NMR: 119.9 (s, CN); 68.2, 67.9 (2t, C(2), C(6)); 27.6 (d, C(3)); 26.5, 23.4 (2t, C(5),
C(4)).
Tetrahydropyran-3-carboxylic acid (10).30 To a solution of NaOH (11.77 g, 294 mmol) in H2O (100 mL)
and EtOH (50 ml) was added 9 (3.254 g, 29.31 mmol), dissolved in a small amount of EtOH, and the
mixture was stirred for 2.5 h under reflux. After cooling to 0 °C, conc. HCl (33.5 mL) was added and
EtOH evaporated. The residue was extracted with CH2Cl2 (3×) and dried over MgSO4. Recrystallization
from CH2Cl2 yielded 3.61 g (95%) of 10 as colorless crystals. IR (KBr): 2952vs, 2859s, 1706vs, 1469m,
1453m, 1438m, 1418m, 1282s, 1196vs, 1145m, 1105s, 1082s, 1035m, 1014m, 968m, 913s, 861s, 834m,
813m, 733m, 648w. 1H-NMR: 4.01 (ddd, J = 11.4, 4.0, 1.2, 1 H of CH2(2)); 3.85–3.80 (m, 1 H of CH2(6));
3.64 (dd, J = 11.4, 8.7, 1 H of CH2(2)); 3.53–3.45 (m, 1 H of CH2(6)); 2.68–2.59 (m, CH(3)); 2.08–2.00
(m, 1 H of CH2(4)); 1.86–1.59 (m, 1 H of CH2(4), 2 H of CH2(5)). 13C-NMR: 178.3 (s, CO); 68.5, 68.0 (2t,
C(2), C(6)); 41.1 (d, C(3)); 25.5, 24.4 (2t, C(5), C(4)).
N-Methyl-N-phenyltetrahydropyran-3-carboxamide (11). Thionylchloride (1.2 mL, 1.95 g, 16.41 mmol)
was added slowly to 10 (0.30 g, 2.305 mmol) and the mixture heated to reflux. After 2 h, the evolution of
SO2 ceased, and after an additional 1 h, the mixture was cooled to rt, the excess of SOCl2 was evaporated
under high vacuum, and the residue dried under high vacuum yielding 0.34 g (99%)
tetrahydropyran-3-carboxylic acid chloride as a brownish oil. This acid chloride (0.34 g, 2.288 mmol)
was dissolved in CH2Cl2, and N-methylaniline (0.30 mL, 2.739 mmol) and triethylamine (0.35 mL, 2.534
mmol) were added drop-wise. The mixture was stirred for 4 h at rt, the solvent evaporated, the residue
dissolved in ethyl acetate (AcOEt) and filtered. After CC (30 g SiO2, hexane/AcOEt 2:1) and drying
under high vacuum, 0.451 g (90%) of 11 were obtained as colorless solid; mp 96–97 °C. IR (KBr): 3059w,
2980m, 2953s, 2926s, 2848s, 1645vs, 1593s, 1495s, 1456s, 1421vs, 1383vs, 1362s, 1344m, 1328m, 1310s,
1289s, 1254m, 1215s, 1176m, 1103vs, 1083vs, 1035s, 1024m, 995s, 969m, 938w, 912s, 876m, 860m,
1
790w, 777s, 729w, 701vs, 670s. H-NMR: 7.46–7.33 (m, 3 arom. H); 7.20–7.16 (m, 2 arom. H);
3.87–3.76 (m, 1 H of CH2(2), 1 H of CH2(6)); 3.51 (t, J = 10.9, 1 H of CH2(2)); 3.33 (dt, J = 11.9, 2.5, 1 H
of CH2(6)); 3.22 (s, MeN); 2.60–2.53 (m, CH(3)); 1.86–1.78 (m, CH2(4)); 1.53–1.35 (m, CH2(5)).
13C-NMR: 172.8 (s, CO); 143.6 (s, 1 arom. C); 129.7, 127.8, 126.9 (3d, 5 arom. CH); 69.5, 67.7 (2t, C(2),
C(6)); 40.2 (d, C(3)); 37.1 (q, MeN); 26.5, 24.7 (2t, C(5), C(4)). CI-MS (NH3): 221 (14), 220 (100,
[M+H]+), 107 (5, [M–C6H9O2+H]+). Anal. Calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39: Found: C,
71.18; H, 7.36; N, 6.29.

HETEROCYCLES, Vol. 82, No. 2, 2011
1275
N-Methyl-N-phenyltetrahydropyran-3-thiocarboxamide (12). A suspension of 11 (0.509 g, 2.321 mmol)
and Lawesson-Reagens (1.136 g, 2.809 mmol) in toluene (9 mL) was heated to 110 °C for 2.5 h. After
cooling to rt, the mixture was filtered through Celite. The residue was purified by CC (SiO2,
hexane/AcOEt 1:2), the solvent evaporated, and the residue dried under high vacuum overnight. After
additional CC (SiO2, CH2Cl2), 0.396 g (74%) of 12 were obtained as colorless solid; mp 103–104 °C. IR
(KBr): 2971m, 2943s, 2923s, 2854s, 1591m, 1492vs, 1451vs, 1381vs, 1362s, 1342m, 1323m, 1302m,
1274s, 1220s, 1184s, 1172s, 1099vs, 1077vs, 1028vs, 999m, 984m, 959w, 911vs, 884m, 861m, 837s,
1
796m, 777s, 734s, 701vs, 624m. H-NMR: 7.52–7.40 (m, 3 arom. H); 7.16 (d, J = 6.8, 2 arom. H);
3.83–3.72 (m, CH2(2), 1 H of CH2(6)); 3.68 (s, MeN); 3.36 (dt, J = 12.1, 2.4, 1 H of CH2(6)); 2.90–2.80
(m, CH(3)); 2.09 (m, 1 H of CH2(4)); 1.82–1.77 (m, 1 H of CH2(4)); 1.52 (dd, J = 13.5, 1.9, 1 H of
CH2(5)); 1.43–1.33 (m, 1 H of CH2(5)). 13C-NMR: 205.8 (s, CS); 145.3 (s, 1 arom. C); 130.1, 128.6, 125.3
(3d, 5 arom. CH); 72.6, 67.7 (2t, C(2), C(6)); 47.6 (d, C(3)); 45.2 (q, MeN); 30.7, 25.0 (2t, C(5), C(4)).
CI-MS (NH3): 238 (5), 237 (15), 236 (100, [M+H]+). Anal. Calcd for C13H17NOS: C, 66.35; H, 7.28; N,
5.95; S, 13.62. Found: C, 66.34; H, 6.70; N, 5.89; S, 13.64.
N-Methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a). To a stirred solution of 12 (0.858 g,
3.645 mmol) in CH2Cl2 (4.9 mL) containing 3 drops of DMF at 0 °C, a 2M solution of phosgene (2.35 mL,
(4.700 mmol) in toluene was added (CO2 evolution). After stirring for 1 h at rt, the solvent was
evaporated, the residue was dissolved in THF (10 mL), and 1,4-diazabicyclo[2.2.2]octane (DABCO) (530
mg, 4.713 mmol) was added. After stirring for 40 min at rt, the brownish precipitate was filtered off under
an N2 atmosphere and washed twice with DMF (10 mL). To the filtrate was added NaN3 (766 mg, 11.786
mmol), and the mixture was stirred for 4 d at rt under N2. Then, Et2O was added to the mixture, which
was filtered through Celite. After CC (SiO2, hexane/CH2Cl2/AcOEt = 1:0.5:2), a mixture of 11 (7%) and
6a was obtained as a yellow, viscous oil (1H-NMR): 649 mg (corresponds to 604 mg of 6a, 82% yield).
IR (film): 2941m, 2841m, 1756vs (νC=N), 1600s, 1502s, 1459w, 1422w, 1355w, 1320m, 1285w, 1257w,
1237w, 1113w, 1086s, 1028w, 949w, 906w, 755m, 693m. 1H-NMR: 7.61–7.09 (m, 5 arom. H); 3.09–3.66
(m, 2 CH2O); 3.50 (s, MeN); 1.92–1.74 (m, CH2(7), CH2(8)). 13C-NMR: 165.7 (s, C(2)); 142.1 (s, 1 arom.
C); 129.2, 123.5, 116.9 (3d, 5 arom. CH); 74.6, 67.7 (2t, 2 CH2O); ca. 46 (broad, C(3)); ca. 37 (broad,
C(7)); ca. 34 (broad, MeN); 32.3 (t, C(8)). The signals for C(2), C(3), C(7), and Me could be detected
only after 6.5 h measurement. CI-MS (NH3): 218 (16), 217 (100, [M + H]+). Anal. Calcd for C13H16N2O:
C, 72.19 ; H, 7.46 ; N, 12.95. Found: C, 72.14 ; H, 7.35 ; N, 13.08.
Reaction of N-methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a) with thiobenzoic acid.
N-{3-[(N-Methyl-N-phenylamino)thioxomethyl]tetrahydropyran-3-yl}benzamide (13). To a solution of 6a

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HETEROCYCLES, Vol. 82, No. 2, 2011
(73 mg, 0.338 mmol) in CH2Cl2 (5 mL) at 0 °C was added drop-wise a solution of freshly distilled
thiobenzoic acid (54 mg, 0.389 mmol). After stirring for 10 min, the reaction was almost complete (DC).
The solvent was evaporated after stirring for 13 h at rt, and the crude yellow product was purified by CC
(SiO2, hexane/CH2Cl2/AcOEt 2:0.5:1) and recrystallized from AcOEt/hexane yielding 112 mg (93%) of
13 as colorless crystals; mp 136–137 °C. Suitable crystals for the X-Ray crystallography were obtained
from AcOEt/hexane by slow evaporation of the solvent. IR (KBr): 3330m, 3058w, 3028w, 2999w, 2960m,
2942m, 2914w, 2853m, 1664vs, 1601m, 1590m, 1581m, 1519vs, 1486vs, 1462vs, 1448vs, 1431s, 1371vs,
1288s, 1251s, 1227m, 1204w, 1180w, 1173w, 1147m, 1102vs, 1086vs, 1073s, 1042s, 1027s, 1000s, 984m,
1
932m, 922m, 901w, 867w, 847s, 800m, 780s, 733m, 721s, 709vs, 695s, 670m, 641w, 623m. H-NMR:
7.48–7.43 (m, 3 arom. H); 7.35–7.28 (m, 2 arom. H); 7.11–7.09 (m, 5 arom. H); 5.94 (br. s, NH); 4.27 (dd,
J = 11.4, 3.0, 1 H of CH2(2)(Thp)); 3.96 (d, J = 11.4, 1 H of CH2(2)(Thp)); 3.86 (dd, J = 11.5, 4.7, 1 H of
CH2(6)(Thp)); 3.69 (s, MeN); 3.43 (dt, J = 11.5, 3.2, 1 H of CH2(6)(Thp)); 2.96 (dt, J = 13.4, 5.0, 1 H of
CH2(4)(Thp)); 2.77-2.71 (m, 1 H of CH2(4)(Thp)); 1.55-1.50 (m, CH2(5)(Thp)). 13C-NMR: 203.5 (s, CS);
165.4 (s, CO); 147.4, 133.8 (2s, 2 arom. C); 131.4, 129.3, 128.1, 127.5, 126.7, 125.0 (6d, 10 arom. CH);
75.1, 68.0 (2t, C(2)(Thp), C(6)(Thp)); 64.4 (s, C(3)(Thp)); 50.7 (q, MeN); 32.8, 22.1 (2t, C(4)(Thp),
C(5)(Thp)). ESI-MS: 377 (100, [M + Na]+), 361 (25). Anal. Calcd for C20H22N2O2S: C, 67.77; H, 6.26; N,
7.90; S, 9.05. Found: C, 67.83; H, 6.32; N, 7.85; S, 9.28.
Reaction of N-methyl-N-phenyl-5-oxa-1-azaspiro[2.5]oct-1-en-2-amine (6a) with Z–Phe–OH. Benzyl
N-[(S)-1-Benzyl-2-({(R,S)-3-[(N-methyl-N-phenylamino)oxomethyl]tetrahydropyran-3-yl}amino)-2-oxo-
ethyl]carbamate (14). To a solution of 6a (200 mg, 0.925 mmol) in MeCN (2 mL) at 0 °C, a solution of
Z-Phe-OH (304 mg, 1.018 mmol) in MeCN (1.5 mL) was added. After stirring for 60 h at rt, the solvent
was evaporated. Chromatographic purification (CC, SiO2, hexane/CH2Cl2/AcOEt 1:0.5:1) of the residue
yielded 476 mg (99%) of dipeptid 14 as a ca. 1:1 mixture of diastereoisomers. Colorless solid; mp
80–82 °C. IR (KBr): 3299s, 3061m, 3031m, 2955m, 2854m, 1678vs, 1639vs, 1593vs, 1494vs, 1453vs,
1372s, 1237vs, 1152m, 1089vs, 1041s, 1028s, 1002w, 934w, 909w, 868w, 847w, 773m, 738s, 699vs,
680m. 1H-NMR (diastereoisomers): 7.42–7.18 (m, 13 arom. H); 7.07–7.04 (m, 2 arom. H); 5.92, 5.29 (2s,
NH); 5.26–5.23 (m, NH); 5.13–5.00 (m, PhCH2O); 4.15–4.02 (m, CH(α)(Phe), 1 H of CH2(2)(Thp));
3.64–3.53 (m, 1 H of CH2(2)(Thp), 1 H of CH2(6)(Thp)); 3.28–3.19 (m, 1 H of CH2(6)(Thp)); 3.16, 3.15
(2s, MeN); 3.09–2.86 (m, CH2(Phe)); 2.27–2.02 (m, CH2(4)(Thp)); 1.27–1.07 (m, CH2(5)(Thp)).
13C-NMR (diastereoisomers): 169.8, 169.5 (2s, 2 CO); 155.8 (s, CO(carbamate)); 144.1, 136.4, 136.3,
136.1 (4s, 3 arom. C); 129.4, 129.2, 128.5, 128.4, 128.1, 128.0, 127.9, 127.7, 127.2, 127.1, 126.8 (11d, 15
arom. CH); 71.6, 71.1 (2t, C(2)(Thp)); 67.8, 67.5, 66.8 (3t, PhCH2O, C(6)(Thp)); 59.4, 59.1 (2s,
C(3)(Thp)); 55.5 (d, C(α)H(Phe)); 40.7 (q, MeN); 37.8, 37.5 (2t, CH2(Phe)); 29.6, 29.1, 20.9, 20.8 (4t,

HETEROCYCLES, Vol. 82, No. 2, 2011
1277
C(4)(Thp), C(5)(Thp)). ESI-MS: 538 (100, [M + Na]+). Anal. Calcd for C30H33N3O5: C, 69.88; H, 6.45; N,
8.15. Found: C, 69.58; H, 6.40; N, 8.02.
As it was not possible to separate the diastereoisomers by means of CC, HPLC separation was undertaken.
For analytical HPLC, a good separation was achieved with CH2Cl2/MeOH 150:1 (tR1 = 62.9 min, tR2 =
85.6 min), whereas for preparative HPLC CH2Cl2/MeOH 100:1 (tR1 = 44.9 min, tR2 = 55.7 min) was
appropriate.
1
Data of the faster eluting diastereoisomer (14’): tR = 44.9 min. H-NMR: 7.38–7.12 (m, 13 arom. H);
7.10–7.02 (m, 2 arom. H); 5.65 (br. s, NH); 5.13–5.03 (m, PhCH2O, NH); 4.13 (d, J = 12.3, 1 H of
CH2(2)(Thp)); 4.00 (br. s, CH(α)(Phe)); 3.65–3.61 (m, 1 H of CH2(2)(Thp), 1 H of CH2(6)(Thp)); 3.26 (t,
J = 3.7, 1 H of CH2(6)(Thp)); 3.16 (s, MeN); 3.08–2.91 (m, CH2(Phe)); 2.16–2.04 (m, CH2(4)(Thp));
1.28–1.23 (m, CH2(5)(Thp)). 13C-NMR: 169.9, 169.6 (2s, 2 CO); 155.7 (s, CO(carbamate)); 144.2, 136.4,
136.2 (3s, 3 arom. C); 129.5, 129.4, 128.6, 128.5, 128.3, 128.0, 127.8, 127.2, 127.0 (9d, 15 arom. CH);
71.2 (t, C(2)(Thp)); 67.7, 67.1 (2t, PhCH2O, CH2(6)(Thp)); 59.3 (s, C(3)(Thp)); 55.7 (d, C(α)H(Phe));
40.9 (q, MeN); 37.7 (t, CH2(Phe)); 30.1, 21.0 (2t, C(4)(Thp), C(5)(Thp)).
1
Data of the slower eluting diastereoisomer (14”): tR = 55.7 min. H-NMR: 7.32–7.16 (m, 13 arom. H);
7.08–7.02 (m, 2 arom. H); 5.85 (br. s, NH); 5.15–5.01 (m, PhCH2O, NH); 4.03 (d-like, C(α)H(Phe), 1 H
2
of CH2(2)(Thp)); 3.65 (d-like (1 H of CH2(6)(Thp)); 3.55 (d, J = 11.4, 1 H of CH2(2)(Thp)); 3.30–3.21
(m, 1 H of CH2(6)(Thp)); 3.17 (s, MeN); 3.09–3.02, 2.94–2.88 (2m, CH2(Phe)); 2.28–2.04 (m,
CH2(4)(Thp)); 1.35–1.17 (m, CH2(5)(Thp)). 13C-NMR: 169.7 (s, 2 CO); 155.9 (s, CO(carbamate)); 144.2,
136.4, 136.2 (3s, 3 arom. C); 129.4, 128.6, 128.5, 128.2, 128.0, 127.8, 127.4, 127.0 (8d, 15 arom. CH);
71.9 (t, C(2)(Thp)); 67.9, 67.0 (2t, PhCH2O, CH2(6)(Thp)); 59.6 (s, C(3)(Thp)); 55.6 (d, C(α)H(Phe));
41.0 (q, MeN); 38.0 (t, CH2(Phe)); 29.2, 21.1 (2t, C(4)(Thp), C(5)(Thp)).
Deprotection
of
dipeptide
(14).
Selective
deprotection
of
the
amino
group:
N-[3-(R,S)-[(N-Methyl-N-phenylamino)carbonyl]tetrahydropyran-3-yl]-2-(S)-amino-3-phenylpropan-
amide (15). To a solution of 14 (100 mg, 0.194 mmol) in MeOH (4 mL) was added Pd (10%)/C and the
suspension was stirred in a H2 atmosphere for 3 h at rt. Then, the mixture was filtered through Celite and
the solvent evaporated. The product consisted of two diastereoisomers in a ratio of ca. 1:1. Colorless
solid; mp 119–121 °C. IR (KBr): 3398m, 3337s, 3058w, 2946m, 2916m, 2846m, 1669vs, 1638vs, 1593s,
1493vs, 1450s, 1370s, 1314m, 1291m, 1275m, 1233w, 1204m, 1177w, 1149w, 1091vs, 1026m, 920w,
864w, 845w, 785m, 758m, 715m, 704s, 667w. ESI-MS: 538 (5), 448 (5), 418 (14), 404 (100, [M+Na]+),
289 (3), 275 (15, [M–C7H8N]+).
The two diastereoisomers of the product (15) were separated by CC (SiO2, CH2Cl2/MeOH =15:1).

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Data of the faster eluting diastereoisomer (15’): Yield: 20 mg (27%). DC: Rf (CH2Cl2/MeOH 15:1) = 0.61.
1H-NMR: 7.43–7.05 (m, 10 arom. H, NH); 4.13 (dd, J = 11.5, 2.4, 1 H of CH2(2)(Thp)); 3.83 (d, J = 11.4,
1 H of CH2(2)(Thp)); 3.70–3.60 (m, 1 H of CH2(6)(Thp)); 3.40–3.31 (m, 1 H of CH2(6)(Thp)); 3.24 (s,
MeN); 3.20–3.15 (m, 1 H of CH2(Phe), C(α)H(Phe)); 2.53–2.44 (m, 1 H of CH2(Phe), 1 H of
13
CH2(4)(Thp)); 2.36–2.26 (m, 1 H of CH2(4)(Thp)); 1.42–1.39 (m, CH2(5)(Thp)). C-NMR: 172.7, 170.0
(2s, 2 CO); 145.0, 137.7 (2s, 2 arom. C); 129.1, 128.6, 127.3, 127.0, 126.7 (5d, 10 arom. CH); 72.8, 68.0
(2t, C(2)(Thp), C(6)(Thp)); 59.1 (s, C(3)(Thp)); 56.5 (d, C(α)H(Phe)); 41.1 (q, MeN); 40.0 (t, CH2(Phe));
28.2, 21.2 (2t, C(4)(Thp), C(5)(Thp)). Anal. Calcd for C22H27N3O3 ⋅ 1/3 H2O: C, 69.21; H, 7.20; N, 10.85.
Found: C, 69.34; H, 6.97; N, 10.31.
Data of the slower eluting diastereoisomer (15”): Yield: 21 mg (28%). DC: Rf (CH2Cl2/MeOH 15:1) =
1
0.47. H-NMR: 7.38–7.16 (m, 10 arom. H, NH); 4.36 (dd, J = 11.6, 2.3, 1 H of CH2(2)(Thp); 3.86–3.79
(m, 1 H of CH2(2)(Thp), 1 H of CH2(6)(Thp)); 3.43–3.25 (m, 1 H of CH2(6)(Thp), C(α)H(Phe), 1 H of
CH2(Phe)); 3.23 (s, MeN); 2.47 (dd-artig, 1 H of CH2(Phe)); 2.31–2.12 (m, CH2(4)(Thp)); 1.62–1.44 (m,
13
CH2(5)(Thp)). C-NMR: 172.6, 170.8 (2s, 2 CO); 145.0, 138.2 (2s, 2 arom. C); 129.1, 129.1, 128.5,
127.3, 127.1, 126.6 (6d, 10 arom. CH); 70.9, 67.6 (2t, C(2)(Thp), C(6)(Thp)); 58.2 (s, C(3)(Thp)); 56.6 (d,
C(α)H(Phe)); 40.9 (q, MeN); 40.1 (t, CH2(Phe)); 30.9, 21.2 (2t, C(4)(Thp), C(5)(Thp)).
Selective deprotection of the carboxyl group: 3-({2-[(Benzyloxycarbonyl)amino]-3-phenylpropanoyl}-
amino)tetrahydropyran-3-carboxylic acid (16). To a solution of 14 (200 mg, 0.388 mmol) in THF (3 mL)
at 0 °C was added 6N HCl in H2O/THF 1:1 (3 mL), and the mixture was stirred at rt for 4 h. Then, the
solvent was evaporated, and CC of the residue (SiO2, CH2Cl2/MeOH/AcOH 100:4:1) yielded 50 mg
(25%) of starting 14 and 96 mg (58%, 78% with regard to consumed 14) 16 as colorless crystals (1:1
mixture of diastereoisomers (1H-NMR)); mp 76–79 °C. IR (KBr): 3306s, 3063s, 3031s, 2956s, 2859s,
2632w, 1715vs, 1670vs, 1582m, 1530vs, 1498vs, 1466s, 1454s, 1384m, 1289s, 1245vs, 1202s, 1152m,
1
1091vs, 1055s, 1039s, 1003w, 937w, 906w, 869w, 846m, 773w, 744s, 698vs, 646w, 608w. H-NMR
(diastereoisomers): 10.72 (broad s, COOH); 7.34–6.92 (m, 10 arom. CH, NH); 5.98, 5.88 (2d, J = 7.2, 7.1,
NH(Phe)); 5.04, 5.03 (2s, PhCH2O); 4.60–4.53 (m, C(α)H(Phe)); 3.91–3.73 (m, CH2(2)(Thp)); 3.66–3.51,
3.38–3.26 (2m, CH2(6)(Thp)); 3.14–2.97 (m, CH2(Phe)); 2.27–2.20, 2.00–1.88 (2m, CH2(4)(Thp));
13
1.44–1.31 (m, CH2(5)(Thp)). C-NMR (diastereoisomers): 176.1, 173.9, 173.8 (3s, 2 CO); 156.2 (s,
CO(carbamate)); 136.3, 136.2, 136.0 (3s, 2 arom. C); 129.4, 129.3, 128.5, 128.4, 128.3, 127.9, 127.8,
126.8 (8d, 10 arom. H); 71.3, 71.2 (2t, C(2)(Thp)); 68.0 (t, PhCH2O); 66.9 (t, C(6)(Thp)); 57.9, 57.8 (2s,
C(3)(Thp)); 38.2, 38.0 (2t, CH2(Phe)); 28.0, 27.6 (2t, C(4)(Thp)); 20.9, 20.7 (2t, C(5)(Thp)). CI-MS
(NH3): 444 (8, [M+NH4]+), 427 (10, [M+H]+), 409 (100, [M–OH]+), 398 (7), 220 (8), 108 (26).
The separation of the diastereoisomers by means of CC was not possible.

HETEROCYCLES, Vol. 82, No. 2, 2011
1279
X-Ray Crystal-Structure Determination of 13 (Figure 1).42 All measurements were made on a Nonius
KappaCCD area-detector diffractometer43 using graphite-monochromated MoK radiation (λ = 0.71073
α
Å) and an Oxford Cryosystems Cryostream 700 cooler. Data collection and refinement parameters are
given below, and a view of the molecule is shown in Figure 1. Data reduction was performed with HKL
Denzo and Scalepack.44 The intensities were corrected for Lorentz and polarization effects, and an
absorption correction based on the multi-scan method45 was applied. Equivalent reflections were merged.
The structure was solved by direct methods using SIR92,46 which revealed the positions of all
non-hydrogen atoms. The non-hydrogen atoms were refined anisotropically. The amide H-atom was
placed in the position indicated by a difference electron density map and its position was allowed to refine
together with an isotropic displacement parameter. All remaining H-atoms were placed in geometrically
calculated positions and refined by using a riding model where each H-atom was assigned a fixed
isotropic displacement parameter with a value equal to 1.2Ueq of its parent atom (1.5Ueq for the methyl
group). The refinement of the structure was carried out on F2 by using full-matrix least-squares
procedures, which minimized the function Σw(Fo2–Fc2)2. A correction for secondary extinction was
applied. Neutral atom scattering factors for non-H-atoms were taken from ref.,47 and the scattering factors
for H-atoms were taken from ref.48 Anomalous dispersion effects were included in F ;49 the values for ƒ’
c
and ƒ” were those of ref.50 The values of the mass attenuation coefficients are those of ref.51 All
calculations were performed using the SHELXL97 program.52 Crystal data for 13: Crystallized from
AcOEt/hexane, C20H22N2O2S, M = 354.47, colorless, prism, crystal dimensions 0.13 × 0.15 × 0.25 mm,
monoclinic, space group P21/n, Z = 4, reflections for cell determination 40559, 2θ range for cell
determination 4–60°, a = 7.6476(1) Å, b = 18.0707(3) Å, c = 13.3764(2) Å, b = 105.9588(7)°, V =
1777.34(5) Å3, DX = 1.325 g⋅cm–3, µ(MoKα) = 0.198 mm–1, T = 160(1) K, φ and ω scans, 2θmax = 60°,
transmission fractors (min; max) 0.770; 0.977, total reflections measured 51740, symmetry independent
reflections 5194, reflections with I > 2σ(I) 3611, reflections used in refinement 5194, parameters refined
232, final R (on F; I > 2σ(I) reflections) = 0.0507, wR (all data) = 0.1397 (w = [σ2(Fo2) + (0.0638P)2 +
0.5508P]–1 where P = (Fo2 + 2Fc2)/3, goodness of fit 1.051, secondary extinction coefficient 0.016(2),
final Δmax/σ = 0.001, Δρ (max; min) = 0.71; –0.33 e Å–3.
ACKNOWLEDGEMENTS
We thank the analytical services of our institute for spectra and analyses and F. Hoffmann-La Roche AG,
Basel, for financial support.
REFERENCES AND NOTES
1.
Diploma thesis of M.L., University of Zürich, 2006.

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2.
3.
4.
B. V. Venkataram Prasad, P. Balaram, and E. Benedetti, CRC Crit. Rev. Biochem., 1984, 16, 307.
A. W. Burgess, Proc. Natl. Acad. Sci. USA, 1994, 91, 2649.
R. Schweitzer-Stenner, W. Gonzales, G. T. Bourne, J. A. Feng, and G. R. Marshall, J. Am. Chem.
Soc., 2007, 129, 13095.
5.
6.
7.
C. Toniolo and F. Formaggio, Wiley Encyclopedia of Chemical Biology, 2009, 3, 606.
L. Whitmore and B. A. Wallace, Nucleic Acid Res., 2004, 32, D593 (Peptaibol Database).
C. Toniolo and H. Brückner (eds.), ‘Peptaibiotics: Fungal Peptides Containing α-Dialkyl α-Amino
Acids’, Wiley-VCH, Weinheim, 2009.
8.
J. K. Chugh and B. A. Wallace, Biochem. Soc. Trans., 2001, 29, 565.
H. Duclohier, Chem. Biodivers., 2007, 4, 1023.
9.
10.
M. Shi, H.-N. Wang, S.-T. Xie, Y. Luo, C.-Y. Sun, X.-L. Chen, and Y.-Z. Zhang, Molecular
Cancer, 2010, 9, 26.
11.
12.
13.
R. Zand and I. Izquierdo, Neurochem. Res., 1980, 5, 1.
A. Avenoza, J. H. Busto, N. Canal, and J. M. Peregrina, J. Org. Chem., 2005, 70, 330.
a) P. Wipf and H. Heimgartner, Helv. Chim. Acta, 1988, 71, 258; b) P. Wipf, R. W. Kunz, and H.
Heimgartner, Helv. Chim. Acta, 1988, 71, 268.
14.
15.
B. Di Blasio, V. Pavone, A. Lombardi, C. Pedone, and E. Benedetti, Biopolymers, 1993, 33, 1037.
a) Y. Morimoto and K. Achiwa, Chem. Pharm. Bull., 1987, 35, 3845; b) R. M. Williams and G. J.
Fegley, Tetrahedron Lett., 1992, 33, 6755.
16.
a) D. M. Walker and E. W. Logusch, Tetrahedron Lett., 1989, 30, 1181; b) K. Lavrador, D.
Guillerm, and G. Guillerm, Bioorg. Med. Chem. Lett., 1988, 8, 1629.
M. Hatanaka and T. Ishimaru, Bull. Chem. Soc. Jpn., 1973, 46, 2515.
a) Y. Takano, M. Oba, M. Tanaka, and H. Suemune, Pept. Sci. 2003, 2004, 40, 137; b) C. L.
Wysong, T. S. Yokum, G. A. Morales, R. L. Gundry, M. L. McLaughlin, and R. P. Hammer, J.
Org. Chem., 1996, 61, 7650; c) A. Schousboe, P. Thorbek, L. Hertz, and P. Krogsgaard-Larsen, J.
Neurochem., 1979, 33, 181.
17.
18.
19.
a) B. Unterhalt and A. Scheppan, Sci. Pharmaceutica, 2001, 69, 271; b) M. M. Federici and F. J.
Lotspeich, Biochem. Pharmacol., 1979, 28, 1689; c) S. K. Bhattacharjee, K. K. Chacko, and R.
Zand, J. Cryst. Mol. Struct., 1976, 5, 403.
20.
21.
22.
A. O. Tosunyan, M. R. Bagdasaryan, V. N. Madakyan, and S. A. Vartanyan, Dokl. Vses. Konf.
Khim. Atsetilena, 1972, 1, 239 (Chem. Abstr., 1973, 79, 115409).
P. Jacobsen, K. Schaumburg, and P. Krogsgaard-Larsen, Acta Chem. Scand., Sect. B, 1980, 834,
319.
H. Heimgartner, Angew. Chem., Int. Ed. Engl., 1991, 30, 238.

HETEROCYCLES, Vol. 82, No. 2, 2011
1281
23.
24.
J. M. Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97, 2243.
a) W. Altherr, A. Linden, and H. Heimgartner, Chem. Biodivers., 2007, 4, 1144; b) S. Stamm and
H. Heimgartner, Tetrahedron, 2006, 62, 9671; c) N. Pradeille, O. Zerbe, K. Moehle, A. Linden,
and H. Heimgartner, Chem. Biodivers., 2005, 2, 1127; d) R. T. N. Luykx, A. Linden, and H.
Heimgartner, Helv. Chim. Acta, 2003, 86, 4093; e) P. Wipf and H. Heimgartner, Helv. Chim. Acta,
1990, 73, 13.
25.
26.
a) I. Dannecker-Dörig, A. Linden, and H. Heimgartner, Coll. Czech. Chem. Commun., 2009, 74,
901; b) T. Jeremic, A. Linden, and H. Heimgartner, J. Pept. Sci., 2008, 14, 1051; c) T. Jeremic, A.
Linden, K. Moehle, and H. Heimgartner, Tetrahedron, 2005, 61, 1871.
a) P. Köttgen, A. Linden, and H. Heimgartner, Z. Naturforsch., 2009, 64b, 689; b) P. Köttgen, A.
Linden, and H. Heimgartner, Helv. Chim. Acta, 2006, 89, 731; c) B. Iliev, A. Linden, R. Kunz, and
H. Heimgartner, Tetrahedron, 2006, 62, 1079; d) K. N. Koch, A. Linden, and H. Heimgartner,
Tetrahedron, 2001, 57, 2311.
27.
a) S. Stamm, A. Linden, and H. Heimgartner, Helv. Chim. Acta, 2003, 86, 1371; b) J. L. Räber, K.
A. Brun, and H. Heimgartner, Heterocycles, 2007, 74, 397.
28.
29.
C. Strässler, A. Linden, and H. Heimgartner, Helv. Chim. Acta, 1997, 80, 1528.
J. M. Villalgordo and H. Heimgartner, Tetrahedron, 1993, 49, 7215.
30. a) K. Szöri, G. Szöllösi, and M. Bartók, New J. Chem., 2008, 32, 1354; b) H. C. Silberman, J. Org.
Chem., 1960, 25, 151; c) G. Dumas and P. Rumpf, Compt. Rend., 1956, 242, 2574; d) R. H. Hall,
Chem. Ind. (London), 1955, 1772.
31.
H. C. Brown, J. V. N. Vara Prassad, and S. H. Lee, J. Org. Chem., 1985, 50, 1582; see also G.
Zweifel and J. Plamondon, J. Org. Chem., 1970, 35, 898.
32.
33.
34.
35.
36.
J. Herscovici and K. Antonakis, J. Chem. Soc., Chem. Commun., 1980, 561.
O. H. Oldenziel and A. M. van Leusen, Tetrahedron Lett., 1973, 16, 1357.
K. Dietliker and H. Heimgartner, Helv. Chim. Acta, 1983, 66, 262.
M. Rens and L. Ghosez, Tetrahedron Lett., 1970, 43, 3765.
As in other cases,27 it was not possible to remove 11 completely. But is is known that the amides
do not take part in reactions of aminoazirines with acids.
37.
38.
C. K. Johnson, ORTEP II, Report ORNL-5138, Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
a) G. Müller, M. Kurz, and H. Kessler, Proteins, Structure, Function and Genetics, 1993, 15, 235;
b) G. D. Rose, L. M. Gierasch, and J. A. Smith, Adv. Protein Chem., 1985, 37, 1.
G. Suter, S. S. Stoykova, A. Linden, and H. Heimgartner, Helv. Chim. Acta, 2000, 83, 2961.
J. Buddrus, H. Herzog, and H. Bauer, Liebigs Ann. Chem. 1983, 1950.
39.
40.

1282
HETEROCYCLES, Vol. 82, No. 2, 2011
41.
42.
E. Müller and H. Huber, Chem. Ber., 1963, 96, 2319.
CCDC-782039 contains the supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
43.
44.
R. Hooft, KappaCCD Collect Software, Nonius BV, Delft, The Netherlands, 1999.
Z. Otwinowski and W. Minor, in ‘Methods in Enzymology’, Vol. 276, ‘Macromolecular
Crystallography’, Part A, ed. by C. W. Carter Jr. and R. M. Sweet, Academic Press: New York
1997, pp. 307–326.
45.
46.
R. H. Blessing, Acta Crystallogr., Sect. A, 1995, 51, 33.
A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, and M.
Camalli, SIR92, J. Appl. Crystallogr., 1994, 27, 435.
47.
E. N. Maslen, A. G. Fox, and M. A. O'Keefe, in ‘International Tables for Crystallography’, ed. by
A. J. C. Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 6.1.1.1, p. 477.
R. F. Stewart, E. R. Davidson, and W. T. Simpson, J. Chem. Phys., 1965, 42, 3175.
J. A. Ibers and W. C. Hamilton, Acta Crystallogr., 1964, 17, 781.
48.
49.
50.
D. C. Creagh and W. J. McAuley, in ‘International Tables for Crystallography’, ed. by A. J.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.6.8, pp. 219–222.
D. C. Creagh and J. H. Hubbell, in ‘International Tables for Crystallography’, ed. by A. J. C.
Wilson, Kluwer Academic Publishers, Dordrecht, 1992, Vol. C, Table 4.2.4.3, pp. 200–206.
G. M. Sheldrick, SHELXL97, Program for the Refinement of Crystal Structures, University of
Göttingen, Germany, 1997.
51.
52.