Synthesis and use of 2H-azirin-3-amines as dipeptide synthons

Article abstract of DOI:10.1002/1522-2675(200203)85:3<885::AID-HLCA885>3.0.CO;2-Z

The synthesis of the new 2H-azirin-3-amines ('3-amino-2H-azirines') 11, 20, 28, and 33 as dipeptide synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding thioamides, and consecutive treatment with COCl₂, 1,4-diazabicyclo[2.2.2]octane (DABCO), and NaN₃ led to the desired products. It is shown that these 2H-azirin-3-amines can conveniently be used as building blocks of the dipeptides Aib-(Me)Axx (Axx=alanine, valine), Aib-Homoproline, and Iva-Pro in the synthesis of several model peptides. However, some limitations apply for the synthesis of such 2H-azirin-3-amines. The starting material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H-azirin-3-amines could not be obtained in all cases from the thioamides prepared.

Full text of DOI:10.1002/1522-2675(200203)85:3<885::AID-HLCA885>3.0.CO;2-Z

Helvetica Chimica Acta Vol. 85 (2002)
885
Synthesis and Use of 2H-Azirin-3-amines as Dipeptide Synthons
by Roland A. Breitenmoser1) and Heinz Heimgartner*
Organisch-chemisches Institut der Universit‰t Z¸rich, Winterthurerstrasse 190, CH-8057 Z¸rich
The synthesis of the new 2H-azirin-3-amines (−3-amino-2H-azirines×) 11, 20, 28, and 33 as dipeptide
synthons is described. The reactions of the starting amides with Lawesson reagent gave the corresponding
thioamides, and consecutive treatment with COCl2, 1,4-diazabicyclo[2.2.2]octane (DABCO), and NaN3 led to
the desired products. It is shown that these 2H-azirin-3-amines can conveniently be used as building blocks of
the dipeptides Aib-(Me)Axx (Axx ˆ alanine, valine), Aib-Homoproline, and Iva-Pro in the synthesis of several
model peptides. However, some limitations apply for the synthesis of such 2H-azirin-3-amines. The starting
material for the azirine synthesis, the corresponding thioamides, cannot generally be synthesized, and the 2H-
azirin-3-amines could not be obtained in all cases from the thioamides prepared.
Introduction. In the last few years, we have shown in extensive studies that 2H-
azirin-3-amines (−3-amino-2H-azirines×) are versatile synthons for a,a-disubstituted
glycines (a,a-disubstituted a-amino acids) in peptide synthesis. One procedure for the
introduction of such amino acids into peptides is the so-called −azirine/oxazolone
method× [1], which was developed as a convenient preparative access to such peptides.
This strategy has been employed in the synthesis of linear oligopeptides [2 8],
endothiopeptides [9 10], cyclic peptides [11 14], and cyclic depsipeptides [14 17]
containing a,a-disubstituted glycines.
Peptides that contain a,a-disubstituted a-amino acids are considerably restricted in
their conformational freedom, i.e., secondary structures such as b-turns, and a- or 310-
helices are stabilized or induced (cf. [18], and refs. cit. therein). Two of these amino
acids, Aib (a-aminoisobutyric acid) and Iva (isovaline), are characteristic members of
the peptaibols, an important family of natural peptide antibiotics that show bactericidal
and hemolytic activity [19][20]. Due to the severe steric hindrance, the synthesis of
related peptides is difficult [21 23].
Some years ago, 2H-azirin-3-amines became available that are enantiomerically
pure, such as the (S)-isovaline (Iva) synthon 1 [24] and the (S)-2-(methyl)phenyl-
alanine (Phe(Me)) synthon 2 [4]. They have been used to synthesize stereochemically
pure peptides. Furthermore, the first three representatives of a novel class of 2H-azirin-
3-amines, namely methyl (S)-N-(2,2-dimethyl-2H-azirin-3-yl)prolinate (3) [25], meth-
yl (S)-N-(1-aza-6-oxaspiro[2.5]oct-1-en-2-yl)prolinate (4) [6], and (2S,4R)-4-(benzyl-
oxy)-N-(2,2-dimethyl-2H-azirin-3-yl)prolinate (5) [8], have been prepared and found
to be suitable as dipeptide synthons for the sequences Aib-Pro, 4-aminotetrahydropyr-
an-4-carboxylic acid-Pro, and Aib-Hyp2). These synthons have been successfully used
1
)
)
Part of the Ph. D. thesis of R. A. B., Universit‰t Z¸rich, 2001.
Hyp ˆ (4S,4R)-4-hydroxyproline.
2

886
Helvetica Chimica Acta Vol. 85 (2002)
in the syntheses of Trichovirin I 1B and I 4A [7], an analogue of the C-terminal
nonapeptide of Trichovirin I 1B [6], and model peptides.
On the basis of these findings, we postulated that further dipeptide synthons for the
sequence −a,a-disubstituted a-amino acid-(homo)proline× or −a,a-disubstituted a-
amino acid-N-methylated amino acid× should be preparatively available [26]. In the
present paper, we describe the attempts to prepare such 2H-azirin-3-amines with the
aim of showing how far this principle can be generalized. Their applicability in peptide
synthesis is demonstrated in the preparation of several model peptides.
Results and Discussion. 1. Synthesis of a Racemic Aib-(Me)Ala Synthon. First of
all, we intended to replace the amino acid proline in the synthon 3 by N-methylated
glycine ((Me)Gly), alanine ((Me)Ala), valine ((Me)Val)3), a,a-dimethyl glycine
((Me)Aib), and phenylalanine ((Me)Phe) with the aim of obtaining 2H-azirin-3-
amines of type A (Scheme 1) as synthons for dipeptides of type B.
Scheme 1
In a first approach (Scheme 2), the synthesis started from methyl/ethyl alaninate
hydrochloride, which was treated with isobutyryl chloride in the presence of Et3N
(Schotten-Baumann conditions) to form methyl/ethyl (S)-N-(2-methylpropanoyl)ala-
ninate (6) in 92/90% yield. N-Methylation with NaH/MeI in the presence of LiClO4
(suppression of O-methylation) [27]4) gave racemized methyl/ethyl (S/R)-N-methyl-
3
)
)
Taken in part from the Diploma thesis of R. A. B., Universit‰t Z¸rich, 1997.
After longer reaction times at 608, the corresponding acid 7 was isolated. A possible mechanism is the
halolyses described by Eschenmoser and co-workers [27].
4

Helvetica Chimica Acta Vol. 85 (2002)
887
N-(2-methylpropanoyl)alaninate (8) in 58/79% yield. Thionation with a Davy reagent
in refluxing toluene led to methyl/ethyl (S/R)-N-methyl-N-[2-(methyl)thiopropanoyl]-
alaninate (9) in 71/70% yield. In analogy to the procedure described in [25][7], the
reactions of 9 in CH2Cl2 with a solution of COCl2 in toluene in the presence of catalytic
amounts of DMF led to the chloroenamines 10. Evaporation of the solvent, dissolution
of the residue in THF, addition of 1,4-diazabicyclo[2.2.2]octane (DABCO), filtration,
and treatment of the solution with NaN3 for 5 h gave methyl/ethyl (S/R)-N-(2,2-
dimethyl-2H-azirin-3-yl)-N-methylalaninate (11) in 39/52% yield.
Scheme 2
Reactions of 11 with PhCOSH and PhCOOH. For the chemical characterization of
the 2H-azirin-3-amines 11, reactions with PhCOSH and PhCOOH were performed in
CH2Cl2 at 08 ! r.t. (Scheme 3). In the case of 11b, the N-benzoyl endothiodipeptide 12c
and N-benzoyl dipeptide 12d were obtained in 56 60% yield after 17 h and
chromatographic workup. When the reactions with 11a were carried out for 1 h, the
yield of the N-benzoyl endothiodipeptide 12a was within the same range. However, the
yield of 12b remained lower (44%), thus indicating the slower coupling reaction with
PhCOOH.
Scheme 3

888
Helvetica Chimica Acta Vol. 85 (2002)
Reactions of 11 with Amino Acids. With the aim of testing the utility of 11 as a
dipeptide synthon, the reactions of the N-protected amino acids 13 (Boc-Trp-OH, Boc-
Val-OH, and Z-Phe-OH, resp.) with 1.0 1.1 equiv. of 11 were carried out in CH2Cl2 or
Et2O at r.t. for 1 22 h (Scheme 4 and Table 1). Chromatographic purification gave the
1
tripeptides 14 in 55 70% yield. However, H-NMR spectra showed the doubling of
some signals (ratio 1:1), i.e., completely racemized 11 had been used.
Scheme 4
Table 1. Synthesis of Tripeptides 14
13
Azirine
P
R'
Tripeptide
Yield [%]
a
b
c
11a
11b
11b
Z
Boc
Boc
PhCH2
Me2CH
Indolyl-CH2
Z-Phe-Aib-(Me)Ala-OEt 5) (14a)
Boc-Val-Aib-(Me)Ala-OMe (14b)
Boc-Trp-Aib-(Me)Ala-OMe (14c)
70
50
55
The racemization must have taken place during the N-methylation. In N-
monosubstituted amino acids, the NH group is more acidic than the a-CH group,
thus protecting the latter against ionization. A free acid group provides the same effect
[28]. In an N,N-disubstituted amino acid ester, none of these effects play a role, and the
a-CH group will be deprotonated more readily.
With the aim of showing the general use of 11 as a dipeptide synthon in peptide
synthesis, 14a5) was selectively deprotected. The Z-protecting group was removed by
catalytic hydrogenation in the presence of Pd/C to yield H-Phe-Aib-(Me)Ala-OEt (15)
in 71% yield. The ethyl ester group of 14a was saponified with LiOH ¥ H2O, yielding
Z-Phe-Aib-(Me)Ala-OH (16) in 67% yield. These N- or C-terminal deprotected
tripeptides can be further used in standard peptide chemistry.
2. GeneralSynthesis of Aib-(Me)Axx Synthons . Treatment of a,a-dimethyl glycine
(Aib) with isobutyryl chloride in the presence of Et3N led to methyl N-(2-
methylpropanoyl)-2,2-dimethylglycinate in 75% yield. The N-methylation (NaH/MeI
in the presence of LiClO4) failed in this case. An analogous case has already been
reported in [29]. Therefore, other methods for the introduction of the N-Me group had
5
)
Z-Phe-Aib-(Me)Ala-OMe (14d) was also prepared in 70% yield.

Helvetica Chimica Acta Vol. 85 (2002)
889
to be found, as N-Me amino acid esters are commercially not readily available. Two
strategies were feasible: 1) Synthesis of N-Me amino acid methyl esters. Various
methods are known, e.g., direct methylation [30], reductive amination [31], prepara-
tion of oxazolidinones, and their subsequent transformation to the N-Me derivatives
[32] (cf. [3], and refs. cit. therein), and the use of immonium ions in Diels-Alder/retro-
Diels-Alder sequences [34]. 2) Esterification of commercially available N-Me amino
acids, which narrows the range of available amino acids but is synthetically more
straightforward and was, therefore, chosen.
As depicted in Scheme 5, the N-methyl-l-amino acids H-(Me)Ala-OMe and H-
(Me)Val-OMe (17a, b) were converted to their methyl esters by treatment with SOCl2
in MeOH. The N-Me amino acid methyl esters of glycine6), alanine, valine6), a,a-
dimethyl glycine7) (Aib), and phenylalanine6) were transformed to the −amides× 18,
which should be converted to the corresponding −thioamides× 19 by treatment with
Lawesson or Davy reagent in refluxing toluene, and further to the 2H-azirin-3-amines
20 by the usual three-step reaction.
Scheme 5
In the case of N-methylalanine (R ˆ Me, R' ˆ H), azirine 20a was obtained in 39%
yield as a 2 :1 mixture of enantiomers8) due to partial racemization during the
6
)
)
)
Commercially available.
For a description of the synthesis, vide infra.
Ratio of the diastereoisomers of Z-Phe-Aib-(Me)Ala-OMe. Rotamers could be excluded on the basis of
EXCY-NMR experiments.
7
8

890
Helvetica Chimica Acta Vol. 85 (2002)
conversion of the amino acid into the methyl ester (for an explanation, vide infra)9)
[35][36].
Starting with methyl sarcosinate (H-Sar-OMe)10), methyl N-methyl-N-(2-methyl-
propanoyl)glycinate (18b), and methyl N-methyl-N-[2-(methyl)thiopropanoyl]glyci-
nate (19b) were obtained in good yields. However, the synthesis of the azirine failed.
Control experiments showed that the reactions with COCl2 and DABCO led to the
chloro-enamine intermediate11). However, after addition of NaN3, only a small
amount of a rapidly decomposing substance was obtained, possibly the expected
azidoenamine (1H-NMR, MS).
Starting with H-(Me)Val-OMe, H-(Me)Aib-OMe, and H-(Me)Phe-OMe
(Scheme 5) 18b, d, and e were obtained in 98, 83, and 86% yield, respectively.
Unfortunately, neither the reaction with Lawesson nor with Davy reagent in refluxing
toluene led to the corresponding −thioamides× of type 19. We assume the steric
hindrance of the side chains to be the main obstacle [37]12). However, when THF
instead of toluene was used for the thionation reaction with Lawesson reagent, methyl
(S)-N-methyl-N-(2-methylthiopropanoyl)valinate (19c) was obtained, albeit in only
27% yield13). According to the standard procedure for azirine synthesis, methyl (S)-N-
(2,2-dimethyl-2H-azirin-3-yl)-N-methylvalinate (20b) was obtained in 46% yield in
optically active form.
Reactions of 20b with Amino Acids and Syntheses of ModelPeptides. With the aim
of testing the usefulness of 20b as a dipeptide synthon, the reactions of Z-Phe-OH
(13a), Fmoc-Val-OH (13d), and Fmoc-Phe-Gly-OH (13e) with 1 equiv. of 20b were
carried out at room temperature (Scheme 6 and Table 2). After stirring overnight, the
expected tri- and tetrapeptides 22 and 23 were obtained in good-to-very-good yields.
The general applicability of the dipeptide synthon 20b in peptide synthesis, was
established by the preparation of the tetrapeptides Fmoc-Val-Aib-(Me)Val-Ala-OMe
(24) and Boc-Ala-Val-Aib-(Me)Val-OMe (25, Scheme 7). Hydrolysis of the methyl
ester 22a with LiOH ¥ H2O led quantitatively to Z-Phe-Aib-(Me)Val-OH, which was
coupled without further purification to H-Ala-OMe ¥ HCl with the coupling reagent O-
(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) in
9
)
It was shown that this azirine is stable for several months at 48. However, when stored for years, the
formation of 1,3,3,6-tetramethylpiperazine-2,5-dione (21) was detected, which can be explained by the
hydrolysis of 20a and subsequent cyclization. It is known that N-Me amino acid containing dipeptides are
prone to cyclize to diketopiperazines [35][36].
10
11
12
)
)
)
Sarˆ N-methylglycine.
Hydrolysis of the intermediate yielded 18b.
We also tried to synthesize the azirines from the −amides× 18 instead of the more reactive −thioamides× 19
with condensed COCl2 according to the procedure of Wipf [37]. Usually, lower yields are to be expected
when using this method, and in the cases of 18d (R ˆ R' ˆ Me) and 18c (R ˆ Me2CH, R' ˆ H) no azirines
could be isolated.
13
)
This method failed for the thionation of 18d.

Helvetica Chimica Acta Vol. 85 (2002)
891
Scheme 6
Table 2. Synthesis of Peptides 22 and 23
13
P
R'
Product
Yield [%]
a
d
e
Z
PhCH2
Me2CH
H
Z-Phe-Aib-(Me)Val-OMe (22a)
Fmoc-Val-Aib-(Me)Val-OMe (22b)
Fmoc-Phe-Gly-Aib-(Me)Val-OMe (23)
8
8
67
3
Fmoc
Fmoc-Phe
3
MeCN in the presence of 1-hydroxybenzotriazole (HOBt) and EtN(i-Pr)2. After
chromatographic workup, the tetrapeptide 24 was obtained in 72% yield. Removal of
the Fmoc group of 22b with Et2NH gave crude H-Val-Aib-(Me)Val-OMe, which was
coupled without further purification to Boc-Ala-OH (TBTU, HOBt, EtN(i-Pr)2).
After chromatographic workup, the tetrapeptide 25 was obtained in 73% yield.
Scheme 7

892
Helvetica Chimica Acta Vol. 85 (2002)
3. Synthesis of an Aib-Homoproline Synthon. As depicted in Scheme 8, (S)-
picoleinic acid14) was converted to methyl (S)-N-(2-methylpropanoyl)homoprolinate
(26), which was then converted by thionation with Lawesson reagent in refluxing
toluene to methyl (S)-N-(2-methylpropanethioyl)homoprolinate (27). Treatment of a
solution of the latter in CH2Cl2 and catalytic amounts of DMF with a solution of COCl2
in toluene, DABCO, and NaN3 led within one day to methyl (S)-N-(2,2-dimethyl-2H-
azirin-3-yl)homoprolinate (28) in 71% yield.
Scheme 8
Reactions of 28 with Amino Acids. The dipeptide synthon 28 was coupled with Z-
Phe-OH (13a), Fmoc-Val-OH (13d), and Boc-Ala-OH (13f), leading to the
corresponding tripeptides 29 in good yields. All reactions were carried out in CH2Cl2
with 1 equiv. of 28 and stirring for 15 24 h at room temperature (Scheme 9 and
Table 3).
Scheme 9
Tripeptide 29c was crystallized from a mixture of CH2Cl2/Et2O/MeOH/hexane and
the structure was established by X-ray crystallography (Fig. 1). The crystals are
enantiomerically pure, however the absolute configuration of the molecule has not
been determined. The enantiomer used in the refinement was based on the known (S)-
configurations at C(2) and C(8)15).
14
)
)
Experiments were also carried out with d/l-picoleinic acid, leading to similar results.
Arbitrary numbering used in Fig. 1.
15

Helvetica Chimica Acta Vol. 85 (2002)
Table 3. Synthesis of Tripeptides 29
893
13
Azirine
P
R'
Tripeptide
Yield [%]
a
d
f
rac-28
28
28
Z
Fmoc
Boc
PhCH2
Me2CH
Me
Z-Phe-Aib-Homoproline-OMe (29a) a)
Fmoc-Val-Aib-Homoproline-OMe (29b)
Boc-Ala-Aib-Homoproline-OMe (29c)
8
91
8
7
3
a) 1 : 1 Mixture of diastereoisomers.
Fig. 1. ORTEP Plot of the molecular structure of 29c (with 50% probability ellipsoids, H-atoms with arbitrary
displacement parameters for clarity; arbitrary numbering of the atoms)
4. Attempted Synthesis of an Aib-Norproline Synthon. As shown in Scheme 10, (S)-
azetidine-2-carboxylic acid was converted to methyl (S)-N-(2-methylpropanoyl)nor-
prolinate, which was thionated with Lawesson reagent in refluxing toluene to give
methyl (S)-N-(2-methylpropanethioyl)norprolinate (30) in 93% yield. Consecutive
treatment of the latter in CH2Cl2 containing catalytic amounts of DMF with COCl2 in
toluene, DABCO, and NaN3 in THF for 2 days did not lead to the expected azirine but
yielded a compound with a molecular formula corresponding to 31 in 67% yield. The
proposed structure of the geminal diazide is in agreement with most of the obtained
spectra (1H-NMR, IR, MS, EA), but not with the 13C-NMR, which, in addition to the
signal for COOMe at 169.5 ppm, shows a second singlet at 159.4 ppm, which could
correspond to C(1') in 31'.
The unexpected formation of the geminal diazide 31 can be explained by the
mechanism depicted in Scheme 11. Treatment of 30 with COCl2 leads to the formation

894
Helvetica Chimica Acta Vol. 85 (2002)
Scheme 10
of chloriminium chloride C. Addition of a second chloride ion gives the geminal
dichloride D, thus revealing the high ring strain of the exocyclic double bond of the
four-membered ring. On treatment with NaN3, the Cl-atoms of D are substituted by N3À
to give 31. The usual reaction pathway via the base-catalyzed deprotonation of C to give
the a-chloroenamine E, which, in the next step, reacts via the ketiminium salt F to give
the a-azidoenamine G and the azirine, can, therefore, not take place.
Scheme 11
5. Synthesis of an Iva-Pro Synthon. Several peptaibols, e.g., emerimicin III and IV
[38][39]16), contain the dipeptide segment Iva-Hyp. Therefore, the corresponding (2H-
azirin-3-yl)prolinate is an attractive building block in the synthesis of analogs of this
class of conformationally restricted, biologically active peptides (cf. [36]). Such a
synthon should be accessible by the methodology described above. The following
synthesis led to a diastereoisomeric mixture17) of the analogous Iva-Pro synthon
(containing (S/R)-Iva [38])18).
16
)
)
)
In the natural emerimicin III and IV, Iva has the (R)-configuration.
The ratio of the diastereoisomers was 58:42 according to HPLC.
The absolute configuration of Iva has only a minimal effect on the solution conformation and the biological
activity [38].
17
18

Helvetica Chimica Acta Vol. 85 (2002)
895
As depicted in Scheme 12, (S)-proline was converted into methyl (S)-N-(2-
methylbutanoyl)prolinate (94% yield) according to the usual protocol. Thionation with
Lawesson reagent in refluxing toluene led to methyl (S)-N-(2-methylbutanethioyl)-
prolinate (32) in 70% yield. Standard reactions with the latter led to methyl (S)-N-(2-
ethyl-2-methyl-2H-azirin-3-yl)prolinate (33, mixture of diastereoisomers) in 50% yield.
Scheme 12
Reaction of 33 with Amino and Peptide Acids. The dipeptide synthon 33 was reacted
with 1 equiv. of Z-Phe-OH (13a), Fmoc-Val-OH (13d), and Fmoc-Phe-Gly-OH (13e),
respectively, at room temperature. After stirring for one night, the expected tri- and
tetrapeptides 34 and 35 were obtained in good-to-very-good yields (Scheme 13 and
Table 4).
Scheme 13
Table 4. Synthesis of Peptides 34 and 35
13
P
R'
Product
Yield [%]
a
b
c
Z
PhCH2
Me2CH
H
Z-Phe-Iva-Pro-OMe (34a)
Fmoc-Val-Iva-Pro-OMe (34b)
Fmoc-Phe-Gly-Iva-Pro-OMe (35)
91
90
99
Fmoc
Fmoc-Phe
Hydrolysis of 34a with LiOH ¥ H2O led quantitatively to Z-Phe-Iva-Pro-OH, which
was coupled without further purification with H-Ala-OMe ¥ HCl (TBTU, HOBt, in
MeCN). After chromatographic workup, the tetrapeptide 36 was obtained in 82%

896
Helvetica Chimica Acta Vol. 85 (2002)
yield. Treatment of 34b with Et2NH led to crude H-Val-Iva-Pro-OMe, which was
coupled with Boc-Ala-OH (TBTU, HOBt, in MeCN). Chromatographic workup gave
the tetrapeptide 37 in 97% yield (Scheme 14).
Scheme 14
The comparison of the yields of the thionation reaction with Lawesson reagent in
the Table 5 reveals the tendency that −amides× that cannot enolize readily are more
reactive towards thionation. Due to the high strain of an exocyclic double bond of a
four-membered ring, this is particularly the case for norproline. On the other hand, for
the azirine synthesis the trend is reversed.
Table 5. Comparison of the Yields of Thionation and Azirine Formation
Norproline
Proline [25]
Homoproline
−Thioamide× [%]
Azirine [%]
93
0
60
52
22
71
In conclusion, we have shown that the 2H-azirin-3-amines 11, 20, 28, and 33 can be
used conveniently as dipeptide synthons for the sequences Aib-(Me)Ala, Aib-
(Me)Val, Aib-Homoproline, and Iva-Pro in the −azirine/oxazolone method×. After
the coupling with amino or peptide acids, which proceeds in good yields, the peptide
chain can be elongated at the N- or C-terminus by standard peptide chemistry.
A serious limitation of the general applicability of the method is the synthesis of the
necessary starting materials, i.e., the corresponding −thioamides×, which was not possible
for all desired cases. However, it can be emphasized that, once these are obtained, the
preparation of the 2H-azirin-3-amines proceeds smoothly.

Helvetica Chimica Acta Vol. 85 (2002)
897
We thank the analytical units of our institute for spectra and analyses, especially Dr. G. Hopp-Rentsch, Ms.
N. Walch, and Mr. S. Jurt for NMR spectra, Dr. L. Bigler and Mr. N. Bild for mass spectra, and Dr. A. Linden for
the crystal-structure determination. Financial support by the Swiss NationalScience Foundation , F. Hoffmann-
La Roche AG, Basel, and the Stiftung f¸r wissenschaftliche Forschung an der Universit‰t Z¸rich is gratefully
acknowledged.
Experimental Part
1. General. Solvents were purified by standard procedures. TLC: Merck 60 F254 SiO2-coated glass plates,
0.25 mm. Column chromatography (CC): Merck 60 230 400 mesh SiO2. M.p.: B¸chi B-540. IR: Perkin-Elmer
1600-FTIR spectrometer, KBr or CHCl3; in cmÀ1. NMR: Bruker ARX-300 spectrometer (1H: 300 MHz, 13C:
75.5 MHz); in CDCl3; chemical shifts d [ppm] refer to residual CHCl3 (7.27 ppm, 1H) and to CDCl3 (77.0 ppm,
13C); J in Hz. MS: Finnigan MAT SSQ-700 (CI) and Finnigan MAT TSQ-700 (ESI) spectrometers; m/z (rel.%).
GeneralProcedure A (GP A). Under cooling with liquid N2, SOCl2 (1 1.1 equiv.) was added to MeOH
keeping the temp. below 58. To this soln., the amino acid (1 equiv.) was added, and the mixture was heated under
reflux for 1 h. Excess MeOH was evaporated.
GeneralProcedure B (GP B). To a soln. of the sticky pale yellow residue of the above experiment (GP A)
or the commercially available amino acid ester in CH2Cl2 and Et3N (3 equiv.), isobutyryl chloride (1 equiv.) was
added at 08. The mixture was stirred at r.t. for several h, the solvent was evaporated, and the residue was
dissolved in Et2O. Then, H2O was added until the precipitated Et3N ¥ HCl dissolved. Extraction with Et2O,
drying (MgSO4), and evaporation of the solvent yielded the −amide×.
GeneralProcedure C (GP C). To a soln. of the −amide× in abs. toluene or abs. toluene/pyridine was added
Lawesson or Davy reagent (synthesis according to the procedure in [40]; 1.0 1.1 equiv.), and the mixture was
heated to 908 reflux temp. for 0.5 22 h. After cooling to r.t. and evaporation, the crude −thioamide× was
purified by CC (SiO2).
GeneralProcedure D (GP D). To a stirred soln. of the −thioamide× in abs. CH2Cl2 and 2 3 drops of DMF,
cooled to 08, was added a soln. of COCl2 (2m in toluene, 3 5 equiv.). The mixture was stirred at 08 ! r.t. for 1 h,
the solvent was evaporated, the residue was dissolved in abs. THF, and 1,4-diazabicyclo[2.2.2]octane (DABCO,
1 equiv.) was added. After stirring for 20 min at r.t., the mixture was filtered under N2, and the residue was
washed with abs. THF. The pale yellow soln. was directly used in the subsequent reaction.
GeneralProcedure E (GP E). To the soln. from the above experiment (GP D) was added NaN3 (3 equiv.),
the mixture was stirred at r.t. for up to several days, filtered though a Celite pad, washed with Et2O, and the
solvent was evaporated. The crude product was purified by CC (SiO2).
GeneralProcedure F (GP F). To a soln. of N-protected amino acid or peptide acid in the given solvent was
added the 2H-azirin-3-amine (1.0 1.1 equiv.), and the mixture was stirred at r.t. After completion of the
reaction (TLC), the soln. was concentrated in vacuo, and the residue was purified by CC (SiO2).
GeneralProcedure G (GP G). To a soln. of terminal-C- and terminal-N-protected peptide in THF/MeOH/
H2O 3 :1:1, LiOH ¥ H2O (3 equiv.) was added. The mixture was stirred until completion of the reaction (TLC),
transferred to a separatory funnel, diluted with 5% KHSO4 soln., and extracted with CH2Cl2 (3Â). The
combined org. phase was dried (MgSO4) and concentrated in vacuo.
GeneralProcedure H (GP H). To a soln. of N-protected amino acid or N-protected peptide, EtN(i-Pr)2 or
Et3N (3 equiv.), and O-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU,
1.05 equiv.) in MeCN was added 1.1 equiv. of amino acid ester or peptide ester. The mixture was stirred at
r.t., until the starting material was completely consumed (TLC). Then, the soln. was concentrated in vacuo and
the crude product purified by CC (SiO2).
2. Synthesis of Ethyl( R/S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (11a). 2.1. Ethyl( S)-N-(2-
Methylpropanoyl)alaninate (6a). According to the GP B, with ethyl (S)-alaninate hydrochloride (19.91 g,
129.61 mmol) in abs. CH2Cl2 (800 ml), Et3N (54.2 ml, 388.84 mmol), and isobutyryl chloride (13.45 ml,
129.61 mmol); reaction time: 1 h. Evaporation yielded 21.80 g (90%) of 6a. Colorless solid. M.p. 45 478. IR
(KBr): 3305s, 3080m, 2966s, 2934s, 2874w, 2799w, 1728s, 1643s, 1548s, 1469s, 1387m, 1373s, 1340s, 1256s, 1226s,
1116s, 1099s, 1054m, 1020w, 933m, 8 79w, 759w. 1H-NMR: 5.98(br. s, NH); 4.60 4.55 (m, CH(a)(Ala)); 4.20 (q,
J ˆ 7.1, MeCH2O); 2.38( sept., J ˆ 7.0, Me2CH); 1.40 (d, J ˆ 7.2, Me(Ala)); 1.28( t, J ˆ 7.1, MeCH2O); 1.17 (d, J ˆ
7.0, Me2CH). 13C-NMR: 176.4, 173.4 (2s, 2 CO); 61.5 (t, MeCH2O); 47.9 (d, CH(a)(Ala)); 35.5 (d, Me2CH);
‡¥
19.5, 19.4 (2q, Me2CH); 18.6 (q, Me(Ala)); 14.0 (q, MeCH2O). EI-MS: 187 (8, M ), 116 (9), 114 (48), 71 (17),
70 (6), 44 (100), 43 (32). Anal. calc. for C9H17NO3 (187.23): C 57.74, H 9.15, N 7.48; found: C 58.30, H 9.15, N
7.40.

898
Helvetica Chimica Acta Vol. 85 (2002)
2.2. Ethyl( R/S)-N-Methyl-N-(2-methylpropanoyl)alaninate (8a). To a soln. of 6a (8.63 g, 46.08 mmol) and
LiClO4 (5.39 g, 50.69 mmol) in abs. THF (400 ml) was added NaH (2.21 g, 55.29 mmol, washed with hexane) at
08. The mixture was stirred for 30 min, then MeI (4.31 ml, 69.12 mmol) was added at 08. After stirring for 3 h at
r.t. and 2 h at 408, the mixture was poured onto ice and extracted with CH2Cl2. The org. phase was washed with
brine and dried (MgSO4) to yield 8.56 g (92%) of crude 8a. CC (Et2O/hexane 1:1) gave 6.49 g (70%) of 8a as a
colorless oil, as well as 0.9 g (10%) of 6a. Yield calc. regarding consumed 6a: 79%. IR (neat): 2980s, 2940s,
2870m, 1740s, 1650s, 1470s, 1410s, 1390m, 1370m, 1310s, 1280s, 1210s, 1180s, 1090s, 1040m, 930w, 8 90w, 8 60w,
750w. 1H-NMR: 5.22 (q, J ˆ 7.3, CH(a)(Ala)); 4.21 4.11 (m, MeCH2O); 2.98( s, MeN); 2.85 2.79 (m,
Me2CH); 1.38( d, J ˆ 7.3, Me(Ala)); 1.25 (t, J ˆ 7.1, MeCH2O); 1.15, 1.13 (2d, J ˆ 4.4, Me2CH). 13C-NMR: 177.3,
172.1 (2s, 2 CO); 61.0 (t, MeCH2O); 52.2 (d, CH(a)(Ala)); 31.4 (q, MeN); 30.5 (d, Me2CH); 19.0 (q, Me2CH);
‡
14.4 (q, Me(Ala)); 14.2 (q, MeCH2O). CI-MS: 203 (10), 202 (100, [M ‡ H] ), 125 (5). Anal. calc. for
C10H19NO3 ¥ 0.1 H2O (203.06): C 59.15, H 9.53, N 6.90; found: C 59.22, H 9.45, N 7.08.
2.3. Ethyl( R/S)-N-Methyl-N-(2-methylpropanethioyl)alaninate (9a). According to the GP C, with 8a
(4.25 g, 21.12 mmol) in abs. toluene/pyridine 1:1 (150 ml) and Davy reagent [41] (4.61 g, 10.56 mmol); reaction
time: 17 h, temp. 1008. The residue was dissolved in Et2O and washed twice with 1n aq. HCl soln., 1n aq. NaOH
soln., and 1n aq. HCl soln. Drying (MgSO4), evaporation, and CC (Et2O/hexane 3 :1) yielded 2.27 g (50%) of
9a as a yellow oil, as well as 1.22 g (29%) of 8a. Yield calc. regarding consumed material: 70%. IR (neat): 2980s,
2940m, 1740s, 1480s, 1440s, 1410s, 1380m, 1280s, 1210s, 1140m, 1110s 1090s, 1010s, 98 0w, 8 60w. 1H-NMR: 6.65 (q,
J ˆ 7.2, CH(a)(Ala)); 4.25 4.15 (m, MeCH2O); 3.20 (s, MeN); 3.23-3.14 (m, Me2CH); 1.48( d, J ˆ 7.3,
Me(Ala)); 1.35 1.24 (m, MeCH2O, Me2CH). 13C-NMR: 213.2 (s, CS); 170.7 (s, CO); 61.4 (t, MeCH2O); 59.4 (d,
CH(a)(Ala)); 37.0 (d, Me2CH); 34.7 (q, MeN); 22.9, 22.8(2 q, Me2CH); 14.2 (q, Me(Ala)); 14.0 (q, MeCH2O).
‡
CI-MS: 219 (8), 218 (78, [ M ‡ H] ), 187 (10), 186 (100).
2.4. Ethyl( R/S)-N-(1-Chloro-2-methylprop-1-enyl)-N-methylalaninate (10a). According to the GP D, with
9a (1.13 g, 5.20 mmol) in abs. CH2Cl2 (15 ml), 2 drops of DMF, 2n COCl2 soln. (3.25 ml, 6.5 mmol), abs. THF
(15 ml), and DABCO (0.59 g, 5.20 mmol).
2.5. Ethyl( R/S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (11a). According to the GP E, with
NaN3 (1.01 g, 15.60 mmol); reaction time: 5 h. The residue was dissolved in AcOEt, washed with sat. aq.
NaHCO3 soln. and brine. Drying (MgSO4), evaporation, and CC (AcOEt) yielded 0.54 g (52%) of 11a as an oil,
as well as 0.32 g (28%) of 8a. IR (neat): 1980m, 1940m, 1770s (azirine CˆN), 1740s, 1640w, 1470m, 1450m,
1370m, 1300m, 1200s, 1100s, 1020m, 8 60w. 1H-NMR: 4.20 (q, J ˆ 7.1, MeCH2O); 4.05 (br. s, CH(a)(Ala)); 3.00 (s,
MeN); 1.52 (d, J ˆ 7.4, Me(Ala)); 1.34, 1.33 (2s, Me2C); 1.27 (t, J ˆ 7.1, MeCH2O). 13C-NMR: 171.5 (s, CO); 61.4
(t, MeCH2O); 59.2 (d, CH(a)(Ala)); 33.1 (q, MeN); 25.2 (q, Me2C); 15.6 (q, Me(Ala)); 14.2 (q, MeCH2O). The
‡
signals for C(2') and C(3') could not be localized. CI-MS (NH3): 200 (11), 199 (100, [M ‡ H] ), 172 (4). Anal.
calc. for C10H18N2O2 ¥ 0.33 H2O (204.27): C 58.80, H 9.24, N 13.71; found: C 58.86, H 9.09, N 13.77.
3. Reactions of 11a with PhCOSH, PhCOOH, and Z-Phe-OH. 3.1. Ethyl( R/S)-N-[2-(Benzoylamino)-2-
methylpropanethioyl]-N-methylalaninate (12a). According to the GP F, with PhCOSH (0.12 ml, 1.05 mmol) in
abs. Et2O (5 ml), 11a (230 mg, 1.16 mmol) in abs. Et2O (5 ml); reaction time: 1 h. CC (hexane/AcOEt 2 :1)
yielded 0.21 g (60%) of 12a. Colorless oil, which solidified under h.v. IR (CHCl3): 3240w, 3000s, 1730s, 1650s,
1580w, 1510s, 1480s, 1380s, 1300m, 1230m, 1100s, 1090s, 1040w, 1020w, 8 8 0w. 1H-NMR: 8.50 (br. s, NH); 7.8 4 (d,
J ˆ 7.5, 2 arom. H); 7.50 7.32 (m, 3 arom. H); 6.48 5.52 ( m, CH(a)(Ala)); 4.25 4.07 (m, MeCH2O); 3.34 (s,
MeN); 1.93, 1.91 (2s, 2 Me(Aib)); 1.52 (d, J ˆ 7.1, Me(Ala)); 1.25 (t, J ˆ 7.1, MeCH2O). 13C-NMR: 208.8 (s, CS);
172.5, 160.1 (2s, 2 CO); 133.7 (s, 1 arom. C); 131.3, 128.4, 126.9 (3d, 5 arom. C); 63.1 (s, C(a)(Aib)); 61.4 (t,
MeCH2O); 52.2 (d, CH(a)(Ala)); 30.5 (q, MeN); 27.4 (q, 2 Me(Aib)); 19.0 (q, Me(Ala)); 14.1 (q, MeCH2O).
‡
CI-MS (NH3): 337 (2, [M ‡ H] ), 322 (24), 293 (5), 292 (16), 291 (100), 204 (5), 202 (26), 188 (27), 145 (6), 130
(12). Anal. calc. for C17H24N2O3S ¥ 0.25 H2O (340.94): C 59.89, H 7.24, N 8.21; found: C 59.85, H 7.06, N 8.06.
3.2. Ethyl( R/S)-N- [2-(Benzoylamino)-2-methylpropanethioyl]-N-methylalaninate (12b). According to the
GP F, with PhCOOH (32 mg, 0.26 mmol) in abs. CH2Cl2 (4 ml), 11a (57 mg, 0.29 mmol) in abs. CH2Cl2 (4 ml);
reaction time: 1 h. CC (hexane/AcOEt 2 :1) yielded 30 mg (44%) of 12b. Colorless oil, which solidified under
h.v. IR (KBr): 3300s, 3000s, 1760s, 1650s, 1620s, 1580m, 1530s, 1490s, 1400s, 1300s, 1220s, 1120s, 1090s, 1030m,
1020w, 940w, 8 70w, 8 00w, 78 0w, 750m, 720s, 700s. 1H-NMR: 7.80 (d, J ˆ 6.7, 2 arom. H); 7.55 (br. s, NH); 7.49
7.39 (m, 3 arom. H); 5.29 (q, J ˆ 7.1, CH(a)(Ala)); 4.20 4.11 (m, MeCH2O); 3.08(br. s, MeN); 1.80 (s,
2 Me(Aib)); 1.44 (d, J ˆ 7.2, Me(Ala)); 1.25 (t, J ˆ 7.1, MeCH2O). 13C-NMR: 173.6, 171.9, 165.6 (3s, 3 CO); 134.8
(s, 1 arom. C); 131.3, 128.4, 126.8 (3d, 5 arom. C); 61.2 (t, MeCH2O); 57.5 (s, C(a)(Aib)); 55.5 (d, CH(a)(Ala));
‡
30.4 (q, MeN); 24.5 (q, 2 Me(Aib)); 19.0 (q, Me(Ala)); 14.2 (q, MeCH2O). ESI-MS: 343 ([M ‡ Na] ). Anal.
calc. for C17H24N2O4 ¥ 0.33 H2O (326.40): C 62.56, H 7.62, N 8.58; found: C 62.50, H 7.65, N 8.45.

Helvetica Chimica Acta Vol. 85 (2002)
899
3.3. Ethyl N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-dimethylglycyl-(R/S)-N-methylalaninate (Z-Phe-
Aib-(Me)Ala-OEt; 14a). According to the GP F, with Z-Phe-OH (13a, 0.43 g, 1.42 mmol) in Et2O (5 ml),
11a (310 mg, 0.56 mmol) in Et2O (5 ml); reaction time: 1 h. CC (hexane/AcOEt 1:1) gave 500 mg (70%) of 14a.
Colorless foam. 1H-NMR (epimers): 7.34 7.18( m, 10 arom. H); 6.82, 5.33 (2br. s, 2 NH); 5.08(br. s,
PhCH2(Z)); 4.90 (q, J ˆ 7.0, CH(a)(Ala)); 4.36 (t, J ˆ 6.8, CH(a)(Phe)); 4.17 4.12 (m, MeCH2O); 3.11 3.03
(m, CH2(Phe)); 2.86, 2.83 (2s, 1:1, MeN); 1.48, 1.47 (2s, 2 Me(Aib)); 1.36 (d, J ˆ 7.2, Me(Ala)); 1.24 (t, J ˆ 7.0,
MeCH2O). 13C-NMR (epimers): 173.6, 172.4, 170.0 (3s, 3 CO); 156.2 (s, CO(carbamate)); 136.6, 136.3 (2s,
2 arom. C); 129.4, 128.5, 128.1, 127.8, 126.8 (5d, 10 arom. C); 66.8( t, PhCH2(Z)); 60.5 (t, MeCH2O); 56.8( s,
C(a)(Aib)); 56.4, 55.2 (2d, CH(a)(Ala), CH(a)(Phe)); 38.2 (t, CH2(Phe)); 32.7, 31.8(2 q, MeN); 25.5, 25.2, 24.6
‡
(3q, 2 Me(Aib), MeCH2O); 14.1 (q, Me(Ala)). CI-MS: 498(19, [ M ‡ H] ), 453 (27), 452 (100), 344 (31), 132
(22).
3.4. Deprotection. 3.4.1. Ethyl( S)-Phenylalanyl-dimethylglycyl-(R/S)-N-methylalaninate (H-Phe-Aib-
(Me)Ala-OEt; 15). To a soln. of 14a (162 mg, 0.34 mmol) in MeOH (10 ml) was added Pd/C, and the resulting
mixture was stirred under H2 for 14 h at r.t. Filtration through a Celite pad, evaporation of the filtrate, and CC
(AcOEt/MeOH 20 :1) yielded 83 mg (71%) of 15. Yellow oil. IR (CHCl3): 3320w, 3000s, 1730s, 1680s, 1630s,
1500s, 1470s, 1450s, 1400s, 1380m, 1300m, 1220s, 1090s, 1040w, 1020w, 910w. 1H-NMR (epimers): 7.99 (br. s, NH);
7.32 7.21 (m, 5 arom. H); 5.05 4.98( m, CH(a)(Ala)); 4.20 4.11 (m, MeCH2O); 3.38( t, J ˆ 7.1, CH(a)(Phe));
2.98(br. s, MeN); 2.83 (s, NH2); 2.38 2.31, 2.08 2.02 (2 m, CH2(Phe)); 1.60 (s, 2 Me(Aib)); 1.35 (d, J ˆ 7.1,
‡
‡
Me(Ala)); 1.25 (t, J ˆ 7.1, MeCH2). CI-MS: 727 (64, [2M ‡ H] ), 365 (20), 364 (100, [M ‡ H] ), 233 (6), 132
(38), 100 (10).
3.4.2. N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-dimethylglycyl-(R/S)-N-methylalanine (Z-Phe-Aib-
(Me)Ala-OH; 16). According to the GP G, with 14a (288 mg, 0.58 mmol) in THF/MeOH/H2O (3 :1 :1),
LiOH ¥ H2O (97 mg, 2.32 mmol). Reaction time: 20 h. Evaporation led to 236 mg (87%) of crude Z-Phe-Aib-
(Me)Ala-OH. CC (AcOEt with a gradient to AcOEt/MeOH 20 :1) gave 183 mg (67%) of 16. Colorless foam.
IR (CHCl3): 3430w, 3340w, 2980s, 1740s, 1720s, 1690s, 1680s, 1630s, 1500s, 1390s, 1370s, 1160s, 1090s, 1040w,
1020w, 920w, 8 70w. 1H-NMR (epimers): 7.78(br. s, OH); 7.37 7.21 (m, 10 arom. H); 6.88 (br. s, NH); 6.10 6.03
(br. d, J ˆ 8.4, NH)); 5.04 (br. s, PhCH2(Z)); 4.67 (s, CH(a)(Ala)); 4.43 (t, J ˆ 7.2, CH(a)(Phe)); 3.08 2.98( m,
‡
CH2(Phe)); 2.78, 2.74 (2s, ratio 1:1, MeN); 1.58 1.31 ( m, Me(Ala), 2 Me(Aib)). CI-MS: 470 (3, [M ‡ H] ),
435 (15), 434 (60), 368(21), 367 (100), 300 (18), 174 (13), 108(9), 104 (67).
4. Synthesis of Methyl( R/S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (11b). 4.1. Methyl( S)-N-
(2-Methylpropanoyl)alaninate (6b). According to the GP B, with methyl (S)-alaninate hydrochloride (24.76 g,
177.39 mmol) in abs. CH2Cl2 (800 ml), Et3N (74.2 ml, 532.17 mmol), and isobutyryl chloride (18.4 ml,
177.39 mmol); reaction time: 1 h. Evaporation yielded 28.24 g (92%) of 6b. Colorless solid. M.p. 53 558. IR
(KBr): 3280s, 3080m, 3000s, 2960s, 1740s, 1640s, 1550s, 1440s, 1370s, 1330s, 1260s, 1220s, 1120s, 1090m, 1050m,
1
990w, 930w, 700m. H-NMR: 6.07 (br. s, NH); 4.62 4.57 (m, CH(a)(Ala)); 3.75 (s, MeO); 2.40 (sept., J ˆ 6.9,
Me2CH); 1.40 (d, J ˆ 7.2, Me(Ala)); 1.16 (d, J ˆ 6.9, Me2CH). 13C-NMR: 176.5, 173.8(2 s, 2 CO); 52.4 (q, MeO);
47.8( d, CH(a)(Ala)); 35.4 (d, Me2CH); 19.5, 19.4 (2q, Me2CH); 18.5 (q, Me(Ala)). CI-MS: 364 (13, [2M ‡
‡
‡
‡
NH4] ), 347 (9, [2M ‡ H] ), 277 (7), 192 (8), 191 (100), 174 (34, [M ‡ H] ).
4.2. Methyl( R/S)-N-Methyl-N-(2-methylpropanoyl)alaninate (8b). To a soln. of 6b (9.20 g, 53.15 mmol)
and LiClO4 (6.24 g, 58.46 mmol) in abs. THF (400 ml) was added NaH (2.55 g, 63.78 mmol, washed with hexane)
at 08. The mixture was stirred for 30 min, then MeI (5.00 ml, 79.72 mmol) was added at 08. After stirring for 3 h
at r.t. and 2 h at 408, the mixture was poured onto ice and extracted with CH2Cl2. The org. phases were washed
with brine and dried (MgSO4) to yield 7.46 g (75%) of crude 8b. CC (Et2O/hexane 1:1) gave 5.78g (58%) of 8b.
Colorless oil. IR (neat): 2980s, 1740s, 1640s, 1460m, 1410m, 1310m, 1270m, 1210s, 1170m, 1090s, 98 0w, 750w.
1H-NMR: 5.20 (q, J ˆ 7.4, CH(a)(Ala)); 3.70 (s, MeO); 3.00 (s, MeN); 2.89 2.80 (m, Me2CH); 1.39 (d, J ˆ 7.4,
Me(Ala)); 1.17 (d, J ˆ 7.0, Me2CH). 13C-NMR: 177.3, 173.7 (2s, 2 CO); 52.1 (q, MeO); 52.0 (d, CH(a)(Ala));
‡
31.5 (q, MeN); 30.1 (d, Me2CH); 19.1, 19.0 (2q, Me2CH); 14.5 (q, Me(Ala)). CI-MS: 375 (11, [2M ‡ H] ), 245
‡
(6), 189 (10), 188 (100, [M ‡ H] ). Anal. calc. for C9H17NO3 ¥ 0.5 H2O (189.04): C 57.18, H 9.17, N 7.41; found: C
57.20, H 9.08, N 7.50.
4.3. (R/S)-N-Methyl-N-(2-methylpropanoyl)alanine (7). When the same mixture as described above was
heated to 608 for longer reaction times, the acid 7 could also be isolated from the reaction mixture. IR (KBr):
2976s, 2943s, 2881s, 2594m, 1730s, 1635s, 1485s, 1460m, 1420m, 1368w, 1351w, 1305m, 1284m, 1207s, 1180s,
1126m, 1097s, 1015w, 938m, 8 15w, 774w, 752m, 727w. 1H-NMR (conformers): 10.3 (br. s, OH); 5.17, 4.68(2 q, J ˆ
7.3, CH(a)(Ala)); 3.02, 2.86 (2s, MeN); 2.88 2.79 (m, Me2CH); 1.49, 1.42 (2d, J ˆ 7.3, Me(Ala)); 1.14, 1.13 (2d,
J ˆ 6.7, Me2CH). 13C-NMR (conformers): 178.1, 175.8 (2s, 2 CO); 54.7, 52.5 (2d, CH(a)(Ala)); 31.6 (q, MeN);

900
Helvetica Chimica Acta Vol. 85 (2002)
30.3 (d, Me2CH); 18.8, 18.7 (2q, Me2CH); 15.6, 14.1 (2q, Me(Ala)). ESI-MS: 423 (30), 401 (30), 369 (15, [2M ‡
‡
‡
‡
Na] ), 196 (100, [M ‡ Na] ), 174 (15, [M ‡ H] ).
4.4. Methyl( R/S)-N-Methyl-N-(2-methylpropanethioyl)alaninate (9b). According to the GP C, with 8b
(4.38g, 23.39 mmol) in abs. toluene/pyridine 1:1 (120 ml) and Davy reagent [41] (6.13 g, 14.04 mmol); reaction
time: 22 h, temp. 1008. The residue was dissolved in Et2O and washed twice with 1n aq. HCl soln., 1n aq. NaOH
soln., and 1n aq. HCl soln. Drying (MgSO4), evaporation, and CC (Et2O/hexane 3 :1) yielded 3.37 g (71%) of
9b. Yellow oil. IR (neat): 2960s, 1740s, 1480s, 1450s, 1405s, 1380s, 1360m, 1270s, 1210s, 1140m, 1110s, 1090s, 1010s,
900w, 8 60w, 8 10w, 78 0w. 1H-NMR: 6.68( q, J ˆ 7.2, CH(a)(Ala)); 3.74 (s, MeO); 3.20 (s, MeN); 3.23 3.14 (m,
Me2CH); 1.48( d, J ˆ 7.2, Me(Ala)); 1.28 1.23 ( m, Me2CH). 13C-NMR: 213.3 (s, CS); 171.3 (s, CO); 59.2 (d,
CH(a)(Ala)); 52.7 (q, MeO); 36.9 (d, Me2CH); 34.6 (q, MeN); 22.6, 22.9 (2q, Me2CH); 14.0 (q, Me(Ala)). CI-
‡
MS: 205 (11), 204 (100, [M ‡ H] ), 172 (43), 170 (15). Anal. calc. for C9H17NO2S ¥ 0.1 H2O (205.09): C 52.71, H
8.45, N 6.83, S 15.63; found: C 52.73, H 7.90, N 6.95, S 15.62.
4.5. Methyl( R/S)-N-(1-Chloro-2-methylprop-1-enyl)-N-methylalaninate (10b). According to the GP D,
with 9b (2.98g, 14.66 mmol) in abs. CH 2Cl2 (50 ml), 3 drops of DMF, 2n COCl2 soln. (9.2 ml, 18.33 mmol), abs.
THF (40 ml) and DABCO (1.65 g, 14.66 mmol).
4.6. Methyl( R/S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (11b). According to the GP E, with
NaN3 (2.86 g, 43.98 mmol); reaction time: 5 h. The residue was dissolved in AcOEt, washed with a sat. aq.
NaHCO3 soln. and brine. Drying (MgSO4), evaporation, and CC (AcOEt) yielded 1.03 g (39%) of 11b. Pale
yellow oil. B.p. 908/0.30 mbar. IR (neat): 2980m, 2940m, 1765s (azirine CˆN), 1745s, 1645s, 1450m, 1370m,
1300m, 1210s, 1100m, 98 0w, 920w, 730m. 1H-NMR: 4.05 (br. s, CH(a)(Ala)); 3.70 (s, MeO); 2.96 (s, MeN); 1.48
(d, J ˆ 7.3, Me(Ala)); 1.29, 1.28(2 s, Me2C). 13C-NMR: 171.8( s, CO); 58 .8 d(, CH(a)(Ala)); 52.2 (q, MeO); 33.2
(q, MeN); 25.0 (q, Me2C); 19.6 (q, Me(Ala)). The signals for C(2') and C(3') could not be assigned. CI-MS: 369
‡
‡
(24, [2M ‡ H] ), 281 (17), 186 (10), 185 (100, [M ‡ H] ), 158(11).
5. Reactions of 11b with PhCOSH, PhCOOH and Amino Acids. 5.1. Methyl( R/S)-N-[2-(Benzoylamino)-2-
methylpropanethioyl]-N-methylalaninate (12c). According to the GP F, with PhCOSH (38mg, 0.31 mmol) in
abs. CH2Cl2 (2 ml), 11b (63 mg, 0.34 mmol) in abs. CH2Cl2 (2 ml); reaction time: 17 h. CC (hexane/AcOEt 4 :1)
yielded 62 mg (60%) of 12c. Colorless oil, which solidified under h.v. IR (KBr): 3340s, 3060m, 3000m, 2920m,
1740s, 1640s, 1580m, 1540s, 1470s, 1380s, 1340s, 1310s, 1220s, 1180s, 1110s, 1090s, 1040s, 8 70m, 720m. 1H-NMR:
8.50 (br. s, NH); 7.8 8 7.8 4m(, 2 arom. H); 7.52 7.40 (m, 3 arom. H); 6.35 5.60 (m, CH(a)(Ala)); 3.73 (s,
MeO); 3.35 (s, MeN); 1.96, 1.93 (2s, 2 Me(Aib)); 1.56 (d, J ˆ 7.1, Me(Ala)). 1H-NMR ((D6)DMSO, 373 K): 8.29
(br. s, NH); 7.88 7.81 (m, 2 arom. H); 7.53 7.41 (m, 3 arom. H); 6.12 (q, J ˆ 7.0, CH(a)(Ala)); 3.62 (s, MeO);
3.25 (s, MeN); 1.79, 1.78(2 s, 2 Me(Aib)); 1.39 (d, J ˆ 7.1, Me(Ala)). 13C-NMR ((D6)DMSO, 373 K): 207.6 (s,
CS); 169.7, 164.5 (2s, 2 CO); 134.4 (s, 1 arom. C); 130.1, 127.3, 126.5 (3d, 5 arom. C); 60.8( d, CH(a)(Ala)); 60.5
(s, C(a)(Aib)); 51.0 (q, MeO); 37.7 (q, MeN); 29.0, 28.5 (2q, 2 Me(Aib)); 13.4 (q, Me(Ala)). CI-MS (NH3): 324
‡
(8), 323 (43, [M ‡ H] ), 320 (6), 293 (5), 292 (17), 291 (100), 237 (6), 204 (5), 188 (7).
5.2. Ethyl( R/S)-N-[2-(Benzoylamino)-2-methylpropanoyl]-N-methylalaninate (12d). According to the GP
F, with PhCOOH (40.6 mg, 0.294 mmol) in abs. CH2Cl2 (2 ml), 11b (60 mg, 0.32 mmol) in abs. CH2Cl2 (2 ml);
reaction time: 17 h. CC (hexane/AcOEt 2 :1) yielded 58mg (56%) of 12d. Colorless oil, which solidified under
h.v. IR (CHCl3): 3360w, 3000s, 1790w, 1740s, 1660s, 1620s, 1580m, 1510s, 1480s, 1400s, 1280m, 1230s, 1090s, 1040w,
1020w, 1000w, 910m, 8 8 w0. 1H-NMR: 7.81 7.77 (m, 2 arom. H); 7.54 (br. s, NH); 7.52 7.38( m, 3 arom. H);
5.06 4.98( m, CH(a)(Ala)); 3.70 (s, MeO); 3.08(br. s, MeN); 1.77 (s, 2 Me(Aib)); 1.44 (d, J ˆ 7.2, Me(Ala)).
13C-NMR: 173.4, 172.1, 165.6 (3s, 3 CO); 134.7 (s, 1 arom. C); 131.4, 129.9, 126.8(3 d, 5 arom. C); 57.3 (s,
C(a)(Aib)); 55.3 (d, CH(a)(Ala)); 52.2 (q, MeO); 30.4 (q, MeN); 24.7, 24.4 (2q, 2 Me(Aib)); 14.1 (q, Me(Ala)).
‡
‡
CI-MS (NH3): 630 (12, [2M ‡ NH4] ), 425 (23), 424 (100), 324 (6, [M ‡ NH4] ), 289 (21). Anal. calc. for
C16H22N2O4 ¥ 0.1 H2O (308.16): C 62.36, H 7.26, N 9.09; found: C 62.18, H 7.02, N 8.98.
5.3. Methyl N-[(tert-Butoxy)carbonyl]-(S)-valyl-dimethylglycyl-(R/S)-N-methylalaninate (Boc-Val-Aib-
(Me)Ala-OMe; 14b). According to the GP F, with Boc-Val-OH (13b; 60 mg, 0.28mmol) in CH 2Cl2 (2 ml), 11b
(51.6 mg, 0.28mmol) in CH 2Cl2 (2 ml); reaction time: 12 h. CC (AcOEt) gave 54 mg (50%) of 14b. Colorless
foam. IR (CHCl3): 3420m, 3300m, 3000s, 1730s, 1720s, 1500s, 1450s, 1400s, 1320s, 1200s, 1080s, 1040s, 910m.
1H-NMR (epimers): 7.06 (br. s, NH); 5.21, 5.18(2 s, NH); 5.05, 4.94 (2s, CH(a)(Ala)); 3.85 3.75 (m,
CH(a)(Val)); 3.71, 3.70 (2s, MeO); 3.00 (br. s, MeN); 2.17 2.03 (m, CH(b)(Val)); 1.62, 1.60 (2s, 2 Me(Aib));
1.43, 1.42 (2s, Me3C); 1.41, 1.40 (2d, J ˆ 7.3, Me(Ala)); 1.00 0.89 (m, 2 Me(Val)). 13C-NMR (epimers): 174.6,
172.8, 172.0, 170.2 (4s, 3 CO); 155.9 (s, CO(carbamate)); 79.9 (s, Me3C); 60.1 (d, CH(a)(Val)); 57.0 (s,
C(a)(Aib)); 55.2 (d, CH(a)(Ala)); 52.1 (q, MeO); 32.9 (q, MeN); 31.0, 30.5 (2d, CH(b)(Val)); 28.2 (q, Me3C);
‡
24.7 (q, 2 Me(Aib)); 19.2, 17.9 (2q, 2 Me(Val)); 14.1 (q, Me(Ala)). CI-MS (NH3): 419 (7, [M ‡ NH4] ), 403 (21),

Helvetica Chimica Acta Vol. 85 (2002)
901
‡
402 (100, [M ‡ H] ), 285 (17), 118 (24). Anal. calc. for C19H35N3O6 (401.50): C 56.84, H 8.79, N 10.47; found: C
56.93, H 8.82, N 10.44.
5.4. Methyl N-[(tert-Butoxy)carbonyl]-(S)-tryptyl-dimethylglycyl-(R/S)-N-methylalaninate (Boc-Trp-Aib-
(Me)Ala-OMe; 14c). According to the GP F, with Boc-Trp-OH (13c, 87 mg, 0.286 mmol) in CH2Cl2 (2 ml), 11b
(58mg, 0.315 mmol) in CH 2Cl2 (2 ml); reaction time: 22 h. CC (AcOEt) and (AcOEt/hexane 1:1) gave 76.9 mg
(55%) of 14c. Colorless foam. IR (KBr): 3320s, 2980m, 1740s, 1720s, 1670s, 1640s, 1500s, 1390s, 1360s, 1240s,
1160s, 1090s, 1020m, 920w, 8 50s, 740m. 1H-NMR: 8.43 (br. s, NH); 7.68 (d, J ˆ 7.7, C(4) of Trp); 7.38( d, J ˆ 7.7,
C(7) of Trp); 6.52 (br. s, NH); 7.21 7.07 (m, 3 arom. H); 5.13 (br. s, NH); 4.97 4.88 (m, CH(a)(Ala)); 4.41 (q,
J ˆ 5.8, CH(a)(Trp)); 3.68( s, MeO); 3.34 3.13 (m, CH2(Trp)); 2.87, 2.84 (2s, MeN, epimers); 1.42 (s, t-Bu);
1.41 1.33 (m, 2 Me(Aib), Me(Ala)). 13C-NMR: 172.7, 170.5 (2s, 3 CO); 155.7 (s, CO(carbamate)); 136.4, 127.3
(2s, 2 arom. C); 123.9, 122.1, 119.6, 118.6, 111.5 (5d, 5 arom. C); 109.9 (s, 1 arom. C); 80.2 (s, Me3C); 56.8( s,
C(a)(Aib)); 55.2 (d, CH(a)(Ala)); 54.8( d, CH(a)(Trp)); 52.2 (q, MeO); 32.8( q, MeN); 28.3 (q, Me3C); 27.9 (t,
‡
‡
CH2(Trp)); 25.2 (q, 2 Me(Aib)); 14.2 (q, Me(Ala)). ESI-MS: 527 (20, [M ‡ K] ), 511 (100, [M ‡ Na] ), 489
(30), 372 (40), 316 (20). Anal. calc. for C25H36N4O6 ¥ 1 H2O (506.60): C 59.27, H 7.56, N 11.06; found: C 59.14, H
7.34, N 10.70.
6. Attempted Synthesis of Methyl N-(2,2-Dimethyl-2H-azirin-3-yl)-2,2,N-trimethylglycinate. 6.1. Methyl N-
(2-Methylpropanoyl)-2,2-dimethylglycinate. According to the GP B, with Aib-OMe (998mg, 8.8mmol) in abs.
CH2Cl2 (40 ml), Et3N (2.12 ml, 29.4 mmol) and isobutyryl chloride (0.76 ml, 7.2 mmol); reaction time: 1.5 h,
temp. r.t. ! 358. Evaporation yielded 1.37 g (75%) of methyl N-(2-methylpropanoyl)-2,2-dimethylglycinate.
Colorless oil which solidified under h.v. IR (KBr): 3327s, 3186w, 2986m, 2952m, 2876w, 1741s, 1649s, 1539s,
1469s, 1438m, 1387m, 1364m, 1285s, 1244s, 1195s, 1150s, 1097m, 1024m, 1003m, 98 0w, 946w, 934w, 904w, 8 59w,
814w, 760w. 1H-NMR: 5.99 (br. s, NH); 3.73 (s, MeO); 2.33 (sept., J ˆ 6.9, Me2CH); 1.54 (s, 2 Me(Aib)); 1.13 (d,
J ˆ 6.9, Me2CH). 13C-NMR: 176.2, 175.2, 169.5 (3s, 3 CO); 56.1 (s, C(a)(Aib)); 52.5 (q, MeO); 35.5 (d,
‡
Me2CH); 24.7 (q, 2 Me(Aib)); 19.3 (q, Me2CH). CI-MS: 375 (7, [2M ‡ H] ), 305 (37), 245 (19), 189 (9), 188
‡
(100, [M ‡ H] ). Anal. calc. for C9H17NO3 ¥ 0.1 H2O (189.04): C 57.18, H 9.18, N 7.41; found: C 57.24, H 9.10, N
7.40.
6.2. Attempted N-Methylation. To a soln. of methyl N-(2-methylpropanoyl)-2,2-dimethylglycinate (367 mg,
1.96 mmol) and LiClO4 (230 mg, 2.16 mmol) in abs. THF/DMF 10 :1 (10 ml) was added NaH (282 mg,
5.88 mmol; washed with hexane) at 08. The mixture was stirred for 30 min, then MeI (0.98ml, 15.7 mmol) was
added at 08. After stirring for 3 h at 308 and 18h at 60 819), the mixture was poured onto ice and extracted with
CH2Cl2. The org. phase was washed with brine and dried (MgSO4) to yield 349 mg (95%) of the starting
material; no N-methyl derivative was detected.
7. Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (20a). 7.1. Methyl( S)-N-
methylalaninate. According to the GP A, with SOCl2 (1.19 ml, 16.30 mmol), MeOH (8.5 ml), and H-(Me)Ala-
OH (1.68g, 16.13 mmol). Yield: quant. Colorless oil. IR (CDCl 3): 2977s, 2702s, 2456m, 1753s, 1570m, 1459m,
1439m, 1386w, 1347w, 1308w, 1248s, 1106m, 1072w, 1045w, 1014w, 977w, 8 76w. 1H-NMR (D2O): 4.32 (q, J ˆ 7.3,
CH(a)(Ala)); 4.03 (s, MeO); 2.93 (s, MeN); 1.36 (d, J ˆ 7.3, Me(Ala)). 13C-NMR: 170.5 (s, CO); 56.2 (d,
‡
CH(a)(Ala)); 53.5 (q, MeO); 30.7 (q, MeN); 13.3 (q, Me(Ala). ESI-MS: 118([ M ‡ H] ).
7.2. Methyl( S)-N-Methyl-N-(2-methylpropanoyl)alaninate (18a). According to the GP B, with H-(Me)Ala-
OMe (0.56 g, 5.43 mmol) in abs. CH2Cl2 (50 ml), Et3N (2.28ml, 16.31 mmol), and isobutyryl chloride (0.56 ml,
5.38mmol); reaction time: 2 h at 30 8. Evaporation and CC (hexane/AcOEt 2 :1) yielded 1.50 g (49%) of 18a.
Colorless oil. The spectroscopic data are identical with those of racemic 8b (vide supra 4.2).
7.3. Methyl( S)-N-Methyl-N-(2-methylpropanethioyl)alaninate (19a). The thionation was carried out as
described in Sect. 4.4. The spectroscopic data are identical with those of 9b (vide supra 4.4).
7.4. Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylalaninate (20a). The reaction was carried out as
described in Sect. 4.6. The spectroscopic data are identical with those of racemic 11b (vide supra 4.6).
7.5. 1,3,3,6-Tetramethylpiperazine-2,5-dione (21). When 20a was stored for 3 years at 48, the whole amount
had cyclized to 21. IR (KBr): 3204m, 3064m, 2989m, 2930m, 1679s, 1651s, 1521m, 1463s, 1406s, 1372m, 1316m,
1224s, 1199s, 1119m, 1040m, 998w, 8 8 5w, 8 47m, 767m, 701w. 1H-NMR: 7.49 (br. s, NH); 3.93 (q, J ˆ 7.0, MeCH);
2.98( s, MeN); 1.55 (d, J ˆ 7.0, MeCH); 1.51, 1.50 (2s, Me2C). 13C-NMR: 169.2, 168.5 (2s, 2 CO); 58.1 (d, MeCH);
‡
55.9 (s, Me2C); 32.4 (q, MeN); 29.9, 28.0 (2q, Me2C); 18.4 (q, MeCH). CI-MS: 188 (100, [M ‡ NH4] ), 171 (85,
‡
[M ‡ H] ). Anal. calc. for C8H14N2O2 (170.21): C 56.45, H 8.29, N 16.46; found: C 56.18, H 8.31, N 16.31.
19
)
A number of similar reactions with different temp., reaction times, and ratio of reagents were also carried
out. In none of the experiments was the desired product obtained.

902
Helvetica Chimica Acta Vol. 85 (2002)
7.6. Reaction of 20a with Z-Phe-OH: Methyl N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-dimethylglycyl-
(S)-N-methylalaninate (Z-Phe-Aib-(Me)Ala-OMe; 14d). According to the GP F, with Z-Phe-OH (110 mg,
0.367 mmol) in CH2Cl2 (2 ml), 20a (76 mg, 0.413 mmol) in CH2Cl2 (2 ml); reaction time: 17 h. CC (hexane/
AcOEt 1:1) gave 124 mg (70%) of 14d. Colorless foam. IR (KBr): 3300s, 3000m, 2940m, 1750s, 1660s, 1630s,
1530s, 1450s, 1400s, 1290s, 1240s, 1090s, 910w, 8 30w, 740m, 700s. 1H-NMR (epimers): 7.42 7.21 (m, 10 arom. H);
6.72, 5.31 (2 br. s, 2 NH); 5.09 (br. s, PhCH2(Z)); 4.91 (q, J ˆ 7.2, CH(a)(Ala)); 4.35 (t, J ˆ 6.9, CH(a)(Phe));
3.96 (s, MeO); 3.08 2.98( m, CH2(Phe)); 2.86, 2.83 (2s, 2 :1, MeN); 1.50, 1.46 (2s, 2 Me(Aib)); 1.36 (d, J ˆ 7.2,
Me(Ala)). 13C-NMR (epimers): 172.5, 172.0, 169.2 (3s, 3 CO); 155.9 (s, CO(carbamate)); 136.3, 136.0 (2s,
2 arom. C); 129.3, 128.5, 128.4, 128.0, 127.9, 126.9 (6d, 10 arom. C); 66.9 (t, PhCH2(Z)); 57.0 (s, C(a)(Aib)); 56.3,
55.0, 54.9 (3d, CH(a)(Phe), CH(a)(Me)Ala)); 52.0 (q, MeO); 38.2 (t, CH2(Phe)); 32.6 (q, MeN); 24.9, 24.7,
‡
‡
‡
24.3 (3q, 2 Me(Aib)); 14.1 (q, Me(Ala)). ESI-MS: 522 ([M ‡ K] ), 506 ([M ‡ Na] ), 484 ([M ‡ H] ), 452
‡
‡
([M À MeO] ), 367 ([M À N(Me)CH(Me)CO2Me] ), 285. Anal. calc. for C26H33N3O6 ¥ 0.33 H2O (489.57): C
63.79, H 6.93, N 8.58; found: C 63.89, H 6.72, N 8.48.
8. Attempted Synthesis of Methyl N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methyl-glycinate. 8.1. Methyl N-
Methyl-N-(2-methylpropanoyl)glycinate (18b). According to the GP B, with methyl sarcosinate hydrochloride
(20.03 g, 143.5 mmol) in abs. CH2Cl2 (700 ml), Et3N (80 ml, 574 mmol), and isobutyryl chloride (14.9 ml,
143.5 mmol); reaction time: 40 min at r.t. and 1.25 h under reflux). Evaporation yielded 18.24 g (77%) of 18b.
Colorless oil. Purity (GC): > 96%. B.p. 1008/0.15 mbar. IR (neat): 3486w, 2972s, 2875m, 1751s, 1651s, 1480s,
1403s, 1364s, 1335s, 1280s, 1210s, 1120s, 1091s, 1011m, 98 3m, 941m, 8 90w, 8 43w, 754m, 705m. 1H-NMR: 4.12 (s,
CH2(Gly)); 3.73 (s, MeO); 3.13 (s, MeN); 2.87 (sept., J ˆ 6.8, Me2CH); 1.15 (d, J ˆ 6.8, Me2CH). 13C-NMR:
177.8, 170.0 (2s, 2 CO); 52.0 (q, MeO); 49.5 (t, CH2(Gly)); 36.4 (q, MeN); 30.2 (d, Me2CH); 19.0 (q, Me2CH).
‡
‡¥
EI-MS: 174 (97, [M ‡ H] ), 173 (43, M ), 142 (16), 114 (71), 104 (59), 102 (97), 86 (18), 84 (28), 72(14), 71
(100), 58(68). Anal. calc. for C 8H15NO3 ¥ 0.25 H2O (177.71): C 54.07, H 8.79, N 7.88; found: C 53.90, H 8.59, N
7.58.
8.2. Methyl N-Methyl-N-(2-methylpropanethioyl)glycinate (19b). According to the GP C, with 18b (18.06 g,
104.27 mmol) in abs. toluene (200 ml) and Lawesson reagent (21.10 g, 52.13 mmol); reaction time: 1.5 h, temp.
908. Then, another 0.1 equiv. of Lawesson reagent was added; reaction time: 1.5 h, temp. 908. The residue was
dissolved in Et2O and washed twice with 1n aq. HCl soln., H2O, sat. aq. NaHCO3 soln., and once with brine.
Drying (MgSO4), evaporation, and CC (Et2O) yielded 17.62 g (89%) of 19b. Yellow oil. Purity (GC): > 97%.
IR (neat): 3479w, 2968s, 2098w, 1748s, 1652w, 1597m, 1494s, 1393s, 1360s, 1336s, 1294s, 1210s, 1090s, 995s, 933w,
914w, 8 90w, 8 73m, 8 40w, 8 04w, 718m. 1H-NMR: 4.78( s, CH2(Gly)); 3.75 (s, MeO); 3.42 (s, MeN); 3.21 (sept., J ˆ
6.6, Me2CH); 1.24 (d, J ˆ 6.6, Me2CH). 13C-NMR: 213.4 (s, CS); 168.1 (s, CO); 57.0 (t, CH2(Gly)); 52.1 (q,
‡
MeO); 40.3 (q, MeN); 36.7 (d, Me2CH); 22.7 (q, Me2CH). CI-MS: 192 (5), 191 (10), 190 (100, [M ‡ H] ), 189
‡¥
(7, M ), 156 (15). Anal. calc. for C8H15NO2S (189.27): C 50.77, H 7.99, N 7.40; found: C 50.97, H 7.73, N 7.27.
8.3. Methyl N-(1-Azido-2-methylprop-1-enyl)-N-methylglycinate. According to the GP D, with 19b (1.59 g,
8.40 mmol) in abs. CH2Cl2 (20 ml), 2 drops of DMF, 2n COCl2 soln. (5 ml, 10 mmol), abs. THF (20 ml), and
DABCO (0.94 g, 8.40 mmol). The crude methyl N-(1-chloro-2-methylprop-1-enyl)-N-methylglycinate was
treated with NaN3 (2.18g, 33.6 mmol) according to GP E; reaction time: 20 h. The residue was dissolved in
AcOEt, washed with a sat. aq. NaHCO3 soln. and brine. Drying (MgSO4), evaporation, and CC (AcOEt, 2%
Et2N) yielded 20 mg (1.2%) of an oil that possibly is the azido-enamine. 1H-NMR: 3.99 (br. s, CH2(Gly)); 3.76 (s,
MeO); 3.07 (s, MeN); 1.351, 1.349 (2s, Me2C). 13C-NMR: 168.9 (s, CO); 123.0, 116.7 (2s, C(1'), C(2')); 52.1 (q,
MeO); 49.4 (t, CH2(Gly)); 40.8( q, MeN); 24.7 (q, Me2C). CI-MS: 224 (13), 223 (100), 172 (6), 171 (69, [M ‡
‡
H] ), 144 (7).
9. Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylvalinate (20b). 9.1. Methyl( S)-N-
Methyl-N-(2-methylpropanoyl)valinate (18c). According to the GP B, with (Me)Val-OMe ¥ HCl (3.19 g,
17.60 mmol) in abs. CH2Cl2 (80 ml), Et3N (7.34 ml, 52.70 mmol), and isobutyryl chloride (2.01 ml, 19.40 mmol);
reaction time: 7 h at 408. Evaporation yielded 3.72 g (98%) of 18c. Colorless oil. B.p. 808/0.15 mbar. IR (neat):
3980s, 1740s, 1640s, 1470s, 1400s, 1370m, 1270s, 1200s, 1170m, 1130m, 1080s, 1010m, 930w, 750w. 1H-NMR: 5.13
(d, J ˆ 10.5, CH(a)(Val)); 3.88 (s, MeO); 3.21 (s, MeN); 3.11-3.01 (m, Me2CH); 2.44 2.37 (m, CH(b)(Val));
1.32 (d, J ˆ 6.6, Me2CH); 1.19, 1.04 (2d, J ˆ 6.6, 2 Me(Val)). 13C-NMR (conformers): 177.6, 171.8(2 s, 2 CO); 61.1
(d, CH(a)(Val)); 51.5 (q, MeO); 31.1 (q, MeN); 30.5 (d, Me2CH); 27.3 (d, CH(b)(Val)); 19.7, 19.6, 19.5, 19.2,
‡¥
18.9, 18.6 (6q, Me2CH, 2 Me(Val)). GC-MS: 215 (M ), 200, 184, 172, 168, 156, 144, 130, 115, 112, 102, 86, 71, 55.
Anal. calc. for C11H21N3O3 ¥ 0.2 H2O (215.29): C 60.36, H 9.85, N 6.40; found: C 60.29, H 9.63, N 6.31.
9.2. Methyl( S)-N-Methyl-N-(2-methylpropanethioyl)valinate (19c). According to the GP C, with 18c
(1531 mg, 7.12 mmol) in abs. THF (40 ml) and Lawesson reagent (1582 mg, 3.91 mmol); reaction time: 23 h,
temp. 608. Drying (MgSO4), evaporation, and two consecutive CC (CH2Cl2/hexane 1:2, AcOEt/hexane 1:4)

Helvetica Chimica Acta Vol. 85 (2002)
903
yielded 304 mg (18%) of 19c and 474 mg (31%) of 18c. Yield calc. with respect to consumed material: 27%.
Yellow oil. IR (neat): 3462w, 2968s, 2923s, 2876s, 1739s, 1648w, 1596w, 1472s, 1407s, 1359s, 1263s, 1207s, 1133s,
1075m, 1015s, 919m, 8 70m, 795w. 1H-NMR (conformers): 6.47 (d, J ˆ 10.2, CH(a)(Val)); 3.76, 3.73 (2s, MeO);
3.35, 3.26 (2s, MeN); 3.32 3.15 (m, Me2CH); 2.39 2.31 (m, CH(b)(Val)); 1.29 1.23 (m, Me2CH); 1.10, 1.05
(2d, J ˆ 6.8Me(Val)); 0.91, 0.88(2 d, J ˆ 6.8, Me(Val)). 13C-NMR (conformers): 214.6, 213.6 (2s, CS); 170.7,
169.1 (2s, CO); 68.3, 67.9 (2d, CH(a)(Val)); 52.4, 51.9 (2q, MeO); 37.1, 36.6 (2d, Me2CH); 34.7 (q, MeN); 28.7,
‡
28.5 (2d, CH(b)(Val)); 23.5, 23.0 (2q, Me2CH); 19.6, 18.7 (2q, 2 Me(Val)). CI-MS: 232 ([M ‡ H] ).
9.3. Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-methylvalinate (20b). According to the GP D, with 19c
(428mg, 1.85 mmol) in abs. CH 2Cl2 (10 ml), 3 drops of DMF, 2n COCl2 soln. (1.40 ml, 2.78mmol), abs. THF
(20 ml), and DABCO (207 mg, 1.85 mmol). The crude methyl (S)-N-(1-chloro-2-methylprop-1-enyl)-N-
methylvalinate was treated with NaN3 (361 mg, 5.55 mmol) according to the GP E; reaction time: 18h.
Evaporation and CC (AcOEt/hexane 1:1) yielded 179 mg (46%) of 20c. Pale yellow oil. IR (neat): 3465w,
2969s, 2877s, 1761s, 1742s, 1653m, 1468s, 1437m, 1391m, 1370s, 1294s, 1262s, 1199s, 1129s, 1088s, 1012s, 927m,
835w, 733m. 1H-NMR: 3.72 (s, MeO); 3.34 (br. s, CH(a)(Val)); 3.00 (s, MeN); 2.29 (br. s, CH(b)(Val)); 1.355,
1.350 (2s, Me2C); 0.97, 0.94 (2d, J ˆ 6.7, 2 Me(Val)). 13C-NMR: 170.6 (s, CO); 168.8 (s, C(3')); 70.5 (d,
CH(a)(Val)); 51.7 (q, MeO); 40.8( s, C(2')); 31.7 (q, MeN); 27.2 (d, CH(b)(Val)); 24.9 (q, Me2C); 19.2, 18.9 (2q,
‡
2 Me(Val)). CI-MS: 214 (15), 213 (100, [M ‡ H] ). Anal. calc. for C11H20N2O2 ¥ 0.33 H2O (218.30): C 60.52, H
9.54, N 12.83; found: C 60.68, H 9.25, N 12.70.
10. Reactions of 20b with Amino Acids and Syntheses of ModelPeptides . 10.1. Methyl N-[(Benzyloxy)-
carbonyl]-(S)-phenylalanyl-dimethylglycyl-(S)-N-methylvalinate (Z-Phe-Aib-(Me)Val-OMe; 22a). According
to the GP F, with Z-Phe-OH (49 mg, 0.165 mmol) in MeCN (5 ml), 20b (35 mg, 0.165 mmol); reaction time:
19 h. CC (hexane/AcOEt 2 :3) gave 70 mg (83%) of 22a. Colorless foam. IR (KBr): 3307s, 3063m, 3032m, 2964s,
2876m, 1736s, 1670s, 1623s, 1539s, 1498s, 1455s, 1395s, 1365m, 1290s, 1238s, 1211s, 1132m, 1084s, 1017s, 912w,
847w, 776w, 744m, 699s. 1H-NMR: 7.36 7.16 (m, 10 arom. H); 6.75 (br. s, NH); 5.42 (d, J ˆ 8.1, NH); 5.06 (br. s,
PhCH2(Z)); 4.70 (d, J ˆ 9.9, CH(a)((Me)Val)); 4.48 4.33 ( m, CH(a)(Phe)); 3.67 (s, MeO); 3.05 2.99 (m,
CH2(Phe)); 2.93 (s, MeN); 2.19 2.11 (m, CH(b)((Me)Val)); 1.49, 1.43 (2s, 2 Me(Aib)); 0.99, 0.82 (2d, J ˆ 6.7,
2 Me((Me)Val)). 13C-NMR: 173.2, 171.5, 168.9 (3s, 3 CO); 155.8( s, CO(carbamate)); 136.3, 136.1 (2s, 2 arom.
C); 129.3, 128.6, 128.4, 128.1, 127.9, 126.9 (6d, 10 arom. C); 66.9 (t, PhCH2(Z)); 63.8( d, CH(a)((Me)Val)); 57.2
(s, C(a)(Aib)); 56.3 (d, CH(a)(Phe)); 51.6 (q, MeO); 38.4 (t, CH2(Phe)); 32.4 (q, MeN); 27.1 (d,
‡
CH(b)((Me)Val)); 24.8, 24.3 (2q, 2 Me(Aib)); 19.9, 18.8 (2q, 2 Me((Me)Val)). ESI-MS: 534 ([M ‡ Na] ).
Anal. calc. for C28H36N3O6 (511.62): C 65.73, H 7.29, N 8.21; found: C 65.91, H 7.44, N 8.26.
10.2. Methyl N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-dimethylglycyl-(S)-N-methylvalyl-alaninate (Z-
Phe-Aib-(Me)Val-Ala-OMe; 24). According to the GP G, with 22a (59 mg, 0.115 mmol) in THF/MeOH/H2O
(3 :1:1, 5 ml), LiOH ¥ H2O (15 mg, 0.347 mmol); reaction time: 3 h. Evaporation led to 58mg (quant.) crude Z-
Phe-Aib-(Me)Val-OH. According to the GP H, with crude Z-Phe-Aib-(Me)Val-OH (58mg, 0.115 mmol),
EtN(i-Pr)2 (0.06 ml, 0.348mmol), TBTU (39 mg, 0.122 mmol), HOBt (20 mg, 0.116 mmol), and H-Ala-OMe
(18mg, 0.128mmol) in MeCN (5 ml); reaction time: 42 h. CC (AcOEt/hexane 1:1) gave 48mg (72%) of 24.
Highly viscous oil. IR (neat): 3308s, 3064s, 2966s, 2611m, 1733s, 1660s, 1543s, 1455s, 1399s, 1298s, 1235s, 1084s,
1049m, 1028s, 98 4m, 917m, 8 48w, 8 24w, 775m, 770s, 700s. 1H-NMR: 7.44 7.15 (m, 10 arom. H); 7.03 (br. s, NH);
6.77 (br. s, NH); 5.52 (d, J ˆ 8.2, NH); 5.20 4.97 (m, PhCH2(Z)); 4.70 (d, J ˆ 10.2, CH(a)((Me)Val)); 4.49
4.35 (m, CH(a)(Phe), CH(a)(Ala)); 3.67 (s, MeO); 3.08 2.96 ( m, CH2(Phe)); 2.92 (s, MeN); 2.19 2.13 (m,
CH(b)((Me)Val)); 1.70 (d, J ˆ 5.8, Me(Ala)); 1.49, 1.44 (2s, 2 Me(Aib)); 0.98, 0.82 (2d, J ˆ 6.8, 2 Me-
((Me)Val)). 13C-NMR: 173.1, 171.5, 169.1, 168.5 (4s, 4 CO); 156.3 (s, CO(carbamate)); 136.2, 136.1 (2s, 2 arom.
C); 129.3, 128.7, 128.6, 128.1, 126.9, 126.4 (6d, 10 arom. C); 71.3 (d, CH(a)((Me)Val)); 66.9 (t, PhCH2(Z)); 63.9
(d, CH(a)(Ala)); 57.3 (s, C(a)(Aib)); 56.4 (d, CH(a)(Phe)); 51.6 (q, MeO); 38.4 (t, CH2(Phe)); 32.4 (q, MeN);
32.4 (d, CH(b)((Me)Val)); 27.2, 27.1 (2q, 2 Me(Aib)); 19.9, 18.8 (2q, 2 Me((Me)Val)), 17.5 (q, Me(Ala)). ESI-
‡
MS: 605 ([M ‡ Na] ), 534.
10.3. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-valyl-dimethylglycyl-(S)-N-methylvalinate
(Fmoc-Val-Aib-(Me)Val-OMe; 22b). According to the GP F, with Fmoc-Val-OH (61 mg, 0.179 mmol) in
MeCN (5 ml), 20b (38 mg, 0.179 mmol); reaction time: 22 h. CC (hexane/AcOEt 1:1) gave 80 mg (83%) of
22b. Colorless foam. IR (KBr): 3349s, 3321s, 3066w, 2967m, 2875w, 1734s, 1719s, 1686s, 1616s, 1539s, 1490m,
1470m, 1450m, 1395m, 1336m, 1316m, 1275m, 1236s, 1218s, 1183m, 1100m, 1023m, 960w, 901w, 778w, 775m,
735m. 1H-NMR: 7.75 7.25 (m, 8arom. H); 7.14 (br. s, NH); 5.46 (d, J ˆ 9.3, NH); 4.75 (d, J ˆ 9.2,
CH(a)((Me)Val)); 4.39 4.35 (m, CH2(Fmoc)); 4.19 (t, J ˆ 6.9, CH(Fmoc)); 3.94 (br. s, CH(a)(Val)); 3.67 (s,
MeO); 3.01 (s, MeN); 2.22 2.08( m, CH(b)(Val), CH(b)((Me)Val)); 1.65, 1.59 (2s, 2 Me(Aib)); 0.94 0.75 (m,
2 Me(Val), 2 Me((Me)Val)). 13C-NMR: 172.6, 170.6, 168.5 (3s, 3 CO); 155.4 (s, CO(carbamate)); 142.8, 140.3

904
Helvetica Chimica Acta Vol. 85 (2002)
(2s, 4 arom. C); 126.7, 126.0, 124.0, 119.0 (4d, 8arom. C); 66.0 ( t, CH2(Fmoc)); 63.0, 59.4 (2d, CH(a)(Val),
CH(a)((Me)Val)); 56.5 (s, C(a)(Aib)); 50.8( q, MeO); 46.2 (d, CH(Fmoc)); 31.6 (q, MeN); 30.2, 26.2 (2d,
CH(b)(Val), CH(b)((Me)Val)); 23.9, 23.4 (2q, 2 Me(Aib)); 19.0, 18.2, 17.9, 16.8 (4q, 2 Me(Val), 2 Me((Me)-
‡
Val)). ESI-MS: 574 ([M ‡ Na] ). Anal. calc. for C30H39N3O6 ¥ 0.33 H2O (557.70): C 66.76, H 7.53, N 7.54; found:
C 66.65, H 7.63, N 7.61.
10.4. Methyl N-[(tert-Butoxy)carbonyl]-(S)-alanyl-(S)-valyl-dimethylglycyl-(S)-N-methylvalinate (Boc-
Ala-Val-Aib-(Me)Val-OMe; 25). A soln. of 22b (71 mg, 0.129 mmol) in Et2NH/CH2Cl2 1:1 (2 ml) was stirred
for 5 h at r.t. Evaporation led to crude H-Val-Aib-(Me)Val-OMe which was treated according to the GP H, with
EtN(i-Pr)2 (0.07 ml, 0.387 mmol), TBTU (43 mg, 0.135 mmol), Boc-Ala-OH (27 mg, 0.142 mmol), and MeCN
(5 ml); reaction time: 21 h. CC (AcOEt/hexane 1 :1) gave 47 mg (73%) of 25. Colorless foam. IR (KBr): 3320s,
2974s, 2936s, 2877m, 1740s, 1656s, 1517s, 1470s, 1391s, 1366s, 1317m, 1292m, 1247s, 1210m, 1170s, 1134m, 1083s,
1017m, 935w, 8 63w, 78 2w, 758w. 1H-NMR: 7.28(br. s, NH); 6.74 (d, J ˆ 7.8, NH); 5.17 (d, J ˆ 8.2, NH); 4.74 (d,
J ˆ 9.6, CH(a)((Me)Val)); 4.25 4.07 (m, CH(a)(Val), CH(a)(Ala)); 3.69 (s, MeO); 3.04 (s, MeN); 2.23 2.09
(m, CH(b)(Val), CH(b)((Me)Val)); 1.61, 1.58(2 s, 2 Me(Aib)); 1.45 (s, t-Bu); 1.36 (d, J ˆ 7.0, Me(Ala)); 1.00,
0.94, 0.90, 0.87 (4d, J ˆ 6.5, 2 Me(Val), 2 Me((Me)Val)). 13C-NMR: 173.2, 172.6, 171.4, 169.1 (4s, 4 CO); 156.3 (s,
CO(carbamate); 80.3 (s, Me3C); 63.0, 58.2 (2d, CH(a)(Val), CH(a)((Me)Val)); 57.2 (s, C(a)(Aib)); 51.6 (q,
MeO); 50.6 (d, CH(a)(Ala)); 32.6 (q, MeN); 30.1, 27.0 (2d, CH(b)(Val), CH(b)((Me)Val)); 28.2 (q, Me3C);
24.9, 24.8(2 q, 2 Me(Aib)); 19.9, 19.2, 18.7, 17.8, 17.3 (5q, 2 Me(Val), 2 Me((Me)Val), Me(Ala)). ESI-MS: 523
‡
([M ‡ Na] ).
10.5. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-phenylalanyl-glycyl-dimethylglycyl-(S)-N-
methylvalinate (Fmoc-Phe-Gly-Aib-(Me)Val-OMe; 23). According to the GP F, with Fmoc-Phe-Gly-OH
(53 mg, 0.188 mmol) in MeCN/DMF 50 :1 (5 ml), 20b (40 mg, 0.188 mmol); reaction time: 18 h. CC (AcOEt)
gave 72 mg (67%) of 23. Colorless foam. IR (KBr): 3313s, 3330m, 3064m, 2963m, 1735s, 1655s, 1526s, 1451s,
1395m, 1365m, 1331m, 1252s, 1211m, 1133m, 1083m, 1032m, 939w, 8 58w, 779m, 741s, 701m. 1H-NMR: 7.75 7.18
(m, 13 arom. H, NH); 7.00 (br. s, NH); 5.58( d, J ˆ 8.7, NH); 4.72 (d, J ˆ 10.0, CH(a)((Me)Val)); 4.42 4.36 (m,
CH2(Fmoc)); 4.23 (t, J ˆ 9.8, CH(a)(Phe)); 4.16 4.10 (m, CH(Fmoc)); 3.99 3.73 (m, CH2(Gly)); 3.63 (s,
MeO); 3.19 2.96 (m, CH2(Phe)); 3.01 (s, MeN); 2.23 2.15 (m, CH(b)(Val)); 1.55, 1.53 (2s, 2 Me(Aib)); 0.96,
0.84 (2d, J ˆ 6.4, 2 Me(Val)). 13C-NMR: 173.4, 171.6, 171.5, 167.1 (4s, 4 CO); 156.2 (s, CO(carbamate)); 143.5,
141.2, 136.2 (3s, 5 arom. C); 129.0, 128.6, 127.7, 126.9, 124.8, 119.9 (6d, 13 arom. C); 67.0 (t, CH2(Fmoc)); 64.0 (d,
CH(a)(Val)); 57.1 (s, C(a)(Aib)); 56.6 (d, CH(a)(Phe)); 51.6 (q, MeO); 47.0 (d, CH(Fmoc)); 43.2 (t,
CH2(Gly)); 37.7 (t, CH2(Phe)); 32.5 (q, MeN); 27.1 (d, CH(b)(Val)); 25.4, 25.0 (2q, 2 Me(Aib)); 19.9, 19.0 (2q,
‡
2 Me(Val)). ESI-MS: 679 ([M ‡ Na] ), 625, 512, 307.
11. Attempted Synthesis of Methyl N-(2,2-Dimethyl-2H-azirin-3-yl)-2,2,N-trimethylglycinate. 11.1. Z-
(Me)Aib-OMe. To a soln. of Z-Aib-OH (4.98g, 21.0 mmol) in THF/DMF 10 :1 (150 ml) was added first MeI
(10.5 ml, 168mmol), then NaH (1500 mg, 63 mmol, washed with hexane). After stirring for 26 h at 70 8, the
solvent was evaporated, the residue was dissolved in Et2O, and the org. phase was washed with H2O. Drying
(MgSO4) and CC (AcOEt/hexane, 1:1) gave 5.49 g (96%) of Z-(Me)Aib-OMe. Colorless oil. IR (neat): 3610w,
3065w, 3033m, 2989s, 2952s, 1960w, 1745s, 1699s, 1587w, 1470s, 1393s, 1350s, 1285s, 1213s, 1162s, 1129s, 1028s,
995m, 906w, 8 8 5w, 8 61w, 8 27w, 772s, 753s, 700s. 1H-NMR: 7.36 7.29 (m, 5 arom. H); 5.11 (s, PhCH2); 3.61 (br. s,
MeO); 2.97 (s, MeN); 1.45 (s, 2 Me(Aib)). 13C-NMR: 175.0 (s, CO); 155.8( s, CO(carbamate)); 136.4, 128.3,
127.9 (6 arom. C); 67.2 (PhCH2); 60.7 (s, C(a)(Aib)); 52.0 (q, MeO); 29.6 (q, MeN); 23.8( q, 2 Me(Aib)). EI-
‡¥
‡
MS: 265 (2, (M ), 206 (35, [M À COOMe] ), 162 (16), 92 (7), 91 (100). Anal. calc. for C14H19NO3 (265.31): C
63.38, H 7.22, N 5.28; found: C 63.32, H 7.15, N 5.35.
11.2. H-(Me)Aib-OMe ¥ HBr. Z-(Me)Aib-OMe (4.83 g, 18.2 mmol) was dissolved at 08 in AcOH saturated
with HBr (11 ml) and stirred for 2 h. Then, the solvent was evaporated, the residue was dissolved in H2O
(25 ml), washed twice with Et2O (15 ml), and evaporated to dryness, to give 3.85 g (quant.) of H-(Me)Aib-
OMe ¥ HBr. Colorless hygroscopic solid. IR (KBr): 3450s, 2962s, 2776s, 2431m, 2081w, 1745s, 1615m, 1578m,
1487m, 1430m, 1396m, 1377m, 1298s, 1219s, 1182s, 1112s, 1038w, 1012w, 973m, 8 8 0w, 8 60w, 78 8w, 767w. 1H-NMR
((D6)DMSO): 9.20 (br. s, NH2); 3.78( s, MeO); 2.53 (s, MeN); 1.50 (s, 2 Me(Aib)). 13C-NMR ((D6)DMSO):
171.0 (s, CO); 60.8( s, C(a)(Aib)); 53.3 (q, MeO); 27.5 (q, MeN); 21.1 (q, 2 Me(Aib)). ESI-MS: 343 ([(2M ‡
‡
H) ‡ Br] ).
11.3. Methyl N-(2-Methylpropanoyl)-2,2,N-trimethylglycinate (18d). According to the GP B, with H-
(Me)Aib-OMe ¥ HBr (3.31 g, 15.6 mmol) in abs. CH2Cl2 (100 ml), Et3N (6.52 ml, 46.8mmol), and isobutyryl
chloride (1.82 ml, 17.2 mmol); reaction time: 5 h, temp. r.t. ! 358. Evaporation yielded 2.61 g (83%) of 18d.
Colorless oil. IR (KBr): 3455w, 2983s, 2876m, 1742s, 1641s, 1476s, 1410s, 1382s, 1363s, 1325s, 1275s, 1240s, 1198s,
1158s, 1086s, 1024m, 1001m, 954w, 934w, 901w, 8 60m, 8 05w, 750m, 733m. 1H-NMR: 3.67 (s, MeO); 3.1 (s, MeN);

Helvetica Chimica Acta Vol. 85 (2002)
905
2.79 (sept., J ˆ 6.7, Me2CH); 1.41 (s, 2 Me(Aib)); 1.06 (d, J ˆ 6.7, Me2CH). 13C-NMR: 176.5, 174.6 (2s, 2 CO);
60.2 (s, C(a)(Aib)); 51.8( q, MeO); 31.0 (Me2CH); 30.0 (q, MeN); 23.1 (q, 2 Me(Aib)); 18.7 (q, Me2CH). EI-
‡¥
‡
‡
MS: 201 (3, (M ), 170 (5, [M À COOMe] ), 142 (41), 143 (3), 130 (6, [M À Me2CHCO] ), 72 (100). Anal. calc.
for C10H19NO3 ¥ 0.33 H2O (207.28): C 57.95, H 9.56, N 6.76; found: C 57.96, H 9.54, N 6.63.
11.4. Attempted Thionation of 18d. According to the GP C, with 18d (699 mg, 3.73 mmol) in abs. toluene
(30 ml), and Davy reagent [41] (815 mg, 1.87 mmol); reaction time: 20 h, temp. 1008. The residue was dissolved
in Et2O and washed twice with 1n aq. HCl soln., H2O, sat. aq. NaHCO3 soln., and once with brine. After drying
(MgSO4) and evaporation, only decomposed material was obtained.
12. Attempted Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)-N-(methyl)phenylalaninate. 12.1.
Methyl( S)-N-Methyl-N-(2-methylpropanoyl)phenylalaninate (18e). According to the GP B, with H-(Me)Phe-
OMe (83 mg, 0.43 mmol) in abs. CH2Cl2 (15 ml), Et3N (0.17 ml, 1.29 mmol), and isobutyryl chloride (0.05 ml,
0.47 mmol); reaction time: 20 h at r.t. ! 358. Evaporation yielded 97 mg (86%) of 18e. Colorless oil. 1H-NMR
(conformers): 7.22 7.06 (m, 5 arom. H); 5.24, 4.59 (2dd, J ˆ 11.1, 5.4, CH(a)(Phe)); 3.68, 3.65 (2s, MeO); 3.30
(dd-like, Ha of CH2(Phe)); 3.02 2.93 (m, Hb of CH2(Phe)); 2.82, 2.76 (2s, MeN); 2.59, 2.28(2 sept., J ˆ 6.7,
Me2CH); 0.99, 0.75 (2d, J ˆ 6.7, Me2CH). 13C-NMR: 177.4, 171.5, 170.0 (3s, 2 CO); 137.0 (s, 1 arom. C); 128.8,
128.3, 126.3 (3d, 5 arom. C); 61.4, 58.0 (2d, CH(a)(Phe)); 52.5, 52.1 (2q, MeO); 35.3, 34.7 (2t, CH2(Phe)); 32.8
(q, MeN); 30.2 (d, Me2CH); 18.7 (q, Me2CH).
12.2. Attempted Thionation of 18e. According to the GP C, with 18e (114 mg, 0.43 mmol) in abs. toluene
(15 ml), and Davy reagent [41]20) (96 mg, 0.22 mmol); reaction time: 1 h, temp. 1008. The residue was dissolved
in Et2O and washed twice with 1n aq. HCl soln., 1n aq. NaOH soln., and 1n aq. HCl soln. Drying (MgSO4),
evaporation, and CC (AcOEt/hexane 1:3) yielded 28mg (25%) of 18e. Otherwise, only decomposition could be
detected.
13. Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)homoprolinate (28). 13.1. Methyl( S)-N-(2-
Methylpropanoyl)homoprolinate (26). According to the GPA, with SOCl2 (0.28ml, 3.91 mmol), MeOH (5 ml),
and (S)-picoleinic acid (499 mg, 3.86 mmol). The crude methyl (S)-picoleinate in abs. CH2Cl2 (25 ml) was
treated with Et3N (1.62 ml, 11.6 mmol) and isobutyryl chloride (0.40 ml, 3.9 mmol) according to the GP B;
reaction time: 3 h at r.t. Evaporation yielded 790 mg (96%) of 26. Colorless oil. IR (neat): 3569w, 2910m,
2865m, 1742s, 1647s, 1471m, 1424m, 1383w, 1364w, 1314m, 1244s, 1206s, 1172m, 1155m, 1106w, 1089w, 1076w,
1020m, 994w, 920w, 8 68w, 8 21w, 78 0w, 750w. 1H-NMR: 5.35 (d, J ˆ 5.5, CH(a)(homoproline)); 3.85 (d, J ˆ 14.7,
1 H); 3.75, 3.72 (2s, MeO); 3.23 3.13 (m, 1 H); 2.79 (sept., J ˆ 6.8, Me2CH); 2.22 2.17 (m, 1 H); 1.67 1.02 (m,
5 H); 1.16 1.09 (m, Me2CH). 13C-NMR: 176.8, 171.9 (2s, 2 CO); 52.3 (q, MeO); 51.7 (d, CH(a)(homoproline));
43.1 (t, CH2(e)(homoproline)); 30.0 (d, Me2CH); 26.5, 25.4, 20.9 (3t, CH2(b)-, CH2(g)-, CH2(d)(homoproline));
‡
‡¥
‡
18.7, 18.1 (2q, Me2CH). EI-MS: 214 (0.8, [M ‡ H] ), 213 (3, M ), 154 (19, [M À COOMe] ), 142 (6, [M À
‡
‡
Me2CHCO] ), 85 (6), 84 (100, [M À Me2CHCO À (COOMe ‡ H)] ). Anal. calc. for C11H19NO3 (213.28): C
61.95, H 8.98, N 6.57; found: C 61.71, H 9.13, N 6.53.
13.2. Methyl( S)-N-(2-Methylpropanethioyl)homoprolinate (27). According to the GP C, with 26 (790 mg,
3.70 mmol) in abs. toluene (20 ml) and Lawesson reagent (822 mg, 2.04 mmol); reaction time: 0.5 h, temp. 908.
CC (Et2O/hexane 1:2) and (CH2Cl2/hexane, 2 :1) gave 184 mg (22%) of 27. Colorless oil. IR (CHCl3): 3852w,
3750w, 3675w, 3648w, 3566w, 2955s, 2360w, 1735s, 1646w, 1596w, 1558w, 1540w, 1436s, 1362m, 1336m, 1278s,
1
1167s, 1122m, 1074m, 1009s, 918w, 8 68w, 8 21w. H-NMR: 6.72 (d, J ˆ 5.7, CH(a)(homoproline)); 4.31 (d, J ˆ
14.0, 1 H); 3.71, 3.68(2 s, MeO); 3.34 3.24 (m, 1 H); 3.14 (sept., J ˆ 6.6, Me2CH); 2.33 2.24 (m, 1 H); 1.76
1.41 (m, 5 H); 1.22 1.07 (m, Me2CH). 13C-NMR: 212.7 (s, CS); 170.6 (s, CO); 59.6 (d, CH(a)(homoproline));
52.2 (q, MeO); 46.2 (t, CH2(e)(homoproline)); 36.5 (d, Me2CH); 26.6, 25.7, 20.8(3 t, CH2(b)-, CH2(g)-,
‡
CH2(d)(homoproline)); 23.3, 23.1 (q, Me2CH). CI-MS: 232 (6), 231 (13), 230 (100, [M ‡ H] ). Anal. calc. for
C11H19NO2S (229.34): C 57.61, H 8.35, N 6.11, S 13.98; found: C 57.36, H 8.37, N 5.95, S 14.12.
13.3. Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)homoprolinate (28). According to the GP D, with 27
(163 mg, 0.71 mmol) in abs. CH2Cl2 (10 ml), 2 drops of DMF, 2n COCl2 soln. (1.82 ml, 3.64 mmol), abs. THF
(10 ml), and DABCO (138mg, 0.71 mmol). The crude methyl ( S)-N-(1-chloro-2-methylprop-1-enyl)homo-
prolinate was treated with NaN3 (82 mg, 2.13 mmol) according to the GP E; reaction time: 26 h. CC (AcOEt)
yielded 105 mg (71%) of 2821). Pale yellow solid. M.p. 47 508. IR (CHCl3): 3854w, 3752w, 3676w, 3650w, 3630w,
3568w, 2945s, 2862m, 1770s, 1735s, 1638m, 1458m, 1368m, 1356m, 1310m, 1255m, 1218s, 1155s, 1100w, 1036m,
991m, 968w, 920m, 8 59w, 8 20w, 78 7w. 1H-NMR: 4.35 (br. s, CH(a)(homoproline)); 3.75 (s, MeO); 3.60, 3.41
20
)
)
When the same reaction was carried out with Lawesson reagent, similar results were obtained.
Analogously, rac-28 was synthesized (yield: 47%).
21

906
Helvetica Chimica Acta Vol. 85 (2002)
(2br. s, 2 H); 2.27 2.22 (m, 1 H); 1.85 1.32 (m, 5 H); 1.35 (s, Me2C). 13C-NMR: 171.4 (s, CO); 168.1 (s, C(3'));
58.6, 55.1 (2d, CH(a)(homoproline)); 52.1 (q, MeO); 45.9 (t, CH2(e)(homoproline)); 39.6 (s, C(2')); 26.8, 24.4,
20.8(3 t, CH2(b)-, CH2(g)-, CH2(d)(homoproline)); 24.7, 24.6 (2q, Me2C). CI-MS: 212 (11), 211 (100, [M ‡
‡
H] ). Anal. calc. for C11H18N2O2 ¥ 0.1 H2O (212.08): C 62.30, H 8.65, N 13.20; found: C 62.15, H 8.46, N 12.93.
14. Reactions of 28 with Amino Acids. 14.1. Methyl N-[(tert-Butoxy)carbonyl]-(S)-alanyl-dimethylglycyl-
(S)-homoprolinate (Boc-Ala-Aib-Homoproline-OMe; 29c). According to the GP F, with Boc-Ala-OH (13f,
57 mg, 0.30 mmol) in CH2Cl2 (10 ml), 28 (63 mg, 0.30 mmol); reaction time: 16 h. CC (hexane/AcOEt 1:4) gave
100 mg (83%) of 29c. Colorless, viscous oil which solidified. IR (CHCl3): 3334s, 2979m, 2940m, 2866w, 1746s,
1708s, 1666s, 1624s, 1532s, 1514s, 1447m, 1420s, 1388m, 1377m, 1344m, 1332m, 1296s, 1250s, 1204s, 1154s, 1070m,
1034m, 1024m, 8 74w. 1H-NMR: 5.39 (br. s, NH); 4.98(br. s, NH); 4.23 4.08( m, CH(a)(Ala), CH(a)(ho-
moproline)); 3.73 (s, MeO); 3.18, (br. s, Ha of CH2(e)(homoproline)); 2.27 2.19 (m, Hb of CH2(e)(homopro-
line)); 1.69 1.33 (m, CH2(b)-, CH2(g)-, CH2(d)(homoproline)); 1.63 (s, 2 Me(Aib)); 1.45 (s, t-Bu); 1.34 (d, J ˆ
5.3, Me(Ala)). 13C-NMR: 172.5, 171.6, 170.9 (3s, 3 CO); 155.4 (s, CO(carbamate)); 79.9 (s, Me3C); 56.7 (s,
C(a)(Aib)); 53.2, 50.1 (2d, CH(a)(Ala), CH(a)(homoproline)); 52.0 (q, MeO); 44.3 (t, CH2(e)(homoproline));
28.1 (q, Me3C); 26.5, 25.0, 20.9 (3t, CH2(b)-, CH2(g)-, CH2(d)(homoproline)); 25.2 (q, 2 Me(Aib)); 18.1 (q,
‡
Me(Ala)). ESI-MS: 423, 422 ([M ‡ Na] ). Anal. calc. for C19H33N3O6 (399.23): C 57.13, H 8.33, N 10.52; found:
C 56.99, H 8.44, N 10.43.
Crystal-Structure Determination of 29c22). All measurements were made on
a Rigaku AFC5R
diffractometer with graphite-monochromated MoKa radiation (l ˆ 0.71069 ä) and a 12-kW rotating-anode
generator. The w/2V scan mode was employed for data collection. The intensities were corrected for Lorentz
and polarization effects, but not for absorption. Data collection and refinement parameters are given in Table 6.
A view of the molecule is shown in Fig. 1.
The structure was solved by direct methods using SIR92 [41], which revealed the positions of all non-H-
atoms. The non-H-atoms were refined anisotropically. All of the H-atoms were fixed in geometrically calculated
positions (d(CÀH) ˆ 0.95 ä) and each was assigned a fixed isotropic displacement parameter with a value equal
to 1.2Ueq of its parent atom. Refinement of the structure was carried out on F using full-matrix least-squares
procedures, which minimized the function Sw(j Fo jÀj Fcj )2. A correction for secondary extinction was not
applied. Neutral atom scattering factors for non-H-atoms were taken from [42a], and the scattering factors for
H-atoms were taken from [43]. Anomalous dispersion effects were included in Fc [44]; the values for f ' and f ''
were those of [42b]. The values of the mass attenuation coefficients are those of [42c]. All calculations were
performed using the teXsan crystallographic software package [45].
Each NÀH group forms an intermolecular H-bond with an amide O-atom of the same neighboring
molecule. These interactions link the molecules into infinite one-dimensional chains which run parallel to the x-
axis, and both H-bond interactions have a graph set motif of C(5) [46]. There are no intramolecular H-bonds
(Fig. 2).
14.2. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-valyl-dimethylglycyl-(S)-homoprolinate
(Fmoc-Val-Aib-Homoproline-OMe; 29b). According to the GP F, with Fmoc-Val-OH (13d, 68mg, 0.20 mmol)
in CH2Cl2 (10 ml), 28 (68mg, 0.20 mmol); reaction time: 15 h. CC (AcOEt/hexane, 4 :1) gave 100 mg (91%) of
29b. Colorless, viscous oil which solidified. IR (KBr): 3303m, 3365w, 2950m, 2873m, 1736s, 1667s, 1625s, 1531s,
1467m, 1449s, 1389m, 1362m, 1339m, 1322m, 1218s, 1154s, 1140m, 1108m, 1028m, 928w, 8 69w, 8 22w, 760m, 741m.
1H-NMR: 7.67 7.17 (m, 8arom. H); 5.55 (br. d, J ˆ 8.3, NH); 5.29 (br. s, NH); 4.35 4.05 (m, CH2(Fmoc),
CH(a)(homoproline)); 4.11 (t, J ˆ 7.0, CH(Fmoc)); 3.93 3.88 (m, CH(a)(Val)); 3.62 (s, MeO); 3.03 (br. s, Ha
of CH2(e)(homoproline)); 2.15 1.98( m, Hb of CH2(e)(homoproline), CH(b)(Val)); 1.57, 1.53 (2s, 2 Me(Aib));
1.59 1.09 (m, CH2(b)-, CH2(g)-, CH2(d)(homoproline)); 0.94 0.75 (m, 2 Me(Val)). 13C-NMR: 172.6, 171.6,
169.6 (3s, 3 CO); 156.0 (s, CO(carbamate)); 143.7, 141.2 (2s, 2 arom. C); 127.6, 126.9, 124.9, 119.9 (4d, 8arom.
C); 66.9 (t, CH2(Fmoc)); 60.3 (d, CH(a)(Val)); 57.0 (s, C(a)(Aib)); 53.4 (d, CH(a)(homoproline)); 52.0 (q,
MeO); 47.0 (d, CH(Fmoc)); 44.4 (CH2(e)(homoproline)); 31.2 (d, CH(b)(Val)); 26.5, 24.8, 20.9 (3t, CH2(b)-,
CH2(g)-, CH2(d)(homoproline)); 24.9, 24.2 (2q, 2 Me(Aib)); 18.9, 17.8 (2q, 2 Me(Val)). ESI-MS: 573, 572
‡
([M ‡ Na] ). Anal. calc. for C31H39N3O6 ¥ 0.6 H2O (560.48): C 66.43, H 7.23, N 7.50; found: C 66.25, H 7.48, N
7.20.
22
)
Crystallographic data (excluding structure factors) for structure 29c have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication No. CCDC-167150. Copies of the
data can be obtained, free of charge, on application to the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (fax: ‡44-(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).

Helvetica Chimica Acta Vol. 85 (2002)
Table 6. Crystallographic Data of 29c
907
Crystallized from
CH2Cl2/Et2O/MeOH/hexane
Empirical formula
Formula weight [g molÀ1
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
C19H33N3O6
399.48
]
colorless, plate
0.10 Â 0.43 Â 0.43
173(1)
monoclinic
P21
Crystal system
Space group
Z
2
Reflections for cell determination
25
2V Range for cell determination [8]
Unit-cell parameters a [ä]
26 37
6.175(6)
20.413(5)
8.872(5)
105.52(5)
1078(1)
1.231
b [ä]
c [ä]
b [8]
V [ä3]
Dx [g cmÀ3
]
m(MoKa) [mmÀ1
Scan type
]
0.0913
w/2V
2V(max) [8]
55
Total reflections measured
Symmetry-independent reflections
Reflections used [I > 2s(I)]
Parameters refined
2770
2535
1863
252
Final R
0.0497
0.0436
1.860
wR (w ˆ [s2(Fo) ‡ (0.005Fo)2]À1
)
Goodness-of-fit
Final Dmax/s
Dr (max; min) [e äÀ3
0.0001
0.23; À 0.22
]
14.3. Methyl N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-dimethylglycyl-(R/S)-homoprolinate (Z-Phe-
Aib-Homoproline-OMe; 29a). According to the GP F, with Z-Phe-OH (13a, 55.7 mg, 0.186 mmol) in Et2O
(5 ml), rac-28 (39.1 mg, 0.186 mmol); reaction time: 24 h. CC (AcOEt/hexane, 2 :1) gave 95 mg (87%) of 29a
(mixture of diastereoisomers). Colorless, viscous oil which solidified. IR (KBr): 3296m, 3062w, 3032w, 2946m,
2860w, 1736s, 1670s, 1622s, 1535s, 1498m, 1455m, 1444m, 1364m, 1338m, 1252s, 1211s, 1154m, 1141m, 1108w,
1083w, 1027m, 922w, 8 71w, 8 21w, 778w, 744m, 699m. 1H-NMR: 7.37-7.18( m, 10 arom. H); 7.05, 6.88 (2br. s, NH);
5.41 5.25 (m, NH); 5.08( s, PhCH2(Z)); 4.38 4.34 ( m, CH(a)(Phe)); 4.10 3.93 (m, CH(a)(homoproline));
3.72, 3.70 (2s, MeO); 3.14 2.99 (m, Ha of CH2(e)(homoproline), CH2(Phe)); 2.22 (br. d, J ˆ 12.4, Hb of
CH2(e)(homoproline)); 1.67 1.35 (m, CH2(b)-, CH2(g)(homoproline)); 1.55, 1.51, 1.50, 1.47 (4s, 2 Me(Aib));
1.38 1.21 ( m, CH2(d)(homoproline)). 13C-NMR: 171.6, 168.9 (2s, 3 CO); 156.1 (s, CO(carbamate)); 136.2,
136.1 (2s, 2 arom. C); 129.4, 128.6, 128.4, 128.1, 127.9, 126.9 (6d, 10 arom. C); 67.0 (t, PhCH2(Z)); 57.0 (s,
C(a)(Aib)); 56.3, 56.1 (2d, CH(a)(homoproline), CH(a)(Phe)); 52.1 (q, MeO); 44.2 (t, CH2(e)(homoproline));
38.1 (t, CH2(Phe)); 26.5, 24.8, 20.9 (3t, CH2(b)-, CH2(g)-, CH2(d)(homoproline)); 24.4, 24.3 (2q, 2 Me(Aib)).
‡
‡
‡
ESI-MS: 549, 548([ M ‡ K] ), 532 ([M ‡ Na] ), 537, 510 ([M ‡ H] ), 478, 367. Anal. calc. for C31H39N3O6 ¥
0.5 H2O (518.62): C 64.85, H 7.00, N 8.10; found: C 64.77, H 7.22, N 7.96.
15. Attempted Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)norprolinate. 15.1. Methyl( S)-N-(2-
Methylpropanoyl)norprolinate. According to the GP A, with SOCl2 (0.125 ml, 1.71 mmol), MeOH (2 ml), and
(S)-azetidine-2-carboxylic acid (170 mg, 1.68mmol). The crude methyl ( S)-azetidine-2-carboxylate in abs.
CH2Cl2 (20 ml) was treated with Et3N (0.70 ml, 5.04 mmol) and isobutyryl chloride (0.18ml, 1.68mmol)
according to the GP B; reaction time: 4 h at r.t. Evaporation yielded 288 mg (quant.) of methyl (S)-N-(2-
methylpropanoyl)norprolinate. Colorless oil. IR (neat): 3468w, 2971m, 2890w, 1747s, 1652s, 1474m, 1433s,
1361m, 1318m, 1284m, 1244m, 1208s, 1171m, 1133w, 1090m, 1066m, 98 9w, 928w, 902w, 8 63w, 8 25w, 790w, 751w.
1H-NMR (conformers): 4.88 4.84, 4.71 4.67 (2m, CH(a)(norproline)); 4.31 3.94 (m, CH2(g)(norproline));

908
Helvetica Chimica Acta Vol. 85 (2002)
Fig. 2. Molecular packing projected down the c-
axis showing the H-bonding scheme (equivalent
isotropic spheres for atoms; uninvolved H-atoms
omitted for clarity)
3.81, 3.76 (2s, MeO); 2.69 2.18( m, CH2(a)(norproline), Me2CH); 1.12, 1.09 (2d, J ˆ 6.9, Me2CH). 13C-NMR
(conformers): 177.7, 176.8, 171.5 (3s, 2 CO); 61.2, 58.9 (2d, CH(a)(norproline)); 52.5, 52.2 (2q, MeO); 48.7, 46.2
(2t, CH2(g)(norproline)); 29.6 (d, Me2CH); 20.3, 19.7 (2t, CH2(b)(norproline)); 18.4, 18.2 (2q, Me2CH). CI-MS:
‡
‡
‡
389 (11), 388 (49, [2M ‡ NH4] ), 372 (20), 371 (100, [2M ‡ H] ), 186 (6, [M ‡ H] ). Anal. calc. for C9H15NO3 ¥
0.5 H2O (188.82): C 57.25, H 8.22, N 7.42; found: C 57.46, H 8.21, N 7.79.
15.2. Methyl( S)-N-(2-Methylpropanethioyl)norprolinate (30). According to the GP C, with methyl (S)-N-
(2-methylpropanoyl)norprolinate (489 mg, 2.68 mmol) in abs. toluene (30 ml) and Lawesson reagent (563 mg,
1.39 mmol); reaction time: 1 h, temp. 1008. CC (CH2Cl2/hexane, 2 :1) gave 500 mg (93%) of 30. Colorless oil. IR
(neat): 3626w, 2971m, 2871w, 1745s, 1488s, 1464s, 1439s, 1381w, 1335m, 1255s, 1204s, 1176m, 1117m, 1063m,
1033w, 1008m, 973w, 921w, 8 9w6, 8 5w7, 8 4w1, 8 1w4, 78 w4, 732w. 1H-NMR (conformers): 5.00 4.91 (m,
CH(a)(norproline); 4.46 4.19 (m, CH2(g)(norproline)); 3.82, 3.78 (2s, MeO); 2.83 (sept., J ˆ 6.6, Me2CH);
2.69 2.56, 2.34 2.23 (2m, CH2(b)(norproline); 1.21, 1.20 (2d, J ˆ 6.6, Me2CH). 13C-NMR (conformers): 210.3,
209.3 (2s, CS); 169.6 (s, CO); 63.3, 63.2 (2d, CH(a)(norproline)); 52.9, 52.4 (2q, MeO); 51.7, 51.4 (2t,
CH2(g)(norproline)); 35.7, 35.4 (2d, Me2CH); 22.7, 22.3, 22.2, 21.8(4 q, Me2CH); 19.9, 19.0 (2t, CH2(b)(norpro-
‡
line)). CI-MS: 204 (5), 203 (9), 202 (100, [M ‡ H] ). Anal. calc. for C9H15NO2S (201.29): C 53.70, H 7.51, N 6.90,
S 15.93; found: C 53.55, H 7.58, N 6.90, S 15.77.
15.3. Attempted Synthesis of Methyl( S)-N-(2,2-Dimethyl-2H-azirin-3-yl)norprolinate. According to the GP
D, with 30 (500 mg, 2.48mmol) in abs. CH 2Cl2 (10 ml), 3 drops of DMF, 2n COCl2 soln. (2.5 ml, 5.0 mmol), abs.
THF (15 ml), and DABCO (279 mg, 2.48mmol). The crude intermediate was treated with NaN 3 (485 mg,
7.45 mmol) according to the GP E; reaction time: 48h. CC (AcOEt/hexane, 1 :2) gave 303 mg (67%) of 31. IR
(neat): 3650w, 3339w, 2977m, 2937w, 2876w, 2500w, 2113s, 1745s, 1670w, 1509m, 1459m, 1438m, 1388w, 1368m,
1
1323m, 1261s, 1212s, 1100m, 1070w, 1047w, 996m, 915w, 755w. H-NMR: 4.47 4.39 (m, CH2(g)(norproline));
4.19 4.15 (m, CH(a)(norproline)); 3.80 (s, MeO); 3.20 (sept., J ˆ 6.9, Me2CH); 2.55 2.45, 2.38 2.28 (2 m,
CH2(b)(norproline)); 1.42 (d, J ˆ 6.9, Me2CH). 13C-NMR: 169.5 (s, CO); 159.4 (s); 58.7 (d, CH(a)(norpro-
line)); 52.9, (q, MeO); 42.6 (t, CH2(g)(norproline)); 30.7 (t, CH2(b)(norproline)); 23.8( d, Me2CH); 21.0 (q,
‡
‡
‡
Me2CH). CI-MS: 254 (5, [M ‡ H] ), 226 (5, [M À N2] ), 212 (11), 211 (100, [M À C3H7] ), 114 (10). Anal. calc.
for C9H15N7O2 (253.27): C 42.68, H 5.97, N 38.71; found: C 43.33, H 6.21, N 37.28.
16. Synthesis of Methyl( S)-N-(2-Ethyl-2-methyl-2H-azirin-3-yl)prolinate (33). 16.1. Methyl( S)-N-[(R/S)-
2-Methylbutanoyl]prolinate. According to the GP A, with SOCl2 (2.0 ml, 27.5 mmol), MeOH (10 ml), and H-

Helvetica Chimica Acta Vol. 85 (2002)
909
Pro-OH (2330 mg, 20 mmol). The crude methyl (S)-prolinate in abs. CH2Cl2 (50 ml) was treated with Et3N
(8.35 ml, 60 mmol) and (R/S)-2-methylbutyryl chloride (2.48ml, 20 mmol) according to the GP B; reaction
time: 15 h at r.t. Evaporation and distillation (858, 2 ¥ 10À2 mbar) gave 4012 mg (94%) of methyl (S)-N-[(R/S)-2-
methylbutanoyl)]prolinate. Colorless oil. IR (neat): 3479w, 2965m, 2876m, 1747s, 1646s, 1464m, 1426s, 1367m,
1342m, 1322m, 1280m, 1197s, 1174s, 1095w, 1048w, 1014w, 943w, 8 76w, 796w, 750w. 1H-NMR (diastereoisomers):
4.49 (dd, J ˆ 8.3, 2.7, CH(a)(Pro)); 3.75 3.61 (m, CH2(d)(Pro)); 3.71, 3.70 (2s, MeO); 2.55 2.45 (m, MeCH);
2.23 1.90 (m, CH2(b)-, CH2(g)(Pro)); 1.78 1.66, 1.48 1.36 (2 m, MeCH2); 1.10, 1.09 (2d, J ˆ 6.7, MeCH);
0.97 0.80 (m, MeCH2). 13C-NMR (diastereoisomers): 175.4, 175.3, 172.8(3 s, 2 CO); 58 .6, 58 .4 d(,2
CH(a)(Pro)); 51.8( q, MeO); 46.7 (t, CH2(d)(Pro)); 39.3, 39.1 (2d, MeCH); 31.9, 28.9, 27.0, 26.4, 24.7, 22.3
‡
(6t, CH2(b)-, CH2(g)(Pro), MeCH2); 16.6 (q, MeCH); 11.8, 11.5 (2q, MeCH2). ESI-MS: 236 ([M ‡ Na] ), 214
‡
([M ‡ H] ). Anal. calc. for C11H19NO3 ¥ 0.1 H2O (215.08): C 61.43, H 9.00, N 6.51; found: C 61.57, H 9.03, N 6.73.
16.2. Methyl( S)-N-[(R/S)-2-Methylbutanethioyl]prolinate (32). According to the GP C, with methyl (S)-
N-[(R/S)-2-methylbutanoyl]prolinate (3362 mg, 15.76 mmol) in abs. toluene (80 ml) and Lawesson reagent
(3315 mg, 8.19 mmol); reaction time: 1.25 h, reflux. CC (CH2Cl2/hexane, 2 :1) and distillation (1308, 3 ¥
10À2 mbar) gave 2530 mg (70%) of 32. Pale yellow oil. IR (KBr): 3461w, 2984m, 2959m, 2875m, 1740s, 1470s,
1445s, 1381w, 1357m, 1341m, 1303w, 1269m, 1245w, 1202s, 1164s, 1130m, 1092w, 1040m, 1016w, 997m, 972w,
953m, 928w, 905w, 8 59w, 8 44w, 8 01w, 778w. 1H-NMR (diastereoisomers): 5.08( dd, J ˆ 8.6, 8.3, CH(a)(Pro));
3.96 3.74 (m, CH2(d)(Pro)); 3.72 (s, MeO); 2.91 2.79 (m, MeCH); 2.33 2.04 (m, CH2(b)-, CH2(g)(Pro));
1.91 1.80, 1.61 1.51 (2m, MeCH2); 1.22, 1.21 (2d, J ˆ 6.5, MeCH); 0.95 0.77 (m, MeCH2). 13C-NMR
(diastereoisomers): 209.1, 208.9 (2s, CS); 170.9 (s, CO); 65.1, 64.9 (2d, CH(a)(Pro)); 52.0 (q, MeO); 50.5, 50.3 (t,
CH2(d)(Pro)); 46.7, 45.8(2 d, MeCH); 31.3, 31.1, 30.4, 29.8, 28.7, 24.5 (6t, CH2(b)-, CH2(g)(Pro), MeCH2); 20.7
‡
‡
‡
(q, MeCH); 11.9, 11.7 (2q, MeCH2). ESI-MS: 481 ([2M ‡ Na] ), 284 ([M ‡ Na ‡ MeOH] ), 252 ([M ‡ Na] ),
‡
231 ([M ‡ 1] ). Anal. calc. for C11H19NO2S (229.34): C 57.61, H 8.35, N 6.11, S 13.98; found: C 57.58, H 8.44, N
6.14, S 13.95.
16.3. Methyl( S)-N-[(R/S)-2-Ethyl-2-methyl-2H-azirin-3-yl]prolinate (33). According to the GP D, with 32
(981 mg, 4.28 mmol) in abs. CH2Cl2 (20 ml), 3 drops of DMF, 2n COCl2 soln. (3.20 ml, 6.40 mmol), abs. THF
(30 ml), and DABCO (480 mg, 4.28 mmol). The crude methyl (S)-N-(1-chloro-2-methylbut-1-enyl)prolinate
was treated with NaN3 (835 mg, 12.84 mmol) according to the GP E; reaction time: 21 h. Evaporation and CC
(AcOEt/hexane 2 :1) yielded 450 mg (50%) of 33. Pale yellow oil. IR (neat): 3461w, 2961s, 2879s, 1766s, 1745s,
1649m, 1570w, 1454s, 1417m, 1370s, 1344s, 1283s, 1209s, 1173s, 1093m, 1063m, 1043m, 998m, 969m, 914w, 8 76w,
1
837w, 8 08w, 794w, 747w. H-NMR (diastereoisomers): 4.31 (br. s, CH(a)(Pro)); 3.73 (s, MeO); 3.71 3.51 (m,
CH2(d)(Pro)); 2.34 1.98( m, CH2(b)-, CH2(g)(Pro)); 1.71 1.60 (m, MeCH2); 1.29, 1.26 (2s, Me); 0.84 0.77
(m, MeCH2). 13C-NMR (diastereoisomers): 172.3 (s, CO); 164.7, 164.4 (2s, C(3')); 60.1 (d, CH(a)(Pro)); 52.1 (q,
MeO); 46.7 (t, CH2(d)(Pro)); 43.7, 43.5 (2s, C(2')); 30.4, 30.1 (2t, CH2(b)(Pro), MeCH2); 23.9 (t, CH2(d)(Pro));
‡
23.2, 22.9 (2q, Me); 10.0, 9.8(2 q, MeCH2). CI-MS: 212 (15), 211 (100, [M ‡ H] ).
17. Reaction of 33 with Amino Acids and Syntheses of ModelPeptides. 17.1. Methyl N-[(Benzyloxy)car-
bonyl]-(S)-phenylalanyl-(R/S)-methyl(ethyl)glycyl-(S)-prolinate (Z-Phe-d/l-Iva-Pro-OMe, 34a). According to
the GP F, with Z-Phe-OH (13a, 81 mg, 0.271 mmol) in MeCN (5 ml), 33 (57 mg, 0.271 mmol); reaction time:
22 h. CC (hexane/AcOEt 1:4) gave 124 mg (90%) of 34a. Colorless foam. IR (KBr): 3311s, 3063m, 3032m,
2952s, 2881m, 1745s, 1666s, 1535s, 1497s, 1454s, 1410s, 1370m, 1331m, 1240s, 1212s, 1174s, 1086m, 1049m, 1027s,
1
914w, 8 78w, 775w, 745m, 699s. H-NMR (diastereoisomers): 7.46 (br. s, NH); 7.35 7.16 (m, 10 arom. H); 6.89
(br. s, NH); 5.53, 5.48(2 d, J ˆ 8.1, NH); 5.06 (s, PhCH2(Z)); 4.52 4.48, 4.43 4.39 (2m, CH(a)(Phe),
CH(a)(Pro)); 3.69, 3.68(2 s, MeO); 3.64 3.44 (CH2(d)(Pro)); 3.12 3.03 (m, CH2(Phe)); 2.55 1.81 (m,
CH2(b)-, CH2(g)(Pro), MeCH2); 1.54, 1.50 (2s, Me(Iva)); 0.76 0.65 (m, MeCH2). 13C-NMR (diastereoisom-
ers): 172.8, 172.5, 171.7, 169.1, 168.8 (5s, 3 CO); 155.7 (s, CO(carbamate)); 136.4, 136.3 (2s, 2 arom. C); 129.3,
129.2, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 126.8, 126.7 (10d, 10 arom. C); 66.7 (t, PhCH2(Z)); 61.1, 60.7 (d,
CH(a)(Pro)); 60.2 (s, C(a)(Iva)); 56.5 (d, CH(a)(Phe)); 51.9 (q, MeO); 47.8, 47.6 (2t, CH2(d)(Pro)); 38.4 (t,
CH2(Phe)); 27.6, 26.9, 25.7 (3t, CH2(b)-, CH2(g)(Pro), MeCH2); 21.4 (q, Me(Iva)); 7.8( q, MeCH2). ESI-MS:
‡
‡
‡
548([ M ‡ K] ), 537, 529 ([M ‡ Na] ), 510 ([M ‡ H] ), 381, 308. Anal. calc. for C28H35N3O6 ¥ 0.5 H2O (518.62):
C 64.85, H 7.00, N 8.10; found: C 65.00, H 7.04, N 8.01.
17.2. Methyl N-[(Benzyloxy)carbonyl]-(S)-phenylalanyl-(R/S)-methyl(ethyl)glycyl-(S)-prolyl-(S)-alani-
nate (Z-Phe-d/l-Iva-Pro-Ala-OMe, 36). According to the GP G, with 34a (91 mg, 0.179 mmol) in THF/
MeOH/H2O (3 :1:1, 5 ml), LiOH ¥ H2O (23 mg, 0.537 mmol); reaction time: 4 h. Evaporation led to 90 mg
(quant.) crude Z-Phe-d/l-Iva-Pro-OH. According to the GP H, with Z-Phe-d/l-Iva-Pro-OH (90 mg,
0.179 mmol), EtN(i-Pr)2 (0.09 ml, 0.54 mmol), TBTU (60 mg, 0.188 mmol), H-Ala-OMe (28 mg, 0.197 mmol),
and MeCN (5 ml); reaction time: 18 h. CC (AcOEt) gave 85 mg (82%) of 36. IR (KBr): 3301s, 3063m, 3032m,

910
Helvetica Chimica Acta Vol. 85 (2002)
2948s, 2881m, 1724s, 1655s, 1542s, 1455s, 1408s, 1383s, 1334m, 1253s, 1151s, 1084m, 1058m, 914w, 8 8 w1, 8 46w,
778w, 744m, 699s. 1H-NMR ((D6)DMSO, diastereoisomers): 8.18 (br. d, J ˆ 10.8, NH); 8.08 8.02 (br. s, NH);
7.57 (t-like, NH); 7.35 7.19 (m, 10 arom. H); 5.05 4.90 (m, PhCH2(Z)); 4.36 4.32 (m, CH(a)(Phe),
CH(a)(Pro)); 4.24 4.19 (m, CH(a)(Ala)); 3.61 (s, MeO); 3.56 3.32 (CH2(d)(Pro)); 3.01 2.73 (m,
CH2(Phe)); 1.90 1.63 (m, CH2(b)-, CH2(g)(Pro), MeCH2); 1.32 1.22 (m, Me(Iva), Me(Ala)); 0.78 0.67
(m, MeCH2). 13C-NMR ((D6)DMSO, diastereoisomers): 172.9, 172.0, 171.8, 170.6, 170.3, 170.0 (6s, 4 CO); 155.7
(s, CO(carbamate)); 137.8, 137.0 (2s, 2 arom. C); 129.1, 129.0, 128.1, 127.9, 127.5, 126.1 (6d, 10 arom. C); 65.0 (t,
PhCH2(Z)); 60.6 (d, CH(a)(Pro)); 59.0, 58.9 (2s, C(a)(Iva)); 55.9, 55.6 (2d, CH(a)(Phe)); 51.5 (q, MeO); 47.4
(d, CH(a)(Ala)); 47.1 (t, CH2(d)(Pro)); 38.1 (t, CH2(Phe)); 28.9, 27.7, 27.5, 25.0 (4t, CH2(b)-, CH2(g)(Pro),
‡
MeCH2); 21.1 (q, Me(Iva)); 16.6 (q, Me(Ala)); 7.7 (q, MeCH2). ESI-MS: 603 ([M ‡ Na] ).
17.3. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-valyl-(R/S)-methyl(ethyl)glycyl-(S)-prolinate
(Fmoc-Val-d/l-Iva-Pro-OMe; 34b). According to the GP F, with Fmoc-Val-OH (13d, 78mg, 0.229 mmol) in
MeCN (5 ml), 33 (48mg, 0.229 mmol); reaction time: 17 h. CC (hexane/AcOEt 2 :3) gave 114 mg (91%) of
34b. Colorless foam. IR (KBr): 3325s, 3065m, 2966s, 2879w, 1745s, 1669s, 1623s, 1507s, 1450s, 1410m, 1370m,
1328m, 1288s, 1240s, 1175s, 1095m, 1031m, 948w, 928w, 8 42w, 760s, 741s. 1H-NMR (diastereoisomers): 7.76 7.27
(m, 8arom. H); 7.20 (br. s, NH); 5.51 (d, J ˆ 7.9, NH); 4.55 4.51 (m, CH(a)(Val)); 4.42 4.36 (m, CH2(Fmoc));
4.24 4.18( m, CH(Fmoc)); 4.05 3.99 (m, CH(a)(Pro)); 3.71 (s, MeO); 3.70 3.67 (m, CH2(d)(Pro)); 2.17
1.71 (m, CH2(b)-, CH2(g)(Pro), MeCH2); 1.68, 1.67 (2s, Me(Iva)); 0.98 0.82 ( m, 2 Me(Val), MeCH2).
13C-NMR (diastereoisomers): 172.7, 172.5, 172.0, 171.2, 169.4, 169.2 (6s, 3 CO); 156.2 (s, CO(carbamate)); 143.9,
143.8, 141.2 (3s, 4 arom. C); 127.5, 126.9, 125.0, 119.8(4 d, 8arom. C); 66.9 ( t, CH2(Fmoc)); 61.5 (s, C(a)(Iva));
61.3, 60.9, 60.4 (3d, CH(a)(Val), CH(a)(Pro)); 52.0 (q, MeO); 47.8, 47.7 (2t, CH2(d)(Pro)); 47.1 (d,
CH(Fmoc)); 31.5 (d, CH(b)(Val)); 27.6, 26.8, 25.8 (3t, CH2(b)-, CH2(g)(Pro), MeCH2); 21.6 (q, Me(Iva)); 19.0,
‡
17.6 (2q, 2 Me(Val)); 8.2, 7.9 (q, MeCH2). ESI-MS: 572 ([M ‡ Na] ). Anal. calc. for C31H39N3O6 ¥ 0.5 H2O
(558.68): C 66.65, H 7.22, N 7.52; found: C 66.56, H 7.25, N 7.32.
17.4. Methyl N-[(tert-Butoxy)carbonyl]-(S)-alanyl-(S)-valyl-(R/S)-methyl(ethyl)glycyl-(S)-prolinate (Boc-
Ala-Val-d/l-Iva-Pro-OMe; 37). A soln. of 34b (103 mg, 0.187 mmol) in Et2NH/CH2Cl2 1:1 (2 ml) was stirred at
r.t. for 4 h. Evaporation led to crude H-Val-d/l-Iva-Pro-OMe, which was treated according to the GP H, with
EtN(i-Pr)2 (0.10 ml, 0.56 mmol), TBTU (63 mg, 0.196 mmol), Boc-Ala-OH (39 mg, 0.206 mmol), and MeCN
(8ml); reaction time: 17 h. CC (AcOEt) gave 90 mg (97%) of 37. IR (KBr): 3303s, 2976s, 2880m, 1746s, 1655s,
1623s, 1523s, 1453s, 1409s, 1393m, 1367m, 1327m, 1248s, 1171s, 1124m, 1084s, 1052m, 1027m, 953w, 928w, 8 64w,
825w, 773w, 762w. 1H-NMR ((D6)DMSO): 8.31, 8.25 (2s, NH); 7.90 (d, J ˆ 7.4, NH); 5.51 (t, J ˆ 7.4, NH); 4.29
4.21 (m, CH(a)(Val), CH(a)(Ala)); 4.05 4.00 (m, CH(a)(Pro)); 3.58( s, MeO); 3.31 3.25 (m, CH2(d)(Pro));
2.00 1.71 (m, CH2(b)-, CH2(g)(Pro), CH(b)(Val), MeCH2); 1.37 (s, t-Bu); 1.29, 1.26 (2s, Me(Iva)); 1.16 1.13
(m, Me(Ala)); 0.88 0.78 (m, 2 Me(Val)); 0.74 (t, J ˆ 7.4, MeCH2)). 13C-NMR ((D6)DMSO): 172.6, 172.5, 172.3,
171.2, 169.9, 169,8, 169.6 (7s, 4 CO); 154.8( s, CO(carbamate)); 77.9 (s, Me3C); 59.9, 56.8(2 d, CH(a)(Val),
CH(a)(Pro)); 59.0, 58.2 (2s, C(a)(Iva)); 51.3 (q, MeO); 49.6 (d, CH(a)(Ala)); 47.0 (2t, CH2(d)(Pro)); 30.9 (d,
CH(b)(Val)); 29.2, 27.1, 25.3, 25.1 (4t, CH2(b)-, CH2(g)(Pro), MeCH2); 28.0 (q, Me3C); 21.3 (q, Me(Iva)); 20.0,
‡
19.1, 18.8, 18.2, 18.0, 17.6 (6q, 2 Me(Val), Me(Ala)); 7.3, 7.2 (2q, MeCH2). ESI-MS: 521 ([M ‡ Na] ), 421.
17.5. Methyl N-{[(9H-Fluoren-9-yl)methoxy]carbonyl}-(S)-phenylalanyl-glycyl-(R/S)-methyl(ethyl)glycyl-
(S)prolinate (Fmoc-Phe-Gly-d/l-Iva-Pro-OMe; 35). According to the GP F, with Fmoc-Phe-Gly-OH (13e,
121 mg, 0.271 mmol) in CH2Cl2/DMF 50 :1 (5 ml), 33 (57 mg, 0.271 mmol); reaction time: 20 h. CC (AcOEt)
gave 177 mg (99%) of 35. Colorless foam. IR (KBr): 3310s, 3063m, 2950m, 2881m, 1744s, 1664s, 1531s, 1450s,
1408s, 1332m, 1251s, 1210m, 1174m, 1094m, 1045m, 8 77w, 8 43w, 760m, 741s, 701m. 1H-NMR (diastereoisomers):
7.75 7.20 (m, 13 arom. H, NH); 7.06, 6.89 (2s, NH); 5.68( dd, J ˆ 20.6, 6.8, NH); 4.53 4.50 (m, CH(a)(Phe));
4.43 4.36 (m, CH2(Fmoc)); 4.32 4.26 (m, CH(a)(Pro)); 4.17 4.10 (m, CH(Fmoc)); 3.98 3.93 m( ,
CH2(Gly)); 3.81 3.54 (m, CH2(d)(Pro)); 3.66, 3.65 (s, MeO); 3.20 3.03 (m, CH2(Phe)); 2.13 1.74 (m,
CH2(b)-, CH2(g)(Pro), MeCH2); 1.60, 1.56 (2s, Me(Iva)); 0.85 0.78 (m, MeCH2). 13C-NMR (diastereoisom-
ers): 172.9, 172.6, 171.9, 171.7, 171.4, 171.2, 167.1, 166.6 (8s, 4 CO); 156.0 (s, CO(carbamate)); 143.6, 141.2, 136.5
(3s, 5 arom. C); 129.1, 128.5, 127.6, 127.0, 124.9, 119.9 (6d, 13 arom. C); 67.0 (t, CH2(Fmoc)); 61.0, 60.9 (2s,
C(a)(Iva)); 60.8, 60.2 (2d, CH(a)(Pro)); 56.3 (s, CH(a)(Phe)); 51.9 (q, MeO); 47.9 (t, CH2(d)(Pro)); 46.9 (d,
CH(Fmoc); 43.2 (t, CH2(Gly)); 38.1 (t, CH2(Phe)); 27.6, 27.3, 25.8(3 t, CH2(b)-, CH2(g)(Pro), MeCH2); 21.3 (q,
‡
Me(Iva)); 8.0, 7.0 (2q, MeCH2). ESI-MS: 677 ([M ‡ Na] ), 526, 421, 411, 292, 233, 211.

Helvetica Chimica Acta Vol. 85 (2002)
911
REFERENCES
[1] H. Heimgartner, Angew. Chem., Int. Ed. 1991, 30, 238.
[2] P. Wipf, H. Heimgartner, Helv. Chim. Acta 1990, 73, 13.
[3] J. M. Villalgordo, H. Heimgartner, Tetrahedron 1993, 49, 7215.
[4] C. B. Bucher, H. Heimgartner, Helv. Chim. Acta 1996, 79, 1903.
[5] C. Str‰ssler, A. Linden, H. Heimgartner, Helv. Chim. Acta 1997, 80, 1528.
[6] G. Suter, S. A. Stoykova, A. Linden, H. Heimgartner, Helv. Chim. Acta 2000, 83, 2961.
[7] R. T. N. Luykx, Ph. D. Thesis, Universit‰t Z¸rich, 2000.
[8] R. A. Breitenmoser, T. R. Hirt, R. T. N. Luykx, H. Heimgartner, Helv. Chim. Acta 2001, 84, 972.
[9] J. Lehmann, A. Linden, H. Heimgartner, Helv. Chim. Acta 1999, 82, 888; J. Lehmann, A. Linden, H.
Heimgartner, Tetrahedron 1999, 55, 5359; J. Lehmann, A. Linden, H. Heimgartner, Tetrahedron 1998, 54,
8721; J. Lehmann, H. Heimgartner, Helv. Chim. Acta 1999, 82, 1899.
[10] R. A. Breitenmoser, H. Heimgartner, Helv. Chim. Acta 2001, 84, 768.
[11] I. Dannecker-Dˆrig, Ph. D. Thesis, Universit‰t Z¸rich, 1995.
[12] F. S. Arnhold, Ph. D. Thesis, Universit‰t Z¸rich, 1997.
[13] T. Jeremic, planned Ph. D. Thesis, Universit‰t Z¸rich.
[14] H. Heimgartner, F. S. Arnhold, S. P. Fritschi, K. N. Koch, J. E. F. Magirius, A. Linden, J. Heterocycl. Chem.
1999, 36, 1539.
[15] J. M. Villalgordo, H. Heimgartner, Helv. Chim. Acta 1997, 80, 748.
[16] K. N. Koch, A. Linden, H. Heimgartner, Helv. Chim. Acta 2000, 83, 233; K. N. Koch, H. Heimgartner, Helv.
Chim. Acta 2000, 83, 1881; K. N. Koch, A. Linden, H. Heimgartner, Tetrahedron 2001, 57, 2311.
[17] J. E. F. Magirius, Ph. D. Thesis, Universit‰t Z¸rich, 1995.
[18] S. Vijayalakshmi, R. Balaji Rao, I. L. Karle, P. Balaram, Biopolymers 2000, 53, 8 4.
[19] A. Jaworski, J. Kirschbaum, H. Br¸ckner, J. Pept. Sci. 1999, 5, 341.
[20] S. J. Lee, W. H. Yeo, B. S. Yun, I. D. Yoo, J. Pept. Sci. 1999, 5, 374.
[21] W. Mayr, G. Jung, J. St‰hle, Liebigs Ann. Chem. 1980, 715.
[22] M. T. Leplawy, D. S. Jones, G. W. Kenner, R. C. Sheppard, Tetrahedron 1960, 11, 39.
[23] H. Wenschuh, M. Beyermann, H. Haber, J. K. Seydel, E. Krause, M. Bienert, J. Org. Chem. 1995, 60,
405.
[24] C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1995, 78, 935.
[25] R. Luykx, C. B. Bucher, A. Linden, H. Heimgartner, Helv. Chim. Acta 1996, 79, 527.
[26] R. A. Breitenmoser, Diploma Thesis, Universit‰t Z¸rich, 1997.
[27] F. Elsinger, J. Schreiber, A. Eschenmoser, Helv. Chim. Acta 1960, 43, 113.
[28] J. R. McDermott, N. L. Benoiton, Can. J. Chem. 1973, 51, 2555.
[29] W. D. Jamieson, Can. J. Chem. 1986, 64, 277.
[30] N. L. Benoiton, K. Kuroda, S. T. Cheung, F. M. F. Chen, Can. J. Biochem. 1979, 57, 776.
[31] H. Peter, M. Brugger, J. Schreiber, A. Eschenmoser, Helv. Chim. Acta 1963, 46, 577.
[32] R. M. Freidinger, J. S. Hinkle, D. S. Perlow, B. H Arison, J. Org. Chem. 1983, 48, 77.
[33] L. Aurelio, R. T. C. Brownlee, A. B. Hughes, B. E. Sleebs, Aust. J. Chem. 2000, 53, 425.
[34] P. A. Grieco, A. Bahsas, J. Org. Chem. 1987, 52, 5746.
[35] D. E. Ward, R. Lazny, M. S. C. Pedras, Tetrahedron Lett. 1997, 38, 339.
[36] J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97, 2243.
[37] P. Wipf, Ph. D. Thesis, Universit‰t Z¸rich, 1987.
[38] U. Slomczynska, D. D. Beusen, J. Zabrocki, K. Kociolek, A. Redlinski, F. Reusser, W. C. Hutton, M. T.
Leplawy, G. R. Marshall, J. Am. Chem. Soc. 1992, 114, 4095.
[39] R. C. Pandey, J. C. Cook, K. L. Rinehart, J. Am. Chem. Soc. 1977, 99, 5205.
[40] P. Wipf, C. Jenny, H. Heimgartner, Helv. Chim. Acta 1987, 70, 1001.
[41] A. Altomare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli, SIR92, J.
Appl. Crystallogr. 1994, 27, 435.
[42] a) E. N. Maslen, A. G. Fox, M. A. O×Keefe, in −International Tables for Crystallography×, 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, ibid. Table 4.2.6.8, p. 219; c) D. C. Creagh, J. H. Hubbell, ibid. Table 4.2.4.3,
p. 200.
[43] R. F. Stewart, E. R. Davidson, W. T. Simpson, J. Chem. Phys. 1965, 42, 3175.
[44] J. A. Ibers, W. C. Hamilton, Acta Crystallogr. 1964, 17, 78 1.

912
Helvetica Chimica Acta Vol. 85 (2002)
[45] −teXsan: Single Crystal Structure Analysis Software, Version 1.10b, Molecular Structure Corporation, The
Woodlands, Texas, 1999.
[46] J. Bernstein, R. E. Davis, L. Shimoni, N.-L. Chang, Angew. Chem. 1995, 107, 1689; Angew. Chem., Int. Ed.
1995, 34, 1555.
Received September 3, 2001