New 2 H-azirin-3-amines as synthons for sulfur-heterocyclic α-amino acids

Article abstract of DOI:10.1080/10426507.2012.729114

Three new spiroheterocyclic 2H-azirin-3-amines, which contain a sulfur atom, were prepared and successfully used for the synthesis of oligopeptides containing sulfur-heterocyclic α-amino acids via the azirine/oxazolone method.

Full text of DOI:10.1080/10426507.2012.729114

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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New 2H-Azirin-3-Amines as Synthons for
Sulfur-Heterocyclic α-Amino Acids
Joëlle L. Räber a , Svetlana A. Stoykova a , Christoph Strässler a
Heinz Heimgartner a
&
a Institute of Organic Chemistry, University of Zürich , Zürich ,
Switzerland
Accepted author version posted online: 05 Oct 2012.Published
online: 29 May 2013.
To cite this article: Joëlle L. Räber , Svetlana A. Stoykova , Christoph Strässler & Heinz Heimgartner
(2013) New 2H-Azirin-3-Amines as Synthons for Sulfur-Heterocyclic α-Amino Acids, Phosphorus, Sulfur,
and Silicon and the Related Elements, 188:4, 441-445, DOI: 10.1080/10426507.2012.729114
To link to this article: http://dx.doi.org/10.1080/10426507.2012.729114
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Phosphorus, Sulfur, and Silicon, 188:441–445, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.729114
NEW 2H-AZIRIN-3-AMINES AS SYNTHONS FOR
SULFUR-HETEROCYCLIC α-AMINO ACIDS
Joe¨lle L. Ra¨ber, Svetlana A. Stoykova, Christoph Stra¨ssler,
and Heinz Heimgartner
Institute of Organic Chemistry, University of Zu¨rich, Zu¨rich, Switzerland
GRAPHICAL ABSTRACT
X
O
CN
N(Me)Ph
S
(CH2)n
N
N(Me)Ph
(CH2)n
(CH2)n
(CH2)n
S
S
S
8a n = 1
8b n = 2
1b n = 1
1c n = 2
10
9
Abstract Three new spiroheterocyclic 2H-azirin-3-amines, which contain a sulfur atom, were
prepared and successfully used for the synthesis of oligopeptides containing sulfur-heterocyclic
α-amino acids via the “azirine/oxazolone method.”
Keywords 2H-Azirin-3-amines; Spirothiaheterocycles; Heterocyclic alpha-amino acids
INTRODUCTION
Since the first report on the preparation of 2,2-disubstituted 2H-azirin-3-amines 1
by Rens and Ghosez,1 these cyclic amidines have been shown to be useful synthons for
α,α-disubstituted α-amino acids in syntheses of heterocycles and peptides.2 For example,
the reaction with thiazolidine-2,4-dione leads to the thiadiazocine derivatives 2 via a ring
enlargement reaction,3 whereas the reaction with a peptide acid yields the chain-extended
peptide amide 3 with a terminal 2,2-disubstituted glycine residue4 (Scheme 1). The latter
reaction was used extensively for the synthesis of conformationally restricted natural and
artificial oligopeptides.5
The so-called “azirine/oxazolone method” has also been modified successfully for
the synthesis of endothiopeptides of type 7 containing α,α-disubstituted α-amino acids6
(Scheme 2). Thus, thiocarboxylic acids or peptides with a terminal –COSH group react
with, for example, 1a to give thioamides 5 with an extended peptide chain. Subsequent
acid-catalyzed isomerization via a 1,3-thiazole intermediate yields 6, which can be further
coupled with amino acid esters.
Received 3 July 2012; accepted 6 July 2012.
Financial support of our research project by the Swiss National Science Foundation and F. Hoffmann-La
Roche AG, Basel, is gratefully acknowledged.
Address correspondence to Heinz Heimgartner, Institute of Organic Chemistry, University of Zu¨rich,
Winterthurerstrasse 190, CH-8057 Zu¨rich, Switzerland. E-mail: heimgart@oci.uzh.ch
441

¨
442
J. L. RABER ET AL.
O
R
H
NH
R2
NR3R4
R3
R1
R2
N
COOH
O
R
H
O
N
H
H
S
R4
HN
N
O
N
R1
N
NR3R4
N
H
R1 R2
O
O
S
2
1
3
Scheme 1
R1
R1
S
H
N
N(Me)Ph
CH2Cl2
rt
SH
+
N
N
N(Me)Ph
H
H
N
O
O
1a
4
5
1. ZnCl2, AcOH
2. HCl, AcOH
R1
O
R2
R1
O
H
N
H
N
1. CSA
R2
N
N
CO2Me
N
N(Me)Ph
H
H
H
S
S
2.
H2N
7
6
CO2Me
HOBt, DIEA
Scheme 2
With the aim of preparing synthons for sulfur-containing heterocyclic α-amino car-
boxylic acids, new spiroheterocyclic 2H-azirin-3-amines were synthesized and used in
model reactions.
RESULTS
The original synthesis of 2H-azirin-3-amines 1 starts from N,N-disubstituted 2,2-
dialkyl-acetamides. The reaction with phosgene in toluene followed by addition of a base
like Et3N leads to α-chloroenamines, which on treatment with NaN3 in ether yield 1.1 As
in some cases the reaction of amides with phosgene was sluggish, a modified protocol via
the corresponding thioamides was developed.7 Furthermore, it was shown that the selective
hydrolysis of products 3 of the azirine coupling with a –N(Me)Ph group occurred already
at room temperature.8 Finally, a phosgene-free one-pot synthesis of 1a was elaborated via
formation of the Li-enolate of the N-methyl-N-phenyl 2,2-dialkylacetamide and subsequent
treatment with diphenyl phosphorochloridate (DPPCl) and NaN3 in tetrahydrofuran (THF).9
With these methods we synthesized sulfur-containing spiroheterocyclic 2H-azirin-3-
amines 1b and 1c, starting with tetrahydrothiophene-3-one (8a) and tetrahydrothiopyran-
4-one (8b), respectively (Scheme 3). Transformation to the nitriles 9 by treatment with
Tosmic10 or in a three-step process via NaBH4 reduction, tosylation, and substitution with
NaCN,11 followed by saponification and amide formation via the acid chloride10 or DCC
coupling,11 yielded the amides 10. The latter were used for the azirine synthesis via the

SYNTHONS FOR SULFUR-HETEROCYCLIC α-AMINO ACIDS
443
X
O
CN
N(Me)Ph
S
(CH2)n
N
N(Me)Ph
(CH2)n
(CH2)n
(CH2)n
S
S
S
8a n = 1
8b n = 2
1b n = 1
1c n = 2
10
9
Scheme 3
Li-enolates10 or, after formation of the thioamide by treatment with Lawesson reagent, via
the phosgene method.11
In an analogous manner, the sulfur-heterocyclic dipeptide synthon 1d was prepared
via the thioamide 1112 (Scheme 4).
S
COCl
S
N
N
+
CO2Me
S
N
N
CO2Me
H
X
CO2Me
1d
11
Scheme 4
The reactivity of the new 2H-azirin-3-amines 1b–1d is similar to that of earlier
prepared analogs. For example, the reaction of 1b with thiobenzoic acid in CH2Cl2 at 0 ◦C
led to the corresponding S-heterocyclic N-benzoyl α-aminothiocarboxamide 12 in high
yield11 (Scheme 5).
With the aim of demonstrating the usefulness of 1b–1d as synthons for sulfur-
heterocyclic α-amino acids in the preparation of sterically congested peptides, reactions
with various N-protected α-amino acids or peptide fragments were performed. Thus, reac-
tion of 1b (Tht-synthon) with Fmoc-Val-OH in CH2Cl2 at rt gave the protected dipeptide
amide 13 as a 1:1 mixture of two diastereoisomers, which could be separated by column
3N HCl
MeCN
reflux
S
O
O
H
N
H
N
N(Me)Ph
Fmoc
Fmoc
N
H
N(Me)Ph
N
H
OH
N
O
O
Fmoc-Val-OH
S
S
CH2Cl2, rt
1b
13 (99%)
14 (89%)
Et2NH
rt
CH2Cl2
0 °C
S
O
O
H
N(Me)Ph
S
N
N
H
H2N
N(Me)Ph
O
15 (78%)
S
12 (90%)
Scheme 5

¨
444
J. L. RABER ET AL.
Ph
O
Ph
O
O
H
H
S
Z
N
Z
N
N(Me)Ph
N
N(Me)Ph
N
H
OH
Z-Phe-OH
MeCN, rt
H
O
N
3N HCl
THF/H2O
rt
S
S
1c
16 (85%)
17 (94%)
H-Val-OMe
Ph
PyBOP
Et3N, CH2Cl2
O
H
N
Z
OMe
N
H
N
H
O
O
S
18 (94%)
Scheme 6
chromatography. Then, 13 was deprotected selectively at the C- and N-terminus by treat-
ment with 3N HCl in MeCN/H2O and Et2NH, respectively, leading to 14 or 1511 (Scheme 5).
These dipeptides are suitable building blocks in the synthesis of oligopeptides.
Similarly, 1c (Thp-synthon) was reacted with various N-protected α-amino acids.10,13
For example, coupling with Z-protected Phe-OH gave 16, followed by selective hydrolysis
of the terminal amide group (3N HCl, THF/H2O, rt) to yield 17. The latter was coupled
with H-Val-OMe by standard methods to give 18 (Scheme 6). It was shown by X-ray
crystallography and by 1H-NMR studies that these tripeptides form a β-turn in the crystalline
state as well as in solution, stabilized by an intramolecular hydrogen bond between NH of
valine and C O of the protecting group.
S
O
S
H
N
Boc-Val-OH
N
N
Boc
N
H
THF
0 °C to rt
CO2Me
N
CO2Me
O
1d
19 (44%)
COOH
1.
PhCOSH
THF
0 °C to rt
Br
THF, 0 °C to rt
2.
LiOH
THF/MeOH/H2O
S
rt
S
O
O
N
N
H
N
Ph
N
O
O
H
OMe
Br
CO2Me
S
n
18 (85%)
20a (n = 1)
20b (n = 2)
20c (n = 3)
Scheme 7

SYNTHONS FOR SULFUR-HETEROCYCLIC α-AMINO ACIDS
445
Finally, the reaction of 1d (Thp-Pro-synthon) with thiobenzoic acid occurred
smoothly in THF at room temperature to give the endothiodipeptide 18, whereas the
reaction with protected α-amino acids such as Boc-Val-OH led to tripeptides, for example,
1912 (Scheme 7). It is important to note that 19 in the crystal adopts a conformation, which
is almost identical with a β-turn in spite of the fact that no stabilization by an intramolecular
hydrogen bond is possible. This may be explained by the presence of the α,α-disubstituted
α-amino acid in analogy to the effect of aminoisobutyric acid (Aib; see ref. [14]).
The coupling reaction of 1d with 4-bromobenzoic acid gave 20a, and subsequent
saponification of the ester group led to the corresponding dipeptide acid, which was again
reacted with 1d, yielding tetrapeptide ester 20b. Repetition of these two steps led to the
hexapeptide 20c in good yield (Scheme 7). It was shown by X-ray crystallography and 1H-
NMR studies that these highly congested oligopeptides also exist in a helical conformation
in the crystalline state as well as in solution.
CONCLUSIONS
The new sulfur-containing 2H-azirin-3-amines can be prepared conveniently and
have been shown to be useful building blocks for novel heterocyclic α,α-disubstituted α-
amino acids in the synthesis of conformationally restricted oligopeptides. On the basis of
the general reactivity of 2H-azirin-3-amines, they may also be used for the synthesis of
novel sulfur containing heterocycles.
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