The preparation of optically active α-amino 4H-[1,2,4]oxadiazol-5-ones from optically active α-amino acids

Article abstract of DOI:10.1016/j.tet.2009.09.045

Optically active α-amino 4H-[1,2,4]oxadiazol-5-ones (oxadiazolones) were prepared from optically active α-amino acids in five synthetic steps. The oxadiazolone moiety serves as a bioisosteric replacement for the carboxylic acid. Incorporation of an α-amino oxadiazolone into a representative dipeptide mimic is described.

Full text of DOI:10.1016/j.tet.2009.09.045

Tetrahedron 65 (2009) 9536–9541
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The preparation of optically active a-amino 4H-[1,2,4]oxadiazol-5-ones
from optically active a-amino acids
,
a
a
a
b
John E. Mangette a , Matthew R. Johnson , Van-Duc Le , Rajesh A. Shenoy , Howard Roark ,
*
Michael Stier b, Thomas Belliotti b, Thomas Capiris b, Peter R. Guzzo a
a AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA
b Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 June 2009
Received in revised form 9 September 2009
Accepted 10 September 2009
Available online 15 September 2009
Optically active
a-amino 4H-[1,2,4]oxadiazol-5-ones (oxadiazolones) were prepared from optically active
a-amino acids in five synthetic steps. The oxadiazolone moiety serves as a bioisosteric replacement for
the carboxylic acid. Incorporation of an
described.
a-amino oxadiazolone into a representative dipeptide mimic is
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Oxadiazolone
Bioisostere
Optically active
a
-Amino acid
1. Introduction
for the potential of its incorporation into peptides via standard
coupling methodology.
The structure and function of a-amino acids and peptides have
long fascinated chemists. Alteration of the peptide backbone
through peptide mimetic design with a view on subsequent
function continues to be a richly explored area of research.1
2. Results and discussion
Commercially available, suitably-protected
a-amino acids 1a–e
Isosteric replacements for the carboxylic acid of a-amino acids or
were converted to -amino oxadiazolones 6a–e (Fig. 1). Represen-
a
the C-terminus of peptides have been less explored with tetra-
zoles being the dominant replacement.2 4H-[1,2,4]Oxadiazol-
5-ones (oxadiazolones) have been employed as isosteric
tative examples included lipophilic amino acids (phenylalanine and
valine), an acidic amino acid (aspartic acid), and a basic amino acid
(lysine). A general synthetic route was developed and is depicted in
Scheme 1. The protected amino acids 1a–e were converted to am-
ides 2a–e by a water soluble carbodiimide mediated coupling. The
amides 2a–e were conveniently dehydrated to nitriles 3a–e by
action of cyanuric chloride in DMF. This simple and general pro-
cedure has been reported to proceed without racemization and is
consistent with our results (vide infra).6 The reaction of nitriles 3a–
e with aqueous hydroxylamine provided hydroxyamidines 4a–e.
Oxadiazolones 5a–e were formed by refluxing 4a–e with carbon-
yldiimidazole in THF. Deprotection, and in some cases global
deprotection, of 5a–e was affected by exposure to ethereal hydro-
replacements for carboxylic acids.3 However,
a-amino oxadiazo-
lones have been rarely described in the literature, with a few ex-
amples without side chains,4 and only one citation with side
chains.5 The use of oxadiazolones as a carboxylic acid isostere of
a
-amino acids or peptides may find wider use if efficient syn-
theses and knowledge about their properties were readily avail-
able. This note outlines the preparation of five representative
a
-amino oxadiazolones derived from optically active natural
amino acids. This straight-forward sequence using readily avail-
able starting materials, and here determined to be stereospecific,
to our knowledge has not been previously reported. To further
develop the knowledge base of this class of compounds, analog 6a
was chosen for determination of selected physical properties and
gen chloride to furnish the desired a-amino 4H-[1,2,4]oxadiazol-5-
ones 6a–e as their hydrochloride salts. The product oxadiazolone
hydrochlorides 6a–e were found to be stable, solid materials. Re-
analysis by 1H NMR of a nine-month-old batch of 6a revealed no
decomposition.
The overall route shown in Scheme 1 is efficient and in many
cases the intermediates could be purified by recrystallization. The
* Corresponding author. Tel.: þ1 518 512 2172; fax: þ1 518 512 2081.
E-mail address: john.mangette@amriglobal.com (J.E. Mangette).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.045

J.E. Mangette et al. / Tetrahedron 65 (2009) 9536–9541
9537
Starting
Product
Strecker reactions,7 the scope of available substituents could be
readily extended beyond the standard amino acids. One apparent
limitation observed was an attempt to transform S-benzyl N-Boc-
cysteine through the same general sequence. Although the oxa-
diazolone could be formed in low yield (21%, structure not shown)
from the hydroxyamidine intermediate, all attempts to remove the
Boc-protecting group led to non-specific decomposition.
Amino Acid
4H-[1,2,4]oxadiazol-5-one
H
OH
N
BocHN
H2N
O
O
N
O
HCl
The chiral integrity of oxadiazolones 6a–e was determined by
preparing their Mosher amides.8 Oxadiazolones 6a–e were coupled
with (R)-Mosher chloride to furnish amides 7a–e; 7c (derived from
lysine) was prepared as the bis-Mosher amide. Analysis of 7a–e by 19F
NMR demonstrated negligible loss of optical purity during the syn-
thetic sequence. Analysis of 7d by 1H and 19F NMR demonstrated
greater than90% ee. Accurate quantification beyond this level wasnot
possible due to broadening of signals, most likely due to rotomers.
1a
6a, (>95% ee)
H
N
OH
H2N
HCl
BocHN
O
N
O
O
6b, (>90% ee)
1b
NHBoc
The utility of
could be readily incorporated into peptides. To further demonstrate
the potential of -amino oxadiazolones, optically active 6a, derived
a-amino oxadiazolones would be enhanced if they
NH2
a
from phenylalanine, was coupled with N-Boc-alanine 8 by action of
a water soluble carbodiimide to give dipeptide isostere 9 in good
yield (Scheme 2). Notably, protection of the oxadiazolone func-
tionality was not required for efficient coupling.
H
N
OH
OH
BocHN
H2N
O
O
O
N
O
2HCl
1c
6c, (>95% ee)
CH3
OH
O
O
BocHN
H
N
CH3
8
O
HN
H
H
N
N
H
HCl
N
N
O
H2N
Boc
BocHN
N
O
EDC, HOBT
CH2Cl2
N
O
N
O
O
1d
6d, (>90% ee)
6a
84%
9
t-BuO2C
BocHN
HO2C
H2N
Scheme 2.
H
N
OH
0
O
As a representative example, the pKa s and log P for compound
6a were determined to exemplify this class of compound and to
compare0 with its natural amino acid counterpart, phenylalanine.
Two pKa s for compound 6a were determined by potentiometry:
pKa¼7.34 (ꢀ0.12) and 3.03 (ꢀ0.09) compared with phenylalanine
pKa¼9.2 and 2.6. Based on these data, the oxadiazolone moiety of
6a appears to be comparable or slightly less acidic than the carb-
oxylic acid function of phenylalanine. Interestingly, the amino
group of 6a is considerably less basic than in phenylalanine. Al-
though other factors may be at play, this latter observation may be
partly attributable to the aromatic character of the oxadiazolone
ring, depicted in Figure 2 as the hydroxyoxadiazole tautomer. In
a similar fashion, simple replacement of the carboxyl group of
glycine (pKa¼10.06) with a benzene ring (benzylamine pKa¼9.46)
shows some decrease in pKa.9 The partitioning coefficient (log P) for
compound 6a was determined to be ꢁ1.56 by the shake flask
method compared with the literature value of ꢁ1.44 for the zwit-
terionic form of phenylalanine.10
O
N
O
2HCl
1e
6e, (>95% ee)
Figure 1.
R
R
EDC, HOBT,
NH4OH, THF
50-80%
NH2
BocHN
BocHN
CO2H
O
2
1
50% aq.
NH2OH
Cyanuric
chloride
R
R
NH2
NOH
BocHN
BocHN
CN
DMF
EtOH
3
55-89%
4
66-99%
R
R
CDI
THF
HCl
ether
H
H
N
N
H2N
HCl
BocHN
O
O
reflux
N
O
N
O
76-98%
6
60-84%
5
N
O
R
(R)-MosherCl
H2N
OH
H
N
N
N
O
Na2CO3
THF, H2O
O
F3C
H
OMe
N
O
6a
7
74-95%
Figure 2.
% ee determined by 19F NMR analysis
In conclusion, an efficient synthetic route for the preparation of
Scheme 1.
optically active
a-amino oxadiazolones from optically active a-
route is fairly general, without any interference from the various
substituents defined in Figure 1. With the availability of optically
amino acids was developed. The oxadiazolone moiety can be con-
sidered as an isosteric replacement of the carboxylic acid. Efficient
active
a
-aminonitriles, for example, from various asymmetric
incorporation of a representative a-amino oxadiazolone into

9538
J.E. Mangette et al. / Tetrahedron 65 (2009) 9536–9541
a dipeptide mimic was exemplified. The use of
a
-amino oxadiazo-
and extracted with a 1 M sodium hydroxide solution. The aqueous
lones in peptide mimetic design remains to be more fully
investigated.
layer was diluted with methylene chloride, carefully acidified with
1 M hydrochloric acid to pH 3–4 with ice bath cooling and extracted
with dichloromethane (2ꢂ). The organic layers were combined,
washed with brine, dried over sodium sulfate, filtered, and evap-
orated to afford the desired product 5.
3. Experimental
3.1. General
3.6. General procedure for the preparation of oxadiazolone
hydrochloride (6)
All reactions were performed under a dry nitrogen or argon
atmosphere. Melting points are uncorrected. Proton NMR spectra
were recorded at 300 MHz and Fluorine NMR spectra at 282 MHz.
HPLC analysis was run on a Waters Symmetry C18 column
(4.6ꢂ2 mm) with a flow rate of 1 mL/min and UV detection at
254 nM using a standard solvent gradient program (method A).
To N-Boc-oxadiazolone 5 was added a 2 M solution of hydrogen
chloride in diethyl ether and the mixture was stirred for 18 h. The
precipitated solid was filtered, washed with diethyl ether, and dried
to afford the desired product as a white solid 6.
Method A:
3.7. General procedure for the preparation of oxadiazolone
Mosher amide (7)
Time (min)
%A
%B
0
20
30
90
10
10
10
90
90
To oxadiazolone 6 (1 equiv) in THF and water (1:1 vol, c¼0.1 M)
was added sodium carbonate (2 equiv), followed by R(ꢁ)-
a
-methoxy-a-trifluoromethylphenylacetyl chloride (1 equiv). The
Solvent A¼0.05% trifluoroacetic acid in water.
reaction mixture was stirred at room temperature for 2–18 h. The
mixture was diluted with ethyl acetate and 1 N HCl. The organic
layer was washed with 1 N HCl, dried over sodium sulfate, filtered,
and evaporated to provide 7.
Solvent B¼0.05% trifluoroacetic acid in acetonitrile.
3.2. General procedure for the preparation of amide (2)
To a solution of amino acid (1.0 equiv) in tetrahydrofuran
(c¼0.07 M) was added 1-hydroxybenzotriazole (HOBT, 1.0 equiv)
followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (EDC, 1.15 equiv). After stirring for 0.5 h, concentrated
ammonium hydroxide (2.0 equiv) was added and the reaction
mixture was stirred for 16–60 h. The mixture was concentrated and
the residue was diluted with ethyl acetate. The suspension was
washed with saturated sodium bicarbonate solution and brine,
dried over sodium sulfate, filtered, and concentrated to afford the
desired product 2.
3.7.1. (S)-[1-(N-Hydroxycarbamimidoyl)-2-phenylethyl]-carbamic
acid tert-butyl ester (4a)11. Compound 3a, used to prepare 4a, was
prepared according to a literature procedure.6 According to the
generalproceduredescribed, 3a (4.60 g,18.7 mmol)wasconvertedto
4a (4.4 g, 85%) as a white solid: mp¼158–161 ꢃC; 1H NMR (300 MHz,
DMSO-d6)
d
8.97 (s,1H), 7.14–7.28 (m, 5H), 6.85 (d, J¼9.6 Hz,1H), 5.34
(s, 2H), 4.10–4.19 (m, 1H), 2.79–3.03 (m, 2H), 1.29 (s, 9H); ESI: m/
25
z¼280 (MþH)þ; [
a]
D
þ0.86 (c 1.05, MeOH). Anal. Calcd C14H21N3O3:
C, 60.20; H, 7.58; N, 15.04. Found: C, 60.21; H, 7.64; N, 14.97.
3.7.2. (S)-[1-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-2-phenyl-
ethyl]-carbamic acid tert-butyl ester (5a). According to the general
procedure described, 4a (1.80 g, 6.44 mmol) was converted to 5a
(1.51 g, 77%) as a white solid: mp¼151–153 ꢃC; 1H NMR (300 MHz,
3.3. General procedure for the preparation of nitrile (3)6
To a solution of the amide 2 (1.0 equiv) in N,N-dimethylform-
amide (c¼0.2 M) at 0 ꢃC was added cyanuric chloride (1.4 equiv).
After stirring for 1 h at 0 ꢃC, the reaction mixture was quenched
with a cold 0.5 M sodium hydroxide solution and the mixture
extracted with ethyl acetate (3ꢂ). The organic layers were com-
bined and washed with water and brine (2ꢂ), dried over sodium
sulfate, filtered, and concentrated. The crude residue was purified
by silica gel chromatography to afford the desired nitrile 3.
DMSO-d6)
d
12.5 (br s, 1H), 7.46 (d, J¼8.1 Hz, 1H), 7.19–7.32 (m, 5H),
4.64 (m, 1H), 3.08 (dd, J¼5.6, 13.7 Hz, 1H), 2.94 (dd, J¼9.7, 13.7 Hz,
1H), 1.30 (s, 9H); 13C NMR (DMSO-d6)
d 160.5, 159.6, 154.8, 136.7,
129.1, 128.1, 126.5, 78.5, 48.2, 36.7, 28.0; ESI: m/z¼304 (MꢁH)ꢁ; IR
25
3335, 3122, 1782, 1697, 1525, 1168, 972 cmꢁ1; [
MeOH). Anal. Calcd C15H19N3O4: C, 59.01; H, 6.27; N, 13.76. Found:
C, 58.83; H, 6.27; N, 13.63.
a
]
ꢁ24.93 (c 1.02,
D
3.4. General procedure for the preparation of
hydroxyamidine (4)
3.7.3. (S)-3-(1-Amino-2-phenylethyl)-4H-[1,2,4]oxadiazol-5-one
hydrochloride (6a). According to the general procedure described, 5a
(1.34 g, 4.39 mmol) was converted to 6a (1.05 g, 99%) as a white
solid: mp¼168–171 ꢃC; 1H NMR (300 MHz, CD3OD)
d 7.33–7.43 (m,
To a solution of nitrile 3 (1.0 equiv) in ethanol (c¼0.25 M) was
added 50% w/w aqueous hydroxylamine (4.0 equiv). After stirring
for 18 h at room temperature, the reaction mixture was concen-
trated, the residue suspended in water, and extracted with diethyl
ether (2ꢂ). The organic layers were combined, washed with brine,
dried over sodium sulfate, filtered, and concentrated to afford the
desired product 4.
3H), 7.26–7.29 (m, 2H), 4.69 (t, J¼7.3 Hz, 1H), 3.18–3.36 (m, 2H,
overlapping with MeOD peak); 1H NMR (300 MHz, D2O)
d 7.29–7.37
(m, 3H), 7.19–7.22 (m, 2H), 4.70 (m, 2H, overlapping with HOD peak),
3.29 (dd, J¼7.0, 14.3 Hz, 1H), 3.21 (dd, J¼7.5, 14.3 Hz, 1H); 13C NMR
(DMSO-d6)
d 158.7, 156.7, 134.0, 129.2, 128.6, 127.3, 47.1, 35.8; APCI:
m/z¼206 (MþH)þ; IR 1770 cmꢁ1; [
a]
D
ꢁ23.12 (c 1.00, MeOH). Anal.
25
Calcd C10H11N3O2$1.05HCl: C, 49.33; H, 4.99; N, 17.26, Cl, 15.29.
3.5. General procedure for the preparation of N-Boc-
Found: C, 49.08; H, 4.68; N, 17.30; Cl, 14.97.
oxadiazolone (5)
3.7.4. (R)-3,3,3-Trifluoro-2-methoxy-N-(S)-[1-(5-oxo-4,5-dihydro-
[1,2,4]oxadiazol-3-yl)-2-phenylethyl]-2-phenyl-propionamide
(7a). According to the general procedure described, 6a (50 mg,
0.21 mmol) was converted to 7a (81 mg, 93%) as a white solid; 1H
To a solution of hydroxyamidine 4 (1.0 equiv) in tetrahydrofuran
(c¼0.08 M) was added 1,10-carbonyldiimidazole (1.5 equiv) and the
mixture was heated at reflux for 5–18 h. The reaction mixture was
cooled and concentrated. The residue was dissolved in ethyl acetate
NMR (300 MHz, DMSO-d6)
d
12.50 (br s, 1H), 8.95 (d, J¼8.7 Hz, 1H),

J.E. Mangette et al. / Tetrahedron 65 (2009) 9536–9541
9539
7.37 (m, 1H), 7.15–7.35 (m, 7H), 7.03 (d, J¼7.7 Hz, 1H), 5.25 (ddd,
J¼4.6, 8.7, 10.8 Hz, 1H), 3.38 (s, 3H), 3.19 (dd, J¼4.6, 13.9 Hz, 1H),
3.07 (dd, J¼10.8, 13.9 Hz, 1H); 19F NMR (282 MHz, DMSO-d6)
5H), 4.68 (d, J¼8.4 Hz, 1H), 3.44 (s, 3H), 2.22 (octet, J¼6.7 Hz, 1H),
1.04 (d, J¼6.7 Hz, 3H), 1.00 (d, J¼6.7 Hz, 3H); 19F NMR (282 MHz,
CD3OD)
d
ꢁ70.78 (>90% ee); MS (ESI) m/z 374 [C16H18F3N3O4þH]þ.
d
ꢁ68.86 (98% ee); ESI: m/z¼422 (MþH)þ; HPLC analysis: 99.3%,
The other diastereomer of 7b derived from D-valine (structure not
25.09 min retention time. The other diastereomer of 7a derived
shown) was prepared by analogous procedures to validate the
from
analogous procedures to validate the enantiomeric excess de-
termination. 19F NMR (282 MHz, DMSO-d6)
ꢁ69.07 (98% ee).
D-phenylglycine (structure not shown) was prepared by
enantiomeric excess determination. 19F NMR (282 MHz, CD3OD)
d
ꢁ70.82 (>95% ee).
d
3.7.11. (S)-(5-tert-Butoxycarbonylamino-5-carbamoyl-pentyl)carba-
3.7.5. (S)-(1-Carbamoyl-2-methyl-propyl)-carbamic acid tert-butyl
mic acid tert-butyl ester (2c)13
-Amino acid 1c was prepared by
. L
ester (2b)12. Compound 2b was prepared according to the general
dissolving its dicyclohexyl amine salt (12.0 g, 22.7 mmol) in tolu-
ene (200 mL) and washing with a 10% w/w aqueous solution of
potassium hydrogen sulfate (3ꢂ75 mL). The organic layer was
dried over sodium sulfate, filtered, and concentrated at reduced
pressure. Reaction of 1c with 1-hydroxybenzotriazole (3.18 g,
23.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (5.17 g, 27.0 mmol), and concentrated ammonium
hydroxide (3.20 mL, 47.4 mmol) in tetrahydrofuran (250 mL) and
workup as described in the general procedure followed by re-
crystallization from hexanes/ethyl acetate afforded amide 2c
procedure described, using 1b (4.00 g, 18.4 mmol) and affording 2b
25
(3.2 g, 80%) as a white solid: mp 155–157 ꢃC (lit. 157 ꢃC); [
a
]
ꢁ0.4
D
23
(c 1.46, MeOH), (lit. [
a
]
D
0.3 (c 2.67, EtOH)).
3.7.6. (S)-(1-Cyano-2-methyl-propyl)-carbamic acid tert-butyl ester
(3b). According to the general procedure described, 2b (3.10 g,
14.3 mmol) was converted to 3b (2.25 g, 80%) as a white solid: mp
69–71 ꢃC; 1H NMR (CDCl3)
d
4.92 (br d, J¼9.0 Hz, 1H), 4.49–4.44 (m,
1H), 2.02 (octet, J¼6.7 Hz, 1H), 1.46 (s, 9H), 1.08 (t, J¼6.2 Hz, 6H); 13C
NMR (CDCl3)
d
154.8, 118.4, 81.5, 48.8, 32.2, 28.8, 28.6, 28.3, 18.9,
(6.01 g, 76%) as a white solid: 1H NMR (CDCl3)
d 6.21 (br s, 1H), 5.51
18.3; IR (ATR) 3348, 2973, 1689, 1514, 1341, 1306, 1246, 1155,
(br s, 1H), 5.22–5.10 (m, 1H), 4.62 (br s, 1H), 4.22–4.01 (m, 1H),
1050 cmꢁ1
;
[a
]
ꢁ67.6 (c 1.07, MeOH); MS (APCI) 197
3.15–3.09 (m, 2H), 1.92–1.81 (m, 1H), 1.72–1.62 (m, 2H), 1.56–1.32
25
D
25
[C10H18N2O2ꢁH]ꢁ; MS (ESI) m/z 199 [C10H18N2O2þH]þ. Anal. Calcd
for C10H18N2O2$0.05H2O: C, 60.31; H, 9.16; N,14.07. Found: C, 60.63;
H, 9.56; N, 14.09.
(m, 21H); [
a
]
þ0.3 (c 1.005, methanol); MS (APCI) m/z 345
D
[C16H31N3O5þH]þ.
3.7.12. (S)-(5-tert-Butoxycarbonylamino-5-cyanopentyl)-carbamic
acid tert-butyl ester (3c). Reaction of amide 2c (5.43 g, 15.7 mmol)
with cyanuric chloride (4.03 g, 21.8 mmol) in N,N-dimethylform-
amide (80 mL) followed by workup as described in the general
procedure and silica gel chromatography (eluent: 75:25 hexanes/
ethyl acetate) afforded nitrile 3c (3.31 g, 64%) as a white solid. Re-
crystallization from hexanes/ethyl acetate afforded analytically
3.7.7. (S)-[1-(N-Hydroxycarbamimidoyl)-2-methyl-propyl]-carbamic
acid tert-butyl ester (4b). According to the general procedure de-
scribed, 3b (2.10 g, 10.6 mmol) was converted to 4b (2.07 g, 84%) as
a white solid: mp 138–141 ꢃC; 1H NMR (CDCl3)
d 5.43 (br d,
J¼6.7 Hz, 1H), 4.90 (br s, 2H), 4.68 (br s, 1H), 3.78 (t, J¼8.5 Hz, 1H),
2.11–1.88 (m, 1H), 1.44 (s, 9H), 0.95 (t, J¼6.7 Hz, 6H); 13C NMR
(CDCl3)
d
156.5, 154.7, 80.2, 58.2, 30.9, 28.7, 19.9, 18.9; IR (ATR) 3477,
pure 3c (2.50 g, 48%): mp 79–82 ꢃC; 1H NMR (CDCl3)
1H), 4.62–4.47 (m, 2H), 3.20–3.08 (m, 2H), 1.89–1.79 (m, 2H), 1.57–
1.38 (m, 22H); 13C NMR (DMSO-d6)
155.5, 154.7, 119.8, 79.1, 77.3,
41.8, 31.3, 28.6, 28.2, 27.9, 27.3, 22.2; [
d 5.05 (br s,
3359, 2980, 1665, 1518, 1368, 1327, 1273, 1247, 1169, 1043 cmꢁ1
;
25
[
a]
ꢁ20.9 (c 1.02, MeOH); MS (APCI) m/z 232 [C10H21N3O3þH]þ,
d
D
25
463 [(2ꢂC10H21N3O3)þH]þ. Anal. Calcd for C10H21N3O3: C, 51.93; H,
a
]
ꢁ38.7 (c 1.018, CH2Cl2); IR
D
9.15; N, 18.17. Found: C, 52.20; H, 9.51; N, 18.04.
(ATR) 3357, 2982, 2951, 2288, 1698, 1685, 1522, 1365, 1246, 1164,
947 cmꢁ1. Anal. Calcd for C16H29N3O4: C, 58.69; H, 8.93; N, 12.83.
Found: C, 58.61; H, 9.12; N, 12.67.
3.7.8. (S)-[2-Methyl-1-(5-oxo-2,5-dihydro-[1,2,4]oxadiazol-3-yl)-
propyl]-carbamic acid tert-butyl ester (5b). According to the general
procedure described, 4b (1.8 g, 7.6 mmol) was converted to 5b
(1.70 g, 88%) as a white solid: mp 120–121 ꢃC; 1H NMR (CDCl3)
3.7.13. (S)-[5-tert-Butoxycarbonylamino-5-(N-hydroxycarb-
amimidoyl)pentyl]carbamic acid tert-butyl ester (4c). Reaction of ni-
trile 3c (2.40 g, 7.33 mmol) with 50% w/w aqueous hydroxylamine
(2.43 mL, 39.6 mmol) in ethanol (30 mL) followed by dilution with
water (30 mL) did not provide a solid as described in the general
procedure. The solution was concentrated to half of its original vol-
ume and extracted with dichloromethane (2ꢂ50 mL). The organic
layers were combined, washed with brine, dried over sodium sulfate,
filtered, and concentrated at reduced pressure. The foamy residue
was redissolved in methanol and concentrated again to remove re-
sidual solvents to afford hydroxyamidine 4c (2.40 g, 91%) as a white
d
10.93–9.42 (br s, 1H), 5.21 (br d, J¼8.1 Hz, 1H), 4.37 (t, J¼7.6 Hz,
1H), 2.36–2.22 (m, 1H), 1.45 (s, 9H), 1.04–1.00 (m, 6H); 13C NMR
(CDCl3) 160.5, 159.6, 156.4, 81.7, 53.3, 31.4, 28.6, 19.4,18.4; IR (ATR)
3737, 3337, 3144, 2983, 1802, 1781, 1688, 1514, 1469, 1283,
d
25
1159 cmꢁ1; [
a
]
D
ꢁ44.1 (c 1.04, MeOH); MS (APCI) m/z 256
[C11H19N3O4ꢁH]ꢁ, 513 [(2ꢂC11H19N3O4)ꢁH]ꢁ. Anal. Calcd for
C11H19N3O4: C, 51.35; H, 7.44; N, 16.33. Found: C, 51.28; H, 7.49; N,
16.26.
3.7.9. (S)-3-(1-Amino-2-methyl-propyl)-4H-[1,2,4]-oxadia-zol-5-one
hydrochloride (6b). According to the general procedure described,
5b (1.6 g, 6.2 mmol) was converted to 6b (0.7 g, 60%) as a white
solid: mp 54–58 ꢃC; 1H NMR (CDCl3)
4.84 and 4.76 (2 s, 3H), 4.10–3.98 (m,1H), 3.13–2.98 (m, 2H),1.90–1.54
(2m, 4H), 1.54–1.25 (m, 20H); 13C NMR (DMSO-d6)
155.4, 154.7,
d 7.00 (br s, 1H), 5.05 (br s, 1H),
d
solid: mp 176–180 ꢃC; 1H NMR (CDCl3)
d
4.33 (d, J¼5.8 Hz, 1H), 2.33
153.0, 77.8, 77.2, 51.0, 32.6, 29.0, 28.2, 28.1, 27.5, 22.8; [
a]
ꢁ6.2 (c
25
D
(octet, J¼6.6 Hz, 1H), 1.10 (t, J¼6.6 Hz, 6H); 13C NMR (CDCl3)
d
161.5,
1.01, methanol); IR (ATR) 3343, 2978, 1655, 1511, 1365, 1162 cmꢁ1; MS
(ESI) m/z 361 [C16H32N4O5þH]þ. Anal. Calcd for C16H32N4O5$0.3H2O:
C, 52.53; H, 8.98; N, 15.31. Found: C, 52.62; H, 8.83; N, 15.28.
157.8, 53.7, 31.9, 18.6, 18.3; IR (ATR) 3155, 2815, 2715, 2617, 1764,
25
1728, 1595, 1525, 1494, 1268, 1049 cmꢁ1; [
a]
ꢁ14.7 (c 1.04,
D
MeOH); MS (ESI) m/z 158 [C6H11N3O2þH]þ. Anal. Calcd for
C6H11N3O2$HCl: C, 37.22; H, 6.25; N, 21.70; Cl, 18.31. Found: C, 37.19;
H, 6.19; N, 21.37; Cl, 18.42.
3.7.14. (S)-[5-tert-Butoxycarbonylamino-5-(5-oxo-4,5-dihydro-[1,2,4]-
oxadiazol-3-yl)pentyl]carbamic acid tert-butyl ester (5c). Reaction of
hydroxyamidine 4c (2.20 g, 6.10 mmol) with 1,10-carbon-
yldiimidazole (1.50 g, 9.15 mmol) in tetrahydrofuran (75 mL) as de-
scribed in the general procedure afforded oxadiazolone 5c (1.42 g,
60%) as a white solid: mp (DSC) 122.3–125.2 ꢃC; 1H NMR (CDCl3)
3.7.10. (S)-2-Methoxy-N-[(S)-2-methyl-1-(5-oxo-4,5-dihydro-
[1,2,4]oxadiazol-3-yl)-propyl]-2-phenyl-2-trifluoromethoxy-acetamide
(7b). Yield 28 mg (57%): 1H NMR (300 MHz, CD3OD)
d 7.57–7.40 (m,

9540
J.E. Mangette et al. / Tetrahedron 65 (2009) 9536–9541
d
9.49 (br s, 1H), 5.41 (br s, 1H), 4.68 (br s, 1H), 4.48 (q, J¼7.0 Hz, 1H),
3.23–3.06 (m, 2H), 2.08–1.81 (m, 2H), 1.61–1.33 (m, 22H); 13C NMR
(DMSO-d6) 160.9,159.8,155.5,155.0, 78.5, 77.3, 46.7, 30.8, 28.9, 28.2,
28.0, 27.5, 22.3; [
procedure described above, hydroxyamidine 4d (0.67 g,
2.9 mmol) afforded the desired oxadiazolone 5d (0.47 g, 63%) as
a white solid: mp (DSC) 131.8–134.7 ꢃC and 191.1–191.8 ꢃC; 1H
d
25
a]
ꢁ27.2 (c 1.04, CH2Cl2); IR (ATR) 3366, 3129,
NMR (CD3OD)
(m, 4H), 1.46 and 1.37 (2s, 9H); 13C NMR (DMSO-d6, rotational
isomers) 161.8, 161.3, 159.7, 153.3, 152.6, 79.2, 52.3, 52.1, 46.4,
46.2, 31.4, 30.4, 28.0, 27.8, 23.6, 22.9; [
d 4.8–4.7 (m, 1H), 3.54–3.45 (m, 2H), 2.41–1.82
D
2982, 2936, 1787, 1748, 1683, 1518, 1366, 1248, 1158, 975, 855 cmꢁ1
;
MS (ESI) m/z 385 [C17H30N4O6ꢁH]ꢁ. Anal. Calcd for C17H30N4O6: C,
d
25
52.84; H, 7.82; N, 14.50. Found: C, 52.53; H, 8.00; N, 14.56.
a
]
ꢁ85.7 (c 1.15,
D
methanol); IR (ATR) 2980, 1773, 1666, 1412, 1159, 1128, 958,
760 cmꢁ1; MS (ESI) m/z 156 [C11H17N3O4ꢁBocþH]þ. Anal. Calcd
for C11H17N3O4: C, 51.76; H, 6.71; N, 16.46. Found: C, 51.88; H,
6.76; N, 16.45.
3.7.15. 3-(1,5-Diaminopentyl)-4H-[1,2,4]-oxadiazol-5-one dihydro-
chloride (6c). Reaction of oxadiazolone 5c (0.82 g, 2.1 mmol) with
a 2 M hydrogen chloride solution in ether (50 mL) as described in
the general procedure followed by lyophilization afforded oxadi-
azolone 6c (0.42 g, 76%) as a tan solid: mp (DSC) 152.1–152.3 ꢃC
3.7.21. (S)-3-Pyrrolidin-2-yl-4H-[1,2,4]oxadiazol-5-one hydrochloride
(6d). Following the general procedure described above, oxadiazo-
lone 5d (0.40 g, 1.6 mmol) afforded the desired product 6d (0.28 g,
90%) as a white solid: mp (DSC) 178.8–187.5 ꢃC; 1H NMR (CD3OD)
(endotherm), 235.2–236.3 ꢃC (endotherm); 1H NMR (D2O)
d 4.48 (t,
J¼6.6 Hz, 1H), 2.88 (t, J¼7.6 Hz, 2H), 2.05–1.86 (m, 2H), 1.61 (quint,
J¼7.8 Hz, 2H), 1.38 (quint, J¼7.8 Hz, 2H); 13C (D2O)
d 162.1, 157.5,
25
46.8, 39.3, 30.3, 26.6, 21.4; [
a
]
ꢁ20.9 (c 0.11, methanol); IR (ATR)
d
4.81 (m, 1H), 3.49 (t, J¼7.2 Hz, 2H), 2.45–2.37 (m,1H), 2.22–2.13 (m,
D
25
2919, 1765, 1602, 1492, 949 cmꢁ1
;
MS (APCI) m/z 187
3H); 13C NMR (CD3OD)
d
161.7,157.4, 54.9, 47.6, 29.7, 24.6; [
a
]
ꢁ43.3
D
[C7H14N4O2þH]þ. Anal. Calcd for C7H14N4O2$2HCl$H2O: C, 30.34; H,
(c 1.055, methanol); IR (ATR) 2923, 1769, 1501, 1370, 1268, 942, 892,
728 cmꢁ1; MS (APCI) m/z 156 [C6H9N3O2þH]þ. Anal. Calcd for
C6H9N3O2$HCl: C, 37.61; H, 5.26; N, 21.93; Cl, 18.50. Found: C, 37.51;
H, 5.24; N, 21.68; Cl, 18.60.
6.55; N, 20.22. Found: C, 30.61; H, 6.47; N, 20.29.
3.7.16. (2R,20R)-N,N0-((S)-1-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-
pentane-1,5-diyl)bis(3,3,3-trifluoro-2-methoxy-2-phenylpropanamide)
(7c). 1H NMR (CDCl3)
d
7.61 (d, J¼8.5 Hz, 1H), 7.48–7.36 (m, 10H),
3.7.22. (S)-3-[1-(3,3,3-Trifluoro-2-methoxy-2-phenyl-propionyl)-(S)-
7.21 (t, J¼6.2 Hz, 1H), 4.80 (td, J¼8.6, 5.1 Hz, 1H), 3.45, 3.31 and 3.28
pyrrolidin-2-yl]-4H-[1,2,4]oxadiazol-5-one (7d). Yield 20 mg (52%):
(2s, m, 8H), 2.03–1.88 (m, 1H), 1.84–1.69 (m, 1H), 1.66–1.49 (m, 2H),
1H NMR (300 MHz CDCl3)
d 9.83 (br s, 1H), 7.45–7.38 (m, 5H), 5.13
1.49–1.29 (m, 2H); 19F (CDCl3)
d
ꢁ69.07, ꢁ69.40 (>95% ee); MS (ESI)
(dd, J¼7.9, 2.6 Hz, 1H), 3.66 (t, J¼1.6 Hz, 3H), 3.53–3.43 (m, 1H),
m/z 619 [C27H28F6N4O6þH]þ; HPLC (Waters Symmetry C18 Column,
Detector @ 254 nm) >99%, tR¼11.1 min. The other diastereomer of 7c
2.76–2.78 (m, 1H), 2.48–2.35 (m, 1H), 2.11–1.87 (m, 3H); 19F NMR
(282 MHz, CDCl3)
The other diastereomer of 7d derived from D-proline (structure not
d
ꢁ70.84; MS (ESI) m/z 372 [C16H16F3N3O4þH]þ.
derived from
D-lysine (structure not shown) was prepared by anal-
ogous procedures to validate the enantiomeric excess determination.
shown) was prepared by analogous procedures to validate the
19F NMR (282 MHz, CD3OD)
d
ꢁ69.04, ꢁ69.13 (>95% ee).
enantiomeric excess determination. 19F NMR (282 MHz, CDCl3)
d
ꢁ70.72 (>90% ee).
3.7.17. (S)-2-Carbamoylpyrrolidine-1-carboxylic acid tert-butyl ester
(2d). CAS Registry Number 35150-07-3, 54503-10-5, 70138-72-6.
Following the general procedure described above, amino acid 1d
(8.00 g, 37.2 mmol) afforded the desired product 2c (4.0 g, 50%) as
a white solid, which was used without purification: mp (DSC)
3.7.23. (S)-3-tert-Butoxycarbonylamino-succinamic acid tert-butyl
ester (2e). Following the general procedure described above, amino
acid 1e (4.67 g, 16.1 mmol) afforded the desired amide 2e (3.10 g,
67%) as a colorless foam: 1H NMR (CDCl3)
d 6.56 (br s,1H), 5.90 (br s,
103.6–107.7 ꢃC; 1H NMR (CD3OD)
d
4.15–4.05 (m,1H), 3.65–3.35 (m,
1H), 5.76–5.73 (m, 1H), 4.49 (br s, 1H), 2.85 (dd, J¼16.9, 4.8 Hz, 1H),
2H), 2.24–2.15 (m, 1H), 2.00–1.70 (m, 3H), 1.42 and 1.40 (2s, 9H); IR
2.60 (dd, J¼16.8, 6.1 Hz, 1H), 1.45 (s, 18H); 13C NMR (75 MHz, CDCl3)
(ATR) 3375, 3203, 2974, 1672, 1660, 1406, 1361, 1167, 1118,
d 173.5, 171.1, 155.5, 81.7, 80.3, 50.5, 37.3, 28.3, 28.0; IR (ATR) 3332,
25
25
636 cmꢁ1; MS (APCI) m/z 115 [C10H18N2O3ꢁBocþH]þ; [
a
]
ꢁ42.4 (c
2979, 1674, 1502, 1366, 1249, 1153, 1049, 1025 cmꢁ1; [
a
]
ꢁ6.0 (c
D
D
1.0, methanol).
0.100, MeOH); MS (APCI) m/z 288 [C13H24N2O5þH]þ. Anal. Calcd for
C13H24N2O5: C, 54.15; H, 8.39; N, 9.72. Found: C, 54.45; H, 8.61; N,
9.46.
3.7.18. (S)-2-Cyanopyrrolidine-1-carboxylic acid tert-butyl ester
(3d)14. Following the general procedure described above and pu-
rification by silica gel chromatography (eluent: 1:10 ethyl acetate/
hexanes), amide 2d (3.0 g, 14 mmol) afforded the desired nitrile 3d
3.7.24. (S)-3-tert-Butoxycarbonylamino-3-cyano-propionic acid tert-
butyl ester (3e). Following the general procedure described above,
amide 2e (3.00 g, 10.4 mmol) afforded the desired nitrile 3e (2.50 g,
(1.5 g, 55%) as a thick liquid: 1H NMR (CD3OD)
3.59–3.31 (m, 2H), 2.20–1.81 (m, 4H), 1.52 and 1.50 (2s, 9H); [
d 4.60–4.50 (m, 1H),
25
a
]
89%) as a colorless foam: 1H NMR (CDCl3)
d
5.73–5.70 (m, 1H), 4.89
D
ꢁ95.5 (c 1.3, methanol); IR (ATR) 2978, 1697, 1384, 1366, 1158,
(br s, 1H), 2.78–2.75 (m, 2H), 1.49 (s, 9H), 1.47 (s, 9H); 13C NMR
771 cmꢁ1; MS (ESI) m/z 197 [C10H16N2O2þH]þ.
(CDCl3) d 169.2, 154.1, 117.9, 82.8, 81.2, 38.5, 38.3, 28.1, 27.9; IR (ATR)
3345, 2980, 2935, 1719, 1510, 1368, 1285, 1249, 1149, 1048 cmꢁ1
;
ꢁ43.6 (c 0.174, MeOH); MS (ESI) m/z 271 [C13H22N2O4þH]þ.
25
3.7.19. (S)-2-(N-Hydroxycarbamimidoyl)pyrrolidine-1-carboxylic
acid tert-butyl ester (4d)15. Following the general procedure de-
scribed above, nitrile 3d (1.1 g, 5.6 mmol) afforded the desired
hydroxyamidine 4d (0.85 g, 66%) as a white solid: mp (DSC)
[a
]
D
Anal. Calcd for C13H22N2O4$0.25H2O: C, 56.80; H, 8.25; N, 10.09.
Found: C, 56.81; H, 8.25; N, 10.19.
155.5–158.1 ꢃC; 1H NMR (CD3OD)
(m, 2H), 2.30–1.71 (m, 4H), 1.51 (s, 9H); [
methanol); IR (ATR) 3342, 2973, 1670, 1404, 1165, 1129,
774 cmꢁ1; MS (ESI) m/z 230 [C10H19N3O3þH]þ. Anal. Calcd for
C10H19N3O3: C, 52.39; H, 8.35; N, 18.33. Found: C, 52.52, H, 8.61,
N, 18.15.
d
4.25–4.10 (m, 1H), 3.61–3.39
3.7.25. (S)-3-tert-Butoxycarbonylamino-3-(N-hydroxycarb-
amimidoyl)-propionic acid tert-butyl ester (4e). Following the gen-
eral procedure described above, nitrile 3e (2.25 g, 8.30 mmol)
afforded the desired hydroxyamidine 4e (2.50 g, >99%) as a color-
25
a
]
ꢁ34.6 (c 1.015,
D
less foam: 1H NMR (CDCl3)
d
8.48 (br s, 1H), 5.92 (d, J¼8.8 Hz, 1H),
5.31 (s, 2H), 5.63–4.61 (m, 1H), 2.69 (d, J¼6.7 Hz, 2H), 1.44 (s, 18H);
13C NMR (CDCl3)
171.0, 157.0, 154.3, 81.8, 80.5, 48.5, 38.0, 28.7,
28.3; IR (ATR) 3360, 2978, 2933, 1698, 1663, 1512.0, 1366, 1248,
d
3.7.20. (S)-2-(5-Oxo-4,5-dihydro-[1,2,4]-oxadiazol-3-yl)pyrrolidine-
1-carboxylic acid tert-butyl ester (5d). Following the general
25
1156, 1049 cmꢁ1; [
a]
ꢁ20.9 (c 1.03, MeOH); MS (ESI) m/z 304
D

J.E. Mangette et al. / Tetrahedron 65 (2009) 9536–9541
9541
[C13H25N3O5þH]þ. Anal. Calcd for C13H25N3O5: C, 51.47; H, 8.31; N,
the residue was dissolved in ethyl acetate and washed with a 10%
potassium bisulfate solution, dried over sodium sulfate, filtered,
and concentrated at reduced pressure. Silica gel chromatography
13.85. Found: C, 51.47; H, 8.56; N, 13.53.
3.7.26. (S)-3-tert-Butoxycarbonylamino-3-(5-oxo-4,5-dihydro-[1,2,4]-
oxadiazol-3-yl)-propionic acid tert-butyl ester (5e). Following the
general procedure mentioned above, hydroxyamidine 4e (2.11 g,
6.96 mmol) afforded the desired oxadiazolone 5e (1.92 g, 84%) as
(97:3 dichloromethane/methanol) afforded oxadiazolone
9
(131 mg, 84%) as a white solid. Recrystallization from ethyl acetate
afforded analytically pure product: mp 236–238 ꢃC; 1H NMR
(DMSO-d6)
d
12.33 (s, 1H), 8.35 (d, J¼7.7 Hz, 1H), 7.19–7.38 (m, 5H),
a colorless oil: 1H NMR (CDCl3)
d
9.80 (br s,1H), 5.90 (d, J¼8.1 Hz,1H),
6.88 (d, J¼7.4 Hz, 1H), 4.91 (td, J¼8.0, 6.8 Hz, 1H), 3.84–4.00 (m, 1H),
3.12 (dd, J¼13.8, 6.3 Hz, 1H), 3.03 (dd, J¼13.8, 8.7 Hz, 1H), 1.37 and
1.24 (s and br s, 9H), 1.10 (d, J¼7.0 Hz, 3H); 13C NMR (DMSO-d6)
5.03–5.00 (m, 1H), 2.87 (d, J¼5.8 Hz, 2H), 1.45 (s, 18H); 13C NMR
(CDCl3) d 169.5, 159.7, 158.9, 155.5, 82.5, 81.4 43.7, 36.4, 28.1, 27.9; IR
(ATR) 3323, 2979, 2935, 1779, 1730, 1686, 1521, 1367, 1298, 1250,
d 172.7, 160.0, 159.6, 155.0, 136.5, 129.1, 128.2, 126.7, 78.1, 49.6, 46.5,
25
25
1144, 1054 cmꢁ1; [
a]
D
ꢁ32.0 (c 1.06, MeOH); MS (ESI) m/z 330
36.7, 28.1, 17.9; [
a]
ꢁ56.4 (c 1.0, MeOH); IR (ATR) 3355, 3146, 2977,
D
[C14H23N3O6þH]þ. Anal. Calcd for C14H23N3O6: C, 51.06; H, 7.04; N,
1768, 1739, 1516, 1319, 1162, 975, 733 cmꢁ1; MS (APCI) m/z 375
[C18H24N4O5ꢁH]ꢁ. Anal. Calcd for: C18H24N4O5: C, 57.44; H, 6.43; N,
14.88. Found: C, 57.15; H, 6.27; N, 14.52.
12.76. Found: C, 51.09; H, 7.32; N, 12.70.
3.7.27. (S)-3-Amino-3-(5-oxo-4,5-dihydro-[1,2,4]oxa-diazol-3-yl)-
propionic acid (6e). Following the general procedure described
above, oxadiazolone 5e (0.710 g, 2.16 mmol) afforded the desired
amino acid 6e (0.350 g, 78%) as an off-white solid: mp 196–198 ꢃC;
References and notes
1. (a) Advances in Amino Acid Mimetics and Peptidomimetics; Abell, A., Ed.; JAI:
Greenwich, CT, 1999; Vol. 2; (b) Hruby, V. J. Acc. Chem. Res. 2001, 34, 389; (c)
Hruby, V. J.; Ci, G.; Haskell-Luevano, C.; Shenderovich, M. Biopolymers 1997, 43,
219; (d) Marshall, G. R. Tetrahedron 1993, 49, 3547; (e) Gante, J. J. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1699; (f) Adang, A. E. P.; Hermkens, P. H. H.; Linders, J. T. M.;
Ottenheijm, H. C. J.; Van Staveren, C. J. Recl. Trav. Chim. Pays-Bas 1994, 113, 63.
2. (a) For a review of tetrazoles as replacements for carboxylic acids, see: Herr, R. J.
Bioorg. Med. Chem. 2002, 10, 3379; (b) Demko, Z. P.; Sharpless, K. B. Org. Lett.
2002, 4, 2525.
3. (a) Wustrow, D. J.; Belliotti, T. R.; Capiris, T.; Kneen, C. O.; Bryans, J. S.; Field, M. J.;
Williams, D.; Ayman, E.-K.; Buchholz, L.; Kinsora, J. J.; Lotarski, S. M.; Vartanian,
M. G.; Taylor, C. P.; Donevan, S. D.; Thorpe, A. J.; Schwarz, J. B. Bioorg. Med. Chem.
Lett. 2009, 19, 247; (b) Ruble, J. C.; Wakefield, B. D.; Kamilar, G. M.; Marotti, K. R.;
Melchior, E.; Sweeney, M. T.; Zurenko, G. E.; Romero, D. L. Bioorg. Med. Chem. Lett.
2007, 17, 4040; (c) Gezginci, M. H.; Martin, A. R.; Franzblau, S. G. J. Med. Chem.
2001, 44, 1560; (d) Kohara, Y.; Kubo, K.; Imamiya, E.; Wada, T.; Inada, Y.; Naka.
J. Med. Chem. 1996, 39, 5228; (e) Unangst, P. C.; Shrum, G. P.; Connor, D. T.;
Dyer, R. D.; Schrier, D. J. J. Med. Chem. 1992, 35, 3691.
1H NMR (CD3OD)
d
4.80 (dd, J¼7.2, 5.6 Hz, 1H), 3.13 (dd, J¼17.9,
5.6 Hz, 1H), 3.03 (dd, J¼17.9, 7.2 Hz, 1H); 13C NMR (CD3OD)
d 171.6,
161.3, 157.7, 44.7, 35.4; IR (ATR) 2945.2, 1754.1, 1714.6, 1562.3,
1509.6, 1414.9, 1207.6, 1140.7, 1099.2 cmꢁ1; [
a
]
ꢁ30.2 (c 1.00,
25
D
MeOH); MS (APCI) m/z 173 [C5H7N3O4þH]þ. Anal. Calcd for
C5H7N3O4$HCl$0.15H2O: C, 28.46; H, 4.13; N, 19.56; Cl, 16.87. Found:
C, 28.29; H, 3.94; N, 19.79; Cl, 16.70.
3.7.28. 3-(5-Oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-3-(3,3,3-tri-
fluoro-2-methoxy-2-phenyl-propionylamino)-propionic acid (7e).
Following the general procedure mentioned above, amino acid 6e
(0.039 g, 0.188 mmol) and (S)-Mosher chloride afforded the desired
amino acid derivative 7e (0.054 g, 74%) as a colorless oil; 1H NMR
4. (a) Corinne Elizabeth, A.-S.; Shelly Ann, G.; Terri Stoeber, P. PCT Int. Appl. WO
0076988, 2000; (b) Behrens, C.; Lau, J.; Madsen, P. PCT Int. Appl. WO 0240445,
2002; (c) Mowbray, C. E.; Stobie, A. Eur. Pat. Appl. EP 792874, 1997.
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(300 MHz, CDCl3)
d
10.50 (br s, 1H), 8.34 (br s, 1H), 8.10 (d, J¼8.4 Hz,
1H), 7.57–7.38 (m, 5H), 5.41–5.30 (m, 1H), 3.32 (s, 3H), 3.07 (dd,
J¼18.0, 4.2 Hz,1H), 2.95 (dd, J¼18.0, 8.7 Hz,1H); 19F NMR (282 MHz,
CDCl3)
d
ꢁ69.41 (96% ee); MS (ESI) m/z 390 [MþH]; The other dia-
stereomer of 7e derived from D-aspartic acid (structure not shown)
was prepared by analogous procedures to validate the enantio-
describing the preparation of optically active
preparations, however, involved a different route from that described here and
did not start from readily available -amino acids.
a-amino oxadiazolones; these
meric excess determination. 19F NMR (282 MHz, CDCl3)
(98% ee).
d
ꢁ69.17
a
6. Maetz, P.; Rodriguez, M. Tetrahedron Lett. 1997, 38, 4221.
7. For a review of asymmetric Strecker reactions, see: Yet, L. Angew. Chem., Int. Ed.
2001, 40, 875.
3.7.29. {1-[1-(5-Oxo-4,5-dihydro[1,2,4]oxadiazol-3-yl)-2-phenyl-
8. (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543; (b) Dale, J. A.;
Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512.
9. Um, I.-H.; Lee, S.-E.; Kwon, H.-J. J. Org. Chem. 2002, 67, 8999.
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79.
ethylcarbamoyl]ethyl}carbamic acid tert-butyl ester (9). To a solu-
tion of BOC-L-alanine 8 (78 mg, 0.41 mmol) in dichloromethane
(5 mL) cooled to 0 ꢃC were added 1-hydroxybenzotriazole (73 mg,
0.54 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hy-
drochloride (103 g, 0.537 mmol), and 4-methylmorpholine (50 mg,
0.054 mL, 0.49 mmol). After stirring for 2 h at 0 ꢃC, a solution of
oxadiazolone 6a (150 mg, 0.62 mmol) and 4-methylmorpholine
(50 mg, 0.054 mL, 0.49 mmol) in dichloromethane (3 mL) was
added. The mixture was allowed to warm to room temperature and
stir overnight. The solvent was removed at reduced pressure, and
ˇ
11. Jakopin, Z.; Roskar, R.; Dolenc, M. S. Tetrahedron Lett. 2007, 48, 1465.
12. (a) Houssin, R.; Lohez, M.; Bernier, J. L.; Henichart, J. P. J. Org. Chem. 1985, 50,
2787; (b) Meyers, A. I.; Tavares, F. X. J. Org. Chem. 1996, 61, 8207.
13. Scho¨n, I.; Szirtes, T.; Uberhardt, T.; Csehi, A. J. Org. Chem. 1983, 48, 1916.
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P. T.; Gynther, J. J. Med. Chem. 2002, 45, 4581.
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2002.