Synthesis of (R) and (S) enantiomers of Fmoc-protected 1,2,4-oxadiazole-containing β3-amino acids from Fmoc-(R)-β-HAsp(OtBu)-OH

Article abstract of DOI:10.1016/S0040-4039(03)01471-0

Fmoc-(R)-β-HomoAsp(OtBu)-OH was used for the synthesis of both (R) and (S) enantiomers of various Fmoc-protected 3-substituted 1,2,4-oxadiazole-containing β³-amino acids. The 1,2,4-oxadiazole heterocycle was formed using sodium acetate, a Fmoc-

Full text of DOI:10.1016/S0040-4039(03)01471-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6079–6082
Synthesis of (R) and (S) enantiomers of Fmoc-protected
1,2,4-oxadiazole-containing b3-amino acids from
Fmoc-(R)-b-HAsp(OtBu)-OH
Abdallah Hamze´, Jean-Franc¸ois Hernandez* and Jean Martinez
Laboratoire des Aminoacides Peptides et Prote´ines, CNRS UMR 5810, Universite´s Montpellier I et II, Faculte´ de Pharmacie,
15 avenue Charles Flahault, BP 14491, 34093 Montpellier cedex 5, France
Received 29 April 2003; revised 12 June 2003; accepted 12 June 2003
Abstract—Fmoc-(R)-b-HomoAsp(OtBu)-OH was used for the synthesis of both (R) and (S) enantiomers of various Fmoc-pro-
tected 3-substituted 1,2,4-oxadiazole-containing b3-amino acids. The 1,2,4-oxadiazole heterocycle was formed using sodium
acetate, a Fmoc-compatible and efficient catalyst for cyclodehydration.
© 2003 Elsevier Ltd. All rights reserved.
b-Amino acids have received increasing attention in the
last years. Several reasons account for such an interest,
including their occurrence in natural compounds with
very interesting pharmacological properties,1–4 as well
as their usefulness in the design of peptidomimetics.
b-Peptides, polymers constituted uniquely with b3-
amino acids, have been shown to adopt new stable
well-ordered secondary structures.5–9 Substitution of at
least one a-amino acid for its b3 isomer in a peptide
sequence has also been reported. In that case, the
additional methylene group(s) might impair molecular
recognition by the target by steric hindrance and/or
local conformational disruption, especially when intro-
duced in a turn. Nevertheless, this modification if toler-
ated represents an interesting approach to provide
peptides with increased enzymatic stability.10–13
a diversely substituted amidoxime is O-acylated by an
activated carboxylic acid derivative (here a conveniently
protected amino acid). The heterocycle is subsequently
formed by intramolecular cyclo-dehydration. It can
thus be afforded with a large variety of substituents in
position 3, the amino acyl-derived moiety being
branched on position 5.
b3-Amino acids are efficiently prepared using Arndt–
Eistert homologation of a-amino acid derivatives.22
This method proceeds stereospecifically to a high degree
in most cases and suitable conditions have been found
for a variety of Na-protecting groups, including
Fmoc.23–25 Each enantiomer is obtained from the corre-
sponding a-amino acid derivative.
Here, we report the synthesis of Fmoc-protected 1,2,4-
oxadiazole-containing b3-amino acids, following
We have been interested in the development of new
Fmoc-protected chiral b-amino acids which could be
used as building blocks in the combinatorial synthesis
of pharmacologically active peptide analogs or protease
inhibitors. Recently, we focused our attention on the
synthesis of 1,2,4-oxadiazole-containing amino acids.14
This heterocycle15–17 has been frequently used as ester
or amide bioisostere18–20 and can help with the design
of compounds with improved physico-chemical proper-
ties and bioavailability.21 1,2,4-Oxadiazoles are com-
monly synthesized from amidoximes and carboxylic
acid derivatives in two steps.15–17 During the first step,
Figure 1. Fmoc-b-HAsp derivative precursors of the R enan-
tiomer (R1=H, R2=t-Bu) and the S enantiomer (R1=Allyl,
R2=H) of Fmoc-protected 1,2,4-oxadiazole-containing b3-
amino acids. The oxadiazole ring can be built on anyone of
the two carboxylic groups.
Keywords: b3-amino acid; 1,2,4-oxadiazole; Fmoc.
* Corresponding author. Tel.: 33-(0)4 67 54 86 62; fax: 33-(0)4 67 54
86 54; e-mail: hernandez@colombes.pharma.univ-montp1.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01471-0

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A. Hamze´ et al. / Tetrahedron Letters 44 (2003) 6079–6082
high temperature (above 100°C) in solvents such as
DMF29,30 or pyridine31,32 or at room temperature in the
presence of a strongly basic reagent (TBAF33,34). How-
ever, these conditions were not compatible with the
base-labile Fmoc protecting group. In the case of DMF
and pyridine, this result is probably the consequence of
heating together with the presence of nucleophilic
amino contaminants in these solvents. Heating in neu-
tral solvents and without dehydrating agent has also
been reported for the synthesis of 1,2,4-oxadiazoles.35,36
However, we found that cyclization proceeded too
slowly with the risk of increasing unwanted side reac-
tions. A compromise was found with the use of sodium
acetate in refluxing EtOH/H2O (86°C). These condi-
tions did not induce Fmoc cleavage and cyclization was
completed in less than 5 hours in approximately 60%
yields.37 The final removal of the t-Bu ester protecting
group afforded the chiral Fmoc-(R)-b3-amino acids 4a
and 4b (Table 1 and Ref. 38).
Arndt–Eistert homologation of Fmoc-L-Asp(OtBu)-
OH. We have exploited the symmetry of the resulting
b-HomoAsp (b-HAsp) moiety (Fig. 1) to prepare both
enantiomers, avoiding the use of the expensive
derivative.
D-Asp
Synthesis.26 Both enantiomers of Fmoc-protected 1,2,4-
oxadiazole-containing b3-amino acids were synthesized
from Fmoc-(R)-b-HAsp(OtBu)-OH
1 (Scheme 1).
Compound 1 was obtained by homologation of Fmoc-
-Asp(OtBu)-OH following the Arndt–Eistert proce-
L
dure. Wolff rearrangement of the intermediate
diazoketone was performed using conditions respecting
the N-Fmoc protection and which were shown to pro-
ceed stereospecifically.24
The R enantiomers of the 1,2,4-oxadiazole derivatives
4a and 4b were synthesized in three steps from com-
pound 1 (Fig. 1, R1=H, R2=t-Bu; Scheme 1). The
unprotected carboxylic group of 1 was first condensed
to various amidoximes which were prepared using clas-
sical procedures, i.e. treatment of the corresponding
nitrile compounds with hydroxylamine in refluxing eth-
anol.27,28 Among the coupling reagents that were tested
for the O-acylation of amidoximes, DIC/HOBt
appeared the most satisfactory while others such as
HBTU or EDC/HOBt yielded significant amount of
secondary products. It is important to notice that
acylation of the b-carboxylic group proceeded without
epimerization. The O-acyl amidoximes were isolated
before being subsequently cyclized. Cyclodehydration
to the 1,2,4-oxadiazole ring is generally performed at
The corresponding S enantiomers 5a and 5b were also
obtained from compound 1. Compound 1 was first
converted during a protection–deprotection sequence to
Fmoc-(S)-b-HAsp-OAllyl (90% overall yield).39 Chiral
5a and 5b were then synthesized from Fmoc-(S)-b-
HAsp-OAllyl (Fig. 1, R1=Allyl, R2=H, Scheme 1) in
three steps as described for 4a and 4b, the last step
being in this case cleavage of the allyl ester protecting
group. It is interesting to note that in addition to Fmoc
and tert-butyl ester, as well as Boc, Z and benzyl ester
(unpublished results), the sodium acetate-catalyzed oxa-
diazole formation is compatible with the allyl ester
Scheme 1. Synthesis of S and R enantiomers of Fmoc-protected 1,2,4-oxadiazole-containing b3-amino acids. Reagents and
conditions: (a) isobutylchloroformiate, N-methyl-morpholine, THF, then diazomethane; (b) silver benzoate (0.1 equiv.), triethyl-
amine (1 equiv.), dioxane, water; (c) amidoxime R-C(ꢀNOH)NH2, DIC, HOBt, DCM; (d) allyl bromide, Na2CO3, DMF; (e)
TFA/DCM (50:50); (f) Sodium acetate, EtOH/H2O, 86°C, 5 h; (g) Pd[PPh3]4 (0.4 equiv.), morpholine (1.4 equiv.), THF.

A. Hamze´ et al. / Tetrahedron Letters 44 (2003) 6079–6082
6081
Table 1. Physical data of 1,2,4-oxadiazole-containing b3-
amino acids.
8. DeGrado, W. F.; Schneider, J. P.; Hamuro, Y. J. Peptide
Res. 1999, 54, 206–217.
9. Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem.
Rev. 2001, 101, 3219–3232.
a
Compound
[h]D
Mp (°C)b
tR (min)c
Yield (%)
10. Seebach, D.; Abele, S.; Schreiber, J. V.; Martinoni, B.;
Nussbaum, A. K.; Schild, H.; Schulz, H.; Henneke, H.;
Woessner, R.; Bitsch, F. Chimia 1998, 52, 734–739.
11. Frackenpohl, J.; Arvidsson, P. I.; Schreiber, J. V.; See-
bach, D. Chembiochem 2001, 2, 445–455.
12. Cardillo, G.; Gentilucci, L.; Qasem, A. R.; Sgarzi, F.;
Spampinato, S. J. Med. Chem. 2002, 45, 2571–2578.
13. Sagan, S.; Milcent, T.; Ponsinet, R.; Convert, O.;
Tasseau, O.; Chassaing, G.; Lavielle, S.; Lequin, O. Eur.
J. Biochem. 2003, 270, 939–949.
14. Huck, J. PhD Thesis, University of Montpellier II,
France, 2002.
15. Behr, L. C. In The Chemistry of Heterocyclic Compounds;
Weissberger, A., Ed.; John Wiley: New York, 1962; Vol.
17, pp. 245–262.
4a
5a
4b
5b
+2d
−2f
−7d
+7d
102–104
105–107
135–137
125–127
2.69
2.71
3.41
3.40
48e
33g
40e
43g
a t=20°C.
b Melting points are uncorrected.
c Reverse phase HPLC analyses run on a Chromolith SpeedRod C18
column (0.46×5 cm); gradient from A to B in 5 min, 3 mL/min flow
rate (A: H2O, 0.1% TFA; B: CH3CN, 0.1% TFA); the slight
differences in retention times observed between the enantiomers 4a
and 5a, and 4b and 5b, are not significant.
d c 0.02, DMF.
e Overall yield calculated from 1.
f c 0.014, DMF.
g Overall yield calculated from Fmoc-(S)-b-HAsp-OAllyl.
16. Clapp, L. B. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: New York, 1976;
Vol. 20, pp. 65–116.
17. Hemming, K. J. Chem. Res., Synopses 2001, 209–216 and
601–620.
18. Diana, G. D.; Volkots, D. L.; Nitz, J. T.; Bailey, R. T.;
Long, M. A.; Vescio, N.; Aldous, S.; Peveur, D. C.;
Dutko, F. J. J. Med. Chem. 1994, 37, 2421–2436.
19. Andersen, K. E.; Jorgensen, A. S.; Braestrup, C. Eur. J.
Med. Chem. 1994, 29, 393–399.
20. Andersen, K. E.; Lundt, B. F.; Joergensen, A. S.;
Braestrup, C. Eur. J. Med. Chem. 1996, 31, 417–425.
21. Naka, T.; Kubo, K. Curr. Pharm. Des. 1999, 5, 453–472.
22. Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991–8035.
23. Mu¨ller, A.; Vogt, C.; Sewald, N. Synthesis 1998, 837–841.
24. Ellmerer, E. P.; Bro¨ssner, D.; Maslouh, N.; Tako, A.
Helv. Chim. Acta 1998, 81, 59–65.
protecting group. Physical data for compounds 5a and
5b are presented in Table 1 and Ref. 38.
In conclusion, the use of Fmoc-(R)-b-HAsp(OtBu)-OH
allowed access to (R) and (S) enantiomers of the
presented Fmoc-protected 1,2,4-oxadiazole-containing
b3-amino acids depending on the carboxylic acid func-
tion that is activated. This strategy might be used for
the synthesis of various b-HAsp-derived b3-amino
acids. As numerous nitrile-containing compounds are
available for the synthesis of amidoximes, a large diver-
sity can be attained for the synthesis of this new series
of chiral b3-amino acids. Finally, sodium acetate is a
Fmoc-compatible and efficient catalyst for the forma-
tion of the oxadiazole ring.
25. Ananda, K.; Gopi, H. N.; Suresh Babu, V. V. J. Peptide
Res. 2000, 55, 289–294.
26. Abbreviations of some reagents: DIC, Diisopropylcar-
bodiimide; EDC, N-ethyl-N%-(3-dimethylaminopropyl)-
carbodiimide hydrochloride; HBTU, 2-(1H-benzotria-
Acknowledgements
We are grateful to Mr. Pierre Sanchez for his indispens-
able help in obtaining mass spectrometry data. We
thank the Lebanese University for the award of a
research fellowship to A.H.
zole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophos-
phate; HOBt, 1-hydroxybenzotriazole; Pd[PPh3]4, tetra-
kis(triphenylphosphine)palladium(0); TBAF, tetra-n-
butylammonium fluoride; TFA, trifluoroacetic acid.
27. Eloy, F. R. L. Chem. Rev. 1962, 62, 155–183.
28. Weller, H. N.; Poss, M. A.; E. R. Squibb & Sons, Inc.;
US 5,236,916, 17 Aug. 1993.
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Int. Ed. Engl. 1994, 33, 15–44.
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Pradeepan, S. G.; Mani, U. N.; Yang, M.; Plake, H. R.;
Varkhedkar, V. M.; Lynch, B. A.; MacNeil, I. A.; Loia-
cono, K. A.; Tiong, C. L.; Holt, D. A. Bioorg. Med.
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33. Rice, K.; Nuss, J. M. Bioorg. Med. Chem. Lett. 2001, 11,
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1441–1443.
(m, 1H, CHa), 4.30–4.18 (m, 2H, CH2 Fmoc), 4.19 (t,
J=6.8 Hz, 1H, CH Fmoc), 3.22 (dd, J=15.6 Hz, 6.3 Hz,
1H, CHb), 3.12 (dd, J=15.5 Hz, 6.0 Hz, 1H, CHb), 2.60
(d, J=4.9 Hz, 2H, CH2b%), 2.28 (s, 3H). Compound 5b:
C28H25N3O5; 483.18 g/mol; Rf 0.7 (1% AcOH in EtOAc);
mp 125–127°C; [h]D=+7 (c 0.02, DMF); m/z (ES+) 484.3
35. He´bert, N.; Hannah, A. L.; Sutton, S. C. Tetrahedron
1
(M+H+), 967.2 (2M+H+); H NMR (400 MHz, CDCl3) l
Lett. 1999, 40, 8547–8550.
36. He´bert, N.; Hannah, A. L.; Trega Biosciences, WO 00/
25768 A1, 11 May 2000.
7.75 (d, J=8.1 Hz, 2Ha Fmoc), 7.55 (d, J=7.3 Hz, 2Hd
Fmoc), 7.38 (d, J=7.6 Hz, 2He phenyl), 7.20 (t, J=7.4
Hz, 2Hb Fmoc), 7.20–7.10 (m, 4H, 2Hc Fmoc+2Hf
phenyl), 5.58 (d, J=8.0 Hz, 1H, NH), 4.50–4.32 (m, 1H,
CHa), 4.30–4.12 (m, 2H, CH2 Fmoc), 4.05 (t, J=7.0 Hz,
1H, CH Fmoc), 3.35–3.10 (m, 2H, CH2b), 2.90–2.60 (m,
2H, CH2b%), 2.28 (s, 3H, CH3).
37. Conversion of the acyl-amidoxime 2b to the protected
oxadiazole derivative. A mixture of compound 2b (0.33 g,
0.59 mmol) in ethanol (7 mL) and sodium acetate (0.08 g,
0.59 mmol) in water (2 mL) was heated at 86°C for 5 h.
The product crystallized upon cooling to room tempera-
ture. It was collected by filtration and recrystallized from
ethanol to give the protected oxadiazole derivative (1,1-
dimethylethyl-3-(R)-[[(9H-fluoren-9-ylmethoxy)carbonyl]-
amino] - 4 - [3 - (4 - methylphenyl) - 1,2,4 - oxadiazol - 5 - yl]-
butanoate) as white crystals (0.21 g, 66%): mp 127–
129°C; m/z (ES+) 540.2 (M+H+), 562.2 (M+Na+), 484.3
(M-tBu+H+); HPLC tR: 4.31 min (see conditions under
39. Synthesis of Fmoc-(S)-b-HAsp-OAllyl. A mixture of
Fmoc-(R)-b-HAsp(OtBu)-OH
1 (0.5 g, 1.18 mmol),
sodium carbonate (0.25 g, 2.36 mmol) and allylbromide
(0.18 mL, 2.12 mmol) in DMF (10 mL) was stirred at
room temperature for 18 h. After this period, the solvent
was removed under reduced pressure and the residue was
dissolved in EtOAc. The organic layer was washed with
10% aqueous NaHCO3, 1 M KHSO4, brine, and dried
over MgSO4. Evaporating the solvent under vacuum
afforded crude Fmoc-(R)-b-HAsp(OtBu)-OAllyl which
was purified by flash chromatography on a silica gel
column (EtOAc/hex, 3:7). Colorless oil (0.523 g, 95%): Rf
0.54 (EtOAc/hex, 3:7); m/z (ES+) 466.1 (M+H+), 487.7
(M+Na+), 410.2 (M-tBu+H+), 931.2 (2M+H+); HPLC tR:
1
note c of Table 1); H NMR (400 MHz, CDCl3) l 7.88
(d, J=7.1 Hz, 2Ha Fmoc), 7.65 (d, J=7.5 Hz, 2Hd
Fmoc), 7.50 (t, J=7.0 Hz, 2He phenyl), 7.30 (t, J=7.5
Hz, 2Hb Fmoc), 7.25–7.18 (m, 4H, 2Hc Fmoc+2Hf
phenyl), 5.68 (d, J=8.8 Hz, 1H, NH), 4.52–4.40 (m, 1H,
CHa), 4.38–4.22 (m, 2H, CH2 Fmoc), 4.12 (t, J=6.9 Hz,
1H, CH Fmoc), 3.28 (dd, J=15.6 Hz, 5.8 Hz, 1H, CHb),
3.18 (dd, J=15.5 Hz, 6.0 Hz, 1H, CHb), 2.55 (d, J=5.0
Hz, 2H, CH2b%), 2.38 (s, 3H, CH3), 1.38 (s, 9H, tBu).
38. Compound 4a: C22H21N3O5; 407.15 g/mol; white powder;
mp 102–104°C; [h]D=+2 (c 0.02, DMF); m/z (ES+) 408.0
1
3.79 min; H NMR (400 MHz, CDCl3) l 7.75 (d, J=7.5
Hz, 2Ha Fmoc), 7.60 (d, J=7.3 Hz, 2Hd Fmoc) 7.40 (t,
J=7.4 Hz, 2Hb Fmoc), 7.31 (t, J=7.3 Hz, 2Hc Fmoc),
6.00–5.85 (m, 1H, CH allyl), 5.50 (d, J=8.8 Hz, 1H,
NH), 5.30 (q, J=10.2 Hz, 1.4 Hz, 2H, CꢀCH2 allyl), 4.60
(d, J=5.7 Hz, 2H, O-CH2 allyl), 4.38 (d, J=7.1 Hz, 2H,
CH2 Fmoc), 4.23 (t, J=6.9 Hz, 1H, CH Fmoc), 2.80 (dd,
J=16.6 Hz, 5.7 Hz, 1H, CHb), 2.68 (dd, J=6.1 Hz, 1H,
CHb), 2.60 (t, J=6.8 Hz, 2H, CH2b%), 1.42 (s, 9H, tBu).
The preceding tert-butyl-protected compound (0.517 g,
1.11 mmol) was treated with a 50% TFA solution in
DCM (8 mL) for 2 h at room temperature. The solvents
were then removed under reduced pressure and a mixture
of hexane/diethyl ether was added to the residue. The
compound Fmoc-(S)-b-HAsp-OAllyl precipitated as a
white powder and was collected by filtration (0.425 g,
94%): C23H23NO6; 409.15 g/mol; mp 84–86°C; m/z (ES+)
409.9 (M+H+), 432.2 (M+Na+), 819.0 (2M+H+); HPLC
tR: 2.99 min; 1H NMR (400 MHz, CDCl3) l 7.68 (d,
J=7.5 Hz, 2Ha Fmoc), 7.50 (d, J=7.4 Hz, 2Hd Fmoc),
7.31 (t, J=7.4 Hz, 2Hb Fmoc), 7.22 (t, J=6.8 Hz, 2Hc
Fmoc), 5.90–5.76 (m, 1H, CH allyl) 5.55 (d, J=8.3 Hz,
1H, NH), 5.22 (q, J=9.5 Hz, 1.4 Hz, 2H, CꢀCH2 allyl),
4.50 (d, J=5.4 Hz, 2H, O-CH2 allyl), 4.38–4.28 (m, 2H,
CH2 Fmoc), 4.18 (t, J=6.7 Hz, 1H, CH Fmoc), 2.80–2.58
(m, 4H, CH2b+CH2b%).
1
(M+H+), 815.3 (2M+H+); H NMR (400 MHz, CDCl3) l
7.55 (d, J=7.4 Hz, 2Ha Fmoc), 7.38 (d, J=7.3 Hz, 2Hd
Fmoc), 7.20 (t, J=7.3 Hz, 2Hb Fmoc), 7.15 (t, J=7.2
Hz, 2Hc Fmoc), 5.58 (d, J=8.5 Hz, 1H, NH), 4.48–4.32
(m, 1H, CHa), 4.30–4.12 (m, 2H, CH2 Fmoc), 4.10 (t,
J=6.8 Hz, 1H, CH Fmoc), 3.20 (dd, 1H, CHb), 3.10 (dd,
1H, CHb), 2.70–2.50 (m, 2H, CH2b%), 2.2 (s, 3H, CH3).
Compound 4b: C28H25N3O5; 483.18 g/mol; white powder;
mp 135–137°C; [h]D=−7 (c 0.02, DMF); m/z (ES+) 484.0
1
(M+H+), 506.4 (M+Na+), 967.5 (2M+H+); H NMR (400
MHz, CDCl3) l 7.95 (d, J=7.3 Hz, 2Ha Fmoc), 7.70 (d,
J=7.5 Hz, 2Hd Fmoc), 7.55 (d, J=6.9 Hz, 2He phenyl),
7.30 (t, J=7.1 Hz, 2Hb Fmoc), 7.32–7.20 (m, 4H, 2Hc
Fmoc+2Hf phenyl), 5.80 (d, J=8.6 Hz, 1H, NH), 4.70–
4.50 (m, 1H, CHa), 4.42–4.30 (m, 2H, CH2 Fmoc), 4.20
(t, J=6.4 Hz, 1H, CH Fmoc), 3.40 (dd, J=15.1 Hz, 5.4
Hz, 1H, CHb), 3.31 (dd, 1H, CHb), 2.90–2.70 (m, 2H,
CH2b%), 2.40 (s, 3H, CH3). Compound 5a: C22H21N3O5;
407.15 g/mol; Rf 0.67 (0.05% AcOH in EtOAc); mp
105–107°C; [h]D=−2 (c 0.014, DMF); m/z (ES+) 407.8
1
(M+H+), 815.2 (2M+H+); H NMR (400 MHz, CDCl3) l
7.62 (d, J=7.5 Hz, 2Ha Fmoc), 7.42 (d, J=7.4 Hz, 2Hd
Fmoc), 7.21 (t, J=7.4 Hz, 2Hb Fmoc), 7.16 (t, J=7.4
Hz, 2Hc Fmoc), 5.60 (d, J=8.8 Hz, 1H, NH), 4.48–4.35