Synthesis of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics

Article abstract of DOI:10.1016/j.tetlet.2008.06.091

The synthesis of a new class of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide mimetics is described. The protocol employs a reaction between an N-protected amino acyl fluoride and an amino acid-derived amidoxime. All the three commonly

Full text of DOI:10.1016/j.tetlet.2008.06.091

Tetrahedron Letters 49 (2008) 5133–5136
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,2,4-oxadiazole-linked orthogonally urethane-protected
dipeptide mimetics
*
Vommina V. Sureshbabu , Hosahalli P. Hemantha, Shankar A. Naik
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a new class of 1,2,4-oxadiazole-linked orthogonally urethane-protected dipeptide
mimetics is described. The protocol employs a reaction between an N-protected amino acyl fluoride
and an amino acid-derived amidoxime. All the three commonly employed urethanes have been used
in this protocol for N-protection. The course of the reaction was found to be high yielding and all new
compounds were well characterized by NMR and mass spectroscopy. The O-acyl amidoxime intermediate
has also been isolated as a stable solid.
Received 4 May 2008
Revised 18 June 2008
Accepted 21 June 2008
Available online 25 June 2008
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
1,2,4-Oxadiazole
Peptidomimetics
Deoxo-Fluor
Acylfluoride
O-Acyl amidoxime
1. Introduction
1,10-carbonyldiimidazole (CDI), O-(benzotriazol-1-yl) N,N,N0,N0-
tetramethyluronium tetrafluoroborate (TBTU) and the Burgess
Peptidomimetics1 are being explored largely to circumvent
some of the disadvantages of native peptides and to increase the
bioavailability and potency of peptide-based drugs.2 Several types
of non-natural linkages such as retro-amides, ureas,3 carbamates,4
sulfonamides,5 thiazoles and6 triazoles,7,8 are used as amide bond
replacements to obtain new classes of peptidomimetics with
considerable success. 1,2,4-Oxadiazoles9 are important amongst
biologically active heterocycles, the utility of which has been
extended to many potent classes of drug-related molecules such
as ligands of benzodiazepine receptors,10 muscuranic receptor ago-
nists,11 antiviral compounds, angiotensin II receptor antagonists12
and HIV-1 reverse transcriptase inhibitors.13 In peptide chemistry,
this group has been studied mainly as an efficient amide and ester
bond bioisoester.14,15
The development of a reliable method for the insertion of 1,2,4-
oxadiazole into peptides finds utility in the synthesis of large
libraries of small peptide segments for their biological and
therapeutical scrutiny. The general synthesis of 1,2,4-oxadiazoles
involves coupling of an amidoxime with an activated carboxyl
group, yielding an O-acyl amidoxime followed by its dehydrative
cyclization.16 The cyclization of O-acyl amidoximes has been
carried out employing exhaustive reflux conditions in DMF or pyr-
idine with or without additives such as 1-[3-(dimethylamino)pro-
pyl]-3-ethylcarbodiimide (EDC), dicyclohexylcarbodiimide (DCC),
reagent.17 The use of a strong base such as NaOEt or tetrabutyl-
ammonium fluoride (TBAF) allows completion of the reaction even
at rt.18 1,2,4-Oxadiazoles have been incorporated in the synthesis
of a Phe-Gly segment mimetic in the biologically active peptides
such as dermorphin, and in substance P.19 A new variety of 1,2,4-
oxadiazole-linked peptidomimetics have been reported via reac-
tion of Boc-amino acid-derived amidoximes with succinic/glutaric
acid anhydrides in DMF at reflux.15 Similar chemistry was explored
also for the synthesis of 1,2,4-oxadiazole-containing b3-amino
acids.20 In one report, a solid-phase methodology was employed
wherein Fmoc/Boc amino acid anhydrides were reacted with
resin-bound amidoximes followed by cyclization.21 The Buchanan
group described a reaction between a Boc amino acid succinimidyl
ester and simple amidoximes with the aid of EDCꢀHOBt followed by
cyclization in refluxing pyridine to obtain the corresponding 1,2,4-
oxadiazole.22 To the best of our knowledge, the synthesis of 1,2,4-
oxadiazole-linked orthogonally protected dipeptide mimetics,
which serve as building blocks for preparation of the correspond-
ing oligopeptide mimetics, is yet to be reported. In the present
work, the synthesis of 1,2,4-oxadiazole-linked N,N0-orthogonally
protected dipeptide mimetics by coupling of an N-protected amino
acid-derived amidoxime with another orthogonally protected ami-
no acid fluoride followed by cyclization is described.
The essential intermediate in the preparation of the 1,2,4-
oxadiazole is an amidoxime, which in the present study was
prepared from the corresponding amino acid-derived nitrile.
Initially, Boc-protected alanyl nitrile, obtained by the dehydration
* Corresponding author. Tel.: +91 08 2296 1339/09986312937.
E-mail address: hariccb@rediffmail.com (V. V. Sureshbabu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.091

5134
V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 5133–5136
of Boc-Ala-NH2 using trifluoroacetic anhydride (TFAA)/TEA, was re-
fluxed in ethanol along with hydroxylammonium chloride
(NH2OHꢀHCl) and solid K2CO3 for 2 h (Scheme 1). The insoluble
inorganics were filtered off, and the filtrate was concentrated to
obtain amidoxime 1 as a stable solid. The generality of this reaction
was demonstrated by the synthesis of a series of amidoximes. Or-
ganic bases such as triethyl amine (TEA) and pyridine were avoided
in order to circumvent racemization. The use of powdered K2CO3
facilitated simpler isolation of the product in good yield and purity.
This procedure was applied to several other Boc/Z-amino acid
nitriles, and the corresponding amidoximes were isolated in
satisfactory yields. However, use of the Fmoc group for amine
protection resulted in a lower yield of the amidoxime due to its
deprotection under the basic reaction conditions. The use of bases
including TEA, pyridine, NaOEt and TBAF did not result in any
improvement of the product yield.
15 min, an equimolar quantity of sodium acetate was added and
the reaction mixture was refluxed for 3 h. The resulting 1,2,4-
oxadiazolyl dipeptide 3 was isolated after a simple workup
followed by column chromatography as a pure solid in a yield
exceeding 60% (Scheme 2). Several examples of 1,2,4-oxadiazole-
containing dipeptide mimetics possessing different urethanes at
the amino terminal were prepared, and consistently yields and
purities were observed in all cases (Table 1).
When the reaction was repeated without sodium acetate, the
product 1,2,4-oxadiazole was isolated in low yield (<20%) even
after refluxing for more than 6 h. The structures of all the synthe-
sized 1,2,4-oxadiazolyl dipeptide mimetics 3 were confirmed
through NMR and mass spectroscopy. Also the course of the reac-
tion was proved to be racemization-free as was evident by HPLC
analysis.
The protocol was extended by employing peptidyl counterparts
of acyl fluoride and amidoxime units to prepare several 1,2,4-oxa-
diazole-linked tetrapeptides. The peptidyl amidoximes were pre-
pared starting from the N-protected peptide acids in the same
manner as described for 1. They were isolated as stable solids in
good yields, which were found to be enantiomerically pure as ana-
lyzed by HPLC. In a typical example, Z-Val-Gly-OH derived amidox-
ime 4a was reacted with Fmoc-Ala-Phe-F 5a (prepared by treating
the peptide acid with Deoxo-Fluor) in the presence of sodium ace-
tate in refluxing ethanol to afford the corresponding 1,2,4-oxadiaz-
olyl tetrapeptide 6a after 4 h. The material was isolated after a
simple workup and column chromatography as a gum, which
solidified slowly (Scheme 3).
The oxadiazole formation is a two-step process involving the
formation of O-acyl amidoxime intermediate 7 followed by its
cyclization. Consequently, we turned our interest to the isolation
and characterization of 7. Initially, Z-Val-F was added to a solution
of Boc-Leu-OH derived amidoxime in ethanol followed by NMM at
rt. After complete consumption of the acid fluoride (TLC), the reac-
tion mixture was evaporated without heating and the residue was
washed with water and hexane to afford the O-acyl amidoxime 7
as a stable solid (Scheme 4). Similarly, the reaction was repeated
with a few other combinations of Fmoc/Boc/Z-amino acids and
The N-urethane-protected amino acid fluorides23,24 are well
known as stable and useful acylating agents for racemization-free
peptide coupling reactions. Unlike their acid chloride counterparts,
acid fluorides are accessible to all three types of protecting groups,
such as Fmoc, Z and Boc. Also, amongst various fluorinating
reagents, Deoxo-Fluor25,26 is gaining considerable interest for its
fast and efficient reactivity in the preparation of acid fluorides.
Upon treatment of an N-protected amino acid with Deoxo-Fluor
in the presence of N-methylmorpholine (NMM) for 30 min, the cor-
responding acyl fluoride was isolated after a simple workup and
recrystallization/precipitation. All the N-protected amino acyl flu-
orides prepared in this fashion were isolated as stable compounds.
For assembly of the title molecules, the N-protected amino acyl
fluoride 2 was coupled to amino acid-derived amidoxime 1. In a
typical experiment, Boc-Gly-F was stirred with the amidoxime de-
rived from Z-Ile-OH in the presence of NMM in ethanol. After
R1
R1
NH2OH. HCl
K2CO3, EtOH
, 2 h, 80-90%
NH2
OH
Pg1-NH
CN
Pg1-NH
N
all the corresponding dipeptidyl O-acyl amidoximes
7 were
1
Pg1=Boc, Z
obtained in satisfactory yields and purities (Table 2). Notably, the
isolated O-acyl amidoxime, when subjected to cyclization in the
presence of sodium acetate, gave slightly higher yields (>80%) of
Scheme 1.
R1
R1
R2
R2
1.NMM, Ethanol,
N
rt, 15 min
NH2
F
Pg1-NH
Pg1-NH
NH-Pg2
NH-Pg2
+
2. NaOAc,
N
O
N
O
OH
1
3
2
Pg2= Fmoc, Boc, Z
Scheme 2.
Table 1
1,2,4-Oxadiazole-linked dipeptide mimetics
Compd.
Pg1
R1
Pg2
R2
Yield (%)
Mp (°C)
½ ꢁ (c 1, DMF)
a 2D5
3a
3b
3c
3d
3e
3f
3g
3h
3i
Boc
Boc
Boc
Boc
Z
Z
Z
Z
CH2CH(CH3)2
CH2C6H5
H
Z
CH(CH3)2
CH2C6H5
CH(CH3)CH2CH3
CH2OCH2C6H5
H
CH2C6H5
CH2COOCH2C6H5
C6H5
65
70
76
68
71
73
68
72
60
102
112
98
114
101
116
104
118
109
ꢂ27.14
ꢂ31.36
ꢂ26.80
ꢂ21.84
ꢂ27.65
ꢂ36.26
ꢂ39.80
ꢂ24.10
ꢂ27.31
Fmoc
Z
CH3
Fmoc
Boc
Fmoc
Boc
Fmoc
Boc
CH(CH3)CH2CH3
CH2CH(CH3)2
CH2C6H5
CH2C6H5
CH2CH(CH3)2
Fmoc
CH3

V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 5133–5136
5135
O
R2
O
R3
1.NMM, Ethanol,
rt, 15 min
2. NaOAc,
H
N
Pg1-NH
Pg1-NH
NH2
OH
N
H
F
NH-Pg2
+
R1
N
R4
O
4a-d
5a-d
Amidoxime 4
Acyl fluoride 5
Yield
(%)
R2
R4
O
O
NH-Pg2
N
6a
6b
6c
6d
Z-Val-Gly
Fmoc-Ala-Phe
Z-Leu-Gly
57
73
52
71
N
H
N
R1
H
Boc-Phe-Ala
Fmoc-Val-Met
Boc-Ala-Leu
R3
N
O
Boc-Ala-Ile
Z-Phe-Gly
6a-d
Scheme 3.
R1
In summary, we have developed a simple preparation of 1,2,4-
NMM, Ethanol,
rt, 30 min
oxadiazole-linked N,N0-orthogonally protected dipeptidomimetics
by coupling the N-protected amino acid with another N-protected
amino acid-derived amidoxime utilizing an acid fluoride group as
the coupling agent. The resulting dipeptidomimetic building blocks
were utilized for the preparation of 1,2,4-oxadiazole-linked oligo-
peptides through chain extension on either N-terminal.
NH
2 O
Pg1-NH
1
2
+
NH-Pg2
N
O
R2
7
Scheme 4.
2. General procedure for N-protected amino acid-derived
amidoxime 1
Table 2
List of O-acyl amidoxime intermediates
To a solution of N-protected amino acid nitrile (10 mmol) in
ethanol were added NH2OHꢀHCl (13 mmol) and powdered K2CO3
(13 mmol), and the reaction mixture was refluxed for 2 h. After
the reaction was complete (TLC), the reaction mixture was filtered
and the filtrate was concentrated under vacuum. The residue was
triturated with hexane and the resulting solid was dried.
Product
Amidoxime
Amino acid
Acyl fluoride
Yield
(%)
½ ꢁ
a 2D5
(c 1, DMF)
Pg1
Pg2
Amino acid
7a
7b
7c
7d
7e
Boc
Z
Z
Boc
Z
Leu
Ile
Ala
Phe
Gly
Z
Val
Gly
Phe
Phe
72
76
73
79
70
ꢂ17.88
ꢂ18.56
ꢂ14.26
ꢂ13.50
ꢂ12.74
Boc
Fmoc
Fmoc
Boc
Asp(OBz)
3. General procedure for the synthesis of 1,2,4-oxadiazolyl
dipeptides 3
To a stirred solution of amidoxime 1 (2 mmol) in ethanol was
added N-protected amino acyl fluoride (3 mmol) followed by
NMM (5 mmol) at rt. After 10 min, NaOAc (2 mmol) was added
and the reaction mixture was refluxed for 3 h. After completion
of the reaction (TLC), ethanol was evaporated and the residue
was suspended between ethyl acetate (15 mL) and water
(10 mL). The organic layer was washed with 10% sodium carbonate
solution (10 mL), water (15 mL ꢃ 2) and brine (15 mL). The organic
layer was concentrated and the resulting crude compound was
purified by column chromatography (silica gel 100–200 mesh,
20% ethyl acetate in hexane).
1,2,4-oxadiazoles 3 than those prepared without isolation of the
intermediate (Scheme 5).
Finally, the orthogonality of the urethanes employed to protect
the amino groups in the title compounds 3 was utilized for selec-
tive deprotection and peptide chain extension on either side. In a
case study, 3a was treated with trifluoroacetic acid (TFA) in CH2Cl2
to remove the Boc group. The free amino oxadiazole was reacted
with Boc-Phe-F in the presence of TEA and the resulting peptide
was isolated after a simple workup. Similarly, the procedure was
repeated to couple Boc-Val-F to obtain another tripeptidomimetic
molecule. Finally, 1,2,4-oxadiazole 3a was subjected to catalytic
hydrogenation using Pd-C/H2 to deprotect the Z group. The result-
ing free amine was utilized for chain extension by coupling with
Z-Ile-F or Z-Gly-F in presence of TEA. All the peptides were isolated
in good yields (>70%).
4. Spectral data for selected compounds
Compound 3a: Solid; 1H NMR (300 MHz, CDCl3): d 0.95 (m, 12
H), 1.32 (s, 9H), 1.65 (m, 3H), 2.45 (m, 1H), 4.53 (m, 2H), 5.41 (s,
1.Pd/C/H2
1. TFA/CH2Cl2
N
N
3a
Boc -NH
HN-Xaa-Z
Boc -Xaa-NH
HN-Z
2.
Z-Xaa-F,
NMM
2. Boc-Xaa-F,
N
O
N
O
NMM
9
8
9a: Xaa=Ile (73%)
9b: Xaa=Gly (76%)
8a: Xaa=Phe (74%)
8b: Xaa=Val (75%)
Scheme 5.

5136
V. V. Sureshbabu et al. / Tetrahedron Letters 49 (2008) 5133–5136
2H), 6.35 (m, 2H), 6.9 (m, 5H); 13C NMR (100 MHz, CDCl3): d 16.8,
21.9, 24.1, 31.2, 34.3, 51.3, 63.2, 69.3, 82.5, 127.1, 128.4, 128.8,
142.1, 155.3, 155.9, 156.6, 171.2, 175.5; HRMS calcd for
Compound 9b: Solid; 1H NMR (300 MHz, CDCl3): d 0.89–0.93
(m, 12H), 1.39 (s, 9H), 1.71 (m, 2H), 2.53 (m, 2H), 3.9 (m, 4H), 4.3
(s, 2H), 5.42 (m, 3H), 7.1–7.4 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 18.1, 19.4, 21.0, 23.2, 24.7, 32.0, 43.2, 47.0, 56.0, 59.0, 61.0, 77.0,
128.1, 128.7, 129.0, 129.5, 129.8, 154.0, 167.1, 167.8, 169.0, 171.1;
C
24H36N4NaO5: 483.2583, found 483.2579 [M+Na]; IR: 1701,
1697, 1657, 1634 cmꢂ1
.
Compound 3c: White solid; 1H NMR (300 MHz, CDCl3): d 0.97
(m, 6H), 1.31 (s, 9H), 1.63 (m, 2H), 2.1 (m, 1H), 4.18 (s, 2H), 4.3
(m, 3H), 5.2 (m, 2H), 7.1–7.68 (m, 5H); 13C NMR (100 MHz, CDCl3):
d 16.4, 18.1, 23.1, 24.3, 31.1, 32.1, 45.8, 56.7, 62.8, 127.1, 127.9,
128.1, 128.6, 129.2, 156, 165.2, 170.1. HRMS calcd for C21H30Na-
N4O5: 441.2114, found: 441.2117 [M+Na]; IR: 1702, 1696, 1649,
HRMS calcd for C26H39N5NaO6: 540.2798, found: 540.2792
[M+Na]; IR: 1693, 1642, 1638 cmꢂ1
.
Acknowledgment
The authors thank the Department of Science and Technology
(DST), Government of India, for financial assistance.
1630 cmꢂ1
.
Compound 3f: Off white solid; 1H NMR (300 MHz, CDCl3): d
0.93 (d, J = 6.4 Hz, 6H), 1.24 (t, J = 9.8, 3H), 1.65 (d, J = 6.8 Hz, 2H),
3.12 (m, 2H), 4.12 (d, J = 7.6 Hz, 2H), 4.23 (m, 3H), 5.1 (s, 1H),
5.32 (s, 1H), 6.9–7.7 (m, 18H); 13C NMR (100 MHz, CDCl3): d 14.6,
22.6, 25.1, 38.7, 43.7, 46.8, 50.2, 55.2, 62.0, 67.6, 120.5, 125.5,
127.5, 127.9, 128.2, 128.7, 129, 129.2, 129.7, 129.8, 135.0, 136.2,
141.8, 144.2, 156.0, 171.3, 172.0, 172.6; HRMS calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.06.091.
References and notes
C
38H38N4NaO5: 653.274, found: 653.2781 [M+Na]; IR: 1712,
1696, 1652, 1640 cmꢂ1
.
1. Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997.
2. Hirschmann, R. Angew. Chem., Int. Ed. Engl. 1991, 30, 1278.
3. Sureshbabu, V. V.; Patil, B. S.; Venkataramanarao, R. J. Org. Chem. 2006, 71,
7697.
4. Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P. A.; Adams, C. L.;
Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science 1993, 261, 1303.
5. Moree, W. J.; van-der Marel, G. A.; Liskamp, R. J. J. Org. Chem. 1995, 60,
5157.
6. Wipf, P.; Venkatraman, S. J. Org. Chem. 1996, 61, 8004.
7. Angel, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674.
8. Hitotsuyanagi, Y.; Motegi, S.; Fukaya, S.; Takeya, K. J. Org. Chem. 2002, 67,
3266.
9. Clapp, L. B. In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: New York, 1976; Vol. 20, pp 65–116.
10. Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.; Macleod, A.; Knight, A.;
Merchant, K.; Moseley, J.; Saunders, J.; Swain, C. J.; Wong, E.; Springer, J. P. J.
Med. Chem. 1989, 32, 2282.
11. Messer, W. S., Jr.; Abu, Y. F.; Liu, Y.; Periyasamy, S.; Ngur, D. O.; Edgar, M. A. N.;
El-Assadi, A. A.; Dunbar, P. G.; Nagi, P. I. J. Med. Chem. 1997, 40, 1230.
12. Kohara, Y.; Imamiya, E.; Kubo, K.; Wada, T.; Inada, Y.; Naka, T. Bioorg. Med.
Chem. Lett. 1995, 5, 1903.
13. Medebielle, M.; Ait-Mahand, S.; Burkhloder, C.; Dolbier, W. R., Jr.; Laumond, G.;
Aubertin, A-M. J. Fluorine Chem. 2005, 126, 535.
14. Andersen, K. E.; Lundt, B. F.; Jorgensen, A. S.; Braestrup, C. Eur. J. Med. Chem.
1996, 31, 417.
Compound 6a: Off white solid; 1H NMR (300 MHz, CDCl3): d
0.98 (d, J = 6.6 Hz, 3H), 1.37 (d, J = 6.8 Hz, 6H), 1.81 (m, 3H), 3.9
(m, 3H), 4.2–4.43 (m, 5H), 4.52 (m, 2H), 5.32 (m, 2H), 6.1 (br,
4H), 7.2–8.1 (m, 18 H); 13C NMR (100 MHz, CDCl3): d 16.8, 17.0,
31.5, 36.8, 45.1, 48.1, 50.3, 56.1, 63.4, 65.1, 68.7, 125.0, 126.8,
127.7, 127.9, 128.0, 128.2, 128.3, 128.7, 128.9, 129.6, 138.4,
141.0, 142.2, 144.6, 156.5, 156.9, 163.4, 172.4, 173.0, 176.1; HRMS
calcd for C42H46N6NaO8: 785.3275, found: 785.3281 [M+Na]; IR:
1708, 1698, 1666, 1634 cmꢂ1
.
Compound 6b: White solid; 1H NMR (300 MHz, CDCl3): d 0.91
(d, J = 6.8 Hz, 6H), 1.02 (d, J = 5.8 Hz, 3H), 1.2 (m, 2H), 1.34 (s,
9H), 2.31 (m, 3H), 4.25 (s, 2H), 4.4–4.53 (m, 5H), 5.2 (br, 2H), 5.5
(m, 2H), 7.1–7.9 (m, 10H); 13C NMR (100 MHz, CDCl3): d 14.9,
18.3, 22.9, 27.0, 36.0, 39.3, 42.1, 53.0, 56.0, 61.1, 65.3, 68.6,
121.1, 124.2, 125.3, 125.8, 129.3, 129.9, 131.1, 132.3, 134.5,
149.0, 151.2, 156.0, 160.0, 169.0, 172.5; HRMS calcd for
C
33H44N6NaO7: 659.3169, found: 659.3172 [M+Na]; IR: 1712,
1696, 1652, 1640 cmꢂ1
.
Compound 7a: Solid; 1H NMR (300 MHz, CDCl3): d 0.93–0.96
(m, 12H), 1.41 (s, 9H), 1.68 (m, 2H), 2.31 (m, 2H), 3.7 (t,
J = 8.1 Hz, 2H), 4.13 (m, 2H), 5.54 (m, 2H), 5.87 (br, 2H), 7.2–7.41
(m, 5H); 13C NMR (100 MHz, CDCl3): d 18.2, 19.6, 22.5, 23.1, 29.0,
33.2, 46.5, 53.1, 67.0, 80.0, 129.2, 129.8, 135.0, 136.0, 156.0,
158.5, 171.0, 176.0; HRMS calcd for C24H38N4NaO6: 501.2689,
15. Jakopin, Z.; Roskar, R.; Delenc, M. S. Tetrahedron Lett. 2007, 48, 1465.
16. Crestey, F.; Lebargy, C.; Lasne, M.-C.; Perrio, C. Synthesis 2007, 21, 3406.
17. Katritzky, A. R.; Shestopalov, A. A.; Suzuki, K. ARKIVOC 2005, 36.
18. Bedford, C. D.; Howd, R. A.; Dailey, O. D.; Miller, A.; Nolen, H. W.; Kenley, R. A.;
Kern, J. R.; Winterley, J. S. J. Med. Chem. 1986, 29, 2174.
19. Borg, S.; Vollinga, R. C.; Laberre, M.; Payza, K.; Terenius, L.; Luthman, K. J. Med.
Chem. 1999, 42, 4331.
20. Hamze, A.; Hernandez, J.-F.; Fullrand, P.; Martinez, J. J. Org. Chem. 2003, 68,
7316.
found 501.2684 [M+Na]; IR: 1741, 1709, 1690, 1640 cmꢂ1
.
Compound 7c: Solid; 1H NMR (300 MHz, CDCl3): d 0.98 (d,
J = 6.6 Hz, 3H), 1.86 (d, J = 4.3, 2H), 3.9 (t, J = 7.8 Hz, 1H), 4.2–4.43
(m, 4H), 4.52 (m, 2H), 5.32 (m, 2H), 6.1 (br, 2H), 7.2–8.1 (m, 18
H); 13C NMR (100 MHz, CDCl3): d 16.9, 21.2, 33.2, 37.3, 39.2,
42.4, 56.1, 121.0, 122.2, 124.5, 125.3, 126.0, 128.2, 128.3, 128.6,
129.4, 129.6, 131.2, 131.5, 135.0, 142.0, 156.0, 169.5, 172.4; HRMS
calcd for C35H34N4NaO6: 629.2376, found: 629.2371 [M+Na]; IR:
21. Hebert, N.; Hannah, A.-L.; Sutton, S. C. Tetrahedron Lett. 1999, 40, 8547.
22. Buchanan, J. L.; Vu, C. B.; Merry, T. J.; Corpuz, E. G.; Pradeepan, S. G.; Mani, U.
N.; Yang, N.; Plake, H. R.; Vakhedkar, V. M.; Lynch, B. A. Bioorg. Med. Chem. Lett.
1999, 9, 2359.
23. (a) Carpino, L. A.; Mansour, E. M. E.; El-Faham, A. J. Org. Chem. 1993, 58, 4162;
(b) Kaduk, C.; Wenschuh, H.; Beyermann, M.; Forner, K.; Carpino, L. A.; Bienert,
M. Lett. Pept. Sci. 1995, 2, 285; (c) Sureshbabu, V. V.; Ananda, K. Lett. Pept. Sci.
2000, 7, 41.
24. Note: Several other reagents such as DAST, cyanuric fluoride,
tetramethylfluoroformamidinium
hexafluorophosphate
(TFFH)
and
1747, 1714, 1690, 1634 cmꢂ1
.
Mukaiyama’s reagent are also used for the synthesis of acid fluorides, see:
(a) Sureshbabu, V. V.; Gopi, H. N.; Ananda, K. Indian J. Chem. 2000, 39B, 384; (b)
Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 487.
Compound 8a: White solid; 1H NMR (300 MHz, CDCl3): d 0.91–
0.95 (m, 12H), 1.33 (s, 9H), 1.58–1.62 (m, 2H), 2.41 (m, 4H), 3.81–
3.92 (m, 3H), 4.18 (s, 2H), 5.45–5.6 (m, 3H), 6.9–7.4 (m, 10H); 13C
NMR (100 MHz, CDCl3): d 17.9, 19.5, 20.0, 21.0, 24.2, 28.4, 33.0,
37.1, 38.0, 44.9, 59.0, 66.5, 67.0, 122.0, 124.0, 128.5, 128.7, 129.3,
129.7, 130.0, 131.0, 157.0, 169.1, 169.7 170.0, 171.0; HRMS calcd
for C33H45N5NaO6: 630.3268, found: 630.3271 [M+Na]; IR: 1696,
25. (a) Lal, G. S.; Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem.
1999, 64, 7048; (b) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
26. Deoxo-Fluor was used for the one-pot synthesis of Weinreb amides derived
from Boc-Pro-OH, Boc-Leu-OH and Boc-Phe-OH via the corresponding acyl
fluorides generated in situ using DIPEA. See: (a) Tunoori, A. R.; White, J. M.;
Georg, G. I. Org Lett. 2000, 2, 4091. Similarly, Boc-Pro-NH2 and Boc-Val-NH2
were also prepared usingDeoxo-Fluor: (b) White, J. M.; Tunoori, A. R.; Turunen,
B. J.; Georg, G. I. J. Org. Chem. 2004, 69, 2573.
1645, 1634 cmꢂ1
.