Solution-phase synthesis of linear and cyclic peptidomimetics based on 2-aminoalkyloxazole-4- Or -5-carboxylates

Article abstract of DOI:10.1071/CH03250

The solution-phase synthesis of several small linear and cyclic peptidomimetics based on the coupling of BOC-protected 2-aminoalkyloxazole-4- or -5-carboxylic acids is reported. Cyclic amides have been formed both by sequential coupling and cyclization, o

Full text of DOI:10.1071/CH03250

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 747–758
Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
Based on 2-Aminoalkyloxazole-4- or -5-carboxylates
Matthew O. Cox,A Rolf H. Prager,A,B and Carina E. SvenssonA
A School of Chemistry, Physics and Earth Sciences, Flinders University of South Australia,
Adelaide SA 5001, Australia.
B Author to whom correspondence should be addressed (e-mail: rolf.prager@flinders.edu.au).
The solution-phase synthesis of several small linear and cyclic peptidomimetics based on the coupling of BOC-
protected 2-aminoalkyloxazole-4- or -5-carboxylic acids is reported. Cyclic amides have been formed both by
sequential coupling and cyclization, or by cyclooligomerization.
Manuscript received: 19 September 2003.
Final version: 17 November 2003.
Introduction
These procedures have generally been biomimetic, including
cyclodehydration of amides or thioamides, and subsequent
dehydrogenation or prior oxidation.
The three-dimensional conformation of one such com-
pound, bistratamide C (1, Scheme 1) was investigated
by computational techniques.[10] With three aromatic con-
straints the peptide became nearly flat and the side chains
were perpendicular to the plane of the backbone.[10]
The aim of the present work is to synthesize a range of gen-
erally unknown structures based upon 2-aminoalkyloxazole
carboxylic acids, with the acid functionality at C-4 or C-5,
to connect these units with amide bonds, and to selectively
orient the ring nitrogen or oxygen atom towards the centre
of the macrocycle (e.g. 2 and 3, Scheme 1). The desired
structures would ideally have long side chains derived from
unnatural amino acids, to serve as a hydrophobic upper face,
to aid penetration into cell membranes (see 4, Scheme 2).
It was our aim to build up the appropriate linear amides
in a stepwise manner, followed by cyclization. In addition,
cyclotrimerization/cyclotetramerization of the aminoalkyl
oxazole carboxylic acid can also be achieved, as shown in
A large number of natural and synthetic marine cyclic pep-
tides containing unusual thiazole, thiazoline, oxazole, and
oxazoline rings have been isolated from marine invertebrates
such as sponges and tunicates,[1] and are possibly produced
by symbiotic microorganisms,[2,3] because of the presence of
both d-amino acids and unusual amino acids. In sea sponges
and squirts it is likely that the production of cyclic peptides
is a form of chemical defence.[1] Hydrophobic side chains of
cyclic peptides frequently provide a hydrophobic exocyclic
surface that protects their amide bonds from peptidases and
this also facilitates the crossing of cell membranes.[4]
The 18-membered marine cyclic peptides containing only
aromatic heterocycles constitute an interesting class of these
peptides, but few have been found to occur in nature. Most
oxazole-bearing natural products of both marine and terres-
trial origin have the 2,4-disubstitution pattern, which is a con-
sequence of their biogenesis, and the synthesis of the required
2,4-linked thiazole or oxazoles and their coupling have been
described by Fairlie et al.,[5] Shioiri et al.,[6] Walker and
Heathcock,[7] Wipf and Fritch,[8] and North and Pattenden.[9]
O
R1
O
O
O
O
N
N
H
N
H
N
H
S
S
N
N
N
N
O
O
O
O
R3
NH
HN
NH
NH
HN
HN
N
N
S
O
O
O
R2
S
S
N
1
2
3
Scheme 1.
© CSIRO 2004
10.1071/CH03250
0004-9425/04/080747

748
M. O. Cox, R. H. Prager and C. E. Svensson
the synthesis of the C3-symmetrical westiellamide 5 from
the oxazoline 6 by Wipf and Miller (Scheme 3).[11]
Discussion
Part 1. Solution-Phase Synthesis by the
N-tert-butoxycarbonyl (BOC) Strategy
We have reported a new synthesis of oxazoles[12] and
thiazoles,[13] and the application to the synthesis of the 2-
aminoalkyl-oxazole-4-[14] and-5-carboxylicacids[15] thatare
capable of being elaborated into the biogenetically ‘natural’
cyclic amides 2 and their isomeric ‘unnatural’cyclic amides,
and our initial studies are the subject of this paper.
Our initial investigations of the methods for obtaining lin-
ear oxazole based amides used the readily available amino
ester 7.[14] N-protection gave the ester 8 which was then
hydrolyzed to the N-protected acid 9 (Scheme 4). Treatment
of acid 9 with the amine 7 in the presence of benzotriazol-
1-yloxytris(dimethylamino)phosphonium hexafluorophos-
phate[20] (BOP) and triethylamine produced the amide linked
bis-oxazole 10.
Boss et al.[16] have recently reported the synthesis of
cyclic trimers containing O-benzylated serine and lysine oxa-
zole amino acid derivatives via both the cyclooligomerization
strategy and the traditional stepwise approach. The ‘one-pot’
cyclizations of the oxazole derivatives proceeded with yields
ranging between 10 and 20%, which is in stark contrast to
the high-yielding cyclooligomerization reactions reported for
analogous thiazole systems.[17,18] Rebek et al.[19] have also
observed low yields for the cyclooligomerization of similar
oxazole amino acids.
The progress of the reaction could be followed by 1H NMR
spectroscopy, as the presence of the intermediate activated
ester (11, Scheme 5) was apparent from its oxazole methyl
group, resonating at 2.72 ppm.
After hydrolysis of the ester 10 to the acid 12, the sequence
was repeated, giving the amide-linked tris-oxazole 13 in an
overall yield of 26% from 9 (Scheme 6). The compound
was analyzed by electrospray mass spectrometry (ESI-MS),
giving the [M + Na]+ ion at m/z 583, with daughter ions
appearing at m/z 527 due to loss of 2-methylpropene, and
at m/z 483 due to further loss of carbon dioxide.
R3
R1
R2
The C-terminus was hydrolyzed first to give the acid 14,
then the N-terminus was deprotected, either with anhydrous
hydrogen chloride or with anhydrous−trifluoroacetic acid.The
salt of the amine (15, X− = CF3CO2 ) was obtained in near
quantitative yield.
The macrocyclization of 15 was performed in a 1 mM
DMF solution with diphenylphosphoryl azide (DPPA) and
two equivalents of triethylamine. The resulting product could
not be analyzed by NMR spectroscopy, as it was essen-
tially insoluble in a range of solvents, such as chloroform,
methanol, dimethylsulfoxide, and water. Upon analysis by
electrospray mass spectrometry, a major peak appeared at
4
Scheme 2.
O
O
N
H
1. H2, Pd/C, MeOH
2. DPPA, DMF
O
O
N
N
BOCNH
N
H
O
CbzHN
O
N
NH
20%
HN
H
O
O
N
N
OH
O
O
N
N
O
6
CH3
5
11
Scheme 5.
Scheme 3.
CH3
O
EtO2C
N
HCl · H2N
BOCNH
(BOC)2O, NEt3,
DMAP, CH2Cl2
N
N
1. aq. NaOH, MeOH (70%)
2. 7, BOP, NEt3 (58%)
O
O
HN
CO2Et
CO2R
88%
N
O
CH3
CH3
O
CH3
BOCNH
8
R ꢀ Et
7
9 R ꢀ H
10
Scheme 4.

Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
749
CH3
CH3
O
HOOC
EtO2C
O
N
N
aq. NaOH, MeOH
7, BOP, NEt3
HN
10
HN
O
87%
NHBOC
O
N
N
CH3
N
H
N
O
O
CH3
BOCNH
O
O
CH3
aq. NaOH, MeOH
(46%)
12
13
CH3
O
CH3
O
HOOC
HOOC
O
H3C
O
O
N
H
N
N
CH3
N
N
HN
HN
DPPA, Et3N
71%
TFA
96%
NHꢂ3
O
Xꢁ
NHBOC
N
O
O
NH
HN
N
N
CH3
N
CH3
N
H
N
H
N
O
O
O
O
O
O
O
O
H3C
CH3
H3C
16
15
Scheme 6.
14
O
O
H3C
H3C
O
O
O
N
H
N
H
CH3
O
CH3
O
N
N
N
N
Kꢂ
N
O
NH
NH
HN
HN
N
O
O
O
O
H3C
H3C
16a
16b
dH 4.59
dC 36.92 & 37.01
HN
dH 4.60, d, J 3.9 Hz
dC 37.15
HN
CH2
CH2
dC
dC
128.59
154.23
157.81
161.19
128.35 & 128.38
154.36
157.65 & 157.69
161.29 & 161.35
N
N
O
O
H
N
H
N
CH3
CH3
O
O
dH 2.68
dC 11.25
dH 2.61 & 2.68
dC 11.44
Scheme 8. NMR characteristics of 16b, K+ complex.
Scheme 7. NMR characteristics of 16a.
m/z 453, consistent with 16b (Scheme 8).The presence of the
potassium ion is interesting as the reaction mixture had not
knowingly been in contact with potassium salts at any stage,
although the triethylamine used was dried over potassium
carbonate.
dichloromethane at 0–5◦C for one hour. The residue, 16a,
was now soluble in a mixture of chloroform and methanol,
which made NMR analysis possible. Analysis of this mate-
rial with ESI-MS showed a [M + H]+ ion, but the [M + K]+
ion was not present. The 1H NMR spectrum (summa-
rized in Scheme 7) showed a single oxazole methyl peak
(9H) and methylene peak (6H), consistent with a planar,
A suspension of this compound in dichloromethane
was treated with a solution of hydrogen chloride in

750
M. O. Cox, R. H. Prager and C. E. Svensson
symmetrical molecule. However, the two methylene signals
in the 13C NMR spectrum suggest the ‘planarity’is probably
a consequence of rapid inversion of two conformers.
Since treatment of 16a with Na2CO3 brought about no
change, it is possible that the size of the cavity of the cyclic
polyamide is suitable for a potassium ion but not for the
smaller sodium ion, which was observed as the coordinated
ion with the linear polyamide 15. An unusual potassium-
binding cleft has been reported to form after selective acidic
hydrolysis of the oxazoline rings of ascidiacyclamide.[5]
Unfortunately, attempts to obtain X-ray quality crystals of
the product using different solvents and techniques, such
as slow evaporation, vapour infusion, and solvent diffusion,
were unsuccessful.
Having demonstrated that this procedure could success-
fully be used to generate the cyclic tris-oxazole 16, we wished
to apply the method to the synthesis of a macrocycle 17
(Scheme 9) consisting of four oxazole units with alternating
4- and 5-ethoxycarbonyl functionality. In that way we hoped
to create a cavity suitable for ions or small molecules to bind
to the heterocycle nitrogen or oxygen atoms. Dimerization of
the amino acid from bisoxazole 18 offered an attractive route
to this molecule and a stepwise method of dimerization was
chosen, since the alternative approach to cyclization, involv-
ing deprotection of both termini, appeared likely to produce
polymers or mixtures of ring sizes.
The mother liquors of the initial product were then washed
with aqueous potassium bicarbonate solution to give addi-
tional 16b. The electrospray mass spectrum showed a peak at
m/z 453, again suggesting potassium as the coordinated ion.
1
The H NMR spectrum (summarized in Scheme 8) showed
two singlets in the oxazole methyl region (ratio 2 : 1). The
nonequivalence of the methyl groups was not expected but
may be due to complexation with K+, inducing a tilted struc-
ture where two oxazole units form a plane and the third unit
is forced out of the plane, with its methyl group protruding
more to the centre of the cavity.
CH3
O
O
N
N
H
N
CH3
O
HCl · H2N
O
N
HN
N
O
O
NH
CH3
O
N
H
N
CO2Et
CH3
O
The hydrochloride of the amine 19 was treated with the
acid 9, as above, to give the bis-oxazole 18 (Scheme 10).
Half of this material was deprotected on the N-terminus in
order to obtain the trifluoroacetate 21, while the other half
was hydrolyzed to the acid 20. In the next step the units were
O
H3C
17
19
Scheme 9.
BOCNH
CO2Et
CH3
NHBOC
N
COOH
CH3
N
BOCNH
O
BOP, NEt3, 19
aq. NaOH, MeOH
89%
O
N
O
H
N
COOH
H
N
O
N
68%
O
N
CH3
O
O
CH3
CH3
9
18
20
TFA
100%
CF3COOꢁ
NHꢂ3
CO2Et
CH3
O
N
H
N
O
N
O
CH3
21
CH3
O
O
N
H
N
N
CH3
O
22 R ꢀ Et
23 R ꢀ H
BOP, NEt3
64%
HN
N
RO2C
21 ꢂ 20
NHBOC
O
24 R ꢀ C6F5
O
N
CH3
H
N
O
O
CH3
Scheme 10.

Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
751
connected, affording the amide-linked linear tetraoxazole 22
in an overall yield of 39% from 9. The amide-linked oxazoles
all gave a prominent [M + Na]+ ion upon ESI-MS analysis,
exceptforcompound 21whichappearedasthe[M + H]+ ion.
Macrocyclization with DPPA is generally straightforward,
but the reaction requires low temperatures and proceeds
slowly. Schmidt and Weller[21] have reported the superior-
ity of the pentafluorophenyl ester for the ring closure step
over other methods, such as the diphenylphosphorazidate
or the trichlorophenyl ester applications. It has been sug-
gested that cyclization of the pentafluorophenyl esters is the
most appropriate method for peptides whose linear precur-
sors are conformationally biased against cyclization, since
the higher temperatures can overcome the conformational
constraints.[3] While cyclization using the pentafluorophenyl
ester[22] requires an additional step, the formation of an acti-
vated ester, this in situ cyclization step is reported to be much
faster at the elevated temperatures (50–100◦C).
Consequently, compound 22 was hydrolyzed to the acid
23, which was isolated in 54% yield, then converted to the
corresponding pentafluorophenyl ester 24 using pentafluo-
rophenyl trifluoroacetate in pyridine. The BOC-protecting
group was thereafter removed, and the ring closure reaction
was attempted in a stirred mixture of chloroform and 2 M
aqueous potassium carbonate solution, but no reaction was
observed.
25 was heated in toluene at 100◦C for 25 h at a concentration
of 1 mM, but NMR analysis indicated that no reaction had
occurred. Macrocyclization of the acid 26 was attempted in
dimethylformamide with excess dicyclohexylcarbodiimide
at ambient temperature, but no cyclization occurred using
this coupling reagent; the reaction mixture seemed to con-
sist of several compounds, presumably products of different
chain lengths.
In further attempts to obtain macrocycles with oxygen
atoms within the annulus, the hydrochloride of ethyl 2-
(aminomethyl)-1,3-oxazole-5-carboxylate 28[15] was treated
under the same conditions as those discussed previously
for the 4-carboxylate 7 and ethyl 2-(aminomethyl)-4-methyl-
1,3-oxazole-5-carboxylate 19, but coupling proceeded con-
siderably slower (Scheme 12), and such reactions were not
pursued further.
The synthesis of cyclic peptides containing oxazoles with
the carboxyl functionality at C-5 only was initiated by BOC
protection of the hydrochloride of the amine 28, followed by
hydrolysis of the ester 31, to give the corresponding acid 32
in 46% yield from 28 (Scheme 13). Unfortunately, recrystal-
lization of the acid was low yielding, and it was not used as
the N-terminus due to time constraints.
Part 2. Cyclopolymerization
Pattenden et al.[24] investigated the cyclooligomerization
reactions of valine- and phenylalanine-derived thiazole
amino acids at varying concentrations and with several
coupling reagents. Pentafluorophenyldiphenylphosphinate
(FDPP) activation was found to give consistently high
yields (80–96%) of the desired cyclic products, but the
ratios of cyclic trimer and cyclic tetramer were depen-
dent on the concentration.[24] Concentrations within the
range 10–50 mM gave the best results. The overall trimer
to tetramer ratio was also found to be dependent on both
the stereochemistry of the side chain as well as its steric
encumbrance.
An alternative method for cyclization was demonstrated
by Aguilar and Meyers in the synthesis of bistratamide C,[23]
in which the amino group reacted directly with the ethyl ester
of the C-terminus in boiling toluene. This method is suitable
for precursors containing only fully aromatic heterocycles,
rather than the more sensitive oxazoline and thiazoline moi-
eties. Cyclization of the trifluoroacetate salt of the amine 25
(Scheme 11) was attempted in a similar way.The precursor 22
was deprotected in anhydrous TFA, affording 25. Compound
CH3
O
O
N
H
N
N
CH3
·
HCl H2N
O
BOCNH
25 R ꢀ Et
26 R ꢀ H
N
HN
N
N
NHꢂ3
RO2C
O
O
O
27 R ꢀ C6F5
O
N
CH3
H
N
CO2Et
CO2R
O
28
31 R ꢀ Et
32 R ꢀ H
O
CH3
Scheme 11.
Scheme 13.
NHBOC
N
CO2Et
BOCNH
BOCNH
O
N
N
H
N
28, BOP, NEt3
ꢂ
O
O
O
O
N
N
COOH
O
N
N
O
CH3
CH3
CH3
37%
20%
9
29
30
Scheme 12.

752
M. O. Cox, R. H. Prager and C. E. Svensson
O
O
C
HCl · H2N
HCl · H2N
HCl · H2N
N
N
N
N
C
O
N
O
O
O
COOH
CH3
O
CO2R
CH3
COOH
COOH
CH3
33
34
35
38
OBz
O
C
H3C
O
N
H
CH3
N
O
N
CO
HN
NH
OC
N
BzO
O
O
H3C
HCl · H2N
OBz
39
PyBOP, DIEA,
0ºC, DMF, 5h
N
ꢂ
O
CO2R
44%
OBz
CH3
36 R ꢀ H
37 R ꢀ Et
O
H3C
O
C
CH3
N
H
O
N
BzO
N
CO
HN
N
NH
N
OC
OBz
O
H
N
H3C
C
O
O
CH3
BzO
40
Scheme 14.
In an extension of this work, Pattenden et al.[25] reported
amino acids in the case of the 5-esters, and thus cyclopoly-
merizations with these substrates were abandoned. More
satisfactory results were obtained with 36, prepared from
the phthalimido ester 38.[14] Cyclooligomerization of
36 was performed in a 10 mM anhydrous DMF solu-
tion with the coupling reagent PyBOP (benzotriazole-
1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate)
reagent and DIEA (diisopropylethylamine). After stirring at
0◦C for 5 h, the reaction gave a mixture of the cyclic trimer 39
and cyclic tetramer 40 as a white powder, in a yield of 44%.
Unfortunately 39 and 40 could not be separated by chro-
matography, but neither appeared to complex calcium ions,
present as a binder in the chromatography plate.
the templating effect of metal ions during the cyclooligomer-
ization reaction. Cyclooligomerization of the thiazole amino
acid in the presence of smaller metal ions favoured the forma-
tion of the trimer, whereas the cyclic tetramer was favoured
with larger metal ions, such as cadmium. Recently, Singh
et al.[17] and Pattenden and Thompson[18] reported the syn-
thesis of symmetrical thiazole-containing platforms and their
further elaboration into highly constrained chiral cavitands.
In our strategy to create symmetrical cyclic peptides
consisting of oxazoles with either 2,4- or 2,5-linking and
with unnatural 2-aminoalkyl groups, we initially chose to
use the oxazole amino acids 33–35 (Scheme 14). Hydroly-
sis of the 2-aminomethyl 4- and 5-ethoxycarbonyloxazoles
(7, 19, 28) resulted in low yields of the corresponding
The 1H and 13C NMR spectra for the cyclic trimer/cyclic
tetramer mixture (summarized in Scheme 15) suggested that

Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
753
OBz
CH3
OBz
dC 47.57 or 46.41
dH 8.22
dH 2.54
dC 11.66
O
H3C
C
O
O
H3C
dC 49.72
C
N
H
O
N
H
N
O
N
CH3
BzO
N
O
N
CO
dH 5.53
H
HN
N
CO
H
NH
OC
HN
NH
dH 5.24
dC 39.7
N
OBz
H
N
N
O
OC
BzO
H3C
BzO
O
C
O
O
CH3
dH 2.58
dC 11.56
H3C
dC 39.20
OBz
Scheme 15. NMR characteristics of 39 and 40.
O
H
O
C
N
H
N
O
N
O
O
O
H
PyBOP, DIEA,
0ºC, DMF, 5h
CO
NH
OC
HCl · H2N
HN
N
O
43%
O
H
N
H
CO2H
41
42
O
Scheme 16.
O
the cyclic trimer 39 has high (C3) symmetry. In addition, the
3
vicinal JNHCH value for 39 (6.46 Hz) is comparable to the
value of 6.6 Hz observed by Boss et al.[16] in a similar lysine-
derived cyclic oxazole trimer. These coupling constants
correspond to dihedral angles of 145◦ < θ < 155◦ in both
macrocycles. In contrast, both Singh et al.[17] and Pattenden
H
O
C
N
N
O
H
N
O
O
H
dC 115.69
CO
3
and Thompson[18] have reported that the vicinal JNHCH
NH
OC
HN
dC 49.33
values of lysine- and ornithine-derived thiazole-containing
cyclic trimers lie between the values of 9.1 and 9.3 Hz, which
corresponds to dihedral angles between 165◦ < θ < 175◦.
We speculate that the decreased dihedral angles observed
in the oxazole cyclic trimer may increase the steric conges-
tion between the side chains, and therefore result in a lower
yielding cyclooligomerization reaction compared to the thia-
zole cyclic peptides. Unfortunately, attempts to obtain X-ray
quality crystals of the products using different solvents and
techniques were unsuccessful.
O
dC 37.77
N
H
O
dC 70.47
Scheme 17. 13C NMR characteristics of 42.
Having verified that the cyclooligomerization reaction
could successfully be applied to the synthesis of both a 2,4-
linked cyclic trimer 39 and a cyclic tetramer 40, we decided
to explore its utility to 2,5-linked cyclic oxazole peptides.
Cyclooligomerization of 41 using an identical procedure to
that outlined above gave the cyclic trimer 42 in 43% yield
after purification by radial chromatography (Scheme 16).
Interestingly, none of the corresponding cyclic tetramer was
isolated from the product mixture.
The C3-symmetrical nature of 42 was confirmed by the
13C NMR spectrum which indicated one set of resonances for
the repeating peptide subunit (summarized in Scheme 17).
Analysis of structure 42 with ESI-MS indicated minor
peaks at m/z 961.3538 and 983.3376, which were consistent

754
M. O. Cox, R. H. Prager and C. E. Svensson
with the [M + H]+ and [M + Na]+ respectively, of the antic-
ipated product. Synthesis of linear polymers was believed to
be competing with the cyclooligomerization reaction, hence
giving low yields of the desired products.
2-(N-tert-Butyloxycarbonylaminomethyl)-5-methyl-
1,3-oxazole-4-carboxylic Acid 9
Sodium hydroxide (2.5 M, 3.3 mL) was added dropwise at rt to a solution
of the ester 8 (1.020 g, 3.59 mmol) in methanol (6 mL). TLC analysis
of the mixture showed the starting material to be absent after 30 min,
and the solvent was removed under vacuum. The yellow residue was
adjusted to pH 4 by addition of 0.48 M citric acid (18 mL), and the
resulting suspension was cooled at 0–5◦C overnight. The solid mate-
rial was collected and washed with citric acid (2 × 4 mL), then ice-cold
water (2 × 5 mL) to give an off-white powder. The crude product was
suspended in dichloromethane (6 mL), diluted with ether (16 mL), then
chilled on ice for several hours, affording the pure product as a very
fine powder (642 mg, 2.51 mmol, 70%), mp 165–167◦C. (Found: C
Conclusions
The procedure for the sequential synthesis of amide linked
di-, tri-, and tetra-oxazoles has been outlined. Cyclization
to form cyclic tri-oxazoles was successful, but not of tetra-
oxazoles. The synthesis of symmetrical cyclic peptides based
on both 2-aminoalkyloxazole-4-carboxylic acids and -5-
carboxylic acids has been achieved by the cyclooligomeriza-
tion of their repeatable subunit, in moderate yields. It appears
that PyBOP is a valid alternative for the macrocyclizations,
having given the desired oxazole peptides in the highest
reported yields for the oxazole ring systems. The marked ten-
dency of the linear polyoxazoles to coordinate with sodium
contrasted with the observation of the [M + K]+ ion of the
cyclic amide linked tris-oxazole.
•
51.6, H 6.4, N 11.0%, M+ 256.1077. C11H16N2O5 requires C 51.6,
•
H 6.3, N 10.9%, M+ 256.1059). vmax/cm−1 3349, 1683, 1615, 1524.
δH (CDCl3/CD3OD) 1.45 (9H, s), 2.61 (3H, s), 4.13 (1H, bs), 4.39 (2H,
bs), 5.92 (1H, bs). δC (CDCl3/CD3OD) 11.6, 28.0, 37.3, 80.1, 127.6,
155.9, 156.7, 159.5, 164.0. m/z 256 (M+, 3.6%), 200 (M – C4H8, 86%),
140 (C6H6NO3, 22%), 57 (100%).
N-(4-Ethoxycarbonyl-5-methyloxazol-2-ylmethyl)-
2-(tertbutyloxycarbonylaminomethyl)-5-methyloxazole-
4-carboxamide 10
A solution of the hydrochloride of the amine 7 (324 mg, 1.47 mmol)
and triethylamine (149 mg, 1.47 mmol) in dichloromethane (10 mL)
was added to a mixture of the acid 9 (376 mg, 1.47 mmol), tri-
ethylamine (149 mg, 1.47 mmol), and BOP (652 mg, 1.43 mmol) in
dichloromethane (10 mL) at rt under N2, and the reaction was stirred
for 20 h. The reaction mixture was extracted with 10% potassium bicar-
bonate (2 × 10 mL), followed by water (2 × 10 mL), and the solvent
was then removed under reduced pressure. The residue was dissolved in
ether and extracted with water (3 × 10 mL), the organic layer was dried
and the solvent was removed under vacuum, yielding the product as a
colourless glass (363 mg, 0.859 mmol, 58%). vmax/cm−1 (film) 3341,
1716, 1668, 1634, 1519, 1447, 1368, 1342, 1253, 1179, 1097. δH 1.37
(3H, t, J 7.2), 1.44 (9H, s), 2.55 (3H, s), 2.60 (3H, s), 4.35 (4H, m), 4.71
(2H, d, J 5.7), 6.11 (1H, bs, NH), 8.02 (1H, t, J 5.7, NH). δC 10.9, 11.4,
13.7, 27.8, 35.2, 37.2, 60.4, 79.4, 127.2, 128.2, 153.4, 155.5, 156.2,
158.4, 158.7, 161.6, 161.8. m/z 366 ([M+ −56], 25.8%), 314 (10.1%),
183 (25.5%), 41 (100%).
Experimental
General details have been given in a previous paper.[14] The Attached
Proton Test (APT), was used in the assignment of all 13C NMR sig-
nals and, where additional information was required, heteronuclear
correlation (HETCOR) and homonuclear decoupling experiments were
performed.
ESI-MS were recorded on a Finnigan LCQ spectrometer operating
under following conditions: spray voltage 5.20 kV; capillary tempera-
ture 200◦C; capillary voltage 35V; tube lens offset 55V. The molecular
ion and selected fragment ions are reported as their mass to charge
ratio, as their [M + Na]+, [M + K]+, or [M + H]+ ions. The analyses
wereperformedinmethanolunlessotherwisestated.AdditionalESI-MS
were recorded at the Central Science Laboratory, University of Tasma-
nia, andtheseanalyseswereperformedin m-nitrobenzylalcohol(mnba).
High-resolution MS were recorded on a Kratos MS25RF spectrometer
as above or at the University of Tasmania.
Column chromatography and flash column chromatography used
Riedel–de Haën silica gel S 0.032–0.063 mm (31607) (pH 7, pour
density 0.4 g mL−1, granulation 32–63 µm [230–400 mesh ASTM]).
Centrifugal chromatography was performed with silica gel 60 PF 254
coated glass rotors using a Chromatotron (model 7924T). Analytical
thin layer chromatography (TLC) was carried out using Merck Silica
gel 60 F254 aluminium-backed sheets.
2-{[2-(tert-Butyloxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl]-methyl}-5-methyloxazole-4-carboxylic Acid 12
Ester 10 (345 mg, 0.817 mmol) was hydrolyzed as for 9 above, yield-
ing the acid as a colourless oil, which solidified to a glass (281 mg,
0.713 mmol, 87%), mp 88–89◦C. vmax/cm−1 3444 (2 bands), 1716,
1674, 1634, 1588, 1520, 1505, 1322, 1253, 1205, 1162, 1096. δH
(CDCl3/CD3OD) 1.45 (9H, s), 2.59 (6H, s), 4.36 (2H, s), 4.68 (2H, s),
5.25 (1H, bs, COOH), 6.36 (1H, t, J 5.7, NH), 8.17 (1H, bt, NH).
δC (CDCl3/CD3OD) 10.9, 11.2, 27.6, 35.1, 37.0, 79.7, 127.2, 128.1,
153.7, 155.9, 156.6, 158.6, 162.0, 162.1, 163.4. m/z (ESI) 417.0
([M + Na]+, C17H22N4O7Na requires 417.4), 393.6 ([M − H]+,
C17H21N4O7 requires 393.4).
Ethyl 2-(N-tert-Butyloxycarbonylaminomethyl)-5-methyl-
1,3-oxazole-4-carboxylate 8
4-Dimethylaminopyridine (25 mg, 0.20 mmol) was added to a mixture
of the aminoester 7[14] (912 mg, 4.13 mmol), di-tert-butyl dicarbon-
ate (929 mg, 4.13 mmol), and triethylamine (575 µL, 4.13 mmol) in
dichloromethane (8 mL), and the mixture was stirred at rt for 22 h.
The reaction was diluted with dichloromethane (25 mL) and extracted
with water (2 × 10 mL), then sat. sodium chloride (1 × 10 mL). The
organic layer was dried over sodium sulfate, filtered, and reduced under
high vacuum, affording the title compound (1.029 g, 3.62 mmol, 88%),
as an orange solid, mp 90–92◦C. (Found: C 54.6, H 7.0, N 9.8%,
N-(4-Ethoxycarbonyl-5-methyloxazol-2-ylmethyl)-2-
{[2-(tertbutyloxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl]-methyl}-5-methyloxazole-4-
carboxamide 13
A solution of the amine 7 (159 mg, 0.721 mmol) and triethylamine
(75 mg, 0.741 mmol) in dichloromethane (4.6 mL) was added to a
mixture of the acid 12 (273 mg, 0.692 mmol), triethylamine (67 mg,
0.662 mmol), and BOP (306 mg, 0.671 mmol) in dichloromethane
(5 mL) at rt and the reaction was stirred for 43 h under N2. The reac-
tion mixture was diluted with dichloromethane (10 mL), extracted with
water (10 mL), 10% potassium bicarbonate (2 × 10 mL), and water
(5 mL).The solvent was removed under reduced pressure and the residue
was dissolved in ether and washed with water (3 × 5 mL). The organic
•
•
M+ 284.1398. C13H20N2O5 requires C 54.9, H 7.1, N 9.85%, M+
284.1372). vmax/cm−1 3328, 1738, 1683, 1547, 1342, 1294, 1260, 1179,
1101. δH 1.39 (3H, t, J 6.9), 1.45 (9H, s), 2.61 (3H, s), 4.38 (2H, q,
J 6.9), 4.43 (2H, d, J 6.0), 5.3 (1H, bs, 1H). δC 11.8, 14.1, 28.1, 37.6,
60.8, 80.1, 127.6, 155.6, 156.6, 159.3, 162.2. m/z 284 (M+, 0.7%), 228
(12%), 57 (100%).

Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
755
layer was dried and the solvent was then removed under reduced pres-
sure. The crude product was dissolved in dichloromethane (10 mL)
and extracted with 0.48 M citric acid (2 × 5 mL), followed by water
(2 × 5 mL). Removal of the solvent under vacuum yielded the title com-
pound as a colourless oil (202 mg, 0.360 mmol, 52%). vmax/cm−1 3335,
1718, 1668, 1636, 1520, 1342, 1306, 1261, 1170, 1097. δH 1.37 (3H, t,
J 7.2), 1.44 (9H, s), 2.53 (3H, s), 2.56 (3H, s), 2.57 (3H, s), 4.36 (4H, m),
4.63(4H, d, J5.7), 5.85(1H, bt, NH), 7.92(1H, t, J6.0, NH), 8.07(1H, bt,
NH). δC 11.1, 11.6, 14.0, 28.0, 35.4, 35.4, 37.4, 60.6, 79.7, 127.4, 128.4,
128.4, 153.6, 155.5, 156.6, 158.2, 158.5, 158.6, 161.6, 161.7, 161.9. m/z
(ESI) 583.1 ([M + Na]+ with daughter ions 527 ([M + Na+−56]) and
483 ([M + Na+−100]), C25H32N6O9Na requires 583.6).
δC 11.2, 36.9, 37.0, 128.3, 128.3, 154.3, 157.6, 157.6, 161.2, 161.3.
m/z (ESI) (MeOH/CH2Cl2) 415.1 ([M + H]+ with daughter ion 372.1
([M + H+−43]), C18H19N6O6 requires 415.4).
The dichloromethane solution above was extracted with 10% potas-
sium bicarbonate (2 × 20 mL) and water (20 mL). The addition of ether
allowed an additional amount of the potassium complex 16b to be col-
lected by filtration as a beige powder (14 mg, 0.034 mmol, 23%), mp
285–286◦C. vmax/cm−1 3397, 1683, 1640, 1596, 1528, 1257, 1194,
1144. δH 1.74 (1H, bs), 2.62 (3H, s), 2.68 (6H, s), 4.60 (6H, d, J 3.9),
8.35 (1H, bt, NH). δC 11.4, 37.1, 128.5, 154.2, 157.8, 161.1. m/z (ESI)
452.9 ([M + K]+, C18H18N6O6K requires 453.5).
N-(5-Ethoxycarbonyl-4-methyloxazol-2-ylmethyl)-
2-(tertbutyloxycarbonylaminomethyl)-5-methyloxazole-
4-carboxamide 18
2{[2-(tert-Butyloxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl]-N-[2-aminomethyl-5-methyloxazol-
4-ylcarbamoyl]}-methyl-5-methyloxazole-
4-carboxylic Acid 14
A solution of the hydrochloride of the amine 19[15] (633 mg, 2.87 mmol)
in dichloromethane (3 mL), then triethylamine (400 µL, 2.87 mmol),
were added to a mixture of the acid 9 (735 mg, 2.87 mmol), triethylamine
(400 µL, 2.87 mmol), and BOP (1.34 g, 2.94 mmol) in dichloromethane
(7 mL) at rt, and the reaction was stirred for 16 h under N2. The reaction
mixture was diluted with dichloromethane (10 mL), extracted with water
(10 mL), followed by 10% potassium bicarbonate (2 × 5 mL) then water
(5 mL).The solvent was removed under reduced pressure and the residue
was dissolved in ether (30 mL). The organic layer was extracted with
water (3 × 20 mL), dried, and filtered. Removal of the solvent under vac-
uum yielded the product 18 as a slightly yellow oil (821 mg, 1.94 mmol,
68%). vmax/cm−1 3347, 1718, 1670, 1636, 1522, 1334, 1273, 1253,
1171, 1152, 1103. δH 1.38 (3H, t, J 7.2), 1.44 (9H, s), 2.42 (3H, s),
2.55 (3H, s), 4.37 (4H, m), 4.73 (2H, d, J 6.0), 6.08 (1H, bt, NH),
8.03 (1H, t, J 6.0, NH). δC 11.0, 12.6, 13.8, 27.8, 35.8, 37.2, 60.7,
79.5, 128.2, 137.6, 145.5•, 153.6, 155.6, 158.3, 158.5, 161.8, 162.0. m/z
(ESI) 445.1 ([M + Na]+ with daughter ions 389.0 ([M + Na+−56])
and 345.1 ([M + Na+−100]), C19H26N4O7Na requires 445.4).
Ester 13 (194 mg, 0.346 mmol) was hydrolyzed as for 9 above, yielding
the product as a colourless oil (85 mg, 0.160 mmol, 46%). vmax/cm−1
3331, 1713, 1662, 1629, 1520, 1168. δH 1.43 (9H, s), 2.56 (9H, bs),
4.37 (2H, d, J 4.8), 4.65 (4H, m), 5.74 (1H, bs, NH), 6.55 (1H, bs), 7.87
(1H, bs, NH), 8.06 (1H, bs, NH), 9.7 (1H, bs). δC 11.3, 11.7, 28.1, 35.5,
35.6, 37.5, 80.2, 127.2, 128.5, 128.6, 154.1, 155.8, 157.4, 158.3, 158.8,
159.1, 161.9, 162.0, 164.3.
2{[2-Aminomethyl)-5-methyloxazol-4-ylcarbamoyl}-
N-[2-aminomethyl-5-methyloxazol-4-ylcarbamoyl]}-
methyl-5-methyloxazole-4-carboxylic Acid 15
(a) X− = CF3CO−2 . The BOC-protected amine 14 (85 mg, 0.160 mmol)
was stirred in anhydrous trifluoroacetic acid (2 mL) at rt for 1 h, after
which the solvent was removed under vacuum. The residue was dis-
solved in methanol, and the solvent was removed under vacuum to yield
the product as a colourless oil (84 mg, 0.154 mmol, 96%). δH (CD3OD)
2.53 (3H, s), 2.56 (3H, s), 2.58 (3H, s), 3.35 (15H, s), 3.99 (1H, s), 4.38
(2H, s), 4.62 (4H, bs), 5.02 (1H, bs). δC (CD3OD) 11.6, 12.0, 36.8, 37.0,
37.0, 55.3, 128.9, 130.1, 130.6, 155.6, 156.3, 156.8, 158.4, 160.3, 163.8,
164.3, 165.0.
4-[N-(5-Ethoxycarbonyl-4-methyloxazol-2-ylmethyl)]carbamoyl
(5-methyloxazol-2-yl)methylammonium Trifluoroacetate 21
The protected amine 18 (389 mg, 0.921 mmol) was stirred in anhydrous
trifluoroacetic acid (1.5 mL) at rt under N2 for 1 h. Removal of the
solvent under vacuum afforded the title compound in quantitative yield
(402 mg, 0.921 mmol). vmax/cm−1 3404, 3296, 2700 (br), 1718, 1684,
1654, 1637, 1560, 1541, 1337, 1304, 1205, 1185, 1158, 1139, 1016. δH
(CDCl3/CD3OD) 1.39 (3H, t, J 7.2), 2.44 (3H, s), 2.63 (3H, s), 3.74 (1H,
bs), 4.23 (2H, s), 4.38 (2H, q, J 7.2), 4.69 (2H, s). δC (CDCl3/CD3OD)
11.2, 12.7, 13.9, 35.6, 36.0, 61.3, 129.1, 138.1, 145.51, 154.1, 155.3,
158.7, 161.8, 162.6. m/z (ESI) 323.1 ([M + H]+, C14H19N4O5 requires
323.3).
(b) X− = Cl−. The BOC-protected amine 14 (23 mg, 0.043 mmol)
was added to a saturated solution of anhydrous hydrogen chloride in
dichloromethane (1.2 mL) at 0◦C and the reaction was stirred for 2 h
at 0–5◦C. The mixture was extracted with water, and the aqueous
layer was then reduced under vacuum, giving the product as a colour-
less oil, which solidified on standing (10 mg, 0.021 mmol, 49%), mp
214–215◦C. vmax/cm−1 3374, 1699, 1667, 1626, 1519, 1307, 1189. δH
(CDCl3/CD3OD) 2.59 (3H, s), 2.60 (3H, s), 2.62 (3H, s), 4.31 (2H, s),
4.40 (1H, bs), 4.64 (4H, bs). δC (CDCl3/CD3OD) 10.8, 10.8, 11.3, 35.2,
35.4, 35.5, 127.3, 128.3, 128.8, 154.0, 154.1, 155.0, 156.7, 158.1, 159.0,
161.8, 162.2, 163.5. m/z (ESI) 455.1 ([M + Na]+, C18H20N6O7Na
requires 455.4), 433.1 ([M + H]+, C18H21N6O7 requires 433.4), 467.2
([M + Cl]−, C18H20N6O7Cl requires 467.8).
2-{[2-(tert-Butyloxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl]-methyl}-4-methyloxazole-
5-carboxylic Acid 20
Ester 8 (408 mg, 0.966 mmol) was hydrolyzed as above to give the acid
as a slightly yellow gum (338 mg, 0.857 mmol, 89%). vmax/cm−1 3346,
2700–2200 br, 1696, 1636, 1622, 1522, 1303, 1275, 1254, 1159, 1100.
δH 1.44 (9H, s), 2.41 (3H, s), 2.56 (3H, s), 4.36 (2H, s), 4.75 (2H,
d, J 5.1), 5.84 (1H, bs), 8.03 (1H, bs), 10.06 (1H, bs). δC 11.3, 12.6,
28.0, 36.1, 37.4, 80.1, 128.3, 138.1, 146.0, •154.2, 155.8, 158.8, 160.5,
162.1, 162.5. m/z (ESI) 417.1 ([M + Na]+ with daughter ions 361.1
Cyclic Trisoxazole 16
Diphenylphosphoryl azide (62 µL, 0.288 mmol) was added to a solu-
tion of the trifluoroacetate salt of the amine 15 (79 mg, 0.145 mmol)
and triethylamine (40 µL, 0.287 mmol) in DMF (145 mL) at −4◦C. The
temperature was kept at −4 to −10◦C for 2 days, at +5◦C for a further
3 days, then at 15–16◦C for 3 days. The solvent was removed under vac-
uum below 38◦C, dichloromethane (100 mL) was added, and insoluble
material was collected by filtration as an off-white powder (50 mg). m/z
(ESI) 453.0 ([M + K]+, C18H18N6O6K requires 453.5).
([M + Na −56]) and 317.1 ([M + Na −100]), C17H22N4O7Na requires
•
[M + Na]+ 417.4).
N-(5-Ethoxycarbonyl-4-methyloxazol-2-methyl)-2-
[2-(tert-butoxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl-methyl-4-methyloxazol-5-ylcarbamoyl]
methyl-4-methyloxazol-5-carboxamide 22
A suspension of this compound in dichloromethane was treated with
gaseous HCl at 0–5◦C for 1 h. The solvent was removed under reduced
pressure, the residue was dissolved in chloroform (30 mL) and extracted
with water (2 × 4 mL), then 10% potassium bicarbonate (2 × 4 mL)
followed by water (4 mL). Removal of the organic solvent afforded
the title compound 16 as a white powder (12 mg, 0.029 mmol, 20%),
mp 320–321◦C (dec.) (subl. 245–275◦). vmax/cm−1 3400, 1683, 1672,
1638, 1592, 1528. δH 2.68 (9H, s), 4.59 (6H, s), 8.34 (1H, bs, NH).
A mixture of the trifluoroacetate of the amine 21 (125 mg, 0.286 mmol)
and triethylamine (40 µL, 0.287 mmol) in dichloromethane (1 mL)
was added to a mixture of the acid 20 (128 mg, 0.325 mmol), tri-
ethylamine (47 µL, 0.337 mmol), and BOP (153 mg, 0.336 mmol) in

756
M. O. Cox, R. H. Prager and C. E. Svensson
dichloromethane (2 mL) at rt, and the reaction was stirred for 48 h
under N2. The reaction mixture was then diluted with dichloromethane
(15 mL), extracted with water (2 × 7 mL), followed by 10% potas-
sium bicarbonate (3 × 5 mL) and water (2 × 5 mL). The solvent was
removed under reduced pressure and the residue was dissolved in
dichloromethane (3 mL). Addition of ether (15 mL) then caused excess
BOP to precipitate, which was removed by filtration. The organic layer
was extracted with water (5 × 10 mL), dried, and evaporated to yield the
product as a slightly yellow gum which solidified on standing (127 mg,
0.182 mmol, 64%), mp 86–90◦C. vmax/cm−1 3332, 3055, 1718, 1701,
1654, 1636, 1559, 1541, 1522, 1508, 1334, 1267, 1168, 1103. δH 1.38
(3H, t, J 7.2 Hz), 1.43 (9H, s), 2.37 (3H, s), 2.38 (3H, s), 2.50 (3H,
s), 2.53 (3H, s), 4.36 (4H, m), 4.59 (2H, d, J 6.0), 4.66 (2H, d, J 6.0),
4.72 (2H, d, J 6.3), 5.84, (1H, bs, NH), 8.05 (1H, bt, NH), 8.20 (1H, bs,
NH), 8.44 (1H, bs, NH). δC 11.2, 11.3, 12.4, 12.9, 14.1, 28.1, 35.5, 35.8,
36.0, 37.4, 61.2, 80.14, 128.4, 128.5, 137.9, 139.2, 143.1, 145.6, 153.9,
154.0, 155.8, 158.0, 158.2, 158.5, 158.8, 160.2, 162.0, 162.2, 162.2.
m/z (ESI) 721.2 ([M + Na]+• with daughter ions 665.0 ([M + Na −56])
potassium carbonate (1 mL) was added to the residue, and the reac-
tion was stirred rapidly for 10 min. The aqueous layer was extracted
twice with chloroform. The combined organic layers were analyzed by
1H NMR spectroscopy, and it was concluded that no cyclization had
occurred.
(c)Via 26. To a crude sample of 25 above (40 mg) was added 1.25 M
sodium hydroxide (0.5 mL) at 0◦C and the reaction was stirred at 0–5◦C
for 1 h, after which 3 M HCl was added dropwise to pH 6. The sol-
vent was then removed under vacuum and dimethylformamide (4.5 mL)
followed by dicyclohexylcarbodiimide (20 mg, 0.095 mmol) was added
and the reaction was stirred at rt for 16 h. TLC analysis indicated that
cyclization had not occurred and that the product was probably a mixture
of different chain lengths.
N-(5-Ethoxycarbonyl-oxazol-2-ylmethyl)-2-(tert-
butyloxycarbonylaminomethyl)-5-methyloxazole-
4-carboxamide 29
The hydrochloride of the amine 28[15] (16 mg, 0.077 mmol) then tri-
ethylamine (20 µL, 0.14 mmol) were added to a mixture of the acid
9 (20 mg, 0.078 mmol), triethylamine (14 µL, 0.10 mmol), and BOP
(35 mg, 0.077 mmol) in dichloroethane (1 mL) at rt, and the reaction
was stirred for 20 h under N2. The solvent was removed and the residue
was dissolved in ether (5 mL) and extracted with water (2 × 5 mL), fol-
lowed by 10% potassium bicarbonate (2 × 5 mL), then water (5 mL).
Removal of the solvent under reduced pressure gave an oil consisting of
two products, which were separated by chromatography on silica, elut-
ing with dichloromethane/ethyl acetate (4 : 1).The major product (9 mg)
was characterized as methyl 2-(N-tert-butyloxycarbonylaminomethyl)-
5-methyl-1,3-oxazole-4-carboxylate,•apparently formed from traces of
methanol adhering to 9. (Found: M+ 270.1205. C12H18N2O5 requires
M+• 270.1216). δH 1.45 (9H, s), 2.61 (3H, s), 3.90 (3H, s), 4.42 (2H, d,
J 5.4), 5.15 (1H, bs, NH). δC 11.8, 28.2, 37.7, 51.9, 80.3, 127.5, 155.6,
157.0, 159.4, 162.7. m/z 270 (M+, 1.3%), 214 ([M − C4H8], 100%).
The minor product (20%) was found to be compound 29. δH 1.38
(3H, t, J 7.2), 1.47 (9H, s), 2.62 (3H, s), 4.38 (4H, m), 4.76 (2H, d, J 6.0),
5.09 (1H, bs), 7.51 (1H, t, J 6.0, NH), 7.70 (1H, s).
•
and 621.2 ([M + Na −100]), C31H38N8O11Na requires [M + Na]+
721.7).
4-[N-(2-Aminomethyl-4-methyloxazol-5-ylcarbamoyl)-
N-(2-aminomethyl-5-methyloxazol-4-ylcarbamoyl)-
N-(2-aminomethyl-4-methyloxazol-5-ethoxycarbonyl)]-
5-methyloxazol-2-ylmethylammonium Trifluoroacetate 25
The protected amine 22 (12 mg) was stirred in anhydrous trifluoroacetic
acid(0.1 mL)atrtunderN2 for1 h. Removalofthesolventundervacuum
afforded the title compound, which was used in the next step without
further purification. δH 1.38 (3H, t, J 7.2), 2.42 (3H, s), 2.45 (3H, s),
2.56 (3H, s), 2.58 (3H, s), 4.27 (2H, bs), 4.37 (2H, q, J 7.2 Hz), 4.65
(2H, bd), 4.71 (2H, bd), 7.45 (1H, bs), 7.92 (1H, bs), 8.55 (1H, bs).
N-(5-Carboxy-4-methyloxazol-2-methyl)-2-[2-(tert-
butoxycarbonylaminomethyl)-5-methyloxazol-
4-ylcarbamoyl-methyl-4-methyloxazol-5-ylcarbamoyl]
methyl-4-methyloxazol-5-carboxamide 23
2-(N-tert-Butyloxycarbonylaminomethyl)-1,3-oxazole-
5-carboxylic Acid 32
Ester 22 (127 mg, 0.182 mmol) was hydrolyzed as above to give the
product as a slightly yellow gum. The product precipitated from a mix-
ture of dichloromethane and ether, and was collected after cooling
at 0–5◦C overnight (66 mg, 0.098 mmol, 54%), mp 143–144◦C.
vmax/cm−1 3330, 1717, 1701, 1684, 1670, 1654, 1636, 1629, 1559,
1541, 1523, 1508, 1313, 1263, 1160. δH (CDCl3/CD3OD) 1.46 (9H, s),
2.44 (3H, s), 2.47 (3H, s), 2.61 (6H, m), 3.78 (1H, bs), 4.34 (2H, bs), 4.61
(2H, d, J 5.7 Hz), 4.66 (4H, m), 8.05 (1H, bs, NH), 8.49 (1H, bs, NH).
δC (CDCl3/CD3OD) 11.1, 12.2, 12.5, 27.9, 35.4, 35.5, 35.8, 37.2, 80.2,
128.3, 128.5, 138.4, 139.4, 143.0, 145.5, 154.3, 156.1, 157.9, 158.4,
The hydrochloride of the amine 28 (191 mg, 0.924 mmol) was reacted
with di-tert-butyl dicarbonate as above to give 31, which was used in the
next step without further purification. δH 1.38 (3H, t, J 7.2), 1.45 (9H, s),
4.38 (2H, q, J 7.2), 4.56 (2H, bd), 5.63 (1H, bt, NH), 7.69 (1H, s). δC
13.9, 28.0, 38.0, 61.3, 80.0, 133.8, 142.8, 157.5, 164.5.
The crude ester 31 was hydrolyzed as above to give the crude product
32 as a yellow solid (104 mg, 46% overall). Pure product was obtained by
crystallization from ether, but in a poor yield, mp 103–109◦C. (Found:
M+• 242.0891. C10H14N2O5 requiresM+• 242.0903). vmax/cm−1 3354,
1720, 1677, 1581, 1522, 1297, 1148, 1125. δH (CDCl3/CD3OD) 1.40
(9H, s), 3.26 (1H, s), 4.43 (2H, s), 5.8 (1H, bs, NH), 7.63 (1H, s). δH
(CDCl3/CD3OD) 28.0, 37.9, 80.4, 133.9, 143.4, 155.9, 159.3, 164.6.
m/z 242 (M+, 1.4%), 186 ([M −56], 9.0%), 169 (4.7%), 142 (4.6%), 56
(44.9%), 44 (100%).
•
158.9, 160.1, 160.1, 161.9, 162.2, 162.6. m/z (ESI) 693.2 ([M + Na]+
with daughter ions 637.0 ([M + Na −56]) and 593.1 ([M + Na −100]),
•
C29H34N8O11Na requires [M + Na]+ 693.6).
Attempted Synthesis of 17
(a) Via 25. The tetra-oxazole 22 (12.6 mg, 0.018 mmol) was stirred
in anhydrous trifluoroacetic acid (0.2 mL) at rt for 1 h, after which
excess reagent was removed under vacuum. The residue was dissolved
in dichloromethane (0.5 mL), and triethylamine (4 µL) was added. The
mixture was stirred for 5 min, then carefully heated during dropwise
addition of toluene (18 mL). The reaction mixture was stirred at 100◦C
for 25 h, and the mixture was analyzed by NMR spectroscopy, which
showed that no cyclization had occurred.
2-(Aminomethyl)-5-methyl-1,3-oxazole-4-carboxylic
Acid Hydrochloride 33
Ester 7 (79 mg, 0.36 mmol) was hydrolyzed as above to give the crude
product as a brown-orange oil (60 mg, 87%). δH (CDCl3/CD3OD) 2.6
(3H, s), 4.42 (2H, s), 4.65 (1H, s), 8.9 (1H, bs). δC (CDCl3/CD3OD)
11.4, 35.8, 125.6, 132.9, 157.6, 163.5.
(b) Via 24 and 27. Compound 23 (45 mg, 0.0671 mmol) was
dissolved in dry pyridine (0.5 mL) at 0◦C. Pentafluorophenyl trifluoro-
acetate (14 µL, 0.0798 mmol) was added, and the reaction mixture was
stirred at 0–5◦C for 3 h, then at rt for 17 h. Excess reagent was removed
under vacuum and the residue was cooled to 0◦C, after which anhy-
drous trifluoroacetic acid (1 mL) was added. The reaction was stirred
for 10 min, then at rt for 30 min, after which the excess reagent was
removed under vacuum. A mixture of chloroform (3 mL) and 1 M
2-(Aminomethyl)-4-methyl-1,3-oxazole-5-carboxylic
Acid Hydrochloride 34
Ester 9 (31 mg, 0.14 mmol) was hydrolyzed as above to give the title
compound as an orange powder (ca. 5 mg), which was spectroscopically
•
•
pure. (Found: M+ 156.0534. C6H8N2O3 requires M+ 156.0535). δH
(CDCl3/[D6]DMSO) 2.45 (3H, s), 4.22 (2H, s), 9.3 (1H, bs). m/z 156
(M+, 11.9%), 84 (84.7%), 66 (100%).

Solution-Phase Synthesis of Linear and Cyclic Peptidomimetics
757
2-(Aminomethyl)-1,3-oxazole-5-carboxylic Acid Hydrochloride 35
standing as a white powder, mp 160–163◦C. Cyclic trimer 39: (Found:
[M + Na]+• 1025.3770. C60H54N6O9 requires [M + Na]+• 1025.3850).
Ester 28 (185 mg, 0.895 mmol) was hydrolyzed as above to give the
crude product as an orange solid (111 mg), which was recrystallized
from methanol/ether to afford the pure compound as a beige powder
•
Cyclic tetramer 40: (Found: [M + Na]+ 1359.5150. C80H72N8O12
•
requires [M + Na]+ 1359.5168). vmax/cm−1 3382, 1673, 1634, 1511,
1454, 1372. δH (3 : 1 mixture of 39 and 40, where an asterisk denotes
the cyclic trimer 39) 2.54 (s), 2.58* (s), 3.12–3.38* (m), 4.96–5.05*
(m), 5.24* (dd, J 4.59 and 13.65), 5.53 (dd, J 7.42 and 14.55), 6.92* (d,
J 8.79), 6.87* (d, J 8.79), 7.0 (d, J 8.52, NH), 7.29–7.38* (m), 7.51 (m),
7.87 (bs), 8.22* (d, J 6.46, NH). δC 11.5*, 11.6, 26.2, 26.3, 29.0, 39.2,
39.7*, 46.4, 47.5, 49.7*, 69.9, 112.5, 114.7*, 114.9, 127.16*, 127.4*,
127.8, 127.9*, 128.2, 128.5*, 128.9*, 130.3, 130.4*, 136.7, 136.8*,
153.7*, 154.1, 157.8*, 157.5, 160.3, 160.3*, 160.8*, 160.9. m/z (ESI)
1338.0 ([M + H]+, 1%), 1003.8 ([M + H]+, 15%).
•
(45 mg, 0.25 mmol, 28%), mp 320◦C (dec.). (Found: M+ 142.0381.
•
C5H6N2O3 requires M+ 142.0378). vmax/cm−1 1716, 1598, 1230,
1138. δH (D2O/CD3OD) 4.53 (2H, s), 4.92 (1H, s), 7.92 (1H, s). δH
(D2O/CD3OD) 35.0, 132.5, 144.2, 158.7, 159.7. m/z 142 (M+, 42.9%),
114 (14.4%), 96 (10.9%), 84 (38.6%), 69 (64.1%).
(S)-Ethyl 2-[1-Amino-2-(4-benzyloxyphenyl)ethyl]-
5-methyl-1,3-oxazole-4-carboxylate 38
A solution of the phthalimidooxazole 39[14] (1.8 g, 3.5 mmol) and
hydrazine hydrate (720 µL, 16.2 mmol) in ethanol (100 mL) was stirred
at 68◦C for 3 h.The solvent was evaporated and the residue was extracted
with chloroform (3 × 10 mL). The combined organic extracts were fil-
tered and evaporated to give the title compound (1.33 g, 99%) isolated as
a pale yellow oil, which required no further purification. The racemate
was also synthesized using the above procedure. (Found: M+• 380.1739.
(S)-2-[1-Amino-2-(4-benzyloxyphenyl)ethyl]oxazole-
5-carboxylic Acid Hydrochloride 41
A solution of (S)-ethyl 2-[2-(4-benzyloxyphenyl)-1-phthalimidoethyl]
oxazole-5-carboxylate[15] (0.438 g, 0.88 mmol) and hydrazine hydrate
(176 µL, 3.96 mmol) in ethanol (20 mL) was stirred at 68◦C for 3 h. The
solvent was evaporated to leave an orange solid, which was extracted
with minimal chloroform (2 × 5 mL) and the combined organic
extracts were filtered and evaporated to give (S)-ethyl 2-[1-amino-2-
(4-benzyloxyphenyl)ethyl]-1,3-oxazole-5-carboxylate (0.3 g, 93%) iso-
•
C22H24N2O4 requires M+ 380.1736). vmax/cm−1 1717, 1655, 1514,
1236, 1095. δH 7.29–7.42 (5H, m), 7.05 (2H, d, J 8.79), 6.88 (2H, d,
J 8.79), 5.02 (2H, s), 4.36 (2H, q, J 7.0), 4.23 (1H, dd, J 5.22, 8.38),
3.15 (1H, dd, J 5.22, 13.74), 2.93 (1H, dd, J 8.38, 13.74), 2.58 (3H, s),
2.2 (2H, bs, NH2), 1.37 (3H, t, J 7.0 Hz). δC 164.3, 162.2, 157.7, 156.1,
136.9, 134.2, 130.2, 129.1, 128.5, 127.8, 123.4, 114.9, 69.1, 60.9, 51.3,
41.1, 14.3, 11.9. m/z 380 (M+, 4%), 226 (5), 198 (9), 183 (100), 137
(33), 110 (6), 91 (27).
20
lated as an orange oil, which required no further purification. [α]D
•
−16.6◦ (c 0.84, CHCl3). (Found: [M + H]+ 367.1655. C21H22N2O4
•
requires [M + H]+ 367.1658). vmax/cm−1 3290, 1724, 1511, 1302,
1241, 1145. δH 1.38 (3H, t, J 7.14), 2.99 (1H, dd, J 7.97, 13.59), 3.21
(1H, dd, J 5.49, 13.59), 4.01 (2H, bs, NH2), 4.32 (1H, dd, J 5.49, 7.97),
4.38 (2H, q, J 7.14), 5.02 (2H, s), 6.88 (2H, d, J 8.52), 7.05 (2H, d,
J 8.52), 7.31–7.43 (5H, m), 7.66 (1H, s). δC 14.1, 41.1, 51.6, 61.4, 69.9,
114.9, 127.3, 127.8, 128.5, 128.6, 128.8, 130.2, 133.7, 136.9, 142.4,
157.7, 169.6. m/z 367 ([M + H]+, 5%), 322 (10), 294 (12), 276 (2), 260
(4), 91 (100).
(S)-2-[1-Amino-2-(4-benzyloxyphenyl)ethyl]-
5-methyloxazole-4-carboxylic Acid Hydrochloride 36
Lithium hydroxide hydrate (0.1 g, 2.4 mmol) was added to a solution of
(S)-ethyl 2-[1-amino-2-(4-benzyloxyphenyl)ethyl]-5-methyloxazole-4-
carboxylate 37 (0.45 g, 1.1 mmol) in a mixture of ethanol (1.5 mL),
tetrahydrofuran (1.5 mL), and water (3 mL) at 0◦C. The reaction mix-
ture was stirred at 0◦C for 30 h, when TLC analysis indicated that all
of the starting material had been consumed. The mixture was acidified
to pH 6 by the careful addition of 1% HCl. The product precipitated
as a clean white crystalline powder which was diluted with water
(100 mL) and extracted with ethyl acetate (2 × 50 mL). The combined
organic extracts were then washed with water (2 × 30 mL) and evapo-
rated to give the title compound 36 as a white crystalline powder (0.37 g,
The ester above (0.271 g, 0.7 mmol) was hydrolyzed as above
with lithium hydroxide to give the title compound 41 as a pale
20
brown crystalline powder (0.166 g, 66%), mp >250◦C, [α]D −30◦
•
(c 0.16, CHCl3). (Found: [M + H]+ 335.1032. C19H14N2O4 requires
•
[M + H]+ 335.1035). vmax/cm−1 2935, 1678, 1142. δH (CDCl3/TFA)
3.36–3.53 (2H, m), 5.05 (2H, s), 5.17 (1H, m), 6.96 (2H, d, J 8.65),
7.04 (2H, d, J 8.65), 7.36–7.41 (5H, m), 7.94 (1H, s). δC (CDCl3/TFA)
36.9, 51.3, 70.5, 116.2, 123.2, 127.6, 128.4, 128.7, 130.4, 134.5, 135.9,
143.2, 159.0, 160.9, 162.2. m/z (ESI) 335.1 ([M + H]+, 5%), 317 (2),
289 (3), 91 (100).
•
20
89%), mp >250◦C, [α]D +52.3◦ (c 1.5, CHCl3). (Found: [M + H]+
•
353.1501. C20H20N2O4 requires [M + H]+ 353.1501). vmax/cm−1
2932, 1709, 1676, 1616, 1515, 1456, 1177. δH (CDCl3/TFA) 2.65
(3H, s), 3.32–3.41 (2H, m), 5.02 (1H, m), 5.04 (2H, s), 6.94 (2H, d,
J 8.65), 7.03 (2H, d, J 8.65), 7.36–7.42 (5H, m), 7.94 (2H, bs, NH2).
δC (CDCl3/TFA) 11.8, 36.8, 50.8, 70.4, 116.0, 123.7, 126.5, 127.6,
128.3, 128.7, 130.3, 136.0, 157.7, 158.8, 160.7, 165.7. m/z (ESI) 353.1
([M + H]+, 5%), 335 (23), 307 (2), 262 (13), 246 (12), 91 (100).
(2,5)-Amide-Linked Cyclic Trimer 42
A solution of the oxazole 41 (0.16 g, 0.43 mmol) in anhydrous dimethyl-
formamide (43 mL) was cooled under N2 to 0◦C. PyBOP (0.333 g,
0.64 mmol) was added followed by the dropwise addition of diiso-
propylethylamine (0.066 g, 0.51 mmol). The procedure used with 36
above gave the crude product (0.299 g) as an orange oil which was
purified by radial chromatography (ethyl acetate/light petroleum/TFA
70 : 29 : 1) to give the cyclic trimer 42 (0.065 g, 43%) isolated as an
Cyclooligomerization of (S)-2-[1-Amino-2-(4-benzyloxyphenyl)
ethyl]-5-methyloxazole-4-carboxylic Acid Hydrochloride 36
•
•
•
orange glass. (Found: [M + H]+ 961.3538, [M + Na]+ 983.3376.
•
C57H48N6O9 requires [M + H]+ 961.3561, [M + Na]+ 983.3381).
vmax/cm−1 3389, 1659, 1511, 1454, 1177. δH (CDCl3/TFA) 3.1–3.46
(6H, m), 4.90–5.1 (9H, m), 6.84–7.12 (12H, m), 7.28–7.42 (18H, m),
7.69 (3H, bs, NH). δC (CDCl3/TFA) 37.7, 49.3, 70.4, 115.7, 126.0,
127.6, 128.2, 128.6, 130.1, 132.7, 136.1, 158.2, 160–161. m/z (ESI)
961.4 ([M + H]+, 10%), 948.6 (29), 924.6 (31), 691.2 (100).
A solution of the oxazole 36 (0.177 g, 0.45 mmol) in anhydrous
dimethylformamide (46 mL) was cooled under N2 to 0◦C. PyBOP
(0.355 g, 0.68 mmol) was added followed by the dropwise addition of
diisopropylethylamine (0.071 g, 0.54 mmol). The reaction mixture was
stirred at 0◦C for 5 h. The solvent was evaporated under reduced pres-
sure below 38◦C to give a milky oil (0.6 g), which was dissolved in
ethyl acetate (60 mL) and washed with 3% HCl (2 × 30 mL), water
(20 mL), 5% sodium bicarbonate (30 mL), and saturated sodium chlo-
ride (30 mL).The organic layer was evaporated to give the crude product
(0.32 g) as a yellow oil.The residue was dissolved in a mixture of chloro-
form (2 mL) and trifluoroacetic acid (0.02 g), and then the mixture was
evaporated. The residue was purified by radial chromatography (50%
ethyl acetate/light petroleum) to give a mixture of the cyclic trimer
39 and cyclic tetramer 40 (3 : 1, 0.074 g, 44%) which crystallized on
Acknowledgments
M.O.C. acknowledges the award of a Flinders University
researchscholarship, andC.E.S. isgratefulfortheawardofan
OPRS scholarship from Flinders University. We are grateful
for financial support from the Australian Research Council.

758
M. O. Cox, R. H. Prager and C. E. Svensson
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