5-Aminooxazole as an internal traceless activator of C-terminal carboxylic acid: Rapid access to diversely functionalized cyclodepsipeptides

Article abstract of DOI:10.1002/chem.200500703

A conceptually novel macrolactonization protocol has been developed. It is a domino process involving a sequence of: 1) protonation of 5-aminooxazole leading to the electrophilic iminium salt; 2) trapping of the iminium species by the neighboring C-termin

Full text of DOI:10.1002/chem.200500703

DOI: 10.1002/chem.200500703
5-Aminooxazole as an Internal Traceless Activator of C-Terminal Carboxylic
Acid: Rapid Access to Diversely Functionalized Cyclodepsipeptides
Carine Bughin,[a] Gang Zhao,[a] Hugues BienaymØ,[b] and Jieping Zhu*[a]
Abstract: A conceptually novel macro-
lactonization protocol has been devel-
oped. It is a domino process involving
a sequence of: 1)protonation of 5-ami-
nooxazole leading to the electrophilic
iminium salt; 2)trapping of the imini-
um species by the neighboring C-termi-
nal carboxylic acid leading to a puta-
tive spirolactone; and 3)intramolecular
nucleophilic addition of the tethered
alcohol to the spirolactone followed by
fragmentation. The strategically incor-
porated 5-aminooxazole serves as an
internal traceless activator of the
neighboring C-terminal carboxylic acid,
since it became an integral part of the
peptide backbone after cyclization. No
coupling reagent is required and the
entire sequence is triggered by just a
few equivalents of trifluoroacetic acid
under very mild conditions (MeCN as
the solvent at room temperature). The
spirolactone as an activated form of
the carboxylic acid has been evidenced
by a sulfur-migration experiment. By
combining with
a three-component
synthesis of 5-aminooxazole, a two-step
synthesis of structurally complex cyclo-
depsipeptides from readily accessible
starting materials was developed.
Keywords: cyclization
·
domino
reactions · macrocycles · multicom-
ponent reactions · peptides
Introduction
tant structural and dynamic properties of peptides.[3] 2)They
are more resistant to in vivo enzymatic degradation. The hy-
drophobic side chains of cyclodepsipeptides provide a hy-
drophobic exocyclic surface that can shelter their cleavable
amide bonds from degradative peptidases. 3)The absence of
ionized N and C termini in cyclodepsipeptide facilitates
their crossing lipid membranes and leads to improved bioa-
vailablity.[4] 4)They are useful tools in searching for biologi-
cal processes involved in cellular regulation.[5] Whereas the
synthesis of linear peptides generally proceeds well thanks
to the development of new and efficient coupling reagents,[6]
access to cyclodepsipeptides is much more difficult since
macrocyclization often has low yields.[7] Furthermore, the
cyclization outcome is highly dependent on sequence,[8] and
this makes the synthesis of cyclodepsipeptide libraries par-
ticularly challenging.[9] This last point is particularly unfortu-
nate, since cyclodepsipeptides and cyclopeptides are regard-
ed as privileged structures[10] in medicinal chemistry.[11]
Indeed, among the three newly approved antibiotic drugs
over the past seven years that are efficacious against vanco-
mycin-resistant enterococci (VRE), two of them are cyclo-
depsipeptides. Synercid, approved in 1998 is a mixture of
two macrocycles, one of which is a 17-membered cyclodepsi-
peptide (quinupristin), while daptomycin, approved in 2003,
is a 31-membered cyclodepsipeptide.[12] The ability to sys-
tematically modify the side chains and the size of the macro-
cycle, as well as the connectivity of amino acid residues, is
Cyclodepsipeptides are analogues of cyclopeptides having at
least one ester linkage as part of their peptidic backbone.
They have been found in many natural environments and
show a wide spectrum of biological activities including anti-
cancer, antibacterial, antiviral, antifungal, and anti-inflam-
matory properties.[1] Cyclodepsipeptides and cyclopeptides
are attractive targets for synthesis as they combine several
favorable properties: 1)They adopt fewer conformations
than their acyclic counterparts, and this results in higher and
more specific receptor-binding affinities.[2] Indeed, bioactive
linear peptides can exist in a myriad of different conforma-
tions, very few of which are able to bind to their receptor.
Cyclization is a common approach to force peptides into
adopting bioactive conformations and to assess the impor-
[a] C. Bughin, Dr. G. Zhao, Dr. J. Zhu
Institut de Chimie des Substances Naturelles
CNRS, 91198 Gif-sur-Yvette Cedex (France)
Fax : (+33)1-69-07-72-47
E-mail: zhu@icsn.cnrs-gif.fr
[b] Dr. H. BienaymØ
Pierre Fabre Urologie
11 Avenue A. Einstein, 69100 Villeurbanne (France)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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FULL PAPER
therefore of significant importance and constitutes a bottle-
neck in the search for peptide-based drugs.[13]
Macrolactamization or macrolactonization of a seco acid
is among the most commonly used reactions for the synthe-
sis of cyclodepsipeptides. To perform such transformations,
appropriate activation of the carboxylic acid is a prerequi-
site, usually accomplished by an external coupling reagent
(Scheme 1a). Our long-term interest in the development of
novel macrocyclization reactions[14] led us to investigate a
new strategy for the synthesis of cyclodepsipeptides that
avoids the use of external activating agents.[15] The underly-
ing principle that we sought to pursue is shown in Sche-
me 1b. If a functional group (FG)were incorporated into
Scheme 2. A projected synthesis of cyclodepsipeptide by combined use of
a three-component reaction and a new cyclization methodology.
tions. Fleury et al. meticulously examined the hydrolysis
mechanism in the 1970s and concluded that hydrolysis is ini-
tiated by protonation at C-4 leading to imidate salt 9, which
is trapped by a molecule of water to give 10, fragmentation
of which provides diamide 8 (Scheme 3).[19] The fact that 5-
Scheme 1. Macrocyclization of a seco acid: general considerations and a
new activation mode.
the peptide backbone near the C-terminal carboxylic acid
and could react with the nearby C-terminal carboxylic acid
to produce a more electrophilic carbonyl group, then cycli-
zation would be expected if a tethered nucleophile were
available. To make this approach synthetically useful, an
ideal FG must fulfill the following criteria: 1)Its introduc-
tion into the peptide backbone should be facile, and the re-
sulting linear peptide should have sufficient shelf stability;
2)Its ability to activate the carboxylic acid should be trig-
gered under very mild conditions without using sophisticat-
ed reagents; 3)Activation and cyclization should be per-
formed under the same conditions without requiring isola-
tion of any intermediate; 4)After serving as an activating
group, it should become an integral part of the peptide
backbone (traceless activating group). We report now that
5-aminooxazole satisfied all these stringent criteria and led
to a conceptually new activation/cyclization strategy. In
combination with the three-component synthesis of 5-ami-
nooxazole developed by us,[16,17] we report herein a three-
step synthesis of complex cyclodepsipeptides (1 and 2)from
readily accessible starting materials by combination of a
multicomponent reaction and a novel cyclization concept
(Scheme 2).[18]
Scheme 3. Mechanism of hydrolysis of 5-aminooxazole under acidic con-
ditions.
aminooxazole is a masked dipeptide equivalent was elegant-
ly exploited by Lipshutz et al.[20] for the synthesis of a cyclo-
peptide alkaloid[21] by a sequence of intramolecular N-alky-
lation of 5-aminooxazole followed by hydrolysis.
Based on this mechanistic proposal, a conceptually novel
cyclization methodology involving activation of the terminal
carboxylic acid by an internal oxazole function was ad-
vanced (Scheme 4). Treatment of a suitably functionalized
oxazole 11 under acidic conditions should produce iminium
cation 12 according to Fleury et al. This electrophilic species
could then be trapped either by an external nucleophile
leading to simple hydrolysis or, under favorable circum-
Background and design of concept: 5-Aminooxazole is a
surrogate of an a-acylamino amide (or a dipeptide)and is
readily hydrolyzed back to the diamide under acidic condi-
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J. Zhu et al.
Scheme 5. Heimgartnerꢁs macrolactonization protocol.
the two steps, namely, activation and cyclization, envisaged
in Scheme 4 for the conversion of 11 to 15 was known. To
simplify the interpretation of experimental results, we decid-
ed to first separate these two steps and to examine whether
the concept of activating the terminal carboxylic acid by an
oxazole could be realized. For this purpose, oxazole 19 was
synthesized and submitted to hydrolysis conditions
(Scheme 6). Treatment of an ethanol solution of 19 with tri-
fluoroacetic acid (TFA, 50 equiv)led to tripeptide 20 in
over 95% yield. The formation of 20 can be explained on
the basis of the simple hydrolysis of the oxazole without par-
ticipation (activation)of the terminal methyl ester. If the
methyl ester were activated during the hydrolysis of oxazole,
Scheme 4. 5-Aminooxazole as an internal traceless activator of the neigh-
boring carboxylic acid.
stance, by the neighboring carbonyl oxygen atom to give spi-
rolactone 13. Being highly electrophilic, the carbonyl carbon
atom of intermediate 13 could be attacked by the tethered
nucleophile to give, after fragmentation, the desired macro-
cycle. Besides being conceptually novel, the overall transfor-
mation is mechanistically intriguing. In fact, it consists of a
new domino process[22] involving 1)protonation of oxazole,
2)trapping of the iminium species by the neighboring car-
bonyl oxygen atom, and 3)trapping of the putative spirolac-
tone by a second internal nucleophile to produce a macrocy-
cle. While an oxazole has been used as a masked form of ac-
tivated carboxylic acid under photolysis conditions and has
been elegantly exploited by Wasserman et al. for macrolac-
tone synthesis,[23] to the best of our knowledge the reaction
sequence depicted in Scheme 4 is unknown. The most rele-
vant example, though conceptually different, is the so-called
direct amide cyclization, elegantly developed by Heimgart-
ner et al. for the synthesis of cyclodepsipeptides containing
a,a-disubstituted amino acid residues.[24] They demonstrated
that cyclization of suitably functionalized oligo(a,a-dimethyl
glycine) 16 can be realized under acidic conditions (toluene,
gaseous HCl, 1008C, Scheme 5)via 1,3-oxazol-5(4 H)-one in-
termediate 17. The cyclization in this case is favored by the
particular conformational preference of this type of linear
peptides, which have pronounced tendency to adopt helical
conformations (310 helices).[25]
Results and Discussion
Activation of carboxylic acid by an internal oxazole func-
tion; proof of concept: At the outset of this work, neither of
Scheme 6. Activation of a carboxylic acid by a vicinal oxazole: model
studies and proof of concept.
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Functionalized Cyclodepsipeptides
FULL PAPER
Table 1. Intermolecular esterification; amidation of oxazole 20 under acidic conditions.[a]
tripeptide 22 with an ethyl ester
at the C terminus would be pro-
duced via, for example, inter-
mediate 21.
The failure of the oxazole to
activate the methyl ester in 19
might be explained by the in-
sufficient nucleophilicity of the
ester carbonyl oxygen atom.
Indeed, in our mechanistic hy-
pothesis, the putative iminium
intermediate needed to be trap-
ped by the carbonyl oxygen
atom of the carboxylic ester. In
other words, to increase the
electrophilicity of the carbonyl
[a]
Entry
NuH (equiv)Solvent
Compound
Yield[b] [%]
1
2
3
4
5
iPrOH
iPrOH
26a
26b
26c
26d
26e
60
41
44
0
tert-butanol (8)MeCN
EtSH (8)MeCN
aniline (10)MeCN
p-nitroaniline (3)MeCN
78
[a] Reaction conditions: room temperature, 4 h. [b] Yield of isolated product after chromatography on silica
gel.
carbon atom, the carbonyl oxygen atom should first act as a
nucleophile. The simplest way to increase the nucleophilicity
of the carbonyl oxygen atom in 19 is its hydrolysis to a car-
boxylic acid. Based on this assumption, oxazole 19 was con-
verted to the lithium salt of the corresponding carboxylic
acid 23 under standard conditions (THF/H2O, 1 equiv
LiOH, evaporation to dryness). Gratifyingly, when a solu-
tion of 23 in EtOH was treated with 50 equiv of TFA, a
clean transformation occurred to afford the ethyl ester of
tripeptide 22 (90%). To demonstrate the key role of oxazole
in the esterification of 23, a lithium salt of tripeptide 24 was
synthesized (Scheme 7). Treatment of 24 under the identical
boxylic acid. Aniline failed to react under these conditions,
due most probably to protonation of the amine function.
However, less basic p-nitroaniline was acylated to afford the
corresponding tripeptide 26e in good yield (Table 1,
entry 5).
Synthesis of oxazole by a three-component reaction: Having
validated the concept of activating a C-terminal carboxylic
acid by an internal oxazole, we turned our attention to the
synthesis of oxazole-containing linear peptides. Synthesis of
oxazole has attracted renewed interest due to its presence in
a number of bioactive marine natural products[26] and its po-
tential application in the design of conformationally restrict-
ed peptidomimetics.[27] Recently, polyfunctionalized oxa-
zoles[28] and oxazole-containing macrocycles[29] have also
been designed and used for multidirectional elaboration of
combinatorial libraries and for selective molecular recogni-
tion of small molecular targets. Thus, new synthetic method-
ologies are being developed constantly.[30,31] We recently un-
covered an expeditious three-component synthesis of 5-ami-
nooxazole from an aldehyde, an amine, and an a-substituted
a-isocyano acetamide. Pleasingly, isocyano dipeptide 5[32]
participated well in this multicomponent reaction leading to
an efficient synthesis of highly functionalized oxazole 6 (cf.
Scheme 2). Thus, simply heating a methanol solution of al-
dehyde 3, amine 4, and dipeptide isocyanide 5 led to the for-
mation of 5-aminooxazole 6 in good to excellent isolated
yield. From five aldehydes, nine amines, and six isocyanides
(Figure 1), some representative oxazoles were synthesized
(Figure 2). This three-component reaction is highly efficient
and is applicable to a wide range of substrates.
Scheme 7. Hydrolysis of lithium salt of a tripeptide carboxylic acid.
conditions as for 23 (50 equiv TFA in EtOH)did not lead to
even trace amounts of ester, and only the corresponding
acid 25 was isolated. This control experiment clearly indicat-
ed that the oxazole is responsible for esterification of 23,
and hence activation of the carboxylic acid. We speculated
that the more pronounced nucleophilicity of the carboxylic
acid facilitated formation of spirolactone 21. Ring opening
of this putative intermediate by ethanol led then to the ob-
served product 22.
Although exact structural information on the activated
form of the carboxylic acid is still lacking, we set out to ex-
amine the reactivity of this intermediate by reaction of 23
with representative nucleophiles under acidic conditions
(Table 1). Acylation took place even with sterically hindered
tert-butanol to provide the corresponding tripeptide 26b in
reasonable yield (Table 1, entry 2). This result is indicative
of the high electrophilicity of the activated form of the car-
Macrolactonization under mild acidic conditions; develop-
ment and generality: The projected domino activation/mac-
rocyclization sequence was examined with 6a as test sub-
strate. Saponification of the methyl ester (LiOH, THF/H2O)
gave the corresponding lithium salt, which was subjected to
varying solvents and acids.[33] Some representative results
are summarized in Table 2. The reaction proceeded as plan-
ned. Trifluoroacetic acid proved to be the acid of choice
among those investigated (Table 2, entry 1 vs entries 5 and
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J. Zhu et al.
ploited by Oberhauser et al.[34] and Takeya et al.[35] The se-
lectivity of the protonation step was higher in the case of cy-
clopeptides and especially in the case of oxazolophanes.[20]
By use of the following optimized reaction conditions
(LiOH, THF/H2O, then MeCN/TFA, 0.001m), oxazoles 6a–
6w were converted to their respective macrocyclodepsispeti-
des 1 and 2 (Figures 3 and 4). Keeping in mind its potential
application in combinatorial synthesis, the conversion has
not been individually optimized. Evidently, the novel macro-
lactonization protocol is applicable to a wide range of sub-
strates. It is neither sensitive to the amino acid residues nor
to ring size. Indeed, good to excellent yields were obtained
with 12-, 13-, 14-, 15-, 16-, and 18-membered macrocycles
with different peripheral substituents. The configuration of
the linear precursor has only a minor effect, if any, on cycli-
zation efficiency, since both diastereomers 6j and 6k cy-
clized to provide their respective cyclodepsipeptides 1j and
1k with comparable yields. The acetate functionality of oxa-
zoles 6q to 6x was hydrolyzed simultaneously with the sapo-
nification of the methyl ester, and thus an additional depro-
tection step was avoided. Furthermore, the ring type can
also be modulated by means of the location of the hydroxyl
group. When the hydroxyl group was tethered to the amine,
this two-step sequence afforded cyclodepsipetides 1a–1p re-
lated to head-to-tail cyclization. However, when the hydrox-
yl group was tethered to the aldehyde, the same sequence
provided a cyclodepsipeptide that is structurally related to a
side chain to C-terminal cyclization. Since the linear peptide
is synthesized from three readily accessible starting materi-
als, the ring substituents at the periphery of the macrocycle
(R1 to R7, see general structure of 1 and 2 in Scheme 1)and
the ring size of the cyclodepsipeptide can thus be varied
easily by changing systematically one of the three starting
materials.
Overall, the present synthesis of cyclodepsipeptide is
highly efficient in terms of the ability to generate molecular
complexity and molecular diversity. Scheme 8 details the
synthesis of 18-membered cyclodepsipeptide 1p from hepta-
nal (3a)dipeptidic alcohol 4h, and an a-isocyano dipeptide
5d. In this transformation, the only external reagents re-
quired are LiOH and TFA, while water and low molecular
weight alcohol (MeOH)are the only side products pro-
duced. The present approach is thus both atom-economic[36]
and ecologically benign.[37]
Figure 1. Building blocks for three-component synthesis of oxazole.
6). Curiously, the cyclization worked in both nonpolar and
polar aprotic solvents; toluene and acetonitrile were the
best reaction media. The tolerance to large spectrum of sol-
vents may have significant future implications when one
considers transferring this methodology to solid-phase syn-
thesis. In MeCN, a moderate asymmetric induction in the
protonation of the oxazole was observed, which led to two
diastereomers in 2:1 ratio. The structure of 1a was deter-
mined by detailed NMR studies. The molecular weight of
the cyclodepsipeptides was determined by ESI-MS at high
dilution, which enabled us to differentiate between cyclic
monomer and cyclic dimer.
Since the new chiral center was generated before the mac-
rocyclization, the observed low 1,4-asymmetric induction
across the planar aromatic ring of the flexible linear mole-
cule was not unexpected. Site-selective epimerization of cy-
clopeptides via a 5-aminooxazole intermediate has been ex-
Evidence for the formation of spirolactone intermediate:
While the concept of activating the terminal carboxylic acid
by an internal oxazole function seems to be operative, all at-
tempts to detect the presence of the proposed spirolactone
intermediate by spectroscopic methods failed. Careful ex-
amination of our mechanistic hypothesis led us to propose
the following control experiment in order to identify the re-
active intermediate. If the reaction did occur as depicted in
the Scheme 4, then the formation of two spiro intermediates,
that is, 27 and 28, would be expected with thiocarboxylic
acid 26 as a starting material. Since the sulfur atom should
in principle be more nucleophilic than the oxygen atom, 27
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Functionalized Cyclodepsipeptides
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Figure 2. Structure of oxazoles synthesized by three-component reactions.
Table 2. Domino activation/cyclization sequence; survey of cyclization conditions.[a]
position (Scheme 9). Without
optimization, compound 26 was
prepared from lithium salt 23
via a mixed anhydride inter-
mediate (EtOCOCl, Et3N, then
NaSH, DMF).[38] The yield of
26 was only moderate at best
due to concurrent formation of
a carboxylic acid and other by-
products under these condi-
tions. The crude mixture, after
filtration and evaporation, was
directly subjected to acidic con-
ditions (MeOH, TFA, room
temperature). Thioamide 29
and methyl ester 20 (cf.
Scheme 6)were produced in
yields of 21 and 31%, respec-
tively. The structure of 29 was
Entry
Solvent[a]
Acid
Yield [%][b]
dr (A:B)[c]
1
2
3
4
5
6
toluene
MeCN
DMF
THF
toluene
toluene
TFA
TFA
TFA
TFA
TsOH
HClO4
85
81
63
59
9
1:1
1:2
1:1.9
1:2.1
1:1.7
1:2.3
7
[a] Reaction conditions: room temperature, concentration of substrate: 0.001m. [b] Yield of isolated product
after column chromatography. [c] dr=diastereomeric ratio; the stereochemistry of diastereomers A and B was
not determined. Abbreviations: MeCN=acetonitrile, DMF=N,N-dimethylformamide, THF=tetrahydrofuran,
TFA=trifluoroacetic acid, TsOH=4-methylbenzenesulfonic acid.
should be produced predominantly over 28. Ring opening of
27 by methanol would then afford thioamide 29 in which
the sulfur atom has moved from the terminal to the internal
determined by detailed spectroscopic analysis. In the
13C NMR spectrum, the appearance of a lower field signal at
d=205 ppm is characteristic for the thioamide function. The
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J. Zhu et al.
Figure 3. Structure of cyclodepsipeptides from head-to-tail cyclization. All cyclodepsipeptides were produced as a mixture of two separable diastereom-
ers.
formation of thioamide 29 is highly informative, clear-cut
evidence for the existence of a spirolactone-type intermedi-
ate. From preparative point of view, the present mechanistic
study (Scheme 9)constitutes a powerful method for the spe-
cific introduction of a thioamide unit into a given peptide, a
difficult task that is much sought after in searching for bio-
active peptidomimetics.[39]
Efficient activation of the carboxylic acid and favorable
conformation of the linear precursor are two key factors
that dictate the outcome of a given cyclization. In terms of
entropic factor, any structural element that is favorable to
the turn conformation would favor the cyclization.[40,41] The
forces responsible for favoring one conformation over an-
other are covalent bonds, hydrogen bonding, and steric and
electronic interactions of different nature, such as electro-
static interactions, repulsive forces, polarization, and charge
transfer. The interplay of these factors of different strengths
and to different degrees contributes to the conformation of
molecules and hence also to pre-organization of reactive
centers. While the carboxylic acid in the form of spirolac-
tone 31 (Figure 5)was certainly activated enough for nucle-
ophilic attack, we think that the cyclization is also driven by
the reduced entropic loss. Indeed, comparing the structure
of 31 and that of the classic cyclization precursor 32 reveals
that the former has at least six fewer free bond rotations,
and this decreases the conformational mobility and conse-
quently facilitates end-to-end macrocyclization.
Conclusion
We have developed a conceptually novel macrolactonization
protocol that involves a sequence of: 1)protonation of 5-
aminooxazole leading to the electrophilic iminium salt;
2)trapping of the iminium species by the neighboring C-ter-
minal carboxylic acid leading to a putative spirolactone in-
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Functionalized Cyclodepsipeptides
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Scheme 9. Spirolactone intermediate as an activated form of C-terminal
carboxylic acid: clear-cut evidence.
Figure 4. Structure of cyclodepsipeptide from side chain to C-terminal
cyclization. All cyclodepsipeptides were produced as a mixture of two
separable diastereomers.
tic acid under very mild condi-
tions (MeCN as solvent at room
temperature). The key 5-amino-
oxazole, after serving as an in-
ternal activator, becomes an in-
tegral part of the peptide back-
bone. It is thus a traceless inter-
nal activator. Combination of
this domino process with our
previously developed three-com-
ponent synthesis of 5-aminooxa-
zole allowed us to develop a
two-step synthesis of structurally
complex
cyclodepsipeptides
from readily accessible starting
materials. The synthesis report-
ed herein is different from any
other reported approaches for
cyclodepsipeptide synthesis and
Figure 5. Conformational con-
sideration of macroclactoniza-
is particularly appealing in di- tion.
versity-oriented synthesis pro-
grams.[42]
Experimental Section
Scheme 8. Novel synthesis of cyclodepsipeptide by combined use of a
multicomponent reaction and a domino process.
Experimental details and ananlytical data for compounds 1b–p, 2q–s,
2u–x, 3d–e, 5b–f, 6b–x, and 29 are given in the Supporting Information.
General procedure for the synthesis of isocyano dipeptide: A solution of
N-formyl Phe-sarcosine methyl ester (1.5 g, 5.4 mmol)and triethylamine
(4.4 mL, 27.0 mmol)in CH 2Cl2 (75 mL)was cooled to ꢀ308C. Phospho-
rus oxychloride (0.8 mL, 8.1 mmol)was added dropwise to the above so-
lution. After being stirred at ꢀ208C for 2 h, the reaction mixture was
quenched by adding a saturated aqueous solution of NaHCO3 and the
termediate; 3)intramolecular nucleophilic addition of the
tethering alcohol to the spirolactone followed by fragmenta-
tion. No coupling reagent is required and the entire se-
quence is triggered by just a few equivalents of trifluoroace-
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J. Zhu et al.
aqueous phase was extracted with CH2Cl2. The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, and evaporated
to dryness under reduced pressure. The crude residue was subjected to
flash chromatography (silica gel, heptane/EtOAc 4/1!heptane/EtOAc
1:1)to give compound 5a (1.3 g, 96%)as a white solid. M.p. 104–106 8C;
Rf (EtOAc/heptane 1:5) = 0.17; [a]D =ꢀ8 (c=0.12, CHCl3); 1H NMR
(300 MHz, CDCl3, ppm), two rotamers (4:1): d=3.08 (3.02)(s, 3H), 3.15
(dd, 1H, J=8.7, 14.0 Hz), 3.28 (dd, 1H, J=5.3, 14.0 Hz), 3.76 (s, 3H),
4.02 (3.90)(d, 1H, J=17.3 (17.2)Hz), 4.26 (4.09) (d, 1H, J=17.3
(17.2)Hz), 4.62 (4.39)(dd, 1H, J=5.3 (5.5), 8.7 (8.8) Hz), 7.20–7.36 (5H,
m); 13C NMR (62.5 MHz, CDCl3, ppm), two rotamers (4:1): d=36.7
(35.9), 38.6 (39.0), 50.1 (51.2), 52.4 (52.8), 55.8, 127.7, 128.8 (2C), 129.5
(2C), 135.2, 160.0, 165.8, 168.9; IR (CHCl3): n˜ =3009, 2142, 1751, 1677,
1497, 1456, 1439, 1407, 1366, 1238, 1183, 1121, 1080, 1032 cmꢀ1; MS (EI):
m/z: 260 [M]+, 233; elemental analysis (%)calcd for C 14H16N2O3: C
64.62, H 6.15, N 10.77; found: C 64.77, H 6.07, N 10.74.
diluted): m/z: 460 [M+H]+; HRMS: m/z: calcd for C26H41N3O4 +H:
460.3176; found: 460.3192.
Compound 2t: Cyclization of 6t was performed under identical condi-
tions as described for 1a. The light yellow residue was subjected to purifi-
cation by preparative TLC (CH2Cl2/MeOH 1:1)to give 2t (isomer A,
69 mg)and 2t’ (isomer B, 68 mg)(78% total.) Isomer A: White solid;
yield 39%; 1H NMR (300 MHz, CDCl3, ppm), two rotamers: d=1.20–
1.80 (m, 6H), 2.14–2.48 (m, 4H), 2.76 (dd, 1H, J=4.0 Hz, 11.1 Hz), 3.00
(2.86) (s, 3H), 2.87–3.10 (m, 2H), 3.23 (d, 1H, J=16,9 Hz), 3.55–3.67 (m,
4H), 3.71–3.80 (m, 1H), 4.16–4.20 (4.05–4.10) (m, 1H), 4.64 (4.42) (d,
1H, J=16.9 (18.7 Hz)), 5.16 (5.41) (m, 1H), 6.71 (6.80) (d, 1H, J=9.8
(6.8 Hz)), 7.16–7.30 (m, 5H); 13C NMR (CDCl3, 75 MHz, ppm): d=26.5,
27.8, 28.1, 37.9, 38.5, 49.0, 51.0, 51.2, 63.8, 67.3, 69.9, 127.2, 128.9 (2C),
129.6 (2C), 136.6, 168.5, 171.3, 173.4; IR (CHCl3): n˜ =1505, 1648, 1673,
1739, 3016, 3372 cmꢀ1; MS (IE): m/z: 417 [M]+.
Isomer B: White solid; yield 39%; 1H NMR (300 MHz, CDCl3, ppm),
two rotamers: d=1.12–1.80 (m, 6H), 2.06–2.14 (m, 2H), 2.24–2.38 (m,
2H), 2.57–2.62 (m, 1H), 2.9–3.01 (m, 2H), 3.11 (s, 3H), 3.24 (d, 1H, J=
15,6 Hz), 3.47–3.60 (m, 4H), 4.01–4.06 (m, 2H), 4.58 (d, 1H, J=15.6 Hz),
5.38 (5.06)(m,1H), 7.09–7.19 (m, 5H); 13C NMR (CDCl3, 75 MHz, ppm):
d = 27.8, 28.4, 29.6, 38.1, 38.3, 48.1, 51.9, 52.4, 54.1, 67.2, 67.6, 69.8,
127.2, 128.9, 129.6, 136.7, 168.7, 173.0, 173.0%; IR (CHCl3): n˜ =3372,
3016, 1739, 1673, 1648, 1505 cmꢀ1; MS (IE): m/z: 417 [M]+; MS (ESI,
positive mode): m/z: 440.2 [M+H]+; HRMS: m/z: calcd for
C22H31N3O5 +Na: 440.21.61; found: 440.2161.
General procedure for three-component synthesis of oxazole 6: A solu-
tion of heptanal (3a, 23 mg, 0.2 mmol)and aminohexanol ( 4a; 23 mg,
0.2 mmol)in dry methanol (2 mL)was stirred at room temperature for
15 min, and isocyanide 5a (52 mg, 0.2 mmol)was then added to the solu-
tion. The reaction mixture was heated to 708C for 3 h. The solvent was
then removed under reduced pressure. The crude product was purified
by flash column chromatography (silica gel, CH2Cl2/MeOH 95:5)to give
aminooxazole 6a (56.0 mg, 59%)as a yellow oil. Rf (MeOH/CH2Cl2
1:20)
=
0.28; 1H NMR (250 MHz, CDCl3, ppm): d=0.86 (t, 3H, J=
6.6 Hz), 1.13–1.60 (m, 16H), 1.68–1.84 (m, 2H), 2.48 (t, 2H, J=7.9 Hz),
2.87 (s, 3H), 3.59 (t, 2H, J=6.5 Hz), 3.65 (t, 1H, J=6.1 Hz), 3.68 (s, 3H),
3.71 (s, 2H), 3.85 (s, 2H), 7.15–7.27 (m, 5H); 13C NMR (CDCl3,
62.5 MHz, ppm): d=14.0, 22.5, 25.6, 25.9, 27.0, 29.0, 29.9, 31.6, 32.6, 34.5,
40.8, 47.5, 51.8, 55.9, 57.0, 62.5, 62.5, 122.1, 126.0, 128.3 (4C), 139.8, 151.4,
159.9, 170.6; IR (CHCl3): n˜ =3690, 3013, 2933, 1749, 1675, 1602, 1456,
Acknowledgement
Financial support from Rhodia and CNRS are gratefully acknowledged.
C.B. thanks the Minist›re de lꢁEnseignement SupØrieur et de la Recher-
che for a doctoral fellowship. G.Z. thanks Rhodia for a postdoctoral fel-
lowship.
1406, 1265, 1223, 1183, 1012 cmꢀ1
;
MS (EI): m/z: 473 [M]+, 388
[MꢀC6H13]+.
General procedure for macrocyclization: A solution of 5-aminooxazole
6a (43 mg, 0.09 mmol)and LiOH·H 2O (42 mg, 0.10 mmol)in THF/H 2O
(4 mL, 3:1)was stirred at room temperature for 3 h and evaporated to
dryness in vacuo. The residue obtained was dissolved in MeCN (200 mL,
c=10ꢀ3 m), and TFA (405 mg, 9.20 mmol) was added under a stream of
argon. The reaction mixture was stirred at room temperature for 2 h.
When the reaction was completed, the volatile substances were evaporat-
ed under reduced pressure. The residue obtained was dissolved in ethyl
acetate and washed with a saturated aqueous solution of potassium bicar-
bonate. The organic phase was dried over anhydrous Na2SO4, filtered,
and evaporated to dryness under reduced pressure. The light yellow resi-
due was subjected to purification by preparative TLC (heptane/EtOAc
1:1)to give 1a (isomer A, 18 mg)and compound 1a’ (isomer B, 17 mg)
(85%, total 35%). Isomer A: white solid; yield 43%; Rf (EtOAc/heptane
1.5:1) = 0.39; 1H NMR (300 MHz, CDCl3, ppm): d=0.89 (t, 3H, J=
6.6 Hz), 1.15–1.70 (m, 19H), 2.46–2.56 (m, 2H), 2.75 (s, 3H), 2.97–3.10
(m, 3H), 3.17 (d, 1H, J=16.5 Hz), 3.88 (m, 1H), 4.47 (m, 1H), 4.51 (d,
1H, J=16.5 Hz), 5.15 (dt, 1H, J=4.7, 8.0 Hz), 7.23–7.27 (m, 5H), 7.86
(d, 1H, J=8.0 Hz, NH); 13C NMR (CDCl3, 75 MHz, ppm): d=14.2, 22.7,
25.1, 25.2, 26.1, 28.9, 29.2, 29.3, 31.7, 34.5, 36.9, 40.0, 47.8, 50.0, 51.7, 64.8,
65.2, 127.0, 128.4 (2C), 129.6 (2C), 136.6, 169.0, 171.7, 174.7; IR (CHCl3):
n˜ =3355, 3005, 2932, 2858, 1734, 1645, 1496, 1456, 1418, 1267, 1189,
1131 cmꢀ1; MS (EI): m/z: 459 [M]+; MS (APCI, diluted): m/z: 460
[M+H]+; HRMS: m/z: calcd for C26H41N3O4 +H: 460.3176; found:
460.3189.
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Received: June 19, 2005
Published online: October 20, 2005
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