Bioactive 2-oxazolines: A new approach via one-pot, four-component reaction

Article abstract of DOI:10.1021/ol070694h

Substituted 2-oxazolines of the general structure shown above are found in several families of bioactive natural products and can be prepared In an efficient and general one-pot, four-component condensation.

Full text of DOI:10.1021/ol070694h

ORGANIC
LETTERS
2007
Vol. 9, No. 10
2015-2017
Bioactive 2-Oxazolines: A New
Approach via One-Pot, Four-Component
Reaction
Lijun Fan, Emil Lobkovsky, and Bruce Ganem*
Department of Chemistry & Chemical Biology, Baker Laboratory, Cornell UniVersity,
Ithaca, New York 14853-1301
bg18@cornell.edu
Received March 21, 2007
ABSTRACT
Substituted 2-oxazolines of the general structure shown above are found in several families of bioactive natural products and can be prepared
in an efficient and general one-pot, four-component condensation.
Oxazolines are widely used in polymer chemistry as synthetic
reagents and most recently as ligands in asymmetric syn-
thesis.1 Alkyl- and aryl-substituted 2-oxazolines are also
present in marine natural products2 and are important
pharmacophores in numerous bioactive natural products that
display cytotoxic, antitumor, neuroprotective, antibiotic, or
antifungal properties.
family of mammalian siderophores that utilize the 2-hydroxy-
phenyloxazoline carboxamide substructure (box) to sequester
iron in macrophages.5
We have been interested in developing convergent syn-
thetic routes to such complex oxazolines utilizing a multi-
component reaction (MCR) to assemble the key heterocyclic
pharmacophore in a single flask. Here, we report a powerful
and versatile 4-component condensation that efficiently
produces 2-substituted oxazoline-4-carboxamides and their
congeners as highlighted in 1-3 in good yields.
Some representative examples (Figure 1) include the
cytotoxic agent brasilibactin 1,3 a family of five antitumor
The approach we envisioned was based on the known
biosynthesis of many peptide-derived oxazolines, which
usually involves cyclization of N-acyl serine residues. We
initially considered an Ugi reaction using R-diazoketones
(readily prepared from acid chlorides using CH2N2) in place
of simple aldehydes or ketones. However, mixtures of
R-diazoketones, amines, isonitriles, and carboxylic acids
proved unreactive, even when heated to 60-70 °C.
(1) Review: Wong, G. S. K.; Wu, W. Chem. Heterocycl. Compd. 2004,
50, 331.
(2) Davidson, B. S. Chem. ReV. 1993, 93, 1771.
(3) Tsuda, M.; Yamakawa, M.; Oka, S.; Tanaka, Y.; Hoshino, Y.;
Mikami, Y.; Sato, A.; Fujiwara, H.; Ohizumi, Y.; Kobayashi, J. J. Nat.
Prod. 2005, 68, 462.
Figure 1. Substituted 2-oxazolines in bioactive natural products.
(4) Tsukamoto, M.; Murooka, K.; Nakajima, S.; Abe, S.; Suzuki, H.;
Hirano, K.; Kondo, H.; Kojiri, K.; Suda, H. J. Antibiot. 1997, 50, 815.
(5) Moody, D. B.; Young, D. C.; Cheng, T.-Y.; Rosat, J.-P.; Roura-mir,
C.; O’Connor, P. B.; Zajonc, D. M.; Walz, A.; Miller, M. J.; Levery, S. B.;
Wilson, I. A.; Costello, C. E.; Brenner, M. B. Science 2004, 303, 527.
substances represented by B32030A 2 and B32030B 3,4 and
the recently discovered T-cell antigen didehydroxymyco-
bactin 3, a complex lipopeptide related to the mycobactin
10.1021/ol070694h CCC: $37.00
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We therefore investigated Ugi condensations of the cor-
responding (and much more electrophilic) â-ketomesylates
4 (Scheme 1), which are readily available by the known
Scheme 1. Proposed MCR Approach to Substituted
2-Oxazolines
Figure 2. ORTEP diagram of the X-ray crystal structure of
oxazoline 6a. Hydrogen atoms are omitted for clarity. Selected bond
distances (Å) and angles (deg): N(1)-C(18) ) 1.270(3), O(1)-
C(18) ) 1.369(3), C(1)-N(1) ) 1.474(3), O(1)-C(17) ) 1.444(3);
N(1)-C(1)-C(17) ) 104.45(18), N(1)-C(18)-O(1) ) 118.5(2),
C(18)-O(1)-C(17) ) 105.55(18), C(10)-C(1)-C(17) ) 110.7(2),
C(10)-C(1)-C(2) ) 106.70(19).
insertion reaction6 of diazoketones with CH3SO3H. Our
expectation was that if imine formation at the carbonyl group
in 4 using ammonia were faster than displacement of the
mesylate, then the intermediate diamide 5 might spontane-
ously cyclize in situ to the desired oxazoline 6.
Using the â-ketomesylate 4a (Scheme 2) as a test case, a
solution of 4a in CH3OH was stirred with NH3 and benzoic
Several examples of trisubstituted 2-oxazolines prepared
by this four-component condensation illustrate the scope and
generality of the method (Table 1). Precondensing the
Scheme 2. One-Pot Synthesis of 2-Oxazolines
Table 1. Synthesis of 2-Oxazolines 6 from Ketomesylates 4
ketomesylate
R′CO2H
R′ )
R′′NC
R′′ )
product
(% yield)
4a-e
4a, R ) Ph(CH2)2
C6H5
CH3
CH3
cyclohexyl
cyclohexyl
tert-butyl
cyclohexyl
CH2CO2Et
tert-butyl
tert-butyl
CH2CO2Et
tert-butyl
tert-butyl
tert-butyl
CH2CO2Et
tert-butyl
CH2CO2Et
6a (61)
6b (71)
6c (73)
6d (64)a
6e (60)
6f (80)
6g (38)
6h (63)
6i (60)
Boc-(S)-Phe
i-C3H7
CH3
Cbz-Gly
CH3
i-C3H7
CH3
CH3
b
4b, R ) n-C7H15
acid (1 equiv each) for 30 min at 0 °C. After adding
cyclohexylisonitrile (1.1 equiv) then stirring at rt for 24 h,
solvent evaporation led directly to roughly equal quantities
of the target oxazoline 6a together with the corresponding
three-component Passerini product 7a.
4c, R ) cyclohexyl
4d, R ) Phb
6j (63)
c
4e, R ) CH3
6k (60)
6l (68)
6m (58)d
6n (63)d,e
C6H5
o-(OH)C6H4
o-(OH)C6H4
Increasing the quantities of ammonia and benzoic acid
slightly improved the yield of 6a but did not suppress
formation of 7a. A more dramatic improvement was achieved
by replacing methanol as solvent with 2,2,2-trifluoroethanol,
which has been shown to improve Ugi reactions involving
ammonia.7 Under optimal conditions (4 equiv each of NH3,
PhCO2H), 6a was obtained in 61% yield (mp 89 °C)
accompanied by ca. 5% of 7a. Interestingly, no products
derived from simple nucleophilic substitution of the mesylate
group in 4a were observed.
a Obtained as a mixture of diastereomers. b Cho, B. T.; Yang, W. K.;
Choi, O. K. J. Chem. Soc. Perkin Trans. 1 2001, 1204. c Lodaya, J. S.;
Koser, G. J. Org. Chem. 1988, 53, 210. d CH3OH was used as solvent in
this reaction. e 2 equiv of isonitrile was used in this reaction.
carboxylic acid ammonium salt (4 equiv) and the keto-
mesylate in CF3CH2OH for 30 min at 0 °C is sufficient to
minimize the formation of Passerini products like 7.
As the examples in Table 1 indicate, a broad range of
carboxylic acids and isonitriles (including examples of both
compound families derived from naturally occurring R-amino
acids) underwent smooth reaction with various ketomesylates
and ammonia to form the desired 2-oxazolines. Even
Figure 2 shows the X-ray crystal structure of 6a, which
confirmed the presence of the 2,4,4-trisubstituted oxazoline
ring.
(6) Nogrady, T.; Doyle, T. W.; Morris, L. J. Med. Chem. 1965, 8, 656.
(7) Kazmaier, U.; Hebach, C. Synlett 2003, 1591.
2016
Org. Lett., Vol. 9, No. 10, 2007

resonance-stabilized ketomesylates such as PhCOCH2OMs
4d were reactive enough to form the desired oxazoline
carboxamides, e.g., 6j, in good yield.
Scheme 4. Assembly of 2-Oxazoline Substructures in 1-3
When ammonia was replaced with a primary amine, such
as benzyl or allylamine, the multicomponent reaction took
a different course, affording aminoesters like 9a (Scheme
3) as the exclusive product from ketomesylate 4a. The
In summary, we have developed an efficient four-
component reaction that affords 2-substituted oxazoline-4-
carboxamides in a one-pot process from readily available
starting materials. With their widespread occurrence in
bioactive natural products, such functionalized oxazolines
may be considered privileged structures, i.e., molecular
frameworks exhibiting medicinally useful binding properties.
The multicomponent synthesis reported here rapidly as-
sembles promising lead compounds containing this hetero-
cyclic system for use in drug discovery endeavors.
Scheme 3. MCR Route to Aminoesters from Ketomesylates 4
structure of 9a, which was also confirmed by single-crystal
X-ray diffraction analysis, most likely arose via hydrolysis
of an intermediate oxazolinium ion like 8a. Interestingly,
none of the isomeric amido alcohol 10a was detected.
The new oxazoline synthesis could also be applied
(Scheme 4) to a one-pot assembly of the 2-hydroxyphenyl-
4-methyloxazoline-4-carboxamide substructure found in natu-
ral products like 1-3. Initial attempts using salicylic acid
as the carboxylic acid component failed in trifluoroethanol
because of the insolubility of ammonium salicylate. However,
the problem was overcome by switching to methanol as
solvent. Gratifyingly, the desired oxazoline 6n was produced
in 63% yield. Furthermore, no phenol protecting group was
required, in contrast to earlier total synthesis efforts in the
mycobactin series.8
Acknowledgment. L.F. wishes to thank the Sien Moo
Tsang endowment for a graduate fellowship. Support of the
Cornell NMR Facility has been provided by the NSF (CHE
7904825; PGM 8018643) and NIH (RR02002).
Supporting Information Available: Representative ex-
perimental procedures for the synthesis of 2-oxazolines
described in Table 1, as well as supporting spectroscopic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL070694H
(8) (a) Hu, J.; Miller, M. J. J. Am. Chem. Soc. 1997, 119, 3462. (b)
Maurer, P. J.; Miller, M. J. J. Am. Chem. Soc. 1983, 105, 240.
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