Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles

Article abstract of DOI:10.1039/c1ob05390f

Amino acid-derived propargylic amides are cyclised in a one-pot, Au(iii)-catalysed operation to yield 5-bromomethyl oxazoles. These compounds are further elaborated to bis-heterocycles, dipeptide mimics and more.

Full text of DOI:10.1039/c1ob05390f

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Gold-catalysed synthesis of amino acid-derived 2,5-disubstituted oxazoles†
Christopher L. Paradise, Pooja R. Sarkar, Mina Razzak and Jef K. De Brabander*
Received 12th March 2011, Accepted 4th April 2011
DOI: 10.1039/c1ob05390f
Amino acid-derived propargylic amides are cyclised in a
one-pot, Au(III)-catalysed operation to yield 5-bromomethyl
oxazoles. These compounds are further elaborated to bis-
heterocycles, dipeptide mimics and more.
propargylic amides would provide access to a wide range of 2,5-
disubstituted oxazoles. Unfortunately, we were unsuccessful in
identifying conditions to perform this transformation on internal
alkynes (Scheme 1, 3 → 4, R¢ π H),15 thereby severely limiting
the scope of this reaction to the synthesis of 5-Me-substituted
oxazoles (4, R¢ = H). During these explorative studies, Hashmi
et al. reported that the Au(III)-catalysed cyclisation of terminal
propargylic amides 3 (R¢ = H) yields 5-methyl-substituted oxazoles
4 (R¢ = H) via an isolable methyleneoxazoline intermediate of type
5 (Scheme 1).16,17 From these studies, we postulated that one could
intercept this intermediate in situ with an electrophile to generate
oxazoles bearing a reactive handle at the 5-methylene position (6),
thus providing an entry to expand the range of available oxazoles
via subsequent manipulation at this position (6 → 4, R¢ π H).
Herein, we report the reduction of this concept to practice.
The oxazole heterocycle is a prevalent subunit in many natural
and synthetic bioactive small molecules.1 Natural products such
as diazonamide A (1)2 and bengazole (2)3 (Fig. 1) are just two of the
multitude of scaffolds which incorporate the motif. Their inclusion
in compounds with antiviral, antibacterial, antineoplastic and
antineuropathic activity highlights the significance of the oxazole
nucleus in medicinal chemistry.4
Fig. 1 Diazonamide A (1) and bengazole (2).
Many naturally occurring oxazoles are derived from the enzy-
matic post-translational modification of peptide-based precursors
via dehydrative cyclisation of serine or threonine residues onto a
preceding carbonyl, followed by a two electron oxidation.5,6 This
transformation endows favourable pharmacological properties
including resistance to proteases and increased cell permeability.7
As such, these heterocycles have been valued as subunits in pep-
tidomimetic design and other medicinal chemistry programmes.8
Laboratory preparations of oxazoles include conventional cy-
clodehydration of acyclic precursors,9 oxidation of oxazolines,10
functionalisation (via metallation) of readily available oxazole
starting materials,11 copper-catalysed amidation of vinyl halides
followed by cyclisation12 and others.1,9,13
Scheme 1 Experimental design.
A preliminary screen identified bromine as the most compe-
tent electrophile to trap the methyleneoxazoline intermediate 5
(generated in situ from the Au(III)-catalysed cycloisomerisation of
terminal propargylic amides 3), delivering bromomethyl oxazole
(6, E = Br) in good yield.18–22 Many naturally occurring oxazoles
bear amino acid-derived side chains, thus the scope was extended
to include these moieties. Initial experiments revealed that Fmoc-
protected amino acid-derived propargylic amides were not ideal
substrates, however Boc-protected amide 3a was converted to 5-
bromomethyl derivative 7a in 50% yield (Table 1). The modest
yield was attributed to opportunistic HBr catalysing the cleavage
of the Boc group. A screen of bases revealed that 2,6-lutidine
best ameliorated this effect to give 7a in 88% yield with no
epimerization of the stereogenic centre.22
Based on our studies related to the cycloisomerisation of
w-hydroxy alkynes,14 we postulated that cycloisomerisation of
Department of Biochemistry and Simmons Comprehensive Cancer Cen-
ter, University of Texas Southwestern Medical Center at Dallas, 5323,
Harry Hines Blvd., Dallas, Texas 75390. E-mail: jef.debrabander@
utsouthwestern.edu; Fax: +1214 648 7808; Tel: +1214 648 0320
† Electronic supplementary information (ESI) available: Experimental
details, spectroscopic data and copies of NMR spectra for new compounds.
See DOI: 10.1039/c1ob05390f
Having optimised the reaction conditions, the substrate scope
was expanded as shown in Scheme 2. The reactions proceeded
with similar efficiency and could be performed on a gram-scale
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Table 1 Optimisation of amino acid-derived oxazole formation
Table 3 bis-Heterocycles by dipolar cycloadditiona
Base
Yielda
Base
Yielda
Azide
R
R¢
Product
Yield
70
none
i-Pr2NEt
K2CO3
50
51
52
pyridine
2,4,6-collidine
2,6-lutidine
55
82
88
12a
(S)-CHMeEt
16a
a Isolated yield (%).
12b
12a
CHMe2
(S)-CHMeEt
17a
16b
72
81
12b
12a
CHMe2
(S)-CHMeEt
17b
16c
84
84
12b
12a
CHMe2
(S)-CHMeEt
17c
16d
85
80
12b
CHMe2
17d
88
12b
CHMe2
-(CH2)5Me
17e
64
Scheme 2 5-Bromomethyl oxazoles derived from sequential cycloisomeri-
sation–bromination of propargylic amides. Reaction conditions: amide 3
(0.2 M in CHCl3), 5 mol% AuCl3, RT; 2,6-lutidine (1.1 eq), Br2 (1.0 eq,
2.0 M in CHCl3), 0 ◦C to RT. Isolated yields in brackets.
a Reaction conditions: azide (0.1 M in THF), alkyne (1.0 eq), Et3N (1.2 eq)
and 10 mol% CuI, RT, 16 h. b Isolated yield (%).
(10 mol% CuI, Et3N)26 in the coupling between azido oxazoles
12a–b with a range of commercially available alkynes to produce
the bis-heterocycles 16a–d and 17a–e in good yields (Table 3). The
cycloaddition proceeded well regardless of the nature of the alkyne
substituent—aromatic and alkyl (cyclic and acyclic) groups were
tolerated.
without complication, highlighting their utility in the preparation
of large quantities of these interesting 5-bromomethyl oxazoles.23
Next, we explored the displacement of the bromide with a
variety of nucleophiles. The substrates proved extremely versatile,
reacting with a wide range of nucleophiles in good to excellent
yields (Table 2). The success of the azide (12, 98%) and L-
valinol (15, 71%) substitutions prompted us to focus on these
transformations for further elaboration.
First, we sought to take advantage of the Huisgen 1,3-dipolar
cycloaddition to access 1,4-disubstituted 1,2,3-triazoles.24,25 This
heterocycle is known to be biologically inert and is therefore
commonly used as a robust linking group in medicinal chemistry
and in the preparation of optically active chemical probes.25a We
were able to successfully employ modified Sharpless conditions
The success of the bromide displacement by amino alcohols
inspired the preparation of peptidomimetics expressing two amino
acid side chains. Compounds of this type have potential use in bi-
ological research; it is well documented that they are metabolically
more stable and benefit from improved bioavailability profiles than
peptides themselves.27 As shown in Table 4, direct displacement
of bromomethyl oxazoles with amino alcohols provided efficient
access to oxazoyl-based peptidomimetics bearing two stereocen-
tres. To the best of our knowledge, these are the only examples
of dipeptide isosteres with this 2,5-oxazole substitution pattern.
Additionally, these adducts, like other amino alcohols that have
enjoyed success as organocatalysts28 and as ligands in metal-based
catalysis,29 may be useful in asymmetric catalysis. Owing to the
ready availability of amino alcohols, a range of peptidomimetics
(18–43) were prepared. The modular nature of these adducts
allows for rapid assembly, covering a wide chemical space. Indeed,
the direct displacement of bromide provided a useful entry to
products of this type, with good yields for L-prolinol, D- and L-
phenylalaninol and L-tyrosinol; only L-tryptophanol suffered poor
conversion (33, 22%). Additionally, no precautions were taken to
prevent over N-alkylation or alcohol substitution;30 the reported
dialkylamines were the only products observed.
Table 2 Nucleophilic substitution of bromide 7aa
Nucleophile Product
Yieldb Nucleophile
Product Yieldb
KCN
8
71
81
89
61
NaN3
12a
13
98
86
65
71
t-BuNH2
PhOH
PhSH
9
NaOAcc
10
11
H2N(CH2)5OH 14
L-valinol 15
a See the ESI† for experimental details. b Isolated yield (%). c Substrate for
this reaction was 7b.
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Table 4 Peptidomimetic library developmenta
7
AA
Amino alcohola
Product
Yieldb
7
AA
Amino alcohola
Product
Yieldb
a
a
a
a
a
a
a
a
b
b
b
b
b
Ile
Ile
Ile
Ile
Ile
Ile
Ile
Ile
Val
Val
Val
Val
Val
D-valinol
18
28
19
29
30
31
32
33
34
20
35
21
36
66
57
60
59
63
46
48
22
78
64
57
60
87
c
c
c
c
c
e
e
e
e
d
d
d
d
Phe
Phe
Phe
Phe
Phe
Pro
Pro
Pro
L-valinol
D-valinol
L-phenylalaninol
D-phenylalaninol
L-prolinol
L-valinol
D-valinol
L-phenylalaninol
D-phenylalaninol
L-valinol
37
22
38
23
39
40
24
41
25
42
26
43
27
63
68
62
63
50
55
54
60
58
72
75
67
79
L-phenylalaninol
D-phenylalaninol
L-isoleucinol
L-prolinol
L-leucinol
L-tyrosinol
L-tryptophanol
L-valinol
D-valinol
L-phenylalaninol
D-phenylalaninol
L-prolinol
Pro
t-BuGly
t-BuGly
t-BuGly
t-BuGly
D-valinol
L-phenylalaninol
D-phenylalaninol
a Reaction conditions: azide (0.2 M in DMF), amino alcohol (2.2 eq), RT, 16 h. b Isolated yield (%).
In this report, we demonstrated that 5-bromomethyl oxazoles
can be prepared from propargylic amides in a one-pot Au(III)-
catalysed procedure in good yields (57–88%). Additionally, amino
acid-derived propargylic amides provided access to a multitude
of chiral, potentially biologically relevant novel oxazole building
blocks. The ease of further elaboration was clearly established in
reactions with a range of nucleophiles, including amino alcohols,
to give a unique class of bis-amino acid-derived oxazoles. Alterna-
tively, azido oxazole derivatives 12 were further elaborated to the
corresponding triazolyl-oxazoyl bis-heterocycles 16 and 17 via a
Cu(I)-catalysed 1,3-dipolar cycloaddition with a range of alkynes.
Further studies on the bioactivity and solution conformations of
these molecules are ongoing and will be reported in due course.
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hydration).
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yl)pivalamide (CDCl3, RT, 1 h) and >90% starting material was
recovered in all cases. The use of NaAuCl4·2H2O resulted in hydration
of the terminal alkyne to a methylketone. As reported by Hashmi
et al.; (ref. 16), only AuCl3 was effective in the cycloisomerisation of
terminal propargylamides to 5-Me-substituted oxazoles.
Acknowledgements
Bo Liu and Veronica St. Claire are acknowledged for initial
experiments. Financial support was provided by the Robert A.
Welch Foundation (Grant I-1422), Reata Pharmaceuticals and
the NIH (Grant CA90349).
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6 Though less widespread, naturally occurring oxazoles bearing a 5-
substituent other than H or Me are also known. In the case of
18 Hashmi et al. reported the trapping of the intermediate vinyl gold
species with N-halosuccinimides, albeit in low to modest yield. See:
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(a) J. P. Weyrauch, A. S. K. Hashmi, A. Schuster, T. Hengst, S. Schetter,
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19 We also tested N-iodosuccinimide, N-bromosuccinimide and tetra-
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22 See the ESI† for details.
23 Yields are for purified material. The actual yields are in most
cases higher because of partial hydrolysis of the bromide during
chromatography. The reaction is sufficiently clean that the bromides
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