Combinatorial synthesis of oxazol-thiazole bis-heterocyclic compounds

Article abstract of DOI:10.1021/co400133a

A combinatorial library of novel oxazol-thiazole bis-heterocycles was synthesized in good to excellent overall yields with high purity using a solution and solid-phase parallel synthesis approach. Oxazole amino acids, prepared from serine methyl ester and

Full text of DOI:10.1021/co400133a

Research Article
pubs.acs.org/acscombsci
Combinatorial Synthesis of Oxazol-Thiazole Bis-Heterocyclic
Compounds
Siva Murru and Adel Nefzi*
Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St Lucie, Florida 34987, United States
S
* Supporting Information
ABSTRACT: A combinatorial library of novel oxazol-thiazole bis-heterocycles was synthesized in good to excellent overall yields
with high purity using a solution and solid-phase parallel synthesis approach. Oxazole amino acids, prepared from serine methyl
ester and amino acids via coupling and cyclodehydration, were treated with Fmoc-NCS and α-haloketones for the parallel
synthesis of diverse bis-heterocycles. Fmoc-isothiocyanate is used as a traceless reagent for thiazole formation. Oxazole diversity
can be achieved by using variety of amino acids, whereas thiazole diversity is produced with various haloketones.
KEYWORDS:
oxidation to yield 1,3-azoles,4c,9 (iii) oxidation of β-hydroxy-
INTRODUCTION
■
(thio)amides β-keto(thio)amide and cyclization (Robinson−
Natural products play an important role in the development of
Gabriel) affords oxazoles and thiazoles,10 and (iv) a
new drugs1 and provide the inspiration to develop new
condensation reaction between N-protected imino ethers and
strategies toward the diversity-oriented synthesis of novel small-
Ser- or Cys-esters.11 Most of these methods report the
molecule libraries. An extraordinary group of biologically active
synthesis of either oxazole or thiazole amino acids and their
natural products, often from a marine environment,2 contains
application to macrocyclic peptide synthesis. The major
bis-thiazoles, bis-oxazoles and bis-oxazol-thiazole systems,
disadvantages of cyclodehydration methods for generation of
which are derived from biosynthetic cyclizations of precursor
thiazoles are the required use of either S-protected Cysteine
amino acids Cys, Ser and Thr.3 Thiazole/oxazole modified
substrates or thioamides, requiring multiple steps.10b Recently,
microcins (TOMMs)3b,c are a widespread natural product
McAlpine et al. reported a multistep synthesis of Sanguinamide-
platform and exhibit a wide range of biological activities,
including cytotoxicity,4a immunosuppression,4b multiple drug
resistance pump inhibition,4c as well as antibacterial and
antiviral activities.4d For example, in the ribosomal peptide
group, microcin B17 is a DNA gyrase inhibitor,5a Goadsporin is
a secondary metabolism inducer,5b and Ritonavir is a HIV-1
protease inhibitor.5c In addition, the heterocyclic motif, either
thiazole or oxazole itself, is potentially bioactive and can
interact with nucleic acids and proteins. The aminothiazole ring
system is a useful structural element in medicinal chemistry and
has found broad applications in drug development as
antihypertensive,6a antibacterial,6b and anti-HIV agents.6c
Many oxazole derivatives are found to be associated with
various biological activities7 such as antifungal, antitubercular,
anti-inflammatory activities, etc.
Biosynthesis of oxazoles and thiazoles occurs in β-hydroxy-
(thio) peptides (Ser, Thr or Cys) via cyclodehydration followed
by an oxidation reaction.3b,c Inspired by this natural pathway,
chemists developed methods for biomimetic synthesis of
oxazole/thiazole based peptides/peptidomimetics. Reported
methods include (i) condensation of thioamide and haloke-
tones (modified Hantzsch’s procedure),8 (ii) cyclodehydration
of β-hydroxy(thio)amides to give 1,3-azolines using either
Mitsunobu conditions or the Burgess reagent, followed by ring
B analogues containing directly linked (C2−C4′) oxazol-
thiazole using thioamide as the thiazole precursor.12 Though
the oxazol-thiazole bis-heterocyclic moiety is encountered in
many bioactive natural products, there is no report on the
parallel synthesis for these pharmacologically important
molecules.
Prompted by the above investigation and in continuation of
our work in the generation of heterocyclic compounds8d,e,13
from amino acids and short peptides, we envisaged the
synthesis of oxazole amino acid building blocks and utilizing
them for the parallel synthesis of oxazol-thiazole bis-hetero-
cycles. Our strategy involves the solution-phase synthesis of
oxazole amino acid building blocks and solid-phase synthesis of
thiazoles. The main advantages of our approach are (i)
biomimetic synthesis of oxazole amino acids and their use as
building blocks for the solid-phase synthesis, (ii) use of Fmoc-
NCS as a thioamide equivalent for the thiazole cyclization, and
(iii) rapid generation of diverse bis-heterocycles using
haloketones. Similar to the biosynthetic pathway, our approach
Received: October 21, 2013
Revised: November 25, 2013
© XXXX American Chemical Society
A
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Scheme 1. Biomimetic Synthesis of Non-Natural Oxazole Amino Acid Building Blocks Starting from Amino Acids and Serine
a
Methyl Ester
a
Reaction conditions: (i) HOBt, DIC, DIPEA, DCM, 0 °C to RT; (ii) DAST, DCM, −78 °C; (iii) BrCCl3, DBU, DCM, 0 °C; (iv) 1N NaOH(aq),
Dioxane/H2O, 10% KHSO4(aq).
Scheme 2. Solid-Phase Parallel Synthesis of Oxazol-Thiazole Bis-Heterocycles (5R × 4Rˈ = 20 RRˈ) via Hantzsch Cyclization
a
Starting from Resin-Bound Oxazole Amino Acids
a
Reaction conditions: (i) MBHA resin, DIEA, DCM, 5 min; (ii) HOBt, DIC, DMF, overnight; (iii) 55% TFA in DCM, 30 min; (iv) Fmoc-NCS (3
equiv), 10 h; (v) Piperidine/DMF (20%), 10 min; (vi) Halo ketone, DMF, 80 °C; (vii) HF-cleavage.
is also based on cyclodehydration of β-hydroxy peptides to
oxazolines followed by oxidation and hydrolysis affording
oxazole amino acids (Scheme 1).
acids (4b−e) in moderate to good overall yields (59%, 64%,
56% and 48%, respectively). These heterocyclic amino acids
served as building blocks for the parallel synthesis of oxazol-
thiazole bis-heterocycles as outlined in Scheme 2.
For our studies, we chose Boc-protected amino acids because
of their compatibility with basic reaction conditions. To
optimize the reaction conditions, we initially used Boc-Leu-
OH as the coupling partner with Ser-OMe. As shown in
Scheme 1, β-hydroxy peptide 2a (Boc-Leu-Ser-OMe) was
synthesized from Boc-Leu-OH (1a) and Ser-OMe·HCl utilizing
standard coupling conditions (DIEA, DIC and HOBt) in DMF.
Following the procedure by Wipf and Williams,14 cyclization of
Boc-β-hydroxypeptide 2a with fluorinating reagent DAST at
−78 °C was performed to yield oxazoline ester, followed by the
addition of BrCCl3 and DBU in the same flask at 0 °C resulted
in the oxidation to oxazole ester (3a, 68%). Boc-oxazole amino
acid 4a is obtained quantitatively (93%) by the hydrolysis of 3a
using of 1N aq. NaOH (3 equiv) at 0 °C. The overall yield after
four reaction steps for 4a is 63%.
To determine if any racemization occurs during the
synthesis, we have prepared possible diasteromers of 4a with
Boc-L-Phe-OH and Boc-L-Val-OH. The LC-MS analysis of
these diastereomers shows very little racemization (2−5%) as
observed by others in a similar methodology.10a,12,14 Con-
sequently, the same synthetic approach was used for other Boc-
protected amino acids such as Boc-Pro-OH (1b), Boc-Val-OH
(1c), Boc-Phe-OH (1d) and Boc-Tyr(Z-2-Br)-OH (1e) and
are converted smoothly to the corresponding oxazole amino
Having oxazole amino acid building blocks in hand, the next
step is to synthesize a library of oxazol-thiazole bis-heterocycles.
Because solid-phase organic synthesis (SPOS)15 is an effective
tool to generate structurally diverse compounds, we employed
the tea-bag approach15b for the rapid solid-phase parallel
synthesis of diverse bis-heterocycles. First, we loaded the
oxazole amino acid building blocks on to p-methylbenzhydryl-
amine (MBHA) resin using DIC and HOBt in DMF. Next, the
resin-bound Boc-oxazole was treated with 55% TFA in DCM to
remove Boc-protection and the resulting free amine was reacted
with Fmoc-isothiocyanate to form the substituted thiourea.
Following Fmoc-deprotection using 20% piperidine in DMF,
monosubstituted thioureas were treated with four different
haloketones while heated overnight at 80 °C in DMF to
generate the corresponding thiazole ring. After completion of
the cyclization, compounds were cleaved from the resin and the
desired 20 diverse oxazol-thiazole bis-heterocycles were
obtained in good yields and high purity (Table 1).
We used four different haloketones for thiazole cyclizations,
namely 1-chloropinacolone (f), 2-bromoacetophenone (g), 2-
chloro-3′,4′-dihydroxyacetophenone (h), 1-adamantyl chloro-
methyl ketone (i). Products were obtained in good yields and
purities. Using proline oxazole (4b), we obtained a cascade of
B
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Table 1. Solid-Phase Parallel Synthesis of Oxazol-Thiazole Bis-Heterocycles
a
b
c
Based on integration of LCMS chromatogram of the crude product. Based on the product obtained after HPLC purification. Purity of the
compounds obtained after HPLC purification.
three distinct heterocycles oxazole, pyrrolidine and thiazole
present in products 9f−9i. It should be noted here that the
combination of two or three heterocyclic cores in one molecule
increases the number of potential targets by the square power
and improves the chances of identifying hits. Many approved
drugs contain five- and six-membered heterocycles, often bis- or
tris-nitrogen heterocycles.16
In conclusion, we have developed an approach for the
parallel synthesis of pharmacologically relevant bis-heterocycles
containing oxazole and thiazole structures in the core. We have
used a variety of amino acids for the oxazole diversity and
different halo-ketones for thiazole diversity. This approach is
useful to incorporate oxazole and thiazole moiety into peptides
and peptidomimetics to generate combinatorial librairies for the
purpose of drug discovery. We are in the process of preparing a
large library of oxazol-thiazole bis-heterocyclic compounds. The
screening results will be reported elsewhere.
solution was cooled to 0 °C, and a solution of DIC (10 mmol,
1.7 mL) was added. After the solution was stirred at 0 °C for 1
h, a solution of L-Ser-OMe·HCl (10 mmol, 1.56 g) was added
and the solution was stirred at room temperature for another 8
h. After filtration and removal of the solvent on rotavap, the
residue was dissolved in ethylacetate and washed with 10%
citric acid (50 mL) followed by saturated NaHCO3(aq)
solution and water wash. The organic extract was dried over
MgSO4 followed by evaporation of the organic solvent obtain
the hydroxy peptide 2a and is used for the next step without
any further purification.
Synthesis of Methyl 2-(1-(tert-Butoxycarbonylamino)-
3-methylbutyl)oxazole-4-carboxylate (3a). Diethylamino-
sulfur trifluoride (DAST) (10 mmol, 1.34 mL) was added
dropwise to the solution of β-hydroxy peptide (2a, obtained
from previous step) in CH2Cl2 at −78 °C (acetone−dryice
bath). After completion of cyclization (monitered by TLC), the
reaction mixture was allowed to warm to 0 °C and
bromotrichloromethane (BrCCl3) (10 mmol, 0.97 mL) was
added dropwise, followed by DBU (10 mmol, 1.5 mL). The
reaction was monitered by TLC till completion and then
quenched with saturated NaHCO3(aq) solution. The reaction
mixture was extracted with EtOAc and dried over MgSO4,
EXPERIMENTAL SECTION
■
Synthesis of Methyl 2-(2-(tert-Butoxycarbonylamino)-
4-methylpentanamido)-3-hydroxy Propanoate (2a). Dii-
sopropylethylamine (10 mmol, 1.8 mL) was added to a solution
of Boc-L-leucine (1a) (10 mmol, 2.49 g) in DCM (8 mL). The
C
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1
filtered, and concentrated on rotavap. Purification of the residue
by flash chromatography (5−10% ethyl acetate in hexane) gave
the desired oxazole ester 3a in 68% yield.
64% yield. H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 3H),
0.88 (s, 3H), 1.37 (s, 9H), 3.74 (s, 1H), 4.51 (brs, 1H), 7.49
(brs, 1H), 8.31 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ
19.0, 19.3, 28.6, 54.6, 60.1, 78.8, 115.4, 125.6, 138.6, 141.1,
155.7, 164.0. ESI-MS: 307 (M + Na). HRMS (ESI-TOF) m/z:
(M + H) calcd for C13H21N2O5, 285.1450; found, 285.1448.
(S)-2-(1-(tert-Butoxycarbonylamino)-2-phenylethyl)-
oxazole-4-carboxylic Acid (4d). A white powder: 1.85 g,
Synthesis of 2-(1-(tert-Butoxycarbonylamino)-3-
methylbutyl)oxazole-4-carboxylic acid (4a). Oxazole
ester 3a (6.8 mmol, 2.31 g) was dissolved in dioxane (12
mL) and added to a 1N NaOH(aq) solution (18 mL) slowly
with the help of a dropping funnel while the solution stirred at
0 °C. The reaction was monitered by TLC till the starting
material disappeared and acidified with 10% KHSO4 to pH 5
followed by removal of the organic solvent in vacuo. Then the
residue is diluted with water and extracted with ethylacetate (3
× 40 mL). Organic fractions were combined and dried over
MgSO4 followed by evaporation of the organic solvent. The
crude product obtained was washed with hexane to get a white
solid in 93% yield.
General Procedure for the Solid-Phase Parallel Syn-
thesis of Oxazol-Thiazole Bis-Heterocycles (8−12 f, g, h,
i). A 20 set of 50 mg sealed polypropylene mesh bags
containing p-methylbenzhydrylamine hydrochloride salt
(MBHA) resin (1.15 m equiv/g, 100−200 mesh) was
prepared.15b Reactions were carried out by placing all the
bags in polyethylene bottles. The bags (containing resin) were
washed with dichloromethane (DCM), isopropanol and DCM
in a sequence followed by the neutralization with 5%
diisopropylethylamine (DIEA) in DCM. Boc-Oxazole amino
acid (4) (2 equiv) was coupled using the conventional reagents
hydroxybenzotriazole (HOBt, 2 equiv) and diisopropylcarbo-
diimide (DIC, 2 equiv) in anhydrous DMF with shaking for
overnight. Completion of the coupling was monitored by the
ninhydrin test.17
Following the removal of the Boc group with 55% TFA/
DCM for 30 min and neutralization with 5% DIEA/DCM, the
solution was treated with Fmoc-NCS to obtain thiourea and the
completion was monitored by the ninhydrin test. Then the
Fmoc group was deprotected with 20% piperidine in DMF (2
× 10 min) and the bags were divided into four sets and treated
with α-haloketones to at 80 °C for overnight. The resin was
then washed with DMF (3×), and DCM (3×) followed by a
HF cleave,18 which provided the desired oxazol-thiazole bis-
heterocycles. All the prodcuts were confirmed by LC-MS and
NMR analysis.
(S)-2-(1-(tert-Butoxycarbonylamino)-3-methylbutyl)-
oxazole-4-carboxylic Acid (4a). A white powder: 1.87 g,
63% yield. 1H NMR (400 MHz, CDCl3): δ 0.87−0.90 (m, 6H),
1.33 (s, 9H), 1.56−1.61 (m, 1H), 1.67−1.70 (m, 2H), 4.96 (d,
1H, J = 8.0 Hz), 6.04 (brs, 1H), 8.20 (s, 1H), 10.77 (brs, 1H).
13C NMR (100 MHz, CDCl3): δ 22.0, 22.5, 24.7, 28.3, 43.2,
47.5, 80.0, 133.2, 144.5, 155.6, 163.8, 167.7. ESI-MS: 321 (M +
Na). HRMS (ESI-TOF): calcd for C14H23N2O5 (M + H+),
299.1607; found, 299.1602.
1
56% yield. H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 3.24
(d, 2H, J = 6.8 Hz), 5.26 (d, 1H, J = 7.6 Hz), 5.99 (brs, 1H),
7.09 (d, 2H, J = 6.0 Hz), 7.27−7.31 (m, 3H), 8.20 (s, 1H),
11.53 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ 28.2, 40.4,
50.4, 67.0, 80.3, 126.8, 127.1, 128.6, 133.2, 135.7, 144.7, 155.3,
164.0, 166.1. ESI-MS: 355 (M + Na). HRMS (ESI-TOF) m/z:
(M + H) calcd for C17H21N2O5, 333.1450; found, 333.1447.
(S)-2-(1-(tert-Butoxycarbonylamino)-2-(4-
hydroxyphenyl)ethyl)oxazole-4-carboxylic Acid (4e). A
white powder: 1.67 g, 48% yield. 1H NMR (400 MHz, DMSO-
d6): δ 1.37 (s, 9H), 2.56 (s, 1H), 2.94−3.00 (m, 1H), 3.08−
3.13 (m, 1H), 4.84 (d, 1H, J = 6.8 Hz), 6.69 (d, 2H, J = 8.0
Hz), 7.03 (d, 2H, J = 8.0 Hz), 8.66 (s, 1H). 13C NMR (100
MHz, DMSO-d6): δ 28.6, 50.8, 63.0, 78.8, 115.4, 127.7, 130.5,
132.4, 141.5, 155.5, 156.3, 162.6, 165.0. ESI-MS: 371 (M +
Na). HRMS (ESI-TOF) m/z: (M + H) calcd for C17H21N2O6,
349.1400; found, 349.1397.
(S)-2-(1-(4-tert-Butylthiazol-2-ylamino)-3-
methylbutyl)oxazole-4-carboxamide (8f). A white powder:
15.1 mg, 78% yield. H NMR (400 MHz, CDCl3): δ 0.96 (d,
1
3H, J = 8.0 Hz), 0.98 (d, 3H, J = 8.0 Hz), 1.22 (s, 9H), 1.71 (m,
1H), 1.84 (m, 2H), 4.90 (t, 1H, J = 7.0 Hz), 5.58 (brs, 1H),
5.86 (brs, 1H), 6.07 (s, 1H), 6.80 (brs, 1H), 8.16 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 22.3, 22.5, 24.7, 29.6, 34.6, 43.5,
52.1, 98.8, 135.6, 141.6, 162.5, 162.7, 164.7, 166.9. ESI-MS: 359
(M + Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C16H25N4O2S, 337.1698; found, 337.1695.
(S)-2-(3-Methyl-1-(4-phenylthiazol-2-ylamino)butyl)-
oxazole-4-carboxamide (8g). A white powder: 12.7 mg,
62% yield. 1H NMR (400 MHz, CDCl3): δ 0.99 (t, 6H, J = 6.4
Hz), 1.74 (m, 1H), 1.86 (m, 2H), 5.03 (t, 1H, J = 7.2 Hz), 5.78
(brs, 2H), 6.71 (s, 1H), 6.79 (brs, 1H), 7.28 (d, 1H, J = 7.2
Hz), 7.36 (t, 2H, J = 7.2 Hz), 7.77 (d, 2H, J = 7.2), 8.17 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 22.2, 22.5, 24.8, 43.4,
52.1, 101.7, 126.0, 127.8, 128.6, 134.6, 135.7, 141.8, 151.4,
162.5, 164.5, 167.5. ESI-MS: 379 (M + Na). HRMS (ESI-
TOF) m/z: (M + H) calcd for C18H21N4O2S, 357.1385; found,
357.1383.
(S)-2-(1-(4-(3,4-Dihydroxyphenyl)thiazol-2-ylamino)-
3-methylbutyl)oxazole-4-carboxamide (8h). A white
powder: 15.2 mg, 68% yield. H NMR (400 MHz, MeOH-
1
d4): δ 0.93 (d, 3H, J = 6.4 Hz), 0.96 (d, 3H, J = 6.4 Hz), 1.68
(m, 1H), 1.76 (m, 1H), 1.87 (m, 1H), 5.15 (dd, 1H, J1 = 14.0
Hz, J2 = 8.0 Hz), 6.70 (d, 1H, J = 8.4 Hz), 6.72 (s, 1H), 7.05
(dd, 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.18 (d, 1H, J = 2.0 Hz), 7.44
(brs, 1H), 7.54 (brs, 1H), 8.13 (d, 1H, J = 8.0 Hz), 8.51 (s,
1H), 8.86 (brs, 1H), 8.93 (brs, 1H). 13C NMR (100 MHz,
MeOH-d4): δ 22.3, 23.0, 24.8, 31.1, 42.5, 50.8, 99.1, 113.8,
116.0, 117.5, 127.1, 136.6, 142.2, 145.4, 145.5, 150.6, 162.3,
165.0, 167.1. ESI-MS: 411 (M + Na). HRMS (ESI-TOF) m/z:
(M+ H) calcd for C18H21N4O4S, 389.1284; found, 389.1279.
(S)-2-(1-(4-Adamantylthiazol-2-ylamino)-3-
methylbutyl)oxazole-4-carboxamide (8i). A white powder:
(S)-2-(1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)oxazole-
4-carboxylic Acid (4b). A white powder: 1.66 g, 59% yield.
1H NMR (400 MHz, CDCl3): δ 1.28, 1.42 (2xs, 9H), 1.91−
1.95 (m, 1H), 1.99−2.06 (m, 2H), 2.10−2.13 (m, 1H), 3.44−
3.63 (m, 2H), 4.98, 5.08 (2xbrs, 1H), 8.18, 8.23 (2xs, 1H), 8.96
(brs, 1H). 13C NMR (100 MHz, CDCl3): δ 28.2, 28.4, 31.3,
32.5, 46.5, 46.8, 54.5, 54.8, 80.5, 138.7, 143.9, 154.0, 154.6,
164.0, 166.0, 166.4. ESI-MS: 305 (M + Na). HRMS (ESI-
TOF) m/z: (M + H) calcd for C13H19N2O5, 283.1294; found,
283.1291.
1
(S)-2-(1-(tert-Butoxycarbonylamino)-2-methylpropyl)-
oxazole-4-carboxylic Acid (4c). A white powder: 1.81 g,
13.32 mg, 56% yield. H NMR (400 MHz, CDCl3): δ 0.95−
0.99 (m, 6H), 1.69−1.86 (m, 15H), 2.03 (brs, 3H), 4.82 (t, 1H,
D
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J = 7.2 Hz), 5.74 (brs, 1H), 6.04 (s, 1H), 6.81 (brs, 1H), 8.16
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 21.6, 21.9, 24.1, 27.9,
35.8, 36.2, 41.1, 42.7, 51.9, 98.0, 135.1, 141.2, 161.8, 163.6,
166.8. ESI-MS: 437 (M + Na). HRMS (ESI-TOF) m/z: (M +
H) calcd for C22H31N4O2S, 415.2168; found, 415.2156.
(S)-2-(1-(4-tert-butylthiazol-2-yl)pyrrolidin-2-yl)-
oxazole-4-carboxamide (9f). A white powder: 15.8 mg, 86%
yield. 1H NMR (400 MHz, CDCl3): δ 1.19 (s, 9H), 2.14−2.18
(m, 1H), 2.25−2.30 (m, 2H), 2.42−2.45 (m, 1H), 3.57 (q, 1H,
J = 8.0 Hz), 3.73 (t, 1H, J = 8.0 Hz), 5.78 (brs, 1H), 6.82 (s,
1H), 6.08 (brs, 1H), 8.12 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 24.4, 29.4, 32.0, 34.6, 50.4, 57.8, 98.8, 135.7, 141.5,
162.6, 164.4, 165.9. ESI-MS: 343 (M + Na). HRMS (ESI-
TOF) m/z: (M + H) calcd for C15H21N4O2S, 321.1385; found,
321.1376.
7.77 (d, 2H, J = 7.2 Hz), 8.19 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 18.5, 18.7, 32.9, 59.3, 101.7, 126.0, 127.8, 128.5,
134.6, 135.6, 141.8, 151.4, 162.4, 163.7, 167.8. ESI-MS: 365 (M
+ Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C17H19N4O2S, 343.1229; found, 343.1221.
(S)-2-(1-(4-(3,4-Dihydroxyphenyl)thiazol-2-ylamino)-
2-methylpropyl)oxazole-4-carboxamide (10h). A white
powder: 13.1 mg, 61% yield. 1H NMR (400 MHz, MeOH-d4):
δ 0.89 (d, 3H, J = 6.8 Hz), 1.04 (d, 3H, J = 6.8 Hz), 2.26 (t, 1H,
J = 6.8 Hz), 4.87 (t, 1H, J = 7.6 Hz), 6.69 (d, 1H, J = 8.4 Hz),
6.71 (s, 1H), 7.04 (dd, 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.18 (s,
1H), 7.45 (brs, 1H), 7.52 (brs, 1H), 8.13 (t, 1H, J = 6.8 Hz),
8.52 (s, 1H), 8.85 (s, 1H), 8.92 (s, 1H). 13C NMR (100 MHz,
MeOH-d4): δ 19.4, 19.5, 32.3, 58.5, 99.2, 113.8, 115.9, 117.5,
127.1, 136.5, 142.2, 145.4, 150.4, 162.3, 163.5, 164.4, 167.4.
ESI-MS: 397 (M + Na). HRMS (ESI-TOF) m/z: (M + H)
calcd for C17H19N4O4S, 375.1127; found, 375.1117.
(S)-2-(1-(4-Phenylthiazol-2-yl)pyrrolidin-2-yl)oxazole-
4-carboxamide (9g). A white powder: 13.5 mg, 69% yield. 1H
NMR (400 MHz, CDCl3): δ 2.16−2.20 (m, 1H), 2.27−2.32
(m, 2H), 2.41−2.45 (m, 1H), 3.57−3.63 (dd, 1H, J1 = 9.2 Hz,
J2 = 7.6 Hz), 3.77−3.81 (m, 1H), 5.18−5.21 (q, 1H, J = 8.0
Hz), 5.65 (brs, 1H), 6.71 (s, 1H), 6.81 (brs, 1H), 7.25 (d, 1H, J
= 5.2 Hz), 7.33 (t, 2H, J = 7.2 Hz), 7.73 (d, 2H, J = 7.2 Hz),
8.16 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 24.3, 32.1, 50.2,
57.7, 101.4, 126.0, 127.6, 128.5, 134.9, 135.8, 152.1, 162.6,
164.6, 166.4. ESI-MS: 363 (M + Na). HRMS (ESI-TOF) m/z:
(M + H) calcd for C17H17N4O2S, 341.1072; found, 341.1065.
(S)-2-(1-(4-(3,4-Dihydroxyphenyl)thiazol-2-yl)-
pyrrolidin-2-yl)oxazole-4-carboxamide (9h). A white
(S)-2-(1-(4-Adamantylthiazol-2-ylamino)-2-
methylpropyl)oxazole-4-carboxamide (10i). A white
1
powder: 13.6 mg, 59% yield. H NMR (400 MHz, CDCl3): δ
0.97 (d, 3H, J = 6.8 Hz), 1.05 (d, 3H, J = 6.8 Hz), 1.74 (m,
6H), 1.86 (d, 6H, J = 2.8 Hz), 2.03 (brs, 3H), 2.29 (m, 1H),
4.61 (d, 1H, J = 6.0 Hz), 5.71 (brs, 2H), 6.03 (s, 1H), 6.80 (brs,
1H), 8.17 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 18.5, 18.7,
28.5, 32.9, 36.5, 36.8, 41.8, 59.7, 98.7, 135.6, 141.7, 162.4,
163.1, 163.8, 167.7. ESI-MS: 423 (M + Na). HRMS (ESI-
TOF) m/z: (M + H) calcd for C21H29N4O2S, 401.2011; found,
401.1998.
1
powder: 15.4 mg, 72% yield. H NMR (400 MHz, MeOH-
(S)-2-(1-(4-tert-Butylthiazol-2-ylamino)-2-
d4): δ 2.12 (m, 3H), 2.15 (m, 1H), 3.51 (m, 1H), 3.67 (m, 1H),
5.10 (dd, 1H, J1 = 8.0 Hz, J2 = 3.2 Hz), 6.68 (d, 1H, J = 8.4 Hz),
6.83 (s, 1H), 7.04 (dd, 1H, J1 = 8.0 Hz, J2 = 2.0 Hz), 7.17 (s,
1H), 7.45 (s, 1H), 7.59 (s, 1H), 8.50 (s, 1H), 8.86 (brs, 1H),
8.95 (brs, 1H). 13C NMR (100 MHz, MeOH-d4): δ 24.4, 32.4,
50.6, 57.8, 99.8, 113.9, 115.9, 117.7, 127.6, 136.8, 142.4, 145.4,
145.6, 151.7, 162.3, 164.6, 166.1. ESI-MS: 373 (M + H).
HRMS (ESI-TOF) m/z: (M + H) calcd for C17H17N4O4S,
373.0971; found, 373.0966.
phenylethyl)oxazole-4-carboxamide (11f). A white pow-
der: 17.4 mg, 82% yield. H NMR (400 MHz, CDCl3): δ 1.23
1
(s, 9H), 3.35 (d, 2H, J = 5.2 Hz), 5.22 (brs, 1H), 5.78 (brs,
1H), 5.92 (brs, 1H), 6.07 (s, 1H), 6.78 (brs, 1H), 7.05 (d, 2H, J
= 7.6 Hz), 7.24 (d, 3H, J = 7.2 Hz), 8.12 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 29.5, 34.6, 54.5, 98.7, 126.9, 128.5,
129.2, 135.8, 136.0, 141.3, 162.5, 162.6, 163.7, 166.1. ESI-MS:
393 (M + Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C19H23N4O2S, 371.1542; found, 371.1531.
(S)-2-(2-Phenyl-1-(4-phenylthiazol-2-ylamino)ethyl)-
oxazole-4-carboxamide (11g). A white powder: 15.9 mg,
71% yield. 1H NMR (400 MHz, CDCl3): δ 3.39 (d, 2H, J = 6.4
Hz), 5.38 (t, 1H, J = 6.4 Hz), 6.19 (brs, 1H), 6.40 (brs, 1H),
6.72 (s, 1H), 6.85 (brs, 1H), 7.10 (d, 2H, J = 6.0 Hz), 7.26 (t,
3H, J = 7.2 Hz), 7.35 (t, 3H, J = 7.2 Hz), 7.77 (d, 2H, J = 7.2
Hz), 8.15 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 54.3, 101.7,
125.9, 127.0, 127.6, 128.4, 128.5, 129.2, 134.7, 135.8, 141.5,
151.1, 162.4, 163.6, 166.7. ESI-MS: 413 (M + Na). HRMS
(ESI-TOF) m/z: (M + H) calcd for C21H19N4O2S, 391.1229;
found, 391.1218.
(S)-2-(1-(4-Adamantylthiazol-2-yl)pyrrolidin-2-yl)-
oxazole-4-carboxamide (9i). A white powder: 15.3 mg, 67%
1
yield. H NMR (400 MHz, CDCl3): δ 1.75 (m, 12H), 1.99 (s,
3H), 2.14 (m, 1H), 2.26 (m, 2H), 2.41 (m, 1H), 3.52 (q, 1H, J
= 7.2 Hz), 3.68 (m, 1H), 5.09 (m, 1H), 5.67 (brs, 1H), 6.01 (s,
1H), 6.82 (brs, 1H), 8.12 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 24.4, 28.6, 28.7, 32.0, 36.6, 37.0, 50.1, 57.6, 98.3,
135.6, 141.4, 162.7, 164.0, 165.0, 165.8. ESI-MS: 421 (M +
Na). HRMS (ESI-TOF) m/z: (M+ H) calcd for C21H27N4O2S,
399.1855; found, 399.1850.
(S)-2-(1-(4-tert-Butylthiazol-2-ylamino)-2-
methylpropyl)oxazole-4-carboxamide (10f). A white
powder: 13.1 mg, 71% yield. H NMR (400 MHz, CDCl3): δ
(S)-2-(1-(4-(3,4-Dihydroxyphenyl)thiazol-2-ylamino)-
1
2-phenylethyl)oxazole-4-carboxamide (11h). A white
1
0.94 (d, 3H, J = 6.8 Hz), 1.07 (d, 3H, J = 6.8 Hz), 1.17 (s, 9H),
2.28 (m, 1H), 4.78 (d, 1H, J = 7.2 Hz), 6.11 (s, 1H), 8.29 (s,
1H). 13C NMR (100 MHz, MeOH-d4): δ 17.8, 17.9, 28.5, 32.3,
34.0, 58.9, 98.0, 135.6, 141.6, 161.2, 163.9, 164.9, 168.0. ESI-
MS: 345 (M + Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C15H23N4O2S, 323.1542; found, 323.1532.
(S)-2-(2-Methyl-1-(4-phenylthiazol-2-ylamino)propyl)-
oxazole-4-carboxamide (10g). A white powder: 12.6 mg,
64% yield. 1H NMR (400 MHz, CDCl3): δ 1.08 (d, 3H, J = 6.8
Hz), 1.07 (d, 3H, J = 6.8 Hz), 2.35 (q, 1H, J = 6.8 Hz), 4.83
(brs, 1H), 5.66 (brs, 1H), 5.74 (brs, 1H), 6.71 (s, 1H), 6.78
(brs, 1H), 7.28 (d, 1H, J = 7.2 Hz), 7.36 (t, 2H, J = 7.2 Hz),
powder: 20.6 mg, 85% yield. H NMR (400 MHz, MeOH-
d4): δ 3.29 (d, 2H, J = 7.6 Hz), 5.25 (q, 1H, J = 7.6 Hz), 6.69
(d, 1H, J = 8.4 Hz), 6.72 (s, 1H), 7.05 (dd, 1H, J1 = 8.0 Hz, J2 =
2.4 Hz), 7.19 (m, 2H), 7.25 (m, 4H), 7.45 (brs, 1H), 7.52 (brs,
1H), 8.31 (d, 1H, J = 8.0 Hz), 8.50 (s, 1H), 8.86 (s, 1H), 8.93
(s, 1H). 13C NMR (100 MHz, MeOH-d4): δ 54.3, 99.4, 113.9,
116.0, 117.5, 127.0, 127.1, 128.8, 129.6, 136.6, 137.6, 142.3,
145.4, 145.5, 150.6, 162.2, 163.5, 164.2, 166.8. ESI-MS: 423 (M
+ H+). HRMS (ESI-TOF) m/z: (M + H) calcd for
C21H19N4O4S, 423.1127; found, 423.1115.
(S)-2-(1-(4-Adamantylthiazol-2-ylamino)-2-
phenylethyl)oxazole-4-carboxamide (11i). A white pow-
E
dx.doi.org/10.1021/co400133a | ACS Comb. Sci. XXXX, XXX, XXX−XXX

ACS Combinatorial Science
Research Article
der: 16.2 mg, 63% yield. 1H NMR (400 MHz, CDCl3 +
DMSO-d6): δ 1.72 (s, 6H), 1.85 (s, 6H), 2.01 (s, 3H), 3.35 (d,
2H, J = 7.2 Hz), 5.17 (d, 1H, J = 7.2 Hz), 6.03 (s, 1H), 6.14
(brs, 1H), 6.82 (brs, 1H), 7.06 (d, 2H, J = 6.8 Hz), 7.23 (m,
3H), 7.32 (d, 1H, J = 6.8 Hz), 8.13 (s, 1H). 13C NMR (100
MHz, CDCl3 + DMSO-d6): δ 28.5, 36.5, 36.8, 41.7, 54.7, 98.7,
127.0, 128.5, 129.2, 135.8, 135.8, 141.5, 162.5, 163.6, 166.3.
ESI-MS: 471 (M + Na). HRMS (ESI-TOF) m/z: (M + H)
calcd for C25H29N4O2S, 449.2011; found, 449.1997.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the State of Florida for the financial support.
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(S)-2-(1-(4-tert-Butylthiazol-2-ylamino)-2-(4-
hydroxyphenyl)ethyl)oxazole-4-carboxamide (12f). A
1
white powder: 18.0 mg, 81% yield. H NMR (400 MHz,
CDCl3): δ 1.21 (s, 9H), 3.24 (d, 2H, J = 4.8 Hz), 5.10 (t, 1H, J
= 5.2 Hz), 6.06 (s, 1H), 6.14 (brs, 1H), 6.71 (d, 2H, J = 6.8
Hz), 6.84 (d, 2H, J = 6.8 Hz), 7.34 (s, 1H), 8.12 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 29.5, 34.6, 38.9, 54.8, 98.7, 115.6,
126.2, 130.2, 135.7, 141.3, 156.2, 162.5, 163.9, 166.4. ESI-MS:
409 (M + Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C19H23N4O3S, 387.1491; found, 387.1480.
(S)-2-(2-(4-Hydroxyphenyl)-1-(4-phenylthiazol-2-
ylamino)ethyl)oxazole-4-carboxamide (12g). A white
1
powder: 14.9 mg, 64% yield. H NMR (400 MHz, MeOH-
d4): δ 3.25 (dd, 2H, J1 = 7.6 Hz, J2 = 2.6 Hz), 5.29 (t, 1H, J =
7.2 Hz), 6.66 (d, 2H, J = 8.4 Hz), 6.82 (s, 1H), 6.98 (d, 2H, J =
8.4 Hz), 7.22 (t, 1H, J = 7.2 Hz), 7.31 (t, 2H, J = 7.2 Hz), 7.72
(d, 2H, J = 7.2 Hz). 13C NMR (100 MHz, MeOH-d4): δ 38.4,
54.6, 101.2, 114.9, 125.6, 127.1, 127.2, 128.0, 129.9, 134.9,
135.6, 141.7, 150.7, 156.0, 163.9, 164.7, 167.7. ESI-MS: 429 (M
+ Na). HRMS (ESI-TOF) m/z: (M + H) calcd for
C21H19N4O3S, 407.1178; found, 407.1166.
(S)-2-(1-(4-(3,4-Dihydroxyphenyl)thiazol-2-ylamino)-
2-(4-hydroxyphenyl)ethyl)oxazole-4-carboxamide
1
(12h). A white powder: 19.2 mg, 76% yield. H NMR (400
MHz, MeOH-d4): δ 3.16 (d, 2H, J = 8.0 Hz), 5.15 (q, 1H, J =
7.6 Hz), 6.64 (d, 1H, J = 8.4 Hz), 6.69 (d, 1H, J = 8.0 Hz), 6.71
(s, 1H), 7.00−7.06 (m, 3H), 7.18 (s, 1H), 7.44 (brs, 1H), 7.52
(brs, 1H), 8.25 (d, 1H, J = 7.2 Hz), 8.48 (s, 1H), 8.86 (s, 1H),
8.93 (s, 1H), 9.23 (s, 1H). 13C NMR (100 MHz, MeOH-d4): δ
38.6, 54.6, 99.3, 113.8, 115.6, 115.9, 117.5, 127.1, 127.5, 130.5,
136.5, 142.2, 145.4, 150.6, 156.5, 162.3, 163.5, 164.4, 166.8.
ESI-MS: 439 (M + Na). HRMS (ESI-TOF) m/z: (M + H)
calcd for C21H19N4O5S, 439.1076; found, 439.1072.
(S)-2-(1-(4-Adamantylthiazol-2-ylamino)-2-(4-
hydroxyphenyl)ethyl)oxazole-4-carboxamide (12i). A
1
white powder: 18.1 mg, 68% yield. H NMR (400 MHz,
MeOH-d4): δ 1.74 (m, 6H), 1.83 (s, 6H), 1.97 (s, 3H), 3.21
(m, 2H), 511 (t, 1H, J = 7.2 Hz), 6.04 (s, 1H), 6.64 (d, 2H, J =
8.4 Hz), 6.94 (d, 2H, J = 8.4 Hz), 8.24 (s, 1H). 13C NMR (100
MHz, MeOH-d4): δ 28.7, 36.2, 36.6, 38.5, 41.5, 54.9, 98.0,
114.8, 127.3, 129.9, 135.6, 141.6, 156.0, 162.2, 163.9, 164.8,
167.3. ESI-MS: 487 (M + Na). HRMS (ESI-TOF) m/z: (M +
H) calcd for C25H29N4O3S, 465.1960; found, 465.1943.
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ASSOCIATED CONTENT
■
S
* Supporting Information
General information and copies of H and 13C NMR spectra
1
and LC-MS and HR-MS chromatograms for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*A. Nefzi. adeln@tpims.org.
■
F
dx.doi.org/10.1021/co400133a | ACS Comb. Sci. XXXX, XXX, XXX−XXX

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