Synthesis of chiral polyaminothiazoles

Full text of DOI:10.1021/cc9001907

J. Comb. Chem. 2010, 12, 315–317
315
acid 1. Following reduction of the amide bonds in the
presence of borane-THF,16 the corresponding resin-bound
diamines 2 were treated with Fmoc-isothiocyanate to
generate the corresponding dithioureas 3. Following Fmoc
deprotection, the resin-bound dithioureas were treated with
a variety of R-halogenoketones to afford following cleav-
age of the solid-support, the desired diaminothiazoles 5.
The compounds were obtained in good yield (80 to 90%)
and high purity (Table 1). The only byproduct observed
was the monothiazole due to an incomplete reaction of
the amine attached to the solid-support with Fmoc-
isothiocyanate. We selected three amino acids, alanine,
proline, valine, and phenylalanine, and three different
halogenoketones, chloroacetone, 3-chloro-2-butanone, and
2-chlorocyclohexanone. Similar results were obtained with
all the amino acids utilized and we did not observe any
detrimental effect of the amino acid side chains on the
reaction. Some incomplete reaction was observed with the
2-chlorocyclohexanone.
Synthesis of Chiral Polyaminothiazoles
Sergey Arutyunyan and Adel Nefzi*
Torrey Pines Institute for Molecular Studies, 11350 SW
Village Parkway, Port Saint Lucie, Florida 34987
ReceiVed December 18, 2009
The thiazole ring system is an important structural
element found in numerous biologically active com-
pounds.1 These have found applications in the develop-
ment and preparation of drugs for the treatment of
allergies,2 inflammation,3 schizophrenia,4 hypertension,5
and bacterial infections.6 Compounds containing the
aminothiazole moiety are also known to be a ligand of
estrogen receptors7 and adenosine receptor antagonists,8
while other analogues exhibit antitumor properties.9
Moreover, thiazole derivatives are reported to be potential
inhibitors of cyclin-dependent kinases (CDKs)10 and
glycogen synthase kinase-3 (GSK-3).11 2-Aminothiazoles
were successfully employed as heterocyclic bioisosteres
of the phenol moiety on dopamine agonists and the widely
used anti-Parkinsonian agent pramipexole. These resulted
in improved pharmacological properties including longer
duration of action and improved bioavailability.12 Con-
jugated polyaminothiazole films were reported to display
electrochemical properties with high thermal stability.13
Herein, we describe an efficient approach for the parallel
synthesis of diversified oligoaminothiazoles. Starting from
resin-bound peptides, a range of differing oligothiazoles
were synthesized.
The same approach was employed for the synthesis of
different lengths of chiral polyaminothiazoles from their
corresponding resin-bound chiral polyamines.17 Table 2
shows examples of tetrathiazoles obtained from resin-bound
tripeptides. All compounds were analyzed by LC-MS and
Thiourea is known to be a convenient starting material
to prepare 2-amino-1,3-thiazoles.14,15 Our approach using
Hantzsc’s synthesis for the solid-phase synthesis of a
variety of diaminothiazoles is outlined in Scheme 1. The
parallel synthesis was performed starting from p-methyl-
benzhydrylamine (MBHA) resin bound acylated amino
1
selected ones by H NMR and 13C NMR.
Because of the well-understood chemistry, the availability
of a wide diversity of chiral amino acids and the excellent
synthetic purity and yields obtained during the solid-phase
synthesis of peptides, the work presented offers a unique
approach toward the synthesis of chiral polyaminothiazoles
using resin-bound amino acids, peptides, and peptidomimet-
ics as starting materials.
* To whom correspondence should be addressed. E-mail:
adeln@tpims.org.
Scheme 1a
a (a) BH3-THF, 65°C, 4 days; (b) piperidine, 65°C, overnight; (c) 6 equiv Fmoc-NCS in DMF (0.3 M), RT, overnight; (d) 20% piperidine/DMF; (e) 20
equiv R-halogenoketones in DMF (0.3 M), 70°C, overnight; (f) HF/anisole, 0°C, 90 min.
10.1021/cc9001907  2010 American Chemical Society
Published on Web 03/10/2010

316 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3
Table 1. Individual Products of Dithiazolo Derivatives
Reports
entry
R1
R2
R3
R4
MW obtaineda
purity (%)b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
-CH3
-H
-H
-H
-H
-H
-H
-H
-H
-H
-CH3
-CH3
-H
269.08 (MH+)
297.11 (MH+)
349.19 (MH+)
345.13 (MH+)
373.15 (MH+)
425.24 (MH+)
297.10 (MH+)
325.14 (MH+)
377.25 (MH+)
297.08 (MH+)
325.11 (MH+)
401.17 (MH+)
453.17 (MH+)
373.17 (MH+)
401.13 (MH+)
477.20 (MH+)
529.30 (MH+)
325.13 (MH+)
353.15 (MH+)
429.21 (MH+)
481.28 (MH+)
322.13 (MH+)
88
84
85
91
86
82
90
88
85
92
87
89
84
90
92
88
84
93
85
89
87
94
-CH3
-CH3
-CH3
-(CH2)4-
-(CH2)4-
-(CH2)4-
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH(CH3)2
-CH(CH3)2
-CH(CH3)2
-CH3
-CH3
-CH3
-H
-CH3
-CH3
-CH3
-H
-CH3
-CH2CH3
-CH3
-CH3
-CH3
-H
-CH3
-CH3
-CH3
-CH2CH3
-CH3
-CH2CH2C6H5
-CH2CH2C6H5
-CH2CH3
-CH3
-(CH2)4-
-(CH2)4
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH(CH3)2
-CH(CH3)2
-CH(CH3)2
-CH(CH3)2
-CH3
-CH3
-CH3
-H
-CH3
-CH3
-CH2CH3
-CH2CH2C6H5
-CH2CH2C6H5
-CH2CH3
-CH3
-CH3
-CH3
-H
-CH3
-CH3
-CH2CH3
-CH2CH2C6H5
-CH2CH2C6H5
5t
5u
5v
-(CH2)4-
c
-(CH2)3 -
-CH3
-CH3
a Determined by ESI-MS. b The products were run on a Vydac column, gradients 5-95% formic acid in ACN in 7 min. The purity was estimated on
analytical traces at λ ) 214 and 254 nm. c Derived from proline.
Table 2. Individual Products of Tetrathiazole Derivatives
entry
R1
R2
R3
MW obtaineda
purity (%)b
PT-1
PT-2
PT-3
PT-4
PT-5
PT-6
PT-7
-CH2C6H5
-CH2C6H5
-CH2CH(CH3)2
-CH2CH(CH3)2
-(CH2C6H5
-CH2CH(CH3)2
-CH2C6H5
-CH2CH(CH3)2
-(CH2CH(CH3)2
771 (MH+)
787 (MH+)
771 (MH+)
737 (MH+)
821 (MH+)
787 (MH+)
752 (MH+)
83
85
88
85
88
85
82
-CH2C6H5
-CH2C6H4OH
-CH2CH(CH3)2
-CH2CH(CH3)2
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H4OH
-CH2C6H4OH
-CH2C6H4OH
-CH2C6H5
-CH2CH(CH3)2
a Determined by ESI-MS. b The products were run on a Vydac column, gradients 5-95% formic acid in ACN in 7 min. The purity was estimated on
analytical traces at λ ) 214 and 254 nm.
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Acknowledgment. The authors would like to thank the
State of Florida Funding, NIH (1R03DA025850-01A1,
Nefzi), NIH (5P41GM081261-03, Houghten), and NIH
(3P41GM079590-03S1, Houghten) for their financial support.
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A. P. J. Med. Chem. 2001, 44, 749–762.
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1988, 23, 501.
Supporting Information Available. Structures of all the
1
compounds, LC-MS, ES, and H NMR of some dithiaz-
oles, and LC-MS of all the tetrathiazoles. This information
is available free of charge via the Internet at http://
pubs.acs.org/.
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10, 215–230.
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Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 3 317
(15) Lin, P. Y.; Hou, R. S.; Wang, H. M.; Kang, I. J.; Chen, L. C.
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timesx10 minutes) followed by the addition of R-halogenoke-
tones (20 equiv, 0.3 M in DMF). The reaction with R-halo-
genoketones was carried out at 70°C overnight. The cleavage
of the product was carried out by the treatment with 100%
anhydrous HF at 00C for 1.5 h, followed by nitrogen gas flow
to remove the HF. The product was extracted by 95% acetic
acid. After lyophilization, the products were characterized by
electrospray LC-MS under ESI conditions and selected
(17) General procedure for the synthesis of dithiazolo derivatives:
100 mg of MBHA resin (loading: 1.1 mmol/g) was sealed
within a polypropylene mesh packet.18 Reactions were carried
out in polypropylene bottles. A solution of N-Boc-amino acid
(6 equiv, 0.1 M in DMF), HOBt (6 equiv, 0.1 M in DMF),
and DIC (6 equiv, 0.1 M in DMF) was added to the reaction
vessel. The reaction mixture was shaken at room temperature
for 2 h, followed by washing with DMF (2 times) and DCM
(2 times). Upon removal of the Boc group with 55% TFA in
DCM for 30 min, the resin was washed and neutralized with
5% DIEA in DCM. The resin-bound amine was reacted with
carboxylic acid (10 equiv, 0.3 M in DMF), and DIC (10 equiv,
0.3 M in DMF) overnight, followed by washing with DMF
(2 times) and DCM (2 times). Air dried resin-bound acylated
peptide was reduced using BH3-THF. Typical reaction condi-
tions for the solid-phase reduction of polyamides consist of
the treatment of resin-bound peptides with BH3-THF at 65°C
for 72 h. The generated resin-bound borane-amine complexes
are then disproportionate following overnight treatment with
neat piperidine at 65°C. The reduction is free of racemization.
The generated amines were treated with Fmoc-isothiocyanate
(6 equiv, 0.3 M in DMF) at room temperature overnight. The
Fmoc group was removed with 20% piperidine in DMF (2
1
1
compounds by H. 5e: H-NMR (500 MHz, DMSO-d6) δ
(ppm) 7.17-7.34 (m, 5H), 3.95 (m, 1H), 3.25 (m, 2H), 3.40
(m, 2H) 2.87 (dd, J ) 5.6 Hz, J ) 13.8 Hz, 1H), 2.78 (dd, J
) 7.7 Hz, J ) 1.4 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.00
(s, 3H), 1.98 (s, 3H); MS (ESI) calcd [MH+] 373.14, found
1
373.3. 5f: H-NMR (500 MHz, DMSO-d6) δ (ppm) 7.16-
7.36 (m, 5H), 6.5 (s, 1H), 3.93 (m, 1H), 3.21 (m, 1H), 2.98
(m, 1H), 2.88 (dd, J ) 5.6 Hz, J ) 14.0 Hz, 1H), 2.78 (dd,
J ) 7.4 Hz, J ) 13.7 Hz, 1H), 2.46 (m, 4H), 2.38 (m, 4H),
1.7 (m, 8H); MS (ESI) calcd [MH+] 425.2, found 425.6. 5p:
1H-NMR (500 MHz, DMSO-d6) δ (ppm) 8.18 (s, 1H), 7.15-
7.30 (m, 10 H), 4.18 (m, 1H), 3.62 (m, 2H), 3.31 (m, 2H),
3.10 (m, 1H), 2.90 (dd, J ) 6 Hz, J ) 13.8 Hz, 1H), 2.75 (m,
1H), 2.63 (m, 1H), 2.49 (s, 3H), 2.07 (s, 3H), 1.97 (s, 3H);
MS (ESI) calcd [MH+] 477.2, found 477.7.
(18) Houghten, R. A Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
CC9001907