Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reactionand desulfanylation

Article abstract of DOI:10.3762/bjoc.7.123

Thirteen difluoromethyl-containing pseudopeptides were synthesized by Ugi reaction using the novel building block 2,2-difluoro-2- (phenylthio)acetic acid (2) as one component, followed by removal of the phenylsulfanyl protecting group in the presence of t

Full text of DOI:10.3762/bjoc.7.123

Novel synthesis of pseudopeptides bearing
a difluoromethyl group by Ugi reaction
and desulfanylation
Jingjing Wu, Hui Li and Song Cao*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1070–1074.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy,
East China University of Science and Technology, Shanghai 200237,
China
doi:10.3762/bjoc.7.123
Received: 07 April 2011
Accepted: 12 July 2011
Published: 08 August 2011
Email:
Song Cao* - scao@ecust.edu.cn
This article is part of the Thematic Series "Multicomponent reactions".
Guest Editor: T. J. J. Müller
* Corresponding author
Keywords:
difluoromethyl functionality; gem-difluoromethylene-containing acid;
pseudopeptides; reductive cleavage; Ugi reaction
© 2011 Wu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Thirteen difluoromethyl-containing pseudopeptides were synthesized by Ugi reaction using the novel building block 2,2-difluoro-2-
(phenylthio)acetic acid (2) as one component, followed by removal of the phenylsulfanyl protecting group in the presence of tri-
butyltin hydride and azobisisobutyronitrile.
Introduction
Fluorinated amino acids and pseudopeptides have increasingly methylene into molecules [14-18]. Only a few examples have
attracted attention in recent years [1-5]. The selective incorpor- been reported of the preparation and bioassay of pseudopep-
ation of fluorine-containing groups, such as trifluoromethyl, tides and peptidomimetics bearing difluoromethyl groups. For
difluoromethyl and difluoromethylene, into peptides or example, compound I can act as bradykinin B1 antagonist or
peptidomimetics often drastically alters the chemical, physical, inverse agonist and can be used in the prevention of inflamma-
and biological properties of the parent compounds [6-9]. Nowa- tion and pain [19]. Compound II is an inhibitor of microsomal
days, difluoromethyl-containing compounds are increasingly triglyceride transfer protein (MTP) and useful for the treatment
being applied in pharmaceuticals and agrochemicals [10-12]. It of obesity and atherosclerosis (Figure 1) [20].
is reported that difluoromethyl functionality (CF2H) is isosteric
and isopolar to the hydroxyl group and can behave as a Among the protocols for the preparation of pseudopeptide
hydrogen donor through hydrogen bonding [13].
derivatives, the Ugi four-component reaction offers significant
advantages over conventional linear-step synthesis [21].
However, to date, most fluorine-containing peptide modifica- Various fluorinated building blocks have been used in the Ugi
tions involve the introduction of trifluoromethyl or difluoro- four-component reaction to construct a fluorinated compound
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Beilstein J. Org. Chem. 2011, 7, 1070–1074.
Figure 1: Two examples of bioactive pseudopeptides bearing a CF2H group.
library [22-25]. Our group has always been interested in devel- concerning the use of difluoroacetic acid as one of the compo-
oping efficient methods for the preparation of difluoromethyl- nents in the Ugi reaction. For a comparative study, acetic acid
containing compounds through multicomponent reactions [26- and trifluoroacetic acid served as the substrates for the Ugi reac-
30]. Recently, we reported a novel and general strategy for the tion under the same reaction conditions as those used for the
construction of a difluoromethyl compound library, and we difluoroacetic acid, and the results indicated that the reaction
further illustrated this strategy by application to the synthesis of proceeded efficiently regardless of reaction conditions, and the
CF2H-bearing pseudopeptides and 1,2,3-triazoles through Ugi Ugi products (5 and 6) were obtained in good yields. The
and click reaction, respectively [27,30]. In continuation of our hydrogen atom next to the CF2 group seems to influence the
interest in the synthesis of diverse difluoromethyl-containing formation of Ugi product.
pseudopeptides, we herein report a novel and efficient syn-
thesis of difluoromethyl-containing pseudopeptides through Ugi In previous studies, we developed a synthetic methodology to
reaction, with gem-difluoromethylene-containing acid as a key prepare functionalized small molecules having a CF2H group
component, followed by reductive cleavage of the phenylsul- [27]. In this work, we first synthesized a protected difluoro-
fanyl group (Scheme 1).
containing building block, 2,2-difluoro-2-(phenylthio)acetic
acid (2). The synthesis of compound 2 is illustrated in
Scheme 3. The ethyl 2,2-difluoro-2-(phenylthio)acetate (1) was
Results and Discussion
For the purpose of screening novel bioactive compounds, we readily prepared by the reaction of ethyl bromodifluoroacetate
recently prepared a variety of diverse difluoromethyl-containing and thiophenol according to the known procedure [32]. The
pseudopeptides. In our initial experiments, we tried to use novel difluorinated acid 2 was obtained by hydrolysis of the
difluoroacetic acid as one component to undergo Ugi reaction to ester under basic condition in nearly quantitative yield.
prepare difluoromethyl-containing pseudopeptides. Unfortu-
nately, the anticipated difluoromethyl-containing product 4a After successful synthesis of the protected functionalized CF2
was not obtained (Scheme 2). Although there are a few exam- building block 2, we tried to use it as one of the components in
ples of acetic acid and trifluoroacetic acid acting as substrates in the preparations of the difluoromethylene-containing
an Ugi reaction [24,31], up to now, no literature was found pseudopeptides by Ugi reaction. Indeed, the reaction of aniline,
Scheme 1: Synthesis of difluoromethyl-containing pseudopeptides (4a–m) by Ugi reaction and desulfanylation.
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Beilstein J. Org. Chem. 2011, 7, 1070–1074.
Scheme 2: The Ugi reaction of aniline, benzaldehyde, (isocyanomethyl)benzene with acetic acid, difluoroacetic acid and trifluoroacetic acid in
methanol or under solvent-free conditions.
Scheme 3: Synthesis of 2,2-difluoro-2-(phenylthio)acetic acid (2).
benzaldehyde, (isocyanomethyl)benzene with 2 proceeded effi- Conclusion
ciently under solvent-free conditions. Finally, we removed the In summary, we have developed a novel and efficient protocol
protecting group (PhS) with Bu3SnH/AIBN according to our for the synthesis of CF2H-containing pseudopeptides by Ugi
previous research, and the desired difluoromethyl-containing reaction of substituted anilines, benzaldehyde, isocyanides and
pseudopeptide was successfully obtained [27].
the novel building block 2,2-difluoro-2-(phenylthio)acetic acid
(2), followed by the cleavage of the phenylsulfanyl group.
To demonstrate the scope of the method, several different
substituted anilines, substituted benzaldehydes, isocyanides and
Experimental
this novel difluorinated building block 2 were subjected to Ugi General
reaction under solvent-free conditions, followed by reductive All reagents were of analytic grade, obtained from commercial
cleavage of the phenylsulfanyl group. It was found that both suppliers and were used without further purification. Melting
Ugi reaction and desulfanylation proceeded smoothly for all points were measured in an open capillary using Büchi melting
substrates used to give the corresponding difluoromethylene- point B-540 apparatus and are uncorrected. 1H NMR and
containing and difluoromethyl-containing pseudopeptides 13C NMR spectra were recorded on a Bruker AM-400 spec-
(3a–m and 4a–m) in good yields (Table 1).
trometer (400 MHz and 100 MHz, respectively) using TMS as
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Beilstein J. Org. Chem. 2011, 7, 1070–1074.
Table 1: Synthesis of difluoromethylene-containing pseudopeptides (3a–m) and difluoromethyl-containing pseudopeptides (4a–m).
3
4
Entry
R1
R2
R3
Yield (%)a
Yield (%)a
a
b
c
d
e
f
Ph
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
82
78
75
79
78
74
72
70
77
70
72
68
66
75
68
74
75
70
67
78
71
75
69
74
66
60
2-MePh
2-MePh
4-MeOPh
Ph
Ph
4-MePh
Ph
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-FPh
4-FPh
4-FPh
Ph
2-MePh
4-MePh
4-FPh
Ph
g
h
i
j
2-MePh
4-MeOPh
Ph
k
l
m
Ph
4-MeOPh
aIsolated yield.
internal standard. The 19F NMR were obtained using a Bruker for 3 h and extracted with EtOAc (3 × 20 mL). The combined
AM-400 spectrometer (376 MHz) and the 19F NMR were organic phases were washed successively with water (20 mL)
measured with external CF3CO2H as standard. Gas chromatog- and brine (20 mL), and dried over anhydrous Na2SO4. After
raphy-mass spectra (GC-MS) were recorded on HP 5973 MSD removal of the solvent, the crude product was purified by chro-
with 6890 GC. High resolution mass spectra (HRMS) were matography to give the desired products 4.
recorded under electron impact conditions using a MicroMass
GCT CA 055 instrument and recorded on a MicroMass LCTTM
Supporting Information
spectrometer. Column chromatography was carried out with
Merck 60 (230–400 mesh) silica gel.
Supporting Information File 1
Experimental procedures and compound characterization.
General procedure for compounds 3a–m
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-123-S1.pdf]
To a stirred amine (1 mmol), the aldehyde (1 mmol) was added
in portions for about 5 min. The mixture was stirred for 30 min
at rt. Then, the reaction mixture was heated to 60 °C, and
isocyanide (1 mmol) and 2,2-difluoro-2-(phenylthio)acetic acid
(2) (1 mmol) were added. Stirring was continued at 60 °C for
1 h (TLC). The crude residue was purified by chromatography
to give the desired products 3.
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072057), the
National Basic Research Program of China (973 Program,
2010CB126101), the Shanghai Foundation of Science and
Technology (09391911800) and the Shanghai Leading Acad-
emic Discipline Project (B507).
General procedure for compounds 4a–m
Bu3SnH (0.58 g, 2 mmol) was added under argon atmosphere to
a solution of 3 (1 mmol) in dry toluene (3 mL). Deoxygenation
was continued for 5 min. Azobisisobutyronitrile (AIBN)
(0.02 g, 0.1 mmol) was added and the solution was heated at
reflux for 9 h (TLC). The mixture was concentrated under
reduced pressure and the residue was dissolved in EtOAc
(5 mL). The solution was stirred with KF/H2O (15 mg/0.15 mL)
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