Regiocontrolled palladium-catalyzed and copper-mediated C-H bond functionalization of protected l-histidine

Article abstract of DOI:10.1039/c4ob00430b

We describe the controlled and regioselective transition-metal-catalyzed C-H bond arylation of protected l-histidine with aryl halides as the coupling partner. Using this approach, a large number of C-2 arylated l-histidines have been synthesized with diverse substitutions bearing electron-donating and electron-withdrawing groups, in good to excellent yields. These synthetic amino acids possessing dual hydrophobic-hydrophilic character are important synthons of bioactive peptidomimetics, which are imperative potent inhibitors of Cryptococcus neoformans. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00430b

Organic &
Biomolecular Chemistry
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Regiocontrolled palladium-catalyzed and
copper-mediated C–H bond functionalization of
protected L-histidine†
Cite this: Org. Biomol. Chem., 2014,
12, 3792
Received 25th February 2014,
Accepted 10th April 2014
Amit Mahindra and Rahul Jain*
DOI: 10.1039/c4ob00430b
www.rsc.org/obc
We describe the controlled and regioselective transition-metal- in a panel of six mammalian cell lines.7 Out of all the peptido-
catalyzed C–H bond arylation of protected L-histidine with aryl mimetics tested against C. neoformans, the most promising are
halides as the coupling partner. Using this approach, a large Arg-His(4-t-butylphenyl)-Arg-NHBzl (NP-2779) and Arg-His-
number of C-2 arylated L-histidines have been synthesized with (biphenyl)-Arg-NHBzl (NP-2777) (shown in Fig. 1).
diverse substitutions bearing electron-donating and electron-with-
The important structural features of these peptidomimetics
drawing groups, in good to excellent yields. These synthetic amino are the presence of a free N-terminus and two guanidinium
acids possessing dual hydrophobic–hydrophilic character are side chains of arginine along with the imidazole ring consti-
important synthons of bioactive peptidomimetics, which are tuting the indispensable charged moieties of the pharmaco-
imperative potent inhibitors of Cryptococcus neoformans.
phore, whereas the aryl substitution on the L-histidine and
benzylamide group at the C-terminus conveys the required
lipophilic bulk.
Invasive fungal infections, such as Candidiasis, Cryptococcosis
and Aspergillosis, have increased considerably over the past few
years, and are devastating in humans.1 These infections
mainly develop in immunocompromised patients and affect
more than a million people, especially in the resource-limited
countries.2 Cryptococcus alone contributes to approximately
625 000 deaths by attacking the CNS system, resulting in death
due to cryptococcal meningitis.3 The seriousness of crypto-
coccal meningitis can be realized from a recent report released
by the Center for Disease Control (CDC) claiming that the mor-
tality from cryptococcal meningitis exceeds the death rate from
tuberculosis.4 Despite extensive efforts to develop new antifun-
gal agents by numerous research groups, the armament of
available drugs remains limited.5 The currently used antimyco-
tic agents target a limited repertoire of fungal-specific cell
walls and presents several serious issues such as drug related
toxicity, non-optimal pharmacokinetics, poor solubility and
serious drug–drug interactions.6 In our current endeavour to
discover a new pharmacophore against deadly C. neoformans,
we recently disclosed a series of peptidomimetics wherein a
number of analogues exhibited activity that was several fold
higher than the currently used drug amphotericin B. The pep-
tidomimetics also did not exhibit cytotoxicity when examined
The potent activity exhibited by the above-mentioned pepti-
domimetics created a greater need for various C-2 arylated his-
tidines. We recently disclosed a method for regioselective
direct C-2 arylation of N-α-trifluoroacetyl-L-histidine methyl
ester using arylboronic acids.8 The substrate scope for this
transformation is quite broad; however, low overall yields
(15–55%), more specifically in the case of electron-withdrawing
groups containing aryl substituents (15–20%), limits its poten-
tial application. Another shortcoming of this method is the
use of expensive arylboronic acids and their limited avail-
ability. Thus, we set as our goal the quest for an improved
method for the regioselective C-2 arylation of histidine,
which would be superior in terms of the above-mentioned
factors.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research, Sector 67, S. A. S. Nagar, Punjab 160 062, India.
E-mail: rahuljain@niper.ac.in; Fax: +91 (172)2214692; Tel: +91 (172) 2292024
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00430b
Fig. 1 Structural formula of NP-2779 and NP-2777.
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More recently, we published the microwave (MW)-assisted
The reaction of 1 with benzyl bromide in the presence of
direct C–H arylation at the C-5 position of fully protected L-his- silver carbonate led to the regioselective formation of Ac-His-
tidine via a palladium-catalyzed transformation reaction.9 This (1-Bn)-OMe (1a). Next, C–H arylation of 1a keeping the above
is the first catalytic example on histidine to construct a C–C reaction conditions was examined. We did not observe the ary-
bond with aryl halides as the coupling partner. In recent years, lation reaction at 140 °C over a period of 48–72 h. In order to
researchers have started searching for novel approaches to provide sufficient energy to activate and subsequently functio-
develop clean and efficient synthetic methods based on C–H nalize the C–H bond, we then used MW irradiation. We
activation to construct useful scaffolds, which can be incorpor- observed arylation of 1a in the presence of 2a (2 equiv.) using
ated into the lead molecules to optimize their activity.10 The Pd(OAc)2 (20 mol%), PPh3 (40 mol%), K2CO3 (3 equiv.), CuI
other methods for C–C bond construction include the (2 equiv.) and pivalic acid (40 mol%) in DMF under MW
renowned conventional Suzuki-, Negishi-, Hiyama-, and irradiation (140 °C, 45 min, 100 W) to provide overall low yield
Kumada-cross-coupling reactions.11 The advantages of C–H of a mixture of fully protected arylated L-histidines [2-aryl
activation over cross-coupling reactions are the exclusion of (3a, 10%), 5-aryl (3b, 8%) and 2,5-diaryl (3c, 5%)] (Scheme 1).
pre-activated substrates and elimination of undesired by-
We then set as our goal to identify the catalytic system com-
products. Thus, the ideal organic transformations would be bination required for the regiocontrolled formation of C-2 ary-
initiated from the easily available and inexpensive chemicals. lated products. The reactivity at different positions of
In this context, the direct transformation of the C–H bond, a L-histidine is governed by different factors, thereby creating an
ubiquitous group in the organic world, into desired functional- underlying problem associated with the direct arylation of the
ities has drawn much attention and interest.12
imidazole ring of histidine. In general, nucleophilicity at the
Herein, we report the regiocontrolled C–H bond functionali- C-5 and the acidic nature of C–H at the C-2 positions have
zation of protected L-histidine using inexpensive aryl halides been documented in the past.19 In order to provide a method
as the coupling partner. This arylation reaction is proficient for regioselective arylation of the five-membered imidazole
with various aryl iodides containing both electron-withdrawing ring containing histidine residue at the most electron-deficient
and electron-donating substituents to give access to a diverse center, we screened various palladium catalysts substituted
library of 2-aryl-L-histidine analogues.
with diverse groups along with phosphine ligands.
A number of reports involving C–H activation have been
As shown in Table 1, all possible regioisomers (3a, 3b and
reported in a wide range of substrates, including heterocyclic 3c) formed when Pd(OAc)2 was used in the presence of PPh3,
scaffolds.13 In these heterocyclic scaffolds, the selectivity PCy3 and P(2-furyl)3 (entry no. 1, 2 and 3). Changing the
among the electron-deficient and electron-rich sites is always a ligand to P(n-Bu)(1-adamantyl)2 while keeping the catalyst
dubious question. A limited number of regioselective direct intact resulted in substantially higher conversion of 1a to 3a
arylation reports have been available over the past few years,14 (75%) with enhanced yield (52%), and absolute regioselectivity
but regioselective arylation of amino acids has received much (entry no. 4). The change of the ligand to P(t-Bu)3HBF4 pro-
less attention.15 In the year 2007, Bellina and Rossi published duced a significant amount of C-2 arylated product (42%),
regioselective Pd- and Cu-mediated reactions on a large variety but not complete regioselectivity (entry no. 5). To confirm the
of π-electron-deficient heteroarenes.16 In another report, role of CuI in the C-2 arylation, we also performed a reaction
Fagnou and his co-workers described Pd-catalyzed direct aryla- while keeping the catalytic system intact [Pd(OAc)2–P(n-Bu)-
tion of a wide range of heterocycles with aryl halides.17 In sub- (1-adamantyl)2], but excluded CuI (entry no. 6). The predomi-
sequent years, Sames and other research groups published a nance of C-5 arylation confirms the formation of a π-complex
number of research articles on the direct C–H activation.18 After of Cu with a C–H bond at the C-2 position and its conversion
taking clues from several earlier reports, we first attempted the into a C–Cu bond followed by a transmetallation reaction with
direct arylation of commercially available Ac-His-OMe (1) with the palladium catalyst. No reaction was observed when
4-iodobenzotrifluoride (2a, 2 equiv.) using Pd(OAc)2 (20 mol%), Pd2(dba)3 was used as a catalyst in the presence of P(n-Bu)-
PPh3 (40 mol%), K2CO3 (3 equiv.), CuI (2 equiv.) and pivalic (1-adamantyl)2 (entry no. 7). We further tried to enhance the
acid (40 mol%) in DMF at 140 °C for 72 h. But to our disap- yield by using various palladium catalysts such as
pointment no arylation took place, probably due to the interfer- Pd(PPh3)2Cl2 and Pd(CH3CN)2Cl2 possessing electron-with-
ence of the reactive imidazole ring NH group. In our earlier drawing substituents, and P(n-Bu)(1-adamantyl)2 as a ligand.
work on the regioselective Pd-catalyzed direct C-5 arylation of However, these catalytic combinations under the reaction con-
protected histidine, we discussed the merits and demerits of ditions also gave a mixture of 3a, 3b and 3c (entry no. 8, 9 and
various NH protecting groups.9 A careful examination of various
protective groups resulted in the observation that the benzyl
group is most suitable for the reaction. The use of the benzyl
group is not only favoured by the moderate conditions of its
incorporation and removal, but also favoured by the fact that its
presence introduces more lipophilicity into the histidine, a criti-
cal requirement for the antifungal peptides, where it is essential
for potent activity against C. neoformans.
Scheme 1 MW-assisted direct arylation of 1a with 2a.
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Table 1 Screening of catalysts and ligands for the conversion of 1a to 3aa
S. no.
Catalyst
Ligand
CuI
C-2
C-5
C-2 and C-5
Conv. (%)
1.
2.
3.
4.
5.
6.
7.
8.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(TFA)2
PPh3
PCy3
CuI
CuI
CuI
CuI
CuI
—
CuI
CuI
CuI
CuI
CuI
10
38
20
52
42
2
—
26
30
40
23
8
5
8
12
—
2
3
—
3
3
—
2
45
70
55
75
60
58
—
70
55
65
40
15
18
—
5
38
—
6
2
—
2
P(2-furyl)3
P(n-Bu)(1-adamantyl)2
P(t-Bu)3HBF4
P(n-Bu)(1-adamantyl)2
P(n-Bu)(1-adamantyl)2
P(n-Bu)(1-adamantyl)2
P(n-Bu)(1-adamantyl)2
P(n-Bu)(1-adamantyl)2
P(n-Bu)(1-adamantyl)2
9.
10.
11.
PdCl2(dppf)2
a Reaction conditions: 1a (1 equiv.), 2a (2 equiv.), CuI (2 equiv.), catalyst (20 mol%), ligand (40 mol%), K2CO3 (3 equiv.), PivOH (40 mol%), DMF
(2 mL), 140 °C, 45 min, MW.
11). The use of Pd(TFA)2 in the presence of P(n-Bu)(1-adaman- was used as a solvent in place of DMF (entry no. 8, 10 and 12).
tyl)2 resulted in lower yield (40%), but with regioselectivity In contrast, the use of a solvent such as DMF, N-methyl-2-pyr-
intact (entry no. 10).
rolidone (NMP), N,N-dimethylacetamide (DMA) or dimethyl
Next, we examined the possible influence of some reaction sulfoxide (DMSO) possessing mildly basic characteristics
parameters like solvent and base on the outcome of the regio- offered higher yields, with NMP emerging as the solvent of
selective C-2 arylation. The use of heterogeneous bases such as choice (entry no. 7). All these experiments led us conclude that
Cs2CO3, CsF and K3PO4 did not offer any advantage over the use of Ar–X (2 equiv.), Pd(OAc)2 (20 mol%), P(n-Bu)(1-ada-
K2CO3 (entry no. 2, 3 and 6, Table 2). The use of a homo- mantyl)2 (40 mol%), CuI (2 equiv.), t-BuOK (3.0 equiv.), and
geneous stronger base such as t-BuOK led to higher conversion PivOH (40 mol%), in NMP as a solvent at 140 °C for 45 min
with enhanced yield of 3a, probably due to the inherent selecti- under MW irradiation offered the best conditions for the
vity of the base for acidic sites within the hetero ring (entry no. direct regiocontrolled formation of 3a.
4). Moreover, we observed that no reaction occurred when
We then applied the newly developed direct arylation con-
acetonitrile (ACN), 1,4-dioxane or 1,2-dichloroethane (DCE) ditions to other aryl counterparts to obtain a number of C-2
arylated products with absolute regioselectivity in good to
excellent yields. The results of the arylation reaction are given
Table 2 Screening of bases and solvents for the conversion of 1a
in Table 3. As is evident, a long (45–60 min) reaction time was
to 3aa
Conv.
Entry
1.
Base
Solvent
DMF
Catalyst/ligand
(%)
75
45
46
79
51
32
89
—
45
—
60
—
Table 3 Direct C-2 arylation of 1a with aryl halides under MW
irradiationa
K2CO3
Cs2CO3
CsF
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
Pd(OAc)2/P(n-Bu)-
(1-adamantyl)2
2.
DMF
3.
DMF
4.
t-BuOK
DBU
DMF
Entry
Product no.
Ar–X
R
Yields (%)
5.
DMF
6.
K3PO4
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
DMF
1
2
3
4
5
6
7
8
3a
3d
3e
3f
3g
3h
3i
3j
3k
3l
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–I
Ar–Br
Ar–Br
Ar–Br
4-Trifluorophenyl
3-Trifluorophenyl
2-Trifluorophenyl
4-Cyanophenyl
4-Chlorophenyl
Phenyl
4-t-Butylphenyl
4-Methylphenyl
4-Methoxyphenyl
Biphenyl
78
74
72
76
77
70
65
65
64
69
69
48
36
38
7.
NMP
8.
ACN
9.
DMSO
1,4-Dioxane
DMA
10.
11.
12.
9
10
11
12
13
14
3m
3a
3f
2-Naphthyl
4-Trifluorophenyl
4-Cyanophenyl
4-Chlorophenyl
DCE
3g
a Reaction conditions: 1a (1 equiv.), 2a (2 equiv.), CuI (2 equiv.), PivOH a Reaction conditions: 1a (1.0 equiv.), Ar–X (2.0 equiv.), Pd(OAc)2
(40 mol%), catalyst (20 mol%), ligand (40 mol%), base (3 equiv.), (20 mol%), P(t-Bu)(1-adamantyl)2 (40 mol%), CuI (2 equiv.), t-BuOK
solvent (2 mL), 140 °C, 45 min, MW.
(3.0 equiv.), PivOH (40 mol%), NMP, MW (140 °C, 45–60 min, 100 W).
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required, depending on the aryl iodide used. Both electron- ChiralPak-WH column. We have also synthesized 2-(4-trifluoro-
rich and electron-deficient aryl iodides reacted with 1a to give phenyl)-D-histidine·2HCl to differentiate between the retention
good isolated yield of 3. The sterically hindered aryl iodide times of the enantiomers. It was clear from the HPLC chroma-
(entry no. 2 and 3) also produced the desired product in good tograms of the enantiomers that chiral integrity was well main-
yield. Importantly, these reaction conditions proved compati- tained in this reaction (see ESI†).
ble in the presence of reactive functional groups such as cyano
and chloro on the aromatic ring, which may be subjected to
further synthetic manipulations. The successful coupling reac-
tion with the polyaromatic 4-iodobiphenyl and 2-iodonaphtha-
Conclusions
lene showed the wide range of this transition-metal-catalyzed We have developed an efficient, regioselective and direct C–H
reaction (entry no. 10 and 11). The reaction was found to also arylation reaction of Ac-His(Bn)-OMe effectively catalyzed by
offer products when using aryl bromides as the coupling the Pd(OAc)2–P(n-Bu)(1-adamantyl)2–CuI catalytic system
partner, but in much lower yields (entry no. 12, 13 and 14) under MW irradiation. The reaction offers high yields and
when compared to the aryl iodides.
absolute regioselectivity when t-BuOK is used as a base in the
On the basis of experimental observations and earlier presence of NMP as the solvent medium. This protocol is
reports,20 a plausible mechanism of the Pd/Cu-catalyzed direct equally compatible with electron-deficient and electron-with-
arylation of 1a might involve a base-assisted cupration of the drawing aryl partners. The 2-aryl-L-histidines obtained using
1a to give the aryl-Cu species (TS-I, Fig. 2). Subsequently, TS-I this versatile procedure are important building blocks of
undergoes transmetallation with an aryl-Pd complex TS-II potent and promising antifungal peptides. Further appli-
(TS-II formed by the oxidative addition of Pd0 to aryl iodide) to cations of these arylated amino acids in the synthesis of new
give intermediate TS-III, which undergoes reductive elimin- structural classes of peptides are currently under study.
ation to furnish the product 3a with the concomitant use of
both Pd and Cu catalysts.
The protecting groups of 3a were removed at the very end by
Experimental section
using earlier reports.21 For debenzylation, a suspension of 3a
in 10% Pd–C in methanol was treated with ammonium formate All arylation reactions were carried out under an argon atmos-
and the mixture was refluxed for 18 h to afford 4 in 85% yield. phere, unless otherwise stated. Reaction times refer to the
Finally, the removal of α-amino and α-carboxyl protecting hold time at the desired set temperature and not to the total
groups in 4 was achieved by refluxing in aqueous 6 N HCl for irradiation time. Reaction cooling is performed by compressed
24 h. The 2-(4-trifluorophenyl)-L-histidine·2HCl (5) was obtained air automatically after the heating period has elapsed. All the
by the evaporation of the acidic solution (Scheme 2).
solid reagents were weighed in air and placed in a 10 mL MW
To confirm the chiral integrity of the synthesized C-2 vial equipped with a magnetic stir bar. To a 10 mL capacity
arylated amino acids, chiral HPLC of 5 was performed on a MW vial, t-BuOK (3.0 equiv., 4.98 mmol), Pd(OAc)2 (20 mol%,
0.34 mmol), P(n-Bu)(1-adamantyl)2 (40 mol%, 0.66 mmol), CuI
(2 equiv., 3.32 mmol) and PivOH (40 mol%, 0.66 mmol) and
1a (1 equiv., 1.66 mmol) were added and the reaction mixture
was purged with argon. The appropriate aryl halide, if solid (2,
2 equiv., 3.32 mmol), was added at this point. The reaction
mixture was purged with argon and NMP (2 mL) was added.
The aryl halide, if liquid (2, 2 equiv., 3.32 mmol), is added at
this point. Addition of solvent was done under positive argon
pressure with stirring. The sealed reaction vial was then placed
in the MW reactor (CEM Discover®) and stirred at 140 °C for
the indicated time. The solution was then cooled to ambient
temperature and diluted with EtOAc, washed with H2O
(3 times), dried over MgSO4, filtered, and evaporated under
reduced pressure. The reaction mixture was purified on a
Biotage® automated flash column chromatography system to
give the desired product.
Fig. 2 Plausible mechanism of the direct C-2 arylation.
Acknowledgements
Amit Mahindra thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for the award of a Senior Research
Fellowship.
Scheme 2 Removal of the protecting groups of 3a.
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