Facile regiospecific syntheses of N-α,N-1(τ)-dialkyl-L-histidines

Article abstract of DOI:10.1002/jhet.5570440607

(Chemical Equation Presented) Two diverse methodologies describe the first synthesis of suitably protected N-α,N-1(τ)-dialkyl-L-histidine derivatives. Synthesis of suitably protected N-α,N-1(τ)-dialkyl-L- histidines 7-9 containing different alkyl groups a

Full text of DOI:10.1002/jhet.5570440607

Nov-Dec 2007
1265
Facile Regiospecific Syntheses of N-ꢀ,N-1(ꢁ)-Dialkyl-L-Histidines
Surendra Kumar Nayak, Vikramdeep Monga, Navneet Kaur† and Rahul Jain*
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
Received September 7, 2006
O
H/CH3
O
N
N
NCO2R1
R2
R
Two diverse methodologies describe the first synthesis of suitably protected N-ꢀ,N-1(ꢁ)-dialkyl-L-
histidine derivatives. Synthesis of suitably protected N-ꢀ,N-1(ꢁ)-dialkyl-L-histidines 7-9 containing
different alkyl groups at the N-ꢀ and N-1(ꢁ) positions was achieved in four steps starting from L-histidine
methyl ester. Whereas, in the one-step alternate route N-ꢀ-Boc-L-histidine methyl ester upon direct and
simultaneous N-ꢀ and N-1(ꢁ) alkylation with various alkyl halides in the presence of sodium hydride in
DMF easily afforded N-ꢀ,N-1(ꢁ)-dialkyl-L-histidines 14 containing identical alkyl group at the N-ꢀ and N-
1(ꢁ) positions in high yields. Both procedures allowed facile entry to methyl and other higher alkyl groups
at the N-ꢀ-position of the histidine ring
J. Heterocyclic Chem., 44, 1265 (2007).
protected forms for incorporation into the target peptoids
by solid-phase synthesis. Although, a range of synthetic
methods have been employed to prepare N-ꢀ-methyl
amino acids [17], none are easily adapted for the synthesis
of N-ꢀ-alkylated histidines suitable for solid phase
peptide synthesis. More recently, a unified synthetic
procedure for the twenty natural amino acids through the
generation of intermediate 5-oxazolidinone and its
subsequent transformation to N-ꢀ-methyl derivative by
reductive cleavage in the presence of triethylsilane in
trifluoroacetic acid (TFA) was reported [18, 19]. This
procedure provides N-ꢀ-methyl-L-histidine derivative
protected with N-ꢀ-carbobenzyloxy (Cbz) and N-1(ꢁ)-
dinitrophenyl (DNP) groups in six overall steps. However,
due to the use of acidic conditions in several of the
synthetic steps, we concluded that the procedure is not
useful for the preparation of tert-butoxycarbonyl (t-Boc)
group protected N-ꢀ-alkyl-L-histidines required for t-Boc
solid-phase peptide synthesis protocol [20]. Furthermore,
5-oxazolidinone intermediate based synthetic method-
ology could not be applied to synthesize N-ꢀ,N-1(ꢁ)-
dialkyl groups containing L-histidines. In continuation of
our search for easy availability of novel modified L-
histidines, this article describes two efficient synthetic
routes to N-ꢀ,N-1(ꢁ)-dialkyl-L-histidines.
INTRODUCTION
Backbone modification by conformational restriction of
amide bond is an attractive strategy to obtain useful
information about bioactive conformation of peptides [1,
2]. Such modifications introduce local backbone
constraints, e.g. N-ꢀ-alkylation greatly limits the ꢂ
torsional angle that restricts the affected residue and the
amino acid preceding it to an extended conformation [3],
eliminates the potential intramolecular hydrogen bonding
capability of the amide bond nitrogen, increase resistance
to proteolytic enzymes cleavage sites and also the
hydrophobicity of the peptide [4]. Incorporation of N-ꢀ-
methyl amino acid in a peptide ligand has often been
found to increase their potency or selectivity and resulting
peptoids are increasingly recognized as potentially useful
therapeutics. For example, in one such study conducted
recently, potential effects of N-ꢀ-methylation of peptide
bond NH groups on binding affinity and receptor subtype
specificity of synthetic analogues of somatostatin
octapeptide agonist and antagonist was examined, and
some analogues displayed greatly enhanced affinity and
specificity [5–7].
Synthetic design of modified histidine derivatives is a
tedious task due to the basic and high nucleophilic
character of the imidazole ring at the side chain. One of
the major efforts of our laboratory has been the design
and synthesis of novel derivatized L-histidines and we
have previously reported syntheses for some of these
scaffolds [8–15]. Recently, our requirement of N-ꢀ,N-
1(ꢁ)-dialkyl-L-histidines [16] as components of
antimicrobial and CNS selective peptide analogues
created a need for these building blocks in suitably
RESULTS AND DISCUSSION
We have earlier reported a facile synthesis of N-1(ꢁ)-
alkyl-L-histidines via a quaternary imidazolium salt
intermediate [8]. We utilized this procedure to achieve our
objective of synthesizing fully protected N-1(ꢁ)-alkyl-L-
histidine intermediates required for target amino acids.
Reaction of commercial L-histidine methyl ester

1266
S. K. Nayak, V. Monga, N. Kaur and R. Jain
Vol 44
then devised. Accordingly, commercially available N-ꢁ-
Boc-L-histidine methyl ester 13 upon direct ring N-1(ꢀ)
and side chain ꢁ-position alkylation with methyl iodide or
ethyl iodide in the presence of NaH in DMF for 12 h at
ambient temperature cleanly afforded N-ꢁ-(tert-butoxy-
carbonyl)-N-ꢁ,N-1(ꢀ)-dimethyl-L-histidine methyl ester
8a and N-ꢁ-(tert-butoxycarbonyl)-N-ꢁ,N-1(ꢀ)-diethyl-L-
histidine methyl ester 14a in excellent yields. However,
the method was found to provide unreacted starting
material and some unidentifiable products when it was
tried with benzyl bromide. Alternatively, N-ꢁ-Boc-L-
histidine methyl ester 13 upon reaction with benzyl
bromide in the presence of NaH in DMF at 80 °C for 10 h
produced N-ꢁ-(tert-butoxycarbonyl)-N-ꢁ,N-1(ꢀ)-dibenz-
yl-L-histidine methyl ester 14b in 61% yield (Scheme 2).
Fully deprotected amino acids, N-ꢁ,N-1(ꢀ)-diethyl-L-
histidine hydrochloride 15a and N-ꢁ,N-1-dibenzyl-L-
histidine hydrochloride 15b were obtained by the
deprotection of 14a and 14b with refluxing solution of
them in 6 N HCl. Evaporation of the solution produced
the amino acid hydrochlorides 15a–b as described earlier.
The results summarized establish the first synthesis of
previously inaccessible N-ꢁ,N-1(ꢀ)-dialkyl-L-histidines.
Two diverse and facile synthetic methodologies which
produce different or identical N-ꢁ and N-1(ꢀ) alkyl groups
containing L-histidines are described herein. These
methodologies allowed easy access to N-ꢁ-Boc-N-ꢁ,N-1(ꢀ)-
dimethyl-L-histidines required by us for solid-phase peptide
synthesis and were conveniently extended to introduce a
diverse range of higher primary and secondary alkyl groups.
dihydrochloride with 1,1'-carbonyl-diimidazole in DMF
provided the cyclic urea, which upon alkylation with
methyl iodide or benzyl bromide in refluxing CH3CN for
16 h provided quaternary imidazolium salts 2–3 in
excellent yields (Scheme 1) [8]. The imidazolium salts 2–
3 were then reacted with an alcohol in the presence of
N,N-diisopropylethylamine at reflux temperature for 2–4
days, to give fully protected N-1(ꢀ)-alkyl-L-histidine
deriveatives 4–6 [8,21,22]. Reaction of the latter com-
pounds 4–6 with NaH at ambient temperature for 30 min
in anhydrous DMF under nitrogen atmosphere, followed
by addition of the appropriate commercially available
alkyl iodides and stirring for 4 h readily afforded fully
protected N-ꢁ,N-1(ꢀ)-dialkyl-L-histidines 7–9.
The reaction allows easy entry to not only N-ꢁ-methyl-
L-histidine derivatives, but also to higher alkyl groups
such as ethyl, n-propyl and i-propyl containing L-
histidines (Table 1), and can also be conveniently adapted
to include many other alkyl groups. The N-ꢁ,N-1(ꢀ)-
dialkyl-L-histidines were obtained by the deprotection of
7a and 8a with refluxing solution of them in 6 N HCl.
Evaporation of the solution produced the amino acid
hydrochlorides 10–11 respectively. Selective deprotection
of compounds 8a in the presence of LiOH.H2O in a
mixture of H2O-MeOH at ambient temperature for 30 min
afforded N-ꢁ-(tert-butoxycarbonyl)-N-ꢁ,N-1(ꢀ)-dimethyl-
L-histidine 12, suitable for t-Boc solid-phase peptide
synthesis methodology (Scheme 1).
A shorter one-step route which provides N-ꢁ,N-1(ꢀ)-
dialkyl-L-histidines containing identical alkyl group was
CO2CH3
i-ii
NH2.2HCl
CO2CH3
CO2CH3
NH
iii
R
N
N
N
HN
N
NHCO2R1
N
X-
R
O
1
4.
2.
3.
R=CH3, R1=CH2Ph
5. R=CH3, R1=C(CH3)3
6.
R=CH3
R=CH2Ph
R= CH2Ph, R1=C2H5
iv
CO2H
CO2CH3
CO2H
v
vi
N
N
N
N
N
N
NH.HCl
R2
NCO2R1
R2
NCO2R1
R2
R
R
R
7a-d; 8a-d; 9a-d
R2= CH3, C2H5, C3H7, CH(CH3)2
12.
10.
R=R2=CH3, R1=C(CH3)3
R=R2=CH3
11. R=CH2Ph, R2=CH3
Reagents and conditions: i. CDI, DMF, 60 oC, 8 h; ii. RX, CH3CN, reflux, 16 h; iii. R1OH, DIEA,
Scheme 1.
reflux, 48-96 h; iv. R2I, NaH, DMF, rt, 4 h; v. 6N HCl, 100 oC, 8 h; vi. LiOH.H2O, CH3OH, rt, 30 min.
CO2CH3
NH-Boc
CO2CH3
N-Boc
CO2H
ii
i
N
N
N
HN
N
N
NH.HCl
R
R
R
R
13
8a, 14a-b
R = CH3, C2H5, CH2C6H5
10, 15a-b
Scheme 2.
i. CH I/C H I, NaH, DMF, rt, 12 h or C H CH Br, NaH, DMF, 80 oC, 10
3 2 5 6 5 2
Reagents and conditions:
h; ii. 6N HCl, 100 oC, 8 h

Nov-Dec 2007
Facile Regiospecific Syntheses of N-ꢀ,N-1(ꢁ)-Dialkyl-L-Histidines
1267
Table 1
Physical data of N-ꢀ,N-1(ꢁ)-dialkyl-L-histidine methyl esters 7-9 and 14
Product
7a
7b
7c
7d
8a
8b
8c
8d
9a
9b
9c
9d
14a
14b
R
CH3
CH3
CH3
CH3
CH3
CH3
CH3
R1
R2
CH3
C2H5
C3H7
CH(CH3)2
CH3
C2H5
% Yield
84
62
17
14
91a, 99b
60
16
[ꢀ]D
25
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
C2H5
C2H5
C2H5
C2H5
C(CH3)3
C(CH3)3
+10.5 (c 1, CHCl3)
+8.2 (c 1, CHCl3)
+7.9 (c 1, CHCl3)
+7.5 (c 1, CHCl3)
+13.7 (c 1, CHCl3)
+9.3 (c 1, CHCl3)
+7.3 (c 1, CHCl3)
+4.3 (c 1, CHCl3)
+9.2 (c 1, CHCl3)
+8.1 (c 1, CHCl3)
+5.7 (c 1, CHCl3)
+5.4 (c 1, CHCl3)
+14.7 (c 1, CHCl3)
-5.1 (c 1, CHCl3)
C3H7
CH3
CH(CH3)2
CH3
C2H5
C3H7
CH(CH3)2
C2H5
14
87
68
15
15
85
61
CH2C6H5
CH2C6H5
CH2C6H5
CH2C6H5
C2H5
CH2C6H5
CH2C6H5
aNaH (4.8 mmol), MeI (2.85 mmol), DMF, rt, 4 h; bNaH (3 mmol), MeI (5 mmol), DMF, rt, 12 h
N-ꢀ-(Carbobenzyloxy)-N-ꢀ,N-1(ꢁ)-dimethyl-L-histidine
methyl ester (7a). Yield: 84%; mp 57-59 °C; 1H nmr (CDCl3): ꢂ
3.25-3.30 (m, 2H), 3.78 (s, 3H), 3.85 (s, 6H), 4.55-4.60 (m, 1H),
5.08 (s, 2H), 7.14 (s, 1H), 7.34 (m, 5H), 9.55 (s, 1H); ESIMS:
m/z 332 (M+1); [ꢀ]D +10.5 (c 1, CHCl3). Anal. Calcd. for
C17H21N3O4: C, 61.62; H, 6.39; N, 12.68. Found, C, 61.63; H,
6.45; N, 12.77.
EXPERIMENTAL
Melting points were recorded on Mettler DSC 851 or
1
capillary melting point apparatus and are uncorrected. H
25
spectra were recorded on 300 MHz Bruker FT-NMR
(Avance DPX300) spectrometer using tetramethylsilane as
internal standard and the chemical shifts are reported in ꢂ
units. Mass spectra were recorded on either GCMS
(Shimadzu QP 5000 spectrometer) auto sampler/direct
injection (EI/CI) or HRMS (Finnigan Mat LCQ
spectrometer) (APCI/ESI). FT-IR spectra (ꢃmax in cm-1)
N-ꢀ-(Carbobenzyloxy)-N-ꢀ-ethyl,N-1(ꢁ)-methyl-L-histi-
dine methyl ester (7b). Yield: 62%; semi-solid; 1H nmr
(CDCl3): ꢂ 1.18 (m, 3H), 3.22-3.30 (m, 2H), 3.84 (s, 3H), 4.11
(m, 5H), 4.49-4.54 (m, 1H), 5.02 (s, 2H), 7.12 (s, 1H), 7.28 (s,
25
5H), 9.65 (s, 1H); ESIMS: m/z 346 (M+1); [ꢀ]D +8.2 (c 1,
were recorded on
a Nicolet spectrometer. Elemental
CHCl3). Anal. Calcd. for C18H23N3O4: C, 62.59; H, 6.71; N,
12.17. Found, C, 62.78; H, 7.03; N, 11.85.
analyses were recorded on Elementar Vario EL
spectrometer. All chromatographic purification was
performed with silica gel 60 (230-400 mesh), whereas all
TLC (silica gel) development was performed on silica gel
coated (Merck Kiesel 60 F254, 0.2 mm thickness) sheets.
All chemicals were purchased from Aldrich Chemical Ltd
(Milwaukee, WI, USA). Solvents used for the chemical
synthesis acquired from commercial sources were of
analytical grade, and were used without further
purification unless otherwise stated.
N-ꢀ-(Carbobenzyloxy)-N-ꢀ-propyl,N-1(ꢁ)-methyl-L-histi-
dine methyl ester (7c). Yield: 17%; semi-solid; 1H nmr
(CDCl3): ꢂ 0.94 (m, 3H), 1.45 (m, 2H), 3.21-3.29 (m, 2H), 3.70
(s, 3H), 3.85 (s, 3H), 3.99-4.02 (m, 2H), 4.51-4.57 (m, 1H), 5.12
(s, 2H), 7.15 (s, 1H), 7.30 (s, 5H), 9.55 (s, 1H); ESIMS: m/z 360
25
(M+1); [ꢀ]D +7.9 (c 1, CHCl3). Anal. Calcd. for C19H25N3O4:
C, 63.49; H, 7.01; N, 11.69. Found, C, 63.88; H, 7.08; N, 11.47.
N-ꢀ-(Carbobenzyloxy)-N-ꢀ-isopropyl,N-1(ꢁ)-methyl-L-
1
histidine methyl ester (7d). Yield: 14%; semi-solid; H nmr
Typical procedure for the synthesis of N-ꢀ-
(Carboalkoxy)-N-ꢀ,N-1(ꢁ)-dialkyl-L-histidine methyl esters
(7–9). Sodium hydride (60% suspension, 4.8 mmol) was washed
with petroleum ether (2 ꢄ 5 mL) and dried under vacuum. N-ꢀ-
carboalkoxy-1-alkyl-L-histidine methyl ester [8] (4–6, 1.89
mmol) in anhydrous DMF (20 mL) was added under a nitrogen
atmosphere. The reaction mixture was stirred for another 30 min
at ambient temperature, then alkyl iodide (2.85 mmol) was
added and the reaction mixture was stirred for another 4 h under
N2. The reaction was quenched by addition of saturated NH4Cl
solution (5 mL) and the solvent removed under reduced
pressure. The solid residue was extracted with chloroform (2 ꢄ
25 mL), and the combined organic layers were dried over
Na2SO4. The solvent was removed under reduced pressure and
the crude product was purified by silica gel (230–400 mesh)
column chromatography eluting with 2% CH3OH in CH2Cl2 to
afford N-ꢀ-(carboalkoxy)-N-ꢀ,N-1(ꢁ)-dialkyl-L-histidine methyl
esters (7–9) [22].
(CDCl3): ꢂ 1.48 (d, 6H, J = 6.6 Hz), 3.25-3.30 (m, 2H), 3.75 (m,
3H), 3.85 (s, 3H), 4.04-4.06 (m, 1H), 4.50-4.55 (m, 1H), 5.21 (s,
2H), 7.12 (s, 1H), 7.34 (s, 5H), 9.47 (s, 1H); ESIMS: m/z 360
25
(M+1); [ꢀ]D +7.5 (c 1, CHCl3). Anal. Calcd. for C19H25N3O4:
C, 63.49; H, 7.01; N, 11.69. Found, C, 63.81; H, 7.26; N, 11.78.
N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-dimethyl-L-histi-
dine methyl ester (8a). Yield: 91%; semi-solid; 1H nmr
(CDCl3): ꢂ 1.41 (s, 9H), 3.24-3.27 (m, 2H), 3.81 (s, 3H), 3.97 (s,
3H), 4.01 (s, 3H), 4.51-4.60 (m, 1H), 7.32 (s, 1H), 9.70 (s, 1H);
ESIMS: m/z 298 (M+1); [ꢀ]D25 +13.7 (c 1, CHCl3). Anal. Calcd.
for C14H23N3O4: C, 56.55; H, 7.80; N, 14.13. Found, C, 56.51; H,
7.69; N, 14.34.
N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ-ethyl,N-1(ꢁ)-methyl-L-
1
histidine methyl ester (8b). Yield: 60%; semi-solid; H nmr
(CDCl3): ꢂ 1.40 (s, 9H), 1.61 (t, 3H, J = 7.3 Hz), 3.20-3.26 (m,
2H), 3.79 (s, 3H), 4.02 (s, 3H), 4.24 (q, 2H, J = 7.2 Hz), 4.50-
4.58 (m, 1H), 7.26 (s, 1H, 5-H), 9.89 (s, 1H); ESIMS: m/z 312

1268
S. K. Nayak, V. Monga, N. Kaur and R. Jain
Vol 44
25
(M+1); [ꢀ]D +9.3 (c 1, CHCl3). Anal. Calcd. for C15H25N3O4:
C, 57.86; H, 8.09; N, 13.49. Found, C, 57.93; H, 8.34; N, 13.58.
N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ-propyl,N-1(ꢁ)-methyl-L-
2H), 7.43-7.48 (m, 5H), 7.66 (s, 1H), 9.11 (s, 1H); ESIMS: m/z
260 (M+1); [ꢀ]D –12.7 (c 1, H2O). Anal. Calcd. for
C14H18ClN3O2: C, 56.85; H, 6.13; N, 14.21. Found, C, 56.64; H,
6.47; N, 14.59.
25
1
histidine methyl ester (8c). Yield: 16%; semi-solid; H nmr
Synthesis of N-ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-
dimethyl-L-histidine (12). N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ,N-
1(ꢁ)-dimethyl-L-histidine methyl ester (8a, 1.68 mmol) was
dissolved in methanol (30 mL). A solution of LiOH.H2O (2.52
mmol) in water (5 mL) was added, and reaction mixture was
stirred at ambient temperature for 30 min. Solvent was removed
under reduced pressure and crude product was purified by silica
gel (230-400 mesh) column chromatography eluting with 10%
CH3OH in CH2Cl2 to afford 12. Yield: 91%; mp 122-124 °C; 1H
nmr (CD3OD): ꢂ 1.41 (s, 9H), 2.83-3.04 (m, 2H), 3.69 (s, 3H),
3.71 (s, 3H), 4.30-4.38 (m, 1H), 6.89 (s, 1H), 7.60 (s, 1H);
ESIMS m/z 284 (M+1); [ꢀ]D25 +14.2 (c 1, CH3OH). Anal. Calcd.
for C13H21N3O4: C, 55.11; H, 7.47; N, 14.83. Found, C, 55.02; H,
7.25; N, 14.74.
Typical procedure for the synthesis of N-ꢀ-(tert-
butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-dimethyl-L-histidine methyl
ester (8a) and N-ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-diethyl-
L-histidine methyl ester (14a). Sodium hydride (60%
suspension, 3 mmol) was washed with petroleum ether (2 ꢃ 5
mL) and dried under vacuum. N-ꢀ-(tert-butoxycarbonyl)-L-
histidine methyl ester (13, 1 mmol) in anhydrous DMF (20 mL)
was added under a nitrogen atmosphere. The reaction mixture
was stirred for another 30 min at ambient temperature. Methyl
iodide or ethyl iodide (5 mmol) was added and the reaction
mixture was stirred for another 12 h under N2 at ambient
temperature. The reaction was quenched by addition of saturated
NH4Cl solution (5 mL) and the solvent removed under reduced
pressure. The solid residue was extracted with chloroform (2 ꢃ
15 mL), and the combined organic layers were dried over
Na2SO4. The solvent was removed under reduced pressure and
the crude product was purified by silica gel (230–400 mesh)
column chromatography eluting with 2-4% CH3OH in CH2Cl2 to
afford N-ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-dimethyl-L-histidine
methyl ester (8a) and N-ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-
diethyl-L-histidine methyl ester (14a).
(CDCl3): ꢂ 1.00 (m, 3H), 1.40 (s, 9H), 1.60 (m, 2H), 3.22-3.26
(m, 2H), 3.79 (s, 3H), 3.89-3.92 (m, 2H), 4.05 (s, 3H), 4.53-4.60
(m, 1H), 7.30 (s, 1H), 9.84 (s, 1H); ESIMS: m/z 326 (M+1);
[ꢀ]D25 +7.3 (c 1, CHCl3). Anal. Calcd. for C16H27N3O4: C, 59.06;
H, 8.36; N, 12.91. Found, C, 58.78; H, 8.22; N, 13.25.
N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ-isopropyl,N-1(ꢁ)-methyl-
1
L-histidine methyl ester (8d). Yield: 14%; semi-solid; H nmr
(CDCl3): ꢂ 1.43 (s, 9H), 1.52 (d, 6H, J = 6.7 Hz), 3.20-3.27 (m,
2H), 3.83 (s, 3H), 3.90-3.94 (m, 1H), 4.05 (s, 3H), 4.55-4.61 (m,
25
1H), 7.28 (s, 1H), 9.80 (s, 1H); ESIMS: m/z 326 (M+1); [ꢀ]D
+4.3 (c 1, CHCl3). Anal. Calcd. for C16H27N3O4: C, 59.06; H,
8.36; N, 12.91. Found, C, 59.34; H, 8.64; N, 12.67.
N-ꢀ-(Ethoxycarbonyl)-N-ꢀ-methyl,N-1(ꢁ)-benzyl-L-histidine
methyl ester (9a). Yield: 87%; mp 68-69 °C; 1H nmr (CDCl3): ꢂ
1.16 (m, 3H), 3.25-3.30 (m, 2H), 3.71 (s, 3H), 3.92-3.97 (m,
5H), 4.55-4.60 (m, 1H), 5.47 (s, 2H), 7.32-7.36 (m, 5H), 7.14 (s,
25
1H); 9.81 (s, 1H); ESIMS: m/z 332 (M+1); [ꢀ]D +9.2 (c = 1,
CHCl3). Anal. Calcd. for C18H23N3O4: C, 62.59; H, 6.71; N,
12.17. Found, C, 62.68; H, 6.84; N, 12.06.
N-ꢀ-(Ethoxycarbonyl)-N-ꢀ-ethyl,N-1(ꢁ)-benzyl-L-histidine
methyl ester (9b). Yield: 68%; mp 62-63 °C; 1H nmr (CDCl3): ꢂ
1.06-1.18 (m, 6H), 3.18-3.24 (m, 2H), 3.63 (s, 3H), 3.91-3.94
(m, 2H), 4.16 (q, 2H, J = 7.2 Hz), 4.45-4.58 (m, 1H), 5.45 (s,
2H), 7.29-7.32 (m, 5H), 7.45 (s, 1H), 9.91 (s, 1H); ESIMS: m/z
25
360 (M+1); [ꢀ]D +8.1 (c 1, CHCl3). Anal. Calcd. for
C19H25N3O4: C, 63.49; H, 7.01; N, 11.69. Found, C, 63.63; H,
7.09; N, 11.78.
N-ꢀ-(Ethoxycarbonyl)-N-ꢀ-propyl,N-1(ꢁ)-benzyl-L-histidine
1
methyl ester (9c). Yield: 15%, semi-solid; H nmr (CDCl3): ꢂ
1.10-1.20 (m, 6H), 1.89-1.94 (m, 2H), 3.20-3.25 (m, 2H), 3.70
(s, 3H), 3.91-3.94 (m, 2H), 4.20-4.24 (m, 2H), 4.47-4.53 (m,
1H), 5.41 (s, 2H), 7.24-7.27 (m, 5H), 7.40 (s, 1H), 9.87 (s, 1H);
25
ESIMS: m/z 374 (M+1); [ꢀ]D +5.7 (c 1, CHCl3). Anal. Calcd.
for C20H27N3O4: C, 64.32; H, 7.27; N, 11.25. Found, C, 64.47; H,
7.15; N, 11.08.
N-ꢀ-(Ethoxycarbonyl)-N-ꢀ-isopropyl,N-1(ꢁ)-benzyl-L-
histidine methyl ester (9d). Yield: 15%, semi-solid; H nmr
N-ꢀ-(tert-Butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-diethyl-L-histidine
methyl ester (14a). Yield: 85%, oil; 1H nmr (CDCl3): ꢂ 1.41 (s,
9H), 1.60-1.65 (m, 6H), 3.09-3.12 (m, 2H), 3.68 (s, 3H), 4.28-
4.32 (m, 4H), 4.53-4.57 (m, 1H), 7.24 (s, 1H), 9.67 (s, 1H);
ESIMS: m/z 326 (M+1); [ꢀ]D25 +14.7 (c 1, CHCl3). Anal. Calcd.
for C16H27N3O4 (325.4): C, 59.06; H, 8.36; N, 12.91. Found, C,
59.31; H, 8.39; N, 13.06.
Synthesis of N-ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-
dibenzyl-L-histidine methyl ester (14b). Sodium hydride (60%
suspension, 1.11 mmol) was washed with petroleum ether (2 ꢃ 5
mL) and dried under vacuum. N-ꢀ-(tert-butoxycarbonyl)-L-
histidine methyl ester (13, 0.37 mmol) dissolved in DMF (5 mL)
was added and reaction mixture stirred for 2 h at ambient
temperature under N2. Benzyl bromide (1.85 mmol) was then
added and reaction mixture stirred for 10 h at 80 ºC. The
reaction was quenched by addition of saturated NH4Cl solution
(5 mL) and the solvent removed under reduced pressure. The
solid residue was extracted with chloroform (2 ꢃ 10 mL), and
the combined organic layers were dried over Na2SO4. The
solvent was removed under reduced pressure and the crude
product was purified by silica gel (230–400 mesh) column
chromatography eluting with 4% CH3OH in CH2Cl2 to afford N-
ꢀ-(tert-butoxycarbonyl)-N-ꢀ,N-1(ꢁ)-dibenzyl-L-histidine methyl
1
(CDCl3): ꢂ 1.14-1.13 (m, 3H), 1.60 (d, 6H, J = 6.6 Hz), 3.21-
3.24 (m, 2H), 3.72 (s, 3H), 3.90-3.92 (m, 2H), 4.20-4.24 (m,
1H), 4.43-4.48 (m, 1H), 5.46 (s, 2H), 7.21-7.24 (m, 5H), 7.34 (s,
25
1H), 9.80 (s, 1H); ESIMS: m/z 374 (M+1); [ꢀ]D +5.4 (c 1,
CHCl3). Anal. Calcd. for C20H27N3O4: C, 64.32; H, 7.27; N,
11.25. Found, C, 64.17; H, 7.14; N, 11.16.
Typical procedure for the synthesis of N-ꢀ,N-1(ꢁ)-dialkyl-
L-histidine hydrochloride (10–11). A solution of 7a or 9a (1
mmol) in 6 N HCl (15 mL), was heated at reflux for 8 h. The
hydrochloride salts 10–11 of the N-ꢀ,N-1(ꢁ)-dialkyl-L-histidines
were obtained directly by evaporation of the acidic hydrolysis
solution.
N-ꢀ,N-1(ꢁ)-Dimethyl-L-histidine hydrochloride (10).
1
Yield: 98%; mp 164-166 °C (dec); H nmr (CD3OD): ꢂ 3.32-
3.50 (m, 2H), 3.91 (s, 3H), 3.93 (s, 3H), 4.40-4.50 (m, 1H), 4.52
(brs, 1H), 7.59 (s, 1H), 8.95 (s, 1H); ESIMS: m/z 184 (M+1);
[ꢀ]D25 –10.2 (c 1, H2O). Anal. Calcd. for C8H14ClN3O2: C, 43.74;
H, 6.42; N, 19.13. Found, C, 43.54; H, 6.73; N, 19.35.
N-ꢀ-Benzyl,N-1(ꢁ)-methyl-L-histidine hydrochloride (11).
Yield: 94%, mp 178-180 °C (dec); 1H nmr (CD3OD) ꢂ 3.38-3.41
(m, 2H), 3.92 (s, 3H), 4.45-4.48 (m, 1H), 5.0 (brs, 1H), 5.44 (s,

Nov-Dec 2007
Facile Regiospecific Syntheses of N-ꢀ,N-1(ꢁ)-Dialkyl-L-Histidines
1269
1
[6] Rajeswaran, W. G.; Hocart, S. J.; Murphy, W. A.; Taylor, J.
E.; Coy, D. H. J. Med. Chem. 2001, 44, 1416.
[7] Rajeswaran, W. G.; Murphy, W. A.; Taylor, J. E.; Coy, D. H.
Bioorg. Med. Chem. 2002, 10, 2023.
[8] Jain, R.; Cohen, L. A. Tetrahedron 1996, 52, 5363.
[9] Jain, R.; Cohen, L. A.; El-Kadi, N. A.; King, M. M.
Tetrahedron 1997, 53, 2365.
ester (14b). Yield: 61%, oil; H nmr (CDCl3): ꢂ 1.34 (s, 9H),
3.00-3.04 (m, 2H), 3.39 (s, 3H), 4.53-4.58 (m,1H), 5.55-5.57 (m,
4H), 7.33-7.40 (m, 10H), 7.48 (s, 1H), 9.79 (s, 1H); ESIMS: m/z
25
450 (M+1); [ꢀ]D -5.1 (c 1, CHCl3). Anal. Calcd. for
C26H31N3O4 (449.5): C, 69.47; H, 6.95; N, 9.35. Found, C, 69.12;
H, 7.24; N, 8.97.
Typical procedure for the synthesis of N-ꢀ,N-1(ꢁ)-diethyl-
L-histidine hydrochloride (15a) and N-ꢀ,N-1(ꢁ)-dibenzyl-L-
histidine hydrochloride (15b). These compounds were
synthesized using procedure described above for compounds 10-
11.
[10] Jain, R.; Cohen, L. A.; King, M. M. Tetrahedron 1997, 53,
4539.
[11] Jain, R.; Avramovitch, B.; Cohen, L. A. Tetrahedron 1998,
54, 3235.
[12] Narayanan, S.; Suryanarayana, V.; Jain, R. Bioorg. Med.
Chem. Lett. 2001, 11, 1133.
[13] Jain, R. Suryanaryana, V.; Jain, M.; Kaur, N.; Singh, S.;
Singh, P. P. Bioorg. Med. Chem. Lett. 2002, 12, 1701.
[14] Chandna, P.; Nayyar, A.; Jain, R. Synth. Commun. 2003, 33,
2925.
N-ꢀ,N-1(ꢁ)-Diethyl-L-histidine hydrochloride (15a). Yield:
1
90%, mp 178-180 °C (dec); H nmr (CD3OD): ꢂ 0.96 (m, 3H),
1.21 (m, 3H), 3.35-3.41 (m, 6H), 4.22-4.25 (m, 1H), 4.90 (brs,
1H), 7.62 (s, 1H), 8.94 (s, 1H); ESIMS: m/z 212 (M+1); [ꢀ]D
–
25
14.6 (c 1, H2O). Anal. Calcd. for C10H18ClN3O2: C, 48.48; H,
7.32; N, 16.96. Found, C, 48.70; H, 7.51; N, 17.07.
[15] Kaur, N.; Monga, V.; Jain, R. Tetrahedron Lett. 2004, 45,
6883.
[16] Currently accepted numbering and naming of the
regioisomers are both included to avoid confusion: IUPAC-IUB
Commission on Biochemical Nomenclature J. Biol. Chem. 247, 977
(1972).
N-ꢀ,N-1(ꢁ)-Dibenzyl-L-histidine hydrochloride (15b).
Yield: 92%, mp 191-193 °C (dec); H nmr (CD3OD): ꢂ 3.31-
3.37 (m, 2H), 4.40-4.45 (m, 1H), 4.95 (brs, 1H), 5.21-5.25 (m,
1
4H), 7.25-7.30 (m, 10H), 7.65 (s, 1H), 8.97 (s, 1H); ESIMS: m/z
336 (M+1); [ꢀ]D –10.1 (c 1, H2O). Anal. Calcd. for
[17] a) Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273.
b) Wiꢀniewski, K.; Koꢁodziejczyk, A. S. Tetrahedron Lett. 1997, 38,
483. c) Luke, R. W. A.; Boyce, P. G. T.; Dorling, E. K. Tetrahedron
Lett. 1996, 37, 263. d) Reddy, G. V.; Rao, G. V.; Iyengar, D. S.
Tetrahedron Lett. 1998, 39, 1985. e) Ruckle, T.; Dubray, B.; Hubler, F.;
Mutter, M. J. Pept. Sci. 1999, 5, 56. f) Chruma, J. J.; Sames, D.; Polt, R.
Tetrahedron Lett. 1997, 38, 5085. g) O'Donnell, M. J.; Bruder, W. A.;
Daugherty, B. W.; Liu, D.; Wojciechowski, K. Tetrahedron Lett. 1984,
25, 3651. h) Grieco, P. A.; Bahsas, A. J. Org. Chem. 1987, 52, 5746. i)
Oppolzer, W. A.; Tamura, O. Tetrahedron Lett. 1990, 31, 991. j) Dorow,
R. L.; Gingrich, D. E. J. Org. Chem. 1995, 60, 4986. k) Fukuyama, T.;
Jow, C. K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373. l) Hall, D. G.;
Laplante, C.; Manku, S.; Nagendran, J. J. Org. Chem. 1999, 64, 698.
[18] Aurelio L.; Brownlee, R. T. C.; Hughes, A. B. Org. Lett.
2002, 4, 3767.
25
C20H22ClN3O2: C, 64.60; H, 5.96; N, 11.30. Found, C, 64.94; H,
5.77; N, 11.58.
Acknowledgement. Navneet Kaur and Vikramdeep Monga
thank the University Grants Commission (UGC), India, and the
Council of Scientific and Industrial Research (CSIR, Grant No.
01(1861)/03/EMR-II), India, respectively for the award of
Senior Research Fellowship.
REFERENCES AND NOTES
†
Present address: Laboratory of Anticancer Research, Korea
Research Institute of Bioscience and Biotechnology (KRIBB), 52,
Eoeundong, Yuseonggu, Daejeon 305-333, South Korea.
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[22] The optical purity of modified histidine analogues were
assessed on HPLC using CHIRALPAK WH chiral column (ID 0.46 cm,
particle size 10μm), and results indicate presence of ꢃ1.2% of the D-
enatiomer in all cases.
[3] Manavalan, P.; Momany, F. A. Biopolymers 1980, 19, 1943.
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