Amino Acyl conjugates of nitrogen heterocycles as potential pharmacophores

Article abstract of DOI:10.1021/jo100625y

Figure presented 2-Methyl- and 4-methylpyridine and 2-methylquinoline are converted by benzotriazole-activated (Cbz)-protected amino acids into chiral potential novel pharmacophore aminoacyl conjugates (33-53%).

Full text of DOI:10.1021/jo100625y

pubs.acs.org/joc
isozymes,12 effective biochemical markers of bone resorption,13
Amino Acyl Conjugates of Nitrogen Heterocycles as
Potential Pharmacophores
efficient organogelators,14 and bacterial growth inhibitors.15
Amino acids and peptides attached to a drug scaffold can
increase solubility, selectivity, and bioavailability; thus, the
biological activity of 6,11-dimethyl-6H-indolo[2,3-b]quinoline
is increased in amino acid derivatives.16 The antitumor acti-
vity of N-L-leucine-doxorubicin shows increased selectivity
over doxorubicin (Dox).17
Alan R. Katritzky,* Kiran Bajaj, Mael Charpentier, and
Ebrahim Ghazvini Zadeh
Center for Heterocyclic Compounds, University of Florida,
Department of Chemistry, Gainesville, Florida 32611-7200
N-Acylbenzotriazoles are advantageous for (i) N-acyla-
tion in the preparation of primary, secondary, tertiary,18 and
heterocyclic amides,19 Weinreb amides,20 and N- acylindoles,17
(ii) C-acylation in the preparation of β-ketosulfones,21 primary
and secondary R-cyanonitriles,22 R-nitroketones,23 ketones,24
and R-ketoazines,25 and (iii) O-acylation of aldehydes26 and
of steroids27 to give esters.
katritzky@chem.ufl.edu
Received April 1, 2010
C-Acylation28,29 of 2-methylnicotinamides has previously
been achieved using Weinreb amides in the presence of LDA/
TMEDA and i-PrMgCl/THF (Scheme 1, 70%)29 and coup-
ling reagents such as HOBt, but the procedures lead to race-
mization under a variety of conditions.29
2-Methyl- and 4-methylpyridine and 2-methylquinoline
are converted by benzotriazole-activated (Cbz)-protected
amino acids into chiral potential novel pharmacophore
aminoacyl conjugates (33-53%).
SCHEME 1
R-Amino acids and their derivatives are central to the
chemistry and biology of peptides and proteins as well as
versatile synthetic building blocks for pharmaceutical appli-
cations, precursors for the generation of molecular diversity,
important templates in asymmetric catalysis, and common sub-
units in many bioactive compounds and natural products.1
Pyridine and quinoline scaffolds possess important pharma-
cological activities including anti-inflammatory,2,3 anti-
convulsant,4,5 antibacterial,6,7 antihistaminic,8 and anti-
cancer.9 Pyridines substituted by R-aminoacyl groups include
useful drugs for osteoporosis and other metabolic bone
diseases,10,11 potent inhibitors of nitric oxide synthase (NOS)
We now report a convenient one-step conversion of
2-methyl- and 4-methylpyridine and 2-methylquinoline
into protected amino acyl conjugates as potential model
pharamacophores; a single analogous example was published
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3938 J. Org. Chem. 2010, 75, 3938–3940
Published on Web 05/11/2010
DOI: 10.1021/jo100625y
r
2010 American Chemical Society

Katritzky et al.
JOCNote
TABLE 1. Preparation of N-Cbz-Protected (R-Aminoacyl)methylenepyridines and -quinolines
reactant
Het-CH3
product
% keto form
yield (%)
[R]25
D
Z-L-Ala-Bt 1a
Z-L-Val-Bt 1b
Z-L-Ile-Bt 1c
Z-L-Trp-Bt 1d
Z-L-Ala-Bt 1a
Z-L-Val-Bt 1b
Z-L-Ala-Bt 1a
Z-DL-Ala-Bt (1a þ 1a0)
Z-L-Val-Bt 1b
Z-L-Ile-Bt 1c
2-methylpyridine
2-methylpyridine
2-methylpyridine
2-methylpyridine
4-methylpyridine
4-methylpyridine
2-methylquinoline
2-methylquinoline
2-methylquinoline
2-methylquinoline
2-methylquinoline
2-methylquinoline
Z-Ala-CH2-2-(pyridyl) (3a þ 4a)
Z-Val-CH2-2-(pyridyl) (3b þ 4b)
Z-Ile-CH2-2-(pyridyl) (3c þ 4c)
Z-Trp-CH2-2-(pyridyl) (3d þ 4d)
Z-Ala-CH2-4-(pyridyl) 6a
71
59
59
67
100
100
0
0
0
0
0
50
50
53
33
44
46
48
32
53
52
49
52
þ7.57
þ2.00
-11.03
þ26.25
-5.00
Z-Val-CH2-4-(pyridyl) 6b
þ19.25
Z-Ala-CH2-2-(quinolinyl) 9a
Z-Ala-CH2-2-(quinolinyl) (9a þ 9a0)
Z-Val-CH2-2- (quinolinyl) 9b
Z-Ile-CH2-2-(quinolinyl) 9c
Z-Trp-CH2-2-(quinolinyl) 9d
Z-Lys(Z)-CH2-2-(quinolinyl) 9e
-25.5
Racemic
-79.8
-70.26
þ6.63
Z-L-Trp-Bt 1d
Z-L-Lys(Z)-Bt 1e
0
-39.3
SCHEME 2
SCHEME 3
previously with optical rotation as the only measurement of
chirality.30
SCHEME 4
Lithiation of 2-methylpyridine using n-BuLi in dry THF-
hexamethylphosphoramide (HMPA) at -78 °C followed by
reaction of 2 with N-Cbz-R-aminoacylbenzotriazoles31 (1a-d)
gave 2-(N-Cbz-R-aminoacyl)methylpyridines (3a-d and 4a-d)
(33-53%) (Scheme 2, Table 1).
In CDCl3 solution, these compounds exist as mixtures of
keto 3a-d and enol 4a-d tautomers as demonstrated by
1
their H and 13C NMR spectra. The ratios of the keto and
enolic forms (given in Table 1) are calculated from 1H NMR
1
integrals. The H NMR spectrum of (3a þ 4a) showed an
enolic methine proton singlet at δ 5.17 and a characteristic
AB quartet for the R-methylene carbon of the keto form at
δ 4.10 and 4.00. The 13C NMR spectrum of (3aþ4a) showed
the enolic methine carbon signal at δ 91.8 and that for the
R-methylene carbon of the keto form at δ 48.5.
Similarly, lithiation of 4-methylpyridine using LDA at -78 °C
in dry THF and treatment with N-Cbz-protected (R-amino-
acyl)benzotriazoles (1a,b) gave N-(R-Cbz-aminoacyl)methylene
heterocycles (6a,b) (44-46%) (Scheme 3, Table 1). Compounds
6a,b exist essentially completely in the keto forms (6a,b). Thus,
the 1H NMR spectrum of 6a showed the R-methylene proton of
the keto form as a singlet at δ 3.80. The 13C NMR spectrum
showed signals for the carbonyl group and for the R-methylene
carbon of the keto form at δ 204.9 and 44.9, respectively. No
enolic OH signal was found.
pounds exist in CDCl3 solution essentially completely in their
enolic forms (9a-e, (9aþ9a0)). Thus, the 1H NMR spectrum of
9a showed a methine proton singlet at δ 5.37 and the 9a 13C
NMR spectrum showed the δ 88.9 signal characteristic of an
enolic methine carbon. No quinolin-2-CH2 group signal was
found.
As discussed above, the compounds derived from 2-pico-
line exist in CDCl3 solution as mixture of the keto 3a-d
(58-70%) and enol 4a-d (30-42%) tautomers. The com-
pounds derived from 2-methylquinoline exist essentially in
the enolic form 9a-e or (9a þ 9a0), which are stabilized by
intramolecular H-bonds from the enolic OH group with the
nitrogen of the heterocycle. By contrast, compound 6a and
6b (derived from 4-picoline) where these could be no intra-
molecular H-bonding in the enols, exist essentially comple-
tely as keto forms.
Again, treatment of N-(Cbz-R-aminoacyl)benzotriazoles
(1a-e, (1a þ 1a0)) with lithiated 2-methylquinoline (8) gave
N-Cbz-protected (R-aminoacyl)methylene heterocycles (9a-e,
(9a þ 9a0)) in 32-53% yield. (Scheme 4, Table 1) These com-
(30) Katritzky, A. R.; Zuoquan, W.; Hall, D., C. ARKIVOC 2008, x, 26.
(31) Katritzky, A. R.; Singh, A.; Haase, D. N.; Yoshioka, M. ARKIVOC
2009, viii, 47.
The chiral integrity of compound 9a was established
by normal-phase hexane/2-propanol chromatography on a
J. Org. Chem. Vol. 75, No. 11, 2010 3939

Katritzky et al.
JOCNote
TABLE 2. Synthesis of N-Protected (R-Aminoacyl)benzotriazoles
at -20 °C for 1-3 h, quenched with water (20 mL), and extracted
with ethyl acetate (150 mL). The organic layer was washed with
saturated sodium carbonate solution (1 M, 3 ꢀ 50 mL) and dried
over anhydrous magnesium sulfate and solvent removed under
reduced pressure. The residue was purified by column chromato-
graphy on silica gel using a mixture of hexanes/ethyl acetate as
eluent to give the expected product.
(S)-Benzyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (3aþ4a):
yellow oil (50%); 1H NMR (300 MHz, CDCl3) δ (keto form 3a)
8.53 (d, J=3.6 Hz, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.42-7.28 (m,
5H), 7.30-7.16 (m, 2H), 5.84-5.77 (m, 1H), 5.17-5.06 (m, 2H),
4.58-4.47 (m, 1H), 4.08 (d, J = 15.6 Hz, 1H, A part of AB
system), 4.00 (d, J=15.9 Hz, 1H, B part of AB system), 1.40 (d,
J=6.9 Hz, 3H), (enol form 4a) 8.03 (d, J=5.4 Hz, 0.4H), 7.53 (t,
J = 6.8 Hz, 0.8H), 7.42-7.28 (m, 2.0H), 6.92-6.83 (m, 0.8H),
5.42 (s, 0.4H), 5.17-5.06 (m, 0.8H), 5.02-4.98 (m,0.4H),
4.44-4.32 (m, 0.4H), 1.40 (d, J = 6.9 Hz, 1.2H); 13C NMR
(75 MHz, CDCl3) keto þ enol form (3a þ 4a) δ 205.8, 155.7,
154.2, 149.5, 141.5, 137.4, 136.8, 136.3, 128.5, 128.1, 128.0,
124.2, 122.2, 121.2, 117.0, 91.8, 66.9, 55.7, 51.4, 48.5, 20.1,
17.6. Anal. Calcd for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39.
Found: C, 68.08; H, 6.50; N, 9.20.
1a-e, 1a0
products (1)
mp (°C)
lit. mp (°C)
[R]25
-8.0
D
Z-L-Ala-Bt (1a)
Z-DL-Ala-Bt (1a þ 1a0)
114-115.5
111.0-112.0
106.8-108.3
77.5-78.8
104.0-105.0
74.0-83.0
114.0-115.0
112.0-113.0
73.0-74.0
73.0-75.0
100.0-101.0
novel
racemic
-30.5
Z-L-Val-Bt (1b)
Z-L-Ile -Bt (1c)
-3.93
Z-L-Trp-Bt (1d)
Z-L-Lys(Z)-Bt (1e)
þ25.27
-24.50
Chiralcel OD-H column with (þ) ESI-MS: 9a showed one
major peak (retention time 34.4 min). By contrast, racemic
mixture (9aþ9a0) revealed two peaks with retention times of
34.4 and 61.4 min but each of mass 348. Clearly, the peak at
34.4 min is the L-isomer 9a and the peak at 61.4 min is the
D-isomer 9a0. Compound 9a and racemic mixture (9a þ 9a0)
were also analyzed via reversed-phase gradient nonchiral
C-18 HPLC-MS. Each displayed only one major peak (MW
348), eluting at essentially the same retention time (40.34 and
40.22 min, respectively).
In conclusion, we have described a general and convenient
one-step preparation of chirally pure aminoacyl conjugates
of pyridine and quinoline (33-53%) with simple preparative
and purification procedures. The literature method29 for the
preparation of these bioactive compounds involved several
steps and a coupling reagent (HOBt on i-PrMgCl) and led to
racemization, speculated to result from H-bonding between
the pyridine nitrogen and enolic OH group.29 In contrast,
our synthesized example 9a (alanine-quinoline conjugate),
which exists essentially in the enolic form, is chirally pure.
The advantages of using Bt-activation include: (a) good
yields, (b) simple preparative and purification procedures,
(c) applicability to a variety of carbobenzyloxy (Cbz)-protected
amino acids, and (d) low cost.
(S,Z)-Benzyl 3-hydroxy-4-(quinolin-2-yl)but-3-en-2-ylcarbamate
9a: yellow crystals; mp 56.4 °C (48%); H NMR (300 MHz,
1
CDCl3) δ 14.69 (s, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.50 (t, J =
7.4 Hz, 2H), 7.41-7.28 (m, 6H), 7.28-7.18 (m, 1H), 6.70 (d, J=
9.0 Hz, 1H), 5.72 (d, J = 6.3 Hz, 1H), 5.37 (s, 1H), 5.20-5.04
(m, 2H), 4.48-4.34 (m, 1H), 1.41 (d, J=6.6 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 192.6, 155.7, 153.5, 136.9, 136.7, 136.4,
131.1, 128.4, 128.0, 127.9, 127.6, 123.6, 122.8, 121.9, 117.1, 88.9,
66.5, 53.5, 20.3. Anal. Calcd for C21H20N2O3: C, 72.39; H, 5.79;
N, 8.04. Found: C, 72.16; H, 5.45; N, 8.05.
General Procedure for the Preparation of N-Cbz-protected
(r-Aminoacyl)methylene Heterocycles 6a,b. To 4-picoline (1 equiv)
in dry THF (30 mL) was added LDA (2.0 equiv) dropwise during
15 min at -78 °C and the mixture stirred for 3 h. The temperature
was then allowed to rise to -20 °C, and a solution of N-Cbz-R-amino-
acyl-Bt (1 equiv) in dry THF (20 mL) was added by syringe at
-20 °C under nitrogen. The resulting mixture was stirred at -20 °C
for 1 h, quenched with ammonoium chloride solution (20 mL), and
extracted with ethyl acetate (150 mL). The organic layer was washed
with saturated sodium carbonate solution (1M, 3 ꢀ 50 mL) and
dried over anhydrous magnesium sulfate and solvent removed
under reduced pressure. The residue was recrystallized from ethyl
ether to give the desired product.
(S)-Benzyl (3-oxo-4-(pyridin-4-yl)butan-2-yl)carbamate 6a:
yellow powder; mp 95.0-98.0 °C (44%); 1H NMR (300 MHz,
CDCl3) δ 8.52 (br s, 2H), 7.33 (br s, 5H), 7.14-7.08 (m, 2H), 5.70
(d, J=5.7 Hz, 1H), 5.09 (br s, 2H), 4.46 (t, J=7.1 Hz, 1H), 3.80
(s, 2H), 1.38 (d, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
204.9, 155.7, 149.8, 142.1, 136.0, 128.5, 128.2, 128.0, 124.7, 67.0,
55.5, 44.9, 17.2; HRMS Calcd for C17H19N2O3 [M þ H]þ
299.1390, found 299.1389.
Experimental Section
General Procedure for the Preparation of N-Cbz-protected
(r-Aminoacyl)benzotriazoles 1a-e. Compounds are synthesized
following our established procedure (Tables 2).31
(S)-Benzyl 6-(1H-benzo[d][1,2,3]triazol-1-yl)-6-oxohexane-1,5-
diyldicarbamate (Z-Lys(Z)-Bt) (1e): white-tan powder; mp 74.0-
83.0 °C (50%); 1H NMR (300 MHz, CDCl3) δ 8.25 (d, J=8.1 Hz,
1H), 8.13 (d, J=8.1 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.52 (t, J=
7.5 Hz, 1H), 7.31 (br s, 9H), 7.11 (br s, 1H), 5.92-5.86 (br s, 1H),
5.82-5.72 (m, 1H), 5.13-5.08 (m, 2H), 5.08-5.02 (m, 2H), 4.92
(br s, 1H), 3.29-3.06 (m, 2H), 2.20-2.02 (m, 1H), 1.99-1.82 (m,
1H), 1.66-1.42 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 171.9,
156.8, 156.3, 146.1, 136.7, 136.2, 131.2, 130.8, 128.6, 128.3, 128.1,
126.6, 120.5, 114.5, 67.4, 66.8, 54.6, 40.3, 32.4, 29.4, 22.6. Anal.
Calcd for C28H29N5O5: C, 65.23; H, 5.67; N, 13.58. Found: C,
65.37; H, 6.04; N, 13.33.
General Procedure for the Preparation of N-Cbz-protected
(r-Aminoacyl)methylene Heterocycles 3a-d, 4a-d, 9a-e, and 9a0.
Asolutionofn-BuLi (2.5 equiv, 1.6 M in hexane) and HMPA (6 equiv)
was added dropwise to a solution of 2 or 6 (1 equiv) in dry THF
(30 mL) at -78 °C, and the mixture was stirred for 3 h. The tempe-
rature was then allowed to rise to -20 °C, and a solution of
N-Cbz-R-aminoacyl-Bt (1 equiv) in dry THF (20 mL) was added by
syringe at -20 °C under nitrogen. The resulting mixture was stirred
Acknowledgment. We thank Dr. C. D. Hall for help with
the preparation of this manuscript and Dr. J. V. Johnson for
HPLC studies.
Supporting Information Available: Compound characteri-
zation data for (3aþ4a), (3bþ4b), (3cþ4c), (3dþ4d), 6b, (9aþ
9a0), and 9b-e. This material is available free of charge via the
Internet at http://pubs.acs.org
3940 J. Org. Chem. Vol. 75, No. 11, 2010