A novel synthesis of chromone based unnatural α -amino acid derivatives

Article abstract of DOI:10.1007/s12039-017-1328-9

An efficient method for the preparation of chromone based α -amino acid derivatives by alkylation of glycinate schiff base with 3-bromomethyl chromone as well as 2-bromomethyl chromone has been described. Using this method, 2-amino-3-(4-oxo-2-chromenyl)propanoic acid and 2-amino-3-(4-oxo-3-chromenyl)propanoic acid, two novel chromone-amino acid conjugates have been prepared. Furthermore, the separation of chromone amino acid enantiomers by chiral column chromatography was accomplished. Graphical Abstract?: Synopsis: An efficient method for the preparation of chromone based α -amino acid derivatives by alkylation of glycinate schiff base with 3-bromomethyl chromone as well as 2-bromomethyl chromone has been described. These conjugates can be considered as analogues of phenyl alanine where phenyl group has been replaced by chromone moiety.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-017-1328-9

J. Chem. Sci.
© Indian Academy of Sciences
DOI 10.1007/s12039-017-1328-9
REGULAR ARTICLE
α
A novel synthesis of chromone based unnatural -amino acid
derivatives†
VENU KANDULAa,b, RAMAKRISHNA GUDIPATIa, ANINDITA CHATTERJEEb,
MURALIDARAN KALIYAPERUMALAa, SATYANARAYANA YENNAMa and
MANORANJAN BEHERAa,∗
aDepartment of Medicinal Chemistry, GVK Biosciences Pvt. Ltd., Survey No. 125, 126 IDA, Mallapur,
Hyderabad, Telangana 500 076, India
bDepartment of Chemistry, K L University, Vaddeswaram, Guntur, Andhra Pradesh 522 502, India
E-mail: Manoranjan.Behera@gvkbio.com
MS received 23 March 2017; revised 18 May 2017; accepted 19 June 2017
α
Abstract. An efficient method for the preparation of chromone based -amino acid derivatives by
alkylation of glycinate schiff base with 3-bromomethyl chromone as well as 2-bromomethyl chromone has
been described. Using this method, 2-amino-3-(4-oxo-2-chromenyl)propanoic acid and 2-amino-3-(4-oxo-3-
chromenyl)propanoic acid, two novel chromone-amino acid conjugates have been prepared. Furthermore, the
separation of chromone amino acid enantiomers by chiral column chromatography was accomplished.
Keywords. Chromone; unnatural aminoacids; isoflavones; alkylation; hybrid molecules; glycine derivatives.
1. Introduction
activities but also for other applications such as prepa-
ration of fluorescent probes due to the photochemical
properties of chromones.12
Chemically, chromones (4H-chromene-4-ones) are het-
erocyclic compounds with the benzo- -pyrone frame-
γ
α
-
Unnatural amino acids, the non-proteinogenic
work. Molecules containing the chromone or benzopy-
rone ring have a wide range of biological activities.1
They have been shown to be tyrosine and protein kinase
inhibitors,2,3 as well as anti-inflammatory,4 antiviral,5
antioxidant6 and antihypertensive agents.5 Chromone
derivatives are also active as benzodiazepine receptors,7
on lipooxygenase and cyclooxygenase.8 In addition
to this, they have shown to be anticancer agents.9
Chromones may also have application in cystic fibrosis
treatment, as they activate the cystic fibrosis trans-
membrane conductance regulator.10 The vast range
of biological effects associated with this scaffold has
resulted in the chromone ring system being considered
as a privileged structure.11 The main objectives of the
chromone synthesis are not only for the development
of more diverse and complex molecules for biological
amino acids that either occurs naturally or chemically
synthesized have been used widely as chiral building
blocks. They have also been used as molecular scaf-
folds in constructing combinatorial libraries.13 In recent
years, both pharmaceutical companies and academics
became interested in the design and synthesis of pep-
tidomimetics and peptide analogues as new therapeutic
drugs.14–16 The progress of Medicinal Chemistry in
these fields was probably inspired by the biochemical
advancements in the recognition of new naturally occur-
ring peptides possessing useful biological activities and
in the elucidation of their physiological functions.17
However, peptides assembled with natural amino acids
present several drawbacks related to metabolic insta-
bility, deficiency in selective interactions and reduced
oral absorption that prevent their use in therapy.18 On
the other hand, peptidomimetics offer the advantages
of nearly countless manipulations in order to control
the biological functions, stability, potency, and ADME
parameters.19 In particular, the inclusion of the amino
acid framework in a cyclic or bicyclic structure con-
*
For correspondence
†
th
Dedicated to Prof. Sambasivarao Kotha on the occasion of his 60
birthday.
Electronic supplementary material: The online version of this article (doi:10.1007/s12039-017-1328-9) contains supplementary material,
which is available to authorized users.

Venu Kandula et al.
R''
N
R''
HN
O
O
R'
O
O HN
O
R'
O
R'''
OH
O
HN
R
R
R
6
3
H
OH
O
R
O
NH O
R'''
2
NH
2
R
8
3
2
1
HN
O
OMe
O
O
Br
O
O
NHAr
NHAr
NHCBz
O
O
Cl
5
4
Figure 1. Chromone derivatives as β-turn peptidomimetcis.
fers specific features to the synthesized molecules: preparation of chromone based amino acid in the lit-
well-defined secondary structure, structural rigidity, erature.35 However, the method suffers from several
enhanced binding activity and selectivity.20,21 The sem- disadvantages such as low yield, formation of side
inal work on synthesis of unnatural amino acids has products, use of concentrated acid and isolation of
been done by O’Donnell22 and Maruoka23 indepen- polar compounds in each step was cumbersome. In
dently which accelerated the application of this amino our continuation of endeavour to prepare novel hybrid
acid for practical application.
molecules consisting a variety of natural products,36
β-turn peptidomimetics (1, Figure 1) has attracted the we developed an interest in the synthesis of chromone-
attention of many researchers in the design of struc- based amino acid hybrid and herein we report our
tures24,25 due to the importance of this fragment in results.
protein folding and in the protein-receptor interaction
process.26,27 Luthman et al., has proposed chromones
with different functionalized substituents as mimetics
of short peptides.28,29 The reason for their proposal is
2. Experimental
that the conformation of a β-turn of a peptide (1, Fig-
2.1 Materials and characterization
ure 1) corresponds well with 2,3,6,8-tetrasubstituted
chromone (2, Figure 1). The same group has also
prepared the chromone derivative 3 as a potential
β-turn peptidomimetics with the incorporation of an
amino group in the 3-position and a carboxy func-
tionality in the 6-position (3, Figure 1).30 Also, the
chromone derivatives 4 and 5 were prepared using dif-
ferent synthetic methodology as β-turn peptidomimet-
ics.28,31
Synthesis of hybrid natural products has gained
momentum in recent years.32,33 It is expected that com-
bining features of more than one biologically active
natural segment in a single molecule may result in
pronounced pharmacological activity while retaining
high diversity and biological relevance.34 Taking into
consideration these two biologically significant struc-
Compound 6a (95% purity) was purchased from Spec-
trochem, India. Dry solvents were purchased from chemical
suppliers and used without further purification. All melting
points were taken in open capillaries and are uncorrected.
Analytical thin-layer chromatography (TLC) was performed
on commercially available Merck TLC Silica gel 60 F254
.
Silica gel column chromatography was performed on silica
gel 60 (spherical 100–200 μm). FTIR spectra were recorded
on Perkin-Elmer FT/IR-4000 spectrophotometer and only the
characteristic peaks are reported. Mass spectra were scanned
1
on a Shimadzu LCMS 2010 spectrometer. H NMR spec-
tra were recorded on Varian-400 (400 MHz) spectrometer.
Chemical shifts of 1H NMR spectra were reported rela-
tive to tetramethylsilane. 13C NMR spectra were recorded
on Varian-400 (100 MHz) spectrometer. Chemical shifts of
13C NMR spectra were reported to relative to CDCl3 (77.0).
Splitting patterns were reported as s, singlet; d, doublet;
t, triplet; q, quartet; m, multiplet; dd, double doublet; br,
broad.
α
tures (chromone and -amino acid), we plan to develop
a general method for the synthesis of chromone-
amino acid hybrids. There is a report describing the

Synthesis of chromone based unnatural amino acids
2.2 Experimental procedure for the preparation of
4-oxo-4H-chromene-3-carbaldehyde (7a):
2.3a 3-(hydroxymethyl)-6-methyl-4H-chromen-4-one
(8b): The compound was prepared according to the proce-
dure similar to compound 8a. M.R: 136–140◦C; FT-IR: (KBr,
To a solution of compound 6a (20 g, 147.12 mmol) in DMF cm−1): 3417, 3065, 2923, 1636, 1481, 1330, 1202, 1020, 814,
(57 mL, 735.02 mmol) was added (COCl)2 (62.5 mL, 735.01 693. 1H NMR (400 MHz, CDCl3): δ 8.0 (s, 1H, Ar-H), 7.91,
mmol) in a dropwise manner at 0◦C under argon atmo- (s, 1H, Ar-H), 7.49 (d, J =2 Hz, 1H, Ar-H), 7.38 (d, J =8.8
sphere; then was added 50 mL of DMF and stirred at RT Hz, 1H, Ar-H), 4.58 (d, J =6 Hz, 2H, CH2), 2.97 (t, 1H, OH),
for 16 h. The progress of the reaction was monitored by 2.47 (s, 3H, Ar-CH3); MS: (EI): m/z 191 (M+1, 100).
TLC analysis (20% EtOAc/pet ether). After completion of
the reaction, the reaction mixture was quenched with water;
2.4 Experimental procedure for the preparation of
brown solids were formed. Filtered the solids and washed
3-(bromomethyl)-4H-chromen-4-one (9a):
with water to give the compound 7a (20 g, 80% yield) as
a brown solid. (Melting Range) M.R: 149–153◦C; FT-IR:
To a solution of compound 8a (7 g, 39.70 mmol) in CH2Cl2
(KBr, cm−1): 3059, 2867, 1647, 1460, 1307, 1145, 1105,
(70 mL) was added PBr3 (12.88 g, 47.70 mmol) at 0◦C and
847, 765. 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H,
stirred the reaction mixture at RT for 1 h. The progress of
CHO), 8.5 (s, 1H, Ar-H), 8.3 (dd, J = 8.4, 1.6 Hz, 1H,
the reaction was monitored by TLC analysis (20% EtOAc/pet
Ar-H), 7.76 (t, 1H, Ar-H), 7.53 (m, 2H, Ar-H); 13C NMR
ether). After the reaction was completed, the reaction mixture
(100 MHz, CDCl3): δ 188.6 (C-11), 175.9 (C-4), 160.6 (C-
was quenched with ice and extracted with EtOAc (3×100
2), 156.1(C-9), 134.8 (C-7), 126.6 (C-5), 126.1 (C-6), 125.2
mL). Combined organic layers were washed with water, brine
(C-10), 120.2 (C-3), 118.5 (C-8); MS: (EI): m/z 175 (M + 1,
and dried over anhydrous Na2SO4. Evaporation of the solvent
100); HRMS: (ESI): Calcd. for C10H6O3 [M+H]: 175.0392;
under vacuum gave the compound 9a (8 g, 84% yield) as a
Found: 175.0395.
light yellow solid. M.R: 143–147◦C; FT-IR: (KBr, cm−1):
1
2925, 2853, 1645, 1617, 1569, 1465, 1172, 753; H NMR
2.2a 6-methyl-4-oxo-4H-chromene-3-carbaldehyde
(400 MHz, CDCl3): δ 8.3 (dd, J = 8.0 Hz, 1H, Ar-H), 8.15 (s,
(7b): The compound was prepared according to the proce-
1H, Ar-H), 7.7 (t, 1H, Ar-H), 7.45 (m, 2H, Ar-H), 4.45(s, 2H,
dure similar to compound 7a. M.R: 166–170◦C; FT-IR: (KBr,
CH2); 13CNMR (100 MHz, CDCl3); δ 175.7, 156.9, 154.6,
cm−1): 3427, 3076, 2920, 2852, 1652, 1477, 1329, 1190, 946,
133.9, 126.0, 125.5, 121.8, 123.7, 118.1,23.6; MS:(ESI):m/z
887, 769, 698. 1H NMR (400 MHz, CDCl3): δ 10.39 (s, 1H,
238 (M + 2,100). HRMS (ESI): Calcd. for C10H7BrO2 [M +
H]: 238.9714; Found: 238.9708.
CHO), 8.53 (s, 1H, Ar-H), 8.08 (d, J = 1.2 Hz, 1H, Ar-H),
7.55 (dd, J = 8.4 Hz, 1H, Ar-H), 7.44 (d, J = 1.2 Hz, 1H,
Ar-H), 2.49 (s, 3H, Ar-CH3); MS: (EI): m/z 189 (M + 1,
100).
2.4a
3-(bromomethyl)-6-methyl-4H-chromen-4-one
(9b): The compound was prepared according to the pro-
cedure similar to compound 9a. M.R: 150–154◦C; FT-IR:
(KBr, cm−1): 3299, 3065, 2938, 1733, 1647, 1546, 1483,
1309, 1246, 1024, 816.; 1H NMR (400 MHz, CDCl3): δ 8.09
(s, 1H, Ar-H), 8.04 (d, J = 4 Hz, 1H, Ar-H), 7.37 (s, 1H,
Ar-H), 7.35 (s, 1H, Ar-H), 4.40 (s, 2H, CH2), 2.46 (s, 3H,
Ar-CH3); MS:(ESI):m/z 255 (M + 2,100).
2.3 Experimental procedure for the preparation of
3-(hydroxymethyl)-4H-chromen-4-one (8a):
To a solution of compound 7a (8 g, 45.90 mmol) in THF
(80 mL) was added dropwise to 1 M BH3 in THF (92
mL, 91.90 mmol) under argon atmosphere at 0◦C. Then
slowly warmed the reaction mixture to RT and stirred for
16 h. The progress of the reaction was monitored by TLC
2.5 Experimental procedure for the preparation of
analysis (30% EtOAc/pet ether). After completion of the methyl 2-(diphenylmethyleneamino)-3-(4-oxo-4H-
reaction, the reaction mixture was quenched with saturated
NH4Cl (50 mL) and extracted with EtOAc (3×100 mL).
chromen-3-yl)propanoate(11a):
The organic layers were combined, washed with water, brine To a solution of compound 9a (0.5 g, 2.09 mmol) in CH3CN
and dried over anhydrous Na2SO4. Evaporation of the sol- (10 mL) was added methyl 2-(diphenylmethyleneamino)
vent under vacuum gives the compound 8a (7.0 g, 87% acetate (10) (0.52 g, 2.09 mmol) and K2CO3 (0.86 g, 6.27
yield) as a pale yellow solid. M.R: 104–108◦C; FT-IR: mmol) and stirred for 24 h at reflux temp. The progress of
(KBr, cm−1): 3363, 3067, 2293, 1637, 1604, 1466, 1350, the reaction was monitored by TLC analysis (30% EtOAc/pet
1162, 1026; 1H NMR (400 MHz, DMSO): δ 8.3 (s, 1H, ether). After the reaction was completed, the reaction mix-
Ar-H), 8.15, (dd, J = 10, 2 Hz,1H, Ar-H), 7.8 (t, 1H, Ar- ture was quenched with water (20 mL) and extracted with
H), 7.65 (d, J = 11.2 Hz, 1H, Ar-H), 7.55 (t, 1H, Ar-H), EtOAc. Organic layer was separated and washed with water,
5.2 (t,1H, OH), 4.45 (d, J = 7.6 Hz, 2H, CH2); 13C NMR brine and dried over anhydrous Na2SO4. Evaporation of the
(100 MHz, DMSO) δ 175.9, 155.9, 153.5, 134.0, 125.2, solvent under vacuum gave the crude product which was puri-
124.8, 124.0, 123.1, 118.4, 55.3, MS: (EI): m/z 177 (M+1, fied by silica gel column chromatography (20% EtOAc/Pet
100).HRMS: (ESI): Calcd. for C10H8O3 [M+H] :177.0542; ether) to give the pure compound 11a (0.7 g, 81% yield) as an
Found:177.0552
off white solid. M.R: 118–122◦C; FT-IR: (KBr, cm−1): 3059,

Venu Kandula et al.
2950, 2927, 2852, 1737, 1644, 1613, 1465, 782, 761; 1HNMR 2.87 (dd, J = 14.4 Hz, 1H, CH2), 2.49 (s, 3H, CH3); MS:
(400 MHz, CDCl3): δ 8.06 (d, J = 8.0 Hz, 1H, Ar-H), 7.85 (s, (EI): m/z 262 (M + 1,100).
1H, Ar-H), 7.6 (m, 3H, Ar-H), 7.35 (m, 7H, Ar-H), 7.2 (t, 2H,
Ar-H), 6.85 (d, J = 7.2 Hz, 2H, Ar-H), 4.5 (m, 1H, CH), 3.72
(s, 3H, OCH3), 3.32 (dd, J = 14.4 Hz, 1H, CH2), 2.85 (dd,
methyl 2-(tert-butoxycarbonylamino)-3-(4-oxo-4H-
J = 13.6, 8.8 Hz, 1H, CH2); 13C NMR (100 MHz, CDCl3) δ
2.7 Experimental procedure for the preparation of
chromen-3-yl)propanoate(13):
176.9, 172.1, 171.5, 156.2, 153.6, 139.3, 139.3, 135.6, 133.2,
133.2, 130.4, 130.0, 130.0, 130.0, 128.8, 128.7, 128.6, 128.6,
To a solution of compound 12 (0.2 g, 0.81 mmol) in diox-
128.0, 128.0, 123.8, 120.4, 118.0, 62.8, 52.1, 29.6; MS (EI):
aneb(10 mL) was added Et3N (0.24 g, 2.43 mmol) followed
m/z 412 (M+1, 100). HRMS: (ESI): Calcd. for C26H21NO4
by Boc2O (0.358 g, 1.618 mmol) at 0◦C and the reaction mix-
[M + H]:412.1522; Found: 412.1549.
ture was stirred at RT for 16 h. The progress of the reaction
was monitored by TLC analysis (20% EtOAc/pet ether). After
2.5a Methyl2-(diphenylmethyleneamino)-3-(6-methyl
-4-oxo-4H-chromen-3-yl)propanoate (11b): The com-
pound was prepared according to the procedure similar to
compound 11a. M.R: 102–106◦C; FT-IR: (KBr, cm−1): 3441,
2927,1736, 1640, 1481, 1437, 1280, 1164, 783, 694.; 1HNMR
(400 MHz, CDCl3): δ 7.854 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H),
7.58 (dd, J = 1.2 Hz, 2H, Ar-H), 7.44 (d, J=1.6 Hz, 1H, Ar-
H), 7.42 (d, J = 1.6 Hz, 1H, Ar-H), 7.37 (m, 4H, Ar-H), 7.20
(t, J=12.4 Hz, 2H, Ar-H), 6.88 (d, J = 5.6 Hz, 2H, Ar-H),
4.47 (m, 1H, CH), 3.72 (s, 3H, OCH3), 3.30 (dd, J = 10.8
Hz, 1H, CH2), 2.81 (dd, J = 11.2 Hz, 1H, CH2), 2.44 (s,2H,
Ar-CH3); MS (EI): m/z 426 (M + 1, 100).
completion of the reaction, the reaction mixture was quenched
with water (10 mL) and extracted with EtOAc. The combined
organic layers was washed with water, brine and dried over
anhydrous Na2SO4. Evaporation of the solvent under vac-
uum to give the crude product which was purified by silica
gel column chromatography (15 % EtOAc/Pet ether) to give
the pure compound 13 (0.210 g, 75% yield) as an off-white
solid. M.R: 123–127◦C. FT-IR: (KBr, cm−1):. 3306, 2979,
2927, 1751, 1717, 1630, 1600,1522, 1363, 1164, 1058, 1015;
1H NMR (400 MHz, CDCl3): δ 8.23 (dd, J = 6.4 Hz, 1H, Ar-
H), 7.8 (s, 1H, Ar-H), 7.675–7.655 (m, 1H, Ar-H), 7.45–7.39
(m, 2H, Ar-H), 5.73 (bs,1H, NH), 4.51 (bs, 1H, CH), 3.75 (s,
3H, OCH3), 3.02–2.89 (m, 2H, CH2),1.39 (s, 9H, C(CH3)3);
13C NMR (100 MHz, DMSO) δ 178.0, 172.1, 156.4, 155.3,
153.8, 133.7, 126.0, 125.1, 123.6, 119.9, 118.0, 79.7, 53.5,
52.3, 28.4, 28.2, 28.2, 28.2: MS: (EI): m/z 348 (M+1, 100).
HRMS: (ESI): Calcd. for C18H21NO6 [M + H]:348.1424;
Found: 348.1447
2.6 Experimental procedure for the preparation of
methyl 2-amino-3-(4-oxo-4H-chromen-3-yl)
propanoate hydrochloride (12):
To a solution of compound 11a (0.2 g, 0.486 mmol) in Et2O
(10 mL) was added 1N HCl (1 mL) at 0◦C. The reaction mix-
ture was stirred at RT for 2 h. The progress of the reaction
was monitored by TLC analysis (20% EtOAc/pet ether) which
indicated completion of the reaction. After completion of the
reaction, ether layer was separated. Lyophilization of aque-
ous layer gave the compound 12 (off-white solid) as HCl salt
(0.110 g, 80% yield). M.R: 207–210◦C; FT-IR: (KBr, cm−1):
2988, 2957, 2924, 2852, 1741, 1644, 1463, 1347, 1246, 114;
1H NMR (400 MHz, D2O): δ 8.25 (s, 1H, Ar-H), 8.1 (d, J =
8 Hz, 1H, Ar-H), 7.85 (t, 1H, Ar-H), 7.69 (d, J = 8.4 Hz, 1H,
Ar-H), 7.5 (t, 1H, Ar-H), 4.3 (t, 1H, CH), 3.7 (s, 3H, OCH3)
3.06 (dd, J = 14.4 Hz, 1H, CH2), 2.87 (dd, J = 14.4 Hz, 1H,
CH2); 13C NMR (100 MHz, DMSO) δ 176.7, 169.2, 155.9,
155.8, 134.2, 125.4, 124.9, 123.1, 118.3, 117.0, 52.8, 50.4,
26.6; MS: (EI): m/z 248 (M + 1,100). HRMS: (ESI): Calcd.
for C13H13NO4 [M + H]: 248.0931; Found: 248.0923.
2.7a
Methyl 2-(tert-butoxycarbonylamino)-3-(6-
methyl-4-oxo-4H-chromen-3-yl)propanoate (17): The
compound was prepared according to the procedure simi-
lar to compound 13. M.R: 116–120◦C. FT-IR: (KBr, cm−1):
3323, 2970, 2923, 1754, 1716, 1637, 1531, 1164, 1045, 807;
1H NMR (400 MHz, CDCl3): δ 8.00 (d, J = 8 Hz, 1H, Ar-
H), 7.77 (s, 1H, Ar-H), 7.48 (dd, J = 8.8 Hz, 1H, Ar-H),
7.34 (d, J = 8.8 Hz, 1H, Ar-H), 5.76 (bs,1H, NH), 4.49
(bs, 1H, CH), 3.74 (s, 3H, OCH3), 3.02 (d, J = 4.8 Hz,
2H, CH2), 2.45 (s, 3H, Ar-CH3), 1.39 (s, 9H, C(CH3)3);
13C NMR (100 MHz, DMSO) δ 178.1, 172.1, 155.4, 154.7,
153.7, 135.1, 135.0,125.2, 123.3, 119.7, 117.7, 79.7, 53.6,
52.3, 29.6, 28.4,28.3,28.2, 20.9.: MS: (EI): m/z 362 (M+1,
100).
2.8 Experimental procedure for the preparation of
methyl 3-(4-oxo-4H-chromen-3-yl)-2-pivalamidopro-
panoate (14):
2.6a Methyl 2-amino-3-(6-methyl-4-oxo-4H-
chromen-3-yl)propanoatehydrochloride(16): Thecom-
pound was prepared according to the procedure similar
to compound 12. M.R: 212–216◦C; FT-IR: (KBr, cm−1): To a solution of compound 12 (0.2 g, 0.809mmol) in dioxane
3427, 2022, 1750, 1640, 1484, 1237, 1125, 1046, 814, 700.: (10 mL) was added Et3N (0.245 g, 2.43 mmol) followed by
1H NMR (400 MHz, DMSO): δ 8.43 (bs, 3H, NH2.HCl), 8.25 pivolyl chloride (0.194 g, 1.618 mmol) at 0◦C and then the
(s, 1H, Ar-H), 7.85 (d, J = 1.2 Hz, 1H, Ar-H), 7.66 (t, J = reaction mixture was stirred at RT for 16 h. The progress of
8 Hz, 1H, Ar-H), 7.58 (d, J = 8 Hz, 1H, Ar-H), 4.28 (s, 1H, the reaction was monitored by TLC analysis (20% EtOAc/pet
CH), 3.74 (s, 1H, OCH3), 2.99 (dd, J = 14.4 Hz, 1H, CH2) ether). After completion of the reaction, water was added to

Synthesis of chromone based unnatural amino acids
the reaction mixture and extracted with EtOAc. The combined 15 was purified by chiral HPLC using Chiralcel OX-H, Hex-
organic layers were washed with water, brine and dried over ane/EtOH (70:30) as eluent.
anhydrous Na2SO4. Evaporation of the solvent under vacuum
to give the crude product which was purified by silica gel col-
umn chromatography (15 % EtOAc/Pet ether) to give the pure
compound 14 (0.205 g, 77% yield) as an off-white solid. M.R:
118–122◦C. FT-IR (KBr, cm−1): 3334, 2974, 1738, 1636,
1533, 1467, 1248, 1147, 1008; 1H NMR (400 MHz, CDCl3):
δ 8.23 (dd, J = 8 Hz 1H, Ar-H), 7.83 (s, 1H, Ar-H), 7.71–
7.67 (m, 1H, Ar-H), 7.47–7.41 (m, 3H, Ar-H), 4.62 (t, 1H,
CH), 3.72 (s, 3H, OCH3), 2.99 (m, 2H, CH2),1.18 (s, 9H,
C(CH3)3); 13C NMR (100 MHz, DMSO): δ 178.8, 171.6,
156.4, 154.2, 154.2, 133.9, 125.8, 125.4, 123.5, 120.3, 118.1,
53.6, 52.2, 38.4, 27.7, 27.3, 27.3, 27.3; MS: (EI): m/z 332
(M+1, 100); HRMS: (ESI): Calcd. for C18H21NO5 [ M + H]
:332.1554; Found: 332.1498.
2.9a Methyl 2-acetamido-3-(4-oxo-4H-chromen-3-yl)
propanoate 15i (-): M.R: 152–156◦C, FT-IR: (KBr,
cm−1): 3295, 3063, 2925, 1729, 1647, 1538, 1465, 1315,
1
1254,1021; H NMR (400 MHz, CDCl3): δ 8.23 (dd, J =
8 Hz 1H, Ar-H), 7.84 (s, 1H, Ar-H), 7.72–7.68 (m, 1H, Ar-
H), 7.41–7.52 (m, 2H, Ar-H), 7.26 (bs, 1H, Ar-H), 4.69 (m,
1H, CH), 3.73 (s, 3H, OCH3), 2.98 (d, 2H, CH2),2.0 (s, 3H,
CH3); 13C NMR(100 MHz, CDCl3): δ 178.9, 171.6, 170.3,
156.5, 154.3, 134.1, 126.0, 125.5, 123.6, 120.2, 118.2, 53.5,
52.4, 28.2, 23.1; MS (EI): m/z 290 (M+1, 100); HRMS: (ESI):
Calcd. for C15H16NO5 [M+H]: 290.1021; Found: 290.1028;
25
α
Specific Rotation: [ ] (C=0.25%,CHCl3)= −7.024
2.9b Methyl 2-acetamido-3-(4-oxo-4H-chromen-3-yl)
propanoate15i(+): M.R:149–153◦C, FT-IR:(KBr, cm−1):
3295, 3063, 2954, 1730, 1647, 1539, 1465, 1314, 1275,1020;
1H NMR (400 MHz, CDCl3): δ 8.23 (dd, J = 8 Hz 1H, Ar-H),
7.84 (s, 1H, Ar-H), 7.72–7.68 (m, 1H, Ar-H), 7.41–7.52 (m,
2H, Ar-H), 7.26 (bs, 1H, Ar-H), 4.69 (m, 1H, CH), 3.73 (s,
3H, OCH3), 2.98 (d, 2H, CH2), 2.0 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): δ 178.9, 171.6, 170.3, 156.5, 154.3,
134.1, 126.0, 125.5, 123.6, 120.2, 118.2, 53.5, 52.4, 28.2,
23.1; MS: (EI): m/z 290 (M+1, 100).HRMS (ESI): Calcd.
2.8a Methyl 3-(6-methyl-4-oxo-4H-chromen-3-yl)-2-
pivalamidopropanoate (18): The compound was pre-
pared according to the procedure similar to compound 14.
M.R: 99–104◦C. FT-IR (KBr, cm−1): 3364, 2963, 2924, 1745,
1641, 1523, 1481, 1268, 753.; 1H NMR (400 MHz, CDCl3):δ
8.01 (s, 1H, Ar-H), 7.80 (s, 1H, Ar-H), 7.51 (dd, J = 4.8 Hz
2H, Ar-H), 7.36 (s, 1H, NH), 4.61 (t, J = 6.4 Hz, 1H, CH),
3.72 (s, 3H, OCH3), 2.98 (t, J=7.2 Hz, 2H, CH2), 2.46 (s,
3H, Ar-CH3), 1.24 (s, 9H, C(CH3)3); 13C NMR (100 MHz,
DMSO): δ 178.9,178.9, 171.6, 154.7, 154.1, 135.4, 135.3,
125.0, 123.2, 120.1, 117.8, 53.7, 52.2, 38.47, 27.8,27.8, 27.8,
27.3,20.9. MS: (EI): m/z 346 (M+1, 100);
for C15H16NO5 [M+H]: 290.1022; Found: 290.1028; Spe-
25
α
cific Rotation:[ ] (C=0.25%, CHCl3)= +7.76
2.9c Methyl 2-acetamido-3-(6-methyl-4-oxo-4H-
chromen-3-yl)propanoate (19): The compound was pre-
pared according to the procedure similar to compound 15.
M.R: 159–163◦C, FT-IR: (KBr, cm−1): 3433, 3298, 3065,
2924, 1735, 1636, 1478, 1329, 814, 697, 595; 1H NMR (400
MHz, CDCl3): δ 8.0 (d, J = 8 Hz 1H, Ar-H), 7.81 (s, 1H,
Ar-H), 7.51 (dd, J = 8.8 Hz 2H, Ar-H), 7.37 (bs, 1H, NH),
4.68 (d, J = 6.4 Hz, 1H, CH), 3.72 (s, 3H, OCH-3), 2.96 (d,
J = 6 Hz, 2H, CH2), 2.46 (s, 3H, -Ac), 2.01 (s, 3H, Ar-CH3);
13C NMR (100 MHz, CDCl3): δ 178.9, 171.5, 170.2, 154.7,
154.2, 135.4, 135.3, 125.1, 123.2, 119.8, 117.8, 53.5, 52.3,
28.1, 23.0, 20.9,; MS: (EI): m/z 304 (M+1, 100).
2.9 Experimental procedure for the preparation of
methyl 2-acetamido-3-(4-oxo-4H-chromen-3-yl)
propanoate (15):
To a solution of compound 12 (0.25 g, 1.01 mmol) in THF
(10 mL) was added Et3N (0.306 g, 3.03 mmol) fallowed by
acetyl chloride (0.157 g, 2.02 mmol) at 0◦C. Then the reac-
tion mixture was stirred at RT for 24 h. The progress of the
reaction was monitored by TLC analysis (20% EtOAc/ pet
ether). After completion of the reaction, the reaction mix-
ture was quenched with water (10 mL) and extracted with
EtOAc. The combined organic layers was washed with water, 2.10 Experimental procedure for the preparation of
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent under vacuum to give the crude product which was
ethyl 4-oxo-4H-chromene-2-carboxylate (20a):
purified by silica gel column chromatography to give pure To a solution of compound 6a (5 g, 36.71 mmol) in THF (50
compound 15 (0.230 g, 79% yield) as an off-white solid. mL) was added 21% NaOEt in EtOH (25 mL) at 0◦C in drop
M.R: 130–134◦C, FT-IR: (KBr, cm−1): 3328, 3059, 2943, wise manner under argon atmosphere. Then diethyl oxalate
1
1741, 1644, 1534, 1462, 1356, 1284, 1043; H NMR (400 was added in drop wise manner and stirred at 60◦C for 3 h.
MHz, CDCl3): δ 8.23 (dd, J = 8 Hz 1H, Ar-H), 7.84 (s, 1H, Then cooled the reaction mixture to 0◦C and slowly added
Ar-H), 7.72–7.68 (m, 1H, Ar-H), 7.41–7.52 (m, 2H, Ar-H), 20 mL of 36% HCl and stirred at 60◦C. The progress of the
7.26 (bs, 1H, Ar-H), 4.69 (m, 1H, CH), 3.73 (s, 3H, OCH-3), reaction was monitored by TLC analysis (10% EtOAc/pet
2.98 (d, 2H, CH2), 2.0 (s, 3H, CH3); 13C NMR (100 MHz, ether). After completion of the reaction, solvent was distilled
CDCl3): δ 178.9, 171.6, 170.3, 156.5, 154.3, 134.1, 126.0, off and quenched with water. Solid was formed, filtered the
125.5, 123.6, 120.2, 118.2, 53.5, 52.4, 28.2, 23.1; MS: (EI): solid and washed with water to give the pure compound 20a (7
m/z 290 (M+1, 100); HRMS: (ESI): Calcd. for C15H16NO5 g, 87% yield) as a brown solid. M.R: 71–75◦C; FT-IR: (KBr,
[M+H] :290.1039; Found: 290.1028. The racemic compound cm−1): 3073, 2924, 1738, 1627, 1584, 1465, 1304, 1245, 750;

Venu Kandula et al.
1H NMR (400 MHz, CDCl3): δ 8.22 (dd, J = 8.0 Hz, 1H, Ar- RTfor1h. TheprogressofthereactionwasmonitoredbyTLC
H), 7.8 (t, 1H, Ar-H), 7.63 (d, J = 8 Hz, 1H, Ar-H), 7.4 (t, analysis (20% EtOAc/pet ether). After completion of the reac-
1H, Ar-H), 7.1 (s, 1H, Ar-H), 4.5 (m, 2H, CH2), 1.45 (t, 3H, tion, the reaction mixture was quenched with ice and extracted
CH3); 13C NMR (100 MHz, CDCl3): δ 178.3, 160.5, 155.9, with EtOAc (3×100mL). Organic layers were combined and
152.8, 134.2, 125.4, 125.7, 124.4, 118.3, 114.7, 62.8, 14.4;. washed with water, brine and dried over anhydrous Na2SO4.
MS: (EI): m/z 219 (M+1, 100); HRMS: (ESI): Calcd. for Evaporation of the solvent in vacuum gave the pure compound
C12H10O4 [M+H]: 219.0666; Found: 219.0657
22 (1.1 g, 82% yield) as light yellow solid. M.R: 122−126◦C;
FT-IR (KBr,cm1): 3348, 3066, 3037, 2975, 1667, 1631, 1463,
1
1386, 1220, 1117; H NMR: (400 MHz, CDCl3): δ = 8.19
2.10a Ethyl6-methyl-4-oxo-4H-chromene-2-carboxy-
late (20b): The compound was prepared according to the
procedure similar to compound 20a. M.R: 108–112◦C; FT-
IR: (KBr, cm−1): 3043, 2917, 1749, 1653, 1481, 1242, 1096,
1019, 949, 832. 1H NMR (400 MHz, CDCl3): δ 7.98 (s, 1H,
Ar-H), 7.54 (m, 2H, Ar-H), 7.11 (s, 1H, Ar-H), 4.47 (q, 2H,
OCH2), 2.47 (s, 3H, Ar-CH3), 1.43 (t, J = 5.6 Hz, 3H, CH3);
MS: (EI): m/z 233 (M+1, 100)
(d, J = 8 Hz,1H, Ar-H), 7.8 (t, 1H, Ar-H), 7.50 (d, J = 9.6
Hz, 1H, Ar-H), 7.43 (t,1H, Ar-H),6.45(s,1H, Ar-H),4.3(s,2H,
CH2);13CNMR:(100 MHz,CDCl3); δ=178.0, 162.5, 156.3,
134.1, 125.6, 125.4, 118.0, 117.8, 111.2, 27.3; MS (EI): m/z
239(M, 100); HRMS (ESI): Calcd. for C10H7BrO2 [M+H]
:238.9708; Found: 238.9708.
2.12a 2-(bromomethyl)-6-methyl-4H-chromen-4-one
(22b):: The compound was prepared according to the pro-
cedure similar to compound 22a. M.R : 124 − 128◦C; FT-IR
(KBr,cm1): 3045, 1636, 1621, 1479, 1431, 1372, 1283, 1216,
1122, 968, 874, 811.; 1H NMR: (400 MHz, CDCl3): δ = 7.97
(d, J = 1.2 Hz, 1H, Ar-H), 7.51 (dd, J = 9.2 Hz 1H, Ar-
H), 7.39 (d, J = 8.8 Hz, 1H, Ar-H), 6.38 (s,1H, Ar-H), 4.25
(s,2H, CH2), 2.45 (s, 3H, Ar-CH3); MS (EI): m/z 255(M+2,
100).
2.11 Experimental procedure for the preparation of
2-(hydroxymethyl)-4H-chromen-4-one (21a):
To a solution of compound 20a (3 g, 13.70 mmol) in MeOH
(60 mL) was added NaBH4 (0.99 g, 27.5 mmol) under argon
atmosphere at 0◦C and stirred the reaction mixture at RT
for 16 h. The progress of the reaction was monitored by
TLC analysis (30% EtOAc/pet ether). After completion of
the reaction, the reaction mixture was quenched with 1N HCl
(20 mL) and extracted with EtOAc (3×100 mL). Combined
organic layers was washed with water, brine and dried over
anhydrous Na2SO4. Evaporation of the solvent under vac-
uum gave the pure compound 21a (2.0 g, 82% yield) as
an off-white solid. M.R: 162–166◦C; FT-IR: (KBr-cm−1):
3858, 3359, 3077, 2930, 2449, 1639, 1598, 1570, 1464,
2.13 Experimental procedure for the preparation of
methyl 2-(diphenylmethyleneamino)-3-(4-oxo-4H-
chromen-2-yl)propanoate (23a):
To a solution of compound 22a (0.5 g, 2.09 mmol) in CH3CN
(10 mL) was added methyl 2-(diphenylmethyleneamino)
acetate 10 (0.52 g, 2.09 mmol) and K2CO3 (0.865 g, 6.27
mmol) at RT and the reaction mixture was stirred for 24 h
at reflux temp. The progress of the reaction was monitored
by TLC analysis (30% EtOAc/pet ether). After completion
of the reaction, water was added to the reaction mixture and
extracted with EtOAc. Organic layer was washed with water,
brine and dried over anhydrous Na2SO4. Evaporation of the
solvent under vacuum gave the crude product which was puri-
fied by silica gel column chromatography to give compound
23a (0.6 g, 70% yield) as an off-white solid. M.R: 116–120◦C;
FT-IR: (KBr, cm−1): 3057, 2950, 1982, 1741, 1659, 1618,
1468, 1381, 1276, 1166; 1H NMR: (400 MHz, CDCl3): δ =
8.15 (dd, J = 7.6, 1.6 Hz, 1H, Ar-H), 7.6 (m, 3H, Ar-H),
7.35 (m, 5H, Ar-H), 7.3 (m, 2H, Ar-H), 7.12 (d, J = 8.4 Hz,
1H, Ar-H), 6.89 (d, J = 6.8 Hz, 2H, Ar-H), 6.2 (s,1H, Ar-
H), 4.65 (dd, J = 9.6, 4 Hz, 1H, CH), 3.8 (s, 3H, OCH3),
3.30 (dd, J = 14.0, 3.6 Hz, 1H, CH2), 3.21(dd, J = 14.0,
9.6 Hz,1H, CH2); 13C NMR: (100 MHz, CDCl3): δ 177.8,
172.3, 171.1, 165.3, 156.1, 138.8, 138.8, 135.4, 133.3, 133.3,
130.7, 130.7, 128.8, 128.7, 128.3, 128.3, 128.0, 128.0, 125.6,
124.9, 123.5, 117.8, 112.0, 62.7, 52.6, 38.4; MS (EI): m/z 412
1
1402, 1354, 1225, 1118, 1089, 756; H NMR (400 MHz,
DMSO): δ 8.04 (dd, J = 7.6 Hz, 1H, Ar-H), 7.8 (t, 1H, Ar-
H), 7.62 (d, J = 8 Hz, 1H, Ar-H), 7.55 (t, 1H, Ar-H), 6.35
(s, 1H, Ar-H), 5.8 (t, 1H, OH), 4.45 (d, J = 6.4 Hz, 2H,
CH2); 13C NMR (100 MHz, DMSO) δ 176.7, 169.6, 155.6,
134.0, 125.2, 124.8, 123.3, 118.1, 107.2, 59.7.; MS: (EI): m/z
177 (M+1,100); HRMS: (ESI): Calcd. for C10H8O3 [M+H]
:177.0541; Found:177.0552.
2.11a 2-(hydroxymethyl)-6-methyl-4H-chromen-4-
one (21b): The compound was prepared according to the
procedure similar to compound 21a. M.R: 154–158◦C; FT-
IR: (KBr-cm−1): 3360, 2831, 1736, 1649, 1607, 1479, 1363,
1225, 1091, 960, 812.; 1H NMR (400 MHz, CDCl3): δ 7.98
(d, J = 7.2 Hz, 1H, Ar-H), 7.48 (dd, J = 8.8 Hz, 1H, Ar-H),
7.32 (d, J = 8.4 Hz, 1H, Ar-H), 6.48 (s, 1H, Ar-H), 4.6 (s, 2H,
CH2), 2.45 (s, 3H, Ar-CH3); MS: (EI): m/z 191 (M+1,100).
2.12 Experimental procedure for the preparation of
2-(bromomethyl)-4H-chromen-4-one (22a):
To a solution of compound 21a (1g, 5.6 mmol) in CH2Cl2 (20 (M+1, 100). HRMS (ESI): Calcd. for C26H21NO4 [ M+H]:
mL) was added PBr3 (1 mL, 11.36 mmol) at 0◦C and stirred at 412.1528; Found: 412.1549.

Synthesis of chromone based unnatural amino acids
2.13a
Methyl 2-(diphenylmethyleneamino)-3-(6- anhydrous Na2SO4. Evaporation of the solvent under vacuum
methyl-4-oxo-4H-chromen-2-yl)propanoate(23b): The gave the crude product which was purified by silica gel col-
compound was prepared according to the procedure similar to umn chromatography to give compound 25 (0.198 g, 70%
compound 23a. M.R: 138–142◦C; FT-IR: (KBr, cm−1): 3054, yield) as an off-white solid. M.R.: 111–115◦C; FT-IR: (KBr,
1735, 1645, 1434, 1370, 1278, 1217, 1072, 954, 820, 694.; cm−1):. 3286, 3044, 2932, 1756, 1646, 1536, 1463, 1394,
1H NMR: (400 MHz, CDCl3): δ = 7.92 (s, 1H, Ar-H), 7.53 1168, 967; 1H NMR (400 MHz, CDCl3): δ 8.18 (d, J = 6.0
(dd, J= 6 Hz, 2H, Ar-H), 7.41-7.39 (m, 3H, Ar-H), 7.38-7.35 Hz 1H, Ar-H), 7.65 (t, 1H, Ar-H), 7.39 (t, 2H, Ar-H), 6.17
(m, 2H, Ar-H), 7.29-7.27 (m, 2H, Ar-H), 7.03 (dd, J = 6.8 (s, 1H, Ar-H), 5.22 (bs,1H, NH), 4.75 (bs,1H, CH), 3.81 (s,
Hz, 1H, Ar-H), 6.87 (s, 2H, Ar-H), 6.17 (s, 1H, Ar-H), 4.62 3H, OCH3), 3.21 (dd,J=12.0 Hz 1H, CH2),3.10 (dd, J =
(m,1H, CH), 3.79 (s, 3H, OCH3), 3.29-3.16 (m, 2H, CH2), 11.2 Hz 1H, CH2),1.40 (s, 9H, C(CH3)3); 13C NMR(100
2.43 (s,3H, Ar-CH-3); MS (EI): m/z 426 (M+1, 100).
MHz, DMSO): δ 177.5, 171.2, 164.0, 156.3, 154.8, 133.7,
125.7, 125.2, 123.6, 117.7, 112.1, 80.4, 52.7, 51.5, 37.3,
28.1, 28.1, 28.1;MS:(EI): m/z 348 (M+1, 100).HRMS:
(ESI): Calcd. for C18H21NO6 [M+H] :348.1448; Found:
348.1447.
2.14 Experimental procedure for the preparation of
methyl 2-amino-3-(4-oxo-4H-chromen-2-yl)
propanoate hydrochloride (24):
2.15a
Methyl 2-(tert-butoxycarbonylamino)-3-(6-
To a solution of compound 23a (0.2 g, 0.486 mmol) in Et2O
(10 mL) was added 1N HCl (1 mL) at 0◦C. Then, the reaction
mixture was stirred at RT for 2 h. The progress of the reac-
tion was monitored by TLC analysis (20% EtOAc/pet ether).
After completion of the reaction, ether layer was separated.
Lyophilisationofaqueouslayergavecompound 24asHClsalt
(0.1 g, 73% yield) as an off-white solid. M.R: 148–152◦C; FT-
IR: (KBr, cm−1): 3729, 3625, 2326, 2899, 2690, 1752, 1495,
1331,1281, 1181; 1H NMR: (400 MHz, D2O): δ 8.13 (d, J =
10.8 Hz, 1H, Ar-H), 7.9 (t, 1H, Ar-H), 7.65 (m, 2H, Ar-H), 6.5
(s, 1H, Ar-H), 4.8 (m, 1H, CH), 3.9 (s,3H, OCH3), 3.51 (d, J
= 8.8 Hz, 2H, CH2); 13C NMR: (100 MHz, DMSO) δ 180.9,
169.1, 164.8, 156.4, 136.2, 126.6, 126.2, 124.7, 118.7, 112.2,
53.9, 50.9, 34.5; MS: (EI): m/z 248 (M+1, 100); HRMS (ESI):
Calcd. for C13H13NO4 [M+H] : 248.0921; Found: 248.0923.
methyl-4-oxo-4H-chromen-2-yl)propanoate (29): The
compound was prepared according to the procedure similar to
compound 25. FT-IR: (KBr, cm−1): 3331, 2978, 1713, 1649,
1487, 1369, 1268, 1165, 1055, 822, 756.; 1H NMR(400MHz,
CDCl3): δ 7.95 (s, 1H, Ar-H), 7.95 (dd, J = 6.4 Hz, 1H, Ar-H),
7.28 (d, J = 6.8 Hz, 1H, Ar-H), 6.15 (s, 1H, Ar-H), 5.20 (bs,
1H, NH), 4.73 (bs, 1H, CH), 3.79 (s, 3H, OCH3), 3.18 (dd, J
= 11.6 Hz 1H, CH2),3.09 (dd, J = 11.2 Hz 1H, CH2), 2.44 (s,
3H), 1.56 (s, 9H, C(CH3)3); 13C NMR(100 MHz,DMSO): δ
178.0, 171.2, 163.9, 154.8, 154.5, 135.1, 134.9, 125.0, 123.2,
117.5, 111.9, 80.4, 52.7, 51.5, 37.3, 28.1, 28.1, 28.1, 20.8;
MS:(EI): m/z 362 (M+1, 100).
2.16 Experimental procedure for the preparation of
methyl 3-(4-oxo-4H-chromen-2-yl)-2-pivalamidopro-
panoate (26):
2.14a Methyl 2-amino-3-(6-methyl-4-oxo-4H-chromen
-2-yl)propanoate hydrochloride (28): The compound
was prepared according to the procedure similar to compound
24. M.R:185–189◦C;FT-IR:(KBr, cm−1):. 3406, 2925, 2102,
To a solution of compound 24 (0.2 g, 0.809 mmol) in dioxane
(10 mL) was added Et3N (0.245 g, 2.43 mmol) at 0◦C and
pivaloyl chloride (0.194 g, 1.618 mmol) Then, the reaction
mixture was stirred at RT for 16 h. The progress of the reac-
tion was monitored by TLC analysis (20% ethyl acetate/pet
ether). After the reaction was complete, water was added to
the reaction mixture and extracted with EtOAc. The organic
layer was washed with water, brine and dried over anhydrous
Na2SO4. The solvent was evaporated to give the crude prod-
uct which was purified by silica gel column chromatography
to give the compound 26 (0.217 g, 81% yield) as an off-white
solid. M.R: 114–116◦C; FT-IR: (KBr, cm−1): 3358, 2958,
1
1739, 1645, 1437, 1222, 1065, 956, 755.; H NMR: (400
MHz, D2O): δ 7.80 (s, 1H, Ar-H), 7.66 (d, J = 8.8Hz, 1H, Ar-
H), 7.45 (d, J = 8.4 Hz, 1H, Ar-H), 6.43 (s, 1H, Ar-H), 4.71
(m, 1H, CH), 3.89 (s,3H, OCH3), 3.45 (d, J = 3.6 Hz, 2H,
CH2), 2.44 (s, 3H, Ar-CH3),; 13C NMR: (100MHz, DMSO) δ
176.8, 169.6, 168.7, 162.8, 154.2, 124.06, 122.9, 118.0, 112.1,
111.9, 53.0, 49.7, 34.1, 20.4.; MS: (EI): m/z 262 (M+1, 100);
2.15 Experimental procedure for the preparation of
methyl 2-(tert-butoxycarbonylamino)-3-(4-oxo-4H-
chromen-2-yl)propanoate(25):
1
1736, 1650, 1523, 1465, 1388, 1220, 1121, 759; H NMR
(400 MHz, CDCl3): δ 8.18 (dd, J = 6.4 Hz, 1H, Ar-H), 7.67–
7.64 (t, 1H, Ar-H), 7.42–7.35 (m, 2H, Ar-H), 6.39 (bs,1H,
To a solution of compound 24 (0.2 g, 0.809 mmol) in diox- NH), 6.12 (s,1H, Ar-H), 4.98 (dd, J = 10.0 Hz, 1H, CH), 3.83
ane (10 mL) was added Et3N (0.245 g, 2.43 mmol) at 0◦C; (s, 3H, OCH3), 3.28 (dd, J = 11.6 Hz, 1H, CH2), 3.15 (dd, J =
then added Boc2O (0.358 g, 1.618 mmol). Then the reac- 11.6 Hz, 1H, CH2), 1.25 (s, 9H, C(CH3)3); 13C NMR:(100
tion mixture was stirred at RT for 16 h. The progress of the MHz, DMSO) δ 178.2, 177.7, 171.3, 164.1, 156.2, 133.8,
reaction was monitored by TLC analysis (20% EtOAc/pet 125.8, 125.2, 123.5, 117.6, 112.1, 52.8, 50.3, 38.7, 36.7,
ether). After the reaction was completed, water was added 27.3, 27.3, 27.3.; MS: (EI): m/z 332 (M+1,100); HRMS:
to the reaction and extracted with EtOAc. The organic lay- (ESI): Calcd. for C18H21NO5 [ M+H]:332.1496; Found:
ers were combined, washed with water, brine and dried over 332.1498.

Venu Kandula et al.
2.16a Methyl3-(6-methyl-4-oxo-4H-chromen-2-yl)-2- 2.17b Methyl2-acetamido-3-(4-oxo-4H-chromen-2-yl)
pivalamidopropanoate (30): The compound was pre- propanoate (27i (+)): M.R.:128–132◦C FT-IR (KBr,
pared according to the procedure similar to compound 26. cm−1): 3301, 3071, 2954, 1731, 1659, 1538, 1459, 1380,
M.R: 139–143◦C; FT-IR: (KBr, cm−1): 3340, 2959, 1754, 1277, 1023; 1H NMR: (400 MHz, CDCl3): δ 8.18 (dd, J = 8
1
1647, 1530, 1433, 1339, 1211, 1033, 972, 830.; H NMR Hz 1H, Ar-H), 7.64–7.68 (m, 1H, Ar-H), 7.35–7.42 (m, 2H,
(400 MHz, CDCl3): δ 7.95 (d, J = 1.2 Hz, 1H, Ar-H), 7.47 Ar-H), 6.19 (bs, 1H, Ar-H),6.15 (s, 1H, NH),5.01 (m, 1H,
(dd, J = 8.4 Hz, 1H, Ar-H), 7.24 (s, 1H, Ar-H), 6.36 (bs,1H, CH), 3.83(s, 3H, OCH3), 3.11-3.26(m, 2H, CH2), 2.01(s, 3H,
NH), 6.09 (s, 1H, Ar-H), 4.96 (dd, J = 12.8 Hz, 1H, CH), CH3); 13C NMR: (100 MHz, DMSO): δ 177.9, 171.2, 169.9,
3.82 (s, 3H, OCH3), 3.25 (dd, J = 14.4 Hz, 1H, CH2), 3.13 164.1, 156.3, 133.9, 125.8, 125.3, 123.6, 117.7, 112.1, 52.9,
(dd, J = 14.4 Hz, 1H, CH2), 2.44 (s, 3H, Ar-CH3), 1.17 (s, 50.4, 36.9, 23.0.; MS (EI): m/z 290 (M+1, 100); HRMS (ESI):
9H, C(CH3)3); 13C NMR:(100 MHz, DMSO) δ 178.2, 177.9, Calcd. for C15H16NO5 [M+H] :290.1029; Found: 290.1028;
25
α
171.3, 163.9, 154.5, 135.3, 135.0, 125.1, 123.2, 117.4, 112.0, Specific Rotation: [ ] (C=0.25%,CHCl3)= +107.024
52.8, 50.4, 38.7, 36.7, 27.4,27.4, 27.4, 20.9..; MS: (EI): m/z
346 (M+1,100).
2.17c Methyl 2-acetamido-3-(6-methyl-4-oxo-4H
-chromen-2-yl)propanoate (31): The compound was pre-
pared according to the procedure similar to compound 27.
2.17 Experimental procedure for the preparation of
methyl 2-acetamido-3-(4-oxo-4H-chromen-2-yl)
propanoate (27):
M.R: 132–136◦C.: FT-IR (KBr, cm−1): 3374, 3052, 2930,
1747, 1652, 1540, 1436, 1370, 1281, 1182, 966, 825, 749.:
1H NMR: (400 MHz, CDCl3): δ 7.97 (d, J = 8 Hz 1H, Ar-H),
7.49 (dd, J = 8.8 Hz, 1H, Ar-H), 7.28 (s, 1H, Ar-H), 6.23
(bs, 1H, NH), 6.14 (s, 1H, Ar-H), 5.02 (m, 1H, CH), 3.82 (s,
3H, OCH3), 3.25 (dd, J = 14.4 Hz, 1H, CH2), 3.16 (dd, J
= 14.4 Hz,1H, CH2) 2.46 (s, 3H, Ac), 2.26 (s, 3H, Ar-CH3);
13C NMR: (100 MHz, CDCl3): δ 177.9, 171.1, 169.7, 163.7,
154.5, 135.3, 135.0, 125.1, 123.2, 117.4, 111.9, 52.9, 50.4,
36.8, 23.0, 20.8..; MS (EI): m/z 304 (M+1, 100);
To a solution of compound 24 (0.25 g, 1.01mmol) in THF
(10 ml) was added Et3N (0.306 g, 3.03 mmol) followed by
acetyl chloride (0.157 g, 2.02 mmol) at 0◦C. Then, the reac-
tion mixture was stirred at RT for 24 h. The progress of the
reaction was monitored by TLC analysis (20% EtOAc/pet
ether). After the reaction was completed, water was added to
the reaction mixture and extracted with EtOAc. The organic
layer was washed with water, brine and dried over anhydrous
Na2SO4. Evaporation of the solvent under vacuum gave the
crude product which was purified by silica gel column chro-
matography to give compound 27 (0.220 g, 75% yield) as
an off-white solid. M.R: 144–148◦C; FT-IR: (KBr, cm−1) :
3307, 3073, 2948, 2848, 1734, 1657, 1545, 1459, 1381, 1117,
1022; 1H NMR: (400 MHz, CDCl3): δ 8.18 (dd, J = 8 Hz, 1H,
Ar-H), 7.64–7.68 (m, 1H, Ar-H), 7.35–7.42 (m, 2H, Ar-H),
6.19 (bs, 1H, NH),6.15 (s, 1H, Ar-H),5.01 (m, 1H, CH), 3.83
3. Results and Discussion
3.1 Synthesis
Our synthesis started from commercially available 2-
hydroxy acetophenone 6a (Scheme 1). Thus, compound
6a was treated with oxalyl chloride in DMF at RT
(s, 3H, OCH3), 3.11–3.26 (m, 2H, CH2), 2.01 (s, 3H, CH3); according to literature procedure to prepare the 3-formyl
13C NMR (100 MHz, DMSO) δ 177.9, 171.2, 169.9, 164.1,
156.3, 133.9, 125.8, 125.3, 123.6, 117.7, 112.1, 52.9, 50.4,
36.9, 23.0.; MS: (EI): m/z 290 (M+1, 100); HRMS(ESI):
Calcd. for C15H16NO5 [M+H]:290.1069; Found:290.1028.
Theracemiccompound27waspurifiedbychiralHPLCusing,
Chiralcel OX-H, Hexane/EtOH (70:30) as eluent.
chromone 7a.37 The reduction reaction of formyl group
was tried using NaBH4 in THF which was not suc-
cessful. We have tried a couple of reduction reaction
conditions viz. NaCNBH3, LiBH4, etc. without much
success. Finally, using BH3 in THF conditions, we
were able to prepare the methyl alcohol 8a in good
yields. The conversion of 3-hydroxymethyl chromone
8a to bromo derivative 9a was achieved using PBr3
in DCM condition. The key alkylation reaction was
performed by reaction of bromomethyl chromone 9a
with N-(diphenylmethylene) glycine methyl ester 10 in
K2CO3/CH3CN reflux condition to give the compound
11a in very good yield. The compound 11a was well
characterized by 1H NMR, 13C-NMR and MS data. The
appearance of signals at δ 3.33 (dd, 1H) and 2.83 (dd,
1H) corresponding to the CH2 protons attached to the
chromone ring and peak at δ 4.49 (m, 1H) correspond-
2.17a Methyl2-acetamido-3-(4-oxo-4H-chromen-2-yl)
propanoate (27i (-)): M.R.: 129–133◦C; FT-IR: (KBr,
cm−1): 3301, 3071, 2954, 1730, 1659, 1538, 1428, 1380,
1275,1022; 1H NMR: (400 MHz, CDCl3): δ 8.18 (dd, J
= 8 Hz 1H, Ar-H), 7.64–7.68 (m, 1H, Ar-H), 7.35–7.42
(m, 2H, Ar-H), 6.19 (bs, 1H, Ar-H),6.15 (s, 1H, NH),5.01
(m, 1H, CH), 3.83 (s, 3H, OCH3), 3.11–3.26 (m, 2H,
CH2), 2.01 (s, 3H, CH3); 13CNMR:(100 MHz, DMSO)
δ 177.9, 171.2, 169.9,164.1, 156.3, 133.9, 125.8, 125.3,
123.6, 117.7, 112.1, 52.9, 50.4, 36.9, 23.0;MS (EI): m/z
290 (M+1, 100).HRMS: (ESI): Calcd. for C15H16NO5
25
α
ing to -proton of amino acid peak at δ 6.86 (s, 1H)
α
[M+H]: 290.1069; Found: 290.1028; Specific Rotation: [ ]
(C=0.25%,CHCl3)= -108.064.
corresponding to chromone olefinic proton in 1H-NMR

Synthesis of chromone based unnatural amino acids
O
O
O
O
O
O
R1
PBr3, DCM
R1
R1
OH
Br
R1
(COCl)2, DMF
RT, 16 h, 80%
1M BH3 in THF
H
RT, 1 h, 84%
O
THF, RT, 24 h, 87%
O
OH
9a R1=H: 84%
9bR1=Me 78%
8a R1=H: 87%
8b R1=Me: 70%
7a R1=H: 80%
7bR1=Me: 78%
6a R1=H
6b R1=Me
Ph
K2CO3, CH3CN,
80°C, 16 h
OMe
Ph
R1
N
O
10
Ph
Ph
N
O
O
O
O
O
O
O
R1
R1
Boc2O/piv-Cl/AcCl
TEA, dioxane
1N HCl, Et2O
RT, 10 h, 80%
OMe
OMe
HN
R
NH2
O
O
OMe
RT, 16 h
13: R1=H, R = Boc; 75%
14: R1=H, R = Piv; 77%
15: R1=H, R = Ac: 81%
17: R1=Me,R=Boc: 87%
18: R1=Me,R=Piv: 85%
19: R1=Me,R=Ac: 82%
11a R1=H: 81%
11b R1=Me: 85%
12 R1=H: 80%
16 R1=Me: 68%
α
Scheme 1. Synthesis of 3-substituted chromone based -amino acid.
O
O
O
O
R1
R1
Diethyl oxalate,
R1
R1
PBr3, DCM
NaBH4, MeOH
RT, 16 h, 82%
21% NaOEt in EtOH, THF
OEt
Br
OH
O
RT, 1 h, 82%
O
60°C, 16 h,
O
OH
then conc.HCl, 87%
O
21a
21b
R1=H: 82%
R1=Me: 70%
20a
20b
22a
22b
R1=H: 87%
R1=Me: 80%
R1=H: 82%
R1=Me: 79%
6a
6b
R1=H
R1=Me
Ph
K2CO3, CH3CN,
80°C, 16 h
OMe
Ph
N
10
O
O
O
O
O
O
O
R1
O
OMe
Boc2O/Piv-Cl/AcCl
TEA, dioxane
R1
OMe
NH2HCl
R1
O
OMe
N
1N HCl, Et2O
RT, 10 h, 80%
R
N
O
RT, 16 h
H
25: R1=H, R = Boc; 70%
26: R1=H, R = Piv; 81%
27: R1=H, R = Ac: 78%
29: R1=Me,R=Boc: 82%
30: R1=Me,R=Piv: 84%
31: R1=Me,R=Ac: 78%
Ph
Ph
24 R1=H: 73%
28 R1=Me: 67%
23a
23b
R1=H: 70%
R1=Me: 75%
α
Scheme 2. Synthesis of 2-substituted chromone based -amino acid.
spectrum confirmed the formation of the compound 11a. The relative configuration of the enantiomer 15i and 15ii
Then, the compound 11a was treated with 1N aqueous was assigned with reference to the configuration of ala-
HCl at RT and the reaction mixture was freeze dried to nine based on the specific rotation.
give the designed chromone based hybrid amino acid
The success of synthetic route for the preparation of
12 as its HCl salt. The compound 16 was prepared compound 12 and 16 encouraged us to focus on the
following the similar procedure as 12 starting from pro- preparation of 2-substitued chromone hybrid amino acid
cedure 2-hydroxy-5-methy-acetophenone 6b in a five 24 and 28. Thus, the reaction of 2-hydroxy acetopheone
step synthetic sequence. Various N-protected chromo 6a with diethyl oxalate in presence of NaOEt at 60◦C
based amino acid derivatives (13–19) were prepared gave the ethyl 4-oxo-4H-chromene-2-carboxylate 20a
using the standard protecting group procedure.38 The (Scheme 2). The reduction reaction of ester moiety was
N-acetyl protected amino acid 15 was subjected to chi- achieved using NaBH4 in MeOH conditions to obtain
ral HPLC separation using Chiralcel OX-H column and the methyl alcohol 21a in good yields. The conver-
hexane/EtOH (70:30) as the mobile phase (Figure 2). sion of 3-hydroxymethyl chromone to bromo derivative
Thechiralpurityoftheobtainedpureenantiomer15iand 22a was achieved using PBr3 in DCM condition. The
15ii was analysed by chiral HPLC and specific rotation. key alkylation reaction was performed by reaction bro-

Venu Kandula et al.
α
Table 1. The yields and purity of the novel chromone based -amino acids derivatives.
momethyl chromone 22a with N-(diphenylmethylene) to chromone olefinic proton in 1H-NMR confirmed the
glycine methyl ester 10 in K2CO3/CH3CN reflux con- and also the formation of the compound 24a. Then the
dition to give the compound 24a in very good yield. compound 24a was treated with 1N aqueous HCl at RT
The compound 24a was thoroughly characterized by and the reaction mixture was freeze dried to give the
1
1H NMR, 13C-NMR and MS data. H-NMR of com- designed chromone based hybrid amino acid 24 as its
pound 24a shows peaks at δ 3.31 (dd, 1H) and 3.21 HCl salt in good yields. The compound 28 was prepared
(dd, 1H) corresponding to the CH2 protons attached to following the similar procedure as 24 starting from pro-
the chromone ring and peak at δ 4.63 (dd, 1H) corre- cedure 2-hydroxy-5-methy-acetophenone 6b in a five
α
sponding to 1H) corresponding to -proton of amino step synthetic sequence. Various N-protected chromo
acid. Also, the peak at δ 6.19 (s, 1H) corresponding based amino acid derivatives (25–31) were prepared

Synthesis of chromone based unnatural amino acids
O
O
O
NHAc
OMe
OMe
NHAc
O
O
O
27
i
15
i
O
O
O
O
O
O
O
O
NHAc
OMe
NHAc
OMe
OMe
NHAc
OMe
NHAc
O
O
O
O
(+)27ii
(-)27i
(-)15i
(+)15ii
i) Chiral HPLC: Chiralcel OX-H, Hexane/EtOH (70:30)
Figure 2. The racemic compound 15 & 27 was purified by chiral HPLC.
using standard conditions.38 The N-acetyl protected Acknowledgements
amino acid 27 was subjected to chiral HPLC separa-
Authors are grateful to GVK Biosciences Pvt. Ltd. for the
financial support and encouragement. Help from the analyti-
cal department for the analytical data is appreciated. We thank
Dr. Sudhir Kumar Singh for his invaluable support and moti-
vation.
tion using Chiralcel OX-H column and hexane/EtOH
(70:30) as the mobile phase (Figure 2). The chiral
purity of the obtained pure enantiomer 27i and 27ii was
analysed by chiral HPLC and specific rotation (See Sup-
plementary Information). The relative configuration of
the enantiomer 27i and 27ii was assigned with refer-
ence to the configuration of alanine based on the specific
rotation.
References
1. Nian-Guang Li, Zhi-Hao Shi, Yu-Ping Tang, Hong-Yue
Ma, Jian-Ping Yang, Bao-Quan Li, Zhen-Jiang Wang,
Shu-LinSongandJin-AoDuan2010Syntheticstrategies
in the construction of chromones J. Heterocycl. Chem.
47 785
2. Leaby J J J, Golding B T, Griffin R J, Hardcastle I R,
Richardson C, Rigoreau L and Smith G C M 2004 Identi-
fication of a highly potent and selective DNA-dependent
protein kinase (DNA-PK) inhibitor (NU7441) by screen-
ing of chromenone libraries Biorg. Med. Chem. Lett. 14
6083
It is noteworthy to mention here that previously
inaccessible 2-chromone amino acid conjugates (25-
31) were synthesized in good yields as indicated in
Table 1. The 3-chromone amino acid conjugates (13-
19) were prepared in five easy synthetic steps in
good yield. All these compounds were well charac-
1
terized by H-NMR, 13C-NMR, LC-MS and HRMS
analysis.
3. Griffin R J, Fontana G, Golding B T, Guird S, Hard-
castle I R, Leahy J J J, Martin N, Richardson C,
Rigoreau L, Stockley M and Smith G C M 2005 Selective
Benzopyranone and Pyrimido[2,1-a]isoquinolin-4-one
Inhibitors of DNA-Dependent Protein Kinase: Synthe-
sis, Structure-Activity Studies and Radio-sensitization
of a Human Tumor Cell Line in Vitro J. Med. Chem. 48
569
4. Conclusions
We have developed an efficient and accessible route to
synthesize chromone based amino acid hybrid which
can act as β-turn peptidomimetics. Further application
of these chromone-amino acid conjugates to peptides is
underway in our laboratory.
4. Kim H P, Son K H, Chang H W and Kang S S 2004
Anti-inflammatory Plant Flavonoids and Cellular Action
Mechanisms J. Pharmacol. Sci. 96 229
Supplementary Information (SI)
5. Bhatt A S, Whetstone J L and Btueggemeier R W 1999
Novelsyntheticroutessuitableforconstructingbenzopy-
rone combinatorial libraries Tetrahedron Lett. 40 2469
6. (a) Marie-Laure L, Mahesh U, Grace Y.J C and Shao Q Y
2004 Developing site-Specific immobilization strategies
of peptides in a microarray Bioorg. Med. Chem. 12 2079;
The spectroscopic data (1H-NMR, 13C-NMR, IR and HRMS)
of the synthesized compounds are presented in the Supple-
mentary Information which is available at www.ias.ac.in/
chemsci.

Venu Kandula et al.
(b) Krisnamachari V, Levin L H, Zhou C and Pare P W 22. O’Donnell M J 2001 The preparation of optically active
α
2004 In Vitro Flavon-3-ol Oxidation Mediated by a B
Ring Hydroxylation Pattern Chem. Res. Toxicol. 17 795
-amino acids from the benzophenone imines of glycine
derivatives Aldrichimica Acta 34 3
7. Marder M, Viola H, bacigaluppo J A, Colombo M I, 23. Hashimoto T and Maruoka K 2007 Recent development
Wasowski C, Wolfman C, Medina V, Ruveda V and
Paladini A C 1998 Detection of benzodiazepine recep-
and application of chiral phase-transfer catalysts Chem.
Rev. 107 5656
tor ligands in small libraries of flavone derivatives 24. Kotha S, Goyal D and Chavan A S 2013 Diversity-
α
synthesized by solution phase combinatorial chemistry
Biochem. Biophys. Res. Commun. 249 481
Oriented Approaches to Unusual -Amino Acids and
Peptides: Step Economy, Atom Economy, Redox Econ-
8. Hoult J R S, Moroney M A and Paya M 1994
omy, and Beyond J. Org. Chem. 78 12288
Actions of flavonoids and coumarins on lipoxygenase 25. Ball J B, Hughes R A, Alewood P F and Andrews P R
and cyclooxygenase Methods. Enzymol. 234 443 1993 β-turn topography Tetrahedron 49 3467
9. Parmar V S, Bracke M E, Philippe J, Wengel J, Jain S C, 26. Lesma G, Colombo A, Sacchetti A and Silvani V 2008
Olsen C E, Bisht K S, Sharma N K, Courtens A, Sharma
S K, Vennekens K, Van Marck V, Singh S K, Kumar N,
Kumar A, Malhothra S, Kumar R, Rajwanshi V K, Jain R
A new spirocyclic proline-based lactam as efficient type
IIꢀ β-turn inducing peptidomimetic Tetrahedron Lett. 49
7423
and Mareel M M 1997 Anti-invasive activity of alkaloids 27. Mercelino A M C and Gierasch L M 2008 Roles of beta-
and polyphenolics in vitro Bioorg. Med. Chem. 5 1609
10. Galietta L J V, Springsteel M F, Eda M, Neidzinsk E
turns in protein folding: from peptide models to protein
engineering Biopolymers 89 380
J, By K, Haddadin M J, Nantz M H and Verkman A S 28. Wallen E A A, Dahlen K, Grotli M and Luthman K
2001 Novel CFTR Chloride Channel Activators Identi-
fied by Screening of Combinatorial Libraries Based on
2007 Synthesis of 3-Aminomethyl-2-aryl-8-bromo-6-
chlorochromones Org. Lett. 9 389
Flavone and Benzoquinolizinium Lead Compounds J. 29. Friden-Saxin M, Seifert T, Malo M, Anderson K, Pem-
Biol. Chem. 276 19723
berton N, Dyrager C, Friberg A, Dahlen A, Wallen E
A A, Grotli M and Luthman K 2016 Chroman-4-one
and chromone based somatostatin β-turn mimetics Eur.
J. Med. Chem. 114 59
11. Horton D A, Bourne G T and Smythe M L 2003 The
Combinatorial Synthesis of Bicyclic Privileged Struc-
tures or Privileged Substructures Chem. Rev. 103 893
12. Protti S, Mezzetti A, Lapouge C and Cornard J 30. Friden-Saxin M, Seifert T, Hansen L K, Grotli M, Erde-
P 2008 Photochemistry of metal complexes of 3-
hydroxyflavone: towards a better understanding of the
influence of solar light on the metal–soil organic matter
interactions Photochem. Photobiol. Sci. 7 109
lyi M and Luthman K 2012 Proline-mediated formation
of novel chroman-4-one tetrahydropyrimidines Tetrahe-
dron 68 7035
31. Teimouri M B, Moghaddam P A and Golbaghi G
2011 Pseudo-Five-Component Reaction between 3-
Formylchromones, Meldrum’s Acid, Isocyanides and
Primary Arylamines: Diversity-Oriented Synthesis of
Novel Chromone-Containing Peptidomimetics ACS
Comb. Sci. 13 659
32. Tietze L F, Bell H P and Chandrasekhar S 2003 Natural
product hybrids as new leads for drug discovery Angew
Chem. Int. Ed. Eng. 42 3996
33. Mehta G and Singh V 2002 Hybrid systems through nat-
ural product leads: An approach towards new molecular
entities Chem. Soc. Rev. 31 324
34. Decker M 2011 Hybrid molecules incorporating natural
products: applications in cancer therapy, neurodegener-
ative disorders and beyond Curr. Med. Chem. 18 1464
35. Jones W D 1981 Aminolysis and hydrolysis of
chromonyl oxazolones and some condensation reactions
of 2-methylchromone leading to novel chromones J.
Chem. Soc. Perkin Trans. 1 344
13. Kotha S 2003 The Building Block Approach to Unusual
α
-Amino Acid Derivatives and Peptides Acc. Chem. Res.
36 342
14. Dougherty D A 2000 Unnatural amino acids as probes of
protein structure and function Curr. Opin. Chem. Biol. 4
645
15. Rossi E, Pirovano V, Negrato M, Abbiati G and
Dell’Acqua M 2015 Synthesis of constrained analogues
of tryptophan Beilstein J. Org. Chem. 11 1997
16. Craik D J, Fairlie D P, Liras S and Price D 2013 The
future of peptide-based drugs Chem. Biol. Drug Des. 81
136
17. Góngora-Benítez M, Tulla-Puche J and Albericio F 2014
Multifaceted Roles of Disulfide Bonds. Peptides as Ther-
apeutics Chem. Rev. 114 901
18. Vagner J, Qu H and Hruby V J 2008 Peptidomimetics, a
synthetic tool of drug discovery Curr. Opin. Chem. Biol.
12 292
19. Liskamp R M J, Rijkers D T, Kruijtzer J A and Kemmink 36. (a) Ravi Kumar P, Behera M, Raghavulu K, Jaya Shree
J 2011 Peptides and proteins as a continuing exciting
source of inspiration for peptidomimetics Chem. Bio.
Chem. 12 1626
A and Yennam S 2012 Synthesis of novel isoxazole-
benzoquinone hybrids via 1,3-dipolar cycloaddition
reaction as key step Tetrahedron Lett. 53 4108; (b) Ravi
Kumar P, Behera M, Sambaiah M, Venu K, Nagaraju
P, Jaya Shree A and Yennam S 2014 Design and Syn-
thesis of Novel Isoxazole Tethered Quinone-Amino
Acid Hybrids Journal of Amino Acids. Article ID 2014
721291; (c) Balakrishna C, Nagaraju P, Yennam S, Uma
Devi P and Behera M 2015 Synthesis of new kojic acid
20. Hanessian S and Auzzas L 2008 The practice of ring con-
straint in peptidomimetics using bicyclic and polycyclic
amino acids Acc. Chem. Res. 41 1241
21. Stevenazzi A, Marchini M, Sandrone G, Vergani B and
Lattanzio M 2014 Amino acidic scaffolds bearing unnat-
ural side chains: an old idea generates new and versatile
tools for the life sciences Biorg. Med. Chem. Lett. 24
5349
α
based unnatural -amino acid derivatives Bioorg. Med.
Chem. Lett. 25 4753

Synthesis of chromone based unnatural amino acids
37. China Raju B, Nagaswara Rao R, Suman P, Yogeeswari
P, Sriram D, Thokhir B S and Shasi V K 2011
Synthesis, structure–activity relationship of novel 38. Theodora W G and Peter G M W 1999 In Protective
anticancer agents Biorg. Med. Chem. Lett. 21
2855
substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-
5-carboxylates as potential anti-mycobacterial and
Group in Organic Synthesis 3rd edn. (New York: John
Wiley) p. 494