Synthesis of a new fluorescent macrocyclic α-amino acid derivative via tandem cross-enyne/ring-closing metathesis cascade catalyzed by ruthenium based catalysts

Article abstract of DOI:10.1016/j.jorganchem.2011.02.019

A simple methodology to a unique macrocyclic α-amino acid (AAA) derivative involving three step synthetic sequence has been reported. In addition, various ruthenium based catalysts were studied to enhance the selectivity of the desired macrocyclic AAA derivative 6. The fluorescence behavior of these AAA derivatives 5 and 6 indicate their potential applications in biological sciences as biomarkers, ion sensors and peptidomimetics.

Full text of DOI:10.1016/j.jorganchem.2011.02.019

Journal of Organometallic Chemistry 696 (2011) 1856e1860
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis of a new fluorescent macrocyclic -amino acid derivative via tandem
a
cross-enyne/ring-closing metathesis cascade catalyzed by ruthenium based
catalysts
*
Sambasivarao Kotha , Deepti Bansal, Kuldeep Singh, Subhasree Banerjee
Department of Chemistry, Indian Institute of Technology- Bombay, Mumbai 400 076, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple methodology to a unique macrocyclic
a-amino acid (AAA) derivative involving three step
Received 16 November 2010
Received in revised form
7 February 2011
synthetic sequence has been reported. In addition, various ruthenium based catalysts were studied to
enhance the selectivity of the desired macrocyclic AAA derivative 6. The fluorescence behavior of these
AAA derivatives 5 and 6 indicate their potential applications in biological sciences as biomarkers, ion
sensors and peptidomimetics.
Accepted 18 February 2011
Ó 2011 Elsevier B.V. All rights reserved.
Keywords:
Ruthenium based catalysts
Tandem metathesis
Fluorescent
Macrocyclic
a
a
-amino acid (AAA) derivatives
-amino acid
1. Introduction
Moreover, reactive rotamer [16] and Thorpe-Ingold effects could
aid the RCM protocol to generate the macrocyclic system 6.
Macrocyclics play an important role in numerous biochemical
functions, and their unique pharmacological properties have led to
the development of new drugs [1]. Macrocyclic peptides often
exhibit an increased affinity to a given biological receptor, at the
same time diminished sensitivity to cellular peptidases [2] and also
help in QSAR (Quantitative StructureeActivity Relationship)
studies [3]. Several methods are available to assemble macrocyclics
[4e12], however, there are no reports for the synthesis of macro-
cyclic AAA by tandem metathesis sequence. In this regard, we
conceived a simple, diversity oriented, fragment coupling approach
for the synthesis of macrocyclic AAA derivatives based on tandem
Based on these considerations, the critical building block 4 has
been assembled starting with diethyl acetamidomalonate
1
(DEAM). Thus, partial hydrolysis of 1 followed by O-propargylation
and C-alkylation led to the enyne building block 4 in good yield.
Finally CEeRCM sequence generates the desired macrocyclic
compound 6. Although it appears to be simple, this methodology
can generate an open chain intermediate 5b (Scheme 1) with
undesired stereochemistry, not suitable for macrocyclic formation.
In view of these side reactions, CEM has some limitations. There-
fore, we plan to study this crucial step in a more detailed manner.
Several groups have tried diverse approaches to achieve regio- and
steroselectivity in CEM by varying the reaction conditions [17e19].
The required stereoisomer may be generated selectively during the
CEM by employing a suitable catalyst. Here, we would like to
describe a simple fragment coupling approach for the synthesis of
macrocyclic AAA derivative 6. In addition, we report fluorescence
studies of AAA derivatives 5 and 6.
cross-enyne/ring-closing metathesis (CEeRCM) as
a key step
[13,14].
The beauty of this strategy (Scheme 1) is that four components
(i.e. amino acid derivative 2, propargyl alcohol, allyl bromide and
1,5-hexadiene) are stitched in three steps to generate the macro-
cyclic system which is reminiscent of biogenetic sesquiterpene
synthesis. In view of the potentially favorable chelate coordination
of the acyl moiety with the ruthenium metal [15], (Fig. 1) the enyne
substrate 4 may undergo a cross-enyne metathesis (CEM) protocol.
2. Results and discussion
To start with, 2-acetamido-3-ethoxy-3-oxopropanoic acid 2 was
prepared by partial hydrolysis of 1 by using the literature procedure
in 76% yield [20,21]. Esterification of acid derivative 2 has been
carried out by treatment with propargyl alcohol to generate
* Corresponding author. Tel.: þ91 22 2576 7160.
E-mail address: srk@chem.iitb.ac.in (S. Kotha).
0022-328X/$ e see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2011.02.019

S. Kotha et al. / Journal of Organometallic Chemistry 696 (2011) 1856e1860
1857
COOC2H5
O
O
Tol-N
Cl
N-Tol
NHCOCH3
PCy3
Ru
RCM
O
COOC2H5
NHCOCH3
Mes-N
Cl
N-Mes
Ph
Ph
H
Cl
Cl
O
Ru
O
Ru
Cl
6
H
5a= Z- isomer
5b= E- isomer
Cl
PCy3
COOC2H5
PCy3
G II
(II)
O
CEM
NHCOCH3
G I
(I)
N-Tolyl
(III)
O
4
PCy3
Mes-N
Cl
N-Mes
Scheme 1. Reterosynthetic pathway for the synthesis of macrocyclic AAA derivative 6.
Mes-N
Cl
N-Mes
Cl
Cl
Ph
Ru
O
Ru
O
Ru
O
S
Cl
O
H3COCHN
C2H5OOC
O
Cl
PCy3
N
Sulfo
(IV)
HG I
(VI)
In
Ru
O
(V)
Fig. 2. Structure of ruthenium catalysts used in the present study.
Fig. 1. Ruthenium metal potentially coordinating with carbonyl group of acyl moiety of
enyne 4.
geometrical constraints the E-isomer does not undergo cyclization,
instead, undergoing methylene transfer with 1,5-hexadiene to
deliver compound 5 as indicated by the magnitude of the coupling
C2H5OOC
C2H5OOC
C2H5OOC
HOOC
constant
d
6.07 (d, J ¼ 16.0 Hz, 1H) in the 1H NMR spectral data.
a
NHCOCH3
NHCOCH3
However, the Z-isomer undergoes cyclization by efficient capture of
the pendant alkene to generate the cyclized product 6 by RCM
protocol. The open chain product 5 and the cyclized compound 6
thus obtained by the cross-enyne/ring-closing metathesis
(CEeRCM) sequence were separated by silica gel column chro-
matograph using ethyl acetate/petroleum ether (15%) as an elutent.
1H NMR and 13C NMR spectral data indicate that 5 is a CEM product
while the compound 6 is derived from CEeRCM cascade. Forma-
tions of acyclic product 5 indicates that most likely pathway to
generate the cyclized product 6 involve CEM followed by RCM
sequence of the Z-isomer (Scheme 3).
1
2
COOC2H5
NHCOCH3
O
c
b
4
O
3
Scheme 2. Synthesis of the enyne building block 4. Reagents and conditions: (a)
NaOH, 1,4-dioxane, rt, 15 h, 76%. (b) propargyl alcohol, toluene, p-TsOH, reflux, 4 h, 31%.
(c) allyl bromide, Cs2CO3, CH3CN, rt, 6 h, 99%.
To improve and understand the selectivity aspect of CEM for the
formation of the macrocyclic product 6, the role of various ruthe-
nium based metathesis catalysts was studied. After screening six
different catalysts (Fig. 2) with substrate 4 (Table S1), we found that
the cyclized product 6 was obtained selectively in 86% yield with
the first-generation HoveydaeGrubbs catalyst (HG I). At the
conclusion of the reaction (TLC monitoring), the ruthenium catalyst
was removed by a short silica gel column chromatography and the
resulting product was qualitatively analyzed by HPLC (Table 1). The
compounds 5 and 6 show distinct peaks with a retention time of
3.376 and 3.257 min respectively in HPLC (Table 1 entry 6). When
the metathesis reaction was carried out with HG I catalyst only
1-ethyl-3-prop-2-ynyl-2-acetamidomalonate 3 in 31% yield by
using a DeaneStark apparatus. Due to the presence of several
reactive functionalities in the substrate 2, various conditions to
improve the yield of 3 were futile in our hands. Since Cs2CO3 is
known to give C-alkylated product [22], allylation of 3 with allyl-
bromide in the presence of Cs2CO3 in acetonitrile gave the enyne
substrates 4 in quantitative yield (Scheme 2).
Later, the enyne substrate 4 was subjected to CEM with 1,5-
hexadiene. When the enyne substrate 4 was treated with Grubbs
second-generation catalyst (G II) in DCM in the presence of 1,5-
hexadiene, both E and Z-isomers were obtained as expected
according to the known mechanism [19] (Scheme 3). Due to
O
*
O
COOC2H5
NHCOCH3
RCM
COOC2H5
NHCOCH3
X
O
COOC2H5
NHCOCH
O
O
(40%)
6
Z- isomer
3 CEM
a
X=RuLn
O
methylene
transfer
*
COOC2H5
NHCOCH3
COOC2H5
NHCOCH3
O
X
O
4
O
O
E- isomer
5
(54%)
Scheme 3. CEeRCM cascade of enyne building block 4. Reagents and conditions: (a) 10 mol% G II, 1,5-hexadiene, DCM, rt, 72 h.

1858
S. Kotha et al. / Journal of Organometallic Chemistry 696 (2011) 1856e1860
Table 1
Retention times of peaks under various catalyst conditions in HPLC studies.
S.No.
Catalyst
used
Number of peaks
in HPLC
Retention time
of peaks (min)
Product formed
1
2
3
4
5
6
G I
G II
N-Tolyl
Sulfo
In
2
2
2
2
2
1
3.326, 3.280
3.375, 3.257
3.362, 3.263
3.327, 3.270
3.399, 3.284
3.259
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
6
HG I
Table 2
d
values of marked set of protons in open chain product 5 and cyclized product 6 in
1H NMR spectroscopy studies.
S.No.
Catalyst used
Chemical shifts
Products
formed
Relative ratio
(ppm) in 1H NMR
of 6:5a
1
2
3
4
5
6
G I
G II
N-Tolyl
Sulfo
In
4.814, 4.620
4.816, 4.619
4.818, 4.621
4.816, 4.619
4.821, 4.620
4.619
5 and 6
5 and 6
5 and 6
5 and 6
5 and 6
6
0.91:1
0.74:1
0.70:1
1:1
0.87:1
1
Fig. 3. Normalised fluorescence spectra of compound (i) 5 and (ii) 6 in acetonitrile at
lex ¼ 340 nm.
HG I
a
Ratio of integrations of marked protons in Scheme 3.
cyclized product 6, with a retention time of 3.259 min, was
observed. In one instance, we separated compounds 5 and 6 by
tedious column chromatography and characterized them fully. For
the remaining experiments we utilized 1H NMR data of the mixture
to determine the relative ratio of two products 5 and 6 (Table 2).
The 1H NMR spectral data of the open chain product 5 (isolated by
column chromatography) shows a peak at 4.81 ppm for the
methylene protons (indicated by a *carbon in Scheme 3) whereas
the cyclized product 6 showed a peak at 4.61 ppm for the methy-
lene protons. The 1H NMR of reaction mixture obtained under
different metathesis catalyst conditions showed two peaks in the
region 4.5e4.9 ppm. However, with catalyst HG I, only cyclized
product 6 was obtained selectively as indicated by the presence of
one peak at
d
4.61 in the 1H NMR spectrum.
Based on our screening studies, we felt that the nature of the
catalysts played a critical role in deciding the outcome of stereo-
chemistry of CEM product. Also, the E- and Z- isomers are in dynamic
equilibrium with each other. Based on the literature precedence one
can envision that under HG I catalyst conditions the E-isomer
converts to Z-isomer [19] by electrocyclization (Scheme 4). In the Z-
Fig. 4. Fluorescence decays of compounds (i) 5 and (ii) 6 at lem ¼ 400 nm in aceto-
nitrile and the resolution is 7 ps per channel. The instrument response functions are
shown by the dashed line.
COOC2H5
NHCOCH3
COOC2H5
NHCOCH3
O
LnRu
O
LnRu
H
O
)
O
y
r
o
t
E- isomer
a
t
o
r
n
o
c
(
-
e
O
4
COOC2H5
NHCOCH3
O
COOC2H5
NHCOCH3
LnRu
fast
RCM
O
O
Z- isomer
6
Scheme 4. Proposed conversion of E-isomer to Z-isomer by reversible electrocyclization [19].

S. Kotha et al. / Journal of Organometallic Chemistry 696 (2011) 1856e1860
1859
isomer the vinyl carbene is positioned close to pendant alkene for
a favorable RCM sequence. Intramolecular cyclization of the Z-
isomer would give RCM product 6. Also, the reactive rotamer [16]
and ThorpeeIngold effect [23] aids the formation of the cyclized
product. We can also explain our observation on the basis of the
CurtineHammett principle. According to this principle “for a reac-
tion that has a pair of reactive intermediates or reactants that
interconvert rapidly, each going irreversibly to a different product,
the product ratio will depend only on the difference in the free
energy of the transition state going to each product, and not on the
equilibrium constant between the intermediates” [24]. So, under HG
I catalyst the cyclized product is generated selectively, although it is
derived from a less stable Z-isomer.
Chemical Co (India). Ruthenium catalysts were purchased from
Aldrich and Strem chemicals. All the commercial reagents were
used as such without further purification. Infrared (IR) spectra were
recorded on Nicolet Impact-400 FT IR spectrometer in KBr/CHCl3/
CCl4. Proton Nuclear Magnetic Resonance (400 MHz, 1H NMR)
spectra and Carbon Nuclear Magnetic Resonance (100.6 MHz, 13C
NMR) spectra were recorded on Bruker/Varian spectrometers. The
high-resolution mass measurements were carried out using JEOL
JMS-DX 303 GCeMS instrument or Micro mass Q-Tof spectrometer.
4.1.1. Fluorescence
The steady state absorption spectra have been recorded on
a JASCO V-570 spectrophotometer and the steady state fluorescence
spectra were recorded on a Perkin Elmer LS55 Luminescence
spectrometer (lex ¼ 360 nm), with a band width of 5 nm. The
solution was prepared by using HPLC grade acetonitrile purchased
from Spectrochem, Mumbai, India. Time resolved fluorescence
decay was recorded in a time correlated single photon counting
(TCSPC) system, from IBH, UK, using lex ¼ 341 nm. The fullwidth at
half maxima of the instrument response function was 800 ps. The
fluorescence decays were collected with emission polarizer at
a magic angle 54.7ꢀ and was analyzed by using IBH DAS 6.0 software.
The decays were fitted with a biexponential function: I(t) ¼ I(0)
Next, we studied the photophysicalpropertiesofcompound 5 and
6. The absorption spectra for both the compounds show maxima at
357 nm (Fig. S1). Both the compounds show fluorescence in the blue
region. Each spectrum consists of three maxima at 405 nm, 425 nm
and 452 nm (Fig. 3). pe
p* transitions in the diene moiety in these
molecules may be a probable origin of this fluorescence spectra. The
excitation spectra map the absorption spectra, indicating that the
fluorescence is from the compound and not from some fluorescent
impurity(Figs. S1eS3). The fluorescencedecays (Fig. 4) were found to
be bimodal for lem ¼ 405 nm, 425 nm and 452 nm for both the
compounds at lex ¼ 341 nm (Figs. S4 and S5). The predominant
component in the fluorescence decayof 5 is a 550 ps onewhile that in
6 is 750 ps. The longer component of 3 ns contributes very little to the
decay (Tables S2 and S3). The longer component may be assigned to
the fluorescence from the FranckeCondon excited state, while the
shorter component is likely to be due to an ultrafast relaxation
process that occurs post excitation [25].
[A1exp(ꢁt/
s
1) þ A2exp(ꢁt/
s2)], where s1 and s2 are the two lifetimes
and A1 and A2 are their amplitudes. A1þA2 ¼ 1, lex ¼ 341 nm.
4.2. Synthesis
4.2.1. 1-Ethyl-3-prop-2-ynyl-2-acetamidomalonate 3
To a suspension of 2 (2.0 g, 10.58 mmol) in toluene (200 mL) was
added p-toluenesulfonic acid (10 mg) and propargyl alcohol (10 mL,
excess), and the reaction mixture was heated at reflux with stirring.
The water formed during the reaction was removed by using
a DeaneStark trap. After complete conversion of 2 (TLC monitoring,
4 h), toluene was removed, and the semisolid obtained was taken
up in ethyl acetate and washed with water; the aqueous layer was
extracted with ethyl acetate (3 ꢂ 25 mL). The combined organic
layer was washed with brine, dried with Na2SO4 and concentrated
in vacuo. Purification of the crude product by column chromatog-
raphy (SiO2; ethyl acetate/petroleum ether, 35%) gave compound 3
(727 mg, 31%) as a white solid.
3. Conclusions
In summary, we have developed a simple methodology for the
synthesis of a novel macrocyclic AAA derivative 6 from commer-
cially available simple starting materials using metathesis as a key
step. This methodology may be extended to higher macrocyclic
AAA derivatives by varying the length of alkene and alkyne
component during the alkylation sequence. The present study
clearly indicates that HG I ruthenium based catalyst gave the
cyclized product 6 in 86% yield. In addition, a photophysical study
of these AAA derivatives 5 and 6 revealed that their fluorescent
nature is in the blue region. After suitable protection-deprotection
these unusual AAA derivatives may be incorporated into a peptide
chains and the resulting peptides may function as biomarkers, ion
sensors and peptidomimetics.
Rf: 0.35 (50% ethyl acetate/petroleum ether); mp: 86 ꢀC; 1H
NMR (400 MHz, CDCl3):
d
¼ 1.31 (t, J ¼ 7.6 Hz, 3H), 2.09 (s, 3H), 2.52
(t, J ¼ 2.8 Hz, 1H), 4.27e4.30 (m, 2H), 4.78e4.81 (m, 2H), 5.23 (d,
J ¼ 7.2 Hz, 1H), 6.58 (bs, 1H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 13.9, 22.7, 53.6, 56.2, 62.9, 75.8, 76.3, 165.8, 165.9, 169.8 ppm;
HRMS m/z (Q-Tof): calcd for C10H14NO5 [M þ H]ꢁ 228.0872, found
4. Experimental
at 228.0867; IR: (KBr) nmax 1744, 1663, 2127, 3271 cmꢁ1
.
4.1. General information
4.2.2. 1-Ethyl-3-prop-2-ynyl-2-acetamido-2-allylmalonate 4
To a solution of 3 (100 mg, 0.44 mmol) in acetonitrile was added
Cs2CO3 (162 mg, 0.49 mmol) under nitrogen. Then, allyl bromide
(122 mg, 0.15 mL, 1.76 mmol) was added slowly by syringe. The
resulting light-brown solution was stirred at room temperature for
7 h till the completion of the reaction (TLC monitoring). The reac-
tion mixture was diluted with ethyl acetate and filtered over celite
with the help of a sintered funnel. The organic layer was concen-
trated in vacuo to yield an oily product. Purification of the crude
product by column chromatography (SiO2; ethyl acetate/petroleum
ether 30%) gave compound 4 (116.6 mg, 100%) as a white solid.
Rf: 0.62 (50% ethyl acetate/petroleum ether); mp: 66e68 ꢀC; 1H
All the reactions were monitored by employing TLC technique
using appropriate solvent systems for development. Reactions
involving air/oxygen sensitive reagents or catalysts were performed
in degassed solvents. Transfer of moisture sensitive materials were
carried out in a glove box, using standard syringe-septum tech-
niques and the reactions were maintained under nitrogen atmo-
sphere until the work up. Acetonitrile was distilled over calcium
hydride. Ethyl acetate was distilled over calcium carbonate.
Magnesium sulfate was dried in oven at 130 ꢀC for one day. All the
solvent extracts were washed successively with water, brine
(saturated sodium chloride solution) and dried over anhydrous
magnesium sulfate and concentrated at reduced pressure on
a Buchi R-114 rotary evaporator. Yields reported are isolated yields
of the materials. Allyl bromide was purchased from E-Merck
NMR (400 MHz, CDCl3):
d
¼ 1.28 (t, J ¼ 6.8 Hz, 3H), 2.04 (s, 3H), 2.49
(t, J ¼ 2.4 Hz, 1H), 3.05e3.11 (m, 2H), 4.27 (q, J ¼ 6.8 Hz, 2H),
4.66e4.85 (m, 2H), 5.11e5.15 (m, 2H), 5.54e5.58 (m, 1 H), 6.74 (bs,
1H) ppm; 13C NMR (100 MHz, CDCl3):
d
¼ 14.1, 23.2, 37.1, 53.8, 63.1,

1860
S. Kotha et al. / Journal of Organometallic Chemistry 696 (2011) 1856e1860
66.2, 75.6, 75.7, 120.4, 131.1, 167.1, 167.5, 169.3 ppm; HRMS (Q-Tof):
University Grants Commission, New Delhi for the scholarship. We
thank DST, New Delhi for the financial support. SK thanks the DST
for the award of J. C. Bose fellowship.
calcd for C13H18NO5 [M þ H]ꢁ 268.1185, found at 268.1182; IR: (KBr)
nmax 1596, 1678, 1745, 2126, 3283 cmꢁ1
.
4.2.3. Cross-enyne/Ring-closing metathesis of enyne 4
To a solution of enyne 4 (67.9 mg, 0.25 mmol) in dry degassed
DCM (15 mL) was added 1,5-hexadiene (0.3 mL) followed by G II
(20.9 mg, 10 mol%, 0.02 mmol). The reaction mixture was stirred at
rt for 72 h (TLC monitoring) and then concentrated in vacuo.
Purification of the crude product by column chromatography (SiO2;
ethyl acetate/petroleum ether,15%) afforded product 5 (47 mg, 54%)
as a thick light yellow liquid.
Appendix. Supplementary data
Supplementary data related to this article can be found online at
doi:10.1016/j.jorganchem.2011.02.019.
References
Rf 0.66 (25% ethyl acetate/petroleum ether); 1H NMR (400 MHz,
CDCl3):
d
1.25 (t, J ¼ 6.8 Hz, 3H), 2.03 (s, 3H), 2.15e2.21 (m, 4H),
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Rf 0.55 (25% ethyl acetate/petroleum ether); 1H NMR (400 MHz,
CDCl3):
d
1.25 (t, J ¼ 6.8 Hz, 3H), 2.03 (s, 3H), 2.11e2.19 (m, 4H), 3.08
(d, J ¼ 8.0 Hz, 2H), 4.22e4.26 (m, 2H), 4.61e4.62 (m, 2H), 5.09e5.13
(m, 2H), 5.55e5.58 (m, 1H), 5.80e5.87 (m, 3H), 6.77 (bs, 1H) ppm;
13C NMR (100.6 MHz, CDCl3):
d 14.2, 22.0, 22.2, 23.2, 37.1, 62.8, 66.4,
68.7, 120.1, 124.2, 126.2, 127.9, 130.6, 131.4, 167.8, 167.8169.2 ppm;
HPLC tR: 3.257 min (100% acetonitrile, flow rate 1 mL/min, detector
wavelength 254 nm, reverse phase C18 column); UVevis (aceto-
nitrile): lmax 357 nm; HRMS (Q-Tof): calcd. for C17H24NO5 [M þ H] ꢁ
322.1654; found 322.1667; IR: nmax 1624, 1671, 1727, 2926 cmꢁ1
.
Acknowledgements
[24] F.A. Carey, R.J. Sundberg, Advanced Organic Chemistry, Part A, Structure and
Mechanisms, fifth ed. Springer, New York N.Y., 2007, 296e297.
[25] D. Panda, S. Khatua, A. Datta, J. Phys. Chem. B. 111 (2007) 1648e1656.
We thank SAIF IIT-Bombay for spectral data. We also thank Prof.
Anindya Datta for his help in fluorescence studies; DB thanks