Utilizing the high dielectric constant of water: efficient synthesis of amino acid-derivatized cyclobutenones

Article abstract of DOI:10.1016/j.tetlet.2008.01.121

This work reports the use of water as a solvent to facilitate an efficient syntheses of amino acid-derivatized cyclobutenone. Kinetics studies in different solvents reveals that high dielectric constants of the solvents are the primary attribute for the h

Full text of DOI:10.1016/j.tetlet.2008.01.121

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2128–2131
Utilizing the high dielectric constant of water: efficient synthesis
of amino acid-derivatized cyclobutenones
Jun Li, Yongbin Han, Teresa B. Freedman, Shifa Zhu, Deborah J. Kerwood,
Yan-Yeung Luk *
Department of Chemistry, Syracuse University, NY 13244, United States
Received 20 November 2007; revised 26 January 2008; accepted 28 January 2008
Available online 1 February 2008
Abstract
This work reports the use of water as a solvent to facilitate an efficient syntheses of amino acid-derivatized cyclobutenone. Kinetics
studies in different solvents reveals that high dielectric constants of the solvents are the primary attribute for the high yielding and fast
rate for this reaction. This class of substitution reactions in water also proceeds efficiently with a wide range of amino acids.
Ó 2008 Elsevier Ltd. All rights reserved.
As many sophisticated chemical transformations susta-
ining life occur in aqueous environments, we are inter-
ested in developing new methodologies and reactions that
utilize the unique properties of water to enable the efficient
synthesis of molecules of therapeutic potential or funda-
mental interests. Such efficient synthesis should support
shortening of the route to the product, and lessening the
use of protecting groups. Water as a solvent has been
explored for many types of organic transformations.1–9
Apart from being environmentally friendly, water offers
several relatively unexplored advantageous properties to
facilitate the transformation of organic reactions. First,
water has the highest dielectric constant among other polar
protic and aprotic solvents, which promotes the polari-
zation of reactants to enhance their reactivity.10 Second,
the strong hydrogen bonding capability of water molecules
can provide a means to activate specific bonds in a mole-
cule through specific hydrogen bonds. Recently, there are
significant advances in using hydrogen bonds albeit in
organic solvents to catalyze a reaction.11–15,9 Third, water
possesses a wide range of anomalous properties as a
liquid,16 but the effect and utilization of these properties
has not been explored. In a recent study, we have demon-
strated that water, as a solvent, can be used to impart high
chemoselectivity in a designed organic reaction between
squarate derivative and cysteine amino acids, or cysteine-
containing peptides.9 In this work, we report the utilization
of the high dielectric constant to facilitate a route-short-
ened, high yielding synthesis of amino acid-derivatized
cyclobutenones using unprotected amino acids.
Cyclobutenones are strained molecules that are useful as
synthetic intermediates for making complicated struc-
tures17–21 and potential therapeutic agents.18,22–25 Recently,
amino acid-derivatized cyclobutenones are shown to exhi-
bit antagonistic activities25 against a class of membrane
proteins (integrin) on mammalian cells, which are impor-
tant targets for developing therapeutic agents.26 In that
work, the key synthesis of amino acid-derivatized cyclo-
butenones was carried out in two steps in organic solvents,
where 3-ethoxycyclobutenone was first converted to
1,4-cyclobutandione and followed by the treatment of
amino acids. This two-step synthesis was required because
the authors observed that the direct substitution of 3-eth-
oxy cyclobutenone with amino acids did not yield any
desirable conversion in organic solvents.27,25 Here, we
postulate that because of the ring strain and the conjuga-
tion, the ester characteristics in 3-ethoxycyclobutenone
are more activated and more prone to hydrolysis and
*
Corresponding author. Tel.: +1 315 443 7440; fax: +1 315 443 4070.
E-mail address: yluk@syr.edu (Y.-Y. Luk).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.121

J. Li et al. / Tetrahedron Letters 49 (2008) 2128–2131
2129
Table 2
R2
R2
R'
NH
OEt
H2N
R'
Base
Substitution reactions of different cyclobutenones with L-serine
R1
O
R1
O
Cyclobut-enones
Product (yield (%))
ka (L molÀ1 sÀ1
)
+
Solvents
CO2H
CO2H
H
OEt
1: R1, R2 = -(CH3)3 -
2: R1, R2 = -(CH3)4 -
3: R1 = Et, R2 = Me
9 Â 10À4
N
OH
CO2H
O
1
O
5, (80)b
Scheme 1.
H
OEt
substitution than a generic ester.28,23 As such, we set to
investigate whether a polar solvent with a high dielectric
constant, particularly water, can drive a direct substitution
of various 3-cyclobutenones by different amino acids
(Scheme 1).
N
OH
1 Â 10À4
CO2H
O
O
4e, (74)b
2
Me
H
Et
OEt
N
OH
0.2 Â 10À4
Cyclobutenones 1–3 were synthesized by adopting the
reported literatures.29–31 Examining this substitution reac-
tion in different solvents reveals that this substitution reac-
tion indeed does not proceed well in organic solvents
(Table 1).32,33 Substitution reaction of cyclobutenone 2
with L-serine shows that the rate in DMSO-d6
(5 Â 10À5 L molÀ1 sÀ1) is slightly higher than that in
CD3OD (3.5 Â 10À5 L molÀ1 sÀ1). Notably, both the yield
(74%, Table 2) and the rate (10 Â 10À5 L molÀ1 sÀ1) are the
highest in water mixed with 10% DMSO. DMSO is added
in water to ensure a complete solubilization of the reac-
tants. Overall, the rate of the reaction increases when the
dielectric constant of the solvent is increased. Adding urea,
a weak hydrogen bond donor, to DMSO, the rate of the
reaction seems to be slightly suppressed (Table 1, entry
3). When CF3CD2OD is used as the solvent, which has a
low dielectric constant but strong hydrogen bonding capa-
bility, there is no observable transformation for this reac-
tion (Table 1, entry 5). In contrast to ours9 and other
reports that use urea to catalyze organic reactions via
hydrogen bonding,34,35 these results suggest that hydrogen
bonding is not catalyzing, nor facilitating the transforma-
tion of this substitution reaction. Consequently, the high
dielectric constant of solvent appears to be the major attri-
bute for promoting both the rate and the yield of the
reaction.
CO2H
O
O
6, (75)b
3
a
Reaction conditions: cyclobutenone (1.0 equiv), Ser (1.0 equiv), NaOH
(1.0 equiv), C0 = 109 mM.
b
Isolated yield.
Next, we studied the effect of the structure of the 3-
ethoxycyclobutenones on their reactivity of being substi-
tuted by amino acids in water (with 10% DMSO). The
structure includes bicyclic 3-ethoxy cyclobutenones 1 and
2, and alkyl-substituted 3-ethoxy cyclobutenone 3. As the
ring size increases from cyclobutane to cyclopentane, and
to an open form, the strain and the electronegativity
decrease in the cyclobutenone ring of the molecules. Exam-
ining the rate of substitution of 1, 2, and 3 by L-serine
amino acid in D2O/DMSO-d6 with one equivalent of
NaOH indicates that the substitution of 1 is about 9 times
faster than 2, and 45 times faster than 3 (Table 2).32 Past
studies on cyclic rings have inferred an increase in the s-
character of the ring C–H bond as the ring gets smaller,
and thus impose an electron-withdrawing effect.36,37 Con-
sistent with this rationale, we believe that our result is con-
sistent with the increase in the polarization of the
cyclobutenone ring due to the attached cyclic alkane, which
enhances the rate of the substitution of the amino acids.
Next, we examined the scope of this substitution reac-
tion with eight amino acids including L-tryptophan, L-tyro-
sine, L-lysine, L-glycine, L-serine, L-cystine, L-proline, and
L-cysteine.38 While these amino acids vary greatly in their
structures, high yield is obtained for all of these amino
acids except for proline (yield ꢀ64%, Table 3, entry 7)
and for cysteine (yield ꢀ36%, Table 3, entry 8). For cys-
teine, we believe that the thiolate group, being a strong
nucleophile in solutions with high pH values, first displaces
the ethoxy group on the cyclobutenone. At high pH, this
thiolate can either proceed with hydrolysis39 or with a
S?N acyl transfer that affords the observed product.40
These two competing processes result in a low yield of
the observed product. Notably, the amino acids bearing
aromatic residues (tryptophan and tyrosine) afford the
highest yields among this collection of amino acids.
Table 1
Substitution reaction of 2 with L-serine in different solvents
H
H2N
N
OEt
OH
CO2H
OH
+
CO2H
O
O
Entry Solvent
Dielectric constanta kb (L molÀ1 sÀ1
)
1
2
3
4
5
D2O/DMSO-d6 (9:1)
DMSO-d6
4 M urea in DMSO-d6
CD3OD
—
46.45
—
32.66
26.67
100 Â 10À6
50 Â 10À6
30 Â 10À6
35 Â 10À6
c
CF3CD2OD
—
a
Ref. 13.
b
Reaction condition: 2 (1.0 equiv), Ser (1.0 equiv), NaOH (1.0 equiv),
C0 = 109 mM.
c
Product not detected.

2130
J. Li et al. / Tetrahedron Letters 49 (2008) 2128–2131
Table 3
O
OEt
Substitution reactions of 2 with different amino acidsa
OEt
Entry Amino
acids
Time Product
(h)
(yield)b
O
NHR
O
7
H
H2N
N
1
3
Scheme 2.
CO2H
CO2H
NH
NH
O
derivative 7 (Scheme 2) reacts with cysteine amino acids
or cysteine bearing peptides at neutral pHs, whereas 3-
ethoxy cyclobutenones require a basic condition for the
substitution to occur (Scheme 2).
4a, (98%)
H
N
H2N
2
3
72
13
CO2H
CO2H
Finally, we determined the preferred conformation of
the amino acid residue relative to the cyclobutenone ring
in the products by using nuclear overhauser enhanced spec-
troscopy (NOESY) spectroscopy (see Supplementary
data). In general, the amino acid-derivatized cyclobute-
nones adopt ‘cis-like’ conformations, in which the chiral
carbon on the amino acids is ‘cis’ relative to the double
bond in the cyclobutenones—a structure that appears to
minimize the steric congestion between the cyclopentane
ring and the amino acid residue (Scheme 1).
OH
OH
O
O
4b, (91%)
H
N
CO2H
H2N
CO2H
NH2
NH2
4c, (88%)
H
N
CO2H
To conclude, while water has been used as a solvent for
a wide variety of organic reactions, the demonstration of
the explicit use of the high dielectric constant of water to
drive a reaction is rare. In this work, we show that the sub-
stitution of 3-ethoxycyclobutenones with amino acids,
which were reported not to proceed in organic solvents,
proceeds with the fastest rate and the highest yield in an
aqueous solution. Based on the kinetic studies of this sub-
stitution reaction in different solvents, the primary attribute
of the solvent effect appears to be the high dielectric pro-
perty of water rather than hydrogen bonding or hydro-
phobic effects. Whether water as a solvent will increase
the reactivity of other strained molecules in general is the
subject of our ongoing research.
4
5
H2N
CO2H
13
10
O
4d, (77%)
H
N
OH
CO2H
H2N
OH
CO2H
O
4e, (74%)
H
N
2*
S
S
CO2H
O
O
H2N
4g, (36%)
S
6
48
2
CO2H
H
N
NH2
CO2H
S
Acknowledgments
CO2H
4h, (53%)
We thank the Chemistry Department of SU, Syracuse
Center for Excellence CARTI award supported by US
Environmental Protection Agency [Grant Nos.: X-
83232501-0] and NSF-CMMI [Grant No: 0727491] for
financial support. We also thank Professor Boddy and
Sponsler for helpful discussion.
N
CO2H
7
8
CO2H
13
48
N
H
O
4f, (64%)
H
N
Supplementary data
S
H2N
SH
2
CO2H
Measurement of rate constants of 1–3 reacting with L-
serine in different solvents, and conformational study of
4d and 4e by 1H NOESY. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2008.01.121.
CO2H
O
4g, (38%)
a
Reaction conditions: 2 (1.0 equiv), amino acid (1.5 equiv), NaOH
(1.5 equiv), solvent: H2O (0.9 mL)–DMSO (0.1 mL).
b
Isolated yield.
References and notes
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(MeOH-d4) d (ppm) 7.60 (1H, dt, J = 7.8, 0.6 Hz), 7.29 (1H, dt,
J = 8.1, 0.6 Hz), 7.06 (1H, s), 6.98–7.03 (2H, m), 4.12 (1H, m), 4.11
(1H, s), 3.42–3.48 (1H, m), 3.10–3.19 (1H, m), 1.57–1.80 (8H, m); 13
C
NMR (MeOH-d4) d 193.63, 177.03, 175.54, 136.97, 128.10, 123.69,
121.30, 118.72, 118.36, 111.25, 110.36, 95.83, 67.00, 61.32, 30.67,
30.25, 28.67, 26.67, 26.64; ESIMS 325.1 [M+1]+. Compound 4b: 1H
NMR (MeOH-d4) d (ppm) 6.97 (2H, dd, J = 7.2, 2.1 Hz), 6.62 (2H,
dd, J = 6.6, 2.1 Hz), 4.29 (1H, s), 4.06 (1H, m), 3.15 (1H, m), 2.85
(1H, m), 1.55–1.69 (8H, m); 13C NMR (MeOH-d4) d 193.83, 177.43,
172.99, 156.45, 130.51, 127.70, 115.25, 96.40, 67.14, 60.32, 37.05,
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amino acid—3-ethoxyspiro[3.4]-oct-2-en-1-one (2) with L-serine: A
solution 2 (20 mg, 0.12 mmol), L-serine (19 mg, 0.18 mmol), and
NaOH (7.2 mg, 0.18 mmol) in water (0.9 mL) and DMSO (0.1 mL)
was stirred at room temperature for 10 h. The solution was washed
with ether (2.0 mL) twice and then acidified with 1.0 N HCl to
67.35, 59.41, 53.59, 40.59, 39.01, 30.70, 30.42, 26.80; ESIMS 361.0
[M+1]+.
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