The trans opening of ethylene diamine tetra acetic acid bis anhydride (EDTAA) with cystine-di-OMe: One-step synthesis of bihelical systems Respectfully dedicated to Professor M.V. George on the occasion of his 85th birthday

Article abstract of DOI:10.1016/j.tetlet.2013.11.078

The generation of a bihelical (figure of 8) motif has been illustrated by trans opening of EDTAA with l-cystine-di-OMe and d-penicillamine disulfide-di-OMe. In the former case the open cyclic system, arising by cis addition, was secured as a minor product.

Full text of DOI:10.1016/j.tetlet.2013.11.078

Tetrahedron Letters 55 (2014) 1132–1135
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The trans opening of ethylene diamine tetra acetic acid bis anhydride
(
EDTAA) with cystine-di-OMe: one-step synthesis of bihelical systems
Santhosh Reddy Naini , Subramania Ranganathan , Jhillu Singh Yadav a, , A. V. S. Sarma b, , d,
a
a,
⇑
⇑
⇑
b,
⇑
c,
⇑
d
⇑
K. V. S. Ramakrishna , Ramakrishnan Nagaraj , J. Richard Premkumar , G. Narahari Sastry
a
Discovery Lab, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Center for NMR, Indian Institute of Chemical Technology, India
Centre for Cellular and Molecular Biology, Hyderabad 500 007, India
Molecular Modeling Group, Organic Chemical Sciences, Indian Institute of Chemical Technology, India
b
c
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The generation of a bihelical (figure of 8) motif has been illustrated by trans opening of EDTAA with
-cystine-di-OMe and -penicillamine disulfide-di-OMe. In the former case the open cyclic system, arising
by cis addition, was secured as a minor product.
Received 4 October 2013
Revised 1 November 2013
Accepted 12 November 2013
Available online 3 December 2013
L
D
Ó 2013 Elsevier Ltd. All rights reserved.
Respectfully dedicated to Professor M.V.
George on the occasion of his 85th birthday
Keywords:
Helicenes
Anhydride
Cystine-di-OMe
Bihelical
Synthesis
Introduction
crystallization from ether, afforded cyst-di-OMe di hydrochloride
7
2, mp: 164 °C in quantitative yields. The free base 3, generated
Bihelical (figure of 8) structures represent a versatile motif in
several domains, with total synthesis of bihelical alanine t-RNA
in ꢀ74% yields with aqueous sodium carbonate, extracted with
methylene chloride and then evaporated, was used without delay.
1
(
Yeast), the role of such motifs in the initiation of transcription
An ice cooled and stirred suspension of 1 in CH
with, in drops, over 1 h, to an equivalent amount of freshly pre-
pared 3 in CH Cl gave a clear solution. The product precipitated
2 2
Cl , when mixed
2
and the key role it played in the first total synthesis of a gene have
made creation of such systems as an objective in several DNA–pro-
tein interaction studies. Figure of 8 motifs are increasingly found in
2
2
slowly and was completed by leaving stirred for overnight and fil-
tered to afford a powdery white solid, whose mass spectra con-
firmed the formation of a 1:1 adduct (73%, mp: 178–184 °C). The
adduct was insoluble in most solvents. To a suspension of this in
MeOH freshly prepared diazomethane was added and the resulting
tetramethyl ester chromotographed on silica gel. Elution with
chloroform/methanol = 98:2 afforded 0.150 g of solid that showed
3
toxic cyclic peptides.
In continuation of our interest in figure of 8 motifs4 we report
here the one step formation to such systems by reaction of
L
-cyst-di-OMe(3) and EDTAA.5,6 It was envisioned that compound
1
2 2
with a staggered NCH CH N bridge is likely to undergo a trans
addition with cyst-di-OMe, harboring an orthogonally disposed –
S–S– unit, leading to a bihelical system. In the event this proved
largely correct (Scheme 1).
molecular weight expected for the 1:1 adduct ester (57%). However
1
the H NMR in CDCl
8
3
showed the presence of two amide protons at
both the amide
protons were shifted to 8.36 and 8.22, respectively).
HPLC performed in a biomed C column and elution with a lin-
ear gradient of A–B (A = H O, 0.1% TFA; B = CH CN, 0.1% TFA)
.45 and 8.1 ppm in the ratio of ꢀ7:3 (in DMSO-d
6
Synthesis
4
The reaction of
L-cystine with trimethylsilyl chloride in dry
2
3
MeOH solution stirring overnight and concentration, followed by
showed largely a mixture of two peaks in the ratio of 75:25 with
retention times, 9.016 and 12.039 min, respectively.
⇑
Corresponding authors. Fax: +91 (40)27160512 (S.R.).
E-mail address: srgiict@gmail.com (S. Ranganathan).
Careful chromatography enabled the separation of the mixture
to their pure components. The mass spectra showed that both were
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.078

S. R. Naini et al. / Tetrahedron Letters 55 (2014) 1132–1135
1133
O
O
O
N
O
O
H N COOMe
O
COOMe
H C
2
NH2
O
HN
a
N
MeOOC
H3C
MeOOC
3
CH3
COOMe
N
S
S
S
S
S
H3C
CH3
H3C
N
S
CH3
MeOOC
b
CH3
N
O
N
NH
COOMe
9
O
O
H2N COOMe
O
H2N
O
O
O
1
c
3
Scheme 3. Opening of EDTAA with D-penicillamine disulfide-di-OMe.
b
a
c
a
Cis
Trans
opening
opening
2 3 2
di-OMe, where the –SCH – pairs of 3 are replaced by –S(CH ) –,
precisely under conditions described for 3. The reaction exclusively
afforded in 62% yields 9, the methyl analog of the bihelical 4
(Scheme 3), whose spectral properties were completely in agree-
ment with the assigned structure.
O
O
H
N
COOMe
NH
HOOC
HOOC
N
N
COOMe
S
S
S
S
1H NMR studies
MeOOC
N
N
HN
O
COOMe
HN
O
COOH
HOOC
The primary focus of NMR studies was on 4 and 9, which have
been assigned bihelical structures and 5, a cyclic profile. Com-
pounds 4 and 5 arise respectively, by the trans opening of 1 and
CH2N2,
MeOH
CH2N2,
MeOH
the alternate cis mode with
L-cystine di-OMe (Scheme 1). The ste-
O
rically crowded -pencillaminedisulfide-di-OMe offered only bihe-
D
O
H
N
COOMe
NH
lical 9 by trans opening of 1 (Scheme 3). Extensive studies clearly
show that 4 and 9 have a compact profile in contrast to a flexible
one for 5. Temperature dependent NMR studies in DMSO-d in
6
MeOOC
N
COOMe
MeOOC
N
S
S
S
S
the range of 30–60 °C showed for the NH protons of pure 4 and
5, dd/dT values ꢁ3 ppb/K and ꢁ2.5 ppb/K and linear decay of their
chemical shifts, suggesting strongly that the amide NH is involved
in intra molecular hydrogen bonding in both cases.
MeOOC
N
N
HN
HN
COOMe
COOMe
MeOOC
O
O
4
5
1
The H NMR of bihelical 4 as well as 9 and cyclic 5 is in support
of the structural assignment and clearly distinguishes the struc-
tural profile. In 4, 5, and 9 each proton of CH COOMe and NCH CO
2 2
Scheme 1. Opening of EDTAA with L-cyst-di-OMe.
is clearly resolved as doublet suggestive of distal positioning of
these groups.
1
:1 adducts. The major isomer is identified as 4 and the minor 5.
An expanded version of 1H NMR of bihelical 4 and cyclic 5
1
13
Their H and C NMR (S1–S4) had a similar profile excepting for
the significant differences in the appearance of the amide and
C H Protons. Detailed studies (vide infra) have established the bih-
elical structure for 4, arising from a trans opening of 1 and an open
cyclic structure for 5 from the alternate cis mode (Scheme 1).
Further proof for the bihelical structure for 4 was secured from
(
Fig. 1) in the region d 2.7–3.6 ppm presented below suggests
features that are in agreement with the proposed structures.
In 4 the ꢁNCH CH Nꢁ protons appear as clean doublets at d
.7 and 2.92 ppm and in 5 as a clustered multiplet at 2.87. We sug-
gest that in the bihelical structure 4 the orthogonal placement of
S–S bridge makes such divergence in chemical shifts. The b CH
a
2
2
2
6
obtained in quantitative yields from methanolic opening of 1
Scheme 2) for which MO calculations showed an overwhelming
preference for a configuration having transoriented CH COOMe
groups and a staggered conformation for the –NCH CH N– bridge,
2
(
doublets) protons in 4 and 5 are seen as a pair of doublet of dou-
(
2
blets. The eight NCH CO protons (doublets) are seen in 4 (d: 3.3,
2
3
.49, 3.53, 3.6) and in 5 (d: 3.34, 3.44, 3.50, 3.56). We feel that in
the bihelical 4 the ring NCH CO protons appear as cluster with
the external NCH CO as widely separated doublets. A similar pro-
2
2
an arrangement that is expected to undergo cyclization, in a trans
mode with cyst-di-OMe, leading to 4. Indeed, the condensation of 6
with cyst-di-OMe (3) gave exclusively 4.
2
2
file like 4 was seen in the bihelical 9. In the cyclic 5 they are closely
spaced.
To explore the effect of steric factors on the course of the adduct
3
The ROESY spectra of 4, 5, and 9 (500 MHz, CDCl ) clearly pro-
formation,
1
was condensed with
D-penicillamine disulfide
vided support for the structural assignments. At the outset a ROESY
spectrum of the mixture enabled a direct comparison of the spatial
connectivities of the amide NH at d 8.45 ppm of 4 and that of 5 at d
O
OH
8
.2 ppm. The ROESY spectrum of 4 (Fig. S7, Supplementary data)
O
O
N
OH
O
H2N
showed that the NH peak at 8.45 ppm exhibited spatial relation-
MeO
OMe
O
a
N
2 2 2 2
ship with –NCH CH N-(weak), b CH and NCH CO, and C H
MeO
3
S
protons.
EDCI, HOBt
DIPEA, DCM
O
S
4
The ROESY spectrum of 5 (Fig. S8, Supplementary data) showed
that the NH peak at 8.2 ppm is spatially connected to –NCH CH
CO, and C H protons. The ROESY spec-
N
N
O
6
OMe
2
2
MeO
NH2
HO
a
2 2
N-(strong), b CH –, NCH
OMe
O
HO
O
trum of 9 (Fig. S9, Supplementary data) exhibited the spatial rela-
tionship between the amide protons with that of the methyl
O
protons, the well separated –NCH
2
CH
2
N– protons as well as dou-
COOMe with clarity.
blets formed by protons of NCH CO and –CH
2
2
Scheme 2. Condensation of 6 with cyst-di-OMe.

1
134
S. R. Naini et al. / Tetrahedron Letters 55 (2014) 1132–1135
compound 4
3
.60
3.50
3.40
3.30
3.20
3.10
3.00
2.90
2.80
COMPOUND-5
3
.60
3.50
3.40
3.30
3.20
3.10
3.00
2.90
2.80
Figure 1. Expanded spectrum of compound 4 and 5.
4
4
5x10
1
0x10
4
0
5
x10
4
5x10
0
4
θ
θ
-4x10
200
220
Wave number (nm)
240
2
00
220
240
Wave number (nm)
Figure 2. CD spectrum of 4.
Figure 4. CD spectrum of 9.
In conclusion the 2D NMR studies clearly support the assigned
of 4 and 9. The CD of 4, secured from L-cystine, showed a band at
structures for 4, 5, and 9.
211 nm with positive ellipticity (Fig. 2) similar to the spectra of
peptides adopting a b-turn configuration. The CD of 9 (Fig. 4), from
Optical Rotation
D-penicillamine disulfide showed a mirror profile to that of 4, with
a negative band at 211 nm, again suggesting a b-turn configura-
tion. The CD of 5 in TFE (Fig. 3) showed a shallow positive band
at 219 nm, suggesting a flexible conformation.
The optical rotation of 4, secured from
L
-cystine exhibited a va-
) and for 9 from -penicillamine
). These suggest, as reported
2
3
lue of ½
a
ꢂ
+112.4° (c = 0.5 CHCl
3
D
D
a
2
3
disulfide ½
ꢂ
ꢁ106.8°(c = 0.25 CHCl
3
D
4
in our earlier work, that the chirality of the bihelical topology is
Molecular orbital calculations
largely controlled by that of the linker. In sharp contrast, the opti-
2
D
3
cal rotation of the open module 5 was found to be ½
c = 0.4 CHCl ).
a
ꢂ
ꢁ30.0°
Optimized energy calculations were done using ab initio and
⁄
(
3
high level density functional theory (M06-2X/6-31G ) using GAUSS-
8
IAN 09 program. As described in the present work, the bihelical
Circular Dichroism Studies
compound 4 has been secured by transition state that overwhelm-
ingly prefers a trans mode of amidation of EDTAA (1) and the
The results from CD studies in trifluoroethanol(TFE) for com-
pounds 4, 5, and 9, provided strong support for the bihelical nature
4
3
x10
0
4
-
5x10
θ
1
0, 0.00
11, 0.15
2
00
220
240
⁄
Wave number (nm)
Scheme 4. The M06-2X/6-31G energy minimized structures of EDTAA in two
conformations. M06-2X/cc-pVTZ//M06-2X/6-31G , relative energies are given in
⁄
Figure 3. CD spectrum of 5.
kcal/mol.8

S. R. Naini et al. / Tetrahedron Letters 55 (2014) 1132–1135
1135
methanol opened di ester 6 with cyst-di-OMe harboring an orthog-
onally disposed –S–S– profile. Molecular orbital calculations show
that 1 has two closely related minimum energy representations 10
and 11, where both the representations have staggered –NCH
CH N– conformation (Scheme 4).
Calculation shows that the methanolic opening overwhelmingly
2
2
prefers a trans mode suggesting a conformation of 12 over 13
thus supporting the bihelical structure for the condensation
product with cyst-di-OMe (Scheme 5). These findings clearly
support the bihelical structure for the condensation product with
cyst-di-OMe (Scheme 2).
The energy minimized conformations for the bihelical 4 and 9
and the cyclic 5 are presented in Figure 5.
Apart from mechanistic and spectral considerations the M.O
calculations provide a clean picture of the double helical nature
of 4, 9 and a cyclic profile for 5.
1
2, 0.00
13, 7.30
In compound 4 from
right handed helix while the –NCH
handed. The situation is precisely reversed in 9 derived from
-D-penicillamine disulfide. As expected in the open 5 these two
L
-cystine the –S–S– bridge forms part of a
Scheme 5. Enery minimized conformations of possible methanol opened product
of 1, optimized at M06-2X/6-31G level of theory. The M06-2X/cc-pVTZ//M06-2X/
-31G relative energies are given in kcal/mol.
2
CH N– containing link is left
2
⁄
⁄
6
D
elements are nearly parallel.
Compound 4
Conclusion
The present work suggests a simple strategy for securing bihe-
lical modules with diverse capabilities. Indeed 4 and 9 endowed
with pair of CH COOMe and COOMe can be precursors for protein
2
clusters, DNA recognition systems, and potential drug targets.
Acknowledgments
Financial support from CSIR, New Delhi is gratefully
acknowledged.
Compound 5
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2013.11.078.
References and notes
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8
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⁄
Figure 5. The M06-2X/6-31G energy minimized structures of 4, 5, and 9.