Dithiane- and trithiane-based photolabile scaffolds for molecular recognition

Article abstract of DOI:10.1021/ol015933u

(formula presented) A modular synthetic approach to novel dithlane- and trithlane-based photolabile molecular hosts equipped with elements of molecular recognition is developed. The approach provides ready access to a family of amino-derivatized photocleavable molecular systems capable of hydrogen-bonding-based recognition of biologically relevant molecules, e.g., ureas, barbiturates etc. These systems undergo efficient photofragmentation in the presence of external (e.g., benzophenone) or internal (e.g., nitropyridine) electron-transfer sensitizers.

Full text of DOI:10.1021/ol015933u

ORGANIC
LETTERS
2
001
Vol. 3, No. 12
841-1844
Dithiane- and Trithiane-Based
Photolabile Scaffolds for Molecular
Recognition
1
Oleg D. Mitkin, Alexei N. Kurchan, Yongqin Wan, Brian F. Schiwal, and
Andrei G. Kutateladze*
Department of Chemistry and Biochemistry, UniVersity of DenVer,
DenVer, Colorado 80208-2436
akutatel@du.edu
Received April 3, 2001
ABSTRACT
A modular synthetic approach to novel dithiane- and trithiane-based photolabile molecular hosts equipped with elements of molecular recognition
is developed. The approach provides ready access to a family of amino-derivatized photocleavable molecular systems capable of hydrogen-
bonding-based recognition of biologically relevant molecules, e.g., ureas, barbiturates etc. These systems undergo efficient photofragmentation
in the presence of external (e.g., benzophenone) or internal (e.g., nitropyridine) electron-transfer sensitizers.
4
With so much effort directed over the past two decades
toward improving our understanding of the underlying
principles of molecular recognition, the elementary events
involved in such processes are much better understood now
cleavable systems. The next logical step was to equip such
molecules with specific elements of molecular recognition
and assess the compatibility of these elements with the
photodisassembly step. For reasons mentioned above we
focused on amino-derivatizationsamides, ureas, and amino-
pyridines.
1
than ever before. Although predicting protein folding or
docking patterns for relatively large polypeptides is still a
task bordering on peering into a crystal ball, the behavior of
much simpler systems is remarkably well understood. For
example, hydrogen-bond-mediated self-association of various
derivatives of urea and related heterocycles is becoming
commonplace in supramolecular chemistry and is utilized
widely for molecular templating etc.2
Although one can readily envision numerous potential
applications of this methodology, at this time our strategic
goal is in design and development of photoremovable
inhibitors for biological systems.
(2) (a) Mertz, E.; Mattei, S.; Zimmerman, S. C. Org. Lett. 2000, 2, 2931.
b) Corbin, P. S.; Zimmerman, S. C. J. Am. Chem. Soc. 2000, 122, 3779.
c) Mak, T. C. W.; Xue, F. J. Am. Chem. Soc. 2000 122, 9860. (d) Suarez,
M.; Lehn, J.-M.; Zimmerman, S. C.; Skoulios, A.; Heinrich, B. J. Am. Chem.
Soc. 1998, 120, 9526. (e) Koyano, H.; Bissel, P.; Yoshihara, K.; Ariga, K.;
Kunitake, T. Langmuir 1997, 13, 5426. (f) S a´ nchez-Quesada, J.; Seel, C.;
Prados, P.; de Mendoza, J. J. Am. Chem. Soc. 1996, 118, 277 (g) Nowick,
J. S.; Mahrus, S.; Smith, E. M.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118,
(
(
Our current interest is in developing molecular objects
capable of photofragmentation, based on electron-transfer-
induced C-C bond cleavage in hydroxyalkyl dithianes,
3
which we previously reported. In this context we developed
a modular synthetic strategy utilizing spiro-bis-dithiane as a
photolabile tether for assembling macromolecular photo-
1
066.
(
3) McHale, W. A.; Kutateladze, A. G. J. Org. Chem. 1998, 63, 9924.
4) (a) Wan, Y.; Mitkin, O.; Barnhurst, L.; Kurchan, A.; Kutateladze,
(
(
1) For recent reviews on various aspects of molecular recognition, see
A. Org. Lett. 2000, 2, 3817. (b) Mitkin, O. D.; Wan. Y.; Kurchan, A. N.;
Kutateladze, A. G. Synthesis 2001, in press.
special issue of Chem. ReV. 1997, 97, issue 5, Gellman, S. H., Guest Editor.
1
0.1021/ol015933u CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/15/2001

We first developed a straightforward synthetic approach
5
to primary amines 1 via addition of 2-lithio-1,3-dithiane to
Table 1. Quantum Efficiencies of Photoinduced Cleavage in
Acetonitrile with Benzophenone as an External ET-Sensitizer
6
N-silylated benzaldimines, generated in situ from aromatic
aldehydes and lithium bis(trimethylsilyl)amide (LHMDS).
Amines 1 were then treated with various electrophiles,
including benzoyl chlorides, phenylisocyanate or 2-fluoro-
quantum yield
5
-nitropyridine to furnish a diverse set of photolabile
7
molecules 2-4.
Z ) CH ; X ) OH
Z ) CH2; X ) p-NO2PhC(O)NH- (2b)
Z ) CH2; X ) PhC(O)NH- (2a )
Z ) CH2; X ) PhNHC(O)NH- (3a )
Z ) S; X ) PhC(O)NH- (5)
Z ) S; X ) OH (6)
0.119
0.143
0.121
0.067
0.172
0.068
2
Scheme 1
the resulting amine with phenylisocyanate. Potassium acetate
dissolves readily in the acetonitrile solution of 3b, and the
proton NMR spectrum of the resulting solution shows
significant downfield changes in chemical shifts of the amide
protons (∆δ > 2 ppm, Figure 1) indicating that the expected
coordination of the acetate anion to the urea moiety does
8
indeed occur.
We also found that sym-trithiane can be used in place of
1,3-dithiane in these synthetic sequences. For example, an
analogous reaction with lithiated 1,3,5-trithiane afforded
benzamide 5 (Scheme 2).
Scheme 2
Figure 1. Binding of potassium acetate in acetonitrile.
Irradiation of adducts 2, 3, and 5 in acetonitrile in the
presence of benzophenone as an external ET-sensitizer leads
to a photofragmentation similar to what we described earlier
Utilizing novel spiro-bis-dithiane as a photolabile tether
we synthesized more elaborate bidentate molecular hosts,
such as 8 (Scheme 3), suitable for dicarboxylate binding.
Judging by signal broadening in proton NMR spectra,
diastereomers 8 are heavily self-associated in nonpolar
solvents, e.g., chloroform. Expectedly, such hydrogen-bond-
based self-association is disrupted in methanol or acetonitrile.
As it follows from Scheme 1 we also introduced the
5-nitro-2-aminopyridine moiety as yet another element of
molecular recognition. The nitro group not only facilitates
the aromatic nucleophilic substitution of fluorine but also
shifts the UV absorption band of the product to λmax ) 335
nm, rendering 4 suitable for self-sensitization. Direct irradia-
3
for dithiane-carbonyl adducts, with comparable quantum
efficiencies (see Table 1). For a fair comparison we also
measured the quantum yield for the photocleavage in
trithiane-benzaldehyde adduct 6.
The modular nature of our synthetic approach allows us
to build hybrid molecular hosts by combining urea units with
various other moieties, e.g., crown-ethers for enhanced
complexation of alkali carboxylates (Figure 1). Host 3b, for
instance, was synthesized readily starting from 2-formyl-
benzo-18-crown-6, LHMDS, and lithiodithiane, working up
1842
Org. Lett., Vol. 3, No. 12, 2001

11
even to mimic nucleotides. Aminopyridine 4 thus combines
molecular recognition functionality with the ability to induce
fragmentation upon direct irradiation.
Scheme 3
Just as with bisurea 8, bidentate compounds bearing two
aminopyridine moieties can be synthesized from spiro-bis-
dithiane-based diamine 7 and excess 2-fluoro-5-nitropyri-
dine. An alternative general approach to bi- or tridentate
molecular hosts is to utilize multiply lithiated trithiane. It
has been reported in the literature that 1,3,5-trithiane can
form di- and even trianions when treated with excess
1
2
butyllithium. We therefore were able to synthesize di- and
trisubstituted trithianes 9 and 10 bearing amino groups, which
can be readily modified.
For example, treating diamine 9 (Ar ) p-ethoxyethox-
yphenyl) with 2 molar equiv of 2-fluoro-5-nitropyridine
1
3
furnished compound 11.
tion of 4 in acetonitrile using a medium-pressure mercury
lamp and Pyrex filter resulted in an efficient photofragmen-
9
tation reaction. 2-Aminopyridines are known to serve as a
molecular recognition moiety for carboxylic derivatives or
10
Scheme 4
(5) Typical Experimental Procedure. A solution of 4.56 g (28 mmol)
of 1,1,1,3,3,3-hexamethyldisilazane in 100 mL of freshly distilled THF was
cooled to 0 °C, and 19.4 mL of n-butyllithium (1.6 M solution in hexanes,
3
0 mmol) was added with stirring under N2 atmosphere. The reaction
mixture was stirred at this temperature for 1.5 h. Next, 3 g (28 mmol) of
benzaldehyde was slowly added, and the resulting mixture was stirred at 0
°
C for 1 h. Lithiated dithiane was prepared by adding 19.4 mL of 1.6 M
n-butyllithium (30 mmol) to a solution of 3.39 g (28 mmol) of 1,3-dithiane
in 100 mL of freshly distilled THF at -20 to -25 °C and stirring at this
temperature for 2 h. The solution of lithiodithiane was added slowly to the
solution of silylated benzaldimine, the cooling bath was removed, and the
reaction mixture was stirred overnight at room temperature. The resulting
red solution was washed with 100 mL of saturated NH4Cl, and THF was
removed in a vacuum, producing a yellow oil, which was dissolved in 200
mL of EtOAc and extracted with 2 × 100 mL of 10% HCl. The acid extracts
were combined, pH was adjusted to 12 with 20% NaOH, and the water
layer was extracted with 3 × 100 mL of EtOAc. Organic extracts were
combined and washed with water 3 × 100 mL. The organic layer was dried
over anhydrous MgSO4, and the solvent was removed in a vacuum,
furnishing 1a (Ar ) Ph, 6.2 g, 97%) as a yellow oil, which was used without
1
further purification. H NMR (CDCl3) δ (ppm) 7.42-7.22 (5H, m), 4.25
(
2
1H, d, J ) 6.6 Hz), 4.22 (1H, d, J ) 6.6 Hz), 2.92-2.73 (4H, m), 2.12-
.04 (1H, m), 1.82-1.92 (1H, m).
6) Gyenes, F.; Bergmann, K. E.; Welch, J. T. J. Org. Chem. 1998, 63,
824.
(
Photolabile host 11 is capable of binding urea, as
2
evidenced by signal shifts in proton NMR. Although the
(
(
7) More experimental details can be found in the Supporting Information.
8) Downfield shift of N-H protons is indicative of H-bonding; see, for
example: (a) O¨ sapay, K.; Case, D. A. J. Am. Chem. Soc. 1991, 113, 9436.
b) Wishart, D. S.; Sykes, B. D.; Richards, F. M. J. Mol. Biol. 1991, 222,
11. (c) Williamson, M. P.; Asakura, T. J. Magn. Res. 1993, B 101, 63.
9) (a) Photophysical details for this cleavage and a more complete
(10) (a) Karle, I. L.; Ranganathan, D.; Haridas, V. J. Am. Chem. Soc.
1996, 118, 7128. (b) Garcia-Tellado, F.; Geib, S. J.; Goswami, S.; Hamilton,
A. D. J. Am. Chem. Soc. 1991, 113, 9265.
(11) Hildbrand, S.; Blaser, A.; Parel, S. P.; Leumann, C. J. J. Am. Chem.
Soc. 1997, 119, 5499.
(12) Schumaker, R. R.; Rajeswari, S.; Joshi, M. V.; Cava, M. P.; Takassi,
M. A.; Metzger, R. M. J. Am. Chem. Soc. 1989, 111, 308.
(13) (a) p-Ethoxyethoxybenzaldehyde was used for improved solubility
in organic solvents. (b) We did not separate individual diastereomers of 11
(2:1 ratio by NMR). 2,4-Disubstituted trithianes, formed by electrophilic
quenching of lithiated trithianes, are believed to have cis geometry (see
Fukunaga, M.; Sugawara, T.; Oki, M. Chem. Lett. 1972, 1, 55), and we
therefore assume that the observed diastereomers are the meso and d,l pair
as a result of the two chiral benzylic centers generated as a result of the
anion addition to imine, not the cis-trans isomers.
(
3
(
quantum yield study for a variety of substituted 2-5 will be reported in
the full paper. (b) Although the C-C bond cleavage in the self-sensitized
reaction of 4 was expected by analogy with the previously observed
photofragmentations, we carried out the product study and investigated the
mass balance for the reaction of 4b (the adduct of a DHP-protected
p-hydroxybenzaldehyde, Ar′ ) p-DHP-O-C6H4). Direct irradiation of 4b
in acetonitrile produced only the corresponding imine and products of its
hydrolysis. After chromatographic separation, 17% of the imine, Ar′CHd
N-Py, was isolated along with 35% of the aldehyde, Ar′CHO, 39% of
2
7
-amino-5-nitropyridine and 21% of unreacted 4b, accounting for at least
1% in C-C bond cleavage.
Org. Lett., Vol. 3, No. 12, 2001
1843

S
C -symmetric and has the urea molecule positioned equi-
distantly from the two aminopyridine fragments (Figure 3).
The structure is practically free from steric strain, with two
benzylamine fragments being in a nearly staggered confor-
mation with respect to the trithiane’s sulfurs.
To quantitatively evaluate the complexation ability of 11
in chloroform we carried out a NMR titration experiment
with a CDCl -soluble urea derivative, imidazolidone. Upon
3
addition of the guest, NMR spectra showed a similar
downfield shift of the N-H protons in 11, with calculated
dissociation constant K ) 32.2 mM (Figure 4).
D
Figure 2. Free 11 (top) in acetonitrile and changes in NMR due
to its complexation with urea (bottom).
changes in chemical shifts are not as pronounced as in the
case of ionic acetate binding to 3b, addition of urea to an
acetonitrile-d solution of 11 causes the signal of its N-H
3
proton to shift downfield by about 0.3 ppm. (Figure 2).
We also optimized the geometry of the complex of meso-
1
1 with urea by utilizing a DFT level of theory and
Figure 4. Changes in the chemical shift of N-H protons of 11 in
CDCl as a function of imidazolidone concentration (solid line is
a calculated fit for K ) 32.2 mM).
constraining the urea-aminopyridines fragment to planarity.
Although there were no other constraints to impose a vertical
plane of symmetry, the optimized structure is very close to
3
D
We are currently investigating the complexation properties
for compounds of type 8 and 11, which will be reported in
the full paper. To summarize, we have developed a general
modular approach for assembly of photolabile molecules,
outfitted with hydrogen-bond-capable elements of molecular
recognition.
Acknowledgment. Support of this research by the
National Science Foundation (Career Award CHE-9876389)
and the National Institutes of Health (GM62773-01) is
gratefully acknowledged.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 3. B3LYP/6-31G* geometry of meso-11‚urea.
OL015933U
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Org. Lett., Vol. 3, No. 12, 2001