Reversible thiazolidine exchange: A new reaction suitable for dynamic combinatorial chemistry

Article abstract of DOI:10.1021/ol901104a

New dynamic combinatorial libraries (DCLs) were generated using the reversible aminothiol exchange reaction of thiazolidines and aromatic aldehydes. The reaction proceeded in aqueous buffered media at pH 4 and room temperature to generate thermodynamically controlled mixtures of heterocycles. The synthesis of an enantiomerically pure thiazolidinyloxazolidine is also reported. The oxazolidine moiety could be exchanged in CH₂Cl₂ in the presence of catalytic p-TsOH.

Full text of DOI:10.1021/ol901104a

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3170-3173
Reversible Thiazolidine Exchange: A
New Reaction Suitable for Dynamic
Combinatorial Chemistry
Cecilia Saiz,† Peter Wipf,‡ Eduardo Manta,† and Graciela Mahler*,†
Laboratorio de Qu´ımica Farmace´utica, DQO, Facultad de Qu´ımica, UniVersidad de la
Repu´blica, CC 115, MonteVideo, Uruguay, and Department of Chemistry, UniVersity of
Pittsburgh, Pittsburgh, PennsylVania 15260
gmahler@fq.edu.uy
Received March 16, 2009
ABSTRACT
New dynamic combinatorial libraries (DCLs) were generated using the reversible aminothiol exchange reaction of thiazolidines and aromatic
aldehydes. The reaction proceeded in aqueous buffered media at pH 4 and room temperature to generate thermodynamically controlled mixtures
of heterocycles. The synthesis of an enantiomerically pure thiazolidinyloxazolidine is also reported. The oxazolidine moiety could be exchanged
in CH2Cl2 in the presence of catalytic p-TsOH.
Dynamic combinatorial chemistry (DCC) has considerable
potential in the discovery of small molecule ligands for
artificial receptors and large biomolecules. DCC is largely
based on the use of reversible reactions to generate compound
mixturessdynamic combinatorial libraries (DCLs)sthat are
in thermodynamic equilibrium. The composition of the
library is determined by the properties of each of the library
members under the particular conditions of the experiment;
this equilibrium is likely to respond to the presence of a
template or another change in the environment.1
Four different types of substrates have previously been
used to generate DCLs from carbonyl compounds by acetal
exchange (Figure 1): (a) diols in the presence of catalytic
Figure 1. Cyclic acetal formations suitable for DCL.
The covalent reversible reactions usable in DCC are
relatively rare compared to the irreversible processes favored
in traditional synthetic chemistry, and most of the former
involve carbonyl compounds, imines, and acetals.
TfOH,2 H2SO4,3 or p-TsOH;4 (b) aminoalcohols, leading to
mixtures of imines, oxazinanes, and oxazolines;5 (c) thiols
† Universidad de la Repu´blica.
‡ University of Pittsburgh.
6a
in the presence of catalytic Zn(OTf)2 or Hf(OTf)4;6b and
(1) For reviews, see: (a) Ladame, S. Org. Biomol. Chem. 2008, 6, 219–
226. (b) Ludlow, R. F.; Otto, S. Chem. Soc. ReV. 2008, 37, 101–108. (c)
Lehn, J.-M. Chem. Soc. ReV. 2007, 36, 151–160. (d) Corbett, P. T.; Leclaire,
J.; Vial, L.; West, K. R.; Wietor, J.-L.; Sanders, J. K. M.; Otto, S. Chem.
ReV. 2006, 106, 3652–3711.
(d) diamines in aqueous buffered media at pH 4, conditions
described by our group for the formation of pyrazolotriazi-
none heterocycles.7
10.1021/ol901104a CCC: $40.75
Published on Web 07/08/2009
 2009 American Chemical Society

The acid-catalyzed transacetylation of thiazolidines and
related compounds attracted our closer attention as a possible
extension of the latter heterocycle formation process.
Thiazolidines 3 were selected as simple models to identify
equilibration conditions for DCL formation. In spite of a
literature report on the reversible formation of thiazolidines
under basic conditions,8 this transformation has not been
previously reported as useful for DCC. 4-Carboxyl ethyl-2-
arylthiazolidines can be readily obtained by condensation of
aldehydes (1) and cysteine ethyl ester (2) in EtOH at room
temperature (Scheme 1).
Table 1. Optimization of Thiazolidine Exchange Reaction of 3a
entry reaction conditionsa time (h) 3a/3b ratiob 2 (%)c
1
2
3
4
5
6
7
8
pH 4, rt
pH 4, rt
pH 4, rt
pH 5, rt
pH 5, rt
pH 5, rt
pH 6, rt
pH 6, rt
pH 6, rt
pH 7, rt
pH 4, 35 °C
pH 4, 35 °C
24
48
72
24
48
72
24
48
72
72
24
48
45/55
44/56
46/54
71/29
68/32
52/48
96/4
97/3
90/10
98/2
3
2
10
5
10
9
0
Scheme 1. Thiazolidine Formation from Cysteine
0
0
0
9
10
11
12
45/55
35/65
18d
16e
a Starting concentration of each component was 1 mM; the reaction
mixture was stirred in a buffered acetate solution at pH 4 and pH 5, and in
a phosphate solution at pH 6 and pH 7. b Ratio was determined by 1H NMR.
c Mass balance was quantitative. d Total yield 3a + 3b (64%). e Total yield
3a + 3b (49%).
The discovery of new reversible reactions compatible with
an aqueous environment is an important objective for the
use of biomolecules as templates in DCLs. We screened
different aqueous conditions, with variations in pH and
reaction time, in order to establish optimal thermodynamic
exchange conditions for the thiazolidine exchange. The
reaction of 3a with equimolar amounts of p-Cl-benzaldehyde
(1b) at room temperature was used as a reference (Table 1).
Thermodynamic equilibration of a mixture of 3a and 1b
occurred at pH 4 over 24 to 48 h at room temperature.9 After
3 d, heterocycles 3a and 3b were stable in the aqueous
environment and thiazolidines (90-98%) and ester 2
(2-10%) were recovered (entries 1, 2, and 3). Equilibration
at pH 5 was slower, but after 3 d, the ratio indicated that
equilibrium was reached (entries 4, 5, and 6). Equilibration
at pH 6 was not complete after 3 d at rt (entries 7, 8, and 9).
Equilibration at pH 7 did not proceed during 3 d at rt (entry
10) and the presence of ester 2 was not detected. The method
of choice for blocking further equilibration is a simple raise
of pH to 7; since we did not observe any further equilibration
at this pH, the yields of recovered products were quantitative.
When the temperature was increased to 35 °C at pH 4,
the equilibration occurred faster, but significant amounts
of cysteine ester 2 were observed. The total recovered
yield for thiazolidines was 64 and 49% after 1 and 2 d,
respectively (Table 1, entries 11 and 12). The mass balance
was decreasing, probably due to ester hydrolysis in
compound 2.
Thiazolidines 3a and 3b have different stabilities depend-
ing on pH; at pH 4-5 thiazolidine hydrolysis occurs to an
acceptable extent (2-10%) at rt over 3 d. Temperature seems
to play an important role in these systems; higher temper-
(2) (a) Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. J. Am. Chem.
Soc. 2005, 127, 13666–13671. (b) Fuchs, B.; Nelson, A.; Star, A.; Stoddart,
J. F.; Vidal, S. Angew. Chem., Int. Ed. 2003, 42, 4220–4224. (c)
Cacciapaglia, R.; Di Stefano, S.; Mandolini, L.; Mencarelli, P.; Ugozzoli,
F. Eur. J. Org. Chem. 2008, 186–195.
(3) Berkovich-Berger, D.; Lemcoff, N. G. Chem. Commun. 2008, 1686–
1688.
(4) Lemcoff, N. G.; Fuchs, B. Org. Lett. 2002, 4, 731–734.
(5) (a) Star, A.; Goldberg, I.; Fuchs, B. Angew. Chem., Int. Ed. 2000,
39, 2685–2689. (b) Star, A.; Goldberg, I.; Fuchs, B. J. Organomet. Chem.
2001, 630, 67–77.
Scheme 2
.
Exchange Reaction between Thiazolidines 3a and
Aldehydes 1b,1d-fa
(6) (a) Sutton, L. R.; Donaubauer, W. A.; Hampel, F.; Hirsch, A. Chem.
Commun. 2004, 1758–1759. (b) Wu, Y.-C.; Zhu, J. J. Org. Chem. 2008,
73, 9522–9524.
(7) Wipf, P.; Mahler, S. G.; Okumura, K. Org. Lett. 2005, 7, 4483–
4486.
(8) (a) Woodward, G. E.; Schroeder, E. F. J. Am. Chem. Soc. 1937, 59,
1690–1694. (b) Szilagyi, L.; Gyorgydeak, Z. J. Am. Chem. Soc. 1979, 101,
427–432.
(9) Typical procedure: A solution of compound 3a (20.8 mg, 0.09 mmol)
and p-Cl-benzaldehyde (12.3 mg, 0.09 mmol) in a mixture of acetate buffer
at pH 4 (63 mL) and MeOH (27 mL) was stirred at rt for 2 d. The pH was
raised to 7 by adding a saturated solution of NaHCO3, and the reaction
mixture was extracted with CH2Cl2. The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo (temperature should never
exceed 22 °C). The residue was analyzed by 1H NMR to determine the
ratio and products were confirmed by preparative isolation of 3a + 3b (26
mg, 98% yield).
a Yields in parentheses reflect the equilibrium distribution. The ratio
was determined by H NMR and confirmed by preparative isolation.
1
Org. Lett., Vol. 11, No. 15, 2009
3171

atures accelerate the exchange process but under concomitant
hydrolysis of the thiazolidine and the cysteine ethyl ester.
We also probed the reversibility of the system by starting
from products 3b and 3c at pH 4 (Table 2). If equilibration
products (the original starting materials and two crossover
derivatives) was formed. Small amounts of penicillamine
methyl ester (3%) and cysteine ethyl ester (7%) were also
detected, but 90% of the thiazolidine products was recovered
after 3 d.
As a means to increase diversity in the side chains at the
4-position of the heterocycles, the ester moiety of thiazo-
lidines 3a-b was converted to the alcohol by reduction with
NaBH4. When the aminoalcohols 5a-b were individually
treated with aldehydes 1a-b in acid media (p-TsOH), the
fused thiazolidine-oxazolidines 6 were formed. This class
of compounds represents a new example of a bicyclic DCC
scaffold (Scheme 4).10 Even though aminoalcohols 5 were
Table 2. Thiazolidine Exchange Processes Starting with 3b or
3c
entry reaction conditionsa time (h) 3b/3c ratiob 2 (%)
1
2
3b, 1c
3c, 1b
48
48
25/75
24/76
4
3
a Starting concentration of each component was 1 mM, the reaction
Scheme 4
.
Synthesis of Fused Thiazolidine-Oxazolidine
mixture was stirred at rt in a buffered acetate solution at pH 4. b Ratio was
Heterocycles
1
determined by H NMR and confirmed by preparative isolation.
was reached, the distribution pattern should be identical. At
pH 4, equilibration required 48 h at rt, providing a compa-
rable product ratio as observed for the inverse process (entries
1 and 2, Table 2).
Thiazolidine 3a was allowed to equilibrate with aldehydes
1b and 1d-f; the starting concentrations of the mixture
components were kept at 1 mM each. The distribution of
the corresponding heterocycles varied slightly for thiazo-
lidines 3a,b,e and f (20-24%) except for 3d (11%) after
2 d. Thiazolidine 3d bearing an EDG on the benzene ring
has the lowest stability in the acidic medium. The mass
balance indicated a 93% yield of thiazolidines and 7% of
ester 2 after 4 d, and the distribution remained unchanged.
Even though some formation of compound 2 was observed,
thiazolidines are stable in the acid media (pH 4) for 4 d.
This stability enables this DCL for the observation of
template effects.
used as a 1:1 mixture of diastereomers, only anti-6 was
formed. The relative configuration was confirmed by NOE
experiments. This result is not completely unexpected due
to the fact that thiazolidines undergo facile ring-opening and
closure reactions.11
We hypothesize that this reaction proceeds by a thermo-
dynamic equilibration, with anti-6 being the more stable
fused heterocycle.
Thiazolidinyloxazolidine heterocycles present interesting
opportunities for exchange processes: products include
thiazolidine 5R, oxazolidine 8R, the fused heterocycles at the
thiazolidine or the oxazolidine site 6RR, and also the imine
isomers 9R,12 as shown in Scheme 5.
We also studied the possibility for direct side-chain
metathesis of thiazolidines. An equimolecular mixture of 3a
and 4b, which differ by their substitution at 2, 4 and
5-positions of the heterocycles, was equilibrated during 2 d
at pH 4 and rt (Scheme 3). As expected, a mixture of four
When bicycle 6aa [10 mM] in CH2Cl2 was equilibrated
at rt with an equimolar amount of aldehyde 1b in the
Scheme 3.
Metathesis of Thiazolidinesa
(10) Related fused thiazolidine-oxazolidinones and thiazolidine-oxazo-
lidines were obtained when aminoalcohol 5a was treated with phosgene.
Gonza´lez, A.; Lavilla, R.; Piniella, J. F.; Alvarez-Larena, A. Tetrahedron
1995, 51, 3015–3024.
(11) (a) Deroose, F. D.; De Clercq, P. J. J. Org. Chem. 1995, 60, 321–
330, and ref 8b.
(12) In ref 5a, Fuchs and coworkers report traces of imine in a DCL
constructed from aminoalcohols.
(13) Typical procedure: A mixture of compound 6aa (100 mg, 0.36
mmol) and p-Cl-benzaldehyde (50 mg, 0.36 mmol) in CH2Cl2 (35.5 mL)
and p-toluenesulfonic acid (10 mg, 0.13 mmol) was stirred at rt for 2 d.
The reaction mixture was poured into water, the pH was adjusted to pH 7,
and the mixture was extracted with CH2Cl2 (3 × 30 mL). The organic layers
were dried and filtered, and the solvent was removed under reduced pressure.
The residue was analyzed by 1H NMR to determine the product ratio, and
the products were confirmed by preparative isolation.
a Yields in parentheses reflect the equilibrium distribution. The ratio
was determined by H NMR and confirmed by preparative isolation.
1
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Org. Lett., Vol. 11, No. 15, 2009

concentration, and we found no evidence of exchange or
decomposition after 3 d. This observation is indicative that
the products are stable and that the exchange requires acid
catalysis.
Scheme 5
.
Potential Library of Thiazolidine-Oxazolidine
Heterocycles
It is important to point out that conditions for the synthesis
and exchange of these bicycles are quite similar, that is,
CH2Cl2 and p-TsOH. In the acidic media, the diasteromeric
mixture of alcohol 5 is in a fast equilibration by ring-opening
and closing. During this equilibration only the acetal N-C
bond of thiazolidine would be broken and the R1 side chain
remains linked to the sulfur atom, probably via a sulfenium
cation. This mechanism explains that we did not observe
the formation of 6R2R1 in the synthesis of 6R1R2 and also why
the exchange occcurred only at the oxazolidine site.
In summary, we explored a new exchange reaction
between thiazolidines and carbonyl compounds. The ther-
modynamic exchange proceeds in an acidic aqueous environ-
ment (pH 4) and represents a new reversible reaction useful
for DCC methodologies. A structural diversification of the
core scaffolds can be accomplished by modifications at the
2, 4 and 5-positions of the heterocycles. The thiazolidines
3a-f are stable in buffered media over 4 d, and these
conditions are suitable for the generation of DCLs as well
as for the direct screening of these libraries. Moreover, the
exchange reaction can be stopped by raising the pH to 7,
thus providing a convenient way to analyze the compound
distribution patterns. As an important extension of this work,
we also present the synthesis of fused thiazolidine-oxazoli-
dine heterocycles such as anti-6, representing a new com-
pound class. These bicycles are stable under neutral or basic
conditions but can be equilibrated at the oxazolidine moiety
in CH2Cl2 in the presence of catalytic p-TsOH.
presence of catalytic p-TsOH, only the mixture of the
exchanged products 6aa and 6ab and free aminoalcohol 5a
was obtained (Scheme 6).13 To identify the products, it was
Scheme 6
.
Exchange Reaction of Bicycle 6aaa
a
1
Ratio was established by H NMR.
Acknowledgment. This work was supported by the
National Institutes of Health-FIRCA (R03TW007772), and
NIH CA078039. C.S. thanks UdelaR (CSIC-No 349). We
thank H. Pezaroglo of Nuclear Magnetic Resonance Labora-
tory, UdelaR for NMR spectra.
necessary to perform a chiral-HPLC (Chiralcel-OD) analysis
of the possible products 6ba and 6ab, because they have
almost identical signals in the 1H NMR spectra. The
chromatographic analysis indicated that the exchange was
limited to the N-C-O linkage, forming 6ab. Alternative
species like imines 9a, 9b or oxazolidines 8a, 8b were not
detected in the H NMR spectra or the HPLC traces.
We also performed an experiment in absence of p-TsOH
in CDCl3 with compound 6aa and aldehyde 1b at a 10 mM
Supporting Information Available: Experimental pro-
cedures, 1H NMR and HPLC of DCLs, and spectral data for
compounds 4b, 5b, 6aa, 6ab, 6ba, and 6bb. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
OL901104A
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