A concise organocatalytic and enantioselective synthesis of isotetronic acids

Article abstract of DOI:10.1039/b711192d

A concise enantioselective route to isotetronic acids using an organocatalyzed aldol reaction between α-oxocarboxylic acids and aldehydes has been developed, leading to the titled compounds in reasonable yields and good enantioselectivities. The Royal Soc

Full text of DOI:10.1039/b711192d

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COMMUNICATION
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A concise organocatalytic and enantioselective synthesis of isotetronic
acids{
Jean-Marc Vincent,* Chryste`le Margottin, Muriel Berlande, Dominique Cavagnat, Thierry Buffeteau and
Yannick Landais*
Received (in Cambridge, UK) 23rd July 2007, Accepted 30th August 2007
First published as an Advance Article on the web 10th September 2007
DOI: 10.1039/b711192d
A concise enantioselective route to isotetronic acids using an
organocatalyzed aldol reaction between a-oxocarboxylic acids
and aldehydes has been developed, leading to the titled
compounds in reasonable yields and good enantioselectivities.
Isotetronic acids are ubiquitous in Nature and exhibit a wide range
Scheme 2 Isotetronic acids through BIP (4)-catalyzed aldol reaction.
of biological activities. Their simple butenolide structural motif has
also attracted a lot of interest as a building block in syntheses of
a-ketoacid III and an aldehyde II acting respectively as carbonyl
complex natural products, such as erythronolide A and tetro-
donor and acceptor (Scheme 2). Organocatalyzed aldol reactions
toxin.1 Sotolon 1,2 found in both racemic and enantioenriched
have been the subject of a tremendous development in the last few
form in raw sugarcane, fenugreek seeds or botrytized wine, (+)-
years and a wealth of data is now available.9 In this context, we
leptosphaerin 2,3 a metabolite isolated from marine fungi lepto-
disclose here our preliminary results on aldol reactions between
sphaeria oraemaris, or WF-36814 3 isolated from chaetomella
a-ketoacids 5 and a series of aldehydes 6 using the benzoimidazole-
raphigera and exhibiting aldose reductase inhibitory activity
pyrrolidine 4, a proline surrogate that was recently designed in our
constitutes some representative members of this family
laboratory as an efficient organocatalyst for a number of amino-
(Scheme 1). Other natural and more complex butyrolactones have
catalyzed processes.10
recently been described that possess promising antiproliferative
Oxo-butyric acid ethyl ester was used in preliminary studies but
activity against various carcinoma thus justifying the interest for
soon appeared as a poor substrate. Much better yields were
this class of targets.5
obtained using directly a-ketoacids 5 which were finally used
Numerous strategies have been devised to access these
throughout the investigation (Table 1). 10 mol% catalyst was used
butenolides.6 Enantioselective approaches based on chiral pool
during this work, except with poorly reactive aromatic aldehydes
synthesis using carbohydrates, amino-acids and ascorbic acid were
which required the use of 30 mol%. Oxo-butyric acid 5 (R9 = Me)
shown to afford the titled compounds in an enantiomerically pure
was used as the model carbonyl donor. Several aldehydes were
form, but these approaches generally suffer from long synthetic
tested and showed that both aromatic and aliphatic aldehydes led
sequences.7 Diastereoselective and catalytic enantioselective strate-
to promising results. Better yields and enantioselectivities were
gies have also been described. Copper-bisoxazoline and proline
observed with aromatic substrates, particularly those having
have been used as chiral inducers in aldol reactions involving
pyruvates both as carbonyl donors and acceptors.8 While high
electron-withdrawing groups (C6F5 or p-NO2Ar) (entries 9, 11,
12).11 It should to be noted that proline proved to be a poor
level of enantioselectivities were generally attained, the scope of
catalyst for this transformation. In a reaction run in DMSO using
these reactions were limited to pyruvate acceptors. Based on these
L-proline (10 mol%), the reactive p-nitrobenzaldehyde and
premises, it was anticipated that the key furanone skeleton I in
oxobutyric acid afforded 7e in only 26% yield and 36% ee.
butenolides 1–3 could be assembled in a one-pot operation
Electron-rich aromatic aldehydes provided both lower yields and
through an organocatalyzed aldol type reaction between a reactive
ee (entries 13–15). Isobutyraldehyde led to 7a in moderate yields
but excellent enantioselectivity in good agreement with pioneering
studies which showed that branched aliphatic aldehydes are good
substrates for amino-catalyzed aldol reactions (entries 1–4).12 In
line with this result, acetaldehyde led only to a trace amount of
sotolon 1. Increasing the reactivity of the aldehyde using ethyl
glyoxylate (entry 5) led to 7b in good yield but surprisingly to no
Scheme 1 Naturally occurring isotetronic acids.
enantioselectivity. Substitution of the ethyl group for a t-Bu led to
a similar result. Steric hindrance however plays an important role
in this aldol reaction when the bulky group is close to the reactive
carbonyl function as shown with pivalaldehyde which gave no
reaction even after 5 days at rt (entry 6). The nature of the solvent
was also varied and we observed that the reaction was equally
efficient in water when liquid or viscous aldehydes were employed
University Bordeaux-1, CNRS-UMR 5255, Institut des Sciences
Mole´culaires, 351, cours de la libe´ration, 33405, Talence, France.
E-mail: jm.vincent@ism.u-bordeaux1.fr; y.landais@ism.u-bordeaux1.fr;
Fax: (+33) 540006286; Tel: (+33) 540002289
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b711192d
4782 | Chem. Commun., 2007, 4782–4784
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Table 1 Isotetronic acids synthesis through an aldol process mediated
by organocatalyst 4
Yielda eeb
Scheme 3 Aldol reaction with tribromoacetaldehyde 8.
Entry R R9
Mol% 4 Product Solvent
t/d (%)
(%)
using a direct aldol reaction between 5 and the corresponding
linear aldehydes.
i
Me Pr
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
10
7a
7a
7a
7a
7b
7c
7d
7d
7e
7e
7f
THFc
DMF
H2O
DCM
THF
THF
THF
H2O
4
4
4
44
30
26
76
80
87
90
0
i
Me Pr
i
Me Pr
Absolute configuration of isotetronic acids was obtained
through vibrational circular dichroism (VCD) associated with
ab initio calculations (vide infra). VCD is a well-established method
for determination of absolute configuration and solution con-
formation of chiral molecules.17 The method entails comparison of
the observed VCD spectrum with spectra calculated at the density
functional theory (DFT) level for conformers of a specified
absolute configuration.18 Because enantiomers have VCD inten-
sities of opposite sign for each vibrational mode, the VCD
spectrum provides a unique and rich signature of the absolute
configuration.
i
Me Pr
4 ,5
Me CO2Et
Me tBu
Me Ph
Me Ph
Me p-NO2C6H4 10
Me p-NO2C6H4 10
Me C6F5
Me C6F5
Me p-BrC6H4
Me p-MeOC6H4 30
Me p-MeOC6H4 10
4
5
4
4
4
6
5
5
5
7
7
63
—
90
65
77
—
77
69
60
10
20
—
70
68
83
—
84
90
67
36
63
—
87
90
9
THF
H2O
10
11
12
13
14
15
16
17
18
a
10
30
30
THF
H2O–THFd
THF
THF
H2O
THF
THF
THF
7f
7g
7h
7h
7i
7j
7k
H
p-NO2C6H4 10
10 ,5
5
5
Ph C6F5
Et C6F5
30
10
45
71
VCD spectrum of isotetronic acid 7f (R9 = C6F5), was recorded
in CDCl3 as solvent. Calculations of optimized geometry,
vibrational frequencies, absorption, and VCD intensities were
calculated by Gaussian 03 program at the DFT level with the
B3PW91 functional and cc-pVTZ basis set for two conformations
of the (R)-7f (R9 = C6F5) isomer. Indeed, the monomer of 7f can
assume two conformations that differ by a 180u rotation of the
COH group, labeled 7fa (the hydroxyl group points toward
the methyl group) and 7fb (the hydroxyl group points toward
the ketone group) (Fig. 1). On the other hand, B3PW91/cc-pVTZ
calculations predict that the fluoro phenyl group is locked
nearly perpendicular to the furanone ring, due to the steric
repulsion between the fluorine atom and both the oxygen atom
and the methyl substituent of the five-membered ring. The
optimized structures and relative Gibbs energies calculated for
the two conformers are shown in Fig. 1. 7fb is the most stable
conformer and its relative population is almost 100% at room
temperature. The calculated VCD spectrum for the 7fb conformer
is compared to experiment in Fig. 2, where the experimental
intensities have been adjusted to 100% ee. The computed VCD
spectrum reproduces fairly well the intensity and the sign of
the bands observed in the experimental spectrum, allowing the
definitive determination of the (R) configuration and the
conformation (7fb) for 7f and by analogy to other isotetronic
acids 7a–k.
b
c
Isolated yields. ee estimated from chiral HPLC. Anhydrous
d
THF. THF (100 mL) was added to the reaction mixture to
facilitate the stirring.
(entries 3, 8, 12, 15). This is worthy of note as enantioselectivity in
most cases is also significantly improved in such media (entries 3,
12, 15). This may be indicative of a hydrophobic effect amplifying
the chiral organocatalysis.13 Better stabilization of the polar
transition state (vide infra) by water may also be invoked. Recently,
a few examples of enamine-based organocatalyzed aldol processes
were reported for which good enantioselectivities were effectively
observed when the reactions were run in water13,14 or in the
presence of water.15,16 This seems to be the case in this study where
the aldehydes do not dissolve homogeneously in water.
The aldol process was successfully extended to other a-ketoacids
such as phenylpyruvic and 2-oxovaleric acids (entries 17, 18).
Starting from pentafluorobenzaldehyde the corresponding bute-
nolides 7j and k were obtained in moderate to good yields and
good enantioselectivities. Surprisingly, under the same conditions,
pyruvic acid provided the expected isotetronic acid 7i but only in
trace amount (entry 16). Interestingly, efficient enantioenrichment
can be achieved by simple recrystallization. For instance,
enantiomerically pure 7f (entries 11 and 12) was obtained after a
recrystallization by slow diffusion of hexane vapours into a toluene
solution of 7f (initial ee 84%). Similarly, 7k (entry 18) can be
isolated almost enantiomerically pure (ee 98%) by crystallization
from the crude reaction mixture.
The aldol process was also extended to more reactive
a,a,a-tribromoaldehyde 8 which led to the desired butenolide 9a
in modest yield but good enantioselectivity, along with the
debrominated butenolide 9b (Scheme 3). Similar enantioselectivity
of both products suggest that debromination occurred only after
the aldol reaction. This result is noteworthy as 9a and b are
separable and may be functionalized further to provide enan-
tioenriched aliphatic isotetronic acids that are difficult to obtain
Fig. 1 Optimized structures and relative Gibbs energies of (R)-7f (R9 =
C6F5) conformations.
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Fig. 2 Comparison of the experimental VCD spectrum of 7f (ee 90%,
R9 = C6F5) in CDCl3 solution with the computed VCD spectrum of the
7fb conformer.
Fig. 3 Transition state model for catalyst 4-mediated aldol reaction.
11 General procedure for the preparation of isotetronic acids: A mixture
of the a-ketoacid (1 mmol), the aldehyde (1 mmol) and the catalyst (10–
30 mol%) in solution (or in suspension) in the desired solvent (1 mL) was
stirred at room temperature for the period specified in Table 1. After
removal of the solvent, the crude mixture was purified by column
chromatography over silica gel (CH2Cl2–MeOH) to furnish the desired
compounds.
12 B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,
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This configuration may be rationalized invoking a chair-like
transition state as illustrated in Fig. 3. Protonation of the
benzoimidazole ring by acid 5 likely provides a zwitterionic species
IV which carboxylate moiety participates to the stabilization of the
assembly, explaining the high level of enantioselectivity.
In summary we have described along these lines a new access to
isotetronic acids, a class of butenolides with relevant biological
activities. The method is straightforward and may be applied to a
wide range of aldehydes, leading to moderate to good yields of the
desired compounds with good level of enantioselectivity.
Interestingly, the reaction may also be performed in water
affording the butenolides in some cases with improved enantio-
selectivities.
16 For a discussion about the terminology employed for reactions run in
aqueous media, see: A. P. Brogan, T. J. Dickerson and K. D. Janda,
Angew. Chem., Int. Ed., 2006, 45, 8100; Y. Hayashi, Angew. Chem., Int.
Ed., 2006, 45, 8103.
We acknowledge the CNRS and Re´gion Aquitaine for financial
support.
17 T. B. Freedman, X. Cao, R. K. Dukor and L. A. Nafie, Chirality, 2003,
15, 743, and references therein; T. Buffeteau, L. Ducasse, A. Brizard,
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Notes and references
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18 P. J. Stephens and F. J. Delvin, Chirality, 2000, 12, 172.
4784 | Chem. Commun., 2007, 4782–4784
This journal is ß The Royal Society of Chemistry 2007