Novel chiral tetramic acid-derived diols: Organocatalytic facile synthesis and unique structural properties

Article abstract of DOI:10.1039/c4ra05405a

Organocatalytic tandem reactions of l-phenylalanine-derived tetramic acid with aldehydes allow a one-pot and high-yielding access to a diverse range of novel chiral diols in enantiomerically pure forms. In addition, a new entry of the diols, featuring their unique structures associated with C_2- and pseudo C_2--symmetric chiral motifs, is reported.

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COMMUNICATION
Novel chiral tetramic acid–derived diols: organocatalytic facile synthesis
and unique structural properties†
Tetsuya Sengoku,a Kosuke Suzuki,a Ken Nakayama,a Fumitoshi Yagishita,b Masami Sakamoto,b Masaki
Takahashia and Hidemi Yoda*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Organocatalytic tandem reactions of
L–phenylalanine–
derived tetramic acid with aldehydes allow a one–pot and
high–yielding access to a diverse range of the novel chiral
10 diols in enantiomerically pure forms. In addition, a new entry
of the diols, featuring their unique structures associated with
C2– and pseudo C2–symmetric chiral motifs, is reported.
Chiral diols have been extensively used as effective ligands for
chiral catalysts, which are involved in a multitude of powerful
15 applications in asymmetric organic synthesis, and therefore
belong to an important class of privileged molecules.1–6 In
general, these chiral diols are designed to have the C2–symmetry
element in conformationally rigid systems, featuring two
spacially close pairs of hydroxyl groups asymmetrically disposed
20 across the mirror planes of their entire structures to create chiral
environment for expressing enantiomeric recognition. Over the
past few decades, impressive progress has been made in the
development of enantioselective synthetic methods promoted by
asymmetric catalysis of metals and/or prochiral molecules under
25 the influence of the chiral diols, such as diethyl tartrate (DET),2
hydrobenzoin,3 α,α,α′,α′–tetraaryl–1,3–dioxolan–4,5–dimethanol
(TADDOL),4 1,1′–bi–2–naphthol (BINOL),5 and 1,1′–biaryl–
2,2′–dimethanol (BAMOL)6 (Figure 1). Currently available chiral
diols fulfilling the structural and functional requirements for
30 efficient use as ligands are generally limited to just a few simple
compounds. Hence, it is a subject of great importance to develop
a new alternative series of chiral diols for future progress in
stereocontrolled syntheses of complex target molecules, which
will be beneficial for chemical, biological, and medicinal
35 applications. In the present communication, we report a new
entry of chiral tetramic acid–derived diols possessing C2– and
pseudo C2–symmetric elements, which are easily available on a
gram scale by simple organocatalytic procedures and can be
custom–designed with respect to their steric and conformational
40 properties according to structural and functional attributes of the
composition.
50
Fig. 1 Structures of representative chiral diols.
Scheme 1 Pathway for diols 3.
expected to react with aldehydes 2 to give a new type of chiral
diols 3 via the intermediacy of α,β–unsaturated 1,3–diketones
55 (ene–diones) 4 as illustrated in Scheme 1, one may encounter
difficulties in controlling the stereochemistry of reaction
products, largely due to high susceptibility of the tetramic acid
cores to suffer troublesome epimerization even under mild
conditions.10 In fact, when a 2:1 mixture of
L–phenylalanine–
60 derived tetramic acid 1a and formaldehyde 2a (37% aqueous
solution) was subjected to the analogous reaction conditions with
20 mol % of piperidine (relative to 2a) in ethanol, a smooth
reaction occurred at r.t. to reach completion after 3 h and the
chiral diol 3a was obtained in 73% isolated yield (Table 1, entry
1
65 1). To our disappointment, the H NMR analysis of this product
ensured detectable loss of the stereochemical integrity, being
contaminated with about 6% of its C5 epimeric isomer. Such a
behavior was reproduced using the catalytic amount of
pyrrolidine, which gave a 90:10 epimeric mixture of 3a in 78%
70 yield after 2 h (Table 1, entry 2). For both cases, we also found
that the stereochemical quality seriously suffered with prolonged
reaction times, thereby resulting in considerable decrease of the
diastereomeric purity of the product (see Supporting
Information).
Our initial synthetic efforts have been made to exploit an
interesting finding of unique reactivity of simple cyclic β–
diketones toward one–pot synthesis of structurally analogous
45 racemic diols,7 which can be understood to arise from the base–
catalyzed tandem reactions of Knoevenagel condensation8
followed by Michael addition. Applying this method to
biologically attractive chiral tetramic acids 1,9 which can be
75
However, a dramatic change was observed when the catalytic
amount of
L
–proline was used instead of the above two bases. In
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Table 1 Catalyst screening for the reaction of 1a.
Table 2 Scope of proline–catalyzed reaction of 1 with aldehydes 2.a
Entry
1
2
R
Time [h]
3
Yield [%]b
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
2c
2d
2e
2f
2–methylbutyl 26
3c
3d
3e
3f
3g
3h
3i
82
100
90
99
99
96
96
96
Ph
3
4–tBuPh
3–ClPh
4–NO2Ph
1–naphtyl
2–naphtyl
Et
2
3
2
26
20
1
2g
2h
2i
Entry
2
Catalyst
([mol%])
Solvent
T
t [h]
3
Yield
[%]a
1bc 2b
3b'
1
2
3
4
5
2a Piperidine
(20)
2a Pyrrolidine
(20)
2a LꢀProline
(20)
2b LꢀProline
(20)
2b Pyrrolidine/
AcOH = 1/1
(20)
2b LꢀSerine
(20)
2b LꢀLysine
(20)
2b LꢀAspartic
acid (20)
EtOH
EtOH
EtOH
EtOH
EtOH
r.t.
3
2
5
2
3
3ab
3ab
3a
73
35 a Conditions: aldehyde (0.12–0.30 mmol), tetramic acid (0.24–0.60
mmol), L–proline (20 mol %), EtOH (0.5–0.9 mL), r.t. b Isolated yield. c
NꢀBoc derivative of 1a.
r.t.
78
r.t.
96
O
O
R
HN
Bn
HN
Bn
L
-proline
O
0 ºC
0 ºC
3b
3b
100
100
R'
R
R'
1a 2j
EtOH, rt
or acetone = 2/1)
: R = 9-anthryl, R' = H
acetone: R = R' = Me
O
O
(
/
1a
2j
4j
5
(100%)
(100%)
6
EtOH
EtOH
EtOH
H2O
0 ºC
0 ºC
0 ºC
r.t.
49
20
291
5
3b
3b
3b
3b
3b
99
83
91
93
100
Scheme 2 Reaction of 1 with 2j and acetone.
7
40 loading as low as 1 mol % (Table 1, entries 9 and 10).
8
Having identified proline as the optimal catalyst, investigation
into the substrate scope of this methodology was next explored
with a number of aldehydes. The results presented in Table 2
demonstrate that the proline catalyzed reaction has a high degree
45 of functional–group tolerance with respect to the aldehyde
substituents (Table 2, entries 1–7). It is remarkable to note that
sterically hindered aldehydes such as 2c, 2h, and 2i also reacted
with 1a, albeit sluggishly, leading to good to high yields of the
corresponding diols 3c, 3h, and 3i, respectively (Table 2, entries
50 1, 6, and 7). The versatility of this catalytic system was further
enhanced by applicability of the reaction to a Boc–protected
tetramic acid 1b, a substitute for 1a, which resulted in rapid and
high–yield production of the desired Boc derivative of 3b
(denoted as 3b') (Table 2, entry 8). In contrast to these results, we
55 must also note that the most sterically hindered 9–anthraldehyde
2j exhibited exceptional reactivity, ultimately leading to
exclusive formation of the ene–dione 4j. Additionally, the
reaction with acetone as a representative example of ketones in
9
2b LꢀProline
(20)
2b LꢀProline
(1)
10c
EtOH
r.t.
1
a Isolated yield. b Epimeric products were obtained in 3a:epiꢀ3a ratios of
94:6 (for entry 1) and 90:10 (for entry 2). See supporting Information. c
The reaction was conducted on a gram scale (1.23 g of 3b).
5
this case, the reaction proceeded smoothly at r.t. to allow efficient
production of 3a as an enantiomerically pure form in 96% yield
without any other reaction products after a reaction time of 5 h
(Table 1, entry 3). This catalytic system was also effective for the
10 reaction with propanal 1b. Indeed, the reaction proceeded very
rapidly at r.t. to reach completion within 20 min with a
quantitative product yield of the enantiopure diol 3b, and still
took place very efficiently over 2 h even at 0 °C to give the
essentially same result (Table 1, entry 4). In order to search for a
15 replacement of
L–proline, we next explored the possibility of
using neutral species as a catalyst. When an equimolar mixture of
pyrrolidine and acetic acid, which represents structural
components of the proline architecture, was employed for the
reaction at 0 °C, closely comparable results were obtained with
20 quantitative yield of enantiopure 3b (Table 1, entry 5). The other
the presence of catalytic even stoichiometric amounts of Lꢀproline
60 also gave the relevant ene–dione 5 quantitatively in each case
(Scheme 2).
Since the above result had given an indication for a reaction
mechanism involving intermediacy of 4, which would generate 3,
we next attempted to confirm this mechanistic possibility by
65 reconsidering the reaction trajectory. In the case of entry 7, the
reaction progress could be followed visually through monitoring
the reaction mixtures by thin layer chromatography (TLC), which
showed a spot assignable to 4h, together with those of 1a and 3h.
At the reaction time of 5 h, the resulting mixture allowed efficient
70 column separation where the fraction was flushed through the
silica–gel column, isolating 4h in 62% yield as an inseparable
mixture of cis– and trans–isomers.14 With 4h in hand, we then
examined the reaction of 4h with 1.0 equiv of 1a at r.t. in the
amino acids such as L–serine, L–lysine, and L–aspartic acid were
also found effective but underwent rather slow reactions to reach
99%, 83%, and 91% product yields for prolonged reaction
periods of 49, 20, and 291 h, respectively (Table 1, entries 6–8).
25 Obviously, the cyclic amino acid, proline, has substantial promise
for the efficient catalysis of the reactions to afford the chiral
diols,11 where chemical reactivity of carbonyl electrophiles
present in the reaction mixture would be enhanced through
formation of proline–derived iminium intermediates.12,13 Also
30 worthy of note is that with the use of L–proline, the approach
provided another option to use aqueous media for the reaction as
well as allowed easy access in ethanolic solution at r.t. to a gram
scale quantity (1.23 g, 100% isolated yield) of 3b with a catalyst
presence and absence of the catalytic amount (20 mol %) of L–
75 proline. As a result, the catalytic conditions proved potentially
reactive to give rise to 3h with 83% isolated yield after a period
2
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35 preference of the pseudo C2–symmetric chiral diols, a single
crystal X–ray diffraction study was undertaken on p–nitrophenyl–
substituted diol 3g, whose X–ray quality crystals were grown by
slow evaporation from a chloroform–methanol solution. Indeed,
the X–ray results show that the compound adopts the chiral space
40 group P212121 where the asymmetric unit cell contains one
constituent molecule with an encapsulated methanol solvent as
depicted in Figure 3.15,16 In this structure, two tetramic acid
groups are oriented preferentially in the opposite direction so as
to form intramolecular hydrogen bond between one of the amide
45 oxygen atoms and enolic proton of another tetramic acid group
with a short O(3)•••O(6) distance of 2.47 Å.17 It is of interest to
note that the other set of the hydrogen–bond donor and acceptor
is separated by a long O(4)•••O(5) distance of 4.26 Å and is
substantially in a geometry unfavorable to interact with each
50 other. Thus, as suggested by its 1H NMR spectrum, the two
tetramic acid groups are shown to behave differently due to the
chemical non–equivalence of the enolic functions. This symmetry
breaking must be a result of deformation imposed by the p–
nitrophenyl ring, which favors CH–π interactions with the two
55 side phenyl groups to give a W–shaped conformation in the
crystalline state,18 and brings the pseudo C2–symmetric nature
along the vertical axis of the model into its structural property.
In conclusion, the results of these extensive studies have
shown that the proline–catalyzed methodology allows a one–pot
60 and high–yielding access to a diverse range of the chiral diol
analogues in enantiomerically pure forms via the tandem
processes, and provide an entry of novel tetramic acid–derived
diols that present unique structural features associated with the
C2– and pseudo C2–symmetric motifs. In addition, we put
65 particular emphasis on the synthetic utility of the current reaction,
offering ready availability for the preparation of custom–designed
Fig. 2 1H NMR spectra (300 MHz, DMSO–d6) for (a) 3a and (b) 3b.
Fig. 3 ORTEP diagram for the absolute configuration of 3g with 50%
thermal ellipsoid probability.
5
of 50 h, whereas no reaction was found to occur without
L–
proline. Thus, the mechanistic pathway can be understood as the
tandem Knoevenagel condensation/Michael addition sequence, in
which either the cis– or trans–isomer of the resultant ene–diones
chiral diols on
a gram scale, which will provide new
opportunities for the future development of effective and
potentially versatile chiral ligands.
10 equally reacts with the remaining tetramic acids to converge to
form the uniform structures with the given molecular chirality.
Figure 2 illustrates 1H NMR spectroscopic characteristics of 3a
and 3b, obtained with DMSO–d6 as a solvent. There is a marked
difference in the spectral features between these compounds. As
15 represented in Figure 2a, the methylene–bridged diol 3a displays
simple resonance patterns, indicating a genuine spectroscopic
equivalence of the structural units. This observation is well in
accordance with our assumption that 3a should adopt the C2–
symmetric structure. In contrast to this, the 1H NMR spectrum for
20 3b shows more complex patterns with two sets of proton
resonances for the relevant tetramic acid segments, indicating
unsymmetrical nature of the tetramic acid cores (Figure 2b). This
suggests that the tetramic acid units are less free to rotate at r.t.
around the single bonds connecting the methine junction. To our
25 surprise, this spectral appearance essentially remains unchanged
upon changing the solvent to acetone–d6 and methanol–d4 as well
as upon heating up to 55 °C in methanol–d4 (see Supporting
Information), indicating that energy barrier for the internal
rotations is too high to allow coalescence of the separated
70
We thank Dr. Toshiyasu Inuzuka (Gifu University) for
performing mass spectral analyses. We also thank Ms. Saki
Matsuura for partial support of this research. This work was
supported financially in part by a Grant–in–Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
75 Science and Technology, Japan and the JGC–S Scholarship
Foundation.
Notes and references
a Department of Applied Chemistry, Graduate School of Engineering,
Shizuoka University, 3–5–1 Johoku, Naka–ku, Hamamatsu, Shizuoka
80 432–8561, Japan. Fax: +81 53 478 1150; Tel: +81 53 478 1150; E-mail:
tchyoda@ipc.shizuoka.ac.jp
b Department of Applied Chemistry and Biotechnology, Graduate School
of Engineering, Chiba University, 1–33 Yayoi–cho, Inage–ku, Chiba 263–
8522, Japan.
85 † Electronic Supplementary Information (ESI) available: Experimental
details, characterization data, 1H and 13C NMR spectra for the compounds
3a–i, 3b', 4h, 4j and 5. See DOI: 10.1039/b000000x/
1
K. C. Bhowmick, N. N. Joshi, Tetrahedron: Asymmetry, 2006, 17,
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30 resonances and the molecule adopts
a severely restricted
90
2
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characteristic of the overall geometry, which should be
categorized as a pseudo C2–symmetric system.
In an attempt to have a better understanding of conformational
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DOI: 10.1039/C4RA05405A
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14 The product ratio, cis–/trans–isomers, was not determined because
the observed 1H NMR data for the isomeric mixture of the ene–dione
are essentially indistinguishable from each other.
50 15 Crystal data for 3g: orthorhombic, space group P212121,
10.4426(6) Å, b = 12.0149(7) Å, c = 21.1390(13) Å, V = 2652.2(3)
Å3, Z = 4, = 1.359 Mgmꢀ3, (CuKα) = 0.809 mmꢀ1, T = 173 K; in the
final least–squares refinement cycles on F2, the model converged at
R1 = 0.1071 (I > 2 (I)), wR2 = 0.2861, and GOF = 1.107 for 4427
a =
ρ
ꢀ
ρ
55
reflections and 367 parameters (CCDC deposition number 963494).
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good agreement with the calculated values for C29H25N3O6·CH3OH
(C, 66.29; H, 5.38; N, 7.73).
17 The O(3)•••HO(6) bond length is estimated to be 1.93 Å.
60 18 S. Paliwai, S. Geib, C. S. Wilcox, J. Am. Chem. Soc., 1996, 116,
4497–4498.
4
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