Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini reaction under eco-friendly reaction conditions

Article abstract of DOI:10.1039/c2ob26247a

An eco-friendly synthesis of highly functionalized epoxides and their incorporation into an organocatalytic multicomponent approach are reported. For this, a modified class of diarylprolinol silyl ethers was designed to enable high catalytic activity in an environmentally benign solvent system. The one-pot procedure showed great efficiency in promoting stereoselective multicomponent transformations in a tandem, 'green' fashion. Because of its non-residual, efficient and selective character, this synthetic design shows promise for large-scale applications in both diversity and target-oriented syntheses. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob26247a

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COMMUNICATION
Organocatalytic asymmetric epoxidation and tandem epoxidation/Passerini
reaction under eco-friendly reaction conditions†
Anna Maria Deobald,a Arlene G. Corrêa,*a Daniel G. Riverab and Márcio Weber Paixão*a
Received 30th June 2012, Accepted 8th August 2012
DOI: 10.1039/c2ob26247a
The sequence includes the organocatalytic asymmetric synthesis
of epoxy aldehydes and their subsequent utilization in an iso-
cyanide-based MCR, all over in one pot.
An eco-friendly synthesis of highly functionalized epoxides
and their incorporation into an organocatalytic multicompo-
nent approach are reported. For this, a modified class of
diarylprolinol silyl ethers was designed to enable high catalytic
activity in an environmentally benign solvent system. The
one-pot procedure showed great efficiency in promoting
stereoselective multicomponent transformations in a tandem,
‘green’ fashion. Because of its non-residual, efficient and
selective character, this synthetic design shows promise for
large-scale applications in both diversity and target-oriented
syntheses.
A variety of natural and non-natural products containing the
epoxy functionality are known to exhibit important biological
activities.11 These strained moieties are not only important
synthetic targets but also valuable intermediates that allow for
accessing either complex epoxide-containing active principles or
ring-opened derivatives.12 Despite the wide variety of reports on
the stereoselective syntheses of epoxides,13 an eco-friendly route
to stereodefined epoxides and its tandem combination with a
multicomponent approach has remained unexplored.
Chart 1 outlines the development of an eco-friendly protocol
for the organocatalytic asymmetric synthesis of epoxy aldehydes.
After a set of exploratory experiments, which include variation
of the solvent mixture, temperature, oxidizing agents, and con-
centration of reactants (see ESI†), the focus was shifted towards
assessing the scope of the organocatalyst structure.
In contemporary organic chemistry, there is great interest in the
development of environmentally benign technologies and pro-
cedures capable of reducing waste, cost and tedious work-up.1
Thus, several advancements including the replacement of hazar-
dous organic solvents,2 the use of microwave-assisted synthesis,3
sonication4 and multicomponent reactions (MCRs) have been
recognized as efficient tools to achieve this goal.5
In this sense, tandem approaches have proven great success, as
they have the potential to rapidly increase molecular complexity
by forming several covalent bonds in one pot.6 The main advan-
tages of such tandem protocols are the reduction of manual oper-
ations – thus circumventing the isolation of often highly reactive
intermediates – and the minimal use of protecting groups.
Indeed, both factors help saving of time and cost as well as
improving the greener character of the whole procedure.7
In recent years, asymmetric organocatalytic MCRs have been
utilized in the synthesis of enantiomerically enriched molecules.8
Since the seminal report by Jørgensen and co-workers,9 enantio-
enriched epoxy aldehydes have been employed frequently as
versatile intermediates in the synthesis of natural and non-natural
products of biological relevance.10
The structure of this modified class of diarylprolinol silyl
ethers was designed based on the concept developed indepen-
dently by Barbas14 and Hayashi,15 which enables the high
organocatalytic activity in aqueous media.16 All catalysts evalu-
ated were able to promote the oxidative transformation, albeit the
reaction outcome varies as a function of the alkyl side-chain
length. Thus, when the length of the hydrophobic alkyl chain
was increased from hexyl (3a) to dodecyl (3b), the desired
epoxide was obtained with slight erosion on the chemical yield
and selectivity. Interestingly, the yield and stereoselectivity were
also dropped when the sulfur atom in the organocatalyst was
replaced by an oxygen atom, however the reason behind this fact
is not fully understood (3c and 3d). The best result – with
respect to yield, diastereo- and enantioselectivity – was achieved
with catalyst 3a. Also, the best conditions turned out to be the
treatment of the α,β-unsaturated aldehyde 1 with aqueous hydro-
gen peroxide (35 wt%) as an oxidant in the presence of the orga-
nocatalyst 3a (10 mol%), in a mixture of 3 : 1 (v/v) ethanol–
water as a reaction medium.
Herein we report an efficient and highly stereoselective
approach for the synthesis of highly functionalized epoxides.
aDepartamento de Química, Universidade Federal de São Carlos,
São Carlos, SP 13565-905, Brazil. E-mail: mwpaixao@ufscar.br,
agcorrea@ufscar.br; Tel: +55 55 3351 8215
Next, we investigated the scope of the epoxidation reaction
with a variety of α,β-unsaturated aldehydes under the optimal
reaction conditions (see ESI†).17 Good yields as well as excel-
lent enantio- and diastereoselectivity were accomplished with a
number of cinnamaldehydes bearing either electron-donating or
electron-withdrawing substituents at the aromatic ring. In
bCenter for Natural Products Study, Faculty of Chemistry, University of
Havana, La Habana 10400, Cuba
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26247a
This journal is © The Royal Society of Chemistry 2012
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Table 1 Asymmetric
organocatalytic
epoxidation
under
environmentally benign solvent systems – scope assessment of the
α,β-unsaturated aldehydea
Entry
1
Product
Yieldb (%)
85
drc
eed,e
98
75 : 25
2
3
4
79
88
92
98 : 2
93 : 7
99 : 1
90
97
99
5
6
7
86
90
90
93 : 7
94 : 6
96 : 4
95
90
87
Chart 1 Catalyst screening in the asymmetric organocatalytic epoxida-
tion under an environmentally benign solvent system. aReaction con-
ditions: aldehyde (0.25 mmol), catalyst 3a–d (10 mol%), and hydrogen
peroxide (1 mmol) in a mixture EtOH–H2O (3 : 1, v/v, 1 mL) at room
temperature. bYield after isolation from flash chromatography. cDeter-
mined on the major diastereomer by HPLC analysis on a chiral station-
ary phase after the reduction to the corresponding alcohol.
general, the electronic nature and steric properties of the substitu-
ents attached to the aromatic ring have a slight effect on the
stereoselectivity of this catalytic system (Table 1, entries 2–4).
Moreover, the procedure proved successful also with linear
α,β-unsaturated aldehydes of different chain lengths (Table 1,
entries 5 and 6). Functionalities such as isolated double bonds
and benzyloxy groups were well-tolerated, and the corresponding
epoxide products 2g–h were isolated in good yields with high
diastereo- and enantioselectivity (Table 1, entries 7 and 8). These
latter products are of significant interest due to their potential
utilization as chiral building blocks in diversity and target-
oriented synthesis.18
8
40
93 : 7
78
a Unless otherwise specified, all reactions were carried out using
aldehyde (0.3 mmol), catalyst 3a (10 mol%), and hydrogen peroxide
(0.9 mmol) in a mixture EtOH–H2O (3 : 1, v/v, 0.6 mL) at room
temperature. b Yields after isolation by flash chromatography.
c Determined by crude 1H-NMR spectroscopy and chiral-phase HPLC.
d Determined on the major diastereomer by HPLC analysis on a chiral
stationary phase either after the reduction to the corresponding alcohol
or reduction/esterification to the ester (see ESI† for details). e Absolute
configuration assigned by comparison with literature data.9
To demonstrate that the developed eco-friendly epoxidation
procedure is also suitable for scale-up chemistry, we were
pleased to prove that catalyst 3a (10 mol%) catalyzed at room
temperature the reaction between trans-pentenal (1e, 5 mmol)
and hydrogen peroxide (15 mmol), in high yield (89%) and
good diastereo- and enantioselectivity (94 : 6 dr, 90% ee).
Nowadays, the introduction of high levels of molecular com-
plexity with a minimal number of operations by means of multi-
step, one-pot sequences is a challenge that has attracted the
interest of the academic and industrial community.19 In this
sense, isocyanide-based MCRs have become predominant
approaches in modern organic synthesis, owing to the great
levels of molecular complexity and diversity that generate with
low synthetic cost.20 Accordingly, we envisioned the possibility
of combining this eco-friendly epoxidation procedure with the
Passerini three-component reaction (Passerini-3CR), one of the
MCRs of greater success in drug discovery and natural products
synthesis.21
The Passerini-3CR is the condensation between an oxo-
compound (i.e., aldehyde or ketone), a carboxylic acid and an
isocyanide to afford an α-acyloxy carboxamide moiety,21 which
is of great occurrence in bioactive natural products like the depsi-
peptides. Thus, we turned to expand the structural diversity of
the chiral epoxides by developing a tandem organocatalytic
epoxidation/Passerini-3CR approach toward a distinctive type
compound encompassing the α-acyloxy-α,β-epoxy-carboxamide
moiety. Table 2 depicts the optimization studies of this approach,
wherein the chiral 2,3-epoxy aldehyde – produced in situ by
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Table 2 Tandem asymmetric organocatalytic epoxidation/Passerini
3CR – optimization studiesa
Entry Solvent
Conc. Yieldb (%) drc
eed
1
2
3
EtOH
2
2
1
0.5
1
52
73
72
51
83
62 : 32 : 2
65 : 30 : 5
63 : 32 : 5 96
65 : 31 : 4
68 : 28 : 4
94
92
EtOH–H2O (3 : 1)
EtOH–H2O (3 : 1)
EtOH–H2O (3 : 1)
EtOH–H2O (3 : 1)
5
88
96
5e
a Unless otherwise specified, all reactions were carried out using
aldehyde (0.3 mmol), catalyst 3a (10 mol%), and hydrogen peroxide
(0.9 mmol) in a mixture EtOH–H2O (3 : 1, v/v, 0.6 mL) at room
temperature for 16 h, then, acid (0.3 mmol), isocyanide (0.5 mmol).
b Yield after isolation by flash chromatography. c Determined by crude
1H-NMR spectroscopy and chiral-phase HPLC. d Determined on the
major diastereomer by HPLC analysis on a chiral stationary phase.
e Isolated epoxy aldehyde was used.
Fig. 1 Assessment of the substrate scope in the tandem asymmetric
organocatalytic epoxidation/Passerini-3CR under an eco-friendly solvent
system.23
with both aliphatic and aromatic carboxylic acids with similar
success, thus leading to compounds 4e and 4f, respectively. As
noticed by analysis of Table 2 and Fig. 1, there is no significant
stereochemical induction in the Passerini-3CR, despite the pres-
ence of stereogenic centers at both the α and β positions. Never-
theless, this is an expected result considering that the
diastereoselectivity of Passerini-3CRs with chiral aldehydes (i.e.,
α- or β-substituted) is moderate in nearly all reported cases.21
In summary, we have designed and obtained a modified class
of diarylprolinol silyl ethers for the asymmetric organocatalytic
epoxidation of α,β-unsaturated aldehydes under eco-friendly
reaction conditions. These results are similar or even superior to
those obtained by the traditional 2-[bis-(3,5-bis-trifluoromethyl-
asymmetric organocatalysis – is subsequently entrapped by
addition of an isocyanide and a carboxylic acid. To our delight,
we found that the overall process could be efficiently accom-
plished in an eco-friendly solvent system, as the conditions pre-
viously established for the asymmetric organocatalytic protocol
were fully compatible with the multicomponent process.22 After
some exploratory experiments, the best conditions for the
sequential organocatalytic epoxidation of trans-2-decenal and
condensation with tert-butyl isocyanide and benzoic acid turned
out to be the use of EtOH–H2O (3 : 1, v/v) as a solvent system at
a concentration of 1 M for the starting material. Importantly, the
whole procedure could be performed in one-pot without isolation
of intermediates, thus affording 4a in 72% yield over two steps
and a dr of 32 : 63, with 96% ee of the major diastereoisomer
(Table 2, entry 3). Obviously, the overall yield improves with the
isolation of the epoxy aldehyde intermediate.
With the optimized conditions for the tandem approach in
hand, the next step was to assess the substrate scope of the two-
step, one-pot sequence. As outlined in Fig. 1, trans-2-decenal
was employed as a model reagent to examine – in terms of
efficiency and selectivity – the effect of the isocyanide and car-
boxylic acid structures in the reaction outcomes. For example,
the reaction of 4-iodobenzoic acid and cyclohexyl isocyanide
with the chiral 2,3-epoxy aldehyde – formed in situ by organoca-
talytic epoxidation – afforded the desired product 4b without
erosion of the yield and selectivity. Further studies on the sub-
strate scope revealed that, e.g., both enantiomers of N-Boc-
proline were successfully applied as acid components in the reac-
tion sequence, thus affording compounds 4c and 4d (Fig. 1)
with similar diastereoselectivity, although lower overall yield.
These results clearly indicate that there are no matched–mis-
matched interactions between the chiral 2,3-epoxy aldehydes and
the chiral acid (L- and N-Boc-D-proline). Additionally, it was
proven that an aromatic 2,3-epoxyaldehyde could be combined
phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine in
a water–
alcohol solution using hydrogen peroxide as the oxidation
reagent.9b Therefore, we believe that this new catalytic system
will be complementary to the current protocols for the prep-
aration of optically active 2,3-epoxy aldehydes. Furthermore,
this is the first report on the combination of an asymmetric orga-
nocatalytic epoxidation and the Passerini-3CR for the synthesis
of highly functionalized epoxides. Further applications of this
new type of organocatalyst in the synthesis of complex bioactive
compounds will be reported in due course.
Acknowledgements
We gratefully acknowledge FAPESP (09/07281-0) and CNPq
(INCT-Catálise and INBEQMeDI) for financial support. A.M.D
thanks FAPESP for a PhD fellowship.
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23 aUnless otherwise specified, all reactions were carried out using aldehyde
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7684 | Org. Biomol. Chem., 2012, 10, 7681–7684
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