Enantio- and Diastereoselective Synthesis of exo-Peroxyacetals: An Organocatalyzed Peroxyhemiacetalization/oxa-Michael Addition Cascade

Article abstract of DOI:10.1002/anie.201511165

An unprecedented enantioselective peroxyhemiacetalization/oxa-Michael addition cascade of ortho-formyl homochalcones has been developed using cinchona-alkaloid-based chiral bifunctional organocatalysts to provide cis-configured exo-peroxyacetals, a new class of organic peroxide, in good yields with excellent enantio- and diastereoselectivities. The resulting cis-configured exo-peroxyacetals were converted into the corresponding trans-configured peroxyacetals without affecting the enantioselectivity. Furthermore, the displacement of the peroxide moiety of exo-peroxyacetals with various nucleophiles has been demonstrated to afford 1,3-disubstituted isochromans with high diastereoselectivities and excellent enantioselectivities.

Full text of DOI:10.1002/anie.201511165

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International Edition: DOI: 10.1002/anie.201511165
German Edition: DOI: 10.1002/ange.201511165
Asymmetric Synthesis
Enantio- and Diastereoselective Synthesis of exo-Peroxyacetals: An
Organocatalyzed Peroxyhemiacetalization/oxa-Michael Addition
Cascade
Sanjay Maity, Biswajit Parhi, and Prasanta Ghorai*
Abstract: An unprecedented enantioselective peroxyhemiace-
talization/oxa-Michael addition cascade of ortho-formyl
homochalcones has been developed using cinchona-alkaloid-
based chiral bifunctional organocatalysts to provide cis-
configured exo-peroxyacetals, a new class of organic peroxide,
in good yields with excellent enantio- and diastereoselectivities.
The resulting cis-configured exo-peroxyacetals were converted
into the corresponding trans-configured peroxyacetals without
affecting the enantioselectivity. Furthermore, the displacement
of the peroxide moiety of exo-peroxyacetals with various
nucleophiles has been demonstrated to afford 1,3-disubstituted
isochromans with high diastereoselectivities and excellent
enantioselectivities.
knowledge, the synthesis of enantio- and diastereoselective
exo-peroxyacetals has not yet been established.[13]
We envisioned a peroxyhemiacetalization/oxa-Michael
addition cascade of the substrate A (Scheme 1), where the
reversibly formed peroxyhemiacetal intermediate B could be
converted into the oxa-Michael adduct C by a dynamic kinetic
T
he design and synthesis of structurally distinct classes of
chiral organic peroxides have always remained attractive
because of their considerable appearance in natural products
and bioactive molecules.[1–5] However, to date, the corre-
sponding catalytic enantioselective strategies for the synthesis
of chiral peroxides are less explored.[6–9] Moreover, as per our
knowledge, there is still a scarcity of methods for the catalytic
enantio- and diastereoselective synthesis of peroxides.
Scheme 1. Catalytic enantio- and diastereoselective synthesis of the
exo-peroxyacetals. EWG=electron-withdrawing group.
Inspired by the antimalarial drug candidate artemisinin
(Figure 1),[10] having a peroxyacetal pharmacophore, several
peroxyacetals have been evaluated for antimalarial,[11] anti-
tumor, anti-HIV, and anti-hepatitis B activity.[12] However,
enantioselective methods for the synthesis of chiral peroxy-
acetals are exceedingly rare. In this regard, the pioneering
reports by Rovis and co-workers for the synthesis of endo-
peroxyacetals are remarkable.[9] However, to the best of our
resolution process catalyzed by a chiral amino-thiourea/
squaramide catalyst.[14,15] Nevertheless, overcoming the
direct conjugate addition of peroxide on an a,b-unsaturated
moiety remains a potential barrier to this strategy.[16] Further,
both enantioselective acetalization[15,17] and oxa-Michael
reactions[18–21] are challenging tasks because of their inherent
reversibility. Herein we report the very first synthesis of exo-
peroxyacetals (C) in excellent enantio- and diastereoselectiv-
ity, thus providing the sterically hindered cis-stereoisomer.
Furthermore, it can also be converted into the trans-stereo-
isomer D by a simple acid-catalyzed process without loss in
enantioselectivity.
We began our investigation of the ortho-formyl homo-
chalcone 1a as a starting substrate, aimed at the synthesis of
the exo-peroxyacetal-containing isochroman 3a (see Table 1).
Notably, the isochroman units are frequently found in variety
of natural products and bioactive molecules.[22,23] Moreover,
the targeted exo-peroxyacetals could potentially be converted
into other important bioactive cores which are shown in
Figure 2.
By using tBuOOH as peroxide source, a variety of chiral
cinchona alkaloid derived catalysts (2a–g) were surveyed in
toluene as the solvent at room temperature (Table 1,
entries 1–5). As shown in entry 5, the catalyst 2g was found
to catalyze the reaction cleanly to furnish the exo-peroxy-
Figure 1. Natural products and bioactive molecules possessing a chiral
peroxyacetal pharmacophore.
[*] S. Maity, B. Parhi, Dr. P. Ghorai
Department of Chemistry, Indian Institute of Science Education and
Research (IISER) Bhopal
Bhopal By-pass Road, Bhauri, Bhopal-462066 (India)
E-mail: pghorai@iiserb.ac.in
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201511165.
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Figure 2. Natural products and bioactive molecules possessing 1- and
3-substituted isochromans, 1-hydroxy-3-substituted isochromans, and
isocoumarines.
Table 1: Optimization of reaction conditions[a]
Scheme 2. Substrate scope. Reaction conditions: 1 (0.1 mmol),
tBuOOH (0.5 mmol, 5 equiv), 2g (0.005 mmol, 5 mol%) in Et2O at RT.
The diastereomeric ratio (d.r.) was determined by 1H NMR analysis of
the unpurified reaction mixtures. Unless stated otherwise, yields are of
pure isolated major diastereomers. The ee value of the major diaste-
reomer was determined by chiral-phase HPLC analysis. FG=functional
group.
Using these optimized reaction conditions, we explored
the substrate scope, which proved to be quite general
(Scheme 2). Excellent yields, diastereoselectivities (> 20:1 in
all cases), and enantioselectivities (almost all cases 99% ee)
were obtained with substrates containing substituted aryls
(3a–e and 3g–i) and heteroaryl (3 f) groups. Furthermore,
substitutions on the central aryl moiety (3j–n) were well
tolerated. Replacement of tBuOOH with cumene hydroper-
oxide provided the corresponding peroxide 3o in excellent
stereoselectivity. Not only aryl moieties on the a,b-unsatu-
rated ketone, but also an alkyl group was also tolerated (3p).
However, a decrease in yield and stereoselectivity was
observed. Even upon scaling up (1 g, 4 mmol) the reaction
of 1a, the corresponding product 3a was obtained without any
loss of stereoselectivity. The cis stereochemistry of the
product was confirmed based on the crystal structure of 3c
(Figure 3).
Entry
2
Solvent
t [h]
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
2a–c
2d
2e
2 f
2g
toluene
toluene
toluene
toluene
toluene
Et2O
12
12
12
12
7
–
–
–
35
55
55
70
74
19:1
19:1
13:1
21:1
24:1
40
93
62
99
99
2g
4
[a] Reactions were performed on a 0.02 mmol scale of aldehyde. [b] Yield
was calculated based on 1NMR spectroscopy of the crude reaction
mixture using diphenyl acetonitrile as the internal standard. [c] The
diastereomeric ratio was determined by 1H NMR analysis of the crude
reaction mixture. [d] Enantiomeric excess was determined by HPLC
analysis using a chiral stationary phase.
acetal 3a (70% yield; NMR) with excellent diastereo- and
enantioselectivity (> 20:1 d.r. and 99% ee). Further, screen-
ing of various organic solvents (see the Supporting Informa-
tion) using 2g revealed that Et2O is the best solvent as it led to
an improved yield (74%), as well as diastereoselectivity
(> 20:1 d.r.; entry 6). However, the corresponding thiourea
catalysts were not suitable here (see the Supporting Informa-
tion). Notably, replacement of hydroperoxide with an alcohol
such as MeOH provided the corresponding exo-acetal, which
was found to be unstable (see the Supporting Information).
Figure 3. Crystal structure of 3c.[24]
An epimerization at the peroxyacetal center was observed
when the synthesized cis products were stored in either
commercial CHCl3, CH2Cl2, or CDCl3 (Scheme 3a). Presum-
ably, the trace acid content in the solvent is responsible for
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Scheme 3. Epimerization of peroxyacetals. The diastereomeric ratio
Scheme 6. Late-stage manipulation of the products. Reaction condi-
was determined by 1H NMR analysis. The ee value was determined by
tions: a) In(OTf)3 (2 mol%), allyltrimethylsilane (1.5 equiv), dry
CH2Cl2, RT. b) Catechol borane (3 equiv), dry toluene, 08C to RT.
c) In(OTf)3 (2 mol%), TMSCN (1.2 equiv), CH2Cl2, 08C to RT. d) In-
(OTf)3 (10 mol%), 3-ethanol indole, dry CH2Cl2, 08C to RT. e) PPh3
(2 equiv), CH2Cl2, RT. f) IBX (1.2 equiv), EtOAc/DMSO (9:1), reflux.
DMSO=dimethylsulfoxide, IBX=o-iodoxybenzoic acid, Tf =trifluoro-
methanesulfonyl, TMS=trimethylsilyl.
HPLC analysis using a chiral stationary phase.
such a phenomenon, thus leading to the corresponding
sterically stable trans isomers via the formation of an
oxocarbenium ion. However, such epimerization was sup-
pressed by using acid-free solvents (passed through a plug of
basic alumina). As shown in Scheme 3b, various cis ster-
eoisomers were converted into the corresponding trans isom-
ers with excellent d.r. values (> 15:1), without affecting the
enantioselectivity.
To explore the generality of the reaction conditions, ortho-
homoformyl chalcones (4) were examined (Scheme 4). In
general, the reactions worked equally well, but the diastereo-
selectivities remained moderate.
such chiral building blocks (Scheme 6). For instance, Lewis
acid catalyzed allylation, hydride addition, cyanation, and
À
indole addition enabled the selective conversion of a C OO
À
À
bond into either a C C bond or C H bond without loss of
enantiopurity, thus, 1,3-disubstituted isochromans (8, 10–11)
were obtained with a high level of optical purity. Notably, the
current protocol could be superior compared to our previous
report in terms of enantioselectivity for the synthesis of the 3-
substituted isochroman 9.[21,23] It is noteworthy that such
substitution of a peroxide moiety is not usual in literature.
Furthermore, the decomposition of a peroxy linkage can give
the corresponding 1-hydroxy-3-substituted isochromans (12).
Subsequently, oxidation of a hydroxy into a carbonyl func-
tionality provides the chiral isocoumarine core 13. And the
corresponding aliphatic peroxy-tetrahydrofurans 7a–c could
be a potential substrate for enantiopure g-lactones. The
absolute stereochemistry of 9 was confirmed by the correla-
tion with the literature value.[21b]
Scheme 4. Substrate scope: 1,3-Disubstituted isochromans. For reac-
tion conditions, see: Scheme 2. [a] The ee value of the major diastereo-
mer.
To explain the observed absolute stereochemical out-
come, a bifunctional mechanism similar to those previously
proposed for the squaramide/thiourea-catalyzed oxa/aza-
Michael reaction of enones[15,19–21] may be invoked
(Scheme 7). The re-face of the enone in either TS-1 or TS-2
is in perfect alignment to drive the formation of the product
with the desired stereochemistry. As shown in TS-1, the OOR
group at the b-position imposes a steric hindrance with the
bicyclic skeleton of the catalyst, thus prohibiting the inter-
action of the catalyst with the substrate. Whereas, in TS-2 the
OOR group is situated away from the bicyclic skeleton, and
thus does not hinder the catalyst–substrate association.
Next, we turned our attention to the corresponding
cyclization of substrates without a phenyl linker (Scheme 5).
5-Peroxy 2-substituted tetrahydrohydrofurans (7a–c) can be
synthesized with good yields and excellent enantioselectiv-
ities. However, moderate diastereoselectivities were
observed.
Intrigued by the recurrent existence of 1-/3-substituted
isochromans and isocoumarines in natural products and
bioactive molecules (Figure 2),[22] the versatility and potential
application of the stereoenriched exo-peroxyacetals were
illustrated for the site-selective transformations to construct
Scheme 5. Substrate scope: Aliphatic linker. For reaction conditions,
see: Scheme 2. [a] The ee value of the major diastereomer.
Scheme 7. Proposed model for enantioselectivity-determining step.
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In summary, a sequential peroxyhemiacetalization fol-
lowed by an enantioselective intramolecular oxa-Michael
reaction of ortho-formyl homochalcones and ortho-homo-
formyl chalcones have been developed using a chiral bifunc-
tional organocatalyst. This process provides the very first,
promising approach for the synthesis of exo-peroxyacetals
with excellent enantio- and diastereoselectivities. The meth-
odology contributes to the development of new catalytic
asymmetric protocols for the synthesis of chiral peroxides.
Based upon this oxa-Michael reaction of peroxyhemiacetals,
the synthesis of chiral lactones is under active consideration in
our group.
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Acknowledgements
This work has been funded by CSIR, New Delhi and IISER
Bhopal. S.M. and B.P. thank UGC and CSIR, respectively,
New Delhi, India for the fellowship. We are thankful to Mr. L.
M. Jha and Ms. A. Upadhyay for the crystal analysis. The
support from Mr. Barnala Ravindra (IISER-B) is acknowl-
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Keywords: asymmetric synthesis · heterocycles ·
Michael addition · organocatalysis · peroxides
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7723–7727
Angew. Chem. 2016, 128, 7854–7858
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Received: December 2, 2015
Revised: January 4, 2016
Published online: February 19, 2016
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