An asymmetric synthesis of 1,2,4-trioxane anticancer agents via desymmetrization of peroxyquinols through a Bronsted acid catalysis cascade

Article abstract of DOI:10.1021/ja3052427

The desymmetrization of p-peroxyquinols using a Bronsted acid-catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cancer cell-growth inhibition.

Full text of DOI:10.1021/ja3052427

Communication
pubs.acs.org/JACS
An Asymmetric Synthesis of 1,2,4-Trioxane Anticancer Agents via
Desymmetrization of Peroxyquinols through a Brønsted Acid
Catalysis Cascade
David M. Rubush,† Michelle A. Morges,‡ Barbara J. Rose,‡ Douglas H. Thamm,‡ and Tomislav Rovis†,*
†Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
‡Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
a
Table 1. Reaction Optimization
ABSTRACT: The desymmetrization of p-peroxyquinols
using a Brønsted acid-catalyzed acetalization/oxa-Michael
cascade was achieved in high yields and selectivities for a
variety of aliphatic and aryl aldehydes. Mechanistic studies
suggest that the reaction proceeds through a dynamic
kinetic resolution of the peroxy hemiacetal intermediate.
The resulting 1,2,4-trioxane products were derivatized and
b
c
show potent cancer cell-growth inhibition.
entry
variation from “standard” conditions
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
none
92
90
46
<5
93
93
88
65
85
96
88
95
−
86
96
95
95
96
no 4 Å MS
rioxanes are important scaffolds that appear in molecules
Texhibiting antimalarial, anticancer, and antibacterial
activities.1 In particular, artemisinin, administered as a part of
a combination therapy for the frontline treatment of malaria,
contains a 1,2,4-trioxane as the key pharmacophore. The recent
emergence of an artemisinin-resistant malaria strain2 combined
with the fact that artemisinin’s mode of action remains under
debate3 has increased the difficulty of treating malaria and
makes the pursuit of novel therapeutic agents more urgent. One
potential solution has been the development of new synthetic
endoperoxides.4 Enantiomers of a few synthetic trioxanes have
shown similar antimalarial activities,5 but stereochemistry has a
demonstrated impact on anticancer activity.6 Current methods
for the enantioselective synthesis of trioxanes are lengthy and
use chiral starting materials or reagents.5−8
We envisioned that enantioenriched trioxanes could be
accessed quickly and enantioselectively through a desymmet-
rization of p-peroxyquinols via an acetalization/oxa-Michael
cascade first reported by Jefford.9,10 Cascade catalysis11−13 and
desymmetrizations14 are powerful methods utilized by our
group and others to construct complex molecules containing
multiple stereocenters in a rapid and efficient manner. Both
enantioselective acetalization15 and oxa-Michael16 reactions are
relatively unsolved problems. We were cognizant of the
potential difficulties in this approach due to the inherent
reversibility of both transformations, particularly under acidic
conditions. Nevertheless, we were emboldened by recent
successes in this area.17
no 7
no 6a
10 mol% 5 instead of 6a, no 7
no 7, 6a (10 mol %)
6a (2 mol %), 72 h
6b instead of 6a
23 °C, 48 h instead of 50 °C, 24 h
a
Reactions were performed on a 0.1 mmol scale (0.25 M solution).
Isolated yields of analytically pure material. Determined by HPLC
using a chiral stationary phase.
b
c
by List15e,18 improved the enantioselectivity to 96%. Other
biindane Brønsted acids were screened, but the parent acid 6a
gave the best results. Lowering the catalyst loading from 10 mol
% gave decreased reactivity, which could be restored through
the use of thiourea 7 as a cocatalyst. A catalyst loading as low as
2 mol % could be used at the expense of a longer reaction time
(Table 1, entry 7). The use of thiourea 7 alone led to no
product.
With our optimized reaction conditions in hand, we explored
the aldehyde scope of the reaction (Table 2). Paraformaldehyde
and a variety of sterically hindered aliphatic aldehydes work
well. Aldehydes containing alkyl halides, protected alcohols, and
protected amines are tolerated, affording trioxanes with
We began our investigation by studying the desymmetriza-
tion of p-peroxyquinol 2a, trivially accessed from cresol, using
chiral Brønsted acid catalyst 5 (TRIP), which afforded the
desired trioxane in good yield as a single diastereomer with 86%
ee (Table 1, entry 5). Switching to bis(2,4,6-
triisopropylphenyl)spirobiindane phosphoric acid 6a developed
Received: May 30, 2012
Published: August 7, 2012
© 2012 American Chemical Society
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dx.doi.org/10.1021/ja3052427 | J. Am. Chem. Soc. 2012, 134, 13554−13557

Journal of the American Chemical Society
Communication
a
a
Table 2. Aldehyde Substrate Scope
Table 3. Peroxyquinol Substrate Scope
a
See Table 2, footnote a.
delight, trioxane 4ac was formed in good yield as a single
diastereomer with 94% ee. This suggests that peroxyhemiacetal
8ac is resolved through a dynamic kinetic resolution (eq 1).
Additionally, when we monitored the reaction under the
standard conditions with catalyst 6a by HPLC, we noted that
the peroxyhemiacetal remained as a racemate throughout the
course of the reaction. A crossover experiment in which 4ac
was reacted with n-butyraldehyde showed that the oxa-Michael
step is not reversible under the reaction conditions (eq 2).20
The 1,2,4 trioxane products of the desymmetrization have a
variety of synthetic handles for subsequent derivatization.
Luche reduction of 4ac formed the allylic alcohol in 4:1 dr, and
subsequent directed epoxidation delivered highly oxygenated
cyclohexane 9 (Figure 1). Bromination of 4ac followed by
elimination formed vinyl bromide 10, allowing the incorpo-
ration of a variety of functional groups though cross-coupling.
Chemoselective reduction of the olefin in the presence of the
a
Conditions: 2a (0.3 mmol), 3 (1.25 equiv). All products formed as
single diastereomers (>20:1). Enantiomeric excess determined by
HPLC using a chiral stationary phase. The absolute configuration of
4an was established by X-ray analysis. The rest were assigned by
analogy. ent-6a was used as the catalyst.
b
c
excellent selectivities. Aromatic aldehydes also participate in the
reaction with high enantioselectivities but slightly decreased
yields (Table 2).
The reaction also proved tolerant of substitution on the p-
peroxyquinol. Products with esters, ethers, and multiple
tetrasubstituted stereocenters all were isolated in good yields
and selectivities (Table 3).
The enantiodetermining step is likely the oxa-Michael event,
in view of the high enantioselectivity of the product formed
from paraformaldehyde.19 We propose that the reaction
proceeds via a dynamic kinetic resolution of peroxy hemiacetal
( )-8a (eq 1). As a further test of this hypothesis, racemic
peroxyhemiacetal 8ac was formed by heating p-peroxyquinol 2a
with isobutyraldehyde. After excess aldehyde was removed,
unpurified ( )-8ac was reacted with chiral acid 6a. To our
Figure 1. Trioxane derivatizations.
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Journal of the American Chemical Society
Communication
Ringwald, P.; Silamut, K.; Imwong, M.; Chotivanich, K.; Lim, P.;
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peroxide was achieved under the aegis of Rh/Al2O3 and Adams’
catalyst. This product was further reduced under acidic
conditions to reveal the previously unreported diol 12.
In addition to serving as a frontline antimalarial agent,
artemisinin is cytotoxic toward cancer cells, and the 1,2,4-
trioxane is believed to play an important role.1 Our products
and their derivatives were screened for cytotoxicity against a
variety of cancer cell lines. Compounds 4ac, 4ao, and 11
showed promising activity toward bone and lung cancer cell
lines with in vitro IC50 values of 3.4−25 μM (Figure 2).
Importantly, the significant antitumor activity of the semi-
reduced trioxane 12 demonstrates that their activity is not due
solely to the presence of the Michael acceptor.
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Figure 2. Anticancer activity of 1,2,4-trioxane products.
In conclusion, we have reported the first catalytic
enantioselective synthesis of trioxanes using a desymmetriza-
tion of p-peroxyquinols via an acetalization/oxa-Michael
cascade. We propose that the reaction proceeds via a dynamic
kinetic resolution of a peroxyhemiacetal intermediate. The
1,2,4-trioxane products are easily derivatized and show
promising cancer growth inhibition. Further development of
this reaction, antimalarial testing of these trioxanes, and
investigation of the mode of antineoplastic action are currently
underway.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, crystallographic data for 4an (CIF),
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
Notes
■
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank NIGMS (GM72586) for support and Kevin Oberg
for X-ray analysis of 4an. T.R. thanks Amgen and Roche for
unrestricted support.
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