Quaternary ammonium (Hypo)iodite catalysis for enantioselective oxidative cycloetherification

Article abstract of DOI:10.1126/science.1188217

It is desirable to minimize the use of rare or toxic metals for oxidative reactions in the synthesis of pharmaceutical products. Hypervalent iodine compounds are environmentally benign alternatives, but their catalytic use, particularly for asymmetric transformations, has been quite limited. We report here an enantioselective oxidative cyeloetherification of ketophenols to 2-acyl-2,3-dihydrobenzofuran derivatives, catalyzed by in situ-generated chiral quaternary ammonium (hypo)iodite salts, with hydrogen peroxide as an environmentally benign oxidant. The optically active 2-acyl 2,3- dihydrobenzofuran skeleton is a key structure in several biologically active compounds.

Full text of DOI:10.1126/science.1188217

Quaternary Ammonium (Hypo)iodite Catalysis for Enantioselective
Oxidative Cycloetherification
Muhammet Uyanik et al.
Science 328, 1376 (2010);
DOI: 10.1126/science.1188217
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REPORTS
0820382, and DMR-0706031), U.S. Department of
fellowship). This research was performed while Z.W. held
a National Research Council Research Associateship
Award at Naval Research Laboratory of the United States.
Z.W. thanks H. Qi at NRL for providing doped silicon
wafers, evaporating gold layers on mica, and taking
scanning electron micrograph images of GO sheets on
gold and silicon substrates. E.R. thanks T.-D. Li and
M. Lucas for support with CAFM.
Supporting Online Material
www.sciencemag.org/cgi/content/full/328/5984/1373/DC1
Materials and Methods
Figs. S1 to S8
References and Notes
Energy (DE-FG02-06ER46293 and PECASE), the Institute
for Nanoscience at Naval Research Laboratory (NRL),
the Office of Naval Research of the United States, the
Defense Advanced Research Projects Agency (DARPA)
Tip-Based Nanomanufacturing program, and Georgia
Institute of Technology (Georgia Tech Research
9 February 2010; accepted 29 April 2010
10.1126/science.1188119
Foundation, COE Cutting Edge Research Award, and COPE
peroxide (Fig. 1B). The chiral 2-substituted 2,3-
dihydrobenzofuran skeleton is a key structure in
several biologically active compounds of me-
dicinal interest (12–19). Earlier preparations of
optically active 2-alkenyl-2,3-dihydrobenzofuran
derivatives have relied on transition metal ca-
talysis (20–23).
The catalytic or stoichiometric oxidation of
3-(2-hydroxyphenyl)-1-phenylpropan-1-one (1)
with phenyl-l3-iodanes gave a complex mixture,
and the desired (2,3-dihydrobenzofuran-2-yl)
(phenyl)methanone (2) was not detected (Fig.
2A, entries 1 and 2). In sharp contrast, and to our
delight, the oxidation of 1 with two equivalents
of hydrogen peroxide [30 weight percent (wt %)
in water] in the presence of 10 mole percent (mol
%) of tetrabutylammonium iodide (Bu4NI) in
acetonitrile at room temperature gave 2 in 87%
Quaternary Ammonium (Hypo)iodite
Catalysis for Enantioselective
Oxidative Cycloetherification
Muhammet Uyanik,1 Hiroaki Okamoto,1 Takeshi Yasui,1 Kazuaki Ishihara1,2
*
It is desirable to minimize the use of rare or toxic metals for oxidative reactions in the
synthesis of pharmaceutical products. Hypervalent iodine compounds are environmentally
benign alternatives, but their catalytic use, particularly for asymmetric transformations, has
been quite limited. We report here an enantioselective oxidative cycloetherification of ketophenols
to 2-acyl-2,3-dihydrobenzofuran derivatives, catalyzed by in situ–generated chiral quaternary
ammonium (hypo)iodite salts, with hydrogen peroxide as an environmentally benign oxidant.
The optically active 2-acyl 2,3-dihydrobenzofuran skeleton is a key structure in several biologically
active compounds.
ver the past two decades, hypervalent catalytic ion pairs of chiral quaternary ammonium yield (Fig. 2A, entry 3) (24). Furthermore, the
iodine compounds have been increasingly iodide (Fig. 1A, right) (10, 11). Specifically, we tar- oxidation of 1 was much faster in diethyl ether
explored as environmentally benign oxi- geted enantioselective oxidative cycloetherification (Et2O), tetrahydrofuran (THF), or ethyl acetate
O
dation reagents in place of rare or toxic heavy of ketophenols to 2-acyl-2,3-dihydrobenzofuran (EtOAc) (Fig. 2A, entry 4, and table S1). Notably,
metal oxidants (1, 2). However, their stoichio- derivatives, using a C2-symmetric chiral binaphthyl- the oxidation of 1 did not occur on substitution
metric use has been limited because of potentially based quaternary ammonium (hypo)iodite cata- of tetrabutylammonium bromide or chloride for
explosive shock-sensitivity and/or poor solubility lyst generated in situ by reaction with hydrogen Bu4NI. Excellent chemoselectivity was observed
in common organic solvents (1, 2). Thus, the de-
velopment of hypervalent iodine-catalyzed re-
actions using more convenient stoichiometric
co-oxidants is needed (3, 4). Harnessing chiral
hypervalent iodine compounds for enantioselec-
tive oxidative coupling has proven a particular
challenge in asymmetric catalysis. There are sev-
eral examples of catalysis by in situ–generated
chiral aryl-l3- or aryl-l5-iodane (5) with meta-
chloroperbenzoic acid (m-CPBA) as a co-oxidant
(Fig. 1A, left) (6–9); these include Quideau et al.’s
enantioselective hydroxylative dearomatization of
phenols (6), Altermann et al.’s enantioselective a-
oxysulfonylation of ketones (7), and Dohi et al.’s
and our independently reported enantioselective
oxidative spirolactonizations of 1-napthol deriv-
atives (8, 9). In contrast, no strong examples have
emerged of asymmetric catalysis using chiral cat-
ions paired with inorganic iodine-derived oxo-
acids, such as hypoiodous acid [IOH, I(I)], iodous
acid [O=IOH, I(III)], iodic acid [(O=)2IOH, I(V)],
and periodic acid [(O=)3IOH, I(VII)].
We report here an implementation of this
strategy, using the atom-economical hydrogen per-
oxide as a mild stoichiometric oxidant to activate
1Graduate School of Engineering, Nagoya University, Furo-cho,
Fig. 1. (A) (Left) Known in situ–generated aryl-l3- or aryl-l5-iodane catalysis. (Right) In situ–generated
Chikusa, Nagoya, 464-8603, Japan. 2Core Research for Evo-
hypoiodite(I) or iodite(III) catalysis. (B) Design of inorganic iodide precatalyst paired with a chiral
quaternary ammonium counter ion for the enantioselective oxidative cycloetherification of ketophenols to
2-acyl-2,3-dihydrobenzofuran derivatives. Ar, aryl; L, ligand; M+, metal or onium cation, R, alkyl or aryl
group. Symbols (Ar and L) marked with asterisks represent chiral groups.
lutional Science and Technology, Japan Science and Technology
Agency, Furo-cho, Chickusa, Nagoya, 463-8603, Japan.
*To whom correspondence should be addressed. E-mail:
ishihara@cc.nagoya-u.ac.jp
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11 JUNE 2010 VOL 328 SCIENCE www.sciencemag.org

REPORTS
Fig. 2. (A) Oxidative cycloetherification
of 1. Isolated yields of 2 are reported. Ts,
p-toluenesulfonyl. (B) Enantioselective
oxidative cycloetherification of 4a. Iso-
lated yields of 2 are reported. ee was
determined by chiral stationary-phase
high-performance liquid chromatography
(HPLC). Ph, phenyl; Pr, propyl; Bu, butyl;
h, hours.
under the present oxidation. We detected no phenol
oxidation products, which are well known to form
in reactions with aryl-l3-iodanes (1–9).
To render the catalysis asymmetric, we exam-
ined N-spiro–type quaternary ammonium iodide
precatalysts (3) bearing chiral 3,3′-disubstituted
1,1’-binaphthyl skeletons, analogous to Ooi and
Maruoka’s chiral phase-transfer catalysts (Fig.
2B) (25). As a result, we found that a 1-phenyl-1H-
imidazol-2-yl moiety (Z) at the 1-position of the
substrates (4a) was effective for inducing high
Fig. 3. Conversion of 5a to (R)-ethyl ester 6. MeOTf, methyl trifluoromethanesulfonate; MS, molecular
sieves; DBU, 1,8-diazobicyclo[5.4.0]undec-7-ene.
enantioselectivity (26) (Fig. 2B and table S3). crucial for increasing not only the enantioselec- 3f in place of bis(1,1′-binaphthyl-2,2′-dimethyl)
The oxidation of 4a with two equivalents of hy- tivity but also the chemical yield of 5a (Fig. 2B, ammonium iodide (3c) gave moderate enantio-
drogen peroxide (30 wt % in water) in the pres- entries 1 to 4). Ammonium cations bearing bulky selectivities (Fig. 2B, entries 5 and 6 versus entry
ence of 10 mol % of 3a in mixed toluene/water and electron-deficient substituents {Ar = 3,5- 3). Notably, moderate-to-high enantioselectivities
solvent (5/1, v/v) gave 2a in 54% yield, but with [3,5-(CF3)2C6H3]C6H3} at the 3,3′-positions gave were observed, regardless of the polarity of the
very low enantioselectivity [2% enantiomeric ex- the best results (1 hour, 99% yield, 88% ee) (Fig. solvent (table S3). In particular, 5a was obtained
cess (ee)] (Fig. 2B, entry 1). The substituents at 2B, entry 4). The use of mono(1,1′-binaphthyl- in 99% yield with 90% ee in mixed diethyl ether/
the 3,3′-positions of the binaphthyl moiety were 2,2′-dimethyl)ammonium iodides such as 3e and water solvent (5/1, v/v) (Fig. 2B, entry 7). 1.1 equiv-
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REPORTS
alent of hydrogen peroxide was suitable as a co- ide, 5a was obtained with higher enantioselec- as tremetone (12, 22), fomannoxin (28), and ano-
oxidant for quantitative conversion (Fig. 2B, entry tivity (92% ee) in diethyl ether (Fig. 2B, entry 9). dendroic acid (Fig. 3) (28).
8). Importantly, nearly enantiomerically pure The 5 products are very useful chiral inter- To explore the generality and scope of the
5a was obtained after a single recrystallization mediates for further synthetic elaboration (26). present enantioselective oxidative cyclization, we
(99% ee) (Fig. 2B, entry 8). When anhydrous For instance, 5a was transformed efficiently into prepared and examined several ketophenol deriv-
tert-butylhydroperoxide (TBHP) was used as a the known (R)-ethyl ester (6) (12, 27), which is a atives (4) as substrates under optimized condi-
co-oxidant in place of aqueous hydrogen perox- synthetic intermediate for natural products such tions (Table 1). The oxidation of 4-substituted
phenol derivatives 4b to 4f bearing electron-
donating or electron-withdrawing groups gave
the corresponding dihydrofuran derivatives 5b
to 5f in excellent yields with high enantiose-
Table 1. Scope of the enantioselective oxidative cycloetherification of 4. Unless otherwise noted, the
reactions were performed with 0.1 mmol of 4 and 0.2 mmol of co-oxidant in the presence of 3d (10 mol %).
lectivities (91 to 93% ee) (Table 1, entries 1 to
7). In most cases, we observed high enantiose-
lectivities using method A or B, though method
B offered substantially higher yield and ee in
the case of the 3,5-dimethoxy-substituted phe-
nol derivative 4g (Table 1, entries 8 and 9). The
2-alkenyl-derivative of compound 5g is a synthetic
intermediate for natural products such as ent-
remirol and ent-remiridol (29). The reaction was
effective for the 2-napthol derivative 4i (Table 1,
entry 11), as well as for penta-substituted phenol
derivative 4j (Table 1, entry 12). Oxidation of 2-
methyl-substituted substrate 4k gave a product
(5k) bearing a tetrasubstituted stereogenic center
in 96% ee (Table 1, entry 13). The precatalyst
loading of 3d could be reduced to 1 mol % with-
out affecting the chemical yield and enantio-
selectivity (Table 1, entry 14). Compound 5k and
its analogs would potentially offer a different route
to biologically active targets, such as peroxisome
proliferator–activated receptor a agonists (15).
To understand the reaction pathway, we con-
ducted several control experiments directed toward
identifying an active hypervalent iodine species
(table S4). No oxidation of 1 occurred in the pres-
ence of stoichiometric amounts of tetrabutylam-
monium iodate(V) or periodate(VII). Thus, the
iodate(V) and periodate(VII) active species were
ruled out. Additionally, the stoichiometric oxidation
of 1 with N-iodosuccinimide or molecular iodine
(I2) gave a complex mixture, and desired product 2
was not detected. Notably, no iodinated products
were detected, even in the oxidation of electron-
rich phenol 4h under our catalytic conditions (Table
1, entries 8 and 9). In contrast, the oxidation of
1 with I2 in the presence of two equivalents of
tetrabutylammonium hydroxide ([Bu4N]+[OH]–)
gave desired product 2 in 91% yield (30, 31).
This result suggests that in situ–generated tetra-
butylammonium hypoiodite {[Bu4N]+[IO]–, I(I)}
may be an active oxidant species for 1. However,
[Bu4N]+[IO]– may also disproportionate to tetra-
butylammonium iodite {[Bu4N]+[IO2]–, I(III)}
and Bu4NI under our reaction conditions, imply-
ing that [Bu4N]+[IO2]– is another potential actual
oxidant species. Thus, we propose a catalytic
cycle involving chiral quaternary ammonium
hypoiodite ([R4N]+[IO]–) or iodite ([R4N]+[IO2]–),
which should be generated in situ from ammonium
iodide (R4NI) and a co-oxidant (Fig. 1A, right).
These results highlight the substantial scope
of chiral salt catalysis using inorganic iodine-
derived oxoacids in place of aryliodane or tran-
sition metal catalysts.
The isolated yields of 5 are reported. ee was determined by chiral stationary-phase HPLC. Bn, benzyl.
*Reaction was performed in toluene instead of Et2O.
†The reaction was performed with 2 mmol of 5k with 4 mmol of TBHP in the
presence of 1 mol % of 3d. ‡Absolute configuration of 5k was determined by transformation into the known (R)-methyl ketone ( 24).
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30. Potassium hypoiodite (IOK) is generated in situ from I2
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32. Financial support for this project was partially provided
by a Grant-in-Aid for Scientific Research (#20245022)
from the Japan Society for the Promotion of Science, the
New Energy and Industrial Technology Development
Organization, the Shionogi Award in Synthetic Organic
Chemistry, Japan, and the Global Centers of Excellence
Program in Chemistry of Nagoya University from the
Ministry of Education, Culture, Sports, Science and
Technology.
5. According to International Union of Pure and Applied
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Materials and Methods
SOM Text
Scheme S1
Tables S1 to S4
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11 February 2010; accepted 23 April 2010
10.1126/science.1188217
dothermy arose several times during species
evolution and developed independently in sev-
eral lineages. For example, partial endothermy is
known in sharks, tunas, and even in some insects
and flowers (6–8). The origin and spreading of en-
dothermy are still a matter of great debate (9–11);
its oldest occurrence could be as early as the Per-
mian, with the appearance and radiation of the
Synapsida. Among archosaurs, mass homeother-
my or even endothermy have been proposed for
dinosaurs (12) and pterosaurs (13) and suggested
for the ancestors of crocodilians, because of the
existence of a four-chambered heart, which
modern crocodiles share with mammals and
birds (11).
Regulation of Body Temperature by
Some Mesozoic Marine Reptiles
Aurélien Bernard,1 Christophe Lécuyer,1,2* Peggy Vincent,3 Romain Amiot,1
Nathalie Bardet,3 Eric Buffetaut,4 Gilles Cuny,5 François Fourel,1 François Martineau,1
Jean-Michel Mazin,1 Abel Prieur1
What the body temperature and thermoregulation processes of extinct vertebrates were are
central questions for understanding their ecology and evolution. The thermophysiologic status
of the great marine reptiles is still unknown, even though some studies have suggested
that thermoregulation may have contributed to their exceptional evolutionary success as apex
predators of Mesozoic aquatic ecosystems. We tested the thermal status of ichthyosaurs, plesiosaurs,
and mosasaurs by comparing the oxygen isotope compositions of their tooth phosphate to those
of coexisting fish. Data distribution reveals that these large marine reptiles were able to maintain
a constant and high body temperature in oceanic environments ranging from tropical to cold
temperate. Their estimated body temperatures, in the range from 35° T 2°C to 39° T 2°C, suggest
high metabolic rates required for predation and fast swimming over large distances offshore.
Large marine reptiles, including ichthyosaurs,
plesiosaurs, and mosasaurs, inhabited the oceans
from the Triassic to the Cretaceous. They repre-
sent three different lineages that became second-
arily adapted to a marine mode of life. Ichthyosaurs
evolved from basal neodiapsid reptiles, with the
he metabolic status of extinct vertebrates isfied by adopting predatory behavior, as shared most obvious aquatic adaptations: a dolphin-like
is a key to understand their feeding strat- by many carnivorous mammals, except scav- streamlined body without a neck, paddles, and a
egy, which was critical for satisfying their engers. Endothermy is the ability to generate and fish-like tail. Plesiosaurs are derived diapsids,
T
daily energy requirements, as well as their po- retain enough heat to elevate body temperature to which belong to the Sauropterygia, the sister
tential to exploit cold environments. Phylogeny a high but stable level, whereas homeothermy is group of the Lepidosauria (lizards and snakes).
and ecology most likely had a large influence on the maintenance of a constant body temperature They are highly adapted for submarine locomo-
the thermophysiology of past vertebrates. High in different thermal environments (1, 2). Such tion, with powerful paddle-like limbs and heavily
metabolic rates mean the need to access large internal production of heat is not restricted to reinforced limb girdles. Motani (14) already dis-
amounts of high-quality food, which may be sat- mammals and birds. Heat generation can have cussed the possibility that plesiosaurs could not
several origins: digestive organs in mammals and have had a typical reptilian physiology, thus indi-
1CNRS UMR 5125, Paléoenvironnements et Paléobiosphère,
birds (1) or muscles in endothermic lamniform cating high metabolic activity. Mosasaurs constitute
Université Lyon 1, Lyon, 2 Rue Raphaël Dubois, 69622 Vil-
sharks (3). Paladino et al. (4) proposed that some a family of Late Cretaceous varanoid anguimorphs
leurbanne Cedex, France. 2Institut Universitaire de France, 103
Boulevard Saint-Michel, 75005 Paris, France. 3CNRS UMR 5143,
Département Histoire de la Terre, Muséum National d'Histoire
Naturelle, 8 Rue Buffon 75231 Paris, France. 4CNRS UMR 8538,
Laboratoire de Géologie de l’Ecole Normale Supérieure, 24 Rue
Lhomond, 75231 Paris, France. 5Natural History Museum of
Denmark, University of Copenhagen, Øster Voldgade 5-7,
1350 Copenhagen, Denmark.
marine reptiles such as leatherback turtles dis- highly adapted to marine life; they are derived
play endothermy instead of inertial homeother- lepidosaurs with an elongate body, deep tail, and
my, thus helping them to feed in cold waters. paddle-like limbs (15). Both tooth morphology
However, Lutcavage et al. (5) showed that the and the stomach contents of these three groups of
studied gravid female specimens raised their marine reptiles indicate predatory behavior. Their
metabolic rates because of egg laying, thus bias- anatomy could afford high cruising speeds and a
ing the evaluation of their true metabolic status. basal metabolic rate similar to that of modern
Most biologists agree that full or incomplete en- tunas (16). Moreover, the bone structure of adult
*To whom correspondence should be addressed. E-mail:
clecuyer@univ-lyonl.fr
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