Asymmetric cooperative catalysis of strong bronsted acid-promoted reactions using chiral ureas

Article abstract of DOI:10.1126/science.1182826

Cationic organic intermediates participate in a wide variety of useful synthetic transformations, but their high reactivity can render selectivity in competing pathways difficult to control. Here, we describe a strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral catalyst interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in cycloadditions with electron-rich alkenes (the Povarov reaction). A detailed experimental and computational analysis of this catalyst system has revealed the precise nature of the catalyst-substrate interactions and the likely basis for enantioinduction.

Full text of DOI:10.1126/science.1182826

Asymmetric Cooperative Catalysis of Strong Brønsted Acid−
Promoted Reactions Using Chiral Ureas
Hao Xu et al.
Science 327, 986 (2010);
DOI: 10.1126/science.1182826
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30 September 2009; accepted 5 January 2010
10.1126/science.1182669
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a broad range of chiral urea and thiourea deriv-
atives that were developed and studied previously
in our laboratory, as well as several different
Brønsted acids, were evaluated as catalysts for
this transformation (table S1) (19). With this ap-
proach, we found that the combination of the
bifunctional sulfinamido urea derivative 1a (20)
and ortho-nitrobenzenesulfonic acid (NBSA)
catalyzed the model reaction with high enantio-
selectivity (Fig. 1, B and C, entry 1). The im-
portance of both the urea and sulfinamide groups
in the catalyst became evident in structure-
reactivity/enantioselectivity studies. Thiourea de-
rivative 1b is an efficient catalyst, but it induced
lower enantio- and diastereoselectivity (Fig. 1C,
entry 2), whereas the diastereoisomeric (R,R,S)-
sulfinamido urea 1c promoted a much slower
and poorly selective reaction (Fig. 1C, entry 3).
In addition, reactions catalyzed by phosphinic
Asymmetric Cooperative Catalysis of
Strong Brønsted Acid–Promoted
Reactions Using Chiral Ureas
Hao Xu, Stephan J. Zuend, Matthew G. Woll, Ye Tao, Eric N. Jacobsen*
Cationic organic intermediates participate in a wide variety of useful synthetic transformations,
but their high reactivity can render selectivity in competing pathways difficult to control. Here, we
describe a strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a
chiral catalyst interacts with the highly reactive intermediate through a network of noncovalent
interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows
high enantioselectivity in cycloadditions with electron-rich alkenes (the Povarov reaction).
A detailed experimental and computational analysis of this catalyst system has revealed the precise
nature of the catalyst-substrate interactions and the likely basis for enantioinduction.
he proton (H+) is the simplest, and ar- covery of anion-binding pathways (12, 13) in amide urea 1d displayed a modest selectivity,
guably the most versatile, catalyst for reactions catalyzed by chiral, small-molecule, and pivalamide urea 1e and amino urea 1f both
organic reactions, mediating an extraor- H-bond donor catalysts such as urea and thiourea induced low reactivity and selectivity (Fig. 1C,
T
dinary range of biological and synthetic trans- derivatives (14) suggests an alternative strategy entries 4 to 6). These results suggest a coopera-
formations (1). Although a proton cannot be that combines elements of both approaches. In tive role for the urea and sulfinamide groups of
rendered chiral, enantioselective Brønsted acid this scenario, a chiral catalyst might associate 1a in the rate- and enantioselectivity-determining
catalysis is attainable through the influence of with a protonated substrate through the counter- steps of the catalytic reaction.
the acid’s conjugate base and through medium anion and induce enantioselectivity in nucleo-
Under optimized conditions, the Povarov re-
effects. The former strategy, involving the use of philic addition reactions to the cationic electrophile action that is catalyzed by 1a was found to be
chiral acids, has proven particularly useful, as through specific secondary interactions with the applicable to different nucleophiles and a wide
demonstrated in the design and application of charged species.
variety of N-aryl imines (Fig. 2, A and B). The
chiral phosphoric acids (2–4), N-triflyl phos- This idea was explored in the context of the highest enantioselectivities were observed in re-
phoramides (5), aryl sulfonic acids (6), and formal [4+2] cycloaddition of N-aryl imines and actions that were carried out under cryogenic
Lewis acid– (7, 8) or thiourea-assisted Brønsted electron-rich olefins, also known as the Povarov conditions with a 2:1 ratio of 1a to NBSA, which
acids (9, 10). The use of medium effects has been reaction (15). This Brønsted acid–catalyzed re- was used to ensure complete suppression of the
less straightforward, and chiral solvents have been action affords tetrahydroquinoline derivatives racemic pathway catalyzed by NBSA alone.
investigated in asymmetric catalysis with com- with the concomitant generation of up to three Lactam-substituted tetrahydroquinoline deriva-
paratively limited success (11). The recent dis- contiguous stereogenic centers, and enantiose- tives 6exo were obtained in high enantio- and
lective Lewis acid– or phosphoric acid–catalyzed diastereoselectivities by reaction of benzaldimines
variants have been identified recently (16–18). 2 with vinyllactam 5. Tricyclic hexahydropyrrolo-
Department of Chemistry and Chemical Biology, Harvard
The acid-catalyzed Povarov reaction between [3,2-c]quinoline derivatives 8exo were generated
benzylidene aniline 2a and 2,3-dihydrofuran 3 in an analogous manner by the cyclization of
was selected as a model reaction (Fig. 1A), and N-Cbz–protected 2,3-dihydropyrrole 7 with 2.
University, Cambridge, MA 02138, USA.
*To whom correspondence should be addressed. E-mail:
jacobsen@chemistry.harvard.edu
986
19 FEBRUARY 2010 VOL 327 SCIENCE www.sciencemag.org

REPORTS
Fig. 1. (A)ModelPovarov
reaction cocatalyzed by o-
nitrobenzenesulfonic acid
and chiral ureas/thioureas.
(B) Some of the chiral cat-
alysts evaluated in optimi-
zation studies. (C)Resultsof
catalyst structure-reactivity/
enantioselectivity studies.
dr, diastereomeric ratio;.
Both dr and ee were de-
termined by supercritical
fluid chromatography anal-
ysis using commercially
available chiral columns
(19).
quinoline structure of a variety of important,
biologically active compounds (21–23), includ-
ing martinelline (11, Fig. 2C), a naturally oc-
curring nonpeptide natural product that has been
identified as a bradykinin B1 and B2 receptor
antagonist (24). The enantioselective catalytic
Povarov method provides an efficient enantiose-
lective route to this natural product and its analogs
(25), thereby solving a longstanding synthetic
challenge.
The cooperative activity of an acid and a
chiral organic molecule may represent a general
strategy for asymmetric catalysis (9, 10), and we
thus undertook a detailed experimental and com-
putational study to elucidate the mechanism of
catalysis in the Povarov reaction and the basis for
the high levels of stereoselectivity induced by 1a.
Similar enantioselectivities were achieved with a
variety of sulfonic acids under homogeneous
conditions, and we selected the 1a/HOTf cocata-
lyzed reaction between 2a and 3 as a model for
mechanistic analysis (HOTf, triflic acid, HO3SCF3).
The reaction between 2a (0.2 to 0.8 M) and 3 (0.4
to 1.6 M) promoted by catalytic quantities of HOTf
(0.2 to 2.0 mM) alone in toluene was monitored
by reaction calorimetry and 1H nuclear magnetic
resonance (NMR) spectroscopy (table S4). Ki-
netic analysis of reactions carried out at 28°C
revealed a first-order dependence on [3] and
[HOTf], and a zeroth-order dependence on imine
[2a] (Eq. 1). These data indicate that imine 2a
undergoes quantitative protonation by HOTf
under the reaction conditions, and that protio-
iminium triflate 2a•HOTf represents the resting
state of the achiral acid catalyst under the reaction
conditions.
Fig. 2. (A and B) Asymmetric Povarov reactions catalyzed by 1a/NBSA with enamide 5 and
enecarbamate 7 as the nucleophilic reacting partners. Molecular sieves (5 Å) serve to sequester water
introduced with the hygroscopic NBSA reagent, thereby preventing competing imine hydrolysis pathways.
See tables S2 and S3 for yields and selectivities obtained with each substrate. (C) Martinelline (11), a
natural-product inhibitor of bradykinin B1 and B2 G protein-coupled receptors (median inhibitory
concentration IC50 = 6.4 and 0.25 mM, respectively). A previous study demonstrated that a racemic form
of ester 10b could be converted to (T)11 after epimerization of the corresponding aldehyde, so the
enantioselective synthesis of 10b described here constitutes a formal enantioselective synthesis of
martinelline (25).
Rate ¼ d½4ꢀ=dt
0
1
1
¼ krac½imineꢀ ½3ꢀ ½HOTfꢀtot
ð1Þ
Although moderate diastereoselectivities favor- derived from glyoxylate esters—underwent reac-
ing the exo diastereomer were obtained in this tion more rapidly in the Povarov reaction, but
case (8exo/8endo = 1.4 to 4.2:1), this product was uniformly high enantioselectivities were obtained
also generated in high enantiomeric excess (ee) despite these reactivity differences.
Here, t is time and krac is the second-order rate
constant for the nonenantioselective cyclo-
addition of 2a•HOTf and 3.
Consistent with this conclusion, the reaction
of imine 2a with one equivalent of HOTf re-
sulted in the quantitative formation of protio-
iminium triflate 2a•HOTf as a moisture-sensitive
salt that is sparingly soluble in nonpolar solvents
(90 to 98% ee) and could be isolated in
Povarov reactions between glyoxylate imines
diastereomerically pure form in useful yields 9a or 9b with 2,3-dihydropyrrole 7 provide the
(45 to 73%). In general, imines derived from endo products in high enantioselectivity. This
electron-deficient aldehydes—especially imines represents a direct route to the core tetrahydro-
www.sciencemag.org SCIENCE VOL 327 19 FEBRUARY 2010
987

REPORTS
1
(~2.0 mM in C6D6). The solubility of 2a•HOTf up-field shift of the H NMR resonance of the
Markedly different effects are observed when
increases by a factor of 4 in the presence of formyl proton of 2a•HOTf, consistent with 2a•HOTf is treated with solutions of bifunctional
achiral urea 12 through the formation of the 1:1 increased charge separation. These observations sulfinamidourea 1a, which increases the solubil-
1
complex (Fig. 3A). H NMR chemical shifts of can be attributed to a hydrogen-bonding inter- ity of 2a•HOTf by more than one order of mag-
the formyl proton are sensitive probes of charge action between 12 and the triflate anion of nitude; however, dissolution is accompanied by a
separation in iminium ions (26). We observed 2a•HOTf that leads to both solubilization and 0.92-ppm down-field shift of the 1H NMR
that the 1:1 complex of 2a•HOTf with achiral greater charge separation between the iminium resonance of the formyl proton of 2a•HOTf,
urea 12 exhibits a 0.14 parts per million (ppm) ion and the triflate anion.
which is consistent with a less–charge-separated
Fig. 3. (A) Formation of a complex between urea 12 and iminium sulfonate Plot of initial rate of the Povarov reaction versus [1a] at three different
2•HOTf. 1H NMR chemical shifts of the formyl proton of 2a as free and urea-bound concentrations of HOTf. [2a] = 0.2 or 0.4 M, [3] = 1.6 M. The black curves
salts. (B) Geometry and energy-minimized structures of 2a•HOTf•1a calculated at represent least-squares fits to the rate law derived from the kinetic scheme depicted
the B3LYP/6-31G(d) level of density functional theory. Ar = 3,5-(CF3)2C6H3. in (C). (E) Plot of ee of 4aexo versus [1a] at three different concentrations of HOTf.
Selected bond distances are shown in angstroms. (C) Kinetic parameters of racemic (F) Plot of initial rate of the racemic Povarov reaction cocatalyzed by achiral urea
and enantioselective Povarov reaction of 2a and 3 cocatalyzed by 1a and HOTf. (D) 12 and HOTf versus [12] with HOTf = 0.80 mM, [2a] = 0.2 M, [3] = 1.6 M.
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19 FEBRUARY 2010 VOL 327 SCIENCE www.sciencemag.org

REPORTS
iminium ion. Computational analysis (27) of the sistent with binding constants determined be- mechanism of addition of dihydrofuran 3 to the
ternary 2a•HOTf•1a complex suggests the basis tween tetraalkylammonium salts and ureas and protioiminium sulfate 2•HOTf•1a. In principle,
for the observed effect. Four energetic minima of thioureas (31, 32).
any of several elementary steps in this process
may represent the rate- and enantioselectivity-
determining event (Fig. 4A, steps a to d). The
absence of a primary kinetic isotope effect on the
ortho hydrogens of the aniline group of 2 in-
dicates that rearomatization (step d) is kinetically
rapid (Fig. 4B). A positive Hammett correlation
comparable stability were identified (Fig. 3B),
with the 1a-triflate complex acting as a dual H-
Rate ¼ d½4ꢀ=dt
¼ krac½imine HOTfꢀ½3ꢀ þ
bond acceptor through the triflate and sulfina-
mide groups, and the iminium ion acting as a
dual H-bond donor through the iminium nitrogen
and formyl protons (28).
•
kasym½imine HOTf 1aꢀ½3ꢀ
ð2Þ
•
•
The additional stabilizing interactions involv- Here, kasym is the second-order rate constant was obtained in the analysis of the effect of
ing the catalyst-sulfinamide group and iminium for the enantioselective cycloaddition between anilino substituents on the rate of reaction (r =
ion formyl proton group have a pronounced 2a•HOTf•1a and 3.
+1.96 T 0.06, fig. S17). This result indicates that
effect on the rate of the Povarov reaction. Kinetic
The observation of tight binding between either the first step of a stepwise process (step a)
analysis of the reaction between 2a and 3 that protio-iminium triflate 2a•HOTf and sulfinamido or a concerted cycloaddition (step c) may be rate-
was cocatalyzed by HOTf and chiral sulfinami- urea 1a serves to explain how high enantioselec- limiting, but it is inconsistent with the cyclization
dourea 1a under homogeneous conditions re- tivity is obtained during the formation of 4a, even step of a stepwise process (step b) representing
vealed that 1a induces a substantial decrease in under conditions where the HOTf-catalyzed race- the slow step. Definitive distinction between
reaction rate (Fig. 3D). In contrast, the simple mic pathway is several times more rapid than the steps a and c is more challenging (33), but the
achiral urea 12 has a slight accelerating effect enantioselective pathway (Fig. 3, C and E). The kinetic isotope effect data suggest that partial
(Fig. 3F). In the presence of 1a, the reaction rate equilibrium constant for complex formation is suf- rehybridization of the ortho-carbon of the aniline
can be expressed by a two-term rate law in which ficiently high that virtually no free iminium ion occurs in the rate-limiting step (34), and this is
the pathway catalyzed by HOTf alone dominates exists, and the reaction is thus channeled through indicative of a concerted, albeit highly asyn-
at low [1a], and a HOTf/1a cocatalyzed pathway the asymmetric pathway. The enantioselectivity in chronous [4+2] cycloaddition. This conclusion
dominates at high [1a] (Eq. 2). A binding con- the formation of 4aexo is increased further to syn- was supported by a computational analysis of the
stant of K = 9000 T 2000 M−1 for the interaction thetically useful levels by carrying out the reaction reaction leading to 4exo, which predicts that the
between 1a and 2a•HOTf can be determined at lower temperatures (that is, –55°C, 97% ee).
from the kinetic data (Fig. 3D and fig. S11). This
To glean insight into the basis for stereo- cycloaddition and a comparatively rapid depro-
relatively high value stands in sharp contrast to induction in the Povarov reaction by sulfina- tonation/rearomatization step (fig. S19).
the much weaker binding between chiral H-bond midourea catalyst 1a, we carried out a full The catalyst-bound iminium ions depicted in
lowest-energy pathway involves an endothermic
donors and neutral substrates (29, 30), but is con- experimental and computational analysis of the Fig. 3B each have one p face exposed to solvent
Fig. 4. (A) Possible
mechanisms and rate-
limiting steps in the
asymmetric Povarov re-
action. Z, an electron-
donating or withdrawing
substituent. (B) Kinetic
isotope-effect experiments
to distinguish between
different possible rate-
limiting steps. (C) Geome-
try and energy-minimized
lowest-energy transition
structure for cycloaddi-
tion calculated at the
B3LYP/6-31G(d) level of
density functional theory.
Selected bond distances
are shown in angstroms.
Ar, 3,5-(CF3)2C6H3. (D)
Alternate view of the
structure in (C) highlight-
ing the stabilizing p–p
interaction between the
aryl groups of the catalyst
and the imimium ion un-
dergoing cycloaddition.
(E) Analogous view of
the transition structure
leading to the minor en-
antiomer of product. This
transition structure lacks
stabilizing p–p interac-
tions and is disfavored relative to the structure in (D) by 1.3 kcal/mol in calculations using the B3LYP/6-31G(d) method, and by 3.6 to 3.9 kcal/mol using M05-
2X/6-31+G(d,p) or MP2/6-31G(d) single-point calculations. See table S17 for further details.
www.sciencemag.org SCIENCE VOL 327 19 FEBRUARY 2010
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are all expected to be energetically accessible thiourea derivatives to bind a wide range of
under the reaction conditions. Computational anions, the strategy demonstrated here is appli-
analyses using either density functional theory cable, in principle, to cationic intermediates with
or ab initio methods (Fig. 4, C to E) predict that a variety of counterion structures.
the enantioselectivity-determining cycloaddition
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the experimentally observed (R)-enantiomer
of product 4aexo. The lowest-energy cyclo-
addition transition structure displays iminium
N–H···Osulfinamide and formyl C–H···Osulfonate
hydrogen bonds (Fig. 4C), and is predicted to
have ≥1.3-kcal/mol lower energy than alterna-
tives arising from complexes II to IV, which
is consistent with the experimental data. The
basis for enantioselectivity may be ascribed
to a stabilizing p–p interaction between the
(CF3)2-C6H3N component of the catalyst and
the cationic aniline moiety of the substrate. This
interaction is evident in transition structures
leading to the major enantiomer of 4aexo (Fig.
4D), but it is absent in transition structures
leading to the minor enantiomer (Fig. 4E).
Enantioselective catalysis by 1a of a strong
Brønsted acid–catalyzed Povarov reaction thus
involves tight binding to a highly reactive cationic
intermediate through multiple, specific H-bonding
interactions, and these noncovalent interac-
tions are maintained in the subsequent stereo-
determining cycloaddition event. One of the four
energetically accessible ground-state complexes
undergoes reaction with the nucleophile prefer-
entially, illustrating the ability of bifunctional
catalyst 1a to control precisely the outcome of
this reaction through noncovalent interactions
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Supporting Online Material
www.sciencemag.org/cgi/content/full/327/5968/986/DC1
Materials and Methods
SOM Text
Figs. S1 to S19
Tables S1 to S17
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J. Am. Chem. Soc. 131, 4598 (2009).
19. Materials and methods are available as supporting
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the Mesozoic seas have been a handful of bony
fishes confined to a brief 20-million-year window
during the Jurassic (Callovian-Tithonian, 165
to 145 million years ago) and known almost ex-
clusively from European deposits (9–12). These
enigmatic taxa belong to the extinct family
†Pachycormidae (the dagger symbol indicates
extinct groups), a stem-teleost clade that is
otherwise composed of pelagic predators con-
vergent upon tunas and billfishes (10). Giant
†pachycormids include the largest bony fish of
all time (the ~9 m †Leedsichthys) (9, 13), but
their short stratigraphic range had implied that
they were an inconsequential component of
100-Million-Year Dynasty of Giant
Planktivorous Bony Fishes in the
Mesozoic Seas
Matt Friedman,1* Kenshu Shimada,2,3 Larry D. Martin,4 Michael J. Everhart,3 Jeff Liston,5
Anthony Maltese,6 Michael Triebold6
Large-bodied suspension feeders (planktivores), which include the most massive animals to have ever
lived, are conspicuously absent from Mesozoic marine environments. The only clear representatives of
this trophic guild in the Mesozoic have been an enigmatic and apparently short-lived Jurassic group
of extinct pachycormid fishes. Here, we report several new examples of these giant bony fishes
from Asia, Europe, and North America. These fossils provide the first detailed anatomical information
on this poorly understood clade and extend its range from the lower Middle Jurassic to the end of
the Cretaceous, showing that this group persisted for more than 100 million years. Modern
large-bodied, planktivorous vertebrates diversified after the extinction of pachycormids at the
Cretaceous-Paleogene boundary, which is consistent with an opportunistic refilling of vacated ecospace.
1Department of Earth Sciences, University of Oxford, Parks
Road, Oxford OX1 3PR, UK. 2Environmental Science Program
and Department of Biological Sciences, DePaul University,
2325 North Clifton Avenue, Chicago, IL 60614, USA.
3Sternberg Museum of Natural History, Fort Hays State Uni-
versity, 3000 Sternberg Drive, Hays, KS 67601, USA. 4Natural
History Museum and Biodiversity Research Center, University
of Kansas, 1345 Jayhawk Boulevard, Lawrence, KS 66045,
USA. 5Division of Ecology and Evolutionary Biology, Faculty
of Biomedical and Life Sciences, University of Glasgow,
University Avenue, Glasgow G12 8QQ, UK. 6Triebold Paleon-
tology and Rocky Mountain Dinosaur Resource Center, 201
South Fairview Street, Woodland Park, CO 80863, USA.
he largest vertebrates—fossil or living— array of giant suspension feeders found in Ceno-
are marine suspension feeders. Modern zoic marine environments, this guild has appeared
T
clades adopting this ecological strategy to be absent during most of the Mesozoic, an
diversified in the Paleogene (66 to 23 million interval that is marked by the ecological ascend-
years ago) (1–3) and include baleen whales and ance of modern plankton groups (5, 6). Possible
four independent lineages of cartilaginous fishes candidates have been proposed (7, 8), but the
*To whom correspondence should be addressed. E-mail:
(sharks and rays) (4). In striking contrast to the clearest examples of large-bodied planktivores in mattf@earth.ox.ac.uk
990
19 FEBRUARY 2010 VOL 327 SCIENCE www.sciencemag.org