Asymmetric phosphoric acid-catalyzed four-component Ugi reaction

Article abstract of DOI:10.1126/science.aas8707

The Ugi reaction constructs a-acylaminoamide compounds by combining an aldehyde or ketone,an amine,a carboxylic acid,and an isocyanide in a single flask.Its appealing features include inherent atom and step economy together with the potential to generate products of broad structural diversity.However,control of the stereochemistry in this reaction has proven to be a formidable challenge.We describe an efficient enantioselective four-component Ugi reaction catalyzed by a chiral phosphoric acid derivative that delivers more than 80 a-acylaminoamides in good to excellent enantiomeric excess.Experimental and computational studies establish the reaction mechanism and origins of stereoselectivity.

Full text of DOI:10.1126/science.aas8707

RESEARCH
◥
the CPA and carboxylic acid brings about a dual
effect: enhanced acidity of the catalyst and
nucleophilicity of the carboxylic acid. Both of
these favor the catalytic enantioselective Ugi-4CR.
A myriad of well-established or custom CPAs
with well-defined chiral pockets could be readily
applied, potentially leading to complete stereo-
control. A CPA that could suppress the Passerini
and other side reactions would enable rapid
imine formation and its preferential activation
over the carbonyl group.
RESEARCH ARTICLE SUMMARY
ORGANIC CHEMISTRY
Asymmetric phosphoric acid–catalyzed
four-component Ugi reaction
Jian Zhang*, Peiyuan Yu*, Shao-Yu Li, He Sun, Shao-Hua Xiang, Jun (Joelle) Wang,
Kendall N. Houk†, Bin Tan†
RESULTS: A catalytic asymmetric Ugi-4CR was
accomplished with 1,1′-spirobiindane-7,7′-diol
INTRODUCTION: The four-component Ugi
reaction (Ugi-4CR) assembles peptide-like
a-acylaminoamides through one-pot reaction
of a carbonyl compound, an amine, an acid,
and an isocyanide. Ugi-4CR is well suited for
diversity-oriented synthesis applicable in drug
discovery, as it facilitates rapid access to diverse
libraries of biologically important molecules.
The high step economy and atom efficiency of
the reaction, as well as its convergent nature,
foster its wide use in the synthesis of hetero-
cyclic scaffolds, natural products, macrocycles,
polymers, and other target molecules. Despite
these practical advantages, the long-standing
stereochemical challenges of the Ugi reaction
have yet to be fully addressed. Consequently,
access to chiral Ugi products for drug candidate
exploration is hindered.
(SPINOL)–derived CPA4
and CPA6 as organoca-
talysts. The reaction ex-
hibited broad substrate
compatibility and good to
excellent enantioselectiv-
ity [up to 99% enantio-
◥
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RATIONALE: The chiralphosphoric acid (CPA)
framework was targeted as a catalyst for asym-
metric Ugi-4CR. The heightened acidity of CPAs
over carboxylic acids is perceived to accelerate
the kinetics of the enantioselective Ugi reaction
so as to outcompete the background reaction.
Also, self-assembled heterodimerization between
meric excess (ee)]. Activation of the imine might
be accomplished by CPA–carboxylic acid het-
erodimer catalysis via a bifunctional activation
mode, which was supported by experiments
(carboxylic acids with varying pKa values and
steric properties yielded products with a range
of ee values) and density functional theory (DFT)
calculations (lowest energy among all the con-
sidered activation modes). The calculated free
energy profile for the catalytic Ugi reaction gave
three CPA-combined key transition states, which
highlighted the bifunctional property of the
CPA. In the favored enantio-determining tran-
sition states, the aryl groups fit into the pocket
formed by the two substituents (cyclohexyl
rings) of the catalyst, revealing the importance
of noncovalent interactions in controlling the
stereochemical outcome of this reaction.
Catalytic asymmetric 4-component Ugi reaction
R1 = alkyl
R1 = aryl
41 examples
up to 96% yield
up to 99% ee
45 examples
up to 96% yield
up to 94% ee
• Readily available reactants
• Structural tunability of products
• Organocatalysis and mild conditions
CONCLUSION: This operationally simple one-
pot enantioselective Ugi-4CR harnesses in-
herent benefits of multicomponent reaction
and organocatalysis to access up to 86 en-
antioenriched a-acylaminoamides, which are
otherwise challenging to obtain via conven-
tional methods, from four achiral building
blocks in excellent yields and enantioselec-
tivities. DFT calculations gave a detailed cat-
alytic mechanism, especially with respect to
activation modes and enantio-determining
transition states. Because amide functionality
constitutes the defining primary linkage in
proteins, we foresee multiple uses of this asym-
metric four-component Ugi protocol for the
synthesis of chiral peptides and components
of natural products. We also anticipate that
this work will initiate the further development
Key points in design
1. Tunable chiral pocket
Chiral phosphoric acids
2. Enhanced nucleophilicity
3. Enhanced acidity
4. Reactivity: imine > carbonyl
CPA4
CPA6
Favorable enantio-determining transition states
1.94Å
1.82Å
of asymmetric multicomponent chemistry.
▪
The list of author affiliations is available in the full article online.
*These authors contributed equally to this work.
†Corresponding author. Email: tanb@sustc.edu.cn (B.T.);
houk@chem.ucla.edu (K.N.H.)
for N-aryl imine
for N-alkyl imine
Cite this article as J. Zhang et al., Science 361, eaas8707
(2018). DOI: 10.1126/science.aas8707
Design and exploration of catalytic asymmetric Ugi-4CR.
Zhang et al., Science 361, 1087 (2018)
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RESEARCH
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cent decades reveals that the Ugi-4CR can also
be applied to the synthesis of heterocyclic scaf-
folds (22–24), macrocycles (25, 26), polymers
(27, 28), and other compounds.
RESEARCH ARTICLE
ORGANIC CHEMISTRY
Despite these practical advantages, the long-
standing stereochemical challenges of the Ugi re-
action have yet to be fully addressed (29). Whereas
a single absolute configuration is strictly required
of drug candidates, Ugi condensation products
are often racemic. Conventionally, enantiomeri-
cally pure amino acids are used as chiral build-
ing blocks toward a-acylaminoamides (Fig. 2A).
The lengthy route, limited choices of chiral amino
acids, and inefficiency in generating structural
diversity greatly restrict this protocol. Alterna-
tively, enantiopure substrates could be used for
chiral induction in a diastereoselective Ugi-4CR
(Fig. 2B). However, this method suffers from
poor or moderate diastereoselectivities (30–32)
unless specialized amines are used. Catalytic
enantioselective synthesis (Fig. 2C) offers flex-
ibility in catalyst choice and facile delivery of
distinct stereoisomers by inversion of the cat-
alyst configuration. This approach would accom-
modate a broader substrate scope encompassing
commercially available starting materials and
would deliver products that cover substantial
chemical space by modulating the components
in each substrate quadrant. However, the advent
of this approach is long overdue, probably im-
peded by several hurdles: the complexity of a
four-component reaction system, the competition
from the uncatalyzed background reaction, the
difficulty in achieving stereocontrol of the a-
addition of an isocyanide to the imine, and
Asymmetric phosphoric acid–catalyzed
four-component Ugi reaction
Jian Zhang1*, Peiyuan Yu2*, Shao-Yu Li1, He Sun1, Shao-Hua Xiang1,
Jun (Joelle) Wang1, Kendall N. Houk2†, Bin Tan1†
The Ugi reaction constructs a-acylaminoamide compounds by combining an aldehyde or
ketone, an amine, a carboxylic acid, and an isocyanide in a single flask. Its appealing features
include inherent atom and step economy together with the potential to generate products of
broad structural diversity. However, control of the stereochemistry in this reaction has proven to
be a formidable challenge. We describe an efficient enantioselective four-component Ugi
reaction catalyzed by a chiral phosphoric acid derivative that delivers more than 80
a-acylaminoamides in good to excellent enantiomeric excess. Experimental and computational
studies establish the reaction mechanism and origins of stereoselectivity.
he prototypical four-component Ugi reac-
tion (Ugi-4CR), first disclosed by Ugi in 1959
(1), assembles a-acylaminoamides through
one-pot reaction of a carbonyl compound,
an amine, an acid, and an isocyanide (Fig.
(12–15). It has facilitated rapid access to diverse
libraries of biologically important molecules be-
cause of its ease of synthetic operation (Fig. 1B)
(2–6). In industrial applications, Dömling and
co-workers reported an elegant two-step multi-
component synthesis of praziquantel, a drug to
treat the parasitical disease schistosomiasis,
via Ugi-cyclization cascade (Fig. 1D) (16). This
strategy reduced the materials costs and offered
a strategy for the synthesis of analogs to address
plausible onset of resistance (17). In natural
product studies (18), the convergent nature of
the Ugi-4CR enabled one-step assembly of an
intermediate containing more than half of the
atoms in the final product from four building
blocks in the total synthesis of ecteinascidin 743
(Fig. 1E) (19). The development of isocyanide-
based multicomponent reactions (20, 21) in re-
T
1A). The peptide-like moiety is abundant in bio-
logically important molecules (Fig. 1B) (2–6) as
well as natural products (Fig. 1C) (7). Although
the precise mechanistic scenario may vary, the
simplified contours involve preceding imine ac-
tivation by a carboxylic acid for sequential
nucleophilic addition of isocyanide and car-
boxylate trapping of the thus-formed nitrilium
intermediate. Rearrangement via acyl group mi-
gration onto the nitrogen atom derived from the
imine generates the final product (Fig. 1A) (8–11).
The Ugi reaction is well suited for diversity-
oriented synthesis applicable in drug discovery
1Department of Chemistry, Shenzhen Grubbs Institute,
Southern University of Science and Technology, Shenzhen
518055, China. 2Department of Chemistry and Biochemistry,
University of California, Los Angeles, CA 90095, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: tanb@sustc.edu.cn (B.T.);
houk@chem.ucla.edu (K.N.H.)
Fig. 1. The classic four-component Ugi reaction in chemistry. (A) The
simplified mechanism for the reaction. (B) Selected examples of bioactive
molecules prepared directly via Ugi-4CR or involving Ugi-4CR as the key step.
(C) The recently identified natural product dudawalamide A bearing an
a-acylaminoamide scaffold. (D) Two-step synthesis of the anti-schistosomiasis
drug praziquantel via Ugi-4CR. (E) Ugi-4CR as a key step in the total synthesis
of ecteinascidin 743. Atoms in orange were incorporated by the Ugi reaction.
Me, methyl; rt, room temperature; quant., quantitative; MsOH, methanesulfonic
acid; MOM, methoxymethyl acetal; TBDPS, t-butyldiphenylsilyl; Bn, benzyl;
Boc, t-butoxycarbonyl; PMP, 4-methoxyphenyl.
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competition from the Passerini reaction or other
side reactions.
We speculated that a mild reaction system
with a chiral phosphoric acid (CPA) derivative
as catalyst might meet the aforementioned chal-
lenges. This robust class of organocatalyst has
been commonly used for asymmetric nucleo-
philic addition to imines after seminal reports
by the groups of Akiyama and Terada (33, 34).
The heightened acidity of chiral phosphoric acids
over carboxylic acids is perceived to accelerate
the kinetics of the desired reaction so as to out-
compete the background reaction. Also, pioneer-
ing reports by List and co-workers suggested that
the self-assembled heterodimerization between
the CPA and the carboxylic acid brings about a
dual effect: enhanced acidity of the catalyst and
nucleophilicity of the carboxylic acid (35–37); both
of these favor the catalytic enantioselective Ugi-
4CR. A myriad of well-established or custom CPAs
with well-defined chiral pockets can be readily
applied (38–41), leading to complete stereocon-
trol in a-addition of the isocyanide to imine.
Rapid imine formation or its preferential activa-
tion over the carbonyl group is viable with a CPA
to suppress the Passerini and other side reac-
tions. Elegant isocyanide-based Ugi-type two- or
three-component reactions catalyzed by CPAs
(42–44) as well as chiral carboxylic acid (45) have
been reported. For example, Wang, Zhu, and co-
workers achieved an important advance by using
a CPA as a catalyst to accomplish the enantiose-
lective Ugi four-center three-component reaction of
2-formylbenzoic acids, anilines, and isonitriles for
the syntheses of isoindoline derivatives in high
yields with 80 to 90% enantiomeric excess (ee) (44).
Fig. 2. Strategies for entry to enantioenriched a-acylaminoamides. (A) Asymmetry originates
from natural amino acid. (B) Substrate-induced asymmetric Ugi-4CR. (C) Chiral catalyst–induced
asymmetric Ugi-4CR. CPA, chiral phosphoric acid.
Catalyst optimization
After some initial trials (tables S1 to S4), we set
out to optimize the model catalytic asymmetric
Ugi-4CR between pentanal (1a), 4-nitroaniline
(2a), 3-phenylpropanoic acid (3a), and cyclohexyl
isocyanide (4a) in CH2Cl2 at room temperature
with 5-Å molecular sieves as a dehydrating ad-
ditive (Fig. 3). A strong background reaction was
observed in the absence of catalyst under these
reaction conditions, whereas moderate to good
enantioselectivities were afforded with the addi-
tion of 5 mole percent (mol %) of Brønsted acid
CPAs. 1,1′-Spirobiindane-7,7′-diol (SPINOL)–derived
phosphoric acid CPA6 with a bulky 2,4,6-tricyclo-
hexylphenyl group at the 6,6′-position was found
to be the best catalyst, providing the desired
product 5 in 64% yield and 82% ee. Further
investigations revealed that a 0.3 equivalent
excess of 1a, 2a, and 4a at –20°C and double
the initial scale improved the chemical yield to
90%, with 92% ee (see table S11); the Passerini
Fig. 3. Optimizing CPA structure in a model reaction. Notations for CPAs: *The reaction of 1a
(0.05 mmol), 2a (0.05 mmol), 3a (0.05 mmol), 4a (0.055 mmol), and catalyst (5 mol %) was carried
out in 1 ml of CH2Cl2. †The reaction of 1a (0.13 mmol), 2a (0.13 mmol), 3a (0.10 mmol), 4a (0.13 mmol),
and catalyst CPA6 (5 mol %) was carried out in 2 ml of CH2Cl2 at –20°C. Isolated yields are shown.
The ee values were determined by chiral HPLC analysis. Negative ee refers to inverted configuration of
the more abundant product enantiomer. MS, molecular sieve; Ph, phenyl; iPr, isopropyl; 1-Ad, 1-
adamantyl; Cy, cyclohexyl.
1
product was virtually absent according to H
nuclear magnetic resonance (NMR) analysis of
the crude reaction mixture.
Asymmetric Ugi reaction with
aliphatic aldehydes
and isocyanides (Fig. 4). The reaction was ap-
plicable to a wide range of aliphatic aldehydes.
The chain length of alkyl substituents had a
negligible effect on the stereochemical outcome,
providing corresponding products 6 to 9 in
92% ee. 3-Phenylpropanal possessing a b-aryl
moiety furnished the desired product 10 in
91% yield and 90% ee. 3-Methylbutanal and
2-phenylacetaldehyde were also suitable sub-
strates to afford 11 and 12. A thioether (13)
With the optimal reaction conditions in hand,
we explored the substrate scope with respect to
aliphatic aldehydes, amines, carboxylic acids,
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Fig. 4. Substrate scope of the enantioselective Ugi-4CR with aliphatic
aldehydes. Colors in (A) to (D) correspond to component colors at upper
left. (A) Scope of aldehydes. (B) Scope of amines. (C) Scope of acids.
The absolute structure of 34 was defined by means of single-crystal x-ray
diffraction with radiation wavelength of 0.71073 Å (Mo-Ka) at 100.0 K,
and the Flack x parameter was determined as 0.000(4). (D) Scope of
isocyanides. Isolated yields are shown. The ee values were determined
by chiral HPLC analysis. *The 10.9:1 dr for 18 was calculated on the basis
of chiral HPLC analysis (the response factor was 1:1 for equimolar
diastereoisomers calculated from the chiral HPLC trace).
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substituent was well tolerated, and ether
substituents (14, 15, and 16) afforded excellent
enantioselectivities (95 to 96% ee) presumably
due to the chelating effect as previously observed
by Schreiber and colleagues (46). A symmetrical
dialdehyde with a central N-tert-butoxycarbonyl
group underwent a dual reaction at both car-
bonyls with a 10.9:1 diastereomeric ratio (dr) and
99% ee. Aside from 4-nitroaniline, amines with
varied functionalities reacted smoothly to give
compounds 19 to 23, and excellent enantiose-
lectivities (94 to 97% ee) were achieved with
chelating aldehydes (24–28). The generality of
the acid component was broad, as products of
linear alkyl carboxylic acids (29–32), benzyl car-
boxylic acids (33 and 34), a-branched isobutyric
acid (35), a-halogenated acetic acid (36), alkenyl
carboxylic acids (37 and 40), aromatic carboxyl-
ic acid (38), and heteroaromatic carboxylic
acid (39) could all be generated with good en-
antioselectivities (83 to 91% ee). The absolute
configuration of 34 was determined by x-ray
crystallographic analysis after recrystallization,
and those of other products in Fig. 4 were as-
signed by analogy. Although benzyl isocyanide
formed 44 with moderate optical purity, primary,
secondary, tertiary, and aromatic isocyanides
Fig. 5. Substrate scope of the enantioselective Ugi-4CR with
aromatic aldehydes. Colors in (A) to (D) correspond to component
colors at upper left. (A) Scope of aldehydes. (B) Scope of amines.
(C) Scope of isocyanides. (D) Scope of acids. Isolated yields are shown.
The ee values were determined by chiral HPLC analysis. *For 50, the
reaction time was extended to 7 days. †For 63, the reaction time
was extended to 72 hours. ‡For 77, 2.0 equiv of isocyanide was added
to the reaction. tBu, tert-butyl; Et, ethyl.
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formed Ugi products (41–43, 45) with good
enantioselectivities, regardless of the extent
of steric encumbrance.
conditions, we evaluated a number of aromatic
aldehydes, amines, carboxylic acids, and isocya-
nides (Fig. 5). It was apparent that the positions
and electronic properties of the substituents on
the aromatic ring of the aldehydes exerted very
limited influence on the stereoselectivity of the
process (47–57); only slight decreases in en-
antioselectivity were observed for compounds
58 to 61 derived from aldehydes bearing strongly
electron-withdrawing groups. The 2-naphthaldehyde
and furfural were also applicable substrates for
this transformation, affording 62 and 63 with 92%
and 93% ee, respectively, although an extended
reaction time was required for the latter. The
reaction worked efficiently with different amines.
Although benzyl amine delivered compound 73
in slightly compromised optical purity, all other
linear amines of various chain length including
an ether gave rise to products (64–70, 75) in good
enantiomeric excess. Similarly, 4-phenyl butylamine,
3-phenyl propylamine, and 3-methyl butanamine
formed products 71, 72, and 74 in satisfactory
enantiomeric excess. Also, replacing the benzyl
isocyanide with other isocyanides produced cor-
responding Ugi products 76 to 79 without dimin-
ishing enantioselectivity (87 to 91% ee). Tolerance
toward structural and electronic variations of the
acids afforded access to a series of a-acylaminoamides
with excellent optical purities. Products of aro-
matic acids bearing electron-donating (81–85),
neutral (80), or electron-withdrawing (86 and 87)
moieties at varying positions on the phenyl ring
were formed in 90 to 94% ee. In addition, 2-naphthyl
carboxylic acid and trans-cinnamic acid were suit-
able substrates, providing corresponding products
(88 and 89) in good yield and enantioselectiv-
ity. Product 90 was assembled from aliphatic
cyclohexanecarboxylic acid in 84% yield and 87% ee.
The absolute configuration of 73 was assigned
as (R) by comparing the high-performance liquid
chromatography (HPLC) spectrum of the reac-
tion product with the known configuration of
(S)-73 synthesized from protected L-phenylglycine
(Fig. 6B). Those of other products were assigned
analogously.
Asymmetric Ugi reaction with
aromatic aldehydes
We next examined the compatibility of our reac-
tion protocol with aromatic aldehydes. Consid-
ering their distinct properties, we reoptimized
the conditions (see tables S5 to S10, S12, and S13)
with benzaldehyde (1b), butylamine (2b), 4-
chlorobenzoic acid (3b), and benzyl isocyanide
(4b) as model substrates. Product 46 was ob-
tained in 95% yield and 74% ee with chiral
phosphoric acid CPA1 as catalyst in cyclohexane.
We further varied the solvent, reaction temper-
ature, and catalyst to identify the following op-
timal protocol: Reactants 1b (0.13 mmol), 2b
(0.10 mmol), 3b (0.10 mmol), and 4b (0.13 mmol)
were combined with a newly synthesized catalyst
CPA4 (10 mol %) in cyclohexane at 20°C for
36 hours to afford the expected Ugi product
46 in 91% isolated yield and 92% ee. To assess
the substrate generality and limitations of these
To further evaluate the practicality of the pro-
tocol, we performed a gram-scale reaction to pre-
pare 46. As shown in Fig. 6A, 46 was obtained
Fig. 6. Syntheses of (R)-46 and (S)-73, and control experiments.
(A) Gram-scale synthesis of 46 via catalytic enantioselective Ugi-4CR.
(B) Synthesis of (S)-73 from enantiopure amino acid source. Conditions:
(a) benzylamine, N,N-diisopropylethylamine (DIEA), O-(benzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), CH2Cl2, –20°C,
24 hours; (b) trifluoroacetic acid, CH2Cl2, rt, 10 hours; (c) benzaldehyde,
MgSO4, CH2Cl2, rt, 10 hours; (d) NaBH4, MeOH/H2O, rt, 4 hours;
(e) p-chlorobenzoyl chloride, NEt3, CH2Cl2, 0°C, 2 hours. (C) Control
experiments. Isolated yields are shown. The ee values were determined
by chiral HPLC analysis. LG, leaving group; nBu, n-butyl.
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with the same enantioselectivity but in higher
yield. Our strategy is more efficient than the
conventional method (Fig. 6B), which requires
multiple steps and suffers from moderate over-
all yield (50%; Fig. 6B).
Mechanism studies
which implies that the active catalyst is the chiral
phosphoric acid itself rather than phosphate or
other deprotonated species. Also, the reaction
outcome of mixing preformed imine 95 with
carboxylic acid 3b and isocyanide 4b was similar
To gain mechanistic insights, we conducted con-
trol experiments and density functional theory
(DFT) calculations. The reaction did not proceed
in the presence of two equivalents of amine,
Fig. 7. Calculated activation modes and energy profile of catalytic Ugi
reaction. (A) DFT-optimized transition state structures and computed activation
energies for the nucleophilic addition of the isocyanide to the imine. Barriers
are relative to imine, isocyanide, and acid dimer. (B) DFT-computed reaction
pathway for the catalytic Ugi reaction of 2′, 4′, and 6′. PNP, p-nitrophenyl. Color
code: gray, carbon; white, hydrogen; blue, nitrogen; red, oxygen; orange, phosphorus.
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Fig. 5, but CPA6 also works); the lowest-energy
TSs for two different imine substrates are shown
in Fig. 8. The favored transition states lead to
(S)-product for N-aryl imine and to (R)-product
for N-alkyl imine, in accord with the experi-
mental observations. The difference is larger for
TS-6-(R) and TS-6-(S) (1.9 kcal/mol at room
temperature). Although no obvious steric clashes
are detected in these transition states, the im-
portant factor is the orientation of the aryl
groups of the substrates relative to the 2,4,6-
tricyclohexyl group of the catalyst. In the favored
TSs, the aryl groups fit into the pocket formed by
the two cyclohexyl rings of the catalyst, whereas
the aryl groups occupy the empty quadrant in the
three-dimensional space left by the bulky sub-
stituents of the catalyst in the disfavored TSs. It
is likely that the favorable noncovalent inter-
actions between the aryl groups of the substrates
and the cyclohexyl groups of the catalyst are
responsible for the observed enantioselectivities.
A general model for predicting the stereochem-
istry of phosphoric acid–catalyzed reactions of
imines based primarily on steric effects (47, 48)
failed to predict the correct stereochemistry in
this case, pointing to the importance of nonco-
valent interactions and their interplay with (and
sometimes overriding of) steric effects in chiral
phosphoric acid-catalyzed reactions (49, 50). The
bifunctional property of the chiral phosphoric
acid plays a profound role in the reaction pro-
cesses (fig. S1) with respect to generation of the
heterodimer, activation of the imine for a-addition
of isocyanide, control of the enantioselectivity, and
promotion of the Mumm rearrangement.
Fig. 8. Density functional theory calculations for enantioselectivity. (A) DFT-optimized
enantio-determining transition state structures and their relative energies for N-aryl imine substrate.
(B) DFT-optimized enantio-determining transition state structures and their relative energies for
N-alkyl imine substrate.
to the four-component variant, suggesting earlier
imine formation as well as the key intermediacy
of trans-imine. Carboxylic acids with varying pKa
and steric properties gave products with a range
of ee values—91% ee (31), 88% ee (35), and 83%
ee (38) in Fig. 4 as well as 94% ee (87), 92% ee
(81), and 87% ee (90) in Fig. 5—that hinted at the
participation of this component in the enantio-
determining step of the reaction mechanism,
which could be the a-addition step of isocyanide
to imine. Thus, we posited that lowest unoccupied
molecular orbital (LUMO) activation of the imine
might be accomplished by CPA–carboxylic acid
heterodimer catalysis via a bifunctional activation
mode (41). DFT calculations strongly support
such a scenario, as transition state TS-1 (Fig. 7A),
resulting from 5′ (Fig. 7B), has the lowest energy
among all the considered transition states. For
the nucleophilic addition of the isocyanide to
the trans-imine, four different modes (Fig. 7A)
of catalysis were explored and compared. The
chiral phosphoric acid is modeled with a di-
methyl model catalyst. All these TS structures
involve LUMO activation of the imine by the
catalyst, as well as activation (directing) of the
isocyanide via either electrostatic interaction
(TS-1) or C–H···O hydrogen bonding (TS-1a–TS-
1c). The acid-heterodimer catalysis via TS-1 has
the lowest energy barrier (15.7 kcal/mol). It fea-
tures favorable electrostatic interactions between
the positively charged nitrogen atom of the iso-
cyanide and the carbonyl oxygen atom of the
carboxylic acid.
acetic acid 2′ form a relatively stable heterodimer
3′ (5.2 kcal/mol exergonic) as suggested by List
and co-workers (35). Imine coordination at the
Brønsted acid site of the phosphoric acid gen-
erates heterotrimer 5′. The activated imine then
undergoes a nucleophilic attack by isocyanide 6′
to form the nitrilium intermediate 7′. Accompany-
ing the proton delivery, the carboxylate attacks
the nitrilium carbon via TS-2 to form the imidate
8′ rapidly; the difference in energy between TS-2
and 7′ is only 3 kcal/mol. Subsequently, phos-
phoric acid 1′ promotes a Mumm rearrangement
to release the desired product 14′ and regenerate
the catalyst. The overall rate-determining step
is the nucleophilic addition of the isocyanide 6′
to the imine-catalyst complex 5′ via TS-1. The
subsequent Mumm rearrangement catalyzed by
phosphoric acid has a lower barrier (11.9 kcal/mol,
via TS-3) than the first C-C bond-forming step
(15.7 kcal/mol, via TS-1). For comparison, the
Mumm rearrangement catalyzed by acetic acid
has a much higher barrier (18.4 kcal/mol via
TS-3a; fig. S2). This difference not only defines
the rate-limiting step of the overall process, but
also plays an important role in the stereochemical
outcome of the reaction, as the enantioselectivity
could be alternatively determined at the Mumm
rearrangement step. For example, Zhu and co-
workers attributed asymmetric induction in the
Ugi variant they reported (44) to a dynamic
kinetic resolution of the primary Ugi adduct,
rather than to the C-C bond-forming process.
Thus, the present work differs substantially from
that previous work in the mode of selectivity.
Enantio-determining TS structures were also
explored with catalyst CPA6 (CPA4 is used in
Methods
1H NMR, 13C NMR, and 19F NMR spectra of 46
to 90 were recorded at 80°C in DMSO-d6 on a
400 MHz instrument with tetramethylsilane
(TMS) as internal standard. 1H NMR, 13C NMR,
31P NMR, and 19F NMR spectra of other com-
pounds were recorded at room temperature in
CDCl3 on a 400 MHz/500 MHz instrument
with TMS as internal standard. Data for 1H NMR
are recorded as follows: chemical shift (ppm),
multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant (Hz),
integration. Data for 13C NMR are reported in
terms of chemical shift (d, ppm). High-resolution
mass spectra (HRMS) were recorded on a LC-
TOF spectrometer (Micromass). ESI-HRMS data
were acquired using a Thermo LTQ Orbitrap XL
Instrument equipped with an ESI source and
controlled by Xcalibur software. Enantioselec-
tivities were recorded on Shimadazu/Agilent
HPLC, using a chiral stationary phase column
(IC/ID, Daicel Co. CHIRALPAK). The chiral HPLC
methods were calibrated with the corresponding
racemic mixtures. Dichloromethane and cyclo-
hexane were purchased from J&K. 5-Å molecular
sieve was purchased from Acros. The silica gel
(300–400 mesh) for flash column chromatog-
raphy was purchased from Accela. Other chem-
icals were purchased from TCI, Energy, Adamas,
Meryer, Acros, and Alfa Aesar, and used as
received.
In the calculated free energy profile for the
reaction (Fig. 7B; see fig. S1 for full reaction
pathway), the model phosphoric acid 1′ and
Zhang et al., Science 361, eaas8707 (2018)
14 September 2018
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RESEARCH
| RESEARCH ARTICLE
All calculations were performed with the
Gaussian 09 package (51). Geometry optimiza-
tions were performed with B3LYP (52, 53) and
the 6-31G(d) basis set. Normal vibrational mode
analysis at the same level of theory confirmed
that the optimized structures are minima (zero
imaginary frequency) or saddle points (one ima-
ginary frequency). Single-point energies and sol-
vent effects in dichloromethane were computed
with the dispersion-corrected density functional
method B3LYP-D3 (54) with a Becke-Johnson
(BJ) damping function (55) and the 6-311+G (d,p)
basis set using the CPCM solvation model (56, 57).
The relative energies with ZPE corrections and free
energies (at 298.15 K) are in kcal/mol. Single-point
energies were also evaluated within the CPCM
model using the M06-2X (58), wB97X-D (59), and
B3LYP functionals to compare the stereoselectiv-
ities computed with or without dispersion correc-
tions. DFT-optimized structures are illustrated
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by the Extreme Science and Engineering Discovery Environment
(XSEDE), which is supported by the NSF (OCI-1053575).
Author contributions: B.T. conceived of and directed the
project; J.Z. developed the catalytic asymmetric Ugi-4CR
and conducted most of the experiments; S.-Y.L. and H.S.
performed parts of substrate screening experiments; P.Y.
conducted the DFT calculations and provided mechanism
analysis; K.N.H. directed the DFT calculations and mechanism
analysis; J.W. and S.-H.X. helped the direction of the project;
and P.Y., S.-H.X., J.W., K.N.H., and B.T. co-wrote the
manuscript. Competing interests: The authors declare
no competing interests. Data and materials availability: The
x-ray crystallographic coordinates for the structure of 34 are
available free of charge from the Cambridge Crystallographic
Data Centre under deposition number CCDC 1588496.
and all other data supporting the findings are available in the
supplementary materials.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/361/6407/eaas8707/suppl/DC1
Materials and Methods
Supplementary Text
Tables S1 to S16
Figs. S1 to S5
NMR Spectra
References (61–63)
Movies S1 and S2
ACKNOWLEDGMENTS
Funding: Supported by the National Natural Science Foundation
of China (Nos. 21572095, 21772081), Shenzhen special funds
for the development of biomedicine, internet, new energy,
and new material industries (JCYJ20170412151701379,
KQJSCX20170328153203). B.T. thanks the Thousand Young
Talents Program for financial support. P.Y. and K.N.H.
acknowledge the computational resources provided by the
Institute of Digital Research and Education (IDRE) at UCLA, and
28 December 2017; resubmitted 25 May 2018
Accepted 16 July 2018
10.1126/science.aas8707
Experimental procedures, characterization of new compounds,
Zhang et al., Science 361, eaas8707 (2018)
14 September 2018
9 of 9

Asymmetric phosphoric acid−catalyzed four-component Ugi reaction
Jian Zhang, Peiyuan Yu, Shao-Yu Li, He Sun, Shao-Hua Xiang, Jun (Joelle) Wang, Kendall N. Houk and Bin Tan
Science 361 (6407), eaas8707.
DOI: 10.1126/science.aas8707
Steering together all four Ugi pieces
The nearly 60-year-old Ugi reaction is a remarkably efficient means of linking together four molecular building
blocks: an aldehyde, an amine, a carboxylic acid, and an isocyanide. Because each component is independently tunable,
the reaction is especially well suited to the assembly of diverse compound libraries. However, stereoselectivity has been
a challenge. Zhang et al. now show that chiral phosphoric acids can catalyze the four-component coupling with high
enantioselectivity (see the Perspective by Riva). Theory suggests that a hydrogen-bonded complex involving the
phosphoric acid and carboxylic acid sets the stereochemistry for isocyanide attack on an imine intermediate.
Science, this issue p. eaas8707; see also p. 1072
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