Catalytic Enantioselective Construction of Quaternary
Stereocenters: Assembly of key building blocks for the
synthesis of biologically active molecules.
Yiyang Liu
,
Seo-Jung Han
,
Wen-Bo Liu
, and
Brian M. Stoltz
*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering,
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East
California Boulevard, MC 101-20, Pasadena, California 91125, United States
CONSPECTUS:
The ever-present demand for drugs with better efficacy and fewer side effects continually
motivates scientists to explore the vast chemical space. Traditionally, medicinal chemists have
focused much attention on achiral or so-called “flat” molecules. More recently, attention has
shifted toward molecules with stereogenic centers since their three-dimensional structures
represent a much larger fraction of the chemical space and have a number of superior properties
compared with flat aromatic compounds. Quaternary stereocenters, in particular, add greatly to the
three-dimensionality and novelty of the molecule. Nevertheless, synthetic challenges in building
quaternary stereocenters have largely prevented their implementation in drug discovery. The lack
of effective and broadly general methods for enantioselective formation of quaternary
stereocenters in simple molecular scaffolds has prompted us to investigate new chemistry and
develop innovative tools and solutions. In this Account, we describe three approaches to
constructing quaternary stereocenters: nucleophilic substitution of 3-haloindoles, conjugate
addition of boronic acids to cyclic enones, and allylic alkylation of enolates. In the first approach,
malonic ester nucleophiles attack electrophilic 3-halooxindoles, mediated by a copper(II)-
bisoxazoline catalyst. A variety of oxindoles containing a benzylic quaternary stereocenter can be
accessed through this method. However, it is only applicable to the specialized 3,3-disubstituted
oxindole system. To access benzylic quaternary stereocenters in a more general context, we turned
our attention to the enantioselective conjugate addition of carbon nucleophiles to
α
,
β
-unsaturated
carbonyl acceptors. We discovered that in the presence of catalytic palladium-pyridinooxazoline
complex, arylboronic acids add smoothly to
β
-substituted cyclic enones to furnish ketones with a
β
-benzylic quaternary stereocenter in high yields and enantioselectivities. The reaction is
compatible with a wide range of arylboronic acids,
β
-substituents, and ring sizes. Aside from
benzylic quaternary stereocenters, a more challenging motif is a quaternary stereocenter not
adjacent to an aromatic group. Such centers represent more general structures in chemical space,
but are more difficult to form by asymmetric catalysis. To address this greater challenge, and
motivated by the greater reward, we entered the field of palladium-catalyzed asymmetric allylic
alkylation of prochiral enolate nucleophiles about a decade ago. On the basis of Tsuji’s work,
which solved the issue of positional selectivity for unsymmetrical ketones, we discovered that the
*
Corresponding Author:
stoltz@caltech.edu.
HHS Public Access
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phosphinooxazoline ligand effectively rendered this reaction enantioselective. Extensive
investigations since then have revealed that the reaction exhibits broad scope and accepts a range
of substrate classes, each with its unique advantage in synthetic applications. A diverse array of
carbonyl compounds bearing
α
-quaternary stereocenters are obtained in excellent yields and
enantioselectivities, and more possibilities have yet to be explored. As an alternative to palladium
catalysis, we also studied iridium-catalyzed asymmetric allylic alkylations that generate vicinal
quaternary and tertiary stereocenters in a single transformation. Overall, these methods provide
access to small molecule building blocks with a single quaternary stereocenter, can be applied to
various molecular scaffolds, and tolerate a wide range of functional groups. We envision that the
chemistry reported in this Account will be increasingly useful in drug discovery and design.
Graphical Abstract
1. Introduction
As humanity settles into the second decade of the 21
st
Century, science continues to press
forward with new advances that alter our experiences on a daily basis. The fields of
medicinal and pharmaceutical chemistry are no different, with new medicines becoming
available to treat the most threatening and problematic maladies of the day. Although the
landscape of drug discovery and the pharmaceutical industry continue to change, particularly
with the vibrant increase in new types of large molecule medicinal agents, small molecule
chemistry is likely to continue to play a critical role in the discovery of new active
pharmaceutical ingredients (API) well into the future. Therefore, it is critical that academic
chemists continue to develop thoughtful strategies, implement sound tactical maneuvers, and
invent robust new technologies for the synthesis of biologically rich, complex small
molecules that will allow medicinal chemists to explore new molecular space with
functional compounds having better properties.
For many years, medicinal chemists have focused attention on achiral aromatic and
heteroaromatic molecules as potential drug candidates.
1
This is in part due to the relative
ease of their preparation, especially since the emergence of cross-coupling chemistries and
parallel synthesis, and their biased population in screening suites at most companies. While
many of such compounds have been developed into successful drugs, their lack of
stereochemistry presents a number of drawbacks at a fundamental level. First, achiral or
“flat” molecules occupy only a small fraction of chemical space. From a structural diversity
perspective, a vast number of possibilities have not been explored. Second, the two-
dimensional nature of aromatic molecules implies that their interaction with target proteins,
which have a three-dimensional structure, will be limited. Therefore, high selectivity for
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binding to the desired protein (for instance) over undesired ones is difficult to achieve, and
side effects such as cytotoxicity often pose a challenge. Finally, polyaromatic molecules tend
to interact strongly with one another due to
π
-stacking, thereby resulting in low solubility
and poor bioavailability.
A promising solution to the issues raised above is to incorporate sp
3
-hybridized carbon
stereocenters into the molecule. This topic has been the subject of recent review articles and
essays.
2
In particular, quaternary stereocenters, which bear four different carbon substituents
at the four vertices of a tetrahedron, add greatly to the three-dimensionality of a molecule.
However, construction of quaternary stereocenters via chemical synthesis is extremely
challenging.
3
While 21 compounds out of the top 200 drugs by US retail sales in 2012
4
have
quaternary stereocenters (>10%, examples shown in Figure 1), all of those structures are
derived from natural products. These include terpenoid (
1
–
5
and
9
) and morphine (
6
–
8
)
derivatives, where the quaternary stereocenters are made by nature and the API is typically
produced by peripheral derivatization.
Within those 200 top pharmaceuticals, none have a
quaternary stereocenter built by chemical synthesis
. This dichotomy reflects the paucity of
synthetic methods available for the construction of quaternary stereocenters and
consequently the lack of their applications in drug discovery.
Traditional chemical approaches to quaternary stereocenters include the Claisen
rearrangement
5
and the Diels–Alder reaction.
6
While these reactions are well established,
the formation of the quaternary stereocenter is often accompanied by formation of other
stereocenters nearby. From a drug discovery perspective, this potentially introduces
unnecessary complexity, collaterally obscuring structure-activity relationship (SAR) studies.
Construction of a single quaternary stereocenter in a simple molecular scaffold is much
more desirable. Most critical would be to develop robust methods that allow one to perform
rigorous SAR studies while maintaining the quaternary center as a constant.
During the past decade, our research group has strategically tackled this problem by
implementing an array of orthogonal approaches. The most well studied tactics that have
emerged from our laboratories involve the alkylation of 3-halooxindole electrophiles, the
conjugate addition of boronic acids to cyclic enones, and the allylic alkylation of enolates. In
all three approaches, we have achieved catalytic asymmetric construction of quaternary
stereocenters in high yield and enantioselectivity with broad substrate scope. We believe that
these methods will greatly expand the medicinal chemist’s synthetic toolbox and facilitate
access to potential drug candidates containing quaternary stereocenters.
2. Enantioselective syntheses of C(3) all carbon quaternary centers on
oxindoles by alkylation of 3-bromooxindoles
3,3-Disubstituted oxindoles and their derivatives are widely encountered in numerous
biologically active natural products
7
and pharmaceutical compounds.
8
A considerable
amount of effort has thus been devoted toward the construction of 3,3-disubstituted
oxindoles over the past decade.
9
,
10
However, a non-traditional use of the oxindole core as an
electrophile rather than as a nucleophile toward the catalytic enantioselective generation of
C(3) quaternary substituted oxindoles was unprecedented and discovered by our laboratory.
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In 2007, we reported a method for the construction of 3,3-disubstituted oxindoles in good
yields by alkylation of malonate nucleophiles with 3-halooxindoles as electrophiles,
presumably via indolones
11
(Scheme 1A).
11
Additionally, by employing these mild
conditions, we could access the core structures of the complex polycyclic alkaloid natural
products communesin F (
19
) and perophoramidine (
20
, Scheme 1B).
12
In view of these
promising results, we turned our attention to the asymmetric synthesis of C(3) all-carbon
quaternary substituted oxindoles.
13
We envisioned that employing a chiral Lewis acid
catalyst would facilitate an asymmetric variant of our alkylation reactions under mild basic
conditions. Gratifyingly, we found that smooth enantioselective alkylation of 3-
bromooxindole by malonates was achieved in good yields and high enantioselectivities by
implementing a chiral Cu•BOX catalyst with a weakly coordinating counter ion such as
SbF
6
(Table 1). A variety of substituted alkyl chain lengths were tolerated in the chemistry,
as were numerous functional groups. Additionally, 3-aryl-3-chlorooxindoles were also
alkylated to produce the corresponding 3,3-disubstituted oxindoles in good yields and high
enantioselectivities. Our method stands as one of the only that allows the preparation of both
C3-alkyl and C3-aryl quaternary oxindoles with a single catalyst system.
Mechanistically, we envision that prochiral indolone
11
is likely to be an intermediate, since
racemic starting materials remain throughout the course of the reaction and are converted to
products of high ee (Scheme 2A), and alkylation reactions employing
N
-Me oxindole
21
as
electrophiles are unsuccessful under our standard conditions (Scheme 2B).
3. Palladium-catalyzed asymmetric conjugate addition of arylboronic
acids to cyclic enones to furnish benzylic quaternary centers
Although the alkylation of malonate nucleophiles to halooxindoles produces a quaternary
benzylic carbon stereocenter, it does so in a very specialized system, the 3,3-disubstituted
oxindole series. In order to produce benzylic quaternary centers in a more general way, we
turned to the catalytic asymmetric conjugate addition of a carbon-based nucleophiles to
β
-
substituted
α
,
β
-unsaturated carbonyl acceptors.
14
For transition metal approaches, there
have been two successful major catalytic systems, copper and rhodium. To date, most
nucleophiles employed in copper-catalyzed conjugate additions are highly reactive
organometallic species such as diorganozinc,
15
triorganoaluminum,
16
and organomagnesium
reagents.
17
The air- and moisture-sensitive nature of these nucleophiles requires strictly
anhydrous reaction conditions. On the other hand, air-stable organoboron reagents have been
used in rhodium-catalyzed conjugate additions,
18
although there are relatively few examples
of quaternary stereocenter formation.
19
In one report, it was shown that sodium
tetraarylborates and arylboroxines could add to
β
,
β
-disubstituted enones to deliver
β
-
quaternary ketones.
20
From a practical standpoint, using commercially available arylboronic
acids as nucleophiles will make conjugate addition a much more valuable method for
quaternary stereocenter generation. Additionally, the ultra-high cost of Rhodium can often
be prohibitive. As a remedy for these substantial hurdles, we embarked on a program to
develop Pd catalysts that could be employed with aryl boronic acids for this purpose.
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Palladium-catalyzed conjugate addition of arylboronic acids to enones has been widely
studied and has led to development of addition reactions that form enantioenriched tertiary
stereocenters.
21
More recently, Lu reported a bipyridine-palladium complex-catalyzed
conjugate addition to form quaternary stereocenters in racemic form.
22
We envisioned that
by using chiral ligands, enantioselective formation of quaternary stereocenters might be
achieved.
23
With 3-methyl-2-cyclohexenone and phenylboronic acid as model reactants, we
examined a range of reaction parameters, and discovered that a combination of easily
accessible chiral pyridinooxazo-line (PyOx) ligand, a commercial palladium(II)
trifluoroacetate precatalyst, and 1,2-dichloroethane as solvent provided the desired
β
-
quaternary ketone in high yield and excellent ee. Notably, the reaction was not sensitive to
oxygen or moisture, and thus could be performed under ambient atmosphere without the
need for anhydrous solvents.
With the optimal conditions in hand, we explored the substrate scope of palladium-catalyzed
conjugate addition of arylboronic acids to cyclic enones (Table 2). In addition to a variety of
substituents on the aromatic ring of the boronic acid, 5-, 6-, and 7-membered cyclic enones
are all competent substrates for the reaction. Enones bearing more complex substituents at
the
β
-position also undergo conjugate addition smoothly to afford the corresponding
β
-
quaternary ketones in good yields and good to high ee.
During scale-up studies, we found that addition of water was necessary for the complete
conversion of starting material (Scheme 3). With 5 equiv of water, a 22 mmol scale reaction
proceeded smoothly to furnish 3-methyl-3-phenylcyclohexanone (
33
) in 97% yield and 91%
ee. Further investigation revealed that addition of water and ammonium
hexafluorophosphate had a synergistic effect in increasing reaction rate. Thus, more
challenging substrates such as
ortho
-substituted arylboronic acid could also be employed in
conjugate addition to give the desired products in much better yields compared with the
previous conditions (Table 3).
24
Finally, a series of experimental and computational mechanistic studies revealed that a likely
mechanistic path for the reaction is shown in Scheme 4.
24
The catalytic cycle consists of
transmetalation from boron to palladium, insertion of the enone substrate into the arylmetal
bond, and protonolysis of the resulting palladium-enolate
30
. These investigations suggest
that the bond-forming palladium species is an arylpalladium(II) cation (
28
), and
enantioselectivity is governed by steric repulsions between the
t
-Bu group of the chiral
ligand and the
α
-methylene hydrogens of the cyclohexenone substrate.
4. Palladium-Catalyzed Enantioselective Allylic Alkylation of Prochiral
Enolates
The first two sections of this manuscript discuss benzylic quaternary centers, yet a
potentially greater challenge to asymmetric catalysis lies in bond forming chemistries that
have no proximal aromatic groups. It is often the case that asymmetric reactions may
function at benzylic positions and then fail upon extension to the alkyl variant. For the
construction of quaternary centers, the case is no different. It was precisely this limitation,
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and our concomitant efforts in the context of a multi-step synthesis, that guided our entry
into this entire field, more than a decade ago.
25
Palladium-catalyzed asymmetric allylic alkylation is a powerful C–C bond forming process
that allows for the construction of stereogenic centers.
26
A typical catalytic cycle involves
the oxidative generation of a
π
-allylpalladium intermediate from an allyl electrophile,
followed by nucleophilic attack on the allyl terminus, resulting in reduction of the metal
center (Scheme 5). The pioneering earlier works of Trost,
27
Helmchen,
28
and others focused
mainly on prochiral allyl electrophiles. Although this reaction mode enjoys success with a
broad range of substrates and has found numerous applications in natural products synthesis,
it typically produces only tertiary stereocenters. Formation of quaternary stereocenters by C-
nucleophilic addition to prochiral allyl electrophiles has been carried out with other metals,
such as copper.
29
Another mode of reactivity makes use of a prochiral nucleophile. A quaternary stereocenter
may be formed if the nucleophile possesses three distinct substituents. One typical example
of such nucleophiles is a tetrasubstituted enolate, generated by deprotonation of a carbonyl
compound. However, position-selective enolate generation can be particularly challenging if
the carbonyl compound bears multiple, similarly acidic
α
-protons. For example,
deprotonation and alkylation of nonsymmetrical ketones generally lead to an intractable
mixture of positional isomers (Scheme 6A). To address this selectivity issue, two strategies
have been classically pursued. One of them installs a blocking group at the undesired
α
-
position (Scheme 6B).
30
The other strategy introduces an electron-withdrawing group at one
of the
α
-positions to dramatically lower its p
ft
a and stabilize the enolate thus formed
(Scheme 6C).
31
Although these tactics circumvent the positional selectivity problem, they
require additional functional groups that potentially need removal or manipulation, thus
reducing overall efficiency and synthetic utility.
We were drawn to the pioneering work of Tsuji to provide an alternative solution to this
position selectivity problem in the context of enantioselective catalysis. In the early 1980s,
the Tsuji group reported the non-enantioselective allylic alkylation of silyl enol ethers, enol
carbonates, and
β
-ketoesters derived from nonsymmetrical, nonstabilized ketones, in the
presence of catalytic palladium and phosphine ligand (Scheme 7).
32
The first substrate class
involves separate nucleophiles and electrophiles (Scheme 7A), while the other two classes
build the latent enolate nucleophile and the allyl electrophile into one molecule (Scheme 7B
and C). The Tsuji allylic alkylation furnishes simple
α
-quaternary ketones with high
positional fidelity, and the reaction proceeds under mild and nearly neutral conditions, with
no exogenous base required. Despite these important advantages, the Tsuji allylic alkylation
saw little application in organic synthesis for two decades and no asymmetric version was
known until our first report in 2004.
33
We became interested in developing an enantioselective variant of the Tsuji allylic alkylation
because of its regiochemical fidelity and the synthetic utility of its products. We envisioned
that a chiral phosphine ligand might impart asymmetric induction in the reaction, leading to
preferential formation of one of the enantiomers. With allyl enol carbonate
33
as substrate,
we examined a number of chiral bidentate phosphine ligands of various scaffolds and
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different chelating atoms and were pleased to discover that the phosphinooxazoline ligand
(
S
)-
t
-Bu-PHOX (
36
) provided excellent reactivity and high enantioselectivity (96% yield,
88% ee; see Scheme 8).
Since this initial discovery, we have intensely investigated the scope of this catalysis and
found it to be extensive. From a practical standpoint, an important finding was our ability to
initiate the chemistry starting from a range of substrate classes. Specifically, in addition to
the prototypical enol allyl carbonate, silyl enol ethers, allyl
β
-ketoesters, allyl enol ethers,
and trimethyl silyl ethyl keto esters can serve as nearly equivalent masked enolate substrates
(Figure 2). The electrophilic allyl unit can bear carbonates, acetates, sulphonates, and in
some instances even halides as the leaving group. The great flexibility in substrate choice
allows for strategic implementation in the context of multi-step synthesis, with each
substrate class engendering different and unique tactical advantages.
A wide array of quaternary ketones with various scaffolds and substituents can be accessed
through our allylic alkylation chemistry with high yield and enantioselectivity (Table 4).
33
,
34
Substitutions at the
α
-position, the 2-allyl position, and on the ring are all well tolerated.
Substrates with seven- and eight-membered rings undergo the alkylation reaction smoothly.
In addition to quaternary stereocenters, fully substituted tertiary centers can also be built by
the reaction.
35
During our investigations, we became aware of the ligand electronic effects on reaction rate
and selectivity. In many cases, the electron-deficient phosphinooxazo-line ligand (
S
)-(CF
3
)
3
-
t
-Bu-PHOX (
37
, Table 5) lead to faster reaction rates and higher enantioselectivities, as
compared with the standard (
S
)-
t
-Bu-PHOX ligand. This modification of ligand electronics
allowed us to improve the reaction’s performance with more challenging classes of
substrates such as cyclobutanones
36
and lactams.
37
Fully substituted tertiary carbonyl
compounds, such as morpholinones,
37
α
-fluorolactams,
37
and piperazines
38
can all be
obtained through this chemistry.
A mechanistic rationale has been proposed for the catalytic cycle (Scheme 9). Oxidative
addition of Pd(0) to the allyl–O bond of
34
generates complex
39
, which undergoes
decarboxylation to form allyl palladium enolate
40
, a key intermediate that can be formed
from other starting materials such as silyl enol ether
31
and allyl enol carbonate
33
.
Reductive elimination furnishes quaternary ketone product (–)-
35
and regenerates the active
Pd(0) catalyst
38
.
For the past decade, other labs have also contributed significantly to the field with related
methods. Trost reported related palladium-catalyzed asymmetric allylic alkylation using a
C
2
-symmetric diamine-based ligand.
39
Nakamura and Paquin each expanded the scope of
our method for the enantioselective synthesis of
α
-fluoroketones using the Pd/(
S
)-
t
-Bu-
PHOX catalyst system.
40
Tunge employed the same catalyst/ligand combination for the
deacylative allylic alkylation of ketones.
41
The requisite allyl palladium enolate species can
also be generated by fragmentation of fused 5–4 ring systems
42
(Scheme 10A) or copper-
catalyzed conjugate addition of silanes to enones (Scheme 10B).
43
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Since the reaction involves an enolate nucleophile, we envisioned trapping it with
electrophiles other than the allyl fragment. Such electrophiles need to meet two
requirements: 1) they do not interfere with oxidative addition or enolate generation; and 2)
their reaction with the enolate is faster than direct enolate allylic alkylation. After
examination of various carbon electrophiles, we found that arylidenemalononitrile-type
Michael acceptors exhibited desired reactivity and produced cyclic ketones bearing adjacent
quaternary and tertiary stereocenters (Scheme 11).
44
5. Iridium-Catalyzed Allylic Alkylation for the Construction of Vicinal
Quaternary and Tertiary Stereocenters
Based on the intriguing diastereochemical issues encountered in the Pd-enolate trapping
chemistry, we became interested in other methods for direct generation of vicinal
quaternary-tertiary relationships. Recently, by employing prochiral
α
-substituted cyclic
β
-
ketoester enolates as nucleophiles, we developed an Ir-catalyzed direct enantioselective
allylic alkylation reaction for the construction of vicinal quaternary-tertiary arrays.
45
,
46
We
explored the reaction with commonly used iridium catalyst systems, derived from
[Ir(cod)Cl]
2
and phosphoramidite ligands. The catalyst derived from Feringa ligand (
L1
)
47
affords the desired branched product in an equal amount of two diastereoisomers (1:1 dr),
although the ee of the isomers are nearly perfect (96% and 99% ee, respectively; see Scheme
12).
48
In contrast, the [Ir(cod)Cl]
2
•
N
-arylphosphoramidite (
L3
) complex
49
was found to
furnish the desired product in 98% ee, >20:1 dr and excellent branched to linear ratio.
The reaction proceeds with high yield and selectivity using a wide range of substrates
variable on the enolate portion as well as the electrophile (Table 6). With further exploration,
we found that a modified protocol is amenable to acyclic
β
-ketoesters as well, again with
tolerance to a wide array of substituent groups and functionality (Table 7).
50
Combining our fluoride-triggered decarboxylative allylic alkylation
51
and the iridium
chemistry together, we have developed a sequential double allylic alkylation procedure to
selectively program the diastereomer that is furnished within the stereochemical dyad. We
found that 2-(trimethylsilyl)ethyl
β
-ketoester substrates successfully engage in iridium-
catalyzed allylic alkylation to generate the desired product with excellent regio- and
enantioselectivity. Subsequently, treatment of the product (
44
) with allyl methyl carbonate
and catalyst derived from Pd
2
(dba)
3
and PHOX ligand (
L4
), in the presence of
tetrabutylammonium difluorotriphenylsilicate (TBAT), generated the desired dialkylated
α
-
quaternary ketone
45B
in good yield and diastereoselectivity (Table 8, entry 1). Through
choice of ligand, we can alter the selectivity to favor the ketone
45A
in high dr (12:1–18:1)
and yield (80–87%) with several 2-substituted allyl carbonates (entries 2–4).
6. Conclusions
The development of a suite of catalytic asymmetric transformations by our group for the
preparation of quaternary stereocenters provides access to a broad range of enantioenriched,
high-value, small molecule building blocks (Figure 3). We have developed methods that
readily produce 3,3-disubstituted oxindoles,
β
-quaternary ketones,
α
-quaternary ketones,
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and
α
-quaternary lactams. These building blocks can be further derivatized to a much larger
collection of compounds bearing quaternary stereogenicity. We anticipate that the synthetic
methods developed by our group and the advancements that synthetic chemists are making
as a whole toward the synthesis of challenging stereochemically rich molecules will find
increasing future application in drug discovery and design. These methods move us into
previously unexplored chemical space that may be brought to bear on problems of a
medicinal nature, with potential enhancements in biochemical, pharmacological, and
physiological properties.
ACKNOWLEDGMENT
The authors are indebted to the efforts of many members of the Stoltz Research Group whose dedicated efforts
produced the chemistry described within this account. For financial support, we thank NIH-NIGMS
(R01GM080269), Amgen, the Gordon and Betty Moore Foundation, Caltech, and the Resnick Sustainability
Institute at Caltech (graduate fellowship to Y.L.). S.-J.H. thanks Fulbright (Foreign Student Program, No.
15111120) and the Ilju Foundation of Education & Culture (Predoctoral Research Fellowship) for financial support.
Shanghai Institute of Organic Chemistry (SIOC) is thanked for a postdoctoral fellowship to W.-B. L.
Biographies
Yiyang Liu
received his B.S. degree in Chemistry from Peking University in 2010 under the
direction of Prof. Jianbo Wang and Prof. Yan Zhang. He then moved to the California
Institute of Technology and began his doctoral studies under the guidance of Professor Brian
M. Stoltz. His graduate research focuses on chemical synthesis using renewable resources.
Seo-Jung Han
graduated with a B.S. in chemistry from Sogang University in 2008. She
received her M.S. degree in 2010 from Sogang University under the direction of Professor
Duck-Hyung Lee. She then moved to Caltech and began her doctoral studies under the
guidance of Professor Brian M. Stoltz. Her graduate research focuses on total synthesis of
complex polycyclic natural products.
Wen-Bo Liu
was born in China and he received his Bachelor’s Degree in Chemistry from
the Nankai University in 2006. He obtained his Ph.D. in organic chemistry (2011) from the
Shanghai Institute of Organic Chemistry (SIOC) under the supervision of Professor Li-Xin
Dai and Professor Shu-Li You. Then he joined the laboratory of Professor Brian M. Stoltz at
Caltech as a postdoctoral scholar, working on asymmetric catalysis and sustainable
chemistry.
Brian M. Stoltz
was born in Philadelphia, PA in 1970 and obtained his B.S. degree from the
Indiana University of Pennsylvania in Indiana, PA. After graduate work at Yale University in
the labs of John L. Wood and an NIH postdoctoral fellowship at Harvard with E. J. Corey he
took a position at the California Institute of Technology. A member of the Caltech faculty
since 2000, he is currently Professor of Chemistry. His research interests lie in the
development of new methodology for general applications in synthetic chemistry.
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