Ligand-controlled C(sp3)-H arylation and olefination in synthesis of unnatural chiral α-amino acids

Article abstract of DOI:10.1126/science.1249198

The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp³)-H bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a rare example of catalyst-controlled C(sp³)-H arylation using pyridine and quinoline derivatives: The former promotes exclusive monoarylation, whereas the latter activates the catalyst further to achieve diarylation. Successive application of these ligands enables the sequential diarylation of a methyl group in an alanine derivative with two different aryl iodides, affording a wide range of β-Ar-β-Ar?-α-amino acids with excellent levels of diastereoselectivity (diastereomeric ratio > 20:1). Both configurations of the β-chiral center can be accessed by choosing the order in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables C(sp³)-H olefination of a protected alanine.

Full text of DOI:10.1126/science.1249198

Ligand-Controlled C(sp3)−H Arylation and Olefination in Synthesis of
Unnatural Chiral α−Amino Acids
Jian He et al.
Science 343, 1216 (2014);
DOI: 10.1126/science.1249198
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RESEARCH ARTICLES
action sequence provides an alternative syn-
thetic disconnection to the existing asymmetric
hydrogenation method for the synthesis of chi-
ral b-Ar-b-Ar′-a–amino acids (Fig. 1C) (8–11).
Fundamentally, the development of appropriate
ligands to confer selectivity for primary or sec-
ondary b-C(sp3)–H bonds on a weakly coordi-
nating substrate can greatly improve C(sp3)–H
activation reactions (12–20).
Herein, we report the discovery that a pyridine-
based ligand promotes monoarylation of pri-
mary b-C(sp3)–H bonds exclusively and that a
second, quinoline-based ligand enables intro-
duction of a distinct aryl group via subsequent
secondary b-C(sp3)–H activation in one pot.
The reactions proceed with excellent levels of
diastereoselectivity with respect to the starting
configuration at the a carbon (Fig. 1B). As such,
both configurations at the new b-stereogenic cen-
ter can be constructed by simply choosing the
order of aryl group installation. We further demon-
strate that the use of the quinoline-based ligand
enables the C(sp3)–H olefination of an alanine-
derived substrate to afford olefin-substituted chiral
Ligand-Controlled C(sp3)–H Arylation
and Olefination in Synthesis
of Unnatural Chiral a–Amino Acids
Jian He,* Suhua Li,* Youqian Deng, Haiyan Fu, Brian N. Laforteza, Jillian E. Spangler,
Anna Homs, Jin-Quan Yu†
The use of ligands to tune the reactivity and selectivity of transition metal catalysts for C(sp3)–H
bond functionalization is a central challenge in synthetic organic chemistry. Herein, we report a
rare example of catalyst-controlled C(sp3)–H arylation using pyridine and quinoline derivatives:
The former promotes exclusive monoarylation, whereas the latter activates the catalyst further
to achieve diarylation. Successive application of these ligands enables the sequential diarylation
of a methyl group in an alanine derivative with two different aryl iodides, affording a wide
range of b-Ar-b-Ar′-a–amino acids with excellent levels of diastereoselectivity (diastereomeric
ratio > 20:1). Both configurations of the b-chiral center can be accessed by choosing the order
in which the aryl groups are installed. The use of a quinoline derivative as a ligand also enables
C(sp3)–H olefination of a protected alanine.
ver the past decade, substantial pro-
We reasoned that a ligand-controlled strat- a–amino acids.
gress has been achieved in the palladium- egy could provide an ideal solution for the syn-
catalyzed activation of the inert b-C(sp3)–H thesis of b-Ar-b-Ar′-a–amino acids. Specifically,
A Ligand for Monoarylation
O
bonds of aliphatic carboxylic acid derivatives we envisioned the application of two different Our first challenge in the development of a ver-
using chiral oxazolines (1), the 8-aminoquinoline ligands: one that would selectively promote pri- satile method for the preparation of stereo-defined
auxiliary (2, 3), and a variety of weakly coordi- mary b-C(sp3)–H arylation [without further arylat- b-Ar-b-Ar′-a–amino acids from alanine (Fig. 1B)
nating amide directing groups (4, 5). In partic- ing the remaining, now secondary, b-C(sp3)–H was to achieve selective monoarylation of pri-
ular, the synthesis of unnatural amino acids via bonds] and another that would enable further mary C(sp3)–H bonds without further arylating
the direct b-functionalization of a–amino acids secondary b-C(sp3)–H arylation, thereby intro- the secondary C(sp3)–H bonds. Our group has
has been an area of extensive research since a ducing both aryl substituents successively onto recently focused on the development of sim-
seminal report by Reddy et al. (6). We envi- a single substrate in one pot (Fig. 1B). This re- ple auxiliaries, such as N-methoxyamides and
sioned that a sequential diarylation of alanine
with two different aryl iodides could potentially
provide an efficient route for the preparation of
b-Ar-b-Ar′-a–amino acids containing a b-chiral
center (Fig. 1). Although the more strongly co-
ordinating 8-aminoquinoline auxiliary developed
by Zaitsev et al. (2) is a powerful directing group
for the b-arylation of alanine, this auxiliary pro-
vides predominantly b,b-homo-diarylated products,
which prevents the sequential installation of two
different aryl groups. It is possible to use a spe-
cifically designed 2-methylthioaniline auxiliary
to achieve monoarylation of alanine in mod-
erate yield and then use a different auxiliary to
perform the secondary C(sp3)–H arylation with
a distinct aryl iodide (Fig. 1A) (7). However,
this hypothetical route has not yet been used
for preparing b-Ar-b-Ar′-a–amino acids be-
cause the removal and installation of the second
auxiliary would add three synthetic steps to the
sequence. In addition, the basic reaction condi-
tions used in the first arylation step partially
racemize the amino acid to 90% enantiomeric
excess (7).
The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, CA 92037, USA.
Fig. 1. Methods for synthesizing chiral b-Ar-b-Ar′-a–amino acids. (A) C(sp3)–H activation using
substrate-bound auxiliaries to govern selectivity. NPG, protected amino groups; COX, amides; Me, methyl.
(B) C(sp3)–H activation using catalyst-bound ligands to govern selectivity. (C) Asymmetric hydrogenation.
*These authors contributed equally to this work.
†Corresponding author. E-mail: yu200@scripps.edu
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RESEARCH ARTICLES
perfluorinated arylamides, to direct a wide range mote primary C(sp3)–H activation, thereby allowing full recovery of the remaining starting material
of C(sp3)–H activation reactions by weak coor- for highly monoselective arylation of alanine- (Fig. 2A). Additional attempts to fine-tune var-
dination to palladium catalysts (4, 5). However, derived amide 1.
ious reaction parameters, including increasing
to date we have found that these auxiliaries To obtain preliminary information regarding the catalyst loading to 30 mol %, failed to improve
are incompatible with the functionalization of the reactivity of the CONHArF amide auxiliary the reaction conversion. The low conversion was
the C(sp3)–H bonds of a–amino acids (4, 5). with amino acid substrates, we initiated our ex- found to result primarily from product inhibition
We recently demonstrated that the use of an perimental efforts by studying C(sp3)–H arylation (see supplementary materials: table S2, entry 16).
alkoxypyridine ligand can match the weak co- of 1 under a variety of different reaction con- Alternative aryl iodide coupling partners reacted
ordination of the amide auxiliary (CONHArF) ditions in the absence of an ancillary ligand. in even lower yields (Fig. 2A, 2m to 2p). These
and facilitate secondary C(sp3)–H activation Through extensive screening, we found that the findings point to the need for the identification of
(albeit, with only simple aliphatic amides) (21), use of 20 mol % trifluoroacetic acid (TFA) pre- a ligand that will promote the activation of pri-
indicating that pyridine-based ligands are ca- vented substrate decomposition, which had been mary b-C(sp3)–H bonds exclusively but not the
pable of lowering the transition state energy of observed with 1 under previously developed secondary b-C(sp3)–H bonds in the product. Hence,
C(sp3)–H activation. This finding prompted us basic conditions (21). Under the best conditions a library of pyridine ligands was tested for their
to test a diverse array of monodentate pyridine- from this initial screen, monoarylated product efficiency of promoting monoarylation in the pres-
derived ligands for their ability to selectively pro- 2 could be obtained in 47% yield, along with ence of TFA. Pyridine and 4-dimethylaminopyridine
(L1 and L2) are highly selective for monoaryla-
tion, but neither enhances conversion substantial-
ly relative to the ligand-free catalyst. In contrast,
we found that 2,6-dimethoxypyridine, acridine,
2,6-lutidine, and 2-picoline (L4 to L7) promote
substantially higher conversion, though the use
of L4 to L6 leads to appreciable quantities of
the undesired diarylated product 3 as well. The
2-picoline ligand (L7) seems to possess an op-
timal balance of steric and electronic properties
to provide 2 in high yield with an excellent level
of selectivity for monoarylation [nuclear mag-
netic resonance (NMR) yield of 94%]. The mono-
arylation reaction also proceeded in the presence
of 5 mol % of Pd(TFA)2 and 10 mol % of L7 to
give the desired product 2 in 79% yield (table
S2, entry 4).
The applicability of this ligand-controlled mono-
arylation protocol in the preparation of diverse
chiral b-Ar-b-Ar′-a–amino acids is shown in Fig.
2A: Phenylalanine derivatives with electron-rich
or electron-poor groups in the ortho, meta, or
para positions can be synthesized in high yields.
This reaction is tolerant of halide substituents and
a wide range of polar functional groups. Arylation
with 4-methylthiophenyl iodide also proceeds to
give the arylated product (2p) in a synthetically
useful yield, indicating that the pyridine ligand
is able to out-compete the methylthio group
for coordination at Pd(II). The reaction of 1 with
2-iodonaphthalene to give 2q is particularly
useful, as the resulting product could be applied
to synthesis of bioactive peptides that block cell
cycle progression in HeLa cells (22). Arylation
with disubstituted aryl iodides is also efficient,
giving 2r to 2t in >85% yields.
When conducted at 100°C, these reactions
are typically complete within 20 hours, and no
racemization of the a-chiral center is observed.
Subsequent removal of the auxiliary can be ac-
complished under mild conditions without loss
of enantiomeric purity (Fig. 2B), and the mono-
arylated products are readily converted to the cor-
responding N-fluorenylmethyloxycarbonyl–protected
unnatural amino acids following literature proce-
dures (see supplementary materials). The auxilia-
ry 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline is
readily prepared from octafluorotoluene ($0.47/g)
on a 100-g scale or purchased directly from Aldrich.
Fig. 2. Palladium-catalyzed arylation of primary C(sp3)–H bonds. (A) Ligand-promoted mono-
arylation of auxiliary-substituted alanine. Phth, phthalimido; DCE, 1,2-dichloroethane (B) Removal of amide
auxiliary and determination of enantiomeric purity of N-Phth–protected chiral a–amino acid. Ac, acetyl; RT,
room temperature; ee, enantiomeric excess; HPLC, high-performance liquid chromatography.
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RESEARCH ARTICLES
Due to these practical advantages, we have pre- the use of ligand L10 is crucial to achieve this verted to the biaryl (23). The remaining aryl iodide
pared a variety of monoarylated alanines on a reactivity.
10-mmol scale to facilitate peptide drug discovery
is outcompeted by a large excess of the second
aryl iodide (3 equivalents), thus avoiding par-
ticipation in a second arylation event. This one-
One-Pot Diarylation
in collaboration with Bristol-Myers Squibb (2c to
2e, 2g, 2h, 2j, 2l, and 2r).
Ligands L7 and L10, which enable the arylation pot procedure is successfully applied with both
of primary and secondary b-C(sp3)–H bonds, electron-rich and electron-deficient aryl iodides
respectively, can be employed for the sequential to prepare a variety of diarylated amino acids
A Ligand for Diarylation
We next sought to identify a second ligand that one-pot incorporation of two distinct aryl groups (7a to 7f) in good yields with excellent levels
could promote the subsequent arylation of the onto the b carbon of alanine-derivative 1 (Fig. 4). of diastereoselectivity (24). By simply switch-
secondary b-C(sp3)–H bonds. As previously men- Thus, after the completion of the monoarylation ing the order of the addition of the two different
tioned, our recently disclosed procedure for the of 1 with an aryl iodide using L7, we can add aryl iodides, the inverse configuration at the
ligand-promoted arylation of secondary C(sp3)–H L10 and a second aryl iodide to provide a b-Ar- b-stereogenic center can be obtained, as shown
bonds under basic reaction conditions (21) is b-Ar′-a–amino acid. The aryl iodide (1.5 equiv- with 7e and 7f (absolute configuration of 7f was
not compatible with amino acid substrates. How- alents) used in the first step is mostly incorporated confirmed by x-ray crystallography). When the
ever, the formation of minor amounts of the into the product, with small amount being con- sequential hetero-diarylation of 1 was conducted
diarylated product 3 from amide 1 with ligand
L4 (13% yield, Fig. 2A) suggested that these
new conditions could be effective for secondary
b-C(sp3)–H bond arylation with an appropriate
ligand. We were pleased to find that the arylation
of phenylalanine-derived amide 2, in the presence
of ligand L4, afforded the desired product 3 in
47% yield. The modest success of this ligand and
our previously reported 2-alkoxylquinoline ligand
L9 (21) led us to explore a variety of electron-rich
2-alkoxylpyridine and 2-alkoxylquinoline ligands
for this secondary C(sp3)–H bond arylation.
A substantial improvement in reaction effi-
ciency using ligand L8 or L9 suggested that the
2-substituted quinoline motif possesses favor-
able steric and electronic properties that promote
C(sp3)–H activation. Next, we examined the im-
pact of further increasing the electron-donating
ability of the alkoxyl group by synthesizing
the tricyclic ligand L10, in which the confor-
mation of the lone pairs on the oxygen atom is
rigidified to favor p-conjugation with the pyr-
idine ring. The use of this new ligand led to a
dramatic improvement in reaction efficiency,
affording product 3 in 92% yield (90% iso-
lated yield). Further modifications of L10 to
weaken or strengthen the coordinating ability
of the quinoline led to a decrease in product
yield (L11 and L12).
Under these optimized reaction conditions,
phenylalanine-derived amide 2 can be arylated
with a broad range of electron-rich and electron-
poor aryl iodides in high yields (Fig. 3A). De-
spite the known steric hindrance associated with
the arylation of secondary C(sp3)–H bonds (3j),
ortho-substituted aryl iodides are also compatible
with this reaction. To demonstrate the general-
ity of this ligand effect for secondary C(sp3)–H
activation, we also performed the arylation of
four representative open-chain and cyclic alkyl
amino acids. Amide substrates derived from
lysine, L-2-aminobutyric acid, 1-aminocyclobutane-
1-carboxylic acid, and 1-aminocyclopropane-1-
carboxylic acid were successfully arylated using
ligand L10 to give the corresponding b-alkyl-b-
aryl-a–amino acid derivatives in good to excel-
lent yields (Fig. 3B). These arylation reactions all
Fig. 3. Palladium-catalyzed arylation of secondary C(sp3)–H bonds. (A) Ligand-promoted
proceeded with high levels of diastereoselectivity.
These aliphatic secondary C(sp3)–H bonds are
arylation of phenylalanine-derived substrate. d.r., diastereomeric ratio. (B) Arylation of alkyl amino
less reactive than benzylic C(sp3)–H bonds, and acid derivatives. R, alkyl.
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in one pot on a 5-mmol scale (2.2 g), the de- afforded synthetically useful yields (Fig. 5A). substrate 1, and we observed efficient reactivity
sired product 7b was isolated in 60% yield.
These heteroaryl-containing unnatural amino acids under slightly modified reaction conditions. The
The superior reactivity of ligand L10 prompted are especially desirable for developing peptide subsequent lactamization in situ also ensured the
us to revisit previously unsuccessful arylation drug molecules.
with heteroaryl iodides. Although secondary
monoselectivity of the reaction. With the use of
established procedures, lactam 8 is converted to
N-Boc–protected product 10 (Fig. 5B). Further
C(sp3)–H arylation of 2 with heteroaryl iodides
Olefination with Ligand L10
proved inefficient, primary C(sp3)–H arylation of We also examined the feasibility of using ligand improvement of this olefination reaction could
1 with pyridyl, indolyl, and thiophenyl iodides L10 to effect the olefination of alanine-derived lead to a useful method for the preparation of
b-olefinated a–amino acids that is complementary
to the asymmetric hydrogenation route (25). The
olefinated product 10 can be subjected to cross
metathesis to afford olefinated products 11 and 12
with high levels of E/Z selectivity or hydro-
genated to provide the corresponding alkylated
product 13 (Fig. 5C).
Mechanistic Studies
Whereas C(sp3)–H arylation with aryl iodides
likely proceeds via a Pd(II)/Pd(IV) catalytic cy-
cle, olefination probably proceeds via a Pd(II)/
Pd(0) redox manifold. The considerable ligand
effect observed in these distinct reaction path-
ways implicates the intimate involvement of
the ligand in the C(sp3)–H cleavage step as the
common step. This is further substantiated by
the intramolecular kinetic isotope effect ob-
served in the arylation reaction, which showed
a noticeable and consistent dependence on the
ligand (without ligand, intramolecular isotope
effect value kH/kD = 6.0; with L7, kH/kD = 8.1;
with L10, kH/kD = 10.7; see supplementary
materials).
To obtain further insights into the coordi-
nation of the substrate and ligands at the Pd(II)
centers, we have successfully characterized the
C–H insertion intermediates (intermediate A and
intermediate B), formed via primary and second-
ary C(sp3)–H activation, respectively (Fig. 6A). The
Fig. 4. Synthesis of b-Ar-b-Ar′-a–amino acids via sequential C(sp3)–H arylations in one pot. formation of these C(sp3)–H insertion intermediates
Fig. 5. Further applications of Pd catalysis with L10. (A) Ligand-enabled
C(sp3)–H arylation with heteroaryl iodides. (B) C(sp3)–H olefination of alanine
derivatives. DCM, dichloromethane; Et, ethyl; Boc, tert-butoxycarbonyl; HMDS,
hexamethyldisilazide. (C) Unnatural a–amino acid elaboration.
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Fig. 6. Mechanistic studies. (A) Synthesis and crystallography of primary and secondary C(sp3)–H activation intermediates. Oak Ridge thermal
ellipsoid plots (30% probability ellipsoids) of intermediate A and intermediate B are shown. (B) Catalytic reactivity of intermediates in C(sp3)–H
arylation reactions.
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Acknowledgments: We gratefully acknowledge The Scripps
Research Institute, the NIH (National Institute of
General Medical Sciences, grant 2R01GM084019),
and Bristol-Myers Squibb for financial support. H.F. is
a visiting scholar sponsored by Sichuan University.
J.H. developed C(sp3)–H arylation and olefination and
conducted most of the experiments; S.L. synthesized
quinoline ligands; Y.D., H.F., B.N.L., and J.E.S. performed
large-scale reactions; A.H. obtained the crystal structures
shown in Fig. 6; and J.-Q.Y. directed the project. Metrical
parameters for the structures of 7f, intermediate A,
and intermediate B are available free of charge from
the Cambridge Crystallographic Data Centre under
reference numbers CCDC-985675, -985676, and
-985677, respectively. A provisional patent application
has been filed and is available under patent application
no. U.S. 61/946165.
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Supplementary Materials
www.sciencemag.org/content/343/6176/1216/suppl/DC1
Supplementary Text
Figs. S1 to S3
Tables S1 to S6
NMR Spectra
References (27–31)
2 December 2013; accepted 19 February 2014
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