Palladium(II)-catalyzed enantioselective C(sp3)-H activation using a chiral hydroxamic acid ligand

Article abstract of DOI:10.1021/ja504196j

An enantioselective method for Pd(II)-catalyzed cross-coupling of methylene β-C(sp³)-H bonds in cyclobutanecarboxylic acid derivatives with arylboron reagents is described. High yields and enantioselectivities were achieved through the development of chiral mono-N-protected α-amino-O- methylhydroxamic acid (MPAHA) ligands, which form a chiral complex with the Pd(II) center. This reaction provides an alternative approach to the enantioselective synthesis of cyclobutanecarboxylates containing α-chiral quaternary stereocenters. This new class of chiral catalysts also show promises for enantioselective β-C(sp³)-H activation of acyclic amides.

Full text of DOI:10.1021/ja504196j

Article
pubs.acs.org/JACS
Palladium(II)-Catalyzed Enantioselective C(sp3)−H Activation Using a
Chiral Hydroxamic Acid Ligand
Kai-Jiong Xiao, David W. Lin, Motofumi Miura, Ru-Yi Zhu, Wei Gong, Masayuki Wasa, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: An enantioselective method for Pd(II)-catalyzed
cross-coupling of methylene β-C(sp3)−H bonds in cyclobutanecar-
boxylic acid derivatives with arylboron reagents is described. High
yields and enantioselectivities were achieved through the develop-
ment of chiral mono-N-protected α-amino-O-methylhydroxamic acid
(MPAHA) ligands, which form a chiral complex with the Pd(II)
center. This reaction provides an alternative approach to the
enantioselective synthesis of cyclobutanecarboxylates containing α-
chiral quaternary stereocenters. This new class of chiral catalysts also
show promises for enantioselective β-C(sp3)−H activation of acyclic amides.
broadly applicable methods for enantioselective functionaliza-
tion of less reactive C(sp3)−H bonds have remained elusive. To
address this issue, the design and synthesis of novel chiral
ligands are currently needed.
1. INTRODUCTION
Enantioselective functionalization of prochiral unactivated C−
H bonds remains a significant challenge. Although carbenoid
and nitrenoid insertion1,2 as well as metal insertion3 processes
have been developed to enantioselectively functionalize
prochiral C−H bonds, the scope of substrates and trans-
formations falls short of the standard demonstrated in other
areas of asymmetric catalysis. In particular, both intra-4,5 and
intermolecular6−13 enantioselective C−H activation reactions
are still limited to a few classes of substrates. Alternative
approaches of C−H activation followed by asymmetric
carbometalation or hydrometalation to construct chiral centers
have also met with difficulties.14
Enantiopure cyclobutanes are important structural features
found in many bioactive natural products (Figure 1).19 Many
Building on the stereomodel of palladium-catalyzed diaster-
eoselective C−H oxygenation,15 our laboratory has further
developed diverse enantioselective C(sp2)−H functionalization
reactions that include cross-coupling with organoboron
reagents,7 olefination,8 oxidation,9 and iodination10 using chiral
mono-N-protected amino acid (MPAA) ligands. The ability of
MPAA ligands to accelerate or enable16 palladium(II)-catalyzed
C−H functionalization reactions is crucial for achieving high
enantioselectivities. This approach has also been applied to the
enantioselective functionalization of prochiral C(sp3)−H
bonds. Using a MPAA ligand, the first intermolecular example
was reported for the alkylation of methyl C−H bonds in 38%
yield and 37% ee.7a This was later followed by the cross-
coupling of methylene C−H bonds in cyclopropanecarboxylic
acid derivatives with arylboron reagents.11 Keys to the
development of this method were the use of an electron-
deficient amide as a weakly coordinating directing group17 on
the cyclopropane substrate and development of a novel chiral
MPAA ligand, featuring a bulky and electron-deficient
carbamate which was essential for achieving high enantiose-
lectivity. However, this method was limited to the functional-
ization of relatively acidic18 cyclopropyl C−H bonds, and more
Figure 1. Natural products containing cyclobutanes with chiral
quaternary stereocenters.
methods have been developed for the asymmetric synthesis of
chiral cyclobutanes.20 However, the enantioselective construc-
tion of cyclobutanes with chiral quaternary stereocenters21 is
still limited.20a,b Although elegant methods to construct
quaternary stereocenters on cyclobutyl rings have been recently
reported by Toste20d and Stoltz,20f but these methods are
applicable to the synthesis of cyclobutanones only. We
envisioned that a Pd(II)-catalyzed enantioselective C−H
functionalization of cyclobutanecarboxylic acid derivatives
could offer a new and complementary method.22 Herein we
report the first example of enantioselective coupling of
cyclobutanes with arylboron reagents using a chiral mono-N-
protected α-amino-O-methylhydroxamic acid (MPAHA) ligand
Received: April 30, 2014
© XXXX American Chemical Society
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(Scheme 1), providing a new route for the synthesis of
cyclobutanes with chiral quaternary stereocenters. The
acid substrates,11 gave a significantly lower yield (37%) and
enantioselectivity (32% ee) with the cyclobutanecarboxylic acid
substrate 1a.
Scheme 1. Enantioselective C(sp3)−H Activation via
Desymmetrization of Prochiral C−H Bonds
Reasoning that modifying the electronic property of the
ligand might enhance the stereoselection, we sought to replace
the anionic carboxylate group of the ligand with a more Lewis
basic counterpart. Inspired by our previous finding that the O-
methylhydroxamic acid group is highly efficient in facilitating
Pd(II)−catalyzed C−H bond activation,23,24 we converted N-
Boc-leucine to the corresponding O-methylhydroxamic acid L7.
The stronger coordination between this ligand and the Pd(II)
center could also further rigidify the transition state and
improve the stereoselection. We were pleased to observe that
L7 in fact provided a significant boost in enantioselectivity
(79% ee). This motivated us to screen other O-alkylhydroxamic
acids; however, increasing the steric bulk of hydroxamate
protecting group (L8−9) led to a marked decrease in
enantioselectivity.
To further explore the effect of ligand structure on yield and
enantioselectivity, a wide range of MPAHA ligands was
prepared (Table 2). A number of different amine protecting
groups were screened (L10−14); however, only reductions in
enantioselectivities were observed. Ligands containing different
α-substituents were also prepared and screened. Ligands
featuring aromatic side chains appeared to give the superior
enantioselectivities (L18 and L19), so a series of different
aromatic side chains were screened (L20−25, see Supporting
Information (SI) for ligand screening data). Remarkably, the
(2,6-diphenyl)phenylalanine O-methylhydroxamic acid ligand
L22 gave a significant boost to both yield and ee. Since this
type of ligands can be readily synthesized by our ortho-C-H
coupling reaction directed by the sulfonamide group (see SI),
we prepared various 2,6-disubstituted phenylalanine-derived
ligands (L22−25) for optimization. Of the ligands prepared,
the [2,6-di(4-fluorophenyl)]phenylalanine O-methylhydroxa-
mic acid ligand L25 gave the best yield and enantioselectivity
of 67% and 88%, respectively. The use of the parent amino acid
ligand bearing the same backbone as L25 gave significantly
lower yield and ee (38% yield, 45% ee), demonstrating the
distinct property of hydroxamic acid ligands for inert C(sp3)−
H activation.
feasibility of using this ligand to achieve enantioselective
C(sp3)−H activation of prochiral gem-dimethyl groups is also
demonstrated.
2. RESULTS AND DISCUSSION
We began our studies by investigating the reactivity of 1-ethyl-
1-cyclobutanecarboxylic acid derivative 1a with an electron-
deficient amide directing group. Initially we focused on the C−
H cross-coupling reactions with phenylboronic acid pinacol
ester using mono-N-protected amino acid (MPAA) ligands
(Table 1). Modest yields and enantioselectivities of the C−H
coupling reactions were obtained using commercially available
MPAA ligands such as N-Boc-leucine (L1−5). Surprisingly,
chiral MPAA ligand L6, which gave enantioselectivities in
excess of 90% ee with a broad range of cyclopropanecarboxylic
a b
,
Table 1. Screening of Ligands
Encouraged by the improved yields and ee’s using this new
hydroxamic acid ligand, we began to systematically optimize the
reaction conditions. Among the bases screened, sodium
carbonate gave the best yield and enantioselectivity (see
Table S1). Examination of reagent stoichiometries led to the
observation that 2.5 equiv of silver(I) carbonate gave the
optimum yield and enantioselectivity (Table S2). Solvent
effects and palladium source were also examined to reveal that
2-methyl-2-butanol (t-AmylOH) and palladium(II) acetate
were the optimal solvent and palladium source (Tables S3
and S4). Finally, a screen of amide directing groups found that
the 4-cyano-2,3,5,6-tetrafluoroaryl group (ArF) gave the best ee
(Table S5). Altogether, these optimized reaction conditions
resulted in cross-coupling yield of 75% and enantioselectivity of
92% ee.
With the optimized reaction conditions in hand, we explored
the substrate scope of this method (Table 3). The reaction was
found to work well with a variety of arylboronic acid pinacol
esters (2a−m). Trifluoromethyl- or fluoro- phenylboronic acid
pinacol esters are amenable to the reaction conditions (2e−g).
Functional groups such as aryl chlorides and bromides (2h, 2i),
esters (2j), ethers (2k), and anilides (2l) are well tolerated.
a
Reaction conditions: substrate 1a (0.1 mmol), Ph−BPin (2.0 equiv),
Pd(OAc)2 (10 mol %), ligand (11 mol %), Ag2CO3 (1.5 equiv),
Na2CO3 (2.0 equiv), BQ (0.5 equiv), H2O (5.0 equiv), t-AmylOH (0.5
b
mL), N2, 70 °C, 24 h. The yield was determined by 1H NMR analysis
of the crude product using CH2Br2 as an internal standard. The ee
values were determined by HPLC analysis on a chiral stationary phase.
B
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a b
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a b
,
,
Table 2. Development of MPAHA Ligands
Table 3. Substrate Scope
a
b
Reaction conditions as described in Table 1. The yield and ee were
determined as described in Table 1.
Although the presence of an α-hydrogen to amide carbonyl
group decreased the yield and ee (2c), the reaction worked well
with various 1-substituted 1-cyclobutanecarboxylic acid deriv-
atives (2n−s). The enantioselective cross-coupling of n-butyl
substituted substrate gave 72% yield and 88% ee (2n). Sterically
hindered 1-(isopropyl)-1-cyclobutane (2o) and 1-(cyclopen-
tyl)-1-cyclobutane (2p) substrates are functionalized in high
yield and ee, demonstrating that this reaction can be used to
prepare highly sterically congested quaternary all-carbon
stereocenters on cyclobutanes. Heteroatom substituents such
as halogens (2q), oxygen (2r), and nitrogen (2s) are tolerated
on the exocyclic alkyl side chain of the cyclobutane substrate.
These substituents are amenable for further synthetic
elaborations thereby broadening the diversity of the products.
Although the current scope of the cyclobutane substrates for
C−H activation is still limited to relatively simple scaffold,
asymmetric syntheses of these products via other methods
would require the use of a wide range of substrates to
incorporate different aryl groups.
a
Reaction conditions: substrate 1 (0.1 mmol), Ar−BPin (2.0 equiv),
Pd(OAc)2 (10 mol %), L25 (11 mol %), Ag2CO3 (2.5 equiv), Na2CO3
(2.0 equiv), BQ (0.5 equiv), H2O (5.0 equiv), t-AmylOH (0.5 mL),
b
N2, 70 °C, 24 h. Isolated yields. The ee values were determined by
HPLC analysis on a chiral stationary phase.
(Scheme 2). The absolute configuration of 2r was also
determined to be (1R,2R) by X-ray crystallographic analysis,
providing information for understanding the origin of
enantioselectivity (Figure 2).
A preliminary examination of acyclic C(sp3)−H activation
substrates was also conducted using the geminal dimethyl
substrate 4a (Table 4). We found through a preliminary ligand
screening (see SI) that, using the α-amino-O-methylhydroxa-
mic acid ligand L7 and the newly optimized reaction
conditions, cross-coupling of 4a proceeded with an aryltri-
Treatment of 2o with conc. HCl resulted in removal of the
auxiliary to give the carboxylic acid product 3 in 94% yield
C
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Scheme 2. Auxiliary Cleavage
4. EXPERIMENTAL SECTION
General Precedure for the Enantioselective C(sp3)−H
Activation of Cyclobutanecarboxylic Acid Derivatives (Table
3). Substrate 1 (0.1 mmol, 1.0 equiv), Pd(OAc)2 (0.1 equiv), Ar-BPin
(2.0 equiv), L25 (0.11 equiv), Ag2CO3 (2.5 equiv), Na2CO3 (2.0
equiv), BQ (0.5 equiv), H2O (5.0 equiv), and t-AmylOH (0.5 mL)
were added into a 10 mL sealed tube. The reaction vessel was
evacuated and backfilled with nitrogen (×3). The reaction mixture was
heated to 70 °C for 24 h under vigorous stirring. After being cooled to
room temperature, the reaction mixture was diluted with EtOAc and
filtered through a pad of Celite, eluting with EtOAc. The filtrate was
concentrated under vacuum, and the resulting residue was purified by
preparative TLC using EtOAc/hexanes as the eluent to give the
desired product. The ee value was determined on a Hitachi LaChrom
HPLC system using commercially available chiral columns.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. Absolute Configuration of 2r.
ab
,
AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
■
Table 4. Desymmetrization of Prochiral Methyl Groups
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by The Scripps Research Institute
and the National Institutes of Health (NIGMS,
2R01GM084019).
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