PdII-catalyzed enantioselective activation of C(sp 2)-H and C(sp3)-H bonds using monoprotected amino acids as chiral ligands

Article abstract of DOI:10.1002/anie.200801030

(Chemical Equation Presented) The relay of chiral information from the α-carbon atom of the amino acid ligand is believed to be crucial for chiral induction in the Pd^II-catalyzed enantioselective C-H activation/C-C coupling reaction of diphenyl

Full text of DOI:10.1002/anie.200801030

Communications
DOI: 10.1002/anie.200801030
À
C H Activation
II
2
3
À
À
Pd -Catalyzed Enantioselective Activation of C(sp ) H and C(sp ) H
Bonds Using Monoprotected Amino Acids as Chiral Ligands**
Bing-Feng Shi, Nathan Maugel, Yang-Hui Zhang, and Jin-Quan Yu*
Dedicated to Professor E.J.Corey on the occasion of his 80th birthday
À
À
Enantioselective C H activation has been a longstanding
challenge in catalysis and organic chemistry. The insertion of
chiral products with new C C bonds in excellent enantiose-
lectivity [Eq. (1)].
À
metal-bound carbenes or nitrenes into C H bonds has been
employed to develop highly enantioselective carbon–carbon
and carbon–nitrogen bond-forming reactions.[1] The enantio-
3
À
selective lithiation of C(sp ) H bonds adjacent to the nitro-
gen atom in N-tert-butyloxycarbonylpyrrolidine using sec-
BuLi/(À)sparteine has provided a broadly useful method for
3
[2]
À
the differentiation of prochiral C(sp ) H bonds. Investiga-
À
tions into the biomimetic oxidation of C H bonds using chiral
metal–porphyrin complexes[3] and other synthetic catalysts[4]
continue to provide inspiration for the development of
À
methods for the asymmetric oxidation of C H bonds.
À
Remarkable progress in understanding the fundamental
Directed C H activation reactions assisted by functional
[5]
À
mechanisms of C H activation by means of metal insertion
groups within the substrate [Eq. (1)] were selected in this
investigation. Success in asymmetric catalysis using this
approach to control stereoselectivity has previously demon-
strated its advantage and broad utility.[12] We began by
has spurred the development of metal-catalyzed carbon–
carbon and carbon–heteroatom bond-forming reactions in
organic molecules containing functional groups.[6] Such reac-
tions will impact synthetic and medicinal chemistry in the
context of retrosynthetic analysis[7] by providing unprece-
À
À
developing an efficient C H activation/C C coupling reac-
tion using the prochiral substrate 1.[13] We hoped to use this
dented and more efficient strategic disconnections.[8] A major
hurdle remaining in Pd -catalyzed C H activation reactions,
reaction as a model system for enantioselective C H activa-
À
II
À
tion directed by a wide range of functional groups. After
screening various conditions, we found that the coupling of 1
with BuB(OH)2 proceeded via a proposed six-membered
palladacycle to give the desired racemic butylation product 1a
however, is the need for an external ligand that coordinates to
the PdII species and controls the chemo-, regio-, and
À
stereoselectivity of its insertion into C H bonds. With this
in mind, we embarked on the development of a PdII-catalyzed
[Eq. (2)]. Benzoquinone (BQ) is required for the C H
À
À
À
enantioselective C H activation/C C coupling reaction, a
process previously unknown owing to the difficulty in differ-
entiating prochiral C H bonds through metal insertions.
[9–11]
À
Herein we demonstrate a proof of concept by the design of a
PdII/amino acid complex capable of catalyzing asymmetric
2
3
À
À
activation of prochiral C(sp ) H and C(sp ) H bonds to form
[*] Dr. B.-F. Shi, Dr. Y.-H. Zhang, Prof. Dr. J.-Q. Yu
Department ofChemistry
The Scripps Research Institute
La Jolla, CA 92037 (USA)
Fax: (+1)858-784-2409
activation[14] and reductive-elimination steps.[15] Ag2O reox-
idizes the Pd0 species back to PdII to close the catalytic cycle.
The obtained triarylmethane derivatives are widely used in
medicinal and material sciences.[16] Notably, the triaryl-
substituted chiral carbon centers are difficult to make by
current asymmetric methods owing to the lack of sufficient
steric difference between the aryl rings.[17]
We obtained the X-ray crystal structure of the dimeric Pd
complex 2b, which was synthesized by reacting diphenyl(2-
pyridyl)methane (2) with Pd(OAc)2 in CH2Cl2 at 608C
(Scheme 1). The structure of 2b suggested a working model
E-mail: yu200@scripps.edu
N. Maugel
Department ofChemistry
Brandeis University
Waltham, MA 02454 (USA)
[**] We thank The Scripps Research Institute and Brandeis University for
financial support, the Camille and Henry Dreyfus Foundation for a
New Faculty Award, and the A.P. Sloan Foundation for a fellowship
(J.-Q.Y.).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
À
for the chiral recognition of prochiral C H bonds as shown in
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yield and 46% ee (Scheme 2). To gain insight into
the origin of the improved enantioselectivity, we
evaluated ligands 3–6. While the opposite enan-
tioselectivities obtained with the enantiomeric
pair 3 and 5 are expected, the switch of the sense
of chiral induction between 3 and 4 suggests that
the chirality of the a-carbon center plays a
dominant role. Most strikingly, the use of ligand
6 afforded racemic alkylation products which
were not expected from the mechanistic model
shown in Scheme 1.
Based on these experimental data and the
previously established coordination mode
between acetyl-protected amino acids and PdII
metallacycles,[21] we hypothesize that both the NH
moiety and the carboxylate coordinate with the
PdII center in a bidentate manner in the precur-
sors (Scheme 3). Surprisingly, the NH moiety is
1
not deprotonated, as indicated by H NMR data
in the literature.[21] The pyridine from the sub-
strate is likely to coordinate in a trans position
relative to the carbamate nitrogen based on a
known analogous structure.[21] In the cyclopalla-
À
Scheme 1. Proposed working model for the enantioselective C H activation ofa
2
À
prochiral C(sp ) H bond in compound 2.
À
Scheme 1. We propose that enantioselective C H activation
can be achieved by replacing the nonbridging acetates in the
precursor 2a with chiral carboxylates while maintaining the
bridging acetates to preserve the restricted steric environment
necessary for the chiral recognition. The key question,
therefore, became whether the conformation of the coordi-
nated chiral carboxylic acids in 2c would be sufficiently
restricted to lead to good enantioselection. We had some
reason for optimism, since we had previously shown that the
involvement of a trinuclear m-bridging PdII complex with
similar topology was crucial for the diastereoselective iodi-
Scheme 2. Cyclopropane amino acid ligands used for the enantioselec-
tive butylation ofcompound 1.
À
nation and acetoxylation of prochiral C H bonds using a
classical chiral-auxiliary approach.[18] In that example, how-
ever, the chiral influence came from a chiral center in the
functional group of the substrates.
We therefore evaluated a number of commercially
Scheme 3. Key intermediates in the mechanism for the enantioselec-
À
available chiral carboxylates for the enantioselective C H
À
tive C H activation. Boc=tert-butyloxycarbonyl, o-Tol=ortho-tolyl.
activation of substrate 1. Although we were pleased to obtain
selectivities of around 20% ee with 20 mol% of the chiral
carboxylate ligands (see the Supporting Information),
improving upon these results by optimizing reaction con-
ditions or by using other chiral carboxylates or phosphoric
acids proved challenging.[19]
dation step, the driving force to minimize the steric repulsion
between the substitutents on the newly generated chiral
center and the Boc group on the nitrogen center will favor 3a
over 3b when chiral ligand 3 is used. The resulting cyclo-
palladated complexes then react with BuB(OH)2 to give the
enantiomerically pure products and Pd0 which will be
reoxidized to regenerate PdII species for the next catalytic
cycle. It is worth noting that the sense of the chiral induction
could be reversed if the conformation of the cyclic transition
state is drastically different from 3a and 3b. The determi-
nation of the absolute configuration of the products and the
cyclopalladated intermediates will offer further insights into
the origin of the stereoselectivity.
In retrospect, the poor enantioselectivity observed with
chiral carboxylic acids is not entirely surprising since the R*
group is relatively free to rotate. This could lead to different
chiral environments with opposite senses of chiral induction,
thus resulting in the erosion of enantioselectivity. We there-
fore sought to restrict the possible conformations in the
backbone of the chiral carboxylic acids. It has been estab-
lished that adjacent substituents on cyclopropane exert
significant steric repulsion owing to their eclipsed conforma-
tion, which results in effective conformational restriction.[20]
Indeed, butylation of 1 using cyclopropane amino acid 3
under the previously described conditions afforded 1a in 46%
The lack of enantioselectivity with ligand 6 is consistent
with the revised mechanistic model, as the steric difference of
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Communications
the a-carbon in 6a is minimized. Therefore, we reasoned that
following important information consistent with our model.
First, esterification of 7a leads to a complete loss of ee
(entry 12, Table 1). Second, the use of diprotected amino
acids 7d and 7e, or 7 f containing a poor coordinating NHPiv
group, afforded the alkylated product in less than 10% ee
(entries 13–15, Table 1). Third, the reduction in the sizes of
the protecting group from Boc to methoxycarbonyl, acetyl,
and formyl groups resulted in steady decrease of selectivity
(entries 16–18, Table 1).
the use of Boc-protected amino acids could lead to improved
enantioselectivity owing to the larger steric difference
between the a-hydrogen and the side chain. Gratifyingly,
À
À
the asymmetric C H activation/C C coupling reaction of 1 in
the presence Boc-l-leucine 7a gave the alkylation product 1a
in 90% ee and 63% yield (entry 1, Table 1).[22] The Boc-
protected amino acids 8–15 afforded selectivities of 52–
88% ee (entries 2–9, Table 1).
The replacement of the Boc by a methyl group or removal
of the Boc group led to a full recovery of the starting material,
suggesting that an electron-withdrawing group attached to the
N atom is necessary to maintain the electrophilicity of the PdII
Based on this information, we replaced the Boc group in
ligand 7a with a bulkier menthoxycarbonyl group and
discovered that ligands 7k and 7l gave greatly improved
yields and also good ee values (entries 20 and 21, Table 1).
The lack of influence of the chirality of the menthyl group on
À
catalyst for C H activation (entries 10 and 11, Table 1).
Systematic structural modifications of 7a indicated the
Table 1: Inlfuence ofthe ligand on enantioselectivity ofthe butylation of 1.[a]
Entry
1
Ligand
Yield [%][b]
63
ee [%][c]
Entry
12
Ligand
Yield [%][b]
86
ee [%][c]
90
0
2
3
60
69
52
70
13
14
74
63
7
6[d]
4
5
6
85
60
66
72
80
81
15
16
17
58
53
74
7
6
80
7
8
9
83
47
65
83
85
88
18
19
88
89
79
85
20
21
87
91
85
87
10
11
n.r.[e]
n.r.[e]
–
–
[a] All reactions were performed with 1 (0.2 mmol) and BuB(OH)2 (0.6 mmol) in the presence ofPd(OAc) (10 mol%), chiral ligand (20 mol%),
2
benzoquinone (0.5 equiv), and Ag2O (1.0 equiv) in 2 mL ofanhydrous THF at 60 8C for 20 h. Piv=pivaloyl. [b] Yields were based on isolated products.
[c] Enantiomeric excesses (ee values) were determined by HPLC on a chiral stationary phase. [d] The opposite enantiomer was obtained. [e] No
reaction.
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the enantioselectivity is also consistent with the proposed
mechanistic model (Scheme 3).
With ligand 7l in hand, we further optimized reaction
conditions and obtained the product in 95% ee at 508C
(entry 2, Table 2). Importantly, the ligand load could be
reduced to 10 mol% without affecting the enantioselectivity
the metal center is believed to be crucial for the enantiocon-
trol, although detailed understanding must await full charac-
terization of the intermediates and also kinetic studies. This
À
newly established approach for chiral recognition in the C H
activation step and the accumulated knowledge of using chiral
amino acids in asymmetric catalysis[23] are likely to open new
avenues for the development of
À
enantioselective C H activation
reactions with broad substrate
scope.
À
À
Table 2: Enantioselective C H activation/C C Coupling.
Experimental Section
General procedure for the alkylation
reaction: In a 20 mL Teflon cap-sealed
tube, the substrate (0.2 mmol, 1 equiv),
Pd(OAc)2 (4.5 mg, 0.02 mmol,
10 mol%), boronic acid (0.6 mmol,
3equiv), Ag 2O (46.3mg, 0.2 mmol,
Entry
Substr.
R1
R
T [8C]
7l [mol%]
t [h]
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
1
1
1
2
2
1
1
17
18
19
20
o-Me
o-Me
o-Me
H
nBu
nBu
nBu
nBu
nBu
Et
60
50
60
80
80
60
60
60
80
80
80
20
20
10
20
10
10
10
10
10
10
10
20
20
20
20
20
20
20
40
20
20
20
91
50
96
47
56
81
61
58
55
43
61
87
95
88
79
74
84
89
84
54
72
78
1 equiv),
benzoquinone
(10.8 mg,
0.1 mmol, 0.5 equiv), and 7l (6.3mg,
0.02 mmol, 10 mol%) were dissolved in
2 mL of anhydrous THF under atmos-
pheric air. The tube was sealed with a
Teflon-lined cap, and the reaction mix-
ture was stirred at the desired temper-
ature. The reaction mixture was filtered
through a pad of Celite, and the Celite
was washed with 20 mL of CH2Cl2. The
filtrate was concentrated under vacuum.
The residue was then purified by column
chromatography on silica gel with hex-
H
o-Me
o-Me
m-Me
m-OMe
m-OAc
p-Me
Cy[c]
nBu
nBu
nBu
nBu
8[d]
9[d]
10[d]
11
[a] Yield ofisolated product. [b] ee values were determined by HPLC on a chiral stationary phase. [c] Cy=
cyclopropyl. [d] Alkylation occured only at the less hindered position.
(entries 3, 5–11, Table 2,). The high yield also suggests that
anes/ethyl acetate and enantiomeric excess (ee) was determined by
this ligand does not affect the reaction adversely. We are
pleased to find that this enantioselective alkylation reaction
can also be used with other boronic acids (entries 6 and 7,
Table 2,). Not surprisingly, substrates 17–20 lacking ortho
substituents react with lower enantioselectivity; this can be
explained by the reduction in steric bulk (entries 8–11,
Table 2,).
HPLC on a chiral stationary phase (see the Supporting Information).
Received: March 4, 2008
Published online: May 16, 2008
À
Keywords: amino acids · boronic acids · C C coupling ·
.
À
C H activation · enantioselectivity
To test whether this protocol can be extended to
3
À
enantioselective alkylation of C(sp ) H bonds, substrate 21
À
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