Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acids

Article abstract of DOI:10.1021/ja909571z

(Chemical Equation Presented) Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acid substrates has been achieved through the use of monoprotected chiral amino acid ligands. The absolute configuration of the resulting olefinated products

Full text of DOI:10.1021/ja909571z

Published on Web 12/17/2009
Pd(II)-Catalyzed Enantioselective C-H Olefination of Diphenylacetic Acids
Bing-Feng Shi, Yang-Hui Zhang, Jonathan K. Lam, Dong-Hui Wang, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
Received November 11, 2009; E-mail: yu200@scripps.edu
Despite substantial progress in developing various Pd-catalyzed
C-heteroatom and C-C bond-forming reactions via C-H activation,1
achieving enantioselectivity in these reactions through a stereoselective
Pd insertion step remains a significant challenge.2–9 In our ongoing
studies to design and evaluate new ligands to effect asymmetric C-H
cleavage, two major problems have become apparent. First, the
simultaneous binding of both the substrate and the chiral ligand to the
Pd(II) center is often difficult to achieve. Second, even if such
complexes are assembled, the ligand often strongly inhibits C-H
activation because it either induces an unwanted conformational change
or adversely affects the electronic properties of the Pd(II) center.
We recently found that monoprotected amino acid ligands and
2-benzylpyridine substrates coordinate with Pd(II) in a one-to-one ratio
with high fidelity.3 Importantly, the resulting chiral Pd(II) complexes
were found to induce asymmetric C-H cleavage with high enantio-
selectivity (up to 95% ee). Of critical importance for the viability of
this process is the precise match between the binding ability of the
pyridine substrate and the chiral ligand. This observation, however,
calls into question whether this chiral ligand scaffold is broadly
applicable to synthetically useful substrates, including those that contain
weakly coordinating functional groups. Herein, we report an enantio-
selective C-H olefination reaction of R,R-diphenylacetic acids using
monoprotected amino acids as chiral ligands. This new development
represents an encouraging step toward the realization of synthetically
useful Pd-catalyzed enantioselective C-H activation reactions.
We previously reported that both inorganic and organic cations
dramatically accelerate carboxyl-directed C-H activation reactions.10
Our current hypothesis, based on the structure of a C-H insertion
intermediate,10b is that the σ-chelation of the carbonyl oxygen of the
carboxylate salt with Pd(II) is responsible for the facile C-H cleavage
promoted by the complex-induced proximity effect. Following this
hypothesis, we anticipated that a chiral carbon-Pd intermediate B
could be formed in analogy to intermediate A, which is formed
following enantioselective C-H activation using a pyridyl directing
group. Subsequently, we envisioned that this intermediate would
undergo olefination to give the corresponding chiral product (Figure
1). The proposed boat conformations of A and B are based on a crystal
structure of a similar 1,4-cyclohexadiene-like cyclopalladated com-
pound.3
substrates,11 the olefination reaction of 1a in the presence of L1 gave
the desired product in 46% yield, accompanied by substantial amounts
of the decarboxylation byproduct. Nonetheless, the high enantiose-
lectivity observed (95% ee) was encouraging (Table 1, entry 1).
Through extensive screening, we found that through the use of the
preformed sodium salt of 1a as the starting material and KHCO3 as
the base, the yield could be improved to 73% with 97% ee (entry 3).
Surprisingly, the unique combination of the sodium salt of 1a and
KHCO3 was crucial for the success of the reaction. Other alternatives
decreased both the enantioselectivity and yield (entries 4-14). We
then screened an array of monoprotected R-amino acids (Table 2).
Boc-Ile-OH was the optimal chiral ligand, with Boc-Tyr(t-Bu)-OH
giving similar enantioselectivity (96% ee) but significantly lower yield
(45%).
Table 1. Effect of Inorganic Cations and Basesa
entry
M
base
% yieldb % eec entry
M
base
% yieldb % eec
d
1
2
3
4
5
6
7
H
Na
KHCO3
-
46
51
73e
-
49
-
25
95
86
97
-
84
-
87
8
9
Na NaHCO3
Na Na2CO3
56
61
-
37
44
57
53
89
91
-
83
85
79
91
Na KHCO3
NH4 KHCO3
10 Na Cs2CO3
11 Na K2HPO4
12 Na Li2CO3
13 Na NaOTsf
K
Cs
KHCO3
KHCO3
Na K2CO3
14
K
NaHCO3
a Conditions: 0.5 mmol of 1a, 5 mol % Pd(OAc)2, 10 mol % L1, 5 mol
% BQ, 0.5 equiv of base, and 1 atm O2 in 3 mL of tert-amyl alcohol at 90
°C for 48 h. b Determined by 1H NMR analysis using CH2Br2 as a
calibrated internal standard. c Determined by chiral HPLC analysis.
d Using 2 equiv of KHCO3. e Isolated yield. f Using 1 equiv of NaOTs.
Table 2. Evaluation of Amino Acidsa
%
yield ee
%
%
yield ee
%
entry
ligand
entry
ligand
1
2
3
4
5
6
7
8
Boc-Ala-OH
Boc-Abu-OH
Boc-Nva-OH
Boc-Nle-OH
Boc-Val-OH
Boc-Ser(Bzl)-OH
Boc-Phe-OH
46 54
51 67 10 Boc-Tle-OH
63 61 11 Boc-Ile-OH ·0.5H2O 73 97
59 81 12 Boc-Leu-OH
39 93 13 Formyl-Leu-OH
61 91 14 PG1-Leu-OH
25 93 15 PG2-Leu-OH
9
Boc-Tyr(t-Bu)-OH
45 96
43 94
To test this hypothesis, we began by establishing reaction conditions
for a Pd(II)-catalyzed olefination reaction of R,R-diphenylacetic acid
1a using Boc-L-isoleucine (Boc-Ile-OH) L1 as a chiral ligand. Through
a procedure developed for the racemic olefination of phenylacetic acid
60 86
44 79
57 84
44 69
37 65
Boc-Thr(t-Bu)-OH 50 86 16 PG3-Leu-OH
a The reaction conditions were identical to those described in Table 1.
We next proceeded to establish the scope of the styrene coupling
partner. Styrenes with para and meta alkyl substitutents gave high
enantioselectivity (92-97% ee; Table 3, entries 2, 3, and 7) while
Figure 1
9
460 J. AM. CHEM. SOC. 2010, 132, 460–461
10.1021/ja909571z  2010 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Enantioselective C-H Activation/Olefination Using
o-methyl-substituted styrene gave only 81% ee (entry 4). p-Chlorosty-
rene afforded both high enantioselectivity (96% ee) and reactivity (74%
yield); however, p-fluorostyrene gave both decreased yield and
enantioselectivity (entry 6).
Acrylates as the Coupling Partnersa b
,
Different carboxylic acid substrates were also subjected to this
reaction protocol. Alkyl-substituted sodium carboxylates 1h-k were
converted to the corresponding products with good to high enantiose-
lectivity (entries 8-11). Boc-Tyr(t-Bu)-OH was found to be a better
chiral ligand for sodium carboxylates 1h, 1j, and 1k. The reaction
was also found to tolerate substrates containing electron-donating
groups (p-OPiv, 1l; entry 12) and moderately electron-withdrawing
groups (p-Cl, 1m; entry 13), although olefination of 1m gave 2m in
only 35% yield. 3,4-Disubstituted substrates were also olefinated
effectively, giving moderate to high levels of enantioselectivity (entries
14-16). Reactions of sodium 2,2-diphenylbutanoate (1q) and sodium
2,2-diphenylpentanoate (1r) with styrene gave lower enantioselectivity
(entries 17 and 18). Unfortunately, the reaction of R-hydrogen-
containing 1s gave only 58% ee, and it was found that 2s was partially
racemized under the reaction conditions (entry 19). Notably, the
absolute configuration of the olefination product 2e was determined
to be R by X-ray crystallographic analysis (Figure 2), which was
consistent with the proposed intermediate B (Figure 1).
a The reaction conditions were identical to those described in Table 1.
The product ratio and dr were determined by H NMR analysis.
b
1
Scheme 2. Derivatization of the Olefination Products
Finally, these olefinated products could be readily converted to
aldehydes or lactones by simple chemical transformations with
complete retention of stereochemistry (Scheme 2).
In summary, we have demonstrated that monoprotected R-amino
acids are effective chiral ligands for Pd(II)-catalyzed enantioselective
C-H activation reactions of carboxylic acid substrates. Expansion of
this asymmetric technology to enantioselective sp3 C-H functional-
ization is underway.
Table 3. Enantioselective C-H Activation/Olefination Using
Substituted Styrenes as the Coupling Partnersa
Acknowledgment. We gratefully acknowledge The Scripps
Research Institute, the National Institutes of Health (NIGMS, 1 R01
GM084019-01A1), Amgen, and Lilly for financial support.
% eec
(config)
entry
2
R
R1
R2
% yieldb
1
2
3
4
5
6
7
8
9
2a Me
2b Me
2c Me
2d Me
2e Me
2f Me
2g Me
H
H
H
H
H
H
H
H
73
71
63
51
74
51
51
63
58
63
45
51
35
47
40
39
61
52
69
97
97
92
80
Supporting Information Available: X-ray diffraction analysis of 2e
(CIF), experimental procedures, and characterization data for all new
compounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
p-Me
m-Me
o-Me
p-Cl
p-F
p-t-Bu
H
H
H
H
H
H
H
H
H
H
H
H
96 (R)d
89
95
References
2h Me p-Me
2i Me m-Me
90e
92
(1) For recent reviews, see: (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (b) Daugulis, O.; Zaitsev, V. G.; Shabashov, D.; Pham, Q.-N.;
Lazareva, A. Synlett 2006, 3382. (c) Yu, J.-Q.; Giri, R.; Chen, X. Org.
Biomol. Chem. 2006, 4, 4041. (d) Campeau, L.-C.; Stuart, D. R.; Fagnou,
K. Aldrichimica Acta 2007, 40, 35. (e) Rubin, M.; Rubina, M.; Gevorgyan,
V. Chem. ReV. 2007, 107, 3117.
10 2j Me 3,4-dimethyl
11 2k Me p-t-Bu
12 2l
82e
88e
95
Me p-OPiv
13 2m Me p-Cl
87
90
75
89
(2) For a review of stereoselective C-H functionalization, see: Giri, R.; Shi,
B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. ReV. 2009, 38, 3242.
(3) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 4761.
(4) For a Ru-catalyzed atropselective alkylation, see: Kakiuchi, F.; Le Gendre,
P.; Yamada, A.; Ohtaki, H.; Murai, S. Tetrahedron: Asymmetry 2000, 11,
2647.
(5) For a Pd(0)-catalyzed enantioselective arylation, see: Albicker, M. R.;
Cramer, N. Angew. Chem., Int. Ed. 2009, 48, 9139.
(6) For enantioselective hydroarylation and hydroacylation, see: (a) Bosnich,
B.; Wang, X. Organometallics 1994, 13, 4131. (b) Mikami, K.; Hatano,
M.; Terada, M. Chem. Lett. 1999, 28, 55. (c) Thalji, R. K.; Ellman, J. A.;
Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192. (d) Coulter, M. M.;
Dornan, P. K.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 6932. (e) Shibata,
Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552.
14 2n Me 3-chloro-4-methoxy
15 2o Me 3-methyl-4-methoxy
16 2p Me 4-methoxy-3-trifluoromethyl
17 2q Et
18 2r Pr
H
H
H
72
76e
58f
19 2s
H
a The reaction conditions were identical to those described in Table 1.
b Isolated yield. c Determined by chiral HPLC analysis. d The absolute
configuration was determined by analysis of the X-ray crystal structure.
e Boc-Tyr(t-Bu)-OH was used as the ligand. f Racemization occurred during
the reaction.
(7) For enantioselective carbenoid and nitrenoid insertions, see: (a) Davies,
H. M. L.; Manning, J. R. Nature 2008, 451, 417. (b) Doyle, M. P. J. Org.
Chem. 2006, 71, 9253. (c) Du Bois, J.; Zalatan, D. N. J. Am. Chem. Soc.
2008, 130, 9220. (d) Milczek, E.; Boudet, N.; Blakey, S. Angew. Chem.,
Int. Ed. 2008, 47, 6825.
(8) For enantioselective Heck and cross-coupling reactions, see: (a) Sato, Y.;
Sodeoka, M.; Shibasaki, M. J. Org. Chem. 1989, 54, 4738. (b) Carpenter,
N. E.; Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989, 54, 5846. (c)
Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482.
(9) For enantioselective oxidation of alcohols, see: (a) Ferreira, E. M.; Stoltz,
B. M. J. Am. Chem. Soc. 2001, 123, 7725. (b) Jensen, D. R.; Pugsley,
J. S.; Sigman, M. S. J. Am. Chem. Soc. 2001, 123, 7475.
(10) (a) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008,
47, 5215. (b) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(11) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science [Online early
access]. DOI: 10.1126/science.1182512. Published Online: Nov 26, 2009.
Figure 2. Absolute configuration of olefination product 2e.
Acrylates were also found to be efficient coupling partners under
these conditions, affording 99% ee. However, a mixture of the
desired olefination product and the corresponding conjugated
addition product was obtained (Scheme 1). The use of sodium
carboxylate salt also improved the yield.
JA909571Z
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