Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes

Article abstract of DOI:10.1021/ja207607s

Systematic ligand development has led to the identification of novel mono-N-protected amino acid ligands for Pd(II)-catalyzed enantioselective C-H activation of cyclopropanes. A diverse range of organoboron reagents can be used as coupling partners, and the reaction proceeds under mild conditions. These results provide a new retrosynthetic disconnection for the construction of enantioenriched cis-substituted cyclopropanecarboxylic acids.

Full text of DOI:10.1021/ja207607s

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pubs.acs.org/JACS
Pd(II)-Catalyzed Enantioselective CÀH Activation of Cyclopropanes
Masayuki Wasa, Keary M. Engle, David W. Lin, Eun Jeong Yoo, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
Scheme 1. Desymmetrization of Prochiral CÀH Bonds
ABSTRACT: Systematic ligand development has led to the
identification of novel mono-N-protected amino acid li-
gands for Pd(II)-catalyzed enantioselective CÀH activation
of cyclopropanes. A diverse range of organoboron reagents
can be used as coupling partners, and the reaction proceeds
under mild conditions. These results provide a new retro-
synthetic disconnection for the construction of enantioen-
riched cis-substituted cyclopropanecarboxylic acids.
ecently, Pd-catalyzed asymmetric CÀH activation reactions
R
using a chiral auxiliary1 or chiral ligand have been demon-
strated.2À6 Spectroscopic and crystallographic investigations have
provided valuable insights into the process by which [Pd(II)À
mono-N-protected amino acid] catalysts asymmetrically cleave
prochiral CÀH bonds.2 Nevertheless, achieving high levels of
enantioselectivity in these reactions remains a significant chal-
lenge, largely because of the paucity of suitable ligand scaffolds
capable of effecting stereoinduction during CÀH cleavage. In
our previous work, high enantioselectivity was obtained in the
desymmetrization of prochiral aryl CÀH bonds (up to 95% ee;
Scheme 1), and promising initial results were also found in
asymmetric alkyl CÀH activation (up to 37% ee) by using
[Pd(II)Àmono-N-protected amino acid] catalysts.2a
Scheme 2. Asymmetric Cyclopropane CÀH Activation
CÀH bonds with vinylboron reagents (1c and 1d). The use of
boronic acid pinacol esters (BPin) and NaHCO3 were crucial for
arylation and vinylation, while potassium trifluoroborate salts
(BF3K) and Li2CO3 were optimal for alkylation. The presence of
40 mol % dimethyl sulfoxide (DMSO) was found to promote
arylation and vinylation (1aÀd),13 while the addition of N,N-
dimethylformamide (DMF) as a cosolvent was beneficial for
alkylation (1eÀh). Importantly, even when the temperature was
lowered to 40 °C, substrate 1 could still be arylated without a major
decline in yield (78%, mono:di =2.7:1).
With the mild cross-coupling protocol at 40 °C in hand, we
proceeded to examine systematically mono-N-protected amino
acid ligands in an effort to develop an enantioselective protocol
(Table 2). We initially focused on screening mono-N-protected
L-leucine and found that carbamate groups gave superior ee and
mono selectivity compared with amide groups. The mono selec-
tivity also improved proportionally with the ee [for complete
ligand screening data, see the Supporting Information (SI)]. On
the basis of this observation, we further optimized the conditions
using Fmoc-Leu-OH as the ligand and discovered that loadings
of 5 mol % catalyst and 10 mol % ligand at 40 °C gave the highest
ee (50%). The ee dropped to 12% when the temperature was
raised to 70 °C. Increasing the catalyst loading to 10 mol % gave
an improved yield (60%) but decreased the ee (40%); impor-
tantly, adding the catalyst and ligand in two batches gave high
Encouraged by these precedents, we sought to develop
enantioselective CÀH activation reactions of cyclopropanes.7
Because of the prominence of enantiopure cyclopropanes in
natural products and pharmaceuticals, a diverse collection of
transition metal-mediated transformations have been developed
for their synthesis.8 Herein we report a complementary method
that constitutes the first example of enantioselective cyclopropyl
CÀH activation/organoboron cross-coupling (Scheme 2).9,10
A diverse collection of aryl-, alkyl-, and vinylboron coupling part-
ners are compatible with these reaction conditions. Systematic
ligand tuning has led to the development of a protocol that gives
high levels of stereoinduction under mild conditions. This reac-
tion provides a versatile route for the synthesis of cis-substituted
chiral cyclopropanecarboxylates.
On the basis of our recent success in utilizing acidic N-
arylamides as weakly coordinating directing groups for a diverse
range of alkyl and aryl CÀH functionalization reactions,11,12 we
first sought to establish a robust reaction to cross-couple 1, the
amide derivative of 1-methylcyclopropanecarboxylic acid, with
phenylboronic acid pinacol ester (PhÀBPin) in the absence of a
chiral ligand. Extensive screening revealed that a 2:1 mixture of
mono- and diarylated products (1a) could be obtained in 91%
yield at 100 °C. Gratifyingly, aryl-, alkyl-, and vinylboron reagents
were all suitable coupling partners (Table 1). Importantly, this is
the first example of Pd(II)-catalyzed cross-coupling of alkyl
Received: August 12, 2011
Published: November 07, 2011
r
2011 American Chemical Society
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Table 1. Racemic Cross-Coupling of Cyclopropyl CÀH
Table 3. Screening of Amino Acid Side Chainsa,b
Bonds with Organoboron Reagentsa
a The mono:di ratio was determined by 1H NMR analysis of the crude
product using CH2Br2 as an internal standard. b Conditions: 0.1 mmol of
substrate, 10 mol % Pd(OAc)2, 2.0 equivofArÀBPin, 1.5 equiv of Ag2CO3,
3.0 equiv of NaHCO3, 0.5 equiv of BQ, 5 equiv of H2O, 40 mol % DMSO,
0.5 mL of t-Amyl-OH, 100 °C, N2, 12 h. c Conditions: 0.1 mmol of
substrate, 10 mol % Pd(OAc)2, 1.2 equiv of vinylÀBPin, 1.5 equiv of
Ag2CO3, 3.0 equiv of NaHCO3, 0.5 equiv of BQ, 40 mol % DMSO, 0.5 mL
of THF, 100 °C, N2, 6 h. d Conditions: 0.1 mmol of substrate, 10 mol %
Pd(OAc)2, 2.0 equiv of alkylÀBF3K, 1.5 equiv of Ag2CO3, 3.0 equiv of
Li2CO3, 0.5 equiv of BQ, 0.1 mL of DMF, 0.5 mL of THF, 100 °C, N2, 12 h.
a The conditions are identical to those given in Table 2. b The yields were
determined by 1H NMR analysis of the crude products using CH2Br2 as
an internal standard. Stereochemical assignments are tentative.
Table 2. Screening of Ligand Protecting Groupsa,b
yield (74%) while maintaining the ee (48%). The addition of
DMSO improved the yield but led to erosion of the ee, pre-
sumably because DMSO is capable of competing with the ligand
for coordination to Pd. The presence of H2O enhanced the yield
(likely by promoting transmetalation)7 without reducing the ee.
Of the various carbamate protecting groups that were tested,
2,2,2-trichloro-tert-butyloxycarbonyl (TcBoc) afforded the best
ee (78%) and yield (47%).
We subsequently investigated the effect of the amino acid
backbone. Although TcBoc-Leu-OH gave the highest ee, we in-
stead focused on Fmoc-protected amino acids because of their
commercial availability (Table 3). As expected, achiral Fmoc-
Gly-OH (L1) gave a racemic mixture of products. The carboxylic
acid moiety was found to be essential for stereoinduction, as
Fmoc-alanine methyl ester (L3) gave no ee. Fmoc-protected
aminoacids containinghydrophobicalkyl chains(L2 and L4ÀL6)
gave ee values between 43 and 50%. Intriguingly, coordinating
functional groups on the side chain, such as an ester (L7), thio-
ether (L8), or ether (L9), gave improved ee of 65À73%; however,
the conversion dropped to <40% in each case. We then screened
amino acids with aryl side chains (L10 and L11). To our delight,
Fmoc-Phe-OH and its derivatives gave improved ee values of
68% and above, with Fmoc-Tyr(t-Bu)-OH (L11) giving 80% ee
and 49% product yield. Fmoc-Trp(Boc)-OH (L12) also gave
73% ee. These combined findings signaled to us that having an aryl
group on the amino acid side chain is crucial for obtaining high ee.
Having established that both the TcBoc protecting group and
phenylalanine backbone are beneficial for enantioselectivity, we
a Conditions (unless otherwise specified): 0.1 mmol of substrate,
5 mol % Pd(OAc)2, 10 mol % ligand, 1.0 equiv of PhÀBPin, 1.0 equiv of
Ag2CO3, 3.0 equiv of NaHCO3, 0.5 equiv of BQ, 5 equiv of H2O, 0.5 mL
of t-Amyl-OH, 40 °C, N2, 12 h. b Theyields were determined by 1H NMR
analysis of the crude products using CH2Br2 as an internal standard.
Stereochemical assignment is tentative.
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Table 4. Systematic Tuning of the Amino Acid Liganda,b
Table 5. Asymmetric Cyclopropane CÀH
Functionalizationa,b
a Conditions: (first batch) 0.1 mmol of substrate, 5 mol % Pd(OAc)2,
10 mol % ligand, 1.0 equiv of PhÀBPin, 0.75 equiv of Ag2CO3, 2.0 equiv
of NaHCO3, 0.25 equiv of BQ, 3 equiv of H2O, 0.5 mL of t-Amyl-OH,
40 °C, N2, 6 h; (second batch) 5 mol % Pd(OAc)2, 10 mol % ligand, 0.5
equiv of PhÀBPin, 0.75 equiv of Ag2CO3, 1.0 equiv of NaHCO3, 0.25
equiv of BQ, 1 equiv of H2O, 0.2 mL of t-Amyl-OH, 40 °C, N2, 6 h.
b Isolated yields are given. Stereochemical assignments are tentative.
c Conditions: (first batch) 0.1 mmol of substrate, 5 mol % Pd(OAc)2,
10 mol % ligand, 0.5 equiv of vinylÀBPin, 0.75 equiv ofAg2CO3, 2.0 equiv
of NaHCO3, 0.25 equiv of BQ, 0.5 mL of THF, 50 °C, N2, 6 h; (second
batch) 5 mol % Pd(OAc)2, 10 mol % ligand, 0.5 equiv of vinylÀBPin,
0.75 equiv of Ag2CO3, 1.0 equiv of NaHCO3, 0.25 equiv of BQ, 0.2 mL
of THF, 50 °C, N2, 6 h. d Conditions: (first batch) 0.1 mmol of substrate,
5 mol % Pd(OAc)2, 10 mol % ligand, 1.0 equiv of n-BuÀBF3K, 0.75
equiv of Ag2CO3, 1.5 equiv of Li2CO3, 0.25 equiv of BQ, 3 equiv of H2O,
0.5 mL of THF, 70 °C, N2, 6 h; (second batch) 5 mol % Pd(OAc)2,
10 mol % ligand, 0.5 equiv of n-BuÀBF3K, 0.75 equiv of Ag2CO3,
0.75 equiv of Li2CO3, 0.25 equiv of BQ, 0.2 mL of THF, 70 °C, N2, 6 h.
a The conditions are identical to those given in Table 2. b The yields were
determined by 1H NMR analysis of the crude products using CH2Br2 as
an internal standard. Stereochemical assignment is tentative.
synthesized a series of TcBoc-protected amino acids (L13ÀL18).
We confirmed that TcBoc-Phe-OH (L17) gave better ee (85%)
than those with alkyl side chains (L13ÀL15) (Table 4). TcBoc-
PhG-OH (L16) and TcBoc-MePhe-OH (L18), both of which
possess an aryl group, however, gave significantly lower ee.
Further optimization of the protecting group on phenylalanine
was carried out. While retaining the CCl3 moiety present in
TcBoc, we varied the two alkyl groups and found that L23 and
L24 improved the ee to 90 and 91%, respectively. Subsequently,
the newly designed protecting group (PG7) in L23 was installed
on commercially available phenylalanine derivatives (L25ÀL27).
Substitution on the phenyl ring was found to have a modest effect
on the enantioselectivity, with L27 improving the ee to 93%. To
investigate in more detail whether the CCl3 moiety of the TcBoc
group has a dominant effect on the enantioselectivity, we exten-
sively screened a variety of sterically hindered protecting groups
with phenylalanine (see the SI); however, only 48À62% ee was
obtained. The CCl3 moiety presumably serves not only as a
sterically bulky group but also tunes the electronic properties of
the nitrogen atom through its electron-withdrawing character.
With the optimized reaction conditions in hand, we performed
enantioselective CÀH/organoboron cross-coupling of cyclopropane
1 with PhÀBPin, 1-cyclohexenylÀBPin and n-butylÀBF3K
(Table 5). The reagents (excluding the substrate) were added in
two batches, using 5 mol % catalyst and 10 mol % ligand (L27) in
each batch to give the optimal yield and ee. The addition of the
reactants in a single batch resulted in inferior and inconsistent
results. The apparent dependence of the ee's on the catalyst
concentration remains to be investigated. Phenylated product 1a
was obtained in 81% yield and 91% ee. The cross-coupling of
1-cyclohexenyl- and n-butylboron reagents required elevated
temperatures of 50 and 70 °C to obtain appreciable product
formation, which decreased the ee values to 82 and 62%, res-
pectively. Primary alkyl, isopropyl, and cyclopentyl groups at
the α-position of the cyclopropane were tolerated, giving good
ee values (2aÀ7a). β-Benzyl ethers (8a) and γ-phthalimide-
protected amines (9a) were compatible, as was α-substitution
with an aryl group (10a and 11a). Substitution of the aryl ring
with electron-withdrawing halide groups suppressed competitive
ortho-C(aryl)ÀH functionalization. The chiral cyclopropane pro-
ducts could also undergo further CÀH coupling reactions to give
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cis-1,2,3-substituted cyclopropanes under the same conditions in
the absence of ligands, albeit in low yields (20À38%). Unfortu-
nately, substrates containing an α-hydrogen atom or α-hetero-
atoms gave poor yields and ee's at 40 °C. Detailed mechanistic
studies through spectroscopic and crystallographic analyses as
well as further optimization of the ligand and the reaction
conditions are underway to solve these problems.14
In summary, the first example of enantioselective CÀH
activation of cyclopropanes has been achieved through systematic
tuning of the mono-N-protected amino acid ligand and reaction
conditions. Enantioselective CÀH/RÀBXn cross-coupling with
aryl-, vinyl-, and alkylboron reagents provides a new disconnec-
tion for the synthesis of cis-substituted chiral cyclopropanecar-
boxylic acids. Studies to expand the substrate scope and extend
this methodology to other prochiral methyl and methylene CÀH
bonds are ongoing in our laboratory.
Lett. 1999, 28, 55. (b) Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am.
Chem. Soc. 2004, 126, 7192.
(6) For enantioselective carbenoid and nitrenoid insertion reac-
tions, see: (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
(b) Doyle, M. P. J. Org. Chem. 2006, 71, 9253. (c) Zalatan, D. N.;
Du Bois, J. J. Am. Chem. Soc. 2008, 130, 9220. (d) Milczek, E.; Boudet,
N.; Blakey, S. Angew. Chem., Int. Ed. 2008, 47, 6825.
(7) For stoichiometric metalation of cyclopropyl CÀH bonds, see:
(a) Periana, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1984, 106, 7272.
(b) Ruhland, K.; Herdtweck, E. Adv. Synth. Catal. 2005, 347, 398. (c)
Eaton, P. E.; Daniels, R. G.; Casucci, D.; Cunkle, G. T.; Engel, P. J. Org.
Chem. 1987, 52, 2100.
(8) For reviews of asymmetric cyclopropanation, see: (a) Doyle,
M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds: From Cyclopropanes to Ylides; Wiley:
New York, 1998. (b) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette,
A. B. Chem. Rev. 2003, 103, 977. (c) Davies, H. M. L.; Antoulinakis, E. G.
Org. React. 2001, 57, 1. (d) Denmark, S. E.; Beutner, G. In Cycloaddition
Reactions in Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.;
Wiley-VCH: Weinheim, Germany, 2002; pp 85 ff.
’ ASSOCIATED CONTENT
(9) For reviews of B-alkyl SuzukiÀMiyaura cross-coupling, see:
(a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544. (b) Doucet, H. Eur. J. Org. Chem. 2008, 2013.
(c) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48, 9240.
(10) For pioneering examples of asymmetric alkylÀalkyl SuzukiÀ
Miyaura cross-couplingreactions, see: (a) Saito, B.;Fu, G. C. J. Am. Chem.
Soc. 2008, 130, 6694. (b) Lundin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11027. (c) Owston, N. A.; Fu, G. C. J. Am. Chem. Soc. 2010,
132, 11908.
S
Supporting Information. Experimental procedures and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
(11) (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 9886. (b) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed.
2010, 49, 1275. (c) Wasa, M.; Yu, J.-Q. Tetrahedron 2010, 66, 4811.
(d) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680.
(e) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378.
(f) Wasa, M.; Chan, K. S. L; Yu, J.-Q. Chem. Lett. 2011, 40, 1004.
(12) For recent reviews of Pd-catalyzed alkyl CÀH activation, see:
(a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074. (b) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.;
Baudoin, O. Chem.—Eur. J. 2010, 16, 2654. (c) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (d) Wasa, M.; Engle, K. M.; Yu, J.-Q.
Isr. J. Chem. 2010, 50, 605.
(13) Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348.
(14) The reaction can be scaled up to 0.3 mmol of substrate without
a major decline in ee or yield (1a, 71% yield, 86% ee), provided that
vigorous stirring is maintained throughout the course of the reaction.
For details on scalability, see the SI.
’ ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute,
the National Institutes of Health (NIGMS, 1 R01 GM084019-
02), Amgen, Novartis, and Eli Lilly for financial support. We
thank Bristol-Myers Squibb (predoctoral fellowship to M.W.);
the NSF GRFP, the NDSEG Fellowship Program, and the
Skaggs-Oxford Scholarship Program (predoctoral fellowships
to K.M.E.); and the Korean Government (NRF-2009-352-
C00077, postdoctoral fellowship to E.J.Y.). We are grateful to
Professor R. Ghadiri for the generous donation of Fmoc-
protected amino acids and Frontier Scientific for the gift of
organoboron reagents.
’ REFERENCES
(1) (a) Giri, R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005,
44, 2112. (b) Giri, R.; Liang, J.; Lei, J.-G.; Li, J.-J.; Wang, D.-H.; Chen, X.;
Naggar, I. C.; Guo, C.; Foxman, B. M.; Yu, J.-Q. Angew. Chem., Int. Ed.
2005, 44, 7420. (c) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q.
Chem. Soc. Rev. 2009, 38, 3242.
(2) (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 4882. (b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang,
D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460.
(3) For recent examples of asymmetric Pd(0)-catalyzed intramole-
cular CÀH functionalization reactions using chiral phosphine or car-
bene ligands, see: (a) Albicker, M. R.; Cramer, N. Angew. Chem., Int. Ed.
2009, 48, 9139. (b) Renaudat, A.; Jean-Gꢀerard, L.; Jazzar, R.; Kefalidis,
C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49, 7261. (c)
Nakanishi, M.; Katayev, D.; Besnard, C.; K€undig, E. P. Angew. Chem., Int.
Ed. 2011, 50, 7438. (d) Anas, S.; Cordi, A.; Kagan, H. B. Chem. Commun.
2011, 47, 11483.
(4) For an example of Ru-catalyzed atropselective alkylation, see:
Kakiuchi, F.; Le Gendre, P.; Yamada, A.; Ohtaki, H.; Murai, S. Tetrahedron:
Asymmetry 2000, 11, 2647.
(5) For examples of CÀH activation followed by enantioselective
addition to olefins, see: (a) Mikami, K.; Hatano, M.; Terada, M. Chem.
19601
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