Chemo- and Enantioselective Pd/B Hybrid Catalysis for the Construction of Acyclic Quaternary Carbons: Migratory Allylation of O-Allyl Esters to α- C-Allyl Carboxylic Acids

Article abstract of DOI:10.1021/jacs.8b02783

We describe herein the asymmetric synthesis of α-allyl carboxylic acids containing an α-quaternary stereocenter by a chiral hybrid catalyst system comprising palladium and boron complexes. The reaction proceeded through palladium-catalyzed ionization of α,α-disubstituted O-allyl esters for the generation of chiral π-allyl palladium complex as an electrophile, boron-catalyzed enolization of the carboxylate part for the generation of chiral α,α-disubstituted carboxylic acid-derived enolates as a nucleophile, and enantioselective coupling between the thus-generated nucleophile and electrophile. Proper combinations of chiral ligands for the boron and palladium catalysts were crucial. The reaction proceeded chemoselectively at the α-position of the carboxylic acid group.

Full text of DOI:10.1021/jacs.8b02783

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Chemo- and Enantioselective Pd/B Hybrid Catalysis for the
Construction of Acyclic Quaternary Carbons: Migratory
Allylation of O-Allyl Esters to #-C-Allyl Carboxylic Acids
Taiki Fujita, Tomohiro Yamamoto, Yuya Morita, Hongyu Chen, Yohei Shimizu, and Motomu Kanai
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b02783 • Publication Date (Web): 24 Apr 2018
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Chemo- and Enantioselective Pd/B Hybrid Catalysis for the Construc-
tion of Acyclic Quaternary Carbons: Migratory Allylation of O-Allyl Es-
ters to -C-Allyl Carboxylic Acids
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Taiki Fujita,† Tomohiro Yamamoto,† Yuya Morita,† Hongyu Chen,† Yohei Shimizu,*,†,§ Motomu
Kanai*,†
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Supporting Information Placeholder
ABSTRACT: We describe herein the asymmetric synthesis of
α-allyl carboxylic acids containing an -quaternary stereocenter
by a chiral hybrid catalyst system comprising palladium and bo-
ron complexes. The reaction proceeded through palladium-
catalyzed ionization of ,-disubstituted O-allyl esters for the
generation of chiral -allyl palladium complex as an electrophile,
boron-catalyzed enolization of the carboxylate part for the genera-
tion of chiral ,-disubstituted carboxylic acid-derived enolates
as a nucleophile, and enantioselective coupling between the thus-
generated nucleophile and electrophile. Proper combinations of
chiral ligands for the boron and palladium catalysts were crucial.
The reaction proceeded chemoselectively at the α-position of the
carboxylic acid group.
Transition metal-catalyzed asymmetric allylic alkylation
(AAA) of carbonyl compounds is among the most versatile meth-
ods for carbon-skeleton construction of organic molecules con-
comitant with chirality control. The importance of the reaction is
reflected by the number of reports of catalytic AAA reactions of
aldehydes, ketones, and 1,3-dicarbonyl compounds (e.g., malo-
We previously developed a method for chemoselective enolate
generation from carboxylic acids using a boron catalyst and
nates and -keto esters).1 Current major challenges in this reaction
category are as follows; (1) expansion of the nucleophile scope to
amines, enabling carboxylic-acid Mannich and aldol reactions.10
carboxylic acid derivatives containing less acidic α-C‒H bonds,2‒6
Chemoselective acidification of the α-C‒H bond in carboxylic
and (2) construction of all-carbon quaternary stereocenters in
acid through reversible boron carboxylate formation allowed for
acyclic molecules.3,4,7‒9 The methods selected for the generation
the selective generation of a carboxylic acid-derived boron eno-
of geometrically-defined tetrasubstituted enolates or their equiva-
late in the presence of a mild amine base. This enolization was
lents in the carboxylic acid oxidation state are critical toward
applied to a catalytic asymmetric carboxylic-acid Mannich reac-
achieving such goals. Evans reported the strategic use of N-
lithiated prochiral anions derived from α-disubstituted nitriles as
equivalents for carboxylic acid-derived enolates (Scheme 1a).
Hou reported a reaction using an amide enolate containing a steri-
cally-demanding diphenylamine moiety (Scheme 1b). Stoltz and
Marek recently developed an intriguing approach involving the
cis-carbometalation of ynecarbamates, oxidation, and O-
allyloxycarbonylation for the generation of geometrically-defined
tetrasubstituted O-allyloxycarbonyl enolates, followed by a palla-
dium-catalyzed decarboxylative AAA reaction (Scheme 1c).4
Despite the progress, the functional-group tolerance and atom
economy can still be improved. Herein we report an AAA reac-
tion of carboxylic acids promoted by two-component hybrid ca-
talysis comprising palladium and boron complexes that produces
α-quaternary carboxylic acids under mild conditions (Scheme 1d).
tion by introducing chiral ligands on the boron atom.10a Although
the structure of the thus-generated transient boron enolate is un-
known, it is hypothesized to be geometrically symmetric diboryl
enediolate 3 (Scheme 1d) on the basis of Evans’ seminal work.11
We envisioned that this feature would be advantageous for con-
structing α-quaternary stereocenters of carboxylic acids, which
require geometrically-defined tetrasubstituted enolates.
Our reaction design involving Pd/B hybrid catalysis is shown in
Scheme 1d.12,13 We devised allyl esters 1 as a source for both the
carboxylic acid and allyl moieties of the target products.14 Ioniza-
tion of allyl ester 1 by a palladium catalyst generates -
allylpalladium species 4 concomitant with liberation of the car-
boxylate moiety, which is trapped and enolized by a boron cata-
lyst and an amine base to generate boryl enediolate 3. The two
reactive species, 3 and 4, couple to provide α-C-allyl carboxylic
acid 2. Because the two asymmetric catalysts cooperate with each
Scheme 1. Catalytic AAA for the Synthesis of α-Quaternary
Carboxylic Acid Derivatives
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other by introducing independent chiral ligands onto the palladi-
L2 (ent-L2; N-4-MeO-C6F4SO2-D-Val) was used in combination
um and boron atoms, respectively, high enantio-induction is pos-
sible despite the challenging quaternary carbon construction in an
acyclic system.
Table 1. Influence of the Reaction Conditionsa
with L1 (entry 7).
1
2
3
4
5
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8
The boron source also affected the reaction (entries 10 and 11).
A borane-THF complex (BH3•THF), which was the best catalyst
precursor in Mannich and aldol reactions using carboxylic acids
as pronucleophiles,10 was totally ineffective (entry 10, 0% yield).
This was probably because boron carboxylate could not be formed
from the carboxylate generated through palladium-catalyzed ioni-
zation of 1a.13 On the other hand, BCl3 exhibited reactivity com-
parable to that of (AcO)4B2O, although the enantioselectivity was
lower (entry 11, 96% yield, 71% ee). Finally, we studied the ef-
fects of the base (entries 12–14). Although less basic and sterical-
ly-demanding NEt3 did not promote the reaction (entry 12), steri-
cally less-demanding N-methylpyrrolidine provided the product
with higher enantioselectivity than DBU (entry 13, 55% yield,
97% ee). The yield was improved by increasing the amount of the
boron catalyst (entry 14, 83% yield, 96% ee). Thus, we used ei-
ther DBU or N-methylpyrrolidine as a base, depending on the
reactivity of the substrates in the following substrate scope studies.
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We then examined the substrate scope of the reaction (Table 2).
Because of the unsatisfactory reactivity in most of the substrates
compared with 1a, we increased boron catalyst loading to 10
mol % (AcO)4B2O and 20 mol % L2, while maintaining the pal-
ladium catalyst loading (2.5 mol % [Pd(allyl)Cl]2 and 5 mol %
L1). Substrates with α-aryl groups containing various substitution
patterns and electronic characteristics afforded good reactivity and
high enantioselectivity when using the proper base, DBU or N-
methylpyrrolidine (2a–2i). The yield of α-ethyl-substituted 2j was
slightly lower than that of α-methyl-substituted 2a; but the enanti-
omeric excess of 2j was higher than that of 2a (69% yield and
99% ee for 2j vs. 75% yield and 96% ee for 2a). α-Hetero atom-
substituted substrates were also competent (2k and 2l).
α,α-Dialiphatic-substituted ester 1m is a particularly challeng-
ing substrate due to the difficulties in sterically and electronically
differentiating the two substituents at the -carbon, as well as the
greater pKa value of the -proton compared with -aryl-
substituted substrates. The standard combination of chiral ligands
L1 and L2 was not effective; 2m was obtained up to 23% yield at
60 °C. Further exploration of the chiral ligands revealed that
(Sp,Sp,R,R)-DMM-Mandyphos was the best ligand for the palladi-
um catalyst in combination with ent-L2 for the boron catalyst; 2m
was obtained in 93% yield with 80% ee. The same conditions
were applicable to 1n, providing 2n in 92% yield with 68% ee.
When the allyl group contained an aliphatic substituent (R3 =
aliphatic), the reaction proceeded under the standard conditions
with complete terminal position-selectivity of the allyl group (2o,
2p, and 2q). When R3 was an aromatic group (2r and 2s), howev-
er, (R)-Ph-SDP afforded better results than L1.16 It should be
noted that 5r, which contains a branched allyl group as a 1:1 dia-
stereomixture, can be convergently transformed to linear 2r with
high enantioselectivity comparable to that obtained when using
linear allyl ester 1r as the starting material. This result supports
our hypothesis that the reaction proceeds via two independent
active species, boron enolate 3 and π-allyl palladium 4, and not
via Ireland-Claisen rearrangement (see below).
aOptimized reaction conditions: 1a, [Pd(allyl)Cl]2 (2.5 mol %), L1
(5 mol %), (AcO)4B2O (5 mol %), L2 (10 mol %), DBU (1.5
equiv), toluene (0.15 M), room temperature, 12 h. Yield was de-
1
termined by H NMR analysis of a crude mixture using 1,1,2,2-
tetrachloroethane as an internal standard. Enantiomeric excess
b
(ee) was determined by chiral HPLC analysis. Yield of isolated
c
d
product in parenthesis. Reaction time was 24 h. (AcO)4B2O (10
mol %) and L2 (20 mol %) were used.
After intensive studies using allyl α-phenylpropionate (1a) as a
model substrate, we determined the optimized conditions as
shown in Table 1, entry 1 (91% yield, 90% ee); (R,R,R)-Xyl-SKP
(L1)15 as a ligand for the palladium catalyst, N-4-MeO-C6F4SO2-
L-Val (L2) as a ligand for the boron catalyst, and DBU (1.5 equiv)
as a base. We identified critical parameters during the optimiza-
tion studies. First, both the palladium and boron catalysts were
essential for promoting the reaction (entries 2 and 3); in the ab-
sence of either catalyst component, the reaction did not proceed at
all. Second, the combination of L1 and L2 was critical for the
high yield and enantioselectivity (entries 4‒9). Replacing L1 with
an achiral ligand (xantphos, entry 4; 92% yield and 30% ee) or
(R,R)-Ph-BPE (entry 5; 99% yield and 55% ee) significantly di-
minished the enantioselectivity. The same tendency was observed
for the ligands on the boron atom; omitting or replacing L2 with
other ligands10a (entries 6‒9) diminished the enantioselectivity
and/or yield. Specifically, the chirality matching between the two
ligands was critical for the high enantioselectivity; the enantio-
meric excess of the product was only 4% when the enantiomer of
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Table 2. Substrate Scopea
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aGeneral reaction conditions: 1 (300 μmol), [Pd(allyl)Cl]2 (7.5 μmol), L1 (15 μmol), (AcO)4B2O (30 μmol), L2 (60 μmol), DBU (450
b
c
μmol), toluene (2.0 mL), room temperature, 12 h. Isolated yield is shown. (AcO)4B2O (5 mol %) and L2 (10 mol %) were used. N-Me-
d
pyrrolidine was used instead of DBU and the reaction time was 24 h. Isolated yield was determined after conversion of the product into
e
f
methyl ester. (Sp,Sp,R,R)-DMM-Mandyphos and ent-L2 were used instead of L1 and L2, respectively. (R)-Ph-SDP was used instead of
L1. gFrom 5r. The reaction time was 20 h. hFrom 5s. i1:1 diastereomixture.
Next, we assessed the functional group compatibility. The alkyl
chloride group was intact; byproducts derived from elimination or
substitution of the chloride, which should proceed under strongly
basic conditions, were not observed at all (2t).17 Other enolizable
functional groups, i.e., nitrile (1u), amide (1v), ester (1w), and
ketone (1x), were all compatible. Importantly, the allyl group was
introduced chemoselectively at the α-position of the carboxylic
acid functionality. This selectivity is due to chemoselective eno-
late formation from the carboxylic acid moiety by the boron cata-
lyst. The conditions were applicable to an anti-inflammatory drug,
loxoprofen (1x), indicating that this method can be used for late-
stage structural diversification of drug lead compounds.
using allyl acetate as an allyl donor (Scheme 2b). The reaction
proceeded under the standard conditions for migratory allylation
shown in Table 2, and the enantioselectivity of the products was
comparable between the two conditions.18 These results support
our notion that both the migratory allylation in Table 2 and inter-
molecular allylation in Scheme 2b proceed through the same reac-
tive species (3 and 4).
In summary, we developed a boron/palladium hybrid catalysis
for an asymmetric migratory -C-allylation of allyl esters. The
combined use of two distinct chiral catalysts allowed us to fine
tune the asymmetric environment during C–C bond formation for
the construction of acyclic chiral quaternary carbon centers with
generally high enantioselectivity. The allylation reaction proceed-
ed chemoselectively at the α-position of the carboxylic acid func-
tionality despite the presence of intrinsically more-readily enoliz-
able functional groups such as nitrile, amide, ester, and ketone.
The finding might be useful for late-stage, chemoselective asym-
metric introduction of an allyl group into multifunctional mole-
cules.
Because the reaction is a formal rearrangement, we assessed
whether or not the allyl transfer is an intramolecular process. We
conducted a shuffling experiment under the standard conditions
using an equimolar mixture of 1u and 1c (Scheme 2a). The reac-
tion produced all four possible products, 6u, 6a, 6y, and 6c in
excellent total yield (96%). This result indicates that the lifetimes
of boron enolate 3 and -allyl palladium 4, generated through
ionization of allyl ester substrate 1, were long enough to escape
from the solvent cage and combine in an intermolecular fashion.
Scheme 2. Support for the Intermolecular Nature of the Al-
lylation Step and Application to Intermolecular AAA
This finding led us to investigate an intermolecular variant of
the catalytic enantioselective -C-allylation of carboxylic acids 7
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2011, 34, 169-208. (g) Hethcox, J. C.; Shockley, S. E.; Stolz, B. M. ACS
Catal. 2016, 6, 6207-6213.
1
(2) For catalytic AAA reactions producing α-tertiary carboxylic acid
derivatives, see: (a) Schwarz, K. J.; Amos, J. L.; Klein, J. C.; Do, D. T.;
Snaddon, T. N. J. Am. Chem. Soc. 2016, 136, 5214-5217. (b) Trost, B. M.;
Lehr, K.; Michaelis, D. J.; Xu, J.; Buckl, A. K. J. Am. Chem. Soc. 2010,
132, 8915-8917. (c) Trost, B. M.; Michaelis, D. J.; Charpentier, J.; Xu, J.
Angew. Chem. Int. Ed. 2012, 51, 204-208. (d) Jiang, X.; Beiger, J. J.;
Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 87-90. (e) Saito, A.; Kumagai,
N.; Shibasaki, M. Angew. Chem. Int. Ed. 2017, 56, 5551-5555. (f)
Spoehrle, S. S. M.; West, T. H.; Taylor, J. E.; Slawin, A. M. Z.; Smith, A.
D. J. Am. Chem. Soc. 2017, 139, 11895-11902. (g) Braun, M.; Meletis, P.;
Visse, R. Adv. Synth. Catal. 2011, 353, 3380-3384. (h) Jiang, X.; Boehm,
P.; Hartwig, J. F. J. Am. Chem. Soc. 2018, 140, 1239-1242.
(3) Catalytic AAA reactions producing α-quaternary acyclic carboxylic
acid derivatives have utilized nitriles or amides as pronucleophiles. Those
methods have required stoichiometric amounts of a strong base, LiHMDS.
(a) Turnbull, B. W. H.; Evans, P. A. J. Am. Chem. Soc. 2015, 137, 6156-
6159 (nitriles). (b) Zhang, K.; Peng, Q.; Hou, X.-L.; Wu, Y.-D. Angew.
Chem. Int. Ed. 2008, 47, 1741-1744 (amides).
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(4) Starkov, P.; Moore, J. T.; Duquette, D. C.; Stoltz, B. M.; Marek, I. J.
Am. Chem. Soc. 2017, 139, 9615-9620.
(5) For catalytic AAA reactions producing α-quaternary lactones, see:
(a) Li, X.-H.; Wan, S.-L.; Chen, D.; Liu, Q. R.; Ding, C.-H.; Fang, P.; Hou,
X.-L. Synthesis 2016, 48, 1568-1572. (b) Teng, B.; Chen, W.; Dong, S.;
Kee, C. W.; Gandamana, D. A.; Zong, L.; Tan, C.-H. J. Am. Chem. Soc.
2016, 138, 9935-9940. (c) James, J.; Guiry P. J. ACS Catal. 2017, 7, 1397-
1402.
(6) Amino acid Schiff base substrates are exceptionally suitable sub-
strates for catalytic AAA reaction due to high acidity of the α-proton and
chelation control of the E/Z geometry of enolate. For selected examples,
see: (a) Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew.
Chem. Int. Ed. 2003, 42, 2054-2056. (b) Huo, X.; He, R.; Fu, J.; Zhang, J.;
Yang, G.; Zhang, W. J. Am. Chem. Soc. 2017, 139, 9819-9822. (c) Wei,
L.; Zhu, Q.; Xu, S.-M.; Chang, X.; Wang, C.-J. J. Am. Chem. Soc. 2018,
140, 1508-1513. (d) Huo, X.; Zhang, J.; Fu, J.; He, R.; Zhang, W. J. Am.
Chem. Soc. 2018, 140, 2080-2084.
(7) For selected examples of catalytic AAA reactions producing α-
quaternary aldehydes, see: (a) Mukherjee, S.; List, B. J. Am. Chem. Soc.
2007, 129, 11336-11337. (b) Jiang, G.; List, B. Angew. Chem. Int. Ed.
2011, 50, 9471-9474. (c) Yoshida, M.; Masaki, E.; Terumine, T.; Hara, S.
Synthesis, 2014, 46, 1367-1373. (d) Krautwald, S.; Sarlah, D.; Schafroth,
M. A.; Carreira, E. M. Science 2013, 340, 1065-1068. (e) Wright, T. B.;
Evans, P. A. J. Am. Chem. Soc. 2016, 138, 15303-15306.
(8) For selected examples of catalytic AAA reactions producing cyclic
α-quaternary ketones, see: (a) Trost, B. M.; Schroeder, G. M. Chem. Eur.
J. 2005, 11, 174-184. (b) Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stoltz,
B. M. J. Am. Chem. Soc. 2015, 137, 1040-1043. (c) Chen, W.; Hartwig, J.
F. J. Am. Chem. Soc. 2014, 136, 15825-15828. (d) Pupo, G.; Properzi, R.;
List, B. Angew. Chem. Int. Ed. 2016, 55, 6099-6102.
(9) An example of AAA reactions for α-tetrasubstituted acyclic ketones,
see: Jiang, X.; Chen, W.; Hartwig, J. F. Angew. Chem. Int. Ed. 2016, 55,
5819-5823.
(10) (a) Morita, Y.; Yamamoto, T.; Nagai, H.; Shimizu, Y.; Kanai, M. J.
Am. Chem. Soc. 2015, 137, 7075-7078. (b) Nagai, H.; Morita, Y.; Shimizu,
Y.; Kanai, M. Org. Lett. 2016, 18, 2276-2279. (c) Ishizawa, K.; Nagai, H.;
Shimizu, Y.; Kanai, M. Chem. Pharm. Bull. 2018, 66, 231-234.
(11) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am. Chem.
Soc. 1981, 103, 3099-3111.
(12) For a seminal example of hybrid catalysis in the AAA reaction us-
ing -cyano ester donors, see: Sawamura, M.; Sudoh, M.; Ito, Y. J. Am.
Chem. Soc. 1996, 118, 3309-3310.
(13) For a working hypothesis of the catalytic cycle and structure of the
boron catalyst, see Supporting Information (SI).
aFor 7a and 7c, base = DBU, 12 h. For 7f and 7g, base = N-Me-
pyrrolidine, 24 h.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
shimizu-y@sci.hokudai.ac.jp
kanai@mol.f.u-tokyo.ac.jp
Present Address
§Y.S.: Department of Chemistry, Faculty of Science, Hokkaido
University, Sapporo 060-0810, Japan
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant Number
JP17H06442 (MK) (Hybrid Catalysis), Grant-in-Aid for Scientific
Research (C) from JSPS (YS), and the research grant of Astellas
Foundation for Research on Metabolic Disorders (YS). TF and
HC thank Tobe Maki Scholarship and Kobayashi International
Scholarship, respectively, for their fellowships.
(14) This reaction type can be also viewed as a catalytic enantioselec-
tive formal Ireland-Claisen rearrangement (ICR). Previously-reported
asymmetric ICR required excess amounts of chiral activators. (a) Corey, E.
J.; Lee, D.-H. J. Am. Chem. Soc. 1991, 113, 4026-4028. (b) Kazmaier, U.;
Mues, H.; Krebs, A. Chem. Eur. J. 2002, 8, 1850-1855.
(15) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Angew. Chem. Int. Ed.
2012, 51, 936-940.
(16) When L1 was used, 2r was obtained in 85% yield and 70% ee.
(17) When the corresponding substrate containing more reactive bro-
mide was used, however, the target product was not obtained.
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(18) Substrate scope of the intermolecular reaction is slightly narrower
than migratory allylation. See SI for more details.
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ACS Paragon Plus Environment