Stereodivergent allylic substitutions with aryl acetic acid esters by synergistic iridium and lewis base catalysis

Article abstract of DOI:10.1021/jacs.6b11692

The preparation of all possible stereoisomers of a given chiral molecule bearing multiple stereocenters by a simple and unified method is a significant challenge in asymmetric catalysis. We report stereodivergent allylic substitutions with aryl acetic acid esters catalyzed synergistically by a metallacyclic iridium complex and benzotetramisole. Through permutations of the enantiomers of the two chiral catalysts, all four stereoisomers of the products bearing two adjacent stereocenters are accessible with high diastereoselectivity and enantioselectivity. The resulting chiral activated ester products can be converted readily to enantioenriched amides, unactivated esters, and carboxylic acids in a onepot manner.

Full text of DOI:10.1021/jacs.6b11692

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Communication
Stereodivergent Allylic Substitutions with Aryl Acetic Acid
Esters by Synergistic Iridium and Lewis Base Catalysis
Xingyu Jiang, Jason J Beiger, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 15 Dec 2016
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Stereodivergent Allylic Substitutions with Aryl Acetic Acid
Esters by Synergistic Iridium and Lewis Base Catalysis
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Xingyu Jiang, Jason J. Beiger and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
Scheme 1. Proposed Mechanism for Synergistic Catalysis.
ABSTRACT: Preparation of all possible stereoisomers
of a given chiral molecule bearing multiple stereocenters
by a simple and unified method is a significant challenge
in asymmetric catalysis. Herein we report stereodiver-
gent allylic substitutions with aryl acetic acid esters cata-
lyzed synergistically by a metallacyclic iridium complex
and benzotetramisole. Through permutations of enanti-
omers of two chiral catalysts, all four stereoisomers of
the products bearing two adjacent stereocenters are ac-
cessible with high diastereoselectivity and enantioselec-
tivity. The resulting chiral activated ester products can
be converted readily to enantioenriched amides, unacti-
vated esters, and carboxylic acids in a one-pot manner.
would be compatible with our iridium catalysts. We envi-
sioned that the allylation reaction between A as an electro-
phile and B as a nucleophile would be highly regio-, dia-
stereo- and enantioselective. Furthermore, the iridium
complex and the Lewis base (LB) could dictate the config-
urations of the two stereogenic centers of the product aris-
ing from the electrophile (marked blue) and the nucleophile
(marked red), respectively. Thus, our proposed allylation
method could access all four possible stereoisomers of the
product by simple permutations of enantiomers of the two
catalysts (IrR+LBR, IrS+LBR, IrR+LBS, IrS+LBS).9
A critical concern that underlies our proposed transfor-
mation is the turnover of the Lewis base catalyst. Regen-
eration of this catalyst typically requires an intramolecular
acyl transfer to a proximal nucleophile on the acyl ammo-
nium intermediate. In this case, only lactones and lactams
are accessible as the products.8c,d,10 Although external nu-
cleophiles can be employed as acyl acceptors,11 this exter-
nal nucleophile can react with intermediate C before allyla-
tion occurs. In addition, the direct allylation of an external
nucleophile can compete or override the allylation of the
enolate.
We considered that a “rebound” strategy disclosed re-
cently by Scheidt12, Smith13 and Snaddon14 could be fol-
lowed to regenerate the Lewis base. In this scenario, the
electron-deficient phenolate (Scheme 1, OAr-) substituted
by the Lewis base catalyst serves as an acyl acceptor after
α-functionalization of the ester. The low concentration and
low nucleophilicity of the electron-deficient phenolate
would prevent the direct allylation of the phenolate.
Transition metal-catalyzed allylic substitutions are useful
methods for the enantioselective construction of carbon-
carbon bonds.1 If both the nucleophiles and electrophiles of
the allylation reactions are prochiral, synthetically useful
adducts that contain two contiguous stereocenters can be
constructed in one step. However, most reported reactions
of this type that afford products enantioselectively and dia-
stereoselectively form one out of two possible relative con-
figurations(anti vs. syn).2 Few methods provide stereodi-
vergent access to all four possible stereoisomers of the
products with either anti or syn configuration. Recently,
Carreira et al. reported the allylation of aldehydes in a ste-
reodivergent fashion by the synergistic reactivity of iridium
and amine catalysts under acidic conditions.3 Zhang et al.
reported the combination of iridium and zinc catalysts for
the related allylation of α-hydroxy phenones.4 An approach
to the stereodivergent allylation of carbonyl compounds in
the carboxylic acid oxidation state has not been published.5
Mechanistic studies6 have revealed that metallacyclic
iridium complexes7 developed in our group govern the ge-
ometry, facial selectivity, and regioselectivity of the allyl
moiety in allylation reactions (Scheme 1, A). Lewis basic
chiral tertiary amines are known to react with acyl precur-
sors to form C1-ammonium enolates that have a well-
defined geometry and that react with high facial selectivity
(Scheme 1, B).8 The metalacyclic iridium catalyst for al-
lylic substitution we discovered7 operates under basic con-
ditions. Thus, a system with a Lewis basic catalyst displac-
ing an alkoxide or phenoxide anion to generate the enolate
Herein, we report stereodivergent allylic substitutions
with aryl acetic acid esters catalyzed synergistically by the
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this reaction, various cinnamyl alcohol derivatives were
Table 1. Evaluation of Reaction Conditions for the Allyla-
tion of 1aa
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subjected to the reaction conditions (Table 1). The reaction
conducted with t-butyl cinnamyl carbonate 2a gave (S,S)-
3aa in the highest yield (97%) with >20:1 dr and >99% ee
(entry 7). Only the branched product was observed. A simi-
lar result was obtained in the absence of iPr2NEt, indicating
that the t-butoxide generated from oxidative addition of 2a
and subsequent decarboxylation acted as a base to deproto-
nate the acyl-BTM adduct (entry 8).
9
Metallacyclic iridium catalysts with different aryl sub-
stituents on the phosphoramidite ligands were evaluated.
Reactions conducted with [Ir]-3 and [Ir]-4 bearing naph-
thyl substituents on the ligands afforded (S,S)-3aa quantita-
tively with excellent diastereoselectivity and enantioselec-
tivity (>20:1 dr, >99% ee, entry 10-11). However, the reac-
tion conducted with [Ir]-2 bearing 2-methoxyphenyl sub-
stituents on the ligand gave (S,S)-3aa in lower yield of 71%
with lower dr of 11:1 (entry 9).
When the reaction was conducted with (R)-BTM as the
Lewis base catalyst instead of (S)-BTM, the diastereoselec-
tivity was completely reversed; (R,S)-3aa was obtained,
instead of (S,S)-3aa, in 97% yield with >20:1 dr and >99%
ee (entry 12). A small amount of linear product was ob-
served when conducting the reaction with the catalyst com-
bination of [Ir]-1 and (R)-BTM. However, the formation of
the linear product was suppressed by employing [Ir]-4 and
(R)-BTM as the catalysts, while maintaining high dr and ee
(entry 15).
To examine the stereodivergence of our allylation meth-
od, 1a and 2a were treated with four different combinations
of the enantiomers of two catalysts under otherwise identi-
cal conditions (Scheme 2). As a result, all four stereoiso-
mers of 3aa were obtained individually in high yield with
excellent diastereoselectivity and enantioselectivity, indi-
cating nearly complete control of the configuration at the
allyl electrophile by the metallacyclic iridium complex and
the enolate nucleophile by the BTM base and dominance of
catalyst control of these configurations over potential sub-
strate control. The absolute configurations of the products
are consistent with the stereochemical model that is based
on previous mechanistic studies on the iridium complex6
and BTM catalyst16 (Scheme S1), rendering the stereo-
chemical outcome of our allylation method predictable.
The scope of aryl acetic acid esters that underwent the
Scheme 2. Synthesis of All Stereoisomers of 3aa.
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aThe absolute configuration of (S,S)-3aa was assigned by analogy.
bDetermined by 1H NMR analysis of the crude reaction mixtures.
d
cDetermined by chiral SFC analysis of the major isomer. Combined
yield of two diastereomers of the branched product and the linear
1
product. Determined by H NMR analysis with mesitylene as an in-
ternal standard. The yield within parentheses is that of all isomers
isolated. e(R)-BTM was used instead of (S)-BTM.
metallacyclic iridium complex and a chiral Lewis base. By
varying the combinations of enantiomers of two catalysts,
all four possible stereoisomers of the products are formed
with high diastereoselectivity and enantioselectivity. The
resulting chiral activated esters are readily converted to
enantioenriched amides, unactivated esters, and carboxylic
acids in a one-pot manner.
To develop a stereodivergent allylation of aryl acetic acid
i
esters, we treated 1a with 2a in the presence of Pr2NEt as
base, iridium catalyst [Ir]-1, and a range of Lewis base
catalysts (Table S1). These studies revealed that benzo-
tetramisole (BTM)15 was compatible with our proposed
synergistic catalysis (>99% yield, >20:1 dr, see SI for de-
tails). Reactions conducted with other Lewis bases, such as
tetramisole and quinine, delivered the corresponding prod-
uct in lower yields (<40%) or with lower diastereoselectivi-
ty (<4:1). The use of the pentafluorophenyl ester as the
nucleophile precursor is critical; the reactions conducted
with esters derived from other electron-deficient phenols,
such as 4-nitrophenol and 2,4,6-tricholorophenol, gave the
corresponding products with low yield and dr (Table S2,
see SI for details).
To test the effect of leaving group on the allyl moiety in
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Table 3. Scope of Allylic Carbonates for the Allylationa
Table 2. Scope of Esters for the Allylationa
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aThe yields were reported as the combined yields of two diastere-
omers isolated. The branched products were obtained exclusively.
aThe yields were reported as the combined yields of two diastere-
omers isolated. The branched products were obtained exclusively.
b20 mol% of (R)-BTM was used. cReaction time was extended to 9 h.
d1.1 equiv of iPr2NEt was added.
curred with allylic carbonates containing heteroaryl and
alkenyl substituents. Allylic carbonates bearing a thiazole
ring (2j) and a pyrimidine ring (2k) reacted to form the
product 3aj and 3ak, respectively, with high diastereoselec-
tivity and enantioselectivity (>20:1 dr, >99% ee). The reac-
tion with t-butyl sorbyl carbonate proceeded smoothly,
furnishing the product 3al in 90% yield with 17:1 dr and
>99% ee.
To further demonstrate the stereodivergence of this al-
lylation reaction, both diastereomers of 3ca, 3ea, 3ja, 3ac,
3ad, 3ak were prepared in high yield with high regio-, dia-
stereo- and enantio-selectivity (Table 4).
stereodivergent allylic substitutions is summarized in Table
2. Various para-substituted phenyl acetic acid esters were
suitable for this transformation. Electron-donating (3aa,
3da, 3ea), electron-neutral (3ba, 3ca) and electron-
withdrawing (3fa) functional groups on the phenyl ring of
phenyl acetic acid esters were tolerated in this reaction,
furnishing the corresponding products in high yields
(≥77%), high dr (≥11:1) and excellent ee (≥97%). The reac-
tion with 4-methylsulfonyl phenyl acetic acid ester (1m), a
substrate bearing a readily enolizable position, due to the
strong electron-withdrawing effect of the sulfonyl group,
formed the product 3ma in high yield (88%), but with
modest dr (3.8:1). Further investigations showed that the
low diastereoselectivity resulted from competing reaction
of 1m with 2a occurring without participation of BTM, not
from racemization of the product (Table S4).
The pentafluorophenyl ester products generated from this
allylation are readily elaborated under mild conditions.
i
Addition of benzyl amine and Pr2NEt into the reaction
mixture at the end of the allylation reaction resulted in the
formation of amide 4aa in a one-pot manner (98% yield
Table 4. Examples of Stereodivergencea
Substitutions at the ortho (3ga, 3ha) or meta (3ia) posi-
tion on the phenyl ring of phenyl acetic acid esters had little
effect on the allylation reaction; the corresponding products
were all obtained in ≥89% yield with ≥11:1 dr and ≥98%
ee. The allylation also occurred with heteroaryl acetic acid
esters. For example, 1l, which is derived from the non-
steroidal anti-inflammatory drug indomethacin, was al-
lylated in 92% yield with >20:1 dr and >99% ee. In the
i
cases of 3ga and 3la, addition of 1.1 equiv of Pr2NEt was
necessary to reach full conversion of the starting allylic
carbonates within 9 h, presumably by accelerating the
enolazation of the acyl-BTM intermediate.
The scope of allylic carbonates that underwent the ste-
reodivergent allylic substitutions with aryl acetic acid esters
is summarized in Table 3.17 Various substituents on the
phenyl ring of cinnamyl carbonates were tolerated, giving
the corresponding products in ≥90% yield, ≥17:1 dr, and
≥98% ee (3aa – 3ah). The allylic substitutions also oc
aSee SI for experimental details.
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Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2068. (c) Chen, W.;
with >20:1 dr and >99% ee). Similarly, one-pot syntheses
of the methyl ester 5aa and carboxylic acid 6aa were
realized with 4-dimethylaminopyridine (DMAP) as the
catalyst for methanolysis and hydrolysis of 3aa. Finally,
the primary alcohol 7aa was obtained through reduction of
3aa in 98% yield with >20:1 dr and >99% ee.
Hartwig, J. F. J. Am. Chem. Soc. 2013, 136, 377. (d) Liu, W.-B.;
Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298. (e)
Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem.
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Sci. 2015, 6, 4525. (i) Zhuo, C.-X.; Cheng, Q.; Liu, W.-B.; Zhao, Q.;
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Am. Chem. Soc. 2016, 138, 5234. (l) Wu, Q.-F.; Zheng, C.; Zhuo, C.-
X.; You, S.-L. Chem. Sci. 2016, 7, 4453.
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In summary, we show that the combination of a metal-
Scheme 3. Derivatizations of (R,R)-3aaa
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2015, 54, 14363.
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aConditions: (a) iPr2NEt (1.5 equiv), BnNH2 (1.3 equiv), r.t., 12 h; (b)
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Org. Lett. 2015, 17, 5824.
o
DMAP (0.2 equiv), Et3N (5.0 equiv), MeOH/THF, 65 C, 12 h; (c)
DMAP (0.2 equiv), Et3N (5.0 equiv), H2O/THF, 65 oC, 12 h; (d)
LiAlH4 (1.5 equiv), THF, r.t., 12 h.
lacyclic iridium complex and a chiral Lewis base catalyzes
the stereodivergent allylic substitutions with aryl acetic
acid esters. All four possible stereoisomers of the resulting
products containing two contiguous stereocenters are ac-
cessible by simple permutations of the enantiomers of the
two catalysts. The activated pentafluorophenyl esters as
nucleophile precursors in this reaction allowed regeneration
of the Lewis base catalyst through a “rebound” strategy,
while simultaneously allowing the resulting allylation
products to be converted readily to enantioenriched amides,
unactivated esters and carboxylic acids. Studies to expand
the scope with respect to general aliphatic carboxylic acid
derivatives are undergoing in our laboratory.
ASSOCIATED CONTENT
Experimental procedures, spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
ACKNOWLEDGEMENTS
Dr. Antonio DiPasquale is acknowledged for X-ray crystal-
lographic analysis and support from NIH Shared Instru-
mentation Grant S10-RR027172. We thank the NIH (GM-
55382) for support.
(11) Lee, S. Y.; Neufeind, S.; Fu, G. C. J. Am. Chem. Soc. 2014,
136, 8899.
(12) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem.
Soc. 2009, 131, 18028.
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J. Am. Chem. Soc. 2014, 136, 4476.
(14) Schwarz, K. J.; Amos, J. L.; Klein, J. C.; Do, D. T.; Snaddon,
T. N. J. Am. Chem. Soc. 2016, 138, 5214.
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R'
R'
O
O
O
LB*
O
R'
R'
O
O
R
or
or
R
OAr
LB*
OAr
OAr
OAr
OAr
R
R
R
R
LB* = chiral Lewis base
Synergistic
Catalysis
[Ir]*
6
R'
[Ir]*
R'
X
7
all 4 stereoisomers accessible
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