Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries

Article abstract of DOI:10.1021/ja205107x

A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.

Full text of DOI:10.1021/ja205107x

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pubs.acs.org/JACS
Highly Enantioselective Direct Alkylation of Arylacetic Acids with
Chiral Lithium Amides as Traceless Auxiliaries
Craig E. Stivala and Armen Zakarian*
Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, United States
S Supporting Information
b
ABSTRACT: A direct, highly enantioselective alkylation of
arylacetic acids via enediolates using a readily available chiral
lithium amide as a stereodirecting reagent has been devel-
oped. This approach circumvents the traditional attachment
and removal of chiral auxiliaries used currently for this type
of transformation. The protocol is operationally simple, and
the chiral reagent is readily recoverable.
Figure 1. Selected C2-symmetric amines evaluated for the enantiose-
lective allylation of phenylacetic acid (enantioselectivity is shown).
he enantioselective alkylation of carboxylic acids at the
R-position is a transformation of fundamental importance
T
Scheme 1. Outline of the Direct Enantioselective Alkylation
of Arylacetic Acids
in chemical synthesis. The chiral-auxiliary-based methodology
has remained dominant in this area, especially for the installation
of unactivated primary and secondary alkyl groups.1 The exten-
sively utilized oxazolidinone2 and pseudoephedrine3 auxiliaries
have set the standards for generality, high stereocontrol, and
practicality since their first introduction into enolate alkylation
methodology.4,5 The auxiliary-based alkylation of carboxylic
acids necessitates a three-stage process: (1) attachment of an
appropriate auxiliary, (2) stereoselective alkylation, and (3)
hydrolytic removal and recovery of the auxiliary. With the goal
of developing an alternative single-step method, we initiated a
study of direct enantioselective alkylation of carboxylic acids
through the intermediacy of enediolates employing chiral lithium
amides as noncovalent stereodirecting agents.6 Our preliminary
findings with aryl- and heteroarylacetic acids indicate that high
enantioselectivity is realized by this approach following an
operationally simple protocol described herein.
styrene oxide was developed by chemists at Amgen, making it
a readily available reagent.6
The direct allylation of phenylacetic acid (shown in Scheme 1)
was used for initial optimization studies, and some of the key
findings are illustrated in Table 1. In all cases, a clean transforma-
tion was observed, providing mixtures of the allylation product
and the starting material only. The chiral amine was recovered by
a simple extraction with aqueous HCl in nearly quantitative yield.
The stoichiometry of the chiral amine and n-butyllithium is
among the reaction parameters essential for high enantio-
selectivity.4,5 In control experiments with 4.0 equiv of n-butyl-
lithium relative to phenylacetic acid, the enantioselectivity eroded
substantially when less than 1.0 equiv of (R)-2 was employed
(entries 1 and 2). Somewhat lower ee’s were noted with 2 equiv of
the chiral amine (entries 4 and 5). Reproducibly high enantioselec-
tivity was achieved when only a slight excess of the amine
(1.03À1.05 equiv) was used (entry 3). With the free amine instead
of its bislithium amide as the additive (2.0 equiv of n-BuLi), racemic
product is formed while high conversion is maintained (entry 6).
During early experimentation, we found that the level of enantios-
electivity was dependent on the quality of n-butyllithium, which we
As reactive intermediates, enediolates offer the advantages of
superior nucleophilicity and geometrical symmetry, eliminating
the issue of E/Z selectivity during enolization and confining the
problem to facial selectivity in the enediolate alkylation step. The
promise of this approach was first recognized more than two
decades ago by the groups of Shioiri7 and subsequently Koga.8
Although moderate yields and enantioselectivities were reported,
these seminal studies provided a conceptual basis for the use of
chiral lithium amide aggregates for stereoselective alkylation of
carboxylic acids. In our work, we discovered that application of
readily available9 dimeric chiral tetramine bases results in a drastic
improvement in both yield and enantioselectivity, providing a
straightforward protocol for a direct enantioselective alkylation
of carboxylic acids even with less reactive secondary alkyl iodides.
A preliminary screening of C2-symmetric tetramines, a repre-
sentative group of which is shown in Figure 1, revealed that
tetramine 2 containing piperidine subunits and a three-carbon
linker exerted the highest enantiodirecting power.10,11 A two-
step, multikilogram-scale preparation of enantiopure 2 from
Received: June 2, 2011
Published: July 11, 2011
r
2011 American Chemical Society
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Table 1. Optimization Studies for Enantioselective Allylation
of Phenylacetic Acid with (R)-2
by the observation of drastically lower enantioselectivity when the
allylation reaction was carried out in the presence of lithium
n-butoxide or lithium bromide (entries 8 and 9). Among solvents
evaluated in this protocol (ethyl ether, toluene, 1,2-dimethoxyethane,
2-methyltetrahydrofuran), tetrahydrofuran (THF) proved to be the
optimal solvent for high enantioselectivity and high conversion.
High enantioselectivity is maintained with a broad range of
alkyl halides and in fact appears to improve with less reactive,
sterically more hindered alkylating agents (Table 2). With more
hindered reagents, the high nucleophilicity of enediolates offers a
particular advantage. Methylation with iodomethane was com-
plete within seconds and proceeded effectively as a titration,
affording (S)-2-methylphenylacetic acid in 83% isolated yield
and 88% ee (entry 1). Ethylation of phenylacetic acid was also
rapid (10 min), giving the product in 81% yield and 96% ee
(entry 2). Higher enantioselectivity was observed with more
hindered isobutyl (98% ee), isopropyl (97% ee), and cyclopentyl
iodides (96% ee), which required longer reaction times (5À24 h)
(entries 5À7). Activated electrophiles such as benzyl bromide
and methallyl bromide afforded alkylation products with 92 and
91% ee, respectively (entries 3 and 4). Functionalized alkylating
agents are also suitable. For example, alkylation with 4-(tert-
butyldimethylsiloxy)-1-iodobutane12 took place in 87% yield and
93% ee (entry 8), while alkylation with 3-bromomethyl-2-
fluoropyridine13 occurred in 93% yield and 91% ee (entry 9).
High lithium amide-controlled diastereoselectivity was realized
with chiral alkyl iodides (entries 10À12). When (S)-1-iodo-2-
methylbutane was used,14 highly diastereoselective alkylations
(99% dr) were achieved with (R)-2 or (S)-2 (entries 10 and 11).
No influence of the alkylating agent stereochemistry on diaster-
eoselectivity was noted. Alkylation with a more functionalized
(S)-2,2-dimethyl-4-iodoethyldioxolane15 provided the expected
product in 74% yield and 91% dr, while the same alkylation with
lithium diisopropylamide (LDA) afforded a ∼1:1 mixture of dia-
stereomers (entry 12). Importantly, alkylations with valuable func-
tionalized and chiral alkyl halides were performed using a nearly
stoichiometric amount of the reagent (1.0À1.2 equiv for entries
8À12). The unreacted halide could be recovered if necessary, as no
side reactions such as elimination or amide N-alkylation were observed.
The scope of aryl- and heteroarylacetic acids was evaluated
using enantioselective alkylation with iodoethane as a reference
reaction (Table 3, entries 1À16). Uniformly, the reactions were
characterized by a clean alkylation process, and in most cases the
yields closely corresponded to the conversions, exceeding 90%
based on recovered starting material. Substitution at the para
position with fluorine, chlorine, or bromine had virtually no effect
on the enantioselectivity, which maintained high values in the
range 93À96% ee (entries 1À3).16 A slight decrease in enantios-
electivity to 89% was observed during ethylation of 4-methox-
yphenylacetic acid (entry 4). Methyl and methoxy groups at the
ortho and meta positions had no significant effect on enantios-
electivity and conversion (entries 5À8). Alkylations of disubsti-
tuted 3,4-dichlorophenylacetic acid occurred in 92% ee (entry 9),
while those of 1- and 2-naphthylacetic acids gave products in 92
and 96% ee with notably higher conversion, which appeared to be
general for this type of substrate (entries 10, 11, 21, and 24).
Heteroarylacetic acids also proved to be substrates, showing
high enantioselectivities for a diverse range of substrates. 2-Fur-
ylacetic acid was ethylated in higher enantioselectivity (97%;
entry 12), but the conversion was ∼65%. A similar level of
enantioselectivity was observed with 3-benzofuranacetic acid and
2-thiopheneacetic acid, and conversion was restored to typical
entry
reaction conditionsa
ee (%) conversion (%)
1
2
3
4
5
6
7
8
n-BuLi (4.0 equiv), (R)-2 (0.8 equiv)
n-BuLi (4.0 equiv), (R)-2 (0.9 equiv)
n-BuLi (4.0 equiv), (R)-2 (1.03 equiv)
n-BuLi (4.0 equiv), (R)-2 (1.10 equiv)
n-BuLi (4.0 equiv), (R)-2 (2.05 equiv)
n-BuLi (2.0 equiv), (R)-2 (1.05 equiv)
n-BuLi (4.0 equiv), (R)-2 (1.10 equiv)b
n-BuLi (4.0 equiv), (R)-2 (1.10 equiv),
n-BuOLi (1.0 equiv)
67
67
68
88
93
91
80À95
75
85À95
89
0
88
57
77
52
48
9
n-BuLi (4.0 equiv), (R)-2 (1.10 equiv),
LiBr (1.0 equiv)
9
23
a n-BuLi, PhCH2CO2H (0.70 mmol), and (R)-2 were combined at 0 °C
in THF. After 15 min, allyl bromide was added at À78 °C over 10 min.
See the Supporting Information for additional experimental details.
b Deprotonation with n-BuLi was carried out at À78 °C, not 0 °C.
Table 2. Scope of the Alkylating Agenta
a Enantiomeric excess was determined by HPLC using a chiral stationary
phase (see the Supporting Information for details). With the exception of
entry 11, all reaction were performed with the R enantiomer of 2. b 1.2 equiv
of the alkylating agent was used. c 1.0 equiv of the alkylating agent was used.
d 1.3:1 dr was obtained with LDA. e 1:1 dr was obtained with LDA.
attributed to the presence of ionic lithium contaminants (LiOBu-n,
LiOH, etc.) in aged reagent bottles. This conjecture was confirmed
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Table 3. Enantioselective Alkylation: Carboxylic Acid Scopea
a Enantiomeric excess was determined by HPLC using a chiral stationary phase (see the Supporting Information for details). b Isolated yield of the
corresponding alcohol over two steps after reduction of the acid with LiAlH4.
Scheme 2. Large-Scale Direct Enantioselective Alkylation
Experiment
Scheme 3. Asymmetric Synthesis of γ-Secretase Inhibitor 1
by Enantioselective Alkylation
values with the latter substrate (entries 13 and 14). Remarkably,
R-ethylation of 3-pyridylacetic acid closely matched that of
phenylacetic acids in terms of enantioselectivity (95% ee, 61%
yield; entry 16), while 2-pyridylacetic acid was unreactive and
displayed poor enantioselectivity (entry 15).17
To gain a broader overview of the reaction scope, the
alkylating agent was varied to include iodomethane and 2-iodo-
propane in the next set of experiments. Direct R-methylation of
N-methyl-3-indoleacetic acid, which we anticipated to be among
the more challenging processes, took place in good yield (71%)
with a reasonably high enantioselectivity of 84% (entry 17). A
number of known nonsteroidal anti-inflammatory drugs (NSAIDs)
have been prepared by direct enantioselective R-methylation of the
corresponding arylacetic acids. Naproxen, flurbiprofen, and fenopro-
fen were readily produced in 94, 85, and 88% ee and high isolated
yields, respectively, (entries 18, 20, and 21). Methylation of 4-biphe-
nylacetic acid proceeded in higher enantioselectivity relative to (2-
fluorobiphen-4-yl)acetic acid (entry 18). The exquisitely high
enantioselectivity and yield in the methylation of (6-methoxy-
naphthalen-2-yl)acetic acid to give naproxen was characteristic of
naphthaleneacetic acids. With less reactive 2-iodopropane, high ena-
ntioselectivity was maintained for 4-methoxyphenyl-, 3-(trifluo-
romethyl)phenyl-, and 3-naphthaleneacetic acids (97, 91, and 96% ee,
respectively; entries 22À24).
(Scheme 2). High enantioselectivity and yield were maintained
on this scale, and the chiral amine was recovered in pure form in
99% yield by a simple extraction with aqueous hydrochloric acid.
In fact, both the enantioselectivity and yield improved upon
scale-up.
The direct enantioselective alkylation was applied to the
synthesis of γ-secretase modulator 1, which has been investi-
gated in preclinical studies for its potential in treatment of
Alzheimer’s disease (Scheme 3).18 Consecutive bromination of
ethyl (3-chloro-4-hydroxyphenyl)acetate and O-alkylation of the
resulting substituted phenol with (bromomethyl)cyclopropane
afforded 2, which was advanced further by a SuzukiÀMiyaura
cross-coupling with 4-(trifluoromethyl)phenylboronic acid fol-
lowed by hydrolysis to give carboxylic acid 3. Direct enantiose-
lective alkylation of 3 with isobutyl iodide using the protocol
developed in our studies delivered 1 in 97% ee and 72%
isolated yield.
A large-scale application of the protocol was illustrated by
direct alkylation of 10 g of phenylacetic acid with 2-iodopropane
In closing, an operationally simple protocol for direct enan-
tioselective alkylation of aryl- and heteroarylacetic acids has been
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COMMUNICATION
developed. This protocol offers a one-step alternative to tradi-
tional auxiliary-based methods and utilizes a readily accessible
chiral lithium amine that can be recovered with high efficiency by
a simple extraction with aqueous acid. Applications on scale and
with functionalized substrates and alkylating agents have been
demonstrated. Efficient alkylations with unreactive alkyl halides
are enabled by the high nucleophilicity of enediolates. Further
studies to probe the origin of the stereoselectivity19 and expand
the scope of the alkylation process to other types of carboxylic
acids are underway.20
(c) Hung, K.-y.; Harris, P. W. R.; Brimble, M. A. J. Org. Chem. 2010,
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(9) For a kilogram-scale preparation of (R)-2 from styrene
oxide, see: Frizzle, M. J.; Caille, S.; Marshall, T. L.; McRae, K.; Nadeau,
K.; Guo, G.; Wu, S.; Martinelli, M. J.; Moniz, G. A. Org. Process Res. Dev.
2007, 11, 215–222.
(10) We carried out a more comprehensive survey of the bases than
that shown in Figure 1. Its detailed presentation is beyond the scope of
this communication and will be described separately.
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40, 2803–2806.
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(13) (a) Universite, L.; Attardo, G.; Tripathy, S.; Gagnon, M. Methyl
Sulfanyl Pyrimidines Useful as Antiinflammatories, Analgesics, and
Antiepileptics. WIPO Pat. Appl. WO2010/132999 A1, 2010. (b) Wagner,
S.; Breyholz, H.-J.; Law, M. P.; Faust, A.; H€oltke, C.; Schr€oer, S.; Haufe, G.;
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, characterization data, copies of 1H and 13C NMR spectra,
and HPLC traces for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
zakarian@chem.ucsb.edu
’ ACKNOWLEDGMENT
We thank Amgen for the donation of more than 100 g of
amine (R)-2 that enabled the research described in this article,
and the assistance of Dr. Seb Caille (Amgen, Thousand Oaks,
CA) is especially appreciated. Financial support was provided by
the National Institutes of Health National Institute of General
Medical Sciences (R01 GM077379) and kind gifts from Amgen
and Eli Lilly, with additional support from the Tobacco-Related
Disease Research Program (predoctoral award to C.E.S.). We are
grateful to Dr. Hongjun Zhou for continued assistance with
NMR spectroscopy.
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