Synthesis of Complex Tertiary Glycolates by Enantioconvergent Arylation of Stereochemically Labile α-Keto Esters

Article abstract of DOI:10.1021/jacs.7b00943

Enantioconvergent arylation reactions of boronic acids and racemic β-stereogenic α-keto esters have been developed. The reactions are catalyzed by a chiral (diene)Rh(I) complex and provide a wide array of β-stereogenic tertiary aryl glycolate derivatives

Full text of DOI:10.1021/jacs.7b00943

Article
pubs.acs.org/JACS
Synthesis of Complex Tertiary Glycolates by Enantioconvergent
Arylation of Stereochemically Labile α‑Keto Esters
Samuel L. Bartlett, Kimberly M. Keiter, and Jeffrey S. Johnson*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: Enantioconvergent arylation reactions of bor-
onic acids and racemic β-stereogenic α-keto esters have been
developed. The reactions are catalyzed by a chiral (diene)Rh(I)
complex and provide a wide array of β-stereogenic tertiary aryl
glycolate derivatives with high levels of diastereo- and
enantioselectivity. Racemization studies employing a series of
sterically differentiated tertiary amines suggest that the steric
nature of the amine base additive exerts a significant influence
on the rate of substrate racemization.
aminations employing α-alkyl, aryl branched imines that
presumably racemize via enamine intermediates.7 The cyclo-
hexanecarboxaldehyde derivatives utilized by Ward and co-
workers likely racemize via an analogous pathway.3e Dynamic
kinetic hydrogenations of nonactivated aldehydes and ketones
have been shown to occur in the presence of tert-butoxide
bases.8 Nevertheless, with the consideration that facile
racemization is essential, the execution of DKRs employing
compounds of lower acidity is more challenging.9 However, in
this context the use of less activated substrates would allow
access to heretofore unknown glycolate architectures.
INTRODUCTION
■
The conversion of racemic α-stereogenic ketones to
enantiomerically enriched alcohol building blocks through
transformation of the carbonyl functionality is an enabling
chemical transformation.1 Transition-metal-catalyzed dynamic
kinetic hydrogenation reactions, pioneered by Noyori, have
been widely employed for the production of enantioenriched
secondary alcohols (Scheme 1A).2 The synthesis of tertiary
alcohols through the enantioconvergent addition of stabilized
carbon nucleophiles to configurationally labile electrophiles is
comparatively less common.3 Reported examples employ basic
catalysts or additives to promote simultaneous activation of the
pro-nucleophile and enantiomerization of the electrophile.
Considering this dual role of base in the context of designing
other stereoconvergent processes, the transition-metal-cata-
lyzed addition of nonstabilized carbon nucleophiles to ketones
emerged as a compelling opportunity to generate complex
tertiary alcohols not accessible through other methods (Scheme
1B). The Hayashi−Miyaura-type reactions typically rely on the
base promoted transmetalation of an organoboron or organo-
silicon pro-nucleophile to a chiral metal complex.4 As an
example, the enantioselective addition of arylboronic acids to
carbonyl derivatives, including α-keto esters, has been widely
developed (Scheme 1C).5 Considering their chemical stability,
ease of handling, and broad commercial availability,6 we
envisioned that the deployment of arylboronic acids in an
enantioconvergent addition to racemic α-keto ester electro-
philes would facilitate the production of diverse, stereochemi-
cally complex glycolate architectures. The purpose of this article
is to convey experimental findings related to the dynamic
kinetic 1,2-addition of arylboronic acids to racemic α-keto
esters (Scheme 1D).
RESULTS AND DISCUSSION
■
In light of the considerations described above, the β-alkyl, aryl-
substituted α-keto ester derivative 1a was chosen as a model
substrate for this transformation (Table 1). Our group has
previously developed dynamic kinetic resolutions of α-keto
esters that occur in the presence of tertiary amines;2l−n,3a
therefore, we reasoned that an amine base would promote
substrate racemization. Sterically hindered Hunig’s base
̈
(iPr2NEt) was initially selected in an effort to minimize
interference with the Rh(I)-catalyst through nonproductive
binding. A substoichiometric quantity of potassium hydroxide
was employed because analogous conditions promote the
Hayashi−Miyaura arylation of isatins and 1a is sensitive to
stoichiometric hydroxide base.10 An initial evaluation of ligands
revealed that the Ph-substituted norbornadiene derived ligand
A developed by Hayashi and co-workers11 provided promising
levels of enantioselectivity, although low conversion was
observed under these conditions (entry 1). Further screening
showed that the 4-CF3C6H4- and 3,5-(CF3)2C6H3-substituted
analogues B and C provided higher levels of enantioselection;
however, conversion remained low (entries 2 and 3). The
Carbonyl electrophiles and their derivatives lacking electron
withdrawing functionality (i.e., ketone, ester, or halogen) at the
chiral α center are underutilized in dynamic kinetic resolutions
(DKR). List and Zhao have reported dynamic kinetic reductive
Received: January 27, 2017
© XXXX American Chemical Society
A
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Scheme 1. Background and Proposed Enantioconvergent
Arylation
Table 1. Reaction Optimization
supposed low acidity of these substrates caused us to wonder if
a simple kinetic resolution was occurring under these
conditions, but this possibility was ruled out by isolation of
racemic unreacted 1a from entry 3. Interestingly, the benzyl-
substituted ligand D provided low enantioselectivity slightly in
favor of the opposite enantiomer, while also exhibiting
drastically lower levels of diastereocontrol over the formation
of 3a (entry 4). Switching the inorganic base promoter from
potassium hydroxide to CsF while increasing the loading to 3.0
equiv allowed for full conversion to the desired aryl glycolate,
albeit with a striking drop in enantioselectivity (entry 5).
a
b
All reactions were conducted on a 0.10 mmol scale. Determined by
c
1H NMR analysis of the crude reaction mixture. Determined by
HPLC using a chiral stationary phase. Reaction time = 36 h. 3.0
equiv CsF. 6.0 equiv of Et3N. CHCl3 as solvent. Reaction time = 48
d
e
f
g
h
i
j
k
h. Reaction was run at 60 °C. 3.0 equiv PhB(OH)2, Substrate ester =
l
tBu. Substrate ester = CH2Ph
Simply replacing Hunig’s base with triethylamine restored the
̈
previously observed levels of enantioselectivity (entry 6).
Further increasing the amount of triethylamine to 6.0 equiv
provided higher levels of enantioselectivity (entry 7), although
a longer reaction time was necessary to achieve full conversion
under these conditions. Satisfactory levels of enantioselectivity
were achieved when chloroform was used as solvent in place of
methylene chloride (entry 8). At this stage of optimization it
was noted that both the 4-CF3C6H4- and 3,5-(CF3)2C6H3-
substituted norbornadiene ligands B and C provided identical
levels of enantioselectivity (entries 8 and 9). Running the
reaction at 60 °C does not influence the enantio- or
diastereoselectivity of the process (entry 10). Substituting the
Finally, although phosphine5b and phosphite5a ligands have
been utilized in Hayashi−Miyaura-type arylation reactions of α-
keto esters, a complex of triphenylphosphite (E, entry 13) as
well as hydroxy[(S)-BINAP]rhodium(I) dimer (F, entry 14)
failed to catalyze this transformation.
At this juncture we sought to understand the large
contribution to product enantioselectivity associated with the
superficially similar structure of the amine base additive. We
hypothesize that this difference might arise from a faster rate of
starting material racemization under the action of triethylamine.
Using Hunig’s base in conjunction with low inorganic base
̈
concentration resulted in high levels of product enantioselec-
tivity, and the unreacted starting material recovered from the
reaction was not enantioenriched (entry 3, Table 1), suggesting
t
ethyl ester of 1a with bulkier Bu or Bn groups (entries 11 and
12, respectively) did not result in improved enantioselectivity.
B
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that an efficient dynamic kinetic resolution is occurring under
these conditions. We postulate that under conditions of low
inorganic base concentration the arylation reaction is slow
for a particular substrate. Ultimately, electron-rich arylboronic
acids were found to be suitable reaction partners as the p-tolyl
adduct 3b was formed in high yield with high levels of
diastereo- and enantiocontrol. Electron-poor arylboronic acids
could also be used; however, in the case of p-fluoro- and p-
chlorophenylboronic acid, a larger excess was required to
achieve good yields. Nevertheless, high levels of diastereo- and
enantioselectivity were still observed for addition products 3c
and 3d. Substitution of the arylboronic acid at the m-position
was also tolerated. For instance, the m-methoxy and m-tolyl
adducts 3e and 3f were obtained in good yield, with high levels
of stereocontrol. Electron withdrawing substituents were also
tolerated at this position, and the use of m-chlorophenylboronic
acid afforded the desired arylation product 3g in good yield
with high levels of stereocontrol. Polyaromatic boronic acids
were also suitable substrates for this transformation, as the 2-
naphthyl adduct 3h could be obtained in good yield with
similarly high levels of diastereo- and enantiocontrol. The
sterically demanding o-methoxy adduct 3i was formed in good
yield with high levels of enantiocontrol, although in this
instance a relatively large excess of the boronic acid substrate
was required to achieve full conversion. Finally, we found that
even unprotected 6-indoylboronic acid could be employed,
furnishing adduct 3j, while maintaining reaction efficiency. It
should be noted that at this stage of optimization certain
electron-poor arylboronic acid substrates cannot be used, as the
4-pyridyl and 5-indazole adducts 3k and 3l were not detected.
In addition, the reaction with 2-thienylboronic acid only
reached 11% conversion after 36 h under the optimized
reaction conditions (not shown). Efforts to address these
limitations are currently underway in our laboratory.
relative to Hunig’s base promoted racemization (k > kfast)9
̈
rac
resulting in a dynamic kinetic resolution. However, in entry 5
the higher loading of CsF results in a faster arylation reaction
for both substrate enantiomers, presumably due to higher rates
of transmetalation, while the rate of racemization by Hunig’s
̈
base occurs too slowly for efficient dynamic kinetic
resolution.12 To gain further insight into this phenomenon
and to provide support for our hypothesis we studied the rate
of racemization of 1a using an array of tertiary amine bases
(Figure 1). At room temperature racemization with triethyl-
Next, we explored the scope of the reaction with respect to
the α-keto ester reaction partner (Table 2). Substrates bearing
electron donating substituents at the para-position of the aryl
ring were suitable reaction partners. For example, the p-tolyl-
substituted product 3m was obtained in good yield with high
levels of stereocontrol. Higher levels of enantioselectivity were
observed with this substrate when 2-naphthylboronic acid was
employed as a nucleophile furnishing addition product 3n.
Apparently, the electron-rich p-methoxy-substituted substrate
was subject to facile racemization under the reaction conditions,
as product 3o could also be obtained in good yield with high
levels of stereocontrol. An o-F-substituted α-keto ester was
subject to phenylboronic acid addition, producing 3p in
acceptable yield and high diastereoselectivity and decent levels
of enantiocontrol. The o-tolyl product 3q was afforded in 57%
yield, and 94:6 er, while the m-tolyl product 3r was formed in
88% yield with 96:4 er, suggesting that the steric nature of the
α-keto ester aryl component has a slight impact on reaction
efficiency and enantioselectivity. A 2-naphthyl-substituted α-
keto ester could also be used, affording addition product 3s
with high levels of enantio- and diastereoselectivity. Product 3s
could be enriched to 97.5:2.5 er following a single
crystallization. Notably, arylation of an unprotected 3-indole-
substituted α-keto ester with 6-indoleboronic acid afforded
bis(indole) adduct 3t in good yield with high levels of
selectivity. The use of 2-naphthyl and m-tolylboronic acid was
also successful with this α-keto ester (see Supporting
Information). Larger alkyl substituents at the β-position were
tolerated, and the β-ethyl-substituted product 3u was obtained
in good yield with acceptable levels of enantiocontrol. Product
3u could be obtained as a single enantiomer in acceptable yield
following a single recrystallization. The arylation reaction
Figure 1. Influence of base structure on racemization rate. Superscript
a indicates trial conducted at 40 °C, with 6.0 equiv of Hunig’s base.
̈
amine was rapid; within 8 min the extent of racemization had
reached 87%, and complete racemization occurred after 20 min.
Tri-n-butylamine exhibited a noticeably slower racemization
profile, but was still nearly complete within 20 min. In contrast
to triethylamine and tri-n-butylamine, the alkyl branched
Hunig’s base displayed a slow racemization profile, and 1a
̈
was still measurably enriched after approximately 1.7 h at room
temperature. When studied at 40 °C in the presence of 6 equiv
of Hunig’s base, racemization of 1a was enhanced, but complete
̈
racemization only occurred after 1 h. Thus, although Hunig’s
̈
base exhibits greater thermodynamic basicity than triethyl-
amine, it is less effective at promoting the racemization of 1a.13
Finally, N-methylpyrroldine, which possesses lower thermody-
namic basicity than triethylamine,14 displayed the fastest
racemization profile, promoting complete racemization of 1a
in under 2 min. The observed trend suggests the kinetic basicity
of the tertiary amine exerts a larger influence on the
racemization of 1a than its thermodynamic basicity. This
observation may prove to be generally important in the de novo
design of novel dynamic kinetic resolutions involving enolizable
carbonyl substrates.
With optimal reaction conditions in hand we began to study
the scope of the process with respect to the arylboronic acid
component (Table 2). It should be noted that while catalysts B
and C provide identical levels of selectivity for product 3a, in
certain cases it was found that one catalyst was more selective
C
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a
Table 2. Scope of Dynamic Kinetic Arylation Reaction
a
Reactions run on 0.1 mmol scale for 48 or 60 h (see SI for individual reaction times and boronic acid equivalents); reported yields and er values are
b
c
averages of two runs. Values in parentheses represent recrystallized yields and enantiomeric ratios. Catalyst B employed. Catalyst C employed.
exhibited functional group chemoselectivity in the presence of
competing functionality as the bromoaryl- and β-allyl-
substituted product 3v was obtained in acceptable yield with
high levels of stereocontrol. Notably, less than 10% of Heck-
type coproducts15 were observed during formation of 3v.
Additionally, no Suzuki-type products are observed in this
process. The branched diester product was formed in excellent
yield. Although lower levels of enantiocontrol were observed in
this reaction, product 3w can be accessed as a single
enantiomer in acceptable yield following a single crystallization.
Finally, although pyridine containing boronic acids are not
successful reaction partners at this stage of optimization, a 3-
pyridyl-substituted α-keto ester was tolerated under the
reaction conditions and afforded arylation product 3x in good
yields with high diastereo- and enantiocontrol. Product 3x
could also be recovered as a single enantiomer, albeit in lower
yield, after a single crystallization. Substrates bearing only
aliphatic substitution at the β-position have not been tested at
this juncture; presumably, these substrates are less acidic and
would be challenging to implement under the present reaction
conditions.
Scheme 2. Millimole Scale Arylation and Stereochemical
Model
using 0.5 mol % of the catalyst (1 mol % Rh) to afford 3y in
good yield with high levels of diastereo- and enantiocontrol.
Product 3y could be recrystallized to 99:1 er allowing the
absolute stereochemistry of 3y to be determined via X-ray
crystallography. The configuration of the other arylation
products 3a−3x were assigned by analogy.16 The observed
stereochemistry can be attributed to the C2-symmetric nature of
(R,R)-catalyst C which enforces high levels of enantiocontrol in
this reaction by effectively blocking the shaded quadrants in the
stereochemical model shown in Scheme 2; the bulky sp3 center
is guided to the top left quadrant. The diastereoselectivity of
this transformation is in accord with the Felkin−Ahn model.17
Having learned the scope of the DKR arylation process, we
sought to examine the effect of increasing the scale of the
reaction while simultaneously decreasing the catalyst loading
(Scheme 2). The 4-bromo-substituted α-keto ester 1y under-
went arylation with 2-naphthylboronic acid on a 1 mmol scale
D
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ORCID
Aromatic interactions appear to be important for achieving
high levels of enantio- and diastereoselectivity as evidenced by
the inferior results using the benzyl-substituted catalyst D.
Finally, considering the sterically encumbered nature of the
tertiary alcohol installed in the arylation reaction, we wondered
if this functionality could be leveraged in downstream
transformations. Preliminary findings have been promising.
For instance, unsaturated alcohol 3v undergoes iodoether-
ification to tetrahydrofuran 4v in 66% yield albeit without
diastereoselectivity (Scheme 3). The diastereomers of 4v were
easily separated by silica gel column chromatography.
Jeffrey S. Johnson: 0000-0001-8882-9881
Notes
The authors declare no competing financial interest.
CCDC 1502349, CCDC 1502350, and CCDC 1529845
contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge from the
Cambridge Crystallographic Date Centre via www.ccdc.cam.ac.
uk/data_request/cif.
ACKNOWLEDGMENTS
■
The project described was supported by Awards R01
GM103855 and R35 GM118055 from the National Institute
of General Medical Sciences. K.M.K. gratefully acknowledges
support from the Matthew Neely Jackson Undergraduate
Research Fellowship. X-ray crystallography was performed by
Dr. Peter White.
Scheme 3. Iodoetherification of 3v
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b00943.
■
S
Crystallographic data for C22H21O3Br (CIF)
Crystallographic data for C46H24Cl2F24Rh2 (CIF)
Crystallographic data for C42H28Cl2F12Rh2 (CIF)
Experimental procedures, and spectral and analytical data
(PDF)
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AUTHOR INFORMATION
Corresponding Author
*jsj@unc.edu
■
E
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