Palladium-Catalyzed Enantioselective Three-Component Synthesis of α-Arylglycines

Article abstract of DOI:10.1021/acs.orglett.6b02045

A general Pd-catalyzed, enantioselective three-component synthesis of α-arylglycines starting from sulfonamides, glyoxylic acid derivatives, and boronic acids was developed. This operationally straightforward procedure enables the preparation of a wide variety of α-arylglycines in high yields and excellent levels of enantioselectivity from a simple set of readily available starting materials. Incorporation of Pbf-amides gives a racemization-free access to N-unprotected α-arylglycines.

Full text of DOI:10.1021/acs.orglett.6b02045

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Enantioselective Three-Component Synthesis of
α‑Arylglycines
Tamara Beisel, Andreas M. Diehl, and Georg Manolikakes*
Department of Organic Chemistry and Chemical Biology, Goethe-University Frankfurt am Main, Max-von-Laue-Strasse 7, 60438
Frankfurt am Main, Germany
S
* Supporting Information
ABSTRACT: A general Pd-catalyzed, enantioselective three-
component synthesis of α-arylglycines starting from sulfona-
mides, glyoxylic acid derivatives, and boronic acids was
developed. This operationally straightforward procedure
enables the preparation of a wide variety of α-arylglycines in
high yields and excellent levels of enantioselectivity from a
simple set of readily available starting materials. Incorporation
of Pbf-amides gives a racemization-free access to N-unprotected α-arylglycines.
imino ester, would provide an attractive, more practical
alternative for the preparation of α-arylglycines.
α-Arylglycines are an important class of unnatural or non-
proteinogenic α-amino acids.1 The α-arylglycine fragment can be
found in many natural products and drugs, including peptide or
glycopeptide antibiotics, such as vancomycin2 or feglymycin,3 β-
lactam antibiotics (e.g., amoxicllin4 or cefprozil),5 or in the
antiplatelet agent clopidogrel.6 Optically active α-arylglycines
have been widely used as privileged chiral building blocks in the
preparation of biological active molecules, auxiliaries, or ligands.7
Consequently, the asymmetric synthesis of α-arylglycines has
received much attention. A variety of methods for the
preparation of this important compound class have been
developed.1,8 Among them, addition of arylboronic acids to α-
imino acids, the Petasis or borono-Mannich reaction, has
emerged as an attractive strategy due to the widespread
commercial availability of a large number of structural diverse
boronic acids.9 However, only electron-rich (hetero)aryl- or
vinylboronic acids are efficient coupling partners, and to the best
of our knowledge, no general catalytic asymmetric version of the
Petasis reaction for the synthesis of arylglycines has been
reported so far.10 The transition-metal-catalyzed addition of
boronic acids to preformed or in situ generated imines offers an
attractive alternative since it allows the utilization of less reactive
arylboronic acids.11 Whereas the Rh-, Pd-, and Ru-catalyzed
asymmetric addition of arylboronic acids to aryl- and aldimines
has been well-established,12 there are only few examples of
stereoselective, transition-metal-catalyzed reactions with α-
imino acids or esters.13 Ellman, Batey, Lu, and Xu reported
Rh- and Pd-catalyzed diastereoselective addition reactions of
arylboronic acids to N-tert-butanesulfinylimino esters.14 Cata-
lytic asymmetric arylations of preformed α-imino esters with
arylboronic acids were developed by Lu, Miyaura, and Zeng.15 In
general, the additional step for the preparation of the α-imino
esters, the difficult purification, and the instability of these highly
electrophilic compounds16 severely restrict the practicability of
these methods. A transition-metal-catalyzed, asymmetric multi-
component reaction,17 based on the in situ formation of the α-
Herein, we report the first general Pd-catalyzed asymmetric
three-component synthesis of α-arylglycine derivatives starting
from sulfonamides, arylboronic acids, and glyoxylic acid
derivatives (Scheme 1). The obtained N-sulfonyl α-arylglycine
products are versatile building blocks for subsequent trans-
formations.
Scheme 1. α-Arylglycine Syntheses by Addition of Boronic
Acids to α-Imino Acid Derivatives
Recently, we could develop a Pd-catalyzed enantioselective
three-component synthesis of α-arylamines using sulfonamides,
arylboronic acids, and either aryl or alkyl aldehydes.18 To our
delight, the same catalyst system, a combination of 10 mol % of
Pd(TFA)2 and 15 mol % of the readily available chiral
bisoxazoline (S,S)-iPrBox,19 could catalyze the three-component
reaction between phenylboronic acid, p-toluenesulfonamide, and
ethyl glyoxalate as the aldehyde component, furnishing the
Received: July 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02045
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Letter
a
desired α-arylglycine 4a in 82% yield and >99:1 er (Scheme 2).
This reaction exhibits several features, which lead to an
Scheme 3. Variation of Glyoxalates
a
Scheme 2. Variation of Sulfonamides
a
Yields of the isolated products. Enantiomeric ratios determined by
chiral HPLC analysis. TFA = trifluoroacetic acetate. iPr = isopropyl.
Box = 4,4′,5,5′-tetrahydro-2,2′-bioxazole. Ts = para-tosyl. Bn = benzyl.
a
Scheme 4. Variation of Boronic Acids
a
Yields of the isolated products. Enantiomeric ratios determined by
chiral HPLC analysis. TFA = trifluoroacetic acetate. tBu = tert-butyl.
Box = 4,4′,5,5′-tetrahydro-2,2′-bioxazole. p-Tol = para-tolyl.
operational simple process and are worth mentioning. A simple
catalyst system is sufficient for this efficient and highly
enantioselective transformation. No exogenous base, desiccant,
or additives such as silver salts have to be added. The reaction can
be performed without the exclusion of air and moisture because
imine hydrolysis is not an issue in the three-component reaction.
All starting materials are commercially available and can be
employed without further purification. Indeed, the purity of the
phenylboronic acid has been reported to be crucial for the
success in other transformations.12a,20 Most strikingly, commer-
cially available, technical ethyl glyoxalate, a solution of the
polymeric form in toluene, can be used directly.21 Various other
sulfonamides are suitable amide components for this reaction.
High yields and excellent enantioselectivities were obtained with
aromatic, heteroaromatic, or aliphatic sulfonamides. Steric or
electronic effects did not significantly affect yield or enantiose-
lectivities. Indeed, no influence of the sulfonamide structure on
the stereoselectivity was observed, and all products (4a−4k)
were formed with an enantiomeric ratio of 99:1 or better.
Moreover, several glyoxylic ester derivatives can be used as
aldehyde component (Scheme 3). Reactions of the methyl,
isopropyl, and benzylic esters furnished the desired α-arylglycine
derivatives 4l−4n in 83−86% yields and excellent enantiose-
lectivities (99:1 er or better).
a
Yields of the isolated products. Enantiomeric ratios determined by
chiral HPLC analysis. TFA = trifluoroacetic acetate. iPr = isopropyl.
Box = 4,4′,5,5′-tetrahydro-2,2′-bioxazole.
not react at all. Again, no substituent effects on the
enantioselectivity of the reaction were observed, and α-
arylglycines were isolated almost enantiopure.
From a synthetic point of view N-sulfonyl-protected α-
arylglycines can be problematic. Removal of common sulfonyl
protecting groups, such as the tosyl or the nosyl group, is
achieved under basic or reducing conditions.22 However, α-
arylglycines are prone to base-catalyzed racemization of the α-
stereocenter.1 Therefore, the incorporation of a sulfonamide,
which allows facile removal of the sulfonyl group under acidic
conditions, ideally with full compatibility to standard peptide
synthesis, would be highly desirable. Based on these require-
ments, we identified the 2,2,4,6,7-pentamethyl-2,3-dihydroben-
zofuran-5-sulfonyl (Pbf) group as most promising candidate.
The Pbf group, originally introduced for the side chain
protection of arginine, can be cleaved with acid, similar to the
conditions applied for Boc deprotection.23 It is compatible with
solid-phase peptide synthesis, and the corresponding sulfona-
mide 1b is readily available.24 The reaction of 1b with ethyl
glyoxalate and phenylboronic acid using our standard protocol
furnished the N-Pbf-protected α-arylglycine 4y in 82% yield and
Next, we explored the scope in terms of the boronic acid
component (Scheme 4). Various arylboronic acids were found to
be efficient starting materials and furnished the corresponding N-
sulfonyl α-arylglycines 4o−4x in high yields and excellent
enantioselectivities (er ≥99:1). Only the sterically hindered o-
tolyl and the electron-poor m-CF3-phenylboronic acid afforded
the products in lower yields, albeit with excellent stereo-
selectivity. Unfortunately, aryl boronic acids bearing stronger
electron-withdrawing substituents, such as −CN or −CO2Et, did
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Letter
>99:1 er (Scheme 5). Removal of the Pbf group with TFA and
DMS can be achieved with complete retention of configuration.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: g.manolikakes@chemie.uni-frankfurt.de.
Notes
Scheme 5. Examples with Pbf-Sulfonamide and Their
Deprotection
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Fonds der
Chemischen Industrie (Liebig fellowship to G.M.) and the
Stiftung Polytechnische Gesellschaft Frankfurt am Main (Ph.D.
fellowship to T.B.). We thank Prof. Michael Gobel (Goethe-
̈
University Frankfurt am Main) for his support, and BASF SE,
Evonik Industries AG, and Rockwood Lithium GmbH for the
generous donation of chemicals.
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02045.
Full experimental details and characterization data (PDF)
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DOI: 10.1021/acs.orglett.6b02045
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