The Enantioselective Dakin-West Reaction

Article abstract of DOI:10.1002/anie.201509863

Here we report the development of the first enantioselective Dakin-West reaction, yielding α-acetamido methylketones with up to 58 % ee with good yields. Two of the obtained products were recrystallized once to achieve up to 84 % ee. The employed methylimidazole-containing oligopeptides catalyze both the acetylation of the azlactone intermediate and the terminal enantioselective decarboxylative protonation. We propose a dispersion-controlled reaction path that determines the asymmetric reprotonation of the intermediate enolate after the decarboxylation.

Full text of DOI:10.1002/anie.201509863

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201509863
German Edition: DOI: 10.1002/ange.201509863
Organocatalysis
The Enantioselective Dakin–West Reaction
Raffael C. Wende, Alexander Seitz, Dominik Niedek, Sçren M. M. Schuler, Christine Hofmann,
Jonathan Becker, and Peter R. Schreiner*
Dedicated to Professor Wolfgang Steglich
Abstract: Here we report the development of the first
enantioselective Dakin–West reaction, yielding a-acetamido
methylketones with up to 58% ee with good yields. Two of the
obtained products were recrystallized once to achieve up to
84% ee. The employed methylimidazole-containing oligopep-
tides catalyze both the acetylation of the azlactone intermediate
and the terminal enantioselective decarboxylative protonation.
We propose a dispersion-controlled reaction path that deter-
mines the asymmetric reprotonation of the intermediate enolate
after the decarboxylation.
According to the currently accepted mechanism,[6] the
reaction of an amino acid with the anhydride leads to the N-
acetyl derivative 1 and subsequently to the mixed anhydride 2
(Scheme 2). Cyclization of 2 provides the oxazol-5(4H)-one
(azlactone) 3. Such azlactones are acidic owing to the
formation of resonance stabilized enolate 4 upon deprotona-
tion. Subsequent acetylation may occur at the enolate oxygen
atom (affording 5) or directly at the carbon atom to give 6.[7]
However, 6 is exclusively produced under the typical DW
reaction conditions because of concomitant O!C acyl trans-
fer (Steglich rearrangement).[8] Opening of 6 with acetic acid,
formed in previous steps, to the mixed anhydride 7 and
transacylation gives the b-keto acid 8,[6f] which is prone to
decarboxylation upon deprotonation. This final reaction step
affords the desired a-acetamido methylketone 10, likely via
enolate 9. Other pathways, for example, the acylation of 2 to
directly give 7,[9] were discussed as well but have been shown
to be rather improbable. It is evident from this mechanistic
picture that the intermediacy of 4 and 9 (Scheme 2) leads to
the observed complete racemization, making an asymmetric
reaction a difficult endeavor. We surmized, however, that an
enantioselective decarboxylative protonation[10] of 8 (via 9)
would afford enantioenriched products. Herein we show that
this is indeed possible with a tailor-made catalytic system.
We chose synthetic oligopeptides as catalysts[11] as these
should be well-suited for binding the amino acid derived
intermediates, as demonstrated for such platforms in acyl
transfer reactions.[12] Incorporation of catalytically active p-
methylhistidine (Pmh) in a dual role as Lewis base for the
acetyl transfer (Scheme 2) and as Brønsted base in the
decarboxylative protonation (Scheme 2) may allow perform-
ing the entire reaction by employing a single catalyst.
E
ven though the Dakin–West (DW) reaction dates back to
1928,[1] it is still one of the most effective synthetic procedures
to prepare a-acylamido ketones from primary a-amino
acids.[2] Generally, the treatment of an amino acid with an
acid anhydride and base, typically pyridine, at elevated
temperature provides the desired product upon liberation of
CO2 (Scheme 1). Numerous modifications of the original
reaction conditions were developed,[2] including catalytic
variants,[3] broadening its scope and applicability. Unsurpris-
ingly, the DW reaction found application in the preparation of
a-acylamido ketones as valuable precursors for various
biologically active compounds,[4] and even in Woodwardꢀs
fundamental total synthesis of strychnine.[5] Remarkably, no
asymmetric variant has been developed to date, thus restrict-
ing the use of this important reaction in modern synthetic
chemistry.
Our investigation commenced with an evaluation of
appropriate reaction conditions for the proposed reaction
sequence starting from dl-phenylalanine and our previously
successfully employed acylation catalyst 11[12] (Scheme 3; see
the Supporting Information for details). We found that the
methylimidazole moiety itself is not sufficiently basic to
deprotonate the azlactone 3a (pKa ꢀ 9[13] vs. pKa = 7.3 for
protonated N-methylimidazole)[14] and acetic acid is contin-
uously formed during the reaction. Addition of a base
significantly increases the reaction rate but has a deleterious
effect on enantioselectivity. Thus, we concluded that the
mechanistic complexity of the reaction necessitates well-
balanced reaction conditions to separate the acetylation of 3
and the decarboxylation. The use of a carbodiimide helps
overcome these challenges: it enables fast cyclization of 1 to 3,
acts as auxiliary base in the deprotonation step, and converts
Scheme 1. The Dakin–West reaction of a-amino acids.
[*] M. Sc. R. C. Wende, B. Sc. A. Seitz, M. Sc. D. Niedek,
Dipl.-Chem. S. M. M. Schuler, Dr. C. Hofmann,
Prof. Dr. P. R. Schreiner
Institute of Organic Chemistry
Justus-Liebig University, 35392 Giessen (Germany)
E-mail: prs@uni-giessen.de
Dr. J. Becker
Institute of Inorganic and Analytical Chemistry
Justus-Liebig University, 35392 Giessen (Germany)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201509863.
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Scheme 2. Proposed mechanism for the Dakin–West reaction.
Scheme 3. Testing and optimizing reaction conditions for selected catalysts. Reactions were performed on an analytical scale (0.1 mmol). The
absolute configuration of 10a was determined to be S by comparison of the retention times of an authentic sample on chiral-phase HPLC.
Enantiomeric excesses (a negative sign indicates the formation of the opposite enantiomer) for 6a and 10a were determined by chiral-phase GC.
Conversion was >95% for the individual reaction steps as judged by GC-MS unless noted otherwise. For complete catalyst library see the
Supporting Information.
the acetic acid produced back into the anhydride. Most
importantly, the only side-product formed is the correspond-
ing urea derivative, which cannot participate as a base in the
final decarboxylation step and therefore does not erode
enantioselectivity. Indeed, 3a immediately forms when N,N’-
diisopropylcarbodiimide (DIC) is used as an additive. Addi-
tion of acetic anhydride then furnishes the key intermediate
6a with full conversion of 3a. Further addition of acetic acid
initiates the decarboxylation step, thus leading to the
formation of the a-acetamido methylketone 10a with 33%
ee, enriched in the S-configured enantiomer (Scheme 3). We
were able to monitor the reaction by GC-MS and observed
some of the intermediates (see the Supporting Information,
Figure S2).
The feasibility of our catalyst design concept was next
evaluated using different turns instead of the adamantane
amino acid (Scheme 3).[15] Incorporation of a d-Pro-Aib-turn
(12), frequently used by Miller et al.,[11a,16] or an 2-Abz-d-Pro
pseudo-b-hairpin (13),[17] resulted in 5% and 8% ee, respec-
tively. We also studied (S)-tetramisol (14) and the chiral (S)-
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PPY* 15,[18] reported by Fu and co-workers, as both catalysts
From this point on, we used 18 for substrate screening and
were previously employed in an asymmetric Steglich rear-
rangement.[8,19] With 14 only traces of enantioenriched 6a
(25% ee) formed, and 10a could not be detected. Remark-
ably, 15 gave 22% ee for the desired product and may be
considered a potential catalyst for further optimization. To
gain further insight into the factors determining enantiose-
lectivity and to improve catalyst performance, we modularly
built the catalyst from the C-terminal Pmh. Thus, Boc-l-Pmh-
OMe (16) and dipeptide 17 did not provide enantioenriched
product as neither catalyst is able to form a dynamic binding
pocket[12] for the enolate 9a, and they also lack the necessary
hydrogen bonding contacts. However, when tripeptides were
used the selectivities substantially increased (see the Support-
ing Information for complete catalyst library), with 18,
bearing cyclohexylalanine, being the best catalyst. The strik-
ingly better performance of the shorter tripeptide 18 com-
pared to that of the tetrapeptide 11 is probably a result of the
N,N’-dicyclohexylcarbodiimide (DCC) instead of DIC
because it is easier to remove the corresponding urea
derivative in the purification of the final products
(Scheme 4). Thus, 10a was isolated in 69% yield with
36% ee. Substrates with sterically less demanding side
chains, such as alanine and methionine derivatives, afforded
the desired products with low selectivities but with high yields
(10b and 10e). The product 10c, derived from leucine, was
isolated with appreciable higher enantioselectivity (54%)and
63% yield. The tyrosine-derived 1d gave 31% ee with 77%
yield, whereas polar functional groups led to low selectivities
(10 f: 17%). We next employed sterically more demanding
amino acids bearing aromatic side chains, namely, naphthyl-
and anthranylalanine derivatives, 1g and 1h, respectively.
Lower enantioselectivity (31% ee, 78% yield) resulted for
10g, whereas 10h was obtained in racemic form in a moderate
52% yield. Strongly electron-withdrawing side-chains, such as
that in 1i, afforded the product with excellent yield but lower
selectivity (10i: 18% ee, 96% yield), and probably resulting
from racemization (see the Supporting Information). To our
delight, as seen for 1c, the selectivity was further enhanced to
58% ee (67% yield) when the aliphatic cyclohexylalanine 1j
was used as a substrate. Importantly, 10a and 10d could be
obtained, with up to 84% ee (for 10a), after one recrystal-
lization.
=
C-terminal Pmh (interchange of the amide NH and C O
groups), which leads to more efficient substrate binding.
Note that most of the catalysts employed were also able to
enantioselectively acetylate the azlactone intermediate. How-
ever, no correlation is apparent from the selectivity obtained
for 6a and the final product 10a, and no amplification of
stereoselectivity was observed. That is, the enantioenrichment
of 10a does not ensue from kinetic resolution of 6a. As we
anticipated by the proposed mechanism, the selectivity for 6a
is not preserved in the product and only results from the final
decarboxylation and enantioselective enolate reprotonation.
To further prove this observation, DMAP was used as an
achiral catalyst for the in situ formation of 6a, and 18 was only
added for the decarboxylation step. However, the selectivities
differed only marginally (see the Supporting Information,
Table S5).
The observed selectivities can effectively compete with
previously reported organocatalytic enantioselective decar-
boxylative protonation reactions which are typically in the
range of 30–60% ee.[10a,c,d] Organocatalytic variants that
achieve higher enantioselectivities (above 70% ee) are
rare.[20] Higher selectivities (> 90% ee) have, so far, only
been achieved either in the presence of stoichiometric
amounts of base[21] or by employing transition metals, for
Scheme 4. Substrate scope and limitations. Stereochemistry for the products was assigned as S by analogy to 10a. Enantiomeric excesses were
determined by chiral-phase GC or HPLC. Yields refer to those of isolated products. Values within parentheses correspond to recrystallized
products.
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example, palladium complexes[22] or enzymes.[10a,23] Unlike the
former examples, as well as decarboxylative addition reac-
tions,[10c,d,24] the DW reaction described herein is particularly
challenging as it presupposes the stereoselective transfer of
the smallest electrophile, a proton, in the presence of
significant amounts of acid in a complex multistep reaction
(Scheme 2).
Although the exact nature of the decarboxylation step is
not yet clear, the stereoinduction probably arises from the
deprotonation of b-keto acid 8 (Scheme 2) by the catalyst,
release of CO2, and subsequent enantioselective reprotona-
tion as reported for related organocatalytic decarboxylative
protonation reactions.[10a,c,d,25] Thus, we computationally iden-
tified possible adducts of the protonated catalyst 18 and
enolate 9j as minima wherein the transferred proton is in
close proximity to the a-carbon atom of the intermediate
(1.94 Š for both structures), thus supporting our mechanistic
proposal (Figure 1). These data also emphasized the impor-
recently confirmed experimentally by NMR studies for the
performance of 11 in enantioselective acylation reactions.[12,27]
The present example provides further evidence for the
importance of attractive dispersion interactions in catalysis,
even in the presence of hydrogen bonds or ion pairs.[28]
The development of the first enantioselective Dakin–West
reaction opens a new avenue to further develop related
reactions. We now focus on the detailed investigation and
elucidation of the decarboxylation step with the goal to
rationally design novel and highly selective catalysts. More-
over, we will investigate the applicability of functionalized
anhydrides, for example, towards the synthesis of enantio-
merically enriched halo- and acyloxymethyl ketones that are
frequently found chemical warheads in serine, cysteine, and
threonine protease inhibitors.[29]
Acknowledgments
We gratefully acknowledge financial support by the Deutsche
Forschungsgemeinschaft (SPP1807 Dispersion, Schr 597/27-
1).
Keywords: amino acids · noncovalent interactions ·
organocatalysis · peptides · protonation
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2719–2723
Angew. Chem. 2016, 128, 2769–2773
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Received: October 21, 2015
Revised: December 6, 2015
Published online: January 25, 2016
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