CL-150826
Received: September 3, 2015 | Accepted: October 7, 2015 | Web Released: October 20, 2015
Nonenzymatic, Enantioconvergent Dynamic Kinetic Resolution (DKR)
of Racemic 2-(1H-Pyrrol-1-yl)alkanoic Acids as α-Amino Acid Equivalents
Eri Tokumaru, Atsushi Tengeiji, Takayoshi Nakahara, and Isamu Shiina*
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(E-mail: shiina@rs.kagu.tus.ac.jp)
We report an effective dynamic kinetic resolution (DKR)
system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which
consists of a rapid racemization step via an activating substrate
and an enantio-discriminating step via catalytic esterification.
The combination of pivalic anhydride as an activating agent,
bis(α-naphthyl)methanol as an achiral alcohol, (R)-BTM as a
chiral acyl-transfer catalyst, and Hünig’s base converted racemic
2-(1H-pyrrol-1-yl)alkanoic acids to the corresponding chiral
carboxylates, which can be transformed into chiral α-amino acid
derivatives with maintained high enantiopurity.
as the chiral acyl-transfer catalyst. In this procedure, a racemic
mixture of α-arylpropanoic acids was separated into the corre-
sponding chiral carboxylates and the recovered chiral carboxylic
acids with high selectivity. A mechanistic study24 revealed that
this enantioselective esterification proceeds through a mixed
anhydride (MA), a reactive intermediate formed from the
substrate and the coupling reagent, followed by formation of a
transition state (TS) with the achiral alcohol and chiral BTM.
Furthermore, acceleration of the racemization process in a polar
reaction media such as DMF led to the development of the
corresponding DKR system for α-arylpropanoic acids.25
Despite the growing number of DKR systems reported to
date, there has yet been no example of a catalytic DKR system
for protected α-amino acids via direct esterification using acyclic
precursors. Moreover, to the best of our knowledge, there are no
examples of catalytic DKR systems for any racemic α-nitrogen-
containing carboxylic acids. In the present study, we report the
first DKR of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which
can then be converted to α-amino acids.
In general, rapid racemization of substrates bearing an
amino group at the α-position seemed to be a significant
challenge because of the low acidity of α-protons, which results
from the presence of very electron-rich amino groups. In order
to achieve both rapid racemization of the intermediates and
enantioselective esterification, one solution was to modify the
α-amino group in an appropriate manner. Thus, a variety of
propanoic acids bearing modified α-amino groups were screened
using the similar conditions established in our previous study:25
1.0 equiv of bis(α-naphthyl)methanol, 2.4 equiv of Piv2O,
4.8 equiv and i-Pr2NEt, 5 mol % (R)-BTM, and DMF (Table 1).
First, N-benzoyl alanine (1a), N-Boc alanine (1b), and
N-Cbz alanine (1c) were tested as commonly used substrates
containing a protected α-amino group (Entries 1, 2, and 3). We
expected DKR to proceed smoothly and only one enantiomeric
isomer of the corresponding ester to be obtained in over 50%
yield. However, contrary to our expectations, the yields and
enantiopurities of the obtained esters 2a, 2b, and 2c were both
poor (¯42% yield, ¯10% ee).
α-Amino acids have long been considered fundamental
moieties in organic chemistry, and the enantio-controlled and
catalytic construction of the chiral α-position of α-amino acids
has been targeted as an attractive synthetic goal.1-6
In order to provide large amounts of chiral α-amino acids
from racemic α-amino acids, dynamic kinetic resolution
(DKR)7,8 has been anticipated to be an ideal method. While a
wide range of enzymatic DKRs9-11 for α-amino acid derivatives
has been disclosed as reliable methodologies, non-enzymatic
DKRs have also emerged as promising approaches during the
last decade. However, major examples of the successful non-
enzymatic DKR of chiral α-amino acids have involved the
catalytic ring-opening alcoholysis of cyclic precursors, such as
racemic urethane-protected α-amino acid N-carboxyanhydrides
(Deng12) and racemic 2-phenylazlactones (Seebach,13 Fu,14
Berkessel,15-17 Connon,18,19 Birman,20,21 etc.). Note that the
DKR systems for racemic 2-phenylazlactones principally al-
lowed production of N-benzoyl amino acids with high enantio-
purities.
As illustrated in Figure 1, we have reported the effective
kinetic resolution (KR) of racemic α-arylpropanoic acids22 using
carboxylic anhydride as the coupling agent, bis(α-naphthyl)-
methanol as the achiral alcohol, and benzotetramisole (BTM)23
Kinetic Resolution
α
(
-Np)2CHOH (0.5 equiv),
Given the similarity in size and aromaticity of these α-
substituents to the α-phenyl group, it was anticipated that a
promising precursor of an α-amino acid would contain a
substituent similar to a benzene ring with a nitrogen atom at
the α-position, such as an N-heteroaromatic ring. Therefore,
racemic 2-(1H-pyrrol-1-yl)propanoic acid (1d) was next sub-
jected to screening (Entry 4). As we anticipated, the reaction
proceeded with high enantioselectivity, and the yield of the
major isomer of the corresponding ester exceeded 50% (72%
yield, 89% ee), thus the occurrence of the aimed DKR was
evident.
(R)-BTM (5 mol%),
+
Piv2O, i-Pr2NEt, toluene
α
Me
CO2H
Me
CO2CH( -Np)2
Me
CO2H
45% yield, 85% ee
47% yield, 65% ee
Dinamic Kinetic Resolution
S
α
(
-Np)2CHOH (1.2 equiv),
(R)-BTM (5 mol%),
N
N
Piv2O, i-Pr2NEt, DMF
Ph
α
CO2CH( -Np)2
Me
CO2H
Me
(R)-BTM
88% yield, 92% ee
Furthermore, other substrates 1e-1g bearing N-hetero-
aromatic rings at the α-position were investigated (Entries 2-4
Figure 1. Previous studies of KR/DKR via asymmetric
esterification.
© 2015 The Chemical Society of Japan
Tokumaru, Eri
