Kinetic resolution of racemic carboxylic acids using achiral alcohols by the promotion of benzoic anhydrides and tetramisole derivatives: Production of chiral nonsteroidal anti-inflammatory drugs and their esters

Article abstract of DOI:10.1002/ejoc.200800942

A variety of optically active carboxylic esters were produced by kinetic resolution of racemic carboxylic acids by using achiral alcohols, benzoic anhydrides, and Birman's tetramisole-type catalysts. Bis(α-naphthyl) methanol is a very effective reagent for producing the corresponding esters with high ee values in the presence of 4-methoxybenzoic anhydride (PMBA) as the coupling reagent by promotion of benzotetramisole derivatives (BTM, α-Np-BTM, and β-Np-BTM). This protocol directly provides chiral carboxylic esters from free carboxylic acids and achiral alcohols by utilizing a transacylation process to generate the mixed anhydrides from the acid components with benzoic anhydride derivatives in the presence of chiral catalysts. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800942

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200800942
Kinetic Resolution of Racemic Carboxylic Acids Using Achiral Alcohols by the
Promotion of Benzoic Anhydrides and Tetramisole Derivatives: Production of
Chiral Nonsteroidal Anti-Inflammatory Drugs and Their Esters
Isamu Shiina,*[a] Kenya Nakata,[a] and Yu-suke Onda[a]
Keywords: Kinetic resolution / Carboxylic acids / Anhydrides
A variety of optically active carboxylic esters were produced
by kinetic resolution of racemic carboxylic acids by using
achiral alcohols, benzoic anhydrides, and Birman’s tetramis-
ole-type catalysts. Bis(α-naphthyl)methanol is a very effec-
tive reagent for producing the corresponding esters with high
ee values in the presence of 4-methoxybenzoic anhydride
(PMBA) as the coupling reagent by promotion of benzo-
tetramisole derivatives (BTM, α-Np-BTM, and β-Np-BTM).
This protocol directly provides chiral carboxylic esters from
free carboxylic acids and achiral alcohols by utilizing a trans-
acylation process to generate the mixed anhydrides from the
acid components with benzoic anhydride derivatives in the
presence of chiral catalysts.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Results and Discussion
The synthesis of optically active carboxylic acids and
esters is of utmost importance due to the significant roles
that these compounds play in the fields of medicinal and
pharmaceutical chemistry.[1] Some chiral resolving agents
(e.g., chiral amines) were developed for the derivatization
of racemic carboxylic acids to form pairs of diastereomers
that can be separated by conventional recrystallization.
However, this process requires several repetitions of salt for-
mation between a carboxylic acid and an amine followed
by recrystallization and subsequent separation of the chiral
auxiliaries from the acid component to obtain a pure en-
antiomer. Recently, a very effective method for providing
chiral carboxylic esters derived from α-arylalkanoic acid by
the enantioselective C-acylations of ketenes by using planar
chiral heterocycles was pioneered by Fu.[2] However, to the
best of our knowledge, direct and practical kinetic resolu-
tion of racemic 2-arylalkanoic acids by using achiral
alcohols by the promotion of a chiral catalyst has not yet
been reported. Here we present the first effective method
for producing a variety of nonsteroidal anti-inflammatory
drugs such as ibuprofen, ketoprofen, fenoprofen, flurbip-
rofen, naproxen, and their esters by the kinetic resolution
of racemic 2-arylalkanoic acids with the use of achiral
alcohols, benzoic anhydride, and Birman’s tetramisole-type
catalysts.
In recent years, we established effective esterification and
lactonization by using benzoic anhydride derivatives as a
condensation reagent to produce the desired coupling prod-
ucts from free carboxylic acids and alcohols (or ω-hydroxy-
carboxylic acids).[3] Furthermore, a novel and useful kinetic
resolution reaction of racemic secondary alcohols by using
free and achiral carboxylic acids by the promotion of ben-
zoic anhydrides and chiral catalysts has successfully been
developed.[4] In this reaction, the tetramisole-type chiral
reagents created by Birman[5] effectively promoted the ki-
netic resolution of racemic 1-phenyl alkanols. These results
prompted us to explore a new method for the preparation
of optically active α-substituted alkanoic acid derivatives by
starting from racemic carboxylic acids with achiral alcohols
and by using our mixed anhydride formation technology.[6]
First, the reactions of racemic 2-phenylpropionic acid (1)
with several achiral alcohols were chosen as model cases for
the optimization of the structure of the nucleophile
(Table 1). In the presence of benzoic anhydride as a coup-
ling reagent, (+)-benzotetramisole (BTM)[5] was used for
chiral induction according to the standard reaction condi-
tions established in our preceding paper.[4] As shown in En-
try 1 of Table 1, the esterification did not proceed at all
when a tertiary alcohol was used as the nucleophile, and
the reaction of cyclohexanol afforded the desired ester 2 in
good yield, but 2 was found to be an absolutely racemic
compound (Table 1, Entry 2). In contrast, it was revealed
that benzyl alcohol and diphenylmethanol produced a rela-
tively improved enantioselectivity of the corresponding car-
boxylic esters (33% ee; Table 1, Entries 3 and 4, respec-
tively).
[a] Department of Applied Chemistry, Faculty of Science, Tokyo
University of Science Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
Fax: +81-3-3260-5609
E-mail: shiina@rs.kagu.tus.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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I. Shiina, K. Nakata, Y. Onda
SHORT COMMUNICATION
Table 1. Kinetic resolution of (Ϯ)-2-phenylpropionic acid.
(Table 2, Entries 5–8). The optically active ibuprofen ester
(92% ee), ketoprofen ester (77% ee), fenoprofen ester (82%
ee), and flurbiprofen ester (83% ee) were easily prepared by
the reaction with 3 in the presence of PMBA and BTM
under the standard reaction conditions.
Table 2. Kinetic resolution of (Ϯ)-2-phenylpropionic acid deriva-
tives.
Next, several achiral diphenylmethanol derivatives were
examined as nucleophiles for the kinetic resolution of 1
The kinetic resolution of naproxen (6), a widely-used
(Table 1, Entries 5–8). Substitution of the aryl ring of di- anti-inflammatory drug, by the present method with achiral
phenylmethanol diminished the selectivities (Table 1, En- alcohol was next examined, and the results are summarized
tries 5 and 6), and the use of bis(β-naphthyl)methanol af- in Figure 1. The reaction of racemic naproxen with 3 in the
forded results similar to those obtained when di- presence of PMBA and (–)-BTM afforded the correspond-
phenylmethanol was used (Table 1, Entry 7; cf. Entry 4). ing ester 7 in 48% yield with moderate enantioselectivity
Fortunately, we determined that the kinetic resolution of 1 (76% ee), and 40% of the resulting (R)-naproxen was reco-
could be attained effectively by employing bis(α-naphthyl)- vered in 59% ee (s = 13). Furthermore, we prepared several
methanol (3) as the achiral nucleophile, which resulted in BTM derivatives including novel compounds and applied
the corresponding ester and the recovery of (S)-2-phenyl- them to the kinetic resolution of 6 by combining PMBA
propionic acid with good enantiomeric excesses (82 and and 3. We found that the reaction using (S)-α-Np-BTM
80% ee, respectively); the s-value also dramatically in- produced 7 with a relatively better enantiomeric excess
creased to 24 (Table 1, Entry 8). Similar to the kinetic reso- (88% ee, s = 25), and it was also found that (S)-β-Np-BTM
lution of secondary alcohols in the previous paper,[4] 4- was a very effective catalyst to promote the kinetic resolu-
methoxybenzoic anhydride (PMBA) also proved to be a tion of the racemic naproxen, which afforded the desired
suitable coupling reagent and the s-value reached 25 ester 7 in good yield with a high enantiomeric excess (49%
(Table 1, Entry 9).
yield, 93% ee, s = 61).
A variety of examples of the resolution of 2-arylpro-
The assumed reaction pathway is illustrated in Figure 2.
pionic acid derivatives 4 with bis(α-naphthyl)methanol (3) First, a mixed anhydride (MA) forms in situ as a key inter-
by promotion with PMBA and BTM is listed in Table 2. All mediate from the racemic carboxylic acid and benzoic anhy-
the reactions using the 2-phenylpropionic acid derivatives dride by the promotion of basic catalysts. Actually, when
substituted at the 4-position on the aromatic ring produced racemic 2-phenylpropionic acid (1) was treated with benzoic
the corresponding esters in good enantiomeric excess (4-H, anhydride in the presence of triethylamine with (+)-BTM,
91% ee; 4-Me, 83% ee; 4-MeO, 86% ee; 4-Cl, 83% ee); facile formation of the mixed anhydrides [(R)- and (S)-MA]
1
therefore, it is postulated that there is not a very large elec- was observed by H NMR spectroscopy. In the second cy-
tronic effect on the aromatic ring of the substrates (Table 2, cle, half of the mixed anhydride [(R)-MA] will be selectively
Entries 1–4). Several derivatives of 2-phenylpropionic acid, activated by (+)-BTM, which then reacts with a half an
such as ibuprofen (4e), ketoprofen (4f), fenoprofen (4g), equivalent of the nucleophilic alcohol to afford the desired
and flurbiprofen (4h), are used as nonsteroidal anti-inflam- (R)-carboxylic ester with a high ee. The remaining half of
matory drugs for clinical treatment, so that the kinetic reso- the mixed anhydride [(S)-MA] would be hydrolyzed to pro-
lution of these valuable compounds was next examined duce the unreacted (S)-carboxylic acid. The efficiency of the
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Eur. J. Org. Chem. 2008, 5887–5890

Kinetic Resolution of Racemic Carboxylic Acids
Figure 1. Kinetic resolution of (Ϯ)-naproxen.
kinetic resolution completely depends on the structure of
the alcohol as shown in Table 1; thus, it is anticipated that
the second cycle includes the most important stage for de-
termining the enantioselectivity of this multiple transacyl-
ation process.
Experimental Section
Typical Procedure for the Preparation of Optically Active Naproxen
(6) and Its Ester from Racemic Naproxen (6) by Using PMBA with
(S)-β-Np-BTM: To a solution of PMBA (68.5 mg, 0.239 mmol),
(Ϯ)-naproxen (6) (45.8 mg, 0.199 mmol), and bis(α-naphthyl)meth-
anol (28.4 mg, 99.9 µmol) in dichloromethane (2.0 mL) at room
temperature was successively added diisopropylethylamine
(62.7 µL, 0.360 mmol) and (S)-β-Np-BTM (2.9 mg, 9.6 µmol). The
mixture was stirred for 12 h at room temperature and then
quenched with saturated aqueous NH4Cl. The organic layer was
separated, and the aqueous layer was extracted with diethyl ether.
The combined organic layer was dried with Na2SO4. After fil-
tration of the mixture and evaporation of the solvent, the crude
product was purified by preparative thin-layer chromatography on
silica to afford the corresponding ester (S)-7 (49.1 mg, 49% yield,
93% ee) and the recovered optically active naproxen [(R)-6]
(23.4 mg, 51% yield, 74% ee). [s = 60.9, Figure 1, Run 3].
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures; characterization of the products; 1H
and 13C NMR spectra of the optically active carboxylic acids and
esters.
Figure 2. Proposed reaction pathway of the kinetic resolution.
Acknowledgments
We would like to thank Dr. M. Itagaki (Organic Synthesis Research
Laboratory, Sumitomo Chemical Co., Ltd.) for his generous gift of
2-amino-2-naphthylethanols, which served as the precursors for the
catalysts in this study. This study was partially supported by a Re-
Conclusions
We developed a new practical method for providing op-
tically active 2-arylalkanoic acids and their esters by kinetic search Grant from the Center for Green Photo-Science and Tech-
nology, and Grants-in-Aid for Scientific Research from the Minis-
try of Education, Science Sports and Culture, Japan.
resolution of racemic carboxylic acids with the use of achi-
ral alcohols, benzoic anhydride, and tetramisole derivatives.
A combination of PMBA, 1,1-diarylmethanol, and a BTM-
type catalyst is best to produce the corresponding esters [1] For reviews on the routes available for the preparation of op-
tically active arylpropionic acids, see: a) H. R. Sonawane, N. S.
Bellur, J. R. Ahuja, D. G. Kulkarni, Tetrahedron: Asymmetry
1992, 3, 163–192; b) J.-P. Rieu, A. Boucherle, H. Cousse, G.
Mouzin, Tetrahedron 1986, 42, 4095–4131.
from 2-arylpropionic acid derivatives with a high ee under
mild reaction conditions. This method was successfully uti-
lized for the kinetic resolution of ibuprofen, ketoprofen,
fenoprofen, flurbiprofen, and naproxen by modification of
the structure of the nucleophiles and BTM-type catalysts.
Further studies on the present method to provide chiral car-
boxylic acid derivatives and other applications of this novel
protocol to the syntheses of useful complex molecules are
now in progress.
[2] a) B. L. Hodous, J. C. Ruble, G. C. Fu, J. Am. Chem. Soc. 1999,
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SHORT COMMUNICATION
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Received: September 26, 2008
Published Online: November 4, 2008
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Eur. J. Org. Chem. 2008, 5887–5890