Enantioselective benzoylation of α-amino esters using (S)-1-benzoyl-2-(α-acetoxyethyl)benzimidazole, a chiral benzimidazolide

Article abstract of DOI:10.1021/jo070962p

(Chemical Equation Presented) A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic α-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for α-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.

Full text of DOI:10.1021/jo070962p

Similarly, Mioskowski et al. used N-acetyl-(1S,2S)-bis(trifluo-
romethanesulfonamide) for kinetic resolution of (()-phenyla-
lanine methyl ester with 80% ee.4
Many of these reported methods suffer from the disadvantage
of use of expensive starting materials or synthetically incon-
venient routes. We describe herein a novel route which employs
synthetically easily accessible and inexpensive materials for
enantioselective benzoylation of R-amino esters resulting in the
kinetic resolution of the same.
Enantioselective Benzoylation of r-Amino Esters
Using (S)-1-Benzoyl-2-
(r-acetoxyethyl)benzimidazole, a Chiral
Benzimidazolide
Anil V. Karnik* and Suchitra S. Kamath
Department of Chemistry, UniVersity of Mumbai, Vidyanagari,
Santacruz (E), Mumbai 400098, India
Enantiomerically pure R-amino esters are particularly im-
portant synthons for the preparation of pharmaceuticals,5a-e
agrochemicals, and food ingredients and are fundamental
building blocks in important bioactive molecules, such as
peptides, proteins, and many other natural products.5f They are
extensively used as a source of chiral materials in stereoselective
organic synthesis.6
aVkarnik@chem.mu.ac.in
ReceiVed May 8, 2007
Azolides or N-acylazoles are powerful acylation agents.7 The
carbonyl carbon of the acyl group of azolides is electrophilic,
and different carbon and heteroatom nucleophiles react easily
with the same under mild conditions. Moreover, the azole part
offers an effective leaving group in acylation reactions. So far,
there seems to be no effort to use these powerful acylating agents
for enantioselective acylation/kinetic resolution of R-amino
esters. Benzimidazolide, the N-acylbenzimidazole, can be
obtained very easily, and a chiral center can be incorporated in
the benzimidazole part by reaction of o-phenylene diamine with
requisite chiral carboxylic acid.8 We report the development of
(S)-1-benzoyl-2-(R-acetoxyethyl)benzimidazole (BAEB) 3, a
novel chiral benzimidazolide, as an effective chiral acylating
agent for kinetic resolution of R-amino esters.
A new chiral benzimidazolide is developed as a nonenzy-
matic acylating agent for enantioselective benzoylation of
racemic R-amino esters. The process is highly efficient,
which exhibits uniformly high enantioselectivity for R-amino
esters with or without aryl substituents under mild reaction
conditions. The chiral benzimidazolide is inexpensive and
is easily accessible.
Condensation of o-phenylene diamine with (S)-lactic acid is
reported to afford (S)-2-(R-hydroxyethyl)benzimidazole (1).9
This molecule has a chiral substituent on the benzimidazole side
Nonenzymatic enantioselective nucleophilic acylating agents
for kinetic resolution have attracted a lot of attention in recent
years.1 Effective kinetic resolution requires the presence of one
or more stereocenters with additional binding sites in the chiral
acylating agent for rigid diastereomeric transition states. Al-
though kinetic resolution of R-amino esters by enzymatic
processes is abundantly documented,2 some very effective
nonenzymatic enantioselective acylating agents for kinetic
resolution have been reported and they exhibit excellent
stereodiscrimination properties. For example, Atkinson reported
the use of N-benzoyl-N-ethanoylamino-2-[(S)-1-tert-butyldim-
ethylsilyloxy-2-methylpropyl]quinazolin-4(3H)-one for kinetic
resolution of racemic valine methyl ester with 94% ee.3
(4) Arseniyadis, S.; Valleix, A.; Wagner, A.; Mioskowski, C. Angew.
Chem., Int. Ed. 2004, 43, 3314.
(5) (a) Bommarius, A. S.; Schwarm, M.; Drauz, K. J. Mol. Catal. B:
Enzymatic 1998, 5, 1. (b) Angle, S. R.; Henry, R. M. J. Org. Chem. 1997,
62, 8549. (c) Paruszewski, R.; Strupinska, M.; Stables, J. P.; Swiader, M.;
Czuczwar, S.; Kleinrok, Z.; Turski, W. Chem. Pharm. Bull. 2001, 49, 629.
(d) Fedi, V.; Altamura, M.; Balacco, G.; Canfarini, F.; Criscuoli, M.;
Giannotti, D.; Giolitti, A.; Giuliani, S.; Guidi, A.; Harmat, N. J. S.;
Nannicini, R.; Pasqui, F.; Patacchini, R.; Perrotta, E.; Tramontana, M.;
Triolo, A.; Maggi, C. A. J. Med. Chem. 2004, 47, 6935. (e) Yurek-George,
A.; Habens, F.; Brimmell, M.; Packham, G.; Ganesan, A. J. Am. Chem.
Soc. 2004, 126, 1030. (f) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV.
1997, 97, 2243.
(6) (a) Shiraiwa, T.; Ohta, A.; Miyazaki, H.; Gogun, Y.; Kurokawa, H.
Chirality 1997, 9, 386. (b) Krasnov, V. P.; Zhdanova, E. A.; Solieva, N.
Z.; Sadretdinova, L. S.; Bukrina, I. M.; Demin, A. M.; Levit, G. L.;
Ezhikova, M. A.; Kodess, M. I. Russ. Chem. Bull. Int. Ed. 2004, 53, 1331.
(c) Marin, J.; Didierjean, C.; Aubry, A.; Casimir, J.-R.; Briand, J.-P.;
Guichard, G. J. Org. Chem. 2004, 69, 130. (d) Krasnov, V. P.; Levit, G.
L.; Korolyova, M. A.; Bukrina, I. M.; Sadretdinova, L. S.; Andreeva, I. N.;
Charushin, V. N.; Chupakhin, O. N. Russ. Chem. Bull. Int. Ed. 2004, 53,
1253. (e) Katritzky, A. R.; Jiang, R.; Suzuki, K. J. Org. Chem. 2005, 70,
4993.
* To whom correspondence should be addressed. Tel: +91 022 26526091.
Fax: +91 022 26528547. E-mail: avkarnik@chem.mu.ac.in.
(1) (a) Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 14264. (b)
Suzuki, Y.; Yamauchi, K.; Muramatsu, K.; Sato, M. Chem. Commun. 2004,
2770. (c) Al-Sehemi, A. G.; Atkinson, R. S.; Fawcett, J.; Russell, D. R.
Tetrahedron Lett. 2000, 41, 2239. (d) Kawabata, T.; Yamamoto, K.;
Momose, Y.; Yoshida, H.; Nagaoka, Y.; Fuji, K. Chem. Commun. 2001,
2700. (e) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (f) Birman, V. B.; Li,
X. Org. Lett. 2006, 8, 1351. (g) Miller, S. J.; Copeland, G. T.; Papaioannou,
N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629.
(2) (a) Cho, B.-K.; Park, H.-Y.; Seo, J.-H.; Kinnera, K.; Lee, B.-S.; Kim,
B.-G. Biotechnol. Bioeng. 2004, 88, 512. (b) Zhao, H.; Malhotra, S. V.
Biotechnol. Lett. 2002, 24, 1257. (c) Brown, S. A.; Parker, M.-C.; Turner,
N. J. Tetrahedron: Asymmetry 2000, 11, 1687.
(7) (a) Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek,
R.; Steel, P. J. J. Org. Chem. 2005, 70, 9211. (b) Katritzky, A. R.; Wang,
Z.; Wang, M.; Wilkerson, C. R.; Hall, C. D.; Akhmedov, N. G. J. Org.
Chem. 2004, 69, 6617. (c) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org.
Chem. 2000, 65, 8210. (d) Katritzky, A. R.; Mohapatra, P. P.; Fedoseyenko,
D.; Duncton, M.; Steel, P. J. J. Org. Chem. 2007, 72, 4268.
(8) Phillips, M. A. J. Chem. Soc. 1928, 2393.
(9) (a) Katritzky, A. R.; Aslan, D. C.; Leeming, P.; Steel, P. J.
Tetrahedron: Asymmetry 1997, 8, 1491. (b) Katritzky, A. R.; Aslan, D.
C.; Oniciu, D. C. Tetrahedron: Asymmetry 1998, 9, 2245.
(3) Al-Sehemi, A. G.; Atkinson, R. S.; Fawcett, J. J. Chem. Soc., Perkin
Trans. 1 2002, 257.
10.1021/jo070962p CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/22/2007
J. Org. Chem. 2007, 72, 7435-7438
7435

SCHEME 1. Preparation of BAEB 3
SCHEME 2. Enantioselective Benzoylation of r-Amino Esters
arm, which offered the chiral environment required in the azole
part. Reaction of 1 with acetic anhydride in pyridine yielded
(S)-2-(R-acetoxyethyl)benzimidazole (2) as the only product.
This on benzoylation yielded the chiral benzimidazolide (S)-1-
benzoyl-2-(R-acetoxyethyl)benzimidazole (BAEB) 3 (Scheme
1). Pyridine was the most suitable reagent as well as solvent
for carrying out the benzoylation reaction among the other
reaction conditions (THF, DMAP; THF, triethylamine; aceto-
nitrile, K2CO3; THF, 2 equiv of 2). The formation of 2 from 1
offered a dual advantage; it protected the hydroxyl group of 1
to eliminate a competitive reaction site for benzoyl transfer form
3 to the amino group, and it also offered the advantage of the
presence of a bulky group with an additional heteroatom close
to the reaction site for possible conformationally rigid diaster-
eomeric transition states.
The utility of BAEB in kinetic resolution of R-amino esters
was to be next investigated. Reaction of 1 equiv of BAEB was
carried out with 2 equiv of various racemic R-amino esters. It
was found that BAEB preferentially acylated the S isomer of
R-amino ester to yield (S)-N-benzoyl amino esters (4). The
unreacted R-amino esters were converted to N-benzoyl amino
esters (5) and were found to be of R configuration. The only
other product isolated was 2 (Scheme 2). The ester group of 3
was found to be unaffected during the benzoyl transfer reaction.
Evidently, the acetyl group of the ester part does not enjoy the
advantage of the azolide acyl (benzoyl) group, namely, more
electrophilic character and better leaving group ability after acyl
transfer reaction. This is in agreement with the noted powerful
acyl transferring ability of the azolides discussed above. Chiral
identities of N-benzoyl amino esters were established by
comparison with rotation of authentic compounds reported in
literature.10
The enantiomeric excesses of N-benzoyl amino esters were
determined by HPLC using a chiral stationary phase (Chiralcel
OD, n-hexane/2-propanol 98/2, Table 1). The best result in terms
of enantioselective acylation was observed for the ester of
phenylglycine (91.8%) (Table 1, compound 4e), and lowest
enantioselectivity was observed for the ester of alanine (89.1%)
(Table 1, compound 4a). Thus BAEB seems to be almost
equally effective against R-amino esters with the presence of
aryl substituents such as esters of phenylalanine and phenylg-
lycine (Table 1, entries 3 and 5) as well as with aliphatic side
chains as in esters of alanine, leucine, and valine (Table 1, entries
1, 2, and 4). Some of the previously reported kinetic resolving
agents do not exhibit this level of uniform enantioselectivities.
The selectivity factors (s ) rate of fast-reacting enantiomer/
rate of slow-reacting enantiomer) obtained for enantioselective
benzoylation of R-amino esters ranged from s ) 51.4 at 49.9%
conversion to s ) 73.6 at 49.7% conversion at -10 °C. When
the reaction of alanine ethyl ester with BAEB was carried out
at rt, it showed a much lower selectivity factor, s ) 1.7 at 52.6%
conversion. The reaction at rt was faster and was completed in
90 min as compared to 12 h required for completion at
-10 °C. The % enantioselectivity at rt was a mere 19.1 for
benzoylated alanine ethyl ester and 21.2 for unreacted alanine
ethyl ester.
In summary, the synthesis of BAEB is quite easy, convenient,
and cost-effective. BAEB serves as an effective reagent for
kinetic resolution of R-amino esters. The use of benzimidazolide
BAEB offers mild neutral reaction conditions. The level of
stereoselectivity furnished by BAEB ranges from good to
excellent and is comparable or better than most nonenzymatic
methods reported so far for this purpose. This is the first ever
example of the use of an azolide for enantioselective acylation/
kinetic resolution of R-amino esters.
(10) (a) Liang, J.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1998, 63, 3154.
(b) Jones, J. B.; Niemann, C.; Hein, G. E. Biochemistry 1965, 4, 1735. (c)
Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1977, 99, 6262. (d) Dondoni,
A.; Perrone, D.; Semola, T. Synthesis 1995, 181.
(11) (a) Bellemin-Laponnaz, S.; Tweddell, J.; Ruble, J. C.; Breitling, F.
M.; Fu, G. C. Chem. Commun. 2000, 1009. (b) Suarez, A.; Downey, C.
W.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 11244. (c) Schaus, S. E.;
Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A. E.;
Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307.
Experimental Section
Preparation of (S)-2-(R-Acetoxyethyl)benzimidazole 2. A
solution of 1 (4.86 g, 30 mmol) and Ac2O (3.8 mL, 40 mmol) in
50 mL of dry pyridine was stirred at 0 °C for 5 h. The reaction
mixture was poured into cold water to give a white crystalline solid
which was filtered and washed with water to give 4.8 g of pure
7436 J. Org. Chem., Vol. 72, No. 19, 2007

TABLE 1. Enantiomeric Excess % Data of Enantioselective Benzoylation of r-Amino Esters
a The conversion was calculated by the equation: conversion ) (ee of starting material)/[(ee of starting material) + (ee of product)].11 b Equation used
to calculate the selectivity factor (s ) kfast/kslow): s ) ln[1 - conversion(1 + ee of product)]/ln[1 - conversion(1 - ee of product)].11
compound 2: yield 78%; mp 159-161 °C; [R]19D ) -156.9 (c 1,
CHCl3); IR (KBr) 3454, 3053, 2987, 2935, 2831, 2732, 2671, 2631,
1746, 1592, 1541, 1484, 1444 cm-1; 1H NMR (500 MHz, CDCl3)
δ ) 9.6 (s, 1H), 7.80-7.78 (m, 1H), 7.44-7.43 (m, 1H), 7.28-
7.26 (m, 2H), 6.08 (q, J ) 6.7 Hz, 1H), 2.14 (s, 3H), 1.85 (d, J )
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ) 171.25, 152.90,
123.08, 66.91, 31.04, 21.11, 18.88. Anal. Calcd for C11H12N2O2:
C, 64.71; H, 5.88; N 13.73. Found: C, 64.66; H, 5.91; N, 13.76;
m/z: 205.89 [M + H]+.
Preparation of (S)-1-Benzoyl-2-(R-acetoxyethyl)benzimidazole
(BAEB) 3. Benzoyl chloride (3.5 mL, 30 mmol) was added
dropwise to a stirred solution of 2 (4.08 g, 20 mmol) in 40 mL of
dry pyridine at 0 °C. The solution was stirred at the same
temperature for further 6 h. The reaction mixture was poured onto
ice pieces. The solid obtained was filtered and washed with ice-
cold water. The crude compound was crystallized using CHCl3/
petroleum ether to give 4.9 g of compound 3 as white crystals:
yield 80%; mp 87-89 °C; [R]19D ) +167.8 (c 1, CHCl3); IR (KBr)
J. Org. Chem, Vol. 72, No. 19, 2007 7437

3057, 3040, 2988, 2935, 1731, 1706, 1596, 1531, 1489, 1453 cm-1
;
The organic extract was dried over anhyd Na2SO4, which on
evaporation afforded (S)-N-benzoyl amino ester (4). The unreacted
R-amino ester was recovered from aqueous layer and on derivati-
zation with benzoyl chloride in the presence of pyridine yielded
(R)-N-benzoyl amino ester (5).
1H NMR (300 MHz, CDCl3) δ ) 7.81-7.79 (m, 2H), 7.74-7.68
(m, 1H), 7.56-7.51 (m, 2H), 7.31-7.24 (m, 2H), 7.14-7.08 (m,
1H), 6.67 (d, J ) 8.0 Hz, 1H), 6.19 (q, J ) 6.6 Hz, 1H), 2.01 (s,
3H), 1.86 (d, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ )
170.47, 168.61, 155.48, 142.17, 134.44, 133.59, 132.99, 130.36,
129.19, 124.45, 124.13, 120.54, 113.41, 66.24, 20.86, 19.02. Anal.
Calcd for C18H16N2O3: C, 70.13; H, 5.20; N, 9.09. Found: C, 70.19;
H, 5.16; N, 9.05; m/z: 309.78 [M + H]+.
1
Supporting Information Available: IR, H NMR, 13C NMR,
and mass spectra of 3, spectral characterization of (S)-N-benzoyl
amino esters 4a-e, chiral HPLC analysis of N-benzoyl amino esters
4a-e and 5a-e. This material is available free of charge via the
Internet at http://pubs.acs.org.
Representative Procedure for Enantioselective Benzoylation
of R-Amino Esters. A solution of 3 (2 mmol) and racemic R-amino
ester (4 mmol) in 30 mL of THF was stirred at -10 °C for 12 h.
The reaction was quenched with aq HCl and extracted with CHCl3.
JO070962P
7438 J. Org. Chem., Vol. 72, No. 19, 2007