Enantioselective hydrolysis of N-acylated α-amino esters at a biphasic interface: Tandem reaction kinetic resolution using a chiral complexing agent

Article abstract of DOI:10.1021/ol026517s

equation presented Highly enantioselective hydrolytic kinetic resolutions of esters derived from N-acylated α-amino acids proceed rapidly at hydrocarbon/water interfaces in the presence of a proline-derived chiral selector. When performed in tandem with an enantioselective biphasic esterification reaction, esters of 100% enantiomeric excess are obtained.

Full text of DOI:10.1021/ol026517s

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3283-3286
Enantioselective Hydrolysis of
N-Acylated r-Amino Esters at a
Biphasic Interface: Tandem Reaction
Kinetic Resolution Using a Chiral
Complexing Agent
Seth E. Snyder* and William H. Pirkle*
School of Chemical Sciences, UniVersity of Illinois at Urbana-Champaign,
Urbana, Illinois 61801
sesnyder@uiuc.edu
Received July 14, 2002
ABSTRACT
Highly enantioselective hydrolytic kinetic resolutions of esters derived from N-acylated r-amino acids proceed rapidly at hydrocarbon/water
interfaces in the presence of a proline-derived chiral selector. When performed in tandem with an enantioselective biphasic esterification
reaction, esters of 100% enantiomeric excess are obtained
The design of metal-free organocatalysts that effect enanti-
oselective reactions has been an active area of research in
recent years.1 One such approach involves the kinetic
resolution of racemic substrates.2 By using low molecular
weight organic catalysts such as peptides,3 cinchona alka-
loids,4 proline-derived catalysts,5 and template-imprinted
polymers,6 a variety of highly enantioselective kinetic
resolutions have been developed for different types of organic
transformations. In these systems, most of which are
homogeneous, assorted noncovalent interactions contribute
to the observed chiral recognition. Interestingly, rather scant
attention has been paid to nonenzymatic kinetic resolutions
conducted in biphasic liquid systems.7,8 We herein report the
kinetic resolution of N-acylated R-amino acids and their
esters using a biphasic solvent system containing a chiral
complexing agent that differentially affects the reactivities
of the enantiomers.
(1) For a review, see: Dalko P. I.; Moisan L. Angew. Chem., Int. Ed.
2001, 40, 3726-3748.
(2) For pertinent reviews on kinetic resolution, see: (a) Keith J. M.;
Larrow, J. F.; Jacobsen, E. N. AdV. Synth. Catal. 2001, 343, 5-26. (b)
Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249-330.
(3) Miller, S. J.; Copeland, G. T.; Papaioaaou, N.; Horstmann, T. E.;
Ruel, E. M. J. Am. Chem. Soc. 1998, 120, 1629-1630.
(4) Chen, Y.; Tian, S.; Deng, L. J. Am. Chem. Soc. 2000, 122, 9542-
9543.
The use of a chiral selector initially developed for the
chromatographic separation of enantiomers was recently
reported to be efficacious as one component of a two-
(5) (a) Oriyama, T.; Hori, Y.; Imai, K.; Sasaki, R. Tetrahedron Lett.
1996, 37, 8543-8546. (b) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem.
Lett. 1999, 265-266.
(6) Sellergren, B.; Shea, K. J. Tetrahedron: Asymmetry 1994, 5, 1403-
1406.
(7) For relevant articles dealing with enantioselective ester hydrolysis
at a micellar interface, see: (a) Scrimin, P.; Tecilla, P.; Tonellato, U. J.
Org. Chem. 1994, 59, 4194-4201. (b) Cleij, M. C.; Scrimin, P.; Tecilla,
P.; Tonellato, U. Langmuir 1996, 12, 2596-2560. (c) Cleij, M. C.; Drenth,
W.; Nolte, R. J. M. J. Org. Chem. 1991, 56, 3883-3891.
10.1021/ol026517s CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/29/2002

component chiral phase transfer catalyst employed for the
biphasic kinetic resolution of a racemic N-acylated R-amino
acid.9 In particular, a combination of an (S)-proline-derived
selector and an achiral phase transfer catalyst such as
tetrahexylammonium bromide (TBAB) suffices to preferen-
tially transport one enantiomer of a racemic N-3,5-dinitro-
benzoyl amino acid (such as leucine) from an aqueous
carbonate or bicarbonate solution into an immiscible organic
phase containing an alkylating agent. After reaction with 0.5
molar equiv of the alkylating agent, the organic phase
contains enantioenriched ester, the aqueous phase contains
enantiodepleated N-acyl amino acid. Nonpolar solvents (e.g.,
hexane, decane) afford the greatest enantioselectivity. Ser-
endipitously, it was noted that prolonged stirring of the
reaction mixture, long past consumption of the alkylating
agent, causes gradual loss of the ester from the organic layer
with a concomitant increase in its enantiomeric purity. It was
suspected that enantioselective hydrolysis was occurring, and
if so, this could be used to increase the enantiomeric purity
of the product ester.
Table 1. Enantioselective Biphasic Hydrolysis of Esters of
N-Acylated R-Amino Acidsa
(S)-4
T
entry
ester
(equiv) (°C)
solvent
% eee
sf
b
b
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1b
1b
1b
1c
1c
1d
1e
1e
1f
2.0
2.0
2.0
2.0
2.0
0.5
0.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
rt
0
rt
0
rt
rt
0
rt
0
rt
rt
rt
rt
0
rt
0
rt
0
CCl4/CH2Cl2
CCl4/CH2Cl2
Hex/CH2Cl2
Hex/CH2Cl2
CCl4/CH2Cl2
Hex/CH2Cl2
Hex/CH2Cl2
Hex/CH2Cl2
Hex/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
Hex/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
CCl4/CH2Cl2
65
84
83
92
79
59
67
86
92
65
70
79
61
75
41
62
57
74
20
31
9.0
30.3
27.8
80.4
20.3
6.9
10.0
36.7
80.4
9.0
11.7
20.3
7.5
15.5
3.5
c
c
b
c
c
c
c
9
b
10
11
12
13
14
15
16
17
18
19
20
That enantioselective hydrolysis is occurring was tested
by stirring a variety of racemic esters in nonpolar organic
solvents with 2 M sodium hydroxide in the presence of a
water-immiscible solution of the chiral selector. We presently
restrict ourselves to the hydrolysis of N-3,5-dinitrobenzoyl
esters of racemic carboxylate acids (1a-i) and R-amino-
phosphonic acids (2), as well as an N-3,5-dinitrobenzoyl
derivative of a racemic R-aminolactam (3).10 Selector (S)-4
was used as a chiral complexing agent.11 Table 1 provides
several examples of the effects of selector concentration,
temperature, and organic solvent on the apparent stereo-
selectivity factor, s, of hydrolysis of carboxylate esters 1a-
i. The enantioselectivities in Table 1 are reported for
hydrolysis of 50% of the ester initially present, the required
times varying between 30 min and 6 h.12 Preferential
hydrolysis of the less complexed enantiomer is observed in
all cases, reaction rate increasing markedly with stirring speed
(although stirring rate has no influence on enantioselectivity).
b
d
b
b
b
b
b
b
b
b
1f
1g
1g
1h
1h
1i
7.9
6.3
14.6
1.8
rt
0
1i
2.5
a Standard conditions entailed use of 0.023 mmol (1 molar equiv) of
racemic ester and the indicated number of molar equiv of (S)-4 in the
indicated organic solvent and 3.0 mL of 2 M sodium hydroxide. The reaction
was rapidly stirred magnetically. Aliquots were assayed periodically by
chiral HPLC. b Racemic ester and (S)-4 dissolved in 2.5 mL of CCl4 and
0.5 mL of CH2Cl2. c Racemic ester and (S)-4 dissolved in 2.9 mL of hexane
and 0.15 mL of CH2Cl2. d Racemic ester and (S)-4 dissolved in 2.5 mL of
hexane and 0.5 mL of CH2Cl2. e % ee of both the residual ester (enriched
in (S) enantiomer) and the product DNB amino acids (enriched in the (R)
enantiomer) at 50% conversion determined by using a chiral stationary phase
(1a, 1h, and 1i, N-(10-undecenoyl)-(S)-proline-3,5-dimethylanilide column
i
(30% PrOH in hexane) developed in these laboratories;11 1b, 1f, 1g, and
1d, (R,R)-Whelk O1 (13% iPrOH in hexane) available from Regis
Technologies; 1c and 1e, (D)-leucine (10% iPrOH in hexane) available from
Regis Technologies). Absolute configurations were assigned by comparison
with authentic samples. f Stereoselectivity factor.
(8) For the biphasic kinetic resolution of racemic aldols using aldolase
antibodies, see: Turner, J. M.; Bui, T.; Lerner, R. A.; Barbas, C. F., III;
List, B. Chem. Eur. J. 2000, 6, 2772-2774.
(9) Pirkle, W. H.; Snyder, S. E. Org. Lett. 2001, 3, 1821-1823.
(10) For preparation of racemates used in this study, see: (a) Pirkle, W.
H.; Hyun, M. H.; Bank, B. J. Chromatogr. 1984, 316, 585-604. (b) Pirkle,
W. H.; Pochapsky, T. C.; Mahler, G. S.; Field, R. M. J. Chromatogr. 1985,
348, 89-96. (c) Pirkle, W. H.; Burke, J. A., III. J. Chromatogr. 1991, 557,
173-185.
Clearly, reaction occurs at the interface since reaction rate
increases with increased interfacial surface area. Hydrolysis
occurs more rapidly in the absence of the selector, demon-
strating that complexation inhibits hydrolysis. Increasing the
concentration of the selector slows hydrolysis but increases
enantioselectivity. The presence of a phase transfer catalyst
is not essential to the hydrolysis but does influence rate,
presumably by increasing the concentration of the anionic
nucleophile on the aqueous side of the interface. Once
hydrolysis has proceeded to the desired extent, isolation and
acidification of the aqueous layer liberates the enantioen-
riched carboxylic acid. The chiral selector and the enan-
tioenriched ester remain in the organic layer and can be
recovered either by chromatography on silica or by hydroly-
sis of the ester and extraction of the enantioenriched acid.
(11) For preparation of (S)-4, see: Pirkle, W. H.; Koscho, M. E. J.
Chromatogr. A 1999, 840, 151-158.
(12) Typical Procedure for Biphasic Hydrolysis. Racemic 1 (0.023
mmol) and (S)-4 (0.046 mmol) were dissolved in 2.9 mL of hexane and
0.15 mL of CH2Cl2. The solution was stirred rapidly at room temperature,
and 3.0 mL of 2 M sodium hydroxide was added. Reaction progress was
monitored periodically by HPLC using a (DL)-phenylglycine column or a
Whelk O1 column available from Regis Technologies (the selector, (S)-4,
was used as an internal standard.) The reaction was stirred for 1 h, at which
point HPLC indicated approximately 50% conversion. The layers were
separated, and the aqueous layer was extracted three times with CH2Cl2.
The combined organic layers were dried over MgSO4, filtered, and
concentrated under reduced pressure. Separation of 1 and (S)-4 was done
by flash column chromatography (SiO2, hexane/ethyl acetate). The original
aqueous layer was acidified with 2 M HCl and extracted three times into
ethyl acetate. Following methylation of the N-protected amino acids,
enantiomeric excess was determined by using a chiral stationary phase
i
((R,R)-Whelk O1, (10% PrOH in hexane)).
3284
Org. Lett., Vol. 4, No. 19, 2002

gives s factors between 10 and 15, 50% conversion being
achieved after 2 days of rapid stirring at room temperature.
Hydrolysis of racemic 3 under standard conditions gives s
factors between 2 and 3, 50% conversion being achieved in
approximately 1 week.
Because the biphasic alkylation reaction preferentially
esterifies the acid enantiomer most strongly associated with
the chiral selector whereas it is the less strongly associated
ester enantiomer that is preferentially hydrolyzed, the hy-
drolysis reaction can be used to scavenge the minor enan-
tiomer produced during esterification. Thus, it is possible to
run these reactions sequentially in the presence of a phase
transfer catalyst to obtain each enantiomer in substantially
enriched form, one as the acid, the other as the ester (Scheme
1). Sodium bicarbonate is employed for the esterification
In the absence of a phase transfer catalyst, hydrolysis of
these esters is at least 20 times faster in hexane than in
methylene chloride and the enantioselectivity is greater as
well. This rate enhancement is presumed to stem from the
poorer solvating ability of hexane leading to increased
adsorption of the ester onto the aqueous interface where
hydrolysis occurs. It should be pointed out that both the
relative and absolute rates of reaction of two compounds may
be quite different depending on whether the reaction occurs
in homogeneous solution or while the compounds are
adsorbed onto a liquid interface, especially with the incoming
reagent being contained in but one of the two liquid phases.13
Owing to the dynamic complexity of these systems, the s
factors depend on the concentration of the selector but remain
essentially constant (under the described conditions) through-
out the reaction once a 2-fold excess of selector is present.
At lower concentrations of selector, the calculated s factors
increase throughout the reaction. Although a variety of factors
may contribute to the observed enantioselectivities, the extent
of differential complexation between (S)-4 and with the
enantiomers of 1a-i appears to be an important factor.
Indeed, esters showing higher chromatographic separation
factors on a chiral stationary phase derived from (S)-4 also
give higher s factors for hydrolysis. Notably, dimethyl esters
of glutamic acid (1h) give substantially higher s factors than
the corresponding esters of aspartic acid (1i), a result
consistent with chromatographic data.14 In the later case, the
remote carbonyl group presumably reduces chiral recognition
by providing an alternative hydrogen-bonding site close to
the stereocenter for the otherwise less strongly complexed
enantiomer. For the less strongly complexed enantiomer of
an ester of glutamic acid, this alternative potential interaction
site is even more remote and consequently interferes less
with the chiral recognition process.
Scheme 1
reaction to minimize competitive hydrolysis of the alkylating
agent. Since the hydrolysis is relatively slow, increasing the
pH of the aqueous solution (by addition of 2 M NaOH) once
the esterification reaction is complete facilitates the overall
process.15 The interplay between concentration of the various
components, reaction times, yields, and enantiomeric purities
is complex. Under typical conditions, with 0.5 molar equiv
of phenacyl bromide for each equivalent of racemic N-3,5-
dinitrobenzoyl leucine, 38% of enantiomerically pure ester
was obtained after workup (maximum possible conversion
being 50%).16 Higher conversions of enantiomerically pure
ester can be achieved by increasing the quantity of phenacyl
bromide; the optimum amount will need to be determined
by experiment for each amino acid and each alkylating agent.
Dimethyl sulfate, diethyl sulfate, and various phenacyl
halides have been employed successfully as alkylating agents.
In summary, we have demonstrated a method of perform-
ing enantioselective hydrolysis reactions occurring at the
aqueous/organic interface. Furthermore, we have described
a one-pot enantioselective esterification/hydrolysis approach.
In one sense, this simple biphasic-chiral selector combination
emulates the kind of chemistry afforded by esterases but with
Biphasic enantioselective hydrolysis reactions are possible
with other hydrolytically labile compounds such as racemic
phosphonate esters (2) and racemic lactams (3), albeit with
substantially reduced rates. Hydrolysis of 2 under the
standard reaction conditions using 2 molar equiv of (S)-4
(15) Typical Procedure for Tandem Esterification/Hydrolysis Reac-
tion. A solution of phenacyl bromide (0.05 mmol), (S)-4 (0.10 mmol), and
tetrahexylammonium bromide (0.003 mmol) in 2.75 mL of carbon
tetrachloride and 0.10 mL of methylyne chloride was stirred with a solution
of N-3,5-dinitrobenzoyl leucine (0.10 mmol) in 1.25 mL of saturated sodium
bicarbonate for 27 h. At this point, 1.25 mL of 2 M NaOH was added, and
the reaction mixture was stirred for an additional 4 h. The layers were
separated and worked up as described in ref 12.
(16) Immediately following the addition of 2 M sodium hydroxide, the
organic layer turns dark purple. The color disappears following acidic
workup. The effect is attributed to the formation of a transient Meisenheimer
complex stabilized by the quaternary ammonium cation. This secondary
process is currently under investigation.
(13) For a recent article dealing with control over regioselectivity by
orientation at interfaces, see: Buijnsters P. J. J. A.; Feiters, M. C.; Nolte,
R. J. M.; Sommerdijk, N. A. J. M.; Zwanenburg, B. Chem. Commun. 2001,
269-270.
(14) Isolation of products from the hydrolysis of the dimethyl esters of
glutamic and aspartic acid reveals that both methyl groups are cleaved.
Org. Lett., Vol. 4, No. 19, 2002
3285

some important differences. For example, unlike the tandem
reaction herein described, an esterase preferentially promotes
both the forward and reverse reaction for the same enanti-
omer (microscopic reversibility). While resolution of the
compounds described herein is of but minor practical
consequence, we have demonstrated that chiral complexing
agents can alter the reactivity of a complexed enantiomer to
the point that highly enantioselective reactions can be
performed. Potentially, this methodology might be applied
to a variety of hydrolytically labile organic compounds,
provided that a suitable chiral complexing agent is present.
Furthermore, the method can be used to identify the ideal
chiral agent for a specific substrate through simple chro-
matographic screening. We are now in the process of
unraveling the mechanistic details governing chiral discrimi-
nation with the hope of designing a broader base of chiral
selectors that influence the stereochemistry of specific
organic reactions.
Acknowledgment. This work was financially supported
by gifts from the estate of Louise V. Leonard and from
AstraZeneca and a grant from the University of Illinois
Research board to S.E.S. We would like to thank James R.
Carey from the University of Illinois for invaluable discus-
sions and paper review.
OL026517S
3286
Org. Lett., Vol. 4, No. 19, 2002