Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via Phase-Transfer Catalytic Base Hydrolysis

Article abstract of DOI:10.1021/acscatal.8b00693

Asymmetric base hydrolysis of α-chiral esters with synthetic small-molecule catalysts is described. Quaternary ammonium salts derived from quinine were used as chiral phase-transfer catalysts to promote the base hydrolysis of N-protected amino acid hexafluoroisopropyl esters in a CHCl₃/NaOH (aq) via dynamic kinetic resolution, providing the corresponding products in moderate to good yields (up to 99%) with up to 96:4 er. Experimental and computational mechanistic studies using DFT calculation and pseudotransition state (pseudo-TS) conformational search afforded a TS model accounting for the origin of the stereoselectivity. The model suggested π-stacking and H-bonding interactions play essential roles in stabilizing the TS structures.

Full text of DOI:10.1021/acscatal.8b00693

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Letter
Dynamic Kinetic Resolution of N-Protected Amino Acid
Esters via Phase-Transfer Catalytic Base Hydrolysis
Eiji Yamamoto, Kodai Wakafuji, Yuho Furutachi, Kaoru Kobayashi, Takashi Kamachi, and Makoto Tokunaga
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00693 • Publication Date (Web): 21 May 2018
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ACS Catalysis
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Dynamic Kinetic Resolution of N-Protected Amino Acid Esters via
Phase-Transfer Catalytic Base Hydrolysis
†
†
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∥
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Eiji Yamamoto,* Kodai Wakafuji, Yuho Furutachi, Kaoru Kobayashi, Takashi Kamachi, Ma-
§
koto Tokunaga*
§Department of Chemistry, Graduate School of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka 819-0395,
Japan
∥Department of Life, Environment and Materials Science, Fukuoka Institute of Technology, 3-30-1 Wajiro-higashi, Hi-
gashi-ku, Fukuoka, 811-0295, Japan
Supporting Information Placeholder
the nucleophilic attack of hydroxide on carbonyls. Herein,
ABSTRACT: Asymmetric base hydrolysis of α-chiral esters
we describe phase-transfer catalytic asymmetric base hydrol-
ysis of N-protected amino acid esters, affording the corre-
sponding α-chiral unnatural amino acids9 with up to 96:4 er.
This reaction is suitable for the synthesis of enantioenriched
amino acid derivatives bearing a bulky or aryl substituent at
the α-tertiary chiral center, which are difficult to prepare by
phase-transfer catalyst (PTC)-catalyzed asymmetric alkyla-
tion and SNAr reactions.10-12 In addition, the reaction pro-
ceeded through dynamic kinetic resolution by racemization
of the α-proton. In contrast, conventional enzymatic hydrol-
ysis of amino acid esters13 has been reported to involve kinet-
ic resolution, which inherently has a theoretical maximum
yield of 50%, and dynamic kinetic resolution-type enzymatic
hydrolysis developed by Aron group requires additional rac-
emization catalysts and limited to unprotected amino acid
esters (Scheme 1).14 Detailed experimental and computational
studies with DFT calculation and rapid conformational
search were also performed to elucidate the origin of the
stereoselectivity.
with synthetic small-molecule catalysts is described. Quater-
nary ammonium salts derived from quinine were used as
chiral phase-transfer catalysts to promote the base hydrolysis
of N-protected amino acid hexafluoroisopropyl esters in a
CHCl3/NaOH (aq) via dynamic kinetic resolution, providing
the corresponding products in moderate to good yields (up
to 99%) with up to 96:4 er. Experimental and computational
mechanistic studies using DFT calculation and pseudo-
transition state (TS) conformational search afforded a TS
model accounting for the origin of the stereoselectivity. The
model suggested π-stacking and H-bonding interactions play
essential roles in stabilizing the TS structures.
KEYWORDS: base hydrolysis, conformational search, ester,
dynamic kinetic resolution, phase-transfer catalysis
Asymmetric ester hydrolysis, one of the most fundamen-
tal transformations in biological systems, has been widely
employed for the preparation of optically active building
blocks in both laboratory- and industrial-scale chemistry.1
However, notwithstanding the recent advances in asymmet-
ric catalysis, including reactions with water,2 stereocontrol in
ester hydrolysis with synthetic catalysts has remained a for-
midable challenge, probably due to the small size of water,
formation of complex hydrogen bonding networks, and low
reactivity of ester substrates toward hydrolysis under neutral
to acidic conditions. In fact, precedent studies on asymmet-
ric ester hydrolysis with synthetic catalysts, such as metal
complexes,3 micellar catalysts,4 and biomimetic catalysts,5
had limited scopes, and the systems usually required highly
diluted conditions and a large excess of the catalyst.
Conventional Method: Enzymatic Hydrolysis
O
O
O
H
H
H
hydrolase
N
N
N
PG
OR
PG
OH
PG
OR
aqueous buffer
R
R
R
kinetic resolution——— yield: up to 50%
racemic
Enzymatic DKRꢀtype Hydrolysis with Racemization Catalysts
Lewis Acid (cat.)
O
O
O
hydrolase
RCHO (cat.)
H2N
H2N
H2N
OR
OR
OH
OH
H2O
base
R
R
R
This Work:
PTCꢀCatalyzed DKRꢀtype Base Hydrolysis of Esters
O
O
O
H
H
H
chiral PTC
N
N
N
PG
OR
PG
OR
PG
base
baseꢀhydrolysis
R
R
R
The Use of OH – : Environmentally benign and costꢀeffective
DKR Type Base Hydrolysis
Chiral phase-transfer catalysis is one of the major cata-
lytic principles involving ionic reagents in asymmetric syn-
thesis.6 Previously, we reported the enantioselective protona-
tion of alkenyl esters via phase-transfer catalytic base hydrol-
ysis using environmentally benign and inexpensive alkali-
metal hydroxide bases.7,8 Encouraged by the success of
phase-transfer catalytic base hydrolysis, we envisioned that
chiral quaternary ammonium hydroxide species could also
discriminate the two enantiomers of the α-chiral esters in
Features
Direct Access to -Chiral N-Protected Amino Acids
Scheme 1. Asymmetric hydrolysis of N-protected
amino acid esters.
We initially explored the reaction with N-benzoyl tert-
leucine methyl ester (1a) and PTC 3a derived from quinine
(Table 1). Base hydrolysis of 1a at 0 °C in CHCl3 as solvent
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proceeded to afford the corresponding hydrolyzed product
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15
3d 4-CF3-Bz (CF3)2CH
3d Boc (CF3)2CH
CHCl3
CHCl3
45 82.5:17.5
52 64:36
1
2
3
4
5
6
7
8
2a but resulted in poor yield (entry 1, 6%). To improve the
reactivity, esters prepared from fluoroalcohols were exam-
ined, and reactions with 2,2,2-trifluoroethyl or hexafluoroi-
sopropyl esters (1b and 1c, respectively) resulted in a signifi-
cant increase in both the stereoselectivity and the reactivity
(entries 2 and 3). The reaction with PTC 3b derived from
cinchonidine or pseudo-enantiomeric PTC 3c showed lower
selectivity and a significant decrease in the yield (entries 4
and 5). Fortunately, PTC 3d bearing a 2-cyanobenzyl group
afforded the product in quantitative yield with high stereose-
lectivity (entry 6, 95:5 er, >99%). The use of O-allylated PTC
3e resulted in a considerable decrease in yield and er (entry
7), and incorporation of a 2,6-dicyanobenzyl group into PTC
3f led to a loss of most of the catalytic activity, providing
almost racemic product (entry 8). These results indicated
that the 9-OH group of the catalyst is essential for this trans-
formation and that the reaction occurred close to the 9-OH
group. For the other solvents screened, CH2Cl2 showed
slightly lower yield and stereoselectivity, and other non-
halogenated solvents resulted in significantly lower ers. (en-
tries 9–12). Next, we investigated the effect of the N-
protecting group. Introduction of electron-rich or electron-
deficient substituents onto the benzoyl group led to lower
yields and ers (entries 13 and 14, ester 1d, 23%, 88:12 er; ester
1e, 45%, 82.5:17.5 er, respectively). The reaction with N-Boc
substrate 1f resulted in a significant loss of stereoselectivity
(entry 15, 52%, 64:36 er).
aReaction conditions: N-Protected amino acid ester (0.10
mmol), 1 M NaOH (aq) (250 ꢀL), chiral PTC 3 (10 mol %) in
b
CHCl3 (400 ꢀL) at 0 °C for 24 h. Stirring speed: 200 rpm. I-
solated yield of 2.
With the optimized conditions in hand, we then ex-
plored the substrate scope for this reaction (Table 2). Initially,
sterically hindered substrate 1b’ was examined, and it pro-
vided product 2b’ in low yield (35% with 95:5 er). After fur-
ther exploration of the reaction conditions, we found that
the use of 8 equiv of 1 M NaOH (aq) improved the yield sig-
nificantly (2b’, 78%, 96:4 er). Thus, these reaction conditions
were also applied to other substrates. Esters with bulky sub-
stituents provided the corresponding N-benzoyl amino acids
with good to high ers in moderate to good yields (2c’, 53%,
94:6 er; 2d’, 58%, 93.5:6.5 er; 2e’, 65%, 86:14 er). Reactions
with esters having secondary alkyl groups also showed good
ers and moderate yields (2f’, 41%, 86.5:13.5 er; 2g’, 89%,
92.5:7.5 er; 2h’, 85%, 86:14 er; 2i’, 94%, 83.5:16.5 er). N-
Benzoyl phenyl glycine ester 1j’ also afforded the correspond-
ing product 2j’ with good er in moderate yield (39%, 88.5:11.5
er). The stereoselectivity of the reactions with substrates
containing a primary alkyl group at the α-position decreased
significantly (2k’, 90%, 57:43 er; 2l’, 51%, 51.5:48.5 er).
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Table 2. Scope of rac-N-benzoyl amino acid esters 1’.a
Table 1. Optimization of the reaction conditions.a
Entry PTC PG
R
Solvent Yieldb er
1
3a Bz
3a Bz
3a Bz
3b Bz
3c Bz
3d Bz
3e Bz
Me
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
6
–
2
CF3CH2
26 67:33
3
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
(CF3)2CH
79 86.5:13.5
aReaction conditions: N-Benzoyl amino acid ester (0.20
mmol), 1 M NaOH (aq) (1.6 mL), PTC 3d (10 mol %) in CHCl3
(800 ꢀL) at 0 °C for 24 h. Stirring speed: 200 rpm. Isolated
4
5
14
17
80:20
27:73
6
7
>99 95:5
b
yields are presented. 1 M NaOH (aq) (2.5 eq, 500 ꢀL) was
trace
5
–
used.
8
9
10
11
12
13
3f
Bz
47:53
61:39
55.5:44.5
93:7
N-Alloc and N-Boc aryl glycine esters were also exam-
ined (Table 3). Substrate 1m’’ provided the corresponding N-
Alloc phenyl glycine (2m’’) in good yield and er (79% with
89:11 er), while Boc substrate 1n’’ provided the product in low
yield (35%, 90:10 er). An N-Alloc substrate bearing a 4-
methoxyphenyl group provided the corresponding N-Alloc
3d Bz
3d Bz
3d Bz
3d Bz
toluene 31
Mes
16
91
CH2Cl2
Et2O
56 56:44
23 88:12
3d 4-OMe-Bz (CF3)2CH
CHCl3
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ACS Catalysis
aryl glycine 2o’’ in good yield with moderate er (75%,
83.5:16.5 er).
dynamic kinetic resolution of 6a via base hydrolysis
would subsequently occur. To assess the hypothesis, we
performed the reaction with 6a, which provided the hy-
drolyzed product 2a in significantly lower er than that
obtained with substrate 1c (78:22 er, Scheme 3B). In ad-
dition, hydrolytic kinetic resolution of ester 1c and fol-
lowing dynamic kinetic resolution of 6a is a possible
reaction pathway. Thus, we confirmed the er of recov-
ered substrate 1c under standard conditions (Scheme
3C). The recovered substrate 1c was almost racemic (13%
yield, 51:49 er), excluding the scenario. Furthermore, two
possible racemization/hydrolysis pathways still remains;
direct deprotonation/protonation of ester 1c followed by
1
2
3
4
5
6
7
8
Table 3. Scope of racemic N-carbamate protected aryl
glycine esters 1’’.a
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aReaction conditions are the same as described in Table 2,
footnote a. Isolated yields are presented.
base hydrolysis of ester 1c (pathway
via azlactone 6a formation/ring opening with HFIP fol-
lowed by base hydrolysis of ester 1c (pathway ). To as-
sess the direct racemization of 1c, enantiopure -Boc
A) or racemization
B
To highlight the utility of this reaction, we conducted
transformations of hydrolyzed product 2a (Scheme 2). Com-
pound 2a was subjected to methylation/LiAlH4 reduction
reactions, providing the corresponding alcohol 4a in good
yield without any loss of optical purity. In addition, we also
carried out acid hydrolysis and subsequent Boc protection of
the hydrolyzed product. The corresponding N-Boc tert-
leucine 2f was obtained in 80% yield with 91.5:8.5 er.
N
substrate (S)-1f (>99.5:0.5 er) was subjected to the
standard reaction conditions (Scheme 3D). The er of the
recovered 1f was >99.5:0.5 as well as the hydrolyzed
product 2a, suggesting that direct racemization of 1c is
unlikely in this system. Furthermore, to investigate the
possibility of azlactone ring opening with HFIP, the re-
action of azlactone 6a in the presence of 1 equivalent of
HFIP was performed, and ester formation was observed
(Scheme 3E). These results support racemiza-
H
i) methylation
74% yield
(2 steps)
>99:1 er
H
N
O
Ph
N
ii) LiAlH4 reduction
OH
Ph
OH
O
t-Bu
(S)ꢀ4a
H
O
O
t-Bu
i) acid hydrolysis
ii) Boc protection
tion/hydrolysis pathway B. Taking these results into
80% yield
(2 steps)
2f 91.5:8.5 er
N
(S)ꢀ2a, >99:1 er
Boc
OH
(S)ꢀ
consideration, the pathway affording the major enanti-
omer is likely to be the direct base hydrolysis of ester 1c
while both base hydrolysis of 1c and azlactone 6a are
possible for the pathways providing the minor enantio-
mer (Scheme 3F).
t-Bu
Scheme 2. Transformations of hydrolyzed product 2a.
To obtain mechanistic insights, we investigated the
stability of the nitrile group in the PTC 3d under the
reaction conditions. After the asymmetric hydrolysis
reaction of ester 1c with 8 equivalent of 1 M NaOH (aq)
for 24 h, the PTC 3d was recovered in 77%, and nitrile-
hydrated PTC was not observed based on 1H NMR analy-
sis (See, Supporting Information).
Next, we explored the byproducts formed in the re-
action. As mentioned in Table 2, increasing the amount
of 1 M NaOH (aq) from 2.5 eq to 8.0 eq improved the
yield (ester 1b’, 35% vs 78%). We hypothesized that
product inhibition by forming the ammonium carbox-
ylate ion pair would occur. Consistent with this hypoth-
esis, addition of (S)-2a (>99.5:0.5 er) resulted in obtain-
ing the product in low yield and the formation of hy-
droxyoxazole 5a-H or the corresponding salt 5a-Na in
50–55% yield (Scheme 3A). In addition, ammonium ben-
zoate salt derived from PTC 3d also showed low catalytic
activity, which also supports the hypothesis (See, Sup-
porting Information). Furthermore, the reaction of 1c in
the presence of a catalytic amount of (S)-2a and hex-
afluoroisopropyl alcohol (HFIP) proceeded to provide
the product 2a in 47% yield in 91:9 er (Scheme 3A). The-
se results indicate that the alkoxide derived from HFIP
mitigates the inhibition effect.
The observation of cyclic byproduct 5a-H/Na sug-
gests that azlactone 6a was formed in the system and
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Scheme 4. Improvement of Product Yield by the Ad-
dition of Catalytic Amount of HFIP.
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To investigate the necessity of the N–H group in the
substrate, the reaction of N-methylated substrate 1p was
carried out, affording the corresponding product in signifi-
cantly lower er (Scheme 5). This result suggests that either
the H-bonding interaction of the N–H group or the steric
effect of the N–Me group in the substrate is significantly in-
volved in the stereodetermining step.
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Scheme 5. Reaction with racemic N–Me substrate 1p.
We further performed a theoretical investigation to elu-
cidate the origin of the stereoselectivity (Figure 1). Im-
portantly, identification of intermolecular transition state
(TS) structures determining the stereoselectivity of a reaction
has been a difficult issue in the field of asymmetric organoca-
talysis due to the complex non-covalent interactions and the
generation of numerous complex TS candidates.15,16 Thus, a
conformational search for the active species-substrate com-
plex in which the distances of the atoms directly involved in
the bond formation or dissociation are fixed to an appropri-
ate length for the presumed TS structure (pseudo-TS con-
formational search) was performed with the ConFinder pro-
gram, which adopts a low-mode conformational search
method with semiempirical quantum mechanical calcula-
tions.15b We considered four initial structures of the substrate
1c-PTC 3d complex classified by the stereochemistry of the
enantiofaces attacked by the hydroxide and the substrate’s α-
carbon center: Re-R, Si-R, Re-S, Si-S. The C···O distance be-
tween the carbonyl carbon of the substrate ester and oxygen
atom of the hydroxide was fixed to 2.0 Å in the conforma-
tional search to keep the geometry close to the correspond-
ing TS structures. The conformation search generated 2103 to
3275 conformations for each of the complexes, and the ener-
gies for the obtained conformers were further assessed by
single-point energy (SPE) calculations at the RI-B97D/SV(P)
level of theory. After the refinement of the conformers, fur-
ther partial optimization was carried out at the RI-
B97D/SV(P) level of theory (see the Supporting Information
for details). The geometries of the TS structures were then
optimized at the M06-2X/TZVP level of theory. The most
stable TS structures leading to the S- or R-product were suc-
cessfully located, as shown in Figure 1 (TS-Re-S and TS-Si-R,
respectively). The difference in Gibbs free energy at 273.15 K
between TS-Re-S and TS-Si-R is in good agreement with the
ꢁꢁG values based on the experimental results [2.1 (calcd.) vs
1.6 (exptl.) kcal/mol]. In addition, both TS structures indicate
the π-stacking between the quinoline ring or 2-cyanophenyl
ring in 3d and Ph group in 1c and H-bonding interactions
between the hydrogen atoms in the MeO group or one of the
benzylic protons in the 2-cyanobenzyl group and the oxygen
atom in the Bz group (O–CH2H···O=C and N+CHH···O=C).17
These non-bonding interactions play important roles in sta-
Scheme 3. Mechanistic Investigations and Proposed
mechanism.
Based on the above mechanistic considerations, we ex-
pected that addition of a catalytic amount of HFIP would
suppress the product inhibition by forming the ammonium
carboxylate ion pair and lead to improve the reaction effi-
ciency with substrates that provided the products in low to
moderate yield. Thus, the reaction of substrate 1e’ in the
presence of a catalytic amount of HFIP (10 mol %) was con-
ducted to provide the corresponding hydrolyzed product 2e’
in high yield without significant loss of the stereoselectivity
(83% yield, 85.5:14.5 er, Scheme 4).
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bilizing the TS structures. Furthermore, the H-bonding in-
Notes
1
2
3
4
5
6
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teraction between the hydrogen atom in the MeO group and
the nitrogen atom in the cyano group was observed in the
TS-Re-S structure, whereas the two groups were distant in
the TS-Si-R structure (2.72 and 3.49 Å, respectively). Other TS
structures without the H-bonding interaction (O–
CH2H···O=C) also resulted in a significant increase in energy
(>3.8 kcal/mol; see the Supporting Information), indicating
the importance of the interactions. Furthermore, the favored
TS-Re-S structure demonstrates the existence of a H-bonding
interaction between the oxygen atom in the ester group and
the ortho-hydrogen atom in the 2-cyanobenzyl group in PTC
3d (2.45 Å), which was not observed in the TS-Si-R structure.
Thus, the lack of this H-bonding interaction would explain
the energy differences between the TS structures. The N–H
group in the substrate does not display H-bonding interac-
tions in the TS structures, suggesting that the significant loss
of selectivity with N–Me substrate 1p is attributable to the
conformational change caused by the steric effect.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by JSPS KAKENHI Grant number
16H07042, 15K05431 and 23655087, and a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysts” from The Ministry of
Education, Culture, Sports, Science and Technology, Japan
(No. 24105524 and 26105744). Computations were partially
carried out using the computer facilities at the Research In-
stitute for Information Technology, Kyushu University. We
appreciate the reviewer for the valuable suggestions in the
peer-review process.
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Figure 1. Calculated TS structures leading to each
enantiomer at the M06-2X/TZVP level of calculation.
In conclusion, we reported the first asymmetric base hy-
drolysis of α-chiral esters based on phase-transfer catalysis.
This reaction proceeded via dynamic kinetic resolution, af-
fording the hydrolyzed products in moderate to good yields
with up to 96:4 er. Detailed experimental studies suggest
that the stereodetermining step is the nucleophilic attack of
the hydroxide on the carbonyl carbon in the ester substrate.
In addition, computational studies using pseudo-TS confor-
mational search with ConFinder and DFT calculation indi-
cated the essential non-covalent interactions between the
substrate and the catalyst. Further studies on developing new
PTCs that provide high stereocontrol in reactions with α-
chiral esters and applying the pseudo-TS conformational
search method with the ConFinder program are now under-
way in our group.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
E-mail for E.Y.: eiyam@chem.kyushu-univ.jp
E-mail for M.T.: mtok@chem.kyushu-univ.jp
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Author Contributions
†K.W. and Y.F. contributed equally.
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