Transesterification of α-amino esters catalyzed by a tetranuclear zinc cluster: Zn4(OCOCF3)6O

Article abstract of DOI:10.1055/s-0031-1290096

Transesterification of amino acid ester derivatives was developed using a tetranuclear zinc cluster, Zn₄(OCOCF₃)₆O, as the catalyst. Because the reaction conditions were very mild, a variety of N-protective groups and functional groups on side chains were tolerated. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1290096

LETTER
137
Transesterification of a-Amino Esters Catalyzed by a Tetranuclear Zinc
Cluster: Zn4(OCOCF3)6O
T
a
ransesterification
u
of
a
-Amino
s
E
sters uke Maegawa,a Kazushi Agura,b Yukiko Hayashi,a Takashi Ohshima,*b Kazushi Mashima*a
Department of Chemistry, Graduate School of Engineering Science, Osaka University and CREST, JST, Toyonaka,
Osaka 560-8631, Japan
E-mail: mashima@chem.es.osaka-u.ac.jp
Graduate School of Pharmaceutical Sciences, Kyushu University and CREST, JST, Higashi-ku, Fukuoka 812-8582, Japan
E-mail: ohshima@phar.kyushu-u.ac.jp
b
Received 17 August 2011
cessfully applied to a few glycine esters and dipeptides.13b
These preliminary results encouraged us to investigate the
transesterification of a-amino acid esters with a broader
scope of N-protective groups, alcohols, and side chains.
Abstract: Transesterification of amino acid ester derivatives was
developed using a tetranuclear zinc cluster, Zn4(OCOCF3)6O, as the
catalyst. Because the reaction conditions were very mild, a variety
of N-protective groups and functional groups on side chains were
tolerated.
CF3
Key words: transesterification, esters, zinc, amino acids, clusters
CF3
O
O
Zn
Zn
O
O
F3C
F3C
O
O
O
CF3
CF3
O
O
Amino acids are the most important organic components,
and their N-protected esters are utilized as building blocks
for synthesizing natural and non-natural peptides1 as well
as medicinal compounds such as antiviral,2 anticancer,3
anti-inflammatory,4 and anti-ischemic5 agents. Tremen-
dous efforts in both academic and industrial laboratories
have been directed toward developing highly efficient
synthetic methodologies to prepare N-protected amino
acid esters from the corresponding amino acids without
any racemization. Coupling reactions of N-protected ami-
no acids and alcohols assisted by condensation reagents6
such as DCC7 are used to prepare the corresponding es-
ters, but these reactions produce more than a stoichiomet-
ric amount of waste, and in some cases racemization is
induced despite the controlled conditions. With respect to
environmental concerns, catalytic transesterification,8 in
which treatment of a methyl ester with alcohol directly af-
fords the corresponding ester, is an attractive alternative
for preparing a variety of N-protected amino acid esters.
Although many catalysts, such as aluminum alkoxide,9 ti-
tanium alkoxide,10 and distannoxane,11 have been exten-
sively applied to the transesterification of various esters,
catalytic transesterification of N-protected amino acid es-
ters has been rarely investigated due to severe side reac-
tions, such as the decomposition of functional groups at
side chains, cleavage of N-terminal protective groups, and
epimerization at the a-position of the amino acid.12 We re-
cently developed a m4-oxo-tetranuclear zinc cluster
[Zn4(OCOCF3)6O] (1) (Figure 1) as a versatile catalyst
that efficiently catalyzed the transesterification of various
methyl esters under mild conditions preserving various
functional groups sensitive to acidic and basic condi-
tions.13 In our previous report, transesterification was suc-
O
O
O
O
Zn
O
Zn
O
O
CF3
CF3
Zn4(OCOCF3)6O (1)
O
Figure
Zn4(OCOCF3)6O (1)
1
Structure of the m-oxo tetranuclear zinc cluster
We examined the Zn cluster catalyzed transesterification
of various N-protected glycine methyl esters (such as 2aa)
with 1-butanol (3b) in refluxed diisopropyl ether for 18
hours, and the results are summarized in Table 1. All re-
actions proceeded smoothly without any deprotection to
afford the corresponding butyl esters in high yield. More-
over, a shorter reaction time (18 h) than those in prelimi-
nary studies (up to 42 h) was sufficient in most cases.13b
Noteworthy was that carbamate groups such as Cbz (2aa)
and Boc (2ba) remained intact (Table 1, entries 1 and 2),
in sharp contrast to report that transesterification reactions
of substrates with these carbamate protection groups re-
sults in an exchange of the alkoxy moiety of the carbamate
group by externally added alcohol in the presence of tita-
nium alkoxide.14 Other carbamates, such as Fmoc (2ca),
Alloc (2da), and Troc (2ea), also did not decompose dur-
ing the reaction course (Table 1, entries 3–5). Because the
transesterification conditions were completely neutral, Ns
(2fa) and Fmoc (2ca) groups, which are sensitive to basic
conditions and nucleophiles, did not decompose at all
(Table 1, entries 3 and 6). No ring opening of the Pht
group was observed in the reaction of Pht-glycine methyl
ester (2ga), and butyl ester 2gb was obtained in 95% after
refluxing for 24 hours (Table 1, entry 7).
Scope and limitations for alcohols were explored by the
transesterification of Cbz-glycine methyl ester (2aa), and
the results are summarized in Table 2. Reactions of 2aa
SYNLETT 2012, 23, 137–141
Advanced online publication: 09.12.2011
DOI: 10.1055/s-0031-1290096; Art ID: U05911ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

138
Y. Maegawa et al.
LETTER
(Table 2, entries 6 and 10), in accordance with the previ-
ous observation for 1-catalyzed transesterification.13b Re-
actions with allylic alcohols 3i and 3j (Table 2, entries 7
and 8) and benzyl alcohol 3k (Table 2, entry 9)13b pro-
ceeded with good yields without any side reactions, such
as ether formation of allylic alcohols or benzyl alcohol.
Table 1 Transesterification of Glycine Methyl Esters with Various
N-Protective Groupsa
Zn4(OCOCF3)6O (1)
PG1
On-Bu
PG1
OMe
(1.25 mol%)
N
PG2
N
n-BuOH
+
PG2
O
i-Pr2O, reflux, 18 h
– MeOH
O
3b
Entry
(PG1)(PG2)N
Methyl
ester
Yield of butyl
Table 2 Transesterification of Cbz-Glycine Methyl Ester with Var-
ester 2 (%)b
ious Alcoholsa
O
Zn4(OCOCF3)6O (1)
Cbz
OR
(1.25 mol%)
1
2
2aa
2ab 97
2bb 99
Cbz
OMe
N
+ROH
N
Ph
O
N
H
H
i-Pr2O, reflux, 18 h
– MeOH
H
O
O
2aa
3
O
2ba
2ca
3
Yield of product 2 (%)b
2ac 90
O
N
H
Entry
R
O
1
2
3
4
n-C18H37
CH2t-Bu
3c
3d
3e
3f
O
N
2ad 99
3
2cb 95
H
CH(n-Pr)2
c-Hex
2ae 79
2af >99
O
O
4
5
2da
2ea
2db 93
2eb 98
O
N
H
5c
3g
2ag 92
Cl3C
O
N
H
6
7
t-Bu
3h
3i
2ah n.d.d
2ai 98
O
O
S
6c
2fa
2fb 84
allyl
N
H
NO2
8
3j
3k
3l
2aj 99
Ph
O
9
Bn
Ph
2ak 96
2al n.d.d
7d
8
2ga
2ha
2gb 95
2hb 93
N
O
10
a Reaction conditions: A mixture of Cbz-glycine methyl ester (2aa,
1.0 mmol), alcohol 3c–l (1.2 mmol), and 1 (0.0125 mmol, 1.25 mol%)
in i-Pr2O (1.7 mL) was refluxed for 18 h under argon atmosphere.
b Isolated yield.
O
Ph
N
H
c Reaction time was 48 h.
d Product was not detected.
a Reaction conditions: A mixture of methyl ester (1.0 mmol), 3b (1.2
mmol), and 1 (0.0125 mmol, 1.25 mol%) in i-Pr2O (1.7 mL) was re-
fluxed for 18 h under an argon atmosphere.
b Isolated yield.
The present transesterification was applied to the conver-
sion of various methyl esters of N-Cbz-protected amino
acids to the corresponding butyl esters, in which steric
congestion at the a-position and applicability of the func-
tional group were systematically assessed, and the results
are summarized in Table 3. Transesterification of the me-
thyl esters of alanine (4aa), leucine (7aa), proline (8aa),
and phenylalanine (9aa) with 1-butanol (3b) proceeded
smoothly to give the corresponding butyl esters 4ab, 7ab,
8ab, and 9ab in high yield (Table 3, entries 1 and 6–8).
c 12% of the starting material was recovered (95% based on the recov-
ered starting material).
d Reaction time was 24 h.
with primary alcohols, 1-octadecanol (3c) and neopentyl
alcohol (3d), gave the corresponding esters 2ac in 90%
and 2ad in 99% yield (Table 2, entries 1 and 2). Second-
ary alcohols, 4-heptanol (3e) and cyclohexanol (3f), also
worked well to give the corresponding esters 2ae in 79%
and 2af in >99% yield (Table 2, entries 3 and 4), while re-
action with D-menthol (3g) was rather slow, presumably
due to steric hindrance, and was completed by a prolonged
reaction time (48 h) to afford Cbz-glycine D-menthyl ester
(2ag) in 92% yield without any epimerization at the 1-po-
sition of the menthyl group (Table 2, entry 5).13b The re-
actions with tert-butanol (3h) and phenol (3l) were limited
and did not proceed due to their low nucleophilicity
Reaction rates of methyl esters of valine (5aa) and isoleu-
cine (6aa), both of which have congested secondary ali-
phatic side chains, were retarded, and the transformations
were suppressed, resulting in rather low yields of 41% for
5ab and 44% for 6ab (Table 3, entries 2 and 4); however,
the addition of DMAP (20 mol%)15,16 accelerated these
transesterifications, increasing the yields to 95% and 90%
Synlett 2012, 23, 137–141
© Thieme Stuttgart · New York

LETTER
Transesterification of a-Amino Esters
139
Table 3 Transesterification of Methyl Esters Derived from Various
yields, respectively (Table 3, entries 3 and 5). Phenylgly-
cine derivatives are, in general, racemized much more
easily than any natural amino acid esters in peptide cou-
pling reactions operated under basic conditions because of
the higher acidity of the proton at the benzylic chiral cen-
ter.17 The catalyst 1 was advantageous in that no racem-
ization was observed for the smooth transesterification of
N-Cbz-protected phenylglycine methyl ester 10aa with
3b to give 10ab (Table 3, entry 9). Because the phenolic
hydroxy group did not participate in the present catalysis,
N-Cbz-protected tyrosine methyl ester 11aa reacted with-
out the protection of the hydroxy group (Table 3, entry
10). This catalyst system could be applied to the transes-
terification of other N-Cbz-protected amino acid methyl
esters bearing an additional protective group, such as
MOM ether (13aa), thioether (14aa and 15aa), a trityl
group on imidazole (20aa), and different kinds of func-
tionalities such as cyano (18aa) and indole (19aa) groups
(Table 3, entries 12–14 and 17–19). Double transesterifi-
cation of Cbz-aspartic acid a,b-dimethyl ester (16aa) with
four equivalents of 1-butanol (3b) afforded the corre-
sponding a,b-dibutyl ester 16ab in 91% (Table 3, entry
15). The reaction of Cbz-asparagine methyl ester (17aa)
bearing a primary amide group on the side chain afforded
Cbz-asparagine butyl ester (17ab) in only 25% yield be-
cause intramolecular cyclization occurred, affording a cy-
clic imide 22 (Figure 2) in 45% yield (Table 3, entry 16).
Unfortunately, the reaction of Na-Cbz-Nw-Ts-arginine me-
thyl ester (21aa) with 1-butanol resulted in a low yield
(33%), presumably due to the coordinating nature of the
guanidine group (Table 3, entry 20).
Amino Acidsa (continued)
R4
R4
Zn4(OCOCF3)6O (1)
(1.25 mol%)
Cbz
OMe
+
Cbz
On-Bu.
n-BuOH
3a
∗
∗
N
N
i-Pr2O, reflux, 18 h
– MeOH
H
H
O
O
Entry
Methyl ester
Yield of butyl ester (%)b
6
7ab 97
Cbz
N
OMe
H
O
7aa
OMe
7
8
9
8ab 97
9ab 96
10ab 90
N
Cbz
O
8aa
Ph
O
Cbz
OMe
OMe
N
H
9aa
Ph
Cbz
N
H
O
10aa
OH
10
11
11ab 87
12ab 90
Cbz
OMe
N
H
Table 3 Transesterification of Methyl Esters Derived from Various
O
O
Amino Acidsa
11aa
R4
R4
Zn4(OCOCF3)6O (1)
H
N
(1.25 mol%)
Cbz
OMe
+
Cbz
Cbz
On-Bu.
n-BuOH
3a
∗
∗
N
N
i-Pr2O, reflux, 18 h
– MeOH
H
Cbz
12aa
Cbz
OMe
H
O
N
H
O
Entry
1
Methyl ester
Yield of butyl ester (%)b
OMOM
OMe
O
Cbz
N
OMe
OMe
4ab 95
12
13e
14
13ab 87
14ab 84
15ab 84
N
H
H
O
4aa
13aa
SMe
OMe
Cbz
2
5ab 41
5ab 95
6ab 44
6ab 90
N
H
Cbz
N
H
O
O
5aa
5aa
14aa
Cbz
3c
4d
5c,d
S
Ph
OMe
N
H
Cbz
OMe
N
H
O
O
15aa
6aa
6aa
© Thieme Stuttgart · New York
Synlett 2012, 23, 137–141

140
Y. Maegawa et al.
LETTER
Table 3 Transesterification of Methyl Esters Derived from Various
O
Amino Acidsa (continued)
NH
R4
R4
Zn4(OCOCF3)6O (1)
Cbz
(1.25 mol%)
N
Cbz
OMe
+
Cbz
On-Bu.
n-BuOH
3a
∗
H
∗
O
N
N
i-Pr2O, reflux, 18 h
– MeOH
H
H
22
O
O
Figure 2
Entry
Methyl ester
Yield of butyl ester (%)b
OMe
We previously reported that the zinc cluster 1 served as a
catalyst for the hydroxy group selective acylation of ami-
no alcohols, in which the hydroxy group was acylated in
a highly chemoselective manner in the presence of a nu-
cleophilic aliphatic amino group.13a We anticipated that
this selectivity allowed for the transesterification of amino
acid esters bearing a primary or secondary aliphatic amino
group. In fact, transesterification of N-protection-free va-
line methyl ester 5ia with 1-butanol (3b) afforded the bu-
tyl ester 5ab in 69% yield upon treatment with CbzCl
(Scheme 1).18 As a substrate with a secondary aliphatic
amino group, the reaction of N-benzyl glycine methyl es-
ter 2ja gave the corresponding butyl ester 2jb in 89%
yield (Scheme 2). Acylation of the amino group was not
observed in either reaction.
O
16ab 91
(dibutyl ester)
15f,g
Cbz
N
OMe
H
O
16aa
O
NH2
16h
17ab 25
18ab 79
Cbz
N
OMe
H
O
17aa
CN
Cbz
OMe
17
N
H
O
18aa
Zn4(OCOCF3)6O
H
(1.25 mol%)
N
OMe
n-BuOH
On-Bu
+
H2N
H2N
i-Pr2O, reflux, 18 h
O
O
5ib
18
19f
20
19ab 99
20ab 76
21ab 33i
5ia
3b
Cbz
OMe
N
H
O
CbzCl (1.3 equiv)
19aa
Cbz
On-Bu
NaHCO3 (aq)
r.t.., overnight
Trt
N
N
H
O
5ab
69%
N
Cbz
OMe
Scheme 1
N
H
O
20aa
Zn4(OCOCF3)6O
(1, 1.25 mol%)
OMe
On-Bu
H
Ph
N
Ph
N
HN
N
n-BuOH
+
H
H
Ts
i-Pr2O, reflux, 18 h
O
O
NH
2ja
3b
2jb
89%
3
Cbz
OMe
N
H
Scheme 2
O
21aa
In this report, we demonstrated the zinc cluster 1 cata-
lyzed transesterification of various a-amino acid methyl
esters with alcohols other than tertiary alcohol and phenol.
The greatest advantage of this reaction protocol is its tol-
erance to many functional groups on the amino acid side
chains, including heterocycles, MOM ether, and aliphatic
amino groups, and a wide scope of N-protective groups
such as Cbz, Boc, Fmoc, Alloc, Troc, Ns, and Fmoc. The
addition of a catalytic amount of DMAP improved the
yields for the transesterification of sterically hindered less
reactive esters. In addition, we demonstrated that N-pro-
tection-free amino acid esters could be transesterified
without amide formation.
a Reaction conditions: A mixture of methyl ester (1.0 mmol), 1-BuOH
(3b, 1.2 mmol), and 1 (0.0125 mmol, 1.25 mol%) in i-Pr2O (1.7 mL)
was refluxed for 18 h under an argon atmosphere.
b Isolated yield.
c DMAP (0.20 mmol, 20 mol%) was added to the reaction mixture.
d Reaction time was 20 h.
e Reaction time was 16 h.
f Reaction time was 24 h.
g 1-BuOH (4.0 mmol) was used.
h Cyclic imide 22 was obtained in 45% yield.
i Estimated by 1H NMR analysis.
Synlett 2012, 23, 137–141
© Thieme Stuttgart · New York

LETTER
Transesterification of a-Amino Esters
141
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Acknowledgment
This work was supported by CREST from JST, Grant-in-Aid for
Scientific Research and Scientific Research on Innovative Areas
from MEXT, Kurata Grants, and Uehara Memorial Foundation.
Y.M. and Y.H. thank Global COE Program ‘Global Education and
Research Center for Bio-Environmental Chemistry’ of Osaka Uni-
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