Tantalum-Catalyzed Amidation of Amino Acid Homologues

Article abstract of DOI:10.1021/jacs.9b08415

A tantalum-catalyzed solvent-free approach for the construction of amide bonds with 1-(trimethylsilyl)imidazole is developed, and the mild reaction conditions are applicable to a wide variety of electrophilic amino acid homologues. This approach delivers a new class of peptides in high yields without any epimerization.

Full text of DOI:10.1021/jacs.9b08415

Subscriber access provided by UNIV OF WESTERN ONTARIO
Communication
Tantalum-Catalyzed Amidation of Amino Acid Homologs
Wataru Muramatsu, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b08415 • Publication Date (Web): 15 Nov 2019
Downloaded from pubs.acs.org on November 16, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Tantalum-Catalyzed Amidation of Amino Acid Homologs
Wataru Muramatsu* and Hisashi Yamamoto*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Molecular Catalyst Research Center, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi 487-8501.
Supporting Information Placeholder
amide bond formation (Scheme 1a), that affords moder-
ABSTRACT: A tantalum-catalyzed solvent-free ap-
proach for the construction of amide bonds with 1-
(trimethylsilyl)imidazole is developed, and the mild re-
action conditions are applicable to a wide variety of
electrophilic amino acid homologs. This approach deliv-
ers a new class of peptides in high yields without any
epimerization.
ate to high yields of the desired dipeptides without any
epimerization.9 However, the substrate scope of this
methodology is limited to Ser, Thr, and their derivatives
only. We subsequently extended the hydroxy-group-
directed strategy to a solvent-free amidation of N-
hydroxy-α-imino esters (Scheme 1b).10 The obtained N-
hydroxy-α-imino amides could be diastereoselectively
hydrogenated under palladium catalysis to prepare the
corresponding L,L-dipeptides. Unfortunately, the N-
hydroxy-β-imino esters were unstable and immediately
transformed to the stable isoxazolones (Scheme 1c).11
More recently, we reported a solvent-free peptide bond-
forming methodology for most natural α-amino acids
which proceed under protecting-group-directed Lewis
acid catalysis (Scheme 1d).12 However, the N-protected
β-homoamino acid methyl esters were not suitable sub-
strates for peptide synthesis using this methodology
(Scheme 1e) as the transition state of the 8-membered
ring generated by the coordination of the Lewis acid
catalyst to the N-protected β-homoamino acid methyl
esters is generally less stable than the 7-membered ring
transition state generated using the N-protected α-amino
acid methyl esters. Because β-amino acids and β-
peptides possess unique properties in biological and
structural aspects,13 potentially game-changing strategies
to address their synthesis problems are clearly required.
We present herein, a powerful Lewis acid catalysis ap-
proach for preparation of NH–CO linkages using elec-
trophilic amino acid homologs with high generality and
broad functional group tolerance (Scheme 1f).
Amide bond formation using carboxylic acids and
amines is a classical reaction encountered widely in or-
ganic synthesis and bioorganic chemistry.1 The typical
approaches for this transformation involve the use of
coupling-reagent-mediated strategies which proceed via
formation of an active ester and have been extensively
used in pharmaceutical, agrochemical, cosmetic, and
polymer material syntheses.2 For many years, considera-
ble efforts have been devoted to the development of
powerful and useful coupling reagents.3 However, the
coupling-reagent-mediated CO–NH bond formation
methodologies usually require large amounts of reaction
solvents4 and typically suffer from racemization prob-
lems3b in addition to the production of chemical waste
related to the coupling reagents.5 A catalytic version of
the amide bond formation between carboxylic acids and
amines has attracted considerable attention in the last
quarter century, and several metal catalyses have been
developed for this transformation.1b,6 However, most of
these metal-catalyzed amidations requir high tempera-
tures and use of a Dean-Stark trap6c and/or molecular
sieves6a–b for promoting the conversion of the hydroxy
group into an active leaving group by removal of water.
Furthermore, these approaches can sometimes cause
racemization challenges during peptide synthesis. Argu-
ably, considerable room for improvement and innovation
exists in this area of amide bond formation.
Scheme 1. Our Strategies for Lewis-Acid-Catalyzed
Amidation Reactions
We recently developed three original strategies based
on a substrate-directed approach7 to solve racemization
problems in CO–NH bond formations and to significant-
ly reduce the associated environmental challenges8 due
to chemical waste generation. We initially introduced a
hydroxy-group-directed Lewis acid catalysis approach to
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 7
a)
b)
H
O
cat. Ta(OEt)5
HO
HO
O
L
-AA-Ot-Bu
H
1
2
3
4
5
6
7
8
[Ta]
Table 1. Tantalum Catalysis for Solvent-Free Amidation of
Boc-L-β-HoAla-OH with L-Val-Ot-Bu
Boc
OMe
Boc
N
N
H
N
H
Ot-Bu
Ot-Bu
toluene
Boc
O
N
H
O
O
O
O
R'
R'
OMe
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
H
O
cat. Nb(OEt)5
-AA-Ot-Bu
R
R
O
O
H
N
H
N
L
L
-Val-Ot-Bu
H
N
H
N
OH
N
[Nb]
HO
OMe
OMe
HO
Boc
N
N
Boc
Ot-Bu
solvent-free
solvent-free
40 °C, 48 h
O
O
R
O
i-Pr
OMe
(2.0 equiv)
1
"optimized" conditions
c)
d)
O
N
O
N
rapidly transformed
HO
entry
variation from
the “optimized” conditions
yield of
drb
R
O
R
unstable
stable
1 (%)a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
97 (94)c
97 (95)c
>99:1
>99:1
nd
t-BuO
1
2
none
cat. Ta(OMe)5
-AA-Ot-Bu
R
R
O
O
H
N
L
HN
R
Boc
OMe
Boc
[Ta]
L-Val-Ot-Bu･HCl
no Ta(OMe)5
no TMSIM
Ta(OEt)5
N
H
N
H
Ot-Bu
solvent-free
O
O
O
R'
3
0
0
OMe
e)
4
nd
t-BuO
cat. Ta(OMe)5
O
H
N
[Ta]
L
-AA-Ot-Bu
OMe
5
96
93
2
>99:1
>99:1
nd
HN
R
no reaction
Boc
X
O
solvent-free
R
O
6
Ta(OBu)5
Ta2O3
OMe
unstable
7
cat. Ta(OMe)5
f)
t-BuO
8
TaCl5
10
96
86
5
>99:1
>99:1
>99:1
nd
L
-AA-Ot-Bu
O
O
[Ta]
H
N
H
N
H
N
TMSIM
OH
HN
R
n
Boc
O
OTMS
n
9
Nb(OEt)5
Ti(Oi-Pr)4
BSTFA
Boc
Ot-Bu
solvent-free
R
O
R
O
R'
n
10
11
12
13
14
15d
We began our studies by screening a large number of
BSA
4
nd
Lewis acid catalysts and commonly available silylating
agents for peptide bond construction between Boc-L-β-
HoAla-OH and L-Val-Ot-Bu. The reaction conditions
evaluated for the optimization and several varied condi-
tions are shown in Table 1. When L-Val-Ot-Bu was
treated with 2.0 equiv. of Boc-L-β-HoAla-OH in the
presence of 10 mol% Ta(OMe)5 and 2.2 equiv. of 1-
(trimethylsilyl)imidazole (TMSIM), the catalytic
Ta(OMe)5 activated the carbonyl group of the silyl ester,
which is generated in situ by the reaction of Boc-L-β-
HoAla-OH with TMSIM, toward nucleophilic attack by
L-Val-Ot-Bu, smoothly providing the desired dipeptide 1
in the best yield (97% yield) without any epimerization
(entry 1). The gram-scale synthesis of 1 was also suc-
cessful under the optimized conditions (94 and 95%
yields, entries 1 and 2). Amino acid tert-butyl esters are
usually commercially available as their HCl salts due to
their overwhelmingly longer storage stability without
racemization and/or polymerization.14 To exploit their
use for amide bond formation, the availability of general
methods for amidation using HCl salts of the amines, in
addition to free amines is necessary. In this context, our
method allows for the use of a more diverse set of nu-
cleophilic counterparts that are HCl salts without any
loss in yield (97% yield, entry 2). This trial revealed that
the imidazole, generated by the silylation of Boc-L-β-
HoAla-OH with TMSIM, had a significant role as a base
for neutralization of L-Val-Ot-Bu･HCl in the reaction.
Both Ta(OMe)5 and TMSIM are essential for this pep-
tide bond-forming reaction (entries 3, 4). A series of tan-
talum alkoxides and other metal alkoxides were evaluat-
ed as a Lewis acid catalyst for this reaction, and most of
them gave comparable results with 86–96% yields,
while a more suitable silylating agent was not found for
improving yield (entries 5–15).
TBSIM
40
24
0
>99:1
>99:1
nd
HMDS
TMSI-H
aIsolated yields. bdrs were determined by 1H NMR. cConducted at
d
50 °C on a gram scale synthesis of 1. TMSI-H = HMDS (2) :
TMSCl (1) : pyridine (10).
Having optimized the reaction conditions, we investi-
gated the tunability of this solvent-free tantalum cataly-
sis with respect to both protecting groups and nucleo-
philic amino acid esters. As summarized in Scheme 2, a
range of N-protecting groups from acyl (Ac, Bz, and
Pht) to sulfonyl (Bs) and carbonate (Cbz) groups were
compatible with the Ta(OMe)5/TMSIM system and fur-
nished the amides 2a–e in up to 97% yield. Unfortunate-
ly, the Fmoc group was found to be largely sensitive in
the presence of the free amines such as L-Val-Ot-Bu or
imidazole, and afforded a lower yield of 2f (up to 68%
yield) due to the cleavage of the group from Fmoc-L-β-
HoAla-OH and/or the produced 2f.15 Nucleophilic α-
amino acid esters and their HCl salts bearing hydropho-
bic side chains were amenable to the peptide bond-
forming reaction with Boc-L-β-HoAla-OH, used as a
model electrophilic counterpart, and formed the desired
dipeptides 2g–k in excellent yields without loss of stere-
ochemical integrity. Furthermore, a broad variety of
functional groups, including the ester group in Asp, am-
ide group in Asn, hydroxy group in Ser, amino groups in
His and Lys, and the sulfide group in Met were well tol-
erated under reaction conditions, and successfully deliv-
ered the corresponding dipeptides 2l–r in high yields
without any formation of side products. Peptide bond
formation between β-amino acids was also evaluated
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
under the optimal conditions, affording the coupling
(97% yield of 2g) was replaced with Me-L-Ala-Ot-Bu
(73% yield of 3v). We have solved such a steric issue by
switching the use of silylating agents,18 and were
pleased to find that the less sterically hindered silylating
agent 1-(dimethylsilyl)imidazole (DMSIM), generated
in situ from chlorodimethylsilane and imidazole, signifi-
cantly increased the yields of 3s and 3v–x.
1
2
3
4
5
6
7
8
products 2s–u in 91–95% yields.
Scheme 2. Scope of Protecting Groups and Nucleo-
philic Amino Acidsa
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
H
L-AA-Ot-Bu or L-AA-Ot-Bu•HCl
H
N
H
N
N
OH
Ot-Bu
PG
PG
m
solvent-free
R
O
r.t.–55 °C, 48 h
R
O
R'
O
Scheme 3. Scope of Electrophilic/Nucleophilic Amino
Acidsa
R = H or Me
(2.0 equiv)
AA = Amino Acid
m = 0–1
>99:1 dr
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
H
H
H
H
H
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
-AA-OR" or L-AA-OR"•HCl
N
N
N
N
N
N
Ac
Ot-Bu
Bz
Ot-Bu
Pht
Ot-Bu
H
H
H
L
N
OH
N
N
OR"
O
s-Bu
O
s-Bu
O
s-Bu
Boc
Boc
m
solvent-free
40–55 °C, 48 h
Ac-β-HoGly–L-Ile-Ot-Bu
2a: 96% yield (98% yield)
Bz-β-HoGly–L-Ile-Ot-Bu
2b: 97% yield (97% yield)
Pht-β-HoGly–L-Ile-Ot-Bu
2c: 82% yield (80% yield)
R
O
R
O
R'
O
2.0 equiv
AA = Amino Acid
m = 0–1, R" = t-Bu or Et
>99:1 dr
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
Bs
Ot-Bu
Cbz
Ot-Bu
Fmoc
Ot-Bu
O
s-Bu
O
i-Pr
O
i-Pr
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
Bs-β-HoGly–L-Ile-Ot-Bu
2d: 95% yield (90% yield)
Cbz-D-β-HoAla–L-Val-Ot-Bu
2e: 95% yield (95% yield)
Fmoc-L-β-HoAla–L-Val-Ot-Bu
2f: 9% yielda (48% yield)
9% yieldb (68% yield)b
Boc
Ot-Bu
Boc
Ot-Bu
Boc
Ot-Bu
O
s-Bu
i-Pr
O
i-Pr
i-Pr
O
STrt
-Cys-Ot-Bu
3c: 95% yield (89% yield)
Boc-β-HoGly–L-Ile-Ot-Bu
3a: >99% yield (>99% yield)
Boc-
L
-β-HoVal–
L
-Val-Ot-Bu
3b: 95% yield (94% yield)
Boc-L-β-HoVal–L
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
Boc
Ot-Bu
Boc
Ot-Bu
Boc
Ot-Bu
O
O
H
N
H
N
H
N
H
N
H
H
N
O
O
t-Bu
O
i-Bu
N
Ot-Bu
Boc
Ot-Bu
Boc
Ot-Bu
Boc
Boc-L-β-HoAla–L-Ala-Ot-Bu
2g: 97% yield (97% yield)
Boc-L-β-HoAla–L-Tle-Ot-Bu
2h: 97% yield (96% yield)
Boc-L-β-HoAla–L-Leu-Ot-Bu
2i: 97% yield (97% yield)
O
t-BuO
Bn
O
Bn
O
O
Ot-Bu
-Ser-Ot-Bu
3e: >99% yield (>99% yield)
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
Boc-β-HoAib– -Thr-Ot-Bu
3d: 99% yield (97% yield)
L
Boc-
L
-β-HoPhe–
L
Boc-
L
-β-HoPhe–L-β-HoAla-Ot-Bu
3f: 96% yield
Boc
Ot-Bu
Boc
Ot-Bu
Boc
Ot-Bu
O
s-Bu
O
Bn
O
O
O
H
N
H
N
H
N
H
N
H
N
H
N
CO2t-Bu
Ot-Bu
Boc
Ot-Bu
Boc
Ot-Bu
Boc
Boc-L-β-HoAla–L-Ile-Ot-Bu
2j: 99% yield (98% yield)
Boc-L-β-HoAla–L-Phe-Ot-Bu
2k: 97% yield (>99% yield)
Boc-L-β-HoAla–L-Asp-Ot-Bu
2l: 98% yield (>99% yield)
(
)
4
( )
4
Ph
O
O
O
Ph
O
NHBoc
CbzHN
Boc-
BnO
O
O
O
Boc-
L
-β-HoPhg–L
3g: 97% yield (96% yield)
-Lys-Ot-Bu
L
-β-HoLys– -Ala-Ot-Bu
3h: 91% yield (92% yield)
D
Boc- -β-HoThr–L-β-HoPhg-Ot-Bu
L
H
N
H
N
H
N
H
N
H
N
H
N
3i: 90% yield
Boc
Ot-Bu
Boc
Ot-Bu
Ot-Bu
Boc
Ot-Bu
O
O
H
N
O
O
O
H
N
H
N
H
N
H
N
CONH2
5-Imid(Trt)
Ot-Bu
Boc
Ot-Bu Boc
Ot-Bu
Boc-L-β-HoAla–L-Asn-Ot-Bu
2m: 92% yield (92% yield)
Boc-L-β-HoAla–L-Ser-Ot-Bu
2n: >99% yield (>99% yield)
Boc-L-β-HoAla–L-His-Ot-Bu
2o: 95% yield
(
)
2
(
)
( )
2
2
i-Bu
i-Bu
O
N
O
O
O
MeS
Boc-
MeS
CO2t-Bu
Boc
-β-HoPro–L-Glu-Ot-Bu
O
O
Boc-
L
L
-β-HoMet–
3j: 94% yield (97% yield)
L
-Leu-Ot-Bu Boc- -β-HoMet–L-β-HoLeu-Ot-Bu
L
H
N
H
N
H
N
H
N
H
N
3l: 92% yield (92% yield)
3k: >99% yield
N
Boc
Ot-Bu
NHBoc
Boc
Ot-Bu
SMe
Boc
(
)
( )
2
4
O
H
N
O
H
N
O
H
CO2t-Bu
O
O
O
N
Boc
N
N
Ot-Bu
Ot-Bu
Boc
Ot-Bu
Boc-L-β-HoAla–L-Lys-Ot-Bu
2p: 96% yield (95% yield)
Boc-L-β-HoAla–L-Met-Ot-Bu
2q: 97% yield (94% yield)
Boc-L-β-HoAla–L-Pro-Ot-Bu
2r: 99% yield (99% yield)
(
)
3
N
O
Boc
O
O
i-Pr
3-Ind(Boc)
NH
H
N
H
N
H
N
H
N
H
N
H
N
Ot-Bu
Ot-Bu
Ot-Bu
HN
NHMtr
Boc
Boc
Boc
Boc- -β-HoPro–
3m: 97% yield (>99% yield)
L
L
-Trp-Ot-Bu
Boc-
L
-β-Pro–
3n: 98% yield
L
-Arg-Ot-Bu
Boc-L-Pic(3)–L-Val-Ot-Bu
3o: 91% yield (90% yield)
O
O
O
i-Bu
Boc-L-β-HoAla–L-β-HoAla-Ot-Bu Boc-L-β-HoAla–L-β-HoLeu-Ot-BuBoc-L-β-HoAla–L-β-HoPhe-Ot-Bu
2s: 93% yield 2t: 91% yield 2u: 95% yield
O
O
Bn
O
O
H
O
H
N
O
H
N
H
N
N
N
Ot-Bu
aPercentages are the isolated yields when L-AA-Ot-Bu were used.
Percentages in parentheses are the isolated yields when L-AA-Ot-
Bu･HCl were used. bPerformed in CHCl3.
Boc
Ot-Bu
Ot-Bu Boc
N
H
O
NH
O
O
O
Ph(Ot-Bu)
Boc
Boc- -Pic(3)–
3p: 90% yield (85% yield)
L
L
-Tyr-Ot-Bu
Boc-2-Abz–Gly-Ot-Bu
3q: 72% yieldb (70% yield)b
Boc-L-β-HoAla–L-Ala–L-Ala-Ot-Bu
3r: 91% yield
NHBoc
O
NHBoc
H
O
H
N
H
N
H
H
N
Having evaluated protecting group compatibility, we
studied the reaction system with a multitude of amino
acid combinations (Scheme 3). The amidation of amino
acids bearing hydrophobic side chains afforded 3a and
3b in >99% and 95% yields, respectively. Substrates
carrying sulfur atoms often impair the performance of
metal catalysts due to their stronger binding affinities.16
Such limitations were not observed in our system, and L-
Cys(Trt)-Ot-Bu and its HCl salt were compatible with
the reaction conditions and afforded 3c in favorable
yields comparable to those of 3a and 3b. Irrespective of
the nature of the functional group variations on amino
acids, the reactions proceeded to furnish all of the de-
sired dipeptides 3d–q and tripeptide 3r in high yields. α-
Substituted-β-amino acids were also converted smoothly
into the corresponding dipeptides 3o–q and 3s without
any epimerization. The steric effect of the N-Me group
was evident from the loss of yield17 when L-Ala-Ot-Bu
N
N
Boc
Ot-Bu
Boc
Ot-Bu
O
i-Pr
-Val-Ot-Buc
3s: 40% yield (42% yield)
X
O
O
i-Pr
Boc-
L
-Dap–
L
X = Ph, Boc-L-β-HoPhg–L-Dap–L-Val-Ot-Bu, 3t: 92% yield
X = Bn, Boc-
L
-β-HoPhe–
L
-Dap–
L
-Val-Ot-Bu, 3u: 90% yield
97% yieldd (97% yield)d
O
O
O
H
N
H
N
H
N
H
N
H
N
N
Boc
Ot-Bu
Boc
OEt
Boc
Ot-Bu
O
O
O
Boc-
L
-β-HoAla–Me-
3v: 73% yieldb (69% yield)b
77% yieldd (75% yield)d
L
-Ala-Ot-Bu
Boc-β-HoAib–cPropn-OEt
3w: 87% yieldb (83% yield)
95% yieldd (95% yield)d
Boc-β-HoGly–Aib-Ot-Bu
3x: 35% yieldb (27% yield)b
88% yieldd (86% yield)d
aPercentages are the isolated yields when L-AA-OR” were used.
Percentages in parentheses are the isolated yields when L-AA-
OR”･HCl were used. bPerformed at 70 °C for 72 h. Boc-L-
Dap(Boc)-OH ･ DCHA was used. dChlorodimethylsilane (2.2
equiv) and imidazole (4.4 equiv) were used instead of TMSIM.
The reactions were performed in CHCl3.
c
To probe the mechanism of these amide bond-forming
reactions, we tested a series of reaction conditions
(Scheme 4-A). Initially, Boc-L-β-HoAla-OH was reacted
with TMSIM alone, and the formation of the silyl ester
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
1
A. Mechanistic studies
4a was confirmed by H and 29Si NMR spectra (4a:
24.40 ppm, TMSIM: 13.16 ppm).18 The crude 4a was
successfully converted to 1 in the presence of L-Val-Ot-
Bu or L-Val-Ot-Bu･HCl. Next, a model experiment us-
ing hexanoic acid was conducted to verify whether these
amidation reactions with electrophilic β-amino acids
proceeded via cyclic transition state TS-B as shown in
Scheme 4-B, which is assembled by directing effects of
the N-protecting groups as well as with α-amino acids
reported in the previous study. Remarkably, the reaction
of hexanoic acid with L-Ile-Ot-Bu or L-Ile-Ot-Bu･HCl
under the reaction conditions led to the formation of 4b
in 97% or >99% yield. This result clearly points to the
broad applicability of the developed methodology for
peptide synthesis employing a wide range of amines and
carboxylic acids (Scheme 5-C). Subsequently, several
competitive reactions were tested. In a tantalum-
catalyzed competitive reaction using α- and β-amino
acids, the α-amino acids Boc-Gly-OH and Boc-L-Ala-
OH preferentially reacted with L-Ile-Ot-Bu to afford 4c
and 4d, respectively. Further, the competitive amide
bond-forming reactions of hexanoic acid with Boc-Gly-
OH or Boc-β-HoGly-OH (Boc-β-Ala-OH) afforded 4c
or 3a as the major products, respectively.
O
H
H
N
H
H
(a)
(b)
1
2
3
4
5
6
7
8
N
OTMS
OH
N
N
Boc
Boc
Boc
Ot-Bu
O
O
O
i-Pr
4a: 24.40 ppm (29Si)
TMSIM (13.16 ppm, 29Si)Ref. 16
(2.0 equiv)
Boc-L-HoAla–L-Val-Ot-Bu
1: 95% yield (96% yield)
(a) TMSIM (2.2 equiv), 40 °C, overnight.
(b)
L
-Val-Ot-Bu or
L
-Val-Ot-Bu•HCl (1.0 equiv), Ta(OMe)5 (10 mol%), 40 °C, 48 h
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
L-Ile-Ot-Bu or L-Ile-Ot-Bu•HCl
O
H
N
OH
Ot-Bu
solvent-free
40 °C, 48 h
O
O
s-Bu
(2.0 equiv)
4b: 97% yield (>99% yield)
9
R
R
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
N
Boc
OH
Boc
N
H
N
H
Ot-Bu
O
O
s-Bu
R = H: Boc-Gly– -Ile-Ot-Bu
4c: 50% yield
R = Me: Boc- -Ala– -Ile-Ot-Bu
L
(2.0 equiv)
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
-Ile-Ot-Bu•HCl
L
L
4d: 71% yield
L
+
+
solvent-free
50 °C, 48 h
O
H
N
H
N
H
N
OH
Boc
Boc
Ot-Bu
R
O
R
O
s-Bu
(2.0 equiv)
R = H: Boc-β-HoGly–
3a: 20% yield
R = Me: Boc-
L
-Ile-Ot-Bu
L
-β-HoAla–
L
-Ile-Ot-Bu
Ot-Bu
2j: 28% yield
O
H
N
OH
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
-Ile-Ot-Bu•HCl
O
O
s-Bu
4b: 7% yield
(2.0 equiv)
+
L
+
solvent-free
50 °C, 48 h
O
H
N
Boc
OH
N
H
Boc
N
H
Ot-Bu
O
O
s-Bu
-Ile-Ot-Bu
4c: 70% yield
(2.0 equiv)
Boc-Gly–L
O
On the basis of these results, a plausible mechanistic
pathway of the process is depicted in Scheme 4-B. Ini-
tially, PG-L-amino acid homologs react with TMSIM to
generate the corresponding silyl esters and imidazole in
situ (step a). Subsequently, the more Lewis basic car-
bonyl oxygen atoms of PG (PG = Boc, Cbz, etc.) prefer-
entially coordinate with the tantalum catalyst followed
by the possible secondary coordination of carbonyl oxy-
gen atoms of silyl ester moieties that may assist the as-
sembly of TS-A. Although the TS-A seems to be rela-
tively unstable, as seen in the unsuccessfully attempted
transformation shown in Scheme 1e, the activated silyl
ester moieties could react with amines to form amide
bonds because the lower pKa values of silyl esters
(TMSOH: 11, MeOH: 16) potentially render them as
better leaving groups.19 According to the magnitude of
strain energy, stable TS-A could be formed. Otherwise, a
tantalum-migration may occur to form TS-B from TS-A.
Next, the free amine, formed by the in situ neutralization
of the amino acid tert-butyl ester HCl salt with imidaz-
ole (step c), approaches the activated silyl ester moiety,
and the ensuing peptide bond-forming reaction forges
the smooth production of the corresponding dipeptides
(step d). Finally, the tantalum catalyst is regenerated,
thus completing the catalytic cycle (step e).
H
N
OH
Ot-Bu
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
-Ile-Ot-Bu•HCl
O
O
s-Bu
(2.0 equiv)
+
4b: 24% yield
L
+
solvent-free
50 °C, 48 h
O
H
N
H
N
H
N
OH
Boc
Boc
Ot-Bu
O
O
s-Bu
Boc-β-HoGly– -Ile-Ot-Bu
3a: 55% yield
(2.0 equiv)
L
B. Plausible mechanistic pathway
H
N
OH
+
n
TMSIM
PG
R1
O
imidazole
Silylation (a)
H
N
H
N
OR4
n
PG
m
H
N
R1
O
R3
O
Coordination (b)
OTMS
n
PG
Ta(OMe)5
R1
O
(e)
Amidation (d)
R2
H2N
OR4
O
n
[Ta]
m
HN
R1
R3
O
O
OTMS
imidazole•HCl
TS-A
Neutralization (c)
by imidazole
or
PG = protecting group
(R2CO)
R2
HCl•H2N
OR4
m
O
n
[Ta]
HN
R1
R3
O
O
OTMS
TS-B
aPercentages are the isolated yields when L-AA-Ot-Bu were used.
Percentages in parentheses are the isolated yields when L-AA-Ot-
Bu･HCl were used.
Finally, the Ta(OMe)5/TMSIM system was extended
to the chemoselective amidation reaction (Scheme 5-A),
application to the amidation of a series of electrophilic γ-
to λ-homoamino acids (Scheme 5-B), and the synthesis
of typical amides and thioesters (Scheme 5-C). The
chemoselective reaction of mono-methyl glutarate with
L-Ile-Ot-Bu or L-Ile-Ot-Bu･HCl led to the formation of
5 in 86% yield without any observation of side products
Scheme 4. Mechanistic Studies and Plausible Mecha-
nistic Pathwaya
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
(silyl ester vs. methyl ester as an electrophile). The reac-
group tolerance under solvent-free conditions. Notably,
the present catalytic system offers an expedient solution
for chemoselective amidation (e.g., silyl ester vs. methyl
ester). Overall, this approach will open a general path to
CO–NH bond formation. Further studies on the applica-
tions of tantalum catalysis and reaction mechanism are
currently under investigation in our laboratory.
1
2
3
4
5
6
7
8
tion of Boc-γ-HoGly-OH with Gly-Ot-Bu or its HCl salt
gave 6a in 80% yield. Additionally, 6b–d were obtained
in higher yields when Boc-γ-HoGly-OH was replaced
with Boc-δ-HoGly-OH, Boc-ε-HoGly-OH, Boc-λ-
HoGly-OH, and their HCl salts. Furthermore, the dipep-
tide 6e and tripeptide 6f were successfully obtained from
Boc-L-γ-HoIle-OH in 86–93% yields without any epi-
merization. The protocol is also applicable to the synthe-
sis of typical amides without any observation of side
reactions and it may be significantly helpful for the
preparation of thioacid precursors for the emerging
chemical ligation.1a,20
ASSOCIATED CONTENT
Supporting Information
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization data, 1H- and 13C NMR
spectra, HPLC data, and GC data (PDF)
Scheme 5. Chemoselective Amidation, Scope of Elec-
trophilic Amino Acid Homologs, and Application to
the Typical Reactionsa
AUTHOR INFORMATION
Corresponding Author
A. Chemoselective amidation
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
L-Ile-Ot-Bu or L-Ile-Ot-Bu•HCl
*Email for W.M.: muramatsu@isc.chubu.ac.jp
*Email for H.Y.: hyamamoto@isc.chubu.ac.jp
O
H
N
MeO
OH
MeO
Ot-Bu
solvent-free
40 °C, 48 h
O
O
O
O
s-Bu
ORCID
(2.0 equiv)
5: 86% yield (86% yield)
Wataru Muramatsu: 0000-0001-7183-7981
Hisashi Yamamoto: 0000-0001-5384-9698
B. Screning of γ,δ,ε,λ-homoamino acids
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
Gly-Ot-Bu or Gly-Ot-Bu•HCl
O
H
N
H
N
H
N
OH
n
Boc
n
Ot-Bu
Boc
solvent-free
50 °C, 48 h
O
Notes
O
(2.0 equiv)
n = 2: Boc-γ-HoGly–Gly-Ot-Bu
6a: 80% yieldb (80% yield)b
n = 3: Boc-δ-HoGly–Gly-Ot-Bu
6b: 97% yield (98% yield)
The authors declare no competing financial interests.
ACKNOWLEDGMENT
n = 4: Boc-ε-HoGly–Gly-Ot-Bu
6c: 94% yield (92% yield)
n = 10: Boc-λ-HoGly–Gly-Ot-Bu
6d: 94% yield (94% yield)
Support has been provided by the Japan Science and Tech-
nology Agency (JST), Adaptable and Seamless Technology
Transfer Program through Target-driven R&D (A-STEP).
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
O
H
N
H
N
H
N
L
-Tyr(t-Bu)-Ot-Bu or
L
-Tyr(t-Bu)-Ot-Bu•HCl
OH
2
Boc
Ot-Bu
2
Boc
solvent-free
50 °C, 48 h
s-Bu
O
s-Bu
O
Ph(4-Ot-Bu)
REFERENCES
(2.0 equiv)
Boc-
L
-γ-HoIle–L-Tyr(t-Bu)-Ot-Bu
6e: 93% yield (91% yield)
(1) (a) Pattabiraman, V. R.; Bode, J. W. Rethinking Amide Bond
Synthesis. Nature 2011, 480, 471–479. (b) de Figueiredo, R. M.;
Suppo, J.–S.; Campagne, J.–M. Nonclassical Routes for Amide Bond
Formation. Chem. Rev. 2016, 116, 12029–12122.
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
Boc-L-Dap-L-Val-Ot-Bu
NHBoc
O
H
H
H
N
H
N
OH
N
N
2
Boc
2
Boc
Ot-Bu
solvent-free
50 °C, 48 h
s-Bu
O
s-Bu
O
O
i-Pr
(2.0 equiv)
Boc- -γ-HoIle–Boc-
L
L
-Dap–
L
-Val-Ot-Bu
(2) (a) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A
Knowledge-Based Approach in Designing Combinatorial or Medici-
nal Chemistry Libraries for Drug Discovery. 1. A Qualitative and
Quantitative Characterization of Known Drug Databases. J. Comb.
Chem. 1999, 1, 55–68. (b) Vinogradov, A. A.; Yin, Y.; Suga, H. Mac-
rocyclic Peptides as Drug Candidates: Recent Progress and Remain-
ing Challenges. J. Am. Chem. Soc. 2019, 141, 4167–4181.
(3) (a) Albericio, F.; Chinchilla, R.; Dodsworth, D. J.; Nájera, C.;
New Trends in Peptide Coupling Reagents. Org. Prep. Proced. Int.
2001, 33, 203–303. (b) EI-Faham, A.; Albericio, F. Peptide Coupling
Reagents, More than a Letter Soup. Chem. Rev. 2011, 111, 6557–
6602.
(4) (a) Bayer, E.; Mutter, M. Liquid Phase Synthesis of Peptides.
Nature 1972, 237, 512–513. (b) Isidro-Llobet, A.; Kenworthy, M. N.;
Mukherjee, S.; Kopach, M. E.; Wegner, K.; Gallou, F.; Smith, A. G.;
Roschangar, F. Sustainability Challenges in Peptide Synthesis and
Purification: From R&D to Production. J. Org. Chem. 2019, 84.
4615–4628.
6f: 86% yield
C. Synthesis of general amides and thioesters
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
H
N
R
+
RCO2H
H2NR'
R'
solvent-free
50 °C, 48 h
O
R = Ph
R = 3-cyclohexenyl
R' = i-Bu
R' = Bn
6g: >99% yield
6h: 95% yield
6i: 92% yield
6j: 97% yield
6k: 99% yield
R = (2-cyclopentenyl)methyl R' = Bn
R = (2-furyl)methyl
R = (2-naphtyl)methyl
R' = CH2Cy
R' = CH2Cy
Ta(OMe)5 (10 mol%)
TMSIM (2.2 equiv)
TrtSH
H
N
H
N
OH
STrt
n
Boc
n
Boc
solvent-free
50 °C, 48 h
O
O
(2.0 equiv)
n = 0: Boc-Gly-STrt
6l: 66% yield
n = 1: Boc-β-HoGly-STrt
6m: 59% yield
aPercentages are the isolated yields when L-AA-Ot-Bu were used.
Percentages in parentheses are the isolated yields when L-AA-Ot-
Bu･HCl were used. b70 °C.
(5) (a) Trost, B. M. The Atom Economy–a Search for Synthetic Ef-
ficiency. Science 1991, 254, 1471–1477. (b) Sheldon, R. A. Organic
Synthesis; Past, Present and Future. Chem. Ind. (London), 1992, 903–
906. (c) Sheldon, R. A. The E Factor: Fifteen Years on. Green Chem.
2007, 9, 1273–1283.
In conclusion, we found that Ta(OMe)5 is a highly ef-
ficient catalyst for amide bond formation between a
wide range of carboxylic acids and amines, and proceeds
without any epimerization in the presence of silylating
agents. The reaction proceeded with broad functional
(6) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. 3,4,5-
Trifluorobenzeneboronic Acid as an Extremely Active Amidation
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
Catalyst. J. Org. Chem. 1996, 61, 4196–4197 (b) Noda, H.; Furutachi,
Peptide Structures. J. Comput. Chem. 2006, 27, 20–38. (d) Karlsson,
A. J.; Pomerantz, W. C.; Neilsen, K. J.; Gellman, S. H.; Palecek, S. P.
Effect of Sequence and Structural Properties on 14-Helical β-Peptide
Activity against Candida Albicans Planktonic Cells and Biofilms.
ACS Chem. Biol. 2009, 4, 567–579. (e) Kudo, F.; Miyanaga, A.; Egu-
chi, T. Biosynthesis of Natural Products Containing β-Amino Acids.
Nat. Prod. Rep. 2014, 31, 1056–1073. (f) Cabrele, C.; Martinek, T.
A.; Reiser, O.; Berlicki, U. Peptides Containing β-Amino Acid Pat-
terns: Challenges and Successes in Medicinal Chemistry. J. Med.
Chem. 2014, 57, 9718–9739.
(14) Anderson, G. W.; Callahan, F. M. t-Butyl Esters of Amino
Acids and Peptides and Their Use in Peptide Synthesis. J. Am. Chem.
Soc. 1960, 82, 3359–3363.
(15) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups
in Organic Synthesis 4th edn (Wiley, 2007). (b) Isidro-Llobet, A.;
Álvarez, M.; Albericio, F. Amino Acid-Protecting Groups. Chem. Rev.
2009, 109, 2455–2504.
M.; Asada, Y.; Shibasaki, M.; Kumagai, N. Unique Physicochemical
and Catalytic Properties Directed by the B3NO2 Ring System. Nat.
Chem. 2017, 9, 571–577. (c) Sabatini, M. T.; Boulton, L. T.; Shep-
pard, T. D. Borate Esters: Simple Catalysts for the Sustainable Syn-
thesis of Complex Amides. Sci. Adv. 2017, 3, e1701028. (d) Sabatini,
M. T.; Boulton, L. T.; Sheddon, H. F.; Sheppard, T. D. A Green
Chemistry Perspective on Catalytic Amide Bond Formation. Nat.
Catal. 2019, 2, 10–17. (e) Hollanders, K.; Maes, B. U. W.; Ballet, S.
A New Wave of Amide Bond Formations for Peptide Synthesis. Syn-
thesis 2019, 51, 2261–2277.
(7) (a) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Substrate-
Directable Chemical Reactions. Chem. Rev. 1993, 93, 1307–1370. (b)
Bhadra, S.; Yamamoto, H. Substrate Directed Asymmetric Reactions.
Chem. Rev. 2018, 118, 3391–3446. (c) Sawano, T.; Yamamoto, H.
Substrate-Directed Catalytic Selective Chemical Reactions. J. Org.
Chem. 2018, 83, 4889–4904.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(8) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G.
R.; Leazer, Jr. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearl-
man, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Key Green Chemistry
Research Areas–a Perspective from Pharmaceutical Manufacturers.
Green Chem. 2007, 9, 411–420.
(9) Tsuji, H.; Yamamoto, H. Hydroxy-Directed Amidation of Car-
boxylic Acid Esters using a Tantalum Alkoxide Catalyst. J. Am. Chem.
Soc. 2016, 138, 14218–14221.
(10) Muramatsu, W.; Tsuji, H.; Yamamoto, H. Catalytic Peptide
Synthesis: Amidation of N-Hydroxyimino Esters. ACS Catal. 2018, 8,
2181–2187.
(11) An, D.; Guan, X.; Guan, R.; Jin, L.; Zhang, G.; Zhang, S. Or-
ganocatalytic Nucleophilic Addition of Pyrazoles to 2H-Azirines:
Asymmetric Synthesis of 3,3-Disubstituted Aziridines and Kinetic
Resolution of Racemic 2H-Azirines. Chem. Commun. 2016, 52,
11211–11214.
(12) Muramatsu, W.; Hattori, T.; Yamamoto, H. Substrate-Directed
Lewis-Acid Catalysis for Peptide Synthesis. J. Am. Chem. Soc. 2019,
141, 12288–12295.
(13) (a) Porter, E. A.; Wang, X.; Lee, H.–S.; Weisblum, B.;
Gellman, S. H. Non-Haemolytic β-Amino-Acid Oligomers. Nature
2000, 404, 565. (b) Stephens, O. M.; Kim. S.; Welch, B. D.; Hodsdon,
M. E.; Kay, M. S.; Schepartz, A. Inhibiying HIV Fusion with a β-
Peptide Foldamer. J. Am. Chem. Soc. 2005, 127, 13126–13127. (c)
Beke, T.; Somlai, C.; Perczel, A. Toward a Rational Design of β-
(16) (a) Forzatti, P.; Lietti, L. Catalyst Deactivation. Catalysis To-
day 1999, 52, 165–181. b) Bartholomew, C. H. Mechanism of Cata-
lyst Deactivation. Appl. Catal. A 2001, 212, 17–60.
(17) Opie, C. R.; Noda, H.; Shibasaki, M.; Kumagai, N. All Non-
Carbon B3NO2 Exotic Heterocycles: Synthesis, Dynamics, and Catal-
ysis. Chem. Eur. J. 2019, 25, 4648–4653.
(18) (a) Lopyrev, V. A.; Larina, L. I.; Voronkov, M. G. Trime-
thylsilylazoles Chemistry. Russ. J. Org. Chem. 2001, 37, 149–193. (b)
Tozawa, T.; Yamane, Y.; Mukaiyama, T. A Convenient Method for
Preparations of 1-Acylimidazoles and Carboxamides by Using Novel
Imidazolylsilane Derivatives. Chem. Lett. 2005, 34, 734–735.
(19) Kagiya, T.; Sumida, Y.; Tachi, T. An infrared spectroscopic
study of hydrogen bonding interaction. Structural studies of proton-
donating and -accepting powers. Bull. Chem. Soc. Jpn. 1970, 43,
3716–3722.
(20) (a) Kent, S. B. H. Total Chemical Synthesis of Proteins. Chem.
Soc. Rev. 2009, 38, 338–351. (b) Narendra, N.; Thimmalapura, V. M.;
Hosamani, B.; Prabhu, G.; Kumar, L. R.; Sureshbabu, V. V. Thioacid
– Synthons for Amide Bond Formation and Ligation Reactions: As-
sembly of Peptides and Peptidomimetics. Org. Biomol. Chem. 2018,
16, 3524–3552. (c) Kulkarni, S. S.; Sayers, J.; Premdjee, B.; Payne, R.
J. Rapid and Efficient Protein Synthesis through Expansion of the
Native Chemical Ligation Concept. Nat. Rev. Chem. 2018, 2, 0122.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
Insert Table of Contents artwork here
4
5
6
7
8
H
N
OH
n
PG
cat. Ta(OMe)5
TMSIM
R
O
9
+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Solvent-Free
H2N
OR"
OR"
up to >99% yield
all >99:1 dr
m
R'
O
H
N
H
N
H2N
OR"
n
m
PG
m
•HCl
R'
O
R
O
R'
O
7
ACS Paragon Plus Environment