Synthesis of Dipeptides by Boronic Acid Catalysis

Article abstract of DOI:10.1055/s-0036-1589130

We have found that a boronic acid catalyzed amidation of an N -hydroxy amino acid methyl ester with amino acid tert -butyl esters gave N -hydroxy dipeptide derivatives in good yields without any racemization. The protecting groups on the nitrogen atom could be easily removed by heterogeneous hydrogenation conditions.

Full text of DOI:10.1055/s-0036-1589130

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
Synlett
H. Tsuji, H. Yamamoto
Letter
Synthesis of Dipeptides by Boronic Acid Catalysis
Hiroaki Tsuji*1
OH
O
Hisashi Yamamoto*
N
Bn
OMe
Me
95:5 dr)
Molecular Catalyst Research Center, Chubu University,
OH
O
R
O
R
(
cat. ArB(OH)2
cat. Pd
H2
1200 Matsumoto-cho, Kasugai, Aichi 487-8501, Japan
N
H2N
+
tsuji@isc.chubu.ac.jp
hyamamoto@isc.chubu.ac.jp
Bn
N
2
CO t-Bu
N
2
CO t-Bu
toluene
H
H
R
1
00 °C, 18 h
Me
Me
Ar = 3,4,5-F3C6H2
3
examples
69% yield (R = Me)
H2N
CO2t-Bu
up to 93% yield
95:5 dr
>95:5 dr
R = Me, i-Pr, Bn
9
Received: 08.08.2017
Accepted after revision: 16.10.2017
Published online: 24.11.2017
focused on the use of N-hydroxy amino acid esters, which
have a β-hydroxy moiety for the directed amidation reac-
tion, and the N–O bond is able to cleave after the reaction
leading to dipeptide synthesis from nonhydroxy-containing
DOI: 10.1055/s-0036-1589130; Art ID: st-2017-u0614-l
Abstract We have found that a boronic acid catalyzed amidation of an
N-hydroxy amino acid methyl ester with amino acid tert-butyl esters
gave N-hydroxy dipeptide derivatives in good yields without any racem-
ization. The protecting groups on the nitrogen atom could be easily re-
moved by heterogeneous hydrogenation conditions.
10
amino acids.
a) Previous results
Ta(OEt)5
OH
O
R2
OH
O
R2
(10 mol%)
R1
BocHN
R1 = H, Me
OMe
+
R1
BocHN
43–82% yield
H N
2
CO Me
2
N
2
CO Me
Key words N-hydroxy amino acid esters, amidation, boronic acid
catalysis, N-hydroxy dipeptides, substrate-controlled reaction
toluene
H
6
0–100 °C
R2 = Me, i-Pr, i-Bu
sec-Bu
24 h
b) This work: Catalytic synthesis of N-hydroxy dipeptides using a boronic acid
Peptides have been attracting considerable attention
2
because of their potential utility in pharmaceuticals, mate-
OH
N
O
3
4
rial science, and asymmetric catalysis. Therefore, the de-
velopment of an efficient method for realizing the chemical
synthesis of peptides is of significant importance in syn-
thetic organic chemistry. Catalytic synthesis of peptides
from carboxylic acid derivatives and amines is one of the
most ideal choices for achieving safe and atom-economical
Bn
OMe
cat. Pd
H2
OH
N
O
R
O
R
Me
+
cat. ArB(OH)2
Bn
H2N
N
CO2t-Bu
N
CO2t-Bu
H
H
R
Me
Me
H2N
CO2t-Bu
5
Scheme 1 Catalytic synthesis of dipeptide derivatives
approaches to these valuable molecules. Some catalytic
systems that enable straightforward access to dipeptides
from carboxylic acid derivatives and amines have been es-
During the course of the study, we found that a boronic
acid showed an amazing reactivity in the amidation of an
N-hydroxy amino acid ester. In this communication, we re-
port the boronic acid catalyzed hydroxyl-directed amida-
tion for the synthesis of natural dipeptide derivatives
(Scheme 1, b).
6,7
tablished. However, developing the new strategy for the
catalytic synthesis of dipeptides from carboxylic acid deriv-
atives and amines is still in high demand, since the previ-
ously reported methods are unsatisfactory in terms of scal-
ability of peptides preparation and applicability in poly-
peptide synthesis.
We began our study from the reaction between N-
hydroxy amino acid ester 1 and H-L-Ala-OMe (2) in the
presence of the previously efficient metal catalyst (Scheme
2). Disappointingly, Ta(OEt)5 did not catalyze the desired
amidation reaction. The other Lewis acid catalysts such as
Nb(OEt) , Sc(OTf) , and Ti(Oi-Pr) were also not effective for
We have recently developed the tantalum ethoxide cat-
alyzed hydroxy-directed amidation of carboxylic acid es-
ters, and its application to the catalytic synthesis of dipep-
8
tide derivatives (Scheme 1, a). The hydroxy-directed ami-
dation is quite effective for the catalytic dipeptide
synthesis. Unfortunately, the method could not be applied
to nonhydroxy-containing amino acids. We therefore
5
3
4
this reaction. We assumed that the Lewis acidity of the cat-
alyst was quenched probably due to the basic amino group.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Synlett
H. Tsuji, H. Yamamoto
Letter
Table 1 Evaluation of Boronic Acid Catalystsa
Ta(OEt)5
OH
HN
O
OH
HN
O
Me
(
10 mol%)
Me
+
OMe
toluene
0 °C, 18 h
N
CO2Me
OH
N
O
ArB(OH)2
OH
N
O
Me
H2N
CO2Me
H
Me
(10 mol%)
6
Me
Me
+
Bn
OMe
Bn
N
CO2Me
(
3.0 equiv)
<1% yield
H2N
CO2Me toluene
100 °C, 16 h
H
1
2
3
Me
Me
9
8.5:1.5 er
(1.5 equiv)
Scheme 2 Catalytic synthesis of N-hydroxy dipeptide derivatives by
using metal-catalyzed hydroxy-directed amidation reaction
4
2
5
Entry
1d
Ar
Yield (%)b
drc
3,4,5-F
3
C
6
H
2
56
<1
69
57
59
57
47
19f
>97:3e
–
We also examined the reaction in the presence of 10
mol% of 3,4,5-trifluoroboronic acid under the reaction con-
ditions. However, the desired dipeptide 3 was not obtained.
Based on the results in Scheme 2, we have prepared N-
protected hydroxy amino acid methyl ester 4 from L-Ala-
OMe·HCl (Scheme 3), see Supporting Information. Nitrone
S3 was prepared by using the method reported by Bode and
2d
C F
6
5
3d
3,5-(CF
3
)
2
C
6
H
3
99:1
99:1
99:1
99:1
99:1
98:2
4
5
6
7
8
4-CF
3
C
6
H
4
3-NO
4-NO
2
C
6
H
4
2
C
6
H
4
11
co-workers. Reduction of S3 with NaBH CN in methanol at
2-IC
6 4
H
3
room temperature gave the desired N-protected hydroxy
amino acid methyl ester 4 in 99% yield without any signifi-
cant loss of optical purity.
Ph
a
Reaction conditions: 4 (0.25 mmol), 2 (0.375 mmol), and boronic acid
(0.025 mmol) in toluene (1 mL) at 100 °C for 16 h.
b
Isolated yields.
The dr was determined by chiral HPLC analyses.
The er of the substrate is 99.5:0.5.
During the HPLC analysis, we observed a trace amount of overlapped peak
c
O
O
N
O
NaBH3CN
AcOH
OH
N
O
d
ref. 11
e
Cl H3N
Ph
Ph
OMe
OMe
OMe
in the minor diastereomer.
MeOH
r.t.
Me
Me
Me
f
NMR yield.
S3
3% yield
4
7
99% yield
To evaluate the applicability of the boronic acid cata-
Scheme 3 Preparation of N-hydroxy amino acid methyl ester 4
lyzed amidation for the synthesis of N-hydroxy dipeptide
derivatives, some amino acid esters were employed
(Scheme 4).14 3,4,5-Trifluorophenylboronic acid catalyzed
the reaction of N-hydroxy amino acid methyl ester 4 with 3
equiv of H-L-Ala-Ot-Bu (6a) at 100 °C to give the desired
product 7a in a 66% yield without racemization. Further-
more, H-L-Val-Ot-Bu (6b) and H-L-Phe-Ot-Bu (6c) also par-
ticipated in the reaction, providing the dipeptide deriva-
tives 7b and 7c in 69% and 93% yields, respectively, without
loss of the optical purity derived from the substrate.
With the desired N-hydroxy amino acid methyl ester 4
in hand, we next tested the amidation of N-protected hy-
droxy amino acid methyl ester 4 (Table 1). Gratifyingly, the
use of 3,4,5-trifluorophenylboronic acid, which was used
for the amidation reaction between carboxylic acids and
12
amines in 1996, was found to be effective for the amida-
tion reaction, giving N-hydroxy dipeptide derivative 5 in a
56% yield with >97:3 dr (Table 1, entry 1). Pentafluorophenyl-
boronic acid did not promote the amidation reaction, prob-
ably due to existence of ortho-fluorine atoms on the phenyl
ring that would suppress the exchange reaction between
the hydroxy group of 4 and B–OH (mechanistic details, see
Scheme 5; Table 1, entry 2). The other boronic acid catalysts
bearing electron-withdrawing substituents such as trifluo-
romethyl and nitro groups also showed catalytic activity in
this reaction (Table 1, entries 3–6). The use of 2-iodophen-
ylboronic acid led to a slight decrease in yield (Table 1,
entry 7). Phenylboronic acid was not suitable for this reac-
tion as catalyst, resulting in a low yield (Table 1, entry 8).
This result revealed that boronic acids having an electron-
deficient phenyl ring are necessary for achieving high cata-
lytic activity. We also examined the reaction of N-protected
hydroxy amino acid methyl ester 4 with 3 equiv of H-L-Ala-
OH
N
O
ArB(OH)2
(12 mol%)
OH
N
O
R
R
OMe + H2N
Bn
Bn
N
2
CO t-Bu
CO2t-Bu
toluene
100 °C, 18 h
H
Me
Me
95:5 er
(3.0 equiv)
95:5 dr
F
4
6
7
Ar =
F
F
OH
N
O
Me
OH
N
O
i-Pr
CO2t-Bu
13
Bn
N
CO2t-Bu
Bn
N
H
H
Me
6
Me
OH
N
O
Bn
7a
6% yield
7b
69% yield
Bn
N
H
CO2t-Bu
Me
7
c
9
3% yield
Scheme 4 Boronic acid catalyzed the synthesis of N-hydroxy dipeptide
derivatives. Reagents and conditions: 4 (0.25 mmol), 6 (0.75 mmol),
Ot-Bu (6a) in the presence of 10 mol% of Ta(OEt) in toluene
5
at 100 °C for 16 h. Unfortunately, however, the desired di-
peptide was not produced under the reaction conditions.
ArB(OH) (0.03 mmol) in toluene at 100 °C for 18 h. The dr were deter-
mined by chiral HPLC analyses.
2
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
Synlett
H. Tsuji, H. Yamamoto
Letter
Both benzyl and hydroxy groups on the nitrogen atom
of N-hydroxy dipeptide derivative 7a were easily removed
under the heterogeneous hydrogenation conditions, giving
dipeptide 8 in a 69% yield (Scheme 5). This result showed
that the boronic acid catalysis would be applicable to the
synthesis of dipeptides derived from various amino acids.
a)
ArB(OH)2
H
N
O
H
N
O
Me
Me
(12 mol%)
+
Bn
OMe
Bn
N
2
CO Me
H3N
CO2Me
toluene
100 °C, 18 h
H
Me
9
Me
2
10
F
(
3.0 equiv)
<1%
(93% recovery of 9)
Ar =
F
Pd(OH)2/C (10 w/w%)
OH
N
O
Me
O
Me
F
H2 (1 atm)
b)
2
H N
Bn
N
CO2t-Bu
N
2
CO t-Bu
ArBX2
H
AcOH, r.t., 24 h
H
Me
Me
X = OH or OMe
95:5 dr
69% yield, >95:5 dr
7a
8
7
+
MeOH
4
Scheme 5 Deprotection of the amino group of N-hydroxy dipeptide
1
7
a. The dr was determined by H NMR analysis of the crude reaction
mixture. Reagents and conditions: 7a (0.137 mmol), Pd(OH) /C (10
2
w/w%) in AcOH (0.7 mL) at r.t. under H (1 atm) for 24 h.
R
2
NH2 + HX
HX
6
Finally, we studied the reaction mechanism of the ami-
dation of N-hydroxy amino acid methyl ester (Scheme 6). To
identify the role of the hydroxy group, nonhydroxy-
containing substrate 9 was subjected to the reaction condi-
tions. However, the amidation reaction did not take place,
and this result showed that the hydroxy group of 7a plays a
key role in this transformation as a directing group (Scheme
Ar
X
δ–
B
δ–
δ+
Ar
δ+
B
N
O
O
O
O
N
or
Bn
OMe
Bn
OMe
Me
Me
X
A
B
Scheme 6 Mechanistic investigation. a) Reaction using nonhydroxy-
containing amino acid methyl ester 9; b) possible catalytic cycle.
6, a). Although the exact reaction mechanism is still un-
clear, possible reaction pathways are shown in Scheme 6
15
(
b). A condensation reaction between the boronic acid
and N-hydroxy amino acid methylester 4 takes place, gen-
tide synthesis derived from various amino acids in solution
phase. Detailed mechanistic studies and further investiga-
tion are currently ongoing in our laboratory.
16
erating intermediate A. Although the coordination of the
oxygen atom to the boron center is expected to accelerate
the activation of the carbonyl group with the boron cata-
lyst, the activated ester group reacts with amine 6 to give
the desired N-hydroxy dipeptide derivatives 7 along with
the formation of the boron catalyst and methanol. However,
any other Lewis acids including a Ta catalyst did not pro-
duce the amide bond at all. On the other hand, the boron
center is amenable to coordination from both the oxygen
Funding Information
This work was supported by Japan Science and Technology Agency
(JST), Adaptable and Seamless Technology transfer Program, through
Target-driven (R&D) (A-STEP), and JST ACT-C Grant Number JPM-
JCR12ZD, Japan.
)(
17
and nitrogen atoms. We believe the three-membered ring
ammonium salt B would be responsible for the reaction and
thus the subsequent reaction of reactive B with amine 6
produced the desired product 7.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589130.
S
u
p
p
ortioIgnfmr oaitn
S
u
p
p
o
nrtogI
i
f
rm oaitn
In conclusion, we have developed the boronic acid cata-
lyzed hydroxy-directed amidation of the N-hydroxy amino
acid methyl ester with amino acid tert-butyl esters.18 This
method allowed access to the N-hydroxy dipeptide deriva-
tives in good yields without any racemization. The amino
protecting group can be removed by heterogeneous hydro-
genation conditions. Since the N-hydroxy amino acid deriv-
atives are readily prepared from the corresponding amino
acids, the present method would be applicable to the pep-
References and Notes
(1) Hiroaki Tsuji, Department of Chemistry, College of Humanities
Sciences, Nihon University, Sakurajosui, Setagaya-ku, Tokyo
56-8550, Japan. Following e-mail address is also active:
&
1
tsuji@chs.nihon-u.ac.jp.
(2) (a) Albericio, F.; Kruger, G. H. Future Med. Chem. 2012, 4, 1527.
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Synlett
H. Tsuji, H. Yamamoto
Letter
(
4) (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (b) Colby
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(14) As a preliminary experiment, we also examined the reaction of
N-hydroxyphenylalanine methyl ester (95:5 er) with L-Ala-OMe
under our catalyst system to give the desired dipeptide in 58%
yield (95:5 dr). This result clearly shows that our catalyst
system would be applicable to the other N-hydroxy amino acid
methyl esters.
1
(
2
(5) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(
6) Examples of catalytic synthesis of dipeptides with base catalyst:
(15) The activation of the ester group through internal H-bonding
interaction is also possible, see ref. 12. We excluded out this
possibility because dichlorophenylborane also catalyzed the
reaction of 4 with 6a at 100 °C to give 7a in 49% yield.
(16) Boronic acid catalyzed amidation reaction of hydroxy group
containing substrates, see: Yamashita, R.; Sakakura, A.; Ishihara,
K. Org. Lett. 2013, 15, 3654.
(a) Ohshima, T.; Hayashi, Y.; Agura, K.; Fujii, Y.; Yoshiyama, A.;
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(
c) Caldwell, N.; Campbell, P. S.; Jamieson, C.; Potjewyd, F.;
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d) Caldwell, N.; Jamieson, C.; Simpson, I.; Watson, A. J. B. ACS
(
Sustainable Chem. Eng. 2013, 1, 1339. With boronic acid ana-
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S.; Whiting, A. Eur. J. Org. Chem. 2013, 5692. (f) Mohy El Dine, T.;
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(18) General Procedure for the Boronic Acid Catalyzed Amidation
Reaction: Typical Procedure for the Reaction of (2S)-Methyl
2-(benzylhydroxyamino)propanoate (4) with H-L-Ala-Ot-Bu
(6a)
80, 4532. (g) Fatemi, S.; Gernigom, N.; Hall, D. G. Green Chem.
2
015, 17, 4016. (h) Mohy El Dien, T.; Rouden, J.; Blanchet, J.
(2S)-Methyl 2-(benzylhydroxyamino)propanoate (4, 52.3 mg,
0.25 mmol, 1.0 equiv), H-L-Ala-Ot-Bu (6a, 108.9 mg, 0.75 mmol,
3.0 equiv), and 3,4,5-trifluorophenylboronic acid (5.3 mg, 0.03
mmol, 12 mol%) were charged into an oven-dried test tube
equipped with a magnetic stir bar. The test tube was sealed
Chem. Commun. 2015, 51, 16084. (i) Noda, H.; Furutachi, M.;
Asada, Y.; Shibasaki, M.; Kumagai, N. Nat. Chem. 2017, 9, 571.
With Ru catalyst: (j) Krause, T.; Baader, S.; Erb, B.; Gooßen, L. J.
Nat. Commun. 2016, 7, 1.
(
7) Catalytic synthesis of cyclic peptides from β-amino alcohols,
see: Gnanaprakasam, B.; Balaraman, E.; Ben-David, Y.; Milstein,
D. Angew. Chem. Int. Ed. 2011, 50, 12240.
with a rubber septum and refilled with N . Toluene (1 mL, 0.25
M) was added to the test tube, and the reaction mixture was
stirred at 100 °C for 18 h. The resulting mixture was allowed to
2
(
(
8) Tsuji, H.; Yamamoto, H. J. Am. Chem. Soc. 2016, 138, 14218.
9) For a review, see: (a) Ottenheijm, H. C. J.; Herscheid, J. D. M.
Chem. Rev. 1986, 86, 697. For N-hydroxy amino acids for peptide
synthesis, see: (b) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew.
Chem. Int. Ed. 2006, 45, 1248. (c) Harmand, T. J.; Murar, C. E.;
Bode, J. W. Curr. Opin. Chem. Biol. 2014, 22, 115.
cool to r.t., and then sat. NaHCO solution (1 mL) was added. The
3
aqueous phase was extracted with CH Cl (3 × 3 mL). The com-
2
2
bined organic extracts were washed with brine (1 × 3 mL) and
dried over Na SO . After removal of the solvent, the resulting
2
4
crude mixture was purified by silica gel column chromatogra-
phy (hexane/EtOAc = 7:3, 65:35) to give the desired product 7a
(53.6 mg, 0.166 mmol, 66% yield, 95:5 dr) as a yellow oil. IR
(neat): 3364, 2981, 1732, 1649, 1518, 1453, 1368, 1148, 748,
(
10) (a) Grundke, G.; Keese, W.; Rimpler, M. Synthesis 1987, 1115.
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M. M.; Davankov, V. A.; Beletskaya, I. P. Adv. Synth. Catal. 2012,
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450.
12) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996, 61,
(
–1 1
697 cm
. H NMR (400 MHz, CDCl , major diastereomer): δ =
3
3
7.42–7.28 (m, 5 H), 7.09 (d, J = 7.2 Hz, 1 H), 5.40 (br s, 1 H), 4.53
(qd, J = 7.2, 7.2 Hz, 1 H), 4.00 (d, J = 13.2 Hz, 1 H), 3.83 (d, J = 13.6
Hz, 1 H), 3.46 (q, J = 6.8 Hz, 1 H), 1.46 (s, 9 H), 1.41 (d, J = 6.8 Hz,
(
(
3
13
3 H), 1.40 (d, J = 7.2 Hz, 3 H). C NMR (100 MHz, CDCl ): δ =
3
4
196. (b) Maki, T.; Ishihara, K.; Yamamoto, H. Tetrahedron 2007,
172.8, 172.6, 137.2, 129.4, 128.3, 127.4, 82.1, 66.4, 60.6, 48.0,
24
63, 8645.
27.9, 18.4, 13.9. [α]D +11.88 (c 1.01, CHCl ). HLPC conditions:
3
(13) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int. Ed.
DAICEL CHIRALPACK IC, hexane/i-PrOH = 4:1, flow rate = 1
2008, 47, 2876.
mL/min, λ = 207 nm, retention time; tR (major) = 8.75 min, tR
+
(
minor) = 14.19 min. HRMS (ESI ): m/z calcd for C17H26N O Na
2
4
+
[
M + Na] : 345.1785; found: 345.1774.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D