Synthesis of Acylborons by Ozonolysis of Alkenylboronates: Preparation of an Enantioenriched Amino Acid Acylboronate

Article abstract of DOI:10.1002/anie.201707933

A concise synthesis of acylborons was achieved by ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid) boronates. This reaction exhibits excellent functional-group tolerance and is applicable to various acyl MIDA boronates and potassium acyltriflurobor

Full text of DOI:10.1002/anie.201707933

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Accepted Article
Title: Synthesis of Acylborons by Ozonolysis of Alkenylboronates:
Preparation of an Enantioenriched Amino Acid Acylboronate
Authors: Jumpei Taguchi, Toshiki Ikeda, Rina Takahashi, Ikuo Sasaki,
Yasushi Ogasawara, Tohru Dairi, Naoya Kato, Yasunori
Yamamoto, Jeffrey W. Bode, and Hajime Ito
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707933
Angew. Chem. 10.1002/ange.201707933
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10.1002/anie.201707933
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Acylborons by Ozonolysis of Alkenylboronates:
Preparation of an Enantioenriched Amino Acid Acylboronate
Jumpei Taguchi,[a] Toshiki Ikeda,[a] Rina Takahashi,[a] Ikuo Sasaki,[b] Yasushi Ogasawara,[a] Tohru
Dairi,[a] Naoya Kato,[a] Yasunori Yamamoto,[a] Jeffrey W. Bode*[c] and Hajime Ito*[a]
Abstract: A concise synthesis of acylborons was achieved by
ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid) boronates.
This reaction exhibits excellent functional group tolerance and is
applicable to various acyl MIDA boronates and potassium
acyltrifluroborates (KATs) that could not be synthesized by previous
methods. In addition, α-amino acylborons, which would be essential
for peptide ligations, were prepared for the first time. The acylboron
of L-alanine was obtained in high enantiopurity and found to be
configurationally stable. Oligopeptide synthesis between the α-amino
KATs and amino acid in dilute aqueous media was studied.
a result, this method was applied for the synthesis of various
functionalized acylborons, including the first synthesis of glycine
and L-alanine type α-amino acylborons. Furthermore,
oligopeptide synthesis by amide forming reaction between α-
amino acylborons and amino acid derivatives in diluted aqueous
media was also investigated.
(A) Previous approaches to synthesize acylborons
a) Nozaki, Yamashita (2007) et al.
c) Bode (2014)
Ar Li
SEt
BF3
O
+ [B]-
+
+
M
N
O
R
X
Acylborons are studied enthusiastically due to their unique
reactivity.[1,2,3] In 2012, Bode and Molander reported rapid and
highly chemoselective amide-bond forming reaction between
potassium acyl trifluoroborates (KATs) and hydroxylamines that
is called KAT ligation.[2a] This reaction proceeds without any
condensation reagents or catalysts under mild conditions at
dilute concentrations in aqueous media at room temperature,
and tolerates unprotected functional groups. Since these
features are attractive for bioconjugation, KAT ligation has been
applied to site-specific functionalization of unprotected
peptides.[2b,2c,2d] Conjugation between peptides consisting of
natural amino acids with KAT ligation has, however, not been
achieved. To accomplish this, a route to α-amino acylborons is
required, but currently there has been no reported preparations
of α-amino acylborons.
R
[B]
b) Molander, Bode (2012)
Bt
d) Yudin (2012)
OH
Acylborons
R
O
+
[B] X
[B]
[B]
R
R
OR'
(B) Ozonolysis of alkenyl MIDA boronate (This work)
R'
Me
O
Me
N
KHF2
ozonolysis
N
B
R
B
R
O
BF3K
R
O
O
O
O
O
O
O
Acyltrifluoroborate
Alkenyl MIDA boronate
Acyl MIDA boronate
Scheme 1. (A) Previous approaches to synthesize acylborons. (B) Acylboron
synthesis by ozonolysis of alkenyl MIDA boronate. Bt = benzotriazole, MIDA =
N-methyliminodiacetic acid.
Herein, we report a concise acylboron synthesis by the
ozonolysis of alkenyl MIDA (N-methyliminodiacetic acid)
boronates (Scheme 1B). This new method has the following two
important features; (a) synthesis of alkenyl boronates are well-
studied, they can be readily available by hydroboration of
alkynes, cross-coupling of alkenyl halides or C–H borylation of
alkene,[4] and they are transformed to MIDA boronates easily by
Burke’s method;[5] and (b) ozonolysis can be conducted under
mild conditions and exhibits good functional group tolerance. As
There are only four known approaches for preparation of
acylborons (Scheme 1A). First one is the reaction of a boryl
metal species and carbonyl electrophile such as acyl chlorides
(Scheme 1A-a).[6a–6d] In the second approach, acyl anion
equivalents trap boryl electrophiles to afford acylborons
(Scheme 1A-b).[3e,6e] In the third, Bode developed a reagent
derived from thioformamide that acts as electrophilic KAT
equivalent in 2014. This reagent reacts with aryl or heteroaryl
lithium reagent to give KAT in one step (Scheme 1A-c).[6f] In
each of these three approaches, a highly reactive and unstable
nucleophile, such as boryl metal species or organolithium
compounds are required and thus they exhibit low functional
group tolerance. The only exception is the Pd-catalyzed
borylation reaction of acyl chlorides with a boryl-zinc reagent
reported by Aldridge in 2015, although access to the boron
species is challenging.[6d] Yudin developed a conceptually new
acylboron synthesis containing Dess-Martin oxidation of α-
hydroxy boronate. This method proceeds under relatively mild
condition and is the only reported procedure for α-heteroatom
substituted acylboron, such as α-bromo acylboron or oxalyl
boron, but this approach requires multi-step reaction from
alkenylboronate (Scheme 1A-d).[3a] Despite these advances, it
has been difficult to prepare more functionalized acylboron such
as α-amino acylboron, which contains an amino-substituted
stereocenter at the α-position. Furthermore, one great concern
[a]
J. Taguchi, T. Ikeda, R. Takahashi, Dr. Y. Ogasawara, Prof. Dr. T.
Dairi, N. Kato, Prof. Dr. Y. Yamamoto, and Prof. Dr. H. Ito
Division of Applied Chemistry and Frontier Chemistry Center,
Faculty of Engineering, Hokkaido University
Kita 13 Nishi 8 Kita-ku, Sapporo, Hokkaido 060-8628 (Japan)
E-mail: hajito@eng.hokudai.ac.jp
[b]
[c]
Dr. I. Sasaki
Department of Chemistry and Biological Science, College of
Science and Engineering, Aoyama Gakuin University
5-10-1, Fuchinobe, Chuo-ku, Sagamihara-shi 252-5258 (Japan)
Prof. Dr. J. W. Bode
Laboratorium für Organische Chemie
Department of Chemistry and Applied Bioscience
ETH Zürich, 8093 Zürich (Switzerland)
E-mail: bode@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/xx.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707933
Angewandte Chemie International Edition
COMMUNICATION
for application of KAT ligation to peptide synthesis is there is no
information on the configurational stability of optically active α-
amino acylboron in the ligation step.
the desired acyl trifluoroborate. To improve selectivity of 4a over
5a, we investigated the reaction solvent. Ozonolysis in
acetonitrile or EtOAc decreased the ratio of 4a:5a (entry 2: 70:30,
and entry 3: 56:44). When the ozonolysis was conducted in
methanol, a complex mixture with 4a as a minor product was
obtained (entry 4). The use of PPh3 or Zn instead of Me2S
resulted in low yield and low selectivity (entries 5 and 6),
however reduction with pyridine resulted in high yield of 4a of
94% as sole product (entry 7).[10]
1.0 mol% IMesCuCl
Ph
5.0 mol% NaOH
Ph
Ph
B2(pin)2 (1.1 equiv)
MeOH (2.0 equiv)
CPME, rt, 22 h
Ph
B(pin)
3, 87%
2
We next investigated the scope of this reaction with respect
to the alkenyl MIDA boronates. The substrates were prepared
from alkynes according to the procedure depicted in Scheme 2.
The ozonolysis of 1b proceeded in high yield with high selectivity
(Table 2, entry 1: 87%, 94:6), and ozonolysis of 1c, which had a
sterically hindered secondary alkyl group also proceeded in high
yield with high selectivity (entry 2: 84%, >95:<5). This method
can also be applied to a styrene derivative; ozonolysis of 1d
gave acylboron in high yield with high selectivity with pyridine as
the reducing agent (entry 3: 90%, >95:<5); the same reaction
using Me2S gave low selectivity (64:36). Acylborons bearing a
chloride group 4e or ketone group 4f can also be synthesized by
this reaction conditions in high yield with good selectivity (4e:
94%, 84:16, 4f: 88%, >95:<5). The functional group compatibility
was investigated by the ozonolysis of b-borylated allyl alcohol
bearing various protecting group on hydroxyl group. The
ozonolysis proceeded in good to high yield with high selectivity
with alkenyl MIDA boronate with ether and ester (4g: 85%, 93:7,
4h: 84%, 82:18). On the other hand, silyl protected α-hydroxy
acylboron 4i was obtained with medium selectivity (entry 8: 66%,
74:26). Synthesis of such α-hydroxy acylboronates has not been
achieved by any known preparation approach because their
synthetic intermediate may decompose through rapid b-
elimination. These results also indicate that substrates bearing
exomethylene moiety can also be employed for this reaction.
Next, synthesis of α-amino alkenyl boronates were
investigated. As a result, N-Phth, N-Cbz, N-Boc and N-Fmoc
protected α-amino alkenyl MIDA boronate can be used in this
reaction and gave the desired glycine acylboron analog in good
yields and high selectivity (entries 9–12, 4j: 90%, >95:<5, 4k:
88%, 90:10, 4l: 91%, 95:5, 4m: 65%, 93:7). The structure of 4j
was confirmed by X-ray crystallography (Figure 1).
Ph
MIDA (6.2 equiv)
HC(OEt)3 (4.0 equiv)
Me
N
B
Ph
O
DMSO, 100ºC, 48 h
O
O
1a, 42%
O
Scheme 2. Preparation of alkenyl MIDA boronate 1a.
Based on the known tolerance of MIDA boronates to ozonolysis,
we sought to employ alkenyl MIDA boronates as precursors to
KATs.[7] We selected 1a as a model compound, as it can be
easily prepared by Cu(I)-catalyzed protoboration of alkyne
2,[4c,4e] followed by conversion of pinacol boronate 3 to MIDA
boronate 1a, according to a modified procedure based on the
Burke’s method (Scheme 2).[5c] When the ozonolysis of 1a was
conducted in acetone at –78ºC, the substrate was consumed
within 1 minute and the desired acylboron 4a was obtained in
good yield (Table 1, entry 1). In the crude reaction mixture of
ozonolysis, we detected acyloxyboronate 5a as a minor side-
product in addition to 4a.[8] The ratio of 4a and 5a was
determined by 11B NMR as 87:13.[9] The ozonolysis of potassium
alkenyl trifluoroborate was also investigated; however, the crude
solution contained a complex mixture and we could not detect
Table 1. Optimization of reaction conditions[a]
.
O
Ph
1) O3 bubbling
solvent, –78ºC
B(MIDA)
Ph
Me
4a
+
N
B
Ph
O
2) reductant, 5 min
O
O
O
O
1a
E/Z = >20:<1
OB(MIDA)
Ph
5a
We applied this protocol to the synthesis of an optically
active, L-alanine type acylboron (Scheme 3). Optically active
propargyl amine (S)-7 was obtained from the commercially
available propargyl alcohol (R)-6 (>98% ee) by Mitsunobu
reaction with CbzNHNs （Ns: 2-nitrobenzenesulfonyl） and Ns
deprotection (60%, two steps). Cu(I)-catalyzed protoboration
proceeded smoothly to give alkenyl pinacol boronate (S)-8 in
69% yield without any loss of enantiopurity.[4f] Exchange of the
boron ligands afforded alkenyl MIDA boronate (S)-1n in 39%
yield. Ozonolysis of (S)-1n gave alanine acylboron analog (S)-
4n in high yield with high selectivity (93%, >95:<5) and high
enantiospecificity (99% ee).[11] This compound would be difficult
4a:5a
Entry
Solvent
Reductant
Yield (%)[b]
Ratio[c]
87:13
70:30
1
2
Acetone
CH3CN
Me2S
Me2S
85
88
3
EtOAc
MeOH
Me2S
Me2S
-
-
56:44
4
-
5[d]
6[e]
7[f]
Acetone
Acetone
Acetone
PPh3
85
-
80:20
-
Zn/AcOH
Pyridine
94
>95:<5
[a] Reaction conditions: a) O3, acetone, –78ºC. b) Me2S (excess),
acetone, –78ºC, 5 min. [b] Combined isolated yields of products (4a+5a)
are reported. [c] Product ratio (4a:5a) in the crude reaction mixture were
determined by 11B NMR spectroscopy analysis. [d] PPh3 (3.0 equiv) was
used as reductant. [e] Zn (1.5 equiv) and AcOH (0.3 M H2O) were used as
reductant. [f] Reaction conditions: O3, pyridine (3.0 equiv), acetone, –
78ºC.
Figure 1. Crystal Structure of 4j·CH3CN. CH3CN was omitted for clarification.
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10.1002/anie.201707933
Angewandte Chemie International Edition
COMMUNICATION
Table 2. Substrate scope.[a]
to synthesize by conventional methods because their harsh
conditions will cause racemization at α-position.
R1
Me
Me
N
O
Me
N
N
ozonolysis
O
α-Amino acylboron compounds could potentially be used
as a building block in peptide conjugation using KAT ligation. As
a preliminary experiment towards this goal, we investigated
oligopeptide synthesis using the amide-forming reaction of KATs
and amines in the presence of a chlorinating agent reported by
Bode (Scheme 4).[3g] According to the reported procedure,
MIDA-protected 4m could easily be converted to potassium acyl
trifluoroborate 9 in 85% yield (Scheme 4A).[2c] The reaction
between 9 and glycine benzyl ester 10 in the presence of DCH
(1,3-dichloro-5,5-dimethylhydantoin) was performed in aqueous
solvent at room temperature. The reaction finished within 1 h at
a concentration of 0.1 M, and the ligation product 11 was
obtained in 72% yield; even at a concentration of 1.0 mM, 11
was obtained in 50% yield. Tetrapeptide synthesis from
dipeptide KAT 12 and dipeptide 13 afforded 14 in 61% (Scheme
4B). The diastereomeric ratio of 14 was 98:2, indicating that α-
amino acylborons have configurational stability under the ligation
conditions.
R2
+
B
R2
B
O
O
B
O
O
O
R2
O
O
O
O
O
O
O
O
1b–1m
4b–4m
5b–5m
yield
con-
dition
4:5
entry
1
substrate
product
ratio[c]
(%)[b]
Ph
O
A
A
87
94:6
[B]
[B]
1b
4b
Ph
O
[B]
2
84
>95:<5
[B]
1c
Ph
4c
O
A
B
-
64:36
[B]
3
4
[B]
90
>95:<5
1d
4d
CbzNHNs
thioglycolic acid
DIAD, PPh3 LiOH·H2O
Ph
HO
CbzHN
O
CH2Cl2 DMF, 60% (2 steps)
Cl
A
94
84:16
Cl
Me
Me
(S)-7
[B]
[B]
(R)-6, >98% ee
1e
4e
Ph
B2(pin)2
SIMesCuCl
Na(OtBu)
O
O
O
A
B
88
88
85:15
MIDA
HC(OEt)3
5
6
7
8
[B]
[B]
>95:<5
CbzHN
CbzHN
1f
4f
B(MIDA)
B(pin)
MeOH
THF, 78%
DMSO, 39%
Me
(S)-1n, 98% ee
Me
(S)-8, 98% ee
O
A
B
85
81
93:7
95:5
AcO
AcO
[B]
[B]
1g
4g
O3 bubbling
Sudan III
O
acetone, –78ºC, 1 min
O
A
B
84
80
82:18
85:15
CbzHN
BnO
BnO
B(MIDA)
[B]
[B]
then Me2S
Me
(S)-4n, 99% ee
1h
4h
93% (4n:5n = >95:<5)
O
TIPSO
TIPSO
A
A
66
90
74:26
Scheme 3. Synthesis of alanine type acyl MIDA boronate (S)-4n.
[B]
[B]
1i
4i
TMS
(phth)N
O
In summary, we have developed a concise synthesis of
functionalized acylboronates by the ozonolysis of alkenyl MIDA
boronates. Ozonolysis of substrates containing various
functional groups such as chlorides, ketones, esters, benzyl
ether, amino groups afforded the corresponding products.
Importantly, α-amino acylboron which bearing asymmetric
carbon, could be synthesized with high enantiospecificity and
found to be configurationally stable. Furthermore, peptide
synthesis by amide-forming reaction between α-amino acylboron
and amino acid was achieved. The development of a method to
install acylborons onto the C-terminus of protein will be a great
step in achieving protein-protein conjugation by KAT ligation.
9
(phth)N
>95:<5
[B]
[B]
1j
4j
O
CbzHN
CbzHN
10
11
A
A
A
88
91
65
90:10
95:5
93:7
[B]
[B]
1k
4k
O
BocHN
BocHN
[B]
[B]
1l
4l
O
12[d]
FmocHN
1m
FmocHN
[B]
[B]
4m
[a]Reaction condition A: a) 1 (0.3 mmol), O3, acetone, –78ºC. b) Me2S
(excess), acetone, –78ºC, 5 min. Reaction condition B: 1 (0.3 mmol), O3,
pyridine (3.0 equiv), acetone, –78ºC. [b] Combined isolated yields of
products (4+5) are reported. [c] Product ratio (4:5) in the crude reaction
mixture were determined by 11B NMR spectroscopy analysis. [d] 0.03 mol%
of Sudan III was added. (phth)N = phthalimide. [B] = N-methyliminodiacetyl
boronate.
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10.1002/anie.201707933
Angewandte Chemie International Edition
COMMUNICATION
(A)
Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy, J. F. Hartwig, Chem.
Rev. 2010, 110, 890; e) Y. D. Bidal, F. Lazreg, C. S. J. Cazin, ACS
Catal. 2014, 4, 1564; f) H. Jang, A. R. Zhugralin, Y. Lee, A. H. Hoveyda,
J. Am. Chem. Soc. 2011, 133, 7859.
O
O
KHF2 (4.5 equiv)
FmocHN
FmocHN
THF/H2O (2:1)
rt, 24 h, 85%
B(MIDA)
BF3K
4m
9
[5]
[6]
a) E. P. Gillis, M. D. Burke, J. Am. Chem. Soc. 2007, 129, 6716; b) B. E.
Uno, E. P. Gillis, M. D. Burke, Tetrahedron 2009, 65, 3130; c) E. M.
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2010, 132, 6941; d) E. M. Woerly, J. E. Miller, M. D. Burke, Tetrahedron
2013, 69, 7732.
OBn
TfO-·H3N+
O
O
10, 1.0 equiv
FmocHN
OBn
N
H
DCH (1.1 equiv)
THF/pH 3.0 buffer (1:1, 1 mM)
rt, 24 h
O
a) M. Yamashita, Y. Suzuki, Y. Segawa, K. Nozaki, J. Am. Chem. Soc.
2007, 129, 9570; b) Y. Segawa, Y. Suzuki, M. Yamashita, K. Nozaki, J.
Am. Chem. Soc. 2008, 130, 16069; c) J. Monot, A. Solovyev, H. Bonin-
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E. Lacôte, Angew. Chem. Int. Ed. 2010, 49, 9166; d) R. Frank, J.
Howell, J. Campos, R. Tirfoin, N. Phillips, S. Zahn, D. M. P. Mingos, S.
Aldridge, Angew. Chem. Int. Ed. 2015, 9586; Angew. Chem. 2015, 127,
14365; e) A. M. Dumas, J. W. Bode, Org. Lett. 2012, 14, 2138; A. M.
Dumas, G. A. Molander, J. W. Bode, Angew. Chem. Int. Ed. 2012, 51,
5683; Angew. Chem. 2012, 124, 5781. f) G. Erös, Y. Kushida, J. W.
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7734.
(Fmoc)Gly–Gly(OBn) (11), 50%
(B)
FmocHN
O
H
N
N
Cl-·H3N+
+
BF3K
O
COOBn
O
Me
12
13, 1.0 equiv
O
H
DCH (1.1 equiv)
N
N
FmocHN
N
THF/pH 3.0 buffer (1:1, 0.1 M)
rt, 1 h
H
O
Me
O
COOBn
(Fmoc)Gly–Ala–Gly–Pro(OBn) (14)
[7]
Tolerance of C–B bond in organoboron compounds in ozonolysis was
reported; a) G. A. Molander, D. J. Cooper, J. Org. Chem. 2007, 72,
3558; b) J. D. St Denis, A. Zajdlik, J. Tan, P. Trinchera, C. F. Lee, Z. He,
S. Adachi, A. K. Yudin, J. Am. Chem. Soc. 2014, 136, 17669; c) D. J.
Brauer, G. Pawelke, J. Organomet. Chem. 2000, 604, 43.
61%, dr = 98:2
Scheme 4. Oligopeptide synthesis between α-amino KAT and amino acid
using chlorinating agent in water. (A) Dipeptide synthesis in highly diluted
solution. (B) Preservation of stereochemistry in tetrapeptide synthesis.
[8]
[9]
In 2012, Yudin has also reported that acyloxy MIDA boronate could be
synthesized by the oxidation of acyl MIDA boronates using m-CPBA
(See ref. 3a)
a) G. Büchi, H. Wüest, J. Am. Chem. Soc. 1978, 100, 294; b) K. Igawa,
Y. Kawasaki, K. Tomooka, Chem. Lett. 2011, 40, 233.
Acknowledgements
[10] R. Willand-Charnley, T. J. Fisher, B. M.Johnson, P. H. Dussault, Org.
Lett. 2012, 14, 2242.
This study was financially supported by the MEXT (Japan)
program (Strategic Molecular and Materials Chemistry through
Innovative Coupling Reactions) of Hokkaido University, as well
as the JSPS (KAKENHI Grant Numbers 15K13633, 15H03804
and 17H06370). J. T. would like to thank the JSPS for
scholarship funding (KAKENHI Grant Number 16J01384). We
would also like to thank Mingoo Jin and Dr. Tomohiro Seki for
their help analyzing the X-ray crystallography data.
[11] The enantiomeric excess of (S)-4n slightly increased from (S)-1n. This
would be caused by precipitation in the purification process of (S)-4n.
Keywords: Amino acids • Boron • Chemical ligation • MIDA
boronate • Ozonolysis
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10.1002/anie.201707933
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jumpei Taguchi, Toshiki Ikeda, Ikuo
Sasaki, Rina Takahashi, Yasushi
Ogasawara, Tohru Dairi Naoya Kato
Yasunori Yamamoto, Jeffrey W. Bode*
and Hajime Ito*
Highly functionalized acylborons were easily prepared by ozonolysis of alkenyl
MIDA boronates. The first synthesis of α-amino acylborons including the
enantiopure alanine-type acylboron was achieved using this method. They are
essential for the protein–protein conjugation by KAT ligation. Oligopeptide synthesis
using α-amino acylborons revealed that peptide-bond-formation proceed even in
highly diluted aqueous medium and alanine-type acylboron is configurationally
stable under ligation condition.
Page No. – Page No.
Synthesis of Acylborons by
Ozonolysis of Alkenylboronates:
Preparation of an Enantioenriched
Amino Acid Acylboronate
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