Catalytic dehydrative peptide synthesis with gem-diboronic acids

Article abstract of DOI:10.1021/acscatal.9b03894

Alkane-gem-diboronic acids have emerged as versatile organoboron catalysts for dehydrative amidation of α-Amino acids. A phenol-substituted multiboron catalyst with a B-C-B structure outperformed simple arylboronic acids in the condensation of α-Amino acids with suppressed epimerization of electrophiles. gem-diboronic acid catalysis were compatible with various O, N, and S-functionalized α-Amino acids bearing N-protecting groups including common carbamates used in peptide synthesis (Boc, Cbz, Fmoc). N-Trifluoroacetyl protection enabled an unprecedented catalytic dehydrative peptide synthesis at room temperature. Preliminary mechanistic studies revealed carboxylate-binding nature of gem-diboronic acids, orthogonal to the activation of carboxylic acids by arylboronic acids. The distinctive reactivity of the gem-diboronic acids would open prospects for mild catalytic peptide condensation.

Full text of DOI:10.1021/acscatal.9b03894

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Letter
Catalytic Dehydrative Peptide Synthesis with gem-Diboronic Acids
Kenichi Michigami, Tatsuhiko Sakaguchi, and Yoshiji Takemoto
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b03894 • Publication Date (Web): 12 Dec 2019
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ACS Catalysis
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Catalytic Dehydrative Peptide Synthesis with gem-Diboronic Acids
Kenichi Michigami, Tatsuhiko Sakaguchi, Yoshiji Takemoto*
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Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan
Supporting Information Placeholder
tetragonal boron species suggested bidentate Lewis acid-activation
of the carboxy groups. The pathway involving II was further
supported by a more detailed spectroscopic analysis by Ishihara.6l
The analogous intermediate III with a B–N–B unit within B3NO2
heterocycles has also been proposed by Shibasaki as a crucial
structure for carboxy activation (Scheme 1A).6k,6n,8d However, α-
amino acids would give the low-reactive, five-membered complex
IV through the coordination of both the acid and a proximal
nitrogen toward arylboronic acids.7b The formation of the
dimerized “active” species might thereby be hampered, preventing
further development of simple arylboronic acids as catalysts for
peptide synthesis (Scheme 1B). To circumvent this dilemma, we
envisaged the efficient bidentate carboxy activation of α-amino
acids with a B–C–B structure, leading to the design of gem-
diboronic acid (denoted here as “gem-DBA”) (Scheme 1C).9
Because gem-DBAs possess “pseudo-active” B–C–B moiety in
advance, the more efficient acid activation could be expected in the
presence of N-protecting groups of the α-amino acids. The
structural and electronic tuning of the catalyst, in respect to the
central carbon, as well as the B–OH, would disclose unknown
reactivity of gem-DBAs towards amidation.10
ABSTRACT: Alkane-gem-diboronic acids have emerged as
versatile organoboron catalysts for dehydrative amidation of α-
amino acids. A phenol-substituted multi-boron catalyst with a B–
C–B structure outperformed simple arylboronic acids in the
condensation of α-amino acids with suppressed epimerization of
electrophiles. gem-diboronic acid catalysis were compatible with
various O, N, and S-functionalized α-amino acids bearing N-
protecting groups including common carbamates used in peptide
synthesis (Boc, Cbz, Fmoc). N-trifluoroacetyl protection enabled
an unprecedented catalytic dehydrative peptide synthesis at room
temperature. Preliminary mechanistic studies revealed carboxylate-
binding nature of gem-diboronic acids, orthogonal to the activation
of carboxylic acids by arylboronic acids. The distinctive reactivity
of the gem-diboronic acids would open prospects for mild catalytic
peptide condensation.
keywords: organoboron catalyst, gem-diboronic acid, dehydrative
amidation, peptide synthesis, oligopeptide, carboxylate activation
In the last half century, the practical synthesis using low-
electrophilic carboxylic acids has been broadened by virtue of
condensation reagents.1 In particular, reagent-driven dehydrative
amidation has largely contributed to the mass production of amide-
containing entities, including artificial pharmaceuticals, bioactive
peptides, and functional polymers.2 Therefore, this highly reliable
methodology is still in the forefront of organic synthesis,
notwithstanding the stoichiometric generation of chemical wastes.
In contrast, the recent high demand for environment-friendly
alternatives has led to the exploitation of catalytic amide C–N bond
construction.3,4 In 1996, Yamamoto reported catalytic amide
condensation using arylboronic acids, which release only water as
the side product.5 This innovative discovery triggered off the
research to establish highly active organoboron catalysts.6 Yet,
severe limitations have confronted arylboronic acids in catalytic
peptide synthesis: the reactions still suffer from insufficient catalyst
performance and restrictions in the protecting and functional
groups. The development of new catalysts for peptide condensation
is thus still in its nascent stage, because, to date, only a few catalysts
are capable of coupling carbamate-protected, heteroatom-
functionalized α-amino acids.6,7
(A) Proposed Structure of the Intermediates of Boron-Catalyzed Amidation
Whiting-Sheppard's
model
Yamamoto's
model
O
R
O
Ar
O
H
Ar
R
OH
OH
B
B
H
O
N
O
+
B
O
R
N
B
B
Ar
1/2
O
O
R'
R''
O
B
Ar
I
O
O
-H2O
-H2O
O
R
HO
O
B
Ar
R
II
III
Brønsted acid
activation
Lewis acid
activation
Shibasaki's proposal
(B) Proposed Deactivation of Arylboronic Acid Catalysts with -Amino Acids
R'
O
HO
OH
O
Ar
O
Ar
B
Ar
H
N
B
B
RO
RO
O
OH
N
O
O
R''
O
O
B
Ar
-2H2O
O
R'
O
R''
coordinating N-function
IV
(C) This Work: Replacement of O, N to C
unaffected carboxy activation
R1 R2
R1 R2
• Scarce Examples
• Pseudo-active structure
• Structural & electronic
HO
OH
X
X
B
B
B
B
O
O
HO
OH
O
O
H
N
R''
RO
gem-diboronic acid
(gem-DBA)
tuning of B–C–B & B–OH
H
R'
O
To tackle these issues, we focused on the structure of the
intermediates in organoboron-catalyzed amidation. Since
Yamamoto’s original mechanistic proposal,5 Brønsted acid-
activation of the carbonyl group in a “monomeric” mixed
anhydride I has been widely accepted.8a,b In sharp contrast, Whiting
and Sheppard demonstrated a more feasible intermediate based on
spectroscopic observations and isolation of the mixed anhydride
II.8c The structure of II features “diboroxane”, a bridged B–O–B
motif, which can be formed by dehydrative dimerization of I. This
Scheme 1. Structure of the Intermediates and Catalyst Design
On the basis of the catalyst design described above, we initiated our
studies by evaluating the reactivity of methylenediboronic acid (A),
the simplest gem-DBA,10c as a catalyst. Extensive reagent
screening revealed that a 5 mol% of catalyst A coupled N-Boc-Gly
(1a) with benzylamine (2) to afford amide 3a in 99% yield in the
presence of molecular sieves 5 Å (5 Å MS) in toluene at 80 ºC
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(Table 1, entry 1). Nonetheless, N-Boc-L-Phe (1b) was completely
was a promising nucleophile, giving dipeptide 5ba in 88% yield at
80 ºC.6l,7c The other N-protecting groups, including carbamates (1c,
1d), amides (1e, 1f6l) and a sulfonamide (1g), also afforded the
corresponding dipeptides in good yields, although epimerization
occurred in all cases (vide infra). The N-phthaloyl group (1h) was
not a suitable protecting group for this system (Figure 1), in contrast
to the results with arylboronic acids.7b Remarkably, in case of 1f,
unprecedented catalytic dehydrative peptide synthesis at room
temperature was achieved. The turnover frequency was still very
low, the result suggested the feasibility of peptide condensation
under mild conditions by further modification of the gem-DBA
catalysts.
1
2
3
4
5
6
7
8
inert under the same conditions (entry 2), which prompted us to
investigate the substituent effects on the central carbon atom of
gem-DBA. Examination of several gem-DBAs illustrated the
strong influence of steric effects around the central carbon atom:
no reaction occurred with bulky catalyst B (entry 3), while
relatively small monoalkyl-substituted catalyst C furnished 3b in
82% yield (entry 4). However, a considerable drop in the yield was
observed at 65 ºC (entry 5). We assumed this lack of efficiency
arose from the over-binding of amino acids to form C’: bidentate
activation of only two carboxy groups left two residues that would
merely encumber the nucleophilic attack. Hence, we expected that
the use of the ortho-hydroxyphenyl-substituted catalyst D would
reduce the bulkiness around the activated carbonyls by in situ
cyclocondensation to produce D’. The putative less hindered
complex D’’ might thus exhibit higher reactivity towards the
addition of amines (below Table 1).11 The catalytic performance of
D was much greater than that of C, affording 3b in 96% yield
without racemization (entry 6). Investigation of other parameters
uncovered that low-polarity solvents gave better results (entries 7–
10) and lowering temperature diminished the yield (entry 11). No
amidation occurred in the absence of either the catalyst or
molecular sieves, indicating that the carboxy activation and the
removal of water were both indispensable (entries 12 and 13).12
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Ph
O
Ph
D (5 mol%)
N
CO2H
•HCl
N
+
N
H
CO2Bn
5 Å MS, toluene
80 ºC, 48 h
H2N
CO2Bn
Ph
Ph
1b–1h (1 equiv)
4a (1 equiv)
5ba–5ha
N =
O
O
O
O
tBuO
N
H
BnO
N
H
O
N
H
Ph
N
H
Boc (1b)
88%, dr 96:4
Cbz (1c)
87%, dr 93:7
Fmoc (1d)
78%, dr 94:6
Bz (1e)
67%, dr 93:7
O
O
O
O
S
N
N
F3C
N
H
H
O
Me
Table 1. Optimization of the Reaction Conditions.
Tfa (1f)
92%, dr 89:11 (48%, dr 94:6a)
Ts (1g)
87%, dr 98:2
Phth (1h)
23%
O
BocHN
CO2H
catalyst (5 mol%)
BocHN
H2N
Ph
N
H
Ph
+
R
5 Å MS, solvent
temp., 12 h
Figure 1. Variation of N-Protecting Groups of Electrophile.
R
1a (R = H)
1b (R = Bn)
Isolated yields are shown. Drs were estimated by Chiral HPLC
2 (1 equiv)
3a or 3b
a
analysis. The reaction was carried out using 20 mol% catalyst D
entry substrate catalyst solvent temp. (ºC) 3b (%)a
in CH2Cl2 at rt for 120 h.
The potent activity of catalyst D toward dehydrative peptide
synthesis motivated us to explore the scope of α-amino acids
endowed with various functionalized side chains (Figure 2). The
coupling of N-Boc-protected amino acids and 4a unveiled that 1b
underwent the amidation at 65 ºC to give 5ba in better yield than
the reaction at 80 ºC. Notably, a terminal alkyne (1i), a sulfide (1j),
an ester (1k), and an amide (1l) were compatible, providing the
corresponding dipeptides 5ia–5la in good yields. In addition, the
presence of imidazole nitrogen did not affect the formation of 5ma.
Furthermore, though a prolonged reaction time was necessary, N-
Boc-L-proline provided the corresponding dipeptide 5na in 73%
yield. The versatility of gem-DBA towards the amino ester
counterparts was next probed using 1b. Importantly, a range of
alkyl-substituted nucleophiles could be applied, giving the leucine
derivative 5bb, as well as the bulky valine- and tert-leucine-derived
dipeptides 5bc and 5bd in good yields. The cyclopropane ring in
5be survived, and protected tyrosine (5bf) and lysine (5bg) were
also tolerated. Moreover, the nucleophiles bearing unprotected
thiol (5bh) and indole (5bi) groups also underwent the amidation,
which could offer further direct transformations of the side chains.
Markedly, the temperature could be lowered to 65 ºC for 5bb and
5be. For all reactions of dipeptide synthesis, the commercial
amine·HCl salts could be directly engaged in the catalytic
amidation, enabling a simple protocol free from pre-treatments and
external bases. Meanwhile, significant counteranion effects were
realized that 5bb was obtained in high yield with HCl salt 4b,
whereas the efficiency was drastically deteriorated with the
different counteranion analogues of 4b (e.g. HBr or HOTs
salts).13,14
1
2
3
4
5
6
7
8
9
10
11
12
13c
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
A
A
B
C
C
D
D
D
D
D
D
none
D
toluene
toluene
toluene
toluene
toluene
toluene
PhF
(CH2Cl)2
CPME
DMF
80
80
80
80
65
65
65
65
65
65
50
65
65
99
0
0
82
31
96b
78
68
85
0
toluene
toluene
toluene
77
0
0
Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2 (0.20 mmol, 1.0 equiv),
catalyst (10 μmol, 5 mol%), 5 Å MS (200 mg), solvent (2.0 mL), 12 h.
aYields were determined by 1H NMR analysis using 1,3,5-
trimethoxybenzene as an internal standard. bThe er was estimated by chiral
HPLC analysis as >99:1. cThe reaction was performed without 5 Å MS.
HO
B
OH
B
(HO)2B
OH
B(OH)2
B(OH)2
B(OH)2 Ph
B(OH)2
B(OH)2
Ph
Ph
O
O
B(OH)2
A
B(OH)2 Ph
HO
D
B
C
D'
Nu
Ph
Ph
R'
R'
linker
Nu
BocHN
NHBoc
O
O
O
O
B
B
B
B
O
O
O
O
O
O
O
O
O
O
NHBoc
NHBoc
BocHN
BocHN
H
H
H
H
R'
R'
R'
R'
C'
D''
With the optimal conditions in hand, the applicability of the
dehydrative amidation of 1b with catalyst D in peptide synthesis
was evaluated. To our delight, the amino ester hydrochloride 4a
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ACS Catalysis
R2
O
Me
CO2Bn
Dipeptide-electrophile
TfaHN CO2H
O
O
R2
catalyst D (5 mol%)
•HCl
H2N
BocHN
CO2H
BocHN
1
2
3
4
5
6
7
8
+
TfaHN
N
H
5
CO2R
Me
CO2Bn
5 Å MS, toluene
65 ºC, 48 h
CO2R
•HCl
N
H
R1
1 (1 equiv)
a
R1
+
H2N
4 (1 equiv)
Ph
1f (1 equiv)
Ph
For 1 (with 4a, R1 = Bn)
4j (1 equiv)
5fj: 91% (dr 88:8:4)
Ph
Ph
Ph
Dipeptide-nucleophile
OBn
O
O
O
BocHN
BocHN
BocHN
FmocHN
CO2H
N
H
CO2Bn
N
H
CO2Bn
N
H
CO2Bn
OBn
FmocHN
Me
N
H
CO2tBu
•HCl
a
MeS
+
Me
Ph
H2N
CO2tBu
5ba: 90%, dr 98:2
5ia: 95%, dr 98:2
5ja: 82%, dr 97:3
Me
1o (1 equiv)
Coupling of Dipeptide Fragments
Me
Ph
Ph
4k (1 equiv)
5ok: 80% (dr 94:6)
O
O
9
BocHN
BocHN
OBn
N
CO2Bn
N
H
CO2Bn
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
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40
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42
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44
45
46
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48
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50
51
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53
54
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56
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58
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60
O
Me
O
H
H
5fj
BnO2C
TrHNOC
b
TfaHN
N
N
H
N
H
CO2tBu
a'
5ka: 89%, dr 95:5
5la: 79%, dr 98:2 (80 ºC)
O
Me
Ph
Ph
5ok
c
O
Ph
6: 57%
Me
O
Boc
BocHN
N
H
CO2Bn
N
Scheme 2. Catalytic Coupling of the Dipeptide-Derived
Electrophile and Nucleophile
N
H
CO2Bn
N
TrN
5ma: 88%, dr >99:1 (80 ºC)
Reaction conditions: a) catalyst D (5 mol%), 5 Å MS, toluene, 80 ºC, 48 h;
a’) catalyst D (15 mol%), 5 Å MS, toluene, 80 ºC, 48 h; b) 10% Pd/C (10
mol% Pd), THF, rt, H2 (1 atm); c) piperidine, DMF, rt.
5na: 73%, dr 91:9 (80 ºC, 72 h)
For 4 (with 1b, R2 = Bn)
Me
Me
Me Me
Me
O
Me
Generally, reagent-driven and boron-catalyzed peptide synthesis
frequently induce considerable epimerization of the
electrophiles.18,19 Indeed, the epimerization-prone cysteine and
aspartic acid-derived electrophiles underwent approximately 20%
of enantiopurity loss by strong carboxy activation with the electron-
deficient boron catalysts6l,7d and the B3NO2 heterocycle.7c In
marked contrast, the gem-DBA catalysis significantly suppressed
the stereochemical erosion of aspartic acid derivatives 1p and 1q
as well as the cysteine electrophile 1r (Scheme 3A). Meanwhile,
enantiopurity of the nucleophiles was eroded, which was supported
by the independent exposure of electrophile 1b or neutralized
nucleophile 4a’ or amide 5ba to the optimal conditions, leading to
a slight racemization of only 4a’ (Scheme 3B).20 The reagent
sensitivity trend toward epimerization was inverted under the gem-
DBA catalysis, offering a complementary alternative to the known
boron catalysts that promote epimerization of the electrophiles.
O
Me
CO2Bn
O
BocHN
Ph
BocHN
Ph
BocHN
Ph
N
H
N
H
CO2Bn
N
H
CO2Bn
5bb: 94%, dr 99:1
5bc: 97%, dr >99:1 (80 ºC)
5bd: 78%, dr >99:1 (80 ºC)
OBn
NHCbz
O
O
O
BocHN
Ph
BocHN
BocHN
Ph
N
H
CO2Et
N
H
CO2Bn
N
H
CO2Bn
Ph
5be: 97%, er 99:1
5bf: 77%, dr 93:7 (80 ºC)
5bg: 79%, dr 97:2:1 (80 ºC)
NH
SH
O
O
BocHN
BocHN
CO2Me
N
H
N
H
CO2Me
Ph
Ph
5bh: 74%, dr 96:2:2 (80 ºC, 72 h)
5bi: 67%, dr 96:4 (80 ºC)
Ph
A) Amidation of Epimerization-Prone Electrophiles
O
Figure 2. Scope of N-Boc Amino Acids 1 in Dipeptide Synthesis
with 4a. Isolated yields are shown. Drs were estimated by chiral
HPLC analysis.
BocHN
CO2H
BocHN
Ph
D (5 mol%)
N
H
CO2Bn
·HCl
5 Å MS
toluene
X
X
+
H2N
CO2Bn
O
O
65 ºC, 48 h
The remarkable performance of gem-DBAs towards activation of
α-amino acids provided the opportunity for catalytic oligopeptide
synthesis (Scheme 2).7c Several studies revealed the crucial effect
of the protecting groups for both the N- and C-termini.4c,4e,6m,7b
Since the electron-rich N-Boc protection hampered the amidation
of dipeptide carboxylic acids, we prepared the electron-
withdrawing N-trifluoroacetyl-protected 5fj by coupling 1f and
4j.6l For the C-terminus of the dipeptide nucleophile, a tert-butyl
ester protection was suitable to avoid intramolecular cyclization.15
The dipeptide 5ok was thus prepared, and after deprotection,
catalytic interconnection of dipeptide segments successfully
provided tetrapeptide 6 in moderate yield with a high catalyst
loading. In particular, this Fmoc-based method would be expedient
for the application of the gem-DBA catalysis in solid-phase peptide
synthesis.16,17
1p (X = OBn)
1q (X = NHTr)
4a
4b
5pa (X = OBn): 87%, dr 95:3:2
5qa (X = NHTr): 90%, dr 96:2:2
Me
O
Me
Me
D (5 mol%)
FmocHN
FmocHN
TrS
CO2H
·HCl
N
H
CO2Bn
Me
5 Å MS
toluene
+
TrS
H2N
CO2Bn
65 ºC, 48 h
1r
5rb: 92%, dr 92:6:2
(lit. 7c: 86%, dr 77:23)
B) Epimerization Tests
BocHN
CO2H
BocHN
Ph
CO2H
D (5 mol%)
5 Å MS, toluene
80 ºC, 48 h
Ph
1b (er >99:1)
1b (er >99:1)
Ph
Ph
D (5 mol%)
H2N
CO2Bn
5 Å MS, toluene
80 ºC, 48 h
H2N
CO2Bn
4a' (er 97:3)
4a' (er >99:1)
Ph
Ph
O
O
D (5 mol%)
BocHN
Ph
BocHN
Ph
N
H
CO2Bn
N
H
CO2Bn
5 Å MS, toluene
80 ºC, 48 h
5ba (dr 98:2)
5ba (dr 98:2)
Scheme 3. Sensitivity of the Electrophiles and Nucleophiles toward
Epimerization Under the gem-DBA Catalysis
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The above unusual behavior of gem-DBA led us to attempt to
and mechanistic studies, is actively ongoing in our laboratory, and
the results will be reported in due course.
1
2
3
4
5
6
7
8
observe the intermediates to gain mechanistic insights into the
reaction. First, the phenolic protons were quickly disappeared upon
the treatment of D with 5 Å MS in toluene-d8 to give cis-D’, and
the structure was unambiguously determined by X-ray
crystallography.21,22 cis-D’ possesses a bent HO–BCB–OH unit,
which was theoretically more stable than trans-D’ by ca. 9 kcal/mol,
consistent with the obtained structure.23 Remarkably, no
dehydration of cis-D’ and 1b occurred even in the presence of 5 Å
MS and excess 1b (1~5 equiv). Both the two boron atoms of cis-D’
remained trigonal in 11B NMR analysis. The inertness of cis-D’
toward 1b would be attributed to the lower Lewis acidity of gem-
diborylalkane moiety relative to the arylboronic acids that easily
form mixed anhydrides with carboxylic acids.6l,7c Instead,
equimolar amount of cis-D’, 1b, and proton sponge in toluene-d8
produced new species. The observed negative chemical shift of B–
CH–B proton was consistent with the proximity of boronate
anions.24 The 11B NMR analysis revealed that both the two boron
atoms became tetragonal. However, switching the solvent to CDCl3
gave a different species with unsymmetrical aromatic protons of
cis-D’, and 11B NMR showed the existence of both trigonal and
tetragonal boron atoms.21 Moreover, the negative ESI-MS
spectroscopy of the mixture represented a m/z peak at 512.2032,
implying the existence of a dehydrated complex E consisting of cis-
D’ and 1b in 1:1 ratio ([M]–: calcd m/z = 512.2057) (Scheme 4).6o
Although the structure of E is still unclear, the spectroscopic
aspects would indicate a unique bidentate “carboxylate-activation”
nature of gem-DBAs, orthogonal to arylboronic acids and B3NO2
heterocycles activating carboxylic acids.6g,6o,7d The anion-binding
property would give rise to suppress epimerization of the
electrophiles, while the epimerization of nucleophiles might be
induced by the coordination of amines to the boron atoms. Besides
analytically, catalytic amidation of 1b/4b’ salt proceeded, whereas
a proton source was necessary for the reaction of the quaternary
ammonium salt (Schemes S1 and S4). Thus, gem-DBAs involve
the acid/base “salt form” into the catalytic cycle, where the proton
source might play a crucial role for the reaction progress. The
distinctive reactivity of gem-DBAs would open prospects for
catalyst modifications based on unconventional approaches in
respect to their propensity as anion acceptors.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at http://pubs.acs.org.
X-ray data file (CIF)
Experimental procedures and analytical data for all new
compounds.
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AUTHOR INFORMATION
Corresponding Author
*E-mail: takemoto@pharm.kyoto-u.ac.jp
ORCID
Kenichi Michigami: 0000-0001-8025-0461
Yoshiji Takemoto: 0000-0003-1375-3821
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
This work was financially supported by JSPS KAKENHI,
grant numbers JP16H06384 and JP19K16315. We thank Dr.
Hiroyasu Sato (Rigaku Corporation) for analyzing the X-ray
structures.
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1b (1~5 equiv)
CO2H remained
only trigonal B
toluene-d8
or CDCl3
rt
CCDC 1944639
proton sponge-H
5 Å MS
NHBoc
Ph
D
toluene-d8
or CDCl3
rt
B
O
O
B
O
B
HO
OH
B
H
OH
O
H
H
–H
O
1b (1 equiv)
O
proton sponge
(1 equiv)
H
E
CDCl3, rt
predicted by 1H & 11B NMR
detected on ESI-MS
cis-D'
(~9 kcal/mol stable than trans-D')
Scheme 4. Preliminary Attempts to Gain Mechanistic Insights
In summary, we have developed gem-DBAs as peptide
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ACS Catalysis
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investigation, see Scheme S3.
(21) For detailed NMR and ESI-MS studies, see the Supporting
Information.
(22) The crystal twinning occurred with cis-D’ likely due to
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Supporting Information.
(23) All levels of DFT calculation performed gave 8.5~9.3
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O
R2
PGHN
CO2H
PGHN
R1
N
H
CO2R
+
R1
R2
HO
B
OH
B
•HCl
H
H
• O, N, S functions
• Direct use of amine·HCl
• Room temp.~80 ºC
• Up to 97% yield
H2N
CO2R
O
O
O
R2
PGHN
N
H
CO2H
• Peptide coupling
R1
cat. gem-DBA
+
O
R4
O
R2
O
R4
H
N
H2N
PGHN
N
H
CO2R
N
H
N
H
CO2R
H2O
R3
R1
O
R3
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