Asymmetric Synthesis of α-Aminoboronates via Rhodium-Catalyzed Enantioselective C(sp3)-H Borylation

Article abstract of DOI:10.1021/jacs.9b12013

α-Aminoboronic acids, isostructural boron analogues of α-amino acids, have received much attention because of the important biomedical applications implicated for compounds containing this structure. Additionally, the inherent versatility of α-aminoboronic acids as synthetic intermediates through diverse carbon-boron bond transformations makes the efficient synthesis of these compounds highly desirable. Here, we present a Rh-monophosphite chiral catalytic system that enables a highly efficient enantioselective borylation of N-adjacent C(sp³)-H bonds for a range of substrate classes including 2-(N-alkylamino)heteroaryls and N-alkanoyl- or aroyl-based secondary or tertiary amides, some of which are pharmaceutical agents or related compounds. Various stereospecific transformations of the enantioenriched α-aminoboronates, including Suzuki-Miyaura coupling with aryl halides and the Rh-catalyzed reaction with an isocyanate derivative of α-amino acid, affording a new peptide chain elongation method, have been demonstrated. As a highlight of this work, the borylation protocol was successfully applied to the catalyst-controlled site-selective and stereoselective C(sp³)-H borylation of an unprotected dipeptidic compound, allowing remarkably streamlined synthesis of the anti-cancer drug molecule bortezomib and offering a straightforward route for the synthesis of privileged molecular architectures.

Full text of DOI:10.1021/jacs.9b12013

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Article
Asymmetric Synthesis of #-Aminoboronates via
3
Rhodium-Catalyzed Enantioselective C(sp)–H Borylation
Ronald L. Reyes, Miyu Sato, Tomohiro Iwai, and Masaya Sawamura
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 Dec 2019
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Asymmetric Synthesis of -Aminoboronates via Rhodium-Catalyzed
Enantioselective C(sp3)–H Borylation
Ronald L. Reyes,†,‡ Miyu Sato,‡ Tomohiro Iwai,‡ and Masaya Sawamura†,‡*
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† Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
‡ Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
KEYWORDS: a-aminoboronic acids, borylation, asymmetric synthesis, C–H activation
ABSTRACT: a-Aminoboronic acids, isostructural boron analogues of a-amino acids, have received much attention because of the im-
portant biomedical applications implicated for compounds containing this structure. Additionally, the inherent versatility of a-aminoboronic
acids as synthetic intermediates through diverse carbon–boron bond transformations make the efficient synthesis of these compounds highly
desirable. Here, we present a Rh-monophosphite chiral catalytic system that enables a highly efficient enantioselective borylation of N-
adjacent C(sp3)–H bonds for a range of substrate classes including 2-(N-alkylamino)heteroaryls and N-alkanoyl or aroyl-based secondary or
tertiary amides, some of which are pharmaceutical agents or related compounds. Various stereospecific transformations of the enantioen-
riched a-aminoboronates including Suzuki–Miyaura coupling with aryl halides and the Rh-catalyzed reaction with an isocyanate derivative of
a-amino acid affording a new peptide chain elongation method have been demonstrated. As a highlight of this work, the borylation protocol
was successfully applied to the catalyst-controlled site- and stereoselective C(sp3)–H borylation of an unprotected dipeptidic compound al-
lowing remarkably streamlined synthesis of the anti-cancer drug molecule bortezomib, offering a straightforward route for the synthesis of
privileged molecular architectures.
found widespread application in asymmetric synthesis as salient
chirogenic auxiliaries (Figure 1A).10–12
INTRODUCTION
Organoboronic acids represent an interesting class of enzyme
inhibitors prominently in the area of protease inhibition.1 The
emergence of isostructural boron analogues of a-amino acids (Fig-
Established protocols to access enantioenriched a-
aminoboronates often heavily rely on the utilization of diastereose-
lective chemical reactions requiring stoichiometric amount of chiral
auxiliaries including the classical Matteson’s one-carbon homologa-
ure 1A), collectively called a-aminoboronic acids or boro(amino
acid)s,2,3 has resulted in the enhancement of the specificity and
potency. A variety of alkyl- or arylboronic acids including peptidyl-
boronic acid analogues have been implicated in numerous thera-
peutic interventions.1 Among these, bortezomib finds particularly
significant clinical applications as an anti-cancer drug as it reversi-
bly inhibits the action of 26S proteasome with remarkable selectivi-
ty and potency through covalent boron–oxygen bond formation
between the boronate moiety and the N-terminal threonine residue
at the chymotrypsin-like active site of the protein.4,5 Moreover,
ValboroPro and ProboroPro are successful inhibitors of dipeptidyl
peptidase IV (DPP IV) providing a strategy for the treatment of
type-2 diabetes (Figure 1B).6,7
tion of optically active pinanediol-based boronates using a-
halocarbanions.13 Among the limited success on catalytic asymmet-
ric synthesis of a-aminoboronates, enantioselective boryl addition
to N-protected imines14–16 are notable, while the applicability to
aliphatic substrates has not been satisfactory.17–19 One desirable but
unmet method is the direct asymmetric borylation of N-adjacent
C(sp3)–H bonds that discriminates between the two hydrogen
atoms on a single carbon center.
We recently reported the synthesis of enantioenriched a-
chirogenic alkylboronates via the iridium-catalyzed asymmetric
borylation of unactivated methylene C(sp3)–H bonds using a
triisopropylsilyloxy(TIPS)-modified BINOL-based monophos-
phite ligand (R, R)-L*.20 Quantum chemical calculations using the
artificial force induced reaction (AFIR) method21,22 suggested that
the interplay between the substrate and the catalytic system
through multiple noncovalent interactions within a chiral narrow
reaction pocket was crucial to achieve the observed catalytic activi-
ty and enantioselectivity.
Such growing demands for pharmaceutically active boron-
containing compounds amplify the necessity to develop practical
strategies for synthesizing a-chirogenic a-aminoboronic acid de-
rivatives.8,9 Furthermore, alkylboronates participate in a number of
transformations to give an array of products resulting from the
intrinsic versatility of boronic acids and their derivatives as funda-
mental intermediates in synthesis, giving access to highly function-
alized molecules including intermediate metabolites, amine-
derived organocatalysts, and N-a-substituted compounds that have
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A
Transformations of !-aminoboronates
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R
R
H
H
H
H
HO
HO
FG
OR
OH
OH
B
N
N
N
B
N
N
B
N
HO
O
H
OR
OH
O
boro(amino acid)s
chiral N-containing
building blocks
!-amino acid
!-aminoboronic acid
8
9
Therapeutically significant !-aminoboronates
B
HO
O
B
OH
26S Proteasome
β-subunit
L
-boroleucine
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pyrazinoyl
N
N-terminal threonine
H2
N
O
H
N
β
H3C
β
NH2
N
NH3
OH
H
N
N
H
B
H
H
ValboroPro
O
H
O
O
OH
O
H
H3C
O
B
N
N
OH
OH
OH
bortezomib
L
-phenylalanine
H
B
bortezomib
B
OH
O
OH
HO
ProboroPro
bortezomib
THIS WORK
C
N-adjacent
C(sp3)–H bonds
Si
O
O
O
O
O
O
(RN,O)
(RN,O)
H
H
H
B
P
O
O
O
cat. [Rh–L*]
(–HBpin)
R2
R2
+
B B
N
R1
N
R1
O
L*
BINOL-based monophosphite
!-aminoboronates
up to 99% ee
Figure 1. N-adjacent C–H bond functionalization. (A) Isostructural boron analogues of a-amino acids, bo-
ro(amino acid)s are indispensable bioactive compounds and are versatile intermediates in synthesis. (B) Repre-
sentative examples of a-aminoboronates exhibiting significant therapeutic activities as proteasome inhibitors.
The boron atom in bortezomib binds with the active site of 26S proteasome with remarkable affinity and speci-
ficity leading to the overall proteasome inhibition. (C) Catalytic borylation of N-adjacent C(sp3)–H bonds
providing a direct access to a-aminoboronic acid derivatives.
Herein, we report our finding that a rhodium catalyst system
RESULTS AND DISCUSSION
with the identical chiral phosphite ligand L* enabled a highly enan-
Reaction development (Table 1). We initially investigated
the synthesis of an N-pyridyl boroproline derivative from 2-
(pyrrolidine-1-yl)pyridine (1a) via the borylation of the N-
adjacent methylene C(sp3)–H bond of the pyrrolidinyl moiety
using bis(pinacolato)diboron (pinB–Bpin) under Ir or Rh catalysis
[cyclopentylmethyl ether (CPME) 2 mL as solvent, 60 °C, 15 h]
(Table 1). However, the initial investigation on iridium catalysis (3
mol% Ir, Ir/P 1:1) utilizing (R, R)-L* resulted in merely low sub-
strate conversion. In stark contrast, the use of [Rh(OH)(cod)]2
satisfyingly promoted the N-adjacent C(sp3)–H borylation of 1a
giving the boroproline derivative 2a in moderate yield with a prom-
ising enantiomeric excess (ee) of 75%, favoring the R isomer. These
observed contrasting activities between Ir and Rh catalysis is analo-
gous to our previous observation with achiral Silica-TRIP and chi-
ral phosphoramidite ligands.23,24 We have also examined other vari-
ants of the biaryl monophosphite ligand, showing that the combi-
nation of (R, R)-L* and [Rh(OH)(cod)]2 provided the best catalyt-
ic system (see Supporting Information, Table S1–S4).
tioselective borylation of N-adjacent C(sp3)–H bonds allowing the
direct asymmetric synthesis of chiral a-aminoboronates (Figure
1C). Importantly, the protocol was applicable not only to N-
heteroarylamines but also to N-alkanoyl or aroyl-based secondary
or tertiary amides. The extended substrate scope led us to propose
an interesting mechanistic feature of this catalysis that the amide
substrates were favorably bound to the catalyst with the crucial
participation of dispersive noncovalent interactions that occur
between an aromatic group of the substrate and the concave surface
of the catalyst. Remarkably, the aromatic rings as noncovalent in-
teraction donors could be situated in various regions in the sub-
strate including the N-heteroaromatic moiety, N-acyl group and N-
alkyl substituent such as a benzyl group. Stereospecific transfor-
mations of carbon–boron bonds of the C–H borylation products
allow a direct route for the utilization of these a-aminoboronates
including their use as building blocks for a new peptide elongation
strategy. Moreover, a straightforward synthesis of the anti-cancer
drug molecule bortezomib through late stage site- and stereoselec-
tive borylation of the N-adjacent C(sp3)–H bond in the pro-
boroleucine residue of the parent dipeptidic compound has been
achieved, overturning the strenuous manipulations of sensitive
organoboron compounds, collectively embodying the versatility
and potential of the asymmetric borylation presented herein.
The solvent has a strong impact on both the reactivity and enan-
tioselectivity (Table 1). Ethereal solvents like THF and t-butyl
methyl ether (TBME) were useful while non-polar solvents like
hexane led to diminished reactivities and enantioselectivities. Re-
placing CPME with acetonitrile showed a marked improvement
giving (R)-2a at an enhanced yield (72%) and enantioselectivity
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(90% ee). The use of isobutyronitrile likewise exhibited favorable enantioselectivity of 95% ee, even allowing a gram-scale prepara-
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effects although less pronounced (63%, 85% ee) compared with
MeCN. Other polar aprotic solvents like nitromethane and DMSO
led to the loss of reactivity.
tion without detrimental effects on the enantioselectivity (Table 1).
Notably, the reaction using 1 equiv each of 1a and 2,6-lutidine
relative to pinB–Bpin gave the product at a comparable enantio-
meric excess (93% ee) and a moderate yield [68% (1H NMR), 53%
(isolated) based on 1a] (Table S3), but, for easier product separa-
tion, we used 2 equiv of alkylamine substrates for further explora-
tion of the substrate scope.
Table 1. Asymmetric borylation of N-adjacent methylene
C(sp3)–H bond of 2-pyrrolidinopyridine (1a): Optimization of
reaction conditions
N-Heteroarene substrates (Table 2). The suitability of this
protocol was examined across a variety of different substrate clas-
ses. At first, we explored 2-(N-alkylamino)pyridines including aza-
cycloalkane frameworks that are common synthetic building
blocks, and are reminiscent of natural alkaloids and bioactive com-
pounds. Thus, the 4-methylpyridine-substituted pyrrolidine also
gave the corresponding N-pyridyl boroproline derivative (R)-2b in
excellent yield and enantioselectivity (96% ee). Expansion of the
azacycloalkyl group with the piperidinyl moiety delivered the boron
analogue of L-homoproline esters (S)-2c and (S)-2d with excellent
enantioselectivity (99% ee), providing a derivative of pipecolic acid
that is implicated as a diagnostic marker of pyridoxine-dependent
epilepsy.25 Likewise, the borylation of 2-morpholinopyridines pro-
vided the 2-(pinacolatoboryl)morpholine derivatives (S)-2e (97%
ee) and (S)-2f (95% ee) even withstanding a gram-scale prepara-
tion. This protocol was also useful for acyclic amine system as ex-
emplified by the synthesis of the enantioenriched (R)-2g (92% ee)
from the monoborylation of N-adjacent C–H bond in 2-(N,N-
diethylamino)pyridine.
Bpin
N
N
O
O
O
O
H
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[Rh(OH)(cod)]2 (Rh: 3 mol%)
H
B
B
(R,R)-L* (3 mol%)
+
N
N
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CPME (2 mL), 60 ℃, 15 h
1a
pinB–Bpin
(0.30 mmol)
(R)-2a
N-pyridyl boroproline
(–HBpin)
(0.60 mmol)
solvent (2 mL)
THF
47%, 73% ee iPrCN
63%, 85% ee
Si
O
TBME 58%, 74% ee MeNO2 trace
hexane 25%, 63% ee DMSO trace
O
O
P
O
MeCN 72%, 90% ee
(50 mol% 2,6-lutidine)
98%, 95% ee
(R,R)-L*
85%, 95% ee 2 mol% Rh, Rh:L* 1:1
50 mol% 2,6-lutidine
61%, 75% ee
24 h, 1.10 g 2a, isolated
We then explored the utilization of additives that can trap the in
situ generated HBpin and at the same time compete with the unde-
sired substrate–boron interactions based on our knowledge of fa-
vorable additive effects in our recent work20 (Table S2, Figure S4).
The use of 2,6-lutidine (50 mol%) as an additive led to optimal
results delivering the product (R)-2a at 98% yield with an excellent
3
a
a
Table 2. Asymmetric synthesis of -aminoboronates by Rh-catalyzed borylation of N-adjacent C(sp )–H bonds
2-(alkylamino)pyridines
Bpin
F3C
Bpin
Bpin
N
N
N
Bpin
Me
Bpin
N
N
Bpin
N
Me
N
N
Me
N
N
N
N
O
O
Me
(S)-2e
(R)-2b
98%, 96% ee
(S)-2c
92%, 99% ee
(S)-2d
90%, 99% ee
(S)-2f
97%, 95% ee
92%, 2.31 g, 95% ee
(R)-2g
93%, 97% ee
75%, 92% ee
92%, 1.87 g, 97% ee
2-(alkylamino)quinolines
2-aminoalkyl-1,3-azoles
Bpin
N
pinB
Bpin
pinB
O
NBoc
Bpin
N
N
H
N
N
N
N
N
N
(S)
N
O
N
N
O
Me
H
Me
(S)-2h
(S)-2i
(S)-2j
(S)-2k
2l
93%, 97% ee
93%, 97% ee
85%, 95% ee
(85 ºC, 18 h)
72%, 99% ee
87%, 99% de
boryl analogue of
quipazine derivative
serotonin receptor antagonist
decahydroisoquinoline
AMPA receptor antagonist
aReaction conditions: pinB–Bpin (0.30 mmol), substrates 1b–l (2 equiv, 0.60 mmol), [Rh(OH)(cod)]2 (3 mol% Rh), (R,R)-L* (3 mol%), 2,6-
lutidine (50 mol%), MeCN (2 mL), 60 ºC, 15 h. Yields given are isolated yields of the product. Enantiomeric excess was determined by chiral HPLC
analysis. Absolute configurations of the products were determined by the preparation of authentic samples, comparison and/or structural correlation
with known compounds.
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We then used several azacycloalkane derivatives bound to the gave product 4j (90% ee, R) with exclusive site-selectivity towards
pharmaceutically important quinoline scaffold (Table 2).26 Thus,
the diversely bioactive 2-morpholinoquinoline underwent the N-
adjacent methylene C–H borylation to give the corresponding
product (S)-2h (97% ee). An N-Boc-quipazine derivative, a pipera-
zine-based nonselective serotonin receptor antagonist known for its
antidepressant and oxytocic activity,27a also showed reactivity giving
(S)-2i (97% ee).
the N-ethyl arm, while substrate 3k with a N,N-diethylamino group
failed in delivering the corresponding product 4k.
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3
4
5
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7
8
Following this lead, the potency of pharmacologically important
N-aroyl-N,N-dialkylamines29 towards asymmetric N-adjacent C–H
borylation was explored (Table 3). Replacing the pivaloyl group in
4f to an o-methoxy-substituted benzoyl group in 3l delivered a
borophenylglycine derivative 4l with an enhanced enantioselectivi-
ty (92% ee, R), suggesting that an aromatic environment is favored
near the coordinating donor atom. This feature implies the exist-
ence of substrate–ligand p/p interactions as in the previously re-
ported Ir-catalyzed asymmetric borylation of unactivated C(sp3)–
H bonds.20 Notably, the C(sp2)–H bond ortho to the carbonyl di-
recting group remained untouched. A m-methylbenzamide deriva-
tive 3m containing an N-benzyl-N-ethyl moiety delivered the boro-
alanine derivative 4m (91% ee, R). Introducing an N-isopentyl arm
as a replacement to the N-ethyl group in 3n maintained the ob-
served site preference favoring the N-adjacent methylene C–H
Next, we evaluated substrates bearing 1,3-azole units as these
heteroaromatic cores are also frequently encountered in natural
products and pharmacologically active compounds (Table 2). 2-
Morpholinobenzoxazole gave the enantioenriched product (S)-2j
(95% ee), while benzimidazole derivatives proved to be viable sub-
strates as demonstrated by the isolation of the a-
tetrahydroquinoline boronate (S)-2k (99% ee). This result is in-
dicative of the applicability of the protocol towards anilide deriva-
tives. Likewise, a benzimidazolyl substrate bearing trans-
decahydroisoquinoline moiety gave the borylated product 2l with
exclusive diastereoselectivity (>99% de), giving access to the boro-
nate analogue of decahydroisoquinoline-3-carboxylic acid, the
fundamental scaffold in numerous putative AMPA receptor antag-
onist.27b
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1
bond (75%, H NMR) in the isopentyl chain rather than benzylic
1
C–H bond (7%, H NMR), providing 4n (90% ee, R) despite the
steric bulk imposed by the elongated branched substituent. The
borophenylglycine derivative 4o with a naphthamide core, com-
mon in natural products and pharmaceutical molecules, was ob-
tained with excellent enantioselectivity (96% ee, R). A structurally
related functional component of the coenzyme NAD, N,N-
diethylnicotinamide 3p, delivered the desired product 4p (92% ee,
R) efficiently. The borylation of indole derived tubulin inhibitor30
3q that exhibits anti-mitotic activity gave the indole carboxamide
boronate 4q as the only product (93% ee, R) demonstrating anoth-
er case of anilide borylation [c.f. Table 2, (S)-2k].
As described above, the C–H borylation protocol exhibited ex-
cellent enantioselection ability toward various 2-(N-
alkylamino)heteroaryl compounds, while the sense of stereoselec-
tion depended on the substrate structure and is not easily predicta-
ble.
Amide substrates (Table 3). Considering the general phar-
macological significance of amides, we investigated the propensity
of using N-alkanoyl (3a-k) and N-aroyl derivatives (3l-q). The
initial assessment of amide substrates with simple N-alkanoyl
groups such as 3a-e resulted in poor reactivities. We argued that the
low reactivity of amides 3a-e is presumably because of the weaker
coordinating ability of the amide motif and also due to the simplici-
ty of the substrate lacking an additional moiety that can facilitate
interaction with the catalytic system.28 In contrast, however, the
tertiary amide N,N-dibenzylpivalamide 3f with a more sterically
demanding N-alkanoyl group gave the borophenylglycine deriva-
tive 4f in 81% yield at enantioselectivity as high as 88% ee, favoring
In contrast to the reactivity trend with the N-alkanoyl deriva-
tives, the N-aroyl derivatives underwent site-selective C–H boryla-
tion at the aliphatic N-substituents regardless of the existence or
absence of the N-benzyl group. This should be due to the existence
of the aromatic ring in the N-aroyl group as a p-donor moiety.
Gratifyingly, the synthetic significance of this reaction protocol
was substantially enhanced as even secondary amides were amena-
ble to the borylation reaction as exemplified by the production of
4r (98% ee, S) starting from N-benzylbenzamide 3r in a straight-
forward manner (Table 3). Notably, compound 4r was previously
accessed through multistep diastereoselective synthesis involving
Matteson homologation reaction of optically active pinanediol
phenylboronate.31–33 Furthermore, we applied the present protocol
for the borylation of bioactive compounds. Hence, the reaction of
the antidepressant drug molecule moclobemide (3s)34 gave com-
pound 4s as the sole product (95% ee, S) from the selective boryla-
tion of the N-adjacent C–H bond in the (2-
morpholinoethyl)amine chain. In a similar fashion, the extensively
used antiemetic drug molecule trimethobenzamide (3t)35 having a
terminal N,N-dimethylamino group gave the boronate 4t exclusive-
ly with excellent enantioselectivity (93% ee, S). Note that all the
tested secondary amide substrates were converted into the S-
configurated borylation products, while the borylation products
4l–4q from the tertiary amides had the R configuration.
the
R
configuration. Furthermore, the use of N,N-
dibenzyladamantanecarboxamide 3g with an even bulkier alkanoyl
group led to much higher enantioselectivity (4g, 95% ee, R),
demonstrating the crucial role of the extended bulky substituents in
the N-alkanoyl moieties.
Surprisingly, the borylation of N-benzyl-N-ethylpivalamide 3h
occurred at the N-ethyl arm rather than at the benzylic position
with exclusive site-selectivity to give 4h (89% ee, R), while the reac-
tivity was completely lost using substrate 3i with an N,N-
diethylamino moiety (Table 3). This means that the N-benzyl
groups did not present a reactive C–H bond but induced the reac-
tivity of the N-adjacent C–H bond in the N-ethyl group, suggesting
the occurrence of a favorable noncovalent interactions, most prob-
ably a ligand–substrate p/ p interaction, provided by the aromatic
ring of the N-benzyl group. In fact, the same observation was elicit-
ed using the adamantane carboxamide derivatives 3j and 3k. Thus,
substrate 3j bearing an N-benzyl-N-ethyl adamantane carboxamide
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Table 3. Rh-catalyzed borylation of N-adjacent C(sp3)–H bonds in N-alkanoyl or N-aroyl N,N-dialkylamines and secondary ben-
zamide derivativesa
1
2
3
4
N-alkanoyl-N,N-dialkylamines
5
6
7
8
Bpin
Bpin
Ph
Bpin
Ph
O
Me
O
Me
O
Bpin
O
O
Bpin
Ph
Me
Me
N
Ph
Me
N
N
Me
N
Me
N
Ph
Ph
Ph
Ph
4a
4b
4c
5% (1H NMR)
4d
7% (1H NMR)
4e
12% (1H NMR)
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
0%
trace
Bpin
O
Bpin
Ph
O
Bpin
Ph
O
O
Bpin
Me
O
Bpin
Me
Bpin
Me
O
Me
Me
Me
Me
Me
Me
N
N
Me
N
N
N
N
Me
Me
Me
Ph
Ph
Me
Ph
Ph
Me
(R)-4g
63%, 95% ee
(R)-4h
4i
0%
(R)-4f
81%, 88% ee
(R)-4j
4k
5% (1H NMR)
95%, 89% ee
89%, 90% ee
N-aroyl-N,N-dialkylamines
O
Bpin Me
MeO
O
O
Bpin
Ph
Bpin
Me
Me
Me
N
Me
N
N
Ph
Ph
Ph
(R)-4l
88%, 92% ee
(R)-4m
81%, 91% ee
(R)-4n
72%, 90% ee
O
Bpin
Ph
Bpin
O
O
Bpin
Me
MeO
N
N
N
N
MeO
Ph
Me
OMe
(R)-4o
92%, 96% ee
(R)-4p
65%, 92% ee
(R)-4q, 74%, 93% ee
borylation of a tubulin inhibitor:
anti-mitotic agent
secondary benzamide derivatives
Bpin
Bpin
O
O
O
Bpin
O
N
MeO
MeO
NMe2
N
H
N
H
N
H
Cl
O
OMe
(S)-4r, 55%, 98% ee
(S)-4s, 79%, 95% ee
(S)-4t, 63%, 93% ee
borylation of moclobemide:
monoamine oxidase inhibitor with
antidepressant activity
borylation of trimethobenzamide:
antiemetic drug
Reaction conditions: pinB–Bpin (0.30 mmol), substrate (2 equiv, 0.60 mmol), [Rh(OH)(cod)]2 (3 mol% Rh), (R,R)-L* (3 mol%), 2,6-lutidine (50
mol%), MeCN (2 mL), 60 ºC, 15 h. Yields given are isolated yields of the product unless otherwise indicated. Enantiomeric excess was determined by
chiral HPLC analysis. Absolute configurations of the products were determined by the preparation of authentic samples, comparison and/or struc-
tural correlation with known compounds.
Synthetic transformations (Scheme 1). Oxidation of the N-
pyridyl boroproline derivative (R)-2a with sodium perborate gave
the corresponding 2-hydroxypyrrolidine derivative (R)-5 with
complete retention of configuration (Scheme 1A). The boropro-
line derivative 2a also underwent a facile stereoretentive one-
carbon homologation with bromochloromethane/BuLi reagent
tion of organoboronates to isocyanates, which was previously
demonstrated only with combinations of arylboronic acid deriva-
tives and achiral isocyanates by Murakami and co-workers,36 has
been applied to the reaction between (R)-2a and an isocyanate
derivative of L-valine to provide the dipeptide (S,S)-7 with no epi-
merization at the both stereogenic centers, demonstrating the po-
tential of a-aminoboronates as a new type of building blocks for
peptide chain elongation to be studied in the future.
1
furnishing the N-adjacent secondary alkylboronate (87% H NMR
yield) followed by direct oxidation with NaBO3, delivering the
pyridyl prolinol derivative (S)-6. Moreover, the Rh-catalyzed addi-
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1
2
Scheme 1. Synthetic transformations and functionalizations
3
4
5
6
1) BrCH2Cl (2.5 equiv)
nBuLi (2.0 equiv)
THF, –78 ℃ to r.t., 5 h
OH
OH
N
N
A
NaBO3·4H2O (3 equiv)
THF/H O, 1:1
N
N
2
2) NaBO3•4H2O (3.0 equiv)
r.t., 3 h
(R)-5
(S)-6
THF/H
2O (1:1)
7
8
9
91%, 95% ee
71%, 95% ee
r.t., 24 h
O
O
N
B
O
N
N
C
O
H
O
(1.5 equiv)
PhBr (1.2 equiv)
Pd(dba)2 (5 mol%)
XPhos (10 mol%)
N
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
(R)-2a
95% ee
N
retention
OMe
N
N
[Rh(OH)(cod)]2, 2.5 mol%
THF, r.t., 12 h
O
N
K2CO3 (3 equiv), H2O (2 equiv)
toluene, 90 °C, 24 h
(S,S)-7
79%, 95% de
(S)-8
77%, 94% ee
retention
B
N
Ph
Ph
N
PhBr (1.2 equiv)
optimized
borylation condition
Pd(dba)2 (5 mol%), XPhos (10 mol%)
N
Me
N
Me
Ph
K2CO3 (3 equiv), H2O (2 equiv)
toluene, 90 ℃, 24 h
%
1H NMR boronate
(S)-9
2m: 88% (methylene)
2m’: 6% (benzylic)
1m
69%, 98% ee
Me
inversion
Bpin
O
O
C
Pd(dba)2 (5 mol%), XPhos (10 mol%)
+
Br
Me
N
H
N
H
K2CO3 (3 equiv), H2O (2 equiv)
toluene, 90 °C, 24 h
(1. 2 equiv)
(S)-4r ,98% ee
(S)-10, 31%, 96% ee
retention
Bpin
Me
Ph
O
O
Ph
Me
Me
Pd(dba)2 (5 mol%), XPhos (10 mol%)
N
N
Me
+
Br
K2CO3 (3 equiv), H2O (2 equiv)
toluene, 90 °C, 24 h
Ph
(1. 2 equiv)
(R)-4m, 91% ee
(S)-11, 21%, 91% ee
OSiMe2tBu
OSiMe2tBu
N
D
MeOTf (1.2 equiv)
NaBH4 (3.0 equiv)
HN
N
CH3CN
–20 ℃, 1 h
MeOH
–20 ℃ to 0 ℃, 30 min
(S)-6-OTBS, 95% ee
(S)-12, 83%, 95% ee
Ph
N
Ph
Ph
MeOTf (1.2 equiv)
NaBH4 (3.0 equiv)
HN
Me
Ph
N
Me
CH3CN
0 ℃ to r.t., 15 min
MeOH
0 ℃, 1 h
(S)-9, 98% ee
(S)-13, 75%, 98% ee
(A) Transformations of the boroproline derivative 2a at mild reaction conditions gave the corresponding a-amino alcohol
5, pyridyl prolinol derivative 6, dipeptide 7 from the direct addition of 2a to an isocyanate derivative of L-valine, and a-
arylation product 8 formed through Suzuki–Miyaura cross-coupling. (B) One-pot borylation/cross-coupling protocol
provided access to an acylic a-functionalized amino derivative. (C) Stereospecific cross-coupling reaction of the a-
aminoboronates derived from amides. (D) Removal of the pyridine directing group via a quaternization–hydride reduc-
tion protocol allowed the isolation of the enantioenriched free amine. All reactions were carried out at 0.20–0.50 mmol
scale.
Meanwhile, we sought the utility of (R)-2a towards N-adjacent
arylation via a Suzuki–Miyaura-type cross-coupling reaction em-
ploying the reaction conditions previously reported by Ohmura
and Suginome31,32 in the cross-coupling between a-(N-
acylamino)benzylboronic esters and bromobenzene with a
Pd(dba)2/XPhos catalyst system (Scheme 1A). In fact, this reac-
tion occurred similarly but in contrast to the reported case, with
retention of configuration, affording the coupling product (S)-8 with
almost completely preserved enantiomeric purity (94% ee).37
A
one-pot borylation/cross-coupling transformation was also ex-
plored (Scheme 1B). Thus, starting from substrate 1m, the enanti-
oselective borylation of the N-adjacent C–H bond of the N-ethyl
1
moiety (2m, 88% H NMR) followed by the Suzuki–Miyaura
cross-coupling reaction afforded product 9 with 98% ee (S) in 69%
overall yield. This successful borylation–arylation sequence further
highlight the synthetic significance of the present protocol allowing
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the asymmetric arylation of N-adjacent C(sp3)–H bonds, as only a
few notable strategies for such functionalization have been reported
so far.38–40
The observed stereoselectivity of the C–H borylation of 14 with
1
2
3
4
5
6
7
8
the Rh-(S,S)-L* catalyst system was due to catalyst control as the
reaction with (R,R)-L* resulted in a reversed selectivity (dr 10:90)
and a lower chemical yield (31%) for a diastereomeric mixture of
15. The use of the supported achiral ligand Silica-TRIP23 resulted
in the formation of a complex mixture with a low conversion of 14
(7%). Considering the general importance of the aromatic moiety
in the substrates indicated throughout this study, participation of
the aromatic ring in the phenylalanine residue of 14 in ligand–
substrate noncovalent interactions is strongly suggested in the ca-
talysis with (S,S)-L*.
As described above, in contrast to Ohmura and Suginome’s re-
port, the cross-coupling reaction of the a-aminoboronate (R)-2a
derived from a 2-(N,N-dialkylamino)pyridine derivative proceeded
with stereoretention (see Scheme 1A). To delve into this, we have
performed a cross-coupling reaction with the highly enantioen-
riched borophenylglycine 4r (98% ee, S) derived from a secondary
amide, confirming the stereochemical inversion as previously dis-
closed by Ohmura and Suginome with the identical substrate with a
moderate enantiomeric purity (Scheme 1C, 87% ee, S).31,32 In di-
rect contrast, the cross-coupling reaction of the tertiary amide
boronate (R)-4m proceeded with complete stereoretention similar to
the observed stereochemical outcome in the cross-coupling of (R)-
2a. These contrasting observations with the secondary and tertiary
amide boronates support an assumption that the stereoinvertive
cross-coupling with the secondary amide occurred though depro-
tonation of the NH moiety under the basic conditions.
We also assessed the feasibility of removing the pyridyl group by
exploiting a reported quaternization–hydride reduction strategy
(Scheme 1D).41 Thus, the TBS-protected pyrrolidinyl a-amino
alcohol 6-OTBS (95% ee, S) was treated with slight excess of me-
thyl triflate to give an N-methylpyridinium salt which was subse-
quently reduced using NaBH4 under mild conditions, resulting in
the isolation of the prolinol product 12 (95% ee, S).42 Likewise,
removal of the pyridyl group to isolate the free amine in product
(S)-9 gave the corresponding enantioenriched N-benzyl-1-
phenylethan-1-amine [(S)-13] without erosion of the enantiomeric
purity (98% ee).43
Synthesis of bortezomib. On the basis of the observed broad
substrate scope, we sought to demonstrate the versatility of the
present borylation methodology by the synthesis of the anti-cancer
drug molecule bortezomib,4 an L-boroleucine derivative and the first
therapeutic proteasome inhibitor. Bortezomib consists of three
structural units linked together by peptide bonds: pyrazinoyl, L-
phenylalanyl, and the a-aminoboronic acid unit L-boroleucine (see
Figure 1B). Industrially, bortezomib is prepared through a multi-
step sequence16,44 which suffers from drawbacks connected to the
utilization of protecting groups, process complexity, and stereocon-
trol. Thus, we contemplated the synthesis of bortezomib through a
direct, site- and stereoselective borylation of the N-adjacent C–H
bond of the pro-boroleucine residue of the parent dipeptidic com-
pound (14), which was prepared from N-(pyrazinoyl)-L-
phenylalanine and isopentylamine, both commercially available
(Scheme 2).45
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 synthesis of bortezomib described herein represents an inno-
vative advancement from previously reported methodologies16,44 in
lieu of a straightforward C–H borylation strategy enabling the late-
stage installation of the boryl group, and thus eliminating tedious
synthesis routes and circumventing the laborious manipulations of
sensitive organoboron compounds. In view of this reactivity, we
envisage the potential of the present protocol for the borylation and
functionalization of more complex systems including peptidic sub-
strates and for the diversification of a broad spectrum of pharma-
ceutical compounds and natural products.
Scheme 2. Synthesis of bortezomib
EDC·HCl (1 equiv)
Et3N (3 equiv)
DMAP (2.5 equiv)
N
N
N
O
O
H
N
H
N
H2N
+
N
OH
N
H
DCM (50 mL)
0 ºC to r.t., 18 h
O
O
(3.7 mmol)
(1 equiv)
14, 91%
commercially available starting materials
PhB(OH)2
(3 equiv)
pentane
[Rh(OH)(cod)]2
(Rh:3 mol%)
(S,S)-L* (3 mol%)
N
N
N
H
O
O
O
H
H
H
N
H
OH
N
N
N
H
B
N
B2pin2 (0.30 mmol)
CPME/MeCN
(1:1, 2 mL)
MeOH
1 N HCl (aq)
r.t., 12 h
H
Ph
O
OH
H
15
bortezomib
53%, >98:2 dr
80 °C
14
(0.30 mmol, 1 equiv)
CONCLUSION
Herein, we showed a direct synthesis of enantioenriched a-
aminoboronates from the corresponding achiral N-alkylamine
derivatives through the highly enantioselective Rh-catalyzed
borylation of N-adjacent C(sp3)–H bonds. The reaction protocol
presents multifold synthetic advantages, providing a direct catalytic
route for the preparation of a-aminoboronates and allowing the
preparation of bioactive compounds and chiral a-aminoboronic
acids. The chiral monophosphite ligand enabled the asymmetric
discrimination of N-adjacent enantiotopic C(sp3)–H bonds across
a wide-range of substrate classes under the rhodium catalysis
through catalyst–substrate noncovalent interactions in a well-
defined catalytic pocket, demonstrating the versatility of the
monophosphite ligand, which similarly allowed the borylation of
unactivated methylene C–H bonds under the iridium catalysis.20
We envisage that the exceptional and unparalleled site-and stere-
oselectivities demonstrated in this work will provide opportunities
for the development of synthetically useful transformations that
will have rippling effects in the creation of novel molecules from
simple and readily available starting materials.
To our delight, the reaction of 14 with the modified borylation
protocol using the antipode of the monophosphite ligand [(S,S)-
L*] (3 mol% Rh-L*, 14/B2pin2 1:1, MeCN/CPME 1:1, 80 °C, 36
h) occurred cleanly with the desired site- and stereoselectivities,
furnishing spectroscopically pure bortezomib (15, >98:2 dr) in 53%
yield upon transesterification46 of the pinacol ester with phenyl-
boronic acid (Scheme 2). Remarkably, the reaction required nei-
ther an excessive amount of the substrate 14 nor any additive such
as 2,6-lutidine. Furthermore, the protection or pre-
functionalization of the secondary amide NH groups within the
dipeptide chain was unnecessary while the other N-adjacent
C(sp3)–H bonds present in the phenylalanine residue, which are
more acidic than those in the N-isopentyl group, remained intact.
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(15) Hong, K.; Morken, J. P. Catalytic Enantioselective One-pot Amino-
borylation of Aldehydes: A Strategy for Construction of Nonracemic α-
Amino Boronates. J. Am. Chem. Soc. 2013, 135, 9252–9254.
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
9
(16) (a) Beenen, M. A.; An, C.; Ellman, J. A. Asymmetric Copper-catalyzed
Synthesis of Alpha-amino Boronate Esters from N-tert-Butanesulfinyl
Aldimines. J. Am. Chem. Soc. 2008, 130, 6910–6911. (b) Shibli, A.; Srebnik,
M. Synthesis of Novel α‐Aminoboronate Complexes of Aminoboranes and
Aminocyanoboranes. Eur. J. Inorg. Chem. 2006, 1686–1689. (c) Hu, N.;
Zhao, G.; Zhang, Y.; Liu, X.; Li, G.; Tang, W. Synthesis of Chiral α-Amino
Tertiary Boronic Esters by Enantioselective Hydroboration of α-
Arylenamides. J. Am. Chem. Soc. 2015, 137, 6746–6749. (d) Nishikawa, D.;
Hirano, K.; Miura, M. Asymmetric Synthesis of α-Aminoboronic Acid
Derivatives by Copper-catalyzed Enantioselective Hydroamination. J. Am.
Chem. Soc. 2015, 137, 15620–15623.
Experimental procedures and the characterization of all new com-
pounds are provided in the Supporting Information. The Supporting
Information is available free of charge on the ACS Publications web-
site.
AUTHOR INFORMATION
Corresponding Author
*sawamura@sci.hokudai.ac.jp
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Notes
(17) Selected examples of N-adjacent C(sp3)–H functionalization: (a)
Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Enantioselective amine a-
functionalization via palladium catalysed C–H arylation of thioamides. Nat.
Chem. 2016, 9, 140–144. (b) Pan, S.; Endo, K.; Shibata, T. Ir(I)-Catalyzed
Enantioselective Secondary sp3 C–H Bond Activation of 2-
(Alkylamino)pyridines with Alkenes. Org. Lett. 2011, 13, 4692–4695. (c)
Pan S.; Matsuo, Y.; Endo, K.; Shibata, T. Cationic iridium-catalyzed enan-
tioselective activation of secondary sp3 C–H bond adjacent to nitrogen
atom. Tetrahedron 2012, 68, 9009–9015. (d) Chatani, N.; Asaumi, T.;
Ikeda, T.; Yorimitsu, S.; Ishii, Y.; Kakiuchi, F.; Murai, S. Carbonylation at
sp3 C−H Bonds Adjacent to a Nitrogen Atom in Alkylamines Catalyzed by
Rhodium Complexes. J. Am. Chem. Soc. 2000, 122, 12882–12883. (e)
Querard, P.; Perepichka, I.; Zysman-Colman, E.; Li, C.-J. Copper-catalyzed
asymmetric sp3 C–H arylation of tetrahydroisoquinoline mediated by a
visible light photoredox catalyst. Beilstein J. Org. Chem. 2016, 12, 2636–
2643. (f) Pastine, S. J.; Gribkov, D. V.; Sames, D. sp3 C−H Bond Arylation
Directed by Amidine Protecting Group:ꢀ α-Arylation of Pyrrolidines and
Piperidines. J. Am. Chem. Soc. 2006, 128, 14220–14221.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by JST ACT-C Grant Number
JPMJCR12YN, MEXT KAKENHI Grant Number JP15H05801 in
Precisely Designed Catalysts with Customized Scaffolding, and JSPS
KAKENHI Grant Number JP18H03906 in Grant-in-Aid for Scientific
Research (A) to M.Sawamura. R.L. thanks the Japanese Government
(MEXT) scholarship for the support during his Ph.D. studies.
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B-Rh-L*-ent
Enantiotopic / Diastereotopic
N
N
H
O
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O
H
H
H
O
O
H
H
cat.
Rh-L*
H Bpin
N
N
H
N
N
B2pin2
H
Ph
9
bortezomib
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