Rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides

Article abstract of DOI:10.1021/jacs.9b10578

Chiral α- and β-aminoboronic acids exhibit unique biological activities. General methods for the synthesis of these bioisosteres of amino acids are highly desirable. We report a facile preparation of these compounds through rhodium-catalyzed regiodivergent and enantioselective hydroboration of enamides. Catalytic asymmetric synthesis of α- and β-aminoboronic esters with high regio-, diastereo-, and enantioselectivities were achieved through effective catalyst control and tuning substrate geometry. Starting from easily available materials this strategy provides a unified synthetic access to both enantioenriched α-boration and β-boration products. The synthetic utility of these methods was demonstrated by efficient synthesis of an anticancer drug molecule and diverse transformations of the boration products.

Full text of DOI:10.1021/jacs.9b10578

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Article
Rhodium-Catalyzed Regiodivergent and
Enantioselective Hydroboration of Enamides
Xiao-Yan Bai, Wei Zhao, Xin Sun, and Bi-Jie Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b10578 • Publication Date (Web): 19 Nov 2019
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Journal of the American Chemical Society
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Rhodium-Catalyzed Regiodivergent and Enantioselective
Hydroboration of Enamides
Xiao-Yan Bai‡, Wei Zhao‡, Xin Sun and Bi-Jie Li*
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Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, 100084, China
ABSTRACT: Chiral α- and β-aminoboronic acids exhibit unique biological activities. General methods for the synthesis of these
bioisosteres of amino acids are highly desirable. We report a facile preparation of these compounds through rhodium-catalyzed
regiodivergent and enantioselective hydroboration of enamides. Catalytic asymmetric synthesis of α- and β-aminoboronic esters
with high regio-, diastereo-, and enantioselectivities were achieved through effective catalyst control and tuning substrate geometry.
Starting from easily available materials, this strategy provides a unified synthetic access to both enantioenriched α-boration and β-
boration products. The synthetic utility of these methods was demonstrated by efficient synthesis of an anticancer drug molecule
and diverse transformations of the boration products.
1. Introduction
aminoboronic esters has been developed recently, with
strategies that are vastly different from that for the synthesis of
α-aminoboronic esters.13 To the best of our knowledge, none
of these existing methods provides a unified entry to both
enantioenriched α- and β-aminoboronic esters.6 General
enantioselective methods for the preparation of both α- and β-
aminoboronic esters from easily available starting materials
remain to be developed.
Due to the unique electronic and physicochemical
properties, chiral boron-containing compounds have attracted
increasing attention in pharmaceutical industry for the
development of novel therapeutic agents.1 These compounds
exhibit useful biological activities including antibacterial,
anticancer and antiviral activities.2 In particular, α-
aminoboronic acids, bioisosteres of α-amino acids, display
distinct utility as reversible covalent inhibitors in a diverse
range of therapeutic applications. The successful approval of
boronic acid anti-cancer drugs bortezomib, ixazomib and
vaborbactam demonstrates the potential of α-aminoboronic
acids in drug discovery.3 On the other hand, β-aminoboronic
acids, bioisosteres of β-amino acids, also exhibit substantial
potential in medicinal chemistry.4 For example, β-
aminoboronic acid has been identified as a new class of highly
selective antimicrobial peptidomimetics that exhibits activity
against Mycobacterium tuberculosis.5 Therefore, practical
enantioselective methods to access both α-and β-aminoboronic
acids are highly desirable in medicinal chemistry (Scheme 1).6
Scheme
1.
Aminoboronic
Acids
by
Enamide
Hydroboration
-Aminoboronic acids
Ph
O
OH
Cl
O
OH
H
H
N
B
N
N
N
B
N
OH
Me
N
OH
H
H
O
O
Me
Me
Cl
Me
Bortezomib
Ixazomib
-Aminoboronic acids
O
Me OH
Although a number of methods,7 including Matteson’s
homologation,8 lithiation-borylation9 and borylation of imines
with pinacol diborane,10 have been developed for the synthesis
of enantioenriched α-aminoboronic acids,11 significant
limitations remain to be solved. First, very few catalytic
asymmetric methods are viable for the preparation of α-alkyl
α-aminoboronic esters.10h,11b Second, the asymmetric synthesis
of chiral α-amino tertiary boronic esters is particularly rare.12
Recently, Tang’s group described an efficient synthesis of
chiral α-amino tertiary boronic esters through rhodium-
catalyzed protoboration of enamide.12a Negishi’s group
reported a directed lithiation and enantiospecific borylation for
the preparation of chiral α-amino tertiary boronic esters.12b
Both methods were limited to the generation of α-aryl α-
aminoboronic esters. Third, with few exceptions,11g all these
borylation methods generate α-aminoboronic esters with a
single stereocenter and are not capable for the synthesis of α-
aminoboronic esters containing two adjacent stereocenters. On
the other hand, catalytic asymmetric synthesis of β-
B
H2N
N
OH
H
NH2
antitubercular agent
This Work: Regiodivergent and Enantioselective Hydroboration
Ph
Bpin
Bpin
O
O
Rh(I)
Duanphos
R2
R1
R1
N
N
R2 R3
H
H
R3
O
up to 99% ee
>20:1 dr
up to 99% ee
R1
N
H
+
O
HBPin
Rh(I)
Walphos
Bpin
R1
N
H
R2
up to 82% ee
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Recently, our group reported regio- and enantioselective
strategy provides access to both α- and β-aminoboronic esters
by simply changing the olefin geometry.
Table 1. Optimization of
Hydroboration of Enamidea
1
2
3
4
5
6
7
8
hydroalkynylations of enamides to produce both α-
alkynylation and β-alkynylation products.14 We surmised
whether the enantioselective hydrofunctionalization strategy
could be harness to access aminoboronic esters. Specifically, if
suitable catalysts could be identified for the regio- and
enantioselective hydroboration of enamides, we would be able
to directly prepare both enantioenriched α- and β-
aminoboronic esters from a common set of starting material
(Scheme 1). However, the regiodivergent and enantioselective
hydroboration of enamides faces several challenges. First,
current enantioselective hydroborations15 are mostly limited to
terminal alkenes,16 styrenes,17 and internal alkenes with a
coordinating group.18 Catalytic asymmetric hydroboration of
electron-rich olefins is rare.12a,19 Highly enantioselective
hydroboration of multi-substituted enamides with hydroborane
is unknown.20 In addition, very few catalytic systems have
been developed for the hydroboration of trisubstituted alkenes
to generate two stereocenters21 or a quaternary stereocenter.22
Furthermore, suitable catalysts must be identified for the
catalytic hydroboration with tunable regioselectivity while
maintaining high enantioselectivity.
Rhodium-Catalyzed
Bpin
O
Rh(COD)2OTf (5.0 mol%)
Ligand (6.0 mol%)
HBpin (2 equiv)
Bn
N
tBu
O
H
2a
tBu
N
Bn
O
THF, 50 oC, 12 h
H
Bn
N
tBu
1a
H
Bpin
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3a
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Yield (%) c
Ratio    b
1a
Entry
Ligand
Z
Z
Z
Z
E
1
DPPF
3 : 1
1 : 1
12
2
DtBuPF
DCyPF
DiPrPF
DiPrPF
13
3
36 : 1
18 : 1
1 : 15
53
4d
5d
83 (75)
94 (88)
PPh2
PPh2
PtBu2
PCy2
PiPr2
Fe
Fe
Fe
Fe
PtBu2
PCy2
PiPr2
DPPF
DtBuPF
DCyPF
DiPrPF
Herein, we report the successful implementation of an
unprecedented enamide hydroboration strategy for the
regiodivergent synthesis of α- and β-aminoboronic esters. In
addition, an efficient rhodium catalyst has been identified for
the hydroboration of multi-substituted enamides, generating α-
amino tertiary boronic esters and α-aminoboronic esters
containing two adjacent stereocenters with high regio-,
diastereo- and enantioselectivity. By switching the ligand and
olefin geometry, catalytic hydroboration of enamides provides
enantioenriched β-aminoboronic esters. Finally, efficient
synthesis of an anticancer drug molecule and diverse
transformations of the boration products were further
demonstrated.
a
1a
Reaction conditions:
(1.0 equiv), HBpin (2.0 equiv), Rh(COD)2OTf (5.0
mol%), Ligand (6.0 mol%), 50 oC, 12 h. b Ratios were determined by GC.
Yields were determined by GC using n-dodecane as an internal standard.
Isolated yield in parenthesis. d 3.0 mol% of catalyst.
c
Table 2. Hydroboration of Enamidea
Bpin
2
O
Rh(COD)2OTf (3.0 mol%)
DiPrPF (3.6 mol%)
HBpin (2 equiv)
Bn
N
R
O
H
R
N
Bn
O
THF, 30-50 oC, 12 h
H
Bn
N
R
1
H
Bpin
3
Enamide
O
1-
Boration (from Z)
1
-Boration (from -E)
2. Results and Discussion
O
Bpin
O
2.1.
Reaction
Development
of
Regiodivergent
Bn
N
Me
Me
Bn
N
H
Bn
N
Me
iPr
Ph
H
H
Bpin
Hydroboration. To verify our hypothesis, catalytic
hydroboration of enamide 1a-Z with pinacolborane (HBpin)
was conducted to identify a suitable catalyst (Table 1). The
catalysts formed from Rh(COD)2OTf and a series of
1b
2b
3b
    5 : 1, 73%
    1 : 5, 49%
O
O
Bpin
O
bisphosphine
ligands
were
tested.
When
1,1-
iPr
N
H
Bn
Bn
Bn
N
iPr
Bn
N
H
bis(diphenylphosphino)ferrocene (DPPF) was used as a
ligand, the reaction provided a mixture of α- and β-
aminoboronic esters with low selectivity and low yield (entry
1). Thus, a series of DPPF analogues were further tested. The
substituents on the ferrocene ligand had a significant impact
on the yield and regioselectivity. Similar low yield and low
selectivity were obtained with DtBuPF as a ligand (entry 2).
However, significantly improved selectivity for α-
aminoboronic ester was observed with DCyPF ligand,
although the yield was moderate (entry 3). When DiPrPF was
used as the ligand, α-aminoboronic ester was obtained in both
high yield and high regioselectivity, even at lower catalyst
loading (entry 4). These results indicate that appropriate steric
hindrance of the alkyl substituent on the phosphine atom is
crucial for both the reactivity and the regioselectivity.
H
Bpin
1c
2c
    5 : 1, 66%
3c
    1 : 7, 74%
O
O
Bpin
O
Bn
N
Ph
Ph
N
H
Bn
N
H
H
Bpin
1d
2d
3d
    1 : 1, 24%
   > 20 : 1, 88%
a Isolated yields were reported. See SI for details.
Hydroborations with various enamides showed that the
substituents on the amide had an influence on the yield and
regioselectivity (Table 2). Slightly decreased yields and
regioselectivities were obtained in the hydroboration of the
acetyl and isobutoyl enamides (1b and 1c). The reaction of a
benzoyl substituted Z-enamide afforded the α-boration product
in 88% yield, while the reaction of E-enamide provided the β-
boration product in low yield and low selectivity. Thus, the
Further experiments were conducted to assess the reactivity
of E-enamide 1a-E. To our surprise, the regioselectivity was
completely reversed under the same conditions, favoring β-
boration product (entry 5) (see SI for more details). Thus, this
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pivaloyl amide provided the best results in terms of both effect of the substrate. For example, when a cyclohexylmethyl
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reactivity and selectivity.
substituted substrate was tested, it had little impact on the
reactivity and regioselectivity for the hydroboration (2n, 3n).
However, while the reaction of an iso-propyl substituted Z-
enamide provided high selectivity for α-boration,
hydroboration of E-enamide generated α-boration and β-
boration products in a 1:1 ratio (2o, 3o). These results suggest
that the steric effect of the substrate may also affect the
regioselectivity. Unlike many other catalyst systems,
hydroboration of vinyl enamide did not provide solely anti-
Markovnikov product (2p, 3p). Finally, a free NH group is
important for reactivity, as no desired product was observed in
the reaction with an N-methyl enamide.
2.2. Scope of Regiodivergent Hydroboration. The scope
of the Rh-catalyzed regiodivergent hydroboration of enamides
is further demonstrated in Table 3. The reactions occurred
with a range of alkyl substituted enamides in good yields and
regioselectivity. A series of Z- and E-enamides were
investigated. The α-hydroboration products were selectively
formed from Z-enamides, whereas β-hydroboration products
were selectively formed from E-enamides. Functional groups
including alkyl halide (2h, 3h), ester (2i, 3i), carbamate (2j,
3j), silyl ether (2k, 3k), and acetal (2l-m, 3l-m) were all
compatible with the reaction conditions. A disubstituted
alkene was not tolerated. We further investigated the steric
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Table 3. Scope of Rh-Catalyzed Hydroboration of β-substituted Enamidesa
Bpin
2a
O
Rh(COD)2OTf (3.0 mol%)
R
N
tBu
O
DiPrPF (3.6 mol%)
H
R
HBpin (2 equiv)
tBu
N
O
THF, 30-50 oC, 12 h
H
R
N
tBu
1
H
Bpin
3a
Enamide
O

1

1
Enamide
O

1

1
Boration (from -Z)
-Boration (from -E)
Boration (from -Z)
-Boration (from -E)
Bpin
Bpin
O
O
O
O
Bpin
N
Bpin
N
N
N
N
H
N
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
H
H
H
H
H
Me
Me
Me
1e
2e
3e
1k
2k
3k
OTBS
OTBS
OTBS
    12 : 1, 61%
    1 : 10, 81%
    6 : 1, 81%
    1 : 3, 67%
Bpin
Bpin
O
O
O
O
O
O
Bpin
Bpin
N
N
N
H
N
N
H
N
tBu
tBu
tBu
tBu
H
H
H
H
1f
2f
3f
1l
2l
3l
O
O
OEt
O
OEt
Me
Me
Cl
Me
Me
Cl
O
O
OEt
Me
Me
Cl
    11 : 1, 85%
    1 : 10, 88%
    13 : 1, 60%
    1 : 12, 87%
Bpin
Bpin
O
O
O
O
O
O
Bpin
Bpin
O
N
N
N
H
N
N
H
N
tBu
tBu
tBu
tBu
H
H
H
H
1g
2g
3g
1m
2m
3m
OBn
OBn
Me
Me
OBn
Me
    5 : 1, 81%
    1 : 10, 88%
    15 : 1, 63%
    1 : 9, 70%
Bpin
Bpin
O
O
O
O
O
O
Bpin
Bpin
Cy
N
N
N
H
N
N
H
N
tBu
tBu
tBu
tBu
H
H
H
H
Cy
Cy
1h
2h
3h
1n
2n
3n
    14 : 1, 56%
    1 : 8, 66%
    13 : 1, 80%
    1 : 9, 87%
Bpin
Bpin
O
O
O
O
O
O
Bpin
Bpin
Me
N
N
N
H
N
N
H
Me
N
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
H
H
H
H
O
O
O
O
Me
Me
Me
Me
1i
2i
3i
1o
2o
3o
O
O
Ph
O
Ph
O
O
Ph
    7 : 1, 55%
    1 : 10, 72%
    20 : 1, 87%
    1 : 1, 30%
Bpin
Bpin
O
O
O
O
O
O
Bpin
Bpin
N
N
N
H
N
N
H
N
Me
tBu
tBu
tBu
tBu
H
H
H
H
O
O
1j
2j
3j
1p
2p
3p
NMe2
O
NMe2
NMe2
    1 : 1, 58%
    7 : 1, 66%
    1 : >20, 75%
a Isolated yields were reported. See SI for details.
Next we probed the regioselectivity of the hydroboration of
disubstituted enamides (Table 4). When β,β-disubstituted
enamides were used, α-boration products with two vicinal
stereocenters were obtained exclusively (2q-t). On the other
hand, when α,β-disubstituted enamides were tested, β-boration
products were obtained exclusively (3w-x). In all these cases,
excellent diastereoselectivities were observed. This
stereospecific syn-addition provides support against
a
mechanism involving enamide to imine isomerization
followed by imine hydroboration. It appears that in the
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hydroboration of these disubstituted enamides, the steric effect energy due to steric repulsion (see SI for more details). For all
1
2
3
4
5
6
7
8
of the substrate overrides the regioselectivity directed by the
amide group.
these substrates, the major regioisomer predicted by
computation is in good agreement with the experimental
observations.
Bpin
NHPiv
Et
Table 4. Scope of Rh-Catalyzed Hydroboration of
Disubstituted Enamidesa
NHPiv
Et
Et
Bpin
P
(17.5
)
(18.9
)
Rh
Et
NH
tBu
H
O
R1
H
Pr
Bpin
O
Rh(COD)2OTf (3 mol%)
DiPrPF (3.6 mol%)
O
R1
P
P
O
R2
P
R2
Bpin
R2
Rh
NH
or
Rh
NH
N
tBu
tBu
N
N
tBu
Int-1
(0.0)
P
HBpin (2 eq.)
THF, 30 oC, 24 h
H
O
P
O
Bpin
Int-4b
(10.5)
R3
, R1 = H
H
H
tBu
R3
Bpin
tBu
, R3 = H
3
1
-E
2
Int-4a
(15.4)
9
HBpin
-Borylation

-Borylation

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11
12
13
14
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16
17
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-disubstituted enamide:

Bpin
Bpin
O
O
Bpin
O
Ph
N
N
tBu
Me
tBu
N
tBu
Ph
H
H
H
H
NHPiv
Et
H
Et
NHPiv
H
Me
2s
Me
Me
P
P
Rh
2q
H
Rh
2r
Et
NHPiv
H
H
H
P
P
P
 :  > 20 : 1, 71%
 :  > 20 : 1, 80%
 :  > 20 : 1, 81%
Bpin
Bpin
Rh
TS-4a
H
H
P
TS-3b
(21.8
)
TS-3a
(20.5
)
Bpin
Bpin
O
Bpin
O
Bpin
O
Int-2
(13.4)
Me
N
tBu
N
tBu
N
tBu
Me
5
H
H
H
O
Me
Me
Fig. 1. Reaction pathways for hydroboration.
2v
 :  > 20 : 1, 92%
2u
2t
 :  > 20 : 1, 74%
Analysis of the transition state structures provides insight
into the origin of regioselectivity. One iso-propyl group on the
ligand is in close proximity with the substrate. This repulsive
interaction determines the orientation of the enamide during
migratory insertion. For example, the iso-propyl group has
more repulsion with the alkyl group of the enamide in TS-6a,
TS-7a and TS-8b than that with the hydrogen in TS-6b, TS-
7b and TS-8a. The iso-propyl group experience repulsion with
hydrogen atom in both TS-5a and TS-5b, and consequently
the energy difference between TS-5a and TS-5b is not as
significant as that in TS-6, TS-7 and TS-8. However, this
repulsion is more severe in TS-5b because the hydrogen in
TS-5b is closer to the ligand. These computational results
indicate that the repulsive interaction of the ligand with the
substrate during migratory insertion is crucial for controlling
the regioselectivity of the hydroboration.
 :  > 20 : 1, 91%
-disubstituted enamide:

Me
O
O
Me
O
Me
Me
N
N
N
tBu
Me
tBu
tBu
H
H
H
Bpin
Bpin
3x
Bpin
3w
3y
   > 20 : 1, 79%
   > 20 : 1, 45%
   = 15 : 1, 80%
a Isolated yields were reported. Diastereomeric ratio (dr) >20:1 in all cases. See SI for
details.
The catalytic hydroborations can be conducted at larger
scale. With 1.0 mol% catalyst, the hydroboration of enamides
1f-Z and 1f-E on 1.0 mmol scale proceeded to completion,
affording products 2f and 3f in 90% and 89% yield
respectively (Eq. 1, 2).
O
Rh(COD)2OTf (1.0 mol%)
DiPrPF (1.2 mol%)
Bpin
O
nBu
Computation
Experiment
+
HBpin
N
tBu
(1)
N
tBu
H
THF (0.6 M), 50 oC, 12 h
nBu
H
iPr
P
iPr
H
H
iPr
H
iPr
Rh
NHPiv
Et
Et
NHPiv
1.0 mmol scale
P
Bpin
1f-Z
2f
, 90%
Rh
vs
NHPiv
NHPiv
H
H
H
P
Et
P
Et
Bpin
Bpin
Rh(COD)2OTf (1.0 mol%)
DiPrPF (1.2 mol%)
TS-5a
TS-5b
, 20.5 kcal/mol
, 21.8 kcal/mol
O
O
nBu
nBu
(2)
+
HBpin
iPr
iPr
iPr
N
H
Et
N
H
iPr
tBu
tBu
H
H
THF (0.3 M), r.t, 12 h
Et
NHPiv
H
Et
P
Bpin
P
NHPiv
NHPiv
Bpin
Rh
1.0 mmol scale
vs
Rh
NHPiv
1f-E
3f
, 89%
H
H
P
H
Et
P
Bpin
Bpin
TS-6a
TS-6b
, 26.9 kcal/mol
, 29.6 kcal/mol
Me
2.3. Origin of Regiodivergence. To understand the origin
of the regioselectivity, computational studies were conducted.
The reaction starts with the oxidative addition of
pinacolborane to an enamide bound rhodium complex (Int-1)
to afford a boryl rhodium hydride intermediate (Int-2).
Migratory insertion of the alkene into rhodium hydride
generates a rhodacycle with coordination of the carbonyl
group. Finally, C-B forming reductive elimination delivers the
boration product. The activation free energies of the reaction
profile indicate that migratory insertion (TS-3a vs TS-3b)
determines the regioselectivity (Fig. 1). Accordingly,
transition state structures for the migratory insertion of β-
substituted, β,β-disubstituted and α,β-disubstituted enamides
were extensively computed, and the two transition states with
lowest activation energies for each substrate were shown in
Fig. 2. The stereoisomeric transition state structures with
alkene coordination through the opposite face are higher in
iPr
iPr
iPr
iPr
H
NHPiv
Me
Me
Me
P
P
NHPiv
Me
NHPiv
vs
Rh
Rh
Me
NHPiv
NHPiv
H
H
Me
Me
Me
H
P
P
Bpin
Bpin
Bpin
TS-7a
TS-7b
, 21.4 kcal/mol
, 24.3 kcal/mol
iPr
iPr
iPr
Me
iPr
H
NHPiv
Me
Bpin
P
P
Me
NHPiv
NHPiv
Rh
Rh
vs
Me
H
H
H
P
Me
Me
P
Me
Bpin
Bpin
TS-8a
TS-8b
, 22.4 kcal/mol
, 28.1 kcal/mol
Fig. 2. Computed energies for migratory insertions.
2.4. Enantioenriched α-Aminoboronic Esters. Further
effort was directed towards the development of
enantioselective hydroborations of enamide. In the presence of
Rh(COD)2OTf as a catalyst precursor, a series of chiral
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Journal of the American Chemical Society
ligands were tested in the hydroboration of enamides 1a-Z
Table 6. Scope of Asymmetric Hydroboration of α,β-
Disubstituted Enamidesa
1
2
3
4
5
6
7
8
with pinacolborane (see SI for more details). Eventually,
Duanphos23 was identified as an efficient ligand, promoting
the hydroboration of enamide 1a-Z to afford α-hydroboration
product 4a with high regio- and enantioselectivity (Eq. 3). The
absolute configuration of the product was determined by
comparison of the optical rotation with authentic sample.
Rh(COD)2OTf (3 mol%)
Duanphos (3.6 mol%)
O
Bpin
O
R2
+
HBpin
R1
R1
N
H
N
R2 R3
THF, 50 oC, 24 h
H
R3
4
1-Z
Bpin
Et
O
Bpin
Et
O
Bpin
Bpin
Me
O
O
Rh(COD)2OTf (3.0 mol%)
Duphos (3.6 mol%)
P
tBu
N
H
tBu
N
tBu
H
N
H
4j
N
tBu
tBu
1a-Z
H
(3)
H
H
Bn
HBpin (2 equiv)
Toluene, 50 oC, 24 h
4k
4l
9
CF3
F
P
tBu
4a
72%, 97% ee
88%, 99% ee
88%, 98% ee
Ph
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
 :  > 20 : 1
88%, 98% ee
Bpin
Et
Bpin
Bpin
O
O
O
Et
Et
The scope of the Rh-catalyzed enantioselective
hydroboration of Z-enamides is demonstrated in Table 5.
Enantioenriched α-aminoboronic esters were selectively
formed from Z-enamides. The reactions occurred with a range
of alkyl substituted enamides in good yields and high regio-
and enantioselectivities. Both electron-withdrawing (4a-4b)
and electron-donating (4c-4e) groups on the phenyl ring were
tolerated. Functional group including thiophene, benzyl ether,
acetal and ester were all compatible with the reaction
conditions (4f-4i).
N
H
N
H
N
tBu
tBu
Ph
OMe
H
4m
4n
4o
90%, 97% ee
86%, 97% ee
90%, 98% ee
O
Bpin
Me
O
Bpin
Et
N
N
H
H
Cl
Cl
Me
4p
71%, 91% ee
4q
76%, 98% ee
Table 5. Scope of Asymmetric Hydroboration of 1,2-
a Isolated yields were reported. The ee values were determined by HPLC on a chiral
stationary phase. See SI for details.
Disubstituted Z-Enamidesa
Bpin
O
O
Rh(COD)2OTf (3.0 mol %)
Duanphos (3.6 mol %)
R
+
HBPin
N
N
tBu
tBu
toluene, 50 oC, 24 h
We further tested the asymmetric hydroboration of β,β-
disubstituted enamides (Table 7). Under these conditions, α-
boration products with two adjacent stereocenters were
obtained exclusively. In all these cases, excellent
diastereoselectivities were observed (4r-4ab), owing to the
stereospecificity of the catalytic hydroboration process. The
absolute configuration was determined by X-ray structure of
4s. These results showed that the stereospecific syn-addition
ensures the complete diastereoselectivity and the effective
catalyst control gives rise to the high enantioselectivity.
H
H
R
1
4
Bpin
Bpin
Bpin
O
O
O
N
N
N
tBu
tBu
tBu
H
H
H
4a
79%, 96% ee
4b
4c
68%, 97% ee
80%, 98% ee
F
Cl
Me
Bpin
Bpin
Bpin
O
O
O
N
N
N
tBu
tBu
tBu
H
H
H
S
4d
4e
4f
58%, 97% ee
90%, 98% ee
80%, 93% ee
OMe
SMe
Bpin
Bpin
Bpin
O
O
O
N
N
N
tBu
tBu
tBu
H
H
H
O
4g b
67%, 98% ee
4h b
4i
OBn
O
OBn
O
Ph
45%, 98% ee
71%, 85% ee
a Isolated yields were reported. The ee values were determined by HPLC on a chiral
stationary phase. See SI for details. b 5 mol% Rh catalyst.
Next we probed the asymmetric hydroboration of
disubstituted enamides. When α,β-disubstituted enamides were
tested, α-boration products with a quaternary stereocenter were
obtained exclusively with high enantioselectivity (Table 6).
With this catalyst, the catalyst control overrides the steric
control, which is in contrast with that observed in the racemic
reaction. Several aryl or alkyl substituted enamides were
tolerated in the reaction (4j-4q). The absolute configuration
was determined by X-ray structure of 4q.
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Table 7. Scope of Asymmetric Hydroboration of β,β-
yields and enantioselectivities. Both electron-withdrawing and
Disubstituted Enamidesa
electron-donating groups on the phenyl ring were tolerated
(5a-5e). Functional group including thiophene, benzyl ether,
acetal and ester did not interfere with the catalyst (5f-5i).
Hydroboration of disubstituted enamides did not proceed
under these conditions so far.
1
2
3
4
5
6
7
8
Bpin
O
Rh(COD)2OTf (3 mol%)
Duanphos (3.6 mol%)
O
R2
R2
R1
N
H
+
HBpin
N
R1
THF, 50 oC, 24 h
H
R3
R3
4
1
Bpin
O
Table 8. Scope of Asymmetric Hydroboration of 1,2-
Bpin
O
Disubstituted E-Enamidesa
Me
N
H
tBu
N
tBu
Rh(COD)2OTf (5.0 mol %)
Walphos (6.0 mol %)
H
O
O
Me
Bpin
R
+
HBPin
4r
4s
N
Cl
tBu
9
N
H
toluene, 40 oC, 24 h
tBu
H
R
80%, 95% ee
dr > 20 : 1
73%, 96% ee
dr > 20 : 1
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
1
5
Bpin
Bpin
Bpin
O
O
O
O
O
O
Bn
N
N
tBu
Bn
N
H
Ph
Cl
Ph
Bpin
Bpin
Bpin
H
H
N
N
H
N
tBu
tBu
tBu
Pr
Me
Me
H
H
4t
4v
4u
88%, 92% ee
dr > 20 : 1
88%, 97% ee
dr > 20 : 1
68%, 98% ee
dr > 20 : 1
5a
5b
5c
Bpin
O
 :  = 1 : 13
76%, 76% ee
 :  = 1 : 15
73%, 76% ee
Bpin
O
 :  = 1 : 12
83%, 78% ee
Bpin
O
Me
F
Cl
Me
N
Ph
Et
H
N
Ph
N
Ph
H
H
O
O
O
O
Me
4w
4x
4y
Bpin
Bpin
Bpin
N
N
N
tBu
tBu
tBu
89%, 99% ee
dr = 16 : 1
90%, 99% ee
dr = 16 : 1
90%, >99% ee
H
H
H
Bpin
Bpin
Bpin
O
O
O
S
5d
5e
5f
Me
N
N
H
N
H
Ph
Ph
 :  = 1 : 12
79%, 80% ee
H
 :  = 1 : 9
82%, 78% ee
 :  = 1 : 13
72%, 78% ee
Me
Cl
OMe
Bpin
SMe
4z
90%, >99% ee
4aa
4ab
86%, 99% ee
61%, 91% ee
O
O
O
Bpin
Bpin
a Isolated yields were reported. The ee values were determined by HPLC on a chiral
stationary phase. See SI for details.
tBu
tBu
tBu
N
N
N
H
H
H
O
5g
5h
5i
OBn
O
OBn
O
Ph
 :  = 1 : 12
79%, 80% ee
 :  = 1 : >20
81%, 80% ee
 :  = 1 : >20
89%, 82% ee
The stereospecific syn-addition of the catalytic
hydroboration allows the diastereoselectivity of the product to
be tuned by simply changing the geometry of the enamide.
Indeed, hydroboration of Z-enamide 1r-Z generated the other
diastereomer of 4t (Eq. 4). Therefore, all four possible
stereoisomers of 4t could be obtained through the
hydroboration process by switching the olefin geometry and
the ligand configuration.
a Isolated yields were reported. The ee values were determined by HPLC on a chiral
stationary phase. See SI for details.
2.6. Synthetic Application. To demonstrate the
practicability of these methods, asymmetric synthesis of
Bortezomib was conducted (Scheme 2). Hydroboration of
enamide 6, obtained through Cu-catalyzed C-N coupling, gave
the hydroboration product 7 with high diastereoselectivity.
Bpin
O
O
Rh(COD)2OTf (3 mol%)
Duanphos (3.6 mol%)
Me
Bn
Me
Bn
(4)
N
H
tBu
tBu
N
H
HBpin
+
THF, 50 oC, 24 h
4t'
Following the literature method,10a compound
transformed to Bortezomib through sequence of
deprotection, amidation and hydrolysis. This method provided
a straightforward synthesis of the drug molecule from easily
available starting materials.
7 was
85%, 96% ee
dr > 20 : 1
1r
-Z
a
2.5. Enantioenriched β-Aminoboronic Esters. With a
method for enantioselective α-hydroboration established, we
Scheme 2. Synthesis of Bortezomib.
sought to identify
a catalyst for enantioselective β-
Ph Me
Me
Ph
CuI
DMEDA
hydroboration. For the hydroboration of E-enamide 1a-E,
Walphos was found to be the best ligand so far, delivering the
β-hydroboration product in good regio- and enantioselectivity
(Eq. 5).
Me
Me
H
N
+
NH2
BocHN
BocHN
I
Cs2CO3
O
O
Rh(I) (5 mol%)
6
, 78%
Duanphos (6 mol%)
HBpin (2.5 equiv)
O
P(xyl)2
Rh(COD)2OTf (5.0 mol%)
Walphos (6.0 mol%)
Bpin
P(xyl)2
N
tBu
(5)
1a-E
H
Fe
HBpin (2 equiv)
Toluene, 40 oC, 24 h
Ph
1. HCl (4 M)
2. (2-Pyrazine)CO2H
Ph
H
N
5a
O
H
Ph
N
Bpin
Me
Me
B(OH)2
Me
N
N
 :  = 1 : 15
TBTU, iPr2NEt
BocHN
N
H
O
78%, 76% ee
3. iBuB(OH)2, HCl (1 M)
O
Bortezomib
7
Me
A series of β-substituted E-enamides were tested under
these conditions (Table 8). The enantioenriched β-
hydroboration products were selectively formed. The reactions
occurred with a range of alkyl substituted enamides in good
61%, dr = 16 : 1
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Journal of the American Chemical Society
In addition, the β-boronic ester provided a useful handle for
ACKNOWLEDGMENT
various further functionalizations (Scheme 3).24 For example,
Treatment of 3f with KHF2 provided the corresponding
potassium trifluoroborate salt 8 in 83% yield. Oxidation,
alkenylation and heteroarylation of 3f generated β-hydroxyl
amide 9, homoallylic amide 10 and β-aryl amide 11,
respectively.25,26 Additionally, β-boronic ester 3y underwent
Suzuki coupling to deliver the arylation product 12 in two
steps with 62% yield.27
1
2
3
4
5
6
7
8
This work was supported by the National Natural Science
Foundation of China (Grant No. 21971139 and No. 91856107)
and 111 Project (B16028).
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Peptidomimetics – A Novel Class of Selective Anti-tubercular Drugs.
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Gao, F.; Bhadury, P. S.; Fan, E.; Sun, Z. Metal free catalytic
Scheme 3. Synthetic Transformation of β-Aminoboronic
Esters.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
a
b
BF3K
OH
nBu
N
N
H
tBu
tBu
tBu
H
nBu
, 83%
O
8
9
, 88%
Bpin
nBu
N
tBu
H
O
O
O
3f
c
d
S
N
H
N
H
tBu
tBu
nBu
, 86%
nBu
, 42%
10
11
Me
O
Me
a, e
Bpin
N
H
N
H
tBu
3y
12
, 62%
Reaction conditions: (a) KHF2, MeOH/H2O, r.t. (b) NaBO3.4H2O, THF/H2O, r.t.
(c) (i) Vinylmagnesium bromide, THF, -78 oC, (ii) I2, MeOH, -78 oC to 0 oC. (d)
(i) Thiophene, nBuLi, THF, -78 oC, (ii) NBS, THF, -78 oC to r.t. (e) PhBr,
Pd(OAc)2, Ad2PnBu, Cs2CO3, toluene/H2O, 100 oC.
3. Conclusion
In summary, we have developed a rhodium-catalyzed
regiodivergent and stereoselective hydroboration of enamides.
The regioselectivity of the hydroboration could be tuned by
simply changing the olefin geometry. Computational studies
revealed the origin of this unusual selectivity. In addition, we
have achieved enantioselective hydroborations of enamides to
access both α- and β-aminoboronic esters. Particularly, chiral
α-amino tertiary boronic esters and α-aminoboronic esters
containing two adjacent stereocenters have been synthesized
with high regio- and enantioselectivities, which would be
otherwise challenging to prepare. Furthermore, our methods
enabled the efficient synthesis of a drug molecule with short
synthetic steps. The boration products underwent diverse
transformations to afford valuable building blocks. Further
mechanistic studies are currently ongoing in our laboratory.
ASSOCIATED CONTENT
Supporting
Information.
Experimental
procedures,
characterization of new compounds and spectroscopic data are
provided in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bijieli@mail.tsinghua.edu.cn
Notes
The authors declare no competing financial interests.
Author Contributions
‡These authors contributed equally.
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up to 99% ee
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Bpin
R1
HBPin
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