Diastereo- and Enantioselective Synthesis of β-Aminoboronate Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1-Bis[(pinacolato)boryl]alkanes to Imines

Article abstract of DOI:10.1002/anie.201705829

Reported herein is an efficient copper(I)-catalytic system for the diastereo- and enantioselective 1,2-addition of 1,1-bis[(pinacolato)boryl]alkanes to protected imines to afford synthetically valuable enantioenriched β-aminoboron compounds bearing contiguous stereogenic centers. The reaction exhibits a broad scope with respect to protected imines and 1,1-bis[(pinacolato)boryl]alkanes, thus providing β-aminoboronate esters with excellent diastereo- and enantioselectivity. The synthetic utility of the obtained β-aminoboronate ester was also demonstrated.

Full text of DOI:10.1002/anie.201705829

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Diastereo- and Enantioselective Synthesis of β-Aminoboronate
Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1-
Bis[(pinacolato)boryl]alkanes to Imines
Authors: Jeongho Kim, Kwangwook Ko, and Seung Hwan Cho
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201705829
Angew. Chem. 10.1002/ange.201705829
Link to VoR: http://dx.doi.org/10.1002/anie.201705829
http://dx.doi.org/10.1002/ange.201705829

10.1002/anie.201705829
Angewandte Chemie International Edition
COMMUNICATION
Diastereo- and Enantioselective Synthesis of β-Aminoboronate
Esters by Copper(I)-Catalyzed 1,2-Addition of 1,1-
Bis[(pinacolato)boryl]alkanes to Imines
Jeongho Kim, Kwangwook Ko, and Seung Hwan Cho*[a]
This work is dedicated to professor Jaiwook Park on the occasion of his 60th birthday
Abstract: We report an efficient Cu(I)-catalytic system for the
diastereo- and enantioselective 1,2-addition of 1,1-
stereoselective coupling of 1,1-bis[(pinacolato)boryl]alkanes with
suitable electrophiles. In particular, we described a copper-
catalyzed diastereoselective 1,2-addition of diborylmethane to N-
tert-butanesulfinyl imines, providing access to enantiomerically
enriched β-aminoboronate esters with high efficiency (Scheme
1b).[8c] Although this protocol constitutes an efficient approach to
prepare enantioenriched β-aminoboronate esters, the reaction
required the use of a stoichiometric amount of a chiral auxiliary
and displayed limited scope of 1,1-bis[(pinacolato)boryl]alkanes.
Therefore, we decided to investigate a more broadly applicable
chiral catalytic system for the 1,2-addition of imines with 1,1-
bis[(pinacolato)boryl]alkanes to protected imines to afford
synthetically valuable enantioenriched β-aminoboron compounds
bearing contiguous stereogenic centers. The reaction exhibits a broad
scope
with
respect
to
protected
imines
and
1,1-
bis[(pinacolato)boryl]alkanes, providing β-aminoboronate esters with
excellent diastereo- and enantioselectivity. The synthetic utility of the
obtained β-aminoboronate ester was also demonstrated.
Chiral organoborons are an important class of synthetic
intermediates that can undergo a range of carbon-carbon and
carbon-heteroatom bond-forming reactions via stereospecific
couplings.[1] The synthesis of such compounds containing a
nitrogen functionality at the β-position of the chiral boron unit is of
significant importance in synthetic chemistry because they serve
as versatile building blocks in many biologically active
compounds.[2] Consequently, several synthetic methods have
been developed to afford chiral β-aminoborons (Scheme 1a). A
typical approach for the synthesis of a chiral β-aminoboron
involves a one-carbon homologation reaction of chiral β-
aminoborons with LiCH2Cl.[3] However, this method requires
harsh reaction conditions and shows limited substrate scope. In
this context, several elegant catalytic enatioselective methods
have emerged for the preparation of chiral β-aminoborons under
mild conditions. For examples, Miura[4] and others[5] described a
diastereo- and enantioselective inter- or intramolecular copper-
catalyzed 1,2-aminoboration of unactivated alkenes employing
bis(pinacolato)diboron and hydroxylamines as coupling partners.
bis[(pinacolato)boryl]alkanes. Herein, we report
a
highly
diastereo- and enantioselective synthesis of β-aminoboronate
esters by the copper-catalyzed 1,2-addition reaction of 1,1-
bis[(pinacolato)boryl]alkanes to N-protected imines (Scheme 1c).
Moreover, we demonstrate that the obtained β-aminoboronate
ester serve as a useful synthetic intermediate, which can undergo
oxidations and C-C bond formations to generate synthetically
valuable compounds with two vicinal stereocenters.
At the outset of our study, we initially focused on the reaction
of 1,1-bis[(pinacolato)boryl]ethane (2a) and cyclic aldimine 1a,
which has been reported to be an effective substrate for transition-
metal-catalyzed 1,2-addition reactions with organoboron
compounds,[12] in the presence of CuBr (5 mol %), an (R)-BINOL
-
a
rev ous a roac es or e s n es s o enan omer ca enr c e
am no orons
P
i
pp
h
f
th y th
i
f
ti
i
lly
i h d
i
b
β
)
u
R2
C
/L
[
]
R2
,
n
N
R
B2pi
O
2
NH
LiCH2Cl
R3
R4
-
R1
R1
Bpi
-
ne car on
n
o
,
b
am no ora on
ti
1 2
i
b
omo o a on
h
l
g
ti
R2
R3
N
*
R4
Lin and co-workers demonstrated
a
copper-catalyzed
*
R1
hydroboration of N-protected dehydroamino esters to afford β-
boron-α-amino acids with excellent enantioselectivity and low
n
Bpi
u
C
n
/L
[
]
R4
e
,
,
PGHN
B2pi
M OH
n
Pd /L B pi
2
s
NT
[
]
2
2
diastereoselectivity.[6]
A palladium-catalyzed borylated ring-
ro ora on
ti
r n o en n
hyd
b
i
g
p
i
g
Ph
-
e
M O2C
opening reaction of chiral 2-arylaziridines was also documented.[7]
Despite these advances, the development of a new approach
from readily accessible imines remains elusive but is highly
desirable.
-
-
a
"
"
,
u s ra e con ro e
on o
s
naco a o or me ane o su
n
m nes
i
b
S b t
t
t
ll d 1 2 dditi
f bi pi
[(
l t
b
)
yl
]
th
t
N
lfi yl i
)
u
u
tB
tB
u
C
[
]
S
S
ac ra
os ne
hi l ph phi
+
n
Bpi
n
pi B
N
HN
O
O
,
LiOtB 50 o
C
u
n
Bpi
Recently, our group[8] and others[9-11] reported chemo- and
r
A
r
A
H
-
,
x ens ve c ra aux ar s nee e
m e sco e o
Li it d
f 1 1 bi pi
[(
s
naco a o or
a
anes
b yl lk
)
E p
i
hi
l
ili y i
d d
p
l t
]
-
-
-
s
"
"
,
,
s wor :
n r
n
r
n
m n
c
a a
s
co o e
a
o
n
o
aco a o
o
b
)
a
a es o es
Thi
k
t ly t
t
ll d 1 2 dditi
f 1 1 bi pi
[(
l t
yl lk
]
t
i i
C
)
u
PG
R
PG
C
[
]
R
HN
r
N
c
ra
os ne
hi l ph phi
+
-
,
50 o
C
u r
t
J. Kim, K. Ko, and Prof. Dr. S. H. Cho
Department of Chemistry
Pohang University of Science and Technology (POSTECH),
Pohang, 37673, Rep. of Korea
n
Bpi
n
pi B
LiOtB
r
A
A
H
n
Bpi
-
xce en as ereo
ll t di
u
o >
:
an enan ose ec
v
u
o
ee
E
t
p t 20 1
d
ti ti ity p t 99
l
%
(
)
(
)
roa su s ra e sco
e
b t p
n
Sy
e
c u
B
d
t
th ti tility
E-mail: seunghwan@postech.ac.kr
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Strategies for the synthesis of enantioenriched β-aminoborons.
This article is protected by copyright. All rights reserved.

10.1002/anie.201705829
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Evaluation of reaction conditions[a]
Table 2. Scope of cyclic aldimines and 1,1-bis[(pinacolato)boryl]alkanes[a]-[d]
2
R2
R
e
M
Me
n
n
n
Bpi
n
pi B
pinB
Bpin
pi B
pinB
Bpi
Bpin
a
2
2
2
.
2a
.
O
O
O
O
u
C
r
mo
0
l
%
u
r
mo
mo
B
1
5
O
O
O
C B 5 0
l %
CuBr (5.0 mol %)
O
O
O
(
)
O
CuBr (5.0 mol %)
O
O
(
)
)
)
O
O
O
O
O
O
O
S
S
mo
l
%
)
H O
N HCO
NaHCO33
an
L
H O
N HCO
NaHCO33
S
S
10
H2O22
S
S
lig
d
10
l
H2O22
%
L1 (10 mol %)
NH
NH
S
S
S
S
(
O
O
ligand (10 mol %)
a2
e u v
(
a 2
.
.
N
N
NH
NH
O
O
O
O
N
N
NH
NH
O
O
O
O
u
u
e u v
LiOtB 2 0 q i
LiOtBu (2.0 equiv)
LiOtB 2 0 q i
LiOtBu (2.0 equiv)
2
(
)
R2
(
l
R
e
M
e
-
,
M
Me
Me
so ven
x
o ane o uene
t
1
1 4 di
/t l
THF
THF
THF
THF
H
H
R1
solvent
H
H
1,4-dioxane/toluene
1
R
R1
,
,
,
,
r
R
r
r
r
O
H
OH
t 24 h
rt, 24 h
t 3 h
rt, 3 h
t 24 h
rt, 24 h
t 3 h
rt, 3 h
n
Bpi
OH
OH
Bpin
a
a
a
4
4a
1
3
1
1
4
4
1a
3a
r
A
a co e o c c c a m nes
S
p f y li ldi
i
)
r
Ar
A
Ar
e
e
O
O
O
O
O
O
O
O
M
e
M
Me
O
O
Me
,
,
=
=
=
=
e
NM
NEt
L1
L1
O
O
R
R
R
R
S
S
S
, R = NMe22
O
P N
O
P N
NH
NH
NH
O
O
O
S
L2
L2
, R = NEt22
e
M
NH
O
O
O
M
Me
O
P
P
R
R
Me
O
r
e
e
e
M
M
M
,
,
L3
L3
L4
L4
N
N M
H
H
C
)
2 2
2 2
B
C
O
, R = N(CH CH ) O
e
(
2
M
e2
n
A
r
Ar
-
O
O
A
Ar
r
, R = N(Me)Bn
(
)
H
OH
H
O
O
,
=
e
L5
L5
A
4
M
(
H
C
)
6
6
OH
, Ar = 4-(Me)C H
4
4
e
M
e
M
O
F
,
,
,
,
4d
a
c
4
4b
7
4
98%
. .
9 %
93%
89%
. .
. .
. .
,
,
,
,
r
>
:
r
ee
:
r
ee
:
r
ee
:
15 1 d 98
%
ee
20 1 d 99
18 1 d 98
15 1 d 98
%
%
%
Yield of
Entry
L
Solvent
dr[c]
ee [%][d]
4a [%][b]
O
O
O
O
O
O
O
O
S
S
NH
NH
O
O
S
S
NH
NH
O
O
e
e
M
M
1
2
3
4
5
6
7
L1
L1
L1
L2
L3
L4
L5
dioxane
THF
94
93
14:1
98
99
e
e
M
M
H
H
O
O
H
OH
O
11:1
e
M
l
C
r
B
l
C
98(98)[e]
87
>20:1
>20:1
>20:1
>20:1
n.d.
99
,
,
,
7
20 1 d 96
,
4h
17 1 d 97
dioxane/toluene (1:1)
dioxane/toluene (1:1)
dioxane/toluene (1:1)
dioxane/toluene (1:1)
dioxane/toluene (1:1)
e
4
4f
7
4g
83%
. .
8 %
9 %
. .
69%
. .
. .
,
,
,
,
>
:
r
ee
:
r
ee
:
r
ee
:
r
ee
11 1 d 99
10 1 d 97
%
%
%
%
98
O
O
O
O
O
O
O
O
S
S
NH
O
NH
O
S
S
NH
NH
O
O
95
99
e
e
M
M
e
e
M
e
M
M
O
H
O
OH
94
98
H
H
O
O
O
O
<1
n.d.
-
a e
[ ]
,
,
,
,
4k 7
en
4i
4
j
4
86%
. .
64%
1%
t
98%
. .
. .
,
r
,
,
. .
,
r
:
r
ee
:
r
ee
:
9 1 d 95
%
ee
[a] Reaction conditions: 1 (0.20 mmol), 2a (1.5 equiv), CuBr (5.0 mol %), ligand
(10 mol %), base (2.0 equiv) in solvent (0.4 mL) at rt for 24 h and then NaHCO3
and H2O2 in THF at rt for 3 h. [b] The yield was determined by 1H NMR analysis
[c] Diastereomeric ratio was determined by 1H-NMR analysis of the crude
mixture. [d] Enantiomeric excess (% ee) was determined by HPLC analysis. [e]
Isolated yield is given in parentheses. n.d. = not determined
15 1 d 98
18 1 d 98
%
%
>
:
ee
20 1 d 99
%
-
,
f
[ ]
co e o
b S f 1 1 bi pi
[(
s
naco a o or
l t
a anes
yl lk
]
p
b
)
)
O
O
O
O
O
O
S
S
S
NH
NH
O
O
NH
O
e
M
TB
S
O
Ph
H
H
O
O
H
O
-derived phosphoramidite ligand (L1, 10 mol %) and LiOtBu as a
base in dioxane at room temperature. We found that a 14:1
diastereomeric mixture of β-amino alcohol 4a was obtained in
94% yield with 98% ee (Table 1, entry 1) after oxidation of the
Bpin unit of 3a in the presence of H2O2 and NaHCO3. Switching
the solvent from 1,4-dioxane to THF provided 4a with a slightly
lower diastereoselectivity (93% yield, 11:1 d.r., 99% ee, entry 2).
We were pleased to observe that the use of an equal mixture of
1,4- dioxane and toluene as a solvent gave the desired product4a
in 97% yield with >20:1 d.r. and 99% ee (entry 3), whereas the
reaction in toluene led to no additional product formation.[13] Chiral
phosphoramidite ligands with varying amino groups (L2-L4) were
also effective (entries 4-6) in this transformation, furnishing 4a
with excellent diastereo- and enantioselectivities. The reaction of
1a with 2a in the presence of CuBr with a taddol-derived
phosphoramidite ligand (L5) did not provide the desired product
(entry 7). Because chiral ligand L1 is commercially available, we
chose CuBr and L1 as our standard catalytic system. The
absolute and relative configurations of product 3a were assigned
as (S, R), as determined by single-crystal X-ray analysis.
,
,
n
81%
,
m
4
4
69 %
. .
4l 77
20 1 d 99
%
. .
,
,
. .
,
>
>
2
0
:
r
ee
:
r
ee
93%
>
:
r
ee
2
1 d
1 d
0
99%
%
O
O
O
O
O
O
S
S
S
NH
O
O
NH
O
e
M
NH
O
O
e
M
H
O
H
O
H
,
O
,
,
o
4
4p
4q
7
42
83
%
6
%
%
ee
%
. .
. .
. .
,
r
,
,
>
>
>
:
r
ee
:
r
ee
:
20 1 d 93
20 1 d 98
20 1 d 99
%
%
[a] Reaction conditions: 1 (0.20 mmol), 2 (1.5 equiv), CuBr (5.0 mol %), L1 (10
mol %), base (2.0 equiv) in 1,4-dioxane/toluene (0.4 mL, 1:1) at rt for 24 h and
then NaHCO3 and H2O2 in THF at rt for 3 h. [b] Diastereomeric ratio was
determined by 1H-NMR analysis of the crude mixture. [c] Enantiomeric excess
(% ee) was determined by HPLC analysis. [d] Isolated yields are given. [e] ent-
L1 was used as a ligand instead of L1. [f] Experiments were performed at 50 °
C in the presence of 2 equivalents of 2.
substituents on the arene ring (4b, 4c and 4g) underwent the 1,2-
addition reactions in excellent yields with high diastereoselectivity
(>20:1-15:1 d.r.) and enantioselectivity (>96% ee). The reactions
of cyclic aldimines bearing halides, such as fluoro (4d), chloro (4e
and 4h) and bromo (4f) groups, remained intact in this reaction,
and the corresponding β-amino alcohols were formed in good
with high diastereo- (>10:1) and
enantioselectivity (>97% ee). The cyclic aldimine containing
substituent at the 8-position was also a suitable electrophile,
Having identified an efficient catalytic system for the copper-
catalyzed diastereo- and enantioselective 1,2-addition reaction of
1a with 2a, we investigated the scope of cyclic aldimines with 2a
(Table 2). Cyclic aldimines containing electron-donating
yields (69-89%)
This article is protected by copyright. All rights reserved.

10.1002/anie.201705829
Angewandte Chemie International Edition
COMMUNICATION
Next, we studied the feasibility of the 1,2-addition reaction with
other N-protected imine electrophiles (Table 3). Although no
reactions took place when N-phosphinoyl- or N-Boc-protected
imines were used as substrates, the reaction of an N-tosyl-
protected imine (5a) catalyzed by CuBr/L3 in THF at room
temperature gave the corresponding 1,2-amino alcohol in 92%
yield (Table 3, entry 1) with moderate levels of diastereoselectivity
(3.2:1 d.r.), forming syn-6a as the major isomer.[13],[14] In this case,
syn-6a was highly enantioenriched (94% ee), while anti-6a was
formed in moderate ee (67% ee). The reactions with other 1,1-
bis[(pinacolato)boryl]alkanes 2 also provided the corresponding
products 6b (entry 2) and 6c (entry 3) at 50 oC in good to
moderate yields with increase of diastereo- and enantioselectivity.
Interestingly, the enantiomeric exess of anti-6b and anti-6c
products was higher than that of anti-6a, indicating that the chain
length of the substituent (R2) of 2 has an effect on the
enantiselectivity of 1,2-addition process. The reactions of N-tosyl-
protected imines bearing electron-donating (entry 4) or electron-
withdrawing (entry 5) substituents at the 4-position on the arene
ring with 2a also furnished the products 6d and 6e at room
temperature in good yields with moderate diastereoselectivity and
good enantioselectivity.
Table 3. Scope of N-Ts imines and 1,1-bis[(pinacolato)boryl]alkanes[a]
2
R2
R
n
n
Bpi
Bpin
pi B
pinB
2
2
.
u
r
mo
l %
C B 5 0
CuBr (5.0 mol %)
(
10
)
s
s
NHT
NHTs
NHT
NHTs
s
mo
l
H O
N HCO
NaHCO33
T
L3
L3
%
H2O22
Ts
(10 mol %)
(
)
a 2
R2
R
+
.
N
N
2
2
R2
u
e u v
LiOtB 2 0 q i
R
LiOtBu (2.0 equiv)
(
)
+
1
1
R1
R1
R
THF
THF
rt, 24 h
THF
THF
R
H
H
OH
OH
1
O
H
OH
R1
,
,
r
r
R
t 24 h
t 3 h
rt, 3 h
-
-
an
ti
6
6
s n
5
5
6
6
y
syn-
anti-
Yield
[%][b]
Entry
R1
R2
dr[c]
Product
ee [%][d]
1
H
Me
92
67
53
72
65
3.2:1
3.5:1
4.9:1
3.6:1
3.2:1
6a
6b
6c
6d
6e
94(67)
98(91)
98(94)
96(76)
96(77)
2[e]
3[e]
4
H
n-Pr
(CH2)2Ph
Me
H
4-Me
4-Cl
5
Me
[a] Reaction conditions: 5 (0.20 mmol), 2 (1.5 equiv), CuBr (5.0 mol %), L3 (10
mol %), LiOtBu (2.0 equiv) in THF (1.0 mL) at rt for 24 h and then NaHCO3 and
H2O2 in THF at rt for 3 h. [b] Combined isolated yields of the two diastereomers
are given. [c] Diastereomeric ratio was determined by 1H-NMR analysis of the
crude mixture. [d] Enantiomeric excess was determined by HPLC analysis.
Values in parenthesis indicated the enantiomeric excess of anti-isomer [e]
Experiments were performed at 50 °C in the presence of 2.0 equivalents of 2.
+
a
a
2
1
.
mmo
l
s an ar
t
d d
con ons
diti
5 0
sca e
l
O
O
providing 4i in 86% yield with 15:1 d.r. and 98% ee. Protected
catechol- and naphthyl-containing cyclic aldimines also
underwent the 1,2-addition process, giving 4j and 4k in
moderateto good yields with good diastereo- and
enantioselectivity (18:1 and 9:1 d.r. and 98% ee and 95% ee,
respectively). Finally, the opposite enantiomer of 4a was obtained
in 98% yield with >20:1 d.r. and 99% ee when the reaction was
conducted with the (S)-BINOL-derived phosphoramidite ligand
(ent-L1).
S
oc
M
H
NHB
O
NH
O
e
e
M
n
,
a
b
H
O
Bpi
,
,
a
3
8
68
90
%
%
. .
,
-
>
:
r
ee
a er recr s a za on
20 1 d 98
ft
>
y t lli ti
%
a
ra
o
f 3
(
)
X
y
[
]
. .
,
:
r
ee
20 1 d 99
%
, ,
,
c
e a
d
d g
O
O
e
M
S
O
O
N
O
The standard 1,2-addition reaction conditions were then applied
to the reaction of a range of 1,1-bis[(pinacolato)boryl]alkanes with
oc
e
M
NHB
S
e
N
O
M
O
e
M
e
M
1a.
However,
when
1a
was
reacted
(2b), the
with
1,1-
desired
O
bis[(pinacolato)boryl]propylbenzene
H
O
,
,
,
9
10 5
8
%
11 7
9%
:
20 1 d 99
89
enantioenriched β-aminoboronate ester 4l was formed only in
23% yield. Further examination of the reaction temperature
revealed that the
reaction performed at 50 ° C provided 4l in 77% yield with
excellent diastereo- (>20:1) and enantioselectivity (>99% ee).
Under this slightly modified conditions, various 1,1-
bis[(pinacolato)boryl]alkanes underwent the reaction with 1a to
generate addition products in good yields with high
stereoselectivity. For example, the reaction of 1a with 1,1-
bis[(pinacolato)boryl]butane (3c) afforded the product 4m in 69%
%
. .
. .
. .
,
r
,
,
>
>
>
:
r
ee
:
r
ee
ee
%
20 1 d 98
20 1 d 98
%
%
Scheme 2. Reaction conditions: [a] H2O2, NaHCO3, THF, rt for 3 h. [b] LiAlH4,
THF, 60 oC for 2 h and then Boc2O at rt for 1 h. [c] DEAD, PPh3, CH2Cl2, 0 oC
to rt, 10 h. [d] MeI, K2CO3, CH3CN, rt, 12 h. [e] ClCH2I, n-BuLi, THF, -78 oC for
4 h. [g] furan, n-BuLi, NBS, THF, -78 oC for 5 h.
The reaction of 1a with 2a can be scaled up (5.0 mmol) with
good efficiency, producing the enantiopure β-aminoboronate
ester 3a in 90% yield (>20:1 d.r., 99% ee) after recrystallization
from a mixture of n-hexane and diethyl ether at -20 °C. We
demonstrated the utility of the obtained product 3a as illustrated
in Scheme 2. After the oxidation of the Bpin unit of 3a with H2O2,
a desulfonylation reaction was achieved upon treatment with
LiAlH4 followed by Boc protection of the amino group, furnishing
2-(1-amino-2-hydroxypropyl)phenol 8 in 68% yield (2 steps; >20:1
d.r., 98% ee).[15] Treatment of 8 with diethyl azodicarboxylate
(DEAD) and PPh3 at 0 oC to room temperature gave the
corresponding 3-amino-2-methylcoumaran derivative 9 in 89%
yield (>20:1 d.r., 98% ee).[16] The product 3a was also utilized for
yield with >20:1 d.r. and 99% ee. Additionally,
a 1,1-
bis[(pinacolato)boryl]alkane-containing TBS-protected alcohol
and masked aldehyde underwent the 1,2-addition process,
forming 4n and 4o in good yields with high stereoselectivity (>20:1
d.r., 93% ee). Finally, the 1,1-bis[(pinacolato)boryl]alkanes
possessing an alkene moiety reacted with 1a in 83% and 67%
yields (4p and 4q) with excellent diastereo- (>20:1 d.r.) and
enantioselectivity (>98% ee). Note that the enantioenriched β-
amino boronate esters 3 obtained in this study could be isolated
by recrystallization.[13]
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10.1002/anie.201705829
Angewandte Chemie International Edition
COMMUNICATION
carbon-carbon bond forming reactions. After protection of the
(NRF) funded by the Ministry of Science, ICT & Future Planning
(NRF-2015R1C1A1A02036326). We thank Dr. Sarah Y. Lee (UC
Berkeley) and Prof. Jun Hee Lee (Dongguk University) for helpful
discussions.
amine moiety of 3a with methyl iodide,
a one-carbon
homologation with LiCH2Cl and oxidation gave the corresponding
γ-amino alcohol 10 in moderate yield (58% in 2 steps; >20:1 d.r.,
98% ee). Moreover, when the reaction of 4a with 2-lithiated furan
was conducted under the reaction conditions reported by
Aggarwal,[17] the arylated product 11 was obtained in 76% yield
with preservation of the optical purity.
Keywords: copper • imines • enantioselective • chiral β-
aminoboronate esters • 1,1-bis[(pinacolato)boryl]alkanes
Scheme 3 represents our proposed reaction pathway for the
developed transformation. First, an anion exchange between
CuBr ligated by the chiral phosphoramidite ligand and LiOtBu
affords the copper species A. Based on the literature
precedents,[10a,d,e] the formation of chiral α-boryl-alkyl-copper
[1]
[2]
a) D. S. Matteson, Stereodirected Synthesis with Organoboranes;
Springer: New York, 1995; b) C. M. Crudden, D. Edwards, Eur. J. Org.
Chem. 2003, 2003, 4695; c) R. Jana, T. P. Pathak, M. S. Sigman, Chem.
Rev. 2011, 111, 1417; d) H. K. Scott, V. K. Aggarwal, Chem. Eur. J. 2011,
17, 13124; e) D. Leonori, V. K. Aggarwal, Acc. Chem. Res. 2014, 47,
3174; f) D. S. Matteson, J. Org. Chem. 2013, 78, 10009.
species
B is expected to occur by an enantioselective
a) A. S. Gorovoy, O. Gozhina, J.-S. Svendsen, G. V. Tetz, A. Domorad,
V. V. Tetz, T. Lejon, J. Pept. Sci. 2013, 19, 613; b) A. S. Gorovoy, O. V.
Gozhina, J. S. Svendsen, A. A. Domorad, G. V. Tetz, V. V. Tetz, T. Lejon,
Chem. Biol. Drug. Des. 2013, 81, 408.
transmetalation of 1,1-bis[(pinacolato)boryl]alkane with A. A
subsequent nucleophilic addition of the chiral copper species B to
cyclic aldimines 1 forms C. Finally, a transmetalation between C
and LiOtBu regenerates the active copper species A with
concomitant generation of the product D and the hydrolysis of D
by workup converts D to 3. The observed high levels of
diastereoselectivity in this study is presumably determined by the
facial selectivity in the addition of copper species B to cyclic
aldimine 1.
[3]
[4]
C. Sole, H. Gulyas, E. Fernandez, Chem. Commun. 2012, 48, 3769.
a) N. Matsuda, K. Hirano, T. Satoh, M. Miura, J. Am. Chem. Soc. 2013,
135, 4934; b) R. Sakae, N. Matsuda, K. Hirano, T. Satoh, M. Miura, Org.
Lett. 2014, 16, 1228; c) R. Sakae, K. Hirano, M. Miura, J. Am. Chem.
Soc. 2015, 137, 6460; d) R. Sakae, K. Hirano, T. Satoh, M. Miura, Angew.
Chem. 2015, 127, 623; Angew. Chem. Int. Ed. 2015, 54, 613; e) D.
Nishikawa, K. Hirano, M. Miura, M. Org. Lett. 2016, 18, 4856.
a) A. Parra, L. Amenós, M. Guisán-Ceinos, A. López, J. L. García Ruano,
M. Tortosa, J. Am. Chem. Soc. 2014, 136, 15833; b) C.-H. Yang, Y.-S.
Zhang, W.-W. Fan, G.-Q. Liu, Y.-M. Li, Angew. Chem. 2015, 127, 623;
Angew. Chem. Int. Ed. 2015, 54, 12636; c) H.-C. Jiang, X.-Y. Tang, M.
Shi, Chem. Commun. 2016, 52, 5273.
O
O
O
O
[5]
*
r
/
Li tB
LiOtBu
u
B L
C
CuBr/L*
Li
Li
S
S
N
N
O
O
u
O
2
R2
R
H
O
H22O
1
r
LiB
R1
3
3
LiBr
R
n
Bpi
Bpin
2
R2
R
*
D
D
u
C
)
u
L
OtB
(L*)Cu OtBu
(
[6]
[7]
[8]
Z.-T. He, Y.-S. Zhao, P. Tian, C.-C. Wang, H.-Q. Dong, G.-Q. Lin, Org.
Lett. 2014, 16, 1426.
n
pi B
pinB
n
Bpi
Bpin
A
A
2
2
Y. Takeda, A. Kuroda, W. M. C. Sameera, K. Morokuma, S. Minakata,
Chem. Sci. 2016, 7, 6141.
u
Li tB
O
LiOtBu
a) W. Jo, J. Kim, S. Choi, S. H. Cho, Angew. Chem. 2016, 128, 9842;
Angew. Chem. Int. Ed. 2016, 55, 9690; b) J. Kim, S. Park, J. Park, S. H.
Cho, Angew. Chem. 2016, 128, 1520; Angew. Chem. Int. Ed. 2016, 55,
1498; c) J. Park, Y. Lee, J. Kim, S. H. Cho, Org. Lett. 2016, 18, 1210; d)
Y. Lee, S.-YBaek, J. Park, S.-T. Kim, S. Tussupbayev, J. Kim, M.-H Baik,
S. H. Cho, J. Am. Chem. Soc. 2017, 139, 976; e) J. Kim, S. H. Cho,
Synlett 2016, 27, 2525.
O
O
O
O
*
u
L
C
( )
S
S
Cu(L*)
*
2
L
R2
u
C
)
N
N
O
O
(L*)Cu
R
(
2
R2
R
n
Bpi
Bpin
1
R1
R
n
Bpi
Bpin
B
B
C
C
1
1
[9]
a) J. C. H. Lee, R. McDonald, D. G. Hall, Nat. Chem. 2011, 3, 894; b) X.
Feng, H. Jeon, J. Yun, Angew. Chem. 2013, 125, 4081; Angew. Chem.
Int. Ed. 2013, 52, 3989; c) J. C. H. Lee, H.-Y. Sun, D. G. Hall, J. Org.
Chem. 2015, 80, 7134.
Scheme 3. Proposed catalytic cycle.
In summary, we have developed a copper-catalyzed, highly
diastereo- and enantioselective 1,2-addition of 1,1-
[10] Examples
for
enantioselective
couplings
of
1,1-
bis[(pinacolato)boryl]alkanes, see: a) C. Sun, B. Potter, J. P. Morken, J.
Am. Chem. Soc. 2014, 136, 6534; b) J. R. Coombs, L. Zhang, J. P.
Morken, J. Am. Chem. Soc. 2014, 136, 16140; c) B. Potter, A. A.
Szymaniak, E. K. Edelstein, J. P. Morken, J. Am. Chem. Soc. 2014, 136,
17918; d) M. V. Joannou, B. S. Moyer, S. J. Meek, J. Am. Chem. Soc.
2015, 137, 6176; e) S. A. Murray, J. C. Green, S. B. Tailor, S. J. Meek,
Angew. Chem. 2016, 128, 9211; Angew. Chem. Int. Ed. 2016, 55, 9065;
f) Y. Shi, A. H. Hoveyda, Angew. Chem. 2016, 128, 3516; Angew. Chem.
Int. Ed. 2016, 55, 3455; g) M. Zhan, R.-Z Li, Z.-D. Mou, C.-G. Cao, J. Liu,
Y.-W. Chen, D. Niu, ACS Cat. 2016, 6, 3381.
bis[(pinacolato)boryl]alkanes to N-protected imines. With
CuBr/chiral phosphoramidite as a catalyst and LiOtBu as a base,
the 1,2-addition reactions proceed to generate a broad range of
β-aminoboronate esters with contiguous stereocenteres in high
yields. The products are highly synthetically useful, as
demonstrated by further functionalizations of the Bpin unit to form
new C-O or C-C bonds upon C-B bond cleavage. Efforts to
expand the scope of the diastereo- and enantiostereoselective
1,2-addition employing 1,1-bis[(pinacolato)boryl]alkanes are
currently underway in our laboratory.
[11] Examples
for
non-enantioselective
couplings
of
1,1-
bis[(pinacolato)boryl]alkanes, see: a) K. Endo, T. Ohkubo, M. Hirokami,
T. Shibata, J. Am. Chem. Soc. 2010, 132, 11033; b) K. Endo, T. Ohkubo,
T. Shibata, Org. Lett. 2011, 13, 3368; c) K. Endo, T. Ohkubo, T. Ishioka,
T. Shibata, J. Org. Chem. 2012, 77, 4826; d) K. Hong, X. Liu, J. P.
Morken, J. P. J. Am. Chem. Soc. 2014, 136, 10581; e) H. Li, Z. Zhang,
X. Shangguan, S. Huang, J. Chen, Y. Zhang, J. Wang, Angew. Chem.
2014, 126, 12115; Angew. Chem. Int. Ed. 2014, 53, 11921; f) M. V.
Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
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10.1002/anie.201705829
Angewandte Chemie International Edition
COMMUNICATION
Joannou, B. S. Moyer, M. J. Goldfogel, S. J. Meek, Angew. Chem. 2015,
127, 14347; Angew. Chem. Int. Ed. 2015, 54, 14141; g) A. Ebrahim-
Alkhalil, Z.-Q. Zhang, T.-J. Gong, W. Su, X.-Y.Lu, B. Xiao,; Y. Fu, Chem.
Commun. 2016, 52, 4891; h) Z.-Q. Zhang, B. Zhang, X. Lu, J.-H. Liu, X.-
Y. Lu, B. Xiao, Y. Fu, Org. Lett. 2016, 18, 952; i) W. N. Palmer, C. Zarate,
P. Chirik, J. J. Am. Chem. Soc. 2017, 139, 2589; j) W. Lu, T. Zhang, W.
Sun, Z. He, C. Xia, Y. Lan, C. Liu, J. Am. Chem. Soc. 2017, 139, 5257.
[12] Selected examples for enantioselective couplings of cyclic aldimines with
organoboron compounds, see: a) Y. Luo, A. J. Carnell, H. W. Lam,
Angew. Chem. 2012, 124, 6866; Angew. Chem. Int. Ed. 2012, 51, 6762;
b) Y. Luo, H. B. Hepburn, N. Chotsaeng, H. W. Lam, Angew. Chem. 2012,
124, 8434; Angew. Chem. Int. Ed. 2012, 51, 8309; c) H. Wang, T. Jiang,
M.-H. Xu, J. Am. Chem. Soc. 2013, 135, 971; d) H. B. Hepburn, H. W.
Lam, Angew. Chem. 2014, 126, 11789; Angew. Chem. Int. Ed. 2014, 53,
11605; e) C. Jiang, Y. Lu, T. Hayashi, Angew. Chem. 2014, 126, 10094;
Angew. Chem. Int. Ed. 2014, 53, 9936; f) T. Jiang, Z. Wang, M.-H. Xu,
Org. Lett. 2015, 17, 528; g) Y. Huang, R.-Z. Huang, Y. Zhao, J. Am.
Chem. Soc. 2016, 138, 6571; h) J. I. Martínez, J. J. Smith, H. B. Hepburn,
H. W. Lam, Angew. Chem. 2016, 128, 1120; Angew. Chem. Int. Ed. 2016,
55, 1108.
[13] See the Supporting Information for details.
[14] The absolute and relative configuration of the major and minor
stereoisomers of 6a was assigned by comparison of their HPLC with that
of authentic samples. We assigned the absolute and relative
stereochemistry of 6b-6e by analogy. See the Supporting Information for
details.
[15] Y.-Q. Wang, C.-B. Yu, D.-W. Wang, X.-B. Wang, Y.-G. Zhou, Org. Lett.
2008, 10, 2071.
[16] F. Bertolini, P. Crotti, V. Di Bussolo, F. Macchia, M. Pineschi, J. Org.
Chem. 2007, 72, 7761.
[17] A. Bonet, M. Odachowski, D. Leonori, S. Essafi, V. K. Aggarwal, Nat.
Chem. 2014, 6, 584.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
P
G
.
ca
Li tB
LiOtBu
J. Kim, K. Ko, and S. H. Cho*
PG
*
r
u
,
u
P
G
PG
t C B /L
cat. CuBr/L*
HN
HN
R
R
N
N
O
+
R
R
+
r
,
A
n
Bpi
Bpin
n
pi B
pinB
Ar
Page No. – Page No.
o uene oxane r
t l
di
toluene/dioxane, rt, 24 h
r
t 24 h
/
A
H
H
Ar
n
Bpi
Bpin
Diastereo- and Enantioselective
Synthesis of β-Aminoboronates by
Cu(I)-Catalyzed 1,2-Addition of 1,1-
bis[(pinacolato)boryl]alkanes to
Imines**
-
>
xce en as ereo
ll t di
u
o
:
an enan ose ec v
u
o
ee
E
t
p t 20 1
d
ti ti ity p t 99
l
%
Excellent diastereo- (up to >20:1) and enantioselectivity (up to 99% ee)
(
)
(
)
roa su s ra e sco e
b t
Broad substrate scope
n
e c u
th ti tility
B
d
t
p
Sy
Synthetic utility
We report an efficient Cu(I)-catalytic system for the diastereo- and enantioselective
1,2-addition of 1,1-bis[(pinacolato)boryl]alkanes to protected imines to afford
synthetically valuable enantioenriched β-aminoboron compounds bearing contiguous
stereogenic centers.
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