Catalytic Asymmetric Conjugate Addition of a Borylalkyl Copper Complex for Chiral Organoboronate Synthesis

Article abstract of DOI:10.1002/anie.201909712

We report the catalytic enantioselective conjugate addition of a borylalkyl copper nucleophile generated in situ from a 1,1-diborylmethane derivative to α,β-unsaturated diesters. In the presence of a chiral N-heterocyclic carbene (NHC)–copper catalyst, this method facilitated the enantioselective incorporation of a CH₂Bpin moiety at the β-position of the diesters to yield β-chiral alkyl boronates in up to 86 % yield with high enantioselectivity. The alkylboron moiety in the resulting chiral diester products was converted into various functional groups by organic transformation of the C?B bond.

Full text of DOI:10.1002/anie.201909712

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201909712
German Edition: DOI: 10.1002/ange.201909712
Asymmetric Catalysis
Catalytic Asymmetric Conjugate Addition of a Borylalkyl Copper
Complex for Chiral Organoboronate Synthesis
Won Jun Jang and Jaesook Yun*
Abstract: We report the catalytic enantioselective conjugate
addition of a borylalkyl copper nucleophile generated in situ
from a 1,1-diborylmethane derivative to a,b-unsaturated die-
sters. In the presence of a chiral N-heterocyclic carbene
(
NHC)–copper catalyst, this method facilitated the enantiose-
lective incorporation of a CH Bpin moiety at the b-position of
2
the diesters to yield b-chiral alkyl boronates in up to 86% yield
with high enantioselectivity. The alkylboron moiety in the
resulting chiral diester products was converted into various
functional groups by organic transformation of the CÀB bond.
T
he catalytic asymmetric conjugate addition of organome-
tallic reagents to a,b-unsaturated compounds is one of the key
methods for CÀC bond formation with the efficient con-
[
1]
struction of new carbon stereogenic centers. In the past
decades, air-sensitive nonstabilized organometallic nucleo-
philes, such as Grignard reagents, organozinc reagents,
[
2]
[3]
[
4]
[5]
organoaluminum reagents, and organozirconium reagents,
have been used. However, the use of stoichiometric amounts
of these reagents and difficulties in handling them generally
limited their synthetic efficiency. Organoboron compounds
have drawn attention as alternative reagents owing to their
excellent functional-group tolerance, nontoxicity, stability,
and easy handling. Nevertheless, their limited use in asym-
metric conjugate addition may be attributed to their lower
reactivity than that of the aforementioned organometallic
reagents. Asymmetric conjugate addition using aryl and
alkenyl boronic acid derivatives has been extensively devel-
oped with precious transition metals, such as rhodium and
Scheme 1. Conjugate addition with organoboron reagents and reac-
tions of 1,1-diborylalkanes.
1,1-Diborylalkanes, which contain two boryl groups at the
3
same sp -carbon atom, are attractive reagents for stereose-
lective CÀC coupling reactions with diverse electrophiles
owing to the retention of a single boryl moiety even after
[
11,12]
catalytic activation of one of the CÀB bonds.
Since the
[
6,7]
palladium catalysts.
conjugate addition has been reported using sp -carbon-
Copper-catalyzed enantioselective
Shibata group first reported the use of 1,1-diborylalkanes in
2
[13]
palladium-catalyzed chemoselective Suzuki coupling,
[8a,b]
[8c]
based nucleophiles, including aryl-,
alkenyl-, and alle-
a number of advances with transition-metal catalysts were
reported (Scheme 1A,b): enantioselective Suzuki coupling
[
8d]
nylboron reagents (Scheme 1A,a). In comparison, the use
of alkylboron reagents in asymmetric conjugate addition is
extremely rare, with one known report by the Sawamura
group involving the copper-catalyzed enantioselective con-
jugate addition of alkyl-9-BBN, prepared from alkenes and 9-
borabicyclo[3.3.1]nonane (9-BBN-H), to unusual imidazolyl
[
14]
reactions with aryl and vinyl halides, SN2’-selective allylic
[15]
substitution with allylic electrophiles, SN2 substitution with
[
16]
propagylic electrophiles, and diastereo- and enantioselec-
[
17a]
[17b]
tive 1,2-addition to aldehydes,
nes.
a-ketoesters,
and imi-
[
17c]
However, conjugate addition using 1,1-diborylalkanes
3
3
a,b-unsaturated ketones for C(sp )ÀC(sp ) bond formation
is unknown and remains unexplored.
[9,10]
(
Scheme 1A,a).
However, this method yielded products
We envisioned that copper-catalyzed enantioselective
conjugate addition of a 1,1-diborylmethane derivative to
a,b-unsaturated carbonyl compounds would provide versatile
products carrying a borylmethyl group at the b-position
with nonfunctional alkyl groups, which limited further trans-
formation of the resulting products.
(
Scheme 1B). The resulting chiral alkylboron compounds
[
*] W. J. Jang, Prof. J. Yun
Department of Chemistry, Sungkyunkwan University
Suwon 16419 (Korea)
could be utilized for further stereospecific organic trans-
formations.
[
18]
To assess the feasibility of the envisioned reaction design,
we started our investigation with commercially available
diethyl benzylidenemalonate (1a) and bis[(pinacolato)boryl]-
methane (2) in the presence of copper chloride with a chiral
E-mail: jaesook@skku.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201909712.
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phosphoramidite ligand, as such ligands have proven efficient
in copper-catalyzed 1,2-addition reactions with 1,1-diborylal-
kanes. Under the reaction conditions, the desired product
was obtained in 97% yield, but a racemic product was
obtained (Table 1, entry 1). The chiral bisphosphine ligand
catalyst and that higher temperatures might be necessary
for an efficient reaction (entry 6). When the temperature was
increased to 608C, the product was obtained in increased
yield without significantly affecting the enantiomeric ratio
(entry 7). We further examined the reaction with various
chiral NHC ligands. Changing the R substituent on the alkyl
tether of the NHC ligand from tert-butyl to phenyl (L5) or
indanol (L6) resulted in lower yields and enantioselectivities
[
17]
[
a]
Table 1: Optimization of the reaction conditions.
(entries 8 and 9). NHC ligand L7 containing a 2,6-isopropyl-
phenyl group was less efficient than L4, resulting in 49% yield
and an enantiomeric ratio of 54:46 (entry 10). Therefore, the
conditions using L4 ligand (entry 7) were selected as optimal
[21]
for the addition reaction. The optimized conditions were
[
b]
[c]
Entry
Ligand [L]
Cu/L ratio
T [8C]
Yield [%]
e.r.
then applied to various a,b-unsaturated acceptors
[22]
1
2
3
4
5
6
7
8
9
L1
L2
–
L3
L4
L4
L4
L5
L6
L7
1:1
1:1
–
1:1
1:1
1:2
1:2
1:2
1:2
1:2
RT
RT
RT
RT
RT
RT
60
60
60
60
97
95
91
95
74
41
86
26
73
49
50:50
50:50
–
50:50
69:31
93:7
(Table 2). A monoester was unreactive, and other diester
and dinitrile compounds exhibited decreased enantioselec-
tivity as compared to diethyl diester compounds (entries 2–4).
[
a]
Table 2: Screening of a,b-unsaturated compounds.
94:6
86:14
53:47
54:46
1
0
[a] General reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), CuCl
(
0.025 mmol), ligand (0.025 mmol), LiOtBu (1 mmol), THF (1 mL),
1
2
[b]
[c]
Entry
Substrate (Z , Z )
Yield [%]
e.r.
–
room temperature; see the Supporting Information for details. [b] Yield
of the isolated product. [c] The enantiomeric ratio was determined by
HPLC analysis.
1
2
3
4
CO Et, H
0
84
58
77
2
CO Me, CO Me
84:16
87:13
54:46
2
2
CO tBu, CO tBu
2
2
CN, CN
[a] General reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), CuCl
(0.025 mmol), ligand (0.05 mmol), LiOtBu(1 mmol), THF (1 mL), room
temperature. [b] Yield of the isolated product. [c] The enantiomeric ratio
was determined by HPLC analysis.
Next, various a,b-unsaturated diethyl diesters 1 with
[
23]
different b-substituents were examined (Table 3).
The
conjugate addition resulted in the corresponding b-chiral
alkylboronate compounds in good yields with high enantio-
selectivity. Reactions of b-aryl-substituted diesters containing
a halogen or an electron-withdrawing or electron-donating
group yielded the desired products 3b–f and 3h. For the less
electrophilic diester 1g containing a strongly electron donat-
ing p-methoxyphenyl group, decreased yield and enantiose-
lectivity were observed (product 3g). Diesters containing
meta- and ortho-substituted aryl groups and heteroaryl groups
were also tolerated under the optimal reaction conditions
(products 3i–n). Besides aryl substituents, diesters with
primary and secondary alkyl substituents provided enantio-
merically enriched organoboronates 3o and 3p in good yields
(
R,R)-methyl-Duphos (L2) also resulted in a good yield but
with 0% ee (entry 2). We suspected a possible background
reaction for the low ee values and found that a severe
background reaction even occurred in the absence of
a ligand (entry 3). This extremely facile background reaction
inhibited asymmetric conversion in the addition reaction;
therefore, N-heterocyclic carbene (NHC) ligands, which
coordinately tightly to copper, were considered as good
[
19]
ligand candidates.
We examined the reactions using copper catalysts with
chiral NHC ligands L3 and L4 (Table 1, entries 4 and 5), and
with high enantiomeric ratios. We determined the site
[20]
[24]
found that L4 bearing a hydroxy coordinating substituent
yielded promising results with a moderate enantiomeric ratio
69:31). When the molar ratio of copper to ligand was
selectivity (1,4- vs. 1,6-addition)
of the addition with
a,b,g,d-unsaturated dienoates 1q and 1r. Both reactions
afforded only the 1,4-addition product 3q or 3r in good yield
with high enantioselectivity without 1,6-addition. Finally,
when the reaction was carried out on a larger scale
(3 mmol), reduced amounts of catalyst and ligand resulted
in the desired product 3a without reduction in yield or
enantioselectivity.
(
changed to 1:2 to minimize the presence of ligand-free copper
catalyst, the yield of the desired product decreased to 41%,
but the enantiomeric ratio was greatly improved (entry 6).
The results indicated the decreased reactivity of the L4–
copper complex as compared to the ligand-free copper
2
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Table 3: Copper-catalyzed asymmetric conjugate addition of bis[(pina-
colato)boryl]methane to a,b-unsaturated diesters.
We explored the diastereoselectivity of the catalyst with
enantiomerically pure a,b-unsaturated diesters 1s and 1s’
Scheme 2). In contrast to the formation of 3s from 1s in good
[
a]
(
yield with excellent diastereoselectivity, the reaction of 1s’
resulted only in the substrate-controlled product 3s’, the
Scheme 2. Conjugate addition to chiral a,b-unsaturated diesters.
enantiomer of 3s, in very low yield. The current chiral
borylalkyl copper species preferentially approaches the Re
face of the b-carbon atom of a,b-unsaturated esters; however,
steric hindrance between the copper catalyst and the OTBS
group of the mismatched substrate 1s’ completely inhibited
[
25]
the synthesis of the other diastereomer.
To demonstrate the synthetic applicability of the resulting
chiral alkylboron products, we carried out several organic
transformations (Scheme 3). Chiral g-lactone 4 was obtained
by intramolecular transesterification of 3a through oxidation
[
26a]
and decarboxylation.
Stereospecific functionalization of
[
26b]
the CÀB bond to give a CÀC bond by metal-free vinylation
[
26c]
and heteroarylation
yielded 5 and 6 without deterioration
of enantioselectivity. The Bpin group of 3a was tolerated
[a] Yields are for the isolated product from reactions on a 0.5 mmol scale.
The enantiomeric ratio was determined by HPLC analysis. [b] The
reaction was carried out with 2.5 mol% of the copper catalyst and
3
.75 mol% of the ligand on a 3 mmol scale. [c] The reaction was carried
out with 1.5 equivalents of LiOtBu.
Scheme 3. Transformation of chiral organoboron compounds.
Bn=benzyl, DMSO=dimethyl sulfoxide, NBS=N-bromosuccinimide.
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[
26e]
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[27]
In summary, we have described the copper-catalyzed
enantioselective conjugate addition of a 1,1-diborylmethane
to a,b-unsaturated diesters. Severe background reactions
were suppressed by using a chiral N-heterocyclic-carbene–
copper catalyst, and the reaction provided a new class of
enantiomerically enriched alkylboronates in good yields with
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Conflict of interest
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The authors declare no conflict of interest.
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Keywords: asymmetric catalysis · boron · conjugate addition ·
copper · diborylmethane
Chem. Lett. 2011, 40, 928.
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[
[
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[
[
[
[
[
21] See Table S1 in the Supporting Information for more screening
results.
22] See Tables S1 and S2 in the Supporting Information for more
screening results.
Manuscript received: August 1, 2019
Accepted manuscript online: September 3, 2019
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
W. J. Jang, J. Yun*
&&&& — &&&&
Catalytic Asymmetric Conjugate Addition
of a Borylalkyl Copper Complex for Chiral
Organoboronate Synthesis
Neat as a new Bpin: Asymmetric catalytic
conjugate addition of a borylalkyl copper
nucleophile generated in situ from a 1,1-
diborylmethane to a,b-unsaturated di-
esters enabled the enantioselective
incorporation of a CH Bpin moiety at the
2
b-position of the diesters. The resulting b-
chiral alkylboronates were obtained in up
to 86% yield with high enantioselectivity
(see scheme).
6
www.angewandte.org
ꢀ 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!