Copper-Catalyzed Asymmetric Reduction of β,β-Disubstituted Alkenylboramides

Article abstract of DOI:10.1021/acs.orglett.9b03400

A highly enantioselective copper-catalyzed reduction of β,β-disubstituted alkenylboron compounds was developed using hydrosilane. The copper hydride catalyst coordinated with chiral Josiphos ligand efficiently discriminated β-geminal substituents to generate corresponding β-chiral alkylboramides with excellent enantioselectivities up to 99% ee. The enantioselective reduction protocol provides a facile approach to β-chiral alkylboron compounds with less sterically discriminating substituents and spans a wide substrate range including aryl-substituted borylalkenes with effective functional group tolerance.

Full text of DOI:10.1021/acs.orglett.9b03400

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Asymmetric Reduction of β,β-Disubstituted
Alkenylboramides
Yeji Park and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 16419, Korea
*
S Supporting Information
ABSTRACT: A highly enantioselective copper-catalyzed reduction of β,β-
disubstituted alkenylboron compounds was developed using hydrosilane. The
copper hydride catalyst coordinated with chiral Josiphos ligand efficiently
discriminated β-geminal substituents to generate corresponding β-chiral
alkylboramides with excellent enantioselectivities up to 99% ee. The
enantioselective reduction protocol provides a facile approach to β-chiral
alkylboron compounds with less sterically discriminating substituents and spans a wide substrate range including aryl-
substituted borylalkenes with effective functional group tolerance.
hiral organoboron compounds represent an important
Recently, our group reported a copper-catalyzed enantiose-
lective hydroboration of nonfunctionalized 1,1-alkenes without
coordinating and directing groups, yielding β-chiral organo-
C
class of synthetic precursors due to their versatility in
1
organic synthesis. Therefore, the development of enantiose-
lective catalytic strategies for these compounds is desirable
with advances in stereospecific transformation of C−B bonds
7
boron compounds with high enantioselectivity. The method-
ology successfully enabled enantiodiscrimination between
geminal alkyl substituents for the synthesis of β-chiral
organoboronates (Scheme 1, b). However, the discrimination
between methyl and primary alkyl groups at the geminal
carbon was a challenge due to moderate enantioselectivity
2
into other functionalities. While asymmetric hydroboration of
alkenes is the most widely used approach to chiral organo-
3
boron compounds, asymmetric hydrogenation of prochiral
alkenylboron precursors is an attractive alternative to over-
come possible regioselectivity issues and the limited substrate
scope involved in hydroboration. Enantioselective hydro-
genations of alkenylboron compounds (Scheme 1, a) have
(
64% ee). Furthermore, transition-metal-catalyzed carbobora-
8
tions of alkenes can provide facile access to β-branched
organoboron compounds; however, only a single report of
8d
enantioselective methylboration of alkene is available to date
(Scheme 1, c) with moderate enantioselectivity (76−78% ee)
for aliphatic olefins. Moreover, the hydrogenation protocols
did not resolve such challenges. Therefore, a new synthetic
approach for the development of enantioenriched β-chiral
organoboron compounds containing sterically less discriminat-
ing alkyl groups at the geminal carbon is desirable and remains
unexplored.
4
5
6
been developed using Rh, Ir, and Ni catalysts since the first
reported Rh-catalyzed hydrogenation of vinyl-bis(boronates)
4a
by the Morken group. However, the use of high hydrogen
pressure often limits their efficient application in organic
synthesis.
Scheme 1. Synthesis of β-Chiral Organoboron Compounds
Alkenylboron compounds containing a 1,8-naphthalenedia-
minatoboryl (Bdan) group previously served as regioselective
substrates in our investigation of copper-catalyzed asymmetric
9
hydroboration for the synthesis of 1,1-diborylalkanes despite
10
the low Lewis acidity of the Bdan group. We envisioned that
11
successful enantioselective CuH reduction of such substrates
provides β-chiral organoboron compounds, which are other-
wise difficult to obtain. Herein, we report copper-catalyzed
enantioselective synthesis of β-chiral organoboron compounds
via asymmetric reduction of β,β-disubstituted alkenylbora-
mides using hydrosilane as the stoichiometric reductant under
mild reaction conditions.
We initiated our investigation using (E)-alkenylboramide
containing β-methyl and phenethyl substituents (1a) as a
Received: September 25, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03400
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
model substrate in the presence of copper(II) acetate,
hydrosilane, tert-butyl alcohol, and a chiral bisphosphine
ligand under various reaction conditions (Table 1). Instead
the substrate scope of the reaction (Scheme 2). A variety of
β,β-disubstituted alkenylboramides were examined to obtain
a
Scheme 2. Scope of CuH-Catalyzed Asymmetric Reduction
Table 1. Optimization of Reaction Conditions
a
b
entry
ligand (L)
silane
% conv
ee (%)
c
1
2
3
4
5
6
7
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
DEMS
23
38
31
32
54
92
94
92
95
91
92
92
94
93
DEMS
DEMS
DEMS
DEMS
TMDSO
d
>99 (95)
80
>99 (89)
81
39
>99 (90)
e
f
d
d
PMHS
g
8
9
DEMS
DEMS
DEMS
h
i
1
0
a
1
Conversion of 1a was determined by H NMR analysis using DMF
b
as an internal standard. ee was determined by chiral HPLC analysis.
c
d
Methyldiethoxysilane ((EtO) MeSiH). Isolated yields of 2a are
2
e
f
indicated in parentheses. 1,1,3,3-Tetramethyldisiloxane. Poly-
g
h
(
methylhydrosiloxane). Et O was used as solvent. THF was used
2
i
as solvent. 60 °C.
of alkenyl boramides, reduction of alkenyl pinacol boronates
resulted in low conversion or formation of deborylated alkene
products and could not be used efficiently under current
1
2
conditions. Among the chiral bisphosphine ligands screened
Figure 1), the use of chiral Josiphos ligand (L5) resulted in
(
a
Reactions were conducted using 0.30 mmol of alkene (1) in toluene
b
(
0.2 M) at 60 °C for 12 h unless otherwise stated. Room
c
Figure 1. Structures of the chiral ligands screened.
temperature was used for 1b and 1c. Determined by HPLC analysis
d
of the corresponding hydroxyl compound after oxidation. Using 4
equiv of (EtO) MeSiH and 24 h. Using 4 equiv of (EtO) MeSiH and
e
2
2
1
3
high reactivity and enantioselectivity yielding 2a using
methydiethoxysilane (DEMS) as the reducing reagent. Other
ligands did not facilitate the effective conversion of the starting
material, although good enantioselectivities were observed
36 h.
the corresponding β-chiral alkylboramides with high degrees of
13
enantioselectivity. Alkenylboramides (1b−1i) carrying meth-
yl and primary alkyl groups at the β-carbon were efficiently
reduced to yield products with excellent enantioselectivities
(92−99% ee), and various functional groups including chloro,
nitrile, ether, amine, and ester groups were tolerated. Reactions
using substrates (1j and 1k) with secondary alkyl groups
yielded products with good yield and high enantioselectivity.
Substrates (1l and 1m) carrying a TMS substituent showed
excellent enantioselectivity in the reduction; however, in
general, substrates with a bulky group such as tert-butyl led
(
entries 1−5). Dimeric hydrosilane (TMDSO) and polymeric
hydrosilane (PMHS) were less effective in asymmetric
reduction, resulting in slightly lower product yields and ee
values (entries 6 and 7). Changing the solvent from toluene to
ethereal solvents such as diethyl ether or tetrahydrofuran did
not improve the yield or enantioselectivity (entries 8 and 9),
and when the reaction temperature was increased, the
enantioselectivity was slightly decreased as expected (entry
1
0).
After establishing the optimized conditions for the
enantioselective reduction of alkenyl boramides, we explored
14
to partial conversion. Surprisingly, the substrate (1n) with
primary alkyl groups at the β-carbon was appropriate for
B
DOI: 10.1021/acs.orglett.9b03400
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
enantiodiscrimination, but a slightly decreased ee value (90%
ee) was observed. The Josiphos−copper catalyst was also
efficient for aryl- and methyl-substituted alkenylboramides
Scheme 4. Proposed Catalytic Cycle
(1o−1s), resulting in the corresponding products in good yield
with moderate to good enantioselectivities (83−91% ee).
Overall, the current catalytic system is sensitive to steric
hindrance of the β-carbon reaction center and most efficient in
discriminating methyl and primary alkyl groups, encompassing
substrates with alkyl and aryl substituents.
The gram-scale reaction was successfully conducted with a
reduced amount of catalyst and ligand to afford 2a in 89% yield
without decrease in enantioselectivity, although a longer
reaction time was required for complete conversion (Scheme
3
, a). The Bdan group of enantioenriched 2b was directly
Scheme 3. Gram-Scale Synthesis and Organic
Transformations of Chiral Dialkyl Boron 2b
can even be used for aryl-substituted alkenylboramides. The
resulting chiral products were further transformed to other
organic functionalities, demonstrating their utility in organic
synthesis.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03400.
Experimental procedures, characterization data, and
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: jaesook@skku.edu.
ORCID
Jaesook Yun: 0000-0003-4380-7878
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was supported by National Research Foundation
o f K o r e a g r a n t s ( 2 0 1 9 R 1 A 2 C 2 0 0 5 7 0 6 a n d
■
2
019R1A4A2001440), funded by the Korean government
(
MEST).
15
converted to the corresponding Bpin (3b) and hydroxyl
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asymmetric reduction of β,β-disubstituted alkenylboramides
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DOI: 10.1021/acs.orglett.9b03400
Org. Lett. XXXX, XXX, XXX−XXX