Rh-Catalyzed Asymmetric Hydrogenation of α,β- and β,β-Disubstituted Unsaturated Boronate Esters

Article abstract of DOI:10.1002/chem.202000703

A highly enantioselective hydrogenation of α,β-unsaturated boronate esters catalyzed by Rh-(S)-DTBM-Segphos complex has been developed. Both (Z)-α,β- and β,β-disubstituted substrates can be successfully hydrogenated to afford chiral boronates with excellent enantioselectivities, up to 98 % ee. Furthermore, the obtained chiral boronate esters, as important versatile synthetic intermediates are successfully transformed to the corresponding chiral alcohols, amines and other important derivatives with maintained enantioselectivities.

Full text of DOI:10.1002/chem.202000703

A Journal of
Accepted Article
Title: Rh-Catalyzed Asymmetric Hydrogenation of α,β- and β,β-
Disubstituted Unsaturated Boronate Esters
Authors: Qiaozhi Yan, Xin Shen, Guofu Zi, and Guohua Hou
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10.1002/chem.202000703
Chemistry - A European Journal
COMMUNICATION
Rh-Catalyzed Asymmetric Hydrogenation of α,β- and β,β-
Disubstituted Unsaturated Boronate Esters
Qiaozhi Yan,[a, b] Xin Shen,[a] Guofu Zi[a] and Guohua Hou*[a]
Dedication ((optional))
[a]
Dr. Q. Yan, X. Shen, Prof. G. Zi, G. Hou
Key Laboratory of Radiopharmaceuticals, College of Chemistry
Beijing Normal University
Beijing, 100875, China
E-mail: ghhou@bnu.edu.cn
[b]
Dr. Q. Yan
School of Water Resources and Environment
Hebei GEO University
Shijiazhuang, 050031, China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract:
A
highly enantioselective hydrogenation of α,β-
Miyaura group initially reported the asymmetric hydrogenation of
1-phenylethenylboronates catalyzed by rhodium complexes of
chiral diphosphine ligands with moderate yields and
enantioselectivities.[7] The first asymmetric hydrogenation of vinyl
1,2-bis(boronates) and alkenylboronates was subsequently
presented by Morken and co-workers using the Rh-Walphos
complex as the catalyst.[8] Although the better results were
achieved, the high catalyst loading and long reaction time were
required. Andersson and coworkers obtained comparable results
in the asymmetric hydrogenation of aryl vinylboronates with
complexes of iridium and chiral P,N-ligands under lower catalyst
loading, but alkyl substrates gave only poor enantioselectivities.[9]
Pfaltz then reported the highly enantioselective hydrogenation of
alkyl 1,1-disubstituted and trisubstituted (E)-alkenylboronates
catalyzed by Ir-P/N complexes.[10] Recently, Mashima found that
chloride-bridged chiral dinuclear rhodium(III) complexes
exhibited high performance in asymmetric hydrogenation of
simple olefins, in which two examples of aryl alkenylboronates
were evaluated and could be hydrogenated under 2 mol%
catalyst loading with nBu4NCl as additive in good
enantioselectivities.[11] More recently, Zhang and Dong
developed the Ni-catalyzed asymmetric hydrogenation of β-
boronic ester substituted α,β-unsaturated carboxylic esters with
excellent enantioselectivities.[12] Despite these great progresses
made, the substrate scope is still limited and most of the
substrates investigated are E-isomers which provide satisfactory
results. Whereas, the asymmetric hydrogenation of Z-isomers is
rarely explored and remains a challenge. Therefore, both the
suitable efficient catalysts for unsaturated boronates, especially
for Z-substrates and broader substrate scope are highly
desirable. Herein, we report rhodium-catalyzed asymmetric
hydrogen of (Z)-α,β-unsaturated boronates including both α,β-
disubstituted and β,β-disubstituted substrates with excellent
enantioselectivities of up to 98% ee (scheme 1).
unsaturated boronate esters catalyzed by Rh-(S)-DTBM-Segphos
complex has been developed. Both (Z)-α,β- and β,β-disubstituted
substrates can be successfully hydrogenated to afford chiral
boronates with excellent enantioselectivities, up to 98% ee.
Furthermore, the obtained chiral boronate esters, as important
versatile synthetic intermediates are successfully transformed to the
corresponding chiral alcohols, amines and other important
derivatives with maintained enantioselectivities.
Optically active organoboronate esters as
a class of
extremely important synthetic intermediates are usually
prevalent in construction of various chemical bonds, such as C-
C, C-N and C-O bonds. In particular, these chiral boronate
esters play significant roles in synthesis of chiral amines, chiral
alcohols and other various chiral scaffolds which widely present
in pharmaceuticals, biologically active molecules, and natural
products.[1] Therefore, the synthesis of chiral boronates has
attracted considerable attention from chemists and is of great
importance. Up to now, some important methods including
asymmetric hydroboration of C = C bonds,[2] and asymmetric
homologation of α-haloboronic esters or primary alcohols,[1c, 3-4]
have been developed successfully with good enantioselectivities.
In the past few decades, the catalytic enantioselective
hydroboration of various olefins has been extensively
investigated by many groups and some transition-metal
complexes with chiral ligands have been successfully employed
as
efficient
catalysts
achieving
good
yields
and
enantioselectivities.[2, 5-6] However, most of these catalysts can
only exhibit high activity and enantioselectivity for 1,1- or 1,2-
disubstituted olefins. The suitable substrate scope of this
method is still limited. In addition to enantioselectivity, the
regioselectivity of the hydroboration is also another challenge.
In contrast, asymmetric hydrogenation of prochiral
unsaturated boronates as one of the most atom-economic,
environmentally friendly methods for the synthesis of chiral
boronates should be an attractive approach without the
bothering regioselectivity problem which has to be considered in
the hydroboration. Moreover, a broader substrate scope and
relatively lower catalyst loading may well be achieved. The
1
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Scheme 1. Asymmetric Hydrogenation of (Z)-α,β- and β,β-Disubstituted
Unsaturated Boronate Esters.
Figure 1. Structures of the Phosphine Ligands Screened for Hydrogenation of
1a.
Initially, (Z)-4,4,5,5-tetramethyl-2-(2-phenylprop-1-en-1-yl)-
1,3,2-dioxaborolane 1a was chosen as the model substrate and
the hydrogenation was performed under 80 atm of H2 in CH2Cl2
for 24 h at room temperature using the complex of [Rh(COD)Cl]2
and (R,R)-f-spiroPhos (L1) which was proved an efficient ligand
for Rh/Ir-catalyzed asymmetric hydrogenation of various
substrates.[13] Surprisingly, the extremely poor activity was
exhibited and there was no desired product observed (Table 1,
entry 1). To our delight, when the cationic [Rh(NBD)2]BF4 was
used as the metal precursor, the full conversion was obtained
albeit with only moderate enantioselectivity (65% ee) achieved
(Table 1, entry 2). On the basis of this promising result, a brief
screening of chiral phosphorus ligands available in our
laboratory was subsequently carried out. It was revealed that
most of the ligands (Figure 1) including monodendate (S)-
MonoPhos (L2), (R)-SIPHOS (L3), and bidentate (S,R)-
DuanPhos (L4), (R)-JosiPhos-1 (L5), (S)-Segphos (L6) were
inefficient for this hydrogenation. Either poor conversions or
enantioselectivities (Table 1, entries 3 − 7) were obtained. It was
noteworthy that the ligand (R)-DM-Segphos (L7) could provide
the desired product with higher enantioselectivity, 84% ee, in
spite of the incomplete conversation, 78% (Table 1, entry 8).
Moreover, an increased enantioselectivity was observed when
the ligand DTBM-Segphos (L8) with more steric hindrance was
used (Table 1, entry 9). Notably, the metal precursor was
replaced with [Rh(COD)2]OTf, not only the full conversion but
excellent enantioselectivity, 98% ee, was achieved (Table 1,
entry 10). It could be presumably attributed to the introduction of
the OTf group with bulkier steric hindrance which perhaps had
an positive effect on the catalyst performance. Subsequently,
the effect of solvents was also explored and had a significant
influence on the conversion and enantioselectivity. In ethyl
acetate, 1,4-dioxane, Et2O, DME or toluene, the hydrogenation
only gave poor conversions (Table 1, entries 11−15). Although
DCE could provide high enantioselectivity, only moderate
conversion of 60% was obtained (Table 1, entry 16). It was
remarkable that this hydrogenation still could complete in shorter
reaction time under relatively lower hydrogen pressure without
any loss of enantioselectivity (Table 1, entry 17).
Table 1. Asymmetric Hydrogenation of 1a, Optimizing Reaction Conditions.[a]
entry
1
ligand
L1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
precursor
solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EA
Con.(%)[b]
trace
> 99
5
ee.(%)[c]
ND
65
[Rh(COD)Cl]2
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
Rh(COD)2OTf
2
3
ND
ND
ND
ND
54
4
9
5
8
6
16
7
81
8
78
84
9
69
91
10
11
12
13
14
15
16
17[d]
> 99
3
98
ND
ND
ND
ND
ND
93
1,4-dioxane
Et2O
trace
12
DME
trace
4
toluene
DCE
60
CH2Cl2
> 99
98
[a] Unless otherwise mentioned, all reactions were carried out with
a
Rh/phosphine /substrate ratio of 1.0 : 2.1 : 100, CH2Cl2, 80 atm H2, r.t., 24 h.
[b] Determined by 1H NMR spectroscopy or GC analysis. [c] Determined by
HPLC analysis using a chiral stationary phase. [d] 50 atm H2, 6 h, r.t..
2
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Encouraged by the promising result obtained in the
hydrogenation of the substrate 1a, a variety of β,β-disubstituted
unsaturated boronates 1 were first employed under optimized
reaction conditions. As the results illustrated in Table 2, the
electronic properties of the substituent had no obvious influence
on the enantioselectivity. The substrates bearing electron-
donating or -withdrawing substituents on the phenyl group could
provide the satisfactory conversions with excellent ee values, 94
– 98% ee achieved. The substrates (Z)-1a and (Z)-1b gave the
corresponding products 2a and 2b with the highest
enantioselectivity, 98% ee. But the reactivity of substrates was
effected by the electronic properties of the substituent on phenyl
group. The substrates, such as 1d and 1f, with an electron-
donating substituent showed relatively lower reactivity and a
longer reaction time or a higher hydrogenation pressure was
required for full conversion but without any erosion of
electronic properties of substituents on the aryl group, all the
substrates could be hydrogenated to furnish the products with
pretty high ee values, 92 – 98% ee. Generally, the substrates
with electron-withdrawing substituents on the phenyl ring gave
relatively higher enantioselectivity than those with electron-
donating substituents. For instance, the substrate (Z)-3d with an
ortho-methoxy group gave 94% ee, while the substrates with an
ortho-fluoro ((Z)-3b), or ortho-chloro substituent ((Z)-3c), yielded
4b, and 4c with as high as 98% ee and 97% ee, respectively. It
was found that the ortho-substituted substrates 3b – 3d
exhibited a slightly lower reactivity and 93 – 98% conversions
were obtained. Remarkably, in higher concentration the
transformation could still proceed smoothly with full conversions
and comparable enantioselectivities. The substrates (Z)-3b, (Z)-
3d, (Z)-3i, and (Z)-3k were successfully hydrogenated with full
conversions and excellent enantioselectivities in the higher
concentration (2.0 mL CH2Cl2). Even if under the much higher
concentration of substrates, the catalyst could retain excellent
performance. The substrate (Z)-3c was converted to the
corresponding product 4c with 97% ee using 1.0 mL CH2Cl2 as
solvent.
enantioselectivity. The substrates with
a
larger 3-alkyl
n
substituent such as Et ((Z)-1h), and Pr ((Z)-1i), could also be
successfully hydrogenated by the catalyst system to afford the
desired products in full conversions and comparable
enantioselectivities under a higher hydrogen pressure and
longer reaction time, which was perhaps attributed to the
increased steric hindrance. However, the dialkyl substituted
subatrate 1j only exhibited very poor reactivity.
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of α,β-Disubstituted
Unsaturated Boronates.[a,b,c]
Table 2. Rh-Catalyzed Asymmetric Hydrogenation of β,β-Disubstituted
Unsaturated Boronates.[a, b, c]
[a] Unless otherwise mentioned, all reactions were carried out with
a
[a] Unless otherwise mentioned, all reactions were carried out with
a
Rh(COD)2OTf /(S)-DTBM-Segphos/substrate ratio of 1.0 : 1.1 : 100, CH2Cl2,
50 atm H2, r.t., 6 h. [b] Determined by 1H NMR spectroscopy or GC analysis.
[c] Determined by HPLC analysis using a chiral stationary phase. [d] 80 atm of
H2, r.t., 24 h.
[Rh(COD)2]OTf/(S)-DTBM-Segphos/substrate ratio of 1.0 : 1.1 : 100, CH2Cl2,
80 atm H2, r.t., 24 h. [b] Determined by 1H NMR spectroscopy or GC analysis.
[c] Determined by HPLC analysis using a chiral stationary phase. [d] 2.0 mL
CH2Cl2. [e] 100 atm, 60 °C , 24 h, 1.0 mL CH2Cl2. [f] 2 mol% cat, 80 atm, rt, 48
h, 1.0 mL CH2Cl2.
To our delight, in addition to β,β-disubstituted unsaturated
boronates, this catalyst system similarly exhibited excellent
enantioselectivity in the asymmetric hydrogenation of α,β-
disubstituted unsaturated boronates 3 (Table 3). Regardless of
The chiral boronates 2 and 4 are versatile synthetic
intermediates that can be easily converted to various significant
derivatives including chiral alcohols, chiral amines, and other
3
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coupling reagent and successfully transformed into the
compound 5 with high enantioselectivities.[15] In addition, the
product 4a could also be converted to chiral secondary amine,
which is extremely important building blocks present in a number
of biologically active molecules, natural products and
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In conclusion, we have developed a highly enantioselective
Rh-catalyzed asymmetric hydrogenation of (Z)-α,β-unsaturated
boronates including both β,β-disubstituted and α,β-disubstituted
substrates for synthesis of chiral boronate esters with high
yields and excellent enantioselectivities of up to 98% ee. This
strategy can also be used as an efficient approach to chiral
alcohols, chiral amines, and other significant chiral compounds.
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We thank the National Natural Science Foundation of China
(Grant Nos. 21672024, 21272026, and 21871029), Beijing
Natural Science Foundation (2182025), and Beijing Municipal
Commission of Education for generous financial support.
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Keywords: Asymmetric hydrogenation • Unsaturated boronate •
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4
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Entry for the Table of Contents
A highly enantioselective hydrogenation of both (Z)-α,β- and β,β-disubstituted α,β-unsaturated boronate esters catalyzed by Rh-(S)-
DTBM-Segphos complex has been developed to afford chiral boronates with excellent enantioselectivities, up to 98% ee. The
obtained chiral boronate esters are further successful converted to the corresponding chiral alcohols, amines and other important
derivatives with maintained enantioselectivities.
5
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