Enantioselective Rh-Catalyzed Hydroboration of Silyl Enol Ethers

Article abstract of DOI:10.1021/jacs.1c06697

The asymmetric hydroboration of alkenes has proven to be among the most powerful methods for the synthesis of chiral boron compounds. This protocol is well suitable for activated alkenes such as vinylarenes and alkenes bearing directing groups. However, the catalytic enantioselective hydroboration of O-substituted alkenes has remained unprecedented. Here we report a Rh-catalyzed enantioselective hydroboration of silyl enol ethers (SEEs) that utilizes two new chiral phosphine ligands we developed. This approach features mild reaction conditions and a broad substrate scope as well as excellent functional group tolerance, and enables highly efficient preparation of synthetically valuable chiral borylethers.

Full text of DOI:10.1021/jacs.1c06697

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Enantioselective Rh-Catalyzed Hydroboration of Silyl Enol Ethers
Wenke Dong,# Xin Xu,# Honghui Ma, Yaqin Lei, Zhenyang Lin, and Wanxiang Zhao*
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ABSTRACT: The asymmetric hydroboration of alkenes has proven to be among the most powerful methods for the synthesis of
chiral boron compounds. This protocol is well suitable for activated alkenes such as vinylarenes and alkenes bearing directing groups.
However, the catalytic enantioselective hydroboration of O-substituted alkenes has remained unprecedented. Here we report a Rh-
catalyzed enantioselective hydroboration of silyl enol ethers (SEEs) that utilizes two new chiral phosphine ligands we developed.
This approach features mild reaction conditions and a broad substrate scope as well as excellent functional group tolerance, and
enables highly efficient preparation of synthetically valuable chiral borylethers.
he ability to selectively and efficiently manipulate
Tcarbon−boron bonds into carbon−carbon or carbon−
heteroatom bonds can greatly simplify and expedite synthetic
routes, thus leading to numerous applications of alkyl
boronates in medicinal chemistry, materials science, and the
synthesis of natural products and fine chemicals.1 The
hydroboration of alkenes as one of the most straightforward
and reliable synthetic methods for the preparation of alkyl
boronates has been well developed.2 However, the catalytic
asymmetric version of this reaction still have important
limitations. For instance, the alkenes are largely limited to C-
substituted alkenes (X = H, Figure 1a),3 such as vinylarenes,4
electron deficient alkenes (X = CN, ketone, ester, amide, etc.),5
and the ones with a directing group (X = DG).6 Catalytic
enantioselective hydroborations of heteroatom-substituted
alkenes are rarely explored (X = B, N, Si, P, S),7 and the
heteroatom-substituted alkenes employed previously typically
have a conjugated electron-withdrawing group. For example, S-
and P-substituted alkenes participated in the asymmetric
hydroboration in the form of α,β-unsaturated sulfones7g and
phosphonates,7f respectively. With regard to O-substituted
alkenes,8 their asymmetric catalytic hydroboration is yet to be
reported to our knowledge (X = O, Figure 1a), but it is highly
anticipated given that the desired chiral β-hydroxy boronic
esters and their derivatives could serve as multifaceted
precursors to various high-value chemical products.9
The catalytic enantioselective hydroboration of O-substi-
tuted alkenes will meet various issues according to our
experience in the borylation of O-substituted alkenes,10 which
makes it challenging (Figure 1b). The first issue would be the
Figure 1. (a) Catalytic asymmetric hydroboration of alkenes. (b)
undesired cleavage of the C−O bond via oxidative addition of
Challenges in hydroboration of enol ethers. (c) Enantioselective Rh-
catalyzed hydroboration of SEEs.
the C−O bond or β-O elimination to form alkene I in the
presence of borane.10a The resulting alkene can further react
with borane to furnish a hydroboration product or undergo
dehydrogenative borylation to afford vinylboronate II.10b In
Received: June 29, 2021
Published: July 13, 2021
addition, the O-substituted alkene can also go through
deconjugative isomerization and hydroboration to give
boronate III.10c The control of the regioselectivity and
enantioselectivity would be another great challenge based on
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© 2021 American Chemical Society
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a
Table 1. Reaction Condition Optimization
a
Reactions conditions: 1 (0.1 mmol), HBpin (1.5 equiv), [RhCl(cod)]2 (4 mol %), ligand (8 mol %), LiOAc (30 mol %), solvent (0.5 mL), rt, 24
b
c
d
e
h. 1H NMR yield. Ee were determined by chiral HPLC. Without LiOAc. T = 40 °C. cod = 1,5-cyclooctadiene, DME = dimethoxyethane, THF
= tetrahydrofuran, TIPS = triisopropylsilyl, TDS = thexyldimethylsilyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl.
the previous hydroboration of enol ethers.8 To overcome these
issues, silyl enol ethers would be an ideal starting point due to
their ready availability, ease of deprotection, and the adjustable
steric hindrance of silyl groups,11 which would be crucial to
avoid the undesired C−O bond cleavage and isomerization.
Herein, we reported the first Rh-catalyzed asymmetric
hydroboration of silyl enol ethers, allowing access to chiral
β-borylethers in high yields and ee’s (Figure 1c).
To explore the possibility of catalytic asymmetric hydro-
boration of O-substituted alkenes, silyl enol ether 1a was
selected as the model substrate. Initially, chiral bidentate
phosphine ligands were investigated in the presence of
[RhCl(cod)]2, HBpin, and LiOAc. (R)-Segphos and (R)-
BINAP resulted in no reaction. In addition, the more electron-
rich ligands including Ph-BPE, Me-Duphos, DIOP, BDDP, and
MeO-BIBOP gave a trace amount of hydroboration product
3a12 along with large quantities of undesired 3a′,10c although
full conversions were observed. We next turned our attention
to monodentate phosphine ligands. To our delight, the desired
product 3a was exclusively obtained in moderate ee (54% and
34%) without the formation of 3a′, when the commercially
available ligands L1 and L2 were employed.13 Encouraged by
these delightful results, we then focused on the ligand
modification. As shown in Table 1, the position of substituents
has great impact on the enantioselectivity (L2 → L5), and the
ee was improved to 82% by fine-tuning the two methoxy
groups to 2′- and 6′-positions (L5). Although the enantiose-
lectivity was decreased to 57% when the methoxy was replaced
with a tert-butyl group (L6), the ligand L7 gave a much higher
enantioselectivity (92% ee) with full conversion. The further
ligand modification revealed that the steric ligands such as L8,
L10, and L11 led to a decrease in enantiomeric excess, and the
ligand L9 with a 3,5-dimethoxyphenyl group was the best for
this asymmetric hydroboration of silyl enol ethers. The
investigation of silyl groups indicated that increasing the steric
bulk improved the enantioselectivity (entries 1−4, Table 1).
The effect of solvents was also evaluated. The ee was slightly
decreased in the THF (entry 5), while nonpolar solvents such
as hexane and toluene gave no reaction (entries 6−7). Notably,
no conversion was observed in the absence of LiOAc (entry 8).
Furthermore, the hydroboration product 3a was obtained in
76% isolated yield at elevated temperature (40 °C) without
erosion of the ee (95% ee, entry 9).
With the optimal reaction conditions in hand, we examined
the scope of silyl enol ethers for this Rh-catalyzed
enantioselective hydroboration in the presence of the chiral
ligand L9. As demonstrated in Table 2, a wide range of silyl
enol ethers successfully participated in this asymmetric
hydroboration to give the desired products in good yields
and excellent enantioselectivities. A variety of aromatic
substituents including phenyl groups with different functional
groups such as −CF3, −F, and −NH2 (3b−e), furan (3f),
thiophene (3g), protected and unprotected indoles (3h−i),
and naphthalene (3j) were tolerated, affording the correspond-
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a
Table 2. Scope of Alkyl Silyl Enol Ethers
a
Reactions conditions: 1 (0.2 mmol), HBpin (1.5 equiv), [RhCl(cod)]2 (2 mol %), L9 (4 mol %), LiOAc (30 mol %), DME (0.5 mL), 40 °C, 24
b
c
d
h; isolated yield. [RhCl(cod)]2 (4 mol %), L9 (8 mol %), 30 °C, 48 h. HBpin (3.5 equiv). HBpin (2.5 equiv).
ing diols in good yields and excellent ee’s. The optimized
conditions were also applicable to benzyl substituted substrate
to afford 3k in 90% ee and 83% yield without the occurrence of
double-bond isomerization/hydroboration.10c Gratifyingly,
methyl silyl enol ether was competent to furnish the desired
product 3l in high efficiency albeit with moderate enantiose-
lectivity due to the small size of the methyl group. Noticeably,
both products 3m and 3n were obtained in 91% ee, regardless
of the chain length. The reaction is amenable to secondary and
tertiary alkyl groups (3o−p). It is worth noting that numerous
functional groups were tolerated, such as −OBz (3q), −OBn
(3r), −OTBS (3s), −OTs (3t), −OH (3u), sulfamide (3v),
−NHBoc (3u), −Bpin(2x), −Cl (3y), −CF3 (3z), and −F
(3aa), affording the corresponding products in 88−92% ee.
Particularly noteworthy, the silyl enol ether derived from cholic
acid reacted smoothly to give product 3ab and ent-3ab in good
yields and diastereoselectivities.
was conducted in toluene at −20 °C in the presence of L12.
The scope of aryl substituted SEEs was then explored. As
shown in Table 3, a series of aryl SEEs with various
substituents at different positions on the phenyl group all
reacted smoothly to deliver the diols in high yields and ee. The
reaction of the substrates with substituents at the ortho-, meta-,
or para-position all proceeded efficiently to generate the
desired products 3ad−af in 92−96% ee. It is worth mentioning
that a diverse set of functional groups were compatible with the
established reaction conditions, including electron-donating
and electron-withdrawing groups, such as −NMe2 (3ag),
−OBn (3ai), acetal (3aj), phenyl (3ak), −F (3al), −Bpin
(3ao), and −CF3 (3ap). The susceptible functionalities, like
−Cl (3am), −Br (3an), and −CN (3aq), were readily
accommodated. Moreover, aryl substituents other than the
phenyl, such as indole, furan, pyridine, and naphthalene, could
be successfully incorporated into the products (3as−av).
Finally, the substrate prepared from β-estradiol was suitable to
provide the products 3aw and ent-3aw in good yields and
diastereoselectivities.
The enantioselective hydroboration of Z-aryl substituted
silyl enol ethers was then investigated. Under the standard
reaction conditions for the alkyl SEEs (entry 9, Table 1), diol
3ac was produced in only 50% ee. However, pleasingly, the
enantiomeric excess was improved to 95% when the reaction
Next, we sought to extend this strategy to enantioselective
hydroboration of E/Z mixtures of silyl enol ethers given that
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a
Table 3. Scope of Aryl Silyl Enol Ethers
a
Reactions conditions: 1 (0.3 mmol), HBpin (1.5 equiv), [RhCl(cod)]2 (2 mol %), (R,R)-3,5-iPr2-DIOP (4 mol %), LiOAc (30 mol %), toluene
b
c
d
(1.0 mL), −20 °C, 12 h; isolated yield. AgOAc as base. The reaction was performed for 18 h. The substrate is 1ao (see Supporting Information
for details).
SEEs are typically synthesized as a mixture of E/Z isomers.11a
Additionally, the E and Z isomers may give opposite
enantioselectivities,14 making asymmetric hydroboration of
E/Z mixtures of SEEs challenging. As demonstrated in Table 4,
we first treated (E)-1a with the standard conditions shown in
Table 2. Delightfully, the desired 3a was isolated in 70% yield
and 85% ee, and showed the same (S)-configuration as Z-1a
did. Additionally, the enantioselectivity of 3a could be
improved when the ratio of E-1a/Z-1a decreased. This method
was proved to be compatible with a broad range of E/Z
mixtures of SEEs (synthesized from the corresponding
aldehydes, ratios from 1/14.7 to 1/1.2). It is noteworthy that
substituents such as p-methoxyphenyl (3d), thienyl (3g),
−OBz (3q), −OTBS (3s), −Bpin (2x), −Cl (3y), and pyridyl
(3ax) were well tolerated, furnishing the products in good
yields and enantioselectivities. However, the standard reaction
conditions used in Tables 2 and 3 were unsuitable for the E-
aryl substituted silyl enol ethers, which led to low
enantioselectivities (see Supporting Information). To our
delight, the hydroboration of E-aryl substituted SSEs could
give moderate enantioselectivities when (S,S)-Me-Duphos was
used as the ligand. For instance, the product 3ac was obtained
in 79% yield and 69% ee in the presence of (S,S)-Me-Duphos
(eq 1, Figure 2a).
to the standard conditions used in Table 2 and quenched after
2 h, providing the product 3a in 23% and 46% yields (eqs 2
and 3, Figure 2a), respectively. In addition, the substrate 1a
was recovered in the form of a mixture of Z- and E-isomers,
suggesting the isomerization occurred during the reaction of
hydroboration. However, based on these results, we cannot
conclude that the isomerization is responsible for the resulting
same configuration in view of the different ee’s obtained from
the E-and Z-isomers (85% for E-1a and 95% for Z-1a). To
obtain more information, DFT calculations were carried out.
We hypothesize that the origin of enantioselectivity observed
in the hydroboration reactions is closely related to the
insertion of a silyl enol ether substrate molecule into a
[Rh]−H bond. In the presence of LiOAc and HBpin, it is
reasonable to assume that a [Rh]−H active species can be
formed from the precatalyst [RhCl(COD)]2. According to the
reaction conditions (Rh:phosphine = 1:1) together with an
early report of an X-ray crystal structure of a closely related
rhodium norbornene complex,7c we consider [(COD)LRhH]
as the active species for the insertion. On the basis of this
assumed active species, we performed DFT calculations (at the
level of ωB97X-D) to obtain the barriers for the insertion
reactions of the substrates Z-1a and E-1a with [(COD)
L9RhH] by considering insertion taking place at both faces of
each substrate molecule’s double bond.
To better understand the reason why both Z- and E-isomers
gave the product 3 in the (S)-configuration, a couple of control
experiments are worthy of note. First, to figure out whether the
same configuration obtained was caused by the isomerization
between Z- and E-isomers, pure E-1a and Z-1a were subjected
We first calculated the insertion of Z-1a and located a pair of
transition state structures that would eventually lead to the S-
and R-products, respectively. The two structures show an
energy difference of 4.0 kcal/mol, favoring the experimentally
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a
Table 4. Scope of E/Z-Silyl Enol Ethers
a
Reaction conditions: 1 (0.2 mmol), HBpin (1.5 equiv), [RhCl(cod)]2 (2 mol %), L9 (4 mol %), LiOAc (30 mol %), DME (0.5 mL), 40 °C, 24 h;
b
isolated yield. [RhCl(cod)]2 (4 mol %), L9 (8 mol %), 30 °C, 48 h.
Figure 2. (a) Control experiments. (b and c) Structures calculated for the pair of transition states that would eventually lead to the S- and R-
products for the insertion reactions of the substrates Z-1a and E-1a with [(COD)L9RhH]. The relative free energies are given in kcal/mol.
observed enantiomer. This DFT result gives reasonably/
qualitatively good prediction regarding the experimentally
obtained ee of 95%. The result also indicates that L9 is able to
create an excellent chiral pocket for the asymmetric hydro-
boration in the current catalytic system. Figure 2b schemati-
cally illustrates the structures calculated for the pair of
transition states. Each structure adopts approximately a
square-pyramidal geometry in which the phosphine ligand
occupies the apical position. From the Newman projections
shown in Figure 2b, we can see that the biaryl group on the
phosphine ligand exerts the most steric influence that causes
the enantiomeric discrimination. This conclusion is further
supported by the calculations on the insertion of E-1a, in
which the energy difference is reduced by 2.9 kcal/mol (1.1
versus 4.0 kcal/mol) (Figure 2c). The results also explain why
both the Z- and E-silyl enol ethers afford the product with the
same absolute configuration.
In addition to the pair of transition state structures shown in
Figure 2a for the insertion reaction of Z-1a, we also located
another pair of noticeably unstable transition state structures.
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Figure 3. (a) Gram-scale reaction and synthetic applications. Reaction conditions: (i) bromochloromethane (2.5 equiv), nBuLi (2.3 equiv), −78
°C to rt, 2 h; NaOH (1.5 equiv), H2O2 (1.5 equiv). (ii) furan (1.5 equiv), nBuLi (1.5 equiv), NBS (1.5 equiv), −78 °C to rt, 15 h. (iii)
vinylmagnesium bromide (4.0 equiv), I2 (4.0 equiv), −78 °C, 0.5 h. (iv) MeONH2 (3.0 equiv), nBuLi (3.0 equiv), −78 to 60 °C, 15 h. (b)
Synthesis of benazepril hydrochloride. (c) Synthesis of solriamfetol.
These unstable structures were obtained by moving the apical
(chiral) phosphine ligand to the opposite side of the square
base, which are in fact the diastereomers of those presented in
Figure 2b. For readers’ convenience, these diastereomers are
given in the SI (Figure S1). In view of the instability of these
diastereomers, we did not carry out the corresponding
calculations for E-1a.
To test the scalability of the reaction, we carried out a gram-
scale reaction. With 1 mol % of the catalyst, the product 2ac
was isolated in 0.76 g and 94% ee. To demonstrate the
robustness and practicability of this protocol, the trans-
formations of 2ac are outlined in Figure 3. The synthesis of
one-carbon-homologated alcohol 4 was achieved in 76% yield
via the Matteson reaction and subsequent oxidation.15 The
sp2−sp3 coupling of furan and 2ac led to the formation of 5 in
67% yield and 94% ee.16 Furthermore, the product 2ac can
undergo the alkenylation to provide the allylbenzene derivative
6.17 Finally, amination of 2ac with MeONH2 was carried out,
providing the desired amination product 7 in 81% yield and
94% ee.18 The synthetic utilities of this approach were further
demonstrated by the synthesis of solriamfetol that acts as a
dopamine and norepinephrine reuptake inhibitor and the key
diol intermediate in the synthesis of benazepril hydrochloride
(Figure 3b and c).19
In summary, we have developed a Rh-catalyzed asymmetric
hydroboration of silyl enol ethers using two new phosphine
ligands we developed to construct valuable chiral boronic
esters in good yields and enantioselectivities. Both alkyl- and
aryl-substituted silyl enol ethers are competent substrates.
Importantly, the amenability of E/Z mixtures of alkyl SEEs in
this approach is particularly attractive from the perspective of
practical applicability. Control experiments and DFT calcu-
lations disclosed that the chiral ligand is responsible for the
same configuration obatined from the E and Z isomers in the
hydroboration. The utility of this method is illustrated by a
gram-scale reaction and the transformations of borylether
products. Enantioselective hydroborations of silyl enol ethers
derived from ketones are currently in progress.
Experimental procedures, characterization and NMR
spectra for obtained compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wanxiang Zhao − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, 410082 Changsha, Hunan,
P. R. China; orcid.org/0000-0002-6313-399X;
Email: zhaowanxiang@hnu.edu.cn
Authors
Wenke Dong − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, 410082 Changsha, Hunan,
P. R. China
Xin Xu − Department of Chemistry, The Hong Kong
University of Science and Technology, 999077 Kowloon,
Hong Kong, P. R. China
Honghui Ma − State Key Laboratory of Chemo/Biosensing
and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, 410082 Changsha, Hunan,
P. R. China
Yaqin Lei − State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, 410082 Changsha, Hunan,
P. R. China
Zhenyang Lin − Department of Chemistry, The Hong Kong
University of Science and Technology, 999077 Kowloon,
Hong Kong, P. R. China; orcid.org/0000-0003-4104-
8767
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c06697
Author Contributions
#W.D. and X.X. contributed equally.
Notes
The authors declare no competing financial interest.
ASSOCIATED CONTENT
■
ACKNOWLEDGMENTS
Financial support from the National Natural Science
Foundation of China (Grant Nos. 21971059, 21702056), the
sı
* Supporting Information
■
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c06697.
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National Program for Thousand Young Talents of China and
the Fundamental Research Funds for the Central Universities,
and the Research Grants Council of Hong Kong (HKUST
16302418) is greatly appreciated.
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