Highly Enantiospecific Borylation for Chiral α-Amino Tertiary Boronic Esters

Article abstract of DOI:10.1002/anie.201809389

Herein we report a highly efficient and enantiospecific borylation method to synthesize a wide range of enantiopure (>99 % ee) α-amino tertiary boronic esters. The configurationally stable α-N-Boc substituted tertiary organolithium species and pinacolborane (HBpin) underwent enantiospecific borylation at ?78 °C with the formation of a new stereogenic C?B bond. This reaction has a broad scope, enabling the synthesis of various α-amino tertiary boronic esters in excellent yields and, importantly, with universally excellent enantiospecificity (>99 % es) and complete retention of configuration.

Full text of DOI:10.1002/anie.201809389

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Accepted Article
Title: Highly Enantiospecific Borylation for Chiral α-Amino Tertiary
Boronic Esters
Authors: Qingqing Qi, Xuena Yang, Xiaoping Fu, Shiqing Xu, and Ei-
ichi Negishi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201809389
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10.1002/anie.201809389
Angewandte Chemie International Edition
COMMUNICATION
Highly Enantiospecific Borylation for Chiral α‑Amino Tertiary
Boronic Esters
Qingqing Qi,[a] Xuena Yang,[a] Xiaoping Fu,[a] Shiqing Xu,*[a] and Ei-ichi Negishi*[a]
Abstract: Herein we report a highly efficient and enantiospecific
borylation method to synthesize a wide range of enantiopure (>99%
ee) α‑amino tertiary boronic esters. The configurationally stable α-N-
Boc substituted tertiary organolithium species and pinacolborane
(HBpin) underwent enantiospecific borylation at -78 °C with the
formation of a new stereogenic C−B bond. This reaction has a broad
scope, enabling the synthesis of various α‑amino tertiary boronic
esters in excellent yields and, importantly, with universally excellent
enantiospecificity (>99% es) and complete retention of configuration.
Chiral boronic acids and their derivatives are highly versatile
building blocks in modern asymmetric synthesis. Their
stereospecific conversion into a broad range of useful functional
groups is a continually growing and important research area.[1]
Additionally, many unique biological activities of boron-containing
compounds have been revealed.[2] Among them, chiral α-
aminoboronic acids have received significant attention since they
are the key pharmacophores in protease inhibitions such as
Bortezomib (Velcade, an anti-cancer drug and the first therapeutic
proteasome inhibitor) and Ixazomib (Ninlaro, a drug for the
treatment of multiple myeloma).[3] In addition, many other α-
Figure 1. Examples of α-aminoboronate drugs and biologically active molecules.
aminoboronic acid compounds showed excellent anticancer,
antiviral, and antibacterial activities.[2,3] From the success of these
compounds, there has been an increased interest in searching α-
the stereoselective construction of N-substituted quaternary
carbon stereogenic centers (Scheme 1). For example, significant
lower enantioselectivities were observed for the synthesis of
amino boronate-containing small bioactive molecules (Figure 1).
sterically hindered α‑amino tertiary boronic esters compared to
secondary boronic esters by borylation of imines[7d] and Cu-
catalyzed hydroamination of alkenyl dan-boronates[9]. Recently,
Ellman reported a copper-catalyzed diastereoselective borylation
of chiral N-tert-butanesufinyl ketimines with involvement of a
chiral auxiliary to synthesize α‑amino tertiary boronic esters
(Scheme 1, eq 1).[7g] In another approach, Tang described an
elegant enantioselective rhodium-catalyzed hydroboration of α-
arylenamides (Scheme 1, eq 2).[12] Very recently, Ready and
Studer developed transition-metal catalyzed enantioselective and
In view of their broad biological activities, substantial efforts
have been made to develop synthetic methods for the asymmetric
construction of α-aminoboronic acids and their derivatives.[4]
Examples include Matteson’s homologation,[5] sparteine-
mediated enantioselective lithiation-borylation,[6] metal-catalyzed
and metal-free borylation of imines,[7] Cu-catalyzed borylation of
enamides,[8]
boronates,[9] Curtius rearrangement of chiral α-borylcarboxylic
Cu-catalyzed hydroamination of alkenyl dan-
acid
derivatives,[10]
and
Ni-catalyzed
decarboxylative
borylation.[11] These approaches by either use of chiral auxiliaries
or asymmetric catalytic transformations have been utilized for the
diastereoselective
multi-component
coupling
involving
indolylboron ate complexes to provide α-substituted indoline
boronic esters, respectively (Scheme 1, eq 3 and eq 4).[13]
efficient preparation of
derivatives, whereas they mainly limited to the construction of
a variety of α-aminoboronic acid
chiral α-amino secondary boronic esters.
Despite recent progress, there remains a great challenge for
the synthesis of α‑amino tertiary boronic esters with high
enantiopurity in a general manner. Herein, we report a general
method to prepare enantiopure (>99% ee) chiral α‑amino tertiary
boronic esters that makes use of the enantiospecific borylation of
configurationally stable α-N-substituted tertiary organolithium
species (Scheme 1, eq 5). This strategy is very attractive
because: i) chiral amines are ubiquitous in natural products as
well as in synthetic compounds, and numerous methods for chiral
amine synthesis are well established;[14] ii) excellent enantiopurity
is general and predictable that is independent of electronic and
steric perturbations of substrates if the overall process proceeds
with full stereospecificity.
Indeed, there have been only a limited number of reports on
asymmetric approaches to more sterically congested α‑amino
tertiary boronic esters, which involves a particular challenge for
[a]
Dr. Q. Qi, Dr. X. Yang, Dr. X. Fu, Dr. S. Xu, Prof. Dr. E. Negishi
Herbert C. Brown Laboratories of Chemistry, Purdue University
560 Oval Drive, West Lafayette, IN-47907 (USA)
E-mail: xu197@purdue.edu, negishi@purdue.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201809389
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COMMUNICATION
Table 1. Optimization of the enantiospecific borylation[16]
Boron
Borylation
Yield
[%][a]
<2
ee
[%][b]
-
Entry
DG
reagent
iPrOBpin
condition
1
2
3
4
Boc
Boc
Boc
Boc
-78°C, 2.5 h
-78 to 23 °C
slowly in 12 h
-78°C, 2.5 h
-78 to 23 °C
slowly in 12 h
-78 °C, 2.5 h
-78 °C, 2.5 h
-78 °C, 2.5 h
-78 °C, 2.5 h
iPrOBpin
MeOBpin
MeOBpin
55
<2
56
80
-
88
5
6
7
8
Boc
B(OMe)3
HBpin
HBcat
75[c]
99
80[d]
>99
-
Boc
Boc
28[c]
CON(iPr)2
HBpin
80
97
[b]
[a] Isolated yields. Determined by HPLC-analysis on chiral stationary phase.
[c]
Determined by crude 1H NMR analysis. [d] Determined by HPLC-analysis on
chiral stationary phase of the corresponding pinacol boronic ester.
hindered and more reactive boron electrophile reagents to
promote the borylation at low temperature with excellent
enantiospecificity. We were very delighted to find that
pinacolborane (HBpin)[17] reacted readily with α-N-substituted
organolithium species in Et2O at -78 °C to give exclusively a
borylated product in 99% yield and >99% ee (Table 1, entry 6).
When directing group of Boc was replaced with CON(iPr)2, the
corresponding borylated product was obtained in 80% yield and
97% ee (Table 1, entry 8).
Scheme 1. Asymmetric approaches to α‑amino tertiary boronic esters.
α-Lithiated tertiary N-benzylic carbamates have been reported
as configurationally stable organolithium intermediates, which
react with various electrophiles to generate a new C−C, C−Si, or
C−Sn bond with the asymmetric formation of a quaternary
stereocenter.[15] To the best of our knowledge, no such C−B bond
formation has been reported for the synthesis of N-substituted
tertiary α‑aminoboronic esters with high enantiopurity. To check
the feasibility of our strategy, we first used N-Boc-N-methyl-1-
phenylethanamine 1 as the standard substrate for screening
enantiospecific borylation (Table 1). The lithiation of 1 using sec-
BuLi in Et2O at -78 °C was completed in 30 min to generate the
corresponding organolithium species with 100% retention of the
stereoconfiguration. Then we focused on the examination of
various conditions for the enantiospecific borylation of α-lithiated
tertiary N-benzylic carbamate. We began our investigation by
using iPrOBpin and MeOBpin as borylation reagents, but no
borylation occurred at -78 °C (Table 1, entries 1 and 3). To
facilitate the borylation, the reaction was carried out initially at
-78 °C and slowly increased the reaction temperature to 23 °C in
12 h. In these cases, the desired borylated product 2a (DG = Boc)
was obtained in 55% and 56% yield, but only in 80% ee and 88%
ee, respectively (Table 1, entries 2 and 4). The low enantiopurities
are most likely to result from increasing reaction temperature to
enable the sluggish desired borylation of the tertiary α-N-
substituted organolithium species with less nucleophilicity due to
the steric hindrance and the adjacent electron-withdrawing N-DG
group. This problem could be circumvented by using less
After establishing the optimal reaction conditions, we then
looked into the substrate scope of this enantiospecific borylation.
As can be seen in Scheme 2, various substituents of N-Boc
protected amines, such as aryls with electron-withdrawing (Cl, F,
CF3) and electron-donating (OMe) groups, alkyls with OMe, Br,
and double bond, can undergo lithiation−borylation process
smoothly affording a series of α-amino tertiary boronic esters in
excellent yields and extremely high enantiopurities. Notably, this
enantiospecific borylation was also tolerant of N-Boc protected
tetrahydroisoquinoline providing 2j in 92% yield with >98% ee. In
the case of 2c, the lithiation occurred at both positions adjacent
to nitrogen of N-Boc due to OMe group acting as an additional
directing group for lithiation at CH2N-Boc, thus furnishing an
approximate 1:2 ratio of CH2/benzylic borylated products.
Switching s-BuLi to n-BuLi as the base resulted in a completely
regioselective deprotonation at the benzylic position and
subsequent addition of HBpin provided 2c in 82% yield with
complete stereocontrol (>99% ee).
The enantiospecific borylation process can be easily extended
to the substrates with multiple chiral centers. As shown in Scheme
3, the reaction was tolerant of N-Boc protected amines containing
various functional groups such as halides (3a, 3b), olefin (3d-e,
3h-k), alkyne (3c), OTBPDS (3i), hetero-rings (3b, 3f, 3h), and
CF3 (3l). In all cases, the desired α-amino tertiary boronic esters
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10.1002/anie.201809389
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Scheme 2. Standard reaction conditions of the enantiospecific borylation: i)
amine (0.25 mmol, 1.0 equiv), s-BuLi (1.2 equiv) in Et2O at -78 °C for 0.5 h, ii)
neat HBpin (1.5 equiv) at -78 °C for 2.5 h. [a] s-BuLi was replaced with n-BuLi.
3 were obtained in good to excellent yields and, importantly, with
universally complete retention of configuration, as determined by
X-ray crystallographic analysis of 3a and 3b.[18] The coordination
between the boron atom and the carbonyl group of Boc makes
such α-amino tertiary boronic esters highly stable. The absolute
configuration of the other α-amino boronic esters is based on
assumed retention at the organolithium center. Notably, both
enantiopure α-amino tertiary boronic esters (R,S)-3d and (S,S)-
3e were prepared from the corresponding (R,S)- and (S,S)-N-Boc
amines with complete enantiospecificity in 96% and 90% yield,
respectively. This result indicates that there is no
matched/mismatched issue here, which can often complicate
reaction outcomes.
Scheme 3. Standard reaction conditions of the enantiospecific borylation as
shown in Scheme 2. [a] s-BuLi was replaced with n-BuLi and TMEDA (1.5 equiv).
It should be noted that the distinguish rotamers from
diastereomers is critically important to determine the
enantiospecificity of borylation in circumstances where the
possibilities of both isomers exist. For example, during the
synthesis of 3a, the 11B NMR spectrum (EtOAc as solvent) of the
crude reaction mixture showed two peaks at 14.7, and 9.7 ppm
(indicating the strong coordination between B and the carbonyl
group of Boc). Furthermore, two new spots were observed in TLC
which can be isolated by common silica gel column
chromatography. Interestingly, the compound 3aa of higher Rf
value rapidly converts to the compound 3ab of lower Rf value in
d-chloroform in less than 5 minutes even at low temperature,
whereas 3aa is quite stable in other solvents such as hexanes,
ethyl acetate, acetone, and acetonitrile. The 1H and 13C NMR (d-
acetone) spectra of 3aa indicate it is a mixture of several
Figure 2. Comparison of rotamers and diastereomers of 3a by 1H NMR (d-
acetone, a-c).
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10.1002/anie.201809389
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isomers.[19] The fast conversion of 3aa to 3ab implies these
compounds are rotamers since epimerization in neutral solvent is
usually negligible. Comparison of the spectra of an intentionally
prepared diastereomeric mixtures of (S,S)- and (R,S)-3a (Figure
2, c) with (R,S)-3a (Figure 2, b) further supports the conclusion
about the identity of 3aa and 3ab as rotamers. The existence of
highly stable and chromatographically separable rotamers is likely
due to the energetic barriers for the pseudo-rotation of the boron-
containing five-membered ring which was supported by the
observation of a superstructure of 3c with four rotamers A-D
related by pseudo-rotation and pseudo-translation (Figure 3).[20]
produced amide 6 in 88% yield over two steps. Similarly, peptide
7 was synthesized in 55% overall yield from 2a of >99% ee, and
importantly, only a single diastereomer was obtained.
In conclusion, we have successfully developed a new and
highly efficient enantiospecific borylation route to various chiral
α‑amino tertiary boronic esters. This route employs N-Boc
protected amines which are lithiated at -78 °C to generate
configurationally stable organolithium species followed by the
treatment with HBpin to undergo enantiospecific borylation,
enabling the synthesis of a series of enantiopure (>99% ee)
α‑amino tertiary boronic esters with the formation of a new
stereogenic C−B bond. Importantly, universally excellent
enantiospecificity (>99% es) and complete retention of
configuration were observed. The current method is also
applicable for gram-scale synthesis of 2a and 3a without erosion
of enantiospecificity. The α-amino tertiary boronic esters can be
further functionalized to provide various chiral compounds which
hold a great potential for peptidomimetics of boron-based
bioactive molecules.
Acknowledgements
We thank the Negishi-Brown Institute, Purdue University and
Teijin Limited for the support of this research. We would also like
to thank Dr. Matthias Zeller for X-ray crystal structure analysis.
Figure 3. X-ray crystal structures of four different rotamers of α‑amino tertiary
boronic ester 3c.
Keywords: α‑aminoboronates • borylation • quaternary centers •
asymmetric synthesis • rotamer
The chiral α-amino tertiary boronic esters can be employed for
further transformations to synthesize various chiral compounds.
For example, 3a was transformed to 4 in 58% yield and 5 in 72%
yield by Pd-catalyzed borylation[21] and Pd-catalyzed Negishi
coupling[22], respectively. Treatment of 2k with 4N HCl to remove
the Boc group followed by amidation with 4-nitrobenzoyl chloride
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Scheme 4. Derivatization of chiral α‑amino tertiary boronic esters.
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[18]
a) CCDC 1862092 (3a) and CCDC 1862091 (3b) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre.
[19] The full spectra of rotamers 3aa see supporting information.
[20] CCDC 1862090 (3c) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Qingqing Qi, Xuena Yang, Xiaoping Fu,
Shiqing Xu,* and Ei-ichi Negishi*
Page No. − Page No.
Highly Enantiospecific Borylation for
Chiral α‑Amino Tertiary Boronic Esters
Enantiospecific borylation: A highly enantiospecific borylation of configurationally
stable α-N-Boc substituted tertiary organolithium species and HBpin has been
developed to synthesize various α‑amino tertiary boronic esters through the formation
of a new C−B bond with excellet enantiopurities and complete retention of configuration.
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