Copper-Catalyzed Asymmetric Protoboration of β-Amidoacrylonitriles and β-Amidoacrylate Esters: An Efficient Approach to Functionalized Chiral α-Amino Boronate Esters

Article abstract of DOI:10.1021/acs.orglett.7b01740

A copper-catalyzed asymmetric protoboration of both Z-β-amidoacrylonitriles and ethyl E-β-amidoacrylates using bis(pinacolato)diboron has been developed for the first time. The process tolerates a vast array of substrates, delivering a series of stable functionalized chiral α-amino boronate esters in good yields and enantioselectivities under mild reaction conditions. The current method is also applicable for gram-scale synthesis without erosion of enantioselectivity. This work provides an attractive and complementary approach to synthesizing enantioriched chiral α-amino boronate esters.

Full text of DOI:10.1021/acs.orglett.7b01740

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Asymmetric Protoboration of
β‑Amidoacrylonitriles and β‑Amidoacrylate Esters: An Efficient
Approach to Functionalized Chiral α‑Amino Boronate Esters
Lili Chen,†,‡,§ Xiaoliang Zou,†,§ Haonan Zhao,† and Senmiao Xu*,†
†State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute, Lanzhou Institute of Chemical Physics
(LICP), Chinese Academy of Sciences, Lanzhou 73000, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed asymmetric protoboration
of both Z-β-amidoacrylonitriles and ethyl E-β-amidoacrylates
using bis(pinacolato)diboron has been developed for the first
time. The process tolerates a vast array of substrates, delivering
a series of stable functionalized chiral α-amino boronate esters
in good yields and enantioselectivities under mild reaction
conditions. The current method is also applicable for gram-
scale synthesis without erosion of enantioselectivity. This work provides an attractive and complementary approach to
synthesizing enantioriched chiral α-amino boronate esters.
Scheme 1. Transition-Metal-Catalyzed Asymmetric Synthesis
of Chiral α-Amino Boronate Esters
hiral α-amino boronic acid derivatives are widely used as
C
therapeutically important protease inhibitors1 such as
Bortezomib,2 Delanzomib,3 and Ixazomib4 as well as DPP4
inhibitors, e.g., Talabostat5 and Dutogliptin.6 In addition, their
use in fluorescent sensor applications7 and stereospecific
transformations insyntheticchemistry8 hasalsogainedincreasing
interests. Thus, considerable effort has been dedicated to the
development of efficient methods to synthesize chiral α-amino
boronate esters.1b However, most of the current methods rely on
diastereoselective transformations with involvement of a
stoichiometric amount of chiral auxiliaries. Examples include
Matterson’s homologation with chiral pinanediol-derived
boronate esters,9 copper-catalyzed boron addition to chiral N-
tert-butanesulfinyl10 and N-phosphinyl11 aldimines, and Curtius
rearrangement with optically active α-borylacetic acid.12 To date,
only a handful of examples of transition-metal-catalyzed systems
have been documented to access α-amino boronate esters via
́
asymmetric catalysis. Morken,13 Fernandez,14 Lin,15 Liao,16
Tang,17 and Miura18 have provided efficient methods in the
synthesis of simple α-amino boronate esters (Scheme 1a−d). In
contrast, the development of more complex, functionalized α-
aminoboronateesterswithsidechainsthatcontainfunctionalities
(e.g., carbonyl, halide, azido, etc.) has received less attention
although they serve as important synthetic intermediates for the
preparation of bioactive molecules such as analogues of aspartic
and glutamic acids.19 Methods to prepare these compounds
usually require multistep procedures, and efficient asymmetric
catalytic synthesis remains virtually unexplored.18,20
Transition-metal-catalyzed asymmetric hydro- and protobora-
tionreactions ofprochiral CCbondshaveemerged aspowerful
tools for the synthesis of chiral organoboronate esters.21,22 In
particular, copper-catalyzed asymmetric protoboration of α,β-
unsaturated compounds has become a valuable access to
enantioriched α-boronate esters.23 In theory, asymmetric
protoboration of β-amino-α,β-unsaturated compounds could be
considered as a viable strategy to deliver optically active
functionalized α-amino boronate esters. However, there have
notbeenanyreportspertainingtothedevelopmentofstereogenic
C−B bond forming reaction using such substrates. The shortage
of research is mostly likely due to deactivation of substrates that is
caused by the interaction of a lone pair of electrons on the
Received: June 9, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nitrogen atom with the conjugated π-system of the olefin
moiety.24 In addition, the deamination process could also
complicate the reaction process.25 We considered that substrates
with a judicious choice of substituents on nitrogen could be
poised to minimize the deactivation and deamination, therefore
providing an attractive and complementary approach to the
synthesis of enantioriched chiral α-amino boronate esters.
Here, we disclose the first Cu-catalyzed asymmetric proto-
boration reactions of β-amidoacrylonitriles and β-amidoacrylate
esters with good enantioselectivities. We also demonstrate that
the current method could be amendable to synthesizing α-amino
boronate esters in gram scale without stereoselectivity erosion.
Our study commenced with reaction of Z-β-amidoacrylonitrile
1a. Preliminary examination using 10 mol % of (S)-BINAP (L1)/
CuCl showed reaction of 1a with bis(pinacolato)diboron
(B2pin2) in the presence of 10 mol % of NaOMe and 2.0 equiv
of MeOH at rt in CH2Cl2 for 18 h delivering the desired α-amino
boronate ester 2a in 76% yield and 49% ee (Table 1, entry 1).26
Control experiments showed no product was observed without
either the ligand or MeOH under otherwise identical reaction
conditions. These preliminary results demonstrate that the
phosphine ligand is capable of accelerating this protoboration
reaction. Next, a variety of axially chiral bidentate phosphine
ligands combined with CuCl were investigated. (S)-Tol-BINAP
(L2) and (S)-3,5-xyl-BINAP (L3) gave superior chiral induction
(Table 1, entries 2 and 3). MeO-BIPHEP ligands L4 and L5 were
also found to be insufficient in terms of chiral induction (Table 1,
entries 4 and 5). Fortunately, we found that when bulky ligand
(S)-DTBM-SEGPHOS (L8) was employed, 2a was obtained
with a moderate result (Table 1, entry 8, 82% yield, 87% ee).
Subsequent investigation of base candidates and solvent effect
revealed that the combination of NaOMe and CH2Cl2 was
optimal in controlling reactivity and enantioselectivity. The
temperature also plays an important role in this reaction. When
the reaction was carried out at 10 °C, the ee value could be
elevated to 92% with an 84% isolated yield (Table 1, entry 16).
With optimized reaction conditions in hand, the substrate
scope of asymmetric protoboration reaction of Z-β-amidoacrylo-
nitriles 1 was then performed. As shown in Scheme 2, reactions
Scheme 2. Substrate Scope of Asymmetric Protoboration of β-
a
Amidoacrylonitriles 1
Table 1. Reaction Optimization of Asymmetric Protoboration
a
of β-Amidoacrylonitrile 1a
b
c
entry
L
MOR
solvent
yield (%)
ee (%)
1
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOtBu
KOtBu
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
76
77
73
83
43
73
77
82
59
70
71
69
80
77
45
84
73
62
83
49
62
68
73
57
59
66
87
67
73
64
79
80
71
3
2
3
4
5
6
7
8
9
a
10
11
12
13
14
15
toluene
1,4-dioxane
Et2O
Unless otherwise noted, the reaction conditions were as follows: 1
(0.2 mmol), ligand (0.02 mmol), CuCl (0.02 mmol), NaOMe (0.02
mmol), B2Pin2 (0.30 mmol), and DCM (1 mL) under a N2
atomsphere at 10 C. The products were isolated by column
chromatography on silica gel. Enantiomeric excesses of 2 was
determined by chiral HPLC.
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
LiOtBu
NaOMe
NaOMe
NaOMe
NaOMe
d
16
92
87
84
90
e
17
with a series of N-benzoyl-N-methyl substrates went smoothly,
affording the corresponding α-amino boronate esters 2a−j with
good enantioselectivities (86−94% ee) in moderate to good
yields (50−96%). Reaction of substrates bearing 1-naphthoyl and
2-naphthoyl groups also gave the corresponding products 2k and
2l in good ee’s (91% and 89%, respectively), while an inferior ee
value (81%) and yield (36%) were observed with furan-2-
carbonyl substituted substrate 1p. The reaction isvery sensitive to
the alkyl substituent on nitrogen. For example, N-ethyl
acrylonitrile 1m gave the product 2m with an inferior result
d
,
,
f
18
19
d
g
a
Unless noted, reactions were performed with 1a (0.20 mmol), B2pin2
(0.30 mmol), NaOMe (0.02 mmol), CuCl (0.02 mmol), L (0.02
mmol), and MeOH (0.40 mmol) in solvent (1.0 mL) at rt for 18 h.
b
c
d
Isolated yields. Determined by HPLC analysis. The reaction was
e
performed at 10 °C. The reaction was performed at 0 °C for 24 h.
f
g
The reaction was carried out with 1.0 equiv of MeOH. The reaction
was carried out with 3.0 equiv of MeOH.
B
DOI: 10.1021/acs.orglett.7b01740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(62% yield, 84% ee) compared to its methyl analogue (2a), while
N-propyl 1n only gave a trace amount of product 2n. Reaction of
acrylonitrile 1o bearing a δ-lactam unit in the β-position
proceeded smoothly to afford desired product 2o in 96% yield
and 90% ee. The absolute configuration of compound 2i was
confirmed to be S by single crystal X-ray diffraction analysis, and
the configurations of others are provisionally assigned by analogy.
The crystal structure clearly shows the dative bond present
between the carbonyl oxygen of the amido moiety and boron
atom,17 which makes such α-amino boronate esters highly stable
at ambient temperature and easily isolable by column
chromatography.
We next explored the ability of the catalyst to control the
reactivity and enantioselectivity in reactions of β-amidoacrylates.
The reaction of ethyl Z-β-amidoacrylates Z-3a under the
aforementioned standard conditions afforded the corresponding
product in 73% yield and only 4% ee, whereas a moderate yield
(60%) and good ee value (92%) were observed with its E-isomer
3a. Therefore, we chose E-β-amidoacrylate 3a as our model
substrate to survey this reaction. Further scrutiny of reaction
conditions revealed that (S)-MeO-BIPHEP (L4) was the best
performing ligand for this substrate class, producing 4a in 98%
yield and 93% ee in THF at rt within 12 h.27,28
catalyst loading. The R group in the ester moiety significantly
affected enantioselectivities as well as reactivity. For example,
alkyl acrylates 3a−d performed better than phenyl acrylate 3e
(>80% ee vs 7o% ee). The more bulky the substituent R is, the
lower the ee values were. Reaction of a variety of ethyl E-β-
amidoacrylates 3 gave the corresponding products in good ee’s
(84−94%). In contrast to 1m and 1n, reactions of N-ethyl and N-
propyl substrates (3q and 3r) gave 4q and 4r in excellent yields
and good ee values (91% and 81%, respectively). Reaction of
acrylates bearing δ- or ε-lactam units in the β-position gave
superior results, affording the corresponding products in 94% ee
valueswithquantitativeyields(4uand4v). Althoughweobserved
complete formation of product 4t by GC-MS, it is not stable
enough to isolate. Interestingly, the presence of an unprotected
N−H group did not adversely affect the reactivity, but it affected
the enantioselectivity (60%). Surprisingly, reaction of Z-3w gave
ent-4w in quantitative yield and 88% ee. The absolute
configuration of compound 4m was unambiguously confirmed
to be R by single crystal X-ray diffraction analysis, and the
configurations of others are tentatively assigned by analogy.
Our method is also amendable to gram-scale synthesis as
illustrated in eq 1. Reaction of 3a (1.17 g, 5.0 mmol) under a
The substrate scope of the asymmetric protoboration reaction
of E-β-amidoacrylate 3 is summarized in Scheme 3. Compared to
their nitrile analogues, the reactivity of these substrates is higher.
Allthereactionswerecompletedwithin12husing10mol%ofthe
reduced catalyst loading and more concentrated conditions (0.5
M) by prolonging the reaction time to 36 h furnished 4a in 70%
yield (1.26 g) without erosion of enantioselectivity (92% ee).
The Bpin and ester groups in product 4a could be readily
transformed. For example, deprotection of Bpin and hydrolysis of
estercouldbeconductedinonepot(eq2). Reactionof4awith3.0
equiv of BCl3 at −78 °C followed by addition of wet MeOH at rt
afforded an analogue of substituted aspartic acid 5 in 69%
yield.13,17
Scheme 3. Substrate Scope of Asymmetric Protoboration of
a
Ethyl β-Amidoacrylates 3
In summary, we have developed copper-catalyzed asymmetric
protoboration reactions of Z-β-amidoacrylonitriles and ethyl E-β-
amidoacrylates for the first time, which allows for accessing a
series of stable functionalized chiral α-amino boronate esters in
good yields and enantioselectivities under mild reaction
conditions. We also demonstrate that the current method is
applicable to gram-scale synthesis without erosion of stereo-
selectivity. Further transformations of products and development
of related enantioselective protoboration reactions are currently
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b01740.
Experimental procedures, spectroscopic data (PDF)
Crystallographic data (CIF, CIF)
a
Unless otherwise noted, the reaction conditions were as follows: 3
(0.1 mmol), ligand (0.01 mmol), CuCl (0.01 mmol), NaOtBu (0.01
mmol), B2Pin2 (0.2 mmol), and THF (1 mL) under a N2 atomsphere
at rt. The products were isolated by column chromatography on silica
gel. Enantiomeric excesses of 4 were determined by chiral HPLC.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: senmiaoxu@licp.cas.cn.
C
DOI: 10.1021/acs.orglett.7b01740
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Senmiao Xu: 0000-0003-0249-8765
Author Contributions
§L.L.C. and X.L.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
̀
2014, 53, 6530. (i) Carmers, L.; Carreaux, F.; Carboni, B.; Mortier, J.
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We thank the “1000-Youth Talents Plan”, a Start-up Grant from
Lanzhou Institute of Chemical Physics, National Natural Science
Foundation of China (21573262), and Natural Science
Foundation of Jiangsu Province (BK20161259) for generous
financial support. We also thank Prof. Zhiqiang Liu from
Shandong University and Prof. Yuanyuan Zhu from Hefei
University of Technology for solving the crystal structure of 4m.
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DOI: 10.1021/acs.orglett.7b01740
Org. Lett. XXXX, XXX, XXX−XXX