Enantioselective Synthesis of α-Amidoboronates Catalyzed by Planar-Chiral NHC-Cu(I) Complexes

Article abstract of DOI:10.1021/jacs.8b05045

The first highly selective catalytic hydroboration of alkyl-substituted aldimines to provide medicinally relevant α-amidoboronates is disclosed. The Cu(I)-catalyzed borylation proceeds with excellent facial selectivity when a set of planar-chiral N-heterocyclic carbenes (NHCs) were employed as ligands. Density functional theory computations suggest that interactions between BPin and the planar-chiral catalyst are responsible for the observed stereoselectivity. Important pharmacophores, such as the boronate analogue of isoleucine, can be prepared using a chromatography-free protocol starting from commercially available reagents. The application of these NHC ligands in these Cu(I)-catalyzed processes offers a significant contribution to existing strategies for laboratory-scale preparation of enantioenriched α-amidoboronates.

Full text of DOI:10.1021/jacs.8b05045

Subscriber access provided by University of Winnipeg Library
Communication
Enantioselective Synthesis of #-Amidoboronates
Cata-lyzed by Planar-Chiral NHC-Cu(I) Complexes
C. Benjamin Schwamb, Keegan P Fitzpatrick, Alexander C. Brueckner,
H. Camille Richardson, Paul Ha-Yeon Cheong, and Karl A. Scheidt
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05045 • Publication Date (Web): 13 Aug 2018
Downloaded from http://pubs.acs.org on August 13, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
Enantioselective Synthesis of α-Amidoboronates Catalyzed by
1
2
3
4
5
6
7
Planar-Chiral NHC-Cu(I) Complexes
†
†
‡
C. Benjamin Schwamb, Keegan P. Fitzpatrick, Alexander C. Brueckner, H. Camille Richard-
‡
‡
†*
son, Paul H.–Y. Cheong, and Karl A. Scheidt
8
9
†
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Northwestern University, Silver-
‡
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
man Hall, Evanston, Illinois 60208. scheidt@northwestern.edu. Department of Chemistry, Oregon State University,
153 Gilbert Hall, Corvallis, Oregon 97331. paulc@science.oregonstate.edu
α-amidoboronates could serve as potential metal-
catalyzed cross-coupling partners, if both aryl and al-
kyl substitutued species could be accessed with high
levels of efficiency and selectivity.
ABSTRACT The first highly selective catalytic hy-
droboration of alkyl-substituted aldimines to provide
medicinally relevant α-amidoboronates is disclosed.
The Cu(I)-catalyzed borylation proceeds with excel-
lent facial selectivity when a set of planar chiral
NHCs were employed as ligands. DFT computations
suggest that interactions between BPin and the pla-
nar chiral catalyst are responsible for the observed
stereoselectivity. Important pharmacophores, such
as the boronate analog of isoleucine, can be prepared
using a chromatography-free protocol starting from
commercially available reagents. The application of
these NHC ligand in these Cu(I)-catalyzed processes
offers a significant contribution to existing strategies
for laboratory-scale preparation of enantioenriched
While enantioselective imine borylations to access
alkyl amidoboronates currently operate at levels below
synthetic utility, some alternative approaches to con-
struct this motif via alkene functionalization have re-
cently emerged.12 For example, Miura disclosed an ele-
gant Cu(I)-catalyzed hydroamination of alkenyl boro-
nates to produce tertiary amines,12a while Tang ac-
cessed enantioenriched tertiary aminoboronates via a
Rh(I)-catalyzed hydroboration.12b Given the increasing
utility of α-alkyl amidoboronates and the dearth of
processes to produce them enantioselectively, we
sought to develop a system that could (1) deliver α-
alkylamidoboronates directly from imines, (2) use
starting materials readily prepared from commercially
available reagents, and (3) leverage the unique steric
and topological characteristics of our family of planar
chiral N-heterocyclic carbene ligands.
α-amidoboronates.
Boronic acids are widely useful reagents in organic
synthesis and constitute an important class of medici-
nal pharmacophores.1 Since the discovery of the inhibi-
tory properties of boronic acids against serine proteas-
es,2 α-amidoboronic acids have emerged as particularly
useful for selective proteosome inhibition.3 Conse-
quently, the α-amidoboronate moiety can be used as
an electrophilic “warhead” for covalent protease inhibi-
tion, guided by the peptide to which it is attached.3c,3e,4
The approval of Velcade (Figure 1) in 2003 was a break-
through clinical application of a boronic acid pep-
tidomimetic,5 and since then a rise in the number of
therapeutics using the α-amidoboronate motif has
been accompanied by increasing efforts towards their
efficient synthesis.6 The majority of therapeutically
relevant α-amidoboronates bear α-alkyl functionality,7
yet surprisingly there are limited means to access these
compounds in a catalytic enantioselective manner.8 In
1980, Matteson reported the homologation of a chiral
pinanediol to yield an α-chloroboronic ester and sub-
sequent nucleophilic displacement to yield the α-
amino adduct.9 Alternatively, the diastereoselective
borylation of N-tert-butylsulfinyl aldimines by Ellman
avoids the use of organolithium reagents and is dia-
stereoselective in nature (Figure 1).10 Very recently,
Baran has reported a decarboxylative approach to in-
stall boronic acids that can accommodate α-amino acid
substrates.11 In addition to their therapeutic potential,
ACS Paragon Plus Environment

Journal of the American Chemical Society
cant gap in the knowledge to date. We initiated our
Page 2 of 8
1
2
3
4
5
6
7
8
studies on this reaction, first with respect to identify-
ing compatible imine substrates for our catalysts. A
preliminary reaction screen using Cu(I)-NHC catalyst
A, B2Pin2 and 10 mol % NaOt-Bu in toluene revealed N-
benzoyl-protected α-tosylamines (e.g. 1a, Table 1) as
ideal imine precursors. N-benzoyl cyclohexylimine
generated in situ via deprotonation of 1a with excess
8c
Cs2CO3 gave adequate yields of the desired α-
9
amidoboronate 2a. (Figure 2A, entry 2). Further evalu-
ation identified catalyst C as capable of facilitating the
reaction with high enantioselectivity (97:3 er). Surpris-
ingly, catalysts bearing larger substitution on the wing-
tip N-aryl ring or the cyclopentadienyl (Cp) ring of the
ferrocene decreased both er and yield (entries 1–7). In
the absence of CuCl, no significant conversion was ob-
served using the precursor imidazolium chloride to C,
thus discounting a metal-free mechanism.10c In con-
trast to the analogous hydroboration of alkenes,16 we
found that protic additives completely suppressed the
reaction (entry 11). Other alkoxide bases led to de-
creased er in all cases (entries 12–14). Switching from
Cs2CO3 to K2CO3 negatively impacted yield, presuma-
bly due to slower aldimine formation, however er re-
mained unaffected (entry 16).
We were intrigued by the wide variability in reaction
enantioselectivity among the different Cu(I)-NHC
catalysts screened. For instance, pentaphenyl-Cp de-
rived catalysts B, D and G all gave product with uni-
formly low yield (~40%) and modest er (~70:30). To
gain a better sense of the steric demand presented by
these ligands in comparison to other known classes of
chiral NHC ligands, we calculated buried volume
(%VBur) on a subset of our NHC-metal complexes. This
parameter provides a useful relative assessment of the
overall steric encumbrance around a hypothetical met-
al center for a set of ligands.17 Our analyses revealed
that functionalization of the pendant Cp ring (e.g.,
pentamethyl-Cp C vs pentaphenyl-Cp G) had the
greatest effect on calculated total buried volume (Fig-
ure 2B). Notably, 51.3% of the simulated coordination
sphere was occupied for NHC G. This value is extreme-
ly large for Arduengo-type NHCs, which typically
range between 20-35%.17b Among carbenes, the ex-
tremely large %VBur of G is only approached by Ber-
trand’s CAAC-type NHC ligands (51.2 %VBur)18 and Glo-
rius’s (−)-menthone-derived IBiox NHC (47.8 %VBur).19
Examining other Cp*-derived NHCs revealed the wing-
tip N-aryl group had minimal impact on calculat-
ed %VBur (39.5 %VBur for C). All complexes examined
were characterized by a large occupancy in their
“southwest” quadrant (as depicted), where the bulky
Cp rings are positioned. The large difference in %VBur
between C and G demonstrates the potential tunability
of these ligands through either simple modulation of
the Cp base of the planar NHC scaffold or more com-
plex N-aryl substituents.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Overview of α-amidoboronate synthesis strate-
gies.
We have been engaged in developing Lewis bases for
organocatalysis and transition metal-mediated pro-
cesses,13 with a focus on new classes of N-heterocyclic
carbenes (NHCs). We disclosed the development of a
distinct class of planar chiral NHCs in 2015,14 which are
based on the pyridine-annulated iron sandwich com-
plexes pioneered by Fu.15 These ferrocene-based imid-
azolium derivatives possess tunable elements, allowing
for a variety of substituents to be introduced on either
the iron-complexed N-heterocyclic scaffold and/or the
lower Cp ring. We anticipated that the atypical stereo-
chemical environment presented by these NHCs as
ligands could be exploited to enable asymmetric or-
ganometallic transformations that remain unsolved
using the current state of the art. To enhance our lim-
ited understanding of the relevant molecular and
structural interactions present in this otherwise unex-
plored class of NHCs, we anticipated that modeling
studies (empirical and in silico) would be crucial to
benchmark the reactivity and selectivity of these NHCs
as ligands for asymmetric organometallic catalysis.
A survey of asymmetric transformations facilitated
by chiral Cu(I)-NHC complexes identified the asym-
metric diboration of alkyl aldimines remains a signifi-
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
Figure 2.a A) Optimization. B) Buried volume analysis.
A. Reaction optimization
Bz
Bz
1
2
3
Me
Me
aSee Supp. Information for details. bDetermined by 1H
NMR spectroscopy. cDetermined by HPLC (chiral station-
ary phase).
HN
Me
HN
5 mol % C
O
O
O
O
Me
Me
Me 6 mol % NaOtꢀBu
B
B
Ts
BPin
Me
3 equiv. Cs2CO3
THF, 23 ºC
Me
1a
2a
4
5
entry
erc
yield (%)b
modification
91
78
42
36
54
89
36
51
68
52
0
88
82
74
69
74
85
97:3
6
7
8
9
none
A instead of C
1
2
69:31
71:29
68:32
57:43
88:12
68:32
92:8
80:20
96:4
ꢀ
93:7
95:5
79:21
93:3
94:6
97:3
B instead of C
D instead of C
3
4
E instead of C
5
F instead of C
G instead of C
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
CH2Cl2 instead of THF
PhMe instead of THF
Boc instead of Bz
8
9
10
11
12
13
14
15
16
17
MeOH instead of NaOtꢀBu
KOt-Bu instead of NaOtꢀBu
LiOt-Bu instead of NaOtꢀBu
NaOsꢀamyl instead of NaOtꢀBu
0 ºC instead of 23 ºC
K2CO3 instead of Cs2CO3
2.0 instead of 3.0 equiv. Cs2CO3
R
R1
general catalyst structure
MeO
Me
R1
Me
Me Et
Ph Et
Me OMe
Ph Me
Me iꢀPr
Me OiꢀPr Me
Ph OMe
A
B
C
D
E
F
N
N
N
N
Ph
Fe
Cu
Cl
Me
Me
Fe
R
Cu
Cl
R
R
R1
Me
H
R
R
G
Me
B. Buried volume analysis
G
C
NW
NE
SE
SW
NHC
%VBur Total
33.2
31.9
28.0
46.3
51.5
68.8
45.3
58.2
C
G
39.5
51.3
Table 1. Substrate Scopea
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
O
O
Ar
1
2
3
4
5 mol % C
HN
R1
5 mol % C
6 mol % NaO
HN
Ar
BF3K
HN
Ar
O
6 mol % NaOtꢀBu
KF, tartaric acid
tꢀBu
B
2
then
R1
R1
Ts
O
O
3 equiv. Cs2CO3
THF, 23 ºC
MeCN:MeOH (1:1)
23 ºC
3 equiv. Cs2CO3
THF, 23 ºC
Me
Me
1
not
isolated
3
2
Me
Me
5
6
7
8
9
O
Br
NHBz
BXn
NHBz
NHBz
BXn
Me
NHBz
BXn
NHBz
Me
Me HN
BXn
Me
Me
BXn
ORTEP 2b
Me
BXn
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2d:b 61%, 99:1 er
3db: 85%
≡
2a: 65%, 97:3 er
3a: 87%
2b: 55%, 97:3 er
3b: 74%
2c: 48%, 95:5 er
3c: 62%
2f:c 72%, 99:1 er
3f: 74%
2e: 62%, 99:1 er
3e: 74%
Ph
Ph
Ph
Ph
HN
OBn
HN
O
HN
HN
O
H, 2j;d; 25%, 91:9 er
=
Me, 2kd; 45%, 93:7 er
R2
O
O
B
B
B
B
Ph
n
ꢀheptyl
O
O
O
O
O
O
O
O
R2
Me
Me
OMe, 2le;
Me
Me
Me
Me
Me
Me
Me
2g
67%, 92:8 er
2i
44%, 95:5 er
2h
37%, 85:15 er
Me
Me
Me
Me
46%, 99:1 er
Me
Me
Me
aIsolated yields. Enantiomeric ratio was determined by chiral HPLC analysis of the corresponding MIDA boronates. (See sup-
porting information for details.) bCatalyst H was used instead of C. cNot isolated (see SI for details) d solvent = MTBE. e solvent =
DCM
We next explored the scope of the asymmetric
borylation promoted by catalyst C using our optimized
conditions. A variety of primary and secondary α-
amido-pinacolatoboronate esters (2) were obtained in
excellent enantioselectivity (Table 1). Interestingly,
isobutyl-substituted 2d was obtained with diminished
er using catalyst C, however substituting catalyst H
furnished 2d in excellent er (99:1). Product 2f pos-
sessing a more sterically encumbered o-bromobenzoyl
protecting group was also formed with excellent enan-
tioselectivity (99:1). Aryl substrates (2j–2l) required
alternative solvents to observe good enantioselectivi-
ties (MTBE and DCM), albeit with lower isolated yields.
Finally, the absolute stereochemistry of 2b was as-
signed through X-ray crystallography, revealing cata-
lyst (–)-C produced 2b in the (S)–configuration.
While we identified conditions that could provide a
range of α-amidoboronates with high enantioselectivi-
ty, certain products exhibited a large discrepancy be-
tween isolated and NMR spectroscopy-based yields.
The diminished mass recovery is attributed to SiO2-
catalyzed protodeborylation of the products during
conventional chromatographic purification. Potassium
trifluoroborate (BF3K) salts typically exhibit markedly
improved stability in relation to their acid and ester
analogs, as well as diminished solubility in organic sol-
vents, which often allows their isolation to be conduct-
ed via simple precipitation.20 Thus, we sought means
to convert the crude α-amidoboronates (2) to their
BF3K salts (3) in an additional workup step that might
circumvent the need for chromatography altogether.
Initial attempts at converting some unpurified pinacol
esters to their corresponding salts via exposure to an
aqueous solution of KHF2 afforded the desired tri-
fluoroborate in low yields.21 However, milder condi-
tions developed by Lennox22 allowed for direct conver-
sion of unpurified enantioenriched α-amido-BPin es-
ters 2 to the corresponding BF3K salts 3 in a two-step,
chromatography-free procedure with considerably im-
proved yields (Table 1, 3a–3f).
Cu(I)-mediated borylations are currently understood
to proceed through a 4-membered transition state in-
volving initial alignment of the Cu–B and X=C bonds.23
With this foundation, we surmised that in the course
of this reaction, copper(I) chloride precatalyst C is first
converted to active alkoxide I, which can then undergo
σ-bond metathesis with B2Pin2, to yield copper boryl
species II. (Figure 3A).
A. Proposed catalytic cycle
N
N
R
Cu
N
H
R1
PinB
‡
H
R1
R
IV
N
HOtBu
N
N
B2Pin2
Cu
B
O
Me
Me
O
Me Me
III
HOtBu
PinB NHR
PinB
PinB NR
R1
H
R
N
R1
Cs2CO3
2
H
1
5
R1
H
N
N
N
N
4
NaOtBu
Cu OtBu
Cu BPin
NHCꢀCuCl
C
I
II
B2Pin2
B. TS model & buried volume analysis
33.2
28.0
open
closed
open
closed
N
φ
Bz
N
N
R
Cu
B
O
O
closed
closed
closed
Fc
51.5
45.3
(−)ꢀC (%Vbur
III
4-membered TS
(major)
)
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
Figure 3. A) Proposed catalytic cycle B) Comparison of
1
2
major TS model and buried volume analysis of catalyst C
(see Supp Info for details).
3
4
5
6
7
8
9
After deprotonation of sulfinyl species 1, the result-
ant imine (4) can undergo σ-bond metathesis as de-
picted in transition state III. Protonolysis of amidate
(IV) with tert-butanol could yield the product (2), or
exchange of IV with an additional equivalent of B2Pin2
could afford bis(boronate) 5, and then subsequent pro-
tonolysis would also lead to product 2.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A model for the observed selectivity in the aldimine
borylation is depicted in Figure 3B. Analysis of the
crystal structure of catalyst (−)-C, as well as buried
volume calculations (see Figure 2), reveal a clearly dis-
cernable “open” northwest quadrant. The proposed
major transition state (III) depicts an approach of the
E-aldimine via the top face of the NHC anti- to the fer-
rocene. In this arrangement, the benzoyl group occu-
pies the open quadrant, minimizing steric repulsion
with the out-of-plane catalyst o,o-dimethoxyphenyl
ring, possibly participating in stabilizing π-stacking
with the ferrocene and its adjacent ring. To fashion a
deeper understanding of the composite energetic fac-
tors governing catalyst selectivity, we initiated DFT
studies to further elucidate the origins of selectivity in
the borylation reaction. The computed major and mi-
nor borylation transition states of imine 4 by catalyst C
are shown in Figure 4. The Major-TS leading to the
experimentally favored enantiomeric product is 2.3
kcal/mol more stable than the Minor-TS, in good
agreement with experiments (∆G‡ = 2.1 kcal/mol).
Distortion-interaction analyses of the transition
states were performed. The relative imine distortion
energies and the interaction energies are small and
inconsequential (∆G = 0.7 and –1.1 kcal/mol, respec-
tively). The bulk of the selectivity arises from the dif-
ferences in distortion energies of the copper-Bpin spe-
cies (∆G = 2.6 kcal/mol).
Figure 4. The computed major and minor imine boryla-
tion transition structures. Distances in Å and energies in
kcal/mol. Cyclohexanes are represented by a single purple
sphere.24
Overlaying these copper-Bpin species found in the
two transition states reveals two major differences (see
SI): 1) the ferrocene is eclipsed in the Minor-TS and
staggered in the Major-TS; 2) one of the Bpin oxygens
is in closer proximity to the ferrocene in the Major-TS
than the Minor-TS (O-Fe distance is 5.1 vs 5.4 Å, two
C-H•••O interactions vs one, respectively). We had
originally hypothesized that the eclipsed vs staggered
ferrocene conformations may be responsible for the
selectivity. To test this hypothesis, we computed the
eclipsed and staggered conformations of the copper
boryl species II. The staggered was indeed found to be
more stable than the eclipsed, but only slightly so (∆G
= 0.5 kcal/mol). This suggested that the Bpin oxygen
ferrocene interaction is responsible for the bulk of the
difference, and therefore the bulk of the stereoselectiv-
ity (~2 kcal/mol).25
In summary, we have developed the first highly se-
lective catalytic hydroboration of alkyl-substituted al-
dimines. This approach involves the deployment of
new planar chiral N-heterocyclic carbene-copper com-
plexes to control the delivery of the boron nucleophile
to the in-situ formed imine. This ligand set provides a
distinctive tuneable buried volume parameter that
could be advantageous in other transition-metal cata-
lysed processes. DFT computations provide strong evi-
dence for the stereochemical rationale. The overall
synthetic process has been streamlined to be entirely
chromatography-free in most cases. This platform can
now provide the community with rapid access to a
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
411; (f) Han, L.-Q.; Yuan, X.; Wu, X.-Y.; Li, R.-D.; Xu, B.; Cheng,
range of α-amidoboronates with medicinally relevant
properties that could also serve as versatile building
blocks in other metal catalysed transformations.
Q.; Liu, Z.-M.; Zhou, T.-Y.; An, H.-Y.; Wang, X.; Cheng, T.-M.;
Ge, Z.-M.; Cui, J.-R.; Li, R.-T. Eur. J. Med. Chem. 2017, 125, 925–
939; (g) Manasanch, E. E.; Orlowski, R. Z. Nat Rev Clin Oncol
2017, 14, 417-433.
1
2
3
4
5
6
7
8
9
Supporting Information. Experimental procedures,
spectral data for new compounds, crystallographic data,
computed energies and structures. This material is
available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Sole, C.; Gulyas, H.; Fernandez, E. Chem. Commun. 2012,
48, 3769–3771; (b) Hong, K.; Morken, J. P. J. Am. Chem. Soc. 2013,
135, 9252–9254; (c) Zhang, S.-S.; Zhao, Y.-S.; Tian, P.; Lin, G.-Q.
Synlett 2013, 24, 437–442; (d) Wang, D.; Cao, P.; Wang, B.; Jia, T.;
Lou, Y.; Wang, M.; Liao, J. Org. Lett. 2015, 17, 2420–2423; (e)
Chen, L.; Zou, X.; Zhao, H.; Xu, S. Org. Lett. 2017, 19, 3676-3679;
(f) López, A.; Clark, T. B.; Parra, A.; Tortosa, M. Org. Lett. 2017,
19, 6272–6275.
(9) (a) Wityak, J.; Earl, R. A.; Abelman, M. M.; Bethel, Y. B.;
Fisher, B. N.; Kauffman, G. S.; Kettner, C. A.; Ma, P.; McMillan, J.
L. J. Org. Chem. 1995, 60, 3717–3722; (b) Matteson, D. S. J. Org.
Chem. 2013, 78, 10009–10023; (c) Ammoscato, V.; Bishop, J. E.;
Chiu, F. T.; Geiser, A.; Gomez, J. M.; Hett, R.; Koellner, C.;
Kulkarni, V. R.; Lo, Y.; Munk, S. In Google Patents; USPTO, Ed.;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Acknowledgements
Financial support was generously provided by the
NSF (CHE-1665141; CHE-1152010). PHYC gratefully
acknowledges financial support from the Vicki & Pat-
rick F. Stone family. PHYC and ACB thank the Nation-
al Science Foundation (NSF, CHE-1352663 and CHE-
1102637).
Millennium
Pharmaceuticals,
Inc.:
USA,
2016;
Vol.
US20160362449.
(10) (a) Beenen, M. A.; An, C.; Ellman, J. A. J. Am. Chem. Soc.
2008, 130, 6910–6911; (b) Robak, M. T.; Herbage, M. A.; Ellman, J.
A. Chem. Rev. 2010, 110, 3600–3740; (c) Wen, K.; Chen, J.; Gao, F.;
Bhadury, P. S.; Fan, E.; Sun, Z. Org. Biomol. Chem. 2013, 11, 6350–
6356; (d) Wen, K.; Wang, H.; Chen, J.; Zhang, H.; Cui, X.; Wei,
C.; Fan, E.; Sun, Z. J. Org. Chem. 2013, 78, 3405–3409; (e)
Buesking, A. W.; Bacauanu, V.; Cai, I.; Ellman, J. A. J. Org. Chem.
2014, 79, 3671–3677; (f) Chen, J.; Chen, L.-y.; Zheng, Y.; Sun, Z.
RSC Advances 2014, 4, 21131–21133.
(11) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, D. S.;
Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, M.;
Baran, P. S. Science 2017, 356.
(12) (a) Nishikawa, D.; Hirano, K.; Miura, M. J. Am. Chem. Soc.
2015, 137, 15620-15623; (b) Hu, N.; Zhao, G.; Zhang, Y.; Liu, X.; Li,
G.; Tang, W. J. Am. Chem. Soc. 2015, 137, 6746–6749.
(13) (a) Izquierdo, J.; Orue, A.; Scheidt, K. A. J. Am. Chem. Soc.
2013, 135, 10634–10637; (b) McCusker, E. O.; Scheidt, K. A. Angew
Chem Int Ed Engl 2013, 52, 13616–13620; (c) Jang, K. P.; Hutson, G.
E.; Johnston, R. C.; McCusker, E. O.; Cheong, P. H.; Scheidt, K. A.
J. Am. Chem. Soc. 2014, 136, 76–79; (d) Liu, K.; Hovey, M. T.;
Scheidt, K. A. Chem. Sci. 2014, 5, 4026-4031; (e) Wang, M. H.;
Cohen, D. T.; Schwamb, C. B.; Mishra, R. K.; Scheidt, K. A. J. Am.
Chem. Soc. 2015, 137, 5891-5894; (f) Hovey, M. T.; Cohen, D. T.;
Walden, D. M.; Cheong, P. H. Y.; Scheidt, K. A. Angew. Chem.
Int. Ed. 2017, 56, 9864-9867.
(14) Check, C. T.; Jang, K. P.; Schwamb, C. B.; Wong, A. S.; Wang,
M. H.; Scheidt, K. A. Angew. Chem. Int. Ed. 2015, 54, 4264–4268.
(15) (a) Rios, R.; Liang, J.; Lo, M. M. C.; Fu, G. C. Chem. Commun.
2000, 377-378. (b) For a relevant dscription of the evoliution and
application of planar chiral ligands in asymmetric catalysis, see:
Fu, G. C. Acc. Chem. Res. 2006, 39, 853-860.
(16) Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3160-3161.
(17) (a) Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone,
F.; Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009, 2009, 1759-
1766; (b) Clavier, H.; Nolan, S. P. Chem. Commun. 2010, 46, 841-
861.
(18) Lavallo, V.; Frey, G. D.; Kousar, S.; Donnadieu, B.; Bertrand,
G. Proc. Nat. Acad. Sci. 2007, 104, 13569-13573.
(19) Würtz, S.; Lohre, C.; Fröhlich, R.; Bergander, K.; Glorius, F. J.
Am. Chem. Soc. 2009, 131, 8344–8345.
(20) (a) Molander, G. A.; Wisniewski, S. R. J. Am. Chem. Soc.
2012, 134, 16856–16868; (b) Molander, G. A. J. Org. Chem. 2015,
80, 7837–7848; (c) Molloy, J. J.; Watson, A. J. B. B-Protected
Boronic Acids: Methodology Development and Strategic
Application. In Boron Reagents in Synthesis; Coca, A., Ed.; ACS
Symposium Series; American Chemical Society: Washington,
DC, 2016; pp 379–413.
REFERENCES
(1) (a) Yang, W.; Gao, X.; Wang, B. Medicinal Research Reviews
2003, 23, 346–368; (b) Trippier, P. C.; McGuigan, C.
MedChemComm 2010, 1, 183–198; (c) Ni, N.; Wang, B.
Applications of Boronic Acids in Chemical Biology and
Medicinal Chemistry. In Boronic Acids; Hall, D. G., Ed.; Wiley-
VCH Verlag GmbH & Co. KGaA: 2011; pp 591–620; (d) Das, B. C.;
Thapa, P.; Karki, R.; Schinke, C.; Das, S.; Kambhampati, S.;
Banerjee, S. K.; Van Veldhuizen, P.; Verma, A.; Weiss, L. M.;
Evans, T. Future Medicinal Chemistry 2013, 5, 653–676; (e)
Leśnikowski, Z. J. Expert Opinion on Drug Discovery 2016, 11,
569–578.
(2) Philipp, M.; Bender, M. L. Proc. Nat. Acad. Sci. 1971, 68, 478–
480.
(3) (a) Valery, M. D.; Abed Al Aziz, Q.; Morris, S. Mini-Reviews in
Medicinal Chemistry 2004, 4, 1001–1018; (b) Matteson, D. S.
Medicinal Research Reviews 2008, 28, 233–246; (c) Milo, L. J.; Lai,
J. H.; Wu, W.; Liu, Y.; Maw, H.; Li, Y.; Jin, Z.; Shu, Y.; Poplawski,
S. E.; Wu, Y.; Sanford, D. G.; Sudmeier, J. L.; Bachovchin, W. W.
J. Med. Chem. 2011, 54, 4365–4377; (d) Touchet, S.; Carreaux, F.;
Carboni, B.; Bouillon, A.; Boucher, J.-L. Chem. Soc. Rev. 2011, 40,
3895–3914; (e) Micale, N.; Scarbaci, K.; Troiano, V.; Ettari, R.;
Grasso, S.; Zappalà, M. Medicinal Research Reviews 2014, 34,
1001–1069.
(4) Ballatore, C.; Huryn, D. M.; Smith, A. B. ChemMedChem 2013,
8, 385–395.
(5) (a) Kane, R. C.; Bross, P. F.; Farrell, A. T.; Pazdur, R. The
Oncologist 2003, 8, 508–513; (b) Adams, J.; Kauffman, M. Cancer
Investigation 2004, 22, 304–311; (c) Kane, R. C.; Dagher, R.;
Farrell, A.; Ko, C.-W.; Sridhara, R.; Justice, R.; Pazdur, R. Clinical
Cancer Research 2007, 13, 5291–5294.
(6) (a) Andres, P.; Ballano, G.; Calaza, M. I.; Cativiela, C. Chem.
Soc. Rev. 2016, 45, 2291–2307; (b) Clark, T. B. Asian Journal of
Organic Chemistry 2016, 5, 31–42.
(7) (a) Cunningham, C. C. Expert Opinion on Investigational
Drugs 2007, 16, 1459–1465; (b) White, J. Drugs of today
(Barcelona, Spain: 1998) 2011, 47, 99–107; (c) Seavey, M. M.; Lu, L.
D.; Stump, K. L.; Wallace, N. H.; Ruggeri, B. A. International
Immunopharmacology 2012, 12, 257–270; (d) Hecker, S. J.; Reddy,
K. R.; Totrov, M.; Hirst, G. C.; Lomovskaya, O.; Griffith, D. C.;
King, P.; Tsivkovski, R.; Sun, D.; Sabet, M.; Tarazi, Z.; Clifton, M.
C.; Atkins, K.; Raymond, A.; Potts, K. T.; Abendroth, J.; Boyer, S.
H.; Loutit, J. S.; Morgan, E. E.; Durso, S.; Dudley, M. N. J. Med.
Chem. 2015, 58, 3682–3692; (e) Shirley, M. Drugs 2016, 76, 405–
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
(21) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.;
Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020–3027; (b) Buesking,
A. W.; Ellman, J. A. Chem. Sci. 2014, 5, 1983–1987.
(24) Structures were optimized using B3LYP-D3BJ/6-
31G(d)//SMD(THF) level of theory. Final energy refinements
were computed using M06/6-31G(d)//SMD(THF). See
Supporting Information for full list of citations.
(25) Similar interactions have been proposed to be important for
stereoselectivity in planar-chiral organocatalytic reactions
involving the ferrocene based organocatalyst PPY*, see:
Pattawong, O.; Mustard, T. J. L.; Johnston, R. C.; Cheong, P. H.-
Y. Angew. Chem. Int. Ed. 2013, 52, 1420–1423.
1
2
3
4
5
6
7
8
(22) (a) Lennox, A. J. J. Organotrifluoroborate Preparation. In
Organotrifluoroborate Preparation, Coupling and Hydrolysis;
Springer Theses; Springer International Publishing: Cham, 2013;
pp 11–36; (b) Lennox, A. J. J.; Lloyd-Jones, G. C. Angew. Chem. Int.
Ed. 2012, 51, 9385–9388.
(23) (a) Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem.
Soc. 2008, 130, 5586–5594; (b) Chong, C. C.; Kinjo, R. ACS
Catalysis 2015, 5, 3238–3259; (c) Kubota, K.; Jin, M.; Ito, H.
Organometallics 2016, 35, 1376–1383.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
TOC Graphic:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment