Iridium-Catalyzed Asymmetric Borylation of Unactivated Methylene C(sp3)-H Bonds

Article abstract of DOI:10.1021/jacs.9b01952

Herein, we show the highly enantioselective borylation of unactivated methylene C(sp³)-H bonds in 2-alkylpyridines and 2-alkyl-1,3-azole derivatives using an iridium-BINOL-based chiral monophosphite catalyst system. Quantum chemical calculations using the artificial force induced reaction (AFIR) method suggested that a monophosphite-Ir-tris(boryl) complex generates a narrow chiral reaction pocket where the differentiation of the enantiotopic methylene C-H bonds is accomplished through an assembly of multiple noncovalent interactions.

Full text of DOI:10.1021/jacs.9b01952

Subscriber access provided by UNIV OF LOUISIANA
Communication
Iridium-catalyzed Asymmetric Borylation
3
of Unactivated Methylene C(sp)–H Bonds
Ronald L. Reyes, Tomohiro Iwai, Satoshi Maeda, and Masaya Sawamura
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01952 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 15, 2019
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 7
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Iridium-catalyzed Asymmetric Borylation of Unactivated Methylene
C(sp3)–H Bonds
Ronald L. Reyes,1,2 Tomohiro Iwai,1 Satoshi Maeda,1,2,* and Masaya Sawamura1,2,*
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
1 Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
2 Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Sapporo 001-0021, Japan
Supporting Information Placeholder
the directing group. Significantly, we found that some
soluble homogeneous monophosphines including chiral
phosphoramidite ligands can also promote these trans-
formations with moderate enantioselectivities.8,9
ABSTRACT: Herein, we show the highly enantioselective
borylation of unactivated methylene C(sp3)–H bonds in 2-
alkylpyridines and 2-alkyl-1,3-azole derivatives using an iridi-
um-BINOL-based chiral monophosphite catalyst system.
Quantum chemical calculations using the artificial force in-
duced reaction (AFIR) method suggested that a monophos-
phite-Ir-tris(boryl) complex generates a narrow chiral reaction
pocket where the differentiation of the enantiotopic methylene
C–H bonds is accomplished through an assembly of multiple
noncovalent interactions.
a
R1 R2
R1 R2
R1 R2
[M]L*
FG
H
[M]L*
H
FG
H
H
C–H activation
*
*
Enantiotopic carbons
Desymmetrization
Functionalization
b
[M]L*
[M]L*
FG
H
H
H
FG
H
R1
R1
R1
R2
R1
R1
C–H activation
*
*
Enantiotopic
methylene C–H bonds
Discrimination of
enantiotopic protons
Transformative synthetic strategies that circumvent
challenges in the activation of C(sp3)–H bonds remain
underdeveloped despite the significant advances in re-
cent years.1 A common theme in asymmetric C(sp3)–H
activation involves the inception of chirality by the
desymmetrization of symmetrical molecules through
differentiation of enantiotopic carbons that leads to an
array of stereochemistry-generating C–H functionaliza-
tion (Figure 1a).2 A more challenging stereocenter-
generating transformation involves the discrimination of
enantiotopic C(sp3)–H bonds situated on a single meth-
ylene carbon center (Figure 1b). While a greater number
of reports exist on transformations of considerably acti-
vated methylene C–H bonds located α-to-heteroatoms3
or at benzylic positions,4 asymmetric discrimination of
unactivated enantiotopic methylene C–H bonds is rela-
tively rare and has been a long-standing challenge in
organic synthesis. Successful strategies in this area in-
clude mechanistically outer sphere processes5 and inner-
sphere asymmetric C(sp3)–H cleavage through a con-
certed metalation-deprotonation pathway.6
O
c
DA
cat. [Ir–L*]
O
H
B
O
O
O
H
DA
H
+
B
B
(–HBpin)
R
R
O
*
Our Previous Work
This Work
Achiral Heterogeneous System
Chiral Homogeneous System
P
Si
Si
O
SiMe3
O
O
O
P
O
O
Si
Si
O
O
O
O
O
O
SiO2
Silica-SMAP
up to 99% ee
Figure 1. C(sp3)–H bond activation strategies featuring the
desymmetrization of enantiotopic carbons (a) or by the dif-
ferentiation of enantiotopic methylene C–H bonds (b). (c)
Site-selective borylation of methylene C(sp3)–H bonds by
the achiral or chiral Ir-catalyst systems. FG: Functional
group; DA: Donor atom.
Encouraged by the preliminary outcome, we investi-
gated the readily modifiable monophosphite family
(Figure 2). Simple atropisomeric BINOL-based mono-
phosphite bearing an unsubstituted phenolic moiety L1
for the borylation of 2-propylpyridine (1a) with
bis(pinacolato)diboron (2) under iridium catalysis [1a/2
2:1, Ir: 3 mol %, Ir/P 1:1, cyclopentyl methyl ether
(CPME) as a solvent, 80 °C, 15 h] followed by oxidation
of the corresponding secondary alkylboronate 3a
showed an inadequate performance. Modifications to the
phenolic moiety at the two ortho-positions with Me
We previously described the heteroatom-directed
borylation of unactivated methylene C(sp3)–H bonds by
employing a heterogeneous Ir-catalyst system based on
silica-supported monophosphine ligand, Silica-SMAP
(Figure 1c).7 The 1:1 metal/P ratio and the proximity
effect due to the heteroatom-to-metal coordination are
both indispensable to allow the efficient site-selective
borylation of C–H bonds situated γ to the heteroatom in
ACS Paragon Plus Environment

Journal of the American Chemical Society
groups (L2) resulted in limited reactivity and low enan-
Page 2 of 7
Next, we investigated the substrate scope (Table 1).
Thus, 2-pentylpyridine underwent the enantioselective
borylation-oxidation reaction to give the corresponding
product 4b (96% ee, entry 1). The presence of both elec-
tron-donating and electron-withdrawing groups at the
pyridyl moiety were tolerated to give products 4c and 4d
with excellent enantioselectivities of 94% ee and 97% ee,
respectively (entries 2 and 3). The borylation of 2-(3-
phenylpropyl)pyridine occurred with exclusive site se-
lectivity giving 4e (93% ee) in 75% yield (entry 4).
1
2
3
4
5
6
7
8
tioselectivity. In contrast, the enantioselectivity was sig-
nificantly improved when Ph groups were introduced
instead (L3). Homologous P-substitution by a 1-
naphthol moiety (L4) further enhanced the enantioselec-
tivity up to 76% ee, pointing out an intuitive trend favor-
ing an extended aromatic environment. This prompted
us to introduce a second BINOL group. To our satisfac-
tion, the reported phosphite L510 delivered the product at
80% ee. Furthermore, the modification of the OH group
with a TIPS group produced even better performing lig-
and L6, leading to a jump up of enantioselectivity to
90% ee, despite the formation of undesired pyridyl
C(sp2)–H borylation products (9%).
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
Table 1. Ir-catalyzed asymmetric borylation of methylene
C(sp3)–H bonds (Scope of the borylation-oxidation protocol).a
yield of ee of 4
entry
1d
oxidation product 4
4 (%)b
(%)c
[Ir(OMe)(cod)]2 (3 mol% Ir)
Ligand (L, 3 mol%)
O
O
O
O
N
OH
Bpin
Me
N
N
H
H
4b
87
96 (S)
+
B
B
Me
CPME (2 mL), 80 ℃, 15 h
Me
(–HBpin)
(S)-3a
N
OH
2 (B2pin2, 0.30 mmol)
1a (2.0 equiv)
2d
4c
4d
4e
85
65
75
94 (S)
97 (S)
93 (S)
N
H
OH
Me
NaBO3 • 4H2O (3 equiv)
THF/H2O (1:1), r.t., 3 h
Me
F3C
Me
N
OH
3d, e
4
(S)-4a
Ligand, Isolated yield of 4a (based on 2), % ee
Me
N
OH
Ph
O
O
O
P
R
O
R
P
O
N
OH
O
O
5
4f
54
91 (R)
N
H
OtBu
(R)-L1 (R = H ), trace (1H NMR)
(R)-L2 (R = Me), 30%, 30% ee
(R)-L3 (R = Ph), 25%, 63% ee
N
N
N
OH
(R)-L4, 49%, 76% ee
6d
7
4g
4h
4i
52
78
53
95 (R)
94 (R)
92 (R)
OSiMe2tBu
OH
Si
O
OMe
O
O
O
P
OH
O
HO
O
8d
O
P
O
O
O
N
OH
OH
OH
(R,R)-L6
9e
4j
4k
4l
95
86
75
93 (S)
98 (S)
96 (R)
55%, 90% eea
N
Me
75%, 98% ee (2,6-lutidine 20 mol%)
(R)-L5, 52%, 80% ee
Me
2,6-lutidine 20 mol%
3 equiv 1a, 36 h
2 mol% Ir, 2,6-lutidine 20 mol%
2 equiv 1a, 36 hb, 1.10 g (S)-4a
83%, 99% ee
N
N
N
96%, 99% ee
10
11e
Ph
N
Me
Figure 2. Ligand effects in the Ir-catalyzed asymmetric
borylation of 1a. Borylation conditions: 1a (0.60 mmol), 2
(0.30 mmol), [Ir(OMe)(cod)]2 (Ir: 3 mol%), L1-6 (3 mol%),
CPME (2 mL), 80 °C, 15 h. Oxidation conditions:
NaBO3·4H2O (0.90 mmol), THF (1 mL), H2O (1 mL), r.t., 3
N
Ph
Me
OH
12d
4m
87
95 (R)
h, open air. C(sp2)–H borylation product (9%) was ob-
a
N
Me
b
served. Gram-scale reaction: 1a (16.5 mmol), 2 (8.25
mmol), [Ir(OMe)(cod)]2 (Ir: 2 mol%), (R,R)-L6 (2 mol%),
2,6-lutidine (20 mol%), CPME (10 mL), 80 °C, 36 h.
13d, e
14d
4n
4o
4p
87
71
78
92 (S)
92 (R)
90 (R)
N
N
N
OH
S
Me
OH
Interestingly, the use of 2,6-lutidine (20 mol%) as an
additive was effective in not only suppressing the pyri-
dine ring borylation but also increasing the enantioselec-
tivity, giving 4a as the sole product in 75% yield at 98%
ee (see Figure 2). This result was further enhanced by
using 3 equiv of 1a in the presence of 20 mol% of 2,6-
lutidine, isolating the product in 83% yield at 99% ee.11,
S
Ph
OH
Ph
15d, e
O
a
Borylation conditions: 1 (0.90 mmol, 3 equiv), 2 (0.30
mmol), [Ir(OMe)(cod)]2 (3 mol% Ir), (R,R)-L6 (3 mol%),
CPME (2 mL), 80 ℃, 15 h. Oxidation conditions:
NaBO3·4H2O (0.90 mmol), THF (1 mL), H2O (1 mL), r.t., 3
12
The protocol is also applicable at a larger scale (2
b
c
h. Isolated yield of 4 based on 2. Enantiomeric excess
mol% Ir-L6 cat., 1a 2eq). The absolute configuration of
4a was determined to be S by comparing its optical rota-
tion with the literature value.13
(ee) was determined by chiral HPLC analysis. d 20 mol% of
ACS Paragon Plus Environment

Page 3 of 7
Journal of the American Chemical Society
e
2,6-lutidine was used as an additive. The borylation was
conducted for 24 h.
tures produced manually through the rotation of the Ir–P
bond (ca. 120° and 240°). The resulting twelve (2x2x3)
apprTSs were fully optimized without artificial force
using M06-L density functional including D3 empirical
dispersion correction (SDD for Ir, 6-31G*). The IRC
analysis was then conducted for all of the DFT-
optimized TSs.17 Finally, single point energy calcula-
tions were done using MN15 density functional [SMD
(Et2O), SDD for Ir, 6-311G(2d,p)].
Chemical diagrams and relative free energies of the
optimized local minima (PC-S and PD-S) and transition
states (TS-S) for the C(sp3)–H bond cleavage reaction
pathway that goes through the most stable TS (PC-S–
TS-S–PD-S) with an energy barrier of 23.8 kcal mol–1 is
shown in Figure 3. The precursor complex (PC-S) has a
C–H···Ir(III) agostic interaction and the product com-
plex (PD-S) has the Ir(V) center σ-bonded to the C(sp3)
and H atoms, indicating that this step is a concerted
C(sp3)–H bond oxidative addition to the Ir(III) center.
1
2
3
4
5
6
7
8
An N-Boc-aminoalkyl substrate allowed the boryla-
tion of a C(sp3)–H at the position γ to the pyridine N
atom and adjacent to the N atom of the secondary amino
group, giving the enantioenriched α-N-Boc-amino alco-
hol 4f (91% ee, Table 1, entry 5). Substrates with a silyl-
or MOM-protected hydroxyl group also gave the corre-
sponding enantioenriched products 4g (95% ee) or 4h
(94% ee), respectively (entries 6 and 7). The reaction of
a substrate possessing a cyclic acetal moiety occurred
cleanly to give 4i (92% ee) (entry 8).
Other 2-alkylheteroaryl derivatives were suitable
substrates. The C(sp3)–H borylation of benzimidazole
derivatives occurred efficiently with exclusive site selec-
tivity, giving 4j and 4k at excellent enantioselectivities
(Table 1, entries 9 and 10). The borylation of more con-
gested 2-(2-phenylethyl)benzimidazole or the corre-
sponding cyclohexyl-substituted substrate also proceed-
ed smoothly with excellent enantioselectivities (4l, 96%
ee, 4m, 95% ee, entries 11 and 12), demonstrating a sig-
nificant tolerance of this protocol toward steric hin-
drance. Other benzo-fused substrates including benzo-
thiazole and benzoxazole derivatives also gave the enan-
tioenriched alcohols 4m–p with high enantioselectivities
(entries 13–15).
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
B2pin
B2pin
H
B2pin
pinB3
pinB1
pinB3
pinB1
pinB3
pinB1
H
Ir
H
Ir
N
N
N
Ir
H
H
H
H
H
Me
P
H
Me
P
P
P = (R,R)-L6
H
Me
H
H
PC-S
0
TS-S
+23.8
PD-S
+17.4
State
ΔG rel (kcalmol–1
)
Figure 3. Chemical diagrams and relative free energies of
the DFT-optimized local minima (PC-S and PD-S) and
transition states (TS-S) for the most favorable C(sp3)–H
bond cleavage reaction pathway.
Kinetic analysis using 1a or 2-(2,2,3,3,3-
pentadeuterioprop-1-yl)pyridine (1a-d5) with 2 and the
Ir-L6 catalyst system gave a significant kinetic isotope
effect value, kH/kD = 3.6. This value implied that a turn-
over-limiting step of the Ir catalysis involved the cleav-
age of a C(sp3)–H bond (see Supporting Information for
details of the kinetic studies).14 Based on this result, we
conducted preliminary quantum chemical calculations,
focusing on C–H bond cleavage by the catalyst. Consid-
ering an ambiguity and difficulty in locating appropriate
transition states (TS) for a large-scale full reaction sys-
tem with standard DFT methods, we employed the arti-
ficial force induced reaction (AFIR) method implement-
ed in the GRRM program.15,16 For an initial setup, we
explored the conformations of L6 using the single-
component mode of the AFIR method (SC-AFIR),
which generated a total of 93 conformers.
Among them, the 10 lowest energy conformers were
selected for the three-component complexation with
Ir(Bpin)3 and 2-propylpyridine (1a) under artificial forc-
es in the multi-component mode (MC-AFIR). This led to
the finding of a reasonable P,N-coordinated precursor Ir
complex that exhibited an agostic interaction between
the pro-S hydrogen atom γ to the pyridine N atom and
the Ir(III) center. Then, 1a was relocated manually at the
Ir coordination sphere for interchanges of enantiotopic
C–H bonds and N/C–H coordination sites for following
SC-AFIR searches that explore four (2x2) approximate
transition states (apprTSs). Then, the same workflow
was applied for other two L6-Ir(Bpin)3 backbone struc-
Three-dimensional representations with important
geometrical features of the most stable S-producing TS
(TS-S) are shown in Figure 4a in comparison with those
of the most relevant R-producing TS (TS-R) (Figure 4b).
The former is 2.8 kcal mol–1 lower in energy than the
latter at 80 °C.18 The L6-Ir(Bpin)3 backbones are virtual-
ly superimposable between the two TSs (Figure S8).
Thus, this comparison should be useful to discuss how
the catalyst in the specific conformation is able to differ-
entiate the enantiotopic C(sp3)–H bonds. The bulky
TIPS group fills a space on the backside of the P lone
pair, making the silyloxy-substituted naphthalene ring
stand upward approaching the Ir(Bpin)3 site. As a result,
two of the ligand naphthalene rings and the three Bpin
groups produce a narrow chiral reaction pocket with the
deeply embedded Ir center, in which the 2-alkylpyridine
substrate, in either TS-S or TS-R, is accommodated not
only through metal-centered coordination but also with
the assembly of weak attractive interactions such as π/π,
C–H/π, and C–H···O interactions.19–21
Mapping of noncovalent interaction surfaces by
NCIPlot and VMD analysis visualizes stabilizing effects
within the reaction pocket (Figure 4).22,23 The pyridine
ring and the naphthalene ring are stacked to each other
in the more stable TS-S, while they are more angular in
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 7
TS-R. Thus, the former has more gain of stabilization
energy in terms of π/π interactions. In addition, stabili-
zation of TS-S by C–H/π interactions is significant be-
tween the pyridine moiety and a methyl group of the
B2pin moiety, while such interactions are present only in
a diminished magnitude in TS-R. Moreover, non-
classical hydrogen bonds that occur between C(sp3)–H
or C(sp2)–H bonds in the substrate and O atoms present-
ed in the surface of the catalytic pocket may also con-
tribute to the difference in stability between the two
TSs.19–21
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
Figure 4. 3-D representations with geometrical features of the transition states leading to the major enantiomer (TS-S) (a)
and the minor enantiomer (TS-R) (b). The binaphthyl moieties of L6 are shown in green, the TIPS group in pale blue (iPr)
and pale yellow (Si), and the substrate in yellow. All atomic distances are given in Å.
In summary, the asymmetric borylation of unactivat-
ed methylene C(sp3)–H bonds was achieved with excel-
lent enantioselectivity resulting from the efficient dis-
crimination of enantiotopic C–H bonds by the catalyst.
Crucial to the reactivity and enantioselectivity is the
generation of a monophosphite-Ir-tris(boryl) complex
that provides a narrow chiral reaction pocket conceptual-
ly analogous to an enzyme active site with the multiple
secondary attractive interactions between the substrate
and the catalyst.14c Further experimental work to expand
the scope of asymmetric C–H borylation and more ad-
vanced computational studies to explore full catalytic
cycles are in progress.
Supporting Information
Experimental procedures, the characterization of all new com-
pounds, and details on the computational studies are provided in
the Supplementary Information. The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*sawamura@sci.hokudai.ac.jp; *smaeda@eis.hokudai.ac.jp
ACKNOWLEDGMENT
This work was supported by JST ACT-C Grant Number
JPMJCR12YN, MEXT KAKENHI Grant Number JP15H05801 in
Precisely Designed Catalysts with Customized Scaffolding, and
JSPS KAKENHI Grant Number JP18H03906 in Grant-in-Aid for
Scientific Research (A) to M. S. R. L. R. thanks MEXT for the
ASSOCIATED CONTENT
ACS Paragon Plus Environment

Page 5 of 7
Journal of the American Chemical Society
catalyzed enantioselective alkynylation of unbiased methylene
scholarship support during his Ph.D. studies. This research used
computational resources provided by the Academic Center for
Computing and Media Studies, Kyoto University. We thank
FUJIFILM Wako Pure Chemical Corporation for providing Sili-
ca-SMAP used in the preparation of racemic products.
C(sp3)–H bonds using 3,3’-fluorinated-BINOL as a chiral ligand. J.
Am. Chem. Soc. 2019, 141, 4558–4563.
1
2
3
4
5
6
7
8
(7) (a) Kawamorita, S.; Murakami, R.; Iwai, T.; Sawamura, M. Syn-
thesis of primary and secondary alkylboronates through site-selective
C(sp3)–H activation with silica-supported monophosphine–Ir catalysts.
J. Am. Chem. Soc. 2013, 135, 2947–2950. (b) Murakami, R.; Tsunoda,
K.; Iwai, T.; Sawamura, M. Stereoselective C–H borylations of cy-
clopropanes and cyclobutanes with silica-supported monophosphane-
Ir catalysts. Chem. Eur. J. 2014, 20, 13127–13131. (c) Murakami, R.;
Iwai, T.; Sawamura, M. Site-selective and stereoselective C(sp3)–H
borylation of alkyl side chains of 1,3-azoles with a silica-supported
monophosphine-Iridium catalyst. Synlett 2016, 27, 1187–1192.
(8) Reyes, R. L.; Harada, T.; Taniguchi, T.; Monde, K.; Iwai, T.;
Sawamura, M. Enantioselective Rh- or Ir-catalyzed directed C(sp3)–H
borylation with phosphoramidite chiral ligands. Chem. Lett. 2017, 46,
1747–1750.
REFERENCES
(1) Reviews on enantioselective C–H functionalization: (a) Saint-
Denis, T. G.; Zhu, R.-Y.; Chen, G.; Wu, Q.-F.; Yu, J.-Q. Enantiose-
lective C(sp3)–H bond activation by chiral transition metal catalysts.
Science 2018, 359, eaao4798. (b) Newton, C. G.; Wang, S.-G.;
Oliveira, C. C.; Cramer, N. Catalytic enantioselective transformations
involving C–H bond cleavage by transition-metal complexes. Chem.
Rev. 2017, 117, 8908–8976. (c) Lu, Q.; Glorius, F. Radical enantiose-
lective C(sp3)–H functionalization. Angew. Chem. Int. Ed. 2017, 56,
49–51.
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
(2) Selected examples of stereochemistry-generating C(sp3)–H func-
tionalization that caused desymmetrization of symmetrical molecules
through differentiation of enantiotopic carbons: (a) He, J.; Shao, Q.;
Wu, Q.; Yu, J.-Q. Pd(II)-catalyzed enantioselective C(sp3)–H boryla-
tion. J. Am. Chem. Soc. 2017, 139, 3344–3347. (b) Fu, J.; Ren, Z.;
Basca, J.; Musaev, D. G.; Davis, H. M. L. Desymmetrization of cy-
clohexanes by site- and stereoselective C–H functionalization. Nature
2018, 564, 395–399. (c) Milan, M.; Bietti, M.; Costas, M. Highly
enantioselective oxidation of nonactivated aliphatic C–H bonds with
hydrogen peroxide catalyzed by manganese complexes. ACS Cent. Sci.
2017, 3, 196–204. (d) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.;
Yu, J.-Q. Pd(II)-catalyzed enantioselective C–H activation of
cyclopropanes. J. Am. Chem. Soc. 2011, 133, 19598−19601. (e) Xiao,
K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, W.; Wasa, M.; Yu,
J.-Q. Palladium(II)-catalyzed enantioselective C(sp3)−H activation
using a chiral hydroxamic acid ligand. J. Am. Chem. Soc. 2014, 136,
8138−8142.
(3) (a) Pan, S.; Endo, K.; Shibata, T. Ir(I)-catalyzed enantioselective
secondary sp3 C–H bond activation of 2-(alkylamino)pyridines with
alkenes. Org. Lett. 2011, 13, 4692–4695. (b) Pan, S.; Matsuo, Y.;
Endo, K.; Shibata, T. Cationic iridium-catalyzed enantioselective
activation of secondary sp3 C–H bond adjacent to nitrogen atom.
Tetrahedron 2012, 68, 9009–9015. (c) Tahara, Y.-K.; Michino, M.;
Ito, M.; Kanyiva, K. S.; Shibata, T. Enantioselective sp3 C–H alkyla-
tion of γ-butyrolactam by a chiral Ir(I) catalyst for the synthesis of 4-
substituted γ-amino acids. Chem. Comm. 2015, 51, 16660–16663.
(4) (a) Zhang, F.-L.; Hong, K.; Li, T.-J.; Park, H.; Yu, J.-Q. Function-
alization of C(sp3)–H bonds using a transient directing group. Science
2016, 351, 252–256. (b) Wang, H.; Tong, H.-R.; He, G.; Chen, G. An
enantioselective bidentate auxiliary directed Palladium-catalyzed
benzylic C−H arylation of amines using a BINOL phosphate ligand.
Angew. Chem. Int. Ed. 2016, 55, 15387–15391. (c) Murakami, R.;
Sano, K.; Iwai, T.; Taniguchi, T.; Monde, K.; Sawamura, M. Palladi-
um-catalyzed asymmetric C(sp3)–H allylation of 2-alkylpyridines.
Angew. Chem. Int. Ed. 2018, 57, 9465–9469.
(5) (a) Liao, K.; Negretti, S.; Musaev, D. G.; Bacsa, J.; Davies, H. M.
L. Site-selective and stereoselective functionalization of unactivated
C–H bonds. Nature 2016, 533, 230–234. (b) Liao, K.;ꢀ Yang, Y.-F.; Li,
Y.; Sanders, J. N.; Houk, K. N.; Musaev, D. G.; Davies, H. M. L.
Design of catalysts for site-selective and enantioselective
functionalization of nonactivated primary C–H bonds. Nat. Chem.
2018, 10, 1048–1055.
(6) (a) Chen, G.; Gong, W.; Zhuang, Z.; Andrä, M. S.; Chen, Y.-Q.;
Hong, X.; Yang, Y. F.; Liu, T.; Houk, K. N.; Yu, J.-Q. Ligand-
accelerated enantioselective methylene C(sp3)–H bond activation.
Science 2016, 353, 1023–1027. (b) Yan, S.-B.; Zhang, S.; Duan, W.-L.
Palladium-catalyzed asymmetric arylation of C(sp3)–H bonds of ali-
phatic Amides: Controlling enantioselectivity using chiral phosphoric
amides/amines. Org. Lett. 2015, 17, 2458–2461. (c) Yan, S.-Y.; Han,
Y.-Q.; Yao, Q.-J.; Nie, X.-L.; Liu, L.; Shi, B.-F. Palladium(II)-
catalyzed enantioselective arylation of unbiased methylene C(sp3)–H
bonds enabled by a 1-pyridynylisopropyl auxiliary and chiral phos-
phoric acids. Angew. Chem. Int. Ed. 2018, 57, 9093–9097. (d) Han,
Y.-Q.; Ding, Y.; Zhou, T.; Yan, S.-Y.; Song, H.; Shi, B.-F. Pd(II)-
(9) Zou, X.; Zhao, H.; Li, Y.; Gao, Q.; Ke, Z.; Xu, S. Chiral bidentate
boryl ligand enabled iridium-catalyzed asymmetric C(sp2)–H boryla-
tion of diarylmethylamines. J. Am. Chem. Soc. 2019, 141, 5334–5342.
(10) (a) Gavrilov, K. N.; Lyubimov, S. E.; Petrovskii, P. V.; Zheglov,
S. V.; Safronov, A. S.; Skazov, R. S.; Davankov, V. A. Facile one-pot
synthesis of BINOL- and H8-BINOL-based aryl phosphites and their
use in palladium catalyzed asymmetric allylation. Tetrahedron 2005,
61, 10514–10520. (b) Gavrilov, K. N.; Zheglov, S. V.; Gavrilova, M.
N.; Novikov, I. M.; Maksimova, M. G.; Groshkin, N. N.; Rastorguev,
E. A.; Davankov, V. A. Phosphites and diamidophosphites based on
mono-ethers of BINOL: a comparison of enantioselectivity in asym-
metric catalytic reactions. Tetrahedron 2012, 68, 1581–1589. (c)
Gavrilov, K. N.; Lyubimov, S. E.; Zheglov, S. V.; Benetsky, E. B.;
Petrovskii, P. V.; Rastorguev, E. A.; Grishina, T. B.; Davankov, V. A.
MOP-type binaphthyl phosphite and diamidophosphite ligands and
their application in catalytic asymmetric transformations. Adv. Synth.
Catal. 2007, 349, 1085–1094.
(11) The use of one equivalent of the substrate 1a in the presence of
2,6-lutidine (100 mol%) similarly gave the product at 73% (1H NMR)
and 98% ee. However, the use of stoichiometric amount of 2,6-
lutidine led to difficulty in product purification.
(12) See Supporting Information for details of effects of the additive
and the use of the excess substrate.
(13) Rendler, S.; Plefka, O.; Karatas, B.; Auer, G.; Fröhlich, R.;
Müch-Lichtenfeld, C.; Grimme, S.; Oestreich, M. Stereoselective
alcohol silylation by dehydrogenative Si–O coupling: scope, limita-
tions, and mechanism of the Cu-H-catalyzed non-enzymatic kinetic
resolution with silicon-stereogenic silanes. Chem. Eur. J. 2008, 14,
11512–11528.
(14) In previous theoretical studies, the C–H activation step was
shown to be the rate-determining step. See (a) Tamura, H.; Yamazaki,
H.; Sato, H.; Sakaki, S. Iridium-catalyzed borylation of benzene with
diboron. Theoretical elucidation of catalytic cycle including unusual
iridium(V) intermediate. J. Am. Chem. Soc. 2003, 125, 16114–16126.
(b) Huang, G.; Kalek, M.; Liao, R.-Z.; Himo, F. Mechanism, reactivi-
ty, and relectivity of the iridium-catalyzed C(sp3)–H borylation of
chlorosilanes. Chem. Sci. 2015, 6, 1735–1746. (c) Haines, B. E.; Saito,
Y.; Segawa, Y.; Itami, K.; Musaev, D. G. Flexible reaction pocket on
bulky diphosphine−Ir complex controls regioselectivity in para-
selective C−H borylation of arenes. ACS Catal. 2016, 6, 7536−7546.
See also ref. 9.
(15) Maeda, S.; Harabuchi, Y.; Takagi, M.; Taketsugu, T. Morokuma,
K. Artificial force induced reaction (AFIR) method for exploring
quantum chemical potential energy surfaces. Chem. Rec. 2016, 16,
2232–2248.
(16) Sameera, W. M. C.; Maeda, S.; Morokuma, K. Computational
catalysis using the artificial force induced reaction method. Acc.
Chem. Res. 2016, 49, 763–773.
(17) At obtained stationary structures, Gibbs free energy values were
estimated through the harmonic vibrational analysis, where all fre-
quencies below 50 cm–1 were replaced by 50 cm–1, see: Ryu, H.; Park,
J.; Kim, H. K.; Park, J. Y.; Kim, S.-T.; Baik, M.-H. Pitfalls in compu-
tational modeling of chemical reactions and how to avoid them. Or-
ganometallics 2018, 37, 3228−3239.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 7
(18) A computationally estimated product enantiomer ratio is S/R
77:23 when all of the examined twelve TSs are considered. This pop-
ulation is in accord with the trend of the reaction favoring the S iso-
mer, while not matching quantitatively to the experimental value.
(19) Johnston, R. C.; Cheong, P. H.-Y. C–H···O non-classical hydro-
gen bonding in the stereomechanics of organic transformations: theo-
ry and recognition. Org. Biomol. Chem. 2013, 11, 5057–5064.
(20) Ishii, T.; Ryo, W.; Moriya, T.; Ohmiya, H.; Mori, S.; Sawamura,
M. Cooperative catalysis of metal and O–H⋅⋅⋅O/sp3-C–H⋅⋅⋅O two-
point hydrogen bonds in alcoholic solvents: Cu-catalyzed enantiose-
lective direct alkynylation of aldehydes with terminal alkynes. Chem.
Eur. J. 2013, 19, 13547–13553.
1
2
3
4
5
6
7
8
9
(21) Schwarzer, M. S.; Fujioka, A.; Ishii, T.; Ohmiya, H.; Mori, S.;
Sawamura, M. Enantiocontrol by assembled attractive interactions in
copper-catalyzed asymmetric direct alkynylation of α-ketoesters with
terminal alkynes: OH⋯O/sp3-CH⋯O two-point hydrogen bonding
combined with dispersive attractions. Chem. Sci. 2018, 9, 3484–3493.
(22) Johnson, E.R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García,
J.; Cohen, A. J.; Yang, W. Revealing noncovalent interactions. J. Am.
Chem. Soc. 2010, 132, 6498–6506.
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
(23) Humphrey, W.; Dalke, A.; Schulten, K. VMD - Visual molecular
dynamics. J. Molec. Graphics 1996, 14, 33–38.
ACS Paragon Plus Environment

Page 7 of 7
Journal of the American Chemical Society
1
2
3
For Table of Contents (TOC) Only
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