Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study

Article abstract of DOI:10.1021/jacs.9b05583

Because of the inherent difficulty in differentiating two olefins, the development of metal-catalyzed asymmetric cyclization of 1,6-dienes remains challenging. Herein, we describe the first rhodium(III)-catalyzed asymmetric borylative cyclization of cyclohexadienone-tethered mono-, 1,1-di-, and (E)-1,2-disubstituted alkenes (1,6-dienes), affording optically pure cis-bicyclic skeletons bearing three or four contiguous stereocenters with high yields (25-93%), and excellent diastereoselectivities (>20:1 dr) and enantioselectivities (90-99% ee). This mild catalytic approach is generally compatible with a wide range of functional groups, which allows several facile conversions of the cyclization products. Furthermore, on the basis of our SAESI-MS experiment and computational study, a Rh(I)/(III) catalytic cycle is proposed in this tandem reaction, and the Rh(I) active species catalyzes the overall transformation via sequential oxidative addition of B₂pin₂, olefin insertion, cyclizing conjugate addition, and reductive elimination. The irreversible conjugate addition determines the overall regioselectivity of borylative cyclization, and the ring strain favors the formation of 5,6-bicyclic structure. This highlights the control of ring strain in diene cyclizations, which provides a useful basis for future reaction designs.

Full text of DOI:10.1021/jacs.9b05583

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Article
Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of
Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study
Yun-Xuan Tan, Fang Zhang, Pei-Pei Xie, Shuo-Qing Zhang, Yi-
Fan Wang, Qing-Hua Li, Ping Tian, Xin Hong, and Guo-Qiang Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b05583 • Publication Date (Web): 25 Jul 2019
Downloaded from pubs.acs.org on July 25, 2019
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Page 1 of 21
Journal of the American Chemical Society
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Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of
Cyclohexadienone-Containing 1,6-Dienes: An Experimental and
DFT Study
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†
‡
§
§
†
‡
Yun-Xuan Tan, Fang Zhang, Pei-Pei Xie, Shuo-Qing Zhang, Yi-Fan Wang, Qing-Hua Li,
,
†,‡
,§
,†,‡
Ping Tian,* Xin Hong,* and Guo-Qiang Lin*
†CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
‡
The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI),
Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China
§
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou, 310027, China
Supporting Information
ABSTRACT: Due to the inherent difficulty in differentiating two olefins, development of metal-catalyzed asymmetric
cyclization of 1,6-dienes remains challenging. Herein, we describe
Rh(I)-Rh(III)
Catalytic Cycle
Bpin
H
the first rhodium(III)-catalyzed asymmetric borylative cyclization
of cyclohexadienone-tethered mono-, 1,1-di- and (E)-1,2-di-
substituted alkenes (1,6-dienes), affording optically pure cis-
bicyclic skeletons bearing three or four contiguous stereocenters
with high yields (25-93%), excellent diastereoselectivities (> 20:1
dr), and enantioselectivities (90-99% ee). This mild catalytic
approach is generally compatible with a wide range of functional
groups, which allows several facile conversions of the cyclization
products. Furthermore, based on our SAESI-MS experiment and
computational study, a Rh(I)/(III) catalytic cycle is proposed in
this tandem reaction and the Rh(I) active species catalyzes the
B
O
3
R
[
Rh(Phebox)]
B2pin2
O
O
R2
*
O
O
O
R3
X
N
Rh
N
N
Rh
N
**
R1
*
R2
X
Bpin
Bpin
X = O or N
R1
DFT
SAESI-MS
Analysis
calculations
2
5-93 yield, 90-99% ee
An Experimental Study
O
A DFT Study
anti-Markovnikov vs. Markovnikov Borylation (R2=R3=H)
O
91% yield
5% ee
39% yield
98% ee
9
O
Me
E/Z mixture
O
Me
Me
1,6-diene
6
Rh
VS
Rh
O
O
25% yield
73% yield
98% ee
94% ee
O
1
O
Me
1,6-diene
Me
Bpin
 = 0.0 kcal/mol
Bpin
G
 = 2.5 kcal/mol
Me
tert-alkyl-Rh
O
6

G
intermediate
2 2
overall transformation via sequential oxidative addition of B pin , olefin insertion, cyclizing conjugate addition and reductive
elimination. The irreversible conjugate addition determines the overall regioselectivity of borylative cyclization, and the ring
strain favors the formation of 5,6-bicyclic structure. This highlights the control of ring strain in diene cyclizations, which
provides a useful basis for future reaction designs.
more attractive. To the best of our knowledge, only a Pd-

INTRODUCTION
catalyzed asymmetric silylative cyclization of 1,6-dienes has
been reported to proceed with good enantioselectivities (79-
The development of efficient asymmetric annulation
protocols is particularly important in organic synthesis due
to the wealth of carbo- and heterocycles in natural products,
pharmaceutical compounds, and functional materials. In
view of their importance, great efforts have been devoted to
the development of transition-metal-catalyzed asymmetric
cyclizations of 1,6-bifunctional molecules, typically involving
1,6-enynes and 1,6-dienes. In comparison to 1,6-enynes, the
metal-catalyzed asymmetric cyclization of 1,6-dienes remains
more challenging due to the requisite differentiation of the
two olefins in 1,6-dienes. In recent years, a handful of Ni-, Pt-
4
9
1% ee, Scheme 1a). Herein, we present the first rhodium-
catalyzed asymmetric borylative cyclization of
cyclohexadienone-containing 1,6-dienes with high to
excellent yields and excellent enantioselectivities.
In 2003, Morken and coworkers described the first
enantioselective diboration of simple alkenes catalyzed by a
1
2
chiral rhodium(I) catalyst with bis(catecholato)diboron
5
(
2
B cat
2
). However, this efficient catalytic system was
supposed
bis(pinacolato)diboron (B
to
be
ineffective
for
activation
of
2
pin ) since the reactivity of the
2
,
and Rh-catalyzed asymmetric cycloisomerizations of 1,6-
tetraalkoxydiboranes is considerably lower than that of the
3
dienes have been successfully achieved. However, the
described reactions only employ intramolecular C‒C bond
formation with hydrogen atom transfer, and the lack of
functional groups limits the potential for further elaboration
of the products. In order for a direct derivatization of
products, transition-metal-catalyzed asymmetric cyclization
initiated by an external nucleophile consequentially becomes
6
catecholate analogs. Ten years later, Nishiyama and
coworkers realized the asymmetric diboration of non-
activated terminal alkenes with B
pincer rhodium(III)
bis(oxazolinyl)phenyl] complex (Scheme 1b). During the
catalytic process, the bulky rhodium was placed at the less
2
pin
2
using a chiral NCN-
complex,
rhodium-
7
[
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Page 2 of 21
Scheme 1. Strategic Design
boron is placed at either external carbon [β-bororhodation
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(anti-Markovnikov bororhodation, R = H)] or internal
2
carbon [α-bororhodation (Markovnikov bororhodation, R =
a) Palladium-Catalyzed Asymmetric Silylative Cyclization of 1,6-Dienes[4]
H)], affording the corresponding borylated alkylrhodium
intermediates TS3 or TS9. The interaction between the
rhodium and cyclohexadienone enables the subsequent
intramolecular conjugate addition in a syn-facial manner to
Pd
SiEt3
H
R
R
R
R
HSiEt3
b) Rhodium(III)-Catalyzed Asymmetric Diboration of Terminal Alkenes[7]
Rh(Phebox)] Catalyst
[
furnish highly enantioenriched cis-fused bicyclic frameworks
B2pin2
Markovnikov
Bororhodation
2
3
(5,6-bicycles) or 4 (6,6-bicycles) bearing three (R = H) or
O
O
Bpin
Bpin
2
11
four (R  H) contiguous stereogenic carbon centers.
R
Rh
Bpin
N
Rh
N
Considering the ring strain of the fused carbocycles, the 5-
membered ring-closure is favored with respect to a 6-
membered ring-closure, and thus the 5,6-bicycles 3 are the
main products. Whatever, the selective borylation taking
place at the non-activated alkenes, rather than the activated
alkenes, i.e. cyclohexadienones, is an intrinsic paradox and
still remains particularly challenging.
R
R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
i-Pr AcO
OAc i-Pr
OH2
c) Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of 1,6-Dienes
Bpin
activated
R2
"B"
alkene
three or four
contiguous
stereogenic
centers
O
H
(S,S)-[Rh(Phebox-i-Pr)]
H
O
B2pin2 (2)
R2
X
X
R1
non-activated
R1
3
alkene
TS1

RESULTS AND DISCUSSION
1
O
O
Regioselectivity
favorable
Enantioselectivity
Reaction Development and Optimization. We began
our investigation using the cyclohexadienone-tethered
terminal alkene 1a as a model substrate and the results are
N
Rh
N
?
?
Bpin
Bpin

Bisboryl-
Rhodium(III)
Complex
C
N
N
N
C
Bpin Rh Bpin
 Bpin
summarized in Table 1. In the presence of Nishiyama’s [(S,S)-
R2
N
Bpin
O
R2
-Bororhodation
Rh
.
O
TS2
TS3
Rh(Phebox-Me)(OAc)
2
2
H O]
catalyst
C1
at
room

anti-Markovnikov
Bororhodation
X
temperature, it’s exciting that the desired diastereoselectively
pure (d.r. > 20:1) borylative cyclization product 3a was
acquired, albeit with low yield (30%) and moderate
enantioselectivity (76% ee) (Table 1, Entry 1). In contrast to

(
IF R2 = H)
secondary
interaction
R1
X
1
R
-Bororhodation (anti-Markovnikov Bororhodation, R2 = H) Pathway

X
-Bororhodation (Markovnikov Bororhodation, R2 = H) Pathway

8
C
N
Aggarwal’s observations, the regioselectivity of addition to
N
N
C
Bpin
R2
X
the terminal alkene was reversed to favor the anti-
Bpin Rh Bpin
H
N
2
-Bororhodation
Rh
X
Bpin
O
12
R
R2
Markovnikov carboboration product. Several other of
O
Markovnikov
O unfavorable

Nishiyama’s catalysts C2−C6 were subsequently screened,13
Bororhodation
2
Bpin
TS9
 TS8
X
(IF R = H)

R1
.
however, only [(S,S)-Rh(Phebox-i-Pr)(OAc) H O] (C2) and
2
2
X
R1
R1
4
.
[
2 2
(S,S)-Rh(Phebox-s-Bu)(OAc) H O] (C3) provided both good
yield and excellent enantioselectivity (Table 1, Entries 2−6).
As for catalyst C2, prolonging the reaction time to 24 h could
lead to an increase in yield to 92% (Table 1, Entry 7). Raising
hindered terminal carbon atom, and such a Markovnikov
bororhodation regioselectivity was confirmed by the latest
report of Aggarwal and coworkers on rhodium(III)-catalyzed
Markovnikov hydroboration of terminal alkenes. However,
as a limitation of Nishiyama’s method, 1,2-disubstituted
o
the reaction temperature to 40 C allowed for the use of
lesser equivalents of B
time while maintaining excellent yield and enantioselectivity
Table 1, Entry 8). As for catalyst C3, both excellent yield and
2 2
pin (2) with a shortened reaction
8
(
enantioselectivity could be achieved by simply prolonging
the reaction time (Table 1, Entry 9); but either lowering the
7
alkenes failed to undergo the reaction. To overcome this
limitation, we hypothesized that incorporation of additional
functional groups on the substrate may promote the
reactivity of these non-activated disubstituted alkenes,
causing by the secondary interaction between alkenes and
the additional functional groups. To test this hypothesis, the
cyclohexadienone-tethered non-activated alkenes 1 were
prepared (Scheme 1c), hoping that the interaction between
the alkene and cyclohexadienone could significantly enhance
the reactivity of the non-activated alkenes.
2 2
B pin (2) loading or raising the reaction temperature led to
different levels of erosion in both yields and
enantioselectivities (Table 1, Entries 10−12). In line with our
expectations, no 6,6-fused bicyclic product 4a was detected
in all cases.
Substrate Scope of Cyclohexadienone-Tethered Non-
activated Alkenes (1,6-Dienes). Having established the
optimal reaction conditions for this rhodium-catalyzed
asymmetric borylative cyclization of cyclohexadienone-
tethered alkenes (1,6-dienes), we focused our effort on the
substrate scope of this cascade transformation. First,
In Nishiyama’s diboration reaction, a bis(pinacolatoboryl)-
Rh(III) species was also speculated in the proposal of an
9
alternative catalytic cycle. We envisage that this bisboryl-
cyclohexadienone-tethered
monosubstituted
terminal
Rh(III) species, rather than monoboryl-Rh(III) complex,
involves the bororhodation of alkenes. In our case, as the
direct conjugate borylation is largely impeded by the bulk
alkenes were investigated with respect to various
cyclohexadienone components and the results are
1
summarized in Table 2. With the R substituents as alkyl,
1
0
neighboring steric repulsion, the bororhodation proceeds
preferentially on the non-activated alkenes rather than
cyclohexadienones. During the bororhodation process, the
cycloalkyl, vinyl, allyl, benzyl, and phenyl groups, the
reactions occurred smoothly with high to excellent yields
(
81–93%) and excellent enantioselectivities (94–96% ee,
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Journal of the American Chemical Society
Table 1. Reaction Development and Optimizationa,b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
anti-Markovnikov
Markovnikov
carboboration
carboboration
Bpin
H
B2pin2 (2)
Catalyst (5 mol%)
H
O
O
Bpin
O
+
t-BuONa (10 mol %)
MeOH (2.5 equiv)
THF
O
O
O
Me
Me
3a
Me
4a
1a
Chiral rhodium-[bis(oxazolinyl)phenyl] catalysts: [Rh(Phebox)]
[Rh(Phebox-s-Bu)] (C3)
C1: R = Me [Rh(Phebox-Me)]
C2: R = i-Pr [Rh(Phebox-i-Pr)]
C3: R = s-Bu [Rh(Phebox-s-Bu)]
C4: R = i-Bu [Rh(Phebox-i-Bu)]
C5: R = t-Bu [Rh(Phebox-t-Bu)]
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
(
S)
Rh N (S)
OAc
(S)
(S)
N (S)
N
N
Rh
AcO
R AcO
OAc
OH2
R
(S)
OH2
C6: R = Bn
[Rh(Phebox-Bn)]
o
conv (%)c
100
89
yield of 3a (%)c
ee of 3a (%)d
entry
catalyst
C1
1a:2
temp ( C)
time (h)
1
1:2
1:2
rt
rt
16
16
16
16
16
16
24
10
24
24
10
7
30
88
76
93
94
91
2
3
4
5
6
7
8
9
C2
C3
1:2
rt
68
66
C4
C5
1:2
rt
39
30
1:2
rt
15
-
-
C6
C2
1:2
rt
100
100
100
100
87
36
81
1:2
rt
92
93
92
95
95
94
93
C2
1:1.2
1:2
40
rt
93
96(91)e
C3
1
0
C3
1:1.8
1:1.2
1:1.2
rt
84
1
1
C3
40
50
100
78
92
12
C3
71
a
Reactions were carried out with 1a (0.2 mmol, 1.0 equiv), B
2
pin
2
(2), rhodium catalyst (5 mol %), t-BuONa (10 mol %), MeOH
b
c
1
(
2.5 equiv), and THF (1.0 mL) under Ar atmosphere. All d.r. > 20:1. Determined by H NMR analysis of unpurified mixtures with
d
e
2 2
CH Br as an internal standard. Determined by HPLC analysis. Yield of isolated product 3a.
Table 2, 3a–3i). Introduction of para-substituents, including
F, Br, CN groups, on the phenyl ring had almost no impact
on the reaction, uniformly resulting in excellent levels of
enantiocontrol (96% ee) (Table 2, 3j–3m). With a heteroatom
intramolecular conjugate addition.14 It is noteworthy that in
all cases employing cyclohexadienone-tethered terminal
alkenes, carboboration products were delivered with
exclusive anti-Markovnikov regioselectivity, i.e. C–B bond
1
8,12
(
O, Si, N, Cl or Br) as part of R substituent in substrates 1,
formation occurring at the terminal carbon atoms.
both reaction yields and enantioselectivities remained high
to excellent (76–92% yield, 94–96% ee, Table 2, 3n−3u).
Notably, chloro- and bromoalkyl groups in substrates 1t and
As described above, we were particularly interested in
applying this approach to the cyclohexadienone-tethered 1,2-
disubstituted alkenes. As for 1,2-disubstituted cis-alkene (Z)-
5b, no desired cyclization product was observed; whereas for
1,2-disubstituted trans-alkene (E)-5b, we were encouraged to
find the expected borylative bicyclic product bearing four
contiguous stereogenic carbon centers, which was produced
as a single isomer with 37% yield and 98% ee (Table 2, 6b).
Subsequently, a mixture of E/Z-isomers of 1,2-disubstituted
alkenes 5c derived from the trans/cis mixture (95:5) of crotyl
alcohol was subjected to this reaction. In line with our
expectations, only a single isomer is furnished with 39% yield
and 98% ee, suggestive that cis-internal alkenes are not
competent in the reaction (Table 2, 6c). Several other
cyclohexadienone-tethered trans-1,2-disubstituted internal
alkenes were examined next. With a heteroatom (O, Si, or N)
1
3
u were well tolerated in this transformation (Table 2, 3t and
u). As for the N-linked 1,6-diene 1v, the corresponding cis-
hydroindole product 3v was also uneventfully constructed
with good diastereoselectivity (5:1 dr) and excellent
enantioselectivities for both isomers. The readily available
terminal alkenes 1w and 1x derived from dehydrocholic acid
and estrone were subjected to this transformation, affording
cis-hydrobenzofuran products with good yields and excellent
catalyst-controlled diastereoselectivities (Table 2, 3w, 3w’, 3x,
and 3x’).
Much to our surprise and delight, the cyclohexadienone-
tethered 1,1-disubstituted terminal alkene 5a was also feasible
for this transformation, albeit in low yield (Table 2, 6a). This
finding suggests that the involvement of a bulky tertiary
alkyl-rhodium intermediate is capable of undergoing
2
as part of R substituents in substrates 5, the reactions
proceeded equally well with excellent enantioselectivities
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Table 2. Substrate Scope of Cyclohexadienone-Tethered Alkenes (1,6-Dienes)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
R3 Bpin
B2pin2 (2)
C2 or C3 (5 mol % )
3/4 Contiguous Stereogenic Carbon Centers
Generally >20:1 dr, Up to 99% ee
anti
O
R2
R3
H
R4
O
R2
-Markovnikov Carboboration (Terminal Alkenes)
X
t-BuONa (10 mol%)
MeOH (2.5 equiv)
THF
R1
X = O or N
or 5
R4
X
Broad Substrate Scope
R1
Good Functional Group Compatibility
1
3 or 6
Monosubstituted Terminal Alkenes (R2 = R3 = R4 = H): a
Bpin
H
Bpin
H
Bpin
H
Bpin
Bpin
H
Bpin
H
H
O
O
O
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
O
O
O
O
Me
Et
i-Pr
t-Bu
Cy
3
a, 91% yieldc
3b, 84% yield
>20:1 dr, 95% ee
3c, 88% yield
>20:1 dr, 94% ee
3d, 93% yield
>20:1 dr, 95% ee
3e, 93% yield
>20:1 dr, 95% ee
3f, 84% yield
>20:1 dr, 96% ee
20:1 dr,d 95% eee
>
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
H
O
H
O
H
O
H
O
H
O
H
O
O
O
O
O
O
O
F
j, 74% yield
>20:1 dr, 96% ee
Br
CN
3g, 81% yield
20:1 dr, 95% ee
3h, 87% yield
>20:1 dr, 95% ee
3i, 82% yield
>20:1 dr, 95% ee
3
3k, 87% yield
>20:1 dr, 96% ee
3m, 86% yield
>20:1 dr, 96% ee
>
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
H
O
H
O
H
O
H
O
H
O
H
O
O
O
O
O
O
O
CO2Me
OAc
OTBS
NHBoc
CO2Me
Cl
3t, 92% yield
>20:1 dr, 95% ee
3n, 87% yield
3p, 85% yield
3q, 85% yield
3r, 89% yield
3s, 76% yield
>20:1 dr, 94% ee
>
20:1 dr, 94% ee
>20:1 dr, 96% ee
>20:1 dr, 96% ee
>20:1 dr, 95% ee
Bpin
Bpin
Bpin
Bpin
O
H
Me
O
O
H
O
H
O
H
O
H
O
H
H
H
O
O
N
O
H
Me
O
H
H
Ts Me
Br
O
O
Me
H
O
Me
dehydrocholic acid derivative
with (S,S)-C2, 3w, 84% yield, 96:4 dre
with (R,R)-C2, 3w', 85% yield, 4:96 dre
3v,b 65% yield, 5:1 dr
major isomer: 90% ee
minor isomer: 90% ee
b
estrone derivativeb
3
u, 87% yield
>20:1 dr, 95% ee
with (S,S)-C2, 3x, 88% yield, 95:5 dre
with (R,R)-C2, 3x', 84% yield, 5:95 dre
1
,1-Disubstituted Terminal Alkene: b
tertiary alkyl-Rh
intermediate
Bpin
H
O
Rh
O
Me
O
Condition
B
Me
a
O
Me
Me
5
6a, 25% yield
>20:1 dr, 94% ee
ORTEP of 3a
ORTEP of 6a
ORTEP of 6b
1
,2-Disubstituted Internal Alkenes: b
Bpin
Bpin
H
O
O
Me
O
Rh
Rh
*
H
Rh
no desired
product
H
O
H
O
(E)
*
*
*
Condition
B
Condition
B
Condition
B
O
Me
O
(Z)
O
Me
O
Me
O
Me
Me
Me
(
Z)-5b
(E)-5b
6b, 37% yield
5c
6c, 39% yield
>20:1 dr, 98% ee
>
20:1 dr, 98% ee
E/Z = 95/5
MeO
H
Bpin
H
BnO
Bpin
TBSO
Bpin
H
NPhth
Bpin
O
Rh
H
H
O
N
O
O
O
O
H
H
H
Condition
B
R2
O
NPhth =
Me
O
O
O
O
5d-5g
Me
Me
Me
Me
O
6d, 38% yield
20:1 dr, 97% ee
6e, 62% yield
>20:1 dr, 97% ee
6f, 66% yield
>20:1 dr, 98% ee
6g, 45% yield
>20:1 dr, 99% ee
>
a
2 2
Condition A: Reactions were performed using 1 (0.2 mmol, 1.0 equiv), B pin (2.0 equiv), C3 (5 mol %), t-BuONa (10 mol %),
b
MeOH (2.5 equiv), THF (1.0 mL) under Ar atmosphere, rt, 24 h. Condition B: Reactions were performed using 5 (0.2 mmol, 1.0
o
equiv), B
2
pin
2
(1.2 equiv), C2 (5 mol %), t-BuONa (10 mol %), MeOH (2.5 equiv), THF (1.0 mL) under Ar atmosphere, 40 C, 10 h.
c
d
1
e
Yield of isolated product. Determined by H NMR analysis of unpurified mixtures. Determined by HPLC analysis.
ACS Paragon Plus Environment

Page 5 of 21
Journal of the American Chemical Society
(
97–99% ee, Table 2, 6d–6g). The absolute configuration of
Scheme 2. The Competitive Borylative Cyclization
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the cyclization products 3a, 6a and 6b was unambiguously
1
5
(a) The Competitive Borylative Cyclization Between Two Formal 1,6-Dienes
established by X-ray crystallography. The data summarized
in Table 2 support that the order of reactivity of substrates is
mono- > (E)-1,2-di-  1,1-di- ≫ (Z)-1,2-di-substituted alkenes.
"
B" 1,6-diene
O
O
Bpin
H
B2pin2 (2) (1.2 equiv)
Catalyst: C2 (5 mol%)
O
H
O
O
t-BuONa (10 mol %)
MeOH (2.5 equiv)
THF, 40 oC, 10 h
Me
The Competitive Borylative Cyclization of the Multi-
functionalized 1,6-Dienes. To further support that
additional interaction from the appended dienone promotes
reactivity of non-activated alkenes, substrate 5h (two formal
O
1,6-diene
Me
5h
6h, 73% yield
>20:1 dr, 98% ee
(b) The Competitive Borylative Cyclization Between Formal 1,6-Enyne & 1,6-Diene
1
,6-dienes) containing one non-activated monosubstituted
terminal alkene, one non-activated trans-1,2-disubstituted
internal alkene and two activated cis-1,2-disubstituted
alkenes, was prepared. When subjected to the standard
reaction conditions, regioselective borylation takes place at
the internal alkene rather than the more reactive terminal
alkene and activated alkenes, and the corresponding
cyclization product 6h is afforded in high yield (73%) and
excellent enantioselectivity (98% ee, Scheme 2a). Equal
regioselectivity was also observed in reaction of substrate 5i
"B" 1,6-diene
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
B2pin2 (2) (1.2 equiv)
O
Bpin
H
Catalyst: C2 (5 mol%)
O
O
t-BuONa (10 mol %)
MeOH (2.5 equiv)
THF, 40 oC, 10 h
O
Me
H
1
,6-enyne
O
Me
5i
6i, 58% yield
>
20:1 dr, 98% ee
addition with B
2 2
pin to afford the bisboryl-Rh(III) species III,
(
composed of a 1,6-enyne as well as 1,6-diene) containing an
which was observed by SAESI-MS analysis. Then the terminal
alkene of 1a is coordinated and inserted into bisboryl-Rh(III)
complex III (anti-Markovnikov), and the resulting complex V
undergo successive intramolecular conjugate addition,
reductive elimination and protonation to offer the final
borylative cyclization product 3a and regenerate the Rh(I)-
complex II. It should be noted that the interaction between
alkene and enone may play an important role during the
alkene insertion step. Path B: the Rh(I)-complex II
coordinates with 1a to form the complex VIII, which was also
detected by SAESI-MS analysis. The Rh(I)-complex VIII
undergoes oxidative cyclometallation to generate the Rh(III)-
complex IX. Subsequently, the Rh(III)-complex IX could also
produce the final borylative cyclization product 3a and
regenerate the Rh(I)-complex II through σ-metathesis,
reductive elimination and protonation.
internal alkyne, internal alkene and cyclohexadienone
components (Scheme 2b). These findings proved once again
that the aforementioned interaction between alkene and
cyclohexadienone indeed promoted the reactivity of non-
activated alkenes.
Proposed Reaction Mechanisms. Based on our
6a,7,9
experiments and literature report,
mechanisms are illustrated in Scheme 3. In the beginning,
the monoboryl-Rh(III) complex I is obtained from Rh-
precatalyst C3 through σ-metathesis with
Subsequently, its dissociation of water and reductive
elimination of boronate (X-Bpin) affords a key Rh(I)-complex
II, which is the catalytic active species and initiates the
catalytic cycles. From II, there are two tentative catalytic
cycles. Path A: the Rh(I)-complex II undergoes oxidative
the proposed reaction
B pin
2
2
(2).
Scheme 3. Proposed Reaction Mechanisms
C3
B2pin2
t-BuONa
metathesis
O
O
N
Rh
N
O
O
O
O
s-Bu Bpin
X
s-Bu
OH2
conjugate
addition
N
Rh
N
N
Rh
N
X = OAc or Ot-Bu
s-Bu
Bpin
Bpin s-Bu
I
s-Bu Bpin
s-Bu
O
H
H
O
dissociation
and R.E.
Bpin
O
O
N
reductive
elimination
reductive
elimination
VI
O
VI
O
X
Bpin
H2O
Me
B2pin2
Me
metathesis
N
Rh
O
Bpin
s-Bu
Bpin
s-Bu
Bpin
Bpin
O
Bpin
Bpin
H
H
O
O
Me
O
O
N
O
O
V
O
O
Me
VII
N
Rh
II
N
Me
VII
N
Rh
H
MeOH
MeOH
s-Bu
B2pin2
s-Bu
s-Bu
s-Bu
insertion
protonation
protonation
O
MeOBpin
O
MeOBpin
Me
IX
3a
3a
oxidative
addition
1a
Path B
coordination
O
O
Path A
oxidative
cyclometalation
N
Rh
N
Bpin
H
O
O
Bpin
s-Bu
s-Bu
O
O
N
N
Rh
coordination
s-Bu
s-Bu
secondary
interaction
N
Rh
N
O
Me
O
O
s-Bu Bpin
Bpin s-Bu
Me
VIII
O
III
IV
1a
bisboryl-Rh(III)
Rh(I)-complex
detected by SAESI-MS
detected by SAESI-MS
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 21
Several Transformations of the Cyclization Product
Scheme 4. Gram-Scale Experiment and Several
Transformations of the Cyclization Product 3a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3a. As a demonstration of the practicality and robustness of
this method, the transformation of cyclohexadienone-
tethered terminal alkene 1a was carried out on a 4-mmol
Bpin
O
H
o
Catalyst: C3 (1 mol%)
scale at 40 C (Scheme 4). We were able to lower the catalyst
O
+
B2pin2
t-BuONa (2 mol %)
loading to 1 mol% with no decrease in enantioselectivity
95% ee) despite a slight loss in yield (83%). To further
demonstrate the utility of this methodology, several
transformations were conducted and elaborated in Scheme 4.
3
Upon treatment of 3a with NaBO , the resulting primary
alcohol in situ underwent an intramolecular oxa-Michael
addition to give the six-membered O-bridged cyclic product
O
Me
MeOH (2.5 equiv)
THF, 40 C, 30 h
O
o
(
Me
3a, 0.97 g
4
.0 mmol, 1a
6.0 mmol, 2
83% yield, 95% ee
MeO2C
H
H
S
O
S
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
O
O
7
a
in almost quantitative yield, and the absolute
Me
(d)
(e)
Me
10a
11a, 86% yield
configuration of the newly formed ether was established by
67% yield, 98% ee
96% ee, >20:1 dr
1
5
X-ray crystallographic analysis (Scheme 4a). Alternatively,
the primary alcohol 8a could also be isolated using H as
Bpin
H
Bpin
H
Me
2 2
O
OH
(c)
O
(a)
oxidant (Scheme 4b). Next, the selective Luche reduction of
the enone led to the formation of chiral allylic alcohol 9a,
and the absolute configuration of the secondary alcohol was
also confirmed by X-ray crystallographic analysis (Scheme
O
O
O
O
O
Me
Me
3a
9a, 87% yield
7a, 98% yield
94% ee, >20:1 dr
95% ee
95% ee, >20:1 dr
1
5
4
c).
Additionally, the alkyl-boronate 3a was easily
(b)
converted, through Suzuki-Miyaura cross-coupling to an
OH
aryl-product 10a (Scheme 4d). Lastly, according to
H
16
O
Aggarwal’s coupling protocol, successive treatment of
boronic ester 3a with 2-thienyllithium and NBS readily
affords thienyl-coupling product 11a accompanying by the
thienyl addition to the ketone (Scheme 4e). All the above
transformations proceeded smoothly with almost no loss of
the enantiomeric purity.
O
Me
8a
ORTEP of 9a
55% yield, 95% ee
ORTEP of 7a
.4H
Conditions: (a) NaBO
(
3
2
O, THF/H
2
O, rt, 2 h. (b) H
2
O
2
.
o
30% aq.), THF, rt, 16 h. (c) NaBH
0 min. (d) KHF , MeOH/H
bromobenzoate, Pd(OAc) , PPh
4
3 2
, CeCl 7H O, MeOH, 0 C,
Computational Studies of Reaction Mechanisms and
Origins of Regioselectivity. We next studied the reaction
mechanism and regioselectivity of the rhodium catalysis
1
2
2
O, rt, 5 h; then methyl 4-
o
2
3
, K
2
CO
3
, toluene/H
2
O, 95 C,
o
o
10 h. (e) 2-thienyllithium, THF, -78 C; then NBS, -78 C.
1
7
through density functional theory (DFT) calculations using
the experimental catalyst C2 and 1,6-diene substrate 1a. DFT-
computed free energy changes of the most favorable pathway
1
8
are shown in Figure 1. From the Rh(I) active catalyst 12, the
oxidative addition with B pin is quite facile through TS1,
the rate-determining cyclization step via TS3 requires a 22.9
kcal/mol overall barrier. Our mechanistic model also applies
to the 1,2-disubstituted internal alkene. The rate-determining
cyclization step is insensitive to the 1,2-disubstitution (Figure
S9), which is consistent with the experimental reactivities
(Table 2).
2
2
generating the bisboryl-Rh(III) intermediate 14. Subsequent
endergonic 1,6-diene complexation leads to intermediate 15,
which undergoes the alkene enone-facilitated insertion via
TS2 to afford the alkylrhodium(III) species 16. This enone-
facilitation originates from the non-covalent interaction
between the enone moiety and the inserting alkene, which
was confirmed by Independent Gradient Model (IGM)
The
proposed
pathway
B
involving
oxidative
cyclometalation is significantly less favorable than pathway A,
and the DFT-computed free energy changes are in Figure 2.
From the Rh(I) catalyst 12, the exergonic coordination of
terminal double bond of 1,6-diene leads to the complex 23.
Subsequent oxidative cyclometalation via TS7 requires an
unsurmountable barrier of 35.0 kcal/mol to generate the five-
membered rhodacycle intermediate 25. Comparing the
determining transition states of the two proposed pathways
1
9
analysis (Figure S5). The insertion of cyclohexadienone
double bond is significantly less favorable (Figure S6), which
highlights the ability of Rh(I) catalyst to differentiate the two
double bonds of 1,6-diene substrate. From 16, the
coordination of cyclohexadienone allows the subsequent
cyclization via TS3, leading to the bicyclic intermediate 18. 18
then undergoes a facile rhodium migration through TS4 to
20
the corresponding oxygen-coordinated intermediate 19.
(
TS7 of Pathway B vs. TS3 of Pathway A), pathway B is less
This migration allows the B−O reductive elimination via TS5
to generate the Rh(I) species 20. Subsequent solvent-
favorable by 15.9 kcal/mol. Therefore, pathway B is not
operative for this transformation due to the difficult
oxidative cyclometalation.
21
facilitated methanolysis occurs in a cyclic fashion via TS6,
which regenerates the active Rh(I) catalyst 12 and eventually
produce the observed product 3a. Based on the computed
free energy profile, the proposed pathway A is operative. The
alkylrhodium(III) species 16 is the on-cycle resting state, and
ACS Paragon Plus Environment

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Journal of the American Chemical Society
Figure 1. DFT-Computed Free Energy Changes of the Most Favorable Pathway
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6

G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ
O
O
O
O
O
O
N
Rh
N
N
N
N
Rh
N
H
i-Pr
Bpin
Bpin i-Pr
O
O
i-Pr
i-Pr
Bpin
Bpin i-Pr
H
HBpin
i-Pr
O
N
Rh
N
H
O
O
O
i-Pr
i-Pr
O
Bpin
Bpin
Me
Me
TS4
Me
TS1
O
TS3
TS2
11.6
TS3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
.8
6.7
TS2
1a
O
N
O
1
5
B2pin2
Rh
N
0
12
.0
0.3
-1.1 TS1
i-Pr
i-Pr
H
O
Bpin
Bpin
-
1
2.6
4
13
-6.7
O
O
O
17
O
O
Me
O
O
N
Rh
N
N
Rh
N
TS5
i-Pr
i-Pr
Bpin
N
Rh
N
Bpin
i-Pr
Bpin i-Pr
-
11.3
16
i-Pr
Bpin
i-Pr
S
O
Bpin
O
O
O
B
Me
[
Rh] = 12
O
O
O
[
Rh] H
O
H
-
25.8
18
N
Rh
N
Bpin
Bpin
-
26.8
H
O
-26.4
i-Pr
Bpin
i-Pr
Bpin
TS4
O
O
S
TS5
O
O
O
N
O
N
Me
N
Bpin
Rh
N
Bpin i-Pr
O
Me
-
32.9
19
-32.9
TS6
Rh
i-Pr
O
O
i-Pr
H
Bpin i-Pr
N
Rh
N
Bpin
O
R
S
-37.3
21
(
I)
i-Pr
i-Pr
O
S
O
O
2 HOMe
O
O
Me
Me
N
Rh
N
12
15
i-Pr
Bpin i-Pr
HOMe + 12
H
O
Bpin
-52.1
2
+
0
MeO Bpi
O
O
Bpin
Bpin
O
n
H
H
O
Me
-57.3
22
N
Rh
N
OH
O
O
O
i-Pr
Bpin
i-Pr
HOMe
H
N
Rh
N
OH
O
Me
Me
i-Pr
i-Pr
-71.2
O
Bpin OMe
Bpin
H
O Bpin
3a
Me
2
1
22
3a
O
Me
isomer-
ization
reductive
metha-
nolysis
product
liberation
oxidation addition
olefin insertion
cyclization
elimination
Figure 2. Comparisons of the Proposed Pathway B
Our mechanistic model provides a useful rationale for the

G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYP-
regioselectivity of olefin insertion. Figure 3a includes the free
energy changes of the competing regioisomeric borylations.
From the bisboryl-Rh(III) intermediate 15, the insertion of
terminal double bond of 1,6-diene is reversible via TS2 and
D3(BJ)/6-31G(d)-LANL2DZ
27.5
O
O
TS7
N
Rh
N
22
TS8. This leads to the equilibrium between the two
alkylrhodium(III) intermediates 16 and 26. Subsequent
irreversible cyclization overrules the regioselectivity of olefin
insertion, favoring the anti-Markovnikov borylation by 2.5
kcal/mol (TS3 and TS9). These cyclization transition states
are differentiated by the ring strain of the forming bicyclic
structure (Figure 3b). The 6,6-bicyclic moiety of TS9 is more
strained than the 5,6-bicyclic moiety of TS3, which is
confirmed by the calculations of the corresponding
carbocycles. Therefore, the DFT calculations highlight the
importance of ring strain that can serve as a control of
i-Pr
i-Pr
O
H
O
Me
O
O
N
Rh
N
-1.0 i-Pr
i-Pr
1
2
O
24
0.0
1a
O
Me
-
4.9
overall
regioselectivity
of
1,6-diene
cyclizing
O
O
O
O
25
-
7.5
N
Rh
I)
N
functionalization.
N
Rh
N
(
23
O
O
i-Pr
i-Pr
i-Pr
i-Pr
N
Rh
N
i-Pr
i-Pr
H
O
O
O
Me
O
Me
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Figure 3. Competition between anti-Markovnikov and Markovnikov Borylation
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a)

G(kcal/mol), M06/6-311+G(d,p)-SDD-SMD(tetrahydrofuran)//B3LYP-D3(BJ)/6-31G(d)-LANL2DZ
Markovnikov borylation
anti-Markovnikov borylation
O
O
O
O
O
O
O
O
N
Rh
N
N
Rh
N
N
Rh
N
N
Rh
N
i-Pr Bpin
H
i-Pr Bpin
i-Pr
Bpin
i-Pr
Bpin i-Pr
Bpin
H
H
i-Pr
i-Pr
Bpin
Bpin
i-Pr
Bpin
O
O
H
H
O
O
O
O
O
Me
Me
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
O
1
4.1
TS9
11.0
TS8
11.6
TS3
6.8
6.7
15
TS2
O
O
N
Rh
N
-
6.0
i-Pr Bpin
Bpini-Pr
H
-
7.0
-6.7
17
27
26
O
O
O
O
O
O
O
Me
O
N
Rh
N
i-Pr
Bpin i-Pr
N
Rh
N
N
Rh
N
S
O
i-Pr
Bpin
i-Pr -Pr Bpin
i
i-Pr
Bpin
-11.3
16
Bpin
Bpin
O
-22.6
-25.8
18
R
O
Me
R
28
O
O
O
Me
Me
O
N
H
O
O
O
O
O
Rh
N
N
Rh
N
N
Rh
N
i-Pr
Bpin i-Pr
i-Pr
Bpin
Bpin
i-Pr
Bpin i-Pr
i-Pr
H
Bpin
O
S
Bpin
R
O
R
O
S
S
S
O
Me
S
O
O
Me
Me
b)
R
H
H
R
O
O
O
O
Me
Me
0.0 kcal/mol R= Bin 4.8 kcal/mol
0.0 kcal/mol R= H
4.8 kcal/mol
O
O
O
N
i-Pr
Bpin
O
Rh
N
Rh
N
Rh
Rh
N
H
i-Pr
Bpin
Bpin i-Pr
Bpin
i-Pr
O
O
H
O
H
O
Me
Me
TS3
TS9
Bpin
Bpin



G = 0.0 kcal/mol
G = 2.5 kcal/mol
and enone functional groups in the cyclization products
could be subjected to various transformations for
elaborating the synthetic utility. DFT calculations revealed
a Rh(I)-Rh(III) catalytic cycle involving bisboryl-Rh(III)
intermediate. The tandem reaction proceeds via olefin
insertion, conjugate addition and subsequent reductive
elimination. The cyclizing conjugate addition is the
regioselectivity-determining step, and ring strain favors the
formation of 5,6-bicyclic carbocycle. Further investigation
and applications of cyclohexadienone-tethered alkenes (1,6-
dienes) in organic synthesis are underway in our laboratory
and will be reported in due course.

CONCLUSIONS
In conclusion, the rhodium(III)-catalyzed asymmetric
borylative cyclization between cyclohexadienone-tethered
alkenes (1,6-dienes) and B pin has been accomplished to
afford optically pure cis-hydrobenzofuran frameworks
bearing three or four contiguous stereocenters. This
versatile method was applicable to cyclohexadienone-
tethered mono-, 1,1-di- and (E)-1,2-di-substituted alkenes,
and tolerated a wide range of functional groups on both
cyclohexadienone and alkene components. Especially for
2
2
cyclohexadienone-tethered
carboboration products were offered with exclusive anti-
terminal
alkenes,
their
Markovnikov regioselectivity. Moreover, the alkyl-boronate
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pinacolborane. J. Am. Chem. Soc. 2017, 139, 6526−6529. (d) Chen, J.;

ASSOCIATED CONTENT
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Han, X.; Lu, X. Enantioselective synthesis of tetrahydropyrano[3,4-
b]indoles: palladium(II)-catalyzed aminopalladation/1,4-addition
sequence. Angew. Chem., Int. Ed. 2017, 56, 14698−14701. (e)
Gollapelli, K. K.; Donikela, S.; Manjula, N.; Chegondi, R., Rhodium-
catalyzed highly regio- and enantioselective reductive cyclization
of alkyne-tethered cyclohexadienones. ACS Catal. 2018, 8,
Supporting Information
The Supporting Information is available free of charge on
the ACS Publications website at DOI: xxxxxxxxxxxxx.
Experimental procedures, characterizations, and
analytical data of new compounds, X-ray diffraction
data for 3a, 6a, 6b, 7a and 9a, and spectra of NMR
and HPLC for new compounds (PDF)
1
440−1447. For selected examples on metal-catalyzed borylative
cyclization of tethered pi-systems, see: (f) Onozawa, S.-y.;
Hatanaka, Y.; Tanaka, M. Palladium-catalysed borylsilylation of
alkynes and borylsilylative carbocyclization of diynes and an enyne
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Matsuda, T.; Ito, Y. Nickel-catalyzed silaborative dimerization of
alkynes. Organometallics 1998, 17, 5233−5235. (h) Marco-Martínez,
J.; López-Carrillo, V.; Buñuel, E.; Simancas, R.; Cárdenas, D. J. Pd-
catalyzed borylative cyclization of 1,6-enynes. J. Am. Chem. Soc.
2007, 129, 1874−1875. (i) Persson, A. K.; Jiang, T.; Johnson, M. T.;
Bäckvall, J. E. Palladium-catalyzed oxidative borylative
carbocyclization of enallenes. Angew. Chem., Int. Ed. 2011, 50,
6155−6159. (j) Jiang, T.; Bartholomeyzik, T.; Mazuela, J.; Willersinn,
J.; Bäckvall, J. E. Palladium(II)/Bronsted acid-catalyzed
enantioselective oxidative carbocyclization-borylation of enallenes.
Angew. Chem., Int. Ed. 2015, 54, 6024−6027. (k) Posevins, D.; Qiu,
Y.; Bäckvall, J. E. Highly diastereoselective palladium-catalyzed
X-ray data for compound 3a (CIF)
X-ray data for compound 6a (CIF)
X-ray data for compound 6b (CIF)
X-ray data for compound 7a (CIF)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
X-ray data for compound 9a (CIF)

AUTHOR INFORMATION
Corresponding Author
*
*
*
tianping@sioc.ac.cn or tianping@shutcm.edu.cn (P.T.)
hxchem@zju.edu.cn (X.H.)
lingq@sioc.ac.cn (G.-Q.L.)
oxidative carbocyclization of enallenes assisted by
a weakly
ORCID
coordinating hydroxyl group. J. Am. Chem. Soc. 2018, 140, 3210−3214.
For a recent review, see: (l) Buñuel, E.; Cárdenas, D. J. Borylative
cyclization reactions. Eur. J. Org. Chem. 2016, 5446−5464.
Ping Tian: 0000-0002-5612-0664
Xin Hong: 0000-0003-4717-2814
(
3) (a) Bogdanović, B. Selectivity control in nickel-catalyzed
olefin oligomerization. Adv. Organomet. Chem. 1979, 17, 104-140. (b)
Böing, C.; Franciò, G.; Leitner, W. Nickel catalysed asymmetric
cycloisomerisation of diethyl diallylmalonate. Chem. Commun.
2005, 1456-1458. (c) Böing, C.; Franciò, G.; Leitner, W. Cationic
nickel complexes with weakly coordinating counterions and their
application in the asymmetric cycloisomerisation of 1,6-dienes. Adv.
Synth. Catal. 2005, 347, 1537−1541. (d) Feducia, J. A.; Campbell, A.
N.; Doherty, M. Q.; Gagné, M. R. Modular catalysts for diene
cycloisomerization: rapid and enantioselective variants for
bicyclopropane synthesis. J. Am. Chem. Soc. 2006, 128, 13290−13297.
(e) Böeing, C.; Hahne, J.; Franciò, G.; Leitner, W. Stereoselective
nickel-catalyzed cycloisomerization of 1,6-dienes. Adv. Synth. Catal.
Notes
The authors declare no competing financial interest.

ACKNOWLEDGMENT
Financial support was generously provided by the National
Natural Science Foundation of China (Nos. 21871184,
21572251, and 21572253; 21702182 and 21873081, X.H.); the
Shanghai Municipal Education Commission (2019-01-07-00-
10-E00072); the Science and Technology Commission of
Shanghai Municipality (18401933500); the Ministry of
Science and Technology of the People's Republic of China
2
008, 350, 1073−1080. (f) Schmitz, C.; Leitner, W.; Franciò, G. Ni-
catalyzed asymmetric cycloisomerization of dienes by using
TADDOL phosphoramidites. Chem. Eur. J. 2015, 21, 10696−10702. (g)
Park, J.-W.; Chen, Z.; Dong, V. M. Rhodium-catalyzed
enantioselective cycloisomerization to cyclohexenes bearing
quaternary carbon centers. J. Am. Chem. Soc. 2016, 138, 3310−3313.
(h) Li, K.; Li, M.-L.; Zhang, Q.; Zhu, S.-F.; Zhou, Q.-L. Highly
enantioselective nickel-catalyzed intramolecular hydroalkenylation
of N- and O-tethered 1,6-dienes to form six-membered
heterocycles. J. Am. Chem. Soc. 2018, 140, 7458−7461.
(
973 project 2015CB856600); the Chinese Academy of
Sciences (Nos. XDB 20020100 and QYZDY-SSW-SLH026);
“
(
Fundamental Research Funds for the Central Universities”
X.H.); Zhejiang University (X.H.) and China Postdoctoral
Science Foundation (2018M640546, S.–Q. Z.). Calculations
were performed on the high-performance computing
system at the Department of Chemistry, Zhejiang
University. We thank Jie Sun (SIOC) for X-ray
crystallographic analysis and Dr. Hanqing Dong (Arvinas
Inc.) for manuscript preparation.
(
4) (a) Perch, N. S.; Widenhoefer, R. A. Asymmetric cyclization /
hydrosilylation of functionalized 1,6-dienes catalyzed by
enantiomerically pure palladium pyridine-oxazoline complexes. J.
Am. Chem. Soc. 1999, 121, 6960−6961. (b) Pei, T.; Widenhoefer, R. A.
Use of pentamethyldisiloxane in the palladium-catalyzed
cyclization/hydrosilylation of functionalized dienes. Org. Lett.
2000, 2, 1469−1471. (c) Perch, N. S.; Pei, T.; Widenhoefer, R. A.
Enantioselective diene cyclization/hydrosilylation catalyzed by
optically active palladium bisoxazoline and pyridine−oxazoline
complexes. J. Org. Chem. 2000, 65, 3836−3845. (d) Pei, T.;
Widenhoefer, R. A. Palladium-catalyzed asymmetric diene
cyclization/hydrosilylation employing functionalized silanes and
disiloxanes. J. Org. Chem. 2001, 66, 7639−7645. (e) Widenhoefer, R.
A. Synthetic and mechanistic studies of the cycloisomerization and
cyclization/hydrosilylation of functionalized dienes catalyzed by
cationic palladium(II) complexes. Acc. Chem. Res. 2002, 35, 905-913.
(5) Morgan, J. B.; Miller, S. P.; Morken, J. P. Rhodium-catalyzed
enantioselective diboration of simple alkenes. J. Am. Chem. Soc.
2003, 125, 8702−8703.

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an
X-ray
single-crystal
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a
theoretical
calculations
of
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data for this paper. These data can be obtained free of charge from
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Crystallographic
Data
Centre
via
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2
3
by SAESI-MS analysis of our reaction mixture (for details, see
Supporting Information).
V. K. Enantiospecific sp -sp coupling of secondary and tertiary
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10) (a) Shiomi, T.; Adachi, T.; Toribatake, K.; Zhou, L.;
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Information.
(18) The generation of the Rh(I) active catalyst 12 is very facile
from the catalyst precursor S-1, related computational results are
included in Figure S4.
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(
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anti-
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the explored alternatives are included in Figure S7 and S8.
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Markovnikov borylation. Having the enone fragment proximal to
the insertion alkene leads to an unfavorable isomer of TS8. Details
are included in the Supporting Information (Figure S10).
8
, 32. (d) Shu, T.; Zhao, L.; Li, S.; Chen, X. Y.; von Essen, C.;
Rissanen, K.; Enders, D. Asymmetric synthesis of spirocyclic β-
lactams through copper-catalyzed Kinugasa/Michael domino
reactions. Angew. Chem., Int. Ed. 2018, 57, 10985−10988.
(
12)
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anti-Markovnikov
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X.; Xu, M. Y.; Yu, C. G.; Xu, Z. Y.; Yu, H. Z.; Xiao, B.; Fu, Y. Ligand-
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chiral rhodium(2,6-bisoxazolinylphenyl) catalysts. Chem. Eur. J.
2
005, 12, 63−71. (b) Morisaki, K.; Sawa, M.; Yonesaki, R.; Morimoto,
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1
2
3
4
5
6
7
8
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For Table of Contents Only
Rh(I)-Rh(III)
Catalytic Cycle
Bpin
B
O
3
R
H
[
Rh(Phebox)]
B2pin2
O
O
R2
*
O
O
O
R3
X
N
Rh
N
N
Rh
N
**
R1
X = O or N
*
R2
Bpin
X
Bpin
R1
DFT
calculations
SAESI-MS
Analysis
25-93 yield, 90-99% ee
An Experimental Study
O
A DFT Study
anti-Markovnikov vs. Markovnikov Borylation (R2=R3=H)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
4
4
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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9
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0
O
91% yield
39% yield
98% ee
95% ee
O
Me
E/Z mixture
O
Me
Me
1
,6-diene
Rh
VS
Rh
O
O
25% yield
73% yield
98% ee
94% ee
6
O
1
O
Me
1,6-diene
Me
Bpin
 = 0.0 kcal/mol
Bpin
G
 = 2.5 kcal/mol
Me tert-alkyl-Rh
O
6

G
intermediate
1
1
ACS Paragon Plus Environment

Journal of the American Chemical Society
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Table of Contents
8
2x44mm (300 x 300 DPI)
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Page 13 of 21
Journal of the American Chemical Society
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Strategic Design
8
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Journal of the American Chemical Society
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Reaction Development and Optimization
1
15x49mm (300 x 300 DPI)
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Page 15 of 21
Journal of the American Chemical Society
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Substrate Scope of Cyclohexadienone-Tethered Alkenes (1,6-Dienes)
1
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Journal of the American Chemical Society
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The Competitive Borylative Cyclization
83x58mm (300 x 300 DPI)
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Page 17 of 21
Journal of the American Chemical Society
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Proposed Reaction Mechanisms
1
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Journal of the American Chemical Society
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Gram-Scale Experiment and Several Transformations of the Cyclization Product 3a
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Journal of the American Chemical Society
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DFT-Computed Free Energy Changes of the Most Favorable Pathway
170x135mm (300 x 300 DPI)
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Journal of the American Chemical Society
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Comparisons of the Proposed Pathway B
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Journal of the American Chemical Society
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Competition between anti-Markovnikov and Markovnikov Borylation
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ACS Paragon Plus Environment