Copper(I)-Catalyzed Asymmetric Conjugate 1,6-, 1,8-, and 1,10-Borylation

Article abstract of DOI:10.1002/anie.202016081

Catalytic asymmetric remote conjugate borylation is challenging as the control of regioselectivity is not trivial, the electrophilicity of remote sites is extenuated, and the remote asymmetric induction away from the carbonyl group is difficult. Herein, catalytic asymmetric conjugate 1,6-, 1,8- and 1,10-borylation was developed with excellent regioselectivity, which delivered α-chiral boronates in moderate to high yields with high enantioselectivity. The produced chiral boronate smoothly underwent oxidation, cross-coupling, and one-carbon homologation to give synthetically versatile chiral compounds in moderate yields with excellent stereoretention. Furthermore, a stereomechanistic analysis was conducted using DFT calculations, which provides insights into the origins of the regioselectivity. Finally, the present 1,6-borylation was successfully applied in an efficient one-pot asymmetric synthesis of (?)-7,8-dihydrokavain.

Full text of DOI:10.1002/anie.202016081

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9493–9499
International Edition: doi.org/10.1002/anie.202016081
German Edition: doi.org/10.1002/ange.202016081
Homogeneous Catalysis
Copper(I)-Catalyzed Asymmetric Conjugate 1,6-, 1,8-, and 1,10-
Borylation
Chang-Yun Shi+, Jungmin Eun+, Timothy R. Newhouse,* and Liang Yin*
Dedicated to the 100th Anniversary of Chemistry at Nankai University
Abstract: Catalytic asymmetric remote conjugate borylation is
challenging as the control of regioselectivity is not trivial, the
electrophilicity of remote sites is extenuated, and the remote
asymmetric induction away from the carbonyl group is
difficult. Herein, catalytic asymmetric conjugate 1,6-, 1,8- and
1,10-borylation was developed with excellent regioselectivity,
which delivered a-chiral boronates in moderate to high yields
with high enantioselectivity. The produced chiral boronate
smoothly underwent oxidation, cross-coupling, and one-car-
bon homologation to give synthetically versatile chiral com-
pounds in moderate yields with excellent stereoretention.
Furthermore, a stereomechanistic analysis was conducted
using DFT calculations, which provides insights into the
origins of the regioselectivity. Finally, the present 1,6-boryla-
tion was successfully applied in an efficient one-pot asymmet-
ric synthesis of (À)-7,8-dihydrokavain.
issue of regioselectivity.[7] In 2013, the Kobayashi group
disclosed the first example of catalytic asymmetric 1,6-
borylation, in which the complex of Cu(OH)2 and a chiral
bipyridine ligand was employed as the catalyst in water
(Scheme 1a).[8a,b] Later, the Lam group discovered a powerful
copper(I)-catalyzed high regio- and enantioselective 1,6-
addition of B2(Pin)2 to a,b,g,d-unsaturated esters and ketones
with alkyl substituents at d-positions (Scheme 1b).[9a] How-
ever, a substrate bearing a phenyl group at the d-position
generated a complex mixture of unidentified products, which
led to an imperfect substrate scope. The similar reaction
tendency was also observed in the copper(I)-catalyzed
enantioselective 1,6-borylation of a,b,g,d-unsaturated phos-
phonates.[9b] In 2018, the Lam group found that both Z-allylic
and E-allylic boronates can be obtained as the major product
with high enantioselectivity, simply by tuning the reaction
solvent and the concentration in the copper(I)-catalyzed 1,6-
borylation of a,b,g,d-unsaturated ketones.[9c]
Introduction
In 2015, Liao and co-workers reported a copper-catalyzed
enantioselective 1,6-conjugate borylation of para-quinone
with a sulfoxide-phosphine ligand (Scheme 1c), which pro-
vided an attractive method for the construction of chiral gem-
diarylmethine boronates.[10a] Almost at the same time, the
Tortosa group also realized a copper-catalyzed 1,6-conjugate
borylation of para-quinone with DM-SEGPHOS (Sche-
me 1c).[10b] In both cases, the produced chiral gem-diary-
lmethine boronates were successfully employed either in
Suzuki–Miyaura coupling or in the coupling with furans to
furnish chiral triarylmethanes with excellent stereoretention.
1,8-Borylation has been rarely accomplished and 1,8-
borylated product was only found as a side product with low
enantioselectivity in Kobayashiꢀs pioneering 1,6-borylation
(Scheme 1a).[8b] In fact, as far as 1,8-conjugate addition is
concerned, only several examples of non-enantioselective
metal-catalyzed reaction have been reported.[11] In 2012, Ooi
and co-workers uncovered a highly regio-, diastereo- and
enantioselective 1,8-addition of azalactones to trienyl N-
acylpyrroles.[12] In 2014, Minnaard and Feringa reported two
enantioselective examples of conjugate 1,8-addition with
a copper catalyst and Grignard reagents.[13] However, low to
moderate regio- and enantioselectivities were observed. To
the best of our knowledge, these were the only two reports of
catalytic asymmetric 1,8-conjugate addition. Moreover, there
is no report of 1,10-borylation in literature. Only sporadic
non-enantioselective metal-catalyzed 1,10-conjugate addi-
tion[14] and one catalytic asymmetric version have been
described.[13] Minnaard and Feringa disclosed two examples
of copper-catalyzed enantioselective conjugate 1,10-addition
Organoboron compounds are versatile synthetic inter-
mediates, which can undergo a variety of transformations to
construct C C, C O and C N bonds.[1] Among them, a-chiral
boronates are employed in various stereospecific reactions to
rapidly assemble chiral molecules.[2] Therefore, there is an
increasing need for the easy and reliable methods to prepare
such organoboron compounds. One of the most common and
intensively investigated methods is the catalytic asymmetric
conjugate 1,4-borylation, which leads to the generation of a-
chiral boronates in high yields together with high enantiose-
lectivity.[3–6] Chiral catalysts based on transition metals,
especially on copper,[3,4] have significantly contributed to
the fast development in this fascinating field.
À
À
À
However, compared to catalytic asymmetric 1,4-boryla-
tion, 1,6-borylation was much less studied largely due to the
[*] C.-Y. Shi,[+] Prof. Dr. L. Yin
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)
E-mail: liangyin@sioc.ac.cn
J. Eun,[+] Prof. Dr. T. R. Newhouse
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-8105 (USA)
E-mail: timothy.newhouse@yale.edu
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016081.
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10 mol% CuPF6(CH3CN)4, 12 mol% (R)-TOL-BI-
NAP and 10 mol% LiOtBu, conjugate 1,6-borylation
afforded product 3a in 58% yield with 28% ee
(entry 1). Switching the ligand to (R)-DIFLUOR-
PHOS increased both the yield and the enantiose-
lectivity (entry 2). Unfortunately, other bisphosphine
ligands, such as (R)-DTBM-SEGPHOS, (R,R)-QUI-
NOXP* and (R,R)-Ph-BPE, led to inferior reaction
results (entries 3–5). Ferrocene-embedded bisphos-
phine ligands, (R)-(S)-JOSIPHOS and (R,RP)-TA-
NIAPHOS enhanced the enantioselectivity (en-
tries 6,7). Notably, product 3a was obtained in 78%
ee in the case of (R,RP)-TANIAPHOS (entry 6).
By increasing the amount of LiOtBu to 1 equiv-
alent, the reaction with (R,RP)-TANIAPHOS had an
increased yield but with decreased ee while the
reaction with (R)-(S)-JOSIPHOS had a slightly de-
creased yield but with increased ee (entries 8,9). The
yield was further enhanced by increasing the amount
of B2(Pin)2 to 3 equivalents (entry 10). Then, a simple
screening of five commercially available derivatives
of (R)-(S)-JOSIPHOS (from Strem Chemicals, Inc.)
was performed. However, no enhanced enantiose-
lectivity was observed but (R)-(S)-JOSIPHOS-5 led
to the highest yields (entries 11–15). Screening of the
copper(I) source identified CuF(PPh3)3·2MeOH as
the best catalyst, as 3a was obtained in 85% yield
with 91% ee. A beneficial alcohol effect,[9,10] gen-
erally presenting in the copper(I)-catalyzed conju-
gate 1,4-borylation,[16] was not detected in the
Scheme 1. Prior arts in catalytic asymmetric 1,6-borylation and our catalytic
asymmetric 1,6-, 1,8-, and 1,10-borylation.
with Grignard reagents.[13] Unfortunately, very low regio- and
enantioselectivity were obtained.
present 1,6-borylation (entry 17).
Under the optimized reaction conditions, the scope of aryl
and heteroaryl groups in 2 was assessed as depicted in Table 2.
Both electron-donating groups (such as methoxyl, methylthio,
methyl, and tbutyl) and electron-withdrawing groups (such as
fluoro, bromo, and iodo) were acceptable (3a–3k). The
enantioselectivity was not sensitive to the position (ortho-,
meta-, and para-) of a substituent on the phenyl ring.
Intriguingly, labile para-iodo-phenyl group was not touched
by the highly nucleophilic Cu–BPin species (3 f). Moreover,
several heteroaryls (including 2-furyl, 3-furyl, 2-thienyl, 3-
thienyl, and benzo[b]thiophen-2-yl) were well tolerated (3l–
3p). Generally, 1,6-borylated products were obtained in
moderate to high yields with high enantioselectivity (ca.
90% ee). It should be noted that in Lamꢀs catalytic
asymmetric 1,6-conjugate borylation,[9a] aryls were not toler-
ated and only alkyls without significant steric hindrance were
well accepted. Therefore, the present methodology serves as
a nice complement to Lamꢀs report.
It is evident that considerable difficulties exist in the
remote asymmetric conjugate borylation. First, the regiose-
lectivity is inevitably a troublesome issue. 1,4-Addition, 1,6-
addition, 1,8-addition and 1,10-addition would compete with
one another, which could lead to a complex reaction mixture.
Second, the electrophilicity of remote sites gradually de-
creases as those sites are more distal to the carbonyl group
(C4 > C6 > C8 > C10). Third, the remote asymmetric addition is
remarkably challenging as the reactive sites are far away from
the coordinating carbonyl group. Therefore, catalytic asym-
metric conjugate 1,8- and 1,10-borylation has been rarely
achieved. Here, by using a powerful copper(I)-JOSIPHOS
catalyst, we develop asymmetric 1,6-, 1,8-, and 1,10-borylation
of unsaturated dioxinones with excellent regio- and high
enantioselectivities. Previously, we disclosed a copper(I)-
NHC complex-catalyzed asymmetric 1,6-allylation of 2,2-
dimethyl-6-alkenyl-4H-1,3-dioxin-4-ones.[15] The 2,2-dimeth-
yl-4H-1,3-dioxin-4-one group was easily transformed to b-
keto-ester, a,b-unsaturated ester, and pyrazole in moderate
yields, which demonstrated its synthetical versatility.
The scope of alkyl groups was evaluated. Substrates with
n
linear alkyls (such as ethyl, npropyl, npentyl, and heptyl) led
to the boronates in good to high yields with high enantiose-
lectivity (3q–3t). a-Branched alkyls (such as ipropyl, cpropyl,
cpentyl, and chexyl), b-branched alkyl (ibutyl), and g-branched
alkyl (2-phenyl-ethyl) did not disturb the enantioselectivity
(3u–3z). Moreover, functionalized alkyls (containing ben-
zoxyl, tosylate, alkyl chloride, and phthalimide) were nicely
tolerated (3aa–3ad), which allow further structure elabora-
tion. Substrate 2ae derived from (+)-citronellal underwent
Results and Discussion
At the outset, the reaction of 1 and (E)-2,2-dimethyl-6-
styryl-4H-1,3-dioxin-4-one (2a) was studied for the optimi-
zation of reaction conditions (Table 1). In the presence of
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Table 1: Optimization of the reaction conditions with 2a.[a]
the targeted boronates were gener-
ated in moderate yields with good
enantioselectivity. Particularly
noteworthy were 7g and 7h as the
olefin group and alkyl chloride
group paved the way for further
structure modification. For 1,8- and
1,10-borylation, when R = Ph, com-
plicated reaction mixtures were ob-
tained, which were indicated by
both messy TLC and messy crude
1H NMR spectra. Evidently, the
Entry
Copper(I) source
Ligand
x
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuPF6(CH3CN)4
CuF(PPh3)3·2MeOH
CuF(PPh3)3·2MeOH
(R)-TOL-BINAP
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
–
58
64
43
trace
78
50
67
71
61
80
88
84
83
89
84
85
67
28
47
(R)-DIFLUORPHOS
(R)-DTBM-SEGPHOS
(R,R)-QUINOXP*
(R,R)-Ph-BPE
À21
–
À23
(R,Rp)-TANIAPHOS
(R)-(S)-JOSIPHOS
(R,RP)-TANIAPHOS
(R)-(S)-JOSIPHOS
(R)-(S)-JOSIPHOS
(R)-(S)-JOSIPHOS-1
(R)-(S)-JOSIPHOS-2
(R)-(S)-JOSIPHOS-3
(R)-(S)-JOSIPHOS-4
(R)-(S)-JOSIPHOS-5
(R)-(S)-JOSIPHOS-5
(R)-(S)-JOSIPHOS-5
78
66 control of the regioselectivity failed
67
89
89
77
10
19
À4
89
91
89
in these two cases.
9
Transformations of product 3a
10[d]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
17[d,e]
À
toward construction of C O bonds
À
and C C bonds were carried out
(Scheme 2). The oxidation of C–
BPin was easily accomplished to
afford chiral alcohol 8 in excellent
yield with a slight erosion of ee. By
comparing the optical rotation of 8
with reported data,[17] the absolute
configuration of 3a was determined
to be S. Moreover, the absolute
configurations of 5a and 7a were
determined to be R by their trans-
formations (for the details, see the
Supporting Information). Analo-
gously, the absolute configurations
of 3, 5, and 7 were deduced as
shown in Tables 1–3. By following
Aggarwalꢀs powerful enantiospecif-
ic sp3–sp2 coupling of secondary
boronic ester with electron-rich
heteroarenes,[18] 2-furanyl was suc-
–
[a] 1a, 0.10 mmol; 2, 0.15 mmol. [b] Determined by 1H NMR analysis of reaction crude mixture using
mesitylene as an internal standard. [c] Determined by chiral-stationary-phase HPLC analysis. [d] 3 equiv
B2(Pin)2 used. 2 h. [e] 2 equiv iPrOH added.
1,6-borylation in 70% yield with 5/1 dr, whereas substrate 2af
derived from (À)-citronellal led to 1,6-borylated product 3af
in 70% yield with 24/1 dr, which clearly demonstrated
a “match and mismatch” phenomenon in asymmetric induc-
tion. Furthermore, substrate 2ag prepared from lithocholic
acid delivered product 3ag in moderate yield with excellent
diastereoselectivity.
Conjugate 1,8-borylation is historically challenging, pre-
sumably owing to the extenuated electrophilicity at the
remote 8-position and competing 1,4- and 1,6-borylation,
which is reflected by the shortage of examples in literature.
When substrate 4a was submitted to the present reaction
conditions, unusual 1,8-borylation instead of 1,6-borylation
was observed with excellent regioselectivity. Then, a prelimi-
nary substrate scope of catalytic asymmetric 1,8-borylation
was described in Table 3. In substrate 4, linear alkyls (5a and
5b), a-branched alkyl (5c), and functionalized alkyls (5d, 5e,
and 5 f) were well accepted. Six chiral allylic boronates were
isolated in moderate yields with good enantioselectivity and
good to excellent E/Z ratio. Encouragingly, the present
reaction protocol was further extended to very challenging
and unprecedented catalytic asymmetric 1,10-borylation.
Although the E,E/others ratio was moderate in some cases,
cessfully introduced to give 9 in 64% yield with enantiose-
lectivity maintained. Meanwhile, the coupling of chiral
boronic ester 3a and thiophene smoothly occurred to
generate 10 in 70% yield with enantioselectivity retained.
Moreover, a reported procedure[19] was employed to enable
the one-carbon homologation of 3a, which furnished chiral
alcohol 11 in 60% yield with slightly decreased enantiose-
lectivity after oxidation. It should be note that absolute
configurations of the products (8–11) were retained.
To understand the interesting regio- and enantioselectiv-
ity observed in this study, DFT calculations were performed
for the reactions of 5a and 7a (Figure 1 and Figure 2) at the
B3LYP-D3/LANL2DZ(Cu,Fe)/6-31G(d) level of theory with
the SMD continuum solvation model for THF.[20–22] The
calculated DDG° values were found to favor the formation of
the experimentally observed products via INT21,8 and INT21,10
(for 5a and 7a, respectively). These terminal addition
products were the most kinetically and thermodynamically
favored products. However, one surprising finding to note is
that calculations suggested high regioselectivity even though
the 1,8-borylation reaction of 7a involved the formation of
a more stable coordinated intermediate INT11,8 (Figure 2).
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Table 2: Substrate scope of catalytic asymmetric 1,6-borylation.[a]
Table 3: Substrate scope of catalytic asymmetric 1,8- and 1,10-boryla-
tion.[a]
[a] 1, 0.6 mmol; 4 or 6, 0.2 mmol. Isolated yield was reported. (E)/(Z)
ratio or (E,E)/others ratio was determined by the 1H NMR analysis of
crude reaction mixture. Ee was determined by chiral-stationary-phase
HPLC analysis. [b] Conditions in entry 7 in Table 1 were employed.
2 equiv B2(Pin)2 was employed.
[a] 1, 0.6 mmol; 2, 0.2 mmol. Isolated yield was reported. The ee was
determined by chiral-stationary-phase HPLC analysis. [b] Reaction
performed on a 1-mmol scale (2). [c] Diastereoselectivity was deter-
mined by chiral-stationary-phase HPLC analysis. [d] Diastereoselectivity
was determined by 1H NMR analysis.
Of particular utility is the structural information provided
through the transition state calculations, which provides
insight into the specific interactions that drive the regio-
and enantioselectivity. It is evident that proximal additions
would suffer steric interaction between the dioxinone and the
metal substituents.[21c,23] Additionally, our stereomechanistic
analysis highlighted by the insert in Figure 2 shows one
important feature dictating the facial selectivity. For the
major enantiomer, a less severe steric interaction is observed
Scheme 2. Transformations of product 3a.
À
between the substrateꢀs alkenyl C H and the phosphine
ligand, rather than the substrateꢀs terminal substituent (here,
methyl). This analysis provides visual insight into the
observed outcome while also suggesting future ligand modi-
fications.
vain, which was isolated from Kava plant (Piper methysti-
cum). Kavalactones are thought to be the main active
components responsible for the medication for a range of
conditions including anxiety, stress, and insomnia.[24] The one-
pot synthesis started from the copper(I)-catalyzed asymmet-
ric 1,6-borylation of 2z, which afforded the chiral alcohol
after oxidation. The subsequent deprotection and etherifica-
Finally, the present methodology was applied in the
catalytic asymmetric synthesis of (À)-7,8-dihydrokavain
(Scheme 3), the enantiomer of natural (+)-7,8-dihydroka-
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Scheme 3. One-pot asymmetric synthesis of (À)-7,8-dihydrokavain.
Conclusion
Copper(I)-catalyzed asymmetric conjugate 1,6-borylation
was achieved in moderate to high yields with high regio- and
enantioselectivity. A series of a-chiral boronates was pre-
pared with a broad substrate scope including aryls, hetero-
aryls, simple alkyls, and functionalized alkyls. It was partic-
ularly outstanding that the present reaction protocol was
successfully applied to the challenging and unprecedented
catalytic asymmetric 1,8- and 1,10-borylation in moderate
yields with high enantioselectivity. Moreover, the generated
a-chiral boronate was successfully transformed to syntheti-
À
À
cally useful compounds through C O bond and C C bond
formations. Importantly, a stereomechanistic analysis clarifies
the non-covalent interactions that dictate the regioselectivity
and enantioselectvity. Finally, the methodology found appli-
cation in the efficient one-pot asymmetric synthesis of (À)-
7,8-dihydrokavain. Expansion of the present reaction proto-
col to other processes is currently underway in our laborato-
ries.
Figure 1. Calculated energy profile of 1,6- (top) and 1,8-addition
(bottom) of 5a. Bond lengths are in angstroms and energies in
kcal molÀ1 at the B3LYP-D3/LANL2DZ(Cu,Fe)/6-31G(d) level of theory.
Acknowledgements
L.Y. gratefully acknowledges the financial support from the
“Thousand Youth Talents Plan”, the National Natural Science
Foundation of China (No. 21672235, No. 21871287 and No.
21922114), the Science and Technology Commission of
Shanghai Municipality (No. 20JC1417100), the Strategic
Priority Research Program of the Chinese Academy of
Sciences (No. XDB20000000), CAS Key Laboratory of
Synthetic Chemistry of Natural Substances, and Shanghai
Institute of Organic Chemistry. T.R.N. gratefully acknowl-
edges NIH for providing financial support (GR100045) and
Yale Universityꢀs High Performance Computing (HPC)
Center for providing resources for this work.
Figure 2. Calculated energy profile of 1,6-, 1,8-, and 1,10-addition of
7a. Bond lengths are in angstroms and energies in kcal molÀ1 at the
B3LYP-D3/LANL2DZ(Cu,Fe)/6-31G(d) level of theory.
Conflict of interest
tion furnished (À)-7,8-dihydrokavain in 68% total yield with
92% ee for four steps. It was noteworthy that most reported
synthetic approaches gave less than 32% overall yield in more
than five steps.[25]
The authors declare no conflict of interest.
Keywords: 1,6-addition ·1,8-addition ·1,10-addition ·
borylation ·copper catalysts
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Manuscript received: December 2, 2020
Revised manuscript received: January 22, 2021
Accepted manuscript online: February 4, 2021
Version of record online: March 18, 2021
Angew. Chem. Int. Ed. 2021, 60, 9493 –9499
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