Kinetic Resolution and Dynamic Kinetic Resolution of γ-Aryl-Substituted Butenolides via Copper-Catalyzed 1,4-Hydroboration

Article abstract of DOI:10.1002/adsc.202001353

Kinetic resolution (KR) and dynamic kinetic resolution (DKR) of γ-aryl and heteroaryl-substituted butenolides via CuH-catalyzed 1,4-hydroboration using pinacolborane is reported. With a copper-Ph-BPE catalyst, selectivity factors were extremely high (s=>400) with regard to the kinetic resolution of β-methyl-γ-phenyl butenolide; DKR was possible in the presence of an amine base (DBU), which facilitated racemization of the starting unsaturated lactones. The reaction provided easy access to highly enantioenriched γ-butyrolactones (>99% ee) containing β,γ-substituents. (Figure presented.).

Full text of DOI:10.1002/adsc.202001353

Title: Kinetic Resolution and Dynamic Kinetic Resolution of γ-Aryl-
substituted Butenolides via Copper-Catalyzed 1,4-Hydroboration
Authors: Jaesook Yun, Soyeon Lee, and Do Hyun Ryu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202001353
Link to VoR: https://doi.org/10.1002/adsc.202001353

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
COMMUNICATION
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Kinetic Resolution and Dynamic Kinetic Resolution of γ-Aryl-
substituted Butenolides via Copper-Catalyzed 1,4-
Hydroboration
a
a
a
Soyeon Lee, Do Hyun Ryu, and Jaesook Yun *
a
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon, 16419, Korea
E-mail: jaesook@skku.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Kinetic resolution (KR) and dynamic kinetic copper-hydride species from suitable copper
resolution (DKR) of γ-aryl and heteroaryl-substituted precursors and pinacolborane has become possible
[
6d,e,g,7]
butenolides via CuH-catalyzed 1,4-hydroboration under mild conditions without alkoxide bases,
using pinacolborane is reported. With a copper-Ph- we decided to expand our hydroboration method to
BPE catalyst, selectivity factors were extremely high (s kinetic resolution of unsaturated compounds.
=
>400) with regard to the kinetic resolution of β-
In 2005, Buchwald and coworkers first utilized β,γ-
disubstituted butenolides as the subject of DKR
through copper-catalyzed asymmetric conjugate
methyl-γ-phenyl butenolide; DKR was possible in the
presence of an amine base (DBU), which facilitated
racemization of the starting unsaturated lactones. The
reaction provided easy access to highly
reduction in an effort to achieve asymmetric total
[4b]
synthesis of eupomatilone-3.
However, all other
enantioenriched
containing β,γ-substituents.
γ-butyrolactones
(>99%
ee)
butenolide substrates containing a simple aryl group at
the γ-position differed from the unsaturated lactone
[8]
precursor for eupomatilone synthesis, resulting in
moderate enantioselectivity (67–87% ee) and
remained a challenge. Therefore, we initiated an
investigation with γ-phenyl butenolide, rac-1a, as a
model substrate, with the goal of finding a highly
enantioselective ligand-copper catalytic system for
1,4-hydroboration of β,γ-disubstituted butenolides
(Table 1). Use of copper(I) chloride and NaOtBu as
Keywords: Copper; Dynamic kinetic resolution;
Hydroboration; Kinetic resolution; Lactones
Copper-hydride (CuH) catalyzed asymmetric
reduction with silanes has been established as a
[1]
powerful synthetic method in organic synthesis. Due
to the low cost of copper salts, easy accessibility of
reducing silane reagents and chiral ligands, high
selectivity, and mild reaction conditions for copper-
hydride catalysis, the process has become a practical
method for synthetic chemists.
catalytic precursors in the presence of C -symmetric
2
tol-BINAP ligand (L1) and pinacolborane was not
effective, resulting in racemic 2a with poor mass
balance (entry 1). Therefore, we changed the precursor
to a copper carboxylate such as CuOAc and CuTC,
which could be activated by pinacolborane in the
absence of an alkoxide base. However, L1 displayed
low reactivity and selectivity under both conditions
(entries 2 and 3). Changing the ligand to the bulkier
Dynamic kinetic resolution (DKR) is an effective
approach for preparation of enantiomerically enriched
compounds compared to traditional kinetic resolution,
given the expected yield and efficiency of the
process.[ While a number of transition metal-
catalyzed asymmetric hydrogenation and transfer
hydrogenation reactions of organic compounds
through dynamic kinetic resolution including rare Ir,
dtbm-Segphos (L2), a highly efficient ligand for
2]
[6b,c]
hydroboration of alkenes,
yielded improved
selectivity (s = 17) with reduced reaction time (entry
4). Further ligand screening showed that MeO-
BIPHEP (L3) was more selective than L2 or the P-
chiral QuinoxP* ligand (L4) (entries 5 and 6). Finally,
Josiphos (L5) and Ph-BPE (L6) ligands were highly
selective and reactive in the kinetic resolution reaction;
the BPE ligand (L6) finally was chosen as the optimal
ligand for kinetic resolution of rac-1a (entry 8).
Moreover, in the absence of a phosphine ligand, the
reaction did not proceed (entry 9), indicating that
hydroboration of 1a with CuTC and L6 was a true
[3]
Rh, Pd, and Ru catalysts have been reported, few
DKR examples have been reported via CuH
catalysis[
4,5]
in asymmetric reductions involving
[4c]
silanes and hydrogen as a stoichiometric reducing
agent. Our group previously reported that stable
pinacolborane (pinBH) could be used for generation of
copper-hydride instead of hydrosilanes, which was
applied to hydroboration of alkenes and alkynes, and
,4-hydroboration of coumarins. Since generation of
[6]
[7]
1
1
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
ligand-accelerated reaction with no background
reduction. In contrast, addition of NaOtBu yielded a
Table 1. Optimization of the kinetic resolution of rac-1a.[a]
Entry [Cu]
Ligand Time [h] Conv. [%][b] Yield [%][c]
ee of (S)-1a [%][d] ee of 2a [%][d] s[e]
1
CuCl/
L1
24
68
35
–
0
–
NaOtBu
CuOAc
2
3
4
5
6
7
8
9
1
L1
L1
L2
L3
L4
L5
L6
None
None
72
72
2
12
3.5
0.2
1.2
24
24
38
35
48
46
49
51
50
0
38
28
46
47
46
45
50
–
8
8
13
15
71
87
66
92
98
–
1.4
1.5
17
32
9.2
93
458
–
[
f]
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
71
74
63
95
98
–
0
CuTC/
50
39
–
–
–
NaOtBu
[
a]
General reaction conditions: rac-1a (0.3 mmol), HBpin (0.6 mmol), [Cu] (0.015 mmol) and ligand (0.015 mmol) in THF
1 mL).
Conversion of 1a was determined by GC analysis using tetradecane as an internal standard.
Isolated yield of 2a.
The % ee was determined by HPLC analysis on a chiral phase.
Selectivity factor, s = ln[(1–c)(1–ee)]/ln[(1–c)(1+ee)].
Copper(I) thiophene-2-carboxylate.
(
[
[
[
[
[
b]
c]
d]
e]
f]
Figure 1. Structure of ligands.
significant quantity of the rac-2a product even in the
absence of ligand (entry 10), suggesting that a
significant background reaction is possible during the
reaction.
We then briefly carried out KR of butenolides
containing bulkier β-substituent, such as isopropyl and
phenyl using the optimized conditions found in the KR
of rac-1a (Scheme 1). Both substrates reached around
5
0% conversion in an extended reaction time, but with
good selectivity factors.
2
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
Scheme 1. Kinetic resolution of butenolides.
Table 2. Optimization of the dynamic kinetic resolution of rac-1a.[a]
Entry
Base[b]
NaO-tBu
Time [h]
24
12
12
12
12
12
12
12
Conv. [%][c]
Yield [%][d]
ee of 1a [%][e] ee of 2a [%][e]
1
2
3
4
5
6
7
8
9
28
82
80
57
55
85
66
76
84
90
20
78
72
56
53
79
57
66
78
85
0
56
60
97
93
95
93
95
99
99
99
Cs
2
CO
3
10
23
95
84
17
13
15
19
47
TEA
DIPEA
DIPA
DABCO
DBN
DBU
DBU
24
36
1
0[f]
DBU
[
a]
General reaction conditions: 1a (0.3 mmol), HBpin (0.6 mmol), CuTC (0.015 mmol), (S,S)-Ph-BPE (0.015 mmol) and
base (0.33 mmol) in THF (1 mL).
[
b]
TEA = trimethylamine, DIPEA = N,N-diisopropylethylamine, DIPA = diisopropylamine, DABCO = 1,4-diazabicyclo
2.2.2]octane, DBN = 1,5-diazabicyclo[4.3.0]non-5-ene, DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
Conversion was determined by GC analysis and H NMR analysis using tetradecane and DMF, as an internal standard,
[
[
c]
1
respectively.
[
[
[
d]
e]
f]
Isolated yield of 2a.
The % ee was determined by HPLC analysis of chiral phase.
The reaction was conducted at 0 ˚C.
Next, we sought to extend the kinetic resolution
compatible and produced an increased yield and high
ee of 2a (entries 3–8). Triethylamine resulted in 97%
ee of reduction product 2a with significantly
racemized starting material 1a. However, bulky
isopropyl-substituted amines such as DIPEA and
DIPA were not suitable for facile racemization of the
starting material (entries 4 and 5). Cyclic amines were
more efficient than TEA in terms of racemization of
the starting material (entries 6–8), and DBU was
selected as optimal for the DKR process (entry 8).
Elongation of reaction duration resulted in additional
conversion and increased yield of chiral 2a in 99% ee
method to the DKR of the unsaturated lactone 1a using
a highly stereoselective copper-L6 catalyst (Table 2).
In most reported DKR examples using CuH catalysis,
use of an alkoxide base was necessary for catalyst
activation and racemization of the starting substrates
[4,5]
such as enones, lactones, and unsaturated esters.
However, in our hydroboration case, NaOtBu was not
compatible with the catalytic conditions, resulting in
low conversion and a low ee value of the product due
to background reduction (entry 1). Therefore, we
attempted to use other bases to facilitate racemization
of rac-1a, and found that amine bases were generally
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
(
entry 9); however, reducing the reaction temperature
to 0 ˚C led to slower racemization (entry 10).
On the basis of the success of the DKR of rac-1a,
we next examined the scope of the DKR method for
other γ-aryl-substituted unsaturated lactones (Scheme
2
). All reduction products (2b–2i) were formed from
γ-aryl-β-methyl butenolides with high
enantioselectivity (>99%) without formation of other
stereoisomeric products. Substrates with an electron
withdrawing substituent (-CF , -Cl, -Br) on the
3
aromatic group or electron donating substituent were
all reactive, suggesting no clear dependence on an
electronic factor. Ortho-substituted aryl (1g) and
heteroaryl containing substrates (1h and 1i) at the γ-
position and substrates with a primary alkyl at the β-
position (1j and 1k) were appropriate for the reaction
as well. When the steric bulkiness of the β-substituent
was increased to isopropyl (1l) and phenyl (1m), the
efficiency of the process was lower than that of kinetic
resolution (Scheme 1); isopropyl and phenyl
substituted substrates yielded the reduced product in
Scheme 3. Proposed catalytic cycle.
A proposed catalytic cycle for DKR of butenolides
via copper-catalyzed 1,4-hydroboration using
pinacolborane in the presence of an amine base is
shown in Scheme 3. The successful reaction featured
in-situ generation of Cu-H from the CuTC precursor
and pinacolborane in the absence of an alkoxide base,
racemization of rac-1a via amine, and selective 1,4-
hydrocupration of (R)-1a.
~
50% yield and high ee, but the remaining substrates
were racemized (0–9% ee) by DBU.
In conclusion, we successfully achieved CuH-
catalyzed 1,4-hydroboration of β,γ-disubstituted
butenolides with pinacolborane via dynamic kinetic
resolution. The new catalytic system uses a highly
enantioselective copper-Ph-BPE catalyst, mild
reaction conditions, and operational simplicity using
an amine base and pinacolborane reagent. Extension
of this process to other types of compounds is
underway.
Experimental Section
General Procedure for Copper-Catalyzed Dynamic
Kinetic Resolution of Butenolides with Pinacolborane;
Pinacolborane (87.1 µL, 0.6 mmol) was added to a mixture
of CuTC (2.8 mg, 0.015 mmol), and (S,S)-Ph-BPE (7.6 mg,
0
.015 mmol) in THF (0.5 mL) in a Schlenk tube, and stirred
for 15 min under an atmosphere of nitrogen. Racemic
substrate rac-1 (0.3 mmol) in THF (0.5 mL) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (49.6 µL, 0.33 mmol) were
added to the reaction tube. The reaction mixture was stirred
at room temperature for 24 h and monitored by TLC and GC.
After that, the reaction mixture was quenched with water.
The aqueous layer was extracted with diethyl ether (3×10
mL), and the combined organic layers were washed with
brine, dried over MgSO
product was purified by silica gel chromatography.
4
, and concentrated in vacuo. The
Scheme 2. Substrate scope. [a] For this, 14% inseparable 1i Acknowledgements
was co-eluted.
This research has been supported by grants from the
National Research Foundation of Korea (NRF)
2019R1A2C2005706 and 2019R1A4A2001440).
(
References
4
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
[
[
[
1] For reviews, see: a) S. Rendler, M. Oestreich, Angew.
Chem. Int. Ed. 2007, 46, 498; b) C. Deutsch, N. Krause,
B. H. Lipshultz, Chem. Rev. 2008, 108, 2916; c) B. H.
Lipshultz in Copper-Catalyzed Asymmetric Synthesis
[5] CuH catalyzed kinetic resolution: a) S. Rendler, G. Auer,
M. Oestreich, Angew. Chem. Int. Ed. 2005, 44, 7620; b)
J. T. Issenhuth, S. Dagorne, S. Bellemin-Laponnaz, J.
Mol. Catal. A. 2008, 286, 6; c) X. Dong, A.
Weickgenannt, M. Oestreich, Nat. Commun. 2017, 8,
15547; d) X. Dong, Y. Kita, M. Oestreich, Angew. Chem.
Int. Ed. 2018, 57, 10728.
(
Eds.: A. Alexakis, N. Krause, S. Woodward), Wiley-
VCH, Weinheim, 2014, pp. 179–199.
2] a) R. Noyori, M. Tokunaga, M. Kitamura, Bull. Chem.
Soc. Jpn. 1995, 68, 36; b) S. Caddick, K. Jenkins, Chem.
Soc. Rev. 1996, 25, 447; c) O. Pàmies, J.-E. Bäckvall,
Chem. Rev. 2003, 103, 3247; d) H. Pellissier,
Tetrahedron 2003, 59, 8291; d) V. Bhat, E. R. Welin, X.
Guo, B. M. Stoltz, Chem. Rev. 2017, 117, 4528.
[6] a) D. Noh, H. Chea, J. Ju, J. Yun, Angew. Chem. Int. Ed.
2009, 48, 6062; b) D. Noh, S. K. Yoon, J. Won, J. Y.
Lee, J. Yun, Chem. Asian J. 2011, 6, 1967; c) X. Feng,
H. Jeon, J. Yun, Angew. Chem. Int. Ed. 2013, 52, 3989;
d) H. Lee, B. Y. Lee, J. Yun, Org. Lett. 2015, 17, 764;
e) W. J. Jang, W. L. Lee, J. H. Moon, J. Y. Lee, J. Yun,
Org. Lett. 2016, 18, 1390; f) W. J. Jang, S. M. Song, J.
H. Moon, J. Y. Lee, J. Yun, J. Am. Chem. Soc. 2017, 139,
3] a) R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M.
Kitamura, H. Takaya, S. Akutagawa, N. Sayo, T. Saito,
T. Taketomi, H. Kumobayashi, J. Am. Chem. Soc. 1989,
1
3660; g) W. J. Jang, B.-N. Kang, J. H. Lee, Y. M. Choi,
1
11, 9134; b) L. Schwink, T. Ireland, K. Püntener, P.
C,-H. Kim, J. Yun. Org. Biomol. Chem. 2019, 17, 5249.
Knochel, Tetrahedron: Asymmetry 1998, 9, 1143; c) K.
Murata, K. Okano, M. Miyagi, H. Iwane, R. Noyori, T.
Ikariya, Org. Lett. 1999, 1, 1119; For recent reviews, d)
P.-G. Echeverria, T. Ayad, P. Phansavath, V.
Ratovelomanana-Vidal, Synthesis 2016, 48, 2523; e) A.
Matsunami, Y. Kayaki, Tetrahedron Lett. 2018, 59, 504;
f) G. Talavera, A. Santana Fariña, A. Zanotti-Gerosa, H.
G. Nedden, Top. Organomet. Chem. 2019, 65, 73; g) R.
M. Betacourt, P.-G. Echeverria, T. Ayad, P. Phansavath,
V. Ratovelomanana-Vidal, Synthesis 2020, DOI:
[7] H. Kim, J. Yun, Adv. Synth. Catal. 2010, 352, 1881.
[
8] Asymmetric synthesis of eupomatilones: a) S. Mitra, S.
R. Gurrala, R. S. Coleman, J. Org. Chem. 2007, 72,
8
724; b) J. B. Johnson, E. A. Bercot, C. M. Williams, T.
Rovis, Angew. Chem. Int. Ed. 2007, 46, 4514; c) Y.
Hirokawa, M. Kitamura, M. Mizubayashi, R. Nakatsuka,
Y. Kobori, C. Kato, Y. Kurata, N. Maezaki, Eur. J. Org.
Chem. 2013, 721; d) H. Choi, H. Jang, H. Kim, K. Lee,
Org. Lett. 2019, 21, 7857.
1
0.1055/s-0040-1705918.
[
4] a) V. Jurkauskas, S. L. Buchwald, J. Am. Chem. Soc.
2
002, 124, 2892; b) M. P. Rainka, J. E. Milne, S. L.
Buchwald, Angew. Chem. Int. Ed. 2005, 44, 6177; c) O.
V. Zatolochnaya, S. Rodriguez, Y. Zhang, K. S. Lao, S.
Tcyrulnikov, G. Li, X.-J. Wang, B. Qu, S. Biswas, H. P.
R. Mangunuru, D. Rivalti, J. D. Sieber, J. -N. Desrosiers,
J. C. Leung, N. Grinberg, H. Lee, N. Haddad, N. K. Yee,
J. J. Song, M. C. Kozlowski, C. H. Senanayake, Chem.
Sci. 2018, 9, 4505; d) L. Hu, Y. Zhang, G.-O. Chen, B.-
J. Lin, Q.-W. Zhang, Q. Yin, X. Zhang, Org. Lett. 2019,
2
1, 5575.
5
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202001353
COMMUNICATION
Kinetic Resolution and Dynamic Kinetic
Resolution of γ-Aryl-substituted Butenolides via
Copper-Catalyzed 1,4-Hydroboration
Adv. Synth. Catal. Year, Volume, Page – Page
Soyeon Lee, Do Hyun Ryu, Jaesook Yun*
6
This article is protected by copyright. All rights reserved.