Copper-catalyzed asymmetric 1,4-hydroboration of coumarins with pinacolborane: Asymmetric synthesis of dihydrocoumarins

Article abstract of DOI:10.1002/adsc.201000310

An efficient asymmetric addition of pinacolborane to 4-substituted coumarins proceeded with high enantioselectivity in the presence of a copper(I)-QuinoxP complex as a catalyst to produce the corresponding 1,4-hydroboration products. Treatment of the intermediates with electrophiles, without isolation, resulted in enantioenriched dihydrocoumarins. The utility of this protocol was demonstrated in the formal synthesis of biologically active molecules.

Full text of DOI:10.1002/adsc.201000310

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DOI: 10.1002/adsc.201000310
Copper-Catalyzed Asymmetric 1,4-Hydroboration of Coumarins
with Pinacolborane: Asymmetric Synthesis of Dihydrocoumarins
Hyohyun Kima and Jaesook Yuna,*
a
Department of Chemistry and Institute of Basic Science, Sungkyunkwan University, Suwon 440-746, Korea
Fax : (+82)-31-290-7075; e-mail: jaesook@skku.edu
Received: April 22, 2010; Revised: June 28, 2010; Published online: August 16, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000310.
Abstract: An efficient asymmetric addition of pina-
colborane to 4-substituted coumarins proceeded
with high enantioselectivity in the presence of a
copper(I)-QuinoxP complex as a catalyst to pro-
duce the corresponding 1,4-hydroboration products.
Treatment of the intermediates with electrophiles,
without isolation, resulted in enantioenriched dihy-
drocoumarins. The utility of this protocol was dem-
onstrated in the formal synthesis of biologically
active molecules.
alyzed asymmetric conjugate reduction of prochiral
a,b-unsaturated compounds.[3] So far, boranes have
been employed for the site-specific generation of a
boron enolate from b-monosubstituted enones[3] or
unsaturated esters[4] in the presence of a copper cata-
lyst.
Recently, the asymmetric reduction of coumarin de-
rivatives has proven to be useful in the synthesis of
biologically active target molecules.[5] However, a
highly enantioselective and chemoselective reduction
to dihydrocoumarins has not been realized; either low
to moderate enantioselectivity,[5a,b] or over-reduction,
still remain a problem. For example, recent reports by
Lipshultz et al.[5c,d] have shown that CuH reduction of
coumarins in the presence of silane led to the corre-
sponding lactols through a double reduction. In this
communication, we describe the development of a
Keywords: copper; coumarins; dihydrocoumarins;
hydroboration; pinacolborane; reduction
Asymmetric conjugate reduction catalyzed by chiral catalytic asymmetric 1,4-hydroboration of coumarin
CuH species represents a useful and practical method derivatives with copper catalysts. We thought that
for the synthesis of carbonyl and related compounds chiral boron enolates (2) possessing a b-stereocenter
with b-stereocenters.[1] Since the first report by Buch- could be prepared from prochiral coumarins (1) with
wald and co-workers on the CuH-catalyzed asymmet- the use of stable pinacolborane (PinBH) and that the
ric conjugate reduction of a,b-unsaturated esters,[2a] resulting enolates could be further transformed to di-
CuH reduction has been employed to reduce various verse enantioenriched 3,4-dihydrocoumarins[6] by
types of Michael acceptors.[2] While most studies use taking advantage of enolate chemistry (Scheme 1).[4,7]
silanes as a source of hydride to generate copper hy-
First, our efforts focused on checking the reactivity
dride, boranes are rarely employed in the copper-cat- of pinacolborane as the reducing agent in the reduc-
Scheme 1. Hydroboration of coumarins.
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Hyohyun Kim and Jaesook Yun
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Table 1. Asymmetric reduction of 1a with pinacolborane and various ligands.
Entry
Copper catalyst
Ligand
Conversion [%][a]
ee [%][b]
1[c]
2
3
4
5
CuCl/NaO-t-Bu
CuCl/NaO-t-Bu
CuCl/NaO-t-Bu
CuCl/NaO-t-Bu
CuCl/NaO-t-Bu
CuCl/NaO-t-Bu
CuOAc
Dppbz
Dppbz
A
56
92
91
70
76
90
99
100
100
–
–
80
93
64 (S)
92
95
96
95
N
E
6
7
R
T
ACHTUNGTRENNUNG
8[d]
9[e]
CuTc
CuTc
[a]
Conversion was determined by GC analysis with an internal standard.
The % ee was determined by HPLC analysis on a chiral phase.
Room temperature.
The reaction time is 3 h.
THF was used instead of toluene.
[b]
[c]
[d]
[e]
tion of a model coumarin substrate (1a). Based on tion of the reaction in 3 h to yield the product with
our previous success on the hydroboration of styr- 96% ee (entry 8). The reduction of 1a could be con-
enes,[8] we conducted the initial experiments using a ducted in THF with equal efficiency (entry 9).
catalytic amount of CuCl and NaO-t-Bu, and a race-
Next, various coumarins were subjected to reaction
mic ligand, 1,2-bis(diphenylbenzene) (dppbz). The re- with pinacolborane using the Cu(I)-QuinoxP catalyst
action resulted in moderate conversion at room tem- in toluene or in a mixture of THF and toluene, de-
perature (entry 1, Table 1), but the conversion further pending on the solubility of coumarin. The results are
increased to a satisfactory level at 408C in toluene summarized in Table 2. The catalyst system gave high
(entry 2, Table 1). In contrast to pinacolborane, cate- levels of enantioselectivity (92–98% ee) for both 4-
cholborane and alkylboranes, such as 9-BBN or dieth- aryl (1b–g) and alkyl-substituted (1h, 1i) coumarins.[9]
ylborane showed no conversion under the same con- Most of the reactions proceeded to completion within
ditions. Once the feasibility of using pinacolborane as a 3 h reaction time. However, the reaction of 1e pos-
the reducing agent had been checked, a survey on re- sessing an ortho-tolyl substituent at the reaction site
action conditions was undertaken to identify the opti- needed more catalyst loading (5 mol%) and a longer
mal chiral ligand and the copper source (Table 1).
reaction time (12 h) for completion (entry 4). Substi-
A series of chiral copper-phosphine complexes was tution on the fused benzene ring did not significantly
screened for catalytic activity and enantioselectivity. affect the reactivity and enantioselectivity of the cur-
The lactone (3a) was obtained as a single product and rent catalytic system (entries 5, 6 and 8).
good conversion and high enantioselectivity was ob-
A catalytic cycle for copper-catalyzed hydrobora-
served in the presence of the QuinoxP ligand tion is proposed in Scheme 2. A copper enolate
(entry 6). Reactions with other types of ligands result- formed through the reaction between CuH and cou-
ed in either lower conversion or enantioselectivity marin undergoes transmetalation with pinacolborane
(entries 3–5) and all the screened reactions that em- to form a chiral boron enolate of coumarin and the
ployed CuCl and NaO-t-Bu did not proceed to com- active CuH catalyst. The chiral boron enolate prod-
pletion (entries 3–6). However, reaction with cop- ucts were easily utilized for further transformations,
per(I) thiophene-2-carboxylate (CuTc) as the copper as shown in Scheme 3. For example, treatment of the
precursor showed better reactivity, leading to comple- reaction mixture of 1a with D2O or acetone after
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Copper-Catalyzed Asymmetric 1,4-Hydroboration of Coumarins with Pinacolborane
Table 2. Asymmetric reduction of coumarins.
Entry
Substrate (1)
R
R’
Yield [%][a]
ee [%][b]
1
2
1b
1c
1d
1e
1f
1g
1h
1i
p-Me-C6H4
p-MeO-C6H4
p-F-C6H4
o-Me-C6H4
Ph
Ph
Me
Me
H
H
H
H
6-Me
6-MeO
H
89
88
83
85
82
87
80
89
96
93
94
97
98
95
93
92
3
4[c]
5
6
7
8
7-MeO
[a]
Yield of the isolated product.
The % ee was determined by HPLC analysis on a chiral phase.
5 mol% CuTc, 5.5 mol% (R,R)-QuinoxP and 12 h.
[b]
[c]
of a copper catalyst and by quenching the reaction
with water. Excellent enantiomeric excesses and high
yields were obtained by using the P-chiral QuinoxP
ligand. We also demonstrated that the 1,4-hydrobora-
tion intermediates could be utilized in a useful trans-
formation in the synthesis of a biologically active mol-
ecule.
Experimental Section
Scheme 2. Proposed mechanism for the copper-catalyzed hy-
droboration of coumarins.
General Information
THF and toluene were distilled from sodium benzophenone
ketyl under nitrogen. Copper(I) thiophene-2-carboxylate, pi-
nacolborane and other commercial substrates were pur-
chased and used as received. Coumarins were prepared ac-
cording to the literature procedures. All reduction proce-
dures were carried out with standard Schlenk tube tech-
niques under a nitrogen atmosphere. Flash chromatography
was performed on silica gel from Merck (70–230 mesh). All
1H NMR spectra were obtained on a Varian Mercury 300
system and reported in parts per million (ppm) downfield
from tetramethylsilane. 13C NMR spectra are reported in
ppm referenced to deuteriochloroform (77.16 ppm). HPLC
analysis was performed on a Younglin Acme 9000 series. El-
emental analysis and high resolution mass spectra (HR-MS)
were obtained at Organic Reactions Research Center,
Sogang University (Seoul, Korea) and reported in the form
of m/z (intensity relative to base peak=100).
being subjected to the 1,4-hydroboration reaction
conditions produced the corresponding 3,4-substituted
dihydrocoumarins as a single diastereomer[10] in 96%
ee. This strategy was also applied to a formal synthesis
of SB-209670 and SB-217242, which are non-peptide
endothelin antagonists under development.[11] The key
intermediate 7 was easily prepared from the corre-
sponding coumarin in a one-pot reaction by quench-
ing the hydroboration mixture with piperonal 6 and
stirring for 24 h. The (4R)-isomer was produced in
85% yield, which leads to the opposite enantiomer of
the target molecules. The absolute configuration of
the C-4 position and ee (97% ee) were determined
with the reduced lactone product.[12] Friedel-Crafts al-
kylation and functional group transformations, as re-
ported by Wood et al.,[13] would complete the synthe-
sis.
General Procedure for the Copper-Catalyzed
Asymmetric 1,4-Hydroboration of Coumarins with
Pinacolborane
In summary, we have a developed an efficient pro-
tocol for producing enantiomerically enriched dihy-
drocoumarins through stereoselective 1,4-hydrobora-
tion and subsequent reaction with electrophiles. Che-
moselective reduction of coumarins to lactones was
A mixture of CuTc (0.015 mmol, 2.9 mg), (R,R)-QuinoxP
(0.0165 mmol, 5.5 mg) in anhydrous toluene (0.4 mL) was
possible by employing pinacolborane in the presence stirred for 10 min in a Schlenk tube under an atmosphere of
Adv. Synth. Catal. 2010, 352, 1881 – 1885
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1883

Hyohyun Kim and Jaesook Yun
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Scheme 3. Synthetic applications of chiral boron enolates of coumarins.
nitrogen. Pinacolborane (0.70 mmol, 101.6 mL) was added to References
the reaction mixture and the mixture was stirred for 10 min
at room temperature. Coumarin (0.50 mmol) in toluene
(0.6 mL) and THF (1.0 mL) was added. The reaction tube
was sealed and stirred at 408C. The reaction was monitored
by TLC and GC. Upon completion of the reaction, the reac-
tion mixture was cooled to room temperature and quenched
with water. The layers were separated and the aqueous
layer was extracted with Et2O (3ꢁ20 mL). The combined or-
ganic layers were washed with brine, dried over MgSO4, and
concentrated under vacuum. The product was purified by
chromatography.
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Acknowledgements
This research was supported by the Basic Science Research
Program through the National Research Foundation of
Korea (NRF-20090085824).
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Adv. Synth. Catal. 2010, 352, 1881 – 1885

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