Conjugate boration of β,β-disubstituted unsaturated esters: Asymmetric synthesis of functionalized chiral tertiary organoboronic esters

Article abstract of DOI:10.1002/chem.201002361

Challenging tertiary organoboronic esters containing a β-ester group were prepared enantioselectively via the asymmetric conjugate boration of β,β-disubstituted α,β-unsaturated esters with a copper-phosphine catalyst (see scheme). The functionalized organoboron derivatives can be utilized as a carbon nucleophile to form all-carbon quaternary centers. Copyright

Full text of DOI:10.1002/chem.201002361

COMMUNICATION
DOI: 10.1002/chem.201002361
Conjugate Boration of b,b-Disubstituted Unsaturated Esters: Asymmetric
Synthesis of Functionalized Chiral Tertiary Organoboronic Esters
Xinhui Feng and Jaesook Yun*[a]
Catalytic conjugate addition of a boron nucleophile (M-
B) to unsaturated carbonyl substrates[1] has emerged as a
novel synthetic tool to afford b-boryl carbonyl compounds,[2]
an important class of organoboron compounds. While sever-
al important and efficient methodologies for conjugate bora-
tion have been developed,[3] the asymmetric conjugate bora-
tion of b,b-disubstituted a,b-unsaturated esters is especially
challenging because of the low reactivity and poor enantio-
selectivity exhibited by these substrates. The lower reactivity
of b,b-disubstituted a,b-unsaturated esters, compared to
enones[1b,j] and b-monosubstituted substrates, is due to the
inherently lower electrophilicity and greater steric bulkiness
at the reaction site. As is often practiced with catalysts to
address this type of challenge, the development of a more
efficient catalytic system to enhance reactivity and enantio-
selectivity is required. In this communication, we describe a
highly efficient catalytic system for the asymmetric conju-
gate boration of b,b-disubstituted a,b-unsaturated esters
that produces tertiary organoboron compounds with a qua-
ternary boron-substituted carbon center[4] and ester func-
tional group. We also report the successful application of
these organoboranes as carbon nucleophiles in a rhodium-
catalyzed addition reaction.
RT).[7] Inclusion of proton accelerators[1c] seemed necessary
to promote the conversion of the enolate intermediate to
borylated product. Since we have observed greatly enhanced
catalytic activity of copper-mediated nucleophiles through
coordination with select ligands,[1c,8] we started our investiga-
tion of the conjugate boration of b,b-disubstituted a,b-unsa-
turated esters with diboron (1) by screening ligands and
proton sources. For the initial screening, we chose (E)-ethyl-
3-phenylbut-2-enoate (2a) as a model substrate (Table 1).
A large difference in catalytic activity was observed de-
pending on the chiral ligand employed. Josiphos and
BINAP led to very poor conversions, while chiral phosphine
ligands with a short tether between the two phosphines
showed comparable reaction conversions (entries 3–5). The
optimal ligand was determined to be MeDuphos, which re-
sulted in complete conversion to the product with excellent
Table 1. Optimization conditions.[a]
Entry Ligand
Additive
(2 equiv)
t
Conv.
ee
Recently, Shibasaki and co-workers reported an efficient
copper-catalyzed asymmetric conjugate boration of b-substi-
tuted cyclic enones in DMSO solvent.[5] However, in light of
a major difficulty, the ketoQenol isomerization of b-borylat-
ed C-bound Cu ester enolate intermediates in copper-cata-
lyzed borations, compared with enones,[6] we predicted and
observed that b,b-disubstituted a,b-unsaturated esters would
not be efficiently converted to products under the same con-
[h] [%][b]
[%][c]
1
2
3
4
N
MeOH
MeOH
MeOH
MeOH
15
24
24
24
0
5
83
91
–
–
93 (R)
60 (R)
5
6
7
8
U
MeOH
–
PhOH
AcOH
20
24
20
20
100[d]
8
14
93 (S)
–
92 (S)
–
ditions (CuPF6ACHTUNGTRENNUNG(CH3CN)4, LiOtBu, (R,R)-QuinoxP, DMSO,
10
[a] RT=17–188C. [b] Determined by GC analysis with an internal stan-
dard. [c] Determined by chiral HPLC analysis. [d] Isolated yield = 91%.
[a] X. Feng, Prof. J. Yun
Department of Chemistry and Institute of Basic Science
Sungkyunkwan University, Suwon 440-746 (Korea)
Fax : (+82)31-290-7075
E-mail: jaesook@skku.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002361.
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13609

enantioselectivity (entry 5). However, reactions without
methanol or with other proton sources, such as phenol or
acetic acid proceeded in low conversion, even in the pres-
ence of the Duphos ligand (entries 6–8). The optimized con-
ditions were determined to be a combination of CuCl/
NaOtBu[9] and MeDuphos in the presence of MeOH as an
additive.
Scheme 1. Asymmetric conjugate boration of b,b-disubstituted a,b-unsa-
turated ketones.
Various b,b-disubstituted a,b-unsaturated substrates were
then investigated via optimized catalytic conditions
(Table 2). In general, b-aryl-b-alkyl-substituted unsaturated
esters (2b, 2e–g) afforded borylated products with high
electron-withdrawing group than our previous conditions[3a,b]
for b-monosubstituted unsaturated compounds.
Organoboron derivatives are
important synthetic intermedi-
ates in organic synthesis, due to
Table 2. Asymmetric conjugate boration of b,b-disubstituted a,b-unsaturated esters.
their versatility in various trans-
formations and low toxicity.[10]
Along with alkenyl boron de-
rivatives, the use of alkyl boron
derivatives as sp3-hybridized
carbon nucleophiles has recent-
ly increased,[11] and notable ex-
amples of stereoretentive cou-
pling reactions of chiral alkyl
boron derivatives have recently
been reported by Crudden[12]
and Aggarwal.[13] In this regard,
the feasibility of using our
chiral tertiary organoboron
product 3a as a carbon nucleo-
phile possessing an ester func-
tionality was tested for the first
time in a rhodium-catalyzed ad-
dition reaction under Aggar-
Entry
Substrate (2)
Yield [%][a]
ee [%][b]
1
2
3
4
2b: R1 =Ph, R2 =CH3, EWG=C(O)OMe
2c: R1 =Ph, R2 =CH3, EWG=C(O)OtBu
2d: R1 =Ph, R2 =CH3, EWG=CN
91
85[c]
90
97
95
85
88
90
95
91
94 (S)
88 (S)
84 (S)
94
94
91 (S)
92
84
69
92
2e: R1 =p-MeOC6H4, R2 =CH3, EWG=C(O)OEt
2 f: R1 =p-FC6H4, R2 =CH3, EWG=C(O)OEt
2g: R1 =Ph, R2 =CH2CH3, EWG=C(O)OEt
2h: R1 =cyclohexyl, R2 =CH3, EWG=C(O)OEt
2i: R1 =PhCH2, R2 =CH3, EWG=C(O)OEt
2j: R1 =PhOCH2, R2 =CH3, EWG=C(O)OEt
2k: R1 =2-thienyl, R2 =CH3, EWG=C(O)OEt
5
6[d,e]
7[f]
8
9
10[d]
[a] Yield of the isolated product. [b] Determined by Chiral HPLC analysis. [c] 91% conversion. [d] 15 mol%
NaOtBu was used and the reaction temperature was 308C. [e] 5–9% of protodeboronated product was ob-
tained. [f] 15 mol% NaOtBu was used. 96% conversion.
enantioselectivity. The electronic nature of substituents on
the aryl group did not affect the yield nor enantioselectivity
(entries 4–5). However, when the conjugated EWG group is
a bulkier tert-butyl ester or nitrile group, lower enantioselec-
tivities were observed for the borylated products (entries 2–
3). b-Ethyl-substituted cinnamate required a slightly higher
reaction temperature for completion, and 5–9% of the pro-
todeboronated byproduct was formed (entry 6). b,b-Dialkyl-
substituted esters gave good to modest asymmetric induc-
tions (entries 7–9). In the case of primary alkyl and methyl-
substituted cases (2i and 2j), the smaller steric difference
between the substituents at the b-position is reflected, giving
lower ee values, compared to b-aryl-b-alkyl-substituted sub-
strates. In addition, the heteroaromatic thiophene-substitut-
ed substrate 2k was smoothly borylated, with a high level of
enantioselectivity at a slightly elevated reaction temperature
(entry 10).
Next, the conjugate boration of acyclic b,b-disubstituted
a,b-unsaturated ketones were briefly investigated using the
same catalytic conditions (Scheme 1). The borylated prod-
ucts, however, were formed with moderate levels of enantio-
meric excess. These results and the data (entries 1–3) in
Table 2 indicate that the current copper–Duphos ligand cat-
alytic system is more sensitive to the size and nature of the
walꢁs conditions (Scheme 2). The boronic ester 3a was suc-
cessfully converted to the corresponding trifluoroborate salt
5 with 85% yield.[14] The reaction of 5 with p-nitrobenzalde-
hyde with a rhodium catalyst gave the addition products
(d.r. 1:1.1),[15] which were then oxidized to the corresponding
ketone. The keto-ester product 6 was obtained in 90% yield
over the two steps and was measured to be 93% ee by
chiral HPLC analysis, proving the addition occurred with
complete transfer of chirality. Notably, the fragile stereogen-
ic center of the new organoboronic compound was pre-
served without erosion of chirality, and the all-carbon qua-
ternary center was made successfully without interruption of
b-hydride elimination or protodeboronation using this pro-
tocol.
In conclusion, we have developed a catalytic enantioselec-
tive conjugate boration system for b,b-disubstituted a,b-un-
saturated esters to afford chiral tertiary organoboronic
esters. The utility of the organoboron reagents prepared by
this protocol as carbon nucleophiles was demonstrated by a
rhodium-catalyzed coupling reaction with aldehydes to pro-
duce all carbon quaternary centers.
13610
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Chem. Eur. J. 2010, 16, 13609 – 13612

Functionalized Chiral Tertiary Organoboronic Esters
COMMUNICATION
loch,
R. P.
Tooze,
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Experimental Section
General procedure: A mixture of CuCl (0.025 mmol, 2.5 mg), NaOtBu
(0.05 mmol, 5.0 mg), and (S,S)-MeDuphos (0.025 mmol, 7.7 mg) in anhy-
drous THF (0.4 mL) was stirred for 30 min in a Schlenk tube under an at-
mosphere of nitrogen. Bis(pinacolato)diboron (0.55 mmol, 140.0 mg) was
added to the reaction mixture and stirred for 10 min at room tempera-
ture. Starting material (0.5 mmol) including tetradecane (0.25 mmol) as
an internal standard was added, followed by MeOH (1 mmol, 40 mL).
The reaction tube was washed with another THF (0.3 mL), sealed, and
the reaction was monitored by TLC and GC. The reaction mixture was
filtered through a pad of Celite and concentrated. The product was puri-
fied by flash silica gel chromatography.
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[7] 36% conversion in 24 h were obtained in our hands.
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This work was supported by the Mid-career Researcher Program through
a National Research Foundation (NRF) grant funded by the Ministry of
Education, Science and Technology, Republic of Korea (No. R01-2008-
000-20332-0). We thank Professor S. Lee and Y.-M. Jung for X-ray analy-
sis.
Keywords: asymmetric synthesis
·
boron
·
conjugate
addition · enantioselectivity · quaternary stereocenters
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J. Yun and X. Feng
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Received: July 14, 2010
Published online: November 4, 2010
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Chem. Eur. J. 2010, 16, 13609 – 13612