Catalytic asymmetric synthesis of chiral tertiary organoboronic esters through conjugate boration of β-substituted cyclic enones

Article abstract of DOI:10.1021/ja9045839

(Chemical Equation Presented) The first catalytic enantioselective conjugate boration of β-substituted cyclic enones was developed to produce enantiomerically enriched tertiary organoboronates. The optimized asymmetric catalyst includes a QuinoxP^*

Full text of DOI:10.1021/ja9045839

Published on Web 08/04/2009
Catalytic Asymmetric Synthesis of Chiral Tertiary Organoboronic Esters
through Conjugate Boration of ꢀ-Substituted Cyclic Enones
I-Hon Chen, Liang Yin, Wataru Itano, Motomu Kanai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo113-0033, Japan
Received June 5, 2009; E-mail: mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Optimization of Reaction Conditions
Catalytic asymmetric conjugate addition reactions are a funda-
mental synthetic methodology to introduce functionalities at the
ꢀ-position of carbonyl groups.1 Despite the plethora of catalytic
asymmetric conjugate addition reactions using ꢀ-monosubstituted
R,ꢀ-unsaturated carbonyl substrates, methods applicable to the
synthesis of ꢀ-tetrasubstituted carbonyl compounds using ꢀ,ꢀ-
disubstituted substrates are still limited.2 This is partly due to the
markedly lower reactivity of ꢀ,ꢀ-disubstituted substrates compared
to ꢀ-monosubstituted substrates. In addition, chirality is difficult
to control due to the smaller steric difference between the
ꢀ-substituents. Enhanced catalyst activity and enantioselectivity are
required to achieve catalytic asymmetric ꢀ-tetrasubstituted carbon
construction.
entry
M
ligand
solv.
MeOH
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
Na rac-BINAP
DMF
DMF
DMSO
DMF
-
-
+
-
-
-
-
-
-
-
-
-
10
55
11
82
23
90
55
78
90
88
61
57
-
-
-
Li
Li
Li
Li
Li
Li
Li
Li
rac-BINAP
rac-BINAP
tol-BINAP
DTBM-SEGPHOS DMF
Ph-BPE
JOSIPHOS
QuinoxP*
QuinoxP*
QuinoxP*
48
11
27
20
91
98
98
96
93
DMF
DMF
DMF
DMSO
DMSO
DMSO
DMSO
To overcome these hurdles, we focused on Cu(I)-catalyzed
conjugate boration using bis(pinacolato)diboron (2). The basic
methodology was originally developed independently by Hosomi3
and Miyaura4 in racemic systems. The reaction proceeds through
a borylcopper species generated via transmetalation.5 Yun recently
identified the remarkable acceleration effects of protic additives in
developing the first enantioselective version using linear ꢀ-mono-
substituted R,ꢀ-unsaturated carboxylic acid derivatives as substrates
and phosphines as ligands,6a-d and subsequently Ferna´ndez and
Guiry employed chiral NHC and P-N ligands, respectively.6e,f
Chiral organoboron compounds are versatile synthetic intermediates
due to the convertibility of C-B bonds to a variety of functional
groups.7,8 Furthermore, chiral organoboronic acids exhibiting unique
biological activities were identified.9 Based on the reaction mech-
anism for an analogous Cu-catalyzed allylic boration proposed by
Ito and Sawamura,10 chirality on the copper atom of the borylcopper
species exists proximal to the prochiral carbon in the four-membered
cyclic (Cu-B-ꢀ-C-R-C) transition state. This is advantageous for
the strict enantio-differentiation required to overcome the above-
mentioned difficulty in enantio-selection. Here we report a catalytic
enantioselective conjugate boration of ꢀ-substituted cyclic enones
that produces enantiomerically enriched tertiary organoboronates.
We first optimized racemic reaction conditions using 3-phenyl-
2-cyclohexen-1-one (1a) as a substrate and racemic BINAP as a
ligand (Table 1, entries 1-3). Using a CuOtBu complex generated
in situ from CuCl and NaOtBu in the presence of 2 equiv of MeOH
in THF (Yun’s conditions), the reaction did not proceed at all. On
the other hand, product 3a was obtained in 10% yield in DMF in
the absence of MeOH (entry 1). After a systematic survey of copper
sources and metal alkoxides, the optimized conditions were
determined to be a combination of CuPF6(CH3CN)4 and LiOtBu;
3a was obtained in 55% yield (entry 2). The detrimental effects of
additive MeOH in this reaction were confirmed again at this point;
yield decreased to 11% in the presence of 2 equiv of MeOH
(entry 3).
10d Li
11d Na QuinoxP*
12d
K
QuinoxP*
a In entry 1, CuCl was used. In other entries, CuPF6(CH3CN)4 was
used. b Isolated yield. c Determined by chiral GC. d 5 mol % of catalyst.
excellent enantioselectivity (91% ee) was obtained with a yield of
78% (entry 8). DMSO was a better solvent than DMF, affording
3a in 90% yield with 98% ee (entry 9). Catalyst loading was reduced
to 5 mol % without affecting the enantioselectivity (entry 10).
Interestingly, the enantioselectivity was not very sensitive to the
hard metals of t-butoxides. The chemical yield, however, was
significantly lower when using NaOtBu and KOtBu instead of
LiOtBu (entries 10-12).
The substrate scope was then investigated under the optimized
conditions (Table 2). Generally high enantioselectivity (93-98%
ee) was obtained from ꢀ-aromatic-substituted enones. Neither
electron-donating nor withdrawing para- and meta-substitution on
the ꢀ-aromatic ring affected the yield or enantioselectivity (entries
1-6). Methyl- and branched-alkyl substituted enones were com-
petent substrates as well (entries 7-9). In addition to the 6-mem-
bered cyclic enones, 5- and 7-membered cyclic enones produced
excellent to synthetically useful enantioselectivity (entries 10-12).
This reaction is a useful platform for the synthesis of various
chiral building blocks that are otherwise difficult to access (Scheme
8b
1). Oxidation of 3a with NaBO3 afforded tertiary alcohol 4 in
high yield with minimum loss of enantioselectivity (eq 1). Unique
chiral tertiary organoboronic acid 5, which might be an interesting
pharmaceutical lead, was produced through acid hydrolysis (eq 2).
Unlike Yun’s conditions,6 the present reaction did not require protic
additives. Therefore, the products in the reaction mixtures are
corresponding boron enolates that can react further with electro-
philes. This advantage was illustrated by extension to a catalytic
asymmetric three-component reaction using 1a, 2, and benzaldehyde
(eq 3). Product 6, derived through enantioselective conjugate
The optimized conditions were next extended to an asymmetric
version in the presence of chiral phosphines (entries 4-8). (R,R)-
QuinoxP* containing a P-chirality11 was the optimum chiral ligand;
9
11664 J. AM. CHEM. SOC. 2009, 131, 11664–11665
10.1021/ja9045839 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Enantioselective Conjugate Boration of
ꢀ-Substituted Cyclic Enones
Acknowledgment. Financial support was provided by Grant-
in-Aid for Scientific Research (S) and (B) from JSPS. We thank
T. Nitabaru and Y. Kimura for X-ray crystallographic studies of
3a. I.H. thanks Iwaki Pharmaceutical Company for financial support.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
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98d
93
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81
94
85
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70
98
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R ) p-Me-C6H4, n ) 1 (1c)
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a Isolated yield. b Determined by chiral GC or HPLC. NaOtBu was
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boration, diastereoselective aldol reaction, and oxidation in one pot,
was obtained in 71% yield with 91% ee (only two diastereomers
were detected; dr ) 6.5/1). Thus, the stereochemistries of three
contiguous stereogenic centers involving a tetrasubstituted carbon
were controlled in a high level, including their absolute configu-
ration.12
Although it is not yet clear why protic additives are not necessary
for this reaction, we currently believe that a catalytic amount of
LiPF6 generated in the active catalyst (CuOtBu) formation step from
CuPF6 and LiOtBu accelerates the probable turnover-limiting
catalyst regeneration step.14,15 The acceleration effect of LiPF6 was
confirmed by comparison with a reaction using Li-free CuOtBu16
catalyst (5 mol %); 3a was obtained only in 31% yield with 75%
ee (cf. Table 2, entry 1). The yield of 3a improved to 80% (87%
ee) when LiPF6 (5 mol %) was added to this reaction mixture.
In conclusion, we developed an enantioselective conjugate
boration of ꢀ-substituted cyclic enones to produce enantiomerically
enriched tertiary boronates, catalyzed by a Cu-QuinoxP* complex.
Catalytic LiPF6 had positive effects on reactivity. Detailed mecha-
nistic studies especially upon the role of LiPF6 are currently
ongoing.
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