Multinuclear Cu-catalysts based on SPINOL-PHOS in asymmetric conjugate addition of organozinc reagents

Article abstract of DOI:10.1021/ol300748d

Multinuclear Cu/Zn complex-catalyzed efficient asymmetric conjugate addition of organozinc reagents to acyclic and cyclic enones has been developed in the presence of a wide variety of regioisomeric chiral diols bearing phosphorus moieties as ligands. The

Full text of DOI:10.1021/ol300748d

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2342–2345
Multinuclear Cu-Catalysts Based on
SPINOL-PHOS in Asymmetric Conjugate
Addition of Organozinc Reagents
Kohei Endo,*,†,‡ Daisuke Hamada,§ Sayuri Yakeishi,§ Mika Ogawa,§ and
Takanori Shibata*,§
Division of Material Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma, Kanazawa 920-1192, Japan, PRESTO, Japan Science
and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan,
and Department of Chemistry and Biochemistry, School of Advanced Science and
Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan
kendo@se.kanazawa-u.ac.jp; tshibata@waseda.jp
Received March 25, 2012
ABSTRACT
Multinuclear Cu/Zn complex-catalyzed efficient asymmetric conjugate addition of organozinc reagents to acyclic and cyclic enones has been
developed in the presence of a wide variety of regioisomeric chiral diols bearing phosphorus moieties as ligands. The regioisomeric SPINOL-
PHOS ligands based on a SPINOL architecture showed an unexpected inversion of stereoselectivity.
Multinuclear catalysts have recently attracted consider-
able attention due to their role in various asymmetric
reactions as powerful tools for preparing chiral molecules.1
We previously reported the self-assembled metal-linked
phosphine ligands to generate multinuclear complexes
(Figure 1). The deprotonation reaction of hydroxyprotons
using a dialkylzinc reagent and the subsequent addition of
a Cu-salt gives oligomeric multinuclear Cu/Zn-complexes.
Especially, the multinuclear catalysts derived from a
Figure 1. Metal-linked multinuclear complexes.
† Kanazawa University.
‡ Japan Science and Technology Agency.
3,30-diarylphosphino-2,20-binol achieved the highly effi-
§ Waseda University.
cient Cu-catalyzed asymmetric conjugate addition of or-
ganozinc reagents to enones; the use of 0.05 mol % Cu
catalyst was enough to give the product quantitatively and
realized a turnover frequency (TOF) of 300 hꢀ1 with excel-
lent enantioselectivity.2 Furthermore, the Pd/Zn-complexes
(1) (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
(b) Majima, K.; Takita, R.; Okada, A.; Oshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2003, 125, 15837. (c) Matsunaga, S.; Yoshida, T.; Morimoto,
H.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8777.
(d) Takacs, J. M.; Reddy, D. S.; Moteki, S. A.; Wu, D.; Palencia, H.
J. Am. Chem. Soc. 2004, 126, 4494. (e) Shibasaki, M.; Matsunaga, S.
Chem. Soc. Rev. 2006, 35, 269. (f) Chen, Z.; Morimoto, H.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (g) Trost, B. M.;
€
Muller, C. J. Am. Chem. Soc. 2008, 130, 2438. (h) Shibasaki, M.; Kanai,
M.; Matsunaga, S.; Kumagai, N. Acc. Chem. Res. 2009, 42, 1117 and
references cited therein.
(2) Endo, K.; Ogawa, M.; Shibata, T. Angew. Chem., Int. Ed. 2010,
49, 2410.
r
10.1021/ol300748d
Published on Web 04/20/2012
2012 American Chemical Society

We embarked on the development of novel architectures
for the design and construction of multinuclear complexes.
The Cu-catalyzed asymmetric conjugate addition of Et2Zn
to (E)-chalcone (1a) was carried out in THF at 0 °C as a
model reaction in the presence of SP1 ligand based on a
SPINOL architecture as a novel BP1 analogue.4 The
screening of Cu-salts showed that Cu(acac)2 was suitable
to give the product 2a in excellent yield with high enantio-
selectivity (Table 1, entry 2). Notably, the use of Cu(OAc)2
as a Cu-salt gave the opposite major enantiomer (entry 4).
Alexakis et al. reported that Cu-salts affected the yields
and enantioselectivities in the asymmetric conjugate addi-
tion of organozinc reagents to enones due to the incor-
poration of a counteranion derived from a Cu-salt in the
CꢀC bond forming process.5 However, the reversal of
enantioselectivity with Cu-salts in the conjugate addition
of organozinc reagents seems to be rare.6
Figure 2. Switch-point strategy.
Table 1. Screening of Reaction Conditions for SP1
a NMR yields. Ee was determined by chiral HPLC analysis. b SP1
(10 mol %) was used. c Copper(I) (thiophene-2-carboxylate).
Further examination of the regioisomeric ligands based
on a BINOL or SPINOL as novel architectures revealed
an unexpected influence on the catalytic performance
(Table 2). We previously reported that the reaction in the
Figure 3. Representative regioisomeric ligands.
derived from 3,30-diphenylphosphino-2,20-binol (BP1)
achieved the highly enantioselective ring-opening reaction
of oxabicyclic alkenes.3
presence of CuCl2 2H2O and BP1 gave the product 2a in
3
more than 98% yield with 94% ee (S) (entry 1).2 The
regioisomer of BP1, namely (R)-4,40-BINOL-PHOS BP2,
decreased the yield and ee; notably, the major enantiomer
of the product 2a was R (entry 2). Furthermore, the use
of (R)-6,60-BINOL-PHOS BP3 gave the product 2a in
low yield with poor enantioselectivity (entry 3). Further
screening of ligand effect clarified the characteristic fea-
tures of SPINOL-PHOS derivatives. The reaction using
We further focused on the novel “switch-point” strategy
in ligand architectures (Figure 2). Our hypothesis based on
a phosphinophenol moiety would manipulate the global
structures of multinuclear complexes. Hence, the represen-
tative ligand architectures based on a BINOL or a SPI-
NOL are new entries to the novel design of multinuclear
complexes (Figure 3). In this work, we report the dramatic
influence of regioisomeric ligands as pillars of multinuclear
complexes, which are highly versatile catalysts for the
asymmetric conjugate addition of organozinc regents.
(4) For reviews of Cu-catalyzed asymmetric addition: (a) Feringa,
B. L. Acc. Chem. Res. 2000, 33, 346. (b) Alexakis, A.; Benhaim, C. Eur. J.
€
Org. Chem. 2002, 3221. (c) Alexakis, A.; Backvall, J. E.; Krause, N.;
ꢀ
ꢁ
Pamies, O.; Dieguez, M. Chem. Rev. 2008, 108, 2796.
(5) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem.
Soc. 2002, 124, 5262.
(3) Endo, K.; Tanaka, K.; Ogawa, M.; Shibata, T. Org. Lett. 2011,
13, 868.
(6) Okamoto, M.; Yamamoto, Y.; Sakaguchi, S. Chem. Commun.
2009, 7363.
Org. Lett., Vol. 14, No. 9, 2012
2343

(S)-6,60-SPINOL-PHOS SP1 (5 mol %) gave the product
2a in more than 98% yield with 90% ee (S) (entry 4). To
our surprise, the use of (S)-4,40-SPINOL-PHOS SP2
(5 mol %) showed a dramatic inversion of stereoselectivity
(entry 5).6 Imamoto et al. reported the use of P-chiral
ortho-phosphinophenol derivatives as a ligand for Cu-
catalyzed asymmetric conjugate addition of organozinc
reagents to enones, where the P,O-bidentate coordination
to the Cu-center seems to be essential. In contrast, our
ligand system, especially for SP2, indicated that the P,O-
bidentate coordination should not be necessary.7
(entries 29ꢀ32). The opposite major enantiomer was
obtained in low enantioselectivity when SP2 (10 mol %)
was used (entry 32).
The ESI-MS analyses of the complexes derived from
SPINOL-PHOS ligands were performed. The treatment of
SP1 with Et2Zn in THF gave the mixture, the ESI-MS ana-
lysis of which suggested the presence of [(SP1ꢀ2H)2Zn2 þ
H]þ (m/z = 1369.3) as a major fragment formed in
solution; the proposed structure is shown (Figure 4).8
Table 3. Screening of Acyclic Enones
Table 2. Remarkable Effect of Switch-Point Strategy
a NMR yields. Ee was determined by chiral HPLC analysis. b Cu-
(acac)2 was used.
The reaction of a wide variety of acyclic enones is des-
cribed in the presence of a Cu-salt and SP1 or SP2 (Table 3).
Alexakis reported that the substituents, such as aromatic
and aliphatic or sterically hindered and less hindered, in
acyclic enones required an appropriate Cu-salt and sol-
vent, respectively.5 In contrast, we found that the reaction
of various acyclic enones in the presence of CuCl2 2H2O
3
and SP1 or SP2 gave the opposite major enantiomers as
products respectively with high enantioselectivities. The
reaction of 1aꢀe gave the products in high yields with high
enantioselectivities (entries 1ꢀ10). The reaction of 1fꢀi in
the presence of SP1 diminished the yields and/or enantio-
selectivities (entries 11, 13, 15, 17, and 19). In contrast, the
use of SP2 gave good to high yields with high enantios-
electivities (entries 12, 14, 16, 18, and 20). The aliphatic
enones gave the desired products in moderate to good
yields with moderate to high enantioselectivities, respec-
tively (entries 21ꢀ28). Furthremore, the asymmetric con-
jugate addition to cyclohexenone 1o was also investigated.
The use of SP1 gave a better enantioselectivity of product
2o than SP2; the use of SP1 (10 mol %) was effective
(7) Takahashi, Y.; Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi,
K.; Imamoto, T. J. Org. Chem. 2005, 70, 9009.
(8) Examples of multinuclear Zn-complexes based on BINOL for the
a Cu(acac)2 was used (entries 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27,
29, and 30). CuCl2 2H2O (entries 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26,
3
28, 31, and 32). Ligand (10 mol %) was used (entries 30 and 32). b Isolated
yields. Ee was determined by chiral HPLC analysis or chiral GC analysis.
€
reaction of enones, see: (a) Minatti, A.; Dotz, K. H. Synlett 2004, 1634.
€
(b) Minatti, A.; Dotz, K. H. Eur. J. Org. Chem. 2006, 268. (c) Wang, H.;
Wang, Z.; Ding, K. Tetrahedron Lett. 2009, 50, 2200.
2344
Org. Lett., Vol. 14, No. 9, 2012

generates insoluble precipitates in the reaction mixture,
which seem to be oligomeric complexes. This information
suggests the incorporation of multinuclear Cu- and Zn-
atoms in equilibrium between molecular and oligomeric
complexes. To elucidate the structures of active complexes,
further investigation would be required.
In conclusion, we discovered a dramatic effect of regioi-
someric ligands for the construction of multinuclear Cu/
Zn-complexes in the asymmetric conjugate addition of
organozinc reagents to enones. The regioisomeric ligands
gave the opposite major enantiomer of products, respec-
tively. The present results based on our original strategy of
multinuclear complexes would contribute to the design of
new ligand architectures for asymmetric catalysis. Further
examination of the influence of regioisomeric ligands on
various asymmetric reactions is underway in our laboratory.
Acknowledgment. This work was supported by the JST
PRESTO program, Grant-in-Aid for Young Scientists (B)
(Nos. 21750108 and 23750049) from the Japan Society for
the Promotion of Science, and Waseda University Grant
for Special Research Project.
Figure 4. ESI-MS analysis of Zn/SP1-complexes.
The complicated isotope pattern of the detected peak
suggests the incorporation of Zn-atoms. The subsequent
treatment of the Zn-complexes with a Cu-salt predomi-
nantly gave oligomers, the ESI-MS analysis of which
showed a complicated spectrum with various unidentified
peaks. Furthermore, SP2 also was not a suitable ligand to
find identical Zn- and Cu/Zn-complexes; the ESI-MS
spectra gave many unidentified peaks. The reaction using
Et2Zn and a Cu-salt with SPINOL-PHOS derivatives
Supporting Information Available. The experimental
procedure and physical property of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
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